US2012184523A1PendingUtilityA1
C-Met Modulators and Method of Use
Est. expirySep 26, 2023(expired)· nominal 20-yr term from priority
Inventors:Lynne Canne BannenDiva Sze-Ming ChanJeff ChenLisa Esther DalrympleTimothy Patrick ForsythTai Phat HuynhVasu JammalamadakaRichard George KhouryJames William LeahyMorrison B. MacGrace MannLarry W. MannJohn M. NussJason Jevious ParksCraig Stacy TakbuchiYong WangWei Xu
A61P 9/00A61P 9/10A61P 35/02A61P 43/00A61P 37/00A61P 3/10A61P 35/00A61P 37/02A61P 37/08A61P 37/06A61P 25/00A61P 29/00A61P 27/02A61P 1/00A61P 19/00A61P 17/06A61P 19/02A61P 1/04A61P 17/02C12Q 1/485A61K 31/505C07D 413/14C07D 417/12A61K 31/4709A61K 31/4725A61K 31/517A61K 31/501A61K 31/506C07D 215/38C07D 403/12A61K 31/5377C07D 215/22C07D 215/36C07D 413/12A61K 31/496C07D 405/14C07D 215/46C07D 239/94C07D 239/88C07D 295/15C07D 215/233C07D 401/12A61K 31/47G01N 2500/04C07D 401/14Y02A50/30
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Claims
Abstract
The present invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. More specifically, the invention provides quinazolines and quinolines which inhibit, regulate, and/or modulate kinase receptor, particularly c-Met, KDF, c-Kit, flt-3 and flt-4, signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions. The present invention also provides methods for making compounds as mentioned above, and compositions which contain these compounds.
Claims
exact text as granted — not AI-modified1 . A compound of formula I,
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein,
R 1 is selected from —H, halogen, —OR 3 , —NO 2 , —NH 2 , —NR 3 R 4 and optionally substituted lower alkyl;
A 1 is selected from ═N— and ═C(H)—;
Z is —O—;
Ar is either a group of formula II, or of formula III,
wherein,
R 2 is selected from —H, halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 4 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 and optionally substituted lower alkyl;
q is 0 to 4;
G is selected from:
each E is selected from —O—, —N(R 13 )—, —CH 2 — and —S(O) 0-2 —;
M is selected from —O—, —N(R 13 )—, —CH 2 — and —C(═O)N(R 13 )—;
each V is independently either ═N— or ═C(H)—;
each methylene in any of the above formulae is independently optionally substituted with one or two R 25 ;
R 25 is selected from halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 4 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl and optionally substituted lower alkyl; or two of R 25 , together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic; or two of R 25 on a single carbon can be oxo;
J is selected from —S(O) 0-2 —, —O—, and —NR 15 —;
R 3 is —H or R 4 ;
R 4 is selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl and optionally substituted lower heterocyclylalkyl; or
R 3 and R 4 , when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S and P;
A 2 and A 3 are each independently selected from ═N— and ═C(R 2 )—;
D is selected from —O—, —S(O) 0-2 — and —NR 15 —;
R 50 is R 3 ;
R 13 is selected from —H, —C(═O)R 3 , —C(═O)OR 3 , —C(═O)SR 3 , —SO 2 R 4 , —C(═O)N(R 3 )R 3 and optionally substituted lower alkyl; or, two R 13 , together with the atom or atoms to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R 60 , said heteroalicyclic can have up to four annular heteroatoms, and said heteroalicyclic can have an aryl or heteroaryl fused thereto, in which case said aryl or heteroaryl is optionally substituted with an additional one to four of R 60 ;
R 14 is selected from —H, —NO 2 , —NH 2 , —N(R 3 )R 4 , —CN, —OR 3 , optionally substituted lower alkyl, optionally substituted heteroalicyclylalkyl, optionally substituted aryl, optionally substituted arylallyl and optionally substituted heteroalicyclic;
R 15 is a group -M 1 -M 2 , wherein M 1 is selected from absent, —C(═S)N(R 13 )—, —C(═NR 14 )N(R 13 )—, SO 2 N(R 13 )—, —SO 2 —, —C(═O)N(R 13 )—, —C(═O)C(═O)N(R 13 )—, —C 0-4 alkylene-, —C(═O)— and an optionally substituted four to six-membered heterocyclyl annular containing between one and three heteratoms including at least one nitrogen; and M 2 is selected from —H, —C 0-6 alkyl, alkoxy, —C(═O)C 0-4 alkylQ, —C 0-4 alkylQ, —OC 0-4 alkylQ-, —N(R 13 )C 0-4 alkylQ- and —C(═O)N(R 13 )C 0-4 alkylQ;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R 20 ;
R 20 is selected from —H, halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 4 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 and optionally substituted lower alkyl; and
R 60 is selected from —H, halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 4 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl and optionally substituted arylalkyl; or two of R 60 , when attached to a non-aromatic carbon, can be oxo;
with the proviso that the conditions of:
Z is —O—;
Ar is according to formula II; and
the portion of G directly attached to Ar selected from the table below:
are not met at the same time; and
with the proviso that when Ar is phenylene or substituted phenylene, then the portion of G directly attached to Ar cannot contain
wherein R 70 is selected from —H, C 1-4 alkyl, and C 1-4 alkoxyl.
