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FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS (AMENDMENT) RULES, 2006
COMPLETE SPEC1FICATION
(See section 10, rule 13)
"NOVEL QUINOLINE-CARBAXAMIDES AS JACK3 KINASE
MODULATORS"
ASTRAZENECA AB of SE-151 85 Sodertalje, Sweden.
The following speC1fication particularly describes the invention and the manner in which it 15 to be performed.
-1-
WO 2005/075429
PCT/SE2005/000156
2-
Novel quinoline-carbaxamides as JAK3 kinase modulators
The present invention relates to novel compounds which are JAK3 Kinase inhibitors, 5 processes for their preparation, pharmaceutical compositions containing them and their in therapy.
use
Intemational application No;
INTERNATIONAL SEARCH REPORT PCT/SE05/000156
Box II.2
Consequently, the search has been carried out for those parts of the application which appear to be clear and conC1se, namely those compounds reC1ted in the examples 1-274
Form
PCT/1SA/210 (extra sheet) (January 2004)
WO 2005/075429
PCT/SE2005/000156
Novel quinoline-carbaxamides as JAK3 kinase modulators
The present invention relates to novel compounds which are JAK3 Kinase inhibitors,
5 processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
Janus Kinase 3 (JAK3) 15 a member of the Janus family of protein kinases. Although the other members of th15 family are expressed by essentially all t15sues, JAK3 expression 15
10 limited to hematopoetic cells. Th15 15 cons15tent with its essential role in signaling through the receptors for IL-2, IL-4, IL-7, JJL-9, IL-13 and IL-15 by non-covalent assoC1ation of JAK3 with the gamma chain common to these multichain receptors. These cytokines all have a shared function in mat they are involved in lymphocyte differentiation and proliferation. XSCGD patient populations have been identified with severely reduced levels
15 of JAK3 protein or with genetic defects to the common gamma chain, suggesting that immunosupression should result from blocking signaling through the JAK3 pathway. Animal studies have suggested that JAK3 not only play a critical role in B- and T-lymphocyte maturation, but that JAK3 15 constitutively required to maintain T-cell function. Modulation of immune activity through th15 novel mechan15m can prove useful in the
20 treatment of T-cell proliferative d15orders such as transplant rejection and autoimmune diseases.
The role of JAK3 in mast cells has been described in knockout mice. Thus, IgE/antigen
induced degranulation and mediator release were substantially reduced in mast cells
25 generated from JAK3 defiC1ent mice. JAK3 defiC1ency does not affect mast cell
proliferation in vitro, it has also been shown that IgE receptor levels and mediator contents are identical in JAK3-/- and JAK3 +/+ mast cells. Therefore, JAK3 appears essential for the complete response of IgE challenged mast cells. The role of JAK3 in mast cell activation has been well establ15hed in murine system, however, there 15 no publ15hed data on mast cell
INTERNATIONAL SEARCH REPORT
International application No. PCT/SE05/000156
Box II.2
Consequently, the search has been carried out for those parts of the application which appear to be clear and conC1se, namely those compounds reC1ted in the examples 1-274
Form PCT/15A/210 (extra sheet) (January 2004)
INTERNATIONAL SEARCH REPORT
International application No.
PCT/SE 2005/000156
C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT
Category*
C1tation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No
A EP 0336544 Al (SMITHKLINE BECKMAN INTERCREDIT
B.V.), 11 October 1989 (11.10.1989), Formula I
1-23
A US 3362954 A (ALEXANDER R. SURREY ET AL), 9 January 1968 (09.01.1968), claims 1-21
1-23
A WO 9843960 Al (AMERICAN CYANAMID COMPANY), 8 October 1998 (08.10.1998), Formula I
1-23
Form PCT/15 A/210 (continuation of second sheet) (January 2004)
INTERNATIONAL SEARCH REPORT International application No.
01/04/2005 PCT/SE 2005/000156
EP 0259174 Al 09/03/1988 SE 0259174 T3
AT 73776 T 15/04/1992
AU 598299 B 21/06/1990
AU 7874187 A 24/03/1988
CA 1308106 A,C 29/09/1992
CN 1019802 B 30/12/1992
CN 87106163 A 16/03/1988
CZ 9103982 A 16/02/1994
DE 3777505 A 23/04/1992
DK 159308 B,C 01/10/1990
DK 245888 A 05/05/1988
EG 18408 A 28/02/1993
ES 2033316 T 16/03/1993
FI 88919 B,C 15/04/1993
FI 882089 A 04/05/1988
GB 8621425 D 00/00/0000
GR 3004692 T 28/04/1993
HU 47913 A 28/04/1989
HU 199804 B 28/03/1990
IE 61104 B 05/10/1994
IE 872370 L 05/03/1988
IL 83691 A 18/08/1993
JP 1500664 T 09/03/1989
JP 7000602 B 11/01/1995
KR 9513850 B 17/11/1995
MX 9203550 A 01/09/1992
NO 172388 B,C 05/04/1993
NO 881940 A 04/05/1988
NZ 221663 A 29/08/1989
PH 23695 A 27/09/1989
PT 85651 A,B 01/10/1987
US 4806549 A 21/02/1989
US 4806550 A 21/02/1989
WO 8801621 A 10/03/1988
ZA 8706581 A 26/04/1989
16787 A 25/05/1988
Form PCT/15A./210 (patent family annex) (January 2004)
function in the AR-SC1D patients. Targeting JAK3 provides the basis for new and effective treatment of mast cell mediated allergic reactions.
JAK3 inhibitors which have been d15closed to date include quinazolines (Sudbeck, E. A. et. Clinical
5 Cancer Res. 5(1999)1569-82, WO 00/0202) and pyrrolo[2,3-d]pyrimidines (Blumenkopf, T. A. et al. WO 99/65909). 4-anilinoquinoline-3-carboxamides having JAK3 inhibitory activity are described in WO 02/092571. In WO 00/18761 and WO 98/43960 there are disclosed substituted quinoline-3-carbonitrile derivatives which are stated to have kinase inhibitory activity.
10
Quinoline derivatives having other pharmaceutical uses, for example as antiulcer agents, phosphodiesterase inhibitors or gastric acid secretion inhibitors are described in EP 0 259 174, EP 0 346 208, EP 0 480 052 and WO 2004/10399
15. he present invention provides a compound of formula (I)
(I)
or a pharmaceutically acceptable salt or solvate thereof, wherein
X15-CHOHor-C=0;
20 R1 and R2, which may be the same or different, represent nitro, cyano, Q-Cg alkyl, C1-C8
alkoxy, hydroxy, aryl, Y(CR32)pNR4, Y(CR32)pCONR4R5, Y(CR32)pC02R6, Y(CR32)pOR6
, Y(CR32)pR6, Y(CR32)POCOR6
or Rl and R2 are linked together as –OCH2O- or -OCH2CH20-;
R3 groups are independently hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy or halogen;
25 p 15 0,1,2, 3,4 or 5;
Y 15 oxygen, CH2 OSO2- or NR7
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R4 and R5 each independently represent hydrogen or a group selected from C1-C8 alkyl, -C1-C8 alkoxy, -CO-(C1-C8) alkyl, -CO-( C1-C8) cycloalkyl, -SO2-(C1-C2) alkyl, -CO-( C1-C8) alkoxy, -CO-NR7(Cg-C8) alkyl, C3-Cg cycloalkyl, each of which groups may optionally be substituted by one or more hydroxy, cyano, -CONH2 or -CO-( C1-C8) alkoxy groups,
5 or R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 7-membered, saturated or aromatic heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by at least one substituent selected from hydroxy, C1-C8 alkyl, =0, C1-C8 alkoxy or (Cg-C8 alkoxy)-CO-, or one of R4 and R5 15 hydrogen or C1-C8 alkyl and
10 the other is a 5- or 6-membered heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom;
R6 is hydrogen, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, cyano, halogen or amino groups), phenyl, benzyl, -CO(C1-C8) alkyl or a saturated monocyclic 4-to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected
15 from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected from C1-C8 alkyl, C1-C8 alkoxy, =0 , C1-C2 alkyl -CO-,or (C1-C8 alkoxy)-CO- where any C1-C8 alkyl 15 optionally substituted by one or more hydroxy, cyano, halogen or amino groups; R7 15 hydrogen or Cg-C8 alkyl;
20 Ra is hydrogen or C1-C8 alkyl;
Rx is a group selected from C1-C8 alkyl, C3-C8 cycloalkyl or a saturated monocyclic 4- to 7-membered ring compr15ing one or more heteroatoms selected from nitrogen, oxygen and sulphur, wherein any C3-C8 cycloalkyl group or saturated monocyclic 4- to 7-membered ring is optionally substituted by one or more groups selected from hydroxy, azido, cyano,
25 amino, halogen, -CONH2-, C1-C8 alkyl, (C1-C8 a!kyl)CO-, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO-, and any Q-Q alkyl, C1-C8 alkyl)CO-, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO- group 15 itself optionally substituted by one or more substituents selected from hydroxy, azido, cyano, amino, halogen or phenyl; or Rx 15 a group Ar, Ar 15 selected from phenyl, tetrahydronaphthenyl, indolyl, pyrazolyl, dihydroindenyl, 1-
30 oxo-23-dihydroindenyl, indazolyl, dihydro15oquinolyl, oxodihydro15oquinolyl.
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tetrahydro15oquinolyl or oxotetrahydro15oquinolyl, each of which can be optionally substituted by one or more groups, which may be the same or different, selected from halogen, hydroxy, cyano, C1-C8 alkoxy, C02R8, CONR9R10, C1-C8 alky]-NR8-CrC8 alkyl, C1-C8 alkyl-CONR8-C1-C8 alkyl, C1-C8 alkyl-CONR9R10, NR8COC1-C8 alkyl, C1-C8
5 thioalkyl, C]-C8 alkyl (itself optionally substituted by one or more hydroxy, azido or cyano groups or fluorine atoms), C1-C8alkyl-NRnR12 C1-C8alkyl-OR12, CrC8 alkyl-SR12; R8 15 hydrogen or C1-C8 alkyl;
R9 and R10 are each independently hydrogen or C1-C8 alkyl Rn 15 hydrogen or Q-C8 alkyl;
10 R12 15 hydrogen or a group selected from C1-C8 alkyl, -(CR132)nR14 , -CO-(CRI32)„R14, -SO2-(CR13R14 ;
n is between 0 and 5;
R13 groups are independently hydrogen, C1-Q alkyl, hydroxy, C1-C8 alkoxy, hydroxy(C1-C8 )alkyl, amino or halogen;
15 R14 is hydrogen or a group selected from -NR,15R16, C1-C8 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -COOH, -S(C1-C8 alkyl), -SO(C1-C8 alkyl^-CONR15R16, -CO(C1-C8 alkyl),
-CO-O(C1C8- alkyl), or a saturated or unsaturated 4- to 10-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur, each of which groups may be optionally substituted by one or more hydroxy, C1-C8
20 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl, nitro, -CONH2 groups), C1-C8 alkoxy, C1-C8 hydroxyalkyl,-C=0, cyano, amino, nitro, halogen, C1-C8 alkylsulphonyl or aminosulphonyl groups or by a
25 saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur;
or R1' and R12, together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen , the ring itself being
30 optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl(which
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may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, C1-C8 alkyl, nitro, -CONH2 groups), nitro, cyano, -CONH2, amino, =0 or -COOH groups or by a
5 saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO-; and R15 and R16, which may be the same or different, represent hydrogen, C1-C8 alkyl, -CONH2
10 or-C(NH2)=NH;
provided that when
Rx 15 Ar, X 15 -CO and R1 and R2 are independently nitro, cyano, Ct-C« alkyl, Q-Cg alkoxy,
15 hydroxyl, aryl, YCCR^VMRV, YCCR^CONRV, YfCR^COjR6, YCCR^OR6, Y(CR32)pR6. -CH^CH^OCOR* or R1 and R2 are linked together as -OCH2O- or -OCH2CH20- ,
where each R3 group 15 independently hydrogen, C1-C8 alkyl, hydroxy, or halogen, R4 and R5 each independently represent hydrogen or Cg-Cg alkyl or R4 and R5 together with 20 the nitrogen atom to which they are attached form an unsubstituted 4- to 7-membered saturated or aromatic heterocyclic ring system optionally containing a further oxygen, sulphur or NR6 group or one of R4 and R5 15 hydrogen or C1-C8 alkyl and the other 15 a 5- or 6-membered heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom;
25 and R6 15 selected from hydrogen, (C1-C8) alkyl, -CO(C1-C8)alkyl, hydroxy substituted
(C1-C8) alkyl, halogen substituted (Cg-Cg) alkyl, phenyl or benzyl,
then
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Ar 15 selected from dihydro15oquinolyl, oxodihydro15oquinolyl, tetrahydro15oquinolyl or oxotetrahydro15oquinolyl, each of which may be optionally substituted, or Ar 15 phenyl substituted by at least one substituent selected from azido substituted C1-C8 alkyl, C1-C8alkyl-NRnR12 C1-C8alkyl-ORl2or CrC8alkyl-SR12,
5 wherein R12 is selected from -(CR,32)„R14 ,-CO-(CRI32)„R14, -SO2 -(CR'32)nR14 or R14' and R12, together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl(which
10 may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated
heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, C1-C8 alkyl, nitro, -CONH2 groups), nitro, cyano, -CONH2. amino, =0 or -COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or
15 more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1(-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO-, provided that Ar is not phenyl substituted by one or more groups selected from
C1-C8 alkyl-NR11- C1-C8 alkyl, Q-Cg alkyl-O-C1-C8 alkyl or C1-C8 alkanoyloxy C1-C6 alkyl
20
Unless otherw15e indicated, the term 'alkyl' when used alone or in combination, refers to a straight chain or branched chain alkyl moiety. A CrCg alkyl group has from one to eight carbon atoms including methyl, ethyl, n-propyl, 15opropyl, tert-butyl, n-pentyl, n-hexyl and the like. References to individual alkyl groups such as "propyl" are specific for the
25 straight-chain version only, references to individual branched-chain alkyl groups such as "15opropyl" are speC1fic for the branched-chain version only.
Analogously, the term 'C1-C8 alkoxy', when used alone or in combination, will be understood to refer to straight or branched chain groups having from one to eight or from
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one to four carbon atoms respectively and includes such groups as methoxy, ethoxy, propoxy, 15opropoxy and butoxy.
The term 'cycloalkyl', when used alone or in combination, refers to a saturated alicyclic
5 moiety having from three to eight carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term aryl includes phenyl and naphthyl groups.
10 A C2-C4 alkenyl group 15 for example vinyl or allyl. A C2-C4 alkynyl group is for example ethynyl or propyn-2-yl.
'Optionally substituted' 15 used herein to indicate optional substitution by the group or groups speC1fied at any suitable available position.
15
A 'heteroatom' is a nitrogen, sulphur or oxygen atom. Where rings include nitrogen atoms, these may be substituted as necessary to fulfil the bonding requirements of nitrogen or they may be linked to the rest of the structure by way of the nitrogen atom. Nitrogen atoms may also be in the form of N-oxides. Sulphur atoms may be in the form of S, S(0) or SO2. In a
20 heterocyclic ring, a -CH2- group can optionally be replaced by a -C(0).
As used herein, the term 'halogen’ includes fluorine, chlorine, bromine and iodine.
A 'saturated or unsaturated 4- to 10-membered ring, which ring may optionally compr15e
25 one or more heteroatoms selected from nitrogen, oxygen and sulphur' may be a saturated, partially saturated or unsaturated monocyclic or bicyclic ring. The ring may be a carbocylic (that 15 an alicyclic ring having ring carbon atoms only) or 15 a heterocyclic ring containing four to ten atoms of which at least one 15 a heteroatom selected from nitrogen, oxygen and sulphur and which ring may, unless otherw15e speC1fied, be carbon or nitrogen linked.
30 Examples of suitable carbocyclic rings include cyclobutyl, cyclopentyl, cyclohexyl and
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cycloheptyl. Suitably a 4- to 10-membered heterocyclic ring may be pyridyl, imidazolyl, 15oxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, thiazolyl, oxazolyl, 15othiazolyl,, triazolyl, tetrazolyl, thienyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, morpholinyl, tetrahydrofuranyl, piperazinyl, imidazopyrrole, indole,
5 15oindole, indoline, 15oindazole, benzimidazole, purine, quinolyl (for example, 1,2-
dihydroquinolinyl or 1,2,3,4-tetrahydroquinolinyl), 15oquinolyl, C1nnolinyl, quinazolinyl, quinoxalinyl.benzoxazole, benzothiazole, imidazopyridinyl, imidazopyrimidinyl, imidazopyrazinyl. A saturated monocyclic 4- to 7- membered ring compr15ing one or more heteroatoms selected from nitrogen, oxygen and sulphur will accordingly be understood to
10 mean a heterocyclic ring containing four to seven atoms and which may, unless otherw15e speC1fied, be carbon or nitrogen linked. Particular examples of such ring systems include pyrrolidinyl and piperidinyl as included in the above l15t
A '4-to 7-membered heteroaromatic ring compr15ing at least one ring heteroatom selected 15 from nitrogen, oxygen and sulphur' is a fully unsaturated, aromatic monocyclic ring
containing from four to seven atoms of which at least one 15 a heteroatom selected from nitrogen, oxygen and sulphur, which ring may, unless otherwise specified, be carbon or nitrogen linked. Particular examples of such ring systems include pyridyl, imidazolyl, 15oxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, thiazolyl,
20 oxazolyl, 15othiazolyl,, triazolyl, tetrazolyl or thienyl as given above.
It will be appreC1ated that the number and nature of substituents on rings in the compounds of the invention will be selected so as to avoid sterically undesirable combinations.
25 In one particular embodiment, the invention provides a compound of formula (la)
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(la)
or a pharmaceutically acceptable salt or solvate thereof, wherein
5 X15-CHOHor-C=0;
one of R1 and R2 represents nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, aryl,
Y(CR32)PNR4RS, Y(CR3CONR4R5, Y(CR32)pCOzR6, Y(CR32)pOR6 , Y(CR32)pR6 ,
Y(CR32)pOCOR6
or R1 and R2 are linked together as -OCH2O- or -OCH2CH20- ;
10 R3 groups are independently hydrogen, Cg-Cg alkyl, hydroxy, Cg-Cg alkoxy or halogen; p 15 0,1,2,3,4 or 5; Y 15 oxygen, CH2' –OSO2- or NR7
R4 and R5 each independently represent hydrogen or a group selected from C1-C8 alkyl, C1-C8 alkoxy, -CCHQ-Cg) alkyl, -CO-( Cg-Cg) cycloalkyl, -SO2 –(C1-C2g) alkyl, -CO-( C1-C8)
15 alkoxy, -CO-NR7(C1-C8) alkyl, C1-C8 cycloalkyl, each of which groups may optionally be substituted by one or more hydroxy, cyano, -CONH2 or -CO-( C1-C8) alkoxy groups, or R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 7-membered, saturated or aromatic heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being
20 optionally substituted by at least one substituent selected from hydroxy, C1-C8 alkyl, =0, C1-C8 alkoxy or (C1-C8 alkoxy)-CO-, or one of R4 and R5 15 hydrogen or CrC8 alkyl and the other 15 a 5- or 6-membered heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom; R6 15 hydrogen, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, cyano,
25 halogen or amino groups), phenyl, benzyl, -CO(C1-C8) alkyl or a saturated monocyclic 4-to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected
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from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected from C1-C8 alkyl, C1-C8 alkoxy, =0, C1-C8 alkyl -CO-,or (C1-C8 alkoxy)-CO- where any C1-C8 alkyl 15 optionally substituted by one or more hydroxy, cyano, halogen or amino groups;
5 R7 is hydrogen or C1-C8 alkyl;
Rx 15 hydrogen or C1-C8 alkyl
Rx is a group selected from C1- C8 alkyl, C3-C8 cycloalkyl or a saturated monocyclic 4- to 7-membered ring compr15ing one or more heteroatoms selected from nitrogen, oxygen and sulphur, wherein any C3-C8 cycloalkyl group or saturated monocyclic 4- to 7-membered
10 ring 15 optionally substituted by one or more groups selected from hydroxy, azido, cyano, amino, halogen, -CONH2-, C1-C8 alkyl, (C1-C8 alkyl)CO-, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO-, and any Q-Cg alkyl, C1-C8 alkyl)CO-, C1-C8 alkoxy, or (C1-C8 alkoxy)- group is itself optionally substituted by one or more substituents selected from hydroxy, azido, cyano, amino, halogen or phenyl; or RK 15 a group Ar,
15 Ar 15 selected from phenyl, tetrahydronaphthenyl, indolyl, pyrazolyl, dihydrotndenyl, 1-oxo-2,3-dihydroindenyl, indazolyl, dihydro15oquinolyl, oxodihydro15oquinolyl, tetrahydro15oquinolyl or oxotetrahydro15oquinolyl, each of which can be optionally substituted by one or more groups, which may be the same or different, selected from halogen, hydroxy, cyano, C1-C8 alkoxy, C02R8, CONR9R10, C1-C8 alkyI-NR8-C1C8 alkyl,
20 C1-C8 alkyl-CONR8-C1-C8 alkyl, C1-C8 alkyl-CONR9R10, NR8COC1-C8 alkyl, C1-C8
thioalkyl, C(-Cg alkyl (itself optionally substituted by one or more hydroxy, azido or cyano groups or fluorine atoms) , C1-C8 aIkyI-NR,,Rl2,Cl-Cg alkyl-OR12, C1-Cg alkyl-SR12; R8 15 hydrogen or C1-C8 alkyl; R9 and R10 are each independently hydrogen or C1-C8 alkyl
25 Rn 15 hydrogen or C1-Cg alkyl;
R12 15 hydrogen or a group selected from C1-C8 alkyl, -(CR132)nR14 ,
-CO-(CR,32)nRl4,-S02-
n is between 0 and 5;
R13 groups are independently hydrogen, C1 -Cs alkyl, hydroxy, C1-C8 alkoxy,
30 hydroxy(C1 -Cg )alkyl, amino or halogen;
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R ,415 hydrogen or a group selected from -NR,5R16, C1-C8 alkyl, C2-CA alkenyl, C2-C* alkynyl, -COOH, -S(C1-C8 alkyl), -SO(C1-C8alkyl),-CONRI5R16, -CO(C1-C8 alkyl), -CO-0-(Cg-C8 alkyl), or a saturated or unsaturated 4- to 10-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and
5 sulphur, each of which groups may be optionally substituted by one or more hydroxy, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-Q alkyl, nitro, -CONH2 groups), d-C8alkoxy, C1-C8 hydroxyalkyl,-C=0,
10 cyano, amino, nitro, halogen , C1-C8 alkylsulphonyl or aminosulphonyl groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur; or R11 and R12, together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated or unsaturated heterocyclic ring system optionally containing one or
15 more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, Q-Cg alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8
20 alkyl, nitro, -CONH2 groups), nitro, cyano, -CONH2, amino, =0 or -COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO-; and
25 R15 and R16, which may be the same or different, represent hydrogen, C1-C8 alkyl, -CONH2 or-C(NH2)=NH;
and the other of R1 and R2 15 Y(CR32)pNR4R5, Y(CR32)pC01SfR4R5, Y(CR32)pC02R6, Y(CR32)pOR6, Y(CR32)pR6 or Y(CR32)pOCOR6,
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where at least one R3 15 C1 -Cg alkoxy, or one of R4 and R5 15 selected from optionally substituted -CO-( C1 -C8) alkyl, -CO-( C1 -C8) cycloalkyl, -S02-( C1,-C8) alkyl, -CO-( C1,-C8) alkoxy, -CO-NR7(C C1 -C8) alkyl or C3-C8 cycloalkyl, or R4 and R5 together with the nitrogen atom to which they are attached form a substituted 4- to 7-membered saturated or aromatic
5 heterocyclic ring system optionally containing a further oxygen, sulphur or NR6 group, or R6 15 selected from -CO( C1 -Cg) alkyl, or an optionally substituted saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur, and which may be optionally substituted by at least one substituent selected from C1 -Cg alkyl, C1-C8 alkoxy, C1 -C8 alkyl -CO-, =0 or (C1 -C8
10 alkoxy)-CO-where any C1-C8 alkyl 15 optionally substituted by one or more hydroxy, cyano, halogen or amino groups;
In another particular embodiment, the invention provides a compound of formula (lb)
15
x
(lb)
or a pharmaceutical ly acceptable salt or solvate thereof, wherein
20 X is-CHOH or-C=0;
R1 and R2, which may be the same or different, represent nitro, cyano, C1-C8 alkyl, C1-C8
alkoxy, hydroxy, aryl, Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR32)pC02R6, Y(CR32)pOR6
, Y(CR32)pR6 , Y(CR32)pOCOR6
or R1 and R2 are linked together as –OCH2O-or-OCH2CH2O- ;
25 R3 groups are independently hydrogen, C1 -Cg alkyl, hydroxy, C1 -C8 alkoxy or halogen;
p 15 O, 1,2, 3,4 or 5;
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where at least one R3 15 C1-C8 alkoxy, or one of R4 and R5 15 selected from optionally substituted -CO-( C1-C8) alkyl, -CO-( C1-C8) cycloalkyl, -S02-( C1-C8) alkyl, -CO-(CrC8) alkoxy, -CO-NR7(C1-C8) alkyl or C3-C8 cycloalkyl, or R4 and R5 together with the nitrogen atom to which they are attached form a substituted 4- to 7-membered saturated or aromatic
5 heterocyclic ring system optionally containing a further oxygen, sulphur or NR6 group, or R6 15 selected from -CO(C1-C8) alkyl, or an optionally substituted saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur, and which may be optionally substituted by at least one substituent selected from d-C8 alkyl, d-C8 alkoxy, C1-C8 alkyl -CO-, =0 or (C1-C8
10 alkoxy)-CO-where any C1-C8 alkyl 15 optionally substituted by one or more hydroxy, cyano, halogen or amino groups;
In another particular embodiment, the invention provides a compound of formula (lb)
15
x
(lb)
or a pharmaceutical ly acceptable salt or solvate thereof, wherein
20 X15-CHOHor-C=0;
R1 and R2, which may be the same or different, represent nitro, cyano, Q-C8 alkyl, C1-C8
alkoxy, hydroxy, aryl, Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR32)pC02R6, Y^R^OR6
, Y(CR32)pR6 , Y(CR32)„OCOR6
or R1 and R2 are linked together as -OCH20- or -OCH2CH20- ; 25 R3 groups are independently hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy or halogen;
p15O, 1,2, 3,4 or 5;
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Ar 15 selected from dihydro15oquinolyl, oxodihydro15oquinolyl, tetrahydro15oquinolyl or oxotetrahydro15oquinolyl, each of which can be optionally substituted by one or more groups, which may be the same or different, selected from halogen, hydroxy, cyano, Cg-C8 alkoxy, CO2R8, CONRV0, C1-C8 alkyl-NR8-C1-C8 alkyl, C1-C8 alkyl-CONR8-C1-C8 alkyl,
5 C1-C8 alkyl-CONR'R10, NR8COC1-C8 alkyl, C1-C8 thioalkyl, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, azido or cyano groups or fluorine atoms), C1-C8 alkyl-NRUR12. C1-C8 alkyl-OR12, C1-C8 alkyl-SR12;
or Ar 15 phenyl substituted by at least one substituent selected from azido substituted C1-C8 alkyl, C1-C8 alkyl-NRuR12a, C1-C8 alkyl-OR12*, C1-C8 alkyl-SR12*,
10 wherein R12t 15 selected from -(CRl32WR14 ,-CO-(CRl32)tlR14, -SCMCR'^R14 : R8 15 hydrogen or C1-C8 alkyl;
R9 and R10 are each independently hydrogen or C1-C8 alkyl R1' 15 hydrogen or C|-C« alkyl; R12 15 hydrogen or a group selected from Q-C8 alkyl, -
15 -CO-(CRI32)^,4,-S02-(CR,32WR14; n 15 between 0 and 5;
R13 groups are independently hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy, hydroxy(C1-C8 )alkyl, amino or halogen; R M15 hydrogen or a group selected from -NR,5R16, C1-C8 alkyl, C2-C4 alkenyl, C2-C4
20 alkynyl, -COOH, -S(C1-C8 alkyl), -SO(C1-C8 alkyl),-CONR,5R16, -CO(C1-C8 alkyl),
-CO-0-(C1-C8 alkyl), or a saturated or unsaturated 4- to 10-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur, each of which groups may be optionally substituted by one or more hydroxy, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or
25 unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl, nitro, -CONH2 groups), C1-C8 alkoxy, C1-C8 hydroxyalkyl,-C=0, cyano, amino, nitro, halogen, C1-C8 alkylsulphonyl or aminosulphonyl groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or
30 more heteroatoms selected from nitrogen, oxygen and sulphur,
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>
or R1' and R12, together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen , the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl(which
5 may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated
heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, Cg-Cg alkyl, nitro, -CONH2 groups), nitro, cyano, -CONH2. amino, =0 or -COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or
10 more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO-; and
R15 and R16, which may be the same or different, represent hydrogen, C1-C8 alkyl, -CONH2 or-C(NH2)=NH,
15 provided mat Ar is not phenyl substituted by one or more groups selected from
C1-C8 alkyl-NR11- C1-C8 alkyl. C1-C8 alkyl-O-C1-C8 alkyl or C1-Q alkanoyloxy d-Q alkyl.
Suitably X is -CHOH or -C=0, preferably -C=0.
20
In one embodiment, Rx 15 a group selected from C1-C8 alkyl, C3-Cg cycloalkyl or a saturated monocyclic 4- to 7-membered ring compr15ing one or more heteroatoms selected from nitrogen, oxygen and sulphur, wherein any C3-Cg cycloalkyl group or saturated monocyclic 4- to 7-membered ring 15 optionally substituted by one or more groups selected
25 from hydroxy, azido, cyano, amino, halogen, -CONH2-, C1-C8 alkyl, (Cg-Cg alkyl)CO-, C»-Cg alkoxy, or (C1-C8 alkoxy)-CO-, and any C1-C8 alkyl, (C1-C8 alkyl)CO-, C1-C8 alkoxy, or (Cg-Cg alkoxy)-CO- group 15 itself optionally substituted by one or more substituents selected from hydroxy, azido, cyano, amino, halogen or phenyl.
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In one preferred embodiment, Rx is C3-C8 cycloalkyl or a saturated monocyclic 4- to 7-membered ring compr15ing one or more heteroatoms selected from nitrogen, oxygen and sulphur, each of which groups is optionally substituted as described above. Preferably Rx is cyclohexyl, pyrrolidinyl or piperidinyl, optionally substituted as described above.
5
Substituents may be present on any suitable position of the R" group and more than one substituted, which may be the same or different, may be present. Where Rx is substituted, th15 15 preferably by one or two substituents.
10 Preferred substituents on Rx include Cg-Cg alkyl, (C1-C8 alkyl)CO-, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO-, optionally substituted with one or more substituents selected from hydroxy, azido, cyano, amino, halogen, -CONH2, C1-C8 alkoxy, (C1-C8 alkoxy)-CO- or phenyl.
Particularly preferred substituents on Rx include methyl, ethyl, benzyl, (CH3)C-O-CO-,
15 -COCN.
In another embodiment, R" is a group Ar.
Suitably Ar 15 selected from phenyl, tetrahydronaphthenyl, indolyl, pyrazolyl,
20 dihydtoindenyl, l-oxo-2,3-dihydroindenyl or indazolyl optionally substituted as described above. Substituents can be present on any suitable position of the Ar group. More than one substituent can be present, and these can be the same or different. Preferably Ar is optionally substituted dihydro15oquinolyl, oxodihydro15oquinolyl, tetrahydro is oquinolyl, oxotetrahydro15oquinolyl or phenyl, most preferably phenyl.
25
Where Ar 15 phenyl, th15 15 preferably substituted by one and espeC1ally two substitutents. Preferred substituents include C1-C8 alkyl, such as methyl or ethyl, hydroxy(C1-C8)alkyl, for example hydroxymethyl or hydroxyethyl, or a CrC8 alkyl-NR11.R12,C1-C8 alkyl-OR12, C1-C8 alkyl-SR12 group such as CH2SR12, CH2ORl2or espeC1ally -CH2NR11R12.
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In one preferred embodiment, Ar 15 phenyl substituted by at least one substituent selected C1-C8 alkyl-NR1'Ra12a, C1-C8 alkyl-OR12a, C1-C8 alkyl-SR, 12a, wherein R, 12a is selected from -(CR132)n R14 .-CO-(CR132)N R14,-SO2-(CR132)nR14 ; provided that Ar is not phenyl substituted by one or more groups selected from
5 C1-C8 alkyl-NR11- C1-C8 alkyl, C1-C8 alkyl,-C1-C8 alkyl or C1-C6 alkanoyloxy C1-C6 alkyl.
In one embodiment, R11 is preferably hydrogen
In another embodiment, R12 is preferably a group -(CR132)nR14
10
R13 is preferably hydrogen
R14 may be hydrogen, -NR15R16 or C1-C8 alkyl but is preferably a saturated or unsaturated 4- to 10-membered ring, which ring may optionally comprise one or more heteroatoms
15 selected from nitrogen, oxygen and sulphur, each of which groups may be optionally
substituted by one or more hydroxy, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, C1-C8 alkyl, nitro, -CONH2 groups), C1-C8 alkoxy,
20 C1-C8 hydroxyalkyl,-C=0, cyano, amino, nitro, halogen , C1-C8 alkylsulphonyl or
aminosulphonyl groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur;
25 In a particular embodiment, R11 and R12 together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen , the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered
30 saturated or unsaturated heterocyclic ring system optionally containing a further oxygen.
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sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, C1-C8 alkyl, nitro, -CONH2 groups), nitro, cyano, -CONH2, amino or -COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally comprise one or more heteroatoms selected from nitrogen, oxygen and sulphur and which
5 may be optionally substituted by one or more substituents selected from C1-C8 alkyl, C1(-C8 alkoxy or (C1-C8 alkoxy)-CO-;
Ra is hydrogen or C1-C8 alkyl such as methyl or ethyl. Where Ra 15 C1-C8 alkyl, it is preferably methyl. 10
In one embodiment, R4 is C1-C8 alkyl, especially methyl.
In a particular embodiment, R" is hydrogen.
