IP Library › Granted Patent US 7,772,271

Granted Patent B2

US 7,772,271 · App. 11/653,448 · Granted Aug 10, 2010

Methods for treating hepatitis C

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Quick Facts

Patent No.: US 7,772,271
App. No.: 11/653,448
Granted: Aug 10, 2010
Kind: B2

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Abstract

The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.

Claims (688)

1. A compound of formula IIa

or a pharmaceutically acceptable salt thereof, wherein:

X is -cyano;

Y is -aryl substituted with one or more substituents independently selected from:

(1) -halos;

(2) —C 1 to C 6 alkyl; haloalkyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or cyclopropylmethyl;

(3) -alkoxy optionally substituted with one or more substituents independently selected from:

(i) -one or more halos;

(ii) -5 or 6 membered heterocyclo;

(iii) —SO 2 -alkyl; or (iv) —C(O)NH-alkyl;

(4) -hydroxy;

(5) -amino

(a) optionally substituted with one or more substituents independently selected from:

(i) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

(ii) —C 1 to C 6 alkyl optionally and independently substituted with one or more alkoxy, halo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aryl, or 5 or 6 membered heteroaryls, wherein aryl is optionally substituted with one or more C 1 to C 6 alkyls, alkoxy, halos, haloalkyls or haloalkoxys;

(iii) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from aryl, C 1 to C 6 alkyls, hydroxyls, halos or haloalkyls, wherein aryl is optionally substituted with one or more C 1 to C 6 alkyls, halos, or haloalkyls; (iv) -aryl optionally substituted with one or more substituents independently selected from cyano, C 1 to C 6 alkyls, alkoxys, —C(O)-alkyl, halos, haloalkyls or haloalkoxys; (v) —C(O)-amino-(R x ) 2 , wherein R x is hydrogen or C 1 to C 6 alkyl; (6) —OC(O)NHR x , wherein R x , is C 1 to C 6 alkyl; C 2 to C 6 alkenyl; -aryl optionally substituted with one or more—mono- or dialkyl-amino; cyclopropyl; cyclobutyl; cyclopentyl or cyclohexyl;

(7) —OC(O)N(R x ) 2 ; wherein R x is independently selected from C 1 to C 6 alkyl optionally and independently substituted with alkoxy or aryl

(8) —OC(O)NH(OR x ), wherein R x is —C 1 to C 6 alkyl;

(9) —OC(O)NR x (OR x ), wherein R x is independently selected from —C 1 to C 6 alkyl;

(10) —OC(O)N(OR x ) 2 , wherein R x is independently selected from —C 1 to C 6 alkyl;

(11) —OC(O)R ab , wherein R ab is a 5 or 6 membered heterocyclo optionally substituted with a 5 or 6 membered heteroaryl, wherein heteroaryl is optionally substituted with one or more haloalkyls;

(12) —NR p COR p ,

wherein R p is:

(i) —C 1 to C 6 alkyl;

(ii) -amino optionally substituted with cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or one or more C 1 to C 6 alkyls, which C 1 to C 6 alkyls are optionally and independently substituted with one or more aryls or alkoxys;

(iii) -5 or 6 membered heterocyclo optionally substituted with one or more C 1 to C 6 alkyls or aryls;

(iv) -cyclopropyl;

(v) -cyclobutyl;

(vi) -cyclopentyl;

(vii) -cyclohexyl; or

(viii) -cyclopropylmethyl;

and wherein R o is: -hydrogen; or —C 1 to C 6 alkyl;

(13) —NR q CONR q R r ,

wherein R q is hydrogen;

and wherein R r is:

(i) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from: -halo; -hydroxy; -alkoxy; -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -aryl optionally substituted with one or more halos;

(ii) —C 2 to C 6 alkenyl optionally substituted with one or more halos;

(iii) —C 1 to C 6 alkoxy;

(iv) -5 or 6 membered heterocyclo;

(v) -5 or 6 membered heteroaryl optionally substituted with cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl;

(vi) -cyclobutyl;

(vii) -cyclopentyl;

(viii) -cyclopropyl;

(ix) -cyclohexyl; or

(x) -cyclopropylmethyl;

(14) —SO 2 R aa , wherein R aa is:

(i) -5 or 6 membered heterocyclo optionally substituted with hydroxyl or one or more C 1 to C 6 alkyls, wherein C 1 to C 6 alkyl is optionally substituted with hydroxyl;

(ii) —C 1 to C 6 alkoxy; or

(iii) —C 1 to C 6 alkyl;

(15) —COR m , wherein R m is:

(i) -amino optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or one or more C 1 to C 6 alkyls, wherein the C 1 to C 6 alkyls are optionally substituted with an aryl, 5 or 6 membered heteroaryl or a 5 or 6 membered heterocyclo, wherein aryl is optionally substituted with one or more alkoxy, halos or haloalkyls; or

(ii) -3 to 7 membered heterocyclo optionally substituted with hydroxyl or C 1 to C 6 alkyl, which alkyl is optionally substituted with -alkoxy or dialkyl-amino;

(16) —NR t COOR u ,

wherein R t is hydrogen,

and wherein R u is:

(i) —C 1 to C 12 alkyl optionally substituted with one or more substituents independently selected from: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -aryl optionally substituted with one or more halos or haloalkyls; -alkoxy optionally substituted with one or more alkoxys; -amino optionally substituted with one or more C 1 to C 6 alkyls; -halo; —SO 2 -alkyl, -5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo;

(ii) —C 2 to C 6 alkenyl;

(iii) -aryl optionally substituted with halo;

(iv) -5 or 6 membered heterocyclo optionally substituted with —C(O)-alkyl; —C(O)-alkoxy wherein alkoxy is optionally substituted with one or more alkoxys; —SO 2 -alkyl; —SO 2 -cyclopropyl; —SO 2 -cyclobutyl; —SO 2 -cyclopentyl or —SO 2 -cyclohexyl; (v) -dioxo-tetrahydro-thiopyran;

(vi) -cyclobutyl;

(vii) -cyclopentyl;

(viii) -cyclopropyl; or

(ix) -cyclohexyl;

(17) —NHR bb , wherein R bb is: —C(═S)NH 2 ; —C(═S)NH-alkyl; —C(═S)NH-cyclopropyl; —C(═S)NH-cyclobutyl; —C(═S)NH-cyclopentyl;

—C(═S)NH-cyclohexyl; —C(═N—CN)—NH-cyclopropyl; —C(═N—CN)—NH-cyclobutyl; —C(═N—CN)—NH-cyclopentyl; —C(═N—CN)—NH-cyclohexyl; —S(═O)-alkyl; —S + (O − )-alkyl; PO(OR x ) 2 , wherein R x is independently selected from —C 1 to C 6 alkyl or -dioxo-tetrahydro-thiopyran; (18) —N[═CH-amino-(R x ) 2 ], wherein R x is independently selected from hydrogen or C 1 to C 6 alkyl;

(19) -5 or 6 membered heteroaryloxy;

(20) —NR v SO 2 R w ,

wherein R v is hydrogen

and wherein R w is:

(i) —C 1 to C 6 alkyl optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or aryl, wherein aryl is optionally substituted with one or more halos or haloalkyls;

(ii) -amino optionally substituted with —C(O)O-alkyl or a -5 or 6 membered heterocyclo;

(iii) mono- or -dialkyl-amino optionally substituted on alkyl with halo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or -5 or 6 membered heterocyclo;

(iv) -aryl;

(v) -cyclopropyl;

(vi) -cyclobutyl;

(vii) -cyclopentyl;

(viii) -1-methylcyclopropyl; or

(ix) -1-ethylcyclopropyl;

Z is:

(a) —C 1 to C 6 alkyl,

(b) -cyclopropyl,

(d) -cyclopentyl,

(e) -cyclopropylmethyl; or

(f) -cyclohexyl;

R is hydrogen;

R 1 is (a) -hydrogen;

(b) -5 or 6 membered heterocyclo;

(1) -amino optionally substituted with heterocyclo;

(2) -amido optionally substituted with C 1 to C 6 alkyl;

(3) -5 or 6 membered heterocyclo optionally substituted with C 1 to C 6 alkyl;

(4) -5 or 6 membered heteroaryl; and

(5) -aryl;

(d) —C 1 to C 6 alkoxy optionally substituted with one or more substituents independently selected from:

(1) -amino optionally substituted with heterocyclo;

(2) -amido optionally substituted with C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(3) -5 or 6 membered heterocyclo optionally substituted with C 1 to C 6 alkyl;

(4) -5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl; and

(5) -aryl; or

(6) hydroxyl;

(e) —(O)-5 or 6 membered heterocyclo;

(f) —(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: cyano, halo, nitro, —C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 haloalkyl, amino optionally mono or disubstituted with —C 1 to C 6 alkyl, or 5 or 6 membered heterocyclo;

(g) —C(O)-3,4,5 or 6 membered heterocyclo optionally substituted with one or more C 1 to C 6 alkyls, wherein C 1 to C 6 alkyl is optionally substituted with hydroxy;

(h) —CONH 2 optionally substituted with one or more C 1 to C 6 alkyls, wherein C 1 to C 6 alkyl is optionally substituted with alkoxy;

(h) —SO 2 R x , wherein R x is C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from:

(1) -5 or 6 membered heterocyclo;

(2) -aryl; and

(3) -5 or 6 membered heteroaryl; or

(i) -alkylthio optionally substituted with one or more substituents independently selected from:

(1) -5 or 6 membered heterocyclo;

(2) -aryl; and

(3) -5 or 6 membered heteroaryl;

R 2 is (a) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from:

(1)-5 or 6 membered heterocyclo;

(2)-5 or 6 membered heteroaryl;

(3)-aryl;

(4)-amido optionally substituted with C 1 to C 6 alkyl; and

(5) -amino optionally substituted with one or more substituents independently selected from (i) heterocyclo, (ii) alkoxy and (iii) alkyl, which alkyl is optionally substituted with one or more alkoxys;

(b)-alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;

(c)-alkylthio optionally substituted with 5 or 6 membered heterocyclo;

(d)-alkylthio optionally substituted with aryl;

(e)-alkylthio optionally substituted with C 1 to C 6 alkyl;

(f) —SO 2 R x , wherein R 1 to C 6 alkyl optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C 1 to C 6 alkyls;

(g) —SO 2 R x , wherein R x is C 1 to C 6 alkyl optionally substituted with 5 or 6 membered heterocyclo;