2 . The compound according to claim 1 , wherein Ar is according to one of formula IIa, IIb) and IIa:
3 . The compound according to claim 1 , wherein A 1 is ═C(H)—.
4 . The compound according to claim 2 , wherein Ar is of formula IIa and A 1 is ═N—.
5 . The compound according to claim 2 , wherein D is —O— and R 1 is —OR 3 .
6 . The compound according to claim 5 , wherein —O—R 50 and R 1 are interchangeably located at the 6-position and 7-position of the quinazoline or quinoline according to formula I.
7 . The compound according to claim 6 , wherein R 1 is —OH or —OC 1-6 alkyl.
8 . The compound according to claim 7 , wherein G is selected from:
wherein Q, R 13 , E and R 60 are as defined above; each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with one or two R 25 ; and R 25 is selected from halogen, trihalomethyl, oxo, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 4 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl and optionally substituted lower alkyl; or two of R 25 , together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic.
9 . The compound according to claim 8 , wherein Q is selected from:
wherein R 20 is defined as above, and P is a five- to seven-membered ring, including the two shared carbons of the aromatic ring to which P is fused, P optionally containing between one and three heteroatoms.
10 . The compound according to claim 9 , wherein Ar is according to formula IIb, and G is selected from:
wherein Q, R 13 , E, and R 60 are as defined above, and each methylene in any of the above formulae, other than those depicted in a ring, is independently optionally substituted with one or two R 25 ; and R 25 is selected from halogen, trihalomethyl, oxo, —CN, —NO 2 , —NH 2 , —OR 3 , NR 3 R 4 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl and optionally substituted lower alkyl; or two of R 25 , together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic.
11 . The compound according to claim 10 , wherein the methylene between the two carbonyls of G is di-substituted with either optionally substituted lower alkyl, or an optionally substituted spirocycle.
12 . The compound according to claim 10 , wherein R 50 is a heteroalicylic or a C 1-6 alkyl-heteroalicylic.
13 . The compound according to claim 12 , wherein at least one of R 2 is halogen.