15 Suitably R1 and R2 are independently selected from hydrogen, halogen, nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, aryl, Y(CR32)NR4R5, Y(CR32)pCONR4R5, Y(CR32)pCO2R6, YCCR^OR6 , Y(CR32)pR6 ,Y(CR32)pOCOR6; or R1 and R2 are linked together as -OCH2O- or -OCH2CH2O-.
20 In one embodiment, R1 and R2 independently preferably represent C1-C8 alkoxy,
Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR32)pC02R6, Y(CR32)pOR6 , Y(CR32)pOCOR6, Y(CR32)pR6 .
In one embodiment, one or both of R1 and R2 is Y(CR32)pNR4R5, Y(CR32)pCONR4R5,
25 Y(CR32)pC02R6, Y(CR32)pOR6, Y(CR32)pR6 or Y(CR32)pOCOR6, wherein at least one R3 15 alkoxy, or one of R4 and R5 is a group selected from -CO-( C1-C8) alkyl, -CO-( C1-C8) cycloalkyl, -S02-( C1-C8) alkyl, -CO-(C1-C8) alkoxy, -CO-NR7(C1-C8) alkyl or C3-C8 cycloalkyl, each of which groups may optionally be substituted by one or more hydroxy, cyano, -CONH2 or -CO-( C1-C8) alkoxy groups, or R4 and R5 together with the nitrogen
30 atom to which they are attached form a 4- to 7-membered saturated or aromatic heterocyclic
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ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, which ring system 15 substituted by at least one substituent selected from hydroxy, C1-C8 alkyl, =0, C1-C8 alkoxy or (C1-C8 alkoxy)-CO-, or R6 is selected from -CO(C1-C8) alkyl or a saturated monocyclic 4- to 7-membered ring, which ring may
5 optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO-.
In a further embodiment, R and R independently preferably represent methoxy, ethoxy, -
10 0(CH2)2 NRV, -0(CH2)3 NR4R5, -OR6, -0(CH2)2R6 , -N(CR3) 2 NRV, - N(CR3) 3 NR4R5, - NCCR3) 2 OR6, - N(CR3) 3 OR6.
Each R3 group independently may suitably represent hydrogen, C1-C8 alkyl, hydroxy, Q-Cg alkoxy or halogen but preferably each R3 independently represents hydrogen or C1-C8
15 alkoxy such as methoxy or ethoxy.
R4 and R5 each independently preferably represent hydrogen or a group selected from C1-C8 alkyl, -CO-(d-Cg) alkyl, -S02-( C1-C8) alkyl, C3-Cg cycloalkyl, each of which groups may be optionally substituted as described above, or R4 and Rs together with the nitrogen atom to
20 which they are attached form a 4- to 7-membered, substituted or unsubstituted, saturated or aromatic heterocyclic ring system optionally containing a further oxygen, sulphur or NR6 group. Particularly preferably, R4and R5each independently represent hydrogen, -CH3, -(CH2)2CN, -COCH3 -COCH(CH3)2, -CH(CH3)2, cyclopropyl, -CO-cyclopropyl, -S02CH3,, -C(=0)-0-C(CH3)3, or R4 and R5 together represent an optionally substituted piperidinyl,
25 pyrrolidinyl, piperazinyl, 1,2,4-triazolyl, 2,5-dioxopyrrolidinyl or 2,5-dioxoimidazolidinyl group.
In a particular embodiment, R1 and R2 are both C1-C8 alkoxy, or one of R1 and R2 15 C1-C8 alkoxy and the other 15 Y(CR32)PNR4R5, Y(CR32)pCONR4R5, Y(CR32)pC02R6,
30 Y(CR32)pOR6, Y(CR32)pR6 or Y(CR32)pOCOR6.
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Where Rl and R2 are both Cg-Cs alkoxy, this is preferably methoxy or ethoxy. In one particular embodiment, R1 and R2 are both methoxy or ethoxy.
5 Preferred compounds of the invention include:-
6,7-diethoxy-4-{[2-ethyl-3-(lH-imidazol-l-ylmethyl)phenyl]amino}quinoline-3-
carboxamide
6,7-diethoxy-4-{[2-methyl-3-(lH-l,2,4-triazol-l-ylmethyl)phenyl]amino}quinoline-3-10 carboxamide
6,7-diethoxy-4- {[2-ethyl-3-(morpholin-4-ylmethyl)phenyl]amino }quinoIine-3-carboxamide
6,7-diethoxy-4- {[3-( lH-imidazol- l-ylmemyl)-2-memyIphenyl]amino }quinoline-3-
carboxamide
4-{[3-azidomediyl)-2-inethylphenyl]amino}-6,7-emoxyquinoUne-3^aiboxamide
15 6,7-dietfioxy-4-{ [2-meuiyl-3K4H-l,2,4-^azol-4-ylrnethyl)phenyl]amino}quinoline-3-
carboxamide
4-{ [3-({ [4-(aininosulfonyl)benzyl]amino}methyl)-2-ethylphcnyl]amino}-6,7-
dimethoxyquinoline-3-carboxamide
4-( {2-ethyl-3-[( 1H-1,2,4-triazol-5-ylamino)methyl]phenyl} amino)-6,7-dimethoxyquinoline-20 3-carboxamide
4-{[2-ethyl-3-(lH-imidazoI-l-ylmethyl)phenyl]amino}-6,7-dimethoxyquinoline-3-
carboxamide
6,7-diethoxy-4-({ 2-ethyl-3-[(pyrimidin-2-ylamino)mediyI]phenyI} amino)quinoline-3-
carboxamide
25 6,7-diethoxy-4-[(2-ethyl-3-{ [(2-hydroxycyclohexyl)amino]methyl}
3-carboxamide
phenyl )amino]quinoline-6,7-diethoxy-4-[(2-ethyl-3- {[(3-thienylmethyl)amino]methyl }phenyl)amino]quinoline-3-
carboxamide
6,7-diemoxy-4-({2ethyl-3-{[lH-imidazol-2-ylthio)methyl]phenyl}amino)quinoline-3-30 carboxamide
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6,7-diethoxy-4- {[2-ethyl-3-(thiomorpholin-4-yImethyl)phenyI]amino }quinoline-3-
carboxamide
6,7-diethoxy-4-[(2-ethyl-3-{[(3-thienylmethyl)amino]methyl}phenyl)amino]quinoline-3-
carboxamide
5 4-({2^thyl-3-[(4-nitro-lH-imidazol-l-yl)mcthyl]phenyl}amino)-6,7-dimethoxyquinoline-3-
carboxamide
4-[(2^thyl-3-{[4-(hydroxymethyl)-lH-iraidazol-l-yl]methyl}phenyl)amino]-6,7-
dimethoxyquinoline-3-carboxamide trifluoroacetate (salt)
4-({2-ethylO-[(2-methyl-lH-inudazol-l-yl)methyl]phenyl}amino)-6,7diemethoxyquinoline-
10 3-carboxamide
I-(3-{[3-(amininocabonyl)-6,7-methoxyquinolin-4-yl]amino}-2-ethylbenzyl)-lH-
imidazole-4-caiboxylic aC1d
4-({ 3-[(cyclopentylamino)methyl]-2-cthylphenyi }amino)-6,7-dimethoxyquinolinc-3-
carboxamide
15 4-{ [2-ethyl-3-({ [2-(lH-imidazol-4-yl)ethyl]amino }methyl)phenyl]amino}-6,7-
dimethoxyquinolinc-3-carboxamide
4-[(2-ethyl-3- {[(2-hydroxy-1,1 -dimethyl)amino]methyl} phenyl)amino]-6,7-
dimethoxyquinoline-3-carboxamide
4-({2^thyl-3-[(l,3-thiazoI-2-ylamino)methyl]phenyl}amino)-6,7-dimethoxyquinoline-3-
20 carboxamide
4-[(2-ethyl-3-{[(2-hydroxypropyl)amino]methyl}phenyl)amino]-6,7-dimethoxyquinoline-3-
carboxamide
4-[(2-cthyl-3- {[(2-hydroxy-2-phenylethyl)amino]methyl }phenyl)amino]-6,7-
dimethoxyquinoline-3-carboxamideb15(trifluoroacetate)
25 4-{ [2-ethyl-3-({ [4-(methylsulfonyl)benzyl]amino }methyl)phenyl]amino}-6,7-
dimethoxyquinoline-3-carboxamide
4-({ 3-[(benzylamino)methyl]-2-cthylphenyl }amino)-6,7-dimethoxyquinoline-3-
carboxamide
4-({2-ethyl-3-[(3-methyl-2,5-dioxoimidazolidin-l-yl)methyl]phenyl}amino)-6,7-30 dimethoxyquinoline-3-carboxamide
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4-({2-ethyl-3-[(lH-tetrazol-5-ylamino)methyl]phenyl}amino)-6,7-dimethoxyquinoline-3-
carboxamide
4-({3-[(5-amino-lH4etrazol-I-yI)methyl]-2^thylphenyl}amino)-6,7-dimethoxyquinolinc-
3-carboxamide
5 4-{ [2-ethyl-3-({ [2-(2-oxoimidazolidin-l-yl)ethyl]amino}methyl)phenyl]amino}-6,7-
dimethoxyquinoline-3-carboxamide
4-{ [2-ethyl-3-({ [(2S)-2-hydroxycyclohexyl]amino}methyl)phenyl]amino}-6,7-
dimethoxyquinoline-3-carboxamide
4-( {2-ethyl-3-[(piperidin-4-ylamino)methyl]phenyl} amino)-6,7-dimethoxyquinoline-3-
10 carboxamide
4-{[2-ethyl-({[(lR)-(hydroxymethyl)-3-mcthylbutyl]amino}methyl)phenyI]a
dimethoxyquinoline-3-carboxamide
6,7-diethoxy-4-[(2-cthyl-3-{[4-(3-metiioxyphcnyl)piperazin-l-
yl]methyl}phenyl)amino]quinoline-3-caiboxamide
15 6,7-
yl]methyl} phenyl)amino]quinoline-3-carboxaniidc
6,7-diethoxy-4-[(2-ethyl-3-{[2-(hydroxyincthyl)piperidin-l-
yl]methyl }phenyl)amino]quinoline-3-carboxamide
4- {[3-( 1 t4'-bipiperidin-1 '-ylmethyl)-2-ethylphenyl]amino} -6,7-diethoxyquinoline-3-
20 arboxamide
4-[(3-{ [4-(aminocarbonyl)piperidin-l-yl]methmyl }-2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
4-[(3-{ [4-(2-cyanophenyl)piperazin-l-yl]methyl }-2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
25 4-[(3-{ [4-(5-cyanopyridin-2-yl)piperazin-l-yl]methyl }-2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-[(2-ethyl-3-{[(3-furylmethyl)amino3methyl}phenyl)amino]quinoline-3-
carboxamide
6,7-diethoxy-4-[(2-ethyl-3-{[4-(2-hydroxyethyl)piperazin-l-
30 yl]methyl} phenyl)amino]quinoline-3-carboxamide
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6,7-diethoxy-4-({2-ethyl-3-[(4-hydroxypiperidin-l-yl)methyI]phenyl}amino)quinoline-3-
carboxamide
4- {[3-( {[2-( 1,3-benzodioxol-5-yl)ethyl]amino}methyl)-2-ethylphenyl]amino} -6,7-
diethoxyquinoline-3-carboxamide
5 6,7-diethoxy-4-{ [2-ethyl-3-( {[2-(2-thienyl)ethyl]amino} methyl)phenyl]amino }quinoline-3-
carboxamide
4-{[3-({[(2,5-dimethyl-3-furyl)methyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-{[2-cthyl-3-({[3-(2-oxopyrrolidin-l-
10 yl)propyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
4-{ P-({ [2-(3^Worophcnyl)ethyl]amino}methyl)-2-ethylphcnyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
4-{ [3-({ [2-(4-chlorophenyl)ethyl]amino}methyl)-2-ethylphcnyl]amino}-6,7-
diethoxyquinoline-3-caiboxamide
15 4-{ [3-({ [2-(2H;hlon)phenyl)ethyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-caiboxamide
6,7-diethoxy-4-[(2-ethyl-3-{[(2-hydroxy-2-
phenylethyl)amino]methyl}phenyl)amino]quinoline-3-carboxamide
4-({3-[(cyclopentylamino)methyl]-2-ethylphenyl}amino)-6,7-dicthoxyquinoIine-3-
20 carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [2-(lH-imidazol-4-
yi)ethyl]amino}methyl)phenyl]amino}quinoline-3-carboxarnide
6,7-diethoxy-4-[(2-ethyl-3-{[4-(2-morpholin-4-ylethyl)piperazin-l-
yI]methyl}phenyl)amino]quinoline-3-carboxamide
25 4-{ [3-({ [(2,2-dimethyl-l,3-dioxolan-4-yl)methyl]amino}methyI)-2-ethylphenyl]amino }-
6,7-diethoxyquinoline-3-carboxamide
6,7-diethox y-4-( {2-ethyl-3-[( 1,3-thiazol-2-ylamino)methyl]phenyl} amino)quinoline-3-
carboxamide
6,7-diethoxy-4-{[2-ethyl-3-(l,3-thiazolidin-3-ylmethyl)phenyl]amino}quinoline-3-
30 carboxamide
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6,7-diethoxy-4-[(2-ethyl-3-{[(2-pyridin-2-ylethyl)amino]methyl}phenyl)amino]quinoline-3-
carboxamide
6,7-diethoxy-4-({ 2-ethyl-3-[(lH-1,2,4-triazol-3-ylamino)methyl]phenyI} amino)quinoline-3-
carboxamide
5 6,7-diethoxy-4-{ [2-ethyl-3-({ [4-(2-thienyl)benzyl]amino}methyl)phenyl]amino}quinoline-
3-carboxamide
4-{[3-({[4-(aminosulfonyl)benzyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoJine-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [2-(lH-indol-3-
10 yl)ethyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [3-
yl)propyl]amino}methyl)phenyl]amino}quinoHne-3-caitooxamidc
6,7-ethoxy-4-[(2-ediyl-3-{[(l-methylpipcridinO-yl)amino ]methyl}phenyl)amino
3-caiboxamide
15 6,7-diethoxy-4-[(2-emyl-3-{ [4-(pyridin-4-ylmethyl)pipcrazin-l-
yl(methyl }phenyl)amino]quinoline-3-carboxamide
6,7-diethoxy-4-[(2-ethyl-3- {[(pyridin-4-yImethyl)amino]methyl} phenyl)amino]quinoline-3-
carboxamide
6,7-iethoxy^[(methyl-3-{[(pyridinO-ybnethyl)amino]methyl}phenyl)amino]quinoline-3-20 carboxamide
4-( {3-[(benzylamino)methyl]-2-ethylphenyl }amino)-6,7-dicthoxyquinoline-3-carboxaniide
6,7-diedioxy-4-[(2-ethyl-3-{[(2-furylmethyl)amino]methyl}phenyl)amino]quinoline-3-
carboxamide
6,7 ethoxy[(methyl-3-{[(2-memoxyethyl)arruno]methyl}phenyl)amino]quinolinc-3-
25 carboxamide
6,7-diethoxy-4-[(2-ethyl-3- {[(2-hydroxypropyl)amino]methyl} phenyl)amino]quinoline-3-
carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [4-(lH-pyrazoi-l-
yI)benzyI]amino} methyl)phenyl]amino }quinoline-3-carboxarnide
WO 2005/075429
4-( {3-[({ 2-[4-(aminosulfonyl)phenyl]ethyl} amino)methyl]-2-ethylphenyl} amino)-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-{[2-ethyl-3-({[2-(l-methylpyrrolidin-2-
yl)ethyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
5 4-[(3-{ [(4-chlorobenzyl)amino]methyl }-2-ediylphenyl)amino]-6,7-diethoxyquinoline-3-
carboxamide
4-[(3-{ [(l-benzylpiperidin-4-yl)amino]methyl }-2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
6,7^ethoxy^[(2^thyl-3-{[(3-methoxybenzyl)amino]methyl}phenyl)amino]quinoline-3-
10 carboxamide
6,7 ethoxy^[(2^thyl-3-{[(4-mcthoxybenzyl)amino)]methyl}phenyl)amino]quinoIinc-3-
carboxamide
6,7-dicthoxy-4-{ [2-ethyl-3-({ [3-(lH-imidazol-l-
yl)propyl]amino}methyl)phenyl]amino)}quiiwline-3-uboxamidc
15 6J^ethoxy^{[2--lH-mdcn-l-
yl]amino}methyl)phenyl]amino}quinoline-3-caiboxamidc b15(trifluoroacetate) (salt)
6,7-dicthoxy^-{[2-ethyl-3-(lt2-hydix)xy-l-(lH-indol-2-
ylmethyl)ethyl]amino} methyl)phenyl]amino }quinoline-3-carboxamide b15(trifluoroacetate)
(salt)
20 6,7-diethoxy-4-{ [2-ethyl-3-({ [(lR)-2-hydroxy-l-
phenylethyljamino} methyl)phenyl]amino }quinoline-3-carboxamide b15(trifluoroacetate)
(salt)
6,7-Diethoxy-4-{2-ethyl-3-[(2-hydroxy-l-methylcarbamoyl-propylamino)-m
ethyl]-phenylamino}-quinoline-3-carboxylic aC1d amide
25 6,7-diethoxy-4-{ [2-ethyl-3-({ [(lR,2S)-2-hydroxy-l-(hydroxymethyl)propyl]amino}methyl)
phenyl]amino }quinoIine-3-carboxamide
6,7-diethoxy^-{ [2-ethyl-3-({ [(lR,2R)-2-hydroxy-l-
(hydroxymethyl)propyl]amino} methyl)phenyl]amino }quinoline-3-carboxamide
methyl N-(3-{ [3-(aminocaibonyl)-6,7-diemoxyquinolin-4-yl]amino }-2-ethyl benzyl )serinate
30 b15(trifluoroacetate)
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6,7-diethoxy-4-{ [2-ethyl-3-({ [2-hydroxy-l-
(hyd^xymethyl)ethyl]amino}methyl)phenyl]amino}quinoUne-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [l-(hydroxymethyl)-3-
methylbutyl]amino} methyl)phenyl]amino }quinoline-3-caiboxamide
5 6,7-diethoxy-4-[(2-ethyl-3-{ [(2-pyrrolidin-1-
ylethyl)amino]methyl} phenyl)amino]quinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyI-3-({ [(lS,2R)-2-hydroxy-l-
(hydroxymethyl)propyl]amino}methyl)phenyl]amino}quinoline-3-caiboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [(lS)-l-(hydroxymcthyl)-3-
10 methylbutyl]amino}methyl)phcnyl]amino}quinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [1-
(hydroxymethyl)butyl]ainiiH>}inediyl)phenyl]aniino}quinoUne-3-caibox
4-{3^(l<:artjamoyl-2>
-6,7-dietfioxy-quinoline-3-carix>xylic aC1d amide
15 6,7-dicthoxy-4-[(2-ethyI-3-{[[(lR,2R)-2-hydioxy-l-methyI-2-
phenyletfiyl](methyl)amino]methyl} phenyl)amJno]quinoline-3-carboxamide
6,7-diethoxy-4-[(2-ethyl-3-{[(2-hydn>xy-l-roethyl-2-
phenylethyl)amino]methyl}phenyl)amino]quinoline-3-caiboxamide
4-{[3^{[2^3,4^hydroxyphenyl)-2-hydioxyethyl]anuno}methyl)-2^thylphenyl]amino}-
20 6,7-diethoxyquinoline-3-carboxamide
6J^iethoxy^[(2^thyl-3-{[(2-hydroxypropyl)amino]methyl}phcnyl)amino]quinoline-3-
carboxamide
6,7-diethoxy-4-[(2-ethyI-3-{[(2-hydroxy-l-
methylethyl)amino]methyl}phenyl)amino]quinoline-3-caiboxamide
25 6,7-diethoxy-4-[(2-ethyl-3-{ [(2-hydroxyethyl)amino]methyl }phenyl)amino]quinoline-3-
carboxamide
4-[(3-{ [(2,3-dihydroxypropyl)amino]methyl} -2-ethylphenyl)amino]-6,7-diethoxyquinoline-
3-carboxamide
6,7-diethoxy-4-{ [2-cthyl-3-({ (2-30 (hydroxymediyi)phenyl]amino}methyl)phenyl]amino}qiiinoHnc-3-caitK>xamidc
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4-{[3K{[(lS)-l-benzyl-2-hydroxyethyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide b15(trifluoroacetate) (salt)
4-{ [3-({ [2-(dimethyIamino)ethyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide tr15(trifluoroacetate) 5 6,7-diethoxy-4-{[2-ethyl-3-({[4-
(methylsulfonyl)phenyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
b15(trifluoroacetate)
6,7-diethoxy-4-{ [2-ethyl-3-({ [(lS>2-hydroxy-l-
phenylethyl]amino}methyl)phenyl]amino}quinoline-3
6,7-diethoxy-4-[(2-cthyl-3-{ [(2R>2-(hydroxymethyl)pynrolidin-l-
yl]methyl}phenyl)amino}quinoline-3-cait)Oxamide b15(trifluocoacetate) (salt)
6jHlicthoxy^{[2^^ylOK{[(lS3)-2-hydroxy-l-(hydioxymcthyl)-2-
phenylethyl]amino}methyl)phenyl]amino}quinoline-3-carboxai^ 15 (salt)
6,7-dicthoxy-4-[(2-cthyl-3-{ [(2-morpholin-4-
ylethyl)amino]methyl }phcnyl)amino]quinoline-3-caiboxamide tr15(trifluoroacetate)
6,7-diethoxy-4-{ [2-cthyl-3-({ [(lR^S)-2-hydroxy-2-(4-hydroxyphenyl)-l-
methylethyl]amino}methyl)phenyl]amino}quinoline-3^arboxamidcb15(trifluoroacetate) 20 (salt)
6,7-diethoxy-4-{ [2-cthyl-3-({ [(lR,2R)-2-hydroxy-l-(hydroxymethyl)-2-
phenylethyl]amino} methyl)phenyl]amino }quinoline-3-carboxamide b15(trifluoroacetate)
(salt)
6,7-Diethoxy-4-{2-ethyl-3-[(2-hydroxy-l-hydroxymethyl-2-phenyl-ethylam
25 ino)-methyl]-phenylamino}-quinoline-3-carboxylic aC1d amide b15(trifluoroacetate)
4-[(3-{[(2-cyanoethyl)amino]methyl}-2-ethylphenyl)amino]-6,7-diethoxyquinoline-3-
carboxamide b15(trifluoroacetate)
6,7-diethoxy-4-{ [2-ethyl-3-({ [l-(hydroxymethyl)-2-
methylpropyl]amino}methyl)phenyl]amino}quinoline-3^arboxamideb15(trifluoroacetate) 30 (salt)
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6,7-diethoxy-4-{ [2-ethyl-3-({ [4-
(methylsulfonyl)benzyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
b15(trifluoroacetate)
tert-butyl (3-{ [3-(aminocarbonyl)-6,7-diethoxyquinolin-4-yl]amino}-2-5 ethylbenzyl)carbamate
4-{[3-(aminomethyl)-2^thylphenyl]amino}-6J-Kiicthoxyquinoline-3-carboxamidc
4-{[3^aminomethyl)-2-methylphenyl]amino}-6,7-diethoxyquinolinc-3-cari)oxamide
6,7-diethoxy-4-( {2-ethyl-3-[(L-tyrosylamino)methyl]phenyl} amino)quinolinc-3-
carboxamide b15(trifluoroacetatc) 10 6,7-diethoxy-4-{[3-({[(ethylamino)carbonyl]amino}methyI)-2-
methylphenyljamino }quinoIine-3-carboxamide
4^{3-[(acetylamino)mediyl]-2-methylphenyl}amino)^J^edioxyquinoline-3-carboxamide
6t7-dicthoxy-4-({ 2-methyl-3-[({ [(4-methyl-2r5-dioxoimidazolidin^-
yl)methyl]sulfonyl}amino)roethyl]phcnyl}amiiK))quinolinc-3-cartK>xamide
15 4-({ 3-[(acetylamino)methyl]-2-ethylphenyl }amino)-6J-dimetiK>xyquinoline-3-carboxamide
4- {[2-ethyl-3-( {[(ethylamino)carbonyI]amino} mediyl)phetiyl]ainino} -6,7-
dimethoxyquinoline-3-carboxamide
4-[(2-ethyl-3- {[(methylsulfonyl)amino]methyl} phenyl)amino]-6,7-dimethoxyquinoline-3-
carboxamide
20 4-({2-ethyl-3-[(L-valylamino)methyl]phenyl}amino)-6,7-diniethoxyquinoline-3-
carboxamide
4-[(3-{ [(3-cyclohexyl-L-alany])amino]methyl }-2-ethylphenyl)amino]-6,7-
dimethoxyquinoline-3-carboxamide
6,7-diethoxy-4-( {2-ethyl-3-[(L-methionylamino)methyl]phenyl} amino)quinoline-3-25 carboxamide b15(trifluoroacetate)
6,7-diethoxy-4-({2-ethyl-3-[(L-prolylamino)methyl]phenyl}amino)quinoline-3-
carboxamide b15(trifluoroacetate)
6,7-diethoxy-4-( {2-ethyl-3-[(L-threonylamino)methyl]phenyl} amino)quinoline-3-
carboxamide b15(trifiuoroacetate)
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N~ 1 ~-(3- {[3-(aminocarbonyl)-6,7-diethoxyquinolin-4-yI]amino} -2-ethylbenzyl)-L-alpha-
glutamine b15(trifluoroacetate)
6J^ethoxy^-({2^thyl-3-[(I^valylamino)methyl]phenyl}amino)quinoline-3-carboxamide
b15(trifluoroacetate) 5 4-({3-[G^-arginylamino)methyl]-2-ethylphenyl}amino)-6,7-diethoxyquinoline-3-
carboxamide tr1
5 (trifluoroacetate)
4-({ 3-[(L-alanylamino)mcthyl]-2-cthylphenyl} amino)-6,7-diethoxyquinoline-3-
carboxamide b15(trifluoroacetate)
6J^ethoxy-4^{2^thylO-[(D-serylamino)methyl]phenyl}anuno)quinoline-3-
4-[(3-{ [(3-cyclohexyI-L-alanyl)amino]methyl }-2-cthylphcnyl)amino]-6,7-
diethoxyquinoline-3-carboxamide b15(trifluoroacctate)
6,7-dicthoxy-4-{ [2-«thyl-3-({ [(4S)-13-thiazolidin-4-
ylcarix>nyl]amiiK>}inethyl)phenyl]ainiiK>}quin
15 6,7-diethoxy4-{ [2-cthyl-3-({ [(4R)-4-hydroxy-L-
prolyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide b15(trifluoroacetate) (salt)
6,7-diethoxy-4-({ 2-ethyl-3-[(D-leucylamino)methyl]phcnyl) amino)quinoline-3-
carboxamide b15(trifluoroacetate)
N~ 1 ~-(3- {[3-(aminocarbonyl)-6,7-diethoxyquinolin-4-yl]amino} -2-ethylbenzyl)-L-
20 aspartamide b15(trifluoroacetate)
6,7-diethoxy-4-{ [2-ethyl-3-({ [(2S)-piperidin-2-
ylcarbonyl]amino}methyl)phenyl]amino}quinoline-3-carboxamideb15(trifluoroacetate)
4-[(3-{ [(3-cyC1ohexyl-D-alanyl)amino]methyl }-2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide b15(trifluoroacetate) 25 6,7-diethoxy-4-{ [2-ethyl-3-({ [(2R)-piperidin-2-
ylcart>onyl]amino}methyl)phenyl]arnino}quinoIine-3-carboxaiTiideb15(trifluoroacetate)
4- {[3-( {[(2S)-2-aminopent-4-enoyl]amino} methy l)-2-ethylphenyl]amino} -6,7-
dicthoxyquinoline-3-carboxamide b15(trifluoroacetate)
4-{ [3-({ [(2S)-azetidin-2-ylcarbonyl]amino}methyl)-2-ediylphenyl]ainino}-6,7-
30 diethoxyquinoline-3-carboxamide b15(trifluoroacetate)
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-*r3|
6,7-diethoxy-4-[(2-ethyl-3- {[(5-methyl-L-
norleucyl)amino]methyl} phenyl)amino]quinoline-3-carboxamide b15(trifluoroacetate)
6,7-diethoxy-4-{ [2-ethyl-3-({ [(4R)-l,3-thiazolidin-4-
ylcarbonyl] amino} methyl)phenyl]amino} quinoline-3-carboxamide b15(trifluoroacetate) 5 6,7-diethoxy-4-[(2-€thyl-3- {[(4-nitro-D-
phenylalanyl)amino]mcthyl }phenyl)amino]quinoline-3-carboxamide b15(trifluoroacetate)
4-{ [3-({ [(l-amino-2,3-dihydro-lH-inden-l-yl)carbonyl]amino}methyl)-2-
ethylphenyljamino }-6,7-diethoxyquinoline-3-caiboxamide b15(trifluoroacetate)
4-{ [3-({ [(l-aminocyclohcxyl)caibonyl]amino }mcthyl)-2-ethylphcnyl]amino}-6,7-10 diethoxyquinoline-3-carboxamide b15(trifluoroacetate)
6,7-diethoxy-4-{ [2-cthyl-3-({ [(3R>1,2,3,4-tetrahydro15oquinolin-3-
ylcaibonyl]amino} methyl)phenyl]amino }quinoline-3-carboxamidc b15(trifluoroacctate)
4-{[3^{[(2R)-2-amino^phcnylbutanoyl]ainino}methyl)-2-ethylphcnyI]amino}-6,7-
dicthoxyquinoline-3-carboxamidc b15(trifluoroacetate) 15 6,7-diethoxy-4-{ [2-ethyl-3-{{ [(3S)-l^,3,4-tetrahydro15oquiiiolin-3-
ylcaitK>nyl]ainiiK>}methyl)phenyI]annino}quiiK>line-3^:aiboxamidc b15(trif1uoroacctate)
6J-diethoxy-4-[(2-ethyl-3-{[(4-piperidin-4-yl-L-
prolyl)amino]methyl }phenyI)amino]quinoline-3-carboxamide tr15(trifluoroacetate)
4-[(3- {[(3-amino-L-alanyl)amino]methyl} -2-ethylphenyI)amino]-6,7-dicthoxyquinoline-3-20 caiboxamide tr15(trifluoroacetate)
6J^ethoxy^({2^thyl-3-[(D-phenylaIanylamino)methyl]phenyl}amino)quinoHne-3-
carboxamide b15(trifluoroacetate)
4- {[3-( {[(2S)-2-amino-4-phenylbutanoyl]amino} methyl)-2-ethylphenyl]amino} -6,7-
diethoxyquinoline-3-carboxamideb15(trifluoioacetate) 25 6,7-diethoxy-4-{ [2-ethyl-3-({ [(3S)-piperidin-3-
y]carbonyl]amino}methyl)phenyl]amino}quinoHnc-3-carboxamideb15(trifluoroacetate)
6,7-diethoxy-4-{ [2-ethyl-3-({ [(3R>piperidin-3-
ylcarbonyl]amino} methyl)phenyl]amino }quinoline-3-carboxamide b15(trifluoroacetate)
4-{ f3-({ [(2S)-2-amino-2-phenylacetyl]amino}methyl)-2-ethylphenyl]amino}-6t7-30 diethoxyquinoline-3-carboxamide b15(trifluoroacetate)
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6,7-diethoxy-4-({2-ethyl-3-[(L-leucylamino)methyl]phenyl}amino)quinoline-3-
carboxamide b15(trifluoroacetate)
6,7-diethoxy-4-({2-ethyl-3-[(D-prolylamino)methyl]phenyl}amino)quinoline-3-
carboxamide b15(trifluoroacetate) 5 4-{ [3-({ [(2S)-2,5^hydro-lH-pyirol-2-ylcaitonyl]amino}methy])-2-ethylpheny]]amino}-
6,7-diethoxyquinoline-3-carboxamideb15(trifluoroacetate)
6J^iethoxy^({2^thylO-[(glycylamino)methyl]phenyl}amino)quinoline-3-caiboxamide
b15(trifluoroacetate)
4-{ [3-({ [2-amino^^methykulfinyl)butanoyl]amino}methyl)-2-ethylphenyl]amino}-6,7-10 diethoxyquinoline-3-carboxamide b15(trifluoroacetate)
6,7-diethoxy-4-{ [2-ethyl-3-({ [3K2-fuiyl>L-alanyl]anuno}methyl)phcnyl]aniino}quinoline-
3-carboxamide b15(trifluoroacetate)
6,7-dicthoxy-4-[(2-ethyl-3-{[(3-pyridin-2-yl-L-
alanyl)amino]methyl }phenyl)amino]quinoline-3-carboxamide tr15(trifluoroacetate) 15 6,7-diethoxy-4-{[2-ethyl-3-({[3-(2-thicnyi)-L-
alanyl]amino} methyl )phenyl]amino }quinoline-3-carboxamide b15(trifluoroacctate)
6,7-diethoxy-4-{[2-ethyl-3-({[3-(l,3-thiazol-4-yl)-L-
alanyl]amino} methyl)phenyl]amino} quinoline-3-carboxamide tr15(trifluoroacetate)
4-{ [3-({ [(2S>2-amino-2-cyclopentylacetyl]anndno }medryl)-2-cthylphenyl]amino}-6,7-20 diethoxyquinoline-3-carboxamide b15(trifluoroacetate)
4-{ [3-({ [(2S)-2-aminopent-4-ynoyl]amino}methyl)-2-cthylphenyl]aiiiino}-6,7-
diethoxyquinoline-3-carboxamideb15(trifluoroacetate)
6J^iethoxy^({2^thyl-3-[(L-norvalylamino)methyl]phenyl}amino)quinoline-3-
carboxamide b15(trifluoroacetate) 25 4-{ [3-({ [(2R)-2-amino-2-phenylacetyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamideb15(trifluoroacetate)
6,7-diethoxy-4-{ [2-ethyl-3-({ [(4R)-4-hydroxy-D-
prolyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide b15(trifluoroacetate) (salt)
4-({3-[(beta-alanylamino)methyl]-2-ethylphenyl}amino)-6,7-dicthoxyquinoline-3-30 caiboxamide b15(trifluoroacetate)
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6,7-diethoxy-4-[(2-ethyl-3- {[(3-pyridin-3-yl-L-
alanyl)amino]methyl}pheny])amino]quinoline-3-cait)oxamidetr15(trifluoroacetate)
6,7-diethoxy-4-[(2-ethyl-3- {[(3-pyridin-3-yl-D-
alanyl)amino]methyl }phenyl)amino]quinoline-3-carboxamide tr15(trifluoroacetate) 5 4-{ [3-({ [N~5~-(aminocarbonyl)-L-omithyI]amino}nwthyI)-2-ethyiphcnyl]amino}-6,7-
diethoxyquinoline-3-carboxamideb15(trifluoroacetate)
6,7-diethoxy-4-[(2-ethyl-3-{[(5-methyl-D-
norleucyl)amino]methyl }phenyl)amino]quinoline-3-carboxamide b15(trifluoroacetate)
^[(3-{[(23^hydro-lH-15oindol-l-ylcarbonyl)amino]methyl}-2-ethylphcnyl)amino]-6f7-10 diethoxyquinoline-3-carboxamide b15(trifluoroacetatc)
6,7^ethoxy-4^{2-ethyl-3-[(I^15oleucylamino)methyl]phenyl}amino)quinoline-3-
carboxamide b15(trifluoroacetate)
6,7-dicthoxy-4-({ 2-ethyI-3-[(D-valylamino)methyl]pbenyl }amino)quiiiolinc-3-caiboxamide
b15(trifluoroacetate) 15 4- {[3-( {[(1 -aminocyclopcntyl)carbonyl]amino} methyl)-2-ethylphenyl]amino} -6,7-
diethoxyquinoline-3-carboxamide b15(trifluoroacetate)
4-{ [2-ethyl-3-(hydroxymethyl)phenyl]amino)-7-{ 3-[15obutyryl(15opropyl)amino]propoxy}-
6-mcthoxyquinoline-3-caiboxamide
7-{3-[acetyl(15opropyl)amino]propoxy}-4-{[2-ethyl-3-(hydroxynwthyl)phenyl]aiiiino}-6-20 methoxyquinoline-3-carboxamide
6-[2-(acetylamino)ethoxy]-4-[(2^thylphenyl)ainino]-7-methoxyquinoline-3-cai1x)xainidc
6- {2-[acetyl(methyl)amino]ethoxy} -4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-
carboxamide
6-{2-[acetyl(15opropyI)amino]ethoxy}-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-25 carboxamide
4-[(2-ethylphenyl)amino]-6-{2-[15obutyryl(methyl)amino]ethoxy}-7-methoxyquinolinc-3-
carboxamide
4-[(2-ethylphenyl)amino]-6-{2-[15obutyryl(15opropy])amino)ethoxy}-7-methoxyquinoline-
3-carboxamide
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I
7- {3-[acetyl(methyl)amino]propoxy} -4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -6-
methoxyquinoline-3-carboxamide
4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -7-{ 3-[15obutyryl(methyl)amino]propoxy} -6-
methoxyquinoline-3-carboxamide 5 7- {3-[acetyl(cyclopropyl)amino]propoxy} -4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -6-
methoxyquinoline-3-carboxami de
7-{3-[cyclopropyl(15obutyryl)amino]propoxy}-4-{[2-cthyl-3-
(hydroxymethyl)phenyl]amino} -6-methoxyquinoline-3-carboxamide
7-[3-(acetylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-10 methoxyquinoline-3-carboxamide
4-{[2-cthyl^Khydroxymethyl)phcnyl]amino}-7-[3-(15obutyrylamino)propoxy]-6-
methoxyquinoline-3-carboxamide
6-{2-[(cyclopropylcaibonylXmethyl)amino]cthoxy}-4-[(2-ethylphcnyI)aniino]-7-
methoxyquinoline-3-carboxamide 15 6-{ 2-[(cyclopropylcarbonylX15opropyl)amino]cthoxy }-4-[(2-cthylphenyl)amino]-7-
methoxyquinoline-3-catboxamide
4-{ [2-ethyl-3-(hydroxymcthyl)phenyl]amino }-7-{ 3-
[15opropyl(methylsulfonyl)amino]propoxy} -6-methoxyquinoline-3-caiboxamide
4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino }-6-methoxy-7- {3-20 [(methylsulfonyl)amino]propoxy }quinoline-3-carboxamide
tert-butyl {3-[(3-(aminocaibonyl)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-
methoxyquinolin-7-yl)oxy]propyl} 15opropylcarbamate
4-{ [2-ethyl-3-(hydroxymcthyl)phenyl]amino }-7-(3-
{15opropyl [(15opropylamino)carbonyl]amino} propoxy)-6-methoxyquinoline-3-carboxamide 25 7-[3-(cyclopropylamino)propoxy]-4-{[2-cthyI-3-(hydroxymethyl)phenyl]amino}-6-
