Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use

Abstract

Provided are compounds of Formula I: ##STR00001##
or a pharmaceutically acceptable salt thereof, wherein R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, X, Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 and m are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula I, or a pharmaceutically acceptable salt thereof.

Claims

1. A compound of Formula I: ##STR00217## or a pharmaceutically acceptable salt thereof, wherein: Z.sup.1, Z.sup.3 and Z.sup.4 are each CR.sup.1 and Z.sup.2 is N; R.sup.1, at each occurrence, is independently selected from the group consisting of hydrogen, halogen, CN, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)OR.sup.a, C(O)NR.sup.bR.sup.c, OR.sup.a, NR.sup.bR.sup.c, C.sub.6-10 aryl and 5-10 membered heteroaryl; R.sup.2 is selected from the group consisting of C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, 5-10 membered heteroaryl and NR.sup.bR.sup.c, wherein each of the C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, (CH.sub.2).sub.nOR.sup.a, (CH.sub.2).sub.nOC(O)R.sup.a, (CH.sub.2).sub.nOC(O)OR.sup.a, (CH.sub.2).sub.nOC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)C(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(S)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dS(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2NR.sup.bR.sup.c, (CH.sub.2).sub.nC(O)R.sup.a, (CH.sub.2).sub.nC(O)OR.sup.a, (CH.sub.2).sub.nC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(S)R.sup.a, (CH.sub.2).sub.nC(S)OR.sup.a, (CH.sub.2).sub.nC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nSR.sup.a, (CH.sub.2).sub.nS(O)R.sup.a, (CH.sub.2).sub.nSO.sub.2R.sup.a, (CH.sub.2).sub.nSO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nC.sub.6-10 aryl and (CH.sub.2).sub.n5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nC.sub.6-10 aryl and (CH.sub.2).sub.n5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents; R.sup.4 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.bR.sup.c and SO.sub.2R.sup.a; R.sup.5 and R.sup.6 are each independently selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl; or alternatively, R.sup.5 and R.sup.6 together with the carbon atom to which they are bound form a group selected from the group consisting of C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl and 3-8 membered heterocycloalkenyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR.sup.a, OC(O)R.sup.a, OC(O)OR.sup.a, NR.sup.bR.sup.c, C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.bR.sup.c, S(O)R.sup.a, SO.sub.2R.sup.a, SO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl; R.sup.7 is selected from the group consisting of C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl and 5-10 membered heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR.sup.a, OC(O)R.sup.a, OC(O)OR.sup.a, OC(O)NR.sup.bR.sup.c, NR.sup.bR.sup.c, NR.sup.dC(O)R.sup.a, NR.sup.dC(O)OR.sup.a, NR.sup.dC(O)NR.sup.bR.sup.c, NR.sup.dC(O)C(O)NR.sup.bR.sup.c, NR.sup.dC(S)R.sup.a, NR.sup.dC(S)OR.sup.a, NR.sup.dC(S)NR.sup.bR.sup.c, NR.sup.dC(NR.sup.e)NR.sup.bR.sup.c, NR.sup.dS(O)R.sup.a, NR.sup.dSO.sub.2R.sup.a, NR.sup.dSO.sub.2NR.sup.bR.sup.c, C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.bR.sup.c, C(S)R.sup.a, C(S)OR.sup.a, C(S)NR.sup.bR.sup.c, C(NR.sup.e)NR.sup.bR.sup.c, SR.sup.a, S(O)R.sup.a, SO.sub.2R.sup.a, SO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl, and 5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents; R.sup.8 and R.sup.9, at each occurrence, are each independently selected from the group consisting of hydrogen, halogen and C.sub.1-6 alkyl; X is a bond; R.sup.a, at each occurrence, is independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents; R.sup.b and R.sup.c, at each occurrence, are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl, 5-10 membered heteroaryl, C(O)R.sup.g, C(O)OR.sup.g, C(O)NR.sup.iR.sup.j and SO.sub.2R.sup.g, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents; R.sup.d, at each occurrence, is independently selected from the group consisting of hydrogen and C.sub.1-6 alkyl; R.sup.e, at each occurrence, is independently selected from the group consisting of hydrogen, CN, OH, C.sub.1-6 alkoxy, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl; R.sup.f, at each occurrence, is independently selected from the group consisting of halogen, CN, OR.sup.h, OC(O)R.sup.h, OC(O)OR.sup.h, OC(O)NR.sup.iR.sup.j, NR.sup.iR.sup.j, NR.sup.dC(O)R.sup.h, NR.sup.dC(O)OR.sup.h, NR.sup.dC(O)NR.sup.iR.sup.j, NR.sup.dC(O)C(O)NR.sup.iR.sup.j, NR.sup.dC(S)R.sup.h, NR.sup.dC(S)OR.sup.h, NR.sup.dC(S)NR.sup.iR.sup.j, NR.sup.dC(NR.sup.e)NR.sup.iR.sup.j, NR.sup.dS(O)R.sup.h, NR.sup.dSO.sub.2R.sup.h, NR.sup.dSO.sub.2NR.sup.iR.sup.j, C(O)R.sup.h, C(O)OR.sup.h, C(O)NR.sup.iR.sup.j, C(S)R.sup.h, C(S)OR.sup.h, C(S)NR.sup.iR.sup.j, C(NR.sup.e)NR.sup.iR.sup.j, SR.sup.h, S(O)R.sup.h, SO.sub.2R.sup.h, SO.sub.2NR.sup.iR.sup.j, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.k substituents; or two R.sup.f substituents bound to a single carbon atom, together with the carbon atom to which they are both bound, form a group selected from the group consisting of carbonyl, C.sub.3-8 cycloalkyl and 3-8 membered heterocycloalkyl; R.sup.g, at each occurrence, is independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, phenyl, naphthyl, and C.sub.7-11 aralkyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, OH, C.sub.1-6 alkoxy, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl; R.sup.h, at each occurrence, is independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.k substituents; R.sup.i and R.sup.j, at each occurrence, are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl, 5-10 membered heteroaryl, C(O)R.sup.g, and C(O)OR.sup.g, wherein each of the C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, OH, C.sub.1-6 alkoxy, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl; R.sup.k, at each occurrence, is independently selected from the group consisting of halogen, CN, oxo, OH, C.sub.1-6 alkoxy, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, NHC(O)C.sub.1-6 alkyl, NHC(O)C.sub.7-11 aralkyl, NHC(O)OC.sub.1-6 alkyl, NHC(O)OC.sub.7-11 aralkyl, C(O)C.sub.1-6 alkyl, C(O)C.sub.7-11 aralkyl, C(O)OC.sub.1-6 alkyl, C(O)OC.sub.7-11 aralkyl, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein each C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.7-11 aralkyl substituent is optionally substituted with 1, 2 or 3 substituents selected from the group consisting of OH, C.sub.1-6 alkoxy, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl).sub.2, NHC(O)C.sub.1-6 alkyl, NHC(O)C.sub.7-11 aralkyl, NHC(O)OC.sub.1-6 alkyl, and NHC(O)OC.sub.7-11 aralkyl; m is 1; n, at each occurrence, independently is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.8 and R.sup.9 are each hydrogen.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.6 are each C.sub.1-6 alkyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.6 are each methyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.6 together with the carbon atom to which they are bound form a group selected from the group consisting of C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl and 3-8 membered heterocycloalkenyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR.sup.a, OC(O)R.sup.a, OC(O)OR.sup.a, NR.sup.bR.sup.c, C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.bR.sup.c, S(O)R.sup.a, SO.sub.2R.sup.a, SO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.6 together with the carbon atom to which they are bound form C.sub.3-8 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR.sup.a, OC(O)R.sup.a, OC(O)OR.sup.a, NR.sup.bR.sup.c, C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.bR.sup.c, S(O)R.sup.a, SO.sub.2R.sup.a, SO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.6 together with the carbon atom to which they are bound form a group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR.sup.a, OC(O)R.sup.a, OC(O)OR.sup.a, NR.sup.bR.sup.c, C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.bR.sup.c, S(O)R.sup.a, SO.sub.2R.sup.a, SO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.6 together with the carbon atom to which they are bound form cyclobutyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR.sup.a, OC(O)R.sup.a, OC(O)OR.sup.a, NR.sup.bR.sup.c, C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.bR.sup.c, S(O)R.sup.a, SO.sub.2R.sup.a, SO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.6 together with the carbon atom to which they are bound form cyclobutyl optionally substituted with one or two halogens.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 and R.sup.6 together with the carbon atom to which they are bound form a group selected from the group consisting of cyclobutyl, 3-fluorocyclobutyl and 3,3-difluorocyclobutyl.

11. The compound of claim 1, wherein the compound is a compound of Formula IV(f), or a pharmaceutically acceptable salt thereof: ##STR00218## wherein R.sup.m and R.sup.n are each independently selected from the group consisting of hydrogen, halogen and C.sub.1-6 alkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein one of R.sup.m and R.sup.n is hydrogen and the other is halogen.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein the halogen and R.sup.7 are in a trans configuration with respect to one another on the cyclobutyl ring.

14. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein the halogen and R.sup.7 are in a cis configuration with respect to one another on the cyclobutyl ring.

15. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein one of R.sup.m and R.sup.n is hydrogen and the other is fluorine.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.7 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR.sup.a, OC(O)R.sup.a, OC(O)OR.sup.a, OC(O)NR.sup.bR.sup.c, NR.sup.bR.sup.c, NR.sup.dC(O)R.sup.a, NR.sup.dC(O)OR.sup.a, NR.sup.dC(O)NR.sup.bR.sup.c, NR.sup.dC(O)C(O)NR.sup.bR.sup.c, NR.sup.dC(S)R.sup.a, NR.sup.dC(S)OR.sup.a, NR.sup.dC(S)NR.sup.bR.sup.c, NR.sup.dC(NR.sup.e)NR.sup.bR.sup.c, NR.sup.dS(O)R.sup.a, NR.sup.dSO.sub.2R.sup.a, NR.sup.dSO.sub.2NR.sup.bR.sup.c, C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.bR.sup.c, C(S)R.sup.a, C(S)OR.sup.a, C(S)NR.sup.bR.sup.c, C(NR.sup.e)NR.sup.bR.sup.c, SR.sup.a, S(O)R.sup.a, SO.sub.2R.sup.a, SO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl, and 5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.7 is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR.sup.a, OC(O)R.sup.a, OC(O)OR.sup.a, OC(O)NR.sup.bR.sup.c, NR.sup.bR.sup.c, NR.sup.dC(O)R.sup.a, NR.sup.dC(O)OR.sup.a, NR.sup.dC(O)NR.sup.bR.sup.c, NR.sup.dC(O)C(O)NR.sup.bR.sup.c, NR.sup.dC(S)R.sup.a, NR.sup.dC(S)OR.sup.a, NR.sup.dC(S)NR.sup.bR.sup.c, NR.sup.dC(NR.sup.e)NR.sup.bR.sup.c, NR.sup.dS(O)R.sup.a, NR.sup.dSO.sub.2R.sup.a, NR.sup.dSO.sub.2NR.sup.bR.sup.c, C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.bR.sup.c, C(S)R.sup.a, C(S)OR.sup.a, C(S)NR.sup.bR.sup.c, C(NR.sup.e)NR.sup.bR.sup.c, SR.sup.a, S(O)R.sup.a, SO.sub.2R.sup.a, SO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl, and 5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R.sup.7 is pyridyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR.sup.a, OC(O)R.sup.a, OC(O)OR.sup.a, OC(O)NR.sup.bR.sup.c, NR.sup.bR.sup.c, NR.sup.dC(O)R.sup.a, NR.sup.dC(O)OR.sup.a, NR.sup.dC(O)NR.sup.bR.sup.c, NR.sup.dC(O)C(O)NR.sup.bR.sup.c, NR.sup.dC(S)R.sup.a, NR.sup.dC(S)OR.sup.a, NR.sup.dC(S)NR.sup.bR.sup.c, NR.sup.dC(NR.sup.e)NR.sup.bR.sup.c, NR.sup.dS(O)R.sup.a, NR.sup.dSO.sub.2R.sup.a, NR.sup.dSO.sub.2NR.sup.bR.sup.c, C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.bR.sup.c, C(S)R.sup.a, C(S)OR.sup.a, C(S)NR.sup.bR.sup.c, C(NR.sup.e)NR.sup.bR.sup.c, SR.sup.a, S(O)R.sup.a, SO.sub.2R.sup.a, SO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, phenyl, naphthyl, C.sub.7-11 aralkyl, and 5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R.sup.7 is 2-pyridyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, OR.sup.a, OC(O)R.sup.a, OC(O)OR.sup.a, OC(O)NR.sup.bR.sup.c, NR.sup.bR.sup.c, NR.sup.dC(O)R.sup.a, NR.sup.dC(O)OR.sup.a, NR.sup.dC(O)NR.sup.bR.sup.c, NR.sup.dC(O)C(O)NR.sup.bR.sup.c, NR.sup.dC(S)R.sup.a, NR.sup.dC(S)OR.sup.a, NR.sup.dC(S)NR.sup.bR.sup.c, NR.sup.dC(NR.sup.e)NR.sup.bR.sup.c, NR.sup.dS(O)R.sup.a, NR.sup.dSO.sub.2R.sup.a, NR.sup.dSO.sub.2NR.sup.bR.sup.c, C(O)R.sup.a, C(O)OR.sup.a, C(O)NR.sup.bR.sup.c, C(S)R.sup.a, C(S)OR.sup.a, C(S)NR.sup.bR.sup.c, C(NR.sup.e)NR.sup.bR.sup.c, SR.sup.a, S(O)R.sup.a, SO.sub.2R.sup.a, SO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, phenyl, naphthyl, C.sub.7-11 aralkyl, and 5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C.sub.6-10 aryl, C.sub.7-11 aralkyl and 5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, (CH.sub.2).sub.nOR.sup.a, (CH.sub.2).sub.nOC(O)R.sup.a, (CH.sub.2).sub.nOC(O)OR.sup.a, (CH.sub.2).sub.nOC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)C(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(S)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dS(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2NR.sup.bR.sup.c, (CH.sub.2).sub.nC(O)R.sup.a, (CH.sub.2).sub.nC(O)OR.sup.a, (CH.sub.2).sub.nC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(S)R.sup.a, (CH.sub.2).sub.nC(S)OR.sup.a, (CH.sub.2).sub.nC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nSR.sup.a, (CH.sub.2).sub.nS(O)R.sup.a, (CH.sub.2).sub.nSO.sub.2R.sup.a, (CH.sub.2).sub.nSO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, CN, oxo, (CH.sub.2).sub.nOR.sup.a, (CH.sub.2).sub.nOC(O)R.sup.a, (CH.sub.2).sub.nOC(O)OR.sup.a, (CH.sub.2).sub.nOC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)C(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(S)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dS(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2NR.sup.bR.sup.c, (CH.sub.2).sub.nC(O)R.sup.a, (CH.sub.2).sub.nC(O)OR.sup.a, (CH.sub.2).sub.nC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(S)R.sup.a, (CH.sub.2).sub.nC(S)OR.sup.a, (CH.sub.2).sub.nC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nSR.sup.a, (CH.sub.2).sub.nS(O)R.sup.a, (CH.sub.2).sub.nSO.sub.2R.sup.a, (CH.sub.2).sub.nSO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from the group consisting of pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of halogen, CN, oxo, (CH.sub.2).sub.nOR.sup.a, (CH.sub.2).sub.nOC(O)R.sup.a, (CH.sub.2).sub.nOC(O)OR.sup.a, (CH.sub.2).sub.nOC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)C(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(S)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dS(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2NR.sup.bR.sup.c, (CH.sub.2).sub.nC(O)R.sup.a, (CH.sub.2).sub.nC(O)OR.sup.a, (CH.sub.2).sub.nC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(S)R.sup.a, (CH.sub.2).sub.nC(S)OR.sup.a, (CH.sub.2).sub.nC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nSR.sup.a, (CH.sub.2).sub.nS(O)R.sup.a, (CH.sub.2).sub.nSO.sub.2R.sup.a, (CH.sub.2).sub.nSO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from the group consisting of pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with a substituent selected from the group consisting of (CH.sub.2).sub.nC(O)OR.sup.a and (CH.sub.2).sub.nC(O)NR.sup.bR.sup.c; and optionally substituted with 1, 2 or 3 additional substituents selected from the group consisting of halogen, CN, oxo, (CH.sub.2).sub.nOR.sup.a, (CH.sub.2).sub.nOC(O)R.sup.a, (CH.sub.2).sub.nOC(O)OR.sup.a, (CH.sub.2).sub.nOC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)C(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(S)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dS(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2NR.sup.bR.sup.c, (CH.sub.2).sub.nC(O)R.sup.a, (CH.sub.2).sub.nC(O)OR.sup.a, (CH.sub.2).sub.nC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(S)R.sup.a, (CH.sub.2).sub.nC(S)OR.sup.a, (CH.sub.2).sub.nC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nSR.sup.a, (CH.sub.2).sub.nS(O)R.sup.a, (CH.sub.2).sub.nSO.sub.2R.sup.a, (CH.sub.2).sub.nSO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from the group consisting of furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with (CH.sub.2).sub.nC(O)NR.sup.bR.sup.c.

25. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from the group consisting of pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with (CH.sub.2).sub.nNR.sup.dC(O)R.sup.a, wherein R.sup.a is C.sub.1-6 alkyl or 3-8 membered heterocycloalkyl, each optionally substituted with 1, 2 or 3 additional substituents selected from the group consisting of halogen, CN, oxo, (CH.sub.2).sub.nOR.sup.a, (CH.sub.2).sub.nOC(O)R.sup.a, (CH.sub.2).sub.nOC(O)OR.sup.a, (CH.sub.2).sub.nOC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)C(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(S)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dS(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2NR.sup.bR.sup.c, (CH.sub.2).sub.nC(O)R.sup.a, (CH.sub.2).sub.nC(O)OR.sup.a, (CH.sub.2).sub.nC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(S)R.sup.a, (CH.sub.2).sub.nC(S)OR.sup.a, (CH.sub.2).sub.nC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nSR.sup.a, (CH.sub.2).sub.nS(O)R.sup.a, (CH.sub.2).sub.nSO.sub.2R.sup.a, (CH.sub.2).sub.nSO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from the group consisting of furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl, each optionally substituted with (CH.sub.2).sub.nNR.sup.dC(O)R.sup.a, wherein R.sup.a is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 alkyl-OH and C.sub.1-6 alkyl-NH.sub.2, each optionally substituted with 1, 2 or 3 additional substituents selected from the group consisting of halogen, CN, (CH.sub.2).sub.nOR.sup.a, (CH.sub.2).sub.nOC(O)R.sup.a, (CH.sub.2).sub.nOC(O)OR.sup.a, (CH.sub.2).sub.nOC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dSO.sub.2R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2NR.sup.bR.sup.c, (CH.sub.2).sub.nC(O)R.sup.a, (CH.sub.2).sub.nC(O)OR.sup.a, (CH.sub.2).sub.nC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nSR.sup.a, (CH.sub.2).sub.nS(O)R.sup.a, (CH.sub.2).sub.nSO.sub.2R.sup.a, (CH.sub.2).sub.nSO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl.

27. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from the group consisting of indolyl, indazolyl, benzimidazolyl, benzoxazolyl and benzoisoxazolyl, each optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of halogen, CN, oxo, (CH.sub.2).sub.nOR.sup.a, (CH.sub.2).sub.nOC(O)R.sup.a, (CH.sub.2).sub.nOC(O)OR.sup.a, (CH.sub.2).sub.nOC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(O)C(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(S)R.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)OR.sup.a, (CH.sub.2).sub.nNR.sup.dC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nNR.sup.dS(O)R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2R.sup.a, (CH.sub.2).sub.nNR.sup.dSO.sub.2NR.sup.bR.sup.c, (CH.sub.2).sub.nC(O)R.sup.a, (CH.sub.2).sub.nC(O)OR.sup.a, (CH.sub.2).sub.nC(O)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(S)R.sup.a, (CH.sub.2).sub.nC(S)OR.sup.a, (CH.sub.2).sub.nC(S)NR.sup.bR.sup.c, (CH.sub.2).sub.nC(NR.sup.e)NR.sup.bR.sup.c, (CH.sub.2).sub.nSR.sup.a, (CH.sub.2).sub.nS(O)R.sup.a, (CH.sub.2).sub.nSO.sub.2R.sup.a, (CH.sub.2).sub.nSO.sub.2NR.sup.bR.sup.c, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (CH.sub.2).sub.nC.sub.3-8 cycloalkyl, (CH.sub.2).sub.n3-8 membered heterocycloalkyl, (CH.sub.2).sub.nphenyl, (CH.sub.2).sub.nnaphthyl and (CH.sub.2).sub.n5-10 membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R.sup.f substituents.

28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.1, at each occurrence, is selected from the group consisting of hydrogen, halogen, CN, CF.sub.3 and methyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein R.sup.1, at each occurrence, is hydrogen.

30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is hydrogen.

31. A compound selected from the group consisting of 4-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-3-pyridyl)benzamide; 3-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-3-pyridyl)benzamide; 3-(6-{[2-(4-fluorophenyl)ethyl]amino}-3-pyridyl)benzamide; 3-(6-{[(2S)-2-(4-fluorophenyl)propyl]amino}-3-pyridyl)benzamide; 3-(6-{[(2R)-2-(4-fluorophenyl)propyl]amino}-3-pyridyl)benzamide; and 3-[5-fluoro-6-({[3-fluoro-1-(3-fluoro(2-pyridyl)) cyclobutyl]methyl}amino)-3-pyridyl]benzamide; or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

33. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition is formulated for oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration.

34. The pharmaceutical composition of claim 33, wherein the pharmaceutical composition is formulated for oral administration.

Description

EXAMPLE 1

(S)-2-(4-Fluorophenyl)propan-1-amine

(1) ##STR00021##

(2) (S)-4-Benzyl-3-(2-(4-fluorophenyl)acetyl)oxazolidin-2-one. To a cooled (78 C.) solution of (S)-4-benzyloxazolidin-2-one (10 g, 58 mmol, 1.0 equiv) in 100 mL THF was added dropwise n-BuLi (40 mL, 1.6 M in hexanes, 64 mmol, 1.1 equiv). After stirring for 30 minutes, 4-fluorophenylacetyl chloride (10 g, 0.58 mmol, 1.0 equiv) was added dropwise. After stirring for an additional 30 minutes, the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated aq. NH.sub.4Cl, extracted with dichloromethane, and washed with brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel (10-20% EtOAc/hexanes) provided the title compound as a thick oil (14.7 g, 81%).

(3) ##STR00022##

(4) (S)-4-Benzyl-34(S)-2-(4-fluorophenyl)propanoyl)oxazolidin-2-one. To a room-temperature solution of (S)-4-Benzyl-3-(2-(4-fluorophenyl)acetyl)oxazolidin-2-one (5.1 g, 16.3 mmol, 1.0 equiv) in dry THF (100 mL) was added iodomethane (1.0 mL, 16.2 mmol, 1.0 equiv) by syringe. The resulting mixture was cooled to 78 C., and NaHMDS (8.15 mL, 2M in THF, 16.3 mmol, 1.0 equiv) was added dropwise by syringe. After stirring for 15 minutes at 78 C., the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated. aq. NH.sub.4Cl, and diluted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification by silica gel chromatography (7-20% EtOAc/hexanes) provided the title compound (2.6 g, 49%).

(5) ##STR00023##

(6) (S)-2-(4-Fluorophenyl)propan-1-ol. To a room-temperature solution of (S)-4-benzyl-3-((S)-2-(4-fluorophenyl) propanoyl)oxazolidin-2-one (1.8 g, 5.5 mmol, 1.0 equiv) in THF (18 mL) was added a solution of NaBH.sub.4 (1.0 g, 26.4 mmol, 4.8 equiv) in water (6.0 mL). The reaction mixture was stirred for 3 h at room temperature and then quenched by the careful addition of aq. 1 M HCl. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the organic layer was subsequently washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification by silica gel chromatography (10-75% EtOAc/Hexanes) provided the title compound (0.824 g, 97%).

(7) ##STR00024##

(8) (S)-2-(2-(4-Fluorophenyl)propyl)isoindoline-1,3-dione. To a solution of (S)-2-(4-fluorophenyl)propan-1-ol (0.82 g, 5.35 mmol, 1.0 equiv), phthalimide (0.82 g, 5.6 mmol, 1.05 equiv), and triphenyl phosphine (2.1 g, 8.03 mmol, 1.5 equiv) in dry THF (18 mL) was added dropwise diethylazodicarboxylate (3.6 mL, 15% in toluene, 8.0 mmol, 1.5 equiv). The reaction mixture was stirred over 72 h and then concentrated in vacuo. Purification by silica gel chromatography (15-25% EtOAc/Hexanes) provided the title compound (0.9 g, 59%).

(9) ##STR00025##

(10) (S)-2-(4-Fluorophenyl)propan-1-amine. To a room-temperature solution of (S)-2-(2-(4-fluorophenyl)propyl)isoindoline-1,3-dione (900 mg, 3.2 mmol, 1.0 equiv) in toluene (14 mL) was added hydrazine hydrate (1.4 mL, 45 mmol, 14 equiv) by syringe. The resulting mixture was heated to 80 C. for 30 minutes and then cooled to room temperature. The resulting solution was decanted from the solid in the reaction mixture, and the solid was washed with additional toluene. The combined organic layers were combined and concentrated in vacuo to provide the title compound (491 mg, 99%), which was used without further purification.

EXAMPLE 2

2-(4-Fluorophenyl)-2-methylpropan-1-amine

(11) ##STR00026##

(12) To a solution of 4-fluorophenylacetonitrile (50 g, 370 mmol, 1.0 equiv) and iodomethane (70 mL, 1.1 mol, 3 equiv) in THF (370 mL) was added KOt-Bu (124 g, 1.1 mol, 3 equiv) as a solid in portions such that the reaction mixture did not exceed 50 C. The reaction mixture was stirred overnight and then quenched by the addition of brine. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to provide 2-(4-fluorophenyl)-2-methylpropanenitrile as a yellow oil (57 g, 94%), which was used without further purification in the next step. To a solution of the nitrile in dry THF (800 mL) was added a solution of lithium aluminum hydride (210 mL, 2 M in ether, 420 mmol, 1.2 equiv). After the mixture was heated at reflux overnight, the reaction was allowed to cool to room temperature, and a Fieser and Fieser work-up (300 uL water/mmol, 1.0 mL 3N NaOH/mmol, 300 uL water/mmol) was performed. Filtration of the resulting solids provided the title compound as an orange oil (57 g, 92%).

