# US 8,772,272 B2 · Pyrido-and pyrimidopyrimidine derivatives as anti-proliferative agents

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- Number: US 8,772,272 B2
- Document ID: US8772272B2
- Status: Granted
- Kind: B2
- Application number: 12/724,203
- Filed: 2010-03-15
- Published: 2010-07-08
- Granted: 2014-07-08
- Earliest claimed: 2003-12-18
- Assignees: Janssen Pharmaceutica NV
- Applicants: Eddy Jean Edgard Freyne; Marc Willems; Pierre Henri Storck; Virginie Sophie Poncelet; Kristof Van Emelen; Peter Jacobus Johnnes Antonius Buijnsters; Werner Constant Johan Embrechts; Timothy Pietro Suren Perera
- Inventors: Eddy Jean Edgard Freyne; Marc Willems; Pierre Henri Storck; Virginie Sophie Poncelet; Kristof Van Emelen; Peter Jacobus Johnnes Antonius Buijnsters; Werner Constant Johan Embrechts; Timothy Pietro Suren Perera
- Web page: https://patentgrep.com/patent/US8772272B2

## CPC

- C07D 498/16: Peri-condensed systems
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 487/16: Peri-condensed systems
- C07D 487/22: in which the condensed system contains four or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein a1-a2=a3-a4 represents a divalent radical selected from N—CH═CH—CH, N—CH═N—CH or CH—CH═N—CH; Z represents NH; Y represents —C3-9alkyl-, —C1-5alkyl-NR13—C1-5alkyl-, —C1-6alkyl-NH—CO— or —CO—NH—C1-6alkyl-; X1 represents —O— or —NR11—; X2 represents —C1-2alkyl-, —O—C1-2alkyl, —O— or —O—CH2—; R1 represents hydrogen or halo; R2 represents hydrogen, cyano, halo, hydroxycarbonyl-, C1-4alkyloxycarbonyl-, Het16-carbonyl- or Ar5; R3 represents hydrogen; R4 represents hydroxy, C1-4alkyloxy-, Ar4—C1-4alkyloxy or R4 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het2-; R11 represents hydrogen; R12 represents hydrogen, C1-4alkyl- or C1-4alkyl-oxy-carbonyl-; R13 represents Het14-C1-4alkyl, in particular morpholinyl-C1-4alkyl; Het2 represents a heterocycle selected from morpholinyl or piperidinyl optionally substituted with C1-4alkyl-, preferably methyl; Het14 represents morpholinyl; Het16 represents a heterocycle selected from morpholinyl or pyrrolidinyl; Ar4 represents phenyl; Ar5 represents phenyl optionally substituted with cyano.

## Claims

### Claim 1

A compound having the formula
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
a1-a2=a3-a4 represents a divalent radical selected from N—CH═CH—CH or N—CH═N—CH;
Y represents —C3-9alkyl-, —C1-5alkyl-NR13—C1-5alkyl-, —C1-6alkyl-NH—CO— or —CO—NH —C1-6alkyl-;
R1 represents hydrogen or halo;
R2 represents hydrogen, cyano, halo, hydroxycarbonyl-, C1-4alkyloxycarbonyl-, Het16-carbonyl- or Ar5;
R4 represents hydroxy, C1-4alkyloxy-, Ar4—C1-4alkyloxy or R4 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy- or Het2-;
R11 represents hydrogen;
R13 represents Het14-C1-4alkyl;
Het2 represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl wherein said Het2 is optionally substituted with one or where possible two or more substituents selected from hydroxy, amino or C1-4alkyl-;
Het14 represents morpholinyl;
Het16 represents a heterocycle selected from morpholinyl or pyrrolidinyl;
Ar4 represents phenyl;
Ar5 represents phenyl optionally substituted with cyano.

