R2 is independently selected from: (Ci-C6)alkyl, (Ci-C6)alkoxy, CO2H, halo, OH and NH2; all other substituents and variables are as defined in the second embodiment; or a pharmaceutically acceptable salt or a stereoisomer thereof. In a fourth embodiment the inhibitors of the instant invention are illustrated by the

Formula C:


wherein: a is 0 or 1 ; b is 0 or 1 ; m is 0, 1 or 2; p is 0, 1 or 2;

R2 is selected from: (Ci-C6)alkyl, (Ci-C6)alkoxy, CO2H, halo, OH and NH2;

Ring X is a 3-7 membered cycloalkyl or 4-7 membered heterocyclyl optionally substituted with one to three R3;

Ring Y is 4-7 membered cycloalkyl or a 5-7 membered heterocyclyl optionally substituted with one to three R4;

Rl is selected from: H, oxo, (C=0)aOb(Ci-Cio)alkyl, (C=O)aOb-aryl, (C=0)aOb(C2-Cio)alkenyl, (C=0)aOb(C2-Cio)alkynyl, CO2H, halo, OH, Ob(Ci- C6)perfluoroalkyl, (C=O)aNR7R8, CN, (C=O)aOb(C3-C8)cycloalkyl, S(O)mNR7R8, SH, S(0)m-(Ci-Cio)alkyl and (C=O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R6;

R3 is independently selected from: (Ci-C6)alkyl, CO2H, halo, OH, (Ci- C[omicron])alkoxy, (C2-Cio)alkenyl;

R4 is independently selected from: (Ci-C6)alkyl, CO2H, halo, OH, (Ci- C6)alkoxy, (C2-Cio)alkenyl; R6 is: (C=0)aObCi-Cio alkyl, (C=O)aObaryl, C2-C10 alkenyl, C2-C10 alkynyl,

(C=O)3Ob heterocyclyl, CO2H, halo, CN, OH, ObCi-C6 perfluoroalkyl, Oa(C=O)bNR7R8, oxo, CHO, (N=O)R7R8, S(O)mNR7R8, SH, S(0)m-(Ci-Cio)alkyl or (C=O)aObC3-C8 cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R6a; R6a is selected from: (C=O)3Ob(Ci -C io)alkyl, Oa(Ci-C3)perfluoroalkyl, (Co-

C6)alkylene-S(O)mRa, SH, oxo, OH, halo, CN, (C2-Cio)alkenyl, (C2-Cio)alkynyl, (C3- C6)cycloalkyl, (Co-C6)alkylene-aryl, (Co-C6)alkylene-heterocyclyl, (Co-C6)alkylene-N(Rb)2, C(O)R<a>, (Co-C6)alkylene-C[theta]2R<a>, C(O)H, and (Co-C6)alkylene-C02H, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from Rb, OH, (Ci-C6)alkoxy, halogen, CO2H, CN, Oa(C=O)b(Ci-C6)alkyl, oxo, and N(Rb)2;

R7 and R8 are independently selected from: H, (C=O)3Ob(Ci -C io)alkyl, (C=O)aOb(C3-C8)cycloalkyl, (C=O)aOb-aryl, (C=O)aOb-heterocyclyl, (C2-C io)alkenyl, (C2- Cio)alkynyl, SH, SO2Ra, ^d (C=O)aNRb2, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R6a, Or R7 and R8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocylcic or bicyclic heterocycle optionally substituted with one or more substituents selected from R6a;

R<a> is (Ci-C6)alkyl, (C3-C6)cycloalkyl, aryl, or heterocyclyl; and

Rb is independently: H, (Ci-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl, (C=O)aOb(Ci-C6)alkyl, or S(O)mRa; or a pharmaceutically acceptable salt or a stereoisomer thereof.

