WO2018038667A1

WO2018038667A1 - Respiratory syncytial virus inhibitors

Info

Publication number: WO2018038667A1
Application number: PCT/SE2017/050846
Authority: WO
Inventors: Susana Ayesa; Johan Bylund; Karolina Ersmark; Lourdes Salvador Oden; Fernando Sehgelmeble
Original assignee: Medivir Ab
Priority date: 2016-08-25
Filing date: 2017-08-23
Publication date: 2018-03-01
Also published as: TW201811781A

Abstract

Compounds of Formula (I): wherein W is NR^1A or CR^1BR^1B; Z is N or CH; R^1A is C₁-C₃alkyl, C₁-C₃haloalkyl C₃-C₄cycloalkyl or phenyl wherein cycloalkyl or phenyl is optionally mono-, di- or tri-substituted with substituents each independently selected from C₁- C₃alkyl, halo, amino and C₁-C₃alkoxy; the two R^1B together with the carbon atom to which they are attached combine and form C₃-C₆cycloalkyl or heterocyclyl, wherein the cycloalkyl is substituent with C(=O)OR^1C, NHC(=O)OR^1C or NHS(=O)₂R^1C, and the heterocyclyl is substituent with C(=O)R^1C, C(=O)OR^1C, S(=O)₂ R^1C, C(=O)NH₂ or C(=O)NR^1CR^1C'; n is 0, 1 or 2; n, q, R^1C, R^1C', R² and R³ are as defined herein, their use as inhibitors of RSV and related aspects.

Description

RESPIRATORY SYNCYTIAL VIRUS INHIBITORS

FIELD OF THE INVENTION

The present invention relates to isoquinoline analogues and their use as inhibitors of replication of the respiratory syncytial virus (RSV), pharmaceutical compositions containing such analogues, and methods of using these analogues in the treatment and prevention of RSV infection.

BACKGROUND OF THE INVENTION

Globally, the annual death rate from RSV is estimated at more than 160,000 and the clinical burden of RSV infection is comparable to that of influenza (Bourgeois et al., 2009; Boyce et al., 2000; Hall et al., 2009; Stockman et al., 2012). The epidemic season for RSV runs from late fall through early spring. The primary populations at risk for poor outcome are children below 5 years of age, immunocompromised patients and older adults, particularly those who are institutionalized or have chronic underlying disease (Hall et al., 2009; Falsey et al., 2005). There is generally no available therapy for RSV infection, except for supportive care. Inhaled ribavirin is approved for the treatment of laboratory-diagnosed RSV infection but is administered only to some bone marrow transplant and immunocompromised patients, because of its limited effectiveness, complexity of administration and mutagenicity potential for patients and staff. Because of the absence of effective therapy for RSV infections and the significance of RSV morbidity and/or morality in at-risk populations, the introduction of an effective RSV agent will be considered a major breakthrough in the care of these patients.

SUMMARY OF THE INVENTION

The present invention provides a novel series of compounds that exhibit inhibitory activity on the replication of the RSV.

Further objects of this invention arise for the one skilled in the art from the following description and the examples.

One aspect of the invention provides a compound, represented by Formula (I), or racemate, enantiomer, diastereoisomer or tautomer thereof.

In one embodiment, the invention relates to a compound having Formula (I) or racemate, enantiomer, diastereoisomer or tautomer thereof:

wherein W is NR^1A or CR^{1 B}R^{1 B};

Z is N or CH;

R^1A is Ci-C₃alkyl, Ci-C₃haloalkyl C₃-C₄cycloalkyl or phenyl wherein cycloalkyl or phenyl is optionally mono-, di- or tri-substituted with substituents each independently selected from C C₃alkyl, halo, amino and Ci-C₃alkoxy;

the two R^{1 B} together with the carbon atom to which they are attached combine and form C₃- C₆cycloalkyl or heterocyclyl, wherein the cycloalkyl is substituent with C(=0)OR^1G,

NHC(=0)OR^1G or NHS(=0)₂R^1C, and the heterocyclyl is substituent with C(=0)R^1C, C(=0)OR^1G, S(=0)₂R^1C, C(=0)NH₂ or C(=0)NR^1CR^1C';

R^1C is C C₆alkyl, C₃-C₅cycloalkyl or heterocyclyl, any of which is optionally substituted with one, two or three substituents independently selected from fluoro, amino, trifluoromethyl, C C₃alkyl, C C₃alkoxy and C C₃alkylamino;

R^1C is H or C C₃alkyl, or R^1C and R^1C together with the nitrogen atom to which they are attached combine and form a 4-, 5- or 6-membered cyclic amine;

R² is halo, cyano, hydroxy, C C₃alkyl, C(=0)NH₂ or trifluoromethyl;

R³ is each independently selected from fluoro, chloro, cyano, C C₃alkyl, Ci-C₃alkoxy and trifluoromethyl; n is 0, 1 or 2;

q is 0, 1 or 2

heterocyclyl is a 4, 5 or 6 membered saturated ring containing 1 or 2 heteroatoms

independetnly selected from N and O.

or a salt thereof.

Another aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

Also within the scope of this invention is the use of a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of RSV infection in a human being.

Included within the scope of this invention is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

According to a further aspect of this embodiment the pharmaceutical composition according to this invention further comprises a therapeutically effective amount of at least one other antiviral agent. The invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of an RSV infection in a human being having or at risk of having the infection.

Another aspect of the invention involves a method of treating or preventing RSV infection in a human being by administering to the human being an anti-RSV virally effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately.

An additional aspect of this invention refers to an article of manufacture comprising a composition effective to treat RSV infection; and packaging material comprising a label which indicates that the composition can be used to treat infection by RSV; wherein the composition comprises a compound of Formula (I) according to this invention or a pharmaceutically acceptable salt thereof.

Still another aspect of this invention relates to a method of inhibiting the replication of RSV comprising exposing the virus to an effective amount of the compound of Formula (I), or a salt thereof, under conditions where replication of RSV is inhibited.

Further included in the scope of the invention is the use of a compound of Formula (I), or a salt thereof, to inhibit the replication of RSV.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

DEFINITIONS

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to. In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C C₆alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named subgroup is the radical attachment point. For example, the substituent "aryld-Caalkyl" means an aryl group which is bound to a CrC₃alkyl group, with the CrC₃alkyl group bound to the core.

In case a compound of the present invention is depicted in the form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. The designation,— , may be used in partial formulas to indicate the bond which is connected to the core molecule as defined. Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, atropisomers) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of

diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.

One skilled in the art would know how to separate, enrich, or selectively prepare the

enantiomers of the compounds of the present invention. Preparation of pure stereoisomers, e.g. enantiomers and diastereomers, or mixtures of desired enantiomeric excess (ee) or

enantiomeric purity, are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof. These resolution methods generally rely on chiral recognition and include but not limited to chromatography using chiral stationary phases, enantioselective host- guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R.P.W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by

Chromatography, Am. Chem. Soc, 2000. Furthermore, there are equally well-known methods for the quantitation of enantiomeric excess or purity, including but not limited to GC, HPLC, CE, or NMR, and assignment of absolute configuration and conformation, including but not limited to CD, ORD, X-ray crystallography, or NMR.

The term "d-C_nalkyl", wherein n is an integer from 2 to n, either alone or in combination with another radical means an acyclic, saturated, branched or linear monovalent hydrocarbon radical with 1 to n C atoms. For example the term C_1-3alkyl embraces the radicals H₃C-, H₃C-CH₂-, H₃C- CH₂-CH₂- and H₃C-CH(CH₃)-.

The term CrC_nalkylene wherein n is an integer from 2 to n, means an acyclic, saturated, branched or linear divalent hydrocarbon radical with 1 to n C atoms. For example the term Ci-C₃alkylene embraces the radicals -CH₂-, -CH₂CH₂-, -CH(CH₃)-, -CH₂CH₂CH₂-, -CH₂CH(CH₃)- and -CH(CH₃)CH₂-.

The term Ci-C_nhaloalkyl refers to Ci-C_malkyl, wherein at least one C atom is substituted with a halogen, preferably chloro or fluoro. An exemplary Ci-C_nhaloalkyl is trifluoromethyl. The term d-C_nalkoxy or Ci-C_nalkyloxy means a radical -0-Ci-C_nalkyl which is linked via the oxygen atom, wherein Ci-C_nalkyl is as defined above, and includes i.a. methoxy, ethoxy, n- propoxy, isopropoxy, t-butoxy, n-butoxy and isobutoxy.

The term "amino" means NH₂.

The term "aminod-C_nalkyl" means a CrC_nalkyl which is substituted with NH₂, wherein Ci- C_nalkyl is as defined above.

The term "CrC_nalkylamino" means an amino group which is substituted with CrC_nalkyl, wherein CrC_nalkyl is as defined above.

The term "halo" or "halogen" includes fluoro, chloro, bromo and iodo.

The term "carbocyclyl" or "carbocycle" as used herein, either alone or in combination with another radical, means a mono-, bi- or tricyclic ring structure consisting of 3 to 14 carbon atoms. The term "carbocyclyl" or "carbocycle" refers to fully saturated and aromatic ring systems and partially saturated ring systems. The term "carbocyclyl" or "carbocycle" encompasses fused, bridged and spirocyclic systems.

The term "C₃-C_mcycloalkyl", wherein m is an integer 3 to m, either alone or in combination with another radical, means a cyclic, saturated, unbranched hydrocarbon radical with 3 to m C atoms. For example the term C₃-₇cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "C₃-C_mcycloalkxy" means a radical -0-C₃-C_mcycloalkyl which is linked via the oxygen atom, wherein C₃-C_mcycloalkyl is as defined above.

The term "oxo" or (=0) is used to indicate an oxygen atom which is double bonded to a carbon or sulfurus atom, thus providing a carbonyl C(=0), sulfoxide S(=0) or sulfonyl S(=0)₂ moiety.

The term "aryl" as used herein, either alone or in combination with another radical, means a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to one or more 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

The term "heterocyclyl" or "heterocycle" means, unless otherwise defined, a saturated or unsaturated mono-, bi- or tricyclic ring system including aromatic ring systems consisting of 3 to 14 ring atoms and containing one, two, three or four heteroatoms each independently selected from N, O and S. The term "heterocyclyl" or "heterocycle" is intended to include all the possible isomeric forms and all fused, bridged and spiro forms. The "heterocyclyl" may optionally be substituted with one or more substituents.

The term "heterocycloxy" means a radical -O-heterocyclyl which is linked via the oxygen atom, wherein heterocyclyl is as defined above.

The term "heteroaryl" means a mono- bi- or tricyclic ring system containing one, two, three or four heteroatoms each independently selected from N, O and S, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of an aromatic ring. The term "heteroaryl" is intended to include all the possible isomeric forms and all fused, bridged and spiro forms. The "heteroaryl" may be optionally substituted with one or more substituents.

The expression "C₃-C_mcycloalkylC₀-C_nalkyl " wherein m is an integer from 3 to m, and n is an integer from 1 to n as used herein is meant to include a C₃-C_mcycloalkyl moiety as defined above which is directly bonded (C₀) or bonded through an intermediate CrC_nalkylene linker as defined above.

The expression "carbocyclylC₀-C_nalkyl " wherein n is an integer from 1 to n as used herein is meant to include a carbocyclyl moiety which is directly bonded (C₀) or bonded through an intermediate CrC_nalkylene linker as defined above.

The expression "heterocyclylC₀-C_nalkyl" wherein n is an integer from 1 to n as used herein is meant to include a heterocyclyl moiety which is directly bonded (C₀) or bonded through an intermediate CrC_nalkylene linker as defined above.

The expression "heteroarylC₀-C_nalkyl" wherein n is an integer from 1 to n as used herein is meant to include a heteroaryl moiety which is directly bonded (C₀) or bonded through an intermediate d-C_nalkylene linker as defined above.

The expression "arylC₀-C_nalkyl" wherein n is an integer from 1 to n as used herein is meant to include a aryl moiety which is directly bonded (C₀) or bonded through an intermediate C

C_nalkylene linker as defined above.

Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.

The phrase "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio. The phrase "pharmaceutically acceptable salts" as used herein refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include acetates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, Ca-edetates/edetates, camsylates, carbonates, chlorides/hydrochlorides, citrates, edisylates, ethane disulfonates, estolates esylates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycollylarsnilates, hexylresorcinates, hydrabamines, hydroxymaleates,

hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, mesylates, methylbromides, methylnitrates, methylsulfates, mucates, napsylates, nitrates, oxalates, pamoates, pantothenates, phenylacetates,

phosphates/diphosphates, polygalacturonates, propionates, salicylates, stearates subacetates, succinates, sulfamides, sulfates, tannates, tartrates, teoclates, toluenesulfonates, triethiodides, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines and procaines. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, (also see Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1 -19).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention also comprise a part of the invention.

As used herein, the term "treatment" means the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of RSV disease and/or to reduce viral load in a patient.

As used herein, the term "prevention" means the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus, to prevent the appearance of symptoms of the disease.

The term "therapeutically effective amount" means an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician. The amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.

In the following embodiments, groups and substituents of the compounds of Formula (I) according to this invention are described in detail. Any and each of the definitions below may be combined with each other.

In one embodiment of compounds of formula (I), W is NR^1A, thus providing compounds of formula (la):

In one configuration of compounds of formula (la), R^1A is C C₆alkyl or C C₆haloalkyl.

Representative values for R^1A according to this configuration is CrC₃fluoroalkyl, such as 2,2,2- trifluoroethyl.

In an alternative configuration of compounds of formula (la), R^1A is optionally substitutedC₃- C₆cycloalkyl, such as cyclopropyl..

In one embodiment of compounds of formula (I), W represents a group of formula (A1 ) or (A2):

(A1) (A2)

wherein R^{1 B'} is C(=0)R^1C, C(=0)OR^1G or S(=0)₂R^1C;

R^1C is C C₆alkyl, C₃-C₅cycloalkyl or heterocyclyl, any of which is optionally substituted with one, two or three substituents independently selected from fluoro, amino, trifluoromethyl, CrC₃alkyl and C C₃alkylamino. In one configuration according to this embodiment, R^{1 B} is C(=0)OR^1G.

In another configuration according to this embodiment, R^{1 B} is C(=0)R^1C.

In another configuration according to this embodiment, R^{1 B} is S(=0)₂R^1C.

Typically in configurations wherein R^{1 B'} is C(=0)OR^1G, C(=0)R^1C or S(=0)₂R^1C, R^1C is Me or cyclopropyl substituted with methyl.

In one configuration of (A1 ) and (A2), R^{1 B'} is C(=0)OMe.

In another configuration of (A1 ) and (A2), R^{1 B'} is (=0)Me.

In another configuration of (A1 ) and (A2), R^{1 B'} is S(=0)₂Me.

Accordingly, in one embodiment the invention provides compounds having formula (lb') or (lb"):

wherein R^{1 B'} is C(=0)R^1C, C(=0)OR^1G or S(=0)₂R^1C;

R^1C is Ci-C₆alkyl, C₃-C₅cycloalkyl or heterocyclyl, any of which is optionally substituted with one two or three substituents independently selected from fluoro, amino, trifluoromethyl, d-C₃alkyl and Ci-C₃alkylamino.

In an alternative embodiment of compounds of formula (I), W represents a group of formula (B):

wherein

R^{1 B"} is NHC(=0)OR^1G, NHC(=0)R^1C or NHS(=0)₂R^1C;

R^1C is C C₆alkyl, C₃-C₅cycloalkyl or heterocyclyl, any of which is optionally substituted with one or two substituents independently selected from fluoro, amino, trifluoromethyl, C C₃alkyl, C C₃alkoxy and C C₃alkylamino.

In one configuration according to this embodiment, R^{1 B} is NHC(=0)OR^1G.

Typically in this configuration, R^{1 B"} is NHC(=0)OMe.

In another configuration according to this embodiment, R^{1 B} is NHS(=0)₂R^1C.

Typically in this configuration, R^{1 B} is NHS(=0)₂Me. In one embodiment of the invention, Z is CH.

In an alternative embodiment, Z is N.

In typical embodiments of compounds of formula I or any subgroup of formula I , q is 0.

In one embodiment of the invention n is 0.

In an alternative embodiment of the invention, n is 1 . Representative values for R³ according to this embodiment is d-C₃alkyl, fluoro or chloro. Typically, R³ is methyl.

In one embodiment of the invention where n is 1 , R³ is located in the 7-position of the isoquinoline moiety, thus providing compounds of the general formula:

Typical values for R³ according to this embodiment is fluoro, chloro or methyl.

In one configuration according to this embodiment, R³ is fluoro.

In a further configuration according to this embodiment, R³ is chloro.

In a further configuration according to this embodiment, R³ is methyl.

In a representative embodiment, the invention provides compounds of formula (I la) :

wherein

Z is CH or N;

R^{1 B'} is C(=0)R^{1 C}, C(=0)OR^{1 G} or S(=0)₂R^{1 C}

R^{1 C} is Ci-C₃alkyl, C₃-C₅cycloalkyl or a 4-, 5- or 6-membered heterocyclyl, any of which is optionally substituted with one, two or three substituents independently selected from methyl, amino, fluoro and trifluoromethyl

R³ is fluoro, chloro or methyl;

n is 0 or 1 .

In one embodiment of compounds of formula ( I la) Z is CH or N;

R^{1 B'} is C(=0)OR^1G;

R^1C is Ci-C₃alkyl;

R³ is chloro or methyl

n is 1 .

In a further representative embodiment, the invention provides compounds of formula (lib):

B'

wherein

Z is CH or N;

R^{1 B'} is C(=0)R^1C, C(=0)OR^1G or S(=0)₂R^1C;

R^1C is Ci-C₃alkyl, C₃-C₅cycloalkyl or a 4-, 5- or 6-membered heterocyclyl, any of which is optionally substituted with one, two or three substituents independently selected from methyl, amino, fluoro and trifluoromethyl

R³ is fluoro, chloro or methyl;

n is 0 or 1 .

In one embodiment of compounds of formula (lib)

Z is CH or N;

R^{1 B'} is C(=0)R^1G or S(=0)₂R^1c;

R^1C is methyl, cyclopropyl or cyclopropyl which is substituted with trifluoromethyl;

R³ is chloro or methyl

n is 1 .

In representative embodiments of compounds of formula (lla) and (lib), Z is N.ln one embodiment of compounds of formula (lla) and (lib), R^1C is methyl.

In one embodiment of compounds of formula (lla) and (lib), R^{1 B} is C(=0)R^1C, and R^1C is cyclopropyl which is substituted with trifluoromethyl.

In one embodiment of compounds of formula (lla) and (lib), n is 1 and R³ is chloro or methyl. In one embodiment of the invention, the compound of formula I is selected from: Methyl 2^,-oxo-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[azetidine-3,3'-indoline^ carboxylate,

5-(3-((1 -(1 -Aminocyclopropanecarbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1 '- yl)methyl)isoquinolin-4-yl)pyrimidine-2-carboxamide,

1 -(Methylsulfonyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[piperidine-4,3'-pyr^^ c]pyridin]-2'(1 'H)-one,

1 -(1 -Aminocyclopropanecarbonyl)-1 '-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3- y methy spirolpiperidine^^'-pyrrolo^^-clpyridinl^ I 'HJ-one,

1 '-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperi pyrrolop.a-clpyridinl-^il 'HJ-one,

1 -(1 -Aminocyclopropanecarbonyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[piperidine- 4,3'-pyrrolo[2,3-c]pyridin]-2'(1 ^,l-l)-one,

1 '-(1 -Aminocyclopropanecarbonyl)-1 -((6-fluoro-4-(pyrimidin-5-yl)isoquinolin-3- yl)methyl)spiro[indoline-3,4'-piperidin]-2-one,

1 '-((4-(Pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cyclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2'(1 ^,l-l)-one,

1 -(Piperidine-4-carbonyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[piperi

pyrrolop.a-clpyridinl-^il 'HJ-one,

1 '-((4-(Pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(3,3,3-trifluoropropanoyl)spiro[piperidin pyrrolop.a-clpyridinl-^il 'HJ-one,

1 -(1 -Amino-3,3-difluorocyclobutanecarbonyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3- y methy spirolpiperidine^^'-pyrrolo^^-clpyridinl^ I 'HJ-one,

1 '-((4-(Pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -((2,2,2-trifluoroethyl)sulfonyl)spiro[piperi 4,3'-pyrrolo[2,3-c]pyridin]-2'(1 ^,l-l)-one,

Methyl 1 ^,-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxospiro[azetidine-3,3'-indoli 1 -carboxylate,

Methyl 1 '-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)^

1 -carboxylate,

1 -(Piperidine-4-carbonyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[azetidine indolin]-2'-one,

3-((4-(Pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(2,2,2-trifluoroethyl)-1 H-imidazo[4,5-c]pyridin- 2(3H)-one,

Methyl 2^,-oxo-1 ^,-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 ^,,2^,-dihydrospiro[azetidine-3,3'- pyrrolo[2,3-c]pyridine]-1 -carboxylate, Methyl 1 '-((7-cyano-4-(pyrimidin-5-yl)isoquinolin-3-yl)^

1 -carboxylate,

1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)m

ργΓΓθΙο[2,3- γπ ίη]-2'(1 Ή)-οηθ,

1 -(1 -Aminocyclopropanecarbonyl)-1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3- y methy spirolpiperidine^^'-pyrrolo^^-clpyridinl^ I 'HJ-one,

1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

¹ '-((4-(Pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(3,3,3-trifluoropropanoyl)spiro[azetidi indolin]-2'-one,

1 -(2-Amino-3,3,3-trifluoropropanoyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3- y methy spirolpiperidine^^'-pyrrolo^^-clpyridinl^ I 'HJ-one,

1 '-(2-amino-3-hydroxypropanoyl)-1 -((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[indo piperidin]-2-one,

1 '-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cyclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2'(1 ^,l-l)-one, 1 '-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cyclopropanecarbonyl)spiro[azetidine-3,3'-pyrrolo[2,3-c]pyridin]-2'(1 ^,l-l)-one,

(R)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(pyrrolidine-2-carbonyl)spiro[pipe

ργΓΓθΙο[2,3-φγπ ίη]-2'(1 Ή)-οηθ,

Methyl 1 '-((7-methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2^,-oxospiro[azetidine-3,3'- indoline]-1 -carboxylate,

1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperi

Methyl 1 '-((7-methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)m

3, 3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

1 '-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[azetidine-3,^

Methyl 1 ^,-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ^,,2^,-dihydrospiro[azetidine- 3, 3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[azetidine-3,3

Methyl 1 ^,-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ^,,2^,-dihydrospiro[azetidine- 3, 3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate, 1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

Methyl ((1 s,3S)-1 '-((7 luoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2^,-oxospiro[cyclobutane- 1 ,3'-indolin]-3-yl)carbamate,

Methyl ((1 R,3R)-1 '-((7 luoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2^,-oxospiro[cyclobutane- 1 ,3'-indolin]-3-yl)carbamate,

3-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(2,2,2-trifluoroethyl)-1 H-imidazo[4,5- c]pyridin-2(3H)-one,

3-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(2,2,2-trifluoroethyl)-1 H-imidazo[4,5- c]pyridin-2(3H)-one,

1 '-((7-Methoxy-8-methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -

(methylsulfony spirolpiperidine^^'-pyrrolo^^-clpyridinl^ I 'HJ-one,

Methyl 2'-oxo-1 '-((4-(pyrimidin-5-yl)-7-(trifluoromethyl)isoquinolin-3-yl)methyl)-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

Methyl 1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[piperidine-4,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

N-((1 S,3S)-1 '-((6-fluoro-1 -(pyrimidin-5-yl)naphthalen-2-yl)methyl)-2'-oxospiro[cyclobutane-1 ,3'- indolin]-3-yl)acetamide,

N-((1 R,3R)-1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2^,-oxospiro[cyclobutane-1 ,3'- indolin]-3-yl)methanesulfonamide,

N-((1 S,3S)-1 '-((6-chloro-l -(pyrimidin-5-yl) isoquinolin -3-yl)methyl)-2'-oxospiro[cyclobutane-1 ,3'- indolin]-3-yl)methanesulfonamide,

Methyl 1 ^,-((7 luoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2^,-dihydrospiro[piperidine- 4,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cyclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2'(1 ^,l-l)-one, 1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

1 -Methylcyclopropyl 1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spi

pyrrolo[2,3-c]pyridin]-2'(1 'l-l)-one,

Methyl (1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxospiro[cyclobutane-1 ,3'- indolin]-3-yl)carbamate, Methyl 1 '-((y-methyl^^pyrimidin-S-y isoquinolin-S-y methy ^'-oxo-l ',2'- dihydrospiro[piperidine-4,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

1 -Methylcyclopropyl 2'-oxo-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

1 -Methylcyclopropyl 1 '-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate.

In a typical embodiment of the invention, the compound of formula I is selected from:

1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cyclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2^,(1 'H)-one,

1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperidine-4,3'- pyrrolo[2,3-c]pyridin]-2'(1 'H)-one and

Methyl ^-((y-methyl^^pyrimidin-S-y isoquinolin-S-y methy ^'-oxo-l '^'-dihydrospiroIazetidine- 3,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate.

GENERAL SYNTHETIC METHODS

Compounds of the present invention may be prepared by a variety of methods e.g. as depicted in the illustrative synthetic schemes shown and described below. The starting materials and reagents used are available from commercial suppliers or can be prepared according to literature procedures set forth in references using methods well known to those skilled in the art.

For simplicity, in the general synthesis schemes below the moiety will be referred to as R building block or R moiety.

In general, compounds of the invention are in typically prepared using either of the two general approaches, Method A and Method B, outlined in Scheme 1 .

Scheme 1

Coupling of a chloromethyl or bromomethyl isoquinoline derivative (1 A) with a bicyclic amide or urea derivative (1 B) typically performed under basic conditions using a base like cesium carbonate, sodium hydride or potassium tert. butoxide or similar in an organic solvent like DMF or acetonitrile or the like provides the N-alkylated derivative (1 C). The pyrimidyl group is then suitably introduced using for instance a Suzuki reaction, i.e. reaction with the suitable boronic acid derivative (1 D) in the presence of a palladium catalyst thus providing the diaryl compound (1 E). Representative palladium catalysts for this purpose include but is not limited to palladium(ll)chloride diphenylphosphine, 1 , 1 '-bis(diphenylphosphino)ferrocene]

dichloropalladium(ll) complex with dichloromethane, tetrakis-(triphenylphoshine)-Pd(0) and similar. Alternatively, the pyrimidyl group may be introduced by a Stille reaction or any other convenient diaryl coupling method known to the skilled person. An alternative approach to compounds of the invention is illustrated by Method B wherein the two steps are performed in the reverse order, i.e. the synthesis starts with the diaryl coupling, i.e. coupling of 4-halo-3- (halomethyl)isoquinoline (1 a) with the suitable pyrimidyl derivative (1 D) as described for Method A, followed by alkylation of the halomethyl isoquinoline derivative (1 C) with the desired bicyclic amide or urea derivative (1 B).

