Diarylamine-containing compounds and compositions, and their use as modulators of c-kit receptors
View Patent ↗Described herein are compounds that include a diarylamine structural feature. Also described herein are methods for making such compounds, methods for using such compounds to modulate the activity of c-kit receptors, and pharmaceutical compositions and medicaments comprising such compounds. Also described herein are methods of using such compounds, pharmaceutical compositions and medicaments to treat and/or prevent and/or inhibit and/or ameliorate the pathology and/or symptomology diseases or conditions associated with the activity of c-kit receptors.
1. A compound according to Formula (23), Formula (24), Formula (45), Formula (50), Formula (51), or Formula (52):
wherein:
M is selected from the group consisting of H, OH, SH, NO 2 , CN, NR″ 2 , and an optionally substituted moiety selected from -L 7 -alkyl, -L 7 -cycloalkyl, -L 7 -heteroalkyl, -L 7 -haloalkyl, -L 7 -aryl, -L 7 -heterocycloalkyl, and -L 7 -heteroaryl; wherein L 7 is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O) 2 —, —OC(O)—, —C(O)NR″(CR″ 2 ) 1-6 C(O)O—, —CR″2NR″CR″ 2 C(O)O—, —C(O)NR″Y 1 C(O)O—, —C(O)NR″NR″C(O)O—, —S(O)NH—, —C(O)NR″CR″ 2 C(O)W—, —CR″ 2 NR″WO—, —CR″ 2 NR″Y 1 C(O)O—, and —C(O)NR″O—; W is C 1-6 alkylene; Y 1 is optionally substituted arylene or optionally substituted heteroarylene; wherein said optional substituents are selected from halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl and halo- C 1-6 alkoxy; provided that M is not H in Formula (23) or Formula (50);
each R 1 is independently an optionally substituted moiety selected from -L 1 -H or -L 1 -alkyl; wherein L 1 is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O) 2 —, —C(O)NH(CR″ 2 ) 1-6 C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—;
R 5 is selected from the group consisting of hydrogen and C 1-6 alkyl;
each R″ is independently H, OH, halogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, aryl, haloaryl, or heteroaryl;
each X is independently selected from N or CR 2 , provided that at least one but no more than 2 X groups are N;
each R 2 is independently selected from the group consisting of H, OH, halogen, and an optionally substituted moiety selected from -L 2 -alkyl, -L 2 -cycloalkyl, -L 2 -heteroalkyl, -L 2 -haloalkyl, -L 2 -aryl, -L 2 -heterocycloalkyl, and -L 2 -heteroaryl;
wherein L 2 is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O) 2 —, —C(O)NR″(CR″ 2 ) 1-6 C(O)O—, —OC(O)—, —CR″ 2 NR″CR″ 2 C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—; wherein said optional substituents are selected from halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, and halo-C 1-6 alkoxy;
or any two adjacent R 2 groups together may form an optionally substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl ring;
