EA040266B1 - PYRAZOLOPYRIMIDINES WITH ACTIVITY AGAINST RESPIRATORY SYNCYTIAL VIRUS (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 respiratory syncytial virus (RSV) replication. 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 a (bad) cold with 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 three 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. The other two drugs, RespiGam® (RSV-IG) and Synagis® (palivizumab), immunostimulants based on polyclonal and monoclonal antibodies, are intended for prophylactic use. Both are very expensive and require parenteral administration.

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 that show activity against RSV are disclosed in WO 2016/174079 and WO 2016/091774.

The compounds of the present invention unexpectedly show more preferable plasma concentration profiles than the pyrazolopyrimidine compounds of WO 2016/174079 containing a substituted pyrrolidine moiety, as demonstrated in pharmacological example E.2.

Detailed description of the invention

The present invention relates to compounds of formula (I)

And including to their any stereochemically isomeric form,

where A represents ® ¹ ) or (a-2) ;

n is 0, 1 or 2;

m is 1 or 2;

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

X ¹ is CR ¹¹ , and

X ² is CR ¹¹ , and

X ³ is CR ¹¹ or

X ¹ is N and X ² is CR ¹¹ and X ³ is CR ¹¹ , or

X ¹ is CR ¹¹ and X ² is N and X ³ is CR ¹¹ , or

X ¹ is N and X ² is CR ¹¹ and X ³ is N,

- 1 040266 where R ¹¹ in each case is independently selected from the group consisting of hydrogen, halogen, hydroxy,

Cmalkyl, C _{1-4αalkyloxy} , C _1-4alkyloxy -C _1-4alkyloxy and hydroxy-C _1-4 alkyloxy;

R ¹ is CH ₃ ;

R ² is hydrogen or halogen;

R ³ is halogen;

R ⁴ is C ₃ . ₆ cycloalkyl; phenyl; phenyl substituted with one substituent selected from halogen, cyano, C _1-4 αkyl, polyhalo-C _1-4 alkyl and C _1-4 alkyloxy; or heteroaryl;

R ⁵ is hydrogen, C _1-4 alkyl or hydroxy-C _1-4 alkyl;

each R ⁶ is independently selected from the group consisting of hydrogen, C _1-4 alkyl, hydroxy, halogen, and C _1-4 αkyloxy;

each R ^6a is independently selected from the group consisting of hydrogen and halogen;

R ⁷ is hydrogen, C _1-4 alkyl or hydroxy-C _1-4 alkyl;

R ⁸ is

-OH,

-CN,

- O-(CO)-NR ¹² R ¹³ ,

- C ₁ _ ₄ alkyl-(CO)-NR ¹² R ¹³ ,

- (CO)-NR ¹² R ¹³ ,

- (CS)-NR ¹² R ¹³ ,

- (CO) -NR ¹² -CN,

- (CO) -NR ¹² -SO2-R ¹⁴ ,

- NR ¹² -(CO) -R ¹⁴ ,

- NR ¹² -(CO) -OR ¹⁴ ,

- NR ¹² -SO2-R ¹⁴ ,

- NH2,

- NR ¹² -R ¹⁵ ;

- SO2-R ¹⁴ ,

- SO2-NR ¹² R ¹³ ,

- SO2-NR ¹² -(CO)-R ¹⁴ , or

- SO(=NH)(-R ¹⁴ ), or g heteroaryl ¹ ;

where each of R ¹² and R ¹³ is independently selected from hydrogen and C ₁ . ₄ alkyl;

R ¹⁴ is C ₁ . ₄ alkyl or polyhalo-C ₁ . ₄ alkyl;

R ¹⁵ is di(C ₁ . ₄ alkyl)-(P=O)- or polyhalo-C ₁ . ₄ alkyl;

or R ⁷ and R ⁸ may be taken together to form -CH ₂ -(SO ₂ )-CH ₂ - or -CH ₂ -O-CH ₂ -;

each R ⁹ is independently selected from the group consisting of hydrogen and C ₁ . ₄ alkyl;

R ¹⁰ is hydrogen;

if n=1 and m=1, then R ⁸ and R ⁹ can be taken together to form -CH ₂ -(CO)-O-;

g heteroaryl is pyridinyl or pyrimidinyl, each heteroaryl being optionally substituted with one substituent selected from halogen;

heteroaryl 1 is tetrazolyl or 5-oxo-4,5-dihydro-1,2,4-oxadiazolyl, or their pharmaceutically acceptable acid addition salts.

When used in the above definitions:

halogen is the general term for fluorine, chlorine, bromine, and iodine;

_C1 . ₄ αlkyl 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;

_C1 . ₆ alkyl implies the inclusion of C ₁ . ₄ alkyl and its higher homologues containing 5 or 6 carbon atoms, such as, for example, 2-methylbutyl, pentyl, hexyl, etc.;

_C3 . ₆ cycloalkyl is a general term for cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

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

- (CO) - or (CO) means carbonyl;

- (CS)- or (CS) means thiocarbonyl.

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 as having a specific configuration (e.g., R, S) with respect to one or more atoms , includes every possible stereoisomer or mixture of two or more stereoisomers.

Throughout this document, the terms compound of formula (I) and pro-intermediates of the synthesis 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 related as mirror images. 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.

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 in accordance with the Cahn-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 identified, this means that said stereoisomer is substantially free of other stereoisomers, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1% of 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.

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.

For the avoidance of ambiguity, the compounds of formula (I) may contain the indicated atoms in any of their natural or artificial isotopic forms. In this regard, embodiments of the present invention that may be mentioned include those wherein (a) the compound of formula (I) is not isotopically enriched or labeled with respect to any atom of the compound and (b) the compound of formula (I) is isotopically enriched or labeled with respect to one or more atoms of the compound. Compounds of formula (I) which are isotopically enriched or labeled (with respect to one or more atoms of the compound) with one or more stable isotopes include, for example, compounds of formula (I) isotopically enriched or labeled with one or more atoms, such as deuterium, ¹³ C, ¹⁴ C, ¹⁴ N, ¹⁵ O or the like.

The first group of compounds are compounds of formula (I) described above, where X ¹

- 3 040266 is CR ¹¹ and X ² is CR ¹¹ and X ³ is CR ¹¹ .

The second group of compounds are compounds of formula (I) described above, where

X ¹ is N and X ² is CR ¹¹ and X ³ is CR ¹¹ ; or X ¹ is CR ¹¹ and X ² is N and X ³ is CR ¹¹ ; or X ¹ is N and X ² is CR ¹¹ and X ³ is N.

The third group of compounds are compounds of formula (I) described above, where radical A is characterized by formula (a-1).

The fourth group of compounds are compounds of formula (I) described above, wherein n is 0 and m is 1.

The fifth group of compounds are compounds of formula (I) described above, wherein n is 1 and m is 1.

In a further embodiment, the present invention relates to compounds of formula (I)

including any stereochemically isomeric form thereof, where A is n is 0 or 1;

m is 1;

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

X ¹ is CR ¹¹ and X ² is CR ¹¹ and X ³ is CR ¹¹ where R ¹¹ in each case is hydrogen;

R ¹ is CH ₃ ;

R ² is hydrogen;

R ³ is halogen;

R ⁴ is C ₃ _ ₆ cycloalkyl or heteroaryl;

R ⁵ is hydrogen;

each R ⁶ is independently selected from the group consisting of hydrogen, hydroxy and halogen;

each R ^6a is hydrogen;

R ⁷ is hydrogen or hydroxy-C ₁ _ ₄ alkyl;

R ⁸ is

-OH,

-C ₁ _ ₄ alkyl-(CO)-NR ¹² R ¹³ or

-(CO)-NR ¹² R ¹³ where each of R ¹² and R ¹³ is independently selected from hydrogen and C ₁ _ ₄ alkyl;

R ¹⁰ is hydrogen;

heteroaryl is pyridinyl, or to their pharmaceutically acceptable acid addition salts.

In another additional embodiment, the present invention relates to compounds of formula (I)

including their any stereochemically isomeric form,

where A is ( ^a - ¹ )

- 4 040266 n is 1;

m is 1;

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

X ¹ is CR ¹¹ and X ² is CR ¹¹ and X ³ is CR ¹¹ where R ¹¹ in each case is hydrogen;

R ¹ is CH ₃ ;

R ² is hydrogen;

R ³ is halogen;

R ⁴ is C _3-6 cycloalkyl;

R ⁵ is hydrogen;

each R ⁶ is independently selected from the group consisting of hydrogen, hydroxy and halogen;

each R ^6a is hydrogen;

R ⁷ is hydrogen or hydroxy-C _1-4 alkyl;

R ⁸ is -OH or -(CO)-NR ¹² R ¹³ , where R ¹² and R ¹³ are each independently selected from hydrogen and C _1-4 alkyl,

R ¹⁰ is hydrogen, or to their pharmaceutically acceptable acid addition salts.

In another additional embodiment, the present invention relates to compounds of formula (I)

And including to their any stereochemically isomeric form.

where A is (a- ¹ ) ;

n is 1;

m is 1;

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

X ¹ is CR ¹¹ and X ² is CR ¹¹ and X ³ is CR ¹¹ where R ¹¹ in each case is hydrogen;

R ¹ is CH3;

R ² is hydrogen;

R ³ is halogen;

R ⁴ is C _3-6 cycloalkyl;

R ⁵ is hydrogen;

each R ⁶ is independently selected from the group consisting of hydrogen and hydroxy;

each R ^6a is hydrogen;

R ⁷ is hydrogen;

R ⁸ is -OH or -(CO)-NR ¹² R ¹³ , where R ¹² and R ¹³ are each independently selected from hydrogen and C _1-4 alkyl,

R ¹⁰ is hydrogen, or to their pharmaceutically acceptable acid addition salts.

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) A is a radical of formula (a-2); or

c) R ¹ is methyl; or

d) R ² is hydrogen; or

e) R ³ is fluorine; or

f) R ⁴ is cyclopropyl; or

g) R ⁴ is phenyl; or

h) R ⁴ is pyridinyl; or

i) n is 0 and m is 1; or

j) n is 0 and m is 2; or

k) n is 1 and m is 1; or

- 5 040266

l) n is 1 and m is 2; And

m) n is 2 and m is 1.

Specific examples of compounds of formula (I) are:

Compounds of formula (I) can generally be prepared by reacting an intermediate of formula (II) with an intermediate of formula (III) in a reaction inert solvent.

Compounds of formula (I) can also be prepared by reacting an intermediate of formula (IV) with an intermediate of formula (V) in a reaction inert solvent.

- 6 040266

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 herein above can be synthesized in the form of racemic mixtures of enantiomers which can be separated from each other following separation procedures known in the art. Such compounds of formula (I) which are obtained in racemic form may be converted to the corresponding diastereomeric salt forms by reaction with an appropriate chiral acid. Said forms of the diastereomeric salts are then separated, for example by selective or fractional crystallization, and the enantiomers are isolated therefrom with 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 respective starting materials, provided that the reaction proceeds stereospecifically. Preferably, if a particular stereoisomer is desired, said compound will be synthesized using stereospecific preparation methods. These methods will advantageously employ 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 infections caused by Pneumoviridae and, in particular, human and bovine respiratory syncytial virus (RSV). A number of compounds of the present invention, in addition, is active against mutant strains of RSV. In addition, many of the compounds of the present invention exhibit a favorable pharmacokinetic profile and attractive bioavailability properties, including acceptable half-life, AUC and peak values, as well as 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 test described in the experimental part of the description, and can also be demonstrated using the virus yield reduction assay. The in vivo antiviral activity of the compounds of the present invention against RSV can be demonstrated in a cotton rat test model as described by Wyde et al. in Antiviral Research, 38, p. 3142 (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).

For the purpose of preparing the pharmaceutical compositions of the present invention, an effective amount of a particular compound in the form of a base or acid addition salt as an active ingredient is combined in a homogeneous mixture with at least one pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired. for an introduction. These pharmaceutical compositions are preferably in unit dosage form suitable preferably 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, in which 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 ingredient. Injectable solutions can be prepared, for example, using a pharmaceutical carrier containing saline solution, glucose solution or a mixture thereof. Suspen

- 7 040266 injections can also be obtained 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 introduction of the active ingredient into the skin and/or to facilitate the preparation of the desired compositions. These topical compositions can be administered in various 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 the present invention in unit dosage form for ease of administration and dosage uniformity. Unit dosage form as used herein means physically discrete units suitable as unit doses, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including divisible or coated tablets), capsules, pills, pouches of powdered product, strips, injection solutions or suspensions, heaped teaspoons, heaped tablespoons, and the like. ., 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 softgels 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 means, 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 acacia), non-aqueous vehicles (for example, almond 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, this concentration may range from about 0.04 to 0.1% (w/v) of the final composition. The bulk sweetener can be effectively used at higher concentrations ranging 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. Each flavor may be present in the final composition at a concentration ranging 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 bolus injection

- 8 040266 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 ingredient may be presented in powder form for mixing with a suitable carrier vehicle, 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 ingredient per unit dosage form.

The precise dosage and frequency of administration will depend upon the particular compound of formula (I) used, the particular 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, and other medical treatments. , which the individual can receive, which is well known to specialists in this field of 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.

The present invention will be further illustrated in this document with reference to the following non-limiting examples.

experimental part A. Abbreviations (±)-BINAP (±)-2,2'-bis - (diphenylphosphino)-1,1'-binaphthalene CAS [98327-87-8] microwaves under the influence of microwave radiation ASON acetic acid aq. water Vos ₂ O di-otreoth-butyl dicarbonate - CAS [24424-99-5] br wide CDI 1,G-carbonyldiimidazole - CAS [530-62-1] SRME cyclopentyl methyl ether - CAS [5614-37-9]

- 9 040266

d doublet DBU 1,8-diazabicyclo[5.4.0]undec-7-ene - CAS [6674-22-2] DCM dichloromethane DIPE diisopropyl ether DIPEA N,A-diisopropylethylamine DMAP 4-(dimethylamino)pyridine DMF dimethylformamide DMSO dimethyl sulfoxide _Et2O diethyl ether Et ₃ N triethylamine EtOAc ethyl acetate EtOH ethanol _H2 hydrogen 4. hour I l TT T 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium 11Xy1 and hexafluorophosphate - CAS [148893-10-1] HMDS hexamethyldisilazane - C AS [999-97-3] z-PrOH isopropyl alcohol KOAC potassium acetate LiHMDS lithium bis(trimethylsilyl)amide - C AS [4039-32-1] m multiplet mass/charge mass-to-charge ratio zw-CPBA 3-chloroperbenzoic acid - C AS [937-14-4] MeCN acetonitrile MeOH methanol min. minute(s) N ₂ nitrogen NaOLBu zzz/zezzz-sodium butoxide NBS A-bromosuccinimide - CAS [128-08-5] NMP methylpyrrolidone - CAS [872-50-4] NMR Nuclear magnetic resonance o/n during the night Pd(OAc) ₂ palladium(II) acetate - CAS [3375-31-3] Pd(PPh ₃ ) ₄ tetrakis(triphenylphosphine)palladium(0) - CAS [14221-01-3]

- 10 040266

Pd ₂ (dba) ₃ tris(dibenzplidenacetone)dipalladium(0) - CAS [51364-51-3] PdCl ₂ (dtbpf) [1,1'-bis(di-ot/2w-butylphosphino)ferrocene]dichloropalladium(II) CAS[95408-45-0] RRASA propylphosphonic anhydride - CAS [68957-94-8] PPm Pt/C parts per million platinum on activated carbon q quin quartet quintuplet k.t. room temperature s singlet t triplet LBuOK potassium otreot-butoxide TFA trifluoroacetic acid - CAS [76-05-1] THF tetrahydrofuran TMSC1 chlorotrimethylsilane - CAS [75-77-4] TTBP hbf ₄ tri-t/2w-butylphosphonium tetrafluoroborate - CAS [131274-22-1] weight. by weight Xantphos 4,5-bis(d iphenylphosphino)-9,9-d imethylxanthene CAS[161265-03-8] XPhos 2-dicyclohexylphosphino-2',46'-triisopropylbiphenyl CAS[564483-18-7]

Δ heat

The stereochemical configuration for some compounds was designated as R* or S* (or *R or *S) if the absolute stereochemical configuration was not determined, although the compound itself was isolated as a single stereoisomer and is enantiomerically pure.

B. Synthesis of compounds.

General scheme

Connection 1.

-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}-3-fluorophenyl )pyrrolidine-3-carbonitrile

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5carbonyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline [ 2035421-61-3] (0.20 g, 0.39 mmol), pyrrolidine-3carbonitrile [10603-53-9] (45.7 mg, 475 µmol) and cesium carbonate (387 mg, 1.19 mmol) with nitrogen . 1,4-dioxane (2 ml) was added and the mixture was degassed with nitrogen. Palladium acetate (17.8 mg, 79.1 µmol) and XantPhos (45.8 mg, 79.1 µmol) were added. The reaction mixture was purged with nitrogen and stirred at 100° C. for 3 hours. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The mixture was filtered through a pad of Celite® and rinsed with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel flash chromatography (24 g cartridge, 15-40 µm, mobile phase gradient: heptane/EtOAc, 70:30 to 50:50). The purified fractions were collected and evaporated to dryness. The residue (0.16 g) was taken up with DIPE. The solid was filtered off and dried in vacuo to give Compound 1 (127 mg, 62%).

Connection 2 and connection 3.

Intermediate connection I1.

(3R)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-3-fluorophenyl)pyrrolidine-3-carbonitrile

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5a]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (1.00 g, 1.91 mmol), (R)-pyrrolidine-3-carbonitrile hydrochloride [1153950-54-9] (304 mg, 2.29 mmol), cesium carbonate ( 1.87 g, 5.73 mmol) and XantPhos (111 mg, 191 µmol) and purged with nitrogen. 1,4-dioxane (20 ml) was added and the mixture was again purged with nitrogen. Palladium acetate (42.9 mg, 191 µmol) was added. The reaction mixture was purged with nitrogen and stirred at 100° C. for 17 hours. The 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 removed under reduced pressure. 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 I1 (879 mg, 88%) as a pale yellow solid.

Intermediate I2.

(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-carbonitrile

Intermediate I2 was synthesized from (S)-n-pyrrolidine-3-carbonitrile hydrochloride [1153950-49-2] and (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5- a]pyrimidine-5-carbonyl]1-methyl-1,2,3,4-tetrahydroisoquinoline [2035421-61-3] according to the procedure given for the synthesis of intermediate I1. Purification was performed by preparative LC (irregular SiOH, 15-40 μm, 40 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 90:10 to 40:60). The residue (997 mg) was taken up with MeCN and concentrated under reduced pressure to give intermediate I2 (840 mg, 84%) as a yellow solid.

Connection 2.

(1 R)-2-(7-Cyclopropyl-2- {2-fluoro-4-[(3R)-3 -(1H-1,2,3,4-tetrazol-5 -yl)pyrrolidin-1 yl] phenyl}pyrazolo[1,5-а]pyrimidine-5-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline

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In a closed tube, to a mixture of intermediate I1 (170 mg, 327 µmol), copper iodide (93.3 mg, 0.49 mmol) and ammonium chloride (52.4 mg, 0.98 mmol) in DMF (5 mL) was added sodium azide (212 mg, 3.27 mmol). The reaction mixture was stirred at 100° C. for 18 hours. EtOAc, 1N was added. aqueous HCl solution and saline solution. The layers were separated and the aqueous phase was extracted with EtOAc (3 times). The combined organic extracts were dried over MgSO ₄ , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g GraceResolv™, dry-loaded (Celite®), mobile phase gradient: DCM/(MeOH/AcOH 9:1), from 100:0 up to 94:6). The product was taken up in EtOAc and 1N was added. aqueous solution of HCl. The layers were separated and the organic phase was washed with 1N. aqueous HCl solution (twice), dried over MgSO ₄ , filtered and the solvent was removed under reduced pressure. The residue (88 mg) was triturated with MeOH. The solid was filtered off and dried in high vacuum at 50°C for 18 hours to give compound 2 (76 mg, 41%) as an orange solid.

Connection 3.

(1 R)-2-(7-Cyclopropyl-2- {2-fluoro-4-[(3 S)-3 -(1H-1,2,3,4-tetrazol-5-yl)pyrrolidin-1 - yl] phenyl} pyrazolo[1,5-a] pyrimidine-5-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline

Compound 3 was synthesized from intermediate I2 according to the procedure given for the synthesis of compound 2. Purification was performed by preparative LC (irregular SiOH, 15-40 μm, 12 g GraceResolv™, dry-loaded (Celite®), gradient running phase: DCM/(MeOH/AcOH 9:1), 100:0 to 94:6). The residue was triturated with MeOH. The solid was filtered off and dried under high vacuum at 50° C. 68%) as an orange solid.

Connection 4.

within h to obtain compound 3 (126 mg,

Intermediate I3.

(Z,3S)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-а]pyrimidine -2-yl} -3-fluorophenyl)-N'-hydroxypyrrolidine-3-carboximidamide

To a suspension of intermediate I2 (300 mg, 0.58 mmol) and sodium carbonate (244 mg, 2.31 mmol) in EtOH (8 mL) was added hydroxylamine hydrochloride (120 mg, 1.73 mmol). The reaction mixture was stirred at reflux for 24 hours and the solvent was evaporated off under reduced pressure. DCM and H2O were added to the residue. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure to give Intermediate I3 (331 mg, 90%, 87% pure) as a yellow gum.

Intermediate I4.

(Z)- {Amino[(3 S)-1 -(4-{7-cyclopropyl-5-[( 1 R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] pyrazolo[ 1,5-a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]methylidene}aminophenyl carbonate

YF.

χ-Ν H ₂ n

R*1

ST

Phenyl chloroformate (98.0 µl, 0.78 mmol). The reaction mixture was stirred at rt. within 18 hours. The reaction mixture was diluted with DCM and H2O. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/EtOAc, 100:0 to 90:10). The residue (210 mg) was taken up with MeCN and concentrated under reduced pressure (twice) to give Intermediate I4 (189 mg, 52%) as a yellow gum.

Connection 4.

3-[(3 S)-1 -(4- {7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a ]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one

In a closed tube, potassium carbonate (41.1 mg, 0.30 mmol) was added to a solution of intermediate I4 (172 mg, 0.25 mmol) in DMF (1 ml). The reaction mixture was stirred at 50°C for 20 hours was Added saline, 1N. aqueous solution of HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine (4 times), dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was crystallized from MeOH and the solid was filtered off and dried in high vacuum at 50°C for 3 h. The solid (110 mg) was purified by preparative LC (SiOH with irregular grains, 15-40 µm, 24 g GraceResolv™ , liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 97:3). The residue was recrystallized from MeOH, filtered and dried in high vacuum at 50°C for 3 h to obtain compound 4 (81 mg, 56%) as a pale yellowish solid.

Compound 5.

(1R)-2-[7-Cyclopropyl-2-(2-fluoro-4-{2-oxa-6-azaspiro[3.4]octan-6-yl}phenyl)pyrazolo[1,5а]pyrimidine-5-carbonyl ]-1-methyl-1,2,3,4-tetrahydroisoquinoline

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (150 mg, 0.28 mmol), 2-oxa-6-azaspiro[3.4]octane hemioxalate [1408075-00-2] (89.2 mg, 0.28 mmol), carbonate cesium (276 mg, 0.85 mmol) and XantPhos (16.3 mg, 28.2 µmol) and purged with nitrogen. 1,4-dioxane (4.5 ml) was added and the mixture was again purged with nitrogen. Palladium acetate (6.33 mg, 28.2 µmol) was added. The reaction mixture was purged with nitrogen and stirred at 100° C. for 17 hours. The reaction mixture was diluted with EtOAc and H2O. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgSO4, filtered and

- 14 040266 the solvent was removed under reduced pressure. 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). The residue was crystallized from MeOH, filtered and dried in high vacuum at 50°C for 20 h to obtain compound 5 (112 mg, 74%) as a yellow solid.

Compound 6.

6-[4-(7-Cyclopropyl-5-{[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl]-3 -fluorophenyl)-2X ⁶ -thia-6-azaspiro[3.4]octane-2,2-dione

Compound 6 was synthesized from (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5a]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] and 2-thia-6-azaspiro[3.4]octane 2,2-dioxide [1823947-89-2] according to the procedure given for the synthesis of compound 5. Compound 6 (86 mg, 58 %) was obtained as a yellow solid.

Connection 7 and connection 8.

Synthesis of intermediates I5 and I6.

(R): [147081-49-0] (S): [147081-44-5] (R): [550371-67-0] -17 (S) . [114636-37-2] -18 (R): [1246277-40-6] - 15 (S) . [1246277-44-0]-16

Intermediate connection I7.

tert-Butyl-(3R)-3-acetamidopyrrolidine-1-carboxylate

To a mixture of (R)-(+)-1-boc-3-aminopyrrolidine [147081-49-0] (1.00 g, 5.37 mmol), triethylamine (1.12 ml, 8.05 mmol) and DMAP (32.8 mg, 0.27 mmol) in DCM (20 ml) was added dropwise acetic anhydride (0.56 ml, 5.91 mmol). The reaction mixture was stirred at rt. within 18 hours the Reaction mixture was diluted with DCM and H ₂ O. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure to give Intermediate I7 (1.64 g) as an oil.

Intermediate connection I8.

tert-Butyl-(3S)-3-acetamidopyrrolidine-1-carboxylate

Intermediate I8 (1.97 g) was synthesized from (S)-(-)-1-boc-3-aminopyrrolidine [147081-44-5] according to the procedure given for the synthesis of intermediate I7.

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Intermediate connection I5.

N-[(3R)-Pyrrolidin-3-yl]acetamide hydrochloride

A mixture of intermediate I7 (1.64 g, 4.53 mmol, 63% purity) and chlorotrimethylsilane (2.30 mL, 18.1 mmol) in MeOH (20 mL) was stirred at rt. over 24 hours. The mixture was evaporated under reduced pressure to give intermediate I5 (1.12 g).

Intermediate connection I6.

N-[(3S)-Pyrrolidin-3-yl]acetamide hydrochloride

Intermediate I6 (1.34 g) was synthesized from intermediate I8 according to the procedure given for the synthesis of intermediate I5.

Synthesis of compounds 7 and 8.

Connection 7.

N-[(3R)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-а] pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]acetamide

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (250 mg, 0.48 mmol), intermediate I5 (180 mg, 0.72 mmol, 66% purity) and cesium carbonate (782 mg, 2.40 mmol) and purged with nitrogen . 1,4-dioxane (10 ml) was added and the mixture was degassed with nitrogen. Palladium acetate (16.2 mg, 72.0 µmol) and XantPhos (41.6 mg, 72.0 µmol) were added. The reaction mixture was stirred at 100° C. for 7 hours. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated 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: DCM/MeOH/aq. NH ₃ , from 100:0:0 up to 98:2:0.2). The residue (191 mg) was co-evaporated with EtOH (5 times) and triturated with EtOH/Et ₂ O (1:9). The solid was filtered off and dried in high vacuum at 50° C. for 2 h to give compound 7 (140 mg, 53%) as a yellow solid.

Connection 8.

N-[(3 S)-1 -(4-{7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a ]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]acetamide

Compound 8 (107 mg, 40%) was synthesized from (1 R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-carbonyl]-1- methyl-1,2,3,4-tetrahydroisoquinoline [2035421-61-3] and intermediate I6 according to the procedure given for the synthesis of compound 7.

Connection 9 and connection 10.

Vg about

-HCI (R): [1884705-13-8] -19 (S): [1312686-80-8] -110

------------->Pd(OAc) ₂ , XantPhos

Cs ₂ CO ₃ dioxane

Yu0°С, 18 hours

(S): 10

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Synthesis of intermediates I9 and I10.

MeOH GDI, Et ₃ N

DMF k.t., 18 hours

MeON c.g., 24 h.

TMSCI

(R) . [147081-49-0] (S) . [147081-44-5] (R) . [1884705-14-9]-111fS): [1334550-71-8]-112 (R): [1884705-13-8]-19 (S); [1312686-80-8] -110

Intermediate connection I11.

tert-Butyl-(3R)-3-[(methoxycarbonyl)amino]pyrrolidine-1-carboxylate

In a closed tube to a mixture of (R)-(+)-1-boc-3-aminopyrrolidine [147081-49-0] (500 mg, 2.69 mmol) and triethylamine (1.49 ml, 10.7 mmol) in DMF (10 ml) was added CDI (653 mg, 4.03 mmol). The reaction mixture was stirred at rt. MeOH (10 ml, 247 mmol) was added and the reaction mixture was stirred at rt. over 18 hours H ₂ O, brine and EtOAc were added and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. 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 intermediate I11 (344 mg, 52%).

Intermediate connection I12.

tert-Butyl-(3S)-3-[(methoxycarbonyl)amino]pyrrolidine-1-carboxylate o. O

-7^ n

112

Intermediate I12 (444 mg, 68%) was synthesized from (S)-(-)-1-boc-3-aminopyrrolidine [147081-44-5] according to the procedure given for the synthesis of intermediate I11.

Intermediate I9.

Methyl-N-[(3R)-pyrrolidin-3-yl] carbamate hydrochloride

IOX th ^υ *HC1

A mixture of intermediate I11 (344 mg, 1.41 mmol) and chlorotrimethylsilane (0.72 ml, 5.63 mmol) in MeOH (10 ml) was stirred at rt. within 24 h. The mixture was evaporated under reduced pressure to obtain intermediate compound I9 (225 mg, quant.).

Intermediate connection I10.

Methyl-N-[(3S)-pyrrolidin-3-yl]carbamate hydrochloride

110

Intermediate I10 (310 mg, 92%) was synthesized from intermediate I12 according to the procedure given for the synthesis of intermediate I9.

Synthesis of compounds 9 and 10.

Connection 9.

Methyl-N-[(3R)-1 -[4-{7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5- a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]carbamate

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (250 mg, 0.48 mmol), intermediate I9 (130 mg, 0.72 mmol) and cesium carbonate (782 mg, 2.40 mmol) and purged with nitrogen. 1,4-dioxane (10 ml) was added and the mixture was degassed with nitrogen. Palladium acetate (10.7 mg, 48.0 µmol) and XantPhos (27.8 mg, 48.0 µmol) were added. The reaction mixture was stirred at 100°C for

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h. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated 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: DCM/MeOH/aq. NH ₃ , from 100:0:0 up to 98:2:0.2). The residue (221 mg) was co-evaporated with EtOH (5 times) and triturated with Et ₂ O. The solid was filtered off and dried in high vacuum at 50° C. for 18 h to give compound 9 (102 mg, 37%) as a yellow solid.

Compound 10.

Methyl-N-[(3S)-1-[4-{7-cyclopropyl-5-[( 1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] pyrazolo[1,5 -a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]carbamate

Compound 10 (145 mg, 53%) was synthesized from (1 R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-carbonyl]-1- methyl-1,2,3,4-tetrahydroisoquinoline [2035421-61-3] and intermediate I10 according to the procedure given for the synthesis of compound 9.

Connection 11 and connection 12.

n

HCI fS): [1312686-83-1]-114

Pd(OAc) ₂ , XantPhos Cs ₂ CO ₃ dioxane 100°C, 7 h.

(S): 12

Synthesis of intermediates I13 and I14.

NHj (R): [147081-49-0] (S) . [147081 -44-5]

MeSO ₂ CI Et ₃ N

DCM c.t., 6 p.m.

(R) . 115(S): [1312686-84-2]-116

Yo TMSCI* o'\ meon

k.t., 24 hours

n o HCI (R): FROM (S): [1312686-83-1] -114

Intermediate connection I15.

tert-Butyl-(3R)-3-methanesulfonamidopyrrolidine-1-carboxylate

Methansulfonyl chloride (0.50 ml, 6.44 mmol) was added dropwise to a solution of (R)-(+)-1-boc-3aminopyrrolidine [147081-49-0] (1.00 g, 5.37 mmol) and triethylamine (1.50 ml, 10.7 mmol) in DCM (20 ml). The reaction mixture was stirred at rt. within 18 hours the Reaction mixture was diluted with DCM and H ₂ O. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure to give Intermediate I15 (2.00 g) as an oil.

Intermediate connection I16.

tert-Butyl-(3S)-3-methanesulfonamidopyrrolidine-1-carboxylate

Intermediate I16 (2.4 g) was synthesized from (S)-(-)-1-boc-3-aminopyrrolidine [147081-44-5] according to the procedure given for the synthesis of intermediate I15.

Intermediate I13.

N-[(3R)-Pyrrolidin-3-yl]methanesulfonamide hydrochloride

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A mixture of intermediate I15 (2.00 g, 5.37 mmol, 71% purity) and chlorotrimethylsilane (2.73 mL, 21.5 mmol) in DCM (20 mL) was stirred at rt. within 24 hours. The mixture was evaporated under reduced pressure to obtain intermediate compound I13 (1.20 g).

Intermediate connection I14.

N-[(3S)-Pyrrolidin-3-yl]methanesulfonamide hydrochloride, _e1 n l

V—' X ^x * on

114

Intermediate I14 (1.68 g) was synthesized from intermediate I16 according to the procedure given for the synthesis of intermediate I13.

Synthesis of compounds 11 and 12.

Compound 11.

N-[(3R)-1 -(4-{7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a] pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]methanesulfonamide

YR to I x\__/ X to/ I o X ^N Xi'X [ίο Ϊ

M 11

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (250 mg, 0.48 mmol), intermediate I13 (181 mg, 0.72 mmol, 80% purity) and cesium carbonate (782 mg, 2.40 mmol) and purged with nitrogen . 1,4-dioxane (10 ml) was added and the mixture was degassed with nitrogen. Palladium acetate (16.2 mg, 72.0 µmol) and XantPhos (41.6 mg, 72.0 µmol) were added. The reaction mixture was stirred at 100° C. for 7 hours. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were 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: DCM/MeOH/aq. NH ₃ , from 100:0:0 up to 98:2:0.2). The residue (256 mg) was co-evaporated with EtOH (5 times) and triturated with EtOH/Et ₂ O (1:9). The solid was filtered off and dried in high vacuum at 50° C. for 2 h to give compound 11 (148 mg, 52%) as a yellow solid.

Compound 12.

N-[(3 S)-1 -(4-{7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a ]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]methanesulfonamide

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (250 mg, 0.48 mmol), intermediate I14 (226 mg, 0.72 mmol, 64% purity) and cesium carbonate (782 mg, 2.40 mmol) and purged with nitrogen . 1,4-dioxane (10 ml) was added and the mixture was degassed with nitrogen. Palladium acetate (10.8 mg, 48.0 µmol) and XantPhos (27.8 mg, 48.0 µmol) were added. The reaction mixture was stirred at 100° C. for 7 hours. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were 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: DCM/MeOH/aq. NH ₃ , from 100:0:0 up to 98:2:0.2). The residue (158 mg) was co-evaporated with EtOH (5 times) and triturated with EtOH/Et ₂ O (1:9). The solid was filtered off and dried in high vacuum at 50° C. for 2 h. The purification sequence was repeated: purification by preparative LC (irregularly shaped SiOH, 15-40 µm, 40 g GraceResolv™, injection of liquid phase (DCM), mobile phase gradient: DCM/MeOH/aq NH ₃ , 100:0:0 to 98:2:0.2). The residue was co-evaporated with EtOH (3 times) and triturated with Et ₂ O. The solid was filtered off and dried under high vacuum at 50° C. to give compound 12 (99 mg, 35%) as a yellow solid.

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Compound 13.

(3R)-1 -(4-{7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-3-fluorophenyl)pyrrolidin-3-ol

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (250 mg, 0.48 mmol), (R)-3-pyrrolidinol hydrochloride [104706-47-0] (77.6 μL, 0.96 mmol) and sodium tert-butoxide ( 138 mg, 1.44 mmol) and purged with nitrogen. Toluene (10 ml) was added and the mixture was degassed with nitrogen. Tris-(dibenzylideneacetone)dipalladium (43.9 mg, 48.0 µmol) and (±)-BINAP (59.7 mg, 96.0 µmol) were added. The reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was poured into water and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 25 g Interchim®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 80:20 to 0:100). The residue (65 mg) was taken up with MeCN and DIPE and partially evaporated. The solid was filtered off and dried under high vacuum at 50° C. for 16 h and then at 60° C. for 24 h to give compound 13 (45 mg, 18%).

Connection 14.

(3S)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-3-fluorophenyl)pyrrolidin-3-ol

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (200 mg, 0.38 mmol), (S)-3-pyrrolidinol [100243-39-8] (167 mg, 1.92 mmol) and cesium carbonate (625 mg, 1, 92 mmol) and purged with nitrogen. 1,4-dioxane (8 ml) was added and the mixture was degassed with nitrogen. Palladium acetate (8.61 mg, 38.4 µmol) and XantPhos (22.2 mg, 38.4 µmol) were added. The reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was diluted with H ₂ O 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 removed under reduced pressure. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 25 g Interchim®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 80:20 to 0:100). The residue was taken up with MeCN and Et ₂ O and evaporated to dryness. The solid was triturated with Et ₂ O, filtered and dried in high vacuum at 60° C. for 18 h to give Compound 1 (64 mg, 33%) as a yellow solid.

Compound 77.

(3R)-1 -(4-{7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-3-fluorophenyl)pyrrolidin-3-ylcarbamate

To a solution of compound 13 (3.39 g, 6.63 mmol) in THF (25 ml) was added CDI (2.15 g, 13.3 mmol). The reaction mixture was stirred at rt. for 1 h. Ammonia (28% in H ₂ O, 24.8 ml, 367 mmol) was added and the reaction mixture was stirred at rt. within 18 hours the Reaction mixture was diluted with H ₂ O, saline and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). 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, 330 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/EtOAc, 100:0 to 80:20). The residue (2.8 g) was triturated with MeCN. The solid was filtered off and dried in high vacuum at 50°C for 2 hours. The solid (1.87 g) was again triturated with MeCN, filtered and dried in high vacuum at 50°C overnight. The product (1.32 g) was suspended in MeOH (20 ml) and the solution was stirred at rt. for 18 hours. The solid was filtered off and dried under high vacuum at 50° C. to give compound 77 (951 mg, 26%) as a pale yellow solid.

Compound 78.

(3S)-1-(4-{7-Cyclopropnyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-3-fluorophenyl)pyrrolidin-3-ylcarbamate

To a solution of compound 14 (3.11 g, 6.07 mmol) in THF (23 ml) was added CDI (1.97 g, 12.1 mmol). The reaction mixture was stirred at rt. over 1 h. Ammonia (28% in H ₂ O, 22.7 ml, 336 mmol) was added and the reaction mixture was stirred at RT. within 6 hours the Reaction mixture was diluted with H ₂ O, saline and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). 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, 330 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/EtOAc, 100:0 to 80:20). The residue (2.4 g) was triturated with MeCN. The solid was filtered off and dried under high vacuum at 50°C. The solid was again triturated with MeCN, filtered and dried in high vacuum at 50° C. overnight. The product (1.03 g) was suspended in MeOH (25 ml) and stirred at rt. for 18 hours. The solid was filtered off and dried in high vacuum at 50°C to obtain compound 78 (825 mg, 25%) as a yellow solid.

Compound 15 and Compound 16.

Synthesis of intermediates I17 and I18.

Intermediate I19.

tert-Butyl-(3R)-3-[(methylcarbamoyl)oxy]pyrrolidine-1-carboxylate

119

In a closed tube, CDI (871 mg, 5 37 mmol). The reaction mixture was stirred at rt. over 1 h. Methylamine (40% in H2O, 10 ml, 116 mmol) was added and the reaction mixture was stirred at rt. within 2 hours Added H ₂ O, saline and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure. 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 intermediate I19 (700 mg, quant., 94% pure).

Intermediate connection I20.

tert-Butyl-(3S)-3-[(methylcarbamoyl)oxy]pyrrolidine-1-carboxylate

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120

Intermediate I20 (610 mg, 93%) was synthesized from (S)-(+)-N-boc-3-pyrrolidinol

[101469-92-5] according to the procedure given for the synthesis of intermediate I19.

Intermediate connection I17.

(3R)-Pyrrolidin-3-yl-N-methylcarbamate hydrochloride

117

A mixture of intermediate I19 (700 mg, 2.67 mmol, 93% purity) and chlorotrimethylsilane (1.35 ml, 10.7 mmol) in MeOH (10 ml) was stirred at rt. within 24 h. The mixture was evaporated under reduced pressure to obtain intermediate compound I17 (525 mg).

Intermediate connection I18.

(3S)-Pyrrolidin-3-yl-N-methylcarbamate hydrochloride

ΙηιΛΛ^ J .HCI iv

Intermediate I18 (475 mg) was synthesized from intermediate I20 according to the procedure given for the synthesis of intermediate I17.

Synthesis of compounds 15 and 16.

Compound 15.

(3R)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl } -3 -fluorophenyl)pyrrolidin-3 -yl-N-methylcarbamate

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (250 mg, 0.48 mmol), intermediate I17 (143 mg, 0.72 mmol, 91% purity) and cesium carbonate (782 mg, 2.40 mmol) and purged with nitrogen . 1,4-dioxane (10 ml) was added and the mixture was degassed with nitrogen. Palladium acetate (10.8 mg, 48.0 µmol) and XantPhos (27.8 mg, 48.0 µmol) were added. The reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were 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: DCM/MeOH/aq. NH ₃ , from 100:0:0 up to 98:2:0.2). The second purification was performed by reverse phase chromatography (C18 spherical beads, 25 μm, 40 g YMC-ODS-25, dry-load (Celite®), mobile phase gradient: (0.2% aq. NH4HCO ₃ )/MeCN , from 40:60 to 0:100). The residue was co-evaporated with EtOH (3 times) and triturated with EtOH. The solid was filtered off and dried in high vacuum at 50° C. for 18 h to give compound 15 (75 mg, 27%) as a yellow solid.

Compound 16.

(3S)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]pyrazolo[1,5a]pyrimidin-2-yl } -3 -fluorophenyl)pyrrolidin-3 -yl-N-methylcarbamate

Compound 16 was synthesized from (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] and intermediate I18 according to the procedure given for the synthesis of compound 15. The crude mixture was purified by preparative LC (SiOH with irregular grains, 15-40 μm, 40 g

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GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH/aq. NH3, from 100:0:0 to 98:2:0.2). The second purification was performed by reverse phase chromatography (C18 spherical beads, 25 µm, 40 g YMC-ODS-25, dry-load (Celite®), mobile phase gradient: (0.2% aq. NH4HCO3)/MeCN, from 40:60 to 0:100). The residue was co-evaporated with EtOH (5 times) and triturated with EtOH/Et ₂ O (1:9). The solid was filtered off and dried in high vacuum at 50° C. for 2 h to give compound 16 (54 mg, 20%) as a white solid.

Compound 17 and Compound 18.

Compound 17.

(1R)-2-(7-Cyclopropyl-2-{2-fluoro-4-[(3R)-3-methanesulfonylpyrrolidin-1-yl]phenyl}pyrazolo[1,5

a]pyrimidine-5-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (150 mg, 288 µmol), (R)-3-(methylsulfonyl)pyrrolidine [1234576-84-1] (53.4 mg, 288 µmol), cesium carbonate (276 mg, 846 µmol) and XantPhos (19.7 mg, 34.0 µmol) and purged with nitrogen. 1,4-dioxane (6 ml) was added and the mixture was purged with nitrogen. Palladium acetate (7.88 mg, 35.1 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 brine. The layers were separated and the aqueous phase was extracted. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated under reduced pressure. 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, 50:50 to 0:100). The second purification was carried out using preparative LC (C18 with grains of 25 μm spherical shape, 40 g YMC-ODS-25, loading (MeCN, H ₂ O), mobile phase gradient: (0.2% aq. NH ₄ HCO ₃ )/ MeCN, 50:50 to 0:100). Fractions containing the product were combined and 10% aqueous KHSO4 solution was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue (105 mg) was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc 50:50 to 0:100) . The residue was triturated and co-evaporated with Et ₂ O (twice) and dried in high vacuum at 50° C. for 18 h to give compound 17 (54 mg, 32%) as a yellow solid.

Compound 18.

(1 R)-2-(7-Cyclopropyl-2- {2-fluoro-4-[(3 S)-3-methanesulfonylpyrrolidin-1 -yl] phenyl} pyrazolo[1,5a] pyrimidine-5-carbonyl)- 1-methyl-1,2,3,4-tetrahydroisoquinoline

Compound 18 was synthesized from (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] and (S)-3-(methylsulfonyl)pyrrolidine [290328-57-3] according to the procedure given for the synthesis of compound 17. The crude mixture was purified by preparative LC (SiOH with irregular grains , 15-40 µm, 40 g GraceResolv™ , liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 50:50 to 0:100). The second purification was carried out using preparative LC (C18 with grains

- 23 040266 25 µm spherical, 40 g YMC-ODS-25, loading (MeCN, H ₂ O), mobile phase gradient (0.2% aq NH ₄ HCO3)/MeCN, 50:50 to 0:100 ). Fractions containing product were combined and 10% aqueous KHSO4 was added. The layers were separated and the aqueous phase was extracted with EtOAc. The organic phase was washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue was triturated and co-evaporated with Et ₂ O (twice) and dried in high vacuum at 50° C. for 18 h to give compound 18 (67 mg, 40%) as a pale red solid.

Compound 19.

1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}-3- fluorophenyl)pyrrolidine-3-sulfonamide

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (400 mg, 768 µmol), pyrrolidine-3-sulfonamide [1208507-46-3] (115 mg, 768 µmol), sodium tert-butoxide (105 mg, 1.09 mmol), and (±)-BINAP (100 mg, 161 μmol) and purged with nitrogen. 1,4-dioxane (10 ml) was added and the mixture was again purged with nitrogen. Tris-(dibenzylideneacetone)dipalladium (140 mg, 153 µmol) was added. The reaction mixture was purged with nitrogen and stirred at 100° C. for 18 hours. A 10% aqueous solution of KHSO4 was added until pH 6 was reached. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H2O, dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 95:5). The second purification was performed by preparative LC (C18 with 25 μm spherical grains, 40 g YMC-ODS-25, loading (MeCN, H2O), mobile phase gradient: (0.2% aq. NH ₄ HCO ₃ )/MeCN, from 50:50 to 0:100). The product was lyophilized to give compound 19 (48 mg, 11%) as a yellow solid.

Compound 20.

N-{[1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-3-fluorophenyl)pyrrolidin-3-yl]sulfonyl}acetamide

A mixture of compound 19 (215 mg, 0.37 mmol), acetic anhydride (53.0 μl, 0.56 mmol) and DBU (83.8 μl, 0.56 mmol) in DCM (2 ml) was stirred at rt . within 7 hours the Reaction mixture was diluted with EtOAc and saline. The layers were separated and the aqueous phase was extracted. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (C18 spherical beads, 25 μm, 40 g YMC-ODS-25, loading (MeCN, H ₂ O), mobile phase gradient: (0.2% aq. NH ₄ HCO ₃ ) /MeCN, from 15:85 to 65:35). The product was lyophilized to give compound 20 (40 mg, 17%) as a yellow solid.

Compound 21.

1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}-3- fluorophenyl)-N-methylpyrrolidine-3-sulfonamide

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (200 mg, 384 µmol),

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N-methylpyrrolidine-3-sulfonamide hydrochloride [1423025-73-3] (77.0 mg, 384 µmol), sodium tert-butoxide (50.0 mg, 0.52 mmol) and (±)-BINAP (47.8 mg, 76.8 µmol) and purged with nitrogen. Added 1,4-dioxane (9 ml) and the mixture was again purged with nitrogen. Tris-(dibenzylideneacetone)dipalladium (70.3 mg, 76.8 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 brine. The layers were separated and the aqueous phase was extracted. The combined organic extracts were washed with H2O, dried over MgSO ₄ , filtered and evaporated under reduced pressure. 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, 50:50 to 0:100). The second purification was performed using preparative LC (C18 with grains of spherical shape 25 μm, 40 g YMC-ODS-25, loading (MeCN, H ₂ O), mobile phase gradient (0.2% aq. NH ₄ HCO ₃ )/MeCN , from 50:50 to 0:100). Fractions containing the product were combined and 10% aqueous KHSO4 solution was added. The layers were separated and the aqueous phase was extracted with EtOAc. The organic phase was washed with H ₂ O, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was triturated and co-evaporated with Et ₂ O (twice) and dried in high vacuum at 50° C. for 18 h to give compound 21 (109 mg, 48%) as a pale red solid.

Compound 22.

-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}-3-fluorophenyl )-N,N-dimethylpyrrolidine-3-sulfonamide

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl-1,2, 3,4-tetrahydroisoquinoline [2035421-61-3] (250 mg, 480 µmol), N,N-dimethyl-3-pyrrolidinesulfonamide hydrochloride [1825309-05-4] (155 mg, 720 µmol) and sodium tert-butoxide ( 231 mg, 2.40 mmol) in 1,4-dioxane (10 ml). Palladium acetate (11.0 mg, 72.0 µmol) and XantPhos (27.8 mg, 48.0 µmol) were added. The reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO4, 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: DCM/MeOH, 100:0 to 96:4). The residue was co-evaporated with EtOH (5 times) and triturated with it. The solid was filtered off and dried in high vacuum at 50° C. for 18 h to give compound 22 (150 mg, 52%) as a yellow solid.

Compound 79.

____________1159__________ PdlOAch, XantPhos ''Chx^'h JWJ Cs ₂ co ₃ JWJ dioxane |А/ UxJ 100°C, 16 4. Uxj [2035421-61-3] Synthesis of intermediate I159. - ,O Mel _o 0 | n—v / aq. NaOH Γ*N , aq. HCl ^{Me0H 0—} \ MeOH k.t., 72 4. k.t., 16 4. [935845-19-5] 1160 O CA ¹ o4 sst A o™-. ^b C KT, 16 h. 1162 1163 οίΥ νΆ _F Z ^{N 4} jun _F( A ⁿ ' ^{x 3} \__/ k. t, 72 4. ^F ' ^C 1164 1159 Λη 79 HCl 1161 CF ₃ CONH ₂ Phl(OAc) ₂ Rh ₂ (OAc) ₄ , MgO - J. DCM / 0°C to rt, 16 h

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Intermediate connection I160.

tert-Butyl-(3R)-3-(methylsulfanyl)pyrrolidine-1-carboxylate

1160

To a mixture of (R)-tert-butyl-3-(acetylthio)pyrrolidine-1-carboxylate [935845-19-5] (7.00 g, 28.5 mmol) and sodium hydroxide (1.0 M in H ₂ O , 31 ml, 31.0 mmol) in MeOH (140 ml) was added methyl iodide (3.9 ml, 62.8 mmol). The reaction mixture was stirred at rt. within 72 hours the Reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated in vacuo to give intermediate I160 (5.2 g, 84%).

Intermediate connection I161.

(3R)-3-(Methylsulfanyl)pyrrolidine hydrochloride

1161

A mixture of intermediate I160 (5.20 g, 23.9 mmol) and hydrogen chloride (3.0 M in H ₂ O, 80 ml, 239 mmol) in MeOH (185 ml) was stirred at rt. over 16 h. The mixture was evaporated to dryness and co-evaporated with MeOH to give intermediate I161 (3.7 g, quant.).

Intermediate I162.

Benzyl-(3R)-3-(methylsulfanyl)pyrrolidine-1-carboxylate

To a mixture of intermediate I161 (3.70 g, 24.1 mmol) and DIPEA (10.3 ml, 60.2 mmol) in DCM (122 ml) was added benzyl chloroformate (3.8 ml, 26.5 mmol). The reaction mixture was stirred at rt. within 16 hours Added an aqueous solution of NaHCO ₃ , saline and DCM. The layers were separated and the aqueous phase was extracted with DCM (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, 220 g Interchim®, liquid phase injection (DCM/heptane), mobile phase gradient: heptane/EtOAc from 100:0 to 50:50) to give the intermediate compound I162 (3.22 g, 53%).

Intermediate I163.

Benzyl-(3R)-3-methanesulfinylpyrrolidine-1-carboxylate

To a solution of intermediate I162 (3.22 g, 12.8 mmol) in DCM (128 ml) at 0°C was added m-CPBA (3.16 g, 14.1 mmol, 77% purity) in portions. The reaction mixture was stirred at 0° C. for 1 h. A 10% aqueous solution of NaHCO ₃ and H ₂ O was added. The layers were separated and the aqueous phase was extracted with DCM. 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, 120 g Interchim®, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 99.8:0.2 to 95:5) to give intermediate I163 (1.63 g, 48%).

Intermediate I164.

Benzyl-(3R)-3-[methyl(oxo)[(trifluoroacetyl)imino]-λ ⁶ -sulfanyl]pyrrolidine-1-carboxylate

To a mixture of intermediate I163 (1.63 g, 6.10 mmol), trifluoroacetamide (1.03 g, 9.15 mmol) and magnesium oxide (983 mg, 24.4 mmol) in DCM (85 ml) at 0° C was added rhodium acetate dimer (90.0 mg, 0.41 mmol) and (diacetoxyiodo)benzene (2.95 g, 9.15 mmol). The reaction mixture was stirred at 0°C for 1 h and at room temperature. over 16 hours. Celite® was added and the mixture was evaporated to dryness. The crude mixture was purified by preparative LC (SiOH with regular grains, μm, 80 g Interchim®, dry-loaded (Celite®), mobile phase gradient: DCM/MeOH, 100:0 to

95:5) to give intermediate I164 (1.47 g, 64%).

Intermediate I159.

2,2,2-Trifluoro-N-[methyl(oxo)(3R)-pyrrolidin-3-yl-λ ⁶ -sulfanylidene]acetamide

A mixture of intermediate I164 (1.47 g, 3.89 mmol) and Pd/C (10 wt.% and in 50% H ₂ O, 4.13 g, 1.94 mmol) in EtOH (50 ml) was stirred in atmosphere H ₂ (20 bar) at r.t. for 72 hours. The reaction mixture was filtered through a pad of Celite® and rinsed with EtOH (twice). The filtrate was evaporated to dryness to give intermediate I159 (838 mg, 88%).

Compound 79.

[(3R)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidine- 2-yl}-3-fluorophenyl)pyrrolidin-3-yl](imino)methyl-X ⁶ -sulfanone

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (300 mg, 0.59 mmol), intermediate I159 (217 mg, 0.89 mmol), cesium carbonate (580 mg, 1.78 mmol) and 1,4-dioxane (9 .5 ml). The mixture was degassed with nitrogen and palladium acetate (13.3 mg, 5.94 µmol) and XantPhos (34.3 mg, 5.94 µmol) was added sequentially. The reaction mixture was stirred at 100°C for 16 h. H2O (3.8 ml) was added and the reaction mixture was stirred at rt. within 1 h. The reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. 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, 25 g Interchim®, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 99.8:0.2 to 90:10) . The residue was solubilized in EtOAc and the mixture was evaporated in vacuo (twice). The residue was dissolved in EtOAc and a precipitate was observed upon addition of heptane. The solid was filtered off and dried in high vacuum at 40° C. for 16 h to give compound 79 (143 mg, 42%).

Compound 23 and Compound 24.

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Synthesis of intermediate compound I21.

Intermediate connection I25.

tert-Butyl-3-(2-ethoxy-2-oxoethyl)-3-methylpyrrolidine-1-carboxylate

A mixture of tert-butyl-(3E)-3-(2-ethoxy-2-oxoethylidene)pyrrolidine-1-carboxylate [664364-28-7] (3.50 g, 13.7 mmol), chlorotrimethylsilane (63.8 ml , 54.8 mmol) and cuprous iodide (3.02 g, 15.8 mmol) in THF (150 mL) were stirred at rt. within 1 h. The reaction mixture was cooled to -30°C and added dropwise methylmagnesium bromide (3.0 M in Et ₂ O, 27.4 ml, 82.3 mmol). The reaction mixture was slowly heated to rt. and stirred overnight. Added EtOAc and 1N. aqueous solution of HCl. The layers were separated and the organic phase was washed with brine, dried over MgSO ₄ , filtered and the solvent was removed under reduced pressure. 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 70:30) to give intermediate I25 (2.0 g, 54%).