The substituents to the core structure are introduced on the isoquinoline and R¹ building blocks prior to coupling or they can be introduced after the coupling step. Alternatively, precursors to the final substituents may be present on the building blocks and transformed to the desired substituents at a later stage of synthesis of final compounds. Isoquinoline building block useful for the preparation of compounds of the invention are commercially available or can be prepared as outlined herein. For example, 4-bromo-3- (bromomethyl)isoquinoline can be prepared as illustrated in Scheme 2

Bromination of commercially available 3-methylisoquinoline effected by treatment with hydrobromic acid and bromine using e.g. the procedures as described in J. Org. Chem., 1991 , 56(8), 2805-2809, provides bromo derivative (2A), followed by benzylic bromination effected by treatment with N-bromosuccinimide and carbontetra chloride provides the desired building block (2B).

An alternative approach to a halo substituted isoquinoline building block is illustrated in Scheme 3.

Reaction of optionally substituted benzaldehyde with prop-2-yn-1 -ol which may be hydroxy protected, in a cross-coupling reaction under Sonogashira conditions, i.e. using a Pd catalyst such as bis(triphenylphosphine)palladium(ll) chloride or equivalent and a copper halide such as copper iodide or the like, in the presence of a base such as triethylamine or similar, provides the acetylene derivative (3A). Reaction with tert. butylamine in the presence of magnesium sulfate or similar followed by iodine, and optionally hydroxy deprotection, provides isoquinoline derivative (3B). The benzylic hydroxy group can then be transformed to a suitable leaving group such as chloro or bromo. Typically, the chloro derivative (3C) is achieved by treatment of the alcohol with phosgene, whereas the bromo derivative (3D) is typically achieved by treatment of the alcohol with carbontetra chloride in the presence of triphenylphosphine. Alternatively, the iodo derivative (3B) may be further reacted to introduce a desired R² substituent or suitable precursor thereof.

Various R¹ building blocks are commercially available or can be prepared according to literature procedures. For example, the below shown R¹ moieties, which are used for the preparation of compounds of the present invention, constitute part of the prior art and are disclosed e.g. as follows:

A useful intermediate for R¹ building blocks wherein W is CR^{1 B}R^{1 B} and the two R^{1 B} together with the carbon atom to which they are attached form an azetidine moiety can be prepared, for example, as illustrated in Scheme 4.

Scheme 4

Coupling of the desired amino derivative (4A) and acid (4B) under peptide coupling conditions such as in the presence of coupling agent like HATU, EDC or similar in the presence of an amine like DIEA or the like provides the amide (4C). Protection of the amide nitrogen with a suitable protecting group (Pg²), for a instance p-methoxy benzyl group or a 2,4- dimethoxy benzyl group, introduced by reaction with the corresponding benzyl chloride in the presence of a base like potassium carbonate or similar, provides the N-protected derivative (4D). Subsequent palladium catalysed ring closure using for instance palladium acetate and

tricyclohexylphosphine or similar and a base such as sodium tert.butoxide or the like, provides the spirotricycle (4E). Removal of the two N-protecting groups using the appropriate conditions according to the protecting group used, such as acidic treatment in the case of Boc and p- methoxybenzyl provides the unprotected the unprotected spirotricycle (4F). The amino function is then either transformed to the group desired in the final compound, or protected with a suitable protecting group, typically a Boc group

Amino containing spirotricycles, prepared as outlined in Scheme 4, commercially available or available through literature procedures are then substituted on the N-atom either with the group desired in the final compound, or protected with a suitable protecting group, typically a Boc group as outlined in Scheme 5.

Scheme 5

The afforded amine can then be transferred to an amide (5B) by reaction with an acid

R^1GC(=0)OH under peptide coupling conditions, or with an acid chloride R^1CC(=0)CI, or to a carbamate (5C) by reaction with a chloroformate R^1GOC(=0)CI or anhydride

R^1cOC(=0)OC(=0)OR^1G or similar. Reaction of the amine with a sulfonylchloride R^1CS(=0)₂CI provides a sulfonamide(5D) whereas reaction with carbonyl diimidazole or phosgene or similar followed by an amine H₂NR^1C or HNR^1CR^1C' provides a urea (5E).

A route to R¹ building block useful for the preparation of compounds of formula I wherein Z¹ is NR^1A and R^1A is optionally substituted C₃-C₄cycloalkyl in Scheme 9.

Scheme 6

Reaction of nitro substituted aryl halide (6A) in a substitution reaction with a suitably protected cycloalkylamine (9B) using conditions like in the presence of a base such as

diisopropylethylamine or similar in a solvent like DMF and typically at an elevated temperature, provides the substituted aniline derivative (6C). Reduction of the nitro group effected for instance by catalytic hydrogenation using a catalyst like palladium on carbon in a solvent like MeOH or EtOH or the like or similar conditions provides the aniline (6D). Ring formation is then performed by reaction with carbonyl diimidazole or phosgene or triphosgene in the presence of a base like triethylamine or similar, thus providing the bicyclic compound (6E).

Compounds of the invention wherein Z¹ is NR^1A and R^1A is optionally substituted d-C₃alkyl are commercially available, or can be prepared according to literature procedures for instance as illustrated in Scheme 7.

Scheme 7

Coupling of the desired substituted alkylamine H₂N-R^1A with the nitro substituted aryl halide 10A followed by reduction of the nitro group to the amine and subsequent ring formation effected by reaction with carbonyldiimidazole or the like, provides the bicycle (7D) carrying the desired substituent

PHARMACEUTICAL COMPOSITION

Suitable preparations for administering the compounds of the invention will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders, etc. The content of the pharmaceutically active compound(s) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or more compounds of the invention with known excipients, for example inert diluents, carriers, binders, disintegrants, adjuvants, surfactants and/or lubricants. The tablets may also consist of several layers.

Suitable inhalatives may be obtained, for example, by administering one or more compounds of the invention in the form of a solution, dry powder or suspension. The compounds of the invention may be administered via inhalation of a solution in nebulized or aerosolized doses.

The dose range of the compounds of the invention applicable per day is usually from 0.01 to 100 mg/kg of body weight, preferably from 0.1 to 50 mg/kg of body weight. Each dosage unit may conveniently contain from 5% to 95% active compound (w/w). Preferably such

preparations contain from 20% to 80% active compound.

The actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.

COMBINATION THERAPY

When the composition of this invention comprises a combination of a compound of the invention and one or more additional therapeutic or prophylactic agent, both the compound and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen. Therefore, according to one embodiment, the pharmaceutical composition of this invention additionally comprises one or more antiviral agents.

Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the production and/or replication of a virus in a human being, including but not limited to agents that interfere with either host or viral mechanisms necessary for the production and/or replication of a virus in a human being. Such agents can be selected from: RSV Fusion inhibitors, such as MDT-637 (MicroDose), BTA-9881 (Biota); RSV Polymerase inhibitors, such as ALS-81 12 (Alios), ALS-8176 (Alios) and Virazole (ribavirin); others, such as GS-5806 (Gilead Sciences) and RSV-604 (Novartis); antibodies, such as Synagis® (palimizumab), RespiGam® (RSV-IG), MEDI-557 (Medlmmune/AstraZeneca), ALX- 0171 (Ablynx), motavizumab (Medlmmune/AstraZeneca); other biological, such as ALN-RSV-01 (Alnylam) and Vaccines, such as MEDI-559 (Medlmmune/AstraZeneca), RSV F (Novavax), MEDI-534 (Medlmm u ne/AstraZen eca) .

In addition to the definitions above, the following abbreviations are used in the synthetic schemes above and the examples below. If an abbreviation used herein is not defined, it has its generally accepted meaning

ABC Ammonium bicarbonate

Ac Acetyl

ACN Acetonitrile

AcOH Acetic acid

Bn Benzyl

Boc ferf-butyloxycarbonyl

BOP-CI Bis(2-oxo-3-oxazolidinyl)phosphinic chloride

CDI 1 , 1 '-Carbonyldiimidazole

DCC Dicyclohexylcarbodiimide

DCM Dichloromethane DIEA Diisopropylethylamine

DIPEA Diisopropylethylamine

DMAP 4-Dimethylaminopyridine

DME 1 ,2-Dimethoxyethane

DMEM Dulbecco's modified Eagle's medium

DMF N, N- D i m ethy If o rm am ide

DMSO Dimethyl sulfoxide

EC₅₀ 50% effective concentration

ED AC 1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide

Et Ethyl

EtOAc Ethyl acetate

Et₃N Triethylamine

EtOH Ethanol

Et₂0 Diethyl ether

LC Liquid chromatography

HATU [0-(7-azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate]

HDMS Hexamethyldisilazane

HOAc Acetic acid

HOBt Hydroxybenzotriazole

HPLC High performance liquid chromatography

Me Methyl

MeCN Acetonitrile

MeO Methoxy

MeOH Methanol

MS Mass spectrometry

PCC Pyridinium chlorochromate

g Protecting group

Ph Phenyl

PCy₃ Tricyclohexylphosphine

rt Room temperature (18 to 22 ^eC)

TBAF Tetrabutylammonium fluoride

TEA Triethylamine

TEST bis(triethoxysilyl)propyl-tetrasulfide

TFA Trifluoroacetic acid

TFAA Trifluoroacetic anhydride

THF Tetrahydrofuran EXAMPLES

Other features of the present invention will become apparent from the following non-limiting examples which illustrate the principles of the invention. As is well known to a person skilled in the art, reactions are performed in an inert atmosphere (including but not limited to nitrogen or argon) where necessary to protect reaction components from air or moisture. Temperatures are given in degrees Celsius CO). Solution percentages and ratios express a volume to volume relationship, unless stated otherwise. The reactants used in the examples below may be obtained from commercial sources or they may be prepared from commercially available starting materials as described herein or by methods known in the art.

The compounds of the invention including intermediates are prepared as described in the Examples and in the general schemes herein. It will be apparent to a skilled person that analogous synthetic routes may be used, with appropriate modifications, to prepare the compounds of the invention as described herein. The progress of the reactions described herein were followed as appropriate by e.g. LC, GC or TLC, and as the skilled person will readily realise, reaction times and temperatures may be adjusted accordingly.

NMR spectra were recorded on a Bruker AVANCE II spectrometer operating at 500 MHz for ¹ H NMR and at 126 MHz for ¹³C NMR using CDCI₃ (deuterated chloroform) or DMSO-c/₆

(deuterated DMSO, dimethyl-c/₆ sulfoxide) as solvent. Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS) which was used as internal reference, or to residual solvent peak.

NMR shifts indicated with an asterisk were obtained using an automated process wherein residual solvent and/or impurities may be present, integrals and chemical shifts may not be completely accurate, signals may be broad with a low signal to noise ratio and may overlap with signals from residual solvents, and multiplicities may have been misinterpreted. Despite this, all spectra obtained by the automated process are supporting the structure of each of the analysed compounds.

The compounds illustrated in Table 1 are described in the literature and used as intermediates in the synthesis of compounds of the invention and referred to as indicated

TABLE 1

Preparation of intermediates

Intermediate 1

1-1 a Mb Mc

Step a) 2-nitro-N-(2,2,2-trifluoroethyl)aniline (1-1 a)

To a solution of the HCI salt of 2,2,2-trifluoroethylamine (1 .0 g, 7.38 mmol, 1 eq) in DMF (8.4 mL) were added DIPEA (1 .6 ml_, 9.2 mmol, 1 .25 eq) and 1 -flouro-2-nitro-benzene (0.65 ml_, 6.15 mmol, 0.83 eq). The mixture was stirred at 80 °C for 16 h, then poured into an aqueous citric acid solution (10%) and stirred for 5 minutes. The mixture was extracted with EtOAc (3x30 mL) and washed with brine (2x10 mL). The organic layer was dried over anhyd. Na₂S0₄, filtered and concentrated under reduced pressure. The afforded crude material was purified by column chromatography on silica gel (100-200 mesh) using 20% EtOAc/ hexane which gave the title compound (0.84 g, 51 .7%) as a solid.

Step b) N1 -(2,2,2-trifluoroethyl)benzene-1 ,2-diamine (1-1 b)

To an ethanolic solution (50 mL) of compound 1-1 a (5.0 g, 22.7 mmol) was added Pd/C (50% moisture, 500 mg) and the mixture was stirred in Parr shaker at room temperature under 40 psi of hydrogen pressure for 4 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The crude compound was purified by column

chromatography (100-200 mesh silica gel) using 30% EtOAc in hexane as eluent which gave the title compound (2.8 g, 65%).

Step c) 1 -(2,2,2-trifluoroethyl)-1 H-benzo[dlimidazol-2(3H)-one (1-1 c)

To a stirred solution of compound 1-1 b (4.5 g, 23.5 mmol, 1 eq) in DCM (50 mL) was added DIPEA (12.3 mL, 70 mmol, 3 eq), followed by CDI (6.1 g, 37.7 mmol, 1 .6 eq) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred for 3h, then diluted with water and was extracted with DCM. The organic layer was washed with brine, dried over anhyd. Na₂S0₄ and concentrated under reduced pressure. The afforded crude compound was purified by silica gel (100-200 mesh) column chromatography using 40% EtOAc in hexane which gave the title compound (1 .2 g, 23%) as a solid.

¹ H NMR 400 MHz, DMSO-d6 δ 4.68-4.75 (q, J = 9.4 Hz, 2H), 7.01 -7.10 (m, 3H), 7.21 - 7.22 (m, 1 H), 1 1 .1 1 (s, 1 H). Intermediate 2

l-2d l-2e , |-2f, R = H

^SteP 9 |.₂g, R = Boc

Step a) 1 -tert-butyl 3-ethyl 2-(3-nitropyridin-4-vDmalonate (l-2a)

To the stirred solution 4-chloro-3-nitropyridine (1 1 g, 69.6 mmol) in THF (100 mL) was added NaH (60% in mineral oil, 8.3 g, 209 mmol) at 0 °C under N₂ atmosphere. The mixture was stirred at 15 °C for 1 h, then cooled to 0 °C and a solution of tert-butyl ethyl malonate (14.5 g, 76.5 mmol) in THF (50 mL) was added drop wise. The resulting reaction mixture was stirred at 15 °C for 1 h and then quenched with saturated aq. solution of NH₄CI. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried (Na₂S0₄) and concentrated under reduced pressure to afford crude title compound (8 g) as an oil which was used for the next step without further purification.

Step b) ethyl 2-(3-nitropyridin-4-yl)acetate (l-2b)

To a stirred solution of l-2a (25 g, 80.64 mmol) in DCM (150 mL) was added TFA (25 mL ) dropwise at 0 °C under N₂ atmosphere and the resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated by distilling out the volatiles completely and slowly diluted by ice cold water. Aq. NaHC0₃ solution was added and the mixture was extracted with EtOAc. The Organic layer was then washed with water and brine, dried (Na₂S0₄) and concentrated in vacuo. The afforded crude compound was purified by column chromatography on silica gel (100-200 mesh) using 25% EtOAc/ hexane as eluent to obtain the title compound (12.5 g, 74%) as a liquid. MS (ES+) 21 1 .0 [M+H]⁺.

Step c) ethyl 2-(3-aminopyridin-4-yl)acetate (l-2c)

10% Pd/C (50% moist) was under nitrogen added to a solution of l-2b (1 g, 4.7 mmol) in methanol (10 mL). The mixture was stirred under hydrogen atmosphere (50 psi) at ambient temperature in Parr shaker for 4h, then filtered through Celite and the filtrate was concentrated in vacuo to afford the title compound (550 mg, 64%) as an oil which was used for the next step without further purification. MS (ES+) 181 .2 [M+H]⁺. Step d) 1 H-pyrrolof2,3-clPyridin-2(3H)-one hydrochloride (l-2d)

To a stirred solution of l-2c (30 g, 167 mmol) in 1 .4 N aq. HCI was added di isopropyl ether and the resulting mixture was stirred at ambient temperature for 16 h. From the reaction mixture, diisopropyl ether was separated and the aqueous part was washed with DCM. The aqueous layer was collected and concentrated in vacuo. The afforded crude compound was triturated with ethyl acetate and filtered to afford the title compound (15 g, 67%) as a solid.

Step e) 1 -benzylspiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (l-2e)

To a stirred solution of l-2d (1 1 g, 82 mmol) in THF (200 mL) was added 1 M LiHMDS/ THF solution (234 mL) at -78 °C over a period of 15 min. The resulting reaction mixture was slowly warmed up to 0 °C and was added N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine under nitrogen atmosphere at 0^*Ό. The resulting reaction mixture was then stirred under reflux for 12h. The reaction mixture was quenched with a 10% aq. NH₄CI solution, diluted with water and the organic components were extracted with EtOAc. The organic part was washed with water and brine, dried (Na₂S0₄) and concentrated under reduced pressure to get crude compound as light brown solid. The crude compound was purified by silica gel (100-200 mesh) column chromatography using 5% MeOH/ DCM to obtain compound 8 (3g, 12%) as an off white solid. MS (ES+) 293.7 [M+H]⁺.

Step f) spiro[piperidine-4,3'-pyrrolof2,3-clPyridinl-2'(1 'H)-one (l-2f)

10% Pd/C (50% moist) was added under nitrogen to a solution of l-2e (5 g, 17 mmol) in methanol (80 mL). The resulting reaction mixture was stirred under hydrogen atmosphere (50 psi, 50 °C) in Parr shaker for 15 h, then filtered through Celite and the filtrate was concentrated in vacuo to obtain crude title compound (3 g, 86%) as an oil. The crude compound was used in the next step without further purification. MS (ES+) 204.3 [M+H]⁺.

Step q) tert-butyl 2'-oxo-1 ',2'-dihvdrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (I- 2gi

To a stirred solution of l-2f (3.5 g, 17.2 mmol) in methanol (40 mL) was added di-tert-butyl dicarbonate (3.9 g, 17.2 mmol) at 0 °C and the mixture was stirred at ambient temperature for 16h. The reaction mixture was concentrated in vacuo and the crude material was purified by silica gel (100-200 mesh) column chromatography using 5% MeOH/ DCM to afford the title compound (3.9 g, 75%) as a solid. MS (ES+) 304.2 [M+H]⁺. Intermediate 3

Step a) tert-butyl 3-((2-bromophenvncarbamovnazetidine-1 -carboxylate (l-3a)

To a stirred solution of 2-bromoaniline (5 g, 29.42 mmol, 1 eq) and DMAP (4.6 g, 37.5 mmol, 1 .3 eq) in DCM (83 mL) were added 1 -(tert-butoxycarbonyl)azetidine-3-carboxylic acid ( 5.85 g, 29.10 mmol, 1 eq ) followed by EDAC-HCI (7.24 g, 37.93 mmol, 1 .3 eq) at 23 °C and the resulting reaction mixture was stirred at ambient temperature for 12 h. The reaction mixture was then washed with 10% citric acid aqueous solution, water, saturated aqueous Na₂C0₃ solution, brine, and the organic components were extracted into DCM. The organic layer was dried over anhyd. Na₂S0₄ and evaporated under reduced pressure to afford crude compound. The crude compound was purified by silica gel (100-200 mesh) column chromatography using 15% EtOAc in Hexane as the eluent to afford the title compound (6 g, 57.6% ) as an off white solid.

Step b) tert-butyl 3-((2-bromophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1 -carboxylate (l-3b) To a stirred solution of compound l-3a (6 g, 16.9 mmol, 1 eq) and 1 -(chloromethyl)-4- methoxybenzene (4.02 g, 25.7 mmol) in acetonitrile (80 mL) was added K₂C0₃ (7.24 g, 50.72 mmol, 3 eq) and the resulting reaction mixture was stirred under reflux for 12 h. The reaction mixture was filtered and the solid residue was washed with acetonitrile. The filtrate was concentrated in vacuo and the crude product was triturated with hexane/ethyl acetate (30:1 ), which gave the title compound (6.5g, 81 .25%) as an off white solid.

Step c) tert-butyl 1 '-(4-methoxybenzyl)-2'-oxospiro[azetidine-3,3'-indolinel-1 -carboxylate (l-3c) To the stirred, degassed with argon solution of compound l-3b (0.5 g, 1 .27 mmol, 1 eq) and 'BuONa (0.182 g, 1 .9mmol, 1 .5 eq) in dioxane (4ml_) were added Pd(OAc)₂ ( 0.0071 g, 0.03 mmol, 0.025 eq) and PCy₃ (0.0088 g, 0.03 mmol, 0.025 eq) and the resulting mixture was further degassed with argon for 5 min. The reaction mixture was then stirred under microwave irradiation in a microwave reactor at 120 °C for 1 h. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure to obtain a crude mass which was washed with water and brine. The organic component was extracted into EtOAc and dried over anhyd. sodium sulphate and concentrated in vacuo to dryness. The crude material was then purified on silica gel (230-400 mesh) gravity column using 7% EtOAc-Hexane as eluent which gave the title compound.

Step d) spiro[azetidine-3,3'-indolinl-2'-one (l-3d)

To a solution of compound l-3c (0.3 g, 0.76 mmol, 1 eq) in TFA (1 .2ml_) was added CF₃S0₃H (0.20 ml_, 2.28 mmol, 3 eq) and the resulting mixture was stirred at 23 °C for 12 h. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in water and washed with DCM. From the aqueous layer, water was completely distilled out to obtain corresponding salt of the title compound which was used directly in the next step.

Step e) methyl 2'-oxospiro[azetidine-3,3'-indolinel-1 -carboxylate (l-3e)

To a stirred solution of compound l-3d (0.167 g, 0.96 mmol, 1 eq) in DMF, were added TEA (0.404 mL 2.89 mmol, 3 eq) and Methyl chloroformate (0.075 ml_, 0.95 mmol, 1 eq) at 0 °C and the resulting reaction mixture was stirred at room temperature for 4 h, The reaction mixture then diluted with water and the organic components were extracted with ethyl acetate. The organic layer was washed with brine and dried over anhyd. sodium sulphate and concentrated in vacuo to obtain a crude title compound.

Step f) tert-butyl 2'-oxospiro[azetidine-3,3'-indolinel-1 -carboxylate (l-3f)

To a stirred solution of compound l-3d (1 .1 g, 6.32 mmol, 1 eq) in water (50 ml) were added K₂C0₃ (2.6 g, 18.96 mmol, 3 eq), THF (30 ml) and (Boc)₂0 (1 .4 ml, 6.32 mmol, 1 eq) at 0 °C and then stirred at ambient temperature for 12 h. The reaction mixture was diluted with EtOAc and washed with brine, dried over anhyd. Na₂S0₄ and concentrated under reduced pressure to obtain crude material which was triturated with pentane and diethyl ether to obtain the title compound (1 g, 58%) as a solid. MS (ES-) 273.2 [M-H]^".

Intermediate 4

l-3d 1-4

1 -(Methylsulfonyl)spiro[azetidine-3,3'-indolinl-2'-one (I-4) Triethylamine (2.6 mL) and methanesulfonyl chloride (0.48 mL) were added at 0 °C to a stirred solution of l-3d (1 .8 g) in DMF (15 mL). The resulting mixture was stirred at 0 °C for 1 h, then diluted with ice water and stirred for 10 minutes, solid was formed and filtered and dried which gave the title compound (480 mg, 30%) as a solid. MS (ES+) 253.14 [M+H]⁺.

Intermediate 5

Spiro[cvclobutane-1 ,3'-indolinel-2',3-dione (I-5)

To a stirred solution of 3-aminospiro[cyclobutane-1 ,3'-indolin]-2'-one (1 ,0 g, 5.3 mmol, prepared as described in WO2014/06041 1 ) in THF (30 mL) was added TEA (1 .48 mL, 10.6 mol) at rt under nitrogen. The reaction mixture was cooled to 0 °C, then methyl chloroformate (493 μΙ, 6.38 mmol) was added The resulting reaction mixture was stirred at rt for 1 h, diluted with water (100 mL), extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water (100 mL) and saturated bicarbonate solution (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent 1 % MeOH in DCM), which gave the title compound (700 mg, 49% ) as a solid. MS (ES+) 247.20 [M+H]⁺.

Intermediate 6

1-6

Tert-butyl (1 -(2'-oxospiro[azetidine-3,3'-indolinl-1 -ylcarbonvDcvclopropyDcarbamate (I-6)

To a stirred solution of 1 -((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (1 .36 g, 6.77 mmol) in DMF (20 mL) was added ED AC (1 .20 g, 6.24 mmol), HOBt (0.960 g, 6.24 mmol), Et₃N (2.1 mL, 20.8 mmol) and l-3d (1 .50 g, 5.20 mmol) at rt. The resulting reaction mixture was stirred at room temperature for 16h, then diluted with water (30 mL) and extracted with EtOAc (2x30 mL). The organic layer was washed with water (3x50 mL), dried (Na₂S0₄), filtered and concentrated under reduced pressure which gave the title compound (800 mg, 41 %) as a solid. MS (ES+) 358.26 [M+H]⁺. Intermediate 7

l-2f 1-7

Step a) methyl 2'-oxo-1 ',2'-dihvdrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (I-7) To a stirred solution of compound l-2f (0.5 g, 2.46 mmol, 1 eq) in THF (3 mL) was added TEA (1 mL, 7.38 mmol, 3 eq) followed by addition of methyl chloroformate (0.2 mL, 2.46 mmol, 1 eq). The mixture was stirred at ambient temperature for 16 h, then diluted with water and the organic components were extracted into ethyl acetate and washed with water and brine. The organic layer was dried over anhyd. Na₂S0₄ and concentrated under reduced pressure. The afforded crude product was purified by silica gel (100-200 mesh) column chromatography using 5% MeOH in DCM to afford the title compound (250 mg, 39%) as a solid. MS (ES+) 262.1 [M+H]⁺.

Intermediate 8

Step a) 4-iodo-3-methylisoquinoline (l-8a)

To a stirred solution of 7-chloro-3-methylisoquinoline (4.80 g, 20.8 mmol) in acetic acid (50 mL) was added N-lodo succinimide (5.7 g, 25.3 mmol). The mixture was heated at 80 °C for 3 days, then cooled to rt. and the reaction was quenched with saturated sodium hydroxide solution (100 mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic phases were washed with saturated sodium thiosulfate solution (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The afforded crude compound was purified by column chromatography on silica gel eluted with 10% EtOAc in p. ether. Pure fractions were collected and concentrated under reduced pressure which gave the title compound (4 g, 62%). The structure was confirmed by ¹ H NMR.

