Spiro-Sulfonamide Derivatives As Inhibitors Of Myeloid Cell Leukemia-1 (MCL-1) Protein

Abstract

The disclosure is directed to compounds of Formula IPharmaceutical compositions comprising compounds of Formula I as well as methods of their use and preparation, are also described.

What is claimed: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof; 
         wherein 
         Z is CH or N; 
         Q is —O—, —S—, —S(O)—, or —S(O) 2 —; 
         the moiety -W 1 -W 2 -W 3  is —CR 2 R 2A —CR 2 R 2A —CR 2 R 2A —, —O—CR 2B R 2C —CR 2 R 2A —, —CR 2 R 2A —CR 2B R 2C —O—, —NR 2B —CR 2B R 2C —CR 2 R 2A —, —CR 2 R 2A —CR 2B R 2C —NR 2B —, —S—CR 2B R 2C —CR 2 R 2A , or —CR 2 R 2A —CR 2B R 2C —S—; 
         L 1  is absent or is optionally substituted —C 1 -C 6 alkylene-; 
         L 2  is absent or is optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene; 
         L 3  is absent, or is —(CR 4 R 5 ) p —, —(CR 4 R 5 ) p O—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, —NR 6 —, —OC(═O)—, —C(═O)O—, —NR 6A C(O)—, —C(═O)NR 6A —, —OC(═O)N(R 6A )—, —NR 6A C(O)O—, —S(═O)NR 6A —, —NR 6A S(O)—, —S(═O) 2 NR 6A —, or —NR 6A S(O) 2 —; 
         L 4  is absent, or is —(CR 4 R 5 ) p Q 1 (CR 4 R 5 ) q —, wherein Q 1  is absent, —CR 4A ═CR 4B —, —O—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, —NR 6 —, —OC(═O)—, —C(═O)O—, —NR 6A C(O)—, —C(═O)NR 6A —, —NR 6A C(O)R 6B —, —OC(═O)N(R 6A )—, —NR 6A C(O)O—, —S(═O)NR 6A —, —NR 6A S(O)—, —S(═O) 2 NR 6A —, or —NR 6A S(O) 2 —; or is —(CR 4 R 5 ) p —(CR 4A ═CR 4B )—(CR 4 R 5 ) q —O—; 
         L 5  is absent, or is —C 1 -C 6  alkylene-, —C 2 -C 6  alkenylene-, —C 2 -C 6  alkynylene-, -arylene-, -heteroarylene-, -cycloalkenylene-, -cycloalkylene-, -heterocycloalkylene-, wherein said C 1 -C 6  alkylene, C 2 -C 6  alkenylene, C 2 -C 6  alkynylene, arylene, heteroarylene, cycloalkenylene, cycloalkylene, or heterocycloalkylene groups are optionally substituted; 
         L 6  is absent, or is —(CR 7 R 8 ) s —, —(CR 7 R 8 ) s O(CR 7 R 8 ) t —, —(CR 7 R 8 ) s NR 9 (CR 7 R 8 ) t —, —(CR 7 R 8 ) s S(CR 7 R 8 ) t —, —(CR 7 R 8 ) s S(O)(CR 7 R 8 ) t —, —(CR 7 R 8 ) s S(O) 2 (CR 7 R 8 ) t —, —(CR 7 R 8 ) s NR 9A C(O)(CR 7 R 8 ) t —, —(CR 7 R 8 ) s OC(O)NR 9A (CR 7 R 8 ) t —, —(CR 7 R 8 ) s NR 9A C(O)O(CR 7 R 8 ) t —, —(CR 7 R 8 ) s NR 9A C(O)NR 9B (CR 7 R 8 ) t —, —(CR 7 R 8 ) s NR 9A S(O)(CR 7 R 8 ) t —, —(CR 7 R 8 ) s NR 9A S(O) 2 (CR 7 R 8 ) t —; —(CR 7 R 8 ) s —CR 4A ═CR 4B —(CR 7 R 8 ) t —, —(CR 7 R 8 ) s C(═O)(CR 7 R 8 ) t —; —(CR 7 R 8 ) s C(═O)(CR 7 R 8 ) t —O—, or —(CR 7 R 8 ) s C(═O)(CR 7 R 8 ) t —NR 6 —; 
         each n is independently 0-3; 
         each m is independently 0-2; 
         each p is independently 0-4; 
         each q is independently 0-4; 
         each s is independently 0-3; 
         each t is independently 0-4; 
         each R is independently -D, -halo, —CN, —NO 2 , —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 1 -C 6 alkoxy, -cycloalkyl, —OR a , —SR a , —C(O)R b , —C(O)OR a , —NR c R d , —C(O)NR c R d , or —S(O) 2 R a ; 
         wherein said —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 1 -C 6 alkoxy, or -cycloalkyl is optionally substituted; 
         each R 1  is independently -D, -halo, —CN, —NO 2 , —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OR a , —SR a , —NR c R d , —C(O)R b , —OC(O)R b , —C(O)OR a , —C(O)NR c R d , —S(O) 2 R a ; -aryl, -heteroaryl, -cycloalkyl, or -heterocycloalkyl, wherein said —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, -cycloalkyl, -heterocycloalkyl, -aryl, or -heteroaryl is optionally substituted; 
         each R 2 , R 2A , or R 2a  is independently H, D, halo, OR a , optionally substituted C 1 -C 6 alkyl, or R 2  and R 2A  that are attached to the same carbon atom may, together with the carbon atom to which they are both attached, form an optionally substituted cycloalkyl ring; 
         each R 2B  and R 2C  is independently H, D, optionally substituted C 1 -C 6 alkyl, or R 2B  and R 2C  may, together with the carbon atom to which they are both attached, form an optionally substituted cycloalkyl ring; 