Intermediate I21.

Ethyl 2-(3-methylpyrrolidin-3-yl)acetate hydrochloride

To a solution of intermediate I25 (550 mg, 2.03 mmol) in DCM (10 ml) was added HCl (4.0 M in dioxane, 2.53 ml, 10.1 mmol). The reaction mixture was stirred at rt. overnight and the solvent was evaporated under reduced pressure. Product I21 was used in the next step without further purification.

Synthesis of compounds 23 and 24.

Intermediate I22.

Ethyl 2-[1 -(4-{7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-а]pyrimidine- 2-yl}-3-fluorophenyl)-3-methylpyrrolidin-3-yl]acetate

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5a]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline was purged with nitrogen [2035421-61-3] (474 mg, 0.94 mmol), Intermediate I21 (390 mg, 1.88 mmol), cesium carbonate (0.92 g, 2.82 mmol) and XantPhos (54.3 mg , 93.9 µmol). 1,4-dioxane (15 ml) was added and the mixture was again purged with nitrogen. Palladium acetate (21.1 mg, 93.9 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 extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent was removed under reduced pressure. 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 70:30) to give intermediate I22 (490 mg, 88%).

Intermediates I23 and I24.

2-[(3*R)-1 -(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[ 1,5- a]pyrimidin-2-yl}-3-fluorophenyl)-3-methylpyrrolidin-3-yl]acetic acid and

2-[(3*S)-1 -(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[ 1,5- a]pyrimidin-2-yl}-3-fluorophenyl)-3-methylpyrrolidin-3-yl]acetic acid:

- 28 040266

To a solution of intermediate I22 (490 mg, 823 µmol) in THF (10 ml), MeOH (3 ml) and H ₂ O (1.2 ml) was added lithium hydroxide monohydrate (104 mg, 2.45 mmol). The reaction mixture was stirred at rt. within 3 hours Added a few drops of H ₂ O followed by the addition of 3n. aqueous solution of HCl. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g Grace®, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 97:3) to give mixtures of diastereomers (250 mg, 53%). Purification was carried out with chiral SFC (stationary phase: Chiralpak AS-H, 5 μm, 250x20 mm, mobile phase: 65% CO ₂ , 35% ϊ-ΡγΟΗ) to give diastereomers I23 (120 mg, 26%) and I24 (122 mg, 26%). The diastereomers were purified individually by preparative LC (irregular SiOH, 15-40 µm, 12 g Grace®, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 97:3) with obtaining compound I23 (95 mg, 20%) and compound I24 (92 mg, 20%).

Compound 23.

2-[(3*R)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5- a]pyrimidin-2-yl}-3-fluorophenyl)-3-methylpyrrolidin-3-yl]acetamide

A mixture of intermediate I23 (80.0 mg, 0.14 mmol), HMDS (35.9 µl, 0.17 mmol), HATU (80.4 mg, 0.21 mmol) and DIPEA (36.4 µl, 0 .21 mmol) in DMF (2 ml) was stirred at rt. within 2 hours was Added N ₂ O and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H ₂ O, brine, dried over MgSO ₄ and concentrated to dryness. The crude mixture was purified by silica gel flash chromatography (15-40 μm, 12 g Grace®, mobile phase gradient: DCM/MeOH, 100:0 to 97:3). The purified fractions were collected and evaporated to dryness. The residue (53 mg) was crystallized from DIPE to give compound 23 (35.6 mg, 44%).

Compound 24.

2-[(3*S)-1 -(4-{7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[ 1,5- a]pyrimidin-2-yl}-3-fluorophenyl)-3-methylpyrrolidin-3-yl]acetamide

Compound 24 (29 mg, 32%) was synthesized from intermediate I24 according to the procedure given for the synthesis of compound 23.

Compound 25 and Compound 26.

- 29 040266

Intermediate I26.

Ethyl 2-[1-(4-{7-cyclopropyl-5-[(4*K)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl] pyrazolo[1,5-а]pyrimidin-2-yl}-3-fluorophenyl)-3-methylpyrrolidin-3-yl]acetate

Mixture

2-(4-bromo-2-fluorophenyl)-7-cyclopropyl-5-[(4R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2

c]pyridine-5-carbonyl]pyrazolo[1,5-a]pyrimidine [2035419-01-1] (517 mg, 1.01 mmol), intermediate I21 (420 mg, 2.02 mmol), cesium carbonate ( 0.99 g, 3.03 mmol) and XantPhos (80.1 mg, 0.14 mmol) were purged with nitrogen. 1,4-dioxane (12 ml) was added and the mixture was degassed with nitrogen. Palladium acetate (22.7 mg, 0.10 mmol) 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 extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent was removed under reduced pressure. 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 70:30) to give intermediate I26 (440 mg, 72%).

Intermediates I27 and I28.

2-[(3*K)-1-(4-{7-Cyclopropyl-5-[(4*K)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 5carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)-3-methylpyrrolidin-3-yl]acetic acid and

2-[(3*S)-1-(4-{7-cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 5carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)-3-methylpyrrolidin-3-yl]acetic acid:

To a solution of intermediate I26 (440 mg, 0.73 mmol) in THF (10 ml), MeOH (3 ml) and H2O (1.2 ml) was added lithium hydroxide monohydrate (92.1 mg, 2.19 mmol). The reaction mixture was stirred at rt. within 18 hours Added a few drops of H ₂ About followed by the addition of 3N. aqueous solution of HCl. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with H2O, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g Grace®, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 97:3). Diastereoisomers (220 mg) were separated using chiral SFC (stationary phase: Chiralpak AS-H, 5 μm, 250x20 mm, mobile phase: 65% CO ₂ , 35% i-PrOH) to give compound I27 (94 mg) and compound I28 (94 mg). The two separated diastereoisomers were taken up with DIPE and the solids were filtered off and dried in vacuo at 50°C. Diastereoisomers were purified separately by preparative LC (irregular SiOH, 15-40 µm, 12 g Grace®, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 97:3) with obtaining intermediate compounds I27 (78 mg, 18%) and I28 (70 mg, 17%).

Compound 25.

2-[(3*K)-1-(4-{7-Cyclopropyl-5-[(4*K)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 5

- 30 040266 carbonyl] pyrazolo [1,5-а] pyrimidin-2-yl}-3-fluorophenyl)-3-methylpyrrolidin-3-yl]acetamide

A solution of intermediate I27 (78.0 mg, 0.14 mmol), HMDS (34.6 µl, 0.16 mmol), HATU (77.5 mg, 0.20 mmol) and DIPEA (46.9 µl, 0 .27 mmol) in DMF (2 ml) was stirred at rt. within 5 hours the Reaction mixture was diluted with H ₂ O and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H ₂ O, brine, dried over MgSO ₄ and concentrated to dryness. The crude mixture was purified by silica gel flash chromatography (15-40 μm, 12 g Grace®, mobile phase gradient: DCM/MeOH, 100:0 to 97:3). The purified fractions were collected and evaporated to dryness. The residue (32 mg) was crystallized from DIPE to give compound 25 (18 mg, 23%).

Compound 26.

2-[(3*S)-1-(4-{7-Cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 5carbonyl] pyrazolo [1,5-a] pyrimidin-2-yl }-3-fluorophenyl)-3-methylpyrrolidin-3-yl]acetamide

Compound 26 (28 mg, 40%) was synthesized from intermediate I28 according to the procedure given for the synthesis of compound 25.

Compound 27 and Compound 28.

(R/S): 132

(R/S): 134 (R*S): 28

Synthesis of intermediates I29 and I30.

1) LiHMDS, THF -10°С, 1 h.

1) LiHMDS, THF

-10°C, 1 hour

-------------------------------------------------- -------------------------------------------------- -------------------2) Mel

c.t., 4 h.

[664364-29-8]

- 31 040266

Intermediate I35.

tert-Butyl-3 - (1 -ethoxy-1 -oxopropan-2-yl) pyrrolidine-1 -carboxylate ^Ε "Ά ₀

135

To a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate [664364-29-8] (1.7 g, 6.61 mmol) in THF (60 ml) at -10° Lithium bis(trimethylsilyl)amide (1.5 M in THF, 10.6 ml, 15.9 mmol) was added over 1 h. Iodomethane (0.98 ml, 15.9 mmol) was added and the reaction mixture was stirred at rt. within 4 hours was Added N ₂ O and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. Intermediate I35 was used in the next step without further purification.

Intermediates I36 and I37.

tert-Butyl-(3*R)-3-(1-ethoxy-2-methyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate and tert-butyl-(3*S)-3 -(1 - ethoxy-2-methyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate:

EIU^° ₀ EIU^R ₀

MOVE

136 137

Lithium bis-(trimethylsilyl)amide (1.5 M in THF, 18.4 ml, 27.6 mmol) was added to a solution of intermediate I35 (2.50 g, 9.21 mmol) in THF (37.5 ml) at -10°C under nitrogen atmosphere. The reaction mixture was stirred at -10° C. for 2 h. Iodomethane (1.37 mL, 22.1 mmol) was added and the reaction mixture was stirred at rt. within 4 hours the Reaction mixture was diluted with EtOAc and the organic phase was washed with H ₂ O, saline, dried over MgSO ₄ and the solvent was evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 μm, 24 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 100:0 to 70:30). The enantiomers were separated by chiral SFC (stationary phase: Lux Amylose-2, 5 μm, 250x21.2 mm, mobile phase: 90% CO ₂ , 10% i-PrOH) to give intermediates I36 (850 mg, 32%) and I37 (850 mg, 32%).

Intermediate I29.

Ethyl 2-methyl-2-[(3*R)-pyrrolidin-3-yl]propanoate hydrochloride

EtO^zP

4^7% ns.

129

To a solution of intermediate I36 (250 mg, 876 µmol) in DCM (5 ml) was added HCl (4.0 M in dioxane, 1.1 ml, 4.40 mmol). The reaction mixture was stirred at rt. during the night. The solvent was evaporated under reduced pressure and the product I29 was used in the next step as soon as possible without further purification.

Intermediate connection I30.

Ethyl 2-methyl-2-[(3*S)-pyrrolidin-3-yl]propanoate hydrochloride

EU^xP

130

Intermediate I30 was synthesized from intermediate I37 according to the procedure given for the synthesis of intermediate I29. The product was used in the next step without further purification.

Synthesis of compounds 27 and 28.

Intermediate connection I31.

Ethyl 2-[(3 *R)-1 -(4-{7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] pyrazolo[1, 5-а]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]-2-methylpropanoate

- 32 040266

Mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-carbonyl]-1methyl-1,2,3,4-tetrahydroisoquinoline [2035421 -61-3] (228 mg, 0.45 mmol), intermediate I29 (150 mg, 0.68 mmol), cesium carbonate (441 mg, 1.35 mmol) and XantPhos (26.1 mg, 45.1 µmol) was purged with nitrogen. 1,4-dioxane (7 ml) was added and the mixture was again purged with nitrogen. Palladium acetate (10.1 mg, 45.1 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 extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent was evaporated under reduced pressure. 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 75:25) to give intermediate I31 (190 mg, 69%).

Intermediate I32.

Ethyl-2-[(3*S)-1 -(4-{7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1, 5-а]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]-2-methylpropanoate

Y ^F \ «ΑΛ/μΑΛJI

GT

132

Intermediate I32 (125 mg, 57%) was synthesized from 1,2,3,4-tetrahydroisoquinoline [203542161-3] and intermediate I30 according to the procedure given for the synthesis of compound I31, while the reaction time is shorter and is 3 hours.

Intermediate I33.

2-[(3*R)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[ 1,5- a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]-2-methylpropanoic acid

Lithium hydroxide monohydrate (65.4 mg, 1.56 mmol) was added to a solution of intermediate I31 (0.19 g, 0.31 mmol) in THF (5 ml), MeOH (2 ml) and H ₂ O (0. 4 ml). The reaction mixture was stirred at rt. within 24 h and at 60°C for 24 h Added a few drops of H ₂ O followed by the addition of 3n. aqueous solution of HCl. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated under reduced pressure. Product I33 (210 mg) was used in the next step without further purification.

Intermediate I34.

2-[(3*S)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[ 1,5- a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]-2-methylpropanoic acid

Intermediate I34 was synthesized from intermediate I32 according to the procedure given for the synthesis of intermediate I33. The reaction mixture was stirred at 60° C. for 24 hours. Product I34 (155 mg) was used in the next step without further purification.

Compound 27.

2-[(3 *R)-1 -(4-{7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl] pyrazolo [1,5-a] pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]-2-methylpropanamide

- 33 040266

Mixture of Intermediate I33 (190 mg, 327 µmol), HMDS (83.2 µl, 392 µmol), HATU (186 mg, 0.49 mmol) and DIPEA (112 µl, 0.65 mmol) in DMF (5 ml) stirred at rt. within 2 hours was Added N ₂ O and the aqueous phase was extracted with EtOAc. The organic phase was washed with H ₂ O, brine, dried over MgSO ₄ and concentrated to dryness. The crude mixture was purified by silica gel flash chromatography (Grace® 12 g, 15-40 µm, mobile phase gradient: DCM/MeOH, 100:0 to 97:3). The purified fractions were collected and evaporated to dryness. The residue (85 mg) was taken up with DIPE and the solid was filtered off and dried in vacuo to give compound 27 (50 mg, 26%).

Compound 28.

2-[(3*S)-1 -(4-{7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5- a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]-2-methylpropanamide

Compound 28 was synthesized from intermediate I34 according to the procedure given for the synthesis of compound 27. The crude mixture was purified by flash chromatography on silica gel (15-40 μm, 12 g Grace®, mobile phase gradient: DCM/MeOH, from 100: 0 to 97:3). The purified fractions were collected and evaporated to dryness. The product was lyophilized with MeCN/H ₂ O (80:20) to give compound 28 (56 mg, 36%).

Compound 29.

Intermediate connection I38.

Ethyl-2-[(3*R)-1-(4-{7-cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c] pyridine-5carbonyl]pyrazolo[1,5-а]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]-2-methylpropanoate

- 34 040266

2-(4-Bromo-2-fluorophenyl)-7-cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2c]pyridine-5-carbonyl] mixture pyrazolo[1,5-a]pyrimidine [2035419-01-1] (300 mg, 0.59 mmol), intermediate I29 (195 mg, 0.88 mmol), cesium carbonate (573 mg, 1.76 mmol) and XantPhos (33.9 mg, 58.6 µmol) were purged with nitrogen. 1,4-dioxane (7 ml) was added and the mixture was degassed with nitrogen. Palladium acetate (13.2 mg, 58.6 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 extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 100:0 to 75:25) to give intermediate I38 (120 mg, 33%).

Intermediate I39.

2-[(3*R)-1-(4-{7-Cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 5carbonyl]pyrazolo[1,5-а]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]-2-methylpropanoic acid

To a solution of intermediate I38 (0.12 g, 195 µmol) in THF (5 ml), MeOH (1 ml) and H ₂ O (0.6 ml) was added lithium hydroxide monohydrate (24.5 mg, 0.59 mmol ). The reaction mixture was stirred at rt. for 24 h and at 60°C for another 24 h Added a few drops of H ₂ About followed by the addition of 3N. aqueous solution of HCl. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with H2O, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 4 g Grace®, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 97:3) to give intermediate I39 (75 mg, 65%).

Compound 29.

2-[(3*R)-1-(4-{7-Cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine- 5carbonyl]pyrazolo[1,5-а]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]-2-methylpropanamide

A solution of intermediate I39 (75.0 mg, 0.13 mmol), HMDS (32.5 µl, 0.15 mmol), HATU (72.8 mg, 0.19 mmol) and DIPEA (44.0 µl, 0 .26 mmol) in DMF (2 ml) was stirred at rt. within 2 hours. The reaction mixture was diluted with H2O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The organic phase was washed with H ₂ O, brine, dried over MgSO ₄ and concentrated to dryness. The crude compound was purified by silica gel flash chromatography (15-40 μm, 4 g Grace®, mobile phase gradient: DCM/MeOH, 100:0 to 97:3). The purified fractions were collected and evaporated to dryness. The product was lyophilized (MeCN/H ₂ O, 80:20) to give compound 29 (41 mg, 55%).

Compound 30 and Compound 31.

(S):141

(S): I43 (S): 31

- 35 040266

Intermediate connection I40.

tert-Butyl-N-(3R)-1 -(4-{7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-a ]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]carbamate

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5a]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (500 mg, 0.95 mmol), (R)-3-(boc-amino)pyrrolidine [122536-77-0] (355 mg, 1.91 mmol), cesium carbonate ( 1.09 g, 3.34 mmol) and toluene (20 ml). The mixture was purged with nitrogen. (±)-BINAP (59.3 mg, 95.3 µmol) and tris(dibenzylideneacetone)dipalladium (87.2 mg, 95.3 µmol) were added. The reaction mixture was purged with nitrogen and stirred at 100° C. for 20 hours. The reaction mixture was diluted with brine and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. 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 90:10 to 60:40) to give intermediate compound I40 (542 mg, 93%) as a yellow foam.

Intermediate I41.

tert-Butyl-N-[(3S)-1-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5- a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]carbamate

Intermediate I41 was synthesized from (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-carbonyl]-1-methyl-1,2,3 ,4-tetrahydroisoquinoline [2035421-61-3] and (S)-3-(boc-amino)pyrrolidine [122536-76-9] according to the procedure given for the synthesis of intermediate I40. Intermediate I41 (570 mg, 98%) was obtained as a yellow foam.

Intermediate I42.

(3R)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl } -3-fluorophenyl)pyrrolidine-3-amine

To a solution of intermediate I40 (401 mg, 65.7 µmol) in DCM (8 ml) was added TFA (1.60 ml, 20.9 mmol). The reaction mixture was stirred at rt. within 1 h was Added DCM and saturated aqueous solution of NaHCO ₃ . The layers were separated and the organic phase was dried over MgSO ₄ , filtered and the solvent was removed under reduced pressure to give intermediate I42 (358 mg) as a yellow gum. The product was used in the next step without further purification.

Intermediate I43.

(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-amine

Intermediate I43 was synthesized from intermediate I41 according to the procedure given for the synthesis of intermediate I42. Intermediate I43

- 36 040266 (450 mg) was obtained as a yellow gum and used in the next step without further purification.

Compound 30.

(1C)-2-(7-Cyclopropyl-2-{4-[(ZK)-3-[(dimethylphosphoryl)amino]pyrrolidin-1-yl]-2-fluorophenyl}pyrazolo[1,5-a]pyrimidine- 5-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline

Dimethylphosphine chloride (360 µl, 0.72 mmol). The reaction mixture was stirred at rt. within 2 hours the Reaction mixture was diluted with DCM and washed with 10% aqueous NaHCO ₃ . The organic phase was dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase: DCM/MeOH gradient from 100:0 to 96:4). The residue was taken up in MeOH, evaporated and triturated with Et ₂ O. The solid was filtered off and dried under high vacuum at 50° C. for 2 h to give compound 30 (199 mg, 53%) as a yellowish solid.

Compound 31.

(1Р)-2-(7-Cyclopropyl-2-{4-[(38)-3-[(dimethylphosphoryl)amino]pyrrolidin-1-yl]-2-fluorophenyl}pyrazolo[1,5-а]pyrimidin- 5-carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline

Compound 31 was synthesized from intermediate compound 143 according to the procedure given for the synthesis of compound 30. The product was dried in high vacuum at 50°C for 20 h to obtain compound 31 (233 mg, 58%) as a yellowish solid.

Compound 76.

N-[(3 S)-1 -(4- {7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[ 1,5-a ]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidin-3-yl]-2,2,2-trifluoroacetamide

In a closed tube, to a solution of intermediate 143 (100 mg, 196 μmol) in MeOH (0.8 ml) were added Et ₃ N (32 μl, 0.23 mmol) and ethyl trifluoroacetate (30 μl, 0.25 mmol). The reaction mixture was stirred at rt. within 18 hours the Reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure. 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). The residue was crystallized from MeOH. The solid was filtered off and dried in high vacuum at 50° C. for 20 h to give compound 76 (53 mg, 45%) as a yellow solid.

Compound 32, Compound 33, Compound 34 and Compound 35.

-37040266

hh ₂

Η

144

Synthesis of intermediate compound I44.

Vos ₂ O Et ₃ N, DMAP

DCM c.t., 4 p.m.

148

Intermediate I47.

-tert-Butyl-3-methyl-5-methyl-1 H-pyrrole-1,3-dicarboxylate

A closed tube was loaded with DMAP (8.78 mg, 71.8 µmol), 5-methylN-pyrrole-3-carboxylic acid methyl ester [40611-76-5] (100 mg, 0.72 mmol), Boc ₂ O (154 μl, 0.72 mmol), triethylamine (0.30 ml, 2.16 mmol) and anhydrous DCM (2 ml). The reaction mixture was stirred at rt. within 18 hours was Added N ₂ O, saturated aqueous solution of NaHCO ₃ and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure to give intermediate I47 (170 mg, 99%).

Intermediate I48.

-tert-Butyl-3-methyl-5-methylpyrrolidine-1,3-dicarboxylate

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In an autoclave, a mixture of intermediate I47 (1.25 g, 5.22 mmol) and platinum on carbon (1 wt%, 4.1 g, 209 µmol) in EtOH (38 mL) was stirred at rt. at a pressure of 35 bar H ₂ for 16 hours was Added platinum on carbon (1 wt.%, 1.02 g, 52 μmol) and the reaction mixture was stirred at room temperature. at a pressure of 40 bar H2. Platinum on charcoal (1 wt%, 1.02 g, 52 µmol) was added and the reaction mixture was stirred at rt. at a pressure of 40 bar H ₂ . The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. 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 0:100) to give intermediate I48 (850 mg, 67%) as a colorless oil.

Intermediate I44.

Methyl-5-methylpyrrolidine-3-carboxylate hydrochloride

ABOUT

144

To a solution of intermediate I48 (850 mg, 3.49 mmol) in MeOH (5.0 ml) was added dropwise hydrochloric acid (3.0 M in CPME, 12.5 ml, 37.5 mmol). The reaction mixture was stirred at rt. within 18 h and the solvent was removed under reduced pressure. The residue was co-evaporated with toluene to give intermediate I44 (627 mg, quant) as a colorless oil.

Synthesis of compounds 32, 33, 34 and 35.

Intermediate I45.

Methyl-1-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}- 3-fluorophenyl)-5-methylpyrrolidine-3-carboxylate

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (703 mg, 1.39 mmol), intermediate I44 (250 mg, 1.39 mmol) and cesium carbonate (1.36 g, 4.18 mmol) and purged with nitrogen. 1,4-dioxane (11 ml) was added and the mixture was degassed with nitrogen. Palladium acetate (31.2 mg, 0.14 mmol) and XantPhos (80.5 mg, 0.14 µmol) were added. The reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ 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, 90:10 to 50:50) to give intermediate I45 (260 mg, 33%) as a yellowish solid.

Intermediate I46.

1-(4-{7-Cyclopropyl-5-[(1C)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-

a] pyrimidin-2-yl}-3-fluorophenyl)-5-methylpyrrolidin-3-carboxylic acid

To a solution of intermediate I45 (680 mg, 1.20 mmol) in THF (27 ml) and H ₂ O (6.8 ml) was added lithium hydroxide monohydrate (151 mg, 3.59 mmol). The reaction mixture was stirred at rt. over 16 h. 10% aqueous KHSO4 solution was added until pH 6 was achieved. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H2O, dried over MgSO ₄ , filtered and evaporated under reduced pressure. 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/AcOH, from 80:19.5:0, 5 to 40:58.5:1.5) to give Intermediate I46 (660 mg, quant.).

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Connections 32, 33, 34 and 35.

(3 *R, 5 *R)~1 -(4-{7-cyclopropyl-5-[(17?)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[ 1, 5- a] pyrimidin-2-yl } -3-fluorophenyl)-5-methylpyrrolidin-3 carboxamide (3 *R, 5 *5)-1 - (4- { 7-cyclopropyl-5 - [(17?) -1 - methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl } -3-fluorophenyl)-5-methylpyrrolidin-3 carboxamide (3*5.5*7?) -1 - (4- { 7-cyclopropyl-5 - [(17?) -1 -methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl] pyrazolo[ 1, 5-a] pyrimidin-2-yl } - 3-fluorophenyl)-5-methylpyrrolidine-3 carboxamide (3 * 5.5 * 5) -1 - (4- { 7-cyclopropyl-5 - [(17?) -1 -methyl-1,2,3,4 -tetrahydroisoquinoline-2carbonyl]pyrazolo[ 1,5-a]pyrimidin-2-yl } -3-fluorophenyl)-5-methylpyrrolidin-3 carboxamide

hh ₂

A mixture of intermediate I46 (660 mg,

1.19 mmol), HATU (680 mg, 1.79 mmol) and DIPEA (616 μl, 3.58 mmol) in DMF (20 ml) were stirred at rt. within 1 h. Ammonia (28% in H ₂ O, 403 μl, 5.96 mmol) was added and the reaction mixture was stirred at RT. within 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% aqueous NaHCO ₃ solution (twice), dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/i-PrOH, 100:0 to 80:20) to give a mixture of diastereoisomers (550 mg, 83%) as a yellow oil.

The sample was combined with another sample (123 mg) and the diastereoisomers were separated using chiral SFC (stationary phase: CHIRACEL OJ-H, 5 μm, 250x30 mm, mobile phase: 58% CO ₂ , 42% MeOH (0.3% i-PrNH ₂ )). Four fractions were isolated (A, B, C and D). After evaporation of the solvent, the residue of fraction A was taken up with EtOH, the solid was filtered off and dried in vacuo at 50° C. for 16 h to give compound 32 (94 mg, 11%). The rest of fraction B was crystallized from EtOAc, filtered off and dried in vacuo at 50° C. for 16 h to give compound 35 (168 mg, 20%). The rest of fraction C was crystallized from EtOAc. The solid was filtered off and dried in vacuo at 50° C. for 16 h to give compound 34 (94 mg, 11%). The rest of fraction D was taken up with EtOH, the solid was filtered off and dried in vacuo at 50° C. for 16 h to give compound 33 (164 mg, 20%).

Compounds 80, 81, 82 and 83.

and he. _Ng oh ^he

THF:H ₂ O \z ^N X

k.t., 16 hours,] then 50°C, 6 hours.

1167

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Synthesis of intermediate compound I165.

Ethyl 2-methylpyrrolidine-3-carboxylate hydrochloride

A mixture of ethyl 1-benzyl-2-methyl-4,5-dihydro-1H-pyrrole-3-carboxylate [161692-15-5] (3.60 g,

14.7 mmol) and Pd/C (10%, 1.56 g, 1.47 mmol) in EtOH (73 ml) were stirred at rt. under hydrogen atmosphere (40 bar) for 72 hours. The reaction mixture was filtered through a pad of Celite® and hydrogen chloride (3.0 M in CPME, 5.9 ml, 18 mmol) was added to the filtrate. The solvent was evaporated in vacuo to give intermediate I165 (2.6 g, 91%). The product was used as such in the next step.

Synthesis of compounds 80, 81, 82 and 83.

Intermediate I166.

Ethyl-1-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}- 3-fluorophenyl)-2-methylpyrrolidine-3-carboxylate

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] (2.81 g, 5.56 mmol), intermediate I165 (1.40 g, 7.23 mmol) and cesium carbonate (5.44 g, 16.7 mmol). The mixture was purged with nitrogen. 1,4-dioxane (45 ml) was added and the mixture was degassed with nitrogen. Palladium acetate (125 mg, 556 µmol) and XantPhos (322 mg, 556 µmol) were added. The reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 120 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 90:10 to 60:40) to give intermediate I166 (1.93 g, 60%) as a yellowish solid.

Intermediate I167.

1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetraαhydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}-3- fluorophenyl)-2-methylpyrrolidine-3-carboxylic acid

To a solution of intermediate I166 (1.93 g, 3.32 mmol) in THF (34 ml) and H ₂ O (11 ml) was added lithium hydroxide monohydrate (995 mg, 23.7 mmol). The reaction mixture was stirred at rt. for 16 h and at 50° C. for 6 h. A 10% aqueous KHSO4 solution 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. crude mixture

- 41 040266 was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc/AcOH, from 80:19.5:0 .5 to

30:68:2 to give intermediate I167 (1.59 g, 87%).

Compounds 80, 81, 82 and 83.

(2*L,3*A)-1-(4-{7-cyclopropyl-5-[(1L)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-a ]pyrimidin-2-yl}-3-fluorophenyl)-2-methylpyrrolidin-3carboxamide (2*R, 3*5)-1 -(4-{7-cyclopropyl-5-[(17?)-1 -methyl- 1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-а]pyrimidin-2-yl}-3-fluorophenyl)-2-methylpyrrolidin-3carboxamide (2*5(3*7?)-1- (4-{7-cyclopropyl-5-[(17?)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-а]pyrimidin-2-yl}-3-fluorophenyl )-2-methylpyrrolidine-3-carboxamide (2*uz *5). [1,5-а]pyrimidin-2-yl}-3-fluorophenyl)-2-methylpyrrolidin-3carboxamide

A mixture of intermediate I167 (1.59 g, 2.87 mmol), HATU (1.64 g, 4.31 mmol) and DIPEA (1.49 ml, 8.62 mmol) in DMF (48 ml) was stirred at .T. for 1 h. Ammonia (28% in H ₂ O, 1.0 ml, 14.4 mmol) was added and the reaction mixture was stirred at rt. within 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% aqueous NaHCO ₃ solution (twice), 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: DCM/i-PrOH, 100:0 to 80:20) to give a mixture of diastereoisomers (1.3 g, 82%). Diastereoisomers (700 mg) were separated using chiral SFC (stationary phase: CHIRALPAK AS-H, 5 μm, 250x20 mm, mobile phase: 60% CO ₂ , 40% MeOH (0.3% i-PrNH ₂ )). The separated diastereoisomers were taken up with Et ₂ O. The solid was filtered off and dried in vacuo at 50° C. for 16 h to give compound 81 (60 mg, 4%), compound 80 (180 mg, 11%) and compound 82 (65 mg, 4%). The last residue was taken up with EtOH. The solid was filtered off and dried in vacuo at 50° C. for 16 h to give compound 83 (215 mg, 14%).

General scheme

Compound 36.

(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-carboxamide

- 42 040266

A mixture of (3S)-1-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidine- 2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid [2035416-78-3] (10.5 g, 18.4 mmol), HATU (10.5 g, 27.6 mmol) and DIPEA (10 ml, 58.0 mmol) in DMF (180 ml) was stirred at rt. for 1 h. Ammonia (28% in H ₂ O, 15 ml, 222 mmol) was added and the reaction mixture was stirred at rt. within 18 hours Added H ₂ O, saline and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine (3 times), dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 330 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 98:2). The residue was crystallized from MeCN, filtered off and dried in vacuo at 50° C. for 2 h to give compound 36 (6.47 g, 65%) as a yellow solid.

Compound 37.

(3S)-1-(4-{7-Cyclonronyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-3-fluorophenyl)-N-methylpyrrolidine-3-carboxamide

Mixture of (3 S)-1-(4-{7-cyclopropyl-5-[( 1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] pyrazolo[1,5-a]pyrimidine -2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid [2035416-78-3] (180 mg, 333 µmol), HATU (190 mg, 500 µmol) and DIPEA (172 µl, 1.00 mmol) in DMF (9 ml) was stirred at rt. over 1 h. Methylamine (40% in H2O, 144 µl, 1.67 mmol) was added and the reaction mixture was stirred at rt. within 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% aqueous NaHCO ₃ solution (twice), dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/i-PrOH, 100:0 to 80:20) to give compound 37 (135 mg, 73%) as a yellow oil.

Compound 38.

(3S)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5α]pyrimidin-2-yl }-3-fluorophenyl)-N,N-dimethylpyrrolidine-3-carboxamide

Compound 38 was synthesized from (3S)-1-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a ]pyrimidin-2-yl }-3-fluorophenyl)pyrrolidine-3-carboxylic acid [2035416-78-3] and dimethylamine (2.0 M in THF) [124-40-3] according to the procedure given for the synthesis compound 37. 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, 40:60 to 0:100 ) to give compound 38 (102 mg, 54%) as a yellow oil.

Connection 39.

(3 S)-N-Cyano-1 -(4-{7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5- a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxamide

- 43 040266

Compound 39 was synthesized from (3S)-1-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a ]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid [2035416-78-3] and cyanamide [420-04-2] according to the procedure given for the synthesis of compound 37. The crude mixture was purified using preparative LC (irregular SiOH, 15-40 µm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/i-PrOH, 100:0 to 50:50) to give a yellow oil ( 90 mg). The second purification was performed using preparative LC (C18 spherical beads, 25 μm, 40 g YMC-ODS-25, dry-load (Celite®), mobile phase gradient: (0.2% aq. NH4HCO ₃ )/MeCN, from 85:15 to 45:55) to give Compound 39 (70.0 mg, 27%) after lyophilization as a yellow solid.

Compound 40.

(3S)-1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-3-fluorophenyl)-N-methanesulfonylpyrrolidine-3-carboxamide

A mixture of (3S)-1-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl].

pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid [2035416-78-3] (200 mg, 371 µmol) and CDI (180 mg, 1.11 mmol) in MeCN (5 ml) was stirred at room temperature. for 2 h. DBU (221 μl, 1.48 mmol) and methanesulfonamide [3144-09-0] (141 mg, 1.48 mmol) were added and the reaction mixture was stirred at 80°C for 16 h. , 1n. aqueous solution of HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with a solution based on water and saline (1:1), dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (C18 spheroid, 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 the product were combined and added 1N. aqueous solution of HCl and EtOAc. The layers were separated and the aqueous phase was extracted. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The mixture was purified by preparative LC (C18 spherical, 25 μm, 40 g YMC-ODS-25, dry-loaded (Celite®), mobile phase gradient (0.2% aq. NH ₄ HCO ₃ )/MeCN, from 75:25 to 50:50). The residue (182 mg) was dissolved in MeCN (5 ml) and CDI (180 mg, 1.11 mmol) was added. The mixture was stirred at rt. for 2 h and DBU (221 μl, 1.48 mmol) and methanesulfonamide (141 mg, 1.48 mmol) were added. The reaction mixture was stirred at 80°C for 16 hours was Added saline, 1N. aqueous solution of HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with a solution based on water and saline (1:1), dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (C18 spheroid, 25 μm, 40 g YMC-ODS-25, dry-load (Celite®), mobile phase gradient: (0.2% aq. NH ₄ HCO ₃ )/MeCN , 85:15 to 45:55) to give compound 40 (131 mg, 57%) after lyophilization as a yellow solid.

Compound 41.

(3S)-1-(4-{7-Cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl]pyrazolo [1,5-а]pyrimidin-2-yl}-3-fluorophenyl)-N-methanesulfonylpyrrolidin-3-carboxamide

A mixture of (3S)-1-(4-{7-cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5carbonyl]pyrazolo[ 1,5-a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxylic acid [203541665-8] (153 mg, 0.28 mmol) and CDI (54.6 mg, 0.34 mmol) in MeCN (3 ml) was stirred at room temperature. during

- 44 040266

h. DBU (62.8 μl, 0.42 mmol) and methanesulfonamide [3144-09-0] (40.0 mg, 0.42 mmol) were added. The resulting mixture was stirred at 80°C for 16 hours Was added saline, 1N. aqueous solution of HCl and DCM. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with a solution based on water and saline (1:1), dried over MgSO ₄ , filtered and evaporated under reduced pressure. 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 99:1). The residue was crystallized from MeOH, filtered and dried in high vacuum at 50°C for 18 h to obtain compound 41 (93 mg, 53%) as a yellow solid.

Compound 84.

General scheme

PdCI ₂ (dtbpf) K ₃ RO ₄ dioxane:H ₂ O • waves, load, 2.30 min.

aq. _NH3HATU , DIPEA

DMF k.t., 16 h.

Synthesis of intermediate compound I168.

[1224740-13-9]

1171

1172

Intermediate I171.

Methyl 2-bromo-7-(pyridin-2-yl)pyrazolo[1,5-а]pyrimidine-5-carboxylate

A mixture of methyl 2-hydroxy-4-oxo-4-(pyridin-2-yl)but-2-enoate [1224740-13-9] (730 mg, 3.52 mmol) and

- 45 040266

3-bromo-1H-pyrazole-5-amine [950739-21-6] (628 mg, 3.88 mmol) in MeOH (17 mL) was stirred at reflux for 18 h. The reaction mixture was cooled to rt. T. and the precipitate was filtered off, rinsed with MeOH and dried. The residue (546 mg) was purified with achiral SFC (stationary phase: Lux Cellulose-2, 5 μm, 250x30 mm, mobile phase: 60% CO ₂ , 40% MeOH) to give intermediate I171 (147 mg, 13%) in form of a yellow solid.

Intermediate I172.

Methyl-2-bromo-7-(pyridin-2-yl)pyrazolo[1,5-а]pyrimidine-5-carboxylic acid

Lithium hydroxide monohydrate (21.1 mg, 883 µmol) was added to a solution of intermediate I171 (147 mg, 0.44 mmol) in THF (5 ml) and H ₂ O (2.5 ml). The reaction mixture was stirred at rt. over 4 hours. A 10% aqueous solution of KHSO4 was added until pH3 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 I172 (134 mg, 95%) as a yellow solid.

Intermediate I168.

(1 R)-2-[2-Bromo-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline

To a mixture of intermediate I172 (134 mg, 420 µmol), (1R)-1-methyl-1,2,3,4-tetraαhydroisoquinoline [84010-66-2] (68.0 mg, 462 µmol) and DIPEA (220 µl, 1.26 mmol) in DMF (3.8 ml) was added HATU (207 mg, 546 µmol). The reaction mixture was stirred at rt. within 16 hours the Reaction mixture was diluted with H ₂ O. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine (3 times), dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 12 g GraceResolv™, dry-load (SiOH), mobile phase gradient: heptane/EtOAc, 90:10 to 60:40) to give the intermediate I168 (113 mg, 60%) as a yellow solid.

Synthesis of compound 84.

Intermediate I169.

Methyl-(3 S)-1 -(3-fluoro-4-{5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(pyridine-2yl) pyrazolo[1,5-а]pyrimidin-2-yl} phenyl)pyrrolidin-3-carboxylate

Intermediate I168 (98.0 mg, 219 µmol), methyl(3S)-1-[3-fluoro-4-(tetraαmethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin- 3-carboxylate [2035422-46-7] (84.0 mg, 0.24 mmol), tribasic potassium phosphate (141 mg, 0.67 mmol), 1,4-dioxane (3.2 ml) and H ₂ O (0.6 ml) and purged with nitrogen. [1,1'-bis-(di-tert-butylphosphino)ferrocene]palladium dichloride (14.5 mg, 22.3 µmol) was added and the mixture was purged with nitrogen again. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was combined with another fraction (15 mg, 33.5 μmol) and 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 in vacuo. The crude mixture was purified by flash chromatography (Missed SiOH

- 46 040266 forms, 15-40 µm, 12 g GraceResolv™, dry loaded (SiOH, mobile phase gradient: heptane/EtOAc, 70:30 to 0:100) to give Intermediate I169 (113 mg, 75%) in the form of orange foam.

Intermediate connection I170.

(3S)-1-(3-Fluoro-4-{5-[(1 R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(pyridin-2yl)pyrazolo[ 1,5-a]pyrimidin-2-yl}phenyl)pyrrolidin-3-carboxylic acid

To a solution of intermediate I169 (113 mg, 191 µmol) in THF (1.2 ml) and H2O (0.6 ml) was added lithium hydroxide monohydrate (13.7 mg, 574 µmol). The reaction mixture was stirred at rt. over 3 hours. 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 I170 (117 mg, quant, 95% pure) as an orange solid .

Compound 84.

(3 S)-1-(3-Fluoro-4-{5-[(1 R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(pyridin-2yl)pyrazolo [1,5-a]pyrimidin-2-yl}phenyl)pyrrolidin-3-carboxamide

A mixture of intermediate I170 (117 mg, 193 µmol, 95% purity), HATU (110 mg, 289 µmol) and DIPEA (100 µl, 578 µmol) in DMF (1.9 ml) was stirred at rt. within 10 min. Ammonia (30% in H ₂ O, 365 µl, 5.78 mmol) was added and the reaction mixture was stirred at rt. within 16 hours. The reaction mixture was diluted with EtOAc and H2O. The layers were separated and the organic phase was washed with H2O and brine (twice), dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 50:50 to 0:100). The residue (88 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, 65:35 to 0:100). Fractions containing product were combined, concentrated to dryness and co-evaporated with MeOH and MeCN (twice). The solid was dried in high vacuum at 60° C. for 16 h to give compound 84 (58 mg, 52%) as an orange solid.

Compound 42 and Compound 43.

(S): 43

Synthesis of intermediates I49 and I50.

- 47 040266

[60811-18-9] (R): [1024038-31-0] (S): [1024038-33-2]

Pd(OAc) ₂ K ₃ PO ₄ , TTBP.HBF ₄ dioxane 100°C, 18 h.

LiOH.H ₂ O

THF: _H2O

K.T., 3 days

(R): I53 (S) . I54(R). 151 (SJ: I52

(R); 155 (S): 156 lead. _NH3

THF k.g., 2 4.

KOAc dioxane 110°C, 18 hours

(R): 149 (S): 150

Intermediate 151.

Methyl 2-[(3E)-1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl]acetate

151

A Schlenk vessel was charged with 4-bromo-1-chloro-2-fluorobenzene [60811-18-9] (1.02 ml, 8.35 mmol), tribasic potassium phosphate (4.73 g, 22.3 mmol), methyl -(3K)-3-pyrrolidinyl acetate hydrochloride [1024038-31-0] (1.00 g, 5.57 mmol) and 1,4-dioxane (45 ml) and purged with nitrogen for 5 minutes. Tri-t-butylphosphonium tetrafluoroborate (0.16 g, 0.56 mmol) and palladium acetate (62.5 mg, 0.28 mmol) were added and the reaction mixture was purged with nitrogen for 2 minutes. 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 extracts were dried over MgSO ₄ , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g GraceResolv™, liquid phase injection (DCM/heptane), mobile phase gradient: heptane/EtOAc, 80:20 to 60:40) to give Intermediate 151 (880 mg, 58%) as a colorless oil.

Intermediate 152.

Methyl 2-[(38)-1-(4-chloro-3-fluorophenyl)pyrrolidin-3-yl]acetate

Cl

I52

Intermediate 152 was synthesized from 4-bromo-1-chloro-2-fluorobenzene [60811-18-9] and methyl-(38)-3-pyrrolidinyl acetate hydrochloride [1024038-33-2] according to the procedure given for the synthesis of intermediate compound 151. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g GraceResolv™, dry-load (SiOH), mobile phase: heptane/EtOAc 80:20) to give intermediate 152 (830 mg, 55%) as a colorless oil.

Intermediate 153.

2-[(3E)-1-(4-Chloro-3-fluorophenyl)pyrrolidin-3-yl]acetic acid

153

Intermediate 151 (880 mg, 3.24 mmol) was solubilized in THF (10 ml) and a solution of lithium hydroxide monohydrate (680 mg, 16.2 mmol) in H ₂ O (5 ml) was added. The reaction mixture was stirred at rt. within 3 days. A 10% aqueous solution of KHSO ₄ and EtOAc was added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure to give Intermediate 153 (840 mg, quant.) as a white solid.

Intermediate 154.

2-[(38)-1-(4-Chloro-3-fluorophenyl)pyrrolidin-3-yl]acetic acid D

154

-48040266

Intermediate I54 was synthesized from intermediate I52 according to the procedure given for the synthesis of intermediate I53. Intermediate I54 (800 mg, quant.) was obtained as a white solid.

Intermediate connection I55.

2-[(3R)-1-(4-Chloro-3-fluorophenyl)pyrrolidin-3-yl]acetyl chloride

To a solution of intermediate I53 (840 mg, 3.26 mmol) in DCM (30 mL) was added thionyl chloride (307 μL, 4.24 mmol). The reaction mixture was stirred at rt. within 90 min. The mixture was evaporated under reduced pressure to give intermediate I55 (900 mg, quant.). The product was used in the next step without any purification.

Intermediate connection I56.

2-[(3S)-1-(4-Chloro-3-fluorophenyl)pyrrolidin-3-yl]acetyl chloride

Intermediate I56 (856 mg, quant.) was synthesized from intermediate I54 according to the procedure given for the synthesis of intermediate I55.

Intermediate I57.

2-[(3R)-1-(4-Chloro-3-fluorophenyl)pyrrolidin-3-yl]acetamide

To a solution of intermediate I55 (900 mg, 3.26 mmol) in THF (30 ml) was added ammonia (28% in H ₂ O, 30 ml, 444 mmol). The reaction mixture was stirred at rt. for 2 hours. The reaction mixture was diluted with brine and with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH/aq. NH ₃ , from 100:0:0 to 90:10:1) to give Intermediate I57 (588 mg, 63%, 90% pure) as a white solid.

Intermediate I58.

2-[(3S)-1-(4-Chloro-3-fluorophenyl)pyrrolidin-3-yl]acetamide

Intermediate I58 was synthesized from intermediate I56 according to the procedure given for the synthesis of intermediate I57. Intermediate I58 (741 mg, 85%, 91% pure) was obtained as a white solid.

Intermediate I49.

2-[(3R)-1-[3-Fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]acetamide

NMj

149

A closed tube was charged with intermediate I57 (541 mg, 2.11 mmol), bis-(pinacolato)diboron (0.64 g, 2.53 mmol), acetic acid potassium salt (0.41 g, 4.22 mmol) and 1,4-dioxane (14 ml) and purged with nitrogen for 10 minutes. XPhos (301 mg, 0.63 mmol) and tris-(dibenzylideneacetone)dipalladium (193 mg, 0.21 mmol) were added and the reaction mixture was purged with nitrogen. The reaction mixture was stirred at 110° C. for 18 hours. The reaction mixture was filtered through Celite®. EtOAc and brine were added to the filtrate. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g GraceResolv™, dry-load (SiOH), mobile phase gradient: DCM/MeOH/aq. NH ₃ , 100:0:0 to 90:10:1) to obtain an intermediate

- 49 040266 compound I49 (587 mg, 67%, 84% purity) as a gray solid.

Intermediate connection I50.

2-[(3S)-1-[3-Fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]acetamide

Intermediate I50 was synthesized from intermediate I58 according to the procedure given for the synthesis of intermediate I49. Intermediate I50 (935 mg, 77%, 83% purity) was obtained as a gray solid.

Synthesis of compounds 42 and 43.

Compound 42.

2-[(3K)-1-(4-{7-Cyclopropyl-5-[(4*K)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5- carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]acetamide

2-bromo-7-cyclopropyl-5-[(4*K)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl]pyrazolo[1 ,5-a]pyrimidine [2035420-09-6] (200 mg, 0.479 mmol), Intermediate I49 (278 mg, 0.67 mmol, 84% purity), tribasic potassium phosphate (305 mg, 1.44 mmol) , 1,4-dioxane (6 ml) and H ₂ O (2 ml) and purged with nitrogen. [1,1'-bis-(di-tert-butylphosphino)ferrocene]dichloropalladium (31.2 mg, 47.9 µmol) was added and the reaction mixture was purged with nitrogen. The reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was filtered through Celite®. EtOAc and brine were added to the filtrate. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH/aq. NH ₃ , from 100:0:0 up to 96:4:0.4). The residue was co-evaporated with MeOH and triturated with MeOH. The solid was filtered off and dried in high vacuum at 50° C. for 24 h to give compound 42 (115 mg, 43%) as a yellow solid.

Compound 43.

2-[(3S)-1-(4-{7-Cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5- carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]acetamide

Compound 43 was synthesized from 2-bromo-7-cyclopropyl-5-[(4*K)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl]pyrazolo[1 ,5-a]pyrimidine [2035420-09-6] and intermediate I50 according to the procedure given for the synthesis of compound 42. Compound 43 (161 mg, 60%) was obtained as a yellow solid.

Compound 44 and Compound 45.

Synthesis of intermediates I59 and I60.

- 50 040266

Intermediates I61 and I62.

(*K)-Methyl-1-(4-chloro-3-fluorophenyl)-3-methylpyrrolidine-3-carboxylate and (*S)-methyl-1-(4-chloro-3fluorophenyl)-3-methylpyrrolidine-3- carboxylate

4-bromo-1-chloro-2-fluorobenzene [60811-18-9] (4.0 ml, 32.8 mmol), tribasic potassium phosphate (15.3 g, 72.3 mmol), methyl -3-methylpyrrolidine-3-carboxylate [1111943-58-8] (3.45 g, 24.1 mmol), tri-tert-butylphosphonium tetrafluoroborate (638 mg, 2.20 mmol) and 1,4-dioxane (163 ml) and purged with nitrogen (3 times). Palladium acetate (247 mg, 1.10 mmol) was added and the reaction mixture was stirred at 100° C. for 16 h. 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 evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 120 g GraceResolv™, liquid phase injection (heptane), mobile phase gradient: heptane/EtOAc, 100:0 to 70:30). Enantiomers (3.81 g) were separated using chiral SFC (stationary phase: Whelk 01 (S, S) 5 μm, 250x21.1 mm, mobile phase: 90% CO ₂ , 10% MeOH) to give compound I61 (1, 7 g, 26%) as a colorless oil and compound I62 (1.67 g, 26%) as a colorless oil.

Intermediate I63.

(3*K)-1-(4-Chloro-3-fluorophenyl)-3-methylpyrrolidine-3-carboxylic acid

Lithium hydroxide monohydrate (344 mg, 8.19 mmol) was added in a closed tube to a solution of intermediate I61 (445 mg, 1.64 mmol) in THF (13 ml) and H ₂ O (6.5 ml). The reaction mixture was stirred at rt. within 20 h. Added 10% aqueous solution of KHSO4 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The residue (465 mg) was taken up in Et ₂ O and evaporated under reduced pressure to give intermediate I63 (415 mg, 98%).

Intermediate I64.

(3*S)-1-(4-Chloro-3-fluorophenyl)-3-methylpyrrolidine-3-carboxylic acid

Intermediate I64 was synthesized from intermediate I62 according to the procedure given for the synthesis of intermediate I63. Intermediate I64 (395 mg, 99%) was obtained as a yellow solid.

Intermediate I65.

(3*K)-1-(4-Chloro-3-fluorophenyl)-3-methylpyrrolidine-3-carbonyl chloride

- 51 040266

To a solution of intermediate I63 (395 mg, 1.53 mmol) in DCM (14 mL) was added thionyl chloride (145 μL, 2.00 mmol). The reaction mixture was stirred at rt. for 1.5 h. The mixture was evaporated under reduced pressure to give intermediate I65 (423 mg, quant.). The product was used in the next step without any purification.

Intermediate I66.

(3*S)-1-(4-Chloro-3-fluorophenyl)-3-methylpyrrolidine-3-carbonyl chloride

K ^{with 1}

166 ⁰

Intermediate I66 was synthesized from intermediate I64 according to the procedure given for the synthesis of intermediate I65. Intermediate I66 (401 mg, quant.) was used in the next step without any purification.

Intermediate I67.

(3*R)-1-(4-Chloro-3-fluorophenyl)-3-methylpyrrolidine-3-carboxamide

F

167

To a solution of intermediate I65 (423 mg, 1.53 mmol) in THF (14 ml) was added ammonia (28% in H ₂ O, 14 ml, 207 mmol). The reaction mixture was stirred at rt. for 2 hours. The reaction mixture was diluted with brine and with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH/aq. NH ₃ , from 100:0:0 to 90:10:1) to give intermediate I67 (286 mg, 73%) as a yellowish solid.

Intermediate I68.

(3*S)-1-(4-Chloro-3-fluorophenyl)-3-methylpyrrolidine-3-carboxamide

F#8

Intermediate I68 was synthesized from intermediate I66 according to the procedure given for the synthesis of intermediate I67. Intermediate I68 (259 mg, 69%) was obtained as a yellowish solid.

Intermediate I59.

(3 *R)-1-[3-Fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methylpyrrolidine-3 carboxamide

A stoppered tube was charged with intermediate I67 (286 mg, 1.11 mmol), bis-(pinacolato)diboron (567 mg, 2.23 mmol), potassium acetic acid (219 mg, 2.23 mmol), and 1.4 -dioxane (10 ml) and purged with nitrogen. Tris-(dibenzylideneacetone)dipalladium (102 mg, 0.11 mmol) and XPhos (159 mg, 0.33 mmol) were added and the mixture was purged with nitrogen. The reaction mixture was stirred at 110° 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 extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g Grace®, dry-loaded (Celite®), mobile phase gradient: DCM/MeOH, 100:0 to 95:5) to give intermediate I59 (393 mg, 73%, 72% purity) as a yellowish oil which crystallized on standing.

Intermediate connection I60.

(3*S)-1-[3-Fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methylpyrrolidine-3 carboxamide

- 52 040266

Intermediate I60 was synthesized from intermediate I68 according to the procedure given for the synthesis of intermediate I59. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g Grace®, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 95:5) to give intermediate I60 (449 mg, 89%, 70% pure) as a yellowish oil which crystallized

elk when defending.

Synthesis of compounds 44 and 45.

Compound 44.

(3*R)-1-(4-{7-Cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl ]pyrazolo[1,5-а]pyrimidin-2-yl}-3-fluorophenyl)-3-methylpyrrolidin-3-carboxamide

2-bromo-7-cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl]pyrazolo[1 ,5-a]pyrimidine [2035420-09-6] (248 mg, 0.59 mmol), intermediate I59 (345 mg, 0.71 mmol, 72% purity), tribasic potassium phosphate (431 mg, 2.03 mmol), 1,4-dioxane (11 ml) and H ₂ O (4 ml) and it was purged with nitrogen. [1,1'-Bis-(di-tert-butylphosphino)ferrocene]dichloropalladium (42.7 mg, 65.4 µmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc and H ₂ O. The layers were separated and the organic phase was washed with saline, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g GraceResolv™, mobile phase gradient: heptane/(EtOAc/MeOH 9:1), 70:30 to 50:50). The residue was triturated with pentane and the solid was filtered off and dried in high vacuum at 50° C. for 30 h to give compound 44 (193 mg, 58%) as a yellow solid.

Compound 45.

(3*S)-1-(4-{7-Cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl ]pyrazolo[1,5-а]pyrimidin-2-yl}-3-fluorophenyl)-3-methylpyrrolidin-3-carboxamide

Compound 45 was synthesized from 2-bromo-7-cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl]pyrazolo[1 ,5-a]pyrimidine [2035420-09-6] and intermediate I60 according to the procedure given for the synthesis of compound 44. Compound 45 (275 mg, 71%) was obtained as a yellow solid.

Compound 46.

Synthesis of intermediate compound I69.

- 53 040266

Intermediate connection I70.

(3S)-1-(4-Chloro-3-fluorophenyl)pyrrolidine-3-carboxylic acid

To a solution of methyl-(3S)-1-(4-chloro-3-fluorophenyl)pyrrolidine-3-carboxylate [2035422-44-5] (4.10 g, 15.9 mmol) in THF (100 ml) and H ₂ O (50 ml) was added lithium hydroxide monohydrate (3.34 g, 79.6 mmol). The reaction mixture was stirred at rt. within 24 hours Added 10% aqueous solution of KHSO4 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give Intermediate I70 (3.8 g, 98%) as an orange solid.

Intermediate I71.

(3S)-1-(4-Chloro-3-fluorophenyl)pyrrolidine-3-carbonyl chloride

To a solution of intermediate I70 (200 mg, 0.82 mmol) in DCM (8 ml) was added thionyl chloride (77.4 μl, 1.0.7 mmol). The reaction mixture was stirred at rt. for 10 min and evaporated under reduced pressure to give intermediate I71 (215 mg, quant.).

Intermediate I72.

