US2024043414A1PendingUtilityA1
Compounds for the Treatment of Kinase-Dependent Disorders
Est. expiryJan 26, 2038(~11.5 yrs left)· nominal 20-yr term from priority
C07D 215/48C07F 9/60Y02P20/55A61P 35/02C07D 413/12C07D 215/22C07D 401/12C07D 405/12C07D 413/10C07D 498/04A61K 31/47A61K 31/4709C07D 401/04C07D 401/06C07D 405/04C07D 413/04A61P 35/00
70
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Claims
Abstract
Disclosed herein are compounds of formula I. Compounds of formula I inhibit, regulate and/or modulate kinase receptor, particularly Axl and Mer signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions. The present invention also provides methods for making compounds as mentioned above, and compositions which contain these compounds.
Claims
exact text as granted — not AI-modified1 - 93 . (canceled)
94 . A compound of formula B-1
or a pharmaceutically acceptable salt thereof,
R a1 is optionally substituted (C 1 -C 6 ) alkyl;
R 1 is
wherein “ ” indicates the point of attachment, wherein:
Y 1 is absent;
Y 2 is absent or is —O—, —NH—, —NHO—, —NH—NH—, or —N—(C 1 -C 6 ) alkyl-; or
Y 2 is optionally substituted
wherein ring A is a 3, 4, 5, 6, or 7-membered ring, wherein “ ” indicates points of attachment,
Z 1 is O, NH, N—(C 1 -C 6 ) alkyl, NHO, or NO—(C 1 -C 6 ) alkyl; and
R a is —H, —(C 1 -C 6 ) alkyl, 4-6-membered heterocycloalkyl, 3-6-membered cycloalkyl, —(C 2 -C 6 ) alkylene-OH, —CH 2 CHOH—(C 2 -C 6 ) alkylene-OH, —(C 2 -C 6 ) alkylene-NH 2 , —(C 2 -C 6 ) alkylene-NH(C 1 -C 6 ), —(C 2 -C 6 ) alkylene-N(C 1 -C 6 ) 2 , or —(C 2 -C 6 ) alkylene-(4-6-membered heterocycloalkyl), wherein heterocycloalkyl is optionally substituted;
R 3 is —H or halo;
R 4 is —H or halo;
R 14 is —H or halo;
Y is —O—;
the subscript n is an integer of 1, 2, 3, or 4;
the subscript m is an integer of 1, 2, 3, 4, or 5; and
the subscript p is an integer of 0, 1, 2, 3, or 4,
wherein at each occurrence, “optionally substituted” means optionally substituted with 1, 2, 3, 4, or 5 independently selected R b substituents;
each R b is independently selected from the group consisting of halo, oxo, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-, (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-, (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-, (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-, —CN, —OH, —NH 2 , —NO 2 , —NHOR c , —OR c , —SR c , —C(O)R c , —C(O)NR c R c , —C(O)OR c , —C(O)NR c S(O) 2 R c , —OC(O)R c , —OC(O)NR c R c , —C(═NOH)R c , —C(═NOH)NR c , —C(═NCN)NR c R c , —NR c C(═NCN)NR c R c , —C(═NR c )NR c R c , —NR c C(═NR c )NR c R c , —NHR c , —NR c R c , —NR c C(O)R c , —NR c C(═NR c )R c , —NR c C(O)OR c , —NR c C(O)NR c R c , —NR c S(O)R c , —NR c S(O) 2 R c , —NR c S(O) 2 NR c R c , —S(O)R c , —S(O)NR c R c , —S(O) 2 R c , —S(O) 2 NR c C(O)R c , —Si(R c ) 3 , —P(O)R c R c , —P(O)(OR c )(OR c ), —B(OH) 2 , —B(OR c ) 2 , and —S(O) 2 NR c R c , wherein the (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-, (C 3 -C 10 ) cycloalky-(C 1 -C 4 ) alkylene-, (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-, and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R b are each further optionally substituted with 1, 2, or 3 independently selected R d substituents;
each R c is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-, (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-, (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-, and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-, wherein the (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl, (C 3 -C 10 ) cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-, (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-, (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-, and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R e are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R f substituents;
