WO2018038668A1 - Respiratory syncytial virus inhibitors - Google Patents

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)₂ R^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'; q, n, 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 or two 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, 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.

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 "Ci-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 d-C₃alkyl 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 CrC_nhaloalkyl refers to C C_malkyl, wherein at least one C atom is substituted with a halogen, preferably chloro or fluoro. An exemplary CrC_nhaloalkyl is trifluoromethyl.

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

The term "Ci-C_nalkylamino" means an amino group which is substituted with Ci-C_nalkyl, wherein Ci-C_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_mcycloalkylCo-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 d-C_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 CrC_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, hexylresorci nates, 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 is d-C₆alkyl or Ci-C₆haloalkyl.

Representative values for R^1A according to this configuration is Ci-C₃fluoroalkyl, such as 2,2,2- trifluoroethyl.

In an alternative configuration of compounds of formula (la), R^1A is optionally substituted C₃- 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.

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 the formula (lb') or (lb"):

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 C 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 rovides compounds of formula (I la):

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 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 .

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

ZisCH orN;

R^1B' 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)

ZisCH orN;

R^1B' is C(=0)R^1GorS(=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 (Ma) and (lib), Z is N.

In one embodiment of compounds of formula ( I la) and (lib), R^1C is methyl.

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

In one embodiment of compounds of formula ( I la) 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-(pyridazin-4-yl)isoquinolin-3-yl)methyl)spiro[azetidine-3,3'-indoline]-1- carboxylate,

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

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

1'-((4-(Pyridazin-4-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 luoro-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 \2'-dihydrospiro[piperidi 4,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

1 '-((7 luoro-4-(pyridazin-4-yl)isoquinolin-3-yl)m

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

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

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

1 '-((7-Chloro-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperidi pyrrolop.a-clpyridinl-^il 'HJ-one,

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

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

(trifluoromethyl)cyclopropanecarbonyl)spiro[azetidine-3,3'-pyrrolo[2,3-c]pyridin]-2'(1 ^,l-l)-one, 1 '-((7-Chloro-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-1 -(1 -

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

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

1 '-((7-Methyl-4-(pyridazin-4-yl)isoquinolin-3-yl)me

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

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

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

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

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

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

1 '-((7-Methyl-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[azetidine-3,3'- indolin]-2'-one and

1 '-((7-Methyl-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[azetidine-3,3'- pyrrolo[2,3-c]pyridin]-2'(1 'l-l)-one.

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.

referred to as R¹ building block or R¹ moiety.

Compounds of the invention are in typically prepared using either of the two general

approaches, Method A and Method B, outlined in Scheme 1 .

is transferred to W;

X is Br or I; Y is CI or Br

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 pyridazinyl group is then suitably introduced using for instance a Stille cross coupling reaction, i.e. reaction with the suitable tin derivative (1 D) in the presence of a base and a palladium catalyst thus providing the diaryl compound (1 E). Representative palladium catalysts for this purpose include but is not limited to bis(tri-tert-butylphosphine)palladium(0) or similar. Alternatively, the pyridazinyl group may be introduced by a Suzuki 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 pyridazinyl 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, thus providing the N-substituted compound (4G).

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

DMAP 4-Dimethylaminopyridine

DME 1 ,2-Dimethoxyethane

DMEM Dulbecco's modified Eagle's medium DMF A/,A/-Dimethylformamide

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 (°C). 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.

General method for N-alkylation

W is W or a group which subsequently is transferred to W;

X is bromo, iodo or optionally substituted pyridazinyl;

Y is chloro or bromo

A solution of compound 1 A (1 eq) and cesium carbonate (3 eq) in acetonitrile (10 mL) is stirred for 15 min at rt, then isoquinoline derivative 1 B (1 eq) is added in portions. The solution is stirred at rt and the progress of the reaction is monitored by TLC and/or LCMS and when deemed completed (-1 -18 h), the mixture is concentrated in vacuo and the crude compound purified by column chromatography on silica gel typically eluted with a gradient of heptane : EtOAC or MeOH : DCM, thus providing the compound 1 C. General method for Stille coupling

W is W or a group which subsequently is transformed to W

X is bromo or iodo; WL.

Y is chloro, bromo or a group of the formula: <>=<

N

A solution of 4-(tributylstannyl)pyridazine 1 E (1 .4 eq) in acetonitrile (10 mL) and base, e.g. sodium carbonate (3 eq) are added under argon to a solution of halo-isoquinoline derivative 1 D or 1 G (1 eq) in acetonitrile. The reaction mixture is purged with argon for 15 min then bis(tri-tert- butylphosphine)palladium(O) (-0.1 eq) is at rt added under argon. The reaction mixture is then stirred and heated either on an oil bath or by irradiation in a microwave reactor at 100-130 °C. The progress of the reaction is monitored by TLC and/or LCMS and when deemed

completed (-1 -16 h), the reaction mixture is cooled to rt, water is added and the mixture is extracted with EtOAc (x2), the organic layer is dried, filtered and concentrated and the obtained residue purified by flash chromatography on silica gel. Appropriate fractions are pooled and concentrated and if required further purified by prep C18 HPLC, thus providing the compound 1 F or 1 H.

Preparation of intermediates

Intermediate 1

1-1 a 1-1 b 1-1 c

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 DIEA (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 DIEA (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

Step a) 1 -tert-butyl 3-ethyl 2-(3-nitropyridin-4-yl)malonate (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 °C. 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'-pyrrolo[2,3-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 1 5 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, 1 7.2 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-bromophenyl)carbamoyl)azetidine-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 1 0% 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-bromophenvn(4-methoxybenzvncarbamovnazetidine-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

1-5

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

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

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]⁺.

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-(bromomethyl)-7-fluoroisoquinoline (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-vncarbamovnazetidine-1 -carboxylate (1-1 1 )

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]⁺.

Intermediate 12

Step a) 4-bromo-3-(bromomethyl)-7-(trifluoromethyl)isoguinoline (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)isoauinolin-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. 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-(pyridazin-4-yl)isoquinolin-3-yl)methanol N-oxide (1-13c)

Compound 1-13b (5.0 g, 13 mol) was reacted was reacted with 4-(tributylstannyl)pyridazine according to the general method for Stille coupling, using an oil bath at 1 10 °C for heating, sodium carbonate as base, 1 ,4 dioxane as solvent and 16 h reaction time, which gave the title compound (3.58 g, 25%) as a solid. MS (ES+) 268.1 1 [M+H]⁺. Step d) 3-(chloromethvn-7-methyl-4-(pyridazin-4-vnisoguinoline (1-13d)

PCI₃ (3 mL, 34.3 mmol) was added at 0 °C under nitrogen to a stirred solution of 1-13c (950 mg,

3.55 mmol) in DCM (25 mL). The resulting reaction mixture was stirred at 50 °C for 1 h, then concentrated under reduced pressure, triturated with diethyl ether (2 x 50 mL). The solvent was decanted and the formed solid dried under high vacuum to afford the title compound (1 .05 g,

51 %). MS (ES+)

270.09 [M+H]⁺.