(3S)-1-(4-Chloro-3-fluorophenyl)pyrrolidine-3-carboxamide

To a solution of intermediate I71 (3.23 g, 12.3 mmol) in THF (120 ml) was added ammonia (28% in H ₂ O, 120 ml, 1.77 mol). The reaction mixture was stirred at rt. within 15 min. The reaction mixture was diluted with brine and with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 96:4) to give intermediate I72 (2.38 g, 80%) as a white solid.

Intermediate I69.

(3 S)-1-[3-Fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-3-carboxamide

A closed tube was charged with intermediate I72 (3.22 g, 13.3 mmol), bis(pinacolato)diboron (6.75 g, 26.6 mmol) and potassium acetate (2.61 g, 26.6 mmol) in 1,4-dioxane (115 ml) and purged with nitrogen. Tris-(dibenzylideneacetone)dipalladium (1.22 g, 1.33 mmol) and XPhos (1.90 g, 3.98 mmol) were added and the mixture was purged with nitrogen. The reaction mixture was stirred at 110° C. for 18 hours. The reaction mixture was filtered through Celite®. EtOAc, brine and H2O were added to the filtrate. 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 concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g Grace®, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 96:4) to give intermediate I69 (5.24 g, 78%, 66% purity) as a colorless oil.

Synthesis of compound 46.

- 54 040266 (3S)-1-(4-{7-Cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5- carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidine-3-carboxamide

2-bromo-7-cyclopropyl-5-[(4*R)-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl]pyrazolo[1 ,5-a]pyrimidine [2035420-09-6] (200 mg, 0.48 mmol), Intermediate I69 (291 mg, 0.58 mmol, 66% purity), potassium phosphate (0.31 g, 1, 44 mmol), 1,4-dioxane (5 ml) and H ₂ O (1.5 ml) and it was purged with nitrogen. [1,1'-Bis-(di-tert-butylphosphino)ferrocene]dichloropalladium (23.4 mg, 35.9 µmol) was added and the mixture was purged with nitrogen. The reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was filtered through Celite®. EtOAc and brine were added to the filtrate. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g Grace®, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 96:4). The residue was co-evaporated with MeOH and triturated in MeOH. The solid was filtered off, rinsed with MeOH and dried in high vacuum at 50° C. for 24 h to give compound 46 (210 mg, 80%) as a yellow solid.

Compound 47.

hh ₂

1)(COC1) ₂

DCM, 10°C to rt, then FeCl ₃ -10°C to rt, 16 h.

PdCI ₂ (dtbpf) K ₃ PO ₄ dioxane 80°С, 2 h.

Synthesis of intermediate compound I73.

[1583-88-6]

2) H ₂ SO ₄ MeOH from 0 ° C to the temperature [105871 -02-1] - I74 reflux formation, [269402-41 -7] - I75 16 hours.

Intermediate I74.

N-[2-(4-Fluorophenyl)ethyl]acetamide

174

To a mixture of 2-(4-fluorophenyl)ethylamine [1583-88-6] (34.6 g, 249 mmol) and Et ₃ N (52.0 ml, 373 mmol) in DCM (200 ml) at 0°C by acetyl chloride (0.27 mmol, 20.0 ml) was added dropwise. The resulting mixture was stirred at rt. within 72 hours the Reaction mixture was diluted with DCM. The mixture was washed with 10% aqueous NaHCO ₃ , brine, dried over MgSO ₄ , filtered and the solvent was removed in vacuo to give intermediate I74 (48.2 g, quant.).

- 55 040266

Intermediate I75.

7-Fluoro-1-methyl-3,4-dihydroisoquinoline

To a solution of intermediate I74 (48.2 g, 266 mmol) in DCM (2.7 L) at 10°C was added oxalyl chloride (2.0 M in DCM, 67.5 mL, 135 mmol) and pure oxalyl chloride ( 11.5 ml, 136 mmol). The resulting mixture was stirred at rt. for 30 min and cooled to -10°C. Iron(III) chloride [7705-08-0] (52.0 g, 0.32 mol) was added in portions. The reaction mixture was stirred at rt. within 16 hours the Reaction mixture was extinguished by adding 3n. aqueous HCl solution and diluted with DCM. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgSO ₄ , filtered and the solvent was removed in vacuo. The residue (59.2 g) was dissolved in MeOH (2.4 L) and sulfuric acid (2.26 mol, 120 ml) was carefully added dropwise at 0°C. The resulting mixture was stirred at reflux for 16 hours. The solvent was removed in vacuo. The residue was dissolved in DCM and 3N was added. aqueous solution of HCl. The layers were separated and the organic phase was washed with 3N. aqueous HCl solution (once). The combined aqueous extracts were basified with ammonia (28% in H ₂ O) and extracted with DCM (twice). The combined organic extracts were dried over MgSO ₄ , filtered and the solvent removed in vacuo to give intermediate I75 (34.3 g, 63%, 80% pure).

Intermediates I76 and I77.

(1*R)-7-Fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride and (1*S)-7-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride:

The reaction was performed in two batches of 84 mmol compound I75.

To a solution of intermediate I75 (17.2 g, 84.0 mmol, 80% purity) in EtOH (500 mL) was added Pd/C (10 wt%, 1.80 g, 1.70 mmol). The reaction mixture was stirred at rt. in an atmosphere of H ₂ (1 bar) for 6 hours Two batches were combined. The reaction mixture was filtered through Celite® and HCl (3.0 M in CPME, 67.2 ml, 0.20 mol) was added to the filtrate at 0°C. The resulting mixture was stirred at rt. for 5 min and evaporated to dryness. The residue was triturated in Et ₂ O and the solid was filtered off to give a mixture of enantiomers (33 g) as a white solid. Enantiomers were separated using chiral SFC (stationary phase: Chiralpak AD-H 5 μm, 250x30 mm, mobile phase: 78% CO ₂ , 22% i-PrOH (1.0% i-PrNH ₂ )) to give compound I76 (11 .5 g) and compound I77 (15.5 g). Intermediate I76 was taken up with HCl (3.0 M in CPME, 25 ml) and EtOH (10 ml). The resulting suspension was stirred for 5 min and Et ₂ O (200 ml) was added. The solid was filtered off and dried to give intermediate I76 (10.5 g, 31%). Intermediate I77 was taken up with DCM and 1M aqueous NaOH. The layers were separated and the aqueous phase was extracted with DCM (once). The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent was removed in vacuo. The residue (11.1 g) was dissolved in EtOH (100 ml) and HCl (3.0 M in CPME, 25 ml) was added at 0°C. The mixture was evaporated to dryness. The solid was triturated with Et ₂ O, filtered and dried to give intermediate I77 (11.6 g, 34%).

Intermediate I73.

(1*R)-2-{2-Bromo-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5-carbonyl}-7-fluoro-1-methyl-1,2,3,4tetrahydroisoquinoline

To a mixture of 2-bromo-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-potassium carboxylate [2035418-56-3], intermediate I76 (2.46 g, 12.3 mmol) and DIPEA (4.90 ml, 28.4 mmol) in DMF (54 ml) to

- 56 040266 HATU (5.34 g, 14.1 mmol) was added. The reaction mixture was stirred at rt. within 20 hours Was added a saturated aqueous solution of NaHCO ₃ , saline and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine (4 times), dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 220 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 100:0 to 60:40). A first fraction of purified intermediate I73 (1.20 g, 30%) was obtained, while the second fraction containing impurities was again purified by preparative LC (irregular SiOH, 40 μm, 120 g, mobile phase: 100% DCM ). A second crop of intermediate I73 was isolated (1.3 g, 32%). Intermediate I73 (2.50 g, 62%) was obtained as a white foam.

Synthesis of compound 47.

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

(1*R)-2-{2-bromo-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5carbonyl}-7-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline I73 was loaded into a closed tube (200 mg, 0.47 mmol), intermediate I69 (283 mg, 0.56 mmol), tribasic potassium phosphate (297 mg, 1.40 mmol), 1,4-dioxane (5 ml) and H ₂ O ( 1.5 ml) and purged with nitrogen. [1,1'-bis-(di-tert-butylphosphino)ferrocene]dichloropalladium (22.8 mg, 34.9 µmol) was added and the mixture was purged with nitrogen again. The reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was filtered through Celite®. EtOAc and brine were added to the filtrate. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 96:4). Purified fractions were pooled, with fractions containing impurities subjected to a second purification by preparative LC (irregular SiOH, 15-40 µm, 80 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 98:2). The residue was co-evaporated with MeOH and triturated in MeOH. The solid was filtered off, rinsed with MeOH and dried in high vacuum at 50° C. for 24 h to give compound 47 (185 mg, 71%) as a yellow solid.

Compound 48.

Synthesis of intermediate compound I78.

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1) (COC1) ₂

CH ₃ COCI Et ₃ N

DCM from (GS to c.t., 16 h.

DCM, 10°C to rt, then FeCl ₃ -10°C to rt, 18 h.

[404-70-6]

[125058-99-3] - 181

2) H ₂ SO ₄ MeOH from 0°C to reflux temperature, 16 hours.

[1176414-50-8] - I82

To a mixture of 3-fluorophenethylamine [404-70-6] (25.0 g, 180 mmol) and Et ₃ N (38.5 ml, 270 mmol) in DCM (500 ml), 225 mmol) at 0°C. The reaction mixture was stirred at rt. within 16 hours the Reaction mixture was extinguished by adding an aqueous solution of NaHCO ₃ . The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent removed in vacuo to give Intermediate 181 (35.3 g, quant) as a yellow oil.

Intermediate 182.

6-Fluoro-1-methyl-3,4-dihydroisoquinoline

IB2

In a 5 L jacketed reactor equipped with a thermostat and a mechanical stirrer, to a solution of intermediate 181 (35.3 g, 180 mmol) in DCM (1.7 L) at 10°C was added oxalyl chloride (2.0 M in DCM, 108 ml, 216 mmol). The resulting mixture was stirred at rt. for 30 min and cooled to -10°C. Ferric chloride [7705-08-0] (35.0 g, 216 mmol) was added in portions. The reaction mixture was stirred at rt. within 18 hours. The reaction mixture was quenched by adding Zn. aqueous HCl solution and diluted with DCM. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgSO ₄ , filtered and the solvent was removed in vacuo. The residue (43.6 g) was dissolved in MeOH (1.6 L) in a 5 L jacketed reactor equipped with a thermostat and a mechanical stirrer. Sulfuric acid (1.54 mol, 82.0 ml) was carefully added dropwise at 0°C. The resulting mixture was stirred at reflux for 16 hours. The solvent was removed in vacuo. The residue was dissolved in DCM and 3n was added. aqueous solution of HC1. The layers were separated and the organic phase was washed with 3n. aqueous solution of HC1 (twice). The combined aqueous extracts were basified with ammonia (28% in H ₂ O) and extracted with DCM (twice). The combined organic extracts were dried over MgSO ₄ , filtered and the solvent removed in vacuo to give Intermediate 182 (28.9 g, 90% pure).

Intermediates 183 and 184.

(1*K)-6-Fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline (183) and (1*8)-6-fluoro-1-methyl-1,2,3,4- tetrahydroisoquinoline (184):

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EtOH (400 mL) and Pd/C (10%, 3.39 g, 3.19 mmol) were charged into a Parr flask. A solution of intermediate I82 (28.9 g, 159 mmol, 90% purity) in EtOH (500 mL) was added. The reaction mixture was pressurized with H ₂ to 1 bar and stirred at rt. for 18 hours. The reaction mixture was filtered through a pad of Celite® and rinsed with MeOH. The filtrate was treated with HCl (3.0 M in CPME, 63.8 ml, 191 mmol) at 0°C. The resulting mixture was stirred at rt. for 5 min and evaporated to dryness. The residue was triturated in Et ₂ O and the solid was filtered off. The solid was purified by preparative LC (irregular SiOH, 15-40 µm, 330 g Grace®, dry-load (Celite®), mobile phase gradient: DCM/MeOH/aq. NH ₃ , from 98:2:0 .2 to 96:4:0.4) to give a mixture of enantiomers (20.3 g). The enantiomers were separated using chiral SFC (stationary phase: Chiralpak AD-H 5 μm, 250x30 mm, mobile phase: 80% CO ₂ , 20% i-PrOH (0.3% i-PrNH ₂ )) to give compound I83 (9 .73 g) and compound I84 (9.68 g). The enantiomers were processed separately. Intermediates I83 and I84 were dissolved in EtOAc and an aqueous solution of NaHCO3 was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over MgSO ₄ , filtered and the solvent removed in vacuo to give intermediates I83 (8.74 g, 32%) and I84 (8.34 g, 30%) as colorless oils.

Intermediate I78.

(1*R)-2-{2-Bromo-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5-carbonyl}-6-fluoro-1-methyl-1,2,3,4 tetrahydroisoquinoline b

178

To a mixture of 2-bromo-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-potassium carboxylate [2035418-56-3] (3.23 g, 10.1 mmol), intermediate I83 (2.00 g, 12.1 mmol) and DIPEA (4.35 ml, 25.2 mmol) in DMF (50 ml) was added HATU (6.91 g, 18.2 mmol). The reaction mixture was stirred at rt. within 18 hours Was added a saturated aqueous solution of NaHCO ₃ , saline, N ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with a solution based on saline and water (9:1) (3 times), dried over MgSO ₄ , filtered, rinsed with EtOAc and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 90:10 to 70:30) to give intermediate I78 (4.5 g, quant.) as a white gum.

Synthesis of intermediate compound I79.

Methyl 2-[(3S)-1-[3-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]acetate

A stoppered tube was charged with intermediate I52 (1.40 g, 5.15 mmol), bis-(pinacolato)diboron (1.57 g, 6.18 mmol), acetic acid potassium salt (1.01 g, 10.3 mmol) and 1,4-dioxane (35 ml) and purged with nitrogen. XPhos (737 mg, 1.55 mmol) and tris(dibenzylideneacetone)dipalladium (472 mg, 0.52 mmol) were added and the mixture was purged with nitrogen. The reaction mixture was stirred at 100° C. for 18 hours and then at 110° C. for 2 hours. The reaction mixture was filtered through a pad of Celite®. EtOAc and brine were added to the filtrate. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 95:5 to 80:20) to give intermediate I79 (1.1 g, 59%) as a gray solid.

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Synthesis of compound 48.

Intermediate connection I80.

Methyl 2-[(3S)-1-(4-{7-cyclopropyl-5-[(1*R)-6-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[ 1,5-a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-yl]acetate

In a closed tube, intermediate I78 (253 mg, 0.59 mmol), intermediate I79 (300 mg, 0.83 mmol), tribasic potassium phosphate (376 mg, 1.77 mmol), 1,4-dioxane (7 ml) and H2O (2.5 ml) and purged with nitrogen. [1,1'-bis-(di-tert-butylphosphino)ferrocene]palladium dichloride (38.4 mg, 59.0 µmol) was added. The reaction mixture was purged with nitrogen and stirred at 80° C. for 2 hours. The reaction mixture was filtered through Celite®. EtOAc and brine were added to the filtrate. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure. 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 intermediate I80 (271 mg, 75%, 95% pure) as a yellow solid.

Compound 48.

(3aS,6aR)-6-(4-{7-Cyclopropyl-5-[(1*R)-6-fluoro-1-methyl-1,2,3,4-tetraαhydroisoquinoline-2carbonyl]pyrazolo[1,5 -a]pyrimidin-2-yl}-3-fluorophenyl)hexahydro-2H-furo[2,3-b]pyrrol-2-one

..

Intermediate I80 (271 mg, 0.44 mmol, 95% purity) was solubilized in THF (5 ml) and a solution of lithium hydroxide monohydrate (92.2 mg, 2.19 mmol) in H ₂ O (2.5 ml) was added . The reaction mixture was stirred at rt. within 3 days. Saline, 10% aqueous KHSO4 and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 25 g Interchim®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc/AcOH, 90:10:0.25 to 60: 40:1). The residue was co-evaporated with MeOH and triturated in MeOH. The solid was filtered off, rinsed with MeOH and dried under high vacuum at 50° C. for 2 days to give a white solid (250 mg). The batch was split into two samples, A and B, which were independently purified by preparative LC (stationary phase: 40 g misshaped SiOH, mobile phase: 98% DCM, 2% MeOH). Compound 48 was dried under high vacuum to give a yellow solid (50 mg, 20%).

General scheme

Compound 49.

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Synthesis of intermediate compound I85.

Intermediate I86.

Methyl-(3S)-1-(6-fluoropyridin-2-yl)pyrrolidin-3-carboxylate

A mixture of 2,6-difluoropyridine [1513-65-1] (1.00 g, 8.69 mmol), (S)-3-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] (1.58 g, 9.56 mmol) and potassium carbonate (3.60 g, 26.1 mmol) in NMP (65 ml) was stirred at 80°C for 18 hours. The reaction mixture was diluted with EtOAc and H ₂ O. The layers were separated and aqueous the phase was extracted with EtOAc (5 times). The organic extracts were combined and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 120 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 100:0 to 50:50) to give intermediate I86 (1.6 g, 82%) as a colorless oil.

Intermediate I87.

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

Intermediate I86 (1.60 g, 7.14 mmol) and NBS [128-08-5] (1.65 g, 9.28 mmol) in MeCN (36 ml) were stirred at rt. within 18 hours the Mixture was evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 100:0 to 50:50) to give intermediate I87 (1.58 g, 61%, 84% purity) as a colorless oil.

Intermediate I88.

(3S)-1-(5-Bromo-6-fluoropyridin-2-yl)pyrrolidin-3-carboxylic acid

_Lithium hydroxide monohydrate (41.9 mg, 1.00 mmol ). The reaction mixture was stirred at rt. over 16 hours. 10% aqueous 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 under reduced pressure. 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/AcOH, 60:39:1 to 20: 80:2) to give intermediate I88 (96 mg, quant.).

Intermediate I85.

(3S)-1-(5-Bromo-6-fluoropyridin-2-yl)pyrrolidine-3-carboxamide

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A mixture of intermediate I88 (96.3 mg, 0.33 mmol), HATU (165 mg, 0.43 mmol) and DIPEA (172 μl, 1.0 mmol) in DCM (1.9 ml) was stirred at rt . for 1 h. Ammonia (28% in H ₂ O, 0.11 ml, 1.67 mmol) was added and the reaction mixture was stirred at rt. within 18 hours the Reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice), dried over MgSO ₄ and evaporated under reduced pressure. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 12 g GraceResolv™, dry-loaded (Celite®), mobile phase gradient: DCM/MeOH/aq. NH3, 99:1:0.1 to 90:10:1). The residue was suspended in DCM and filtered to give Intermediate I85 (62 mg, 65%) as a yellow solid.

Synthesis of compound 49.

(3 S)-1 -(5-{7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidine-2- yl}-6-fluoropyridin-2-yl)pyrrolidine-3-carboxamide

Intermediate I85 (62.0 mg, 0.22 mmol), (1R)-2-[7-cyclopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1.5 -a] pyrimidine-5-carbonyl] -1-methyl1,2,3,4-tetrahydroisoquinoline [2035421-36-2] (190 mg, 0.22 mmol, 52% purity), tribasic potassium phosphate (137 mg, 0 .65 mmol), 1,4-dioxane (2.2 ml) and H ₂ O (0.5 ml) and it was purged with nitrogen. [1,1'-bis-(di-tert-butylphosphino)ferrocene]palladium dichloride (14.0 mg, 21.5 µmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 24 g Interchim®, liquid phase injection (DCM), mobile phase gradient: DCM/i-PrOH, 100:0 to 80:20). The second purification was performed by preparative LC (SiOH with regular grains, 30 μm, 24 g Interchim®, liquid phase injection (DCM), mobile phase gradient: DCM/i-PrOH, from 100:0 to 80:20). The mixture (79 mg) was purified by preparative LC (C18 spherical 25 μm, 40 g YMC-ODS-25, dry-load (Celite®), mobile phase gradient: (0.2% aq. NH4HCO ₃ )/MeCN , from 65:35 to 25:75). The residue was taken up with MeCN and DIPE, concentrated under reduced pressure and dried in high vacuum at 50° C. for 16 h to give compound 49 (70 mg, 60%) as a white solid.

Compound 50.

Synthesis of intermediate compound I89.

(3S)-1-(5-Bromo-6-fluoropyridin-2-yl)-N-methylpyrrolidin-3-carboxamide

A mixture of intermediate I88 (220 mg, 761 µmol), HATU (434 mg, 1.14 mmol) and DIPEA (393 µl, 2.28 mmol) in DMF (21 ml) was stirred at rt. over 1 h. Methylamine (2.0 M in THF, 1.9 ml, 3.81 mmol) was added and the reaction mixture was stirred at rt. within 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% aqueous NaHCO ₃ solution (twice), dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregularly shaped SiOH,

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15-40 µm, 12 g GraceResolv™, liquid phase injection (DCM, mobile phase gradient: DCM/i-PrOH, 100:0 to 80:20) to give Intermediate I89 (220 mg, 96%) as yellow oil.

Synthesis of compound 50.

(3S)-1-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-6-fluoropyridin-2-yl)-N-methylpyrrolidin-3-carboxamide

Intermediate I89 (220 mg, 0.73 mmol), (1R)-2-[7cyclopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a ]pyrimidine-5-carbonyl]-1-methyl1,2,3,4-tetrahydroisoquinoline [2035421-36-2] (538 mg, 0.73 mmol, 62% purity), tribasic potassium phosphate (0.46 g, 2 .18 mmol), 1,4-dioxane (5.0 ml) and H ₂ O (1.3 ml) and it was purged with nitrogen. [1,1'-bis-(di-tert-butylphosphino)ferrocene]palladium dichloride (47.5 mg, 72.8 µmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc and the organic phase was washed with brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 30 μm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/i-PrOH, 99:1 to 80:20). The second purification was performed by reverse phase chromatography (C18 with 25 μm spherical beads, 40 g YMC-ODS-25, liquid phase addition (MeCN/H ₂ O), mobile phase gradient: (0.2% aq. NH4HCO ₃ )/MeCN, from 65:35 to 25:75). The residue was taken up with MeCN. The solid was filtered off and dried in high vacuum at 50° C. for 16 h to give compound 50 (190 mg, 47%).

Compound 51.

Intermediate connection I90.

Methyl-(3S)-1-(5-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidine -2-yl}-6-fluoropyridin-2-yl)pyrrolidin-3-carboxylate

In a closed tube was loaded Intermediate I87 (180 mg, 0.50 mmol, 84% purity), (1R)-2-[7-cyclopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo [1,5-a] pyrimidine-5-carbonyl] 1-methyl-1,2,3,4-tetrahydroisoquinoline [2035421-36-2] (289 mg, 0.50 mmol, 69% purity), tribasic potassium phosphate (323 mg, 1.52 mmol), 1,4-dioxane (5.5 ml) and H ₂ O (1.4 ml) and purged with nitrogen. [1,1'-bis-(di-tert-butylphosphino)ferrocene]palladium dichloride (33.2 mg, 50.9 µmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc and the organic phase was washed with brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 80:20 to 60:40) to give the intermediate I90 (200 mg, 72%) as a yellow foam.

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Intermediate I91.

(3S)-1-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-6-fluoropyridin-2-yl)pyrrolidin-3-carboxylic acid

Lithium hydroxide monohydrate (45.4 mg, 1.08 mmol) was added to a solution of intermediate I90 (200 mg, 361 μmol) in THF (3.1 ml) and H ₂ O (980 μl). The reaction mixture was stirred at rt. for 16 h. A 10% KHSO4 aqueous solution was added until pH 6 was reached and the aqueous phase was extracted with EtOAc. The organic phase was washed with H ₂ O, dried over MgSO ₄ , filtered and concentrated under reduced pressure. 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/AcOH, from 30:46.5:1, 5 to 0:97.5:2.5 to give Intermediate I91 (160 mg, 82%).

Compound 51.

(3S)-1-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-6-fluoropyridin-2-yl)-N-methanesulfonylpyrrolidine-3-carboxamide

A mixture of intermediate I91 (160 mg, 260 μmol) and CDI (57.2 mg, 0.35 mmol) in MeCN (3 mL) was stirred at rt. over 2 hours. DBU (65.8 μl, 0.44 mmol) and methanesulfonamide [3144-09-0] (41.9 mg, 0.44 mmol) were added. The reaction mixture was stirred at 80°C for 16 hours was Added saline, 1N. aqueous solution of HCl and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with a solution based on water and saline (1:1), dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 92:8) to give compound 51 (60 mg, 33%) as a yellow foam.

Compound 86.

Synthesis of intermediate compound I176.

Intermediate I179.

Methyl-(3S)-1-(6-fluoro-4-methoxypyridin-2-yl)pyrrolidine-3-carboxylate

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Mixture of 2,6-difluoro-4-methoxypyridine [1184172-35-7] (100 mg, 689 µmol), (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] (114 mg, 689 µmol) and potassium carbonate (286 mg, 2.07 mmol) in MeCN (6.9 ml) was stirred at rt. for 18 hours. The reaction mixture was filtered through a pad of Celite® and the filtrate was 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, 90:10 to 60:40) to give intermediate I179 (68 mg, 38%) as a yellow oil.

Intermediate I176.

Methyl-(3S)-1-(5-bromo-6-fluoro-4-methoxypyridin-2-yl)pyrrolidine-3-carboxylate

A mixture of intermediate I179 (425 mg, 1.67 mmol) and NBS (298 mg, 1.67 mmol) in MeCN (8.4 mL) was stirred at rt. within 18 hours 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, 99:1 to 40:60) to give intermediate I176 (556 mg, 87%).

Synthesis of compound 86.

Intermediate I177.

Methyl-(3 S)-1 -(5-{7-cyclopropyl-5-[( 1 R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5-a]pyrimidine -2-yl}-6-fluoro-4-methoxypyridin-2-yl)pyrrolidine-3-carboxylate

Intermediate I176 (120 mg, 0.36 mmol), (1R)-2-[7cyclopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a ]pyrimidine-5-carbonyl]-1-methyl1,2,3,4-tetrahydroisoquinoline [2035421-36-2] (236 mg, 0.36 mmol, 70% purity), tribasic potassium phosphate (229 mg, 1.08 mmol), 1,4-dioxane (3.1 ml) and H ₂ O (0.8 ml) and it was purged with nitrogen. [1,1'-Bis-(di-tert-butylphosphino)ferrocene]palladium dichloride (23.5 mg, 36.0 µmol) was added and the mixture was again purged with nitrogen. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc. The layers were separated and the organic phase was 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 phase injection (DCM), mobile phase gradient: heptane/EtOAc, 80:20 to 20:80) to give intermediate I177 (195 mg, 93%).

Intermediate I178.

(3S)-1-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-6-fluoro-4-methoxypyridin-2-yl)pyrrolidin-3-carboxylic acid

To a solution of intermediate I177 (195 mg, 334 µmol) in THF (2.9 ml) and H ₂ O (0.9 ml) was added lithium hydroxide monohydrate (41.9 mg, 1.00 mmol). The reaction mixture was stirred at rt. over 16 hours. 10% aqueous 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 to give intermediate I178 (185 mg, 97%).

Compound 86.

- 65 040266 (3S)-1-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5a]pyrimidine- 2-yl}-6-fluoro-4-methoxypyridin-2-yl)pyrrolidine-3-carboxamide

A mixture of intermediate I178 (185 mg, 324 µmol), ammonium chloride (69.4 mg, 1.30 mmol) and DIPEA (467 µl, 2.71 mmol) in 1,4-dioxane (2.5 ml) was stirred at 0°C. PPAC (50 wt% in EtOAc, 463 μl, 778 μmol) was added slowly. The reaction mixture was stirred at 0°C for 10 min and at rt. within 4 hours the Reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with 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 by preparative LC (C18 spheroid, 25 μm, 40 g YMC-ODS-25, dry-load (Celite®), mobile phase gradient: (0.2% aq. NH ₄ HCO ₃ )/MeCN , from 75:25 to 35:65). The residue was solubilized in Et ₂ O and evaporated in vacuo. The product was dried in vacuo at 50°C for 72 h and at 65°C for 8 h to give compound 86 (100 mg, 54%).

Compound 87.

[2035421-36-2]

1161

PdCI ₂ (dtbpf) K ₃ RO ₄ dioxane: H ₂ O fovol. naked| 80°C, 30 min.

LiOH.HjO

THF:H _Z O k.t., 16 hours

_NH4CI DIPEA

_NH2

Intermediate I183.

2,6-Difluoro-4-(2-methoxyethoxy)pyridine

Synthesis of intermediate compound I180.

To a mixture of 2,4,6-trifluoropyridine [3512-17-2] (300 mg, 2.25 mmol) and 2-methoxyethanol [109-86-4] (179 µl, 2.25 mmol) in MeCN (9, 4 ml) sodium hydride (60% in mineral oil, 90.2 mg, 2.25 mmol) was added. The reaction mixture was stirred at rt. for 18 hours. The reaction mixture was diluted with

- 66 040266 using EtOAc. The organic phase was washed with H2O, 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 phase injection (DCM), mobile phase gradient:

heptane/EtOAc, 90:10 to 40:60) to give intermediate I183 (230 mg, 54%).

Intermediate I184.

Methyl-(3S)-1-[6-fluoro-4-(2-methoxyethoxy)pyridin-2-yl]pyrrolidin-3-carboxylate 'H84

Mixture of intermediate I183 (230 mg, 1.22 mmol), (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] (201 mg, 1.22 mmol) and potassium carbonate (504 mg, 3.65 mmol) in MeCN (12 ml) was stirred at 80° C. for 18 hours. The reaction mixture was filtered through a pad of Celite® and the filtrate was 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 intermediate I184 (150 mg, 41%) as a yellow oil.

Intermediate connection I180.

Methyl-(3S)-1-[5-bromo-6-fluoro-4-(2-methoxyethoxy)pyridin-2-yl]pyrrolidine-3-carboxylate

A mixture of intermediate I184 (150 mg, 503 µmol) and NBS (89.5 mg, 503 mmol) in MeCN (2.5 mL) was stirred at rt. within 18 hours the Solvent was evaporated 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 40:60) to give intermediate I180 (218 mg, 93%) as a yellow oil.

Synthesis of compound 87.

Intermediate I181.

Methyl-(3S)-1 -(5-{7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-а] pyrimidin-2-yl}-6-fluoro-4-(2-methoxyethoxy)pyridin-2-yl)pyrrolidin-3-carboxylate

Intermediate I180 (124 mg, 329 µmol), (1R)-2-[7-cyclopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a ]pyrimidine-5-carbonyl]1-methyl-1,2,3,4-tetrahydroisoquinoline [2035421-36-2] (215 mg, 329 µmol, 70% purity), tribasic potassium phosphate (209 mg, 986 µmol), 1,4-dioxane (2.8 ml) and H ₂ O (0.7 ml) and it was purged with nitrogen. [1,1'-Bis-(di-tert-butylphosphino)ferrocene]palladium dichloride (21.4 mg, 32.9 µmol) was added and the mixture was purged with nitrogen again. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc. The organic phase was 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 phase injection (DCM), mobile phase gradient: heptane/EtOAc, 80:20 to 20:80) to give intermediate I181 (185 mg, 90%).

Intermediate I182.

(3S)-1-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-6-fluoro-4-(2-methoxyethoxy)pyridin-2-yl)pyrrolidin-3-carboxylic acid

To a solution of intermediate I181 (185 mg, 294 µmol) in THF (2.6 ml) and H ₂ O (0.8 ml)

- 67 040266 lithium hydroxide monohydrate (37.0 mg, 883 µmol) was added. The reaction mixture was stirred at

k.t. for 16 h. A 10% KHSO4 aqueous solution was added until pH 6 was reached and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H2O, dried over MgSO ₄ , filtered and concentrated to give intermediate I182 (170 mg, 94%).

Compound 87.

(3S)-1-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-6-fluoro-4-(2-methoxyethoxy)pyridin-2-yl)pyrrolidine-3-carboxamide

A mixture of intermediate I182 (170 mg, 277 µmol), ammonium chloride (17.8 mg, 332 µmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (51.5 mg, 332 µmol) and 1-hydroxybenzotriazole hydrate ( 63.5 mg, 415 μmol) in DMF (14 ml) was stirred at 0°C. DIPEA (238 μl, 1.38 mmol) was added slowly and the reaction mixture was stirred at rt. within 18 hours the Reaction mixture was evaporated in vacuo. The residue was dissolved in brine and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was purified by reverse phase chromatography (stationary phase: YMC-actus Triart C18 10 μm, 30x150 mm, mobile phase gradient: (0.2% aq. NH ₄ HCO ₃ )/MeCN, 70:30 to 30 :70). The residue was suspended in MeCN (~2 ml) and stirred at reflux until solubilization was complete. The heating source was turned off and the flask was left in an oil bath with gentle stirring, during which crystallization occurred (4 hours). The solid was filtered off, washed with MeCN and dried in vacuo at 50° C. for 18 h to give compound 87 (115 mg, 68%) as a white solid.

Compound 52.

Synthesis of intermediate compound I92.

[357927-50-5] [216311-60-3] I95

I92

Intermediate I95.

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

I95

2-bromo-4-fluoropyridine [357927-50-5] (200 mg, 1.14 mmol), (S)-methylpyrrolidine-3-carboxylate hydrochloride [216311-60-3] (188 mg, 1 .14 mmol) and cesium carbonate (1.11 g, 3.41 mmol) and purged with nitrogen. 1,4-dioxane (9.2 ml) was added and the mixture was degassed with nitrogen.

- 68 040266

Palladium acetate (25.5 mg, 0.11 mmol) and XantPhos (65.8 mg, 0.11 mmol) were added. The reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc and filtered through Celite®. The filtrate was washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. 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, 90:10 to 40:60) to give intermediate I95 (32 mg, 13%) as a colorless oil.

Intermediate I92.

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

192

A mixture of intermediate I95 (60.0 mg, 268 µmol) and NBS (47.6 mg, 268 µmol) in MeCN (2.7 ml) was stirred at rt. within 18 hours the Mixture was evaporated under reduced pressure. The crude product 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 50:50) to give intermediate I92 (68 mg, 84%) as a colorless oil.

Synthesis of compound 52.

Intermediate I93.

Methyl-(3 S)-1 -(5 - {7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] pyrazolo[1,5-a] pyrimidin-2-yl}-4-fluoropyridin-2-yl)pyrrolidin-3-carboxylate

Intermediate I92 (234 mg, 0.77 mmol), (1C)-2-[7-cyclopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1.5 -a]pyrimidine-5-carbonyl]1-methyl-1,2,3,4-tetrahydroisoquinoline [2035421-36-2] (472 mg, 0.77 mmol, 75% purity), tribasic potassium phosphate (492 mg, 2.32 mmol), 1,4-dioxane (7.8 ml) and H ₂ O (2.0 ml) and it was purged with nitrogen. [1,1'-bis-(di-tert-butylphosphino)ferrocene]palladium acetate (50.3 mg, 77.2 µmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 80 g Interchim®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 40:60 to 0:100) to give the intermediate I93 (400 mg, 93%) as a yellow oil.

Intermediate I94.

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

To a solution of intermediate I93 (400 mg, 0.72 mmol) in THF (6.3 ml) and H ₂ O (2.0 ml) was added lithium hydroxide monohydrate (90.8 mg, 2.16 mmol). The reaction mixture was stirred at rt. for 16 h. A 10% KHSO4 aqueous solution was added until pH 6 was reached and the aqueous phase was extracted with EtOAc. The organic layer was washed with H ₂ O, dried over MgSO ₄ , filtered and concentrated under reduced pressure. 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/AcOH, from 80:19.5:0, 5 to 0:97.5:2.5) to give intermediate I94 (380 mg, 97%).

Compound 52.

(3S)-1-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-4-fluoropyridin-2-yl)pyrrolidin-3-carboxamide

- 69 040266

A mixture of intermediate I94 (180 mg, 333 µmol), HATU (190 mg, 499 µmol) and DIPEA (172 µl, 1.0 mmol) in DMF (9 ml) was stirred at rt. within 1 h. Ammonia (28% in H ₂ O, 113 μl, 1.67 mmol) was added and the reaction mixture was stirred at rt. within 18 hours the Reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 µm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/i-PrOH, 100:0 to 70:30). The residue (120 mg) was dissolved in DCM and washed with 1% aqueous NaHCO ₃ (3 times), brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give compound 52 (90 mg, 50%).

Compound 53.

Synthesis of intermediate compound I96.

Intermediate I97.

(3S)-1-(5-Bromo-4-fluoropyridin-2-yl)pyrrolidin-3-carboxylic acid

197

Lithium hydroxide monohydrate (66.4 mg, 1.58 mmol) was added to a solution of intermediate I92 (160 mg, 0.53 mmol) in THF (12 ml) and H ₂ O (3.0 ml). The reaction mixture was stirred at rt. for 16 h. A 10% KHSO4 aqueous solution was added until pH 6 was reached and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H2O, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give Intermediate I97 (150 mg, 98%) as a yellow foam.

Intermediate I96.

(3S)-1-(5-Bromo-4-fluoropyridin-2-yl)-N-methylpyrrolidin-3-carboxamide

A mixture of intermediate I97 (150 mg, 519 µmol), HATU (296 mg, 0.78 mmol) and DIPEA (268 µl, 1.56 mmol) in DMF (8 ml) was stirred at rt. over 1 h. Methylamine (2.0 M in THF, 1.30 ml, 2.59 mmol) was added and the reaction mixture was stirred at rt. within 18 hours the Reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated. The organic phase was washed with 1% aqueous NaHCO ₃ (twice), dried over MgSO ₄ and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/i-PrOH, 100:0 to 80:20) to give Intermediate I96 (140 mg, 89%) as a yellow oil.

Synthesis of compound 53.

(3S)-1-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl }-4-fluoropyridin-2-yl)-N-methylpyrrolidin-3-carboxamide

- 70 040266

Intermediate 196 (140 mg, 0.46 mmol), (1C)-2-[7-cyclopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1.5 -a]pyrimidine-5-carbonyl]1-methyl-1,2,3,4-tetrahydroisoquinoline [2035421-36-2] (212 mg, 0.46 mmol, 63% purity), tribasic potassium phosphate (0.29 g, 1.39 mmol), 1,4-dioxane (3.2 ml) and H ₂ O (0.8 ml) and it was purged with nitrogen. [1,G-bis-(di-tert-butylphosphino)ferrocene]palladium dichloride (30.2 mg, 46.3 µmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc and the organic phase was washed with brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/i-PrOH, 99:1 to 80:20) . The second purification was performed by reverse phase chromatography (C18 with 25 μm spherical beads, 40 g YMC-ODS-25, liquid phase addition (MeCN, H ₂ O), mobile phase gradient (0.2% aq. NH ₄ HCO ₃ )/MeCN, from 65:35 to 25:75). The residue was crystallized from EtOH, filtered off and dried in high vacuum at 50° C. for 16 h to give compound 53 (90 mg, 35%).

Compound 54.

(3S)-l-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5a]pyrimidin-2-yl }-4-fluoropyridin-2-yl)^-methanesulfonylpyrrolidine-3-carboxamide

A mixture of intermediate 194 (185 mg, 342 µmol) and CDI (83.2 mg, 0.51 mmol) in MeCN (3.5 mL) was stirred at rt. over 2 hours. DBU (102 μl, 0.68 mmol) and methanesulfonamide [3144-09-0] (65.1 mg, 0.68 mmol) were added. The reaction mixture was stirred at 80°C for 16 hours was Added 1N. aqueous solution of HC1 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with a solution based on water and saline (1:1), dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 92:8). A second purification was performed: preparative LC (C18 spherical 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). The product was lyophilized to give compound 54 (140 mg, 66%) as a white solid.

Compound 88.

nh ₄ ci DIPEA

Synthesis of intermediate compound 1185.

-71 040266

Intermediate I188.

Methyl-(3S)-1-(6-fluoropyrazin-2-yl)pyrrolidine-3-carboxylate

Mixture of 2,6-difluoropyrazine [33873-09-5] (726 mg, 6.26 mmol), (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] (1.14 g, 6.88 mmol ) and potassium carbonate (2.59 g, 18.8 mmol) in MeCN (48 ml) was stirred at 80°C for 18 h. The reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated in vacuo to give intermediate I188 (1.1 g, 77%).

Intermediate I185.

Methyl-(3S)-1-(5-bromo-6-fluoropyrazin-2-yl)pyrrolidine-3-carboxylate

A mixture of intermediate I188 (1.00 g, 4.59 mmol) and NBS (817 mg, 4.59 mmol) in MeCN (51 mL) was stirred at rt. within 18 hours the Reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with aqueous NaHCO ₃ (twice), dried over MgSO ₄ , filtered and concentrated in vacuo to give intermediate I185 (1.42 g).

Synthesis of compound 88.

Intermediate I186.

Methyl-(3S)-1 -(5 - {7-cyclopropyl-5 -[(1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] pyrazolo[1,5-a] pyrimidin-2-yl}-6-fluoropyrazin-2-yl)pyrrolidin-3-carboxylate

Intermediate I185 (207 mg, 682 µmol), (1R)-2-[7-cyclopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a ]pyrimidine-5-carbonyl]1-methyl-1,2,3,4-tetrahydroisoquinoline [2035421-36-2] (527 mg, 1.02 mmol, 89% purity), tribasic potassium phosphate (434 mg, 2, 05 mmol), 1,4-dioxane (13 ml) and H ₂ O (2 ml) and it was purged with nitrogen. [1,1'-Bis-(di-tert-butylphosphino)ferrocene]palladium dichloride (44.4 mg, 68.2 µmol) was added and the mixture was again purged with nitrogen. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc and brine. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H ₂ O (twice), dried over MgSO ₄ , filtered and concentrated 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: DCM/EtOAc, 100:0 to 70:30).

The second purification was performed using preparative LC (SiOH with irregular grains, 15-40 μm, 24 g GraceResolv™ , liquid phase injection (DCM), mobile phase gradient: heptane/(EtOAc/MeOH (9:1)), from 90 :10 to 60:40) to give intermediate I186 (100 mg, 26%) as a pale yellow solid.

Intermediate I187.

(3 S)-1 -(5 -{7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo [1,5а]pyrimidine-2- yl}-6-fluoropyrazin-2-yl)pyrrolidin-3-carboxylic acid

- 72 040266

To a solution of intermediate I186 (100 mg, 0.18 mmol) in THF (5.2 ml) and H ₂ O (1.3 ml) was added lithium hydroxide monohydrate (41.6 mg, 0.99 mmol). The reaction mixture was stirred at rt. within 4 hours Added 10% aqueous solution of KHSO ₄ to ensure pH 6 and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H ₂ O, dried over MgSO ₄ , filtered and evaporated in vacuo to give Intermediate I187 (90 mg, 81%, 88% purity) as a yellow oil.

Compound 88.

(3S)-1-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl } -6-fluoropyrazin-2-yl)pyrrolidin-3-carboxamide

Mixture of intermediate I187 (80.0 mg, 0.13 mmol, 88% purity), ammonium chloride (8.34 mg, 156 µmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (27.6 µl, 156 µmol) and 1-hydroxybenzotriazole hydrate (29.9 mg, 195 µmol) in DMF (6.4 ml) were stirred at 0°C. DIPEA (112 μl, 0.65 mmol) was added slowly. The reaction mixture was stirred at rt. within 18 hours the Reaction mixture was evaporated in vacuo. The residue was dissolved in brine and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over MgSO ₄ , filtered and evaporated in vacuo. The residue was triturated with MeCN. The solid was filtered off and dried. The residue (45 mg) was purified by reverse phase chromatography (stationary phase: YMC-actus Triart C18 10 μm, 30x150 mm, mobile phase gradient: (0.2% aq. NH ₄ HCO ₃ )/MeCN, from 65: 35 to 25:75). The residue (24 mg) was solubilized in MeCN (2 ml), diluted with water (10 ml) and lyophilized to give compound 88 (19 mg, 27%) as a yellow friable substance.

Compound 89.

Synthesis of intermediate compound I189.

THF:MeOH: _H2O

80°C, 18 hours

Fe nh ₄ ci

1194

Intermediate I193.

Methyl-(3S)-1-(5-fluoro-3-methyl-2-nitrophenyl)pyrrolidine-3-carboxylate

- 73 040266

1193

A mixture of 1,5-difluoro-3-methyl-2-nitrobenzene [1616526-80-7] (125 mg, 722 µmol), (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] (132 mg, 795 µmol) and potassium carbonate (299 mg, 2.17 mmol) in MeCN (7.2 ml) were stirred at rt. for 18 hours. The reaction mixture was filtered through a pad of Celite® and the filtrate was evaporated 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, 99:1 to 60:40) to give intermediate I193 (118 mg, 58%) as a yellow oil.

Intermediate I194.

Methyl-(3S)-1-(4-bromo-5-fluoro-3-methyl-2-nitrophenyl)pyrrolidine-3-carboxylate

A mixture of intermediate I193 (725 mg, 2.57 mmol) and NBS (457 mg, 2.57 mmol) in MeCN (12.8 ml) was stirred at rt. for 18 hours. The solvent was evaporated in vacuo to give intermediate I194 (1.10 g, 95%, 80% pure).

Intermediate I189.

Methyl-(3S)-1-(2-amino-4-bromo-5-fluoro-3-methylphenyl)pyrrolidine-3-carboxylate

1189

In a closed tube, a mixture of intermediate I194 (1.10 g, 2.44 mmol, 80% purity), iron (680 mg, 12.2 mmol) and ammonium chloride (1.31 g, 24.4 mmol) in THF ( 7.7 ml), MeOH (7.7 ml) and H ₂ O (3.9 ml) were stirred at 80°C for 18 hours. The reaction mixture was diluted with EtOAc and H ₂ O. The layers were separated and the organic phase was washed 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 Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 99:1 to 60:40) to give intermediate I189 (666 mg, 83%) as a colorless oil.

Synthesis of compound 89.

Intermediate I190.

Methyl-(3S)-1 -(2-amino-4-{7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo[1,5- a]pyrimidin-2-yl}-5-fluoro-3-methylphenyl)pyrrolidin-3-carboxylate

Intermediate I189 (615 mg, 1.86 mmol), (1R)-2-[7-cyclopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1.5 -a]pyrimidine-5-carbonyl]1-methyl-1,2,3,4-tetrahydroisoquinoline [2035421-36-2] (1.22 g, 1.86 mmol, 70% purity), tribasic potassium phosphate (1 .18 g, 5.57 mmol), 1,4-dioxane (15.8 ml) and H ₂ O (4.0 ml) and it was purged with nitrogen. [1,1'-Bis-(di-tert-butylphosphino)ferrocene]palladium dichloride (121 mg, 186 µmol) was added and the mixture was again purged with nitrogen. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc. The organic phase was washed with brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude mixture was combined with other samples (105 mg, 317 µmol and 50 mg, 151 µmol) and purified by preparative LC (irregular SiOH, 15-40 µm, 40 g Grace®, liquid phase injection (DCM), gradient mobile phase: heptane/EtOAc, 80:20 to 20:80) to give intermediate I190 (1.4 g, 78%, 75% pure).

Intermediate I191.

Methyl-(3S)-1 -(4-{7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]

- 74 040266 pyrazolo [1,5-a] pyrimidin-2-yl} -3-fluoro-5-methylphenyl) pyrrolidine-3-carboxylate

In a closed tube, a mixture of intermediate I190 (700 mg, 901 µmol, 75% purity) and tert-butyl nitrite (118 µl, 991 µmol) in THF (14.7 ml) was stirred at 80°C for 18 h. The solvent was evaporated in vacuum. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 24 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 80:20 to 0:100) to give intermediate I191 (186 mg, 36%).

Intermediate I192.

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

To a solution of intermediate I191 (280 mg, 493 µmol) in THF (4.3 ml) and H ₂ O (1.3 ml) was added lithium hydroxide monohydrate (62.1 mg, 1.48 mmol). The reaction mixture was stirred at rt. for 16 h. A 10% KHSO4 aqueous solution 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 to give intermediate I192 (250 mg, 92%) as a yellow foam.

Compound 89.

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

A mixture of intermediate I192 (220 mg, 397 µmol), ammonium chloride (85.0 mg, 1.59 mmol) and DIPEA (572 µl, 3.32 mmol) in DCM (2.2 ml) was stirred at 0°C. PPAC (50 wt% in EtOAc, 572 μl, 0.96 mmol) was added slowly. The reaction mixture was stirred at 0°C for 10 min and at rt. over 4 h. The reaction mixture was cooled to 0°C and ammonium chloride (85.0 mg, 1.59 mmol), DIPEA (572 μl, 3.32 mmol) and PPAC (50 wt% in EtOAc, 572 µl, 0.96 mmol). The reaction mixture was stirred at 0°C for 10 min and at rt. within 4 hours the Reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with 10% aqueous KHSO ₄ and 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 phase injection (DCM), mobile phase gradient: DCM/i-PrOH, 99:1 to 85:15) . A second purification was performed by preparative LC (C18 spherical 25 μm, 40 g YMCODS-25, dry loaded (Celite®), mobile phase gradient: (0.2% aq. NH ₄ HCO ₃ )/MeCN, from 65 :35 to 25:75). The residue was solubilized in EtOAc, concentrated to dryness and dried in vacuo at 50°C for 72 h and at 65°C for 8 h to give compound 89 (100 mg, 46%).

Compound 55.

- 75 040266

Pd(OAc) ₂ , XantPhos CS2CO3

Synthesis of intermediate compound I98.

[399-94-0] [1099646-61-3] dioxane 100°С, 18 h.

198

Intermediate connection I101.

Methyl-(3S)-1-(2,5-difluorophenyl)pyrrolidine-3-carboxylate

A mixture of (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] (1.00 g, 6.04 mmol), 1-bromo-2,5-difluorobenzene [399-94-0] (1, 02 ml, 9.06 mmol) and cesium carbonate (5.90 g, 18.1 mmol) in 1,4-dioxane (50 ml) with nitrogen for 15 min. XantPhos (349 mg, 0.60 mmol) and palladium acetate (136 mg, 0.60 mmol) were added and the resulting mixture was purged with nitrogen. The reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was filtered through a pad of Celite®. EtOAc and brine were added to the filtrate. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 80 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 100:0 to 80:20) to give the intermediate I101 (780 mg, 54%) as a colorless oil.

Intermediate I98.

Methyl-(3S)-1-(4-bromo-2,5-difluorophenyl)pyrrolidine-3-carboxylate

To a solution of intermediate I101 (780 mg, 3.23 mmol) in MeCN (28 ml) was slowly added NBS (633 mg, 3.56 mmol). The reaction mixture was stirred at rt. within 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. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (SiOH with regular grains, 30 μm, 80 g Grace®, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 100:0 to 90:10) to give the intermediate I98 (817 mg, 79%) as a white powder.

Synthesis of compound 55.

Intermediate I99.

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

- 76 040266

Intermediate I98 (200 mg, 625 µmol), (1R)-2-[7-cyclopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a ]pyrimidine-5-carbonyl]1-methyl-1,2,3,4-tetrahydroisoquinoline [2035421-36-2] (551 mg, 625 µmol, 52% purity), tribasic potassium phosphate (451 mg, 2.12 mmol ), 1,4-dioxane (10 ml) and H ₂ O (3 ml) and it was purged with nitrogen. [1,1'-bis-(di-tert-butylphosphino)ferrocene]palladium dichloride (44.8 mg, 68.8 µmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc and the organic phase was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 80 g Grace®, dry-load (SiOH), mobile phase gradient: heptane/EtOAc, 100:0 to 60:40). The residue (397 mg) was purified by preparative LC (C18 spherical 25 μm, 40 g YMC-ODS-25, dry load (C18), mobile phase gradient: (0.2% aq. NH ₄ HCO ₃ )/ MeCN, 60:40 to 0:100) to give Intermediate I99 (320 mg, 88%) as a yellow solid.

Intermediate connection I100.

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

To a solution of intermediate I99 (320 mg, 0.56 mmol) in THF (9 ml) and H ₂ O (1.8 ml) was added lithium hydroxide monohydrate (117 mg, 2.80 mmol). The reaction mixture was stirred at rt. within 20 h. Added 10% aqueous solution of KHSO4 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (C18 spherical 25 μm, 40 g YMC-ODS-25, dry-load (C18), mobile phase gradient: (0.2% aq. NH ₄ HCO ₃ )/MeCN, from 75:25 to 35:65) to give Intermediate I100 (280 mg, 90%) as a yellow solid.

Compound 55.

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

A mixture of intermediate I100 (142 mg, 255 µmol), HATU (145 mg, 382 µmol) and DIPEA (132 µl, 0.76 mmol) in DMF (7 ml) was stirred at rt. within 1 h. Ammonia (28% in H ₂ O, 86.1 μl, 1.27 mmol) was added and the reaction mixture was stirred at rt. within 18 hours the Reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (C18 spherical 25 μm, 40 g YMC-ODS-25, dry load (C18), mobile phase gradient (0.2% aq. NH ₄ HCO ₃ )/MeCN, from 60 :40 to 0:100). A second purification was performed: preparative LC (C18 spherical 25 μm, 40 g YMC-ODS-25, dry load (C18), mobile phase gradient: (0.2% aq. NH ₄ HCO ₃ )/MeCN, from 60 :40 to 0:100). The residue (80 mg) was purified by reverse phase chromatography (stationary phase: YMC-actus Triart C18 10 μm, 30x150 mm, mobile phase gradient: (0.2% aq. NH ₄ HCO ₃ )/MeCN, from 50:50 to 0:100) to give compound 55 (60 mg, 47%) as a white solid.

Compound 85.

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Intermediate I174 (3R)-Pyrrolidin-3-ylcarbamate hydrochloride

PdCI ₂ (dtbpf) K ₃ PO ₄ dioxane:H ₂ 0 microwave, heated, 80°C, 30 min.

Synthesis of intermediate compound I173.

Solution of tert-butyl-(3R)-3-(carbamoyloxy)pyrrolidine-1-carboxylate [109384-14-7] (4.28 g, 18.6 mmol) and chlorotrimethylsilane (9.5 ml, 74.8 mmol) in MeOH (90 ml) was stirred at room temperature. for 24 hours. The mixture was evaporated in vacuo to give intermediate I174 (3.02 g, 98%).

Intermediate I175.

(3R)-1-(6-Fluoropyridin-2-yl)pyrrolidin-3-ylcarbamate

A mixture of 2,6-difluoropyridine [1513-65-1] (628 mg, 5.46 mmol), intermediate I174 (1.00 g, 6.00 mmol) and potassium carbonate (2.26 g, 16.4 mmol ) in MeCN (42 ml) was stirred at 80°C for 18 h. The reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). 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, 24 g GraceResolv™, dry-loaded (Celite®), mobile phase gradient: heptane/EtOAc, 90:10 to 50:50) to give intermediate I175 (187.9 mg, 15%) as a white solid.

Intermediate I173.

(3R)-1-(5-Bromo-6-fluoropyridin-2-yl)pyrrolidin-3-ylcarbamate

A mixture of intermediate I175 (188 mg, 834 µmol) and NBS (149 mg, 834 µmol) in MeCN (9.2 ml) was stirred at rt. within 18 hours the Reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with NaHCO ₃ (twice), 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™, dry-loaded (Celite®), mobile phase gradient: heptane/EtOAc, 80:20 to 50:50) to give intermediate I173 (180 mg, 71%) as a white solid.

Synthesis of compound 85.

(3R)-1-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl } -6-fluoropyridin-2-yl)pyrrolidin-3-ylcarbamate

Intermediate I173 (120 mg, 395 µmol), (1R)-2-[7-cyclopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a ] pyrimidine-5-carbonyl] 1-methyl-1,2,3,4-tetrahydroisoquinoline [2035421-36-2] (305 mg, 592 µmol, 89% purity), tribasic

- 78 040266 potassium phosphate (251 mg, 1.18 mmol), 1,4-dioxane (7.3 ml) and H ₂ O (1.1 ml) and it was purged with nitrogen. [1,1'-Bis-(di-tert-butylphosphino)ferrocene]palladium dichloride (25.7 mg, 39.5 µmol) was added and the mixture was purged with nitrogen again. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc and brine. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H ₂ O (twice), 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: DCM/EtOAc, 100:0 to 80:20). The residue (100 mg) was triturated with MeCN. The solid was filtered off and dried in high vacuum at 50° C. for 2 h to give compound 85 (28 mg, 13%) as a pale yellow solid.

