US2020331860A1PendingUtilityA1
C-Met Modulators and Methods 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 TakeuchiYong WangWei Xu
C07D 215/22A61P 19/00C07D 215/46A61P 17/06C07D 215/36C07D 401/14A61P 25/00C07D 239/94A61K 31/5377A61P 37/00C07D 295/15C07D 215/233C07D 401/12A61K 31/501A61P 17/02A61P 1/04A61K 31/47C12Q 1/485C07D 413/12C07D 413/14A61K 31/4709A61P 37/06A61P 35/00A61P 37/08A61P 19/02A61P 27/02A61P 37/02A61K 31/496C07D 239/88A61P 29/00C07D 405/14A61K 31/517A61K 31/506C07D 215/38A61P 9/10A61P 1/00Y02A50/30C07D 403/12A61P 35/02A61K 31/505A61P 3/10C07D 417/12A61K 31/4725G01N 2500/04A61P 43/00A61P 9/00Y02A50/393
75
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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, KDR, 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-modifiedWhat is claimed is:
1 . A compound for modulating kinase activity according to 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—, ═C(H)—, and ═C(CN)—;
Z is selected from —S(O) 0-2 —, —O—, and —NR 5 —;
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 a group —B-L-T, wherein
B is selected from absent, —N(R 3 )—, —N(SO 2 R 13 )—, —O—, —S(O) 0-2 —, and —C(═O)—;
L is selected from absent, —C(═S)N(R 3 )—, —C(═NR 14 )N(R 3 )—, —SO 2 N(R 3 )—, —SO 2 —, —C(═O)N(R 13 )—, —N(R 13 )—, —C(═O)C 1-2 alkylN(R 13 )—, —N(R 13 )C 1-2 alkyC(═O)—, —C(═O)C 0-1 alkylC(═O)N(R 13 )—, —C 0-4 alkylene-, —C(═O)C 0-1 alkylC(═O)OR 3 —, —C(═NR 14 )C 0-1 alkylC(═O)—, —C(═O)—, —C(═O)C 0-1 alkylC(═O)—, and an optionally substituted four to six-membered heterocyclyl containing between one and three annular heteroatoms including at least one nitrogen; and
T is selected from —H, —R 13 , —C 0-4 alkyl, —C 0-4 alkyQ, —OC 0-4 alkylQ, —C 0-4 alkylOQ, —N(R 13 )C 0-4 alkylQ, —SO 2 C 0-4 alkylQ, —C(═O)C 0-4 alkylQ, —C 0-4 alkylN(R 13 )Q, and —C(═O)N(R 13 )C 0-4 alkylQ, wherein each of the aforementioned C 0-4 alkyl is optionally substituted;
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—, ═C(R 2 )—;
R 5 is —H or optionally substituted lower alkyl;
D is selected from —O—, —S(O) 0-2 —, and —NR 5 ;
R 50 is either R 3 , or according to formula IV;
wherein X 1 , X 2 , and optionally X 3 , represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X 1 , X 2 , and X 3 ; wherein,
each X 1 is independently selected from —C(R 6 )R 7 —, —O—, —S(O) 0-2 —, and —NR 8 ;
each X 2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen;
each X 3 is independently selected from —C(R 6 )R 7 —, —O—, —S(O) 0-2 —, and —NR 8 —;
Y is either:
an optionally substituted lower alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X 2 when X 2 is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R 6 or R 7 ; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R 6 or R 7 ;
or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is —SO 2 —, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system;
m and p are each independently 1-4;
n is 0-2, when n=0, then there is a single bond between the two bridgehead X 2 's;
R 6 and R 7 are each independently selected from —H, halogen, trihalomethyl, —CN, —NH 2 , —NO 2 , —OR 3 , —NR 3 R 4 , —S(O) 0-2 R 4 , —SO 2 NR 3 R 4 , —CO 2 R 3 , —C(O)NR 3 R 4 , —N(R 3 )SO 2 R 4 , —N(R 3 )C(O)R 3 , —NCO 2 R 3 , —C(O)R 3 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted lower arylalkyl, optionally substituted heterocyclyl, optionally substituted lower heterocyclylalkyl, and a bond to either Y or D; or
R 6 and R 7 , when taken together are oxo; or
R 6 and R 7 , when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
R 8 is selected from —R 3 , Y, —SO 2 NR 3 R 4 , —CO 2 R 4 , —C(O)NR 3 R 3 , —SO 2 R 4 , and —C(O)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)R 3 , and optionally substituted lower alkyl,
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 arylalkyl 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 hetercyclyl 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; and
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;
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;
two of R 60 , when attached to a non-aromatic carbon, can be oxo;
with the proviso, only when Ar is according to formula I, if Y is a C 1-6 alkylene; Z is —NH— or —N(CH 3 )—; R 1 is a C 1-6 alkyl optionally substituted in the 2-position by —OH or a C 1-4 alkoxy group; R 2 is —H or halogen; n=0; and the atoms, X 1 , of one bridge of the saturated bridged ring system, when combined with both bridgehead atoms, X 2 , of the saturated bridged ring system, represent:
1) either a pyrrolidine or a piperidine, and any atom, X 1 or X 2 , of either of said pyrrolidine or said piperidine is attached to Y, then the other bridge of said saturated bridged ring system cannot be any one of —OC(O)CH 2 —, —CH 2 OC(O)—, —OC(O)CH 2 CH 2 —, —CH 2 OC(O)CH 2 —, —CH 2 CH 2 OC(O)—, —OC(O)CH 2 NH—, —OC(O)CH 2 N(C 1-4 alkyl)-, and —OC(O)CH 2 O—; or
2) either a piperazine or a 4-(C 1-4 alkyl)-piperazine, and any atom, X 1 or X 2 , of either of said piperazine or said 4-(C 1-4 alkyl)-piperazine is attached to Y, then the other bridge of said saturated bridged ring system, only when attached via the 2- and the 3-position of either of said piperazine or said 4-(C 1-4 alkyl)-piperazine, cannot be one of —CH 2 OC(O)CH 2 —, —CH 2 CH 2 OC(O)—, and either of the two aforementioned bridges optionally substituted by one or two C 1-2 alkyl groups; or
3) a piperazine, and any atom, X 1 or X 2 , of said piperazine is attached to Y, then the other bridge of said saturated bridged ring system, only when attached via the 3- and the 4-position of said piperazine, cannot be one of —C(O)OCH 2 CH 2 —, —CH 2 OC(O)CH 2 —, and either of the two aforementioned bridges optionally substituted by one or two C 1-2 alkyl groups, and only when either of the two aforementioned bridges are attached to the 3-position of said piperazine via their left-hand end as depicted above; or
4) a 2-oxomorpholine, said 2-oxomorpholine attached to Y via its 4-position, then the other bridge of said saturated bridged ring system, only when attached via the 5- and the 6-position of said 2-oxomorpholine, cannot be one of —(CH 2 ) g —, —CH 2 WCH 2 —, —CH 2 WCH 2 CH 2 —, and —CH 2 CH 2 WCH 2 —, wherein W is —O—, —S(O) 0-2 —, —NH—, or —N(C 1-4 alkyl)- wherein g is 2, 3, or 4;
and with the proviso that when Z is-O—, Ar is according to formula II, and the portion of G directly attached to Ar is selected from:
then R 50 must be of formula IV;
and with the proviso that when Ar is phenylene or substituted phenylene, Z is —S(O) 0-2 — or —O—, then the portion of G directly attached to Ar cannot contain,
when R 70 is selected from —H, C 1-4 alkyl, and C 1-4 alkoxyl.
2 . The compound according to claim 1 , wherein In one example, the compound is according to paragraph [0033], wherein Z is either —O— or —NR 5 —.
3 . The compound according to claim 2 , wherein G is selected from the following:
wherein Q, R 20 , and R 13 are as defined above; 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 R 25 ; and 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; 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, two of R 25 on a single carbon can be oxo.
4 . The compound according to claim 3 , wherein Ar is according to one of formula IIa, IIb, and IIIa.
5 . The compound according to claim 4 , 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 A 1 is ═N— or ═C(H)—.
9 . The compound according to claim 8 , wherein G is selected from:
wherein Q, R 20 , 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 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; 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.
10 . The compound according to claim 9 , 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.
11 . The compound according to claim 10 , wherein Ar is according to formula IIa, and G is selected from:
wherein Q, R 20 , R 13 , E, and R 60 are as defined above, and each methylene in any of the above formulae, other than those in a depicted ring, is independently optionally substituted with R 25 and R 2 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; 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.
