WO2022148879A1 - Quinazoline derivatives useful as modulators of ackr3 - Google Patents

Quinazoline derivatives useful as modulators of ackr3 Download PDF

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Publication number
WO2022148879A1
WO2022148879A1 PCT/EP2022/050415 EP2022050415W WO2022148879A1 WO 2022148879 A1 WO2022148879 A1 WO 2022148879A1 EP 2022050415 W EP2022050415 W EP 2022050415W WO 2022148879 A1 WO2022148879 A1 WO 2022148879A1
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Prior art keywords
ring atoms
compound
alkyl
mmol
heteroaryl
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PCT/EP2022/050415
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French (fr)
Inventor
Rick RIEMENS
Reggie BOSMA
Marta ARIMONT SEGURA
Rob Leurs
Iwan DE ESCH
Maikel WIJTMANS
Henry VISSCHER
Maria WALDHOER
Aurélien RIZK
Mirjam ZIMMERMANN
Susanne ROTH
Nadine DOBBERSTEIN
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Stichting Vu
Interax Biotech Ag
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Publication of WO2022148879A1 publication Critical patent/WO2022148879A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present disclosure relates to compounds of formula (I) comprising a heteroaryl, such as derivatives of quinazolines, which can act as modulators of ACKR3.
  • the present disclosure also relates to the use of these compounds as a drug.
  • Chemokines and G protein-coupled chemokine receptors play an important role in the immune defense system by controlling the migration, activation, differentiation, and survival of leukocytes. Endogeneous chemokine proteins stabilize their cognant chemokine receptors in an active conformation that facilitates intracellular signal transduction by interactions with G proteins and/or arrestins. Because of their crucial role in the migration of immune cells, chemokine receptors are promising drug targets for various immune-related diseases, including chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, HIV-1 infection and cancer. Molecular pharmacology, medicinal chemistry, and molecular modeling studies have provided insights into molecular determinants of chemokine receptor modulation by proteins, peptides, and small-molecule ligands.
  • the receptor is overexpressed in many cancer types indicating a vital role in the development of the disease.
  • In vitro investigation of the ACKR3 receptor showed that overexpression and activation of the receptor by CXCL12 leads to oncogenic events such as angiogenesis, metastasis and trans endothelial cell-migration.
  • ACKR3 knock-out models or ACKR3 inhibition by small-molecule ligands led to reduced oncogenic effects.
  • the ACKR3 has been claimed to scavenge a broad range of opioid peptides, which might lead to a broadened application of a potential drug.
  • R1 and R2 are independently selected from H, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -(CO)-
  • Ring B is a ring selected from the group consisting of C3-C 12 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , -CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -(CO)-R’, -0-(C0)-R’, -(CO)-O- R ⁇
  • R’ is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms;
  • R” and R"' are independently selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, -(C 1 -C 6 alkyl)-(heterocyclyl having 5 to 10 ring atoms); said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , -CN, and C 1 -C 6 alkyl;
  • R” and R"' together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, or a heteroaryl having 5 to 10 ring atoms, said heterocyclyl, and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, - OH, -NO 2 , -CN, and C 1 -C 6 alkyl, and pharmaceutically acceptable salts, solvates and esters thereof.
  • the disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.
  • the disclosure relates to a compound of the present disclosure for use as a drug.
  • the disclosure relates to a compound of the present disclosure for use in treating cancer, autoimmune disorders, inflammatory diseases, transplant rejection, fibrosis, or pain.
  • C 1 -C 12 alkyl refers to a linear or branched alkyl functional group having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms.
  • Suitable alkyl groups include methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, s-butyl and f-butyl, pentyl and its isomers (e.g. n-pentyl, /so-pentyl), and hexyl and its isomers (e.g. n- hexyl, /so-hexyl).
  • C 3 -C 12 cycloalkyl refer to a saturated or unsaturated cyclic group having 3 to 12 carbon atoms, preferably 3 to 6.
  • the cycloalkyl can have a single ring or multiple rings fused together.
  • the cycloalkyl can also include spirocyclic rings.
  • Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • halogen refers to a fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-1) group.
  • C 1 -C 6 haloalkyl refer to a C 1 -C 6 alkyl as defined herein that is substituted by one or more halogen group as defined herein.
  • Suitable C 1 -C 6 haloalkyl groups include trifluoromethyl and dichloromethyl.
  • C 1 -C 12 heteroalkyl refer to a straight or branched hydrocarbon chain consisting of 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and from one to three, heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized (for example: a sulfoxide or a sulfone) and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • C 1 -C 6 alkoxy refer to a -O-alkyl group, wherein the alkyl group is a C 1 -C 6 alkyl as defined herein.
  • Suitable C 1 -C 6 alkoxy groups include methoxy, ethoxy, propoxy.
  • C 1 -C 6 haloalkoxy refer to a C 1 -C 6 alkoxy group as defined herein, that is substituted by one or more halogen group as defined herein. Suitable haloalkoxy include trifluoromethoxy.
  • C 1 -C 12 alkylene used alone or as part of another substituent, refer to a divalent saturated, straight-chained or branched hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 6.
  • C 1 -C 12 heteroalkylene refer to a divalent heteroalkyl as defined above.
  • heteroatoms can also occupy either or both of the chain termini.
  • aryl having 6 to 10 ring atoms refer to a polyunsaturated, aromatic hydrocarbyl group having a single ring or multiple aromatic rings fused together, containing 6 to 10 ring atoms, wherein at least one ring is aromatic.
  • the aromatic ring may optionally include one to two additional rings (cycloalkyl, heterocyclyl or heteroaryl as defined herein) fused thereto.
  • Suitable aryl groups include phenyl, naphtyl and phenyl ring fused to a heterocyclyl, like benzopyranyl, benzodioxolyl, benzodioxanyl and the like.
  • heteroaryl having 5 to 10 ring atoms refer to a polyunsaturated, aromatic ring system having a single ring or multiple aromatic rings fused together or linked covalently, containing 5 to 10 atoms, wherein at least one ring is aromatic and at least one ring atom is a heteroatom selected from N, O and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • Such rings may be fused to an aryl, cycloalkyl or heterocyclyl ring.
  • Non-limiting examples of such heteroaryl include: furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, purinyl, benzothiadiazolyl, quinolinyl
  • heterocyclyl having 5 to 10 ring atoms refer to a saturated or unsaturated cyclic group having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • the heterocycle can include fused or bridged rings as well as spirocyclic rings.
  • heterocycle examples include, but are not limited to, tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, 1- azepanyl, imidazolinyl, 1 ,4-dioxanyl and the like.
  • organic group refers to any organic substituent group, regardless of functional type, having one free valence at a carbon atom.
  • the present disclosure encompasses the compounds of the present disclosure, their tautomers, enantiomers, diastereomers, racemates or mixtures thereof, and their hydrates, esters, solvates or pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this disclosure and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with organic acids and/or inorganic acids.
  • Pharmaceutically acceptable base addition salts can be formed with organic bases and/or inorganic bases.
  • esters include C 1 -C 6 alkyl esters.
  • the present disclosure first relates to a compound of formula (I):
  • Z is N or CR3
  • R1 and R2 are independently selected from H, C 1 -C 6 alkyl, C3-C 12 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , -CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -(CO)-R’, -0-(C0)-R’
  • R1 and R2 together with the N or C atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, a C 3 -C 6 cycloalkyl, an aryl having 6 to 10 ring atoms, or a heteroaryl having 5 to 10 ring atoms, said heterocyclyl, cycloalkyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , -CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -(CO)-R’, -0-(C0)-R
  • R3 is present or absent when the C atom forms a double bond, and if present, R3 is selected from H and C 1 -C 6 alkyl;
  • X is N or CH, preferably X is N;
  • Ring A is aromatic, and is selected from the group consisting of aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said aryl and heteroaryl being optionally substituted with one or more substituents independently selected from halogen, -OH, -NO 2 , -CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -(CO)-R’, -0-(C0)-R’, -(CO)-O- R’, -(CO)-NR”R"' -NR”-(CO)-R’, and -NR”R"';
  • Y is O or NR; wherein R is H or an organyl group, preferably Y is NR;
  • L is a divalent linker selected from the group consisting of C1-C 12 alklylene or heteroalkylene, said alkylene and heteroalkylene being optionally interspersed with one or more groups selected from - (C 3 -C 6 cycloalkyl)-, and -(heterocyclyl having 5 to 10 ring atoms)-, said alkylene, heteroalkylene cycloalkyl and heterocyclyl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , -CN, C1-C6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -(CO)-
  • Ring B is a ring selected from the group consisting of C 3 -C 12 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , -CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -(CO)-R’, -0-(C0)-R’, -(CO)-O-
  • R” and R"' are independently selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, -(C 1 -C 6 alkyl)-(heterocyclyl having 5 to 10 ring atoms), said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , -CN, and C 1 -C 6 alkyl;
  • R” and R"' together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, or a heteroaryl having 5 to 10 ring atoms, said heterocyclyl, and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, - OH, -NO 2 , -CN, and C 1 -C 6 alkyl, and pharmaceutically acceptable salts thereof.
  • the compound of formula (I) is a modulator of ACKR3.
  • a modulator of ACKR3 is an ACKR3 antagonist.
  • an ACKR3 antagonist refers to a compound which directly binds to ACKR3, and which competitively inhibits the binding of reference ACKR3 binding compound.
  • an ACKR3 antagonist of the present disclosure is a compound which directly binds to ACKR3 and is capable of displacing the binding of labelled ACKR3 binding reference compound A, as measured in vitro, typically as measured with the displacement assay using the tritium labelled ACKR3 binding reference compound: [ 3 H]compound A. More details of such displacement assay are described in the Examples. [ 3 H] compound A can be synthesized as mentioned in the Examples. [ 3 H] compound A has the following structure:
  • said ACKR3 antagonist, or modulator, of the present disclosure has preferably a pK, greater than or equal to 5.0, typically comprised between 5.0 and 7.0, and for example comprised between 5.7 and 7.0, as measured by the displacement assay with tritium labelled ACKR3 binding reference compound: [ 3 H] compound A.
  • the pKi can be obtained from said displacement assay using the resulting IC50 values.
  • said ACKR3 antagonist, or modulator, of the present disclosure has a pK, greater than or equal to 5.5, or at least 5.7, or at least 6.0, or at least 6.4.
  • Z is N, and R1 and R2, together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, said heterocyclyl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , - CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
  • ring A is aromatic, and is selected from the group consisting of aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said aryl and heteroaryl being optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.
  • R is H or an organyl group.
  • the organyl group is preferably selected from C1-C 12 alkyl, Ci- C 12 heteroalkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , -CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy
  • L is selected from the group consisting of C1-C 12 alklylene or heteroalkylene, said alkylene and heteroalkylene being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , C 1 -C 6 alkyl, and -CN.
  • ring B is an aryl having 6 to 10 ring atoms, said aryl being optionally substituted with one or more substituents independently selected from oxo, halogen, - OH, -NO 2 , -CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -(CO)-R', -0-(C0)-R', -(CO)-O-R', -(CO)-NR''R'”, -NR”-(CO)-R', -NR”R"', -(C 1 -C 6 alkyl)-NR”R"', and -(C 1 -C 6 al
  • R' is selected from C 1 -C 6 alkyl.
  • R” and R"' are independently selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms and -(C 1 -C 6 alkyl)-(heterocyclyl having 5 to 10 ring atoms) said alkyl, cycloalkyl, and heterocyclyl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , -CN, and C 1 -C 6 alkyl.
  • R” and R' together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, said heterocyclyl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , -CN, and C 1 -C 6 alkyl.
  • the compound of formula (I) is a compound of formula (II):
  • Ring A, Y, L and ring B are as defined herein;
  • Each R4 is independently selected from oxo, halogen, -OH, -NO 2 , -CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having
  • R’, R”, and R"' are as defined herein; m is an integer between 0 and 5, and preferably m is 0 or 1 . According to an embodiment, each R4 is independently selected from oxo, halogen, -OH, -NO 2 , -
  • R4 is a C 1 -C 6 alkyl.
  • the compound of formula (I) is a compound of formula (III)
  • R4 and m are as defined herein;
  • Each R5 is independently selected from halogen, -OH, -NO 2 , -CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -(CO)-R', -O-(C0)-R’, -(CO)-O-R’, - (CO)-NR”R"' -NR"-(CO)-R', and -NR"R"';
  • R’, R”, and R"' are as defined herein; n is an integer between 0 and 4, and preferably n is 0, 1 or 2.
  • each R5 is independently selected from halogen, C 1 -C 6 alkyl, and C 1 - C 6 alkoxy.
  • the compound of formula (I) is a compound of formula (IV)
  • L and ring B are as defined herein;
  • R4 and m are as defined herein;
  • R5 and n are as defined herein;
  • R is H or an organyl group selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , -CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -(CO)-R
  • R’, R”, and R"' are as defined herein.
  • R is H or Ci-C6 alkyl optionally substituted with NR”R"'.
  • the compound of formula (I) is a compound of formula (V)
  • R4 and m are as defined herein;
  • R5 and n are as defined herein;
  • R is as defined herein;
  • Each R6 is selected from halogen, -OH, -NO 2 , -CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C 1 - C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -(CO)-R’, -O-(CO)-R’, -(CO)-O-R’, -(CO)-NR”R"' - NR”-(CO)-R ⁇ -NR”R"', -(C 1 -C 6 alkyl)-NR”R"', and -(C 1 -C 6 alkyl)-OH;
  • each R6 is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CO)-R', -(CO)-O-R', -(CO)-NR”R"', -(C 1 -C 6 alkyl)-NR”R"', and -(C 1 -C 6 alkyl)-OH.
  • the compound of formula (I) is a compound of formula (VI):
  • R4 and m are as defined herein; R5 and n are as defined herein; R is as defined in claim herein; R6 and p are as defined herein.
  • the compound of formula (I) is a compound of formula (VII):
  • R4 and m are as defined herein;
  • R5 and n are as defined herein;
  • R7 and R8 are independently selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, -(C 1 -C 6 alkyl)-(heterocyclyl having 5 to 10 ring atoms), said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO 2 , -CN, and C 1 -C 6 alkyl;
  • R7 and R8 together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, or a heteroaryl having 5 to 10 ring atoms, said heterocyclyl, and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, - OH, -NO 2 , -CN, and C 1 -C 6 alkyl.
  • R7 and R8 are independently selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, -(C 1 -C 6 alkyl)-(heterocyclyl having 5 to 10 ring atoms), said alkyl, cycloalkyl, and heterocyclyl, being optionally substituted with one or more substituents independently selected from -OH, and C 1 -C 6 alkyl;
  • R7 and R8 together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, said heterocyclyl being optionally substituted with one or more substituents independently selected from -OH, and C 1 -C 6 alkyl.
  • the compound of formula (I) is selected from:
  • the compound of formula (I) is selected from
  • the compound of formula (I) is selected from :
  • composition also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the disclosure and at least one pharmaceutically acceptable carrier.
  • compositions naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and sex of the patient, etc.
  • the pharmaceutical compositions of the disclosure can be formulated for a topical, oral, intranasal, intraocular, intravenous, intramuscular or subcutaneous administration and the like.
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, emulsions, syrups, elixirs, aerosols, or any other appropriate compositions; and comprise at least one compound according this disclosure.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • tablets may be sugar coated or enteric coated by standard techniques.
  • the tablets or pills can be coated to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pills can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • the compound of the disclosure and the further agent may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for oral formulation.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected or infused.
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected or infused.
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions or solutions for infusion.
  • the pharmaceutical forms suitable for injection or infusion include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions and solutions for infusion are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • the solution may be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage could be dissolved in 1 ml of isotonic NaCI solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences" 15th Edition, pages 1035-1038 and 1570-1580).
  • Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the compound of the disclosure and the further agent are preferably supplied in finely divided from along with a surfactant and propellant.
  • the surfactant must, of course, be nontoxic, and preferably soluble in the propellant.
  • Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
  • Mixed esters, such as mixed or natural glycerides may be employed.
  • a carrier can also be included, as desired, as with, e.g., lecithin for intranasal delivery.
  • An example includes a solution in which each milliliter included 7.5 mg NaCI, 1.7 mg citric acid monohydrate, 3 mg disodium phosphate dihydrate and 0.2 mg benzalkonium chloride solution (50%) (Gozes et al sharp J Mol Neurosci. 19(1-2):167-70 (2002)).
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g. aerosol administration.
  • the doses used for the administration can be adapted as a function of various parameters, and in particular as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment. It will be appreciated that appropriate dosages of the compounds, and compositions comprising the compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments described herein.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side- effects.
  • the dose used for the administration can be of about 1-1000 mg of the compound of the disclosure for a subject of about 50-70 kg.
  • the compounds of the disclosure exhibit valuable pharmaceutical properties as indicated in the in vitro tests provided in the examples and are therefore indicated for therapy.
  • the compounds of the disclosure are useful in the prevention or treatment of disorders relating to the ACKR3 receptor.
  • the disclosure also relates to a compound of the disclosure for use as a medicament.
  • the disclosure also relates to a compound of the disclosure for use in a method for treating cancer, autoimmune disorders, inflammatory diseases, transplant rejection, fibrosis, or pain.
  • the disclosure also relates to a compound of the disclosure for use in a method for treating disorders relating to the ACKR3 receptor or its ligands.
  • ACKR3 receptor or its ligands diseases or disorders relating to the ACKR3 receptor or its ligands are diseases involving ACKR3 and / or CXCL12 and / or CXCL11 mediated metastasis, chemotaxis, cell adhesion, trans-endothelial migration, cell proliferation and/or survival.
  • diseases or disorders relating to the ACKR3 receptor or its ligands are proliferative diabetic retinopathy; West Nile virus encephalitis; pulmonary vascular diseases, acute renal failure, ischemia including cerebral ischemia, acute coronary syndrome, injured central nervous system, hypertension, pulmonary hypertension, Shiga-toxin-associated heomolytic uremic syndrome, preeclampsia, vascular injury, HIV / AIDS, angiogenesis, and brain and neuronal dysfunctions (such as inflammatory components of Alzheimer's disease), stress- related disorders (such as anxiety, depression, and posttraumatic stress disorder), and diseases involving opioid receptors.
  • a further particular disease or disorder relating to the ACKR3 receptor or its ligands is especially pulmonary hypertension.
  • cancer has its general meaning in the art and includes an abnormal state or condition characterized by rapidly proliferating cell growth.
  • the term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues or organs, irrespective of histopathologic type or stage of invasiveness.
  • cancer includes malignancies of the various organ systems, such as affecting skin, lung, breast, thyroid, lymphoid, gastrointestinal, and genito-urinary tract, as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the oesophages.
  • cancer examples include, but are not limited, to hematological malignancies such as 13- cell lymphoid neoplasm, T-cell lymphoid neoplasm, non-hodgkin lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), NK-cell lymphoid neoplasm, and myeloid cell lineage neoplasm.
  • hematological malignancies such as 13- cell lymphoid neoplasm, T-cell lymphoid neoplasm, non-hodgkin lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), NK-cell lymphoid neoplasm, and mye
  • non- hematological cancers include, but are not limited to, skin cancer, colon cancer, breast cancer, lung cancer, brain cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, colorectal cancer, bone cancer, cervical cancer, liver cancer, oral cancer, esophageal cancer, thyroid cancer, kidney cancer, stomach cancer and testicular cancer.
  • autoimmune disorders include (inflammatory) demyelinating diseases; multiple sclerosis (MS); Guillain Barre syndrome; rheumatoid arthritis (RA); inflammatory bowel diseases (IBD, especially comprising Crohn's disease and ulcerative colitis); systemic lupus erythematosus (SLE); lupus nephritis; interstitial cystitis; celiac disease; autoimmune encephalomyelitis; osteoarthritis; and type I diabetes.
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • IBD inflammatory bowel diseases
  • SLE systemic lupus erythematosus
  • SLE systemic lupus erythematosus
  • interstitial cystitis celiac disease
  • osteoarthritis and type I diabetes.
  • inflammatory diseases include chronic rhinosinusitis, asthma, chronic obstructive pulmonary disorder, atherosclerosis, myocarditis, and sarcoidosis.
  • transplant rejection examples include renal allograft rejection, cardiac allograft rejection, and graft-versus-host diseases brought about by hematopoietic stem cell transplantation.
  • fibrosis examples include liver fibrosis, liver cirrhosis, lung fibrosis, especially idiopathic pulmonary fibrosis.
  • the disclosure relates to a method for treating cancer, autoimmune disorders, inflammatory diseases, transplant rejection, fibrosis, or pain, said method comprising administering to a subject in need thereof, preferably a human, a therapeutically efficient amount of
  • the disclosure relates to a method for treating disorders relating to the ACKR3 receptor or its ligands said method comprising administering to a subject in need thereof, preferably a human, a therapeutically efficient amount of
  • the term “treating” includes reversing, alleviating, inhibiting the progression of, preventing or reducing the likelihood of the disease, disorder, or condition to which such term applies, or one or more symptoms or manifestations of such disease, disorder or condition. Preventing refers to causing a disease, disorder, condition, or symptom or manifestation of such, or worsening of the severity of such, not to occur. Accordingly, the presently disclosed compounds can be administered prophylactically to prevent or reduce the incidence or recurrence of the disease, disorder, or condition.
  • the terms “therapeutically efficient amount” of a compound refer to an amount of the compound that will elicit the biological or medical response of a subject, for example, ameliorate the symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease.
  • the disclosure also relates to the use of a compound of the disclosure, for the manufacture of a medicament for the treatment of cancer, autoimmune disorders, inflammatory diseases, transplant rejection, fibrosis, or pain.
  • a compound of the disclosure for the manufacture of a medicament for the treatment of cancer, autoimmune disorders, inflammatory diseases, transplant rejection, fibrosis, or pain.
  • HEK293T cells Two million HEK293T cells were seeded per 10 cm 2 dish and were transfected the next day using DNA/PEI-mix containing 0.25 ⁇ g plasmid DNA encoding for the ACKR3, 4.75 pg pcDEF3 plasmid DNA and 30pg linear PEI. Two days after transfection, cells were harvested, during which cells and all used solutions were kept on ice: Cells were washed with PBS (137 mM NaCI, 2.57 mM KCI, 1 .5 mM KH2P04, 8 mM Na2HP04) and pelleted by centrifugation steps.
  • PBS 137 mM NaCI, 2.57 mM KCI, 1 .5 mM KH2P04, 8 mM Na2HP04
  • Cell pellets were transferred into ice-cold membrane buffer (15 mM Tris, 0.3 mM EDTA, 2 mM MgCI2, pH 7.4 at 4°C) and were dounce-homogenized by plunging the pestle 10 times with 1500 rpm. Cell homogenates were then subjected to two freeze-thaw cycles using liquid nitrogen, cell-membranes were consecutively pelleted by centrifugation at 40,000 g and pellets were reconstituted in Tris-sucrose buffer (20 mM Tris, 250 mM Sucrose, pH 7.4 at 4°C). Finally, the membrane samples where homogenized using a 23-gauge needle, snap-frozen with liquid nitrogen and stored until further experimentation at -80 °C.
  • Radioligand binding experiments where performed by incubating 4 pg (protein content) of membranes with 4 nM [ 3 H] compound A and increasing concentrations unlabelled ligand (10 -4 M - 10 -1 1 M). All dilutions were prepared in HBSS supplemented with 0.2% BSA. Binding reactions were incubated for 2 hours and then terminated by washing the solutions over a PEI-coated GF/C filter using a cell harvester, followed by wash steps using ice-cold buffer (50 mM HEPES, 1.2 mM 5 mM 0.5 M NaCI, pH 7.4 at 4°C).
  • the compound [ 3 H] compound A has the following structure
  • the enantiopure R-isomer [ 3 H] compound A was prepared by starting with the enantiopure R-2-(1- methylpyrrolidin-2-yl)ethan-1 -amine 2b as previously disclosed (Wijtmans et al., European Journal of Medicinal Chemistry 51 (2012) 184-192).
  • An indirect reductive amination of aldehyde 1 (prepared from 2-fluorobenzaldehyde) with enantiopure amine 2b yields enantiopure key intermediate 3b.
  • Reagents and conditions a) KOH, H2O, EtOH, 24 h, 0 °C ® rt; b) (i) Na 2 SO 4 , DCM, 24 h, rt, TEA, (ii) NaBH 4 , MeOH, 0.5 h, 0 °C, 3b ee > 95%;.
  • the peak multiplicities are defined as follows: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; ddd, doublet of doublets of doublets; dt, doublet of triplets; dq, doublet of quartets; td, triplet of doublets; tt, triplet of triplets; br, broad signal; m, multiplet; app, apparent.
  • the eluent program 'acidic mode’ used is as follows: flow rate: 1 .0 mL/min, start 95% A in a linear gradient to 10% A over 4.5 min, hold 1 .5 min at 10% A, in 0.5 min in a linear gradient to 95% A, hold 1.5 min at 95% A, total runtime: 8.0 min.
  • Compound purities were calculated as the percentage peak area of the analyzed compound by UV detection at 254 nm.
  • High-resolution mass spectra (HRMS) were recorded on a Bruker micrOTOF mass spectrometer using ESI in positive ion mode (HRMS).
  • General method G The first step was conducted following general method F, using the indicated dihaloalkane instead of Mel.
  • the obtained mixture of the mono alkyl halide and elimination product was mixed with the indicated amine with K2CO3 in DMF.
  • the resulting mixture was heated at 65 °C for 2 h.
  • the volatiles were evaporated in vacuo.
  • the residue was dissolved in EtOAc.
  • the mixture was extracted with 2.0 M NaOH (aq), water and brine.
  • the organic layer was dried over anhydrous Na 2 SO 4 , filtered and evaporated in vacuo.
  • the resulting crude mixture was purified by column chromatography.
