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Title:
PYRAZOLOPYRIMIDINES HAVING ACTIVITY AGAINST THE RESPIRATORY SYNCYTIAL VIRUS (RSV)
Document Type and Number:
WIPO Patent Application WO/2019/106004
Kind Code:
A1
Abstract:
The invention concerns compounds having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns pharmaceutical compositions comprising these compounds and the compounds for use in the treatment of respiratory syncytial virus infection. Formula (Ia).

Inventors:
LANÇOIS, David Francis Alain (TSA, 92787 Issy-les-Moulineaux Cedex 9, 92787, FR)
GUILLEMONT, Jérôme Émile Georges (TSA, 92787 Issy-les-Moulineaux Cedex 9, 92787, FR)
RABOISSON, Pierre Jean-Marie Bernard (Avenue Denis Diderot 5, 1300 Wavre, 1300, BE)
ROYMANS, Dirk André Emmy (2340 Beerse, 2340, BE)
RIGAUX, Peter (2340 Beerse, 2340, BE)
MICHAUT, Antoine Benjamin (Boulevard Sébastien Brant BP, 67405 Illkirch Cedex, 67405, FR)
MERCEY, Guillaume Jean Maurice (TSA, 92787 Issy-les Moulineaux Cedex 9, 92787, FR)
Application Number:
EP2018/082828
Publication Date:
June 06, 2019
Filing Date:
November 28, 2018
Export Citation:
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Assignee:
JANSSEN SCIENCES IRELAND UNLIMITED COMPANY (Barnahely Ringaskiddy, Co Cork, IE)
International Classes:
C07D487/04; A61K31/381; A61P31/16; C07D495/04; C07D513/04; C07D519/00
Domestic Patent References:
WO2016174079A12016-11-03
WO2016091774A12016-06-16
WO2016174079A12016-11-03
WO2016091774A12016-06-16
Other References:
WYDE ET AL., ANTIVIRAL RESEARCH, vol. 38, 1998, pages 31 - 42
J. ORG. CHEM., vol. 81, 2016, pages 4359 - 4363
HALLAK LK; SPILLMANN D; COLLINS PL; PEEPLES ME: "Glycosaminoglycan sulfation requirements for respiratory syncytial virus infection", JOURNAL OF VIROLOGY, vol. 74, no. 22, 2000, pages 10508 - 13
Attorney, Agent or Firm:
VERBERCKMOES, Filip (Turnhoutseweg 30, 2340 Beerse, 2340, BE)
Download PDF:
Claims:
Claims

1. A compound of formula (I), including any stereochemically isomeric form thereof, wherein

including any stereochemically isomeric form thereof, wherein

n is 0, 1, or 2;

m is 1 or 2;

X1, X2 and X3 are selected from X1 is CR1 d X2 is CR11 and X3 is CR1

or X1 is N and X2 is CR11 and X3 is CR1

or X1 is CR11 and X2 is N and X3 is CR1

or X1 is CR11 and X2 is CR11 and X3 is N,

or X1 is N and X2 is CR11 and X3 is N,

wherein each R11 is independently selected from the group consisting of hydrogen, halo, hydroxy, C | _4al ky 1,

C| -4alkyloxy,

and hydroxyC

R1 is CH3 or CH2CH

R2 is hydrogen, halo

R3 is halo or CH30;

R4 is C3-6cycloalkyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each individually selected from halo, hydroxy, cyano, C^alkyl, polyhaloC| -4alkyl, and C| -4alkyloxy; Heteroaryl; or C| -4alkyl substituted with Heteroaryl;

R5 is hydrogen, C| -4alkyl or hydroxyC| -4alkyl;

each R6 is independently selected from the group consisting of hydrogen, C| -4alkyl, hydroxy, halo and C| -4alkyloxy; each R6a is independently selected from the group consisting of hydrogen and halo; R7 is hydrogen, C| -4alkyl, or hydroxyC| -4alkyl;

R8 is -OH,

-CN,

-0-(C0)-NR12R13,

-C i _4alkyl-(CO)-NR12R13 ,

-(CO)-NR12R13,

-(CS)-NR12R13,

-(CO)-NR12-CN,

-(C0)-NR12-S02-R14,

-NR12-(CO)-R14,

-NR12-(C0)-0-R14,

-NR12-SO2-R14,

-NH2,

-NR12-R15;

-SO2-R14,

-SO2-NR12R13,

-S02-NR12-(C0)-R14, or

-SO(=NH)(-R14), or

Heteroaryl1;

wherein

R12 and R13 are each independently selected from hydrogen and C^alkyl, and;

R14 is C^alkyl, or polyhalo C^alkyl;

R15 is di(C1.4alkyl)-(P=0)- or polyhaloC| -4alkyl;

or R7 and R8 may be taken together to form -CH2-(S02)-CH2- or -CH2-0-CH2- ; each R9 is independently selected from the group consisting of hydrogen and

Ci_4alkyl;

R10 is hydrogen, halo or C^alkyl;

when n = 1 and m=l, R8 and R9 may be taken together to form -CH2- ;

when n = 1 and m=l, R5 and R9 may be taken together to form -CH2CH2- ;

when n=l and m=l, R8 and R9 may be taken together to form -CH2-(CO)-0- ; Heteroaryl is pyridinyl or pyrimidinyl, wherein each Heteroaryl is optionally

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

Heteroaryl1 is tetrazolyl or oxadiazolyl;

or a pharmaceutically acceptable acid addition salt thereof.

2. The compound as claimed in claim 1 wherein

wherein

n is 0, 1, or 2;

m is 1 or 2;

X1, X2 and X3 are selected from X1 is CR1 d X2 is CR11 and X3 is CR1 ^

or X1 is N and X2 is CR11 and X3 is CR1 ^

or X1 is CR11 and X2 is N and X3 is CR1 ^

or X1 is N and X2 is CR11 and X3 is N,

wherein each R11 is independently selected from the group consisting of hydrogen, halo, hydroxy, C^alkyl,

C|_4alky

hy droxy

R1 is CH3;

R2 is hydrogen, or halo;

R3 is halo;

R4 is C3_6cycloalkyl; phenyl; phenyl substituted with 1 substituent selected from halo, cyano, C | _4alky 1 , polyhaloC| -4alkyl, and C| -4alkyloxy; or Heteroaryl;

R5 is hydrogen, C| -4alkyl or hydroxyC| -4alkyl;

each R6 is independently selected from the group consisting of hydrogen, C| -4alkyl, hydroxy, halo and C| -4alkyloxy;

each R6a is independently selected from the group consisting of hydrogen and halo; R7 is hydrogen, C| -4alkyl, or hydroxyC| -4alkyl;

R8 is -OH,

-CN,

-0-(C0)-NR12R13,

-C i _4alkyl-(CO)-NR12R! 3 ,

-(CO)-NR12R13,

-(CS)-NR12R13,

-(CO)-NR12-CN,

-(C0)-NR12-S02-R14,

-NR12-(CO)-R14,

-NR12-(C0)-0-R14,

-NR12-SO2-R14,

-NH2,

-NR12-R15;

-SO2-R14,

-SO2-NR12R13,

-S02-NR12-(C0)-R14, or -SO(=NH)(-R14), or

Heteroaryl1;

wherein

R12 and R13 are each independently selected from hydrogen and C| -4alkyl, and;

or R7 and R8 may be taken together to form -CH2-(S02)-CH2- or -CH2-0-CH2- ; each R9 is independently selected from the group consisting of hydrogen and

Ci_4alkyl;

R10 is hydrogen;

when n=l and m=l, R8 and R9 may be taken together to form -CH2-(C0)-0- ;

Heteroaryl is pyridinyl or pyrimidinyl, wherein each Heteroaryl is optionally

substituted with one substituent selected from halo;

Heteroaryl1 is tetrazolyl or 5-oxo-4, 5-dihydro- 1, 2, 4-oxadiazolyl;

3. The compound as claimed in claim 1 wherein X1 is CR1 d X2 is CR11 and X3 is CR11.

4. The compound as claimed in claim 1 wherein wherein X1 is N and X2 is CR11 and X3

5. The compound as claimed in any one of claims 1 to 4 wherein radical A is of formula (a-l).

6. The compound as claimed in any one of claims 1 to 5 wherein n is 0 and m is 1.

7. The compound as claimed in any one of claims 1 to 5 wherein n is 1 and m is 1.

8. The compound as claimed in claim 1 wherein

m is 1;

X1, X2 and X3 are selected from X1 is CR1 ^nd X2 is CR11 and X3 is CR1 wherein each R11 is hydrogen; R1 is CH3;

R2 is hydrogen;

R3 is halo;

R4 is C3-6cycloalkyl or Heteroaryl;

R5 is hydrogen;

each R6 is independently selected from the group consisting of hydrogen, hydroxy, and halo;

each R6a is hydrogen;

R7 is hydrogen or hydroxyC| -4alkyl;

R8 is -OH,

-C i _4alkyl-(CO)-NR12R! 3 , or

-(CO)-NR12R13,

wherein

R12 and R13 are each independently selected from hydrogen and C | _4al ky 1, R10 is hydrogen;

Heteroaryl is pyridinyl;

or a pharmaceutically acceptable acid addition salt thereof.

9. The compound as claimed in claim 1 wherein

A is

n is 1;

m is 1;

X1, X2 and X3 are selected from X1 is CR1 d X2 is CR11 and X3 is CR1 ' , wherein each R11 is hydrogen;

R1 is CH3;

R2 is hydrogen;

R3 is halo;

R4 is C3.6cycloalkyl;

R5 is hydrogen;

each R6 is independently selected from the group consisting of hydrogen, hydroxy, and halo;

each R6a is hydrogen;

R7 is hydrogen or hydroxyC| -4alkyl;

R8 is -OH, or -(CO)-NR12R13,

wherein

R12 and R13 are each independently selected from hydrogen and C^alkyl,

R10 is hydrogen;

or a pharmaceutically acceptable acid addition salt thereof.

10. The compound as claimed in claim 1 wherein

A is

n is 1;

m is 1;

X1, X2 and X3 are selected from X1 is CR1 d X2 is CR11 and X3 is CR1 wherein each R11 is hydrogen;

R1 is CH3;

R2 is hydrogen;

R3 is halo;

R4 is C3_6cycloalkyl;

R5 is hydrogen;

each R6 is independently selected from the group consisting of hydrogen and hydroxy; each R6a is hydrogen;

R7 is hydrogen;

R8 is -OH, or

-(CO)-NR12R13,

wherein

R12 and R13 are each independently selected from hydrogen and C^alkyl,

R10 is hydrogen;

or a pharmaceutically acceptable acid addition salt thereof.

11. The compound according to claim 1 , wherein the compound is selected from

or a pharmaceutically acceptable acid addition salt thereof.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in any one of claims 1 to 11.

13. The pharmaceutical composition according to claim 12, which further comprises another antiviral agent.

14. The pharmaceutical composition according to claim 13, wherein the other antiviral agent is a respiratory syncytial virus (RSV) inhibiting compound.

15. A process for preparing a pharmaceutical composition as claimed in any one of claims 12 to 14 wherein a therapeutically active amount of a compound as claimed in any one of claims 1 to 11 is intimately mixed with a pharmaceutically acceptable carrier.

16. A compound as claimed in any one of claims 1 to 11 for use as a medicine.

17. A compound as claimed in any one of claims 1 to 11, or a pharmaceutical composition as claimed in any one of claims 12 to 14, for use in the treatment of a respiratory syncytial virus infection.

18. A method of treating a respiratory syncytial virus (RSV) infection comprising

administering to a subject in need thereof an anti-virally effective amount of a compound of formula (I) as defined in any one of claims 1 to 11.

Description:
PYRAZOLOPYRIMIDINES HAVING ACTIVITY AGAINST THE RESPIRATORY

SYNCYTIAL VIRUS (RSV)

Field of the Invention

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

Background

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

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

Today only three drugs have been approved for use against RSV infection. A first one is ribavirin, a nucleoside analogue that provides an aerosol treatment for serious RSV infection in hospitalized children. The aerosol route of administration, the toxicity (risk of teratogenicity), the cost and the highly variable efficacy limit its use. The other two drugs, RespiGam® (RSV-IG) and Synagis® (palivizumab), polyclonal and monoclonal antibody immunostimulants, are intended to be used in a preventive way. Both are very expensive, and require parenteral administration.

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

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

WO-2016/091774. The compounds of the present invention have unexpected better plasma concentration profiles than the pyrazolopyrimidine compounds of WO-2016/174079 bearing 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)

including any stereochemically isomeric form thereof, wherein

n is 0, 1, or 2;

m is 1 or 2;

X 1 , X 2 and X 3 are selected fro

wherein each R 11 is independently selected from the group consisting of hydrogen, halo, hydroxy, C | _ 4 al ky 1,

C | -4 alkyloxy,

and hydroxyC

R 1 is CH 3 or CH 2 CH

R 2 is hydrogen, halo

R 3 is halo or CH 3 0;

R 4 is C 3.6 cycloalkyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each

individually selected from halo, hydroxy, cyano, C | -4 alkyl, polyhaloC | -4 alkyl, and C | -4 alkyloxy; Heteroaryl; or C | -4 alkyl substituted with Heteroaryl; R 5 is hydrogen, C | -4 alkyl or hydroxyC | -4 alkyl;

each R 6 is independently selected from the group consisting of hydrogen, C | -4 alkyl, hydroxy, halo and C | -4 alkyloxy;

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

R 7 is hydrogen, C | -4 alkyl, or hydroxyC | -4 alkyl;

R 8 is -OH,

-CN,

-0-(C0)-NR 12 R 13 ,

-C i _ 4 alkyl-(CO)-NR 12 R 13 ,

-(CO)-NR 12 R 13 ,

-(CS)-NR 12 R 13 ,

-(CO)-NR 12 -CN,

-(C0)-NR 12 -S0 2 -R 14 ,

-NR 12 -(CO)-R 14 ,

-NR 12 -(C0)-0-R 14 ,

-NR 12 -SO 2 -R 14 ,

-NH 2 ,

-NR 12 -R 15 ;

-SO 2 -R 14 ,

-SO 2 -NR 12 R 13 ,

-S0 2 -NR 12 -(C0)-R 14 , or

-SO(=NH)(-R 14 ), or

Heteroaryl 1 ;

wherein

R 12 and R 13 are each independently selected from hydrogen and C | _ 4 al ky 1, and;

or R 7 and R 8 may be taken together to form -CH 2 -(S0 2 )-CH 2 - or -CH 2 -0-CH 2 - ;

each R 9 is independently selected from the group consisting of hydrogen and C | -4 alkyl; R 10 is hydrogen, halo or C | -6 alkyl;

when n = 1 and m=l, R 8 and R 9 may be taken together to form -CH 2 - ;

when n = 1 and m=l, R 5 and R 9 may be taken together to form -CH 2 CH 2 - ;

when n=l and m=l, R 8 and R 9 may be taken together to form -CH 2 -(CO)-0- ;

Heteroaryl is pyridinyl or pyrimidinyl, wherein each Heteroaryl is optionally substituted with one or two substituents each independently selected from C | -4 alkyl, halo, amino, and aminocarbonyl;

Heteroaryl 1 is tetrazolyl, oxadiazolyl or 5-oxo-4, 5-dihydro- 1, 2, 4-oxadiazolyl; or a pharmaceutically acceptable acid addition salt thereof.

As used in the foregoing definitions:

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

- C | _ 4 alky 1 defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl,

l-methylethyl, 2-methylpropyl and the like;

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

- C3_ 6 cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

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

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

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

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

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

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

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

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

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

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

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

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

When a specific stereoisomer is identified, this means that said stereoisomer is

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

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

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

The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form. These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.

Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butane-dioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p toluenesulfonic, cyclamic, salicylic, p aminosalicylic, pamoic and the like acids.

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

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

For the avoidance of doubt, compounds of formula (I) may contain the stated atoms in any of their natural or non-natural isotopic forms. In this respect, embodiments of the invention that may be mentioned include those in which (a) the compound of formula (I) is not isotopically enriched or labelled with respect to any atoms of the compound; and (b) the compound of formula (I) is isotopically enriched or labelled with respect to one or more atoms of the compound. Compounds of formula (I) that are isotopically enriched or labelled (with respect to one or more atoms of the compound) with one or more stable isotopes include, for example, compounds of formula (I) that are isotopically enriched or labelled with one or more atoms such as deuterium, 13 C, 14 C, 14 N, 15 0 or the like.

The present invention also relates to compounds of formula (I)

including any stereochemically isomeric form thereof, wherein n is 0, 1, or 2;

m is 1 or 2;

X 1 , X 2 and X 3 are selected fro

wherein each R 11 is independently selected from the group consisting of hydrogen, halo, hydroxy, C | _ 4 al ky 1,

C | _4alkylo

hydroxyC

R 1 is CH 3 or CH 2 CH 3 ;

R 2 is hydrogen, halo or C | -4 alkyl;

R 3 is halo or CH 3 0;

R 4 is C 3.6 cycloalkyl; phenyl; phenyl substituted with 1, 2 or 3 substituents each

individually selected from halo, hydroxy, cyano, C | -4 alkyl, polyhaloC | -4 alkyl, and C | -4 alkyloxy; Heteroaryl; or C | -4 alkyl substituted with Heteroaryl;

R 5 is hydrogen or C | -4 alkyl;

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

each R 6a is hydrogen;

R 8 is -OH,

-CN,

-0-(C0)-NR 12 R 13 ,

-C i _ 4 alkyl-(CO)-NR 12 R! 3 ,

-(CO)-NR 12 R 13 ,

-(CO)-NR 12 -CN,

-(C0)-NR 12 -S0 2 -R 14 ,

-NR 12 -(CO)-R 14 ,

-NR 12 -(C0)-0-R 14 ,

-NR 12 -SO 2 -R 14 ,

-NR 12 -R 15 ; -SO R 14 ,

-SO 2 -NR 12 R 13 ,

-S0 2 -NR 12 -(C0)-R 14 , or

-SO(=NH)(-R 14 ), or

Heteroaryl 1 ;

wherein

R 12 and R 13 are each independently selected from hydrogen and C | _ 4 al ky 1 ; R 14 is C^alkyl, or polyhalo C^alkyl;

R 15 is di(C 1.4 alkyl)-(P=0)-;

or R 7 and R 8 may be taken together to form -CH 2 -(S0 2 )-CH 2 - or -CH 2 -0-CH 2 - ;

each R 9 is independently selected from the group consisting of hydrogen and C | -4 alkyl; R 10 is hydrogen, halo or C | -6 alkyl;

when n = 1 and m=l, R 8 and R 9 may be taken together to form -CH 2 - ;

when n = 1 and m=l, R 5 and R 9 may be taken together to form -CH 2 CH 2 - ;

when n=l and m=l, R 8 and R 9 may be taken together to form -CH 2 -(CO)-0- ;

Heteroaryl is pyridinyl or pyrimidinyl, wherein each Heteroaryl is optionally substituted with one or two substituents each independently selected from C | -4 alkyl, halo, amino, and aminocarbonyl;

Heteroaryl 1 is tetrazolyl or oxadiazolyl;

or a pharmaceutically acceptable acid addition salt thereof.

In a first embodiment the invention concerns compounds of formula (I), including any stereochemically isomeric form thereof,

wherein

n is 0, 1, or 2;

m is 1 or 2;

X 1 , X 2 and X 3 are selected fro

wherein each R 11 is independently selected from the group consisting of hydrogen, halo, C | -4 alkyl, C | -4 alkyloxy, and

C i _ 4 alky loxyC | _ 4 alkyloxy ;

R 1 is CH 3 ;

R 2 is hydrogen, or halo;

R 3 is halo;

R 4 is C3_ 6 cycloalkyl; phenyl; phenyl substituted with 1 substituent selected from halo, cyano, C | _ 4 alky 1 , polyhaloC | -4 alkyl, and C | -4 alkyloxy; or Heteroaryl; R 5 is hydrogen or C | -4 alkyl;

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

each R 6a is hydrogen;

R 7 is hydrogen or C | -4 alkyl;

R 8 is -OH,

-CN,

-0-(C0)-NR 12 R 13 ,

-C i _ 4 alkyl-(CO)-NR 12 R 13 ,

-(CO)-NR 12 R 13 ,

-(CO)-NR 12 -CN,

-(C0)-NR 12 -S0 2 -R 14 ,

-NR 12 -(CO)-R 14 ,

-NR 12 -(C0)-0-R 14 ,

-NR 12 -SO 2 -R 14 ,

-NR 12 -R 15 ;

-SO 2 -R 14 ,

-SO 2 -NR 12 R 13 ,

-S0 2 -NR 12 -(C0)-R 14 , or

-SO(=NH)(-R 14 ), or

Heteroaryl 1 ;

wherein

R 12 and R 13 are each independently selected from hydrogen and C | -4 alkyl;

or R 7 and R 8 may be taken together to form -CH 2 -(S0 2 )-CH 2 - or -CH 2 -0-CH 2 - ;

each R 9 is independently selected from the group consisting of hydrogen and C | -4 alkyl; R 10 is hydrogen, halo or C | -6 alkyl;

when n=l and m=l, R 8 and R 9 may be taken together to form -CH 2 -(CO)-0- ;

Heteroaryl is pyridinyl or pyrimidinyl, wherein each Heteroaryl is optionally substituted with one substituent selected from halo;

Heteroaryl 1 is tetrazolyl or oxadiazolyl;

or a pharmaceutically acceptable acid addition salt thereof. In a second embodiment the invention concerns compounds of formula (I),

including any stereochemically isomeric form thereof, wherein

wherein

n is 0, 1, or 2;

m is 1 or 2;

X 1 , X 2 and X 3 are selected fro

wherein each R 11 is independently selected from the group consisting of hydrogen, halo, hydroxy, C^alkyl,

C | _4alky

hy droxy

R 1 is CH 3 ;

R 2 is hydrogen, or halo;

R 3 is halo;

R 4 is C3_ 6 cycloalkyl; phenyl; phenyl substituted with 1 substituent selected from halo, cyano, C^alkyl, polyhaloC | -4 alkyl, and C | -4 alkyloxy; or Heteroaryl;

R 5 is hydrogen, C | -4 alkyl or hydroxyC | -4 alkyl;

each R 6 is independently selected from the group consisting of hydrogen, C | -4 alkyl, hydroxy, halo and C | -4 alkyloxy;

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

R 7 is hydrogen, C | -4 alkyl, or hydroxyC | -4 alkyl;

R 8 is -OH,

-CN,

-0-(C0)-NR 12 R 13 , -C i _ 4 alkyl-(CO)-NR 12 R! 3 ,

-(CO)-NR 12 R 13 ,

-(CS)-NR 12 R 13 ,

-(CO)-NR 12 -CN,

-(C0)-NR 12 -S0 2 -R 14 ,

-NR 12 -(CO)-R 14 ,

-NR 12 -(C0)-0-R 14 ,

-NR 12 -SO 2 -R 14 ,

-NH 2 ,

-NR 12 -R 15 ;

-SO 2 -R 14 ,

-SO 2 -NR 12 R 13 ,

-S0 2 -NR 12 -(C0)-R 14 , or

-SO(=NH)(-R 14 ), or

Heteroaryl 1 ;

wherein

R 12 and R 13 are each independently selected from hydrogen and C ) -4 alkyl, and;

or R 7 and R 8 may be taken together to form -CH 2 -(S0 2 )-CH 2 - or -CH 2 -0-CH 2 - ;

each R 9 is independently selected from the group consisting of hydrogen and C | -4 alkyl; R 10 is hydrogen;

when n=l and m=l, R 8 and R 9 may be taken together to form -CH 2 -(CO)-0- ;

Heteroaryl is pyridinyl or pyrimidinyl, wherein each Heteroaryl is optionally substituted with one substituent selected from halo;

Heteroaryl 1 is tetrazolyl or 5-oxo-4, 5-dihydro- 1, 2, 4-oxadiazolyl;

or a pharmaceutically acceptable acid addition salt thereof.

A first group of compounds are compounds of formula (I) wherein X 1 is CR 1 ' and X 2 is CR 1 1 and X 3 is CR 1 1 .

A second group of compounds are compounds of formula (I) wherein X 1 is N and X 2 is

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

A fourth group of compounds are compounds of formula (I) wherein X 1 is CR 1 1 and X 2 is CR 1 1 and X 3 is N.

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

In a further embodiment the invention concerns compounds of formula (I),

including any stereochemically isomeric form thereof, wherein

wherein

n is 0 or 1 ;

m is 1;

X 1 , X 2 and X 3 are selected from X 1 is CR 1 d X 2 is CR 1 1 and X 3 is CR 1 ' , wherein each

R 1 1 is hydrogen;

R 1 is CH 3 ;

R 2 is hydrogen;

R 3 is halo;

R 4 is C3_6cycloalkyl or Heteroaryl;

R 5 is hydrogen;

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

each R 6a is hydrogen;

R 7 is hydrogen or hydroxyC | -4 alkyl;

R 8 is -OH,

-C i _ 4 alkyl-(CO)-NR 12 R! 3 , or -(CO)-NR 12 R 13 ,

wherein

R 12 and R 13 are each independently selected from hydrogen and C | _ 4 al ky 1, R 10 is hydrogen;

Heteroaryl is pyridinyl;

or a pharmaceutically acceptable acid addition salt thereof.

In another further embodiment the invention concerns compounds of formula (I),

including any stereochemically isomeric form thereof, wherein

wherein

n is 1;

m is 1;

X 1 , X 2 and X 3 are selected from X 1 is CR 1 d X 2 is CR 1 1 and X 3 is CR 1 ' , wherein each

R 1 1 is hydrogen;

R 1 is CH 3 ;

R 2 is hydrogen;

R 3 is halo;

R 4 is C3_ 6 cycloalkyl;

R 5 is hydrogen;

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

each R 6a is hydrogen;

R 7 is hydrogen or hydroxyC ^alkyl;

R 8 is -OH, or

-(CO)-NR 12 R 13 ,

wherein

R 12 and R 13 are each independently selected from hydrogen and C | _ 4 al ky 1, R 10 is hydrogen;

or a pharmaceutically acceptable acid addition salt thereof.

In yet another further embodiment the invention concerns compounds of formula (I),

including any stereochemically isomeric form thereof, wherein

wherein

n is 1;

m is 1;

X 1 , X 2 and X 3 are selected from X 1 is CR 1 d X 2 is CR 1 1 and X 3 is CR 1 ' , wherein each

R 1 1 is hydrogen;

R 1 is CH 3 ;

R 2 is hydrogen;

R 3 is halo;

R 4 is C3_ 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 ,

wherein

R 12 and R 13 are each independently selected from hydrogen and C ^alkyl,

R 10 is hydrogen;

or a pharmaceutically acceptable acid addition salt thereof. Interesting compounds of formula (I) are those compounds of formula (I) wherein one or more of the following restrictions apply :

a) A is a radical of formula (a-l); 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 fluoro; 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

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.

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

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

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

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

The compounds of formula (I) show antiviral properties. Viral infections treatable using the compounds and methods of the present invention include those infections brought on by Pneumoviridae and in particular by human and bovine respiratory syncytial virus (RSV). A number of the compounds of this invention moreover are active against mutated strains of RSV. Additionally, many of the compounds of this invention show a favorable pharmacokinetic profile and have attractive properties in terms of bioavailabilty, including an acceptable half-life, AUC and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention.

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

Additionally the present invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I). Also provided are pharmaceutical compositions comprising a pharmaceutically acceptable carrier, a therapeutically active amount of a compound of formula (I), and another antiviral agent, in particular a RSV inhibiting compound.

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

percutaneous administration or parenteral injection.

For example in preparing the compositions in oral dosage form, any of the usual liquid pharmaceutical carriers may be employed, such as for instance water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral injection compositions, the pharmaceutical carrier will mainly comprise sterile water, although other ingredients may be included in order to improve solubility of the active ingredient. Injectable solutions may be prepared for instance by using a pharmaceutical carrier comprising a saline solution, a glucose solution or a mixture of both. Injectable suspensions may also be prepared by using appropriate liquid carriers, suspending agents and the like. In compositions suitable for percutaneous administration, the pharmaceutical carrier may optionally comprise a penetration enhancing agent and/or a suitable wetting agent, optionally combined with minor proportions of suitable additives which do not cause a significant deleterious effect to the skin. Said additives may be selected in order to facilitate administration of the active ingredient to the skin and/or be helpful for preparing the desired compositions. These topical compositions may be administered in various ways, e.g., as a transdermal patch, a spot-on or an ointment. Addition salts of the compounds of formula (I), due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.

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

For oral administration, the pharmaceutical compositions of the present invention may take the form of solid dose forms, for example, tablets (both swallowable and chewable forms), capsules or gelcaps, prepared by conventional means with pharmaceutically acceptable excipients and carriers such as binding agents (e.g. pregelatinised maize starch,

polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like), fillers (e.g. lactose, microcrystalline cellulose, calcium phosphate and the like), lubricants (e.g. magnesium stearate, talc, silica and the like), disintegrating agents (e.g. potato starch, sodium starch glycollate and the like), wetting agents (e.g. sodium laurylsulphate) and the like. Such tablets may also be coated by methods well known in the art.

Liquid preparations for oral administration may take the form of e.g. solutions, syrups or suspensions, or they may be formulated as a dry product for admixture with water and/or another suitable liquid carrier before use. Such liquid preparations may be prepared by conventional means, optionally with other pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non aqueous carriers (e.g. almond oil, oily esters or ethyl alcohol), sweeteners, flavours, masking agents and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners useful in the pharmaceutical compositions of the invention comprise preferably at least one intense sweetener such as aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose (4,l',6'-trichloro-4,r,6'-trideoxygalactosucrose) or, preferably, saccharin, sodium or calcium saccharin, and optionally at least one bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey. Intense sweeteners are conveniently used in low concentrations. For example, in the case of sodium saccharin, the said concentration may range from about 0.04% to 0.1% (weight/volume) of the final formulation. The bulk sweetener can effectively be used in larger concentrations ranging from about 10% to about 35%, preferably from about 10% to 15% (weight/volume).

The pharmaceutically acceptable flavours which can mask the bitter tasting ingredients in the low-dosage formulations are preferably fruit flavours such as cherry, raspberry, black currant or strawberry flavour. A combination of two flavours may yield very good results. In the high-dosage formulations, stronger pharmaceutically acceptable flavours may be required such as Caramel Chocolate, Mint Cool, Fantasy and the like. Each flavour may be present in the final composition in a concentration ranging from about 0.05% to 1% (weight/volume). Combinations of said strong flavours are advantageously used.

Preferably a flavour is used that does not undergo any change or loss of taste and/or color under the circumstances of the formulation.

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

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

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

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

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

The invention will hereinafter be illlustrated with reference to the following, non-limiting examples.

Experimental part

A. Abbreviations

The stereochemical configuration for some compounds has been designated as R* or S* (or

*R or *S) when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure.

B. Compound synthesis

General scheme

Compound 1

1 -(4- [7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidine-3 -carbonitrile

A mixture of (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[l, 5- a]pyrimidine-5-carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquino line [2035421-61-3] (0.20 g, 0.39 mmol), pyrrolidine-3 -carbonitrile [10603-53-9] (45.7 mg, 475 pmol) and cesium carbonate (387 mg, 1.19 mmol) was purged with nitrogen.1 ,4-Dioxane (2 mL) was added and the mixture was degassed with nitrogen. Palladium acetate (17.8 mg, 79.1 pmol) and XantPhos (45.8 mg, 79.1 pmol) were added. The reaction mixture was purged with nitrogen and stirred at l00°C for 3 h. The reaction mixture was poured out 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 MgS0 4 , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by flash chromatography over silica gel (cartridge 24 g, 15-40 pm, mobile phase gradient: heptane / EtOAc from 70:30 to 50:50). The pure fractions were collected and evaporated to dryness. The residue (0.16 g) was taken up in DIPE. The solid was filtered off and dried under vacuum to give compound 1 (127 mg, 62%).

Compound 2 and Compound 3

Intermediate II

(3 R)- 1 -(4- [7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidine-3 -carbonitrile

A Schlenk tube was charged with (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (1.00 g, 1.91 mmol), (7?)-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 Litnol) and purged with nitrogen. l,4-Dioxane (20 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (42.9 mg, 191 pmol) was added. The reaction mixture was purged with nitrogen and stirred at l00°C for 17 h. The mixture was diluted with EtOAc and H 2 0. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 50:50) to afford intermediate II (879 mg, 88%) as a pale yellow solid.

Intermediate 12

(3 S)- 1 -(4- [7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidine-3 -carbonitrile

Intermediate 12 was synthesized from (S)-pyrrolidinc-3-carbonitrilc hydrochloride

[1153950-49-2] and (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[l, 5- a]pyrimidine-5 -carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421-61-3] according to the procedure reported for the synthesis of intermediate II. The purification was carried out by preparative LC (irregular SiOH, 15-40 pm, 40 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 40:60). The residue (997 mg) was taken up in MeCN and concentrated under reduced pressure to afford

intermediate 12 (840 mg, 84%) as a yellow solid.

Compound 2

(l7?)-2-(7-Cyclopropyl-2-{2-fluoro-4-[(37?)-3-(lH-l,2,3,4-te trazol-5-yl)pyrrolidin-l- yl]phenyl}pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline

In a sealed tube, sodium azide (212 mg, 3.27 mmol) was added to a mixture of

intermediate II (170 mg, 327 pmol), copper iodide (93.3 mg, 0.49 mmol) and ammonium chloride (52.4 mg, 0.98 mmol) in DMF (5 mL). The reaction mixture was stirred at l00°C for 18 h. EtOAc, 1N aqueous solution of HC1 and brine were added. The layers were separated and the aqueous phase was extracted with EtOAc (3 times). The combined organic extracts were dried over MgS0 4 , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15- 40 pm, 12 g GraceResolv™, dry loading (Celite ® ), mobile phase gradient: DCM / (MeOH/AcOH 9: 1) from 100:0 to 94:6). The product was taken up in EtOAc and a 1N aqueous solution of HC1 was added. The layers were separated and the organic phase was washed with 1N aqueous solution of HC1 (twice), dried over MgS0 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 under high vacuum at 50°C for 18 h to afford compound 2 (76 mg, 41%) as an orange solid.

Compound 3

(l7?)-2-(7-Cyclopropyl-2-{2-fluoro-4-[(35)-3-(lH-l,2,3,4-tet razol-5-yl)pyrrolidin-l- yl]phenyl}pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline

Compound 3 was synthesized from intermediate 12 according to the procedure reported for the synthesis of compound 2. The purification was carried out by preparative LC (irregular SiOH, 15-40 pm, 12 g GraceResolv™, dry loading (Celite ® ), mobile phase gradient: DCM / (MeOH/AcOH 9: 1) from 100:0 to 94:6). The residue was triturated with MeOH. The solid was filtered off and dried under high vacuum at 50°C for 18 h to afford compound 3 (126 mg, 68%) as an orange solid.

Compound 4

Intermediate 13

( Z,3S )- 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)-N'-hydroxypyrrolidine-3- carboximidamide

Hydroxylamine hydrochloride (120 mg, 1.73 mmol) was added to a suspension intermediate 12 (300 mg, 0.58 mmol) and sodium carbonate (244 mg, 2.31 mmol) in EtOH (8 mL). The reaction mixture was stirred under reflux for 24 h and the solvent was evaporated under reduced pressure. DCM and LEO 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 MgS0 4 , filtered and evaporated under reduced pressure to afford intermediate 13 (331 mg, 90%, 87% purity) as a yellow gum.

Intermediate 14

( Z )- (Amino[(35)- 1 -(4- (7-cyc lopropyl-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} - amino phenyl carbonate

Phenyl chloroformate (98.0 pL, 0.78 mmol) was added to a mixture of intermediate 13 (331 mg, 0.52 mmol, 87% purity) and triethylamine (220 pL, 1.58 mmol) in DCM (7 mL) at 0°C. The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with DCM and H 2 0. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 mhi, 24 g GraceResolv™, liquid injection (DCM), mobile phase gradient: DCM / EtOAc from 100:0 to 90: 10). The residue (210 mg) was taken up in MeCN and concentrated under reduced pressure (twice) to give intermediate 14 (189 mg, 52%) as a yellow gum.

Compound 4

3-[(35)- 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]-4,5-dihydro- 1 ,2,4-oxadiazol-5-one

In a sealed tube, potassium carbonate (41.1 mg, 0.30 mmol) was added to a solution of intermediate 14 (172 mg, 0.25 mmol) in DMF (1 mL). The reaction mixture was stirred at 50°C for 20 h. Brine, a 1N aqueous solution of HC1 and EtOAc were added. 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 MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was crystallized from MeOH, and the solid was filtered off and dried under high vacuum at 50°C for 3 h. The solid (110 mg) was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv™, liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 97:3). The residue was re-crystallized from MeOH, filtered off and dried under high vacuum at 50°C for 3 h to afford compound 4 (81 mg, 56%) as a pale yellowish solid.

Compound 5

(l7?)-2-[7-Cyclopropyl-2-(2-fluoro-4-{2-oxa-6-azaspiro[3.4]o ctan-6- yl}phenyl)pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline

A sealed tube was charged with (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]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), cesium carbonate (276 mg, 0.85 mmol) and XantPhos (16.3 mg, 28.2 prnol) and purged with nitrogen. l,4-Dioxane (4.5 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (6.33 mg, 28.2 pmol) was added. The reaction mixture was purged with nitrogen and stirred at l00°C for 17 h. The reaction mixture was diluted with EtOAc and H 2 0. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was removed under reduced pressure.

The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 50:50). The residue was crystallized from MeOH, filtered off and dried under high vacuum at 50°C for 20 h to afford compound 5 (112 mg, 74%) as a yellow solid.

Compound 6

6-[4-(7-Cyclopropyl-5- j [( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl]-3-fluorophenyl)-2 6 -thia-6-azaspiro[3.4]octane-2,2-dione

Compound 6 was synthesized from (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]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 reported for the synthesis of compound 5. Compound 6 (86 mg, 58%) was obtained as a yellow solid.

Compound 7 and Compound 8

Synthesis of intermediates 15 and 16

Intermediate 17

7¾r/-butyl (3/?)-3-acctamidopyrrolidinc- 1 -carboxylate

Acetic anhydride (0.56 mL, 5.91 mmol) was added dropwise to a mixture of (/?)-(+)- 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). The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with DCM and H 2 0. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated under reduced pressure to afford intermediate 17 (1.64 g) as an oil. Intermediate 18

7¾r/-butyl (35)-3-acetamidopyrrolidine- 1 -carboxylate

Intermediate 18 (1.97 g) was synthesized from (S)-(-)-l-boc-3-aminopyrrolidine [147081- 44-5] according to the procedure reported for the synthesis of intermediate 17.

Intermediate 15

N-[(3/?)-Pyrrolidin-3-yl] acetamide hydrochloride

15

A mixture of intermediate 17 (1.64 g, 4.53 mmol, 63% purity) and chlorotrimethylsilane (2.30 mL, 18.1 mmol) in MeOH (20 mL) was stirred at rt for 24 h. The mixture was evaporated under reduced pressure to afford intermediate 15 (1.12 g).

Intermediate 16

N-[(35)-Pyrrolidin-3-yl]acetamide hydrochloride

16

Intermediate 16 (1.34 g) was synthesized from intermediate 18 according to the procedure reported for the synthesis of intermediate 15.

Synthesis of compounds 7 and 8

Compound 7

N-[(3/?)- 1 -(4- (7-Cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydro isoqui noli nc-2- carbonyljpyrazolo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrro lidin-3 -yl] acetamide

A sealed tube was charged with (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (250 mg, 0.48 mmol), intermediate 15 (180 mg, 0.72 mmol, 66% purity) and cesium carbonate (782 mg, 2.40 mmol) and purged with nitrogen. l,4-Dioxane (10 mL) was added and the mixture was degassed with nitrogen. Palladium acetate (16.2 mg, 72.0 pmol) and XantPhos (41.6 mg, 72.0 pmol) were added. The reaction mixture was stirred at l00°C for 7 h. The reaction mixture was poured out into water and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated to dryness. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient: DCM / MeOH / aq.NFT from 100:0:0 to 98:2:0.2). The residue (191 mg) was co-evaporated with EtOH (5 times) and triturated with EtOH/Et 2 0 (1 :9). The solid was filtered off and dried under high vacuum at 50°C for 2 h to give compound 7 (140 mg, 53%) as a yellow solid.

Compound 8

N-[(35)- 1 -(4- (7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2- carbonyljpyrazolo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidin-3 -yl] acetamide

Compound 8 (107 mg, 40%) was synthesized from (li?)-2-[2-(4-bromo-2-fluorophenyl)-7- cyclopropylpyrazolo [ 1 ,5-a]pyrimidine-5-carbonyl] - 1 -methyl- 1 ,2,3 ,4-tetrahydroiso- quinoline [2035421-61-3] and intermediate 16 according to the procedure reported for the synthesis of compound 7. Compound 9 and Compound 10

(R): [147081 -49-0] (R): [1884705-14-9] - 111 (R): [1884705-13-8] - I9

(S)·. [147081 -44-5] (S) [1334550-71 -8] - 112 (S) [1312686-80-8] - 110 Intermediate Ill

7¾r/-butyl (3 ?)-3-[(mcthoxycarbonyl)ami no] pyrrolidine- 1 -carboxylate

111

In a sealed tube, CDI (653 mg, 4.03 mmol) was added to a mixture of (/?)-(+)- l-boc-3- aminopyrrolidine [147081-49-0] (500 mg, 2.69 mmol) and triethylamine (1.49 mL, 10.7 mmol) in DMF (10 mL). The reaction mixture was stirred at rt. MeOH (10 mL, 247 mmol) was added and the reaction mixture was stirred at rt for 18 h. H 2 0, brine and EtOAc were added and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g

GraceResolv™, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90:10 to 70:30) to afford intermediate Ill (344 mg, 52%). Intermediate 112

7¾r/-butyl (35)-3-[(methoxycarbonyl)amino]pyrrolidine- 1 -carboxylate

112

Intermediate 112 (444 mg, 68%) was synthesized from (5)-(-)-l-boc-3-aminopyrrolidine [147081-44-5] according to the procedure reported for the synthesis of intermediate Ill.

Intermediate 19

Methyl N-[(37?)-pyrrolidin-3-yl]carbamate hydrochloride

19

A mixture of intermediate Ill (344 mg, 1.41 mmol) and chlorotrimethylsilane (0.72 mL, 5.63 mmol) in MeOH (10 mL) was stirred at rt for 24 h. The mixture was evaporated under reduced pressure to afford intermediate 19 (225 mg, quant.).

Intermediate IIP

Methyl N-[(35)-pyrrolidin-3-yl]carbamate hydrochloride

no

Intermediate 110 (310 mg, 92%) was synthesized from intermediate 112 according to the procedure reported for the synthesis of intermediate 19.

Synthesis of compounds 9 and 10

Compound 9

Methyl N-[(3/?)- 1 -[4- { 7-cyclopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydro isoqui noli nc-2- carbonyljpyrazolo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidin-3 -yl] carbamate

A sealed tube was charged with (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (250 mg, 0.48 mmol), intermediate 19 (130 mg, 0.72 mmol) and cesium carbonate (782 mg, 2.40 mmol) and purged with nitrogen. l,4-Dioxane (10 mL) was added and the mixture was degassed with nitrogen. Palladium acetate (10.7 mg, 48.0 pmol) and

XantPhos (27.8 mg, 48.0 pmol) were added. The reaction mixture was stirred at l00°C for 18 h. The reaction mixture was poured out into water and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated to dryness. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient: DCM / MeOH / aq.NFT from 100:0:0 to 98:2:0.2). The residue (221 mg) was co-evaporated with EtOH (5 times) and triturated with Et 2 0. The solid was filtered off and dried under high vacuum at 50°C for 18 h to afford compound 9 (102 mg, 37%) as a yellow solid.

Compound 10

Methyl N-[(35)- 1 -[4- (7-cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2- carbonyljpyrazolo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidin-3 -yl] carbamate

Compound 10 (145 mg, 53%) was synthesized from (li?)-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 110 according to the procedure reported for the synthesis of compound 9. Compound 11 and Compound 12

115

Methanesulfonyl chloride (0.50 mL, 6.44 mmol) was added dropwise to a solution of (R)- (+)-l-boc-3-aminopyrrolidine [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 for 18 h. The reaction mixture was diluted with DCM and LLO. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated under reduced pressure to afford intermediate 115 (2.00 g) as an oil.

Intermediate 116

7b/ -butyl (3S)-3-methanesulfonamidopyrrolidine- 1 -carboxylate

116

Intermediate 116 (2.4 g) was synthesized from (S)-(-)-l-boc-3-aminopyrrolidine [147081- 44-5] according to the procedure reported for the synthesis of intermediate 115.

Intermediate 113

N-[(37?)-pyrrolidin-3-yl]methanesulfonamide hydrochloride

113

A mixture of intermediate 115 (2.00 g, 5.37 mmol, 71% purity) and chlorotrimethylsilane (2.73 mL, 21.5 mmol) in DCM (20 mL) was stirred at rt for 24 h. The mixture was evaporated under reduced pressure to give intermediate 113 (1.20 g).

Intermediate 114

N-[(35)-pyrrolidin-3-yl]methanesulfonamide hydrochloride

114

Intermediate 114 (1.68 g) was synthesized from intermediate 116 according to the procedure reported for the synthesis of intermediate 113.

Synthesis of compounds 11 and 12

Compound 11

N-[(3/?)- 1 -(4- (7-Cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydro isoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidin-3-yl]methane- sulfonamide

A sealed tube was charged with (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (250 mg, 0.48 mmol), intermediate 113 (181 mg, 0.72 mmol, 80% purity) and cesium carbonate (782 mg, 2.40 mmol) and purged with nitrogen. l,4-Dioxane (10 mL) was added and the mixture was degassed with nitrogen. Palladium acetate (16.2 mg, 72.0 pmol) and XantPhos (41.6 mg, 72.0 pmol) were added. The reaction mixture was stirred at l00°C for 7 h. The reaction mixture was poured out into water and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and concentrated to dryness. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient: DCM / MeOH / aq.NEb from 100:0:0 to 98:2:0.2). The residue (256 mg) was co evaporated with EtOH (5 times) and triturated with EtOH/Et 2 0 (1 :9). The solid was filtered off and dried under high vacuum at 50°C for 2 h to afford compound 11 (148 mg, 52%) as a yellow solid.

Compound 12

N-[(35)- 1 -(4- (7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 , 2,3, 4-tetrahydroisoquino line-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidin-3-yl]methane- sulfonamide

A sealed tube was charged with (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (250 mg, 0.48 mmol), intermediate 114 (226 mg, 0.72 mmol, 64% purity) and cesium carbonate (782 mg, 2.40 mmol) and purged with nitrogen. l,4-Dioxane (10 mL) was added and the mixture was degassed with nitrogen. Palladium acetate (10.8 mg, 48.0 pmol) and XantPhos (27.8 mg, 48.0 pmol) were added. The reaction mixture was stirred at l00°C for 7 h. The reaction mixture was poured out into water and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and concentrated to dryness. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient: DCM / MeOH / aq.NTb from 100:0:0 to 98:2:0.2). The residue (158 mg) was co- evaporated with EtOH (5 times) and triturated with EtOH/Et 2 0 (1 :9). The solid was filtered off and dried under high vacuum at 50°C for 2 h. The purification sequence was repeated: purification by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient: DCM / MeOH / aq.NFT from 100:0:0 to 98:2:0.2). The residue was co-evaporated with EtOH (3 times) and triturated with Et 2 0.

The solid was filtered off and dried under high vacuum at 50°C to afford compound 12 (99 mg, 35%) as a yellow solid.

Compound 13

(37?)- 1 -(4- (7-Cyclopropyl-5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidin-3-ol

A sealed tube was charged with (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (250 mg, 0.48 mmol), (7?)-3-pyrrolidinol hydrochloride [104706-47-0] (77.6 pL,

0.96 mmol) and sodium /erf-butoxidc (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 pmol) and (±)-BINAP (59.7 mg, 96.0 pmol) were added. The reaction mixture was stirred at l00°C for 18 h. The reaction mixture was poured out into water and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and concentrated to dryness. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 25 g Interchim ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 80:20 to 0: 100). The residue (65 mg) was taken up in 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 afford compound 13 (45 mg, 18%).

