WO2019111218A1 - Novel heterocyclic compounds as irak4 inhibitors - Google Patents

Novel heterocyclic compounds as irak4 inhibitors Download PDF

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WO2019111218A1
WO2019111218A1 PCT/IB2018/059745 IB2018059745W WO2019111218A1 WO 2019111218 A1 WO2019111218 A1 WO 2019111218A1 IB 2018059745 W IB2018059745 W IB 2018059745W WO 2019111218 A1 WO2019111218 A1 WO 2019111218A1
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carboxamide
isoquinoline
pyrrolo
oxazol
oxohexahydro
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PCT/IB2018/059745
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French (fr)
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Rajiv Sharma
Rajesh Bahekar
Pradip JADAV
Amitgiri Goswami
Rajendra CHOPADE
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Cadila Healthcare Limited
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Publication of WO2019111218A1 publication Critical patent/WO2019111218A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to novel heterocyclic compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs.
  • the invention also relates to processes for the preparation of the compounds of invention, pharmaceutical compositions containing the compounds, which are useful for the treatment or prevention of cancer and inflammatory diseases associated with Interleukin-1 Receptor Associated Kinase (IRAK), and more particularly compounds that act as IRAK4 inhibitors.
  • IRAK Interleukin-1 Receptor Associated Kinase
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention with IRAK4 inhibitory activity.
  • the invention also relates to process for the manufacture of said compounds, and pharmaceutical compositions containing them and their use.
  • the present invention is directed to compounds which act as interleukin- 1 (IL-1) receptor-associated kinase 4 (IRAK4) inhibitors and are useful in the prevention or treatment of inflammatory, cell proliferative and immune -related conditions and diseases, associated with IRAK-4 enzyme.
  • IL-1 interleukin- 1
  • IRAK4 receptor-associated kinase 4
  • Protein kinases are key regulatory enzymes of large number of cell activities; participate in the signaling events that control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, protein kinases fall into two major groups; those which preferentially phosphorylate serine and / or threonine residues and those which preferentially phosphorylate tyrosine residues (S.K. hanks and T. Hunter, FASEB /., 1995, 9, 576-596).
  • cytokines appear to play key roles in these processes, particularly IL-1 and TNF. These cytokines play key roles in a large number of pathological conditions, including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, cancer etc.
  • Interleukin-1 (IL-1) Receptor-Associated Kinase -4 (IRAK4) is a serine/threonine kinase enzyme that plays an essential role in signal transduction by Tol/IL-1 receptors (TIRs).
  • TIRs Tol/IL-1 receptors
  • IRAK enzymes are key components in the signal transduction pathways mediated by interleukin-1 receptor (IL-1R) and Toll- like receptors (TLRs) (Janssens, S and Beyaert, R., Mol. Cell 2003, 11(2), 293-302).
  • IRAKI interleukin-1 receptor
  • IRAK2 Toll- like receptors
  • IRAK proteins are characterized by a typical N-terminal death domain that mediates interaction with MyD88-family adaptor proteins and a centrally located kinase domain.
  • the IRAK protein play a role in transducing signals other than those originating from IL-1R receptors, including signals triggered by activation of IL-18 receptors (Kanakaraj, et al., /. Exp. Med. 1999, 189(7): 1129-1138) and LPS receptors (Yang et ah, /. Immunol. 1999, 163(2), 639-643).
  • IRAK4 is considered to be the “master IRAK”. Under overexpression conditions, all IRAKs can mediate the activation of nuclear factor-kB (NF-kB) and stress-induced mitogen activated protein kinase (MAPK)- signaling cascades. However, only IRAK-1 and IRAK-4 have been shown to have active kinase activity. While IRAK-1 kinase activity could be dispensable for its function in IL-1 induced NF-kB activation (Kanakaraj et ah, /. Exp. Med.
  • IRAK-4 requires its kinase activity for signal transduction (Li, S., Strelow, A., Fontana, E.J., and Wesche, H Proc. Natl. Acad. Sci. USA 2002, 99(8), 5567-5572 and Lye, E et ah, /. Biol. Chem. 2004, 279(39), 40653-40658).
  • IRAK4 inhibitors Given the central role of IRAK4 in Toll-like / IL-IR signaling and immunological protection, IRAK4 inhibitors have been implicated as valuable therapeutics in inflammatory diseases, sepsis and autoimmune disorders (Wietek, C and O Neill, L. A., Mol. Interv, 2002, 2, 212-215).
  • mice lacking IRAK4 are viable and show complete abrogation of inflammatory cytokine production in response to IL-1, IL-18 or LPS (Suzuki, et ah, Nature 2002, 416(6882), 750-756). Similarly, human patients lacking IRAK4 are severely immune - compromised and are not responsive to these cytokines (Medvedev et al., /. Exp. Med. 2003, 198(4), 521-531 and Picard et al., Science 2003, 299(5615), 2076-2079). Knock-in mice containing inactive IRAK4 were completely resistant to lipopolysaccharide and CpG-induced shock (Kim T.
  • WO/2012/007375 US/8293923: WO/2013/066729: WO/2013/106612: WO/2013/106535:
  • WO/2013/106641 WO/2013/042137; WO/2013/106614; WO/2014/058685; WO/2014/008992; WO/2014/143672; WO/2014/074657; WO/2014/121931; WO/2014/121942; WO/2014/011911; WO/2014/011906; WO/2014/011902; W 0/2014/074675 ; WO/2014/058691; WO/2015/164374; WO/2015/048281; WO/2015/006181 ; WO/2015/104662; WO/2015/068856; WO/2015/193846; WO/2015/091426; WO/2015/104688; WO/2015/103453; WO/2015/150995; W 0/2017/053771 ; WO/2017/011390; WO/2017/144849; WO/2017/053770; WO/2017/053772; US/2017/03118
  • Present invention provide novel compounds that are inhibitors of IRAK4, pharmaceutical compositions and a method for treating IRAK4 -mediated and associated conditions or diseases that comprises administering IRAK4 inhibitors.
  • the present invention relates to novel compounds of the general formula (I) their tautomeric forms, their enantiomers, their diastereoi somers, their pharmaceutically accepted salts, or pro-drugs thereof, which are useful for the treatment or prevention of cancer and inflammatory diseases associated with Interleukin- 1 Receptor Associated Kinase (IRAK), and more particularly compounds that modulate the function of IRAK4.
  • IRAK Interleukin- 1 Receptor Associated Kinase
  • An embodiment of the present invention provides novel compounds of the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their suitable mixtures.
  • compositions containing compounds of the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
  • novel compounds of the present invention as IRAK4 inhibitors, by administering a therapeutically effective and non-toxic amount of compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals for the treatment of autoimmune diseases.
  • composition comprising the compounds of formula (I) along with at least a second suitable medicament for the treatment of autoimmune diseases.
  • the present invention relates to compounds of the general formula (I) represented below and includes their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their solvates, hydrates as well as their pharmaceutically acceptable salts and includes their suitable pharmaceutically acceptable formulations.
  • W is -CH 2 , -CHR I , -NH, -NRi, O, S, or S(0).
  • W is -CH 2 or -CHR R
  • Ri at each occurrence is independently selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl(Ci_ 6 )alkyl, heterocycloalkyl(Ci_ 6 )alkyl, arylalkyl, heteroarylalkyl, aryloxy, heteroaryloxy, heterocyclyloxy, wherein each of these groups, whenever applicable, is further substituted with one to three substituent(s) independently selected from hydroxy, (Ci_4)alkoxy, halo, cyano, amino, (Ci_ 6 )alkylamino, nitro, COO(Ci_ 4 )alkyl, S(0) n , S(0) n NH 2 , S(0) n NH(Ci_ 6 )
  • X, X’, Y and Y’ are each independently -CR 2 , -N or -N + -0 .
  • Z is independently -CR 2 , -N or -N + -0 . provided that no more than three of X, X’, Y, Y’ and Z are N; and no more than one of X, X’, Y, Y’ or Z is -N + -0
  • R 2 at each occurrence is independently selected from hydrogen, halo, cyano, nitro, hydroxy, optionally substituted groups selected from amino, Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci_ 6 alkoxy, C 2-6 alkenoxy, C 2-6 alkynyloxy, cycloalkoxy, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl(Ci_ 6 )alkyl, heterocycloalkyl(Ci_ 6 )alkyl, aralkyl, heteroarylalkyl, aryloxy, heteroaryloxy, heterocyclyloxy, wherein each of these groups, whenever applicable, is further substituted with one to three substituent(s) independently selected from hydroxy, (Ci_ 4) alkoxy, halo, cyano, amino, (Ci_ 6 )alkylamino, nitro, COO(Ci
  • R 3 is selected from the following heterocyclic ring systems
  • R 4 at each occurrence wherever applicable is independently selected from hydrogen, halo, amino, cyano, hydroxy, optionally substituted groups selected from Cl -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(Ci_ 6 )alkyl, heterocycloalkyl(Ci_ 6 )alkyl, S(0) n (Ci_ 6 )alkyl, S(0) n (Ci_ 6 )aryl, S(0) n NH 2 , S(0) favorNH(C 1-6 )alkyl, S(0) favorNHcycloalkyl, S(0) n NHaryl, S(0) n NHheteroaryl, (Ci_ 6 )alkylamino, COO(Ci_ 4 )alkyl, C(0)(Ci_ 6 )alkyl, groups.
  • R 6 is hydrogen, (Ci_ 6 )alkyl, (Ci_ 6 )alkylcarbonyl or -(CH 2 ) n COOH;
  • Preferred W is O.
  • Preferred Ri may be selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl(Ci_ 6 )alkyl, heterocycloalkyl(Ci_ 6 )alkyl, arylalkyl, heteroarylalkyl, aryloxy, heteroaryloxy, heterocyclyloxy, wherein each of these groups, whenever applicable, is further substituted with one to three substituent(s) independently selected from hydroxy, (Ci_4)alkoxy, halo, cyano, amino, (Ci_ 6 )alkylamino, nitro, COO(Ci_4)alkyl, S(0) n , S(0) n NH 2 , S(0) favorNH(C 1-6 )alkyl, C(O), C(0)NH(Ci- 6 )alkyl groups.
  • Preferred X, X’ may be selected independently as CR 2 , Y and Y’ may be each independently selected from -CR 2 or -N , Z is independently -CR 2 or -N
  • Preferred R 2 is selected from hydrogen and alkyl
  • Preferred R 3 is selected from below mentioned list:
  • Preferred R 4 at each occurrence may be independently selected from hydrogen, halo, amino, hydroxyl ,cyano, optionally substituted groups selected from (Ci_ 6 )alkyl, (C 2- 6 )alkenyl, (C 2-6 )alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(Ci_ 6 )alkyl or heterocycloalkyl(Ci_ 6 )alkyl, C(0)(Ci_ 6 )alkyl group, R4 is further substituted from hydrogen, halo, haloalkyl, amino, cyano, hydroxy, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl.
  • R5 may be selected from -C(0)NHR 6 or cyano and R 6 is hydrogen or (C l-6 ) alkyl.
  • the substituents when any of the groups defined above is further substituted, the substituents, if present, may be selected from those defined above.
  • the groups, radicals described above may be selected from:
  • Alkyl as well as other groups having the prefix“alk”, such as alkoxy and alkanoyl, means carbon chain which may be substituted with an oxygen atom as is well understood by a skilled artisan, which may further be either linear or branched, and combinations thereof, unless the carbon chain is defined otherwise.
  • alkyl group include but not are limited to methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, tert.- butyl, pentyl, hexyl etc.
  • the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, Ci_ 6 is intended.
  • alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.
  • alkenyl include but not limited to vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, l-propenyl, 2-butenyl, 2- methyl-2-butenyl etc.
  • the term alkenyl also includes cycloalkenyl groups and combinations of linear, branched and cyclic structures. When no number of carbon atoms is specified, C ( 2- 6) is intended.
  • Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3 -methyl- 1 -pen tynyl etc. When no number of carbon atoms is specified, C (2-6) is intended.
  • carbocycle or “carbocyclic residue” is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • carbocycle is intended to include, wherever applicable, the groups representing cycloalkyl
  • Cycloalkyl is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. A cycloalkyl group generally is monocyclic unless otherwise stated. Cycloalkyl groups are saturated unless and otherwise stated.
  • alkoxy refers to the straight or branched chain alkoxides of the number of carbon atoms specified.
  • alkylamino refers to straight or branched alkylamines of the number of carbon atoms specified.
  • Aryl means a mono- or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
  • Heterocycle and“heterocyclyl” refer to saturated or unsaturated non-aromatic rings or ring systems containing at least one heteroatom selected from O, S, N further optionally including the oxidized forms of sulfur, namely SO & S0 2 .
  • heterocycles include tetrahydrofuran (THF), dihydrofuran, l,4-dioxane, morpholine, l,4-dithiane, piperazine, piperidine, l,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3- dioxane, l,3-dithiane, oxathiane, thiomorpholine etc.
  • THF tetrahydrofuran
  • dihydrofuran dihydrofuran
  • l,4-dioxane morpholine
  • l,4-dithiane piperazine
  • piperidine l,3-dioxolane
  • imidazoline imidazolidine
  • pyrrolidine pyrroline
  • tetrahydropyran
  • Heteroaryl means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to the other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic.
  • heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolin
  • Halo/ Halogen refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.
  • Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • “Pharmaceutically acceptable salts” refer 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 the basic residues.
  • Such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1, 2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucohep tonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, is
  • Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein.
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • the term‘optional’ or‘optionally’ means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not.
  • ‘optionally substituted alkyl’ means either‘alkyl’ or‘substituted alkyl’.
  • an optionally substituted group means unsubstituted.
  • the compounds of the formula (I) as constituents of the inventive combinations may, depending on their structure, exist in different stereoisomeric forms, i.e. in the form of configurational isomers or else optionally as conformational isomers (enantiomers and/or diastereomers, including those in the case of atropisomers).
  • the present invention therefore encompasses the enantiomers and diastereomers, and the respective mixtures thereof.
  • the stereoisomerically homogeneous constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatography processes are preferably used for this purpose, especially HPLC chromatography on an achiral or chiral phase.
  • the present invention also encompasses all suitable isotopic variants of the inventive compounds.
  • An isotopic variant of an inventive compound is understood here to mean a compound in which at least one atom within the inventive compound has been exchanged for another atom of the same atomic num ber but with a different atomic mass from the atomic mass which usually or predominantly occurs in nature.
  • isotopes which can be incorporated into an inventive compound are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36CI, 82Br, 1231, 1241, 1291 and 1311.
  • Particular isotopic variants of an inventive compound may be beneficial, for example, for the examination of the mechanism of action or of the active ingredient distribution in the body; because of the comparative ease of preparability and detectability, particularly compounds labelled with 3H or 14C isotopes are suitable for this purpose.
  • the incorporation of isotopes for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required; such modifications of the compounds may therefore possibly also constitute a preferred em bodiment of the present invention.
  • Isotopic variants of the compounds can be prepared by the processes known to those skilled in the art, for example by the methods described further down and the procedures specified in the working examples, by using corresponding isotopic modifications of the respective reagents and/or starting compounds
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • Particularly useful compounds may be selected from but not limited to the following: 7-isoproxy- l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-6- carbonitrile;
  • useful compounds may be selected from but not limited to the following; l-((lR,5S)-3,6-diazabicyclo[3.l.l]heptan-6-yl)-7-methoxyisoquinoline-6- carboxamide;
  • novel compounds of the present invention were prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art.
  • the reactions can be performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
  • Preferred methods include, but not limited to those described below, where all symbols are as defined earlier unless and otherwise defined below.
  • Substituted benzaldehyde (1) can be treated with bromine in an appropriate solvent to give compound (2) or can be prepared by the method reported in literature along with their suitable modifications as may be necessary.
  • Compound (2) can be treated with an alkylating agent such as Mel, iPrBr and a base like K 2 C0 3 or CS 2 CO 3 in a suitable solvent to give compound (3).
  • Knoevenagel condensation of Compound (3) with malonic acid typically in pyridine and piperidine can afford acrylic acid (4), which may be converted to acyl azide of the formula (5) by a variety of means known to one skill in art, for example sequential treatment with ethyl chloroformate followed by reaction with sodium azide.
  • acyl azide (5) may undergo cyclization via Curtius reaction to afford isoquinolone (6).
  • Cyanation of isoquinolone (6) via methods known to those skill in art such as treatment with zinc cyanide under palladium catalysis or Rosenmund-von Braun reaction using excess of copper (I) cyanide may provide compound (7), which upon treatment with phosphorous oxychloride in suitable system facilitated the formation of intermediate-1.
  • General Scheme-1 :
  • Novel compounds of general formula (I) of the present invention can be prepared by treating intermediate-1 with the appropriate substituent R 3 .
  • R 3 can also be prepared using the methods available in the literature, modifying the literature procedure or by various methods known to those skilled in art (WO 2007/087231, WO 2009/153554, WO 2009/109576, US 2010/0216839, WO 2008/014311, WO 2014/014874, JP 2009/298713, WO 2011030349 & / Med. Chem. 57(8) 3430-3449, 2014 etc.).
  • the compounds of the present invention with structural formula (I) can be prepared by coupling of Intermediate- 1 (obtained from the Scheme-1), with substituent-R 3 using appropriate reagent such as CS2CO3, K2CO3, /BuOK, DIEA, TEA KHMDS or nBuLi in solvents such as l,4-dioxane, tetrahydrofuran, N,N-dimethyl acetamide, N, N-dimethyl form amide or N-methyl-2- pyrrolidinone.
  • Reaction of Intermediate-1 with substituent-R3 can also be carried out by Ullmann type of reaction using various copper catalysts and methods available in the literature (for e.g. J. Am. Chem. Soc.
  • the base-catalyzed conversion of nitrile to amide by hydrogen peroxide provides the compounds of the general formula (I). Conversion of nitrile to amide can also be performed by means of acid or base catalyzed hydrolysis according to reported literature methods or by methods known to those skilled in art.
  • Compounds of the present invention can be isolated either as free amine form or as a salt corresponding to the acid used such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, oxalic acid, maleic acid, fumeric acid, succinic acid, p-toluene sulfonic acid or benzene sulfonic acid.
  • the compounds can be purified where ever required, by recrystallization, trituration, precipitation, preparative thin layer chromatography, flash chromatography or by preparative HPLC method.
  • ESI-Q- TOF-MS measurements were performed with a micrOTOF-Q II (Bruker Daltonics) mass spectrometer.
  • HPLC analysis were carried out at kmax 220 nm using column ODS C-18, 150 mm x 4.6 mm x 4 pm on AGILENT 1100 series. Reactions were monitored using thin layer silica gel chromatography (TLC) using 0.25 mm silica gel 60F plates from Merck. Plates were visualized by treatment with UV, acidic p- anisaldehyde stain, KMn0 4 stain with gentle heating. Products were purified by column chromatography using silica gel 100-200 mesh and the solvent systems indicated.
  • Step-4 (E)-3-(3-bromo-4-isopropoxyphenyl) acryloyl azide (15) To a stirred solution of compound (E)-3-(3-bromo-4-isopropoxyphenyl) acrylic acid (14) (60 g, 2.10 mmol) in acetone (1.05 L), Et 3 N (21.3 g, 2.10 mmol) was added and the mixture was cooled to about -5 °C. Ethyl chloroformate (29.7 g, 2.73 mmol) was added dropwise, maintaining the temperature at about -5 °C. After completion of the addition, the mixture was stirred for approximately an additional 1 h at about -5 °C.
  • 6-bromo-7-isopropoxyisoQuinolin-l (2H)-one (16) (27 g, 9.57 mmol) and zinc cyanide (14.6 g, 12.43 mmol) were added to dry DMF (540 ml) and stirred for about 5 min at RT.
  • the reaction mixture was degassed with nitrogen for about 30 minutes, then tetra(kis)triphenylphosphinepalladium(0) (6.64 g, 0.574 mmol) was added and the reaction mixture was stirred for about 5 min at RT then mixture was heated to about 100 °C. The mixture was maintained for about 16 hours at about 100 °C.
  • the reaction mixture was cooled to about 25 °C, diluted with EtOAc (270 ml), and stirred for about 30 minutes.
  • the mixture was filtered through celite, which was washed with EtOAc (60 ml).
  • the combined filtrate was concentrated under pressure at about 75 °C.
  • Water (270 ml) was added to the residue and the mixture was stirred for about 0.5 h.
  • the precipitate was filtered, washed with water (60 ml) and dried under vacuum at about 60 °C.
  • the precipitate was stirred for about 0.5 h with MTBE (270 ml) and filtered.
  • Step-l tert- butyl 2,5-dihydro- 1 H-pyrrole- 1 -carboxylate (9)
  • Step-2 tert- butyl 6-oxa-3-azabicvclor3. l.01hexane-3-carboxylate (10)
  • Reaction mixture was washed sequentially with aqueous saturated sodium hydrogen sulfite solution, 5% aq K 2 C0 3 solution and brine (100 ml each) organic layer was separated, dried and evaporated to dryness under reduced pressure to get / -butyl 6-oxa-3- azabicyclo[3.l.0]hexane-3-carboxylate (10) as a thick oil (11.89 g, 100% yield).Product was used as such in next reaction step without any purification.
  • Step-3 tert- butyl /ra/7v-3-azido-4-hvdroxypyrrol idine- 1 -carboxylate (11)
  • Step-4 tert-butyl /ra/7.v-3-amino-4-hvdroxypyrrolidine- 1 -carboxylate (12)
  • Step-5 /er/-butyl frc// .v-3-((tert-butoxycarbonyl )amino)-4-hydroxynyrrolidine- 1 - carboxylate (13)
  • Step-7 tert- butyl 2-oxohexahvdro-5H-pyrrolor3,4-d1oxazole-5-carboxylate (15)
  • Step-l Synthesis of 7-isoproxy-l-(2-oxohexahvdro-5H-pyrrolor3,4-d1oxazol-5- yl)isoquinoline-6-carbonitrile (Compound-1)
  • Compound 25 7-methoxy-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5-yl)isoquinoline-6-carbonitrile.
  • Compound 70 l-(5-(2-cyanoacetyl)-3, 4, 5, 6-tetrahydropyrrolo [3, 4-c] pyrrol- 2(lH)-yl)-7-methoxyisoquinoline-6-carboxamide.
  • Compound 72 7-methoxy-l-(2-oxo-l-oxa-3, 8-diazaspiro [4.5] decan-8-yl) isoquinoline-6-carboxamide.
  • Compound 75 7-isopropoxy-l-(3-oxo-l-oxa-4, 9-diazaspiro [5.5] undecan-9-yl) isoquinoline-6-carboxamide.
  • Compound 80 7-isopropoxy- 1 -(4-(3-oxopiperazin- l-yl)piperidin- 1 -yl)isoquinoline- 6-carboxamide.
  • Compound 81 7 -isopropoxy- 1 -(2-oxo- 1 ,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6- carboxamide.
  • Compound 82 7-methoxy- 1 -(2-oxo- l,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6- carboxamide.
  • Compound 85 7-methoxy-l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5-yl)isoquinoline-6-carbonitrile.
  • compositions and methods according to the invention use compounds of formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof possess therapeutic role of inhibiting IRAK4 kinase useful for the treatment of autoimmune diseases, inflammatory diseases, and proliferative diseases.
  • autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, gout and psoriasis.
  • Test compounds were screened in the TR-FRET assay with IRAK4 kinase obtained from Millipore. 5 ng of IRAK4 kinase was used for the assay. The compound was incubated with the kinase for 30 minutes at room temperature. After the incubation, substrate mixture [Biotin Histone H3 as substrate at a concentration of lOOnM and ATP at a concentration of 20 mpj was added. The above reaction was stopped by the addition of 40 mp EDTA after the 30 minutes kinase reaction followed by the addition of 0.5 nM of Eu-labelled antiphospho tyrosine antibody from Perkin Elmer.
  • novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • the compounds of formula (I) or pharmaceutical compositions containing them are useful as a medicament for the inhibition of IRAK4 enzyme activity and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
  • the quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon several factors such as the particular application method, the potency of the particular compound and the desired concentration.
  • novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • compositions according to this invention can exist in various forms.
  • the pharmaceutical composition is in the form of a powder or solution.
  • the pharmaceutical compositions according to the invention are in the form of a powder that can be reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration.
  • a compatible reconstitution diluents include water.
  • compositions according to the invention are in the form ready to use for oral or parenteral administration.
  • the pharmaceutical composition and / or other pharmaceutically active ingredients disclosed herein may be administered by any appropriate method, which serves to deliver the composition or its constituents or the active ingredients to the desired site.
  • the method of administration can vary depending on various factors, such as for examples, the components of the pharmaceutical composition and nature of the active ingredients, the site of the potential or actual infection, severity of infection, age and physical condition of the subject.