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1.01 mmol, 1.0 eq
  • amine A 2-amino-A/-methyl-A/-phenylethane-1- sulfinamide (277 mg, 1.11 mmol, 1.1 eq)
  • EtOAc 10 mL
  • DIPEA 350 ⁇ L, 2.01 mmol, 2.0 eq
  • amine B piperidine (298 ⁇ L, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used.
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1.01 mmol, 1.0 eq
  • amine A phenylethylamine (160 mg, 1.3 mmol, 1.3 eq)
  • EtOAc 10 mL
  • DIPEA 350 ⁇ L, 2.01 mmol, 2.0 eq
  • amine B piperidine (298 ⁇ L, 3.02 mmol, 3.0 eq) and DIPEA (350 ⁇ L, 2.01 mmol, 2.0 eq) were used.
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1.01 mmol, 1.0 eq
  • amine A (1-methylpiperidin-4-yl)methanamine (179 mg, 1.40 mmol, 1.39 eq)
  • EtOAc 10 mL
  • DIPEA DIPEA
  • amine B piperidine (298 ⁇ L, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used.
  • the crude product was purified by reverse phase column chromatography (FhO, ACN 0-70%). The product fractions were made basic with aq. 2.0 M NaOH and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 , filtered and evaporated in vacuo to give an off-white solid (211 mg, 62 %).
  • LCMS (acidic mode) Rt 2.348 min, purity 99 %, [M+H] + calculated 340.25, found 340.20 [M+H] + .
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1.01 mmol, 1.0 eq
  • amine A 3-(piperidin-1-yl)propan-1 -amine (210 ⁇ L, 1 .3 mmol, 1 .29 eq)
  • EtOAc 10 mL
  • DIPEA 350 ⁇ L, 2.01 mmol, 2.0 eq
  • amine B piperidine (298 ⁇ L, 3.02 mmol, 3.0 eq) and DIPEA (350 ⁇ L, 2.01 mmol, 2.0 eq) were used.
  • N-(2-phenoxyethyl)-2-(piperidin-1-yl)quinazolin-4-amine (57) This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1 .01 mmol, 1 .0 eq
  • amine A 2-phenoxyethan-1 -amine (152 mg, 1 .11 mmol, 1.1 eq)
  • EtOAc 10 mL
  • DIPEA 3350 ⁇ L, 2.01 mmol, 2.0 eq
  • amine B piperidine (298 ⁇ L, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used.
  • the crude product was purified by column chromatography (40-70 % EtOAc in cHex) to give a white solid (155 mg, 44 %).
  • LCMS acidic mode
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1.01 mmol, 1 .0 eq
  • amine A 3-phenylpropan-1 -amine (150 mg, 1.11 mmol, 1.1 eq)
  • EtOAc 10 mL
  • DIPEA 350 ⁇ L, 2.01 mmol, 2.0 eq
  • amine B piperidine (298 ⁇ L, 3.02 mmol, 3.0 eq) and DIPEA (350 ⁇ L, 2.01 mmol, 2.0 eq) were used.
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1.01 mmol, 1.0 eq
  • amine A 3-(2-aminoethoxy)benzoate (210 mg, 1.11 mmol, 1.1 eq)
  • EtOAc 10 mL
  • DIPEA 350 ⁇ L, 2.01 mmol, 2.0 eq
  • amine B piperidine (298 ⁇ L, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used.
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1.01 mmol, 1.0 eq
  • amine A 2-(indolin-1-ylsulfonyl)ethan-1 -amine (290.4 mg, 1.01 mmol, 1.1 eq)
  • EtOAc 10 mL
  • DIPEA DIPEA
  • amine B piperidine (298 ⁇ L, 3.02 mmol, 3.0 eq) and DIPEA (350 ⁇ L, 2.01 mmol, 2.0 eq) were used.
  • the crude product was purified by column chromatography (10-40 % EtOAc in cHex) to give a white solid (281 mg, 64 %).
  • LCMS acidic mode
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1.01 mmol, 1.0 eq
  • amine A 2-amino-1-phenylethan-1-one (190 mg, 1.11 mmol, 1.1 eq)
  • EtOAc 10 mL
  • DIPEA 350 ⁇ L, 2.01 mmol, 2.0 eq
  • amine B piperidine (298 ⁇ L, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used.
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1.01 mmol, 1.0 eq
  • amine A 2-(3-methoxyphenyl)ethan-1-amine (167 mg, 1.11 mmol, 1.1 eq)
  • EtOAc 10 mL
  • DIPEA 350 ⁇ L, 2.01 mmol, 2.0 eq
  • amine B piperidine (298 ⁇ L, 3.02 mmol, 3.0 eq) and DIPEA (350 ⁇ L, 2.01 mmol, 2.0 eq) were used.
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1.01 mmol, 1.0 eq
  • amine A 3-phenoxypropan-1 -amine (168 mg, 1.11 mmol, 1.1 eq)
  • EtOAc 10 mL
  • DIPEA 350 ⁇ L, 2.01 mmol, 2.0 eq
  • amine B piperidine (298 ⁇ L, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used.
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 100 mg, 487 pmol, 1.0 eq
  • amine A A/,A/-dimethyl-2-(2- (methylamino)ethoxy)benzamide (132 mg, 594 pmol, 1 .22 eq)
  • EtOAc 10 mL
  • DIPEA 175 ⁇ L, 1.00 mmol, 2.0 eq
  • amine B piperidine (200 ⁇ L, 2.02 mmol, 4.15 eq) and DIPEA (175 ⁇ L, 1.00 mmol, 2.0 eq) were used.
  • This compound was prepared according to general method B.
  • Intermediate compound 63 100 mg, 0.255 mmol, 1.0 eq
  • HATU 116 mg, 0.306 mmol, 1.2 eq
  • DIPEA 133 ⁇ L, 0.764 mmol, 3.0 eq
  • DMF 5 mL
  • 1-methylpiperazine 57 ⁇ L, 0.51 mmol, 2.0 eq
  • the crude product was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1.0 M aq. NaOH.
  • This compound was prepared according to general method B.
  • Intermediate compound 63 100 mg, 0.255 mmol, 1.0 eq
  • HATU 116 mg, 0.306 mmol, 1.2 eq
  • DIPEA 133 ⁇ L, 0.764 mmol, 3.0 eq
  • DMF 5 mL
  • (1-methylpiperidin-4-yl)methanamine 65 mg, 0.51 mmol, 2.0 eq
  • the crude product was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1.0 M aq. NaOH.
  • This compound was prepared according to general method B.
  • Intermediate compound 63 100 mg, 0.255 mmol, 1.0 eq
  • HATU 116 mg, 0.306 mmol, 1.2 eq
  • DIPEA 133 ⁇ L, 0.764 mmol, 3.0 eq
  • DMF 5 mL
  • 1-methylpiperidin-4-amine 63 mL, 0.51 mmol, 2.0 eq
  • the crude product was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1 .0 M aq. NaOH.
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1.01 mmol, 1.0 eq
  • amine A A/,A/-dimethyl-3-(2- (methylamino)ethoxy)benzamide (246 mg, 1.11 mmol, 1.1 eq)
  • EtOAc 10 mL
  • DIPEA 350 ⁇ L, 2.01 mmol, 2.0 eq
  • amine B piperidine (298 ⁇ L, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used.
  • This compound was prepared according to general method A.
  • 2,4- dichloroquinazoline 200 mg, 1.01 mmol, 1.0 eq
  • amine A A/,A/-dimethyl-2-(2- (aminoethoxy)benzamide (246 mg, 1.11 mmol, 1.1 eq)
  • EtOAc 10 mL
  • DIPEA 350 ⁇ L, 2.01 mmol, 2.0 eq
  • This compound was prepared according to general method G. (3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone (125 mg, 0.281 mmol, 1.0 eq), THF (9.0 mL), NaH (168 mg, 4.21 mmol, 1.5 eq), 1 ,4-dibromobutane (100 ⁇ L, 0.84 mmol, 3.0 eq), Me 2 NH (2.0 M in EtOH, 424 ⁇ L, 0.843 mmol, 3.0 eq), K2CO3 (116 mg, 0.843 mmol, 3.0 eq) and DMF (2 mL) were used.
  • This compound was prepared according to general method G. (3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone (125 mg, 0.281 mmol, 1.0 eq), THF (9.0 mL), NaH (168 mg, 4.21 mmol, 1.5 eq), 1 ,5-dibromopentane (114 ⁇ L, 0.843 mmol, 3.0 eq), Me2NH (2.0 M in EtOH, 424 ⁇ L, 0.843 mmol, 3.0 eq), K2CO3 (116 mg, 0.843 mmol, 3.0 eq) and DMF (2 mL) were used.
  • This compound was prepared according to general method G. (3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone (125 mg, 0.281 mmol, 1.0 eq), THF (9.0 mL), NaH (168 mg, 4.21 mmol, 1.5 eq), 1 ,3 -dibromopropane (85 ⁇ L, 0.843 mmol, 3.0 eq), Me2NH (2.0 M in EtOH, 424 ⁇ L, 0.843 mmol, 3.0 eq), K2CO3 (116 mg, 0.843 mmol, 3.0 eq) and DMF (2 mL) were used.
  • This compound was prepared according to general method G. (3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone (125 mg, 0.281 mmol, 1.0 eq), THF (9.0 mL), NaH (168 mg, 4.21 mmol, 1.5 eq), 1 ,4-dibromobutane (100 ⁇ L, 0.84 mmol, 3.0 eq), piperidine (83 ⁇ L, 0.843 mmol, 3.0 eq), K2CO3 (116 mg, 0.843 mmol, 3.0 eq), DMF (2 mL) were used.
  • This compound was prepared according to general method G. (3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone (125 mg, 0.281 mmol, 1.0 eq), THF (9.0 mL), NaH (168 mg, 4.21 mmol, 1.5 eq), 1 ,5-dibromopentane (114 ⁇ L, 0.843 mmol, 3.0 eq), piperidine (83 ⁇ L, 0.843 mmol, 3.0 eq), K2CO3 (116 mg, 0.843 mmol, 3.0 eq), DMF (2 mL) were used.
  • This compound was prepared according to general method G. (3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone (125 mg, 0.281 mmol, 1.0 eq), THF (9.0 mL), NaH (168 mg, 4.21 mmol, 1.5 eq), 1 ,5-dibromopentane (114 ⁇ L, 0.843 mmol, 3.0 eq), morpholine (73 ⁇ L, 0.843 mmol, 3.0 eq), K2CO3 (116 mg, 0.843 mmol, 3.0 eq), DMF (2 mL) were used.
  • This compound was prepared according to general method A.
  • 2,4-dichloro-6,7- dimethoxy-quinazoline 100 mg, 0.386 mmol, 1.0 eq
  • amine A (3-(2- aminoethoxy)phenyl)(pyrrolidin-1-yl)methanone (152 mg, 0.649 mmol, 1.68 eq)
  • DIPEA 540 mL, 3.07 mmol, 7.95 eq
  • EtOAc 10 mL
  • amine B piperidine (230 ⁇ L, 2.32 mmol, 6.00 eq) were used.
  • This compound was prepared according to general method A.
  • 2,4-dichloro-5- methylquinazoline 100 mg, 469 ⁇ mol, 1.0 eq
  • amine A (3-(2-aminoethoxy)phenyl)(pyrrolidin-1- yl)methanone (132 mg, 563 pmol, 1.20 eq)
  • DIPEA (170 ⁇ L, 0.966 mmol, 2.06 eq)
  • EtOAc 10 mL
  • amine B piperidine (500 ⁇ L, 5.03 mmol, 10.1.0 eq) and DIPEA (170 ⁇ L, 0.966 mmol, 2.06 eq) were used.
  • This compound was prepared according to general method A.
  • 2,4- dichloropyrido[3,2-d]pyrimidine 100 mg, 500 pmol, 1.0 eq
  • amine A (3-(2- aminoethoxy)phenyl)(pyrrolidin-1-yl)methanone (152 mg, 0.649 mmol, 1.30 eq)
  • DIPEA (170 ⁇ L, 966 mhioI, 1.5 eq)
  • EtOAc 10 mL
  • amine B piperidine (500 mL, 5.03 mmol, 10.1.0 eq) and DIPEA (170 mL, 966 mhioI, 1.5 eq) were used.
  • This compound was prepared according to general method A.
  • 6-bromo-2,4- dichloroquinazoline 100 mg, 0.378 mmol, 1.0 eq
  • amine A (3-(2-aminoethoxy)phenyl)(pyrrolidin- 1-yl)methanone (107 mg, 0.457 mmol, 1.21.0 eq)
  • DIPEA 130 mL, 0.742 mmol, 2.0 eq
  • EtOAc 10 mL
  • amine B piperidine (149 mL, 1.51 mmol, 3.0 eq) and DIPEA (130 mL, 0.742 mmol, 2.0 eq) were used.
  • 2,4,6-trichloroquinazoline (100 mg, 0,428 mmol) was added to a microwave tube containing 3 ml ethyl acetate, DIPEA (82.0 mI, 0,471 mmol) and 3- phenoxypropan-1 -amine (64.8 mg, 0,428 mmol). The mixture was stirred at room temperature until TLC shows completion of the starting material. Methylpiperazine (0.5 mL, 4.49 mmol) was added to the mixture, and the mixture is heated to 120°C for 10 minutes under microwave irradiation. The obtained solution is diluted with ethyl acetate and washed with water and brine. The organic phase is than dried over Na 2 SO 4 and the solvent is evaporated. The product is then purified using flash column chromatography (90% EtOAc, 5% Et3N, 5% MeOH). The title compound was obtained as a sticky amber colored liquid (148 mg, 0.359 mmol, 84%).
  • 2,4,6-trichloroquinazoline (498 mg, 2,13 mmol) was added to a microwave tube containing 5 ml 1 ,4-dioxane, DIPEA (2.34 mL, 10.7 mmol) and methyl 3-(2-aminoethoxy)benzoate (500 mg, 2.56 mmol). The mixture was stirred at room temperature for 1 hour. The solvents were evaporated and the crude was flushed over silica (1 :1 Ethyl acetate heptane).
  • the crude was dissolved in ethyl acetate and methylpiperazine (0.5 mL, 4.49 mmol) was added to the mixture, and the mixture is heated to 120°C for 30 minutes under microwave irradiation.
  • the obtained solution is diluted with ethyl acetate and washed with water and brine.
  • the organic phase is than dried over Na 2 SO 4 and the solvent is evaporated.
  • the product is then purified using flash column chromatography (90% EtOAc, 5% Et3N, 5% MeOH). The title compound was obtained as an off-white solid (620 mg, 1.360 mmol, 64 %).
  • This compound was prepared according to general method B. 4-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)benzoic acid (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 ⁇ L, 0.764 mmol, 3.0 eq), DMF (5 mL) and Me 2 NH (2.0 M in MeOH, 510 ⁇ L, 1.02 mmol, 4.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (70 mg, 55 %). LCMS (acidic mode) Rt 3.98 min, purity 99 %, [M+H] + calculated 420.24, found 420.25.
  • This compound was prepared according to general method B. the corresponding acid (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 ⁇ L, 0.764 mmol, 3.0 eq), DMF (5 mL) and a solution of Nhh in MeOH (7M, 144 ⁇ L, 1 .02 mmol, 4.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (85 mg, 85%). LCMS (acidic mode) Rt 3.12 min, purity 99%, [M+H]+ calculated 392.21 , found 392.25.
  • This compound was prepared according to general method B.
  • the corresponding acid 100 mg, 0.255 mmol, 1.0 eq
  • HATU 116 mg, 0.306 mmol, 1.2 eq
  • DIPEA 133 ⁇ L, 0.764 mmol, 3.0 eq
  • DMF 5 mL
  • 1-methylpiperidin-4-amine 63 ⁇ L, 0.51 mmol, 2.0 eq
  • the crude product was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and an aqueous solution of NaOH (1 .0 M).
  • This compound was prepared according to general method B.
  • the corresponding acid 100 mg, 0.255 mmol, 1.0 eq
  • HATU 116 mg, 0.306 mmol, 1.2 eq
  • DIPEA 133 ⁇ L, 0.764 mmol, 3.0 eq
  • DMF 5 mL
  • 1-methylpiperazine 57 ⁇ L, 0.51 mmol, 2.0 eq
  • the crude product was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and an aqueous solution of NaOH (1 .0 M).
  • This compound was prepared according to general method B. the corresponding acid (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 ⁇ L, 0.764 mmol, 3.0 eq), DMF (5 mL) and pyrrolidine (42.0 ⁇ L, 0.510 mmol, 2.0 eq) were used.
  • the crude product was purified by column chromatography (40-100 % EtOAc in cHex) to give a white solid (97 mg, 85 %).
  • LCMS acidic mode
  • This compound was prepared according to general method B. the corresponding acid (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 ⁇ L, 0.764 mmol, 3.0 eq), DMF (5 mL) and azepane (51 mg, 0.51 mmol, 2.0 eq) were used.
  • the crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (101 mg, 84 %).
  • LCMS acidic mode
  • This compound was prepared according to general method B. the corresponding acid (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 ⁇ L, 0.764 mmol, 3.0 eq), DMF (5 mL) and piperidine (43 mg, 0.51 mmol, 2.0 eq) were used.
  • the crude product was purified by column chromatography (0-60 % EtOAc in cHex) to give a white solid (101 mg, 86 %).
  • LCMS acidic mode
  • This compound was prepared according to general method C. 2-(((Benzyloxy)carbonyl)amino)ethyl methanesulfonate (13 g, 30 mmol, 1.0 eq), DMF (100 mL), CS2CO3 (18 g, 54 mmol, 1.8 eq) and methyl 3-hydroxybenzoate (5.6 g, 36 mmol, 1.2 eq) were used.
  • the crude product was purified by column chromatography (25-65% EtOAc in cHex) to give a white solid (24 g, 98 %).
  • LCMS acidic mode
  • This compound was prepared according to general method B. 3-(2- (((Benzyloxy)carbonyl)amino)ethoxy)benzoic acid (1.2 g, 3.3 mmol, 1.0 eq), DMF (20 mL), DIPEA (2.3 mL, 13 mmol, 4.0 eq), HATU (1.9 g, 4.8 mmol, 1.5 eq) and Me 2 NH (2.0 M in THF, 2.1 mL, 4.2 mmol, 1.3 eq) were used. The product was purified by column chromatography (cHex, 0-70% EtOAc) to give the product as colorless oil (580 mg, 1 .69 mmol, 50%).
  • This compound was prepared according to general method E. Benzyl (3-(2-(dimethylcarbamoyl) phenoxy)ethyl)carbamate (788 mg, 2.30 mmol, 1.0 eq), MeOH (41 mL) and Pd/C (79 mg) were used. The title compound was obtained as a colorless oil (398 mg, 83 %).
  • This compound was prepared according to general method B. 3-(2- (((Benzyloxy)carbonyl)amino)ethoxy)benzoic acid (1.2 g, 3.3 mmol, 1.0 eq), DMF (20 mL), DIPEA (2.3 mL, 13 mmol, 4.0 eq), HATU (1 .9 g, 4.8 mmol, 1 .5 eq) and pyrrolidine (0.34 mL, 4.2 mmol, 1 .3 eq) were used. The crude product was purified by column chromatography (25-65% EtOAc in cHex) to give a white solid (1.3 g, 93 %).
  • This compound was prepared according to general method C. 2-(((E3enzyloxy)carbonyl)amino)ethyl methanesulfonate (13 g, 30 mmol, 1.0 eq), DMF (100 mL), CS2CO3 (18 g, 54 mmol, 1.8 eq) and methyl 4-hydroxybenzoate (5.6 g, 36 mmol, 1.2 eq) were used. The crude product was purified by column chromatography (25-65% EtOAc in cHex) to give a white solid (20.8 g, 85 %).
  • This compound was prepared according to general method B. 4-(2- (((Benzyloxy)carbonyl)amino)ethoxy)benzoic acid (1.2 g, 3.3 mmol, 1.0 eq), DMF (20 mL), DIPEA (2.3 mL, 13 mmol, 4.0 eq), HATU (1.9 g, 4.8 mmol, 1.5 eq) and Me 2 NH (2.0 M in THF, 2.1 mL, 4.2 mmol, 1.3 eq) were used. The product was purified by column chromatography (cHex, 0-70% EtOAc) to give the product as a white solid (539 mg, 49%).
  • This compound was prepared according to general method C. 2-(((E3enzyloxy)carbonyl)amino)ethyl methanesulfonate (13 g, 30 mmol, 1.0 eq), DMF (100 mL), CS2CO3 (18 g, 54 mmol, 1.8 eq) and methyl 2-hydroxybenzoate (5.6 g, 36 mmol, 1.2 eq) were used. The crude product was purified by column chromatography (25-65% EtOAc in cHex) to give a white solid (20.0 g, 82 %). LCMS (acidic mode) Rt 4.54 min, purity 99 %, [M+H] + calculated 330.13, found 330.00.

Abstract

The present disclosure relates to compounds of formula (I) comprising a heteroaryl, such as derivatives of quinazolines, which can act as modulators of ACKR3. The present disclosure also relates to the use of these compounds as a drug.

Description

QUINAZOLINE DERIVATIVES USEFUL AS MODULATORS OF ACKR3
Technical field
The present disclosure relates to compounds of formula (I) comprising a heteroaryl, such as derivatives of quinazolines, which can act as modulators of ACKR3. The present disclosure also relates to the use of these compounds as a drug.
Background art
Chemokines and G protein-coupled chemokine receptors (GPCRs) play an important role in the immune defense system by controlling the migration, activation, differentiation, and survival of leukocytes. Endogeneous chemokine proteins stabilize their cognant chemokine receptors in an active conformation that facilitates intracellular signal transduction by interactions with G proteins and/or arrestins. Because of their crucial role in the migration of immune cells, chemokine receptors are promising drug targets for various immune-related diseases, including chronic obstructive pulmonary disease, multiple sclerosis, rheumatoid arthritis, HIV-1 infection and cancer. Molecular pharmacology, medicinal chemistry, and molecular modeling studies have provided insights into molecular determinants of chemokine receptor modulation by proteins, peptides, and small-molecule ligands.
The chemokine receptor ACKR3, formerly called CXCR7, is activated by the chemokine peptides and majorly by chemokine CXCL12. The receptor is overexpressed in many cancer types indicating a vital role in the development of the disease. In vitro investigation of the ACKR3 receptor showed that overexpression and activation of the receptor by CXCL12 leads to oncogenic events such as angiogenesis, metastasis and trans endothelial cell-migration. ACKR3 knock-out models or ACKR3 inhibition by small-molecule ligands led to reduced oncogenic effects. Recently, the ACKR3 has been claimed to scavenge a broad range of opioid peptides, which might lead to a broadened application of a potential drug.
However, to date, no drug has been developed targeting the ACKR3 receptor. Thus, in this context, it is desirable to develop molecules that can act as modulators of ACKR3.
Summary of the disclosure
The inventors surprisingly found that some compounds comprising a heteroaryl, such as derivatives of quinazolines, can act as modulators of ACKR3.
Consequently, in a first aspect, the present disclosure relate to a compound formula (I):
(I) Wherein Z is N or CR3; R1 and R2 are independently selected from H, C1-C6 alkyl, C3-C12 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)- -O-(CO)- -(CO)-O-
Figure imgf000003_0002
Or R1 and R2, together with the N or C atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, a C3-C6 cycloalkyl, an aryl having 6 to 10 ring atoms, or a heteroaryl having 5 to 10 ring atoms, said heterocyclyl, cycloalkyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)- -O-(CO)- - (CO)-O- -(CO)- -N -(CO)- , and - R3 is present or absent when the C atom forms a double bond, and if present, R3 is selected from H and C1-C6 alkyl; X is N or CH, preferably X is N; Ring A is aromatic, and is selected from the group consisting of aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said aryl and heteroaryl being optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)- -O-(CO)- -(CO)-O-
Figure imgf000003_0001
Y is O or NR; wherein R is H or an organyl group, preferably Y is NR; L is a divalent linker selected from the group consisting of C1-C12 alklylene or heteroalkylene, said alkylene and heteroalkylene being optionally interspersed with one or more groups selected from (C3-C6 cycloalkyl)-, and (heterocyclyl having 5 to 10 ring atoms)-, and said alkylene, heteroalkylene, cycloalkyl and heterocyclyl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -O-(CO)-R’, -(CO)-O- R’, -(CO)-NR”R"', -NR”-(CO)-R’, and -NR”R"';
Ring B is a ring selected from the group consisting of C3-C12 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -0-(C0)-R’, -(CO)-O- R\ -(CO)-NR”R"' -NR”-(CO)-R’, -NR”R"', -(C1-C6 alkyl)-NR”R"', and -(C1-C6 alkyl)-OH;
R’ is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms;
R” and R"' are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, -(C1-C6 alkyl)-(heterocyclyl having 5 to 10 ring atoms); said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, and C1-C6 alkyl;
Or R” and R"', together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, or a heteroaryl having 5 to 10 ring atoms, said heterocyclyl, and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, - OH, -NO2, -CN, and C1-C6 alkyl, and pharmaceutically acceptable salts, solvates and esters thereof.
In a second aspect, the disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.
In a third aspect, the disclosure relates to a compound of the present disclosure for use as a drug.
In a fourth aspect, the disclosure relates to a compound of the present disclosure for use in treating cancer, autoimmune disorders, inflammatory diseases, transplant rejection, fibrosis, or pain.
Detailed description
Definitions
As used herein, the terms “C1-C12 alkyl”, by itself or as part of another substituent, refer to a linear or branched alkyl functional group having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, s-butyl and f-butyl, pentyl and its isomers (e.g. n-pentyl, /so-pentyl), and hexyl and its isomers (e.g. n- hexyl, /so-hexyl).
As used herein, the terms “C3-C12 cycloalkyl” refer to a saturated or unsaturated cyclic group having 3 to 12 carbon atoms, preferably 3 to 6. The cycloalkyl can have a single ring or multiple rings fused together. The cycloalkyl can also include spirocyclic rings. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term "halogen" refers to a fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-1) group.