Compound 14

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

A sealed tube was charged with (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (200 mg, 0.38 mmol), (5)-3-pyrrolidinol [100243-39-8] (167 mg, 1.92 mmol) and cesium carbonate (625 mg, 1.92 mmol) and purged with nitrogen. l,4-Dioxane (8 mL) was added and the mixture was degassed with nitrogen. Palladium acetate (8.61 mg, 38.4 pmol) and XantPhos (22.2 mg, 38.4 pmol) were added. The reaction mixture was stirred at l00°C for 18 h. The reaction mixture was diluted with H 2 0 and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 25 g Interchim ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 80:20 to 0: 100). The residue was taken up in MeCN and Et 2 0 and evaporated to dryness. The solid was triturated with Et 2 0, filtered off and dried under high vacuum at 60°C for 18 h to afford compound 14 (64 mg, 33%) as a yellow solid.

Compound 77

(37?)- 1 -(4- (7-Cyclopropyl-5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidin-3-yl carbamate

CDI (2.15 g, 13.3 mmol) was added to a solution of compound 13 (3.39 g, 6.63 mmol) in THF (25 mL). The reaction mixture was stirred at rt for 1 h. Ammonia (28% in H 2 0, 24.8 mL, 367 mmol) was added and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with H 2 0, brine and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 330 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / EtOAc from 100:0 to 80:20). The residue (2.8 g) was triturated with MeCN. The solid was filtered off and dried under high vacuum at 50°C for 2 h. The solid (1.87 g) was triturated again with MeCN, filtered off and dried under 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 h. 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

(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 carbamate

CDI (1.97 g, 12.1 mmol) was added to a solution of compound 14 (3.11 g, 6.07 mmol) in THF (23 mL). The reaction mixture was stirred at rt for 1 h. Ammonia (28% in H 2 0, 22.7 mL, 336 mmol) was added and the reaction mixture was stirred at rt for 6 h. The reaction mixture was diluted with H 2 0, brine and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 330 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / EtOAc from 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 triturated again with MeCN, filtered off and dried under high vacuum at 50°C overnight. The product (1.03 g) was suspended in MeOH (25 mL) and stirred at rt for 18 h. The solid was filtered off and dried under high vacuum at 50°C to give compound 78 (825 mg, 25%) as a yellow solid.

Compound 15 and Compound 16

Synthesis of intermediates 117 and 118

Intermediate 119

Tert- butyl (3i?)-3-[(methylcarbamoyl)oxy]pyrrolidine- 1 -carboxylate

119

In a sealed tube CDI (871 mg, 5.37 mmol) was added to a solution of (i?)-(-)-N-boc-3- pyrrolidinol [109431-87-0] (503 mg, 2.69 mmol) in THF (10 mL). The reaction mixture was stirred at rt for 1 h. Methylamine (40% in H 2 0, 10 mL, 116 mmol) was added and the reaction mixture was stirred at rt for 2 h. H 2 0, brine and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv™, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90:10 to 70:30) to give intermediate 119 (700 mg, quant., 94% purity).

Intermediate 120

A/t-butyl (3S)-3-[(mcthylcarbamoyl)oxy] pyrrolidine- 1 -carboxylate

120

Intermediate 120 (610 mg, 93%) was synthesized from (5)-(+)-N-boc-3-pyrrolidinol

[101469-92-5] according to the procedure reported for the synthesis of intermediate 119. Intermediate 117

(37?)-Pyrrolidin-3-yl N-methylcarbamate hydrochloride

117 A mixture of intermediate 119 (700 mg, 2.67 mmol, 93% purity) and chlorotrimethylsilane (1.35 mL, 10.7 mmol) in MeOH (10 mL) was stirred at rt for 24 h. The mixture was evaporated under reduced pressure to afford intermediate 117 (525 mg).

Intermediate 118

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

118 Intermediate 118 (475 mg) was synthesized from intermediate 120 according to the procedure reported for the synthesis of intermediate 117.

Synthesis of compounds 15 and 16

Compound 15

(37?)- 1 -(4- (7-Cyclopropyl-5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-y l N-methylcarbamate

A sealed tube was charged with (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (250 mg, 0.48 mmol), intermediate 117 (143 mg, 0.72 mmol, 91% purity) and cesium carbonate (782 mg, 2.40 mmol) and purged with nitrogen. l,4-Dioxane (10 mL) was added and the mixture was degassed with nitrogen. Palladium acetate (10.8 mg, 48.0 gmol) and XantPhos (27.8 mg, 48.0 prnol) were added. The reaction mixture was stirred at l00°C for 18 h. The reaction mixture was poured out into water and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and concentrated to dryness. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient: DCM / MeOH / aq.NEb from 100:0:0 to 98:2:0.2). A second purification was performed by reverse phase (spherical C18, 25 pm, 40 g YMC-ODS-25, dry loading (Celite ® ), mobile phase gradient: (0.2% aq.NH 4 HC0 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 under high vacuum at 50°C for 18 h to afford compound 15 (75 mg, 27 %) as a yellow solid.

Compound 16

(3 S)- 1 -(4- (7-Cyclopropyl-5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-y l N-methylcarbamate

Compound 16 was synthesized from (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] and intermediate 118 according to the procedure reported for the synthesis of compound 15. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient: DCM / MeOH / aq.NFT from 100:0:0 to 98:2:0.2). A second purification was performed by reverse phase (spherical C18, 25 pm, 40 g YMC-ODS-25, dry loading (Celite ® ), mobile phase gradient: (0.2% aq.NH 4 HC0 3 ) / MeCN from 40:60 to 0: 100). The residue was co-evaporated with

EtOH (5 times) and triturated with EtOH/Et 2 0 (1 :9). The solid was filtered off and dried under 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

(l7?)-2-(7-Cyclopropyl-2-{2-fluoro-4-[(37?)-3-methanesulfony lpyrrolidin-l-yl]phenyl}- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline

A sealed tube was charged with (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (150 mg, 288 pmol), ( ?)-3-(mcthylsulfonyl [pyrrolidine [1234576-84-1] (53.4 mg,

288 pmol), cesium carbonate (276 mg, 846 pmol) and XantPhos (19.7 mg, 34.0 pmol) 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 pmol) was added. The reaction mixture was purged with nitrogen and stirred at l00°C for 18 h. 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 0, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 50:50 to 0:100). A second purification was performed by preparative LC (spherical C18 25 pm, 40 g YMC-ODS-25, loading (MeCN, H 2 0), mobile phase gradient: (0.2% aq. NH4HCO3) / MeCN from 50:50 to 0:100). The fractions containing the product were combined and a 10% aqueous solution of KHSO4 was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, dried over MgS0 4 , filtered and evaporated under reduced pressure. The residue (105 mg) was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 50:50 to 0:100). The residue was triturated and co evaporated with Et 2 0 (twice) and dried under high vacuum at 50°C for 18 h to give compound 17 (54 mg, 32%) as a yellow solid.

Compound 18

(l7?)-2-(7-Cyclopropyl-2-{2-fluoro-4-[(3S)-3-methanesulfonyl pyrrolidin-l-yl]phenyl}- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline

Compound 18 was synthesized from (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 -

61-3] and (A)-3-(mcthylsulfonyl [pyrrolidine [290328-57-3] according to the procedure reported for the synthesis of compound 17. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 50:50 to 0:100). A second purification was performed by preparative LC (spherical C18 25 pm, 40 g YMC-ODS-25, loading (MeCN, H 2 0), mobile phase gradient (0.2% aq.NH 4 HC0 3 ) / MeCN from 50:50 to 0: 100). The fractions containing the product were combined and a 10% aqueous solution of KHS0 4 was added. The layers were separated and the aqueous phase was extracted with EtOAc. The organic phase was washed with H 2 0, dried over MgS0 4 , filtered and evaporated under reduced pressure. The residue was triturated and co-evaporated with Et 2 0 (twice) and dried under 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-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidine-3 -sulfonamide

A sealed tube was charged with (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (400 mg, 768 pmol), pyrrolidine-3 -sulfonamide [1208507-46-3] (115 mg, 768 pmol), sodium te/t-butoxidc (105 mg, 1.09 mmol) and (±)-BINAP (100 mg, 161 pmol) and purged with nitrogen. l,4-Dioxane (10 mL) was added and the mixture was purged again with nitrogen. Tris(dibenzylideneacetone)dipalladium (140 mg, 153 pmol) was added. The reaction mixture was purged with nitrogen and stirred at l00°C for 18 h. A 10% aqueous solution of KHS0 4 was added until pH 6. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 80 g GraceResolv™, liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 95:5). A second purification was performed by preparative LC (spherical C18 25 pm, 40 g YMC-ODS-25, loading (MeCN, H 2 0), mobile phase gradient: (0.2% aq.MTiHCCE) / MeCN from 50:50 to 0: 100). The product was freeze-dried to give compound 19 (48 mg, 11%) as a yellow solid.

Compound 20

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

A mixture of compound 19 (215 mg, 0.37 mmol), acetic anhydride (53.0 pL, 0.56 mmol) and DBU (83.8 pL, 0.56 mmol) in DCM (2 mL) was stirred at rt for 7 h. 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 0, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (spherical C18 25 pm, 40 g YMC-ODS-25, loading (MeCN, H 2 0), mobile phase gradient: (0.2% aq. NH 4 HC0 3 ) / MeCN from 15:85 to 65:35). The product was freeze-dried to give compound 20 (40 mg, 17%) as a yellow solid.

Compound 21

1 -(4- (7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)-N -methylpyrro lidine-3 -sulfonamide

A sealed tube was charged with (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (200 mg, 384 pmol), N-methylpyrrolidine-3-sulfonamide hydrochloride [1423025-

73-3] (77.0 mg, 384 pmol), sodium fc/ -butoxidc (50.0 mg, 0.52 mmol) and (±)-BINAP (47.8 mg, 76.8 pmol) and purged with nitrogen. l,4-Dioxane (9 mL) was added and the mixture was purged again with nitrogen. Tris(dibenzylideneacetone)dipalladium (70.3 mg, 76.8 pmol) was added. The reaction mixture was purged with nitrogen and stirred at l00°C for 18 h. 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 0, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g

GraceResolv™, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 50:50 to 0:100). A second purification was performed by preparative LC (spherical C18 25 pm, 40 g YMC-ODS-25, loading (MeCN, H 2 0), mobile phase gradient (0.2%

aq.NH 4 HC0 3 ) / MeCN from 50:50 to 0:100). The fractions containing the product were combined and a 10% aqueous solution of KHS0 4 was added. The layers were separated and the aqueous phase was extracted with EtOAc. The organic phase was washed with H 2 0, dried over MgS0 4 , filtered and evaporated under reduced pressure. The residue was triturated and co-evaporated with Et 2 0 (twice) and dried under high vacuum at 50°C for 18 h to give compound 21 (109 mg, 48%) as a pale red solid.

Compound 22

1 -(4- [7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-3-fluorophenyl)-N,N-dimethylp yrrolidine-3-sulfonamide

In a sealed tube a mixture of (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (250 mg, 480 pmol), N,N-dimethyl-3-pyrrolidinesulfonamide hydrochloride

[1825309-05-4] (155 mg, 720 Ltmol) and sodium /e/V-butoxidc (231 mg, 2.40 mmol) in l,4-dioxane (10 mL) was degassed with nitrogen. Palladium acetate (11.0 mg, 72.0 Ltmol) and XantPhos (27.8 mg, 48.0 Ltmol) were added. The reaction mixture was stirred at l00°C for 18 h. The reaction mixture was poured out into water and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and concentrated to dryness. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv™, liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 96:4). The residue was co-evaporated (5 times) and triturated with EtOH. The solid was filtered off and dried under high vacuum at 50°C for 18 h to give compound 22 (150 mg, 52%) as a yellow solid.

Compound 79

Synthesis of intermediate 1159

Intermediate 1160

7¾r/-butyl (37?)-3-(methylsulfanyl)pyrrolidine- 1 -carboxylate

1160

Methyl iodide (3.9 mL, 62.8 mmol) was added to a mixture of (R)- ter [-butyl 3- (acethylthio)pyrrolidine-l -carboxylate [935845-19-5] (7.00 g, 28.5 mmol) and sodium hydroxide (1.0 M in H 2 0, 31 mL, 31.0 mmol) in MeOH (140 mL). The reaction mixture was stirred at rt for 72 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was evaporated in vacuo to afford intermediate 1160 (5.2 g, 84%). Intermediate 1161

(37?)-3 -(Methylsulfanyl)pyrrolidine hydrochloride

1161

A mixture of intermediate 1160 (5.20 g, 23.9 mmol) and hydrogen chloride (3.0 M in H 2 0, 80 mL, 239 mmol) in MeOH (185 mL) was stirred at rt for 16 h. The mixture was evaporated to dryness and co-evaporated with MeOH to afford intermediate 1161 (3.7 g, quant.).

Intermediate 1162

Benzyl (37?)-3-(methylsulfanyl)pyrrolidine- 1 -carboxylate

Benzyl chloroformate (3.8 mL, 26.5 mmol) was added to a mixture of intermediate 1161 (3.70 g, 24.1 mmol) and DIPEA (10.3 mL, 60.2 mmol) in DCM (122 mL) at 0°C. The reaction mixture was stirred at rt for 16 h. An aqueous solution of NaHC0 3 , brine and DCM were added. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was evaporated in vacuo. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 220 g Interchim ® , liquid injection (DCM / heptane), mobile phase gradient: heptane / EtOAc from 100:0 to 50:50) to afford intermediate 1162 (3.22 g, 53%).

Intermediate 1163

Benzyl (3/?)-3-mcthancsulfinyl pyrrolidine- 1 -carboxylate

1163 m-CPBA (3.16 g, 14.1 mmol, 77% purity) was added portionwise to a solution of intermediate 1162 (3.22 g, 12.8 mmol) in DCM (128 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 h. A 10% aqueous solution of NaHCCh and H 2 0 were added. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried over MgS0 4 , filtered and the solvent was evaporated in vacuo. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 120 g

Interchim ® , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 99.8:0.2 to 95:5) to afford intermediate 1163 (1.63 g, 48%).

Intermediate 1164

Benzyl (3R)-3- [methyl(oxo) [(trifluoroacctyl)imino]A 6 -sulfanyl]pyrro lidine- 1 -carboxylate

To a mixture of intermediate 1163 (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 rt for 16 h. Celite ® was added and the mixture was evaporated to dryness. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 80 g Interchim ® , dry loading (Celite ® ), mobile phase gradient: DCM / MeOH from 100:0 to 95:5) to afford intermediate 1164 (1.47 g, 64%).

Intermediate 1159

2,2,2-Trifluoro-N-[methyl(oxo)(37?)-pyrrolidin-3-yl 6 -sulfanylidene]acetamide

1159

A mixture of intermediate 1164 (1.47 g, 3.89 mmol) and Pd/C (10% wt and in 50% H 2 0, 4.13 g, 1.94 mmol) in EtOH (50 mL) was stirred under H 2 atmosphere (20 bars) at rt for 72 h. The reaction mixture was filtered over a pad of Celite ® and rinsed with EtOH (twice). The filtrate was evaporated to dryness to give intermediate 1159 (838 mg, 88%).

Compound 79

[(3/?)- 1 -(4- {7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-3-fluorophenyl)pyrrolidin-3-y l](imino)methyl 6 - sulfanone

In a Schlenk tube were added (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (300 mg, 0.59 mmol), intermediate 1159 (217 mg, 0.89 mmol), cesium carbonate (580 mg, 1.78 mmol) and l,4-dioxane (9.5 mL). The mixture was degassed with nitrogen and palladium acetate (13.3 mg, 5.94 pmol) and XantPhos (34.3 mg, 5.94 pmol) were added successively. The reaction mixture was stirred at l00°C for 16 h. H 2 0 (3.8 mL) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was evaporated in vacuo. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 25 g Interchim ® , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 99.8:0.2 to 90:10). The residue was solubilized in EtOAc and the mixture was evaporated under vacuum (twice). The residue was dissolved in EtOAc and a precipitate was observed upon the addition of heptane. The solid was filtered off and dried under high vacuum at 40°C for 16 h to give compound 79 (143 mg, 42%). Compound 23 and Compound 24

Synthesis of intermediate 121

Intermediate 125

7¾r/-butyl 3-(2-ethoxy-2-oxoethyl)-3-methylpyrrolidine- 1 -carboxylate

A mixture of tert- butyl (3 )-3-(2-cthoxy-2-oxocthylidcnc)pyrrolidinc- 1 -carboxylatc

[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) was stirred at rt for 1 h. The reaction mixture was cooled down to -30°C and methylmagnesium bromide (3.0 M in Et 2 0, 27.4 mL, 82.3 mmol) was added dropwise. The reaction mixture was slowly warmed to rt and stirred overnight. EtOAc and 1N aqueous solution of HC1 were added. The layers were separated and the organic phase was washed with brine, dried over MgS0 4 , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 80 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 70:30) to afford intermediate 125 (2.0 g, 54%).

Intermediate 121

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

121

HC1 (4.0 M in dioxane, 2.53 mL, 10.1 mmol) was added to a solution of intermediate 125 (550 mg, 2.03 mmol) in DCM (10 mL). The reaction mixture was stirred at rt overnight and the solvent was evaporated under reduced pressure. The product 121 was used in the next step without further purification.

Synthesis of compounds 23 and 24

Intermediate 122

Ethyl-2-[ 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)-3-methylpyrrolidin-3-yl]acetate

122 A mixture of (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[l, 5- a]pyrimidine-5 -carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421-61-3] (474 mg, 0.94 mmol), intermediate 121 (390 mg, 1.88 mmol), cesium carbonate (0.92 g, 2.82 mmol) and XantPhos (54.3 mg, 93.9 pmol) was purged with nitrogen. l,4-Dioxane (15 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (21.1 mg, 93.9 pmol) was added. The reaction mixture was purged with nitrogen and stirred at l00°C for 18 h. The reaction mixture was diluted with EtOAc and H 2 0. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 70:30) to afford intermediate 122 (490 mg, 88%).

Intermediates 123 and 124

2-[(3*/?)- 1 -(4- (7-Cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydro isoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)-3-methylpyrrolidin-3-yl]acetic acid

2-[(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)-3-methylpyrrolidin-3-yl]acetic acid

Lithium hydroxide monohydrate (104 mg, 2.45 mmol) was added to a solution of intermediate 122 (490 mg, 823 pmol) in THF (10 mL), MeOH (3 mL) and LEO (1.2 mL). The reaction mixture was stirred at rt for 3 h. Few drops of LEO were added followed by the addition of a 3N aqueous solution of HC1. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with LEO, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g Grace ® , liquid injection (DCM), mobile phase gradient: DCM /MeOH from 100:0 to 97:3) to deliver a mixture of diastereomers (250 mg, 53%). A purification was performed via chiral SFC (Stationary phase: Chiralpak AS-H 5pm 250*20mm, Mobile phase: 65% C0 2 , 35% i- PrOH) to afford the diastereomers 123 (120 mg, 26%) and 124 (122 mg, 26%). The diastereomers were purified separately by preparative LC (irregular SiOH, 15-40 pm, 12 g Grace ® , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 97:3) to give 123 (95 mg, 20%) and 124 (92 mg, 20%).

Compound 23

2-[(3*/?)- 1 -(4- (7-Cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydro isoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)-3-methylpyrrolidin-3- yljacetamide

A mixture of intermediate 123 (80.0 mg, 0.14 mmol), HMDS (35.9 pL, 0.17 mmol), HATU (80.4 mg, 0.21 mmol) and DIPEA (36.4 pL, 0.21 mmol) in DMF (2 mL) was stirred at rt for 2 h. H 2 0 was added and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, brine, dried over MgS0 4 and concentrated to dryness. The crude mixture was purified by flash chromatography over silica gel (15-40 pm, 12 g Grace ® , mobile phase gradient: DCM / MeOH from 100:0 to 97:3). The pure 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-[( 1 R)- 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 124 according to the procedure reported for the synthesis of compound 23.

Compound 25 and Compound 26

Intermediate 126

Ethyl 2-[l-(4-{7-cyclopropyl-5-[(4*i?)-4-methyl-4,5,6,7-tetrahydro -thieno[3,2-c]pyridine- 5 -carbonyljpyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)-3 -methylpyrrolidin-3 - yl] acetate

A mixture of 2-(4-bromo-2-fluorophenyl)-7-cyclopropyl-5-[(47?)-4-methyl-4 ,5,6,7- tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]pyrazolo[l ,5-a]pyrimidine [2035419-01 - 1 ] (517 mg, 1.01 mmol), intermediate 121 (420 mg, 2.02 mmol), cesium carbonate (0.99 g, 3.03 mmol) and XantPhos (80.1 mg, 0.14 mmol) was purged with nitrogen. l,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 l00°C for 18 h. The reaction mixture was diluted with EtOAc and H 2 0. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 70:30) to afford intermediate 126 (440 mg, 72%).

Intermediates 127 and 128

2-[(3*7?)-l-(4-{7-Cyclopropyl-5-[(4*7?)-4-methyl-4,5,6,7-tet rahydro-thieno[3,2-c]pyridine- 5 -carbonyljpyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3-fluorophcnyl)-3-mcthyl pyrrol idin-3-yl]acctic acid

2-[(3*5)-l-(4-{7-Cyclopropyl-5-[(4*7?)-4-methyl-4,5,6,7-tetr ahydro-thieno[3,2-c]pyridine- 5 -carbonyljpyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)-3 -methylpyrrolidin-3 -yljacetic acid

Lithium hydroxide monohydrate (92.1 mg, 2.19 mmol) was added to a solution of intermediate 126 (440 mg, 0.73 mmol) in THF (10 mL), MeOH (3 mL) and LEO (1.2 mL). The reaction mixture was stirred at rt for 18 h. Few drops of LEO were added followed by the addition of a 3N aqueous solution of HC1. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with H 2 0, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g Grace ® , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 97:3). The diastereoisomers (220 mg) were separated via chiral SFC (Stationary phase: Chiralpak AS- H 5pm 250*20mm, Mobile phase: 65% C0 2 , 35% z-PrOH) to give 127 (94 mg) and 128 (94 mg). The two separated diastereoisomers were taken up in DIPE and the solids were filtered off and dried under vacuum at 50°C. The diastereoisomers were purified separately by preparative LC (irregular SiOH, 15-40 pm, 12 g Grace ® , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 97:3) to afford intermediates 127 (78 mg, 18%) and 128 (70 mg, 17%).

Compound 25

2-[(3*/?)-l-(4-{7-Cyclopropyl-5-[(4*i?)-4-methyl-4,5,6,7-tet rahydro-thieno[3,2-c]pyridine- 5-carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)-3-methylpyrrolidin-3- yljacetamide

A solution of intermediate 127 (78.0 mg, 0.14 mmol), HMDS (34.6 pL, 0.16 mmol), HATU (77.5 mg, 0.20 mmol) and DIPEA (46.9 pL, 0.27 mmol) in DMF (2 mL) was stirred at rt for 5 h. The reaction mixture was diluted with H 2 0 and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, brine, dried over MgS0 4 and concentrated to dryness. The crude mixture was purified by flash chromatography over silica gel (15-40 pm, 12 g Grace ® , mobile phase gradient: DCM / MeOH from 100:0 to 97:3). The pure 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)-l-(4-{7-Cyclopropyl-5-[(4*7?)-4-methyl-4,5,6,7-tetr ahydro-thieno[3,2-c]pyridine- 5 -carbonyljpyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)-3 -methylpyrrolidin-3 - yljacetamide

Compound 26 (28 mg, 40%) was synthesized from intermediate 128 according to the procedure reported for the synthesis of compound 25.

Compound 27 and Compound 28

Synthesis of intermediates 129 and 130

129 130

Intermediate 135

7¾r/-butyl 3-( 1 -ethoxy- 1 -oxopropan-2-yl)pyrrolidine- 1 -carboxylate

135 Lithium bis(trimethylsilyl)amide (1.5 M in THF, 10.6 mL, 15.9 mmol) was added to a solution of tert- butyl 3 -(2-ethoxy-2-oxoethyl)pyrrolidine-l -carboxylate [664364-29-8] (1.7 g, 6.61 mmol) in THF (60 mL) at -l0°C for 1 h. Iodomethane (0.98 mL, 15.9 mmol) was added and the reaction mixture was stirred at rt for 4 h. H 2 0 was added and the aqueous phase was extracted with EtO Ac (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated under reduced pressure. Intermediate 135 was used in the next step without further purification. Intermediates 136 and 137

7br/-butyl (3 *R)~ 3 -( 1 -ethoxy-2-methyl- 1 -oxopropan-2-yl)pyrrolidine- 1 -carboxylate 7br/-butyl (3 *S)-3 -( 1 -ethoxy-2-methyl- 1 -oxopropan-2-yl)pyrro lidine- 1 -carboxylate

Lithium bis(trimethylsilyl)amide (1.5 M in THE, 18.4 mL, 27.6 mmol) was added to a solution of intermediate 135 (2.50 g, 9.21 mmol) in THE (37.5 mL) at -l0°C under nitrogen. The reaction mixture was stirred at -l0°C for 2 h. Iodomethane (1.37 mL, 22.1 mmol) was added and the reaction mixture was stirred at rt for 4 h. The reaction mixture was diluted with EtOAc and the organic phase was washed with H 2 0, brine, dried over MgS0 4 and the solvent was evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 70:30). The enantiomers were separated via chiral SEC (Stationary phase: Lux amylose 2 5pm 250*21.2mm, Mobile phase: 90% C0 2 , 10% /-PrOH) to afford intermediates 136 (850 mg, 32%) and 137 (850 mg, 32%).

Intermediate 129

Ethyl 2-methyl-2-[(3*7?)-pyrrolidin-3-yl]propanoate hydrochloride

HC1 (4.0 M in dioxane, 1.1 mL, 4.40 mmol) was added to a solution of intermediate 136 (250 mg, 876 pmol) in DCM (5 mL). The reaction mixture was stirred at rt overnight. The solvent was evaporated under reduced pressure and the product 129 was used in the next step as soon as possible without further purification.

Intermediate 130

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

130

Intermediate 130 was synthesized from intermediate 137 according to the procedure reported for the synthesis of intermediate 129. The product was used in the next step without further purification.

Synthesis of compounds 27 and 28

Intermediate 131

Ethyl 2- [(3 *R)~ l-(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]-2- methylpropanoate

A mixture of (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[l, 5- a]pyrimidine-5 -carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421-61-3] (228 mg, 0.45 mmol), intermediate 129 (150 mg, 0.68 mmol), cesium carbonate (441 mg, 1.35 mmol) and XantPhos (26.1 mg, 45.1 pmol) was purged with nitrogen. l,4-Dioxane (7 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (10.1 mg, 45.1 pmol) was added. The reaction mixture was purged with nitrogen and stirred at l00°C for 18 h. The reaction mixture was diluted with EtOAc and EEO. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15- 40 pm, 12 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 75:25) to afford intermediate 131 (190 mg, 69%). Intermediate 132

Ethyl 2-[(3 *S)- 1 -(4- j 7-cyclopropyl-5-[( 1 /?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidin-3-yl]-2- methylpropanoate

Intermediate 132 (125 mg, 57%) was synthesized from (li?)-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 130 according to the procedure reported for the synthesis of compound 131 with a shorter reaction time of 3 h.

Intermediate 133

2-[(3*/?)- 1 -(4- (7-Cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydro isoqui noli nc-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 131 (0.19 g, 0.31 mmol) in THF (5 mL), MeOH (2 mL) and LEO ( 0.4 mL). The reaction mixture was stirred at rt for 24 h and at 60°C for 24 h. Few drops of H 2 0 were added followed by the addition of a 3N aqueous solution of HC1. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with FEO, dried over MgS0 4 , filtered and evaporated under reduced pressure. The product 133 (210 mg) was used in the next step without further purification. Intermediate 134

2-[(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]-2- methylpropanoic acid

Intermediate 134 was synthesized from intermediate 132 according to the procedure reported for the synthesis of intermediate 133. The reaction mixture was stirred at 60°C for 24 h. The product 134 (155 mg) was used in the next step without further purification.

Compound 27

2-[(3*/?)- 1 -(4- (7-Cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydro isoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidin-3-yl]-2- methylpropanamide

A mixture of intermediate 133 (190 mg, 327 pmol), HMDS (83.2 pL, 392 pmol), HATU (186 mg, 0.49 mmol) and DIPEA (112 pL, 0.65 mmol) in DMF (5 mL) was stirred at rt for 2 h. H 2 0 was added and the aqueous phase was extracted with EtOAc. The organic phase was washed with H 2 0, brine, dried over MgS0 4 and concentrated to dryness. The crude mixture was purified by flash chromatography over silica gel (Grace ® 12 g, 15-40 pm, mobile phase gradient: DCM / MeOH from 100:0 to 97:3). The pure fractions were collected and evaporated to dryness. The residue (85 mg) was taken up in DIPE and the solid was filtered off and dried under vacuum to give compound 27 (50 mg, 26%).

Compound 28

2-[(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]-2- methylpropanamide

Compound 28 was synthesized from intermediate 134 according to the procedure reported for the synthesis of compound 27. The crude mixture was purified by flash

chromatography over silica gel (15-40 pm, 12 g Grace ® , mobile phase gradient: DCM / MeOH from 100:0 to 97:3). The pure fractions were collected and evaporated to dryness. The product was lyophilized with MeCN / H 2 0 (80:20) to give compound 28 (56 mg, 36%).

Compound 29

Intermediate 138

Ethyl 2-[(3*7?)-l-(4-{7-cyclopropyl-5-[(4*7?)-4-methyl-4,5,6,7-tet rahydro-thieno[3,2- c]pyridine-5-carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidin-3-yl]-2- methylpropanoate

A mixture of 2-(4-bromo-2-fluorophenyl)-7-cyclopropyl-5-[(4*7?)-4-methyl- 4,5,6,7- tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]pyrazolo[l ,5-a]pyrimidine [2035419-01 - 1 ] (300 mg, 0.59 mmol), intermediate 129 (195 mg, 0.88 mmol), cesium carbonate (573 mg, 1.76 mmol) and XantPhos (33.9 mg, 58.6 pmol) was purged with nitrogen. l,4-Dioxane (7 mL) was added and the mixture was degassed with nitrogen. Palladium acetate (13.2 mg, 58.6 pmol) was added. The reaction mixture was purged with nitrogen and stirred at l00°C for 18 h. The reaction mixture was diluted with EtOAc and EEO. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15- 40 pm, 24 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 75:25) to give intermediate 138 (120 mg, 33%).

Intermediate 139

2-[(3*7?)-l-(4-{7-Cyclopropyl-5-[(4*7?)-4-methyl-4,5,6,7-tet rahydro-thieno[3,2-c]pyridine- 5 -carbonyljpyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidin-3 -yl] -2-methyl- propanoic acid

Lithium hydroxide monohydrate (24.5 mg, 0.59 mmol) was added to a solution of intermediate 138 (0.12 g, 195 pmol) in THF (5 mL), MeOH (1 mL) and H 2 0 (0.6 mL). The reaction mixture was stirred at rt for 24 h and at 60°C for another 24 h. Few drops of H 2 0 were added followed by a 3N aqueous solution of HC1. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with H 2 0, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 4 g Grace ® , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 97:3) to afford intermediate 139 (75 mg, 65%).

Compound 29

2-[(3*7?)-l-(4-{7-Cyclopropyl-5-[(4*7?)-4-methyl-4,5,6,7-tet rahydro-thieno[3,2-c]pyridine- 5 -carbonyljpyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidin-3 -yl] -2-methyl- propanamide

A solution of intermediate 139 (75.0 mg, 0.13 mmol), HMDS (32.5 pL, 0.15 mmol), HATU (72.8 mg, 0.19 mmol) and DIPEA (44.0 pL, 0.26 mmol) in DMF (2 mL) was stirred at rt for 2 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The organic phase was washed with H 2 0, brine, dried over MgS0 4 and concentrated to dryness. The crude compound was purified by flash chromatography over silica gel ( 15 -40pm, 4 g Grace ® , mobile phase gradient: DCM / MeOH from 100:0 to 97:3). The pure fractions were collected and evaporated to dryness. The product was lyophilized (MeCN / H 2 0, 80:20) to give compound 29 (41 mg, 55%).

Compound 30 and Compound 31

Intermediate 140

Tert- butyl N-[(37?)- 1 -(4- (7-cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline- 2-carbonyl]pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidin-3 -yl] carbamate

A Schenlk tube was charged with (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 -

61-3] (500 mg, 0.95 mmol), (7?)-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 ltmol) and

tris(dibenzylideneacetone)dipalladium (87.2 mg, 95.3 Ltmol) were added. The reaction mixture was purged with nitrogen and stirred at l00°C for 20 h. 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 MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 60:40) to afford intermediate 140 (542 mg, 93%) as a yellow foam.

Intermediate 141

7¾r/-butyl N-[(35)- 1 -(4- (7-cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline- 2-carbonyl]pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidin-3 -yl] carbamate

Intermediate 141 was synthesized from (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclo- propylpyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421-61-3] and (5)-3-(boc-amino)pyrrolidine [122536-76-9] according to the procedure reported for the synthesis of intermediate 140. Intermediate 141 (570 mg, 98%) was obtained as a yellow foam.

Intermediate 142

(37?)- 1 -(4- (7-Cyclopropyl-5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidin-3-amine

TFA (1.60 mL, 20.9 mmol) was added to a solution of intermediate 140 (401 mg, 65.7 pmol) in DCM (8 mL). The reaction mixture was stirred at rt for 1 h. DCM and a saturated aqueous solution of NaHC0 3 were added. The layers were separated and the organic phase was dried over MgS0 4 , filtered and the solvent was removed under reduced pressure to afford intermediate 142 (358 mg) as a yellow gum. The product was engaged in the next step without further purification.

Intermediate 143

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

Intermediate 143 was synthesized from intermediate 141 according to the procedure reported for the synthesis of intermediate 142. Intermediate 143 (450 mg) was obtained as a yellow gum and engaged in the next step without further purification.

Compound 30

(l7?)-2-(7-Cyclopropyl-2-{4-[(37?)-3-[(dimethylphosphoryl)am ino]pyrrolidin-l-yl]-2- fluorophenyl}pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl)- 1 -methyl- 1 ,2,3,4-tetrahydro- isoquinoline

Dimethylphosphinic chloride (360 pL, 0.72 mmol) was added to a mixture of intermediate 142 (354 mg, 638 pmol, 92% purity), DIPEA (242 pL, 1.40 mmol) and DMAP (7.79 mg, 63.8 pmol) in DCM (5.6 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM and washed with a 10% aqueous solution of NaHC0 3 . The organic phase was dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g

GraceResolv , liquid injection (DCM), mobile phase: gradient DCM / MeOH from 100:0 to 96:4). The residue was taken up in MeOH, evaporated and triturated with Et 2 0. 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

(li?)-2-(7-Cyclopropyl-2-{4-[(35)-3-[(dimethylphosphoryl)ami no]pyrrolidin-l-yl]-2- fluorophenyl}pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl)- 1 -methyl- 1 ,2,3,4-tetrahydro- isoquinoline

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

Compound 76

N-[(35)- 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]-2,2,2- trifluoroacetamide

In a sealed tube Et 3 N (32 pL, 0.23 mmol) and ethyl trifluoroacetate (30 pL, 0.25 mmol) were added to a solution of intermediate 143 (100 mg, 196 pmol) in MeOH (0.8 mL). The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 60:40). The residue was crystallized from MeOH. The solid was filtered off and dried under high vacuum at 50°C for 20 h to give compound 76 (53 mg, 45%) as a yellow solid.

Compounds 32, Compound 33, Compound 34 and Compound 35

Intermediate 147

l-7¾r/-butyl 3-methyl 5-methyl-lH-pyrrole-l,3-dicarboxylate

A sealed tube was charged with DMAP (8.78 mg, 71.8 qmol), 5 -methyl- lH-pyrrole-3- carboxylic acid methyl ester [40611-76-5] (100 mg, 0.72 mmol), Boc 2 0 (154 pL, 0.72 mmol), triethylamine (0.30 mL, 2.16 mmol) and anhydrous DCM (2 mL). The reaction mixture was stirred at rt for 18 h. H 2 0, a saturated aqueous solution of NaHCCh and

EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated under reduced pressure to afford intermediate 147 (170 mg, 99%). Intermediate 148

l-7¾r/-butyl 3-methyl 5-methylpyrrolidine-l,3-dicarboxylate

148

In an autoclave, a mixture of intermediate 147 (1.25 g, 5.22 mmol) and platinium on carbon (1 wt%, 4.1 g, 209 pmol) in EtOH (38 mL) was stirred at rt under 35 bar of ¾ for 16 h. Platinium on carbon (1 wt%, 1.02 g, 52 pmol) was added and the reaction mixture was stirred at rt under 40 bar of ¾. Platinium on carbon (1 wt%, 1.02 g, 52 pmol) was added and the reaction mixture was stirred at rt under 40 bar of H 2 . The reaction mixture was filtered over Celite ® and the filtrate was concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g

GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 80:20 to 0: 100) to afford intermediate 148 (850 mg, 67%) as a colorless oil.

Intermediate 144

Methyl 5-methylpyrrolidine-3-carboxylate hydrochloride

Hydrochloric acid (3.0 M in CPME, 12.5 mL, 37.5 mmol) was added dropwise to a solution of intermediate 148 (850 mg, 3.49 mmol) in MeOH (5.0 mL). The reaction mixture was stirred at rt for 18 h and the solvent was removed under reduced pressure. The residue was co-evaporated with toluene to give intermediate 144 (627 mg, quant.) as a colorless oil.

Synthesis of compounds 32, 33, 34 and 35

Intermediate 145

Methyl 1 -(4- (7-cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydroisoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)-5-methylpyrrolidine-3- carboxylate

A sealed tube was charged with (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (703 mg, 1.39 mmol), intermediate 144 (250 mg, 1.39 mmol) and cesium carbonate (1.36 g, 4.18 mmol) and purged with nitrogen. l,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 mmol) were added. The reaction mixture was stirred at l00°C for 18 h. The reaction mixture was poured out into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS0 4 and concentrated to dryness. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 50:50) to afford intermediate 145 (260 mg, 33%) as a yellowish solid.

Intermediate 146

1 -(4- (7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)-5 -methylpyrrolidine-3 -carboxylic acid

Lithium hydroxide monohydrate (151 mg, 3.59 mmol) was added to a solution of intermediate 145 (680 mg, 1.20 mmol) in THF (27 mL) and H 2 0 (6.8 mL). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHS0 4 was added until pH 6. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g

GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc / AcOH from 80: 19.5:0.5 to 40:58.5: 1.5) to afford intermediate 146 (660 mg, quant.).

Compounds 32, 33, 34 and 35

(3 *R, 5 *R)- 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)-5-methylpyrrolidine-3- carboxamide

(3 *R, 5 *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)-5-methylpyrrolidine-3- carboxamide

(3 *S, 5 *R)- 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)-5-methylpyrrolidine-3- carboxamide

(3 *S, 5 *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)-5-methylpyrrolidine-3- carboxamide

A mixture of intermediate 146 (660 mg, 1.19 mmol), HATU (680 mg, 1.79 mmol) and DIPEA (616 pL, 3.58 mmol) in DMF (20 mL) was stirred at rt for 1 h. Ammonia (28% in H 2 0, 403 uL, 5.96 mmol) was added and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the organic phase was washed with a 1% aqueous solution of NaHC0 3 (twice), dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 80 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / z-PrOH from 100:0 to 80:20) to afford a mixture of diasteroisomers (550 mg, 83%) as a yellow oil.

The sample was combined with another sample (123 mg) and the diastereoisomers were separated via chiral SFC (Stationary phase: CHIRACEL OJ-H 5pm 250*30mm, Mobile phase: 58% C0 2 , 42% MeOH(0.3% /-PrNFb)). Four fractions (A, B, C and D) were isolated. After evaporation of the solvent, the residue of fraction A was taken up in EtOH, the solid was filtered off and dried under vacuum at 50°C for 16 h to give compound 32 (94 mg, 11%). The residue of fraction B was crystallized from EtOAc, filtered off and dried under vacuum at 50°C for 16 h to give compound 35 (168 mg, 20%). The residue of fraction C was crystallized from EtOAc. The solid was filtered off and dried under vacuum at 50°C for 16 h to give compound 34 (94 mg, 11%). The residue of fraction D was taken- up in EtOH, the solid was filtered off and dried under vacuum at 50°C for 16 h to give compound 33 (164 mg, 20 %).

Compounds 80, 81, 82 and 83

Synthesis of intermediate 1165

Ethyl 2-methylpyrrolidine-3-carboxylate hydrochloride

A mixture of ethyl l-benzyl-2-methyl-4,5-dihydro-lH-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) was stirred at rt under hydrogen atmosphere (40 bars) for 72 h. The reaction mixture was filtered over 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 under vacuum to afford intermediate 1165 (2.6 g, 91%). The product was engaged in the next step as such. Synthesis of compounds 80, 81, 82 and 83

Intermediate 1166

Ethyl 1 -(4- (7-cyc lopropyl-5-[( 1 R)- 1 -methyl- 1,2,3 ,4-tetrahydroisoquino line-2-carbonyl] - pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)-2-methylpyrrolidine-3 -carboxylate

In a sealed tube were added ( l /?)-2-[2-(4-bromo-2-fluorophcnyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (2.81 g, 5.56 mmol), intermediate 1165 (1.40 g, 7.23 mmol) and cesium carbonate (5.44 g, 16.7 mmol). The mixture was purged with nitrogen. l,4-Dioxane (45 mL) was added and the mixture was degassed with nitrogen. Palladium acetate (125 mg, 556 pmol) and XantPhos (322 mg, 556 pmol) were added. The reaction mixture was stirred at l00°C for 18 h. The reaction mixture was poured out into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and evaporated to dryness. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 120 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 60:40) to afford intermediate 1166 (1.93 g, 60%) as a yellowish solid.

Intermediate 1167

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

Lithium hydroxide monohydrate (995 mg, 23.7 mmol) was added to a solution of intermediate 1166 (1.93 g, 3.32 mmol) in THF (34 mL) and H 2 0 (11 mL). The reaction mixture was stirred at rt for 16 h and at 50°C for 6 h. A 10% aqueous solution of KHS0 4 was added until pH 6 and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, dried over MgS0 4 , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 80 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc / AcOH from 80: 19.5:0.5 to 30:68:2 to afford intermediate 1167 (1.59 g, 87%).

Compounds 80, 81, 82 and 83

(2*R,3*R)- 1 -(4- {7-Cyclopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydroisoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)-2-methylpyrrolidine-3- carboxamide

(2*i?,3 *5)- 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)-2-methylpyrrolidine-3- carboxamide

(2*5,3 *R)~ 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)-2-methylpyrrolidine-3- carboxamide

(2*5,3 *5)- 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)-2-methylpyrrolidine-3- carboxamide

A mixture of intermediate 1167 (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 rt for 1 h. Ammonia (28% in H 2 0, 1.0 mL, 14.4 mmol) was added and the reaction mixture was stirred at rt for 18 h.

The reaction mixture was diluted with LEO and EtOAc. The layers were separated and the organic phase was washed with 1% aqueous solution of NaHC0 3 (twice), dried over MgS0 4 , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 mhi, 80 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / z-PrOH from 100:0 to 80:20) to deliver a mixture of diastereoisomers (1.3 g, 82%). The diastereoisomers (700 mg) were separated by chiral SFC (Stationary phase: CHIRALPAK AS-H 5pm 250*20mm, Mobile phase: 60% C0 2 , 40% MeOH (0.3% i- PrNH 2 )). The separated diastereoisomers were taken up in Et 2 0. The solid was filtered off and dried under vacuum at 50°C for 16 h to give compound 81 (60 mg, 4%), compound 80 (180 mg, 1 1%) and compound 82 (65 mg, 4%). The last residue was taken up in EtOH. The solid was filtered off and dried under vacuum at 50°C for 16 h to give compound 83 (215 mg, 14%).

General Scheme

Compound 36

(35)- 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)pyrrolidine-3-carboxamide

A mixture of (35 * )- 1 -(4- (7-cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-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 0, 15 mL, 222 mmol) was added and the reaction mixture was stirred at rt for 18 h. H 2 0, brine and EtOAc were added. 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 MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 330 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 98:2). The residue was crystallized from MeCN, filtered off and dried under vacuum at 50°C for 2 h to give compound 36 (6.47 g, 65%) as a yellow solid.

Compound 37

(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)-N-methylpyrrolidine-3- carboxamide

A mixture of (3S)- 1 -(4- (7-cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidine-3-carboxylic acid [2035416-78-3] (180 mg, 333 mchoΐ), HATU (190 mg, 500 pmol) and DIPEA (172 pL,

1.00 mmol) in DMF (9 mL) was stirred at rt for 1 h. Methylamine (40% in H 2 0, 144 pL, 1.67 mmol) was added and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the organic phase was washed with a 1% aqueous solution of NaHCCh (twice), dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / z-PrOH from 100:0 to 80:20) to give compound 37 (135 mg, 73%) as a yellow oil.

Compound 38

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

Compound 38 was synthesized from (35)-l-(4-{7-cyclopropyl-5-[(l7?)-l-methyl-l, 2,3,4- tetrahydroisoquinoline-2-carbonyl]pyrazo lo [ 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 reported for the synthesis of compound 37. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 40:60 to 0:100) to give compound 38 (102 mg, 54%) as a yellow oil.

Compound 39

(3S)-N-Cyano- 1 -(4- j 7-cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydro isoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidine-3-carboxamide

Compound 39 was synthesized from (3S)- 1 -(4- j 7-cyc lopropyl-5-[( l R)- \ -methyl- 1 ,2,3,4- tetrahydroisoquinoline-2-carbonyl]pyrazolo[l,5-a]pyrimidin-2 -yl}-3-fluorophenyl)- pyrrolidine-3 -carboxylic acid [2035416-78-3] and cyanamide [420-04-2] according to the procedure reported for the synthesis of compound 37. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / z-PrOH from 100:0 to 50:50) to give a yellow oil (90 mg). A second purification was performed by preparative LC (spherical Cl 8, 25 pm, 40 g YMC- ODS-25, dry loading (Celite ® ), mobile phase gradient: (0.2% aq.NLLHCCL) / MeCN from 85:15 to 45:55) to give after freeze-drying compound 39 (70.0 mg, 27%) as a yellow solid. Compound 40

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

A mixture of (35)-l-(4-{7-cyclopropyl-5-[(li?)-l-methyl-l,2,3,4-tetrahydr oisoquinoline-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidine-3-carboxylic acid [2035416-78-3] (200 mg, 371 pmol) and CDI (180 mg, 1.11 mmol) in MeCN (5 mL) was stirred at rt for 2 h. DBU (221 pL, 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. Brine, 1N aqueous solution of HC1 and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with a solution of water and brine (1 :1), dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (spherical Cl 8, 25 pm, 40 g YMC-ODS-25, dry loading (Celite ® ), mobile phase gradient: (0.2% aq.NH 4 HC0 3 ) / MeCN from 85:15 to 45:55). The fractions containing the product were combined and 1N aqueous solution of HC1 and EtOAc were added. The layers were separated and the aqueous phase was extracted. The organic phase was washed with brine, dried over MgS0 4 , filtered and evaporated under reduced pressure. The mixture was purified by preparative LC (spherical Cl 8 25 pm, 40 g YMC-ODS-25, dry loading (Celite ® ), mobile phase gradient (0.2% aq.NH 4 HC0 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 pL, 1.48 mmol) and

methanesulfonamide (141 mg, 1.48 mmol) were added. The reaction mixture was stirred at 80°C for 16 h. Brine, an aqueous solution of 1N HC1 and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with a solution of water and brine (1 :1), dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (spherical C18 25 pm, 40 g YMC-ODS-25, dry loading (Celite ® ), mobile phase gradient: (0.2% aq.NH 4 HC0 3 ) / MeCN from 85:15 to 45:55) to give after freeze- drying compound 40 (131 mg, 57%) as a yellow solid. Compound 41

(35)-l-(4-{7-Cyclopropyl-5-[(4*7?)-4-methyl-4,5,6,7-tetrahyd ro-thieno[3,2-c]pyridine-5- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)-N-methanesulfonylpyrrolidine- 3 -carboxamide

A mixture of (35)-l-(4-{7-cyclopropyl-5-[(4*i?)-4-methyl-4,5,6,7-tetrahyd ro-thieno[3,2- c]pyridine-5-carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidine-3- carboxylic acid [2035416-65-8] (153 mg, 0.28 mmol) and CDI (54.6 mg, 0.34 mmol) in MeCN (3 mL) was stirred at rt for 2 h. DBU (62.8 pL, 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 h. Brine, 1N aqueous solution of HC1 and DCM were added.