methoxyquinoline-3-carboxamide
6^[3-(cyclopropylarruno)propoxy]^-{[2^thyl-3-(hyoYoxymethyI)phenyl]amino}-7-
methoxyquinoline-3-carboxamide
7-{ 3-[(2-cyanoethyl)(methyl)amino]propoxy }-4-{ [3-(hydroxymethyl)-2-
30 methylphenyl]amino} -6-methoxyquinoline-3-carboxamide b15(trifluoroacetate) (salt)
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4- {[3-(hydroxymethyl>2-methylphenyl]amino} -6-methoxy-7-[3-(2-methylpiperidin-1 -
yl)propoxy]quinoline-3-carboxamide
7- {3-[(2-cyanoethyl)(methyl)amino]propoxy} -4- {[3-(hydroxymethyl)-2-
methylphenyl]amino}-6-methoxyquinoline-3-carboxamide
5 4-{[3-(hydroxymethy])-2-methylpheny]]amino}-7-[3-(3-hydroxypiperidin-l-yl)propoxy]-6-
methoxyquinoline-3-carboxamide
4-{[3-(hydroxymethyl)-2-methylphenyl]amino}-7-[3-(4-hydroxypiperidin-l-yl)propoxy]-6-
raethoxyquinoline-3-carboxamide
6-methoxy-^[(2-methylphenyl)amino]-7-[3-(2-nMthylpiperidin-l-yl)propoxylquinoline-3-10 carboxamidc
7-[3^3-hydroxypipcridin-l-yl)propoxy]^methoxy^[(2-methylphenyl)aniino]quinoUnc-
carboxamide
7-[3^4-hydroxypipOTdin-l-yl)propoxy]^methoxy-4-[(2-mediylphenyl)amino]quinoline-3-
caiboxamide
15 4-{ (3Khydroxymethyl>-2HnethylphenylJamino}-7-[3K3-ty
6-methoxyquinoUnc-3-carboxamide
4-{[2^thyIOKhydroxymethyI)phenyl]amino}^mrthoxy-7-[3KlH-l,2,4-triazol-l-
yl)propoxy]quinoline-3-carboxamide b15(trifluoroacetate) (salt)
7-[2-(cyclopropylamino)ethoxy]^{[3-(hydroxyniethyl)-2-inethylphenyl]amino}-6-
20 methoxyquinoline-3-carboxamide b15(trifluoroacetate) (salt)
6-[2-(cyclopropylamino)ethoxy]-4-{[3-(hydroxynicdiyl)-2-methylphenyl]amino}-7-
methoxyquinoline-3-carboxamide b
(trifluoroacetate) (salt)
6-[2-(cyclopropylamino)ethoxy]-4-[(4-ethylphenyl)amino]-7-niethoxyquinoline-3-
carboxamide
25 6-C2-(cyclopropylamino)ethoxy]-4-[(3-ethylphcnyI)ainino]-7-medioxyquinoline-3-
carboxamide
6-[2-(cyclopropylamino)ethoxy]-7-medioxy-4-[(2-methylphenyl)amino]quinolinc-3-
carboxamide b15(trifluoroacetate)
6- {2-[(2-cyanoethyl)amino]ethoxy} -4- {[3-(hydroxymethyl)-2-methylphenyl]aiiiino} -7-
30 methoxyquinoline-3-caiboxamide b15(trifluoroacetate) (salt)
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6-[3-(cyclopropylamino)propoxy]-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-
carboxamide b15(trifluoroacetate)
6- {3-[(cyanomethyl)amino]propoxy} -4-[(2-ethylphcnyl)amino]-7-methoxyquinoline-3-
carboxamide
5 6-[3-(Carbamoylmethyl-amino)-propox
y]-4-(2-ethyl-phenylaniino)-7-methox
y-quinoline-3-carboxylic aC1d amide b15(trifluoroacetate)
methyl N-[3-( {3-(aminocarbonyl)-4-[(2-ethylphenyl)amino]-7-methoxyquinolin-6-
yl }oxy)propyl]glyC1nate b15(trifluoroacetate)
10 7-(3-cyanopropoxy)-4- {[2-ethyl-3-(hydroxymethy l)phenyl]amino} -6-methoxyquinoline-3-
carboxamide trifluoroacetate (salt)
2-[(3-(aminocarbonyl)-4- {[2-ethyl-3-(hydroxymediyl)phenyl]amino }-6-methoxyquinolin-7-
yl)oxy]ediyl acetate trifluoroacetate (salt)
6-[2^cyclropylamino)edK>xy]^[(2-emylphenyl)amino]-7-inedwxyquinoline-3-
15 carboxamide
7-[3-(2,5-dioxopyrrolidin-1 -yl)propoxy]-4-{ [2-ethyl-3-(hydroxymethyl)phenyl]amino} -6-
methoxyquinoline-3-carboxamide
4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(3-mediyl-2,5-
dioxoimidazolidin-l-yl)propoxy]quinoline-3-carboxamide
20 4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -6-methoxy-7-[3-(3,4,4-trimethyl-2,5-
dioxoimidazolidin-l-yl)propoxy]quinoline-3-carboxamide
7-(cyclopentyloxy)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-
carboxamide
6-(cyclopentyloxy)-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide
25 l-{ 3-[(3-(aminocaibonyl)-4-{ [3-(hydroxymethyl)-2-methylphenyl]amino}-6-
methoxyquinolin-7-yl)oxy]propyl }-l-methylpynolidinium iodide
tert-butyl 4-[(3-(aminocarbonyl)-4-{ [2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-
medioxyquinolin-7-yl)oxy]piperidine-l-carboxylate
tert-butyl 4-( {3-(aminocarbonyl)-4-[(2-ethylphenyl)amino]-7-methoxyquinolin-6-
30 yl}oxy)piperidine-l-carboxylate
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>
3-(aminocarbonyl)-4-[(2-ethylphenyl)amino]-7-methoxyquinolin-6-ylpropane-2-sulfonate
4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(piperidin-4-yloxy)quinoline-3-
carboxamide
4-[(2^thylphenyl)amino]-7-methoxy-6-(piperidin^yloxy)quinoline-3-carboxamide
5 6-[3-(cyclopropylamino)-2-hydroxypropoxy]-4-[(2-ethylphenyl)amino]-7-
methoxyquinoline-3-carboxamide
6-{ 3-[(2-cyanoethyI)amino]-2-hydroxypropoxy} -4-[(2-ethylphenyl)amino]-7-
methoxyquinoline-3-carboxamide
4-[(2^thylphcnyl)amino]^[2-hydroxy-3-(2-hydroxypyrrolidin-l-yl)propoxy]-7-
10 methoxyquinoline-3-carboxamide
4-[(2^thylpheny1)amim)]-^2-hydroxy-3-piperazin-l-ylpropoxy)-7-methoxyquinoline-3-
carboxamide
6-{[(2R)-3^cyclopix^ylanuno)-2-hydroxy-2-n»ediylpropyl]oxy)-4-[(2-cdiylphenyl)amino]-
7-medioxyquinoline-3-caiboxamide
15 6- {[(2S)-3-
7-methoxyquinoIine-3-carboxamide
6-[3-(cyclopropylamino)-2-hydroxypropoxy)-4-{[2-cthyl-3-
(hydroxymethyl)phenyl]amino} -7-raethoxyquinoline-3-caitK>xamide
6-{ [(2R)-3-(cyclopropylaniino)-2-hydioxypn>pyl]oxy} -4-[(2-ethylphenyl)amino]-7-
20 methoxyquinoIine-3-carboxamide
6-{[(2S)-3-(cyclopropylaniino)-2-hydroxypropyl]oxy}-4-[(2-cthylphenyl)amino]-7-
methoxyquinoline-3-carboxamide
3-(aminocartx>nyl)^[(2^thylphenyl)amino]-7-methoxyquinolin-6-yl2-methylpropanoate
6,7-diethoxy-4-[(4-methyl-l-oxo-l,2-dihydro15oquinolin-5-yl)amino]quinoline-3-
25 carboxamide
6J-diethoxy^[(4-methyl-l^xo-l,23.4-tetn^ydro15oquinolin-5-yl)amino]quinoline-3-
carboxamide
tert-butyl 4-{ [3-(aminocarbonyl)-6,7-diethoxyquinolin-4-yl]amino}-3t4-
dihydro15oquinoline-2(lH)-carboxylate 30 6,7-dicthoxy-4-( 1,2f3.4-tctrahydro15oquinolin-5-ylamino)quinoline-3-carboxamide
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4-{[3-(azidomethyl)-2-ethylphenyl]amino}-6-[3-(cyclopropylamino)propoxy]-7-
methoxyquinoline-3-carboxamide
4-{[3-(anTinomethyl)-2-cthylphenyI]amino}-6-[3-(cyclopropylamino)propoxy]-7-
methoxyquinoline-3-carboxamide
5 4-{ [3-(aminomethyl)-2-ethylphenyl]amino}-7-{ 3-[15obutyryl(15opropyl)amino]propoxy }-6-
methoxyquinoline-3-carboxamide
4-{[3-(azidomethyl)-2-ethylphenyl]amino}-6-[3-(cyclopropylamino)-2-hydroxypropoxy]-7-
methoxyquinoline-3-carboxamide
4-{[3-(aminomethyl)-2^thylphenyl]amino}-6-[3-(cyclopropylamino)-2-hydroxypropoxy]-
10 7-methoxyquinoline-3-caiboxamide
4-( {3-[(acetylamino)methyl]-2-cthylphenyl} amino)-6- {3-[acetyl(cyclopropyl)amino]-2-
hydroxypropoxy}-7-methoxyquinoline-3-carboxamide
6-[3
ylmethyl)phenyl]amino)-7-methoxyquinoline-3-carboxamidc
15 6-[3-(cycloprc^)ylamino)-2-hydroxypropoxy]-4-{ [2-ethyl-3-(lH-pyrazoM-
ylmethyl)phenyl]amino )-7-methoxyquinoline-3-carboxamide
6-{[(2S)-3^cyclopropylanuno)-2-hydroxypropyl]oxy}^-{[2^thyl-3rpholJn-4-
ylmethyl)phcnyl]amino}-7-methoxyquinoline-3-carboxamide
amino{6,7-diethoxy-4-[(2-ethylphenyl)amino]quinolin-3-yl}methanol
20 6-[3-(cyclopit)pylanuno)propoxy]^{[2^thyl-3-(lH-imidazol-l-ylmethyl)phenyl]amino}-
7-methoxyquinoline-3-carboxamide
4- {[2-ethyl-3-( lH-imidazol-1 -ylmethyl)phenyl]amino }-6-methoxy-7-(2-
inethoxyethoxy)quinoline-3-carboxamide
6-(ethylamino)-4-{ [2-ethyl-3-(lH-imidazol-l-ylmethyl)phenyl]amino }-7-
25 methoxyquinoline-3-carboxamide
6-[(2,2-dimethoxyethyl)amino]-4-[(2-ethylphenyI)amino]-7-methoxyquinoline-3-
carboxamide
6-[(3,3-diethoxypropyI)amino]-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-
carboxamide
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tert-butyl [2-({3-(aminocarbonyl>4-[(2-ethylphenyl)amino]-7-methoxyquinolin-6-
yl }amino)ethyl]carbamate
tert-butyl {2-[(3-(aminocarbonyl)-4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -7-
methoxyquinolin-6-yl)amino]ethyl}carbamate
5 6-{[3-(cyC1opropylamino)propyl]amino}-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-
carboxamide
4-(23-dihydro-lH-inden-l-ylaraino)-6,7-dimethoxyquinoline-3-carboxamide
6J-diethoxy-4-[(2-methylcyclohexyl)amino]quinoline-3-carboxamide
4- {l(3S)-1 -(cyanoacetyl)pyrrolidin-3-yl]amino} -6,7-dimethoxyquinoline-3-carboxamide
10 4-{[(3S)-l-(cyanoacetyl)piperidini3-yl]amino}-6J-dimethoxyquinoline-3-caiboxamide
and pharmaceutically acceptable salts and solvates of any one thereof.
Where the compounds according to the invention contain one or more asymmetrically substituted carbon atoms, the invention includes all stereo15omers, including enantiomers
15 and diastereomers, and mixtures including racemic mixtures thereof. Tautomers and mixtures thereof are also included.
Racemates may be separated into individual enantiomers using known procedures (cf. Advanced Organic Chem15try: 3rd Edition: author J March, pl04-107). A suitable
20 procedure involves formation of diastereomeric derivatives by reaction of the racemic
material with a chiral auxiliary, followed by separation, for example by chromatography, of the diastereomers and then cleavage of the auxiliary speC1es.
The compounds according to the invention may be provided as pharmaceutically acceptable
25 salts. Suitable pharmaceutically acceptable salts include base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calC1um or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino aC1ds for example lysine. In another aspect, where the compound 15 suffiC1ently basic, suitable salts
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include aC1d addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, C1trate, maleate and salts formed with phosphoric and sulphuric aC1d.
The present invention further provides a process for the preparation of a compound of
5 formula (I) as defined above, or a pharmaceutically acceptable salt thereof, which compr15es:
(a) reaction of a compound of formula (II):
10 (ID
in which R1 and R2 are as defined in formula (I) or are protected derivatives thereof and R20 15 a leaving group, with a compound of formula (HI):
15 R*-N(Ra)H (HI)
in which R* and Ra are as defined in formula (I) or a protected derivative thereof, or (b) for compounds of formula (I) where R1 and/or R2 are groups Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR3)pC02R6, Y(CR32)pOR6 or Y(CR32)PR6 where Y 15 oxygen,
20 reaction of a compound of formula (TV):
NFT
R1\ ^^ ^ ^X^ ,
NH2
*' ^ ^' (IV)
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10
where the R1' or R2' to be converted into a group Y(CR32)pNR4, Y(CR3)pCONR4, Y(CR3)pC02R6, Y(CR32)p OR6 or Y(CR32)pR6 15 hydroxy and the other R1' or R2' together with R* are as defined above for process (a) with a compound of formula (V):
5
L-(CR32)pR21 (V)
where R21 15 NR*RS, CONRV, CO2R6, OR6 or R6 and R4, R5 and R6 are as defined in formula (I) or are protected derivatives thereof,
and optionally thereafter process (a) or (b)
• removing any protecting groups
• converting a compound of formula (I) into a further compound of formula (I)
• forming a pharmaceutically acceptable salt or solvate.
15
In process (a) the group R30 15 a leaving group such as halogen, in particular chloro. The reaction can be carried out in an inert solvent such as DMF at elevated temperature, for example at about 100°C.
20 In process (b) the leaving group L 15 preferably halogen, in particular chloro. The reaction can be carried out in the presence of a base such as cesium carbonate in an inert solvent such as DMF or ethanol.
Compounds of formula (II) can be prepared by reacting compounds of formula (VI):
25
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in which R1, R2 and R20 are as defined in formula (II) with a chlorinating agent such as thionyl chloride, and reaction of the corresponding aC1d chloride with ammonia.
5
Compounds of formula (VI) can be prepared using methods conventional in the art.
Compounds of formula (I) can be converted into further compounds of formula(I) using standard procedures conventional in the art.
10
Examples of the types of conversion reactions that may be used include introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, aUcylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art and are illustrated in die Examples
15 below. By way of example, a hydroxy group may be replaced with a chloro group by
reaction with a chlorinating agent such as thionyl chloride and the chloro group may itself undergo nucleophilic substitution. Alternatively a chloro substituent may be treated with sodium azide to replace the chloro group with an azido group which in turn may be reduced to an amine group. Amine groups may conveniently be acylated with aC1d chlorides or
20 15ocyanates and converted into amides by treatment with appropriate aC1ds.
It will be appreC1ated that certain functional groups may need to be protected using standard protecting groups. The protection and deprotection of functional groups 15 for example, described in 'Protective Groups in Organic Chem15try', edited by J. W. F. McOmie, Plenum
25 Press (1973), and 'Protective Groups in Organic Synthes15', 3rd edition, T. W. Greene & P. G. M. Wuts, Wiley-IntersC1ence (1999).
D15eases mediated by JAK3 include inflammatory, immunological, and bronchopulmonary d15orders.
30
WO 2005/075429
The present invention also relates to a pharmaceutical composition for (a) treating or preventing a d15order or condition selected from organ transplant rejection, lupus, multiple scleros15, rheumatoid arthrit15, psorias15, Type I diabetes and complications from diabetes, cancer, asthma, rhinit15, atopic dermatit15, autoimmune thyroid d15orders, ulcerative colit15,
5 Crohn's d15ease, Alzheimer's d15ease, leukemia, and other autoimmune d15eases or (b) the inhibition of protein tyrosine kinases or Janus kinase 3 (JAK3) in a mammal, including a human, compr15ing an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective in such d15orders or conditions and a pharmaceutically acceptable carrier.
10
Preferably the compounds of the invention are used for the treatment of asthma, rheumatoid arthrit15, and host versus graft rejection/transplantation.
The present invention also relates to a pharmaceutical composition for (a) treating or
15 preventing a d15order or condition selected from organ transplant rejection, lupus, multiple scleros15, rheumatoid arthrit15, psorias15, Type I diabetes and complications from diabetes, cane, asthma, rhinit15, atopic dermatit15, autoimmune thyroid d15orders, ulcerative colit15, Crohn's d15ease, Alzheimer's d15ease, leukemia, and odier autoimmune d15eases or (b) the inhibition of protein tyrosine kinases or Janus kinase 3 (JAK3) in a mammal, including a
20 human, compr15ing an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with a T-cell immunosuppresant or anti-inflammatory agents, effective in such d15orders or conditions and a pharmaceutically acceptable carrier.
The present invention also relates to a method for the inhibition of protein tyrosine kinases
25 or Janus Kinase 3 (JAK3) in a mammal, including human, compr15ing admin15tering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition of the present invention compr15ing a compound as herein described or a pharmaceutically acceptable salt thereof along with a pharmaceutically acceptable adjuvant, diluent or carrier showed surpr15ing effect. Therefore, die said composition 15 synerg15tic.
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The dose of the compound to be admin15tered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physiC1an. The dosage will preferably be in the range of from 0.1 mg/kg to 100 mg/kg.
5 The compounds may be admin15tered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols or dry powder formulations, e.g. formulations in the inhaler device known as the Turbuhaler®; or systemically, e.g. by oral admin15tration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral admin15tration, e.g. in the form of sterile parenteral solutions or suspensions, or by rectal
10 admin15tration, e.g. in the form of suppositories.
The compounds of the invention may be admin15tered on their own or as a pharmaceutical composition compr15ing the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are 15 compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.
Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be admin15tered by oral or nasal inhalation. For inhalation the compound 15 desirably
20 finely divided. The finely divided compound preferably has a mass median diameter of less than 10 |J,m, and may be suspended in a propellant mixture with the ass15tance of a d15persant, such as a C8-C2o fatty aC1d or salt thereof, (e.g. oleic aC1d), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable d15persant.
25
The compounds of the invention may also be admin15tered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
30 One possibility 15 to mix the finely divided compound with a carrier substance, e.g. a mono-
WO 2005/075429 PCT/SE2005/000156
, di- or polysaccharide, a sugar alcohol, or an other polyoi. Suitable carriers are sugars, e.g. lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be d15pensed into hard gelatine capsules, each containing the
5 desired dose of the active compound.
Another possibility 15 to process the finely divided powder into spheres which break up during the inhalation procedure. Th15 spheronized powder may be filled into the drug reservoir of a multidose inhaler, e.g. that known as the Turbuhaler* in which a dosing unit
10 meters the desired dose which 15 then inhaled by the patient With th15 system the active, compound, with or without a carrier substance, 15 delivered to the patient
For oral admin15tration the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol; a starch, e.g. potato starch, com starch or
15 amylopectin; a cellulose derivative; a binder, e.g. gelatine or polyvinylpyrrolidone, and/or a lubricant, e.g. magnesium stoarate, calC1um stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, die cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the
20 tablet may be coated with a suitable polymer d15solved in a readily volatile organic solvent.
For the preparation of soft gelatine capsules, the compound may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above mentioned exC1pients for tablets. Also liquid or sem15olid
25 formulations of the drug may be filled into hard gelatine capsules.
Liquid preparations for oral application may be in die form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may
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contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other exC1pients known to those skilled in art
The compounds of the invention may also be admin15tered in conjunction with other 5 compounds used for the treatment of the above conditions.
The term 'medical therapy' as used herein 15 intended to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals. The terms "therapeutic" and "therapeutically" will be understood accordingly.
10
The following Examples illustrate the invention.
General methods
15 All reactions were performed in dried glassware in an argon atmosphere at room
temperature, unless otherw15e noted. All solvents and reagents and solvents were used as received. Merck Silica gel 60 (0.040-0.063 mm) was used for preparative silica gel chromatography. A Kromasil KR-10O-5-C18 column (250 x 20 mm, Akzo Nobel) and mixtures of acetonitrile/water at a flow rate of 10 ml/min was used for preparative HPLC.
20 Reactions were monitored at 254 nm by analytical HPLC, using a Kromasil C-18 column (150 x 4.6 mm) and a gradient (containing 0.1% trifluoroacetic aC1d) of 5 to 100% of acetonitrile in water at a flow rate of 1 ml/min. Evaporations of solvents were performed under reduced pressure using a rotary evaporator at a maximum temperature of 40°C. Products were dried under reduced pressure at 40 CC.
25 ' H-NMR spectra were recorded on a Varian Inova-400 or Unity-500+ instrument. The
central solvent peak of chloroform-d (SH 7.27 ppm), dimethylsulfoxide-d* (6H 2.50 ppm) or methanol-d* (5H 3.35 ppm) were used as internal references. Low resolution mass spectra obtained on a Hewlett Packard 1100 LC-MS system equipped with a APC1 ion15ation chamber.
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Merck Silica gel 60 (0.040-0.063 mm) was used for preparative silica gel chromatography. A Kromasil KR-100-5-C18 column (250 x 20 mm, Akzo Nobel) and mixtures of acetonitrile/water at a flow rate of 10 ml/min was used for preparative HPLC. Reactions were monitored at 254 5mm by analytical HPLC, using a Kromasil C-18
5 column (150 x 4.6 5 mm) and a gradient (containing 0.1% trifluoroacetic aC1d) of 5 to 100% of acetonitrile in water at a flow rate of 1 ml/min. Evaporations of solvents were performed under reduced pressure using a rotary evaporator at a maximum temperature of 40 °C. Products were dried under reduced pressure at 40 °C.
10 Example 1
6,7-diethoxy-4- {[2-emyl-3-(lH-inudazol-l-ylmethyl)phenyl]ainino }quinoline-3-carboxamide
15 a)6,7-diethoxy-4-{ [2^myl-3-(hydroxyn^myl)phenyl]amino}quinoline-3-carboxarnide The title compound was prepared according to the method described in WO 02/092571
b)4-{ [3-(chloromethyl)-2-ethylphenyl]amino}-6,7-diethoxyquinoline-3-carboxamide
20 To a suspension of 6,7-diethoxy-4-{ [2-ethyl-3-(hydroxymethyl) phenyl] amino Jquinoline-
3-carboxamide (1.1 g, 2.7 mmol) in CH2Cl2(7 ml) was added thionyl chloride (0.7 g, 5.77
mmol). After fifteen minutes the suspension was d15solved. Azeotropic evaporation of
excess thionyl chloride with toluene gave the title compound 1.15 g (100%) as a yellow
powder.
25 lH NMR (400MHz, CDC13): 8 12.5 (IH, s); 9.12 (IH, s); 8.69 (IH, br s); 8.08 (IH, br s);
7.52 (IH, d); 7.45 (IH, s); 7.33 (IH, t); 7.23 (IH, d); 6.63 (IH, s); 4.92 (2H, s);
4.18 (2H, q); 3.72 (2H, br s); 2.83 (2H, br s); 1.39 (3H, t); 1.17 (3H, t); 1.05 (3H, t);
APC1-LC/MS m/z: 428.4 [MET]
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V
6,7-diethoxy-4-{[2-ethyl-3-(l//-imidazol-l-ylmethyl)phenyl]amino} quinoline-3-
carboxamide
Imidazole (110 mg, 1.6 mmol) was added to a solution of 4-{ [3-(chloromethyl)-2-
ethylphenyl]amino}-6,7-diemoxyquinoline-3-caitK>xarriide (40.2 mg, 0.094 mmol) In 1-
5 methyl-2-pyrrolidinone (2 ml) .The mixture was heated for two hours at 70 C, cooled to
room temperature and diluted with water. The product was purified by preparative HPLC.
After freeze-drying the title compound was obtained as a white powder.
'H NMR (400MHz, DMSCwfc) 6 10.96 (IH, s), 8.88 (IH, s), 8.30 (IH, s), 7.70 (IH, s), 7.63
(IH, s), 7.22 (IH, s), 7.09 (IH, s), 7.04 (2H, t), 6.93 (IH, s), 6.87 (IH, d), 6.60 (2H, d), 6.55
10 (IH, s), 5.31 (2H, s), 4.14 (2H, q), 2.85 (2H, q), 1.36 (3H, t), 1.02 (5H, dd)
APC1-LC/MS m/z: 460.2 [MHT]
The title compounds of examples 2-115 were prepared in analogous manner to example 1.
15 Example 2
6,7^emcoiy-4-{[2-memyl-3-(lH-l^,4-triazol-l-ylmethyl)phenyl] amino} quinoline-3-
carboxamide
APC1LC-MS m/z: 447.5[MH+]
20 Example 3
6,7-diethoxy-4-{ [2-ethyl-3-(morpholin-4-ylmethyl)phenyl]amino }quinoline-3-carboxamide 'H NMR (400 MHz, DMSO-4$) 5 10.97 (IH, s), 8.87 (IH, s), 8.29 (IH, s), 7.60 (IH, s), 7.21 (IH, s), 7.03 (2H, d), 6.98 (2H, t), 6.61 (IH, s), 6.56 (2H, d), 4.14 (2H, q), 3.57 (5H, s), 3.51 (3H, s), 2.87 (2H, q), 2.38 (4H, s), 1.36 (3H, t), 1.24 (3H, t), 1.01 (3H, t)
25 APC1 LC-MS m/z: 479.4 MH+]
Example 4
6,7
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Example 5
4- {[3-(azidomethyI)-2-methyIphenyI]amino} -6,7-diethoxyquinoline-3-carboxamide
APC1LC-MS m/z: 421.5[MH+] 5
5
Example 6
6,7-diethoxy-4-{[2-methyl-3-(4H-l^,4-triazol-4-ylmethyl)phenyl]amino} quinoline-3-
carboxamide
APC1 LC-MS m/z: 447.5[MH+] 10
10
Example 7
4-{[3K([4Ka»n
dimethoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 550.4[MH+]
15
Example 8
4-({2-ethyl-3-[(lH-l,2,4-tnazol-5-ylaimno)memy
3-caiboxamide
APC1 LC-MS m/z: 448.2[MH+]
20
Example 9
4-{[2-ethyl-3-(lH-imidazo]-l-ylmethyl)phenyl]amino}-6,7-dimethoxyquinoline-3-
carboxamide
IH NMR (399.99 MHz, DMSO-4,) 8 11.01 (s, IH), 8.90 (s, IH), 8.32 (s, IH), 7.72 (s,
25 IH), 7.64 (s, IH), 7.25 (s, IH), 7.09 (s, IH), 7.06 (d, IH), 6.93 (s, IH), 6.87 (d, IH), 6.64
(d, IH), 6.56 (s, IH), 5.33 (s, 2 H), 3.88 (s, 3H), 3.17 (s, 3H), 2.86 (q, 2H), 1.03 (t, 3H)
APC1 LC-MS m/z: 432.4[MH+]
Example 10
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6,7^diethoxy-4-({2-ethyl-3-I(pyrimidin-2-ylamino)methyl]phenyl}amino)quinoline-3-
carboxamide
APC1LC-MS m/z: 487.1[MH+]
5 Example 11
6,7-diethoxy-4-[(2-ethyl-3- {[(2-hydroxycyclohexyl)amino]methyl} phenyl)
amino]quinoline-3-carboxamide
APC1 LC-MS m/z: 507.5[MH+]
10 Example 12
6,7-diethoxy-4-[(2-ethyl-3-{ [(3-mienylmethyl)amino]metiiyl }phenyl)amino]quinoline-3-
carboxamide
APC1 LC-MS m/z: 505.6[MH+]
15 Example 13
6,7-diethoxy-4-({ 2-ethyl-3-[( lH-imidazol-2-yltfuo)methyl]phenyl} amino) quinoline-3-
carboxamide
APC1 LC-MS m/z: 492.6[MH+]
20 Example 14
6,7-diethoxy-4- {[2-ethyl-3-(thiomorpholin-4-ylmethyl)phenyl]amino }quinoline-3-
carboxamide
APC1 LC-MS m/z: 495.6[MH+]
25 Example 15
6,7-diethoxy-4-[(2-ethyl-3-{[(3-thienylmethyl)amino]methyl}phenyl)amino]quinoline-3-
carboxamide
APC1 LC-MS m/z: 505.6[MH+]
30
Example 16
WO 2005/075429 PCT/SE2005/000156
4-({2-emyl-3-[(4-nitro-lH-imidazol-l-yl)methyl]phenyl}amino)-6,7-dimcthoxyquinoline-3-
carboxamide
APC1LC-MS m/z: 477.2[MH+]
5 Example 17
4-[(2-ethyl-3-{[4-(hydroxymethyl)-lH-imidazol-l-yl]memyl}phenyl)amino]-6,7-dimethoxyquinoline-3-carboxamide trifluoroacetate (salt) APC1 LC-MS m/z: 462.5[MH+]
10 Example 18
4-({2-emyl-3-[(2-memyl-lH-imidazoI-l-yl)memyl]phen^
3-carboxamide
APC1 LC-MS m/z: 446.5[MH+]
15 Example 19
l-(3-{[3-(aininocaibonyl)-6,7-diiTiemoxyquiiK)lin-4-yl]anuno)-2-ethylbenzyl)-lH-imidazole-4-carboxyIic aC1d APC1 LC-MS m/z: 476.5[MH+]
20 Example 20
4-({3-[(cyclopentylamino)methyl]-2-ethylphenyl}amino)-6,7-dimethoxyquinoline-3-
carboxamide
'NMR (400 MHz, DMSO-dd) 8 11.03 (IH, s), 8.87 (IH, s), 8.28 (IH, s), 7.59 (IH, s), 7.22
(IH, s), 7.12 (IH, d), 7.00 (IH, t), 6.63 (IH, s), 6.57 (IH, d), 3.87 (3H, s), 3.73 (2H, s), 3.19
25 (3H, s), 3.03 (IH, t), 2.86 (2H, q),1.73 (2H, mult), 1.61 (2H, mult),1.46 (2H, mult),1.35
(2H, mult), 1.21 (3H, t)
APC1 LC-MS m/z: 449.2[MH+]
Example 21
WO 2005/075429
PCT/SE2005/000156
4- {[2-ethyl-3-({ [2-(lH-imidazol-4-yl)ethyl]amino }methyl)phenyl]amino} -6,7-dimethoxyquinoline-3-caitx)xamideb15(trifluoroacetate)
'H NMR (400 MHz, DMSO-4$) 8 9.20 (IH, s), 9.00 (2H, d), 8.60 (IH, s), 8.07 (IH, s), 7.52 (2H, s), 7.48 (2H, d), 7.37 (2H, mult), 7.23 (IH, d), 6.67 (IH, s), 4.34 (2H, s), 3.94 (4H, s),
5 3.40 (3H, t), 3.20 (4H, s), 3.11 (3H, t), 2.81 (2H, s), 1.14 (3H, t) APC1LC-MS ra/z: 475.2[MH+]
Example 22
4-[(2-ethyl-3-{ [(2-hydroxy-l,l-dimethylethyl)amino]methyl}phenyl)amino]-6,7-10 dimethoxyquinoline-3-caiboxamide
*H NMR (400 MHz. DMSCMs) 811.03 (IH. s), 8.87 (IH. s), 8.28 (IH, s). 7.59 (IH, s),
7.22 (IH. s), 7.12 (IH, d), 7.00 (IH, t), 6.62 (2H, s), 6.58 (2H, d). 4.59 (IH, s), 3.86 (3H, s),
3.68 (2H, s), 3.25 (2H. d), 3.19 (3H. s), 2.87 (2H, d). 1.23 (3H, t), 1.02 (6H. s).