Step b) 4-bromo-3-(bromomethyl)-7-chloroisoquinoline (l-8b)

To a stirred solution of compound l-8a (4 g) in CCI₄ (400 mL), were added azobisisobutyronitrile (425 mg) and N-bromosuccinimide (9.3 g) at rt under nitrogen. The resulting reaction mixture was at reflux for 18 h, then cooled to rt. A saturated solution of Na₂S₂0₃ (100 mL) was added and the mixture was extracted with DCM (2x250 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 15-20% EtOAc in p. ether, which gave the title compound together with an inseparable by-product (2.1 g). The material was used as such in following steps without further purification.

Intermediate 9

Step a) N-(3-fluorobenzyl)-1 ,1 -dimethoxypropan-2-amine (l-9a)

To a stirred solution of (3-fluorophenyl)methanamine (20.0 g) in 1 ,2-dichloroethane (800 mL) was added pyruvic aldehyde dimethyl acetal (28.3 g) at rt followed by addition of sodium triacetoxyborohydride (67.7 g) the mixture was stirred for 16 h, then aqueous 2 N NaOH (100 mL) solution was added and the mixture was stirred until the organic layer was almost clear. The layers were separated, the aqueous layer was extracted with DCM (2x50

mL).The combined organics were dried over Na₂S0₄, filtered and concentrated under reduced pressure to obtain crude title compound (32 g). MS (ES+) 228.17 [M+H]⁺.

Step b) 7-fluoro-3-methylisoquinoline (l-9b)

N-(3-fluorobenzyl)-1 ,1 -dimethoxypropan-2-amine (32 g, 141 mmol) was added dropwise at <5 °C to chlorosulfonic acid (96.5 mL, 1 .41 mmol). The mixture was heated to 100 °C for 10 min, then cooled and poured into ice (700 g). The mixture was washed with MTBE (700 mL), the aqueous layer was cooled to 5 °C and basified pH14 with 50% aq NaOH solution (400 mL). The aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na₂S0₄, filtered and concentrated under reduced pressure to obtain crude title

compound (1 1 g, 34%). MS (ES+) 162.09 [M+H]⁺.

Step c) 7-fluoro-4-iodo-3-methylisoquinoline (l-9c)

N-iodo succinimide (8.38 g) was added to a stirred solution of l-9b (5 g) in acetic acid (50 mL). The reaction mixture was heated at 80 °C for 3 days, then cooled to rt. Sodium hydroxide solution (150 mL) was added and the mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed with saturated sodium thiosulfate solution (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude compound was purified by column chromatography on silica gel eluted with 10% EtOAc in p. ether. Pure fractions were pooled and concentrated under reduced pressure which gave the title compound (2, 3 g, 33%). MS (ES+) 288.01 [M+H]⁺. Step d) 4-bromo-3-(bromomethvn-7-fluoroisoguinoline (l-9d)

Azobisisobutyronitrile (343 mg) and N-bromosuccinimide (7.44 g) were added at rt under nitrogen to a stirred solution of compound l-9c (3.0 g, 10.4 mmol) in CCI₄ (300 mL). The resulting mixture was stirred at reflux for 18 h, then cooled to rt. A solution of Na₂S₂0₇ (100 mL) was added and the mixture was extracted with DCM(2 x 250 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was combined with a previously prepared batch and purified by column chromatography on silica eluting with 15-20% EtOAc in p. ether. Pure fractions were pooled and concentrated under reduced pressure which gave the title compound.

Intermediate 10

1-10c

1-1 Od

Step a) tert-butyl 3-((4-bromopyridin-3-yl)carbamoyl)azetidine-1 -carboxylate (1-10a)

To a solution of 3-amino-4-bromopyridine (5.05 g, 29.2 mmol) and N -boc-azetidine-3- carboxylic acid (6.17 g, 30.6 mmol) in dry DCM (100 mL) was added DMAP (4.64 g, 38.0 mmol) and EDAC'HCI (7.27 g, 38.0 mmol). The mixture was stirred at rt for three days, then diluted with EtOAc and washed twice with water and brine. The water phase was extracted once with EtOAc and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The product was isolated by silica gel chromatography eluted with 0 to 3% MeOH in DCM, which gave the title compound (9.6 g, 92%). MS (ES+) 356.2 & 358.2

[M+H]⁺.

Step b) Tert-butyl 3-((4-bromopyridin-3-yl)(2,4-dimethoxybenzyl)carbamoyl)azetidine-1 - carboxylate (1-10b)

To a solution of 1-10a (7.12 g, 20.0 mmol) in dry DMF (25 mL) was added cesium carbonate (1 .63 g, 50.0 mmol) and the mixture was stirred for 30 minutes at rt. A solution of 1 - (chloromethyl)-2,4-dimethoxybenzene (8.77 g, 47.0 mmol) in benzene (-10 mL) was added and the mixture was stirred for two h at rt. Water was added and the mixture extracted three times with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The product was purified by silica gel chromatography eluted with DCM and 10 to 50% EtOAc, which gave the title compound (10.1 g, 79%).

Step c) Tert-butyl 1 '-(2,4-dimethoxybenzyl)-2'-oxo-1 ',2'-dihvdrospiro[azetidine-3,3'-pyrrolo[2,3- clpyridinel-1 -carboxylate (1-10c)

Sodium-tert-butoxide (2.28 g, 23.7 mmol), palladium(ll)acetate (355 mg, 1 .58 mmol) and tricyclohexylphosphine (443 mg, 1 .58 mmol) were added under argon to a solution of 1-10b in dry dioxane (85 mL). The mixture was stirred under argon for at 95 °C two hours, then cooled to rt and added to a saturated ammonium chloride solution. The mixture was extracted four times with DCM, the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The product was isolated by silica gel chromatography eluted with DCM and 20 to 60% EtOAc, which gave the title compound (6.72 g, 80%). MS (ES+) 426.4 [M+H]⁺.

Step d) Tert-butyl 2'-oxo-1 ',2'-dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (I- 10d)

A solution of 1-10c (3.22 g, 7.58 mmol) in acetonitrile (80 mL) was added to an ice cooled solution of ammonium cerium nitrate (3.29 g) in water (40 mL). The reaction mixture was stirred for two hours at rt, then additional ammonium cerium nitrate (1 ,64 g) was added and the mixture was stirred for two more hours at rt. 5% potassium carbonate solution (400mL) was added and the mixture was extracted four times with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The product was isolated by silica gel chromatography eluted with DCM and 2 to 8% MeOH, which gave the title compound (1 .05 g, 50%). MS (ES+) 276.3 [M+H]⁺.

Intermediate 1 1

Step a) tert-butyl 3-((4-bromopyridin-3-yl)carbamoyl)azetidine-1 -carboxylate (1-1 1 a)

To a stirred solution of 6-fluoro-3-methylisoquinoline (100 mg) in acetic acid (3 mL) was added N-iodo succinimide(168 mg). The reaction mixture was heated at 80 °C for 3 days, then cooled to rt. Saturated sodium hydroxide solution (20 mL) was added and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with saturated sodium thiosulfate solution (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude compound was purified by column chromatography on silica gel eluted with 10% EtOAc in p. ether. Pure fractions were collected and concentrated under reduced pressure which gave the title compound (30 mg, 14%). MS (ES+) 287.97 [M+H]⁺. Step b) 6-fluoro-3-methyl-4-(pyrimidin-5-yl)isoquinoline (1-1 1 b)

Pyrimidin-5-ylboronic acid (237 mg, 1 .92 mmol) and sodium carbonate (554 mg, 5.22 mmol) were added under argon to a solution of compound 1-1 1 a (500 mg, 1 .74 mmol) in 1 ,2- dimethoxyethane (20 mL) and water(10 mL). The reaction mixture was degassed with argon for 15 minutes then 1 , 1 '-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) complex with DCM (127 mg, 0.174 mmol) was added under argon at rt. The reaction mixture was stirred at 100 °C in a sealed vessel for 16 h, then cooled to rt. Water was added (30 mL) and the mixture was extracted with ethyl acetate (2 x 50 mL). The organic phase was dried over sodium

sulfate, filtered and concentrated. The obtained crude compound was purified by column chromatography on silica eluted with 30% EtOAc in p. ether which gave the title compound (300 mg). MS (ES+) 240.23 [M+H]⁺.

Step c) 3-(bromomethyl)-6-fluoro-4-(pyrimidin-5-yl)isoquinoline (1-1 1 c)

N-bromosuccinimide (0.123 g) and azo-iso-butyronitrile (15 mg) were added under N₂ at rt to a stirred solution of compound 1-1 1 c (150 mg) in CCI₄ (30 mL). The reaction mixture was stirred at reflux for 3 h, then a saturated solution of sodium thiosulphate (10 mL) was added and the mixture was extracted with DCM (2 x 30 mL).The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under vacuo. The afforded crude was used in the following step without further purification.

Intermediate 12

Step a) 4-bromo-3-(bromomethyl)-7-(trifluoromethyl)isoquinoline (1-12a)

The title compound was prepared from (3-(trifluoromethyl)phenyl)methanamine (10 g, 57.1 mmol) according to the procedure described in Intermediate 9. Yield 3.8 %. MS (ES+) 369.85

[M+H]⁺.

Step b) Tert-butyl 1 '-((4-bromo-7-(trifluoromethyl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate(l-12b)

To a stirred solution of compound 1-1 Od (0.495 g, 1 .80 mmol) in acetonitrile (20 mL) was added cesium carbonate (2.35 g, 7.21 mmol) at rt under nitrogen. The resulting suspension was stirred for 15 min, then compound 1-12a (0.85 g, 1 .80 mmol) was added and suspension was stirred at rt for 4 h. The reaction mixture was diluted with 5% MeOH in DCM (40 mL) and washed with water (2 X 8 mL). The organic phase was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography using on silica gel eluted with 5% MeOH in DCM) which gave the title compound (0.720 g, 70%) as a solid. MS (ES+) 565.05 [M+H]⁺².

Step c) Tert-butyl 2'-oxo-1 '-((4-(pyrimidin-5-yl)-7-(trifluoromethyl)isoquinolin-3-yl)methyl)-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (1-12c)

Compound 1-12b (250 mg, 0.32 mmol), pyrimidin-5-ylboronic acid (44.00 mg, 0.36 mmol) and sodium carbonate (84.00 mg, 0.79 mmol) were taken in 1 ,2-dimethoxyethane (6 mL) and water (0.7 mL) in a microwave vial. The resulting suspension was purged with argon for 5 min, then, [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) chloride^«CH₂CI₂ (12 mg, 0.016 mmol) was added and the mixture was purged with argon for 5 min. The resulting mixture was heated by microwave irradiation at 120 °C for 90 min. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 20 mL). The aqueous layer was washed with EtOAc (2 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂S0₄, filtered and concentrated under reduced pressure. The obtained crude was combined with another batch of the same compound and purified by silica gel column chromatography eluted with 5%

MeOH in DCM, which gave the title compound as a solid. MS (ES+) 563.19 [M+H]+.

Step d) 1 '-((4-(Pyrimidin-5-yl)-7-(trifluoromethyl)isoguinolin-3-yl)methyl)spiro[azetidine-3,3'- pyrrolof2.3-clPyridinl-2'(1 'H)-one (1-12d)

TFA (1 .5 mL, 9.47 mmol) was added at 0 °C under nitrogen to a stirred solution of compound I- 12c (0.25 g, 0.438 mmol) in DCM (5 mL). The solution was stirred for at 0 °C 2 h, then allowed to attain rt. Water (30 mL) was added and the suspension was extracted with EtOAc (2x50 mL). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude was purified by column chromatography on silica gel eluted with 15% of MeOH in DCM, which gave the title compound (135 mg, 59%) as a solid. MS (ES+) 463.14 [M+H]⁺. Intermediate 13

Step a) 5-methyl-2-(3-((tetrahvdro-2H-pyran-2-yl)oxy)prop-1 -vn-1 -yl)benzaldehyde (1-13a) 2-(Prop-2-yn-1 -yloxy)tetrahydro-2H-pyran (1 .15 g) was added to a stirred solution of 2-iodo-5- methylbenzaldehyde (1 g) in triethylamine (50 mL) and DMF (10 mL). The solution was purged with argon for 10 min, then Pd(PPh₃)₂CI₂ (30 mg) and copper(l)iodide (15 mg) were added. The reaction mixture was degassed with argon for 15 min and then heated at 80 °C under argon atmosphere for 3 h. The reaction mixture was poured into ice cold water (120 mL) and extracted with EtOAc (2 x 120 mL). The combined organic layers were washed with water (300 mL) and brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The afforded crude compound was purified by column chromatography using silica gel eluted with 3% EtOAc in p. ether. Appropriate fractions were pooled and concentrated under reduced pressure to afford the title compound (850 mg, 79%) as a solid. MS (ES+) 259.1 [M+H].

Step b) (4-iodo-7-methylisoquinolin-3-yl)methanol N-oxide (1-13b)

To a solution of 1-13a (850 mg) in ethanol (20 mL) were added hydroxylamine hydrochloride (345 mg) and pyridine (0.5 mL) and the reaction mixture was stirred at rt for 30 min. Iodine (2.5 g) was added and the reaction mixture was stirred at rt for 2 h, then concentrated. The resulting residue was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with sodium thiosulfate (200 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure which gave the title compound (800 mg, 67%) as a solid. MS (ES+) 316.1 [M+H].

Step c) (7-methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methanol (1-13c)

A stirred solution of 1-13b (800 mg), pyrimidin-5-ylboronic acid (685 mg) and sodium carbonate (702 mg) in 1 ,2-dimethoxyethane (36 mL) and water (4 mL) was purged with argon for 10 min, then [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) chloride^«CH₂CI₂ (165 mg) was added and the solution was purged again with argon for 10 minutes. The reaction mixture was stirred at 120 °C in a sealed tube for 16h, then, filtered through Celite and the filtrate was concentrated under vacuum. The afforded crude was purified by column chromatography using silica gel eluted with 3% methanol in DCM, which gave the title compound (300 mg, 42%) as a solid. MS (ES+) 268.2 [M+H].

Step d) 3-(Chloromethvn-7-methyl-4-(pyrimidin-5-vnisoguinoline (1-13d)

PCI₃ (0.6 mL) was added at 0 °C to a stirred solution of compound 1-13c (300 mg) in DCM (10 ml_). The reaction mixture was stirred at 40 °C for 2 h, then concentrated under vacuum.

Sodium bicarbonate solution was added and the mixture was extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, which gave the crude title compound (190 mg, 66 %) as a solid. MS (ES+) 270.13 [M+H].

Step e) 1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[azetidine-3,3'-pyrrolo[2,3- clpyridinl-2'(1 'H)-one (l-13e)

Cesium carbonate (510 mg, 1 .56 mmol) was added at rt to a stirred solution of 1-1 Od (160 mg, 0.519 mmol) in MeCN (10 mL). The solution was stirred for 30 min, then 1-13d (200 mg, 0.519 mmol) was added and the mixture was stirred at rt for 16 h. Water (50 mL) was added and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The afforded compound was dissolved in DCM (5 mL), TFA (0.5 mL, 3.49 mmol) was added under nitrogen at 0 °C. The resulting solution was stirred at 0 °C for 2 h, then concentrate under reduced pressure, which gave the title compound (180 mg, 34%) as a solid. MS (ES+) 409.22 [M+H].

Intermediate 14

Step a) Tert-butyl 1 '-((4-bromoisoquinolin-3-yl)methyl)-2'-oxo-1 ',2'-dihvdrospiro[piperidine-4,3'- pyrrolo[2,3-clpyridine1-1 -carboxylate (1-14a)

Cesium carbonate (1 .62 g, 4.98 mmol) was heated under vacuum for 5 min, then allowed to cool to rt and the flask was flushed with nitrogen. MeCN (10 mL) and l-2g (504 mg, 1 .66 mmol) were added and the solution was stirred at rt for 30 minutes, then 4-bromo-3- (bromomethyl)isoquinoline (500 mg, 1 .66 mmol) was added dropwise. The reaction mixture was stirred for 18 h, then water (5 mL) was added and the MeCN was removed by evaporation and the resulting slurry was diluted with EtOAc. The phases were separated and the organic phase was washed with brine and (Na₂S0₄), filtered and concentrated. The afforded crude was purified by column chromatography on silica gel eluting with EtOAc, which gave the title compound (759 mg, 87%). MS (ES+) 523.10 & 525.09 [M+H]⁺.

Step b) tert-butyl 2'-oxo-1 '-((4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-1 '.2'- dihvdrospiro[piperidine-4.3'-pyrrolo[2.3-clpyridinel-1 -carboxylate (1-14b)

A stirred solution of compound 1-14a (560 mg, 1 .07 mmol), pyrimidin-5-ylboronic acid (199 mg, 1 .60 mmol) and sodium carbonate (283 mg) in 1 ,2-dimethoxyethane (10 mL) and water (5 mL) was purged with argon for 5 minutes. [1 ,1 '-Bis(diphenylphosphino)ferrocene]palladium(ll) chloride^«CH₂CI₂ (78.3 mg) was added and the reaction mixture was purged again with argon for 10 minutes. The reaction mixture was stirred and heated by microwave irradiation at 100 °C for 1 h, then filtered through Celite. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (2X20 mL), the combined organic layers were over sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude was purified by column

chromatography on silica and eluted with 4% MeOH in DCM. Fractions containing desired product were pooled and concentrated under reduced pressure which gave the title compound (450 mg, 72%) as a solid. MS (ES+) 523.5 [M+H]⁺.

Step b) 1 '-((4-(Pyrimidin-5-yl)isoauinolin-3-yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl- 2'(1 'H)-one (1-14c)

TFA (1 .97 mL) was added at 0 °C to a stirred solution of compound 1-14b (450 mg) in DCM (20 ml). The resulting mixture was stirred at rt for 5 h, then concentrated under reduced pressure, basified with saturated sodium bicarbonate solution and extracted with DCM (4 x 20 mL). The combined organic layers were dried over Na₂S0₄, filtered and concentrated to give the title compound (350 mg, 93%) as a solid. MS (ES+) 423.3 [M+H]⁺.

Intermediate 15

H

Step a) tert-butyl 1 '-((4-bromo-7-fluoroisoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (1-15a)

Compound l-9d (946 mg, 2.97 mmol) and l-2g (900 mg, 2.97 mmol) were reacted according to the method described in Example 2 step b, which gave the title compound (900 mg, 54%). MS (ES+) 541 .2 [M+H]⁺. Step b) tert-butyl 1 '-((7-fluoro-4-(pyrimidin-5-vnisoauinolin-3-vnmethvn-2'-oxo-1 ',2'- dihvdrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (1-15b)

To a stirred solution of compound 1-15a (800 mg) in 1 ,2-dimethoxyethane(20 mL) and water (10 mL) was added pyrimidin-5-ylboronic acid (274 mg) and sodium carbonate (626 mg) under argon. The reaction mixture was degassed with argon for 5 minutes then 1 , 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with DCM (241 mg) was added under argon at rt. The reaction mixture was stirred at 80 °C for 6 h in a sealed tube, then cooled to rt. Water (100 mL) was added and the mixture was extracted with ethyl acetate (2X250 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The obtained crude was purified along with a previously prepared badge of the same compound by column chromatography on silica gel eluted with 30-40% of ethyl acetate in p. ether. Pure fractions were combined and concentrated under reduced pressure which gave the title compound. MS (ES+) 541 .5 [M+H]⁺.

Step c) 1 '-((7-fluoro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3- clpyridinl-2'(1 'H)-one (l-15c)

TFA (2.5 mL) was added at 0 °C to a stirred solution of compound 1-15b (600 mg, 1 .1 1 mmol) in DCM (20 ml). The mixture was stirred at rt for 18h, then_water was added and the layers separated. The aqueous layer was washed with DCM (3 x 50 mL), then basified with saturated sodium bicarbonate solution and extracted with DCM (4 x100 mL). The combined organic layers were dried over Na₂S0₄, filtered and concentrated which gave the title compound (380 mg, 74%) as a solid. MS (ES+) 441 .3 [M+H]⁺.

Intermediate 16

Step a) tert-butyl 1 '-((4-bromoisoquinolin-3-yl)methyl)-2'-oxospiro[azetidine-3,3'-indolinel-1 - carboxylate (1-16a)

A solution of compound l-3f (449 mg, 1 .64 mmol) and cesium carbonate (1 .60 g, 4.91 mmol) in acetonitrile (10 mL) was stirred for 15 min at rt, then compound A-1 (493 mg, 1 .64 mmol) was added in addition in portions. The solution was stirred at rt for 16h, the concentrated in vacuo and the crude product was purified by column chromatography on silica eluted with a gradient of heptane: EtOAc, which gave the title compound (750 mg, 93%). MS (ES+) 496.1 [M+H]⁺. Step b) 1 '-((4-(pyrimidin-5-v0isoquinolin-3-v0m (1-16b)

Compound 1-16a (191 mg, 0.386 mmol), pyrimidin-5-ylboronic acid (71 .8 mg, 0.580 mmol), K₂C0₃ (214 mg, 1 .54 mmol) and PdCI₂(PPh₃)₂ (27.1 mg, 0.039 mmol) was dissolved in MeCN, the reaction vessel was sealed then heated by microwave irradiation to 130 °C for 1 h. The solid was filtered of and the solution concentrated. The crude was purified by silica chromatography using a gradient of MeOH in DCM. Appropriate fractions were pooled, concentrated and dissolved in DCM (3 mL). TFA (0.5 mL) was added and the solution was stirred for 1 h then concentrated in vacuo and co-evaporated twice from toluene which gave the title compound as the TFA salt (90 mg, 59%) as a solid. MS (ES+) 394.3.

Intermediate 17

Step a) tert-butyl 1 '-((4-bromoisoquinolin-3-yl)methyl)-2'-oxo-1 ',2'-dihvdrospiro[azetidine-3,3'- pyrrolo[2,3-clpyridinel-1 -carboxylate (1-17a)

Compound A1 (107 mg, 0.356 mmol) was reacted with 1-1 Od (140 mg, 0.356 mmol) as described in Intermediate 16 step a, which gave the title compound (170 mg, 96%). MS (ES+) 495.2.

Step b) 1 '-((4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)spiro[azetidine-3,3'-pyrrolo[2,3-clpyridinl- 2'(1 'H)-one (1-17b)

To a solution of 1-17a (84 mg, 0.170 mmol) in dioxane (2 mL), DMF (0.5 mL), water (0.3 mL) under argon was added pyrimidine-5-boronic acid (33.6 mg, 0.271 mmol), sodium hydrogen carbonate (42.7 mg, 0.509 mmol) and 1 , 1 '-bis(diphenylphosphino) ferrocene]- dichloropalladium(ll) (12.4 mg, 0.017 mmol. The mixture was flushed with argon and heated at 120° by microwave irradiation for 1 h. The reaction was added to saturated ammonium chloride solution and extracted four times with DCM. The organic phase was dried over sodium sulfate and concentrated under reduced pressure . The product was isolated by silica gel

chromatography eluted with DCM and 2 to 6% methanol. The residue was dissolved DCM (6 mL), TFA was added and the solution was stirred at rt for 1 h, then concentrated under reduced pressure. The product was purified by C18 HPLC, which gave the title compound (51 mg, 37%). MS (ES+) 453.4.

Intermediate 18

Step a) tert-butyl 1 -((6-fluoro-4-(pyrimidin-5-vnisoauinolin-3-vnmethvn-2-oxospiro[indoline-3,4'- piperidinel-1 '-carboxylate (1-18a)

Cesium carbonate (1 .29 mg ) was added under nitrogen at rt to a stirred solution of compound I- 2g (400 mg) in acetonitrile (20 mL). The reaction mixture was stirred at rt for 15 min, then compound 1-1 1 c (503 mg) was added and the stirring was continued for 3 h. The reaction mixture was concentrated, water was added and the mixture was extracted with ethyl acetate (2 x 20 mL), the organic layer was dried over Na₂S0₄ and concentrated under vacuum. The afforded residue was purified by column chromatography on silica gel eluted with 3% MeOH in DCM which gave the title compound (232 mg, 18%) as a solid. MS (ES+) 541 .3 [M+H]⁺.

Step b) 1 -((6-fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[indoline-3,4'-piperidinl-2-one (l-18b)

TFA (2.5 mL) was added at 0 °C to a stirred solution of compound 1-18a (600 mg, 1 .1 1 mmol) in DCM (20 ml). The mixture was stirred at rt for 1 h, then water (100 mL) was added and the layers separated. The aqueous layer was washed with DCM (3 x 50 mL), then basified with saturated sodium bicarbonate solution and extracted with DCM (4 x100 mL). The combined organic layers were dried over Na₂S0₄, filtered and concentrated which gave the title compound (400mg, 60%) as a solid. MS (ES+) 441 .3 [M+H]⁺.

Intermediate 19

Step a) Tert-butyl 1 '-((4-bromo-7-chloroisoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (1-19a)

Cesium carbonate (2.1 g, 6.45 mmol) was added to a solution of l-2g (633mg, 2.09 mmol) in DMF (20 ml). The slurry was stirred at rt for 1 h, then l-8b (700 mg, 2,09 mmol) was added and the slurry was stirred overnight. The reaction mixture was extracted between EtOAc and H₂0. The aq. phase further extracted with EtOAc (x 2). The pooled organic phases were dried over MgS0₄, concentrated and dried in vacuum. The crude material was purified by chromatography on silica gel eluting with 0-5 % MeOH in DCM, which gave the title compound (843 mg, 72 %). MS (ES+) 559.33 [M+H]⁺.

Step b) Tert-butyl 1 '-((7-chloro-4-(pyrimidin-5-vnisoquinolin-3-vnmethvn-2'-oxo-1 ',2'- dihvdrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (1-19b)

Compound 1-19a (1 .30 g, 2.33 mmol) was reacted with pyrimidin-5-ylboronic acid (866 mg, 0.233 mmol) and sodium carbonate (741 mg, 6.99 mmol) according to the method described in 1-12 step b, which gave the title compound (600 mg, 77%) as a solid.

Step c) 1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3- clpyridinl-2'(1 'H)-one (l-19c)

HCI (4 M in dioxane) (5 mL) was added to a solution of compound 1-19b (600 mg) in DCM (15 mL), the resulting mixture was stirred at rt for 2 h, then concentrated under reduced pressure. An aqueous sodium bicarbonate solution was added to the obtained material and the mixture was extracted with DCM (2 x 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, which gave the title compound (500 mg) as a solid. MS (ES+) 457.13 [M+H]⁺.