The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were washed with a solution of water and brine (1 : 1), dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH 15-40 pm, 12 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 99: 1). The residue was crystallized from MeOH, filtered off and dried under high vacuum at 50°C for 18 h to give compound 41 (93 mg, 53%) as a yellow solid.

General Scheme

Compound 84

Synthesis of intermediate 1168

Intermediate 1171

Methyl 2-bromo-7-(pyridin-2-yl)pyrazo lo [ 1 ,5 -a]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 3-bromo-lH-pyrazol-5-amine [950739-21-6] (628 mg, 3.88 mmol) in MeOH (17 mL) was stirred under reflux for 18 h. The reaction mixture was cooled to rt and the precipitate was filtered off, rinsed with MeOH and dried. The residue (546 mg) was purified via achiral SFC (Stationary phase: Lux Cellulose-2 5 pm 250*30mm, mobile phase: 60% C0 2 , 40% MeOH) to afford intermediate 1171 (147 mg, 13%) as a yellow solid.

Intermediate 1172

Methyl 2-bromo-7-(pyridin-2-yl)pyrazo lo [ 1 ,5 -a]pyrimidine-5 -carboxylic acid

1172

Lithium hydroxide monohydrate (21.1 mg, 883 pmol) was added to a solution of intermediate 1171 (147 mg, 0.44 mmol) in THF (5 mL) and H 2 0 (2.5 mL). The reaction mixture was stirred at rt for 4 h. A 10% aqueous solution of KHS0 4 was added until pH 3 and the mixture was diluted with EtOAc. The layers were separated and the organic phase was washed with brine and H 2 0 (twice), dried over MgS0 4 , filtered and concentrated to dryness to afford intermediate 1172 (134 mg, 95%) as a yellow solid.

Intermediate 1168

(li?)-2-[2-Bromo-7-(pyridin-2-yl)pyrazo lo[l, 5 -a]pyrimidine-5 -carbonyl] -1 -methyl- 1,2, 3,4- tetrahydroisoquinoline

HATU (207 mg, 546 pmol) was added to a mixture of intermediate 1172 (134 mg, 420 pmol), ( 17?)- 1 -methyl- 1,2, 3, 4-tetrahydroisoquino line [84010-66-2] (68.0 mg, 462 pmol) and DIPEA (220 pL, 1.26 mmol) in DMF (3.8 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with H 2 0. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine (3 times), dried over MgS0 4 , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g

GraceResolv , dry loading (SiOH), mobile phase gradient: heptane / EtOAc from 90: 10 to 60:40) to afford intermediate 1168 (113 mg, 60%) as a yellow solid.

Synthesis of compound 84

Intermediate 1169

Methyl (3 S)- 1 -(3-fluoro-4- (5-[(17?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- 7-(pyridin-2-yl)pyrazolo [ 1 ,5 -a]pyrimidin-2-yl} phenyl)pyrrolidine-3 -carboxylate

A sealed tube was charged with intermediate 1168 (98.0 mg, 219 pmol), methyl (3S)-l-[3- fluoro-4-(tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrroli dine-3-carboxylate [2035422- 46-7] (84.0 mg, 0.24 mmol), potassium phosphate tribasic (141 mg, 0.67 mmol), 1,4- dioxane (3.2 mL) and H 2 0 (0.6 mL) and purged with nitrogen. [ 1 , 1’-Bis(di-/er/- butylphosphino)ferrocene] palladium dichloride (14.5 mg, 22.3 pmol) was added and the mixture was purged again with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was combined with another fraction (15 mg, 33.5 pmol) and diluted with H 2 0 and EtOAc. The layers were separated and the organic phase was washed with brine (twice), dried over MgS0 4 , filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g GraceResolv , dry loading (SiOH), mobile phase gradient: heptane / EtOAc from 70:30 to 0: 100) to afford intermediate 1169 (113 mg, 75%) as an orange foam.

Intermediate 1170

(3 S)- 1 -(3-Fluoro-4- (5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7- (pyridin-2-yl)pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} phenyl)pyrrolidine-3 -carboxylic acid

Lithium hydroxide monohydrate (13.7 mg, 574 pmol) was added to a solution of intermediate 1169 (113 mg, 191 pmol) in THF (1.2 mL) and H 2 0 (0.6 mL). The reaction mixture was stirred at rt for 3 h. A 10% aqueous solution of KHS0 4 was added until pH 3 and the mixture was diluted with EtOAc. The layers were separated and the organic phase was washed with brine and H 2 0 (twice), dried over MgS0 4 , filtered and concentrated to dryness to afford intermediate 1170 (117 mg, quant., 95% purity) as an orange solid.

Compound 84

(3 S)- 1 -(3-Fluoro-4- (5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7- (pyridin-2-yl)pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} phenyl)pyrrolidine-3 -carboxamide

A mixture of intermediate 1170 (117 mg, 193 mihoΐ, 95% purity), HATU (110 mg, 289 pmol) and DIPEA (100 pL, 578 pmol) in DMF (1.9 mL) was stirred at rt for 10 min. Ammonia (30% in H 2 0, 365 pL, 5.78 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc and EEO. The layers were separated and the organic phase was washed with EEO and brine (twice), dried over MgS0 4 , filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 50:50 to 0:100). The residue (88 mg) was purified by reverse phase (spherical C18, 25 pm, 40 g YMC-ODS-25, dry loading

(Celite ® ), mobile phase gradient: (0.2% aq.NEEElCOs) / MeCN from 65:35 to 0:100). The fractions containing the product were combined, concentrated to dryness and co- evaporated with MeOH and MeCN (twice). The solid was dried under high vacuum at 60°C for 16 h to give compound 84 (58 mg, 52%) as an orange solid.

Compound 42 and Compound 43

Synthesis of the intermediates 149 and 150

Intermediate 151

Methyl 2- [(37?)- 1 -(4-chloro-3 -fluorophenyl)pyrro lidin-3 -yl] acetate

A Schlenk tube was charged with 4-bromo-l-chloro-2-fluorobenzene [60811-18-9] (1.02 mL, 8.35 mmol), potassium phosphate tribasic (4.73 g, 22.3 mmol), methyl (37?)-3- pyrrolidinylacetate hydrochloride [1024038-31-0] (1.00 g, 5.57 mmol) and l,4-dioxane (45 mL) and purged with nitrogen for 5 min. Tri-/e/7-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 min. The reaction mixture was stirred at l00°C for 18 h. The reaction mixture was diluted with EtOAc and H 2 0. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g

GraceResolv , liquid injection (DCM / heptane), mobile phase gradient: heptane / EtOAc from 80:20 to 60:40) to afford intermediate 151 (880 mg, 58%) as a colorless oil. Intermediate 152

Methyl 2- [(35)- 1 -(4-chloro-3-fluorophenyl)pyrrolidin-3-yl] acetate

Intermediate 152 was synthesized from 4-bromo-l-chloro-2-fluorobenzene [60811-18-9] and methyl (35)-3-pyrrolidinylacetate hydrochloride [1024038-33-2] according to the procedure reported for the synthesis of intermediate 151. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv , dry loading (SiOH), mobile phase: heptane / EtOAc 80:20) to afford intermediate 152 (830 mg, 55%) as a colorless oil.

Intermediate 153

2-[(3i?)-l-(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 0 (5 mL) was added. The reaction mixture was stirred at rt for 3 days. A 10% aqueous solution of KHS0 4 and

EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated under reduced pressure to afford intermediate 153 (840 mg, quant.) as a white solid. Intermediate 154

2-[(35)- 1 -(4-Chloro-3-fluorophenyl)pyrrolidin-3-yl]acetic acid

Intermediate 154 was synthesized from intermediate 152 according to the procedure reported for the synthesis of intermediate 153. Intermediate 154 (800 mg, quant.) was obtained as a white solid. Intermediate 155

2-[(37?)-l-(4-Chloro-3-fluorophenyl)pyrrolidin-3-yl]acetyl chloride

155

Thionyl chloride (307 pL, 4.24 mmol) was added to a solution of intermediate 153 (840 mg, 3.26 mmol) in DCM (30 mL). The reaction mixture was stirred at rt for 90 min. The mixture was evaporated under reduced pressure to afford intermediate 155 (900 mg, quant.). The product was used in the next step without any purification. Intermediate 156

2-[(35)- 1 -(4-Chloro-3-fluorophenyl)pyrrolidin-3-yl]acetyl chloride

Intermediate 156 (856 mg, quant.) was synthesized from intermediate 154 according to the procedure reported for the synthesis of intermediate 155. Intermediate 157

2- [(3i?)- 1 -(4-Chloro-3 -fluorophenyl)pyrro lidin-3 -yljacetamide

Ammonia (28% in H 2 0, 30 mL, 444 mmol) was added to a solution of intermediate 155 (900 mg, 3.26 mmol) in THF (30 mL). The reaction mixture was stirred at rt for 2 h. 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 MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / MeOH / aq.NFL from 100:0:0 to 90: 10: 1) to afford intermediate 157 (588 mg, 63%, 90% purity) as a white solid. Intermediate 158

2-[(35)- 1 -(4-Chloro-3-fluorophenyl)pyrrolidin-3-yl]acetamide

Intermediate 158 was synthesized from intermediate 156 according to the procedure reported for the synthesis of intermediate 157. Intermediate 158 (741 mg, 85%, 91% purity) was obtained as a white solid.

Intermediate 149

2-[(3i?)-l-[3-Fluoro-4-(tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]pyrrolidin-3- yljacetamide

149 A sealed tube was charged with intermediate 157 (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 l,4-dioxane (14 mL) and purged with nitrogen for 10 min. 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 1 l0°C for 18 h. The reaction mixture was filtered over 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 MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular

SiOH, 15-40 pm, 24 g GraceResolv , dry loading (SiOH), mobile phase gradient: DCM / MeOH / aq.NEb from 100:0:0 to 90:10:1) to afford intermediate 149 (587 mg, 67%, 84% purity) as a grey solid. Intermediate 150

2-[(35)-l-[3-Fluoro-4-(tetramethyl-l,3,2-dioxaborolan-2-yl)p henyl]pyrrolidin-3- yljacetamide

Intermediate 150 was synthesized from intermediate 158 according to the procedure reported for the synthesis of intermediate 149. Intermediate 150 (935 mg, 77%, 83% purity) was obtained as a grey solid. Synthesis of compounds 42 and 43

Compound 42

2-[(3i?)-l-(4-{7-Cyclopropyl-5-[(4*i?)-4-methyl-4,5,6,7-tetr ahydro-thieno[3,2-c]pyridine- 5 -carbonyljpyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidin-3 -yl] acetamide

A sealed tube was charge with 2-bromo-7-cyclopropyl-5-[(4*7?)-4-methyl-4, 5,6,7- tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]pyrazolo[l,5-a]p yrimidine [2035420-09-6] (200 mg, 0.479 mmol), intermediate 149 (278 mg, 0.67 mmol, 84% purity), potassium phosphate tribasic (305 mg, 1.44 mmol), l,4-dioxane (6 mL) and H 2 0 (2 mL) and purged with nitrogen. [ 1 , 1 '-Bis(di-/er/-butylphosphino)fcrroccnc] dichloropalladium (31.2 mg, 47.9 prnol) was added and the reaction mixture was purged with nitrogen. The reaction mixture was stirred at 80°C for 2 h. The reaction mixture was filtered over 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 MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / MeOH / aq.NEb from 100:0:0 to 96:4:0.4). The residue was co-evaporated with MeOH and triturated with MeOH. The solid was filtered off and dried under high vacuum at 50°C for 24 h to give compound 42 (115 mg, 43%) as a yellow solid.

Compound 43

2-[(35)-l-(4-{7-Cyclopropyl-5-[(4*7?)-4-methyl-4,5,6,7-te trahydro-thieno[3,2-c]pyridine-

5 -carbonyljpyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidin-3 -yl] acetamide

Compound 43 was synthesized from 2-bromo-7-cyclopropyl-5-[(4*7?)-4-methyl-4, 5,6,7- tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]pyrazolo[l,5-a]p yrimidine [2035420-09-6] and intermediate 150 according to the procedure reported for the synthesis of compound 42. Compound 43 (161 mg, 60%) was obtained as a yellow solid.

Compound 44 and Compound 45

Intermediates 161 and 162

(*i?)-Methyl l-(4-chloro-3-fluorophenyl)-3-methylpyrrolidine-3-carboxylat e

(*S)-methyl l-(4-chloro-3-fluorophenyl)-3-methylpyrrolidine-3-carboxylat e

A sealed tube was charged with 4-bromo-l-chloro-2-fluorobenzene [60811-18-9] (4.0 mL, 32.8 mmol), potassium phosphate tribasic (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 l00°C for 16 h. The reaction mixture was diluted with EtOAc and H 2 0. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 120 g GraceResolv , liquid injection

(heptane), mobile phase gradient: heptane / EtOAc from 100:0 to 70:30). The enantiomers (3.81 g) were separated via chiral SFC (Stationary phase: Whelk 01 (S,S) 5pm

250*21. lmm, Mobile phase: 90% C0 2 , 10% MeOH) to afford 161 (1.7 g, 26%) as a colorless oil and 162 (1.67 g, 26%) as a colorless oil.

Intermediate 163

(3 *7?)- 1 -(4-Chloro-3-fluorophenyl)-3-methylpyrrolidine-3-carboxylic acid

In a sealed tube lithium hydroxide monohydrate (344 mg, 8.19 mmol) was added to a solution of intermediate 161 (445 mg, 1.64 mmol) in THF (13 mL) and H 2 0 (6.5 mL). The reaction mixture was stirred at rt for 20 h. A 10% aqueous solution of KHS0 4 and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated under reduced pressure. The residue (465 mg) was taken up in Et 2 0 and evaporated under reduced pressure to afford intermediate 163 (415 mg, 98%).

Intermediate 164

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

Intermediate 164 was synthesized from intermediate 162 according to the procedure reported for the synthesis of intermediate 163. Intermediate 164 (395 mg, 99%) was obtained as a yellow solid.

Intermediate 165

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

Thionyl chloride (145 pL, 2.00 mmol) was added to a solution of intermediate 163 (395 mg, 1.53 mmol) in DCM (14 mL). The reaction mixture was stirred at rt for 1.5 h. The mixture was evaporated under reduced pressure to afford intermediate 165 (423 mg, quant.). The product was used in the next step without any purification.

Intermediate 166

(3 *5)- 1 -(4-Chloro-3-fluorophenyl)-3-methylpyrrolidine-3 -carbonyl chloride

Intermediate 166 was synthesized from intermediate 164 according to the procedure reported for the synthesis of intermediate 165. Intermediate 166 (401 mg, quant.) was used in the next step without any purification.

Intermediate 167

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

Ammonia (28% in H 2 0, 14 mL, 207 mmol) was added to a solution of intermediate 165 (423 mg, 1.53 mmol) in THF (14 mL). The reaction mixture was stirred at rt for 2 h. 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 MgS0 4 , filtered and evaporated under reduced pressure. The crude product was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / MeOH / aq.NFL from 100:0:0 to 90: 10: 1) to afford intermediate 167 (286 mg, 73%) as a yellowish solid.

Intermediate 168

(3 *5)- 1 -(4-Chloro-3-fluorophenyl)-3-methylpyrrolidine-3 -carboxamide

Intermediate 168 was synthesized from intermediate 166 according to the procedure reported for the synthesis of intermediate 167. Intermediate 168 (259 mg, 69%) was obtained as a yellowish solid.

Intermediate 159

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

A sealed tube was charged with intermediate 167 (286 mg, 1.11 mmol),

bis(pinacolato)diboron (567 mg, 2.23 mmol), acetic acid potassium salt (219 mg, 2.23 mmol) and l,4-dioxane (10 mL) and was 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 1 l0°C for 18 h. The reaction mixture was diluted with EtOAc and H 2 0. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g Grace ® , dry loading (Celite ® ), mobile phase gradient: DCM / MeOH from 100:0 to 95:5) to afford intermediate 159 (393 mg, 73%, 72% purity) as a yellowish oil that crystallized on standing.

Intermediate 160

(3 *6)- 1 -[3-Fluoro-4-(tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]-3-methylpyrrolidine-3- carboxamide

Intermediate 160 was synthesized from intermediate 168 according to the procedure reported for the synthesis of intermediate 159. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g Grace ® , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 95:5) to afford intermediate 160 (449 mg, 89%, 70% purity) as a yellowish oil that crystallized on standing.

Synthesis of compounds 44 and 45

Compound 44

(3*7?)-l-(4-{7-Cyclopropyl-5-[(4*7?)-4-methyl-4,5,6,7-tetrah ydro-thieno[3,2-c]pyridine-5- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)-3-methylpyrrolidine-3- carboxamide

A sealed tube was charged with 2-bromo-7-cyclopropyl-5-[(4*7?)-4-methyl-4, 5,6,7- tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]pyrazolo[l,5-a]p yrimidine [2035420-09-6] (248 mg, 0.59 mmol), intermediate 159 (345 mg, 0.71 mmol, 72% purity), potassium phosphate tribasic (431 mg, 2.03 mmol), l,4-dioxane (11 mL) and H 2 0 (4 mL) and purged with nitrogen. [ 1 , 1 '-Bis(di-/er/-butylphosphino)fcrroccnc] dichloropalladium (42.7 mg,

65.4 prnol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was diluted with EtOAc and EEO. The layers were separated and the organic phase was washed with brine, dried over MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , mobile phase gradient: heptane / (EtOAc/MeOH 9:1) from 70:30 to 50:50). The residue was triturated with pentane and the solid was filtered off and dried under high vacuum at 50°C for 30 h to give compound 44 (193 mg, 58%) as a yellow solid.

Compound 45

(3*5)-l-(4-{7-Cyclopropyl-5-[(4*7?)-4-methyl-4,5,6,7-tetrahy dro-thieno[3,2-c]pyridine-5- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)-3-methylpyrrolidine-3- carboxamide

Compound 45 was synthesized from 2-bromo-7-cyclopropyl-5-[(4*7?)-4-methyl-4, 5,6,7- tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]pyrazolo[l,5-a]p yrimidine [2035420-09-6] and intermediate 160 according to the procedure reported for the synthesis of compound 44. Compound 45 (275 mg, 71%) was obtained as a yellow solid.

Compound 46

Synthesis of intermediate 169

Intermediate 170

(35)- 1 -(4-Chloro-3-fluorophenyl)pyrrolidine-3 -carboxylic acid

Lithium hydroxide monohydrate (3.34 g, 79.6 mmol) was added to a solution of methyl (35)-l-(4-chloro-3-fluorophenyl)pyrrolidine-3-carboxylate [2035422-44-5] (4.10 g, 15.9 mmol) in THF (100 mL) and H 2 0 (50 mL). The reaction mixture was stirred at rt for 24 h. A 10% aqueous solution of KHS0 4 and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and concentrated under reduced pressure to afford intermediate 170 (3.8 g, 98%) as an orange solid. Intermediate 171

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

Thionyl chloride (77.4 pL, 1.0.7 mmol) was added to a solution of intermediate 170 (200 mg, 0.82 mmol) in DCM (8 mL). The reaction mixture was stirred at rt for 10 min and evaporated under reduced pressure to afford intermediate 171 (215 mg, quant.).

Intermediate 172

(35)- 1 -(4-Chloro-3-fluorophenyl)pyrrolidine-3 -carboxamide

Ammonia (28% in H 2 0, 120 mL, 1.77 mol) was added to a solution of intermediate 171 (3.23 g, 12.3 mmol) in THF (120 mL). The reaction mixture was stirred at rt for 15 min. 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 MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 80 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 96:4) to afford intermediate 172 (2.38 g, 80%) as a white solid.

Intermediate 169

(35)-l-[3-Fluoro-4-(tetramethyl-l,3,2-dioxaborolan-2-yl)phen yl]pyrrolidine-3- carboxamide

169

A sealed tube was charged with intermediate 172 (3.22 g, 13.3 mmol), bis(pinacolato)- dibroron (6.75 g, 26.6 mmol) and potassium acetate (2.61 g, 26.6 mmol) in l,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 1 l0°C for 18 h. The reaction mixture was filtered over Celite ® . EtOAc, brine and H 2 0 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 MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15- 40 pm, 80 g Grace ® , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 96:4) to give intermediate 169 (5.24 g, 78%, 66% purity) as a colorless oil. Synthesis of compound 46

(3S)-l-(4-{7-Cyclopropyl-5-[(4*i?)-4-methyl-4,5,6,7-tetrahyd ro-thieno[3,2-c]pyridine-5- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)pyrrolidine-3-carboxamide

A sealed tube was charged with 2-bromo-7-cyclopropyl-5-[(4*i?)-4-methyl-4, 5,6,7- tetrahydro-thieno[3,2-c]pyridine-5-carbonyl]pyrazolo[l,5-a]p yrimidine [2035420-09-6] (200 mg, 0.48 mmol), intermediate 169 (291 mg, 0.58 mmol, 66% purity), potassium phosphate (0.31 g, 1.44 mmol), l,4-dioxane (5 mL) and H 2 0 (1.5 mL) and purged with nitrogen. [ 1 , 1 '-Bis(di-/er/-butylphosphino)fcrroccnc] dichloropalladium (23.4 mg, 35.9 pmol) was added and the mixture was purged with nitrogen. The reaction mixture was stirred at 80°C for 2 h. The reaction mixture was filtered over 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 MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 80 g Grace ® , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 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 under high vacuum at 50°C for 24 h to give compound 46 (210 mg, 80%) as a yellow solid.

Compound 47

Intermediate 174

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

174

Acetyl chloride (0.27 mmol, 20.0 mL) was added dropwise to a mixture of 2-(4-fluoro- phenyl)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. The resulting mixture was stirred at rt for 72 h. The reaction mixture was diluted with DCM. The mixture was washed with a 10 % aqueous solution of NaHCCh, brine, dried over MgS0 4 , filtered and the solvent was removed in vacuo to afford intermediate 174 (48.2 g, quant.).

Intermediate 175

7 -Lluoro- 1 -methyl-3 ,4-dihydroisoquino line

175

Oxalyl chloride (2.0 M in DCM, 67.5 mL, 135 mmol) and oxalyl chloride neat (11.5 mL, 136 mmol) were added dropwise to a solution of intermediate 174 (48.2 g, 266 mmol) in DCM (2.7 L) at l0°C. The resulting mixture was stirred at rt for 30 min and cooled down to -l0°C. Iron chloride (III) [7705-08-0] (52.0 g, 0.32 mol) was added portionwise. The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched by the addition of a 3N aqueous solution of HC1 and diluted with DCM. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgS0 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 added dropwise carefully at 0°C. The resulting mixture was stirred under reflux for 16 h. The solvent was removed in vacuo. The residue was dissolved in DCM and a 3N aqueous solution of HC1 was added. The layers were separated and the organic phase was washed with a 3N aqueous solution of HC1 (once). The combined aqueous extracts were basified with ammonia (28% in LfiO) and extracted with DCM (twice). The combined organic extracts were dried over MgS0 4 , filtered and the solvent was removed in vacuo to afford intermediate 175 (34.3 g, 63%, 80% purity). Intermediates 176 and 177

( 1 */?)-7-Fluoro- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc hydrochloride

( 1 * S)-7-Fluoro- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquino line hydrochloride

176 177

The reaction was performed on 2 batches of 84 mmol of 175.

To a solution of intermediate 175 (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 under H 2 atmosphere (1 bar) for 6 h. The two batches were combined. The reaction mixture was filtered over Celite ® and HC1 (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 0 and the solid was filtered off to give a mixture of enantiomers (33 g) as a white solid. The enantiomers were separated via chiral SFC (Stationary phase: Chiralpak AD-H 5pm 250*30mm, Mobile phase: 78% C0 2 , 22% i- PrOH (1.0% /-PrNH 2 )) to give 176 (11.5 g) and 177 (15.5 g). Intermediate 176 was taken up in HC1 (3.0 M in CPME, 25 mL) and EtOH (10 mL). The resulting suspension was stirred for 5 min and Et 2 0 was added (200 mL). The solid was filtered off and dried to give intermediate 176 (10.5 g, 31%). Intermediate 177 was taken up in DCM and 1M aqueous solution of NaOH. The layers were separated and the aqueous phase was extracted with DCM (once). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was removed in vacuo. The residue (11.1 g) was dissolved in EtOH (100 mL) and HC1 (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 0, filtered off and dried to give intermediate 177 (11.6 g, 34%).

Intermediate 173

( 1 *R)-2- (2-Bromo-7-cyclopropylpyrazolo[ 1 ,5-a]pyrimidinc-5-carbonyl [-7-fluoro- 1 - methyl- 1 ,2,3 ,4-tetrahydroisoquino line

To a mixture of potassium 2-bromo-7-cyclopropylpyrazolo[l,5-a]pyrimidine-5-carboxylate [2035418-56-3], intermediate 176 (2.46 g, 12.3 mmol) and DIPEA (4.90 mL, 28.4 mmol) in DMF (54 mL) was added HATU (5.34 g, 14.1 mmol). The reaction mixture was stirred at rt for 20 h. A saturated aqueous solution of NaHCCh, brine and EtOAc were added. 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 MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 220 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 60:40). A first fraction of pure intermediate 173 (1.20 g, 30%) was obtained, while the second fraction containing impurities was purified again by preparative LC (irregular SiOH, 40 pm 120 g, mobile phase: 100% DCM). A second crop of intermediate 173 (1.3 g, 32%) was isolated. Intermediate 173 (2.50 g, 62%) was obtained as a white foam.

Synthesis of compound 47

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

A sealed tube was charged with ( 1 *R)-2- j2-bromo-7-cyclopropylpyrazolo[ 1 ,5- a]pyrimidine-5-carbonyl}-7-fluoro-l-methyl-l,2,3,4-tetrahydr oisoquinoline 173 (200 mg, 0.47 mmol), intermediate 169 (283 mg, 0.56 mmol), potassium phosphate tribasic (297 mg, 1.40 mmol), l,4-dioxane (5 mL) and H 2 0 (1.5 mL) and purged with nitrogen. [l,l'-Bis(di- /er/-butylphosphino)fcrroccnc] dichloropalladium (22.8 mg, 34.9 pmol) was added and the mixture was purged again with nitrogen. The reaction mixture was stirred at 80°C for 2 h. The reaction mixture was filtered over 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 MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15- 40 pm, 80 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 96:4). The pure fractions were combined while fractions containing impurities were subjected to a second purification by preparative LC (irregular SiOH, 15- 40 pm, 80 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 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 under high vacuum at 50°C for 24 h to give compound 47 (185 mg, 71%) as a yellow solid. Compound 48

Synthesis of intermediate 178

1) (COCI) 2

DCM, 10 °C to rt

Intermediate 181

N-[2-(3-Lluorophenyl)ethyl]acetamide

181

Acetyl chloride (16.0 mL, 225 mmol) was added dropwise at 0°C 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). The reaction mixture was stirred at rt for 16 h. The reaction was quenched by the addition of an aqueous solution of NaHC0 3 . The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was removed in vacuo to afford intermediate 181 (35.3 g, quant.) as a yellow oil. Intermediate 182

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

In a 5 L jacketed reactor equiped with a thermoregulator and mechanical stirring, oxalyl chloride (2.0 M in DCM, 108 mL, 216 mmol) was added dropwise to a solution intermediate 181 (35.3 g, 180 mmol) in DCM (1.7 L) at l0°C. The resulting mixture was stirred at rt for 30 min and cooled down to -l0°C. Iron chloride [7705-08-0] (35.0 g, 216 mmol) was added portionwise. The reaction mixture was stirred at rt for 18 h. The reaction mixture was quenched by the addition of a 3N aqueous solution of HC1 and diluted with DCM. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgS0 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 equiped with thermoregulator and mechanical stirring. Sulfuric acid (1.54 mol, 82.0 mL) was added dropwise carefully at 0°C. The resulting mixture was stirred under reflux for 16 h. The solvent was removed in vacuo. The residue was dissolved in DCM and a 3N aqueous solution of HC1 was added. The layers were separated and the organic phase was washed with a 3N aqueous solution of HC1 (twice). The combined aqueous extracts were basified with ammonia (28% in H 2 0) and extracted with DCM (twice). The combined organic extracts were dried over MgS0 4 , filtered and the solvent was removed in vacuo to afford intermediate 182 (28.9 g, 90% purity).

Intermediates 183 and 184

( 1 */?)-6-Fluoro- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc (183) and (l*5)-6-fluoro-l- methyl- 1 ,2,3 ,4-tetrahydroisoquino line (184)

EtOH (400 mL) and Pd/C (10%, 3.39 g, 3.19 mmol) were charged in a Parr flask. A solution of intermediate 182 (28.9 g, 159 mmol, 90% purity) in EtOH (500 mL) was added. The reaction was pressurized with H 2 at 1 bar and stirred at rt for 18 h. The reaction mixture was filtered through a pad of Celite ® and rinsed with MeOH. The filtrate was treated with HC1 (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 0 and the solid was filtered off. The solid was purified by preparative LC (irregular SiOH, 15-40 pm, 330 g Grace ® , dry loading (Celite ® ), mobile phase gradient: DCM / MeOH / aq.NFT from 98:2:0.2 to 96:4:0.4) to afford a mixture of enantiomers (20.3 g). The enantiomers were separated via chiral SFC (Stationary phase: Chiralpak AD-H 5 pm 250*30 mm, Mobile phase: 80% C0 2 , 20% z-PrOH (0.3% /-PrNH 2 )) to give 183 (9.73 g) and 184 (9.68 g). The enantiomers were treated separately. Intermediates 183 and 184 were dissolved in EtOAc and an aqueous solution of NaHC0 3 was added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dired over MgS04, filtered and the solvent was removed in vacuo to give intermediates 183 (8.74 g, 32%) and 184 (8.34 g, 30%) as colorless oils.

Intermediate 178

( 1 *R)-2- j2-Bromo-7-cyclopropylpyrazolo[ 1 ,5-a]pyrimidinc-5-carbonyl [-6-fluoro- 1- methyl- 1 ,2,3 ,4-tetrahydroisoquino line

HATU (6.91 g, 18.2 mmol) was added to a mixture of potassium 2-bromo-7-cyclopropyl- pyrazolo[l,5-a]pyrimidine-5-carboxylate [2035418-56-3] (3.23 g, 10.1 mmol),

intermediate 183 (2.00 g, 12.1 mmol) and DIPEA (4.35 mL, 25.2 mmol) in DMF (50 mL). The reaction mixture was stirred at rt for 18 h. A saturated aqueous solution of NaHCCh, brine, H 2 0 and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with a solution of brine and water (9: 1) (3 times), dried over MgS0 4 , filtered, rinsed with EtOAc and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 80 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 70:30) to give intermediate 178 (4.5 g, quant.) as a white gum.

Synthesis of intermediate 179

Methyl 2-[(3S)-l-[3-fluoro-4-(tetramethyl-l,3,2-dioxaborolan-2-yl)p henyl]pyrrolidin-3- yl] acetate

dioxane

152 110 °C, 2 h 179

A sealed tube was charged with intermediate 152 (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 l00°C for 18 h and then at 1 l0°C for 2 h. The reaction mixture was filtered over 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 MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 80 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 95:5 to 80:20) to give intermediate 179 (1.1 g, 59%) as a grey solid.

Synthesis of compound 48

Intermediate 180

Methyl 2-[(3S)- 1 -(4- (7-cyclopropyl-5-[( 1 */?)-6-fluoro- 1 -methyl- 1 ,2,3,4-tetrahydro- isoquino line-2-carbonyl]pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)pyrrolidin-3 - yl] acetate

A sealed tube was charged with intermediate 178 (253 mg, 0.59 mmol), intermediate 179 (300 mg, 0.83 mmol), potassium phosphate tribasic (376 mg, 1.77 mmol), l,4-dioxane (7 mL) and H 2 0 (2.5 mL) and purged with nitrogen. [l,l'-bis(di-/er/-butylphosphino)- ferrocene] palladium dichloride (38.4 mg, 59.0 pmol) was added. The reaction mixture was purged with nitrogen and stirred at 80°C for 2 h. The reaction mixture was filtered over 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 MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 60:40) to afford intermediate 180 (271 mg, 75%, 95% purity) as a yellow solid.

Compound 48

(3aS,6a/?)-6-(4- {7-Cyclopropyl-5-[( 1 */?)-6-fluoro-l -methyl- 1 ,2,3,4-tctrahydro- isoquinoline-2-carbonyl]pyrazolo[l,5-a]pyrimidin-2-yl}-3-flu orophenyl)-hexahydro-2H- furo[2,3-b]pyrrol-2-one

Intermediate 180 (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 0 (2.5 mL) was added. The reaction mixture was stirred at rt for 3 days. Brine, a 10% aqueous solution of KHS0 4 and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 25 g Interchim ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc / AcOH from 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 afford a white solid (250 mg). The batch was split in two samples A and B that were purified independently by preparative LC (Stationary phase: irregular SiOH 40 g, 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

Synthesis of intermediate 185

Intermediate 186

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

A mixture of 2,6-difluoropyridine [1513-65-1] (1.00 g, 8.69 mmol), (5)-3-methyl pyrrolidine-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 h. The reaction mixture was diluted with EtOAc and H 2 0. The layers were separated and the aqueous 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 pm, 120 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 50:50) to afford intermediate 186 (1.6 g, 82%) as a colorless oil. Intermediate 187

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

Intermediate 186 (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 for 18 h. The mixture was evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 80 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 50:50) to afford intermediate 187 (1.58 g, 61%, 84% purity) as a colorless oil.

Intermediate 188

(35)- 1 -(5-Bromo-6-fluoropyridin-2-yl)pyrrolidine-3-carboxylic acid

Lithium hydroxide monohydrate (41.9 mg, 1.00 mmol) was added to a solution of intermediate 187 (120 mg, 0.33 mmol, 84% purity) in THF (2.9 mL) and H 2 0 (0.9 mL). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHS0 4 was added until pH 6 and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, dried over MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15- 40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc / AcOH from 60:39: 1 to 20:80:2) to afford intermediate 188 (96 mg, quant.).

Intermediate 185

(35)- 1 -(5-Bromo-6-fluoropyridin-2-yl)pyrrolidine-3-carboxamide

A mixture of intermediate 188 (96.3 mg, 0.33 mmol), HATU (165 mg, 0.43 mmol) and DIPEA (172 pL, 1.0 mmol) in DCM (1.9 mL) was stirred at rt for 1 h. Ammonia (28% in H 2 0, 0.11 mL, 1.67 mmol) was added and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice), dried over MgS0 4 and evaporated under reduced pressure. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 12 g GraceResolv , dry loading (Celite ® ), mobile phase gradient: DCM / MeOH / aq.N h from 99: 1 :0.1 to 90: 10: 1). The residue was suspended in DCM and filtered off to afford intermediate 185 (62 mg, 65%) as a yellow solid.

Synthesis of compound 49

(35 * )- 1 -(5- [7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-6-fluoropyridin-2-yl)pyrrolid ine-3-carboxamide

A sealed tube was charged with intermediate 185 (62.0 mg, 0.22 mmol), (li?)-2-[7- cyclopropyl-2-(tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrazolo[ 1 ,5-a]pyrimidine-5- carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquinoline [2035421-36-2] (190 mg, 0.22 mmol, 52% purity), potassium phosphate tribasic (137 mg, 0.65 mmol), l,4-dioxane (2.2 mL) and H 2 0 (0.5 mL) and purged with nitrogen. [1 , 1 '-Bis(di-/er/-butylphosphino)fcrroccnc] palladium dichloride (14.0 mg, 21.5 pmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave

(Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was diluted with EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 24 g Interchim ® , liquid injection (DCM), mobile phase gradient: DCM / /-PrOH from 100:0 to 80:20). A second purification was performed by preparative LC (regular SiOH, 30 pm, 24 g

Interchim ® , liquid injection (DCM), mobile phase gradient: DCM / /-PrOH from 100:0 to 80:20). The mixture (79 mg) was purified by preparative LC (spherical C18 25 pm, 40 g YMC-ODS-25, dry loading (Celite ® ), mobile phase gradient: (0.2% aq.MLHCOs) / MeCN from 65:35 to 25:75). The residue was taken up in MeCN and DIPE, concentrated under reduced pressure and dried under high vacuum at 50°C for 16 h to give compound 49

(70 mg, 60%) as a white solid. Compound 50

Synthesis of intermediate 189

(35)- 1 -(5 -Bromo-6-fluoropyridin-2-yl)-/V-mcthylpyrrolidinc-3-carboxam idc

A mixture of intermediate 188 (220 mg, 761 pmol), HATU (434 mg, 1.14 mmol) and DIPEA (393 mE, 2.28 mmol) in DMF (21 mL) was stirred at rt for 1 h. Methylamine (2.0 M in THF, 1.9 mF, 3.81 mmol) was added and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the organic phase was washed with a 1% aqueous solution of NaHCCh (twice), dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative EC (irregular SiOH, 15-40 pm, 12 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / z-PrOH from 100:0 to 80:20) to afford intermediate 189 (220 mg, 96%) as a yellow oil.

Synthesis of compound 50

(35)- 1 -(5- {7-Cyclopropyl-5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[ 1 ,5-a]pyrimidin-2-yl ;-6-fluoropyridin-2-yl)-/V-mcthylpyrrolidinc-3-carboxamidc

A sealed tube was charged with intermediate 189 (220 mg, 0.73 mmol), (li?)-2-[7- cyclopropyl-2-(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazolo [ 1 ,5 -a]pyrimidine-5 - carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquinoline [2035421-36-2] (538 mg, 0.73 mmol, 62% purity), potassium phosphate tribasic (0.46 g, 2.18 mmol), l,4-dioxane (5.0 mL) and H 2 0 (1.3 mL) and purged with nitrogen. [ 1 , 1’-Bis(di-/vr/-butylphosphino)fcrroccnc] palladium dichloride (47.5 mg, 72.8 pmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was diluted with EtOAc and the organic phase was washed with brine, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 30 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / z-PrOH from 99:1 to 80:20). A second purification was carried out by reverse phase (spherical Cl 8 25 pm, 40 g YMC-ODS-25, liquid injection (MeCN / H 2 0), mobile phase gradient: (0.2% aq.NELElCCb) / MeCN from 65:35 to 25:75). The residue was taken up in MeCN. The solid was filtered off and dried under high vacuum at 50°C for 16 h to give compound 50 (190 mg, 47%).

Compound 51

Intermediate 190

Methyl (35 * )- 1 -(5- (7-cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydroisoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -6-fluoropyridin-2-yl)pyrrolidine-3-carboxylate

A sealed tube was charged with intermediate 187 (180 mg, 0.50 mmol, 84% purity), (li?)- 2- [7-cyclopropyl-2-(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazo lo [ 1 ,5 -a]pyrimidine-5 - carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquinoline [2035421-36-2] (289 mg, 0.50 mmol, 69% purity), potassium phosphate tribasic (323 mg, 1.52 mmol), l,4-dioxane (5.5 mL) and H 2 0 (1.4 mL) and purged with nitrogen. [ 1 , 1’-Bis(di-ter/-butylphosphino)fcrroccnc] palladium dichloride (33.2 mg, 50.9 pmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was diluted with EtOAc and the organic phase was washed with brine, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 80:20 to 60:40) to afford intermediate 190 (200 mg, 72%) as a yellow foam.

Intermediate 191

(35)- 1 -(5- (7-Cyclopropyl-5-[(li?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-6-fluoropyridin-2-yl)pyrrolid ine-3-carboxylic acid

Lithium hydroxide monohydrate (45.4 mg, 1.08 mmol) was added to a solution of intermediate 190 (200 mg, 361 pmol) in THF (3.1 mL) and H 2 0 (980 pL). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHS0 4 was added until pH 6 and the aqueous phase was extracted with EtOAc. The organic phase was washed with H 2 0, dried over MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc / AcOH from 30:46.5:1.5 to 0:97.5:2.5 to afford intermediate 191 (160 mg, 82%).

Compound 51

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

A mixture of intermediate 191 (160 mg, 260 pmol) and CDI (57.2 mg, 0.35 mmol) in MeCN (3 mL) was stirred at rt for 2 h. DBU (65.8 pL, 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 h. Brine, a 1N aqueous solution of HC1 and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with a solution of water and brine (1 :1), dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 92:8) to give compound 51 (60 mg, 33%) as a yellow foam. Compound 86

1176 Intermediate 1179

Methyl (35)- 1 -(6-fluoro-4-methoxypyridin-2-yl)pyrrolidine-3-carboxylate

1179 A mixture of 2,6-difluoro-4-methoxypyridine [1184172-35-7] (100 mg, 689 itmol), (5)- methyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] (114 mg, 689 itmol) and potassium carbonate (286 mg, 2.07 mmol) in MeCN (6.9 mL) was stirred at rt for 18 h. The reaction mixture was filtered over a pad of Celite ® and the filtrate was concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 60:40) to afford intermediate 1179 (68 mg, 38%) as a yellow oil.

Intermediate 1176

Methyl (35)- 1 -(5-bromo-6-fluoro-4-methoxypyridin-2-yl)pyrrolidine-3-carbo xylate

1176

A mixture of intermediate 1179 (425 mg, 1.67 mmol) and NBS (298 mg, 1.67 mmol) in MeCN (8.4 mL) was stirred at rt for 18 h. The solvent was evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 99: 1 to 40:60) to give intermediate 1176 (556 mg, 87%).

Synthesis of compound 86

Intermediate 1177

Methyl (35)- 1 -(5- (7-cyc lopropyl-5-[( 15)- 1 -methyl- 1 , 2,3, 4-tctrahydroisoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -6-fluoro-4-methoxypyridin-2-yl)pyrrolidine-3- carboxylate

A sealed tube was charged with intermediate 1176 (120 mg, 0.36 mmol), (li?)-2-[7- cyclopropyl-2-(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazolo [ 1 ,5 -a]pyrimidine-5 - carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquinoline [2035421-36-2] (236 mg, 0.36 mmol, 70% purity), potassium phosphate tribasic (229 mg, 1.08 mmol), l,4-dioxane (3.1 mL) and H 2 0 (0.8 mL) and purged with nitrogen. [ 1 , 1’-Bis(di-/er/-butylphosphino)fcrroccnc] palladium dichloride (23.5 mg, 36.0 pmol) was added and the mixture was purged again with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was diluted with EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgS0 4 , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 80:20 to 20:80) to afford intermediate 1177 (195 mg, 93%).

Intermediate 1178

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

Lithium hydroxide monohydrate (41.9 mg, 1.00 mmol) was added to a solution of intermediate 1177 (195 mg, 334 pmol) in THF (2.9 mL) and H 2 0 (0.9 mL). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHS0 4 was added until pH 6 and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, dried over MgS0 4 , filtered and concentrated in vacuo to afford intermediate 1178 (185 mg, 97%).

Compound 86

(3 S)- 1 -(5- (7-Cyclopropyl-5-[(li?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-6-fluoro-4-methoxypyridin-2-y l)pyrrolidine-3- carboxamide

A mixture of intermediate 1178 (185 mg, 324 pmol), ammonium chloride (69.4 mg, 1.30 mmol) and DIPEA (467 pL, 2.71 mmol) in l,4-dioxane (2.5 mL) was stirred at 0°C. PPACA (50% wt in EtOAc, 463 m L, 778 pmol) was added slowly. The reaction mixture was stirred at 0°C for 10 min and at rt for 4 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with a 10% aqueous solution of KHS0 4 and brine, dried over MgS0 4 , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (spherical Cl 8 25 pm, 40 g YMC-ODS-25, dry loading (Celite ® ), mobile phase gradient: (0.2% aq.NH 4 HC0 3 ) / MeCN from 75:25 to 35:65). The residue was solubilized in Et 2 0 and evaporated in vacuo. The product was dried under vacuum at 50°C for 72 h and at 65°C for 8 h to give compound 86 (100 mg, 54%).

Compound 87

Synthesis of intermediate 1180

rt, 18 h

[3512-17-2] [109-86-4] 1183

Intermediate 1183

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

1183

To a mixture of 2,4,6-trifluoropyridine [3512-17-2] (300 mg, 2.25 mmol) and 2-methoxy- ethanol [109-86-4] (179 pL, 2.25 mmol) in MeCN (9.4 mL) was added sodium hydride (60% in mineral oil, 90.2 mg, 2.25 mmol). The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc. The organic phase was washed with H 2 0, dried over MgS0 4 , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90:10 to 40:60) to afford intermediate 1183 (230 mg, 54%).

Intermediate 1184

Methyl (35)- 1 -[6-fluoro-4-(2-methoxyethoxy)pyridin-2-yl]pyrrolidine-3-car boxylate

A mixture of intermediate 1183 (230 mg, 1.22 mmol), (5)-methyl pyrrolidine-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 h. The reaction mixture was filtered over a pad of Celite ® and the filtrate was concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 60:40) to afford intermediate 1184 (150 mg, 41%) as a yellow oil.

Intermediate 1180

Methyl (35)- 1 -[5-bromo-6-fluoro-4-(2-methoxyethoxy)pyridin-2-yl]pyrrolidi ne-3- carboxylate

A mixture of intermediate 1184 (150 mg, 503 pmol) and NBS (89.5 mg, 503 mmol) in MeCN (2.5 mL) was stirred at rt for 18 h. The solvent was evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 40:60) to afford intermediate 1180 (218 mg, 93%) as a yellow oil.

Synthesis of compound 87

Intermediate 1181

Methyl (35)- 1 -(5- (7-cyc lopropyl-5-[( 15)- 1 -methyl- 1 , 2,3, 4-tctrahydroisoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -6-fluoro-4-(2-methoxyethoxy)pyridin-2- yl)pyrrolidine-3 -carboxylate

A sealed tube was charged with intermediate 1180 (124 mg, 329 pmol), (li?)-2-[7- cyclopropyl-2-(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazolo [ 1 ,5 -a]pyrimidine-5 - carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquinoline [2035421-36-2] (215 mg, 329 pmol, 70% purity), potassium phosphate tribasic (209 mg, 986 pmol), l,4-dioxane (2.8 mL) and H 2 0 (0.7 mL) and purged with nitrogen. [ 1 , 1’-Bis(di-/er/-butylphosphino)fcrroccnc] palladium dichloride (21.4 mg, 32.9 pmol) was added and the mixture was purged again with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was diluted with EtOAc. The organic phase was washed with brine, dried over MgS0 4 , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 80:20 to 20:80) to afford intermediate 1181 (185 mg, 90%).

Intermediate 1182

(3 S)- 1 -(5- (7-Cyclopropyl-5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -6-fluoro-4-(2-methoxyethoxy)pyridin-2- yl)pyrrolidine-3 -carboxylic acid

1182

Lithium hydroxide monohydrate (37.0 mg, 883 pmol) was added to a solution of intermediate 1181 (185 mg, 294 mhioΐ) in THF (2.6 mL) and H 2 0 (0.8 mL). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHS0 4 was added until pH 6 and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, dried over MgS0 4 , filtered and concentrated to afford intermediate 1182 (170 mg, 94%).

Compound 87

(3 S)- 1 -(5- {7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-6-fluoro-4-(2-methoxyethoxy)p yridin-2-yl)pyrrolidine-3- carboxamide

A mixture of intermediate 1182 (170 mg, 277 pmol), ammonium chloride (17.8 mg, 332 prnol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (51.5 mg, 332 pmol) and 1- hydroxybenzotriazole hydrate (63.5 mg, 415 pmol) in DMF (14 mL) was stirred at 0°C. DIPEA (238 pL, 1.38 mmol) was added slowly and the reaction mixture was stirred at rt for 18 h. 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 MgS0 4 , filtered and evaporated in vacuo. The crude mixture was purified by reverse phase (Stationary phase: YMC-actus Triart C18 lOpm 30* 150mm, Mobile phase gradient: (0.2% aq.NH 4 HC0 3 ) / MeCN from 70:30 to 30:70). The residue was suspended in MeCN (~2 mL) and stirred under reflux until complete solubilization. The heating source was stopped and the flask was left in the oil bath with a gentle stirring while crystallization occurred (4 h). The solid was filtered off, washed with MeCN and dried under vacuum at 50°C for 18 h to give compound 87 (115 mg, 68%) as a white solid.