14 . The compound according to claim 1 , selected from one of the following compounds:
Name
Structure
N-{[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)(methyl)amino] carbonothioyl}-2- phenylacetamide
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl) imidazolidin-2-one
N′-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N- methyl-N-(2- phenylethyl)sulfamide
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)piperidin-2-one
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-4- phenyl-1,3-thiazol-2-amine
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N- (phenylmethyl) benzenesulfonamide
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-(2- phenylethyl) benzenesulfonamide
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-(3- phenylpropyl) benzenesulfonamide
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl (phenylmethyl)carbamate
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-methyl-N- (3-phenylpropyl) benzenesulfonamide
N-[(Z)-[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)amino](imino) methyl]-2-phenylacetamide
N,N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-bis- (3-phenylpropane-1- sulfonamide)
N2-[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)sulfonyl]-N1- phenylglycinamide
N-{[(6-{[6,7- bis (methyloxy)quinolin-4- yl]oxy}pyridin-3- yl)amino]carbonothioyl}-2- phenylacetamide
6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-amine
benzyl-{[4-(6,7-dimethoxy- quinolin-4-yloxy)-3-fluoro- phenylcarbamoyl]-methyl}- carbamic acid tert-butyl ester
N2-acetyl-N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- (phenylmethyl)glycinamide
benzyl-{[6-(6,7-dimethoxy- quinolin-4-yloxy)-pyridin-3- ylcarbamoyl]-methyl}- carbamic acid tert-butyl ester
N2-acetyl-N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-N2- (phenylmethyl)glycinamide
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-4- phenylbutanamide
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- methyl-N2- (phenylmethyl)glycinamide
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-3- phenylpropanamide
N′-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N- (2-phenylethyl)-N- (phenylmethyl)sulfamide
N-{[4-(6,7-dimethoxy- quinolin-4-yloxy)-3-fluoro- phenylcarbamoyl]-methyl}- benzamide
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N,N′- bis(phenylmethyl)sulfamide
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N′-(4- fluorophenyl)propanediamide
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3- [(4-methylphenyl)sulfonyl]-4- (phenylmethyl)imidazolidin- 2-one
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-2-[3-(trifluoromethyl) phenyl]acetamide
6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-(2- piperidin-1-ylethyl)-1,3- benzothiazol-2-amine
6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-(2- pyrrolidin-1-ylethyl)-1,3- benzothiazol-2-amine
6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-{2-[3- (trifluoromethyl)phenyl]ethyl}- 1,3-benzothiazol-2-amine
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2-[3- (trifluoromethyl) phenyl]acetamide
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- (2-phenylethyl)glyeinamide
benzyl-{[5-chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)- pyridin-3-ylcarbamoyl]- methyl}-carbamic acid tert- butyl ester
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2-[3,5- bis(trifluoromethyl) phenyl]acetamide
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- methyl-N2-{[3- (trifluoromethyl) phenyl]methyl}glycinamide
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- methyl-N2-(2- phenylethyl)glycinamide
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridazin-3-yl)-N′-(4- fluorophenyl)propanediamide
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N′-(3- chlorophenyl)propanediamide
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N′-(4- chlorophenyl)propanediamide
(2E)-N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-2- [(ethyloxy)imino] propanamide
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-1- (phenyhnethyl)prolinamide
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-4- (phenylmethyl) imidazolidin-2-one
6,7-bis(methyloxy)-4-({4-[4- (phenylmethyl)piperazin-1- yl]phenyl}oxy)quinoline
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2- (phenylmethyl)alaninamide
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2- (phenylmethyl)leucinamide
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2- (phenylmethyl)valinamide
2-(Benzyl-methyl-amino)-N- [4-(6,7-dimethoxy-quinolin-4- yloxy)-phenyl]-3-methyl- butyramide (note: Alphabetic order of prefixes ignored while selecting parent chain)
2-Benzyloxyimino-N-[4-(6,7- dimethoxy-quinolin-4-yloxy)- phenyl]-2-phenyl-acetamide
4-(4-{3-Chloro-5-[2-(4- fluoro-phenylcarbamoyl)- acetylamino]-pyridin-2- yloxy}-6-methoxy-quinolin-7- yloxymethyl)-piperidine-1- carboxylic acid tert-butyl ester
N-{5-Chloro-6-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-pyridin-3-yl}-N′-(4- fluoro-phenyl)-malonamide
N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)- pyridin-3-yl]-N′-(2,4-difluoro- phenyl)-malonamide
N-{5-Chloro-6-[6-methoxy-7- (3-piperidin-1-yl-propoxy)- quinolin-4-yloxy]-pyridin-3- yl}-N′-(4-fluoro-phenyl)- malonamide
N-{5-Chloro-6-[7-(3- diethylamino-propoxy)-6- methoxy-quinolin-4-yloxy]- pyridin-3-yl}-N′-(4-fluoro- phenyl)-malonamide
N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)- pyridin-3-yl]-N′-phenyl- malonamide