Intermediate 20

1 -(Methylsulfonvnspirofpiperidine-4,3'-pyrrolo[2,3-clPyridinl-2'( 1 'H)-one (I-20)

Triethylamine (2 mL, 13.6 mmol) was added at 0 °C to a suspension of compound l-2f (400 mg, 1 .95 mmol) in DCM (20 mL) followed by addition of a solution of methanesulfonyl chloride (0.15 mL, 2.14 mmol, in DCM (1 mL). The resulting reaction mixture was stirred at rt for 1 h, then concentrated under reduced pressure. The obtained crude was diluted with water (30 mL),and the formed solid was filtered off and dried under vacuum, which gave the title compound as a solid. MS (ES+) 282.07 [M+H]⁺.

Intermediate 21

Step a) Tert-butyl 1 '-((4-bromo-7-fluoroisoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (1-21 a)

Cesium carbonate (1 .63 g, 5.01 mmol) was added to a solution of 1-1 Od (460 mg, 1 .67 mmol) in dry DMF (15 mL). The suspension was stirred for 30 min at rt, then a solution of l-9b in dry DMF (5 mL) was added and the mixture was stirred at rt overnight . The reaction mixture was added to saturated solution of ammonium chloride and extracted three times with EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with DCM and 0 to 8% MeOH, which gave the title compound (650 mg, 76%). MS (ES+) 515.29 [M+H]⁺.

Step b) Tert-butyl 1 '-((7-fluoro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (1-21 b)

Pyrimidine-5-boronic acid, sodium hydrogen carbonate water and the tetrakis- (triphenylphosphine)-Pd(O) (144 mg, 0.125 mmol) were added under argon to a solution of I- 21 a (640 mg, 1 .25 mmol) in dioxane (12 mL). The mixture was flushed with argon and heated in a microwave reactor for 2h at 125°. The reaction mixture was added to a saturated ammonium chloride solution and extracted four times with DCM. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was isolated by silica gel chromatography eluted with DCM and 20 to 50% acetone followed by 4% MeOH in DCM, which gave the title compound (540 mg, 85%). MS (ES+) 513.46 [M+H]⁺.

Step c) 1 '-((7-Fluoro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)spiro[azetidine-3,3'-pyrrolo[2,3- clpyridinl-2'(1 'H)-one (1-21 c)

TFA (1 mL, 13.1 mmol) was added at 0 °C to a solution of 1-21 b (600 mg, 0.85 mmol) in DCM (10 mL) the mixture was stirred at rt for 2h, then basified with sodium bicarbonate solution to pH 8 and extracted with DCM (3 X 70 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated which gave the title compound (260 mg, 41 %) as a solid. MS (ES+) 395.38 [M+H]⁺.

Intermediate 22

Step a) tert-butyl 1 '-((4-bromo-7-chloroisoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (l-22a)

Cesium carbonate (7.2 g, 22.1 mmol ) was added under nitrogen at rt to a stirred solution of I- 10d (2.0 g, 7.26 mmol) in acetonitrile (30 mL). The reaction mixture was stirred for 15 min, then l-8b (2.5 g, 7.45 mmol) was added. The resulting reaction mixture was stirred for 3 h, then concentrated under reduced pressure. The residue was diluted with water (80 mL), extracted with 5% MeOH in DCM (3 x 100 mL). Combined organic layers were washed with water (80 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained solid was triturated with diethyl ether (30 mL), stirred for 15 min and filtered which gave the title compound (2.9 g, 68%) as a solid. The compound was used in next step without further purification. MS (ES+) 531 .07 [M+H]⁺.

Step b) tert-butyl 1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (l-22b)

Sodium carbonate (150 mg, 1 .42 mmol) was added to a mixture of l-22a (300 mg, 0.566 mmol) and pyrimidin-5-ylboronic acid (91 mg, 0.736 mmol) in 1 ,2-dimethoxyethane (10 mL) and water (1 .5 mL). The mixture was degassed with argon for 10 min, then [1 ,1 '- bis(diphenylphosphino)ferrocene]palladium(ll) chloride (62 mg, 0.085 mmol) was added and the mixture was again degassed for 5 min. The resulting mixture was stirred in a microwave reactor at 100 °C for 2 h, then filtered through Celite, concentrated and dried. Obtained crude compound was purified by column chromatography on silica using 0 - 4% MeOH in DCM as a eluent which gave the title compound (500 mg, 34%) as a solid with MS (ES+) 529.2 [M+H]⁺.

Step c) 1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[azetidine-3,3'-pyrrolo[2,3- clpyridinl-2'(1 'H)-one (l-22c)

TFA (2 mL) was added at 0 °C to a solution of l-22b (500 mg, 0.945 mmol ) in DCM (5 mL), the resulting mixture was stirred at rt for 2 h, then basified with sodium bicarbonate solution to pH 8 and extracted with DCM (2 X 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The obtained solid was triturated with diethyl ether (2 x 5 and dried which gave the title compound as a solid (300 mg, 66%) MS (ES+) 429.2 [M+H]⁺.

Intermediate 23

l-23a l-23b

Step a) 3-(Hvdroxyimino)spiro[cvclobutane-1 ,3'-indolinl-2'-one (l-23a)

Hydroxylamine hydrochloride (3.0 g, 43.2 mmol) and sodium carbonate (7.0 g, 66.0 mmol) were added at rt to a stirred solution of spiro[cyclobutane-1 ,3'-indoline]-2',3-dione (4.0 g, 21 .4 mmol) in EtOH (100 mL) and water (100 mL). The resulting mixture was stirred at 100 °C for 2 h, then concentrated under reduced pressure. The formed precipitate was filtered off and washed with water (50 mL) and dried which gave the title compound (3.4 g, 78%) as a solid. MS (ES+) 203.26 [M+H]⁺.

Step b) 3-Aminospiro[cvclobutane-1 ,3'-indolinl-2'-one (l-23b)

A solution of ammonia in MeOH (30 mL) and Raney nickel (4 g) was added at rt to a solution of l-23a (3.5 g) in MeOH (100 mL). The resulting mixture was hydrogenated under hydrogen gas pressure(70 PSI) for 16 h, then filtered through Celite and concentrated under reduced pressure, which gave the title compound as a mixture of diastereomers (3.0g, 89%) as a solid. MS (ES+) 189.15 [M+H]⁺.

Intermediate 24

Step a) tert-butyl 1 '-((7-methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (l-24a)

The title compound was prepared by reaction of 1-13d (622 mg, 2.31 mmol) and l-2g (700 mg, 2.31 mmol) as described in I-22 step a. Yield 400g, 16%. MS (ES+) 537.28 [M+H]⁺. Step b) 1 '-((7-methyl-4-(pyrimidin-5-v0isoqum^

clpyridinl-2'(1 'H)-one (l-24b)

4.0 M HCI in dioxane (4 mL, 16.00 mmol) was added to a solution of l-24a (400 mg, 0.522 mmol) in DCM (15 mL). The solution was stirred at rt for 90 min, then concentrated under reduced pressure. The obtained residue was diluted with water (50 mL) and washed with DCM (2 x 30 mL). The aqueous layer was basified with aqueous sodium bicarbonate and extracted with DCM (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, which gave the title compound (330 mg, 96.%) as a solid. MS (ES+) 437.23 [M+H]⁺.

Intermediate 25

Step a) 1 -(methylsulfonyl)spiro[azetidine-3,3'-pyrrolo[2,3-clpyridin1-2'(1 'H)-one (I-25)

1 )TFA (0.6 mL, 7.78 mmol) was added at rt to a stirred solution of 1-1 Od (400 mg, 1 .26 mmol) in

DCM (4 mL). The solution was stirred at rt for 2 h, then concentrated under reduced pressure.

97.61 %.

2): The residue was dissolved in DCM (5 mL), triethylamine (0.8 mL, 5.724 mmol) and methanesulfonyl chloride (0.15 mL, 1 .938 mmol) were added at 0 °C and the mixture was stirred for 1 h at 0 °C, then diluted with water (10 mL) and extracted with DCM (2 x 15 mL). The combined organic phases were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude compound was combined with a previously prepared batch and purified by flash chromatography on silica gel eluted with 4% MeOH in DCM). Fractions containing the title compound were combined and concentrated and used in following steps without further purification.

MS (ES+) 254.03 [M+H]⁺.

Intermediate 26

Step a) 5-Chloro-2-(3-((tetrahvdro-2H-pyran-2-vnoxy)prop-1 -vn-1 -yl)benzaldehvde (l-26a)

2-bromo-5-chloiObenzaldehyde (3.09 g, 0.01 mol) was dissolved in Et₃N (15 ml_). The mixture was degassed for 5 min by argon bubbling. Then, copper(l) iodide (53.6 mg, 0.28 mmol) and Pd(pph₃)₂CI₂ (98.8 mg, 0.14 mmol) were introduced and the mixture was further degassed for 3- 5 min by argon bubbling. 2-(Prop-2-yn-1 -yloxy)tetrahydro-2H-pyran (2.18 ml_, 0.02 mol) was added. The mixture was stirred at 50 °C for 20 h, then DCM (50 mL) and H₂0 (20 mL) were added and the mixture was filtered through a thin pad of Celite. The organic layer was washed with brine, dried (Na₂S0₄), filtered and concentrated. The product was purified by column chromatography on silica gel, gradient elution with EtOAc in n-which gave the title compound (2.18 g, 56%). MS (ES+) 279.27 [M+H]⁺.

Step b) (7-Chloro-4-iodoisoquinolin-3-yl)methanol N-oxide (l-26b)

Hydroxylamine hydrochloride (0.21 g, 2.96 mmol) was added to a solution of l-26a (550 mg,

1 .97 mmol) and pyridine (0.32 ml, 3.95 mmol) in EtOH (10 mL). The mixture was stirred for 60 min, then iodine (1 .5 g, 5.9 mmol) was added and stirred the mixture was stirred at rt for 1 h.

LCMS showed full conversion to the desired product (a black precipitate formed).

The reaction mixture was concentrated under vacuum and the resulting residue was partitioned between 10% aq. Na₂S₂0₃ (20 mL) and EtOAc (40 mL). The organic layer was

washed with 10% aq. Na₂S₂0₃ (20 mL), dried (Na₂S0₄), filtered and concentrated under reduced pressure which gave the crude title compound (375 mg, 57 %) as a solid. MS (ES+)

336.14 [M+H]⁺.

Step c) (7-Chloro-4-(pyrimidin-5-yl)isoguinolin-3-yl)methanol N-oxide (l-26c)

A mixture of l-26b (0.37 g, 1 .1 1 mmol), pyrimidine-5-boronic acid (0.17 g, 1 .33 mmol),

Pd(dppf)CI₂ (0.04 g, 0.06 mmol) and 2M solution of potassium carbonate aq. (1 .28 mL) in 1 ,4- dioxane (9 mL) was degassed by passing N₂ gas through for 3-5 min. The mixture was heated at 100 °C, after 1 h the temperature was raised to 1 19 -120 °C and the mixture was stirred for 1 h. The mixture was filtered through a pad of Celite, concentrated and the residue dissolved in 5% MeOH in DCM. The mixture was passed through a pad of silica gel, then purified by column chromatography on silica gel, which gave the title compound (200 mg, 63%). LC-MS (ES+) 288.30 [M+H]⁺.

Step d) 7-Chloro-3-(chloromethvn-4-(pyrimidin-5-vnisoguinoline (l-26d)

PCI₃ (0.51 ml, 5.86 mmol) was added at 0°C to a stirred solution of l-26c (0.22 g, 0.75 mmol) in DCM (8 mL). The mixture was stirred at rt for 2 h, then concentrated under vacuum,

neutralized with aq. sat. NaHC0₃ and extracted with DCM (2 x 20 mL). The combined organic layers were dried (Na₂S0₄), filtered and concentrated under reduced pressure which gave the title compound as a solid (128 mg, 59%). LC-MS (ES+) 290.28 [M+H]⁺.

Intermediate 27

Step a) Tert-butyl (3-((4-bromopyridin-3-yl)carbamoyl)cvclobutyl)carbamate (l-27a)

A solution of the 3-amino-4-bromopyridine (1 .73 g, 10.0 mmol) and 3-((tert- butoxycarbonyl)amino)cyclobutanecarboxylic acid (2.13 g, 10.0 mmol) in dry DMF (50 mL) was concentrated in vacuo and dissolved in dry DMF (40 mL). DMAP (1 .59 g, 13.0 mmol) and EDC'HCI (2.49 g, 13.0 mmol) were added and the mixture was stirred for five days at rt, then (1 .59 g, 13.0 mmol) and EDC^«HCI (2.49 g, 13.0 mmol) were added and the mixture was stirred at rt for two days. The mixture was poured into water (300 mL) and extracted with EtOAc (3x100 mL). The organic phase was washed with brine, dried (Na₂S0₄), filtered and

concentrated under reduced pressure. The product was isolated by column chromatography on silica gel eluted with DCM and 0 to 3% MeOH. The residue was purified by column

chromatography on silica gel eluted with acetone, which gave the title compound (1 .75 g, 47%).

Step b) Tert-butyl (3-((4-bromopyridin-3-yl)(4-methoxybenzyl)carbamoyl)cvclobutyl)carbamate (l-27b)

Cesium carbonate (3.07 g, 9.43 mmol) was added to a solution of l-27a (1 .74 g, 4.71 mmol) in dry DMF (30 mL). The solution was stirred at rt for 1 h, then 4-methoxybenzyl chloride (922 mg, 5.89 mmol) was added and the suspension was stirred at rt for 4 h, then poured into 10% ammonium chloride solution and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried (Na₂S0₄), filtered and concentrated under reduced pressure. The product was purified by column chromatography on silica gel eluted with DCM and 20 to 50% EtOAc, which gave the title compound (1 .93 g, 83%) . LC-MS (ES+) 492.40 [M+H]⁺.

Step c) Tert-butyl (1 '-(4-methoxybenzyl)-2'-oxo-1 ',2'-dihydrospiro[cvclobutane-1 ,3'-pyrrolo[2,3- clpyridinl-3-yl)carbamate (l-27c)

Sodium-tert-butoxide (941 g, 9.79 mmol), palladium acetate (1 10 mg, 0.489 mmol) and tricyclohexylphosphine (137 mg, 0.489 mmol) were added under argon to a solution of l-27b (1 .92 g, 3.92 mmol) in dry dioxane (40 mL). The mixture was stirred in a sealed tube at 95 °C for 4 h, then cooled to rt and poured into a saturated solution of ammonium chloride. The mixture was extracted with DCM (x4). The combined organic layers were dried (Na₂S0₄), filtered and concentrated under reduced pressure. The product was isolated by column chromatography on silica gel eluted with DCM and 20 to 30% acetone, which gave the title compound (890 mg, 56%). The residue was combined with a second batch (100 mg) and purified again by column chromatography on silica gel eluted with a gradient of 0 to 30% acetone in toluene, which gave the title compound contaminated by a by-product (990 mg).

Step d) Tert-butyl (2'-oxo-1 ',2'-dihvdrospiro[cvclobutane-1 ,3'-pyrrolo[2,3-clpyridinl-3- vDcarbamate (l-27d)

A solution of cerium ammonium nitrate (2.5 g, 4.6 mmol) in water (5 mL) was added to an ice cooled solution of l-27c (750 mg, 1 .83 mmol) in acetonitrile. The mixture was then stirred at rt ro 18 h. A potassium carbonate solution (20%, 50 mL) was added and the mixture was extracted with DCM (x4). The combined organic layers were dried (Na₂S0₄), filtered and concentrated under reduced pressure. The product was purified by column chromatography on silica gel eluted with a gradient of 0 - 65% MeOH in DCM, which gave the title compound (290 mg, 55%). LC-MS (ES+) 290.39 [M+H]⁺.

Example 1

Step a) Methyl 1 '-((4-bromoisoquinolin-3-yl)methyl)-2'-oxospiro[azetidine-3,3'-indolinel-1 - carboxylate (1 a) TFA (2 ml) was added to a solution of compound 1-16a (324 mg, 0,66 mmol) in DCM (8 ml). The solution was stirred at rt for 2.5h, then concentrated and co-evaporated with toluene (x 3) and dried in vacuum. The residue was dissolved in DCM (8 ml_), triethylamine (0.46 ml, 3.28 mmol) was added followed by addition of methyl chloroformate (65 μΙ, 0.84 mmol) at CC. The reaction was kept at 0°C for 30 min, then and at rt for 1 h. The reaction mixture was diluted with EtOAc, washed with aq.NaHC0₃, aq. citric acid and brine. The organic phase was dried over MgS0₄ and concentrated. The crude product was purified by chromatography on silica eluting with 1 -4% MeOH in DCM, which gave the title compound (238 mg, 80 %) MS (ES+) 452.2 & 454.2 [M+H]⁺.

Step b) Methyl 2'-oxo-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[azetidine-3,3'-indolinel- 1 -carboxylate (1 b)

A solution of compound 1 a (1 15 mg, 0.254 mmol), pyrimidin-5-ylboronic acid (47.3 mg, 0.381 mmol), K₂C0₃ (141 mg, 1 .02 mmol) and PdCI₂(PPh₃)₂ (17.8 mg, 0.025 mmol) in MeCN 2 mL) was sealed heated at 80 °C for 18h, filtered and the filtrate concentrated. The afforded crude was purified by silica chromatography elutes with a gradient of MeOH/DCM. Fractions containing product were pooled, concentrated and purified by

by Prep C18 LCMS at pH7. Pure fractions were pooled and freeze-dried which gave the title compound (51 .8 mg, 45%) as a solid. MS (ES+) 452.2 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.41 (d, J = 0.8 Hz, 1 H), 9.34 (s, 1 H), 8.85 (s, 2H), 8.26 - 8.18 (m, 1 H), 7.80 - 7.70 (m, 2H), 7.63 (dd, J = 7.4, 1 .2 Hz, 1 H), 7.34 - 7.27 (m, 1 H), 7.20 (td, J = 7.8, 1 .3 Hz, 1 H), 7.06 (td, J = 7.6, 1 .0 Hz, 1 H), 6.87 (d, J = 7.8 Hz, 1 H), 4.99 (s, 2H), 4.04 (s, 3H), 3.64 (s, 3H), 3.35 (s, 1 H), 2.55 (s, 1 H), 2.08 (s, OH).

Example 2

Step a) 5-(3-(Bromomethvnisoauinolin-4-vnpyrimidine-2-carbonitrile (2a)

A stirred solution of 4-iodo-3-methylisoquinoline (1 .5 g), 5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyrimidine-2-carbonitrile (1 .67 g) and sodium carbonate (1 .47 g) in 1 ,2- dimethoxyethane (20 mL) and water (5 mL) was purged with argon for 5 minutes. [1 ,1 '- Bis(diphenylphosphino)ferrocene]palladium(ll) chloride^«CH₂CI₂ (0.40 g) was added and the reaction mixture was purged again with argon for 10 minutes. The reaction mixture was stirred in sealed tube at 90 °C for 16 h, then filtered through Celite. The filtrate was diluted with water (25 mL) and extracted with ethyl acetate (2x40 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced. The afforded crude was purified by column chromatography using 100-200 silica mesh and eluted with 25-28% EtOAc : p. ether. Fractions containing desired product were concentrated under reduced pressure which gave the title compound (700 mg, 45%) as a solid. MS (ES+) 247.1 [M+H]⁺.

Step b) Tert-butyl (1 -(1 '-((4-(2-cvanopyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxospiro[azetidine- 3,3'-indolinl-1 -vIcarbonyQcyclopropyQcarbamate (2b)

Cesium carbonate (91 1 mg) was added at rt to a stirred solution of compound I-6 (400 mg, 1 .12 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at rt for 10 minutes, then compound 2a (598 mg, 1 .68 mmol) was added. The temperature was raised to 70 °C and the mixture was stirred for 16 h, then concentrated under reduced pressure. The obtained residue was diluted with water (20 mL) and extracted with ethyl acetate (2x20 mL). The combined organic layers were dried over Na₂S0₄, filtered and concentrated under reduced pressure. The obtained crude was purified by column chromatography using 100-200 silica mesh, eluted with 3.1 % methanol in DCM. Fractions containing the desired product were pooled and concentrated under reduced pressure which gave the title compound (260 mg, 36%). MS (ES+) 602.36

[M+H]⁺.

Step c) 5-(3-((1 -(1 -Aminocvclopropanecarbonyl)-2'-oxospiro[azetidine-3,3'-indolinl-1 '- yl)methyl)isoquinolin-4-yl)pyrimidine-2-carboxamide (2c)

To a stirred solution of compound 2b (220 mg, 0.334 mmol) in DMSO (8 mL) was added potassium carbonate (175 mg, 1 .27 mmol) and 30% hydrogen peroxide (0.8 mL) at 0 °C. The resulting mixture was stirred at rt for 1 h, then diluted with water (15 mL) and extracted with EtOAc (3X15 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated under reduced pressure. The afforded residue was suspended in DCM (10 mL), TFA was added (0.37 mL) and the mixture was stirred at rt for 8 h. The mixture was concentrated under reduced pressure and the residue was co-evaporated twice with toluene, then dissolved in dry DCM (5 mL) and triethylamine (0.3 mL), concentrated and then triturated with water (10 mL) for 3 h, filtered and dried. The afforded crude was grind with mortar and pestle for 30 minutes, which gave the title compound (35 mg, 27%) as a solid. MS (ES+) 520.2 [M+H]⁺.

1 H NMR (500 MHz, DMSO-cfe) δ 9.42 (s, 1 H), 9.04 (s, 1 H), 8.94 (s, 1 H), 8.35 - 8.31 (m, 1 H), 8.27 - 8.20 (m, 1 H), 7.95 - 7.91 (m, 1 H), 7.76 (qd, J= 6.9, 3.5 Hz, 2H), 7.62 - 7.56 (m, 1 H), 7.39 - 7.32 (m, 1 H), 7.19 (td, J = 7.8, 1 .3 Hz, 1 H), 7.08 (t, J = 7.4 Hz, 1 H), 6.83 (d, J= 7.8 Hz, 1 H), 5.07 (s, 1 H), 4.98 (s, 1 H), 4.69 (s, 2H), 4.00 (s, 1 H), 3.95 (s, OH), 3.39 - 3.34 (m, 2H), 2.30 (s, 2H), 1 .12 (s, 1 H), 1 .08 (s, 1 H), 0.72 (s, 2H).

Example 3

Step c) 1 -(MethylsulfonvD-1 '-((4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)spiro[piperidine-4,3'- pyrrolo[2,3-clPyridinl-2'(1 'H)-one (3)

Triethylamine (0.19 mL) and methanesulfonyl chloride(0.03 mL) were added at 0 °C to a stirred solution of compound 3c (150 mg) in DCM (10 mL). The resulting mixture was stirred at rt for 1 h, then diluted with cold water (20 ml) and extracted with DCM (2 x 20 ml). The combined organic layers were washed with brine (20 ml) and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep C18 HPLC. Fractions containing the desired product were pooled and concentrated under reduced pressure to obtained the title compound (73 mg, 41 %) as a solid. MS (ES+) 501 .3 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.39 (d, J = 1 .6 Hz, 2H), 9.00 (s, 2H), 8.29 (d, J= 4.6 Hz, 2H), 8.22 (dd, J = 7.8, 1 .7 Hz, 1 H), 7.77 (dddd, J= 17.1 , 8.1 , 6.9, 1 .3 Hz, 2H), 7.59 (d, J = 4.8 Hz, 1 H), 7.40 - 7.34 (m, 1 H), 5.01 (s, 2H), 3.50 - 3.36 (m, 3H), 2.97 (s, 3H), 2.59 (s, 1 H), 1 .99 (s, OH), 1.91 (ddd, J= 13.3, 8.8, 4.4 Hz, 2H), 1 .79 (dt, J = 13.7, 4.5 Hz, 2H).

Example 4

Step a) Tert-butyl (1 -(1 '-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-1 -ylcarbonvncvclopropyncarbamate (4a)

To a stirred solution of 1 -((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (137 mg, 0.679 mmol) in DMF (10 mL) was added EDAC- hydrochloride (120 mg, 0.627 mmol), HOBt (96.0 mg, 0.627 mmol), triethyl amine (0.292 mL, 2.09 mmol) and compound 1-15c (230 mg, 0.522 mmol) at rt. The resulting reaction mixture was stirred at rt for 4 h, then diluted with ice water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with water (3 x 30 mL), dried over Na₂S0₄, filtered and concentrated which gave the title compound (350 mg, 69%) as a liquid. MS (ES+) 624.5 [M+H]⁺.

Step b) 1 -(1 -Aminocvclopropanecarbonyl)-1 '-((7-fluoro-4-(pyrimidin-5-yl)isoguinolin-3- yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (4b)

TFA (1 .10 mL) was added at 0 °C.to a stirred solution of compound 4a (300 mg, 0.481 mmol) in DCM (20 mL). The resulting reaction mixture was stirred at rt for 1 h, then water was added and the layers separated. The aqueous layer was washed with DCM (3 x 50 mL), then basified with saturated sodium bicarbonate solution and extracted with DCM (4 x 100 mL). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The afforded crude was purified by prep. C18 HPLC, which gave the title compound (95 mg, 37%). MS (ES+) 524.4 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.38 (d, J = 3.4 Hz, 2H), 9.00 (s, 2H), 8.27 (d, J= 5.4 Hz, 2H), 8.04 (dd, J= 9.0, 2.7 Hz, 1 H), 7.70 (td, J = 8.9, 2.7 Hz, 1 H), 7.57 (d, J= 4.8 Hz, 1 H), 7.47 (dd, J = 9.3, 5.1 Hz, 1 H), 5.02 (s, 2H), 3.92 (s, 2H), 3.80 (s, 2H), 3.39 - 3.34 (m, 2H), 2.54 (s, 1 H), 2.30 (s, 2H), 1 .76 (s, 1 H), 1 .68 (d, J = 13.9 Hz, 2H), 0.89 (q, J = 4.4 Hz, 2H), 0.67 (t, J = 3.3 Hz, 2H).

Example 5

1 '-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperidine-4,3'- pyrrolo[2,3-clpyridinl-2'(1 'H)-one (5)

Triethylamine (0.106 mL) and methanesulfonyl chloride(0.018 mL) were added at 0 °C to a stirred solution of compound 1-15c (180 mg) in DCM (3 mL). The reaction mixture was stirred at rt for 2 h, then diluted with cold water (20 mL) and extracted with DCM(2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The afford the crude was purified by prep C18 HPLC. Pure fractions were combined and concentrated under reduced pressure which gave the title

compound (120 mg, 62%) as a solid. (ES+) 519.37 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.38 (d, J = 13.6 Hz, 2H), 9.00 (s, 2H), 8.32 - 8.25 (m, 2H), 8.04 (dd, J= 9.0, 2.7 Hz, 1 H), 7.70 (td, J = 9.0, 2.7 Hz, 1 H), 7.64 - 7.57 (m, 1 H), 7.47 (dd, J = 9.3, 5.1 Hz, 1 H), 5.00 (s, 2H), 3.45 (ddd, J= 12.4, 8.8, 3.7 Hz, 2H), 3.43 - 3.30 (m, 2H), 2.97 (s, 3H), 2.56 - 2.51 (m, 1 H), 1 .91 (ddd, J = 13.3, 8.7, 4.4 Hz, 2H), 1 .79 (dt, J = 9.8, 3.4 Hz, 2H).

