IP Library › Patent Application 16921542

Patent Application

App. No. 16/921,542

C-Met Modulators and Methods of Use

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Patent No.: US None
App. No.: 16/921,542

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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 (1170)

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

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

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

N-{[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)(methyl)amino] carbonothioyl}-2- phenylacetamide

1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)imidazolidin-2- one

1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3- (phenylmethyl)imidazolidin- 2-one

1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3- (phenylacetyl)imidazolidin-2- one

ethyl [(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)amino](oxo) acetate

N-{[(4-{[6,7- bis(methyloxy)quinazolin-4- yl]amino}-3- fluorophenyl)amino] carbonothioyl}-2- phenylacetamide

N′-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N- methyl-N-(2- phenylethyl)sulfamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3- (phenylmethyl)-1,2,4- oxadiazol-5-amine

1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)piperidin-2-one

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (phenylmethyl)ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-4- phenyl-1,3-thiazol-2-amine

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (2-phenylethyl)ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-1- phenylmethanesulfonamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-2- phenylethanesulfonamide

4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N- (phenylmethyl)benzene- sulfonamide

4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-methyl-N- (phenylmethyl)benzene- sulfonamide

4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-(2- phenylethyl)benzene- sulfonamide

4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-methyl-N- (2- phenylethyl)benzene- sulfonamide

4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-(3- phenylpropyl)benzene- sulfonamide

1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)pyrrolidin-2-one

4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl (phenylmethyl)carbamate

4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl (2- phenylethyl)carbamate

4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-methyl-N- (3- phenylpropyl)benzene- sulfonamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- phenylethanediamide

N-{[(3-fluoro-4-{[7-{[(2- methyloctahydrocyclopenta[c] pyrrol-5-yl)methyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}phenyl)amino] carbonothioyl}-2- phenylacetamide

N-[(Z)-[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)amino](imino) methyl]-2-phenylacetamide

4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-[2- (phenyloxy)ethyl]benzene- sulfonamide

N,N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-bis- (3-phenylpropane-1- sulfonamide)

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3- phenylpropane-1-sulfonamide

N2-[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3- fluorophenyl)sulfonyl]-N1- phenylglycinamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-2- phenylacetamide

N-{[(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3- yl)amino]carbonothioyl}-2- phenylacetamide

6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-1,3-benzothiazol-2- amine

6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-amine

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2- phenylacetamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (2-morpholin-4- ylethyl)ethanediamide

benzyl-{[4-(6,7-dimethoxy- quinolin-4-yloxy)-3-fluoro- phenylcarbamoyl]-methyl}- carbamic acid tert-butyl ester

N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- (phenylmethyl)glycinamide

N2-acetyl-N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- (phenylmethyl)glycinamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-1,3-benzothiazol-2- yl)-2-phenylacetamide

benzyl-{[6-(6,7-dimethoxy- quinolin-4-yloxy)-pyridin-3- ylcarbamoyl]-methyl}- carbamic acid tert-butyl ester

N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-N2- (phenylmethyl)glycinamide

N2-acetyl-N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-N2- (phenylmethyl)glycinamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-3- phenylpropanamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-4- phenylbutanamide

N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-N2- methyl-N2- (phenylmethyl)glycinamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- {2-[4- (methyloxy)phenyl]ethyl} ethanediamide

N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- methyl-N2- (phenylmethyl)glycinamide

4-[(2-amino-1,3-benzothiazol- 6-yl)oxy]-6,7-bis(methyloxy)- 1-(2-oxo-2- phenylethyl)quinolinium

N-{[(4-{[6,7- bis(methyloxy)quinolin-4- yl]amino}phenyl)amino] carbonothioyl}-2-phenyl- acetamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-3- phenylpropanamide

N-{[(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)amino]carbonothioyl}-2- phenylacetamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (2,3-dihydro-1H-inden-1- yl)ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (2,3-dihydro-1H-inden-2- yl)ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (1,2,3,4-tetrahydronaphthalen- 1-yl)ethanediamide

N′-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N- (2-phenylethyl)-N- (phenylmethyl)sulfamide

N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- (trifluoroacetyl)glycinamide

