Pyrimidine inhibitors of kinase activity

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Quick Facts

Patent No.: US 8,536,180
App. No.: 12/787,915
Granted: Sep 17, 2013
Kind: B2

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Abstract

Described herein are compounds of formula (I) or pharmaceutical acceptable salts or solvates thereof, wherein G 1 , L 1 , R 2 , R 3 , n, p, Ar 1 , and Ar 2 are defined in the description. Methods of making said compounds, and compositions comprising said compounds which are useful for inhibiting kinases such as IGF-1R are also disclosed.

Claims (138)

1. A compound of formula (I)

or a pharmaceutically acceptable salt, solvate, prodrug, or a combination thereof, wherein

G 1 is formula (i), (ii), (iii), or (iv)

m is 0, 1, 2, 3, or 4;

m′ is 0, 1, or 2;

n is 0, 1, or 2;

p is 0, 1, 2, or 3;

R 1 , R 2 , and R 3 are optional substituents, and when present, are each independently alkyl, halogen, —O(alkyl), —O(haloalkyl), or haloalkyl;

a and b designate the points of attachment at which formula (i), (ii), (iii), and (iv) are bound to formula (I);

L 1 is a bond, O, N(H), or (CR 4 R 5 ) q ;

R 4 and R 5 , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl;

q is 1, 2, 3, or 4;

Ar 1 is aryl or heteroaryl; each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents as represented by T, wherein each T is selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, CN, NO 2 , G 2 , —OR 6 , —OC(O)R 7 , —SR 6 , —S(O)R 7 , —S(O) 2 R 7 , —S(O) 2 N(R 8 )(R 9 ), —N(R 8 )(R 9 ), —N(R 8 )C(O)R 7 , —N(R 8 )C(O)OR 7 , —N(R 8 )S(O) 2 R 7 , —N(R 8 )C(O)N(R 8 )(R 9 ), —N(R 8 )C(O)—(C 1-6 alkylenyl)-N(R 8 )(R 9 ), —N(R 8 )S(O) 2 N(R 8 )(R 9 ), —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 8 )(R 9 ), —(C 1-6 alkylenyl)-G 2 , —(C 1-6 alkylenyl)-OR 6 , —(C 1-6 alkylenyl)-OC(O)R 7 , —(C 1-6 alkylenyl)-SR 6 , —(C 1-6 alkylenyl)-S(O)R 7 , —(C 1-6 alkylenyl)-S(O) 2 R 7 , —(C 1-6 alkylenyl)-S(O) 2 N(R 8 )(R 9 ), —(C 1-6 alkylenyl)-N(R 8 )(R 9 ), —(C 1-6 alkylenyl)-N(R 8 )C(O)R 7 , —(C 1-6 alkylenyl)-N(R 8 )C(O)OR 7 , —(C 1-6 alkylenyl)-N(R 8 )S(O) 2 R 7 , —(C 1-6 alkylenyl)-N(R 8 )C(O)N(R 8 )(R 9 ), —(C 1-6 alkylenyl)-N(R 8 )S(O) 2 N(R 8 )(R 9 ), —(C 1-6 alkylenyl)-C(O)R 6 , —(C 1-6 alkylenyl)-C(O)OR 6 , and —(C 1-6 alkylenyl)-C(O)N(R 8 )(R 9 ),

two substituents on the vicinal carbon atoms of Ar 1 , together with the carbon atoms to which they are attached, optionally form a monocyclic 5- or 6-membered heterocycle containing one or two heteroatoms selected from N(H), O, S, S(O), or S(O) 2 , wherein each of the monocyclic heterocycle is optionally substituted with 1, 2, 3, or 4 alkyl groups;

each occurrence of R 6 and R 9 are each independently hydrogen, alkyl, haloalkyl, —(C 1-6 alkylenyl)-CN, —(C 1-6 alkylenyl)-OH, —(C 1-6 alkylenyl)-C(O)OH, G 3 , or —(C 1-6 alkylenyl)-G 3 ;

each occurrence of R 7 is independently alkyl, haloalkyl, —(C 1-6 alkylenyl)-CN, —(C 1-6 alkylenyl)-OH, G 3 , or —(C 1-6 alkylenyl)-G 3 ;

each occurrence of R 8 is independently hydrogen, alkyl, or haloalkyl;

each occurrence of G 2 is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of G 3 , —(C 1-6 alkylenyl)-G 3 , and R 10 ,

each occurrence of G 3 is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 R 10 groups;

Ar 2 is aryl or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 R 10 groups;

each occurrence of R 10 is independently alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, CN, NO 2 , —OR Z1 , —OC(O)R Z2 , —SR Z1 , —S(O)R Z2 , —S(O) 2 R Z2 , —S(O) 2 N(R Z3 )(R Z4 ), —N(R Z3 )(R Z4 ), —N(R Z3 )C(O)R Z2 , —N(R Z3 )C(O)OR Z2 , —N(R Z3 )S(O) 2 R Z2 , —N(R Z3 )C(O)N(R Z3 )(R Z4 ), —N(R Z3 )S(O) 2 N(R Z3 )(R Z4 ), —C(O)R Z1 , —C(O)OR Z1 , —C(O)N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-OR Z1 , —(C 1-6 alkylenyl)-OC(O)R Z2 , —(C 1-6 alkylenyl)-SR Z1 , —(C 1-6 alkylenyl)-S(O)R Z2 , —(C 1-6 alkylenyl)-S(O) 2 R Z2 , —(C 1-6 alkylenyl)-S(O) 2 N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-N(R Z3 )C(O)R Z2 , —(C 1-6 alkylenyl)-N(R Z3 )C(O)OR Z2 , —(C 1-6 alkylenyl)-N(R Z3 )S(O) 2 R Z2 , —(C 1-6 alkylenyl)-N(R Z3 )C(O)N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-N(R Z3 )S(O) 2 N(R Z3 )(R Z4 ), —(C 1-6 alkylenyl)-C(O)R Z1 , —(C 1-6 alkylenyl)-C(O)OR Z1 , or —(C 1-6 alkylenyl)-C(O)N(R Z3 )(R Z4 );

each occurrence of R Z1 , R Z3 , and R Z4 , are each independently hydrogen, alkyl, or haloalkyl; and

each occurrence of R Z2 is independently alkyl or haloalkyl.

2. The compound according to claim 1 having formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein Ar 2 is optionally substituted phenyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof having formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein

Ar 2 is optionally substituted phenyl; and

Ar 1 is phenyl or monocyclic heteroaryl; each of which is optionally substituted.

4. The compound according to claim 1 having formula (I-i) or a pharmaceutically acceptable salt or solvate thereof

wherein R 1 , R 2 , R 3 , m, n, p, L 1 , Ar 1 , and Ar 2 are as set forth in claim 1 .

5. The compound according to claim 4 having formula (I-i), or a pharmaceutically acceptable salt or solvate thereof, wherein Ar 2 is optionally substituted phenyl.

6. The compound according to claim 4 having formula (I-i), or a pharmaceutically acceptable salt or solvate thereof, wherein

L 1 is a bond, and