Example 6

1 -(1 -Aminocvclopropanecarbonyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[piperidine- 4,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (6)

To a stirred solution of 1 -((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (1 1 1 mg) in DMF (12 mL) were added 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98.0 mg), hydroxybenzotnazole (78.3 mg), triethylamine (0.23 mL) and compound 1-14c (180 mg) at rt. The resulting reaction mixture was stirred at rt for 16 h, then diluted with ice water (20 mL) and extracted with EtOAc (2X20 mL). The organic layer was washed with water (2X30 mL), dried (Na₂S0₄), filtered and concentrated. The residue was dissolved in DCM (10 mL), TFA (0.75 mL) was added at 0 °C and the solution was stirred at rt for 4h, then concentrated. The residue was dissolved in DCM (10 mL) and triethylamine (1 mL) and concentrated. The residue was purified by prep C18 HPLC using 10 mM ammonium bicarbonate in H₂0:acetonitrile as eluent. Fractions containing desired product were pooled and concentrated then lyophilized which gave the title compound (95 mg, 40%) as a solid. MS (ES+) 606.4 [M+H]⁺.

1 H NMR (500 MHz, DMSO-cfe) δ 9.39 (d, J = 8.6 Hz, 2H), 9.00 (s, 2H), 8.31 - 8.23 (m, 2H), 8.25 - 8.19 (m, 1 H), 7.82 - 7.71 (m, 2H), 7.57 (d, J = 4.8 Hz, 1 H), 7.39 - 7.33 (m, 1 H), 5.02 (s, 2H), 3.92 (s, 2H), 3.37 (s, 1 H), 2.54 (s, 1 H), 2.30 (s, 2H), 1 .76 (s, 1 H), 1 .81 - 1 .72 (m, 1 H), 1 .70 (s, 2H), 0.89 (q, J= 4.3 Hz, 2H), 0.67 (t, J = 3.3 Hz, 2H).

Example 7

1 '-(1 -AminocvclopiOpanecarbonvD-1 -((6-fluoro-4-(pyrimidin-5-yl)isoquinolin-3- yl)methyl)spironndoline-3,4'-piperidinl-2-one (7)

Compound 1-18b (300 mg, 0.681 mmol) was reacted with 1 -((tert- butoxycarbonyl)amino)cyclopropanecarboxylic acid (274 mg, 1 .36 mmol) as described in Example 4 step a, followed by N-deprotection as described in Example 4 step b, which gave the title compound (38 mg, 6.6%). MS (ES+) 524.3 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.39 (d, J = 6.6 Hz, 2H), 8.99 (s, 2H), 8.35 (dd, J = 9.1 , 5.7 Hz, 1 H), 8.27 (d, J = 4.3 Hz, 2H), 7.67 (td, J = 8.8, 2.5 Hz, 1 H), 7.58 (d, J = 4.8 Hz, 1 H), 7.09 (dd, J = 10.5, 2.4 Hz, 1 H), 5.01 (s, 2H), 3.92 (s, 2H), 3.80 (s, 2H), 3.36 (s, 1 H), 2.53 (s, 1 H), 2.30 (s, 2H), 1.77 (s, 2H), 1 .69 (d, J = 13.7 Hz, 2H), 0.88 (t, J = 3.4 Hz, 2H), 0.67 (t, J = 3.3 Hz, 2H).

Example 8

1 '-((4-(Pyrimidin-5-yl)isoauinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cvclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (8) DIPEA (240 mg, 129 mmol) and HATU (93 mg, 380 mmol) were added at 0 °C to a solution of the HCI salt of compound 1-14c (37.5 mg, 0.243 mmol) and 1 -

(trifluoromethyl)cyclopropanecarboxylic acid (37.5 mg, 0.243 mmol) in DMF (1 .8 mL). The solution was stirred at rt for 2h, then diluted with DCM (35 mL). The organic phase was washed with saturated NaHC0₃ (20 mL). The aqueous phase was extracted with CH₂CI₂ (5 mL). The combined organic phases were washed with saturated NaCI (10 mL) and concentrated. The crude material was purified by prep C18 HPLC eluted with a gradient of 10 mM NH₄OAc in 95/5 H₂0 and MeCN, pH 7 and10 mM NH₄OAc in 90/10 MeCN - H₂0, pH 7. Fractions containing the product were pooled, concentrated and freeze-dried, which gave the title compound (51 .6 mg, 50%). MS (ES+) 559.3 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.42 - 9.35 (m, 2H), 9.00 (s, 2H), 8.33 - 8.26 (m, 2H), 8.25 - 8.19 (m, 1 H), 7.82 - 7.72 (m, 2H), 7.59 (d, J = 4.6 Hz, 1 H), 7.36 (dd, J = 8.3, 1 .4 Hz, 1 H), 5.02 (s, 2H), 3.93 (dt, J = 13.8, 5.3 Hz, 2H), 3.32 (s, 3H), 1 .79 (s, 2H), 1 .70 (d, J = 13.4 Hz, 2H), 1 .30 (d, J = 28.9 Hz, 4H).

Example 9

1 -(Piperidine-4-carbonyl)-1 W(4-(pyrimidin-5-yl)isoq

pyrrolo[2,3-clPyridinl-2'(1 'H)-one (9)

The HCI salt of compound 1-14c (1 10 mg, 0.222 mmol) was dissolved in DMF (2 mL), HATU and DIEA were added followed by addition of 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (50.9 mg, 0.222 mmol). The reaction was stirred at rt for 1 h, then concentrated in vacuo.

The residue was by chromatography on a silica column eluted with a gradient of DCM and MeOH. Fractions containing the desired product were pooled, concentrated and dissolved in DCM (1 .5 mL) and 4M HCI in dioxane (3 mL) was added. The solution was stirred at rt for 30 min, then concentrated in vacuo and co-evaporated twice from toluene. The afforded solids were dissolved in MeOH, and purified by Prep LCMS at pH 10. Pure fractions were pooled and freeze-dried, which gave the title compound (23.6 mg, 19%). MS (ES+) 534.3 [M+H]⁺.

1 H NMR (500 MHz, DMSO-cfe) δ 9.39 (d, J = 8.8 Hz, 2H), 8.99 (d, J = 2.2 Hz, 2H), 8.31 - 8.22 (m, 2H), 8.22 (dd, J = 7.7, 1 .8 Hz, 1 H), 7.82 - 7.71 (m, 3H), 7.59 (d, J = 4.8 Hz, 1 H), 7.36 (dd, J = 8.3, 1 .3 Hz, 1 H), 5.02 (d, J = 7.3 Hz, 2H), 3.83 (dt, J = 15.1 , 7.0 Hz, 1 H), 3.79 (s, 2H), 3.75 (s, 1 H), 3.76 - 3.62 (m, 1 H), 3.67 (s, 1 H), 2.93 (d, J = 1 1 .7 Hz, 2H), 2.72 (td, J = 1 1 .3, 9.4, 5.7 Hz, 1 H), 2.58 - 2.52 (m, 1 H), 1 .80 - 1 .58 (m, 3H), 1 .57 - 1 .49 (m, 2H), 1 .51 - 1 .42 (m, 1 H).

Example 10

1 '-((4-(Pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(3,3,3-trifluoropropanoyl)spiro[piperidine-4,3'- pyrrolo[2,3-clpyridinl-2'( 1 'H)-one ( 10) Triethylamine (0.3 mL) was slowly added to a solution of compound 1-14c (150 mg) in DCM (5.00 mL). The resulting solution was stirred under nitrogen for 5 minutes, then 3,3,3- trifluoropropionyl chloride (80.0 mg) was added and the solution was stirred at 0 °C under nitrogen for 3 h. The reaction mixture was concentrated under reduced pressure and the afforded residue was diluted with water (20 mL) and extracted with 5% MeOH in DCM (2 X30 mL). The combined both organic layers were washed with brine (15 mL), dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 5 % MeOH in DCM as eluent. Fractions containing the desired compound were combined and concentrated and further purified by C18 prep HPLC. which gave the title compound (25.0 mg, 19%) as a solid. MS (ES+) 533.4 [M+H]⁺.

1 H NMR (500 MHz, DMSO-cfe) δ 9.40 (d, J = 0.8 Hz, 1 H), 9.37 (s, 1 H), 9.00 (t, J = 2.3 Hz, 2H), 8.31 - 8.25 (m, 2H), 8.25 - 8.19 (m, 1 H), 7.82 - 7.72 (m, 2H), 7.57 (d, J = 4.7 Hz, 1 H), 7.36 (dd, J = 8.2, 1 .3 Hz, 1 H), 5.02 (d, J = 3.8 Hz, 2H), 3.90 (ddd, J = 13.4, 6.3, 4.3 Hz, 1 H), 3.84 - 3.61 (m, 5H), 1 .86 - 1 .61 (m, 4H).

Example 1 1

1 -(1 -Amino-3,3-difluorocvclobutanecarbonyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3- yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (1 1 )

DIEA (0,17 ml, 0.98 mmol) was added to a slurry of compound 1-14c (102 mg, 0.21 mmol), 1 - (Boc-amino)-3,3-difluorocyclobutane carboxylic acid (51 .7 mg, 0.21 mmol) and HATU (90 mg, 0.24 mmol) in THF (5 mL) and DCM (2 mL). The mixture was stirred for 2h, then diluted with EtOAc, washed with aq.NaHC0₃, aq. citric acid and brine. The organic phase was dried over MgS0₄ and concentrated. The product was purified by chromatography on silica eluting with 1 - 10 % MeOH in DCM. The residue was dissolved in in DCM (5 ml), TFA (0.5 ml, 6.5 mmol) was added and the solution was stirred at rt for 1 .5 h, then concentrated, co-evaporated with toluene and dried under vacuum. The crude compound was purified by LC-MS, which gave the title compound (41 mg, 37 %). MS (ES+) 556.3 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.39 (d, J = 7.7 Hz, 2H), 8.99 (d, J = 4.1 Hz, 2H), 8.32 - 8.24 (m, 2H), 8.26 - 8.18 (m, 1 H), 7.83 - 7.71 (m, 2H), 7.62 - 7.55 (m, 1 H), 7.36 (dd, J = 8.5, 1 .3 Hz, 1 H), 5.02 (q, J = 15.6 Hz, 2H), 3.94 - 3.85 (m, 1 H), 3.77 (s, 2H), 3.76 (dd, J = 17.7, 1 1 .4 Hz, 1 H), 3.64 (s, 1 H), 3.33 - 3.14 (m, 2H), 2.66 - 2.50 (m, 4H), 1 .89 - 1 .79 (m, 1 H), 1 .73 (dd, J = 16.8, 7.5 Hz, 1 H), 1 .67 (s, 1 H). Example 12

1 '-((4-(Pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -((2,2,2-trifluoroethyl)sulfonyl)spiro[pipe

4,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (12)

2,2,2-Trifluoroethanesulfonyl chloride (200 mg, 1 .10 mmol) was added at 0 °C to a solution of the TFA salt of compound 1-14c (130 mg, 0.238 mmol) and triethylamine (0.2 mL, 1 .44 mmol) in dry DCM (5 mL). After 10 min at 0°C, the reaction was allowed to attain rt and the stirring was continued for 1 h. The residue was diluted with DCM (50 mL) and washed with water (20 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated. The crude compound was purified by prep C18 HPLC. Fractions containing the desired compound were pooled, concentrated and further purified by prep C18 HPLC. Fractions containing the desired compound were pooled, concentrated and further purified by prep C18 HPLC. Pure fractions were collected and concentrated under reduced pressure, the residue was diluted with DCM (50 mL) and washed with water (2x20 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated to afford the title compound (20 mg, 14%) as a solid. MS (ES+) 569.2 [M+H]⁺. ¹ H NMR (500 MHz, DMSO-cfe) δ 9.39 (d, J = 2.4 Hz, 2H), 9.00 (s, 2H), 8.32 - 8.26 (m, 2H), 8.22 (dd, J = 7.7, 1 .7 Hz, 1 H), 7.82 - 7.71 (m, 2H), 7.61 - 7.56 (m, 1 H), 7.37 (dd, J = 8.4, 1 .4 Hz, 1 H), 5.01 (s, 2H), 4.62 (q, J = 10.1 Hz, 2H), 3.59 (ddd, J = 12.6, 8.9, 3.5 Hz, 2H), 3.52 (dt, J = 12.6, 4.9 Hz, 2H), 1 .90 (ddd, J = 13.3, 8.9, 4.2 Hz, 2H), 1 .83 - 1 .74 (m, 2H), 0.99 (s, 1 H).

Example 13

Step a) Methyl 1 '-((4-bromo-7-chloroisoquinolin-3-yl)methyl)-2'-oxospiro[azetidine-3,3'-indolinel- 1 -carboxylate (13a)

Cesium carbonate (4.9 g) was added under nitrogen at rt to a stirred solution of compound l-3e (1 .2 g) in acetonitrile (20 mL). The reaction mixture was stirred at rt for 15 min, then compound l-8b (2.1 g) was added. The reaction mixture was stirred at rt for 3 h, then concentrated. Water (20 mL) was added to the crude and the mixture was stirred for 15 min. Obtained solid was filtered and dried to obtain the title compound (1 .1 g, 43%) as a solid. MS (ES+) 488.21 [M+H]⁺

Step d) Methyl 1 '-((7-chloro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-2'-oxospiro[azetidine-3,3'- indolinel-1 -carboxylate (13b)

Compound 13a (1 g, 1 .95 mmol) was reacted with pyrimidin-5-ylboronic acid (484 mg, 3.91 mmol) and sodium carbonate (518 mg, 4.89 mmol) according to the method described in 1-14 step b. The crude product was purified by silica gel column chromatography followed by prep C18 HPLC, which gave the title compound (570 mg, 50%) as a solid. MS (ES+) 486.07 [M+H]⁺. ¹ H NMR (500 MHz, DMSO-cfe) δ 9.38 (s, 1 H), 9.35 (s, 1 H), 8.87 (s, 2H), 8.37 (d, J = 2.2 Hz, 1 H), 7.76 (dd, J = 9.1 , 2.2 Hz, 1 H), 7.66 - 7.61 (m, 1 H), 7.35 (d, J= 9.1 Hz, 1 H), 7.20 (td, J = 7.8, 1 .2 Hz, 1 H), 7.07 (t, J = 7.5 Hz, 1 H), 6.86 (d, J = 7.8 Hz, 1 H), 4.99 (s, 2H), 4.04 (s, 4H), 3.64 (s, 3H).

Example 14

Step a) Methyl 1 '-((4-bromo-7-fluoroisoquinolin-3-yl)methyl)-2'-oxospiro[azetidine-3,3'-indolinel- 1 -carboxylate (14a)

Compound l-9d (1 .50 g, 4.22 mmol) was reacted with l-3e (1 .00 g, 4.22 mmol) using the method described in Example 13 step a, which gave the title compound (1 .60 g, 76%). MS (ES+) 471 .9 [M+H]⁺.

Step b) Methyl 1 '-((7-fluoro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-2'-oxospiro[azetidine-3,3'- indolinel-1 -carboxylate (14b)

Compound 14a (1 .6 g, 3.4 mmol) was reacted with pyrimidin-5-ylboronic acid (843 mg, 6.80 mmol) using the method described in 1-14 step b. The crude product was purified by silica gel column chromatography followed by prep C18 HPLC, which gave the title compound (845 mg, 52%) as a solid. MS (ES+) 470.01 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.39 (s, 1 H), 9.35 (s, 1 H), 8.86 (s, 2H), 8.04 (dd, J= 9.0, 2.7 Hz, 1 H), 7.72 - 7.61 (m, 2H), 7.40 (dd, J = 9.3, 5.1 Hz, 1 H), 7.20 (td, J= 7.8, 1 .2 Hz, 1 H), 7.06 (t, J= 7.5 Hz, 1 H), 6.87 (d, J = 7.8 Hz, 1 H), 4.98 (s, 2H), 4.07 - 4.02 (m, 3H), 3.64 (s, 3H). Example 1

1 -(Piperidine-4-carbonyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[azeti

indolin1-2'-one (15)

HATU and DIEA were added to a solution of the TFA salt of compound 1-16b (1 10 mg, 0.280 mmol) in DMF (2 mL), followed by addition of the 1 -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (64.1 mg, 0.280 mmol). The reaction was stirred for 16 h at rt, then concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of MeOH/DCM. Fractions containing the product were pooled, and dissolved in DCM (2 mL). TFA (500 μΐ) was added the solution was stirred at rt for 1 h, then concentrated in vacuo and co- evaporated with toluene. The residue was dissolved in water/ acetonitrile and then freeze dried which gave the title compound as the TFA salt (72 mg,71 %).

¹ H NMR (500 MHz, DMSO-cfe) δ 9.41 (s, 1 H), 9.35 (s, 1 H), 8.87 (q, J = 2.9 Hz, 2H), 8.62 (d, J = 1 1 .2 Hz, 1 H), 8.34 (d, J= 10.8 Hz, 1 H), 8.27 - 8.19 (m, 1 H), 7.81 - 7.71 (m, 2H), 7.62 (dd, J = 7.5, 1 .2 Hz, 1 H), 7.35 - 7.28 (m, 1 H), 7.22 (td, J= 7.8, 1 .2 Hz, 1 H), 7.1 1 - 7.04 (m, 1 H), 6.89 (d, J = 7.9 Hz, 1 H), 5.06 - 4.94 (m, 2H), 4.40 - 4.30 (m, 2H), 4.00 (s, 2H), 3.36 - 3.28 (m, 2H), 2.94 (td, J = 13.1 , 1 1.5, 6.3 Hz, 2H), 2.68 - 2.58 (m, 1 H), 1 .94 - 1 .86 (m, 1 H), 1 .84 (dd, J= 14.3, 3.7 Hz, 1 H), 1 .81 - 1 .67 (m, 2H), 1 .30 - 1 .21 (m, 1 H).

Example 16

Step a) 3-((4-Bromoisoquinolin-3-yl)methyl)-1 -(2,2,2-trifluoroethyl)-1 H-imidazo[4,5-clpyridin- 2(3H)-one (16a)

4-Bromo-3-(bromomethyl)isoquinoline (300 mg, 0.997 mmol) and 1 -(2,2,2-trifluoroethyl)-1 H- imidazo[4,5-c]pyridin-2(3H)-one (217 mg, 0.997 mmol) were reacted according to the procedure of 1-16 step a, which gave the title compound (408.7 mg, 70%). MS (ES+) 436.94 & 438.92

[M+H]⁺. Step b) 3-f (4-f Pyrimidin-5-yl)isoauinolin-3-yl)methyl)-1 -(2,2,2-trifluoroethyl)-1 H-imidazof4,5- clPyridin-2(3H)-one (16b)

Compound 16a (150 mg, 0.343 mmol) was reacted with pyrimidin-5-ylboronic acid (43 mg, 0.343 mmol) using the method described in 1-14 step b, which gave the title compound (105 mg, 70%). MS (ES+) 437.15 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.36 (d, J = 2.1 Hz, 2H), 8.96 (s, 2H), 8.31 - 8.24 (m, 2H), 8.24 - 8.18 (m, 1 H), 7.77 (dddd, J = 18.1 , 8.0, 6.9, 1 .4 Hz, 2H), 7.39 - 7.34 (m, 2H), 5.20 (s, 2H), 4.81 (q, J = 9.2 Hz, 2H).

Example 17

Methyl 2'-oxo-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 ',2'-dihvdrospiro[azetidine-3,3'- pyrrolo[2,3-clpyridinel-1 -carboxylate (17)

DIEA (146 mg, 1 .13 mmol) was added to a solution of compound 1-17b (0.1 13 mmol) in dry DCM (6 ml_). The solution was cooled to 0 °C and 1 M methyl chloroformate in DCM (0.15 mL) was added slowly. The reaction was stirred for 30 minutes, then quenched with methanol and concentrated in vacuo . The product was purified by HPLC and freeze dried. Yield 28 mg, 55%. MS (ES+) 453.41 [M+H]⁺

¹ H NMR (500 MHz, DMSO-cfe) δ 9.43 (d, J = 0.9 Hz, 1 H), 9.35 (s, 1 H), 8.90 (s, 2H), 8.35 (d, J = 4.7 Hz, 1 H), 8.27 - 8.19 (m, 2H), 7.81 - 7.71 (m, 3H), 7.35 - 7.29 (m, 1 H), 5.02 (s, 2H), 4.1 1 (s, 2H), 4.03 (d, J= 8.1 Hz, 2H), 3.64 (s, 3H).

Example 18

Methyl 1 '-((7-cvano-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxospiro[azetidine-3,3'-indolinel- 1 -carboxylate (18)

To a solution of compound 13b (200 mg, 0.333 mmol) in N,N-dimethylacetamide (4 mL) was added zinc cyanide (196 mg, 1 .67 mmol), the mixture was degassed for 10 min, then tetrakis(triphenylphosphine)-palladium(0) (77 mg, 0.067 mmol) was added and the mixture was degassed for 10 min. The mixture was then stirred and heated at 130 °C for 1 h by microwave irradiation. Water (10 mL) was added and the crude compound was filtered off and dried under vacuum. The crude compound was combined with another batch and purified by column chromatography on silica gel eluted with 10% methanol in DCM. Pure fractions were pooled, concentrated under reduced pressure and the residue purified by prep C18 HPLC. Pure fractions were collected and concentrated and further purified by SFC, which gave the title compound. MS (ES+) 477.34 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.50 (d, J = 0.8 Hz, 1 H), 9.36 (s, 1 H), 8.89 (d, J = 5.8 Hz, 3H), 8.02 (dd, J = 8.8, 1 .7 Hz, 1 H), 7.64 (dd, J = 7.4, 1 .2 Hz, 1 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.20 (td, J = 7.8, 1 .3 Hz, 1 H), 7.07 (td, J = 7.6, 1 .0 Hz, 1 H), 6.85 (d, J = 7.8 Hz, 1 H), 5.02 (s, 2H), 3.63 (s, 3H), 3.33 (s, 6H).

Example 19

1 '-((7-Chloro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperidine-4,3'- pyrrolo[2,3-clPyridinl-2'( 1 'H)-one ( 19)

Triethylamine (0.16 mL) and methanesulfonyl chloride (0.1 mL) were added at 0 ° C to a stirred solution of 1-19 (180 mg) in DCM (10 mL). The mixture was stirred for 1 h at rt, then poured into ice cold water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The afforded crude compound was purified by prep C18 HPLC, which gave the title compound (53 mg) as a solid. MS (ES+) 535.14 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.40 (s, 1 H), 9.36 (s, 1 H), 9.01 (s, 2H), 8.36 (d, J = 2.2 Hz, 1 H), 8.32 - 8.24 (m, 2H), 7.78 (dd, J = 9.1 , 2.2 Hz, 1 H), 7.60 (d, J = 4.8 Hz, 1 H), 7.42 (d, J = 9.0 Hz, 1 H), 5.01 (s, 2H), 3.43 (dtd, J = 23.2, 12.1 , 4.2 Hz, 4H), 2.97 (s, 3H), 1 .92 (ddd, J = 13.3, 8.6, 4.3 Hz, 2H), 1 .79 (dt, J = 13.6, 4.7 Hz, 2H).

Example 20

1 -(1 -Aminocvclopropanecarbonyl)-1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3- yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (20)

1 ) Triethylamine (0.2 mL) and HATU (540 mg) were added to a stirred solution of 1 -((tert- butoxycarbonyl)amino)cyclopropanecarboxylic acid (215 mg) in DMF (8 ml). The solution was stirred at rt for 10 min, then compound 1-19 (320 mg) was added and the mixture was stirred at rt for 16 h. The reaction mixture was poured into ice cold water (30 mL), extracted with EtOAc (3 X 20 mL) and washed with brine (30 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The afforded crude compound was purified by column chromatography on silica gel eluting with 6% MeOH in DCM. Appropriate fractions were pooled and concentrated.

2) The residue was dissolved in DCM, 4.0 M HCI in dioxane (3 mL) was added and the resulting mixture was stirred at rt for 1 h, then concentrated under reduced pressure. The obtained material was basified with the aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM (2 x 30 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The crude compound was purified by prep C18HPLC which gave the title compound (180 mg). MS (ES+) 540.2 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.38 (d, J = 8.1 Hz, 2H), 9.01 (s, 2H), 8.39 - 8.34 (m, 1 H), 8.27 (d, J = 5.6 Hz, 2H), 7.81 - 7.75 (m, 1 H), 7.58 (d, J = 4.8 Hz, 1 H), 7.41 (d, J = 9.1 Hz, 1 H), 5.02 (s, 2H), 3.92 (s, 2H), 3.80 (s, 2H), 3.43 (s, OH), 3.38 (s, 1 H), 2.73 (s, 1 H), 2.61 (s, 1 H), 2.31 (s, 2H), 1.76 (s, 1 H), 1 .69 (d, J= 13.3 Hz, 2H), 0.88 (s, 2H), 0.69 - 0.64 (m, 2H).

Example

1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cvclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (21 ) The title compound was prepared by reaction of compound 1-19 with 1 - (trifluoromethyl)cyclopropanecarboxylic acid using the method described in Example 8. MS (ES+) 593.4 [M+H]⁺.

¹H NMR (500 MHz, DMSO) δ 1.30 (d, J = 28.7 Hz, 4H), 1.75 (d, J = 40.6 Hz, 4H), 3.78 (s, 2H), 3.93 (dt, J = 13.9, 4.7, 4.7 Hz, 2H), 5.02 (s, 2H), 7.41 (d, J = 9.1 Hz, 1H), 7.59 (d, J = 4.8 Hz, 1 H), 7.78 (dd, J = 9.1 , 2.2 Hz, 1 H), 8.28 (d, J = 4.0 Hz, 2H), 8.37 (d, J = 2.2 Hz, 1 H), 9.01 (s, 2H), 9.37 (s, 1H), 9.38 (s, 1H).

¹³C NMR (126 MHz, DMSO) δ 9.79, 26.65 (q, J= 33.3, 33.1 , 33.1 Hz), 31.06, 43.40, 44.40, 118.35, 124.63, 126.52, 127.72, 128.99, 130.54, 132.08, 132.12, 133.42, 139.18, 141.07, 143.95, 146.91, 152.01, 157.60, 158.22, 162.74, 177.22.