EXAMPLE 3

(1-(4-Fluorophenyl)cyclobutyl)methanamine

(13) ##STR00027##

(14) A solution of 4-fluorophenylacetonitrile (6.7 g, 75 mmol, 1.5 equiv), 1,3-dibromopropane (10 mL, 50 mmol, 1 equiv), KOH (27 g, 150 mmol, 3.0 equiv), and tetrabutylammonium bromide (100 mg) in toluene (135 mL) was heated to 100 C. for 3 hours. The organic layer was separated and concentrated to dryness. Silica gel chromatography using a gradient of 0-30% EtOAc/hexanes resulted in partially purified product which was further purified by Kugelrohr distillation at 200 C. to provide 3.76 g (22 mmol) of the intermediate nitrile product as an oil. The residue was dissolved in dry THF (22 mL) and treated with a solution of lithium aluminum hydride (27 mL, 2 M in ether, 55 mmol, 2.5 equiv). The mixture was stirred at 0 C. for 2 hours followed by a Fieser and Fieser work-up (38 uL water/mmol, 118 uL 3N NaOH/mmol, 38 uL water/mmol). The organic layer was concentrated to dryness to provide the desired product (3.6 g, 40% overall) as a yellow oil.

EXAMPLE 4

(1-(6-Methoxypyridin-2-yl)cyclobutyl)methanamine

(15) ##STR00028##

(16) 2-(3-Fluoropyridin-2-yl)acetonitrile. To a 0 C. solution of 2-chloro-3-fluoropyridine (3.0 g, 23 mmol, 1.0 equiv) and acetonitrile (1.3 mL, 25 mmol, 1.1 equiv) in toluene (50 mL) was added sodium hexamethyldisilazide (NaHMDS) (2.0 M in THF, 13 mL, 25 mmol, 1.1 equiv). The resulting mixture was stirred for 2 hours at 0 C. and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with saturated NaCl, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to provide the crude desired product as an oil which was used without further purification.

(17) ##STR00029##

(18) 1-(6-Fluoropyridin-2-yl)cyclobutanecarbonitrile. Following the same procedure as above for 2-(3-fluoropyridin-2-yl)acetonitrile with 2,6-difluoropyridine (5.0 g, 43 mmol, 1.0 equiv), cyclobutylcarbonitrile (3.5 g, 43 mmol, 1.0 equiv) and NaHMDS (2.0 M in THF, 24 mL, 47 mmol, 1.1 equiv) in toluene (100 mL) gave the desired product (4.9 g, 64%) as a colorless oil following purification over silica gel using 25% EtOAc/hexanes as eluent.

(19) ##STR00030##

(20) 1-(6-Methoxypyridin-2-yl)cyclobutanecarbonitrile. To stirred 6.0 mL of anhydrous methanol at 0 C. under nitrogen was added sodium metal (1 g) and the mixture stirred for 30 minutes. To this was added 1-(6-fluoropyridin-2-yl)cyclobutanecarbonitrile (1.6 g, 9.1 mmol, 1.0 equiv) and the resulting mixture heated to 75 C. for 45 minutes. The solution was cooled to room temperature and partitioned between water and EtOAc. The layers were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated NaCl, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the desired product (1.7 g, 97%) as a colorless oil.

(21) ##STR00031##

(22) (1-(6-Methoxypyridin-2-yl)cyclobutyl)methanamine. To a stirred solution of 1-(6-methoxypyridin-2-yl)cyclobutanecarbonitrile (1.7 g, 8.8 mmol, 1.0 equiv) in THF (20 mL) was added lithium aluminum hydride solution (1.0 M in THF, 11 mL, 11 mmol, 1.1 equiv). The mixture was refluxed for 1.5 hours and allowed to cool to room temperature. Water (0.43 mL) was added slowly followed by 0.43 mL of 3 M NaOH and then three additions of 0.43 mL of water (Fieser and Fieser workup). The resulting mixture was filtered through diatomaceous earth and rinsed with THF. The combined organics were dried over Na.sub.2SO.sub.4 and concentrated to dryness to give the desired product (1.6 g, 97%) as a viscous oil.

EXAMPLE 5

1-(3-Fluoropyridin-2-yl)cyclobutanamine

(23) ##STR00032##

(24) 1-(3-Fluoropyridin-2-yl)cyclobutanecarboxamide. To a 250 mL round bottom flask containing DMSO (60 mL), 1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (2.96 g, 16.8 mmol, 1.0 equiv) was added and the mixture was stirred until homogenous. Potassium carbonate (7.0 g, 50.4 mmol, 3.0 equiv) was then added and the reaction mixture was cooled to 0 C., followed by the addition of 35% hydrogen peroxide (6.5 mL). The reaction was stirred at 0 C. for 30 min and then warmed to room temperature. At this time, the reaction was diluted with water (50 mL) and ethyl acetate (100 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (350 mL). The organic layer was then dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a crude solid that was purified by silica gel chromatography (10% EtOAC/hexanes) to afford 1.92 g (59%) of 1-(3-fluoropyridin-2-yl)cyclobutanecarboxamide as a white solid.

(25) ##STR00033##

(26) Methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate. 1-(3-fluoropyridin-2-yl)cyclobutanecarboxamide (1.92 g, 9.88 mmol, 1.0 equiv) was dissolved in methanol (20 mL) and potassium hydroxide (1.11 g, 19.8 mmol, 2.0 equiv) was added. The mixture was sonicated until homogeneous, followed by the addition of iodosobenzene diacetate (4.77 g, 14.8 mmol, 1.5 equiv). The reaction was stirred for 20 min and then diluted with water (100 mL) and ethyl acetate (125 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were then dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a crude oil that was purified by silica gel chromatography (40% EtOAC/hexanes) to afford 1.47 g (67%) of methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate as a white solid.

(27) ##STR00034##

(28) 1-(3-Fluoropyridin-2-yl)cyclobutanamine. To a 20 mL microwave reaction vial was added methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate (1.47 g, 6.56 mmol, 1.0 equiv), ethanol (12 mL) and 3N aqueous sodium hydroxide (7 mL). The reaction mixture was heated in the microwave reactor at 150 C. for 30 min. The ethanol was evaporated under reduced pressure and the mixture was extracted with ethyl acetate (30 mL). The aqueous layer was then extracted with ethyl acetate (230 mL). The organic layers were combined, dried over Na.sub.2SO.sub.4, filtered, and concentrated to give 1-(3-fluoropyridin-2-yl)cyclobutanamine (1.01 g, 93%) as a crude yellow oil that was used without further purification.

EXAMPLE 6

N-(2-(4-Fluorophenyl)-2-methylpropyl)-6-(2-methylprop-1-enyl)pyridin-2-amine

(29) ##STR00035##

(30) 6-Bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine. To a 5 mL microwave reaction vial was added 2,6-dibromopyridine (1.25 g, 5.0 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (1.06 g, 6 mmol, 1.2 equiv), DIPEA (1.9 mL, 11.0 mmol, 2.2 equiv), and acetonitrile (5 mL). The vial was sealed and heated in an oil bath at 137 C. for 48 h, concentrated, and purified by silica gel column chromatography to give 220 mg (14%) of 6-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine as a white solid (m/z [M+H]=323).

(31) ##STR00036##

(32) N-(2-(4-Fluorophenyl)-2-methylpropyl)-6-(2-methylprop-1-enyl)pyridin-2-amine. To a 5 mL microwave reaction vessel was added 6-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine (220 mg, 0.7 mmol, 1.0 equiv), 2-methylprop-1-enylboronic acid (100 mg, 1 mmol, 1.5 equiv), Cl.sub.2Pd(dppf) (50 mg, 70 mol, 0.1 equiv), potassium carbonate (300 mg, 2.1 mmol, 3.0 equiv), dioxane (4 mL), and water (1 mL). The reaction was heated in a microwave reactor at 135 C. for 35 min and then diluted with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was then dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to afford 14 mg of N-(2-(4-fluorophenyl)-2-methylpropyl)-6-(2-methylprop-1-enyl)pyridin-2-amine (m/z [M+H]=299.4).

EXAMPLE 7

4-Phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine

(33) ##STR00037##

(34) 4-Bromo-N-(1-phenylcyclobutyl)pyridin-2-amine. To a 20 dram vial was added 4-bromo-2-chloropyridine (250 mg, 5.0 mmol, 1.0 equiv), 1-phenylcyclobutanamine (1.0 g, 7 mmol, 1.4 equiv), and NMP (1 mL). The reaction was heated to 120 C., stirred for 72 h, and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer. The organic layer was then dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography, affording 139 mg (9%) of 4-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine as an orange solid.

(35) ##STR00038##

(36) 4-Phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine. To a 3 mL microwave reaction vessel was added 4-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine (50 mg, 165 mol, 1.0 equiv), phenylboronic acid (30 mg, 248 mol, 1.5 equiv), Cl.sub.2Pd(dppf) (12 mg, 16 mol, 0.1 equiv), potassium carbonate (57 mg, 413 mol, 2.5 equiv), dioxane (750 L), and water (250 L). The reaction was heated in a microwave reactor at 140 C. for 20 min and then diluted with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was then dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to afford 9 mg of 4-phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine (m/z [M+H]=301.2).

EXAMPLE 8

5-Phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine

(37) ##STR00039##

(38) 5-Bromo-N-(1-phenylcyclobutyl)pyridin-2-amine. To a 20 dram vial was added 5-bromo-2-fluoropyridine (250 mg, 5.0 mmol, 1.0 equiv), 1-phenylcyclobutanamine (1.0 g, 7 mmol, 1.4 equiv), and NMP (1 mL). The reaction was heated to 120 C., stirred for 72 h, and then diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was then dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography to give 102 mg (26%) of 5-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine as a pale yellow solid.

(39) ##STR00040##

(40) 5-Phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine. To a 3 mL microwave reaction vessel was added 5-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine (102 mg, 340 mol, 1.0 equiv), phenylboronic acid (59 mg, 505 mol, 1.5 equiv), Cl.sub.2Pd(dppf) (25 mg, 34 mol, 0.1 equiv), potassium carbonate (116 mg, 842 mol, 2.5 equiv), dioxane (1 mL) and water (500 L). The reaction was heated in a microwave reactor at 140 C. for 20 min and then diluted with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was then dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (10% EtOAc/hexanes), affording 27 mg of 5-phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine as a white solid (m/z [M+H]=301.2).

EXAMPLE 9

1-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethane-1,2-diol

(41) ##STR00041##

(42) N-(2-(4-Fluorophenyl)-2-methylpropyl)-5-vinylpyridin-2-amine. To a 5 mL microwave reaction vessel was added 5-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyrimidin-2-amine (255 mg, 0.8 mmol, 1.0 equiv), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (285 mg, 1.2 mmol, 1.5 equiv), Cl.sub.2Pd(dppf) (58 mg, 79 mol, 0.1 equiv), potassium carbonate (1.2 mL of a 2N aqueous solution, 2.4 mmol, 3.0 equiv), and dioxane (4 mL). The reaction was heated in a microwave reactor at 115 C. for 20 min. The aqueous layer was removed from the reaction, and the organic layer was directly purified by reverse phase column chromatography to give 158 mg (73%) of N-(2-(4-fluorophenyl)-2-methylpropyl)-5-vinylpyridin-2-amine.

(43) ##STR00042##

(44) 1-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethane-1,2-diol. N-(2-(4-fluorophenyl)-2-methylpropyl)-5-vinylpyridin-2-amine (158 mg, 0.6 mmol, 1.0 equiv) was added to a foil-covered 20 dram vial and then dissolved in a 50% THF/water mixture (6 mL). Osmium tetraoxide (15 mg, 0.06 mmol, 0.1 equiv) and morpholine N-oxide (103 mg, 0.9 mmol, 1.5 equiv) were added, and the reaction was stirred for 1 h. Additional THF (3 mL) was added, and the reaction was stirred for 3 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to give 129 mg (86%) of 1-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethane-1,2-diol (m/z [M+H]=305).

EXAMPLE 10

N-(2-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethyl)-methanesulfonamide

(45) ##STR00043##

(46) tert-Butyl 2-(4-fluorophenyl)-2-methylpropyl(5-(2-hydroxyethyl)pyridin-2-yl)carbamate. To a 20 dram vial was added tert-butyl 2-(4-fluorophenyl)-2-methylpropyl(5-vinylpyridin-2-yl)carbamate (2.4 g, 6.4 mmol, 1.0 equiv) and THF (20 mL). Borane (7.7 mL, 7.7 mmol, 4.0 equiv) was added slowly, and the reaction was heated to 35 C. and stirred for 45 min. The reaction was then cooled to 0 C. followed by the addition of a 50% ethanol/THF mixture (25 mL), 2N sodium hydroxide (13 mL, 25.8 mmol, 4.0 equiv), and 30% hydrogen peroxide (15 mL). The reaction was stirred for 1 h, diluted with brine (10 mL), and extracted with ethyl acetate (20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, concentrated, and then purified by reverse phase column chromatography to give 414 mg (17%) of tert-butyl 2-(4-fluorophenyl)-2-methylpropyl(5-(2-hydroxyethyl)pyridin-2-yl)carbamate.