each R d is independently selected from the group consisting of (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, halo, (C 6 -C 10 ) aryl, 5-10 membered heteroaryl, (C 3 -C 10 ) cycloalkyl, 4-10 membered heterocycloalkyl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-, (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-, (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-, (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-, —CN, —NH 2 , —NHOR e , —OR e , —SR e , —C(O)R e , —C(O)NR e R e , —C(O)OR e , —OC(O)R e , —OC(O)NR e R e , —NHR e , —NR e R e , —NR e C(O)R e , —NR e C(O)NR e R e , —NR e C(O)OR e , —C(═NR e )NR e R e , —NR e C(═NR e )NR e R e , —NR e C(═NOH)NR e R e , —NR e C(═NCN)NR e R e , —S(O)R e , —S(O)NR e R e , —S(O) 2 R e , —NR e S(O) 2 R e , —NR e S(O) 2 NR e R e , and —S(O) 2 NR e R e , wherein the (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 6 -C 10 ) aryl, 5-10 membered heteroaryl, (C 3 -C 10 ) cycloalkyl, 4-10 membered heterocycloalkyl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-, (C 3 -C 10 ) cycloalkyl-(C 1 -C 4 ) alkylene-, (5-10 membered heteroaryl)-(C 1 -C 4 ) alkylene-, and (4-10 membered heterocycloalkyl)-(C 1 -C 4 ) alkylene- of R d are each optionally substituted with 1, 2, or 3 independently selected R f substituents;
each R e is independently selected from the group consisting of —H, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) cycloalkyl-(C 1 -C 4 ) alkylene-, (C 6 -C 10 ) aryl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-, 5- or 6-membered heteroaryl, (5- or 6-membered heteroaryl)-(C 1 -C 4 ) alkylene-, 4-7-membered heterocycloalkyl, (4-7-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 2 -C 4 ) alkenyl, and (C 2 -C 4 ) alkynyl, wherein the (C 1 -C 4 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 6 -C 10 ) aryl, 5 or 6-membered heteroaryl, 4-7-membered heterocycloalkyl, (C 6 -C 10 ) aryl-(C 1 -C 4 ) alkylene-, (5- or 6-membered heteroaryl)-(C 1 -C 4 ) alkylene-, (4-7-membered heterocycloalkyl)-(C 1 -C 4 ) alkylene-, (C 2 -C 4 ) alkenyl, and (C 2 -C 4 ) alkynyl of R e are each optionally substituted with 1, 2, or 3 R f substituents,
each R f is independently selected from the group consisting of halo, —OH, —CN, —COOH, —NH 2 , —NH—(C 1 -C 6 ) alkyl, —N((C 1 -C 6 ) alky) 2 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) alkylthio, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and (C 3 -C 6 ) cycloalkyl, wherein the (C 1 -C 6 ) alkyl, phenyl, (C 3 -C 6 ) cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R f are each optionally substituted with 1, 2, or 3 substituents selected from the group consisting of halo, —OH, —CN, —COOH, —NH 2 , (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, phenyl, (C 3 -C 10 ) cycloalkyl, 5-6 membered heteroaryl, and 4-6 membered heterocycloalkyl;
wherein heteroaryl and heterocycloalkyl each contain 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, sulfur, and oxygen.
95 . The compound of claim 94 or a pharmaceutically acceptable salt thereof, wherein:
R a1 is (C 1 -C 6 ) alkyl;
Y 1 is absent;
Y 2 is O, NH, NHO, NH—NH, or N—(C 1 -C 6 ) alkyl; or
Y 2 is optionally substituted azetidinyl;
Z is O, NH, or N—(C 1 -C 6 ) alkyl; and
R a is H, (C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkylene-OH, —CH 2 CHOH—(C 2 -C 6 ) alkylene-OH, —(C 2 -C 6 ) alkylene-NH 2 , —(C 2 -C 6 ) alkylene-NH(C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkylene-N((C 1 -C 6 ) alkyl) 2 , —(C 2 -C 6 ) alkylene-heterocycloalkyl), and 4-6 membered heterocycloalkyl, wherein heterocycloalkyl is optionally substituted.
96 . The compound of claim 94 or a pharmaceutically acceptable salt thereof, wherein —OR a1 is methoxy.