As used herein, the terms “C1-C6 haloalkyl” refer to a C1-C6 alkyl as defined herein that is substituted by one or more halogen group as defined herein. Suitable C1-C6 haloalkyl groups include trifluoromethyl and dichloromethyl.
As used herein, the terms “C1-C12 heteroalkyl”, refer to a straight or branched hydrocarbon chain consisting of 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and from one to three, heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized (for example: a sulfoxide or a sulfone) and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
As used herein, the terms “C1-C6 alkoxy” refer to a -O-alkyl group, wherein the alkyl group is a C1-C6 alkyl as defined herein. Suitable C1-C6 alkoxy groups include methoxy, ethoxy, propoxy.
As used herein, the terms “C1-C6 haloalkoxy” refer to a C1-C6 alkoxy group as defined herein, that is substituted by one or more halogen group as defined herein. Suitable haloalkoxy include trifluoromethoxy.
As used herein, the terms “C1-C12 alkylene”, used alone or as part of another substituent, refer to a divalent saturated, straight-chained or branched hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 6.
As used herein, the terms “C1-C12 heteroalkylene”, refer to a divalent heteroalkyl as defined above. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini.
As used herein, the terms “aryl having 6 to 10 ring atoms" refer to a polyunsaturated, aromatic hydrocarbyl group having a single ring or multiple aromatic rings fused together, containing 6 to 10 ring atoms, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (cycloalkyl, heterocyclyl or heteroaryl as defined herein) fused thereto. Suitable aryl groups include phenyl, naphtyl and phenyl ring fused to a heterocyclyl, like benzopyranyl, benzodioxolyl, benzodioxanyl and the like.
As used herein, the terms "heteroaryl having 5 to 10 ring atoms" refer to a polyunsaturated, aromatic ring system having a single ring or multiple aromatic rings fused together or linked covalently, containing 5 to 10 atoms, wherein at least one ring is aromatic and at least one ring atom is a heteroatom selected from N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, purinyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl.
As used herein, the terms “heterocyclyl having 5 to 10 ring atoms” refer to a saturated or unsaturated cyclic group having 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocycle can include fused or bridged rings as well as spirocyclic rings. Examples of heterocycle include, but are not limited to, tetrahydropyridyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, piperazinyl, 1- azepanyl, imidazolinyl, 1 ,4-dioxanyl and the like.
As used herein, the terms “organyl group” refer to any organic substituent group, regardless of functional type, having one free valence at a carbon atom.
Various embodiments of the disclosure are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments.
The present disclosure encompasses the compounds of the present disclosure, their tautomers, enantiomers, diastereomers, racemates or mixtures thereof, and their hydrates, esters, solvates or pharmaceutically acceptable salts.
The terms “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this disclosure and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with organic acids and/or inorganic acids. Pharmaceutically acceptable base addition salts can be formed with organic bases and/or inorganic bases.
In many cases, the compounds of the disclosure are capable of forming esters by virtue of the presence of carboxyl groups. Esters include C1-C6 alkyl esters.
Any formula given herein is also intended to represent unlabeled as well as isotopically forms of the compounds, like deuterium labeled compounds or 14C-labeled compounds.
Compound of formula I
The present disclosure first relates to a compound of formula (I):
Figure imgf000006_0001
Wherein Z is N or CR3;
R1 and R2 are independently selected from H, C1-C6 alkyl, C3-C12 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -0-(C0)-R’, -(CO)-O-
Figure imgf000007_0001
Or R1 and R2, together with the N or C atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, a C3-C6 cycloalkyl, an aryl having 6 to 10 ring atoms, or a heteroaryl having 5 to 10 ring atoms, said heterocyclyl, cycloalkyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -0-(C0)-R’, - (CO)-O-R’, -(CO)-NR”R"', -NR”-(CO)-R’, and -NR”R"';
R3 is present or absent when the C atom forms a double bond, and if present, R3 is selected from H and C1-C6 alkyl;
X is N or CH, preferably X is N;
Ring A is aromatic, and is selected from the group consisting of aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said aryl and heteroaryl being optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -0-(C0)-R’, -(CO)-O- R’, -(CO)-NR”R"' -NR”-(CO)-R’, and -NR”R"';
Y is O or NR; wherein R is H or an organyl group, preferably Y is NR;
L is a divalent linker selected from the group consisting of C1-C12 alklylene or heteroalkylene, said alkylene and heteroalkylene being optionally interspersed with one or more groups selected from - (C3-C6 cycloalkyl)-, and -(heterocyclyl having 5 to 10 ring atoms)-, said alkylene, heteroalkylene cycloalkyl and heterocyclyl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R', -0-(C0)-R’, -(CO)-O-R’, - and -NR"R"';
Figure imgf000007_0003
Ring B is a ring selected from the group consisting of C3-C12 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -0-(C0)-R’, -(CO)-O- -(C1-C6 alkyl)-NR"R"', and -(C1-C6 alkyl)-OH;
Figure imgf000007_0002
R’ is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms;
R” and R"' are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, -(C1-C6 alkyl)-(heterocyclyl having 5 to 10 ring atoms), said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, and C1-C6 alkyl;
Or R” and R"', together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, or a heteroaryl having 5 to 10 ring atoms, said heterocyclyl, and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, - OH, -NO2, -CN, and C1-C6 alkyl, and pharmaceutically acceptable salts thereof.
According to a preferred embodiment, the compound of formula (I) is a modulator of ACKR3. In more specific embodiment, a modulator of ACKR3 is an ACKR3 antagonist.
As used herein, the term “ACKR3 antagonist” refers to a compound which directly binds to ACKR3, and which competitively inhibits the binding of reference ACKR3 binding compound. For example, an ACKR3 antagonist of the present disclosure is a compound which directly binds to ACKR3 and is capable of displacing the binding of labelled ACKR3 binding reference compound A, as measured in vitro, typically as measured with the displacement assay using the tritium labelled ACKR3 binding reference compound: [3H]compound A. More details of such displacement assay are described in the Examples. [3H] compound A can be synthesized as mentioned in the Examples. [3H] compound A has the following structure:
Figure imgf000008_0001
In a more specific embodiment, said ACKR3 antagonist, or modulator, of the present disclosure has preferably a pK, greater than or equal to 5.0, typically comprised between 5.0 and 7.0, and for example comprised between 5.7 and 7.0, as measured by the displacement assay with tritium labelled ACKR3 binding reference compound: [3H] compound A. The pKi can be obtained from said displacement assay using the resulting IC50 values. The IC50 values are converted to the Ki by correcting for radioligand concentration and its affinity for the ACKR3 (Kd = 18 nM) using the Cheng-Prusoff equation (Cheng and Prusoff (1973) Biochem. Pharmacol, 22, 3099-3108). More preferably, said ACKR3 antagonist, or modulator, of the present disclosure has a pK, greater than or equal to 5.5, or at least 5.7, or at least 6.0, or at least 6.4.
According to an embodiment, Z is N, and R1 and R2, together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, said heterocyclyl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, - CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.
According to an embodiment, ring A is aromatic, and is selected from the group consisting of aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said aryl and heteroaryl being optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy.
R is H or an organyl group. The organyl group is preferably selected from C1-C12 alkyl, Ci- C12 heteroalkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -0-(C0)-R’, -(CO)-O-R’, -(CO)-NR”R"', -NR”-(CO)-R’, and - NR”R"'. According to an embodiment, R is H or C1-C6 alkyl optionally substituted with NR”R"'.
According to an embodiment, L is selected from the group consisting of C1-C12 alklylene or heteroalkylene, said alkylene and heteroalkylene being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, C1-C6 alkyl, and -CN.
According to an embodiment, ring B is an aryl having 6 to 10 ring atoms, said aryl being optionally substituted with one or more substituents independently selected from oxo, halogen, - OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R', -0-(C0)-R', -(CO)-O-R', -(CO)-NR''R'”, -NR”-(CO)-R', -NR”R"', -(C1-C6 alkyl)-NR”R"', and -(C1-C6 alkyl)-OH.
According to an embodiment, R' is selected from C1-C6 alkyl.
According to an embodiment, R” and R"' are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms and -(C1-C6 alkyl)-(heterocyclyl having 5 to 10 ring atoms) said alkyl, cycloalkyl, and heterocyclyl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, and C1-C6 alkyl.
According to an embodiment R” and R'", together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, said heterocyclyl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, and C1-C6 alkyl.
According to an embodiment, the compound of formula (I) is a compound of formula (II):
Wherein
Ring A, Y, L and ring B are as defined herein;
Each R4 is independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having
5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -0-(C0)-R’, -(CO)-O-
Figure imgf000010_0001
R’, R”, and R"' are as defined herein; m is an integer between 0 and 5, and preferably m is 0 or 1 . According to an embodiment, each R4 is independently selected from oxo, halogen, -OH, -NO2, -
CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, preferably R4 is a C1-C6 alkyl.
According to an embodiment, the compound of formula (I) is a compound of formula (III)
Wherein Y, L and ring B are as defined herein;
R4 and m are as defined herein;
Each R5 is independently selected from halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R', -O-(C0)-R’, -(CO)-O-R’, - (CO)-NR”R"' -NR"-(CO)-R', and -NR"R"';
R’, R”, and R"' are as defined herein; n is an integer between 0 and 4, and preferably n is 0, 1 or 2.
According to an embodiment, each R5 is independently selected from halogen, C1-C6 alkyl, and C1- C6 alkoxy. According to an embodiment, the compound of formula (I) is a compound of formula (IV)
Figure imgf000011_0001
Wherein
L and ring B are as defined herein;
R4 and m are as defined herein;
R5 and n are as defined herein;
R is H or an organyl group selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -O- (CO)-R’, -(CO)-O-R’, -(CO)-NR”R”´ -NR”-(CO)-R', and -NR”R"';
R’, R”, and R"' are as defined herein.
According to an embodiment, R is H or Ci-C6 alkyl optionally substituted with NR”R"'.
According to an embodiment, the compound of formula (I) is a compound of formula (V)
Figure imgf000011_0002
Wherein
L is as defined herein;
R4 and m are as defined herein;
R5 and n are as defined herein;
R is as defined herein;
Each R6 is selected from halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1- C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -O-(CO)-R’, -(CO)-O-R’, -(CO)-NR”R"' - NR”-(CO)-R\\ -NR”R"', -(C1-C6 alkyl)-NR”R"', and -(C1-C6 alkyl)-OH;
R’, R”, and R"' are as defined herein; p is an integer between 0 and 5, preferably p is 1 . According to an embodiment, each R6 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -(CO)-R', -(CO)-O-R', -(CO)-NR”R"', -(C1-C6 alkyl)-NR”R"', and -(C1-C6 alkyl)-OH.
According to an embodiment, the compound of formula (I) is a compound of formula (VI):
Figure imgf000012_0001
Wherein R4 and m are as defined herein; R5 and n are as defined herein; R is as defined in claim herein; R6 and p are as defined herein.
According to an embodiment, the compound of formula (I) is a compound of formula (VII):
Figure imgf000012_0002
Wherein
R4 and m are as defined herein; R5 and n are as defined herein; R7 and R8 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, -(C1-C6 alkyl)-(heterocyclyl having 5 to 10 ring atoms), said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, and C1-C6 alkyl;
Or R7 and R8, together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, or a heteroaryl having 5 to 10 ring atoms, said heterocyclyl, and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, - OH, -NO2, -CN, and C1-C6 alkyl. According to an embodiment, R7 and R8 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, -(C1-C6 alkyl)-(heterocyclyl having 5 to 10 ring atoms), said alkyl, cycloalkyl, and heterocyclyl, being optionally substituted with one or more substituents independently selected from -OH, and C1-C6 alkyl;
Or R7 and R8, together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, said heterocyclyl being optionally substituted with one or more substituents independently selected from -OH, and C1-C6 alkyl.
According to an embodiment, the compound of formula (I) is selected from:
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
According to an embodiment, the compound of formula (I) is selected from
Figure imgf000018_0001
Figure imgf000019_0001
According to an embodiment, the compound of formula (I) is selected from :
Figure imgf000020_0001
Pharmaceutical composition The disclosure also relates to a pharmaceutical composition comprising a compound of the disclosure and at least one pharmaceutically acceptable carrier.
The form of the pharmaceutical compositions, the route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and sex of the patient, etc. The pharmaceutical compositions of the disclosure can be formulated for a topical, oral, intranasal, intraocular, intravenous, intramuscular or subcutaneous administration and the like.
The pharmaceutical compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, emulsions, syrups, elixirs, aerosols, or any other appropriate compositions; and comprise at least one compound according this disclosure.
Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. The tablets or pills can be coated to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pills can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The compound of the disclosure and the further agent may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
According to an embodiment, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for oral formulation.
According to an embodiment, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected or infused. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions or solutions for infusion.
The pharmaceutical forms suitable for injection or infusion include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
Sterile injectable solutions and solutions for infusion are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions or slutions for infusion, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
For parenteral administration in an aqueous solution, for example, the solution may be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCI solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences" 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
For aerosol administration, the compound of the disclosure and the further agent are preferably supplied in finely divided from along with a surfactant and propellant. The surfactant must, of course, be nontoxic, and preferably soluble in the propellant. Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride. Mixed esters, such as mixed or natural glycerides may be employed. A carrier can also be included, as desired, as with, e.g., lecithin for intranasal delivery. An example includes a solution in which each milliliter included 7.5 mg NaCI, 1.7 mg citric acid monohydrate, 3 mg disodium phosphate dihydrate and 0.2 mg benzalkonium chloride solution (50%) (Gozes et al„ J Mol Neurosci. 19(1-2):167-70 (2002)).
Suitable compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g. aerosol administration.
The doses used for the administration can be adapted as a function of various parameters, and in particular as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment. It will be appreciated that appropriate dosages of the compounds, and compositions comprising the compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments described herein. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side- effects. For example, the dose used for the administration can be of about 1-1000 mg of the compound of the disclosure for a subject of about 50-70 kg.
Method of use
The compounds of the disclosure exhibit valuable pharmaceutical properties as indicated in the in vitro tests provided in the examples and are therefore indicated for therapy. In particular, the compounds of the disclosure are useful in the prevention or treatment of disorders relating to the ACKR3 receptor.
The disclosure also relates to a compound of the disclosure for use as a medicament.
The disclosure also relates to a compound of the disclosure for use in a method for treating cancer, autoimmune disorders, inflammatory diseases, transplant rejection, fibrosis, or pain.
The disclosure also relates to a compound of the disclosure for use in a method for treating disorders relating to the ACKR3 receptor or its ligands.
In addition, further diseases or disorders relating to the ACKR3 receptor or its ligands are diseases involving ACKR3 and / or CXCL12 and / or CXCL11 mediated metastasis, chemotaxis, cell adhesion, trans-endothelial migration, cell proliferation and/or survival.
In addition, further particular diseases or disorders relating to the ACKR3 receptor or its ligands are proliferative diabetic retinopathy; West Nile virus encephalitis; pulmonary vascular diseases, acute renal failure, ischemia including cerebral ischemia, acute coronary syndrome, injured central nervous system, hypertension, pulmonary hypertension, Shiga-toxin-associated heomolytic uremic syndrome, preeclampsia, vascular injury, HIV / AIDS, angiogenesis, and brain and neuronal dysfunctions (such as inflammatory components of Alzheimer's disease), stress- related disorders (such as anxiety, depression, and posttraumatic stress disorder), and diseases involving opioid receptors. In a sub-embodiment, such a further particular disease or disorder relating to the ACKR3 receptor or its ligands is especially pulmonary hypertension.
As used herein, the term "cancer" has its general meaning in the art and includes an abnormal state or condition characterized by rapidly proliferating cell growth. The term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues or organs, irrespective of histopathologic type or stage of invasiveness. The term cancer includes malignancies of the various organ systems, such as affecting skin, lung, breast, thyroid, lymphoid, gastrointestinal, and genito-urinary tract, as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the oesophages.
Examples of cancer include, but are not limited, to hematological malignancies such as 13- cell lymphoid neoplasm, T-cell lymphoid neoplasm, non-hodgkin lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), NK-cell lymphoid neoplasm, and myeloid cell lineage neoplasm. Examples of non- hematological cancers include, but are not limited to, skin cancer, colon cancer, breast cancer, lung cancer, brain cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, colorectal cancer, bone cancer, cervical cancer, liver cancer, oral cancer, esophageal cancer, thyroid cancer, kidney cancer, stomach cancer and testicular cancer.
Examples of autoimmune disorders include (inflammatory) demyelinating diseases; multiple sclerosis (MS); Guillain Barre syndrome; rheumatoid arthritis (RA); inflammatory bowel diseases (IBD, especially comprising Crohn's disease and ulcerative colitis); systemic lupus erythematosus (SLE); lupus nephritis; interstitial cystitis; celiac disease; autoimmune encephalomyelitis; osteoarthritis; and type I diabetes.
Examples of inflammatory diseases include chronic rhinosinusitis, asthma, chronic obstructive pulmonary disorder, atherosclerosis, myocarditis, and sarcoidosis.
Examples of transplant rejection include renal allograft rejection, cardiac allograft rejection, and graft-versus-host diseases brought about by hematopoietic stem cell transplantation.
Examples of fibrosis include liver fibrosis, liver cirrhosis, lung fibrosis, especially idiopathic pulmonary fibrosis.
The disclosure relates to a method for treating cancer, autoimmune disorders, inflammatory diseases, transplant rejection, fibrosis, or pain, said method comprising administering to a subject in need thereof, preferably a human, a therapeutically efficient amount of
(i) a compound of the disclosure, or
(ii) a pharmaceutical composition as described herein.
The disclosure relates to a method for treating disorders relating to the ACKR3 receptor or its ligands said method comprising administering to a subject in need thereof, preferably a human, a therapeutically efficient amount of
(i) a compound of the disclosure, or
(ii) a pharmaceutical composition as described herein.
As used herein, the term “treating” includes reversing, alleviating, inhibiting the progression of, preventing or reducing the likelihood of the disease, disorder, or condition to which such term applies, or one or more symptoms or manifestations of such disease, disorder or condition. Preventing refers to causing a disease, disorder, condition, or symptom or manifestation of such, or worsening of the severity of such, not to occur. Accordingly, the presently disclosed compounds can be administered prophylactically to prevent or reduce the incidence or recurrence of the disease, disorder, or condition.
As used herein, the terms “therapeutically efficient amount” of a compound refer to an amount of the compound that will elicit the biological or medical response of a subject, for example, ameliorate the symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease.
The disclosure also relates to the use of a compound of the disclosure, for the manufacture of a medicament for the treatment of cancer, autoimmune disorders, inflammatory diseases, transplant rejection, fibrosis, or pain. Examples
Experimentals
Pharmacology
Two million HEK293T cells were seeded per 10 cm2 dish and were transfected the next day using DNA/PEI-mix containing 0.25 μg plasmid DNA encoding for the ACKR3, 4.75 pg pcDEF3 plasmid DNA and 30pg linear PEI. Two days after transfection, cells were harvested, during which cells and all used solutions were kept on ice: Cells were washed with PBS (137 mM NaCI, 2.57 mM KCI, 1 .5 mM KH2P04, 8 mM Na2HP04) and pelleted by centrifugation steps. Cell pellets were transferred into ice-cold membrane buffer (15 mM Tris, 0.3 mM EDTA, 2 mM MgCI2, pH 7.4 at 4°C) and were dounce-homogenized by plunging the pestle 10 times with 1500 rpm. Cell homogenates were then subjected to two freeze-thaw cycles using liquid nitrogen, cell-membranes were consecutively pelleted by centrifugation at 40,000 g and pellets were reconstituted in Tris-sucrose buffer (20 mM Tris, 250 mM Sucrose, pH 7.4 at 4°C). Finally, the membrane samples where homogenized using a 23-gauge needle, snap-frozen with liquid nitrogen and stored until further experimentation at -80 °C. Radioligand binding experiments where performed by incubating 4 pg (protein content) of membranes with 4 nM [3H] compound A and increasing concentrations unlabelled ligand (10-4 M - 10-1 1 M). All dilutions were prepared in HBSS supplemented with 0.2% BSA. Binding reactions were incubated for 2 hours and then terminated by washing the solutions over a PEI-coated GF/C filter using a cell harvester, followed by wash steps using ice-cold buffer (50 mM HEPES, 1.2 mM 5 mM
Figure imgf000025_0002
0.5 M NaCI, pH 7.4 at 4°C). Filter-bound [3H] compound A was measured by adding 25 μL Microscint-O per well to the dried GF/C-plates and radioactivity was consecutively quantified using the Wallac Microbeta counter (Perkin Elmer). The dose dependent displacement of [3H] compound A-membrane binding was plotted against unlabelled ligand concentration. The resulting IC50 values were converted to the K, by correcting for radioligand concentration and its affinity for the ACKR3 (Kd = 18 nM) using the Cheng-Prusoff equation (Cheng and Prusoff (1973) Biochem. Pharmacol, 22, 3099-3108).
Several compounds have been synthesized and tested. The compounds having a pK, of at least 5 are considered to be modulators of ACKR3. The synthesis of these compounds and the results of their displacement assay are given below.
The compound [3H] compound A has the following structure
Figure imgf000025_0001
It can be synthesized follows. The enantiopure R-isomer [3H] compound A was prepared by starting with the enantiopure R-2-(1- methylpyrrolidin-2-yl)ethan-1 -amine 2b as previously disclosed (Wijtmans et al., European Journal of Medicinal Chemistry 51 (2012) 184-192). An indirect reductive amination of aldehyde 1 (prepared from 2-fluorobenzaldehyde) with enantiopure amine 2b yields enantiopure key intermediate 3b.
Compound 6 was obtained by EDCI-mediated amide coupling using EDCI (0.113 g, 0.59 mmol), DIPEA (0.156 g, 1.23 mmol), amine 3b (0.136 g, 0.49 mmol), HOBt hydrate (0.092 g, 0.60 mmol), 3-hydroxy-4,5-dimethoxybenzoic acid (0.098 g, 0.49 mmol), THF (20 mL) and a reaction time of 24 h. To finally obtain [3H] compound A, [3H]methylnosylate (100 MBq, 100 μL of stock solution in ACN) and 0.5 mg of the precursor 6 were dissolved in 200 μL ACN. Next, 5 mL 5M aq. NaOH was added. The reaction was allowed to proceed for 40 min at 60°C. The mixture was quenched with 0.6 mL of HPLC eluent and the obtained [3H] compound A was purified by HPLC.
Figure imgf000026_0001
Reagents and conditions: a) KOH, H2O, EtOH, 24 h, 0 °C ® rt; b) (i) Na2SO4, DCM, 24 h, rt, TEA, (ii) NaBH4, MeOH, 0.5 h, 0 °C, 3b ee > 95%;.
Figure imgf000026_0002
Reagents and conditions: a) 3-hydroxy-4,5-dimethoxybenzoic acid, HOBt hydrate, EDCI, DIPEA, THF, 24 h, rt; b) NaOH, MeCN, 60° C, 40 min. Chemistry
Unless mentioned otherwise, all reactions were performed under N2 atmosphere. All chemicals and solvents were obtained from commercial suppliers (primarily Sigma-Aldrich, Acros Organics, Fluorochem and Combi-Blocks) and used without purification. DCM, DMF, THF and Et20 were dried by passing through a PureSolv solvent purification system. lUPAC names were adapted from ChemBioDraw Ultra 16.0 (PerkinElmer). Reactions were monitored by thin layer chromatography (Merck Silicagel 60 F254) by visualization under 254 nm lamp. Flash column chromatography was performed with SNAP KP-Sil 50 pm (Biotage) or GraceResolv (Bü chi) cartridges on Isolera One with UV-Vis detection (Biotage). Nuclear magnetic resonance (NMR) spectra were determined with a Briicker Avance 500 Ultrashield or a Br üker Avance 600 Ultrashield plus spectrometer. Chemical shifts are reported in parts per million (ppm) against the reference compound using the signal of the residual non-deuterated solvent (e.g. CDCI3 d = 7.26 ppm (1H), d = 77.16 ppm (13C). NMR spectra were processed using MestreNova 14.1.0 software. The peak multiplicities are defined as follows: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; ddd, doublet of doublets of doublets; dt, doublet of triplets; dq, doublet of quartets; td, triplet of doublets; tt, triplet of triplets; br, broad signal; m, multiplet; app, apparent. Purity determination was performed with Liquid Chromatography using a Shimadzu LC-20AD liquid chromatography pump system with a Shimadzu SPDM20A photodiode array detector and MS detection with a Shimadzu LCMS-2010EV mass spectrometer operating in both positive and negative ionization mode. A Waters XBridge C18 column 5 pm 4.6x50 mm was used at 40°C. The mobile phase used was a mixture of A = Water + 0.1% HCO2H and B = acetonitrile (MeCN) + 0.1% HCO2H. The eluent program 'acidic mode’ used is as follows: flow rate: 1 .0 mL/min, start 95% A in a linear gradient to 10% A over 4.5 min, hold 1 .5 min at 10% A, in 0.5 min in a linear gradient to 95% A, hold 1.5 min at 95% A, total runtime: 8.0 min. Compound purities were calculated as the percentage peak area of the analyzed compound by UV detection at 254 nm. High-resolution mass spectra (HRMS) were recorded on a Bruker micrOTOF mass spectrometer using ESI in positive ion mode (HRMS).
Figure imgf000027_0001
Scheme 1 Synthesis general method A. Reagents and conditions: a) DIPEA, rt, amine (R2). DIPEA, amine (R3), 85 °C.