(47) ##STR00044##

(48) tert-Butyl-5-(2-aminoethyl)pyridin-2-yl(2-(4-fluorophenyl)-2-methylpropyl)-carbamate. Methanesulfonyl chloride (87 L, 1.1 mmol, 1.1 equiv) dissolved in 2 mL ethyl acetate was added to a 20 dram vial. To this stirring mixture was added a mixture of tert-butyl-2-(4-fluorophenyl)-2-methylpropyl(5-(2-hydroxyethyl)pyridin-2-yl)-carbamate (414 mg, 1.1 mmol, 1.0 equiv), TMEDA (167 L, 1.1 mmol, 1.1 equiv), and ethyl acetate (3 mL) in a dropwise manner. The reaction was stirred for 1 h. The reaction mixture was then filtered and washed with saturated sodium bicarbonate and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated. The resultant solid was dissolved in DMF (4 mL), followed by the addition of sodium azide (139 mg, 2.1 mmol, 2.0 equiv). The reaction was stirred for 24 h, then diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated. The crude solid was dissolved in methanol, followed by the addition of 10% palladium on carbon (80 mg), potassium carbonate (100 mg). The reaction was stirred under 45 psi of hydrogen for 24 h, filtered, and concentrated to give tert-butyl 5-(2-aminoethyl)pyridin-2-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate.

(49) ##STR00045##

(50) N-(2-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethyl)-methanesulfonamide. To a 20 dram vial was added tert-butyl 5-(2-aminoethyl)pyridin-2-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate (140 mg, 0.34 mmol, 1.0 equiv), TEA (87 L, 0.67 mmol, 2.0 equiv, THF (3 mL), and methanesulfonyl chloride (29 L, 0.37 mmol, 1.1 equiv). The reaction was stirred for 2 h and then concentrated, followed by the addition of MeOH (1 mL) and 4N HCl/dioxane (3 mL). The reaction was stirred for 1 h, concentrated, and then purified by preparative TLC (5% MeOH/CH.sub.2Cl.sub.2) to give 5 mg of N-(2-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethyl)-methanesulfonamide (m/z [M+H]=366).

EXAMPLE 11

6-(2-(4-Fluorophenyl)-2-methylpropylamino)nicotinamide

(51) ##STR00046##

(52) 6-(2-(4-Fluorophenyl)-2-methylpropylamino)nicotinonitrile. To a solution of 6-chloronicotinonitrile (200 mg, 1.46 mmol, 1.0 equiv) and 2-(4-fluorophenyl)-2-methylpropan-1-amine (290 mg, 1.75 mmol, 1.2 equiv) in isopropanol (3 mL) in a microwave vial equipped with a stir bar was added potassium carbonate (720 mg, 2.19 mmol, 1.5 equiv). The vial was fitted with a microwave vial cap and heated to 120 C. for 20 min. The reaction mixture was filtered to remove the solid potassium carbonate and concentrated in vacuo. After the residue was redissolved in EtOAc and water, the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (1%-3% MeOH/DCM) provided the title compound as a beige solid (104 g, 27%), (m/z [M+H]=270.1).

(53) ##STR00047##

(54) 6-(2-(4-Fluorophenyl)-2-methylpropylamino)nicotinamide. To a cooled (0 C.) suspension of 6-(2-(4-fluorophenyl)-2-methylpropylamino)nicotinonitrile (75 mg, 0.28 mmol, 1.0 equiv) and K.sub.2CO.sub.3 (50 mg, 0.36 mmol, 1.3 equiv) in DMSO (1 mL) was added aq. H.sub.2O.sub.2 (250 uL, 30% by wt., 2.6 mmol, 9 equiv) by syringe. The reaction was allowed to warm to RT and stirred for 30 minutes. The resulting mixture was diluted with EtOAc and washed three times with satd. aq. LiCl and once with brine. The resulting solution was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (2%-10% MeOH/DCM) provided the title compound as an off-white foam (54 mg, 77%), (m/z [M+H]=288.1).

EXAMPLE 12

Methyl(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)methylcarbamate

(55) ##STR00048##

(56) 5-(Aminomethyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine. To a 100 mL round bottom flask was added 6-(2-(4-fluorophenyl)-2-methylpropylamino)nicotinonitrile (1.0 g, 3.7 mmol, 1.0 equiv) and THF (15 mL), followed by the addition of 1M lithium aluminum hydride/THF (14.8 mL, 14.8 mmol, 4.0 equiv). The reaction was heated to reflux for 3 h and allowed to cool to rt. The reaction mixture was then quenched by the sequential slow addition water (0.6 mL), 3N NaOH (0.6 mL), and water (1.7 mL). The resultant precipitate was filtered and the filtrate was then dried (Na.sub.2SO.sub.4) and concentrated to give 1.0 g (99%) of 5-(aminomethyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine.

(57) ##STR00049##

(58) Methyl(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)methylcarbamate. To a 20 dram vial was added 5-(aminomethyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine (100 mg, 0.37 mmol, 1.0 equiv), DIPEA (57 mg, 0.44 mmol, 1.2 equiv) and CH.sub.2Cl.sub.2 (1.2 mL). The mixture was cooled to 0 C., and methyl carbamate (35 mg, 0.4 mmol, 1.0 equiv) was then added. The reaction was allowed to warm to rt and stirred for 2 h. The reaction mixture was then diluted with water (2 mL) and extracted with ethyl acetate (15 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography, affording 20 mg of methyl(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)methylcarbamate (m/z [M+H]=332).

EXAMPLE 13

Preparation of 3-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-3-yl)benzamide

(59) ##STR00050##

(60) Ethyl 2-(3-chlorobenzamido)acetate. To a stirred solution of 3-chlorobenzoyl chloride (6.0 mL, 58 mmol) in dichloromethane (150 mL) were added ethyl glycinate hydrochloride (10 g, 72 mmol) and triethylamine (20 mL, 142 mmol). After stirring for 1 h, the mixture was diluted with saturated NaHCO.sub.3 and the aqueous layer extracted twice with dichloromethane. The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated to dryness in vacuo to give the desired product (9.8 g) as a white solid which was taken on without purification.

(61) ##STR00051##

(62) Ethyl 2-(3-chlorophenylthioamido)acetate. To a stirred solution of ethyl 2-(3-chlorobenzamido)acetate (9.8 g, 40 mmol) in toluene (150 mL) was added phosphorus pentasulfide (18 g, 42 mmol), and the mixture was heated to 120 C. for 1 h. The mixture was filtered, evaporated to dryness, and purified using silica gel chromatography (0-100% EtOAc/hexanes) as eluent gave 7.0 g of crude product which was carried forward without further purification

(63) ##STR00052##

(64) 3-(3-Chlorophenyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one. To a solution of ethyl 2-(3-bromophenylthioamido)acetate (40 mmol) in ethanol (100 mL) was added hydrazine hydrate (5 mL). The mixture was heated to 90 C. for 2 h and allowed to cool to room temperature. Concentration in vacuo gave a yellow solid that was purified over silica gel using 10% MeOH/DCM as eluent to give the desired product (7.0 g) as an off-white solid.

(65) ##STR00053##

(66) 3-(3-Chlorophenyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-6-amine. To a solution of 3-(3-chlorophenyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (6.0 g, 29 mmol) dissolved in dioxane (75 mL) was added MnO.sub.2 (10 g, 120 mmol). The mixture was stirred at 90 C. for 18 h. After filtering through diatomaceous earth and rinsing with hot dioxane, the combined organics were evaporated to dryness in vacuo. The crude residue ( was used) was dissolved in POCl.sub.3 (10 mL, 108 mmol) and heated to 70 C. for 2.5 h. The mixture was allowed to cool to rt and evaporated to dryness in vacuo. The residue was dissolved in EtOAc/ether (1:1) and washed with 1 M NaOH. The organic phase was evaporated to dryness and dissolved in NMP (5.0 mL) in a microwave vial. Potassium carbonate (1.0 g) was added followed by (2-(4-fluorophenyl)-2-methylpropan-1-amine (2.0 g, 12 mmol), and the mixture was heated in a microwave reactor to 165 C. for 20 min. The solution was diluted with EtOAc and washed with saturated NaCl (4), dried over Na.sub.2SO.sub.4, and evaporated to dryness. Purification using silica gel chromatography (0-35% EtOAc/hexanes) gave the desired product (430 mg) as an orange film.

(67) ##STR00054##

(68) 3-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-3-yl)benzonitrile. To a microwave vial containing NiBr.sub.2 (280 mg, 1.3 mmol) and NaCN (120 mg, 2.5 mmol) was added a solution of 3-(3-chlorophenyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-6-amine (450 mg, 1.3 mmol) in NMP (4.0 mL). The vial was purged with nitrogen and sealed. The mixture was heated to 200 C. in a microwave for 25 min and allowed to cool to room temperature. The solution was diluted with EtOAc/ether (1:1), washed with water (3), dried over Na.sub.2SO.sub.4 and evaporated to dryness. Purification using silica gel chromatography (0-65% EtOAc/hexanes) gave the desired product (220 mg) as an off white foam.

(69) ##STR00055##

(70) 3-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-3-yl)benzamide. To a solution of 3-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-3-yl)benzonitrile (220 mg, 0.60 mmol) in DMSO (3.0 mL) was added K.sub.2CO.sub.3 (300 mg, 2.2 mmol) and 30% hydrogen peroxide (0.60 mL, 7.5 mmol). The mixture was stirred 24 h and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2) and the combined organics were dried over Na.sub.2SO.sub.4 and evaporated to dryness in vacuo. Purification using silica gel chromatography (0-100% EtOAc/hexanes) gave the desired product (17 mg), m/z=366.1 [M+H].

EXAMPLE 14

Preparation of 5-(3-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-6-yl)-1H-indazol-3-amine

(71) ##STR00056##

(72) 3-Amino-1,2,4-triazin-2-oxide. To a solution of 1,2,4-triazin-3-amine (2.8 g, 30 mmol) in CH.sub.3CN (25 mL) was added portionwise mCPBA (14 g, 81 mmol). The mixture was refluxed for 2 h and then evaporated to dryness. The residue was mixed with ether and filtered to give the desired product as a yellow solid that was used in the next step without purification.

(73) ##STR00057##

(74) 3-Bromo-1,2,4-triazin-2-oxide. To a solution of 48% (wt/wt) HBr (100 mL) was added 1,2,4-triazin-3-amine-2-oxide (30 mmol), and the mixture was stirred at rt. A solution of NaNO.sub.2 (30 g, 430 mmol) in water (40 mL) was added slowly, and the mixture was stirred for 1 h. The reaction was quenched by the addition of an excess of saturated NaHCO.sub.3 and extracted with dichloromethane. The combined organic layers were evaporated to dryness. Purification using silica gel chromatography (EtOAc/hexanes) gave 1.3 g of the intermediate bromide product.

(75) ##STR00058##

(76) N-(2-(4-Fluorophenyl)-2-methylpropyl)-1,2,4-triazin-3-amine-2-oxide. A solution of 3-bromo-1,2,4-triazin-2-oxide (2.0 g, 11 mmol), (2-(4-fluorophenyl)-2-methylpropan-1-amine (3.0 g, 17 mmol), and diisopropylethylamine (3.0 mL, 17 mmol) in CH.sub.3CN (20 mL) was stirred at rt for 24 h. The solvents were removed and the residue dissolved in EtOAc. The solution was washed with saturated NaHCO.sub.3, dried over Na.sub.2SO.sub.4, and evaporated to dryness. The residue was mixed with ether and then filtered to give the desired product (1.2 g) as a yellow solid.

(77) ##STR00059##

(78) 6-Bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-3-amine-2-oxide. To a solution of N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-3-amine-2-oxide (1.2 g, 7.4 mmol) in a 1:1 mixture of dichloromethane and CH.sub.3CN (40 mL) was added Br.sub.2 (1.0 mL, 19 mmol). The mixture was stirred at room temperature for 72 h. The solvents were evaporated and the residue was dissolved in ether. The solution was filtered through a plug of silica gel and the solvents evaporated to give the desired product (1.5 g, 58%) as an orange sticky solid.

(79) ##STR00060##

(80) 2-Fluoro-5-(3-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-2-oxide-6-yl)benzonitrile. To a solution of 6-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-3-amine-2-oxide (0.48 g, 1.4 mmol, 1.0 equiv), 3-cyano-4-fluorophenylboronic acid (0.35 g, 2.1 mmol), and K.sub.2CO.sub.3 (0.5 g, 3.6 mmol) in DMF (2 mL) was added Pd(dppf)Cl.sub.2 (0.10 g, 0.13 mmol). The mixture was stirred at 75 C. for 4 h and then quenched by addition of excess saturated NaHCO.sub.3. The mixture was extracted with EtOAc and the organic layer was concentrated. Purification using silica gel chromatography (1-40% EtOAc/hexanes) gave the desired product (0.38 g) as a yellow solid.