each of R 3 and R 4 is independently an optionally substituted moiety selected from -Z, -L 3 -Z, -L 3 -H, -L 3 -alkyl, -L 3 -cycloalkyl, -L 3 -heteroalkyl, -L 3 -haloalkyl, -L 3 -aryl, -L 3 -heterocycloalkyl, and -L 3 -heteroaryl; wherein L 3 is selected from a bond, —C(S)—, —C(O)O—, —C(O)NR′″—, —(CR″ 2 ) 1-6 —, —CR′″ 2 S(O)—, —CR′″ 2 S(O) 2 —, —CR′″ 2 S(O)NR′″—, —CR′″ 2 C(O)NR′″—, —(CR′″ 2 ) 1-6 NR′″—, —(CR′″ 2 ) 1-6 O—, —(CR′″ 2 ) 1-6 C(O)O—, —Y 2 C(O)O—, and an optionally substituted C 1-6 alkylene;
wherein:
said optional substituents are selected from halogen, —OH, ═O, —Y 3 , C 1-6 alkyl, C 1-6 alkoxy, halogen or OH substituted C 1-6 alkyl, halogen or OH substituted C 1-6 alkoxy, —(CR′″ 2 ) 1-6 C(O)OR 6 , —C(O)NR′″ 2 , —C(O)R 6 , or —C(O)OR 6 ;
Y 2 is an optionally substituted cycloalkyl ring or optionally substituted non-aromatic heterocyclic ring; wherein said optional substituents are selected from C 1-6 alkyl, halogen, —OH, ═O, and —CN;
Y 3 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted non-aromatic heterocycle; wherein said optional substituents are selected from C 1-6 alkyl, halogen, —OH, ═O, and —CN;
Z is —H, —OH, —CN, —COOR′″, —NR′″ 2 , or —C≡CR′″;
each R′″ is independently H, alkyl, or substituted alkyl;
or two R′″ together may form a 3-6 membered cycloalkyl or heterocyclic ring;
or R 3 and R 4 taken together with the N atom to which they are attached may form an optionally substituted 3 to 8-membered heterocyclic ring;
wherein:
said optional substituents are selected from halogen, —OH, ═O, —Y 3 , C 1-6 alkyl, C 1-6 alkoxy, halogen or OH substituted C 1-6 alkyl, halogen or OH substituted C 1-6 alkoxy, —(CR′″ 2 ) 1-6 Y 4 , —(CR′″ 2 ) 1-6 OR 6 , —C(O)NR′″R 6 , —C(O)OR 6 , —OR 6 , —NR′″C(O)OR 6 , —NR′″C(O)R 6 , —(CR′″ 2 ) 1-6 C(O)OR 6 , —(CR′″ 2 ) 1-6 NR′″C(O)OR 6 , —(CR′″ 2 ) 1-6 NR 7 R 8 , —S(O) 2 NR′″ 2 , —C(O)R 6 , —OC(O)R 6 , —NR 7 R 8 , —(CR′″ 2 ) 1-6 C(O)NR 7 R 8 , S(O) 2 R A , or —C(O)R A ;
Y 4 is aryl, heteroaryl, cycloalkyl, or non-aromatic heterocycle;
R A is selected from —NH 2 , —NEt 2 , and —NH(CH 2 ) 1-6 OH;
R 6 is H, alkyl, substituted alkyl, cycloalkyl, non-aromatic heterocycle, aryl, or heteroaryl;
each of R 7 and R 8 is independently H, OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, or halo-C 1-6 alkoxy;
or R 7 and R 8 taken together with the N atom to which they are attached may form a 3 to 6-membered heterocyclic ring;
T 1 is an optionally substituted moiety selected from -L 4 -, -alkylene-L 4 -, -L 4 -alkylene-, -L 4 -cycloalkylene-, -L 4 -heteroalkylene-, -L 4 -haloalkylene-, -L 4 -arylene-, -L 4 -heteroarylene-, and -L 4 -heterocycloalkylene-; wherein L 4 is selected from a bond, —O—, —NH—, —S—, —CR″ 2 —, —NR′″C(O)—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NR′″—, —S(O)—, —S(O) 2 —, —OC(O)—, —C(O)NR′″(CR″ 2 ) 1-6 C(O)O—, —C(O)NR′″(CR″ 2 ) 1-6 C(O)—, —CR″ 2 NR′″CR″ 2 C(O)O—, —C(O)NR′″NR′″C(O)O—, —C(O)NR′″(CR″ 2 ) 1-6 —, —CR″ 2 C(O)—, and —S(O)NH—; wherein said optional substituents are selected from halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, aryl, haloaryl, and heteroaryl;
or a pharmaceutically acceptable salt, or pharmaceutically acceptable N-oxide thereof.