In a fifth embodiment the inhibitors of the instant invention are illustrated by the Formula D:


wherein: a is 0 or 1 ; b is 0 or 1 ; m is 0, 1 or 2; p is 0, 1 or 2;

R2 is selected from: (Ci-C6)alkyl, (Ci-C6)alkoxy, CO2H, halo, OH and NH2;

Rl is selected from: H, oxo, (C=O)3Ob(Ci -C io)alkyl, (C=O)aOb-aryl, (C=0)aOb(C2-Cio)alkenyl, (C=0)aOb(C2-Cio)alkynyl, CO2H, halo, OH, Ob(Ci- C6)perfluoroalkyl, (C=O)aNR7R8, CN, (C=O)aOb(C3-C8)cycloalkyl, S(O)mNR7R8, SH, S(O)m-(Ci-Ci0)alkyl and (C=O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R6;

R6 is: (C=0)aObCi-Cio alkyl, (C=O)aObaryl, C2-CiO alkenyl, C2-CiO alkynyl, (C=O)aOb heterocyclyl, CO2H, halo, CN, OH, ObCi-Co perfluoroalkyl,

oxo, CHO, (N=O)R7R8, S(O)mNR7R8, SH, S(0)m-(Ci-Cio)alkyl or (C=0)a0bC3-Cs cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R6a;

R6a is selected from: (C=0)aOb(Ci-Cio)alkyl, Oa(Ci-C3)perfluoroalkyl, (Co- C6)alkylene-S(O)mRa, SH, oxo, OH, halo, CN, (C2-Cio)alkenyl, (C2-Cio)alkynyl, (C3- C6)cycloalkyl, (Co-C6)alkylene-aryl, (Co-C6)alkylene-heterocyclyl, (C()-C6)alkylene-N(Rb)2, C(O)R<a>, (Co-C6)alkylene-CO2R<a>, C(O)H, and (Co-C6)alkylene-CO2H, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from Rb, OH, (Ci-C6)alkoxy, halogen, CO2H, CN, Oa(C=O)b(Ci-C6)alkyl, oxo, and N(Rb)2;

R7 and R8 are independently selected from: H, (C=O)aOb(Ci-Cio)alkyl, (C=O)aOb(C3-C8)cycloalkyl, (C=O)aOb-aryl, (C=O)aOb-heterocyclyl, (C2-Cio)alkenyl, (C2- Cio)alkynyl, SH, SO2R<a>, and (C=O)3NRb2, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R6a, or R7 and R8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocylcic or bicyclic heterocycle optionally substituted with one or more substituents selected from R6a;

R<a> is (Ci-C6)alkyl, (C3-C6)cycloalkyl, aryl, or heterocyclyl; and

Rb is independently: H, (Ci-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl, (C=0)a0b(Cl-C6)alkyl, or S(O)mRa; or a pharmaceutically acceptable salt or a stereoisomer thereof.

In a sixth embodiment the inhibitors of the instant invention are illustrated by the Formula E:


wherein: a is 0 or 1 ; b is 0 or 1 ; m is 0, 1 or 2;

Rl is selected from: H, (C=O)aOb(Ci-Cio)alkyl, (C=O)aObaryl, OH, Ob(Ci- C6)perfluoroalkyl, (C=O)aOb(C3-C8)cycloalkyl, and (C=O)aOb-heterocyclyl, said alkyl, aryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R6;

R6 is: (C=O)aObCi-Ci0 alkyl, (C=O)aObaryl, C2-C10 alkenyl, C2-C10 alkynyl, (C=O)aOb heterocyclyl, CO2H, halo, CN, OH, ObQ-Co perfluoroalkyl, Oa(C=O)bNR7R8, oxo, CHO, (N=O)R7R8, S(O)mNR7R8, SH, S(O)1n-(Cl -C i[theta])alkyl or (C=O)aObC3-C8 cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R6a;

R6a is selected from: (C=0)aOb(Ci-Cio)alkyl, Oa(Ci-C3)[rho]erfluoroalkyl, (Co- C6)alkylene-S(O)mRa, SH, oxo, OH, halo, CN, (C2-Cio)alkenyl, (C2-Ci[theta])alkynyl, (C3- C6)cycloalkyl, (C[theta]-C6)alkylene-aryl, (Co-C6)alkylene-heterocyclyl, (Co-C6)alkylene-N(Rb)2, C(O)R<a>, (Co-C6)alkylene-C[theta]2R<a>, C(O)H, and (Co-C6)alkylene-C02H, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from Rb, OH, (Ci-C6)alkoxy, halogen, CO2H, CN, Oa(C=O)b(Ci-C6)alkyl, oxo, and

N(Rb)2; R<a> is (C 1 -C6)alkyl, (C3-C6)cycloalkyl, aryl, or heterocyclyl; and

Rb is independently: H, (Ci-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl,