Compound 52

Synthesis of intermediate 192

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

Intermediate 195

Methyl (35)- 1 -(4-fluoropyridin-2-yl)pyrrolidine-3-carboxylate

195 A sealed tube was charged with 2-bromo-4-fluoropyridine [357927-50-5 ] (200 mg, 1.14 mmol), (5)-methyl pyrrolidine-3 -carboxylate hydrochloride [216311-60-3] (188 mg, 1.14 mmol) and cesium carbonate (1.11 g, 3.41 mmol) and purged with nitrogen. l,4-Dioxane (9.2 mL) was added and the mixture was degassed with nitrogen. Palladium acetate (25.5 mg, 0.11 mmol) and XantPhos (65.8 mg, 0.11 mmol) were added. The reaction mixture was stirred at l00°C for 18 h. The reaction mixture was poured out into water and the aqueous phase was extracted with EtOAc and filtered over Celite ® . The filtrate was washed with brine, dried over MgS0 4 , filtered and evaporated to dryness. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90:10 to 40:60) to afford intermediate 195 (32 mg, 13%) as a colorless oil. Intermediate 192

Methyl (35)- 1 -(5-bromo-4-fluoropyridin-2-yl)pyrrolidine-3-carboxylate

192

A mixture of intermediate 195 (60.0 mg, 268 pmol) and NBS (47.6 mg, 268 pmol) in MeCN (2.7 mL) was stirred at rt for 18 h. The mixture was evaporated under reduced pressure. The crude product was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 50:50) to afford intermediate 192 (68 mg, 84%) as a colorless oil.

Synthesis of compound 52

Intermediate 193

Methyl (35)- 1 -(5- (7-cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydroisoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -4-fluoropyridin-2-yl)pyrrolidine-3-carboxylate

A sealed tube was charged with intermediate 192 (234 mg, 0.77 mmol), (li?)-2-[7- cyclopropyl-2-(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazolo [ 1 ,5 -a]pyrimidine-5 - carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquinoline [2035421-36-2] (472 mg, 0.77 mmol, 75% purity), potassium phosphate tribasic (492 mg, 2.32 mmol), l,4-dioxane (7.8 mL) and H 2 0 (2.0 mL) and purged with nitrogen. [ 1 , 1’-Bis(di-/er/-butylphosphino)fcrroccnc] palladium acetate (50.3 mg, 77.2 pmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was diluted with EtOAc and the organic phase was washed with brine, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 80 g Interchim ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 40:60 to 0:100) to afford intermediate 193 (400 mg, 93%) as a yellow oil.

Intermediate 194

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

Lithium hydroxide monohydrate (90.8 mg, 2.16 mmol) was added to a solution of intermediate 193 (400 mg, 0.72 mmol) in THF (6.3 mL) and H 2 0 (2.0 mL). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHS0 4 was added until pH 6 and the aqueous phase was extracted with EtOAc. The organic layer was washed with H 2 0, dried over MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc / AcOH from 80:19.5:0.5 to 0:97.5:2.5) to afford intermediate 194 (380 mg, 97%).

Compound 52

(3 S)- 1 -(5- (7-Cyclopropyl-5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-4-fluoropyridin-2-yl)pyrrolid ine-3-carboxamide

A mixture of intermediate 194 (180 mg, 333 pmol), HATU (190 mg, 499 pmol) and DIPEA (172 mE, 1.0 mmol) in DMF (9 mL) was stirred at rt for 1 h. Ammonia (28% in H 2 0, 113 pL, 1.67 mmol) was added and the reaction mixture was stirred at rt for 18 h.

The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / z-PrOH from 100:0 to 70:30). The residue (120 mg) was dissolved in DCM and washed with a 1% aqueous solution of NaHC0 3 (3 times), brine, dried over MgS04, filtered and concentrated in vacuo to give compound 52 (90 mg, 50%).

Compound 53

Synthesis of intermediate 196

Intermediate 197

(35)- 1 -(5-Bromo-4-fluoropyridin-2-yl)pyrrolidine-3-carboxylic acid

o

197

Lithium hydroxide monohydrate (66.4 mg, 1.58 mmol) was added to a solution of intermediate 192 (160 mg, 0.53 mmol) in THF (12 mL) and H 2 0 (3.0 mL). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHS0 4 was added until pH 6 and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, dried over MgS0 4 , filtered and concentrated under reduced pressure to afford intermediate 197 (150 mg, 98%) as a yellow foam.

Intermediate 196

(3 S)-l-(5-Bromo-4-fluoropyridin-2-yl)-N-methylpyrrolidine-3-ca rboxamide

196

A mixture of intermediate 197 (150 mg, 519 pmol), HATU (296 mg, 0.78 mmol) and DIPEA (268 pL, 1.56 mmol) in DMF (8 mL) was stirred at rt for 1 h. Methylamine (2.0 M in THF, 1.30 mL, 2.59 mmol) was added and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated. The organic phase was washed with a 1% aqueous solution of NaHC0 3 (twice), dried over MgS0 4 and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / z-PrOH from 100:0 to 80:20) to afford intermediate 196 (140 mg, 89%) as a yellow oil.

Synthesis of compound 53

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

A sealed tube was charged with intermediate 196 (140 mg, 0.46 mmol), (li?)-2-[7- cyclopropyl-2-(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazolo [ 1 ,5 -a]pyrimidine-5 - carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquinoline [2035421-36-2] (212 mg, 0.46 mmol, 63% purity), potassium phosphate tribasic (0.29 g, 1.39 mmol), l,4-dioxane (3.2 mL) and H 2 0 (0.8 mL) and purged with nitrogen. [ 1 , 1 '-Bis(di-/er/-butylphosphino)fcrroccnc] palladium dichloride (30.2 mg, 46.3 pmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was diluted with EtOAc and the organic phase was washed with brine, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / /-PrOH from 99: 1 to 80:20). A second purification was carried out by reverse phase (spherical C18 25 pm, 40 g YMC-ODS-25, liquid injection (MeCN, H 2 0), mobile phase gradient (0.2% aq.NELElCCb) / MeCN from 65:35 to 25:75). The residue was crystallized from EtOH, filtered off and dried under high vacuum at 50°C for 16 h to give compound 53 (90 mg, 35%).

Compound 54

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

A mixture of intermediate 194 (185 mg, 342 pmol) and CDI (83.2 mg, 0.51 mmol) in MeCN (3.5 mL) was stirred at rt for 2 h. DBU (102 pL, 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 h. A 1N aqueous solution of HC1 and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with a solution of water and brine (1 : 1), dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 92:8). A second purification was carried out: preparative LC (spherical Cl 8 25 pm, 40 g YMC-ODS-25, dry loading (Celite ® ), mobile phase gradient: (0.2% aq.NH 4 HC0 3 ) / MeCN from 85: 15 to 45:55). The product was freeze-dried to give compound 54 (140 mg, 66%) as a white solid.

Compound 88

Synthesis of intermediate 1185

Intermediate 1188

Methyl (35)- 1 -(6-fluoropyrazin-2-yl)pyrro lidine-3 -carboxylate

A mixture of 2,6-difluoropyrazine [33873-09-5] (726 mg, 6.26 mmol), (S)-methyl pyrrolidine-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 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and concentrated in vacuo to afford intermediate 1188 (1.1 g, 77%).

Intermediate 1185

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

A mixture of intermediate 1188 (1.00 g, 4.59 mmol) and NBS (817 mg, 4.59 mmol) in MeCN (51 mL) was stirred at rt for 18 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with an aqueous solution of NaHC0 3 (twice), dried over MgS0 4 , filtered and concentrated in vacuo to afford intermediate 1185 (1 -42 g).

Synthesis of compound 88

Intermediate 1186

Methyl (35)- 1 -(5- (7-cyc lopropyl-5-[( 15)- 1 -methyl- 1 , 2,3, 4-tctrahydroisoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -6-fluoropyrazin-2-yl)pyrrolidine-3-carboxylate

A sealed tube was charged with intermediate 1185 (207 mg, 682 pmol), ( 1 R)-2-[l- cyclopropyl-2-(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazolo [ 1 ,5 -a]pyrimidine-5 - carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquinoline [2035421-36-2] (527 mg, 1.02 mmol, 89% purity), potassium phosphate tribasic (434 mg, 2.05 mmol), l,4-dioxane (13 mL) and H 2 0 (2 mL) and purged with nitrogen. [ 1 , 1’-Bis(di-/er/-butylphosphino)fcrroccnc] palladium dichloride (44.4 mg, 68.2 qmol) was added and the mixture was purged again with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. 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 0 (twice), dried over MgS0 4 , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / EtOAc from 100:0 to 70:30). A second purification was performed by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / (EtOAc/MeOH (9:1)) from 90: 10 to 60:40) to afford intermediate 1186 (100 mg, 26%) as a pale yellow solid.

Intermediate 1187

(3 S)- 1 -(5- {7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-6-fluoropyrazin-2-yl)pyrrolid ine-3-carboxylic acid

Lithium hydroxide monohydrate (41.6 mg, 0.99 mmol) was added to a solution of intermediate 1186 (100 mg, 0.18 mmol) in THF (5.2 mL) and H 2 0 (1.3 mL). The reaction mixture was stirred at rt for 4 h. A 10% aqueous solution of KHSO 4 was added until pH 6 and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 O, dried over MgS0 4 , filtered and evaporated in vacuo to afford intermediate 1187 (90 mg, 81%, 88% purity) as a yellow oil.

Compound 88

(3 S)- 1 -(5- (7-Cyclopropyl-5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-6-fluoropyrazin-2-yl)pyrrolid ine-3-carboxamide

A mixture of intermediate 1187 (80.0 mg, 0.13 mmol, 88% purity), ammonium chloride (8.34 mg, 156 pmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (27.6 pL, 156 pmol) and l-hydroxybenzotriazole hydrate (29.9 mg, 195 pmol) in DMF (6.4 mL) was stirred at 0°C. DIPEA (112 pL, 0.65 mmol) was added slowly. The reaction mixture was stirred at rt for 18 h. 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 MgS0 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 (Stationary phase: YMC-actus Triart C18 lOpm 30*150mm, Mobile phase gradient: (0.2% aq.NH 4 HC0 3 ) / MeCN from 65:35 to 25:75). The residue (24 mg) was solubilized in MeCN (2 mL), extended with water (10 mL) and freeze-dried to give compound 88 (19 mg, 27%) as a yellow fluffy solid.

Compound 89

Synthesis of intermediate 1189

Intermediate 1193

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

A mixture of l,5-difluoro-3-methyl-2-nitrobenzene [1616526-80-7] (125 mg, 722 pmol), (S)-mcthyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] (132 mg, 795 pmol) and potassium carbonate (299 mg, 2.17 mmol) in MeCN (7.2 mL) was stirred at rt for 18 h The reaction mixture was filtered over a pad of Celite ® and the filtrate was evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 99: 1 to 60:40) to afford intermediate 1193 (118 mg, 58%) as a yellow oil.

Intermediate 1194

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

1194 A mixture of intermediate 1193 (725 mg, 2.57 mmol) and NBS (457 mg, 2.57 mmol) in MeCN (12.8 mL) was stirred at rt for 18 h. The solvent was evaporated in vacuo to afford intermediate 1194 (1.10 g, 95%, 80% purity).

Intermediate 1189

Methyl (35)- 1 -(2-amino-4-bromo-5-fluoro-3-methylphenyl)pyrrolidine-3-carb oxylate

In a sealed tube a mixture of intermediate 1194 (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 0 (3.9 mL) was stirred at 80°C for 18 h. The reaction mixture was diluted with EtOAc and H 2 0. The layers were separated and the organic phase was washed with brine, dried over MgS0 4 , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 99: 1 to 60:40) to afford intermediate 1189 (666 mg, 83%) as a colorless oil.

Synthesis of compound 89

Intermediate 1190

Methyl (35)- 1 -(2-amino-4- (7-cyc lopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydro- isoquinoline-2-carbonyl]pyrazolo[l,5-a]pyrimidin-2-yl}-5-flu oro-3-methylphenyl)- pyrrolidine-3 -carboxylate

A sealed tube was charged with intermediate 1189 (615 mg, 1.86 mmol), (li?)-2-[7- cyclopropyl-2-(tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazolo [ 1 ,5 -a]pyrimidine-5 - carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquinoline [2035421-36-2] (1.22 g, 1.86 mmol, 70% purity), potassium phosphate tribasic (1.18 g, 5.57 mmol), l,4-dioxane (15.8 mL) and H2O (4.0 mL) and purged with nitrogen. [ 1 , 1’-Bis(di-/er/-butylphosphino)fcrroccnc] palladium dichloride (121 mg, 186 pmol) was added and the mixture was purged again with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was diluted with EtOAc. The organic phase was washed with brine, dried over MgS0 4 , filtered and evaporated in vacuo. The crude mixture was combined with other samples (105 mg, 317 pmol and 50 mg, 151 pmol) and purified by preparative LC (irregular SiOH, 15-40 pm, 40 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 80:20 to 20:80) to afford intermediate 1190 (1.4 g, 78%, 75% purity).

Intermediate 1191

Methyl (3S)- 1 -(4- (7-cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydroisoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluoro-5-methylphenyl)pyrrolidine-3- carboxylate

In a sealed tube a mixture of intermediate 1190 (700 mg, 901 pmol, 75% purity) and tert- butyl nitrite (118 pL, 991 pmol) in THF (14.7 mL) was stirred at 80°C for 18 h. The solvent was evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 80:20 to 0:100) to afford intermediate 1191 (186 mg, 36%). Intermediate 1192

(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-fluoro-5-methylphenyl)pyrrolidine-3- carboxylic acid

Lithium hydroxide monohydrate (62.1 mg, 1.48 mmol) was added to a solution of intermediate 1191 (280 mg, 493 pmol) in THF (4.3 mL) and H 2 0 (1.3 mL). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHS0 4 was added until pH 6 and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, dried over MgS0 4 , filtered and concentrated in vacuo to afford intermediate 1192 (250 mg, 92%) as a yellow foam.

Compound 89

(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-fluoro-5-methylphenyl)pyrrolidine-3- carboxamide

A mixture of intermediate 1192 (220 mg, 397 pmol), ammonium chloride (85.0 mg, 1.59 mmol) and DIPEA (572 pL, 3.32 mmol) in DCM (2.2 mL) was stirred at 0°C. PPACA (50 wt. % in EtOAc, 572 pL, 0.96 mmol) was added slowly. The reaction mixture was stirred at 0°C for 10 min and at rt for 4 h. The reaction mixture was cooled to 0°C and ammonium chloride (85.0 mg, 1.59 mmol), DIPEA (572 pL, 3.32 mmol) and PPACA (50 wt. % in EtOAc, 572 pL, 0.96 mmol) were added slowly. The reaction mixture was stirred at 0°C for 10 min and at rt for 4 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with a 10% aqueous solution of KHS0 4 and brine, dried over MgS0 4 , filtered and evaporated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g Grace ® , liquid injection (DCM), mobile phase gradient: DCM / z-PrOH from 99: 1 to 85: 15). A second purification was carried out by preparative LC (spherical Cl 8 25 pm, 40 g YMC-ODS-25, dry loading (Celite ® ), mobile phase gradient: (0.2% aq.NH 4 HC0 3 ) / MeCN from 65:35 to 25:75). The residue was solubilized in EtOAc, concentrated to dryness and dried under vacuum at 50°C for 72 h and at 65 °C for 8 h to give compound 89 (100 mg, 46%).

Compound 55

Synthesis of intermediate 198

Pd(OAc) 2 , XantPhos

a ’ · dioxane

100 °C, 18 h

[399-94-0] [1099646-61 -3] 1101

198 Intermediate 1101

Methyl (35)- 1 -(2,5-difluorophenyl)pyrrolidine-3-carboxylate

A mixture of (S)-mcthyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] (1.00 g, 6.04 mmol), l-bromo-2,5-difluorobenzene [399-94-0] (1.02 mL, 9.06 mmol) and cesium carbonate (5.90 g, 18.1 mmol) in l,4-dioxane (50 mL) was purged 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 l00°C for 18 h. 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 MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 80 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 80:20) to afford intermediate 1101 (780 mg, 54%) as a colorless oil.

Intermediate 198

Methyl (35)- 1 -(4-bromo-2,5-difluorophenyl)pyrrolidine-3-carboxylate

To a solution of intermediate 1101 (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 for 18 h. The reaction mixture was diluted with EtOAc and ELO. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (regular SiOH, 30 pm, 80 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 90:10) to afford intermediate 198 (817 mg, 79%) as a white powder. Synthesis of compound 55

Intermediate 199

Methyl (3S)- 1 -(4- (7-cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydroisoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -2,5-difluorophenyl)pyrrolidine-3-carboxylate

A sealed tube was charged intermediate 198 (200 mg, 625 pmol), (li?)-2-[7-cyclopropyl-2- (tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyrimidine-5-carbonyl]-l -methyl- l,2,3,4-tetrahydroisoquinoline [2035421-36-2] (551 mg, 625 pmol, 52% purity), potassium phosphate tribasic (451 mg, 2.12 mmol), l,4-dioxane (10 mL) and H 2 0 (3 mL) and purged with nitrogen. [ 1 , 1’-Bis-(di-/er/-butylphosphino)fcrroccnc] palladium dichloride (44.8 mg 68.8 pmol) was added and the mixture was purged with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was diluted with EtOAc and the organic phase was washed with brine, dried over MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 80 g Grace ® , dry loading (SiOH), mobile phase gradient: heptane / EtOAc from 100:0 to 60:40). The residue (397 mg) was purified by preparative LC (spherical Cl 8 25 pm, 40 g YMC-ODS-25, dry loading (Cl 8), mobile phase gradient: (0.2% aq.NH 4 HC0 3 ) / MeCN from 60:40 to 0: 100) to afford intermediate 199 (320 mg, 88%) as a yellow solid.

Intermediate 1100

(3 S)- 1 -(4- [7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-2,5-difluorophenyl)pyrrolidin e-3-carboxylic acid

Lithium hydroxide monohydrate (117 mg, 2.80 mmol) was added to a solution of intermediate 199 (320 mg, 0.56 mmol) in THF (9 mL) and H 2 0 (1.8 mL). The reaction mixture was stirred at rt for 20 h. A 10% aqueous solution of KHS0 4 and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by preparative LC (spherical Cl 8 25 pm, 40 g YMC-ODS-25, dry loading (Cl 8), mobile phase gradient: (0.2% aq.NH 4 HC0 3 ) / MeCN from 75:25 to 35:65), to give intermediate 1100 (280 mg, 90%) as a yellow solid.

Compound 55

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

A mixture of intermediate 1100 (142 mg, 255 pmol), HATU (145 mg, 382 pmol) and DIPEA (132 pL, 0.76 mmol) in DMF (7 mL) was stirred at rt for 1 h. Ammonia (28% in H 2 0, 86.1 pL, 1.27 mmol) was added and the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated under reduced pressure. The crude mixture was purified by preparative LC (spherical Cl 8 25 pm, 40 g YMC-ODS-25, dry loading (Cl 8), mobile phase gradient (0.2% aq.NH 4 HC0 3 ) / MeCN from 60:40 to 0:100). A second purification was carried out: preparative LC (spherical Cl 8 25 pm, 40 g YMC-ODS-25, dry loading (Cl 8), mobile phase gradient: (0.2% aq.NH 4 HC0 3 ) / MeCN from 60:40 to 0:100). The residue (80 mg) was purified by reverse phase (Stationary phase: YMC-actus Triart C18 10 pm 30*l50mm, Mobile phase gradient: (0.2% aq. NH4HCO3) / MeCN from 50:50 to 0:100) to give compound 55 (60 mg, 47%) as a white solid.

Compound 85

Synthesis of intermediate 1173

Intermediate 1174

(37?)-Pyrrolidin-3-yl carbamate hydrochloride

1174

A solution of tert- butyl (3/?)-3-(carbamoyloxy)pyrrolidinc- 1 -carboxylatc [109384-14-7] (4.28 g, 18.6 mmol) and chlorotrimethylsilane (9.5 mL, 74.8 mmol) in MeOH (90 mL) was stirred at rt for 24 h. The mixture was evaporated in vacuo to afford intermediate 1174 (3.02 g, 98%).

Intermediate 1175

(37?)- 1 -(6-Fluoropyridin-2-yl)pyrrolidin-3-yl carbamate

A mixture of 2,6-difluoropyridine [1513-65-1] (628 mg, 5.46 mmol), intermediate 1174 (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 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were dried over MgS0 4 , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , dry loading (Celite ® ), mobile phase gradient: heptane / EtOAc from 90:10 to 50:50) to afford intermediate 1175 (187.9 mg, 15%) as a white solid.

Intermediate 1173

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

A mixture of intermediate 1175 (188 mg, 834 pmol) and NBS (149 mg, 834 pmol) in MeCN (9.2 mL) was stirred at rt for 18 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with NaHC0 3 (twice), dried over MgS0 4 , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , dry loading (Celite ® ), mobile phase gradient: heptane / EtOAc from 80:20 to 50:50) to afford intermediate 1173 (180 mg, 71%) as a white solid.

Synthesis of compound 85

(3 R)- 1 -(5- {7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-6-fluoropyridin-2-yl)pyrrolid in-3-yl carbamate

A sealed tube was charged with intermediate 1173 (120 mg, 395 pmol), ( 1 R)-2-[l- cyclopropyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[ l,5-a]pyrimidine-5- carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquinoline [2035421-36-2] (305 mg, 592 pmol,

89% purity), potassium phosphate tribasic (251 mg, 1.18 mmol), l,4-dioxane (7.3 mL) and H 2 0 (1.1 mL) and purged with nitrogen. [1 , 1’-Bis(di-/er/-butylphosphino)fcrroccnc] palladium dichloride (25.7 mg, 39.5 pmol) was added and the mixture was purged again with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. 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 ELO (twice), dried over MgS0 4 , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 24 g GraceResolv , liquid injection (DCM), mobile phase gradient: DCM / EtOAc from 100:0 to 80:20). The residue (100 mg) was triturated with MeCN. The solid was filtered off and dried under high vacuum at 50°C for 2 h to give compound 85 (28 mg, 13%) as a pale yellow solid.

General Scheme

Synthesis of intermediates 1102 and 1103

Intermediate 1102

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

A mixture of 3-(4-bromo-2-fluorophenyl)-lH-pyrazol-5-amine (15.0 g, 58.6 mmol) and diethyl acetylenedicarboxylate (9.40 mL, 58.6 mmol) in acetic acid (110 mL) was stirred at rt for 36 h. The reaction mixture was diluted with EtOAc and heptane (30:60) (150 mL) and the mixture was stirred for 30 min. The precipitate was filtered off and dried under vacuum to afford intermediate 1102 (18.6 g, 84%).

Intermediate 1103

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

A mixture of intermediate 1102 (15.0 g, 39.5 mmol) in phosphorous (V) oxychloride (147 mL) was stirred under reflux for 18 h. The solvent was evaporated to dryness. LEO was added slowly to the residue and the mixture was stirred at 0°C for 30 min. The precipitate was filtered off and dried under vacuum to afford intermediate 1103 (15.3 g, 97%).

Synthesis of compounds 56 to 64 and 90

Compound 56

Intermediate 1104

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

A mixture of intermediate 1103 (1.50 g, 3.76 mmol) and 2-phenyl-4,4,5,5-tetramethyl- l,2,3-dioxaborolane [24388-23-6] (691 mg, 3.39 mmol) in THF (30 mL) was degassed with nitrogen for 10 min. [1 , 1 '-Bis(diphcnylphosphino)fcrroccnc]dichloropalladium, complex with dichloromethane (308 mg, 376 pmol) and potassium carbonate (2.0 M in H 2 0, 5.64 mL, 11.3 mmol) were added and the reaction mixture was stirred at 70°C for 4 h. The reaction mixture was poured out into water and EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgS0 4 , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (15-40 pm, cartridge 80 g, mobile phase gradient: heptane / EtOAc from 100:0 to 70:30) to afford intermediate 1104 (1.15 g, 69%). The product was used in the next step without further purification.

Intermediate 1105

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

A mixture of intermediate 1104 (1.15 g, 2.61 mmol) and lithium hydroxide (125 mg, 5.22 mmol) in THF (13 mL) and H 2 0 (3 mL) was stirred at rt for 18 h. The solvent was evaporated under reduced pressure. Few drops of H 2 0 were added to the residue. The precipitate was filtered off and dried under vacuum to afford intermediate 1105 (1.2 g). The product was used in the next step without further purification.

Intermediate 1106

(l7?)-2-[2-(4-Bromo-2-fluorophenyl)-7-phenylpyrazolo[l,5-a]p yrimidine-5-carbonyl]-l- methyl- 1 ,2,3 ,4-tetrahydroisoquino line

1106 DIPEA (1.38 mL, 7.89 mmol) and HATU (1.30 g, 3.42 mmol) were added to a mixture of ( 1 R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc hydrochloride [84010-67-3] (0.58 g, 3.16 mmol) and intermediate 1105 (1.10 g, 2.63 mmol) in DMF (30 mL). The reaction mixture was stirred at rt for 24 h. The reaction mixture was poured out into water and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (15-40 pm, 80 g GraceResolv , mobile phase gradient: heptane / EtOAc from 100:0 to 75:25) to afford intermediate 1106 (1.3 g, 66%, 72% purity).

Intermediate 1107

Methyl (3 S)- 1 -(3-fluoro-4- (5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- 7-phenylpyrazolo[l,5-a]pyrimidin-2-yl}phenyl)pyrrolidine-3-c arboxylate

A mixture of intermediate 1106 (1.3 g, 1.73 mmol, 72% purity), (S)-mcthyl pyrrolidine-3- carboxylate hydrochloride [1099646-61-3] (419 mg, 2.08 mmol), cesium carbonate (1.69 g, 5.19 mmol) and XantPhos (100 mg, 0.17 mmol) was purged with nitrogen. l,4-Dioxane (20 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (38.8 mg, 0.17 mmol) was added. The reaction mixture was purged with nitrogen and stirred at l00°C for 18 h. The reaction mixture was diluted with EtOAc and H 2 0. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g Grace ® , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 70:30) to afford intermediate 1107 (550 mg, 54%).

Intermediate 1108

(3 S)- 1 -(3-Fluoro-4- (5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7- phenylpyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} phenyl)pyrrolidine-3 -carboxylic acid

Lithium hydroxide monohydrate (195 mg, 4.66 mmol) was added to a solution of intermediate 1107 (550 mg, 0.93 mmol) in THF (7.6 mL) and H 2 0 (2.5 mL). The reaction mixture was stirred at rt for 24 h. Few drops of H 2 0 were added followed by a 3N aqueous solution of HC1. The layers were separated and the aqueous phase was extracted with DCM (twice). The combined organic extracts were dried over MgS0 4 , filtered and evaporated under reduced pressure to afford intermediate 1108 (470 mg, 88%). The product was used as such in the next step.

Compound 56

(3 S)- 1 -(3-Fluoro-4- (5-[(U?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7- phenylpyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} phenyl)pyrrolidine-3 -carboxamide

A mixture of intermediate 1108 (230 mg, 0.40 mmol), HMDS (102 pL, 0.48 mmol), HATU (228 mg, 0.60 mmol) and DIPEA (138 pL, 0.80 mmol) in DMF (5 mL) was stirred at rt for 18 h. The reaction mixture was diluted with H 2 0 and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, brine, dried over MgS0 4 , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (15-40 pm, 12 g Grace ® , mobile phase gradient: DCM / MeOH from 100:0 to 96:4). The pure fractions were collected and concentrated to dryness. The residue (155 mg) was taken up in Et 2 0, filtered and dried under vacuum to give compound 56 (101 mg, 44%). Compound 57

Intermediate 1109

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

Intermediate 1109 (880 mg, 54%, 87% purity) was synthesized from intermediate 1103 and 4-methoxyphenylboronic acid [5720-07-0] according to the procedure reported for the synthesis of intermediate 1104.

Intermediate 1110

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

Intermediate 1110 (150 mg, 90%) was synthesized from intermediate 1109 and lithium hydroxide monohydrate according to the procedure reported for the synthesis of intermediate 1105.

Intermediate 1111

(l7?)-2-[2-(4-Bromo-2-fluorophenyl)-7-(4-methoxyphenyl)pyraz olo[l,5-a]pyrimidine-5- carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline

Intermediate 1111 (740 mg, 48%) was synthesized from intermediate 1110 and (li?)-l- methyl-l,2,3,4-tetrahydroisoquinolone hydrochloride [84010-67-3] according to the procedure reported for the synthesis of intermediate 1106 with a reaction time of 48 h.

Intermediate 1112

Methyl (35 * )- 1 - j 3-fluoro-4-[7-(4-mcthoxyphcnyl)-5-[( 1 /?)- 1 -methyl- 1 ,2,3,4- tetrahydroisoquinoline-2-carbonyl]pyrazolo[l,5-a]pyrimidin-2 -yl]phenyl}pyrrolidine-3- carboxylate

Intermediate 1112 (290 mg, 67%) was synthesized from intermediate 1111 and (5)-methyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] according to the procedure reported for the synthesis of intermediate 1107 with a shorter reaction time of 5 h.

Intermediate 1113

(35)- 1 - {3-Fluoro-4-[7-(4-mcthoxyphcnyl)-5-[( 15)- 1 -methyl- 1 , 2,3, 4-tctrahydroisoqui no- line-2-carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl]phenyl}pyrrolidine-3-carboxylic acid

Intermediate 1113 was synthesized from intermediate 1112 according to the procedure reported for the synthesis of intermediate 1108. The crude mixture was purified by flash chromatography over silica gel (15-40 pm, cartridge 24 g, mobile phase gradient: DCM / MeOH from 100:0 to 97:3) to afford intermediate 1113 (245 mg, 93%).

Compound 57

(3S 1 - {3-Fluoro-4-[7-(4-mcthoxyphcnyl)-5-[( 1 /?)-l -methyl- 1 ,2,3,4-tctrahydro- isoquino line-2-carbonyl]pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl]phenyl} pyrrolidine-3 -carboxamide

Compound 57 (117 mg, 56%) was synthesized from intermediate 1113 according to the procedure reported for the synthesis of compound 56.

Compound 58

Intermediate 1114

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

Intermediate 1114 (1.35 g, 70%, 88% purity) was synthesized from intermediate 1103 and 4-tolylboronic acid [5720-05-8] according to the procedure reported for the synthesis of intermediate 1104.

Intermediate 1115

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

Intermediate 1115 (1.5 g) was synthesized from intermediate 1114 and lithium hydroxide monohydrate according to the procedure reported for the synthesis of intermediate 1105.

Intermediate 1116

(l7?)-2-[2-(4-Bromo-2-fluorophenyl)-7-(4-methylphenyl)pyrazo lo[l,5-a]pyrimidine-5- carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline

Intermediate 1116 (1.25 g, 65%) was synthesized from intermediate 1115 and (li?)-l- methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure reported for the synthesis of intermediate 1106.

Intermediate 1117

Methyl (3 S)- 1 -(3-fluoro-4- (5-[(li?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- 7-(4-methylphenyl)pyrazolo [ 1 ,5 -a]pyrimidin-2-yl}phenyl)pyrro lidine-3 -carboxylate

Intermediate 1117 (300 mg, 61%) was synthesized from intermediate 1116 and (5)-methyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] according to the procedure reported for the synthesis of intermediate 1107.

Intermediate 1118

(3 S)- 1 -(3-Fluoro-4- (5-[(li?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(4- methylphenyl)pyrazolo[ 1 ,5-a]pyrimidin-2-yl}phenyl)pyrrolidine-3-carboxylic acid

Intermediate 1118 was synthesized from intermediate 1117 according to the procedure reported for the synthesis of intermediate 1107. The crude mixture was purified by flash chromatography on silica gel (15-40 pm, cartridge 12 g, mobile phase gradient: DCM / MeOH from 100:0 to 96:4). The pure fractions were collected and evaporated to dryness to afford intermediate 1118 (255 mg, 87%). Compound 58

(3 S)- 1 -(3-Fluoro-4- (5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-(4- methylphenyl)pyrazolo [ 1 ,5 -a]pyrimidin-2-yl} phenyl)pyrrolidine-3 -carboxamide

Compound 58 (102 mg, 51%) was synthesized from intermediate 1118 according to the procedure reported for the synthesis of compound 56.

Compound 59

Intermediate 1119

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

A mixture of intermediate 1103 (2.00 g, 5.02 mmol) and 4-chlorophenylboronic acid

[1679-18-1] (706 mg, 4.52 mmol) in THF (40 mL) was degassed with nitrogen for 10 min. [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium, complex with dichloromethane (410 mg, 0.50 mmol) and potassium carbonate (2.0 M in H 2 0, 7.53 mL, 15.1 mmol) were added and the reaction mixture was stirred at 70°C for 18 h. The reaction mixture was poured out into water and the precipitated was filtered off. The solid was dried under vacuum at 60°C to afford intermediate 1119 (2.2 g, 92%). The product was sued in the next step without further purification. Intermediate 1120

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

Intermediate 1120 (2.0 g, 95%) was synthesized from intermediate 1119 and lithium hydroxide according to the procedure reported for the synthesis of intermediate 1105. Intermediate 1121

(li?)-2-[2-(4-Bromo-2-fluorophenyl)-7-(4-chlorophenyl)pyrazo lo[l,5-a]pyrimidine-5- carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline

Intermediate 1121 (1.4 g, 55%) was synthesized from intermediate 1120 and (li?)-l- methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure reported for the synthesis of intermediate 1106.

Intermediate 1122

Methyl (35)-l-{4-[7-(4-chlorophenyl)-5-[(li?)-l-methyl-l,2,3,4-tetr ahydroisoquino line-2- carbonyljpyrazolo [ 1 ,5 -a]pyrimidin-2-yl] -3 -fluorophenyl} pyrrolidine-3 -carboxylate

Intermediate 1122 (290 mg, 48%) was synthesized from intermediate 1121 and (5)-methyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] according to the procedure reported for the synthesis of intermediate 1107.

Intermediate 1123

(35)-l-{4-[7-(4-Chlorophenyl)-5-[(li?)-l-methyl-l,2,3,4-tetr ahydroisoquinoline-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl]-3-fluorophenyl}pyrrolidine-3-carboxylic acid

Intermediate 1123 (245 mg, 86%) was synthesized from intermediate 1122 according to the procedure reported for the synthesis of intermediate 1107.

Compound 59

(35)-l-{4-[7-(4-Chlorophenyl)-5-[(li?)-l-methyl-l,2,3,4-tetr ahydroisoquinoline-2- carbonyljpyrazolo [ 1 ,5 -a]pyrimidin-2-yl] -3 -fluorophenyl} pyrrolidine-3 -carboxamide

Compound 59 was synthesized from intermediate 1123 according to the procedure reported for the synthesis of compound 56. The residue (125 mg) was taken up in DIPE. The solid was filtered off and dried under vacuum to give compound 59 (85 mg, 45%).

Compound 60

Intermediate 1124

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

THF

1103 70 °C, 4 h 1124

Intermediate 1124 (940 mg, 48%) was synthesized from intermediate 1103 and 4- fluorobenzeneboronic acid [1765-93-1] according to the procedure reported for the synthesis of intermediate 1119 with a shorter reaction time of 4 h.

Intermediate 1125

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

1124 1125

Intermediate 1125 (940 mg) was synthesized from intermediate 1124 and lithium hydroxide according to the procedure reported for the synthesis of intermediate 1105. Intermediate 1126

(l7?)-2-[2-(4-Bromo-2-fluorophenyl)-7-(4-fluorophenyl)pyrazo lo[l,5-a]pyrimidine-5- carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline

Intermediate 1126 (970 mg, 79%) was synthesized from intermediate 1125 and (l7?)-l- methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure reported for the synthesis of intermediate 1106.

Intermediate 1127

Methyl (35)- 1 - (3-fluoro-4-[7-(4-fluorophenyl)-5-[( 17?)- 1 -methyl- 1 ,2,3,4- tefrahydroisoquinoline-2-carbonyl]pyrazolo[l,5-a]pyrimidin-2 -yl]phenyl}pyrrolidine-3- carboxylate

Intermediate 1127 (340 mg, 65%) was synthesized from intermediate 1126 and (5)-methyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] according to the procedure reported for the synthesis of intermediate 1107.

Intermediate 1128

(35)- 1 - i3-Fluoro-4-[7-(4-fluorophcnyl)-5-[( l /?)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc- 2-carbonyl]pyrazolo[l,5-a]pyrimidin-2-yl]phenyl}pyrrolidine- 3-carboxylic acid

Intermediate 1128 (300 mg, 90%) was synthesized from intermediate 1127 according to the procedure reported for the synthesis of intermediate 1107.

Compound 60

(3S)- 1 - {3-Fluoro-4-[7-(4-fluorophcnyl)-5-[( 1 /?)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc- 2-carbonyl]pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl]phenyl} pyrrolidine-3 -carboxamide

Compound 60 was synthesized from intermediate 1128 according to the procedure reported for the synthesis of compound 56. The residue (190 mg) was taken up in DIPE. The solid was filtered off and dried under vacuum to give compound 60 (125 mg, 42%).

Compound 61

Intermediate 1129

Ethyl 2-(4-bromo-2-fluorophenyl)-7-[4-(trifluoromethyl)phenyl]pyra zolo[l,5-a]- pyrimidine-5 -carboxylate

THF

1103

1129 Intermediate 1129 (1.1 g, 51%) was synthesized from intermediate 1103 and 4- (trifluoromethyl)phenylboronic acid [128796-39-4] according to the procedure reported for the synthesis of intermediate 1104.

Intermediate 1130

Lithio 2-(4-bromo-2-fluorophenyl)-7-[4-(trifluoromethyl)phenyl]pyra zolo[ 1 ,5- a]pyrimidine-5 -carboxylate

1129 1130

Intermediate 1130 (1.1 g) was synthesized from intermediate 1129 and lithium hydroxide monohydrate according to the procedure reported for the synthesis of intermediate 1105 with a reaction time of 48 h.

Intermediate 1131

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

Intermediate 1131 (1.17 g, 74%, 87% purity) was synthesized from intermediate 1130 and ( I R)- 1 -methyl- 1 ,2,3,4-tctrahydroisoquinolinc hydrochloride [84010-67-3] according to the procedure reported for the synthesis of intermediate 1106. Intermediate 1132

Methyl (3 S)- 1 -(3-fluoro-4- (5-[(17?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- 7 - [4-(trifluoromethyl)phenyl]pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} phenyl)pyrro lidine-3 - carboxylate

Intermediate 1132 (240 mg, 57%) was synthesized from intermediate 1131 and (5)-methyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] according to the procedure reported for the synthesis of intermediate 1107.

Intermediate 1133

(3 S)- 1 -(3-Fluoro-4- (5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-[4-

(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-2-yl}phe nyl)pyrrolidine-3-carboxylic acid

Intermediate 1133 (210 mg, 66%) was synthesized from intermediate 1132 according to the procedure reported for the synthesis of intermediate 1107. Compound 61

(3 S)- 1 -(3-Fluoro-4- (5-[(li?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-2-yl}phenyl )pyrrolidine-3-carboxamide

Compound 61 (82 mg, 44%) was synthesized from intermediate 1133 according to the procedure reported for the synthesis of compound 56.

Compound 62

Intermediate 1134

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

Intermediate 1134 (730 mg, 42%) was synthesized from intermediate 1103 and 4- cyanophenylboronic acid [126747-14-6] according to the procedure reported for the synthesis of intermediate 1104.

Intermediate 1135

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

1134 1135

Intermediate 1135 (0.8 g) was synthesized from intermediate 1134 and lithium hydroxide monohydrate according to the procedure reported for the synthesis of intermediate 1105.

Intermediate 1136

4-[2-(4-Bromo-2-fluorophenyl)-5-[(li?)- l-methyl- 1,2,3, 4-tetrahydroisoquinoline-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl]benzonitrile

Intermediate 1136 (620 mg, 61%) was synthesized from intermediate 1135 and (li?)-l- methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure reported for the synthesis of intermediate 1106.

Intermediate 1137

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

1136 Intermediate 1137 (380 mg, 56%) was synthesized from intermediate 1136 and (5)-methyl pyrrolidine-3 -carboxylate hydrochloride [1099646-61-3] according to the procedure reported for the synthesis of intermediate 1107.

Intermediate 1138

(3 S)- 1 - {4-[7-(4-Cyanophcnyl)-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2- carbonyljpyrazolo [ 1 ,5 -a]pyrimidin-2-yl] -3 -fluorophenyl} pyrrolidine-3 -carboxylic acid

Intermediate 1138 was synthesized from intermediate 1137 according to the procedure reported for the synthesis of intermediate 1107. The crude mixture was purified by flash chromatography on silica gel (15-40 pm, Grace ® 12 g, mobile phase gradient: DCM / MeOH from 100:0 to 96:4). The pure fractions were collected and evaporated to dryness to afford intermediate 1138 (265 mg, 71%).

Compound 62

(3 S)- 1 - {4-[7-(4-Cyanophcnyl)-5-[( 1 R)- 1 -methyl- 1 , 2,3, 4-tetrahydroisoquino line-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl]-3-fluorophenyl}pyrrolidine-3-carboxamid e

Compound 62 was synthesized from intermediate 1133 according to the procedure reported for the synthesis of compound 56. The residue (125 mg) was taken up in DIPE and DCM (3 drops). The solid was filtered off and dried under vacuum to give compound 62 (45 mg,

20%).

Compound 63

Intermediate 1139

Ethyl 2-(4-bromo-2-fluorophenyl)-7-(pyridin-4-yl)pyrazolo[l,5-a]py rimidine-5- carboxylate

Intermediate 1139 was synthesized from intermediate 1103 and 4-pyridineboronic acid pinacol ester [181219-01-2] according to the procedure reported for the synthesis of intermediate 1104. The crude mixture was purified by flash chromatography over silica gel (15-40 pm, 40 g GraceResolv , mobile phase gradient: heptane / EtOAc from 90:10 to 50:50) to afford intermediate 1139 (350 mg, 21%).

Intermediate 1140

Lithio 2-(4-bromo-2-fluorophenyl)-7-(pyridin-4-yl)pyrazolo[l,5-a]py rimidine-5- carboxylate

Intermediate 1140 (410 mg) was synthesized from intermediate 1139 and lithium hydroxide monohydrate according to the procedure reported for the synthesis of intermediate 1105.

Intermediate 1141

(l7?)-2-[2-(4-Bromo-2-fluorophenyl)-7-(pyridin-4-yl)pyrazolo [l,5-a]pyrimidine-5- carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline

Intermediate 1141 (345 mg, 67%) was synthesized from intermediate 1140 and (li?)-l- methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure reported for the synthesis of intermediate 1106 with a reaction time of 48 h.

Intermediate 1142

Methyl (3 S)- 1 -(3-fluoro-4- (5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- 7-(pyridin-4-yl)pyrazolo[ 1 ,5-a]pyrimidin-2-yl}phenyl)pyrrolidine-3-carboxylate

Intermediate 1142 was synthesized from intermediate 1141 and (5)-methyl pyrrolidine-3- carboxylate hydrochloride [1099646-61-3] according to the procedure reported for the synthesis of intermediate 1107 with a reaction time of 5 h. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g Grace ® , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 95:5) to afford intermediate 1142 (220 mg, 59%).

Intermediate 1143

(3 S)- 1 -(3-Fluoro-4- (5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7- (pyridin-4-yl)pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} phenyl)pyrrolidine-3 -carboxylic acid

Intermediate 1143 was synthesized from intermediate 1142 according to the procedure reported for the synthesis of intermediate 1107. The crude mixture was purified by flash chromatography on silica gel (15-40 pm, 12 g Grace ® , mobile phase gradient: DCM /

MeOH from 100:0 to 96:4). The pure fractions were collected and evaporated to dryness. The residue (125 mg) was taken up in DIPE. The solid was filtered off and dried under vacuum to afford intermediate 1143 (39 mg, 18%). Compound 63

(3 S)- 1 -(3-Fluoro-4- (5-[(li?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7- (pyridin-4-yl)pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} phenyl)pyrrolidine-3 -carboxamide

Compound 63 was synthesized from intermediate 1143 according to the procedure reported for the synthesis of compound 56. The residue (53 mg) was taken up in DIPE. The solid was filtered off and dried under vacuum to give compound 63 (23 mg, 27%). Compound 64

Intermediate 1144

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

Intermediate 1144 (3.4g) was synthesized from intermediate 1103 and 5-pyrimidineboronic acid pinacol ester [321724-19-0] according to the procedure reported for the synthesis of intermediate 1119 with a shorter reaction time of 3 h.

Intermediate 1145

Lithio 2-(4-bromo-2-fluorophenyl)-7-(pyrimidin-5 -yl)pyrazo lo [ 1 ,5 -a]pyrimidine-5 - carboxylate

Intermediate 1145 (3.0 g, 99%) was synthesized from intermediate 1144 and lithium hydroxide according to the procedure reported for the synthesis of intermediate 1105.

Intermediate 1146

( \R)-2- [2-(4-Bromo-2-fluorophenyl)-7-(pyrimidin-5 -yl)pyrazo lo [ 1 ,5 -a]pyrimidine-5 - carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline

Intermediate 1146 (1.32 g, 34%) was synthesized from intermediate 1145 and (li?)-l- methyl-l,2,3,4-tetrahydroisoquinoline hydrochloride [84010-67-3] according to the procedure reported for the synthesis of intermediate 1106.

Intermediate 1147

Methyl (3 S)- 1 -(3-fluoro-4- (5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- 7-(pyrimidin-5 -yl)pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl}phenyl)pyrro lidine-3 -carboxylate

Intermediate 1147 was synthesized from intermediate 1146 and (5)-methyl pyrrolidine-3- carboxylate hydrochloride [1099646-61-3] according to the procedure reported for the synthesis of intermediate 1107. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 40 g Grace ® , liquid injection (DCM), mobile phase gradient: DCM / MeOH from 100:0 to 96:4) to afford intermediate 1147 (180 mg, 25%).

Intermediate 1148

(3 S)- 1 -(3-Fluoro-4- (5-[(l7?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7- (pyrimidin-5-yl)pyrazolo[ 1 ,5-a]pyrimidin-2-yl}phenyl)pyrrolidine-3-carboxylic acid

Intermediate 1148 was synthesized from intermediate 1147 according to the procedure reported for the synthesis of intermediate 1107. The crude mixture was purified by flash chromatography on silica gel (15-40 pm, 24 g Grace ® , mobile phase gradient: DCM / MeOH from 100:0 to 96:4). The pure fractions were collected and evaporated to dryness to afford intermediate 1148 (130 mg, 74%).

Compound 64

(3 S)- 1 -(3-Fluoro-4- (5-[(17?)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]-7- (pyrimidin-5-yl)pyrazolo[l,5-a]pyrimidin-2-yl}phenyl)pyrroli dine-3-carboxamide

Compound 64 was synthesized from intermediate 1148 according to the procedure reported for the synthesis of compound 56. The residue (75 mg) was taken up in DIPE. The solid was filtered off and dried under vacuum to give compound 64 (40 mg, 42%).

Compound 90

Intermediate 1195

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

1103 THF 1195

70 °C, 16 h

Intermediate 1195 was synthesized from intermediate 1103 and 3-fluoro-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine [719268-92-5] according to the procedure reported for the synthesis of intermediate 1104 with a reaction time of 16 h. The reaction mixture was filtered over a pad of Celite ® and washed with H 2 0 and EtO Ac. The filtrate was decanted and the organic layer was washed with EEO (twice), dried over MgS0 4 , filtered and evaporated to dryness. The crude mixture was purified by flash

chromatography (irregular SiOH, 15-40 pm, 25 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90: 10 to 0: 100) to afford intermediate 1195 (246 mg, 43%) as a yellow solid.

Intermediate 1196

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

Lithium hydroxide monohydrate (86.5 mg, 2.06 mmol) was added to a solution of intermediate 1195 (246 mg, 412 qmol) in THF (10 mL) and H 2 0 (4 mL). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHS0 4 was added until pH 3 and the mixture was diluted with EtOAc. The suspension was filtered off to afford intermediate 1196 (122 mg, 60%, 87% purity).