(h) —SO 2 R x , wherein R x is C 1 to C 6 alkyl optionally substituted with aryl;

(i) —SO 2 R x , wherein R x is C 1 to C 6 alkyl;

(j) —S(O)R x , wherein R x is C 1 to C 6 alkyl optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C 1 to C 6 alkyls;

(k) —S(O)R x , wherein R x is C 1 to C 6 alkyl optionally substituted with 5 or 6 membered heterocyclo;

(l) —S(O)R x , where R x is C 1 to C 6 alkyl optionally substituted with aryl;

(m) (i) —S(O)R x , wherein R x is C 1 to C 6 alkyl;

(ii) —SR x , wherein R x is C 1 to C 6 alkyl;

(iii) —C 2 to C 6 alkenyl-SO 2 —R x , wherein R x is C 1 to C 6 alkyl;

(n)-alkoxy optionally substituted with one or more substituents independently selected from:

(1) -halo;

(2) -hydroxy;

(3) -alkoxy optionally substituted with alkoxy;

(4) -amino optionally substituted with one or more substituents independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo, —SO 2 -alkyl and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -5 or 6 membered heterocyclo, -5 or 6 membered heteroaryl; and -amino optionally substituted with one or more alkyls;

(5) -amido optionally substituted with C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(6) —S-5 or 6 membered heterocyclo;

(7) —S-5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl;

(8) —S—C 1 to C 6 alkyl;

(9) —S-aryl;

(10) -sulfinyl-5 or 6 membered heterocyclo;

(11) -sulfinyl-5 or 6 membered heteroaryl;

(12) -sulfinyl-C 1 to C 6 alkyl;

(13) -sulfinyl-aryl;

(14) -sulfonyl-5 or 6 membered heterocyclo;

(15) -sulfonyl-5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl;

(16) -sulfonyl-C 1 to C 6 alkyl;

(17) -sulfonyl-aryl;

(18) -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from oxo, hydroxy and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

(19) -5 or 6 membered heteroaryl optionally substituted with one or more C 1 to C 6 alkyls or 5 or 6 membered heterocyclo, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

(20) -aryl; or

(21) -cyano;

(o) -aryl;

(p) —NH-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C 1 to C 6 alkyls;

(q) —C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C 1 to C 6 alkyls or aryls;

(r) —C(O)-aryl;

(s) —CONH 2 optionally substituted with one or more of the following:

(1) C 1 to C 6 alkyl, wherein C 1 to C 6 alkyl is optionally substituted with alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5 or 6 membered heterocyclo or 5 or 6 membered heteroaryl;

(2) alkoxy,

(3) cyclopropyl,

(4) cyclobutyl,

(5) cyclopentyl or

(6) cyclohexyl;

(t) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: cyano, halo, nitro, —C 1 to C 6 alkyl C 1 to C 6 alkoxy, C 1 to C 6 haloalkyl, amino optionally mono or disubstituted with —C 1 to C 6 alkyl, or 5 or 6 membered heterocyclo;

(u) -4, 5 or 6 membered heterocyclo optionally having a hetero atom ring member selected from sulfinyl or sulfonyl, wherein heterocyclo is optionally substituted with one or more substituents independently selected from:

(1) -hydroxy;

(2) —C 1 to C 6 alkyl optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(3) —SO 2 R x , wherein R x is C 1 to C 6 alkyl optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(4) —C(O)-aryl;

(5) —C(O)OR x , wherein R x is C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(6) —C(O)R x , wherein R x is C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(7) oxo;

(8) aryl;

(9) cyclopropyl;

(10) cyclobutyl;

(11) cyclopentyl; and

(12) cyclohexyl; or

(v) —OR kk , wherein R kk is:

(1) -aryl;

(2) -5 or 6 membered heterocyclo optionally having a hetero atom ring member selected from sulfinyl or sulfonyl, wherein heterocyclo is optionally substituted with C 1 to C 6 alkyl, which alkyl is optionally substituted with aryl;

(3) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from cyano, halo, nitro, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, —C(O)—C 1 to C 6 alkyl, —S—C 1 to C 6 alkyl, —C(O)O—C 1 to C 6 alkyl, C 1 to C 6 haloalkyl or 5 or 6 membered heterocyclo;

(4) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl;

(5) —Si(R x ) 3 wherein R x is independently selected from —C 1 to C 6 alkyl;

(6) —CONH 2 optionally substituted with one or more C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein C 1 to C 6 alkyl is optionally substituted with alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aryl, 5 or 6 membered heterocyclo or 5 or 6 membered heteroaryl;

(w) —C(O)OH;

and

R 3 is hydrogen;

with the proviso that at least one of Y, R 1 , and R 2 is selected from the following:

Y is -aryl substituted with one or more substituents independently selected from:

(1) -amino optionally substituted with one or more substituents independently selected from: (i) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, substituted with one or more 5 or 6 membered heteroaryls; (ii) —C 1 to C 6 alkyl optionally and independently substituted with one or more alkoxy, halo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aryl, or (iii) 5 or 6 membered heteroaryls, wherein aryl is optionally substituted with one or more C 1 to C 6 alkyls, alkoxy, halos, haloalkyls or haloalkoxys;

(2) —OC(O)NHR x , wherein R x is C 1 to C 6 alkyl; C 1 to C 6 alkenyl; -aryl optionally substituted with one or more mono- or dialkyl-amino; cyclopropyl; cyclobutyl; cyclopentyl or cyclohexyl;

(3) —OC(O)N(R x ) 2 ; wherein R x is independently selected from C 1 to C 6 alkyl optionally and independently substituted with alkoxy or aryl;

(4) —OC(O)NH(OR x ), wherein R x is —C 1 to C 6 alkyl;

(5) —OC(O)NR x (OR x ), wherein R x is independently selected from —C 1 to C 6 alkyl;

(6) —OC(O)N(OR x ) 2 , wherein R x is independently selected from —C 1 to C 6 alkyl;

(7) —OC(O)R ab , wherein R ab is a 5 or 6 membered heterocyclo optionally substituted with a 5 or 6 membered heteroaryl, wherein heteroaryl is optionally substituted with one or more haloalkyls;

(8) —NR o COR p , wherein R p is:

(i) -amino optionally substituted with cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or one or more C 1 to C 6 alkyls, which C 1 to C 6 alkyls are optionally and independently substituted with one or more aryls or alkoxys, or

(ii) -5 or 6 membered heterocyclo substituted with one or more C 1 to C 6 alkyls or aryls;

(iii) -cyclopropyl;

(iv) -cyclobutyl;

(v) -cyclopentyl;

(vi) -cyclohexyl; or

(vii) -cyclopropylmethyl;

(9) —NR q CONR q R r , wherein R r is:

(i) —C 1 to C 6 alkyl substituted with one or more substituents independently selected from: hydroxy; -alkoxy; -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -aryl substituted with one or more halos;

(ii) —C 2 to C 6 alkenyl;

(iii) —C 1 to C 6 alkoxy; or

(iv) -5 or 6 membered heterocyclo;

(v) -5 or 6 membered heteroaryl optionally substituted with cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl;

(vi) -cyclobutyl;

(vii) -cyclopentyl;

(viii) -cyclopropyl;

(ix) -cyclohexyl; or

(x) -cyclopropylmethyl;

(10) —NR t COOR u , wherein R u is:

(i) —C 1 to C 12 alkyl substituted with one or more substituents independently selected from: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -alkoxy substituted with one or more alkoxys; -amino optionally substituted with one or more C 1 to C 6 alkyls; —SO 2 -alkyl and -5 or 6 membered heteroaryl;

(ii) —C 2 to C 6 alkenyl; (iiv) -5 or 6 membered heterocyclo optionally substituted with —C(O)-alkyl; —C(O)-alkoxy wherein alkoxy is optionally substituted with one or more alkoxys; —SO 2 -alkyl; —SO 2 -cyclopropyl; —SO 2 -cyclobutyl; —SO 2 -cyclopentyl or —SO 2 -cyclohexyl; (iv) -dioxo-tetrahydro-thiopyran;

(v) -cyclobutyl;

(vi) cyclopentyl;

(vii) -cyclopropyl; or

(viii) -cyclohexyl; and

R 1 is (a) —C 1 to C 6 alkyl substituted with:

(1) -amido optionally substituted with C 1 to C 6 alkyl; or

(2) -5 or 6 membered heteroaryl;

(b) —C 1 to C 6 alkoxy substituted with:

(1) -amino optionally substituted with heterocyclo;

(2) -amido optionally substituted with C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(3) -5 or 6 membered heterocyclo substituted with C 1 to C 6 alkyl;

(4) -5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl; or

(5) hydroxyl

(d) —(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: cyano, halo, nitro, —C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 haloalkyl, amino optionally mono or disubstituted with —C 1 to C 6 alkyl, or 5 or 6 membered heterocyclo;

(e) —SO 2 R x , wherein R x is C 1 to C 6 alkyl optionally substituted with:

(1)-5 or 6 membered heterocyclo;

(2) -aryl; or

(3) -5 or 6 membered heteroaryl; or

(f)-alkylthio optionally substituted with:

(1)-5 or 6 membered heterocyclo;

(2) -aryl; or

(3) -5 or 6 membered heteroaryl;

(g) —C(O)-3,4,5 or 6 membered heterocyclo optionally substituted with one or more C 1 to C 6 alkyls, wherein C 1 to C 6 alkyl is optionally substituted with hydroxy;

(h) —CONH 2 optionally substituted with one or more C 1 to C 6 alkyls, wherein C 1 to C 6 alkyl is optionally substituted with alkoxy;

and

R 2 is

(a) —C 1 to C 6 alkyl substituted with one or more substituents independently selected from:

(1) -5 or 6 membered heterocyclo;

(2) -5 or 6 membered heteroaryl;

(3) -aryl;

(4) -amido optionally substituted with C 1 to C 6 alkyl; and

(5) -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;

(b)-alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;

(c)-alkylthio optionally substituted with 5 or 6 membered heterocyclo;

(d)-alkylthio optionally substituted with aryl;

(e)-alkylthio optionally substituted with C 1 to C 6 alkyl;

(f) —SO 2 R x , wherein R x is C 1 to C 6 alkyl optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C 1 to C 6 alkyls;

(g) —SO 2 R x , wherein R x is C 1 to C 6 alkyl optionally substituted with 5 or 6 membered heterocyclo;