15 . A compound of formula A-B-C, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein:
A is selected from:
B is selected from:
and
C is selected from:
wherein:
R 2 is selected from —H, halogen, trihalomethyl, —CN, —NH 2 , —NO 2 , —OR 3 , —NR 3 R 3 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 and optionally substituted lower alkyl;
q is 0 to 2;
each R 3 is independently selected from —H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heteroarylalkyl; or, two R 3 , together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from —H, trihalomethyl, —SO 2 R 5 , —SO 2 NR 5 R 5 , —CO 2 R 5 , —C(O)NR 5 R 5 , —C(O)R 5 and optionally substituted lower alkyl;
each R 35 is independently selected from —H, —C(═O)R 3 , —C(═O)OR 3 , —C(═O)SR 3 , —SO 2 R 3 , —C(═O)N(R 3 )R 3 , and optionally substituted lower alkyl; or, two R 35 , together with the nitrogen to which they are attached, can combine to form a heteroalicyclic optionally substituted with between one and four of R 60 , said heteroalicyclic may have an additional annular heteroatom, and said heteroalicyclic may have an aryl fused thereto, said aryl optionally substituted with an additional one to four of R 60 ;
A 1 is selected from ═N— and ═C(H)—;
A 2 is either N— or ═C(H)—;
R 5 is —H or optionally substituted lower alkyl;
R 8 is selected from R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —SO 2 R 3 and —C(O)R 3 , or an R 8 is absent and the alkylene linker of A is covalently bonded to the nitrogen atom in which R 8 is absent;
E 1 is selected from —O—, —CH 2 —, —N(R 5 )— and —S(O) o-2 —;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R 20 ;
R 20 is selected from —H, halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 3 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 and optionally substituted lower alkyl;
R 60 is selected from —H, halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 3 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroarylalkyl and optionally substituted arylalkyl; or, two of R 60 , when attached to a non-aromatic carbon, can be oxo;
each methylene in any of the above formulae is independently optionally substituted with one or two R 25 ; and
each R 25 is independently selected from halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 3 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted aryl, optionally substituted arylalkyl, heteroarylalkyl and optionally substituted lower alkyl; or two of R 25 , together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic; or two of R 25 on a single carbon can be oxo;
with the proviso that the conditions of:
C contains
and
the remaining portion of C contains one of:
are not met at the same time; and
with the proviso that when C contains
directly attached to
and R 70 is selected from —H, C 1-4 alkyl, and C 1-4 alkoxyl, then A 2 is N.
16 . The compound according to claim 15 , wherein Q is selected from phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, benzothieliyl and oxadiazolyl; each optionally substituted with between one and four of R 20 ; wherein each R 20 is independently selected from —H, halogen, trihalomethyl, —CN, —NO 2 , —OR 3 , —NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 and optionally substituted lower alkyl.
17 . The compound according to claim 16 , wherein B is:
wherein A 1 is ═N— or ═C(H)—.
18 . The compound according to claim 17 , wherein R 3 is methyl.
19 . The compound according to claim 18 , wherein C is selected from:
20 . The compound according to claim 19 , wherein R 2 is selected from halogen, trihalomethyl, —CN, —NO 2 , —OR 3 , —NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 and optionally substituted lower alkyl.
21 . The compound according to claim 20 , wherein R 2 is halogen.
22 . The compound according to claim 21 , wherein R 2 is fluorine or chlorine.
23 . A compound according to Formula XI,
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, wherein:
each R 1 is independently selected from halogen, —OR 3 , —NO 2 , —NH 2 , —NR 3 R 4 , -D-R 50 and optionally substituted C 1-6 alkyl;
Q is selected from ═N— or ═C(H)—;
Z is —O—;
Ar is either a five- or six-membered arylene or a five- or six-membered heteroarylene containing between one and three heteroatoms;
G is either an optionally substituted cycloalkyl or an optionally substituted heteroalicyclic;
each R 2 is independently selected from halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 4 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 and optionally substituted C 1-6 alkyl;
each R 3 is independently —H or R 4 ;
each R 4 is independently selected from optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted aryl C 1-6 alkyl, optionally substituted heterocyclyl and optionally substituted heterocyclyl C 1-6 alkyl; or
R 3 and R 4 , when taken together with a common nitrogen to which they are attached, form an optionally substituted five- to seven-membered heterocyclyl, said optionally substituted five- to seven-membered heterocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S and P;
R 5 is —H or optionally substituted C 1-6 alkyl;
each D is independently selected from —O—, —S(O) 0-2 - and —NR S —;
each R 30 is independently selected from halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 4 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 and optionally substituted C 1-6 alkyl;
each R 50 is R 3 ; and
R 70 is selected from —H, halogen, —OR 3 , —S(O) 0-2 R 3 , —NO 2 , —NH 2 , —NR 3 R 4 and optionally substituted C 1-6 alkyl.