Intermediate 1197

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

Intermediate 1197 (100 mg, 72%) was synthesized from intermediate 1196 and (li?)-l- methyl-l,2,3,4-tetrahydroisoquinoline [84010-66-2] according to the procedure reported for the synthesis of intermediate 1106 with a reaction time of 16 h. Intermediate 1198

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

Intermediate 1198 was synthesized from intermediate 1197 and (5)-methyl pyrrolidine-3- carboxylate hydrochloride [1099646-61-3] according to the procedure reported for the synthesis of intermediate 1107. The reaction mixture was filtered over a pad of Celite ® and washed with EtOAc and H 2 0. The filtrate was decanted and the organic phase was washed with H 2 0 (twice), dried over MgS0 4 , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g

GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90:10 to 60:40) to afford intermediate 1198 (81 mg, 75%) as a yellow solid.

Intermediate 1199

(3 A)- 1 - {3-Fluoro-4-[7-(5-fluoropyridin-3-yl)-5-[( 1 /?)- 1 -methyl- 1 ,2,3,4- tetrahydroisoquinoline-2-carbonyl]pyrazolo[l,5-a]pyrimidin-2 -yl]phenyl}pyrrolidine-3- carboxylic acid

Lithium hydroxide monohydrate (17.2 mg, 0.41 mmol) was added to a solution of intermediate 1198 (81.0 mg, 133 pmol) in THF (1.2 mL) and H 2 0 (0.4 mL). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHS0 4 was added until pH 3 and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and concentrated to dryness to afford intermediate 1199 (68 mg, 86%) as an orange solid.

Compound 90

(35 * )- 1 - j 3-Fluoro-4-[7-(5-fluoropyridin-3-yl)-5-[( 1 /?)- 1 -methyl- 1 ,2,3,4-tctrahydro- isoquino line-2-carbonyl]pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl]phenyl} pyrrolidine-3 -carboxamide

In a screw cap vial a mixture of intermediate 1199 (68.0 mg, 114 LUTIO I), HATU (65.0 mg, 171 LUTIO I) and DIPEA (59 pL, 343 pmol) in DMF (1.1 mL) was stirred at rt for 30 min. Ammonia (30% in H 2 0, 216 uL, 3.43 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc and H 2 0. Additional amount of HATU (21 mg, 55 pmol), DIPEA (20 uL, 114 pmol) and ammonia (30% in H2O, 100 uL, 1.58 mmol) were added. The reaction mixture was stirred at rt for 20 h. The layers were separated and the organic phase was washed with H2O and brine (3 times), dried over MgS0 4 , filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 50:50 to 0: 100). The residue (25 mg) was dried under high vacuum at 60°C for 16 h to give compound 90 (18 mg, 27%) as an orange solid.

General scheme

Compound 65

Intermediate 1149

Methyl 2-[ 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)azetidin-3-yl]acetate

A mixture of (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[l, 5- a]pyrimidine-5 -carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421-61-3] (250 mg, 495 Luriol), methyl-3 -azetidineacetate trifluoroacetate salt [1313738-62-3] (144 mg, 594 luriol) and cesium carbonate (645 mg, 1.98 mmol) in l,4-dioxane (5.9 mL) was degassed with nitrogen. Palladium acetate (11.1 mg, 49.5 inriol) and XantPhos (28.6 mg, 49.5 luriol) were added and the mixture was purged again with nitrogen. The reaction mixture was stirred at l00°C for 18 h. The reaction mixture was combined with another fraction (50 mg, 98.9 LUTIO I) and diluted with EtOAc and H 2 0. The mixture was filtered over a pad of Celite ® and the filtrate was decanted. The organic phase was washed with brine, dried over MgS0 4 , filtered and concentrated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90:10 to 20:80) to afford intermediate 1149 (178 mg, 54%) as a yellow foam.

Intermediate 1150

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

Lithium hydroxide (23.1 mg, 965 pmol) was added to a solution of intermediate 1149 (178 mg, 322 pmol) in THF (3.6 mL) and H 2 0 (1.5 mL). The reaction mixture was stirred at rt for 3 h. A 10% aqueous solution of KHS0 4 was added until pH 3 and the mixture was diluted with EtOAc. The layers were separated and the organic phase was washed with brine and H 2 0 (twice), dried over MgS0 4 , filtered and concentrated to dryness to afford intermediate 1150 (183 mg, 95%, 90% purity) as a yellow solid.

Compound 65

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

HATU (174 mg, 458 pmol) was added to a mixture of intermediate 1150 (183 mg, 305 pmol, 90% purity) and DIPEA (158 pL, 916 pmol) in DMF (3 mL). The mixture was stirred at rt for 10 min and ammonia (30% in H 2 0, 578 pL, 9.16 mmol) was added. The reaction mixture was stirred at rt for 16 h. A saturated aqueous solution of NaHCCh, brine and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine (twice), dried over MgS0 4 , filtered and concentrated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 70:30 to 0:100). EtOAc was added and a precipitate was 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.

Compound 66

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

HATU (154 mg, 406 pmol) was added to a mixture of intermediate 1150 (146 mg, 271 pmol) and DIPEA (140 pL, 812 pmol) in DMF (2.6 mL). The reaction mixture was stirred at rt for 10 min and methylamine (2.0 M in THF, 162 pL, 324 pmol) was added. The reaction mixture was stirred at rt for 2 h. Methylamine (2.0 M in THF, 298 pL, 595 pmol) was added again and the reaction mixture was stirred at rt for 16 h. H 2 0, brine and EtOAc were added. The layers were separated and the organic phase was washed with brine (3 times), dried over MgS0 4 , filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g

GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 70:30 to 0:100). EtOAc was added and the mixture was concentrated under reduced pressure to dryness. The product was dried under 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-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)azetidin-3 -o 1

In a screw cap vial were added (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 -

61-3] (250 mg, 495 pmol) 3-hydroxyazetidine hydrochloride [18621-18-6] (65.0 mg, 594 pmol), cesium carbonate (644 mg, 1.98 mmol) and l,4-dioxane (5.9 mL). The mixture was purged with nitrogen. XantPhos (28.6 mg, 49.5 pmol) and palladium acetate (11.1 mg,

49.5 pmol) were added and the reaction mixture was purged again with nitrogen and stirred at l00°C for 18 h. The reaction mixture was filtered over a pad of Celite ® and washed with EtOAc and H 2 0. The filtrate was decanted and the organic phase was washed with H 2 0 (twice), dried over MgS0 4 , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g

GraceResolv , dry loading (SiOH), mobile phase gradient: heptane / EtOAc from 90:10 to 60:40). A second purification by flash chromatography was performed (irregular SiOH,

15-40 pm, 12 g GraceResolv , dry loading (SiOH), mobile phase gradient: heptane / EtOAc from 90:10 to 60:40). The solid (103 mg) was purified by reverse phase (spherical Cl 8, 25 pm, 40 g YMC-ODS-25, dry loading (Celite ® ), mobile phase gradient: (0.2% aq.NH 4 HC0 3 ) / MeOH from 50:50 to 0:100). The fractions containing the product were collected, concentrated to dryness and co-evaporated with MeOH (twice). The product was dried under high vacuum at 60°C for 20 h to give compound 67 (80 mg, 33%) as a yellow solid.

Compound 91

Intermediate 1200

Methyl 1 -(4- (7-cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydroisoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)azetidine-3-carboxylate

A mixture of (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[l, 5- a]pyrimidine-5 -carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421-61-3] (250 mg, 495 pmol), methyl azetidine-3-carboxylate hydrochloride [100202-39-9] (112 mg, 742 pmol) and cesium carbonate (645 mg, 1.98 mmol) in l,4-dioxane (9 mL) was degassed with nitrogen. Tris(dibenzylideneacetone)dipalladium (18.1 mg, 19.8 pmol) and XPhos (21.2 mg, 44.5 pmol) were added and the mixture was purged with nitrogen. The reaction mixture was stirred at l00°C for 18 h. The reaction mixture was filtered over a pad of Celite ® and washed with H 2 0 and EtOAc. The filtrate was decanted and the organic phase was washed with brine (twice), dried over MgS0 4 , filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g GraceResolv , dry loading (SiOH), mobile phase gradient: heptane / EtOAc from 80:20 to 20:80) to afford intermediate 1200 (249 mg, 93%) as a yellow foam. Intermediate 1201

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)azetidine-3-carboxylic acid

Lithium hydroxide monohydrate (38.7 mg, 923 pmol) was added to a solution of intermediate 1200 (249 mg, 461 pmol) in THF (3.5 mL) and EEO (1.5 mL). The reaction mixture was stirred at rt for 2 h. A 10% aqueous solution of KHS0 4 was added until pH 3 and the mixture was diluted with EtOAc. The layers were separated and the organic phase was washed with brine and water (twice), dried over MgS0 4 , filtered and concentrated to dryness to afford intermediate 1201 (245 mg, 89%) as a yellow solid.

Compound 91

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)azetidine-3-carboxamide

At 0°C PPACA (50 wt. % in EtOAc, 617 pL, 1.04 mmol) was added dropwise to a mixture of intermediate 1201 (218 mg, 415 pmol), DIPEA (357 pL, 2.07 mmol) and ammonia (28% in EEO, 841 pL, 12.4 mmol) in DMF (4 mL). The reaction mixture was stirred at rt for 16 h. The layers were separated and the organic phase was washed with 1M aqueous solution of NaOH and brine (3 times), dried over MgS0 4 , filtered and concentrated in vacuo. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 50:50 to 0: 100). The residue (63 mg) was dried under high vacuum at 60°C for 16 h to give compound 91 (58 mg, 27%) as a yellow solid. General scheme

Intermediate 1203

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

Methyl 3-azetidine acetate trifluoroacetate salt [1313738-62-3] (275 mg, 1.13 mmol) and potassium carbonate (426 mg, 3.08 mmol) were added to a solution of 2,6-difluoropyridine [1513-65-1] (93.2 pL, 1.03 mmol) in MeCN (7 mL). The reaction mixture was stirred at 80°C for 18 h. The reaction mixture was filtered over a pad of Celite ® and the filtrate was concentrated to dryness. The crude mixture was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 100:0 to 50:50) to afford intermediate 1203 (195 mg, 85%) as a colorless oil.

Intermediate 1204

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

A mixture of intermediate 1203 (195 mg, 0.87 mmol) and NBS (186 mg, 1.05 mmol) in MeCN (9 mL) was stirred at rt for 18 h. The reaction mixture was concentrated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g GraceResolv , dry loading (SiOH), mobile phase gradient: heptane / EtOAc from 90: 10 to 60:40) to afford intermediate 1204 (147 mg, 56%) as a white solid.

Intermediate 1205

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

1205 Lithium hydroxide monohydrate (61 mg, 1.45 mmol) was added to a solution of intermediate 1204 (147 mg, 485 pmol) in THF (4 mL) and H 2 0 (1.3 mL). The reaction mixture was stirred at rt for 16 h. A 10% aqueous solution of KHS0 4 was added until pH 6 and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with H 2 0, dried over MgS0 4 , filtered and concentrated in vacuo to afford intermediate 1205 (135 mg, 96%) as a white solid.

Intermediate 1202

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

A mixture of intermediate 1205 (135 mg, 467 pmol), HATU (266 mg, 700 pmol) and DIPEA (241 pL, 1.40 mmol) in DMF (2.3 mL) was stirred at rt for 30 min. Ammonia (30% in H 2 0, 884 pL, 14.0 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc and H 2 0. The layers were separated and the organic phase was washed with water and brine (3 times), dried over MgS0 4 , filtered and concentrated. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g GraceResolv , dry loading (SiOH), mobile phase gradient: heptane / EtOAc from 50:50 to 0:100) to afford intermediate 1202 (94 mg, 70%) as a white solid.

Synthesis of compound 92

2-[ 1 -(5- {7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-6-fluoropyridin-2-yl)azetidin -3-yl]acetamide

A sealed tube was charged with (li?)-2-[7-cyclopropyl-2-(tetramethyl-l,3,2-dioxaborolan- 2-yl)pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421-36-2] (150 mg, 203 mihoΐ, 62 % purity), intermediate 1202 (64 mg, 223 pmol), potassium phosphate tribasic (129 mg, 609 pmol), l,4-dioxane (2.5 mL) and H 2 0 (0.6 mL) and purged with nitrogen. [1 , 1’-Bis(di-/er/-butylphosphino)fcrroccnc] dichloropalladium (13.2 mg, 20.3 pmol) was added and the mixture was purged again with nitrogen. The reaction mixture was heated at 80°C using a single mode microwave (Biotage ® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. The reaction mixture was diluted with EtOAc and EEO. The layers were separated and the organic phase was washed with brine (twice), dried over MgS0 4 , filtered and concentrated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 25 g GraceResolv , liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 50:50 to 0:100). The residue was taken up in EtOAc, sonicated and concentrated to dryness. The solid was dried under high vacuum at 60°C for 16 h to give compound 92 (47 mg, 43%) as a yellow solid.

General scheme

Compound 68

Intermediate 1151

Ethyl 1 -(4- (7-cyc lopropyl-5-[( 1 R)- 1 -methyl- 1,2,3 ,4-tetrahydroisoquino line-2-carbonyl] - pyrazolo[l,5-a]pyrimidin-2-yl}-3-fluorophenyl)piperidine-4-c arboxylate

A mixture of (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[l, 5-a]- pyrimidine-5-carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquinoli ne [2035421-61-3] (200 mg, 0.40 mmol), ethyl piperidine-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 pmol) was purged with nitrogen. 1 ,4-Dioxane (5 mL) was added and the mixture was purged again with nitrogen. Palladium acetate (10.6 mg, 47.5 pmol) was added. The reaction mixture was purged with nitrogen and stirred at l00°C for 7 h. The reaction mixture was diluted with EtOAc and H 2 0. The layers were separated and the aqueous phase was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and the solvent was removed under reduced pressure. The crude mixture was purified by flash chromatography over silica gel (Interchim ® 40 g, 30 mM, liquid injection (DCM), mobile phase gradient: heptane / EtOAc from 90:10 to 60:40) to afford intermediate 1151 (180 mg, 78%) as a yellow solid.

Intermediate 1152

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

A mixture of intermediate 1151 (l7lmg, 0.29 mmol) and lithium hydroxide monohydrate (86.4 mg, 2.06 mmol) in THF (5 mL) and H 2 0 (1.5 mL) was stirred at rt for 15 h. An aqueous solution of citric acid (7 equiv. in 10 ml) was added and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS0 4 , filtered and evaporated to dryness to afford intermediate 1152 (160 mg, 98%) as a beige solid.

Compound 68

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

To a solution of intermediate 1152 (0.16 g, 0.29 mmol) in DMF (4 mL) were added DIPEA (0.15 mL, 0.87 mmol) and HATU (0.17 g, 0.43 mmol). The mixture was stirred at rt for 15 min. Ammonia (30% in LEO, 33 iiL, 1.73 mmol) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with LEO and EtOAc. The layers were separated and the organic phase was washed with EEO (3 times) and brine, dried over MgS0 4 , filtered and evaporated to dryness. The crude mixture was purified by flash chromatography over silica gel (Interchim ® 12 g, 30 mM, liquid injection (DCM), mobile phase gradient: DCM / MeOH, from 100:0 to 97:3) to give compound 68 (75 mg, 47%) as a yellow solid.

Compound 69

Intermediate 1153

Methyl 1 -(4- (7-cyc lopropyl-5-[( 1 /?)- 1 -methyl- 1 , 2,3, 4-tctrahydroisoqui noli nc-2- carbonyl]pyrazolo[ 1 ,5-a]pyrimidin-2-yl} -3-fluorophenyl)piperidine-3-carboxylate

Intermediate 1153 was synthesized from (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7- cyclopropylpyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl] - 1 -methyl- 1 ,2,3 ,4-tetrahydro- isoquinoline [2035421-61-3] and methyl piperidine-3 -carboxylate [50585-89-2] according to the procedure reported for the synthesis of intermediate 1151. Intermediate 1153 (0.18 g, 65%) was obtained as a yellow solid.

Intermediate 1154

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

Intermediate 1154 was synthesized from intermediate 1153 according to the procedure reported for the synthesis of intermediate 1152. The reaction mixture was stirred under reflux for 5 h. Intermediate 1154 (0.17 g, 98%) was obtained as a yellow solid.

Compound 69

1 -(4- [7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)piperidine-3 -carboxamide

Compound 69 was synthesized from intermediate 1154 according to the procedure reported for the synthesis of compound 68. Compound 69 (80 mg, 49%) was obtained as a yellow solid. Compound 70

Intermediate 1155

Methyl 2-[ 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)piperidin-4-yl]acetate

Intermediate 1155 was synthesized from (li?)-2-[2-(4-bromo-2-fluorophenyl)-7- cyclopropylpyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl] - 1 -methyl- 1 ,2,3 ,4-tetrahydro- isoquinoline [2035421-61-3] and methyl 2-(piperidine-4-yl)acetate hydrochloride [81270- 37-3] according to the procedure reported for the synthesis of intermediate 1151.

Intermediate 1155 (023 g, 65%) was obtained as a yellow solid.

Intermediate 1156

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

Intermediate 1156 was synthesized from intermediate 1155 according to the procedure reported for the synthesis of intermediate 1152. The reaction mixture was stirred under reflux for 5 h. Intermediate 1156 (0.21 g, quant.) was obtained as a yellow solid.

Compound 70

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

Compound 70 was synthesized from intermediate 1156 according to the procedure reported for the synthesis of compound 68. Compound 70 (85 mg, 40%) was obtained as a beige solid.

Compound 71

Intermediate 1157

Methyl 2-[ 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)piperidin-3-yl]acetate

Intermediate 1157 was synthesized from (li?)-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 reported for the synthesis of intermediate 1151. Intermediate 1157 (0.23 g, 67%) was obtained as a yellow solid.

Intermediate 1158

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

Intermediate 1158 was synthesized from intermediate 1157 according to the procedure reported for the synthesis of intermediate 1152. The reaction mixture was stirred under reflux for 5 h. Intermediate 1158 (214 mg, quant.) was obtained as a yellow solid.

Compound 71

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

Compound 71 was synthesized from intermediate 1158 according to the procedure reported for the synthesis of compound 68. Compound 71 (90 mg, 42%) was obtained as a yellow solid.

Compound 72

1 -(4- {7-Cyclopropyl-5-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazolo[l,5-a]pyrimidin-2-yl}-3-fluorophenyl)-/V-methylpipe ridine-4-carboxamide

To a solution of intermediate 1152 (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 for 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 for 2 h. The reaction mixture was diluted with H 2 0 and EtOAc. The layers were separated and the organic phase was washed with H 2 0 (3 times), brine, dried over MgS0 4 , filtered and evaporated to dryness to give compound 72 (110 mg, 52%) as a beige solid. Compound 73

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

Compound 73 was synthesized from intermediate 1154 according to the procedure reported for the synthesis of compound 72. The product was purified by flash chromatography over silica gel (30 pm, 12 g Interchim ® , liquid injection (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-[( 1 R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)piperidin-4-o 1

In a screw cap vial were added (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (200 mg, 396 pmol), 4-hydroxypiperidine [5382-16-1] (40.0 mg, 396 pmol), sodium fc/ -butoxidc (76.1 mg, 0.79 mmol) and toluene (3.3 mL). The mixture was purged with nitrogen. Palladium acetate (4.44 mg, 19.8 pmol) and (±)-BINAP (12.3 mg, 19.8 pmol) were added and the reaction mixture was purged again with nitrogen. The reaction mixture was stirred at l00°C for 18 h. The reaction mixture was diluted with EtOAc and H 2 0 and filtered over a pad of Celite ® . The filtrate was decanted and the organic phase was washed with H 2 0 (twice), dried over MgS0 4 , filtered and concentrated to dryness. The crude mixture was purified by flash chromatography (irregular SiOH, 15-40 pm, 12 g

GraceResolv , dry loading (SiOH), mobile phase gradient: heptane / EtOAc from 50:50 to 0: 100). The solid was dried under 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-[( I R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl]- pyrazo lo [ 1 ,5 -a]pyrimidin-2-yl} -3 -fluorophenyl)piperidin-3 -o 1

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

Synthesis of compound 93:

Intermediate Jl:

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

In a Schlenk tube, a mixture of (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (300 mg; 0.572 mmol), 6S -3-(BOC-amino)pyrrolidinc (214 mg; 1.15 mmol) and CS2CO3 ( 657 mg; 2.015 mmol) in toluene (12 mL) was degassed with N 2 . BINAP (36 mg; 0.058 mmol) and Pd 2 dba3 (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 h. Brine and EtOAc were added to the reaction mixture, the aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over MgS0 4 and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 pm, 40 g GraceResolv®, mobile phase gradient: from DCM/EtOAc: 100/0 to 70/30) to give Intermediate Jl as a yellow solid (0.315 g, 90%).

Compound 93:

(2-(4-((S)-3-aminopyrrolidin-l-yl)-2-fluorophenyl)-7-cyclopr opylpyrazolo[l,5- a]pyrimidin-5 -yl)((R)- 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone

TFA (1.2 mL; 15 mmol) was added to a solution of intermediate J1 (315 mg; 0.516 mmol) in DCM (6.2 mL). The reaction mixture was stirred at rt for 1 h. DCM and an aqueous solution of NaHCCL (sat) were added. The layers were separated, and the organic layer was dried over MgS0 4 , filtered and the solvent was removed in vacuo to give 226 mg of a yellow foam which was triturated in MTBE then filtered over frit and dried under high vacuum at 50 °C overnight to give compound 93 as a yellow solid (120 mg, 46%).

Compound 94:

(7-cyclopropyl-2-(2-fluoro-4-((S)-3-((2,2,2-trifluoroethyl)a mino)pyrrolidin-l- yl)phenyl)pyrazo lo [ 1 ,5 -a]pyrimidin-5 -yl)((R)- 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)- yl)methanone

In a Schenlk tube, a mixture of (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-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 CS2CO3 (396 mg; 1.22 mmol) in dioxane (5 mL) was degassed with N 2 . Pd(OAc) 2 (5 mg; 24 gmol) 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 h. Brine and EtOAc were added to the reaction mixture, the aqueous layer was extracted with EtOAc (twice). The combined organic layers were dried over MgS0 4 and evaporated in vacuo. The residue was purified by preparative LC

(irregular SiOH, 15-40 pm, 12 g GraceResolv®, mobile phase gradient: from

heptane/EtOAc 90/10 to 60/40) the pure fraction was collected and evaporated to dryness. The residue was purified by Reverse phase (Stationary phase: YMC-actus Triart® C18 10pm 30* 150mm, Mobile phase: Gradient from 35% aq. NH 4 HC0 3 0.2%, 65% MeCN to 0% aq. NH 4 HC0 3 0.2%, 100% MeCN) to give a yellow oil which was taken up in MTBE (~2 mL). Heptane was added until 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%). Compound 95:

(7-cyclopropyl-2-(4-((3R,4S)-3,4-dihydroxypyrrolidin-l-yl)-2 -fluorophenyl)pyrazolo[l,5- a]pyrimidin-5 -yl)((R)- 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone

In a sealed tube, a mixture of (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (250 mg, 0.475 mmol), NaCfBu (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) was degassed with N 2 for 10 min. DavePhos (19 mg, 0.048 mmol) and Pd 2 dba3 (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 (Biotage Initiator® EXP 60) with a power output ranging from 0 to 400 W for 1 h. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (twice), the combined organic layers were dried over MgS0 4 , filtered and concentrated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 pm, 24 g GraceResolv®, mobile phase gradient: from DCM/Isopropanol 99/1 to 88/12)

The fractions containing product were collected and evaporated to dryness. The residue was purified by preparative LC (spherical Cl 8 25 pm, 40 g YMC-ODS-25, dry loading (celite®), mobile phase gradient 0.2% aq. NH4HCO3 / MeCN from 65:35 to 25:75). The 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 with MTBE and stirred at 50 °C for 24 h. The suspension was cooled down to rt, filtered over glass frit and washed with MTBE (2 x 2 mL). The solid was dried under vacuum to give compound 95 as a yellow solid (60 mg, 24%).

Compound 96:

(7-cyclopropyl-2-(2-fluoro-4-((trans)-3 -hydroxy-4 -methoxypyrro lidin- 1 - yl)phenyl)pyrazo lo [ 1 ,5 -a]pyrimidin-5 -yl)((R)- 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)- yl)methanone

A mixture of (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl-pyrazolo[l ,5- a]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 CS2CO3 (371 mg, 1.14 mmol) was charged in a sealed tube 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 h. Water and EtOAc were added to the reaction mixture. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgS0 4 and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 pm, 24 g GraceResolv®, mobile phase gradient: from heptane 75%, EtOAc 25% to Heptane 0%, EtOAc 100%) to give 250 mg of a white gum. The product was purified by preparative LC (spherical Cl 8 25 pm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH4HCO3 / MeCN from 60:40 to 10:90). The fractions containing product were evaporated under vacuum and the residue was taken-up in Et 2 0 and evaporated under vacuum three times and the sample was dried under vacuum to give compound 96 as a yellow solid (110 mg, 53%).

Synthesis of Compound 97:

4,4-difluoro-3 S-hydroxypyrrolidine hydrochloride

4,4-difluoro-3S-hydroxypyrrolidine hydrochloride was synthetized with the same procedure as the 3R enantiomer described in J. Org. Chem. 2016, 81, 4359-4363. Compound 97:

(7-cyclopropyl-2-(4-((S)-3,3-difluoro-4-hydroxypyrrolidin-l- yl)-2- fluorophenyl)pyrazo lo [ 1 ,5 -a]pyrimidin-5 -yl)((R)- 1 -methyl-3 ,4-dihydro isoquino lin-2( 1 H)- yl)methanone

A mixture of (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl-pyrazolo[l ,5- a]pyrimidine-5 -carbonyl] - 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquino line [2035421-61-3] (149 mg, 0.295 mmol) 4,4-difluoro-3S-hydroxypyrrolidine hydrochloride (47 mg, 0.295 mmol) and CS2CO3 (480 mg, 1.47 mmol) was charged in a sealed tube and 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 h. The reaction mixture was poured out into water and extracted with EtOAc. The organic layer was washed with brine, dried (MgS0 4 ) and evaporated till dryness. The residue was purified by preparative LC (irregular SiOH, 15-40 pm, GraceResolv® 24 g, mobile phase gradient: from heptane/EtOAc 80/20 to 0/100). The fractions containing product were evaporated under vacuum. The residue was taken up with Et 2 0 and evaporated to dryness (3 times) to give a yellow solid which was taken-up with Et 2 0 and the suspension was filtered and dried under high vacuum to give compound 97 as 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- [l,3]dioxolo[4,5-c]pyrrol-5-yl)-2-fluorophenyl)-7-cyclopropy lpyrazolo[l,5-a]pyrimidin-5- yl)((R)- 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone

A mixture of (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl-pyrazolo[l ,5- a]pyrimidine-5 -carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421-61-3] (200 mg, 0.396 mmol), [153172-31-7] (0.171 g, 0.594 mmol) and CS2CO3 (387 mg, 1.19 mmol) was charged in a sealed tube and 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 N 2 then was stirred and heated at 100 °C for 18 h. The reaction mixture was poured out into water and extracted with EtOAc. The organic layer was washed with brine, dried (MgS0 4 ), filtered and evaporated till dryness. The residue was purified by preparative LC (irregular SiOH, 15-40 pm, GraceResolv® 24 g, mobile phase gradient: from heptane/EtOAc 99/1 to 30/70). The fractions containing product were evaporated under vacuum to give intermediate J2 (230 mg, 70% purity, 57%)

Intermediate J3:

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

TBAF 1M in THF (238 m L , 0.238 mmol) was added dropwise to a stirred solution of intermediate J2 (230 mg, 0.226 mmol, 70% purity) in THF (4.2 mL) at rt. 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 MgS0 4 , filtered and concentrated in vacuo. The residue was purified by preparative LC (irregular SiOH 15-40 pm, 12 g GraceResolv®, dry loading (celite®), mobile phase gradient: from Heptane/EtOAc 80/20 to 20/80) to give intermediate J3 as a white solid. (135 mg, quant).

Compound 98:

(7-cyclopropyl-2-(4-((2R,3R,4S)-3,4-dihydroxy-2-(hydroxymeth yl)pyrrolidin-l-yl)-2- fluorophenyl)pyrazo lo [ 1 ,5 -a]pyrimidin-5 -yl)((R)- 1 -methyl-3 ,4-dihydro isoquino lin-2( 1 H)- 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 0 (0.8 mL) was stirred at rt for 18 h, then at 50 °C for 18 h. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (twice), the combined organic layers were dried over MgS0 4 , filtered, concentrated in vacuo and coevaporated (3 times) with EtOAc. The residue was purified by preparative LC (irregular SiOH 15-40 pm, 24 g GraceResolv®, mobile phase gradient: from DCM/ PrOH 99/1 to 84/16). The fraction containing product was evaporated and the residue was taken-up in MeCN and evaporated under vacuum three times. Then it was taken-up in MeCN, the suspension was filtered and dried under high vacuum to give compound 98 as yellow solid (54 mg, 43%). Compound 99:

(7-cyclopropyl-2-(2-fluoro-4-((trans)-3 -hydroxy-4 -methylpyrro lidin- 1 - yl)phenyl)pyrazo lo [ 1 ,5 -a]pyrimidin-5 -yl)((R)- 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)- yl)methanone

A mixture of (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl-pyrazolo[l ,5- a]pyrimidine-5 -carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421-61-3] (300 mg; 0.594 mmol), 7> < v-4-Mcthy 1 pyrrol idin-3-ol hydrochloride (82 mg; 0.594 mmol) and K2CO3 (287 mg; 2.08 mmol) was charged in a sealed tube and purged with N 2 . THF (4 mL) was added and the mixture was degassed with N 2 , then DavePhos (23 mg; 59.4 gmol) and Pd 2 (dba)3 (54 mg; 59.4 pmol) were added. The reaction mixture was purged with N 2 then was stirred and heated at 90 °C for 18 h. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (twice), the combined organic layers were dried over MgS0 4 , filtered, concentrated in vacuo and purified by preparative LC (irregular SiOH 15- 40 pm, 24 g GraceResolv®, mobile phase gradient: from DCM / MeOH 100:0 to 90: 10) The fraction containing product was collected and evaporated to dryness. The residue was purified by preparative LC (spherical C18 25 pm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH4HCO3 / MeCN from 50:50 to 0: 100) The fractions containing product were extracted with EtOAc. The organic layer was dried (MgS0 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 yellow solid (105 mg, 34%).

Compound 100:

(7-cyclopropyl-2-(4-((3R,4R)-3,4-dihydroxypyrrolidin-l-yl)-2 -fluorophenyl)pyrazolo[l,5- a]pyrimidin-5 -yl)((R)- 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone

In a sealed tube, a mixture of (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (300 mg; 0.59 mmol), 37?,47?-Pyrrolidinediol (85.7 mg; 0.83 mmol) and K 2 CO 3 (287 mg; 2.08 mmol) in THF (7 mL) was degassed with N 2 for 10 min. DavePhos (23.4 mg;

59.4 gmol) and Pd 2 (dba)3 (54.4 mg; 59.4 pmol) were added and the reaction mixture was purged with N 2 . The mixture was heated at 80 °C for 20 h. Water and EtOAc were added to the mixture and an extraction was performed. The combined organic layers were washed with brine, dried over MgS0 4 , filtered, evaporated and purified by preparative LC

(irregular SiOH, 15-40 pm, 50 g Merck, mobile phase gradient: from DCM/ PrOH 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 coevaporated in PrOAc (3 times) to give compound 100 as a yellow solid (135 mg, 43%).

Compound 101:

(S)- l-(4-(7-cyclopropyl-5-((R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2- carbonyl)pyrazolo[l,5-a]pyrimidin-2-yl)-3-fluorophenyl)pyrro lidine-3-carbothioamide

A mixture of compound 36 (118 mg; 0.22 mmol), Lawesson reagent (53 mg; 0.13 mmol) and DCM (1 mL) was stirred at rt for 2 h. The mixture was directly purified by flash chromatography (irregular SiOH 15-40 pm, 40 g GraceResolv®, mobile phase gradient, Heptane/EtOAc from 90/10 to 30/70). The fractions containing product were evaporated and coevaporated with EtOH. The solid was dried under vacuum to give compound 101 as a yellow solid (73 mg, 60%). Compound 102:

(7-cyclopropyl-2-(4-((3S,4S)-3,4-dihydroxypyrrolidin-l-yl)-2 -fluorophenyl)pyrazolo[l,5- a]pyrimidin-5 -yl)((R)- 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone

Under N 2 , a mixture of (U?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl-pyrazolo[l, 5- a]pyrimidine-5-carbonyl]-l-methyl-l,2,3,4-tetrahydroisoquino line [2035421-61-3] (6.8 g, 13.5 mmol) 35, 4S-Pyrrolidincdiol (1.9 g, 18.8 mmol) and K2CO3 (6.5 g, 47.1 mmol) in THF (125 mL) was degassed with N 2 for 10 min. DavePhos (530 mg, 1.35 mmol) and Pd 2 dba3 (1.2 g, 1.35 mmol) were added and the reaction mixture was purged with N 2 . The mixture was heated at 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 MgS0 4 , filtered, concentrated in vacuo and purified by preparative LC (irregular SiOH 15- 40 pm, 330 g GraceResolv®, mobile phase gradient: from DCM/MeOH 100/0 to 90/10) The fractions containing product were collected and evaporated to dryness. The residue and SiliaMetS® Thiol (1.2 g; 1.61 mmol) in THF (100 mL) was stirred at rt for 3 h, then filtered over celite® and the filtrate was evaporated to dryness to give 4.8 g of a yellow foam. The solid was suspended in EtOAc (-210 mL in total) and heated at reflux until complete solubilization. Then the heating source was stopped (the flask was kept in the oil bath during the crystallization with a gentle stirring allowing slow cooling) for 42 h. The suspension was cooled down to rt, filtered over glass frit, washed with cold EtOAc. The solid was dried under vacuum to give 2.75 g of a first batch of compound 102 as a yellow solid. The filtrate was evaporated, the residue was suspended in EtOAc (~60 mL in total) and heated at reflux until complete solubilization (oil bath 90 °C). Then the heating source was stopped (the flask was kept in the oil bath during the crystallization with a gentle stirring allowing slow cooling) for 42 h. The suspension was cooled down to rt, filtered over glass frit, washed with cooled EtOAc. The solid was dried under vacuum at 50 °C for 2 h 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 h. The suspension was filtered over glass frit, washed with cold EtOAc. The solid was dried under vacuum to give compound 102 as a yellow solid (3.27 g, 46%). Synthesis of compound 103 and 104:

Intermediate J4:

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

A mixture of (l7?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl-pyrazolo[l ,5- a]pyrimidine-5 -carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421-61-3] (325 mg; 0.644 mmol), CS2CO3 (1.05 g; 3.22 mmol) and 3-mcthylidcncpyrrolidinc * TFA (294 mg; 0.644 mmol) was charged in a sealed tube and purged with N 2 . Dioxane (6 ml) was added and the mixture was degassed with N 2 , then Pd 2 dba3 (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 was stirred and heated at 90 °C for 18 h. Water and EtOAc were added, the layers were separated. The aqueous layer was extracted with EtOAc (twice), the combined organic layers were dried over MgS0 4 , filtered, concentrated in vacuo and purified by preparative LC (irregular SiOH 15-40 pm, 40 g GraceResolv®, mobile phase gradient:

Heptane/EtOAc: from 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)pyrro lidin- 1 - yl)phenyl)pyrazo lo [ 1 ,5 -a]pyrimidin-5 -yl)((R)- 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)- yl)methanone

NMO (141 mg; 1.20 mmol) and Os04 2.5% in ThiOEl (0.263 ml; 0.0201 mmol) were added to a solution of J4 (234 mg; 0.401 mmol) in a mixture of acetone (2 ml) and H 2 0 (0.2 ml). The reaction mixture was stirred at rt for 3.5 h. The reaction mixture was quenched with a 10% aqueous solution of Na 2 S 2 0 3 and the resulting mixture was stirred at rt for 30 min. DCM was added and the layers were separated. The aqueous layer was extracted with DCM/MeOH (90/10) mixture (3 times). The organic layers were combined, washed with water, dried over MgS0 4 , filtered and concentrated. The residue was purified by preparative LC (irregular SiOH, 15-40 pm, 12 g GraceResov®, mobile phase gradient: DCM/MeOH: from 99/1 to 95/5). The fraction containing product was combined and evaporated to dryness. The residue was purified by preparative LC (spherical Cl 8, 25 pm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH 4 HC0 3 / MeCN from 65:35 to 25:75) to give 128 mg of a yellow solid. This solid was purified again by preparative LC (spherical C18, 25 pm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH 4 HC0 3 / MeCN from 65:35 to 25:75) the fractions containing product were extended with water and freeze-dried to give a yellow solid. The solid and SiliaMetS® Thiol (30 mg; 0.0401 mmol) in THE (3 mL) was stirred at rt for 18 h, then filtered over PTLE and the filtrate was evaporated to dryness to give Intermediate J5 as yellow solid (80 mg, 37%). Compound 103 & 104:

J5 was separated via chiral SFC (Stationary phase: CHIRALPAK AS-H 5 pm 250*20mm, Mobile phase: 75% C0 2 , 25% EtOH (0.3% TrNH 2 )) the fractions contained product were evaporated to dryness then diluted with MeCN, extented with water and freeze-dried to give 28 mg of compound 103 having a (-) specific optical rotation as a yellow solid and 28 mg of compound 104 having a (+) specific optical rotation as a yellow solid.

Synthesis of compound 105 :

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 K2CO3 (8.76 g; 63.3 mmol) in DMF (80 mL) was stirred at 60°C for 18 h. EtOAc and water were added, and an extraction was performed. The organic layer was washed with brine, dried (MgS0 4 ), filtered, evaporated and purified by preparative LC (irregular SiOH, 15-40 pm, 220 g GraceResolv®, mobile phase gradient: from heptane/EtOAc 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 , "BuLi 1 6M in hexanes (57 mL; 91.9 mmol) was added to THF (100 mL) at - 78°C then a solution of MeCN (4.78 mL; 91.6 mmol) was added dropwise. The resulting slurry was stirred for 1 h 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 warmed to - 45°C and allowed to stir for 1 h. The reaction was quenched with HC1 1N and then extracted with EtOAc. The organic layer was separated, washed with water then brine, dried (MgS0 4 ), filtered and evaporated to give intermediate J7 as orange oil (14.4 g, Quant.).

Intermediate J8 : 3-(2-(allyloxy)-4-bromo-6-fluorophenyl)-lH-pyrazol-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 yellow solid (14.4 g, 96%).

Intermediate J9 : methyl 2-(2-(allyloxy)-4-bromo-6-fluorophenyl)-7-cyclopropyl- pyrazo lo [ 1 ,5 -a]pyrimidine-5 -carboxylate

A mixture of 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) was stirred at 80 °C for 3 h. The mixture was cooled to rt and a precipitate was formed. The precipitate was filtered and dried on the frit to give intermediate J9 as yellow solid (7.96 g, 38%).

Intermediate J10:

(R)-(2-(2-(allyloxy)-4-bromo-6-fluorophenyl)-7-cyclopropylpy razolo[l,5-a]pyrimidin-5- yl)( 1 -methyl-3 , 4-dihydro isoquinolin-2( 1 H)-yl)methanone

A mixture of J9 (7.96 g; 17.8 mmol), LiOH*H 2 0 (4.12 g; 98.1 mmol), THF (80 mL) and LEO (23 mL) was stirred at rt for 2 days. EtOAc and 10% aq. KHS0 4 were added to the mixture and an extraction was performed. The organic layer was washed with brine, dried (MgS0 4 ) and evaporated to give 6.57 g of acid intermediate as yellow solid. The acid (6.57 g; 15.2 mmol), lR-methyl-l,2,3,4-tetrahydroisoquinoline (2.59 g; 17.6 mmol) and DiPEA (13 mL; 76 mmol) in DCM (77 mL) were 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 for 3 h. Water and EtOAc were added. An extraction was performed. The organic layer was washed with brine, dried (MgS0 4 ) and evaporated to give intermediate J10 as a brown foam (9.0 g, Quant.).

Intermediate Jll:

(R)-(2-(4-bromo-2-fluoro-6-hydroxyphenyl)-7-cyclopropylpyraz olo[l,5-a]pyrimidin-5- yl)( 1 -methyl-3 , 4-dihydro isoquinolin-2( 1 H)-yl)methanone

A mixture of J10 (5 g; 8.91 mmol), Wilkinson 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 pm, GraceResolv® 220 g, dry loading (celite®) mobile phase Heptane/EtOAc from 100:0 to 70:30) to give 2 g of intermediate Jll as brown solid, and 2 impure fractions (3 g and 2.4 g). The first impure fraction (3 g) was purified by Reverse phase LC (Stationary phase: spherical C18 25 pm, 300 g YMC-ODS-25, dry loading (Cl 8), Mobile phase: Gradient: 0.2% aq. NH4HCO3 / MeCN, from 50:50 to 0: 100). The fractions containing the product were combined, MeCN was evaporated in vacuo, water and EtOAc were added and an extraction was performed. The organic layer was washed with water, dried over MgS0 4 , filtered and evaporated to give 700 mg of intermediate Jll as a brown oil. The second impure fraction (2.4 g) was purified by Reverse phase LC (Stationary phase: spherical C18 25 pm, 300 g YMC-ODS- 25, dry loading (Cl 8), Mobile phase: Gradient: 0.2% aq. NH 4 HC0 3 / MeCN, from 50:50 to 0: 100). The fractions containing the product were combined, MeCN was evaporated in vacuo, water and EtOAc were added and an extraction was performed. The organic layer was washed with water, dried over MgS0 4 , filtered and evaporated to give 1 g of intermediate Jll as a brown foam (Global yield 80%, 3.7 g).

Intermediate J12:

(R)-(2-(4-bromo-2-fluoro-6-((2-(trimethylsilyl)ethoxy)methox y)phenyl)-7- cyclopropylpyrazolo[l,5-a]pyrimidin-5-yl)(l-methyl-3,4-dihyd roisoquinolin-2(lH)- yl)methanone

A mixture of Jll (2,7 g; 5.18 mmol) and NaH 60% in mineral oil (31 1 mg; 7.77 mmol) in DMF (20 mL) was stirred at 0 °C for 15 min. SEMC1 (1.83 mL; 10.4 mmol) was added slowly at 0 °C under N 2 . The mixture was stirred at rt for 4 h. An extraction was performed with EtOAc and water. The organic layer was washed with brine, dried (MgS0 4 ), evaporated and purified by preparative LC (irregular SiOH, 15-40 pm, 120 g

GraceResolv®, mobile phase gradient: from heptane/EtOAc 100/0 to 70/30) to give intermediate J12 as a colorless oil (2.3 g, 68%).

Intermediate J13:

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

A sealed tube was charged with J12 (800 mg; 1.23 mmol), (5)-methyl Pyrrolidine-3 - carboxylate hydrochloride (238 mg; 1.44 mmol), CS2CO3 (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 purged again 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 h. The mixture was filtered through a pad of celite ®, water and EtOAc were added and an extraction was performed. The combined organic layers were washed with brine, dried over MgS0 4 , filtered, evaporated and purified by preparative LC (irregular SiOH 15-40 pm, 24 g GraceResolv®, mobile phase gradient: from heptane/EtOAc 100/0 to 50/50) to give intermediate J13 as a yellow foam (578 mg, 67%).

Intermediate J14:

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

A mixture of J13 (2.5 g; 3.57 mmol), AcOH (30 mL), THF (10 mL) and H 2 0 (10 mL) was stirred at rt for 18 h. AqNaHCCh and EtOAc were added and an extraction was performed. The organic layer was washed with brine, dried (MgS0 4 ), filtered, evaporated and purified by preparative LC (irregular SiOH 15-40 pm, 220 g GraceResolv®, mobile phase gradient: from heptane/EtOAc 100/0 to 50/50) to give intermediate J14 as a yellow solid (1.56 g,

77%). Intermediate J15

(S)- l-(4-(7-cyclopropyl-5-((R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2- carbonyl)pyrazolo [ 1 ,5 -a]pyrimidin-2-yl)-3 -fluoro-5 -hydroxyphenyl)pyrrolidine-3 - carboxylic acid

A mixture of J14 (600 mg; 1.05 mmol), LiOEEEEO (243 mg; 5.80 mmol), THF (5 mL) and H 2 0 (1 mL) was stirred at rt for 18 h. EtOAc and 10% aq. KHSO4 were added to the mixture and an extraction was performed. The organic layer was washed with brine, dried (MgS0 4 ) and evaporated to give intermediate J15 as yellow solid (550 mg, 94%).

Compound 105:

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

A mixture of J15 (250 mg; 0.45 mmol), ammonium chloride (48 mg; 0.90 mmol), EDCI (140 mg; 0.90 mmol) and HOBt » H 2 0 (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 h. EtOAc and brine were added to the mixture and an extraction was performed. The combined organic layers were washed with brine, dried over MgS0 4 , filtered, evaporated and purified by Reverse phase LC (Stationary phase: spherical C18 25 pm, 40 g YMC-ODS-25, dry loading (C18), Mobile phase: Gradient: 0.2% aq. NH4HCO3 / MeCN, from 65:35 to 25:75). MeCN was evaporated, EtOAc was added and an extraction was performed. The combined organic layers were washed with brine, dried over MgS0 4 , filtered, evaporated and coevaporated 3 times with EtOAc, to give compound 105 as a yellow solid (140 mg, 56%).

Synthesis of compound 106:

Intermediate J16:

(R)-(2-(4-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy )-6-fluorophenyl)-7- cyclopropylpyrazolo[l,5-a]pyrimidin-5-yl)(l-methyl-3,4-dihyd roisoquinolin-2(lH)- yl)methanone

A mixture of Jll (226 mg; 0.43 mmol), (2-bromotethoxy)-tert-butyldimethylsilane (93 itL; 0.43 mmol) and K2CO3 (189 mg; 1.37 mmol) in DMF (5 mL) was stirred at 60 °C for 18 h. EtOAc and water were added and an extraction was performed. The organic layer was washed with brine, dried (MgS0 4 ), evaporated and purified by preparative LC (irregular SiOH, 15-40 pm, 120 g GraceResolv®, mobile phase gradient: from heptane/EtOAc 100/0 to 70/30) to give intermediate J16 as a colorless oil (243 mg, 82%). Intermediate J17:

methyl (S)- 1 -(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(7-cyclopropy l-5-((R)- 1 - methyl- 1,2,3, 4-tetrahydroisoquinoline-2-carbonyl)pyrazolo[l,5-a]pyrimidin -2-yl)-5- fluorophenyl)pyrrolidine-3-carboxylate

A sealed tube was charged with J16 (243 mg; 0.36 mmol), (S) -methyl Pyrrolidine-3 - carboxylate hydrochloride (59 mg; 0.36 mmol), CS2CO3 (349 mg; 1.1 mmol) in dioxane (4 mL) and 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 purged again with N 2 . The mixture was stirred at l00°C for 18 h. EtOAc and water were added to the mixture. An extraction was performed the organic layer was washed with brine, dried (MgS0 4 ) evaporated and purified by preparative LC (irregular SiOH, 15-40 pm, 40 g GraceResolv®, mobile phase gradient: from heptane/EtOAc 100/0 to 40/60) to give intermediate J17 as yellow foam (188 mg, 72%).

Compound 106:

(S)- l-(4-(7-cyclopropyl-5-((R)- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline-2- carbonyl)pyrazolo[l,5-a]pyrimidin-2-yl)-3-fluoro-5-(2-hydrox yethoxy)phenyl)pyrrolidine- 3 -carboxamide

LiOH*H 2 0 (58 mg; 1.4 mmol) was added to a solution of J16 (l88 mg; 0.26 mmol) in THF (7 mL) and H 2 0 (3 mL) and the reaction mixture was stirred at rt for 18 h. An aqueous solution of KHS0 4 10% was added until pH=6 and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, dried over MgS0 4 , filtered and evaporated to give 190 mg of a yellow solid. To this solid, NH 4 Cl (28 mg; 0.52 mmol), EDCEHCl (80 mg; 0.418 mmol) and HOBt » H 2 0 (79 mg; 0.52 mmol) in DMF (4 mL) were added. Then DIPEA (222 pL; 1.3 mmol) was added slowly at 0 °C and the mixture was stirred at rt for 18 h. Brine and EtOAc were added and an extraction was performed. The organic layer was washed with brine (3x), dried (MgS0 4 ), filtered and evaporated to give 182 mg of a yellow solid. TBAF 1M in THF (0.255 mL; 0.255 mmol) and THF (2 mL) were added and the mixture was stirred at rt for 18 h. Brine and EtOAc were added and an extraction was performed. The organic layer was dried (MgS0 4 ), evaporated and purified by preparative LC (spherical C18 25 pm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH 4 HC0 3 / MeCN from 95:05 to 30:70) the fraction containing product was concentrated, EtOAc was added and an extraction was performed. The organic layer was dried (MgS0 4 ), filtered and evaporated to give compound 106 as yellow solid (82 mg, 54%).