APa LC-MS m/z: 453.1[MH+] 15
Example 23
4-({ 2-ethyl-3-[(13-thiazol-2-ylamino)methyl]phenyl }amino)-6,7-dimethoxyquinoline-3-
carboxamide
APC1 LC-MS m/z: 464.1[MH+] 20
Example 24
4-[(2-ethyl-3-{[(2-hydroxypropyl)anMno]memyl}phenyl)amino]-6,7-dimethoxyquinoline-3-
carboxamide
APC1 LC-MS m/z: 439.3[MH+] 25
Example 25
4-[(2-ethyl-3-{ [(2-hydroxy-2-phenylethyl)amino]methyl }phenyl)amino]-6,7-
dimethoxyquinoline-3-carboxamide b15(trifluoroacetate) (salt)
APC1 LC-MS m/z: 501.3[MH+]
WO 2005/075429
PCT/SE2005/000156
^if3
Example 26
4-{[2-ethyl-3-({[4-(methylsulfonyl)benzyl]amino}methyl)phenyl]amino}-6,7-dimethoxyquinoline-3-cart>oxaniide
IH NMR (399.99 MHz, dmso-4$) 8 1103 (IH, s), 8.88 (IH, s), 8.34 (IH, s), 7.88 (2H, d),
5 `7.63 (2H, d), 7.57 (IH, s), 7.22 (IH, s), 7.16 (IH, d), 7.03 (IH, t), 6.63 (IH, s), 6.59 (ia d), 3.87 (3H, s), 3.84 (2H, s), 3.76 (2H, s), 3.18 (6H, s), 2.83 (2ft d), 1.17 (3H, t) APC1LC-MS m/z: 549.3[MH+]
Example 27
10 4-( {3-[(benzylamino)methyl]-2-ethylphenyl} amino)-6,7-dimethoxyquinoline-3-carboxamide
IH NMR (399.99 MHz, DMSO-4s) 5 11.03 (IH, s), 8.88 (ia br s), 8.27 (ia br s), 7.60 (ia s), 7.33 (4a mult), 7.22 (2a mult). 7.16 (ia d). 7.03 (ia t), 6.63 (ia s), 6.59 (ia d), 3.87 (3a s), 3.73 (4a d), 3.18 (3H, s), 2.81 (2a q), 1-16 (3a t)
15 APC1 LC-MS m/z 471.3[MH+]
Example 28
4-({2^myl-3-[(3-methyl-2^-dioxoimidazolidin-l-yl)memyl]phenyl}amino)-6,7-dimethoxyquinoline-3-carboxamide
20 APC1LC-MS m/z 478.5[MH+]
Example 29
4-({2-ethyl-3-[(lH-tetrazol-5-ylamino)meuiyl]phenyl}amino)-6,7-dimethoxyquinoline-3-carboxamide b15(trifluoroacetate)
25 APC1 LC-MS m/z 449.2[MH+]
Example 30
4-( {3-t(5-amino-lH-tetrazol-l-yl)methyl]-2-ethylphenyl }amino)-6,7-dimethoxyquinoline-3-carboxamide b15(trifluoroacetate)
30 APC1 LC-MS m/z 449.2[MH+J
WO 2005/075429
PCT/SE2005/000156
Example 31
4-{[2-ethyl-3-( {[2-(2-oxoimidazolidin-l-yl)ethyl]amino} methyl)phenyl]amino}-6,7-dimethoxyquinoline-3-carboxamide
5 IH NMR (399.99 MHz, DMSO-J5) 8 11.03 (IH, s), 8.87 (IH, s), 8.28 (IH, br s), 7.60 (IH, br s), 7.22 (IH, s), 7.13 (IH, d), 7.01 (IH, t), 6.62 (IH, s), 6.58 (IH, d), 6.22 (IH, s), 3.87 (3H, s), 3.77 (2H, s), 3.29 (2H, t), 3.19 (5H, mult), 3.14 (2H, t), 2.85 (2H, q). APC1LC-MS m/z 493.3[MH+]
10 Example 32
4- {[2-ethyl-3-({ [(2S)-2-hydroxycyclohexyl]amino}methyl)phenyl]amino}-6,7-dimethoxyquinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 479.3[MH+]
15 Example 33
4-({ 2-ethyl-3-[(piperidin-4-ylamino)methyl]phenyl }amino)-6,7-dimethoxyquinoline-3-caiboxamide tr15(trifluoroacetate) APC1 IJC-MS m/z 464.3[MH+]
20 Example 34
4- {[2-ethyl-3-( {[(IR)- l-(hydroxymethyl)-3-methylbutyl Jamino} methyl )phenyl] amino }-6,7-
dimethoxyquinoline-3-carboxamide
APC1 LC-MS m/z 481,5[MH+]
25 Example 35
6,7-diethoxy-4-[(2-ethyl-3- {[4-(3-methoxyphenyl)piperazin-1 -yljmethyl} phenyl)amino]quinoline-3-carboxamide APC1 LC-MS m/z: 584.6 [MH+]
30
Example 36
WO 2005/075429
PCT/SE2005/000156
6,7-diethoxy-4-[(2-ethyl-3-{[4-(hydroxymethyl)piperidin-l-yl]methyl}phenyl)amino]quinoline-3-carboxamide APC1LC-MS m/z: 507.5[MH+]
5 Example 37
6,7-diethoxy-4-[(2-ethyl-3-{[2-(hydroxymethyl)piperidin-l-yl]methyl} phenyl)amino]quinoline-3-carboxamide APC1 LC-MS m/z: 507.6[MH+]
10 Example 38
4-{[3-(l>4'-bipiperidin-r-ylmemyl)-2-emylphenyl]amino}-6J-diethx>xyquinoline-3-
carboxamide
APC1 LC-MS m/z: 560.7[MH+]
15 Example 39
4-[(3- {[4-(aminocarbonyl)piperidin-1 -yl]methyl }-2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 520.5[MH+]
20 Example 40
4-[(3-{ [4-(2-cyanophenyl)piperazin-l-yl]methyl }-2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
APQ LC-MS m/z: 579.7[MH+]
25 Example 41
^-K3-{[4-(5-cyanopyridin-2-yl)piperazin-l-yl]methyl}-2-ethyIphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 580.6[MH+]
30
Example 42
WO 2005/075429
PCT/SE2005/000156
6,7-diethoxy-4-[(2-ethyl-3-{[(3-furylmethyl)amino)methyl}phenyl)amino)quinoline-3-
carboxamide
APC1LC-MS m/z: 489.5[MH+]
5 Example 43
6,7-diethoxy-4-[(2-ethyl-3-{[4-(2-hydroxyethy])piperazin-l-yl]methyl}phenyl)
amino]quinoline-3-caiboxamide
APC1 LC-MS m/z: 522.6[MH+]
10 Example 44
6,7-diethoxy-4-({ 2-ethyl-3-[(4-hydroxypiperidin-l-yl)methyl]phenyl} amino) quinolinc-3-
carboxamide
APC1 LC-MS m/z: 493.5[MH+]
15 Example 45
4-{ [3-({ [2K13-benzodioxol-5-yl)emyl]amino}methyl)-2-emylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 557.6[MH+]
20 Example 46
6,7-diethoxy-4-{[2-ethyl-3-({[2-(2-thienyl)ethyl]amino}methyl)phenyl] amino} quinoline-
3-carboxamide
APC1 LC-MS m/z: 519.5[MH+]
25 Example 47
4-{[3-({[(2,5-dimethyl-3-furyl)methyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoIine-3-carboxamide
APC1 LC-MS m/z: 517.6[MH+]
30
Example 48
WO 2005/075429 PCT/SE2005/000156
6,7-diethoxy-4-{[2-ethyl-3-({[3-(2-oxopyrrolidin-l-yl)propyl]amino}methyl) phenyl]amino} quinoline-3-carboxamide APC1LC-MS m/z: 534.6[MH+]
5 Example 49
4-{ [3-({ [2-(3-chlorophenyl)ethyl]amino}inethyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-caiboxamide
APC1 LC-MS m/z: 547.5[MH+]
10 Example 50
4-{ [3-({ [2-(4-chlcwDphenyl)ethyl]amino} methyl)-2-cthylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 547.6[MH+]
15 Example 51
4-{ [3-({ [2-(2-chlorophenyl)cthyl]amino}methyl)-2-ethylphenyl]amino}-6f7-
diethoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 547.6[MH+]
20 Example 52
6,7-diethoxy-4-[(2-ethyl-3-{[(2-hydroxy-2-phenylethyl)amino]methyl}phenyl)amino]quinoline-3-carboxamide APC1 LC-MS m/z: 529.6[MH+]
25 Example 53
4-({ 3-[(cyclopentylamino)methylJ-2-ethylphenyl }amino)-6,7-diethoxyquinoline-3-
carboxamide
APC1 LC-MS m/z: 477.5[MH+]
30
Example 54
WO 2005/075429
PCT/SE2005/000156
6,7-diethoxy-4-{ [2-ethyl-3-({ [2-(lH-imidazol-4-yl)ethyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide APC1LC-MS m/z: 503.6[MH+]
5 Example 55
6,7-diethoxy-4-[(2-ethyl-3-{ [4-(2-morpholin-4-ylethyl)piperazin-1-
yl]methyl}phenyl)amino]quinoline-3-carboxamide
APC1LC-MS m/z: 591.7[MH+]
10 Example 56
4-{ [3-({ [(2,2^Uniethyl-13^oxolan^yl)methyl]amino}methyl)-2-ethylphenyl]amino}-
6,7-diethoxyquinoline-3-caiboxamide
APC1 LC-MS m/z: 523 J[MH+]
15 Example 57
6,7-diethoxy-4-({2-ethyl-3-[(13-thiazol-2-yIaniino)methyl]phenyl} amino) quinoline-3-
carboxamide
APC1 LC-MS m/z: 492.5[MH+]
20 Example 58
6,7-diethox y-4- {[2-ethyl-3-( 13-thiazolidin-3-ylmethyl)phenyl]amino }quinoline-3-
carboxamide
APC1 LC-MS m/z: 481.5[MH+]
25 Example 59
6,7-diethoxy-4-((2-ethyl-3-{ [(2-pyridin-2-ylethyl)amino]methyl} phenyl )amino]quinoline-3-
carboxamide
APC1LC-MS m/z: 514.5[MH+]
30
Example 60
WO 2005/075429
PCT/SE2005/000156
6,7-diethoxy-4-({2-ethyl-3-[(lH-l,2,4-tria2ol-3-ylamino)methyl]phenyl}amino)quinoline-
3-carboxamide
APC1LC-MS m/z: 476.6[MH+]
5 Example 61
6,7-diethoxy-4-{ [2-ethyl-3-({ [4-(2-thienyl)benzyl]amino}methyl)phenyl] amino} quinoline-
3-carboxamide
APC1 LC-MS m/z: 581.5[MH+]
10 Example 62
^{[3^{[^^^nosulfonyl)benzyl]aiiMno}inemyl)-2-emylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
APC1 LC-MS m/z 578.6[MH+]
15 Example 63
6,7-dicthoxy^-{[2-ethyl-3-
quinoIine-3-carboxamide
APC1 LC-MS m/z: 552.6[MH+]
20 Example 64
6,7-diethoxy-4-{ (2-ethyl-3-({ (3-(4-methylpiperazin-l-yl)propyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide APC1 LC-MS m/z: 549.7[MH+]
25 Example 65
6,7-diethoxy-4-[(2-ethyl-3-{[(l-ethylpiperidin-3-yl)amino]methyl}phenyl)amino]
quinoline-3-carboxamide
APC1 LC-MS m/z: 520.6[MH+]
30
Example 66
WO 2005/075429
PCT/SE2005/000156
6,7-diethoxy-4-[(2-ethyl-3-{[4-(pyridin-4-ylmethyl)piperazin-l-yl]methyl}phenyl)
amino]quinoline-3-carboxamidc
APC1LC-MS m/z: 569.6[MH+]
5 Example 67
6,7-diethoxy-4-[(2-ethyl-3-{ [(pyridin-4-ylmethyl)amino]methyl }phenyl)amino] quinoline-
3-carboxamide
APC1LC-MS m/z: 500.6[MH+]
10 Example 68
6,7-diethoxy-4-[(2-ethyl-3-{ [(pyridin-3-ylmethyl)amino]methyl }phenyl)amino]quinoline-3-
carboxamide
APC1 LC-MS m/z: 500.6[MH+]
15 Example 69
4-({ 3-[(benzylamino)methyl]-2-cthylphenyl }amino)-6,7-diethoxyquinoline-3-carboxamide APC1 LC-MS m/z: 499.5[MH+]
Example 70 20 6,7-diethoxy-4-[(2-ethyl-3- {[(2-furylmethyl)amino]methyl} phenyl)amino ]quinoline-3-carboxamide APC1 LC-MS m/z: 489.6[MH+]
Example 71 25 6,7-diethoxy-4-[(2-ethyl-3- {[(2-methoxyethyl)amino]methyl} phenyl)amino] quinoline-3-carboxamide APC1 LC-MS m/z: 467.5[MH+]
Example 72
WO 2005/075429
PCT/SE2005/000156
6,7-diethoxy-4-[(2-ethyl-3-{ [(2-hydroxypropyl)amino]methyl }pheny])amino] quinoline-3-
carboxamide
APC1LC-MS m/z: 467.5[MH+]
5 Example 73
6,7-diethoxy-4-{[2-ethyI-3-({[4-(lH-pyrazol-l-yl)benzyl]amino} methyl)phenyl]amino} quinoline-3-carboxamide APC1 IJC-MS m/z: 565.6[MH+]
10 Example 74
4-( {3-[( {2-[4-(aminosulfonyl)phenyl]ethyl} amino)methyl]-2-ethylphenyl} amino)-6,7-
diedioxyquinoline-3-carboxamide
APC1 LC-MS m/z: 592.7[MH+]
15 Example 75
6,7-diethoxy-4-{ [2-ethyl-3-({ (2-(l-methylpynolidin-2-yl)ethyl]amino} methyl) phenyl]amino }quinol ine-3-carboxamide APC1 LC-MS m/z: 520.7[MH+]
20 Example 76
^[(3-{[(4-chlorobenzyl)amino]methyl}-2-ethylphenyl)amino]-6,7-diethoxyquinoline-3-
caiboxamide
APC1 LC-MS m/z: 533.5[MH+]
25 Example 77
4-[(3- {[(l-benzylpiperidin-4-yl)amino)methyl} -2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 582.7[MH+]
30
Example 78
WO 2005/075429
PCT/SE2005/000156
6,7-diethoxy-4-[(2-ethyl-3-{[(3-methoxybenzyl)amino]methyl} phenyl) amino] quinoline-3-
carboxamide
APC1LC-MS m/z: 529.5[MH+]
5 Example 79
6,7-diethoxy-4-[(2-ethyl-3-{ [(4-methoxybenzyl)amino]methyl }phenyl)amino] quinoline-3-
carboxamide
APC1LC-MS m/z: 529.7[MH+]
10 Example 80
6J-diemoxy-4-{[2-ethyl-H{[3KlH-iniidaz»l-l-yl)propyl]aniino}inemyl)phenyl] amino }quinoline-3-carboxamide APC1 LC-MS m/z: 517.6[MH+]
15 Example 81
6,7-diethoxy-4-{ [2-ethyl-3-({ [(lIUS)-2-hydroxy-2,3-
20 Example 82
6,7-diethoxy-4-{ [2-ethyl-3-({[2-hydroxy-l-(lH-indol-2-ylmethyl) ethyl] amino} methyl )phenyl]amino}quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 582.5[MH+]
25 Example 83
6,7-diethoxy-4-{ [2-ethyl-3-({ [(lR)-2-hydroxy-l-phenylethyl]amino}methyl) phenyl]amino}quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 524.5[MH+]
30
Example 84
WO 2005/075429
PCT/SE2005/000156
^3 6,7-Diethoxy-4-{2-ethyI-3-[(2-hydroxy-l-methylcarbamoyI-propylamino)-m ethyl]-phenylamino}-quinoline-3-carboxylic aC1d amide b15(trifluoroacetate) (salt) APC1LC-MS m/z 529.5[MH+]
S Example 85
6,7-diethoxy-4-{ [2-ethyl-3-({ [(lR^S)-2-hydroxy-l-(hydroxymethyl)propyl] amino}methyl) phenyl]amino)quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 497.3{MH+]
10 Example 86
6,7-diethoxy-4-{ [2-ethyl-3-({ [(lR^R)-2-hydroxy-l-(hydroxymemyl)piopyl] amino}methyl)phenyl]amino}quinoline-3-caiboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 497.5[MH+]
15 Example 87
methyl N-(3-{ [3-(aniiiKX^u1x>nyI)-6,7-diethoxyquinolin^yl]amino}-2-emylbenzyl)serinate
b15(trifluoroacetate)
APC1 LC-MS m/z 5U.3[MH+]
20 Example 88
6,7-diethoxy-4-{ [2-ethyl-3-({ [2-hydroxy-l-(hydroxymethyl)ethyl]amino} methyl)phenyl]amino}quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 483.5[MH+]
25 Example 89
6,7-diethoxy-4- {[2-ethyl-3-( {[ 1 -(hydroxymethyI)-3-methylbutyl]amino} methyl) phenyl]amino}quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 509.5[MH+]
30
Example 90
WO 2005/075429 PCT/SE2005/000156
6,7-diethoxy-4-[(2-ethyl-3-{[(2-pyrrolidin-l-ylethyl)amino]methyl}phenyl)
amino]quinoline-3-carboxamidetr15(trifluoroacetate)
APC1LC-MS m/z 506.5[MH+]
5 Example 91
6,7-diethoxy-4- {[2-ethyl-3-({ [(1 S,2R)-2-hydroxy- l-(hydroxymethyl)propyl] amino}methyl)phenyl]amino}quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 497.3[MH+]
10 Example 92
6J
15 Example 93
6,7-diethoxy-4-{ [2-ethyl-3-({ [l-(hydroxymethyl)butyl] amino}methyl)phenyl] amino} qui noline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 495.5[MH+]
20 Example 94
4-{3-[(l-Carbamoyl-2-hydroxy-propyl amino)-methyl] -2-ethyl-phenylamino} -6,7-diethoxy-quinoline-3-carboxylic aC1d amide b15(trifluoroacetate) (salt APC1 LC-MS m/z 510.4[MH+]
25 Example 95
6,7-diethoxy-4-[(2-ethyl-3-{[[(lR,2R)-2-hydroxy-l-methyl-2-phenylethyl] (methyl)amino]methyl }phenyl)amino]quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 557.5[MH+]
30
Example 96
WO 2005/075429
PCT/SE2005/000156
6,7-diethoxy-4-[(2-ethyl-3-{[(2-hydroxy-l-methyl-2-phenylethyl)amino ]methyl}phenyl)amino]quinoline-3-carboxamide b15(trifluofoacetate) (salt) APC1LC-MS m/z 543.5[MH+]
5 Example 97
4-{ [3-({ [2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}methyl)-2-ethylphenyl ]amino}-6,7-diethoxyquinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 561.5[MH+]
10 Example 98
6,7-diethoxy-4-[(2-ethyl-3-{ [(2-hydroxypropyl)amino]methyl} phenyl) amino] quinoline-3-caiboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 467.5[MH+]
15 Example 99
6,7-dietfioxy-4-[(2-ethyI-3-{ [(2-hydroxy-l-mediylethyl)amino]methyl {phenyl) amino]quinoline~3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 467.5[MH+]
20 Example 100
6,7-diethoxy-4-[(2-ethyl-3-{ [(2-hydroxyemyl)amino]methyl} phenyl) amino] quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 453.5[MH+]
25 Example 101
4-[(3-{[(2,3-dihydroxypropyl)amino]methyl}-2-ethylphenyl)amino]-6,7-diethoxyquinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 483.5[MH+]
30
Example 102
WO 2005/075429
PCT/SE2005/000156
6,7-diethoxy-4- {[2-ethyl-3-( {[2-(hydroxymethyl)phenyl]amino} methyl)phenyl] amino }quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1LC-MS m/z 515.4[MH+]
5 Example 103
4-{[3-({[(lS)-l-benzyl-2-hydroxyethyl]amino}methyl)-2^thylphenyl]amino}-6,7-diethoxyquinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 549.6[MH+]
10 Example 104
4- {[3-( {[2-(dimethylamino)ethyl]amino} methyl)-2-ethylphenyl]ainino }-6,7-diethoxyquinoline-3-carboxamide tr15(trifluoroacetate) APC1 LC-MS m/z 543.5[MH+]
15 Example 105
6,7-diethoxy-4-{[2-ethyl-3-({[4-(methylsulfonyl)phenyl]amino} methyl) phenyl] amino }quinoline-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z 480.4[MH+]
20 Example 106
6,7-diethoxy-4-{[2-ethyl-3-({[(lS)-2-hydroxy-l-phenylethyl]amino} methyl) phenyl]amino}quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 563.5[MH+]
25 Example 107
6,7-diethoxy-4-[(2-ethyl-3-{ [(2R)-2-(hydroxymethyl)pyrrolidin-l-yl]methyl} phenyl)amino]quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 529.5[MH+]
30
Example 108
WO 2005/075429
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L *7
6,7-diethoxy-4-{ [2-ethyI-3-({ [(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2-
phenylethyl]amino}methyl)phenyl]amino)quinoline-3^arboxamideb15(trifluoroacetate)
(salt)
APC1LC-MS m/z 493.5[MH+] 5
Example 109
6,7-diethoxy-4-[(2-ethyl-3-{[(2-morpholin-4-ylethyl)amino]methyl}phenyl)
amino]quinoline-3-carboxamidetr15(trifluoroacetate)
APC1 LC-MS m/z 559.5[MH+] 10
Example 110
6,7-diethoxy-4-{ [2-ethyl-3-({ [(lR,2S)-2-hydroxy-2-(4-hydroxyphenyl)-l-memylemyl]amino}niefryl)pheny]]anMix>}quinoUitt^ (salt)
15 APC1 LC-MS m/z 52Z4[MH+]
Example HI
6,7-diethoxy-4-{ [2-ethyl-3-({ [(lR,2R>2-hydroxy-l-(hydroxymethyl)-2-phenylethyl]amino} methyl)phenyl]amino }quinoline-3-carboxamide b15(trifluoroacetate)
20 (salt)
APC1 LC-MS m/z 559.5[MH+]
Example 112
6,7-Diethoxy-4- {2-ethyl-3-[(2-hydroxy-l -hydroxymethyl-2-phenyl-
25 ethylamino)-methyl]-phenylamino}-quinoline-3-carboxylic aC1d amide b15(trifluoroacetate) APC1 LC-MS m/z 559.5[MH+]
Example 113
4-[(3-{[(2-cyanoemyl)amino]methyl}-2-ethylphenyl)amino]-6,7-diethoxyquinoline-3-30 caiboxamide b15(tnfluoroacetate)
WO 2005/075429
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APC1LC-MS m/z 462.5[MH+]
Example 114
6,7-diethoxy-4-{[2-ethyl-3-({[l-(hydroxymethyl)-2-methylpropyl] amino} methyl)
5 phenyl]amino}quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z 495.5[MH+]
Example 115
6,7-diethoxy-4-{[2-ethyl-3-({[4-(methylsulfonyl)benzyl]amino} methyl) phenyl]
10 amino }quinoline-3-carboxamideb15(trifluoroacetate) APC1 LC-MS m/z 577.5[MH+]
Example 116 terf-butyl 3-{ [3-(aminocartK>nyl)-6,7-diethoxyquinolin-4-yl]amino}-2-
15 ethylbenzylcarbamate
A mixture of 4-chloro-6,7-diethoxyquinoline-3-carboxamide (96.5 mg, 0.33 mmole), tert-butyl 3-amino-2-ethylbenzylcarbamate (prepared according to WO 02/092571) (119 mg, 0.476) in NMP (2 ml) was heated over night at 115 C. After cooling the solution was diluted with water and basified with NaHCOs. The compound was extracted from the aqueous
20 solution with ethylacetate (3x). The extracts were washed with water (2x), brine (2x), dried (Na2S04>, and evaporated. The residue was purified by silica chromatography (CH2Cl2/MeOH) to give 105 mg (62%) of the title compound as a white powder.
*H NMR (299.946 MHz, DMSO-
25 2.81 (2H, d), 1.39 (9H, s), 1.33 (3H, t), 1.17 (3H, t), 1.02 (3H, t) APC1-LC/MS m/z: 509.4 [MH+]
Example 117 4-{[3-(aminomethyl)-2-ethylphenyl]amino}-6,7-diethoxyquinoline-3-carboxamide
WO 2005/075429
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*-
To a cooled solution of tert -butyl 3-{ [3-(aminocarbonyl)-6,7-diethoxyquinolin-4-yl]amino}-2-ethylbenzylcarbamate (105 mg, 0.21 mmole) in CH2C12 (4 ml) was added TFA (4 ml). After 40 minutes at 0°C the solvent was evaporated of. The residue was d15solved in CH3CN/NH3-aq solution and purified by preparative HPLC After freeze-drying (36 mg,
5 42%) of the title compound was obtained as a white powder.
JH NMR (399.99 MHz, DMSO-d*) 8 10.97 (IH, s), 8.85 (IH, s), 8.27 (IH, s), 7.57 (IH, s),
7.19 (IH, s), 7.17 (IH, s), 7.01 (IH, t), 6.63 (IH, s), 6.54 (IH, d), 4.13 (2H, q), 3.80 (2H, s),
2.81 (2H, q), 1.35 (3H, t),1.18 (3H, t), 1.01 (3H, t)
APC1-LC/MS m/z: 409.2 [MH+]
10
Example 118
4-{ [3-(aminomethyl)-2-methylphenyl]amino }-6,7-diethoxyquinoline-3-carboxamide
The title compound was prepared in an analogues way to example 117.
APC1-LC/MS m/z: 395.2 [MH+]
15
Example 119
6,7-dUemoxy-4-({2-emyl-3-[(L-tyrosylamino)methyl]phenyI}amino)quinoline-3-
carboxamide b15(trifluoroacetate)
To a mixture of boc-L-tyrosine (45 mg, 0.16 mmol), HATU (61 mg, 0.16 mmol), and
20 DIEA (26 mg, 0.2 mmol) in NMP/ dichloromethane (1 ml) 4-{ [3-(aminomethyl)-2-
ethylphenyl]amino}-6,7-diethoxyquinoline-3-carboxamide (15 mg, 0.039 mmol) was added. The reaction was stirred for 1 h at room temperature. TFA ( 50% in DCM, 1ml) was then added and the reaction mixture was stirred further for 1 h. The mixture was then diluted with water (1.0 ml) and purified by preparative HPLC using a gradient of
25 acetonitrile/water at a flow rate of 20ml/min. Freeze drying of the mixture afforded the title compound in 20% yield.
*H NMR (400 MHz, DMSO-^j) 8 9.39 (IH, s, ); 8.98 (IH, s,); 8.85 (IH, s,); 8.54 (IH, s,);
8.20 (3H, s,); 8.02 (IH, s,); 7.28 (IH, s,); 7.16 (IH, s,); 7.04 (2H, d, J=8.5 Hz); 6.72 (2H,
d, J=8.5 Hz); 6.65 (IH, s,); 4.49 (IH, s,); 4.34 (IH, d, J=l 1.3 Hz); 4.20 (2H, q, J=7.0
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Hz); 3.99 (1H, s,); 2.96 (2H, t, J=6.7 Hz); 2.70 (1H, d, J=27.3 Hz); 1.39 (3H, t, J=7.0 Hz); 1.13 (6H, t, J=7.5 Hz); 1.07 (9H, t, J=6.7 Hz). APC1-LC/MS m/z: 572.6 [MH+]
5 The title compounds of examples 120-183 were prepared in analogous manner to example 119 using 4-{ [3-(aminomethyl)-2-ethylphenyl]amino }-6,7-diethoxyquinoline-3-carboxamide, 4-{[3-(aminomethyl)-2-ethylphenyl]amino}-6,7-dimetoxyquinoline-3-carboxamide or 4-{ [3-{aminomethyl)-2-methylphenyl]amino}-6,7-dimetoxyquinoline-3-carboxamide and an appropriate amino aC1d, aC1d chloride or 15ocyanate.