(h) —SO 2 R x , wherein R x is C 1 to C 6 alkyl optionally substituted with aryl;

(i) —SO 2 R x , wherein R x is C 1 to C 6 alkyl;

(j) —S(O)R x , wherein R x is C 1 to C 6 alkyl optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C 1 to C 6 alkyls;

(k) —S(O)R x , wherein R x is C 1 to C 6 alkyl optionally substituted with 5 or 6 membered heterocyclo;

(l) —S(O)R x , wherein R x is C 1 to C 6 alkyl optionally substituted with aryl;

(m) (i) —S(O)R x , wherein R x is C 1 to C 6 alkyl;

(ii) —SR x , wherein R x is C 1 to C 6 alkyl;

(iii) —C 2 to C 6 alkenyl-SO 2 —R x , wherein R x is C 1 to C 6 alkyl;

(n) -alkoxy substituted with:

(1) -alkoxy;

(2) -amino substituted with one or more substituents independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo, —SO 2 -alkyl and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -5 or 6 membered heterocyclos; -5 or 6 membered heteroaryl and -amino optionally substituted with one or more alkyls;

(3) -amido optionally substituted with C 1 to C 6 alkyl; -5 or 6 membered heteroaryl

(4) —S-5 or 6 membered heterocyclo;

(5) —S-5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl;

(6) —S—C 1 to C 6 alkyl;

(7) —S-aryl;

(8) -sulfinyl-5 or 6 membered heterocyclo;

(9) -sulfinyl-5 or 6 membered heteroaryl;

(10) -sulfinyl-C 1 to C 6 alkyl;

(11) -sulfinyl-aryl;

(12) -sulfonyl-5 or 6 membered deterocyclo;

(13) -sulfonyl-5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl;

(14) -sulfonyl-C 1 to C 6 alkyl;

(15) -sulfonyl-aryl;

(16) -5 to 7 membered heterocyclo substituted with one or more substituents independently selected from oxo, hydroxy and C 1 to C 6 alkyl, which alkyl is substituted with one or more C 1 to C 6 alkoxys;

(17) -5 or 6 membered heteroaryl substituted with one or more C 1 to C 6 alkyls or 5 or 6 membered heterocyclo, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

(18) -aryl; or

(19) -cyano;

(o) —C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C 1 to C 6 alkyls aryls;

(p) —C(O)-aryl;

(q) -4, 5 or 6 membered heterocyclo optionally having a hetero atom ring member selected from sulfinyl or sulfonyl, wherein heterocyclo is substituted with one or more substituents independently selected from:

(1) -hydroxy;

(2) —C 1 to C 6 alkyl optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(3) —SO 2 R x , wherein R x is C 1 to C 6 alkyl optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(4) —C(O)-aryl; and

(5) —C(O)OR x , wherein R x is C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(r) —OR kk , wherein R kk is:

(1) -aryl;

(2) -5 or 6 membered heterocyclo optionally having a hetero atom ring member selected from sulfinyl or sulfonyl, wherein heterocyclo is optionally substituted with C 1 to C 6 alkyl or aryl; or

(3) —Si(R x ) 3 , wherein R x is independently selected from —C 1 to C 6 alkyl;

(4) —CONH 2 optionally substituted with one or more C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein C 1 to C 6 alkyl is optionally substituted with alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aryl, 5 or 6 membered heterocyclo or 5 or 6 membered heteroaryl;

(s) —(O)-5 or 6 membered heterocyclo optionally substituted with one or more independently selected C 1 to C 6 alkyls; or

(t) —(O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C 1 to C 6 alkyls.

2. The compound of claim 1 , wherein:

Y is -aryl substituted with one or more substituents independently selected from: (1) -halo; (2) -hydroxy; (3) -alkoxy optionally substituted with one or more substituents independently selected from: -one or more halos; -5 or 6 membered heterocyclo; —SO 2 -alkyl; or —C(O)NH-alkyl; (4) —C 1 to C 6 alkyl, haloalkyl, cyclopropyl; (5) -amino optionally substituted with one or more substituents independently selected from: —SO 2 R x , wherein R x is —C 1 to C 6 alkyl, cyclopropyl; and —C 1 to C 6 alkyl optionally and independently substituted with one or more alkoxy, halo, cyclopropyl, cyclohexyl, aryl, 5 or 6 membered heteroaryls wherein aryl is optionally substituted with one or more C 1 to C 6 alkyls, alkoxy, halos, haloalkyls or haloalkoxys; (6) —OC(O)NHR x , wherein is R x is C 1 to C 6 alkyl; C 2 to C 6 alkenyl; -aryl optionally substituted with one or more mono- or dialkyl-amino; cyclopentyl or cyclohexyl; (7) —NR o COR p , wherein R p is: (i) —C 1 to C 6 alkyl; (ii) -amino optionally substituted with cyclopentyl; or one or more C 1 to C 6 alkyls which C 1 to C 6 alkyls are optionally and independently substituted with one or more aryls or alkoxys; or (iii) -cyclopropyl; and wherein R o is hydrogen; (8) —NR q CONR q R r , wherein R q is hydrogen, and wherein R r is: (i) —C 1 to C 6 alkyl optionally substituted with one or more halos; or -aryl optionally substituted with halo; (ii) -5 or 6 membered heteroaryl substituted with cyclopropyl; (iii) -cyclobutyl; (iv) -cyclopentyl; (9) —SO 2 R aa , wherein R aa is: -5 or 6 heterocyclo optionally substituted with hydroxyl or one or more C 1 to C 6 alkyls, wherein C 1 to C 6 alkyl is optionally substituted with hydroxyl; —C 1 to C 6 alkoxy; or —C 1 to C 6 alkyl; (10) —COR m , wherein R m is: (i) -amino optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or one or more C 1 to C 6 alkyls, wherein the C 1 to C 6 alkyls are optionally substituted with an aryl, 6 membered heteroaryl or a 5 or 6 membered heterocyclo, wherein aryl is optionally substituted with one or more alkoxy or halos; or (ii) -3 to 7 membered heterocyclo optionally substituted with hydroxyl or C 1 to C 6 alkyl, which alkyl is optionally substituted with -alkoxy or dialkyl-amino; (11) —NR t COOR u , wherein R t is hydrogen, and wherein R u is: (i) —C 1 to C 12 alkyl optionally substituted with one or more substituents independently selected from: cyclopropyl; cyclobutyl; cyclopentyl; -aryl optionally substituted with one or more halos or haloalkyls; -halo; —SO 4 -alkyl; and -5 or 6 membered heteroaryl; -aryl optionally substituted with halo; or -5 or 6 membered heterocyclo; (ii) -5 or 6 membered heterocyclo optionally substituted with —C(O)-alkyl; —C(O)-alkoxy wherein alkoxy is optionally substituted with one or more alkoxys; or —SO 2 -alkyl; —SO 2 -cyclopropyl; (iii) -dioxo-tetrahydro-thiopyran; (iv) -cyclobutyl; or (v) -cyclopentyl; (12) —NHR bb , wherein R bb is: —C(═S)NH 2 ; —C(═S)NH-alkyl; —C(═S)NH-cyclopentyl; —C(═N—CN)—NH-cyclohexyl; —S(═O)-alkyl; —S + (O − )-alkyl; or —PO(OR x ) 2 , wherein R x is C 1 to C 6 alkyl or -dioxo-tetrahydro-thiopyran; (13) —NR v SO 2 R w , wherein R v is hydrogen, and wherein R w is: (i) —C 1 to C 6 alkyl optionally substituted with cyclobutyl or aryl, wherein aryl is optionally substituted with haloalkyl; or (ii) -amino optionally substituted with —C(O)O-alkyl, a -5 or 6 membered heterocyclo; (iii) mono- or -dialkyl-amino optionally substituted on alkyl with halo, cyclopropyl, or -5 membered heterocyclo; (iv) -aryl; (v) -cyclopropyl; (vi) -cyclobutyl; (vii) -cyclopentyl; (viii) -1-methylcyclopropyl; or (ix) -1-ethylcyclopropyl;

R 1 is:

(a) -hydrogen;

(b) —C 1 to C 6 alkoxy substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl;

(d) —(O)-5 or 6 membered heteroaryl

optionally substituted with one or more substituents independently selected from: cyano, halo, —C 1 to C 6 alkyl; or

(e)-5 or 6 membered heterocyclo; and

R 2 is:

(a) -alkoxy substituted with one or more substituents independently selected from: (1) -halo; (2) -hydroxy; (3) -alkoxy optionally substituted with alkoxy; (4) -amino optionally substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo, and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl; (5) -amido optionally substituted with C 1 to C 6 alkyl; (6) —S-5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl; (7) —S—C 1 to C 6 alkyl; (8) -sulfinyl-C 1 to C 6 alkyl; (9) -sulfonyl-C 1 to C 6 alkyl; (10) -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more independently selected C 1 to C 6 alkoxys; and (11) -5 or 6 membered heteroaryl optionally substituted with one or more C 1 to C 6 alkyls;

(b) —SO 2 R x , wherein R x is C 1 to C 6 alkyl;

(d) —SR x , wherein R x is C 1 to C 6 alkyl;

(e) —C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C 1 to C 6 alkyls or aryls;

(f) —C(O)-aryl;

(g) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: cyano, halo, nitro, —C 1 to C 6 alkyl C 1 to C 6 alkoxy, C 1 to C 6 haloalkyl, amino optionally mono or disubstituted with —C 1 to C 6 alkyl, or 5 or 6 membered heterocyclo;

(h) -4, 5 or 6 membered heterocyclo having a hetero atom ring member selected from sulfinyl or sulfonyl, wherein heterocyclo is optionally substituted with one or more substituents independently selected from: (1) -one or more halos; (2) —C 1 to C 6 alkyl optionally substituted with cyclopropyl; (3) —SO 2 R x , wherein R x is C 1 to C 6 alkyl optionally substituted with cyclopropyl; (4) —C(O)-aryl; (5) —C(O)OR x , wherein R x is C 1 to C 6 alkyl; (6) —C(O)R x , wherein R x is C 1 to C 6 alkyl or cyclopropyl; and (7) oxo; or

(i) —OR kk , wherein R kk is: (1) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from cyano, halo, nitro, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, —C(O)—C 1 to C 6 alkyl, —S—C 1 to C 6 alkyl, —C(O)O—C 1 to C 6 alkyl, and C 1 to C 6 haloalkyl or -5 or 6 membered heterocyclo; or (2) -5 or 6 membered heterocyclo optionally having a sulfonyl ring member, wherein heterocyclo is optionally substituted with C 1 to C 6 alkyl, which alkyl is optionally substituted with aryl.