(81) ##STR00061##

(82) 5-(3-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-6-yl)-1H-indazol-3-amine. A stirred solution of 2-fluoro-5-(3-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-2-oxide-6-yl)benzonitrile (0.18 g, 0.47 mmol) and hydrazine (0.1 mL, 2.0 mmol) in n-butanol (0.5 mL) was sealed and heated to 119 C. for 1 h. The solvents were removed and the residue dissolved in benzylamine with a minimal amount of CH.sub.3CN. The mixture was sealed and stirred at 177 C. overnight. The mixture was loaded directly onto a reverse phase HPLC for purification using a gradient of CH.sub.3CN/water to give the desired product (28 mg), m/z=378.1 [M+H].

EXAMPLE 15

Preparation of 4-fluoro-3-(3-(2-(3-fluoropyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)benzamide

(83) ##STR00062##

(84) 6-(5-Bromo-2-fluorophenyl)-1,2,4-triazin-3-amine6-Bromo-1,2,4-triazin-3-amine (9.1 g, 40.8 mmol), 5-bromo-2-fluorophenylboronic acid (98.9 g, 40.8 mmol), (dppf)PdCl.sub.2 (3.0 g, 4.0 mmol), nitrogen-sparged dioxane (81.6 mL), and aq. 2 N K.sub.2CO.sub.3 (17 mL) were combined and heated in a round bottom flask at 90 C. for 4 h. The hot mixture was filtered through a pad of celite and diluted with EtOAc and washed with water. Concentration followed by trituration with DCM afforded a tan solid (4.5 g), m/z=269.0 [M+H].

(85) ##STR00063##

(86) 3-Bromo-6-(5-bromo-2-fluorophenyl)-1,2,4-triazine. 6-(5-Bromo-2-fluorophenyl)-1,2,4-triazin-3-amine (4.5 g, 16.7 mmol) was dissolved in 25 mL of bromoform and heated to 80 C. Isoamyl nitrite (9.8 g, 83.5 mmol) was then added and stirred at 85 C. for 1 h. The reaction mixture was then concentrated and silica gel chromatography afforded a yellow solid (4.4 g), m/z=331.1 [M+H].

(87) ##STR00064##

(88) 6-(5-Bromo-2-fluorophenyl)-N-(2-(2-fluorophenyl)propan-2-yl)-1,2,4-triazin-3-amine. 3-Bromo-6-(5-bromo-2-fluorophenyl)-1,2,4-triazine (2.8 g, 8.4 mmol), 2-(2-fluorophenyl)propan-2-amine (2.0 g, 12.6 mmol), K.sub.2CO.sub.3 (2.3 g, 16.8 mmol) and CH.sub.3CN (20 mL) was heated to 90 C. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO.sub.3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified using silica gel chromatography to afford a yellow solid (2.3 g), m/z=406.1 [M+H].

(89) ##STR00065##

(90) 4-Fluoro-3-(3-(2-(2-fluorophenyl)propan-2-ylamino)-1,2,4-triazin-6-yl)benzonitrile. 6-(5-Bromo-2-fluorophenyl)-N-(2-(2-fluorophenyl)propan-2-yl)-1,2,4-triazin-3-amine (2.2 g, 5.6 mmol), zinc cyanide (0.72 g, 6.2 mmol), Pd(PPh.sub.3).sub.4 (2.9 g, 2.8 mmol), and DMF (20 mL) were combined and heated in a round bottom flask at 100 C. for 2 h. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO.sub.3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated and purified using silica gel chromatography to provide a yellow solid (1.7 g), m/z=352.1 [M+H].

(91) ##STR00066##

(92) 4-Fluoro-3-(3-(2-(3-fluoropyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)benzamide. 4-Fluoro-3-(3-(2-(2-fluorophenyl)propan-2-ylamino)-1,2,4-triazin-6-yl)benzonitrile (4.0 g, 11.3 mmol), K.sub.2CO.sub.3 (6.2 g, 21.2 mmol), and DMSO (113 mL) were combined in a round bottom flask and cooled to 0 C. H.sub.2O.sub.2 (38 mL of 35% solution) was then added dropwise and the reaction was warmed to rt and stirred for 1 h. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO.sub.3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified using silica gel chromatography to afford a white solid (3.3 g), m/z=371.1 [M+H].

EXAMPLE 16

Preparation of (1-(6-Methoxypyridin-2-yl)cyclobutyl) methanamine

(93) ##STR00067##

(94) 1-(6-Fluoropyridin-2-yl)cyclobutanecarbonitrile. To a 0 C. solution of 2,6-difluoropyridine (5.0 g, 43 mmol), cyclobutanecarbonitrile (3.5 g, 43 mmol), and toluene (100 mL) was added sodium hexamethyldisilazide (NaHMDS, 2.0 M in THF, 24 mL, 47 mmol). The resulting mixture was warmed to rt and stirred for 2 h. The mixture was then diluted with EtOAc (200 mL) and water (100 mL). The aqueous layer was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, concentrated, and purified using silica gel chromatography to provide the desired product (4.9 g) as a colorless oil.

(95) ##STR00068##

(96) 1-(6-Methoxypyridin-2-yl)cyclobutanecarbonitrile. To anhydrous methanol (6 mL) at 0 C. under nitrogen was added sodium metal (ca 1 g) and the mixture stirred for 30 min. 1-(6-fluoropyridin-2-yl)cyclobutanecarbonitrile (1.6 g, 9.1 mmol) was then added, and the resulting mixture heated to 75 C. for 45 min. The solution was cooled to room temperature and partitioned between water and EtOAc. The layers were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the desired product (1.7 g) as an oil.

(97) ##STR00069##

(98) (1-(6-Methoxypyridin-2-yl)cyclobutyl)methanamine. To a stirred solution of 1-(6-methoxypyridin-2-yl)cyclobutanecarbonitrile (1.7 g, 8.8 mmol) in THF (20 mL) was added lithium aluminum hydride solution (1.0 M in THF, 11 mL, 11 mmol). The mixture was refluxed for 1.5 h and allowed to cool to room temperature. Water (0.43 mL) was slowly added, followed by 0.43 mL of 3 M NaOH, and then three additions of 0.43 mL of water. The resulting mixture was filtered through diatomaceous earth and rinsed with THF. The combined organics were dried over Na.sub.2SO.sub.4 and concentrated to dryness to give the desired product (1.6 g) as a viscous oil.

EXAMPLE 17

Preparation of 1-(3-Fluoropyridin-2-yl)cyclobutanamine Example 5(a)

(99) ##STR00070##

(100) 1-(3-Fluoropyridin-2-yl)cyclobutanecarboxamide. To a 250 mL round bottom flask was added DMSO (60 mL) and 1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (2.96 g, 16.8 mmol), and the mixture was stirred until homogenous. Potassium carbonate (7.0 g, 50.4 mmol) was then added and the reaction mixture was cooled to 0 C., followed by the addition of 35% hydrogen peroxide (6.5 mL). The reaction was stirred at 0 C. for 30 min and then warmed to rt. At this time, the reaction was diluted with water (50 mL) and ethyl acetate (100 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (350 mL). The organic layer was then dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a crude solid that was purified by silica gel chromatography (10% EtOAC/hexanes) to afford 1.92 g of 1-(3-fluoropyridin-2-yl)cyclobutanecarboxamide as a white solid.

(101) ##STR00071##

(102) Methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate. 1-(3-fluoropyridin-2-yl)cyclobutanecarboxamide (1.92 g, 9.88 mmol) was dissolved in methanol (20 mL) and potassium hydroxide (1.11 g, 19.8 mmol, 2.0 equiv) was added. The mixture was sonicated until homogeneous, followed by the addition of iodosobenzene diacetate (4.77 g, 14.8 mmol). The reaction was stirred for 20 min and then diluted with water (100 mL) and ethyl acetate (125 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were then dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a crude oil that was purified by silica gel chromatography (40% EtOAC/hexanes) to afford 1.47 g of methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate as a white solid.

(103) ##STR00072##

(104) 1-(3-Fluoropyridin-2-yl)cyclobutanamine. To a 20 mL microwave reaction vial was added methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate (1.47 g, 6.56 mmol), ethanol (12 mL) and 3N aqueous sodium hydroxide (7 mL). The reaction mixture was heated in the microwave reactor at 150 C. for 30 min. The ethanol was evaporated under reduced pressure and the mixture was extracted with ethyl acetate (30 mL). The aqueous layer was then extracted with ethyl acetate (230 mL). The organic layers were combined, dried over Na.sub.2SO.sub.4, filtered, and concentrated to give 1-(3-fluoropyridin-2-yl)cyclobutanamine (1.01 g) as a crude yellow oil that was used in the next reaction step without further purification.

EXAMPLE 18

Preparation of trans-3-Fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine

(105) ##STR00073##

(106) 1-(3-Fluoropyridin-2-yl)-3-methylenecyclobutanecarbonitrile. To a solution of 3-methylenecyclobutanecarbonitrile (150 g, 1.61 mol, 1 equiv) and 2-chloro-3-fluoropyridine (212 g, 1.61 mmol, 1 equiv) in toluene (1 L) was added NaHMDS (2 M in THF, 885 mL, 1.1 equiv) dropwise at 0-10 C. Upon completion of addition, the reaction mixture was warmed to rt, stirred overnight, and quenched with NH.sub.4Cl.sub.(sat) solution. The organic layer was washed with water (2500 mL) and brine (500 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give the crude title compound (272 g) which was used in next step without further purification, m/z=189.1 [M+H].

(107) ##STR00074##

(108) 1-(3-Fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile. To a mixture of 1-(3-fluoropyridin-2-yl)-3-methylenecyclobutanecarbonitrile (272 g, 1.45 mol) and RuCl.sub.3.H.sub.2O (9.0 g, 0.044 mol) in DCM (1 L), acetonitrile (1 L), and water (1.5 L) mixture was added solid NalO.sub.4 (1235 g, 5.8 mol) portionwise at 10-30 C. Upon the completion of addition, the reaction was stirred 1 h at 15 C. and overnight at rt. The solid precipitate was filtered off and washed with DCM (21000 mL). The organic layer was washed with water (2500 mL) and brine (500 mL), dried over Na.sub.2SO.sub.4, and concentrated to provide a crude title compound as a dark solid (238 g), m/z=191.1 [M+H].

(109) ##STR00075##

(110) 1-(3-Fluoropyridin-2-yl)-3-hydroxycyclobutanecarbonitrile. To a solution of 1-(3-fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile (231 g, 1.22 mol) in a mixture of DCM (2 L) and MeOH (200 mL) was added NaBH.sub.4 portionwise at 78 C. The reaction mixture was stirred at 78 C. for 1 h and quenched with a mixture of methanol and water (1/1). The organic layer was washed with water (500 mL3), dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified on silica gel (50% EtOAc/hexanes) to provide the title compound as an amber oil (185.8 g) m/z=193.2 [M+H].

(111) ##STR00076##

(112) trans-3-Fluoro-1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile. To a solution of 1-(3-fluoropyridin-2-yl)-3-hydroxycyclobutanecarbonitrile (185 g, 0.96 mol) in DCM (1 L) was added DAST portionwise at 0-10 C. Upon the completion of addition, the reaction was refluxed for 6 h. The reaction was cooled to rt and poured onto sat. NaHCO.sub.3 solution. The mixture was separated and the organic layer was washed with water, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified on silica gel (100% DCM) to provide the title compound as a brown oil (116 g, 62%) in a 8:1 trans:cis mixture. The above brown oil (107 g) was dissolved in toluene (110 mL) and hexanes (330 mL) at 70 C. The solution was cooled to 0 C. and stirred at 0 C. overnight. The precipitate was filtered and washed with hexanes to provide the trans isomer as a white solid (87.3 g), m/z=195.1 [M+H].

(113) ##STR00077##

(114) trans-3-Fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine. A mixture of trans-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (71 g, 0.37 mol) and Raney nickel (7 g) in 7N ammonia in methanol (700 mL) was charged with hydrogen (60 psi) for 2 days. The reaction was filtered through a celite pad and washed with methanol. The filtrate was concentrated under high vacuum to provide the title compound as a light green oil (70 g), m/z=199.2 [M+H].

EXAMPLE 19

Preparation of 4-fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-N-methylbenzamide

(115) ##STR00078##

(116) 4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)benzoic acid. 4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)benzonitrile (1.3 g, 74.5 mmol) was diluted in 20 mL of concentrated HCl and heated in a microwave reactor at 110 C. for 30 min. The mixture was then concentrated and carried on to next step without further purification, (m/z [MH]=414.1).

(117) ##STR00079##

(118) 4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-N-methylbenzamide. 4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)benzoic acid (0.5 g, 1.2 mmol) was diluted in 18 mL DMF and treated with HBTU (1.8 g, 4.8 mmol), HOBT (0.65 g, 4.8 mmol), methyl amine hydrochloride (0.32 g, 4.8 mmol), and DIEA (8.4 mL, 48 mmol). The mixture was stirred at 24 C. for 30 min, diluted with EtOAc, washed with water and brine, concentrated, and purified using reverse phase chromatography to afford a tan solid (0.25 g, (m/z [MH]=429.3).