97 . The compound of claim 94 , which is a compound of formula C:
or a pharmaceutically acceptable salt thereof, wherein:
Y 1 is absent;
Y 2 is O, NH, NHO, NH—NH, or N—(C 1 -C 6 ) alkyl; or
Y 2 is optionally substituted azetidinyl;
Z 1 is O, NH, NO—(C 1 -C 6 ) alkyl, or N—(C 1 -C 6 ) alkyl;
R a is H, (C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkylene-OH, —CH 2 CHOH—(C 2 -C 6 ) alkylene-OH, —(C 2 -C 6 ) alkylene-NH 2 , —(C 2 -C 6 ) alkylene-NH(C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkylene-N((C 1 -C 6 ) alkyl) 2 , —(C 2 -C 6 ) alkylene-optionally substituted 4-6 membered heterocycloalkyl, or optionally substituted 4-6 membered heterocycloalkyl;
R 2 is (C 1 -C 6 )alkoxy; and
n and m are each independently integers of 0 to 3.
98 . The compound of claim 97 or a pharmaceutically acceptable salt thereof, wherein:
Y 1 is absent;
Y 2 is O, NH, NHO, NH—NH, or N—(C 1 -C 6 ) alkyl; or
Y 2 is optionally substituted azetidinyl;
Z 1 is O, NH, NO—(C 1 -C 6 ) alkyl, or N—(C 1 -C 6 ) alkyl;
R a is H, methyl, ethyl, —(C 2 -C 6 ) alkylene-OH, —CH 2 CHOH—(C 2 -C 6 ) alkylene-OH, —(C 2 -C 6 ) alkylene-NH 2 , —(C 2 -C 6 ) alkylene-NHMe, —(C 2 -C 6 ) alkylene-N(Me) 2 , —(C 1 -C 6 ) alkylene-morpholinyl, —(C 1 -C 6 ) alkylene-piperidinyl, (C 1 -C 6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azetidinyl, or optionally substituted oxetanyl;
and n and m or each 0 or 1.
99 . The compound of claim 97 , which is a compound of formula C-1.
or a pharmaceutically acceptable salt thereof, wherein:
Y 2 is O, NH, NHO, NH—NH, or N—(C 1 -C 6 ) alkyl; or
Y 2 is optionally substituted azetidinyl,
Z 1 is O, NH, NO—(C 1 -C 6 ) alkyl, or N—(C 1 -C 6 ) alkyl;
R a is H, methyl, ethyl, —(C 2 -C 6 ) alkylene-OH, —CH 2 CHOH—(C 2 -C 6 ) alkylene-OH, —(C 2 -C 6 ) alkylene-NH 2 , —(C 2 -C 6 ) alkylene-NHMe, —(C 2 -C 6 ) alkylene-N(Me) 2 , —(C 1 -C 6 ) alkylene-morpholinyl, —(C 1 -C 6 ) alkylene-piperidinyl, (C 1 -C 6 )alkylene-(optionally substituted pyrrolidinyl), optionally substituted azetidinyl, or optionally substituted oxetanyl.
100 . The compound of claim 94 , which is a compound of formula F:
or a pharmaceutically acceptable salt thereof.
101 . The compound of claim 100 or a pharmaceutically acceptable salt thereof, wherein:
R a1 is methyl; and
R 1 is
wherein:
Y 1 is absent;
Y 2 is —O—, —NH—, —NHO—, —NH—NH—, or N—(C 1 -C 6 ) alkyl; or
Y 2 is optionally substituted azetidinyl;
Z 1 is O, NH, or N—(C 1 -C 6 ) alkyl; and
R a is H, (C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkylene-OH, —CH 2 CHOH—(C 2 -C 6 ) alkylene-OH, —(C 2 -C 6 ) alkylene-NH 2 , —(C 2 -C 6 ) alkylene-NH(C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkylene-N((C 1 -C 6 ) alkyl) 2 , —(C 2 -C 6 ) alkylene-heterocycloalkyl), and 4-6 membered heterocycloalkyl, wherein heterocycloalkyl is optionally substituted.
102 . The compound of claim 94 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
103 . The compound of claim 94 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
104 . The compound of claim 94 which is selected from:
TABLE 1
No.