24 . The compound according to claim 23 , wherein R 70 is hydrogen.
25 . The compound according to claim 24 , wherein at least one of R 1 is -D-R 50 .
26 . The compound according to claim 25 , wherein D is —O— and at least one other R 1 is −OR 3 .
27 . The compound according to claim 26 , of formula XIIIa or XIIIb:
wherein Q 1 is either ═N— or ═C(H)—, R 3a is C 1-6 alkyl, and —N(R 3b )R 4 is selected from the following:
wherein:
J is a five- to ten-membered ring, optionally substituted with between zero and five of R 20 , wherein each R 20 is independently selected from —H, halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 4 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted aryl C 1-6 alkyl, optionally substituted heterocyclyl and optionally substituted heterocyclyl C 1-6 alkyl, or two of R 20 , together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either spiro- to J or fused to J;
E is selected from —O—, —N(R 5 )—, —CH 2 — and —S(O) 0-2 —;
each R 60 is independently selected from halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 4 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl C 1-6 alkyl and optionally substituted aryl C 1-6 alkyl;
each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with one or two R 25 , wherein R 25 is selected from halogen, trihalomethyl, oxo, —CN, —NO 2 , —NH 2 , —OR, —NR 3 R 4 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , optionally substituted aryl, optionally substituted aryl C 1-6 alkyl, heteroaryl C 1-6 allyl and optionally substituted C 1-6 alkyl; or two of R 25 , together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered alicyclic or heteroalicyclic; and
R 3b has the same meaning as R 3 .
28 . The compound according to claim 27 , wherein R 50 is selected from C 1-6 alkyl optionally substituted with at least one of optionally substituted amino, optionally substituted C 1-6 alkyl amino, optionally substituted C 1-6 dialkyl amino, optionally substituted heteroalicylic and a group of formula XII.
29 . The compound according to claim 28 , wherein G is selected from cyclopropyl, aziradine, cyclobutyl and azetidine, each optionally substituted with between zero and four of R 30 .
30 . The compound according to claim 29 , wherein R 2 is selected from —H, halogen, C 1-6 alkyl and perfluoro C 1-6 alkyl.
31 . The compound of claim 23 , wherein (R 30 ) 0-4 is (R 30 ) 0 or methyl.
32 . The compound according to claim 30 , of formula XIVa or XIVb:
wherein R 50 is C 1-6 alkyl substituted with a group selected from optionally substituted amino, optionally substituted alkylamino, optionally substituted dialkylamino and optionally substituted heteroalicylic.
33 . The compound according to claim 32 , wherein Q is —CH═.
34 . The compound according to claim 33 , wherein the heteroalicyclic portion of R 50 is selected from piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, 2-oxo-morpholine, pyrrolidine and azepine.
35 . The compound according to claim 33 , wherein (R 30 ) 0-4 is (R 30 ) 0 or methyl.
36 . The compound according to claim 33 or 34 , wherein R 2 is selected from C 1-6 alkyl, perfluoro C 1-6 alkyl, hydrogen and halogen.
37 . The compound according to claim 34 , wherein R 2 is halogen.
38 . The compound according to claim 34 , wherein R 2 is hydrogen.
39 . The compound according to claim 33 or 34 , wherein R 20 is selected from halogen, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 4 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , optionally substituted heterocyclyl and optionally substituted heterocyclyl C 1-6 alkyl, and (two of R 20 ) together with the atom or atoms to which they are attached, an optionally substituted three- to six-membered heteroalicyclic, said optionally substituted three- to six-membered heteroalicyclic fused to the phenyl as in XIVa or XIVb.
40 . The compound according to claim 39 , wherein R 20 is selected from halogen, —NR 3 R 4 , optionally substituted heterocyclyl and optionally substituted heterocyclyl C 1-6 alkyl, and (two of R 20 ) together with the atom or atoms to which they are attached, an optionally substituted five- to six-membered heteroalicyclic, said optionally substituted five- to six-membered heteroalicyclic fused to the phenyl as in XIVa or XIVb.
41 . The compound according to claim 40 , wherein R 2 is selected from C 1-6 alkyl, perfluoro C 1-6 alkyl and halogen.
42 . The compound according to claim 41 , wherein R 2 is selected from perfluoro C 1-3 alkyl and halogen.