(C=O)aOb(Cl-C6)alkyl, or S(O)mRa; or a pharmaceutically acceptable salt or a stereoisomer thereof. Specific compounds of the instant invention include: 2-{4-[3-(l-methyl-lH-imidazol-4-yl)-9-phenyl[l,2,4]triazolo[3,4-/J-l,6-naphthyridin-8- yl]phenyl}-5,8-dioxaspiro[3.4]octan-2-amine (l-12);

2-[4-(9-phenyl[l,2,4]triazolo[3,4-/J-l,6-naphthyridin-8-yl)phenyl]-5,8-dioxaspiro[3.4]octan-2- amine (1-13);

2-[4-(3-methyl-9-phenyl[l,2,4]triazolo[3,4-/J-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (1-14);

2-[4-(3-ethyl-9-[rho]henyl[l,2,4]triazolo[3,4-/I-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (1-15);

2-[4-(3-isopropyl-9-phenyl[l,2,4]triazolo[3,4-/J-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (l-16); 2-[4-(3-cyclopropyl-9-phenyl[l,2,4]triazolo[3,4-/J-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (l-17);

2-[4-(9-phenyl-3-pyrimidin-2-yl[l,2,4]triazolo[3,4-/J-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (l-18);

2-[4-(9-phenyl-3-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl[l,2,4]triazolo[3,4-fJ-l,6-naphthyridin-8- yl)phenyl]-5,8-dioxaspiro[3.4]octan-2-amine (1-19);

2-{4-[9-phenyl-3-(l,3-thiazol-4-yl)[l,2,4]triazolo[3,4-fJ-l,6-naphthyridin-8-yl]phenyl}-5,8- dioxaspiro[3.4]octan-2-amine (1-20); 8-[4-(2-amino-5,8-dioxaspiro[3.4]oct-2-yl)phenyl]-9-phenyl[l,2,4]triazolo[3,4-f]-l,6- naphthyridin-3-ol (1-21);

2- {4-[3-(2-furyl)-9-phenyl[ 1 ,2,4]triazolo[3,4-f]-l ,6-naphthyridin-8-yl]phenyl} -5,8- dioxaspiro[3.4]octan-2-amine (1-22); 3-{8-[4-(2-amino-5,8-dioxaspiro[3.4]oct-2-yl)phenyl]-9-phenyl[l,2,4]triazolo[3,4-f]-l,6- naphthyridin-3-yl}phenol (1-23); methyl 6-{8-[4-(2-amino-5,8-dioxaspiro[3.4]oct-2-yl)phenyl]-9-phenyl[l,2,4]triazolo[3,4-f]-l,6- naphthyridin-3-yl}pyridine-2-carboxylate (l-24);

2-[4-(9-phenyl-3-pyridin-2-yl[ 1 ,2,4]triazolo[3,4-f]- 1 ,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (1-25);

2-{4-[3-(lH-indol-5-yl)-9-phenyl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8-yl]phenyl}-5,8- dioxaspiro[3.4]octan-2-amine (l-26);

2-[4-(3-isoxazol-3-yl-9-phenyl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (l-27); 2-[4-(9-phenyl-3-pyrazin-2-yl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (1-28); l-{8-[4-(2-amino-5,8-dioxaspiro[3.4]oct-2-yl)phenyl]-9-phenyl[l,2,4]triazolo[3,4-f]-l,6- naphthyridin-3-yl}ethanol (1-29);

2-[4-(9-phenyl-3-pyridin-3-yl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (1-30);

2-[4-(3-cyclobutyl-9-phenyl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (l-31);

2-{4-[3-(cyclopropylmethyl)-9-phenyl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8-yl]phenyl}-5,8- dioxaspiro[3.4]octan-2-amine (l-32); 2-[4-(9-phenyl-3-propyl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (l-33);

2-[4-(3-cyclopent-3-en-l-yl-9-phenyl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (1-34);

2-[4-(9-phenyl-3-piperidin-2-yl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (1-35);

2-{4-[3-(4-methyl-l,3-thiazol-5-yl)-9-phenyl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8- yl]phenyl}-5,8-dioxaspiro[3.4]octan-2-amine (1-36);