N-{[4-(6,7-dimethoxy- quinolin-4-yloxy)-3-fluoro- phenylcarbamoyl]-methyl}- benzamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-N′-(4- fluorophenyl)propanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [(2S)-1,2,3,4- tetrahydronaphthalen-2- yl]ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [2-(4- methylphenyl)ethyl]ethane- diamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (2- phenylpropyl)ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [2-(4- chlorophenyl)ethyl]ethane- diamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N,N′-bis(phenylmethyl) sulfamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N,N′-bis(2-phenylethyl) sulfamide

ethyl [(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)amino](oxo)acetate

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N′-(2- phenylethyl)ethanediamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N′-(4- fluorophenyl)propanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (1,2,3,4-tetrahydronaphthalen- 2-yl)ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [2-(1-methylpyrrolidin-2- yl)ethyl]ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [2-(phenyloxy) ethyl]ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [2-hydroxy-1- (phenylmethyl)ethyl]urea

1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3- [(4-methylphenyl)sulfonyl]-4- (phenylmethyl)imidazolidin- 2-one

N′-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N- methyl-N-(2- phenylethyl)ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- {[3- (trifluoromethyl)phenyl] methyl}ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- {2-[3- (trifluoromethyl)phenyl] ethyl}ethanediamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-3-oxo-4- phenylbutanamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-2-[3- (trifluoromethyl)phenyl] acetamide

6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-[2- (phenyloxy)ethyl]-1,3- benzothiazol-2-amine

6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-(2- piperidin-1-ylethyl)-1,3- benzothiazol-2-amine

6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-methyl-N- (2-phenylethyl)-1,3- benzothiazol-2-amine

6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-(2- pyrrolidin-1-ylethyl)-1,3- benzothiazol-2-amine

6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-{[3- (trifluoromethyl)phenyl] methyl}-1,3-benzothiazol-2- amine

6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-{2-[3- (trifluoromethyl)phenyl] ethyl}-1,3-benzothiazol-2- amine

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N′-[3- (trifluoromethyl)phenyl] propanediamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2-[3- (trifluoromethyl)phenyl] acetamide

N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- {[3- (trifluoromethyl)phenyl] methyl}glycinamide

N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- (2-phenylethyl)glycinamide

N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2- {2-[3- (trifluoromethyl)phenyl] ethyl}glycinamide

benzyl-{[5-chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)- pyridin-3-ylcarbamoyl]- methyl}-carbamic acid tert- butyl ester

N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3- yl)-N2- (phenylmethyl)glycinamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2-[3,5- bis(trifluoromethyl)phenyl] acetamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3- benzothiazol-2-yl)-2-[2- chloro-5- (trifluoromethyl)phenyl] acetamide

N-{3-fluoro-4-[(6- (methyloxy)-7-{[(1- methylpiperidin-4- yl)methyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(2- phenylethyl)ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- (1,2,3,4- tetrahydroisoquinolin-1- ylmethyl)ethanediamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′- [(2-methyl-1,2,3,4- tetrahydroisoquinolin-1- yl)methyl]ethanediamide

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

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 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;

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:

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 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;

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

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N′- (phenylmethyl)cyclopropane- 1,1-dicarboxamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N′- phenylcyclopropane-1,1- dicarboxamide

N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperidin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperidin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N′-(2- phenylethyl)cyclopropane- 1,1-dicarboxamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-methylpyridin- 3-yl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-{4-[(7-chloroquinolin- 4-yl)oxy]-3- fluorophenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-{4-[(7-chloroquinolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinazolin- 4-yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-{5-chloro-6-[(6- (methyloxy)-7-{[(1- methylpiperidin-4- yl)methyl]oxy}quinolin- 4-yl)oxy]pyridin-3-yl}- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-[5-chloro-6-({6- (methyloxy)-7- [(piperidin-4- ylmethyl)oxy]quinolin-4- yl}oxy)pyridin-3-yl]-N′- (4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-[5-chloro-6-({6- (methyloxy)-7- [(phenylmethyl)oxy] quinolin-4-yl}oxy)pyridin-3- yl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide

N-{3-fluoro-4-[(6- (methyloxy)-7-{[(1- methylpiperidin-4- yl)methyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-methylphenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-fluorophenyl)-N′-[2- methyl-6-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)pyridin-3- yl]cyclopropane-1,1- dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloro-2- methylpyridin-3-yl)-N′- (4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-[3-fluoro-4-({7- (methyloxy)-6-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3,5- difluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2,5- difluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-[3-fluoro-4-({7- (methyloxy)-6-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-{3-fluoro-4-[(6- (methyloxy)-7-(2-methyl octahydrocyclo- penta[c]pyrrol-5- ylmethoxy)quinazolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-{3-fluoro-4-[(7- (methyloxy)-6-{[(1- methylpiperidin-4- yl)methyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-[5-fluoro-2-methyl-4- ({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2,3,5- trifluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-2- methylphenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-chloro-5- methylphenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(3-fluoro-4-{[6- hydroxy-7- (methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-fluorophenyl)-N′-[2- methyl-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]cyclopropane- 1,1-dicarboxamide

N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperazin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-{3-fluoro-4-[(6- (methyloxy)-7-{[(1- methylpiperidin-4- yl)methyl]oxy}quinolin- 4-yl)oxy]phenyl]-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-fluorophenyl)-N′-[4- ({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]cyclopropane- 1,1-dicarboxamide

N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-chloro-5- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[6,7- bis(methyloxy)-2- (methylthio)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-fluorophenyl)-N′-(4- {[2-methyl-6,7- bis(methyloxy)quinazolin- 4- yl]oxy}phenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[2-amino-6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(3-fluoro-4-{[2- (methylamino)-6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

(1S,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

(1R,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

N-(4-{[6-{[3- (diethylamino)propyl]oxy}- 7-(methyloxy)quinolin- 4-yl]oxy)-3- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[6-{[2- (diethylamino)ethyl]oxy}- 7-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

1,1-dimethylethyl 4-(3- {[4-[(2-fluoro-4-{[(1- {[(4- fluorophenyl)amino]carbonyl} cyclopropyl)carbonyl] amino}phenyl)oxy]-6- (methyloxy)quinolin-7- yl]oxy}propyl)piperazine- 1-carboxylate

(1R,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

(1R,2R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

N-(4-{[7-{[3- (diethylamino)propyl]oxy}-6- (methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[7-{[3-(4- acetylpiperazin-1-yl) propyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

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

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)-1- (phenylmethyl)azetidine- 3,3-dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)azetidine- 3,3-dicarboxamide

(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

(1R,2R)-N-{3-fluoro-4- [(6-(methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

(1R,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- piperazin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

N-(3-fluoro-4-{[7-({3-[4- (1-methylethyl)piperazin- 1-yl]propyl}oxy)-6- (methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide

(1R,2R)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

(1R,2R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

(1R,2S)-N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

(1R,2S)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide

(1R,2S)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- piperazin-1- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

(1R,2R,3S)-N-[3-fluoro- 4-({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

(1R,2R,3S)-N-{3-fluoro- 4-[(6-(methyloxy)-7-{[3- (4-methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

(1R,2R,3S)-N-[3-fluoro- 4-({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

(1R,2R,3S)-N-{3-fluoro- 4-[(6-(methyloxy)-7-{[3- (4-methylpiperazin-1- yl)propyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide

(2R,3R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

(2R,3R)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide

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

(1R,2R,3S)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide

(1R,2R,3S)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide

N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide

N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2,2- dimethylcyclopropane- 1,1-dicarboxamide

N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6- (methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide

N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide

N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperazin-1- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide

(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

N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide

N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclobutane- 1,1-dicarboxamide

(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

(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

(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

(2R,3R)-N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinazolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

(1R,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- piperazin-1- ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

(2R,3R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[(4- fluorophenyl)methyl] cyclopropane-1,1- dicarboxamide

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;

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;

D is selected from —O—, —S(O) 0-2 —, and —NR 15 —;

R 50 is either R 3 , or according to formula XXIV;

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 ;

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 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:

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.