Figure imgf000028_0001
Scheme 2 Synthesis of functionalized quinazoline ligands. Reagents and conditions: a) MsCI, TEA, DCM, 0 °C b) CS2CO3, phenol, DMF, 85 °C. c) NaOH (aq), MeOH, 60 °C d) HATU, amine, DIPEA, DMF, rt. e) Pd/C, H2, MeOH, rt. f) NaH, Mel, DMF, rt. g) 2,4-dichloroquinazoline, DIPEA, rt, amine (R2). h) DIPEA, amine (R3), 85 °C. i) LAH, THF, 60 °C j) NaH, alkyl halide, DMF, rt. k) K2CO3,
DMF, amine, 65 °C. General method A
To a stirred solution of the indicated 2,4-dichloroquinazoline in the indicated solvent were added amine A and DIPEA. If a precipitate was observed, a few drops of MeOH were added. The reaction mixture was stirred at rt. Upon full consumption of the 2,4-dichloroquinazoline (TLC analysis), amine B and DIPEA were added. The resulting mixture was heated to 85°C. Upon full consumption of the intermediate monochloroquinazoline (TLC analysis), the reaction mixture was cooled to rt and diluted with EtOAc. The mixture was washed with 1.0 M NaOH (aq) and brine. The organic layer was dried with anhydrous Na2SO4, filtered and evaporated in vacuo. The crude mixture was purified by column chromatography.
General method B
To a stirred solution of the indicated acid in DMF was added HATU followed by the slow addition of DIPEA. The reaction mixture was stirred for 15 min at rt followed by addition of the indicated amine. Stirring was continued at rt. Upon full consumption of the starting acid (TLC analysis), volatiles were removed in vacuo. The residue was dissolved in EtOAc and washed with 1 .0 M NaOH (aq) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude mixture was purified by column chromatography.
General method C
To a stirred suspension of 2-(((benzyloxy)carbonyl)amino)ethyl methanesulfonate and CS2CO3 in DMF was added the indicated phenol. The resulting mixture was heated at 65 °C for 2 h. The volatiles were evaporated in vacuo. The residue was dissolved in EtOAc. The mixture was extracted with 2.0 M NaOH (aq), water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The resulting crude mixture was purified by column chromatography.
General method D
To a stirred suspension of the indicated benzoic ester in MeOH was added 2.0 M NaOH (aq). The reaction mixture was heated at 60 °C until full conversion was observed (TLC analysis). The reaction mixture was cooled to rt and acidified by slow addition of 2.0 M HCI (aq). The desired product was collected by vacuum filtration, washing and drying.
General method E
To a stirred solution of the indicated Cbz-protected compound in MeOH was added 5 % Pd/C (10 w% wrt the indicated Cbz-protected compound). The reaction mixture was placed under H2 atmosphere (balloon) and H2 was bubbled through the mixture for 10 min. The mixture was stirred at rt until full conversion was observed (TLC analysis). The reaction mixture was filtered over Celite and washed with MeOH (3 times the volume of the reaction solvent). The combined filtrates were evaporated in vacuo, resulting in the product. General method F
To a stirred solution of the indicated NH-containing compound in THF was added NaH (60% dispersion in mineral oil) portion wise. The reaction mixture was stirred for 10 min at rt. Mel was added. The reaction mixture was stirred at rt until full conversion of the starting material was observed (TLC analysis). The reaction mixture was quenched by slow addition of H2O. The mixture was extracted with EtOAc (1 x). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The resulting crude mixture was purified by column chromatography.
General method G The first step was conducted following general method F, using the indicated dihaloalkane instead of Mel. The obtained mixture of the mono alkyl halide and elimination product was mixed with the indicated amine with K2CO3 in DMF. The resulting mixture was heated at 65 °C for 2 h. The volatiles were evaporated in vacuo. The residue was dissolved in EtOAc. The mixture was extracted with 2.0 M NaOH (aq), water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The resulting crude mixture was purified by column chromatography.
Final compounds
Figure imgf000031_0001
N-methyl-N-phenyl-2-((2-(piperidin-1 -yl)quinazolin-4-yl)amino)ethane-1 -sulfonamide (46)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1.01 mmol, 1.0 eq), amine A: 2-amino-A/-methyl-A/-phenylethane-1- sulfinamide (277 mg, 1.11 mmol, 1.1 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (15- 100 % EtOAc in cHex then 0-20% MeOH in EtOAc) to give a white solid (80 mg, 19 %). LCMS (acidic mode) Rt 3.71 min, purity 99 %, [M+H]+ calculated 426.20, found 426.20. 1H NMR (500 MHz, CDCh) d 7.52-7.48 (m, 1 H), 7.45-7.40 (m, 2H), 7.35 (d, J = 4.4 Hz, 4H), 7.30-7.24 (m, 1 H), 7.06-7.00 (m, 1 H), 4.08 (q, J = 5.8, 2H), 3.86-3.80 (m, 4H), 3.42-3.38 (m, 2H), 3.34 (s, 3H), 1.69- 1.55 (m, 6H). 13C-NMR (126 MHz, CDCh) d 159.4, 158.4*, 152.4*, 141.0, 132.9, 129.6, 127.7, 126.5, 125.9, 121.0, 121.0, 110.2, 48.2, 45.1 , 38.5, 35.6, 26.1 , 25.2. ‘Identified using HMBC. HR- MS m/z [M+H]+ C22H28N5O2S+ calculated 426.1958, found 426.1976.
Figure imgf000031_0002
N-phenethyl-2-(piperidin-1 -yl)quinazolin-4-amine (48)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1.01 mmol, 1.0 eq), amine A: phenylethylamine (160 mg, 1.3 mmol, 1.3 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-50 % EtOAc in cHex) to give a white solid (210 mg, 63 %). LCMS (acidic mode) Rt 4.01 min, purity 99 %, [M+H]+ calculated 333.21 , found 333.10. 1H NMR (500 MHz, CDCh) d 7.52-7.40 (m, 3H), 7.37-7.29 (m, 4H), 7.25- 7.23 (m, 1 H), 6.99-6.96 (m, 1 H), 5.53-5.49 (m, 1 H), 3.90-3.88 (m, 4H), 3.87-3.82 (m, 2H), 3.00- 2.96 (m, 2H), 1.71-1.56 (m, 6H). 13C-NMR (126 MHz, CDCh) d 159.7, 159.2, 152.6, 139.4, 132.4, 128.9, 128.8, 126.6, 125.9, 120.7, 120.6, 110.4, 45.0, 42.5, 35.4, 26.1 , 25.2. HR-MS m/z [M+H]+ C2IH25N4 + calculated 333.2074, found 333.2078.
Figure imgf000032_0001
N-(( 1 -methylpiperidin-4-yl)methyl)-2-(piperidin-1 -yl)quinazolin-4-amine (50)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1.01 mmol, 1.0 eq), amine A: (1-methylpiperidin-4-yl)methanamine (179 mg, 1.40 mmol, 1.39 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used.
For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by reverse phase column chromatography (FhO, ACN 0-70%). The product fractions were made basic with aq. 2.0 M NaOH and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to give an off-white solid (211 mg, 62 %). LCMS (acidic mode) Rt 2.348 min, purity 99 %, [M+H]+ calculated 340.25, found 340.20 [M+H]+. 1H-NMR (500 MHz, d6-DMSO) d 7.96 (dd, J = 8.2, 1 .4 Hz, 1 H), 7.93 (t, J = 5.8 Hz, 1 H), 7.45 (ddd, J = 8.3, 6.8, 1 .4 Hz, 1 H), 7.22 (dd, J = 8.4, 1.1 Hz, 1 H), 7.00 (ddd, J = 8.1 , 6.8, 1 .2 Hz, 1 H), 3.81-3.71 (m, 4H), 3.35 (t, J = 6.1 Hz, 4H), 2.73 (dt, J = 11.4, 3.2 Hz, 2H), 2.11 (s, 3H), 1.83-1.72 (m, 2H), 1.72-1.55 (m, 6H), 1.52-1.46 (m, 4H), 1.29- 1.14 (m, 2H). 13C-NMR (126 MHz, d6-DMSO) d 159.9, 158.4, 152.0, 132.1 , 124.9, 122.7, 120.0,
110.4, 55.3, 46.2, 46.0, 44.3, 34.8, 30.1 , 25.5, 24.7. HR-MS m/z [M+H]+ C2oH3oN5 + calculated 340.2496, found 340.2494.
Figure imgf000032_0002
2-(piperidin-1 -yl)-N-(3-(piperidin-1 -yl)propyl)quinazolin-4-amine (53)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1.01 mmol, 1.0 eq), amine A: 3-(piperidin-1-yl)propan-1 -amine (210 μL, 1 .3 mmol, 1 .29 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-20 % 1 :1 MeOHTEA in EtOAc) to give a white solid (154 mg, 43%). LCMS (acidic mode) Rt 2.41 min, purity 99 %, [M+H]+ calculated 354.27, found 354.20. 1H-NMR (500 MHz, CDCI3) d 7.64-7.59 (m, 1 H), 7.50- 7.39 (m, 2H), 7.04-6.97 (m, 1 H), 3.89-3.83 (m, 4H), 3.65 (t, J = 6.0 Hz, 2H), 2.57-2.34 (m, 6H), 1.85 (p, J = 5.9 Hz, 2H), 1.73-1.48 (m, 12H). 13C-NMR (126 MHz, CDCI3) d 160.1 , 159.6, 152.4, 132.2, 125.7, 121.8, 120.1 , 110.9, 59.7, 55.1 , 45.0, 42.2, 26.3, 26.2, 25.3, 24.5, 24.1. HR-MS m/z
[M+H]+ C2IH32N5 + calculated 354.2652, found 354.2653.
Figure imgf000033_0001
N-(2-phenoxyethyl)-2-(piperidin-1-yl)quinazolin-4-amine (57) This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1 .01 mmol, 1 .0 eq), amine A: 2-phenoxyethan-1 -amine (152 mg, 1 .11 mmol, 1.1 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (40-70 % EtOAc in cHex) to give a white solid (155 mg, 44 %). LCMS (acidic mode) Rt 3.99 min, purity 99 %, [M+H]+ calculated 349.20, found 349.20. 1H-NMR (500 MHz, CDCi3 d 7.52-7.43 (m, 3H), 7.32-7.28 (m, 2H), 7.06- 7.02 (m, 1 H), 7.00-6.94 (m, 3H), 5.89 (s, 1 H), 4.24 (t, J = 5.2 Hz, 2H), 4.04 (q, J = 5.3 Hz, 2H), 3.91-3.84 (m, 4H), 1.69-1.53 (m, 6H). 13C-NMR (126 MHz, CDCI3) d 159.7, 158.7*, 152.2*, 141.8, 132.5, 128.7, 128.6, 126.2, 125.9, 120.6, 120.5, 110.3, 45.0, 40.8, 33.8, 30.9, 26.2, 25.2. ‘Identified using HMBC. HR-MS m/z [M+H]+ C2IH24N40+ calculated 349.2023, found 349.2021 .
Figure imgf000033_0002
N-(3-phenylpropyl)-2-(piperidin-1-yl)quinazolin-4-amine (58)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1.01 mmol, 1 .0 eq), amine A: 3-phenylpropan-1 -amine (150 mg, 1.11 mmol, 1.1 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (97 mg, 28 %). LCMS (acidic mode) Rt 4.20 min, purity 99 %, [M+H]+ calculated 347.22 found 347.15. 1H-NMR (500 MHz, CDCI3) d 7.49-7.41 (m, 2H), 7.33-7.26 (m, 3H), 7.24-
7.20 (m, 3H), 7.01-6.98 (m, 1 H), 3.85-3.81 (m, 4H), 3.64 (t, J = 7.0 Hz, 2H), 2.76 (t, J = 7.5 Hz, 2H), 2.05 (p, J = 7.4 Hz, 2H), 1.68-1.58 (m, 6H). 13C-NMR (126 MHz, CDCI3) d 159.7, 158.7*, 152.2*, 141.8, 132.5, 128.7, 128.6, 126.2, 125.9, 120.6, 120.5, 110.3, 45.0, 40.8, 33.8, 30.9, 26.2, 25.2. ‘Identified using HMBC. HR-MS m/z [M+H]+ C22H27N+ 4 calculated 347.2230, found 347.2232.
Figure imgf000034_0001
methyl 3-(2-((2-(piperidin-1 -yl)quinazolin-4-yl)amino)ethoxy)benzoate (59)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1.01 mmol, 1.0 eq), amine A: 3-(2-aminoethoxy)benzoate (210 mg, 1.11 mmol, 1.1 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (20-100 % EtOAc in cHex) to give a white solid (339 mg, 83 %). LCMS (acidic mode) Rt 3.84 min, purity 99 %, [M+H]+ calculated 407.21 , found 407.20. 1H NMR (500 MHz, CDCI3) d 7.67-7.64 (m, 1 H), 7.61-7.57 (m, 1 H), 7.53-7.40 (m, 3H), 7.36 (t, J = 8.0 Hz, 1 H), 7.14 (ddd, J = 8.3, 2.7, 1.0 Hz, 1 H), 7.04 (t, J = 7.6 Hz, 1 H), 5.87 (s, 1 H), 4.29 (t, J = 5.1 Hz, 2H), 4.06 (q, J = 5.3 Hz, 2H), 3.91 (s, 3H), 3.87-3.85 (m, 4H), 1.71-1.59 (m, 6H). 13C-NMR (126 MHz, CDCI3) d 167.0, 159.8, 159.0, 158.7, 152.7, 132.7, 131.6, 129.7, 126.0, 122.5, 120.8, 120.75, 120.0, 115.0, 110.3, 66.9, 52.4, 45.1 , 40.5, 26.1 , 25.2. HR-MS m/z [M+H]+ C23H27N403+ calculated 407.2078, found 407.2070.
Figure imgf000035_0002
W-(2-(indolin-1 -ylsμLfonyl)ethyl)-2-(piperidin-1 -yl)quinazolin-4-amine (60)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1.01 mmol, 1.0 eq), amine A: 2-(indolin-1-ylsulfonyl)ethan-1 -amine (290.4 mg, 1.01 mmol, 1.1 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used.
For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (10-40 % EtOAc in cHex) to give a white solid (281 mg, 64 %). LCMS (acidic mode) Rt 3.66 min, purity 99 %, [M+H]+ calculated 438.20, found 438.15. 1H-NMR (500 MHz, CDCI3) d 7.53-7.47 (m, 1 H), 7.46- 7.38 (m, 2H), 7.24 (s, 1 H), 7.19-7.13 (m, 2H), 7.05-6.97 (m, 2H), 5.96 (s, 1 H), 4.12 (q, J = 5.8 Hz,
2H), 3.98 (t, J = 8.5 Hz, 2H), 3.81-3.79 (m, 4H), 3.46-3.44 (m, 2H), 3.05 (t, J = 8.5 Hz, 2H), 1 .70- 1.57 (m, 6H). 13C-NMR (126 MHz, CDCI3) d 159.3, 158.8, 152.6, 141.8, 132.9, 131.2, 128.2, 125.9, 125.8, 123.9, 121.0, 120.8, 113.5, 110.1 , 50.3, 487.0, 45.0, 35.6, 28.0, 26.1 , 25.1. HR-MS m/z [M+H]+ C23H28N5O2S+ calculated 438.1958, found 438.1952.
Figure imgf000035_0001
1 -phenyl-2 -((2-(piperidin-1 -yl)quinazolin-4-yl)amino)ethan-1 -one (66)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1.01 mmol, 1.0 eq), amine A: 2-amino-1-phenylethan-1-one (190 mg, 1.11 mmol, 1.1 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (124 mg, 36 %). LCMS (acidic mode) Rt 3.84 min, purity 99 %, [M+H]+ calculated 363.22, found 363.20. 1H-NMR (500 MHz, CDCI3) δ 7.51-7.41 (m, 2H), 7.32 (d, J = 8.3 Hz, 1 H), 7.25-7.23 (m, 1 H), 7.00-6.98 (m, 1 H), 6.86-6.82 (m, 1 H), 6.82-6.77 (m, 2H), 5.50 (s, 1 H), 3.90 (t, J = 5.2 Hz, 4H), 3.84-3.81 (m, 2H), 3.78 (s, 3H), 2.99 (t, J = 7.0 Hz, 2H), 1.71-1.59 (m,
6H). 13C-NMR (126 MHz, CDCI3) d 195.1 , 159.3, 158.7*, 152.6*, 134.9, 134.3, 132.8, 129.1 , 128.1 , 125.9, 121.3, 121.0, 110.4, 47.8, 45.1 , 26.2, 25.2. ‘Identified using HMBC. HR-MS m/z [M+H]+ C2IH23N40+ calculated 347.1687, found 347.1868.
Figure imgf000036_0001
N-(3-methoxyphenethyl)-2-(piperidin-1-yl)quinazolin-4-amine (67)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1.01 mmol, 1.0 eq), amine A: 2-(3-methoxyphenyl)ethan-1-amine (167 mg, 1.11 mmol, 1.1 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (255 mg, 63 %). LCMS (acidic mode) Rt 3.84 min, purity 99 %, [M+H]+ calculated 363.22, found 363.20. 1H-NMR (500 MHz, CDCI3) d 7.51-7.41 (m, 2H), 7.32 (d, J = 8.3 Hz, 1 H), 7.25-7.23 (m, 1 H), 7.00-6.98 (m, 1 H), 6.86-6.82 (m, 1 H), 6.82-6.77 (m, 2H), 5.50 (s, 1 H), 3.90 (t, J = 5.2 Hz, 4H), 3.84-3.82 (m, 2H), 3.78 (s, 3H), 2.99 (t, J = 7.0 Hz, 2H), 1 .71-1 .59 (m, 6H). 13C-NMR (126 MHz, CDCI3) d 160.8*, 160.0, 159.7, 152.3*, 141.0, 132.5, 129.8, 126.0,
121.3, 120.6, 120.6, 114.6, 112.1 , 110.4, 55.3, 45.1 , 42.4, 35.5, 26.2, 25.2. ‘Identified using HMBC. HR-MS m/z [M+H]+ C22H27N40+ calculated 363.2180, found 363.2184.
Figure imgf000036_0002
N-(3-phenoxypropyl)-2-(piperidin-1-yl)quinazolin-4-amine (68)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1.01 mmol, 1.0 eq), amine A: 3-phenoxypropan-1 -amine (168 mg, 1.11 mmol, 1.1 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-35 % EtOAc in cHex) to give a white solid (360 mg, 99 %). LCMS (acidic mode) Rt 3.96 min, purity 99 %, [M+H]+ calculated 363.22, found 363.15. 1H-NMR (500 MHz, CDCI3) d 7.51-7.41 (m, 3H), 7.33-7.28 (m, 2H), 7.03-7.01 (m, 1 H), 7.00-6.91 (m, 3H), 5.94 (s, 1 H), 4.15 (t, J = 5.7 Hz, 2H), 3.87-3.85 (m, 4H), 3.83 (q, J = 6.4 Hz, 2H), 2.22-2.20 (m, 2H), 1 .69-1 .59 (m, 6H). 13C-NMR (126 MHz, CDCI3) d 159.9, 159.2*, 158.8, 152.6*, 132.5, 129.7, 126.0, 121.1 , 120.7, 120.6, 114.5, 110.4, 66.8, 45.0, 39.4, 28.8, 26.2, 25.2. ‘Identified using HMBC. HR-MS m/z [M+H]+ C22H27N4CF calculated 363.2180, found 363.2175.
Figure imgf000037_0001
3-(2-((2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)benzamide (73)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and 7M NH3 in MeOH (144 mL, 1 .02 mmol, 4.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (90 mg, 90%). LCMS (acidic mode) Rt 3.68 min, purity 98 %, [M+H]+ calculated 392.21 , found 392.15. 1H-NMR (500 MHz, CD3OD) d 7.82-7.72 (m, 1 H), 7.54-7.47 (m, 1 H), 7.45-7.40 (m, 1 H), 7.38-7.35 (m, 1 H), 7.26 (td, J = 7.9, 2.3 Hz, 1 H), 7.15-7.06 (m, 1 H), 7.05-6.98 (m, 1 H), 4.26-4.18 (m, 2H), 4.01-3.93 (m, 2H), 3.80-3.71 (m, 4H), 1.71-1.51 (m, 6H). 13C-NMR (126 MHz, CD3OD) d 170.7, 160.5, 159.2, 156.6, 147.7, 135.1 , 133.9, 130.0, 122.8, 122.7, 120.3, 118.9, 118.8, 113.9, 110.7, 66.4, 46.0, 41.0, 26.2, 24.9. HR-MS m/z [M+H]+ q22H26N5q2 + calculated 392.2081 , found 392.2079.
Figure imgf000037_0002
N,N-dimethyl-3-(2-((2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)benzamide (74)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and Me2NH (2.0 M in MeOH, 510 μL, 1.02 mmol, 4.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (95 mg, 89 %). LCMS (acidic mode) Rt 3.76 min, purity 97 %, [M+H]+ calculated 420.24, found 420.25. 1H-NMR (500 MHz, CDsOD) d 7.83 (dd, J = 8.1 , 1.4 Hz, 1 H), 7.52 (ddd, J = 8.3, 7.0, 1.5 Hz, 1 H), 7.37 (dd, J = 8.5, 1 .1 Hz, 1 H), 7.38-7.31 (m, 2H), 7.11-7.04 (m, 2H), 6.98 (dd, J = 2.6, 1 .5 Hz, 1 H), 6.97-6.92 (m, 1 H), 4.32 (t, J = 5.7 Hz, 2H), 3.98 (t, J = 5.8 Hz, 2H), 3.89-3.79 (m, 4H), 3.07 (s, 3H), 2.93 (s, 3H), 1.74-1.67 (m, 2H), 1.65-1.57 (m, 4H). 13C-NMR (126 MHz, CDsOD) d 177.1 , 173.5, 161.7, 160.3, 152.9, 138.6, 133.8, 130.9, 125.2, 123.3, 122.2, 120.2, 117.2, 114.2, 111.8, 67.3, 46.4, 41 .6, 40.2, 39.9, 27.1 , 26.1 . HR-MS m/z [M+H]+ C24H3oN5O2 + calculated 420.2394, found 420.2389.
Figure imgf000038_0002
(3-(2-((2-(piperidin-1 -yl)quinazolin-4-yl)amino)ethoxy)phenyl)(pyrrolidin-1 -yl)methanone (75)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and pyrrolidine (42.0 μL, 0.510 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (40-100 % EtOAc in cHex) to give a white solid (101 mg, 89 %). LCMS (acidic mode) Rt 3.85 min, purity 98%, [M+H]+ calculated 446.26, found 446.20. 1H-NMR
(500 MHz, CD3OD) d 7.81 (dd, J = 8.2, 1 .4 Hz, 1 H), 7.50 (ddd, J = 8.4, 7.0, 1 .5 Hz, 1 H), 7.38-7.30 (m, 2H), 7.09-7.02 (m, 4H), 4.32 (t, J = 5.8 Hz, 2H), 3.97 (t, J = 5.8 Hz, 2H), 3.86-3.79 (m, 4H), 3.54 (t, J = 7.0 Hz, 2H), 3.36 (t, J = 6.7 Hz, 2H), 2.00-1 .91 (m, 2H), 1 .89-1 .79 (m, 2H), 1 .72-1 .66 (m, 2H), 1.63-1.56 (m, 4H). 13C-NMR (126 MHz, CD3OD) δ 178.0, 171.6, 161.7, 160.4, 160.4, 153.1 , 139.3, 133.7, 130.8, 125.3, 123.3, 122.1 , 120.3, 117.6, 114.2, 111.9, 67.3, 50.8, 47.4, 46.3,
41 .6, 27.2, 27.1 , 26.1 , 25.3. HR-MS m/z [M+H]+ C26H32N5O2 + calculated 446.2551 , found 446.2561 .
Figure imgf000038_0001
Figure imgf000038_0003
To an ice-cooled solution of compound (73) (63 mg, 0.16 mmol, 1.0 eq) in THF (5 mL) was added LAH (2.0 M in THF, 317 μL, 0.640 mmol, 4.0 eq) dropwise. The reaction mixture was heated at 60 °C until full conversion of the starting material was observed. The reaction mixture was carefully quenched with H2O and filtered over Celite. The filtrate was diluted with 2.0 M NaOH (aq) and extracted with EtOAc (1x). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The crude material was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1.0 M aq. NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (23 mg, 38 %). LCMS (acidic mode) Rt 2.64 min, purity 97 %, [M+H]+ calculated 378.23, found 378.15. 1H-NMR (500 MHz, CD3OD) d 7.88-7.77 (m, 1 H), 7.71-7.64 (m, 1 H), 7.63- 7.56 (m, 1 H), 7.56-7.47 (m, 1 H), 7.42-7.35 (m, 1 H), 7.14-7.05 (m, 2H), 6.97-6.83 (m, 2H), 4.35- 4.25 (m, 2H), 4.07-3.94 (m, 2H), 3.89-3.71 (m, 6H), 1.67-1.48 (m, 6H). 13C-NMR (126 MHz, CDsOD) d 161.2, 160.4, 152.8, 140.8, 136.2, 132.7, 131.6, 126.2, 124.9, 124.4, 118.4, 117.9, 117.5, 111.0, 66.8, 61.9, 47.5, 26.8, 25.0. HR-MS m/z [M+H]+ C22H28N50+ calculated 378.2289, found 378.2289.
Figure imgf000039_0001
N -(2-(3-((dimethylamino)methyl)phenoxy)ethyl)-2-(piperidin-1-yl)quinazolin-4-amine (77)
To an ice-cooled solution of compound (74) (65 mg, 0.16 mmol, 1.0 eq) in THF (5 mL) was added LAH (2.0 M in THF, 317 μL, 0.640 mmol, 4.0 eq) dropwise. The reaction mixture was heated at 60 °C until full conversion of the starting material was observed. The reaction mixture was carefully quenched with H2O and filtered over Celite. The filtrate was diluted with 2.0 M NaOH (aq) and extracted with EtOAc (1x). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The crude material was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1 .0 M aq. NaOH.