### Claim 2

A process for preparing a compound of formula (I)
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
a1-a2=a3-a4 represents a divalent radical selected from N—CH═CH—CH, N—CH═N—CH or CH—CH═N—CH;
Z represents O, NH or S;
Y represents —C3-9alkyl-, —C3-9alkenyl-, —C 1-5alkyl-oxy-C1 -5alkyl-, —C1-5alkyl-NR13—C1-5alkyl-, —C1-5alkyl-NR14—CO—C1-5alkyl-, —C1-5alkyl-CO—NR15—C1-5alkyl-, —C1-6alkyl-CO—NH—, —C1-6alkyl-NH—CO—, —CO—NH—C1-6alkyl-, —NH—CO—C1-6alkyl-, —CO—C1-7alkyl-, —C1-7alkyl-CO—, C1-6alkyl-CO—C1-6alkyl;
X1 represents a direct bond, O, —O—C1-2alkyl-, CO, —CO—C1-2alkyl-, NR11, —NR11—C1-2alkyl-, NR16—CO—, NR16—CO—C1-2alkyl-, —O—N═CH— or C1-2alkyl;
X2 represents a direct bond, O, —O—C1-2alkyl-, CO, —CO—C1-2alkyl-, NR12, NR12—C1-2alkyl-, NR17—CO—, NR17—CO—C1-2alkyl-, Het20-C1-2alkyl-, —O—N═CH— or C1-2alkyl;
R1 represents hydrogen, cyano, halo, hydroxy, formyl, C1-6alkoxy-, C1-6alkyl-, C1-6alkoxy- substituted with halo,
C1-4alkyl substituted with one or where possible two or more substituents selected from hydroxy or halo;
R2 represents hydrogen, cyano, halo, hydroxy, hydroxycarbonyl-, Het16-carbonyl-, C1-4alkyloxycarbonyl-, C1-4alkylcarbonyl-, aminocarbonyl-, mono- or di(C1-4alkyl)aminocarbonyl-, Het1, formyl, C1-4alkyl-, C2-6alkynyl-, C3-6cycloalkyl-, C3-6cycloalkyloxy-, C1-6alkoxy-, Ar5, Ar1-oxy-, dihydroxyborane,
C1-6alkoxy- substituted with halo,
C1-4alkyl substituted with one or where possible two or more substituents selected from halo, hydroxy or NR5R6,
C1-4alkylcarbonyl- wherein said C1-4alkyl is optionally substituted with one or where possible two or more substituents selected from hydroxy or C1-4alkyl-oxy-;
R3 represents hydrogen, C1-4alkyl, cyano or C1-4alkyl substituted with one or more substituents selected from halo, C1-4alkyloxy-, amino-, mono- or di(C1-4alkyl)amino-, C1-4alkyl-sulfonyl- or phenyl;
R4 represents hydrogen, hydroxy, Ar3-oxy, Ar4-C1-4alkyloxy-, C2-4alkenyloxy- optionally substituted with Het12 or R4 represents C1-4alkyloxy substituted with one or where possible two or more substituents selected from C1-4alkyloxy-, hydroxy, halo, Het2-, —NR7R8,-carbonyl- NR9R10 or Het3-carbonyl-;
R5 and R6 are each independently selected from hydrogen or C1-4alkyl;
R7 and R8 are each independently selected from hydrogen, C1-4alkyl, Het8, aminosulfonyl-, mono- or di (C1-4alkyl)-aminosulfonyl, hydroxy-C1-4alkyl-, C1-4alkyl-oxy-C1-4alkyl-, hydroxycarbonyl-C1-4alkyl-, C3-6cycloalkyl, Het9-carbonyl-C1-4alkyl-, Het10-carbonyl-, polyhydroxy-C1-4alkyl-, Het11-C1-4alkyl- or Ar2—C1-4alkyl-;
R9 and R10 are each independently selected from hydrogen, C1-4alkyl, C3-6cycloalkyl, Het4, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl- or polyhydroxy-C1-4alkyl-;
R11 represents hydrogen, C1-4alkyl, Het5, Het6-C1-4alkyl-, C2-4alkenylcarbonyl- optionally substituted with Het7-C1-4alkylaminocarbonyl-, C2-4alkenylsulfonyl-, C1-4alkyloxyC1-4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4alkyloxy-;
R12 represents hydrogen, C1-4alkyl, C1-4alkyl-oxy-carbonyl-, Het17, Het18-C1-4alkyl-, C2-4alkenylcarbonyl- optionally substituted with Het19-C1-4alkylaminocarbonyl-, C2-4alkenylsulfonyl-, C1-4alkyloxyC1-4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4alkyloxy-;
R13 represents hydrogen, C1-4alkyl, Het13, Het14-C1-4alkyl- or phenyl optionally substituted with one or where possible two or more substituents selected from hydrogen, hydroxy, amino or C1-4alkyloxy-;
R14 and R15 are each independently selected from hydrogen, C1-4alkyl, Het15-C1-4alkyl- or C1-4alkyloxyC1-4alkyl-;
R16 and R17 are each independently selected from hydrogen, C1-4alkyl, Het21-C1-4alkyl- or C1-4alkyloxyC1-4alkyl-;
Het1 represents a heterocycle selected from piperidinyl, morpholinyl, piperazinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het1 is optionally substituted with one or where possible two or more substituents selected from amino, C1-4alkyl, hydroxy-C1-4alkyl-, phenyl, phenyl-C1-4alkyl-, C1-4alkyl-oxy-C1-4alkyl- mono- or di(C1-4alkyl)amino- or amino-carbonyl-;
Het2 represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het2 is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C1-4alkyl-, hydroxy-C1-4alkyl-, C1-4alkyl-oxy-C1-4alkyl-, hydroxy-C1-4alkyl-oxy-C1-4alkyl-, mono- or di(C1-4alkyl)amino-, mono- or di(C1-4alkyl)amino-C1-4alkyl-, aminoC1-4alkyl-, mono- or di(C1-4alkyl)amino-sulfonyl-, aminosulfonyl-;