Structure
Name
5
methyl 4-[4-[[1-[(4- fluorophenyl)carbamoyl] cyclopropanecarbonyl]amino] phenoxy]-7- methoxyquinoline-6- carboxylate
6
4-[4-[[1-[(4- fluorophenyl)carbamoyl] cyclopropanecarbonyl]amino] phenoxy]-7- methoxyquinoline-6- carboxylic acid
7
1-N-[4-(6-carbamoyl-7- methoxyquinolin-4- yl)oxyphenyl]-1-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide
9
1-N-[4-[6-(ethylcarbamoyl)-7- methoxyquinolin-4- yl]oxyphenyl]-1-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide
10
1-N-[4-[6-[2- (dimethylamino)ethylcarbamoyl] 7-methoxyquinolin-4- yl]oxyphenyl]-1-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide
11
1-N′-(4-fluorophenyl)-N-[4-[7- methoxy-6-(2-piperidin-1- ylethylcarbamoyl)quinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
12
1-N′-(4-fluorophenyl)-1-N- [4-[7-methoxy-6-(2-morpholin- 4-ylethylcarbamoyl)quinolin- 4-yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
13
1-N′-(4-fluorophenyl)-1-N- [4-[7-methoxy-6-(oxetan-3- ylcarbamoyl)quinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
14
1-N′-(4-fluorophenyl)-1-N- [4-[7-methoxy-6- [(1-methylazetidin-3- yl)carbamoyl]quinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
15
1-N-[4-[6-(azetidine-1- carbonyl)-7-methoxyquinolin- 4-yl]oxyphenyl]-1-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
16
1-N′-(4-fluorophenyl)-1-N- [4-[6-(3-hydroxyazetidine- 1-carbonyl)-7- methoxyquinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
17
1-N′-(4-fluorophenyl)-1-N- [4-[7-methoxy-6- (methoxycarbamoyl) quinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
20
1-N′-(4-fluorophenyl)-1-N- [4-[6-(hydroxycarbamoyl)-7- methoxyquinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
21
1-N′-(4-fluorophenyl)-1-N- [4-[7-methoxy-6- [[(2R)-pyrrolidin-2- yl]methylcarbamoyl]quinolin- 4-yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
22
1-N′-(4-fluorophenyl)-1-N- [4-[7-methoxy-6- [[(2S)-pyrrolidin-2- yl]methylcarbamoyl]quinolin- 4-yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
26
1-N′-(4-fluorophenyl)-1-N- [4-[7-methoxy-6-(oxetan-3- yloxycarbamoyl)quinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
27
1-N′-(4-fluorophenyl)-1-N- [4-[6- (2-hydroxyethoxycarbamoyl)-7- methoxyquinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
30
1-N-[4-[6-(2,3- dihydroxypropoxycarbamoyl)-7- methoxyquinolin-4- yl]oxyphenyl]-1-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide Enantiomer 1
31
1-N-[4-[6-(2,3- dihydroxypropoxycarbamoyl)-7- methoxyquinolin-4- yl]oxyphenyl]-1-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide Enantiomer 2
32
1-N′-(4-fluorophenyl)-1-N- [4-[6-(hydrazinecarbonyl)-7- methoxyquinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
34
1-N-[4-(6-acetyl-7- methoxyquinolin-4- yl)oxyphenyl]-1-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
35
1-N′-(4-fluorophenyl)-1-N- [4-[7-methoxy-6-[(E)-N- methoxy-C- methylcarbonimidoyl]quinolin- 4-yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
36
1-N′-(4-fluorophenyl)-1-N- [4-[7-methoxy-6- [(Z)-N-methoxy-C- methylcarbonimidoyl]quinolin- 4-yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
98
1-N-[4-[6-carbamoyl-7-(3- morpholin-4- ylpropoxy)quinolin-4- yl]oxyphenyl]-1-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
103
1-N-[4-[6-carbamoyl-7-(2- methoxyethoxy)quinolin-4- yl]oxyphenyl]-1-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
106
1-N-[4-[6-carbamoyl-7-(2- hydroxyethoxy)quinolin-4- yl]oxyphenyl]-1-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
110
1-N′-(4-fluorophenyl)-1-N- [4-[7-(2-hydroxyethoxy)-6- (methylcarbamoyl)quinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
115
1-N-[4-[6-carbamoyl-7-(2- hydroxypropoxy)quinolin-4- yl]oxyphenyl]-1-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
116
1-N′-(4-fluorophenyl)-1-N- [4-[7-(2-hydroxypropoxy)-6- (methylcarbamoyl)quinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
128