12 . The compound according to claim 10 , wherein Ar is according to formula IIb, and G is selected from:
wherein Q, R 20 , 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 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; 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.
13 . The compound according to claim 12 , wherein the methylene between the two carbonyls of the depicted formulae is di-substituted with either optionally substituted lower alkyl, or an optionally substituted spirocycle.
14 . The compound according to claim 11 or claim 12 , wherein R 50 is a heteroalicylic or a C 1-6 alkyl-heteroalicylic.
15 . The compound according to claim 14 , wherein at least one of R 2 is halogen.
16 . The compound according to claim 14 , wherein R 50 is according to formula IV.
17 . The compound according to claim 16 , wherein the saturated bridged ring system according to formula IV has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], [3.1.0], [3.3.3], [3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1].
18 . The compound according to claim 17 , wherein Y is selected from —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 —, —CH 2 —, and absent.
19 . The compound according to claim 18 , wherein n is 0 and the saturated bridged ring system according to formula IV has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and [3.1.0].
20 . The compound according to claim 19 , wherein said saturated bridged ring system contains at least one annular nitrogen or at least one annular oxygen.
21 . The compound according to claim 20 , wherein said saturated bridged ring system contains —NR 8 —, wherein R 8 is selected from —H, optionally substituted lower alkyl, —CO 2 R 3 , —C(O)NR 3 R 3 , —SO 2 R 3 , and —C(O)R 3 .
22 . The compound according to claim 20 , wherein said saturated bridged ring system is of formula V,
wherein U 1 is selected from —O—, —S(O) 0-2 —, —NR 11 —, —CR 6 R 7 —, and absent; and e is 0 or 1.
23 . The compound according to claim 22 , wherein Y is —CH 2 —.
24 . The compound according to claim 23 , wherein U 1 is —NR 8 —, wherein R 8 is selected from —H, optionally substituted lower alkyl, —CO 2 R 3 , —C(O)NR 3 R 3 , —SO 2 R 3 , and —C(O)R 3 .
25 . The compound according to claim 23 , wherein U 1 is —O—.
26 . The compound according to claim 23 , wherein U 1 is absent.
27 . The compound according to claim 20 , wherein Y is selected from —CH 2 CH 2 —, —CH 2 —, and absent.
28 . The compound according to claim 27 , wherein said saturated bridged ring system is of formula VI,
wherein R 9 , R 10 , and R 11 are each independently selected from —H, and —OR 12 ; or
R 9 is selected from —H, and —OR 12 , and R 10 and R 11 , when taken together, are either an optionally substituted alkylidene or an oxo;
R 12 is selected from —H, —C(O)R 3 , optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substituted lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaryl, optionally substituted aryl, optionally substituted lower heterocyclylalkyl, and optionally substituted heterocyclyl;
or two R 12 's, when taken together, form 1) a corresponding spirocyclic ketal when said two R 12 's stem from R 10 and R 11 , or 2) a corresponding cyclic ketal when said two R 12 's stem from R 9 and one of R 10 and R 11 .
29 . The compound according to claim 28 , wherein one of R 10 and R 11 is —OR 12 , wherein R 12 is selected from —H, —C(O)R 3 , and optionally substituted lower alkyl; and R 9 and the other of R 10 and R 11 are both —H.
30 . The compound according to claim 29 , wherein Y is either —CH 2 — or absent.
31 . The compound according to claim 30 , wherein R 9 is an alkyl group containing at least one fluorine substitution thereon.
32 . The compound according to claim 21 , wherein said saturated bridged ring system is of formula VII.
33 . The compound according to claim 32 , wherein Y is either —CH 2 — or absent.
34 . The compound according to claim 33 , wherein R 8 is methyl or ethyl.
35 . The compound according to claim 21 , wherein said saturated bridged ring system is of formula VIII.
36 . The compound according to claim 35 , wherein Y is —CH 2 —.
37 . The compound according to claim 36 , wherein R 8 is methyl or ethyl.
38 . The compound according to claim 20 , wherein said saturated bridged ring system is of formula IX
wherein U 2 is selected from —O—, —S(O) 0-2 —, —NR 8 —, —CR 6 R 7 —, and absent.
39 . The compound according to claim 38 , wherein R 3 of formula IX is selected from —H and optionally substituted alkyl.
40 . The compound according to claim 39 , wherein U 2 is either —CR 6 R 7 — or absent.
41 . The compound according to claim 40 , wherein U 2 is either —CH 2 — or absent.
42 . The compound according to claim 41 , wherein Y is —CH 2 —.
43 . The compound according to claim 21 , wherein said saturated bridged ring system is according to formula X.
44 . The compound according to claim 43 , wherein R 8 is methyl or ethyl.
45 . The compound according to claim 1 , selected from Table 1.
TABLE 1
Entry
Name
Structure
1
N-[({3-fluoro-4-[(6- (methyloxy)-7-{[(3aR,6aS)- octahydrocyclopenta[c]pyrrol- 5-ylmethyl]oxy}quinazolin-4- yl)oxy]phenyl}amino) carbonothioyl]-2-phenyl- acetamide
2
N-{[(3-fluoro-4-{[7- ({[(3aR,6aS)-2- methyloctahydrocyclopenta[c] pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4- yl]oxy}phenyl)amino] carbonothioyl}-2-phenyl- acetamide
3
N-{[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)(methyl)amino] carbonothioyl}-2- phenylacetamide
4
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)imidazolidin-2- one
5
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3- (phenylmethyl)imidazolidin- 2-one
6
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3- (phenylacetyl)imidazolidin-2- one
7
ethyl [(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)amino](oxo) acetate
8
N-{[(4-{[6,7- bis(methyloxy)quinazolin-4- yl]amino}-3- fluorophenyl)amino] carbonothioyl}-2- phenylacetamide
9
N′-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N- methyl-N-(2- phenylethyl)sulfamide
10
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3- (phenylmethyl)-1,2,4- oxadiazol-5-amine
11
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)piperidin-2-one
12
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (phenylmethyl)ethanediamide
13
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-4- phenyl-1,3-thiazol-2-amine
14
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (2-phenylethyl)ethanediamide
15
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-1- phenylmethanesulfonamide
16
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-2- phenylethanesulfonamide
17
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N- (phenylmethyl)benzene- sulfonamide
18
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-methyl-N- (phenylmethyl)benzene- sulfonamide
19
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-(2- phenylethyl)benzene- sulfonamide
20
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-methyl-N- (2- phenylethyl)benzene- sulfonamide
21
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-(3- phenylpropyl)benzene- sulfonamide
22
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)pyrrolidin-2-one
23
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl (phenylmethyl)carbamate
24
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl (2- phenylethyl)carbamate
25
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-methyl-N- (3- phenylpropyl)benzene- sulfonamide
26
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- phenylethanediamide
27
N-{[(3-fluoro-4-{[7-{[(2- methyloctahydrocyclopenta[c] pyrrol-5-yl)methyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}phenyl)amino] carbonothioyl}-2- phenylacetamide
28
N-[(Z)-[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)amino](imino) methyl]-2-phenylacetamide
29
4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-[2- (phenyloxy)ethyl]benzene- sulfonamide
30
N,N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-bis- (3-phenylpropane-1- sulfonamide)
31
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3- phenylpropane-1-sulfonamide
32
N2-[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)sulfonyl]-N1- phenylglycinamide
33
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-2- phenylacetamide
34
N-{[(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3- yl)amino]carbonothioyl}-2- phenylacetamide
35
6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-1,3-benzothiazol-2- amine
36
6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-amine
37
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2- phenylacetamide
38
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (2-morpholin-4- ylethyl)ethanediamide
39
benzyl-{[4-(6,7-dimethoxy- quinolin-4-yloxy)-3-fluoro- phenylcarbamoyl]-methyl}- carbamic acid tert-butyl ester
40
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- (phenylmethyl)glycinamide
41
N2-acetyl-N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- (phenylmethyl)glycinamide
42
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-1,3-benzothiazol-2- yl)-2-phenylacetamide
43
benzyl-{[6-(6,7-dimethoxy- quinolin-4-yloxy)-pyridin-3- ylcarbamoyl]-methyl}- carbamic acid tert-butyl ester
44
N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-N2- (phenylmethyl)glycinamide
45
N2-acetyl-N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-N2- (phenylmethyl)glycinamide
46
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-3- phenylpropanamide
47
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-4- phenylbutanamide
48