Example 22

1'-((4-(Pyrimidin-5-yl)isoauinolin-3-yl)methyl)-1-(3,3,3-trifluoropropanoyl)spiro[azetidine-3,3'- indolinl-2'-one (22)

Compound 1-16b (130 mg, 0.124 mmol) was acylated with 3,3,3-trifluoropropanoyl chloride (71 mg, 0.486 mmol) according to the method described in Example 12, which gave the title compound (62 mg, 92%). MS (ES+) 504.2 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) δ 9.41 (d, J=0.9 Hz, 1H),9.35 (s, 1 H), 8.90 - 8.84 (m, 2H), 8.26 -8.18 (m, 1H), 7.81 -7.71 (m, 2H), 7.60 (dd, J= 7.4, 1.2 Hz, 1H), 7.34-7.28 (m, 1H), 7.21 (td, J=7.8, 1.3 Hz, 1H), 7.08 (td, J= 7.5, 1.0 Hz, 1H), 6.86 (d, J= 7.8 Hz, 1H), 5.03 (d, J= 15.9 Hz, 1 H), 4.97 (d, J = 15.8 Hz, 1 H), 4.40 - 4.32 (m, 2H), 4.04 (d, J = 2.0 Hz, 2H), 3.60 - 3.48 (m, 1H), 3.50- 3.38 (m, 1H).

Example 23

1-(2-Amino-3,3,3-trifluoropropanoyl)-1'-((4-(pyrimidin-5-yl)isoquinolin-3- yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1'H)-one (23) The title compound was prepared from the HCI salt of Compound 1-14c (120 mg, 0.222 mmol) was acylated with (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (108 mg, 0.440 mmol) according to the method described in Example 4 step a. The boc group was then removed by treatment with 4M HCI/dioxane in DCM for 2h, which gave the title compound (19 mg, 15%). MS (ES+) 548.8 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) δ 9.39 (d, J= 13.1 Hz, 2H), 9.00 (q, J= 2.7 Hz, 2H), 8.32-8.24 (m, 2H), 8.22 (dd, J =7.7, 1.7 Hz, 1 H), 7.82 - 7.71 (m, 2H), 7.61 (d, J=4.8 Hz, OH), 7.53 (d, J = 4.8 Hz, 1 H), 7.36 (d, J= 8.2 Hz, 1 H), 5.09 - 5.00 (m, 2H), 4.73 - 4.62 (m, 1 H), 4.00 (dt, J = 13.4, 4.9 Hz, 1 H), 3.97 - 3.84 (m, 1 H), 3.87 - 3.75 (m, 2H), 3.64 (ddd, J = 13.3, 9.7, 3.6 Hz, OH), 3.37-3.32 (m, 1H),2.54 (s, 1H),2.35 (t, J =9.3 Hz, 2H), 1.79 (dddd, J= 17.9, 13.6, 8.1, 4.0 Hz, 1H), 1.73- 1.62 (m, 2H).

Example 24

1'-(2-Amino-3-hvdroxypropanoyl)-1-((4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)spiro[indoline-3,4'- piperidinl-2-one (24)

The title compound was prepared from the HCI salt of compound 1-14c (400 mg, 0.614 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (189 mg, 0.92 mmol) according to the method described in Example 20. Yield 75 mg, 23%. MS (ES+) 510.2 [M+H]⁺.

1H NMR (500 MHz, DMSO-cfe) δ 9.39 (d, J= 10.4 Hz, 2H), 8.99 (d, J= 2.4 Hz, 2H), 8.31 -8.24 (m, 2H), 8.22 (dd, J=7.6, 1.7 Hz, 1 H), 7.82 - 7.71 (m, 2H), 7.54 (dd, J= 11.0, 4.8 Hz, 1H), 7.39 - 7.33 (m, 1 H), 5.05 - 4.96 (m, 2H), 4.73 (s, 1 H), 3.93 - 3.63 (m, 6H), 3.50 - 3.42 (m, 1 H), 1.72 (dddd, J= 48.7, 23.7, 13.4, 5.9 Hz, 2H), 1.71 (s, 2H).

Example 2

1 '-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 - (trifluoromethvncvclopropanecarbonvnspiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2Y1 'H)-one (25) To a slurry of compound 1-15c (150 mg, 0.27 mmol), 1 -(trifluoromethyl)cyclopropanecarboxylic acid (42.0 mg, 0.27 mmol) and HATU (120 mg, 0.32 mmol)) in DMF (8 mL) was added DIEA (0.21 ml, 1 .2 mmol). After 2 h, the reaction mixture was diluted with EtOAc, washed with aq.NaHC0₃, aq. citric acid and brine. The organic phase was dried over MgS0₄

and concentrated._The afforded crude compound was purified by LC-MS, which gave the title compound (60 mg, 38 %).

¹⁹F NMR (376 MHz, dmso) 0 -1 1 1 .51 (dd, J = 10.3, 6.3 Hz), -66.25.

¹ H NMR (500 MHz, DMSO) δ 1.30 (d, J = 29.1 Hz, 4H), 1.70 (m, 2H), 1.79 (m, 2H), 3.78 (m, 2H), 3.93 (m, 2H), 5.01 (s, 2H), 7.46 (dd, J = 9.3, 5.1 Hz, 1 H), 7.59 (dd, J = 4.8, 0.9 Hz,1 H), 7.70 (m, 1 H), 8.04 (dd, J = 9.0, 2.7 Hz, 1 H), 8.29 (m, 2H), 9.00 (s, 2H), 9.38 (m, 2H).

¹³C NMR (126 MHz, DMSO) δ 9.78, 26.64 (q, J = 33.4, 33.2, 33.2 Hz), 31.05, 43.40 , 44.38, 1 10.96 (d, J = 21 .0 Hz), 1 18.35, 121 .92 (d, J = 25.5 Hz), 124.75 , 125.39 (q, J = 274.0 Hz), 127.52 (d, J = 8.8 Hz), 127.97 (d, J = 9.0 Hz), 129.18 , 130.55, 132.19, 139.19, 141 .08, 143.94, 146.04 (d, J = 2.4 Hz), 152.12 (d, J = 5.1 Hz), 157.56, 158.19, 160.30 (d, J = 247.8 Hz), 162.73, 177.16.

Example 2

1 '-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cvclopropanecarbonyl)spiro[azetidine-3,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (26)

1 ) TFA (1 .52 mL, 19.9 mmol) was added to a solution of 1-21 b (170 mg, 0.332 mmol) in dry DCM (10 mL). The solution was stirred at rt for 90 min, then concentrated under reduced pressure and co-evaporated twice with DCM. The residue was dissolved in DCM and basified with 1 M NaOH to pH 14. The organic phase was isolated by a phase separator. The aqueous phase was extracted several times with DCM. Organic phases were combined and

concentrated under vacuum.

2) The residue was dissolved in DMF (3.5 mL), 1 -(trifluoromethyl)cyclopropanecarboxylic acid (69.1 mg, 0.448 mmol), and HATU (173 mg, 0.455 mmol) wer added at 0 °C, followed by addition of DIEA (0.25 mL, 1 .44 mmol). The reaction solution was stirred at rt for 2h, then diluted with DCM (30 mL). The organic phase was washed with saturated NaHC0₃ (20 mL). The aqueous phase was extracted with 20 ml DCM. Organic phases were isolated via a phase separator and combined. Solvent was removed under vacuum to give the crude material as an oil. Purification by preparative HPLC (column Phenomenex Gemini-NX 5 μηι C18, 100 x 30 mm; gradient 30-35% B in A for 13 min, 40 ml/min flow rate; solvent A 10 mM NH₄OAc in 95/5 H₂0 - MeCN, pH 7; solvent B 10 mM NH₄OAc in 90/10 MeCN - H₂0, pH 7) gave the title compound (45.9 mg, 25%).

MS (ES+) 549.3 [M+H].

¹⁹F NMR (376 MHz, DMSO) δ -1 1 1 .39 (dd, J = 8.9, 5.1 Hz, 1 F), -65.57 (3F).

1 H NMR (500 MHz, DMSO) δ 1 .23 (m, 3H), 1 .37 (m, 1 H), 4.14 (m, 2H), 4.41 (m, 2H), 5.02 (s, 2H), 7.43 (dd, J =9.3,. 5.1 Hz, 1 H), 7.69 (td, J = 8.9, 8.8, 2.7 Hz, 1 H), 7.74 (dd, J = 4.7, 0.9 Hz, 1 H), 8.06 (dd, J = 9.0, 2.7 Hz, 1 H), 8.25 (d, J = 0.8 Hz, 1 H), 8.36 (d, J = 4.7 Hz, 1 H), 8.91 (s, 2H), 9.35 (s, 1 H), 9.41 (s, 1 H).

Example 27

(R)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(pyrrolidine-2-carbonyl)spiro[piperidine-4,3'- pyrrolo[2,3-clpyridinl-2'(1 'H)-one (27)

HATU (350 mg), triethyl amine (0.35 mL) and 1-14c (400 mg) were added at 0 °C under nitrogen to a stirred solution of (R)-1 -(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (200 mg) in DMF (15 mL). The resulting mixture was stirred at rt for 2 h, then diluted with water (80 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DCM (10 mL), 4 M HCI in dioxane (10 mL) was added at rt under nitrogen over a period of 2 min. The reaction mixture was stirred at rt for 1 h, then concentrated under reduced pressure. The afforded crude compound was purified by prep. C18 HPLC (mobile phase - 10mM ABC IN H₂0:MeCN).

Appropriate fractions were pooled and concentrated under reduced pressure and the residue was purified by prep C18 HPLC which gave the title compound (85 mg, 40%) as a solid. MS (ES+) 520.59 [M+H] ⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 8.99 (s, 3H), 8.31 - 8.19 (m, 4H), 7.82 - 7.71 (m, 3H), 7.63 (d, J = 4.8 Hz, 1 H), 7.58 (d, J = 4.7 Hz, 1 H), 7.39 - 7.33 (m, 1 H), 5.02 (dd, J = 6.6, 2.0 Hz, 2H), 3.94 (dt, J = 13.3, 5.2 Hz, 1 H), 3.84 (ddd, J = 10.3, 7.3, 4.6 Hz, 2H), 3.79 - 3.68 (m, 1 H), 3.63 (ddd, J = 13.2, 9.4, 3.7 Hz, 1 H), 3.05 - 2.95 (m, 1 H), 2.67 - 2.58 (m, 1 H), 2.00 (ddd, J = 12.8, 6.4, 3.4 Hz, 1 H), 1 .85 (ddd, J = 13.5, 8.0, 5.1 Hz, 1 H), 1 .80 - 1 .52 (m, 4H). Example 28

Methyl 1 '-((7-methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)metriyl)-2'-oxospiro[azetidine-3,3'- indolinel-1 -carboxylate (28)

To a solution of I-5 (160 mg) in acetonitrile (20 mL) was added cesium carbonate (1 .1 g). The mixture was stirred under nitrogen at rt for 30 min, then then compound 1-13d (190 mg) was added and the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated, diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. The obtained crude was purified by prep C18 HPLC. The afforded pure compound was diluted with

acetonitrile (2 mL) : water (5 mL) and lyophilized , which gave the title compound (76 mg, 23.39%) as a solid. (ES+) 466.36 [M+H] ⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.34 (s, 1 H), 9.30 (s, 1 H), 8.83 (s, 2H), 7.98 (d, J = 1 .5 Hz, 1 H), 7.62 (ddd, J = 13.6, 8.1 , 1 .5 Hz, 2H), 7.24 - 7.15 (m, 2H), 7.06 (td, J= 7.5, 1 .0 Hz, 1 H), 6.86 (d, J = 7.8 Hz, 1 H), 4.97 (s, 2H), 3.64 (s, 3H), 3.33 (d, J= 1 .0 Hz, 7H).

Example 29

1 '-((7-Methyl-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperidine-4,3'- pyrrolo[2,3-clPyridinl-2'(1 'H)-one (29)

The title compound was prepared by reaction of 1-13d (227 mg, 0.640 mmol) and I-20 (200 mg, 0.640 mmol) according to the method described in Example 28. Yield 140 mg, 42%. (ES+) 515.41 [M+H] ⁺.

¹ H NMR (500 MHz, DMSO) δ 1.79 (dt, 2H), 1.91 (ddd, 2H), 2.52 (s, 3H), 2.97 (s, 3H), 3.42 (m, 5H), 4.99 (s, 2H), 7.28 (d, 1 H), 7.59 (dd, 1 H), 7.63 (dd, 1 H), 7.98 (m, 1 H), 8.27 (s, 1 H), 8.28 (d, 1 H), 8.98 (s, 2H), 9.28 (m, 1 H), 9.38 (s, 1 H). ¹³C NMR (126 MHz, DMSO) δ 20.95, 31.05, 34.37, 40.52, 43.39, 43.58, 118.39, 123.71 , 124.32, 126.38, 127.29, 129.52, 130.53, 133.17, 133.82, 137.44, 139.34, 141 .08, 143.86, 145.45, 152.12, 157.54, 158.06, 177.08.

Example 30

Methyl 1 '-((7-methyl-4-(pyrimidin-5-v0isoauinolin-3^{^}

3,3'-pyrrolof2,3-clPyridinel-1 -carboxylate (30)

Triethylamine (0.5 mL, 3.49 mmol) and methyl chloroformate (0.02 mL, 0.262 mmol) (prepared as a stock solution in DMF) were added at 0 °C to a stirred solution of compound 1-13e (180 mg, 51 % purity) in DMF (4 mL). The resulting reaction mixture was stirred at 0 °C for 2 h, then diluted with ice water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with ice cold water (5 x 30 mL) and brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure. The obtained crude was purified by prep C18 HPLC, which gave the title compound (45 mg, 55%) as a solid. MS (ES+) 467.41 [M+H] ⁺.

1 H NMR (500 MHz, DMSO) δ 2.51 (d, J = 2.3 Hz, 3H), 3.64 (s, 3H, 35), 4.03 (m, 1 H), 4.1 1 (m, 1 H), 5.00 (s, 1 H), 7.23 (d, J= 8.6 Hz, 1 H), 7.62 (dd, J= 8.7, 1 .4 Hz, 1 H), 7.73 (d, J= 4.7 Hz, 1 H), 7.99 (s, 1 H), 8.24 (s, 1 H), 8.34 (d, J= 4.7 Hz, 1 H), 8.87 (s, 2H), 9.32 (s, 1 H), 9.34 (s, 1 H).

¹³C NMR (126 MHz, DMSO) δ 20.92, 41.72, 44.28, 51.98, 56.55 (m), 118.29, 123.72, 124.42, 126.36, 127.27, 129.46, 130.35, 133.22, 133.80, 137.49, 137.66, 139.92, 144.41 , 145.25, 152.07, 155.98, 157.32, 157.96, 175.04.

Example 31

1 '-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[azetidine-3,3'- pyrrolo[2,3-clPyridinl-2'(1 'H)-one (31 )

TFA (2.27 mg, 20 mmol) was added to a solution of 1-21 b (170 mg, 0.33 mmol) in dry DCM (10 mL) and the solution was stirred for 90 min at rt, then concentrated under reduced pressure and co-evaporated twice with toluene. The residue was dissolved in dry DCM (12 mL), DIEA (429 mg, 3.32 mmol) was added and the solution was cooled in an ice bath and 1 M solution of methane sulfonyl chloride in DCM (0.42 mL) was added slowly. The solution was stirred for 20 min in the ice bath. The reaction was quenched with ethanol and the mixture was evaporated under reduced pressure. The crude product was purified by C18 HPLC and the afforded product freeze dried twice from acetonitrile water. Yield 100 mg, 61 %. MS (ES+) 491 .38 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.42 - 9.38 (m, 1 H), 9.36 (s, 1 H), 8.92 (s, 2H), 8.39 (d, J= 4.7 Hz, 1 H), 8.27 (s, 1 H), 8.05 (dd, J= 9.0, 2.7 Hz, 1 H), 7.73 - 7.62 (m, 2H), 7.44 (dd, J= 9.3, 5.1 Hz, 1 H), 5.01 (s, 2H), 4.13 - 4.05 (m, 4H), 3.18 (s, 3H).

Example 32

Methyl 1 '-((7-fluoro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-2'-oxo-1 ',2'-dihvdrospiro[azetidine- 3,3'-pyrrolof2,3-clPyridinel-1 -carboxylate (32)

The Boc group was removed from compound 1-21 b (170 mg, 0.332 mmol) as described in Example 31 and the thus afforded amine acylated with methyl chloroformate as described in Example 30, which gave the title compound (105 mg, 67%). MS (ES+) 471 .4 [M+H] ⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.41 (s, 1 H), 9.36 (s, 1 H), 8.90 (s, 2H), 8.35 (d, J = 4.7 Hz, 1 H), 8.24 (s, 1 H), 8.05 (dd, J= 9.0, 2.7 Hz, 1 H), 7.74 (dd, J= 4.7, 0.9 Hz, 1 H), 7.69 (td, J = 9.0, 2.7 Hz, 1 H), 7.42 (dd, J= 9.3, 5.1 Hz, 1 H), 5.01 (s, 2H), 4.1 1 (s, 2H), 4.03 (s, 2H), 3.64 (s, 3H).

Example 33

1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[azetidine-3,3'- pyrrolo[2,3-clPyridinl-2'(1 'H)-one (33)

Sulfonylation of l-22c (150 mg, 0.350 mmol) as described in Example 19 gave the title compound (54 mg, 30%). MS (ES+) 507.09 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) δ 9.40 (s, 1H), 9.36 (s, 1H), 8.93 (s, 2H), 8.41 -8.36 (m, 2H), 8.27 (s, 1 H), 7.78 (dd, J= 9.1 , 2.2 Hz, 1 H), 7.68 - 7.62 (m, 1 H), 7.39 (d, J= 9.1 Hz, 1 H), 5.02 (s, 2H), 4.14-4.05 (m, 4H), 3.18 (s, 3H).

Example 34

Methyl 1'-((7-chloro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-2'-oxo-1',2'-dihvdrospiro[azetidine- 3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (34)

Acylation of compound l-22c (150 mg, 0.350 mmol) as described in Example 30 gave the title compound (51 mg, 30%). MS (ES+) 487.15 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) δ 9.40 (d, J= 0.8 Hz, 1H),9.36(s, 1H), 8.91 (s, 2H), 8.36 (dd, J = 14.6,3.5 Hz, 2H), 8.26-8.21 (m, 1H), 7.81 -7.71 (m, 2H), 7.37 (d, J= 9.0 Hz, 1H), 5.02 (s, 2H), 4.12 (s, 2H), 4.04 (s, 2H), 3.64 (s, 3H).

Example

1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cvclopropanecarbonyl)spiro[azetidine-3,3'-pyrrolo[2,3-clpyridinl-2'(1'H)-one (35) Acylation of compound l-22c (210 mg, 0.490 mmol) as described in Example 8 gave the title compound (65 mg, 23%). MS (ES+) 565.13 [M+H]⁺.

¹H NMR^* (500 MHz, DMSO) δ 1.23 (m, 3H), 1.37 (s, 1H), 3.31 (m, 1H), 4.14 (s, 1H), 4.42 (s, 1 H), 5.02 (s, 2H), 7.38 (d, 1 H), 7.76 (m, 2H), 8.24 (s, 1 H), 8.38 (dd, 2H), 8.92 (s, 2H), 9.35 (s, 1H), 9.40 (d, 1H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 8.87, 26.24, 26.51 , 26.78, 27.05, 42.33, 44.84, 118.92, 124.73, 125.23, 126.90, 127.11, 127.13, 128.32, 129.54, 130.96, 132.73, 134.05, 137.99, 140.54, 145.11, 147.31, 152.61, 158.01, 158.77, 164.49, 175.71. Example 36

Step a) methyl (1 '-((4-bromo-7-fluoroisoquinolin-3-yl)methyl)-2'-oxospiro[cvclobutane-1 ,3'- indolinl-3-yl)carbamate (36a)

Cesium carbonate (1 g) was added to a solution of I-5 (300 mg, 0.853 mmol) in acetonitrile (20 ml_). The solution was stirred at rt under nitrogen for 30 min, then l-9d (300 mg) was and the resulting mixture was stirred at rt for 4 h. The reaction mixture was diluted with water (30 mL) and extracted ethyl acetate (2x50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The afforded crude compound was purified by flash chromatography on a silica gel column eluted with 3-5% MeOH in DCM, which gave the two isomers of the title compound (200 mg, 45%) as a solid. MS (ES+) 484.25 [M+H]⁺.

Step b) Methyl ((1 S.3S)-1 '-((7-fluoro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-2'- oxospiro[cvclobutane-1 ,3'-indolinl-3-yl)carbamate (36-cis) &

Methyl ((1 R,3R)-1 '-((7-fluoro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-2'-oxospiro[cvclobutane- 1 ,3'-indolinl-3-yl)carbamate (36-trans)

A stirred solution of 36a (200 mg), pyrimidin-5-ylboronic acid (130 mg) and sodium carbonate (130 mg) in 1 ,2-dimethoxyethane (6 mL) and water (2 mL) was purged with argon for 10 min, then [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) chloride^«CH₂CI₂ (30 mg) was added and purged again with argon for 10 min. The reaction mixture was stirred in sealed tube at 120 °C for 16 h. The reaction mixture was cooled to rt, water (15 mL) was added and the mixture was extracted with ethyl acetate (2x50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography using a silica gel column eluted with 3% MeOH in DCM.

Fractions containing pure compound were combined and concentrated, and the two isomers were then separated by SFC, which gave the two title compounds as separate diastereomers. 36-cis, lsomer-1 ,yield 40 mg.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.39 (s, 1 H), 9.32 (s, 1 H), 8.82 (s, 2H), 8.04 (dd, J= 9.0, 2.7 Hz, 1 H), 7.76 (d, J = 7.6 Hz, 1 H), 7.67 (td, J = 8.9, 2.7 Hz, 1 H), 7.50 (dd, J= 7.5, 1 .2 Hz, 1 H), 7.38 (dd, J= 9.3, 5.1 Hz, 1 H), 7.13 (td, J = 7.8, 1 .2 Hz, 1 H), 7.03 (t, J = 7.2 Hz, 1 H), 6.78 (d, J = 7.8 Hz, 1 H), 4.99 (s, 2H), 4.49 (p, J= 8.5 Hz, 1 H), 3.54 (s, 3H), 2.44 - 2.29 (m, 4H).

lsomer-2, 36-trans, yield 15 mg.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.36 (d, J = 2.2 Hz, 2H), 8.03 (dd, J = 9.0, 2.7 Hz, 1 H), 7.62 (d, J = 8.7 Hz, 1 H), 7.47 (d, J = 7.3 Hz, 1 H), 7.41 (dd, J= 9.3, 5.1 Hz, 1 H), 7.13 (td, J = 7.7, 1 .3 Hz, 1 H), 7.04 (t, J= 7.2 Hz, 1 H), 6.77 (d, J= 7.8 Hz, 1 H), 4.94 (s, 2H), 4.35 (q, J = 8.5 Hz, 1 H), 3.55 (s, 3H), 2.46 - 2.38 (m, 2H).

Example 37

Step a) 3-((4-Bromo-7Tluoroisoquinolin-3-yl)methyl)-1 -(2,2,2-trifluoroethyl)-1 H-imidazo[4,5- clpyridin-2(3H)-one (37a)

Cesium carbonate (540 mg) was added at rt to a stirred solution of compound A-2 (120 mg) in MeCN (10 mL), the solution was stirred for 30 min l-9d (180 mg) was added and reaction mixture was stirred at rt for 13h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The afforded crude was purified by column chromatography on silica eluted with a gradient of 2% MeOH in DCM, which gave the title compound (140 mg, 48%) as a solid. MS (ES+) 457.09 [M+H]⁺.

Step b) 3-((7-Fluoro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-1 -(2,2,2-trifluoroethyl)-1 H- imidazo[4,5-clPyridin-2(3H)-one (37b)

Pyrimidin-5-ylboronic acid (40 mg, 0.312 mmol) and sodium carbonate (45 mg, 0.415 mmol) were added to a stirred solution of 37a (1 10 mg, 0.208 mmol) in 1 , 2-dimethoxyethane (4 mL) and water (1 mL). The solution was purged with argon for 5 min, then [1 ,1'-bis

(diphenylphosphino)ferrocene]palladium(ll) chloride^«CH₂CI₂ (10 mg, 0.010 mmol) was added and resulting reaction mixture was purged again with argon for 5 min, then stirred and heated in a microwave reactor at 1 10 °C for 1 h. The reaction mixture was filtered through Celite, the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over Na₂S0₄, filtered and concentrated under reduced pressure. The obtained crude was purified by prep C18 HPLC and were combined and lyophilized which gave the title compound (33 mg, 35%) as a solid. MS (ES+) 455.30 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.35 (d, J = 12.7 Hz, 2H), 8.97 (s, 2H), 8.31 - 8.24 (m, 2H), 8.03 (dd, J= 9.0, 2.7 Hz, 1 H), 7.70 (td, J = 9.0, 2.7 Hz, 1 H), 7.47 (dd, J = 9.3, 5.1 Hz, 1 H), 7.37 (d, J = 5.3 Hz, 1 H), 5.19 (s, 2H), 4.80 (q, J= 9.2 Hz, 2H).

Example 3

3-((7-Chloro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-1 -(2,2,2-trifluoroethyl)-1 H-imidazo[4,5- clpyridin-2(3H)-one (38)

The title compound was prepared as described in Example 37, but using l-8b instead of l-9d. Yield 5.3%. MS (ES+) 472.99 [M+H]⁺.

¹ H NMR* (500 MHz, DMSO) δ 4.80 (q, 2H), 5.20 (s, 2H), 7.37 (d, 1 H), 7.42 (d, 1 H), 7.79 (dd, 1 H), 8.27 (m, 2H), 8.35 (d, 1 H), 8.97 (s, 2H), 9.34 (s, 1 H), 9.37 (s, 1 H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 41.82, 42.10, 42.37, 42.64, 45.07, 104.72, 121.35, 123.58, 124.75, 125.81 , 127.14, 127.54, 128.26, 129.45, 130.48, 132.68, 132.74, 133.92, 135.17, 143.20, 147.36, 152.78, 153.04, 158.09, 158.81 .