3. A compound of formula IIb

or a pharmaceutically acceptable salt thereof, wherein:

X is cyano;

Y is aryl substituted with one or more substituents independently selected from:

(a) —C 1 to C 6 alkyl; haloalkyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or cyclopropylmethyl;

(b) -amino substituted with C 1 to C 6 alkyl optionally and independently substituted with one or more alkoxy, halo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aryl, or -5 or 6 membered heteroaryls, wherein aryl is optionally substituted with one or more C 1 to C 6 alkyls, alkoxy, halos, haloalkyls or haloalkoxys;

(c) —NR t COOR u , wherein R t is hydrogen, and wherein R u is C 1 to C 12 alkyl optionally substituted with one or more substituents independently selected from: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -aryl optionally substituted with one or more halos or haloalkyls; -alkoxy optionally substituted with one or more alkoxys; -amino optionally substituted with one or more C 1 to C 6 alkyls; -halos; —SO 2 -alkyl, -5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo;

(d) —NR v SO 2 R w , wherein R v is hydrogen, and wherein R w is C 1 to C 6 alkyl optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or aryl, wherein aryl is optionally substituted with one or more halos or haloalkyls;

Z is C 1 to C 6 alkyl; -cyclopropyl; -cyclobutyl; -cyclopentyl; -cyclohexyl; or -cyclopropylmethyl;

R is hydrogen;

R 1 is hydrogen;

R 2 is:

(a) -alkoxy substituted with one or more halos;

(b) -4, 5 or 6 membered heterocyclo optionally having a hetero atom ring member selected from sulfinyl or sulfonyl, wherein heterocyclo is optionally substituted with one or more substituents independently selected from:

(1) -hydroxy;

(2) —C 1 to C 6 alkyl optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(3) —SO 2 R x , wherein R x is C 1 to C 6 alkyl optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(4) —C(O)-aryl;

(5) —C(O)OR x , wherein R x is C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(6) —C(O)R x , wherein R x is C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(7) oxo;

(8) aryl;

(9) cyclopropyl;

(10) cyclobutyl;

(11) cyclopentyl; and

(12) cyclohexyl;

(c) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: cyano, halo, —C 1 to C 6 alkyl; —NO 2 , —C 1 to C 6 alkoxy, C 1 to C 6 haloalkyl, amino optionally mono or disubstituted with —C 1 to C 6 alkyl, or 5 or 6 membered heterocyclo

(d) —C(O)-3 to 7 membered heterocyclo or —C(O)-5 membered heterocyclo optionally substituted with one or more C 1 to C 6 alkyls or aryls; and

(e) —OR kk , wherein R kk is: (1) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from cyano, halo, nitro, and C 1 to C 6 alkyl, C 1 to C 6 alkoxy, —C(O)—C 1 to C 6 alkyl, —S—C 1 to C 6 alkyl, —C(O)O—C 1 to C 6 alkyl, C 1 to C 6 haloalkyl; or (2) -5 or 6 membered heterocyclo optionally substituted with one or more ═O; and

R 3 is hydrogen.

4. A compound of formula IIe

or a pharmaceutically acceptable salt thereof, wherein:

X is -cyano;

Y is -aryl substituted with one or more substituents independently selected from:

(1) -halo;

(2) —C 1 to C 6 alkyl; haloalkyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or cyclopropylmethyl;

(3) -alkoxy, optionally substituted with one or more substituents independently selected from:

(i) -halo;

(ii) -5 or 6 membered heterocyclo;

(iii) —C(O)NH 2 optionally substituted with C 6 to C 8 alkyl;

(iv) —C(O)NH—(C 1 to C 6 )-alkyl;

(4) -hydroxy;

(5) -haloalkyl;

(6) -cyano;

(7) -nitro;

(8) —COOH;

(9) —N═CHN(R x ) 2 wherein R x is independently selected from —C 1 to C 6 alkyl;

(10) -amino optionally substituted with one or more substituents independently selected from:

(i) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(ii) -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from C 1 to C 6 alkyl, halo, haloalkyl, cyano, alkoxy, —COR x , wherein R x is —C 1 to C 6 alkyl, and haloalkoxy;

(iii) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from C 1 to C 6 alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and aryl, wherein aryl is optionally substituted with halo;

(iv) -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, ═O, alkyl and haloalkyl;

(v) —C 1 to C 7 alkyl optionally substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl, wherein heteroaryl is optionally substituted with one more substituents independently selected from C 1 to C 6 alkyl, alkoxy, haloalkoxy, halo, and haloalkyl; -aryl, wherein aryl is optionally substituted with one or more substituents independently selected from C 1 to C 6 alkyl, halo, haloalkyl; -alkoxy; and halo haloalkoxy; and

(vi) —PO 2 R x , wherein R x is C 1 to C 6 alkyl;

(11) —OC(O)NHR x wherein R x is C 1 to C 6 alkyl optionally substituted with vinyl;

(12) —OC(O)N(R u ) 2 , wherein R u is alkyl or aryl, which alkyl or aryl is optionally substituted with dialkylamino;

(13) —OC(O)NH(OR uu ), wherein R uu is -aryl optionally substituted with dialkylamino;

(14) —OC(O)NR x (OR x ), wherein R x is independently selected from —C 1 to C 6 alkyl;

(15) —OC(O)N(OR x ) 2 , wherein R x is independently selected from —C 1 to C 6 alkyl;

(16) —OC(O)R ab , wherein R ab is a 5 or 6 membered heterocyclo optionally substituted with a 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl;

(17) —NR o C(O)R p , wherein R p is:

(i) —C 1 to C 6 alkyl;

(ii) -amino optionally substituted with cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or one or more C 1 to C 6 alkyls, which C 1 to C 6 alkyls are optionally substituted with one or more substituents independently selected from aryl and alkoxy;

(iii) -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from C 1 to C 6 alkyl and aryl;

(iv) -cyclopropyl;

(v) -cyclobutyl;

(vi) -cyclopentyl;

(vii) -cyclohexyl; or

(viii) -cyclopropylmethyl;

and wherein R o is: -hydrogen; or —C 1 to C 6 alkyl;

(18) —NR q CONR q R r , wherein R q is hydrogen, and wherein R r is:

(ii) —C 2 to C 6 alkenyl optionally substituted with one or more halos;

(iii) —C 1 to C 6 alkoxy;

(iv) -5 or 6 membered heterocyclo; or

(v) -5 to 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl;

(vi) -cyclobutyl;

(vii) -cyclopentyl;

(viii) -cyclopropyl;

(ix) -cyclohexyl; or

(x) -cyclopropylmethyl;

(19) —SO 2 R aa , wherein R aa is:

(i) -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy; —C 1 to C 6 alkoxy; and —C 1 to C 6 alkyl; or

(ii) -amino optionally substituted with —C 1 to C 6 alkyl, which —C 1 to C 6 alkyl is optionally substituted with one or more substituents independently selected from: -alkoxy; -hydroxy; -halo;

(20) —COR m , wherein R m is:

(i) -amino optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or one or more C 1 to C 6 alkyls, which C 1 to C 6 alkyls are optionally substituted with 5 or 6 membered heterocyclo or aryl, which heterocyclo or aryl is optionally substituted with one or more substituents independently selected from halo and alkoxy;

(ii) -3 to 7 membered heterocyclo optionally substituted with hydroxyl;

(iii) -3 to 7 membered heterocyclo optionally substituted with C 1 to C 6 alkyl, which —C 1 to C 6 alkyl is optionally substituted with alkoxy or dialkyl-amino;

(21) —NR t COOR u , wherein R t is hydrogen, and wherein R u is:

(i) —C 1 to C 12 alkyl optionally substituted with one or more substituents independently selected from: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -aryl optionally substituted with one or more halos or haloalkyls; -alkoxy optionally substituted with one or more alkoxys; -amino optionally substituted with one or more C 1 to C 6 alkyls; -halo; —SO 2 R w ; —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; -5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo;

(ii) —C 2 to C 6 alkenyl;

(iii) -aryl optionally substituted with halo;

(iv) -4 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: ═O; —SO 2 R w ; —COR p ; and —(CO)O—(C 1 to C 4 alkyl)-O—(C 1 to C 4 alkyl); —C(O)-alkyl; —C(O)-alkoxy wherein alkoxy is optionally substituted with one or more alkoxys; —SO 2 -alkyl; —SO 2 -cyclopropyl; —SO 2 -cyclobutyl; —SO 2 -cyclopentyl or —SO 2 -cyclohexyl;

(v) -dioxo-tetrahydro-thiopyran;

(vi) -cyclobutyl;

(vii) -cyclopentyl;

(viii) -cyclopropyl; or

(ix) -cyclohexyl;

(22) —NHR bb , wherein R bb is:

(i) —C(═S)NH 2 ;

(ii) —C(═S)NHR x , wherein R x is —C 1 to C 6 alkyl; C(═S)NH-cyclopropyl; —C(═S)NH-cyclobutyl; —C(═S)NH-cyclopentyl; —C(═S)NH-cyclohexyl;

(iii) —C(═S)NR x R x , wherein R x is independently selected from —C 1 to C 6 alkyl;

(iv) —C(═N—CN)NHR x , wherein R x is C 1 to C 6 alkyl; —C(═N—CN)—NH-cyclopropyl; —C(═N—CN)—NH-cyclobutyl; —C(═N—CN)—NH-cyclopentyl; —C(═N—CN)—NH-cyclohexyl;

(v) —PO(OR x ) 2 , wherein R x is independently selected from —C 1 to C 6 alkyl;

(vi) —S(═O)-alkyl;

(vii) —S + (O − )-alkyl; or

(viii) -dioxo-tetrahydro-thiopyran;

(23) —N(CONHR w ) 2 ;

(24) —NH(SOR w );

(25) —N(SO 2 R w ) 2 ;

(26) —NR v SO 2 R w , wherein R v is hydrogen or alkyl optionally substituted with 4 to 7 membered heterocyclo;

and wherein R w is:

(i) —C 1 to C 6 alkyl optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;

(ii) -aryl;

(iii) —C 6 to C 8 heteroaryl; or

(iv) -amino optionally substituted with —C(O)O-alkyl, a -5 or 6 membered heterocyclo or alkyl,

which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, alkoxycarbonyl, (CO)O—(C 1 to C 6 ) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;

