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 having the structure of Formula (1) or Formula (46):
wherein:
Ar is selected from an optionally substituted five-membered aromatic heterocycle, an optionally substituted five-membered aromatic carbocycle, an optionally substituted six-membered aromatic heterocycle, and a substituted, optionally further substituted phenyl;
Q is selected from the group consisting of
Q is selected from the group consisting of
wherein:
R A is selected from —NH 2 , —NEt 2 , and —NH(CH 2 ) n OH, and n is 1 to;
R B is selected from the group consisting of
—CH 2 OH, —CH 2 CH 2 OH, and —CH 2 CH 2 CH 2 OH;
R C is at 2, 3, or 4 position of the piperidine ring; and R C is selected from the group consisting of —C(O)NHEt, —C(O)NEt 2 , c-butyl, c-pentyl, —C(O)NH-thiazole, oxazole, thiazole, —S(O) 2 NH 2 , —S(O) 2 NHEt, and —S(O) 2 NEt 2 ;
each R D is independently selected from —(CH 2 ) k OH or —(CH 2 ) k CO 2 H, and k is 1 to 6;
R E is at 2, 3, or 4 position of the piperidine ring; and R E is selected from the group consisting of —C(O)NH 2 , —C(O)NHEt, and —C(O)NEt 2 , and R F is thiazole, pyrazole, or isoxazole;
each R 1 is independently selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -L 1 -alkyl, -L 1 -cycloalkyl, -L 1 -heteroalkyl, -L 1 -haloalkyl, -L 1 -aryl, -L 1 -heterocycloalkyl, and -L 1 -heteroaryl; 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—;
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;
or any two adjacent R 1 groups together may form an optionally substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl ring;
R 5 is selected from the group consisting of hydrogen and C 1-6 alkyl;
or a pharmaceutically acceptable salt or pharmaceutically acceptable N-oxide thereof.
2. The compound of claim 1 , wherein the Ar is a substituted, optionally further substituted six-membered aromatic heterocycle.
3. The compound of claim 1 , wherein said optional substituents are selected from OH, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, aryl, haloaryl, or heteroaryl.
4. The compound of claim 1 , wherein Ar is selected from the group consisting of
5. The compound of claim 1 , wherein Q is selected from the group consisting of
6. The compound of claim 5 , wherein Ar is selected from the group consisting of
7. The compound of claim 1 , wherein the compound having the structure of Formula (1) is selected from Formula (2), Formula (3), or Formula (44):
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″ 2 NR″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 (2);
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;
or a pharmaceutically acceptable salt or pharmaceutically acceptable N-oxide thereof.
8. The compound of claim 1 , wherein the compound having the structure of Formula (46) is selected from Formula (47), Formula (48), or Formula (49):
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″ 2 NR″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 (47);
each R″ 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;
or a pharmaceutically acceptable salt or pharmaceutically acceptable N-oxide thereof.
9. The compound of claim any of claims 7 or 8 , wherein each R 2 is H.
10. A method of making the compound of claim 1 having the structure of Formula (1) or Formula (46), wherein R 5 is H, comprising:
i.) admixing a compound of structure:
with a compound having the structure:
and heating the admixture in a microwave oven, to yield a compound having the structure of Formula (C):
and
ii.) further admixing the compound having the structure of Formula (C) with a compound of structure: ArB(OH) 2 and heating the admixture in the presence of tetrakis(triphenylphosphino)palladium.