2-[4-(9-phenyl-3-pyridin-4-yl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (1-37); 2-{4-[9-phenyl-3-(tetrahydro-2H-pyran-4-yl)[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8- yl]phenyl}-5,8-dioxaspiro[3.4]octan-2-amine (l-38);

2-{4-[3-(l-benzyl-lH-indol-3-yl)-9-phenyl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8-yl]phenyl}-

5,8-dioxaspiro[3.4]octan-2-amine (l-39); l-l[delta]-^^-amino-S^-dioxaspiroCS.^oct^-yOpheny^-Q-pheny^l^^triazolotS^-fl-l^- naphthyridin-3-yl}-2-methylpropan-2-ol (1-40);

2-[4-(3-tert-butyl-9-phenyl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (l-41); 8-[4-(2-Amino-5,8-dioxaspiro[3.4]oct-2-yl)phenyl]-N-ethyl-9-phenyl[l,2,4]triazolo[3,4-/-l,6- naphthyridin-3-amine (2-2); and

N'-{8-[4-(2-amino-5,8-dioxaspiro[3.4]oct-2-yl)phenyl]-9-phenyl[l,2,4]triazolo[3,4-/J-l,6- naphthyridin-3-yl}-N^V-dimethylpropane-l,3-diamine (2-3); or a pharmaceutically acceptable salt or stereoisomer thereof. A compound of the instant invention is:

2- {4-[3-(l -methyl-l//-imidazol-4-yl)-9-phenyl[ 1 ,2,4]triazolo[3,4-/J- 1 ,6-naphthyridin-8- yl]phenyl}-5,8-dioxaspiro[3.4]octan-2-amine (l-12); or a pharmaceutically acceptable salt thereof.

A compound of the instant invention is: 8-[4-(2-Amino-5,8-dioxaspiro[3.4]oct-2-yl)phenyl]-N-ethyl-9-phenyl[l,2,4]triazolo[3,4-/-l,6- naphthyridin-3-amine (2-2); or a pharmaceutically acceptable salt thereof.

A compound of the instant invention is:

N'-{8-[4-(2-amino-5,8-dioxaspiro[3.4]oct-2-yl)phenyl]-9-phenyl[l,2,4]triazolo[3,4-/J-l,6- naphthyridin-3-yl}-N,N-dimethylpropane-l,3-diamine (2-3); or a pharmaceutically acceptable salt thereof.

A compound of the instant invention is:

2-[4-(9-phenyl-3-pyrimidin-2-yl[l,2,4]triazolo[3,4-/j-l,6-naphthyridin-8-yl)phenyl]-5,8- dioxaspiro[3.4]octan-2-amine (1-18); or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon

Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers being included in the present invention. In addition, the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted. For example the following is within the scope of the instant invention: 



Tetrazoles exist as a mixture of 1H/2H tautomers. The tautomeric forms of the tetrazol moiety are also within the scope of the instant invention.

When any variable (e.g. R.2, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety. It is understood that one or more silicon (Si) atoms can be incorporated into the compounds of the instant invention in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon. One of ordinary skill in the art would understand that size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off target activity, packaging properties, and so on. (Diass, J. O. et al. Organometallics (2006) 5:1188-1198; Showell, G.A. et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).

It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase "optionally substituted with one or more substituents" should be taken to be equivalent to the phrase "optionally substituted with at least one substituent" and in such cases the preferred embodiment will have from zero to four substituents, and the more preferred embodiment will have from zero to three substituents. As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, Ci-CiO, as in "(Ci-Cio)alkyl" is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrange-ment. For example, "(Ci-Cio)alkyl" specifically includes methyl, ethyl, w-propyl, /-propyl, w-butyl, t-butyl, /-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.

The term "cycloalkyl" means a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.

"Alkoxy" represents either a cyclic or non-cyclic alkyl group of indicated number of carbon atoms attached through an oxygen bridge. "Alkoxy" therefore encompasses the definitions of alkyl and cycloalkyl above.

If no number of carbon atoms is specified, the term "alkenyl" refers to a non- aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Thus, "(C2- Cio)alkenyl" means an alkenyl radical having from 2 to 10 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. The term "alkynyl" refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Thus, "(C2-Cio)alkynyl" means an alkynyl radical having from 2 to 10 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl, 3- methylbutynyl and so on. The straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.