General scheme

[1135815-14-3] 1102

1103 70°C

R = Ph, 4-OMe-Ph, 4-Me-Ph, 4-CI-Ph,

4-F-Ph, 4-CF ₃ -Ph, 4-CN-Ph, 4-pyridine, pyrimidine, 3-fluoro-5-pyridine

Synthesis of intermediates I102 and I103.

Intermediate I102.

Ethyl 2-(4-bromofluorophenyl)-7-hydroxypyrazolo[1,5-а]pyrimidine-5-carboxylate

[1135815-14-3] 1102

A mixture of 3-(4-bromo-2-fluorophenyl)-1H-pyrazole-5-amine (15.0 g, 58.6 mmol) and diethyl acetylenedicarboxylate (9.40 ml, 58.6 mmol) in acetic acid (110 ml ) were stirred at room temperature. within 36 hours. The reaction mixture was diluted with EtOAc and heptane (30:60) (150 ml) and the mixture was stirred for 30 minutes. The precipitate was filtered off and dried in vacuo to give intermediate I102 (18.6 g, 84%).

Intermediate I103.

Ethyl 2-(4-bromo-2-fluorophenyl)-7-chloropyrazolo[1,5-а]pyrimidine-5-carboxylate

A mixture of intermediate I102 (15.0 g, 39.5 mmol) in phosphorus(V) oxychloride (147 mL) was stirred at reflux for 18 hours. The solvent was evaporated to dryness. H ₂ O was slowly added to the residue and the mixture was stirred at 0° C. for 30 minutes. The precipitate was filtered off and dried in vacuo to give intermediate I103 (15.3 g, 97%).

- 79 040266

Synthesis of compounds 56-64 and 90.

Compound 56.

Intermediate I104.

Ethyl 2-(4-bromo-2-fluorophenyl)-7-phenylpyrazolo[1,5-a]pyrimidine-5-carboxylate

A mixture of intermediate I103 (1.50 g, 3.76 mmol) and 2-phenyl-4,4,5,5-tetramethyl-1,2,3-dioxaborolane [24388-23-6] (691 mg, 3.39 mmol) in THF (30 ml) with nitrogen for 10 min. A complex of [1,1'-bis-(diphenylphosphino)ferrocene]dichloropalladium with dichloromethane (308 mg, 376 µmol) and potassium carbonate (2.0 M in H ₂ O, 5.64 ml, 11.3 mmol) was added and reaction the mixture was stirred at 70° C. for 4 hours. The reaction mixture was poured into water and EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by silica gel flash chromatography (15-40 µm, 80 g cartridge, mobile phase gradient: heptane/EtOAc, 100:0 to 70:30) to give Intermediate I104 (1.15 g, 69% ). The product was used in the next step without further purification.

Intermediate I105.

Lithium-2-(4-bromo-2-fluorophenyl)-7-phenylpyrazolo[1,5-а]pyrimidine-5-carboxylate

A mixture of intermediate I104 (1.15 g, 2.61 mmol) and lithium hydroxide (125 mg, 5.22 mmol) in THF (13 ml) and H ₂ O (3 ml) was stirred at rt. within 18 hours the Solvent was evaporated under reduced pressure. A few drops of H ₂ O were added to the residue. The precipitate was filtered off and dried in vacuo to give intermediate I105 (1.2 g). The product was used in the next step without further purification.

Intermediate I106.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-7-phenylpyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4tetrahydroisoquinoline

To a mixture of (1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] (0.58 g, 3.16 mmol) and intermediate I105 (1.10 g, 2. 63 mmol) in DMF (30 ml) were added DIPEA (1.38 ml, 7.89 mmol) and HATU (1.30 g, 3.42 mmol). The reaction mixture was stirred at rt. within 24 hours the Reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by silica gel flash chromatography (15-40 µm, 80 g GraceResolv™, mobile phase gradient: heptane/EtOAc, 100:0 to 75:25) to give Intermediate I106 (1.3 g, 66 %, purity 72%).

Intermediate I107.

Methyl-(3S)-1-(3-fluoro-4-{5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-phenylpyrazolo[1,5 -a]pyrimidin-2-yl}phenyl)pyrrolidin-3-carboxylate

A mixture of intermediate I106 (1.3 g, 1.73 mmol, 72% purity), (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] (419 mg, 2.08 mmol), cesium carbonate was purged

- 80 040266 (1.69 g, 5.19 mmol) and XantPhos (100 mg, 0.17 mmol) with nitrogen. 1,4-dioxane (20 ml) was added and the mixture was again purged with nitrogen. Palladium acetate (38.8 mg, 0.17 mmol) 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 extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent was removed under reduced pressure. 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 70:30) to give intermediate I107 (550 mg, 54%).

Intermediate I108.

(3S)-1-(3-Fluoro-4-{5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-phenylpyrazolo[1,5а]pyrimidine- 2-yl}phenyl)pyrrolidine-3-carboxylic acid

To a solution of intermediate I107 (550 mg, 0.93 mmol) in THF (7.6 ml) and H2O (2.5 ml) was added lithium hydroxide monohydrate (195 mg, 4.66 mmol). The reaction mixture was stirred at rt. within 24 hours Added a few drops of H ₂ About followed by the addition of 3n. aqueous solution of HCl. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgSO ₄ , filtered and evaporated under reduced pressure to give Intermediate I108 (470 mg, 88%). The product was used as such in the next step.

Compound 56.

(3S)-1-(3-Fluoro-4-{5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-phenylpyrazolo[1,5а]pyrimidine- 2-yl}phenyl)pyrrolidine-3-carboxamide

Mixture of Intermediate I108 (230 mg, 0.40 mmol), HMDS (102 µl, 0.48 mmol), HATU (228 mg, 0.60 mmol) and DIPEA (138 µl, 0.80 mmol) in DMF (5 ml) was stirred at room temperature. for 18 hours. The reaction mixture was diluted with H2O and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H2O, brine, dried over MgSO4, filtered and evaporated to dryness. The crude mixture was purified by silica gel flash chromatography (15-40 μm, 12 g Grace®, mobile phase gradient: DCM/MeOH, 100:0 to 96:4). Purified fractions were collected and concentrated to dryness. The residue (155 mg) was taken up with Et ₂ O, filtered and dried in vacuo to give compound 56 (101 mg, 44%).

Compound 57.

Intermediate I109.

Ethyl 2-(4-bromo-2-fluorophenyl)-7-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate

pos 70°С, 4 h.

Intermediate I109 (880 mg, 54%, 87% purity) was synthesized from intermediate I103 and 4-methoxyphenylboronic acid [5720-07-0] according to the procedure given for the synthesis of intermediate I104.

Intermediate I110.

Lithium-2-(4-bromo-2-fluorophenyl)-7-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate

- 81 040266

Intermediate I110 (150 mg, 90%) was synthesized from intermediate I109 and lithium hydroxide monohydrate according to the procedure given for the synthesis of intermediate I105.

Intermediate I111.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-7-(4-methoxyphenyl)pyrazolo[1,5-а]pyrimidine-5-carbonyl]-1methyl-1,2,3,4 -tetrahydroisoquinoline

Intermediate I111 (740 mg, 48%) was synthesized from intermediate I110 and (1R)-1-methyl-1,2,3,4-tetrahydroisoquinolone hydrochloride [84010-67-3] according to the procedure given for the synthesis of intermediate compound I106, where the reaction time is 48 hours.

Intermediate I112.

Methyl-(3 S)-1 -{3-fluoro-4-[7-(4-methoxyphenyl)-5-[( 1 R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl] pyrazolo [1,5-а]pyrimidin-2-yl]phenyl} pyrrolidine-3-carboxylate

OME

OME

Pd(OAc} ₂ , Xantphos CsjCOg dioxane 100°C, 5 h.

Intermediate I112 (290 mg, 67%) was synthesized from intermediate I111 and (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] according to the procedure given for the synthesis of intermediate I107 where the reaction time is longer short and is 5 hours.

Intermediate I113.

(3S)-1-{3-Fluoro-4-[7-(4-methoxyphenyl)-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1 ,5-a]pyrimidin-2-yl]phenyl}pyrrolidin-3-carboxylic acid

Intermediate I113 was synthesized from intermediate I112 according to the procedure given for the synthesis of intermediate I108. The crude mixture was purified by silica gel flash chromatography (15-40 µm, 24 g cartridge, mobile phase gradient: DCM/MeOH, 100:0 to 97:3) to give Intermediate I113 (245 mg, 93%).

Compound 57.

(3S)-1-{3-Fluoro-4-[7-(4-methoxyphenyl)-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1 ,5-a]pyrimidin-2-yl]phenyl}pyrrolidin-3-carboxamide

- 82 040266

Compound 57 (117 mg, 56%) was synthesized from intermediate I113 according to the procedure given for the synthesis of compound 56.

Compound 58.

Intermediate I114.

Ethyl 2-(4-bromo-2-fluorophenyl)-7-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate

¹¹ 03 70°C, 4 hours

Intermediate I114 (1.35 g, 70%, 88% purity) was synthesized from intermediate I103 and 4-tolylboronic acid [5720-05-8] according to the procedure given for the synthesis of intermediate I104.

Intermediate I115.

Lithium-2-(4-bromo-2-fluorophenyl)-7-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate

Intermediate I115 (1.5 g) was synthesized from intermediate I114 and lithium hydroxide monohydrate according to the procedure given for the synthesis of intermediate I105.

Intermediate I116.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-7-(4-methylphenyl)pyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl1,2,3,4 -tetrahydroisoquinoline

Me

Intermediate I116 (1.25 g, 65%) was synthesized from intermediate I115 and (1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure given for synthesis of intermediate compound I106.

Intermediate I117.

Methyl-(3S)-1-(3-fluoro-4-{5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(4-methylphenyl) pyrazolo[1,5-а]pyrimidin-2-yl}phenyl)pyrrolidin-3-carboxylate

Intermediate I117 (300 mg, 61%) was synthesized from intermediate I116 and (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] according to the procedure given for the synthesis of intermediate I107.

Intermediate I118.

(3S)-1-(3-Fluoro-4-{5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(4-methylphenyl)- 83 040266 pyrazolo[1,5-a]pyrimidin-2-yl}phenyl)pyrrolidin-3-carboxylic acid

Intermediate I118 was synthesized from intermediate I117 according to the procedure given for the synthesis of intermediate I107. The crude mixture was purified by silica gel flash chromatography (15-40 µm, 12 g cartridge, mobile phase gradient: DCM/MeOH, 100:0 to 96:4). Purified fractions were collected and evaporated to dryness to give intermediate I118 (255 mg, 87%).

Compound 58.

(3S)-1-(3-Fluoro-4-{5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(4-methylphenyl)pyrazolo[1 ,5-a]pyrimidin-2-yl}phenyl)pyrrolidin-3-carboxamide

Compound 58 (102 mg, 51%) was synthesized from intermediate I118 according to the procedure given for the synthesis of compound 56.

Compound 59.

Intermediate I119.

Ethyl 2-(4-bromo-2-fluorophenyl)-7-(4-chlorophenyl)pyrazolo[1,5-а]pyrimidine-5-carboxylate CI

Vg

1119

[1679-18-1]

PdCI ₂ (dppf). DCM K ₂ CO ₃ THF 70°С, 18 h.

CI

EY

1103

Degas a mixture of intermediate I103 (2.00 g, 5.02 mmol) and 4-chlorophenylboronic acid [1679-18-1] (706 mg, 4.52 mmol) in THF (40 mL) with nitrogen for 10 min. [1,1'-bis-(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (410 mg, 0.50 mmol) and potassium carbonate (2.0 M in H ₂ O, 7.53 ml, 15.1 mmol) was added and the reaction mixture was stirred at 70° C. for 18 hours. The reaction mixture was poured into water and the precipitate was filtered off. The solid was dried in vacuo at 60° C. to give intermediate I119 (2.2 g, 92%). The product was used in the next step without further purification.

Intermediate connection I120.

Lithium-2-(4-bromo-2-fluorophenyl)-7-(4-chlorophenyl)pyrazolo[1,5-а]pyrimidine-5-carboxylate

Intermediate I120 (2.0 g, 95%) was synthesized from intermediate I119 and lithium hydroxide according to the procedure given for the synthesis of intermediate I105.

Intermediate connection I121.

(1 K)-2-[2-(4-Bromo-2-fluorophenyl)-7-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]-1-methyl1,2,3, 4-tetrahydroisoquinoline

- 84 040266

Intermediate I121 (1.4 g, 55%) was synthesized from intermediate I120 and (1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure given for synthesis of intermediate compound I106.

Intermediate connection I122.

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

Intermediate I122 (290 mg, 48%) was synthesized from intermediate I121 and (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] according to the procedure given for the synthesis of intermediate I107.

Intermediate I123.

(3 S)-1 - {4-[7-(4-Chlorophenyl)-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] pyrazolo[1,5- a]pyrimidin-2-yl]-3-fluorophenyl}pyrrolidin-3-carboxylic acid

Intermediate I123 (245 mg, 86%) was synthesized from intermediate I122 according to the procedure given for the synthesis of intermediate I107.

Compound 59.

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

Compound 59 was synthesized from intermediate I123 according to the procedure given for the synthesis of compound 56. The residue (125 mg) was taken up with DIPE. The solid was filtered off and dried under vacuum to give compound 59 (85 mg, 45%).

Compound 60.

Intermediate I124.

Ethyl 2-(4-bromo-2-fluorophenyl)-7-(4-fluorophenyl)pyrazolo[1,5-а]pyrimidine-5-carboxylate

- 85 040266

Intermediate I124 (940 mg, 48%) was synthesized from intermediate I103 and 4-fluorobenzeneboronic acid [1765-93-1] according to the procedure given for the synthesis of intermediate I119, where the reaction time is shorter at 4 h.

Intermediate I125.

Lithium-2-(4-bromo-2-fluorophenyl)-7-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate

Intermediate I125 (940 mg) was synthesized from intermediate I124 and lithium hydroxide according to the procedure given for the synthesis of intermediate I105.

Intermediate I126.

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

Intermediate I126 (970 mg, 79%) was synthesized from intermediate I125 and (1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure given for the synthesis of intermediate compounds I106.

Intermediate I127.

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

Pd(OAc) ₂ , Xantphos Cs ₂ CO ₃ dioxane 100°С, 18 h.

Intermediate I127 (340 mg, 65%) was synthesized from intermediate I126 and (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] according to the procedure given for the synthesis of intermediate I107.

Intermediate I128.

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

Intermediate I128 (300 mg, 90%) was synthesized from intermediate I127 according to the procedure given for the synthesis of intermediate I107.

Compound 60.

(3 S)-1 - {3-Fluoro-4-[7-(4-fluorophenyl)-5-[(1 R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo [1,5-a]pyrimidin-2-yl]phenyl}pyrrolidin-3-carboxamide

- 86 040266

Compound 60 was synthesized from intermediate I128 according to the procedure given for the synthesis of compound 56. The residue (190 mg) was taken up with DIPE. The solid was filtered off and dried under vacuum to give compound 60 (125 mg, 42%).

Compound 61.

Intermediate I129.

Ethyl 2-(4-bromo-2-fluorophenyl)-7-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]-pyrimidine-5 carboxylate

Intermediate I129 (1.1 g, 51%) was synthesized from intermediate I103 and 4-(trifluoromethyl)phenylboronic acid [128796-39-4] according to the procedure given for the synthesis of intermediate I104.

Intermediate connection I130.

Lithium-2-(4-bromo-2-fluorophenyl)-7-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-а]pyrimidine-5carboxylate

1129 ISO

Intermediate I130 (1.1 g) was synthesized from intermediate I129 and lithium hydroxide monohydrate according to the procedure given for the synthesis of intermediate I105 where the reaction time is 48 hours.

Intermediate I131.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-7-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-5carbonyl]-1-methyl-1,2, 3,4-tetrahydroisoquinoline

Intermediate I131 (1.17 g, 74%, 87% purity) was synthesized from intermediate I130 and (1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure given for the synthesis of intermediate I106.

Intermediate I132.

Methyl-(3S)-1-(3-fluoro-4-{5-[(1 R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-[4-( trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidin-2-yl}phenyl)pyrrolidine-3-carboxylate

- 87 040266

CF,

CF-

[1099646-61-3]

Pd(OAc) ₂ , Xantphos Cs ₂ CO ₃ dioxane 100°С, 18 h.

Intermediate I132 (240 mg, 57%) was synthesized from intermediate I131 and (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] according to the procedure given for the synthesis of intermediate I107.

Intermediate I133.

(3 S)-1 -(3 -Fluoro-4-{5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] -7-[4-(trifluoromethyl)phenyl ]pyrazolo[1,5-а]pyrimidin-2-yl}phenyl)pyrrolidin-3-carboxylic acid

Intermediate I133 (210 mg, 66%) was synthesized from intermediate I132 according to the procedure given for the synthesis of intermediate I107.

Compound 61.

(3 S)-1 -(3 -Fluoro-4-{5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] -7-[4-(trifluoromethyl)phenyl ]pyrazolo[1,5-а]pyrimidin-2-yl}phenyl)pyrrolidin-3-carboxamide

Compound 61 (82 mg, 44%) was synthesized from intermediate I133 according to the procedure given for the synthesis of compound 56.

Compound 62.

Intermediate I134.

Ethyl 2-(4-bromo-2-fluorophenyl)-7-(4-cyanophenyl)pyrazolo[1,5-а]pyrimidine-5-carboxylate

CN

EtO

ABOUT

[126747-14-6]

1103

Vg

PdCI ₂ (dppf).DCM K ₂ CO ₃ THF 70°С, 4 h*

1134

Intermediate I134 (730 mg, 42%) was synthesized from intermediate I103 and 4-cyanophenylboronic acid [126747-14-6] according to the procedure given for the synthesis of intermediate I104.

Intermediate I135.

Lithium-2-(4-bromo-2-fluorophenyl)-7-(4-cyanophenyl)pyrazolo[1,5-а]pyrimidine-5-carboxylate

Intermediate I135 (0.8 g) was synthesized from intermediate I134 and lithium hydroxide monohydrate according to the procedure given for the synthesis of intermediate I105.

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Intermediate I136.

4-[2-(4-Bromo-2-fluorophenyl)-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]niprazolo[1,5-а]pyrimidine- 7-yl]benzonitrile

Intermediate I136 (620 mg, 61%) was synthesized from intermediate I135 and (1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure given for the synthesis of intermediate compounds I106.

Intermediate I137.

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

Intermediate I137 (380 mg, 56%) was synthesized from intermediate I136 and (8)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] according to the procedure given for the synthesis of intermediate I107.

Intermediate I138.

(3 S)-1 - {4-[7-(4-Cyanophenyl)-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] pyrazolo[1,5- a]pyrimidin-2-yl]-3-fluorophenyl}pyrrolidin-3-carboxylic acid

Intermediate I138 was synthesized from intermediate I137 according to the procedure given for the synthesis of intermediate I107. The crude mixture was purified by silica gel flash chromatography (15-40 µm, Grace® 12 g, mobile phase gradient: DCM/MeOH, 100:0 to 96:4). Purified fractions were collected and evaporated to dryness to give intermediate I138 (265 mg, 71%).

Compound 62.

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

Compound 62 was synthesized from intermediate I133 according to the procedure given for the synthesis of compound 56. The residue (125 mg) was taken up with DIPE and DCM (3 drops). The solid was filtered off and dried under vacuum to give compound 62 (45 mg, 20%).

Compound 63.

Intermediate I139.

Ethyl 2-(4-bromo-2-fluorophenyl)-7-(pyridin-4-yl)pyrazolo[1,5-а]pyrimidine-5-carboxylate

- 89 040266

1103 70°C, 4 h,

Intermediate I139 was synthesized from intermediate I103 and 4-pyridineboronic acid pinacol ester [181219-01-2] according to the procedure given for the synthesis of intermediate I104. The crude mixture was purified by silica gel flash chromatography (15-40 μm, 40 g GraceResolv™, mobile phase gradient: heptane/EtOAc, 90:10 to 50:50) to give Intermediate I139 (350 mg, 21%).

Intermediate connection I140.

Lithium-2-(4-bromo-2-fluorophenyl)-7-(pyridin-4-yl)pyrazolo[1,5-а]pyrimidine-5-carboxylate

1139 1140

Intermediate I140 (410 mg) was synthesized from intermediate I139 and lithium hydroxide monohydrate according to the procedure given for the synthesis of intermediate I105.

Intermediate I141.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-7-(pyridin-4-yl)pyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl1,2,3 ,4-tetrahydroisoquinoline

Intermediate I141 (345 mg, 67%) was synthesized from intermediate I140 and (1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure given for the synthesis of intermediate compound I106, where the reaction time is 48 hours.

Intermediate I142.

Methyl-(3 S)-1 -(3-fluoro-4-{5-[(1 R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(pyridine-4yl )pyrazolo[1,5-a]pyrimidin-2-yl}phenyl)pyrrolidin-3-carboxylate

Intermediate I142 was synthesized from intermediate I141 and (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] according to the procedure given for the synthesis of intermediate I107, where the reaction time is 5 h. The crude mixture was purified with preparative LC (irregular SiOH, 15-40 µm, 40 g Grace®, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 95:5) to give intermediate I142 (220 mg, 59%).

Intermediate I143.

(3 S)-1-(3-Fluoro-4-{5-[(1 R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(pyridin-4yl)pyrazolo [1,5-a]pyrimidin-2-yl}phenyl)pyrrolidin-3-carboxylic acid

- 90 040266

Intermediate I143 was synthesized from intermediate I142 according to the procedure given for the synthesis of intermediate I107. The crude mixture was purified by silica gel flash chromatography (15-40 µm, 12 g Grace®, mobile phase gradient: DCM/MeOH, 100:0 to 96:4). The purified fractions were collected and evaporated to dryness. The remainder (125 mg) was taken up with DIPE. The solid was filtered off and dried in vacuo to give intermediate I143 (39 mg, 18%).

Compound 63.

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

Compound 63 was synthesized from intermediate I143 according to the procedure given for the synthesis of compound 56. The residue (53 mg) was taken up with DIPE. The solid was filtered off and dried in vacuo to give compound 63 (23 mg, 27%).

Compound 64.

Intermediate I144.

Ethyl 2-(4-bromo-2-fluorophenyl)-7-(pyrimidin-5-yl)pyrazolo[1,5-а]pyrimidine-5-carboxylate

Intermediate I144 (3.4 g) was synthesized from intermediate I103 and 5-pyrimidineboronic acid pinacol ester [321724-19-0] according to the procedure given for the synthesis of intermediate I119 where the reaction time is shorter at 3 h.

Intermediate I145.

Lithium-2-(4-bromo-2-fluorophenyl)-7-(pyrimidin-5-yl)pyrazolo[1,5-а]pyrimidine-5-carboxylate

Intermediate I145 (3.0 g, 99%) was synthesized from intermediate I144 and lithium hydroxide according to the procedure given for the synthesis of intermediate I105.

Intermediate I146.

(1R)-2-[2-(4-Bromo-2-fluorophenyl)-7-(pyrimidin-5-yl)pyrazolo[1,5-а]pyrimidine-5-carbonyl]-1methyl-1,2,3 ,4-tetrahydroisoquinoline

- 91 040266

Intermediate I146 (1.32 g, 34%) was synthesized from intermediate I145 and (1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure given for synthesis of intermediate compound I106.

Intermediate I147.

Methyl-(3S)-1 -(3-fluoro-4-{5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(pyrimidin5-yl) pyrazolo[1,5-а]pyrimidin-2-yl}phenyl)pyrrolidin-3-carboxylate

Intermediate I147 was synthesized from intermediate I146 and (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] according to the procedure given for the synthesis of intermediate I107. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 µm, 40 g Grace®, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 96:4) to give intermediate I147 (180 mg, 25%).

Intermediate I148.

(3S)-1 -(3-Fluoro-4-{5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(pyrimidin-5 yl)pyrazolo[ 1,5-a]pyrimidin-2-yl}phenyl)pyrrolidin-3-carboxylic acid

Intermediate I148 was synthesized from intermediate I147 according to the procedure given for the synthesis of intermediate I107. The crude mixture was purified by silica gel flash chromatography (15-40 μm, 24 g Grace®, mobile phase gradient: DCM/MeOH, 100:0 to 96:4). Purified fractions were collected and evaporated to dryness to give intermediate I148 (130 mg, 74%).

Compound 64.

(3S)-1 -(3-Fluoro-4-{5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(pyrimidin-5 yl)pyrazolo[ 1,5-а]pyrimidin-2-yl}phenyl)pyrrolidine-3-carboxamide

Compound 64 was synthesized from intermediate I148 according to the procedure given for the synthesis of compound 56. The residue (75 mg) was taken up with DIPE. The solid was filtered off and dried in vacuo to give compound 64 (40 mg, 42%).

Compound 90.

Intermediate I195.

Ethyl 2-(4-bromo-2-fluorophenyl)-7-(5-fluoropyridin-3-yl)pyrazolo[1,5-а]pyrimidine-5-carboxylate

- 92 040266

Intermediate I195 was synthesized from intermediate I103 and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [719268-92-5] according to the procedure , given for the synthesis of intermediate compound I104, where the reaction time is 16 hours, the Reaction mixture was filtered through a pad of Celite® and washed with H ₂ O and EtOAc. The filtrate was decanted and the organic layer was washed with H ₂ O (twice), dried over MgSO ₄ , filtered and evaporated 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 0:100) to give intermediate I195 (246 mg, 43%) as a yellow solid.

Intermediate I196.

2-(4-Bromo-2-fluorophenyl)-7-(5-fluoropyridin-3-yl)pyrazolo[1,5-а]pyrimidine-5-carboxylic acid

To a solution of intermediate I195 (246 mg, 412 μmol) in THF (10 ml) and H ₂ O (4 ml) was added lithium hydroxide monohydrate (86.5 mg, 2.06 mmol). The reaction mixture was stirred at rt. over 16 hours. A 10% KHSO4 aqueous solution was added until pH 3 was reached and the mixture was diluted with EtOAc. The suspension was filtered to give intermediate I196 (122 mg, 60%, 87% purity).

Intermediate I197.

(1 R)-2-[2-(4-Bromo-2-fluorophenyl)-7-(5-fluoropyridin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]-1methyl-1, 2,3,4-tetrahydroisoquinoline

Intermediate I197 (100 mg, 72%) was synthesized from intermediate I196 and (1R)-1-methyl-1,2,3,4-tetraαhydroisoquinoline [84010-66-2] according to the procedure given for the synthesis of intermediate I106, where the reaction time is 16 hours.

Intermediate I198.

Methyl-(3S)-1 -{3-fluoro-4-[7-(5-fluoropyridin-3-yl)-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline- 2carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl]phenyl}pyrrolidin-3-carboxylate

Intermediate I198 was synthesized from intermediate I197 and (S)-methylpyrrolidine-3-carboxylate hydrochloride [1099646-61-3] according to the procedure given for the synthesis of intermediate I107. The reaction mixture was filtered through a pad of Celite® and washed with EtOAc and H2O. The filtrate was decanted and the organic phase was washed with H ₂ O (twice), dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 90:10 to 60:40) with obtaining intermediate compound I198 (81 mg, 75%) as a yellow solid

- 93 040266 substances.

Intermediate I199.

(3S)-1-{3-Fluoro-4-[7-(5-fluoropyridin-3-yl)-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo [1,5-a]pyrimidin-2-yl]phenyl}pyrrolidin-3-carboxylic acid

To a solution of intermediate I198 (81.0 mg, 133 µmol) in THF (1.2 ml) and H ₂ O (0.4 ml) was added lithium hydroxide monohydrate (17.2 mg, 0.41 mmol). The reaction mixture was stirred at rt. over 16 hours. 10% aqueous KHSO4 solution was added until pH 3 was reached and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness to give Intermediate I199 (68 mg, 86%) as an orange solid.

Compound 90.

(3S)-1-{3-Fluoro-4-[7-(5-fluoropyridin-3-yl)-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2carbonyl]pyrazolo [1,5-a]pyrimidin-2-yl]phenyl}pyrrolidin-3-carboxamide

In a screw cap vial, a mixture of intermediate I199 (68.0 mg, 114 µmol), HATU (65.0 mg, 171 µmol) and DIPEA (59 µl, 343 µmol) in DMF (1.1 ml) was stirred at RT. T. within 30 min. Ammonia (30% in H ₂ O, 216 μl, 3.43 mmol) was added and the reaction mixture was stirred at rt. over 16 h. The reaction mixture was diluted with EtOAc and H ₂ O. Additional HATU (21 mg, 55 μmol), DIPEA (20 μl, 114 μmol) and ammonia (30% in H ₂ O, 100 μl, 1 .58 mmol). The reaction mixture was stirred at rt. within 20 hours The layers were separated and the organic phase was washed with H ₂ O and saline (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™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 50:50 to 0:100). The residue (25 mg) was dried in high vacuum at 60° C. for 16 hours to give compound 90 (18 mg, 27%) as an orange solid.

General scheme

functionalization R amide ............................. carboxylic acid, etc.

Compound 65.

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Intermediate I149.

Methyl-2-[1-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidine- 2-yl}-3-fluorophenyl)azetidin-3-yl]acetate

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5carbonyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline was degassed [ 2035421-61-3] (250 mg, 495 µmol), trifluoroacetate salt of methyl 3-azetidine acetate [1313738-62-3] (144 mg, 594 µmol) and cesium carbonate (645 mg, 1.98 mmol) in 1, 4-dioxane (5.9 ml) with nitrogen. Palladium acetate (11.1 mg, 49.5 µmol) and XantPhos (28.6 mg, 49.5 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 combined with another fraction (50 mg, 98.9 μmol) and diluted with EtOAc and H ₂ O. The mixture was filtered through a pad of Celite® and the filtrate was decanted. 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, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 90:10 to 20:80) with obtaining intermediate compound I149 (178 mg, 54%) as a yellow foam.

Intermediate connection I150.

2-[1 -(4-{7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl} -3-fluorophenyl)azetidin-3-yl]acetic acid

To a solution of intermediate I149 (178 mg, 322 µmol) in THF (3.6 ml) and H2O (1.5 ml) was added lithium hydroxide (23.1 mg, 965 µmol). The reaction mixture was stirred at rt. for 3 h. A 10% KHSO4 aqueous solution 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 I150 (183 mg, 95%, 90% purity) as a yellow solid.

Compound 65.

2-[1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl} -3-fluorophenyl)azetidin-3-yl]acetamide

To a mixture of intermediate I150 (183 mg, 305 µmol, 90% purity) and DIPEA (158 µl, 916 µmol) in DMF (3 ml) was added HATU (174 mg, 458 µmol). The mixture was stirred at rt. within 10 min. and ammonia (30% in H ₂ O, 578 μl, 9.16 mmol) was added. The reaction mixture was stirred at rt. within 16 hours Was added a saturated aqueous solution of NaHCO ₃ , saline and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine (twice), dried over MgSO4, filtered and concentrated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 70:30 to 0:100). EtOAc was added and a precipitate formed. The suspension was concentrated under reduced pressure to dryness and the product was dried under high vacuum to give compound 65 (104 mg, 63%) as a yellow solid.

Connection 66.

2-[1 -(4-{7-Cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl} -3-fluorophenyl)azetidin-3-yl]-N-methylacetamide

- 95 040266

To a mixture of intermediate I150 (146 mg, 271 µmol) and DIPEA (140 µl, 812 µmol) in DMF (2.6 ml) was added HATU (154 mg, 406 µmol). The reaction mixture was stirred at rt. within 10 min. and methylamine (2.0 M in THF, 162 µl, 324 µmol) was added. The reaction mixture was stirred at rt. over 2 h. Methylamine (2.0 M in THF, 298 µl, 595 µmol) was added again and the reaction mixture was stirred at rt. over 16 h. H2O, brine and EtOAc were added. The layers were separated and the organic phase was washed with brine (3 times), dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 12 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 70:30 to 0:100). EtOAc was added and the mixture was concentrated under reduced pressure to dryness. The product was dried in high vacuum at 60° C. for 16 h to give compound 66 (72 mg, 48%) as a yellow solid.

Compound 67.

1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}-3- fluorophenyl)azetidin-3-ol

(1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-carbonyl]-1-methyl-1,2, 3,4-tetrahydroisoquinoline [2035421-61-3] (250 mg, 495 µmol) 3-hydroxyazetidine hydrochloride [18621-18-6] (65.0 mg, 594 µmol), cesium carbonate (644 mg, 1.98 mmol ) and 1,4-dioxane (5.9 ml). The mixture was purged with nitrogen. XantPhos (28.6 mg, 49.5 µmol) and palladium acetate (11.1 mg, 49.5 µmol) were added and the reaction mixture was again purged with nitrogen and stirred at 100° C. for 18 h. The reaction mixture was filtered through a pad of Celite ® and washed with EtOAc and H ₂ O. The filtrate was decanted and the organic phase was washed with H ₂ O (twice), dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 12 g GraceResolv™, dry-load (SiOH), mobile phase gradient: heptane/EtOAc, 90:10 to 60:40). A second purification was performed by flash chromatography (irregular SiOH, 15-40 µm, 12 g GraceResolv™, dry-load (SiOH), mobile phase gradient: heptane/EtOAc, 90:10 to 60:40). The solid (103 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 )/MeOH, 50:50 to 0:100). Fractions containing product were collected, concentrated to dryness and co-evaporated with MeOH (twice). The product was dried in high vacuum at 60° C. for 20 h to give compound 67 (80 mg, 33%) as a yellow solid.

Compound 91.

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Intermediate connection I200.

Methyl-1-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl] pyrazolo[1,5-a] pyrimidin-2-yl } -3-fluorophenyl)azetidine-3-carboxylate

A mixture of (1C)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5carbonyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline was degassed [ 2035421-61-3] (250 mg, 495 µmol), methylazetidine 3-carboxylate hydrochloride [100202-39-9] (112 mg, 742 µmol) and cesium carbonate (645 mg, 1.98 mmol) in 1,4-dioxane (9 ml) nitrogen. Tris-(dibenzylideneacetone)dipalladium (18.1 mg, 19.8 µmol) and XPhos (21.2 mg, 44.5 µmol) were added and the mixture was 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 with H ₂ O and EtOAc. The filtrate was decanted and the organic phase was washed with brine (twice), 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: heptane/EtOAc, 80:20 to 20:80) to give the intermediate I200 (249 mg, 93%) as a yellow foam.

Intermediate I201.

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

To a solution of intermediate I200 (249 mg, 461 µmol) in THF (3.5 ml) and H ₂ O (1.5 ml) was added lithium hydroxide monohydrate (38.7 mg, 923 µmol). The reaction mixture was stirred at rt. over 2 hours. 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 water (twice), dried over MgSO4, filtered and concentrated to dryness to give Intermediate I201 (245 mg, 89%) as a yellow solid.

Compound 91.

1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}-3- fluorophenyl)azetidine-3-carboxamide

At 0°C to a mixture of intermediate I201 (218 mg, 415 µmol), DIPEA (357 µl, 2.07 mmol) and ammonia (28% in H ₂ O, 841 µl, 12.4 mmol) in DMF (4 ml ) was added dropwise to PPAC (50 wt% in EtOAc, 617 μl, 1.04 mmol). The reaction mixture was stirred at rt. within 16 hours The layers were separated and the organic phase was washed with 1 M aqueous NaOH solution and saline (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: heptane/EtOAc, 50:50 to 0:100). The residue (63 mg) was dried in high vacuum at 60° C. for 16 h to give compound 91 (58 mg, 27%) as a yellow solid.

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General scheme

Pdci ₂ (dtbpf) K ₃ RO ₄ dioxane: H ₂ O

Compound 92.

functionalization K _amide ......................... carboxylic acid, etc.

n.h. ₂ in

in water ΝΗ ₃ HATU, DIPEA

DMF

PdCI ₂ (dtbpf) K ₃ RO ₄ dioxane: H ₂ O microwave. heat,,

Synthesis of intermediate compound I202.

1202

Intermediate I203.

Methyl 2-[1-(6-fluoropyridin-2-yl)azetidin-3-yl]acetate

To a solution of 2,6-difluoropyridine [1513-65-1] (93.2 µl,

1.03 mmol) in MeCN (7 mL) was added methyl-3-azetidine acetate trifluoroacetate salt [1313738-62-3] (275 mg, 1.13 mmol) and potassium carbonate (426 mg, 3.08 mmol). The reaction mixture was stirred at 80° C. for 18 hours. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated to dryness. 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 50:50) to give intermediate I203 (195 mg, 85%) as a colorless oil.

Intermediate I204.

Methyl 2-[1-(5-bromo-6-fluoropyridin-2-yl)azetidin-3-yl]acetate

A mixture of intermediate I203 (195 mg, 0.87 mmol) and NBS (186 mg, 1.05 mmol) in MeCN (9 mL) was stirred at rt. within 18 hours the Reaction mixture was concentrated to dryness. The crude mixture was purified using flash chromatography (SiOH with irregular grains,

15-40 µm, 12 g GraceResolv™, dry loaded (SiOH, mobile phase gradient: heptane/EtOAc, 90:10 to 60:40) to give Intermediate I204 (147 mg, 56%) as a white solid .

Intermediate I205.

2-[1-(5-Bromo-6-fluoropyridin-2-yl)azetidin-3-yl]acetic acid

1205

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To a solution of intermediate I204 (147 mg, 485 µmol) in THF (4 ml) and H ₂ O (1.3 ml) was added lithium hydroxide monohydrate (61 mg, 1.45 mmol). The reaction mixture was stirred at rt. for 16 h. A 10% KHSO4 aqueous solution 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 to give Intermediate I205 (135 mg, 96%) as a white solid.

Intermediate I202.

2-[1-(5-Bromo-6-fluoropyridin-2-yl)azetidin-3-yl]acetamide

1202

A mixture of intermediate I205 (135 mg, 467 µmol), HATU (266 mg, 700 µmol) and DIPEA (241 µl, 1.40 mmol) in DMF (2.3 ml) was stirred at rt. within 30 min. Ammonia (30% in H ₂ O, 884 μl, 14.0 mmol) was added and the reaction mixture was stirred at rt. within 16 hours the Reaction mixture was diluted with EtOAc and H ₂ O. The layers were separated and the organic phase was washed with water and brine (3 times), dried over MgSO ₄ , filtered and concentrated. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 µm, 12 g GraceResolv™, dry-load (SiOH), mobile phase gradient: heptane/EtOAc, 50:50 to 0:100) to give intermediate I202 (94 mg, 70%) as a white solid.

Synthesis of compound 92.

2-[1-(5-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pirazolo[1,5а]pyrimidin-2-yl} -6-Fluoropyridin-2-yl)azetidin-3-yl]acetamide

(1R)-2-[7-cyclopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2yl)pyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl-1 ,2,3,4-tetrahydroisoquinoline [2035421-36-2] (150 mg, 203 µmol, 62% purity), Intermediate I202 (64 mg, 223 µmol), tribasic potassium phosphate (129 mg, 609 µmol), 1 ,4-dioxane (2.5 ml) and H ₂ O (0.6 ml) and purged with nitrogen. [1,1'-bis-(di-t-butylphosphino)ferrocene]dichloropalladium (13.2 mg, 20.3 µmol) was added and the mixture was purged again with nitrogen. The reaction mixture was heated at 80° C. using a single mode microwave reactor (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes. The reaction mixture was diluted with EtOAc and H2O. 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, 25 g GraceResolv™, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 50:50 to 0:100). The residue was taken up in EtOAc, sonicated and concentrated to dryness. The solid was dried in high vacuum at 60° C. for 16 h to give compound 92 (47 mg, 43%) as a yellow solid.

General scheme

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Compound 68.

Intermediate connection I151.

Ethyl-1 - (4-{7-cyclopropyl-5-[( 1R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] pyrazolo [1,5a] pyrimidin-2-yl} - 3-fluorophenyl)piperidine-4-carboxylate

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]-pyrimidine-5carbonyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline was purged [2035421-61-3] (200 mg, 0.40 mmol), ethylpiperidine 4-carboxylate [1126-09-6] (87.1 mg, 0.55 mmol), cesium carbonate (516 mg, 1.58 mmol) and XantPhos (27.5 mg, 47.5 µmol) with nitrogen. Added 1,4-dioxane (5 ml) and the mixture was again purged with nitrogen. Palladium acetate (10.6 mg, 47.5 µmol) was added. The reaction mixture was purged with nitrogen and stirred at 100° C. for 7 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 removed under reduced pressure. The crude mixture was purified by silica gel flash chromatography (Interchim® 40 g, 30 μM, liquid phase injection (DCM), mobile phase gradient: heptane/EtOAc, 90:10 to 60:40) to give intermediate I151 (180 mg, 78%) as a yellow solid.

Intermediate connection I152.

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

A mixture of intermediate I151 (171 mg, 0.29 mmol) and lithium hydroxide monohydrate (86.4 mg, 2.06 mmol) in THF (5 mL) and H ₂ O (1.5 mL) was stirred at rt. within 15 hours was Added an aqueous solution of citric acid (7 eq. in 10 ml) and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness to give Intermediate I152 (160 mg, 98%) as a beige solid.

Compound 68.

-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}-3-fluorophenyl )piperidine-4-carboxamide

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To a solution of intermediate I152 (0.16 g, 0.29 mmol) in DMF (4 ml) was added DIPEA (0.15 ml, 0.87 mmol) and HATU (0.17 g, 0.43 mmol). The mixture was stirred at rt. within 15 min. Ammonia (30% in H ₂ O, 33 μl, 1.73 mmol) was added and the reaction mixture was stirred at rt. within 1 h. The reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the organic phase was washed with H ₂ O (3 times) and brine, dried over MgSO ₄ , filtered and evaporated to dryness. The crude mixture was purified by silica gel flash chromatography (Interchim® 12 g, 30 μM, liquid phase injection (DCM), mobile phase gradient: DCM/MeOH, 100:0 to 97:3) to give compound 68 (75 mg , 47%) as a yellow solid.

Compound 69.

Intermediate connection I153.

Methyl-1-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]pyrazolo[1,5-a]pyrimidin-2-yl }-3-fluorophenyl)piperidine-3-carboxylate

Intermediate I153 was synthesized from (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-carbonyl]-1-methyl-1,2,3 ,4-tetrahydroisoquinoline [2035421-61-3] and methylpiperidine-3-carboxylate [50585-89-2] according to the procedure given for the synthesis of intermediate I151. Intermediate I153 (0.18 g, 65%) was obtained as a yellow solid.

Intermediate I154.

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

Intermediate I154 was synthesized from intermediate I153 according to the procedure given for the synthesis of intermediate I152. The reaction mixture was stirred at reflux for 5 hours. Intermediate I154 (0.17 g, 98%) was obtained as a yellow solid.

Compound 69.

1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}-3- fluorophenyl)piperidine-3-carboxamide

Compound 69 was synthesized from intermediate I154 according to the procedure given for the synthesis of compound 68. Compound 69 (80 mg, 49%) was obtained as a yellow solid.

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Compound 70.

Intermediate connection I155.

Methyl-2-[1-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidine- 2-yl}-3-fluorophenyl)piperidin-4-yl]acetate

Intermediate I155 was synthesized from (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-carbonyl]-1-methyl-1,2,3 ,4-Tetrahydroisoquinoline [2035421-61-3] and methyl 2-(piperidin-4-yl)acetate hydrochloride [81270-37-3] according to the procedure given for the synthesis of Intermediate I151. Intermediate I155 (023 g, 65%) was obtained as a yellow solid.

Intermediate I156.

2-[1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5a]pyrimidin-2-yl} -3-fluorophenyl)piperidin-4-yl]acetic acid ' . g ⁷

1156

Intermediate I156 was synthesized from intermediate I155 according to the procedure given for the synthesis of intermediate I152. The reaction mixture was stirred at reflux for 5 hours. Intermediate I156 (0.21 g, quant) was obtained as a yellow solid.

Compound 70.

2-[1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5a]pyrimidin-2-yl} -3-fluorophenyl)piperidin-4-yl]acetamide

Compound 70 was synthesized from intermediate I156 according to the procedure given for the synthesis of compound 68. Compound 70 (85 mg, 40%) was obtained as a beige solid.

Compound 71.

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Intermediate I157.

Methyl-2-[1-(4-{7-cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5-a]pyrimidine- 2-yl}-3-fluorophenyl)piperidin-3-yl]acetate

Intermediate I157 was synthesized from (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-carbonyl]-1-methyl-1,2,3 ,4-tetrahydroisoquinoline [2035421-61-3] and methyl 3-piperidinyl acetate [85375-73-1] according to the procedure given for the synthesis of intermediate I151. Intermediate I157 (0.23 g, 67%) was obtained as a yellow solid.

Intermediate connection I158.

2-[1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl} -3-fluorophenyl)piperidin-3-yl]acetic acid

Intermediate I158 was synthesized from intermediate I157 according to the procedure given for the synthesis of intermediate I152. The reaction mixture was stirred at reflux for 5 hours. Intermediate I158 (214 mg, quant) was obtained as a yellow solid.

Compound 71.

2-[1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl} -3-fluorophenyl)piperidin-3-yl]acetamide

Compound 71 was synthesized from intermediate I158 according to the procedure given for the synthesis of compound 68. Compound 71 (90 mg, 42%) was obtained as a yellow solid.

Compound 72.

1-(4-{7-Cyclonpropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}-3- fluorophenyl)-N-methylpiperidine-4-carboxamide

To a solution of intermediate I152 (207 mg, 0.37 mmol) in DMF (2.5 ml) was added DIPEA (0.19 ml, 1.12 mmol) and HATU (0.21 g, 0.56 mmol). The mixture was stirred at rt. within 15 min. and methylamine (2.0 M in THF, 0.11 ml, 2.22 mmol) was added dropwise. The reaction mixture was stirred at rt. within 2 hours the Reaction mixture was diluted with H ₂ O and EtOAc. The layers were separated and the organic phase was washed with H ₂ O (3 times), brine, dried over MgSO ₄ , filtered and evaporated to dryness to give compound 72 (110 mg, 52%) as a beige solid.

Compound 73.

1-(4-{7-Cyclopropyl-5 -[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl] pyrazolo [1,5а]pyrimidin-2-yl}-3- fluorophenyl)-N-methylpiperidine-3-carboxamide

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Compound 73 was synthesized from intermediate I154 according to the procedure given for the synthesis of compound 72. The product was purified by silica gel flash chromatography (30 μm, 12 g Interchim®, liquid phase addition (DCM), mobile phase gradient: DCM/MeOH , from 100:0 to 98:2) to give compound 73 (160 mg, 64%) as a yellow solid.

Compound 74.

1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}-3- fluorophenyl)piperidin-4-ol

(1C)-2-[2-(4-Bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-carbonyl]-1-methyl-1,2, 3,4-tetrahydroisoquinoline [2035421-61-3] (200 mg, 396 µmol), 4-hydroxypiperidine [5382-16-1] (40.0 mg, 396 µmol), sodium tert-butoxide (76.1 mg, 0.79 mmol) and toluene (3.3 ml). The mixture was purged with nitrogen. Palladium acetate (4.44 mg, 19.8 µmol) and (±)-BINAP (12.3 mg, 19.8 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 diluted with EtOAc and H ₂ O and filtered through a pad of Celite®. The filtrate was decanted and the organic phase was washed with 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, 12 g GraceResolv™, dry-load (SiOH), mobile phase gradient: heptane/EtOAc, 50:50 to 0:100). The solid was dried in high vacuum at 60° C. for 16 h to give compound 74 (99 mg, 46%) as a yellow solid.

Compound 75.

1-(4-{7-Cyclopropyl-5-[(1R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]pyrazolo[1,5а]pyrimidin-2-yl}-3- fluorophenyl)piperidin-3-ol

Compound 75 was synthesized from (1C)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4- tetrahydroisoquinoline [2035421-61-3] and 3-hydroxypiperidine [6859-99-0] according to the procedure given for the synthesis of compound 74. Compound 75 (140 mg, 54%) was obtained as a yellow solid.

Synthesis of compound 93.

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Intermediate J1.

tert-Butyl-((S)-1-(4-(7-cyclopropyl-5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrazolo[1,5- a]pyrimidin-2-yl)-3-fluorophenyl)pyrrolidin-3-yl)carbamate

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5a]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4 was degassed in a Schlenk flask. -tetrahydroisoquinoline [2035421-61-3] (300 mg; 0.572 mmol), (S)-3-(boc-amino)pyrrolidine (214 mg; 1.15 mmol) and Cs ₂ CO ₃ (657 mg; 2.015 mmol) in toluene (12 ml) with N ₂ . BINAP (36 mg; 0.058 mmol) and Pd ₂ dba ₃ (53 mg; 0.058 mmol) were added and the reaction mixture was purged with N ₂ . The mixture was heated at 100° C. for 20 hours. To the reaction mixture was added brine and EtOAc, the aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over MgSO ₄ and evaporated in vacuo. The residue was purified by preparative LC (15-40 µm irregular grain SiOH, 40 g GraceResolv®, mobile phase gradient: DCM/EtOAc, 100/0 to 70/30) to give Intermediate J1 as a yellow solid ( 0.315 g, 90%).

Compound 93.

(2-(4-((S)-3-Aminopyrrolidin-1-yl)-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-α]pyrimidin-5yl)-((R)-1-methyl-3 ,4-dihydroisoquinolin-2( 1 H)-yl) methanone

To a solution of Intermediate J1 (315 mg; 0.516 mmol) in DCM (6.2 ml) was added TFA (1.2 ml; 15 mmol). The reaction mixture was stirred at rt. within 1 h was Added DCM and aqueous solution of NaHCO ₃ (sat.). The layers were separated and the organic layer was dried over MgSO ₄ , filtered and the solvent was removed in vacuo to give 226 mg of a yellow foam, which was triturated in MTBE, then filtered through a frit and dried in high vacuum at 50°C overnight to give compound 93 as yellow solid (120 mg, 46%).

Compound 94.

(7-Cyclopropyl-2-(2-fluoro-4-((S)-3-((2,2,2-trifluoroethyl)amino)pyrrolidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine -5-yl)-((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl) methanone

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5a]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4 was degassed in a Schlenk flask. -tetrahydroisoquinoline [2035421-61-3] (127 mg; 0.243 mmol), (3S)-N-(2,2,2-trifluoroethyl)pyrrolidin-3-amine hydrochloride [2107776-76-9] (100 mg; 0.365 mmol)) and Cs ₂ CO ₃ (396 mg; 1.22 mmol) in dioxane (5 ml) with N ₂ . Pd(OAc) ₂ (5 mg; 24 μmol) and XantPhos (14 mg; 0.024 mmol) were added and the reaction mixture was purged with N ₂ . The mixture was heated at 100° C. for 20 hours. To the reaction mixture was added brine and EtOAc, the aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH, 15-40 µm, 12 g GraceResolv®, mobile phase gradient: heptane/EtOAc, 90/10 to 60/40), the pure fraction was collected and evaporated to dryness. The residue was purified by reverse phase chromatography (stationary phase: YMC-actus Triart® C18 10 µm 30x150 mm, mobile phase: gradient from 35% aq. NH4HCO3 (0.2%), 65% MeCN to 0% aq. NH4HCO3 ( 0.2%), 100% MeCN) to give a yellow oil which was taken up with MTBE (~2 ml). Heptane was added until a solid appeared and the mixture was evaporated in vacuo, then dried under high vacuum to give compound 94 as a yellow solid (56 mg, 39%).

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Compound 95.

(7-Cyclopropyl-2-(4-((3R,4S)-3,4-dihydroxypyrrolidin-1-yl)-2-fluorophenyl)pyrazolo[1,5а]pyrimidin-5-yl)-((R)- 1-methyl-3,4-dihydroisoquinolin-2(1 H)-yl) methanone

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl-1,2,3 was degassed in a closed tube ,4-tetrahydroisoquinoline [2035421-61-3] (250 mg, 0.475 mmol), NaOtBu (160 mg, 1.66 mmol) and cis-pyrrolidine-3,4-diol hydrochloride [186393-21-5] (99 mg , 0.712 mmol) in THF (5.6 ml) with N ₂ for 10 min. DavePhos (19 mg, 0.048 mmol) and Pd ₂ dba ₃ (43 mg, 0.048 mmol) were added and the reaction mixture was purged with N ₂ . The 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 hour. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (twice), the combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 µm, 24 g GraceResolv®, mobile phase gradient: DCM/isopropanol, 99/1 to 88/12). Fractions containing product were collected and evaporated to dryness. The residue was purified by preparative LC (C18 spherical 25 μm, 40 g YMC-ODS-25, dry loaded (Celite®), mobile phase gradient 0.2% aq. NH ₄ HCO ₃ /MeCN, from 65:35 until 25:75). Fractions containing product were evaporated, then taken up in EtOAc and evaporated again three times to give 90 mg of a solid which was taken up in MTBE and stirred at 50° C. for 24 hours. The suspension was cooled to rt, filtered through glass frit and washed with MTBE (2x2 ml). The solid was dried in vacuo to give compound 95 as a yellow solid (60 mg, 24%).

Compound 96.

(7-Cyclopropyl-2-(2-fluoro-4-((trans)-3-hydroxy-4-methoxypyrrolidin-1-yl)phenyl)pyrazolo[1,5a]pyrimidin-5-yl)-((R) -1-methyl-3,4-dihydroisoquinolin-2(1 H)-yl) methanone

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl-1,2,3 ,4-tetrahydroisoquinoline [2035421-61-3] (200 mg, 0.38 mmol), trans-4-methoxy-3-pyrrolidinol hydrochloride (70 mg, 0.46 mmol) and Cs ₂ CO ₃ (371 mg, 1 ,14 mmol) and purged with N ₂ . Dioxane (7.9 ml, 93 mmol) was added and the mixture was degassed with N ₂ , then Pd(OAc) ₂ (8.5 mg, 0.038 mmol) and XantPhos (22 mg, 0.038 mmol) were added. The reaction mixture was stirred and heated at 100° C. for 18 hours. Water and EtOAc were added to the reaction mixture. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative LC (15-40 µm irregular grain SiOH, 24 g GraceResolv®, mobile phase gradient: 75% heptane, 25% EtOAc to 0% heptane, 100% EtOAc) to give 250 mg of a white resin. The product was purified by preparative LC (C18 spherical 25 µm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH4HCO3/MeCN, 60:40 to 10:90). Fractions containing product were evaporated in vacuo and the residue was taken up in Et2O and evaporated three times in vacuo and the sample was dried in vacuo to give compound 96 as a yellow solid (110 mg, 53%).

Synthesis of compound 97.

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4,4-Difluoro-3 S-hydroxypyrrolidine hydrochloride.

4,4-Difluoro-3S-hydroxypyrrolidine hydrochloride was synthesized using the same procedure as for the 3R enantiomer described in J. Org. Chem. 2016, 81, 4359-4363.

Compound 97.

(7-Cyclopropyl-2-(4-(^)-3,3-difluoro-4-hydroxypyrrolidin-1-yl)-2-fluorophenyl)pyrazolo[1,5а]pyrimidin-5-yl)-((R) -1-methyl-3,4-dihydroisoquinolin-2( 1 H)-yl) methanone

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl-1,2,3 ,4-tetrahydroisoquinoline [2035421-61-3] (149 mg, 0.295 mmol) 4,4-difluoro-3S-hydroxypyrrolidine hydrochloride (47 mg, 0.295 mmol) and Cs ₂ CO ₃ (480 mg, 1.47 mmol) and it was purged with N ₂ . Dioxane (6.0 ml) was added and the mixture was degassed with N ₂ , then Pd(OAc) ₂ (6.6 mg, 0.030 mmol) and XantPhos (17 mg, 0.030 mmol) were added. The reaction mixture was stirred and heated at 100° C. for 18 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated to dryness. The residue was purified by preparative LC (irregular SiOH, 15-40 µm, GraceResolv® 24 g, mobile phase gradient: heptane/EtOAc, 80/20 to 0/100). Fractions containing the product were evaporated in vacuo. The residue was taken up in Et ₂ O and evaporated to dryness (3 times) to give a yellow solid which was taken up in Et ₂ O and the suspension was filtered and dried under high vacuum to give compound 97 as a yellow solid (65 mg , 40%).