43 . The compound according to claim 23 selected from the following:
Name
Structure
1,1-dimethylethyl 4-(3- {[4-[(2-fluoro-4-{[(1- {[(4- fluorophenyl)amino]carbon- yl}cyclopropyl)carbonyl] amino}phenyl)oxy]-6- (methyloxy)quinolin-7- yl]oxy}propyl)piperazine- 1-carboxylate
N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6- (methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-{[7-{[3-(4- acetylpiperazin-1- yl)propyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(3-fluoro-4-{[7-({3-[4- (1-methylethyl)piperazin- 1-yl]propyl}oxy)-6- (methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6- (methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide
N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide
(1R,2R,3S)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide
N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide
N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6- (methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide
N-(4-{[7-{[3- (diethylamino)propyl]oxy} 6- (methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperazin-1- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperidin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperidin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-{5-chloro-6-[(6- (methyloxy)-7-{[(1- methylpiperidin-4- yl)methyl]oxy}quinolin- 4-yl)oxy]pyridin-3-yl}- N′-(4 fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-[5-chloro-6-({6- (methyloxy)-7- [(piperidin-4- ylmethyl)oxy]quinolin-4- yl}oxy)pyridin-3-yl]-N′- (4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-[5-chloro-6-({6- (methyloxy)-7- [(phenylmethyl)oxy] quinolin-4-yl}oxy)pyridin-3- yl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
N-{3-fluoro-4-[(6- (methyloxy)-7-{[(1- methylpiperidin-4- yl)methyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-fluorophenyl)-N′-[2- methyl-6-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)pyridin-3- yl]cyclopropane-1,1- dicarboxamide
N-[3-fluoro-4-({7- (methyloxy)-6-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-[3-fluoro-4-({7- (methyloxy)-6-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-{3-fluoro-4-[(6- (methyloxy)-7-(2-methyl octahydrocyclo- penta[c]pyrrol-5- ylmethoxy)quinazolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-{3-fluoro-4-[(7- (methyloxy)-6-{[(1- methylpiperidin-4- yl)methyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-[5-fluoro-2-methyl-4- ({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-fluorophenyl)-N′-[2- methyl-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]cyclopropane- 1,1-dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperazin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-{3-fluoro-4-[(6- (methyloxy)-7-{[(1- methylpiperidin-4- yl)methyl]oxy}quinolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-fluorophenyl)-N′-[4- ({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]cyclopropane- 1,1-dicarboxamide
N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-{[6-{[3- (diethylamino)propyl]oxy}- 7-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-{[6-{[2- (diethylamino)ethyl]oxy}- 7-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
44 . The compound according to claim 23 selected from the following:
(1S,2R)-N-[3-fluoro-4-({6- (methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4-fluorophenyl)- 2-methylcyclopropane-1,1- dicarboxamide
(1R,2R)-N-[3-fluoro-4-({6- (methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4-fluorophenyl)- 2-methylcyclopropane-1,1- dicarboxamide
(1R,2R)-N-[3-fluoro-4-({6- (methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinazolin-4- yl}oxy)phenyl]-N′-(4-fluorophenyl)- 2-methylcyclopropane-1,1- dicarboxamide
(1R,2R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6- (methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
1,1-dimethylethyl 4-(3-{[4-[(2-fluoro- 4-{[((1R,2R)-1-{[(4- fluorophenyl)amino]carbonyl}-2- methylcyclopropyl)carbonyl]amino} phenyl)oxy]-6-(methyloxy)quinolin- 7-yl]oxy}propyl)piperazine-1- carboxylate
(1R,2R)-N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4-fluorophenyl)- 2-methylcyclopropane-1,1- dicarboxamide
(1R,2R)-N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4-fluorophenyl)- 2-methylcyclopropane-1,1- dicarboxamide
(1R,2R)-N-{3-fluoro-4-({6- (methyloxy)-7-[(3-piperazin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4-fluorophenyl)- 2-methylcyclopropane-1,1- dicarboxamide