N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-N2- methyl-N2- (phenylmethyl)glycinamide
49
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- {2-[4- (methyloxy)phenyl]ethyl} ethanediamide
50
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- methyl-N2- (phenylmethyl)glycinamide
51
4-[(2-amino-1,3-benzothiazol- 6-yl)oxy]-6,7-bis(methyloxy)- 1-(2-oxo-2- phenylethyl)quinolinium
52
N-{[(4-{[6,7- bis(methyloxy)quinolin-4- yl]amino}phenyl)amino] carbonothioyl}-2-phenyl- acetamide
53
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-3- phenylpropanamide
54
N-{[(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)amino]carbonothioyl}-2- phenylacetamide
55
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (2,3-dihydro-1H-inden-1- yl)ethanediamide
56
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (2,3-dihydro-1H-inden-2- yl)ethanediamide
57
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (1,2,3,4-tetrahydronaphthalen- 1-yl)ethanediamide
58
N′-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N- (2-phenylethyl)-N- (phenylmethyl)sulfamide
59
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- (trifluoroacetyl)glycinamide
60
N-{[4-(6,7-dimethoxy- quinolin-4-yloxy)-3-fluoro- phenylcarbamoyl]-methyl}- benzamide
61
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-N′-(4- fluorophenyl)propanediamide
62
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [(2S)-1,2,3,4- tetrahydronaphthalen-2- yl]ethanediamide
63
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [2-(4- methylphenyl)ethyl]ethane- diamide
64
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (2- phenylpropyl)ethanediamide
65
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [2-(4- chlorophenyl)ethyl]ethane- diamide
66
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N,N′-bis(phenylmethyl) sulfamide
67
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N,N′-bis(2-phenylethyl) sulfamide
68
ethyl [(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)amino](oxo)acetate
69
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N′-(2- phenylethyl)ethanediamide
70
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N′-(4- fluorophenyl)propanediamide
71
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (1,2,3,4-tetrahydronaphthalen- 2-yl)ethanediamide
72
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [2-(1-methylpyrrolidin-2- yl)ethyl]ethanediamide
73
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [2-(phenyloxy) ethyl]ethanediamide
74
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [2-hydroxy-1- (phenylmethyl)ethyl]urea
75
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3- [(4-methylphenyl)sulfonyl]-4- (phenylmethyl)imidazolidin- 2-one
76
N′-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N- methyl-N-(2- phenylethyl)ethanediamide
77
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- {[3- (trifluoromethyl)phenyl] methyl}ethanediamide
78
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- {2-[3- (trifluoromethyl)phenyl] ethyl}ethanediamide
79
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-3-oxo-4- phenylbutanamide
80
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-2-[3- (trifluoromethyl)phenyl] acetamide
81
6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-[2- (phenyloxy)ethyl]-1,3- benzothiazol-2-amine
82
6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-(2- piperidin-1-ylethyl)-1,3- benzothiazol-2-amine
83
6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-methyl-N- (2-phenylethyl)-1,3- benzothiazol-2-amine
84
6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-(2- pyrrolidin-1-ylethyl)-1,3- benzothiazol-2-amine
85
6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-{[3- (trifluoromethyl)phenyl] methyl}-1,3-benzothiazol-2- amine
86
6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-{2-[3- (trifluoromethyl)phenyl] ethyl}-1,3-benzothiazol-2- amine
87
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N′-[3- (trifluoromethyl)phenyl] propanediamide
88
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2-[3- (trifluoromethyl)phenyl] acetamide
89
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- {[3- (trifluoromethyl)phenyl] methyl}glycinamide
90
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- (2-phenylethyl)glycinamide
91
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- {2-[3- (trifluoromethyl)phenyl] ethyl}glycinamide
92
benzyl-{[5-chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)- pyridin-3-ylcarbamoyl]- methyl}-carbamic acid tert- butyl ester
93
N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N2- (phenylmethyl)glycinamide
94
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2-[3,5- bis(trifluoromethyl)phenyl] acetamide
95
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2-[2- chloro-5- (trifluoromethyl)phenyl] acetamide
96
N-{3-fluoro-4-[(6- (methyloxy)-7-{[(1- methylpiperidin-4- yl)methyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(2- phenylethyl)ethanediamide
97
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (1,2,3,4- tetrahydroisoquinolin-1- ylmethyl)ethanediamide
98
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [(2-methyl-1,2,3,4- tetrahydroisoquinolin-1- yl)methyl]ethanediamide
99
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- methyl-N2-{[3- (trifluoromethyl)phenyl] methyl}glycinamide
100
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- methyl-N2-{2-[3- (trifluoromethyl)phenyl] ethyl}glycinamide
101
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- methyl-N2-(2- phenylethyl)glycinamide
102
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-4- (phenylmethyl)imidazolidin- 2-one
103
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridazin-3-yl)-N′-(4- fluorophenyl)propanediamide
104
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N′-(2- chlorophenyl)propanediamide
105
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N′-(3- chlorophenyl)propanediamide
106
N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N2-methyl-N2- (phenylmethyl)glycinamide
107
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N′-(4- chlorophenyl)propanediamide
108
(2E)-N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-2- [(methyloxy)imino] propanamide
109
(2E)-N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-2- [(ethyloxy)imino] propanamide
110
(2E)-N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-2- {[(phenylmethyl)oxy]imino} propanamide
111
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-1- (phenylmethyl)prolinamide
112
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-3-[(4- methylphenyl)sulfonyl]-4- (phenymethyl)imidazolidin- 2-one
113
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-4- (phenylmethyl)imidazolidin- 2-one
114
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-4- (phenylmethyl)-4,5-dihydro- 1,3-oxazol-2-amine
115
6,7-bis(methyloxy)-4-({4-[4- (phenylmethyl)piperazin-1- yl]phenyl}oxy)quinoline
116
1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-4- (phenylmethyl)piperazin-2- one
117
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2- (phenylmethyl)alaninamide
118
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2-methyl- N2- (phenylmethyl)alaninamide
119
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2- (phenylmethyl)leucinamide
120
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2-methyl- N2- (phenylmethyl)leucinamide
121
N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2- (phenylmethyl)valinamide
122
4-(6,7-dimethoxy-quinolin-4- ylamino)-N-(3-phenyl- propyl)-benzamide
123
4-benzyl-1-[4-(6,7- dimethoxy-quinolin-4-yloxy)- phenyl]-tetrahydro-pyrimidin- 2-one
124
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- phenethyl-oxalamide
125
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)
126
N-[4-(6,7-Dimethoxy- quinolin-4-yloxy)-phenyl]-2- phenoxyimino-propionamide
127
2-Benzyloxyimino-N-[4-(6,7- dimethoxy-quinolin-4-yloxy)- phenyl]-2-phenyl-acetamide
128
4-[4-(4-Benzyl-piperidin-1- yl)-phenoxy]-6,7-dimethoxy- quinoline
129
N-[4-(6,7-Dimethoxy- quinolin-4-yloxy)-3-fluoro- phenyl]-N′-(2-isopropyl- 1,2,3,4-tetrahydro- isoquinolin-1-ylmethyl)- oxalamide
130
N-[4-(6,7-Dimethoxy- quinolin-4-yloxy)-3-fluoro- phenyl]-N′-(2-ethyl-1,2,3,4- tetrahydro-isoquinolin-1- ylmethyl)-oxalamide
131
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
132
N-{5-chloro-6-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-pyridin-3- yl}-N′-(4-fluoro-phenyl)- malonamide
133
N-{5-Chloro-6-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-pyridin-3-yl}-N′-(4- fluoro-phenyl)-malonamide
134
N-{4-[7-(3-Diethylamino- propoxy)-6-methoxy- quinolin-4-yloxy]-3-fluoro- phenyl}-N′-phenethyl- oxalamide
135
N-{3-Fluoro-4-[6-methoxy-7- (3-morpholin-4-yl-propoxy)- quinolin-4-yloxy]-phenyl}-N′- phenethyl-oxalamide
136
N-{3-Fluoro-4-[6-methoxy-7- (3-piperidin-1-yl-propoxy)- quinolin-4-yloxy]-phenyl}-N′- phenethyl-oxalamide
137
N-{4-[7-(2-Diethylamino- ethoxy)-6-methoxy-quinolin- 4-yloxy]-3-fluoro-phenyl}-N′- phenethyl-oxalamide
138
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-methyl-N′- phenethyl-oxalamide
139
N-{3-Fluoro-4-[6-methoxy-7- (2-methyl-octahydro- cyclopenta[c]pyrrol-5- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-phenethyl- oxalamide
140
N-{3-Fluoro-4-[6-methoxy-7- (2-methyl-octahydro- cyclopenta[c]pyrrol-5- ylmethoxy)-quinazolin-4- yloxy]-phenyl}-N′-phenethyl- oxalamide
141
2-(3,4-Dihydro-1H- isoquinolin-2-yl)-N-{3-fluoro- 4-[6-methoxy-7-(1-methyl- piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-2- oxo-acetamide
142
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-2- oxo-2-(3-phenyl-pyrrolidin-1- yl)-acetamide