Compound 107:

(7-cyclopropyl-2-(2-fluoro-4-(cis-3 -fluoro-4-hydroxypyrrolidin- 1 -yl)phenyl)pyrazo lo [ 1 ,5 - a]pyrimidin-5 -yl)((R)- 1 -methyl-3 ,4-dihydroisoquino lin-2( 1 H)-yl)methanone

In a sealed tube, a mixture of (li?)-2-[2-(4-bromo-2-fluorophenyl)-7-cyclopropyl- pyrazolo[ 1 ,5-a]pyrimidine-5-carbonyl]- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline [2035421 - 61-3] (200 mg; 0.396 mmol), ;/.v-4-fluoropyrrolidin-3-ol hydrochloride [1434142-02-5]

(79 mg; 0.56 mmol) and K2CO3 (219 mg; 1.58 mmol) in THF (4.7 mL) was degassed with N 2 for 10 min. DavePhos (16 mg; 0.040 mmol) and Pd 2 dba3 (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 h. Water and EtOAc were added and an extraction was performed. The organic layer was dried over MgS0 4 , filtered and concentrated under reduced pressure. The residue was purified by preparative LC (irregular SiOH 15-40 pm, 12 g GraceResolv®, mobile phase gradient: from DCM/MeOH 100/00 to 97/3). The fraction containing product was combined and evaporated to dryness. The residue was purified by Reverse phase

(Stationary phase: YMC-actus Triart® Cl 8 lOpm 30* 150mm, 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 yellow foam. The solid was purified again by Reverse phase (Stationary phase: YMC-actus Triart® C18 lOpm 30* 150mm, Mobile phase: Gradient from 40% aq. NH4HCO3 0.2%, 60% MeCN to 10% aq. NH4HCO3 0.2%, 90% MeCN). The fractions containing product were collected and evaporated. The residue was taken up in MeCN (2 mL) extended with water (10 mL) and freeze-dried to give compound 107 as a fluffy yellow solid (39 mg, 19%).

C. Compound identification

1H-NMR

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

NMR spectra were recorded at ambient temperature unless otherwise stated.

Data are reported as follow: chemical shift in parts per million (ppm) relative to TMS (d =

0 ppm) which was used as internal standard, integration, multiplicity (s = singulet, d = doublet, t = triplet, q = quartet, quin = quintuplet, sex = sextuplet, m = multiplet, b = broad, or a combination of these), coupling constant(s) J in Hertz (Hz).

Compound 1

Major rotamer (65%)

'H NMR (500 MHz, DMSO-de) d ppm 8.03 (t, =8.7 Hz, 1H), 7.32 (d, =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=6.6 Hz, 1H), 3.81 (dd, ,7=13.9, 4.1 Hz, 1H), 3.55 - 3.70 (m, 3H), 3.34 - 3.53 (m, 3H), 2.83 - 3.07 (m, 2H), 2.72 (br d, 7=16.4 Hz, 1H), 2.34 - 2.46 (m, 1H), 2.22 - 2.34 (m, 1H), 1.52 (d, 7=6.9 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.21 - 1.30 (m, 2H).

Minor rotamer (35%)

ppm 8.03 (t, 7=8.7 Hz, 1H), 7.10 - 7.25 (m, 3H), 7.07 (br d, 7=7.6 Hz, 1H), 6.94 - 6.98 (m, 1H), 6.78 (s, 1H), 6.53 - 6.61 (m, 2H), 4.96 (q, 7=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, 7=6.6 Hz, 3H), 1.30

- 1.37 (m, 2H), 1.21 - 1.30 (m, 2H).

Compound 2

Major rotamer (65%)

NMR (400 MHz, DMSO-7 6 ) d ppm 16.31 (br s, 1H), 8.02 (t, 7=8.8 Hz, 1H), 7.32 (br d, 7=7.1 Hz, 1H), 7.06 - 7.26 (m, 3H), 6.92 - 6.97 (m, 1H), 6.81 (s, 1H), 6.58 (br d, 7=9.1 Hz, 1H), 6.51 (dd, 7=14.7, 1.5 Hz, 1H), 5.58 (q, 7=6.7 Hz, 1H), 3.97 (quin, 7=7.2 Hz, 1H), 3.77

- 3.87 (m, 2H), 3.60 (dd, 7=9.9, 6.8 Hz, 1H), 3.42 - 3.54 (m, 3H), 2.85 - 3.06 (m, 2H), 2.71 (br d, 7=16.2 Hz, 1H), 2.44 - 2.57 (m, 1H partially obscured by DMSO peak), 2.25 - 2.35 (m, 1H), 1.52 (d, 7=6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.22 - 1.29 (m, 2H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-7 6 ) d ppm 16.31 (br s, 1H), 8.02 (t, 7=8.8 Hz, 1H), 7.06 - 7.26 (m, 4H), 6.92 - 6.97 (m, 1H), 6.77 (s, 1H), 6.58 (br d, 7=9.1 Hz, 1H), 6.51 (dd, 7=14.7, 1.5 Hz, 1H), 4.96 (q, 7=6.6 Hz, 1H), 4.55 (br d, 7=12.1 Hz, 1H), 3.97 (quin, 7=7.2 Hz, 1H), 3.77 - 3.87 (m, 1H), 3.60 (dd, 7=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 obscured by DMSO peak), 2.25 - 2.35 (m, 1H), 1.55 (d, 7=7.1 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.22 - 1.29 (m, 2H).

Compound 3

Major rotamer (65%)

NMR (400 MHz, DMSO-7 6 ) d ppm 16.34 (br s, 1H), 8.03 (t, 7=8.6 Hz, 1H), 7.32 (d, 7=7.1 Hz, 1H), 7.05 - 7.26 (m, 3H), 6.91 - 6.97 (m, 1H), 6.81 (s, 1H), 6.58 (br d, 7=8.6 Hz, 1H), 6.51 (dd, 7=14.7, 2.0 Hz, 1H), 5.58 (q, 7=6.9 Hz, 1H), 3.98 (quin, 7=7.2 Hz, 1H), 3.77

- 3.88 (m, 2H), 3.60 (dd, 7=9.6, 6.6 Hz, 1H), 3.41 - 3.55 (m, 3H), 2.85 - 3.07 (m, 2H), 2.71 (br d, 7=15.7 Hz, 1H), 2.39 - 2.50 (m, 1H obscured by solvent peak), 2.23 - 2.36 (m, 1H), 1.52 (d, 7=6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.20 - 1.29 (m, 2H). Minor rotamer (35%)

NMR (400 MHz, DMSO-de) d ppm 16.34 (br s, 1H), 8.03 (t, =8.6 Hz, 1H), 7.05 - 7.26 (m, 4H), 6.91 - 6.97 (m, 1H), 6.77 (s, 1H), 6.58 (br d, =8.6 Hz, 1H), 6.51 (dd, =l4.7, 2.0 Hz, 1H), 4.96 (q, J=6.9 Hz, 1H), 4.50 - 4.59 (m, 1H), 3.98 (quin, J=12 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 obscured by solvent peak), 2.23 - 2.36 (m, 1H), 1.55 (d, J=l.\ Hz, 3H), 1.30 - 1.38 (m, 2H), 1.20 - 1.29 (m, 2H).

Compound 4

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 12.43 (br s, 1H), 8.03 (t, =8.8 Hz, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.06 - 7.25 (m, 3H), 6.92 - 6.98 (m, 1H), 6.81 (s, 1H), 6.56 (br d, =8.8 Hz, 1H), 6.48 (br dd, =l4.5, 1.6 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.81 (br dd, =l3.7, 3.6 Hz, 1H), 3.64 - 3.71 (m, 1H), 3.60 (quin, =7.l 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=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.21 - 1.30 (m, 2H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-de) d ppm 12.43 (br s, 1H), 8.03 (t, =8.8 Hz, 1H), 7.06 - 7.25 (m, 3H), 6.92 - 6.98 (m, 1H), 6.78 (s, 1H), 6.75 (d, =8.5 Hz, 1H), 6.56 (br d, =8.8 Hz, 1H), 6.48 (br dd, =l4.5, 1.6 Hz, 1H), 4.96 (q, =6.6 Hz, 1H), 4.52 - 4.58 (m, 1H), 3.64 - 3.71 (m, 1H), 3.60 (quin, J=TA 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

Major rotamer (65%)

ppm 8.00 (t, =8.8 Hz, 1H), 7.31 (d, J=TA Hz, 1H), 7.05 - 7.26 (m, 3H), 6.90 - 6.96 (m, 1H), 6.81 (s, 1H), 6.53 (dd, =8.6, 1.5 Hz, 1H), 6.45 (dd, =l3.9, 1.5 Hz, 1H), 5.58 (q, J=6J Hz, 1H), 4.61 (d, =6.l Hz, 2H), 4.54 (d, =6.l Hz, 2H), 3.81 (br dd, =l4.2, 4.04 Hz, 1H), 3.59 (s, 2H), 3.41 - 3.50 (m, 1H), 3.29 - 3.37 (m, 2H partially obscured by H 2 0 peak), 2.85 - 3.06 (m, 2H), 2.71 (br d, =l6.7 Hz, 1H), 2.29 (t, =6.8 Hz, 2H), 1.51 (d, =7.l Hz, 3H), 1.29 - 1.38 (m, 2H), 1.21 - 1.29 (m, 2H).

Minor rotamer (35%)

ppm 8.00 (t, =8.8 Hz, 1H), 7.05 - 7.26 (m, 4H), 6.90 - 6.96 (m, 1H), 6.77 (s, 1H), 6.53 (dd, =8.6, 1.5 Hz, 1H), 6.45 (dd, =l3.9, 1.5 Hz, 1H), 4.93 (q, J=6A Hz, 1H), 4.61 (d, J=6A Hz, 2H), 4.54 (d, J=6A Hz, 2H), 4.50 - 4.58 (m, 1H), 3.59 (s, 2H), 3.29 - 3.37 (m, 2H partially obscured by H 2 0 peak), 3.21 - 3.29 (m, 1H),

2.85 - 3.06 (m, 3H), 2.29 (t, ,7=6.8 Hz, 2H), 1.54 (d, J=1 A Hz, 3H), 1.29 - 1.38 (m, 2H), 1.21 - 1.29 (m, 2H).

Compound 6

Major rotamer (65%)

ppm 8.02 (t, ,7=8.8 Hz, 1H) 7.32 (d, J=1 A Hz, 1H), 7.06 - 7.25 (m, 3H), 6.92 - 6.96 (m, 1H), 6.81 (s, 1H), 6.52 (dd, ,7=8.6, 2.0 Hz, 1H), 6.46 (dd, =l4.7, 1.5 Hz, 1H), 5.58 (q, ,7=6.4 Hz, 1H), 4.26 (q, ,7=13.1 Hz, 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, ,7=16.2 Hz, 1H), 2.28 - 2.33 (m, 2H), 1.52 (d, ,7=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.29 - 1.21 (m, 2H).

Minor rotamer (35%)

ppm 8.02 (t, ,7=8.8 Hz, 1H), 7.06 - 7.25 (m, 4H) 6.92 - 6.96 (m, 1H), 6.77 (s, 1H), 6.52 (dd, ,7=8.6, 2.0 Hz, 1H), 6.45 (dd, ,7=14.7, 1.5 Hz, 1H),

4.95 (q, ,7=7.1 Hz, 1H), 4.52 - 4.58 (m, 1H), 4.26 (q, ,7=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, ,7=7.1 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.29 - 1.21 (m, 2H).

Compound 7

Major rotamer (65%)

ppm 8.19 (br d, ,7=6.6 Hz, 1H), 8.01 (t, ,7=8.8 Hz, 1H), 7.32 (br d, ,7=7.6 Hz, 1H), 7.05 - 7.25 (m, 3H), 6.91 - 6.96 (m, 1H), 6.80 (s, 1H), 6.52 (br d, ,7=9.1 Hz, 1H), 6.46 (br d, ,7=14.7 Hz, 1H), 5.58 (q, =7. l Hz, 1H), 4.34 - 4.42 (m, 1H), 3.77 - 3.85 (m, 1H), 3.55 (br dd, ,7=10.1, 6.1 Hz, 1H), 3.34 - 3.50 (m, 3H), 3.14 (br dd, ,7=10.1, 3.5 Hz, 1H), 2.85 - 3.06 (m, 2H), 2.71 (br d, ,7=16.7 Hz, 1H), 2.13 - 2.24 (m, 1H),

1.86 - 1.96 (m, 1H), 1.82 (s, 3H), 1.52 (d, ,7=6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.19 - 1.30 (m, 2H).

Minor rotamer (35%)

ppm 8.19 (br d, ,7=6.6 Hz, 1H), 8.01 (t, ,7=8.8 Hz, 1H), 7.05 - 7.25 (m, 4H), 6.91 - 6.96 (m, 1H), 6.77 (s, 1H), 6.52 (br d, ,7=9.1 Hz, 1H), 6.46 (br d, ,7=14.7 Hz, 1H), 4.96 (q, ,7=6.6 Hz, 1H), 4.51 - 4.59 (m, 1H), 4.34 - 4.42 (m, 1H), 3.55 (br dd, ,7=10.1, 6.1 Hz, 1H), 3.34 - 3.50 (m, 2H), 3.21 - 3.30 (m, 1H), 3.14 (br dd, ,7=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, ,7=6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.19 - 1.30 (m, 2H). Compound 8

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 8.19 (d, ,7=6.9 Hz, 1H), 8.01 (t, ,7=8.8 Hz, 1H), 7.32 (d, ,7=7.6 Hz, 1H), 7.21 - 7.25 (m, 1H), 7.10 - 7.21 (m, 2H), 6.94 (d, ,7=3.5 Hz, 1H), 6.81 (s, 1H), 6.53 (br d, ,7=8.8 Hz, 1H), 6.46 (dd, ,7=14.5, 1.9 Hz, 1H), 5.59 (q, ,7=6.8 Hz, 1H), 4.35

- 4.42 (m, 1H), 3.81 (br dd, ,7=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, ,7=10.1, 4.1 Hz, 1H), 2.85 - 3.05 (m, 2H), 2.72 (br d, ,7=16.1 Hz, 1H), 2.15 - 2.23 (m, 1H), 1.88 - 1.95 (m, 1H), 1.82 (s, 3H), 1.52 (d, ,7=6.9 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.22 - 1.30 (m, 2H).

Minor rotamer (35%)

ppm 8.19 (d, J=6.9 Hz, 1H), 8.01 (t, ,7=8.8 Hz, 1H), 7.10

- 7.21 (m, 3H), 7.06 - 7.09 (m, 1H), 6.93 (d, ,7=3.5 Hz, 1H), 6.77 (s, 1H), 6.53 (br d, ,7=8.8 Hz, 1H), 6.46 (dd, ,7=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, ,7=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).

Compound 9

Major rotamer (65%)

ppm 8.00 (t, J=9A Hz, 1H), 7.55 (br d, J=6A Hz, 1H), 7.32 (br d, ,7=7.6 Hz, 1H), 7.05 - 7.25 (m, 3H), 6.90 - 6.96 (m, 1H), 6.80 (s, 1H), 6.51 (br d, ,7=8.6 Hz, 1H), 6.44 (br d, ,7=14.7 Hz, 1H), 5.58 (q, ,7=6.9 Hz, 1H), 4.16 - 4.25 (m, 1H),

3.81 (br dd, ,7=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, ,7=16.2 Hz, 1H), 2.14 - 2.25 (m, 1H), 1.87 - 2.02 (m, 1H), 1.50 (d, J=1.1 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.20 - 1.29 (m, 2H).

Minor rotamer (35%)

ppm 8.00 (t, J=9A Hz, 1H), 7.55 (br d, ,7=6.1 Hz, 1H), 7.05 - 7.25 (m, 4H), 6.90 - 6.96 (m, 1H), 6.77 (s, 1H), 6.51 (br d, ,7=8.6 Hz, 1H), 6.44 (br d, =l4.7 Hz, 1H), 4.96 (q, ,7=6.6 Hz, 1H), 4.55 (br d, ,7=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, ,7=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, ,7=7.1 Hz, 3H), 1.30 - 1.38 (m, 2H) 1.20 - 1.29 (m, 2H). Compound 10

Major rotamer (65%)

ppm 8.00 (t, ,7=8.8 Hz, 1H), 7.55 (br d, ,7=6.1 Hz, 1H),

7.32 (br d, ,7=7.6 Hz, 1H), 7.05 - 7.26 (m, 3H), 6.91 - 6.95 (m, 1H), 6.80 (s, 1H), 6.51 (br d, ,7=9.1 Hz, 1H), 6.45 (dd, ,7=14.7, 1.5 Hz, 1H), 5.58 (q, J=6.6 Hz, 1H), 4.16 - 4.25 (m, 1H), 3.81 (br dd, ,7=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, ,7=17.2 Hz, 1H), 2.13 - 2.24 (m, 1H), 1.88 - 1.99 (m, 1H), 1.52 (d, J=l. \ Hz, 3H), 1.29 - 1.37 (m, 2H), 1.20 - 1.29 (m, 2H).

Minor rotamer (35%)

ppm 8.00 (t, ,7=8.8 Hz, 1H), 7.55 (br d, ,7=6.1 Hz, 1H), 7.05 - 7.26 (m, 4H), 6.91 - 6.95 (m, 1H), 6.77 (s, 1H), 6.51 (br d, ,7=9.1 Hz, 1H), 6.45 (dd, =l4.7, 1.5 Hz, 1H), 4.96 (q, ,7=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, ,7=7.1 Hz, 3H), 1.29 - 1.37 (m, 2H), 1.20 - 1.29 (m, 2H).

Compound 11

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 8.00 (t, ,7=8.6 Hz, 1H), 7.48 (br d, ,7=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, ,7=9.1 Hz, 1H), 6.47 (br d, ,7=14.2 Hz, 1H), 5.54 - 5.62 (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 obscured by H 2 0), 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%)

ppm 8.00 (t, ,7=8.6 Hz, 1H), 7.48 (br d, ,7=7.1 Hz, 1H), 7.05 - 7.25 (m, 4H), 6.94 (br s, 1H), 6.77 (br s, 1H), 6.53 (br d, ,7=9.1 Hz, 1H), 6.47 (br d, ,7=14.2 Hz, 1H), 4.91 - 5.00 (m, 1H), 4.51 - 4.58 (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

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 8.01 (t, ,7=8.7 Hz, 1H), 7.49 (d, J=6.6 Hz, 1H), 7.32 (d, ,7=7.3 Hz, 1H), 7.06 - 7.25 (m, 3H), 6.91 - 6.96 (m, 1H), 6.81 (s, 1H), 6.53 (br d, ,7=8.8 Hz, 1H), 6.47 (br d, ,7=14.8 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 4.05 - 4.13 (m, 1H), 3.81 (br dd, ,7=12.5, 3.3 Hz, 1H), 3.63 (br dd, ,7=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, ,7=16.4 Hz, 1H), 2.23 - 2.33 (m, 1H), 1.93 - 2.03 (m, 1H), 1.52 (d, ,7=6.9 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.21 - 1.30 (m, 2H).

Minor rotamer (35%)

ppm 8.01 (t, ,7=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, ,7=8.8 Hz, 1H), 6.47 (br d, =l4.8 Hz, 1H), 4.96 (q, ,7=6.7 Hz, 1H), 4.52 - 4.59 (m, 1H), 4.05 - 4.13 (m, 1H), 3.63 (br dd, ,7=9.8, 6.6 Hz, 1H), 3.41 - 3.50 (m, 2H), 3.24 - 3.30 (m, 1H), 3.21 (dd, ,7=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, ,7=6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.21 - 1.30 (m, 2H).

Compound 13

Major rotamer (65%)

ppm 7.99 (t, ,7=8.8 Hz, 1H), 7.32 (d, ,7=7.6 Hz, 1H), 7.06

- 7.25 (m, 3H), 6.91 - 6.95 (m, 1H), 6.80 (s, 1H), 6.51 (dd, ,7=8.7, 1.7 Hz, 1H), 6.43 (dd, ,7=14.8, 1.6 Hz, 1H), 5.59 (q, ,7=6.4 Hz, 1H), 5.01 (d, ,7=3.8 Hz, 1H), 4.43 (br s, 1H), 3.82 (br dd, ,7=13.7, 4.3 Hz, 1H), 3.33 - 3.50 (m, 4H), 3.16 (br d, ,7=10.4 Hz, 1H), 2.82 - 3.05 (m, 2H), 2.72 (br d, ,7=16.1 Hz, 1H), 2.02 - 2.11 (m, 1H), 1.89 - 1.96 (m, 1H), 1.52 (d, ,7=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.22 - 1.29 (m, 2H).

Minor rotamer (35%)

ppm 7.99 (t, ,7=8.8 Hz, 1H), 7.06 - 7.25 (m, 4H), 6.91 - 6.95 (m, 1H), 6.76 (s, 1H), 6.51 (dd, ,7=8.7, 1.7 Hz, 1H), 6.43 (dd, ,7=14.8, 1.6 Hz, 1H),

5.01 (d, ,7=3.8 Hz, 1H), 4.97 (q, ,7=6.6 Hz, 1H), 4.52 - 4.58 (m, 1H), 4.43 (br s, 1H), 3.60 (dt, ,7=12.1, 6.1 Hz, 1H), 3.33 - 3.50 (m, 2H), 3.23 - 3.28 (m, 1H), 3.16 (br d, ,7=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, ,7=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.22 - 1.29 (m, 2H).

Compound 14

Major rotamer (65%)

ppm 7.99 (t, ,7=8.8 Hz, 1H), 7.32 (br d, ,7=7.1 Hz, 1H), 7.05 - 7.25 (m, 3H), 6.90 - 6.94 (m, 1H), 6.80 (s, 1H), 6.51 (dd, ,7=8.8, 1.8 Hz, 1H), 6.43 (dd, ,7=14.4, 1.3 Hz, 1H), 5.58 (q, 7=6.6 Hz, 1H), 5.02 (d, 7=3.5 Hz, 1H), 4.42 (br s, 1H), 3.77 - 3.85 (m, 1H), 3.34 - 3.51 (m, 4H), 3.16 (br d, 7=10.1 Hz, 1H), 2.85 - 3.07 (m, 2H), 2.71 (br d, 7=16.2 Hz, 1H), 2.00 - 2.12 (m, 1H), 1.88 - 1.97 (m, 1H), 1.52 (d, 7=7.1 Hz, 3H), 1.21 - 1.37 (m, 4H).

Minor rotamer (35%)

ppm 7.99 (t, 7=8.8 Hz, 1H), 7.05 - 7.25 (m, 4H), 6.90 - 6.94 (m, 1H), 6.76 (s, 1H), 6.51 (dd, 7=8.8, 1.8 Hz, 1H), 6.43 (dd, 7=14.4, 1.3 Hz, 1H),

5.02 (d, 7=3.5 Hz, 1H), 4.96 (q, 7=6.6 Hz, lH), 4.5l - 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, 7=10.1 Hz, 1H), 2.85 - 3.07 (m, 3H), 2.00 - 2.12 (m, 1H), 1.88 - 1.97 (m, 1H), 1.55 (br d, 7=7.1 Hz, 3H), 1.21 - 1.37 (m, 4H).

Compound 15

Major rotamer (65%)

ppm 8.01 (br t, 7=8.8 Hz, 1H), 7.32 (br d, 7=8.1 Hz,

1H), 7.05 - 7.25 (m, 3H), 6.91 - 6.96 (m, 1H), 6.81 (s, 1H), 6.54 (br d, 7=8.6 Hz, 1H), 6.49 (br d, 7=15.2 Hz, 1H), 5.54 - 5.62 (m, 1H), 5.27 (br s, 1H), 3.81 (br d, 7=14.2 Hz, 1H),

3.60 (br dd, 7=10.9, 4.3 Hz, 1H), 3.30 - 3.51 (m, 5H, partially obscured by H 2 0 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, 7=7.1 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.21 - 1.29 (m, 2H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-7 6 ) d ppm 8.01 (br t, 7=8.8 Hz, 1H), 7.05 - 7.25 (m, 4H), 6.91

- 6.96 (m, 1H), 6.77 (s, 1H), 6.54 (br d, 7=8.6 Hz, 1H), 6.49 (br d, 7=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, 7=10.9, 4.3 Hz, 1H), 3.30 - 3.51 (m, 3H partially obscured by H 2 0 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, 7=7.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.21 - 1.29 (m, 2H).

Compound 16

Major rotamer (65%)

NMR (400 MHz, DMSO-7 6 ) d ppm 8.01 (t, 7=8.8 Hz, 1H), 7.32 (br d, 7=7.6 Hz, 1H), 7.05 - 7.25 (m, 4H), 6.91 - 6.95 (m, 1H), 6.81 (s, 1H), 6.55 (br d, 7=9.6 Hz, 1H), 6.48 (br d, 7=14.7 Hz, 1H), 5.58 (q, 7=6.7 Hz, 1H), 5.27 (br s, 1H), 3.81 (br dd, 7=14.2, 3.5 Hz, 1H),

3.61 (br dd, 7=11.1, 4.6 Hz, 1H), 3.34 - 3.51 (m, 4H), 2.85 - 3.07 (m, 2H), 2.71 (br d, 7=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, 7=6.6 Hz, 3H), 1.29 - 1.38 (m, 2H), 1.20 - 1.29 (m, 2H). Minor rotamer (35%)

ppm 8.01 (t, =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, =l4.7 Hz, 1H), 5.27 (br s, 1H), 4.91 - 5.00 (m, 1H), 4.51 - 4.59 (m, 1H), 3.61 (br dd, J=\ 1.1, 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, =7.l Hz, 3H), 1.29 - 1.38 (m, 2H), 1.20 - 1.29 (m, 2H).

Compound 17

Major rotamer (65%)

ppm 8.02 (t, =8.3 Hz, 1H), 7.32 (d, =6.l 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=1 l Hz, 1H), 4.10 - 4.18 (m, 1H), 3.78 - 3.85 (m, 1H), 3.70 (d, J=1 l 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%)

ppm 8.02 (t, =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=1 A 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=1 A Hz, 3H), 1.20 -

1.38 (m, 4H).

Compound 18

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 8.02 (t, =8.6 Hz, 1H), 7.32 (br d, J=1 A 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=1 A Hz, 1H), 4.14 (quin, J=6.1 Hz, 1H), 3.81 (br dd, =l3.6, 4.6 Hz, 1H), 3.70 (d, J=1 A Hz, 2H), 3.32 - 3.65 (m, 3H), 3.09 (s, 3H), 2.85 - 3.06 (m, 2H), 2.71 (br d, =l6.2 Hz, 1H),

2.38 - 2.46 (m, 2H), 1.52 (d, J=1 A Hz, 3H), 1.30 - 1.39 (m, 2H), 1.21 - 1.30 (m, 2H).

Minor rotamer (35%)

ppm 8.02 (t, =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=6A Hz, 1H), 4.51 - 4.59 (m,

1H), 4.14 (quin, J=6.1 Hz, 1H), 3.70 (d, J=1 A 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

Major rotamer (65%)

ppm 8.03 (t, 7=8.8 Hz, 1H), 7.32 (d, J=1 A Hz, 1H), 7.04

- 7.26 (m, 5H), 6.93 - 6.97 (m, 1H), 6.81 (s, 1H), 6.57 (dd, J=9A, 2.0 Hz, 1H), 6.51 (dd, =l4.2, 2.0 Hz, 1H), 5.58 (q, ,7=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, ,7=16.7 Hz, 1H), 2.35 - 2.43 (m, 2H), 1.52 (d, ,7=6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.22 - 1.29 (m, 2H).

Minor rotamer (35%)

ppm 8.03 (t, ,7=8.8 Hz, 1H), 7.04 - 7.26 (m, 6H), 6.93 -

6.97 (m, 1H), 6.78 (s, 1H), 6.57 (dd, ,7=9.1, 2.0 Hz, 1H), 6.51 (dd, .7=14.2, 2.0 Hz, 1H),

4.97 (q, ,7=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, .7=6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.22 - 1.29 (m, 2H).

Compound 20

Major rotamer (65%)

NMR (400 MHz, DMSO-7 6 ) d ppm 11.78 (br s, 1H), 7.96 (t, ,7=8.8 Hz, 1H), 7.25 (d, ,7=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, ,7=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, ,7=16.2 Hz, 1H), 2.29 - 2.39 (m, 2H partially obscured by H 2 0 peak), 1.97 (s, 3H), 1.45 (d, ,7=6.6 Hz, 3H), 1.23 - 1.32 (m, 2H), 1.16 - 1.23 (m, 2H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-7 6 ) d ppm 11.78 (br s, 1H), 7.96 (t, ,7=8.8 Hz, 1H), 6.99 - 7.20 (m, 4H), 6.86 - 6.91 (m, 1H), 6.71 (s, 1H), 6.45 - 6.55 (m, 2H), 4.89 (q, 7=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 obscured by H 2 0 peak),

1.97 (s, 3H), 1.48 (d, 7=7.1 Hz, 3H), 1.23 - 1.32 (m, 2H), 1.16 - 1.23 (m, 2H).

Compound 21

Major rotamer (65%)

ppm 8.02 (t, 7=8.8 Hz, 1H), 7.32 (br d, 7=7.6 Hz, 1H), 7.06 - 7.26 (m, 4H), 6.93 - 6.97 (m, 1H), 6.81 (s, 1H), 6.58 (br d, 7=8.65Hz, 1H), 6.53 (br d, 7=14.7 Hz, 1H), 5.58 (q, 7=7.1 Hz, 1H), 4.08 - 4.16 (m, 1H), 3.81 (br dd, 7=13.9, 3.8 Hz, 1H), 3.34 - 3.73 (m, 5H), 2.85 - 3.07 (m, 2H), 2.71 (br d, 7=16.7 Hz, 1H), 2.64 (d, 7=5.1 Hz, 3H), 2.32 - 2.41 (m, 2H), 1.52 (d, 7=6.6 Hz, 3H), 1.21 - 1.38 (m, 4H). Minor rotamer (35%)

ppm 8.02 (t, ,7=8.8 Hz, 1H), 7.06 - 7.26 (m, 5H), 6.93 - 6.97 (m, 1H), 6.78 (s, 1H), 6.58 (br d, ,7=8.6 Hz, 1H) 6.53 (br d, ,7=14.7 Hz, 1H), 4.96 (q, ,7=6.1 Hz, 1H), 4.51 - 4.59 (m, 1H), 4.08 - 4.16 (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. \ Hz, 3H), 2.32 - 2.41 (m, 2H), 1.55 (br d, J=1 A Hz, 3H), 1.21 - 1.38 (m, 4H).

Compound 22

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 8.02 (br t, ,7=8.6 Hz, 1H), 7.32 (br d, J=1 A 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, ,7=7.3 Hz, 1H), 3.77 - 3.86 (m, 1H), 3.71 (br t, J=9A 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 obscured by DMSO peak), 1.52 (br d, J=6.6 Hz, 3H), 1.21 - 1.38 (m, 4H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-de) d ppm 8.02 (br t, ,7=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, ,7=10.1 Hz, 1H), 4.23 (quin, ,7=7.3 Hz, 1H), 3.71 (br t, J=9A 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 obscured by DMSO peak), 1.55 (br d, J=6.6 Hz, 3H), 1.21 - 1.38 (m, 4H).

Compound 23

Major rotamer (70%)

Hz, DMSO-de) d ppm 7.99 (br t, ,7=8.5 Hz, 1H), 7.37 (br s, 1H), 7.32 (br , 7.06 - 7.25 (m, 3H), 6.75 - 6.95 (m, 3H), 6.48 (d, ,7=8.5 Hz, 1H), 6.39 (d, 5.59 (q, ,7=6.0 Hz, 1H), 3.81 (br dd, ,7=12.8, 3.0 Hz, 1H), 3.22 - 3.50 (m, 3H), 3.12 (br d, ,7=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, ,7=6.6 Hz, 3H), 1.21 - 1.37 (m, 4H), 1.14 (s, 3H).

Minor rotamer (30%)

NMR (500 MHz, DMSO-de) d ppm 7.99 (br t, ,7=8.5 Hz, 1H), 7.37 (br s, 1H), 7.06 - 7.25 (m, 4H), 6.75 - 6.95 (m, 3H), 6.48 (br d, ,7=8.5 Hz, 1H), 6.39 (br d, ,7=14.5 Hz, 1H), 4.96 (q, ,7=6.6 Hz, 1H), 4.55 (br d, ,7=10.7 Hz, 1H), 3.22 - 3.50 (m, 3H), 3.12 (br d, ,7=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, ,7=6.6 Hz, 3H), 1.21 - 1.37 (m, 4H), 1.14 (s, 3H). Compound 24

Major rotamer (70%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (br t, 7=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, 7=8.5 Hz, 1H), 6.39 (d, ,7=14.5 Hz, 1H), 5.59 (q, 7=6.6 Hz, 1H), 3.81 (br dd, 7=13.1, 3.9 Hz, 1H), 3.21 - 3.52 (m, 4H), 3.12 (br d, 7=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, 7=6.6 Hz, 3H), 1.20 - 1.40 (m, 4H), 1.14 (s, 3H).

Minor rotamer (30%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (br t, 7=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, 7=8.5 Hz, 1H), 6.39 (br d, 7=14.5 Hz, 1H), 4.96 (q, 7=6.6 Hz, 1H), 4.55 (br d, 7=14.2 Hz, 1H), 3.21 - 3.52 (m, 4H), 3.12 (br d, 7= 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, 7=6.6 Hz, 3H), 1.20 - 1.40 (m, 4H), 1.14 (s, 3H).

Compound 25

Major rotamer (65%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.96 - 8.03 (m, 1H), 7.34 - 7.40 (m, 2H), 7.02 (d, 7=5.0 Hz, 1H), 6.91 - 6.95 (m, 1H), 6.76 - 6.86 (m, 2H), 6.48 (d, 7=8.5 Hz, 1H), 6.39 (d, 7=14.8 Hz, 1H), 5.53 (q, 7=6.2 Hz, 1H), 3.92 (br dd, 7=13.6, 4.7 Hz, 1H), 3.34 - 3.45 (m, 4H), 3.12 (br d, 7=9.8 Hz, 1H), 2.80 - 3.01 (m, 2H), 2.75 (br d, 7=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, 7=6.6 Hz, 3H), 1.31 - 1.38 (m, 2H), 1.22 - 1.29 (m, 2H), 1.14 (s, 3H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.96 - 8.03 (m, 1H), 7.34 - 7.40 (m, 1H), 7.29 (d, 7=5.4 Hz, 1H), 6.91 - 6.95 (m, 1H), 6.76 - 6.86 (m, 3H), 6.48 (d, 7=8.5 Hz, 1H), 6.39 (d, 7=14.8 Hz, 1H), 4.90 (q, 7=6.9 Hz, 1H), 4.70 (br dd, 7=12.3, 4.1 Hz, 1H), 3.34 - 3.45 (m, 3H), 3.16 - 3.25 (m, 1H), 3.12 (br d, 7=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, 7=6.6 Hz, 3H), 1.31 - 1.38 (m, 2H), 1.22 - 1.29 (m, 2H), 1.14 (s, 3H).

Compound 26

Major rotamer (70%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.95 - 8.03 (m, 1H), 7.34 - 7.41 (m, 2H), 7.02 (d, 7=5.0 Hz, 1H), 6.91 - 6.95 (m, 1H), 6.76 - 6.86 (m, 2H), 6.48 (d, 7=8.8 Hz, 1H), 6.39 (d, 7=14.2 Hz, 1H), 5.53 (q, 7=6.3 Hz, 1H), 3.93 (dd, 7=13.2, 4.4 Hz, 1H), 3.29 - 3.46 (m, 3H), 3.16 - 3.26 (m, 1H), 3.12 (br d, 7=9.8 Hz, lH), 2.8l - 3.00 (m, 2H), 2.75 (br d, 7=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%)

NMR (500 MHz, DMSO-de) d ppm 7.95 - 8.03 (m, 1H), 7.34 - 7.41 (m, 1H), 7.29 (d, ,7=5.0 Hz, 1H), 6.91 - 6.95 (m, 1H), 6.76 - 6.86 (m, 3H), 6.48 (d, ,7=8.8 Hz, 1H), 6.39 (d, =l4.2 Hz, 1H), 4.90 (q, ,7=6.6 Hz, 1H), 4.70 (dd, ,7=12.6, 4.7 Hz, 1H), 3.29 - 3.46 (m, 4H),

3.12 (br d, ,7=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, ,7=6.6 Hz, 3H), 1.21 - 1.39 (m, 4H), 1.14 (s, 3H).

Compound 27

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 7.99 (br t, ,7=8.8 Hz, 1H), 7.32 (br d, ,7=7.3 Hz,

1H), 7.06 - 7.25 (m, 4H), 6.89 - 6.95 (m, 2H), 6.80 (s, 1H), 6.50 (br d, ,7=8.5 Hz, 1H), 6.42 (br d, ,7=15.1 Hz, 1H), 5.59 (q, ,7=6.6 Hz, 1H), 3.81 (br dd, ,7=13.6, 3.5 Hz, 1H), 3.39 - 3.50 (m, 2H), 3.21 - 3.31 (m, 2H), 3.13 (br t, ,7=9.6 Hz, 1H), 2.83 - 3.07 (m, 2H), 2.70 (br d, ,7=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, ,7=6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.22 - 1.29 (m, 2H), 1.13 (s, 6H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-de) d ppm 7.99 (br t, ,7=8.8 Hz, 1H), 7.06 - 7.25 (m, 5H), 6.89

- 6.95 (m, 2H), 6.76 (s, 1H), 6.50 (br d, ,7=8.5 Hz, 1H), 6.42 (br d, ,7=15.1 Hz, 1H), 4.96 (q, ,7=6.5 Hz, 1H), 4.55 (br dd, ,7=12.9, 3.2 Hz, 1H), 3.39 - 3.50 (m, 2H), 3.21 - 3.31 (m, 2H),

3.13 (br t, ,7=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, ,7=6.9 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.22 - 1.29 (m, 2H), 1.13 (s, 6H).

Compound 28

Major rotamer (65%)

ppm 7.99 (t, ,7=8.8 Hz, 1H), 7.32 (d, ,7=7.6 Hz, 1H), 7.05

- 7.25 (m, 4H), 6.89 - 6.95 (m, 2H), 6.80 (s, 1H), 6.50 (d, ,7=8.8 Hz, 1H), 6.42 (dd, ,7=14.8, 1.6 Hz, 1H), 5.58 (q, ,7=6.5 Hz, 1H), 3.81 (br dd, ,7=13.6, 4.1 Hz, 1H), 3.40 - 3.51 (m, 2H),

3.22 - 3.31 (m, 2H), 3.13 (t, ,7=9.6 Hz, 1H), 2.86 - 3.05 (m, 2H), 2.70 (br d, ,7=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, ,7=6.6 Hz, 3H), 1.31 - 1.38 (m, 2H), 1.21 - 1.29 (m, 2H), 1.13 (s, 6H).

Minor rotamer (35%)

ppm 7.99 (t, ,7=8.8 Hz, 1H), 7.05 - 7.25 (m, 5H), 6.89 - 6.95 (m, 2H), 6.76 (s, 1H), 6.50 (d, ,7=8.8 Hz, 1H), 6.42 (dd, ,7=14.8, 1.6 Hz, 1H), 4.96 (q, J=6.5 Hz, 1H), 4.55 (br dd, =l2.9, 2.8 Hz, 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, 3H), 2.55 - 2.63 (m, 1H), 1.92 - 2.00 (m, 1H), 1.75 - 1.85 (m, 1H), 1.55 (d, =6.9 Hz, 3H), 1.31 - 1.38 (m, 2H), 1.21 - 1.29 (m, 2H), 1.13 (s,

6H).

Compound 29

Major rotamer (70%)

ppm 7.99 (t, =8.8 Hz, 1H), 7.38 (d, =5.0 Hz, 1H), 7.13 (br s, 1H), 7.02 (d, =5.0 Hz, 1H), 6.89 - 6.95 (m, 2H), 6.79 - 6.81 (m, 1H), 6.50 (br d, =8.8 Hz, 1H), 6.42 (br d, =l4.8 Hz, 1H), 5.53 (q, =6.8 Hz, 1H), 3.92 (br dd, =l3.7, 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, =l7.0 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%)

ppm 7.98 (t, =8.8 Hz, 1H), 7.29 (d, J=5.0 Hz, 1H), 7.13 (br s, 1H), 6.89 - 6.95 (m, 2H), 6.79 - 6.81 (m, 1H), 6.77 (s, 1H), 6.50 (br d, =8.8 Hz, 1H), 6.42 (br d, =l4.8 Hz, 1H), 4.90 (q, J=6J Hz, 1H), 4.70 (br dd, =l2.8, 4.6 Hz, 1H), 3.38 - 3.45 (m, 2H), 3.09 - 3.29 (m, 3H), 2.90 - 3.01 (m, 3H), 2.55 - 2.62 (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

Major rotamer (65%)

ppm 8.00 (br t, =8.8 Hz, 1H), 7.31 (br d, =7.l Hz,

1H), 7.05 - 7.26 (m, 3H), 6.93 (br s, 1H), 6.80 (s, 1H), 6.51 (br d, =8.6 Hz, 1H), 6.44 (br d, =l5.2 Hz, 1H), 5.55 - 5.62 (m, 1H), 4.66 (br t, J=9A 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%)

NMR (400 MHz, DMSO-de) d ppm 8.00 (br t, =8.8 Hz, 1H), 7.05 - 7.26 (m, 4H), 6.93 (br s, 1H), 6.76 (s, 1H), 6.51 (br d, =8.6 Hz, 1H), 6.44 (br d, =l5.2 Hz, 1H), 4.92 - 4.99 (m, 1H), 4.66 (br t, J=9A Hz, lH), 4.5l - 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), 1.21 - 1.34 (m, 4H). Compound 31

Major rotamer (65%)

ppm 8.00 (t, 7=8.7 Hz, 1H), 7.32 (d, 7=7.3 Hz, 1H), 7.06

- 7.25 (m, 3H), 6.91 - 6.96 (m, 1H), 6.80 (s, 1H), 6.51 (br d, 7=8.5 Hz, 1H), 6.44 (dd, ,7=14.8, 1.3 Hz, 1H), 5.59 (q, 7=6.6 Hz, 1H), 4.66 (t, J=9.0 Hz, 1H), 3.86 - 3.95 (m, 1H), 3.78 - 3.84 (m, 1H), 3.56 (dd, 7=9.8, 6.6 Hz, 1H), 3.42 - 3.50 (m, 2H), 3.08 (dd, 7=9.8, 6.0 Hz, 1H), 2.83 - 3.05 (m, 2H), 2.72 (br d, 7=16.4 Hz, 1H), 2.16 - 2.24 (m, 1H), 1.84 - 1.94 (m, 1H), 1.52 (d, 7=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%)

ppm 8.00 (t, 7=8.7 Hz, 1H), 7.06 - 7.25 (m, 4H), 6.91 - 6.96 (m, 1H), 6.77 (s, 1H), 6.51 (br d, 7=8.5 Hz, 1H), 6.44 (dd, 7=14.8, 1.3 Hz, 1H), 4.96 (q, 7=6.7 Hz, 1H), 4.66 (t, 7=9.0 Hz, 1H), 4.52 - 4.58 (m, 1H), 3.86 - 3.95 (m, 1H), 3.56 (dd, 7=9.8, 6.6 Hz, 1H), 3.42 - 3.50 (m, 1H), 3.23 - 3.30 (m, 1H), 3.08 (dd, 7=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, 7=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

Major rotamer (65%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (br t, 7=8.7 Hz, 1H), 7.51 (br s, 1H), 7.32 (br d, 7=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, 7=8.5 Hz, 1H), 6.45 (br d, 7=14.5 Hz, 1H), 5.59 (q, 7=6.6 Hz, 1H), 4.02 - 4.11 (m, 1H), 3.82 (br dd, 7=13.2, 4.1 Hz, 1H), 3.55 (t, 7=8.5 Hz, 1H), 3.40 - 3.52 (m, 1H), 3.22

- 3.36 (m, 2H partially obscured by H 2 0 peak), 2.84 - 3.06 (m, 2H), 2.72 (br d, 7=16.1 Hz, 1H), 2.11 - 2.21 (m, 1H), 1.91 (br dd, 7=11.8, 6.5 Hz, 1H), 1.52 (br d, 7=6.6 Hz, 3H), 1.30

- 1.37 (m, 2H), 1.21 - 1.29 (m, 2H), 1.16 (d, 7=6.0 Hz, 3H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (br t, 7=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, 7=8.5 Hz, 1H), 6.45 (br d, 7=14.5 Hz, 1H), 4.97 (q, 7=6.5 Hz, 1H), 4.55 (br d, 7=12.6 Hz, 1H), 4.02 - 4.11 (m, 1H), 3.55 (t, 7=8.5 Hz, 1H), 3.40 - 3.52 (m, 1H), 3.22 - 3.36 (m, 2H partially obscured by H 2 0 peak), 2.84 - 3.06 (m, 3H), 2.l l - 2.21 (m, 1H), 1.91 (br dd, 7=11.8, 6.5 Hz, 1H), 1.55 (br d, 7=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.21 - 1.29 (m, 2H), 1.16 (d, 7=6.0 Hz, 3H). Compound 33

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 7.99 (t, 7=8.8 Hz, 1H), 7.49 (br s, 1H), 7.32 (d, 7=7.3 Hz, 1H), 7.05 - 7.26 (m, 3H), 7.01 (br s, 1H), 6.91 - 6.96 (m, 1H), 6.81 (s, 1H), 6.56 (br d, 7=8.8 Hz, 1H), 6.48 (br d, 7=14.8 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.93 - 4.02 (m, 1H), 3.82 (br dd, 7=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, 7=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, 7=6.0 Hz, 3H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (t, 7=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, 7=8.8 Hz, 1H), 6.48 (br d, 7=14.8 Hz, 1H), 4.97 (q, 7=6.6 Hz, lH), 4.5l - 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, 7=6.3 Hz, 3H).

Compound 34

Major rotamer (65%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (br t, 7=8.7 Hz, 1H), 7.51 (br s, 1H), 7.32 (br d, 7=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, 7=8.5 Hz, 1H), 6.45 (br d, 7=14.8 Hz, 1H), 5.59 (q, 7=6.4 Hz, 1H), 4.04 - 4.11 (m, 1H), 3.82 (br dd, 7=13.6, 3.8 Hz, 1H), 3.55 (br t, 7=8.5 Hz, 1H), 3.42 - 3.50 (m, 1H), 3.22 - 3.36 (m, 2H partially obscured by H 2 0 peak), 2.85 - 3.06 (m, 2H), 2.72 (br d, 7=16.4 Hz, 1H), 2.12 - 2.21 (m, 1H), 1.91 (br dd, J=l 1.5, 6.8 Hz, 1H), 1.52 (d, 7=6.9 Hz, 3H),

1.30 - 1.37 (m, 2H), 1.22 - 1.30 (m, 2H), 1.16 (d, 7=6.0 Hz, 3H).