Exampl

Step a) 3-Methoxy-2-methyl-6-(3-((tetrahvdro-2H-pyran-2-yl)oxy)prop-1 -vn-1 -yDbenzaldehyde (39a) Bis(triphenylphosphine) palladium(ll) dichloride (77 mg ) and copper (I) iodide (10 mg) were added to a degassed solution of 6-iodo-3-methoxy-2-methylbenzaldehyde (1 .8 g) and 2-(prop-2- yn-1 -yloxy)tetrahydro-2H-pyran (1 .8 g) in triethylamine (20 mL), the mixture was purged with Argon for 5 min, then stirred at 70 °C under argon for 2 h. The reaction mixture was

concentrated under vacuum, water (50 mL) was added and the mixture was extracted with ethyl acetate (2 x50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude_was purified by column chromatography on silica gel eluted with a gradient of 5-10% ethyl acetate in p. ether which gave the title compound (1 .5 g, 68%) as a syrup. MS (ES+) 289.25 [M+H]⁺.

Step b) (4-lodo-7-methoxy-8-methylisoquinolin-3-yl)methanol N-oxide (39b)

Hydroxylamine hydrochloride (430 mg) and pyridine (0.7 mL) were added at rt under nitrogen to a stirred solution of compound 39a (1 .4 g) in EtOH (70 mL). The reaction mixture was stirred for 1 h at rt, then iodine (3.2 g) was added and the mixture was stirred for 16 h at rt. The reaction mixture was concentrated under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic layers were washed with saturated solution of sodium thiosulfate (100 mL), water (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel column eluted withv5% MeOH in DCM, which gave the title compound (200 mg, 8.3%) as a solid. MS (ES+) 345.96 [M+H]⁺.

Step c) (7-Methoxy-8-methyl-4-(pyrimidin-5-yl)isoguinolin-3-yl)methanol N-oxide (39c)

A stirred solution of compound 39b (200 mg, 0.346 mmol), pyrimidin-5-ylboronic acid (100 mg, 0.799 mmol) and sodium carbonate (120 mg, 1 .13 mmol) in 1 ,2-dimethoxyethane (6 mL) and water (2 mL) was purged with argon for 10 min, then [1 ,1 '- bis(diphenylphosphino)ferrocene]palladium(ll) chloride^«CH₂CI₂ (26 mg, 0.036 mmol) was added and the mixture was purged again with argon for 10 min. The reaction mixture was stirred in a microwave reactor at 100 °C for 1 h, then cooled to rt. Water (15 mL) was added and the mixture was extracted with ethyl acetate (2x25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The afforded crude compound was purified by flash chromatography on silica gel eluted with 3% MeOH in DCM, which gave the title compound (90 mg, 68%) as a solid. MS (ES+) 298.13 [M+H]⁺.

Step d) 3-(Chloromethyl)-7-methoxy-8-methyl-4-(pyrimidin-5-yl)isoquinoline (39d)

PCI₃ (0.5 mL, 5.72 mmol) was added at 0°C to a stirred solution of compound 39c (80 mg, 0.210 mmol) in DCM (5 mL). The reaction mixture was stirred at rt for 2 h, then concentrated under reduced pressure. The residue was washed with diethyl ether (20 mL). A solid was formed which was filtered off and dried under vacuum to afford the crude compound (100 mg, 47%) which was taken to the next step without further purification. MS (ES+) 300.1 1 [M+H]⁺.

Step e) 1 '-((7-Methoxy-8-methyl-4-(pyrimidin-5-yl)isoguinolin-3-yl)methyl)-1 - (methylsulfonyl)spiro[piperidine-4.3'-pyrrolo[2.3-clpyridinl-2'(1 'H)-one (39e)

Cesium carbonate (260 mg, 0.798 mmol) was added at rt to a stirred solution of I-20 (60 mg, 0.209 mmol) in MeCN (10 mL). The reaction mixture was stirred for 20 min, then compound 39d (100 mg, 0.100 mmol) was added and reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by prep C18 HPLC, which gave the title compound (12 mg, 22 %) as a solid. MS (ES+) 545.23 [M+H]⁺.

¹ H NMR (500 MHz, DMSO) δ 1.79 (dt, J = 13.9, 4.1 , 4.1 Hz, 2H), 1.91 (ddd, J = 13.4, 8.8, 4.4 Hz, 2H), 2.60 (s, 3H), 2.97 (s, 3H), 3.43 (m, 4H), 3.91 (s, 3H), 4.97 (s, 2H), 7.22 (d, J = 9.3 Hz, 1 H), 7.59 (d, J = 4.7 Hz, 1 H), 7.64 (d, J = 9.3 Hz, 1 H), 8.28 (d, 1 H), 8.29 (s, 1 H), 8.95 (s, 2H), 9.38 (s, 1 H), 9.49 (s, 1 H).

¹³C NMR (126 MHz, DMSO) δ 9.69, 31.06, 34.38, 40.53, 43.22, 43.59, 56.36, 1 18.38, 1 18.84, 1 19.55, 123.45, 124.31 , 126.96, 129.78, 130.07, 130.58, 139.37, 141 .09, 143.40, 143.83, 149.21 , 154.89, 157.52, 158.04, 177.06.

Example 40

Methyl 2'-oxo-1 '-((4-(pyrimidin-5-yl)-7-(trifluoromethyl)isoauinolin-3-yl)methyl)-1 ',2'- dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (40)

Compound 1-12d (135 mg, 0.269 mmol) was acylated with methyl chloroformate (40 mg, 0.423 mmol) as described in Example 30, which gave the title compound (55 mg, 39%). MS (ES+) [M+H]⁺.

¹ H NMR (500 MHz, DMSO) δ 3.64 (s, 2H), 4.05 (s, 1 H), 4.13 (s, 1 H), 5.06 (s, 2H), 7.57 (d, 1 H), 7.75 (m, 1 H), 8.01 (dd, 1 H), 8.23 (s, 1 H), 8.36 (d, 1 H), 8.76 (s, 1 H), 8.96 (s, 2H), 9.38 (s, 1 H), 9.61 (s, 1 H).

¹³C NMR (126 MHz, DMSO) δ 41.79, 44.28, 52.03, 56.58 (m, 23), 1 18.38, 123.70 (q), 124.63, 125.97, 126.03, 126.18 (d), 126.75 (m), 127.57 (q), 128.81 , 130.33, 136.49, 137.65, 139.88, 144.54, 148.74, 153.88, 156.03, 157.50, 158.28, 175.29. Example 41

41b

Step (a) Methyl 1 '-((4-bromo-7-chloroisoauinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (41 a)

The Boc group of compound 1-19a (501 mg, 0.898 mmol) was removed by stirring the compound with 4M HCI in dioxane (6.75 mL), MeOH (3 mL), and DCM (1 1 mL) for 1 h 15 min at rt. The mixture was concentrated under vacuum, and co-evaporatd twice from toluene. DCM (4 mL) was added to the formed solids, followed by addition of DIEA (0.8 mL, 4.6 mmol) and methyl chloroformate. The mixture was stirred for 1 h 45 min, then concentrated under vacuum, co-evaporated several times with DCM. The obtained oil was purified by column

chromatography on silica (gradient 1 % to 7% MeOH in DCM) which gave the title compound as solids (410 mg, 88%). MS (ES+) 517.3 [M+H]⁺.

Step (b) Methyl 1 '-((7-chloro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (41 b)

A mixture of compound 40a (133 mg, 0.258 mmol), 5-pyrimidine boronic acid, (34.5 mg, 0.278 mmol), NaHC0₃ (62 mg, 0.74 mmol), and Pd(dppf)CI₂ complexed with DCM (36.2 mg, 0.044 mmol) in 4.5 mL degassed solvent (1 ,4-dioxane/water/DMF (v/v/v) 6:2:1 ) in a microwave vial was bubbled with N₂ for 1 min. The reaction mixture was heated in the microwave reactor at 1 10 °C for 1 h and then partitioned between 15 mL water and 15 mL EtOAc. The aqueous phase was extracted with 2 x 15 mL EtOAc. Organic phases were combined, dried (Na₂S0₄), and concentrated in vacuo. The afforded solids were purified by preparative HPLC (column Phenomenex Gemini-NX 5 μηι C18, 100 x 30 mm; gradient 30-40% B in 13 min, 40 ml/min flow rate; solvent A 10 mM NH₄OAc in 95/5 H₂0 - MeCN, pH 7; solvent B 10 mM NH₄OAc in 90/10 MeCN - H₂0, pH 7) which gave the title compound solids (40.1 mg, 30%). MS (ES+) 515.1

[M+H].

¹ H NMR (500 MHz, DMSO) δ 9.38 (s, 1 H), 9.36 (s, 1 H), 9.00 (s, 2H), 8.36 (d, J = 2.1 Hz, 1 H), 8.27 (s, 1 H), 8.26 (s, 1 H), 7.78 (dd, J= 9.1 , 2.2 Hz, 1 H), 7.59 (d, J = 4.8 Hz, 1 H), 7.41 (d, J = 9.1 Hz, 1 H), 5.01 (s, 1 H), 3.74 - 3.65 (m, 4H), 3.64 (s, 3H), 1 .79 - 1 .69 (m, 2H), 1 .65 (dt, J = 13.4, 4.7 Hz, 2H).

¹³C NMR (126 MHz, DMSO) δ 177.26, 158.21 , 157.58, 155.05, 152.00, 146.92, 143.90, 141 .26, 139.17, 133.41 , 132.1 1 , 132.06, 130.48, 128.98, 127.70, 126.51 , 124.60, 1 18.42, 52.28, 44.35, 43.35, 38.52, 30.94.

Example 42

Step a) N-(2'-Oxospiro[cvclobutane-1 ,3'-indolinl-3-yl)acetamide (42a)

Triethylamine (1 .3 mL, 9.35 mmol) and acetyl chloride (0.25 mL, 3.51 mmol) were added under nitrogen at 0 °C to a stirred suspension of l-23b (600 mg, 3.19 mmol) in DCM (10 mL). The resulting reaction mixture was stirred at rt for 1 h, then diluted with water (15 mL) and extracted with DCM (2 X 250 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced which gave the title compound (400 mg, 53%) as a solid. MS (ES+) 231 .15 [M+H]⁺.

Step b) N-(1 '-((1 -Bromo-6-fluoronaphthalen-2-yl)methyl)-2'-oxospiro[cvclobutane-1 ,3'-indolinl-3- vDacetamide (42b)

Cesium carbonate(1 .3 g) was added at rt to a solution of compound 42a (400 mg) in

acetonitrile (10 mL). The mixture was stirred under nitrogen at rt for 30 min, thenl-9d (430 mg) was added and the reaction mixture was stirred at rt for 4 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The afforded crude compound was purified by flash chromatography on silica gel eluted with a gradient of 3-5% MeOH in DCM, which gave the title compound (300 mg, 48%) as a solid. MS (ES+) 468.26 [M+H]⁺.

Step c) N-((1 S.3SH '-((6-f luoro-1 -(Dyrimidin-5-yl)naDhthalen-2-yl)methyl)-2'- oxospiro[cvclobutane-1 ,3'-indolinl-3-yl)acetamide (42c)

A stirred solution of compound 42b (300 mg, 0.641 mmol), pyrimidin-5-ylboronic acid (200 mg, 1 .61 mmol) and sodium carbonate (204 mg, 1 .92 mmol) in 1 ,2-dimethoxyethane (6 mL) and water (2 mL) was purged with argon for 10 min, then [1 ,1 '- bis(diphenylphosphino)ferrocene]palladium(ll) chloride^«CH₂CI₂ (47 mg, 0.064 mmol) was added and the mixture was purged again with argon for 10 min. The reaction mixture was stirred in sealed tube at 120 °C for 16 h, then cooled to rt. Water (15 mL) was added and the mixture was extracted with ethyl acetate (2X50 mL). Combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by flash chromatography on silica gel eluting with 3% MetOH in DCM. Appropriate fractions were combined and concentrated which gave the title compound together with the other diastereomer (140 mg). The mixture was subjected to separation by SFC, which gave the title compound as a single isomer (90 mg, 30%) as a solid.

Preparative SFC Conditions

Column/dimensions (R,R)-Whelk-01 (250 X30) ΓΠΓη,δμ

C0₂ 60.0%

Co solvent 40.0% (100% EtOH )

Total Flow 100.0 g/min

Back Pressure 100.0 bar

UV 217 nm

Stack time 4.5 min

Load/lnj 6.5 mg

Solubility MeOH + Acetonitrile + DCM(20 +

The afforded compound was further purified by prep C18 HPLC, which gave the pure title compound (43 mg) as a solid. MS (ES+) 468.18 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.40 (s, 1 H), 9.32 (s, 1 H), 8.82 (s, 2H), 8.45 (d, J = 7.5 Hz, 1 H), 8.04 (dd, J = 9.0, 2.7 Hz, 1 H), 7.67 (td, J = 9.0, 2.7 Hz, 1 H), 7.51 (d, J = 7.3 Hz, 1 H), 7.38 (dd, J = 9.3, 5.0 Hz, 1 H), 7.13 (t, J = 7.7 Hz, 1 H), 7.03 (t, J = 7.5 Hz, 1 H), 6.79 (d, J = 7.8 Hz, 1 H), 5.00 (s, 2H), 4.70 (h, J = 8.6 Hz, 1 H), 2.35 (d, J = 8.9 Hz, 4H), 1.82 (s, 3H).

¹³C NMR (126 MHz, DMSO-cfe) δ 176.81 , 168.46, 160.27 (d, J = 247.8 Hz), 158.04, 157.12, 152.10 (d, J = 5.0 Hz), 146.41 (d, J = 2.2 Hz), 142.12, 133.06, 132.24, 129.14, 127.89 (d, J = 9.0 Hz), 127.50, 127.39 (d, J = 8.8 Hz), 124.45, 122.32, 121 .92, 121 .88 (d, J

(d, J = 21 .0 Hz), 109.15, 44.12, 41 .73, 39.74, 38.92, 22.39.

Example 43

Step a) N-(1 '-((1 -bromo-6-chloronaphthalen-2-yl)methyl)-2'-oxospiro[cvclobutane-1 ,3'-indolinl-3- vDmethanesulfonamide (43a)

To suspension of l-23b (500 mg, 2.66 mmol) in DCM (10 mL) was added triethylamine (1 .4 mL, 10.0 mmol) followed by methanesulfonyl chloride (0.25 mL, 3.23 mmol) at 0 °C . The resulting reaction mixture was stirred at rt for 3 h, then diluted with DCM (50 mL) and washed with water (25 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated under reduced pressure. The obtained crude was purified by flash chromatography on silica gel in eluted with 1 -2 % MeOH in DCM, which gave the title compound (300 mg, 33%) as a solid. MS (ES+) xxx [M+H]⁺.

Step b) N-(1 '-((4-bromo-7-chloroisoquinolin-3-yl)methyl)-2'-oxospiro[cvclobutane-1 ,3'-indolinl-3- vDmethanesulfonamide (43b)

To a solution of compound 43a (300 mg, 0.789 mmol) in acetonitrile (10 mL) was added cesium carbonate (900 mg, 2.76 mmol) and the mixture was stirred under nitrogen at rt for 30 min, then l-8b (294 mg, 0.789 mmol) was added and the resulting mixture was stirred at rt for 5 h. The reaction mixture was diluted with water (30 mL) and extracted ethyl acetate (2x50 mL). The combined organic layers were dried (Na₂S0₄), filtered and concentrated under reduced pressure and the obtained crude was purified by flash chromatography on silica gel in eluted with 3-5 % MeOH in DCM, which gave the title compound (270 mg, 56%) as a solid. MS (ES+) 522.25 [M+H]⁺. Step c)

N-((1 R,3R)-1 W(7-chloro-4-(pyrimidin-5-yl)isoquinolin-3^l)m

indolinl-3-vDmethanesulfonamide (43c-trans)

&

N-((1 S,3S)-1 '-((6-chloro-1 -(pyrimidin-5-vnisoauinolin-3-vnmethvn-2'-oxospiro[cvclobutane-1 ,3'- indolinl-3-yl)methanesulfonamide (43c-cis)

A stirred solution of compound 43b (250 mg, 0.480 mmol), pyrimidin-5-ylboronic acid (1 18 mg, 0.952 mmol) and sodium carbonate (153 mg, 1 .44 mmol) in 1 ,2-dimethoxyethane (15 mL) and water (2 mL) was purged with argon for 10 min, then [1 ,1 '-bis(diphenylphosphino)ferrocene] palladium(ll) chloride^«CH₂CI₂ (36 mg, 0.049 mmol) was added and the mixture was again purged with argon for 10 min. The reaction mixture was stirred in a sealed tube at 100 °C for 16 h, then cooled to rt. Water (15 mL) was added and the mixture was extracted with ethyl acetate (2X50 mL). The combined organic layers were dried over sodium sulfate, filtered and

concentrated under reduced pressure. The crude material was purified by prep C18 HPLC eluted with 10 mM ammonium bicarbonate in H₂0:acetonitrile. Appropriate fractions were pooled and concentrated under reduced pressure, which gave the two title compounds as a mixture (140 mg). MS (ES+) 520.3 [M+H]⁺.

The two diastereomers were separated by SFC using the following conditions:

Column/dimensions :Lux Amylose-1 (250 X30) ηΐΓΤΐ,δμ

C0₂: 60.0%

Co solvent: 40.0% (100% I PA )

Total Flow: 100.0 g/min

Back Pressure: 100.0 bar

UV: 224 nm

Stack time: 7.0 min

Load/lnj: 9.5 mg

Solubility : Methanol + MeCN + DCM

lsomer-1 (trans): The collected fractions were concentrated under reduced pressure to afford 25 mg as a solid. The solid was washed with pentane (25 mL) and then diluted with MeCN and water and lyophilized which gave the title compound (20 mg, 8.0%) as a solid.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.36 (s, 1 H), 9.35 (s, 1 H), 8.92 (s, 2H), 8.36 (d, J = 2.3 Hz, 1 H), 7.77 (dd, J = 9.2, 2.2 Hz, 1 H), 7.67 (d, J = 9.3 Hz, 1 H), 7.47 (d, J = 7.3 Hz, 1 H), 7.37 (d, J = 9.1 Hz, 1 H), 7.14 (t, J = 7.7 Hz, 1 H), 7.06 (t, J = 7.5 Hz, 1 H), 6.78 (d, J = 7.8 Hz, 1 H), 4.94 (s, 2H), 4.13 (h, J = 8.6 Hz, 1 H), 2.91 (s, 3H), 2.68 - 2.60 (m, 2H), 2.43 (t, J = 10.2 Hz, 2H).

¹³C NMR (126 MHz, DMSO-cfe) δ 179.15, 158.15, 157.37, 152.02, 147.36, 142.52, 133.36, 132.05, 131 .95, 131.60, 129.03, 127.82, 127.58, 126.50, 126.41 , 124.14, 122.66, 122.17, 108.83, 43.47, 42.03, 41.59, 40.94, 40.21 .

lsomer-2 (cis): The collected fractions were concentrated under reduced pressure to afford 50 mg as a solid. The solid was washed with pentane (25 mL) and then diluted with MeCN and water and lyophilized which gave the title compound (45 mg, 18%) as a solid.

¹ H NMR (500 MHz, DMSO-cfe) δ 9.39 (s, 1 H), 9.34 (s, 1 H), 8.85 (s, 2H), 8.37 (s, 1 H), 7.76 (d, J = 9.2 Hz, 1 H), 7.73 (d, J = 7.1 Hz, 1 H), 7.58 (d, J = 7.3 Hz, 1 H), 7.35 (d, J = 9.1 Hz, 1 H), 7.14 (t, J = 7.8 Hz, 1 H), 7.04 (t, J = 7.4 Hz, 1 H), 6.79 (d, J = 7.8 Hz, 1 H), 4.99 (s, 1 H), 4.32 (q, J = 8.3 Hz, 1 H), 2.95 (s, 2H), 2.45 (d, J = 9.1 Hz, 4H).

¹³C NMR (126 MHz, DMSO-cfe) δ 176.60, 158.07, 157.18, 151.98, 147.27, 142.13, 133.42, 132.66, 132.06, 131.99, 128.94, 127.61 , 127.55, 126.50, 126.39, 124.27, 122.20, 122.18, 109.09, 44.04, 42.99, 41.68, 40.51 , 40.28

Example 44

Methyl 1 '-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'-dihvdrospiro[piperidine- 4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (44)

To a stirred solution of 1-15c (200 mg, 0.454 mmol) in DCM (10 mL) was added triethylamine (0.6 mL, 4.30 mmol) at 0 °C. After 30 min a a stock solution of methyl chloroformate (60 mg, 0.635 mmol) in DCM (1 mL) was added at 0 °C under nitrogen and the reaction mixture was then stirred for 2 h at rt. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure and the obtained solid was purified by prep C18 HPLC which gave the title compound (75 mg, 33%) as a solid. MS (ES+) 499.22 [M+H]⁺.

¹ H NMR* (500 MHz, DMSO) δ 1.64 (dt, 2H), 1.74 (ddd, 2H), 3.66 (d, 6H), 5.00 (s, 2H), 7.46 (dd, 1 H), 7.59 (d, 1 H), 7.69 (td, 1 H), 8.04 (dd, 1 H), 8.27 (m, 2H), 8.99 (s, 2H), 9.38 (d, 2H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 30.97, 38.55, 43.38, 44.38, 52.32, 110.90, 1 11.07, 118.45, 121 .84, 122.04, 124.75, 127.51 , 127.58, 127.96, 128.03, 129.21 , 130.53, 132.23, 139.21 , 141 .32, 143.93, 146.07, 146.09, 152.13, 152.17, 155.08, 157.59, 158.22, 177.24. Example 45

1 '-((7-Methyl-4-(pyrimidin-5-vnisoquinolin-3-vnmetrivn-1 -(1 -

(trifluoromethvncvclopropanecarbonvnspiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1 'l-l)-one (45) DIEA (0.2 ml_, 1 .14 mmol) and HATU (210 mg, 0.553 mmol) were added at rt to a stirred solution of 1 -(trifluoromethyl)cyclopropanecarboxylic acid (1 10 mg, 0.714 mmol) in DMF (10 ml_). The solution was stirred for 30 min at rt, then l-24b (300 mg, 0.460 mmol) was added and resulting mixture was stirred at rt for 20 min. Cold water (40 ml) was added and the mixture was extracted with ethyl acetate (2 x 40 ml). The combined organic layers were washed with ice cold water (2 x 50 ml) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The afforded crude compound was purified by prep C18 HPLC. Appropriate fractions were pooled, concentrated and triturated with de-ionized distilled water (30 mL) which gave the title compound (166 mg, 62%) as a solid. MS (ES+) 573.40 [M+H]⁺.

¹ H NMR* (500 MHz, DMSO) δ 1.27 (s, 2H), 1.33 (s, 2H), 1.70 (s, 2H), 1.79 (s, 2H), 3.78 (s, 2H), 3.93 (dt, 2H), 5.00 (s, 2H), 7.27 (d, 1 H), 7.58 (m, 1 H), 7.63 (dd, 1 H), 7.98 (m, 1 H), 8.28 (m, 2H), 8.97 (s, 2H), 9.30 (d, 1 H), 9.37 (s, 1 H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 9.82, 21.00, 26.29, 26.55, 26.82, 27.08, 31.09, 43.52, 44.41 , 1 18.37, 123.78, 124.34, 124.47, 126.43, 126.52, 127.34, 129.57, 130.63, 133.23, 133.86, 137.50, 139.29, 141.1 1 , 143.93, 145.51 , 152.15, 157.59, 158.07, 162.77, 177.16.

Example 46

1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cvclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (46) The title compound was prepared by reaction of I-4 (230 mg, 0.912 mmol) and 1-13d (250 mg, 0.927 mmol) according to the method described in I-22 step a. Yield 61 mg, 14%. MS (ES+) 486.35 [M+H]⁺.

¹ H NMR (500 MHz, DMSO) δ 3.17 (s, 3H), 4.06 (s, 4H), 4.97 (s, 2H), 6.89 (d, 1 H), 7.10 (td, 1 H), 7.22 (m, 2H), 7.60 (td, 2H), 7.98 (s, 1 H), 8.85 (s, 2H), 9.30 (s, 1 H), 9.34 (s, 1 H).

¹³C NMR (126 MHz, DMSO) δ 20.93, 33.25, 40.82, 44.17, 57.83, 109.49, 122.56, 123.13, 123.67, 124.17, 126.37, 127.22, 128.80, 128.91 , 129.55, 133.22, 133.79, 137.42, 142.96, 145.56, 152.08, 157.27, 157.97, 175.17.

Examp

1 -Methylcyclopropyl 1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)metriyl)-2'-oxo-1 ',2'- dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (47)

Sodium hydride (60%, dispersion in mineral oil, 0.05 g, 2.08 mmol) was added at 0 °C to a solution of l-22c (0.34 g, 0.793 mmol) in THF (4 mL). The mixture was stirred at 0 °C for 30 min, then a solution of 1 -methylcyclopropyl (4-nitrophenyl) carbonate (0.38 g, 1 .602 mmol) in THF (4 mL) was added and the mixture was then allowed to attain rt and was stirred for 3 h. Ice water (20 mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The obtained crude compound was purified by prep C18 HPLC and fractions containing pure compound were pooled and concentrated which gave the title compound (63 mg,15%) MS (ES+) 527.3 [M+H]⁺.

¹ H NMR (500 MHz, DMSO) δ 0.64 (d, 2H), 0.83 (s, 2H), 1.50 (s, 3H), 3.99 (d, 2H), 4.06 (d, 2H,), 5.01 (s, 2H), 7.37 (d, 1 H), 7.71 (dd, 1 H), 7.77 (dd, 1 H), 8.23 (s, 1 H), 8.34 (d, 1 H), 8.38 (d, 1 H), 8.91 (s, 2H), 9.35 (s, 1 H), 9.39 (d, 1 H).

¹³C NMR (126 MHz, DMSO) δ 12.47, 21.29, 41.82, 44.32, 56.16, 57.01 , 118.43, 124.73, 126.64, 127.83, 129.06, 130.44, 132.24, 133.57, 137.79, 139.99, 144.59, 146.85, 152.13, 155.29, 157.52, 158.28, 175.29.

Example 48

1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)s

Pyrrolo[2,3-clPyridin1-2'(1 'H)-one (48)

The title compound was prepared by reaction of I-25 (75 mg, 0.296 mmol) and 1-13d (80 mg, 0.296 mmol) according to the method described in I-22 step a. Yield 20 mg, 14% as a solid. MS (ES+) 487.35 [M+H]⁺.

¹ H NMR* (500 MHz, DMSO) δ 2.52 (s, 3H), 3.18 (s, 3H), 4.09 (m, 4H), 5.00 (s, 2H), 7.24 (d, 1 H), 7.63 (m, 2H), 7.99 (s, 1 H), 8.27 (s, 1 H), 8.38 (d, 1 H), 8.89 (s, 2H), 9.32 (s, 1 H), 9.35 (s, 1 H).

