US 7,550,478 B2
Tyrosine kinase inhibitors
Christopher J. Dinsmore, Newton, Mass. (US); Ana Esther Gabarda Ortega, Madrid (Spain); David J. Guerin, Natick, Mass. (US); James P. Jewell, Sandwich, Mass. (US); Jason D. Katz, Newton Highlands, Mass. (US); Jongwon Lim, Lexington, Mass. (US); Michelle R. Machacek, Boston, Mass. (US); Ryan D. Otte, Newton Centre, Mass. (US); and Jonathan R. Young, Southborough, Mass. (US)
Assigned to Merck & Co. Inc., Rahway, N.J. (US)
Filed on Jun. 22, 2006, as Appl. No. 11/473,273.
Prior Publication US 2006/0293358 A1, Dec. 28, 2006
Int. Cl. A01N 43/42 (2006.01); A61K 31/44 (2006.01); C07D 221/00 (2006.01)
U.S. Cl. 514—290  [546/93] 9 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Drawing
or pharmaceutically acceptable salts thereof, wherein:
a dashed line represents an optional double bond;
a is independently 0 or 1;
b is independently 0 or 1;
m is independently 0, 1, or 2;
R1 is selected from halogen, aryl, heterocyclyl, —C(═O)NR10R11, (C═O)OC1-C6 alkyl and NR10R11; each alkyl, aryl and heterocyclyl group optionally substituted with one to five substituents, each substituent independently selected from R8;
R2 and R3 are independently selected from hydrogen, OH, —O—C1-6 alkyl, —O—C(═O)C1-6 alkyl, —O-aryl and NR10R11, each alkyl and aryl optionally substituted with one to five substituents, each substituent independently selected from R8; or
R2 and R3 are combined to form ═O or ═N—ORc;
R4 and R6 and are each independently hydrogen, halogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, OH, —O—C1-6alkyl, —O—C(═O)C1-6 alkyl, —O-aryl, S(O)mRa and NR10R11, each alkyl and aryl optionally substituted with one to five substituents, each substituent independently selected from R8;
R7 is hydrogen;
R5 is selected from hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, OH, —O—C1-16alkyl, —O—C(═O)C1-6 alkyl, —O-aryl, S(O)mRa, —C(═O)NR10R11, —NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl, alkynyl and aryl optionally substituted with one to five substituents, each substituent independently selected from R8;
provided that at least one of R4, R5 and R6 is not hydrogen;
R8 independently is:
1) (C═O)aObC1-10 alkyl,
2) (C═O)aObaryl,
3) C2-C10 alkenyl,
4) C2-C10 alkynyl,
5) (C═O)aOb heterocyclyl,
6) CO2H,
7) halo,
8) CN,
9) OH,
10) ObC1-C6 perfluoroalkyl,
11) Oa(C═O)bNR10R11,
12) S(O)mRa,
13) S(O)2NR10R11,
14) OS(═O)Ra,
15) oxo,
16) CHO,
17) (N═O)R10R11,
18) (C═O)aObC3-C8 cycloalkyl,
19) ObSiRa3, or
20) NO2;
each alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R9;
two R8s, attached to the same carbon atom are combined to form —(CH2)u— wherein u is 3 to 6 and one or two of the carbon atoms is optionally replaced by a moiety selected from O, S(O)m, —N(Ra)C(O)—, —N(Rb)— and —N(CORa)—;
R9 is independently selected from:
1) (C═O)aOb(C1-C10)alkyl,
2) Ob(C1-C3)perfluoroalkyl,
3) oxo,
4) OH,
5) halo,
6) CN,
7) (C2-C10)alkenyl,
8) (C2-C10)alkynyl,
9) (C═O)aOb(C3-C6)cycloalkyl,
10) (C═O)aOb(C0-C6)alkylene-aryl,
11) (C═O)aOb(C0-C6)alkylene-heterocyclyl,
12) (C═O)aOb(C0-C6)alkylene-N(Rb)2,
13) C(O)Ra,
14) (C0-C6)alkylene-CO2Ra,
15) C(O)H,
16) (C0-C6)alkylene-CO2H, and
17) C(O)N(Rb)2,
18) S(O)mRa, and
19) S(O)2NR10R11;
each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with one, two or three substituents selected from Rb, OH, (C1-C6)alkoxy, halogen, CO2H, CN, O(C═O)C1-C6 alkyl, oxo, and N(Rb)2; or
two R9s, attached to the same carbon atom are combined to form —(CH2)u— wherein u is 3 to 6 and one or two of the carbon atoms is optionally replaced by a moiety selected from O, S(O)m, —N(Ra)C(O)—, —N(Rb)— and —N(CORa)—;
R10 and R11 are independently selected from:
1) H,
2) (C═O)ObC1-C10 alkyl,
3) (C═O)ObC3-C8 cycloalkyl,
4) (C═O)Obaryl,
5) (C═O)Obheterocyclyl,
6) C1-C10 alkyl,
7) aryl,
8) C2-C10 alkenyl,
9) C2-C10 alkynyl,
10) heterocyclyl,
11) C3-C8 cycloalkyl,
12) SO2Ra, and
13) (C═O)NRb2,
each alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one, two or three substituents selected from R8, or
R10 and R11 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, each monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R9;
Ra is independently selected from: (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, aryl, —(C1-C6)alkylenearyl, heterocyclyl and —(C1-C6)alkyleneheterocyclyl;
Rb is independently selected from: H, (C1-C6)alkyl, aryl, —(C1-C6)alkylenearyl, heterocyclyl, —(C1-C6)alkyleneheterocyclyl, (C3-C6)cycloalkyl, (C═O)OC1-C6 alkyl, (C═O)C1-C6 alkyl or S(O)2Ra; and
Rc is independently selected from: H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, aryl, —(C1-C6)alkylenearyl, heterocyclyl and —(C1-C6)alkyleneheterocyclyl;
but excluding compounds represented by the following exclusion table (R7a and R7b are H):
 
R1 R2 R3 R4 R5 R6 R7 Dashed line
 
Ph Form ═O H H H Br double bond
Ph Form ═O H H H H double bond
Ph Form ═O H Br H H double bond
Ph Form ═O H H H Cl double bond
Cl Form ═O H H H Br double bond
 
Ph H OH H H H   double bond
 
Ph Form ═O H H H   double bond
 
Ph H H H H H oxazolyl absent.