2. The compound of claim 1 , wherein each R 2 is H.
3. The compound of claim 1 , wherein the compound is selected from the group consisting of:
tert-butyl 2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzamido)acetate,
tert-butyl 2-(4-(2-(4-(2-diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzylamino)acetate,
tert-butyl 2-(4-(2-(4-(2-diethylamino)ethoxy)phenylamino)pyrimidin-5-yl) benzylamino)acetate,
2,2′-(2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenoxy)ethylazanediyl)diethanol,
1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylic acid,
tert-butyl 2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl) benzamido)acetate,
methyl 1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate,
N-(4-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,
1-(2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylic acid,
N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,
tert-butyl 2-(4-(2-(4-(2-morpholinoethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,
tert-butyl 2-(4-(2-(4-(2-(4-carbamoylpiperidin-1-yl)ethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,
4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)phenyl acetate,
ethyl 2-(2-(diethylamino)ethoxy)-5-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoate,
4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl 4-methylpiperazine-1-carboxylate,
5-(4-methoxyphenyl)-N-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)phenyl)pyrimidin-2-amine,
methyl 4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzoate,
N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidin-2-amine,
2-(2-(diethylamino)ethoxy)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benioic acid,
methyl 2-(2-(diethylamino)ethoxy)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoate,
N-(3-(2-(diethylamino)ethoxy)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,
N-(3-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,
1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxamide,
1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-3-carboxamide,
tert-butyl 3-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)propanoate,
5-(4-methoxyphenyl)-N-(4-(piperazin-1-ylmethyl)phenyl)pyrimidin-2-amine,
1-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)ethanone,
(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone,
1-(3-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)propyl)pyrrolidin-2-one,
(S)-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidin-2-yl)methanol,
(R)-N-(4-((2-(methoxymethyl)pyrrolidin-1-yl)methyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,
1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidin-3-ol,
methyl 1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)cyclopentanecarboxylate,
4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)-2-methylpiperazine-1-carboxylic acid,
3-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)propanoic acid,
1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-3-carboxylic acid,
ethyl 2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)acetate,
2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)acetic acid,
1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidine-3-carboxylic acid,
3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl morpholine-4-carboxylate,
3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl 4-methylpiperazine-1-carboxylate,
3-(5-(4-((2-tert-butoxy-2-oxoethylamino)methyl)phenyl)pyrimidin-2-ylamino)phenyl 4-methylpiperazine-1-carboxylate,
methyl 4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazine-1-carboxylate,
4-(5-(4-((2-tert-butoxy-2-oxoethylamino)methyl)phenyl)pyrimidin-2-ylamino)phenyl 4-methylpiperazine-1-carboxylate,
N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide,
2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-1-(4-methylpiperazin-1-yl)ethanone,
N1-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperidine-1,4-dicarboxamide,
3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl 4-methylpiperazine-1-carboxylate,
4-hydroxy-N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperidine-1-carboxamide,
N-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide,
1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxamide,
furan-2-yl(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazin-1-yl)methanone,
5-(4-methoxyphenyl)-N-(4-(2-(piperazin-1-yl)ethyl)phenyl)pyrimidin-2-amine,
N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-N,4-dimethylpiperazine-1-carboxamide,
1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxamide,
1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylic acid,
methyl 4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazine-1-carboxylate,
1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylic acid,
2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)acetic acid,
methyl 2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)acetate,
(3-(hydroxymethyl)piperidin-1-yl)(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,
(3-hydroxypyrrolidin-1-yl)(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,
1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-4-carboxamide,
3-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazin-1-yl)propanoic acid,
(S)-1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)pyrrolidine-2-carboxylic acid,
4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethylamino)cyclohexanecarboxylic acid,
4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide,
1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-3-carboxamide,
N-(3-carbamoylphenyl)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzamide,
1,4′-bipiperidin-1′-yl(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,
(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,
4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(2-(pyridin-2-yl)ethyl)benzamide,
4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide,
(4-(furan-2-carbonyl)piperazin-1-yl)(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,
3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide,
(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(1-methylpiperidin-4-yl)piperazin-1-yl)methanone,
1-(4-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperazin-1-yl)ethanone,
(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,
1,4′-bipiperidin-1′-yl(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,
1-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-3-carboxamide,
N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide,
methyl 4-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenylcarbamoyl)piperazine-1-carboxylate,
(R)-1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylic acid,
(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone,
4-acetyl-N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperazine-1-carboxamide, and
(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone.
4. A compound of claim 1 having the structure:
5. A method of making the compound of claim 1 having the structure of Formula (23), Formula (24), Formula (45), Formula (50), Formula (51), or Formula (52), comprising admixing a compound of structure:
with a compound having the structure
to yield a compound having the structure of Formula (C):
and further admixing the compound having the structure of Formula (C) with a compound selected from:
6. A method of treating a gastrointestinal stromal tumor in an animal, the method comprising administering to the animal a therapeutically effective amount of a compound having the structure of Formula (23), Formula (24), Formula (45), Formula (50), Formula (51), or Formula (52) of claim 1 .