  • compositions to a subject according to this invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, dermal patch, eye drop, ear droop or mouthwash.
  • Compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.
  • Compounds of the invention may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g.
  • hemolytic anemia aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome.
  • additional therapeutic agents which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as "appropriate for the disease, or condition, being treated.”
  • a provided combination, or composition thereof is administered in combination with another therapeutic agent.
  • MS Multiple Sclerosis
  • beta interferon e.g., Avon
  • the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents.
  • additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, and "anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), and adalimumab (Humira®), "anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Haris®), anti-Jak inhibitor
  • the present invention provides a method of treating inflammatory bowel disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.
  • mesalamine Asacol®
  • Amulfidine® antidiarrheals
  • the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).
  • beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), anticholinergic agents such as
  • the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.
  • the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan- JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).
  • additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan- JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis.
  • compositions and method disclosed herein are useful in preventing or for the treatment of inflammatory, cell proliferative and immune-related conditions and diseases associated with IRAK4-mediated signal transduction, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, allergic disease, psoriasis, asthma and cancer.
  • inflammatory, cell proliferative and immune-related conditions and diseases associated with IRAK4-mediated signal transduction such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, allergic disease, psoriasis, asthma and cancer.

Abstract

The present invention relates to novel compounds of the general formula (I) their tautomeric forms, their enantiomers, their diastereoisomers, their pharmaceutically accepted salts, or pro-drugs thereof, which are useful for the treatment or prevention of cancer and inflammatory diseases associated with Interleukin-1 Receptor Associated Kinase (IRAK), and more particularly compounds that modulate the function of IRAK4.

Description

NOVEL HETEROCYCLIC COMPOUNDS AS IRAK4 INHIBITORS
FIELD OF THE INVENTION
The present invention relates to novel heterocyclic compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs. The invention also relates to processes for the preparation of the compounds of invention, pharmaceutical compositions containing the compounds, which are useful for the treatment or prevention of cancer and inflammatory diseases associated with Interleukin-1 Receptor Associated Kinase (IRAK), and more particularly compounds that act as IRAK4 inhibitors. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention with IRAK4 inhibitory activity. The invention also relates to process for the manufacture of said compounds, and pharmaceutical compositions containing them and their use.
Figure imgf000002_0001
BACKGROUND OF THE INVENTION
The present invention is directed to compounds which act as interleukin- 1 (IL-1) receptor-associated kinase 4 (IRAK4) inhibitors and are useful in the prevention or treatment of inflammatory, cell proliferative and immune -related conditions and diseases, associated with IRAK-4 enzyme.
Kinases are key regulatory enzymes of large number of cell activities; participate in the signaling events that control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, protein kinases fall into two major groups; those which preferentially phosphorylate serine and / or threonine residues and those which preferentially phosphorylate tyrosine residues (S.K. hanks and T. Hunter, FASEB /., 1995, 9, 576-596).
The recruitment of immune cells to sites of injury involves the concerted interactions of large number of soluble mediators. Several cytokines appear to play key roles in these processes, particularly IL-1 and TNF. These cytokines play key roles in a large number of pathological conditions, including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, cancer etc.
Interleukin-1 (IL-1) Receptor-Associated Kinase -4 (IRAK4) is a serine/threonine kinase enzyme that plays an essential role in signal transduction by Tol/IL-1 receptors (TIRs). Diverse IRAK enzymes are key components in the signal transduction pathways mediated by interleukin-1 receptor (IL-1R) and Toll- like receptors (TLRs) (Janssens, S and Beyaert, R., Mol. Cell 2003, 11(2), 293-302). There are four members in the mammalian IRAK family: IRAKI, IRAK2, IRAKM/3 and IRAK4. These proteins are characterized by a typical N-terminal death domain that mediates interaction with MyD88-family adaptor proteins and a centrally located kinase domain. The IRAK protein play a role in transducing signals other than those originating from IL-1R receptors, including signals triggered by activation of IL-18 receptors (Kanakaraj, et al., /. Exp. Med. 1999, 189(7): 1129-1138) and LPS receptors (Yang et ah, /. Immunol. 1999, 163(2), 639-643).
Out of four members in the mammalian IRAK family, IRAK4 is considered to be the “master IRAK”. Under overexpression conditions, all IRAKs can mediate the activation of nuclear factor-kB (NF-kB) and stress-induced mitogen activated protein kinase (MAPK)- signaling cascades. However, only IRAK-1 and IRAK-4 have been shown to have active kinase activity. While IRAK-1 kinase activity could be dispensable for its function in IL-1 induced NF-kB activation (Kanakaraj et ah, /. Exp. Med. 1998, 187(12), 2073-2079 and Li, X., Commane, M et ah, Mol. Cell. Biol. 1999, 19(7), 4643-4652), IRAK-4 requires its kinase activity for signal transduction (Li, S., Strelow, A., Fontana, E.J., and Wesche, H Proc. Natl. Acad. Sci. USA 2002, 99(8), 5567-5572 and Lye, E et ah, /. Biol. Chem. 2004, 279(39), 40653-40658).
Given the central role of IRAK4 in Toll-like / IL-IR signaling and immunological protection, IRAK4 inhibitors have been implicated as valuable therapeutics in inflammatory diseases, sepsis and autoimmune disorders (Wietek, C and O Neill, L. A., Mol. Interv, 2002, 2, 212-215).
Mice lacking IRAK4 are viable and show complete abrogation of inflammatory cytokine production in response to IL-1, IL-18 or LPS (Suzuki, et ah, Nature 2002, 416(6882), 750-756). Similarly, human patients lacking IRAK4 are severely immune - compromised and are not responsive to these cytokines (Medvedev et al., /. Exp. Med. 2003, 198(4), 521-531 and Picard et al., Science 2003, 299(5615), 2076-2079). Knock-in mice containing inactive IRAK4 were completely resistant to lipopolysaccharide and CpG-induced shock (Kim T. W., Traschke K., Bulek K et al., / Exp Med. 2007, 204(5), 1025-1036 and Kawagoe T, Sato S, Jung A, et al., /. Exp. Med. 2007, 204(5), 1013-1024) and illustrated that IRAK4 kinase activity is essential for cytokine production, activation of MAPKs and induction of NF-kB regulated genes in response to TLR ligands, that in turn regulate immune and inflammatory responses (Koziczak-Holbro M, Joyce C, Gluck A., et al., /. Bio Chem 2007, 282, 13552-13560).
Inactivation of IRAK4 kinase in mice leads to resistance to EAE due to reduction in infiltrating inflammatory cells into CNS and reduced antigen specific CD4+ T-cell mediated IL-17 production (Kirk A et al., /. Immunol. 2009, 183(1), 568-577).
A number of IRAK4 inhibitors have been disclosed in the literature (WO/2011/043371; WO/2012/097013; WO/2012/084704; WO/2012/ 129258; WO/2012/068546;
WO/2012/007375: US/8293923: WO/2013/066729: WO/2013/106612: WO/2013/106535:
WO/2013/106641 ; WO/2013/042137; WO/2013/106614; WO/2014/058685; WO/2014/008992; WO/2014/143672; WO/2014/074657; WO/2014/121931; WO/2014/121942; WO/2014/011911; WO/2014/011906; WO/2014/011902; W 0/2014/074675 ; WO/2014/058691; WO/2015/164374; WO/2015/048281; WO/2015/006181 ; WO/2015/104662; WO/2015/068856; WO/2015/193846; WO/2015/091426; WO/2015/104688; WO/2015/103453; WO/2015/150995; W 0/2016/053771 ; WO/2016/011390; WO/2016/144849; WO/2016/053770; WO/2016/053772; US/2016/0311839; US/2016/0347760; WO/2016/144844; WO/2016/144846; WO/2016/144847; WO/2016/144848; W 0/2016/127024; WO/2016/ 127025; WO/2016/053769; WO/2016/172560; WO/2016/174183; WO/2017/004133; WO/2016/210036; WO/2016/210037; W 0/2016/210034; WO/2017/004134; WO/2017/009798; WO/2017/049068; WO/2017/049069; WO/2017/025064; WO/2017/024589; US/2017/0152263; WO/2017/108723; WO/2017/067848; WO/2017/023941; WO/2017/025849; WO/2017/127430; WO/2017/033093; WO/2018/083085; US/2018/0230127; WO/018/083085;
US/2018/0298015; WO/2018/209012; US/2018/0051027; WO/2018/178947;
US/2018/0244646; WO/2018/098367; WO/2018/149925; WO/2018/152368).
Despite various disclosures on different kinase inhibitors, however, with the rise in number of patients affected by kinase enzyme mediated diseases, there appears to be unmet need for newer drugs that can treat such diseases more effectively. There is still need for newer kinase inhibitors.
The identification of compounds that inhibit the function of IRAK4 represents an attractive approach to the development of therapeutic agents for the treatment of inflammatory, cell proliferative and immune -related conditions and diseases associated with IRAK4-mediated signal transduction, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, allergic disease, psoriasis, asthma and cancer.
Present invention provide novel compounds that are inhibitors of IRAK4, pharmaceutical compositions and a method for treating IRAK4 -mediated and associated conditions or diseases that comprises administering IRAK4 inhibitors.
SUMMARY OF THE INVENTION
The present invention relates to novel compounds of the general formula (I) their tautomeric forms, their enantiomers, their diastereoi somers, their pharmaceutically accepted salts, or pro-drugs thereof, which are useful for the treatment or prevention of cancer and inflammatory diseases associated with Interleukin- 1 Receptor Associated Kinase (IRAK), and more particularly compounds that modulate the function of IRAK4.
Figure imgf000005_0001
EMBODIMENT(S) OF THE INVENTION
An embodiment of the present invention provides novel compounds of the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their suitable mixtures.
In a further embodiment of the present invention is provided pharmaceutical compositions containing compounds of the general formula (I), their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
In a still further embodiment is provided the use of novel compounds of the present invention as IRAK4 inhibitors, by administering a therapeutically effective and non-toxic amount of compounds of general formula (I) or their pharmaceutically acceptable compositions to the mammals for the treatment of autoimmune diseases.
In yet another embodiment is provided a composition comprising the compounds of formula (I) along with at least a second suitable medicament for the treatment of autoimmune diseases.
In another embodiment is provided processes for preparing the compounds of the present invention.
DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to compounds of the general formula (I) represented below and includes their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their solvates, hydrates as well as their pharmaceutically acceptable salts and includes their suitable pharmaceutically acceptable formulations.
Figure imgf000006_0001
Wherein:
W is -CH2, -CHRI, -NH, -NRi, O, S, or S(0)„ When W is -CH2 or -CHR R | at each occurrence is independently selected from hydrogen, halo, cyano, nitro, hydroxyl, optionally substituted groups selected from amino, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 alkoxy, C2-6 alkenoxy, C2-6 alkynyloxy, cycloalkoxy, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl(Ci_6)alkyl, heterocycloalkyl(Ci_6)alkyl, arylalkyl, heteroarylalkyl, aryloxy, heteroaryloxy, heterocyclyloxy, wherein each of these groups, whenever applicable, is further substituted with one to three substituent(s) independently selected from hydroxy, (Ci_4)alkoxy, halo, cyano, amino, (Ci_ 6)alkylamino, nitro, COO(Ci_4)alkyl, S(0)n, S(0)nNH2, S(0)nNH(Ci_6)alkyl, C(O), C(0)NH(Ci_6)alkyl groups;
When W is -NH, -NRi, O, S, or S(0)n, Ri at each occurrence is independently selected from Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl(Ci_6)alkyl, heterocycloalkyl(Ci_ 6)alkyl, arylalkyl, heteroarylalkyl, aryloxy, heteroaryloxy, heterocyclyloxy, wherein each of these groups, whenever applicable, is further substituted with one to three substituent(s) independently selected from hydroxy, (Ci_4)alkoxy, halo, cyano, amino, (Ci_6)alkylamino, nitro, COO(Ci_4)alkyl, S(0)n, S(0)nNH2, S(0)nNH(Ci_6)alkyl, C(O), C(0)NH(Ci_6)alkyl groups;
Further Ri can form 1 to 7 membered cyclic ring with X when X= -CR2;
X, X’, Y and Y’ are each independently -CR2, -N or -N+-0 . Z is independently -CR2, -N or -N+-0 . provided that no more than three of X, X’, Y, Y’ and Z are N; and no more than one of X, X’, Y, Y’ or Z is -N+-0
R2 at each occurrence is independently selected from hydrogen, halo, cyano, nitro, hydroxy, optionally substituted groups selected from amino, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 alkoxy, C2-6 alkenoxy, C2-6 alkynyloxy, cycloalkoxy, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl(Ci_ 6)alkyl, heterocycloalkyl(Ci_6)alkyl, aralkyl, heteroarylalkyl, aryloxy, heteroaryloxy, heterocyclyloxy, wherein each of these groups, whenever applicable, is further substituted with one to three substituent(s) independently selected from hydroxy, (Ci_ 4)alkoxy, halo, cyano, amino, (Ci_6)alkylamino, nitro, COO(Ci_4)alkyl, S(0)n, S(0)nNH2, S(0)nNH(Ci-6)alkyl, C(O), C(0)NH(Ci-6)alkyl groups;
R3 is selected from the following heterocyclic ring systems
Figure imgf000008_0001
Figure imgf000009_0001
Wherein R4 at each occurrence wherever applicable is independently selected from hydrogen, halo, amino, cyano, hydroxy, optionally substituted groups selected from Cl -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(Ci_6)alkyl, heterocycloalkyl(Ci_6)alkyl, S(0)n(Ci_6)alkyl, S(0)n(Ci_6)aryl, S(0)nNH2, S(0)„NH(C1-6)alkyl, S(0)„NHcycloalkyl, S(0)nNHaryl, S(0)nNHheteroaryl, (Ci_6)alkylamino, COO(Ci_4)alkyl, C(0)(Ci_6)alkyl, groups.
When R4 is substituted, the preferred substituents on R4 wherever applicable are selected from hydrogen, hydroxyl, halo, haloalkyl, amino, cyano, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, hydroxy, - CH2-COOH, -C(=0)-0-methyl, -C(=0)-0-trifluromethyl, -C(=0)-0-ethyl, -C(=0)- O-phenyl, -C(=0)-0-benzyl, -C(=0)-NH-methyl, -C(=0)-NH-ethyl, -C(=0)-NH- propyl, -C(=0)-NH-cyelopropyl, -C(=0)-NH-phenyl,-C(=0)-NH-trifluromethyl, - C(=0)-methyl, -C(=0)-ethyl, -C(=0)CH2-methyl, -C(=0)CH2-phenyl, S(0)2-phenyl, S(0)2-methyl, S(0)2-ethyl, S(0)2-propyl, S(0)2-butyl, S(0)2-cyclopropyl, S(0)2- cyclobutyl, S(0)2-cyclopentyl, S(0)2-cyclohexyl, S(0)2-phenyl, S(0)2-flurophenyl, S(0)2-cynophenyl, S(0)2NH2, S(0)2NH-methyl, S(0)2NH-ethyl; R5 is -C(NH)NHR6, -C(0)NHR6, -C(S)NHR6, -COOR6 or cyano;
R6 is hydrogen, (Ci_6)alkyl, (Ci_6)alkylcarbonyl or -(CH2)nCOOH;
Wherein n = 0-4; Further preferred embodiments are those disclose below:
Preferred W is O.
Preferred Ri may be selected from Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl(Ci_ 6)alkyl, heterocycloalkyl(Ci_6)alkyl, arylalkyl, heteroarylalkyl, aryloxy, heteroaryloxy, heterocyclyloxy, wherein each of these groups, whenever applicable, is further substituted with one to three substituent(s) independently selected from hydroxy, (Ci_4)alkoxy, halo, cyano, amino, (Ci_6)alkylamino, nitro, COO(Ci_4)alkyl, S(0)n, S(0)nNH2, S(0)„NH(C1-6)alkyl, C(O), C(0)NH(Ci-6)alkyl groups.
Preferred X, X’ may be selected independently as CR2, Y and Y’ may be each independently selected from -CR2 or -N , Z is independently -CR2 or -N
Preferred R2 is selected from hydrogen and alkyl
Preferred R3 is selected from below mentioned list:
Figure imgf000010_0001
Preferred R4 at each occurrence may be independently selected from hydrogen, halo, amino, hydroxyl ,cyano, optionally substituted groups selected from (Ci_6)alkyl, (C2- 6)alkenyl, (C2-6 )alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(Ci_ 6)alkyl or heterocycloalkyl(Ci_6)alkyl, C(0)(Ci_6)alkyl group, R4 is further substituted from hydrogen, halo, haloalkyl, amino, cyano, hydroxy, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl.
Preferred R5 may be selected from -C(0)NHR6 or cyano and R6 is hydrogen or (Cl-6) alkyl.
In an alternate embodiment, when any of the groups defined above is further substituted, the substituents, if present, may be selected from those defined above.
In another preferred embodiment, the groups, radicals described above may be selected from:
“Alkyl”, as well as other groups having the prefix“alk”, such as alkoxy and alkanoyl, means carbon chain which may be substituted with an oxygen atom as is well understood by a skilled artisan, which may further be either linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl group include but not are limited to methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, tert.- butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g. from C3-10, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, Ci_6 is intended.
“Alkenyl” means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkenyl include but not limited to vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, l-propenyl, 2-butenyl, 2- methyl-2-butenyl etc. Where the specified number of carbon atoms permits, e. g., from C5-10, the term alkenyl also includes cycloalkenyl groups and combinations of linear, branched and cyclic structures. When no number of carbon atoms is specified, C(2-6) is intended.
“Alkynyl” means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3 -methyl- 1 -pen tynyl etc. When no number of carbon atoms is specified, C(2-6) is intended.
As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable monocyclic or bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). In a broader perspective, the term carbocycle is intended to include, wherever applicable, the groups representing cycloalkyl, phenyl and other saturated, partially saturated or aromatic residues;
“Cycloalkyl” is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. A cycloalkyl group generally is monocyclic unless otherwise stated. Cycloalkyl groups are saturated unless and otherwise stated.
The“alkoxy” refers to the straight or branched chain alkoxides of the number of carbon atoms specified.
The term“alkylamino” refers to straight or branched alkylamines of the number of carbon atoms specified.
“Aryl” means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
“Heterocycle” and“heterocyclyl” refer to saturated or unsaturated non-aromatic rings or ring systems containing at least one heteroatom selected from O, S, N further optionally including the oxidized forms of sulfur, namely SO & S02. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, l,4-dioxane, morpholine, l,4-dithiane, piperazine, piperidine, l,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3- dioxane, l,3-dithiane, oxathiane, thiomorpholine etc.
“Heteroaryl” means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to the other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic. Examples of heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl etc. For heterocyclyl and heteroaryl groups, rings and ring systems containing from 3-15 carbon atoms are included, forming 1-3 rings.
“Halo/ Halogen” refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.
Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
“Pharmaceutically acceptable salts” refer 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 the basic residues. Such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1, 2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucohep tonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.
"Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. The term‘optional’ or‘optionally’ means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not. For example, ‘optionally substituted alkyl’ means either‘alkyl’ or‘substituted alkyl’. Further an optionally substituted group means unsubstituted.
The compounds of the formula (I) as constituents of the inventive combinations may, depending on their structure, exist in different stereoisomeric forms, i.e. in the form of configurational isomers or else optionally as conformational isomers (enantiomers and/or diastereomers, including those in the case of atropisomers). The present invention therefore encompasses the enantiomers and diastereomers, and the respective mixtures thereof. The stereoisomerically homogeneous constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatography processes are preferably used for this purpose, especially HPLC chromatography on an achiral or chiral phase.
The present invention also encompasses all suitable isotopic variants of the inventive compounds. An isotopic variant of an inventive compound is understood here to mean a compound in which at least one atom within the inventive compound has been exchanged for another atom of the same atomic num ber but with a different atomic mass from the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into an inventive compound are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36CI, 82Br, 1231, 1241, 1291 and 1311. Particular isotopic variants of an inventive compound, such as, in particular, those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active ingredient distribution in the body; because of the comparative ease of preparability and detectability, particularly compounds labelled with 3H or 14C isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required; such modifications of the compounds may therefore possibly also constitute a preferred em bodiment of the present invention.