EXAMPLE 20

Preparation of 1-(3-chloropyridin-2-yl)-3,3-difluorocyclobutanecarbonitrile

(119) ##STR00080##

(120) To a 100 mL round bottom flask was added 2,3-dichloropyridine (2.9 g, 20 mmol), 3,3-difluorocyclobutanecarbonitrile (2.1 g, 18 mmol), and toluene (50 mL). The mixture was cooled to C. and sodium hexamethyldisilazide (NaHMDS, 2.0 M in THF, 11 mL, 22 mmol) was added. The reaction mixture was warmed to rt and stirred for 2 h. The mixture was then diluted with EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to provide the desired product (3.4 g) as a colorless oil.

EXAMPLE 21

Preparation of 4-fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-hydroxybenzamide

(121) ##STR00081##

(122) 4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-methoxybenzonitrile. 6-(3-Bromo-6-fluoro-2-methoxyphenyl)-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-1,2,4-triazin-3-amine (448 mg, 0.93 mmol), zinc cyanide (131 mg, 1.1 mmol), Pd(PPh.sub.3).sub.4 (296 mg, 0.3 mmol), and DMF (5 mL) were combined and heated to 100 C. for 2 h. The reaction mixture was cooled and filtered through Celite. The reaction mixture was then diluted with EtOAc and washed with satd. aq. NaHCO.sub.3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified using silica gel chromatography to afford 4-fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-methoxybenzonitrile (229 mg).

(123) ##STR00082##

(124) 4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-methoxybenzamide. 4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-methoxybenzonitrile (229 mg, 0.54 mmol), K.sub.2CO.sub.3 (200 mg, 1.4 mmol), and DMSO (5 mL) were combined in a round bottom flask and cooled to 0 C. H.sub.2O.sub.2 (1 mL of 35% solution) was then added dropwise and the reaction was warmed to rt and stirred for 1 h. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO.sub.3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified using silica gel chromatography to afford 210 mg of 4-fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-methoxybenzamide.

(125) ##STR00083##

(126) 4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-hydroxybenzamide Lithium iodide (1 g), pyridine (20 mL), and 4-fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-methoxybenzamide (210 mg) were added to a round bottom flask. The reaction was heated to 125 C. and stirred for 2 h. The reaction was concentrated, mixed with methanol, filtered, and purified using reverse phase chromatography to afford 24 mg of 4-fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-hydroxybenzamide, m/z=430.1 [M+H].

EXAMPLE 22

Preparation of N-((2-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)thiazol-5-yl)methyl)acetamide

(127) ##STR00084##

(128) 6-(5-((tert-Butyldimethylsilyloxy)methyl)thiazol-2-yl)-1,2,4-triazin-3-amine. Diisopropylamine (13.7 mL, 98 mmol) and THF (100 mL) were added to a round bottom flask. The mixture was cooled to 78 C. and n-BuLi (2.5 M, 40 mL, 100 mmol) was added. The reaction was stirred for 30 min, followed by the addition of (5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl) (17.1 g, 75 mmol). The reaction was stirred to 30 min followed by the addition of zinc bromide (18 g, 69 mmol). The reaction was stirred for 1 h at 78 C. and then warmed to rt.

(129) In a separate flask was added 6-bromo-1,2,4-triazin-3-amine (10.0 g, 57.5 mmol), (PPh.sub.3).sub.4Pd (12.1 g, 11.5 mmol), and THF (200 mL). The mixture was heated to 80 C., followed by the dropwise addition (1 h) of (5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)zinc(II) bromide prepared in the step above. The reaction was then cooled to rt, filtered through a silica pad, concentrated, and then purified using silica gel chromatography to afford 6.7 g the title compound as a light yellow solid.

(130) ##STR00085##

(131) 5-((tert-Butyldimethylsilyloxy)methyl)-2-(3-chloro-1,2,4-triazin-6-yl)thiazole. To a vial was added 6-(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)-1,2,4-triazin-3-amine (2.5 g, 10.7 mmol), tetrabutylammonium chloride (6.3 g, 27.7 mmol) and dichloroethane (25 mL). The mixture was heated to 75 C., followed by the addition of t-butyl nitrite (3.3 mL, 27.7 mmol). The reaction was stirred at 75 C. for 3 h, followed by cooling to rt, quenching with brine (200 mL). The reaction was extracted four times with CH.sub.2Cl.sub.2. The combined organic layers were dried over Na.sub.2SO.sub.4, concentrated, and purified using silica gel chromatography to afford the 1.1 g of the title compound as an off-white solid.

(132) ##STR00086##

(133) (2-(3-(((trans)-3-Fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)thiazol-5-yl)methanol. To a round bottom flask was added 5-((tert-butyldimethylsilyloxy)methyl)-2-(3-chloro-1,2,4-triazin-6-yl)thiazole (1.1 g, 3.2 mmol), trans-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (870 mg, 4.3 mmol), potassium carbonate (1.3 g, 9.4 mmol), and CH.sub.3CN (11 mL). The reaction mixture was heated to 80 C. and stirred for 2 h. The reaction was then diluted with EtOAc, filtered, and concentrated. The crude residue was suspended in methanol and concentrated HCl (1 mL) was added. The reaction was stirred for 30 min and then concentrated. The crude oil was dissolved in ethyl acetate (50 mL) and washed twice with saturated sodium carbonate (50 mL). The organic layers were dried over Na.sub.2SO.sub.4, concentrated, and purified using silica gel chromatography to afford 470 mg of the title compound as an off-white solid.

(134) ##STR00087##

(135) 6-(5-(Aminomethyl)thiazol-2-yl)-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-1,2,4-triazin-3-amine. To a vial containing (2-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)thiazol-5-yl)methanol (457 mg, 1.17 mmol) was added triphenylphosphine (460 mg, 1.75 mmol), phthalimide (257 mg, 1.75 mmol), DIPEA (1 mL), and THF (10 mL). Diisopropylazodicarboxylate (350 mg, 1.75 mmol) was then added, and the reaction was stirred for 30 min. The reaction was quenched with saturated sodium bicarbonate solution (10 mL) and extracted three times with ethyl acetate (50 mL). The organic layers were dried over Na.sub.2SO.sub.4, concentrated, and purified using silica gel chromatography to afford 670 mg of 2-((2-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)thiazol-5-yl)methyl)isoindoline-1,3-dione as an off-white solid. This solid was dissolved in methanol (10 mL) and hydrazine (1 mL). The reaction was stirred for 12 h, concentrated, and then purified using reverse phase chromatography to afford 250 mg of 6-(5-(aminomethyl)thiazol-2-yl)-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-1,2,4-triazin-3-amine.

(136) ##STR00088##

(137) N-((2-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)thiazol-5-yl)methyl)acetamide. To a stirring solution of 6-(5-(aminomethyl)thiazol-2-yl)-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-1,2,4-triazin-3-amine (250 mg, 643 mol) in CH.sub.2Cl.sub.2 (10 mL) was added acetic anhydride (324 mg, 3.2 mol). The reaction was stirred for 30 min, followed by quenched with saturated sodium bicarbonate solution (10 mL) and extracted three times with CH.sub.2Cl.sub.2 (50 mL). The organic layers were dried over Na.sub.2SO.sub.4, concentrated, and purified using reverse phase chromatography to afford 224 mg of N-((2-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)thiazol-5-yl)methyl)acetamide as a white solid, m/z=432.1 [M+H].

EXAMPLE 23

Preparation of 2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carboxamide

(138) ##STR00089##

(139) 6-(5-Bromothiazol-2-yl)-1,2,4-triazin-3-amine. To a vial was added 6-(thiazol-2-yl)-1,2,4-triazin-3-amine (600 mg, 3.4 mmol), methanol (1.2 mL), water (0.6 mL). The mixture was cooled to 0 C. and bromine (816 mg, 5.1 mmol) was added. The reaction was stirred for 45 min and then quenched with saturated sodium bicarbonate solution (20 mL) and extracted three times with ethyl acetate (50 mL). The organic layers were dried over Na.sub.2SO.sub.4, concentrated, and purified using silica gel chromatography to afford 320 mg of 6-(5-bromothiazol-2-yl)-1,2,4-triazin-3-amine as an off-white solid.

(140) ##STR00090##

(141) 2-(3-Amino-1,2,4-triazin-6-yl)thiazole-5-carbonitrile. 6-(5-Bromothiazol-2-yl)-1,2,4-triazin-3-amine (300 mg, 1.15 mmol), zinc cyanide (340 mg, 2.30 mmol), Pd(PPh.sub.3).sub.4 (133 mg, 0.13 mmol), and DMF (5 mL) were combined and heated to 160 C. for 12 h. The reaction mixture was cooled, diluted with CH.sub.2Cl.sub.2 (30 mL), filtered through silica gel, eluted with EtOAc, and concentrated. The crude product was then purified using silica gel chromatography to afford 30 mg of 2-(3-amino-1,2,4-triazin-6-yl)thiazole-5-carbonitrile.

(142) ##STR00091##

(143) 2-(3-Bromo-1,2,4-triazin-6-yl)thiazole-5-carbonitrile. 2-(3-Amino-1,2,4-triazin-6-yl)thiazole-5-carbonitrile (30 mg, 0.15 mmol) was dissolved in 1 mL of bromoform and heated to 90 C. Isoamyl nitrite (88 mg, 0.75 mmol) was added and stirred at 90 C. for 2 h. The reaction mixture was then concentrated and used directly in the next reaction.

(144) ##STR00092##

(145) 2-(3-(2-(3-(Difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carbonitrile. To a scintillation vial was added 2-(3-bromo-1,2,4-triazin-6-yl)thiazole-5-carbonitrile (directly from above reaction), 2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-amine (100 mg, 500 mol), and CH.sub.3CN (2 mL). The reaction was heated to 90 C. and stirred for 12 h. The reaction was then concentrated and purified using silica gel chromatography to afford 15 mg of 2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carbonitrile.

(146) ##STR00093##

(147) 2-(3-(2-(3-(Difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carboxamide. 2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carbonitrile (15 mg, 38 mol), K.sub.2CO.sub.3 (50 mg, 0.35 mmol), and DMSO (1 mL) were combined in a vial and cooled to 0 C. H.sub.2O.sub.2 (0.1 mL of 35% solution) was then added and the reaction was warmed to rt and stirred for 1 h. Acetic acid (0.1 mL) was added, and the reaction was filtered and then purified using reverse phase chromatography to afford 23 mg of 2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carboxamide as a white solid, m/z=408.3 [M+H].

EXAMPLE 24

Preparation of 3-(5-Fluoro-6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridin-3-yl)benzamide

(148) ##STR00094##

(149) 5-Bromo-3-fluoro-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridin-2-amine. To a microwave tube was added 5-bromo-2-chloro-3-fluoropyridine (1.5 g, 7.4 mmol), ((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (2.2 g, 11.1 mmol), and DIPEA (4.9 mL, 29.7 mmol). The tube was sealed, heated at 110 C., and stirred for 12 h. The reaction was then directly purified using silica gel chromatography to afford 2.5 g of 5-bromo-3-fluoro-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridin-2-amine as a white solid.

(150) ##STR00095##

(151) 3-(5-Fluoro-6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridin-3-yl)benzamide. 5-Bromo-3-fluoro-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridin-2-amine (1.0 g, 2.6 mmol), 3-carbamoylphenylboronic acid (0.54 g, 3.2 mmol), potassium carbonate (1.5 g, 10.8 mmol), and methanol (25 mL) was added to a 100 mL round bottom flask and then degassed with nitrogen for 5 min. Silica-supported 1,1-Bis(diphenylphosphino)ferrocene (1.0 g, 0.28 mmol/g) was added, and the reaction was refluxed in methanol for 2 h. The reaction mixture was then filtered, concentrated, and purified using silica gel chromatography to afford 2.0 g of the title compound as a solid, m/z=413.3 [M+H]

EXAMPLE 25

Preparation and Assay of Fast Skeletal Myofibrils

(152) Preparation of fast skeletal myofibrils. Rabbit skeletal myofibrils were prepared based upon the method of Herrmann et al. (Biochem. 32(28):7255-7263(1993). Myofibrils were prepared from rabbit psoas muscle purchased from Pel-Freez Biologicals (Arkansas) within 2 days of ordering, stored on ice. Minced muscle was homogenized in 10 volumes of ice-cold standard buffer (50 mM Tris, pH 7.4, 0.1 M potassium acetate, 5 mM KCl, 2 mM DTT, 0.2 mM PMSF, 10 M leupeptin, 5 M pepstatin, and 0.5 mM sodium azide) containing 5 mM EDTA and 0.5% Triton X-100 using an Omni-Macro homogenizer. Myofibrils were recovered by low speed centrifugation (3000 rpm for 10 minutes) and washed 2 times in the Triton X-100 containing buffer to ensure removal of cellular membrane. Following the Triton washes, myofibrils were washed 3 times in standard buffer containing 2 mM magnesium acetate. A final wash in assay buffer (12 mM PIPES, pH 6.8, 60 mM KCl, 1 mM DTT) was performed and brought to 10% sucrose for flash freezing in liquid nitrogen and storage at 80 C.

