US 9,809,578 B2
Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
Barbara J. Brandhuber, Boulder, CO (US); Yutong Jiang, Boulder, CO (US); Gabrielle R. Kolakowski, Boulder, CO (US); and Shannon L. Winski, Boulder, CO (US)
Assigned to Array BioPharma Inc., Boulder, CO (US)
Appl. No. 14/442,495
Filed by Array BioPharma Inc., Boulder, CO (US)
PCT Filed Nov. 13, 2013, PCT No. PCT/US2013/069897
§ 371(c)(1), (2) Date May 13, 2015,
PCT Pub. No. WO2014/078417, PCT Pub. Date May 22, 2014.
Claims priority of provisional application 61/725,947, filed on Nov. 13, 2012.
Prior Publication US 2016/0280690 A1, Sep. 29, 2016
Int. Cl. C07D 403/14 (2006.01); C07D 401/14 (2006.01); C07D 403/12 (2006.01)
CPC C07D 403/14 (2013.01) [C07D 401/14 (2013.01); C07D 403/12 (2013.01)] 18 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Drawing
or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:
X is O, S, NH or N—CN;
Ring A is

OG Complex Work Unit Drawing
R1 is phenyl optionally substituted with one or more substituents independently selected from halogen and (1-3C)alkyl;
R2 is (1-3C)alkyl optionally substituted with 1 to 5 fluoros or (3-4C)cycloalkyl optionally substituted with one or two fluoros;
R6 is H or CH3;
Ring C is formula C-1

OG Complex Work Unit Drawing
R3 is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar2, hetCyc1, (3-7C)cycloalkyl, or hetAr2;
Ar2 is phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl;
hetCyc1 is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;
hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from (1-6C)alkyl and halogen;
R4 is hetAr4, hetAr5 or hydroxy(1-6C)alkoxy;
hetAr4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and substituted with one or more substituents independently selected from (1-6C)alkyl, halogen, CN, hydroxy(l-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino, difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4C cycloalkyl)amino;
hetAr5 is a group selected from the structures:

OG Complex Work Unit Drawing
where Rz is (3-4C)cycloalkyl or (1-3C)alkyl optionally substituted with 1-3 fluoros, wherein each of said hetAr5 groups is optionally further substituted with one or more substituents independently selected from F and (1-3C)alkyl optionally substituted with 1-3 fluoros; and
R5 is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl, (1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino, aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy; or
R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, or
R4 and R5 together with the atoms to which they are attached form 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyl and oxo, and said sulfur ring atom is optionally oxidized to S(═O) or SO2.