Isotopic variants of the compounds can be prepared by the processes known to those skilled in the art, for example by the methods described further down and the procedures specified in the working examples, by using corresponding isotopic modifications of the respective reagents and/or starting compounds
Unless otherwise stated in the specification, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
In the following examples molecules with a single chiral center, unless otherwise stated, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise stated, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
Particularly useful compounds may be selected from but not limited to the following: 7-isoproxy- l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-6- carbonitrile;
7-isopropoxy-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-6- carboxamide;
7-methoxy-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)isoquinoline-6- carbonitrile ;
7-methoxy-l-(3-methyl-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carbonitrile ;
7-methoxy-l-(3-methyl-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-methoxy-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)isoquinoline-6- carboxamide; 7-isopropoxy-l-((3aR, 6aS)-2-oxohexahydro-5H-pyrrolo [3, 4-d] oxazol-5-yl) isoquinoline-6-carbonitrile ;
7-isopropoxy-l-(2-oxohexahydropyrrolo[3,4-d][l,3]oxazin-6(4H)-yl)isoquinoline-6- carboxamide;
7-methoxy-l-(2-oxohexahydropyrrolo[3,4-d][l,3]oxazin-6(4H)-yl)isoquinoline-6- carboxamide;
7-isopropoxy-l-(2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)-yl)isoquinoline-6- carboxamide;
7-methoxy-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)isoquinoline-6- carboxamide;
l-(6-(4-fluorophenyl)-2-oxohexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl)-7- isopropoxyisoquinoline-6-carboxamide;
7-isopropoxy-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-(prop-2-yn-l- yloxy)isoquinoline-6-carboxamide;
tert-butyl 3-((6-cyano-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinolin- 7-yl)oxy) azetidine-l-carboxylate;
7-(oxetan-3-yloxy)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-6- carboxamide;
tert-butyl 3-((6-carbamoyl-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinolin-7-yl)oxy)azetidine-l-carboxylate;
7-(azetidin-3-yloxy)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-
6-carboxamide;
7-methoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile ; 7-methoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-methoxy-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-(2-oxohexahydropyrrolo [3,4-b]pyrrol-5(lH)-yl)isoquinoline-6- carboxamide;
7-isopropoxy-l-((3aS, 6aR)-2-oxohexahydro-5H-pyrrolo [3, 4-d] oxazol-5-yl) isoquinoline-6-carbonitrile ;
7-methoxy-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile;
7-(difluoromethoxy)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-
6-carboxamide;
l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-(2,2,2- trifluoroethoxy)isoquinoline-6-carboxamide;
l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-(2,2,2- trifluoroethoxy)isoquinoline-6-carbonitrile;
l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-phenoxyisoquinoline-6- carboxamide;
l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-phenoxyisoquinoline-6- carbonitrile;
l-(l-ethyl-2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)-yl)-7- isopropoxyisoquinoline-6-carboxamide;
l-(l,3-diethyl-2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)-yl)-7- isopropoxyisoquinoline-6-carboxamide;
7-isopropoxy-l-(2-oxohexahydro-lH-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)isoquinoline-
6-carboxamide;
7-isopropoxy-l-(2-oxohexahydro-lH-pyrrolo[3,4-b]pyrazin-6(2H)-yl)isoquinoline-6- carboxamide; 7-(cyclopentyloxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-(cyclohexyloxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-cyclobutoxy-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)isoquinoline-6- carboxamide;
7-(cyclopropylmethoxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)-7-(vinyloxy)isoquinoline-6- carboxamide;
l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-(vinyloxy)isoquinoline-6- carbonitrile;
7-(cyclopropylmethoxy)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile ;
7-cyclobutoxy-l-((3aS,6aR)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-cyclobutoxy-l-((3aR,6aS)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-(dicyclopropylmethoxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-((3,3-difluorocyclobutyl)methoxy)-l-((3aR,6aS)-2-oxotetrahydro-2H-pyrrolo[3,4- d]oxazol-5(3H)-yl)isoquinoline-6-carboxamide;
7-(tert-butoxy)-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile ;
7 -(tert-butoxy)- 1 -((3 aR, 6aS)-2-oxotetrahydro-2H-pyrrolo [3 ,4-d] oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-ethoxy- l-((3aR, 6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline- 6-carbonitrile; 7-ethoxy- l-((3aR, 6aS)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-(allyloxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)isoquinoline-6- carboxamide;
Further, useful compounds may be selected from but not limited to the following; l-((lR,5S)-3,6-diazabicyclo[3.l.l]heptan-6-yl)-7-methoxyisoquinoline-6- carboxamide;
1 -(( lR,5S)-3-(2-cyanoacetyl)-3 ,6-diazabicyclo[3.1.1 ]heptan-6-yl)-7 - methoxyisoquinoline-6-carboxamide;
7 -methoxy- 1 -(3 -oxopiperazin- 1 -yl)isoquinoline-6-carboxamide ;
1 -(3-acetamidopiperidin- 1 -yl)-7 -isopropoxyisoquinoline-6-carboxamide ;
7 -isopropoxy- 1 -(3 -(methylsulfonamido)piperidin- 1 -yl)isoquinoline-6-carboxamide ; l-(2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)-7-isopropoxyisoquinoline-6- carboxamide;
7-isopropoxy-l-(3-methyl-2, 4-dioxo- 1, 3, 8-triazaspiro[4.5]decan-8-yl)isoquinoline-6- carboxamide;
1 -(3-acetamidopyrrolidin- 1 -yl)-7 -isopropoxyisoquinoline-6-carboxamide ;
N-(l-(6-carbamothioyl-7-isopropoxyisoquinolin-l-yl)pyrrolidin-3-yl)acetamide; l-(2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)-7-isopropoxyisoquinoline-6- carboxamide;
7 -isopropoxy- 1 -(3 -methyl-2, 4-dioxo- 1 ,3 ,7-triazaspiro[4.4] nonan-7-yl)isoquinoline-6- carboxamide;
l-(3-acetamido-4-hydroxypyrrolidin-l-yl)-7-isopropoxyisoquinoline-6-carboxamide; l-(3-(hydroxymethyl)-4-(2,2,2-trifluoroacetamido)pyrrolidin-l-yl)-7- isopropoxyisoquinoline-6-carboxamide;
1 -(2, 4-dioxo- 1,3, 7-triazaspiro[4.5]decan-7-yl)-7-isopropoxyisoquinoline-6- carboxamide; l-(2,4-dioxo-l,3,7-triazaspiro[4.5]decan-7-yl)-7-methoxyisoquinoline-6- carboxamide;
7-methoxy-l-(3-methyl-2,4-dioxo-l,3,7-triazaspiro[4.5]decan-7-yl)isoquinoline-6- carboxamide;
l-(6,8-dioxo-2,5,7-triazaspiro[3.4]octan-2-yl)-7-isopropoxyisoquinoline-6- carboxamide;
l-(6,8-dioxo-2,5,7-triazaspiro[3.4]octan-2-yl)-7-methoxyisoquinoline-6- carboxamide;
l-(5, 6-dihydropyrrolo [3, 4-c] pyrrol-2(lH, 3H, 4H)-yl)-7-methoxyisoquinoline-6- carboxamide;
l-(5-(2-cyanoacetyl)-3, 4, 5, 6-tetrahydropyrrolo [3, 4-c] pyrrol-2(lH)-yl)-7- methoxyisoquinoline-6-carboxamide;
l-(5-(2-hydroxyacetyl)-3, 4, 5, 6-tetrahydropyrrolo [3, 4-c] pyrrol-2(lH)-yl)-7- methoxyisoquinoline-6-carboxamide;
7-methoxy-l -(2-oxo- l-oxa-3, 8-diazaspiro [4.5] decan-8-yl) isoquinoline-6- carboxamide;
7-isopropoxy-l -(2-oxo- l-oxa-3, 8-diazaspiro [4.5] decan-8-yl) isoquinoline-6- carboxamide;
7-methoxy-l -(3 -oxo- l-oxa-4, 9-diazaspiro [5.5] undecan-9-yl) isoquinoline-6- carboxamide;
7-isopropoxy-l-(3-oxo-l-oxa-4, 9-diazaspiro [5.5] undecan-9-yl) isoquinoline-6- carboxamide;
7-isopropoxy-l-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6-carboxamide;
7-methoxy-l-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6-carboxamide; 7-isopropoxy-l-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)isoquinoline-6-carboxamide; 7-methoxy-l-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)isoquinoline-6-carboxamide;
7 -isopropoxy- 1 -(4-(3-oxopiperazin- 1 -yl)piperidin- 1 -yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-(2-oxo-l,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6-carboxamide;
7-methoxy-l-(2-oxo-l,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6-carboxamide; 7-isopropoxy-l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile ;
7-isopropoxy-l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-methoxy-l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile ;
7-methoxy-l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aS,6aR)-6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6aS)-6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7 -isopropoxy- 1 -(4-(2-oxoimidazolidin- 1 -yl)piperidin- 1 -yl)isoquinoline-6- carbonitrile;
7 -isopropoxy- 1 -(4-(2-oxoimidazolidin- 1 -yl)piperidin- 1 -yl)isoquinoline-6- carboxamide;
benzyl 6-(6-carbamoyl-7-isopropoxyisoquinolin-l-yl)-3-oxooctahydro-lH- pyrrolo[3,4-b]pyrazine- 1 -carboxylate;
8.8-dimethyl- l-((3aR, 6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-8H- pyrano[2,3-h]isoquinoline-6-carbonitrile;
8.8-dimethyl- l-((3aR, 6aS)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)-8H- pyrano[2,3-h]isoquinoline-6-carboxamide;
8.8-dimethyl- l-((3aR,6aS)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)-9, 10- dihydro-8H-pyrano[2,3-h]isoquinoline-6-carboxamide;
Or pharmaceutically acceptable salts of any of the compounds above.
Following is a list of abbreviations used in the description of the preparation of the compounds of the present invention:
ACN : Acetonitrile BOC tert-Butyloxy carbonyl
Cs2C03 Cesium carbonate
DCM Dichloro methane
de diastereomeric excess
DIEA Diisopropyl ethyl amine
DIPE Diisopropyl ether
DMA N,N-Dimethyl acetamide
DMF N,N-Dimethyl formamide
DMSO Dimethyl sulfoxide
EtOH Ethanol
h hours
HC1 Hydrochloric acid
H202 Hydrogen peroxide
HPLC High performance liquid chromatography IPA Isopropyl alcohol
KHMDS Potassium bis(trimethylsilyl)amide solution MeOH Methanol
mCPBA meta- Chloro perbenzoic acid
MsCl Methane sulfonylchlorode
Mel Methyl iodide
Na2C03 Sodium carbonate
Na2S04 Sodium sulfate
NaHC03 Sodium bicarbonate/sodium hydrogen carbonate NMP N -Methyl -2-pyrrolidone
NaN3 Sodium azide
POCl3 Phosphorous oxychloride
PTSA p-Toluene sulphonic acid
/BuOK Potassium rc/t-butoxide
TEA Triethylamine TFA : Trifluoro acetic acid
THF : Tetrahydrofuran
TLC : Thin layer chromatography
The novel compounds of the present invention were prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art.
The reactions can be performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Preferred methods include, but not limited to those described below, where all symbols are as defined earlier unless and otherwise defined below.
The compounds of the formula (I) can be prepared as described in schemes below along with suitable modifications/variations which are well within the scope of a person skilled in the art.
Substituted benzaldehyde (1) can be treated with bromine in an appropriate solvent to give compound (2) or can be prepared by the method reported in literature along with their suitable modifications as may be necessary. Compound (2) can be treated with an alkylating agent such as Mel, iPrBr and a base like K2C03 or CS2CO3 in a suitable solvent to give compound (3). Knoevenagel condensation of Compound (3) with malonic acid typically in pyridine and piperidine can afford acrylic acid (4), which may be converted to acyl azide of the formula (5) by a variety of means known to one skill in art, for example sequential treatment with ethyl chloroformate followed by reaction with sodium azide. Upon exposure to high temperature, acyl azide (5) may undergo cyclization via Curtius reaction to afford isoquinolone (6). Cyanation of isoquinolone (6) via methods known to those skill in art such as treatment with zinc cyanide under palladium catalysis or Rosenmund-von Braun reaction using excess of copper (I) cyanide may provide compound (7), which upon treatment with phosphorous oxychloride in suitable system facilitated the formation of intermediate-1. General Scheme-1:
Figure imgf000025_0001
7 Intermediate-1
Intermediate-1 and the substituents representing R3 present in the compounds of general formula (I) are separately known in the literature or can be conveniently prepared by variety of methods familiar to those skilled in art or by methods described in the literature (for e.g. in WO 2015/150995 including their suitable variations).
Novel compounds of general formula (I) of the present invention can be prepared by treating intermediate-1 with the appropriate substituent R3. Further, R3 can also be prepared using the methods available in the literature, modifying the literature procedure or by various methods known to those skilled in art (WO 2007/087231, WO 2009/153554, WO 2009/109576, US 2010/0216839, WO 2008/014311, WO 2014/014874, JP 2009/298713, WO 2011030349 & / Med. Chem. 57(8) 3430-3449, 2014 etc.).
A synthetic route to compound of present invention is given in Scheme-2. Scheme-2:
Figure imgf000026_0001
As illustrated in Scheme-2, the compounds of the present invention with structural formula (I) can be prepared by coupling of Intermediate- 1 (obtained from the Scheme-1), with substituent-R3 using appropriate reagent such as CS2CO3, K2CO3, /BuOK, DIEA, TEA KHMDS or nBuLi in solvents such as l,4-dioxane, tetrahydrofuran, N,N-dimethyl acetamide, N, N-dimethyl form amide or N-methyl-2- pyrrolidinone. Reaction of Intermediate-1 with substituent-R3 can also be carried out by Ullmann type of reaction using various copper catalysts and methods available in the literature (for e.g. J. Am. Chem. Soc. 137, 11942-11945, 2015; Org. Lett. 14, 3056-3059, 2012; /. Org. Chem.76, 1180-1183, 2011 ; Org. Lett. 4, 581-584, 2002; /. Org. Chem. 71, 3270-3273, 2006) or by various methods known to those skilled in art. The base-catalyzed conversion of nitrile to amide by hydrogen peroxide provides the compounds of the general formula (I). Conversion of nitrile to amide can also be performed by means of acid or base catalyzed hydrolysis according to reported literature methods or by methods known to those skilled in art. Compounds of the present invention can be isolated either as free amine form or as a salt corresponding to the acid used such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, oxalic acid, maleic acid, fumeric acid, succinic acid, p-toluene sulfonic acid or benzene sulfonic acid. The compounds can be purified where ever required, by recrystallization, trituration, precipitation, preparative thin layer chromatography, flash chromatography or by preparative HPLC method.
The invention is further illustrated by the following non-limiting examples which describe the preferred way of carrying out the present invention. These are provided without limiting the scope of the present invention in any way. General Methods
Melting points were recorded on a scientific melting point apparatus and are uncorrected. IR spectra were recorded as neat (for oils) or on KBr pellet (for solid) on
FT-IR 8300 Shimadzu and are reported in wavenumbers v (cm 1). NMR spectra were measured on a Varian Unity 400 (1H at 400 MHz, 13C at 100 MHz), magnetic resonance spectrometer. Spectra were taken in the indicated solvent at ambient temperature. Chemical shifts (d) are given in parts per million (ppm) with tetramethylsilane as an internal standard. Multiplicities are recorded as follows: s = singlet, d = doublet, t = triplet, q = quartet, br = broad. Coupling constants (J values) are given in Hz. Mass spectra are recorded on Perkin -Rimer Sciex API 3000. ESI-Q- TOF-MS measurements were performed with a micrOTOF-Q II (Bruker Daltonics) mass spectrometer. HPLC analysis were carried out at kmax 220 nm using column ODS C-18, 150 mm x 4.6 mm x 4 pm on AGILENT 1100 series. Reactions were monitored using thin layer silica gel chromatography (TLC) using 0.25 mm silica gel 60F plates from Merck. Plates were visualized by treatment with UV, acidic p- anisaldehyde stain, KMn04 stain with gentle heating. Products were purified by column chromatography using silica gel 100-200 mesh and the solvent systems indicated.
All reactions involving air or moisture sensitive compounds were performed under nitrogen atmosphere in flame dried glassware. Tetrahydrofuran (THF) and diethyl ether (Et20) were freshly distilled from sodium/ benzophenone under nitrogen atmosphere. Other solvents used for reactions were purified according to standard procedures. Starting reagents were purchased from commercial suppliers and used without further purification unless otherwise specified.
Synthesis of intermediate-1: [l-chloro-7-isopropoxyisoquinoline-6-carbonitrile (la)]
Figure imgf000027_0001
Synthesis of Intermediate- 1 (l-chloro-7-isopropoxyisoquinoline-6-carbonitrile (la)) was carried out as shown in Scheme-3 and the stepwise procedure is depicted below:
Scheme-3:
Figure imgf000028_0001
Malonic acid, Ethyl chloroformate,
Pyridine, Piperidine TEA, NaN3, acetone,
Figure imgf000028_0003
Figure imgf000028_0002
Figure imgf000028_0004
Step-l: Preparation of 3-bromo-4-hvdroxybenzaldehvde (12)
4-Hydroxybenzaldehyde (II) (100 g, 8.18 mmol) was added to a solution of 1000 ml Chloroform and 100 ml Methanol. Add a mixture of Bromine (142 g, 9.01 mmol) in 200 ml Chloroform within 30 mints. Stir for 2 hrs at RT. Dilute with 1 L DCM and 1L water, wash with aq. Sodium thiosulphate and brine, dried and evaporated to dryness under reduced pressure to get 3-bromo-4-hydroxybenzaldehyde (12) as a solid (151 g, 92.2 % yield). Product was used as such in next reaction step without purification.
1H NMR: (CDCl3, 400 MHz): d 9.87 (s, 1H), 8.05 (d, 1H, / = 2.0Hz), 7.79 (dd, 1H, J] = 2.4Hz, J2 = 8.4Hz), 7.16 (d, 1H, / = 8.4Hz); ESI-MS: (+ve mode) 214.45 (M)+ (100 %). Step-2: 3-bromo-4-isopropoxybenzaldehyde (13)
A mixture of 3-bromo-4-hydroxybenzaldehyde (12) (150 g, 7.5 mmol) and
K2C03 (129 g, 9.3 mmol) in DMF (1.5 L) were treated with 2-bromopropane (10.1 g, 8.2 mmol) and stirred at 55 °C for l8h. An additional 20 g (1.6 mmol) of 2- bromopropane was added and the reaction was continued for additional 4 h. The reaction was cooled to about 30 °C and EtOAc (2.25 L) and water (2.25 L) were added. Layers were separated, and the aqueous layer was extracted with EtOAc (2 X 0.75 L). The combined EtOAc layer were washed with water (2 x 1.5 L) followed by brine (1.5 L), dried over NaoSCU, filtered, and concentrated to provide crude compound. Purified it by column chromatography to obtain 3-bromo-4- isopropoxybenzaldehyde (13) Yield: 118 g (66 %). 1H NMR: (400 MHz, CDCI3); d 9.82 (s, 1 H), 8.04 (d, 1H, / = 2.0Hz), 7.76 (dd, 1H, J} = 2.4Hz, J2 = 8.4Hz), 6.96 (d, 1H, / = 8.4Hz), 4.72-4.66 (m, 1 H), 1.45-1.33 (m, 6 H). ESI-MS: (+ve mode) 244.45 (M+H)+ (100 %). Step-3: Synthesis of (E)-3-(3-bromo-4-isopropoxyphenyl) acrylic acid (14)
3-bromo-4-isopropoxybenzaldehyde (13) (55 g, 2.27mmol) in anhydrous pyridine (231 mL) was treated with malonic acid (30.62 g, 2.94 mmol) and piperidine (9.7 g, 1.13 mmol) and heated to reflux for 2 h. Reaction mixture was added to 10 % HC1 soln. (1.5 L) and stirred for about 0.5 h, to adjust pH to about 4.0 and then the product was collected by filtration, washed with water till neutral pH and dried under fan dryer to provide the title compound (14). Yield: 60 g (93%). 'H NMR: (400 MHz, DMSO-d6); d 12.29 (bs, 1H), 7.94 (d, 1H, , / = 5.6Hz ) 7.66 (dd, 1H, J} = 2.0Hz, J2 = 8.4Hz), 7.52 (d, 1H, , / = l6.0Hz), 7.15-7.12 (d, 1H, , / = 8.8Hz), 6.46 (d, 1H, / = 16.0Hz), 4.76-4.70 (m, 1 H), 1.33 - 1.25 (m, 6H). ESI-MS: (+ve mode) 284.70 (M- H)-
Step-4: (E)-3-(3-bromo-4-isopropoxyphenyl) acryloyl azide (15) To a stirred solution of compound (E)-3-(3-bromo-4-isopropoxyphenyl) acrylic acid (14) (60 g, 2.10 mmol) in acetone (1.05 L), Et3N (21.3 g, 2.10 mmol) was added and the mixture was cooled to about -5 °C. Ethyl chloroformate (29.7 g, 2.73 mmol) was added dropwise, maintaining the temperature at about -5 °C. After completion of the addition, the mixture was stirred for approximately an additional 1 h at about -5 °C. A solution of sodium azide (20.8 g, 3.19 mmol) in water (76 mL) was added slowly at about -5 °C. After the addition of sodium azide solution was complete, the reaction mixture was slowly warmed to about 25 °C and stirred for about 0.5 h. The reaction mass was quenched by addition to water (3 L) and stirring for about 30 minutes at about 25 °C. The precipitate was filtered, washed with water (0.120 L) and dried to provide the title compound (15). Yield: 59 g (91%). 1 H NMR: (400 MHz, DMSO-d6); d 8.05 (s, 1H), 7.75-7.66 (m, 2H), 7.18 (d, 1H, / = 8.4Hz), 6.63 (d, 1H, / = l5.6Hz), 4.78 (t, 1H, / = 5.6Hz), 1.31-1.29 (d, 6H, / = 5.2Hz). ESI- MS: (+ve mode) 311.15 (M+H)+. Step 5. 6-bromo-7-isopropoxyisoquinolin-l (2H)-one (16).
To a mixture of diphenyl ether (219 ml) and tri n-butyl amine (8.97 g, 4.83 mmol) pre -heated to about 230 °C, (E)-3-(3-bromo-4-isopropoxyphenyl) acryloyl azide (15) (15 g, 4.83 mmol) dissolved in diphenyl ether (69 ml) was added while the temperature was maintained at about 230 °C. After the addition was completed, stirring and heating were continued for about 0.5 h. The reaction mixture was cooled to about 25 °C and added slowly to hexane (750 ml). The resulting slurry was cooled to about 0 °C and stirred for about 0.5 h. The crude precipitate was filtered the precipitate was washed with cold hexane (150 ml). The wet cake was dried under vacuum to afford 6 g of crude was purified by chromatography to afford title compound (16). Yield: 3.9 g (29 %). 1 H NMR: (400 MHz, CDCI3): d 11.25 (bs, 1H), 7.83 (s, 2H), 7.11 (d, 1H, / = 6.8Hz), 6.48 (d, 1H, / = 7.2Hz), 4.85-4.79 (m, 1 H), 1.48-1.46 (d, 6H, / = 6.0Hz). ESI-MS: (+ve mode) 283.14 (M+H)+. Step 6. 7-isopropoxy-l-oxo-l, 2-dihydroisoquinoline-6-carbonitrile .
Figure imgf000031_0001
6-bromo-7-isopropoxyisoQuinolin-l (2H)-one (16) (27 g, 9.57 mmol) and zinc cyanide (14.6 g, 12.43 mmol) were added to dry DMF (540 ml) and stirred for about 5 min at RT. The reaction mixture was degassed with nitrogen for about 30 minutes, then tetra(kis)triphenylphosphinepalladium(0) (6.64 g, 0.574 mmol) was added and the reaction mixture was stirred for about 5 min at RT then mixture was heated to about 100 °C. The mixture was maintained for about 16 hours at about 100 °C. The reaction mixture was cooled to about 25 °C, diluted with EtOAc (270 ml), and stirred for about 30 minutes. The mixture was filtered through celite, which was washed with EtOAc (60 ml). The combined filtrate was concentrated under pressure at about 75 °C. Water (270 ml) was added to the residue and the mixture was stirred for about 0.5 h. The precipitate was filtered, washed with water (60 ml) and dried under vacuum at about 60 °C. The precipitate was stirred for about 0.5 h with MTBE (270 ml) and filtered. This process was repeated twice more with Hexane, after which the filter cake was washed with MTBE (25 ml) and dried under vacuum at about 60 °C to provide the title compound (17) . Yield: 22 g (99%) 1 H NMR: (400 MHz, CDCIs); d 10.33 (bs, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.09-7.08 (m, 1H), 6.53 (d, 1H, J = 7.2Hz), 4.90-4.84 (m, 1H), 1.49-1.42 (d, 6H, / = 6.0Hz). ESI-MS: (+ve mode) 229.26 (M+H)+. Step 7. l-chloro-7-isopropoxyisoquinoline-6-carbonitrile (la).
7-isopropoxy-l -oxo-l, 2-dihydroisoquinoline-6-carbonitrile (17) (17 g, 7.44 mmol) and POCI3 (480.2 g, 313.18 mmol) were stirred for about 5 min at about 25 °C, then heated to about 100 °C and maintained at about 100 °C for about 0.5 h. The reaction mixture was cooled to RT and concentrated under reduced pressure at about 60 °C. The residue was quenched with ice (350 g), then neutralized with 25% K2CO3 solution (340 ml) with stirring until the mixture was about pH = 7. The solution was extracted with DCM (3 x 218 ml), and the combined extracts were washed with 10% NaHC03 solution (2 x 170 ml). The DCM was separated, dried over NaoSO^ filtered, and concentrated. N-Heptane (170 ml) was added to the residue and the mixture was stirred for 30 min at RT. The precipitate was filtered and the filter cake was washed with n-heptane (17 mL) and dried under vacuum at about 50 °C to provide the title compound (la) Yield: 16.5 g (90 %) 1H NMR: (400 MHz, dmso-d6); d 8.73 (s, 1 H), 8.31 (d, 1H, / = 5.2Hz), 7.90 (d, 1H, / = 5.2Hz), 7.67 (s, 1H), 5.07-5.01 (m, 1H), 1.43 (d, 6H, J = 6.0Hz). ESI-MS: (+ve mode) 246.65 (M+H)+.
Synthesis of substituent R3 [2-oxohexahydro-2H-pyrrolo[3,4-d]oxazol-5- ium chloride; (2a)]
Figure imgf000032_0001
Synthesis of substituent R3 (2-oxohexahydro-2H-pyrrolo[3,4-d]oxazol-5-ium chloride; 2a) was carried out as shown in Scheme-4 and the stepwise procedure is depicted below:
Scheme-4:
Figure imgf000032_0002
Step-l: tert- butyl 2,5-dihydro- 1 H-pyrrole- 1 -carboxylate (9)
Grubb’s Ist generation catalyst (433 mg, 0.517 mmol) was added to a solution of r <? r/-butyl diallylcarbamate (8) (15 g, 76.14 mmol) in DCM (150 ml). The reaction mixture was stirred for 18h (typically overnight) and then concentrated under reduced pressure. Flash chromatography purification of the residue afforded /e/t-butyl 2,5- dihydro- 1 H-pyrrole- 1 -carboxylate (9) as pale yellow oil (11.45 g, 91% yield).
1H NMR: (CDCl3, 400 MHz): d 5.79-5.76 (m, 2H), 4.15-4.09 (m, 4H), 1.49 (s, 9H); ESI-MS: (+ve mode) 192.1 (M+Na)+ (80 %).
Step-2: tert- butyl 6-oxa-3-azabicvclor3. l.01hexane-3-carboxylate (10)
To a solution of / -butyl 2,5-dihydro- 1 H-pyrrole- 1 -carboxylate (9) (l l.45g, 61.89 mmol), dissolved in DCM (110 ml) was added mCPBA (21.56 g, 81 mmol) portionwise at 0-5 °C. Reaction mixture was stirred for 5 days at 25 °C. Reaction mixture was washed sequentially with aqueous saturated sodium hydrogen sulfite solution, 5% aq K2C03 solution and brine (100 ml each) organic layer was separated, dried and evaporated to dryness under reduced pressure to get / -butyl 6-oxa-3- azabicyclo[3.l.0]hexane-3-carboxylate (10) as a thick oil (11.89 g, 100% yield).Product was used as such in next reaction step without any purification.
1H NMR: (CDCl3, 400 MHz): d 3.84 (d, / = 12.8Hz, 1H), 3.77 (d, / = 12.8Hz, 1H), 3.68 (d, J = 5.2Hz, 2H), 3.33 (dd, = 5.2Hz, J2 = 12.8Hz, 2H), 1.45 (s, 9H); ESI- MS: (+ve mode) 127.5 (M-/Bu)+ (90%).