(153) Activation of Fast Skeletal Myofibrils. Fast fiber activators were identified by measuring the enzymatic activity of muscle myofibril preparations using the proprietary PUMA (see, e.g., U.S. Pat. Nos. 6,410,254, 6,743,599, 7,202,051, and 7,378,254) assay system. Myofibril preparations consisted of rabbit skeletal muscle (approximately 90% fast fibers) that had been mechanically homogenized and washed with a detergent (triton X-100) to remove cellular membranes. This preparation retained all of the sarcomeric components in a native conformation and the enzymatic activity was still regulated by calcium. Compounds were tested using a myofibril suspension and a level of calcium sufficient to increase enzymatic activity of the myofibrils to 25% of their maximal rate (termed pCa25). Enzymatic activity was tracked via a pyruvate kinase and lactate dehydrogenase-coupled enzyme system. This assay regenerates myosin-produced ADP into ATP by oxidizing NADH, producing an absorbance change at 340 nm. The buffering system was 12 mM Pipes, 2 mM MgCl.sub.2, 1 mM DTT at pH 6.8 (PM12 buffer). Data was reported as AC1.4, which is the concentration at which the compound increased the enzymatic activity by 40%. The results are summarized in Table 2 below.

EXAMPLE 26

Preparation and Assay of Sarcomeric Proteins from Skeletal Muscle

(154) Powder Preparation 1. Volumes are given per about 1000 g of the minced muscle. 2. Pre-cut and boil cheesecloth for 10 min in water. Drain and dry. 3. Mince chicken breast in a prechilled meat grinder. 4. Extract with stirring in 2 L of 0.1 M KCl, 0.15 M K-phosphate, pH 6.5 for 10 min at 4 C. Spin 5000 rpm, 10 min, 4 C. in JLA. Collect the pellet. 5. Extract pellets with stirring with 2 L of 0.05 M NaHCO.sub.3 for 5 min. Spin 5000 rpm, 10 min, 4 C. in JLA. Collect the pellet. Repeat the extraction once more. 6. Extract the filtered residue with 2 L of 1 mM EDTA, pH 7.0 for 10 min with stirring. 7. Extract with 2 L of H.sub.2O for 5 min with stirring. Spin 10000 rpm, 15 min, 4 C. in JLA. Carefully collect the pellet, part of which will be loose and gelatinous. 8. Extract 5 times with acetone (2 L of acetone for 10 min each with stirring). Squeeze through cheesecloth gently. All acetone extractions are performed at room temperature. Acetone should be prechilled to 4 C. 9. Drying: Place the filtered residue spread on a cheesecloth in a large glass tray and leave in a hood overnight. When the residue is dry, put in a wide mouth plastic bottle and store at 20 C.

(155) Alternate Powder Preparation (See Zot & Potter (1981) Prep. Biochem. 11(4) pp. 381-395) 1. Dissect left ventricles of the cardiac muscle. Remove as much of the pericardial tissue and fat as possible. Grind in a prechilled meat grinder. Weigh. 2. Prepare 5 volumes of Extract buffer (see below). Homogenize the meat in a blender, 4 times 15 sec on blend with 15 secs in between. Do this with 1 volume (weight/volume) of buffer taken from the 5 volumes already prepared. Add the homogenate back to the extract buffer and stir until well mixed (5 minutes). 3. Filter through one layer of cheesecloth in large polypropylene strainer. Resuspend back into 5 volumes of extract buffer as above. 4. Repeat Step 3 four more times. At the end, do not resuspend in extraction buffer but proceed to Step 5. The pellets should be yellow white. 5. Resuspend in 3 volumes (according to original weight) of 95% cold ethanol. Stir for 5 min and squeeze through cheesecloth as above, repeat two more times. 6. Weigh squeezed residue and then resuspend in 3 volumes (new weight/volume) of cold diethyl ether. 7. Repeat Step 6 a total of three times. 8. Leave overnight in a single layer on a cheesecloth in a glass tray. 9. When dry, collect the powder, weigh and store in a wide-mouth jar at 4 C.
EXTRACT BUFFER: 50 mM KCl, 5 mM Tris pH 8.0 Prepare as 50 times concentrate. For 2 L: 250 mM Tris pH 8.0. Tris Base (121.14 g/mol, 60.6 g), pH to 8.0 with conc. HCl, then add 2.5 M KCl (74.55 g/mol, 372 g).

(156) Actin Preparation 1. Extract powder (as described above) with 20 ml buffer A (see below, add BME and ATP just prior to use in each of the following steps) per gram of powder (200 ml per 10 g). Use a large 4 L beaker for 150 g of powder. Mix vigorously to dissolve powder. Stir at 4 C. for 30 min. 2. Separate extract from the hydrated powder by squeezing through several layers of cheesecloth. Cheesecloth should be pre-sterilized by microwaving damp for 1-2 min. 3. Re-extract the residue with the same volume of buffer A and combine extracts. 4. Spin in JLA10 rotor(s) for 1 hr at 10K rpm (4 C.). Collect supernatant through 2 layers of cheesecloth. 5. Add ATP to 0.2 mM and MgCl.sub.2 to 50 mM. Stir on stir plate at 4 C. for 60 minutes to allow actin to polymerize/form para-crystals. 6. Slowly add solid KCl to 0.6 M (45 g/l). Stir at 4 C. for 30 min. 7. Spin in JLA10 rotor(s) at 10K rpm for 1 hr. 8. Depolymerization: Quickly rinse surface of pellets with buffer A and dispose of wash. Soften the pellets by pre-incubation on ice with small amount of buffer A in each tube (use less than half of final resuspension volume total in all tubes). Resuspend by hand first with cell scraper and combine pellets. Wash tubes with extra buffer using a 25 ml pipette and motorized pipettor, aggressively removing actin from sides of tubes. Homogenize in large dounce in cold buffer A on ice. Use 3 ml per gram of powder originally extracted. 9. Dialyze against buffer A with 4 changes over 48 hour period. 10. Collect dialyzed actin and spin in the 45Ti rotor at 40K rpm for 1.5 hr (4 C.). 11. Collect supernatant (G-Actin). Save a sample for gel analysis and determination of protein concentration. 12. To polymerize G-actin for storage, add KCl to 50 mM (from 3 M stock), MgCl.sub.2 to 1 mM, and NaN.sub.3 to 0.02% (from 10% stock). Store at 4 C. Do not freeze. Buffer A: 2 mM tris/HCl, 0.2 mM CaCl.sub.2, 0.5 mM (36 l/L) 2-mercaptoethanol, 0.2 mM Na.sub.2 ATP (added fresh), and 0.005% Na-azide; pH 8.0.

(157) Purification of Skeletal Muscle Myosin (See Margossian, S. S. and Lowey, S. (1982) Methods Enzymol. 85, 55-123; and Goldmann, W. H. and Geeves, M. A. (1991) Anal. Biochem. 192, 55-58) Solution A: 0.3 M KCl, 0.15 M potassium phosphate, 0.02 M EDTA, 0.005 M MgCl.sub.2, 0.001 M ATP, pH 6.5. Solution B: 1 M KCl, 0.025 M EDTA, 0.06 M potassium phosphate, pH 6.5. Solution C: 0.6 M KCl, 0.025 M potassium phosphate, pH 6.5. Solution D: 0.6 M KCl, 0.05 M potassium phosphate, pH 6.5. Solution E: 0.15 M potassium phosphate, 0.01 M EDTA, pH 7.5. Solution F: 0.04 M KCl, 0.01 M potassium phosphate, 0.001 M DTT, pH 6.5. Solution G: 3 M KCl, 0.01 M potassium phosphate, pH 6.5. All procedures are carried out at 4 C. 1. Obtain approx. 1000 g skeletal muscle, such as rabbit skeletal muscle. 2. Grind twice; extract with 2 L solution A for 15 min while stirring; add 4 L cold H.sub.2O, filter through gauze; dilute with cold H.sub.2O to ionic strength of 0.04, (about 10-fold); let settle for 3 h; collect precipitate at 7,000 rpm in GSA rotor for 15 min. 3. Disperse pellet in 220 ml solution B; dialyze overnight against 6 L solution C; slowly add 400 ml equal volume cold distilled H.sub.2O; stir for 30 min; centrifuge at 10,000 rpm for 10 min in GSA rotor. 4. Centrifuge supernatant at 19,000 rpm for 1 h. 5. Dilute supernatant to ionic strength of 0.04 (8-fold); let myosin settle overnight; collect about 5-6 L fluffy myosin precipitate by centrifuging at 10,000 rpm for 10 min in GSA rotor. 6. Resuspend pellet in minimal volume of solution G; dialyze overnight against 2 L solution D; centrifuge at 19,000 rpm for 2 h, in cellulose nitrate tubes; puncture tubes and separate myosin from fat and insoluble pellet. 7. Dilute supernatant to 5-10 mg/ml and dialyze against solution E extensively, load onto DEAE-sephadex column. 8. Pre-equilibrate with solution E; apply 500-600 g myosin at 30 ml/h; wash with 350 ml solution E; elute with linear gradient of 0-0.5 M KCl in solution E (21 liter); collect 10 ml fractions; pool myosin fractions (>0.1 M KCl); concentrate by overnight dialysis against solution F; centrifuge at 25,000 rpm for 30 min; store as above. 9. The myosin is then cut with chymotrypsin or papain in the presence of EDTA to generate the S1 fragment which is soluble at the low salt conditions optimal for ATPase activity (Margossian, supra).

(158) Preparation and Assay

(159) Myosin is prepared by precipitation from salt extracts of rabbit psoas muscle, and a soluble S1 fraction is prepared by digestion with chymotrypsin (Margossian and Lowey, 1982).

(160) Actin is purified by first preparing an ether powder of cardiac muscle (Zot HG and Potter J D. (1981) Preparative Biochemistry 11:381-395) as described above. Subsequently, actin is cycled between the filamentous and soluble state through rounds of centrifugation and dialysis (Spudich J A and Watt S. (1971) J. Biol. Chem. 246:4866-4871).

(161) Tropomyosin is extracted from the ether powder and separated from the other proteins based on pH dependent precipitations followed by successive ammonium sulfate cuts at 53% and 65% (Smillie L B. (1981) Methods Enzymol 85 Pt B:234-41). The troponins are isolated as an intact complex of TnC, TnT, and TnI. Ether powder is extracted in a high salt buffer. Successive ammonium sulfate cuts of 30% and 45% are done; the precipitate is solubilized by dialysis into a low salt buffer and then further purified on a DEAE Toyopearl column with a 25-350 mM KCl gradient. There is no measurable ATPase in any of the components except for myosin which naturally had a very low basal ATPase in the absence of actin.

(162) Prior to screening, the actin, tropomyosin, and troponin complex are mixed together in the desired ratio (e.g., 7:1:1) to achieve maximal calcium regulation of the actin filament. The screen is conducted at a concentration that gives 25% activation. This calcium concentration is in the physiological range during muscle contraction.

(163) To measure the generation of ADP during the reaction, a pyruvate kinase/lactate dehydrogenase/NADH coupled enzyme system (PK/LDH) is added to the actin. The myosin is kept separately, and added to the regulated thin filaments to initiate the reaction. Oxidation of NADH is monitored in real time, so that kinetic curves are obtained. Compounds are dissolved in DMSO and spotted onto the bottoms of 384 well plates at 10 to 40 g/ml final concentration.

(164) Using procedures similar to those described herein, utilizing reagents and intermediates commercially available (e.g., Sigma-Aldrich,) or readily synthesized by one of skill in the art, the compounds in Table 2 were synthesized, characterized and tested. AC1.4 values were determined according to the procedure described in Example 25, and the reported median AC1.4 values are as follows: A=<1 uM; B=1-10 uM; C=10-20 uM; D=>20 uM.