10
Example 120
6J^ethoxy^{[3-({[(emylaniino)aubonyl]amino}methyl)-2-methylphenyl]amino }quinoline-3-carboxamide APCI LC-MS m/z: 466.5[MH+]
15
Example 121
4-({3-[(acetylaniino)methyl]-2-n>emylphenyl}amino)-6J^emoxyquinoline-3^arix)xamide APC1 LC-MS m/z: 437.4[MH+]
20 Example 122
6,7-diethoxy-4-({2-memyl-3-[({[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]sulfonyl }amino)methyl]phenyl }amino)quinoline-3-carboxamide APC1 LC-MS m/z: 585.1[MH+]
25 Example 123
4-( (3-[(acetylamino)methyl]-2-ethylphenyl} amino)-6,7-dimethoxyquinoline-3-carboxamide APC1 LC-MS m/z: 423.4[MH+]
Example 124
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4-{[2-ethyl-3-( {[(ethylamino)carbonyl]amino }methyl)phenyl]amino}-6,7-
dimethoxyquinoline-3-carboxamide
APC1LC-MS m/z: 585.1 [MH+]
5 Example 125
4-[(2-ethyl-3- {[(methylsulfonyl)amino]methyl }phenyl)amino]-6,7-dimethoxyquinolinc-3-
carboxamide
APC1 LC-MS m/z: 459.2[MH+]
10 Example 126
4-({2-emyl-3-[(I^valylainino)memyl]phenyl}ainino)-6J-dimcthoxyquinoline-3-
caiboxamide
APC1 LC-MS m/z: 480.2[MH+]
15 Example 127
4-[(3-{ [(3-cyclohexyl-L-alanyl)amino]methyl }-2-ethylphenyl)ainino]-6,7-
dimethoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 534.5[MH+]
20 Example 128
6,7-diethoxy-4-( {2-ethyl-3-[(L-methionylamino)methyl]phenyl} amino)quinoline-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z: 540.5[MH+]
25 Example 129
6,7-diethoxy-4-({2-ethyl-3-[(L-prolylamino)memyl]phenyl}amino)quinoline-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z: 506.4[MH+]
30
Example 130
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6,7-diethoxy-4-({ 2-ethyl-3-[(L-threonylamino)methyl]phenyl} amino)quinoline-3-carboxamide b15(trifluoroacetate) APCI LC-MS m/z: 510.4[MH+]
5 Example 131
N~l~K3-{[3-(aminocarbonyl)-6J-^ethoxyquinolin-4-yl]amino}-2-ethylbenzyl)-L-alpha-glutamine b15(trifluoroacetate) APC1 LC-MS m/z: 538.5[MH+]
10 Example 132
6J^iethoxy-4-({2-ethyl-3-[(L-valylamino)mehyl]phenyl}amino)quinoline-3-carboxamide
b15(trifluoroacetate)
APC1 LC-MS m/z: 508.5IMH+]
15 Example 133
4-({ 3-[(L-arginylamino)methyl]-2-ethylphenyl }amino)-6,7-diethoxyquinoline-3-caiboxamide tr15(trifluoroacetate) APC1 LC-MS m/z: 565.6 [MH+]
20 Example 134
4-({ 3-[(L-alanylamino)metiiyl]-2-ethylphenyl }amino)-6,7-diethoxyquinoline-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z: 480.4[MH+]
25 Example 135
6,7-diethoxy-4-( {2-ethyl-3-[(D-serylamino)methyl]phenyl} amino)quinoline-3-carboxamide
b15(trifluoroacetate)
APC1 LC-MS m/z: 496.4[MH+]
30
Example 136
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4-[(3-{[(3-cyclohexyl-L-alanyl)amino]methyl)-2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamideb15(trifluoroacetate)
APCIC-MS m/z: 562.5[MH+]
5 Example 137
6,7-diethoxy-4-{[2-ethyl-3-({[(4S)-l,3-thiazolidin-4-
ylcarbonyl]amino}methyl)phenyl]amino}quinoline^^arboxamideb15(trifluoroacetate) APC1 LC-MS m/z: 524.4[MH+]
10 Example 138
6,7-diethoxy-4-{ [2-ethyl-3-({ [(4RH-hydroxy-L-
prolyl]amino}memyl)phenyl]amino)quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z: 522.5(MH+]
15 Example 139
6,7-diethoxy-4-({2-emyl-3-[0>leucylainino)methyI]phenyl}amino)quinoliiie-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z: 522.5[MH+]
20 Example 140
N~l —(3- {[3-(aminocarbonyl)-6,7-diethoxyquinolin-4-yl]amino)-2-ethylbenzyl)-L-aspartamide b15(trifluoroacetate) APC1 LC-MS m/z: 523.2[MH+]
25 Example 141
6,7-diethoxy-4- {[2-ethyl-3-({ ((2S)-piperidin-2-
ylcarbonyljamino} methyOphenyljamino }quinoIine-3-carboxamide b15(trifluoroacetate)
APC1 LC-MS m/z : 520.5[MH+]
30
Example 142
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4-[(3-{[(3-cyclohexyl-D-alanyl)amino]methyl}-2-ethyIphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamideb15(trifluoroacetate)
APC1LC-MS m/z: 562.5[MH+]
5 Example 143
6,7-diethoxy-4-{ [2-ethyI-3-({ [(2R)-piperidin-2-
ylcarbonyl]amino}methyl)phenyl]amino}quinoline-3-carboxamideb15(trifluoroacetate) APQ LC-MS m/z 520.5[MH+]
10 Example 144
4-{ [3-({ [(2S)-2-aminopent-4-enoyl]ainino} methyl)-2-ethylphenyl]amino }-6,7-diethoxyquinoline-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z: 506.5[MH+]
15 Example 145
4-{ [3-
20 Example 146
6,7-diethoxy-4-[(2-ethyl-3-{ [(5-methyl-L-
norleucyl)amino]methyl} phenyl)amino]quinoline-3-caiboxamide b15(trifluoroacetate)
APC1 LC-MS m/z: 536.5[MH+]
25 Example 147
6,7-diethoxy-4-{ [2-ethyl-3-({ [(4R)-U-thiazolidin-4-
ylcaibonyl]amino} methyl)phenyl]amino }quinoline-3-carboxamide b15(trifluoroacetate)
APC1 LC-MS m/z: 524.4[MH+]
30
Example 148
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6,7-diethoxy-4-[(2-ethyl-3-{[(4-nitro-D-
phenylalanyl)amino]methyl}phenyl)amino]quinoline-3-carboxamideb15(trifluoroacetate) APC1LC-MS m/z: 601.5[MH+]
5 Example 149
4-{ [3-({ [(l-amino-2,3-dihydro-lH-inden-l-yl)carbonyl]amino}methyl)-2-ethylphenyl]amino}-6,7-diethoxyquinoline-3-carboxamideb15(trifluoroacetate) APC1LC-MS m/z: 568.5[MH+]
10 Example 150
4-([3-(l[(l-aminocycl
15 Example 151
6,7-diethoxy-4-{ [2-ethyl-3-({ [(3R)-l,23,4-tetrahydro15oquinolin-3-ylcart>onyl]amino}iTiemyl)phenyl]amino}quinoline-3^arboxamideb15(trifluoroacetate) APC1LC-MS m/z: 568.5[MH+]
20 Example 152
4- {[3-( {[(2R)-2-amino-4-phenylbutanoyl]amino} methyl)-2-etiiylphenyl]amino} -6,7-diethoxyquinoline-3-carboxamide bi s(trifluoroacetate) APC1 LC-MS m/z: 570.5[MH+]
25 Example 153
6,7-diethoxy-4-{ [2-ethyl-3-({ [(3S)-l,2,3,4-tetrahydro15oquinolin-3-ylcarbonyl]amino} methyl)phenyl]amino }quinoline-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z :568.5(MH+]
30
Example 154
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6,7-diethoxy-4-[(2-ethyl-3- {[(4-piperidin-4-yl-L-
prolyl)amino]methyl} phenyl)amino]quinoline-3-carboxamide tr15(trifluoroacetate)
APC1LC-MS m/z: 589.6[MH+]
5 Example 155
4-[(3-{[(3-amino-L-alanyl)amino]methyl}-2-ethylphenyl)amino]-6,7-diethoxyquinoline-3-carboxamide tr15(trifluoroacetate) APC1 LC-MS m/z: 495.4[MH+]
10 Example 156
6J-diethoxy-4K{2-emyl-3-[(D-phenylalanylainino)memyl]phenyl}amino)quinoline-3-carboxamide b15(trifluoroacetate) APO LC-MS m/z: 556.5[MH+]
15 Example 157
4-{ [3-({ [(2S)-2-aiiuno-4-phenylbutanoyl]aniino}niemyl)-2-ethylphenyl]amino}-6,7-diethoxyquinoline-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z: 570.5[MH+]
20 Example 158
6,7-diethoxy-4-{ [2-ethyl-3-({ [(3S)-piperidin-3-
ylcart>onyl]amino}methyl)phenyl]arnino}quinoline-3-carboxamideb15(trifluoroacetate) APC1 LC-MS m/z: 520.5[MH+]
25 Example 159
6,7-diethoxy-4-{ [2-ethyl-3-({ [(3R)-piperidin-3-
ylcarbonyl]amino}nKthyl)phenyl]amino}quinoline-3-carboxanudeb15(trifluoroacetate) APC1 LC-MS m/z: 520.5[MH+]
30
Example 160
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"71
4-{[3-({[(2S)-2-amino-2-phenylacetyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamideb15(trifluoroacetate)
APC1LC-MS m/z: 542.5[MH+]
5 Example161
6,7-diethoxy-4-({2-ethyl-3-[(L-leucylamino)methyl]phcnyl}amino)qtiinoline-3-carboxamide b15(trifluoroacetate) APC1LC-MS m/z: 522.5[MH+]
10 Example 162
6J-dietbx)xy-4-({2-emyl-3-[(I>prolylamino)methyl]phenyl}amino)quinoline-3-caiboxamide b15(trifluoroacetate) APCLLC-MS m/z: 506.5[MH+]
15 Example 163
4-{ [3-({ ((2S)-2,5-dihydn>-lH-pyrrol-2-ylcarixjnyl]anuno^ 6,7-diethoxyquinoline-3-carboxamideb15(trifluoroacetate) APC1 LC-MS m/z: 504.4[MH+]
20 Example 164
6,7-diethoxy-4-({2-ethyl-3-[(glycylamino)methyl]phenyl}amino)quinoline-3-carboxamide
b15(trifluoroacetate)
APa LC-MS m/z: 466.4[MH+]
25 Example 165
4-{[3-({[2-amino-4-(methylsulfinyl)butanoyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamideb15(trifluoroacetate)
APC1 LC-MS m/z: 556.5[MH+]
30
Example 166
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6,7-diethoxy-4-{[2-ethyl-3-({[3-(2-furyl)-L-alanyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide b15(trifluoroacetate) APC1LC-MS m/z: 546.5[MH+]
5 Example 167
6,7-diethoxy-4-[(2-ethyl-3-{[(3-pyridin-2-yl-L-
alanyl)amino]methyl }phenyl)amino]quinoline-3-carboxamide tr15(trifluoroacetate)
APC1 LC-MS m/z: 557.5[MH+]
10 Example 168
6,7-diethoxy-4-{ [2-ethyl-3-({ [3-(2-thienyl)-L-
alanyl]aniino}methyl)phenyl]amino}quinoline-3-carboxamideb15(trifluoroacetate) APC1 LC-MS m/z: 562.4[MH+]
15 Example 169
6,7-diethoxy-4-{[2-ethyl-3-({[3-(l,3-thiazol-4-yl)-L-
alanyljamino} methyl)phenyl]amino} quinoline-3-carboxamide tr15(trifluoroacetate)
APC1 LC-MS m/z: 563.5[MH+]
20 Example 170
4-{ [3-({ [(2S)-2-amino-2-cyclopentylacetyl]amino} methyl)-2-ethylphenyl]amino }-6,7-
diethoxyquinoline-3-carboxamideb15(trifluoroacetate)
APC1 LC-MS m/z: 534.5[MH+]
25 Example 171
4- {[3-( {[(2S)-2-aminopent-4-ynoyl]amino} methyl)-2-ethylphenyl]amino} -6,7-
diethoxyquinoline-3-carboxamideb15(trifluoroacetate)
APC1 LC-MS m/z: 504.4[MH+]
30
Example 172
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6,7-diethoxy-4-( {2-ethyl-3-[(L-norvalylamino)methyI]phenyl} amino)quinoline-3-carboxamide b15(trifluoroacetate) APC1LC-MS m/z: 508.5[MH+]
5 Example 173
4-{[3-({[(2R)-2-amino-2-phenylacetyl]amino}mcthyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamidcb15(trifluoroacetate)
APC1 LC-MS m/z: 542.5[MH+]
10 Example 174
6,7-diethoxy-4-{ [2-ethyl-3-({ [(4R)-4-hydroxy-D-
prolyl]amino}methy!)phenyl]anuno}quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z: 522.4[MH+]
15 Example 17S
4-({ 3-[(bcta-alanylamino)mclhyl]-2-cthylphenyl }amino)-6,7-diethoxyquinoline-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z: 480.4[MH+]
20 Example 176
6,7-diethoxy-4-[(2-ethyl-3- {[(3-pyridin-3-yl-L-
alanyl)amino]methyl}phenyl)amino]quinoline-3-carboxamidetr15(trifluoroacetate) APC1 LC-MS m/z: 557.5[MH+]
25 Example 177
6,7-diethoxy-4-[(2-ethyl-3- {[(3-pyridin-3-yl-D-
alanyl)amino]methyl}phenyl)amino]quinoline-3-carboxamidetr15(trifluoroacetate) APC1 LC-MS m/z: 557.5[MH+]
30
Example 178
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4-{[3-({[N~5—(aminocarbonyl)-L-omithyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamideb15(trifluoroacetate)
APC1LC-MS m/z: 566.5[MH+]
5 Example 179
6,7-diethoxy-4-[(2-ethyl-3- {[(5-methyl-D-
norleucyl)amino]methyl }phenyl)amino]quinoline-3-carboxamide b15(trifluoroacetate)
APC1LC-MS m/z: 536.5[MH+]
10 Example 180
4-[(3-{[(23^ihydro-lH-15oindol-l-ylcarfjonyl)amino]rnethyl}-2-€thylphenyl)amino]-6,7-diethoxyquinoline-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z: 554.5[MH+1
15 Example 181
6,7-diethoxy-4-({ 2-ethyl-3-[(L-15oleucylamino)methyllphenyl }amino)quinoline-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z: 522.5[MH+]
20 Example 182
6J-diemoxy-4-({2-emyl-3-[(D-valylamino)methyl]phenyl}amino)quinoline-3-carboxamide
b15(trifluoroacetate)
APC1 LC-MS m/z: 508.5[MH+]
25 Example 183
4- {P-( {[(1 -aminocyclopentyl)carbonyl]amino} methyl)-2-ethylphenyl]amino} -6,7-diethoxyquinoline-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z: 520.5[MH+]
30
Example 184
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4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-{3-[15obutyryl(15opTX)pyl)amino]propoxy}-6-methoxyquinoline-3-carboxamide
To a solution of 4-{[2^thyl-3-(hydroxymethyl)phenyl]amino}-7-[3-(15opropylamino) propoxy]-6-methoxyquinoline-3-carboxamide, prepared according to the procedure 5 described in WO 02/092571,10 mg, .021 mmole), triethylamine (0.2 ml) in NMP (1ml) was added 15obutiric anhydride (3.8 mg, .024 mmole). The mixture was stirred overnight at ambient temperature. The solution was diluted with water and the product was purified by preparative HPLC. After freeze-drying 6.7mg (59%) was obtained of the title compound as a white powder.
10 lH NMR (399.99 MHz, DMSO-40 8 11.03 (IH, s), 8.87 (IH, s), 8.28 (IH, s), 7.60 (IH, s), 7.21 (2H, mult), 7.04 (IH, t), 6.65 (IH, d), 6.59 (IH, d), 5.16 (IH, t), 4.60 (2H, d), 4.46 (IH, quintet), 4.13 (2H, mult), 3.23 (IH, t), 3.21 (3H, d), 2.81 (3H, mult), 1.96 (2H, s), 1.19 (3H, t), 1.12 (3H, t), 1.05 (3H, d), 0.98 (3H, d), 0.90 (3H, d) APC1-LC/MS m/z: 537.3 [MH+]
15
Following examples 185-202 were prepared in analogous manner to example 184 using the appropriate anhydride, aC1d chloride or 15ocyanate.
Example 185 20 7-{3-[acetyl(15opropyl)amino]propoxy}-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide
XH NMR (399.99 MHz, DMSO-40 5 11.07 (IH, s), 8.87 (IH, s), 8.29 (IH, s), 7.61 (IH, s), 7.24 (IH, s), 7.19 (2H, d), 7.05 (IH, t), 6.65 (IH, d), 6.60 (IH, d), 5.16 (IH, t), 4.59 (2H, d), 4.44 (.5H, t), 4.12 (2H, dt), 4.00 (.5H, quintet), 3.23 (IH, t), 3.21 (3H, d), 2.79 (2H, q), 1.97 25 (5H, mult), 1.19 (3H, t), 1.08 (6H, mult) APC1LC-MS m/z: 509.3[MH+]
Example 186
6-[2^acetylamino)emoxy]^[(2-ethylphenyl)anMnoJ-7-nieuioxyquinoline-3-carboxamide 30 APC1LC-MS m/z: 423.2[MH+]
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Example 187
6- {2-[acetyl(methyl)amino]ethoxy} -4-[(2-ethylphenyl)amino]-7-methoxyquinoline -3-
carboxamide
5 APC1LC-MS m/z: 437.2[MH+]
Example 188
6-{2-[acetyl(15opropyl)amino]ethoxy}-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide 10 APC1 LC-MS m/z: 465.2[MH+]
Example 189
4-[(2-emylphenyl)aniino]^{2-[15obutyi7l(memyl)amiiK»lemoxy}-7-niemoxyqtuiK)Hne-3-carboxamide 15 APC1 LC-MS m/z: 465.2(MH+]
Example 190
4-[(2-emylphenyl)ainino]-6-{2-[15obutyryl(15opropyl)amino]ethoxy}-7-methoxyquinoline-3-carboxamide 20 APC1 LC-MS m/z: 493.3[MH+]
Example 191
7- {3-[acetyl(methyl)amino]propoxy} -4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -6-
methoxyquinoline-3-carboxamide
25 APC1 LC-MS m/z: 481.5[MH+]
Example 192
4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -7-{ 3-[15obutyryl(memyl)amino]propoxy} -6-methoxyquinoline-3-carboxamide 30 APC1 LC-MS m/z: 509.6[MH+]
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S3
Example 193
7-{3-[acetyl(cyclopropyl)amino]propoxy}-4-{[2-ethyl-3-(hydioxymethyl)phenyl]amino methoxyquinoline-3-carboxamide 5 APC1LC-MS m/z: 507.6[MH+]
Example 194
7- {3-[cyclopropyl(15obutyryl)amino]propoxy} -4- {[2-ethyl-3-(hydroxymemyl)pheiiyl]aniino}^-inethoxyquinoline-3-cart)oxamide 10 APC1 LC-MS m/z: 534.7[MH+]
Example 19S
7-[3-(acetylamino)propoxy]^{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-carboxamide 15 APC1 LC-MS m/z: 467.3[MH+]
Example 1%
4-{[2-ethyl-3-(hydK>xymemyl)phenyl]anuno}-7-[3-(15obutyrylamino)propoxy]-6-methoxyquinoline-3-carboxamide 20 APC1 LC-MS m/z: 494.7[MH+]
Example 197
6-{2-[(cyclopropylcarbonylXmethyl)amino]ethoxy}-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide 25 APC1 LC-MS m/z: 463.2[MH+]
Example 198
6-{2-[(cyclopropylcarbonyl)(15opropyl)amino]ethoxy}-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide 30 APC1 LC-MS m/z: 491.2[MH+1
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Example 199
4-{ [2-ethyl-3-(hydroxymethyl)phenyl]amino }-7-{ 3-
[15opropyl(methylsulfonyl)amino]propoxy} -6-methoxyquinoline-3-carboxamide 5 APC1LC-MS m/z: 545.3[MH+]
Example 200
4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-{3-[(methylsulfonyl)amino]propoxy}quinoline-3-carboxamide 10 APC1 LC-MS m/z: 503.6[MH+]
Example 201
terf-butyl {3-[(3-(aminocart)onyl)-4-{[2-cthyl-3-(hydroxymethyl)phenyl]amiiio}-6-
methoxyquinolin-7-yl)oxy]propyl}15opropylcaibamate
15 *H NMR (399.99 MHz, CD3OD) 8 8.79 (s, IH), 7.28 (d, J = 12 Hz, IH), 7.20 (s, IH),
7.12 (t, J = 7.8 Hz, IH), 6.81 - 6.74 (m, 2H), 4.75 (s, 2H), 4.16 (t, J = 5.9 Hz, 3H), 3.36 -
3.31 (m, 2H), 3.28 (s, 3H), 2.94 (q, J = 7.4 Hz, 2H), 2.14 - 2.04 (m, 2H), 1.42 (s, 9H),
1.30 (t, J = 7.5 Hz, 3H), 1.16 (d, J = 6.8 Hz, 6H).
APC1 LC-MS m/z: 567.3[MH+] 20
Example 202
4-{ [2-ethyl-3-(hydroxymethyl)phenyl]amino }-7-(3-
{15opropyl[(15opropylamino)carbonyl]amino}propoxy)-6-methoxyquinoline-3-cart)oxamide
2H NMR (399.99 MHz, DMSO-dg) 811.04 (s, lH),8.88(s, lH),8.29(s, lH),7.61(s, 25 IH), 7.24 (s, IH), 7.19 (d, J = 7.2 Hz, IH), 7.05 (t, J = 7.7 Hz, IH), 6.66 (s, IH), 6.60 (d, J = 7.6 Hz, IH), 5.61 (d, J = 7.8 Hz, IH), 5.17 (t, J = 5.4 Hz, IH), 4.61 (d, J = 5.4 Hz, 2H), 4.22 (quintet, J = 6.7 Hz, IH), 4.12 (t, J = 6.2 Hz, 2H), 3.76 (quintet, J = 6.8 Hz, IH), 3.22 (s, 3H), 3.18 (t, J = 7.3 Hz, 2H), 2.80 (q, J = 7.5 Hz, 2H), 1.99 -1.87 (m, 2H), 1.20 (t, J = 7.4 Hz, 3H), 1.06 - 0.97 (m, 12H) 30 APC1 LC-MS m/z: 552.3[MH+]
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Following examples 203-233 are prepared according to the procedure described in WO 02/092571
5 Example 203
7-[3-(cyclopropylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-
methoxyquinoline-3-carboxamide
APC1LC-MS m/z: 465.4 [MH+]
10 Example 204
6-[3-(cyclopropylamino)propoxy]-4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino }-7-methoxyquinoline-3-carboxamide
*H NMR (399.99 MHz, DMSCMs): 5 11.02 (IH, s); 8.88 (IH, s); 8.29 (IH, br s); 7.61 (IH, br s); 7.23 (IH, s); 7.18 (IH, d, J = 7.4 Hz); 7.04 (IH, t, J = 7.8 Hz); 6.65 (IH, s); 6.60 (IH, 15 d, J = 7.7 Hz); 5.19 (IH, br s); 4.61 (2H, s); 3.88 (3H, s); 3.37 (2H, s); 2.80 (2H, q, J = 7.4 Hz); 1.99 (IH, dquintet, J = 6.7,3.4 Hz); 1.57 (2H, quintet, J = 6.6 Hz); 1.20 (3H, t, J = 7.5 Hz); 0.34 (2H, td, J = 6.4,4.2 Hz); 0.15 (2H, dt, J = 6.1,3.7 Hz). APC1-LC/MS m/z: 465.4 [MH+]
20 Example 205
7- {3-[(2-cyanoethyl)(methyl)amino]propoxy} -4- {[3-(hydroxymethyl)-2-methylphenyl]amino} -6-methoxyquinoline-3-carboxarnide b15(trifluoroacetate) (salt) APC1 LC-MS m/z: 478.3 [MH+]
25 Example 206
4- {[3-(hydroxymethyl)-2-rnethylphenyl]arnino} -6-methoxy-7-[3-(2-methylpiperidin-l-
yl)propoxy]quinoline-3-carboxamide
APC LC-MS m/z: 493.3[MH+]
30
Example 207
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7-{ 3-[(2-cyanoethyl)(methyl)amino] propoxy }-4-{ [3-(hydroxymethyl)-2-methylphenyl]amino}-6-methoxyquinoline-3-carboxamide APC1LC-MS m/z: 478.2[MH+]
5 Example 208
4-{[3-(hydroxymethyl)-2-methylphenyl]amino}-7-[3-(3-hydroxypiperidin-l-yl)propoxy]-6-
methoxyquinoline-3-caiboxamide
APC1 LC-MS m/z: 495.3[MH+]
10 Example 209
4-l[3-(hydroxymethyl)-2-niethylphenyl]amino}-7-[3K4-hydroxypiperidin-l-yl)propoxy]-6-
methoxyquinoline-3-caiboxamide
APC1 LC-MS m/z: 495.3[MH+]
15 Example 210
6-metfioxy-4-[(2-methylphenyI)amino]-7-[3-(2-inemylpiperidin-l-yl)propoxy]quinoline-3-
carboxamide
APC1 LC-MS m/z: 463.3[MH+]
20 Example 211
7-[3-(3-hydroxypiperidin-l-yl)propoxy]-6-memoxy-4-[(2-nMmylphenyl)amino]quinoline-3-
carboxamide
APCI LC-MS m/z: 465.3[MH+]
25 Example 212
7-[3-(4-hydroxypiperidin-l-yl)propoxy]-6-methoxy-4-[(2-methylphenyl)amino]quinoline-3-
carboxamide
APCI LC-MS m/z: 465.3[MH+]
30
Example 213
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4-{[3-(hydroxymethyl)-2-methylphenyl]amino}-7-[3-(3-hydroxypyrrolidin-l-yl)propoxy]-
6-methoxyquinoline-3-carboxamide
APC1LC-MS m/z: 481.1 [MH+]
5 Example 214
4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(lH-l,2,4-tria2ol-l-yl)propoxy]quinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z: 477.6[MH+]
10 Example 215
7-[2-(cyclopropylamino)ethoxy]-4-{ [3-(hydroxymethyl)-2-methylphenyl]amino }-6-methoxyquinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z: 437.5[MH+]
15 Example 216
6-[2-(cyclopropylamino)ethoxy]-4- {[3-(hydroxymethyl)-2-methylphenyl]amino} -7-methoxyquinoline-3-caiboxamide b15(trifluoroacetate) (salt) APC1 LC-MS m/z :437.2[MH+]
20 Example 217
6-[2-(cyclopropylamino)ethoxy]-4-[(4-ethylphenyl)amino]-7-methoxyquinoline-3-
caiboxamide
APC1 LC-MS m/z: 421.5[MH+]
25 Example 218
6-[2-(cyclopropylamino)ethoxy]-4-[(3-ethylphenyl)amino]-7-methoxyquinoline-3-
carboxamide
APC1 LC-MS m/z: 421.5[MH+]
30
Example 219
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6-[2-(cyclopropylamino)ethoxy]-7-methoxy-4-[(2-methylphenyl)amino]quinoline-3-carboxamide b15(trifluoroacetate) APC1LC-MS m/z: 407.2[MH+]
5 Example 220
6-{2-[(2^yanoethyl)amino]ethoxy}-4-{[3-(hydroxymethyl)-2-methylphenyl]amino}-7-methoxyquinoline-3-carboxamide b15(trifluoroacetate) (salt) APC1LC-MS m/z: 450.2[MH+]
10 Example 221
6-[3-(cyclopropylamino)propoxy]-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide b15(trifluoroacetate) APC1 LC-MS m/z: 435.3[MH+]
15 Example 222
6-{ 3-[(cyanomethyl)amino]propoxy} -4-[(2-emylphenyl)amino]-7-methoxyquinoline-3-
carboxamide
APC1 LC-MS m/z: 434.3[MH+]
20 Example 223
6-[3-(Carbamoylmethyl-amino)-propoxy]-4-(2-ethyl-phenylamino)-7-methoxy-quinoline-3-carboxylic aC1d amide b15(trifluoroacetate) APC1 LC-MS m/z: 452.3[MH+]
25 Example 224
methyl N-[3-({3-(aminocarbonyl)-4-[(2-ethylphenyl)amino]-7-methoxyquinolin-6-yl }oxy)propyl]glyC1nate b15(trifluoroacetate) APC1 LC-MS m/z: 467.3[MH+]
30
Example 225
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7-(3-cyanopropoxy)-4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -6-methoxyquinoline-3-carboxamide trifluoroacetate (salt) APC1LC-MS m/z: 435.2[MH+]
5 Example 226
2-[(3-(aminocarbonyl)-4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -6-methoxyquinolin-7-yl)oxy]ethyl acetate trifluoroacetate (salt) APC1 LC-MS m/z: 568.5[MH+]
10 Example 227
6-[2-(cyclopropyIaimno)ethoxy]-4-[(2-emylphenyl)ainino]-7-methoxyquinoline-3-
carboxamide
APC1 LC-MS m/z: 421.1[MH+]
15 Example 228
7-l3-(2^-dioxopyiTolidin-l-yl)r^rwxy]-4~{[2-emyl-3-0»ydroxymethyl)phenyl]amino}-6-
methoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 507.6[MH+]
20 Example 229
4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -6-methoxy-7-[3-(3-methyl-2,5-
dioxoimidazolidin-l-yl)propoxy]quinoline-3-carboxamide
APC1 LC-MS m/z: 522.6[M+]
25 Example 230
4-{[2-emyl-3-(hydroxymemyl)phenyl]amino}-6-methoxy-7-[3-(3,4,4-trimetiiyl-2,5-dioxoimidazolidin-1 -yl)propoxy]quinoline-3-carboxamide APC1 LC-MS m/z: 550.5[MH+]
30
Example 231
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7-(cyclopentyloxy)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinoline-3-
carboxamide
APC1LC-MS m/z: 436.2[MH+]
5 Example 232
6-(cyclopentyloxy)-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide APC1 LC-MS m/z: 406.5[MH+]
Example 233
10 l-{ 3-[(3-(aminocarbonyl)-4-{ [3-(hydroxymethyl)-2-methylphenyl]amino}-6-methoxyquinolin-7-yl)oxy]propyl} -1-methylpyrrolidinium iodide To a mixture of 7-(3--chchlorophropoxy)-4-{[3-(hydroxymemyl)-2-methylphenyl] amino }-6-methoxyquinoline-3-carboxamide (0.050 g, 0.116 mmol) in aceton (4.0 ml) 1-methylpyrolidine (0.040 g, 0.46 mmol) and sodium iodide was added and the mixture
15 heated to 60°C for 24 h. After cooling, aceton was evaporated, the reaction mixture was diluted with water (2.0 ml) and purified by preparative HPLC using a gradient of acetonitrile/water at a flow rate of 20ml/min. Freeze drying of the mixture afforded the title compound.
1H NMR (400 MHz, CD3OD) 5 8.80 (IH, s,); 7.27 (IH, d, J=7.2 Hz); 7.22 (IH, s,); 7.14 20 (IH, t, J=7.6 Hz); 6.86 (IH, d, J=7.5 Hz); 6.81 (IH, s,); 4.70 (2H, s,); 4.26 (2H, t, J=5.2 Hz); 3.61 (7H, m, ); 3.14 (3H, s,); 2.38 (2H, m, ); 2.36 (3H, s, ); 2.25 (3H, m,); 1.91 (3H, s,
)
APC1-LC/MS m/z: 479.4 [M+]
25 Example 234
tert-butyl 4-[(3-(aminocarbonyl)-4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -6-methoxyquinolin-7-yl)oxy]piperidine-1 -carboxylate A mixture of 4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-hydroxy-6-methoxyquinoline-3-carboxamtde ( 112.6 mg, 0.31 mmole), prepared according to die
30 procedure described in WO 02/092571, rert-butyl 4-[(mediylsulfonyl) oxy]piperidine-l-
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carboxylate (99.7 mg, 0.36 mg) and cesium carbonate (158.5 mg, 0.49 mg) in dimethyl sulfoxide (2 ml) was heated at 70°C for 10 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water dried over sodium sulfate, filtrated and concentrated in vacuum. The residue was purified by flash
5 chromatography eluting with dichloromethane/methanol (9.6:0.4) to give the title compound as a yellow powder (39 mg, 23%).
1H NMR (399.99 MHz, DMSO-dtf 511.06 (1H, s), 8.87 (1H, s), 8.37 (1H, s), 7.69 (1H, s), 7.32 (1H, s), 7.17 (1H, s), 7.05 (1H, s), 6.65 (2H, s), 6.62 (2H, d), 5.16 (1H, s), 4.59 (2H, d), 3.69 (2H, mult), 3.19 (5H, s), 2.79 (2H, d), 2.02 (1H, s), 1.53 (2H, mult), 1.39 (9H, s), 1.19
10 (3H,t)
APCI-LC/MS m/z: 551.4 [MH+]
Example 235
tert-butyl 4-({ 3^aimnocarbonyl)^[(2^mylphenyl)amino]-7-methoxyquinolin-6-15 yl}oxy)piperidine-l-carboxylate
The title compound was prepared as described in example 235. APC1-LC/MS m/z: 521.4 [MH+]
Example 236
20 3-(aminocarbonyl)-4;-[(2-ethylphenyl)amino]-7-methoxyquinolin-6-yl propane-2-sulfonate To a solution of 4-[(2^mylphenyl)arnino]-6-hydroxy-7-methoxyquinoline-3-carboxamide trifluoroacetate, prepared according to the procedure described in WO 02/092571, (77.2 mg, 0.17 mmole), triethylamine (0.5 ml, 3.6 mmole) in l-methyl-2-pyrrolidinone was added propane-2-sulfonyl chloride (0.1 ml, 0.89 mmole). After stirring at room temperature for 48
25 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a white solid (24.6 mg, 32 %).
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1H NMR (399.99 MHz, DMSO-4*) 5 11.14 (1H, s), 9.01 (1H, s), 8.36 (1H, s), 7.70 (1H, s),
7.45 (1H, s), 7.34 (1H, dd), 7.20 (1H, s), 7.14 (2H, t), 7.07 (1H, td), 6.75 (1H, d), 3.94 (3H,
s), 3.13 (1H, t), 2.70 (2H, q), 1.17 (6H, d), 1.16 (3H, t)
APC1-LC/MS m/z: 444.1 [MH+] 5
Example 237
4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(piperidin-4-yloxy)quinoline-3-
carboxamide
7erf-butyl 4-[(3-(aminocarbonyl)-4-{ [2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-10 methoxyquinolin-7-yl)oxy]piperidine- 1-carboxylate (32 mg, 0.06 mmole) described in
example 235 was d15solved in dichloromethane (5 ml) cooled on ice and trifluoroacetic acd
(5 ml) was added. After 1 h stirring at room temperature the solvent was evaporated. The
residue was purified by preparative HPLC to give me title compound as a white powder (7
mg, 26%).
15 lH NMR (399.99 MHz, DMSO-4$) 811.03 (1H, s), 8.84 (IH, s), 8.25 (1H, s), 7.56 (IH, s). 7.24 (IH, s), 7.16 (IH, d), 7.03 (IH, t), 6.62 (IH, s), 6.59 (IH, d), 4.63 (3H, s), 3.17 (3H, s), 2.93 (2H, q), 2.77 (2H, q), 2.60 (3H, t), 1.95 (2H, dd), 1.44 (2H, mult), 1.18 (3H, t) APC1-LC/MS m/z: 451.2 [MH+]
20 Example 238
4-[(2-emylphenyl)amino]-7-methoxy-6-(piperidin-4-yloxy)quinoline-3-carboxamide The title compound was prepared as described in example 238
lH NMR (399.99 MHz, DMSO-4J) 8 10.83 (IH, s), 8.88 (IH, s), 8.29 (IH, br s), 7.62 (IH, br s), 7.32 (IH, dd), 7.25 (IH, s), 7.04 (2H, quintet), 6.67 (IH, s), 6.60 (IH, d), 3.87 (3H, s), 25 3.54 (IH, mult), 2.77 (4H, mult), 2.20 (2H, d), 1.48 (2H, s), 1.21 (5H, mult) APC1-LC/MS m/z: 421.2 [MH+]
Example 239
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6-[3-(cyclopropylamino)-2-hydroxypropoxy]-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide
To a mixture of 4-[(2-ethylphenyl)amino]-6-hydroxy-7-methoxyquinoline-3-carboxamide, prepared according to the procedure described in WO 02/092571,(0.070 g, 0.2 mmol) and
5 Cs2C03 (0.100 g, 0.3 mmol) in NMP (3.0 ml) epibromohydrine
(0.034g, 0.25mmol ) was added and the mixture was heated at 90 °C for 0.5 h. After cooling cyclopropylamine (0.05g 0.87 mmol) was added and the mixture heated at 70°C over night. After cooling the reaction mixture was diluted with water (2.0 ml) and purified with preparative HPLC using a gradient of acetonitrile/water at a flow rate of 20ml/min.
10 1H NMR (399.99 MHz, DMSO-^j) 8 10.89 (s, lH),8.89(s, lH),8.29(s, lH),7.61(s, IH), 7.34 - 7.31 (m, IH), 7.26 (s, IH), 7.09 - 7.06 (m, 2H), 6.68 - 6.66 (m, IH), 6.65 (s, IH), 4.83 (d, IH), 3.90 (s, 3H), 3.70 (q, IH), 3.29 - 3.18 (m, 2H), 2.72 (q, 2H), 2.55 -2.45 (m, 2H), 2.05 - 2.00 (m, IH), 1.25 (t, 3H), 0.36 - 0.33 (m, 2H), 0.18-0.14 (m, 2H) APCI-MS m/z: 451.5[MH+]
15
The title compounds of examples 240-247 were prepared in analogous manner to example 239.