Synthesis of compound 98.

Intermediate J2.

(2-(4-((3aR,4R,6aS)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydro-5H[1,3]dioxolo[4,5-c]pyrrole -5-yl)-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-((R)-1methyl-3,4-dihydroisoquinolin-2(1 H)-yl) methanone

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl-1,2,3 ,4-tetrahydroisoquinoline [2035421-61-3] (200 mg, 0.396 mmol), compounds [153172-31-7] (0.171 g, 0.594 mmol) and Cs ₂ CO ₃ (387 mg, 1.19 mmol) and its purged with N ₂ . Dioxane (8.2 ml) was added and the mixture was degassed with N ₂ , then Pd(OAc) ₂ (8.8 mg, 0.040 mmol) and XantPhos (23 mg, 0.040 mmol) were added. The reaction mixture was purged with N2, then stirred and heated at 100°C for 18 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO ₄ ), filtered and evaporated to dryness. The residue was purified by preparative LC (irregular SiOH, 15-40 μm, GraceResolv® 24 g, mobile phase gradient: heptane/EtOAc, 99/1 to 30/70). Fractions containing product were evaporated in vacuo to give Intermediate J2 (230 mg, 70% purity, 57%)

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Intermediate J3.

(7-Cyclopropyl-2-(2-fluoro-4-((3aR,4R,6aS)-4-(hydroxymethyl)-2,2-dimethyltetrahydro-5H[1,3]dioxolo[4,5-c]pyrrole -5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-((R)-1-methyl-3,4-dihydroisoquinolin-2( 1 H)-yl) methanone

To a stirred solution of intermediate J2 (230 mg, 0.226 mmol, 70% purity) in THF (4.2 ml) at rt. 1 M TBAF in THF (238 μl, 0.238 mmol) was added dropwise. The mixture was stirred at rt. for 1 h. Then the mixture was diluted with sat. aq. NaCl and water and extracted with EtOAc. The organic layer was separated, washed with sat. aq. NaCl, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 µm, 12 g GraceResolv®, dry-loaded (Celite®), mobile phase gradient: heptane/EtOAc, 80/20 to 20/80) to give the intermediate J3 as a white solid. (135 mg, quant.).

Compound 98.

(7-Cyclopropyl-2-(4-((2R,3R,4S)-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)-2-fluorophenyl)pyrazolo[1,5-a]pyrimidine -5-yl)-((R)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl) methanone

A mixture of intermediate J3 (135 mg, 0.226 mmol), AcOH (2.1 ml, 36 mmol), in THF (0.8 ml) and H ₂ O (0.8 ml) was stirred at rt. for 18 hours, then at 50°C for 18 hours Added water and EtOAc. The aqueous layer was extracted with EtOAc (twice), the combined organic layers were dried over MgSO ₄ , filtered, concentrated in vacuo and co-evaporated with EtOAc (3 times). The residue was purified by preparative LC (irregular SiOH 15-40 µm, 24 g GraceResolv®, mobile phase gradient: DCM/i-PrOH, 99/1 to 84/16). The fraction containing the product was evaporated and the residue was taken up in MeCN and evaporated three times in vacuo. This was then taken up with MeCN, the suspension was filtered and dried under high vacuum to give compound 98 as a yellow solid (54 mg, 43%).

Compound 99.

(7-Cyclopropyl-2-(2-fluoro-4-((trans)-3-hydroxy-4-methylpyrrolidin-1-yl)phenyl)pyrazolo[1,5a]pyrimidin-5-yl)-((R) -1-methyl-3,4-dihydroisoquinolin-2(1 H)-yl) methanone

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl-1,2,3 ,4-tetrahydroisoquinoline [2035421-61-3] (300 mg; 0.594 mmol), trans-4-methylpyrrolidin-3-ol hydrochloride (82 mg; 0.594 mmol) and K ₂ CO ₃ (287 mg; 2.08 mmol) and it was purged with N ₂ . THF (4 ml) was added and the mixture was degassed with N ₂ , then DavePhos (23 mg; 59.4 µmol) and Pd ₂ (dba) ₃ (54 mg; 59.4 µmol) were added. The reaction mixture was purged with N ₂ , then stirred and heated at 90° C. for 18 hours. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (twice), the combined organic layers were dried over MgSO ₄ , filtered, concentrated in vacuo and purified by preparative LC (SiOH with irregular grains 15-40 μm, 24 g GraceResolv®, mobile phase gradient: DCM /MeOH, 100:0 to 90:10). The fraction containing the product was collected and evaporated to dryness. The residue was purified by preparative LC (C18 spherical 25 μm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH ₄ HCO ₃ /MeCN, 50:50 to 0:100). Fractions containing product were extracted with EtOAc. The organic layer was dried (MgSO ₄ ), evaporated to give 163 mg of a yellow foam which was precipitated with EtOAc and heptane, filtered and dried to give compound 99 as a yellow solid (105 mg, 34%).

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Compound 100.

(7-Cyclopropyl-2-(4-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-2-fluorophenyl)pyrazolo[1,5а]pyrimidin-5-yl)-((R)- 1-methyl-3,4-dihydroisoquinolin-2( 1 H)-yl) methanone

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl-1,2,3 was degassed in a closed tube ,4-tetrahydroisoquinoline [2035421-61-3] (300 mg; 0.59 mmol), 3R,4R-pyrrolidinediol (85.7 mg; 0.83 mmol) and K ₂ CO ₃ (287 mg; 2.08 mmol ) in THF (7 ml) with N2 for 10 min. DavePhos (23.4 mg; 59.4 µmol) and Pd ₂ (dba) ₃ (54.4 mg; 59.4 µmol) were added and the reaction mixture was purged with N2. The mixture was heated at 80° C. for 20 hours. Water and EtOAc were added to the mixture and extraction was performed. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered, evaporated and purified by preparative LC (irregular SiOH, 15-40 µm, 50 g Merck, mobile phase gradient: DCM/i-PrOH, from 100/ 0 to 90/10) to give 145 mg of a yellow oil. This fraction was taken up in MeOH (3 times) and evaporated, then the residue was co-evaporated with i-PrOAc (3 times) to give compound 100 as a yellow solid (135 mg, 43%).

Compound 101.

(S)-1-(4-(7-Cyclopropyl-5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)pyrazolo[1,5а]pyrimidin-2-yl )-3-fluorophenyl)pyrrolidine-3-carbothioamide

A mixture of compound 36 (118 mg; 0.22 mmol), Lawesson's reagent (53 mg; 0.13 mmol) and DCM (1 ml) was stirred at rt. within 2 hours. The mixture was directly purified by flash chromatography (SiOH irregular grains 15-40 μm, 40 g GraceResolv®, mobile phase gradient, heptane/EtOAc, 90/10 to 30/70). Fractions containing product were evaporated and co-evaporated with EtOH. The solid was dried in vacuo to give compound 101 as a yellow solid (73 mg, 60%).

Connection 102.

(7-Cyclopropyl-2-(4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-2-fluorophenyl)pyrazolo[1,5а]pyrimidin-5-yl)-((R) -1-methyl-3,4-dihydroisoquinolin-2( 1 H)-yl) methanone

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5а]pyrimidine-5-carbonyl]-1-methyl-1,2,3,4 -tetrahydroisoquinoline [2035421-61-3] (6.8 g, 13.5 mmol), 3S,4S-pyrrolidinediol (1.9 g, 18.8 mmol) and K ₂ CO ₃ (6.5 g, 47, 1 mmol) in THF (125 ml) with N2 for 10 min. DavePhos (530 mg, 1.35 mmol) and Pd ₂ dba ₃ (1.2 g, 1.35 mmol) were added and the reaction mixture was purged with N ₂ . The mixture was heated under reflux (80° C.) for 16 h. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (twice), the combined organic layers were dried over MgSO ₄ , filtered, concentrated in vacuo and purified by preparative LC (SiOH with irregular grains 15-40 μm, 330 g GraceResolv®, mobile phase gradient: DCM /MeOH, from 100/0 to 90/10). Fractions containing product were collected and evaporated to dryness. The residue and SiliaMetS® thiol (1.2 g; 1.61 mmol) in THF (100 mL) were stirred at rt. for 3 hours, then filtered through Celite® and the filtrate evaporated to dryness to give 4.8 g of a yellow foam. The solid was suspended in EtOAc (~210 ml total) and refluxed until solubilization was complete. Then the heating source was turned off (the flask was kept in an oil bath during crystallization with gentle stirring to ensure slow cooling) for 42 hours.

The suspension was cooled to rt, filtered through a glass frit, washed with cold EtOAc. The solid was dried in vacuo to give 2.75 g of the first batch of compound 102 as a yellow solid. The filtrate was evaporated, the residue was suspended in EtOAc (total ~60 ml) and heated under reflux until solubilization was complete (oil bath 90°C). The heat source was then turned off (the flask was maintained in an oil bath during crystallization with gentle stirring to ensure slow cooling) for 42 hours. The suspension was cooled to rt, filtered through a glass frit, washed with chilled EtOAc. The solid was dried in vacuo at 50° C. for 2 hours to give 0.944 g of a second batch of compound 102 as a yellow solid. Both batches and 22 ml of EtOAc were stirred at rt. for 24 hours. The suspension was filtered through a glass frit, washed with cold EtOAc. The solid was dried in vacuo to give compound 102 as a yellow solid (3.27 g, 46%).

Synthesis of compounds 103 and 104.

Intermediate J4.

(R)-(7-Cyclopropyl-2-(2-fluoro-4-(3-methylenepyrrolidin-1-yl)phenyl)pyrazolo[1,5-а]pyrimidin-5yl)-(1-methyl-3,4 -dihydroisoquinolin-2( 1 H)-yl) methanone

A mixture of (1R)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl-1,2,3 ,4-tetrahydroisoquinoline [2035421-61-3] (325 mg; 0.644 mmol), Cs ₂ CO ₃ (1.05 g; 3.22 mmol) and 3-methylidenepyrrolidine TFA (294 mg; 0.644 mmol) and it was purged with using N ₂ . Dioxane (6 ml) was added and the mixture was degassed with N ₂ , then Pd ₂ dba ₃ (29.5 mg; 0.0322 mmol) and X-Phos (46 mg; 0.096 mmol) were added. The reaction mixture was purged with N ₂ then stirred and heated at 90°C for 18 hours Added water and EtOAc, the layers were separated. The aqueous layer was extracted with EtOAc (twice), the combined organic layers were dried over MgSO ₄ , filtered, concentrated in vacuo and purified by preparative LC (SiOH with irregular grains 15-40 μm, 40 g GraceResolv®, mobile phase gradient: heptane /EtOAc, 90/10 to 60/40) to give Intermediate J4 as a yellow solid (259 mg, 70%).

Intermediate J5.

(7-Cyclopropyl-2-(2-fluoro-4-(3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5а]pyrimidin-5-yl)-((R)- 1-methyl-3,4-dihydroisoquinolin-2( 1 H)-yl) methanone

To a solution of compound J4 (234 mg; 0.401 mmol) in a mixture of acetone (2 ml) and H ₂ O (0.2 ml) was added NMO (141 mg; 1.20 mmol) and 2.5% OsO ₄ in tBuOH (0.263 ml; 0.0201 mmol). The reaction mixture was stirred at rt. within 3.5 hours the Reaction mixture was quenched with 10% aqueous solution of Na ₂ S ₂ O ₃ and the resulting mixture was stirred at room temperature. within 30 min. DCM was added and the layers were separated. The aqueous layer was extracted with a mixture of DCM/MeOH (90/10) (3 times). The organic layers were combined, washed

- 110 040266 water, dried over MgSO ₄ , filtered and concentrated. The residue was purified by preparative LC (irregular SiOH, 15-40 μm, 12 g GraceResov®, mobile phase gradient: DCM/MeOH: 99/1 to 95/5). The fraction containing the product was combined and evaporated to dryness. The residue was purified by preparative LC (C18 spheroid, 25 µm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq NH4HCO3/MeCN, 65:35 to 25:75) to give 128 mg yellow solid. This solid was again purified by preparative LC (C18 spherical, 25 µm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH ₄ HCO ₃ /MeCN, 65:35 to 25: 75); product containing fractions were diluted with water and lyophilized to give a yellow solid. The solid and SiliaMetS® thiol (30 mg; 0.0401 mmol) in THF (3 mL) were stirred at rt. for 18 h, then filtered through PTFE and the filtrate was evaporated to dryness to give Intermediate J5 as a yellow solid (80 mg, 37%).

Compounds 103 and 104.

Compound J5 was separated using chiral SFC (stationary phase: CHIRALPAK AS-H, 5 μm, 250x20 mm, mobile phase: 75% CO ₂ , 25% EtOH (0.3% i-PrNH 2 )), fractions containing the product were evaporated to dryness, then diluted with MeCN, diluted with water and lyophilized to obtain 28 mg of compound 103, characterized by (-)-specific optical rotation, as a yellow solid and 28 mg of compound 104, characterized by (+)-specific optical rotation, as a yellow solid.

Synthesis of compound 105.

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Intermediate J6.

Methyl 2-(allyloxy)-4-bromo-6-fluorobenzoate

A mixture of methyl 4-bromo-2-fluoro-6-hydroxybenzoate [1193162-18-3] (5 g; 20.1 mmol), allyl iodide (5.5 ml; 60.2 mmol) and K ₂ CO ₃ (8 .76 g, 63.3 mmol) in DMF (80 mL) was stirred at 60° C. for 18 hours. EtOAc and water were added and extraction was performed. The organic layer was washed with brine, dried (MgSO ₄ ), filtered, evaporated and purified by preparative LC (irregular SiOH, 15-40 µm, 220 g GraceResolv®, mobile phase gradient: heptane/EtOAc, from 100/0 to 85/15) to give Intermediate J6 as a white solid (5.55 g, 96%).

Intermediate J7.

3-(2-(Allyloxy)-4-bromo-6-fluorophenyl)-3-oxopropanenitrile

Under N ₂ atmosphere, 1.6 M n-BuLi in hexanes (57 ml; 91.9 mmol) in THF (100 ml) at -78°C was added, then MeCN solution (4.78 ml; 91.6 mmol). The resulting slurry was stirred for 1 hour at -78° C., then a solution of intermediate J6 (13.4 g; 46.4 mmol) in THF (150 ml) was added. After 30 min at -78°C, the reaction mixture was heated to -45°C and provided with stirring for 1 h. The reaction mixture was quenched with 1N. HCl and then extracted with EtOAc. The organic layer was separated, washed with water then brine, dried (MgSO ₄ ), filtered and evaporated to give Intermediate J7 as an orange oil (14.4 g, quant.).

Intermediate J8.

3-(2-(Allyloxy)-4-bromo-6-fluorophenyl)-1H-n-pyrazole-5-amine

A mixture of intermediate J7 (14.4 g; 48.3 mmol) and hydrazine hydrate (80% purity) (2.95 ml; 48.3 mmol) in EtOH (192 ml) was stirred at 80°C for 18 h. The mixture was evaporated to give Intermediate J8 as a yellow solid (14.4 g, 96%).

Intermediate J9.

Methyl 2-(2-(allyloxy)-4-bromo-6-fluorophenyl)-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5carboxylate

Mixture of compound J8 (14.4 g; 46.1 mmol) and methyl 4-cyclopropyl-2,4-dioxobutanoate [167408-67-5] (8.26 g; 46.1 mmol) in EtOH (200 ml) stirred at 80° C. for 3 hours. The mixture was cooled to rt and a precipitate formed. The precipitate was filtered and dried on a frit to give Intermediate J9 as a yellow solid (7.96 g, 38%).

Intermediate connection J10.

(K)-(2-(2-(Allyloxy)-4-bromo-6-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-(1methyl-3,4-dihydroisoquinoline-2 ( 1 H)-yl) methanone

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A mixture of J9 (7.96 g, 17.8 mmol), LiOH H2O (4.12 g, 98.1 mmol), THF (80 ml) and H2O (23 ml) was stirred at rt. within 2 days. To the mixture was added EtOAc and 10% aq. KHSO4 and extraction was performed. The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated to give 6.57 g of the acidic intermediate as a yellow solid. Acid (6.57 g; 15.2 mmol), 1R-methyl-1,2,3,4-tetrahydroisoquinoline (2.59 g; 17.6 mmol) and DiPEA (13 ml; 76 mmol) in DCM (77 ml) was stirred at 0°C. T3P (22.6 ml; 37.9 mmol) was added slowly (5 min.) at 0°C. The mixture was stirred at 0°C for 10 min, then at rt. within 3 hours Added water and EtOAc. Extraction was carried out. The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated to give Intermediate J10 as a brown foam (9.0 g, quant.).

Intermediate J11.

da-(2-(4-Bromo-2-fluoro-6-hydroxyphenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-(1-methyl3,4-dihydroisoquinoline-2( 1 H) -yl) methanone

A mixture of compound J10 (5 g; 8.91 mmol), Wilkinson's catalyst (824 mg; 0.89 mmol), DBU (1.33 ml; 8.91 mmol) and EtOH (60 ml) was stirred at rt. for 18 h. The mixture was evaporated and purified by preparative LC (irregular SiOH 15-40 µm, GraceResolv® 220 g, dry-load (Celite®) heptane/EtOAc mobile phase, 100:0 to 70:30) to give 2 g of intermediate J11 as a brown solid and two crude fractions (3 and 2.4 g). The first crude fraction (3 g) was purified by reverse phase LC (stationary phase: C18 with 25 µm spherical grains, 300 g YMC-ODS-25, dry load (C18), mobile phase: gradient: 0.2% aq. NH ₄ HCO ₃ /MeCN, 50:50 to 0:100). Fractions containing product were combined, MeCN was evaporated in vacuo, water and EtOAc were added and extraction was performed. The organic layer was washed with water, dried over MgSO ₄ , filtered and evaporated to give 700 mg of Intermediate J11 as a brown oil. The second crude fraction (2.4 g) was purified by reverse phase LC (stationary phase: C18 with 25 μm spherical grains, 300 g YMC-ODS-25, dry load (C18), mobile phase: gradient: 0.2 % aq NH ₄ HCO ₃ /MeCN, 50:50 to 0:100). Fractions containing product were combined, MeCN was evaporated in vacuo, water and EtOAc were added and extraction was performed. The organic layer was washed with water, dried over MgSO ₄ , filtered and evaporated to give 1 g of intermediate J11 as a brown foam (80% overall yield, 3.7 g).

Intermediate connection J12.

(R)-(2-(4-Bromo-2-fluoro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-7-cyclopropylpyrazolo[1,5a]pyrimidin-5-yl)-( 1 - methyl-3,4-dihydroisoquinolin-2( 1 H)-yl) methanone

A mixture of compound J11 (2.7 g; 5.18 mmol) and 60% NaH in mineral oil (311 mg; 7.77 mmol) in DMF (20 mL) was stirred at 0° C. for 15 min. SEMCl (1.83 ml; 10.4 mmol) was added slowly at 0° C. under N2 atmosphere. The mixture was stirred at rt. for 4 hours. Extraction was carried out with EtOAc and water. The organic layer was washed with brine, dried (MgSO ₄ ), evaporated and purified by preparative LC (irregular SiOH, 15-40 µm, 120 g GraceResolv®, mobile phase gradient: heptane/EtOAc, 100/0 to 70 /30) to give intermediate J12 as a colorless oil (2.3 g, 68%).

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Intermediate connection J13.

Methyl-(S)-1 -(4-(7-cyclopropyl-5-((R)-1 -methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrazolo[1,5-a]pyrimidine -2-yl)-3-fluoro-5-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrrolidine-3-carboxylate

Compound J12 (800 mg; 1.23 mmol), (S)-methylpyrrolidine-3-carboxylate hydrochloride (238 mg; 1.44 mmol), Cs ₂ CO ₃ (1.17 g; 3.59 mmol) and dioxane (13 ml) and purged with N ₂ . XantPhos (69 mg; 0.12 mmol) was added and the mixture was again purged with N ₂ , then Pd(OAc) ₂ (27 mg; 0.12 mmol) was added. The reaction mixture was purged with N ₂ and heated at 100° C. for 17 hours. The mixture was filtered through a pad of Celite®, water and EtOAc were added and extraction was performed. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered, evaporated and purified by preparative LC (irregular SiOH 15-40 µm, 24 g GraceResolv®, mobile phase gradient: heptane/EtOAc, 100/0 to 50/50) to give Intermediate J13 as a yellow foam (578 mg, 67%).

Intermediate connection J14.

Methyl-(S)-1-(4-(7-cyclopropyl-5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrazolo[1,5-a]pyrimidine -2-yl)-3-fluoro-5-hydroxyphenyl)pyrrolidine-3-carboxylate

A mixture of compound J13 (2.5 g; 3.57 mmol), AcOH (30 ml), THF (10 ml) and H ₂ O (10 ml) was stirred at rt. within 18 hours Added aq. NaHCO ₃ and EtOAc and extraction was performed. The organic layer was washed with brine, dried (MgSO ₄ ), filtered, evaporated and purified by preparative LC (irregular SiOH 15-40 µm, 220 g GraceResolv®, mobile phase gradient: heptane/EtOAc, 100/0 to 50/50) to give Intermediate J14 as a yellow solid (1.56 g, 77%).

Intermediate connection J15.

(S)-1-(4-(7-Cyclopropyl-5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)pyrazolo[1,5а]pyrimidin-2-yl )-3-fluoro-5-hydroxyphenyl)pyrrolidine-3-carboxylic acid

A mixture of compound J14 (600 mg; 1.05 mmol), LiOH H ₂ O (243 mg; 5.80 mmol), THF (5 ml) and H ₂ O (1 ml) was stirred at rt. for 18 hours To the mixture was added EtOAc and 10% aq. KHSO4 and extraction was performed. The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated to give Intermediate J15 as a yellow solid (550 mg, 94%).

Connection 105.

(S)-1-(4-(7-Cyclopropyl-5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)pyrazolo[1,5а]pyrimidin-2-yl )-3-fluoro-5-hydroxyphenyl)pyrrolidine-3-carboxamide

A mixture of compound J15 (250 mg; 0.45 mmol), ammonium chloride (48 mg; 0.90 mmol), EDCI (140 mg; 0.90 mmol) and HOBt H ₂ O (138 mg; 0.90 mmol) in DMF (8 ml) was stirred at 0°C. DiPEA (0.39 ml; 2.25 mmol) was added slowly at 0°C. The mixture was stirred at rt. for 18 hours. EtOAc and brine were added to the mixture and extraction was performed. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered, evaporated and purified by reverse phase LC (stationary phase: C18 with 25 µm spherules, 40 g YMC-ODS-25, dry-load ( C18), mobile phase: gradient: 0.2% aq NH ₄ HCO ₃ /MeCN, 65:35 to 25:75). MeCN was evaporated, EtOAc was added and extraction was performed. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered, evaporated and co-evaporated 3 times with EtOAc to give compound 105 as a yellow solid (140 mg, 56%).

Synthesis of compound 106.

OTBS

Intermediate connection J16.

(R)-(2-(4-Bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)- ( 1 -methyl-3,4-dihydroisoquinolin-2( 1 H)-yl) methanone ^TBS

ΧΊ JIB or

Mixture of compound J11 (226 mg; 0.43 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (93 μl; 0.43 mmol) and K ₂ CO ₃ (189 mg; 1.37 mmol) in DMF (5 ml ) was stirred at 60° C. for 18 hours. EtOAc and water were added and extraction was performed. The organic layer was washed with brine, dried (MgSO ₄ ), evaporated and purified by preparative LC (irregular SiOH, 15-40 µm, 120 g GraceResolv®, mobile phase gradient: heptane/EtOAc, 100/0 to 70 /30) to give intermediate J16 as a colorless oil (243 mg, 82%).

Intermediate connection J17.

Methyl-(S)-1 -(3 -(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(7-cyclopropyl-5-((R)-1 -methyl-1,2,3,4tetrahydroisoquinoline -2-carbonyl)pyrazolo[1,5-а]pyrimidin-2-yl)-5-fluorophenyl)pyrrolidine-3carboxylate ^ ^TBS

ABOUT'

Compound J1 6 (243 mg; 0.36 mmol), (S)-methylpyrrolidine-3carboxylate hydrochloride (59 mg; 0.36 mmol), Cs ₂ CO ₃ (349 mg; 1.1 mmol) in dioxane was loaded into a closed tube (4 ml) and it was purged with N ₂ . XantPhos (21 mg; 0.036 mmol) and Pd(OAc) ₂ (8 mg; 0.036 mmol) were added and the mixture was again purged with N ₂ . The mixture was stirred at 100° C. for 18 hours. EtOAc and water were added to the mixture. Extraction was carried out. The organic layer was washed with brine, dried (MgSO ₄ ), evaporated and purified by preparative LC (irregular SiOH, 15-40 µm, 40 g GraceResolv®, mobile phase gradient: heptane/EtOAc, 100/0 to 40 /60) to give intermediate J17 as a yellow foam (188 mg, 72%).

Compound 106.

(S)-1-(4-(7-Cyclopropyl-5-((R)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)pyrazolo[1,5а]pyrimidin-2-yl )-3-fluoro-5-(2-hydroxyethoxy)phenyl)pyrrolidine-3-carboxamide

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To a solution of compound J16 (188 mg; 0.26 mmol) in THF (7 ml) and H ₂ O (3 ml) was added ΕϊΟΗΉ ₂ Ο (58 mg; 1.4 mmol) and the reaction mixture was stirred at rt. within 18 hours Added 10% aqueous solution of KHSO ₄ to ensure pH 6 and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, dried over MgSO ₄ , filtered and evaporated to give 190 mg of a yellow solid. To this solid was added NH ₄ Cl (28 mg; 0.52 mmol), EDCEHCl (80 mg; 0.418 mmol) and HOBt-H ₂ O (79 mg; 0.52 mmol) in DMF (4 ml). Then DIPEA (222 μl; 1.3 mmol) was added slowly at 0°C and the mixture was stirred at rt. for 18 hours Added saline and EtOAc and carried out the extraction. The organic layer was washed with brine (3x), dried (MgSO ₄ ), filtered and evaporated to give 182 mg of a yellow solid. 1 M TBAF in THF (0.255 ml; 0.255 mmol) and THF (2 ml) was added and the mixture was stirred at rt. for 18 hours Added saline and EtOAc and carried out the extraction. The organic layer was dried (MgSO ₄ ), evaporated and purified by preparative LC (C18 with 25 μm spherical beads, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH ₄ HCO ₃ /MeCN, from 95 :05 to 30:70); the fraction containing the product was concentrated, EtOAc was added and extraction was performed. The organic layer was dried (MgSO4), filtered and evaporated to give I06 as a yellow solid (82 mg, 54%).

Compound 107.

(7-Cyclopropyl-2-(2-fluoro-4-(cis-3-fluoro-4-hydroxypyrrolidin-1-yl)phenyl)pyrazolo[1,5а]pyrimidin-5-yl)-((R)-1 -methyl-3,4-dihydroisoquinolin-2( 1 H)-yl)methαnon

A mixture of (1C)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-а]pyrimidine-5-carbonyl]-1-methyl-1,2,3 was degassed in a closed tube ,4-tetrahydroisoquinoline [2035421-61-3] (200 mg; 0.396 mmol), cis-4-fluoropyrrolidin-3-ol hydrochloride [1434142-02-5] (79 mg; 0.56 mmol) and K ₂ CO ₃ (219 mg; 1.58 mmol) in THF (4.7 ml) with N ₂ for 10 min. DavePhos (16 mg; 0.040 mmol) and Pd ₂ dba ₃ (36 mg; 0.040 mmol) were added and the reaction mixture was purged with N ₂ . The mixture was heated at 80° C. for 20 hours. Water and EtOAc were added and extraction was performed. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative LC (irregular SiOH 15-40 µm, 12 g GraceResolv®, mobile phase gradient: DCM/MeOH, 100/00 to 97/3). The fraction containing the product was combined and evaporated to dryness. The residue was purified by reverse phase chromatography (stationary phase: YMC-actus Triart® C18 10 µm, 30x150 mm, mobile phase: gradient from 40% aq. NH4HCO3 (0.2%), 60% MeCN to 10% aq. NH4HCO3 (0.2%), 90% MeCN) to give 102 mg of a yellow gum, which was taken up in a mixture of EtOAc and heptane, evaporated in vacuo to give 100 mg of a yellow foam. The solid was again purified by reverse phase chromatography (stationary phase: YMC-actus Triart® C18 10 µm, 30x150 mm, mobile phase: gradient from 40% aq. NH4HCO3 (0.2%), 60% MeCN to 10% aq. .NH ₄ HCO ₃ (0.2%), 90% MeCN). Fractions containing product were collected and evaporated. The residue was taken up with MeCN (2 ml), diluted with water (10 ml) and lyophilized to give compound I07 as a crumbly yellow solid (39 mg, 19%).

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.

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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 = wide or combination thereof), coupling constant(s) J are in hertz (Hz).

Connection 1.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 8.03 (t, J=8.7 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.10-7 .25 (m, 3H), 6.94-6.98 (m, 1H), 6.82 (br s, 1H), 6.53-6.61 (m, 2H), 5.59 (q, J=6.6Hz, 1H), 3.81(dd, J=13.9, 4.1Hz, 1H), 3.55-3.70(m, 3H), 3.34-3.53 (m, 3H), 2.83-3.07 (m, 2H), 2.72 (br d, J=16.4 Hz, 1H), 2.34-2.46 (m, 1H), 2.222 .34 (m, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.30-1.37 (m, 2H), 1.21-1.30 (m, 2H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.03 (t, J=8.7 Hz, 1H), 7.10-7.25 (m, 3H), 7.07 (br d, J=7.6Hz, 1H), 6.94-6.98(m, 1H), 6.78(s, 1H), 6.53-6.61(m, 2H), 4.96(q , J=6.8 Hz, 1H), 4.51-4.59 (m, 1H), 3.55-3.70 (m, 3H), 3.34-3.53 (m, 2H), 3, 22-3.30 (m, 1H), 2.83-3.07 (m, 3H), 2.34-2.46 (m, 1H), 2.22-2.34 (m, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.21-1.30 (m, 2H).

Connection 2.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 16.31 (br s, 1H), 8.02 (t, J=8.8 Hz, 1H), 7.32 (br d, J=7, 1 Hz, 1H), 7.06-7.26 (m, 3H), 6.92-6.97 (m, 1H), 6.81 (s, 1H), 6.58 (br d, J= 9.1 Hz, 1H), 6.51 (dd, J=14.7, 1.5 Hz, 1H), 5.58 (q, J=6.7 Hz, 1H), 3.97 (quin, J=7.2Hz, 1H), 3.77-3.87(m, 2H), 3.60(dd, J=9.9, 6.8Hz, 1H), 3.42-3.54(m , 3H), 2.85-3.06 (m, 2H), 2.71 (br d, J=16.2 Hz, 1H), 2.44-2.57 (m, 1H, partially covered by DMSO peak ), 2.25-2.35 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.38 (m, 2H), 1.22-1, 29(m, 2H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 16.31 (br s, 1H), 8.02 (t, J=8.8 Hz, 1H), 7.06-7.26 (m, 4H ), 6.926.97 (m, 1H), 6.77 (s, 1H), 6.58 (br d, J=9.1 Hz, 1H), 6.51 (dd, J=14.7, 1 .5 Hz, 1H), 4.96 (q, J=6.6 Hz, 1H), 4.55 (br d, J=12.1 Hz, 1H), 3.97 (quin, J=7, 2 Hz, 1H), 3.77-3.87 (m, 1H), 3.60 (dd, J=9.9, 6.8 Hz, 1H), 3.42-3.54 (m, 3h ), 2.85-3.06 (m, 3h), 2.44-2.57 (m, 1H, partially covered by DMSO peak), 2.25-2.35 (m, 1H), 1.55 ( d, J=7.1 Hz, 3H), 1.30-1.38 (m, 2H), 1.22-1.29 (m, 2H).

Connection 3.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 16.34 (br s, 1H), 8.03 (t, J=8.6 Hz, 1H), 7.32 (d, J=7, 1 Hz, 1H), 7.05-7.26 (m, 3H), 6.91-6.97 (m, 1H), 6.81 (s, 1H), 6.58 (br d, J= 8.6 Hz, 1H), 6.51 (dd, J=14.7, 2.0 Hz, 1H), 5.58 (q, J=6.9 Hz, 1H), 3.98 (quin, J=7.2Hz, 1H), 3.77-3.88(m, 2H), 3.60(dd, J=9.6, 6.6Hz, 1H), 3.41-3.55 (m, 3H), 2.85-3.07 (m, 2H), 2.71 (br d, J=15.7 Hz, 1H), 2.39-2.50 (m, 1H, peaked solvent), 2.23-2.36 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.38 (m, 2H), 1.20-1 .29 (m, 2H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 16.34 (br s, 1H), 8.03 (t, J=8.6 Hz, 1H), 7.05-7.26 (m, 4H ), 6.916.97 (m, 1H), 6.77 (s, 1H), 6.58 (br d, J=8.6 Hz, 1H), 6.51 (dd, J=14.7, 2 .0 Hz, 1H), 4.96 (q, J=6.9 Hz, 1H), 4.504.59 (m, 1H), 3.98 (quin, J=7.2 Hz, 1H), 3, 77-3.88 (m, 1H), 3.60 (dd, J=9.6, 6.6 Hz, 1H), 3.41-3.55 (m, 2H), 3.21-3, 28 (m, 1H), 2.85-3.07 (m, 3H), 2.39-2.50 (m, 1H, solvent peaked), 2.23-2.36 (m, 1H), 1.55 (d, J=7.1 Hz, 3H), 1.30-1.38 (m, 2H), 1.20-1.29 (m, 2H).

Connection 4.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.43 (br s, 1H), 8.03 (t, J=8.8 Hz, 1H), 7.32 (d, J=7, 6 Hz, 1H), 7.06-7.25 (m, 3H), 6.92-6.98 (m, 1H), 6.81 (s, 1H), 6.56 (br d, J= 8.8 Hz, 1H), 6.48 (br dd, J=14.5, 1.6 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.81 (br dd, J=13.7, 3.6 Hz, 1H), 3.64-3.71 (m, 1H), 3.60 (quin, J=7.1 Hz, 1H), 3.38-3 .56 (m, 4H), 2.83-3.06 (m, 2H), 2.62-2.74 (m, 1H), 2.34-2.44 (m, 1H), 2.19 -2.27(m, 1H), 1.52(d, J=6.6Hz, 3H), 1.30-1.37(m, 2H), 1.21-1.30(m, 2H ).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 12.43 (br s, 1H), 8.03 (t, J=8.8 Hz, 1H), 7.06-7.25 (m, 3H ), 6.926.98 (m, 1H), 6.78 (s, 1H), 6.75 (d, J=8.5 Hz, 1H), 6.56 (br d, J=8.8 Hz, 1H), 6.48 (br dd, J=14.5, 1.6 Hz, 1H), 4.96 (q, J=6.6 Hz, 1H), 4.52-4.58 (m, 1H), 3.64-3.71 (m, 1H), 3.60 (quin, J=7.1 Hz, 1H), 3.38-3.56 (m, 3H), 3.23-3 .29 (m, 1H), 2.83-3.06 (m, 3H), 2.34-2.44 (m, 1H), 2.19-2.27 (m, 1H), 1.56 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.21-1.30 (m, 2H).

Compound 5.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.31 (d, J=7, 1 Hz, 1H), 7.05- 7.26 (m, 3H), 6.90-6.96 (m, 1H), 6.81 (s, 1H), 6.53 (dd, J=8.6, 1.5 Hz, 1H) , 6.45 (dd, J=13.9, 1.5 Hz, 1H), 5.58 (q, J=6.7 Hz, 1H), 4.61 (d, J=6.1 Hz, 2H), 4.54 (d, J=6.1 Hz, 2H), 3.81 (br dd, J=14.2, 4.04 Hz, 1H), 3.59 (s, 2H), 3 .41-3.50 (m, 1H), 3.29-3.37 (m, 2H, partially covered by the H ₂ O peak), 2.85-3.06 (m, 2H), 2.71 (br d, J=16.7 Hz, 1H),

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2.29 (t, J=6.8 Hz, 2H), 1.51 (d, J=7.1 Hz, 3H), 1.29-1.38 (m, 2H), 1.21-1 .29 (m, 2H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.05-7.26 (m, 4H), 6.90-6.96 ( m, 1H), 6.77 (s, 1H), 6.53 (dd, J=8.6, 1.5 Hz, 1H), 6.45 (dd, J=13.9, 1.5 Hz , 1H), 4.93 (q, J=6.1 Hz, 1H), 4.61 (d, J=6.1 Hz, 2H), 4.54 (d, J=6.1 Hz, 2H ), 4.50-4.58 (m, 1H), 3.59 (s, 2H), 3.29-3.37 (m, 2H, partially covered by H ₂ O peak), 3.21-3, 29 (m, 1H), 2.85-3.06 (m, 3H), 2.29 (t, J=6.8 Hz, 2H), 1.54 (d, J=7.1 Hz, 3H ), 1.29-1.38 (m, 2H), 1.21-1.29 (m, 2H).

Compound 6.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (t, J=8.8 Hz, 1H), 7.32 (d, J=7.1 Hz, 1H), 7.06-7, 25 (m, 3H), 6.92-6.96 (m, 1H), 6.81 (s, 1H), 6.52 (dd, J=8.6, 2.0 Hz, 1H), 6 .46 (dd, J=14.7, 1.5Hz, 1H), 5.58 (q, J=6.4Hz, 1H), 4.26 (q, J=13.1Hz, 4H) , 3.77-3.84 (m, 1H), 3.60 (s, 2H), 3.38-3.50 (m, 3H), 2.84-3.05 (m, 2H), 2 .71 (br d, J=16.2 Hz, 1H), 2.28-2.33 (m, 2H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1 .37 (m, 2H), 1.29-1.21 (m, 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.02 (t, J=8.8 Hz, 1H), 7.06-7.25 (m, 4H), 6.92-6.96 ( m, 1H), 6.77 (s, 1H), 6.52 (dd, J=8.6, 2.0 Hz, 1H), 6.45 (dd, J=14.7, 1.5 Hz , 1H), 4.95 (q, J=7.1 Hz, 1H), 4.52-4.58 (m, 1H), 4.26 (q, J=13.1 Hz, 4H), 3 .60 (s, 2H), 3.38-3.50 (m, 2H), 3.22-3.30 (m, 1H), 2.84-3.05 (m, 3H), 2.28 -2.33 (m, 2H), 1.54 (d, J=7.1 Hz, 3H), 1.30-1.37 (m, 2H), 1.29-1.21 (m, 2H ).

Connection 7.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.19 (br d, J=6.6 Hz, 1H), 8.01 (t, J=8.8 Hz, 1H), 7.32 (br d, J=7.6 Hz, 1H), 7.05-7.25 (m, 3H), 6.91-6.96 (m, 1H), 6.80 (s, 1H), 6.52 (br d, J=9.1 Hz, 1H), 6.46 (br d, J=14.7 Hz, 1H), 5.58 (q, J=7.1 Hz, 1H), 4.34 -4.42 (m, 1H), 3.77-3.85 (m, 1H), 3.55 (br dd, J=10.1, 6.1 Hz, 1H), 3.34-3, 50 (m, 3H), 3.14 (br dd, J=10.1, 3.5 Hz, 1H), 2.85-3.06 (m, 2H), 2.71 (br d, J= 16.7 Hz, 1H), 2.13-2.24 (m, 1H), 1.86-1.96 (m, 1H), 1.82 (s, 3H), 1.52 (d, J = 6.6 Hz, 3H), 1.30-1.38 (m, 2H), 1.19-1.30 (m, 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.19 (br d, J=6.6 Hz, 1H), 8.01 (t, J=8.8 Hz, 1H), 7.05- 7.25 (m, 4H), 6.91-6.96 (m, 1H), 6.77 (s, 1H), 6.52 (br d, J=9.1 Hz, 1H), 6, 46 (br d, J=14.7 Hz, 1H), 4.96 (q, J=6.6 Hz, 1H), 4.51-4.59 (m, 1H), 4.34-4, 42 (m, 1H), 3.55 (br dd, J=10.1, 6.1 Hz, 1H), 3.34-3.50 (m, 2H), 3.21-3.30 (m , 1H), 3.14 (br dd, J=10.1, 3.5 Hz, 1H), 2.85-3.06 (m, 3H), 2.13-2.24 (m, 1H) , 1.86-1.96 (m, 1H), 1.83 (s, 3H), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.38 (m, 2H ), 1.19-1.30 (m, 2H).

Connection 8.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.19 (d, J=6.9 Hz, 1H), 8.01 (t, J=8.8 Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 7.21-7.25(m, 1H), 7.10-7.21(m, 2H), 6.94(d, J=3.5Hz, 1H ), 6.81 (s, 1H), 6.53 (br d, J=8.8 Hz, 1H), 6.46 (dd, J=14.5, 1.9 Hz, 1H), 5, 59 (q, J=6.8 Hz, 1H), 4.35-4.42 (m, 1H), 3.81 (br dd, J=13.7, 3.6 Hz, 1H), 3.56 ( dd, J=9.9, 6.5 Hz, 1H), 3.33-3.50 (m, 3H), 3.14 (dd, J=10.1, 4.1 Hz, 1H), 2 .85-3.05 (m, 2H), 2.72 (br d, J=16.1 Hz, 1H), 2.15-2.23 (m, 1H), 1.88-1.95 ( m, 1H), 1.82 (s, 3H), 1.52 (d, J=6.9 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1.30 (m , 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.19 (d, J=6.9 Hz, 1H), 8.01 (t, J=8.8 Hz, 1H), 7.10-7 .21 (m, 3H), 7.06-7.09 (m, 1H), 6.93 (d, J=3.5 Hz, 1H), 6.77 (s, 1H), 6.53 ( br d, J=8.8 Hz, 1H), 6.46 (dd, J=14.5, 1.9 Hz, 1H), 4.96 (q, J=6.5 Hz, 1H), 4 .52-4.58 (m, 1H), 4.35-4.42 (m, 1H), 3.56 (dd, J=9.9, 6.5 Hz, 1H), 3.33-3 .50 (m, 2H), 3.23-3.30 (m, 1H), 3.14 (dd, J=10.1, 4.1 Hz, 1H), 2.85-3.05 (m , 3H), 2.15-2.23 (m, 1H), 1.88-1.95 (m, 1H), 1.82 (s, 3H), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1.30 (m, 2H).

Connection 9.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (t, J=9.1 Hz, 1H), 7.55 (br d, J=6.1 Hz, 1H), 7.32 (br d, J=7.6 Hz, 1H), 7.05-7.25 (m, 3H), 6.90-6.96 (m, 1H), 6.80 (s, 1H), 6.51 (br d, J=8.6 Hz, 1H), 6.44 (br d, J=14.7 Hz, 1H), 5.58 (q, J=6.9 Hz, 1H), 4.16 -4.25 (m, 1H), 3.81 (br dd, J=12.9, 2.8 Hz, 1H), 3.51-3.60 (m, 1H), 3.55 (s, 3H), 3.34-3.51 (m, 3H), 3.16 (br dd, J=9.6, 4.6 Hz, 1H), 2.85-3.06 (m, 2H), 2.71 (br d, J=16.2 Hz, 1H), 2.14-2.25 (m, 1H), 1.87-2.02 (m, 1H), 1.50 (d, J = 7.1 Hz, 3H), 1.30-1.38 (m, 2H), 1.20-1.29 (m, 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (t, J=9.1 Hz, 1H), 7.55 (br d, J=6.1 Hz, 1H), 7.05-7 .25 (m, 4H), 6.90-6.96 (m, 1H), 6.77 (s, 1H), 6.51 (br d, J=8.6 Hz, 1H), 6.44 (br d, J=14.7 Hz, 1H), 4.96 (q, J=6.6 Hz, 1H), 4.55 (br d, J=12.6 Hz, 1H), 4.16 -4.25(m, 1H), 3.55(s, 3H), 3.34-3.51(m, 3H), 3.21-3.29(m, 1H), 3.16(br dd, J=9.6, 4.6 Hz, 1H), 2.85-3.06 (m, 3H), 2.14-2.25 (m, 1H), 1.87-2.02 ( m, 1H), 1.55 (d, J=7.1 Hz, 3H), 1.30-1.38 (m, 2H), 1.20-1.29 (m, 2H).

Compound 10.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.55 (br d, J=6.1 Hz, 1H), 7.32 ( br d,

- 118 040266

J=7.6 Hz, 1H), 7.05-7.26(m, 3H), 6.91-6.95(m, 1H), 6.80(s, 1H), 6.51(br d, J=9.1 Hz, 1H), 6.45 (dd, J=14.7,

1.5 Hz, 1H), 5.58 (q, J=6.6 Hz, 1H), 4.16-4.25 (m, 1H), 3.81 (br dd, J=12.9, 3.8 Hz, 1H), 3.52-3.59 (m, 4H),

3.39-3.51 (m, 3H), 3.13-3.20 (m, 1H), 2.82-3.06 (m, 2H), 2.71 (br d, J=17, 2 Hz, 1H), 2.13-2.24 (m, 1H), 1.881.99 (m, 1H), 1.52 (d, J=7.1 Hz, 3H), 1.29-1, 37 (m, 2H), 1.20-1.29 (m, 2H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.55 (br d, J=6.1 Hz, 1H), 7.05- 7.26 (m, 4H), 6.91-6.95 (m, 1H), 6.77 (s, 1H), 6.51 (br d, J=9.1 Hz, 1H), 6, 45 (dd, J=14.7, 1.5 Hz, 1H), 4.96 (q, J=7.1 Hz, 1H), 4.51-4.58 (m, 1H), 4.16 -4.25(m, 1H), 3.52-3.59(m, 3H), 3.39-3.51(m, 2H), 3.21-3.29(m, 1H), 3 .13-3.20 (m, 1H), 2.82-3.06 (m, 3H), 2.67-2.76 (m, 1H), 2.13-2.24 (m, 1H) , 1.88-1.99 (m, 1H), 1.53 (d, J=7.1 Hz, 3H), 1.291.37 (m, 2H), 1.20-1.29 (m, 2H ).

Compound 11.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.6 Hz, 1H), 7.48 (br d, J=7.1 Hz, 1H), 7.29- 7.35 (m, 1H), 7.05-7.25 (m, 3H), 6.94 (br s, 1H), 6.80 (br s, 1H), 6.53 (br d, J =9.1 Hz, 1H), 6.47 (br d, J=14.2 Hz, 1H), 5.545.62 (m, 1H), 4.03-4.13 (m, 1H), 3, 76-3.85 (m, 1H), 3.59-3.67 (m, 1H), 3.39-3.52 (m, 2H), 3.32-3.37 (m, 1H, partially overlapped with H ₂ O), 3.17-3.24 (m, 1H), 3.00 (s, 3H), 2.82-2.98 (m, 2H), 2.65-2.76 (m , 1H), 2.23-2.32 (m, 1H), 1.93-2.04 (m, 1H), 1.47-1.54 (m, 3H), 1.30-1.40 (m, 2H), 1.20-1.30 (m, 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.6 Hz, 1H), 7.48 (br d, J=7.1 Hz, 1H), 7.05-7 .25 (m, 4H), 6.94 (br s, 1H), 6.77 (br s, 1H), 6.53 (br d, J=9.1 Hz, 1H), 6.47 (br d, J=14.2 Hz, 1H), 4.91-5.00 (m, 1H), 4.514.58 (m, 1H), 4.03-4.13 (m, 1H), 3.59 -3.67(m, 1H), 3.39-3.52(m, 2H), 3.24-3.28(m, 1H), 3.17-3.24(m, 1H), 3 .00 (s, 3H), 2.82-2.98 (m, 3H), 2.23-2.32 (m, 1H), 1.93-2.04 (m, 1H), 1.58 -1.53 (m, 3H), 1.30-1.40 (m, 2H), 1.20-1.30 (m, 2H).

Compound 12.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.01 (t, J=8.7 Hz, 1H), 7.49 (d, J=6.6 Hz, 1H), 7.32 (d , J=7.3 Hz, 1H), 7.06-7.25(m, 3H), 6.91-6.96(m, 1H), 6.81(s, 1H), 6.53( br d, J=8.8 Hz, 1H), 6.47 (br d, J=14.8 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 4.05- 4.13 (m, 1H), 3.81 (br dd, J=12.5, 3.3 Hz, 1H), 3.63 (br dd, J=9.8, 6.6 Hz, 1H) , 3.41-3.50 (m, 2H), 3.33-3.36 (m, 1H), 3.21 (dd, J=9.9, 5.5 Hz, 1H), 3.01 (s, 3H), 2.83-2.98 (m, 2H), 2.72 (br d, J=16.4 Hz, 1H), 2.23-2.33 (m, 1H), 1 .93-2.03 (m, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.30-1.38 (m, 2H), 1.21-1.30 (m , 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.01 (t, J=8.7 Hz, 1H), 7.49 (d, J=6.6 Hz, 1H), 7.06-7, 25 (m, 4H), 6.91-6.96 (m, 1H), 6.77 (s, 1H), 6.53 (br d, J=8.8 Hz, 1H), 6.47 ( br d, J=14.8 Hz, 1H), 4.96 (q, J=6.7 Hz, 1H), 4.52-4.59 (m, 1H), 4.05-4.13 ( m, 1H), 3.63 (br dd, J=9.8, 6.6 Hz, 1H), 3.41-3.50 (m, 2H), 3.24-3.30 (m, 1H ), 3.21 (dd, J=9.9, 5.5 Hz, 1H), 3.02-3.06 (m, 1H), 3.01 (s, 3H), 2.83-2, 98 (m, 2H), 2.23-2.33 (m, 1H), 1.93-2.03 (m, 1H), 1.55 (d, J=6.6 Hz, 3H), 1 .30-1.38 (m, 2H), 1.21-1.30 (m, 2H).

Compound 13.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.06-7 .25 (m, 3H), 6.91-6.95 (m, 1H), 6.80 (s, 1H), 6.51 (dd, J=8.7, 1.7 Hz, 1H), 6.43 (dd, J=14.8, 1.6Hz, 1H), 5.59 (q, J=6.4Hz, 1H), 5.01 (d, J=3.8Hz, 1H ), 4.43 (br s, 1H), 3.82 (br dd, J=13.7, 4.3 Hz, 1H), 3.33-3.50 (m, 4H), 3.16 ( br d, J=10.4 Hz, 1H), 2.82-3.05 (m, 2H), 2.72 (br d, J=16.1 Hz, 1H), 2.02-2.11 (m, 1H), 1.89-1.96 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1, 22-1.29 (m, 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.06-7.25 (m, 4H), 6.91-6.95 ( m, 1H), 6.76 (s, 1H), 6.51 (dd, J=8.7, 1.7 Hz, 1H), 6.43 (dd, J=14.8, 1.6 Hz , 1H), 5.01 (d, J=3.8 Hz, 1H), 4.97 (q, J=6.6 Hz, 1H), 4.52-4.58 (m, 1H), 4 .43 (br s, 1H), 3.60 (dt, J=12.1, 6.1 Hz, 1H), 3.33-3.50 (m, 2H), 3.23-3.28 ( m, 1H), 3.16 (br d, J=10.4 Hz, 1H), 2.82-3.05 (m, 3H), 2.02-2.11 (m, 1H), 1, 89-1.96 (m, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1.29 (m, 2H).

Connection 14.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.32 (br d, J=7.1 Hz, 1H), 7.05-7 .25 (m, 3H), 6.90-6.94 (m, 1H), 6.80 (s, 1H), 6.51 (dd, J=8.8, 1.8 Hz, 1H), 6.43 (dd, J=14.4, 1.3Hz, 1H), 5.58 (q, J=6.6Hz, 1H), 5.02 (d, J=3.5Hz, 1H ), 4.42 (br s, 1H), 3.77-3.85 (m, 1H), 3.34-3.51 (m, 4H), 3.16 (br d, J=10.1 Hz, 1H), 2.85-3.07 (m, 2H), 2.71 (br d, J=16.2 Hz, 1H), 2.00-2.12 (m, 1H), 1, 88-1.97 (m, 1H), 1.52 (d, J=7.1 Hz, 3H), 1.21-1.37 (m, 4H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.05-7.25 (m, 4H), 6.90-6.94 ( m, 1H), 6.76 (s, 1H), 6.51 (dd, J=8.8, 1.8 Hz, 1H), 6.43 (dd, J=14.4, 1.3 Hz , 1H), 5.02 (d, J=3.5 Hz, 1H), 4.96 (q, J=6.6 Hz, 1H), 4.51-4.59 (m, 1H), 4 .42 (br s, 1H), 3.34-3.51 (m, 3H), 3.22-3.29 (m, 1H), 3.16 (br d, J=10.1 Hz, 1H ), 2.85- 119 040266

3.07 (m, 3H), 2.00-2.12 (m, 1H), 1.88-1.97 (m, 1H), 1.55 (br d, J=7.1 Hz, 3H ), 1.21-1.37 (m, 4H).

Compound 15.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (br t, J=8.8 Hz, 1H), 7.32 (br d, J=8.1 Hz, 1H), 7.05 -7.25 (m, 3H), 6.91-6.96 (m, 1H), 6.81 (s, 1H), 6.54 (br d, J=8.6 Hz, 1H), 6 .49 (br d, J=15.2 Hz, 1H), 5.54-5.62 (m, 1H), 5.27 (br s, 1H), 3.81 (br d, J=14, 2 Hz, 1H), 3.60 (br dd, J=10.9, 4.3 Hz, 1H), 3.30-3.51 (m, 5H, partially covered by H ₂ O peak), 2.85 -3.07 (m, 2H), 2.64-2.75 (m, 1H), 2.55-2.62 (m, 3H), 2.19-2.29 (m, 1H), 2 .04-2.14 (m, 1H), 1.52 (br d, J=7.1 Hz, 3H), 1.30-1.38 (m, 2H), 1.21-1.29 ( m, 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (br t, J=8.8 Hz, 1H), 7.05-7.25 (m, 4H), 6.91-6.96 ( m, 1H), 6.77 (s, 1H), 6.54 (br d, J=8.6 Hz, 1H), 6.49 (br d, J=15.2 Hz, 1H), 5, 27 (br s, 1H), 4.92-5.00 (m, 1H), 4.51-4.59 (m, 1H), 3.60 (br dd, J=10.9, 4.3 Hz, 1H), 3.30-3.51 (m, 3H partially covered by H ₂ O peak), 3.21-3.28 (m, 1H), 2.85-3.07 (m, 3H), 2.64-2.75(m, 1H), 2.55-2.62(m, 3H), 2.19-2.29(m, 1H), 2.04-2.14(m, 1H ), 1.54 (br d, J=7.6 Hz, 3H), 1.30-1.38 (m, 2H), 1.21-1.29 (m, 2H).