(v) -cyclopropyl;

(vi) -cyclobutyl;

(vii) -cyclopentyl;

(viii) -1-methylcyclopropyl; or —

(ix) -1-ethylcyclopropyl;

(34) -5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:

(i) -halo;

(ii) —C 1 to C 6 alkyl; haloalkyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or cyclopropylmethyl;

(iii) -alkoxy optionally substituted with one or more substituents independently selected from: -halo; -5 or 6 membered heterocyclo; and —C(O)NH 2 optionally substituted with C 6 to C 8 alkyl;

(iv) -hydroxy;

(v) -haloalkyl;

(vi) -cyano;

(vii) -nitro;

(viii) —COOH;

(ix) -amino optionally substituted with one or more substituents independently selected from: —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, —COR x , wherein R x is —C 1 to C 6 alkyl and haloalkoxy; -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -aryl optionally substituted with halo; —C 5 to C 6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and —C 1 to C 7 alkyl optionally substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, or haloalkyls; -aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; -alkoxy; and -halo;

(35) —NR o COR p , wherein R p is:

(i) —C 1 to C 6 alkyl;

(iii) -5 or 6 membered heterocyclo optionally substituted with one or more C 1 to C 6 alkyls or aryls;

(iv) -cyclopropyl;

(v) -cyclobutyl;

(vi) -cyclopentyl;

(vii) -cyclohexyl; or

(viii) -cyclopropylmethyl;

and wherein R o is: hydrogen; or —C 1 to C 6 alkyl;

(36) —NR q CONR q R r , wherein R q is hydrogen, and wherein R r is:

(ii) —C 2 to C 6 alkenyl optionally substituted with one or more halos;

(iii) —C 1 to C 6 alkoxy;

(iv) -5 or 6 membered heterocyclo; or

(v) -5 to 6 membered heteroaryl optionally substituted with —C 1 to C 6 alkyl; cyclopropyl; cyclobutyl; cyclopentyl; or cyclohexyl;

(37) —NR t COOR u ,

wherein R t is hydrogen,

and wherein R u is

(i) —C 1 to C 12 alkyl optionally substituted with one or more substituents independently selected from: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -aryl optionally substituted with one or more halos or haloalkyls; -alkoxy optionally substituted with one or more alkoxys; -amino optionally substituted with one or more C 1 to C 6 alkyls; -halo; —SO 2 R w ; —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; -5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo; and

(38) —NR v SO 2 R w ,

wherein R v is hydrogen or alkyl optionally substituted with 4 to 7 membered heterocyclo; and

wherein R w is

(i) —C 1 to C 6 alkyl optionally substituted with cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl; -aryl; —C 6 to C 8 heteroaryl; or

(ii) -amino optionally substituted with —C(O)O-alkyl or a -5 or 6 membered heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;

Z is —C 1 to C 6 alkyl; -cyclopropyl; -cyclobutyl; -cyclopentyl; -cyclohexyl; or -cyclopropylmethyl;

R is hydrogen;

R 1 is:

(a) -hydrogen;

(b) -a 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: (1) -hydroxy; (2) —C 1 to C 6 alkyl; (3) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; (4) —C(O)-aryl; (5) —COR p ; and (6) —C(O)OR x , wherein R x is —C 1 to C 6 alkyl;

(c) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: (1) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl; (2) -alkoxy; (3) -halo; (4) -alkylthio; (5) -haloalkyl; (6) -cyano; (7) -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from (1) halo, (ii) C 1 to C 6 alkoxy, (iii) hydroxy, (iv) cyano, (v) 5 or 6 membered heterocyclo, and (vi) 5 or 6 membered heteroaryl; (8) -heterocyclo; (9) -nitro; (10) -hydroxy; (11) —COOH; (12) —CO 2 R x , wherein R x is —C 1 to C 6 alkyl; (13) —COR x , wherein R x is —C 1 to C 6 alkyl; (14) —C(O)NH 2 optionally substituted with one or more C 1 to C 6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from (i) halo, (ii) C 1 to C 6 alkoxy, (iii) hydroxy, (iv) 5 or 6 membered heterocyclo, and (v) 5 or 6 membered heteroaryl; (15) -amido optionally substituted with one or more or more substituents independently selected from (i) halo, (ii) C 1 to C 6 alkoxy, (iii) hydroxy, (iv) 5 or 6 membered heterocyclo, (v) 5 or 6 membered heteroaryl, and (vi) C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

(d) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from: (1) -amino optionally substituted with one or more substituents independently selected from (i) heterocyclo, (ii) alkoxy and (iii) alkyl, which alkyl is optionally substituted with one or more alkoxys; (2) -amido optionally substituted with C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (3) -5 or 6 membered heterocyclo optionally substituted with C 1 to C 6 alkyl; (4) -5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl; and (5) -aryl; or (6) hydroxyl;

(e) —C 2 to C 6 alkenyl optionally substituted with —SO 2 R x , wherein R x is —C 1 to C 6 alkyl;

(f) —C 1 to C 6 alkoxy optionally substituted with one or more substituents independently selected from: (1) -halo; (2) -hydroxy; (3) -cyano; (4) -alkoxy optionally substituted with alkoxy; (5) -amino optionally substituted with one or more independently selected from (i) 5 or 6 membered heteroaryl, (ii) 5 or 6 membered heterocyclo and (iii) alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl; (6) -amino optionally substituted with heterocyclo; (7) -amido optionally substituted with C 1 to C 6 alkyl; (8) -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: —C 1 to C 6 alkoxy; and -aryl; (9) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: —C 1 to C 6 alkyl; and -4 to 7 membered heterocyclo; (10) -alkoxy; and (11) -aryl;

(g) —(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: (1) -hydroxy; (2) —C 1 to C 6 alkyl; (3) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; (4) —C(O)-aryl; (5) —COR p ; and (6) —C(O)OR x , wherein R x is —C 1 to C 6 alkyl;

(h) —(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: (1) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from (i) halo, (ii) C 1 to C 6 alkoxy, (ii) hydroxy, (iv) 5 or 6 membered heterocyclo and (v) 5 or 6 membered heteroaryl; (2) -alkoxy; (3) -halo; (4) -alkylthio; (5) -haloalkyl; (6) -cyano; (7) -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, (i) —C 1 to C 6 alkoxy, (ii) hydroxy, (iii) cyano, 5 or 6 membered heterocyclo and (iv) 5 or 6 membered heteroaryl; (8) -heterocyclo; (9) -nitro; (10) -hydroxy; (11) —COOH; (12) —CO 2 R x , wherein R x is —C 1 to C 6 alkyl; (13) —COR x , wherein R x is C 1 to C 6 alkyl; (14) —C(O)NH 2 optionally substituted with one or more substituents independently selected from: (i) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and (ii) -amido optionally substituted with one or more or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys; (15) C 1 to C 6 haloalkyl, or (16) amino optionally mono or disubstituted with —C 1 to C 6 alkyl,

(i) —C(O)NH 2 optionally substituted with one or more C 1 to C 6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;

(j) —C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: (1) -aryl; (ii) -5 or 6 membered heteroaryl; and (iii) —C 1 to C 6 alkyl further optionally substituted with one or more substituted with hydroxys;

(k) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; optionally substituted with one or more substituents independently selected from: (i) -5 or 6 membered heterocyclo; (ii) -aryl; and (iii) -5 or 6 membered heteroaryl; or

(l) -alkylthio optionally substituted with one or more substituents independently selected from: (i) -5 or 6 membered heterocyclo; (ii) -aryl; and (iii) -5 or 6 membered heteroaryl;

(m)-aryl optionally substituted with one or more substituents independently selected from: (1) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from (i) halo, (ii) C 1 to C 6 alkoxy, (iii) hydroxy, (iv) 5 or 6 membered heterocyclo and (v) 5 or 6 membered heteroaryl; (2) -alkoxy; (3) -halo; (4) -alkylthio; (5) -haloalkyl; (6) -cyano; (7) -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from (i) halo, (ii) C 1 to C 6 alkoxy, (iii) hydroxy, (iv) cyano, (v) 5 or 6 membered heterocyclo and (vi) 5 or 6 membered heteroaryl; (8) -heterocyclo; (9) -nitro; (10) -hydroxy; (11) —COOH; (12) —CO 2 R x , wherein R x is —C 1 to C 6 alkyl; (13) —COR x , wherein R x is —C 1 to C 6 alkyl; (14) —C(O)NH 2 optionally substituted with one or more C 1 to C 6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from (i) halo, (ii) C 1 to C 6 alkoxy, (iii) hydroxy, (iv) 5 or 6 membered heterocyclo and (v) 5 or 6 membered heteroaryl; and (15) -amido optionally substituted with one or more substituents independently selected from (i) halo, (ii) C 1 to C 6 alkoxy, (iii) hydroxy, (iv) 5 or 6 membered heterocyclo, (v) 5 or 6 membered heteroaryl, and (vi) C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

(n) —C(O)-5 or 6 membered heteroaryl;

(o) —C(O)-aryl;

(p) —COOH; or

(q) —OR kk , wherein R kk is: (1) -aryl optionally substituted with one or more substituents independently selected from: (i) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (ii) -alkoxy; (iii) -halo; (iv) -alkylthio; (v) -haloalkyl; (vi) -cyano; (vii) -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (viii) -heterocyclo; (ix) -nitro; (x) -hydroxy; (xi) —COOH; (xii) —CO 2 R x , wherein R x is —C 1 to C 6 alkyl; (xiii) —COR x , wherein R x is —C 1 to C 6 alkyl; (xiv) —C(O)NH 2 optionally substituted with one or more C 1 to C 6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and (xv) -amido optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

R 2 is:

(a) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from: (1) -5 or 6 membered heterocyclo; (2) -5 or 6 membered heteroaryl; (3) -aryl; (4) -amido optionally substituted with C 1 to C 6 alkyl; and (5) -amino optionally substituted with one or more substituents independently selected from (i) heterocyclo, (ii) alkoxy and (iii) alkyl, which alkyl is optionally substituted with one or more alkoxy; and (6) —SO 2 R x , wherein R x is —C 1 to —C 6 alkyl;

(b) —C 2 to C 6 alkenyl optionally substituted with SO 2 R x , wherein R x is —C 1 to C 6 alkyl;