The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (53 mg, 81 %). LCMS (acidic mode) Rt 2.72 min, purity 99 %, [M+H]+ calculated 406.26, found 406.25. 1H-NMR (500 MHz, CD3OD) d 8.18 (dd, J = 8.2, 1.3 Hz, 1 H), 7.77 (td, J = 7.7, 1.3 Hz, 1 H), 7.70 (d, J = 8.3 Hz, 1 H), 7.44-7.36 (m, 2H), 7.26 (t, J = 2.1 Hz, 1 H), 7.12-7.04 (m, 2H), 4.39 (t, J = 5.5 Hz, 2H), 4.31 (s, 2H), 4.10 (t, J = 5.4 Hz, 2H), 3.91 (t, J = 5.3 Hz, 4H), 2.84 (s,
6H), 1.67-1.48 (m, 6H). 13C-NMR (126 MHz, CD3OD) d 161.4, 160.6, 152.6, 140.9, 136.3, 132.7, 131.5, 126.1 , 124.8, 124.4, 118.4, 117.7, 117.5, 111.0, 66.8, 61.9, 47.5, 42.9, 42.3, 26.8, 25.0. HR- MS m/z [M+H]+ C24H32N50+ calculated 406.2602, found 406.2619.
Figure imgf000039_0002
2-(piperidin-1 -yl)-N-(2-(3-(pyrrolidin-1 -ylmethyl)phenoxy)ethyl)quinazolin-4-amine (78)
To an ice-cooled solution of compound (75) (71 mg, 0.16 mmol, 1.0 eq) in THF (5 mL ) was added LAH (2.0 M in THF, 317 μL, 0.640 mmol, 4.0 eq) dropwise. The reaction mixture was heated at 60 °C until full conversion of the starting material was observed. The reaction mixture was carefully quenched with H2O and filtered over Celite. The filtrate was diluted with 2.0 M NaOH (aq) and extracted with EtOAc (1x). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The crude material was purified by reverse column chromatography (0-50 % AON in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1.0 M aq. NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (51 mg, 69 %). LCMS (acidic mode) Rt 2.75 min, purity 99 %, [M+H]+ calculated 432.28, found 432.35. 1H-NMR (500 MHz, CD3OD) d 7.81 (dd, J = 8.2, 1.5 Hz, 1 H), 7.49 (ddd, J = 8.3, 6.9, 1.5 Hz, 1 H), 7.36 (dd, J = 8.4, 1.2 Hz, 1 H), 7.19 (t, J = 7.8 Hz, 1 H), 7.05 (ddd, J = 8.1 , 6.9, 1 .2 Hz, 1 H), 6.94-6.91 (m, 1 H), 6.90-6.81 (m, 2H), 4.27 (t, J = 5.9 Hz, 2H), 3.95 (t, J = 5.9 Hz, 2H), 3.88-3.77 (m, 4H), 3.52 (s, 2H), 2.56-2.38 (m, 4H), 1.82-1.72 (m, 4H), 1.70-1.64 (m, 2H), 1.62- 1.53 (m, 4H). 13C-NMR (126 MHz, CD3OD) d 161.7, 160.5, 160.4, 153.2, 140.9, 133.6, 130.3, 125.4, 123.2, 122.9, 122.0, 116.6, 114.7, 111 .9, 67.1 , 61 .5, 54.9, 46.3, 41 .6, 27.1 , 26.1 , 24.0. HR- MS m/z [M+H]+ C26H34N5O+ calculated 432.2758, found 432.2749.
Figure imgf000040_0001
(3-(2-((2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)phenyl)methanol (79)
To a stirred and ice-cooled solution of NaB HH4 (82.7 mg, 2.19 mmol, 3.5 eq) in THF (10 mL) was added dropwise a solution of compound (59) (254 mg, 0.625 mmol, 1.00 eq) in THF (10 mL). The reaction mixture was stirred at rt until full conversion of the starting material. The mixture was quenched with H2O at 0°C and extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude material was purified by column chromatography 0-10% MeOH in EtOAc. Final product was obtained as a white solid (60 mg, 25%). LCMS (acidic mode) Rt 4.43 min, purity 99%, [M+H]+ calculated 379.21 , found 379.15. 1H-NMR (500 MHz, d6-DMSO) d 8.13 (t, J = 5.4 Hz, 1 H), 7.98 (d, J = 8.1 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.28-7.18 (m, 2H), 7.03 (t, J = 7.5 Hz, 1 H), 6.94-6.85 (m, 2H), 6.84-6.79 (m, 1 H), 5.18 (t, J = 5.8 Hz, 1 H), 4.49-4.40 (m, 2H), 4.23 (t, J = 6.0 Hz, 2H), 3.89-3.81 (m, 2H), 3.77-3.75 (m, 4H), 1.64-1.43 (m, 6H). 13C-NMR (126 MHz, d6-DMSO) d 159.9, 158.5, 158.4, 152.0, 144.34, 132.4, 129.17, 125.0, 122.7, 120.2, 118.7, 112.7, 112.4, 110.4, 65.3, 62.8, 62.6, 44.3, 25.5, 24.7. HR-MS m/z [M+H]+ C22H27N4O2 + calculated 379.2129, found 379.2116.
Figure imgf000041_0001
N,N-dimethyl-2-(2-(methyl(2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)benzamide (80)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (100 mg, 487 pmol, 1.0 eq), amine A: A/,A/-dimethyl-2-(2- (methylamino)ethoxy)benzamide (132 mg, 594 pmol, 1 .22 eq), EtOAc (10 mL) and DIPEA (175 μL, 1.00 mmol, 2.0 eq) were used. For the second step, amine B: piperidine (200 μL, 2.02 mmol, 4.15 eq) and DIPEA (175 μL, 1.00 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (40-100 % EtOAc in cHex) to give a white solid (136 mg, 62 %). LCMS (acidic mode) Rt 3.751 min, purity 96 %, [M+H]+ calculated 434.26, found 434.20 [M+H]+. 1H NMR (500 MHz, CDCh) d 7.88-7.85 (m, 1 H), 7.48-7.46 (m, 2H), 7.34-7.30 (m, 1 H), 7.26-7.23 (m, 1 H), 7.03- 6.98 (m, 2H), 6.93-6.90 (m, 1 H), 4.48-4.27 (m, 2H), 4.14-3.96 (m, 2H), 3.83 (t, J = 5.3 Hz, 4H), 3.42 (s, 3H), 2.98 (s, 3H), 2.78 (s, 3H), 1.71-1.57 (m, 6H). 13C-NMR (126 MHz, CDCh) d 169.2*, 163.9*, 157.8*, 154.4*, 154.4, 153.9*, 132.2, 130.4, 128.1 , 126.6*, 126.1 , 125.8, 121.5, 119.9, 111.9, 111.4*, 66.5, 52.4, 45.1 , 41.5, 38.3, 34.8, 26.1 , 25.2. ‘Identified using HMBC. HR-MS m/z [M+H]+ C25H32N5O2 + calculated 434.2551 , found 434.2548.
Figure imgf000041_0002
(4-methylpiperazin-1-yl)(3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)methanone (81)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and 1-methylpiperazine (57 μL, 0.51 mmol, 2.0 eq) were used. The crude product was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1.0 M aq. NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (100 mg, 87 %). LCMS (acidic mode) Rt 2.90 min, purity 99 %, [M+H]+ calculated 475.28, found 475.35. 1H-NMR (500 MHz, CDsOD) d 8.20-8.14 (m, 1 H), 7.83 (ddd, J = 8.5, 7.2, 1.3 Hz, 1 H), 7.70-7.64 (m, 1 H), 7.47 (ddd, J = 8.3, 7.2, 1.1 Hz, 1 H), 7.43 (dd, J = 8.5, 7.4 Hz, 1 H), 7.15 (ddd, J = 8.4, 2.6, 0.9 Hz, 1 H), 7.12-7.10 (m, 1 H), 7.10-7.04 (m, 1 H), 4.41 (t, J = 5.4 Hz, 2H), 4.14 (t, J = 5.4 Hz, 2H), 3.98-3.88 (m, 4H), 3.69 (s, 8H), 2.99-2.94 (m, 3H), 1.89-1.71 (m, 6H). 13C-NMR (126 MHz, CD3OD) d 172.1, 161.6, 160.4, 152.7, 140.9, 136.8, 136.4, 131.2, 126.2, 124.7, 120.5, 118.3, 117.9, 114.5, 111.1 , 68.1 , 66.8, 54.1 , 47.4, 43.7, 42.4, 26.8, 25.1. HR-MS m/z [M+H]+ C27H35N6O2 + calculated 475.2816, found 475.2796.
Figure imgf000042_0001
N-(( 1 -methylpiperidin-4-yl)methyl)-3-(2-((2-(piperidin-1 -yl)quinazolin-4- yl)amino)ethoxy)benzamide (82)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and (1-methylpiperidin-4-yl)methanamine (65 mg, 0.51 mmol, 2.0 eq) were used. The crude product was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1.0 M aq. NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (76 mg, 59 %). LCMS (acidic mode) Rt 3.21 min, purity 99%, [M+H]+ calculated 503.31 , found 503.25. 1H-NMR (500 MHz, CDCI3) d 7.53 (dd, J = 8.1 , 1.4 Hz, 1 H), 7.50-7.42 (m, 2H), 7.40-7.37 (m, 1 H), 7.34-7.26 (m, 2H), 7.06-6.97 (m, 2H), 6.43 (t, J = 6.1 Hz, 1 H), 6.12 (t, J = 5.6 Hz, 1 H),
4.25 (t, J = 5.2 Hz, 2H), 4.01 (q, J = 5.3 Hz, 2H), 3.85 (t, J = 5.3 Hz, 4H), 3.32 (t, J = 6.3 Hz, 2H), 2.91-2.81 (m, 2H), 2.79 (s, 2H), 2.25 (s, 3H), 1 .98-1 .89 (m, 2H), 1 .78-1 .68 (m, 2H), 1 .68-1 .54 (m, 7H), 1.35 (qd, J = 12.1 , 3.9 Hz, 2H). 13C-NMR (126 MHz, CDCI3) d 167.5, 165.0, 159.8, 158.9, 158.9, 152.4, 136.3, 132.7, 129.8, 125.7, 121.0, 120.8, 119.2, 118.0, 113.3, 110.3, 66.7, 55.4, 46.3, 45.5, 45.1 , 40.5, 38.7, 35.4, 30.0, 26.1 , 25.1 . HR-MS m/z [M+H]+ C29H39N6O2 + calculated 503.3129, found 503.3108.
Figure imgf000043_0001
(4-methyl-1,4-diazepan-1-yl)(3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)methanone (83)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq),
DMF (5 mL) and 1 -methyl-1 ,4-diazepane (63 μL, 51 mmol, 2.0 eq) were used. The crude product was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1.0 M aq. NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (100 mg, 81 %). LCMS (acidic mode) Rt 3.21 min, purity 99 %, [M+H]+ calculated 489.30 found 489.30. 1H-NMR d 8.19 (dd, J = 8.3, 1.4 Hz, 1 H), 7.82 (ddd, J = 8.5, 7.2, 1.3 Hz, 1 H), 7.78-7.64 (m, 1 H), 7.47 (ddd, J = 8.3, 7.2, 1 .1 Hz, 1 H), 7.41 (t, J = 7.9 Hz, 1 H), 7.20-7.02 (m, 3H), 4.41 (t, J = 5.5 Hz, 2H), 4.13 (t, J = 5.4 Hz, 2H), 4.00-3.88 (m, 4H), 3.87-3.73 (m, 2H), 3.69-3.63 (m, 2H), 3.59-3.47 (m, 2H), 3.40 (s, 2H), 3.03-2.91 (m, 3H), 2.44-2.05 (m, 2H), 1.89-1.65 (m, 6H). 13C-NMR (126 MHz, CD3OD) 5 160.2, 158.8, 151.3, 139.5, 136.6, 135.0, 129.7, 124.8, 123.4, 119.1 , 117.0, 116.2, 113.0, 109.7, 66.8, 65.5, 55.9, 54.8, 48.1 , 48.0, 48.0, 47.9, 47.8, 47.6, 47.5, 47.3, 47.1 , 46.1 , 43.6, 41.0, 40.7, 25.4, 24.7, 23.7. HR-MS m/z [M+H]+ C28H37N6O2 + calculated 489.2973, found 489.2964.
Figure imgf000043_0002
N-(1-methylpiperidin-4-yl)-3-(2-((2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)benzamide
(84)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and 1-methylpiperidin-4-amine (63 mL, 0.51 mmol, 2.0 eq) were used. The crude product was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1 .0 M aq. NaOH. The organic layer was washed with brine, dried over Na2S Os, filtered and evaporated in vacuo to give a white solid (101 mg, 89 %). LCMS (acidic mode) Rt 2.99 min, purity 99%, [M+H]+ calculated 489.30, found 489.30. 1H-NMR (500 MHz, CDsOD) d 8.14 (dd, J = 8.2, 1.3 Hz, 1 H), 7.78 (ddd, J = 8.5, 7.1 , 1.4 Hz, 1 H), 7.67 (d, J = 8.3 Hz, 1 H), 7.50-7.39 (m, 3H), 7.36 (t, J = 7.8 Hz, 1 H), 7.13 (dd, J = 8.1 , 2.5 Hz, 1 H), 4.40 (t, J = 5.5 Hz, 2H), 4.15 (dq, J = 11.9, 3.8 Hz, 1 H), 4.10 (t, J = 5.5 Hz, 2H), 3.88 (t, J = 5.3 Hz, 4H), 3.62-3.55 (m, 2H), 3.18 (td, J = 13.0, 2.7 Hz, 2H), 2.89 (s, 3H), 2.27-2.15 (m, 2H), 2.00 (qd, J = 13.8, 3.9 Hz, 2H), 1.82-1.65 (m, 6H). 13C-NMR (126 MHz, CDsOD) d 169.4, 161.5, 160.1 , 152.6, 140.9, 136.8, 136.7, 136.3, 130.8, 126.1 , 124.7, 121.0, 119.4, 118.3, 114.5, 111.1 , 66.8, 54.8, 51 .4, 47.4, 46.0, 43.8, 42.4, 30.2, 26.8, 25.0. HR-MS m/z [M+H]+ O28H37N6O2 + calculated
489.2973, found 489.2965.
Figure imgf000044_0001
(4-hydroxypiperidin-1-yl)(3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)methanone (85)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and piperidin-4-ol (52 mg, 51 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (76 mg, 63 %). LCMS (acidic mode) Rt 3.33 min, purity 96 %, [M+H]+ calculated 476.27, found 476.30. 1H-NMR (500 MHz, CDsOD) d 7.89 (dd, J = 8.1 , 1 .4 Hz, 1 H), 7.57 (ddd, J = 8.4, 7.0, 1 .4 Hz, 1 H), 7.46-7.37 (m, 1 H), 7.40-7.32 (m, 1 H), 7.15 (ddd, J = 8.2, 7.0, 1.2 Hz, 1 H), 7.06 (ddd, J = 8.4, 2.6, 1.0 Hz, 1 H), 7.00-6.91 (m, 2H), 4.36-4.30 (m, 2H), 4.15 (dt, J = 9.4, 4.7 Hz, 1 H), 4.05-3.97 (m, 2H), 3.91- 3.81 (m, 5H), 3.63-3.55 (m, 1 H), 3.29 (s, 1 H), 3.20-3.12 (m, 1 H), 1.97-1.91 (m, 1 H), 1.81-1.48 (m, 8H). 13C-NMR (126 MHz, CDsOD) d 172.1 , 161.7, 160.5, 158.6*, 150.3*, 138.4, 134.3, 131.0,
123.8, 123.6, 123.0, 119.9, 117.2, 114.0, 111.7, 67.6, 67.2, 49.5, 49.3, 49.2, 49.0, 48.8, 48.7, 48.5, 46.6, 46.3, 41.8, 40.7, 35.4, 34.7, 27.0, 25.9. HR-MS m/z [M+H]+ C27H34N503+ calculated 476.2656, found 476.2650.
Figure imgf000045_0001
N-cyclopropyl-3-(2-((2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)benzamide (86)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and cyclopropyl amine (29 mg, 0.51 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (85 mg, 77 %). LCMS (acidic mode) Rt 3.86 min, purity 99 %, [M+H]+ calculated 432.24, found 432.20. 1H-NMR (500 MHz, CD3OD) d 7.84 (dd, J = 8.2, 1.5 Hz, 1 H), 7.58-7.50 (m, 1 H), 7.42-7.28 (m, 4H), 7.18- 7.06 (m, 2H), 4.33 (t, J = 5.8 Hz, 2H), 3.99 (t, J = 5.8 Hz, 2H), 3.88-3.77 (m, 4H), 2.89-2.76 (m, 1 H), 1.77-1.55 (m, 6H), 0.87-0.73 (m, 2H), 0.68-0.56 (m, 2H). 13C-NMR (126 MHz, CD3OD) d
171.9*, 161.7, 160.4, 155.9*, 134.1 , 130.8, 129.3, 124.3, 123.5, 122.7, 121.2, 118.9, 114.8, 111.8, 67.3, 64.1 , 62.2, 59.7, 46.5, 41.7, 27.1 , 25.9. ‘Identified using HMBC. HR-MS m/z [M+H]+ C25H30N5O2 + calculated 432.2394, found 432.2404.
Figure imgf000045_0002
(3-hydroxyazetidin-1-yl)(3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)methanone (87)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and azetidin-3-ol (56 mg, 0.51 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (70 mg, 61 %). LCMS (acidic mode) Rt 3.36 min, purity 99%, [M+H]+ calculated 448.23, found 448.20. 1H-NMR (500 MHz, CD3OD) d 7.90-7.84 (m, 1 H), 7.59-7.52 (m, 1 H), 7.43-7.38 (m, 1 H), 7.38-7.32 (m, 1 H), 7.20-7.08 (m, 4H), 4.61-4.55 (m, 1 H), 4.49-4.41 (m, 1 H), 4.39-4.31 (m, 3H), 4.14-4.04 (m, 1 H), 4.00 (t, J = 5.7 Hz, 2H), 3.95-3.88 (m, 1 H), 3.87-3.81 (m, 4H), 1.75-1.60 (m, 6H). 13C-NMR (126
MHz, CD3OD) d 171.9*, 161.7, 160.4*, 155.9, 135.5, 134.1, 130.8, 129.3, 124.3, 123.5, 122.7, 121.2, 118.9, 114.8, 111.8, 67.3, 64.1 , 62.2, 59.7, 46.5, 41.7, 27.1 , 25.9. ‘Identified using HMBC. HR-MS m/z [M+H]+ C25H3ONS03+ calculated 448.2343, found 448.2349.
Figure imgf000046_0001
azepan-1 -yl(3-(2-((2-(piperidin-1 -yl)quinazolin-4-yl)amino)ethoxy)phenyl)methanone (88)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and azepane (51 mg, 0.51 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (51 mg, 42 %). LCMS (acidic mode) Rt 4.50 min, purity 99 %, [M+H]+ calculated 474.29, found 474.30. 1H-NMR d 7.85 (dd, J = 8.2, 1.4 Hz, 1 H), 7.53 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.41-7.34 (m, 2H), 7.13-7.03 (m, 2H), 6.97-6.91 (m, 2H), 4.35 (t, J = 5.7 Hz, 2H), 4.00 (t, J = 5.8 Hz, 2H), 3.91-3.78 (m, 4H), 3.75- 3.59 (m, 2H), 3.42-3.34 (m, 2H), 1.91-1.52 (m, 14H) 13C-NMR (126 MHz, CDsOD) d 173.5, 161.8, 160.5, 160.4, 153.1 , 139.3, 133.7, 131.0, 125.4, 123.3, 122.1 , 119.6, 116.8, 113.7, 111.9, 67.4, 51 .0, 47.4, 46.3, 41 .6, 30.4, 28.8, 28.1 , 27.3, 27.1 , 26.1 . HR-MS m/z [M+H]+ C28H36N5O2 + calculated
474.2864, found 474.2859.
Figure imgf000046_0002
3-(2-((2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)-N-(tetrahydro-2H-pyran-4-yl)benzamide (89)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and tetrahydro-2H-pyran-4-amine (52 mg, 0.51 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (65 mg, 53 %). LCMS (acidic mode) Rt 3.80 min, purity 99 %, [M+H]+ calculated 476.27, found 476.30. 1H-NMR (500 MHz, CD3OD) d 7.88 (dd, J = 8.2, 1.5 Hz, 1 H), 7.56 (ddd, J = 8.3, 7.0, 1.5 Hz, 1 H), 7.43-7.31 (m, 4H), 7.18-7.10 (m, 2H), 4.34 (t, J = 5.8 Hz, 2H), 4.13-4.04 (m, 1 H), 4.04-3.94 (m, 4H), 3.86-3.80 (m, 4H), 3.51 (td, J = 11.9, 2.1 Hz, 2H), 1.87 (ddt, J = 10.8, 4.2, 2.1 Hz, 2H), 1.76- 1.57 (m, 8H). 13C-NMR (126 MHz, CD3OD) d 169.4, 161.7, 160.4, 158.9*, 150.7*, 137.2, 134.2, 130.7, 124.0, 123.5, 122.9, 120.7, 119.0, 114.5, 111.7, 68.1 , 67.2, 47.9, 46.5, 41.7, 33.6, 27.1 , 25.9. ‘Identified using HMBC. HR-MS m/z [M+H]+ C27H34N503+ calculated 476.2656, found 476.2642.
Figure imgf000047_0001
piperidin-1 -yl(3-(2-((2-(piperidin-1 -yl)quinazolin-4-yl)amino)ethoxy)phenyl)methanone (90)
This compound was prepared according to general method B. Intermediate compound 63 (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq),
DMF (5 mL) and piperidine (43 mg, 0.51 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-60 % EtOAc in cHex) to give a white solid (101 mg, 86 %). LCMS (acidic mode) Rt4.53 min, purity 98%, [M+H]+ calculated 460.27, found 46.030. 1H-NMR (600 MHz, CD3OD) d 8.07 (dd, J = 8.2, 1 .3 Hz, 1 H), 7.76 (ddd, J = 8.4, 7.1 , 1 .3 Hz, 1 H), 7.57 (dd, J = 8.4, 1.1 Hz, 1 H), 7.38 (dddd, J = 11 .2, 8.0, 6.3, 1 .7 Hz, 2H), 7.10-7.05 (m, 1 H), 6.98-6.92 (m, 2H), 4.37 (t,
J = 5.5 Hz, 2H), 4.09 (t, J = 5.5 Hz, 2H), 3.92-3.84 (m, 4H), 3.72-3.64 (m, 2H), 3.42-3.34 (m, 2H), 1.83-1.76 (m, 2H), 1.76-1.69 (m, 6H), 1.69-1.62 (m, 2H), 1.55-1.47 (m, 2H). 13C-NMR (151 MHz, CD3OD) d 171.9, 161.6, 160.3, 152.6, 141.5, 138.7, 135.9, 131.0, 125.4, 124.4, 120.1 , 119.6, 117.1 , 114.0, 111.3, 66.9, 50.0, 47.2, 44.3, 42.3, 27.6, 26.8, 25.4, 25.2. HR-MS m/z [M+H]+ q27H34N5q2 + calculated 460.2707, found 460.2698.
Figure imgf000047_0002
NN -dimethyl-3-(2-(methyl(2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)benzamide (92)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1.01 mmol, 1.0 eq), amine A A/,A/-dimethyl-3-(2- (methylamino)ethoxy)benzamide (246 mg, 1.11 mmol, 1.1 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (60-100 % EtOAc in cHex) to give a yellow solid (60 mg, 14 %). LCMS (acidic mode) Rt 4.04 min, purity 99%, [M+H]+ calculated 434.26, observed 434.25. 1H-NMR (500 MHz, CDCh) d 7.86 (dt, J = 8.4, 1.0 Hz, 1 H), 7.50-7.44 (m, 2H), 7.29 (t, J = 8.1 , Hz, 1 H), 7.02-6.92 (m, 4H), 4.36 (t, J = 5.6 Hz, 2H), 4.06 (t, J = 5.6 Hz, 2H), 3.85-3.81 (m, 4H), 3.43 (s, 3H), 3.09 (s, 3H), 2.95 (s, 3H), 1.70-1.55 (m, 6H). 13C-NMR (126 MHz, CDCh) d 171.4, 164.2, 158.8, 158.3, 155.1 , 137.8, 132.2, 129.7, 126.1 , 125.7, 119.8, 119.6, 116.0, 113.2, 111.6, 66.2, 52.4, 45.1 , 41.6, 39.7, 35.4, 26.1 , 25.2. HR-MS m/z [M+H]+ C25H32N5O2 + calculated 434.2551 found 434.2547
Figure imgf000048_0001
N,N-dimethyl-2-(2-((2-(piperidin-1 -yl)quinazolin-4-yl)amino)ethoxy)benzamide (100)
This compound was prepared according to general method A. For the first step, 2,4- dichloroquinazoline (200 mg, 1.01 mmol, 1.0 eq), amine A A/,A/-dimethyl-2-(2- (aminoethoxy)benzamide (246 mg, 1.11 mmol, 1.1 eq), EtOAc (10 mL) and DIPEA (350 μL, 2.01 mmol, 2.0 eq) were used. For the second step, amine B: piperidine (298 μL, 3.02 mmol, 3.0 eq) and DIPEA (350 mL, 2.01 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (60-100 % EtOAc in cHex) to give a yellow solid (112 mg, 27 %). LCMS (acidic mode) Rt 3.987 min, purity 99 %, [M+H]+ calculated 420.24 [M+H]+ found 420.20 [M+H]+. 1H NMR (500 MHz, CDCh) d 7.91-7.85 (m, 1 H), 7.49-7.44 (m, 1 H), 7.45-7.37 (m, 1 H), 7.33-7.27 (m, 1 H), 7.21-7.16 (m, 1 H), 7.07-6.95 (m, 3H), 6.88 (s, 1 H), 4.40-4.33 (m, 2H), 3.94-3.87 (m, 2H), 3.88- 3.82 (m, 4H), 3.12 (s, 3H), 2.86 (s, 3H), 1.70-1.57 (m, 6H). 13C-NMR (126 MHz, CDCh) d 170.1 ,
160.1 , 155.0, 152.3#, 132.3*, 130.6, 128.0, 127.4, 125.5*, 122.3, 122.1 , 120.6*, 115.6, 110.6#, 69.1 ,
45.1 , 40.7, 38.8, 35.0, 26.2, 25.2. ‘Identified using HMBC; identified using HSQC. HR-MS m/z [M+H]+ C24H3oN5O2 + calculated 420.2394, found 420.2384
Figure imgf000048_0002
(3-(2-((4-(dimethylamino)butyl)(2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1 -yl)methanone (101)
This compound was prepared according to general method G. (3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone (125 mg, 0.281 mmol, 1.0 eq), THF (9.0 mL), NaH (168 mg, 4.21 mmol, 1.5 eq), 1 ,4-dibromobutane (100 μL, 0.84 mmol, 3.0 eq), Me2NH (2.0 M in EtOH, 424 μL, 0.843 mmol, 3.0 eq), K2CO3 (116 mg, 0.843 mmol, 3.0 eq) and DMF (2 mL) were used. The crude material was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1 .0 M aq. NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (93 mg, 61 %). LCMS (acidic mode) Rt 3.12 min, purity 99%, [M+H]+ calculated 545.36, found 545.40. 1H-NMR (500 MHz, CDCIs) d 7.73-7.69 (m, 1 H), 7.49-7.43 (m, 2H), 7.27 (t, J = 7.9 Hz, 1 H), 7.06 (dt, J = 7.6, 1.2 Hz, 1 H), 7.03-6.97 (m, 2H), 6.92 (ddd, J = 8.3,
2.6, 0.9 Hz, 1 H), 4.30 (t, J = 5.7 Hz, 2H), 4.01 (t, J = 5.8 Hz, 2H), 3.82 (t, J = 5.4 Hz, 4H), 3.70- 3.64 (m, 2H), 3.61 (t, J = 7.0 Hz, 2H), 3.37 (t, J = 6.7 Hz, 2H), 2.32-2.25 (m, 2H), 2.23 (s, 6H), 2.00-1.79 (m, 6H), 1.70-1.50 (m, 8H), 1.41-1.33 (m, 2H). 13C-NMR (126 MHz, CDCI3) d 169.4, 163.8, 158.6, 158.1 , 154.8, 138.7, 132.1 , 129.5, 126.2, 124.9, 120.0, 119.5, 116.3, 113.1 , 111.7, 66.1 , 59.4, 52.8, 50.2, 49.6, 46.2, 45.5, 45.0, 26.4, 26.2, 26.0, 25.1 , 24.5. HR-MS m/z [M+H]+ C32H45N6C>2+ calculated 545.3599, found 545.3587.
Figure imgf000049_0001
(3-(2-((5-(dimethylamino)pentyl)(2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1 -yl)methanone (102)
This compound was prepared according to general method G. (3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone (125 mg, 0.281 mmol, 1.0 eq), THF (9.0 mL), NaH (168 mg, 4.21 mmol, 1.5 eq), 1 ,5-dibromopentane (114 μL, 0.843 mmol, 3.0 eq), Me2NH (2.0 M in EtOH, 424 μL, 0.843 mmol, 3.0 eq), K2CO3 (116 mg, 0.843 mmol, 3.0 eq) and DMF (2 mL) were used. The crude material was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1 .0 M aq. NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (121 mg, 77 %). LCMS (acidic mode) Rt 3.26 min, purity 99%, [M+H]+ calculated 559.38, found 559.40. 1H-NMR (500 MHz, CDCI3) d 7.74-7.68 (m, 1 H), 7.50-7.42 (m, 2H), 7.27 (t, J = 7.9 Hz, 1 H), 7.06 (dt, J = 7.6, 1.2 Hz, 1 H), 7.04-6.96 (m, 2H), 6.92 (ddd, J = 8.3,
2.6, 0.9 Hz, 1 H), 4.30 (t, J = 5.7 Hz, 2H), 4.01 (t, J = 5.8 Hz, 2H), 3.82 (t, J = 5.4 Hz, 4H), 3.70- 3.58 (m, 4H), 3.37 (t, J = 6.7 Hz, 2H), 2.32-2.24 (m, 2H), 2.23 (s, 6H), 1.99-1.80 (m, 6H), 1.69- 1.62 (m, 2H), 1.56-1.42 (m, 6H), 1.44-1.31 (m, 2H). 13C-NMR (126 MHz, CDCI3) d 169.5, 163.9, 158.7, 158.2, 155.0, 138.7, 132.1 , 129.5, 126.3, 124.9, 120.0, 119.6, 116.4, 113.1 , 111.8, 77.4, 77.2, 76.9, 66.2, 59.8, 53.1 , 50.2, 49.7, 46.3, 45.6, 45.1 , 29.8, 28.5, 27.6, 26.5, 26.1 , 25.2, 25.0,
24.6. HR-MS m/z [M+H]+ C33H47N6CV calculated 559.3755, found 559.3732.
Figure imgf000050_0001
(3-(2-((3-(dimethylamino)propyl)(2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1 -yl)methanone (103)
This compound was prepared according to general method G. (3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone (125 mg, 0.281 mmol, 1.0 eq), THF (9.0 mL), NaH (168 mg, 4.21 mmol, 1.5 eq), 1 ,3 -dibromopropane (85 μL, 0.843 mmol, 3.0 eq), Me2NH (2.0 M in EtOH, 424 μL, 0.843 mmol, 3.0 eq), K2CO3 (116 mg, 0.843 mmol, 3.0 eq) and DMF (2 mL) were used. The crude material was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1 .0 M aq. NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (102 mg, 68 %). LCMS (acidic mode) Rt 3.05 min, purity 98%, [M+H]+ calculated 531 .34, found 531 .40. 1H-NMR (500 MHz, CDCI3) d 7.78 (dt, J = 8.3, 1 .0 Hz, 1 H), 7.50- 7.43 (m, 2H), 7.30-7.24 (m, 1 H), 7.08-6.96 (m, 3H), 6.95-6.88 (m, 1 H), 4.31 (t, J = 5.7 Hz, 2H), 4.02 (td, J = 6.1 , 3.0 Hz, 2H), 3.82 (t, J = 5.4 Hz, 4H), 3.76-3.68 (m, 2H), 3.62 (q, J = 6.9 Hz, 2H), 3.37 (t, J = 6.7 Hz, 2H), 2.33 (t, J = 7.2 Hz, 2H), 2.23 (s, 6H), 2.05-1.96 (m, 2H), 1.96-1.80 (m, 4H), 1.69-1.52 (m, 6H). 13C-NMR (126 MHz, CDCI3) d 169.5, 164.0, 158.7, 158.2, 154.9, 138.7, 132.2, 129.5, 126.3, 125.0, 120.1 , 119.6, 116.4, 116.3, 113.1 , 111.9, 77.4, 77.2, 76.9, 66.2, 57.2, 50.9, 50.6, 49.7, 46.3, 45.7, 45.6, 45.1 , 26.5, 26.5, 26.1 , 25.2, 24.6. HR-MS m/z [M+H]+ C31 H43N6O2 + calculated 531.3442, found 531.3434.
Figure imgf000050_0002
(3-(2-((4-(piperidin-1-yl)butyl)(2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1 -yl)methanone (109)
This compound was prepared according to general method G. (3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone (125 mg, 0.281 mmol, 1.0 eq), THF (9.0 mL), NaH (168 mg, 4.21 mmol, 1.5 eq), 1 ,4-dibromobutane (100 μL, 0.84 mmol, 3.0 eq), piperidine (83 μL, 0.843 mmol, 3.0 eq), K2CO3 (116 mg, 0.843 mmol, 3.0 eq), DMF (2 mL) were used. The crude material was purified by reverse column chromatography (0-50 % ACN in water + 0.1 % FA). The product fractions were combined and extracted with EtOAc and 1.0 M aq. NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (123 mg, 75 %). LCMS (acidic mode) Rt 3.16 min, purity 99%, [M+H]+ calculated 585.39, observed = 585.45. 1H NMR (500 MHz, CDCI3) d 7.72 (d, J = 8.2, Hz, 1 H), 7.51-7.44 (m, 2H), 7.31-7.27 (m, 1 H), 7.09-7.04 (m, 1 H), 7.03-6.98 (m, 2H), 6.92 (dd, J = 8.3, 2.7, 1.0 Hz, 1 H), 4.31 (t, J = 5.7 Hz, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.82 (t, J = 5.4 Hz, 4H), 3.69-3.66 (m, 2H), 3.62 (t, J = 7.0 Hz, 2H), 3.38 (t, J = 6.7 Hz, 2H), 2.40 (s, 6H), 1 .96-1 .92 (m, 2H), 1 .90-1 .80 (m, 4H), 1 .75-1 .40 (m, 14H). 13C-NMR (126 MHz, CDCI3) d 169.5, 163.9, 158.7, 155.0*, 138.8, 132.2, 129.6, 126.3, 125.0, 120.1 , 119.8*, 119.6, 116.3, 113.2, 111.8, 66.3, 54.5, 52.6*, 50.4, 49.7, 46.3, 45.1 , 26.5, 26.1 , 25.7*, 25.2, 24.6, 24.3*. ‘Identified using HMBC. HR-MS m/z [M+H]+ Css^gNeCb* calculated 585.3912 found 585.3907.
Figure imgf000051_0001
(3-(2-((5-(piperidin-1-yl)pentyl)(2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1 -yl)methanone (111)
This compound was prepared according to general method G. (3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone (125 mg, 0.281 mmol, 1.0 eq), THF (9.0 mL), NaH (168 mg, 4.21 mmol, 1.5 eq), 1 ,5-dibromopentane (114 μL, 0.843 mmol, 3.0 eq), piperidine (83 μL, 0.843 mmol, 3.0 eq), K2CO3 (116 mg, 0.843 mmol, 3.0 eq), DMF (2 mL) were used. The crude material was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1.0 M aq. NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (121 mg, 72 %).
LCMS (acidic mode) Rt 3.34 min, purity 90%, [M+H]+ calculated 599.40, found 599.45. 1H-NMR Ή NMR (500 MHz, CDCI3) d 7.70 (dd, J = 8.3, 1.2 Hz, 1 H), 7.49-7.42 (m, 2H), 7.30-7.25 (m, 1 H), 7.06 (dt, J = 7.6, 1.3 Hz, 1 H), 7.03-6.96 (m, 2H), 6.92 (ddd, J = 8.3, 2.7, 1.0 Hz, 1 H), 4.30 (t, J = 5.7 Hz, 2H), 4.00 (t, J = 5.7 Hz, 2H), 3.82 (t, J = 5.4 Hz, 4H), 3.71-3.55 (m, 4H), 3.37 (t, J = 6.6 Hz, 2H), 2.50-2.22 (m, 6H), 1.99-1.90 (m, 3H), 1.90-1.80 (m, 4H), 1.70-1.51 (m, 12H), 1.50-1.40 (m, 2H), 1.34 (p, J = 7.7 Hz, 2H). 13C-NMR (126 MHz, CDCI3) d 169.5, 163.9, 158.7, 158.2, 155.0,
138.7, 132.1 , 129.5, 126.3, 125.0, 120.0, 119.6, 116.4, 113.1 , 111.8, 66.2, 59.5, 54.7, 53.0, 50.2,
49.7, 46.3, 45.1 , 28.5, 26.7, 26.5, 26.1 , 25.9, 25.3, 25.2, 24.6, 24.5. HR-MS m/z [M+H]+ C36H51 Nqq2+ calculated 599.4068, found 599.4072.
Figure imgf000052_0001
(3-(2-((5-morpholinopentyl)(2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1 -yl)methanone (112)
This compound was prepared according to general method G. (3-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone (125 mg, 0.281 mmol, 1.0 eq), THF (9.0 mL), NaH (168 mg, 4.21 mmol, 1.5 eq), 1 ,5-dibromopentane (114 μL, 0.843 mmol, 3.0 eq), morpholine (73 μL, 0.843 mmol, 3.0 eq), K2CO3 (116 mg, 0.843 mmol, 3.0 eq), DMF (2 mL) were used. The crude material was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and 1.0 M aq. NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (121 mg, 72 %). LCMS (acidic mode) Rt 3.21 min, purity 99 %, [M+H]+ calculated 601.39, found 601.35. 1H-NMR (500 MHz, CDCI3) d 7.70 (dd, J = 8.3, 1.3 Hz, 1 H), 7.68-7.50 (m, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.31-7.22 (m, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 7.04-6.96 (m, 2H), 6.90 (dd, J = 8.2, 2.5 Hz, 1 H), 4.30 (t, J = 5.7 Hz, 2H), 4.01 (t, J = 5.7 Hz, 2H), 3.83 (t, J = 5.4 Hz, 4H), 3.74-3.63 (m, 6H), 3.60 (t, J = 7.0 Hz, 2H), 3.36 (t, J = 6.6 Hz, 2H), 2.52-2.37 (m, 4H), 2.37-2.25 (m, 2H), 2.00-1.76 (m, 6H), 1.70-1.47 (m, 8H), 1.42-1.30 (m, 2H). 13C-NMR (126 MHz, CDCI3) d
169.4, 166.4, 163.7, 159.0, 158.6, 138.7, 132.4, 129.5, 124.9, 120.4, 119.6, 119.2, 116.3, 113.1 ,
111.5, 67.0, 66.0, 59.0, 53.8, 52.9, 50.3, 49.7, 46.3, 45.3, 28.3, 26.4, 26.4, 26.0, 25.0, 24.9, 24.5. HR-MS m/z [M+H]+ C35H49N6O3+ calculated 601 , 3861 , found 601 .3858.
Figure imgf000052_0002
(3-(2-((6,7-dimethoxy-2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)phenyl)(pyrrolidin-1- yl)methanone (113)
This compound was prepared according to general method A. For the first step 2,4-dichloro-6,7- dimethoxy-quinazoline (100 mg, 0.386 mmol, 1.0 eq), amine A: (3-(2- aminoethoxy)phenyl)(pyrrolidin-1-yl)methanone (152 mg, 0.649 mmol, 1.68 eq), DIPEA (540 mL, 3.07 mmol, 7.95 eq) and EtOAc (10 mL) were used. For the second step, amine B: piperidine (230 μL, 2.32 mmol, 6.00 eq) were used. The crude product was purified by column chromatography (0- 75 % EtOAc in cHex) to give an off-white solid (115 mg, 57 %). LCMS (acidic mode) Rt 3.99 min, purity 97 %, [M+H]+ calculated 506.28, found 506.30 [M+H]+. 1H NMR (500 MHz, d6-DMSO) d 7.87 (t, J = 5.4 Hz, 1 H), 7.43 (s, 1 H), 7.34-7.30 (m, 1 H), 7.06-7.02 (m, 3H), 6.72 (s, 1 H), 4.27 (t, J = 5.8 Hz, 2H), 3.85-3.82 (m, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.72-3.69 (m, 4H), 3.42 (t, J = 6.9 Hz, 2H), 3.31 (t, J = 6.7 Hz, 2H), 1 .84 (p, J = 6.5, 6.0 Hz, 2H), 1 .76 (p, J = 6.4 Hz, 2H), 1 .62-1 .55 (m, 2H), 1.51-1.44 (m, 4H). 13C-NMR (126 MHz, d6-DMSO) d 167.9, 159.1 , 158.2, 158.0, 153.9, 148.6,
144.7, 138.7, 129.5, 119.3, 116.1 , 112.8, 105.3, 102.9, 102.9, 66.0, 55.9, 55.4, 48.9, 45.9, 44.4,
43.7, 40.0, 25.9, 25.4, 24.7, 23.9, 22.3, 21.7. HR-MS m/z [M+H]+ C28H36N5O4+ calculated 506.2762, found 506.2784.
Figure imgf000053_0001
(3-(2-((6,7-dimethoxy-2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)phenyl)(pyrrolidin-1- yl)methanone (114)
This compound was prepared according to general method A. For the first step 2,4-dichloro-5- methylquinazoline (100 mg, 469 μmol, 1.0 eq), amine A: (3-(2-aminoethoxy)phenyl)(pyrrolidin-1- yl)methanone (132 mg, 563 pmol, 1.20 eq), DIPEA (170 μL, 0.966 mmol, 2.06 eq) and EtOAc (10 mL) were used. For the second step, amine B: piperidine (500 μL, 5.03 mmol, 10.1.0 eq) and DIPEA (170 μL, 0.966 mmol, 2.06 eq) were used. The crude product was purified by column chromatography (0-75 % EtOAc in cHex) to give an off-white solid (114 mg, 53 %). LCMS (acidic mode) Rt 4.02 min, purity 99 %, [M+H]+ calculated 460.27, found 460.25 [M+H]+. 1H NMR (500 MHz, CDCh) d 7.40-7.25 (m, 5H), 7.07 (d, J = 6.9 Hz, 2H), 7.00-6.92 (m, 2H), 4.24 (t, J = 5.3 Hz, 2H), 4.01 (s, 2H), 3.87 (d, J = 5.1 Hz, 4H), 3.62 (t, J = 7.0 Hz, 2H), 3.39 (t, J = 6.6 Hz, 2H), 2.52 (s, 3H), 1.95 (p, J = 6.5 Hz, 2H), 1.86 (p, J = 6.6 Hz, 2H), 1.69-1.59 (m, 6H). 13C-NMR (126 MHz, CDCh) d 169.5, 158.6, 138.7, 132.4#, 129.6, 120.1#, 119.7, 118.4, 116.4, 113.3, 66.8, 49.8, 46.3, 45.1 , 40.5, 26.5, 26.0, 25.2, 24.6. identified using HSQC. Five carbon signals are not visible. HR- MS m/z [M+H]+ C27H34N5O2 + calculated 460.2707, found 460.2726.
Figure imgf000053_0002
(3-(2-((2-(piperidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)ethoxy)phenyl)(pyrrolidin-1- yl)methanone (115)
This compound was prepared according to general method A. For the first step, 2,4- dichloropyrido[3,2-d]pyrimidine (100 mg, 500 pmol, 1.0 eq), amine A: (3-(2- aminoethoxy)phenyl)(pyrrolidin-1-yl)methanone (152 mg, 0.649 mmol, 1.30 eq), DIPEA (170 μL, 966 mhioI, 1.5 eq) and EtOAc (10 mL) were used. For the second step, amine B: piperidine (500 mL, 5.03 mmol, 10.1.0 eq) and DIPEA (170 mL, 966 mhioI, 1.5 eq) were used. The crude product was purified by column chromatography (0-50% EtOAc in cHex) to give an off-white solid (155 mg, 69 %). LCMS (acidic mode) Rt 3.58 min, purity 99 %, [M+H]+ calculated 447.25, found 447.25 [M+H]+. 1H NMR (500 MHz, CDCh) d 8.28-8.23 (m, 1 H), 7.70-7.64 (m, 1 H), 7.42-7.36 (m, 1 H), 7.31-7.27 (m, 1 H), 7.09-7.06 (m, 2H), 6.99 (ddd, J = 8.3, 2.5, 1 .1 Hz, 1 H), 4.24 (t, J = 5.4 Hz, 2H), 4.01 (t, J = 5.3 Hz, 2H), 3.90-3.85 (m, 3H), 3.63 (t, J = 7.0 Hz, 2H), 3.40 (t, J = 6.6 Hz, 2H), 1.94 (p, 2H), 1.85 (p, 2H), 1.70-1.60 (m, 6H). 13C-NMR (126 MHz, CDCI3) d 169.5, 159.6, 158.6, 142.5, 138.7, 132.7, 129.6, 127.6, 119.7, 116.4, 113.2, 66.6, 49.8, 46.3, 45.2, 39.9, 26.5, 26.1 , 25.1 , 24.6. Three signals of quaternary carbons are not visible. HR-MS m/z [M+H]+ C25H31N6O2 + calculated 447.2503, found 447.2525.
Figure imgf000054_0001
(3-(2-((6-bromo-2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)phenyl)(pyrrolidin-1- yl)methanone (116)
This compound was prepared according to general method A. For the first step, 6-bromo-2,4- dichloroquinazoline (100 mg, 0.378 mmol, 1.0 eq), amine A: (3-(2-aminoethoxy)phenyl)(pyrrolidin- 1-yl)methanone (107 mg, 0.457 mmol, 1.21.0 eq), DIPEA (130 mL, 0.742 mmol, 2.0 eq) and EtOAc (10 mL) were used. For the second step, amine B: piperidine (149 mL, 1.51 mmol, 3.0 eq) and DIPEA (130 mL, 0.742 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-50% EtOAc in cHex) to give an off-white solid (201 mg, 98 %). LCMS (acidic mode) Rt 4.21 min, purity 97 %, [M+H]+ calculated 524.17, found 524.10 [M+H]+. 1H NMR (500 MHz, CDCh) d 7.69 (s, 1 H), 7.53 (dd, J = 8.9, 2.2 Hz, 1 H), 7.39-7.33 (m, 1 H), 7.30-7.28 (m, 1 H), 7.11-7.06 (m, 2H), 6.97 (ddd, J = 8.3, 2.6, 1 .0 Hz, 1 H), 6.11 (s, 1 H), 4.21 (t, J = 5.2 Hz, 2H), 3.98 (q, J = 5.4 Hz, 2H), 3.85 (t, J = 5.3 Hz, 4H), 3.64 (t, J = 7.0 Hz, 2H), 3.41 (t, J = 6.6 Hz, 2H), 1 .96 (p, J = 6.6 Hz, 2H), 1.87 (p, J = 6.2 Hz, 2H), 1.69-1.59 (m, 6H). 13C-NMR (126 MHz, CDCh) d 169.5, 158.9, 158.6, 158.6*, 151.1*, 127.1#, 138.8, 135.8, 129.6, 123.8, 119.8, 116.4, 113.2, 111.5, 66.4, 49.8, 46.4, 45.2, 40.7, 29.8, 26.5, 26.1 , 25.1 , 24.6. ‘Identified using HMBC; identified using HSQC. One carbon signal is not visible. HR-MS m/z [M+H]+ C26H31BrN5O2 + calculated 524.1656, found 524.1682.
Figure imgf000055_0002
6-chloro-2-(4-methylpiperazin-1-yl)-N-(3-phenoxypropyl)quinazolin-4-amine (122)
2,4,6-trichloroquinazoline (100 mg, 0,428 mmol) was added to a microwave tube containing 3 ml ethyl acetate, DIPEA (82.0 mI, 0,471 mmol) and 3- phenoxypropan-1 -amine (64.8 mg, 0,428 mmol). The mixture was stirred at room temperature until TLC shows completion of the starting material. Methylpiperazine (0.5 mL, 4.49 mmol) was added to the mixture, and the mixture is heated to 120°C for 10 minutes under microwave irradiation. The obtained solution is diluted with ethyl acetate and washed with water and brine. The organic phase is than dried over Na2SO4 and the solvent is evaporated. The product is then purified using flash column chromatography (90% EtOAc, 5% Et3N, 5% MeOH). The title compound was obtained as a sticky amber colored liquid (148 mg, 0.359 mmol, 84%).
LCMS (acidic mode) Rt 2.93 min, purity 99 %, [M+H]+ calculated 412.19, found 412.10.
1H-NMR (CDCI3): 7.56 (s, 1 H) 7.44-7.36 (m, 2H) 7.32-7.26 (m, 2H) 7.01-6.88 (m, 3H) 6.45 (m, 1 H) 4.12 (t, 2H, j= 5.5Hz) 3.94 (t, 4H, j= 4.8Hz) 3.77 (q, 2H, j= 6.3Hz) 2.49 (t, 4H, J= 5.0Hz), 2.34 (s,
3H) 2.18 (p, 2H, j= 6.0Hz)
13C-NMR (63 MHz, CDCI3) 159.09, 158.52, 158.41 , 149.78, 133.02, 131.75, 130.55, 129.69,
126.83, 126.00, 121.11 , 120.73, 114.35, 111.19, 77.64, 77.13, 76.63, 66.62, 55.03, 46.09, 43.76, 39.59, 28.51
Figure imgf000055_0001
methyl 3-(2-((6-chloro-2-(4-methylpiperazin-1-yl)quinazolin-4-yl)amino)ethoxy)benzoate (123).
2,4,6-trichloroquinazoline (498 mg, 2,13 mmol) was added to a microwave tube containing 5 ml 1 ,4-dioxane, DIPEA (2.34 mL, 10.7 mmol) and methyl 3-(2-aminoethoxy)benzoate (500 mg, 2.56 mmol). The mixture was stirred at room temperature for 1 hour. The solvents were evaporated and the crude was flushed over silica (1 :1 Ethyl acetate heptane). The crude was dissolved in ethyl acetate and methylpiperazine (0.5 mL, 4.49 mmol) was added to the mixture, and the mixture is heated to 120°C for 30 minutes under microwave irradiation. The obtained solution is diluted with ethyl acetate and washed with water and brine. The organic phase is than dried over Na2SO4 and the solvent is evaporated. The product is then purified using flash column chromatography (90% EtOAc, 5% Et3N, 5% MeOH). The title compound was obtained as an off-white solid (620 mg, 1.360 mmol, 64 %).
Figure imgf000056_0001
N,N-dimethyl-4-(2-((2-(piperidin-1 -yl)quinazolin-4-yl)amino)ethoxy)benzamide (129)
This compound was prepared according to general method B. 4-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)benzoic acid (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and Me2NH (2.0 M in MeOH, 510 μL, 1.02 mmol, 4.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (70 mg, 55 %). LCMS (acidic mode) Rt 3.98 min, purity 99 %, [M+H]+ calculated 420.24, found 420.25.
1H-NMR (500 MHz, CDCh) d 7.65 - 7.55 (m, 1 H), 7.54 - 7.42 (m, 2H), 7.41 - 7.30 (m, 2H), 7.08 - 6.98 (m, 1 H), 6.96 - 6.82 (m, 2H), 6.42 (s, 1 H), 4.21 (t, J = 5.5 Hz, 2H), 4.00 (app q, J = 5.5 Hz, 2H), 3.90 - 3.78 (m, 4H), 3.11 - 2.94 (m, 6H), 1 .62 (h, J = 5.8 Hz, 6H). 13C-NMR (126 MHz, CDCh) d 171.6, 159.9, 159.8, 157.8, 150.6, 133.0, 129.2, 128.8, 124.7, 121.4, 121.3, 114.3, 110.2, 66.4, 45.3, 40.6, 39.6*, 35.3*, 26.1 , 25.0. 1 carbon signal missing ‘Identified using HMBC. HR-MS m/z [M+H]+ C24H3ON5O2 + calculated 420.2394, found 420.2391 .
Figure imgf000056_0002
N-(2-(4-((dimethylamino)methyl)phenoxy)ethyl)-2-(piperidin-1-yl)quinazolin-4-amine (130)
A solution of compound 129 (65 mg, 0.16 mmol, 1.0 eq) in THF (5 mL) is cooled with ice. Next, LAH was added (2.0 M in THF, 317 μL, 0.640 mmol, 4.0 eq) dropwise. The reaction mixture was heated at 60 °C until full conversion of the starting material was observed by LCMS. The reaction mixture was cooled to rt, carefully quenched with H20 (CAUTION: H2 gas formation) and filtered over Celite. The filtrate was diluted with an aqueous solution of NaOH (2.0 M) and extracted with EtOAc (1x). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The crude material was purified by reverse column chromatography (H20, ACN 0-50% with 0.1 % formic acid). The product fractions were combined and extracted with EtOAc and 1.0 M aq. NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (44 mg, 68 %). LCMS (acidic mode) Rt 2.74 min, purity 99%, [M+H]+ calculated 406.26, found 406.35. 1H-NMR (500 MHz, CDCI3) d 7.54 - 7.42 (m, 3H), 7.25 - 7.21 (m, 2H), 7.07 - 7.01 (m, 1 H), 6.94 - 6.86 (m, 2H), 5.90 (s, 1 H), 4.24 (t, J = 5.1 Hz, 2H), 4.03 (app q, J = 5.3 Hz, 2H), 3.91 - 3.84 (m, 4H), 3.39 (s, 2H), 2.23 (s, 6H), 1.69 - 1.60 (m, 6H). 13C-NMR (126 MHz, CDCI3) d 159.8*, 158.0, 157.4*, 132.7, 130.6, 130.6*, 130.4*, 120.8, 114.5, 110.3, 66.7, 63.7, 45.2, 45.1 , 40.7, 26.2, 25.2. ‘Identified using HMBC. HR-MS m/z [M+H]+ C24H32N5CF calculated 406.2602, found 406.2610.
Figure imgf000057_0001
2-(piperidin-1 -yl)-N-(2-(4-(pyrrolidin-1 -ylmethyl)phenoxy)ethyl)quinazolin-4-amine (131 )
A solution of the corresponding amide (compound 135, 71 mg, 0.16 mmol, 1.0 eq) in THF (5 mL) was cooled with ice. Next, LAH (2.0 M, 317 mL, 0.640 mmol, 4.0 eq) was added dropwise. The reaction mixture was heated at 60 °C until full conversion of the starting material was observed by LCMS. The reaction mixture was cooled to rt, carefully quenched with H2O (CAUTION: H2 gas formation) and filtered over Celite. The filtrate was diluted with an aqueous solution of NaOH (2.0 M ) and extracted with EtOAc (1x). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The crude material was purified by reverse column chromatography (H2O, ACN 0-50% with 0.1% formic acid). The product fractions were combined and extracted with EtOAc and an aqueous solution of NaOH (1.0 M). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (60 mg, 81 %). LCMS (acidic mode) Rt 2.99 min, purity 97%, [M+H]+ calculated 432.28, found 432.35. 1H-NMR (500 MHz, CDCI3) d 7.54 - 7.40 (m, 3H), 7.29 - 7.22 (m, 3H), 7.03 (ddd, J = 8.2, 6.6, 1.4 Hz, 1 H), 6.94 - 6.86 (m, 2H), 5.89 (t, J = 5.5 Hz, 1 H), 4.23 (t, J = 5.2 Hz, 2H), 4.02 (app q, J = 5.3 Hz, 2H), 3.93 - 3.83 (m, 4H), 3.58 (s, 2H), 2.59 - 2.40 (m, 4H), 1 .84 - 1 .73 (m, 4H), 1 .72 - 1 .56 (m, 6H). 13C-NMR (126 MHz, CDCI3) d 159.8, 159.2, 157.9*, 157.9, 152.7, 132.6, 130.4, 126.0, 120.8, 120.7, 114.5, 110.4, 66.7, 60.0, 54.1 , 45.1 , 40.6, 26.2, 25.2, 23.5. ‘Identified using HMBC.HR-MS m/z [M+H]+ C26H34N50+ calculated 432.2758, found 432.2763.
Figure imgf000057_0002
4-(2-((2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)benzamide (132)
This compound was prepared according to general method B. the corresponding acid (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and a solution of Nhh in MeOH (7M, 144 μL, 1 .02 mmol, 4.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (85 mg, 85%). LCMS (acidic mode) Rt 3.12 min, purity 99%, [M+H]+ calculated 392.21 , found 392.25.1H-NMR (500 MHz, DMSO-d6) d 8.03 - 7.97 (m, 1 H), 7.89 - 7.80 (m, 2H), 7.49 (ddd, J = 8.2, 6.8, 1.4 Hz, 1 H), 7.26 (d, J = 8.3 Hz, 1 H), 7.09 - 6.96 (m, 3H), 4.32 (t, J = 6.0 Hz, 2H), 4.14 (s, 2H), 3.96 - 3.85 (m, 2H), 3.82 - 3.72 (m, 4H), 1.69 - 1.57 (m, 2H), 1.55 - 1.43 (m, 4H).13C-NMR (126 MHz, DMSO) d 167.3, 160.8, 159.9, 158.4, 152.0, 132.3, 129.4, 126.6, 126.6, 125.0, 122.7, 120.1 , 113.9, 110.4, 65.7, 44.3, 39.8, 25.5, 24.6. HR-MS m/z [M+H]+ C22H26N5O2 + calculated 392.2081 , found 392.2086.
Figure imgf000058_0001
N-(1-methylpiperidin-4-yl)-4-(2-((2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)benzamide
(133)
This compound was prepared according to general method B. the corresponding acid (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and 1-methylpiperidin-4-amine (63 μL, 0.51 mmol, 2.0 eq) were used. The crude product was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and an aqueous solution of NaOH (1 .0 M). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (101 mg, 89 %). LCMS (acidic mode) Rt 2.72 min, purity 97%, [M+H]+ calculated 489.30, found 489.40. 1H NMR (500 MHz, CDCI3) d 7.74 - 7.68 (m, 2H), 7.53 - 7.44 (m, 3H), 7.04 (ddd, J = 8.0, 6.5, 1.7 Hz, 1 H), 6.98 - 6.91 (m, 2H), 6.01 - 5.87 (m, 2H), 4.27 (t, J = 5.3 Hz, 2H), 4.04 (q, J = 5.3 Hz, 2H), 4.02 - 3.93 (m, 1 H), 3.91 - 3.82 (m, 4H), 2.90 - 2.81 (m, 2H), 2.31 (s, 3H), 2.18 (t, J = 11.2 Hz, 2H), 2.03 (dd, J = 12.2, 3.5 Hz, 2H), 1.61 (ddd, J = 15.8, 10.1 , 3.4 Hz, 8H). 13C NMR (126 MHz, CDCI3) d 166.3, 161.2, 159.7, 158.9, 158.1 , 152.6, 132.6, 128.7, 127.5, 125.9, 120.7, 120.7, 114.3, 110.2, 66.7, 54.5, 46.2, 45.0, 40.4, 38.6, 32.4, 26.0, 25.1. ‘Identified using HMBC. 1 carbon signal missing. Rotamers observed HR-MS m/z [M+H]+ C28H37N6O2 + calculated 489.2973, found 489.2969.
Figure imgf000058_0002
(4-methylpiperazin-1-yl)(4-(2-((2-(piperidin-1-yl)quinazolin-4- yl)amino)ethoxy)phenyl)methanone (134)
This compound was prepared according to general method B. the corresponding acid (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and 1-methylpiperazine (57 μL, 0.51 mmol, 2.0 eq) were used. The crude product was purified by reverse column chromatography (0-50 % ACN in water + 0.1% FA). The product fractions were combined and extracted with EtOAc and an aqueous solution of NaOH (1 .0 M). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a white solid (100 mg, 87 %). Ή NMR (500 MHz, CDCI3) d 7.65 - 7.53 (m, 2H), 7.49 (ddd, J = 8.4, 7.0, 1 .4 Hz, 1 H), 7.41 - 7.32 (m, 2H), 7.10 - 6.99 (m, 1 H), 6.96 - 6.89 (m, 2H), 4.26 (t, J = 5.3 Hz, 2H), 4.03 (q, J = 5.4 Hz, 2H), 3.95 - 3.82 (m, 4H), 3.80 - 3.31 (m, 4H), 2.31 (s, 7H), 1.70 - 1.57 (m, 6H). 13C NMR (126 MHz, CDCI3) d 170.3, 159.9, 159.8, 133.0, 129.3, 128.5, 121.2, 121.2 120.9, 114.5, 110.2, 66.6, 54.9, 46.2, 40.6, 26.1 , 25.0. Four carbon signal could not be detected even after 2D-NMR analysis, rotamers observed. HR-MS m/z [M+H]+ C27H35N6O2 + calculated 475.2816, found 475.2818
Figure imgf000059_0001
(4-(2-((2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)phenyl)(pyrrolidin-1-yl)methanone
(135)
This compound was prepared according to general method B. the corresponding acid (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and pyrrolidine (42.0 μL, 0.510 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (40-100 % EtOAc in cHex) to give a white solid (97 mg, 85 %). LCMS (acidic mode) Rt 3.64 min, purity 98%, [M+H]+ calculated 446.26, found 446.35. 1H-NMR (500 MHz, DMSO-d6) d 8.12 (t, J = 5.5 Hz, 1 H), 7.97 (dd, J = 8.2, 1 .4 Hz, 1 H), 7.51 - 7.44 (m, 3H), 7.25 (dd, J = 8.4, 1 .1 Hz, 1 H), 7.03 (ddd, J = 7.4, 6.7, 1 .2 Hz, 1 H), 7.01 - 6.95 (m, 2H), 4.29 (t, J = 5.9 Hz, 2H), 3.86 (dt, J = 5.7 Hz, 2H), 3.81 - 3.73 (m, 4H), 3.48 - 3.36 (m, 4H), 1.88 - 1.74 (m, 4H), 1.63 - 1.57 (m, 2H), 1.52 - 1.45 (m, 4H).13C-NMR (126 MHz, d6-DMSO) d 167.8, 159.9, 159.5, 158.3, 152.0, 132.3, 129.3, 129.1 , 125.0, 122.7, 120.1 , 113.9, 110.3, 65.6, 49.0, 46.0, 44.3, 39.9, 26.1 , 25.5, 24.6, 23.9. HR-MS m/z [M+H]+ C26H32N5O2 + calculated 446.2551 , found 446.2563.
Figure imgf000059_0002
azepan-1 -yl(4-(2-((2-(piperidin-1 -yl)quinazolin-4-yl)amino)ethoxy)phenyl)methanone (136)
This compound was prepared according to general method B. the corresponding acid (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and azepane (51 mg, 0.51 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (101 mg, 84 %). LCMS (acidic mode) Rt 4.00 min, purity 99 %, [M+H]+ calculated 474.29, found 474.30. 1H-NMR (500 MHz, CDCI3) d 7.95 - 7.85 (m, 2H), 7.56 - 7.47 (m, 2H), 7.24 - 7.16 (m, 3H), 6.83 - 6.78 (m, 2H), 4.13 (t, J = 5.9 Hz, 2H), 4.00 (app q, J = 5.9 Hz, 2H), 3.84 - 3.74 (m, 4H), 3.70 - 3.63 (m, 2H), 3.43 - 3.35 (m, 2H), 1.88 - 1.79 (m, 2H), 1.74 - 1.50 (m, 12H). 13C-NMR (126 MHz, CDCI3) d 172.1 ,
160.1 , 159.3, 140.2, 134.8, 129.4, 128.2, 124.8, 123.1 , 118.7, 114.4, 109.7, 65.5, 50.2, 46.8, 46.4,
41.1 , 29.5, 28.0, 27.4, 26.5, 25.8, 24.1. Rotamers are observed. One carbon signal could not be detected even after 2D NMR analysis. HR-MS m/z [M+H]+ C28H36N5O2 + calculated 474.2864, found 474.2865.
Figure imgf000060_0001
Piperidin-1 -yl(4-(2-((2-(piperidin-1 -yl)quinazolin-4-yl)amino)ethoxy)phenyl)methanone (137)
This compound was prepared according to general method B. the corresponding acid (100 mg, 0.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and piperidine (43 mg, 0.51 mmol, 2.0 eq) were used. The crude product was purified by column chromatography (0-60 % EtOAc in cHex) to give a white solid (101 mg, 86 %). LCMS (acidic mode) Rt 3.88 min, purity 98%, [M+H]+ calculated 460.27, found 460.35. 1H-NMR (500 MHz, DMSO-d6) d 8.11 - 8.03 (m, 1 H), 7.63 - 7.56 (m, 1 H), 7.44 - 7.36 (m, 1 H), 7.34 - 7.29 (m, 2H), 7.22 - 7.14 (m, 1 H), 7.03 - 6.95 (m, 2H), 4.30 (t, J = 5.7 Hz, 2H), 3.90 (app q, J = 5.6 Hz, 2H), 3.84 - 3.74 (m, 4H), 1.66 - 1.42 (m, 12H). 13C NMR (126 MHz, DMSO-d6) d 168.7, 159.7, 159.6
159.1 , 144.5, 133.2#, 128.7, 128.7, 123.1 , 122.8#, 122.2, 121.5, 114.1 , 110.0, 65.5, 44.8, 40.3, 25.3, 24.2, 24.1 , 24.1. # Identified using HSQC. Two carbon signals could not be detected even after 2D-NMR analysis. HR-MS m/z [M+H]+ C27H34N5O2 + calculated 460.2707, found 460.2713.
Figure imgf000060_0002
N,N-dimethyl-4-(2-((2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)benzamide (138)
This compound was prepared according to general method B. the corresponding acid (100 mg,
O.255 mmol, 1.0 eq), HATU (116 mg, 0.306 mmol, 1.2 eq), DIPEA (133 μL, 0.764 mmol, 3.0 eq), DMF (5 mL) and a solution of Me2NH in MeOH (2.0 M, 510 μL, 1 .02 mmol, 4.0 eq) were used. The crude product was purified by column chromatography (0-100 % EtOAc in cHex) to give a white solid (70 mg, 55 %). LCMS (acidic mode) Rt 3.98 min, purity 99 %, [M+H]+ calculated 420.24, found 420.25. 1H-NMR (500 MHz, CDCI3) d 7.65 - 7.55 (m, 1 H), 7.54 - 7.42 (m, 2H), 7.41 - 7.30 (m, 2H), 7.08 - 6.98 (m, 1 H), 6.96 - 6.82 (m, 2H), 6.42 (s, 1 H), 4.21 (t, J = 5.5 Hz, 2H), 4.00 (app q, J = 5.5 Hz, 2H), 3.90 - 3.78 (m, 4H), 3.11 - 2.94 (m, 6H), 1.62 (h, J = 5.8 Hz, 6H). 13C-NMR (126 MHz, CDCI3) d 171.6, 159.9, 159.8, 157.8, 150.6, 133.0, 129.2, 128.8, 124.7, 121.4, 121.3, 114.3, 110.2, 66.4, 45.3, 40.6, 39.6*, 35.3*, 26.1 , 25.0. ‘Identified using HMBC. One carbon signal could not be detected even after 2D-NMR analysis. HR-MS m/z [M+H]+ C24H3oN5O2 + calculated 420.2394, found 420.2391. Intermediates
Figure imgf000061_0001
2-(((benzyloxy)carbonyl)amino)ethyl methanesulfonate
To a stirred and ice-cooled solution of benzyl (2-hydroxyethyl)carbamate (5.00 g, 23.9 mmol, 1.00 eq) in DCM (60 mL), TEA (13.2 mL, 95.2 mmol, 4.00 eq) was added. Methanesulfonyl chloride (4.6 mL, 60 mmol, 2.50 eq) dissolved in DCM (30 mL) was added dropwise while maintaining the internal temperature below 5°C. After addition, the reaction mixture was stirred at rt overnight. The excess of methanesulfonyl chloride mixture was quenched by addition of satd. aq. NaHCC>3 (50 mL). The organic layer was separated and washed with satd. aq. NaHCC>3 (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to afford the title product as a colorless oil (5.70 g, 87 %). LCMS (acidic mode) Rt 3.62 min, purity 96 %, [M+H]+ calculated 274.07, found 274.00. 1H NMR (500 MHz, CDCI3) d 7.33-7.19 (m, 5H), 5.02 (s, 2H), 4.19 (t, J = 5.1 Hz, 2H), 3.44 (q, J = 5.5 Hz, 2H), 2.89 (s, 3H). 13C-NMR (126 MHz, CDCI3) d 156.4, 136.3, 128.7, 128.4, 128.3, 68.7, 67.1 , 40.5, 37.5.
Figure imgf000061_0002
methyl 3-(2-(((benzyloxy)carbonyl)amino)ethoxy)benzoate
This compound was prepared according to general method C. 2-(((Benzyloxy)carbonyl)amino)ethyl methanesulfonate (13 g, 30 mmol, 1.0 eq), DMF (100 mL), CS2CO3 (18 g, 54 mmol, 1.8 eq) and methyl 3-hydroxybenzoate (5.6 g, 36 mmol, 1.2 eq) were used. The crude product was purified by column chromatography (25-65% EtOAc in cHex) to give a white solid (24 g, 98 %). LCMS (acidic mode) Rt 4.54 min, purity 99 %, [M+H]+ calculated 330.13, found 330.00. 1H NMR (500 MHz, CDCI3) d 7.66-7.63 (m, 1 H), 7.55-7.50 (m, 1 H), 7.39-7.29 (m, 6H), 7.09-7.05 (m, 1 H), 5.12 (s, 2H), 4.09 (t, J = 5.1 Hz, 2H), 3.91 (s, 3H), 3.63 (q, J = 5.4 Hz, 2H). 13C-NMR (126 MHz, CDCI3) d 167.0, 158.5, 156.5, 136.4, 131.6, 129.7, 128.7, 128.4, 128.3, 122.6, 119.9, 114.8, 67.2, 67.1 , 52.4, 40.6.
Figure imgf000061_0003
3-(2-(((benzyloxy)carbonyl)amino)ethoxy)benzoic acid
This compound was prepared according to general method D. Methyl 3-(2-(((benzyloxy)carbonyl) amino)ethoxy)benzoate (1.5 g, 4.4 mmol, 1.0 eq), MeOH (30 mL) and 2.0 M NaOH (aq) (10 mL) were used. The product was obtained as a white solid (1 .2 g, 76 %). LCMS (acidic mode) Rt 3.98 min, purity 89 %, [M+H]+ calculated 316.12, found 316.05. 1H NMR (500 MHz, MeOD) d 7.64 - 7.59 (m, 1 H), 7.59 - 7.52 (m, 1 H), 7.42 - 7.22 (m, 6H), 7.16 (dd, J = 8.3, 2.7 Hz, 1 H), 5.09 (s, 2H), 4.08 (t, J = 5.5 Hz, 2H), 3.53 (q, J = 5.2 Hz, 2H). 13C NMR (126 MHz, MeOD) d 169.7, 160.3, 159.3, 138.6, 133.4, 130.6, 129.5, 128.9, 128.8, 123.3, 120.6, 116.3, 68.1 , 67.5, 41.6, 41.5.
Figure imgf000062_0001
benzyl (2-(3-(dimethylcarbamoyl)phenoxy)ethyl)carbamate
This compound was prepared according to general method B. 3-(2- (((Benzyloxy)carbonyl)amino)ethoxy)benzoic acid (1.2 g, 3.3 mmol, 1.0 eq), DMF (20 mL), DIPEA (2.3 mL, 13 mmol, 4.0 eq), HATU (1.9 g, 4.8 mmol, 1.5 eq) and Me2NH (2.0 M in THF, 2.1 mL, 4.2 mmol, 1.3 eq) were used. The product was purified by column chromatography (cHex, 0-70% EtOAc) to give the product as colorless oil (580 mg, 1 .69 mmol, 50%). LCMS (acidic mode) Rt 3.95 min, purity 99 %, [M+H]+ calculated 343.17, found 343.10. 1H-NMR (500 MHz, CDCh) d 7.36-7.26 (m, 6H), 6.97-6.94 (m, 1 H), 6.92-6.86 (m, 2H), 5.39 (t, J = 6.0 Hz, 1 H), 5.09 (s, 2H), 4.01 (t, J = 5.2 Hz, 2H), 3.57 (q, J = 5.5 Hz, 2H), 3.08 (s, 3H), 2.94 (s, 3H). 13C-NMR. (126 MHz, CDCh) d 171.2, 158.4, 156.5, 137.7, 136.4, 129.6, 128.6, 128.2, 128.2, 119.6, 115.7, 113.0, 67.0, 66.9, 40.5, 39.6, 35.3.
Figure imgf000062_0002
benzyl (2-(3-(dimethylcarbamoyl)phenoxy)ethyl)(methyl)carbamate
This compound was prepared according to general method F. Benzyl (3-(2- (dimethylcarbamoyl)phenoxy)ethyl)carbamate (1.5 g, 4.4 mmol, 1.0 eq), THF (5 mL), Mel (1.3 mL, 21 mmol, 5.0 eq) and NaH (508 mg, 12.7 mmol, 3.01 eq) were used. The product was purified by column chromatography (cHex, 0-100% EtOAc) to give the product as a white solid (1 .34 g, 84 %). LCMS (acidic mode) Rt 4.22 min, purity 99%, [M+H]+ calculated= 357.18, found 357.15. 1H NMR (500 MHz, CDCh) d 7.39-7.24 (m, 6H), 6.96 (d, J 7.5, 1.2 Hz, 1 H), 6.94-6.82 (m, 2H), 5.14 (d, J 6.5 Hz, 2H), 4.14 (t, J 5.4 Hz, 1 H), 4.07 (t, J 5.6 Hz, 1 H), 3.72-3.63 (m, 2H), 3.09 (s, 3H), 3.06 (s, 3H), 2.95 (s, 3H). 13C-NMR (126 MHz, CDCh) d 171.36, 158.64, 156.49, 137.81 , 136.82, 129.66, 128.60, 128.09, 127.96, 119.50, 115.70, 113.21 , 67.26, 66.74, 48.95, 39.65, 36.12, 35.41.
Figure imgf000062_0003
N, N-dimethyl-3-(2-(methylamino)ethoxy)benzamide
This compound was prepared according to general method E. Benzyl (3-(2-(dimethylcarbamoyl) phenoxy)ethyl)(methyl)carbamate (906 mg, 2.54 mmol, 1.0 eq), MeOH (45 mL) and Pd/C (90 mg) were used. The title compound was obtained as a colorless oil (520 mg, 82 %). LCMS (acidic mode) Rt 2.15 min, purity 99%, [M+H]+ calculated= 223.14, found 223.00. 1H-NMR (500 MHz, CDCI3) d 7.32-7.26 (m, 1 H), 6.98-6.90 (m, 3H), 4.07-4.05 (m, 2H), 3.09 (s, 3H), 3.00-2.92 (m, 5H), 2.50 (s, 3H). 13C-NMR (126 MHz, CDCI3) d 171.5, 158.9, 137.8, 129.6, 119.4, 116.0, 113.1 , 67.4, 50.9, 39.7, 36.5, 35.4.
Figure imgf000063_0001
3-(2-aminoethoxy)-N , N-dimethylbenzamide
This compound was prepared according to general method E. Benzyl (3-(2-(dimethylcarbamoyl) phenoxy)ethyl)carbamate (788 mg, 2.30 mmol, 1.0 eq), MeOH (41 mL) and Pd/C (79 mg) were used. The title compound was obtained as a colorless oil (398 mg, 83 %). LCMS (acidic mode) Rt 1.85 min, purity 96%, [M+H]+ calculated 209.13, found 209.00. 1H-NMR (500 MHz, CDCI3) d 7.29 (td, J = 7.5, 1.2 Hz, 1 H), 6.99-6.91 (m, 3H), 3.99 (t, J = 5.1 Hz, 2H), 3.14-3.04 (m, 5H), 2.97 (s, 3H). 13C-NMR (126 MHz, CDCI3) d 171.4, 158.9, 137.7, 129.6, 119.4, 116.0, 113.0, 70.3, 41.6, 39.6, 35.4.
