C-met modulators and methods of use

1. A compound of Formula XXI,

or a pharmaceutically acceptable salt thereof, 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;

there is one of R 1 that is -D-R 50 and another of R 1 that is —OR 3a ;

D is —O—;

—O—R 50 and —OR 3a are interchangeably located at the 6-position and 7-position of the compound of Formula XXI;

—OR 3a is selected from —OH, —OSi(R 5 )(R 5 )R 5 , and optionally substituted —OC 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 N—;

Z is either —O— or —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 para-phenylene as defined by the substitution pattern of —Z— and -B-L-T about said phenylene;

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; or

two R 3 , together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from —H,

trihalomethyl, —SO 2 R 5 , —SO 2 NR 5 R 5 , —CO 2 R 5 , —C(O)NR 5 R 5 , —C(O)R 5 , and optionally substituted lower alkyl;

-B-L-T is either of formula XXV or formula XXVI,

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; or

two of R 20 , together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic, said optionally substituted three- to seven-membered heteroalicyclic either Spiro- to, or fused to, the ring system to which it is attached;

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;

R 13a and R 13b are each independently selected from —H and optionally substituted C 1-6 alkyl;

R 50 is either R 3 or formula XXIV;

wherein X 1 , X 2 , and optionally X 3 , represent the atoms of a saturated bridged ring system, said saturated bridged ring system comprising up to four annular heteroatoms represented by any of X 1 , X 2 , and X 3 ; wherein,

each X 1 is independently selected from —C(R 6 )R 7 —, —O—, —S(O) 0-2 —, and —NR 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 C 1-6 alkylene linker, between D and either 1) any annular atom of the saturated bridged ring system, except X 2 when X 2 is a bridgehead nitrogen, or 2) any heteroatom, represented by any of R 6 or R 7 ; provided there are at least two carbon atoms between D and any annular heteroatom of the saturated bridged ring system or any heteroatom represented by any of R 6 or R 7 ;

or Y is absent, when Y is absent, said saturated bridged ring system, is directly attached to D via an annular carbon of said saturated bridged ring system;

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 C 1-6 alkyl, and a bond to either Y or D; or

R 6 and R 7 , when taken together are oxo; or

R 6 and R 7 , when taken together with a common carbon to which they are attached, form an 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; and

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 .

2. The compound according to claim 1 which is a compound of formula XXIa,

wherein 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.

3. The compound according to claim 2 , wherein Z is —O—;

R 70 is —H; and

R 2 is selected from C 1-6 alkyl, perfluoro C 1-6 alkyl, and halogen.

4. The compound according to claim 3 which is a compound of formula XXIb

5. The compound according to claim 4 , wherein R 2 , if present, is halogen.

6. The compound according to claim 5 , wherein R 2 , if present, is fluorine.

7. The compound according to claim 6 , wherein R 2 , if present, is up to two fluorines ortho to the oxygen of the phenylene to which R 2 is attached.

8. The compound according to any one of claims 1 - 7 , wherein each R 20 is independently selected from —H, halogen, trihalomethyl, 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.

9. The compound according to claim 1 , as depicted in Table 2, or a pharmaceutically acceptable salt thereof:

TABLE 2

Entry

Name

Structure

13

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

14

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

15

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

21

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

26

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

31

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

45

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

53

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

54

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

69

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

73

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

74

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

75

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

79

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

84

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

85

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

86

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

87

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

88

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

89

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

92

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

93

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

94

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

95

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

96

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

10. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

11. A pharmaceutical composition comprising a compound of claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable excipient or carrier.