(c)-alkylthio optionally substituted with one or more substituents independently selected from: (1) -5 or 6 membered heteroaryl optionally substituted with alkyl; (2) -5 or 6 membered heterocyclo; (3) -aryl; and (4) —C 1 to C 6 alkyl;

(d) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; optionally substituted with one or more substituents independently selected from: (1)-5 or 6 membered heteroaryl optionally substituted with one or more C 1 to C 6 alkyls; (2) -5 or 6 membered heterocyclo; (3) -aryl; and (4) —C 1 to C 6 alkyl;

(e) (1) —S(O)R x , wherein R x is —C 1 to C 6 alkyl; optionally substituted with one or more substituents independently selected from: (1) -5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C 1 to C 6 alkyls; (2) -5 or 6 membered heterocyclo; (3) -aryl; and (4) —C 1 to C 6 alkyl;

(ii) —SR x , wherein R x is C 1 to C 6 alkyl;

(iii) —C 2 to C 6 alkenyl-SO 2 —R x , wherein R x is C 1 to C 6 alkyl;

(f)-alkoxy optionally substituted with one or more substituents independently selected from: (1) -halo; (2) -hydroxy; (3) -cyano; (4) -alkoxy optionally substituted with alkoxy; (5) -amino optionally substituted with one or more substituents independently selected from (i) —SO 2 —C 1 to C 4 alkyl, (ii) 5 or 6 membered heteroaryl, (iii) -5 or 6 membered heterocyclo (iv) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls; (6) -amido optionally substituted with C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (7) —S-5 or 6 membered heterocyclo; (8) —S-5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl; (9) —S—C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from: (i) -aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and (ii) —C 5 to C 6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; (10) —S-aryl; (11) -sulfinyl-5 or 6 membered heterocyclo; (12) -sulfinyl-5 or 6 membered heteroaryl; (13) -sulfinyl-C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from: (i) -aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and (ii) —C 5 to C 6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; (14) -sulfinyl-aryl; (15) -sulfonyl-5 or 6 membered heterocyclo; (16) -sulfonyl-5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl; (17) -sulfonyl-C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from: (i) -aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and (ii) —C 5 to C 6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; (18) -sulfonyl-aryl; (19) -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, ═O, heterocyclo, and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: —C 1 to C 6 alkoxy; and -aryl; (20) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: (i) —C 1 to C 6 alkyl optionally substituted with one or more alkoxys; (ii) -4 to 7 membered heterocyclo; and (iii) -alkoxy; and (21) -aryl;

(g)-aryl optionally substituted with one or more substituents independently selected from: (1) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from (i) halo, (ii) C 1 to C 6 alkoxy, (iii) hydroxy, (iv) 5 or 6 membered heterocyclo and (v) 5 or 6 membered heteroaryl; (2) -alkoxy; (3) -halo; (4) -alkylthio; (5) -haloalkyl; (6) -cyano; (7) -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (8) -heterocyclo; (9) -nitro; (10) -hydroxy; (11) —COOH; (12) —CO 2 R x , wherein R x is —C 1 to C 6 alkyl; (13) —COR x , wherein R 1 is —C 1 to C 6 alkyl; (14) —C(O)NH 2 optionally substituted with one or more C 1 to C 6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from (i) halo, (i) C 1 to C 6 alkoxy, (i) hydroxy, (ii) 5 or 6 membered heterocyclo and (iii) 5 or 6 membered heteroaryl; and (15) -amido optionally substituted with one or more substituents independently selected from (i) halo, (i) C 1 to C 6 alkoxy, (ii) hydroxy, (iii) 5 or 6 membered heterocyclo, (iv) 5 or 6 membered heteroaryl, and (v) C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

(h) —(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: (1) -hydroxy; (2) ═O; (3) —C 1 to C 6 alkyl; (4) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; (5) —C(O)-aryl; (6) —COR p ; and (7) —C(O)OR x , wherein R x is —C 1 to C 6 alkyl;

(i) —(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: (1) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from (1) halo, (ii) C 1 to C 6 alkoxy, hydroxy, (iii) 5 or 6 membered heterocyclo and (iv) 5 or 6 membered heteroaryl; (2) -alkoxy; (3) -halo; (4) -alkylthio; (5) -haloalkyl; (6) -cyano; (7) -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (8) -heterocyclo; (9) -nitro; (10) -hydroxy; (11) —COOH; (12) CO 2 R x , wherein R x is —C 1 to C 6 alkyl; (13) —COR x , wherein R x is —C 1 to C 6 alkyl; (14) —C(O)NH 2 optionally substituted with one or more C 1 to C 6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and (15) -amido optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

(j) —C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: (1) -aryl; (2) -5 or 6 membered heteroaryl; and (3) —C 1 to C 6 alkyl optionally substituted with one or more hydroxys;

(k) —C(O)-5 or 6 membered heteroaryl;

(l) —C(O)-aryl;

(m)-amino optionally substituted with one or more substituents independently selected from: (1) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; (2) -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from (i) alkyl, (ii) halo, (iii) haloalkyl, (iv) cyano, (v) alkoxy, (vi) COR x , wherein R x is —C 1 to C 6 alkyl; and (vii) haloalkoxy; (3) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from (i) alkyl, (ii) halo, (iii) haloalkyl, (iv) cyano, (v) alkoxy, (vi) haloalkoxy and (vii) -aryl optionally substituted with halo; (4) —C 5 to C 6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; (5) —C 1 to C 7 alkyl optionally substituted with one or more substituents independently selected from: (i) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; (ii) -aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; (iii) -alkoxy; and (iv) -halo;

(n) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: (1) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from (i) halo, (ii) C 1 to C 6 alkoxy, (iii) hydroxy, (iv) 5 or 6 membered heterocyclo and (v) -5 or 6 membered heteroaryl; (2) -alkoxy; (3) -halo; (4) -alkylthio; (5) -haloalkyl; (6) -cyano; (7) -amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (8) -5 or 6 membered heterocyclo; (9) -nitro; (10) -hydroxy; (11) —COOH; (12) —CO 2 R x , wherein R x is —C 1 to C 6 alkyl; (13) COR x , wherein R x is —C 1 to C 6 alkyl; (14) —C(O)NH 2 optionally substituted with one or more C 1 to C 6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from (i) halo, (ii) C 1 to C 6 alkoxy, (iii) hydroxy, (iv) 5 or 6 membered heterocyclo and (v) 5 or 6 membered heteroaryl; (15) -amido optionally substituted with one or more substituents independently selected from (i) halo, (ii) C 1 to C 6 alkoxy, hydroxy, (iii) 5 or 6 membered heterocyclo, (iv) 5 or 6 membered heteroaryl, and (v) C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

(o) -4, 5 or 6 membered heterocyclo optionally having a hetero atom ring member selected from sulfinyl or sulfonyl, wherein heterocyclo is optionally substituted with one or more substituents independently selected from: (1) -hydroxy; (2) ═O; (3) —C 1 to C 6 alkyl optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (4) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl, which C 1 to C 6 alkyl is optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (5) —C(O)-aryl; (6) —COR p ; (7) —C(O)OR x , wherein R x is to C 6 alkyl, which C 1 to C 6 alkyl is optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (8) —C(O)R x , wherein R x C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (9) aryl; (10) cyclopropyl; (11) cyclobutyl; (12) cyclopentyl; and (13) cyclohexyl;

(p) —OR kk , wherein R kk is: (1) -aryl optionally substituted with one or more substituents independently selected from: (i) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (ii) -alkoxy; (iii) -halo; (iv) -alkylthio; (v) -haloalkyl; (vi) -cyano; (vii) -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (viii) -heterocyclo; (ix) -nitro; (x) -hydroxy; (xi) —COOH; (xii) —CO 2 R x , wherein R x is —C 1 to C 6 alkyl; (xiii) —COR x , wherein R x is —C 1 to C 6 alkyl; (xiv) —C(O)NH 2 optionally substituted with one or more C 1 to C 6 alkyls, which C 1 to C 6 alkyls are optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and (xv) -amido optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys; (2) -5 to 6 membered heterocyclo optionally having a hetero atom ring member selected from sulfinyl or sulfonyl, wherein heterocyclo is optionally substituted with C 1 to C 6 alkyl, which alkyl is optionally substituted with aryl; or (3) -5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from cyano, halo, nitro, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, —C(O)—C 1 to C 6 alkyl, —S—C 1 to C 6 alkyl, —C(O)O—C 1 to C 6 alkyl, 5 or 6 membered heterocyclo and C 1 to C 6 haloalkyl; (4) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; (5) —Si(R x ) 3 , wherein R x is independently selected from —C 1 to C 6 alkyl; or (6) —CONH 2 optionally substituted with one or more C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein C 1 to C 6 alkyl is optionally substituted with alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aryl, 5 or 6 membered heterocyclo or 5 or 6 membered heteroaryl;

(q) —OC(O)NHR x , wherein R x is —C 1 to C 6 alkyl and wherein R x is optionally substituted with -aryl;

(r) —OC(O)N(R x ) 2 , wherein R x is independently —C 1 to C 6 alkyl;

(t) —CONH 2 optionally substituted with one or more of the following:

1) C 1 to C 6 alkyl, wherein C 1 to C 6 alkyl is optionally substituted with alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5 or 6 membered heterocyclo or 5 or 6 membered heteroaryl;

(2) alkoxy,

(3) cyclopropyl,

(4) cyclobutyl,

(5) cyclopentyl or

(6) cyclohexyl; or

(v) —C(O)OH; and

R 3 is hydrogen; or -nitro;

with the proviso that at least one of Y, Z, R 1 , R 2 and R 3 is selected from the following:

Y is -aryl substituted with one or more substituents independently selected from:

(1) -alkoxy substituted with one or more substituents independently selected from:

—C(O)NH 2 optionally substituted with C 6 to C 8 alkyl; and

—C(O)NH—(C 1 to C 6 )-alkyl;

(2) -haloalkyl;

(3) -cyano;

(4) —COOH;

(5) —N═CHN(R x ) 2 , wherein R x is independently selected from —C 1 to C 6 alkyl;

(6) -amino substituted with one or more substituents independently selected from:

(i) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(ii) -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from C 1 to C 6 alkyl, halo, haloalkyl, cyano, alkoxy, wherein R x is —C 1 to C 6 alkyl, and haloalkoxy;

(iv) -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, ═O, alkyl and haloalkyl;