Step-3: tert- butyl /ra/7v-3-azido-4-hvdroxypyrrol idine- 1 -carboxylate (11)
To the /<2 r/-butyl 6-oxa-3-azabicyclo[3.l.0]hexane-3-carboxylate (10) (11.8 g, 63.78 mmol) was added 5: 1 mixture of dioxane/water (120 ml) followed by addition of NaN3 (8.8 g, 135 mmol). The reaction mixture was refluxed for for 48h, cool to room temperature, diluted with mixture of water/ethyl acetate (1: 1, 400 ml). The layers were separated and aqueous layer was extracted with ethyl acetate (3 X 100 ml). Combined organic layer was dried over anhydrous NaoSCU, filtered and evaporated to dryness to give thick oil. Crude residue was purified by column chromatography to obtain tert-butyl /ra/i.v-3-azido-4-hydroxypyrrol idine- 1 - carboxylate (11) as an oil (12 g, 78% yield). 1H NMR: (CDCl3 400 MHz): d 4.26- 4.23 (m, 1H), 3.92 (bs, 1H), 3.70-3.62 (m, 2H), 3.48-3.31 (m, 2H), 1.46 (s, 9H); ESI- MS: (+ve mode) 229.1 (M+H)+ (20%), 173.6 (M-/Bu)+ (70%).
Step-4: tert-butyl /ra/7.v-3-amino-4-hvdroxypyrrolidine- 1 -carboxylate (12)
To /er/-butyl rra/i.v-3-azido-4-hydroxypyrrol idine- 1 -carboxylate (11) (6 g, 26.3 mmol) in ethanol (90 ml) was added 10% palladium on carbon (1 g, 4.7 mmol). The reaction mixture was hydrogenated at latm for 40h. The mixture was filtered through Hyflow Supercell washed with methanol (100 ml). Combined filtrate were concentrated to give rerr-butyl rra/i.v-3-amino-4-hydroxypyrrol idine- 1 -carboxylate (12) as an oil (5.3 g, 100% yield) which was used as such in next reaction step.
1H NMR: (CDCl3, 400 MHz): d 4.00-3.97 (m, 1H), 3.75-3.69 (m, 2H), 3.34-3.27 (m, 2H), 3.11-3.04 (m, 1H), 1.49 (s, 9H); ESI-MS: (+ve mode) 203.1 (M+H)+ (60%).
Step-5: /er/-butyl frc// .v-3-((tert-butoxycarbonyl )amino)-4-hydroxynyrrolidine- 1 - carboxylate (13)
To a solution of tert-butyl rra/i.v-3-amino-4-hydroxypyrrol idine- 1 -carboxylate (12) (5.3 g, 26.2 mmol) in DCM (106 ml) was added TEA (4.38 ml, 31.4 mmol), Boc-anhydride (7.0 ml, 30.1 mmol) and the mixture was stirred at room temperature for l8h. Reaction mixture was then evaporated under reduced pressure and purified by column chromatography to give tert-butyl /ra/i.v-3-((tert-butoxycarbonyl)amino)- 4-hydroxypyrrolidine- 1 -carboxylate (13) (4.5 g, 57% yield) as an oil.
1H NMR: (CDCI3, 400 MHz): d 4.72-4.66 (m, 1H), 4.22 (bs, 1H), 3.93 (bs, 1H), 3.77-3.67 (m, 2H), 3.29-3.19 (m, 2H), 1.47 (s, 18H); ESI-MS: (+ve mode) 303.4 (M+H)+ (90%). Step-6: fert-butyl /ra/7.v-3-((tert-butoxycarbonyl )amin )-4-((methylsulfonyl )oxy) pyrrolidine- 1 -carboxylate (14)
To a solution of /ra/i.v-3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine- 1 -carboxylate (13) (4.5 g, 14.88 mmol) in DCM (135 ml) at 0°C was added TEA (2.5 ml, 17.86 mmol) and methanesulfonyl chloride (1.28 ml, 16.37 mmol). The mixture was stirred at room temperature for 18h. Reaction mixture was then evaporated under reduced pressure and purified by column chromatography to give tert-butyl trans- 3- ((tert-butoxycarbonyl)amino)-4-((methylsulfonyl)oxy)pyrrolidine- 1 -carboxylate (14) (6.5 g, 77% yield) as an oil.
1H NMR: (CDCl3, 400 MHz): d 5.05 (bs, 1H), 4.67 (bs, 1H), 4.23-4.19 (m, 1H), 3.77-3.71 (m, 2H), 3.66-3.62 (m, 1H), 3.46-3.31 (m, 1H), 3.16 (s, 3H), 1.47 (s, 18H); ESI-MS: (+ve mode) 403.1 (M+Na)+ (20%), 280.7 (M-Boc)+.
Step-7: tert- butyl 2-oxohexahvdro-5H-pyrrolor3,4-d1oxazole-5-carboxylate (15)
A solution of tert-butyl /ra/i.v-3-((tert-butoxycarbonyl)amino)-4- ((methylsulfonyl)oxy)pyrrolidine-l -carboxylate (14) (6.5 g, mmol) in dichloroethane was refluxed for l8h (typically overnight). Solvent was evaporated to dryness and the residue was purified by column chromatography to give /erz-butyl 2-oxohexahydro- 5H-pyrrolo[3,4-d]oxazole-5-carboxylate (15) (2.2 g, 56% yield) as an oil.
1H NMR: (CDCI3, 400 MHz): d 6.03 (bs, 1H), 5.13-5.09 (m, 1H), 4.38 (t, / = 6.4Hz, 1H), 3.96 (d, J = 13.6HZ, 1H), 3.77-3.74 (m, 1H), 3.45-3.40 (m, 1H), 3.34-3.29 (m, 1H), 1.47 (s, 9H); ESI-MS: (+ve mode) 245.7 (M+NH4)+ (100%).
Step-8: 2-oxohexahvdro-2H-pyrrolor3,4-d1oxazol-5-ium chloride (2a)
To r e r/-butyl 2-oxohexahydro-5H-pyrrolo[3,4-d]oxazole-5-carboxylate (15) (2.2 g, mmol) was added 4M HC1 in dioxane (10 ml). Clear solution was stirred for 5h. Solvent was then evaporated to dryness and the residue was triturated with ether, solid obtained was dried well to give 2-oxohexahydro-2H-pyrrolo[3,4-d]oxazol-5- ium chloride (2a) (1.52 g, 96% yield).
Figure imgf000036_0001
Step-l: Synthesis of 7-isoproxy-l-(2-oxohexahvdro-5H-pyrrolor3,4-d1oxazol-5- yl)isoquinoline-6-carbonitrile (Compound-1)
Under nitrogen atmosphere l-chloro-7-methoxyisoquinoline-6-carbonitrile (la) (Intermediate- 1) (6.0 g, 24.32 mmol,) and 2-oxohexahydro-2H-pyrrolo[3,4- d]oxazol-5-ium chloride (2a) (substituent-R3; 4.20 g, 25.5 mmol) were suspended in NMP (120 ml). To this reaction mixture added DIEA (12.74 ml, 73.0 mmol) in a single portion and heated to 80°C for 48h. Reaction mixture was then evaporated to dryness and the residue obtained was purified by column chromatography to give 7- isopropoxy-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-6- carbonitrile (Compound-1) (3.05 g, 36% yield) as a light yellow solid.
1H NMR: (DMSO d6, 400 MHz): d 8.52 (s, 1H), 8.09 (d, / = 5.6 Hz, 1H), 7.91 (s, 1H), 7.51 (s, 1H), 7.42 (d, / = 6.0 Hz, 1H), 5.21 (dd, J} = 4.4 Hz, J2 = 7.6 Hz,IH), 4.87 (dd,lH, J} = 6.0 Hz, J2 = 12.0 Hz), 4.44 (dd, J} = 4.8 Hz, J2 = 7.2 Hz,IH), 3.93 (d, / = 12.8 Hz, 1H), 3.80-3.77 (m, 1H), 3.29-3.25 (m, 1H), 3.19-3.15 (m, 1H), 1.44- 1.41 (m, 6H); ESI-MS: (+ve mode) 339.13 (M+H)+ (100 %); UPLC: 97.33 %, Ret.time = 2.759 min. Step-2: Synthesis of 7-isopropoxy-l-(2-oxohexahvdro-5H-pyrrolor3,4-d1oxazol-5- yl)isoquinoline-6-carboxamide ( Compound-2)
Compound of step-l 7-isopropoxy-l-(2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carbonitrile (3.15 g, 9.29 mmol) was dissolved in DMSO (60 ml), to it added K2C03 (3.85 g, 27.8 mmol) at room temperature followed by dropwise addition of 30% aqueous ¾(¾ (17.06 ml, 167.0 mmol) . Reaction mixture was heated to 50°C for an hour. Solvent was evaporated under reduced pressure and residue obtained was purified by column chromatography to give 7- isopropoxy-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-6- carboxamide (Compound-2) as a light yellow solid (3.15 g, 94% yield).
1H NMR: (DMSO-d6 400 MHz): d 8.20 (s, 1H), 8.01 (d, 1H, / = 5.6Hz), 7.91 (s, 1H), 7.74 (bs, 2H), 7.48 (s, 1H), 7.45 (d, 1H, / = 5.6Hz), 5.21 (dd, 1H, J} = 4.0Hz, J2 = 7.6Hz), 4.81 (septet, 1H, / =6.0Hz), 4.43 (dd, 1H, = 4.4Hz, J2 = 7.2Hz), 3.89 (d, 1H, / = l2.8Hz), 3.67 (d, 1H, / = l l.2Hz), 3.39 (dd, 1H, J} = 4.4Hz, J2 = l2.8Hz), 3.16 (dd, 1H, = 4.4Hz, J2 = l l.2Hz), 1.42 (d, 6H, / = 6.0Hz); ESI-MS: (+ve mode) 357.15 (M+H)+ (100 %); UPLC: 99.64 %, Ret.time = 1.707 min.
Using above procedure following compounds were prepared.
Compound 03: 7-methoxy-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carbonitrile (Racemic)
Figure imgf000037_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.52 (s, 1H), 8.09 (d, 1H, / = 5.6Hz), 7.93 (s, 1H), 7.48 (s, 1H), 7.42 (d, 1H, / = 5.6Hz), 5.21 (dd, 1H, J = 4.0Hz, J2 = 7.6Hz), 4.43 (dd, 1H, J} = 4.8Hz, J2 = 7.6Hz), 4.03 (s, 3H),3.92 (d, 1H, / = l2.8Hz), 3.79 (d, 1H, J = 1 l.2Hz), 3.35 (dd, 1H, = 4.4Hz, J2 = l2.4Hz), 3.17-3.13 (m, 1H); ESI-MS: (+ve mode) 310.85 (M+H)+ (100 %); UPLC: 96.86 %, Ret.time = 2.44 min.
Compound 04: 7-methoxy- 1 -(3-methyl-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol- 5(3H)-yl)isoquinoline-6-carbonitrile (Racemic)
Figure imgf000038_0001
1H NMR: (DMSO-d6 400 MHz): d 8.53 (s, 1H), 8.07 (d, 1H, / = 5.6Hz), 7.43 (s, 1H), 7.42 (d, 1H, / = 5.6Hz), 5.14 (dd, 1H, J} = 4.4Hz, J2 = 7.6Hz), 4.41 (dd, 1H, J} = 4.8Hz, J2 = 7.6Hz), 4.15 (d, 1H, / = 12.4Hz), 4.04 (s, 3H), 3.94 (d, 1H, / = l2.8Hz), 3.46 (dd, 1H, = 4.4Hz, J2 = l2.8Hz), 3.12 (dd, 1H, J = 4.4Hz, J2 = l2.4Hz), 2.87
(s, 3H); ESI-MS: (+ve mode) 324.90 (M+H)+ (100 %); UPLC: 96.25 %, Ret.time = 2.728 min.
Compound 05: 7-methoxy- l-(3-methyl-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol- 5(3H)-yl)isoquinoline-6-carboxamide (Racemic)
Figure imgf000038_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.18 (s, 1H), 8.01 (d, 1H, / = 5.6Hz), 7.84 (s, 1H), 7.70 (s, 1H), 7.44 (d, 1H, / = 5.6Hz), 7.36 (s, 1H), 5.14 (dd, 1H, J} = 4.4Hz, J2 = 7.6Hz), 4.42-4.40 (m,lH), 4.11-4.08 (m, 2H), 3.97 (s, 3H), 3.89 (d, 1H, / = l2.4Hz), 3.39 (dd, 1H, = 4.4Hz, J2 = l2.8Hz), 3.06 (dd, 1H, J = 4.4Hz, J2 = l2.4Hz), 2.88 (s, 3H); ESI-MS: (+ve mode) 342.90 (M+H)+ (100 %); UPLC: 98.16 %, Ret.time = 1.775 min.
Compound 06: 7-methoxy-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide (Racemic)
Figure imgf000039_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.20 (s, 1H), 7.99-7.96 (m, 2H), 7.88 (s, 1H), 7.75 (s, 1H), 7.49-7.46 (m, 2H), 7.36 (s, 1H), 5.25 (dd, 1H, J} = 4.4Hz, J2 = 7.6Hz), 4.47 (dd, 1H, J} = 4.4Hz, J2 = 7.2Hz), 4.11-4.08 (m, 2H), 3.99 (s, 3H), 3.92 (d, 1H, / = l2.8Hz), 3.83 (d, 1H, / = l l.2Hz), 3.49 (dd, 1H, J} = 4.4Hz, J2 = l2.4Hz), 3.29-
3.27 (m, 1H); ESI-MS: (+ve mode) 328.85 (M+H)+ (100 %); UPLC: 96.78 %, Ret.time = 1.059 min.
Compound 07: 7-isopropoxy-l-((3aR, 6aS)-2-oxohexahydro-5H-pyrrolo [3, 4-d] oxazol-5-yl) isoquinoline-6-carbonitrile.
Figure imgf000039_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.53 (s, 1H), 8.06 (d, 1H, / = 5.6Hz), 7.93 (s, 1H), 7.53 (s, 1H), 7.41 (d, 1H, / = 5.6Hz), 5.23-5.20 (m, 1H), 4.88 (Septet, 1H, / = 6.0Hz), 4.46-4.43 (m, 1H), 3.94-3.91 (m, 1H), 3.74-3.72 (m, 1H), 3.38-3.34 (m, 1H), 3.25-3.21 (m, 1H), 1.43-1.41 (m, 6H); ESI-MS: (+ve mode) 339.12 (M+H)+ (100 %); UPLC: 93.18%, Ret.time = 2.72min.
Compound 08: 7-isopropoxy- 1 -(2-oxohexahydropyrrolo[3 ,4-d] [ 1 ,3]oxazin-6(4H)- yl)isoquinoline-6-carboxamide
Figure imgf000040_0001
1H NMR: (DMSO-d6 400 MHz): d 8.14 (s, 1H), 7.88 (d, 1H, / = 5.6Hz), 7.74 (bs, 2H), 7.55 (s, 1H), 7.32 (s, 1H), 7.19 (d, 1H, / = 5.6Hz), 4.84 (septet, 1H, / = 6.0Hz), 4.38-4.37 (m, 1H), 4.35-4.34 (m, 1H), 4.27-4.25 (m, lH), 4.06-4.02 (m, 1H), 3.99- 3.98 (m, 1H), 3.89-3.87 (m,lH), 3.77-3.71 (m, 2H), 2.89-2.86 (m, 1H), 1.41 (d, 3H, J
= 6.0Hz) 1.39 (d, 3H, J = 6.0Hz); ESI-MS: (+ve mode) 370.94 (M+H)+ (100 %); UPLC: 99.01 %, Ret.time = 1.637 min.
Compound 09: 7-methoxy-l-(2-oxohexahydropyrrolo[3,4-d][l,3]oxazin-6(4H)- yl)isoquinoline-6-carboxamide
Figure imgf000040_0002
1H NMR: (DMSO-d6 400 MHz): d 8.11 (s, 1H), 7.91 (d, 1H, / = 5.6Hz), 7.84 (s, 1H), 7.70 (s, 1H), 7.52 (s, 1H), 7.34 (s, 1H), 7.21 (d, 1H, / = 5.6Hz), 4.39-4.38 (m, 1H), 4.36-4.34 (m, 1H), 4.28-4.24 (m,lH), 4.07-4.00 (m, 1H), 3.98-3.96 (m, 1H), 3.88-3.86 (m,lH), 3.81 (s, 3H), 3.79-3.71 (m, 2H), 2.84-2.82 (m, 1H); ESI-MS: (+ve mode) 342.92 (M+H)+ (100 %); UPLC: 99.60 %, Ret.time = 0.901 min.
Compound 10: 7-isopropoxy-l-(2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)- yl)isoquinoline-6-carboxamide
Figure imgf000041_0001
1H NMR: (DMSO-d6 400 MHz): d 8.22 (s, 1H), 7.85 (d, 1H, / = 6.4Hz), 7.78 (bs, 2H), 7.67 (s, 1H), 7.42 (d, 1H, / = 5.6Hz), 6.67 (bs, 2H), 4.90 (septet, 1H, / = 6.0Hz), 4.36 (s, 2H), 3.86-3.84 (m, 2H), 3.61-3.60 (m, 1H), 1.41 (d, 6H, J = 6.0Hz); ESI- MS: (+ve mode) 356.15 (M+H)+ (100 %); UPLC: 95.91 %, Ret.time = 1.488 min.
Compound 11: 7-methoxy-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide
Figure imgf000041_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.18 (s, 1H), 8.03 (d, 1H, / = 5.6Hz), 7.95 (s, 1H), 7.86 (s, 1H), 7.45 (d, 2H, / = 6.0Hz), 5.21 (dd, 1H, J}= 4.0Hz, J2 = 7.6Hz), 4.44 (dd, 1H, h= 4.4Hz, J2 = 7.6Hz), 3.98 (s, 3H), 3.90 (d, 1H, / = 12.8Hz ), 3.87 (d, 1H, / = l l.2Hz ), 3.34-3.31 (m, 1H), 3.17-3.10 (m, 1H); ESI-MS: (+ve mode) 329.26 (M+H)+ (100 %); UPLC: 98.03 %, Ret.time = 0.937 min. Compound 12: l-(6-(4-fluorophenyl)-2-oxohexahydropyrrolo[3,4-b]pyrrol-5(lH)- yl)-7-isopropoxyisoquinoline-6-carboxamide
Figure imgf000042_0001
1H NMR: (DMSO-d6 400 MHz): d 8.14 (s, 1H), 7.95 (s, 1H), 7.90 (d, 1H, / = 5.6Hz), 7.69-7.67 (m, 2H), 7.49-7.47 (m, 2H), 7.45 (s, 1H), 7.28 (d, 2H, / = 5.6Hz), 7.23-7.18 (m, 2H), 5.34 (s, 1H), 4.31 (septet, 1H, / = 6.0Hz), 4.12-4.10 (m, 1H), 4.06-4.04 (m, 1H), 4.00-3.99 (m, 1H), 3.21-3.19 (m, 1H), 2.34-2.33 (m, 1H), 2.27- 2.26 (m, 1H), 1.24 (d, 3H, J = 6.0Hz ), 1.18 (d, 3H, J = 6.0Hz ); ESI-MS: (+ve mode) 449.20 (M+H)+ (100 %); UPLC: 97.45 %, Ret.time = 2.396 min.
Compound 13: 7-isopropoxy-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carboxamide
Figure imgf000042_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.20 (s, 1H), 8.01 (d, 1H, / = 5.6Hz), 7.91 (s, 1H), 7.74 (bs, 2H), 7.48 (s, 1H), 7.45 (d, 1H, / = 5.6Hz), 5.21 (dd, 1H, = 4.0Hz, J2 = 7.6Hz), 4.81 (septet, 1H, / =6.0Hz), 4.43 (dd, 1H, J} = 4.4Hz, J2 = 7.2Hz), 3.89 (d, 1H, / = l2.8Hz), 3.67 (d, 1H, / = l l.2Hz), 3.29 (dd, 1H, J} = 4.4Hz, J2 = l2.8Hz), 3.16 (dd, 1H, J] = 4.4Hz, J2 = l l.2Hz), 1.43-1.41 (m, 6H); ESI-MS: (+ve mode) 357.15 (M+H)+ (100 %); UPLC: 97.88 %, Ret.time = 1.630 min; Chiral Purity by HPLC: 98.46%, Ret.time = 9.053 min.; 96.92%ee.
Compound 14: 7-isopropoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carboxamide
Figure imgf000043_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.20 (s, 1H), 8.01 (d, 1H, / = 5.6Hz), 7.91 (s, 1H), 7.74 (bs, 2H), 7.48 (s, 1H), 7.45 (d, 1H, / = 5.6Hz), 5.21 (dd, 1H, J} = 4.0Hz, J2 = 7.6Hz), 4.81 (septet, 1H, 7 =6.0Hz), 4.43 (dd, 1H, J} = 4.4Hz, J2 = 7.2Hz), 3.89 (d, 1H, / = 12.8HZ), 3.67 (d, 1H, / = l l.2Hz), 3.28 (dd, 1H, J} = 4.4Hz, J2 = l2.8Hz),
3.15 (dd, 1H, J] = 4.4Hz, J2 = l l.2Hz), 1.43-1.41 (m, 6H); ESI-MS: (+ve mode)
357.15 (M+H)+ (100 %); UPLC: 98.34 %, Ret.time = 1.639 min; Chiral Purity by HPLC: 98.93%, Ret.time = 14.645 min.; 97.86%ee. Compound 15: l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-(prop-2-yn-l- yloxy)isoquinoline-6-carboxamide
Figure imgf000043_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.15 (s, 1H), 8.03 (d, 1H, J = 5.6Hz), 7.87 (s, 1H), 7.84 (s, 1H), 7.59 (s, 1H), 7.43 (d, 1H, / = 6.0Hz), 5.21 (dd, 1H, J} = 4.0Hz, J2 = 7.6Hz), 5.09-4.97 (m, 2H), 4.43 (dd, 1H, = 4.8Hz, J2 = 7.6Hz), 4.00 (d, 1H, J = l2.8Hz), 3.85 (d, 1H, / = l l.6Hz), 3.66 (t, 1H, / = 2.4Hz), 3.41-3.33 (m, 1H), 3.20- 3.16 (m, 1H); ESI-MS: (+ve mode) 353.12 (M+H)+ (100 %); UPLC: 99.62 %, Ret.time = 1.333 min;
Compound 16: tert-butyl 3-((6-cyano-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5-yl)isoquinolin-7-yl)oxy)azetidine-l-carboxylate
Figure imgf000044_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.60 (s, 1H), 8.12 (d, 1H, / = 5.6Hz), 8.02 (s, 1H), 7.46 (d, 1H, / = 6.0Hz), 7.14 (s, 1H), 5.32-5.30 (m, 1H), 5.22 (dd, 1H, =
4.0Hz, J2 = 7.6Hz), 5.09-4.97 (m, 2H), 4.47-4.44 (m, 3H), 3.98-3.87 (m, 3H), 3.72- 3.69 (m, 1H), 3.33-3.31 (m, 1H), 3.17-3. 13 (m, 1H), 1.41 (s, 9H); ESI-MS: (+ve mode) 452.20 (M+H)+ (20 %), 352.10 (M-Boc)+ (100%); UPLC: 98.08 %, Ret.time = 3.369 min;
Compound 17: 7-(oxetan-3-yloxy)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide
Figure imgf000044_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.61 (s, 1H), 8.12 (d, 1H, = 6.0Hz), 8.05 (s, 1H), 7.72 (bs, 2H), 7.47 (d, 1H, / = 5.6Hz), 7.03 (s, 1H), 5.98-5.58 (m, 1H), 5.22 (dd, 1H, Jj = 4.0Hz, J2 = 7.6Hz), 5.09-5.06 (m, 2H), 4.74-4.68 (m, 2H), 4,46 (dd, 1H, J} = 4.8Hz, J2 = 7.6Hz), 3.87 (d, 1H, / = l2.4Hz), 3.66 (d, 1H, / = l l.2Hz), 3.28 (dd, 1H, J} = 4.4Hz, J2 = l2.4Hz), 3.14 (dd, 1H, J} = 4.4Hz, J2 = l l.2Hz); ESI-MS: (+ve mode) 353.10 (M+H)+ (100%); UPLC: 97.75 %, Ret.time = 2.321 min.