         R 3  is H, D, —C 1 -C 6 alkyl, —C 3 -C 6 alkenyl, —C 3 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, C(O)R b , C(O)OR a , or C(O)NR c R d ; wherein said C 1 -C 6 alkyl, —C 3 -C 6 alkenyl, —C 3 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted; or R 3  is —C 1 -C 6 alkyl substituted at the C 1  carbon atom with —OR 3A  wherein R 3A  is C 1 -C 6 alkyl, —PO 3 H, —C(O)OR 2C , or —C(O)NR 3A R 3B  wherein R 3A  and R 3B  are each independently H, D, optionally substituted C 1 -C 6 alkyl; 
         each R 4  or R 7  is independently H, D, halo, —OH, —CN, —NO 2 , —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, —OR a , —SR a , —NR c R d , —NR a R c , —C(O)R b , —OC(O)R a , —C(O)OR a , —C(O)NR c R d , —S(O)R b , or —S(O) 2 R b , wherein said C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, or heterocycloalkyl is optionally substituted; 
         each R 4A  or R 4B  is independently H, D, -Me, —CF 3  or —F; 
         each R 5  or R 8  is independently H, D, fluoro, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C(O)R b , —C(O)OR a , —C(O)NR c R d , aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein said C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is optionally substituted; 
         or R 4  and R 5  together with the C atom to which they are attached form a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, each optionally substituted; 
         or an R 4  and an R 5  attached to adjacent carbon atoms, together with the C atoms to which they are attached, form a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, each optionally substituted; 
         or R 7  and R 8  together with the C atom to which they are both attached form a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, each optionally substituted, each optionally substituted; 
         or an R 7  and an R 8  attached to adjacent carbon atoms, together with the C atoms to which they are attached, form a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, each optionally substituted; 
         each R 6  or R 9  is independently H, D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OC 1 -C 6 alkyl, —C(O)R b , —C(O)OR a , —C(O)NR c R d , —S(O)R b  or —S(O) 2 R b , aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group, wherein said C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OC 1 -C 6 alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, is optionally substituted; 
         or R 9  together with either an R 7  or an R 8  forms an optionally substituted heterocyclic alkylene; 
         each R 6A , R 6B , R 9A , or R 9B  is independently H, D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein said C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is optionally substituted; 
         or R 6A  and R 6B  together with the N atoms to which they are attached form an optionally substituted heterocycloalkyl or heterocycloalkenyl ring; 
         or R 9A  and R 9B  together with the N atoms to which they are attached form an optionally substituted heterocycloalkyl or heterocycloalkenyl ring; 
         each R a  is independently H, D, —C(O)R b , —C(O)OR c , —C(O)NR c R d , —P(OR c ) 2 , —P(O)R c R b , —P(O)OR c OR b , —S(O)R b , —S(O)NR c R d , —S(O) 2 R b , —S(O) 2 NR c R d , —B(OR c )(OR b ), SiR b   3 , —C 1 -C 10 alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl wherein said C 1 —C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl is optionally substituted; 
         each R b , is independently H, D, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl wherein said —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, aryl, cycloalkyl, cycloalkeneyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl is optionally substituted; 
         each R c  or R d  is independently H, D, —C 1 -C 10  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —OC 1 -C 6 alkyl, —O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein said C 1 -C 10  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —OC 1 -C 6 alkyl, —O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl are each optionally substituted; 
         or R c  and R d , together with the N atom to which they are both attached, form an optionally substituted monocyclic or multicyclic heterocycloalkyl, or optionally substituted monocyclic or multicyclic heterocycloalkenyl group. 
       