Minor rotamer

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (br t, 7=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, 7=8.5 Hz, 1H), 6.45 (br d, 7=14.8 Hz, 1H), 4.97 (q, J=6.2 Hz, 1H), 4.55 (br dd, 7=12.9, 3.2 Hz, 1H), 4.04 - 4.11 (m, 1H), 3.55 (br t, 7=8.5 Hz, 1H), 3.42 - 3.50 (m, 1H), 3.22 - 3.36 (m, 2H partially obscured by H 2 0 peak), 2.85 - 3.06 (m, 3H), 2.12 - 2.21 (m, 1H), 1.91 (br dd, ,7=11.5, 6.8 Hz, 1H), 1.55 (d, 7=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

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 7.99 (br t, =8.8 Hz, 1H), 7.49 (br s, 1H), 7.32 (br d, J=1.6 Hz, 1H), 7.06 - 7.26 (m, 3H), 7.01 (br s, 1H), 6.91 - 6.96 (m, 1H), 6.81 (s, 1H), 6.57 (br d, =8.8 Hz, 1H), 6.48 (br d, =l5.l Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.94 - 4.02 (m, 1H), 3.82 (br dd, =l3.7, 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, =l6.l Hz, 1H), 2.39 - 2.48 (m, 1H), 1.87 - 1.95 (m, 1H), 1.52 (br d, =6.9 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.22 - 1.30 (m, 2H), 1.18 (d, =6.0 Hz, 3H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-de) d ppm 7.99 (br t, =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, =8.8 Hz, 1H), 6.48 (br d, =l5.l Hz, 1H), 4.97 (q, =6.4 Hz, 1H), 4.55 (br d, =l0.4 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, =6.9 Hz, 3H), 1.30 - 1.38 (m, 2H),

1.22 - 1.30 (m, 2H), 1.18 (d, =6.0 Hz, 3H).

Compound 36

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 8.00 (t, =8.8 Hz, 1H), 7.51 (br s, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.06 - 7.25 (m, 3H), 7.01 (br s, 1H), 6.91 - 6.95 (m, 1H), 6.81 (s, 1H), 6.52 (br d, =8.8 Hz, 1H), 6.45 (br d, =l4.5 Hz, 1H), 5.59 (q, =6.8 Hz, 1H), 3.81 (br dd, =l3.6, 3.8 Hz, 1H), 3.46 - 3.54 (m, 1H), 3.34 - 3.46 (m, 3H), 3.29 - 3.32 (m, 1H partially obscured by H 2 0 peak), 3.10 (quin, J=1.6 Hz 1H), 2.85 - 3.05 (m, 2H), 2.72 (br d, =l6.l 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%)

NMR (500 MHz, DMSO-de) d ppm 8.00 (t, =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, =8.8 Hz, 1H), 6.45 (br d, =l4.5 Hz, 1H), 4.96 (q, J=6.6 Hz, 1H), 4.55 (br dd, =l2.6, 3.2 Hz, 1H), 3.46 - 3.54 (m, 1H), 3.34 - 3.46 (m, 2H), 3.29 - 3.32 (m, 1H partially obscured by H 2 0 peak), 3.22 -

3.26 (m, 1H), 3.10 (quin, =7.6 Hz, 1H), 2.85 - 3.05 (m, 3H), 2.16 - 2.24 (m, 1H), 2.06 - 2.15 (m, 1H), 1.55 (d, J=6.9 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.22 - 1.30 (m, 2H).

Compound 37

Major rotamer (65%)

ppm 7.97 - 8.03 (m, 2H), 7.32 (d, =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, =8.8, 1.9 Hz, 1H), 6.45 (dd, =l4.8, 1.9 Hz, 1H), 5.59 (q, 7=6.6 Hz, 1H), 3.81 (br dd, 7=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, 7=16.1 Hz, 1H), 2.62 (d, 7=4.4 Hz, 3H), 2.14 - 2.22 (m, 1H), 2.06 - 2.14 (m, 1H), 1.52 (d, 7=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.22 - 1.30 (m, 2H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.97 - 8.03 (m, 2H), 7.06 - 7.25 (m, 4H), 6.93 (d, 7=3.5 Hz, 1H), 6.77 (s, 1H), 6.52 (dd, 7=8.8, 1.9 Hz, 1H), 6.45 (dd, 7=14.8, 1.9 Hz, 1H),

4.96 (q, 7=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, 7=4.4 Hz, 3H), 2.14 - 2.22 (m, 1H), 2.06 - 2.14 (m, 1H), 1.55 (d, 7=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.22 - 1.30 (m, 2H).

Compound 38

Major rotamer (65%)

ppm 8.00 (t, 7=8.8 Hz, 1H), 7.32 (d, 7=7.3 Hz, 1H), 7.06

- 7.25 (m, 3H), 6.94 (d, 7=3.8 Hz, 1H), 6.80 (s, 1H), 6.53 (dd, 7=8.8, 1.9 Hz, 1H), 6.46 (dd, 7=14.7, 2.1 Hz, 1H), 5.59 (q, 7=6.6 Hz, 1H), 3.81 (br dd, 7=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, 7=16.1 Hz, 1H), 2.18 - 2.26 (m, 1H), 2.06 - 2.14 (m, 1H), 1.52 (d, 7=6.9 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.22 - 1.30 (m, 2H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-7 6 ) d ppm 8.00 (br d, 7=8.8 Hz, 1H), 7.06 - 7.25 (m, 4H), 6.93 (d, 7=3.5 Hz, 1H), 6.77 (s, 1H), 6.53 (dd, 7=8.8, 1.9 Hz, 1H), 6.46 (dd, 7=14.7, 2.1 Hz,

1H), 4.96 (q, 7=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, 7=6.9 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.22 - 1.30 (m, 2H).

Compound 39

Major rotamer (65%)

ppm 8.00 (t, 7=8.8 Hz, 1H), 7.32 (d, 7=7.6 Hz, 1H), 7.05

- 7.26 (m, 4H), 6.91 - 6.96 (m, 1H), 6.80 (s, 1H), 6.52 (br d, 7=9.1 Hz, 1H), 6.45 (br d, 7=14.7 Hz, 1H), 5.58 (q, 7=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, 7=16.2 Hz, 1H), 2.10 - 2.26 (m, 2H), 1.52 (d, 7=6.6 Hz, 3H), 1.30- 1.39 (m, 2H), 1.20 -1.30 (m, 2H).

Minor rotamer (35%)

ppm 8.00 (t, 7=8.8 Hz, 1H), 7.05 - 7.26 (m, 4H), 6.91 -

6.96 (m, 2H), 6.76 (s, 1H), 6.52 (br d, 7=9.1 Hz, 1H), 6.45 (br d, 7=14.7 Hz, 1H), 4.96 (q, J=6A Hz, 1H), 4.51 - 4.58 (m, 1H), 3.35 - 3.55 (m, 5H), 3.09 - 3.19 (m, 1H), 2.84 - 3.07 (m, 3H), 2.10 - 2.26 (m, 2H), 1.54 (d, J=1 A Hz, 3H), 1.30 - 1.39 (m, 2H), 1.20 - 1.30 (m, 2H).

Compound 40

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 11.94 (br s, 1H), 8.01 (t, ,7=8.8 Hz, 1H), 7.32 (d, ,7=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=9A Hz, 1H), 6.47 (dd, ,7=14.9, 1.8 Hz, 1H), 5.58 (q, J=6.6 Hz, 1H), 3.81 (br dd, ,7=13.1, 4.0 Hz, 1H), 3.35 - 3.57 (m, 5H), 3.21 - 3.29 (m, 1H), 3.19 (s, 3H), 2.85 - 3.06 (m, 2H), 2.71 (br d, =l6.2 Hz, 1H), 2.21 - 2.30 (m, 1H), 2.11 - 2.21 (m, 1H), 1.52 (d, ,7=7.1 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.22 - 1.29 (m, 2H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-de) d ppm 11.94 (br s, 1H), 8.01 (t, ,7=8.8 Hz, 1H), 7.05 - 7.25 (m, 4H), 6.91 - 6.97 (m, 1H), 6.77 (s, 1H), 6.54 (br d, ,7=9.1 Hz, 1H), 6.47 (dd, ,7=14.9, 1.8 Hz, 1H), 4.96 (q, ,7=6.2 Hz, 1H), 4.51 - 4.58 (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), 2.11 - 2.21 (m, 1H), 1.55 (d, ,7=6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.22 - 1.29 (m, 2H).

Compound 41

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 11.97 (s, 1H), 8.01 (t, ,7=8.8 Hz, 1H), 7.38 (d, ,7=5.6 Hz, 1H), 7.02 (d, ,7=5.1 Hz, 1H), 6.92 - 6.96 (m, 1H), 6.77 - 6.82 (m, 1H), 6.54 (br d, ,7=8.6 Hz, 1H), 6.48 (br d, ,7=14.7 Hz, 1H), 5.53 (q, ,7=7.1 Hz, 1H), 3.92 (br dd, ,7=13.6, 4.6 Hz, 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, 2H), 2.74 (br d, ,7=14.7 Hz, 1H), 2.23 - 2.31 (m, 1H), 2.12 - 2.21 (m, 1H), 1.46 (d, ,7=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.22 - 1.29 (m, 2H).

Minor rotamer (35%)

ppm 11.97 (s, 1H), 7.98 (t, ,7=8.6 Hz, 1H), 7.29 (d, ,7=5.1 Hz, 1H), 6.92 - 6.96 (m, 1H), 6.77 - 6.82 (m, 2H), 6.54 (br d, ,7=8.6 Hz, 1H), 6.48 (br d, ,7=14.7 Hz, 1H), 4.90 (q, ,7=6.1 Hz, 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, ,7=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.22 - 1.29 (m, 2H). Compound 42

Major rotamer (65%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (t, 7=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, ,7=14.8 Hz, 1H), 5.53 (q, 7=6.5 Hz, 1H), 3.92 (br dd, 7=13.9, 4.7 Hz, 1H), 3.49 (dd, 7=9.0, 7.7 Hz, 1H), 3.36 - 3.45 (m, 2H), 3.27 - 3.31 (m, 1H), 2.82 - 3.01 (m, 3H), 2.75 (br dd, 7=15.9, 2.1 Hz, 1H), 2.58 - 2.68 (m, 1H), 2.24 (d, 7= 7.6Hz, 2H), 2.10 - 2.18 (m, 1H), 1.64 - 1.74 (m, 1H), 1.46 (d, 7=6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.21 - 1.29 (m, 2H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (t, 7=8.8 Hz, 1H), 7.34 - 7.40 (m, 1H), 7.29 (d, 7=5.0 Hz, 1H), 6.92 - 6.95 (m, 1H), 6.77 - 6.86 (m, 3H), 6.50 (br d, 7=8.8 Hz, 1H), 6.41 (br d, 7=14.8 Hz, 1H), 4.90 (q, 7=6.3 Hz, 1H), 4.70 (br dd, 7=12.6, 4.4 Hz, 1H), 3.49 (dd, 7=9.0, 7.7 Hz, 1H), 3.36 - 3.45 (m, 1H), 3.27 - 3.31 (m, 1H), 3.21 (td, 7=12.3 Hz, 1H), 2.82

- 3.01 (m, 4H), 2.58 - 2.68 (m, 1H), 2.24 (d, 7=7.6 Hz, 2H), 2.10 - 2.18 (m, 1H), 1.64 - 1.74 (m, 1H), 1.50 (d, 7=6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.21 - 1.29 (m, 2H).

Compound 43

Major rotamer (65%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (br t, 7=8.8 Hz, 1H), 7.34 - 7.40 (m, 2H), 7.02 (d, 7=5.4 Hz, 1H), 6.91 - 6.95 (m, 1H), 6.77 - 6.86 (m, 2H), 6.50 (br d, 7=8.8 Hz, 1H), 6.41 (br d, 7=14.8 Hz, 1H), 5.53 (q, 7=6.4 Hz, 1H), 3.92 (br dd, 7=13.7, 4.6 Hz, 1H), 3.49 (br t, 7=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, 7=16.1, 2.2 Hz, 1H), 2.58 - 2.68 (m, 1H), 2.24 (d, 7=7.6 Hz, 2H), 2.10 - 2.18 (m, 1H), 1.64

- 1.74 (m, 1H), 1.46 (d, 7=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.22 - 1.30 (m, 2H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (br t, 7=8.8 Hz, 1H), 7.34 - 7.40 (m, 1H), 7.29 (d, 7=5.0 Hz, 1H), 6.91 - 6.95 (m, 1H), 6.77 - 6.86 (m, 3H), 6.50 (br d, 7=8.8 Hz, 1H), 6.41 (br d, 7=14.8 Hz, 1H), 4.90 (q, 7=6.5 Hz, 1H), 4.70 (br dd, 7=12.9, 4.4 Hz, 1H), 3.49 (br t, 7=8.4 Hz, 1H), 3.35 - 3.44 (m, 1H), 3.27 - 3.32 (m, 1H), 3.21 (br td, 7=12.2, 4.3 Hz, 1H), 2.83 - 3.01 (m, 4H), 2.58 - 2.68 (m, 1H), 2.24 (d, 7=7.6 Hz, 2H), 2.10 - 2.18 (m, 1H), 1.64

- 1.74 (m, 1H), 1.50 (d, 7=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.22 - 1.30 (m, 2H).

Compound 44

Major rotamer (65%)

ppm 8.00 (t, 7=8.8 Hz, 1H), 7.35 - 7.40 (m, 2H), 7.00 - 7.05 (m, 2H), 6.92 - 6.95 (m, 1H), 6.77 - 6.82 (m, 1H), 6.49 (br d, 7=8.8 Hz, 1H), 6.41 (dd, 7=14.7, 1.7 Hz, 1H), 5.53 (q, 7=6.6 Hz, 1H), 3.92 (dd, 7=13.7, 4.9 Hz, 1H), 3.72 (d, 7=9.8 Hz, 1H), 3.33 - 3.45 (m, 3H), 3.12 (d, ,7=9.8 Hz, 1H), 2.80 - 3.00 (m, 2H), 2.75 (dd, =l6.2, 2.7 Hz, 1H), 2.33 - 2.40 (m, 1H), 1.85 - 1.92 (m, 1H), 1.46 (d, ,7=6.9 Hz, 3H), 1.31 (s, 3H), 1.21 - 1.29 (m, 4H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-de) d ppm 7.99 (br t, ,7=8.8 Hz, 1H), 7.35 - 7.40 (m, 1H), 7.29 (d, ,7=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, ,7=8.8 Hz, 1H), 6.41 (dd, ,7=14.7, 1.7 Hz, 1H), 4.90 (q, ,7=6.5 Hz, 1H), 4.70 (br dd, ,7=12.8, 4.3 Hz, 1H), 3.72 (d, ,7=9.8 Hz, 1H), 3.33 - 3.45 (m, 2H), 3.21 (td, ,7=12.3, 4.4 Hz, 1H), 3.12 (d, ,7=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, ,7=6.6 Hz, 3H), 1.31 (s, 3H), 1.21 - 1.29 (m, 4H).

Compound 45

Major rotamer (65%)

ppm 8.00 (t, ,7=8.8 Hz, 1H), 7.34 - 7.40 (m, 2H), 7.00 - 7.04 (m, 2H), 6.91 - 6.95 (m, 1H), 6.76 - 6.81 (m, 1H), 6.49 (br d, ,7=9.1 Hz, 1H), 6.40 (dd, ,7=14.7, 2.0 Hz, 1H), 5.53 (q, ,7=6.7 Hz, 1H), 3.92 (dd, ,7=13.9, 5.3 Hz, 1H), 3.72 (d, ,7=10.1 Hz, 1H), 3.33 - 3.45 (m, 3H), 3.12 (d, ,7=10.1 Hz, 1H), 2.81 - 3.01 (m, 2H), 2.75 (dd, ,7=16.4, 2.7 Hz, 1H), 2.34 - 2.41 (m, 1H), 1.84 - 1.93 (m, 1H), 1.46 (d, ,7=7.1 Hz, 3H), 1.31 (s, 3H), 1.22 - 1.29 (m, 4H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-de) d ppm 7.99 (br t, ,7=8.8 Hz, 1H), 7.34 - 7.40 (m, 1H), 7.29 (d, ,7=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, ,7=9.1 Hz, 1H), 6.40 (dd, ,7=14.7, 2.0 Hz, 1H), 4.90 (q, ,7=6.1 Hz, 1H), 4.70 (dd, ,7=12.6, 4.0 Hz, 1H), 3.72 (d, ,7=10.1 Hz, 1H), 3.33 - 3.45 (m, 2H), 3.16 - 3.25 (m, 1H), 3.12 (d, ,7=10.1 Hz, 1H), 2.81 - 3.01 (m, 3H), 2.34 - 2.41 (m, 1H), 1.84 - 1.93 (m, 1H), 1.49 (d, ,7=6.6 Hz, 3H), 1.31 (s, 3H), 1.22 - 1.29 (m, 4H).

Compound 46

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 8.00 (t, ,7=8.8 Hz, 1H), 7.49 (br s, 1H), 7.38 (d, ,7=5.0 Hz, 1H), 7.01 (d, ,7=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, ,7=8.8 Hz, 1H), 6.44 (dd, ,7=14.8, 1.6 Hz, 1H), 5.53 (q, ,7=6.8 Hz, 1H), 3.93 (dd, ,7=13.7, 4.9 Hz, 1H), 3.48 - 3.53 (m, 1H), 3.36 - 3.45 (m, 3H), 3.31 - 3.35 (m, 1H), 3.09 (quin, ,7=7.6 Hz, 1H), 2.80 - 3.00 (m, 2H), 2.75 (dd, ,7=15.9, 2.7 Hz, 1H), 2.16 - 2.24 (m, 1H), 2.06 - 2.15 (m, 1H), 1.46 (d, ,7=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.23 - 1.30 (m, 2H). Minor rotamer (35%)

NMR (500 MHz, DMSO-de) d ppm 7.99 (br t, ,7=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, ,7=14.8, 1.6 Hz, 1H), 4.91 (q, J=6.3 Hz, 1H), 4.71 (br dd, ,7=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

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d 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, ,7=14.8, 1.6 Hz, 1H), 5.60 (q, ,7=6.8 Hz, 1H), 3.83 (br dd, ,7=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, ,7=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%)

NMR (500 MHz, DMSO-de) d 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, ,7=14.8, 1.6 Hz, 1H), 4.98 (q, J=6.4 Hz, 1H), 4.55 (dt, ,7=12.8, 3.7 Hz, 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

Major rotamer (65%)

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, .7=14.2, 2.2 Hz, 1H),

6.16 (d, .7=6.0 Hz, 1H), 5.59 (q, .7=6.4 Hz, 1H), 3.82 (br dd, .7=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), 3.16 - 3.23 (m, 1H), 2.94 - 3.05 (m, 2H), 2.87 - 2.94 (m, 2H), 2.74 (br d, .7=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%)

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, ,7=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, =l2.6, 3.8 Hz, 1H), 3.59 (td, ,7=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=6.6 Hz, 3H), 1.31 - 1.39 (m, 2H), 1.22 - 1.30 (m, 2H).

Compound 49

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 8.36 (t, J=9A Hz, 1H), 7.51 (br s, 1H), 7.32 (d,

J=1 A Hz, 1H), 7.05 - 7.25 (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, =l3.4, 3.8 Hz, 1H), 3.39 - 3.69 (m, 5H), 2.83 - 3.13 (m, 3H), 2.71 (br d, =l6.2 Hz, 1H), 2.15 - 2.25 (m, 1H), 2.04 - 2.15 (m, 1H), 1.52 (d, J=1 A Hz, 3H), 1.30 - 1.38 (m, 2H), 1.20 - 1.30 (m, 2H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-de) d ppm 8.36 (t, J=9A 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, =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

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 8.36 (t, J=9.3 Hz, 1H), 8.00 (q, J=4A Hz, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.06 - 7.26 (m, 3H), 6.91 - 6.97 (m, 1H), 6.83 (s, 1H), 6.53 (br d, =8.2 Hz, 1H), 5.58 (q, J=6.5 Hz, 1H), 3.81 (br dd, =l3.9, 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, =l6.l Hz, 1H), 2.62 (d, J=4A 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%)

ppm 8.36 (t, J=9.3 Hz, 1H), 8.00 (q, J=4A Hz, 1H), 7.06

- 7.26 (m, 4H), 6.91 - 6.97 (m, 1H), 6.79 (s, 1H), 6.53 (br d, =8.2 Hz, 1H), 4.96 (q, J=6J 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=4A Hz, 3H), 2.14 - 2.23 (m, 1H), 2.04

- 2.14 (m, 1H), 1.55 (d, =6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.21 - 1.30 (m, 2H).

Compound 51

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 11.99 (br s, 1H), 8.38 (t, J=9.3 Hz, 1H), 7.32 (d, =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=1.3, 1.0 Hz, 1H), 5.58 (q, J=6.5 Hz, 1H), 3.81 (dd, =l4.0, 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, ,7=16.4 Hz, 1H), 2.23 - 2.32 (m, 1H), 2.13 - 2.22 (m, 1H), 1.52 (d, ,7=6.9 Hz, 3H), 1.24 - 1.37 (m, 4H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-de) d ppm 11.99 (br s, 1H), 8.38 (t, ,7=9.3 Hz, 1H), 7.05 - 7.26 (m, 4H), 6.92 - 6.98 (m, 1H), 6.79 (s, 1H), 6.56 (br dd, ,7=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

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 8.84 (d, J=l 1.1 Hz, 1H), 7.52 (br s, 1H), 7.32 (br d, J=1.6 Hz, 1H), 6.95 - 7.27 (m, 5H), 6.84 (s, 1H), 6.45 (br d, ,7=14.2 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.80 (br dd, .7=13.4, 4.0 Hz, 1H), 3.40 - 3.73 (m, 5H), 2.85 - 3.13 (m, 3H), 2.71 (br d, ,7=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%)

NMR (400 MHz, DMSO-de) d ppm 8.84 (d, J=l 1.1 Hz, 1H), 7.52 (br s, 1H), 6.95 - 7.27 (m, 6H), 6.81 (s, 1H), 6.45 (br d, ,7=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

Major rotamer (65%)

ppm 8.84 (d, ,7=11.1 Hz, 1H), 8.00 (q, ,7=4.6 Hz, 1H), 7.32 (br d, ,7=7.1 Hz, 1H), 7.05 - 7.25 (m, 3H), 6.95 - 7.00 (m, 1H), 6.84 (s, 1H), 6.45 (d, =l4.2 Hz, 1H), 5.58 (q, ,7=6.6 Hz, 1H), 3.80 (br dd, ,7=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, ,7=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%)

ppm 8.84 (d, J=l 1.1 Hz, 1H), 8.00 (q, ,7=4.6 Hz, 1H), 7.05 - 7.25 (m, 4H), 6.95 - 7.00 (m, 1H), 6.81 (s, 1H), 6.45 (d, ,7=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, ,7=4.6 Hz, 3H), 2.03 - 2.23 (m, 2H), 1.48 - 1.58 (m, 3H), 1.22 - 1.38 (m, 4H). Compound 54

Major rotamer (65%)

NMR (500 MHz, DMSO-7 6 ) d ppm 11.97 (br s, 1H), 8.85 (d, J=\ 1.4 Hz, 1H), 7.32 (d, 7=7.3 Hz, 1H), 7.06 - 7.25 (m, 3H), 6.99 (br d, 7=2.8 Hz, 1H), 6.85 (s, 1H), 6.48 (br d, ,7=13.9 Hz, 1H), 5.59 (q, 7=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, 7=16.3 Hz, 1H), 2.21 - 2.30 (m, 1H), 2.12 - 2.21 (m, 1H), 1.52 (d, 7=6.6 Hz, 3H), 1.31 - 1.37 (m, 2H), 1.24 - 1.31 (m, 2H).

Minor rotamer (35%)

ppm 11.97 (br s, 1H), 8.84 (d, 7=11.4 Hz, 1H), 7.06 - 7.25 (m, 4 H), 6.98 (br d, 7=2.8 Hz, 1H), 6.81 (s, 1H), 6.48 (br d, 7=13.9 Hz, 1H), 4.95 (q, 7=6.6 Hz, 1H), 4.52 - 4.58 (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, 1H), 3.18 - 3.28 (m, 2H), 3.22 (s, 3H), 2.86 - 3.05 (m, 3H), 2.21 - 2.30 (m, 1H), 2.12 - 2.21 (m, 1H), 1.54 (d, 7=6.6 Hz, 3H), 1.31 - 1.37 (m, 2H), 1.24 - 1.31 (m, 2H).

Compound 55

Major rotamer (65%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.81 (dd, 7=14.5, 6.9 Hz, 1H), 7.50 (br s, 1H), 7.32 (d, 7=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, 7=13.6, 7.6 Hz, 1H), 5.58 (q, 7=6.6 Hz, 1H), 3.80 (br dd, 7=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, 7=16.1 Hz, 1H), 2.11 - 2.19 (m, 1H), 2.00 - 2.09 (m, 1H), 1.52 (d, 7=6.9 Hz, 3H), 1.31 - 1.38 (m, 2H), 1.22 - 1.30 (m, 2H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.81 (dd, 7=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, 7=7.6 Hz, 1H), 6.97 - 7.03 (m, 2H), 6.81 (s, 1H), 6.64 (dd, 7=13.6, 7.6 Hz, 1H), 4.95 (q, 7=6.7 Hz, 1H), 4.54 (br dd, 7= 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, 7=6.6 Hz, 3H), 1.31

- 1.38 (m, 2H), 1.22 - 1.30 (m, 2H).

Compound 56

Major rotamer (65%)

ppm 8.28 - 8.31 (m, 2H), 7.91 (t, 7=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, 7=8.8 Hz, 1H), 6.45 (br d, 7=14.8 Hz, 1H), 5.63 (q, 7=6.8 Hz, 1H), 3.99 (br dd, 7=14.0, 4.3 Hz, 1H), 3.46 - 3.58 (m, 2H), 3.27 - 3.44 (m, 3H partially obscured by H 2 0 peak), 3.03 - 3.12 (m, 2H), 2.76 (br d, ,7=16.7 Hz, 1H), 2.16 - 2.23 (m, 1H), 2.05 - 2.14 (m, 1H), 1.55 (d, 7=6.9 Hz, 3H).

Minor rotamer (35%)

ppm 8.24 - 8.28 (m, 2H), 7.91 (t, 7=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, 7=8.8 Hz, 1H), 6.45 (br d, 7=14.8 Hz, 1H), 5.14 (q, 7=6.9 Hz, 1H), 4.59 (br dd, 7=12.6, 3.8 Hz, 1H), 3.46 - 3.58 (m, 1H), 3.27 - 3.44 (m, 3H partially obscured by H 2 0 peak), 3.03 - 3.12 (m, 2H), 2.85 - 3.00 (m, 2H), 2.16 - 2.23 (m, 1H), 2.05

- 2.14 (m, 1H), 1.61 (d, 7=6.6 Hz, 3H).

Compound 57

Major rotamer (65%)

ppm 8.39 (d, 7=8.8 Hz, 2H), 7.94 (t, 7=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, 7=8.8 Hz, 1H), 6.45 (br d, 7=14.5 Hz, 1H), 5.63 (q, 7=6.3 Hz, 1H), 3.97 (br dd, 7=13.9, 3.8 Hz, 1H), 3.90 (s, 3H), 3.47 - 3.56 (m, 2H), 3.36 - 3.44 (m, 2H), 3.26 - 3.32 (m, 1H partially obscured by H 2 0 peak), 3.02 - 3.12 (m, 2H), 2.75 (br d, 7=17.0 Hz, 1H), 2.16

- 2.24 (m, 1H), 2.06 - 2.15 (m, 1H), 1.55 (d, 7=6.6 Hz, 3H).

Minor rotamer (35%)

ppm 8.35 (d, 7=8.8 Hz, 2H), 7.94 (t, 7=8.7 Hz, 1H), 7.51 (br s, 1H), 7.32 - 7.36 (m, 1H), 7.09 - 7.27 (m, 6H), 6.98 - 7.05 (m, 2H), 6.51 (br d, 7=8.8 Hz, 1H), 6.45 (br d, 7=14.5 Hz, 1H), 5.12 (q, 7=6.0 Hz, 1H), 4.59 (br dd, 7=13.2, 3.8 Hz, 1H), 3.89 (s, 3H), 3.47 - 3.56 (m, 1H), 3.36 - 3.44 (m, 2H), 3.26 - 3.32 (m, 1H partially obscured by H 2 0 peak), 3.02 - 3.12 (m, 2H), 2.85 - 2.99 (m, 2H), 2.16 - 2.24 (m, 1H), 2.06

- 2.15 (m, 1H), 1.60 (d, 7=6.6 Hz, 3H).

Compound 58

Major rotamer (65%)

NMR (500 MHz, DMSO-7 6 ) d ppm 8.23 (br d, 7=7.9 Hz, 2H), 7.91 (br t, 7=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, 7=8.5 Hz, 1H), 6.45 (br d, 7=14.8 Hz, 1H), 5.63 (q, 7=6.5 Hz, 1H), 3.98 (br dd, 7=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, 7=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, 7=6.6 Hz, 3H). Minor rotamer (35%)

ppm 8.20 (br d, J=1.9 Hz, 2H), 7.91 (br t, ,7=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, .7=8.5 Hz, 1H), 6.45 (br d, .7=14.8 Hz, 1H), 5.13 (q, .7=6.4 Hz, 1H), 4.59 (br dd, =l3.2, 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, ,7=6.6 Hz, 3H).

Compound 59

Major rotamer (65%)

ppm 8.34 (d, ,7=8.5 Hz, 2H), 7.92 (t, ,7=8.7 Hz, 1H), 7.69

- 7.74 (m, 2H), 7.51 (br s, 1H), 7.43 (s, 1H), 7.34 (d, ,7=7.6 Hz, 1H), 7.08 - 7.26 (m, 3H), 7.04 - 7.08 (m, 1H), 7.00 (br s, 1H), 6.50 (br d, ,7=8.8 Hz, 1H), 6.45 (br d, ,7=14.8 Hz, 1H), 5.63 (q, ,7=6.5 Hz, 1H), 3.95 - 4.01 (m, 1H), 3.46 - 3.59 (m, 2H), 3.27 - 3.44 (m, 3H partially obscured by H 2 0 peak), 3.02 - 3.12 (m, 2H), 2.75 (br d, ,7=17.0 Hz, 1H), 2.16 - 2.24 (m, 1H), 2.05 - 2.14 (m, 1H), 1.55 (d, ,7=6.6 Hz, 3H).

Minor rotamer (35%)

ppm 8.31 (d, ,7=8.5 Hz, 2H), 7.92 (t, ,7=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, ,7=8.8 Hz, 1H), 6.45 (br d, ,7=14.8 Hz, 1H), 5.13 (q, ,7=6.6 Hz, 1H), 4.56 - 4.62 (m, 1H), 3.46 - 3.59 (m, 1H), 3.27 - 3.44 (m, 3H partially obscured by H 2 0 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, ,7=6.6 Hz, 3H).

Compound 60

Major rotamer (65%)

ppm 8.34 - 8.44 (m, 2H), 7.92 (t, ,7=8.8 Hz, 1H), 7.45 - 7.54 (m, 3H), 7.41 (s, 1H), 7.34 (d, ,7=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, ,7=8.8 Hz, 1H), 6.45 (dd, ,7=14.5, 1.6 Hz, 1H), 5.63 (q, ,7=6.7 Hz, 1H), 3.98 (br dd, .7=13.4, 3.9 Hz, 1H), 3.47 - 3.57 (m, 2H), 3.27 - 3.45 (m, 3H partially obscured by H 2 0 peak), 3.03 - 3.12 (m, 2H), 2.75 (br d, ,7=16.1 Hz, 1H), 2.16 - 2.24 (m, 1H), 2.05 - 2.15 (m, 1H), 1.55 (d, .7=6.6 Hz, 3H).

Minor rotamer (35%)

ppm 8.34 - 8.44 (m, 2H), 7.92 (t, ,7=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, ,7=8.8 Hz, 1H), 6.45 (dd, .7=14.5, 1.6 Hz, 1H), 5.13 (q, =6.7 Hz, 1H), 4.59 (br dd, ,7=12.8, 4.9 Hz, 1H), 3.47 - 3.57 (m, 1H), 3.27 - 3.45 (m, 3H partially obscured by H 2 0 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, 7=6.6 Hz, 3H).

Compound 61

Major rotamer (65%)

NMR (500 MHz, DMSO-7 6 ) d ppm 8.49 (d, 7=8.2 Hz, 2H), 7.98 - 8.05 (m, 2H), 7.91 (t, 7=8.8 Hz, 1H), 7.42 - 7.51 (m, 2H), 7.34 (d, 7=7.3 Hz, 1H), 7.07 - 7.27 (m, 4H), 6.98 (br s, 1H), 6.49 (br d, 7=8.8 Hz, 1H), 6.45 (dd, 7=14.7, 1.7 Hz, 1H), 5.64 (q, 7=6.5 Hz, 1H), 4.00 (br dd, 7=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, 7=16.7 Hz, 1H), 2.16 - 2.24 (m, 1H), 2.06 - 2.14 (m, 1H), 1.56 (d, 7=6.6 Hz, 3H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-7 6 ) d ppm 8.46 (d, 7=8.2 Hz, 2H), 7.98 - 8.05 (m, 2H), 7.91 (t, 7=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, 7=8.8 Hz, 1H), 6.45 (dd, 7=14.7, 1.7 Hz, 1H), 5.15 (q, 7=6.8 Hz, 1H), 4.59 (br dd, 7=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), 1.61 (d, J=6.6 Hz, 3H).

Compound 62

Major rotamer

NMR (500 MHz, DMSO-7 6 ) d ppm 8.47 (d, 7=8.2 Hz, 2H), 8.09 - 8.14 (m, 2H), 7.90 (t, 7=8.8 Hz, 1H), 7.43 - 7.53 (m, 2H), 7.34 (br d, 7=7.6 Hz, 1H), 7.07 - 7.27 (m, 4H), 7.00 (br s, 1H), 6.49 (br d, 7=8.8 Hz, 1H), 6.45 (br d, 7=15.1 Hz, 1H), 5.63 (q, 7=6.8 Hz, 1H), 3.99 (br dd, ,7=13.1, 3.9 Hz, 1H), 3.46 - 3.57 (m, 2H), 3.28 - 3.44 (m, 3H partially obscured by H2O peak), 3.02 - 3.12 (m, 2H), 2.75 (br d, 7=16.4 Hz, 1H), 2.16 - 2.23 (m, 1H), 2.05 - 2.14 (m, 1H), 1.55 (d, 7=6.9 Hz, 3H).

Minor rotamer

NMR (500 MHz, DMSO-7 6 ) d ppm 8.44 (br d, 7=8.5 Hz, 2H), 8.09 - 8.14 (m, 2H), 7.90 (t, 7=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, 7=8.8 Hz, 1H), 6.45 (br d, 7=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 obscured by H 2 0 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, 7=6.6 Hz, 3H).

Compound 63

Major rotamer (65%)

NMR (500 MHz, DMSO-7 6 ) d ppm 8.84 - 8.91 (m, 2H), 8.28 (br d, 7=5.4 Hz, 2H), 7.93 (br t, 7=8.7 Hz, 1H), 7.49 - 7.58 (m, 2H), 7.34 (br d, 7=7.6 Hz, 1H), 7.06 - 7.27 (m, 4H), 7.00 (br s, 1H), 6.51 (br d, =8.8 Hz, 1H), 6.46 (br d, =l4.5 Hz, 1H), 5.64 (q, J=6.\ 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, =l6.l 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%)

NMR (500 MHz, DMSO-de) d ppm 8.84 - 8.91 (m, 2H), 8.25 (br d, J=5J Hz, 2H), 7.93 (br t, =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, =8.8 Hz, 1H), 6.46 (br d, =l4.5 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

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 9.68 (s, 2H), 9.34 - 9.46 (m, 1H), 7.90 (br t, =8.6 Hz, 1H), 7.67 (s, 1H), 7.50 (br s, 1H), 6.95 - 7.37 (m, 6H), 6.52 (br d, =8.6 Hz, 1H), 6.45 (br d, =l4.7 Hz, 1H), 5.59 - 5.68 (m, 1H), 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=\l .1 Hz, 1H), 2.04 - 2.26 (m, 2H), 1.56 (br d, J=6.\ Hz, 3H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-de) d ppm 9.65 (s, 2H), 9.34 - 9.46 (m, 1H), 7.90 (br t, =8.6 Hz, 1H), 7.63 (s, 1H), 7.50 (br s, 1H), 6.95 - 7.37 (m, 6H), 6.52 (br d, =8.6 Hz, 1H), 6.45 (br d, =l4.7 Hz, 1H), 5.08 - 5.16 (m, 1H), 4.60 (br d, J=\ 1.1 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), 2.04 - 2.26 (m, 2H), 1.61 (br d, J=6.\ Hz, 3H).

Compound 65

Major rotamer (65%)

ppm 7.98 (t, =8.5 Hz, 1H), 7.29 - 7.41 (m, 2H), 7.05 - 7.25 (m, 3H), 6.91 - 6.96 (m, 1H), 6.85 (br s, 1H), 6.81 (s, 1H), 6.31 - 6.41 (m, 2H), 5.58 (q, =6.8 Hz, 1H), 4.04 (t, =7.8 Hz, 2H), 3.81 (br dd, =l3.l, 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, =l6.l Hz, 1H), 2.44 - 2.48 (m, 2H partially obscured by DMSO peak), 1.52 (d, J=6.1 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.21 - 1.29 (m, 2H).

Minor rotamer (35%)

ppm 7.98 (t, =8.5 Hz, 1H), 7.29 - 7.41 (m, 1H), 7.05 - 7.25 (m, 4H), 6.91 - 6.96 (m, 1H), 6.85 (br s, 1H), 6.78 (s, 1H), 6.31 - 6.41 (m, 2H), 4.96 (q, J=6.1 Hz, 1H), 4.51 - 4.59 (m, 1H), 4.04 (t, =7.8 Hz, 2H), 3.59 (dd, J=1.3, 5.9 Hz,

2H), 3.22 - 3.30 (m, 1H), 2.85 - 3.06 (m, 4H), 2.44 - 2.48 (m, 2H partially obscured by DMSO peak), 1.55 (d, J=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.21 - 1.29 (m, 2H).

Compound 66

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 7.98 (t, =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, =8.7, 2.0 Hz, 1H), 6.34 (br d, =l3.6 Hz, 1H), 5.58 (q, J=6.5 Hz, 1H), 4.03 (t, J=1.7 Hz, 2H), 3.81 (br dd, =l3.6, 3.8 Hz, 1H), 3.59 (dd, J=1 A, 5.8 Hz, 2H), 3.42 - 3.50 (m, 1H), 2.81 - 3.05 (m, 3H), 2.71 (br d, =l6.7 Hz, 1H), 2.58 (d, J=4A 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%)

NMR (500 MHz, DMSO-de) d ppm 7.98 (br t, =8.7 Hz, 1H), 7.81 - 7.85 (m, 1H), 7.06

- 7.25 (m, 4H), 6.93 (d, J=3.5 Hz, 1H), 6.78 (s, 1H), 6.37 (dd, =8.7, 2.0 Hz, 1H), 6.34 (br d, =l3.6 Hz, 1H), 4.96 (q, J=6J Hz, 1H), 4.52 - 4.58 (m, 1H), 4.03 (t, J=1.7 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=4A 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

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 7.98 (br t, =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, =6.3 Hz, 1H), 5.58 (q, =7.0 Hz, 1H), 4.58 - 4.65 (m, 1H), 4.16 (t, =7.3 Hz, 2H), 3.81 (br dd, =l3.2, 4.1 Hz, 1H), 3.63 (dd, J=1.9, 4.7 Hz, 2H), 3.43 - 3.50 (m, 1H), 2.83 - 3.06 (m, 2H), 2.72 (br d, =l6.4 Hz, 1H), 1.52 (d, =6.6 Hz, 3H), 1.30 - 1.36 (m, 2H), 1.21 - 1.29 (m, 2H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-de) d ppm 7.98 (br t, =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=6A Hz, 1H), 4.58 - 4.65 (m, 1H), 4.51 - 4.57 (m, 1H), 4.16 (t, J=1.3 Hz, 2H), 3.63 (dd, J=1.9, 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

Major rotamer (65%)

ppm 8.00 (t, 7=9.0 Hz, 1H), 7.28 - 7.36 (m, 2H), 7.06 - 7.25 (m, 3H), 6.95 - 6.99 (m, 1H), 6.92 (br d, 7=8.8 Hz, 1H), 6.88 (br d, 7=15.1 Hz, 1H), 6.83 (s, 1H), 6.80 (br s, 1H), 5.59 (q, 7=6.8 Hz, 1H), 3.89 (br d, 7=12.9 Hz, 2H), 3.82 (br dd, ,7=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, 7=16.4 Hz, 1H), 2.29 - 2.38 (m, 1H), 1.76 - 1.83 (m, 2H), 1.62 (br qd, 7=12.2, 3.6 Hz, 2H), 1.52 (d, 7=6.9 Hz, 3H), 1.31 - 1.38 (m, 2H), 1.24 - 1.30 (m, 2H).

Minor rotamer (35%)

ppm 8.00 (t, J=9.0 Hz, 1H), 7.28 - 7.36 (m, 1H), 7.06 - 7.25 (m, 4H), 6.95 - 6.99 (m, 1H), 6.92 (br d, 7=8.8 Hz, 1H), 6.88 (br d, 7=15.1 Hz, 1H), 6.80 (br s, 1H), 6.79 (s, 1H), 4.97 (q, 7=6.6 Hz, 1H), 4.55 (br dd, 7=12.9, 3.2 Hz, 1H), 3.89 (br d, 7=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, 7=12.2, 3.6 Hz, 2H), 1.55 (d, 7=6.6 Hz,

3H), 1.31 - 1.38 (m, 2H), 1.24 - 1.30 (m, 2H).

Compound 69

Major rotamer (65%)

NMR (400 MHz, DMSO-7 6 ) d ppm 8.00 (t, 7=8.9 Hz, 1H), 7.41 (br s, 1H), 7.32 (d, 7=7.2 Hz, 1H), 7.05 - 7.25 (m, 3H), 6.86 - 7.00 (m, 4H), 6.83 (s, 1H), 5.59 (q, 7=6.6 Hz, 1H), 3.89 (br d, 7=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, 7=16.3 Hz, 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), 1.52 (d, 7=6.8 Hz, 3H), 1.30 - 1.39 (m, 2H), 1.22 - 1.30 (m, 2H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-7 6 ) d ppm 8.00 (t, 7=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, 7=6.6 Hz, 1H), 4.55 (br dd, 7=11.6, 3.9 Hz, 1H), 3.89 (br d, 7=13.0 Hz, 1H), 3.78 - 3.86 (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, 7=6.7 Hz, 3H), 1.30 - 1.39 (m, 2H), 1.22 - 1.30 (m, 2H).

Compound 70

Major rotamer (65%)

ppm 7.99 (t, 7=9.0 Hz, 1H), 7.32 (d, 7=7.6 Hz, 1H), 7.27 (br s, 1H), 7.05 - 7.25 (m, 3H), 6.95 - 6.98 (m, 1H), 6.90 (br d, 7=8.8 Hz, 1H), 6.85 (dd, 7=15.4, 1.9 Hz, 1H), 6.82 (s, 1H), 6.76 (br s, 1H), 5.59 (q, 7=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, ^=11.7 Hz, 2H), 2.72 (br d, =l6.4 Hz, 1H), 2.01 (s, 2H), 1.85 - 1.95 (m, 1H), 1.74 (br d, ^=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%)

NMR (500 MHz, DMSO-de) d 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, =8.8 Hz, 1H), 6.85 (dd, =l5.4, 1.9 Hz, 1H),

6.79 (s, 1H), 6.76 (br s, 1H), 4.97 (q, =6.5 Hz, 1H), 4.55 (br dd, =l3. l, 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, ,7=11.7 Hz, 2H), 2.03 (s, 2H), 1.85 - 1.95 (m, 1H), 1.74 (br d, J=l 1.7 Hz, 2H), 1.55 (d, J=6.6 Hz, 3H), 1.31 - 1.37 (m, 2H), 1.22 - 1.30 (m, 4H).

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 7.99 (br t, =8.9 Hz, 1H), 7.34 (br s, 1H), 7.32 (br d, J=1.9 Hz, 1H), 7.06 - 7.26 (m, 3H), 6.94 - 6.98 (m, 1H), 6.88 (br d, =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, =l6.3 Hz, 1H), 2.63 (dd, =l2. l, 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, =6.8 Hz, 3H), 1.30 -

1.38 (m, 2H), 1.24 - 1.30 (m, 2H), 1.12 - 1.23 (m, 2H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-de) d ppm 7.99 (br t, =8.9 Hz, 1H), 7.34 (br s, 1H), 7.06 -

7.26 (m, 4H), 6.94 - 6.98 (m, 1H), 6.88 (br d, =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, =l2.0, 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, =l2. l, 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=6J Hz, 3H), 1.30 - 1.38 (m, 2H), 1.24 - 1.30 (m, 2H), 1.12 - 1.23 (m, 2H).

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 8.00 (br t, =8.5 Hz, 1H), 7.76 (br d, =3.8 Hz, 1H), 7.32 (br d, =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, =l2.3 Hz, 2H), 3.82 (br d, =9.8 Hz, 1H), 3.46 (br t, J=l 1.2 Hz, 1H), 2.79 - 3.06 (m, 4H), 2.72 (br d, =l5.8 Hz, 1H), 2.58 (d, J=4A Hz, 3H), 2.29 -

2.38 (m, 1H), 1.72 - 1.80 (m, 2H), 1.59 - 1.69 (m, 2H), 1.52 (br d, =6.3 Hz, 3H), 1.30 -

1.38 (m, 2H), 1.23 - 1.30 (m, 2H). Minor rotamer (35%)

ppm 8.00 (br t, =8.5 Hz, 1H), 7.76 (br d, =3.8 Hz,

1H), 7.06 - 7.27 (m, 4H), 6.85 - 7.00 (m, 3H), 6.79 (s, 1H), 4.97 (q, =6.3 Hz, 1H), 4.55 (br d, =9.8 Hz, 1H), 3.89 (d, =l2.3 Hz, 2H), 3.22 - 3.30 (m, 1H), 2.79 - 3.06 (m, 5H), 2.58 (d, J=4.l 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

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 8.00 (br t, =8.8 Hz, 1H), 7.86 (br d, J=4A Hz,

1H), 7.32 (br d, =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=4A Hz, 3H), 2.35 - 2.45 (m, 1H), 1.85 (br d, =l0.7 Hz, 1H),

1.68 - 1.76 (m, 1H), 1.56 - 1.67 (m, 2H), 1.52 (br d, J=6.6 Hz, 3H), 1.31 - 1.38 (m, 2H), 1.23 - 1.30 (m, 2H).

Minor rotamer (35%)

ppm 8.00 (br t, =8.8 Hz, 1H), 7.86 (br d, J=4A 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, =l l.O 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=4A Hz, 3H), 2.35 - 2.45 (m, 1H), 1.85 (br d, =l0.7 Hz, 1H),

1.68 - 1.76 (m, 1H), 1.56 - 1.67 (m, 2H), 1.55 (br d, J=6.6 Hz, 3H), 1.31 - 1.38 (m, 2H), 1.23 - 1.30 (m, 2H).

Compound 74

Major rotamer (65%)

ppm 7.99 (br t, J=9.0 Hz, 1H), 7.32 (br d, =7.3 Hz,

1H), 7.06 - 7.26 (m, 3H), 6.94 - 6.98 (m, 1H), 6.91 (br d, J=9A Hz, 1H), 6.86 (br d, =l5.4 Hz, 1H), 6.83 (s, 1H), 5.59 (q, =6.8 Hz, 1H), 4.72 (d, J=4A Hz, 1H), 3.81 (br dd, =l2.9, 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, =l6.l Hz, 1H), 1.79 - 1.86 (m, 2H), 1.52 (d, =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%)

NMR (500 MHz, DMSO-de) d 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=9A Hz, 1H), 6.86 (br d, =l5.4 Hz, 1H), 6.79 (s, 1H), 4.96 (q, J=6.6 Hz, 1H), 4.72 (d, J=4A Hz, 1H), 4.55 (br dd, =l2.3, 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

Major rotamer (65%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (br t, 7=9.0 Hz, 1H), 7.32 (d, 7=7.3 Hz, 1H), 7.06 - 7.25 (m, 3H), 6.94 - 6.98 (m, 1H), 6.88 (br d, 7=8.8 Hz, 1H), 6.82 (s, 1H), 6.82 (br dd, ,7=15.3, 1.4 Hz, 1H), 5.59 (q, 7=6.6 Hz, 1H), 4.87 (d, 7=4.4 Hz, 1H), 3.81 (br dd, 7=13.7, 3.9 Hz, 1H), 3.71 (br d, 7=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, 7=6.6 Hz, 3H), 1.28 - 1.41 (m, 4H), 1.22 - 1.30 (m, 2H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-7 6 ) d ppm 7.99 (br t, 7=9.0 Hz, 1H), 7.06 - 7.25 (m, 4H), 6.94

- 6.98 (m, 1H), 6.88 (br d, 7=8.8 Hz, 1H), 6.82 (br dd, 7=15.3, 1.4 Hz, 1H), 6.79 (s, 1H), 4.96 (q, 7=6.6 Hz, 1H), 4.87 (d, 7=4.4 Hz, 1H), 4.55 (br dd, 7=12.1, 4.3 Hz, 1H), 3.71 (br d, 7=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, 7=6.6 Hz, 3H), 1.28 - 1.41 (m, 4H), 1.22 - 1.30 (m, 2H).