Compound 18: tert-butyl 3-((6-carbamoyl-l-(2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinolin-7-yl)oxy)azetidine-l-carboxylate
Figure imgf000045_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.19 (s, 1H), 8.05 (d, 1H, / = 6.0Hz), 8.00 (s, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.48 (d, 1H, J = 5.6Hz), 7.05 (s, 1H), 5.23-5.19 (m, 2H), 4.46-4.40 (m, 3H), 4.12-4.10 (m, 1H), 4.09-3.99 (m, 1H), 3.95-3.92 (m, 1H), 3.71-3.63 (m, 1H), 3.28-3.26 (m, 1H), 3.14-3.12 (m,lH), 1.40 (s, 9H); ESI-MS: (+ve mode) 470.19 (M+H)+ (100%); UPLC: 99.35 %, Ret.time = 2.338 min;
Compound 19: 7-(azetidin-3-yloxy)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide
Figure imgf000045_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.29 (s, 1H), 8.15 (s, 1H), 7.99 (d, 1H, / = 6.0Hz), 7.92-7.90 (m, 2H), 7.54 (d, 1H, J = 6.0Hz), 7.10 (s, 1H), 5.39-5.37 (m, 1H), 5.28 (dd, 1H, J} = 4.0Hz, J2 = 7.2Hz), 4.57-4.50 (m, 3H), 4.19-4.17 (m, 2H), 3.84 (d, 1H, / = l l.2Hz), 3.62 (d, 1H, / = l l.6Hz), 3.22 (dd, 1H, J = 4.4Hz, J2 = l2.4Hz), 3.09 (dd, 1H, = 4.4Hz, J2 = l l.2Hz); ESI-MS: (+ve mode) 370.14 (M+H)+
(100%); UPLC: 95.40 %, Ret.time = 0.658 min.
Compound 20: 7-methoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5-yl)isoquinoline-6-carbonitrile
Figure imgf000046_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.54 (s, 1H), 8.10 (d, 1H, / = 6.0Hz), 7.95 (s, 1H), 7.48 (s, 1H), 7.42 (d, 1H, / = 5.6Hz), 5.22 (dd, 1H, = 4.0Hz, J2 = 7.2Hz), 4.44 (dd, 1H, J ] = 4.8Hz, J2 = 7.2Hz), 3.92 (d, 1H, / = 12.4Hz), 3.80 (d, 1H, / = l l.2Hz), 3.38 (dd, 1H, = 4.4Hz, J2 = l2.4Hz), 3.15 (dd, 1H, J = 4.4Hz, J2 = l l.2Hz); ESI- MS: (+ve mode) 311.11 (M+H)+ (100%); UPLC: 98.35 %, Ret.time = 2.208 min.
Compound 21: 7-methoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5-yl)isoquinoline-6-carboxamide
Figure imgf000046_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.18 (s, 1H), 8.03 (d, 1H, / = 5.6Hz), 7.95 (s, 1H), 7.86 (s, 1H), 7.72 (s, 1), 7.45 (s, 1H), 7.44 (d, 1H, / = 5.6Hz), 5.21 (dd, 1H, J} = 4.0Hz, J2 = 7.6Hz), 4.44 (dd, 1H, J} = 4.8Hz, J2 = 7.6Hz), 3.8 (s, 3H), 3.90 (d, 1H, / = l2.4Hz), 3.78 (d, 1H, / = l l.2Hz), 3.35 (dd, 1H, = 4.4Hz, J2 = 12.4Hz), 3.13 (dd, 1H, J] = 4.4Hz, J2 = l l.2Hz); ESI-MS: (+ve mode) 329.08 (M+H)+ (100%); UPLC: 97.55 %, Ret.time = 1.110 min; Chiral Purity by HPLC: 99.92%, Ret.time = 20.748 min.; 99.84%ee.
Compound 22: 7-methoxy-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5-yl)isoquinoline-6-carboxamide
Figure imgf000047_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.18 (s, 1H), 8.03 (d, 1H, / = 5.6Hz), 7.95 (s, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 7.45 (s, 1H), 7.44 (d, 1H, / = 5.6Hz), 5.21 (dd, 1H, J = 4.0Hz, J2 = 7.6Hz), 4.44 (dd, 1H, = 4.8Hz, J2 = 7.6Hz), 3.8 (s, 3H), 3.90 (d, 1H, / = l2.4Hz), 3.78 (d, 1H, / = l l.2Hz), 3.35 (dd, 1H, J} = 4.4Hz, J2 = 12.4Hz), 3.13 (dd, 1H, J] = 4.4Hz, J2 = l l.2Hz); ESI-MS: (+ve mode) 329.08 (M+H)+ (100%); UPLC: 98.01 %, Ret.time = 1.110 min; Chiral Purity by HPLC: 99.47%, Ret.time = 13483 min.; 98.5%ee. Compound 23: 7-isopropoxy-l-(2-oxohexahydropyrrolo [3,4-b]pyrrol-5(lH)- yl)isoquinoline-6-carboxamide
Figure imgf000048_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.17 (s, 1H), 7.95 (d, 1H, / = 5.6Hz), 7.81 (s, 1H), 7.73 (bs, 2H), 7.50 (s, 1H), 7.31 (d, 1H, / = 5.6Hz), 4.86-4.83 (m, 1H), 4.24- 4.21 (m, H), 3.64-3.50 (m, 4H), 3.13-3.09 (m, 1H), 2.61-2.53 (m 1H), 2.20-2.15 (m, 1H), 1.41 (d, 6H, / = 6.0Hz); ESI-MS: (+ve mode) 355.16 (M+H)+ (100%); UPLC:
99.12 %, Ret.time = 1.110 min;
Compound 24: 7-isopropoxy-l-((3aS, 6aR)-2-oxohexahydro-5H-pyrrolo [3, 4-d] oxazol-5-yl) isoquinoline-6-carbonitrile.
Figure imgf000048_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.53 (s, 1H), 8.06 (d, 1H, / = 5.6Hz), 7.93 (s, 1H), 7.53 (s, 1H), 7.41 (d, 1H, / = 5.6Hz), 5.23-5.20 (m, 1H), 4.88 (Septet, 1H, / = 6.0Hz), 4.46-4.43 (m, 1H), 3.94-3.91 (m, 1H), 3.74-3.72 (m, 1H), 3.39-3.35 (m, 1H), 3.25-3.21 (m, 1H), 1.43-1.41 (m, 6H); ESI-MS: (+ve mode) 339.10 (M+H)+ (100 %); UPLC: 98.40%, Ret.time = 2.7lmin.
Compound 25: 7-methoxy-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5-yl)isoquinoline-6-carbonitrile.
Figure imgf000049_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.54 (s, 1H), 8.09 (d, 1H, = 5.6Hz), 7.95 (s, 1H), 7.50 (s, 1H), 7.42 (d, 1H, / = 5.6Hz), 5.26-5.17 (m, 1H,), 4.49-4.43 (m, 1H), 3.93 (d, 3H, / = 12.4 Hz ), 3.81 (d, 2H, / = 12 Hz), 3.41-3.37 (dd, 1H, J = 4.4Hz, J2 = l2.4Hz), 3.20-3.16 (dd, 1H, = 4.8Hz, J2 = 12 Hz); ESI-MS: (+ve mode)
311.1121 (M+H)+ (100 %); UPLC: 97.20 %, Ret.time = 2.221 min;.
Compound 26: 7-(difluoromethoxy)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide.
Figure imgf000049_0002
1H NMR: (DMSO-d6 400 MHz): d 8.12 (d, 1H, / = 6.0Hz), 8.1 (s,lH), 8.00 (s, 1H), 7.91 (s, 1H), 7.76 (s, 2H), 7.48-7.12 (m, 2H), 5.26-5.19 (m, 1H), 4.44-4.41 (m, 1H), 3.96 (d, 1H, / = 12.4 Hz ), 3.78 (d, 1H, / = 11.2 Hz), 3.41-3.37 (m, 1H), 3.27-3.23 (m, 1H); ESI-MS: (+ve mode) 365.0981 (M+H)+ (100 %); UPLC: 99.3 %, Ret.time = 1.177 min; Chiral Purity by HPLC: 48.98: 51.01%, Ret.time = 6.96 min. : 13.07 min. resp;
Compound 27: l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- (2,2,2-trifluoroethoxy)isoquinoline-6-carboxamide.
Figure imgf000050_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.09 (s,lH), 8.06 (d, 1H, / = 5.6Hz), 7.91 (s, 1H), 7.75 (d, 2H, / = 10.4 Hz ), 7.48 (s, 1H), 7.43 (d, 1H, / = 5.6Hz), 5.22-5.19 (m, 1H),
5.0-4.92 (m, 2H), 4.45 -4.42 (m, 1H), 3.95 (d, 1H, = 12.4Hz ), 3.86 (d, 1H, = 11.2 Hz), 3.47-3.43 (m, 1H), 3.22-3.16 (m, 1H); ESI-MS: (+ve mode) 397.1033 (M+H)+ (100 %); UPLC: 99.11 %, Ret.time = 1.811 min;
Compound 28: l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- (2,2,2-trifluoroethoxy)isoquinoline-6-carbonitrile.
Figure imgf000050_0002
1H NMR: (DMSO-d6 400 MHz): d 8.59 (s,lH), 8.11 (d, 1H, / = 5.6Hz), 7.915 (s, 1H), 7.576 (s, 1H ), 7.48 (s, 2H), 7.41 (d, 1H, / = 5.6Hz), 5.23-5.20 (m, 1H), 5.14- 5.08 (m, 2H), 4.01 (d, 1H, / = l2.8Hz), 3.91 (d, 1H, / = l l.6Hz ), 3.52 (m, 1H), 3.48 (m, 1H), 3.28-3.25 (m, 1H); ESI-MS: (+ve mode) 379.1050 (M+H)+ (100 %); UPLC: 97.07 %, Ret.time = 2.939 min;
Compound 29: l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- phenoxyisoquinoline-6-carboxamide.
Figure imgf000051_0001
1H NMR: (DMSO-d6 400 MHz): d 8.18 (s, 1H), 8.06 (d, 1H, = 6Hz), 7.92 (s, 1H), 7.69 (m, 2H), 7.48 (m, 2H), 7.44-7.40 (m, 2H), 7.19-7.17 (m, 1H), 7.09-7.06 (m, 2H), 5.12-5.09 (m, 1H), 4.34-4.31 (m, 1H), 3.28-3.24 (m, 1H ), 3.19-3.15 (m, 1H); ESI-MS: (+ve mode) 391.1337 (M+H)+ (100 %); UPLC: 99.12 %, Ret.time = 1.990 min
Compound 30: l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- phenoxyisoquinoline-6-carbonitrile.
Figure imgf000051_0002
1H NMR: (DMSO-d6, 400 MHz): 8.69 (s, 1H), 8.13 (d, 1H, / = 5.6Hz), 7.66 (s, 1H), 7.52-7.50 (m, 3H), 7.48-7.45 (m, 1H), 7.30-7.26 (m, 1H), 7.23-7.21 (m, 1H), 5.11- 5.1 (m, 1H), 4.43 - 4.31 (m, 1H), 3.83 (d, 1H, / = 12.4 Hz), 3.65 (d, 1H, / = 1 l.6Hz), 3.34-3.27 (m, 1H), 3.23-3.17 (m, 1H); ESI-MS: (+ve mode) 373.1194 (M+H)+ (100 %); UPLC: 97.88 %, Ret.time = 3.070 min
Compound 31: l-(l-ethyl-2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)-yl)-7- isopropoxyisoquinoline-6-carboxamide.
Figure imgf000052_0001
1H NMR: (DMSO-d6 400 MHz): d 8.18 (s, 1H), 7.96 (d, 1H, / = 5.6Hz), 7.73 (bs, 2H), 7.48 (s, 1H), 7.36 (d, 1H, / = 5.6Hz), 6.69 (s, 1H), 4.79 (septet, 1H, 7 =6.0Hz), 4.33 (dd, 1H, J = 4.4Hz, J2 = 7.2Hz), 4.21 (dd, 1H, = 4.4Hz, J2 = 7.2Hz), 3.82 (d, 1H, 7 = 11.6 Hz), 3.63 (d, 1H, / = 11.6 Hz), 3.43 (d, 1H, / = 5.6 Hz), 3.40 (d, 1H, / =
5.6 Hz), 3.22 (q, 1H, / = 16 Hz), 3.00 (q, 1H, / = 16 Hz), 1.40-1.42 (m, 6H), 1.03 (t, 3H, / = 15.6 Hz); ESI-MS: (+ve mode) 384.2 (M+H)+ (100 %); UPLC: 98.62 %, Ret.time = 1.928 min. Compound 32: l-(l,3-diethyl-2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)-yl)-7- isopropoxyisoquinoline-6-carboxamide.
Figure imgf000052_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.18 (s, 1H), 7.97 (d, 1H, / = 5.6Hz), 7.73 (bs, 2H), 7.43 (s, 1H), 7.36 (d, 1H, / = 5.6Hz), 4.80 (septet, 1H, 7 =6.0Hz), 4.30-4.34 (m, 2H), 3.78 (d, 2H, 7 = 11.6 Hz), 3.41 (d, 2H, J = 6.4 Hz), 3.37 (q, 2H, J = 6.4 Hz),
3.05 (q, 2H, 7 = 16 Hz), 1.39-1.40 (m, 6H), 1.03-1.06 (m, 6H); ESI-MS: (+ve mode) 412.2 (M+H)+ (100 %); UPLC: 98.80 %, Ret.time = 2.229 min. Compound 33: 7-isopropoxy-l-(2-oxohexahydro-lH-pyrrolo[3,4-d]pyrimidin-
6(2H)-yl)isoquinoline-6-carboxamide
Figure imgf000053_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.20 (d, 1H, / = 5.6Hz), 7.84 (m, 3H), 7.66 (s, 1H), 7.35 (d, 1H, J = 5.6Hz), 6.42 (s, 1H), 6.32 (s, 1H), 5.76 (m, 1H), 4.29 (m, 1H),
4.01-3.86 (m, 4H), 3.38 (m, 2H), 3.17 (m, 1H), 1.24 (d, 6H, J = 6.0Hz); ESI-MS: (+ve mode) 370.20 (M+H)+ (100 %); UPLC: 98.57 %, Ret.time = 1.553 min.
Compound 34: 7-isopropoxy-l-(2-oxohexahydro-lH-pyrrolo[3,4-b]pyrazin- 6(2H)-yl)isoquinoline-6-carboxamide
Figure imgf000053_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.11 (d, 1H, / = 5.6Hz), 7.84 (d, 1H, / = 5.6Hz), 7.69 (s, 2H), 7.57 (s, 1H), 7.12 (d, 1H, / = 6.0Hz), 4.85-4.79 (m, 1H), 4.11-4.06 (m, 1H), 3.86-3.4 (m, 3H), 3.25-3.15 (m, 4H), 1.24 (d, 6H, J = 6.0Hz); ESI-MS: (+ve mode) 370.15 (M+H)+ (100 %); UPLC: 90.32 %, Ret.time = 1.097 min.
Compound 35: 7-(cyclopentyloxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol- 5(3H)-yl)isoquinoline-6-carboxamide
Figure imgf000054_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.19 (d, 1H, = 5.6Hz), 8.00 (s, 1H), 7.91 (s, 1H), 7.45 (s, 2H), 7.44 (d, 2H, / = 6.0Hz), 5.76 (m, 1H), 5.22-5.19 (m, 1H), 5.09-5.01 (m, 1H), 4.45-4.42 (m, 1H), 3.86-3.84 (m, 1H), 3.66-3.62 (m, 1H), 3.27-3.22 (m, 1H), 3.15-3.13 (m, 1H), 2.09-2.05 (m, 2H), 1.88-1.86 (m, 2H), l.76-l.73(m, 2H) 1.67-1.65
(m, 2H); ESI-MS: (+ve mode) 383.16 (M+H)+ (100 %); UPLC: 98.57 %, Ret.time = 2.088 min.
Compound 36: 7-(cyclohexyloxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol- 5(3H)-yl)isoquinoline-6-carboxamide
Figure imgf000054_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.20 (d, 1H, / = 5.6Hz), 8.00 (s, 1H), 7.84 (d, 1H, / = 5.6Hz), 7.50 (s, 2H), 7.45 (d, 1H, / = 6.0Hz), 7.44 (s, 1H), 5.22-5.19 (m, 1H), 4.44-4.43 (m, 1H), 4.41-4.39 (m, 1H), 3.87-3.82 (m, 1H), 3.60-3.58 (m, 1H), 3.23- 3.15 (m, 2H), 2.02 (s, 2H), 1.73-1.49 (m, 8H); ESI-MS: (+ve mode) 397.17 (M+H)+
(100 %); UPLC: 98.96 %, Ret.time = 2.281 min. Compound 37 : 7-cyclobutoxy- 1 -(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-
5(3H)-yl)isoquinoline-6-carboxamide
Figure imgf000055_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.20 (d, 1H, / = 5.6Hz), 8.00 (s, 1H), 7.43 (d, 1H, J = 5.6Hz), 7.29 (s, 1H), 5.20 (d, 1H, J = 6.0Hz), 4.89-4.86 (m, 1H), 4.45-4.43 (m, lH), 3.88-3.85 (m, 1H), 3.68-3.61 (m, 3H), 3.15-3.11 (m, 2H), 2.60-2.56 (m, 2H), 2.21-2.15 (m, 2H), 1.84-1.77 (m, 2H); ESI-MS: (+ve mode) 369.15 (M+H)+ (100 %); UPLC: 92.51 %, Ret.time = 1.903 min. Compound 38: 7-(cyclopropylmethoxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4- d]oxazol-5(3H)-yl)isoquinoline-6-carboxamide
Figure imgf000055_0002
1H NMR: (DMSO-d6 400 MHz): d 8.23 (d, 1H, / = 5.6Hz), 8.01 (s, 1H), 7.86 (d, 2H, / = 5.6Hz), 7.42 (s, 2H), 5.21-5.18 (m, 1H), 4.43-4.41 (m, 1H), 4.07-4.04 (m, 2H), 3.86-3.84 (m, 1H), 3.72-3.71 (m, 1H), 3.17-3.12 (m, 1H), 1.23 (s, 1H), 0.46-0.45 (m,
2H), 0.44-0.43 (m, 2H): ESI-MS: (+ve mode) 369.14 (M+H)+ (100 %); UPLC: 97.84 %, Ret.time = 1.929 min. Compound 39: l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)-7-
(vinyloxy)isoquinoline-6-carboxamide
Figure imgf000056_0001
1H NMR: (DMSO-d6 400 MHz): d 8.11 (d, 1H, / = 5.6Hz), 8.07 (s, 1H), 8.06 (d, 1H, J = 5.6Hz), 7.90 (s, 1H), 7.85 (s, 1H), 7.73 (s, 2H), 7.46 (d, 1H, J = 6.0Hz), 6.96-6.92 (m, 1H), 5.21-5.18 (m, 1H), 4.86-4.85 (m, 1H), 4.67-4.65 (m, 1H), 4.42-4.41 (m, 1H), 3.95-3.92 (m, 1H) 3.77-3.75 (m, 1H), 3.21-3.19 (m, 1H) 3.16-3.15 (m, 1H); ESI- MS: (+ve mode) 341.04 (M+H)+ (100 %); UPLC: 98.68 %, Ret.time = 1.437 min. Compound 40: l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-
(vinyloxy)isoquinoline-6-carbonitrile
Figure imgf000056_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.63 (d, 1H, / = 5.6Hz), 8.13 (s, 1H), 7.92 (s, 1H), 7.64 (s, 1H), 7.43 (d, 1H, J = 5.6Hz), 7.07 (s, 1H), 5.20 (s, 1H), 5.04-5.00 (m, 1H), 4.81-4.79 (m, 1H), 4.43-4.41 (m, 1H), 4.13-4.08 (m, 2H), 3.25-3.23 (m, 1H),
3.08-3.07 (m, 1H); ESI-MS: (+ve mode) 323.09 (M+H)+ (100 %); UPLC: 91.58 %, Ret.time = 2.563 min. Compound 41 : 7-(cyclopropylmethoxy)- 1 -(2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carbonitrile
Figure imgf000057_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.53 (s, 1H), 8.07 (d, 1H, / = 5.6Hz), 7.93 (s, 1H), 7.48 (s, 1H), 7.40 (d, 1H, / = 5.6Hz), 5.22-5.19 (m, 1H), 4.45-4.42 (m, 1H),
4.10-4.09 (m, 2H), 3.91-3.89 (m, 1H), 3.76-3.75 (m, 1H), 3.39-3.37 (m, 1H), 3.22- 3.21 (m, 1H), 1.36-1.23 (m, lH), 0.47-0.46 (m, 2H), 0.45-0.43 (m, 2H); ESI-MS: (+ve mode) 351.14 (M+H)+ (100 %); UPLC: 88.55 %, Ret.time = 2.840 min.
Compound 42: 7-cyclobutoxy-l-((3aS,6aR)-2-oxotetrahydro-2H-pyrrolo[3,4- d]oxazol-5(3H)-yl)isoquinoline-6-carboxamide
Figure imgf000057_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.18 (s, 1H), 8.02 (d, 1H, / = 5.6Hz), 7.92 (s, 1H), 7.77 (s, 2H), 7.44 (d, 1H, J = 5.6Hz), 7.30 (s, 1H), 5.23-5.20 (m, 1H), 4.89 (d, 1H), 4.45-4.42 (m, 1H), 3.86-3.84 (m, 1H), 3.63-3.62 (m, 1H), 3.34-3.32 (m, 1H), 3.23-3.18 (m, 1H), 3.09 (t, 2H, / = 6.0Hz), 2.58-2.53 (m, 2H) 2.51-2.49 (m, 2H) 1.26- 1.23 (m, 1H); ESI-MS: (+ve mode) 369.10 (M+H)+ (100 %); UPLC: 95.37 %, Ret.time = 1.905 min. .(Chiral Purity by HPLC: 100 % ee) Compound 43: 7-cyclobutoxy-l-((3aR,6aS)-2-oxotetrahydro-2H-pyrrolo[3,4- d]oxazol-5(3H)-yl)isoquinoline-6-carboxamide
Figure imgf000058_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.18 (s, 1H), 8.01 (d, 1H, J = 5.6Hz), 7.92 (s, 1H), 7.73 (s, 2H), 7.44 (d, 1H, / = 5.6Hz), 7.30 (s, 1H), 5.76-5.74 (m, 1H), 5.23-5.20 (m, 1H), 4.45-4.42 (m, 1H), 3.86-3.85 (m, 1H), 3.63-3.61 (m, 1H), 3.34-3.33 (m, 1H), 3.15-3.11 (m, 1H), 2.70-2.60 (m, 2H) 2.53-2.51 (m, 2H) 1.78-1.23 (m, 2H); ESI- MS: (+ve mode) 369.10 (M+H)+ (100 %); UPLC: 96.65 %, Ret.time = 1.905 min. .(Chiral Purity by HPLC: 100 % ee)
Compound 44: 7-(dicyclopropylmethoxy)- l-(2-oxotetrahydro-2H-pyrrolo[3,4- d]oxazol-5(3H)-yl)isoquinoline-6-carboxamide
Figure imgf000058_0002
1H NMR: (DMSO-d6 400 MHz): d 8.22 (s, 1H), 8.00 (d, 1H, / = 5.6Hz), 7.84-7.56 (m, 3H), 7.44 (s, 1H), 7.43 (d, 1H, / = 5.6 Hz), 5.81-5.21 (m, 1H), 4.39-4.01 (m, 1H), 3.86 (d, 1H, / = 12.4 Hz), 3.75 (t, 1H, / = 39.2Hz), 3.63 (d, 1H, / = 11.2 Hz), 3.24 (m, 1H), 3.17 (m, 1H), 1.25 (m, 1H), 0.56-0.39(m, 8H); ESI-MS: (+ve mode) 409.19 (M+H)+ (100 %); UPLC: 92.70 %, Ret.time = 2.313 min. Compound 45: 7-((3,3-difluorocyclobutyl)methoxy)-l-((3aR,6aS)-2-oxotetrahydro- 2H-pyrrolo [3 ,4-d] oxazol-5 (3H)-yl)isoquinoline-6-carboxamide
Figure imgf000059_0001
1H NMR: (DMSO-d6 400 MHz): d 8.13 (s, 1H), 8.03 (d, 1H, / = 6.0Hz), 7.92 (s, 1H), 7.43 (d, 1H, / = 6.8 Hz), 7.44 (d, 2H, / = 5.2 Hz) 5.22 (m, 1H), 4.45 (m, 1H), 4.42 (m, 1H), 3.89 (m, 1H), 3.78 (m, 1H), 3.18-3.12 (m, 2H), 2.73-2.50 (m, 5H); ESI-MS: (+ve mode) 419.15 (M+H)+ (100 %); UPLC: 99.09 %, Ret.time = 2.149 min.