143
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-2- oxo-2-(2-phenyl-morpholin-4- yl)-acetamide
144
N-(2-Dimethylamino-2- phenyl-ethyl)-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
145
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-oxo-2-phenyl-ethyl)- oxalamide
146
N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)- pyridin-3-yl]-2,2-difluoro-N′- (4-fluoro-phenyl)-malonamide
147
N-Benzyl-N′-{3-fluoro-4-[6- methoxy-7-(1-methyl- piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
148
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [2-(2-fluoro-phenyl)-ethyl]- oxalamide
149
N-[2-(3-Chloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
150
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [2-(2-methoxy-phenyl)-ethyl]- oxalamide
151
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-pyridin-3-yl-ethyl)- oxalamide
152
N-Benzyl-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
153
N-[2-(2,5-Dimethoxy- phenyl)-ethyl]-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
154
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [2-(2-trifluoromethyl-phenyl)- ethyl]-oxalamide
155
N-[2-(2-Ethoxy-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
156
N-[2-(2,4-Dimethyl-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
157
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (1S-phenyl-2-p-tolyl-ethyl)- oxalamide
158
N-[2-(4-Chloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
159
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamic acid
160
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [2-(3-fluoro-phenyl)-ethyl]- oxalamide
161
N-[2-(2-Chloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
162
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [2-(3-methoxy-phenyl)-ethyl]- oxalamide
163
N-(1,2-Diphenyl-ethyl)-N′-{3- fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
164
N-[2-(2,4-Dichloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
165
N-[2-(3,4-Dimethoxy- phenyl)-ethyl]-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
166
N-[2-(4-Ethyl-phenyl)-ethyl]- N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
167
N-[2-(4-Ethoxy-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
168
N-[2-(4-Ethoxy-3-methoxy- phenyl)-ethyl]-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
169
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [2-(4-phenoxy-phenyl)-ethyl]- oxalamide
170
N-[2-(3-Ethoxy-4-methoxy- phenyl)-ethyl]-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
171
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-pyridin-2-yl-ethyl)- oxalamide
172
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-pyridin-4-yl-ethyl)- oxalamide
173
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [2-(4-fluoro-phenyl)-ethyl]- oxalamide
174
N-[2-(2-Bromo-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
175
N-[2-(2-Chloro-6-fluoro- phenyl)-ethyl]-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
176
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2R-phenyl-propyl)- oxalamide
177
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- indan-1-yl-oxalamide
178
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-isobutyl- oxalamide
179
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(3-methyl- butyl)-oxalamide
180
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2R- phenyl-propyl)-oxalamide
181
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-phenyl- propyl)-oxalamide
182
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-indan-2-yl- oxalamide
183
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (1R-phenyl-ethyl)-oxalamide
184
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (1S-phenyl-ethyl)-oxalamide
185
N-[2-(3-Bromo-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
186
N-[2-(2,6-Dichloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
187
N-[2-(2,4-Dichloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
188
N-(2-Benzo[1,3]dioxol-5- yl-ethyl)-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
189
N-[2-(3-Bromo-4-methoxy- phenyl)-ethyl]-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
190
N-[2-(3,5-Dimethoxy- phenyl)-ethyl]-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4 yloxy]-phenyl}-oxalamide
191
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-o-tolyl-ethyl)-oxalamide
192
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-m-tolyl-ethyl)-oxalamide
193
N-[2-(3-Ethoxy-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
194
N-[2-(3,4-Dimethyl-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
195
N-[2-(2,5-Dimethyl-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
196
N-[2-(3-Chloro-4-propoxy- phenyl)-ethyl]-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
197
N-[2-(4-Butoxy-3-chloro- phenyl)-ethyl]-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
198
N-[2-(4-tert-Butyl-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
199
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [2-(4-sulfamoyl-phenyl)- ethyl]-oxalamide
200
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [2-(4-hydroxy-3-methoxy- phenyl)-ethyl]-oxalamide
201
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [2-(3-hydroxy-4-methoxy- phenyl)-ethyl]-oxalamide
202
N-(2,4-Dichloro-benzyl)-N′- {3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
203
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (4-fluoro-2-trifluoromethyl- benzyl)-oxalamide
204
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (1-p-tolyl-ethyl)-oxalamide
205
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (3-fluoro-4-trifluoromethyl- benzyl)-oxalamide
206
N-(3-Chloro-4-fluoro-benzyl)- N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
207
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [1-(3-methoxy-phenyl)-ethyl]- oxalamide
208
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (1-naphthalen-2-yl-ethyl)- oxalamide
209
N-(4-Chloro-3- trifluoromethyl-benzyl)-N′- {3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
210
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (1-p-tolyl-ethyl)oxalamide
211
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (6-trifluoromethyl-pyridin-3- ylmethyl)-oxalamide
212
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-methyl-benzyl)-oxalamide
213
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (3-methyl-benzyl)-oxalamide
214
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (4-fluoro-3-trifluoromethyl- benzyl)-oxalamide
215
N-(3,5-Dichloro-benzyl)-N′- {3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
216
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (1R,2,3,4-tetrahydro- naphthalen-1-yl)-oxalamide
217
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (1S,2,3,4-tetrahydro- naphthalen-1-yl)-oxalamide
218
N-Cyclopentyl-N′-{3-fluoro- 4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
219
N-[1-(4-Bromo-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
220
N-(2-Fluoro-benzyl)-N′-{3- fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
221
N-[2-(3,4-Dichloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
222
N-(4-Fluoro-benzyl)-N′-{3- fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
223
N-(2,3-Difluoro-benzyl)-N′- {3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
224
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-phenoxy-ethyl)-oxalamide
225
N-(2,2-Diphenyl-ethyl)-N′-{3- fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
226
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [2-(4-methoxy-phenyl)-ethyl]- oxalamide
227
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-phenyl-propyl)-oxalamide
228
N-[2-(4-Bromo-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
229
N-{4-[7-(1-Ethyl-piperidin-4- ylmethoxy)-6-methoxy- quinolin-4-yloxy]-3-fluoro- phenyl}-2-oxo-2-(2-phenyl- morpholin-4-yl)-acetamide
230
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (3-fluoro-5-trifluoromethyl- benzyl)-oxalamide
231
N-(3,5-Difluoro-benzyl)-N′- {3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
232
N-(2-Chloro-5- trifluoromethyl-benzyl)-N′- {3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
233
N-[4-(6,7-Dimethoxy- quinolin-4-yloxy)-3-fluoro- phenyl]-N′-(2-dimethylamino- 2-phenyl-ethyl)-oxalamide
234
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (4-methoxy-benzyl)- oxalamide
235
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (4-trifluoromethyl-benzyl)- oxalamide
236
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (3-methoxy-benzyl)- oxalamide
237
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (3-trifluoromethyl-benzyl)- oxalamide
238
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (3-trifluoromethoxy-benzyl)- oxalamide
239
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-methoxy-benzyl)- oxalamide
240
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-trifluoromethyl-benzyl)- oxalamide
241
N-(3-Chloro-benzyl)-N′-{3- fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
242
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-trifluoromethoxy-benzyl)- oxalamide
243
N-(2-Chloro-benzyl)-N′-{3- fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
244
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (4-trifluoromethoxy-benzyl)- oxalamide
245
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(4- methoxy-benzyl)-oxalamide
246
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(4- trifluoromethyl-benzyl)- oxalamide
247
N-{4-[7-(Azetidin-3- ylmethoxy)-6-methoxy- quinolin-4-yloxy]-3-fluoro- phenyl}-N′-phenethyl- oxalamide
248
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-azetidin-3- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-phenethyl- oxalamide
