Substituted 4-amino isoxazolo[5,4-d]pyrimidines as kinase inhibitors

1. A compound of the formula I,

the racemic-diastereomeric mixtures, optical isomers, or pharmaceutically-acceptable salts thereof, wherein

the dotted line in the structure of formula (I) represents an optional double bond;

X is CR 1 ; Y is N; Q is O;

R 3 for each occurrence is independently hydrogen, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy;

R 1 is

where Z 100 is nitro, optionally substituted amino,

 or a group optionally substituted with R b selected from the group consisting of cycloalkyl, naphthyl, tetrahydronaphthyl, benzothienyl, furanyl, thienyl, benzoxazolyl, benzothiazolyl,

 thiazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, indolyl, isoxazolyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrazolyl, pyrrolyl, oxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, indolinyl, indazolyl, benzoisothiazolyl, pyrido-oxazolyl, pyrido-thiazolyl, pyrimido-oxazolyl, pyrimido-thiazolyl and benzimidazolyl;

when a is 1 and D 1 , G 1 , J 1 , L 1 and M 1 are each independently selected from the group consisting of CR a and N, provided that at least two of D 1 , G 1 , J 1 , L 1 and M 1 are CR a ; or

when a is 0, and one of D 1 , G 1 , L 1 and M 1 is NR a , one of D 1 , G 1 , L 1 and M 1 is CR a and the remainder are independently selected from the group consisting of CR a and N;

when b is 1 and D 2 , G 2 , J 2 , L 2 and M 2 are each independently selected from the group consisting of CR a and N, provided that at least two of D 2 , G 2 , J 2 , L 2 and M 2 are CR a ; or

when b is 0, and one of D 2 , G 2 , L 2 and M 2 is NR a , one of D 2 , G 2 , L 2 and M 2 is CR a and the remainder are independently selected from the group consisting of CR a and N;

R a and R b each represent one or more substituents and are for each occurrence independently selected from the group consisting of hydrogen, halogen, —CN, —NO 2 , —C(O)OH, —C(O)H, —OH, —C(O)O-alkyl, —Z 105 —C(O)N(R) 2 , —Z 105 —N(R)—C(O)—Z 200 , —Z 105 —N(R)—S(O) 2 —Z 200 , —Z 105 —N(R)—C(O)—N(R)—Z 200 , R c , CH 2 OR e , tetrazolyl, trifluoromethylcarbonylamino, trifluoromethylsulfonamido, and an optionally substituted group selected from the group consisting of carboxamido, alkyl, alkoxy, aryl, alkenyl, aryloxy, heteroaryloxy, arylalkyl, alkynyl, amino, aminoalkyl, amido groups, heteroarylthio and arylthio;

Z 105 for each occurrence is independently a covalent bond or (C 1 -C 6 ) aliphatic;

Z 200 for each occurrence is independently an optionally substituted (C 1 -C 6 ) aliphatic, optionally substituted phenyl, or optionally substituted —(C 1 -C 6 )-phenyl aliphatic group-phenyl;

R c for each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, —CH 2 —NR d R e , —W—(CH 2 ) t —NR d R e , —W—(CH 2 ) t —Oalkyl, —W—(CH 2 ) t —S-alkyl or —W—(CH 2 ) t —OH;

R d and R e for each occurrence are independently H, alkyl, alkanoyl or SO 2 -alkyl; or

R d , R e and the nitrogen atom to which they are attached together form a five- or six-membered heterocyclic ring;

t for each occurrence is independently an integer from 2 to 6;

W for each occurrence is independently a direct bond or O, S, S(O), S(O) 2 , or NR f ;

R f for each occurrence is independently H or alkyl;

Z 110 is a covalent bond, or an optionally substituted (C 1 -C 6 ) aliphatic which is optionally substituted with one or more substituents selected from the group consisting of alkyl, CN, OH, halogen, NO 2 , COOH, optionally substituted amino and optionally substituted phenyl;

Z 111 is a covalent bond, an optionally substituted (C 1 -C 6 ) aliphatic or an optionally substituted —(CH 2 ) n -cycloalkyl-(CH 2 ) n —; where the optionally substituted groups are optionally substituted with one or more substituents selected from the group consisting of alkyl, CN, OH, halogen, NO 2 , COOH, optionally substituted amino and optionally substituted phenyl; or

R 1 is a substituted or unsubstituted carbocyclic or heterocyclic ring fused with ring 2;

A is a covalent bond, —O—; —S—; —S(O) p —; —N(R)—; —N(C(O)OR)—; —N(C(O)R)—; —N(SO 2 R)—; —CH 2 O—; —CH 2 S—; —CH 2 N(R)—; —CH(NR)—; —CH 2 N(C(O)R)—; —CH 2 N(C(O)OR)—; —CH 2 N(SO 2 R)—; —CH(NHR)—; —CH(NHC(O)R)—; —CH(NHSO 2 R)—; —CH(NHC(O)OR)—; —CH(OC(O)R)—; —CH(OC(O)NHR); —CH═CH—; —C(═NOR)—; —C(O)—; —CH(OR)—; —C(O)N(R)—; —N(R)C(O)—; —N(R)S(O) p —; —OC(O)N(R)—; —N(R)—C(O)—(CH 2 ), —N(R)—, —N(R)C(O)O—; —N(R)—(CH 2 ) n+1 —C(O)—, —S(O) p N(R)—; —N(C(O)R)S(O) p —; —N(R)S(O) p N(R)—; —N(R)—C(O)—(CH 2 ) n —O—, —C(O)N(R)C(O)—; —S(O) p N(R)C(O)—; —OS(O) p N(R)—; —N(R)S(O) p O—; —N(R)S(O) p C(O)—; —SO p N(C(O)R)—; —N(R)SO p N(R)—; —C(O)O—; —N(R)P(OR g )O—; —N(R)P(OR g )—; —N(R)P(O)(OR g )O—; —N(R)P(O)(OR g )—; —N(C(O)R)P(OR g )O—; —N(C(O)R)P(OR g )—; —N(C(O)R)P(O)(OR g )O—, or —N(C(O)R)P(OR g )—;

p is 1 or 2;

R for each occurrence is independently H, optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted aryl;

R g for each occurrence is independently H, or an optionally substituted group selected from the group consisting of alkyl, arylalkyl, cycloalkyl and aryl; or

R, R g , the nitrogen atom and the phosphorus atom, together form a five- or six-membered heterocyclic ring when R and R g are in a phosphorus containing group; or

A is NRSO 2 and R, R a and the nitrogen atom together form an optionally substituted five- or six-membered heterocyclic ring fused to ring 1; and

n for each occurrence is independently an integer from 0 to 6.

2. A compound according to claim 1 of formula (III),

wherein

A is selected from the group consisting of a covalent bond, —N(R)C(O)—, and —N(R)—C(O)—(CH 2 ) n —N(R)—;

Z 100 is selected from the group consisting of nitro, amino, substituted amino, and optionally substituted aryl;

R is hydrogen; and n is 0.

3. The compound of claim 2 wherein

A is a covalent bond; and Z 100 is selected from the group consisting of nitro, amino and substituted amino.

4. The compound of claim 3 selected from the group consisting of 3-(4-nitrophenyl)isoxazolo[5,4-d]pyrimidin-4-amine; and 3-(4-aminophenyl)isoxazolo[5,4-d]pyrimidin-4-amine.

5. The compound of claim 2 wherein

A is selected from the group consisting of —N(R)C(O)—, and —N(R)—C(O)—(CH 2 ) n —N(R)—; and Z 100 is optionally substituted aryl.

6. The compound of claim 5 selected from the group consisting of

N-[4-(4-aminoisoxazolo[5,4-d]pyrimidin-3-yl)phenyl]-N′-(3-methylphenyl)urea;

N-[4-(4-aminoisoxazolo[5,4-d]pyrimidin-3-yl)phenyl]-N′-(3-ethylphenyl)urea;

N-[4-(4-aminoisoxazolo[5,4-d]pyrimidin-3-yl)phenyl]-N′-(3-chlorophenyl)urea;

N-[4-(4-aminoisoxazolo[5,4-d]pyrimidin-3-yl)phenyl]benzamide;

N-[4-(4-aminoisoxazolo[5,4-d]pyrimidin-3-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea; and

N-[4-(4-aminoisoxazolo[5,4-d]pyrimidin-3-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea.

7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.