Step e) tert-butyl 1 '-((7-methyl-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-1 ',2'- dihydrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (1-13e)

l-2g (350 mg, 1 .06 mmol) was reacted with 1-13d ( 700 mg, 0.75 mmol) according to the general method for N-alkylation, which gave the title compound (290 mg, 66%) as a solid. MS (ES+) 537.5 [M+H]⁺.

Step f) 1 '-((7-methyl-4-(pyridazin-4-yl)isoguinolin-3-yl)methyl)-1 ',2'-dihvdrospiro[piperidine-4,3'- pyrrolo[2,3-clPyridinel (1-13f)

A 4M solution of HCI in 1 ,4-dioxane (3 mL) was added dropwise at rt to a stirred solution of I- 13e (290 mg, 0.49 mmol) in DCM (2 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under reduced pressure and dried which gave the title compound (255 mg) as a solid.

Intermediate 14

Step a) Tert-butyl 1 '-((4-bromoisoquinolin-3-yl)methyl)-2'-oxo-1 ',2'-dihvdrospiro[piperidine-4,3'- pyrrolo[2,3-clpyridinel-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) 1 '-((4-Bromoisoauinolin-3-yl)methyl)spiro[piperidine-4.3'-pyrrolo[2.3-clpyridinl-2'(1 Ή)- one (l-14b)

To a stirred solution of 1-14a (5.0 g, 8.5 mmol) in DCM (150 mL), was added TFA (4.8 g, 42 mmol) in dropwise over a period of 5 mints at 0 °C under nitrogen. The reaction mass was stirred at rt for 3 h, then concentrated under reduced pressure and diluted with water (50 mL). Saturated bicarbonate solution (50 mL) was added and the mixture was extracted with 5 % MeOH in DCM (2 x200 mL). The combined organic layer was washed with water (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was triturated with diethyl ether (50 mL), stirred for 15 min, filtered and dried which gave the title compound (3.4 g). MS (ES+) 423.32 & 425.30 [M+H]⁺.

Intermediate 15

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

l-2g (1 .30 g, 4.03 mmol) was reacted with l-9d (1 .46 g, 4.03 mmol) according to the general method for N-alkylation, which gave the title compound (1 .8 g, 80%) as a solid.

MS (ES+) 541 .19 & 543.21 [M+H]⁺.

Step b) tert-butyl 1 '-((7-fluoro-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (1-15b)

Compound 1-15a (800 mg, 1 .48 mmol) was reacted with 4-(tributylstannyl)pyridazine according to the general method for Stille coupling, using an oil bath at 130 °C for heating, which gave the title compound (700 mg, 75%). MS (ES+) 541 .27 [M+H]⁺.

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

4.0 M in dioxane HCI (7 mL) was added to a solution of 1-15b (700 mg, 1 .1 1 mmol) in DCM (20 mL). The solution was stirred at rt for 90 min, then concentrated under reduced pressure and the obtained material was diluted with water (50 mL) and washed with DCM (3 x 50 mL). The aqueous layer was basified with aqueous sodium bicarbonate solution and extracted with DCM (2 x 60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, which gave the title compound (450 mg) as a solid. MS(ES+) 441 .18

[M+H]⁺.

Intermediate 16

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

Compound l-3f (449 mg, 1 .64 mmol) was reacted with 4-bromo-3-(bromomethyl)isoquinoline (493 mg, 1 .64 mmol) according to the general method for N-alkylation, which gave the title compound (750 mg, 93%). MS (ES+) 496.1 [M+H]⁺.

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)

4-Bromo-3-(bromomethyl)isoquinoline (107 mg, 0.356 mmol) was reacted with 1-1 Od (140 mg, 0.356 mmol) according to the general method for N-alkylation, which gave the title compound (170 mg, 96%). MS (ES+) 495.2.

Intermediate 18

Step a) 1 -(methylsulfonvnspiro[azetidine-3,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (1-18)

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 19

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

Compound l-2g (633mg, 2.09 mmol) was reacted with l-8b (700 mg, 2,09 mmol) according to General method A Step a, using DMF as solvent. The reaction mixture was extracted between EtOAc and H₂0 and the aq. phase further extracted with EtOAc (x 2) prior to purification by column, which gave the title compound (843 mg, 72 %). MS (ES+) 559.33 [M+H]⁺.

Step b) Tert-butyl 1 '-((7-chloro-4-(pyridazin-4-yl)isoauinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (1-19b)

Compound 1-19a (500 mg, 0.896 mmol) was coupled with 4-(tributylstannyl)pyridazine according to the general method for Stille coupling using sodium carbonate as base, oil bath at 80 C as heating method, which gave the title compound (180 mg, 35%) MS (ES+) 559.04 [M+H]⁺.

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

4 M HCI in 1 ,4-dioxane (3 mL, 12 mmol) was added dropwise at rt under nitrogen to a stirred solution of 1-19b (180 mg, 0.276 mmol) in DCM (3 mL). The resulting mixture was stirred for 1 h at rt, then concentrated under reduced pressure and dried under high vacuum which gave the title compound (138 mg) as a solid. The compound was used in the next step without further purification. 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-fluoroisoauinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (1-21 a)

Compound 1-1 Od (460 mg, 1 .67 mmol) (633mg, 2.09 mmol) was reacted with l-9d (700 mg, 2,09 mmol) according to General method A Step a, using DMF as solvent. The reaction mixture was extracted between EtOAc and NH₄CI (aq) and the aq. phase further extracted with EtOAc (x3) prior to purification by column, which gave the title compound (650 mg, 76%). MS (ES+) 515.29 [M+H]⁺.

Step b) 1 '-((4-bromo-7-fluoroisoquinolin-3-yl)methyl)spiro[azetidine-3,3'-pyrrolo[2,3-clpyridinl- 2'(1 'H)-one (1-21 b)

TFA (10 mL, 131 mmol) was added at rt under nitrogen to a stirred solution of 1-21 a (1 .7 g, 3.31 mmol) in DCM (20 mL). The solution was stirred at rt for 1 h, then concentrated, diluted with water (30 mL) and washed with DCM (2 x 15 ml). The aqueous layer was neutralized with saturated sodium bicarbonate solution (10 mL) and 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 title compound (1 .0 g) as a solid. MS (ES+) 415.25

[M+H]. Intermediate 22

Step a) tert-butyl 1 -bromo^-chloroisoquinolin-S-vOmethvO^'-oxo-l '^'- dihvdrospirofazetidine-S.S'-pyrrolo^.S-clpyridinel-l -cafo^ (l-22a)

Compound 1-1 Od (2.0 g, 7.26 mmol) was reacted with l-8b (2.5 g, 7.45 mmol) according to General method for N-alkylation. When the reaction was deemed complete, the reaction mixture was extracted between 5% MeOH in DCM (3x 100 mL) and H₂0 and the aq. phase further extracted with EtOAc. 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-(pyridazin-4-yl)isoauinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihvdrospiro[azetidine-3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (l-22b)

Compound l-22a (50 mg, 0.094 mmol) was coupled with 4-(tributylstannyl)pyridazine according to the general method for Stille coupling using sodium carbonate as base, oil bath at 100 °C as heating method, which gave the title compound (60 mg, 36%) MS (ES+) 529.25 [M+H]⁺.