249
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-hydroxy-2-phenyl-ethyl)- oxalamide
250
N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)- pyridin-3-yl]-N′-(2,4-difluoro- phenyl)-malonamide
251
N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)- pyridin-3-yl]-N′-(4-fluoro- phenyl)-N′-methyl- malonamide
252
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (1R-phenyl-propyl)- oxalamide
253
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (1R-phenyl-propyl)- oxalamide
254
N-(3,4-Difluoro-benzyl)-N′- {3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
255
N-(2,6-Difluoro-benzyl)-N′- {3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
256
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(4- fluoro-phenyl)-ethyl]- oxalamide
257
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-phenyl- oxalamide
258
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (3-fluoro-phenyl)-oxalamide
259
N-(4-Chloro-3-fluoro- phenyl)-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
260
N-(3,4-Dimethoxy-phenyl)- N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
261
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (3-methyl-butyl)-oxalamide
262
N-(3,3-Dimethyl-butyl)-N′- {3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
263
N-{5-Chloro-6-[6-methoxy-7- (3-piperidin-1-yl-propoxy)- quinolin-4-yloxy]-pyridin-3- yl}-N′-(4-fluoro-phenyl)- malonamide
264
N-{5-Chloro-6-[6-methoxy-7- (3-morpholin-4-yl-propoxy)- quinolin-4-yloxy]-pyridin-3- yl}-N′-(4-fluoro-phenyl)- malonamide
265
N-{5-Chloro-6-[7-(3- diethylamino-propoxy)-6- methoxy-quinolin-4-yloxy]- pyridin-3-yl}-N′-(4-fluoro- phenyl)-malonamide
266
N-(4-Chloro-benzyl)-N′-{3- fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
267
N-(3,5-Dimethoxy-benzyl)- N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
268
N-(4-Butyl-benzyl)-N′-{3- fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
269
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-p-tolyl-ethyl)-oxalamide
270
N-(3,5-Bis-trifluoromethyl- benzyl)-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
271
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- pyrazin-2-ylmethyl-oxalamide
272
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- pyridin-2-ylmethyl-oxalamide
273
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinazolin-4-yloxy]-phenyl}- N′-phenethyl-oxalamide
274
N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4- ylmethoxy)-quinazolin-4- yloxy]-phenyl}-N′-phenethyl- oxalamide
275
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-fluoro-3-trifluoromethyl- benzyl)-oxalamide
276
N-[2-(2-Bromo-6-methoxy- phenyl)-ethyl]-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
277
N-[2-(3,4-Dimethoxy- phenyl)-ethyl]-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N-methyl- oxalamide
278
N-[2-(5-Bromo-2-methoxy- phenyl)-ethyl]-N′-{3-fluoro-4- [6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
279
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-fluoro-5-trifluoromethyl- benzyl)-oxalamide
280
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- [1-(4-fluoro-phenyl)-ethyl]- oxalamide
281
N-(1S-Benzyl-2-oxo-2- pyrrolidin-1-yl-ethyl)-N′-{3- fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
282
N-{3-Fluoro-4-[6-methoxy-7- (octahydro- cyclopenta[c]pyrrol-5- ylmethoxy)-quinazolin-4- yloxy]-phenyl}-N′-phenethyl- oxalamide
283
N-[2-(4-Amino-phenyl)- ethyl]-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
284
2-(4-Benzyl-piperidin-1-yl)- N-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-2- oxo-acetamide
285
N-[4-(6,7-Dimethoxy- quinolin-4-yloxy)-phenyl]-N′- (4-fluoro-phenyl)-malonamide
286
N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)- pyridin-3-yl]-N′-(3-fluoro- phenyl)-malonamide
287
N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)- pyridin-3-yl]-N′-phenyl- malonamide
288
N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)- pyridin-3-yl]-N′-(4-fluoro- phenyl)-2,2-dimethyl- malonamide
289
N-Ethyl-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
290
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- isopropyl-oxalamide
291
N-Butyl-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide
292
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-methoxy-ethyl)-oxalamide
293
N-Cyclopropylmethyl-N′-{3- fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide
294
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-N′- (2-morpholin-4-yl-ethyl)- oxalamide
295
N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-2- oxo-2-pyrrolidin-1-yl- acetamide
296
N-Ethyl-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-N-methyl- oxalamide
46 . A compound for modulating kinase activity 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 —N 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;
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)R 3 , —C(═O)SR 3 , —SO 2 R 3 , —C(═O)N(R 3 )R 3 , and optionally substituted lower alkyl;
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—, ═C(H)—, and ═C(CN)—;
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 ;
R 9 , R 10 , and R 11 are each independently selected from —H, and —OR 1 ; or
R 9 is selected from —H, and —OR 1 , and R 10 and R 11 , when taken together, are either an optionally substituted alkylidene or an oxo; and
R 12 is selected from —H, —C(O)R 3 , optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substituted lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaryl, optionally substituted aryl, optionally substituted lower heterocyclylalkyl, and optionally substituted heterocyclyl;
or two R 12 's, when taken together, form 1) a corresponding spirocyclic ketal when said two R 12 's stem from R 10 and R 1 , or 2) a corresponding cyclic ketal when said two R 12 's stem from R 9 and one of R 10 and R 1 ;
E 1 is selected from —O—, —CH 2 —, —N(R 5 )—, and —S(O) 0-2 —;
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;
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 R 25 ;
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; 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, two of R 25 on a single carbon can be oxo;
with the proviso that when B is selected from:
and C contains
and the remaining portion of C contains one of:
directly attached to
then A must be one of:
and with the proviso that when C contains
and B is selected from:
then the portion of C directly attached to
cannot contain
when R 70 is selected from —H, C 1-4 alkyl, and C 1-4 alkoxyl.
47 . The compound according to claim 46 , 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 , —NH 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.
48 . The compound according to claim 47 , wherein B is either of the following:
wherein A 1 is either ═N- or ═C(H)—.
49 . The compound according to claim 48 , wherein B is
50 . The compound according to claim 49 , wherein C is selected from:
wherein R 2 , R 3 , R 5 , R 20 , R 25 and R 60 are as defined above.
51 . The compound according to claim 50 , 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
52 . The compound according to claim 51 , wherein R 2 is halogen.
53 . The compound according to claim 52 , wherein R 2 is either fluorine or chlorine.
54 . A compound for modulating kinase activity 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;
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;
Q is selected from ═N—, ═C(H)—, and ═C(CN)—;
Z is selected from —S(O) 0-2 —, —O—, and —NR 5 —;
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 5 —;
each R 50 is independently either R 3 , or according to formula XII;
wherein X 1 , X 2 , and optionally X 3 , represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X 1 , X 2 , and X 3 ; wherein,
each X 1 is independently selected from —C(R 6 )R 7 —, —O—, —S(O) 0-2 —, and —NR 8 —;
each X 2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen;
each X 3 is independently selected from —C(R 6 )R 7 —, —O—, —S(O) 0-2 —, and —NR 8 —;
Y is either:
an optionally substituted lower alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X 2 when X 2 is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R 6 or R 7 ; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R 6 or R 7 ;
or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is —SO 2 —, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system;
m and p are each independently one to four;
n is zero to two, when n equals zero, then there is a single bond between the two bridgehead X 2 's;
R 6 and R 7 are each independently selected from —H, halogen, trihalomethyl, —CN, —NH 2 , —NO 2 , —OR 3 , —NR 3 R 4 , —S(O) 0-2 R 4 , —SO 2 NR 3 R 4 , —CO 2 R 3 , —C(O)NR 3 R 4 , —N(R 3 )SO 2 R 4 , —N(R 3 )C(O)R 3 , —NCO 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, optionally substituted heterocyclyl C 1-6 alkyl, and a bond to either Y or D; or
R 6 and R 7 , when taken together are oxo; or
R 6 and R 7 , when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
R 8 is selected from —R 3 , Y, —SO 2 NR 3 R 4 , —CO 2 R 4 , —C(O)NR 3 R 3 , —SO 2 R 4 , and —C(O)R 3 ; and
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.
55 . The compound according to claim 54 , wherein Z is either —O— or —NR 5 —.
56 . The compound according to claim 55 , wherein at least one of R 1 is -D-R 50 .
57 . The compound according to claim 56 , wherein D is —O— and at least one other R 1 is —OR 3 .
58 . The compound according to claim 57 , of formula XIIIa or XIIIb:
wherein Q 1 is either ═N- or ═C(H)—.
59 . The compound according to claim 58 , 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.