(165) TABLE-US-00002 TABLE 2 m/z Mean Compound Structure (M + H) AC1.4 (6-bromo(2-pyridyl))[2-(4-fluorophenyl)-2- methylpropyl]amine 323.0 C [2-(4-fluorophenyl)-2-methylpropyl][6-(2- methylprop-1-enyl)(2-pyridyl)]amine 299.4 D [6-(4-fluorophenyl)(2-pyridyl)][2-(4- fluorophenyl)-2-methylpropyl]amine 339.1 D [4-(4-fluorophenyl)(2-pyridyl)][2-(4- fluorophenyl)-2-methylpropyl]amine 339.1 D 4-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-3-pyridyl)benzamide 00 364.0 B 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-3-pyridyl)benzamide 01 364.0 A 6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}pyridine-3-carbonitrile 02 270.1 C 3-(6-{[2-(4-fluorophenyl)ethyl]amino}-3- pyridyl)benzamide 03 336.1 D 6-{[2-(4-f1uorophenyl)-2- methylpropyl]amino}pyridine-3- carboxamide 04 288.1 C N-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}(3- pyridyl))methyl]methoxycarboxamide 05 332.0 D tert-butyl 2-[(5-bromo-2- pyridyl)amino]acetate 06 288.0 D 3-{6-[2-(4-fluorophenyl)acetylamino]-3- pyridyl}benzamide 07 350.1 D 1-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-3-pyridyl)ethane-1,2- diol 08 305.0 D 3-(6-{[(2S)-2-(4- fluorophenyl)propyl]amino}-3- pyridyl)benzamide 09 350.0 B 3-(6-{[(2R)-2-(4- fluorophenyl)propyl]amino}-3- pyridyl)benzamide 0 350.0 B 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-3-pyridyl)propane- 1,2-diol 319.0 D N-[2-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}(3- pyridyl))ethyl]methoxycarboxamide 346.0 D [2-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}(3- pyridyl))ethyl](methylsulfonyl)amine 366.0 D N-[2-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-3- pyridyl)ethyl]acetamide 330.0 D 2-{[2-(4-fluorophenyl)-2- methylpropyl]amino}quinoline-6- carboxamide 338.1 B (4-phenyl(2- pyridyl))(phenylcyclobutyl)amine 301.2 C (6-phenyl(2- pyridyl))(phenylcyclobutyl)amine 301.2 D (5-phenyl(2- pyridyl))(phenylcyclobutyl)amine 301.2 B 3-[5-fluoro-6-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-3- pyridyl]benzamide 413.3 B 3-(3-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-1,2,4-triazin-6- yl)benzamide 0 366.1 B [6-(3-amino(1H-indazol-5-yl))(1,2,4- triazin-3-yl)][2-(4-fluorophenyl)-2- methylpropyl]amine 378.1 A 3-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-1,2,4-triazin-3- yl)benzamide 366.1 B 3-[6-({[(4- fluorophenyl)cyclobutyl]methyl}amino 1,2,4-triazin-3-yl]benzamide 378.1 A 2-fluoro-5-(3-{[2-(4-fluorophenyl)-2- methylpropyl]amino}(1,2,4-triazin-6- yl))benzamide 369.1 D 2-fluoro-5-[3-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]benzenecarbonitrile 379.1 C (6-(1H-indazol-5-yl)(1,2,4-triazin-3-yl)){[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine 376.1 B [6-(3-amino(1H-indazol-5-yl))(1,2,4- triazin-3-yl)]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine 391.1 B (6-(1H-indazol-5-yl)(1,2,4-triazin-3-yl))[2- (3-fluoro(2-pyridyl))-2-methylpropyl]amine 364.2 C 4-fluoro-3-(3-{[(3-fluoro(2- pyridyl))cyclobutyl]amino}(1,2,4-triazin-6- yl))benzamide 383.2 B 3-{3-[(tert-butyl)amino](1,2(4-triazin-6-yl)}- 4-fluorobenzamide 0 290.1 D 4-fluoro-3-(3-{[(4- fluorophenyl)cyclobutyl]amino}(1,2,4- triazin-6-yl))benzamide 382.1 B 4-fluoro-3-(3-{[1-(4-fluorophenyl)- isopropyl]amino}(1,2,4-triazin-6- yl))benzamide 370.2 A 3-[3-({[6-(difluoromethoxy)(2- pyridyl)]cyclobulyl}amino)(1,2,4-triazin-6- yl)]-4-fluorobenzamide 431.1 A [6-(4-bromophenyl)(1,2,4-triazin-3-yl)]{[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine 415.1 C 3-[3-({1-[6-(difluoromethoxy)(2-pyridyl)]- isopropyl}amino)(1,2,4-triazin-6-yl)]-4- fluorobenzamide 419.1 A [6-(4-aminophenyl)(1,2,4-triazin-3-yl)]{[(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine 350.1 B {[6-(difluoromethoxy)(2- pyridyl)]cyclobutyl}[6-(5-bromo-2- fluorophenyl)(1,2,4-triazin-3-yl)]amine 467.1 B 4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6- yl))benzamide 371.1 B 4-fluoro-3-(3-{[(3-fluoro(2- pyridyl))ethyl]amino}(1,2,4-triazin-6- yl))benzamide 357.1 C 3-[3-({[6-(difluoromethoxy)(2- pyridyl)]methyl}amino)(1,2,4-triazin-6-yl)]- 4-fluorobenzamide 0 391.1 D 3-[3-({[6-(difluoromethoxy)(2- pyridyl)]ethyl}amino)(1,2,4-triazin-6-yl)]-4- fluorobenzamide 405.1 C 1-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}-1,2,4-triazin-6- yl)pyrazole-4-carboxamide 343.1 D 1-(3-{[(3-fluoro-2- pyridyl)cyclobutyl]amino}-1,2,4-triazin-6- yl)pyrazole-4-carboxamide 355.1 D 1-(3-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-1,2,4-triazin-6- yl)pyrazole-4-carboxamide 356.1 B 1-[3-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]pyrazole-4-carboxamide 369.1 B 1-[3-({1-[6-(difluoromethoxy)(2-pyridyl)]- isopropyl}amino)-1,2,4-triazin-6- yl]pyrazole-4-carboxamide 391.3 B 2-[3-({1-[6-(difluoromethoxy)(2-pyridyl)]- isopropyl}amino)-1,2,4-triazin-6-yl]-1,3- thiazole-5-carboxamide 408.3 B 3-(3-{[(2-pyridylcyclobutyl)methyl]amino}- 1,2,4-triazin-6-yl)benzenecarbonitrile 343.2 B 3-(3-{[(2-pyridylcyclobutyl)methyl]amino}- 1,2,4-triazin-6-yl)benzamide 361.2 B 3-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}-1,2,4-triazin-6- yl)benzamide 0 353.1 B 4-fluoro-3-(3-{[1-methyl-1-(6-methyl(2- pyridyl))ethyl]amino}(1,2,4-triazin-6- yl))benzamide 367.1 C 3-(3-{[1-(3-chloro(2-pyridyl))- isopropyl]amino}-1,2,4-triazin-6- yl)benzamide 369.1 B 3-(3-{[1-(3-chloro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6-yl))-4- fluorobenzamide 387.1 B 4-fluoro-3-(3-{[1-(5-fluoro-6-methyl(2- pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))benzamide 385.1 B 4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6- yl))benzoic acid 372.2 C [6-(3-amino-6-fluorophenyl)(1,2,4-triazin- 3-yl)][1-(3-fluoro(2-pyridyl))- isopropyl]amine 343.2 B [4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6- yl))phenyl](methylsulfonyl)amine 421.1 C 5-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}-1,2,4-triazin-6-yl)-1H-2- hydroindazol-3-one 366.1 B 2-fluoro-5-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6- yl))benzoic acid 372.1 D 2-fluoro-5-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6- yl))benzamide 0 371.2 D N-((2S)-2,3-dihydroxypropyl)[4-fluoro-3- (3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6- yl))phenyl]carboxamide 445.3 C N-[4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6- yl))phenyl]methoxycarboxamide 401.1 B amino[4-fluoro-3-(3-{[1-(3-fluoro(2- pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))phenyl]sulfonamide 422.1 B 3-[3-({1-[6-(difluoromethyl)(2-pyridyl)]- isopropyl}amino)(1,2,4-triazin-6-yl)]-4- fluorobenzamide 403.1 B 3-[3-({1-[6-(difluoromethyl)(2-pyridyl)]- isopropyl}amino)(1,2,4-triazin-6-yl)]-4- fluorobenzenecarbonitrile 385.1 B 2-[3-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}-1,2,4-triazin-6- yl)phenyl]acetamide 367.1 D methyl 3-fluoro-4-(3-{[1-(3-fluoro(2- pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))benzoate 386.2 D 3-fluoro-4-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6- yl))benzamide 371.2 D 3-fluoro-4-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6- yl))benzoic acid 372.2 D [4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6- yl))phenyl]methan-1-ol 0 358.3 C {6-[5-(aminomethyl-2-fluorophenyl](1,2,4- triazin-3-yl)}[1-(3-fluoro(2-pyridyl))- isopropyl]amine 357.3 D N-{[4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6- yl))phenyl]methyl}acetamide 399.3 D 4-fluoro-3-(3-{[1-(3-fluoro-6-methyl(2- pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))benzamide 385.1 B 2-amino-N-{[4-fluoro-3-(3-{[1-(3-fluoro(2- pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))phenyl]methyl}acetamide 414.2 B [1-(3-fluoro(2-pyridyl))-isopropyl](6-(1,3- thiazol-2-yl)(1,2,4-triazin-3-yl))amine 317.1 D 4-fluoro-3-[3-({1-methyl-1-[3- (methylsulfonyl)phenyl]ethyl}amino)(1,2,4- triazin-6-yl)]benzamide 430.2 D methyl 4-fluoro-3-[3-({1-methyl-1-[3- (methylsulfonyl)phenyl]ethyl}amino)(1,2,4- triazin-6-yl)]benzoate 445.2 D [2-(3-{[1-(3-chloro(2-pyridyl))- isopropyl]amino}-1,2,4-triazin-6-yl)-1,3- thiazol-5-yl]methan-1-ol 363.0 D 2-[2-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}-1,2,4-triazin-6-yl)-1,3- thiazol-5-yl]acetamide 374.3 D 3-[3-({1-[3-(difluoromethyl)(2-pyridyl)]- isopropyl}amino)(1,2,4-triazin-6-yl)]-4- fluorobenzenecarbonitrile 0 385.1 D 3-[3-({1-[3-(difluoromethyl)(2-pyridyl)]- isopropyl}amino)(1,2,4-triazin-6-yl)]-4- fluorobenzamide 403.1 C {6-[5-(aminomethyl)(1,3-thiazol-2- yl)](1,2,4-triazin-3-yl)}[1-(3-chloro(2- pyridyl))-isopropyl]amine 362.3 D N-{[2-(3-{[1-(3-chloro(2-pyridyl))- isopropyl]amino}-1,2,4-triazin-6-yl)-1,3- thiazol-5-yl]methyl}acetamide 404.3 D 1-(3-{[1-(3-chloro(2-pyridyl))- isopropyl]amino}-1,2,4-triazin-6- yl)pyrazole-4-carboxamide 359.3 D {2-[3-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]-1,3-thiazol-5-yl}methan-1-ol 391.3 B 3-[3-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]benzamide 397.2 A {6-[5-(aminomethyl)(1,3-thiazol-2- yl)](1,2,4-triazin-3-yl)}{[3-fluoro-1-(3- fluoro(2-pyridyl))cyclobutyl]methyl}amine 390.3 B N-({2-[3-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]-1,3-thiazol-5- yl}methyl)acetamide 432.1 B methyl 3-(3-{[2-(3-chloro(2-pyridyl))-2- methylpropyl]amino}(1,2,4-triazin-6-yl))-4- fluorobenzoate 416.2 D methyl 3-[3-({[(3-chloro(2- pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-fluorobenzoate 0 428.2 B methyl 4-fluoro-3-(3-{[(2- pyridylcyclobutyl)methyl]amino}(1,2,4- triazin-6-yl))benzoate 394.3 C 3-[3-({[(3-chloro(2- pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-fluorobenzamide 413.2 A 3-(3-{[2-(3-chloro(2-pyridyl))-2- methylpropyl]amino}(1,2,4-triazin-6-yl))-4- fluorobenzamide 401.2 B 4-fluoro-3-(3-{[(2- pyridylcyclobutyl)methyl]amino}(1,2,4- triazin-6-yl))benzamide 379.3 B 3-[3-({[(3-chloro(2- pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-fluorobenzoic acid 414.2 A 3-(3-{[2-(3-chloro(2-pyridyl))-2- methylpropyl]amino}(1,2,4-triazin-6-yl))-4- fluorobenzoic acid 402.2 B 4-fluoro-3-[3-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]benzamide 415.1 A 3-[3-({[1-(3-chloro(2-pyridyl))-3- fluorocyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]benzamide 413.2 A 3-[3-({[1-(3-chloro(2-pyridyl))-3- fluorocyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-fluorobenzamide 431.2 A 3-[3-({[1-(3-chloro(2-pyridyl))-3- fluorocyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]benzenecarbonitrile 00 395.2 B 3-[3-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]benzamide 01 379.3 B 2-{2-[3-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]-1,3-thiazoI-5-yl}acetamide 02 418.2 C 2-{2-[3-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]-1,3-thiazol-5-yl}acetamide 03 400.3 C {2-[3-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]-1,3-thiazol-5-yl}methan-1-ol 04 373.3 C 4-fluoro-3-[3-({[(3-fluoro(2- pyridyl))cyclobulyl]methyl}amino)(1,2,4- triazin-6-yl)]benzoic acid 05 398.1 B {4-fluoro-3-[3-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]phenyl}-N-methylcarboxamide 06 411.1 B 4-fluoro-3-[3-({[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]benzamide 07 397.1 A {3-[3-({[1-(3-chloro(2-pyridyl))-3- fluorocyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]phenyl}-N-methylcarboxamide 08 427.3 B {3-[3-({[1-(3-chloro(2-pyridyl))-3- fluorocyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-fluorophenyl}-N- methylcarboxamide 09 445.2 A 3-[3-({[1-(3-chloro(2-pyridyl))-3,3- difluorocyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-fluorobenzamide 0 449.2 A {3-[3-({[1-(3-chloro(2-pyridyl))-3,3- difluorocyclobulyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-fluorophenyl}-N- methylcarboxamide 463.2 B {4-fluoro-3-[3-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]phenyl}-N-methylcarboxamide 429.3 B {3-[3-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-hydroxyphenyl}-N- methylcarboxamide 427.2 A 3-[3-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobulyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-hydroxybenzamide 413.2 A {3-[3-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobulyl]methyl}amino)(1,2,4- triazin-6-yl)]phenyl}-N-methylcarboxamide 411.3 B 4-fluoro3-[3-({[3-fluoro-1-(3-fluoro(2- pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]-2-hydroxybenzamide 430.1 A

(166) While the present invention has been described with reference to the specific embodiments described herein, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, modifications may be made to adapt a particular situation, material, composition of matter and/or process to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.