     
     
         2 . The compound according to  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein said compound has the Formula IA-3: 
       
         
           
           
               
               
           
         
         wherein W 1  is —CH 2 — and W 3  is O, or W 1  is —O— and W 3  is —CH 2 —, or W 1  is —CH 2 — and W 3  is —CH 2 — 
       
     
     
         3 . The compound according to  claim 1 , wherein L 2  is optionally substituted cycloalkylene or optionally substituted heterocycloalkylene. 
     
     
         4 . The compound according to  claim 1 , wherein said compound is a compound of Formula IA-4: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof; wherein
 W 1  is —CH 2 — and W 3  is O, or W 1  is —O— and W 3  is —CH 2 —, or W 1  is —CH 2 — and W 3  is —CH 2 —; 
 
         L 3  is absent, or is —(CR 4 R 5 ) p —, —(CR 4 R 5 ) p O—, —S(O)—, —S(O) 2 —, —C(═O)—, —C(═O)O—, —C(═O)NR 6A —, —NR 6A C(O)O—, —S(═O)NR 6A —, —NR 6A S(O)—, —S(═O) 2 NR 6A —, or —NR 6A S(O) 2 —; 
         L 4  is absent, or —(CR 4 R 5 ) p Q 1 (CR 4 R 5 ) q —, wherein Q 1  is absent, —CR 4A ═CR 4B —, —O—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, —NR 6 —, —OC(═O)—, —C(═O)O—, —NR 6A C(O), —C(═O)NR 6A —, —NR 6A C(O)R 6B —, —OC(═O)N(R 6A )—, —NR 6A C(O)O—, —S(═O)NR 6A —, —NR 6A S(O)—, —S(═O) 2 NR 6A —, or —NR 6A S(O) 2 —; 
         L 5  is absent, or is a 6- to 10-membered arylene, 5- to 10-membered heteroarylene, a 3- to 12-membered cycloalkenylene, a 3- to 12-membered cycloalkenylene, a 3- to 7-membered monocyclic cycloalkylene, a 6- to 12 bicyclic cycloalkylene, a 3- to 7-membered monocyclic heterocycloalkylene, or 6- to 12-membered bicyclic heterocycloalkylene group, wherein the 6- to 10-membered arylene, 5- to 10-membered heteroarylene, a 3- to 12-membered cycloalkenylene, a 3- to 12-membered cycloalkenylene, a 3- to 7-membered monocyclic cycloalkylene, a 6- to 12 bicyclic cycloalkylene, a 3- to 7-membered monocyclic heterocycloalkylene, or 6- to 12-membered bicyclic heterocycloalkylene group is optionally substituted; and 
         L 6  is absent, or is —(CR 7 R 8 ) s —, —O(CR 7 R 8 ) t —, —NR 9 (CR 7 R 8 ) t —, —S(CR 7 R 8 ) t —, —S(O)(CR 7 R 8 ) t —, —S(O) 2 (CR 7 R 8 ) t —, —NR 9A C(O)(CR 7 R 8 ) t —, —C(O)NR 9A (CR 7 R 8 ) t —, —R 9A C(O)O(CR 7 R 8 ) t —, —NR 9A C(O)NR 9B (CR 7 R 8 ) t —, —NR 9A S(O)(CR 7 R 8 ) t —, —NR 9A S(O) 2 (CR 7 R 8 ) t —; —CR 4A ═CR 4B —(CR 7 R 8 ) t —, —C(═O)(CR 7 R 8 ) t —; —C(═O)(CR 7 R 8 ) t —O—, or —C(═O)(CR 7 R 8 ) t —NR 6 —. 
       