Compound 16.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.01 (t, J=8.8 Hz, 1H), 7.32 (br d, J=7.6 Hz, 1H), 7.05- 7.25 (m, 4H), 6.91-6.95 (m, 1H), 6.81 (s, 1H), 6.55 (br d, J=9.6 Hz, 1H), 6, 48 (br d, J=14.7 Hz, 1H), 5.58 (q, J=6.7 Hz, 1H), 5.27 (br s, 1H), 3.81 (br dd, J= 14.2, 3.5 Hz, 1H), 3.61 (br dd, J=11.1, 4.6 Hz, 1H), 3.34-3.51 (m, 4H), 2.85- 3.07 (m, 2H), 2.71 (br d, J=16.7 Hz, 1H), 2.54-2.59 (m, 3H), 2.19-2.30 (m, 1H ), 2.08-2.13 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.29-1.38 (m, 2H), 1.20-1, 29(m, 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (t, J=8.8 Hz, 1H), 7.05-7.25 (m, 5H), 6.91-6.95 (m , 1H), 6.77 (s, 1H), 6.55 (br d, J=9.6 Hz, 1H), 6.48 (br d, J=14.7 Hz, 1H), 5.27 (br s, 1H), 4.91-5.00 (m, 1H), 4.51-4.59 (m, 1H), 3.61 (br dd, J=11.1, 4.6 Hz , 1H), 3.34-3.51 (m, 2H), 3.21-3.29 (m, 1H), 2.85-3.07 (m, 3H), 2.64-2.76 (m, 1H), 2.54-2.59 (m, 3H), 2.19-2.30 (m, 1H), 2.08-2.13 (m, 1H), 1.54 (d , J=7.1 Hz, 3H), 1.29-1.38 (m, 2H), 1.201.29 (m, 2H).

Compound 17.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.02 (t, J=8.3 Hz, 1H), 7.32 (d, J=6.1 Hz, 1H), 7.05-7 .25 (m, 3H), 6.93-6.97 (m, 1H), 6.81 (s, 1H), 6.54-6.64 (m, 2H), 5.58 (q, J =7.1 Hz, 1H), 4.10-4.18 (m, 1H), 3.78-3.85 (m, 1H), 3.70 (d, J=7.1 Hz, 2H) , 3.36-3.56 (m, 3H), 3.09 (s, 3H), 2.82-3.06 (m, 2H), 2.68-2.76 (m, 1H), 2 .39-2.46 (m, 2H), 1.52 (br d, J=6.6 Hz, 3H), 1.20-1.38 (m, 4H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (t, J=8.3 Hz, 1H), 7.05-7.25 (m, 4H), 6.93-6.97 (m , 1H), 6.78 (s, 1H), 6.54-6.64 (m, 2H), 4.96 (q, J=6.9 Hz, 1H), 4.51-4.59 ( m, 1H), 4.10-4.18 (m, 1H), 3.70 (d, J=7.1 Hz, 2H), 3.36-3.56 (m, 2H), 3.21 -3.28 (m, 1H), 3.09 (s, 3H), 2.82-3.06 (m, 3H), 2.39-2.46 (m, 2H), 1.55 (br d, J=7.1 Hz, 3H), 1.20-1.38 (m, 4H).

Compound 18.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.02 (t, J=8.6 Hz, 1H), 7.32 (br d, J=7.1 Hz, 1H), 7.05- 7.25 (m, 3H), 6.93-6.98 (m, 1H), 6.82 (s, 1H), 6.54-6.64 (m, 2H), 5.58 (q, J=7.1 Hz, 1H), 4.14 (quin, J=6.7 Hz, 1H), 3.81 (br dd, J=13.6, 4.6 Hz, 1H), 3.70 (d, J=7.1 Hz, 2H), 3.32-3.65 (m, 3H), 3.09 (s, 3H), 2.85-3.06 (m, 2H), 2, 71 (br d, J=16.2 Hz, 1H), 2.38-2.46 (m, 2H), 1.52 (d, J=7.1 Hz, 3H), 1.30-1, 39 (m, 2H), 1.21-1.30 (m, 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.02 (t, J=8.6 Hz, 1H), 7.05-7.25 (m, 4H), 6.93-6.98 ( m, 1H), 6.78 (s, 1H), 6.54-6.64 (m, 2H), 4.96 (q, J=6.1 Hz, 1H), 4.51-4.59 (m, 1H), 4.14 (quin, J=6.7 Hz, 1H), 3.70 (d, J=7.1 Hz, 2H), 3.32-3.65 (m, 2H) , 3.22-3.31 (m, 1H), 3.09 (s, 3H), 2.85-3.06 (m, 3H), 2.38-2.46 (m, 2H), 1 .55 (d, J=6.6 Hz, 3H), 1.30-1.39 (m, 2H), 1.21-1.30 (m, 2H).

Compound 19.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (t, J=8.8 Hz, 1H), 7.32 (d, J=7.1 Hz, 1H), 7.04-7, 26 (m, 5H), 6.93-6.97 (m, 1H), 6.81 (s, 1H), 6.57 (dd, J=9.1, 2.0 Hz, 1H), 6 .51 (dd, J=14.2, 2.0 Hz, 1H), 5.58 (q, J=7.1 Hz, 1H), 3.89-3.97 (m, 1H), 3, 77-3.85 (m, 1H), 3.61-3.73 (m, 2H), 3.37-3.54 (m, 3H), 2.85-3.06 (m, 2H), 2.71 (br d, J=16.7 Hz, 1H), 2.35-2.43 (m, 2H), 1.52 (d, J=6.6 Hz, 3H), 1.30- 1.38 (m, 2H), 1.22-1.29 (m, 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.03 (t, J=8.8 Hz, 1H), 7.04-7.26 (m, 6H), 6.93-6.97 ( m, 1H), 6.78 (s, 1H), 6.57 (dd, J=9.1, 2.0 Hz, 1H), 6.51 (dd, J=14.2, 2.0 Hz , 1H), 4.97 (q, J=7.1 Hz, 1H), 4.51-4.58 (m, 1H), 3.89-3.97 (m, 1H), 3.61- 3.73 (m, 2H), 3.37-3.54 (m, 2H), 3.22-3.29 (m, 1H), 2.85-3.06 (m, 3H), 2. 35-2.43 (m, 2H), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.38 (m, 2H), 1.22-1.29 (m, 2H).

Compound 20.

- 120 040266

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.78 (br s, 1H), 7.96 (t, J=8.8 Hz, 1H), 7.25 (d, J=7, 6 Hz, 1H), 6.99-7.20 (m, 3H), 6.86-6.91 (m, 1H), 6.75 (s, 1H), 6.45-6.55 (m , 2H), 5.52 (q, J=6.9 Hz, 1H), 4.30-4.38 (m, 1H), 3.72-3.78 (m, 1H), 3.58- 3.71 (m, 2H), 3.33-3.46 (m, 3H), 2.78-3.01 (m, 2H), 2.65 (br d, J=16.2 Hz, 1H ), 2.29-2.39 (m, 2H, partially covered by the H ₂ O peak), 1.97 (s, 3H), 1.45 (d, J=6.6 Hz, sH), 1.23 -1.32 (m, 2H), 1.16-1.23 (m, 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d6) δ ppm 11.78 (br s, 1H), 7.96 (t, J=8.8 Hz, 1H), 6.99-7.20 (m, 4H) , 6.866.91 (m, 1H), 6.71 (s, 1H), 6.45-6.55 (m, 2H), 4.89 (q, J=7.1 Hz, 1H), 4, 45-4.52 (m, 1H), 4.30-4.38 (m, 1H), 3.58-3.71 (m, 2H), 3.33-3.46 (m, 2H), 3.15-3.22 (m, 1H), 2.78-3.01 (m, 3H), 2.29-2.39 (m, 2H, partially covered by H ₂ O peak), 1.97 ( s, 3H), 1.48 (d, J=7.1 Hz, 3H), 1.23-1.32 (m, 2H), 1.16-1.23 (m, 2H).

Compound 21.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.02 (t, J=8.8 Hz, 1H), 7.32 (br d, J=7.6 Hz, 1H), 7.06 -7.26 (m, 4H), 6.93-6.97 (m, 1H), 6.81 (s, 1H), 6.58 (br d, J=8.65 Hz, 1H), 6 .53 (br d, J=14.7 Hz, 1H), 5.58 (q, J=7.1 Hz, 1H), 4.08-4.16 (m, 1H), 3.81 (br dd, J=13.9, 3.8 Hz, 1H), 3.34-3.73 (m, 5H), 2.85-3.07 (m, 2H), 2.71 (br d, J =16.7 Hz, 1H), 2.64 (d, J=5.1 Hz, 3H), 2.32-2.41 (m, 2H), 1.52 (d, J=6.6 Hz , 3H), 1.21-1.38 (m, 4H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (t, J=8.8 Hz, 1H), 7.06-7.26 (m, 5H), 6.93-6.97 ( m, 1H), 6.78 (s, 1H), 6.58 (br d, J=8.6 Hz, 1H), 6.53 (br d, J=14.7 Hz, 1H), 4, 96 (q, J=6.1 Hz, 1H), 4.51-4.59 (m, 1H), 4.084.16 (m, 1H), 3.34-3.73 (m, 4H), 3 .21-3.31 (m, 1H), 2.85-3.07 (m, 3H), 2.64 (d, J=5.1 Hz, 3H), 2.32-2.41 (m , 2H), 1.55 (br d, J=7.1 Hz, 3H), 1.21-1.38 (m, 4H).

Compound 22.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (br t, J=8.6 Hz, 1H), 7.32 (br d, J=1, 1 Hz, 1H), 7.05 -7.26 (m, 3H), 6.92-6.98 (m, 1H), 6.81 (s, 1H), 6.52-6.64 (m, 2H), 5.58 (q , J=6.2 Hz, 1H), 4.23 (quin, J=7.3 Hz, 1H), 3.773.86 (m, 1H), 3.71 (br t, J=9.4 Hz, 1H), 3.32-3.60 (m, 5H), 2.90-3.07 (m, 1H), 2.87 (s, 6H), 2.68-2.76 (m, 1H) , 2.24-2.45 (m, 2H, partially covered by DMSO peak), 1.52 (br d, J=6.6 Hz, 3H), 1.21-1.38 (m, 4H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.02 (br t, J=8.6 Hz, 1H), 7.05-7.26 (m, 4H), 6.92-6, 98 (m, 1H), 6.78 (s, 1H), 6.52-6.64 (m, 2H), 4.96 (q, J=6.6 Hz, 1H), 4.55 (br d, J=10.1 Hz, 1H), 4.23 (quin, J=7.3 Hz, 1H), 3.71 (br t, J=9.4 Hz, 1H), 3.32-3 .60 (m, 4H), 3.20-3.29 (m, 1H), 2.90-3.07 (m, 2H), 2.87 (s, 6H), 2.24-2.45 (m, 2H, partially covered by DmSo peak), 1.55 (br d, J=6.6 Hz, 3H), 1.21-1.38 (m, 4H).

Compound 23.

Basic rotamer (70%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (br t, J=8.5 Hz, 1H), 7.37 (br s, 1H), 7.32 (br d, J=7 .3 Hz, 1H), 7.06-7.25 (m, 3H), 6.75-6.95 (m, 3H), 6.48 (d, J=8.5 Hz, 1H), 6 .39 (d, J=14.5 Hz, 1H), 5.59 (q, J=6.0 Hz, 1H), 3.81 (br dd, J=12.8, 3.0 Hz, 1H ), 3.22-3.50 (m, 3H), 3.12 (br d, J=9.8 Hz, 1H), 2.83-3.06 (m, 2H), 2.67-2 .75 (m, 2H), 2.18-2.27 (m, 2H), 1.95-2.03 (m, 1H), 1.77-1.85 (m, 1H), 1.52 (br d, J=6.6 Hz, 3H), 1.21-1.37 (m, 4H), 1.14 (s, 3H).

Minor rotamer (30%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (br t, J=8.5 Hz, 1H), 7.37 (br s, 1H), 7.06-7.25 (m, 4H), 6.756.95 (m, 3H), 6.48 (br d, J=8.5 Hz, 1H), 6.39 (br d, J=14.5 Hz, 1H), 4.96 ( q, J=6.6 Hz, 1H), 4.55 (br d, J=10.7 Hz, 1H), 3.22-3.50 (m, 3H), 3.12 (br d, J =9.8 Hz, 1H), 2.83-3.06 (m, 2H), 2.67-2.75 (m, 2H), 2.18-2.27 (m, 2H), 1, 95-2.03 (m, 1H), 1.77-1.85 (m, 1H), 1.55 (br d, J=6.6 Hz, 3H), 1.21-1.37 (m , 4H), 1.14 (s, 3H).

Compound 24.

Basic rotamer (70%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (br t, J=8.7 Hz, 1H), 7.29-7.40 (m, 2H), 7.06-7, 25 (m, 3H), 6.90-6.95 (m, 1H), 6.74-6.87 (m, 2H), 6.48 (d, J=8.5 Hz, 1H), 6 .39 (d, J=14.5 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.81 (br dd, J=13.1, 3.9 Hz, 1H ), 3.21-3.52 (m, 4H), 3.12 (br d, J=9.5 Hz, 1H), 2.82-3.06 (m, 2H), 2.67-2 .76 (m, 1H), 2.17-2.29 (m, 2H), 1.95-2.05 (m, 1H), 1.77-1.85 (m, 1H), 1.52 (br d, J=6.6 Hz, 3H), 1.20-1.40 (m, 4H), 1.14 (s, 3H).

Minor rotamer (30%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (br t, J=8.7 Hz, 1H), 7.29-7.40 (m, 1H), 7.06-7.25 (m, 4H), 6.90-6.95 (m, 1H), 6.74-6.87 (m, 2H), 6.48 (br d, J=8.5 Hz, 1H), 6 .39 (br d, J=14.5 Hz, 1H), 4.96 (q, J=6.6 Hz, 1H), 4.55 (br d, J=14.2 Hz, 1H), 3 .21-3.52 (m, 4H), 3.12 (br d, J=9.5 Hz, 1H), 2.82-3.06 (m, 3H), 2.17-2.29 ( m, 2H), 1.95-2.05 (m, 1H), 1.77-1.85 (m, 1H), 1.55 (br d, J=6.6 Hz, 3H), 1, 20-1.40 (m, 4H), 1.14 (s, 3H).

Compound 25.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.96-8.03 (m, 1H), 7.34-7.40 (m, 2H), 7.02 (d, J=5, 0 Hz, 1H), 6.916.95 (m, 1H), 6.76-6.86 (m, 2H), 6.48 (d, J=8.5 Hz, 1H), 6.39 (d, J=14.8Hz, 1H), 5.53 (q, J=6.2Hz, 1H), 3.92

- 121 040266 (br dd, J=13.6, 4.7 Hz, 1H), 3.34-3.45 (m, 4H), 3.12 (br d, J=9.8 Hz, 1H) , 2.80-3.01 (m, 2H), 2.75 (br d, J=16.4

Hz, 1H), 2.18-2.27 (m, 2H), 1.96-2.03 (m, 1H), 1.77-1.85 (m, 1H), 1.46 (br d , J=6.6 Hz, 3H), 1.31-1.38 (m, 2H),

1.22-1.29 (m, 2H), 1.14 (s, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.96-8.03 (m, 1H), 7.34-7.40 (m, 1H), 7.29 (d, J=5.4 Hz, 1H), 6.916.95 (m, 1H), 6.76-6.86 (m, 3H), 6.48 (d, J=8.5 Hz, 1H), 6.39 (d, J =14.8 Hz, 1H), 4.90 (q, J=6.9 Hz, 1H), 4.70 (br dd, J=12.3, 4.1 Hz, 1H), 3.34- 3.45 (m, 3H), 3.16-3.25 (m, 1H), 3.12 (br d, J=9.8 Hz, 1H), 2.80-3.01 (m, 3H ), 2.18-2.27 (m, 2H), 1.96-2.03 (m, 1H), 1.77-1.85 (m, 1H), 1.50 (br d, J= 6.6 Hz, 3H), 1.31-1.38 (m, 2H), 1.2-1.29 (m, 2H), 1.14 (s, 3H).

Compound 26.

Basic rotamer (70%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.95-8.03 (m, 1H), 7.34-7.41 (m, 2H), 7.02 (d, J=5.0 Hz, 1H), 6.916.95 (m, 1H), 6.76-6.86 (m, 2H), 6.48 (d, J=8.8 Hz, 1H), 6.39 (d, J =14.2 Hz, 1H), 5.53 (q, J=6.3 Hz, 1H), 3.93 (dd, J=13.2, 4.4 Hz, 1H), 3.29-3 .46 (m, 3H), 3.16-3.26 (m, 1H), 3.12 (br d, J=9.8 Hz, 1H), 2.81-3.00 (m, 2H) , 2.75 (br d, J=15.1 Hz, 1H), 2.18-2.27 (m, 2H), 1.95-2.03 (m, 1H), 1.76-1, 85 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.21-1.39 (m, 4H), 1.14 (s, 3H).

Minor rotamer (30%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.95-8.03 (m, 1H), 7.34-7.41 (m, 1H), 7.29 (d, J=5.0 Hz , 1H), 6.916.95 (m, 1H), 6.76-6.86 (m, 3H), 6.48 (d, J=8.8 Hz, 1H), 6.39 (d, J= 14.2 Hz, 1H), 4.90 (q, J=6.6 Hz, 1H), 4.70 (dd, J=12.6, 4.7 Hz, 1H), 3.29-3, 46 (m, 4H), 3.12 (br d, J=9.8 Hz, 1H), 2.81-3.00 (m, 3H), 2.18-2.27 (m, 2H), 1.95-2.03 (m, 1H), 1.76-1.85 (m, 1H), 1.50 (d, J=6.6 Hz, 3H), 1.21-1.39 ( m, 4H), 1.14 (s, 3H).

Compound 27.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (br t, J=8.8 Hz, 1H), 7.32 (br d, J=7.3 Hz, 1H), 7.06- 7.25 (m, 4H), 6.89-6.95 (m, 2H), 6.80 (s, 1H), 6.50 (br d, J=8.5 Hz, 1H), 6, 42 (br d, J=15.1 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.81 (br dd, J=13.6, 3.5 Hz, 1H ), 3.39-3.50 (m, 2H), 3.21-3.31 (m, 2H), 3.13 (br t, J=9.6 Hz, 1H), 2.83-3 .07 (m, 2H), 2.70 (br d, J=21.1 Hz, 1H), 2.54-2.62 (m, 1H), 1.92-2.00 (m, 1H) , 1.75-1.86 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.38 (m, 2H), 1.22-1.29 (m, 2H), 1.13 (s, 6H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (br t, J=8.8 Hz, 1H), 7.06-7.25 (m, 5H), 6.89-6.95 (m, 2H), 6.76 (s, 1H), 6.50 (br d, J=8.5 Hz, 1H), 6.42 (br d, J=15.1 Hz, 1H), 4 .96 (q, J=6.5 Hz, 1H), 4.55 (br dd, J=12.9, 3.2 Hz, 1H), 3.39-3.50 (m, 2H), 3 .21-3.31 (m, 2H), 3.13 (br t, J=9.6 Hz, 1H), 2.83-3.07 (m, 3H), 2.54-2.62 ( m, 1H), 1.92-2.00 (m, 1H), 1.75-1.86 (m, 1H), 1.55 (d, J=6.9 Hz, 3H), 1.30 -1.38 (m, 2H), 1.22-1.29 (m, 2H), 1.13 (s, 6H).

Compound 28.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.05-7, 25 (m, 4H), 6.89-6.95 (m, 2H), 6.80 (s, 1H), 6.50 (d, J=8.8 Hz, 1H), 6.42 (dd , J=14.8, 1.6Hz, 1H), 5.58 (q, J=6.5Hz, 1H), 3.81 (br dd, J=13.6, 4.1Hz, 1H ), 3.40-3.51 (m, 2H), 3.22-3.31 (m, 2H), 3.13 (t, J=9.6 Hz, 1H), 2.86-3, 05 (m, 2H), 2.70 (br d, J=20.8 Hz, 1H), 2.55-2.63 (m, 1H), 1.92-2.00 (m, 1H), 1.75-1.85(m, 1H), 1.52(d, J=6.6Hz, 3H), 1.31-1.38(m, 2H), 1.21-1.29( m, 2H), 1.13 (s, 6H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.05-7.25 (m, 5H), 6.89-6.95 ( m, 2H), 6.76 (s, 1H), 6.50 (d, J=8.8 Hz, 1H), 6.42 (dd, J=14.8, 1.6 Hz, 1H), 4.96 (q, J=6.5 Hz, 1H), 4.55 (br dd, J=12.9, 2.8 Hz, 1H), 3.40-3.51 (m, 2H), 3.22-3.31(m, 2H), 3.13(t, J=9.6Hz, 1H), 2.86-3.05(m, 3H), 2.55-2.63( m, 1H), 1.92-2.00 (m, 1H), 1.75-1.85 (m, 1H), 1.55 (d, J=6.9 Hz, 3H), 1.31 -1.38 (m, 2H), 1.21-1.29 (m, 2H), 1.13 (s, 6H).

Compound 29.

Basic rotamer (70%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.38 (d, J=5.0 Hz, 1H), 7.13 (br s , 1H), 7.02 (d, J=5.0 Hz, 1H), 6.89-6.95 (m, 2H), 6.79-6.81 (m, 1H), 6.50 ( br d, J=8.8 Hz, 1H), 6.42 (br d, J=14.8 Hz, 1H), 5.53 (q, J=6.8 Hz, 1H), 3.92 ( br dd, J=13.7, 4.6 Hz, 1H), 3.38-3.45 (m, 2H), 3.09-3.29 (m, 3H), 2.90-3.01 (m, 2H), 2.70 (br d, J=17.0 Hz, 1H), 2.55-2.62 (m, 1H), 1.92-2.00 (m, 1H), 1 .75-1.85 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.31-1.37 (m, 2H), 1.21-1.29 (m , 2H), 1.13 (s, 6H).

Minor rotamer (30%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.98 (t, J=8.8 Hz, 1H), 7.29 (d, J=5.0 Hz, 1H), 7.13 (br s, 1H), 6.896.95 (m, 2H), 6.79-6.81 (m, 1H), 6.77 (s, 1H), 6.50 (br d, J=8.8 Hz, 1H), 6.42 (br d, J=14.8 Hz, 1H), 4.90 (q, J=6.7 Hz, 1H), 4.70 (br dd, J=12.8, 4 .6 Hz, 1H), 3.38-3.45 (m, 2H), 3.09-3.29 (m, 3H), 2.90-3.01 (m, 3H), 2.552.62 ( m, 1H), 1.92-2.00 (m, 1H), 1.75-1.85 (m, 1H), 1.50 (d, J=6.6 Hz, 3H), 1.31 -1.37(m, 2H), 1.21-1.29(m, 2H), 1.13(s, 6H).

Compound 30.

- 122 040266

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.00 (br t, J=8.8 Hz, 1H), 7.31 (br d, J=7.1 Hz, 1H), 7, 05-7.26 (m, 3H), 6.93 (br s, 1H), 6.80 (s, 1H), 6.51 (br d, J=8.6 Hz, 1H), 6.44 (br d, J=15.2 Hz, 1H), 5.55-5.62 (m, 1H), 4.66 (brt, J=9.1 Hz, 1H), 3.86-3.95 (m, 1H), 3.77-3.85 (m, 1H), 3.52-3.59 (m, 1H), 3.41-3.51 (m, 2H), 2.85-3 .12 (m, 3H), 2.68-2.76 (m, 1H), 2.15-2.25 (m, 1H), 1.83-1.95 (m, 1H), 1.49 -1.57 (m, 3H), 1.38 (s, 3H), 1.34 (s, 3H), 1.21-1.34 (m, 4H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (br t, J=8.8 Hz, 1H), 7.05-7.26 (m, 4H), 6.93 (br s, 1H), 6.76 (s, 1H), 6.51 (br d, J=8.6 Hz, 1H), 6.44 (br d, J=15.2 Hz, 1H), 4.92- 4.99 (m, 1H), 4.66 (brt, J=9.1 Hz, 1H), 4.51-4.58 (m, 1H), 3.86-3.95 (m, 1H) , 3.52-3.59 (m, 1H), 3.41-3.51 (m, 1H), 3.22-3.29 (m, 1H), 2.85-3.12 (m, 4H), 2.15-2.25 (m, 1H), 1.83-1.95 (m, 1H), 1.49-1.57 (m, 3H), 1.38 (s, 3H) , 1.34 (s, 3H), 1.211.34 (m, 4H).

Compound 31.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.7 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.06- 7.25 (m, 3H), 6.91-6.96 (m, 1H), 6.80 (s, 1H), 6.51 (br d, J=8.5 Hz, 1H), 6, 44 (dd, J=14.8, 1.3Hz, 1H), 5.59 (q, J=6.6Hz, 1H), 4.66 (t, J=9.0Hz, 1H), 3.86-3.95 (m, 1H), 3.78-3.84 (m, 1H), 3.56 (dd, J=9.8, 6.6 Hz, 1H), 3.42- 3.50 (m, 2H), 3.08 (dd, J=9.8, 6.0 Hz, 1H), 2.83-3.05 (m, 2H), 2.72 (br d, J =16.4 Hz, 1H), 2.16-2.24 (m, 1H), 1.84-1.94 (m, 1H), 1.52 (d, J=6.6 Hz, 3H) , 1.38 (s, 3H), 1.35 (s, 3H), 1.30-1.34 (m, 2H), 1.22-1.28 (m, 2H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.7 Hz, 1H), 7.06-7.25 (m, 4H), 6.91-6.96 ( m, 1H), 6.77 (s, 1H), 6.51 (br d, J=8.5 Hz, 1H), 6.44 (dd, J=14.8, 1.3 Hz, 1H) , 4.96 (q, J=6.7 Hz, 1H), 4.66 (t, J=9.0 Hz, 1H), 4.52-4.58 (m, 1H), 3.86- 3.95 (m, 1H), 3.56 (dd, J=9.8, 6.6 Hz, 1H), 3.42-3.50 (m, 1H), 3.23-3.30 ( m, 1H), 3.08 (dd, J=9.8, 6.0 Hz, 1H), 2.83-3.05 (m, 3H), 2.16-2.24 (m, 1H) , 1.84-1.94 (m, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.38 (s, 3H), 1.35 (s, 3H), 1, 30-1.34 (m, 2H), 1.22-1.28 (m, 2H).

Compound 32.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (br t, J=8.7 Hz, 1H), 7.51 (br s, 1H), 7.32 (br d, J= 7.6 Hz, 1H), 7.06-7.26 (m, 3H), 7.02 (br s, 1H), 6.90-6.95 (m, 1H), 6.80 (s, 1H), 6.53 (br d, J=8.5 Hz, 1H), 6.45 (br d, J=14.5 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 4.02-4.11 (m, 1H), 3.82 (br dd, J=13.2, 4.1 Hz, 1H), 3.55 (t, J=8.5 Hz, 1H), 3.40-3.52 (m, 1H), 3.22-3.36 (m, 2H, partially covered by H ₂ O peak), 2.84-3.06 (m, 2H), 2 .72 (br d, J=16.1 Hz, 1H), 2.11-2.21 (m, 1H), 1.91 (br dd, J=11.8, 6.5 Hz, 1H), 1.52 (br d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.21-1.29 (m, 2H), 1.16 (d, J =6.0 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (brt, J=8.7 Hz, 1H), 7.51 (br s, 1H), 7.06-7.26 (m, 4H ), 7.02 (br s, 1H), 6.90-6.95 (m, 1H), 6.77 (s, 1H), 6.53 (br d, J=8.5 Hz, 1H) , 6.45 (br d, J=14.5 Hz, 1H), 4.97 (q, J=6.5 Hz, 1H), 4.55 (br d, J=12.6 Hz, 1H) , 4.02-4.11 (m, 1H), 3.55 (t, J=8.5 Hz, 1H), 3.40-3.52 (m, 1H), 3.22-3.36 (m, 2H, partially covered by H ₂ O peak), 2.84-3.06 (m, 3H), 2.11-2.21 (m, 1H), 1.91 (br dd, J=11, 8, 6.5 Hz, 1H), 1.55 (br d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.21-1.29 (m, 2H), 1.16 (d, J=6.0 Hz, 3H).

Compound 33.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.49 (br s, 1H), 7.32 (d, J=7, 3 Hz, 1H), 7.057.26 (m, 3H), 7.01 (br s, 1H), 6.91-6.96 (m, 1H), 6.81 (s, 1H), 6.56 (br d, J=8.8 Hz, 1H), 6.48 (br d, J=14.8 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.93 -4.02 (m, 1H), 3.82 (br dd, J=13.7, 4.3 Hz, 1H), 3.55-3.62 (m, 1H), 3.42-3, 53 (m, 2H), 2.86-3.06 (m, 3H), 2.72 (br d, J=16.1 Hz, 1H), 2.39-2.47 (m, 1H), 1.87-1.95 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.23-1.30 ( m, 2H), 1.18 (d, J=6.0 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.49 (br s, 1H), 7.05-7.26 (m, 4H ), 7.01 (br s, 1H), 6.91-6.96 (m, 1H), 6.77 (s, 1H), 6.56 (br d, J=8.8 Hz, 1H) , 6.48 (br d, J=14.8 Hz, 1H), 4.97 (q, J=6.6 Hz, 1H), 4.51-4.58 (m, 1H), 3.93 -4.02(m, 1H), 3.55-3.62(m, 1H), 3.42-3.53(m, 1H), 3.22-3.30(m, 1H), 2 .86-3.06 (m, 4H), 2.39-2.47 (m, 1H), 1.87-1.95 (m, 1H), 1.55 (d, J=6.6 Hz , 3H), 1.30-1.37 (m, 2H), 1.23-1.30 (m, 2H), 1.18 (d, J=6.3 Hz, 3H).

Compound 34.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (br t, J=8.7 Hz, 1H), 7.51 (br s, 1H), 7.32 (br d, J=7 .3 Hz, 1H), 7.06-7.25(m, 3H), 7.02(br s, 1H), 6.90-6.96(m, 1H), 6.80(s, 1H ), 6.53 (br d, J=8.5 Hz, 1H), 6.45 (br d, J=14.8 Hz, 1H), 5.59 (q, J=6.4 Hz, 1H ), 4.04-4.11 (m, 1H), 3.82 (br dd, J=13.6, 3.8 Hz, 1H), 3.55 (br t, J=8.5 Hz, 1H), 3.42-3.50 (m, 1H), 3.22-3.36 (m, 2H, partially covered by H ₂ O peak), 2.85-3.06 (m, 2H), 2 .72 (br d, J=16.4 Hz, 1H), 2.12-2.21 (m, 1H), 1.91 (br dd, J=11.5, 6.8 Hz, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1.30 (m, 2H), 1.16 (d, J= 6.0 Hz, 3H).

Minor rotamer (35%).

- 123 040266 ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (br t, J=8.7 Hz, 1H), 7.51 (br s, 1H), 7.06-7, 25 (m, 4H), 7.02 (br s, 1H), 6.90-6.96 (m, 1H), 6.76 (s, 1H), 6.53 (br d, J=8, 5 Hz, 1H), 6.45 (br d, J=14.8 Hz, 1H), 4.97 (q,

J=6.2 Hz, 1H), 4.55 (br dd, J=12.9, 3.2 Hz, 1H), 4.04-4.11 (m, 1H), 3.55 (br t , J=8.5 Hz, 1H), 3.42-3.50 (m, 1H),

3.22-3.36 (m, 2H, partially covered by H ₂ O peak), 2.85-3.06 (m, 3H), 2.12-2.21 (m, 1H), 1.91 ( br dd, J=11.5,

6.8 Hz, 1H), 1.55 (d, J=6.9 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1.30 (m, 2H), 1.16 (d, J=6.0 Hz, 3H).

Compound 35.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (br t, J=8.8 Hz, 1H), 7.49 (br s, 1H), 7.32 (br d, J=7 .6 Hz, 1H), 7.06-7.26(m, 3H), 7.01(brs, 1H), 6.91-6.96(m, 1H), 6.81(s, 1H ), 6.57 (br d, J=8.8 Hz, 1H), 6.48 (br d, J=15.1 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H ), 3.94-4.02 (m, 1H), 3.82 (br dd, J=13.7, 3.6 Hz, 1H), 3.55-3.61 (m, 1H), 3 .42-3.53 (m, 2H), 2.83-3.06 (m, 3H), 2.72 (br d, J=16.1 Hz, 1H), 2.39-2.48 ( m, 1H), 1.87-1.95 (m, 1H), 1.52 (br d, J=6.9 Hz, 3H), 1.30-1.38 (m, 2H), 1, 22-1.30 (m, 2H), 1.18 (d, J=6.0 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (br t, J=8.8 Hz, 1H), 7.49 (br s, 1H), 7.06-7.26 (m , 4H), 7.01 (br s, 1H), 6.91-6.96 (m, 1H), 6.77 (s, 1H), 6.57 (br d, J=8.8 Hz, 1H), 6.48 (br d, J=15.1 Hz, 1H), 4.97 (q, J=6.4 Hz, 1H), 4.55 (br d, J=10.4 Hz, 1H), 3.94-4.02(m, 1H), 3.55-3.61(m, 1H), 3.42-3.53(m, 1H), 3.23-3.30( m, 1H), 2.83-3.06 (m, 4H), 2.39-2.48 (m, 1H), 1.87-1.95 (m, 1H), 1.55 (br d , J=6.9 Hz, 3H), 1.30-1.38 (m, 2H), 1.22-1.30 (m, 2H), 1.18 (d, J=6.0 Hz, 3H).

Compound 36.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.51 (br s, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.067.25 (m, 3H), 7.01 (br s, 1H), 6.91-6.95 (m, 1H), 6.81 (s, 1H), 6.52 ( br d, J=8.8 Hz, 1H), 6.45 (br d, J=14.5 Hz, 1H), 5.59 (q, J=6.8 Hz, 1H), 3.81 ( br dd, J=13.6, 3.8 Hz, 1H), 3.46-3.54 (m, 1H), 3.34-3.46 (m, 3H), 3.29-3.32 (m, 1H, partially covered by H ₂ O peak), 3.10 (quin, J=7.6 Hz 1H), 2.85-3.05 (m, 2H), 2.72 (br d, J= 16.1 Hz, 1H), 2.16-2.24 (m, 1H), 2.06-2.15 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.38(m, 2H), 1.22-1.30(m, 2H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.51 (br s, 1H), 7.06-7.25 (m, 4H), 7.01 (br s, 1H), 6.91-6.95 (m, 1H), 6.77 (s, 1H), 6.52 (br d, J=8.8 Hz, 1H ), 6.45 (br d, J=14.5 Hz, 1H), 4.96 (q, J=6.6 Hz, 1H), 4.55 (br dd, J=12.6, 3, 2 Hz, 1H), 3.46-3.54 (m, 1H), 3.34-3.46 (m, 2H), 3.29-3.32 (m, 1H, partially covered by the H ₂ O peak ), 3.22-3.26 (m, 1H), 3.10 (quin, J=7.6 Hz, 1H), 2.85-3.05 (m, 3H), 2.16-2, 24 (m, 1H), 2.062.15 (m, 1H), 1.55 (d, J=6.9 Hz, 3H), 1.30-1.38 (m, 2H), 1.22-1 .30 (m, 2H).

Compound 37.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.97-8.03 (m, 2H), 7.32 (d, J=7.3 Hz, 1H), 7.06-7.25 ( m, 3H), 6.94 (d, J=3.5 Hz, 1H), 6.80 (s, 1H), 6.52 (dd, J=8.8, 1.9 Hz, 1H), 6.45 (dd, J=14.8, 1.9 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.81 (br dd, J=13.7, 3 .6 Hz, 1H), 3.32-3.54 (m, 5H), 3.04-3.12 (m, 1H), 2.83-3.04 (m, 2H), 2.72 ( br d, J=16.1 Hz, 1H), 2.62 (d, J=4.4 Hz, 3H), 2.14-2.22 (m, 1H), 2.06-2.14 ( m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1.30 (m, 2H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.97-8.03 (m, 2H), 7.06-7.25 (m, 4H), 6.93 (d, J=3.5 Hz, 1H), 6.77 (s, 1H), 6.52 (dd, J=8.8, 1.9 Hz, 1H), 6.45 (dd, J=14.8, 1.9 Hz , 1H), 4.96 (q, J=6.6 Hz, 1H), 4.52-4.58 (m, 1H), 3.32-3.54 (m, 4H), 3.23- 3.30 (m, 1H), 3.04-3.12 (m, 1H), 2.83-3.04 (m, 3H), 2.62 (d, J=4.4 Hz, 3H) , 2.14-2.22 (m, 1H), 2.06-2.14 (m, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1.30 (m, 2H).

Compound 38.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.06- 7.25 (m, 3H), 6.94 (d, J=3.8 Hz, 1H), 6.80 (s, 1H), 6.53 (dd, J=8.8, 1.9 Hz , 1H), 6.46 (dd, J=14.7, 2.1 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.81 (br dd, J=13 .9, 3.5 Hz, 1H), 3.53-3.60 (m, 2H), 3.33-3.51 (m, 4H), 3.09 (s, 3H), 2.89- 3.05 (m, 2H), 2.86 (s, 3H), 2.72 (br d, J=16.1 Hz, 1H), 2.18-2.26 (m, 1H), 2. 06-2.14 (m, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1.30 (m, 2H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (br d, J=8.8 Hz, 1H), 7.06-7.25 (m, 4H), 6.93 (d, J =3.5 Hz, 1H), 6.77 (s, 1H), 6.53 (dd, J=8.8, 1.9 Hz, 1H), 6.46 (dd, J=14.7, 2.1 Hz, 1H), 4.96 (q, J=6.7 Hz, 1H), 4.52-4.58 (m, 1H), 3.53-3.60 (m, 2H), 3.33-3.51 (m, 3H), 3.21-3.30 (m, 1H), 3.09 (s, 3H), 2.89-3.05 (m, 3H), 2, 86 (s, 3H), 2.18-2.26 (m, 1H), 2.06-2.14 (m, 1H), 1.55 (d, J=6.9 Hz, 3H), 1 .30-1.37 (m, 2H), 1.22-1.30 (m, 2H).

Connection 39.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.05- 7.26 (m, 4H), 6.91-6.96 (m, 1H), 6.80 (s, 1H), 6.52 (br d, J=9.1 Hz, 1H), 6, 45 (br d, J=14.7 Hz, 1H), 5.58 (q, J=7.1 Hz, 1H), 3.77-3.85 (m, 1H), 3.35-3, 55 (m, 5H), 3.09-3.19 (m, 1H), 2.84-3.07 (m, 2H), 2.71 (br d, J=16.2 Hz, 1H), 2.102.26 (m, 2H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.39 (m, 2H), 1.20-1.30 (m, 2H) .

- 124 040266

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.05-7.26 (m, 4H), 6.91-6.96 (m, 2H), 6.76 (s, 1H), 6.52 (br d, J=9.1 Hz, 1H), 6.45 (br d, J=14.7 Hz, 1H), 4 .96 (q, J=6.4 Hz, 1H), 4.51-4.58 (m, 1H), 3.353.55 (m, 5H), 3.09-3.19 (m, 1H), 2.84-3.07 (m, 3H), 2.10-2.26 (m, 2H), 1.54 (d, J=7.1 Hz, 3H), 1.30-1.39 ( m,

2H), 1.20-1.30 (m, 2H).

Compound 40.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d6) δ ppm 11.94 (br s, 1H), 8.01 (t, J=8.8 Hz, 1H), 7.32 (d, J=7.6 Hz , 1H), 7.05-7.25 (m, 3H), 6.91-6.97 (m, 1H), 6.80 (s, 1H), 6.54 (br d, J=9, 1 Hz, 1H), 6.47 (dd, J=14.9, 1.8 Hz, 1H), 5.58 (q, J=6.6 Hz, 1H), 3.81 (br dd, J =13.1, 4.0 Hz, 1H), 3.35-3.57 (m, 5H), 3.21-3.29 (m, 1H), 3.19 (s, 3H), 2.853, 06 (m, 2H), 2.71 (br d, J=16.2 Hz, 1H), 2.21-2.30 (m, 1H), 2.11-2.21 (m, 1H), 1.52 (d, J=7.1 Hz, 3H), 1.301.38 (m, 2H), 1.22-1.29 (m, 2H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.94 (br s, 1H), 8.01 (t, J=8.8 Hz, 1H), 7.05-7.25 (m, 4H), 6.916.97 (m, 1H), 6.77 (s, 1H), 6.54 (br d, J=9.1 Hz, 1H), 6.47 (dd, J=14.9, 1.8 Hz, 1H), 4.96 (q, J=6.2 Hz, 1H), 4.514.58 (m, 1H), 3.35-3.57 (m, 5H), 3.21- 3.29 (m, 1H), 3.19 (s, 3H), 2.85-3.06 (m, 3H), 2.21-2.30 (m, 1H), 2.112.21 (m, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.38 (m, 2H), 1.22-1.29 (m, 2H).

Compound 41.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δppm 11.97 (s, 1H), 8.01 (r, J=8.8 Hz, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.02 (d, J=5.1 Hz, 1H), 6.92-6.96 (m, 1H), 6.77-6.82 (m, 1H), 6.54 (br d, J=8.6 Hz, 1H), 6.48 (br d, J=14.7 Hz, 1H), 5.53 (q, J=7.1 Hz, 1H), 3.92 (br dd, J=13.6, 4.6 Hz, 1H), 3.52-3.59 (m, 1H), 3.33-3.48 (m, 4H), 3.27 (s, 3H) , 3.153.26 (m, 1H), 2.81-3.00 (m, 2H), 2.74 (br d, J=14.7 Hz, 1H), 2.23-2.31 (m, 1H), 2.12-2.21 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1 .29 (m, 2H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (s, 1H), 7.98 (t, J=8.6 Hz, 1H), 7.29 (d, J=5.1 Hz , 1H), 6.926.96 (m, 1H), 6.77-6.82 (m, 2H), 6.54 (br d, J=8.6 Hz, 1H), 6.48 (br d, J=14.7Hz, 1H), 4.90(q, J=6.1Hz, m, 1H), 4.67-4.74(m, 1H), 3.52-3.59(m , 1H), 3.33-3.48 (m, 4H), 3.27 (s, 3H), 3.15-3.26 (m, 1H), 2.81-3.00 (m, 3H ), 2.23-2.31 (m, 1H), 2.12-2.21 (m, 1H), 1.50 (d, J=6.6 Hz, 3H), 1.30-1, 37 (m, 2H), 1.22-1.29 (m, 2H).

Compound 42.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.34-7.40 (m, 2H), 7.02 (d, J =5.0 Hz, 1H), 6.92-6.95 (m, 1H), 6.77-6.86 (m, 2H), 6.50 (br d, J=8.8 Hz, 1H ), 6.41 (br d, J=14.8 Hz, 1H), 5.53 (q, J=6.5 Hz, 1H), 3.92 (br dd, J=13.9, 4, 7 Hz, 1H), 3.49 (dd, J=9.0, 7.7 Hz, 1H), 3.36-3.45 (m, 2H), 3.27-3.31 (m, 1H ), 2.823.01 (m, 3H), 2.75 (br dd, J=15.9, 2.1 Hz, 1H), 2.58-2.68 (m, 1H), 2.24 (d , J=7.6 Hz, 2H), 2.10-2.18 (m, 1H), 1.64-1.74 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.30-1.38 (m, 2H), 1.21-1.29 (m, 2H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.34-7.40 (m, 1H), 7.29 (d, J= 5.0 Hz, 1H), 6.92-6.95 (m, 1H), 6.77-6.86 (m, 3H), 6.50 (br d, J=8.8 Hz, 1H) , 6.41 (br d, J=14.8 Hz, 1H), 4.90 (q, J=6.3 Hz, 1H), 4.70 (br dd, J=12.6, 4.4 Hz, 1H), 3.49 (dd, J=9.0, 7.7 Hz, 1H), 3.36-3.45 (m, 1H), 3.27-3.31 (m, 1H) , 3.21 (td, J=12.3 Hz, 1H), 2.82-3.01 (m, 4H), 2.58-2.68 (m, 1H), 2.24 (d, J = 7.6 Hz, 2H), 2.10-2.18 (m, 1H), 1.64-1.74 (m, 1H), 1.50 (d, J=6.6 Hz, 3H) , 1.30-1.38(m, 2H), 1.21-1.29(m, 2H).

Compound 43.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (br t, J=8.8 Hz, 1H), 7.34-7.40 (m, 2H), 7.02 (d, J=5.4 Hz, 1H), 6.91-6.95 (m, 1H), 6.77-6.86 (m, 2H), 6.50 (br d, J=8.8 Hz, 1H), 6.41 (br d, J=14.8 Hz, 1H), 5.53(q, J=6.4 Hz, 1H), 3.92 (br dd, J=13.7, 4 .6 Hz, 1H), 3.49 (bit, J=8.4 Hz, 1H), 3.35-3.44 (m, 2H), 3.27-3.32 (m, 1H), 2 .83-3.01 (m, 3H), 2.75 (br dd, J=16.1, 2.2 Hz, 1H), 2.58-2.68 (m, 1H), 2.24 ( d, J=7.6 Hz, 2H), 2.10-2.18 (m, 1H), 1.641.74 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.30-1.37(m, 2H), 1.22-1.30(m, 2H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (br t, J=8.8 Hz, 1H), 7.34-7.40 (m, 1H), 7.29 (d, J =5.0 Hz, 1H), 6.91-6.95 (m, 1H), 6.77-6.86 (m, 3H), 6.50 (br d, J=8.8 Hz, 1H ), 6.41 (br d, J=14.8 Hz, 1H), 4.90 (q, J=6.5 Hz, 1H), 4.70 (br dd, J=12.9, 4, 4 Hz, 1H), 3.49 (br t, J=8.4 Hz, 1H), 3.35-3.44 (m, 1H), 3.27-3.32 (m, 1H), 3 .21 (br td, J=12.2, 4.3 Hz, 1H), 2.83-3.01 (m, 4H), 2.58-2.68 (m, 1H), 2.24 ( d, J=7.6 Hz, 2H), 2.10-2.18 (m, 1H), 1.641.74 (m, 1H), 1.50 (d, J=6.6 Hz, 3H), 1.30-1.37(m, 2H), 1.22-1.30(m, 2H).

Compound 44.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.35-7.40 (m, 2H), 7.00-7.05 (m, 2H), 6.926.95 (m, 1H), 6.77-6.82 (m, 1H), 6.49 (br d, J=8.8 Hz, 1H), 6.41 (dd , J=14.7, 1.7Hz, 1H), 5.53 (q, J=6.6Hz, 1H), 3.92 (dd, J=13.7, 4.9Hz, 1H) , 3.72 (d, J=9.8 Hz, 1H), 3.33-3.45 (m, 3H), 3.12 (d, J=9.8 Hz, 1H), 2.80- 3.00 (m, 2H), 2.75 (dd, J=16.2, 2.7 Hz, 1H), 2.33-2.40 (m, 1H), 1.85-1.92 ( m, 1H), 1.46 (d, J=6.9 Hz, 3H), 1.31 (s,

- 125 040266

3H), 1.21-1.29 (m, 4H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (br t, J=8.8 Hz, 1H), 7.35-7.40 (m, 1H), 7.29 (d, J =5.0 Hz, 1H), 7.00-7.05 (m, 1H), 6.92-6.95 (m, 1H), 6.77-6.82 (m, 2H), 6, 49 (br d, J=8.8 Hz, 1H), 6.41 (dd, J=14.7, 1.7 Hz, 1H), 4.90 (q, J=6.5 Hz, 1H) , 4.70 (br dd, J=12.8, 4.3 Hz, 1H), 3.72 (d, J=9.8 Hz, 1H), 3.33-3.45 (m, 2H) , 3.21 (td, J=12.3, 4.4 Hz, 1H), 3.12 (d, J=9.8 Hz, 1H), 2.80-3.00 (m, 3H), 2.33-2.40 (m, 1H), 1.85-1.92 (m, 1H), 1.50 (d, J=6.6 Hz, 3H), 1.31 (s, 3H) , 1.21-1.29 (m, 4H).

Compound 45.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.34-7.40 (m, 2H), 7.00-7.04 (m , 2H), 6.916.95 (m, 1H), 6.76-6.81 (m, 1H), 6.49 (br d, J=9.1 Hz, 1H), 6.40 (dd, J =14.7, 2.0 Hz, 1H), 5.53 (q, J=6.7 Hz, 1H), 3.92 (dd, J=13.9, 5.3 Hz, 1H), 3 .72 (d, J=10.1 Hz, 1H), 3.33-3.45 (m, 3H), 3.12 (d, J=10.1 Hz, 1H), 2.813.01 (m, 2H), 2.75 (dd, J=16.4, 2.7 Hz, 1H), 2.34-2.41 (m, 1H), 1.84-1.93 (m, 1H), 1 .46 (d, J=7.1 Hz, 3H), 1.31 (s, 3H), 1.22-1.29 (m, 4H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.99 (br t, J=8.8 Hz, 1H), 7.34-7.40 (m, 1H), 7.29 (d, J =5.1 Hz, 1H), 7.00-7.04 (m, 1H), 6.91-6.95 (m, 1H), 6.76-6.81 (m, 2H), 6, 49 (br d, J=9.1 Hz, 1H), 6.40 (dd, J=14.7, 2.0 Hz, 1H), 4.90 (q, J=6.1 Hz, 1H) , 4.70 (dd, J=12.6, 4.0 Hz, 1H), 3.72 (d, J=10.1 Hz, 1H), 3.33-3.45 (m, 2H), 3.16-3.25(m, 1H), 3.12(d, J=10.1Hz, 1H), 2.81-3.01(m, 3H), 2.34-2.41( m, 1H), 1.84-1.93 (m, 1H), 1.49 (d, J=6.6 Hz, 3H), 1.31 (s, 3H), 1.22-1.29 (m, 4H).

Compound 46.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.49 (br s, 1H), 7.38 (d, J=5.0 Hz , 1H), 7.01 (d, J=5.4 Hz, 1H), 6.98 (br s, 1H), 6.92-6.95 (m, 1H), 6.77-6.81 (m, 1H), 6.52 (br d, J=8.8 Hz, 1H), 6.44 (dd, J=14.8, 1.6 Hz, 1H), 5.53 (q, J =6.8Hz, 1H), 3.93(dd, J=13.7, 4.9Hz, 1H), 3.48-3.53(m, 1H), 3.36-3.45( m, 3H), 3.31-3.35 (m, 1H), 3.09 (quin, J=7.6 Hz, 1H), 2.80-3.00 (m, 2H), 2.75 (dd, J=15.9, 2.7 Hz, 1H), 2.16-2.24 (m, 1H), 2.06-2.15 (m, 1H), 1.46 (d, J =6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.23-1.30 (m, 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (br t, J=8.8 Hz, 1H), 7.49 (br s, 1H), 7.29 (d, J=5, 0 Hz, 1H), 6.98 (br s, 1H), 6.92-6.95 (m, 1H), 6.77-6.81 (m, 2H), 6.52 (br d, J =8.8 Hz, 1H), 6.44 (dd, J=14.8, 1.6 Hz, 1H), 4.91 (q, J=6.3 Hz, 1H), 4.71 (br dd, J=12.5, 4.6 Hz, 1H), 3.48-3.53 (m, 1H), 3.36-3.45 (m, 2H), 3.31-3.35 ( m, 1H), 3.17-3.24 (m, 1H), 3.09 (quin, J=7.6 Hz, 1H), 2.80-3.00 (m, 3H), 2.16 -2.24 (m, 1H), 2.06-2.15 (m, 1H), 1.50 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H ), 1.23-1.30 (m, 2H).

Compound 47.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.49 (br s, 1H), 7.18-7.26 (m, 2H) , 6.91-7.07 (m, 3H), 6.80 (s, 1H), 6.52 (dd, J=8.8, 1.9 Hz, 1H), 6.44 (dd, J =14.8, 1.6 Hz, 1H), 5.60 (q, J=6.8 Hz, 1H), 3.83 (br dd, J=13.6, 4.1 Hz, 1H), 3.47-3.54 (m, 1H), 3.32-3.47 (m, 4H), 3.09 (quin, J=7.6 Hz, 1H), 2.83-3.01 ( m, 2H), 2.71 (br d, J=16.1 Hz, 1H), 2.16-2.25 (m, 1H), 2.06-2.15 (m, 1H), 1, 52 (d, J=6.9 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1.30 (m, 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.49 (br s, 1H), 7.18-7.26 (m, 1H ), 6.91-7.07 (m, 4H), 6.76 (s, 1H), 6.52 (dd, J=8.8, 1.9 Hz, 1H), 6.44 (dd, J=14.8, 1.6Hz, 1H), 4.98 (q, J=6.4Hz, 1H), 4.55 (dt, J=12.8, 3.7Hz, 1H), 3.47-3.54 (m, 1H), 3.32-3.47 (m, 3H), 3.20-3.28 (m, 1H), 3.09 (quin, J=7.6 Hz, 1H), 2.83-3.01 (m, 3H), 2.16-2.25 (m, 1H), 2.06-2.15 (m, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1.30 (m, 2H).

Compound 48.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.09 (t, J=8.8 Hz, 1H), 7.38 (dd, J=8.1, 5.7 Hz, 1H), 6, 99-7.09 (m, 3H), 6.84 (s, 1H), 6.81-6.85 (m, 1H), 6.77 (dd, J=14.2, 2.2 Hz, 1H), 6.16 (d, J=6.0 Hz, 1H), 5.59 (q, J=6.4 Hz, 1H), 3.82 (br dd, J=13.7, 4, 3 Hz, 1H), 3.59 (td, J=8.6, 3.9 Hz, 1H), 3.49-3.55 (m, 1H), 3.41-3.48 (m, 1H ), 3.163.23 (m, 1H), 2.94-3.05 (m, 2H), 2.87-2.94 (m, 2H), 2.74 (br d, J=16.7 Hz , 1H), 2.28-2.35 (m, 1H), 1.78-1.86 (m, 1H), 1.51 (d, J=6.9 Hz, 3H), 1.31- 1.39 (m, 2H), 1.22-1.30 (m, 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.09 (t, J=8.8 Hz, 1H), 7.14 (dd, J=8.5, 6.0 Hz, 1H), 6, 99-7.09 (m, 2H), 6.96 (td, J=8.7, 2.5 Hz, 1H), 6.81-6.85 (m, 1H), 6.80 (s, 1H), 6.77 (dd, J=14.2, 2.2 Hz, 1H), 6.16 (d, J=6.0 Hz, 1H), 4.97 (q, J=6.7 Hz, 1H), 4.54 (dt, J=12.6, 3.8 Hz, 1H), 3.59 (td, J=8.6, 3.9 Hz, 1H), 3.49-3 .55 (m, 1H), 3.24-3.28 (m, 1H), 3.16-3.23 (m, 1H), 2.94-3.05 (m, 3H), 2.87 -2.94 (m, 2H), 2.28-2.35 (m, 1H), 1.78-1.86 (m, 1H), 1.53 (d, J=6.6Hz, 3H ), 1.31-1.39 (m, 2H), 1.22-1.30 (m, 2H).

Compound 49.

Basic rotamer (65%).

- 126 040266 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.36 (t, J=9.4 Hz, 1H), 7.51 (br s, 1H), 7.32 (d, J = 7.1 Hz, 1H), 7.057.25 (m, 3H), 7.00 (br s, 1H), 6.91-6.95 (m, 1H), 6.82 (s, 1H), 6.53 (dd, J=8.6, 1.5 Hz, 1H), 5.58 (q, J=6.9 Hz,

1H), 3.81 (br dd, J=13.4, 3.8 Hz, 1H), 3.39-3.69 (m, 5H), 2.83-3.13 (m, 3H), 2.71 (br d, J=16.2 Hz, 1H), 2.152.25 (m, 1H), 2.04 -2.15 (m, 1H), 1.52 (d, J=7.1 Hz, 3H), 1.30-1.38 (m, 2H), 1.20-1.30 (m, 2H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (t, J=9.4 Hz, 1H), 7.51 (br s, 1H), 7.05-7.25 (m, 4H ), 7.00 (br s, 1H), 6.91-6.95 (m, 1H), 6.79 (s, 1H), 6.53 (dd, J=8.6, 1.5 Hz , 1H), 4.96 (q, J=6.6 Hz, 1H), 4.50-4.59 (m, 1H), 3.39-3.69 (m, 4H), 3.21- 3.29 (m, 1H), 2.83-3.13 (m, 4H), 2.15-2.25 (m, 1H), 2.04-2.15 (m, 1H), 1, 55 (br d, J=6.6 Hz, 3H), 1.30-1.38 (m, 2H), 1.20-1.30 (m, 2H).