Compound 46: 7-(tert-butoxy)-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carbonitrile
Figure imgf000059_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.53 (s, 1H), 8.11 (d, 1H, / = 5.6Hz), 7.88 (s, 1H), 7.77 (s, 1H), 7.43 (d, 1H, / = 5.6Hz), 5.23-5.20 (m, 1H), 4.45-4.42 (m, 1H), 3.99-3.90 (m, 3H), 3.65-3.62 (m, 2H), 3.31-3.28 (m, 2H), 1.51 (s, 9H), 1.24 (s, 2H); ESI-MS: (+ve mode) 353.12 (M+H)+ (100 %); UPLC: 93.68 %, Ret.time = 2.563 mm. Compound 47: 7-(tert-butoxy)-l-((3aR,6aS)-2-oxotetrahydro-2H-pyrrolo[3,4- d]oxazol-5(3H)-yl)isoquinoline-6-carboxamide
Figure imgf000060_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.15 (s, 1H), 8.03 (d, 1H, / = 5.6Hz), 7.88 (s, 1H), 7.70 (s, 1H), 7.44 (d, 1H, / = 5.6Hz), 5.22-5.19 (m, 1H), 4.44-4.41 (m, 1H), 3.89-3.87 (m, 1H), 3.60-3.59 (m, 1H), 3.24-3.21 (m, 2H), 1.51 (s, 9H); ESI-MS: (+ve mode) 371.13 (M+H)+ (100 %); UPLC: 98.98 %, Ret.time = 1.80 min.
Compound 48: 7-ethoxy- l-((3aR, 6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5-yl)isoquinoline-6-carbonitrile
Figure imgf000060_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.53 (s, 1H), 8.07 (d, 1H, / = 5.6Hz), 7.97 (s, 1H), 7.42 (s, 1H), 7.41 (d, 1H, / = 5.6Hz), 5.23-5.20 (m, 1H), 4.60-4.44 (m, 2H), 4.34-4.22 (m, 2H), 4.02-3.81 (m, 2H), 3.81-3.66 (m, 3H), 3.39-3.32 (m, 2H), 3.24- 3.17 (m, 2H) 1.49 (t, 3H, / = 7.2Hz); ESI-MS: (+ve mode) 325.14 (M+H)+ (100 %); HPLC: 95.92 %, Ret.time = 12.294 min. Compound 49: 7-ethoxy- l-((3aR, 6aS)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol- 5(3H)-yl)isoquinoline-6-carboxamide
Figure imgf000061_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.19 (s, 1H), 8.02 (d, 1H, / = 5.6Hz), 7.94 (s, 1H), 7.88 (s, 1H), 7.63 (s, lH),7.45 (d, 2H, / = 5.6Hz), 5.22-5.19 (m, 1H), 4.44-4.41
(m, 1H), 4.30-4.20 (m, 2H), 3.89-3.87 (d, 1H), 3.76-3.75 (m, 1H), 3.34-3.33 (m, 1H), 3.17-3.10 (m, 1H), 1.53 (t, 1H, / = 7.2Hz); ESI-MS: (+ve mode) 343.15 (M+H)+ (100 %); HPLC: 99.90 %, Ret.time = 6.585 min.
Compound 50: 7-(allyloxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide
Figure imgf000061_0002
1H NMR: (DMSO-d6 400 MHz): d 8.15 (s, 1H), 8.01 (d, 1H, / = 5.6Hz), 7.93 (s, 1H), 7.83 (m, 1H), 7.48 (s, 1H), 7.73 (m, 1H), 7.43 (m, 2H), 6.13 (m, 1H), 5.50 (m, 1H), 5.36 (m, 1H), 5.22 (m, 1H), 4.80 (m, 1H), 4.40 (m, 1H), 3.87 (d, 1H, / = 12 Hz),
3.72 (d, 1H, / = l l.2Hz), 3.28 (m, 1H), 3.15 (m, 1H); ESI-MS: (+ve mode) 419.15 (M+H)+ (100 %); UPLC: 99.09 %, Ret.time = 2.149 min. Compound 51: l-((lR,5S)-3,6-diazabicyclo[3.l.l]heptan-6-yl)-7- methoxyisoquinoline-6-carboxamide
Figure imgf000062_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.84 (s, 1H), 8.19 (s, 1H), 7.98 (d, 1H, / = 6.0Hz), 7.87 (s, 1H), 7.75 (s, 1H), 7.38 (d, 1H, / = 6.0Hz), 7.21 (s, 1H), 4.99 (d, 2H, J = 5.2Hz), 3.99 (s, 3H), 3.73-3.69 (m, 2H), 3.48-3.45 (m, 2H), 3.02-3.00 (m, 1H), 2.09-2.08 (m, 1H); ESI-MS: (+ve mode) 298.85 (M+H)+ (100 %); UPLC: 94.83 %, Ret.time = 1.075 min
Compound 52: l-((lR,5S)-3-(2-cyanoacetyl)-3,6-diazabicyclo[3.l.l]heptan-6-yl)-7- methoxyisoquinoline-6-carboxamide
Figure imgf000062_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.16 (s, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.86 (d, 1H, / = 6.0Hz), 7.76 (s, 1H), 7.32 (d, 1H, / = 6.0Hz), 7.21 (s, 1H), 5.09 (bs, 2H), 4.09 (m, 2H), 3.99 (s, 3H), 3.71-3.68 (m, 2H), 3.17 (s, 2H), 2.95-2.93 (m, 1H), 1.75-1.73 (m, 1H); ESI-MS: (+ve mode) 366.05 (M+H)+ (100 %); UPLC: 95.70 %, Ret.time = 1.859 min Compound 53: 7 -methoxy- 1 -(3 -oxopiperazin- 1 -yl)isoquinoline-6-carboxamide
Figure imgf000063_0001
1H NMR: (DMSO-d6 400 MHz): d 8.20 (s, 1H), 8.07 (d, 1H, / = 5.6Hz),7.95 (s, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.50 (d, 1H, / = 6.0Hz), 7.40 (s, 1H), 4.00 (s, 3H), 3.89 (s, 2H), 3.58 (t, 1H, J = 5.6Hz), 3.34 (d, 1H, J = 5.6Hz); ESI-MS: (+ve mode) 300.85
(M+H)+ (100 %); UPLC: 97.99 %, Ret.time = 1.660 min.
Compound 54: 1 -(3-acetamidopiperidin- 1 -yl)-7 -isopropoxyisoquinoline-6- carboxamide
Figure imgf000063_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.19 (s, 1H), 8.01 (d, 1H, / = 5.6Hz), 7.98 (s, 1H), 7.74-7.72 (m, 2H), 7.48 (s, 1H), 7.41 (d, 1H, / = 5.6Hz), 5.04-4.98 (m, 1H), 4.02-4.00 (m, 1H), 3.66-3.63 (m, 1H), 3.54-3.51 (m, 1H), 3.00-2.92 (m, 1H), 2.89- 2.87 (m, 1H), 2.67-2.62 (m, 1H), 1.92-1.90 (m, 2H), 1.83 (s, 3H), 1.48-1.39 (m, 7H); ESI-MS: (+ve mode) 371.15 (M+H)+ (100 %); UPLC: 99.59 %, Ret.time = 1.969 min.
Compound 55: 7-isopropoxy- 1 -(3-(methylsulfonamido)piperidin- 1 -yl)isoquinoline- 6-carboxamide
Figure imgf000064_0001
1H NMR: (DMSO-d6 400 MHz): d 8.20 (s, 1H), 8.03 (d, 1H, = 5.6Hz), 7.98 (s, 1H), 7.74 (bs, 2H), 7.47 (s, 1H), 7.43 (d, 1H, / = 5.6Hz), 4.97-4.91 (m, 1H), 4.02- 4.00 (m, 1H), 3.67-3.61 (m, 2H), 3.48-3.44 (m, 1H), 3.00 (s, 3H), 2.92-2.87 (m, 2H), 2.04-2.02 (m, 1H), 1.93-1.90 (m, 1H), 1.82-1.79 (m, 1H), 1.51-1.49 (m, 1H), 1.42 (d,
6H, J = 6.0Hz); ESI-MS: (+ve mode) 407.15 (M+H)+ (100 %); UPLC: 99.53 %, Ret.time = 2.094 min.
Compound 56: l-(2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)-7- isopropoxyisoquinoline-6-carboxamide
Figure imgf000064_0002
1H NMR: (DMSO-d6 400 MHz): d 10.74 (s, 1H), 8.61 (s, 1H), 8.21 (s, 1H), 8.03 (d, 1H, / = 5.6Hz), 7.73 (bs, 2H), 7.44 (d, 1H, / = 5.6Hz), 7.37 (s, 1H), 4.83 (septet, 1H, / = 6.0Hz), 3.70-3.67 (m, 2H), 3.28-3.23 (m, 2H), 2.34-2.33 (m, 2H), 1.82-1.79 (m, 2H), 1.42 (d, 6H, / = 6.0Hz); ESI-MS: (+ve mode) 398.10 (M+H)+ (100 %); UPLC:
98.34 %, Ret.time = 1.823 min Compound 57: 7-isopropoxy-l-(3-methyl-2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8- yl)isoquinoline-6-carboxamide
Figure imgf000065_0001
1H NMR: (DMSO-d6 400 MHz): d 8.88 (s, 1H), 8.22 (s, 1H), 8.05 (d, 1H, / = 5.6Hz), 7.73 (bs, 2H), 7.44 (d, 1H, / = 5.6Hz), 7.37 (s, 1H), 4.84 (septet, 1H, / =
6.0Hz), 3.71-3.68 (m, 2H), 3.34-3.28 (m, 2H), 2.87 (s, 3H), 2.17-2.16 (m, 2H), 1.77- 1.73 (m, 2H), 1.42 (d, 6H, / = 6.0Hz); ESI-MS: (+ve mode) 412.10 (M+H)+ (100 %); UPLC: 98.00 %, Ret.time = 2.059 min Compound 58: l-(3-acetamidopyrrolidin-l-yl)-7-isopropoxyisoquinoline-6- carboxamide
Figure imgf000065_0002
1H NMR: (DMSO-d6 400 MHz): d 8.18 (d, 1H, / = 6.8Hz), 8.12 (s, 1H), 7.88 (d, 1H, / = 5.6Hz), 7.73 (bs, 2H), 7.59 (s, 1H), 7.14 (d, 1H, / = 5.6Hz), 4.80 (septet, 1H, / = 6.0Hz), 4.33-4.31 (m, 1H), 3.98-3.96 (m, 1H), 3.95-3.87 (m, 1H), 3.80-3.78 (m, 1H),
3.56-3.53 (m, 1H), 2.15-2.13 (m, 1H), 1.89-1.87 (m, 1H), 1.81 (s, 3H), 1.39 (d, 6H, J = 6.0Hz); ESI-MS: (+ve mode) 357.15 (M+H)+ (100 %); UPLC: 99.48 %, Ret.time = 1.852 min.
Compound 59: N-( 1 -(6-carbamothioyl-7-isopropoxyisoquinolin- 1 -yl)pyrrolidin-3- yl)acetamide
Figure imgf000066_0001
1H NMR: (DMSO-d6 400 MHz): d 10.11 (s, 1H), 9.46 (s, 1H), 8.17 (d, 1H, / = 6.4Hz), 7.88 (s, 1H), 7.86 (d, 1H, / = 5.6Hz), 7.52 (s, 1H), 7.10 (d, 1H, / = 5.6Hz), 4.71 (septet, 1H, / = 6.0Hz), 4.31-4.30 (m, 1H), 3.97-3.95 (m, 1H), 3.94-3.86 (m, 1H), 3.77-3.75 (m, 1H), 3.55-3.52 (m, 1H), 2.15-2.13 (m, 1H), 1.91-1.87 (m, 1H),
1.81 (s, 3H), 1.35 (d, 6H, / = 6.0Hz); ESI-MS: (+ve mode) 373.13 (M+H)+ (100 %); UPLC: 98.06 %, Ret.time = 2.196 min
Compound 60: l-(2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)-7- isopropoxyisoquinoline-6-carboxamide
Figure imgf000066_0002
1H NMR: (DMSO-d6, 400 MHz): d 10.84 (s, 1H), 8.59 (s, 1H), 8.15 (s, 1H), 7.91 (d, 1H, / = 5.6Hz), 7.73 (bs, 2H), 7.57 (s, 1H), 7.22 (d, 1H, / = 5.6Hz), 4.83 (septet, 1H, J = 6.0Hz), 4.05-4.03 (m, 2H), 3.97-3.95 (m, 1H), 3.71-3.68 (m, 1H), 2.34-2.33 (m, 1H), 2.19-2.17 (m, 1H), 1.41 (d, 6H, / = 6.0Hz); ESI-MS: (+ve mode) 383.89 (M+H)+ (100 %); UPLC: 96.75 %, Ret.time = 1.763 min. Compound 61: 7-isopropoxy-l-(3-methyl-2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7- yl)isoquinoline-6-carboxamide
Figure imgf000067_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.53 (s, 1H), 8.15 (s, 1H), 7.93 (d, 1H, / = 5.6Hz), 7.73 (bs, 2H), 7.57 (s, 1H), 7.24 (d, 1H, / = 5.6Hz), 4.81 (septet, 1H, / = 6.0Hz), 4.05-4.02 (m, 2H), 3.97-3.95 (m, 1H), 3.71-3.69 (m, 1H), 2.87 (s, 3H), 2.34-
2.33 (m, 1H), 2.19-2.17 (m, 1H), 1.41 (d, 6H, / = 6.0Hz); ESI-MS: (+ve mode) 398.15 (M+H)+ (100 %); UPLC: 97.07 %, Ret.time = 1.971 min.
Compound 62: l-(3-acetamido-4-hydroxypyrrolidin-l-yl)-7-isopropoxyisoquinoline- 6-carboxamide
Figure imgf000067_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.12 (s, 1H), 8.10 (d, 1H, / = 6.0Hz), 7.88 (d, 1H, / = 5.6Hz), 7.73 (bs, 2H), 7.60 (s, 1H), 7.12 (d, 1H, / = 5.6Hz), 5.35 (d, 1H, / = 3.6Hz), 4.83 (septet, 1H, / = 6.0Hz), 4.18-4.07 (m, 4H), 3.53-3.47 (m, 2H), 1.82 (s, 3H), 1.42 (d, 3H, / = 6.0Hz) 1.39 (d, 3H, / = 6.0Hz); ESI-MS: (+ve mode) 373.02 (M+H)+ (100 %); UPLC: 94.60 %, Ret.time = 1.667 min.
Compound 63: l-(3-(hydroxymethyl)-4-(2,2,2-trifluoroacetamido)pyrrolidin-l-yl)-7- isopropoxyisoquinoline-6-carboxamide
Figure imgf000068_0001
1H NMR: (DMSO-d6, 400 MHz): d 9.59 (d, 1H, J = 7.6Hz), 8.13 (s, 1H), 7.89 (d, 1H, / = 6.0Hz), 7.73 (bs, 2H), 7.62 (s, 1H), 7.15 (d, 1H, / = 5.6Hz), 4.83 (septet, 1H, / = 6.0Hz), 4.80-4.77 (m, 1H), 4.77-4.75 (m, 1H), 4.61-4.59 (m, 1H), 4.11-4.09 (m, 1H), 4.07-3.88 (m, 2H), 3.79-3.77 (m, 1H), 3.59-3.58 (m, 1H), 2.64-2.62 (m, 1H), 1.41 (d, 3H, / = 6.0Hz) 1.39 (d, 3H, / = 6.0Hz); ESI-MS: (+ve mode) 440.91 (M+H)+ (100 %); UPLC: 95.32 %, Ret.time = 2.251 min. Compound 64: l-(2,4-dioxo-l,3,7-triazaspiro[4.5]decan-7-yl)-7- isopropoxyisoquinoline-6-carboxamide
Figure imgf000068_0002
1H NMR: (DMSO-d6, 400 MHz): d 10.81 (s, 1H), 8.95 (s, 1H), 8.21 (s, 1H), 8.03 (d, 1H, = 5.6Hz), 7.73 (bs, 2H), 7.63 (s, 1H), 7.46 (d, 1H, / = 5.6Hz), 4.99 (septet, 1H, J = 6.0Hz), 3.63-3.60 (m, 1H), 3.56-3.53 (m, 1H), 3.17-3.16 (m, 1H), 3.05-2,89 (m, 1H), 2.14-2.11 (m, 1H), 1.91-1.78 (m, 3H), 1.43 (d, 3H, / = 6.0Hz) 1.40 (d, 3H, / = 6.0Hz); ESI-MS: (+ve mode) 397.97 (M+H)+ (100 %); UPLC: 98.76 %, Ret.time =
1.729 min.
Compound 65: l-(2,4-dioxo-l,3,7-triazaspiro[4.5]decan-7-yl)-7- methoxyisoquinoline-6-carboxamide
Figure imgf000069_0001
1H NMR: (DMSO-d6, 400 MHz): d 10.79 (s, 1H), 8.99 (s, 1H), 8.18 (s, 1H), 8.05 (d, 1H, / = 5.6Hz), 7.84 (s, 1H), 7.71 (s, 1H), 7.69 (bs, 2H), 7.46 (d, 1H, / = 5.6Hz), 4.0l(s, 3H), 3.66-3.64 (m, 1H), 3.58-3.55 (m, 1H), 3.17-3.16 (m, 1H), 3.02-2,87 (m, 1H), 2.10-2.08 (m, 1H), 1.92-1.82 (m, 3H); ESI-MS: (+ve mode) 369.94 (M+H)+ (100 %); UPLC: 95.88 %, Ret.time = 1.339 min.
Compound 66: 7-methoxy-l-(3-methyl-2,4-dioxo-l,3,7-triazaspiro[4.5]decan-7- yl)isoquinoline-6-carboxamide
Figure imgf000069_0002
1H NMR: (DMSO-d6, 400 MHz): d 9.20 (s, 1H), 8.22 (s, 1H), 8.03 (d, 1H, = 5.6Hz), 7.73 (bs, 2H), 7.64 (s, 1H), 7.46 (d, 1H, / = 5.6Hz), 4.99 (septet, 1H, / = 6.0Hz), 3.65-3.62 (m, 1H), 3.56-3.53 (m, 1H), 3.10-3.07 (m, 1H), 3.00-2,84 (m, 4H), 2.14-2.11 (m, 1H), 1.91-1.78 (m, 3H), 1.43 (d, 3H, / = 6.0Hz) 1.39 (d, 3H, / = 6.0Hz); ESI-MS: (+ve mode) 411.87 (M+H)+ (100 %); UPLC: 96.41 %, Ret.time =
1.994 min.
Compound 67: l-(6,8-dioxo-2,5,7-triazaspiro[3.4]octan-2-yl)-7- isopropoxyisoquinoline-6-carboxamide
Figure imgf000070_0001
1H NMR: (DMSO-d6, 400 MHz): d 10.86 (s, 1H), 8.63 (s, 1H), 8.15 (s, 1H), 7.94 (d, 1H, / = 6.0Hz), 7.73 (bs, 2H), 7.24 (s, 1H), 7.22 (d, 1H, / = 5.6Hz), 4.85 (septet, 1H, / =6.0Hz), 4.64 (d, 2H, / = 9.2Hz), 4.42 (d, 2H, / = 8.8Hz), 1.38 (d, 6H, / = 6.0Hz); ESI-MS: (+ve mode) 370.14 (M+H)+ (100 %); UPLC: 97.35 %, Ret.time = 1.589 min.
Compound 68: l-(6,8-dioxo-2,5,7-triazaspiro[3.4]octan-2-yl)-7- methoxyisoquinoline-6-carboxamide
Figure imgf000070_0002
1H NMR: (DMSO-d6, 400 MHz): d 10.87 (s, 1H), 8.65 (s, 1H), 8.12 (s, 1H), 7.95 (d, 1H, / = 5.2Hz), 7.84 (bs, 1H), 7.70 (bs, 2H), 7.23-7.22 (m, 2H), 4.67 (d, 2H, / = 9.2Hz), 4.45 (d, 2H, / = 8.8Hz), 3.96 (s, 3H); ESI-MS: (+ve mode) 342.11 (M+H)+ (100 %); UPLC: 98.26 %, Ret.time = 0.819 min.
Compound 69: l-(5, 6-dihydropyrrolo [3, 4-c] pyrrol-2(lH, 3H, 4H)-yl)-7- methoxyisoquinoline-6-carboxamide.
Figure imgf000071_0001
1H NMR: (DMSO-d6, 400 MHz): d 9.79 (bs, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.83- 7.78 (m, 3H), 7.30 (d, 1H, J = 6.0Hz), 4.85 (s, 4H), 4.13 (s, 4H), 4.03 (s, 3H); ESI-
MS: (+ve mode) 310.90 (M+H)+ (100 %); UPLC: 98.33 %, Ret.time = 1.33 min.
Compound 70: l-(5-(2-cyanoacetyl)-3, 4, 5, 6-tetrahydropyrrolo [3, 4-c] pyrrol- 2(lH)-yl)-7-methoxyisoquinoline-6-carboxamide.
Figure imgf000071_0002
1H NMR: (DMSO-d6 400 MHz): d 8.19 (s, 1H), 7.90 (s, 2H), 7.80-7.76 (m, 2H), 7.31-7.28 (m, 2H), 4.88 (s, 4H), 4.39 (s, 2H), 4.26 (s, 2H), 4.06 (s, 2H) 4.04 (s, 3H); ESI-MS: (+ve mode) 378.05 (M+H)+ (100 %); UPLC: 87.65 %, Ret.time = 2.11 min.
Compound 71: l-(5-(2-hydroxyacetyl)-3, 4, 5, 6-tetrahydropyrrolo [3, 4-c] pyrrol- 2(lH)-yl)-7-methoxyisoquinoline-6-carboxamide.
Figure imgf000072_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.20 (s, 1H), 7.92 (s, 2H), 7.82 (s, 1H), 7.74 (d, 1H, J = 6.0Hz), 7.31-7.28 (m, 2H), 4.90 (s, 4H), 4.36 (s, 2H), 4.31 (s, 2H), 4.10 (s, 2H) 4.05 (s, 3H); ESI-MS: (+ve mode) 369.05 (M+H)+ (100 %); UPLC: 98.48%, Ret.time = 2.03 min.
Compound 72: 7-methoxy-l-(2-oxo-l-oxa-3, 8-diazaspiro [4.5] decan-8-yl) isoquinoline-6-carboxamide.
Figure imgf000072_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.19 (s, 1H), 8.04 (d, 1H, / = 5.6Hz), 7.84 (s, 1H), 7.71 (s, 1H), 7.57 (s, 1H), 7.43 (d, 1H, J = 5.6Hz), 7.39 (s, 1H), 4.04 (s, 3H), 3.44-3.33 (m, 6H), 2.06-2.03 (m, 4H); ESI-MS: (+ve mode) 357.15 (M+H)+ (100 %); UPLC: 99.78%, Ret.time = 1.43 min.
Compound 73: 7-isopropoxy-l-(2-oxo-l-oxa-3, 8-diazaspiro [4.5] decan-8-yl) isoquinoline-6-carboxamide.
Figure imgf000073_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.21 (s, 1H), 8.03 (d, 1H, / = 5.6Hz), 7.73 (s, 2H), 7.58 (s, 1H), 7.43-7.41 (m, 1H), 4.85 (septet, 1H, / = 6.0Hz), 3.41-3.34 (m, 6H), 2.05-2.03 (m, 4H), 1.42 (d, 6H, / = 6.0Hz); ESI-MS: (+ve mode) 385.20 (M+H)+ (100 %); UPLC: 99.70%, Ret.time = 1.80 min.
Compound 74: 7-methoxy-l-(3-oxo-l-oxa-4, 9-diazaspiro [5.5] undecan-9-yl) isoquinoline-6-carboxamide.
Figure imgf000073_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.17 (s, 1H), 8.01 (d, 1H, / = 5.6 Hz), 8.0-7.95 (m, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.41-7.37 (m, 1H), 4.14-4.07 (m, 2H), 3.98 (s, 3H), 3.50-3.43 (m, 2H), 3.28-3.23 (m, 2H), 3.17 (s, 2H), 2.04-1.99 (m, 2H), 1.70-1.64 (m, 1H), 1.68-1.64 (m, 1H); ESI-MS: (+ve mode) 371.25 (M+H)+ (100 %); UPLC: 96.32%, Ret.time = l.63min.
Compound 75: 7-isopropoxy-l-(3-oxo-l-oxa-4, 9-diazaspiro [5.5] undecan-9-yl) isoquinoline-6-carboxamide.
Figure imgf000074_0001
1H NMR: (DMSO-d6 400 MHz): d 8.20 (s, 1H), 8.01-7.99 (m, 2H), 7.72 (s, 2H), 7.40-7.37 (m, 2H), 4.82 (septet, 1H, / =6.4Hz), 4.14-4.08 (m, 2H), 3.43-3.39 (m, 2H), 3.27-3.23 (m, 2H), 3.17 (s, 2H), 2.00-1.95 (m, 2H), 1.80-1.75 (m, 1H), 1.68-1.64 (m, 1H); ESI-MS: (+ve mode) 399.35 (M+H)+ (100 %); UPLC: 97.99%, Ret.time = l.97min.