Example 240
20 6- {3-[(2-cyanoethyl)amino]-2-hydroxypropoxy} -4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide APC1LC-MS m/z: 464.1 [MH+]
Example 241 25 4-[(2-ethylphenyl)amino]-6-[2-hydroxy-3-(2-hydroxypyrrolidin-l-yl)propoxy]-7-methoxyquinoline-3-carboxamide APC1 LC-MS m/z: 481.3[MH+]
Example 242
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4-[(2-ethylphenyl)amino]-6-(2-hydroxy-3-piperazin-l-ylpropoxy)-7-methoxyquinoline-3-
carboxamide
APC1LC-MS m/z: 480.3[MH+]
5 Example 243
6-{[(2R)-3-(cyclopropylamino)-2-hydroxy-2-methylpropyl]oxy}-4-[(2-ethylphenyl)amino]-
7-methoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 465.6[MH+]
10 Example 244
6-{ [(2S)-3-(cyclopropylamino)-2-hydroxy-2-methylpropyl]oxy} -4-[(2-ethylphenyl)amino]-
7-methoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 465.6[MH+]
15 Example 245
6-[3-(cyclopropylamino)-2-hydroxypropoxy]-4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-methoxyquinoline-3-carboxamide APC1 LC-MS m/z: 481.2[MH+]
20 Example 246
6-{[(2R)-3-(cyclopropylamino)-2-hydroxypropyl]oxy}-4-[(2-ethylphenyl)amino]-7-
methoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 451.5[MH+]
25 Example 247
6-{[(2S)-3-(cyclopropylamino)-2-hydroxypropyl]oxy}-4-[(2-ethylphenyl)amino]-7-
methoxyquinoline-3-carboxamide
APC1 LC-MS m/z: 451.5[MH+]
30 Example 248
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3-(aminocarbonyl)-4-[(2-ethylphenyl)amino]-7-methoxyquinolin-6-yl 2-methylpropanoate The title compound was prepared in an analogues way to example 236. APC1-MS m/z: 408.4[MH+]
5 Example 249
6,7-diethoxy-4-[(4-methyl- 1-oxo-1,2-dihydro15oquinolin-5-yl)amino]quinoline-3-
carboxamide
The title compound was prepared as decribed in WO 02/092571 starting from 5-amino-4-
methyl15oquinolin-l(2//)-one and 4-chloro-6,7-diethoxyquinoline-3-carboxamide.
10 lH NMR (399.99 MHz, DMSO-40 6 11.28 (IH, s), 11.26 (IH, d), 8.85 (IH, s), 8.27 (IH, s), 8.11 (IH, d), 7.58 (IH, s), 7.33 (IH, t), 7.22 (IH, s), 7.11 (IH, d), 6.99 (IH, d), 6.64 (IH, s), 4.14 (2H, mult), 3.37 (3H, mult), 3.25 (2H, mult), 1.35 (3H, t), 0.92 (3H, t) APC1-LC/MS m/z: 433.2 [MH+]
15 Example 250
6,7-diethoxy-4-[(4-methyl-l-oxo-l,2,3,4-tetrahydro15dquinolin-5-yl)amino]quinoline-3-
carboxamide
The title compound was prepared in an analogues manner as described in WO 02/092571
starting from 5-amino-4-methyl-3,4-dihydro15oquinolin-l(2/0-one and 4-chloro-6,7-
20 diethoxyquinoline-3-carboxamide.
*H NMR (399.99 MHz, DMSO-4s) 8 11.28 (IH, s), 11.26 (IH, d), 8.85 (IH, s), 8.27 (IH,
s), 8.12 (IH, d), 7.58 (IH, s), 7.33 (IH, t), 7.22 (IH, s), 7.11 (IH, d), 6.99 (IH, d), 6.64 (IH,
s), 4.14 (IH, quintetd), 3.37 (3H, dq), 3.23 (4H, mult), 1.35 (3H, t), 0.92 (3H, t)
APC1-LC/MS m/z: 435.3 [MH+] 25
Example 251
tert-butyl 5-{ [3-(aminocarbonyl)-6,7-diethoxyquinolin-4-yl]amino }-3,4-
dihydro15oquinoline-2( 1 H)-carboxylate
A mixture of 4-chloro-6,7-diethoxyquinoline-3-carboxamide (178 mg, 0.61 mmole,
30 prepared according to WO 02/092571), tert-butyl 5-amino-3,4-dihydro15oquinoline-2(lH)-
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carboxylate (198 mg, 0.80 mmole), acetic aC1d (7 \)\) in NMP (3 ml) was heated over night at 110 C. The reaction mixture was cooled, partitioned between ethyl acetate and sodium hydrogen carbonate solution.
The organic layer was washed with water, dried over sodium sulfate and concentrated in
5 vacuum. The residue was purified by flash chromatography eluting with
dichloromethane/methanol (10:0.5) to give the title compound as a light brown powder (214 mg, 69 %).
1H NMR (399.99 MHz, DMSO-40 8 10.63 (1H, s), 8.84 (1H, s), 8.24 (1H, br s), 7.58 (1H, br s), 7.22 (1H, s), 7.06 (1H, t), 6.95 (1H, d), 6.65 (2H, s), 6.61 (2H, d), 4.53 (2H, s), 4.15
10 (2H, q), 3.59 (2H, t), 3.49 (2H, d), 2.70 (2H, t), 1.39 (9H, s), 1.36 (3H, t), 1.06 (3H, t). APC1-LC/MS m/z: 507.2 [MH+]
Example 252
6,7-diemoxy^-(l,2,3,4-tetrahydro15oquinolin-5-ylamino)quinoline-3-carboxarnide
15 The title compound was prepared in a similar way described in example 117
1H NMR (399.99 MHz, DUSO-dg) 8 10.62 (1H, s), 8.84 (1H, s), 8.24 (1H, s), 7.58 (1H, s),
7.22 (1H, s), 6.96 (1H, d), 6.80 (1H, d), 6.70 (1H, s), 6.52 (1H, d), 4.15 (2H, d), 3.85 (2H,
s), 3.51 (2H, s), 2.98 (2H, s), 2.61 (2H, s), L37 (3H, s), 1.15 (3H, s)
APC1-LC/MS m/z: 407.2 [MH+] 20
Example 253
4-{[3-(azidomethyl)-2-ethylphenyl]amino}-6-[3-(cyclopropylamino)propoxy]-7-
methoxyquinoline-3-carboxamide
The title compound was prepared analogous manner to example 1 using sodium azid. 25 APC1-LC/MS m/z: 490.3[MH+]
Example 254
4- {[3-(aminomethyl)-2-ethylphenyl]amino} -6-[3-(cyclopropylamino)propoxy]-7-
methoxyquinoline-3-carboxamide
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The title compound was prepared according to the procedure described in WO 02/092571 using 5 % Palladium- charcoal and the compound described in example 253. APC1-LC/MS m/z: 464.3[MH+]
5 Example 255
4-{ [3-(aminomethyl)-2-ethylphenyl]arnino} -7- {3-[15obutyryl(15opropyl)amino]propoxy} -6-
methoxyquinoline-3-carboxamide
The title compound was prepared in an anlogous manner to example 255 using the
compound described in example 185. 10 APC1-LC/MS m/z: 536.4 [MH+]
Example 256
4- {[3-(azidomethyl)-2-ethylphenyllamino }-6-[3-(cyclopropylamino)-2-hydroxypropoxy]-7-methoxyquinoline-3-carboxamide 15 The title compound was prepared in an anlogous manner to example 240 APC1-LC/MS m/z: 506.6 [MH+]
Example 257
4- {[3-(aminomethyl)-2-ethylphenyl]amino} -6-[3-(cyclopropylamino)-2-hydroxypropoxy]-20 7-methoxyquinoline-3-carboxamide
The title compound was prepared in an anlogous manner to example 254 APC1-LC/MS m/z: 480.6 [MH+]
Example 258 25 4-({3-[(acetylamino)methyl]-2-ethylphenyl}amino)-6-{3-[acetyl(cyclopropyl)amino]-2-
hydroxypropoxy} -7-methoxyquinoline-3-carboxamide
The title compound was prepared in an anlogous manner to example 119 using compound
257 and acetic aC1d anhydride.
APC1-LC/MS m/z: 564.6 [MH+] 30
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■W--
The title compounds of examples 259-261 were prepared in analogous manner to example 239.
Example 259
5 6-[3-(cyclopropylamino)-2-hydroxypropoxy]-4-{[2-ethyl-3-(lH-imidazol-l-ylmethyl)phenyl]amino}-7-methoxyquinoline-3-carboxamide APC1-LC/MS m/z: 480.6 [MH+]
Example 260 10 6-[3-(cyclopropylamino)-2-hydroxypropoxy]-4-{ [2-ethyl-3-(lH-pyrazol-l-ylmethyl)phenyl]amino}-7-methoxyquinoline-3-carboxamide The title compound was prepered from 4-{ [2-ethyl-3-(li/-imidazol-l-ylmethyl)phenyl]aniino}^-hydroxy-7-rnethoxyquinoline-3-carboxamide,epibromohydrine and cyclopropylamine as decribed in example 239.
15 1H NMR (400 MHz, DMSO-d*) 811.00 (1H, s, ); 8.90 (1H, s, ); 8.32 (1H, s,); 7.72 (1H, s, ); 7.64 (11H, s, ); 7.26 (1H, s, ); 7.11(1H, s, ); 7.05 (2H, t, J=7.8 Hz); 6.94 (1H, s, ); 6.77 (1H, d, J=7.6 Hz); 6.62 (2H, mult, ); 5.34 (2H, s,); 4.89 (1H, d, J=4.3 Hz); 3.90 (3H, s,); 3.72 (1H, s,); 2.83 (2H, q, J=7.2 Hz); 2.06 (1H, mult,); 0.35 (2H, mult, ); 016 (1H, d, J=1.8Hz)
20 APCI-LC/MS m/z: 531.6 [MH+]
Example 261
6- {[(2S)-3-(cyclopropylarnino)-2-hydroxypropyl]oxy} -4- {[2-ethyl-3-(morpholin-4-ylmethyl)phenyl]amino}-7-methoxyquinoline-3-carboxamide 25 APC1-LC/MS m/z: 550.7 [MH+]
Example 262
amino{6,7-diethoxy-4-[(2-ethylphenyl)amino]quinolin-3-yl}methanol Red-Al (5.3 mg, 0.13 mmol) was added slowly to a mixture of 6,7-diethoxy-4-[(2-
30 ethylphenyl) amino]quinoline-3-carboxamide (l0 mg , 0.26mmol) prepared according to the
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procedure described in WO 02/092571 in the under argon and stirred at 50°C for 18hrs. The resulting mixture was washed with water and the organic layers dried over natriumsulfate, filtered and concentrated. The resulting crude product was purified on HPLC to give lmg (2.62mmol, 10%) of the desired product.
5 APC1-MS: m/z 382.5[MH+]
Example 263
6-[3-(cyclopropylamino)propoxy]-4- {[2-ethyl-3-( lH-imidazol-1 -ylmethyl)phenyl] amino} --methoxyquinoline-3-carboxamide
10 The title compound was prepared in an anlogous manner to example 253 APCI-LC/MS m/z: 515.4 [MH+]
Example 264
4-{[2-ethyl-3-(lH-imidazol-l-ylmethyl)phenyl]amino}-6-methoxy-7-(2-
15 methoxyethoxy)quinoline-3-carboxamide
a) 4-{ [2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-(2-
methoxyethoxy)quinoline-3-carboxamide.
20 A mixture of 4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -7-hydroxy-6-
methoxyquinoIine-3-carboxamide,) prepared according to the procedure described in WO 02/092571, (32.2 mg, 0.09 mmol), 2-bromoethyl methyl ether (23.7 mg, 0.17 mmol), cesium carbonate (45.3 rag, 0.14 mmol) and NMP (1 ml) was heated at 60°C for 4 h. After cooling the reaction mixture was diluted with water and purified by preparative HPLC to
25 give 19 mg of the compound
APC1-LC/MS m/z: 426.3 [MH+].
b) The title compound was then prepared in an anlogous manner to example 1
*H NMR (399.99 MHz, DMSO-de): 5 11.02 (IH, s); 8.89 (IH, d, J = 5.2 Hz); 8.31 (IH, br 30 s); 7.72 (IH, s); 7.64 (IH, br s); 7.26 (IH, s); 7.09 (IH, s); 7.06 (IH, d, J = 7.7 Hz); 6.93
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(1H, s); 6.87 (2H, d, J = 7.5 Hz); 6.64 (1H, d, J = 7.7 Hz); 6.57 (1H, s); 5.33 (2H, s); 4.22 (2H, t, J = 4.3 Hz); 3.70 (2H, t, J = 4.4 Hz); 3.31 (2H, br s); 3.18 (3H, br s); 2.86 (2H, q, J = 7.4 Hz); 1.03 (3H, t, J = 7.4 Hz). APCI-LC/MS m/z: 476.4 [MH+]
5
Example 265
6-(ethylamino)-4- {[2-ethyl-3-(l H-imidazol-1 -ylmethyl)phenyl]amino} -7-
methoxyquinoline-3-carboxamide
a) ethyl 6-(ethylamino)-4-{ [2-ethyl-3-(lf/-imidazol-l-ylmethyl)phenyl]amino}-7-
10 methoxyquinoline-3-carboxylate.
In a schlenk were placed ethyl 6-bromo-4-{[2-ethyl-3-(lH-imidazol-l-ylmethyl)phenyl]amino}-7-methoxyquinoline-3-carboxylate (71.2 mg, 0.14 mmol) prepared in an anlogues way to example 1, tr15(dibenzylideneacetone) dipalladium(O) (12.1 mg, 0.01 mmol) b15(diphenylphospino)l.lnaphtalene (28.3 mg, 0.05 mmol), cesium carbonate (83
15 mg, 0.26 mmol), ethyl amine (0.34 mg, 7.6 mmol) and toluene (10 ml) under argon. The vessel was sealed and heated at 75°C for 48 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtrated and concentrated in vacuum. The residue was purified by preparative HPLC to give 24 mg of the desired product.
20 APC1-LC/MS m/z: 474.3 [MH+]
b) Potassium cyanide (5 mg) and the product from the first step were suspended in dry
methanol (10 ml) saturated with ammonia. The schlenk was sealed and heated at 65°C for
50 h. The reaction mixture was cooled and concentrated in vacuum. The residue was
25 purified by preparative HPLC to give the title compound as a white solid (8 mg, 13%).
1H NMR (399.99 MHz, DMSO-ds): 8 10.65 (1H, s); 8.73 (1H, s); 8.23 (1H, br s); 7.68 (1H, s); 7.56 (1H, br s); 7.12 (1H, s); 7.06 (1H, s); 6.98 (2H, t, J = 7.8 Hz); 6.92 (1H, s); 6.81 (1H, d, J = 7.5 Hz); 6.47 (1H, d, J = 7.8 Hz); 6.05 (1H, s); 5.29 (3H, m); 3.91 (3H, s); 2.84 (2H, d, J = 7.2 Hz); 2.52 (1H, br s); 1.02 (3H, t, J = 7.4 Hz); 0.75 (3H, t, J = 7.1 Hz). 30 APC1-LC/MS m/z: 445.3 [MH+1.
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The title compounds of examples 266-268 were prepared in analogous manner to example 265.
5 Example 266
6-[(2,2-dimethoxyethyl)amino]-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide
1H NMR (399.99 MHz, DMSO-4s): 8 10.61 (IH, s); 8.75 (IH, s); 8.24 (IH, s); 7.57 (IH, s); 7.28 (IH, m); 7.16 (IH, s); 7.00 (2H, m); 6.50 (IH, m); 6.24 (IH, s); 5.24 (IH, t, J = 5.8 10 Hz); 4.15 (IH, t, J = 5.5 Hz); 3.94 (3H, s); 3.12 (6H, s); 2.73 (2H, q, J = 7.5 Hz); 2.65 (2H, t, J = 5.7 Hz); 1.26 (3H, t, J = 7.5 Hz). APC1-LC/MS m/z: 425.4 [MH+]
Example 267
15 6-[(3,3^emoxypropyl)arnino]-4-[(2-ethylphenyl)arnino]-7-methoxyquinoline-3-carboxamide
*HNMR (299.946 MHz, DMSO-4s) 5 10.58 (IH, s), 8.73 (IH, s), 8.28 (IH, brs), 7.62 (IH, br s), 7.24 (IH, mult), 7.13 (IH, s), 6.98 (2H, dquintet), 6.51 (IH, mult), 6.14 (IH, s), 5.42 (IH, t), 4.32 (IH, t), 3.91 (3H, s), 3.49 (2H, mult), 3.36 (2H, mult), 2.72 (2H, q), 2.53 (2H,
20 q), 1.51 (2H, dd), 1.25 (3H, t), 1.08 (6H, t) APC1-LC/MS m/z: 467.4 [MH+]
Example 268
tert-butyl [2-({3-(aminocarbonyl)-4-[(2-ethylphenyl)amino]-7-methoxyquinolin-6-25 yl}amino)ethyl]carbamate
APC1-LC/MS m/z: 480.3[MH+]
Example 269
tert-butyl {2-[(3-(aminocarbonyl)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-
30 methoxyquinolin-6-yl)amino]ethyl} carbamate
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a) Ethyl 6-bromo-4-{[3-({[terr-butyl(dimethyl)silyl]oxy}methyl)-2-ethylphenyl]amino}-7-
methoxyquinoline-3-carboxylate.
5 A mixture of ethyl 6-bromo-4-{ [2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-
methoxyquinoline-3-carboxylate (406 mg, 0.89 mmol), terf-butyl(chloro) dimethylsilane (0.95 g, 6.3 mmol), imidazole (1.9 g, 27.9 mmol) in DMF (3 ml) was stirred under argon at room temperature for 48 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water, dried
10 over sodium sulphate, filtrated and concentrated in vacuum. The residue was purified by flash chromatography eluting with dichloromethane/methanol (97:3) to give the title compound as grey powder (309 mg, 60%).
1H NMR (399.99 MHz, DMSO-d*): 5 10.24 (1H, s); 9.01 (1H, s); 7.54 (1H, s); 7.37 (1H, s); 7.29 (1H, d, J = 7.4 Hz); 7.11 (1H, t, J = 7.8 Hz); 6.81 (1H, d, J = 7.8 Hz); 4.79 (2H, s); 4.31
15 (2H, q, J = 7.1 Hz); 3.94 (3H, s); 2.76 (2H, q, J = 7.5 Hz); 1.32 (3H, t, J = 7.1 Hz); 1.15 (3H, t, J = 7.5 Hz); 0.89 (9H, s, J = 2.9 Hz); 0.09 (6H, s, J = 3.1 Hz). APC1-LC/MS m/z: 573.1, 574.2, 575.1 [M+],[M+l],[M+2]
b) Ethyl 6-({2-[(reit-butoxycarbonyl)amino]ethyl)amino)-4-{[3-({[re/t-
20 butyl(dimethyl)silyl]oxy}methyl)-2-ethylphenyl]amino}-7-methoxyquinoline-3-carboxylate.
A mixture of ethyl 6-bromo-4-{[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethylphenyl]amino}-7-methoxyquinoline-3-carboxylate (250 mg, 0.44 mmol) tr15(dibenzylideneacetone) dipalladium(O) (21 mg, 0.02 mmol) b15(diphenylphospino)
25 1.1 naphtalene (48 mg, 0.08 mmol), cesium carbonate (230 mg, 0.71 mmol), N-(2-
Aminoethyl)carbamic AC1d ter-rbutylester (101 mg, 0.63 mmol) and toluene (8 ml) was placed in a schlenk under argon. The Schlenk vessel was sealed and the reaction mixture was heated at 85°C over night. After cooling the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water dried over sodium
30 sulphate, filtrated and concentrated in vacuum. The residue was purified by flash
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chromatography eluting with dichloromethane/methanol (100:3) to give the title compound as a yellow powder (205 mg, 73%).
lK NMR (399.988 MHz, CDC13): 5 10.21 (IH, s); 9.03 (IH, s); 7.25 (IH, d, J = 7.3 Hz); 7.21 (2H, s); 7.06 (IH, t, J = 7.8 Hz); 6.76 (IH, d, J = 7.8 Hz); 4.83 (2H, s); 4.64 (IH, br s);
5 4.54 (IH, br s); 4.43 (2H, q, J = 7.1 Hz); 3.97 (3H, s); 3.00 - 2.83 (5H, m); 2.83 - 2.61 (4H, m); 1.48 -1.43 (13H, m); 1.31 (3H, t, J = 7.5 Hz); 0.98 (9H, s, J = 2.8 Hz); 0.16 (6H, s, J = 3.0 Hz); APC1-LC/MS m/z: 653.3 [MH+]
10 c) tert-butyl {2-[(3-(aminocarbony)-4-{[2-ethyl-3-(hydtoxymethyl)phenyl]amino}-7-methoxyquinolin-6-yl)amino]ethyl}carbamate
In a high pressure flask were placed ethyl 6-({2-[(tert-butoxycarbonyl)amino]
ethyl }amino)-4-{ [3-({ [tert-butyl(dimethyl)silyl]oxy }methyl)-2-ethylphenyl]amino}-7-
15 methoxyquinoline-3-carboxylate (148 mg, 0.23 mmol), potassium cyanide (7 mg, 0.1
mmol) and dry methanol (10 ml) saturated with ammonia. The flask was sealed and heated at 55°C for 96 hours. After cooling the reaction mixture was concentrated in vacuum and the residue was stirred with tetrabutylammonium fluoride hydrate (150 mg, 0.57 mmol) in tetrahydrofuran (5 ml) for 1 hour. The reaction mixture was partitioned between ethyl
20 acetate and water. The organic layer was washed with water, dried over sodium sulphate, filtered and concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a light yellow powder (52 mg, 44%).
The title compound was prepared in an anlogous manner to example 266 using ethyl 6-bromo-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxylate
25 and (3-Amino-propyl)-cyclopropyl-carbamic acid /tert-butyl ester. Removal of the the carbamaic aC1d terf-butyl ester derivative was performed with TFA according to example 117.
lH NMR (399.99 MHz, DMSO-4s): 8 10.69 (IH, s); 8.73 (IH, s); 8.21 (IH, br s); 7.53 (IH, br s); 7.16 - 7.07 (2H, m); 6.96 (IH, t, J = 7.7 Hz); 6.70 (IH, t, J = 5.3 Hz); 6.45 (IH, d, J =
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7.8 Hz); 6.10 (1H, s); 5.37 (1H, t, J = 4.8 Hz); 5.12 (1H, t, J = 5.3 Hz); 4.59 (2H, d, J = 5.3 Hz); 3.90 (3H, s); 2.81 (4H, m); 1.36 (9H, s); 1.27 (2H, s); 1.21 (3H, t, J = 7.4 Hz); APC1-LC/MS m/z: 510.3 [MH+]
5 Example 270
6- {[3-(cyclopropylamino)propyl]amino} -4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide
a) Ethyl 6-bromo-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxylate was
10 prepared according to WO 02/092571.
1H NMR (399.99 MHz, DMSO-4s): 8 10.12 (1H, s); 9.01 (1H, s); 7.67 (1H, s); 7.44 - 7.38 (2H, m); 7.25 (1H, t, J = 7.3 Hz); 716 (1H, t, J = 12.5 Hz); 6.93 (1H, d, J = 7.7 Hz); 4.27 (2H, q, J = 7.1 Hz); 3.98 (3H, s); 2.71 (2H, q, J = 7.5 Hz); 1.32 (3H, t, J = 7.1 Hz); 1.21 (3H, t, J = 7.5 Hz).
15 APCI-LC/MS m/z: 429.1,431.1 [MH+]
b) (3-Amino-propyl)-cyclopropyl-carbamic acid tert-butyl ester
fgrt-butvlcvclopropvl(3-hvdroxvpropvl)carbamate
20 A mixture of 3-bromopropan-l-ol (4.5 g, 32.4 mmol), cyclopropylamine (12.4 g, 216.5
mmol) and tetrahydrofuranne (40 ml) was heated at 60°C for 7 h. The reaction was cooled
to room temperature, concentrated in vacuum, diluted with a mixture of tetrahydrfuranne
(20 miytriethylamine (10 ml) and again concentrated in vacuum.
To the residue was added di-terf-butyl dicarbonate (7.2 g, 33.0 mmol), tetrahydrofuranne
25 (35 ml) and triethylamine (5 ml). The suspension was heated at 50°C over night then cooled
to room temperature, diluted with ether, filtered and the filtrate was concentrated in vacuum.
The residue was purified by flash chromatography eluting with dichloromethane/methanol
(100:3) to give the title compound as colourless oil (3.1 g, 44 %).
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^
1 HNMR (299.944 MHz, CDC13): 8 3.56 (2H, quintet, J = 5.7 Hz); 3.38 (2H, t, J = 6.1 Hz); 2.45 (IH, ddd, J = 10.8 7.0 3.9 Hz); 1.70 (2H, quintet, J = 8.1 Hz); 1.46 (9H, s); 0.77 - 0.68 (2H,m); 0.62- 0.56 (2H,m).
5 tert-butvl3-bromopropvl(cvclopropvl)carbamate
To an 15 cooled solution of tert-butyl cyclopropyl(3-hydroxypropyl)carbamate (1.6 g, 7.4 mmol), triphenylphosphine (2.5 g, 9.7 mmol) and tetrahydrofuran (25 ml) was added carbon tetrabromide (3.2 g, 9.7 mmol) under 20 minutes. The mixture was stirred for 30 minutes at 0°C and then allowed to reach room temperature. After 3 hours at ambient temperature the
10 reaction mixture was diluted with diethyl ether and the preC1pitate was removed by
filtration. The filtrate was concentrated in vacuum and the residue was purified by flash chromatography eluting with dichloromethane/heptane (2:1) to give the title compound as colourless oil (1.2 g, 59 %).
1H NMR (399.988 MHz, CDC13): 8 3.39 (2H, t, J = 6.7 Hz); 3.33 (2H, t, J = 7.1 Hz); 2.49 15 (IH, septet, J = 5.1 Hz); 2.11 (2H, quintet, J = 6.9 Hz); 1.45 (9H, s); 0.75 (2H, td, J = 7.1 5.1 Hz); 0.60 (2H, m).
tert-butvl 3-azidoproDvl(cvclopropvl)carbamate
A mixture of ferf-butyl 3-bromopropyl(cyclopropyl)carbamate (1.1 g, 3.9 mmol), sodium 20 azide (0.33 g, 5.1 mmol) and l-methyl-2-pyrrolidinone (7 ml) was stirred at ambient temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water dried over sodium sulphate, filtrated and concentrated in vacuum. The residue was purified by flash chromatography eluting with dichloromethane to give the title compound as colourless oil (0.92 g, 96%).
25 1H NMR (399.988 MHz, CDC13): 8 3.29 (4H, q, J = 131 Hz); 2.48 (IH, septet, J = 5.7 Hz); 1.82 (2H, quintet, J = 7.0 Hz); 1.45 (9H, s); 0.74 (2H, m); 0.59 (2H, m).
(3-Amino-propvlVcvclopropvl-carbamic aC1d /e/t-butyl ester
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A mixture of tert-butyl 3-azidopropyl(cyclopropyl)carbamate (0.9 g, 3.7 mmol), 5% palladium on carbon (60 mg) in ethanol (15 ml) and ethyl acetate (15 ml) was stirred vigorously under 1 atmosphere of hydrogen for 19 h. The hydrogen atmosphere was changed twice under the period of reaction time. The catalyst was filtered off and the filtrate
5 was concentrated to give the title compound as colourless oil (0.79 g, 98%).
1H NMR (399.988 MHz, CDC13): 5 3.27 (2H, t, J = 6.9 Hz); 2.70 (2H, t, J = 6.8 Hz); 2.45 (1H, dt, J = 6.9 3.4 Hz); 1.76 (2H, s); 1.69 (2H, quintet, J = 6.9 Hz); 1.44 (9H, s); 0.72 (2H, dd, J = 12.2 6.9 Hz); 0.57 (2H, m).
10 c)6-{[3^cyclopropylaimno)propyl]armno}-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide
The title compound was prepared in an anlogous manner to example 266 using ethyl 6-bromo-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxylate 15 and (3-Amino-propyl)-cyclopropyl-carbamic aC1d terf-butyl ester. Removal of the the
carbamaic aC1d tert-buty] ester derivative was performed with TFA according to example 117.
1H NMR (399.99 MHz, DMSO-4$): 8 10.57 (1H, s); 8.73 (1H, s); 8.22 (1H, br s); 7.55 (1H, br s); 7.27 (1H, m); 7.13 (1H, s); 6.99 (2H, m); 6.50 (1H, m); 6.14 (1H, s); 5.65 (1H, t, J = 20 5.5 Hz); 3.92 (3H, s); 2.74 (2H, q, J = 7.4 Hz); 2.58 (2H, q, J = 6.4 Hz); 2.40 (2H, t, J = 6.2 Hz); 2.00 -1.89 (2H, m); 1.35 -1.22 (5H, m); 0.33 (2H, m); 0.17 (2H, m). APC1-LC/MS m/z: 434.5 [MH+]
The title compounds of Examples 271-274 were prepared in analogous manner to the 25 methods described above.
Example 271
4-(2,3-dihydro-lH-inden-l-ylamino)-6,7-dimethoxyquinoline-3-carboxamide APC1LC-MS m/z: 364.1 [MH+]
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Example 272
6J-diethoxy^[(2-methylcyclohexyl)amino]quinoline-3-carboxamide APC1LC-MS m/z: 372.3 [MH+]
5 Example 273
4-{[(3S)-Hcyanoacetyl)pynohdin-3-yl]aniino}^J^inethoxyquinoline-3Kadx)xaniide APC1 LC-MS m/z: 384.1 [MH+]
Example 274
10 4-{[(3S)-1-(cyanoacetyl)tyl)piperidn-3-yl]amino}-6,7-dimethoxyquinoline-3-uboxarnide APCI LC-MS m/z: 398.1 [MH+]
Pharmacological Data
15 JAK3 HTRF assay
The JAK3 kinase assay utilizes a fusion protein (Jak3 kinase domain fused to Glutathione S-transferase, GST) coexpressed in E.Coli with GroEL/S, and purified by affinity chromatography on Glutathione Sepharose. The enzyme 15 diluted in 10 mM Tr15-HCl, 15O
20 mM NaCl, 5% mannitol, 2 mM 2-mercaptoetanol and 30% glycerol. The substrate in the kinase reaction 15 a biotinylated peptide of the autophosphorylation site of JAK3 (biotin-LPDKDYYVVREPG) used at 2 JIM. Assay conditions are as follows: JAK3, compound and substrate are incubated in 25 mM Trizma base, 5 mM MgCl2,5 mM MnC12,0.05% TntonX-100 and 2 |uM ATP for 45 min at RT. Reaction volume 15 20 pM. Stopsolution 15
25 added for a final concentration of 100 mM EDTA. Finally 0.065 mg/ml PT66-K and 10.42 mM SA-XL665 are added in 50 mM Hepes, 0.5 M KF and 0.1% BSA. The plate 15 read in a D15covery instrument after 60 min incubation.