¹³C NMR* (126 MHz, DMSO) δ 21.00, 33.38, 40.86, 44.37, 57.10, 1 18.21 , 123.81 , 124.47, 126.44, 127.35, 129.56, 130.53, 133.28, 133.89, 137.52, 137.57, 140.03, 144.53, 145.33, 152.16, 157.44, 158.06, 174.39.

Example 49

Step a) methyl (1 '-((4-bromo-7-chloroisoquinolin-3-yl)methyl)-2'-oxospiro[cvclobutane-1 ,3'- indolinl-3-yl)carbamate (49a)

The title compound was prepared by reaction of I-5 (330 mg, 0.938 mmol) and l-8b (378 mg, 1 .01 mmol) according to the method described in I-22 step a. Yield 320 mg, 56% as a solid. MS (ES+) 487.35 [M+H]⁺. Step b) Methyl (1 '-((7-chloro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-2'-oxospirorcvclobutane- 1 ,3'-indolinl-3-yl)carbamate (49b)

A stirred solution of compound 49a (320 mg, 0.639 mmol), pyrimidin-5-ylboronic acid (159 mg, 1 .28 mmol) and sodium carbonate (204 mg, 1 .925 mmol) in 1 ,2-dimethoxyethane (15 mL) and water (2 mL) was purged with argon for 10 min, then [1 ,1 '- bis(diphenylphosphino)ferrocene]palladium(ll) chloride^«CH₂CI₂ (47 mg, 0.064 mmol) was added and the mixture was purged again with argon for 10 min. The reaction mixture was stirred in sealed tube at 100 °C for 16 h, then cooled to rt. Water (15 mL) was added and the mixture was extracted with ethyl acetate (2X50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluted with 3% MeOH in DCM. Fractions containing pure compound were combined and concentrated and purified by prep C18 HPLC which gave the title compound as a mixture of the two diastereomers (126 mg, 39%) as a solid. MS (ES+) 500.36 [M+H]⁺.

The afforded mixture was subjected to chiral separation by SFC, which gave two diastereomers. lsomer-1 : Collected fractions were concentrated and further purified by prep C18 HPLC. The residue was lyophilized which gave pure diastereomer of the title compound (34 mg) as a solid.

¹ H NMR^* (500 MHz, DMSO) δ 2.37 (m, 4H), 3.54 (s, 3H), 4.50 (h, 1 H), 4.99 (s, 2H), 6.77 (d, 1 H), 7.03 (t, 1 H), 7.13 (t, 1 H), 7.33 (d, 1 H), 7.50 (d, 1 H), 7.75 (m, 2H), 8.36 (d, 1 H), 8.83 (s, 2H), 9.32 (s, 1 H), 9.38 (s, 1 H).

¹³C NMR* (126 MHz, DMSO) δ 41.21 , 41.66, 44.10, 51.23, 109.14, 121 .96, 122.33, 124.32, 126.44, 126.55, 127.53, 127.67, 128.99, 132.04, 132.10, 133.01 , 133.48, 142.19, 147.36, 152.03, 155.71 , 157.21 , 158.12, 176.84. lsomer-2: Collected fractions were concentrated and further purified by prep C18 HPLC which gave pure diastereomer of the title compound (28 mg) as a solid.

¹ H NMR^* (500 MHz, DMSO) δ 2.42 (m, 2H), 3.55 (s, 3H), 4.36 (q, 1 H), 4.95 (s, 2H), 6.76 (d, 1 H), 7.05 (m, 1 H), 7.13 (td, 1 H), 7.36 (d, 1 H), 7.63 (d, 1 H), 7.76 (dd, 1 H), 8.36 (d, 1 H), 8.91 (s, 2H), 9.36 (d, 2H).

¹³C NMR^* (126 MHz, DMSO) δ 41.41 , 43.57, 51.26, 108.83, 122.17, 122.70, 124.22, 126.46, 126.55, 127.64, 127.75, 129.08, 132.00, 132.09, 133.43, 142.55, 147.44, 152.05, 155.58, 157.41 , 158.19, 179.38.

Example 50

Methyl 1 '-((7-methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (50)

Triethylamine (0.3 mL, 2.15 mmol) and methyl chloroformate (0.05 mL, 0.646 mmol) were added at 0 °C to a stirred solution of l-24b (300 mg, 0.276 mmol) in DCM (10 mL). The resulting reaction mixture was stirred at rt for 90 min, then poured into ice cold water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated under vacuo.

The crude was purified by prep HPLC. The afforded solid was triturated with de-ionised distilled water (15 mL) and filtered which gave the title compound (75 mg, 55 %) as a solid. MS (ES+) 495.43 [M+H]⁺.

¹ H NMR' (500 MHz, DMSO) δ 1.64 (dt, 2H), 1.74 (ddd, 2H), 2.51 (s, 4H), 3.66 (d, 7H), 4.99 (s, 2H), 7.27 (d, 1 H), 7.61 (m, 2H), 7.98 (s, 1 H), 8.26 (m, 2H), 8.96 (s, 2H), 9.29 (s, 1 H), 9.37 (s, 1 H).

¹³C NMR* (126 MHz, DMSO) δ 20.99, 30.98, 38.56, 43.47, 44.37, 52.32, 1 18.43, 123.77, 124.43, 126.42, 127.33, 129.57, 130.57, 133.23, 133.85, 137.48, 139.28, 141 .31 , 143.88, 145.52, 152.14, 155.09, 157.58, 158.07, 177.20.

Example 51

1 -Methylcyclopropyl 2'-oxo-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 ',2'- dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (51 )

Sodium hydride (60%, dispersion in mineral oil) (40 mg, 1 mmol) was added at 0 °C to a solution of 1-17b (250 mg, 0.34 mmol) in THF (10 mL), the mixture was stirred at 0 °C for 30 min, then a solution of 1 -methylcyclopropyl (4-nitrophenyl) carbonate (200 mg, 0.69 mmol) in THF (10 mL) was added and the mixture was stirred for 24 h and allowed to attain rt. Ice water was added and the aqueous layer was extracted with ethyl acetate (2 x 20 ml_). The organic layer was dried over sodium sulfate, filtered and concentrated. The obtained residue was dissolved in ethyl acetate (50 mL) and washed with 1 N aqueous NaOH solutions. The organic layer was dried over sodium sulfate filtered and concentrated. The crude compound was purified by prep C18 HPLC, and pure fractions were pooled and lyophilized, which gave the title compound (62 mg) as a solid. MS (ES+) 493.24 [M+H]⁺.

¹ H NMR* (500 MHz, DMSO) δ 0.64 (d, 2H), 0.83 (s, 2H), 1 .50 (s, 3H), 3.99 (d, 2H), 4.06 (d, 2H), 5.02 (s, 2H), 7.32 (m, 1 H), 7.71 (dd, 1 H), 7.76 (tt, 2H), 8.23 (d, 2H), 8.34 (d, 1 H), 8.89 (s, 2H), 9.35 (s, 1 H), 9.42 (m, 1 H).

¹³C NMR* (126 MHz, DMSO) δ 12.40, 21.23, 41.75, 44.40, 56.07, 56.98, 118.33, 123.90, 124.60, 127.09, 127.82, 127.93, 129.44, 130.41 , 131 .80, 134.96, 137.74, 139.97, 144.49, 146.17, 152.87, 155.22, 157.45, 158.08, 175.15.

Example 52

1 -Methylcvclopropyl 1 '-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (52)

Compound 1-21 c (250 mg, 0.606 mmol) was reacted with 1 -methylcyclopropyl (4-nitrophenyl) carbonate as described in Example 51 , which gave the title compound (120 mg, 38%). MS (ES+) 51 1 .42 [M+H]⁺.

¹ H NMR* (500 MHz, DMSO) δ 0.64 (m, 2H), 0.83 (s, 2H), 1.50 (s, 3H), 3.98 (d, 2H), 4.06 (d, 2H), 5.01 (s, 2H), 7.42 (dd, 1 H), 7.70 (m, 2H), 8.05 (dd, 1 H), 8.24 (d, 1 H), 8.34 (d, 1 H), 8.90 (s, 2H), 9.35 (s, 1 H), 9.40 (m, 1 H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 21.23, 41.75, 44.26, 56.08, 56.99, 110.93, 1 11.10, 118.35, 121 .87, 122.07, 124.77, 127.54, 127.61 , 127.99, 128.06, 129.19, 130.38, 132.29, 137.75, 139.93, 144.52, 145.89, 145.91 , 152.15, 152.19, 155.22, 157.41 , 158.18, 159.38, 161 .35, 175.17.

Example 53 oc

Step a) Tert-butyl (1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospirofcyclobutane-1 ,3'-pyrrolo[2,3-clpyridinl-3-yl)carbamate (53a)

Cesium carbonate (404 mg, 1 .24 mmol) was added to a solution of l-27d (141 mg, 0.414 mmol) in dry DMF (4 ml_). The suspension was stirred at rt for 1 h, then a solution of l-26d (120 mg, 0.414 mmol) in dry DMF (1 .5 mL) was added and the mixture was stirred at rt for 4 h. The reaction was poured into 10% ammonium chloride solution and extracted with DCM (x3). The combined organic layers were (Na₂S0₄), filtered and concentrated under reduced pressure . The residue was purified by column chromatography on silica gel eluted with a gradient of 0-4% MeOH in DCM, which gave the title compound (165 mg, 73%). MS (ES+) 543.53 [M+H]⁺.

Step b) Methyl ((1 s,3s)-1 '-((7-chloro-4-(pyrimidin-5-yl)isoauinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[cvclobutane-1 ,3'-pyrrolo[2,3-clpyridinl-3-yl)carbamate (53b-cis)

&

methyl ((1 r,3r)-1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospirofcyclobutane-1 ,3'-pyrrolo[2,3-clpyridinl-3-yl)carbamate (53b-trans)

TFA (1 .3 g, 12 mmol) was added to a solution of 53a (80 mg, 0.147) in dry DCM (10 mL). The solution was stirred at rt for 90 minutes, then concentrated and under reduced pressure and co- evaporated twice with toluene. The residue was dissolved in dry DCM (8 mL) and DIEA (190 mg, 1 .47 mmol) was added . The solution was cooled an ice bath and a 1 M solution of methyl chloroformate in dry DCM (0.185 mL) was added. The mixture was stirred for 20 minutes at 0 °C, EtOH was added and the solution was poured into a 10% ammonium chloride solution (50 mL). The mixture was extracted with DCM (x3). The organic phase was washed with brine, dried (Na₂S0₄), filtered and concentrated under reduced pressure. The two isomers were separated by column chromatography on silica gel eluted with a gradient of 2 - 5% MeOH in DCM. Each isomer were then purified by C18 HPLC using 25 to 40% acetonitrile in water with 10 mmol ammonium acetate as mobile phase, which gave the two title compounds. Yield cis isomer 1 1 mg, 15%; yield trans isomer 17 mg, 23%.

Example 54

N-((1 S.3S)-1 '-((7-chloro-4-(pyrimidin-5-vnisoauinolin-3-yl)methvn-2'-oxo-1 '.2'- dihvdrospiro[cvclobutane-1 ,3'-pyrrolo[2,3-clpyridinl-3-yl)methanesulfonamide (54-cis)

&

N-((1 R,3R)-1 '-((7-chloro-4-(pyrimidin-5-vnisoauinolin-3-yl)methvn-2'-oxo-1 ',2'- dihvdrospiro[cvclobutane-1 ,3'-pyrrolo[2,3-clpyridinl-3-yl)methanesulfonamide (54-trans)

TFA was added to a solution of 53a (80 mg, 0.148 mmol) in dry DCM (10 mL). The solution was stirred at rt for 90 minutes, then concentrated under reduced pressure and co-evaporated twice with toluene. The residue was dried in vacuo over night , then dissolved in dry DCM (8 mL), DIEA (191 mg, 1 .48 mmol) was added and the solution was cooled in an ice bath and a fresh prepared 1 M solution of methanesulfonyl chloride in dry DCM (0.19 mL) was added and the mixture was stirred for 10 minutes on the ice bath. EtOH was added and the mixture was poured into to a 10% ammonium chloride solution (50 mL). The water phase was extracted with DCM (x3). The combined organic layers were dried (Na₂S0₄), filtered and concentrated under reduced pressure. The two isomers were separated by column chromatographyon silica gel eluted with a gradient of 2 to 5% MeOH in DCM. Each isomer were then purified by C18 HPLC using 20 to 40% acetonitrile in water with 10 mmol ammonium acetate as mobile phase, which gave the two title compounds.

Cis isomer: Yield 15 mg, 20%;

¹ H NMR (500 MHz, DMSO-d6) δ 9.37 (s, 1 H), 9.36 (d, J = 0.9 Hz, 1 H), 8.95 (s, 2H), 8.36 (dd, J = 6.4, 3.5 Hz, 2H), 8.15 - 8.1 1 (m, 1 H), 7.78 (dd, J = 9.1 , 2.2 Hz, 1 H), 7.70 (s, 1 H), 7.52 (dd, J = 4.7, 0.9 Hz, 1 H), 7.39 (d, J = 9.0 Hz, 1 H), 4.99 (s, 2H), 4.14 (p, J = 8.4 Hz, 1 H), 2.92 (s, 3H), 2.72 - 2.63 (m, 2H), 2.50 - 2.44 (m, 5H).

¹³C NMR (126 MHz, DMSO-d6) δ 178.27, 158.18, 157.45, 152.07, 146.97, 144.27, 139.88, 139.53, 133.37, 132.09,132.02, 129.96, 128.97, 127.65, 126.51 , 126.48, 124.32, 1 17.76, 43.63, 42.13, 41 .44, 40.94, 39.39.

Trans isomer: Yield 23 mg, 30%.

Example A: RSV cytopathic effect

Compounds of the invention are initially tested in a cytopathic effect (CPE)-based viral replication assay using immortalized cells and a laboratory strain of RSV (Long). This assay evaluates the ability of a compound to inhibit viral replication.

Procedure:

Assay plates are prepared by seeding 2,500 HEp-2 cells (ATCC) per well of a 384-well black clear-bottom plate (Greiner Bio-One) in 20 μΙ_ of assay media (defined as DMEM supplemented with 2% heat-inactivated fetal bovine serum and 1 % Penicillin/Streptomycin). Assay plates are incubated overnight at 37 °C in an incubator containing 5% C0₂. The following day, a 10-point serial dilution of test compound is prepared in DMSO. Compounds are subsequently diluted with assay media and 20 μΙ_ of diluted compound (containing 1 .5% DMSO) is transferred to an assay plate for evaluation of antiviral activity.

For the CPE assay, cells are infected at a Multiplicity of Infection (MOI) of 0.015 using 20 μΙ_ of RSV Long (ATCC) diluted in assay media. The DMSO concentration is constant throughout the assay plate, including the negative and positive controls. The assay plate is incubated for 3 days at 37 °C in an incubator containing 5% C0₂. Cell viability is evaluated with the addition of 10 μΐ of CellTiter-Glo (ProMega). Luminescence is measured using an EnVision plate reader (Perkin Elmer). EC₅₀ values are calculated using the raw data from the CPE assays.

The compounds of the invention were tested i the assay described in Example A, the results are as shown in the Table 2.

Table 2

Cmpd # EC₅₀ (nm) Cmpd # EC₅₀ (nm)

1 c 0.46 6 5.4

2c 31 7 30

3 1 .6 8 0.96

4b 13 9 6.8

5 3.2 10 1 .8 Cmpd # EC₅₀ (nm) Cmpd # EC₅₀ (nm)

1 1 6.0 36-s,s 8.2

12 2.8 36-r,r 12

13b 0.85 37b 53

14b 1 .0 38 0.37

15c 5.3 39e 5,5

16b 4.2 40 38

17 2.4 41 b 0.65

18 14 42c 9.2

19 0.28 43c dia-1 3.6

20 2.6 43c dia-2 15

21 1 .1 44 3.9

22 3.9 45 0.61

23 3.6 46 0.35

24 7.9 47 0.76

25 1 .1 48 1 .0

26 9.8 49b dia-1 8.9

27 1 .8 49b dia-2 6.7

28 0.20 50 0.43

29 0.37 51 1 .5

30 0.46 52 3.2

31 9.2 53b-cis 5.3

32 1 1 53b-trans 4.6

33 1 .1 54-cis 7.8

34 0.29 54-trans 3.4

35 5.8

Each reference, including all patents, patent applications, and publications cited in the present application is incorporated herein by reference in its entirety, as if each of them is individually incorporated. Further, it would be appreciated that, in the above teaching of invention, the skilled in the art could make certain changes or modifications to the invention, and these equivalents would still be within the scope of the invention defined by the appended claims of the application.

Claims

1 . A compound of Formula I:

wherein

W is NR^1A or CR^{1 B}R^{1 B};

Z is N or CH;

R^1A is Ci-C₃alkyl, d-C₃haloalkyl, C₃-C₄cycloalkyl or phenyl wherein cycloalkyl or phenyl is optionally mono-, di- or tri-substituted with substituents each independently selected from Ci-C₃alkyl, halo, amino and C C₃alkoxy;

the two R^{1 B} together with the carbon atom to which they are attached combine and form C₃- C₆cycloalkyl or heterocyclyl, wherein the cycloalkyl is substituted with C(=0)OR^1G,

NHC(=0)OR^1G or NHS(=0)₂R^1C, and the heterocyclyl is substituted with C(=0)R^1C, C(=0)OR^1G, S(=0)₂R^1C, C(=0)NH₂ or C(=0)NR^1CR^1C';

R^1C is Ci-C₆alkyl, C₃-C₅cycloalkyl or heterocyclyl, any of which is optionally substituted with one, two or three substituents independently selected from fluoro, amino, trifluoromethyl, C C₃alkyl, C C₃alkoxy and C C₃alkylamino;

R² is halo, cyano, hydroxy, C C₃alkyl, C(=0)NH₂ or trifluoromethyl;

R³ is each independently selected from fluoro, chloro, cyano, C C₃alkyl, C C₃alkoxy and trifluoromethyl; n is 0, 1 or 2;

q is 0, 1 or 2;

heterocyclyl is a 4, 5 or 6 membered saturated ring containing 1 or 2 heteroatoms independently selected from N and O.

or a salt thereof.

2. The compound according to claim 1 , wherein q is 0. The compound according to claim 1 or 2, wherein W represents a group of formula (A1 ) (A2):

(A1) (A2)

wherein R^{1 B'} is C(=0)R^1C, C(=0)OR^1G, S(=0)₂R^1C;

R^1C is C C₆alkyl, C₃-C₅cycloalkyl or heterocyclyl, any of which is optionally substituted with one, two or three substituents independently selected from fluoro, amino, trifluoromethyl, CrC₃alkyl and CrC₃alkylamino.

4. The compound according to claim 3, wherein R^{1 B} is S(=0)₂R^1C.

5. The compound according to claim 4, wherein R^1C is Me or cyclopropyl substituted with methyl.

6. The compound according to claim 1 or 2, wherein W is a group of formula B:

wherein R^{1 B"} is NHC(=0)OR^1G, NHC(=0)R^1C or NHS(=0)₂R^1C;

R^1C is C C₆alkyl, C₃-C₅cycloalkyl or heterocyclyl, any of which is optionally substituted with one or two substituents independently selected from fluoro, amino, trifluoromethyl, C C₃alkyl or Ci-C₃alkylamino.

7. The compound according to claim 6, wherein R^{1 B} is NHC(=0)OR^1G.

8. The compound according to claim 6, wherein R^{1 B} is NHS(=0)₂R^1C.

9. The compound according to any one of claims 1 to 8, wherein n is 1.

10. The compound according to claim 9, wherein R³ is C C₃alkyl, fluoro, chloro or preferably methyl.

1 1 . The compound according to claim 1 having the formula (lla):

Z is N or CH;

R^{1 B'} is C(=0)R^1C, C(=0)OR^1G or S(=0)₂R^1C

R^1C is CrC₃alkyl, C₃-C₅cycloalkyl or a 4-, 5- or 6-membered heterocyclyl, any of which is optionally substituted with one, two or three substituents independently selected from methyl, amino, fluoro and trifluoromethyl;

R³ is fluoro, chloro or methyl;

n is 0 or 1 .

The compound according to claim 1 having the formula (lib):

B^'

wherein

Z is CH or N;

R^{1 B'} is C(=0)R^1C, C(=0)OR^1G or S(=0)₂R^1C

R^1C is Ci-C₃alkyl, C₃-C₅cycloalkyl or a 4-, 5- or 6-membered heterocyclyl, any of which is optionally substituted with one, two or three substituents independently selected from methyl, amino, fluoro and trifluoromethyl;

R³ is fluoro, chloro or methyl;

n is 0 or 1 .

13. The compound according to claim 1 1 or 12, wherein Z is N. 14. The compound according to any one of claims 1 1 to 13, wherein R^1C is methyl. 15. The compound according to any one of claims 1 1 to 13, wherein R^{1 B} is C(=0)R^1C, and R^1C is cyclopropyl which is substituted with trifluoromethyl.

16. The compound according to any one of claims 1 1 to 15, wherein n is 1 and R³ is chloro or methyl.

17. A compound according claim 1 , which is selected from:

Methyl 2^,-oxo-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[azetidine-3,3'-indoline]-1 - carboxylate,

1 -(Methylsulfonyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[piperidine-4,3'- pyrrolo[2,3-c]pyridin]-2'(1 'l-l)-one,

1 -(1 -Aminocyclopropanecarbonyl)-1 '-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3- yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2^,(1 'H)-one,

1 '-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperidine- 4,3^,-pyrrolo[2,3-c]pyridin]-2^,(1 ^,H)-one,

1 -(1 -Aminocyclopropanecarbonyl)-1 '-{{4-{pyrimidin-5-yl)isoquinolin-3- yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2^,(1 'H)-one,

1 '-((4-(Pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

1 -(Piperidine-4-carbonyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[piperidine-4,3'- pyrrolo[2,3-c]pyridin]-2'(1 'l-l)-one,

1 '-((4-(Pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(3,3,3-trifluoropropanoyl)spiro[piperidine- 4,3^,-pyrrolo[2,3-c]pyridin]-2^,(1 ^,H)-one,

1 -(1 -Amino-3,3-difluorocyclobutanecarbonyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3- yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2^,(1 'H)-one,

1 '-((4-(Pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -((2,2,2- trifluoroethyl)sulfonyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2^,(1 'H)-one,

Methyl 1 ^,-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxospiro[azetidine-3,3'- indoline]-1 -carboxylate,

Methyl 1 ^,-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxospiro[azetidine-3,3'- indoline]-1 -carboxylate,

1 -(Piperidine-4-carbonyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[azetidine-3,3'- indolin]-2'-one, 3-{{4-{Pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(2,2,2-trifluoroethyl)-1 H-imidazo[4,5- c]pyridin-2(3H)-one,

Methyl 2^,-oxo-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 \2^,-dihydrospiro[azetidine-3,3'- pyrrolo[2,3-c]pyridine]-1 -carboxylate,

Methyl 1 ^,-((7-cyano-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2^,-oxospiro[azetidine-3,3'- indoline]-1 -carboxylate,

1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperidin 4,3'-pyrrolo[2,3-c]pyridin]-2'(1 ^,l-l)-one,

1 -(1 -Aminocyclopropanecarbonyl)-1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3- yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2^,(1 ^,H)-one,

1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

1 -(2-Amino-3,3,3-trifluoropropanoyl)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3- yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2^,(1 ^,H)-one,

1 '-(2-amino-3-hydroxypropanoyl)-1 -((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)spiro[indoli 3,4'-piperidin]-2-one,

1 '-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

(R)-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(pyrrolidine-2-carbonyl)spiro[pipe 4,3'-pyrrolo[2,3-c]pyridin]-2'(1 ^,l-l)-one,

1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)m

4,3'-pyrrolo[2,3-c]pyridin]-2'(1 ^,l-l)-one,

Methyl 1 ^,-((7-methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

1 '-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[azetidine-3,3'- ργΓΓθΙο[2,3- γπ ίη]-2'(1 Ή)-οηθ,

Methyl 1 '-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate, 1 '-((7-C loro-4-(pyrimidin-5-yl)isoquinolin-3-yl)met yl)-1 -(met ylsulfonyl)spiro[azet

3,3'iDyrrolo[2,3-c]pyridin]-2 1 'l-l)-one,

Methyl 1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

Methyl ((1 s,3S)-1 '-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'- oxospiro[cyclobutane-1 ,3'-indolin]-3-yl)carbamate,

Methyl ((1 R,3R)-1 ^,-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'- oxospiro[cyclobutane-1 ,3'-indolin]-3-yl)carbamate,

3-((7-Fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(2,2,2-trifluoroethyl)-1 H- imidazo[4,5-c]pyridin-2(3H)-one,

3-{{7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(2,2,2-trifluoroethyl)-1 H- imidazo[4,5-c]pyridin-2(3H)-one,

1 '-((7-Methoxy-8-methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 - (methylsulfonyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2^,(1 ^,H)-one,

Methyl 2'-oxo-1 ^,-((4-(pyrimidin-5-yl)-7-(trifluoromethyl)isoquinolin-3-yl)methyl)-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

N-((1 S,3S)-1 '-((6-fluoro-l -(pyrimidin-5-yl)naphthalen-2-yl)methyl)-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-3-yl)acetamide,

N-((1 R,3R)-1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2^,-oxospiro[cyclobutane- 1 ,3'-indolin]-3-yl)methanesulfonamide,

N-((1 S,3S)-1 '-((6-chloro-l -(pyrimidin-5-yl) isoquinolin -3-yl)methyl)-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-3-yl)methanesulfonamide,

Methyl 1 '-((7-fluoro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[piperidine-4,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cyclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2^,(1 ^,H)-one, 1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cyclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-c]pyridin]-2^,(1 ^,H)-one,

1 -Methylcyclopropyl 1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate, 1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfony^

3,3'-ργΓΓθΙο[2,3- γπ ίη]-2 ΐ Ή)-οηθ,

Methyl (1 '-((7-chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2^,-oxospiro[cyclobutane-1 ,3'- indolin]-3-yl)carbamate,

Methyl 1 '-((y-methyl^^pyrimidin-S-y isoquinolin-S-y methy ^'-oxo-l ',2'- dihydrospiro[piperidine-4,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

1 -Methylcyclopropyl 2'-oxo-1 '-((4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate and

18. A compound according claim 1 , which is selected from:

1 '-((7-Chloro-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(1 -

1 '-((7-Methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperidine- 4,3'-pyrrolo[2,3-c]pyridin]-2'(1 'H)-one and

Methyl 1 '-((7-methyl-4-(pyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[azetidine-3,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate.

19. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically

acceptable salt thereof, for the treatment or prevention of RSV infection in a human being.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.