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

TFA (2 mL, 26.1 mmol) was added at 0 °C to a solution of l-22b (300 mg, 0.567 mmol) in DCM (5 mL). The resulting mixture was stirred at rt for 2 h, sodium bicarbonate (aq) was added until pH 8 was reached and the mixture was extracted with DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The obtained solid was triturated with diethyl ether (2 x 5 mL) and dried which gave the title compound (0.2 g, 76%). MS (ES+) 429.1

[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 I- 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 (3.0 g, 89%) as a solid.

MS (ES+) 189.15 [M+H]⁺.

Intermediate 24

Step a) 1 -(methylsulfonvnspiro[azetidine-3,3'-pyrrolo[2,3-clPyridinl-2'(1 'H)-one (I-24)

1 )TFA (4.0 mL, 52 mmol) was added at rt to a stirred solution 1-1 Od (1 .5 g mg, 4.7 mmol) in

DCM (10 mL). The solution was stirred at rt for 2 h, then concentrated under reduced pressure.

2) The residue was dissolved in DMF (15 mL) and triethylamine (3.7 mL, 26 mmol) and methyl chloroformate (590 mg, 6.2 mmol) were added at 0 °C. The resulting reaction mixture was stirred at 0 °C for 1 h, then diluted with ice water (50 mL), and extracted with EtOAc (5 x 50 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 MeOH:DCM, which gave the title compound (800 mg, 42%) as a liquid.

MS (ES+) 234.06 [M+H]⁺. Example 1

Step b) 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 0°C. 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-(pyridazin-4-yl)isoauinolin-3-yl)methyl)spiro[azetidine-3,3'-indolinel- 1 -carboxylate (1 b)

Compound 1 a (1 .0 g, 2.21 mmol) was reacted with 4-(tributylstannyl)pyridazine according to the general method for Stille coupling, using an oil bath at 130 °C for heating. Subsequent to column chromatography the afforded solid was triturated in acetonitrile at 80 °C (x4), which gave the title compound (325 mg, 33%). MS (ES+) 452.39 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cf₆) δ 3.63 (s, 3H), 4.01 (dd, 4H), 4.93 (d, 1 H), 5.07 (d, 1 H), 6.75 (d, 1 H), 7.06 (t, 1 H), 7.18 (t, 1 H), 7.24 (m, 2H), 7.63 (d, 1 H), 7.75 (p, 2H), 7.83 (dd, 1 H), 8.24 (dd, 1 H), 9.18 (s, 1 H), 9.41 (m, 1 H), 9.42 (s, 1 H).

¹³C NMR (126 MHz, DMSO-cQ δ 41.77, 44.26, 51.98, 57.23, 109.27, 122.60, 123.23, 123.51 , 124.91 , 126.90, 127.58, 127.80, 127.98, 128.62, 129.15, 131 .87, 134.01 , 134.29, 142.79, 145.75, 151 .47, 151.66, 153.01 , 156.05, 175.81 . Example 2

Step a) 1 '-((4-Bromoisoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperidine-4,3'-pyrrolo[2,3- clpyridinl-2'(1 'H)-one (2a)

Triethylamine (2 mL) followed by methanesulfonyl chloride (0.5 mL, 6.0 mmol) were added at 0 °C to a solution of 1-14b (2 g, 5.0 mmol) in DCM (25 mL), the resulting mixture was stirred at rt for 3 h, then diluted with water (50 mL) and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The obtained solid was triturated with diethyl ether (20 mL) and dried in vacuo which gave the title compound (1 .8 g, 64%) as a solid. MS (ES+) 501 .08 & 503.06 [M+H]⁺.

Step b) 1 -(MethylsulfonvD-1 '-((4-(pyridazin-4-yl)isoguinolin-3-yl)methyl)spiro[piperidine-4,3'- pyrrolo[2,3-clpyridinl-2'(1 'H)-one (2b)

Compound 2a (250 mg, 0.422 mmol) was reacted according to the general method for Stille coupling, using Na₂C0₃ as base, heating at 100 °C by microwave irradiation and 1 h reaction time. Subsequent to silica flash chromatography, the compound was further purified by C18 HPLC, which gave the title compound (67 mg, 31 %). MS (ES+) 501 .16 [M+H]⁺.

¹ H NMR^* (500 MHz, DMSO-cf₆) δ 1.78 (tt, 2H), 1.91 (ddt, 2H), 2.97 (s, 3H), 3.41 (m, 4H), 4.97 (s, 1 H), 5.02 (s, 1 H), 7.32 (dd, 1 H), 7.60 (d, 1 H), 7.77 (dqd, 2H), 7.99 (dd, 1 H), 8.22 (m, 1 H), 8.24 (s, 1 H), 8.29 (d, 1 H), 9.38 (s, 1 H), 9.42 (dd, 1 H), 9.49 (dd, 1 H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 31.65, 34.98, 41.09, 41.1 1 , 43.83, 44.19, 119.00, 124.18, 125.67, 127.51 , 128.37, 128.55, 131 .02, 132.46, 134.54, 134.86, 139.91 , 141 .66, 144.48, 146.20, 152.17, 152.67, 153.62, 177.80.

Example 3

Step a) Tert-butyl (1 -(1 '-((4-bromoisoauinolin-3-vnmethvn-2'-oxo-1 ',2'-dihvdrospiro[piperidine- 4,3'-pyrrolo[2,3-clpyridinl-1 -ylcarbonvncvclopropyncarbamate (3a)

A solution of 1 -((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (1 .3 g, 6.4 mmol) triethylamine (1 .7 mL, 12 mmol), HATU (3.1 g, 8.0 mmol) in DMF (20 mL), was stirred at 0 °C under nitrogen for 30 minutes, then 1-14b (1 .7 g, 4.0 mmol) was added in portions over a period of 2 minutes at 0 °C. The resulting reaction was stirred at rt for 16 h, then diluted with ice cold water (150 mL) and the stirring was continued for 10 min. The formed solid was collected and dried and triturated with diethyl ether (50 mL), stirred for 15 minutes, filtered and dried which gave the title compound (2.0 g, 80 %) as a solid. ME (ES+) 606.18 & 608.16 [M+H]⁺.