The compounds of the examples have an IC50 less than 10 mM
30
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Claims
1. A compound of formula (I) .x
(D
5 or a pharmaceutical^ acceptable salt or solvate thereof, wherein X15-CHOHor-C=C;
R1 and R2, which may be the same or different, represent nitro, cyano, Q-Q alkyl, Q-Q alkoxy, hydroxy, aryi. Y(CR32)PNR4RS. Y(CR32)/X)NR4RS, Y(CR3a)pC02R*, YCCR^OR* , Y(CR32)pR*, Y(CR32)POCOR*
10 or R1 and R2 are linked together as -OCH2O- or –OCH2CHiO-;
R3 groups are independently hydrogen, C1-C8 alkyl, hydroxy, Q-Cg alkoxy or halogen;
p 15 0,1, 2,3,4 or 5;
Y 15 oxygen, CH2' -OSO2- or NR7
R4 and R5 each independently represent hydrogen or a group selected from Q-Cg alkyl, -
15 C1-C8 alkoxy, -CO-2-( Q-Cg) alkyl, -CO-( C1-C8) alkoxy, -CO-NR7(C1-C8) alkyl, C3-Cg cycloalkyl, each of which groups may optionally be substituted by one or more hydroxy, cyano, -CONH2 or -CO-( Q-Cg) alkoxy groups, or R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 7-membered, saturated or aromatic heterocyclic ring system optionally containing one or
20 more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by at least one substituent selected from hydroxy, C1-C8 alkyl, =0, Cg-Cg alkoxy or (C1-C8 alkoxy)-CO-, or one of R4 and R5 15 hydrogen or C1-C8 alkyl and die other 15 a 5- or 6-membered heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom;
25 R6 15 hydrogen, Q-Cg alkyl (itself optionally substituted by one or more hydroxy, cyano, halogen or amino groups), phenyl, benzyl, -CO(C1-C8) alkyl or a saturated monocyclic 4-
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to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected from C1-C8 alkyl, C1-C8 alkoxy, =0 , C1-C8 alkyl -CO-,or (c1-C8 alkoxy)-CO- where any C1-C8 alkyl 15 optionally substituted by one or more hydroxy,
5 cyano, halogen or amino groups;
R7 is hydrogen or Cg-Cg alkyl;
Ra is hydrogen or Q-Cg alkyl;
Rx 15 a group selected from C1-C8 alkyl, C3-Cg cycloalkyl or a saturated monocyclic 4- to 7-membered ring compr15ing one or more heteroatoms selected from nitrogen, oxygen and
10 sulphur, wherein any Ca-Cg cycloalkyl group or saturated monocyclic 4- to 7-membered ring 15 optionally substituted by one or more groups selected from hydroxy, azido, cyano, amino, halogen, -CONH2-, C1-C8 alkyl, (C1-C8 alkyl)CO-, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO-, and any Q-Cg alkyl, Cg-Cg alkyl)CO-, C1-C8 alkoxy, or (Ct-C8 alkoxy)-CO- group 15 itself optionally substituted by one or more substituents selected from hydroxy, azido,
15 cyano, amino, halogen or phenyl; or Rx 15 a group Ar,
Ar 15 selected from phenyl, tetrahydronaphthenyl, indolyl, pyrazolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl, indazolyl, dihydro15oquinolyl, oxodihydro15oquinolyl, tetrahydro15oquinolyl or oxotetrahydro15oquinolyl, each of which can be optionally substituted by one or more groups, which may be the same or different, selected from
20 halogen, hydroxy, cyano, C1-C8 alkoxy, C02R8, CONRV0, C1-C8 alkyl-NR8-C1-C8 alkyl, C1-C8 alkyl-CONR8-C1-C8 alkyl, C1-C8 alkyl-CONRV0, NR8COC1-C8 alkyl, C1-C8 thioalkyl, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, azido or cyano groups or fluorine atoms) , C1-C8 alkyl-NR1 'R12,C1-C8 alkyl-OR12, C1-C8 alkyl-SR12; R8 15 hydrogen or C1-C8 alkyl;
25 R9 and R10 are each independently hydrogen or C1-C8 alkyl Rn 15 hydrogen or C1-C8 alkyl;
R12 15 hydrogen or a group selected from C1-C8 alkyl, -(CR'^R14 , -CO-(CR132)„R14, -SOz-CCR'^R14 ;
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^H0
n 15 between 0 and 5;
R13 groups are independently hydrogen, Q-Cg alkyl, hydroxy, Cg-Cg alkoxy,
hydroxy(C1-C8 )alkyl, amino or halogen;
R u 15 hydrogen or a group selected from -NR15R16, C1-C8 alkyl, C2-C4 alkenyl, C2-C4
5 alkynyl, -COOH, -S(C1-C8 alkyl), -SO(C1-C8 alkyl),-CONR15R16, -CO(C1-C8 alkyl), -CO-0-(Cg-C8 alkyl), or a saturated or unsaturated 4- to 10-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur, each of which groups may be optionally substituted by one or more hydroxy, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or
10 unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl, nitro, -CONH2 groups), C1-C8 alkoxy, C1-C8hydroxyalkyl,-C=0, cyano, amino, nitro, halogen, C1-C8alkylsulphonyl or aminosulphonyl groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or
15 more heteroatoms selected from nitrogen, oxygen and sulphur;
or R1' and R12, together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen , the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl(which
20 may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated
heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, C1-C8 alkyl, nitro, -CONH2 groups), nitro, cyano, -CONH2, amino, =0 or -COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or
25 more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO-; and
R15 and R16, which may be the same or different, represent hydrogen, C1-C8 alkyl, -CONH2 or-C(NH2)=NH;
30
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provided that when
Rx 15 Ar, X 15 -CO and R1 and R2 are independently nitro, cyano, C1-C8 alkyl, Cg-C8 alkoxy, hydroxyl, aryl, Y(CR32)pNR4R5, YCCR^CONRV, Y(CR32)pC02R6, Y(CR32)pOR6,
5 Y(CR32)pR6, -CH2(CH2)POCOR6 or R1 and R2 are linked together as -OCH20- or -OCH2CH20- ,
where each R3 group 15 independently hydrogen, C1-C8 alkyl, hydroxy, or halogen, R4 and R5 each independently represent hydrogen or C1-C8 alkyl orR4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted 4- to 7-membered
10 saturated or aromatic heterocyclic ring system optionally containing a further oxygen,
sulphur or NR6 group or one of R4 and Rs 15 hydrogen or Ct-C8 alkyl and the other 15 a 5- or 6-membered heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom; and R6 15 selected from hydrogen, (C1-C8) alkyl, -CO(C1-C8) alkyl, hydroxy substituted
15 (C1-C8) alkyl, halogen substituted (C1-C8) alkyl, phenyl or benzyl,
then
Ar 15 selected from dihydro15oquinolyl, oxodihydro15oquinolyl, tetrahydro15oquinolyl or 20 oxotetrahydro15oquinolyl, each of which may be optionally substituted,
or Ar 15 phenyl substituted by at least one substituent selected from azido substituted C1-C8 alkyl, C1-C8 alkyl-NR1 'R12 C1-C8 alkyl-OR12 or C1-C8 alkyl-SR12,
wherein R12 15 selected from -(CR,32)„R14 .-CO-CCR'^R14, -SOHCR'^R'4 or RM and R12, together with the nitrogen atom to which they are attached form a 4- to 10-membered 25 saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen , the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, 30 the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, C1-C8 alkyl,
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nitro, -CONH2 groups), nitro, cyano, -CONH2, amino, =0 or -COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8
5 alkoxy)-CO-,
provided that Ar 15 not phenyl substituted by one or more groups selected from
C1-C8 alkyl-NR1'- C1-C8 alkyl, C1-C8 alkyl-O-C1-C8 alkyl or C1-C^ alkanoyloxy Q-Q
alkyl.
10 2. A compound of formula (la)
(la)
or a pharmaceutical^ acceptable salt or solvate thereof, wherein 15
X15-CHOHor-C=0;
one of R and R represents nitro, cyano, Cg-Cg alkyl, C1-C8 alkoxy, hydroxy, aryl,
Y(CR32)PNR4R5, Y(CR32)pCONR4R5, Y(CR32)PCX)2R6, Y(CR32)pOR6 , Y(CR32)pR6 ,
Y(CR32)pOCOR6 20 or R1 and R2 are linked together as -OCH20- or -OCH2CH20- ;
R3 groups are independently hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy or halogen;
p15O, 1,2, 3,4 or 5;
Y 15 oxygen, CH2 -OS02- or NR7
R4 and R5 each independently represent hydrogen or a group selected from C1-C8 alkyl, C|-25 Cg alkoxy, -CO-(C1-C8) alkyl, -CO-( C1-C8) cycloalkyl, -S02-( C1-C8) alkyl, -CO-( C1-C8)
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alkoxy, -CO-NR7(C1-C8) alkyl, C3-C8 cycloalkyl, each of which groups may optionally be substituted by one or more hydroxy, cyano, -CONH2 or -CO-( C1-C8) alkoxy groups, or R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 7-membered, saturated or aromatic heterocyclic ring system optionally containing one or
5 more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by at least one substituent selected from hydroxy, C1-C8 alkyl, =0, C1-C8 alkoxy or (C1-C8 alkoxy)-CO-, or one of R4 and R5 15 hydrogen or C1-Cs alkyl and the other 15 a 5- or 6-membered heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom;
10 R6 15 hydrogen, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, cyano, halogen or amino groups), phenyl, benzyl, -CO(C1-C8) alkyl or a saturated monocyclic 4-to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected from d-Q alkyl, C1-C8 alkoxy, =0, Q-Cg alkyl -CO-,or (C1-C8
15 alkoxy)-CO- where any C1-C8 alkyl 15 optionally substituted by one or more hydroxy, cyano, halogen or amino groups; R7 15 hydrogen or Q-Cg alkyl; Ra 15 hydrogen or Q-Cg alkyl; R* 15 a group selected from C1-C8 alkyl, C3-Cg cycloalkyl or a saturated monocyclic 4- to
20 7-membered ring compr15ing one or more heteroatoms selected from nitrogen, oxygen and sulphur, wherein any C3-Cg cycloalkyl group or saturated monocyclic 4- to 7-membered ring 15 optionally substituted by one or more groups selected from hydroxy, azido, cyano, amino, halogen, -CONH2-, C1-C8 alkyl, (Cg-Cg alkyl)CO-, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO-, and any C1-C8 alkyl, Q-Cg alkyl)CO-, Q-Cgalkoxy, or (Q-Cg alkoxy)-CO- group 15
25 itself optionally substituted by one or more substituents selected from hydroxy, azido, cyano, amino, halogen or phenyl; or Rx 15 a group Ar;
Ar 15 selected from phenyl, tetrahydronaphthenyl, indolyl, pyrazolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl, indazolyl, dihydro15oquinolyl, oxodihydro15oquinolyl, tetrahydro15oquinolyl or oxotetrahydro15oquinolyl, each of which can be optionally
30 substituted by one or more groups, which may be the same or different, selected from
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halogen, hydroxy, cyano, C1-C8 alkoxy, C02R8, CONRV0, C1-C8 alkyl-NR8-C1-C8 alkyl, C1-C8 alkyl-CONR8-C1-C8 alkyl, C1-C8 alkyl-CONRV0, NR'COC1-Q alkyl, C1-C8 thioalkyl, CrC8 alkyl (itself optionally substituted by one or more hydroxy, azido or cyano groups or fluorine atoms), C1-C8alkyl-NRnR,2,C1-C8alkyl-OR12, C1-C8alkyl-SR12;
5 R8 15 hydrogen or Q-Q alkyl;
R9 and R10 are each independently hydrogen or C1-C8 alkyl
Ru 15 hydrogen or Q-Cg alkyl;
R12 15 hydrogen or a group selected from C1-C8 alkyl, -(CRl32)nRu .
-CO-(CR,32)nRu,-S02-(CR132)nRu ;
10 n 15 between 0 and 5;
R13 groups are independently hydrogen, Q-C8 alkyl, hydroxy, C1-C» alkoxy, hydroxy(C1-C8 )alkyl, amino or halogen;
R ,415 hydrogen or a group selected from -NR15R16, C1-C8 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -COOH, -S(C1-C8 alkyl), -SCXC-CsalkyO.-CONR^R16, -CO(C1-C8 alkyl),
15 -CO-0-(C1-C8 alkyl), or a saturated or unsaturated 4- to 10-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur, each of which groups may be optionally substituted by one or more hydroxy, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or
20 nitrogen atom, the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl, nitro, -CONH2 groups), C1-C8 alkoxy, C1-C8 hydroxyalkyl,-C=0, cyano, amino, nitro, halogen , C1-C8 alkylsulphonyl or aminosulphonyl groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur,
25 or Ru and R12, together with the nitrogen atom to which they are attached form a 4- to
10-membered saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen , the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated
30 heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom,
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W-'
the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, Cg-Cs alkyl, nitro, -CONH2 groups), nitro, cyano, -CONH2. amino, =0 or -COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally 5 substituted by one or more substituents selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO-; and
R,s and R16, which may be the same or different, represent hydrogen, C1-C8 alkyl, -CONH2 or-C(NH2)=NH;
10 and the other of R1 and R2 15 YtCR^ywV, YCCR^CONRV, Y(CR32)pC02R6, Y(CR32)pOR6, Y(CR32)pR6 or Y(CR32)pOCOR6,
where at least one R3 15 C1-C8 alkoxy, or one of R4 and R5 15 selected from optionally substituted -CO-(C1-C8)alkyl,-CO-(C1-C8)cycloalkyl,-SCMC1-C,)alkyl,-CO-(C1-C8) alkoxy, -CO-NR7(C1-C8) alkyl or C3-Cg cycloalkyl, or R4 and R5 together with the nitrogen
15 atom to which they are attached form a substituted 4- to 7-membered saturated or aromatic heterocyclic ring system optionally containing a further oxygen, sulphur or NR6 group, or R6 15 selected from -CO(Cg-Cg) alkyl or an optionally substituted saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur, and which may be optionally substituted by at least one
20 substituent selected from C1-C8 alkyl, C1-C8 alkoxy, =0, C1-C8 alkyl -CO-,or (C1-C8 alkoxy)-CO- where any C1-C8 alkyl 15 optionally substituted by one or more hydroxy, cyano, halogen or amino groups
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(lb)
or a pharmaceutically acceptable salt or solvate thereof, wherein
X15-CHOHor-C=0;
5 R1 and R2, which may be the same or different, represent nitro, cyano, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, aryl, Y(CR32)pNR4R5, Y(CR32)pCONR4R5, Y(CR32)pC02R6, Y(CR32)pOR6 , Y(CR32)pR6 , Y(CR32)pOCOR6
or Rl and R2 are linked together as -OCH20- or -OCH2CH2-; R3 groups are independently hydrogen, C1-C8 alkyl, hydroxy, C1-C8 alkoxy or halogen;
10 p15 0,1,2,3,4 or 5;
Y 15 oxygen, CH2* -OSO2 or NR7
R4 and R5 each independently represent hydrogen or a group selected from C1-C8 alkyl, C1-C8 alkoxy, -CO-(C1-C8) alkyl, -CO-( C,-C«) cycloalkyl, -SOH C1-C8) alkyl, -CO-( C1-C8) alkoxy, -CO-NR7(C1-C8) alkyl, C3-Cg cycloalkyl, each of which groups may optionally be
15 substituted by one or more hydroxy, cyano, -CONH2 or -CO-( C1-C8) alkoxy groups, or R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 7-membered, saturated or aromatic heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen, the ring itself being optionally substituted by at least one substituent selected from hydroxy, C1-C8 alkyl, =0,
20 Cg-Cg alkoxy or (Cg-Cg alkoxy)-CO-, or one of R4 and R5 15 hydrogen or C1-C8 alkyl and the other 15 a 5- or 6-membered heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom;
R 15 hydrogen, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, cyano, halogen or amino groups), phenyl, benzyl, -CO(C1-C8) alkyl or a saturated monocyclic 4-
23 to 7-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent selected from C1-C8 alkyl, C1-C8 alkoxy, =0 , C]-C8 alkyl -CO-,or (Cg-Cg alkoxy)-CO- where any C1-C8 alkyl 15 optionally substituted by one or more hydroxy, cyano, halogen or amino groups;
30 R7 15 hydrogen or C1-C8 alkyl;
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Ra 15 hydrogen or C1-C8 alkyl;
Rx 15 a group selected from C1-C8 alkyl, C3-C8 cycloalkyl or a saturated monocyclic 4- to 7-membered ring compr15ing one or more heteroatoms selected from nitrogen, oxygen and sulphur, wherein any C3-C8 cycloalkyl group or saturated monocyclic 4- to 7-membered
5 ring 15 optionally substituted by one or more groups selected from hydroxy, azido, cyano, amino, halogen, -CONH2-, Cg-Cg alkyl, (C1-C8 alkyl)CO-, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO-, and any C1-C8 alkyl, C1-C8 alkyl)CO-, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO- group 15 itself optionally substituted by one or more substituents selected from hydroxy, azido, cyano, amino, halogen or phenyl; or Rx 15 a group Ar,
10 Ar 15 selected from dihydro15oquinolyl, oxodihydro15oquinolyl, tetrahydro15oquinolyl or oxotetrahydro15oquinolyl, each of which can be optionally substituted by one or more groups, which may be the same or different, selected from halogen, hydroxy, cyano, C1-C8 alkoxy, C02R8, CONR9^0, C1-C8 alkyl-NR8-C1-C8 alkyl, C1-C8 alkyl-CONR8-C1-C8 alkyl, C1-C8 alkyI-CONR9R,°, NR8COC1-C8 alkyl, C1-C8 thioalkyl, d-Q alkyl (itself optionally
15 substituted by one or more hydroxy, azido or cyano groups or fluorine atoms), C1-C8alkyl-NR1 !R12, C1-C8 alkyl-OR12, C1-C8 alkyl-SR12;
or Ar 15 phenyl substituted by at least one substituent selected from azido substituted C1-C8 alkyl, C1-C8 alkyl-NRnR,2\C1-C8 alkyl-OR12*, C1-C8 alkyl-SR12*, wherein R12a 15 selected from -(CR13^14 ,-CO-(CR,32)bRw. -S02-(CR'^R14 :
20 R8 15 hydrogen or d-C8 alkyl;
R9 and R10 are each independently hydrogen or C1-C8 alkyl
Rn 15 hydrogen or C1-C8 alkyl;
R12 15 hydrogen or a group selected from C(-C8 alkyl, -(CRl32)nR14 ,
-CO-CCR^R^-SOHCR13,)^14 ;
25 n 15 between 0 and 5;
R13 groups are independently hydrogen, Q-Q alkyl, hydroxy, C1-C8 alkoxy, hydroxy(C1-C8 )alkyl, amino or halogen;
R,4 15 hydrogen or a group selected from -NR15R16, C1-C8 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -COOH, -S(C1-C8 alkyl), -SCKQ-CgalkylX-CONR^R16, -CO(C1-C8 alkyl),
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-CO-0-(C1-C8 alkyl), or a saturated or unsaturated 4- to 10-membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur, each of which groups may be optionally substituted by one or more hydroxy, Cg-Cg alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or
5 unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl, nitro, -CONH2 groups), C1-C8alkoxy, C1-C8hydroxyalkyl,-C=0, cyano, amino, nitro, halogen, C1-C8 alkylsulphonyl or aminosulphonyl groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or
10 more heteroatoms selected from nitrogen, oxygen and sulphur;
or Rn and R12, together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated or unsaturated heterocyclic ring system optionally containing one or more additional heteroatoms selected from oxygen, sulphur or nitrogen , the ring itself being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl(which
15 may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated
heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, (C1-C8)alkyl, Cg-Cg alkyl, nitro, -CONH2 groups), nitro, cyano, -CONH2. amino, =0 or -COOH groups or by a saturated monocyclic 4- to 7-membered ring, which ring may optionally compr15e one or
20 more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1-C8 alkyl, C1-C8 alkoxy or (C1-C8 alkoxy)-CO-; and
R15 and R16, which may be the same or different, represent hydrogen, C1-C8 alkyl, -CONH2 or-C(NH2)=NH,
25 provided that Ar 15 not phenyl substituted by one or more groups selected from
CrCg alkyl-NR1'- C1-C8 alkyl, C1-C8 alkyl-0-CrC8 alkyl or Q-C6 alkanoyloxy C,-Q alkyl. 4. A compound according to any of claims 1 to 3 wherein X 15 C=0.
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5. A compound according to any of claims 1 to 4 wherein Rx 15 a group selected from Cg-C8 alkyl, C3-C8 cycloalkyl or a saturated monocyclic 4- to 7-membered ring compr15ing one or more heteroatoms selected from nitrogen, oxygen and sulphur, wherein any C3-C8 cycloalkyl group or saturated monocyclic 4- to 7-membered ring 15 optionally substituted by 5 one or more groups selected from hydroxy, azido, cyano, amino, halogen, -CONH2-, C1-C8 alkyl, (C1-C8 alkyl)CO-, Cg~Cg alkoxy, or (C1-C8 alkoxy)-CO-, and any C1-C8 alkyl, (Cg-Cg alkyl)CO-, C\-C% alkoxy, or (C1-C8 alkoxy)-CO- group 15 itself optionally substituted by one or more substituents selected from hydroxy, azido, cyano, amino, halogen or phenyl.
10 6. A compound according to any of claims 1 to 5 wherein Rx 15 a saturated monocyclic 4- to 7-membered ring compr15ing one or more heteroatoms selected from nitrogen, oxygen and sulphur, which ring 15 substituted by one or more C1-C8 alkyl, (C1-C8 alkyl)CO-, C1-C8 alkoxy, or (C1-C8 alkoxy)-CO- groups, each of which groups 15 optionally substituted with one or more substituents selected from hydroxy, azido, cyano, amino, halogen, -CONH2,
15 C1-C8 alkoxy, (C1-C8 alkoxy)-CO- or phenyl.
7. A compound according to any of claims 1 to 4 wherein Rx 15 a group Ar.
8. A compound according to any of claims 1 or 2 wherein Ar 15 phenyl optionally
20 substituted by one or more groups, which may be the same or different, selected from
halogen, hydroxy, cyano, C1-C8 alkoxy, CO2R8, CONRV0, C1-C8 alkyl-NR8-C1-C8 alkyl, C1-C8 alkyl-CONR8-C1-C8 alkyl, C1-C8 alkyl-CONRV0, NR8COC1-C8 alkyl, C1,-C8 thioalkyl, C1-C8 alkyl (itself optionally substituted by one or more hydroxy, azido or cyano groups or fluorine atoms), C1,-C8alkyl-NRnRl2,C1-C8alkyl-OR12, C1rC8alkyl-SR12.
25
9. A compound according to claim 3 or 8 wherein Ar 15 phenyl substituted by at least one
substituent selected from azido substituted CrC8 alkyl, C1|-C8 alkyl-NR1 'R,2a, C1-C8 alkyl-
OR,2a, C1-C8alkyl-SR,2a, wherein R,2a 15 selected from -(CR'^R14 .-CO(CR132)R14 , -
SO2 -(CR132)nR' provided that Ar 15 not phenyl substituted by one or more groups selected
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from d-Cg alkyl-NR1'- d-C8 alkyl, C1-C8 alkyl-O-C1-C8 alkyl or d-C6 alkanoyloxy C1-C6 alkyl.
10. A compound according to claim 9 wherein Ar 15 phenyl substituted by one or more -
5 CH2NRnR12 groups.
11 A compound according to claim 10 wherein R11 and R12 together with the nitrogen
atom to which they are attached form a 4- to 10-membered saturated or unsaturated
heterocyclic ring system optionally containing one or more additional heteroatoms selected
10 from oxygen, sulphur or nitrogen , the ring itself being optionally substituted by one or, more hydroxy, hydroxy(C1-C8)alkyl, C1-C8 alkyl(which may itself optionally be substituted by a 4- to 7-membered saturated or unsaturated heterocyclic ring system optionally containing a further oxygen, sulphur or nitrogen atom, the ring being optionally substituted by one or more hydroxy, hydroxy(C1-C8)alkyl, Q-Cg alkyl, nitro, -CONH2 groups), nitro,
15 cyano, -CONH2, amino, =0 or -COOH groups or by a saturated monocyclic 4- to 7-
membered ring, which ring may optionally compr15e one or more heteroatoms selected from nitrogen, oxygen and sulphur and which may be optionally substituted by one or more substituents selected from C1-C8 alkyl, Cg-Cg alkoxy or (C1-C8 alkoxy)-CO-.
20 12. A compound according to any of claims 1 to 11 wherein R1 and R2 independently represent C1-C8 alkoxy, Y(CR32)PNR4R5, Y(CR32)pCONR4R5, Y(CR32)pC02R6, Y(CR32)pOR6 , Y(CR32)pOCOR6, Y(CR32)pR6 .
13. A compound according to claim 12 wherein R1 and R2 are both C1-C8 alkoxy, or one
25 of R1 and R2 15 C1-C8 alkoxy and the other 15 Y(CR32)pNR4R5 , Y(CR32)pOR6 or
Y(CR32)pR6.
14. A compound according to claim 1 which 15
6,7-diethoxy-4-{[2-ethyl-3-(lH-imidazol-l-ylmethyl)phenyl]amino}quinoline-3-
30 carboxamide
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w
6,7-diethoxy-4-{[2-methyl-3-(lH-l,2,4-triazol-l-ylmethyl)phenyl]amino}quinoline-3-
carboxamide
6,7-diethoxyl-{[2^thyl-3-(morpholin-4-ylmethyl)phenyl]amino}quinoline-3-carboxamide
6,7-diethoxy-4-{[3-(lH-imidazol-l-ylmethyl)-2-methylphenyl]amino}quinoline-3-
5 carboxamide
4- {[3-(azidomethyl)-2-methylphenyl]amino} -6,7-diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-{ [2-methyl-3-(4H-1,2,4-triazol-4-ylmethyl)phenyl]amino }quinoline-3-
carboxamide
4-{ [3-({ [4-(aminosulfonyl)benzyl]amino}methyl)-2-cthylphenyl]amino}-6,7-
10 dimethoxyquinoline-3-carboxamide
4-({2^thyl-3-[(lH-l^,4-triazol-5-ylamino)methyl]phenyl}amino)-6,7-dimethoxyquinolinc-
3-carboxamide
4-{[2^thyl-3^1H-imidazol-l-yImethyI) phenyl]amino}-6,7-dimethoxyquinoline-3-
carboxamide
15 6,7-diethoxy-4-( {2-ethyl-3-[(pyrimidin-2-ylamino)methyl]phenyl} amino)quinoline-3-
carboxamide
6,7 liethoxy-4-[(2-cthyl-3-{[(2-hydroxycyclohcxyl)amino]methyl}phenyl)amino]quinoline-
3-carboxamide
6,7-diethoxy-4-[(2-cthyl-3-{ [(3-thienylmethyl)amino]methyl} phenyI)amino]quinoline-3-
20 carboxamide
6J-diethoxy-4-({2-ethyI-3-[(lH-imidazol-2-yltfiio)methyl]phenyl}amino)quinoline-3-
carboxamide
6,7-diethoxy-4- {(2-ethyl-3-(thiomorpholin-4-ylmethyl)phenyl]amino }quinoline-3-
carboxamide
25 6,7-diethoxy-4-[(2-ethyl-3-{ [(3-thienylmethyl)amino]methyl }phenyl)amino]quinoline-3-
carboxamide
4-( {2-ethyl-3-[(4-nitro- lH-imidazol-1 -yl)methyl]phenyl} amino)-6,7-dimethoxyquinoline-3-
carboxamide
4-[(2-ethyl-3-{[4-(hydroxymethyl)-lH-imidazol-l-yl]methyl}phenyl)amino]-6,7-
30 dimethoxyquinoline-3-carboxamide
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4-( {2-ethyl-3-[(2-methyl-1 H-imidazol-1 -yl) methyl]phenyl} amino)-6,7-dimethoxyquinoline-
3-carboxamide
l-(3- {[3-(aminocarbonyl)-6,7-diTnethoxyquinolin-4-yl]amino} -2-ethylbenzyl)-1H-
imidazole-4-carboxylic aC1d 5 4-({ 3-[(cyclopentylamino)methyl]-2-ethylphenyl }amino)-6,7-dimethoxyquinoline-3-
carboxamide
4-{[2-ethyl-3-({[2-(lH-imidazol-4-yl)ethyl]amino}methyl)phenyl]amino}-6,7-
dimethoxyquinoline-3-carboxaraide
4-[(2^thylO-{[(2-hydroxy-1,1 dimethylethyl)amino]methyl}phenyl)amino]-6,7-10 dimethoxyquinoline-3-carboxamide
4^{2^thyl-3-[(13-thiazol-2-ylamino)methyl]phenyl}amino)-6,7-dimethoxyquinoline-3-
carboxamide
4-[(2-cthyl-3- {[(2-hydroxypropyl)amino] methyl }phenyl)amino]-6,7-dimethoxyquinoline-3-
caiboxamide
15 4-[(2-ethyl-3- {[(2-hydroxy-2-phenylethyl)amino) methyl }phenyl)amino]-6,7-
dimethoxyquinoline-3-carboxamideb15(trifluoroacetate)
4-{ [2-ethyl-3-({ [4-(methylsulfonyl)benzyl]amino }methyl)phenyl]amino}-6,7-
dimethoxyquinoline-3-carboxamide
4-({ 3-[(benzylamino)methyl]-2-cthylphenyl }amino)-6,7-
20 carboxamide
4-( {2-ethyl-3-[(3-methyl-2,5-dioxoimidazolidin- l-yl)methyl]phenyl} amino)-6,7-
dimethoxyquinoline-3-carboxamide
4-({2^diyl-3-[(lH-tetnaol-5-ylamino)mediyl]phenyl}amino)-6,7-dimethoxyquinoline-3-
carboxamide
25 4-({ 3-[(5-amino-lH-tetrazol-l-yl)methyl]-2-ethylphenyl }amino)-6,7-dimethoxyquinoline-
3-carboxamide
4- {[2-ethyI-3-( {[2-(2-oxoimidazolidin-1 -yl)ethyl]amino} methyl)phenyl]amino} -6,7-
dimethoxyquinoline-3-carboxamide
4- {[2-ethyl-3-( {[(2S)-2-hydroxycyclohexyl]amino} methyl)phenyl]amino} -6,7-30 dimethoxyquinoline-3-carboxamide
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4-( {2-ethyl-3-[(piperidin-4-ylamino)methyl]phenyl} amino)-6,7-dimethoxyquinoline-3-
carboxamide
4- {[2-ethyl-3-( {[(lR)-l-(hydroxymethyl)-3-methylbutyl]amino} methyl)phenyl]amino} -6,7-
dimethoxyquinoline-3-carboxamide
5 6,7-diethoxy-4-[(2-ethyl-3-{ [4-(3-methoxyphenyl) piperazin-l-
yl]methyl} phenyl)amino]quinoline-3-caiboxamide
6,7-diethoxy-4-[(2-ethyl-3-{[4-(hydroxyinethyl) piperidin-l-
yl]methyl}phenyl)amino]quinoline-3-carboxamide
6,7-diethoxy-4-[(2-cthyl-3-{[2-(hydroxymethyl)piperidin-l-
10 yl]methyl} phenyl )amino]quinoline-3-carboxamide
4- {[3-(1,4'-bipiperidin-1 '-ylmethyl)-2-ethylphenyl]amino} -6,7-diethoxyquinoline-3-
carboxamide
4-[(3-{ [4-(aminocarbonyl)piperidin-l-yI] methyl }-2-cthylphenyl)amino]-6,7-
diethoxyquinolinc-3-carboxamide
15 4-[(3-{ [4-(2-cyanophenyl)piperazin-l-yl]methyl }-2-ethylphenyl)amino3-6,7-
diethoxyquinoline-3-carboxamidc
4-[(3-{ l4-(5-cyanopyridin-2-yl)piperazin-l-yl]methyl }-2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
6,7 Ucthoxy-4-[(2-cthyl-3-{[(3-fui7lmethyl)amino]methyl}phenyl)aminolquinoline-3-20 carboxamide
6,7-diethoxy-4-[(2-ethyl-3-{[4-(2-hydroxyethyl)piperazin-l-
yl]methyl}phenyl)amino]quinoline-3-carboxamide
6,7-diethoxy-4-({2-ethyl-3-((4-hydroxypiperidin-l-yl)mcthyl]phenyl}amino)quinolinc-3-
carboxamide
25 4- {[3-( {[2-( 1,3-benzodioxol-5-yl)ethyl]amino} methyl)-2-ethylphenyl]amino} -6,7-
diethoxyquinoline-3-carboxamide
6,7-dicthoxy-4- {[2-ethyl-3-( {[2-(2-thienyl)ethyl]amino} methyl)phenyl]amino }quinoline-3-
carboxamide
4-{[3-({[(2,5-dimethyl-3-furyl)methyl]amino}methyl)-2-ethylphenyl]amino}-6,7-30 diethoxyquinoline-3-carboxamide
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6,7-diethoxy-4- {[2-ethyl-3-( {[3-(2-oxopyrrolidin-1-
yl)propyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
4-{[3-({[2-(3-chlorophenyl)ethyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
5 4-{ [3-({ [2-(4-chlorophenyl)ethyl] amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
4-{ [3-({ [2-(2-chlorophenyl)ethyl]amino} methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-[(2-ethyl-3-{[(2-hydroxy-2-
10 phenylethyl)amino]methyl}phenyl)amino]quinoline-3-carboxamide
4-({3-[(cyclopentylanuno)methyl]-2-ethylphenyl }amino)-6,7-diethoxyquinoline-3-
carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [2-(lH-imidazol-4-
yl)ethyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
15 6,7-diethoxy-4-[(2-ethyl-3-{ [4-(2-morpholin-4-ylethyl)piperazin-l-