Compound 50.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.36 (t, J=9.3 Hz, 1H), 8.00 (q, J=4.4 Hz, 1H), 7.32 ( d, J=7.6Hz, 1H), 7.06-7.26(m, 3H), 6.91-6.97(m, 1H), 6.83(s, 1H), 6.53 (br d, J=8.2 Hz, 1H), 5.58 (q, J=6.5 Hz, 1H), 3.81 (br dd, J=13.9, 3.8 Hz, 1H) , 3.63-3.70(m, 1H), 3.55-3.62(m, 1H), 3.40-3.53(m, 3H), 2.82-3.11(m, 3H), 2.72 (br d, J=16.1 Hz, 1H), 2.62 (d, J=4.4 Hz, 3H), 2.14-2.23 (m, 1H), 2 .04-2.14 (m, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.30-1.38 (m, 2H), 1.21-1.30 (m , 2H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.36 (t, J=9.3 Hz, 1H), 8.00 (q, J=4.4 Hz, 1H), 7.06- 7.26 (m, 4H), 6.91-6.97 (m, 1H), 6.79 (s, 1H), 6.53 (br d, J=8.2 Hz, 1H), 4, 96 (q, J=6.7 Hz, 1H), 4.52-4.59 (m, 1H), 3.63-3.70 (m, 1H), 3.55-3.62 (m, 1H), 3.40-3.53 (m, 2H), 3.23-3.30 (m, 1H), 2.82-3.11 (m, 4H), 2.62 (d, J= 4.4 Hz, 3H), 2.14-2.23 (m, 1H), 2.04-2.14 (m, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.38(m, 2H), 1.21-1.30(m, 2H).

Compound 51.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 11.99 (br s, 1H), 8.38 (t, J=9.3 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.05-7.26 (m, 3H), 6.92-6.98 (m, 1H), 6.83 (s, 1H), 6.56 (br dd, J=7 .3, 1.0 Hz, 1H), 5.58 (q, J=6.5 Hz, 1H), 3.81 (dd, J=14.0, 3.9 Hz, 1H), 3.66 -3.73 (m, 1H), 3.58-3.64 (m, 1H), 3.42-3.57 (m, 3H), 3.25 (s, 3H), 3.21-3 .29 (m, 1H), 2.83-3.06 (m, 2H), 2.72 (br d, J=16.4 Hz, 1H), 2.23-2.32 (m, 1H) , 2.13-2.22 (m, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.24-1.37 (m, 4H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.99 (br s, 1H), 8.38 (t, J=9.3 Hz, 1H), 7.05-7.26 (m, 4H), 6.926.98 (m, 1H), 6.79 (s, 1H), 6.56 (br dd, J=7.3, 1.0 Hz, 1H), 4.96 (q, J= 6.6 Hz, 1H), 4.52-4.58 (m, 1H), 3.66-3.73 (m, 1H), 3.58-3.64 (m, 1H), 3.42 -3.57 (m, 2H), 3.25 (s, 3H), 3.21-3.29 (m, 2H), 2.83-3.06 (m, 3H), 2.23-2 .32 (m, 1H), 2.13-2.22 (m, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.24-1.37 (m, 4H).

Compound 52.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (d, J=11.1 Hz, 1H), 7.52 (br s, 1H), 7.32 (br d, J=7, 6 Hz, 1H), 6.95-7.27 (m, 5H), 6.84 (s, 1H), 6.45 (br d, J=14.2 Hz, 1H), 5.59 (q , J=6.6 Hz, 1H), 3.80 (br dd, J=13.4, 4.0 Hz, 1H), 3.40-3.73 (m, 5H), 2.85-3 .13 (m, 3H), 2.71 (br d, J=16.2 Hz, 1H), 2.03-2.25 (m, 2H), 1.48-1.54 (m, 3H) , 1.22-1.40 (m, 4H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (d, J=11.1 Hz, 1H), 7.52 (br s, 1H), 6.95-7.27 (m, 6H ), 6.81 (s, 1H), 6.45 (br d, J=14.2 Hz, 1H), 4.95 (q, J=6.6 Hz, 1H), 4.50-4, 61 (m, 1H), 3.40-3.73 (m, 4H), 3.21-3.30 (m, 1H), 2.85-3.13 (m, 4H), 2.03- 2.25 (m, 2H), 1.52-1.59 (m, 3H), 1.22-1.40 (m, 4H).

Compound 53.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.84 (d, J=11.1 Hz, 1H), 8.00 (q, J=4.6 Hz, 1H), 7.32 ( br d, J=7.1 Hz, 1H), 7.05-7.25 (m, 3H), 6.95-7.00 (m, 1H), 6.84 (s, 1H), 6, 45 (d, J=14.2 Hz, 1H), 5.58 (q, J=6.6 Hz, 1H), 3.80 (br dd, J=13.6, 4.0 Hz, 1H) , 3.56-3.73 (m, 2H), 3.39-3.53 (m, 3H), 2.85-3.11 (m, 3H), 2.68-2.76 (m, 1H), 2.62 (d, J=4.6 Hz, 3H), 2.03-2.23 (m, 2H), 1.48-1.58 (m, 3H), 1.22-1 .38 (m, 4H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (d, J=11.1 Hz, 1H), 8.00 (q, J=4.6 Hz, 1H), 7.05-7 .25 (m, 4H), 6.95-7.00 (m, 1H), 6.81 (s, 1H), 6.45 (d, J=14.2 Hz, 1H), 4.91- 4.99 (m, 1H), 4.51-4.59 (m, 1H), 3.56-3.73 (m, 2H), 3.39-3.53 (m, 2H), 3. 21-3.29 (m, 1H), 2.85-3.11 (m, 4H), 2.62 (d, J=4.6 Hz, 3H), 2.03-2.23 (m, 2H), 1.481.58 (m, 3H), 1.22-1.38 (m, 4H).

Compound 54.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 11.97 (br s, 1H), 8.85 (d, J=11.4 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.06-7.25 (m, 3H), 6.99 (br d, J=2.8 Hz, 1H), 6.85 (s, 1H), 6.48 (br d , J=13.9 Hz, 1H), 5.59 (q, J=6.7 Hz, 1H), 3.77-3.84 (m, 1H), 3.67-3.74 (m, 1H), 3.59-3.65(m, 1H), 3.51-3.58(m, 1H), 3.42-3.51(m, 2H), 3.18-3.28( m, 1H), 3.22 (s, 3H), 2.86-3.05 (m, 2H), 2.71 (br d, J=16.3 Hz, 1H), 2.21-2, 30 (m, 1H), 2.12-2.21 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.31-1.37 (m, 2H), 1 .24-1.31 (m, 2H).

- 127 040266

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.97 (br s, 1H), 8.84 (d, J=11.4 Hz, 1H), 7.06-7.25 (m, 4H), 6.98 (br d, J=2.8 Hz, 1H), 6.81 (s, 1H), 6.48 (br d, J=13.9 Hz, 1H), 4.95 ( q, J=6.6 Hz, 1H), 4.52-4.58 (m, 1H), 3.673.74 (m, 1H), 3.59-3.65 (m, 1H), 3.51 -3.58(m, 1H), 3.42-3.51(m, 1H), 3.18-3.28(m, 2H), 3.22(s, 3H), 2.863.05(m , 3H), 2.21-2.30 (m, 1H), 2.12-2.21 (m, 1H), 1.54 (d, J=6.6 Hz, 3H), 1.31- 1.37 (m, 2H), 1.24-1.31 (m, 2H).

Compound 55.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.81 (dd, J=14.5, 6.9 Hz, 1H), 7.50 (br s, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.21-7.25 (m, 1H), 7.15-7.21 (m, 2H), 6.97-7.03 (m, 2H), 6, 84 (s, 1H), 6.64 (dd, J=13.6, 7.6 Hz, 1H), 5.58 (q, J=6.6 Hz, 1H), 3.80 (br dd, J=13.7, 3.9 Hz, 1H), 3.59-3.66 (m, 1H), 3.53-3.59 (m, 1H), 3.42-3.52 (m, 3H), 2.83-3.07 (m, 3H), 2.71 (br d, J=16.1 Hz, 1H), 2.11-2.19 (m, 1H), 2.00- 2.09 (m, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.31-1.38 (m, 2H), 1.22-1.30 (m, 2H) .

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.81 (dd, J=14.5, 6.9 Hz, 1H), 7.50 (br s, 1H), 7.15-7, 21 (m, 2H), 7.10-7.15 (m, 1H), 7.08 (d, J=7.6 Hz, 1H), 6.97-7.03 (m, 2H), 6 .81 (s, 1H), 6.64 (dd, J=13.6, 7.6 Hz, 1H), 4.95 (q, J=6.7 Hz, 1H), 4.54 (br dd , J=12.6, 3.8 Hz, 1H), 3.59-3.66 (m, 1H), 3.53-3.59 (m, 1H), 3.42-3.52 (m , 2H), 3.22-3.30 (m, 1H), 2.83-3.07 (m, 4H), 2.11-2.19 (m, 1H), 2.00-2.09 (m, 1H), 1.54 (d, J=6.6 Hz, 3H), 1.31-1.38 (m, 2H), 1.22-1.30 (m, 2H).

Compound 56.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 8.28-8.31 (m, 2H), 7.91 (t, J=8.7 Hz, 1H), 7.61-7.68 ( m, 3H), 7.51 (br s, 1H), 7.32-7.40 (m, 2H), 7.09-7.27 (m, 3H), 7.03-7.08 (m , 1H), 7.00 (br s, 1H), 6.51 (br d, J=8.8 Hz, 1H), 6.45 (br d, J=14.8 Hz, 1H), 5, 63 (q, J=6.8 Hz, 1H), 3.99 (br dd, J=14.0, 4.3 Hz, 1H), 3.46-3.58 (m, 2H), 3.273, 44 (m, 3H, partially covered by H ₂ O peak), 3.03-3.12 (m, 2H), 2.76 (br d, J=16.7 Hz, 1H), 2.16-2, 23 (m, 1H), 2.05-2.14 (m, 1H), 1.55 (d, J=6.9 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.24-8.28 (m, 2H), 7.91 (t, J=8.7 Hz, 1H), 7.61-7.68 (m, 3H), 7.51 (br s, 1H), 7.32-7.40 (m, 1H), 7.09-7.27 (m, 4H), 7.03-7.08 ( m, 1H), 7.00 (br s, 1H), 6.51 (br d, J=8.8 Hz, 1H), 6.45 (br d, J=14.8 Hz, 1H), 5 .14 (q, J=6.9 Hz, 1H), 4.59 (br dd, J=12.6, 3.8 Hz, 1H), 3.46-3.58 (m, 1H), 3.273 .44 (m, 3H, partially covered by the H ₂ O peak), 3.03-3.12 (m, 2H), 2.85-3.00 (m, 2H), 2.16-2.23 (m , 1H), 2.052.14 (m, 1H), 1.61 (d, J=6.6 Hz, 3H).

Compound 57.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 8.39 (d, J=8.8 Hz, 2H), 7.94 (t, J=8.7 Hz, 1H), 7.51 (br s, 1H), 7.37 (s, 1H), 7.32-7.36 (m, 1H), 7.09-7.42 (m, 8H), 6.98-7.05 (m, 1H), 6.51 (br d, J=8.8 Hz, 1H), 6.45 (br d, J=14.5 Hz, 1H), 5.63 (q, J=6.3 Hz, 1H), 3.97 (br dd, J=13.9, 3.8 Hz, 1H), 3.90 (s, 3H), 3.47-3.56 (m, 2H), 3.363.44 ( m, 2H), 3.26-3.32 (m, 1H, partially covered by H ₂ O peak), 3.02-3.12 (m, 2H), 2.75 (br d, J=17.0 Hz, 1H), 2.16-2.24 (m, 1H), 2.06-2.15 (m, 1H), 1.55 (d, J=6.6 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.35 (d, J=8.8 Hz, 2H), 7.94 (t, J=8.7 Hz, 1H), 7.51 ( br s, 1H), 7.327.36 (m, 1H), 7.09-7.27 (m, 6H), 6.98-7.05 (m, 2H), 6.51 (br d, J= 8.8 Hz, 1H), 6.45 (br d, J=14.5 Hz, 1H), 5.12 (q, J=6.0 Hz, 1H), 4.59 (br dd, J= 13.2, 3.8 Hz, 1H), 3.89 (s, 3H), 3.47-3.56 (m, 1H), 3.36-3.44 (m, 2H), 3.263.32 (m, 1H, partially covered by H ₂ O peak), 3.02-3.12 (m, 2H), 2.85-2.99 (m, 2H), 2.16-2.24 (m, 1H ), 2.062.15 (m, 1H), 1.60 (d, J=6.6 Hz, 3H).

Compound 58.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 8.23 (br d, J=7.9 Hz, 2H), 7.91 (br t, J=8.7 Hz, 1H), 7.42 -7.48 (m, 3H), 7.31-7.40 (m, 2H), 7.08-7.27 (m, 3H), 6.97-7.08 (m, 2H), 6 .51 (br d, J=8.5 Hz, 1H), 6.45 (br d, J=14.8 Hz, 1H), 5.63 (q, J=6.5 Hz, 1H), 3 .98 (br dd, J=13.1, 3.6 Hz, 1H), 3.45-3.57 (m, 2H), 3.35-3.44 (m, 2H), 3.02- 3.18 (m, 2H), 2.75 (br d, J=16.1 Hz, 1H), 2.41-2.47 (m, 4H), 2.15-2.25 (m, 1H ), 2.05-2.15 (m, 1H), 1.55 (br d, J=6.6 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 8.20 (br d, J=7.9 Hz, 2H), 7.91 (br t, J=8.7 Hz, 1H), 7.42 -7.48 (m, 3H), 7.31-7.40 (m, 1H), 7.08-7.27 (m, 4H), 6.97-7.08 (m, 2H), 6 .51 (br d, J=8.5 Hz, 1H), 6.45 (br d, J=14.8 Hz, 1H), 5.13 (q, J=6.4 Hz, 1H), 4 .59 (br dd, J=13.2, 4.4 Hz, 1H), 3.45-3.57 (m, 2H), 3.35-3.44 (m, 2H), 3.02- 3.18 (m, 1H), 2.85-3.00 (m, 2H), 2.41-2.47 (m, 4H), 2.15-2.25 (m, 1H), 2. 05-2.15 (m, 1H), 1.60 (br d, J=6.6 Hz, 3H).

Compound 59.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.34 (d, J=8.5 Hz, 2H), 7.92 (t, J=8.7 Hz, 1H), 7.69- 7.74 (m, 2H), 7.51 (br s, 1H), 7.43 (s, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.08-7, 26 (m, 3H), 7.04-7.08 (m, 1H), 7.00 (brs, 1H), 6.50

- 128 040266 (br d, J=8.8 Hz, 1H), 6.45 (br d, J=14.8 Hz, 1H), 5.63 (q, J=6.5 Hz, 1H), 3.95-4.01 (m, 1H), 3.46-3.59 (m, 2H),

3.27-3.44 (m, 3H, partially covered by H ₂ O peak), 3.02-3.12 (m, 2H), 2.75 (br d, J=17.0 Hz, 1H), 2.16-2.24 (m, 1H), 2.05-2.14 (m, 1H), 1.55 (d, J=6.6 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 8.31 (d, J=8.5 Hz, 2H), 7.92 (t, J=8.7 Hz, 1H), 7.69-7 .74 (m, 2H), 7.51 (br s, 1H), 7.38 (s, 1H), 7.08-7.26 (m, 4H), 7.04-7.08 (m, 1H), 7.00 (br s, 1H), 6.50 (br d, J=8.8 Hz, 1H), 6.45 (br d, J=14.8 Hz, 1H), 5.13 (q, J=6.6Hz, 1H), 4.56-4.62(m, 1H), 3.46-3.59(m, 1H), 3.27-3.44(m, 3H , partially covered by the H ₂ O peak), 3.02-3.12 (m, 2H), 2.85-2.99 (m, 2H), 2.16-2.24 (m, 1H), 2, 05-2.14 (m, 1H), 1.60 (d, J=6.6 Hz, 3H).

Compound 60.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.34-8.44 (m, 2H), 7.92 (t, J=8.8 Hz, 1H), 7.45-7.54 ( m, 3H), 7.41 (s, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.08-7.27 (m, 3H), 7.03-7.07 (m, 1H), 6.94-7.02 (m, 1H), 6.50 (br d, J=8.8 Hz, 1H), 6.45 (dd, J=14.5, 1, 6 Hz, 1H), 5.63 (q, J=6.7 Hz, 1H), 3.98 (br dd, J=13.4, 3.9 Hz, 1H), 3.47-3.57 (m, 2H), 3.27-3.45 (m, 3H, partially covered by H ₂ O peak), 3.03-3.12 (m, 2H), 2.75 (br d, J=16, 1 Hz, 1H), 2.16-2.24 (m, 1H), 2.05-2.15 (m, 1H), 1.55 (d, J=6.6 Hz, 3H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.34-8.44 (m, 2H), 7.92 (t, J=8.8 Hz, 1H), 7.45-7.54 (m , 3H), 7.36 (s, 1H), 7.08-7.27 (m, 4H), 7.03-7.07 (m, 1H), 6.94-7.02 (m, 1H ), 6.50 (br d, J=8.8 Hz, 1H), 6.45 (dd, J=14.5, 1.6 Hz, 1H), 5.13 (q, J=6.7 Hz, 1H), 4.59 (br dd, J=12.8, 4.9 Hz, 1H), 3.47-3.57 (m, 1H), 3.27-3.45 (m, 3H , partially covered by the H ₂ O peak), 3.03-3.12 (m, 2H), 2.85-3.00 (m, 2H), 2.16-2.24 (m, 1H), 2, 05-2.15 (m, 1H), 1.61 (d, J=6.6 Hz, 3H).

Compound 61.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.49 (d, J=8.2 Hz, 2H), 7.98-8.05 (m, 2H), 7.91 (t, J= 8.8 Hz, 1H), 7.42-7.51 (m, 2H), 7.34 (d, J=7.3 Hz, 1H), 7.07-7.27 (m, 4H), 6.98 (br s, 1H), 6.49 (br d, J=8.8 Hz, 1H), 6.45 (dd, J=14.7, 1.7 Hz, 1H), 5.64 (q, J=6.5 Hz, 1H), 4.00 (br dd, J=13.9, 3.8 Hz, 1H), 3.46-3.58 (m, 2H), 3.27-3 .44 (m, 3H), 3.03-3.12 (m, 2H), 2.76 (br d, J=16.7 Hz, 1H), 2.16-2.24 (m, 1H) , 2.06-2.14 (m, 1H), 1.56 (d, J=6.6 Hz, 3H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.46 (d, J=8.2 Hz, 2H), 7.98-8.05 (m, 2H), 7.91 (t, J= 8.8 Hz, 1H), 7.42-7.51 (m, 2H), 7.07-7.27 (m, 5H), 6.98 (br s, 1H), 6.49 (br d , J=8.8 Hz, 1H), 6.45 (dd, J=14.7, 1.7 Hz, 1H), 5.15 (q, J=6.8 Hz, 1H), 4.59 (br dd, J=13.1, 4.6 Hz, 1H), 3.46-3.58 (m, 1H), 3.27-3.44 (m, 3H), 3.03-3, 12 (m, 2H), 2.85-3.00 (m, 2H), 2.16-2.24 (m, 1H), 2.06-2.14 (m, 1H), l.61( d, J=6.6 Hz, 3H).

Compound 62.

Main rotamer.

1H NMR (500 MHz, DMSO-d6) δ ppm 8.47 (d, J=8.2 Hz, 2H), 8.09-8.14 (m, 2H), 7.90 (t, J=8 .8 Hz, 1H), 7.43-7.53 (m, 2H), 7.34 (br d, J=7.6 Hz, 1H), 7.07-7.27 (m, 4H), 7.00 (br s, 1H), 6.49 (br d, J=8.8 Hz, 1H), 6.45 (br d, J=15.1 Hz, 1H), 5.63 (q, J=6.8 Hz, 1H), 3.99 (br dd, J=13.1, 3.9 Hz, 1H), 3.46-3.57 (m, 2H), 3.28-3.44 ( m, 3H, partially covered by the H ₂ O peak), 3.02-3.12 (m, 2H), 2.75 (br d, J=16.4 Hz, 1H), 2.16-2.23 ( m, 1H), 2.052.14 (m, 1H), 1.55 (d, J=6.9 Hz, 3H).

Minor rotamer.

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.44 (br d, J=8.5 Hz, 2H), 8.09-8.14 (m, 2H), 7.90 (t, J = 8.8 Hz, 1H), 7.43-7.53 (m, 2H), 7.07-7.27 (m, 5H), 7.00 (br s, 1H), 6.49 (br d, J=8.8 Hz, 1H), 6.45 (br d, J=15.1 Hz, 1H), 5.11-5.17 (m, 1H), 4.56-4.62 ( m, 1H), 3.46-3.57 (m, 1H), 3.28-3.44 (m, 3H, partially covered by H ₂ O peak), 3.02-3.12 (m, 2H) , 2.85-2.99 (m, 2H), 2.16-2.23 (m, 1H), 2.05-2.14 (m, 1H), 1.61 (br d, J=6 .6 Hz, 3H).

Compound 63.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.84-8.91 (m, 2H), 8.28 (br d, J=5.4 Hz, 2H), 7.93 (br t, J = 8.7 Hz, 1H), 7.49-7.58 (m, 2H), 7.34 (br d, J=7.6 Hz, 1H), 7.06-7.27 (m, 4H ), 7.00 (br s, 1H), 6.51 (br d, J=8.8 Hz, 1H), 6.46 (br d, J=14.5 Hz, 1H), 5.64 ( q, J=6.1 Hz, 1H), 3.95-4.02 (m, 1H), 3.47-3.58 (m, 2H), 3.36-3.44 (m, 2H) , 3.03-3.12 (m, 3H), 2.75 (br d, J=16.1 Hz, 1H), 2.16-2.24 (m, 1H), 2.06-2, 15 (m, 1H), 1.56 (br d, J=6.6 Hz, 3H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.84-8.91 (m, 2H), 8.25 (br d, J=5.7 Hz, 2H), 7.93 (br t, J = 8.7 Hz, 1H), 7.49-7.58 (m, 2H), 7.06-7.27 (m, 5H), 7.00 (br s, 1H), 6.51 (br d, J=8.8 Hz, 1H), 6.46 (br d, J=14.5 Hz, 1H), 5.10-5.17 (m, 1H), 4.56-4.63 ( m, 1H), 3.47-3.58 (m, 2H), 3.36-3.44 (m, 2H), 3.03-3.12 (m, 2H), 2.85-3, 00 (m, 2H), 2.16-2.24 (m, 1H), 2.06-2.15 (m, 1H), 1.61 (br d, J=6.6 Hz, 3H).

Compound 64.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.68 (s, 2H), 9.34-9.46 (m, 1H), 7.90 (br t, J=8.6 Hz, 1H ), 7.67 (s, 1H), 7.50 (br s, 1H), 6.95-7.37 (m, 6H), 6.52 (br d, J=8.6 Hz, 1H) , 6.45 (br d, J=14.7 Hz, 1H), 5.59-5.68 (m, 1H),

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3.96 (br d, J=9.6 Hz, 1H), 3.45-3.66 (m, 2H), 3.33-3.44 (m, 3H), 3.01-3.20 (m, 2H), 2.75 (br d, J=17.7 Hz, 1H),

2.04-2.26 (m, 2H), 1.56 (br d, J=6.1 Hz, 3H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.65 (s, 2H), 9.34-9.46 (m, 1H), 7.90 (br t, J=8.6 Hz, 1H) , 7.63 (s, 1H), 7.50 (br s, 1H), 6.95-7.37 (m, 6H), 6.52 (br d, J=8.6 Hz, 1H), 6.45 (br d, J=14.7 Hz, 1H), 5.08-5.16 (m, 1H), 4.60 (br d, J=11.1 Hz, 1H), 3.45 -3.66 (m, 1H), 3.33-3.44 (m, 3H), 3.01-3.20 (m, 2H), 2.84-3.01 (m, 2H), 2.042 .26 (m, 2H), 1.61 (br d, J=6.1 Hz, 3H).

Compound 65.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.98 (t, J=8.5 Hz, 1H), 7.29-7.41 (m, 2H), 7.05-7.25 ( m, 3H), 6.916.96 (m, 1H), 6.85 (br s, 1H), 6.81 (s, 1H), 6.31-6.41 (m, 2H), 5.58 ( q, J=6.8 Hz, 1H), 4.04 (t, J=7.8 Hz, 2H), 3.81 (br dd, J=13.1, 3.5 Hz, 1H), 3 .59 (dd, J=7.3, 5.9 Hz, 2H), 3.42-3.51 (m, 1H), 2.85-3.06 (m, 3H), 2.71 (br d, J=16.1 Hz, 1H), 2.44-2.48 (m, 2H, partially covered by DMSO peak), 1.52 (d, J=6.7 Hz, 3H), 1.30- 1.37(m, 2H), 1.21-1.29(m, 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.98 (t, J=8.5 Hz, 1H), 7.29-7.41 (m, 1H), 7.05-7.25 ( m, 4H), 6.916.96 (m, 1H), 6.85 (br s, 1H), 6.78 (s, 1H), 6.31-6.41 (m, 2H), 4.96 ( q, J=6.7 Hz, 1H), 4.51-4.59 (m, 1H), 4.04 (t, J=7.8 Hz, 2H), 3.59 (dd, J=7 .3, 5.9 Hz, 2H), 3.22-3.30 (m, 1H), 2.85-3.06 (m, 4H), 2.44-2.48 (m, 2H, partially overlapped by DMSO peak), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.21-1.29 (m, 2H).

Connection 66.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.98 (t, J=8.5 Hz, 1H), 7.81-7.85 (m, 1H), 7.32 (d, J=7 .6 Hz, 1H), 7.06-7.25 (m, 3H), 6.94 (d, J=3.5 Hz, 1H), 6.81 (s, 1H), 6.37 (dd , J=8.7, 2.0 Hz, 1H), 6.34 (br d, J=13.6 Hz, 1H), 5.58 (q, J=6.5 Hz, 1H), 4, 03 (t, J=7.7 Hz, 2H), 3.81 (br dd, J=13.6, 3.8 Hz, 1H), 3.59 (dd, J=7.4, 5.8 Hz, 2H), 3.42-3.50 (m, 1H), 2.81-3.05 (m, 3H), 2.71 (br d, J=16.7 Hz, 1H), 2, 58 (d, J=4.4 Hz, 3H), 2.47-2.49 (m, 2H), 1.52 (d, J=6.9 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1.30 (m, 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.98 (br t, J=8.7 Hz, 1H), 7.81-7.85 (m, 1H), 7.06-7.25 (m, 4H), 6.93 (d, J=3.5Hz, 1H), 6.78 (s, 1H), 6.37 (dd, J=8.7, 2.0Hz, 1H) , 6.34 (br d, J=13.6 Hz, 1H), 4.96 (q, J=6.7 Hz, 1H), 4.52-4.58 (m, 1H), 4.03 (t, J=7.7 Hz, 2H), 3.59 (dd, J=1.A, 5.8 Hz, 2H), 3.23-3.30 (m, 1H), 2.81- 3.05 (m, 4H), 2.58 (d, J=4.4 Hz, 3H), 2.47-2.49 (m, 2H), 1.55 (d, J=6.6 Hz , 3H), 1.30-1.37 (m, 2H), 1.22-1.30 (m, 2H).

Compound 67.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.98 (br t, J=8.4 Hz, 1H), 7.32 (br d, J=7.3 Hz, 1H), 7.06- 7.26 (m, 3H), 6.92-6.96 (m, 1H), 6.81 (s, 1H), 6.33-6.43 (m, 2H), 5.70 (d, J=6.3Hz, 1H), 5.58(q, J=7.0Hz, 1H), 4.58-4.65(m, 1H), 4.16(t, J=7.3Hz, 2H), 3.81 (br dd, J=13.2, 4.1 Hz, 1H), 3.63 (dd, J=7.9, 4.7 Hz, 2H), 3.43-3, 50 (m, 1H), 2.83-3.06 (m, 2H), 2.72 (br d, J=16.4 Hz, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.36 (m, 2H), 1.21-1.29 (m, 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.98 (br t, J=8.4 Hz, 1H), 7.06-7.26 (m, 4H), 6.92-6.96 ( m, 1H), 6.78 (s, 1H), 6.33-6.43 (m, 2H), 5.70 (d, J=6.3 Hz, 1H), 4.96 (q, J =6.4 Hz, 1H), 4.58-4.65 (m, 1H), 4.51-4.57 (m, 1H), 4.16 (t, J=7.3 Hz, 2H) , 3.63 (dd, J=7.9, 4.7 Hz, 2H), 3.22-3.29 (m, 1H), 2.83-3.06 (m, 3H), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.36 (m, 2H), 1.21-1.29 (m, 2H).

Compound 68.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=9.0 Hz, 1H), 7.28-7.36 (m, 2H), 7.06-7.25 ( m, 3H), 6.956.99 (m, 1H), 6.92 (br d, J=8.8 Hz, 1H), 6.88 (br d, J=15.1 Hz, 1H), 6, 83 (s, 1H), 6.80 (br s, 1H), 5.59 (q, J=6.8 Hz, 1H), 3.89 (br d, J=12.9 Hz, 2H), 3.82 (br dd, J=13.9, 3.8 Hz, 1H), 3.43-3.50 (m, 1H), 2.97-3.05 (m, 1H), 2.91 -2.97 (m, 1H), 2.79-2.91 (m, 2H), 2.72 (br d, J=16.4 Hz, 1H), 2.29-2.38 (m, 1H), 1.76-1.83 (m, 2H), 1.62 (br qd, J=12.2, 3.6 Hz, 2H), 1.52 (d, J=6.9 Hz, 3H), 1.31-1.38 (m, 2H), 1.24-1.30 (m, 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (t, J=9.0 Hz, 1H), 7.28-7.36 (m, 1H), 7.06-7.25 (m , 4H), 6.956.99 (m, 1H), 6.92 (br d, J=8.8 Hz, 1H), 6.88 (br d, J=15.1 Hz, 1H), 6.80 (br s, 1H), 6.79 (s, 1H), 4.97 (q, J=6.6 Hz, 1H), 4.55 (br dd, J=12.9, 3.2 Hz, 1H), 3.89 (br d, J=12.9 Hz, 2H), 3.23-3.30 (m, 1H), 2.91-2.97 (m, 2H), 2.79- 2.91 (m, 3H), 2.29-2.38 (m, 1H), 1.76-1.83 (m, 2H), 1.62 (br qd, J=12.2, 3, 6 Hz, 2H), 1.55 (d, J=6.6 Hz, 3H), 1.31-1.38 (m, 2H), 1.24-1.30 (m, 2H).

Compound 69.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.9 Hz, 1H), 7.41 (br s, 1H), 7.32 (d, J=7.2 Hz, 1H), 7.057.25 (m, 3H), 6.86-7.00 (m, 4H), 6.83 (s, 1H), 5.59 (q, J=6.6 Hz, 1H ), 3.89 (br d, J=13.0 Hz, 1H), 3.78-3.86 (m, 2H), 3.41-3.52 (m, 1H), 2.86-3 .07 (m, 3H), 2.78-2.85 (m, 1H), 2.72 (br d, J=16.3 Hz, 1H), 2.36-2.46 (m, 1H) ,

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1.85-1.93 (m, 1H), 1.68-1.76 (m, 1H), 1.50-1.65 (m, 2H), 1.52 (d, J=6.8 Hz, 3H), 1.30-1.39 (m, 2H), 1.22-1.30 (m, 2H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.9 Hz, 1H), 7.41 (br s, 1H), 7.05-7.25 (m, 4H ), 6.86-7.00 (m, 4H), 6.80 (s, 1H), 4.97 (q, J=6.6 Hz, 1H), 4.55 (br dd, J=1 1.6, 3.9 Hz, 1H), 3.89 (br d, J=13.0 Hz, 1H), 3.783.86 (m, 1H), 3.22-3.31 (m, 1H) , 2.86-3.07(m, 4H), 2.78-2.85(m, 1H), 2.36-2.46(m, 1H), 1.85-1.93(m, 1H), 1.68-1.76 (m, 1H), 1.50-1.65 (m, 2H), 1.55 (br d, J=6.7 Hz, 3H), 1.30- 1.39 (m, 2H), 1.22-1.30 (m, 2H).

Compound 70.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (t, J=9.0 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.27 (br s , 1H), 7.057.25 (m, 3H), 6.95-6.98 (m, 1H), 6.90 (br d, J=8.8 Hz, 1H), 6.85 (dd, J =15.4, 1.9 Hz, 1H), 6.82 (s, 1H), 6.76 (br s, 1H), 5.59 (q, J=6.6 Hz, 1H), 3, 79-3.89 (m, 3H), 3.43-3.50 (m, 1H), 2.98-3.05 (m, 1H), 2.86-2.98 (m, 1H), 2.81 (t, J=11.7 Hz, 2H), 2.72 (br d, J=16.4 Hz, 1H), 2.01 (s, 2H), 1.85-1.95 ( m, 1H), 1.74 (br d, J=11.7 Hz, 2H), 1.52 (d, J=6.6 Hz, 3H), 1.31-1.37 (m, 2H) , 1.22-1.30 (m, 4H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=9.0 Hz, 1H), 7.27 (br s, 1H), 7.05-7.25 (m, 4H ), 6.95-6.98 (m, 1H), 6.90 (br d, J=8.8 Hz, 1H), 6.85 (dd, J=15.4, 1.9 Hz, 1H ), 6.79 (s, 1H), 6.76 (br s, 1H), 4.97 (q, J=6.5 Hz, 1H), 4.55 (br dd, J=13.1, 3.3 Hz, 1H), 3.79-3.89 (m, 2H), 3.23-3.30 (m, 1H), 2.86-2.98 (m, 3H), 2.81 (t, J=11.7 Hz, 2H), 2.03 (s, 2H), 1.85-1.95 (m, 1H), 1.74 (br d, J=11.7 Hz, 2H ), 1.55 (d, J=6.6 Hz, 3H), 1.31-1.37 (m, 2H), 1.22-1.30 (m, 4H).

Compound 71.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (br t, J=8.9 Hz, 1H), 7.34 (br s, 1H), 7.32 (br d, J=7, 9 Hz, 1H), 7.06-7.26 (m, 3H), 6.94-6.98 (m, 1H), 6.88 (br d, J=8.9 Hz, 1H), 6 .83 (s, 1H), 6.80-6.86 (m, 2H), 5.59 (q, J=6.6 Hz, 1H), 3.72-3.86 (m, 3H), 3.42-3.51 (m, 1H), 2.82-3.07 (m, 3H), 2.72 (br d, J=16.3 Hz, 1H), 2.63 (dd, J =12.1, 10.5 Hz, 1H), 1.92-2.14 (m, 3H), 1.74-1.83 (m, 1H), 1.65-1.73 (m, 1H ), 1.52 (br d, J=6.8 Hz, 3H), 1.301.38 (m, 2H), 1.24-1.30 (m, 2H), 1.12-1.23 (m , 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.99 (br t, J=8.9 Hz, 1H), 7.34 (br s, 1H), 7.06-7.26 (m, 4H), 6.946.98 (m, 1H), 6.88 (br d, J=8.9 Hz, 1H), 6.80-6.86 (m, 2H), 6.79 (s, 1H) , 4.97 (q, J=6.5 Hz, 1H), 4.55 (br dd, J=12.0, 3.3 Hz, 1H), 3.72-3.86 (m, 2H) , 3.22-3.31 (m, 1H), 2.82-3.07 (m, 4H), 2.63 (dd, J=12.1, 10.5 Hz, 1H), 1.92 -2.14 (m, 3H), 1.74-1.83 (m, 1H), 1.65-1.73 (m, 1H), 1.55 (br d, J=6.7 Hz, 3H), 1.30-1.38 (m, 2H), 1.241.30 (m, 2H), 1.12-1.23 (m, 2H).

Compound 72.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (br t, J=8.5 Hz, 1H), 7.76 (br d, J=3.8 Hz, 1H), 7.32 ( br d, J=7.3 Hz, 1H), 7.06-7.27 (m, 3H), 6.85-7.00 (m, 3H), 6.83 (s, 1H), 5, 59 (q, J=6.3 Hz, 1H), 3.89 (d, J=12.3 Hz, 2H), 3.82 (br d, J=9.8 Hz, 1H), 3.46 (br t, J=11.2 Hz, 1H), 2.79-3.06 (m, 4H), 2.72 (br d, J=15.8 Hz, 1H), 2.58 (d, J=4.1 Hz, 3H), 2.29-2.38 (m, 1H), 1.72-1.80 (m, 2H), 1.59-1.69 (m, 2H), 1 .52 (br d, J=6.3 Hz, 3H), 1.30-1.38 (m, 2H), 1.23-1.30 (m, 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.00 (br t, J=8.5 Hz, 1H), 7.76 (br d, J=3.8 Hz, 1H), 7.06 -7.27 (m, 4H), 6.85-7.00 (m, 3H), 6.79 (s, 1H), 4.97 (q, J=6.3 Hz, 1H), 4, 55 (br d, J=9.8 Hz, 1H), 3.89 (d, J=12.3 Hz, 2H), 3.22-3.30 (m, 1H), 2.79-3, 06 (m, 5H), 2.58 (d, J=4.1 Hz, 3H), 2.29-2.38 (m, 1H), 1.72-1.80 (m, 2H), 1 .59-1.69 (m, 2H), 1.55 (br d, J=6.6 Hz, 3H), 1.30-1.38 (m, 2H), 1.23-1.30 ( m, 2H).

Compound 73.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (br t, J=8.8 Hz, 1H), 7.86 (br d, J=4.4 Hz, 1H), 7.32 ( br d, J=7.6 Hz, 1H), 7.06-7.26 (m, 3H), 6.85-7.00 (m, 3H), 6.83 (s, 1H), 5, 59 (q, J=6.3 Hz, 1H), 3.78-3.92 (m, 3H), 3.43-3.52 (m, 1H), 2.79-3.06 (m, 3H), 2.67-2.75 (m, 2H), 2.60 (br d, J=4.1 Hz, 3H), 2.35-2.45 (m, 1H), 1.85 ( br d, J=10.7 Hz, 1H), 1.68-1.76 (m, 1H), 1.56-1.67 (m, 2H), l.52(br d, J=6, 6 Hz, 3H), 1.31-1.38 (m, 2H), 1.23-1.30 (m, 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (br t, J=8.8 Hz, 1H), 7.86 (br d, J=4.4 Hz, 1H), 7.06- 7.26 (m, 3H), 6.85-7.00 (m, 4H), 6.79 (s, 1H), 4.97 (q, J=6.0 Hz, 1H), 4.55 (br d, J=11.0 Hz, 1H), 3.78-3.92 (m, 2H), 3.22-3.30 (m, 1H), 2.79-3.06 (m, 4H), 2.67-2.75 (m, 1H), 2.60 (br d, J=4.1 Hz, 3H), 2.35-2.45 (m, 1H), 1.85 ( br d, J=10.7 Hz, 1H), 1.68-1.76 (m, 1H), 1.56-1.67 (m, 2H), l.55(br d, J=6, 6 Hz, 3H), 1.31-1.38 (m, 2H), 1.23-1.30 (m, 2H).

Compound 74.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (br t, J=9.0 Hz, 1H), 7.32 (br d, J=7.3 Hz, 1H), 7.06 -7.26(m,

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3H), 6.94-6.98 (m, 1H), 6.91 (br d, J=9.1 Hz, 1H), 6.86 (br d, J=15.4 Hz, 1H), 6.83 (s, 1H), 5.59 (q, J=6.8 Hz,

1H), 4.72 (d, J=4.1 Hz, 1H), 3.81 (br dd, J=12.9, 4.1 Hz, 1H), 3.65-3.73 (m, 3H), 3.43-3.50 (m, 1H), 2.83-3.06 (m, 4H), 2.72 (br d, J=16.1 Hz, 1H), 1.79- 1.86 (m, 2H), 1.52 (d, J=6.6 Hz, 3H), 1.41-1.50 (m, 2H), 1.31-1.38 (m,

2H), 1.22-1.30 (m, 2H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (br t, J=9.0 Hz, 1H), 7.06-7.26 (m, 4H), 6.94-6.98 (m, 1H), 6.91 (br d, J=9.1 Hz, 1H), 6.86 (br d, J=15.4 Hz, 1H), 6.79 (s, 1H), 4 .96 (q, J=6.6 Hz, 1H), 4.72 (d, J=4.1 Hz, 1H), 4.55 (br dd, J=12.3, 3.2 Hz, 1H ), 3.65-3.73 (m, 3H), 3.23-3.30 (m, 1H), 2.83-3.06 (m, 5H), 1.79-1.86 (m , 2H), 1.55 (d, J=6.9 Hz, 3H), 1.41-1.50 (m, 2H), 1.31-1.38 (m, 2H), 1.22- 1.30 (m, 2H).

Compound 75.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (br t, J=9.0 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.06- 7.25 (m, 3H), 6.94-6.98 (m, 1H), 6.88 (br d, J=8.8 Hz, 1H), 6.82 (s, 1H), 6. 82 (br dd, J=15.3, 1.4Hz, 1H), 5.59 (q, J=6.6Hz, 1H), 4.87 (d, J=4.4Hz, 1H) , 3.81 (br dd, J=13.7, 3.9 Hz, 1H), 3.71 (br d, J=12.6 Hz, 1H), 3.55-3.66 (m, 2H ), 3.42-3.51 (m, 1H), 2.83-3.05 (m, 3H), 2.69-2.76 (m, 2H), 1.87-1.94 (m , 1H), 1.73-1.80 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.28-1.41 (m, 4H), 1.22- 1.30 (m, 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (br t, J=9.0 Hz, 1H), 7.06-7.25 (m, 4H), 6.94-6.98 ( m, 1H), 6.88 (br d, J=8.8 Hz, 1H), 6.82 (br dd, J=15.3, 1.4 Hz, 1H), 6.79 (s, 1H ), 4.96 (q, J=6.6 Hz, 1H), 4.87 (d, J=4.4 Hz, 1H), 4.55 (br dd, J=12.1, 4.3 Hz, 1H), 3.71 (br d, J=12.6 Hz, 1H), 3.55-3.66 (m, 2H), 3.23-3.30 (m, 1H), 2, 83-3.05 (m, 4H), 2.69-2.76 (m, 1H), 1.87-1.94 (m, 1H), 1.73-1.80 (m, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.281.41 (m, 4H), 1.22-1.30 (m, 2H).

Compound 76.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.76 (br s, 1H), 8.02 (t, J=8.9 Hz, 1H), 7.32 (d, J=7.2 Hz, 1H), 7.097.26 (m, 3H), 6.92-6.97 (m, 1H), 6.81 (s, 1H), 6.55 (br d, J=8.7 Hz, 1H), 6.49 (br d, J=14.7 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 4.49-4.59 (m, 1H), 3 .81 (br dd, J=13.6, 4.5 Hz, 1H), 3.64 (dd, J=10.2, 6.8 Hz, 1H), 3.44-3.52 (m, 2H), 3.35-3.44 (m, 1H), 3.28-3.31 (m, 1H), 2.85-3.06 (m, 2H), 2.72 (br d, J =16.1 Hz, 1H), 2.23-2.32 (m, 1H), 2.02-2.12 (m, 1H), 1.52 (d, J=6.7 Hz, 3H) , 1.30-1.38(m, 2H), 1.21-1.30(m, 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.76 (br s, 1H), 8.02 (t, J=8.9 Hz, 1H), 7.09-7.26 (m, 3H ), 7.05-7.09 (m, 1H), 6.92-6.97 (m, 1H), 6.78 (s, 1H), 6.55 (br d, J=8.7 Hz , 1H), 6.49 (br d, J=14.7 Hz, 1H), 4.96 (q, J=6.9 Hz, 1H), 4.49-4.59 (m, 2H), 3.64 (dd, J=10.2, 6.8 Hz, 1H), 3.44-3.52 (m, 1H), 3.35-3.44 (m, 2H), 3.213.28 ( m, 1H), 2.85-3.06 (m, 3H), 2.23-2.32 (m, 1H), 2.02-2.12 (m, 1H), 1.55 (d, J=6.7 Hz, 3H), 1.30-1.38 (m, 2H), 1.21-1.30 (m, 2H).

Compound 77.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.01 (t, J=8.8 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.20-7, 25 (m, 1H), 7.15-7.20 (m, 2H), 6.94 (d, J=3.8 Hz, 1H), 6.81 (s, 1H), 6.66 (br s, 1H), 6.55 (br d, J=8.8 Hz, 1H), 6.52 (br s, 1H), 6.49 (br dd, J=14.5, 1.6 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 5.23 (br s, 1H), 3.81 (br dd, J=13.9, 3.5 Hz, 1H), 3.60 (dd, J=11.5, 4.6 Hz, 1H), 3.41-3.51 (m, 2H), 3.33-3.41 (m, 2H), 2.83- 3.06 (m, 2H), 2.72 (br d, J=16.4 Hz, 1H), 2.19-2.29 (m, 1H), 2.06-2.13 (m, 1H ), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.21-1.30 (m, 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.01 (t, J=8.8 Hz, 1H), 7.15-7.20 (m, 2H), 7.10-7.14 ( m, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.93 (d, J=3.8 Hz, 1H), 6.77 (s, 1H), 6.66 ( br s, 1H), 6.55 (br d, J=8.8 Hz, 1H), 6.52 (br s, 1H), 6.49 (br dd, J=14.5, 1.6 Hz , 1H), 5.23 (br s, 1H), 4.96 (q, J=6.7 Hz, 1H), 4.55 (br dd, J=12.3, 3.8 Hz, 1H) , 3.60 (dd, J=11.5, 4.6 Hz, 1H), 3.41-3.51 (m, 2H), 3.33-3.41 (m, 1H), 3.22 -3.30 (m, 1H), 2.83-3.06 (m, 3H), 2.19-2.29 (m, 1H), 2.06-2.13 (m, 1H), 1 .55 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.21-1.30 (m, 2H).

Compound 78.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.01 (t, J=8.8 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.21-7, 25 (m, 1H), 7.15-7.21 (m, 2H), 6.94 (d, J=3.5 Hz, 1H), 6.81 (s, 1H), 6.66 (br s, 1H), 6.54 (br d, J=8.8 Hz, 1H), 6.52 (br s, 1H), 6.49 (br d, J=14.8 Hz, 1H), 5 .59 (q, J=6.5 Hz, 1H), 5.23 (br s, 1H), 3.81 (br dd, J=14.3, 4.3 Hz, 1H), 3.60 ( dd, J=11.5, 4.6 Hz, 1H), 3.33-3.50 (m, 4H), 2.82-3.06 (m, 2H), 2.72 (br d, J =16.4 Hz, 1H), 2.19-2.29 (m, 1H), 2.05-2.14 (m, 1H), 1.52 (d, J=6.6 Hz, 3H) , 1.30-1.37(m, 2H), 1.21-1.29(m, 2H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.01 (t, J=8.8 Hz, 1H), 7.15-7.21 (m, 2H), 7.10-7.15 ( m, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.93 (d, J=3.8 Hz, 1H), 6.77 (s, 1H), 6.66 ( br s, 1H), 6.54 (br d, J=8.8 Hz, 1H), 6.52 (br s, 1H), 6.49 (br d, J=14.8 Hz, 1H), 5.23 (br s, 1H), 4.96 (q, J=6.8 Hz, 1H), 4.51-4.58 (m, 1H), 3.60 (dd, J=11.5 , 4.6 Hz, 1H), 3.33-3.50 (m, 3H), 3.23-3.30 (m, 1H), 2.82-3.06 (m, 3H), 2, 19-2.29 (m, 1H), 2.05-2.14 (m, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.21-1.29 (m, 2H).

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Compound 79.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (br t, J=8.7 Hz, 1H), 7.38 (br s, 1H), 7.32 (br d, J=7 .3 Hz, 1H), 7.10-7.26 (m, 3H), 6.98-7.03 (m, 1H), 6.93 (br d, J=8.6 Hz, 1H), 6.84-6.90 (m, 2H), 5.59 (q, J=6.8 Hz, 1H), 3.914.01 (m, 1H), 3.77-3.86 (m, 1H) , 3.42-3.52(m, 1H), 3.17-3.32(m, 4H), 2.68-3.15(m, 6H), 2.02-2.21(m, 2H), 1.52 (d, J=6.7 Hz, 3H), 1.31-1.39 (m, 2H), 1.21-1.30 (m, 2H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (br t, J=8.7 Hz, 1H), 7.38 (br s, 1H), 7.10-7.26 (m, 3H), 7.08 (br d, J=7.2 Hz, 1H), 6.98-7.03 (m, 1H), 6.93 (br d, J=8.6 Hz, 1H), 6.84-6.90 (m, 1H), 6.84-6.91 (m, 1H), 6.82 (s, 1H), 4.96 (q, J=6.4 Hz, 1H) , 4.52-4.59(m, 1H), 3.91-4.01(m, 1H), 3.17-3.32(m, 4H), 2.68-3.15(m, 7H), 2.022.21 (m, 2H), 1.55 (br d, J=6.6 Hz, 3H), 1.31-1.39 (m, 2H), 1.21-1.30 ( m, 2H).

Compound 80.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.147.25 (m, 3H), 7.04 (s, 1H), 6.93 (d, J=3.8 Hz, 1H), 6.80 (s, 1H), 6, 54 (dd, J=8.8, 2.2Hz, 1H), 6.43 (dd, J=14.8, 1.9Hz, 1H), 5.59 (q, J=6.8Hz , 1H), 4.20 (quin, J=6.5 Hz, 1H), 3.82 (ddd, J=9.8, 5.4, 1.3 Hz, 1H), 3.41-3, 50 (m, 2H), 3.17-3.25 (m, 1H), 2.86-3.08 (m, 3H), 2.72 (br d, J=16.1 Hz, 1H), 2.27-2.35 (m, 1H), 1.96-2.04 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.37 ( m, 2H), 1.21-1.30 (m, 2H), 1.02 (d, J=6.3 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.14-7.25 (m, 2H) , 7.10-7.15(m, 1H), 7.06-7.09(m, 1H), 7.04(s, 1H), 6.92(d, J=3.8Hz, 1H ), 6.77 (s, 1H), 6.54 (dd, J=8.8, 2.2Hz, 1H), 6.43 (dd, J=14.8, 1.9Hz, 1H) , 4.96 (q, J=6.5 Hz, 1H), 4.55 (ddd, J=12.9, 5.7, 1.9 Hz, 1H), 4.20 (quin, J=6 .5 Hz, 1H), 3.41-3.50 (m, 1H), 3.25-3.29 (m, 1H), 3.17-3.25 (m, 1H), 2.86- 3.08 (m, 4H), 2.27-2.35 (m, 1H), 1.96-2.04 (m, 1H), 1.55 (d, J=6.6 Hz, 3H) , 1.30-1.37 (m, 2H), 1.21-1.30 (m, 2H), 1.02 (d, J=6.3 Hz, 3H).

Compound 81.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.98 (t, J=8.8 Hz, 1H), 7.47 (br s, 1H), 7.32 (d, J=7, 6 Hz, 1H), 7.067.25 (m, 3H), 6.87-6.98 (m, 2H), 6.80 (s, 1H), 6.53 (dd, J=9.0, 1 .7 Hz, 1H), 6.44 (br d, J=14.8 Hz, 1H), 5.59 (q, J=6.9 Hz, 1H), 4.01-4.08 (m, 1H), 3.82 (br dd, J=13.2, 4.1 Hz, 1H), 3.35-3.50 (m, 2H), 3.21-3.30 (m, 1H), 2.823.05 (m, 2H), 2.68-2.75 (m, 2H), 2.20-2.29 (m, 1H), 2.06-2.15 (m, 1H), 1, 52 (d, J=6.9 Hz, 3H), 1.29-1.37 (m, 2H), 1.25-1.29 (m, 2H), 1.22 (br d, J=6 .3 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.98 (t, J=8.8 Hz, 1H), 7.47 (br s, 1H), 7.06-7.25 (m, 4H), 6.87-6.98 (m, 2H), 6.76 (s, 1H), 6.53 (dd, J=9.0, 1.7 Hz, 1H), 6.44 (br d, J=14.8 Hz, 1H), 4.97 (q, J=7.1 Hz, 1H), 4.55 (br dd, J=12.6, 3.8 Hz, 1H), 4 .01-4.08 (m, 1H), 3.35-3.50 (m, 2H), 3.22-3.30 (m, 1H), 2.82-3.05 (m, 3H) , 2.68-2.75 (m, 1H), 2.20-2.29 (m, 1H), 2.06-2.15 (m, 1H), 1.55 (d, J=6, 6 Hz, 3H), 1.29-1.37 (m, 2H), 1.25-1.29 (m, 2H), 1.22 (br d, J=6.3 Hz, 3H).

Compound 82.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.98 (t, J=8.8 Hz, 1H), 7.47 (br s, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.217.25 (m, 1H), 7.15-7.21 (m, 2H), 6.87-6.96 (m, 2H), 6.80 (s, 1H), 6 .53 (br d, J=8.8 Hz, 1H), 6.44 (dd, J=15.0, 1.7 Hz, 1H), 5.58 (q, J=6.5 Hz, 1H ), 4.00-4.08 (m, 1H), 3.82 (br dd, J=13.9, 3.8 Hz, 1H), 3.40-3.50 (m, 2H), 3.283 .35 (m, 1H, _H2O peaked), 2.82-3.06 (m, 2H), 2.68-2.76 (m, 2H), 2.19-2.29 (m, 1H), 2.06-2.14 (m, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.38 (m, 2H), 1.25-1 .30 (m, 2H), 1.22 (d, J=6.3 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.98 (t, J=8.8 Hz, 1H), 7.47 (br s, 1H), 7.15-7.21 (m, 2H), 7.10-7.14 (m, 1H), 7.06-7.10 (m, 1H), 6.87-6.96 (m, 2H), 6.76 (s, 1H) , 6.53 (br d, J=8.8 Hz, 1H), 6.44 (dd, J=15.0, 1.7 Hz, 1H), 4.97 (q, J=6.5 Hz , 1H), 4.55 (br dd, J=12.8, 3.6 Hz, 1H), 4.00-4.08 (m, 1H), 3.40-3.50 (m, 1H) , 3.28-3.35 (m, 1H, H ₂ O peaked), 3.21-3.27 (m, 1H), 2.82-3.06 (m, 3H), 2.68- 2.76 (m, 1H), 2.19-2.29 (m, 1H), 2.06-2.14 (m, 1H), 1.55 (d, J=6.6 Hz, 3H) , 1.30-1.38 (m, 2H), 1.25-1.30 (m, 2H), 1.22 (d, J=6.3 Hz, 3H).