60 . The compound according to claim 59 , wherein R 3a is C 1-6 alkyl.
61 . The compound according to claim 60 , wherein Z is —O—.
62 . The compound according to claim 61 , wherein G is selected from cyclopropyl, aziradine, cyclobutyl, and azetidine, each optionally substituted with between zero and four of R 30 .
63 . The compound according to claim 62 , wherein Q is either ═N- or ═C(H)—.
64 . The compound according to claim 63 , wherein R 2 is selected from —H, halogen, C 1-6 alkyl and perfluoro C 1-6 alkyl.
65 . The compound according to claim 64 , wherein —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 ;
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;
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 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 aryl C 1-6 alkyl, heteroaryl C 1-6 alkyl, 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;
R 3b is equivalent to R 3 as defined above; and
R 4 and R 5 are as defined above.
66 . The compound according to claim 65 , of formula XIVa or XIVb:
67 . The compound according to claim 66 , wherein R 50 is C 1-6 alkyl optionally substituted with a group selected from optionally substituted amino, an optionally substituted alkylamino, optionally substituted dialkylamino, and optionally substituted heteroalicylic.
68 . The compound according to claim 67 , wherein the heteroalicyclic portion of said optionally substituted heteroalicyclic of R 50 is selected from the group consisting of piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, 2-oxo-morpholine, pyrrolidine, and azepine.
69 . The compound according to claim 67 , wherein R 50 is according to formula XII.
70 . The compound according to claim 69 , wherein the saturated bridged ring system according to formula XII has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], [3.1.0], [3.3.3], [3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1].
71 . The compound according to claim 70 , wherein Y is selected from —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 —, —CH 2 —, and absent.
72 . The compound according to claim 71 , wherein n is 0 and the saturated bridged ring system according to formula XII has a geometry selected from the group consisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and [3.1.0].
73 . The compound according to claim 72 , wherein said saturated bridged ring system contains at least one annular nitrogen or at least one annular oxygen.
74 . The compound according to claim 73 , wherein said saturated bridged ring system contains —NR 8 —, wherein R 8 is selected from —H, optionally substituted C 1-6 alkyl, —CO 2 R 3 , —C(O)NR 3 R 3 , —SO 2 R 3 , and —C(O)R 3 .
75 . The compound according to claim 73 , wherein said saturated bridged ring system is of formula XV,
wherein U 1 is selected from —O—, —S(O) 0-2 —, —NR 8 —, —CR 6 R 7 —, and absent; and e is 0 or 1.
76 . The compound according to claim 75 , wherein Y is —CH 2 —.
77 . The compound according to claim 76 , wherein U 1 is —NR 8 —, wherein R 8 is selected from —H, optionally substituted lower alkyl, —CO 2 R 3 , —C(O)NR 3 R 3 , —SO 2 R 3 , and —C(O)R 3 .
78 . The compound according to claim 76 , wherein U 1 is —O—.
79 . The compound according to claim 76 , wherein U is absent.
80 . The compound according to claim 71 , wherein Y is selected from —CH 2 CH 2 —, —CH 2 —, and absent.
81 . The compound according to claim 80 , wherein said saturated bridged ring system is of formula XVI,
wherein R 9 , R 10 , and R 11 are each independently selected from —H, and —OR 12 ; or
R 9 is selected from —H, and —OR 2 , and R 10 and R 11 , when taken together, are either an optionally substituted alkylidene or an oxo;
R 12 is selected from —H, —C(O)R 3 , optionally substituted lower alkylidyne, optionally substituted lower arylalkylidyne, optionally substituted lower heterocyclylalkylidyne, optionally substituted lower alkylidene, optionally substituted lower alkylidenearyl, optionally substituted lower alkylideneheterocyclyl, optionally substituted lower alkyl, optionally substituted lower alkylaryl, optionally substituted aryl, optionally substituted lower heterocyclylalkyl, and optionally substituted heterocyclyl;
or two R 12 's, when taken together, form 1) a corresponding spirocyclic ketal when said two R 12 's stem from R 10 and R 11 , or 2) a corresponding cyclic ketal when said two R 12 's stem from R 9 and one of R 10 and R 11 .
82 . The compound according to claim 81 , wherein one of R 10 and R 11 is —OR 12 , wherein R 1 is selected from —H, —C(O)R 3 , and optionally substituted lower alkyl; and R 9 and the other of R 10 and R 11 are both —H.
83 . The compound according to claim 82 , wherein Y is either —CH 2 — or absent.
84 . The compound according to claim 81 , wherein R 9 is an alkyl group containing at least one fluorine substitution thereon.
85 . The compound according to claim 74 , wherein said saturated bridged ring system is of formula XVII.
86 . The compound according to claim 85 , wherein Y is either —CH 2 — or absent.
87 . The compound according to claim 86 , wherein R 8 is methyl or ethyl.
88 . The compound according to claim 87 , wherein at least one of R 2 is halogen.
89 . The compound according to claim 74 , wherein said saturated bridged ring system is of formula XVIII.
90 . The compound according to claim 89 , wherein Y is —CH 2 —.
91 . The compound according to claim 90 , wherein R 8 is methyl or ethyl.
92 . The compound according to claim 73 , wherein said saturated bridged ring system is of formula XIX
wherein U 2 is selected from —O—, —S(O) 0-2 —, —NR 8 —, —CR 6 R 7 —, and absent.
93 . The compound according to claim 92 , wherein R 3 of formula XIX is selected from —H and optionally substituted alkyl.
94 . The compound according to claim 93 , wherein U 2 is either —CR 6 R 7 — or absent.
95 . The compound according to claim 94 , wherein U 2 is either —CH 2 — or absent.
96 . The compound according to claim 95 , wherein Y is —CH 2 —.
97 . The compound according to claim 74 , wherein said saturated bridged ring system is according to formula XX.
98 . The compound according to claim 97 , wherein R 8 is methyl or ethyl.
99 . The compound according to any of claims 67 through 98 , wherein R 2 is selected from C 1-6 alkyl, perfluoro C 1-6 alkyl, and halogen.
100 . The compound according to claim 99 , wherein R 2 is selected from perfluoro C 1-3 alkyl and halogen.
101 . The compound according to any of claims 67 through 98 , 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.
102 . The compound according to claim 101 , 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.
103 . The compound according to claim 102 , wherein R 2 is selected from C 1-6 alkyl, perfluoro C 1-6 alkyl, and halogen.
104 . The compound according to claim 103 , wherein R 2 is selected from perfluoro C 1-3 alkyl and halogen.
105 . The compound according to claim 54 , selected from Table 2.