Step b) Tert-butyl (1 -(2'-oxo-1 '-((4-(pyridazin-4-yl)isoauinolin-3-yl)methyl)-1 ',2'- dihvdrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-1 -ylcarbonyl)cvclopropyl)carbamate (3b)

Compound 3a (300 mg, 0.480 mmol) was reacted according to the general method for Stille coupling, using K₂C0₃ as base, heating at 100 °C by microwave irradiation and 1 h reaction time, which gave the title compound (120 mg, 40%). MS (ES+) 501 .16 [M+H]⁺.

Step c) 1 -(1 -Aminocvclopropanecarbonyl)-1 '-((4-(pyridazin-4-yl)isoquinolin-3- yl)methyl)spiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (3b)

To a stirred solution of compound 3b (100 mg, 0.165 mmol) in DCM (5 mL), was added 4M HCI in 1 ,4-dioxane (0.9 mL) under nitrogen at rt. The resulting reaction mixture was stirred at rt for 1 h, then concentrated under reduced pressure and co-evaporated with DCM : toluene 1 :2. The afforded crude compound was purified by prep C18 HPLC, which gave the title compound as a solid (52 g, 61 %). MS (ES+) 506.45 [M+H]⁺.

¹ H NMR^* (500 MHz, DMSO-cf₆) δ 0.66 (q, 2H), 0.88 (q, 2H), 1.69 (d, 2H), 1.75 (s, 2H), 2.30 (s, 2H), 3.79 (s, 2H), 3.92 (s, 2H), 4.97 (d, 1 H), 5.04 (d, 1 H), 7.32 (d, 1 H), 7.58 (d, 1 H), 7.77 (dq, 2H), 7.98 (dd, 1 H), 8.25 (m, 3H), 9.41 (d, 2H), 9.48 (d, 1 H).

¹³C NMR^* (126 MHz, DMSO-cf₆) δ 14.30, 29.41 , 31.83, 36.88, 43.91 , 45.29, 118.94, 124.20, 125.79, 127.52, 128.38, 128.55, 130.98, 132.46, 134.56, 134.86, 139.81 , 142.03, 144.46, 146.26, 152.14, 152.67, 153.59, 171 .78, 178.00.

Example 4

Step a) Tert-butyl 2'-oxo-1 W^-fpyridazin^-vOisoquinolin-S-vOmethvO-l '^'- dihvdrospirofpiperidine^.S'-pyrrolo^.S-clpyridinel-l ^^ (4a)

Compound 1-14a (350 mg, 0.631 mmol) was reacted according to the general method for Stille coupling, using K₂C0₃ as base, heating at 100 °C by microwave irradiation and 1 h reaction time, which gave the title compound (180 mg, 50%). MS (ES+) 523.23 [M+H]⁺.

Step b) 1 '-((4-(Pyridazin-4-yl)isoguinolin-3-yl)methyl)-1 -((2,2,2- trifluoroethyl)sulfonyl)spiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (4b)

TFA (1 mL) was added at rt under nitrogen to a stirred solution of compound 4a (160.00 mg) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated under vacuum. The afforded residue was washed with 50% diethyl ether in pentane (2x25 mL) which gave a solid which was dried under vacuum. The obtained solid and triethylamine (0.2 mL, 1 .44 mmol) were dissolved in dry DCM (5 mL). The solution was cooled to 0 °C and 2,2,2- trifluoroethanesulfonyl chloride (208 mg, 1 .14 mmol) was added. After 10 min at 0°C, the reaction mixture was allowed to attain rt and was stirred at rt for 1 h. The residue was diluted with DCM (30 mL) and washed with water (20 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated and the residue was purified by prep C18 HPLC. Appropriate fractions were pooled and concentrated and the residue was dissolved in DCM (20 mL) and washed with water (2x20 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated, diluted with MeCN and water (15 mL) and lyophilized, which gave the title compound (17 mg, 1 1 %) as a solid. MS (ES+) 569.13 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cf₆) δ 1.79 (dtd, J = 15.2, 9.1 , 7.2, 4.4 Hz, 2H), 1.89 (ddt, J = 13.1 , 8.5, 4.1 , 4.1 Hz, 2H), 3.52 (m, 2H), 3.60 (ddt, J = 13.0, 8.9, 4.2, 4.2 Hz, 2H), 4.61 (q, J = 10.1 , 10.1 , 10.1 Hz, 2H), 4.97 (m, 2H), 7.33 (dd, J = 8.2, 1 .4 Hz, 1 H), 7.59 (d, J = 4.8 Hz, 1 H), 7.77 (m, 2H), 7.99 (dd, J = 5.2, 2.3 Hz, 1 H), 8.22 (dd, J = 7.6, 1 .9 Hz, 1 H), 8.24 (s, 1 H), 8.30 (d, J = 4.7 Hz, 1 H), 9.38 (s, 1 H), 9.43 (s, 1 H), 9.49 (dd, J = 5.2, 1 .2 Hz, 1 H).

¹³C NMR (126 MHz, DMSO-cQ δ 31.15, 31.19, 40.36, 43.25, 43.64, 50.73 (q, J = 30.0, 29.7, 29.7 Hz), 1 18.37, 122.64 (q, J = 277.2 Hz), 123.61 , 125.10, 126.93, 127.80, 127.98, 130.51 , 131 .89, 133.95, 134.28, 139.33, 140.89, 143.92, 145.58, 151 .58, 152.10, 153.05, 177.12.

Example 5

Methyl 1 '-((7Tluoro-4-(pyridazin-4-v0isoguinolin-^

4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (5)

Triethylamine (0.3 ml_, 2.04 mmol) and methyl chloroformate (0.05 ml_, 0.51 1 mmol) were added at 0 °C to a stirred solution of compound 1-15c (225 mg, 0.51 1 mmol) in DCM (15 ml_). The resulting reaction mixture was stirred at rt for 1 h then poured into ice water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained crude compound was purified by prep C18 HPLC using 10mM ammonium bicarbonate in H₂0:acetonitrile as mobile phase, followed by further purification by SFC, which gave the title compound (48 mg, 19%) as a solid. MS(ES+) 499.42 [M+H].

Preparative SFC Conditions

Column Chiralpak-ASH (250 X21 ) mm, 5μ

C0₂ 70.0%

Co-solvent 30.0% (100% MeOH)

Total Flow 60.0 g/min

Back Pressure 100.0 bar

UV 217 nm

Stack time 7.2min

Load/lnj 6.0 mg

Solubility 15 ml. of MeOH

¹ H NMR (500 MHz, DMSO-cf₆) δ 1.63 (ddt, 2H), 1.74 (dq, 2H), 3.64 (s, 3H), 3.68 (dt, 4H), 4.95 (d, 1 H), 5.02 (d, 1 H), 7.41 (dd, 1 H), 7.59 (d, 1 H), 7.70 (td, 1 H), 7.98 (dd, 1 H), 8.04 (dd, 1 H), 8.23 (s, 1 H), 8.26 (d, 1 H), 9.37 (s, 1 H), 9.42 (m, 1 H), 9.48 (dd, 1 H).