     
     
         5 . The compound according to  claim 1 , or a pharmaceutically acceptable salt or solvate thereof; wherein
 L 3  absent;   L 4  is —(CR 4 R 5 ) p Q 1 (CR 4 R 5 ) q —, wherein Q 1  is absent, —CR 4A ═CR 4B —, —O—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, —NR 6 —, —OC(═O)—, —C(═O)O—, —NR 6A C(O), —C(═O)NR 6A —, —NR 6A C(O)R 6B —, —OC(═O)N(R 6A )—, —NR 6A C(O)O—, —S(═O)NR 6A —, —NR 6A S(O)—, —S(═O) 2 NR 6A —, or —NR 6A S(O) 2 —;   L 5  is absent; and   L 6  is absent, or is —(CR 7 R 8 ) s —, —O(CR 7 R 8 ) t —, —NR 9 (CR 7 R 8 ) t —, —S(CR 7 R 8 ) t —, —S(O)(CR 7 R 8 ) t —, —S(O) 2 (CR 7 R 8 ) t —, —NR 9A C(O)(CR 7 R 8 ) t —, —C(O)NR 9A (CR 7 R 8 ) t —, —R 9A C(O)O(CR 7 R 8 ) t —, —NR 9A C(O)NR 9B (CR 7 R 8 ) t —, —NR 9A S(O)(CR 7 R 8 ) t —, —NR 9A S(O) 2 (CR 7 R 8 ) t —; —CR 4A ═CR 4B —(CR 7 R 8 ) t —, —C(═O)(CR 7 R 8 ) t —; —C(═O)(CR 7 R 8 ) t —O—, or —C(═O)(CR 7 R 8 ) t —NR 6 —.   
     
     
         6 . The compound according to  claim 1 , wherein
 L 4  is —(CR 4 R 5 ) p Q 1 (CR 4 R 5 ) q —, wherein Q 1  is —CR 4A ═CR 4B —; and   L 6  is absent, —O(CR 7 R 8 ) t —, or —NR 9 (CR 7 R 8 ) t —.   
     
     
         7 . The compound according to  claim 1 , wherein
 p=1;   q=1-4; and   t=1.   
     
     
         8 . The compound according to  claim 1 , or a pharmaceutically acceptable salt or solvate thereof; wherein
 L 3  absent;   L 4  is —(CR 4 R 5 ) p Q 1 (CR 4 R 5 ) q —, wherein Q 1  is absent, —CR 4A ═CR 4B —, —O—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, —NR 6 —, —OC(═O)—, —C(═O)O—, —NR 6A C(O), —C(═O)NR 6A —, —NR 6A C(O)R 6B —, —OC(═O)N(R 6A )—, —NR 6A C(O)O—, —S(═O)NR 6A —, —NR 6A S(O)—, —S(═O) 2 NR 6A —, or —NR 6A S(═O) 2 —;   L 5  is a 6- to 10-membered arylene, 5- to 10-membered heteroarylene, a 3- to 12-membered cycloalkenylene, a 3- to 12-membered cycloalkenylene, a 3- to 7-membered monocyclic cycloalkylene, a 6- to 12 bicyclic cycloalkylene, a 3- to 7-membered monocyclic heterocycloalkylene, or 6- to 12-membered bicyclic heterocycloalkylene group, wherein the 6- to 10-membered arylene, 5- to 10-membered heteroarylene, a 3- to 12-membered cycloalkenylene, a 3- to 12-membered cycloalkenylene, a 3- to 7-membered monocyclic cycloalkylene, a 6- to 12 bicyclic cycloalkylene, a 3- to 7-membered monocyclic heterocycloalkylene, or 6- to 12-membered bicyclic heterocycloalkylene group is optionally substituted; and   L 6  is absent, or is —(CR 7 R 8 ) s —.   
     