Figure imgf000063_0002
benzyl (2-(3-(pyrrolidine-1 -carbonyl)phenoxy)ethyl)carbamate
This compound was prepared according to general method B. 3-(2- (((Benzyloxy)carbonyl)amino)ethoxy)benzoic acid (1.2 g, 3.3 mmol, 1.0 eq), DMF (20 mL), DIPEA (2.3 mL, 13 mmol, 4.0 eq), HATU (1 .9 g, 4.8 mmol, 1 .5 eq) and pyrrolidine (0.34 mL, 4.2 mmol, 1 .3 eq) were used. The crude product was purified by column chromatography (25-65% EtOAc in cHex) to give a white solid (1.3 g, 93 %). LCMS (acidic mode) Rt 4.19 min, purity 99%, [M+H]+ calculated= 369.18, found 369.15. 1H NMR (500 MHz, Methanol-d4) δ 7.36-7.24 (m, 6H), 7.07- 6.97 (m, 3H), 5.07 (s, 2H), 4.04 (t, J = 5.5 Hz, 2H), 3.55 (t, J = 7.0 Hz, 2H), 3.50 (t, J = 5.5 Hz, 2H), 3.39 (t, J = 6.7 Hz, 2H), 1.94 (p, 2H), 1.88-1.81 (m, 2H). 13C-NMR (126 MHz, CD3OD) d 171.43, 160.06, 158.89, 139.23, 138.24, 130.75, 129.41 , 128.91 , 128.71 , 120.31 , 117.39, 114.10, 67.96, 67.40, 50.77, 41.31 , 25.23.
Figure imgf000063_0003
(3-(2-aminoethoxy)phenyl)(pyrrolidin-1-yl)methanone
This compound was prepared according to general method E. Benzyl (3-(2-(pyrrolidine-1- carbonyl)phenoxy)ethyl)carbamate (2.0 g, 5.43 mmol, 1.0 eq), MeOH (41 mL) and Pd/C (79 mg) were used. The title compound was obtained as a colorless oil (1 .25 g, 98 %). LCMS (acidic mode) Rt 2.33 min, purity 99%, [M+H]+ calculated= 235.30, found 235.05. 1H-NMR (500 MHz, CDCI3) d 7.30-7.26 (m, 1 H), 7.07-7.02 (m, 2H), 6.93 (ddd, J = 8.3, 2.6, 1 .0 Hz, 1 H), 4.00 (t, J = 5.1 Hz, 2H), 3.61 (t, J = 7.0 Hz, 2H), 3.40 (t, J = 6.7 Hz, 2H), 3.07 (t, J = 5.1 Hz, 2H), 1.99-1.89 (m, 2H), 1.90- 1.82 (m, 2H). 13C-NMR. 13C-NMR (126 MHz, CDCI3) d 169.5, 158.8, 138.6, 129.5, 119.5, 116.3, 113.1 , 69.7, 49.7, 46.3, 41.3, 26.4, 24.5.
Figure imgf000064_0001
methyl 4-(2-(((benzyloxy)carbonyl)amino)ethoxy)benzoate
This compound was prepared according to general method C. 2-(((E3enzyloxy)carbonyl)amino)ethyl methanesulfonate (13 g, 30 mmol, 1.0 eq), DMF (100 mL), CS2CO3 (18 g, 54 mmol, 1.8 eq) and methyl 4-hydroxybenzoate (5.6 g, 36 mmol, 1.2 eq) were used. The crude product was purified by column chromatography (25-65% EtOAc in cHex) to give a white solid (20.8 g, 85 %). LCMS (acidic mode) Rt 4.59 min, purity 91 %, [M+H]+ calculated 330.13, found 330.15 [M+H]+. 1H NMR (500 MHz, CDCI3) d 7.66-7.63 (m, 1 H), 7.55-7.50 (m, 1 H), 7.39-7.29 (m, 6H), 7.09-7.05 (m, 1 H), 5.12 (s, 2H), 4.09 (t, J 5.1 Hz, 2H), 3.91 (s, 3H), 3.63 (q, J 5.4 Hz, 2H). 13C-NMR (126 MHz, CDCI3) d 167.0, 158.5, 156.5, 136.4, 131.6, 129.6, 128.7, 128.4, 128.3, 122.6, 119.9, 114.8, 67.2, 67.1 , 52.4, 40.6.
Figure imgf000064_0002
4-(2-(((benzyloxy)carbonyl)amino)ethoxy)benzoic acid
This compound was prepared according to general method D. Methyl 4-(2-(((benzyloxy)carbonyl) amino)ethoxy)benzoate (1.5 g, 4.4 mmol, 1.0 eq), MeOH (30 mL) and 2.0 M NaOH (aq) (10 mL) were used. The product was obtained as a white solid (1.1 g, 70 %). LCMS (acidic mode) Rt 4.02 min, purity 89 %, [M+H]+ calculated 316.12, found 316.05. 1H-NMR (500 MHz, CDCI3) d 7.90-7.84 (m, 2H), 7.53 (t, J = 5.7 Hz, 1 H), 7.41-7.26 (m, 5H), 7.05-6.95 (m, 2H), 5.03 (s, 2H), 4.06 (t, J = 5.6 Hz, 2H), 3.39 (q, J = 5.6 Hz, 2H). 13C-NMR (126 MHz, CDCI3) d 167.0, 167.0, 162.0, 156.3, 137.1 , 131.4, 128.4, 127.8, 127.8, 123.1 , 114.3, 66.6, 65.4.
Figure imgf000064_0003
benzyl (2-(4-(dimethylcarbamoyl)phenoxy)ethyl)carbamate
This compound was prepared according to general method B. 4-(2- (((Benzyloxy)carbonyl)amino)ethoxy)benzoic acid (1.2 g, 3.3 mmol, 1.0 eq), DMF (20 mL), DIPEA (2.3 mL, 13 mmol, 4.0 eq), HATU (1.9 g, 4.8 mmol, 1.5 eq) and Me2NH (2.0 M in THF, 2.1 mL, 4.2 mmol, 1.3 eq) were used. The product was purified by column chromatography (cHex, 0-70% EtOAc) to give the product as a white solid (539 mg, 49%). LCMS (acidic mode) Rt 3.98 min, purity 89 %, [M+H]+ calculated 343.17, found 343.05. 1H-NMR (500 MHz, d6-DMSO) 7.39-7.29 (m, 7H), 7.00-6.93 (m, 2H), 5.03 (s, 2H), 4.03 (t, J = 5.7 Hz, 2H), 3.43-3.36 (m, 2H), 2.94 (s, 6H). 13C-NMR
(126 MHz, d6-DMSO) δ 169.9, 159.2, 156.3, 137.1, 129.1 , 128.6, 128.4, 127.8, 127.8, 114.0, 66.4, 65.4. One carbon signal is not visible.
Figure imgf000065_0001
4-(2-aminoethoxy)-N,N-dimethylbenzamide
This compound was prepared according to general method E. Benzyl (4-(2-(dimethylcarbamoyl) phenoxy)ethyl)carbamate (788 mg, 2.30 mmol, 1.0 eq), MeOH (41 mL) and Pd/C (79 mg) were used. The title compound was obtained as a colorless oil (380 mg, 79 %). LCMS (acidic mode) Rt 2.17 min, 99%, [M+H]+ calculated= 209.13, found 209.05. 1H-NMR (500 MHz, d6-DMSO) d 7.43- 7.34 (m, 2H), 7.01-6.96 (m, 2H), 4.15 (t, J = 5.2 Hz, 2H), 3.17 (t, J = 5.2 Hz, 2H), 2.98-2.92 (m, 6H). 13C-NMR. (126 MHz, d6-DMSO) d 169.8, 129.0, 126.7, 120.8, 120.7, 114.0, 64.9, 40.9, 37.7, 34.0.
Figure imgf000065_0002
benzyl (2-(4-(dimethylcarbamoyl)phenoxy)ethyl)(methyl)carbamate
This compound was prepared according to general method F. Benzyl (4-(2- (dimethylcarbamoyl)phenoxy)ethyl)carbamate (1.5 g, 4.4 mmol, 1 eq), THF (5 mL), Mel (1.3 mL, 21 mmol, 5.0 eq) and NaH (508 mg, 12.7 mmol, 3.01 eq) were used. The product was purified by column chromatography (cHex, 0-100% EtOAc) to give the product as white solid (1.48 g, 93 %). LCMS (acidic mode) Rt 4.15 min, purity 99%, [M+H]+ calculated= 357.18, found 357.15. 1H NMR (500 MHz, d6-DMSO) d 7.40-7.28 (m, 7H), 7.00-6.89 (m, 2H), 5.07 (d, J = 6.7 Hz, 2H), 4.14 (t, J = 5.6 Hz, 2H), 3.67-3.58 (m, 2H), 3.01-2.86 (m, 9H). 13C-NMR (126 MHz, d6-DMSO) d 169.9, 159.1 , 159.0, 155.6, 155.4, 137.0, 129.1 , 128.6, 128.4, 127.8, 127.6, 127.5, 114.0, 113.9, 66.3, 66.2, 65.5, 47.9, 47.2, 35.1 , 35.0.
Figure imgf000065_0003
N,N-dimethyl-4-(2-(methylamino)ethoxy)benzamide This compound was prepared according to general method E. Benzyl (4-(2-(dimethylcarbamoyl) phenoxy)ethyl)(methyl)carbamate (906 mg, 2.54 mmol, 1 eq), MeOH (45 mL) and (Pd/C (90 mg) were used. The title compound was obtained as a colorless oil (488 mg, 86%). LCMS (acidic mode) Rt 2.15 min, purity 99%, [M+H]+ calculated= 223.14, found 223.00. 1H NMR (500 MHz, d6- DMSO) d 7.39-7.32 (m, 2H), 7.01-6.90 (m, 2H), 4.04 (t, J = 5.6 Hz, 2H), 2.94 (s, 6H), 2.83 (t, J = 5.6 Hz, 2H), 2.33 (s, 3H). 13C-NMR (126 MHz, d6-DMSO) d 170.4, 159.9, 129.5, 128.8, 114.4, 67.6, 50.6, 36.5.
Figure imgf000066_0001
methyl 2-(2-(((benzyloxy)carbonyl)amino)ethoxy)benzoate
This compound was prepared according to general method C. 2-(((E3enzyloxy)carbonyl)amino)ethyl methanesulfonate (13 g, 30 mmol, 1.0 eq), DMF (100 mL), CS2CO3 (18 g, 54 mmol, 1.8 eq) and methyl 2-hydroxybenzoate (5.6 g, 36 mmol, 1.2 eq) were used. The crude product was purified by column chromatography (25-65% EtOAc in cHex) to give a white solid (20.0 g, 82 %). LCMS (acidic mode) Rt 4.54 min, purity 99 %, [M+H]+ calculated 330.13, found 330.00. 1H NMR (500 MHz, CDCI3) d 7.82 (dd, J = 7.8, 1.8 Hz, 1 H), 7.49-7.43 (m, 1 H), 7.38-7.27 (m, 5H), 7.03-6.99 (m, 1 H), 6.97-6.93 (m, 1 H), 6.03 (t, J = 5.8 Hz, 1 H), 5.12 (s, 2H), 4.14 (t, J = 5.0 Hz, 2H), 3.87 (s, 3H), 3.64 (q, J = 5.3 Hz, 2H). 13C-NMR (126 MHz, CDCI3) d 166.6, 158.5, 156.7, 136.8, 133.9, 131.9, 128.6, 128.1 , 128.1 , 121.1 , 120.4, 114.3, 68.7, 66.7, 52.2, 40.5.
Figure imgf000066_0002
2-(2-(((benzyloxy)carbonyl)amino)ethoxy)benzoic acid
This compound was prepared according to general method D. Methyl 2-(2-(((benzyloxy)carbonyl) amino)ethoxy)benzoate (1.5 g, 4.4 mmol, 1.0 eq), MeOH (30 mL) and 2.0 M NaOH (aq) (10 mL) were used. The product was obtained as a white solid (1 .2 g, 76 %). LCMS (acidic mode) Rt 3.98 min, purity 89 %, [M+H]+ calculated 316.12, found 316.05. 1H NMR (500 MHz, CDCI3) d 8.07-8.01 (m, 1 H), 7.54-7.44 (m, 1 H), 7.36-7.25 (m, 5H), 7.09-7.03 (m, 1 H), 7.01-6.90 (m, 1 H), 5.83-5.70 (m, 1 H), 5.19-5.07 (m, 2H), 4.26-4.11 (m, 2H), 3.70-3.57 (m, 2H). 13C-NMR (126 MHz, CDCI3) d 167.7, 158.1 , 156.9, 136.4, 135.0, 133.5, 128.6, 128.2, 128.1 , 121.9, 118.5, 113.4, 68.8, 67.0, 40.4.
Figure imgf000066_0003
benzyl (2-(2-(dimethylcarbamoyl)phenoxy)ethyl)carbamate
This compound was prepared according to general method B. 2-(2- (((Benzyloxy)carbonyl)amino)ethoxy)benzoic acid (1.2 g, 3.3 mmol, 1.0 eq), DMF (20 mL), DIPEA (2.3 mL, 13 mmol, 4.0 eq), HATU (1.9 g, 4.8 mmol, 1.5 eq) and Me2NH (2.0 M in THF, 2.1 mL, 4.2 mmol, 1.3 eq) were used. The product was purified by column chromatography (cHex, 0-70% EtOAc) to give the product as a white solid (680 mg, 1.69 mmol, 62%). LCMS (acidic mode) Rt
3.98 min, purity 97 %, [M+H]+ calculated 343.17, found 343.05. 1H NMR (500 MHz, d6-DMSO -d6) d 7.43-7.39 (m, 1 H), 7.38-7.29 (m, 5H), 7.15 (dd, J = 7.4, 1.8 Hz, 1 H), 7.07 (dd, J = 8.4, 0.9 Hz, 1 H),
6.98 (td, J = 7.4, 0.9 Hz, 1 H), 5.03 (s, 2H), 4.03 (t, J = 5.7 Hz, 2H), 3.38-3.35 (m, 2H), 2.93 (s, 3H), 2.72-2.69 (m, 3H). 13C-NMR (126 MHz, d6-DMSO) d 167.88, 156.25, 153.98, 137.12, 130.23,
128.42, 127.87, 127.85, 127.83, 126.65, 120.92, 112.34, 66.70, 65.37, 39.85, 37.43, 33.98.
Figure imgf000067_0001
benzyl (2-(2-(dimethylcarbamoyl)phenoxy)ethyl)(methyl)carbamate
This compound was prepared according to general method F. Benzyl (2-(2- (dimethylcarbamoyl)phenoxy)ethyl)carbamate (1.5 g, 4.4 mmol, 1 eq), THF (5 mL), Mel (1.3 mL, 21 mmol, 5.0 eq) and NaH (508 mg, 12.7 mmol, 3.01 eq) were used. The product was purified by column chromatography (cHex, 0-100% EtOAc) to give the product as white solid (1.57 g, 99 %). LCMS (acidic mode) Rt 4.15 min, purity98%, [M+H]+ calculated= 357.18, found 357.15. 1H NMR (500 MHz, d6-DMSO-d6) d 7.37-7.28 (m, 6H), 7.16-7.13 (m, 1 H), 7.09-6.97 (m, 2H), 5.11-5.03 (m, 2H), 4.11 (t, J = 5.5 Hz, 2H), 3.66-3.53 (m, 2H), 2.95-2.89 (m, 6H). 13C-NMR (126 MHz, d6- DMSO) d 167.9, 155.5, 155.3, 153.9, 153.8, 137.0, 136.9, 130.2, 130.2, 128.5, 128.5, 127.9, 127.7, 127.6, 127.6, 126.5, 126.5, 121.0, 120.9, 112.0, 111.9, 66.4, 66.4, 66.2, 66.1 , 48.1 , 47.5, 38.3, 37.4, 37.4, 35.5, 35.1 , 34.0.
Figure imgf000067_0002
2-(2-aminoethoxy)-N,N-dimethylbenzamide
This compound was prepared according to general method E. Benzyl (2-(2-(dimethylcarbamoyl) phenoxy)ethyl)carbamate (788 mg, 2.30 mmol, 1.0 eq), MeOH (41 mL) and Pd/C (79 mg) were used. The title compound was obtained as a colorless oil (244 mg, 51 %). LCMS (acidic mode) Rt 2.15 min, purity 99%, [M+H]+ calculated= 209.13, found 209.05. 1H NMR (500 MHz, d6-DMSO) d 7.37-7.33 (m, 1 H), 7.16-7.13 (m, 1 H), 7.08-7.05 (m, 1 H), 6.99-6.96 (m, 1 H), 4.06-3.94 (m, 2H), 2.97-2.95 (m, 3H), 2.84-2.80 (m, 2H), 2.76 (s, 3H), 0.97 (d, J = 6.2 Hz, 2H). 13C-NMR (126 MHz, d6-DMSO) d 168.1 , 154.3, 154.2, 130.2, 127.6, 127.6, 126.7, 120.8, 120.7, 112.6, 112.5, 70.6, 68.3, 47.8, 45.6, 40.9, 37.7, 37.7, 34.0, 23.0.
Figure imgf000068_0001
N,N-dimethyl-2-(2-(methylamino)ethoxy)benzamide
This compound was prepared according to general method E. Benzyl (2-(2-(dimethylcarbamoyl) phenoxy)ethyl)(methyl)carbamate (906 mg, 2.54 mmol, 1 eq), MeOH (45 mL) and Pd/C (90 mg) were used. The title compound was obtained as a colorless oil (509 mg, 90 %). LCMS (acidic mode) Rt 2.19 min, purity 99%, [M+H]+ calculated= 223.14, found 223.00. 1H NMR (500 MHz, CDCI3) d 7.30-7.26 (m, 1 H), 7.19-7.15 (m, 1 H), 6.96-6.92 (m, 1 H), 6.91-6.84 (m, 1 H), 4.09-4.02 (m, 2H), 3.06-3.02 (m, 3H), 2.89 (t, J = 5.1 Hz, 2H), 2.83-2.80 (m, 3H), 2.40 (s, 3H), 1.92 (s, 1 H). 13C-NMR (126 MHz, CDCI3) d 169.6, 154.6, 154.6, 130.5, 130.4, 128.0, 127.8, 126.4, 126.3, 121.2, 121 .0, 112.4, 111 .8, 67.6, 67.1 , 53.9, 50.6, 41 .2, 38.6, 38.4, 36.2, 34.7.
Figure imgf000068_0002
3-(2-((2-(piperidin-1-yl)quinazolin-4-yl)amino)ethoxy)benzoic acid (Intermediate compound 63)
This compound was prepared according to general method D. compound (59) (1 g, 2.46 mmol, 1 .0 eq), 2.0 M NaOH (aq) (2.5 mL), MeOH (10 mL). The title compound was obtained as a white solid (0.95 g, 97%). LCMS (acidic mode) Rt 3.68 min, purity 99 %, [M+H]+ calculated 393.19, found 393.15. 1H-NMR (500 MHz, d6-DMSO) d 9.72 (s, 1 H), 8.33 (dd, J = 8.3, 1.3 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.76 (ddd, J = 8.5, 7.0, 1 .3 Hz, 1 H), 7.52 (dt, J = 7.6, 1 .3 Hz, 1 H), 7.44 (dd, J = 2.7, 1 .5 Hz, 1 H), 7.39 (q, J = 8.1 Hz, 2H), 7.23-7.17 (m, 1 H), 4.36 (t, J = 5.5 Hz, 2H), 3.96 (q, J = 5.5 Hz, 2H), 3.90-3.82 (m, 4H), 1.73-1.46 (m, 6H). 13C-NMR (126 MHz, d6-DMSO) d 167.1, 159.5, 158.3, 151.8, 141.9, 134.7, 132.2, 129.9, 124.2, 123.9, 121.9, 119.5, 118.1 , 114.6, 109.6, 65.4, 46.0, 40.8, 25.3, 23.7. HR-MS m/z [M+H]+ C22H25N4O+ calculated 393.1912, found 393.1914. Appendix 1 Pharmacological data with lUPAC naming
Rating pK, 5-5.7 = +, pK, >5.7 = ++, pKi>6.4 = +++
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001

Claims

1 . A compound of formula (I):
Figure imgf000072_0001
R1 and R2 are independently selected from H, C1-C6 alkyl, C3-C12 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -0-(C0)-R’, -(CO)-O- R\ -(CO)-NR”R"' -NR”-(CO)-R', and -NR”R"';
Or R1 and R2, together with the N or C atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, a C3-C6 cycloalkyl, an aryl having 6 to 10 ring atoms, or a heteroaryl having 5 to 10 ring atoms, said heterocyclyl, cycloalkyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, , -(CO)-R’, -0-(C0)-R’, - (CO)-O-R’, -(CO)-NR”R"', -NR”-(CO)-R', and -NR”R"';
R3 is present or absent when the C atom forms a double bond, and if present, R3 is selected from H and C1-C6 alkyl;
X is N or CH, preferably X is N;
Ring A is aromatic, and is selected from the group consisting of aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said aryl and heteroaryl being optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -0-(C0)-R’, -(CO)-O- R', -(CO)-NR”R"' -NR”-(CO)-R’, and -NR"R"';
Y is O or NR; wherein R is H or an organyl group, preferably Y is NR;
L is a divalent linker selected from the group consisting of C1-C12 alklylene or heteroalkylene, said alkylene and heteroalkylene being optionally interspersed with one or more groups selected from - (C3-C6 cycloalkyl)-, and -(heterocyclyl having 5 to 10 ring atoms)-, and said alkylene, heteroalkylene, cycloalkyl and heterocyclyl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, , -(CO)-R’, -0-(C0)-R’, -(CO)- O-R’, -(CO)-NR”R"', -NR”-(CO)-R’, and -NR”R"';
Ring B is a ring selected from the group consisting of C3-C12 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, , -(CO)-R’, -0-(C0)-R’, -(CO)- O-R', -(CO)-NR”R"' -NR”-(CO)-R’, -NR”R"', -(C1-C6 alkyl)-NR”R"', and -(C1-C6 alkyl)-OH;
R’ is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms;
R” and R"' are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, -(C1-C6 alkyl)-(heterocyclyl having 5 to 10 ring atoms), said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, and C1-C6 alkyl;
Or R” and R"', together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, or a heteroaryl having 5 to 10 ring atoms, said heterocyclyl, and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, - OH, -NO2, -CN, and C1-C6 alkyl, and pharmaceutically acceptable salts, solvates and esters thereof.
2. Compound according to claim 1 , wherein said compound is a modulator of ACKR3.
3. Compound according to claim 1 or 2, wherein said compound is binding to ACKR3 as measured with a displacement assay using a tritium compound of the following formula:
Figure imgf000073_0001
4. Compound according to claim 3, wherein said compound has a pK, greater than or equal to 5.0 as measured by the displacement assay.
5. Compound according to any of claims 1 to 4, wherein the compound is a compound of formula (II):
Figure imgf000074_0001
Wherein
Ring A, Y, L and ring B are as defined in claim 1 ;
Each R4 is independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, , -(CO)-R’, -0-(C0)-R’, -(CO)- O-R’, -(CO)-NR”R"' -NR”-(CO)-R’, and -NR”R"';
R’, R”, and R"' are as defined in claim 1 ; m is an integer between 0 and 5, and preferably m is 0 or 1 .
6. Compound (I) according to any of claims 1 to 5, wherein the compound is a compound of formula (III)
Figure imgf000074_0002
Wherein
Y, L and ring B are as defined in claim 1 ;
R4 and m are as defined in claim 5;
Each R5 is independently selected from halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R', -0-(C0)-R’, -(CO)-O-R’, - (CO)-NR”R"' -NR"-(CO)-R', and -NR"R"';
R’, R”, and R"' are as defined in claim 1 ; n is an integer between 0 and 4, and preferably n is 0, 1 or 2.
7. Compound (I) according to any of claims 1 to 6, wherein the compound is a compound of formula (IV)
Figure imgf000075_0001
Wherein L and ring B are as defined in claim 1 ;
R4 and m are as defined in claim 5;
R5 and n are as defined in claim 6;
R is H or an organyl group selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, and heteroaryl having 5 to 10 ring atoms, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(CO)-R’, -O- (CO)-R’, -(CO)-O-R’, -(CO)-NR”R"' -NR”-(CO)-R', and -NR”R"'; R’, R”, and R"' are as defined in claim 1 .
8. Compound (I) according to any of claims 1 to 7, wherein the compound is a compound of formula (V)
Figure imgf000075_0002
Wherein
L is as defined in claim 1 ;
R4 and m are as defined in claim 5; R5 and n are as defined in claim 6; R is as defined in claim 1 or 7; Each R6 is selected from halogen, -OH, -NO2, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, Ci- C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, , -(CO)-R’, -O-(CO)-R’, -(CO)-O-R’, -(CO)-NR”R"', - NR”-(CO)-R’ -NR”R"', -(C1-C6 alkyl)-NR”R"', and -(C1-C6 alkyl)-OH; R’, R”, and R"' are as defined in claim 1 ; p is an integer between 0 and 5, preferably p is 1 .
9. Compound according to any of claims 1 to 8, wherein the compound is a compound of formula (VI)
Figure imgf000076_0001
Wherein
R4 and m are as defined in claim 5; R5 and n are as defined in claim 6; R is as defined in claim 1 or 7; R6 and p are as defined in claim 8.
10. Compound according to any of claims 1 to 9, wherein the compound is a compound of formula (VII)
Figure imgf000076_0002
Wherein
R4 and m are as defined in claim 5;
R5 and n are as defined in claim 6;
R7 and R8 are independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl having 5 to 10 ring atoms, aryl having 6 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, -(C1-C6 alkyl)-(heterocyclyl having 5 to 10 ring atoms), said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, -OH, -NO2, -CN, and C1-C6 alkyl;
Or R7 and R8, together with the N atom to which they are linked, form a heterocycle having 5 to 10 ring atoms, or a heteroaryl having 5 to 10 ring atoms, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from oxo, halogen, - OH, -NO2, -CN, and C1-C6 alkyl.
11 . Compound according to claim 1 , wherein the compound is selected from
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
12. Pharmaceutical composition comprising a compound according to any of claims 1 to 11 and a pharmaceutically acceptable carrier
13. Compound according to any of claims 1 to 11 , for use as a drug.
14. Compound according to any of claims 1 to 11, for use in treating cancer, autoimmune disorders, inflammatory diseases, transplant rejection, fibrosis or pain.
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Citations (2)

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