yl]methyl} phenyl)amino]quinoline-3-carboxamide
4- {[3-( {[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]amino} methyl)-2-ethylphenyl]amino} -
6)7-diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-({ 2-ethyl-3-[(l ,3-thiazol-2-ylamino)methyl]phcnyl }amino)quinoline-3-20 carboxamide
6,7-diethoxy-4-{[2-ethyl-3-(l,3-thiazolidin-3-ylmethyl)phenyl]amino}quinoline-3-
caiboxamide
6,7-diethoxy-4-[(2-ethyl-3-{[(2-pyridin-2-ylethyl)amino]methyl}phenyl)amino]quinoline-3-
carboxamide 25 6J-diethoxy-4-({2-ethyl-3-[(lH-l,2,4-triazol-3-ylamino)methyl]phenyl}amino)quinoline-3-
carboxamide
6,7-diethoxy-4- {[2-ethyl-3-({ [4-(2-thienyl)benzyl]amino} methyl)phenyl]amino Jquinoline-
3-carboxamide
4-{ [3-({ [4-(aminosulfonyl)benzyl]amino}methyl)-2-ethylphenyl]amino}-6,7-30 diethoxyquinoline-3-carboxamide
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6,7-diethoxy-4-{ [2-ethyl-3-({ [2-(lH-indol-3-
yl)ethyl]amino }methyl)phenyl]amino }quinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [3-(4-methylpiperazin-l-
yl)propyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide 5 6,7-diethoxy-4-[(2-ethyl-3-{ [(l-ethylpiperidin-3-yl)amino]methyl }phenyl)amino]quinoline-
3-carboxamide
6,7-diethoxy-4-[(2-ethyl-3-{[4-(pyridin-4-ylmethyl)piperazin-l-
yl]methyl}phenyl)amino]quinoline-3-carboxamidc
6,7-diethoxy-4-[(2-ethyl-3- {[(pyridin-4-ylmetfiyl)amino]methyl} phenyl)amino]quinoline-3-10 carboxamide
6,7-diethoxy-4-((2-ethyl-3- {[(pyridin-3-ylmethyI)amino]methyl} phenyl )amino]quinoline-3-
carboxamide
4-( {3-[(benzylamino)methyl]-2-ethylphenyl} amino)-6,7-diethoxyquinoline-3-carboxamide
6J^iiethoxy^[(2-ethyl-3-{[(2-furylmethyl)amino]methyl}phcnyl)amino]quinoline-3-15 carboxamide
6,7-diethoxy-4-[(2-ediyl-3-{ [(2-methoxyethyl)amino]methyl }phenyl)amino]quinoline-3-
caiboxamide
6,7-diethoxy-4-[(2-ethyl-3- {[(2-hydroxypropyl)amino]methyl }phenyl)amino]quinoline-3-
carboxamide 20 6,7-diethoxy-4-{ [2-ethyl-3-({ [4-(lH-pyrazol-l-
yl)benzy]]amino}methyl)phenyl]amino}quinoline-3-carboxamide
4-( {3-[( {2-[4-(aminosulfonyl)phenyl]ethyl} amino)methyl]-2-ethylphenyl }amino)-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [2-(l-methylpyrrolidin-2-25 yl)ethyl]amino}methyi)phenyl]amino}quinoline-3-carboxamide
4-[(3-{[(4-chlorobcnzyl)amino]methyl}-2-ethylphenyl)amino]-6,7-diethoxyquinoline-3-
carboxamide
4-[(3-{ [(l-benzylpiperidin-4-yl)amino]methyl }-2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
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6,7-diethoxy-4-[(2-ethyl-3-{[(3-methoxybenzyl)amino]methyl}phenyl)amino]quinoline-3-
carboxamide
6,7-diethoxy-4-[(2-ethyl-3- {[(4-mcthoxybenzyl)amino]methyl} phenyl)amino]quinoline-3-
carboxamide
5 6,7-diethoxy-4-{ [2-ethyl-3-({ [3-(lH-imidazol-l-
yl)propyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [(lR,2S)-2-hydroxy-2,3-dihydro-lH-inden-l-
yl]amino}methyl)phenyl]amino}quinoline-3-caiboxamide b15(trifluoroacetate) (salt)
6,7-diethoxy-4-{ [2-ethyl-3-({ [2-hydroxy-l-(lH-indol-2-
10 ylmethyl)ethyl]amino}mcthyl)phenyl]amino}quinoline-3-carboxamide b15(trifluoroacetate)
(salt)
6,7-diethoxy-4-{[2-€thyl-3-({[(lR)-2-hydioxy-l-
phenylethyl]amino}methyl)phenyl]amino}quinoline-3^arboxamideb15(trifluoroacetate)
(salt)
15 6,7-Diethoxy-4-{ 2-ethyl-3-[(2-hydroxy-l-methylcarbamoyl-propylamino)-m
ethyl]-phenylamino}-quinoline-3-carboxylic aC1d amide
6,7-emoxy^-{[2^myl-3-({[(lR,2S>2-hydroxy-l-(hydroxyinemyl)pix)pyl]amino}methyl)
phenyl]amino} quinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [(lR,2R)-2-hydroxy-l-
20 (hydroxymethyl)propyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
memylN-(3-{[3-(aminocait>onyl)-6,7-diethoxyquinolin-4-yl]amino}-2-ethylbenzyl)serinate
b15(trifluoroacetate)
6,7-diethoxy-4-{ [2-ethyl-3-({ [2-hydroxy-l-
(hydroxymethyl)ethyl]amino}methyl)phenyl]amino}quinoIine-3-carboxamide
25 6,7-diethoxy-4- {[2-ethyl-3-( {[ 1 -(hydroxymethyl)-3-
methylbutyl]amino} methyl )phenyl]amino }quinoline-3-carboxamide
6,7-diethoxy-4-[(2-ethyl-3-{[(2-pyrrolidin-l-
ylethyl)amino]methyl} phenyl)amino]quinoline-3-carboxamide
6,7-dicthoxy-4-{ [2-ethyl-3-({ [(lS,2R)-2-hydroxy-l-
30 (hydroxymethyl)propyl]amino }methyl)phenyl]amino}quinoline-3-carboxamide
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6,7-diethoxy-4-{ [2-ethyl-3-({ [(lS)-l-(hydroxymethyl)-3-
methylbutyl]amino} methyl)phenyl]amino }quinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({[l-
(hydroxymethyl)butyl]amino }methyl)phenyl]amino }quinoline-3-carboxamide
5 4-{3-[(l-Carbamoyl-2-hydroxy-propylamino)-methyl]-2-ethyl-phenylamino}
-6,7-diethoxy-quinoline-3-caiboxylic aC1d amide
6,7-diethoxy^-[(2-ethyl-3-{ [[(lR^R)-2-hydroxy-l-nQethyl-2-
phenylethyl](methyl)amino]methyl}ph«nyl)amino]quiiK)line-3K;arboxamide
6,7-diethoxy-4-[(2-cthyl-3-{[(2-hydroxy-l-methyl-2-
10 phenylethyl)anMno]methyl}ph«nyl)amino]quinoline-3-carboxamidc
4-{[3-({[2-(3,4-dihydn)xyphenyl)-2-hydix)xyethyl]amino}nMthyl)-2-«thyIphenyI]amino}-
6,7-diethoxyquinoline-3-carboxamide
6,7^iiethoxy^-[(2^thyI-3-{[(2-hydroxypropyl) amino]methyl}phenyl)aminolquinoline-3-
carboxamide
15 6,7-diethoxy-4-[(2-cthyI-3-{ [(2-hydroxy-l-
methylethyl)amino]methyl}phenyl)amino]quinoline-3-carboxamide
6,7-diethoxy-[(2-ethyl-3-{[(2-hydroxyethyl)amino]methyl l}phenyl)amino]quinolinc-3-
carboxamide
4-[(3-{ [(2,3-dihydroxyptopyl)amino]methyl} -2-cthyIphenyI)amino]-6,7-diethoxyquinoIine-20 3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [2-
(hydroxymethyl)phenyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
4- {[3-( {[(15)-1 -benzyl-2-hydroxyethyl]amino} methyl)-2-ethylphenyl]amino} -6,7-
diethoxyquinoline-3-carboxamideb15(trifluoroacetate)
25 4-{ [3-({ [2-(dimethylamino)ethyl]amino }methyl)-2-cthylphenyl]amino }-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({[4-
(methylsulfonyl)phenyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
6,7-diethoxy-4-{[2-ethyl-3-({[(lS)-2-hydroxy-l-
30 phenylethyl]amino} methyl )phenyl]amino }quinoline-3-carboxamide
WO 2005/075429 PCT/SE2005/000156
6,7-diethoxy-4-[(2-ethyl-3-{ [(2R)-2-(hydroxymethyl)pyrrolidin-l-
yl]methyl}phenyl)amino]quinoline-3-caiboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2-
phenylethyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
5 6,7-diethoxy-4-[(2-ethyl-3-{ [(2-morpholin-4-
ylethyl)amino]methyl} phenyl)amino]quinoline-3-carboxamide 6,7-diethoxy-4-{ [2-ethyl-3-({ [(lR,2S)-2-hydroxy-2-(4-hydroxyphenyl)-l-methylethyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide 6,7-diethoxy-4-{ [2-ethyl-3-({ [(lR,2R)-2-hydroxy-l-(hydroxymethyl)-2-
10 phenylethyl]amino} methyl)phenyl]amino }quinoline-3-carboxamide
6,7-Diethoxy-4-{2-ethyl-3-[(2-hydroxy-l-hydroxymethyl-2-phenyl-ethylam
ino)-methyl]-phenylamino}-quinoline-3-caiboxylic aC1d amide 4-[(3-{[(2-cyanoethyl)amino]methyl}-2-cthylphenyl)amino]-6,7-diethoxyquinoline-3-carboxamide
15 6,7-diethoxy-4-{[2-cthyl-3-({[l-(hydroxymethyl)-2-
methylpropyl]amino}methyl)phenyl]amino}quinoline-3-cart)oxamide 6,7-diethox-4-{ [2-ethyl-3-({ [4-
(methylsulfonyl)benzyl]amino} methyl)phenyl]amino }quinoline-3-carboxamide tcrt-butyl (3-{ [3-(aminocarbonyl)-6,7-diethoxyquinolin-4-yl]amino}-2-
20 ethylbenzyl)carbamate
4- {[3-(aminomethyl)-2-ethylphenyl]amino} -6,7-diethoxyquinoline-3-carboxamide 4-{[3^aminomethyl)-2-methylphenyI]amino}-6,7-diethoxyquinoline-3-carboxamide 6,7-diethoxy-4-({2-ethyl-3-[(L-tyrosylamino)methyl]phenyl}amino)quinoline-3-carboxamide
25 6,7-diethoxy-4- {[3-( {[(ediylamino)carbonyl]amino} methyl)-2-methylphenyl]amino}quinoline-3-carboxamide
4-( {3-[(acetylamino)methyl]-2-methylphenyl} amino)-6,7-diethoxyquinoline-3-carboxamide 6,7-diethoxy-4-({2-methyl-3-[({[(4-methyl-2,5-dioxoimidazolidin-4-
yl)methyl]sulfonyl }amino)methyphenyl }amino)quinoline-3-carboxamide
30 4-({3-[(acetylamino)methyl]-2thylphenyl}amino)-6,7-dimethoxyquinoline-3-carboxamide
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4-{ [2-ethyl-3-({ [(ethylamino)carbonyl]amino}methyl)phenyl]amino}-6,7-
dimethoxyquinoline-3-carboxamide
4-[(2-ethyl-3-{[(methylsulfonyl)amino]methyl}phenyl)amino]-6,7-dimethoxyquinoline-3-
carboxamide
5 4-({ 2-ethyI-3-[(L-valyIamino)methyI]phenyl }amino)-6,7-dimethoxyquinoline-3-
carboxamide
4-[(3- {[(3-cyclohexyl-L-alanyl)amino]methyl} -2-ethylphenyl)amino]-6,7-
dimethoxyquinoline-3-carboxamide
6,7-diethoxy-4-({ 2-ethyl-3-[(L-methionyIamino)methyl]phenyl }amino)quinoline-3-
10 carboxamide
6,7-diethoxy^({2^thyl-3-[(L-prolylamino)methyl]phenyl}amino)quinoline-3-
carboxamide
6,7-diethoxy-4-({ 2-ethyl-3-[(L-threonylamino)methyl]phenyl }amino)quinoHne-3-
carboxamide
15 N~l~-(3-{[3-(aminocarbonyl)-6,7-diethoxyquinolin-4-yl]amino}-2-ethylbenzyl)-L-alpha-
glutamine
6,7-diethoxy-4-({ 2-ethyl-3-[(L-valylamino)methyl]phenyl }amino)quinoline-3-carboxamide
4-({ 3-[(L-arginylamino)methyll-2-cthylphenyl }amino)-6,7-diethoxyquinoline-3-
carboxamide
20 4-({3-[(L-alanylamino)methyl]-2-ethylphenyl}amino)-6,7-diethoxyquinoline-3-
carboxamide
6,7 diethoxy-4-({2^thyIO-[(D-sei7lanuno)methyI]phenyl}amino)quinoline-3-carboxamide
4-[(3- {[(3-cyclohexyl-L-alanyl)amino]methyl} -2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
25 6,7-diethoxy-4-{ [2-ethyl-3-({[(4S)-l,3-thiazolidin-4-
ylcarbonyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [(4R)-4-hydroxy-L-
prolyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
6,7-dicthoxy-4-( {2-ethyl-3-[(D-leucylamino)methyl]phenyl} amino)quinoline-3-30 carboxamide
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N~l~-(3-{[3-(aminocarbonyl)-6,7-diethoxyquinolin-4-yl]amino}-2-ethylbenzyl)-L-
aspartamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [(2S)-piperidin-2-
ylcarbonyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
5 4-[(3-{ [(3-cyclohexyl-D-alanyl)amino]methyl }-2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [(2R)-piperidin-2-
ylcarbonyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
4-{ [3-({ [(2S)-2-aminopent-4-cnoyl]amino}methyI)-2-ethyIphenyl]amino}-6,7-10 diethoxyquinoline-3-carboxamide
4-{ [3-({ [(2S-azetidin-2-ylcarbonyl]amino}methyl)-2-ethyiphcnyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-[(2-cthyl-3- {[(5-methyl-L-
norleucyl)amino]methyl}phenyl)amino]quinoline-3-carboxamide
15 6,7-diethoxy-4-{[2-ethyl-3-({[(4R)-l,3-thiazo]idin-4-
ylcarbonyl]amino} methyl)phenyl]amino )quinoline-3-carboxamide
6,7-diethoxy-4-[(2-ethyI-3-{ [(4-nitro-D-
phenylalanyl)amino]methyl}phenyl)amino]quinoline-3-carboxamide
4-{ [3-({ [(l-amino-2,3-dihydro-lH-inden-l-yl)carbonyl]amino}niethyl)-2-20 ethylphenyl]amino}-6,7-diethoxyquinolinc-3-carboxamide
4-{ [3-({ [(l-aminocyclohexyl)carbonyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [(3R)-l,2,3,4-tetrahydro15oquinolin-3-
ylcarbonyljamino} methyl )phenyl]amino}quinoline-3-carboxamide
25 4-{ [3-({ [(2R)-2-amino-4-phenylbutanoyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-{[2-ethyl-3-({[(3S)-l,2,3,4-tetrahydro15oquinolin-3-
ylcarbonyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
6,7-diethoxy-4-[(2-ethyl-3- {[(4-piperidin-4-yl-L-
30 prolyl)amino]methyl }phenyl)amino]quinoline-3-carboxamide
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4-[(3-{[(3-amino-L-alanyl)amino]methyl}-2-ethylphenyl)amino]-6,7-diethoxyquinoline-3-
carboxamide
6,7-diethoxy-4-({2-ethyl-3-[(D-phenylalanylamino)methyl]phenyl}amino)quinoline-3-
carboxamide
5 4-{ [3-({ [(2S)-2-amino-4-phenylbutanoyl]amino}methyl)-2-cthyJphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [(3S)-piperidin-3-
ylcarbonyl]amino}methyl)phenyl]amino}quinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [(3R)-piperidin-3-
10 ylcarbonyljamino }methyl)phenyl]amino }quinoline-3-carboxamide
4-{ [3-({ [(2S)-2-amino-2-phenylacetyl]amino}methyl)-2-cthylphenyl]amino }-6,7-
diethoxyquinoIine-3-carboxamide
6,7-diethoxy-4-(( 2-ethyI-3-[CHeucyIamino)methyi]phenyI} amino)qumoIine-3-
carboxamide
15 6,7-diethoxy-4-( {2-ethyl-3-[(D-prolylamino)methyl]phcnyI} amino)quinoIinc-3-
carboxamide
4-{[3-({[(2S)-2,5KUhydro-lH-pym)l-2-ylcarbonyl]amino}methyI)-2-cthylphenyI]amino}-
6,7-diethoxyquinolinc-3-carboxamide
6,7-diethoxy-4-({2-ethylO-[(glycylamino)methyl]phenyl}amino)quinoline-3-carbxamide
20 4- {[3-( {[2-amino-4-(methylsulfinyl)butanoyl]amino} methyl)-2-ethylphenyl]amino} -6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-( {[3-(2-furyl)-L-alanyl]amino} methyl)phenyl]amino }quinoIine-
3-carboxamide
6,7-diethoxy-4-[(2-ethyl-3- {[(3-pyridin-2-yl-L-
25 alanyl)amino]methyl }phenyl)amino]quinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-{{ [3-(2-thienyl)-L-
alanyl]amino} methyl)phenyl]amino }quinoline-3-carboxamide
6,7-diethoxy-4-{ [2-ethyl-3-({ [3-(l,3-thiazol-4-yl)-L-
alanyl]amino }methyl)phenyl]amino }quinoline-3-carboxamide
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/3^
4- {[3-( {[(2S)-2-amino-2-cyclopentylacetyl]amino} methyl)-2-ethylphenyl]amino} -6,7-
diethoxyquinoline-3-carboxamide
4- {[3-( {[(2S)-2-aminopent-4-ynoyl]amino} methyl)-2-ethylphenyl]amino} -6,7-
diethoxyquinoline-3-carboxamide
5 6,7-diethoxy-4-( {2-ethyl-3-[(L-norvalylamino)methyl]phenyl} amino)quinoline-3-
carboxamide
4-{[3-({[(2R)-2-amino-2-phenylacetyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide . 6,7-diethoxy-4-{ [2-ethyl-3-({ [(4R)-4-hydroxy-D-
10 proly]]amino}methyl)phenyl]amino}quinoline-3-carboxamide
4-( {3-[(beta-alanylamino)methyl]-2-ethylphenyl} amino)-6,7-diethoxyquinoline-3-
carboxamide
6,7-diethoxy-4-[(2-ethyl-3-{[(3-pyridin-3-yl-L-
alanyl)amino]methyl}phenyl)amino]quinotine-3-carboxamide 15 6,7-diethoxy-4-[(2-ethyl-3- {[(3-pyridin-3-yl-D-
alanyl)amino]methyl} phenyl)amino]quinoline-3-carboxamide
4-{ [3-({ (N-5~-(aminocarbonyl)-L-ornithyl]amino)methyl)-2-ethylphenyl]amino }-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-[(2-ethyl-3- {[(5-methyl-D-
20 norleucyl)amino]methyl} phenyl)amino]quinoline-3-carboxamide
4-[(3- {[(2,3-dihydro-lH-1soindol-l-ylcarixnyl)amino]methyl }-2-ethylphenyl)amino]-6,7-
diethoxyquinoline-3-carboxamide
6,7-diethoxy-4-( {2-ethyl-3-[(L-15oleucylamino)methyl]phenyl} amino)quinoline-3-
carboxamide
25 6,7-diethoxy-4-({2-ethyl-3-[(D-valylamino)methyl]phenyl}amino)quinoline-3-carboxamide
4-{[3-({[(l-aminocyclopentyl)carbonyl]amino}methyl)-2-ethylphenyl]amino}-6,7-
diethoxyquinoline-3-carboxamide
4-{ [2-ethyI-3-(hydroxymethyI)phenyI]amino }-7-{ 3-[15obutyryl(15opropyl)amino] propoxy}
6-methoxyquinoline-3-carboxamide
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7-{3-[acetyl(15opropyl)amino]propoxy}-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-
methoxyquinoline-3-carboxamide
6-[2-(acetylamino)ethoxy]-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxaniide
6-{2-[acetyl(methyl)amino]ethoxy}-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-
5 carboxamide
6-{2-[acetyl(15opropyl)amino]ethoxy}-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-
carboxamide
4-[(2^thylphenyl)amino]-6-{2-[15obutyryl(methyl)amino]ethoxy}-7-methoxyquinoline-3-
carboxamide
10 4-[(2-thylphenyl)amino]{2-[15obutyryl(15opropyl)amino]ethoxy}-7-methoxyquinoline-
3-carboxamide
7-{3-[acetyl(methyl)amino]propoxy}-4-{[2-ethyl-3Khydroxymediyl)pheny1]amino}-6-
methoxyquinoIine-3-carboxamide
4- {[2-ethy]-3-(hydroxymethyl)phenyl]amino} -7- {3-[15obutyryl(methyl)amino]propoxy} -6-15 methoxyquinoline-3-carboxamide
7- {3-[acetyl (cyclopropyl)amino]propoxy} -4- {[2-ethyl-3-(hydroxymethyI)phenyI]amino} -6-
methoxyquinoline-3-carboxamide
7-{ 3-[cyclopropyl(15obutyryl)amino]propoxy }-4-{ [2-ethyl-3-
(hydroxymethy])phenyl]amino}-6-methoxyquinoline-3-carboxamide
20 7-[3-(acetylamino)propoxy]-4-{ [2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-
methoxyquinoline-3-carboxamide
4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-[3-(15obutyrylamino)propoxy]-6-
methoxyquinoline-3-carboxamide
6- {2-[(cyC1opropylcarbonyl)(methyl)amino]ethoxy} -4-[(2-ethylphenyl)amino]-7-25 methoxyquinoline-3-carboxamide
6- {2-[(cyclopropylcarbonylK15opropyl)amino]ethoxy} -4-[(2-ethylphenyl)amino]-7-
methoxyquinoline-3-carboxamide
4-{ [2-ethyl-3-(hydroxymethyl)phenyl]amino)-7-{3-
[isopropyl (methylsulfonyl)amino]propoxy}-6-methoxyquinoline-3-carboxamide
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4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-{3-
[(methylsulfonyl)amino]propoxy}quinoline-3-carboxamide
tert-butyl {3-[(3-(aminocarbonyl)-4-{ [2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-
methoxyquinolin-7-yl)oxy]propyl} 15opropylcarbamate
5 4- {[2-ethyl-3-(hydroxymethyI)phenyl]amino} -7-(3-
{15opropyl[(isopropylamino)carbonyl]amino}propoxy)-6-methoxyquinoline-3-carboxamide
7-[3-(cyclopropylamino)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-
methoxyquinoline-3-carboxamide
6-[3-(cyclopropylamino)propoxy]-4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -7-
10 methoxyquinoHne-3-caiboxamide
7-{ 3-[(2-cyanoethylXmethyl)amino]propoxy }-4-{ [3-(hydroxymehtyl)-2-
methylphenyl]amino}-6-methoxyquinoline-3-carboxamide b15(trifluoroacetate) (salt)
4-{[3-(hydroxymethyl)-2-iiiethylphenyl]amino}-6-incthoxy-7-[3-(2-methylpiperidin-l-
yl)propoxy]quinoline-3-carboxamide 15 7-{3-[(2-cyanoethylXmethyl)amino]propoxy }-4-{ [3-(hydroxymethyl)-2-
methylphenyl]amino }-6-methoxyquinoline-3-carboxamide
4-{[3-(hydroxymethyl)-2-inethylphenyl]amino}-7-[3-(3-hydroxypiperidin-l-yl)propoxyl-6-
methoxyquinoline-3-carboxamide
4-{[3-(hydroxymethyl)-2-methylphenynamino}-7-[3-(4-hydroxypiperidin-l-yl)propoxy]-6-20 methoxyquinoline-3-carboxamide
6-methoxy-4-[(2-methylphenyl)amino]-7-[3-(2-mcthylpiperidin-l-yl)propoxy]quinoline-3-
carboxamide
7-[3-(3-hydroxypiperidin-l-yi)propoxy]-6-methoxy-4-[(2-methylphenyl)amino]quinoline-3-
carboxamide
25 7-[3-(4-hydroxypiperidin-1 -yl)propoxy]-6-methoxy-4-[(2-methylphenyl)amino]quinoline-3-
carboxamide
4-{[3-(hydroxymethyl)-2-n^thylphenyl]amino}-7-[3^3-hyclroxypyrrolidin-l-yl)propoxy]-
6-methoxyquinoline-3-carboxamide
4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(lH-l,2,4-triazol-l-
30 yl)propoxy]quinoIine-3-carboxamide
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7-[2-(cyclopropylamino)ethoxy]-4- {[3-(hydroxymethyl)-2-methylphenyl]amino} -6-
methoxyquinoline-3-carboxamide
6-[2-(cyclopropylamino)ethoxy]-4- {[3-(hydroxymethyl)-2-methylphenyl]amino} -7-
methoxyquinoline-3-carboxamide
5 6-[2-(cyclopropylamino)ethoxy]-4-[(4-ethylphenyl)amino]-7-methoxyquinoJine-3-
carboxamide
6-[2-(cyclopropylamino)ethoxy]-4-[(3-ethylphenyl)amino]-7-methoxyquinoline-3-
carboxamide
6-[2-(cyclopropylamino)ethoxy]-7-mcthoxy-4-[(2-methylphenyl)amino]quinoline-3-
10 carboxamide
6-{2-[(2^yanoethyI)amino]ethoxy}^{[3^ydroxymethyl)-2-methylphenyl3amino}-7-
methoxyquinoline-3-carboxamide
6-[3^cyclopropylamino)propoxy]-4-[(2-cthylphenyl)amino]-7-inethoxyquinoline-3-
carboxamide
15 6-{3-[(cyanomethyl)amino]propoxy}-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-
carboxamide
6-[3-(Carbamoylmethyl-amino)-propoxy]-4-(2-cthyl-phcnylanuno)-7-niethoxy-quinolinc-3-
carboxylic acid amide
methyl N-[3-({3-(aminocarbonyl)-4-[(2-ethylphenyl)amino]-7-methoxyquinolin-6-
20 yl}oxy)propyl]glyC1nate
7-(3-cyanopropoxy)-4-{ [2-ethyl-3-(hydroxymethyl)phenyl]amino} -6-methoxyquinoline-3-
carboxamide
2-[(3-(aminocarbonyl)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxyquinolin-7-
yl)oxy]ethyl acetate
25 6-[2-(cyclopropyIamino)ethoxy]-4-[(2-ethylphenyi)amino]-7-methoxyquino]ine-3-
carboxamide
7-[3-(2,5-dioxopyrrolidin-l-yl)propoxy]-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-
methoxyquinoline-3-carboxamide
4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(3-methyl-2,5-
30 dioxoimidazolidin-l-yl)propoxy]quinoline-3-carboxamide
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4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-6-methoxy-7-[3-(3,4,4-trimethyl-2,
dioxoimidazolidin-1 -yl)propoxy]quinoline-3-carboxamide
7-(cyclopentyloxy)-4- {[2-ethyl-3-(hydroxymethyl)phenyl]amino} -6-methoxyquinoline-3-
carboxamide
5 6-(cyclopentyloxy)-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-carboxamide
1 - {3- [(3-(aminocarbonyl)-4- {[3-(hydroxymethyl)-2-methylphenyl ]amino} -6-
methoxyquinolin-7-yl)oxy]propyl }-l-methylpyrrolidinium iodide
tert-butyl 4-[(3-(aminocarbonyl)-4-{ [2-ethyl-3-(hydroxymethyl)phenyllamino }-6-
methoxyquinolin-7-yl)oxy]piperidine-l-caiboxylate
10 tert-butyl 4-({3(aminocarbonyl)-4-[(2-thyIphenyl)amino]-7-methoxyquinoHn-6-
yl }oxy)piperidine-l-carboxylate
3-( aminocarbonyl)-4-[(2-ethylphenyl)amino]-7-inethoxyquinolin-6-ylpropane-2-sulfonate
4-{[2-thyl-3-(hydroxymethyl)phenyl]amino}^methoxy-7-(piperidin-4-yloxy)quinolinc-3-
carboxamide
15 4-[(2-diylphenyl)amino]-7-mcthoxy-ipcridin-4-yloxy)quinoline-3-caiboxainide
6-[3-(cyclopropylamino)-2-hydroxypropoxy]-4-[(2-ethylphenyl)amino]-7-
methoxyquinoline-3-carboxamide
6-{3-[(2^yanoetiiyl)amino]-2-hydroxypropoxy}-4-[(2-ethylpheny])amino]-7-
methoxyquinoline-3-carboxamide
20 4-[(2-ethylphenyl)amino]-6-I2-hydroxy-3-(2-hydroxypyiTolidin-l-yl)propoxy]-7-
methoxyquinoline-3-carboxamide
4-[(2-ethylphenyl)amino]-6-(2-hydroxy-3-piperazin-l-ylpropoxy)-7-methoxyquinoline-3-
carboxamide
6- {[(2R)-3-(cyclopropylamino)-2-hydroxy-2-inethylpropyl]oxy} -4-[(2-ethylphenyl)amino]-25 7-methoxyquinoline-3-carboxamide
6-{[(2S)-3-(cyclopropylamino)-2-hydroxy-2-methylpropyl]oxy}-4-[(2-ethylphenyl)amino]-
7-methoxyquinoline-3-carboxamide
6-[3-(cyclopropylamino)-2-hydroxypropoxy]-4- {[2-ethyl-3-
(hydroxymethyl)phenyl]amino}-7-methoxyquinoIine-3-carboxaiTiide
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6-{[(2R)-3-(cyclopropylamino)-2-hydroxypropyl]oxy}-4-[(2-ethyIphenyl)amino]-7-
methoxyquinoline-3-carboxamide
6-{[(2S)-3-(cyclopropylamino)-2-hydroxypropyl]oxy}-4-[(2-ethylphenyl)amino]-7-
methoxyquinoline-3-carboxamide
5 3-(aminocarbonyl)-4-[(2-ethylphenyl)amino]-7-methoxyquinolin-6-yl2-methylpropanoate
6,7-diethoxy-4-[(4-methyl-l-oxo-l,2-dihydro15oquinolin-5-yl)amino]quinoline-3-
carboxamide
6,7diethoxy-[(4-methyl-l^xo-l,23,4-tctrahydro15oquinolin-5-yl)amino]quinoline-3-
carboxamide
10 tert-butyl 5-{[3-(aminocarbonyl)-6,7-diethoxyquinolin-4r«yl]amino}-3,4-
dihydro15oquinoline-2(lH)-carboxylate
6,7diethoxy-4-(l,2,3,4 tetrahydroisoquinolin-5-ylamino)quinolin-3-carboxamide
4-{ [3-(azidomethyI)-2-ethyIphenyl]amino }-6-[3-(cyclopropylamino)propoxy]-7-
methoxyquinoline-3-carboxamide
15 4-{ [3-(aminomethyl)-2-cthylphcnyl]amino}-6-[3-(cyclopropylamino)propoxy]-7-
methoxyquinoline-3-carboxamide
4-{[3-(aminomethyl)-2-ethylphenyl]amino}-7-{3-[15obutyi7l(15opropyl)amino]propoxy}-6-
methoxyquinoJine-3-carboxamide
4- {[3-(azidomethyl)-2-ethylphenyl]amino} -6-[3-(cyclopropylamino)-2-hydroxypropoxy]-7-20 methoxyquinoline-3-carboxamide
4-{[3-(aminomethyl)-2^thyIphenyl]amino}-^[3-(cyclopropylamino)-2-hydroxypropoxy]-
7-methoxyquinoline-3-carboxamidc
4-({3-[(acetylamino)methyl]-2-ethylphenyl}amino)-6-{3-[acetyl(cyclopropyl)amino]-2-
hydroxypropoxy} -7-methoxyquinoline-3-carboxamide
25 6-[3-(cyclopropylamino)-2-hydroxypropoxy]-4-{ [2-cthyl-3-(lH-imida2ol-l-
yImethyI)phenyI]amino)-7-methoxyquinoHne-3-carboxamide
6-[3-(cyclopropylamino)-2-hydroxypropoxy]-4-{[2-ethyl-3-(lH-pyrazol-l-
ylmethyl)phenyl]amino} -7-methoxyquinoline-3-carboxamide
6-{[(2S)-3-(cyclopropylamino)-2-hydroxypropyl]oxy}-4 -{[2-ethyl-3-(morpholin-4-
30 ylmethyl)phenyl]amino }-7-methoxyquinoline-3-carboxamide
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amino {6,7-diethoxy-4-[(2-ethylphenyl)amino]quinolin-3-yl} methanol
6-[3-(cyclopropylamino)propoxy]-4- {[2-ethyl-3-( 1H-imidazol- l-ylmethyl)phenyl]amino} -
7-methoxyquinoline-3-carboxamide
4-{[2-ethyl-3-(lH-imidazol-l-ylmethyl)phenyl]amino}-6-methoxy-7-(2-
5 methoxyethoxy)quinoline-3-carboxamide
6-(ethylamino)-4-{[2-ethyl-3-(lH-imidazol-l-ylmethyl)phenyl]amino}-7-
methoxyquinoline-3-carboxamide
6-[(2,2-dimethoxyethyl)amino]-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-
carboxamide
10 6-[(3,3-iemoxypropyl)amino]-2-[(2-thylphenyl)amino]-7-methoxyquinoline-3-
carboxamide
tert-butyl [2-({ 3-arninocarbonyl)-4-[(2-ethylphenyl)amino]-7-methoxyquinolin-6-
yl} amino)ethyl]carbamate
tert-butyl {2-[(3-(aminocarbonyl)-4-{[2-ethyl-3-(hydroxymethyl)phenyl]amino}-7-
15 methoxyquinolin-6-yl)amino]ethyl}carbamate
6-{[3-(cyclopropylanuno)propyl]amino}-4-[(2-ethylphenyl)amino]-7-methoxyquinoline-3-
carboxamide
4-(2,3-dihydro-1 H-inden-1 -ylamino)-6,7-dimethoxyquinoline-3-carboxamide
6,7-diethoxy-4-[(2-methyIcyclohexyl)amino]quinoline-3-carboxamide
20 4- {[(3S)-1 -(cyanoacetyl)pyrrolidin-3-yl]amino} -6,7-dimethoxyquinoline-3-carboxamide
4-{[(3S)-l-(cyanoacetyl)piperidin-3-yl]amino}-6,7-dimethoxyquinoline -3-carboxamide
or a pharmaceutically acceptable salt or solvate thereof.
15. A pharmaceutical composition compr15ing a compound as claimed in any one of claims
25 1 to14, or a pharmaceutically acceptable salt thereof, in assoC1ation with a pharmaceutically
acceptable adjuvant, diluent or carrier.
16. A process for the preparation of a pharmaceutical composition as claimed in claim 15
which compr15es mixing a compound as defined in any one of claims 1 to 14 or a
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pharmaceutically acceptable salt thereof ,with a pharmaceutically acceptable adjuvant, diluent or carrier.
17. A compound as claimed in any one of claims 1 to 14 or a pharmaceutically acceptable
5 salt thereof for use in therapy.
18. A compound as claimed in any one of claims 1 to 14 or a pharmaceutically acceptable
salt thereof, for use in treating a d15ease or condition mediated by JAK3 .
10 19. Use of a compound, as claimed in any one of claims 1 to14 or a pharmaceutically
acceptable salt thereof in the manufacture of a medicament for use in the treatment of organ transplant rejection, lupus, multiple scleros15, rheumatoid arthrit15, psorias15, Type I diabetes and complications from diabetes, cancer, asthma, rhinit15, atopic dermatit15, autoimmune thyroid d15orders, ulcerative colit15, Crohn's d15ease, Alzheimer's d15ease, leukemia, and
15 other autoimmune d15eases.
20. Use according to claim 19 in the manufacture of a medicament for the treatment of asthma, host versus graft rejection/transplantation or rheumatoid arthrit15.
20 21. A method of treating a d15ease or condition mediated by JAK3 which compr15es
admin15tering to a patient in need of such treatment a therapeutically effective amount of a compound as claimed in any of claims 1 to 14 or a pharmaceutically acceptable salt thereof
22. A method according to claim 21 in which the d15ease or condition 15 asthma, host versus
25 graft rejection/transplantation or rheumatoid arthrit15.
23. A process for preparing a compound of formula (I) as defined in claim 1 or a
pharmaceutically acceptable salt thereof, which compr15es:
30 (a) reaction of a compound of formula (II):
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in which R and R are as defined in claim 1 or are protected derivatives thereof and R 1s a
5
leaving group, with a compound of formula (HI):
RX-NH2
(III)
in which RK 15 as defined for formula (I) for claim l or a protected derivative thereof, or 10 (b) for compounds of formula (I) where R1 and/or R2 are groups Y(CR32)PNR4R5,
Y(CR32)pCONR4Rs, Y(CR3)pC02R6, Y(CR32)pOR6 or Y(CR32)pR6 where Y 15 oxygen and R3,R4,RsandR6 are as defined in claim 1, reaction of a compound of formula (TV):
m
15 (IV)
where the R1' or R2' to be converted into a group Y(CR32)pNR4Rs, Y(CR32)pCONR4R5, Y(CR3)pC02R6, Y(CR32)POR6 or Y(CR32)pR6 15 hydroxy and the other R1 or R2' together with Rx are as defined above for process (a) with a compound of formula (V):
20
L-(CR32)pR21 (V)
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where R21 15 NR4R5, CONR4, C02R6, OR6 or R6 and R4, R5 and R6 are as defined in formula (I) in claim 1 or are protected derivatives thereof,
and optionally thereafter process (a) or (b)
5 • removing any protecting groups
• converting a compound of formula (I) into a further compound of formula (I)
• forming a pharmaceutically acceptable salt or solvate.
24. A compound of formula and/or a pharmaceutical composition and/or a process for preparation and/or use of a compound and/or a method of treating substantially as herein described with reference to the given examples.
Dated th15 the 28th day of August, 2006.
ABSTRACT
The present invention relates to novel compounds which are JAK3 Kinase inhibitors, methods for their preparation and pharmaceutical compositions compr15ing them. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X is –CHOH or-C=0;
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