(v) —C 1 to C 7 alkyl substituted with one or more substituents independently selected from: -5 or 6 membered heteroaryl, wherein heteroaryl is optionally substituted with one more substituents independently selected from C 1 to C 6 alkyl, alkoxy, haloalkoxy, halo, and haloalkyl; -aryl, wherein aryl is optionally substituted with one or more substituents independently selected from C 1 to C 6 alkyl, halo, haloalkyl; -alkoxy; and haloalkoxy; and

(vi) —PO 2 R x , wherein R x is —C 1 to C 6 alkyl;

(7) —OC(O)NHR x , wherein R x is C 1 to C 6 alkyl optionally substituted with vinyl;

(8) —OC(O)N(R u ) 2 , wherein R u is alkyl or aryl, which alkyl or aryl is optionally substituted with dialkylamino;

(9) —OC(O)NH(OR uu ), wherein R uu is -aryl optionally substituted with dialkylamino;

(10) —OC(O)NR(OR x ), wherein R x is independently selected from —C 1 to C 6 alkyl;

(11) —OC(O)N(OR x ) 2 , wherein R x is independently selected from —C 1 to C 6 alkyl;

(12) —OC(O)R ab , wherein R ab is a 5 or 6 membered heterocyclo optionally substituted with a 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl;

(13) —NR o C(O)R p , wherein R p is:

(i) -amino optionally substituted with cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or one or more C 1 to C 6 alkyls, which C 1 to C 6 alkyls are optionally substituted with one or more substituents independently selected from aryl and alkoxy;

(iii) -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from C 1 to C 6 alkyl and aryl;

(iv) -cyclopropyl;

(v) -cyclobutyl;

(vi) -cyclopentyl;

(vii) -cyclohexyl; or

(viii) -cyclopropylmethyl;

and wherein R o is: -hydrogen; or —C 1 to C 6 alkyl;

(14) —NR q CONR q R r , wherein R q is hydrogen, and wherein R r is:

(i) —C 1 to C 6 alkyl substituted with one or more substituents independently selected from: -hydroxy; -alkoxy; -5 or 6 membered heterocyclo; -5 or 6 membered heteroaryl; and -aryl substituted with halo;

(ii) —C 2 to C 6 alkenyl optionally substituted with one or more halos;

(iii) —C 1 to C 6 alkoxy;

(iv) -5 or 6 membered heterocyclo; or

(v) -5 to 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl;

(vi) -cyclobutyl;

(vii) -cyclopentyl;

(viii) -cyclopropyl;

(ix) -cyclohexyl; or

(x) -cyclopropylmethyl;

(15) —SO 2 R aa , wherein R aa is:

(i) -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: -hydroxy; —C 1 to C 6 alkoxy; and —C 1 to C 6 alkyl; or

(ii) -amino optionally substituted with —C 1 to C 6 alkyl, which —C 1 to C 6 alkyl is optionally substituted with one or more substituents independently selected from: -alkoxy; -hydroxy; or -halo;

(16) —COR m , wherein R m is:

(i) -amino substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or one or more C 1 to C 6 alkyls, which alkyls are substituted with 5 or 6 membered heterocyclo or aryl, which heterocyclo is substituted with one or more substituents independently selected from halos or alkoxys; and which aryl is optionally substituted with one or more substituents independently selected from halos or alkoxys;

(ii) -3 to 7 membered heterocyclo substituted with hydroxyl;

(17) —NR t COOR u ,

wherein R t is hydrogen, and

wherein R u is:

(i) —C 1 to C 12 alkyl substituted with one or more substituents independently selected from: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -aryl substituted with one or more halos or haloalkyls; -alkoxy substituted with one or more alkoxys; -amino optionally substituted with one or more C 1 to C 6 alkyls; —SO 2 R w ; —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; -5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo;

(ii) —C 2 to C 6 alkenyl;

(iii) -4 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: ═O; —SO 2 R w ; —COR p ; and —(CO)O—(C 1 to C 4 alkyl)-O—(C 1 to C 4 alkyl); —C(O)-alkyl; —C(O)-alkoxy wherein alkoxy is optionally substituted with one or more alkoxys; —SO, -alkyl; —SO 2 -cyclopropyl; —SO 2 -cyclobutyl; —SO 2 -cyclopentyl or —SO 2 -cyclohexyl;

(iv) -dioxo-tetrahydro-thiopyran;

(v) -cyclobutyl;

(vi) -cyclopentyl;

(vii) -cyclopropyl; or

(viii) -cyclohexyl;

(18) —NHR bb , wherein R bb is:

(i) —C(═S)NHR x , wherein R x is C 1 to C 6 alkyl; —C(═S)NH-cyclopropyl; —C(═S)NH-cyclobutyl; —C(═S)NH-cyclopentyl; —C(═S)NH-cyclohexyl;

(ii) —C(═S)NR x R x , wherein R x is independently selected from —C 1 to C 6 alkyl;

(iii) —C(═N—CN)NHR x , wherein R x is —C 1 to C 6 alkyl; —C(═N—CN)—NH-cyclopropyl; —C(═N—CN)—NH-cyclobutyl; —C(═N—CN)—NH-cyclopentyl; —C(═N—CN)—NH-cyclohexyl;

(iv) —PO(OR x ) 2 , wherein R x is independently selected from —C 1 to C 6 alkyl;

(v) —S(═O)-alkyl;

(vi) —S + (O − )-alkyl; or

(vii) -dioxo-tetrahydro-thiopyran;

(19) —N(CONHR w ) 2 ;

(20) —NH(SOR w );

(21) —N(SO 2 R w ) 2 ;

(22) —NR v SO 2 R w , wherein R v is alkyl substituted with 4 to 7 membered heterocyclo; and

wherein R w is:

(i) —C 1 to C 6 alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;

(ii) -amino optionally substituted with —C(O)O-alkyl, a -5 or 6 membered heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, alkoxycarbonyl, (CO)O—(C 1 to C 6 )alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;

(iii) -cyclopropyl;

(iv) -cyclobutyl;

(v) -cyclopentyl;

(vi) -1-methylcyclopropyl; or —

(vii) -1-ethylcyclopropyl;

(28) -5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:

(i) -halo;

(ii) —C 1 to C 6 alkyl; haloalkyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or cyclopropylmethyl;

(iii) -alkoxy optionally substituted with one or more substituents independently selected from: -halo; -5 or 6 membered heterocyclo; and —C(O)NH 2 optionally substituted with C 6 to C 8 alkyl;

(iv) -hydroxy;

(v) -haloalkyl;

(vi) -cyano;

(vii) -nitro;

(viii) —COOH;

(29) —NR o COR p ,

wherein R p is:

(ii) -5 or 6 membered heterocyclo optionally substituted with one or more C 1 to C 6 alkyls or aryls;

(iii) -cyclopropyl;

(iv) -cyclobutyl;

(v) -cyclopentyl;

(vi) -cyclohexyl; or

(vii) -cyclopropylmethyl;

and wherein R o is: hydrogen; or —C 1 to C 6 alkyl;

(30) —NR q CONR q R r ,

wherein R q is hydrogen, and

wherein R r is:

(ii) —C 2 to C 6 alkenyl optionally substituted with one or more halos;

(iii) —C 1 to C 6 alkoxy;

(iv) -5 or 6 membered heterocyclo; or

(v) -5 to 6 membered heteroaryl optionally substituted with —C 1 to C 6 alkyl; cyclopropyl; cyclobutyl; cyclopentyl; or cyclohexyl;

(31) —NR t COOR u ,

wherein R t is hydrogen, and

wherein R u is

(i) —C 1 to C 12 alkyl substituted with one or more substituents independently selected from: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; -aryl substituted with one or more halos or haloalkyls; -alkoxy substituted with one or more alkoxys; -amino optionally substituted with one or more C 1 to C 6 alkyls; —SO 2 R w ; —SO 2 R x , wherein R x —C 1 to C 6 alkyl; -5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo; and

(32) —NR v SO 2 R w ,

wherein R v is alkyl substituted with 4 to 7 membered heterocyclo; and wherein R w is:

(i) —C 1 to C 6 alkyl substituted with cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;

(ii) -aryl; and

(iii) -amino substituted with —C(O)O-alkyl or a -5 or 6 membered heterocyclo or alkyl, which heterocyclo is optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and which alkyl is substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;

Z is —C 1 to C 6 alkyl; -cyclopropyl; -cyclobutyl; -cyclopentyl; -cyclohexyl; or -cyclopropylmethyl;

R 1 is:

(a) -a 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: (1) -hydroxy; (2) —C 1 to C 6 alkyl; (3) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; (4) —C(O)-aryl; (5) —COR p , and (6) —C(O)OR x , wherein R x is —C 1 to C 6 alkyl;

(b) -5 or 6 membered heteroaryl substituted with one or more substituents independently selected from: (1) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl; (2) -alkoxy; (3) -halo; (4) -alkylthio; (5) -haloalkyl; (6) -cyano; (7) -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from (i) halo, (ii) C 1 to C 6 alkoxy, (iii) hydroxy, (iv) cyano, (v) 5 or 6 membered heterocyclo, and (vi) 5 or 6 membered heteroaryl; (8) -heterocyclo; (9) -nitro; (10) -hydroxy; (11) —COOH; (12) —CO 2 R x , wherein R x is —C 1 to C 6 alkyl; (13) —COR x , wherein R x is C 1 to C 6 alkyl; (14) —C(O)NH 2 optionally substituted with one or more C 1 to C 6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl; (15) -amido optionally substituted with one or more or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

(1) -amino optionally substituted with one or more substituents independently selected from (i) heterocyclo, (ii) alkoxy and (iii) alkyl, which alkyl is substituted with one or more alkoxys; (2) -amido optionally substituted with C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (3) -5 or 6 membered heterocyclo substituted with C 1 to C 6 alkyl; (4) -5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl; (5) -aryl; or (6) hydroxyl;

(d) —C 2 to C 6 alkenyl optionally substituted with —SO 2 R x , wherein R x is —C 1 to C 6 alkyl;

(e) —C 1 to C 6 alkoxy substituted with one or more substituents independently selected from: (i) -hydroxy; (ii) -cyano; (iii) -alkoxy optionally substituted with alkoxy; (iv) -amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl; (v) -amino optionally substituted with heterocyclo; (vi) -amido optionally substituted with C 1 to C 6 alkyl; (vii) -5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: —C 1 to C 6 alkoxy; and —C 6 to C 8 aryl; (viii) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: —C 1 to C 6 alkyl; and -4 to 7 membered heterocyclo; and (ix) -alkoxy;