¹³C NMR (126 MHz, DMSO-cQ δ 30.96, 38.51 , 43.18, 44.34, 52.28, 1 1 1 .06 (d), 1 18.42, 122.05 (d), 125.34, 127.26 (d), 127.84, 127.92, 130.40, 131 .32, 133.97, 139.16, 141 .27, 143.90, 145.37 (d), 151 .57, 151 .96, 152.31 (d), 155.05, 160.30 (d), 177.25.

Example 6

1 '-((7-fluoro-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperidine-4,3'- pyrrolo[2,3-clPyridinl-2'(1 'H)-one (6) Triethyl amine (0.24 ml_, 1 .53 mmol) and methanesulfonyl chloride (0.1 1 ml_, 1 .53 mmol) were added at 0 °C to a stirred solution of compound 1-15c (225 mg, 0.51 1 mmol) in DCM (15 ml). The solution was stirred for 1 h at rt, then poured into ice cold water (30 mL) and extracted with DCM (2 x 30 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 (60 mg, 22%) as a solid. MS (ES+), 519.41 [M+H].

¹ H NMR^* (500 MHz, DMSO-cf₆) δ 1.78 (ddd, 2H), 1.91 (ddt, 2H), 2.97 (s, 3H), 3.41 (m, 2H), 3.44 (s, 2H), 4.96 (s, 1 H), 5.01 (s, 1 H), 7.42 (dd, 1 H), 7.60 (m, 1 H), 7.70 (td, 1 H), 7.99 (dd, 1 H), 8.04 (dd, 1 H), 8.24 (s, 1 H), 8.29 (d, 1 H), 9.36 (s, 1 H), 9.43 (dd, 1 H), 9.49 (dd, 1 H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 31.65, 35.00, 41.08, 41.10, 43.69, 44.20, 11 1.56, 1 11.73, 1 19.01 , 122.54, 122.74, 125.81 , 127.79, 127.86, 128.41 , 128.48, 128.51 , 130.99, 131 .88, 134.56, 139.85, 141.66, 144.50, 145.90, 145.92, 152.18, 152.54, 152.89, 152.93, 159.89, 161 .86, 177.79.

Example 7

Step a) 1 '-((4-Bromo-7-fluoroisoguinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cvclopropanecarbonyl)spiro[azetidine-3,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (7a) HATU (280 mg, 0.726 mmol) and triethylamine (0.22 mL, 1 .21 mmol) were added at 0 °C to a stirred solution of 1 -(trifluoromethyl)cyclopropanecarboxylic acid (140 mg, 0.907 mmol) in DMF (2.5 mL). The solution was stirred for 30 min, then a solution of 1-21 b (250 mg, 0.605 mmol) in DMF (2.5 mL) was added and resulting reaction mixture was stirred at rt for 2 h. Cold water (30 ml) was added and the mixture was extracted ethyl acetate (2 x 50 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 title compound (300 mg, 85%) was used in the next step without further purification. MS (ES+) 551 .05 [M+H]⁺.

Step b) 1 '-((7-Fluoro-4-(pyridazin-4-yl)isoguinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cvclopropanecarbonyl)spiro[azetidine-3,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (7b) Compound 7a (250 mg, 0.455 mmol) was reacted with 4-(tributylstannyl)pyridazine according to the general method for Stille coupling, using an oil bath at 120 °C for heating and 16 h reaction time. Instead of column chromatography the afforded crude was purified by prep C18 HPLC, which gave the title compound (63 mg, 25%) as a solid. MS (ES+) 549.22 [M+H]⁺. ¹ H NMR^* (500 MHz, DMSO-cf₆) δ 1.23 (q, 3H), 1.26 (s, 1 H), 4.13 (s, 1 H), 4.38 (s, 2H), 5.07 (s, 1 H), 7.37 (dd, 1 H), 7.71 (m, 3H), 7.91 (dd, 1 H), 8.07 (dd, 1 H), 8.16 (s, 1 H), 8.36 (d, 1 H), 9.28 (dd, 1 H), 9.42 (s, 1 H), 9.44 (dd, 1 H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 25.97, 26.23, 41.73, 44.21 , 1 1 1 .06, 1 1 1 .23, 1 18.40, 122.03, 122.24, 124.18, 125.33, 126.36, 127.28, 127.35, 127.72, 127.93, 128.00, 130.29, 131 .39, 134.00, 137.42, 139.94, 144.59, 145.18, 145.20, 151 .57, 151 .76, 152.38, 152.42, 159.39, 161 .37, 163.94, 175.13.

Example 8

1 '-((7-Chloro-4-(pyridazin-4-v0isoguinolin-3-v0^

pyrrolo[2,3-clPyridinl-2'(1 'H)-one (8)

Triethylamine (0.4ml_, 2.878 mmol) and methanesulfonyl chloride (40 mg, 0.349 mmol) were added at 0 °C under nitrogen to a stirred suspension of 1-19c (138 mg, 0.280 mmol) in DCM (5 mL). The resulting mixture was stirred at rt for 1 h, then diluted with DCM (40 mL), and washed with water (2 X 30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by prep C18 HPLC (1 10 mM Ammonium bicarbonate in H₂0:acetonitrile. Appropriate fractions were pooled and concentrated further purified by prep C18 HPLC. Pure fractions were pooled, concentrated and taken in sodium bicarbonate (5 mL) and stirred for 2 min. The solid obtained was collected by filtration, washed with water (3 x10 mL) and dried under high vacuum which gave the title compound (56 mg, 37%) as a solid. MS (ES+) 535.10 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cf₆) δ 1.79 (tt, 2H), 1.91 (ddt, 2H), 2.97 (s, 3H), 3.42 (ddt, 4H), 4.99 (m, 2H), 7.37 (d, 1 H), 7.60 (m, 1 H), 7.79 (dd, 1 H), 8.00 (dd, 1 H), 8.23 (s, 1 H), 8.29 (d, 1 H), 8.37 (d, 1 H), 9.36 (s, 1 H), 9.44 (dd, 1 H), 9.50 (dd, 1 H).

