wherein:

A and E are independently selected from a bond, CH₂, O, NH, S, and S(O)₂;

Z is hydrogen, alkyl, alkoxy, alkoxymethyl, methoxyalkoxymethyl, hydroxymethyl, halo, haloalkyl, haloalkoxy, cyano, cycloalkyl, heterocyclyl, heteroaryl (wherein cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with one to three halo), —O(alk)_yR^a, —O(alk)OR^b, —S(O)R^c, —S(O)₂R^d, —NR^eC(O)R^f, —NR^gSO₂R^h, —OC(O)NRⁱR^j, —C(O)NR^kR^m, —S(O)₂NRⁿR^o, —NR^pR^q, —NR^rC(O)C(O)R^s or —Y-M (wherein Y is bond, O, or SO₂ and M is alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl and heteroaryl are substituted with —O(alk)_yR^a, —O(alk)OR^b, —S(O)R^c, —S(O)₂R^d, —NR^eC(O)R^f, —NR^gS2R^h, —OC(O)NRⁱR^j, —C(O)NR^kR^m, —S(O)₂NRⁿR^o, —NR^pR^q, or —NR^rC(O)C(O)R^s and cycloalkyl, heterocyclyl, and heteroaryl are optionally further substituted with 1 to 3 halo); wherein each y is 0 or 1, each alk is alkylene, and each R^c, R^d, R^f, R^h, and R^s are independently alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; and each R^a, R^b, R^e, R^g, Rⁱ, R^j, R^k, R^m, Rⁿ, R^o, R^p, R^q, R^r, and R^s are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; or, independently of each other, each Rⁱ and R^j, R^k and R^m, Rⁿ and R^o, and R^p and R^q, together with the nitrogen atom to which they are attached form optionally substituted heterocyclyl;

R¹, R², R³, and R⁴ are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, hydroxylalkyl, amino, and aminoalkyl;

or one of R¹ and R², and R³ and R⁴, when attached to the same carbon, combine to form oxo, alkyldienyl, 3 to 6 membered cycloalkylene, or 4 to 6 membered optionally substituted heterocyclylene;

R⁵ and R⁶ are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl, or wherein one of R⁵ and R⁶ is optionally substituted heterocyclyl and the other is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, hydroxylalkyl, amino, and aminoalkyl;

L is bond, O, S, S(O), S(O)₂, or CR⁷R⁸ where R⁷ and R⁸ are independently hydrogen or alkyl;

Z¹ is a group of formula (a):

wherein:

R⁹ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R¹⁰ is hydrogen, alkyl, halo, hydroxy, hydroxyalkyl, —CD₂OH, alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl;

R¹³ is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl;

R¹⁴ is hydrogen, alkyl, or haloalkyl;

R¹¹ is selected from amino and aminoalkyl;

R¹² is selected from hydrogen, cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one to three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano;

or R¹¹ and R¹² together with the carbon atom to which they are attached form a ring of formula (c):

wherein:

e is 0, 1, or 2;

k is 0, 1, or 2 provided e+k is 1, 2, or 3;

q is 0, 1, or 2, or 3;

R¹⁷ and R¹⁸ are independently selected from hydrogen, alkyl, cycloalkyl, and haloalkyl;

each R¹⁹ is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, alkylsulfoxide, alkylsulfonyl, oxo, cycloalkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; or

when two R¹⁹ groups are attached to the same carbon atom, the two R¹⁹ groups together with the carbon atom to which they are attached form cycloalkylene or heterocyclylene;

ring D is absent and one of Q and W is CH₂, O, S, S(O), S(O)₂, or NH; and the other of Q and W is CH₂;

or a pharmaceutically acceptable salt thereof;

the method comprising:

reacting a compound of Formula 1-a with a compound of Formula 1-d or reacting a compound of Formula 1-c with a compound of Formula 1-e:

wherein X¹ is halogen; and M is a metal.