TABLE 2
Entry
Name
Structure
1
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
2
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
3
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N′- (phenylmethyl)cyclopropane- 1,1-dicarboxamide
4
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N′- phenylcyclopropane-1,1- dicarboxamide
5
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
6
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperidin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
7
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperidin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
8
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N′-(2- phenylethyl)cyclopropane- 1,1-dicarboxamide
9
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-methylpyridin- 3-yl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
10
N-{4-[(7-chloroquinolin- 4-yl)oxy]-3- fluorophenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
11
N-{4-[(7-chloroquinolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
12
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
13
N-(4-{[6,7- bis(methyloxy)quinazolin- 4-yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
14
N-(4-{[6,7- bis(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
15
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
16
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
17
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
18
N-[5-chloro-6-({6- (methyloxy)-7- [(phenylmethyl)oxy] quinolin-4-yl}oxy)pyridin-3- yl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
19
N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
20
N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
21
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
22
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-methylphenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
23
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
24
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
25
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloro-2- methylpyridin-3-yl)-N′- (4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
26
N-[3-fluoro-4-({7- (methyloxy)-6-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
27
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3,5- difluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
28
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2,5- difluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
29
N-[3-fluoro-4-({7- (methyloxy)-6-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
30
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
31
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
32
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
33
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2,3,5- trifluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
34
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-2- methylphenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
35
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-chloro-5- methylphenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
36
N-(3-fluoro-4-{[6- hydroxy-7- (methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
37
N-(4-fluorophenyl)-N′-[2- methyl-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]cyclopropane- 1,1-dicarboxamide
38
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperazin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
39
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
40
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
41
N-(4-fluorophenyl)-N′-[4- ({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]cyclopropane- 1,1-dicarboxamide
42
N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
43
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-chloro-5- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
44
N-(4-{[6,7- bis(methyloxy)-2- (methylthio)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
45
N-(4-fluorophenyl)-N′-(4- {[2-methyl-6,7- bis(methyloxy)quinazolin- 4- yl]oxy}phenyl)cyclopropane- 1,1-dicarboxamide
46
N-(4-{[2-amino-6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
47
N-(3-fluoro-4-{[2- (methylamino)-6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
48
(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
49
(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
50
N-(4-{[6-{[3- (diethylamino)propyl]oxy}- 7-(methyloxy)quinolin- 4-yl]oxy)-3- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
51
N-(4-{[6-{[2- (diethylamino)ethyl]oxy}- 7-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
52
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
53
(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
54
(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
55
N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
56
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
57
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
58
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)-1- (phenylmethyl)azetidine- 3,3-dicarboxamide
59
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)azetidine- 3,3-dicarboxamide
60
(1R,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
61
(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
62
(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
63
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
64
N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
65
(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
66
(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
67
(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
68
(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
69
N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
70
(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
71
(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
72
(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
73
(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
74
(1R,2R,3S)-N-{3-fluoro- 4-[(6-(methyloxy)-7-{[3- (4-methylpiperazin-1- yl)propyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide
75
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
76
(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
77
(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
78
N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide
79
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
80
(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
81
N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide
82
(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
83
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
84
N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide
85
N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide
86
N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6- (methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
87
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
88
N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperazin-1- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
89
(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
90
N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide
91
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
92
(1R,2R)-N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6- (methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2- methylcyclobutane-1,1- dicarboxamide
93
(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- methylcyclobutane-1,1- dicarboxamide
94
(2R,3R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide
95
(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
96
(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
97
(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
98
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[(4- fluorophenyl)methyl] cyclopropane-1,1- dicarboxamide
99
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(2- morpholin-4- ylethyl)cyclopropane-1,1- dicarboxamide
100
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[2- (piperidin-1- ylmethyl)phenyl]cyclo- propane-1,1-dicarboxamide
101
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[2- (pyrrolidin-1- ylmethyl)phenyl]cyclo- propane-1,1-dicarboxamide
102
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[3- (morpholin-4- ylmethyl)phenyl]cyclo- propane-1,1-dicarboxamide
103
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[2- (morpholin-4- ylmethyl)phenyl]cyclo- propane-1,1-dicarboxamide
104
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′- phenylcyclopropane-1,1- dicarboxamide
105
N-[3- (aminomethyl)phenyl]-N′- (4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)cyclo- propane-1,1-dicarboxamide
106
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[3- (piperidin-1- ylmethyl)phenyl]cyclo- propane-1,1-dicarboxamide
107
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[3- (pyrrolidin-1- ylmethyl)phenyl]cyclo- propane-1,1-dicarboxamide
106 . A pharmaceutical composition comprising a compound according to any one of claims 1 - 105 and a pharmaceutically acceptable carrier.
107 . A metabolite of the compound or the pharmaceutical composition according to any one of claims 1 - 106 .
108 . A method of modulating the in vivo activity of a kinase, the method comprising administering to a subject an effective amount of the compound or the pharmaceutical composition according to any of claims 1 - 105 .
109 . The method according to claim 108 , wherein modulating the in vivo activity of the kinase comprises inhibition of said kinase.
110 . The method according to claim 108 , wherein the kinase is at least one of c-Met, KDR, c-Kit, flt-3, and flt-4.
111 . The method according to claim 110 , wherein the kinase is c-Met.
112 . 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 or the pharmaceutical composition as described in any one of claims 1 - 106 .
113 . 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 combining a compound according to any one of claims 1 - 105 , and at least one candidate agent and determining the effect of the candidate agent on the activity of said kinase.
114 . A method of inhibiting proliferative activity in a cell, the method comprising administering an effective amount of a composition comprising a compound according any one of claims 1 - 105 to a cell or a plurality of cells.
115 . A process for preparing a compound of Formula XXI,
comprising reaction of a compound of Formula XXII, with a compound of Formula XXIII
wherein,
each R 1 is independently selected from halogen, —OR 3 , —NO 2 , —NH 2 , —NR 3 R 3 , -D-R 50 and optionally substituted C 1-6 alkyl;
R 70 is selected from —H, halogen, —OR 3 , —S(O) 0-2 R 3 , —NO 2 , —NH 2 , —NR 3 R 3 , and optionally substituted C 1-6 alkyl;
J is selected from ═N—, ═C(H)—, ═C(halogen)-, and ═C(CN)—;
Z is selected from —S(O) 0-2 —, —O—, and —NR 5 —;
each R 5 is independently selected from —H, optionally substituted C 1-6 alkyl, optionally substituted aryl, and optionally substituted aryl C 1-6 alkyl;
Ar is either a five- to ten-membered arylene or a five- to ten-membered heteroarylene containing between one and three heteroatoms;
R 2 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 C 1-6 alkyl;
each R 3 is independently selected from —H, —Si(R 5 )(R 5 )R 5 , optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl;
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;
B is selected from absent, —N(R 13 )—, —N(SO 2 R 13 )—, —O—, —S(O) 0-2 —, and —C(═O)—;
L 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 )—, —N(R 13 )—, —C(═O)C 1-2 alkyN(R 13 )—, —N(R 13 )C 1-2 alkylC(═O)—, —C(═O)C 0-1 alkylC(═O)N(R 13 )—, —C(═O)—, —C 0-4 alkylene-, —C(═O)C 0-1 alkylC(═O)OR 3 , —C(═NR 14 )C 0-1 alkylC(═O)—, —C(═O)C 0-1 alkylC(═O)—, and an optionally substituted four- to six-membered heterocyclyl containing between one and three annular heteroatoms and comprising at least one nitrogen;
T is selected from —H, —R 13 , —C 0-4 alkyl, —C 0-4 alkylQ, —OC 0-4 alkylQ, —C 0-4 alkylOQ, —N(R 13 )C 0-4 alkylQ, —SO 2 C 0-4 alkylQ, —C(═O)C 0-4 alkylQ, —C 0-4 alkylN(R 13 )Q, and —C(═O)N(R 13 )C 4 alkylQ, wherein each of the aforementioned C 0-4 alkyl is optionally substituted;
Q is a five- to ten-membered ring system, optionally substituted with between zero and four of R 20 ;
each R 20 is independently 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 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;
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 Q or fused to Q;
D is selected from —O—, —S(O) 0-2 —, and —NR 15 —;
R 50 is either R 3 , or according to formula XXIV;
wherein X 1 , X 2 , and optionally X 3 , represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X 1 , X 2 , and X 3 ; wherein,
each X 1 is independently selected from —C(R 6 )R 7 —, —O—, —S(O) 0-2 —, and —NR 5 —;
each X 2 is independently an optionally substituted bridgehead methine or a bridgehead nitrogen;
each X 3 is independently selected from —C(R 6 )R 7 —, —O—, —S(O) 0-2 —, and —NR 8 —;
Y is either:
an optionally substituted C 1-6 alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X 2 when X 2 is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R 6 or R 7 ; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R 6 or R 7 ;
or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system, unless D is —SO 2 —, in which case said saturated bridged ring system, is directly attached to D via an any annular atom of said saturated bridged ring system;
m and p are each independently one to four;
n is zero to two, when n is zero, then there is a single bond between the two bridgehead X 2 's;
R 6 and R 7 are each independently 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 , —NCO 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, optionally substituted heterocyclyl a C 1-6 lkyl, and a bond to either Y or D; or
R 6 and R 7 , when taken together are oxo; or
R 6 and R 7 , when taken together with a common carbon to which they are attached, form a optionally substituted three- to seven-membered spirocyclyl, said optionally substituted three- to seven-membered spirocyclyl optionally containing at least one additional annular heteroatom selected from N, O, S, and P;
R 8 is selected from —R 3 , Y, —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 ;
R 13 is 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 C 1-6 alkyl;
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 comprising up to four annular heteroatoms, and said heteroalicyclic optionally comprising 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 3 , —CN, —OR 3 , optionally substituted C 1-6 alkyl, optionally substituted heteroalicyclyl C 1-6 alkyl, optionally substituted aryl, optionally substituted aryl C 1-6 alkyl 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 11 )—, —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 containing between one and three heteroatoms but comprising 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 alkyQ, —OC 0-4 alkyQ-, —N(R 13 )C 0-4 alkylQ-, and —C(═O)N(R 13 )C 0-4 alkylQ;
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 C 1-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl C 1-6 alkyl, and optionally substituted aryl C 1-6 alkyl;
two of R 60 , when attached to a non-aromatic carbon, can be oxo;
P 1 is a suitable leaving group; and
P 2 is selected from —H, a metal, and a group removed in-situ when combining XXII and XXIII to make XXI.