¹³C NMR (126 MHz, DMSO-cQ δ 31.07, 34.40, 40.52, 43.12, 43.62, 1 18.44, 125.13, 126.26, 126.62, 127.60, 127.95, 130.41 , 132.1 1 , 132.26, 132.53, 133.78, 139.26, 141 .06, 143.94, 146.22, 151 .62, 151.97, 152.22, 177.26. Example 9

Methyl 1'-((7-chloro-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-2'-oxo-1\2'-dihvdrospiro[azetid 3,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (9)

Triethylamine (0.6 ml_, 4.30 mmol) was added at 0 °C To a stirred solution of l-22c (250 mg, 0.583 mmol) in DCM (20 ml_). After 30 min methyl chloroformate (0.1 ml_, 1.29 mmol) was added at 0°C under nitrogen. The resulting reaction mixture was stirred at rt for 2 h, then concentrated and diluted with cold water (20 ml_). The thus formed solid was filtered off and dried under vacuum and purified by prep C18 HPLC. Pure fractions were pooled, concentrated under reduced pressure and diluted with water (20 ml_). The formed solid was filtered off and dried under vacuum which gave the title compound (147 mg, 52%) as a solid. MS (ES+) 487.28 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) δ 9.43 (dd, J= 5.2, 1.3 Hz, 1H), 9.41 (d, J= 0.8 Hz, 1H), 9.27 (dd, J= 2.3, 1.3 Hz, 1H), 8.39 (d, J= 2.2 Hz, 1H), 8.35 (d, J=4.7 Hz, 1H), 8.12 (d, J= 0.8 Hz, 1H), 7.89 (dd, J= 5.2, 2.3 Hz, 1H), 7.77 (dd, J= 9.1, 2.3 Hz, 1H), 7.74 (dd, J= 4.7, 0.9 Hz, 1H), 7.31 (d, J=9.1 Hz, 1H),5.08(d, J= 16.0 Hz, 1 H), 4.95 (d, J= 16.0 Hz, 1H), 4.56 (t, J=5.5 Hz, 1 H), 4.10 (s, 1 H), 3.98 (s, 1 H), 3.63 (s, 2H), 3.48 (s, 1 H), 3.45 - 3.39 (m, 1 H), 2.07 (s, OH), 1.70 (d, J= 12.2 Hz, OH), 1.63 (s, OH), 1.55 (s, OH), 1.53 - 1.45 (m, OH), 1.43 (td, J= 6.8, 2.6 Hz, OH), 1.23 (s, OH), 1.18-1.09 (m, 1H), 0.93 (d, J=8.9 Hz, OH).

¹³C NMR (126 MHz, DMSO-cfe) δ 175.14, 156.00, 152.24, 151.68, 151.51, 146.04, 144.54, 139.79, 137.64, 133.74, 132.58, 132.28, 132.20, 130.18, 127.65, 127.63, 126.64, 126.26, 125.18, 118.38, 72.14, 60.11 , 57.13 - 56.00 (m), 52.01,44.20, 41.67.

Example 1

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

(trifluoromethyl)cvclopropanecarbonyl)spiro[azetidine-3,3'-pyrrolo[2,3-clpyridinl-2'(1'H)-one (10) HATU (332 mg, 0.874 mmol) and DIEA (230 mg) were added at 0 °C to a solution of 1 - (trifluoromethyl)cyclopropanecarboxylic acid (109 mg, 0.705 mmol) in DMF (5 mL). The resulting mixture was stirred for 10 min, then l-22c (250 mg, 0.583 mmol) was added and the mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (30 mL) and the aqueous layer was extracted with ethyl acetate (2 x 15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated, the obtained crude compound was purified by prep C18 HPLC and then further purified by SFC and lyophilized, which gave the title compound (95 mg, 29%) as a solid. MS (ES+) 565.21 [M+H]⁺.

¹ H NMR^* (500 MHz, DMSO-cf₆) δ 1.23 (s, 2H), 1.37 (s, 1 H), 4.13 (s, 2H), 4.38 (s, 3H), 5.07 (s, 1 H), 7.32 (d, 1 H), 7.77 (m, 2H), 7.91 (dd, 1 H), 8.15 (s, 1 H), 8.37 (d, 1 H), 8.40 (d, 1 H), 9.29 (s, 1 H), 9.41 (s, 1 H), 9.44 (d, 1 H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 8.33, 25.96, 26.23, 41.73, 44.21 , 1 18.41 , 124.18, 125.22, 126.31 , 126.35, 126.69, 127.68, 127.74, 130.29, 132.25, 132.34, 132.63, 133.80, 137.40, 139.93, 144.60, 146.08, 151 .58, 151 .77, 152.29, 163.95, 175.18.

Example 1

1 '-((7-Chloro-4-(pyridazin-4-yl)isoguinolin-3-yl)methyl)-1 -(1 -

(trifluoromethyl)cvclopropanecarbonyl)spiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1 'H)-one (1 1 ) HATU (125 mg, 0.328 mmol), DIEA (0.5 mL, 2.86 mmol) and 1-19c (250 mg, 0.583 mmol) were added at 0 °C to a solution of 1 -(trifluoromethyl)cyclopropanecarboxylic acid (42 mg, 0.262 mmol) in DMF (10 mL). The mixture was stirred at rt for 16 h, then diluted with cold water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The obtained crude compound was purified by prep C18 HPLC. Appropriate fractions were pooled and stirred with saturated aqueous sodium

bicarbonate (5 mL). The thus formed solid was filtered off, washed with water (10 mL) and dried, which gave the title compound (52 mg, 54%) as a solid. MS (ES+) 565.21 [M+H]⁺.

¹ H NMR^* (500 MHz, DMSO-cf₆) δ 1.30 (d, 5H), 1.69 (s, 2H), 1.79 (s, 2H), 3.93 (dt, 2H), 4.98 (s, 1 H), 5.02 (s, 1 H), 7.36 (d, 1 H), 7.59 (d, 1 H), 7.79 (dd, 1 H), 7.99 (dd, 1 H), 8.24 (s, 1 H), 8.28 (d, 1 H), 8.37 (d, 1 H), 9.37 (s, 1 H), 9.43 (m, 1 H), 9.49 (dd, 1 H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 9.82, 26.29, 26.55, 26.81 , 31.1 1 , 43.28, 44.44, 1 18.42, 124.34, 125.31 , 126.33, 126.51 , 126.67, 127.66, 127.99, 130.50, 132.18, 132.30, 132.60, 133.82, 139.21 , 141.10, 144.02, 146.28, 151 .63, 152.02, 152.25, 162.78, 177.31 .

Example 12

Methyl 1 '-((7-chloro-4-(pyridazin-4-yl)isoquinolin-3-yl)metriyl)-2'-oxo-1 ',2'- dihydrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (12)

Triethylamine (0.3 mL, 2.15 mmol) was added at 0 °C under nitrogen to a solution of 1-19c (250 mg, 0.507 mmol) in DCM (8 mL). The solution was stirred for 30 min at rt, then a stock solution of methyl chloroformate (0.06 mL, 0.777 mmol) in DCM was added. The resulting reaction mixture was stirred at rt for 1 h, then diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude compound was purified by Prep C18 and then further purified by preparative SFC, which gave the title compound (13 mg, 5.0 %). MS (ES+) 515.4 [M+H]⁺.

¹ H NMR^* (500 MHz, DMSO-cf₆) δ 1.63 (ddt, 2H), 1.74 (tt, 2H), 3.65 (m, 7H), 4.97 (s, 1 H), 7.36 (d, 1 H), 7.60 (d, 1 H), 7.78 (dd, 1 H), 7.99 (dd, 1 H), 8.22 (s, 1 H), 8.27 (d, 1 H), 8.37 (d, 1 H), 9.37 (s, 1 H), 9.43 (t, 1 H), 9.48 (dd, 1 H).

¹³C NMR^* (126 MHz, DMSO-cf₆) δ 30.99, 38.55, 43.23, 44.39, 52.32, 1 18.47, 125.27, 126.31 , 126.66, 127.65, 127.98, 130.44, 132.16, 132.29, 132.59, 133.81 , 139.18, 141 .30, 143.96, 146.29, 151 .63, 152.01 , 152.24, 155.09, 177.34.

Example 13

1 '-((7-Methyl-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[piperidine-4,3'- pyrrolo[2,3-clPyridinl-2'( 1 'H)-one ( 13) 1-20 and 1-13d were reacted according to the general method for N-alkylation. Purification was performed by extraction with EtOAc followed by prep C18 HPLC and SFC instead of silica gel column chromatography. Yield 53%. MS (ES+) 515.5 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cf₆) δ 1.78 (ddt, 2H), 1.90 (ddt, 2H), 2.97 (s, 3H), 3.42 (m, 4H), 4.97 (m, 2H), 7.23 (d, 1 H), 7.60 (d, 1 H), 7.63 (dd, 1 H), 7.96 (dd, 1 H), 7.98 (s, 1 H), 8.23 (s, 1 H), 8.29 (d, 1 H), 9.28 (s, 1 H), 9.40 (d, 1 H), 9.48 (d, 1 H).

¹³C NMR (126 MHz, DMSO-cf₆) δ 20.94, 31 .05, 34.39, 40.50, 43.17, 43.59, 1 18.40, 123.48, 124.95, 126.46, 127.17, 127.91 , 130.43, 132.27, 133.94, 134.38, 137.52, 139.32, 141 .05, 143.86, 144.76, 151.57, 152.07, 152.31 , 177.17.

Example 14

Methyl 1 '-((7-methyl-4-(pyridazin-4-vnisoquinolin-3-vnmethvn-2'-oxospiro[azetidine-3,3'- indolinel-1 -carboxylate (14)

l-3e and 1-13d were reacted according to the general method for N-alkylation. Purification was performed by prep C18 HPLC and SFC instead of silica gel column chromatography. Yield 20%. MS (ES+) 466.24 [M+H]⁺.

¹ H NMR^* (500 MHz, DMSO-cf₆) δ 3.63 (s, 4H), 4.93 (s, 1 H), 5.04 (s, 1 H), 5.07 (s, 1 H), 6.73 (d, 1 H), 7.06 (td, 2H), 7.16 (m, 3H), 7.61 (m, 3H), 7.81 (dd, 1 H), 8.00 (s, 1 H), 9.14 (dd, 1 H), 9.32 (s, 1 H), 9.40 (dd, 1 H).

¹³C NMR^* (126 MHz, DMSO-cf₆) δ 20.98, 41.80, 44.25, 52.02, 109.31 , 122.61 , 123.26, 123.44, 124.83, 126.53, 127.19, 127.56, 128.64, 129.19, 132.37, 133.97, 134.43, 137.59, 142.84, 144.95, 151 .51 , 151.67, 152.34, 156.08, 175.80.

Example 15

Methyl 1 '-((7-methyl-4-(pyridazin-4-v0isoauinoli^

3, 3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (15)

I-26 and 1-13d were reacted according to the general method for N-alkylation. Subsequent to silica gel column chromatography, the compound was further purified by prep C18 HPLC followed by wash with aqueous NaHC0₃ (x1 ) and water (x2). Yield 14%. MS (ES+) 467.41 [M+H]⁺.

¹ H NMR^* (500 MHz, DMSO-cf₆) δ 3.17 (q, 3H), 3.46 (t, 1 H), 3.53 (d, 1 H), 3.67 (s, 3H), 4.08 (t, 2H), 4.19 (m, 2H), 4.98 (d, 1 H), 5.09 (d, 1 H), 7.21 (d, 1 H), 7.62 (d, 1 H), 7.87 (dd, 1 H), 7.99 (s, 1 H), 8.13 (d, 1 H), 8.19 (s, 1 H), 8.47 (s, 1 H), 8.57 (d, 1 H), 9.27 (d, 2H), 9.45 (d, 1 H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 20.80, 28.89, 42.13, 44.15, 51.86, 56.33, 60.1 1 , 72.05, 1 19.81 , 123.39, 125.09, 125.34, 126.43, 127.15, 127.24, 127.88, 132.38, 133.90, 134.52, 137.76, 140.42, 142.02, 143.93, 151 .28, 151 .78, 152.23, 155.97, 174.71 .

Example 16

Methyl 1 '-((7-methyl-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[piperidine-4,3'-pyrrolo[2,3-clpyridinel-1 -carboxylate (16)

Triethylamine (0.75 ml, 5.396 mmol) and methyl chloroformate (60 mg, 0.63 mmol) were added at 0 °C under nitrogen to a stirred suspension of 1-13f (240 mg, 0.507 mmol) in DCM (5 mL). The resulting reaction mixture was stirred at rt for 90 min, then poured in ice cold water (30 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated under vacuo. The crude compound was purified by Prep C18 HPLC , which gave the title compound (75 mg, 29%) as a solid. MS (ES+) 495.43 [M+H]⁺.

¹ H NMR^* (500 MHz, DMSO-cf₆) δ 1.62 (s, 2H), 1.73 (m, 3H), 2.51 (s, 2H), 3.63 (s, 1 H), 3.68 (dt, 3H), 4.95 (s, 1 H), 7.22 (d, 1 H), 7.61 (m, 2H), 7.96 (m, 2H), 8.22 (s, 1 H), 8.26 (d, 1 H), 9.29 (s, 1 H), 9.38 (dd, 1 H), 9.46 (dd, 1 H).