methyl 4-[2-chloro-4-[[1-[(4- fluorophenyl)carbamoyl] cyclopropanecarbonyl] amino]phenoxy]-7- methoxyquinoline-6- carboxylate
129
methyl 4-[2-fluoro-4-[[1-[(4- fluorophenyl)carbamoyl] cyclopropanecarbonyl] amino]phenoxy]-7- methoxyquinoline-6- carboxylate
130
4-[2-chloro-4-[[1-[(4- fluorophenyl)carbamoyl] cyclopopanecarbonyl] amino]phenoxy]-7- methoxyquinoline-6- carboxylic acid
131
4-[2-fluoro-4-[[1-[(4- fluorophenyl)carbamoyl] cyclopropanecarbonyl] amino]phenoxy]-7- methoxyquinoline-6- carboxylic acid
132
1-N′-[4-(6-carbamoyl-7- methoxyquinolin-4-yl)oxy-3- chlorophenyl]-1-N-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
133
1-N′-[4-(6-carbamoyl-7- methoxyquinolin-4-yl)oxy-3- fluorophenyl]-1-N-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
134
1-N′-[3-chloro-4-[7-methoxy-6 (methylcarbamoyl)quinolin-4- yl]oxyphenyl]-1-N-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
135
1-N′-[3-fluoro-4-[7-methoxy-6 (methylcarbamoyl)quinolin-4- yl]oxyphenyl]-1-N-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
193
1-N′-(4-fluorophenyl)-1-N- [4-[7-methoxy-6-[(E)- methoxyiminomethyl]quinolin- 4-yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
264
1-N′-(2-chloro-4-fluorophenyl)- 1-N-[3-fluoro-4-[7-methoxy-6- (methylcarbamoyl)quinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
274
1-N-(4-chlorophenyl)-1-N′-[3- fluoro-4-[7-methoxy-6- (methylcarbamoyl)quinolin-4- yl]oxyphenyl]cyclopropane- 1,1-dicarboxamide
or a pharmaceutically acceptable salt thereof.
105 . A compound of formula H:
or a pharmaceutically acceptable salt thereof, wherein:
Y is O;
R 1 is selected from the group consisting of —CO—NR 5 R 6 and —CO 2 R 7 ,
R 2 is optionally substituted C 1 -C 6 alkoxy;
R 3 is —H or halo;
R 4 is —H or halo;
R 5 and R 6 are each independently —H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 alkoxy;
R 7 is H or optionally substituted C 1 -C 6 alkyl;
R 8 and R 9 are each independently H and optionally substituted C 1 -C 6 alkyl.
106 . The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein R 3 is H.
107 . The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein R 4 is halo.
108 . The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein R 1 is —CO 2 H, —CO 2 -Me, —CO—NHR 6 , —CO—NH 2 , or —CO—NMeR 6 .
109 . The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
110 . A process for making a compound of Formula H:
or a pharmaceutically acceptable salt thereof, comprising:
reacting a compound of formula IV:
with a compound of formula V:
R 1 is —CO—NR 5 R 6 or —CO 2 R 7 ;
R 2 is optionally substituted C 1 -C 6 alkoxy;
R 3 is —H or halo;
R 4 is —H or halo;
R 5 and R 6 are each independently —H, optionally substituted (C 1 -C 6 ) alkyl, or optionally substituted (C 1 -C 6 ) alkoxy;
R 7 is —H or optionally substituted (C 1 -C 6 ) alkyl;
R 8 and R 9 are each independently —H and optionally substituted (C 1 -C 6 ) alkyl; and
Y is O.
111 . The process of claim 110 , further comprising reacting a compound of Formula VI:
with a compound of Formula VII:
to form a compound of Formula VIII:
and reducing the compound of Formula VIII to provide a compound of Formula V,
wherein:
W is halo.
112 . A pharmaceutical composition comprising a compound of claim 94 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
113 . A method of treating a disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of a protein kinase, comprising administering to a subject in need thereof a compound of claim 94 or a pharmaceutically acceptable salt thereof.
114 . The method of claim 113 , wherein the disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of a protein kinase is cancer.
115 . A method for inhibiting a protein kinase, the method comprising contacting the protein kinase with a compound of claim 94 or a pharmaceutically acceptable salt thereof.
116 . The method of claim 115 , wherein the protein kinase is Axl, Mer, c-Met, KDR, or a combination thereof.Join the waitlist — get patent alerts
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