Compound 76: 7-isopropoxy-l-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6- carboxamide.
Figure imgf000074_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.20 (s, 1H), 8.01 (d, 1H, = 5.6Hz), 7.72 (s, 2H), 7.59 (s, 1H), 7.39 (m, 2H), 4.86-4.80 (septet, 1H, / = 6.4 Hz), 3.33 (s, 3H), 3.16 (s, 2H), 2.33 (s, 2H), 2.16 (s, 4H), 1.42 (d, 6H, / = 6Hz); ESI-MS: (+ve mode) 383.20 (M+H)+ (100 %); UPLC: 97.38 %, Ret.time = 1.776 min;
Compound 77: 7-methoxy-l-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6- carboxamide.
Figure imgf000075_0001
1H NMR: (DMSO-d6 400 MHz): d 8.17 (s, 1H), 8.03 (d, 1H, / = 5.6Hz), 7.84 (s, 1H), 7.70 (s, 1H), 7.59 (s, 1H), 7.41 (d, 1H, J = 5.6Hz), 7.37 (s, 1H), 3.98 (s, 3H),
3.33 (m, 4H), 3.16 (m, 2H), 2.16 (m, 2H), 1.84 (m, 4H); ESI-MS: (+ve mode) 355.20 (M+H)+ (100 %); UPLC: 99.04 %, Ret.time = 1.444 min;
Compound 78: 7-isopropoxy-l-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)isoquinoline- 6-carboxamide.
Figure imgf000075_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.12 (s, 1H), 7.86 (d, 1H, / = 5.6Hz), 7.72 (s, 2H), 7.62 (s, 2H), 7.12 (d, 1H, / = 5.6Hz), 5.0- 4.89 (septet, 1H, / = 6.4 Hz), 3.89 (m, 2H), 3.72 (m, 2H), 3.27 (m, 2H), 2.9 (m, 2H), 1.99 (m, 2H), 1.38 (d, 6H, J = 6.0Hz); ESI-MS: (+ve mode) 369.20 (M+H)+ (100 %); UPLC: 98.28 %, Ret.time = 1.715 min;
Compound 79: 7-methoxy-l-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)isoquinoline-6- carboxamide.
Figure imgf000076_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.09 (s, 1H), 7.86 (m, 1H), 7.82 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.13 (d, 1H, J = 5.6Hz), 3.98 (s, 3H), 3.90 (m, 2H), 3.74 (m, 2H), 3.27 (m, 2H), 2.35-2.24 90 (m, 2H), 2.01-2.97 (m, 2H); ESI-MS: (+ve mode) 341.15 (M+H)+ (100 %); UPLC: 95.66 %, Ret.time = 1.236 min;
Compound 80: 7-isopropoxy- 1 -(4-(3-oxopiperazin- l-yl)piperidin- 1 -yl)isoquinoline- 6-carboxamide.
Figure imgf000076_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.48 (s, 1H), 8.23 (s, 1H), 8.01 (d, 1H, / = 6Hz), 7.75 (bs, 2H), 7.47 (d, 1H, / = 6Hz), 7.39 (s, 1H), 4.85 (septet, 1H, / =6.0Hz), 3.76- 3.99 (m, 7H), 3.45-3.55 (m, 2H), 2.94 (t, 2H, J =6.0Hz), 2.33-2.50- (m, 2H), 2.02- 2.05 (m, 2H), 1.42-1.44 (m, 6H); ESI-MS: (+ve mode) 412.2 (M+H)+ (100 %); UPLC: 95.20 %, Ret.time = 1.386 min .
Compound 81 : 7 -isopropoxy- 1 -(2-oxo- 1 ,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6- carboxamide.
Figure imgf000077_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.20 (s, 1H), 8.02 (d, 1H, / = 5.6Hz), 8.01 (s, 1H), 7.72 (bs, 2H), 7.40 (s, 1H), 7.37 (d, 1H, / = 5.6Hz), 4.78 (septet, 1H, / =6.0Hz), 3.44-3.47 (m, 2H), 3.26-3.28 (m, 2H), 2.22 (t, 2H, / = 16 Hz), 1.93 (t, 2H, / = 16 Hz), 1.84-1.87 (m, 4H), 1.42-1.46 (m, 6H); ESI-MS: (+ve mode) 383.17 (M+H)+ (100 %); UPLC: 97.98 %, Ret.time = 1.84 min.
Compound 82: 7-methoxy- 1 -(2-oxo- l,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6- carboxamide.
Figure imgf000077_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.18 (s, 1H), 8.04 (d, 1H, = 5.6Hz), 8.02 (s, 1H), 7.84 (bs, 2H), 7.41 (s, 1H), 7.35 (d, 1H, / = 5.6Hz), 3.98 (s, 1H), 3.33-3.49 (m, 2H), 3.28-3.30 (m, 2H), 2.27 (t, 2H, / = 15.6 Hz), 1.93 (t, 2H, / = 15.6 Hz), 1.84-1.87 (m, 4H); ESI-MS: (+ve mode) 355.17 (M+H)+ (100 %); UPLC: 97.03 %, Ret.time = 1.50 min.
Compound 83: 7-isopropoxy-l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carbonitrile.
Figure imgf000078_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.52 (s, 1H), 8.06 (d, 1H, / = 5.6Hz), 7.87 (s, 1H), 7.52 (s, lH),7.4l (d, 1H, / = 5.6Hz), 4.85 (septet, 1H, / =6.0Hz), 4.02 (dd, 1H, = 4.4Hz, J2 = 7.2Hz), 3.87 (d, 1H, / = 12.8Hz), 3.70 (d, 1H, / = 7.6Hz), 3.34 (dd, 1H, J] = 4.4Hz, J2 = 12.8Hz), 3.20 (d, 1H, / = 7.6Hz), 1.57 (s, 3H), 1.44-1.41 (m, 6H); ESI-MS: (+ve mode) 353.4 (M+H)+ (100 %); UPLC: 97.05 %, Ret.time = 2.874 min.
Compound 84: 7-isopropoxy-l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carboxamide.
Figure imgf000078_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.21 (s, 1H), 8.00 (d, 1H, / = 5.6Hz), 7.86 (s, 1H), 7.73 (bs, 2H), 7.48 (s, lH),7.43 (d, 1H, / = 5.6Hz), 4.80 (septet, 1H, / =6.0Hz), 4.01 (dd, 1H, J] = 4.4Hz, J2 = 7.2Hz), 3.83 (d, 1H, / = l2.8Hz), 3.65 (d, 1H, / = 7.6Hz), 3.29 (dd, 1H, = 4.4Hz, J2 = l2.8Hz), 3.15 (d, 1H, / = 7.6Hz), 1.57 (s, 3H), 1.43-1.41 (m, 6H); ESI-MS: (+ve mode) 371.4 (M+H)+ (100 %); UPLC: 98.00 %,
Ret.time = 1.946 min.
Compound 85: 7-methoxy-l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5-yl)isoquinoline-6-carbonitrile.
Figure imgf000079_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.54 (s, 1H), 8.08 (d, 1H, / = 5.6Hz), 7.93 (s, 1H), 7.49 (s, 1H), 7.42 (d, 1H, / = 5.6Hz), 4.05 (s, 3H), 3.92 (dd, 1H, = 4.4Hz, J2 =
7.2Hz), 3.89 (d, 1H, / = l2.8Hz), 3.76 (d, 1H, / = 7.6Hz), 3.30 (dd, 1H, Jj = 4.4Hz, J2 = l2.8Hz), 3.25 ((d, 1H, / = 7.6Hz), 1.57 (s, 3H); ESI-MS: (+ve mode) 325.13 (M+H)+ (100 %); UPLC: 96.80 %, Ret.time = 2.426 min.
Compound 86: 7-methoxy-l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5-yl)isoquinoline-6-carboxamide.
Figure imgf000079_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.18 (s, 1H), 8.01 (d, 1H, = 5.6Hz), 7.91 (s, 1H), 7.86 (d, 1H, / = 5.6Hz), 7.72 (bs, 2H), 7.44 (d, 1H, / = 5.6Hz), 4.01 (d, 1H, / = l2.8Hz), 3.98 (s, 3H), 3.85 (d, 1H, J = 7.6Hz), 3.73 (dd, 1H, J} = 4.4Hz, J2 = l2.8Hz), 3.24 (dd, 1H, = 4.4Hz, J2 = 12.8Hz), 3.20 (d, 1H, / = 7.6Hz), 1.57 (s, 3H); ESI-MS: (+ve mode) 343.14 (M+H)+ (100 %); UPLC: 94.54 %, Ret.time =
1.496 min.
Compound 87: 7-isopropoxy-l-((3aS,6aR)-6a-methyl-2-oxohexahydro-5H- pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-6-carboxamide.
Figure imgf000080_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.21 (s, 1H), 8.00 (d, 1H, / = 5.6Hz), 7.87 (s, 1H), 7.74 (bs, 2H), 7.48 (s, lH),7.43 (d, 1H, / = 5.6Hz), 4.80 (septet, 1H, / =6.0Hz), 4.01 (dd, 1H, J] = 4.4Hz, J2 = 7.2Hz), 3.84 (d, 1H, / = l2.8Hz), 3.66 (d, 1H, / = 7.6Hz), 3.29 (dd, 1H, J} = 4.4Hz, J2 = l2.8Hz), 3.16 (d, 1H, / = 7.6Hz), 1.57 (s, 3H), 1.46-1.41 (m, 6H); ESI-MS: (+ve mode) 371.12 (M+H)+ (100 %); UPLC: 98.10 %,
Ret.time = 1.930 min.
Compound 88: 7-isopropoxy-l-((3aR,6aS)-6a-methyl-2-oxohexahydro-5H- pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-6-carboxamide.
Figure imgf000081_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.21 (s, 1H), 8.00 (d, 1H, / = 5.6Hz), 7.87 (s, 1H), 7.74 (bs, 2H), 7.48 (s, 1H), 7.43 (d, 1H, / = 5.6Hz), 4.80 (septet, 1H, / =6.0Hz), 4.01 (dd, 1H, J] = 4.4Hz, J2 = 7.2Hz), 3.84 (d, 1H, / = l2.8Hz), 3.66 (d, 1H, / = 7.6Hz), 3.29 (dd, 1H, = 4.4Hz, J2 = l2.8Hz), 3.15 (d, 1H, / = 7.6Hz),), 1.57 (s, 3H), 1.46-1.41 (m, 6H); ESI-MS: (+ve mode) 371.12 (M+H)+ (100 %); UPLC: 97.82 %, Ret.time = 1.935 min.
Compound 89 : 7 -isopropoxy- 1 -(4-(2-oxoimidazolidin- 1 -yl)piperidin- 1 - yl)isoquinoline-6-carbonitrile.
Figure imgf000081_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.52 (s, 1H), 8.06 (d, 1H, / = 5.6Hz), 7.45 (s, 1H), 7.39 (d, 1H, / = 5.6Hz), 6.32 (bs, 1H), 4.92 (septet, 1H, / =6.0Hz), 3.76-3.82 (m, 3H), 3.37-3.41 (m, 2H), 3.23-3.37 (m, 2H), 2.98 (t, 2H, / = l2.8Hz), 1.93-1.97 (m, 2H), 1.71-1.74 (m, 2H), 1.42-1.44 (m, 6H); ESI-MS: (+ve mode) 379.4 (M+H)+ (100 %); HPLC: 87.73 %, Ret.time = 13.28 min. Compound 90 : 7 -isopropoxy- 1 -(4-(2-oxoimidazolidin- 1 -yl)piperidin- 1 yl)isoquinoline-6-carboxamide.
Figure imgf000082_0001
1H NMR: (DMSO-d6 400 MHz): d 8.21 (s, 1H), 8.01 (d, 1H, / = 5.6Hz), 7.73 (bs, 2H), 7.41 (d, 2H, / = 5.6Hz), 6.32 (bs, 1H), 4.84 (septet, 1H, / =6.0Hz), 3.71-3.77 (m, 3H), 3.34-3.42 (m, 2H), 3.17-3.28 (m, 2H), 2.91 (t, 2H, / = l2.8Hz), 1.90-1.98 (m, 2H), 1.71-1.74 (m, 2H), 1.42-1.44 (m, 6H); ESI-MS: (+ve mode) 398.18 (M+H)+ (100 %); HPLC: 89.17 %, Ret.time = 10.61 min. Compound 91: benzyl 6-(6-carbamoyl-7-isopropoxyisoquinolin-l-yl)-3- oxooctahydro-lH-pyrrolo[3,4-b]pyrazine-l-carboxylate Cbz
Figure imgf000082_0002
1H NMR: (DMSO-d6, 400 MHz): d 8.20 (d, 1H, / = 5.6Hz), 8.14 (s, 1H), 7.87 (d, 1H, / = 5.6Hz), 7.73 (s, 2H), 7.52 (s, 1H), 7.41-7.38 (m, 5H), 7.19 (d, 1H), 5.25-5.19 (m, 2H), 4.88-4.85 (m, 2H), 4.17 (d, 1H), 4.05-4.0 (m, 3H), 3.75-3.73 (m, 2H), 1.24 (d, 6H, J = 6.0Hz); ESI-MS: (+ve mode) 504.20 (M+H)+ (100 %); UPLC: 96.03 %, Ret.time = 2.572 min. Compound 92: 8, 8-dimethyl- l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3, 4- d]oxazol-5-yl)-8H-pyrano[2,3-h]isoquinoline-6-carbonitrile
Figure imgf000083_0001
1H NMR: (DMSO-d6 400 MHz): d 8.37 (s, 1H), 8.04 (d, 1H, / = 5.6Hz), 7.93 (s, 1H), 7.44 (s, 1H), 7.30 (d, 1H, / = 5.6Hz), 5.87-5.85 (m, 1H), 5.17-5.15 (m, 2H), 4.39 (s, 1H), 3.69-3.67 (m, 1H), 3.66-3.65 (m, 1H), 3.46-3.43 (m, 1H), 2.95-2.93 (m, 1H) 1.55 (s, 6H); ESI-MS: (+ve mode) 363.13 (M+H)+ (100 %); UPLC: 92.79 %, Ret.time = 14.237 min.
Compound 93: 8, 8-dimethyl- l-((3aR,6aS)-2-oxotetrahydro-2H-pyrrolo[3, 4- d]oxazol-5(3H)-yl)-8H-pyrano[2,3-h]isoquinoline-6-carboxamide
Figure imgf000083_0002
1H NMR: (DMSO-d6 400 MHz): d 8.10 (s, 1H), 7.98 (d, 1H, / = 5.6Hz), 7.90 (s, 1H), 7.75 (s, 2H), 7.62 (s, 1H), 7.53 (d, 1H, / = 5.6Hz), 5.83-5.81 (m, 1H), 5.16 (s, 1H), 4.39 (s, 1H), 3.72-3.70 (m, 1H), 3.51-3.49 (m, 1H), 3.02-3.01 (m, 1H), 2.93-2.91 (m, 1H), 1.54 (s, 6H); ESI-MS: (+ve mode) 381.16 (M+H)+ (100 %); HPLC: 99.63 %, Ret.time = 10.06 min. Compound 94: 8, 8-dimethyl- l-((3aR,6aS)-2-oxotetrahydro-2H-pyrrolo[3, 4- d]oxazol-5(3H)-yl)-9,l0-dihydro-8H-pyrano[2,3-h]isoquinoline-6-carboxamide
Figure imgf000084_0001
1H NMR: (DMSO-d6, 400 MHz): d 8.04 (s, 1H), 7.99 (d, 1H, / = 5.6Hz), 7.92 (s, 1H), 7.71 (s, 1H), 7.47 (d, 1H, / = 5.6Hz), 5.15-5.13 (m, 1H), 4.38 (s, 1H), 3.51-3.41 (m, 3H), 2.97-2.88 (m, 2H), 1.74 (t, 3H, J = 6.0Hz), 1.44 (s, 6H),; ESI-MS: (+ve mode) 383.14 (M+H)+ (100 %); HPLC: 98.42 %, Ret.time = 10.08 min.
Using the above procedures, following compounds can be prepared. Accompnying
coupling of Intermediate- 1 (obtained from the Scheme- 1), with substituent-R3, using appropriate base such as CS2C03, K2C03, tBuOK, DIEA, TEA KHMDS or nBuLi in solvents such as l,4-dioxane, tetrahydrofuran, N,N-dimethyl acetamide, N, N- dimethyl formamide or N-methyl-2-pyrrolidinone, followed by the base-catalyzed conversion of nitrile to amide by hydrogen peroxide provides the compounds of the general formula (I).
List of compounds as IRAK4 inhibitors
7-cyclopropoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-
(trifluoromethoxy)isoquinoline-6-carboxamide; 7-(3,3-dimethylcyclobutoxy)-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carboxamide;
7-(3,3-difluorocyclobutoxy)-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-
5-yl)isoquinoline-6-carboxamide;
7-(l-methylcyclobutoxy)-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-(l-methylcyclopropoxy)-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-(l-methylcyclopropoxy)-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-cyclopropoxy-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-(3,3-dimethylcyclobutoxy)-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carboxamide;
7-(3,3-difluorocyclobutoxy)-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-
5-yl)isoquinoline-6-carboxamide;
6-(3,3-difluorocyclobutoxy)-4-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5 -yl)quinoline-7 -carboxamide;
6-(3,3-dimethylcyclobutoxy)-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)quinoline-7-carboxamide;
6-isopropoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)quinoline-
7-carboxamide;
6-isopropoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)quinazoline-7-carboxamide;
6-isopropoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-7-carboxamide;
6-methoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-7-carboxamide; 6-cyclopropoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-7-carboxamide;
6-methoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)quinoline-7- carboxamide;
6-methoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)quinazoline-
7-carboxamide;
6-(difluoromethoxy)-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)quinazoline-7-carboxamide;
6-(difluoromethoxy)-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)quinoline-7-carboxamide;
6-(difluoromethoxy)-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-7-carboxamide;
6-cyclobutoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-7-carboxamide;
6-cyclobutoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)quinoline-7-carboxamide ;
6-cyclobutoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)quinazoline-7-carboxamide;
4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6-(prop-2-yn-l- yloxy)quinazoline-7-carboxamide;
4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6-(prop-2-yn-l- yloxy)quinoline-7-carboxamide;
4-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6-(prop-2-yn-l- yloxy)quinoline-7-carboxamide;
6-cyclobutoxy-4-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)quinoline-7-carboxamide ;
6-cyclobutoxy-4-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)quinazoline-7-carboxamide; 6-ethoxy-4-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)quinazoline-7- carboxamide;
6-ethoxy-4-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)quinoline-7- carboxamide;
6-ethoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)quinoline-7- carboxamide;
6-ethoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)quinazoline-7- carboxamide;
6-ethoxy-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline- 7-carboxamide;
7-((2-methylbut-3-en-2-yl)oxy)-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carboxamide;
6-((2-methylbut-3-en-2-yl)oxy)-4-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)quinazoline-7-carboxamide;
7-isopropoxy-l-((3aR,6S,6aR)-6-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5-yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6R,6aR)-6-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol- 5-yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aS,6R,6aS)-6-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6R,6aR)-2-oxo-6-propylhexahydro-5H-pyrrolo[3,4-d]oxazol-
5-yl)isoquinoline-6-carboxamide;
6-isopropoxy-4-((3aR,6R,6aR)-2-oxo-6-propylhexahydro-5H-pyrrolo[3,4-d]oxazol- 5 -yl)quinazoline-7 -carboxamide ;
6-isopropoxy-4-((3aR,6R,6aR)-2-oxo-6-propylhexahydro-5H-pyrrolo[3,4-d]oxazol- 5 -yl)quinoline-7 -carboxamide;
7-methoxy-l-((3aR,6S,6aR)-6-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide; 7- methoxy -l-((3aR,6R,6aR)-6-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7- methoxy -l-((3aS,6R,6aS)-6-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7- methoxy -l-((3aR,6R,6aR)-2-oxo-6-propylhexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
6- methoxy-4-((3aR,6R,6aR)-2-oxo-6-propylhexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)quinazoline-7-carboxamide;
6- methoxy-4-((3aR,6R,6aR)-2-oxo-6-propylhexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)quinoline-7-carboxamide;
4-((3aR,6aR)-6-(hydroxymethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- isopropoxyquinoline-7-carboxamide;
4-((3aR,6aR)-6-(hydroxymethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- isopropoxyquinazoline-7-carboxamide;
l-((3aR,6aR)-6-(hydroxymethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- isopropoxyisoquinoline-6-carboxamide;
l-((3aR,6aR)-6-(fluoromethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- isopropoxyisoquinoline-6-carboxamide;
4-((3aR,6aR)-6-(fluoromethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- isopropoxyquinazoline-7 -carboxamide;
4-((3aR,6aR)-6-(fluoromethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- isopropoxyquinoline-7-carboxamide;
4-((3aR,6aR)-6-(difluoromethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- isopropoxyquinoline-7-carboxamide;
4-((3aR,6aR)-6-(difluoromethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- isopropoxyquinazoline-7-carboxamide;
l-((3aR,6aR)-6-(difluoromethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- isopropoxyisoquinoline-6-carboxamide; 7-isopropoxy-l-((3aR,6aR)-2-oxo-6-(trifluoromethyl)hexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carboxamide;
6-isopropoxy-4-((3aR,6aR)-2-oxo-6-(trifluoromethyl)hexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)quinazoline-7-carboxamide;
6-isopropoxy-4-((3aR,6aR)-2-oxo-6-(trifluoromethyl)hexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)quinoline-7-carboxamide;
4-((3aR,6aR)-6-(hydroxymethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- methoxyquinoline-7-carboxamide;
4-((3aR,6aR)-6-(hydroxymethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- methoxyquinazoline-7-carboxamide;
l-((3aR,6aR)-6-(hydroxymethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- methoxyisoquinoline-6-carboxamide;
l-((3aR,6aR)-6-(fluoromethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- methoxyisoquinoline-6-carboxamide;
4-((3aR,6aR)-6-(fluoromethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- methoxyquinazoline-7-carboxamide;
4-((3aR,6aR)-6-(fluoromethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- methoxyquinoline-7-carboxamide;
4-((3aR,6aR)-6-(difluoromethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- methoxyquinoline-7-carboxamide;
4-((3aR,6aR)-6-(difluoromethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- methoxyquinazoline-7-carboxamide;
l-((3aR,6aR)-6-(difluoromethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- methoxyisoquinoline-6-carboxamide;
7-methoxy-l-((3aR,6aR)-2-oxo-6-(trifluoromethyl)hexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carboxamide;
6-methoxy-4-((3aR,6aR)-2-oxo-6-(trifluoromethyl)hexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)quinazoline-7-carboxamide; 6-methoxy-4-((3aR,6aR)-2-oxo-6-(trifluoromethyl)hexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)quinoline-7-carboxamide;
6-isopropoxy-4-((3aR,6S,6aR)-2-oxo-6-(trifluoromethyl)hexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)quinoline-7-carboxamide;
4-((3aR,6R,6aR)-6-fluoro-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- isopropoxyquinoline-7-carboxamide;
4-((3aR,6R,6aR)-6-fluoro-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- isopropoxyquinazoline-7-carboxamide;
6-isopropoxy-4-((3aR,6aS)-6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)quinazoline-7-carboxamide;
6-isopropoxy-4-((3aS)-6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)quinazoline-7-carboxamide;
4-((3aS,6aS)-6a-fluoro-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- isopropoxyquinazoline-7-carboxamide;
l-((3aS,6aS)-6a-fluoro-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- isopropoxyisoquinoline-6-carboxamide;
l-((3aR,6aR)-6a-fluoro-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- isopropoxyisoquinoline-6-carboxamide;
4-((3aR,6aR)-6a-fluoro-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- isopropoxyquinazoline-7 -carboxamide;
4-((3aR,6aR)-6a-fluoro-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- isopropoxyquinoline-7-carboxamide;
4-((3aR,6aS)-6a-ethyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-6- isopropoxyquinoline-7-carboxamide;
l-((3aR,6aS)-6a-ethyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- isopropoxyisoquinoline-6-carboxamide;
l-(3a-ethyl-2-oxohexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl)-7- isopropoxyisoquinoline-6-carboxamide; l-(3a-ethyl-3-fluoro-2-oxohexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl)-7- isopropoxyisoquinoline-6-carboxamide;
l-(3,3-difluoro-2-oxohexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl)-7- isopropoxyisoquinoline-6-carboxamide;
7-isopropoxy-l-((3aS,6aS)-2-oxohexahydropyrrolo[3,4-b]pyrrol-5(lH)- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6aR)-2-oxohexahydropyrrolo[3,4-b]pyrrol-5(lH)- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6aS)-2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6aS)-2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)- yl)isoquinoline-6-carboxamide;
l-((3aR,6aS)-3a,6a-dimethyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- isopropoxyisoquinoline-6-carboxamide;
l-((3aS,6aR)-3a,6a-dimethyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- isopropoxyisoquinoline-6-carboxamide;
l-(4a-ethyl-4-fluoro-2-oxohexahydropyrrolo[3,4-d][l,3]oxazin-6(4H)-yl)-7- isopropoxyisoquinoline-6-carboxamide;
7-isopropoxy-4-methyl-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-4-
(trifluoromethyl)isoquinoline-6-carboxamide;
7-isopropoxy-3-methyl-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-3- (trifluoromethyl)isoquinoline-6-carboxamide;
l-((3aR,6aR)-6-(aminomethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- isopropoxyisoquinoline-6-carboxamide; l-((3aR,6aR)-4,6-dimethyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- isopropoxyisoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbothioamide;
7-isopropoxy-l-((3aR,6aS)-2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)- yl)isoquinoline-6-carbothioamide;
7-isopropoxy-l-((3aR,6aS)-2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)- yl)isoquinoline-6-carbothioamide;
7-isopropoxy-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbothioamide;
l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-(thiazol-4- yloxy)isoquinoline-6-carboxamide;
7-methoxy-l-(6-oxo-2,5-diazaspiro[3.4]octan-2-yl)isoquinoline-6-carboxamide; 7-methoxy-l-((3a'R,6a'R)-2'-oxotetrahydrospiro[cyclopropane-l,6'-pyrrolo[3,4- d]oxazol]-5'(4'H)-yl)isoquinoline-6-carboxamide;
7-methoxy-l-(2'-oxohexahydro-5'H-spiro[cyclopropane-l,3'-pyrrolo[3,4-b]pyrrol]-5'- yl)isoquinoline-6-carboxamide;
l-(6a-cyclopropyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- methoxyisoquinoline-6-carboxamide;
l-(6a-(cyclopropylmethyl)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7- isopropoxyisoquinoline-6-carboxamide;
7-isopropoxy-l-(3-oxo-2-oxa-4,7-diazabicyclo[3.3.l]nonan-7-yl)isoquinoline-6- carboxamide;
7-isopropoxy-l-(4-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6aS)-4-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6aS)-2-oxo-4-(trifluoromethyl)hexahydro-5H-pyrrolo[3,4- d]oxazol-5-yl)isoquinoline-6-carboxamide; 7-isopropoxy-l-(2-oxo-6-(trifluoromethyl)hexahydropyrrolo[3,4-b]pyrrol-5(lH)- yl)isoquinoline-6-carboxamide.