¹³C NMR^* (126 MHz, DMSO-cf₆) δ 20.99, 30.98, 38.55, 43.31 , 44.37, 52.32, 1 18.44, 123.55, 125.12, 126.51 , 127.23, 127.96, 130.47, 132.34, 133.98, 134.42, 137.59, 139.26, 141 .30, 143.90, 144.85, 151.59, 152.12, 152.34, 155.09, 177.25. Example 1

1 '-((7-Methyl-4-(pyridazin-4-yl)isoquinolin-3-yl)metriyl)-1 -(1 -

(trifluoromethvncvclopropanecarbonvnspiro[piperidine-4,3'-pyrrolo[2,3-clpyridinl-2'(1 'l-l)-one (17) To a stirred solution of 1 -(trifluoromethyl)cyclopropanecarboxylic acid (88 mg, 0.56 mmol) in DMF (10 mL) was added HATU (275 mg, 0.72 mmol), DIEA (1 .1 ml, 6.298 mmol) and 16- AF2449_1 (225 mg, 0.471 mmol) at 0 °C. The resulting reaction mixture was stirred at rt for 3 h, then diluted with cold water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The afforded crude was purified by Prep C18 HPLC which gave the title compound (65 mg, 24%) as a solid. MS (ES+) 573.32 [M+H]⁺.

¹ H NMR^* (500 MHz, DMSO-cf₆) δ 1.26 (s, 2H), 1.33 (s, 2H), 1.68 (s, 2H), 1.78 (s, 2H), 2.52 (s, 3H), 3.78 (s, 2H), 3.92 (dq, 2H), 5.01 (s, 1 H), 7.23 (d, 1 H), 7.58 (m, 1 H), 7.63 (dd, 1 H), 7.96 (dd, 1 H), 7.99 (m, 1 H), 8.24 (s, 1 H), 8.28 (d, 1 H), 9.30 (s, 1 H), 9.38 (dd, 1 H), 9.47 (dd, 1 H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 9.82, 20.99, 26.29, 26.56, 26.82, 27.08, 31.12, 43.36, 44.42, 1 18.38, 123.55, 124.33, 125.15, 126.52, 127.24, 127.96, 130.53, 132.35, 133.99, 134.43, 137.61 , 139.27, 141.1 1 , 143.95, 144.84, 151 .59, 152.12, 152.35, 162.78, 177.22.

Example 18

1 '-((7-Methyl-4-(pyridazin-4-yl)isoauinolin-3-yl)methyl)-1 -(methylsulfonyl)spiro[azetidine-3,3'- indolinl-2'-one (18)

I-4 and 1-13d were reacted according to the general method for N-alkylation. Subsequent to silica gel column chromatography, the compound was further purified by prep C18 HPLC Yield 36%. MS (ES+) 486.38 [M+H]⁺.

¹ H NMR^* (500 MHz, DMSO-cf₆) δ 3.16 (s, 3H), 3.34 (s, 2H), 4.02 (m, 4H), 4.91 (s, 1 H), 6.79 (d, 1 H), 7.10 (t, 1 H), 7.19 (m, 2H), 7.60 (td, 2H), 7.84 (dd, 1 H), 7.99 (s, 1 H), 9.18 (dd, 1 H), 9.31 (s, 1 H), 9.42 (dd, 1 H).

¹³C NMR^* (126 MHz, DMSO-cf₆) δ 20.98, 40.79, 44.19, 57.83, 57.89, 109.41 , 122.66, 123.22, 123.46, 124.82, 126.52, 127.19, 127.65, 128.84, 128.93, 132.36, 133.98, 134.47, 137.59, 142.93, 144.94, 151.55, 151 .76, 152.34, 175.19.

Example 19

1 (7-Methyl-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-1 -(m

pyrrolo[2,3-clpyridinl-2'( 1 'H)-one ( 19)

I-25 (250 mg, 0.631 mmol) and 1-13d (193 mg, 0.631 mmol) were reacted according to the general method for N-alkylation. Subsequent to silica gel column chromatography, the compound was further purified by prep C18 HPLC Yield 19%. MS (ES+) 487.39 [M+H]⁺.

1 H NMR^* (500 MHz, DMSO-cf₆) δ 3.17 (s, 4H), 4.07 (m, 4H), 4.91 (s, OH), 5.05 (s, 1 H), 5.08 (s, OH), 7.19 (d, 1 H), 7.63 (m, 3H), 7.88 (dd, 1 H), 8.00 (d, 1 H), 8.17 (s, 1 H), 8.38 (d, 1 H), 9.25 (dd, 1 H), 9.32 (s, 1 H), 9.43 (dd, 1 H).

¹³C NMR^* (126 MHz, DMSO-cfe) δ 21.00, 40.78, 44.30, 57.07, 57.10, 118.24, 123.56, 125.05, 126.53, 127.25, 127.73, 130.39, 132.38, 134.03, 134.43, 137.48, 137.69, 139.96, 144.58, 144.63, 151 .57, 151.89, 152.38, 174.40.

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 in the assay described in Example A, the results are as shown in the Table 2.

Table 2

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 CrC₃alkyl, CrC₃haloalkyl, C₃-C₄cycloalkyl or phenyl wherein cycloalkyi or phenyl is optionally mono-, di- or tri-substituted with substituents each independently selected from CrC₃alkyl, 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 cycloalkyi 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 or two substituents independently selected from fluoro, amino, trifluoromethyl, C C₃alkyl, Ci-C₃alkoxy and Ci-C₃alkylamino;

R^1C is H or Ci-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, 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;

3. The compound according to claim 1 or 2, wherein W is a group of formula A1 or 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 or 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.

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 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 C 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 9, wherein R³ is methyl.

12. The compound according to claim 1 having the formula ( I la) :

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 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 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 .

14. The compound according to claim 12 or 13, wherein Z is N.

15. The compound according to any one of claims 12 to 14, wherein R^1C is methyl.

16. The compound according to any one of claims 12 to 14, wherein R^{1 B} is C(=0)R^1C, and R^1C is cyclopropyl which is substituted with trifluoromethyl.

17. The compound according to any one of claims 12 to 16, wherein n is 1 and R³ is chloro or methyl.

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

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

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

1 '-((4-(Pyridazin-4-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-fluoro-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-2'-oxo-1 ',2'- dihydrospiro[piperidine-4,3'-pyrrolo[2,3-c]pyridine]-1 -carboxylate,

1 '-((7-fluoro-4-(pyridazin-4-yl)isoquinolin-3-yl)m

ργΓΓθΙο[2,3- γπ ίη]-2'(1 Ή)-οηθ,

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

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

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

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

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

(trifluoromethyl)cyclopropanecarbonyl)spiro[azetidine-3,3'-pyrrolo[2,3-c]pyridin]-2^,(1 ^,l-l)-one, 1 '-((7-Chloro-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-1 -(1 -

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

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

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

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

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

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

1 '-((7-Methyl-4-(pyridazin-4-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-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-1 -(methylsulforiyl)spiro[azetidirie- 3,3'-indolin]-2'-one and

1 '-((7-Methyl-4-(pyridazin-4-yl)isoquinolin-3-yl)methyl)-1 -(methylsulforiyl)spiro[azetidirie- 3,3'-pyrrolo[2,3-c]pyridin]-2'(1 ^,l-l)-one.

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.