Het3, Het4 and Het8 each independently represent a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, furanyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het3, Het4 or Het8 is optionally substituted with one or where possible two or more substituents selected from hydroxy-, amino-, C1-4alkyl-, C3-6cycloalkyl-C1-4alkyl-, aminosulfonyl-, mono- or di(C1-4alkyl)aminosulfonyl or amino-Ci-4alkyl-;
Het5 represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said heterocycle is optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-;
Het6 and Het7 each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het6 and Het7 are optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-;
Het9 and Het10 each independently represent a heterocycle selected from furanyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, dioxolanyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl or pyrrolidinyl wherein said Het9 or Het10 is optionally substituted C1-4alkyl, C3-6cycloalkyl-C1-4alkyl- or amino-C1-4alkyl-;
Het11 represents a heterocycle selected from indolyl or
Het12 represents a heterocycle selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl or dithianyl wherein said Het12 is optionally substituted with one or where possible two or more substituents selected from hydroxy, halo, amino, C1-4alkyl-, hydroxy-C1-4alkyl-, C1-4alkyl-oxy-C1-4alkyl, hydroxy-C1-4alkyl-oxy-C1-4alkyl-, mono- or di(C1-4alkyl)amino- or mono- or di(C1-4alkyl)amino-C1-4alkyl-;
Het13 represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said heterocycle is optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4allkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-;
Het14 represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said heterocycle is optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-;
Het15 and Het21 each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het15 or Het21 are optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-;
Het16 represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl, 1,3,2-dioxaborolane or piperidinyl wherein said heterocycle is optionally substituted with one or more substituents selected from C1-4alkyl;
Het17 represent a heterocycle selected from pyrrolidinyl or piperidinyl wherein said heterocycle is optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-;
Het18 and Het19 each independently represent a heterocycle selected from morpholinyl, pyrrolidinyl, piperazinyl or piperidinyl wherein said Het18 and Het19 are optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-;
Het20 represents a heterocycle selected from pyrrolidinyl, 2-pyrrolidinyl, piperidinyl, piperazinyl or pyrazolidinyl wherein said heterocycle is optionally substituted with one or where possible two or more substituents selected from C1-4alkyl, C3-6cycloalkyl, hydroxy-C1-4alkyl-, C1-4alkyloxyC1-4alkyl or polyhydroxy-C1-4alkyl-; and
Ar1, Ar2, Ar3, Ar4 and Ar5 each independently represent phenyl optionally substituted with cyano, C1-4alkylsulfonyl-, C1-4alkylsulfonylamino-, aminosulfonylamino-, hydroxy-C1-4alkyl, aminosulfonyl-, hydroxy-, C1-4alkyloxy- or C1-4alkyl, said process, comprising;
a) coupling 2-acetoxy-8-chloropyrimido[5,4-d]pyrimidine derivatives (II) anilines of formula (III), to furnish the intermediates of formula (IV), and deprotecting the intermediates of formula (IV) followed by ring closure in the presence of a coupling reagent selected from the group consisting of 1,3-dicyclohexylcarbodiimide (DCC), N.N′-carbonyldiimidazole (CDI), POCl3, TiCl4, sulfur chloride fluoride (SO2ClF) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), wherein V is a protective group selected from the group consisting of methylcarbonyl, t-butyl, methyl, ethyl, benzyl or trialkylsilyl;
;or
b) coupling the known 8-chloro-2(methylthio)-pyrimido[5,4-d]pyrimidine with 2-aminophenol derivatives of formula (XXI), yielding the intermediate compounds of formula (XXII), followed by animating the pyrido[3,2-d]pyrimidine of formula (XXII) using an aminated alcohol (XXIII) that is added dropwise to a mixture of (XXII) in CH2Cl2 in the presence of 1,1′carbonylbis-1H-imidazole, followed by ring closure under Mitsunobu conditions to give the target compounds of formula (I″)

### Claim 3 (depends on 1)

A method of treating ovarian cancer, the method comprising administering to an animal in need of such treatment a therapeutically effective amount of a compound as claimed in claim 1.