Compound 83.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.32 (d, J=7.3 Hz , 1H), 7.157.26 (m, 3H), 7.04 (s, 1H), 6.93 (d, J=3.5 Hz, 1H), 6.80 (s, 1H), 6.54 (br d, J=8.8 Hz, 1H), 6.43 (dd, J=14.8, 1.6 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 4.20 (quin, J=6.5 Hz, 1H), 3.82 (br dd, J=13.6, 3.8 Hz, 1H), 3.41-3.50 (m, 2H), 3.17-3.25 (m, 1H), 2.86-3.07 (m, 3H), 2.72 (br d, J=16.1 Hz, 1H), 2.27-2.35 (m, 1H), 2.00 (dt, J=12.6, 6.6 Hz, 1H), 1.52 (d, J=6.6 Hz, 3H), 1.30-1.37 ( m, 2H), 1.21-1.29 (m, 2H), 1.02 (d, J=6.3 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.15-7.26 (m, 2H ), 7.10-7.15 (m, 1H), 7.06-7.09 (m, 1H), 7.04 (s, 1H), 6.92 (d, J=3.8 Hz, 1H), 6.77 (s, 1H), 6.54 (br d, J=8.8 Hz, 1H), 6.43 (dd, J=14.8, 1.6 Hz, 1H), 4 .97 (q, J=6.6 Hz, 1H), 4.55 (br dd, J=12.9, 3.2 Hz, 1H), 4.20 (quin, J=6.5 Hz, 1H ),

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3.41-3.50 (m, 1H), 3.25-3.29 (m, 1H), 3.17-3.25 (m, 1H), 2.86-3.07 (m, 4H ), 2.27-2.35 (m, 1H), 2.00 (dt, J=12.6,

6.6 Hz, 1H), 1.55 (d, J=6.9 Hz, 3H), 1.30-1.37 (m, 2H), 1.21-1.29 (m, 2H), 1.02 (d, J=6.3 Hz, 3H).

Compound 84.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (d, J=7.8 Hz, 1H), 8.89 (d, J=4.0 Hz, 1H), 8.15-8 .23 (m, 1H), 8.05 (t, J=8.8 Hz, 1H), 7.91 (s, 1H), 7.65-7.72 (m, 1H), 7.52 ( br s, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.06-7.27 (m, 4H), 7.02 (br s, 1H), 6.55 (dd , J=8.9, 1.8Hz, 1H), 6.48 (dd, J=14.6, 1.7Hz, 1H), 5.64 (q, J=6.5Hz, 1H) , 4.07 (br dd, J=13.0, 4.2 Hz, 1H), 3.48-3.54 (m, 2H), 3.34-3.47 (m, 3H), 3. 00-3.14 (m, 2H), 2.77 (br d, J=16.6 Hz, 1H), 2.16-2.26 (m, 1H), 2.07-2.16 (m , 1H), l.56 (d, J=6.7 Hz, 3H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.30 (d, J=8.3 Hz, 1H), 8.86 (br d, J=4.3 Hz, 1H), 8.15- 8.23 (m, 1H), 8.05 (t, J=8.8 Hz, 1H), 7.86 (s, 1H), 7.65-7.72 (m, 1H), 7.52 (br s, 1H), 7.06-7.27 (m, 5H), 7.02 (br s, 1H), 6.55 (dd, J=8.9, 1.8 Hz, 1H), 6.48 (dd, J=14.6, 1.7 Hz, 1H), 5.17 (q, J=7.0 Hz, 1H), 4.57-4.64 (m, 1H), 3 .55-3.59 (m, 1H), 3.34-3.47 (m, 3H), 3.27-3.31 (m, 1H), 3.00-3.14 (m, 1H), 2 .93-3.00 (m, 1H), 2.84-2.91 (m, 1H), 2.162.26 (m, 1H), 2.07-2.16 (m, 1H), 1.61 (d, J=6.8 Hz, 3H).

Compound 85.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (br t, J=9.3 Hz, 1H), 7.32 (br d, J=7.5 Hz, 1H), 7.15- 7.26 (m, 3H), 6.93-6.97 (m, 1H), 6.83 (s, 1H), 6.58 (br d, J=8.3 Hz, 1H), 6, 46-6.72 (m, 2H), 5.58 (q, J=7.0 Hz, 1H), 5.21 (br s, 1H), 3.76-3.85 (m, 1H), 3.60-3.71 (m, 2H), 3.52-3.59 (m, 1H), 3.41-3.52 (m, 2H), 2.81-3.07 (m, 2H ), 2.72 (br d, J=16.5 Hz, 1H), 2.18-2.29 (m, 1H), 2.06-2.15 (m, 1H), 1.52 (br d, J=6.7 Hz, 3H), 1.30-1.39 (m, 2H), 1.211.30 (m, 2H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (br t, J=9.3 Hz, 1H), 7.15-7.26 (m, 2H), 7.09-7.15 ( m, 1H), 7.08 (br d, J=7.6 Hz, 1H), 6.93-6.97 (m, 1H), 6.80 (s, 1H), 6.58 (br d , J=8.3 Hz, 1H), 6.46-6.72 (m, 2H), 5.21 (br s, 1H), 4.96 (q, J=7.0 Hz, 1H), 4.51-4.58(m, 1H), 3.60-3.71(m, 2H), 3.52-3.59(m, 1H), 3.41-3.52(m, 2H ), 2.81-3.07 (m, 3H), 2.18-2.29 (m, 1H), 2.06-2.15 (m, 1H), 1.55 (br d, J= 6.8 Hz, 3H), 1.30-1.39 (m, 2H), 1.211.30 (m, 2H).

Compound 86 Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.52 (br s, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.09-7.25 (m, 3H ), 7.01 (br s, 1H), 6.82 (d, J=12.0 Hz, 2H), 6.00 (s, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.89 (s, 3H), 3.82 (br dd, J=13.7, 3.6 Hz, 1H), 3.62-3.70 (m, 1H), 3.54- 3.62 (m, 1H), 3.48-3.54 (m, 1H), 3.44-3.48 (m, 1H), 3.39-3.44 (m, 1H), 3. 07 (quin, J=7.6 Hz, 1H), 2.81-2.95 (m, 2H), 2.71 (br d, J=16.4 Hz, 1H), 2.14-2, 23 (m, 1H), 2.04-2.14 (m, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.22-1.35 (m, 4H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.52 (br s, 1H), 7.09-7.21 (m, 4H), 7.01 (br s, 1H), 6.80 (d , J=22.1 Hz, 2H), 6.00 (s, 1H), 4.96 (q, J=6.7 Hz, 1H), 4.55 (br dd, J=13.1, 3 .0 Hz, 1H), 3.89 (s, 3H), 3.62-3.70 (m, 1H), 3.54-3.62 (m, 1H), 3.48-3.54 ( m, 1H), 3.39-3.44 (m, 1H), 3.21-3.30 (m, 1H), 3.07 (quin, J=7.6 Hz, 1H), 2.96 -3.04 (m, 2H), 2.81-2.95 (m, 1H), 2.14-2.23 (m, 1H), 2.04-2.14 (m, 1H), 1 .54 (d, J=6.6 Hz, 3H), 1.22-1.35 (m, 4H).

Compound 87.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.50 (br s, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.07-7.25 (m, 3H ), 7.00 (br s, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 6.02 (s, 1H), 5.58 (q, J=6.8 Hz, 1H), 4.26-4.33 (m, 2H), 3.80 (br dd, J=13.9, 3.8 Hz, 1H), 3.67-3.72 (m, 2H ), 3.64 (br t, J=9.1 Hz, 1H), 3.53-3.61 (m, 1H), 3.50 (dd, J=10.4, 6.9 Hz, 1H ), 3.373.48 (m, 2H), 3.29 (s, 3H), 3.03-3.10 (m, 1H), 2.82-2.96 (m, 2H), 2.71 ( br d, J=16.1 Hz, 1H), 2.14-2.22 (m, 1H), 2.04-2.13 (m, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.23-1.34 (m, 4H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.50 (br s, 1H), 7.07-7.25 (m, 4H), 7.00 (br s, 1H), 6.92 (s , 1H), 6.77 (s, 1H), 6.02 (s, 1H), 4.96 (q, J=6.1 Hz, 1H), 4.55 (br dd, J=11.7 , 4.4 Hz, 1H), 4.26-4.33 (m, 2H), 3.67-3.72 (m, 2H), 3.64 (br t, J=9.1 Hz, 1H ), 3.53-3.61 (m, 1H), 3.50 (dd, J=10.4, 6.9 Hz, 1H), 3.37-3.48 (m, 1H), 3, 28 (s, 3H), 3.23-3.28 (m, 1H), 3.03-3.10 (m, 1H), 2.96-3.03 (m, 2H), 2.82- 2.96 (m, 1H), 2.14-2.22 (m, 1H), 2.04-2.13 (m, 1H), 1.54 (d, J=6.6Hz, 3H) , 1.23-1.34 (m, 4H).

Compound 88.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.08 (d, J=5.7 Hz, 1H), 7.53 (br s, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.047.26 (m, 4H), 7.01 (br s, 1H), 6.84 (s, 1H), 5.59 (q, J=6.9 Hz, 1H), 3 .80 (br dd, J=13.9, 3.5 Hz, 1H), 3.74 (dd, J=10.7, 7.9 Hz, 1H), 3.58-3.69 (m, 2H), 3.43-3.57 (m, 2H), 3.08-3.15 (m, 1H), 2.83-3.05 (m, 2H), 2.72 (br d, J =16.1 Hz, 1H), 2.19-2.28 (m, 1H), 2.09-2.17 (m, 1H), 1.52 (d, J=6.9 Hz, 3H) , 1.31-1.38(m, 2H), 1.22-1.30(m, 2H).

Minor rotamer (35%).

- 134 040266 ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.08 (d, J=5.7 Hz, 1H), 7.53 (br s, 1H), 7.04-7.26 (m, 5H), 7.01 (br s, 1H), 6.80 (s, 1H), 4.96 (q, J=7.0 Hz, 1H), 4.55 (br dd, J= 12.9, 3.2 Hz, 1H), 3.74 (dd, J=10.7, 7.9 Hz, 1H), 3.583.69 (m, 2H), 3.43-3.57 (m , 2H), 3.08-3.15 (m, 1H), 2.83-3.05 (m, 3H), 2.19-2.28 (m, 1H), 2.09-2.17 (m, 1H),

1.54 (d, J=6.6 Hz, 3H), 1.31-1.38 (m, 2H), 1.22-1.30 (m, 2H).

Compound 89.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.50 (br s, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.10-7.25 (m, 3H ), 6.99 (s, 1H), 6.84 (s, 1H), 6.81 (d, J=2.2 Hz, 1H), 6.36 (br s, 1H), 6.30 ( dd, J=13.6, 1.9 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.84 (br dd, J=13.9, 3.8 Hz, 1H), 3.44-3.51 (m, 2H), 3.34-3.42 (m, 2H), 3.23-3.31 (m, 1H), 3.07 (quin, J= 7.8 Hz, 1H), 2.82-2.96 (m, 2H), 2.72 (br d, J=16.4 Hz, 1H), 2.37 (s, 3H), 2.15 -2.23 (m, 1H), 2.05-2.14 (m, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.22-1.34 (m, 4H ).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.50 (br s, 1H), 7.10-7.25 (m, 4H), 6.99 (s, 1H), 6.81 ( s, 1H), 6.81 (d, J=2.2 Hz, 1H), 6.36 (br s, 1H), 6.30 (dd, J=13.6, 1.9 Hz, 1H) , 4.99 (q, J=6.6 Hz, 1H), 4.56 (br dd, J=12.8, 3.3 Hz, 1H), 3.44-3.51 (m, 1H) , 3.34-3.42 (m, 2H), 3.23-3.31 (m, 2H), 3.07 (quin, J=7.8 Hz, 1H), 2.96-3.04 (m, 2H), 2.82-2.96 (m, 1H), 2.37 (s, 3H), 2.15-2.23 (m, 1H), 2.05-2.14 (m , 1H), 1.55 (d, J=6.6 Hz, 3H), 1.22-1.34 (m, 4H).

Compound 90.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 9.35 (s, 1H), 8.85 (d, J=2.5 Hz, 1H), 8.68-8.73 (m, 1H) , 7.90 (t, J=8.8 Hz, 1H), 7.62 (s, 1H), 7.51 (br s, 1H), 7.34 (d, J=7.3 Hz, 1H ), 7.06-7.27 (m, 4H), 7.00 (br s, 1H), 6.53 (br d, J=8.8 Hz, 1H), 6.46 (dd, J= 14.8, 1.9 Hz, 1H), 5.64 (q, J=6.8 Hz, 1H), 3.96 (br dd, J=13.9, 4.7 Hz, 1H), 3.513 .58 (m, 1H), 3.46-3.51 (m, 1H), 3.29-3.45 (m, 3H, partially covered by H ₂ O peak), 3.03-3.12 (m , 2H), 2.76 (br d, J=16.4 Hz, 1H), 2.16-2.24 (m, 1H), 2.05-2.14 (m, 1H), 1.56 (d, J=6.6 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 9.31 (s, 1H), 8.84 (d, J=2.8 Hz, 1H), 8.65-8.70 (m, 1H) , 7.90 (t, J=8.8 Hz, 1H), 7.58 (s, 1H), 7.51 (br s, 1H), 7.06-7.27 (m, 5H), 7 .00 (br s, 1H), 6.53 (br d, J=8.8 Hz, 1H), 6.46 (dd, J=14.8, 1.9 Hz, 1H), 5.12 ( q, J=6.8 Hz, 1H), 4.56-4.63 (m, 1H), 3.46-3.51 (m, 1H), 3.29-3.45 (m, 4H, partially covered by the H ₂ O peak), 3.03-3.12 (m, 1H), 2.84-2.99 (m, 2H), 2.16-2.24 (m, 1H), 2.05 -2.14 (m, 1H), 1.62 (d, J=6.6 Hz, 3H).

Compound 91.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.5 Hz, 1H), 7.51 (br s, 1H), 7.32 (d, J=7, 6 Hz, 1H), 7.147.25 (m, 3H), 7.03-7.09 (m, 1H), 6.95 (d, J=3.5 Hz, 1H), 6.82 (s, 1H), 6.36-6.43 (m, 2H), 5.58 (q, J=6.6 Hz, 1H), 4.05 (t, J=8.0 Hz, 2H), 3, 91 (t, J=6.8 Hz, 2H), 3.81 (br dd, J=13.7, 3.9 Hz, 1H), 3.43-3.51 (m, 2H), 2, 83-3.05 (m, 2H), 2.72 (br d, J=16.1 Hz, 1H), 1.52 (d, J=6.9 Hz, 3H), 1.30-1, 37 (m, 2H), 1.22-1.30 (m, 2H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.5 Hz, 1H), 7.51 (br s, 1H), 7.14-7.25 (m, 2H ), 7.10-7.14 (m, 1H), 7.03-7.09 (m, 2H), 6.94 (d, J=3.8 Hz, 1H), 6.78 (s, 1H), 6.36-6.43(m, 2H), 4.96(m, 1H), 4.52-4.58(m, 1H), 4.05(t, J=8.0Hz , 2H), 3.91 (t, J=6.8 Hz, 2H), 3.43-3.51 (m, 1H), 3.23-3.30 (m, 1H), 2.83- 3.05 (m, 3H), 1.55 (d, J=6.6 Hz, 3H), 1.30-1.37 (m, 2H), 1.22-1.30 (m, 2H) .

Compound 92.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.35 (t, J=9.1 Hz, 1H), 7.38 (br s, 1H), 7.32 (br d, J=7 .1 Hz, 1H), 7.05-7.26 (m, 3H), 6.92-6.96 (m, 1H), 6.87 (br s, 1H), 6.84 (s, 1H ), 6.41 (br d, J=7.8 Hz, 1H), 5.58 (q, J=6.7 Hz, 1H), 4.16 (t, J=8.3 Hz, 2H) , 3.80 (br dd, J=13.8, 3.8 Hz, 1H), 3.73 (dd, J=8.4, 5.8 Hz, 2H), 3.41-3.51 ( m, 1H), 2.85-3.07 (m, 3H), 2.71 (br d, J=16.6 Hz, 1H), 2.43-2.47 (m, 2H, partially covered by peak DMSO), 1.52 (d, J=6.8 Hz, 3H), 1.30-1.38 (m, 2H), 1.20-1.29 (m, 2H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.35 (t, J=9.1 Hz, 1H), 7.38 (br s, 1H), 7.05-7.26 (m, 4H ), 6.92-6.96 (m, 1H), 6.87 (br s, 1H), 6.80 (s, 1H), 6.41 (br d, J=7.8 Hz, 1H) , 4.95 (q, J=6.8 Hz, 1H), 4.51-4.59 (m, 1H), 4.16 (t, J=8.3 Hz, 2H), 3.73 ( dd, J=8.4, 5.8 Hz, 2H), 3.22-3.31 (m, 1H), 2.85-3.07 (m, 4H), 2.43-2.47 ( m, 2H, partially covered by DMSO peak), 1.55 (br d, J=6.7 Hz, 3H), 1.30-1.38 (m, 2H), 1.20-1.29 (m, 2H).

Compound 93.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (t, J=8.6 Hz, 1H), 7.32 (br d, J=7.3 Hz, 1H), 7.10- 7.28 (m, 3H), 6.89-6.98 (m, 1H), 6.80 (s, 1H), 6.49 (br d, J=9.4 Hz, 1H), 6, 40 (br d, J=14.7 Hz, 1H), 5.54-5.63 (m, 1H), 3.753.86 (m, 1H), 3.19-3.66 (m, 6H), 2.68-3.06 (m, 4H), 2.01-2.16 (m, 2H), 1.72-1.80 (m, 1H), 1.46-1.59 (m, 3H ), 1.19-1.39 (m, 4H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.6 Hz, 1H), 7.10-7.28 (m, 3H), 7.07 (br d, J=7.5Hz, 1H),

- 135 040266

6.89-6.98 (m, 1H), 6.77 (s, 1H), 6.49 (br d, J=9.4 Hz, 1H), 6.40 (br d, J=14, 7 Hz, 1H), 4.91-5.00 (m, 1H), 4.504.60 (m, 1H), 3.19-3.66 (m, 6H), 2.68-3.06 (m , 4H), 2.01-2.16 (m, 2H), 1.72-1.80 (m, 1H), 1.46-1.59 (m, 3H),

1.19-1.39 (m, 4H).

Compound 94.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.10-7 .26 (m, 3H), 6.87-7.00 (m, 1H), 6.80 (s, 1H), 6.50 (br d, J=8.7 Hz, 1H), 6.43 (br d, J=14.9 Hz, 1H), 5.59 (q, J=6.8r _y , 1H), 3.81 (br dd, J=14.0, 4.2 Hz, 1H) , 3.31-3.60 (m, 7H), 3.06-3.15 (m, 1H), 2.68-3.14 (m, 4H), 2.03-2.21 (m, 1H), 1.781.95 (m, 1H), 1.45-1.60 (m, 3H), 1.17-1.43 (m, 4H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.10-7.26 (m, 3H), 7.08 (d, J= 7.5 Hz, 1H), 6.87-7.00 (m, 1H), 6.77 (s, 1H), 6.50 (br d, J=8.7 Hz, 1H), 6.43 (br d, J=14.9 Hz, 1H), 4.96 (d, J=6.6 Hz, 1H), 4.50-4.60 (m, 1H), 3.31-3.60 (m, 7H), 3.06-3.15 (m, 1H), 2.68-3.14 (m, 4H), 2.03-2.21 (m, 1H), 1.78-1 .95 (m, 1H), 1.45-1.60 (m, 3H), 1.17-1.43 (m, 4H).

Compound 95.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.31 (br d, J=7.6 Hz, 1H), 7.04- 7.27 (m, 3H), 6.90-6.97 (m, 1H), 6.70-6.88 (m, 1H), 6.48 (br d, J=8.8 Hz, 1H ), 6.40 (dd, J=14.7, 1.4Hz, 1H), 5.59 (q, J=6.5Hz, 1H), 4.89-5.01 (m, 2H) , 4.18 (br d, J=3.5 Hz, 2H), 3.82 (br dd, J=13.4, 3.9 Hz, 1H), 3.40-3.55 (m, 3H ), 3.18 (br dd, J=9.8, 3.8 Hz, 2H), 2.81-3.05 (m, 2H), 2.65-2.78 (m, 1H), 1 .48-1.58 (m, 3H), 1.19-1.39 (m, 4H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.04-7.27 (m, 4H), 6.90-6.97 (m , 1H), 6.706.88 (m, 1H), 6.48 (br d, J=8.8 Hz, 1H), 6.40 (dd, J=14.7, 1.4 Hz, 1H), 4.89-5.01 (m, 3H), 4.55 (br dd, J=12.9, 3.2 Hz, 1H), 4.18 (br d, J=3.5 Hz, 2H) , 3.40-3.55 (m, 2H), 3.23-3.28 (m, 1H), 3.18 (br dd, J=9.8, 3.8 Hz, 2H), 2, 81-3.05 (m, 3H), 1.48-1.58 (m, 3H), 1.19-1.39 (m, 4H).

Compound 96.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.5 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.07-7 .25 (m, 3H), 6.91-6.95 (m, 1H), 6.76-6.82 (m, 1H), 6.52 (dd, J=8.8, 1.9 Hz , 1H), 6.45 (dd, J=14.7, 2.0 Hz, 1H), 5.59 (q, J=6.8 Hz, 1H), 5.31 (d, J=3, 8 Hz, 1H), 4.26 (br s, 1H), 3.78-3.85 (m, 2H), 3.43-3.55 (m, 3H), 3.26-3.41 ( m, 4H), 3.20 (d, J=10.7 Hz, 1H), 2.84-3.05 (m, 2H), 2.72 (br d, J=16.4 Hz, 1H) , 1.48-1.58 (m, 3H), 1.21-1.37 (m, 4H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.5 Hz, 1H), 7.07-7.25 (m, 4H), 6.91-6.95 ( m, 1H), 6.766.82 (m, 1H), 6.52 (dd, J=8.8, 1.9 Hz, 1H), 6.45 (dd, J=14.7, 2.0 Hz , 1H), 5.31 (d, J=3.8 Hz, 1H), 4.96 (d, J=6.9 Hz, 1H), 4.52-4.58 (m, 1H), 4 .26 (br s, 1H), 3.78-3.85 (m, 1H), 3.43-3.55 (m, 2H), 3.26-3.41 (m, 5H), 3. 20 (d, J=10.7 Hz, 1H), 2.84-3.05 (m, 3H), 1.48-1.58 (m, 3H), 1.21-1.37 (m, 4H).

Compound 97.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.03 (t, J=8.4 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.06-7, 24 (m, 3H), 6.95-6.98 (m, 1H), 6.78-6.83 (m, 1H), 6.55-6.60 (m, 2H), 6.15 ( d, J=5.4 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 4.364.43 (m, 1H), 3.71-3.84 (m, 4H), 3.43-3.50 (m, 1H), 3.31-3.38 (m, 1H), 2.84-3.05 (m, 2H), 2.72 (br d, J=16, 1 Hz, 1H), 1.49-1.57 (m, 3H), 1.22-1.38 (m, 4H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.03 (t, J=8.4 Hz, 1H), 7.06-7.24 (m, 4H), 6.95-6.98 ( m, 1H), 6.786.83 (m, 1H), 6.55-6.60 (m, 2H), 6.15 (d, J=5.4 Hz, 1H), 4.97 (q, J =6.6 Hz, 1H), 4.52-4.58 (m, 1H), 4.36-4.43 (m, 1H), 3.71-3.84 (m, 3H), 3, 31-3.38 (m, 1H), 3.23-3.28 (m, 1H), 2.84-3.05 (m, 3H), 1.49-1.57 (m, 3H), 1.221.38 (m, 4H).

Compound 98.

Basic rotamer (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.98 (t, J=8.8 Hz, 1H), 7.31 (d, J=7.3 Hz, 1H), 7.07-7, 24 (m, 3H), 6.91-6.95 (m, 1H), 6.75-6.81 (m, 1H), 6.55 (dd, J=8.8, 1.9 Hz, 1H), 6.49 (dd, J=14.8, 1.9 Hz, 1H), 5.59 (q, J=6.8 Hz, 1H), 4.87-4.93 (m, 2H ), 4.83 (d, J=3.8 Hz, 1H), 4.35-4.41 (m, 1H), 4.06 (t, J=3.9 Hz, 1H), 3.82 (br dd, J=13.6, 3.8 Hz, 1H), 3.43-3.61 (m, 4H), 3.38 (dt, J=11.7, 6.7 Hz, 1H) , 2.84-3.07 (m, 3H), 2.72 (br d, J=16.4 Hz, 1H), 1.49-1.57 (m, 3H), 1.22-1, 38(m, 4H).

Minor rotamer (35%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.98 (t, J=8.8 Hz, 1H), 7.31 (d, J=7.3 Hz, 1H), 7.07-7, 24 (m, 3H), 6.91-6.95 (m, 1H), 6.75-6.81 (m, 1H), 6.55 (dd, J=8.8, 1.9 Hz, 1H), 6.49 (dd, J=14.8, 1.9 Hz, 1H), 4.98 (br d, J=6.6 Hz, 1H), 4.87-4.93 (m, 2H), 4.83 (d, J=3.8 Hz, 1H), 4.52-4.57 (m, 1H), 4.35-4.41 (m, 1H), 4.06 (t , J=3.9 Hz, 1H), 3.43-3.61 (m, 3H), 3.38 (dt, J=11.7, 6.7 Hz, 1H), 3.23-3, 26 (m, 1H), 2.84-3.07 (m, 4H), 1.49-1.57 (m, 3H), 1.22-1.38 (m, 4H).

Compound 99.

- 136 040266

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.03-7.36 (m, 4H), 6.87-6.99 (m, 1H), 6.80 (s, 1H), 6.49 (br d, J=8.8 Hz, 1H), 6.41 (br d, J=14.6 Hz, 1H), 5 .59 (q, J=6.6Hz, 1H), 5.16 (d, J=4.5Hz, 1H),

3.94 (quin, J=4.9 Hz, 1H), 3.81 (br dd, J=13.8, 3.7 Hz, 1H), 3.50-3.63 (m, 2H), 3.40-3.50 (m, 1H), 2.65-3.16 (m,

5H), 2.13-2.23 (m, 1H), 1.45-1.61 (m, 3H), 1.19-1.41 (m, 4H), 1.02 (d, J= 6.8 Hz, 3H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (t, J=8.8 Hz, 1H), 7.03-7.36 (m, 4H), 6.87-6.99 ( m, 1H), 6.76 (s, 1H), 6.49 (br d, J=8.8 Hz, 1H), 6.41 (br d, J=14.6 Hz, 1H), 5, 16 (d, J=4.5 Hz, 1H), 4.96 (q, J=6.4 Hz, 1H), 4.49-4.61 (m, 1H), 3.94 (quin, J =4.9 Hz, 1H), 3.50-3.63 (m, 2H), 3.20-3.29 (m, 1H), 2.65-3.16 (m, 5H), 2.132, 23 (m, 1H), 1.45-1.61 (m, 3H), 1.19-1.41 (m, 4H), 1.02 (d, J=6.8 Hz, 3H).

Compound 100.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.8, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.09-7 .26 (m, 3H), 6.906.96 (m, 1H), 6.80 (s, 1H), 6.50 (dd, J=8.7, 1.7 Hz, 1H), 6.42 ( dd, J=14.7, 1.7 Hz, 1H), 5.55-5.62 (m, 1H), 5.17 (d, J=3.2 Hz, 2H), 4.07 (br s, 2H), 3.82 (br dd, J=13.7, 3.6 Hz, 1H), 3.53 (br dd, J=10.2, 3.6 Hz, 2H), 3.43 -3.50 (m, 1H), 3.17 (d, J=10.4 Hz, 2H), 2.68-3.06 (m, 3H), 1.48-1.58 (m, 3H ), 1.21-1.38 (m, 4H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (t, J=8.8, 1H), 7.09-7.26 (m, 3H), 7.07 (d, J= 7.6, 1H), 6.906.96 (m, 1H), 6.76 (s, 1H), 6.50 (dd, J=8.7, 1.7 Hz, 1H), 6.42 (dd , J=14.7, 1.7 Hz, 1H), 5.17 (d, J=3.2 Hz, 2H), 4.93-5.00 (m, 1H), 4.55 (br dd , J=12.9, 3.2 Hz, 1H), 4.07 (br s, 2H), 3.53 (br dd, J=10.2, 3.6 Hz, 2H), 3.22- 3.29 (m, 1H), 3.17 (d, J=10.4 Hz, 2H), 2.68-3.06 (m, 3H), 1.48-1.58 (m, 3H) , 1.21-1.38 (m, 4H).

Compound 101.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.64 (br s, 1H), 9.40 (br s, 1H), 8.00 (t, J=8.7 Hz, 1H), 7 .03-7.40 (m, 4H), 6.88-7.01 (m, 1H), 6.81 (s, 1H), 6.37-6.59 (m, 2H), 5.59 (q, J=6.7 Hz, 1H), 3.81 (br dd, J=13.9, 4.1 Hz, 1H), 3.21-3.67 (m, 6H), 2.71 -3.12 (m, 3H), 2.25 (br d, J=6.1 Hz, 2H), 1.48-1.60 (m, 3H), 1.20-1.40 (m, 4H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.64 (br s, 1H), 9.40 (br s, 1H), 8.00 (t, J=8.7 Hz, 1H), 7.03-7.40 (m, 4H), 6.88-7.01 (m, 1H), 6.77 (s, 1H), 6.37-6.59 (m, 2H), 4, 96 (q, J=6.8 Hz, 1H), 4.55 (br d, J=11.2 Hz, 1H), 3.21-3.67 (m, 6H), 2.71-3, 12 (m, 3H), 2.25 (br d, J=6.1 Hz, 2H), 1.48-1.60 (m, 3H), 1.20-1.40 (m, 4H).

Connection 102.

Basic rotamer (65%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.99 (br t, J=8.7 Hz, 1H), 7.03-7.34 (m, 4H), 6.93 (m, 1H), 6.79 (s, 1H), 6.50 (d, J=8.2 Hz, 1H), 6.42 (d, J=14.8 Hz, 1H), 5.59 (q, J=6.2 Hz, 1H), 5.16 (br s, 2H), 4.08 (br s, 2H), 3.82 (br dd, J=13.6, 4.1 Hz, 1H) , 3.51-3.57 (m, 2H), 3.42-3.51 (m, 1H), 3.17 (d, J=10.4 Hz, 2H), 2.69-3.08 (m, 3H), 1.47-1.59 (m, 3H), 1.22-1.40 (m, 4H).

Minor rotamer (35%).

¹ H NMR (500 MHz, DMSO-d6) δ ppm 7.99 (br t, J=8.7 Hz, 1H), 7.03-7.34 (m, 4H), 6.93 (m, 1H ), 6.75 (s, 1H), 6.50 (d, J=8.2 Hz, 1H), 6.42 (d, J=14.8 Hz, 1H), 5.16 (br s, 2H), 4.92-5.02(m, 1H), 4.48-4.61(m, 1H), 4.08(brs, 2H), 3.51-3.57(m, 2H ), 3.22-3.27 (m, 1H), 3.17 (d, J=10.4 Hz, 2H), 2.69-3.08 (m, 3H), 1.47-1, 59 (m, 3H), 1.22-1.40 (m, 4H).

Compound 103.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.09- 7.27 (m, 3H), 6.89-6.96 (m, 1H), 6.80 (s, 1H), 6.44-6.55 (m, 1H), 6.31-6, 44 (m, 1H), 5.52-5.64 (m, 1H), 4.91 (t, J=5.6 Hz, 1H), 4.85 (s, 1H), 3.77-3 .87 (m, 1H), 3.36-3.56 (m, 6H), 3.12 (br d, J=10.3 Hz, 1H), 2.68-3.08 (m, 3H) , 2.02-2.17 (m, 1H), 1.75-1.87 (m, 1H), 1.40-1.60 (m, 3H), 1.19-1.39 (m, 4H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.8 Hz, 1H), 7.09-7.27 (m, 3H), 7.08 (d, J = 7.1 Hz, 1H), 6.89-6.96 (m, 1H), 6.76 (s, 1H), 6.44-6.55 (m, 1H), 6.31-6, 44 (m, 1H), 4.88-5.00 (m, 2H), 4.85 (s, 1H), 4.504.60 (m, 1H), 3.36-3.56 (m, 5H) , 3.19-3.29 (m, 1H), 3.12 (br d, J=10.3 Hz, 1H), 2.68-3.08 (m, 3H), 2.02-2, 17 (m, 1H), 1.75-1.87 (m, 1H), 1.40-1.60 (m, 3H), 1.19-1.39 (m, 4H).

Compound 104.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (t, J=8.9 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.09-7 .27 (m, 3H), 6.89-6.96 (m, 1H), 6.80 (s, 1H), 6.44-6.55 (m, 1H), 6.34-6.44 (m, 1H), 5.54-5.64 (m, 1H), 4.91 (t, J=5.6 Hz, 1H), 4.85 (s, 1H), 3.76-3.87 ( m, 1H), 3.36-3.53 (m, 6H), 3.12 (br d, J=10.3 Hz, 1H), 2.68-3.08 (m, 3H), 2, 02-2.17 (m, 1H), 1.75-1.87 (m, 1H), 1.46-1.60 (m, 3H), 1.18-1.40 (m, 4H).

Minor rotamer (35%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.00 (t, J=8.9 Hz, 1H), 7.09-7.27 (m, 3H), 7.08 (d, J = 7.1 Hz, 1H), 6.89-6.96 (m, 1H), 6.76 (s, 1H), 6.44-6.55 (m, 1H), 6.34-6, 44 (m, 1H), 4.88-5.00 (m, 2H), 4.85 (s, 1H), 4.50-

- 137 040266

4.60 (m, 1H), 3.36-3.53 (m, 5H), 3.21-3.29 (m, 1H), 3.12 (br d, J=10.3 Hz, 1H ), 2.68-3.08 (m, 3H), 2.02-2.17 (m, 1H), 1.75-1.87 (m, 1H), 1.46-1.60 (m , 3H), 1.18-1.40 (m, 4H).

Connection 105.

Basic rotamer (65%).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.22 (s, 1H), 7.52 (br s, 1H), 7.05-7.35 (m, 4H), 7.02 (br s, 1H), 6.93-6.98 (m, 1H), 6.92 (s, 1H), 6.09 (br d, J=14.7 Hz, 1H), 5.96 (s, 1H), 5.59 (q, J=6.5 Hz, 1H), 3.80 (br dd, J=13.9, 3.9 Hz, 1H), 3.23-3.51 (m, 5H), 2.71-3.11 (m, 4H), 2.05-2.23 (m, 2H), 1.49-1.61 (m, 3H), 1.22-1.37 ( m, 4H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d6) δ ppm 11.21 (s, 1H), 7.52 (br s, 1H), 7.05-7.35 (m, 4H), 7.02 (br s , 1H), 6.93-6.98 (m, 1H), 6.88 (s, 1H), 6.09 (br d, J=14.7 Hz, 1H), 5.96 (s, 1H ), 4.94 (q, J=6.6 Hz, 1H), 4.51-4.60 (m, 1H), 3.23-3.51 (m, 5H), 2.71-3, 11 (m, 4H), 2.05-2.23 (m, 2H), 1.49-1.61 (m, 3H), 1.22-1.37 (m, 4H).

Compound 106.

Basic rotamer (65%).

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.51 (br s, 1H), 7.09-7.36 (m, 4H), 6.95-7.05 (m, 2H), 6 .79 (s, 1H), 6.00-6.14 (m, 2H), 5.59 (q, J=6.8 Hz, 1H), 4.82-4.91 (m, 1H), 4.08-4.20(m, 2H), 3.77-3.90(m, 1H), 3.66-3.75(m, 2H), 3.19-3.58(m, 5H ), 2.69-3.14 (m, 4H), 2.03-2.27 (m, 2H), 1.46-1.61 (m, 3H), 1.21-1.34 (m , 4H).

Minor rotamer (35%).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.51 (br s, 1H), 7.09-7.36 (m, 4H), 6.95-7.05 (m, 2H), 6, 76 (s, 1H), 6.00-6.14 (m, 2H), 4.95 (q, J=6.7 Hz, 1H), 4.82-4.91 (m, 1H), 4 .55 (br d, J=15.5 Hz, 1H), 4.08-4.20 (m, 2H), 3.66-3.75 (m, 2H), 3.19-3.58 ( m, 5H), 2.69-3.14 (m, 4H), 2.03-2.27 (m, 2H), 1.46-1.61 (m, 3H), 1.21-1, 34(m, 4H).

Compound 107.

Basic diastereomer (65%)

1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (t, J=8.9 Hz, 1H), 7.29-7.35 (m, 1H), 7.03-7.28 (m , 3H), 6.897.02 (m, 1H), 6.81 (s, 1H), 6.54 (dd, J=9.0, 2.0 Hz, 1H), 6.49 (dd, J= 14.8, 2.0 Hz, 1H), 5.47-5.65 (m, 2H), 5.13 (dt, J=55.9, 2.0 Hz, 1H), 4.26-4 .49 (m, 1H), 3.81 (br dd, J=13.7, 3.7 Hz, 1H), 3.40-3.70 (m, 4H), 3.16 (t, J= 8.7 Hz, 1H), 2.83-3.08 (m, 2H), 2.72 (br d, J=16.1 Hz, 1H), 1.52 (d, J=6.9 Hz , 3H), 1.17-1.43 (m, 4H).

Minor diastereomer (35%)

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.01 (t, J=8.9 Hz, 1H), 7.03-7.28 (m, 4H), 6.89-7.02 ( m, 1H), 6.77 (s, 1H), 6.54 (dd, J=9.0, 2.0 Hz, 1H), 6.49 (dd, J=14.8, 2.0 Hz , 1H), 5.47-5.65 (m, 1H), 5.13 (dt, J=55.9, 2.0 Hz, 1H), 4.96 (q, J=7.0 Hz, 1H), 4.49-4.63(m, 1H), 4.26-4.49(m, 1H), 3.40-3.70(m, 3H), 3.22-3.28( m, 1H), 3.16 (t, J=8.7 Hz, 1H), 2.83-3.08 (m, 3H), 1.55 (d, J=6.9 Hz 3H), 1 .17-1.43 (m, 4H).

melting temperatures.

For a number of compounds, melting points (m.p.) were determined using a DSC 1 differential scanning calorimeter (Mettler Toledo). Melting points were measured using a temperature gradient of 10°C/min from 25 to 350°C. The indicated values are peak values. Values were obtained with experimental errors, which are usually associated with this analytical method.

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conn. no. T. pl. conn. no. T. pl. 5 220.25°C 57 216.34°С 7 189.00°С 62 173.36°С AND 159.35°С 65 211.64°С 17 258.48°С 66 143.13°С 19 308.63°С 67 205.81°С 32 297.57°С 72 252.4°С 33 292.70°C 74 144.01°C 34 289.10°C 75 197.51°С 35 174.2°С 76 221.20°С 36 237.70°С 78 283.43°С 37 123.18°С 79 285.54°С 42 206.84°С 80 182.93°С 43 214.36°С 81 271.19°С 46 270.00°C 82 294.89°С 47 245.69°С 83 235.56°С 49 239.19°С 84 252.18°С 52 246.17°С 85 277.22°С 53 228.33°С 87 152.28°С 54 254.46°С 90 269.08°C 55 253.3°С 91 236.01°С

optical rotation.

Optical rotation was measured using a polarimeter with sodium D-line light (589 nm) at 20° C. in DMF as solvent. Compound (45) and compound (84) were measured at 546 nm.

conn. no. ["Id ²⁰ Conc. (w/v%) conn. no. Md ²⁰ Conc. (w/v%) 2 -71.71° 0.2301 57 -14.84° 0.256 3 + 16.14° 0.2478 58 -14.56° 0.261 4 +20.58° 0.2478 59 -17.81° 0.219 5 -33.57° 0.28 60 -16.33° 0.245 6 -26° 0.25 62 -15.91° 0.2389 7 -43.31° 0.254 63 -7.22° 0.263 8 -17.93° 0.29 64 -14.6° 0.274

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9 -33.9° 0.2566 65 -33.21° 0.271 10 -22.37° 0.2637 66 -29.77° 0.262 eleven -38.13° 0.278 67 -34.97 0.306 12 -17.67° 0.3 68 -32.74° 0.281 13 -19.36° 0.2583 70 -30.09° 0.216 14 -14.7° 0.2177 72 -30.0° 0.25 15 -59.7° 0.2345 74 -33.22° 0.292 16 +9.48° 0.2531 76 -16° 0.25 17 -5.25° 0.2478 77 -55.36° 0.28 18 -9.69° 0.3097 78 -6.88° 0.32 26 -26.64° 0.289 80 -12.58° 0.302 thirty -52.69° 0.26 81 -46.29° 0.283 31 -3.7° 0.27 82 -9.12° 0.296 32 -53.33° 0.3 83 -47.3° 0.315 33 -59.38° 0.32 84 +5.37° 0.298 36 -17.69° 0.26 85 -79.09° 0.33 37 -24.1° 0.278 86 -39.12° 0.294 38 -13.23° 0.257 87 -30.74° 0.27 39 + 16.45° 0.304 88 -33.33° 0.21 40 -23.33° 0.27 89 -36.49° 0.285 41 -28.71° 0.31 90 -14° 0.25 42 -18.8° 0.266 91 -32.08° 0.265 43 -48.52° 0.27 92 -29.01° 0.262 44 -79.23° 0.26 93 -30.94 0.32 45 +4.69° 0.32 94 -8.93 0.28 46 -25.65° 0.269 95 -31 0.3 47 -19.49° 0.272 96 -29.23 0.26 48 -265.35° 0.254 97 -18.13 0.32 49 -40.77° 0.26 98 -70.35 0.317 50 -35.58° 0.2867 100 -49.64 0.28 51 -27.51° 0.269 101 +33.93 0.28 52 -35.03° 0.294 102 -9.29 0.28 53 -40.42° 0.2301 103 -31.2 0.25 54 -20.06° 0.324 104 +28.57 0.28 55 -9.33° 0.3 105 -17.59 0.29 56 -14.65° 0.2389 106 -38.21 0.28

E. Pharmacological examples.

E.1. antiviral activity.

Black 384-well clear-bottom microplates (Coming, Amsterdam, The Netherlands) were filled by sonic droplet ejection using an Echo liquid manipulation device (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).Then rgRSV224 virus (MO1=1) diluted in culture medium was introduced into the plates.The rgRSV224 virus is an engineered virus that includes an additional GFP gene (Hallak L.K., Spillmann D., Collins P.L., Peeples M.E. Glycosaminoglycan sulfation requirements for respiratory syncytial

- 140040266 virus infection; Journal of virology (2000), 74(22), 10508-13) and licensed from NIH (Bethesda, MD, USA). Finally, 20 μl of HeLa cell suspension (3000 cells/well) was added. Media, virus-infected controls, and sham infection controls were included in each test. The wells contained 0.05% DMSO per volume. Cells were incubated 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. In parallel, the compounds were incubated 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.

__________Data on antiviral activity__________

conn. no. RSV HELA EC50 (µM) TOX. in HELA CC50 (µM) conn. no. RSV HELA EC50 (µM) TOX. in HELA CC50 (µM) 1 0.085 >100 55 0.016 >100 2 0.056 38.7 56 0.032 58.9 3 0.063 43.0 57 0.023 >100 4 0.049 23.0 58 0.036 >100 5 0.118 >25 59 0.047 N.A. 6 0.098 >100 60 0.029 41.3 7 0.037 71.5 61 0.193 >100 8 0.041 51.5 62 0.043 >100 9 0.108 >100 63 0.011 27.2 10 0.070 >100 64 0.029 8.9 AND 0.044 >100 65 0.048 39.1 12 0.041 >100 66 0.040 36.4 13 0.058 80.5 67 0.030 36.5 14 0.039 81.2 68 0.058 26.6 15 0.100 >100 69 0.059 33.2 16 0.110 >100 70 0.104 28.2 17 0.050 >100 71 0.105 29.8 18 0.044 >100 72 0.087 >100 19 0.041 72.3 73 0.101 >100 20 0.052 55.9 74 0.076 48.1 21 0.045 >100 75 0.076 >100 22 0.145 >100 76 0.246 >100 23 0.032 30.3 77 0.082 >100 24 0.030 26.4 78 0.055 47.3 25 0.023 29.6 79 0.476 13.3 26 0.020 29.6 80 0.091 35.9 27 0.089 34.4 81 0.099 38.4 28 0.072 32.2 82 0.033 33.1 29 0.045 43.7 83 0.044 42.4 thirty 0.036 33.9 84 0.006 19.0

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31 0.036 39.1 85 0.152 >100 32 0.060 32.1 86 0.161 49.5 33 0.043 34.5 87 0.215 47.4 34 0.037 23.1 88 0.017 47.6 35 0.033 25.5 89 0.165 33.4 36 0.012 29.3 90 0.046 N.A. 37 0.019 62.0 91 0.036 28.3 38 0.043 >100 92 0.071 41.5 39 0.291 53.1 93 0.039 13.4 40 0.061 52.3 94 0.19 >100 41 0.036 51.1 95 0.018 31.1 42 0.025 28.9 96 0.05 22.5 43 0.017 29.8 97 0.053 26.1 44 0.019 45.2 98 0.039 47.6 45 0.020 31.4 99 0.092 >100 46 0.007 31.3 100 0.011 23.8 47 0.009 41.5 101 0.058 45.4 49 0.024 32.3 102 0.026 44.4 50 0.031 35.1 103 0.019 35.8 51 0.131 67.9 104 0.025 28.2 52 0.014 41.3 105 0.025 83.6 53 0.035 >100 106 0.089 21 54 0.192 77.4 107 0.017 21.2

N.A: No data available.

E.2 Pharmacokinetics after a single intravenous administration to fasting male Beagle dogs.

The test compound was dissolved in a 20% (w/v) solution of hydroxypropyl-β-cyclodextrin (HP-beta-CD) to prepare an intravenous formulation with a final concentration of 2 mg/ml. NaOH was added to the formulations to aid dissolution and after complete dissolution the pH was adjusted with HCl to a value of 8.4. The intravenous (IV) formulation was converted to isotonic with mannitol. Before dosing, all formulations were stored at room temperature and protected from light. The IV formulation was dosed into the cephalic vein at 0.5 ml/kg to a final dose of 1 mg/kg.

Three male beagle dogs with an average weight of 10.9±1.1 kg were used. A complete concentration-time profile was obtained from each individual animal. Animals were not fed overnight prior to dosing. Their standard dry food diet was resumed 2 hours after dosing. Tap water was available ad libitum.

Blood samples were taken from each individual animal at 7 and 20 minutes, 1, 2, 4, 7, 24 and 48 hours after the intravenous dose. Blood was collected from the jugular vein into 2 ml BD vacutainers™ CSE (Becton Dickinson). The samples were directly placed on melting ice and after centrifugation at 4°C for 10 min at about 1900xg, blood plasma was obtained. All samples were covered from daylight and stored at <-18°C until analysis. Blood plasma samples were analyzed using a validated LC-MS/MS method. Key analytical parameters (linearity, upper and lower limit of quantification, reliability and accuracy) of the method were reported along with plasma concentrations. The lower limit of quantification (LLOQ) was 10.0 ng/mL.

Pharmacokinetic analysis was performed using Phoenix™ Professional (version 6.3). All data were subjected to non-compartmental analysis using linear/log trapezoidal integration with linear/log interpolation.

The plasma concentration profile of Compound 37 and Compound 102 of the present invention is shown in FIG. 1 and 2.

The plasma concentration profile of Compound W37 and Compound W38 according to WO 2016/174079 is shown in FIG. 3 and 4.

After intravenous administration of a dose of 1 mg/kg to dogs of compound W37 and W38 according to

- 142 -

Claims (14)

WO 2016/174079 showed a rapid decrease in plasma concentration in the first 8 hours after administration. The plasma concentration profile of Compound 37 and Compound 102 of the present invention did not show such a rapid decline, thus indicating that these compounds have improved metabolic stability properties and improved bioavailability. Description of graphic materials Fig. 1: Compound 102 plasma concentration profile. Fig. 2: Compound 37 plasma concentration profile. Fig. 3: Compound W37 plasma concentration profile according to WO 2016/174079. Fig. 4: Compound W38 plasma concentration profile according to WO 2016/174079. F. Examples of Possible Compositions. As used throughout these examples, the term active ingredient refers to the final compound of formula (I), its pharmaceutically acceptable salts, its solvates and stereochemically isomeric forms and tautomers. Typical examples of formulations for the composition of the present invention are as follows. F.1. Pills. Active ingredient 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 ingredient can be replaced by the same amount of any of the compounds in accordance with the present invention, in particular the same amount of any of the exemplary compounds. 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 prepared by mixing 1.5% by weight of the active ingredient of the present invention in 10% by volume of propylene glycol in water. F.4. Ointment. Active ingredient 5-1000 mg. Stearyl alcohol 3 g. Lanolin 5 g. White vaseline 15 g. Water up to 100 g. In this example, the active ingredient can be replaced by the same amount of any of the compounds in accordance with the present invention, in particular the same amount of any of the exemplary compounds. Permissible variations should not be construed as a deviation from the scope of the present invention. It will be apparent that those skilled in the art may modify the invention thus described in various ways. CLAIM 1. Compound of formula (I) including its any stereochemically isomeric form, where A is ( ^a -0 or (a-2) n is 0, 1 or 2; m is 1 or 2; - 143 040266 X ¹ , X ² and X ³ are selected from the following options: X ¹ is CR ¹¹ and X ² is CR ¹¹ and X ³ is CR ¹¹ , or X ¹ is N and X ² is CR ¹¹ and X ³ is CR ¹¹ , or X ¹ is CR ¹¹ and X ² is N and X ³ is CR ¹¹ , or X ¹ is N and X ² is CR ¹¹ and X ³ is N, where R ¹¹ is each independently selected from the group consisting of hydrogen, halogen, hydroxy, C _1-4 αkyl, C _1-4 αkyloxy, C _1-4 alkyloxy-C _1-4 alkyloxy and hydroxy-C _1-4 alkyloxy; R ¹ is CH ₃ ; R ² is hydrogen or halogen; R ³ is halogen; R ⁴ is C _3-6 cycloalkyl; phenyl; phenyl substituted with one substituent selected from halogen, cyano, C _1-4 αkyl, polyhalo-C _1-4 alkyl and C _1-4 alkyloxy; or heteroaryl; R ⁵ is hydrogen, C _1-4 alkyl or hydroxy-C _1-4 alkyl; each R ⁶ is independently selected from the group consisting of hydrogen, C _1-4 alkyl, hydroxy, halogen, and C _1-4 αkyloxy; each R ^6a is independently selected from the group consisting of hydrogen and halogen; R ⁷ is hydrogen, C _1-4 αkyl or hydroxy-C _1-4 alkyl; R ⁸ is -OH, -CN, - O-(CO)-NR ¹² R ¹³ , - C1-4alkyl-(CO)-NR ¹² R ¹³ , - (CO)-NR ¹² R ¹³ , - (CS)-NR ¹² R ¹³ , - (CO) -NR ¹² -CN, - (CO) -NR ¹² -SO2-R ¹⁴ , - NR ¹² -(CO) -R ¹⁴ , - NR ¹² -(CO) -OR ¹⁴ , - NR ¹² -SO2-R ¹⁴ , - NH2, - NR ¹² -R ¹⁵ ; - SO2-R ¹⁴ , - SO2-NR ¹² R ¹³ , - SO2-NR ¹² -(CO)-R ¹⁴ , or -SO(=NH)(-R ¹⁴ ), or heteroaryl ¹ ; where each of R ¹² and R ¹³ is independently selected from hydrogen and C ₁ . ₄ alkyl; R ¹⁴ is C ₁ _ ₄ alkyl or polyhalo-C ₁ _ ₄ alkyl; R ¹⁵ is di(C ₁ _ ₄ alkyl)-(P=O)- or polyhalo-C ₁ _ ₄ alkyl; or R ⁷ and R ⁸ can be taken together to form -CH ₂ -(SO ₂ )-CH ₂ - or -CH ₂ -O-CH ₂ -; each R ⁹ is independently selected from the group consisting of hydrogen and C ₁ _ ₄ αkyl; R ^{1 0} is hydrogen; if n=1 and m=1, then R ⁸ and R ⁹ can be taken together to form -CH ₂ -(CO)-O-; heteroaryl is pyridinyl or pyrimidinyl, each heteroaryl being optionally substituted with one substituent selected from halogen; heteroaryl ¹ is tetrazolyl or 5-oxo-4,5-dihydro-1,2,4-oxadiazolyl, or a pharmaceutically acceptable acid addition salt thereof. 2. The compound of claim 1 wherein X ¹ is CR ¹¹ and X ² is CR ¹¹ and X ³ is CR ¹¹ . 3. The compound according to claim 1, where X ¹ is N and X ² is CR ¹¹ and X ³ is CR ¹¹ ; or X ¹ is CR ¹¹ and X ² is N and X ³ is CR ¹¹ ; or X ¹ is N and X ² is CR ¹¹ and X ³ is N. 4. The compound according to any one of claims 1 to 3, wherein the radical A is characterized by the formula (a-1). 5. A compound according to any one of claims 1 to 4, wherein n is 0 and m is 1. 6. A compound according to any one of claims 1 to 4, wherein n is 1 and m is 1. 7. Connection according to claim 1, where _r 2 ^l fk| A is AA; n is 0 or 1; m is 1; - 144 040266 X ¹ , X ² and X ³ are selected from the following options: X ¹ is CR ¹¹ and X ² is CR ¹¹ and X ³ is CR ¹¹ where R ¹¹ in each case is hydrogen; R ¹ is CH ₃ ; R ² is hydrogen; R ³ is halogen; R ⁴ is C ₃ - ₆ cycloalkyl or heteroaryl; R ⁵ is hydrogen; each R ⁶ is independently selected from the group consisting of hydrogen, hydroxy and halogen; each R ^6a is hydrogen; R ⁷ is hydrogen or hydroxy-C _1-4 alkyl; R ⁸ is -OH, -C _1-4 alkyl-(CO)-NR ¹² R ¹³ or -(CO)-NR ¹² R ¹³ where each of R ¹² and R ¹³ is independently selected from hydrogen and C _1-4 alkyl; R ^{1 0} is hydrogen; heteroaryl is pyridinyl, or a pharmaceutically acceptable acid addition salt thereof. 8. Connection according to claim 1, where A is n is 1; m is 1; X ¹ , X ² and X ³ are selected from the following options: X ¹ is CR ¹¹ and X ² is CR ¹¹ and X ³ is CR ¹¹ where R ¹¹ in each case is hydrogen; R ¹ is CH3; R ² is hydrogen; R ³ is halogen; R ⁴ is C _3-6 cycloalkyl; R ⁵ is hydrogen; each R ⁶ is independently selected from the group consisting of hydrogen, hydroxy and halogen; each R ^6a is hydrogen; R ⁷ is hydrogen or hydroxy-C _1-4 alkyl; R ⁸ represents -OH or -(CO)-NR ¹² R ¹³ where each of R ¹² and R ¹³ is independently selected from hydrogen and C _1-4 alkyl; R ¹⁰ is hydrogen, or a pharmaceutically acceptable acid addition salt thereof. 9. Connection according to claim 1, where A is n is 1; m is 1; X ¹ , X ² and X ³ are selected from the following options: X ¹ is CR ¹¹ and X ² is CR ¹¹ and X ³ is CR ¹¹ where R ¹¹ in each case is hydrogen; ^{R1 R2 R3 R4} R ⁵ is CH ₃ ; is hydrogen; is a halogen; is C _3-6 cycloalkyl; is hydrogen; each R ⁶ is independently selected from the group consisting of hydrogen and hydroxy; each R ^6a is hydrogen; R ⁷ is hydrogen; R ⁸ represents -OH or -(CO)-NR ¹² R ¹³ where each of R ¹² and R ¹³ is independently selected from hydrogen and C _1-4 alkyl; R ¹⁰ is hydrogen, - 145 040266 or a pharmaceutically acceptable acid addition salt thereof. 10. The connection according to claim 1, where the connection is selected from: or a pharmaceutically acceptable acid addition salt thereof. 11. A pharmaceutical composition containing a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to any one of claims 1-10. 12. A method for preparing a pharmaceutical composition according to claim 11, wherein the therapeutically active amount of a compound according to any one of claims 1 to 10 is intimately mixed with a pharmaceutically acceptable carrier. 13. Use of a compound according to any one of claims 1 to 10 for the treatment of respiratory syncytial virus infection. 14. The use of a pharmaceutical composition according to claim 11 for the treatment of an infection caused by a respiratory syncytial virus. - 146 -