7-(methoxy-d3)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-6- carboxamide;
7-(ethoxy-2,2,2-d3)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-
6-carboxamide;
7-(ethoxy-d5)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-6- carboxamide
7 -(ethoxy- 1 , 1 -d2)- 1 -(2-oxohexahydro-5H-pyrrolo [3 ,4-d] oxazol-5 -yl)isoquinoline-6- carboxamide;
l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-((propan-2-yl- 1,1,1 ,3,3,3-d6)oxy)isoquinoline-6-carboxamide;
7-(ethoxy-2,2,2-d3)-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-(ethoxy-d5)-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-(methoxy-d3)-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide. In some embodiments, the compositions and methods according to the invention use compounds of formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof possess therapeutic role of inhibiting IRAK4 kinase useful for the treatment of autoimmune diseases, inflammatory diseases, and proliferative diseases. The autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, gout and psoriasis. Testing of Compounds of the invention
In vitro IRAK4 inhibitory activity using enzymatic assay:
Test compounds were screened in the TR-FRET assay with IRAK4 kinase obtained from Millipore. 5 ng of IRAK4 kinase was used for the assay. The compound was incubated with the kinase for 30 minutes at room temperature. After the incubation, substrate mixture [Biotin Histone H3 as substrate at a concentration of lOOnM and ATP at a concentration of 20 mpj was added. The above reaction was stopped by the addition of 40 mp EDTA after the 30 minutes kinase reaction followed by the addition of 0.5 nM of Eu-labelled antiphospho tyrosine antibody from Perkin Elmer. The fluorescence excitation at 340 nm and emission at 615 nm/665 nm was measured. The compounds were initially screened at 10, 100 and 1000 nM concentration. The potent compounds were taken for the dose response studies. For IC50 determination 1/3 serial dilution was made from the original stock with the highest concentration of 10 mp and the dose-response curve fitting was done using GraphPad software. In-vitro IRAK4 inhibitory activity (IC50) of some of the representative compounds is listed in Table 4.
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The compounds of formula (I) or pharmaceutical compositions containing them are useful as a medicament for the inhibition of IRAK4 enzyme activity and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon several factors such as the particular application method, the potency of the particular compound and the desired concentration.
The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The pharmaceutical compositions according to this invention can exist in various forms. In some embodiments, the pharmaceutical composition is in the form of a powder or solution. In some other embodiments, the pharmaceutical compositions according to the invention are in the form of a powder that can be reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration. Non-limiting example of such a compatible reconstitution diluents include water.
In some other embodiments, the pharmaceutical compositions according to the invention are in the form ready to use for oral or parenteral administration.
In the methods according to the invention, the pharmaceutical composition and / or other pharmaceutically active ingredients disclosed herein may be administered by any appropriate method, which serves to deliver the composition or its constituents or the active ingredients to the desired site. The method of administration can vary depending on various factors, such as for examples, the components of the pharmaceutical composition and nature of the active ingredients, the site of the potential or actual infection, severity of infection, age and physical condition of the subject. Some non-limiting examples of administering the composition to a subject according to this invention include oral, intravenous, topical, intrarespiratory, intraperitoneal, intramuscular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, dermal patch, eye drop, ear droop or mouthwash.
Compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.
Compounds of the invention may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome.
Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."
In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent. Examples of agents the combinations of this invention may also be combined with include, without limitation: treatments for Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; anti inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors.
In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Haris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T-cell" agents such as abatacept (Orencia®), "anti-IL-6" agents such as tocilizumab (Actemra®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), or any combination(s) thereof.
In another embodiment, the present invention provides a method of treating inflammatory bowel disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.
In another embodiment, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®). In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.
In another embodiment, the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan- JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).
In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis. In general, the pharmaceutical compositions and method disclosed herein are useful in preventing or for the treatment of inflammatory, cell proliferative and immune-related conditions and diseases associated with IRAK4-mediated signal transduction, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, allergic disease, psoriasis, asthma and cancer.

Claims

We claim:
1. Compound having the structure of general formula (I)
Figure imgf000101_0001
their tautomeric forms, their enantiomers, their diastereoisomers, their pharmaceutically acceptable salts wherein:
W is -CH2, -CHRI, -NH, -NRi, O, S, or S(0)„
X, X’, Y and Y’ are each independently -CR2, -N or -N+-0 . Z is independently -CR2, -N or -N+-0 . provided that no more than three of X, X’,
Y, Y’ and Z are N; and no more than one of X, X’, Y, Y’ or Z is -N+-0
When W is -CH2 or -CHR R | at each occurrence is independently selected from hydrogen, halo, cyano, nitro, hydroxyl, optionally substituted groups selected from amino, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 alkoxy, C2-6 alkenoxy, C2-6 alkynyloxy, cycloalkoxy, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl(Ci_6)alkyl, heterocycloalkyl(Ci_6)alkyl, arylalkyl, heteroarylalkyl, aryloxy, heteroaryloxy, heterocyclyloxy, wherein each of these groups, whenever applicable, is further substituted with one to three substituent(s) independently selected from hydroxy, (Ci_4)alkoxy, halo, cyano, amino, (Ci_6)alkylamino, nitro, COO(Ci_ 4)alkyl, S(0)n, S(0)nNH2, S(0)„NH(C1-6)alkyl, C(O), C(0)NH(C1-6)alkyl groups;
When W is -NH, -NRi, O, S, or S(0)n, Ri at each occurrence is independently selected from Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl(Ci_6)alkyl, heterocycloalkyl(Ci_6)alkyl, arylalkyl, heteroarylalkyl, aryloxy, heteroaryloxy, heterocyclyloxy, wherein each of these groups, whenever applicable, is further substituted with one to three substituent(s) independently selected from hydroxy, (Ci_4)alkoxy, halo, cyano, amino, (Ci_6)alkylamino, nitro, COO(Ci_ 4)alkyl, S(0)„, S(0)nNH2, S(0)„NH(C1-6)alkyl, C(O), C(0)NH(C1-6)alkyl groups;
Ri can also form 1 to 7 membered cyclic ring with X when X= -CR2;
R2 at each occurrence is independently selected from hydrogen, halo, cyano, nitro, hydroxyl, optionally substituted groups selected from amino, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 alkoxy, C2-6 alkenoxy, C2-6 alkynyloxy, cycloalkoxy, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl(Ci_6)alkyl, heterocycloalkyl(Ci_6)alkyl, aralkyl, heteroarylalkyl, aryloxy, heteroaryloxy, heterocyclyloxy, wherein each of these groups, whenever applicable, is further substituted with one to three substituent(s) independently selected from hydroxy, (Ci_4)alkoxy, halo, cyano, amino, (Ci_6)alkylamino, nitro, COO(Ci_4)alkyl, S(0)n, S(0)nNH2, S(0)nNH(Ci_ 6)alkyl, C(O), C(0)NH(Ci_6)alkyl groups;
R3 is selected from the following heterocyclic ring systems:
Figure imgf000103_0001
Figure imgf000104_0001
wherein R4 at each occurrence wherever applicable is independently selected from
hydrogen, halo, amino, hydroxyl, cyano, optionally substituted groups selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(Ci_6)alkyl, heterocycloalkyl(Ci_6)alkyl, S(0)n(Ci_ 6)alkyl, S(0)n(Ci-6)aryl, S(0)nNH2, S(0)„NH(C1-6)alkyl, S(0)nNHcyeloalkyl, S(0)nNHaryl, S(0)nNHheteroaryl, (Ci_6)alkylamino, COO(Ci_4)alkyl, C(0)(Ci_ 6)alkyl groups;
When R4 is substituted, the preferred substituents on R4 wherever applicable are selected from hydrogen, halo, haloalkyl, amino, hydroxy, cyano, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, - CH2_COOH, -C(=0)-0-methyl, -C(=0)-0-trifluromethyl, -C(=0)-0-ethyl, - C(=0)-0-phenyl, -C(=0)-NH-methyl, -C(=0)-NH-ethyl, -C(=0)-NH-propyl, -
C(=0)-NH-cyelopropyl, -C(=0)-NH-phenyl,-C(=0)-NH-trifluromethyl, C(=0)-methyl, -C(=0)-ethyl, -C(=0)CH2-methyl, -C(=0)CH2-phenyl, S(0)2- phenyl, S(0)2-methyl, S(0)2-ethyl, S(0)2-propyl, S(0)2-butyl, S(0)2- cyclopropyl, S(0)2-cyclobutyl, S(0)2-cyclopentyl, S(0)2-cyclohexyl, S(0)2- phenyl, S(0)2-flurophenyl, S(0)2-cynophenyl, S(0)2NH2, S(0)2NH-methyl,
S(0)2NH-ethyl;
R5 is -C(NH)NHR6, -C(0)NHR6, -C(S)NHR6, -COOR6 or cyano; R6 is hydrogen, (Ci_6)alkyl, (Ci_6)alkylcarbonyl or -(CH2)nCOOH;
Wherein n = 0-4.
2. Compound of formula (I) as claimed in claim 1, wherein X, X’ are independently CR2, Y and Y’ are each independently selected from -CR2 or -N, Z is independently -CR2 or -N.
3. Compound of formula (I) as claimed in claim 1, wherein W is O.
4. Compound of formula (I) as claimed in claim 1, wherein Ri is selected from Ci_ 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, carbocycle, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkyl(Ci_6)alkyl, heterocycloalkyl(Ci_6)alkyl, arylalkyl, heteroaryl alkyl, aryloxy, heteroaryloxy, heterocyclyloxy, wherein each of these groups.
5. Compounds as claimed in claim 4 wherein Ri is further substituted with one to three substituent(s) independently selected from hydroxy, (Ci_4)alkoxy, halo, cyano, amino, (Ci_6)alkylamino, nitro, COO(Ci_4)alkyl, S(0)n, S(0)nNH2, S(0)nNH(Ci_6)alkyl, C(O), C(0)NH(Ci_6)alkyl groups, Ri can form 1 to 7 membered cyclic ring with X when X= -CR2, wherein R2 is selected from H or alkyl.
6. Compound of formula (I) as claimed in claim 1, wherein R3 is selected from
Figure imgf000106_0001
7. Compound of formula (I) as claimed in claim 1, wherein R4 at each occurrence is independently selected from hydrogen, halo, amino, hydroxy, cyano, which is optionally substituted from Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, carbocycle, heterocycloalkyl, cycloalkyl(Ci_6)alkyl or heterocycloalkyl(Ci_6)alkyl, C(0)(Ci_6)alkyl group,
8. Compound of formula (I) as claimed in claim 7 wherein, R4 is further optionally substituted with hydrogen, halo, haloalkyl, amino, cyano, hydroxy, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl.
9. Compound of formula (I) as claimed in claim 1, wherein R5 is selected from - C(0)NHR6 or cyano, wherein R6 is hydrogen or (Ci_6)alkyl group.
10. Compound of formula (I) as claimed in claim 1 is selected from, 7-isoproxy- l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-6- carbonitrile;
7-isopropoxy-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)isoquinoline-6- carboxamide;
7-methoxy-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)isoquinoline-
6-carbonitrile ;
7-methoxy-l-(3-methyl-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carbonitrile;
7-methoxy-l-(3-methyl-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-methoxy-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)isoquinoline-
6-carboxamide;
7-isopropoxy-l-((3aR, 6aS)-2-oxohexahydro-5H-pyrrolo [3, 4-d] oxazol-5-yl) isoquinoline-6-carbonitrile;
7-isopropoxy-l-(2-oxohexahydropyrrolo[3,4-d][l,3]oxazin-6(4H)- yl)isoquinoline-6-carboxamide;
7-methoxy-l-(2-oxohexahydropyrrolo[3,4-d][l,3]oxazin-6(4H)- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-(2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)-yl)isoquinoline- 6-carboxamide;
7-methoxy-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)isoquinoline-
6-carboxamide;
l-(6-(4-fluorophenyl)-2-oxohexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl)-7- isopropoxyisoquinoline-6-carboxamide;
7-isopropoxy-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-isopropoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide; l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-(prop-2-yn-l- yloxy)isoquinoline-6-carboxamide;
tert-butyl 3-((6-cyano-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinolin-7-yl)oxy)azetidine-l-carboxylate;
7-(oxetan-3-yloxy)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
tert-butyl 3-((6-carbamoyl-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinolin-7-yl)oxy)azetidine-l-carboxylate;
7-(azetidin-3-yloxy)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-methoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile;
7-methoxy-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-methoxy-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-isopropoxy- 1 -(2-oxohexahydropyrrolo [3 ,4-b]pyrrol-5( 1 H)-yl)isoquinoline-6- carboxamide;
7-isopropoxy- 1 -((3 aS, 6aR)-2-oxohexahydro-5H-pyrrolo [3, 4-d] oxazol-5-yl) isoquinoline-6-carbonitrile;
7-methoxy-l-((3aS,6aR)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile;
7-(difluoromethoxy)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-(2,2,2- trifluoroethoxy)isoquinoline-6-carboxamide;
l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-(2,2,2- trifluoroethoxy)isoquinoline-6-carbonitrile; l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-phenoxyisoquinoline-6- carboxamide;
l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-phenoxyisoquinoline-6- carbonitrile;
l-(l-ethyl-2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)-yl)-7- isopropoxyisoquinoline-6-carboxamide;
l-(l,3-diethyl-2-oxohexahydropyrrolo[3,4-d]imidazol-5(lH)-yl)-7- isopropoxyisoquinoline-6-carboxamide;
7-isopropoxy- 1 -(2-oxohexahydro- lH-pyrrolo[3,4-d]pyrimidin-6(2H)- yl)isoquinoline-6-carboxamide;
7-isopropoxy- 1 -(2-oxohexahydro- lH-pyrrolo[3,4-b]pyrazin-6(2H)- yl)isoquinoline-6-carboxamide;
7-(cyclopentyloxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-(cyclohexyloxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-cyclobutoxy-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-(cyclopropylmethoxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)-yl)-7-
(vinyloxy)isoquinoline-6-carboxamide;
l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-7-(vinyloxy)isoquinoline-6- carbonitrile;
7-(cyclopropylmethoxy)-l-(2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile;
7-cyclobutoxy-l-((3aS,6aR)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide; 7-cyclobutoxy-l-((3aR,6aS)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-(dicyclopropylmethoxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-((3,3-difluorocyclobutyl)methoxy)-l-((3aR,6aS)-2-oxotetrahydro-2H- pyrrolo[3,4-d]oxazol-5(3H)-yl)isoquinoline-6-carboxamide;
7-(tert-butoxy)-l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile;
7-(tert-butoxy)-l-((3aR,6aS)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-ethoxy- l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile;
-ethoxy- l-((3aR,6aS)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
7-(allyloxy)-l-(2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)isoquinoline-6-carboxamide;
11. Compound as claimed in claim 1 is selected from
l-((lR,5S)-3,6-diazabicyclo[3.l.l]heptan-6-yl)-7-methoxyisoquinoline-6- carboxamide;
l-((lR,5S)-3-(2-cyanoacetyl)-3,6-diazabicyclo[3. l.l]heptan-6-yl)-7- methoxyisoquinoline-6-carboxamide;
7-methoxy- l-(3-oxopiperazin- 1 -yl)isoquinoline-6-carboxamide;
l-(3-acetamidopiperidin-l-yl)-7-isopropoxyisoquinoline-6-carboxamide;
7-isopropoxy- 1 -(3 -(methylsulfonamido)piperidin- 1 -yl)isoquinoline-6- carboxamide;
l-(2,4-dioxo-l,3,8-triazaspiro[4.5]decan-8-yl)-7-isopropoxyisoquinoline-6- carboxamide;
7-isopropoxy- l-(3-methyl-2,4-dioxo- 1,3, 8-triazaspiro[4.5]decan-8- yl)isoquinoline-6-carboxamide; l-(3-acetamidopyrrolidin-l-yl)-7-isopropoxyisoquinoline-6-carboxamide;
N-( 1 -(6-carbamothioyl-7-isopropoxyisoquinolin- 1 -yl)pyrrolidin-3- yl)acetamide;
l-(2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7-yl)-7-isopropoxyisoquinoline-6- carboxamide;
7-isopropoxy-l-(3-methyl-2,4-dioxo-l,3,7-triazaspiro[4.4]nonan-7- yl)isoquinoline-6-carboxamide;
l-(3-acetamido-4-hydroxypyrrolidin-l-yl)-7-isopropoxyisoquinoline-6- carboxamide;
l-(3-(hydroxymethyl)-4-(2,2,2-trifluoroacetamido)pyrrolidin-l-yl)-7- isopropoxyisoquinoline-6-carboxamide;
l-(2,4-dioxo-l,3,7-triazaspiro[4.5]decan-7-yl)-7-isopropoxyisoquinoline-6- carboxamide;
l-(2,4-dioxo-l,3,7-triazaspiro[4.5]decan-7-yl)-7-methoxyisoquinoline-6- carboxamide;
7-methoxy-l-(3-methyl-2,4-dioxo-l,3,7-triazaspiro[4.5]decan-7- yl)isoquinoline-6-carboxamide;
l-(6,8-dioxo-2,5,7-triazaspiro[3.4]octan-2-yl)-7-isopropoxyisoquinoline-6- carboxamide;
l-(6,8-dioxo-2,5,7-triazaspiro[3.4]octan-2-yl)-7-methoxyisoquinoline-6- carboxamide;
l-(5, 6-dihydropyrrolo [3, 4-c] pyrrol-2(lH, 3H, 4H)-yl)-7- methoxyisoquinoline-6-carboxamide;
l-(5-(2-cyanoacetyl)-3, 4, 5, 6-tetrahydropyrrolo [3, 4-c] pyrrol-2(lH)-yl)-7- methoxyisoquinoline-6-carboxamide;
l-(5-(2-hydroxyacetyl)-3, 4, 5, 6-tetrahydropyrrolo [3, 4-c] pyrrol-2(lH)-yl)-7- methoxyisoquinoline-6-carboxamide;
7-methoxy-l -(2-oxo- l-oxa-3, 8-diazaspiro [4.5] decan-8-yl) isoquinoline-6- carboxamide; 7-isopropoxy-l -(2-oxo- l-oxa-3, 8-diazaspiro [4.5] decan-8-yl) isoquinoline-6- carboxamide;
7-methoxy-l-(3-oxo-l-oxa-4, 9-diazaspiro [5.5] undecan-9-yl) isoquinoline-6- carboxamide;
7-isopropoxy-l -(3 -oxo- l-oxa-4, 9-diazaspiro [5.5] undecan-9-yl) isoquinoline-
6-carboxamide;
7-isopropoxy- l-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6- carboxamide;
7-methoxy-l-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6- carboxamide;
7-isopropoxy- l-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)isoquinoline-6- carboxamide;
7-methoxy-l-(8-oxo-2,7-diazaspiro[4.4]nonan-2-yl)isoquinoline-6- carboxamide;
7-isopropoxy- 1 -(4-(3-oxopiperazin- 1 -yl)piperidin- 1 -yl)isoquinoline-6- carboxamide;
7-isopropoxy-l -(2-oxo- l,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6- carboxamide;
7-methoxy-l-(2-oxo-l,8-diazaspiro[4.5]decan-8-yl)isoquinoline-6- carboxamide;
7-isopropoxy- l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile;
7-isopropoxy- l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide;
7-methoxy-l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carbonitrile;
7-methoxy-l-(6a-methyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5- yl)isoquinoline-6-carboxamide; 7-isopropoxy- l-((3aS,6aR)-6a-methyl-2-oxohexahydro-5H-pyrrolo[3, 4- d]oxazol-5-yl)isoquinoline-6-carboxamide;
7-isopropoxy- l-((3aR,6aS)-6a-methyl-2-oxohexahydro-5H-pyrrolo[3, 4- d]oxazol-5-yl)isoquinoline-6-carboxamide;
7-isopropoxy- 1 -(4-(2-oxoimidazolidin- 1 -yl)piperidin- 1 -yl)isoquinoline-6- carbonitrile;
7-isopropoxy- 1 -(4-(2-oxoimidazolidin- 1 -yl)piperidin- 1 -yl)isoquinoline-6- carboxamide;
benzyl 6-(6-carbamoyl-7-isopropoxyisoquinolin-l-yl)-3-oxooctahydro-lH- pyrrolo[3 ,4-b]pyrazine- 1 -carboxylate;
8.8-dimethyl- l-((3aR,6aS)-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-8H- pyr ano [2,3 -h] isoquinoline-6-carbonitrile ;
8.8-dimethyl- l-((3aR,6aS)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)-8H-pyrano[2,3-h]isoquinoline-6-carboxamide;
8, 8-dimethyl- l-((3aR,6aS)-2-oxotetrahydro-2H-pyrrolo[3,4-d]oxazol-5(3H)- yl)-9,lO-dihydro-8H-pyrano[2,3-h]isoquinoline-6-carboxamide.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as claimed in any of the preceding claims and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.
13. The pharmaceutical composition as claimed in claim 11 provides novel compounds that are inhibitors of IRAK4, pharmaceutical compositions and a method for treating.
14. The pharmaceutical composition as claimed in claim 11 for use in treatment or prevention of autoimmune diseases, inflammatory diseases, proliferative diseases. The autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, gout and psoriasis.
15. A method of treating inflammatory, cell proliferative and immune -related conditions and diseases associated with IRAK4-mediated signal transduction, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, allergic disease, psoriasis, asthma and cancer, in a subject which comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) as claimed in any of the preceding claims or its suitable pharmaceutical composition.
16. The use of compounds of formula (I) or its pharmaceutical compositions as claimed in any of the preceding claim suitable for treatment of diseases wherein IRAK4-mediated and associated conditions or diseases that comprises administering IRAK4 inhibitors.
17. Compound of formula (I) or its pharmaceutical composition as claimed in any of preceding claim in combination with one or more suitable pharmaceutically active agents selected from beta interfero, anti-inflammatory agents, immunomodulatory and immunosuppressive agents, non-steroidal anti inflammatory agents, anti-TNF agents, anti-IL-l agents, anti-IL-6 agents, anti- T-cell agents, beta-2 agonists, antidiarrheals, laxatives.
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