116 . The process according to claim 115 , wherein Ar is para-phenylene as defined by the substitution pattern of —Z— and —B-L-T about said phenylene.
117 . The process according to claim 116 , wherein Z is either —O— or —NR 5 —.
118 . The process according to claim 117 , wherein —B-L-T is selected from the following:
wherein Q, R 20 , and R 13 are as defined above; each E is selected from —O—, —N(R 13 )—, —CH 2 , and —S(O) 0-2 —; M is selected from —O—, —N(R 3 )—, —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 R 25 ; and R 25 is 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 aryl C 1-6 alkyl, heteroaryl C 1-6 alkyl, and optionally substituted C 1-6 alkyl; two of R 25 , together with the carbon or carbons to which they are attached, can combine to form an optionally substituted three- to seven-membered alicyclic or heteroalicyclic; two of R 25 on a single carbon can be oxo.
119 . The process according to claim 118 , wherein there is one of R 1 that is -D-R 50 and another of R 1 that is —OR 3a .
120 . The process according to claim 119 , wherein D is —O—.
121 . The process according to claim 120 , wherein —O—R 50 and —OR are interchangeably located at the 6-position and 7-position of the quinazoline or quinoline according to Formula XXI.
122 . The process according to claim 121 , wherein —OR 3a is selected from —OH, —OSi(R 5 )(R 5 )R 5 , and optionally substituted —OC 1-6 alkyl.
123 . The process according to claim 122 , wherein J is ═N— or ═C(H)—.
124 . The process according to claim 123 , wherein —B-L-T is selected from:
wherein Q, R 20 , 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 R 25 ; and R 25 is selected from halogen, trihalomethyl, oxo, —CN, —NO 2 , —NH 2 , —OR, —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 aryl C 1-6 alkyl, heteroaryl C 1-6 alkyl, and optionally substituted C 1-6 alkyl; two of R 25 , together with the carbon or carbons to which they are attached, can combine to form a three- to seven-membered optionally substituted alicyclic or heteroalicyclic.
125 . The process according to claim 124 , wherein Q is selected from the following three formula:
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.
126 . The process according to claim 125 , wherein —B-L-T is either of formula XXV or formula XXVI,
wherein R 20 is defined as above; G is either an optionally substituted cycloalkyl or an optionally substituted heteroalicyclic; each R 30 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 , and optionally substituted C 1-6 alkyl; and R 3a and R 3b are each independently selected from —H and optionally substituted C 1-6 alkyl.
127 . The process according to claim 126 , wherein a compound of formula XXIIa is combined with a compound of formula XXIIIa to make a compound of formula XXIa,
wherein —B-L-T, Z, J, R 50 , and R 2 are as defined above; R 70 is selected from —H, —NO 2 , —NH 2 , and —NR 3 R 3 ; provided when Z is —N(R 5 )— that R 5 is selected from —H, C 1-3 alkyl, and aryl C 1-3 alkyl; P 1 is selected from halogen, optionally substituted alkyl-S(O) 0-2 —, optionally substituted arylsulfonate, optionally substituted alkylsulfonate, a group containing boron, an azide, a group containing phosphorus, and a metal; and P 2 is selected from —H and a metal.
128 . The process according to claim 127 , wherein P 2 is selected from —H, lithium, sodium, potassium, cesium, copper, palladium, and titanium.
129 . The process according to claim 128 , wherein Z is —O—.
130 . The process according to claim 129 , wherein P 1 is selected from chlorine, bromine, a toluene sulfonate, and trifluoromethansulfonate.
131 . The process according to claim 130 , wherein R 70 is —H.
132 . The process according to claim 131 , wherein J is ═C(H)—.
133 . The process according to claim 132 , wherein R 2 is selected from C 1-6 alkyl, perfluoro C 1-6 alkyl, and halogen.
134 . The process according to claim 133 , wherein XXIIa and XXIIIa are heated together, optionally with a base, optionally with microwave radiation, to form XXIa.
135 . The process according to claim 134 , wherein the base is selected from an organic base, an inorganic base, and a combination of an organic base and an inorganic base.
136 . The process according to claim 135 , wherein the base is selected from 2,6-lutidine, 4-N,N-dimethylaminopyridine, and a metal carbonate.
137 . The process according to claim 136 , wherein XXIIa and XXIIIa are heated together in a solvent with said base, at between about 40° C. and 200° C. for between about one hour and twenty-four hours to form XXIa.
138 . The process according to claim 137 , wherein the solvent is an organic solvent.
139 . The process according to claim 138 , wherein one molar equivalent of XXIIa is combined with between about one quarter and four molar equivalents of XXIIa.
140 . The process according to claim 139 , wherein one molar equivalent of XXIIa is combined with more than one but less than two molar equivalents of XXIIIa.
141 . The process according to claim 140 , wherein XXIIa is combined with XXIIIa and said base in an aromatic solvent to form a mixture, and said mixture is heated to between about 100° C. and 200° C. for between about one and ten hours to form Ia.
142 . The process according to claim 141 , wherein the aromatic solvent is an optionally substituted benzene.
143 . The process according to claim 142 , wherein the aromatic solvent is bromobenzene.
144 . The process according to claim 143 , wherein the base is 4-N,N-dimethylaminopyridine.
145 . The process according to claim 144 , wherein said mixture is heated to reflux for between about three and seven hours.
146 . The process according to claim 145 , wherein said mixture is heated to reflux for between about four and six hours.
147 . The process according to claim 140 , wherein XXIIa is combined with XXIIIa and said base in a non-aromatic solvent to form a mixture, and said mixture is heated to between about 40° C. and 100° C. for between about one and twenty hours to form XXIa.
148 . The process according to claim 147 , wherein the non-aromatic solvent comprises a functional group selected from an amide, and ether, a nitrile, a halide, an ester, an amine, and a ketone.
149 . The process according to claim 148 , wherein the non-aromatic solvent is N,N-dimethylacetamide.
150 . The process according to claim 149 , wherein the base is potassium carbonate.
151 . The process according to claim 150 , wherein said mixture is heated to about 50° C. between about ten and twenty hours.
152 . The process according to claim 151 , wherein the aromatic solvent is an optionally substituted pyridine.
153 . The process according to claim 152 , wherein the aromatic solvent is 2,6-lutidine.
154 . The process according to claim 153 , wherein the base is 2,6-lutidine.
155 . The process according to claim 154 , wherein said mixture is heated to reflux for between about three and seven hours.
156 . The process according to claim 155 , wherein said mixture is heated to reflux for between about four and six hours.
157 . The process according to claim 139 , wherein one molar equivalent of XXIIIa is combined with more than one but less than two molar, equivalents of XXIIa.
158 . The process according to claim 157 , wherein XXIIa is combined with XXIIIa and said base in an aromatic solvent to form a mixture, and said mixture is heated to between about 100° C. and 200° C. for between about ten and twenty hours to form XXIa.
159 . The process according to claim 158 , wherein the aromatic solvent is an optionally substituted pyridine.
160 . The process according to claim 159 , wherein the aromatic solvent is 2,6-lutidine.
161 . The process according to claim 160 , wherein the base is 2,6-lutidine.
162 . The process according to claim 161 , wherein said mixture is heated to between about 150° C. and 200° C. for between about fifteen and twenty hours.
163 . The process according to any of claims 134 - 162 , wherein a compound of formula XXIIb is substituted for the compound of formula XXIIa, and either a compound of formula XXIIIb or a compound of formula XXIIIc is substituted for the compound of formula XXIIIa, in order to make a compound of formula XXIb or a compound of formula XXIc, respectively,
wherein J, R 50 , R 20 and R 2 are as defined above.
164 . The process according to claim 163 , wherein R 2 , if present, is halogen.
165 . The process according to claim 164 , wherein R 2 , if present, is fluorine.
166 . The process according to claim 165 , wherein R 2 , if present, is up to two fluorines ortho to the oxygen of the phenylene to which R 2 is attached.
167 . The process according to claim 115 , used to make a compound listed in either Table 1 or Table 2.
168 . The process according to any of claims 115 - 167 , further comprising converting said compound to a pharmaceutically acceptable salt, hydrate, or prodrug thereof.Cited by (0)
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