(1R,2R)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R,2R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R,2S)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R,2S)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R,2S)-N-{3-fluoro-4-({6- (methyloxy)-7-[(3-piperazin-1- yl)propyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4-fluorophenyl)- 2-methylcyclopropane-1,1- dicarboxamide
(1R,2R,3S)-N-[3-fluoro-4-({6- (methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4-fluorophenyl)- 2,3-dimethylcyclopropane-1,1- dicarboxamide
(1R,2R,3S)-N-[3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4-fluorophenyl)- 2,3-dimethylcyclopropane-1,1- dicarboxamide
(1R,2R,3S)-N-[3-fluoro-4-({6- (methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinazolin-4- yl}oxy)phenyl]-N′-(4-fluorophenyl)- 2,3-dimethylcyclopropane-1,1- dicarboxamide
(1R,2R,3S)-N-[3-fluoro-4-[(6- (methyloxy)-7-{[3-(4-ethylpiperazin- 1-yl)propyl]oxy}quinazolin-4- yl)oxy]phenyl}-N′-(4-fluorophenyl)- 2,3-dimethylcyclopropane-1,1- dicarboxamide
(2R,3R)-N-[3-fluoro-4-({6- (methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4-fluorophenyl)- 2,3-dimethylcyclopropane-1,1- dicarboxamide
(2R,3R)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)- 2,3-dimethylcyclopropane-1,1- dicarboxamide
(1R,2R,3S)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)- 2,3-dimethylcyclopropane-1,1- dicarboxamide
(2R,3R)-N-[3-fluoro-4-({6- (methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinazolin-4- yl}oxy)phenyl]-N′-(4-fluorophenyl)- 2,3-dimethylcyclopropane-1,1- dicarboxamide
(1R,2R)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R,2R)-N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinazolin-4- yl)oxy]phenyl}-N′-(4-fluorophenyl)- 2-methylcyclopropane-1,1- dicarboxamide
(2R,3R)-N-(4-{[7-{[2- (diethylamino)propyl]oxy}-6- (methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)- 2,3-dimethylcyclopropane-1,1- dicarboxamide
(2R,3R)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)- 2,3-dimethylcyclopropane-1,1- dicarboxamide
(1R,2R)-N-{3-fluoro-4-[(6- (methyloxy)-7-[(3-piperazin-1- ylpropyl)oxy]quinazolin-4- yl}oxy)phenyl]-N′-(4-fluorophenyl)- 2-methylcyclopropane-1,1- dicarboxamide
(2R,3R)-N-(4-{[7-{[2- (diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)- 2,3-dimethylcyclopropane-1,1- dicarboxamide
45 . The compound according to claim 33 selected from the following:
Name
Structure
N-(3-fluoro-4-{[7-({3-[4-(1- methylethyl)piperazin-1- yl]propyl}oxy)-6- (methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
(1R-2R)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R-2R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R-2S)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R-2S)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R-2S)-N-[3-fluoro-4-({6- (methyloxy)-7-[(3-piperazin- 1-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R,2R,3S)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,3- dimethylcyclopropane-1,1- dicarboxamide
(1R,2R,3S)-N-{3-fluoro-4- [(6-(methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)-2,3- dimethylcyclopropane-1,1- dicarboxamide
(2R,3R)-N-[3-fluoro-4-({6- (methyloxy)-7-[(3-morpholin- 4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,3- dimethylcyclopropane-1,1- dicarboxamide
(2R,3R)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4-fluorophenyl)-2,3- dimethylcyclopropane-1,1- dicarboxamide
N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4-fluorophenyl)-2,2- dimethylcyclopropane-1,1- dicarboxamide
(1R,2R,3S)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4-fluorophenyl)-2,3- dimethylcyclopropane-1,1- dicarboxamide
N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4-fluorophenyl)-2,2- dimethylcyclopropane-1,1- dicarboxamide
(1R,2R,3S)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4-fluorophenyl)-2,3- dimethylcyclopropane-1,1- dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3-morpholin- 4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,2- dimethylcyclopropane-1,1- dicarboxamide
(2R,3R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4-fluorophenyl)-2,3- dimethylcyclopropane-1,1- dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3-morpholin- 4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3-piperidin- 1-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-{5-chloro-6-[(6- (methyloxy)-7-{[(1- methylpiperidin-4- yl)methyl]oxy}quinolin-4- yl)oxy]pyridin-3-yl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-[5-chloro-6-({6- (methyloxy)-7-[(piperidin-4- ylmethyl)oxy]quinolin-4- yl}oxy)pyridin-3-yl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-[5-chloro-6-({6- (methyloxy)-7- [(phenylmethyl)oxy]quinolin- 4-yl}oxy)pyridin-3-yl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-fluorophenyl)-N′-[2- methyl-6-({6-(methyloxy)-7- [(3-morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)pyridin-3- yl]cyclopropane-1,1- dicarboxamide
N-[3-fluoro-4-({7- (methyloxy)-6-[(3-morpholin- 4-ylpropyl)oxy]quinolin-4- yl}oxyphenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-{3-fluoro-4-[(6- (methyloxy)-7-(2- methyloctahydrocyclo- penta[c]pyrrolo-5- ylmethoxy)quinazolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-[5-fluoro-2-methyl-4-({6- (methyloxy)-7-[(3-morpholin- 4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-fluorophenyl)-N′-[2- methyl-4-({6-(methyloxy)-7- [(3-morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]cyclopropane- 1,1-dicarboxamide
N-[3-fluoro-4-({6- (methyloxy)-7-[(3-piperazin- 1-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-{3-fluoro-4-[(6- (methyloxy)-7-{[(1- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-fluorophenyl)-N′-[4-({6- (methyloxy)-7-[(3-morpholin- 4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]cyclopropane- 1,1-dicarboxamide
N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
(1S,2R)-N-[3-fluoro-4-({6- (methyloxy)-7-[(3-morpholin- 4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R-2R)-N-[3-fluoro-4-({6- (methyloxy)-7-[(3-morpholin- 4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
N-(4-{[6-{[3- (diethylamino)propyl]oxy}-7- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
N-(4-{[6-{[2- (diethylamino)ethyl]oxy}-7- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
1,1-dimethylethyl 4-(3-{[4- [(2-fluoro-4-{[(1-{[(4- fluorophenyl)amino]carbonyl} cyclopropyl)carbonyl]amino} phenyl)oxy]-6- (methyloxy)quinolin-7- yl]oxy}propyl)piperazine-1- carboxylate
N-(4-{[7-{[3-(4- acetylpiperazin-1- yl)propyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
1,1-dimethylethyl 4-(3-{[4- [(2-fluoro-4-{[((1R,2R)-1- {[(4-fluorophenyl)amino] carbonyl}-2- methylcyclopropyl)carbonyl] amino}phenyl)oxy]-6- (methyloxy)quinolin-7- yl]oxy}propyl)piperazine-1- carboxylate
(1S-2S)-N-[3-fluoro-4-({6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy[phenyl}-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R-2R)-N-[3-fluoro-4-({6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
(1R-2R)-N-[3-fluoro-4-({6- (methyloxy)-7-{[3-piperazin- 1-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide
46 . A pharmaceutical composition comprising a compound according to claim 1 , 15 or 23 , and a pharmaceutically acceptable carrier.
47 . A metabolite of the compound according to claim 1 , 15 or 23 .
48 . A method of modulating the in vivo activity of a kinase, the method comprising administering to a subject a therapeutically effective amount of the compound according to claim 1 , 15 or 23 , or a composition containing a therapeutically effective amount of the compound.
49 . The method according to claim 48 , wherein modulating the in vivo activity of the kinase comprises inhibition of said kinase.
50 . The method according to claim 49 , wherein the kinase is at least one of c-Met, KDR, c-Kit, flt-3, and flt-4.
51 . The method according to claim 50 , wherein the kinase is c-Met.
52 . A method of treating diseases or disorders associated with uncontrolled, abnormal, and/or unwanted cellular activities, the method comprising administering, to a mammal in need thereof, a therapeutically effective amount of the compound according to claim 1 , 15 or 23 , or a composition containing a therapeutically effective amount of the compound.
53 . A method of screening for a modulator of a kinase, said kinase selected from c-Met, KDR, c-Kit, flt-3, and flt-4, the method comprising comparing the kinase modulating activity of a compound according to claim 1 , 15 or 23 with the modulating activity of at least one candidate agent, and determining the relative effect of the candidate agent on the activity of said kinase.
54 . A method of inhibiting proliferative activity in a cell, the method comprising administering an effective amount of a composition comprising a cell proliferation inhibiting-effective amount of a compound according to claim 1 , 15 or 23 to a cell or a plurality of cells.Cited by (0)
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