(f) —(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from: (i) -hydroxy; (ii) —C 1 to C 6 alkyl; (iii) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; (iv) —C(O)-aryl; (v) —COR p ; and (vi) —C(O)OR x , wherein R x is —C 1 to C 6 alkyl; or

(g) —(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: (i) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (ii) -alkoxy; (iii) -halo; (iv) -alkylthio; (v) -haloalkyl; (vi) -cyano; (vii) -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, —C 1 to C 6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (viii) -heterocyclo; (ix) -nitro; (x) -hydroxy; (xi) —COOH; (xii) —CO 2 R x , wherein R x is —C 1 to C 6 alkyl; (xiii) —COR x , wherein R x is —C 1 to C 6 alkyl; (xiv) —C(O)NH 2 optionally substituted with one or more substituents independently selected from: —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

(h) —C(O)NH 2 optionally substituted with one or more C 1 to C 6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;

(i) —C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: (i) -aryl; (ii) -5 or 6 membered heteroaryl; and (iii) —C 1 to C 6 alkyl further optionally substituted with one or more substituted with hydroxys;

(j) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; optionally substituted with one or more substituents independently selected from: (i) -5 or 6 membered heterocyclo; (ii) -aryl; and (iii) -5 or 6 membered heteroaryl; or

(k)-alkylthio optionally substituted with one or more substituents independently selected from: (i) -5 or 6 membered heterocyclo; (ii) -aryl; and (iii) -5 or 6 membered heteroaryl;

(l) —C(O)-5 or 6 membered heteroaryl;

(m) —C(O)-aryl;

(n) —COOH; and

(o)—OR kk , wherein R kk is: -aryl optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 haloalkyl;

R 2 is:

(a) —C 1 to C 6 alkyl substituted with one or more substituents independently selected from: (i) -5 or 6 membered heterocyclo; (ii) -5 or 6 membered heteroaryl; (iii) -aryl; (iv) -amido optionally substituted with C 1 to C 6 alkyl; and (v) -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and (vi) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl;

(b) —C 2 to C 6 alkenyl optionally substituted with SO 2 R x , wherein R x is C 1 to C 6 alkyl;

(c) -alkylthio optionally substituted with one or more substituents independently selected from: (i) -5 or 6 membered heteroaryl optionally substituted with alkyl; (ii) -5 or 6 membered heterocyclo; (iii) -aryl; and (iv) —C 1 to C 6 alkyl;

(d) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; optionally substituted with one or more substituents independently selected from: (i) -5 or 6 membered heteroaryl optionally substituted with one or more C 1 to C 6 alkyls; (ii) -5 or 6 membered heterocyclo; (iii) -aryl; and (iv) —C 1 to C 6 alkyl;

(e) (1) —S(O)R x , wherein R x is —C 1 to C 6 alkyl; optionally substituted with one or more substituents independently selected from: (i) -5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C 1 to C 6 alkyls; (ii) -5 or 6 membered heterocyclo; (iii) -aryl; and (iv) —C 1 to C 6 alkyl;

(2) —SR x , wherein R x is C 1 to C 6 alkyl;

(3) —C 2 to C 6 alkenyl-SO 2 —R x , wherein R x C 1 to C 6 alkyl;

(f) -alkoxy substituted with one or more substituents independently selected from: (i) -halo; (ii) -hydroxy; (iii) -cyano; (iv) -alkoxy optionally substituted with alkoxy; (v) -amino substituted with one or more substituents independently selected from —SO 2 —C 1 to C 4 alkyl and alkyl, which alkyl is substituted with one or more substituents independently selected from: -5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls; (vi) -amido substituted with C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (vii) —S-5 or 6 membered heterocyclo; (viii) —S-5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl; (ix) —S—C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from: -aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and —C 5 to C 6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; (x) —S-aryl; (xi) -sulfinyl-5 or 6 membered heterocyclo; (xii) -sulfinyl-5 or 6 membered heteroaryl; (xiii) -sulfinyl-C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from: (i) -aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and —C 5 to C 6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; (xiv) -sulfinyl-aryl; (xv) -sulfonyl-5 or 6 membered heterocyclo; (xvi) -sulfonyl-5 or 6 membered heteroaryl optionally substituted with C 1 to C 6 alkyl; (xvii) -sulfonyl-C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from: -aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and —C 5 to C 6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; (xviii) -sulfonyl-aryl; (xix) -5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, ═O, heterocyclo, and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from: —C 1 to C 6 alkoxy; and -aryl; (xx) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from: —C 1 to C 6 alkyl optionally substituted with one or more alkoxys; -4 to 7 membered heterocyclo; and -alkoxy; and (xxi) -aryl;

(g) -aryl;

(h) —(O)-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from: (i) -hydroxy; (ii) ═O; (iii) —C 1 to C 6 alkyl; (iv) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl; (v) —C(O)-aryl; (vi) —COR p ; and (vii) —C(O)OR x , wherein R x is —C 1 to C 6 alkyl;

(i) —(O)-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from: (i) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (ii) -alkoxy; (iii) -halo; (iv) -alkylthio; (v) -haloalkyl; (vi) -cyano; (vii) -amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (viii) -heterocyclo; (ix) -nitro; (x) -hydroxy; (xi) —COOH; (xii) CO 2 R x , wherein is —C 1 to C 6 alkyl; (xiii) —COR x , wherein R x is —C 1 to C 6 alkyl; (xiv) —C(O)NH 2 optionally substituted with one or more C 1 to C 6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and (xv) -amido optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

(j) —C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from: (i) -aryl; (ii) -5 or 6 membered heteroaryl; and (iii) —C 1 to C 6 alkyl optionally substituted with one or more hydroxys;

(k) —C(O)-5 or 6 membered heteroaryl;

(l) —C(O)-aryl;

(m)-amino substituted with one or more substituents independently selected from: (i) —SO 2 R x , wherein R x is C 1 to C 6 alkyl; (ii) -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR x , wherein R x is —C 1 to C 6 alkyl; and haloalkoxy; (iii) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -aryl optionally substituted with halo; (iv) —C 5 to C 6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; (v) —C 1 to C 7 alkyl optionally substituted with one or more substituents independently selected from: (i) -5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; (ii) -aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl; (iii) -alkoxy; and (iv) -halo;

(n) -5 or 6 membered heteroaryl substituted with one or more substituents independently selected from: (i) —C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (ii) -alkoxy; (iii) -halo; (iv) -alkylthio; (v) -haloalkyl; (vi) -cyano; (vii) -amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (viii) -5 or 6 membered heterocyclo; (ix) -nitro; (x) -hydroxy; (xi) —COOH; (xii) —CO 2 R x , wherein R x is —C 1 to C 6 alkyl; (xiii) COR x , wherein R x is —C 1 to C 6 alkyl; (xiv) —C(O)NH 2 optionally substituted with one or more C 1 to C 6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; (xv) -amido optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C 1 to C 6 alkyl, which alkyl is optionally substituted with one or more C 1 to C 6 alkoxys;

(o) -4, 5 or 6 membered heterocyclo optionally having a hetero atom ring member selected from sulfinyl or sulfonyl, wherein heterocyclo is optionally substituted with one or more substituents independently selected from: (i) -hydroxy; (ii) ═O; (iii) —C 1 to C 6 alkyl optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (iv) —SO 2 R x , wherein R x is —C 1 to C 6 alkyl, which C 1 to C 6 alkyl is optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (v) C(O)-aryl; (vi) —COR p , (vii) —C(O)OR x , wherein R x is C 1 to C 6 alkyl, which C 1 to C 6 alkyl is optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (viii) —C(O)R x , wherein R x is C 1 to C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (ix) aryl; (x) cyclopropyl; (xi) cyclobutyl; (xii) cyclopentyl; and (xiii) cyclohexyl;

(p) —OR kk , wherein R kk is: (i) -aryl optionally substituted with one or more substituents independently selected from halo, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, and C 1 to C 6 haloalkyl; (ii) -5 to 6 membered heterocyclo optionally substituted with C 1 to C 6 alkyl, which alkyl is optionally substituted with aryl; or (iii) -5 to 6 membered heteroaryl substituted with one or more substituents independently selected from halo, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, and C 1 to C 6 haloalkyl; (iv) —SO 2 R x , or (v) —Si(R x ) 3 ;

(q) —OC(O)NHR x , wherein R x is optionally substituted with -aryl;

(r) —OC(O)N(R x ) 2 ; or

R 3 is nitro.

5. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:

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

7. A method for treating a viral infection in a subject in need thereof comprising administering an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to the subject, wherein said viral infection is a Hepatitis C viral infection.

Assignments (5)

RELEASE OF SECURITY INTEREST Recorded Jul 14, 2020

From: MIDCAP FINANCIAL TRUST, AS AGENT

To: PTC THERAPEUTICS, INC.

Reel/Frame 053209/0872 →

CORRECTIVE ASSIGNMENT TO CORRECT THE INCLUSION OF 6420591,6583309,6503713, 5843995,7029846,7056656, 6468969,6486305,6630294, 6989256,6627398,8247167, 9017935 PREVIOUSLY RECORDED ON REEL 042418 FRAME 0774. ASSIGNOR(S) HEREBY CONFIRMS THE SECURITY INTEREST. Recorded Aug 24, 2017

From: PTC THERAPEUTICS, INC.

To: MIDCAP FINANCIAL TRUST, AS AGENT

Reel/Frame 043672/0096 →

SECURITY INTEREST Recorded May 8, 2017

From: PTC THERAPEUTICS, INC.

To: MIDCAP FINANCIAL TRUST, AS AGENT

Reel/Frame 042418/0774 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 29, 2009

From: LI, CHUNSHI; PAGET, STEVEN; ZHANG, NANJING; ZHU, JIN; ZHANG, XIAOYAN

To: PTC THERAPEUTICS, INC.

Reel/Frame 022753/0177 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 8, 2008

From: KARP, GARY MITCHELL; HWANG, PETER SEONGWOO; TAKASUGI, JAMES J.; REN, HONGYU; WILDE, RICHARD G.; TURPOFF, ANTHONY A.; AREFOLOV, ALEXANDER; CHEN, GUANGMING; CAMPBELL, JEFFREY A.

To: PTC THERAPEUTICS, INC.

Reel/Frame 020329/0950 →