     
         9 . The compound according to  claim 1 , wherein L 4  is —(CR 4 R 5 ) p Q 1 (CR 4 R 5 ) q —, wherein Q 1  is —CR 4A ═CR 4B —, —O—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, —OC(═O)—, —C(═O)O—, —OC(═O)N(R 6A )—, or —NR 6A C(O)O—;
 L 5  is a 6- to 10-membered arylene, 5- to 10-membered heteroarylene, a 3- to 7-membered monocyclic cycloalkylene, a 3- to 7-membered monocyclic heterocycloalkylene, wherein the 6- to 10-membered arylene, 5- to 10-membered heteroaryl ene, a 3- to 7-membered monocyclic cycloalkylene, a 3- to 7-membered monocyclic heterocycloalkylene is optionally substituted; and 
 L 6  is absent, or is —(CR 7 R 8 ) s —. 
 
     
     
         10 . The compound according to  claim 1 , or a pharmaceutically acceptable salt or solvate thereof; wherein L 4  is —(CR 4 R 5 ) p Q 1 (CR 4 R 5 ) q — wherein p=1; q=1-3, Q 1  is absent, or —CR 4A ═CR 4B —; L 6  is (CR 7 R 8 ) s  wherein s=1-2, —O(CR 7 R 8 ) t —, —NR 9 (CR 7 R 8 ) t —, —S(CR 7 R 8 ) t —, —S(O)(CR 7 R 8 ) t —, or —S(O) 2 (CR 7 R 8 ) t —, wherein t=1. 
     
     
         11 . The compound according to  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein said compound is a compound of Formula IA-8: 
       
         
           
           
               
               
           
         
         wherein X is O, NR 9 , CR 7 R 8 , S, S(O), SO 2 ; 
         R is halo or C 1 -C 6 alkyl; 
            represents a carbon-carbon single bond in which each carbon atom in the bond is substituted with R 4  and R 5 , an (E)-carbon-carbon double bond, or a (Z)-carbon-carbon double bond; 
         R a*  is R a  wherein R a  is H, —C(O)R b , —C(O)OR c , —C(O)NR c R d , P(OR c ) 2 , P(O)R c R b , P(O)OR c OR b , S(O)R b , S(O)NR c R d , S(O) 2 R b , S(O) 2 NR c R d , B(OR c )(OR b ), SiR b   3 , C 1 -C 10 alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C 1 -C 10  alkyl, C 2 -C 10 alkenyl, C 2 -C 10  alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted; 
         R c * is R c  wherein R c  is H, D, —C 1 -C 10  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —OC 1 -C 6 alkyl, —O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein said C 1 -C 10  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —OC 1 -C 6 alkyl, —O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl are each optionally substituted. 
       
     
     
         12 . The compound according to  claim 11 , wherein   represents a carbon-carbon single bond in which each carbon atom in the bond is substituted with R 4  and R 5 . 
     
     
         13 . The compound according to  claim 11 , wherein   represents a carbon-carbon double bond substituted with R 4A  and R 4B . 
     
     
         14 . The compound according to  claim 13 , wherein   represents a (E)-carbon-carbon double bond substituted with R 4A  and R 4B . 
     
     
         15 . The compound according to  claim 11 , wherein X is —O—, —NR 9 —, or —CR 7 R 8 —. 
     
     
         16 . The compound according to  claim 11 , wherein R a*  is R a  wherein R a  is H, —C(O)R b , —C(O)OR c , —C(O)NR c R d , —S(O) 2 R b , or optionally substituted C 1 -C 6 alkyl; and R c * is R c  wherein R c  is H or optionally substituted C 1 -C 10 alkyl. 
     
     
         17 . The compound according to  claim 11 , wherein R is —Cl. 
     
     
         18 . The compound according to  claim 11 , wherein each R 4  and R 5  is independently H or C 1 -C 6 alkyl. 
     
     
         19 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         20 . A method of inhibiting an MCL-1 enzyme comprising contacting the MCL-1 enzyme with an effective amount of a compound of  claim 1 . 
     
     
         21 . A method of treating a disease or disorder associated with aberrant MCL-1 activity in a subject comprising administering to the subject, a compound of  claim 1 . 
     
     
         22 . The method of  claim 21 , wherein the disease or disorder associated with aberrant MCL-1 activity is colon cancer, breast cancer, small-cell lung cancer, non-small-cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer.