Tricyclic protein kinase inhibitors

A compound of formula 1 having the structure:

• wherein:
• Ar is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atoms;
• or
• Ar is a phenyl ring;
• wherein the phenyl ring may be optionally mono-, di-, or tri-substituted with substituent(s) independently selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 3-9 carbon atoms, N,N-dialkylaminoalkoxy of 4-10 carbon atoms, mercapto, methylmercapto and benzoylamino;
• m is 0-3;
• n is 0-1;
• X is NH or NR;
• R is alkyl of 1-6 carbon atoms;
• Y and Z are both carbon;
• the dashed line indicates an optional double bond;
• R1, R2, R3, and R4 are each, independently, not present, hydrogen, halogen, hydroxy, amino, hydroxyamino, trifluoromethyl, trifluoromethoxy, mercapto, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, mercaptoalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkoxy of 3-8 carbon atoms, alkylthio of 1-6 carbon atoms, cycloalkylthio of 3-8 carbon atoms, alkylsuiphinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, cyano, nitro, carboxy, alkoxycarbonyl of 2-7 carbon atoms, alkanoyl of 2-7 carbon atoms, alkenoyl of 3-7 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, phenoxy, phenyl, thiophenoxy, benzyl, alkylamino of 1-6 carbon atoms, alkanoyloxy of 2-7 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, carbamoyl, N-alkylcarbamoyl of 2-7 carbon atoms, N,N-dialkylcarbamoyl of 3-13 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoyloxymethyl group of 2-7 carbon atoms, alkenoyloxymethyl group of 2-7 carbon atoms, alkynoyloxymethyl group of 2-7 carbon atoms, azido, benzoyl, carboxyalkyl of 2-7 carbons, carboalkoxyalkyl of 3-8 carbon atoms,
• V is (CH2)m, O, S, or NR6;
• R7 is NR6R6, OR6, J, N(R6)3+, or NR6(OR6);
• M is NR6, O, S, N—[(C(R6)2)pNR6R6], or N—[(C(R6)2)p—OR6];
• W is NR6, O, S, or is a bond;
• Het is a heterocycle selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane pyrrole, and tetrahydropyran;
• wherein the heterocycle is optionally mono- or di-substituted on carbon or nitrogen with R6;
• optionally mono- or di-substituted on carbon with hydroxy, —N(R6)2, or —OR6;
• optionally mono or di-substituted on carbon with the mono-valent radicals —(C(R6)2)sOR6 or —[(C(R6)2sN(R6)2];
• or optionally mono or di-substituted on a saturated carbon with divalent radicals ═O or —O(C(R6)2)sO—;
• Ph is a phenyl ring optionally mono-, di- or tri-substituted with halogen, alkyl of 1-6 carbon atoms, trifluoromethyl, nitro, cyano, azido, halomethyl, carboxyl, alkoxycarbonyl, alkylthio, mercapto, mercaptomethyl, —N(R6)2, —OR6, —(C(R6)2)sOR6, —[(C(R6)2)sN(R6)2], or —(C(R6)2)kHet;
• R6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, alkanoyl of 2-7 carbon atoms, carbamoylalkyl of 2-7 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxycycloalkyl of 3-6 carbon atoms, or carboxyalkyl of 2-7 carbon atoms;
• or
• R6 is phenyl optionally mono-, di-, or ri-substituted with substituent(s) independently selected from halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, alkoxycarbonyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino;
• alkanoylamino of 1-6 carbon atoms or alkyl of 1-6 carbon atoms;
• R8 and R9 are each, independently, —[(C(R6)2)rNR6R6], and —[(C(R6)2)rOR6];
• J is independently hydrogen, chlorine, fluorine, or bromine;
• g=1-6;
• k=0-4;
• p=2-4;
• q=0-4;
• r=1-4;
• s=1-6;
• or a pharmaceutically acceptable salt thereof;
• provided that when R6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, the alkenyl or alkynyl moieties are bound to a nitrogen or oxygen atom through a saturated carbon atom in the alkenyl or alkynyl chain;
• provided that when V is NR6 and R7 is NR6R6, N(R6)3+, or NR6(OR6), then g=2-6;
• provided that when M is O or S and R7 is OR6, then p=1-4;
• provided that when V is NR6, O, S, then k=2-4;
• provided that when V is O or S and M or W is O or S, then k=1-4
• provided that when W is not a bond with Het bonded through a nitrogen atom then q=2-4;
• and
• provided when W is a bond with Het bonded through a nitrogen atom and V is O or NR6 or S, then k=2-4.