Compound 76

Major rotamer (65%)

NMR (400 MHz, DMSO-7 6 ) d ppm 9.76 (br s, 1H), 8.02 (t, 7=8.9 Hz, 1H), 7.32 (d, 7=7.2 Hz, 1H), 7.09 - 7.26 (m, 3H), 6.92 - 6.97 (m, 1H), 6.81 (s, 1H), 6.55 (br d, 7=8.7 Hz, 1H), 6.49 (br d, 7=14.7 Hz, 1H), 5.59 (q, 7=6.6 Hz, 1H), 4.49 - 4.59 (m, 1H), 3.81 (br dd, 7=13.6, 4.5 Hz, 1H), 3.64 (dd, 7=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, 7=16.1 Hz, 1H), 2.23 - 2.32 (m, 1H), 2.02 - 2.12 (m, 1H), 1.52 (d, 7=6.7 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.21 - 1.30 (m, 2H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-7 6 ) d ppm 9.76 (br s, 1H), 8.02 (t, 7=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, 7=8.7 Hz, 1H), 6.49 (br d, 7=14.7 Hz, 1H), 4.96 (q, 7=6.9 Hz, 1H), 4.49 - 4.59 (m, 2H), 3.64 (dd, 7=10.2, 6.8 Hz, 1H), 3.44 - 3.52 (m, 1H), 3.35 - 3.44 (m, 2H), 3.21 - 3.28 (m, 1H), 2.85 - 3.06 (m, 3H), 2.23 - 2.32 (m, 1H), 2.02 - 2.12 (m, 1H), 1.55 (d, 7=6.7 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.21 - 1.30 (m, 2H).

Compound 77

Major rotamer (65%)

ppm 8.01 (t, 7=8.8 Hz, 1H), 7.32 (d, 7=7.6 Hz, 1H), 7.20

- 7.25 (m, 1H), 7.15 - 7.20 (m, 2H), 6.94 (d, 7=3.8 Hz, 1H), 6.81 (s, 1H), 6.66 (br s, 1H), 6.55 (br d, =8.8 Hz, 1H), 6.52 (br s, 1H), 6.49 (br dd, =l4.5, 1.6 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 5.23 (br s, 1H), 3.81 (br dd, =l3.9, 3.5 Hz, 1H), 3.60 (dd, J=l 1.5, 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, =l6.4 Hz, 1H), 2.19 - 2.29 (m, 1H), 2.06 - 2.13 (m, 1H), 1.52 (d, =6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.21

- 1.30 (m, 2H).

Minor rotamer (35%)

ppm 8.01 (t, =8.8 Hz, 1H), 7.15 - 7.20 (m, 2H), 7.10 -

7.14 (m, 1H), 7.08 (d, =7.3 Hz, 1H), 6.93 (d, =3.8 Hz, 1H), 6.77 (s, 1H), 6.66 (br s, 1H), 6.55 (br d, =8.8 Hz, 1H), 6.52 (br s, 1H), 6.49 (br dd, =l4.5, 1.6 Hz, 1H), 5.23 (br s, 1H), 4.96 (q, J=6J Hz, 1H), 4.55 (br dd, =l2.3, 3.8 Hz, 1H), 3.60 (dd, J=l 1.5, 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

Major rotamer (65%)

ppm 8.01 (t, =8.8 Hz, 1H), 7.32 (d, =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, =8.8 Hz, 1H), 6.52 (br s, 1H), 6.49 (br d, =l4.8 Hz, 1H), 5.59 (q, J=6.5 Hz, 1H), 5.23 (br s, 1H), 3.81 (br dd, =l4.3, 4.3 Hz, 1H), 3.60 (dd, J=l 1.5, 4.6 Hz, 1H), 3.33 - 3.50 (m, 4H), 2.82 - 3.06 (m, 2H), 2.72 (br d, =l6.4 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%)

ppm 8.01 (t, =8.8 Hz, 1H), 7.15 - 7.21 (m, 2H), 7.10 -

7.15 (m, 1H), 7.08 (d, =7.3 Hz, 1H), 6.93 (d, =3.8 Hz, 1H), 6.77 (s, 1H), 6.66 (br s, 1H), 6.54 (br d, =8.8 Hz, 1H), 6.52 (br s, 1H), 6.49 (br d, =l4.8 Hz, 1H), 5.23 (br s, 1H), 4.96 (q, =6.8 Hz, 1H), 4.51 - 4.58 (m, 1H), 3.60 (dd, J=l 1.5, 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).

Compound 79

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 8.00 (br t, =8.7 Hz, 1H), 7.38 (br s, 1H), 7.32 (br d, =7.3 Hz, 1H), 7.10 - 7.26 (m, 3H), 6.98 - 7.03 (m, 1H), 6.93 (br d, =8.6 Hz, 1H), 6.84

- 6.90 (m, 2H), 5.59 (q, =6.8 Hz, 1H), 3.91 - 4.01 (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%)

NMR (400 MHz, DMSO-de) d ppm 8.00 (br t, =8.7 Hz, 1H), 7.38 (br s, 1H), 7.10 - 7.26 (m, 3H), 7.08 (br d, J=12 Hz, 1H), 6.98 - 7.03 (m, 1H), 6.93 (br d, =8.6 Hz, 1H), 6.84 - 6.90 (m, 1H), 6.84 - 6.91 (m, 1H), 6.82 (s, 1H), 4.96 (q, =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), 2.02 - 2.21 (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

Major rotamer (65%)

ppm 8.00 (t, =8.8 Hz, 1H), 7.41 (s, 1H), 7.32 (d, =7.3 Hz, 1H), 7.14 - 7.25 (m, 3H), 7.04 (s, 1H), 6.93 (d, =3.8 Hz, 1H), 6.80 (s, 1H), 6.54 (dd, J=8.8, 2.2 Hz, 1H), 6.43 (dd, =l4.8, 1.9 Hz, 1H), 5.59 (q, =6.8 Hz, 1H), 4.20 (quin,

J=6.5 Hz, 1H), 3.82 (ddd, =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, =l6.l 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%)

ppm 8.00 (t, =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, =3.8 Hz, 1H), 6.77 (s, 1H), 6.54 (dd, =8.8, 2.2 Hz, 1H), 6.43 (dd, =l4.8, 1.9 Hz, 1H), 4.96 (q, J=6.5 Hz, 1H),

4.55 (ddd, =l2.9, 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, =6.3 Hz, 3H).

Compound 81

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 7.98 (t, =8.8 Hz, 1H), 7.47 (br s, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.06 - 7.25 (m, 3H), 6.87 - 6.98 (m, 2H), 6.80 (s, 1H), 6.53 (dd, =9.0, 1.7 Hz, 1H), 6.44 (br d, =l4.8 Hz, 1H), 5.59 (q, J=6.9 Hz, 1H), 4.01 - 4.08 (m, 1H), 3.82 (br dd, =l3.2, 4.1 Hz, 1H), 3.35 - 3.50 (m, 2H), 3.21 - 3.30 (m, 1H), 2.82 - 3.05 (m, 2H), 2.68 - 2.75 (m, 2H), 2.20 - 2.29 (m, 1H), 2.06 - 2.15 (m, 1H), 1.52 (d, =6.9 Hz, 3H), 1.29 - 1.37 (m, 2H), 1.25 - 1.29 (m, 2H), 1.22 (br d, =6.3 Hz, 3H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-de) d ppm 7.98 (t, =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, =9.0, 1.7 Hz, 1H), 6.44 (br d, =l4.8 Hz, 1H), 4.97 (q, .7=7.1 Hz, 1H), 4.55 (br dd, =l2.6, 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, ,7=6.3 Hz, 3H).

Compound 82

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 7.98 (t, ,7=8.8 Hz, 1H), 7.47 (br s, 1H), 7.32 (d, ,7=7.3 Hz, 1H), 7.21 - 7.25 (m, 1H), 7.15 - 7.21 (m, 2H), 6.87 - 6.96 (m, 2H), 6.80 (s, 1H), 6.53 (br d, ,7=8.8 Hz, 1H), 6.44 (dd, ,7=15.0, 1.7 Hz, 1H), 5.58 (q, J=6.5 Hz, 1H), 4.00 - 4.08 (m, 1H), 3.82 (br dd, ,7=13.9, 3.8 Hz, 1H), 3.40 - 3.50 (m, 2H), 3.28 - 3.35 (m, 1H obscured by H 2 0 peak), 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%)

NMR (500 MHz, DMSO-de) d ppm 7.98 (t, ,7=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, ,7=8.8 Hz, 1H), 6.44 (dd, ,7=15.0, 1.7 Hz, 1H), 4.97 (q, J=6.5 Hz, 1H), 4.55 (br dd, =l2.8, 3.6 Hz, 1H), 4.00 - 4.08 (m, 1H), 3.40 - 3.50 (m, 1H), 3.28 - 3.35 (m, 1H obscured by H2O peak), 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, ,7=6.6 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.25 - 1.30 (m, 2H), 1.22 (d, ,7=6.3 Hz, 3H).

Compound 83

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 8.00 (t, ,7=8.8 Hz, 1H), 7.41 (s, 1H), 7.32 (d, ,7=7.3 Hz, 1H), 7.15 - 7.26 (m, 3H), 7.04 (s, 1H), 6.93 (d, ,7=3.5 Hz, 1H), 6.80 (s, 1H), 6.54 (br d, ,7=8.8 Hz, 1H), 6.43 (dd, ,7=14.8, 1.6 Hz, 1H), 5.59 (q, ,7=6.6 Hz, 1H), 4.20 (quin, ,7=6.5 Hz, 1H), 3.82 (br dd, ,7=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, ,7=16.1 Hz, 1H), 2.27 - 2.35 (m, 1H), 2.00 (dt, ,7=12.6, 6.6 Hz,

1H), 1.52 (d, ,7=6.6 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.21 - 1.29 (m, 2H), 1.02 (d, ,7=6.3 Hz, 3H).

Minor rotamer (35%)

ppm 8.00 (t, ,7=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, ,7=3.8 Hz, 1H), 6.77 (s, 1H), 6.54 (br d, ,7=8.8 Hz, 1H), 6.43 (dd, ,7=14.8, 1.6 Hz, 1H), 4.97 (q, ,7=6.6 Hz, 1H), 4.55 (br dd, ,7=12.9, 3.2 Hz, 1H), 4.20 (quin, ,7=6.5 Hz, 1H), 3.41 - 3.50 (m, 1H), 3.25 - 3.29 (m, 1H), 3.17 - 3.25 (m, 1H), 2.86 - 3.07 (m, 4H), 2.27 - 2.35 (m, 1H), 2.00 (dt, ,7=12.6, 6.6 Hz, 1H), 1.55 (d, =6.9 Hz, 3H), 1.30 - 1.37 (m, 2H), 1.21 - 1.29 (m, 2H), 1.02 (d, =6.3 Hz, 3H).

Compound 84

Major rotamer (65%)

ppm 9.31 (d, =7.8 Hz, 1H), 8.89 (d, =4.0 Hz, 1H),

8.15 - 8.23 (m, 1H), 8.05 (t, =8.8 Hz, 1H), 7.91 (s, 1H), 7.65 - 7.72 (m, 1H), 7.52 (br s, 1H), 7.34 (d, J=1 Hz, 1H), 7.06 - 7.27 (m, 4H), 7.02 (br s, 1H), 6.55 (dd, =8.9, 1.8 Hz, 1H), 6.48 (dd, =l4.6, 1.7 Hz, 1H), 5.64 (q, =6.5 Hz, 1H), 4.07 (br dd, =l3.0, 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, =l6.6 Hz, 1H), 2.16 - 2.26 (m, 1H), 2.07 - 2.16 (m, 1H), 1.56 (d, =6.7 Hz, 3H).

Minor rotamer (35%)

ppm 9.30 (d, =8.3 Hz, 1H), 8.86 (br d, =4.3 Hz, 1H), 8.15 - 8.23 (m, 1H), 8.05 (t, =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, =8.9, 1.8 Hz, 1H), 6.48 (dd, =l4.6, 1.7 Hz, 1H), 5.17 (q, =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), 2.16 - 2.26 (m, 1H), 2.07 - 2.16 (m, 1H), 1.61 (d, =6.8 Hz, 3H).

Compound 85

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 8.38 (br t, =9.3 Hz, 1H), 7.32 (br d, =7.5 Hz,

1H), 7.15 - 7.26 (m, 3H), 6.93 - 6.97 (m, 1H), 6.83 (s, 1H), 6.58 (br d, =8.3 Hz, 1H), 6.46

- 6.72 (m, 2H), 5.58 (q, =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, =l6.5 Hz, 1H), 2.18 - 2.29 (m, 1H), 2.06 - 2.15 (m, 1H), 1.52 (br d, =6.7 Hz, 3H), 1.30 - 1.39 (m, 2H), 1.21 - 1.30 (m, 2H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-de) d ppm 8.38 (br t, =9.3 Hz, 1H), 7.15 - 7.26 (m, 2H), 7.09

- 7.15 (m, 1H), 7.08 (br d, =7.6 Hz, 1H), 6.93 - 6.97 (m, 1H), 6.80 (s, 1H), 6.58 (br d, =8.3 Hz, 1H), 6.46 - 6.72 (m, 2H), 5.21 (br s, 1H), 4.96 (q, =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, =6.8 Hz, 3H), 1.30 - 1.39 (m, 2H), 1.21 - 1.30 (m, 2H). Compound 86

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 7.52 (br s, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.09 - 7.25 (m, 3H), 7.01 (br s, 1H), 6.82 (d, =l2.0 Hz, 2H), 6.00 (s, 1H), 5.59 (q, J=6.6 Hz, 1H),

3.89 (s, 3H), 3.82 (br dd, =l3.7, 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, =7.6 Hz, 1H), 2.81 - 2.95 (m, 2H), 2.71 (br d, =l6.4 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%)

NMR (500 MHz, DMSO-de) d ppm 7.52 (br s, 1H), 7.09 - 7.21 (m, 4H), 7.01 (br s, 1H), 6.80 (d, =22.l Hz, 2H), 6.00 (s, 1H), 4.96 (q, =6.7 Hz, 1H), 4.55 (br dd, =l3.l, 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, =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

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 7.50 (br s, 1H), 7.32 (d, =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, =6.8 Hz, 1H), 4.26 - 4.33 (m, 2H), 3.80 (br dd, =l3.9, 3.8 Hz, 1H), 3.67 - 3.72 (m, 2H), 3.64 (br t, J=9A Hz, 1H), 3.53 - 3.61 (m, 1H), 3.50 (dd, =l0.4, 6.9 Hz, 1H), 3.37 - 3.48 (m, 2H), 3.29 (s, 3H), 3.03 - 3.10 (m, 1H), 2.82 - 2.96 (m, 2H), 2.71 (br d, =l6.l 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%)

NMR (500 MHz, DMSO-de) d 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=l 1.7, 4.4 Hz, 1H), 4.26 - 4.33 (m, 2H), 3.67 - 3.72 (m, 2H), 3.64 (br t, J=9A Hz, 1H), 3.53 - 3.61 (m,

1H), 3.50 (dd, =l0.4, 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=6.6 Hz, 3H), 1.23 - 1.34 (m, 4H).

Compound 88

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 8.08 (d, J=5J Hz, 1H), 7.53 (br s, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.04 - 7.26 (m, 4H), 7.01 (br s, 1H), 6.84 (s, 1H), 5.59 (q, J=6.9 Hz, 1H), 3.80 (br dd, =l3.9, 3.5 Hz, 1H), 3.74 (dd, =l0.7, 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, =l6.l Hz, 1H), 2.19 - 2.28 (m, 1H), 2.09 - 2.17 (m, 1H), 1.52 (d, =6.9 Hz, 3H), 1.31 - 1.38 (m, 2H), 1.22 - 1.30 (m, 2H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-de) d ppm 8.08 (d, J=5.1 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, =7.0 Hz, 1H), 4.55 (br dd, =l2.9, 3.2 Hz, 1H), 3.74 (dd, =l0.7, 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, 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

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 7.50 (br s, 1H), 7.32 (d, =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, =l3.6, 1.9 Hz, 1H), 5.59 (q, J=6.6 Hz, 1H), 3.84 (br dd, =l3.9, 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, =7.8 Hz, 1H), 2.82 - 2.96 (m, 2H), 2.72 (br d, =l6.4 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%)

NMR (500 MHz, DMSO-de) d 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, =l3.6, 1.9 Hz, 1H), 4.99 (q, J=6.6 Hz, 1H), 4.56 (br dd, =l2.8, 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, =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, =6.6 Hz, 3H), 1.22 - 1.34 (m, 4H).

Compound 90

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 9.35 (s, 1H), 8.85 (d, J=2.5 Hz, 1H), 8.68 - 8.73 (m, 1H), 7.90 (t, =8.8 Hz, 1H), 7.62 (s, 1H), 7.51 (br s, 1H), 7.34 (d, =7.3 Hz, 1H), 7.06 - 7.27 (m, 4H), 7.00 (br s, 1H), 6.53 (br d, =8.8 Hz, 1H), 6.46 (dd, =l4.8, 1.9 Hz, 1H),

5.64 (q, =6.8 Hz, 1H), 3.96 (br dd, =l3.9, 4.7 Hz, 1H), 3.51 - 3.58 (m, 1H), 3.46 - 3.51 (m, 1H), 3.29 - 3.45 (m, 3H partially obscured by H 2 0 peak), 3.03 - 3.12 (m, 2H), 2.76 (br d, =l6.4 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%)

ppm 9.31 (s, 1H), 8.84 (d, =2.8 Hz, 1H), 8.65 - 8.70 (m, 1H), 7.90 (t, =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, =8.8 Hz, 1H), 6.46 (dd, =l4.8, 1.9 Hz, 1H), 5.12 (q, =6.8 Hz, 1H), 4.56 - 4.63 (m, 1H), 3.46 - 3.51 (m, 1H), 3.29 - 3.45 (m, 4H partially obscured by H 2 0 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, =6.6 Hz, 3H).

Compound 91

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 8.00 (t, =8.5 Hz, 1H), 7.51 (br s, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.14 - 7.25 (m, 3H), 7.03 - 7.09 (m, 1H), 6.95 (d, =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, =8.0 Hz, 2H), 3.91 (t, =6.8 Hz, 2H), 3.81 (br dd, =l3.7, 3.9 Hz, 1H), 3.43 - 3.51 (m, 2H), 2.83 - 3.05 (m, 2H), 2.72 (br d, =l6.l 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%)

NMR (500 MHz, DMSO-de) d ppm 8.00 (t, =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, =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, =8.0 Hz, 2H), 3.91 (t, =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

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 8.35 (t, J=9A Hz, 1H), 7.38 (br s, 1H), 7.32 (br d, J=1 A 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, =7.8 Hz, 1H), 5.58 (q, J=6.1 Hz, 1H), 4.16 (t, =8.3 Hz, 2H), 3.80 (br dd, =l3.8, 3.8 Hz, 1H), 3.73 (dd, =8.4, 5.8 Hz, 2H), 3.41 - 3.51 (m, 1H), 2.85 - 3.07 (m, 3H), 2.71 (br d, =l6.6 Hz, 1H), 2.43 - 2.47 (m, 2H partially obscured by DMSO peak), 1.52 (d, =6.8 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.20 - 1.29 (m, 2H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-de) d ppm 8.35 (t, J=9A 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, =7.8 Hz, 1H), 4.95 (q, ,7=6.8 Hz, lH), 4.5l - 4.59 (m, 1H), 4.16 (t, =8.3 Hz, 2H), 3.73 (dd, =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 obscured by DMSO peak), 1.55 (br d, J=6.1 Hz, 3H), 1.30 - 1.38 (m, 2H), 1.20 - 1.29 (m, 2H). Compound 93:

Major rotamer (65%)

-de) d ppm 7.99 (t, =8.6 Hz, 1 H), 7.32 (br d, =7.3 Hz, 1 H), 7.10 - 7.28 (m, 3 H), 6.89 - 6.98 (m, 1 H), 6.80 (s, 1 H), 6.49 (br d, J=9A Hz, 1 H), 6.40 (br d, =l4.7 Hz, 1 H), 5.54 - 5.63 (m, 1 H), 3.75 - 3.86 (m, 1 H), 3.19 - 3.66 (m, 6 H), 2.68 - 3.06 (m, 4 H), 2.01 - 2.16 (m, 2 H), 1.72 - 1.80 (m, 1 H), 1.46 - 1.59 (m, 3 H), 1.19 - 1.39 (m, 4 H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-de) d ppm 7.99 (t, =8.6 Hz, 1 H), 7.10 - 7.28 (m, 3 H), 7.07 (br d, J=1.5 Hz, 1 H), 6.89 - 6.98 (m, 1 H), 6.77 (s, 1 H), 6.49 (br d, J=9A Hz, 1 H), 6.40 (br d, =l4.7 Hz, 1 H), 4.91 - 5.00 (m, 1 H), 4.50 - 4.60 (m, 1 H), 3.19 - 3.66 (m, 6 H),

2.68 - 3.06 (m, 4 H), 2.01 - 2.16 (m, 2 H), 1.72 - 1.80 (m, 1 H), 1.46 - 1.59 (m, 3 H), 1.19 -

1.39 (m, 4 H).

Compound 94:

Major rotamer (65%)

-de) d ppm 8.00 (t, =8.8 Hz, 1 H), 7.32 (d, J=1.6 Hz, 1 H), 7.10 - 7.26 (m, 3 H), 6.87 - 7.00 (m, 1 H), 6.80 (s, 1 H), 6.50 (br d, =8.7 Hz, 1 H), 6.43 (br d, =l4.9 Hz, 1 H), 5.59 (q, =6.8 Hz, 1 H), 3.81 (br dd, =l4.0, 4.2 Hz, 1 H), 3.31 - 3.60 (m, 7 H), 3.06 - 3.15 (m, 1 H), 2.68 - 3.14 (m, 4 H), 2.03 - 2.21 (m, 1 H), 1.78 - 1.95 (m, 1 H), 1.45 - 1.60 (m, 3 H), 1.17 - 1.43 (m, 4 H).

Minor rotamer (35%)

z, DMSO-de) d ppm 8.00 (t, =8.8 Hz, 1 H), 7.10 - 7.26 (m, 3 H), 7.08 6.87 - 7.00 (m, 1 H), 6.77 (s, 1 H), 6.50 (br d, =8.7 Hz, 1 H), 6.43 (br , 4.96 (d, J=6.6 Hz, 1 H), 4.50 - 4.60 (m, 1 H), 3.31 - 3.60 (m, 7 H), 3.06 - 3.15 (m, 1 H), 2.68 - 3.14 (m, 4 H), 2.03 - 2.21 (m, 1 H), 1.78 - 1.95 (m, 1 H), 1.45 - 1.60 (m, 3 H), 1.17 - 1.43 (m, 4 H).

Compound 95:

Major rotamer (65%)

ppm 7.99 (t, =8.8 Hz, 1 H) 7.31 (br d, =7.6 Hz, 1 H) 7.04 - 7.27 (m, 3 H) 6.90 - 6.97 (m, 1 H) 6.70 - 6.88 (m, 1 H) 6.48 (br d, =8.8 Hz, 1 H)

6.40 (dd, =l4.7, 1.4 Hz, 1 H) 5.59 (q, J=6.5 Hz, 1 H) 4.89 - 5.01 (m, 2 H) 4.18 (br d,

J=3.5 Hz, 2 H) 3.82 (br dd, =l3.4, 3.9 Hz, 1 H) 3.40 - 3.55 (m, 3 H) 3.18 (br dd, =9.8,

3.8 Hz, 2 H) 2.81 - 3.05 (m, 2 H) 2.65 - 2.78 (m, 1 H) 1.48 - 1.58 (m, 3 H) 1.19 - 1.39 (m,

4 H). Minor rotamer (35%)

ppm 7.99 (t, =8.8 Hz, 1 H) 7.04 - 7.27 (m, 4 H) 6.90 -

6.97 (m, 1 H) 6.70 - 6.88 (m, 1 H) 6.48 (br d, =8.8 Hz, 1 H) 6.40 (dd, =l4.7, 1.4 Hz, 1 H) 4.89 - 5.01 (m, 3 H) 4.55 (br dd, =l2.9, 3.2 Hz, 1 H) 4.18 (br d, =3.5 Hz, 2 H) 3.40 - 3.55 (m, 2 H) 3.23 - 3.28 (m, 1 H) 3.18 (br dd, =9.8, 3.8 Hz, 2 H) 2.81 - 3.05 (m, 3 H)

1.48 - 1.58 (m, 3 H) 1.19 - 1.39 (m, 4 H).

Compound 96:

Major rotamer (65%)

ppm 7.99 (t, =8.5 Hz, 1 H) 7.32 (d, =7.3 Hz, 1 H) 7.07

- 7.25 (m, 3 H) 6.91 - 6.95 (m, 1 H) 6.76 - 6.82 (m, 1 H) 6.52 (dd, =8.8, 1.9 Hz, 1 H) 6.45 (dd, =l4.7, 2.0 Hz, 1 H) 5.59 (q, =6.8 Hz, 1 H) 5.31 (d, =3.8 Hz, 1 H) 4.26 (br s, 1 H) 3.78 - 3.85 (m, 2 H) 3.43 - 3.55 (m, 3 H) 3.26 - 3.41 (m, 4 H) 3.20 (d, =l0.7 Hz, 1 H) 2.84

- 3.05 (m, 2 H) 2.72 (br d, =l6.4 Hz, 1 H) 1.48 - 1.58 (m, 3 H) 1.21 - 1.37 (m, 4 H).

Minor rotamer (35%)

ppm 7.99 (t, =8.5 Hz, 1 H) 7.07 - 7.25 (m, 4 H) 6.91 - 6.95 (m, 1 H) 6.76 - 6.82 (m, 1 H) 6.52 (dd, =8.8, 1.9 Hz, 1 H) 6.45 (dd, =l4.7, 2.0 Hz, 1 H) 5.31 (d, =3.8 Hz, 1 H) 4.96 (d, J=6.9 Hz, 1 H) 4.52 - 4.58 (m, 1 H) 4.26 (br s, 1 H)

3.78 - 3.85 (m, 1 H) 3.43 - 3.55 (m, 2 H) 3.26 - 3.41 (m, 5 H) 3.20 (d, =l0.7 Hz, 1 H) 2.84

- 3.05 (m, 3 H) 1.48 - 1.58 (m, 3 H) 1.21 - 1.37 (m, 4 H).

Compound 97:

Major rotamer (65%)

ppm 8.03 (t, =8.4 Hz, 1 H) 7.32 (d, J=1.6 Hz, 1 H) 7.06

- 7.24 (m, 3 H) 6.95 - 6.98 (m, 1 H) 6.78 - 6.83 (m, 1 H) 6.55 - 6.60 (m, 2 H) 6.15 (d, J=5A Hz, 1 H) 5.59 (q, J=6.6 Hz, 1 H) 4.36 - 4.43 (m, 1 H) 3.71 - 3.84 (m, 4 H) 3.43 - 3.50 (m, 1 H) 3.31 - 3.38 (m, 1 H) 2.84 - 3.05 (m, 2 H) 2.72 (br d, =l6.l Hz, 1 H) 1.49 - 1.57 (m, 3 H) 1.22 - 1.38 (m, 4 H).

Minor rotamer (35%)

ppm 8.03 (t, =8.4 Hz, 1 H) 7.06 - 7.24 (m, 4 H) 6.95 -

6.98 (m, 1 H) 6.78 - 6.83 (m, 1 H) 6.55 - 6.60 (m, 2 H) 6.15 (d, J=5A Hz, 1 H) 4.97 (q, J=6.6 Hz, 1 H) 4.52 - 4.58 (m, 1 H) 4.36 - 4.43 (m, 1 H) 3.71 - 3.84 (m, 3 H) 3.31 - 3.38 (m, 1 H) 3.23 - 3.28 (m, 1 H) 2.84 - 3.05 (m, 3 H) 1.49 - 1.57 (m, 3 H) 1.22 - 1.38 (m, 4 H). Compound 98:

Major rotamer (65%)

ppm 7.98 (t, 7=8.8 Hz, 1 H) 7.31 (d, 7=7.3 Hz, 1 H) 7.07

- 7.24 (m, 3 H) 6.91 - 6.95 (m, 1 H) 6.75 - 6.81 (m, 1 H) 6.55 (dd, 7=8.8, 1.9 Hz, 1 H) 6.49 (dd, ,7=14.8, 1.9 Hz, 1 H) 5.59 (q, 7=6.8 Hz, 1 H) 4.87 - 4.93 (m, 2 H) 4.83 (d, 7=3.8 Hz, 1 H) 4.35 - 4.41 (m, 1 H) 4.06 (t, 7=3.9 Hz, 1 H) 3.82 (br dd, 7=13.6, 3.8 Hz, 1 H) 3.43 -

3.61 (m, 4 H) 3.38 (dt, 7=11.7, 6.7 Hz, 1 H) 2.84 - 3.07 (m, 3 H) 2.72 (br d, 7=16.4 Hz, 1 H) 1.49 - 1.57 (m, 3 H) 1.22 - 1.38 (m, 4 H).

Minor rotamer (35%)

ppm 7.98 (t, 7=8.8 Hz, 1 H) 7.31 (d, 7=7.3 Hz, 1 H) 7.07

- 7.24 (m, 3 H) 6.91 - 6.95 (m, 1 H) 6.75 - 6.81 (m, 1 H) 6.55 (dd, 7=8.8, 1.9 Hz, 1 H) 6.49 (dd, 7=14.8, 1.9 Hz, 1 H) 4.98 (br d, 7=6.6 Hz, 1 H) 4.87 - 4.93 (m, 2 H) 4.83 (d, 7=3.8 Hz, 1 H) 4.52 - 4.57 (m, 1 H) 4.35 - 4.41 (m, 1 H) 4.06 (t, 7=3.9 Hz, 1 H) 3.43 - 3.61 (m, 3 H) 3.38 (dt, 7=11.7, 6.7 Hz, 1 H) 3.23 - 3.26 (m, 1 H) 2.84 - 3.07 (m, 4 H) 1.49 - 1.57 (m, 3 H) 1.22 - 1.38 (m, 4 H).

Compound 99:

Major rotamer (65%)

NMR (400 MHz, DMSO-7 6 ) d ppm 7.99 (t, 7=8.8 Hz, 1 H) 7.03 - 7.36 (m, 4 H) 6.87 - 6.99 (m, 1 H) 6.80 (s, 1 H) 6.49 (br d, 7=8.8 Hz, 1 H) 6.41 (br d, 7=14.6 Hz, 1 H) 5.59 (q, 7=6.6 Hz, 1 H) 5.16 (d, 7=4.5 Hz, 1 H) 3.94 (quin, 7=4.9 Hz, 1 H) 3.81 (br dd, 7=13.8, 3.7 Hz, 1 H) 3.50 - 3.63 (m, 2 H) 3.40 - 3.50 (m, 1 H) 2.65 - 3.16 (m, 5 H) 2.13 - 2.23 (m, 1 H) 1.45 - 1.61 (m, 3 H) 1.19 - 1.41 (m, 4 H) 1.02 (d, 7=6.8 Hz, 3 H).

Minor rotamer (35%)

ppm 7.99 (t, 7=8.8 Hz, 1 H) 7.03 - 7.36 (m, 4 H) 6.87 - 6.99 (m, 1 H) 6.76 (s, 1 H) 6.49 (br d, 7=8.8 Hz, 1 H) 6.41 (br d, 7=14.6 Hz, 1 H) 5.16 (d, 7=4.5 Hz, 1 H) 4.96 (q, 7=6.4 Hz, 1 H) 4.49 - 4.61 (m, 1 H) 3.94 (quin, 7=4.9 Hz, 1 H)

3.50 - 3.63 (m, 2 H) 3.20 - 3.29 (m, 1 H) 2.65 - 3.16 (m, 5 H) 2.13 - 2.23 (m, 1 H) 1.45 -

1.61 (m, 3 H) 1.19 - 1.41 (m, 4 H) 1.02 (d, 7=6.8 Hz, 3 H).

Compound 100:

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 7.99 (t, 7=8.8, 1 H), 7.32 (d, 7=7.6 Hz, 1 H), 7.09 - 7.26 (m, 3 H), 6.90 - 6.96 (m, 1 H), 6.80 (s, 1 H), 6.50 (dd, 7=8.7, 1.7 Hz, 1 H), 6.42 (dd, 7=14.7, 1.7 Hz, 1 H), 5.55 - 5.62 (m, 1 H), 5.17 (d, 7=3.2 Hz, 2 H), 4.07 (br s, 2 H), 3.82 (br dd, 7=13.7, 3.6 Hz, 1H), 3.53 (br dd, 7=10.2, 3.6 Hz, 2 H), 3.43 - 3.50 (m, 1 H), 3.17 (d, 7=10.4 Hz, 2 H), 2.68 - 3.06 (m, 3 H), 1.48 - 1.58 (m, 3 H) 1.21 - 1.38 (m, 4 H). Minor rotamer (35%)

NMR (500 MHz, DMSO-de) d ppm 7.99 (t, ,7=8.8, 1 H), 7.09 - 7.26 (m, 3 H), 7.07 (d, J=1.6, 1 H), 6.90 - 6.96 (m, 1 H), 6.76 (s, 1 H), 6.50 (dd, ,7=8.7, 1.7 Hz, 1 H), 6.42 (dd, =l4.7, 1.7 Hz, 1 H), 5.17 (d, ,7=3.2 Hz, 2 H), 4.93 - 5.00 (m, 1 H), 4.55 (br dd, ,7=12.9, 3.2 Hz, 1 H), 4.07 (br s, 2 H), 3.53 (br dd, .7=10.2, 3.6 Hz, 2 H), 3.22 - 3.29 (m, 1 H), 3.17 (d, ,7=10.4 Hz, 2 H), 2.68 - 3.06 (m, 3 H), 1.48 - 1.58 (m, 3 H) 1.21 - 1.38 (m, 4 H).

Compound 101:

Major rotamer (65%)

NMR (400 MHz, DMSO-de) d ppm 9.64 (br s, 1 H) 9.40 (br s, 1 H) 8.00 (t, ,7=8.7 Hz, 1 H) 7.03 - 7.40 (m, 4 H) 6.88 - 7.01 (m, 1 H) 6.81 (s, 1 H) 6.37 - 6.59 (m, 2 H) 5.59 (q, ,7=6.7 Hz, 1 H) 3.81 (br dd, ,7=13.9, 4.1 Hz, 1 H) 3.21 - 3.67 (m, 6 H) 2.71 - 3.12 (m, 3 H) 2.25 (br d, ,7=6.1 Hz, 2 H) 1.48 - 1.60 (m, 3 H) 1.20 - 1.40 (m, 4 H).

Minor rotamer (35%)

NMR (400 MHz, DMSO-de) d ppm 9.64 (br s, 1 H) 9.40 (br s, 1 H) 8.00 (t, ,7=8.7 Hz, 1 H) 7.03 - 7.40 (m, 4 H) 6.88 - 7.01 (m, 1 H) 6.77 (s, 1 H) 6.37 - 6.59 (m, 2 H) 4.96 (q, ,7=6.8 Hz, 1 H) 4.55 (br d, ,7=11.2 Hz, 1 H) 3.21 - 3.67 (m, 6 H) 2.71 - 3.12 (m, 3 H) 2.25 (br d, ,7=6.1 Hz, 2 H) 1.48 - 1.60 (m, 3 H) 1.20 - 1.40 (m, 4 H).

Compound 102:

Major rotamer (65%)

NMR (500 MHz, DMSO-de) d ppm 7.99 (br t, ,7=8.7 Hz, 1 H) 7.03 - 7.34 (m, 4 H) 6.93 (m, 1 H) 6.79 (s, 1 H) 6.50 (d, ,7=8.2 Hz, 1 H) 6.42 (d, ,7=14.8 Hz, 1 H) 5.59 (q, ,7=6.2 Hz, 1 H) 5.16 (br s, 2 H) 4.08 (br s, 2 H) 3.82 (br dd, ,7=13.6, 4.1 Hz, 1 H) 3.51 - 3.57 (m, 2 H) 3.42 - 3.51 (m, 1 H) 3.17 (d, ,7=10.4 Hz, 2 H) 2.69 - 3.08 (m, 3 H) 1.47 - 1.59 (m, 3 H) 1.22 - 1.40 (m, 4 H).

Minor rotamer (35%)

NMR (500 MHz, DMSO-de) d ppm 7.99 (br t, ,7=8.7 Hz, 1 H) 7.03 - 7.34 (m, 4 H) 6.93 (m, 1 H) 6.75 (s, 1 H) 6.50 (d, ,7=8.2 Hz, 1 H) 6.42 (d, ,7=14.8 Hz, 1 H) 5.16 (br s, 2 H)

4.92 - 5.02 (m, 1 H) 4.48 - 4.61 (m, 1 H) 4.08 (br s, 2 H) 3.51 - 3.57 (m, 2 H) 3.22 - 3.27 (m, 1 H) 3.17 (d, ,7=10.4 Hz, 2 H) 2.69 - 3.08 (m, 3 H) 1.47 - 1.59 (m, 3 H) 1.22 - 1.40 (m, 4 H). Compound 103:

Major rotamer (65%)

, , , , 7.02 (br s, 1 H) 6.93 - 6.98 (m, 1 H) 6.92 (s, 1 H) 6.09 (br d, =l4.7 Hz, 1 H) 5.96 (s, 1 H) 5.59 (q, J=6.5 Hz, 1 H) 3.80 (br dd, =l3.9, 3.9 Hz, 1 H) 3.23 - 3.51 (m, 5 H) 2.71 - 3.11 (m, 4 H) 2.05 - 2.23 (m, 2 H) 1.49 - 1.61 (m, 3 H) 1.22 - 1.37 (m, 4 H). Minor rotamer (35%)

NMR (400 MHz, DMSO-7 6 ) d ppm 11.21 (s, 1 H) 7.52 (br s, 1 H) 7.05 - 7.35 (m, 4 H) 7.02 (br s, 1 H) 6.93 - 6.98 (m, 1 H) 6.88 (s, 1 H) 6.09 (br d, 7=14.7 Hz, 1 H) 5.96 (s, 1 H) 4.94 (q, J=6.6 Hz, 1 H) 4.51 - 4.60 (m, 1 H) 3.23 - 3.51 (m, 5 H) 2.71 - 3.11 (m, 4 H) 2.05 - 2.23 (m, 2 H) 1.49 - 1.61 (m, 3 H) 1.22 - 1.37 (m, 4 H).

Compound 106:

Major rotamer (65%)

'H NMR (400 MHz, DMSO-7 6 ) d ppm 7.51 (br s, 1 H) 7.09 - 7.36 (m, 4 H) 6.95 - 7.05 (m, 2 H) 6.79 (s, 1 H) 6.00 - 6.14 (m, 2 H) 5.59 (q, 7=6.8 Hz, 1 H) 4.82 - 4.91 (m, 1 H) 4.08 - 4.20 (m, 2 H) 3.77 - 3.90 (m, 1 H) 3.66 - 3.75 (m, 2 H) 3.19 - 3.58 (m, 5 H) 2.69 - 3.14 (m, 4 H) 2.03 - 2.27 (m, 2 H) 1.46 - 1.61 (m, 3 H) 1.21 - 1.34 (m, 4 H).

Minor rotamer (35%)

'H NMR (400 MHz, DMSO-7 6 ) d ppm 7.51 (br s, 1 H) 7.09 - 7.36 (m, 4 H) 6.95 - 7.05 (m, 2 H) 6.76 (s, 1 H) 6.00 - 6.14 (m, 2 H) 4.95 (q, 7=6.7 Hz, 1 H) 4.82 - 4.91 (m, 1 H) 4.55 (br d, .7=15.5 Hz, 1 H) 4.08 - 4.20 (m, 2 H) 3.66 - 3.75 (m, 2 H) 3.19 - 3.58 (m, 5 H) 2.69 - 3.14 (m, 4 H) 2.03 - 2.27 (m, 2 H) 1.46 - 1.61 (m, 3 H) 1.21 - 1.34 (m, 4 H).

Compound 107:

Major diastereomer (65%)

'H NMR (400 MHz, DMSO-7 6 ) d ppm 8.01 (t, 7=8.9 Hz, 1 H) 7.29-7.35 (m, 1 H) 7.03 - 7.28 (m, 3 H) 6.89 - 7.02 (m, 1 H) 6.81 (s, 1 H) 6.54 (dd, 7=9.0, 2.0 Hz, 1 H) 6.49 (dd, 7=14.8, 2.0 Hz, 1 H) 5.47 - 5.65 (m, 2 H) 5.13 (dt, J=55.9, 2.0 Hz, 1 H) 4.26 - 4.49 (m, 1 H) 3.81 (br dd, 7=13.7, 3.7 Hz, 1 H) 3.40 - 3.70 (m, 4 H) 3.16 (t, 7=8.7 Hz, 1 H) 2.83 - 3.08 (m, 2 H) 2.72 (br d, 7=16.1 Hz, 1 H) 1.52 (d, 7=6.9 Hz, 3 H) 1.17 - 1.43 (m, 4 H).

Minor diastereomer (35%)

'H NMR (400 MHz, DMSO-7 6 ) d ppm 8.01 (t, 7=8.9 Hz, 1 H) 7.03 - 7.28 (m, 4 H) 6.89 - 7.02 (m, 1 H) 6.77 (s, 1 H) 6.54 (dd, 7=9.0, 2.0 Hz, 1 H) 6.49 (dd, 7=14.8, 2.0 Hz, 1 H)

5.47 - 5.65 (m, 1 H) 5.13 (dt, J=55.9, 2.0 Hz, 1 H) 4.96 (q, 7=7.0 Hz, 1 H) 4.49 - 4.63 (m, 1 H) 4.26 - 4.49 (m, 1 H) 3.40 - 3.70 (m, 3 H) 3.22 - 3.28 (m, 1 H) 3.16 (t, 7=8.7 Hz, 1 H) 2.83 - 3.08 (m, 3 H) 1.55 (d, 7=6.9 Hz 3 H) 1.17 - 1.43 (m, 4 H).

Melting points

For a number of compounds, melting points (m.p.) were determined with a differential scanning calorimeter DSC 1 (Mettler Toledo). Melting points were measured with a temperature gradient of l0°C/minute from 25°C to 350°C. The reported values are peak values. Values are obtained with experimental uncertainties that are commonly associated with this analytical method.

Optical rotation

The optical rotation was measured using a polarimeter with light at the wavelength of the D-line of sodium (589 nm) at a temperature of 20°C in DMF as solvent. Compound (45) and compound (84) were measured at 546 nm.

E. Pharmacological examples

E.l Antiviral activity

Black 384-well clear-bottom microtiter plates (Coming, Amsterdam, The Netherlands) were filled via acoustic drop ejection using the echo liquid handler (Labcyte, Sunnyvale, California). 200 nL of compound stock solutions (100% DMSO) were transferred to the assay plates. 9 serial 4-fold dilutions of compound were made, creating per quadrant the same compound concentration. The assay was initiated by adding 10 pL of culture medium to each well (RPMI medium without phenol red, 10% FBS-heat inactivated, 0.04% gentamycin (50 mg/mL). All addition steps are done by using a multidrop dispenser (Thermo Scientific, Erembodegem, Belgium). Next, rgRSV224 vims (MOI = 1) diluted in culture medium was added to the plates. rgRSV224 vims is an engineered vims that includes an additional GFP gene (Hallak LK, Spillmann D, Collins PL, Peeples ME.

Glycosaminoglycan sulfation requirements for respiratory syncytial vims infection; Journal of virology (2000), 74(22), 10508-13) and was in- licensed from the NIH (Bethesda, MD, USA). Finally, 20 pL of a HeLa cell suspension (3,000 cells/well) were plated. Medium, vims- and mock- infected controls were included in each test. The wells contain 0.05% DMSO per volume. Cells were incubated at 37°C in a 5% C02 atmosphere. Three days post-vims exposure, viral replication was quantified by measuring GFP expression in the cells by an in house developed MSM laser microscope (Tibotec, Beerse, Belgium). The EC50 was defined as the 50% inhibitory concentration for GFP expression. In parallel, compounds were incubated for three days in a set of white 384-well microtiter plates (Coming) and the cytotoxicity of compounds in HeLa cells was determined by measuring the ATP content of the cells using the ATPlite kit (Perkin Elmer, Zaventem, Belgium) according to the manufacturer’s instmctions. The CC50 was defined as the 50%

concentration for cytotoxicity.

Table : antiviral data

N.A. : not available

E.2 Pharmacokinetics after single intravenous administration in the fasted male Beagle dog

The test compound was dissolved in a 20 % (w/v) hydroxypropyl-b- cyclodextrin (HP- beta-CD) solution at a final concentration of 2 mg/mL for the intravenous formulation. NaOH was added to the formulations to facilitate dissolution and after total dissolution the pH was adjusted with HC1 to 8.4. The intravenous (IV) formulation was made isotonic with mannitol. Prior to dosing, all formulations were stored at room temperature and protected from light. The IV formulation was dosed in a cephalic vein at 0.5 mL/kg to obtain a final dose of 1 mg/kg.

Three male Beagle dogs, with a mean weight of 10.9 ± 1.1 kg, were used. A complete concentration time profile was obtained from each individual animal. Prior to dosing, animals were fasted overnight. Their standard dry diet was returned to them at 2 hours post dose. Tap water was available ad libitum.

From each individual animal, blood samples were taken at 7 and 20 minutes, 1, 2, 4, 7, 24 and 48 hours after intravenous dose administration. Blood was collected from a jugular vein into 2 mL BD vacutainers™ K3E (Becton Dickinson). Samples were placed immediately on melting ice and plasma was obtained following centrifugation at 4°C for 10 minutes at approximately 1900 x g. All samples were shielded from daylight and stored at < -l8°C prior to analysis. Plasma samples were analysed using a qualified research LC- MS/MS method. The key analytical performance (linearity, upper and lower limit of quantification, accuracy and precision) of the method was reported together with the plasma concentrations. The lower limit of quantification (LLOQ) was 10.0 ng/mL.

Pharmacokinetic analysis was performed using Phoenix™ Professional (Version 6.3). A non-compartmental analysis using the linear/log trapezoidal rule with linear/log interpolation was used for all data. The plasma concentration profile of Compound (37) and Compound (102) of the present invention has been reproduced in Figures 1 and 2.

The plasma concentration profile of Compound (W37) and Compound (W38) of

WO-2016/174079 has been reproduced in Figures 3 and 4.

After intravenous administration at 1 mg/kg in dogs the compounds (W37) and (W38) of WO-2016/174079 show a rapid decline in plasma concentration in the first 8 hours after administration. The plasma concentration profile of Compound (37) and Compound (102) of the present invention does not show this rapid decline thereby indicating these compounds have improved metabolic stability properties and improved bio-availability.

Description of the drawings :

Figure 1 : plasma concentration profile of Compound (102)

Figure 2 : plasma concentration profile of Compound (37)

Figure 3 : plasma concentration profile of compound (W37) of WO-2016/174079

Figure 4 : plasma concentration profile of compound (W38) of WO-2016/174079

F. Prophetic composition examples

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

stereochemically isomeric forms and the tautomers thereof.

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

F.l. Tablets

Active ingredient 5 to 50 mg

Di calcium phosphate 20 mg

Lactose 30 mg

Talcum 10 mg

Magnesium stearate 5 mg

Potato starch ad 200 mg

In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds. F.2. Suspension

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

F.3. Injectable

A parenteral composition is prepared by stirring 1.5 % by weight of active ingredient of the invention in 10% by volume propylene glycol in water. F.4. Ointment

Active ingredient 5 to 1000 mg

Stearyl alcohol 3 g

Lanoline 5 g

White petroleum 15 g

Water ad 100 g

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

Reasonable variations are not to be regarded as a departure from the scope of the invention. It will be obvious that the thus described invention may be varied in many ways by those skilled in the art.