Alpha-hydroxy phenylacetic acid pharmacophore or bioisostere Mcl-1 protein antagonists

1. A compound of Formula I:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof,

wherein:

b, represented by the symbol , is a single or double chemical bond which may be cis or trans,

Z is selected from C or N;

R 1 is independently selected from H, —C 1-6 haloalkyl, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —(CH 2 CH 2 O) n R a , —C(═O)R a , —C(═O)OR a , —C(═O)NR a R b , —C 1-6 alkyl-O-C 1-6 alkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;

R 1A is H;

each of R 6 , R 8 , R 2A , R 3A , and R 8A is independently selected from H, halo, —C 1-6 haloalkyl, —C 1-6 alkyl, —O—C 1-6 alkyl, —C 2-6 alkenyl, —C 1-6 alkyl-O-C 1-6 alkyl, —(CH 2 CH 2 O) n R a , —SO 2 R a , —C(═O)R a , —C(═O)OR a , —OC(═O)R a , —C(═O)NR a R b , a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 and further wherein R 8 and R 8A may also be OH;

R 2 is H;

R 3 is H;

R 4 is H or C 1-6 alkyl;

R 4A is H;

R 5 is H or C 1-6 alkyl;

R 5A is H;

R 7 is H or C 1-6 alkyl;

R 7A is H;

R 9 is H;

R 10 is halo;

when b is a double bond, R 2A and R 3A are absent;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of the R 1 substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R 11 substituents independently selected from OH, halo, —NR c R d , —C 1-6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OC 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, —O-haloC 1-6 alkyl, —SO 2 R c , —CN, —C(═O)NR c R d , —C(═O)R c , —OC(═O)R a , —C(═O)OR c , a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;

wherein the —C 1-6 alkyl of any of the R 1 , R 6 , R 8 , R 11 , R 2A , R 3A , and R 8A substituents is unsubstituted or substituted by 1, 2 or 3 R 12 substituents independently selected from OH, —OC 1-6 alkyl, —C 1-6 alkyl-O-C 1-6 alkyl, halo, —O-haloC 1-6 alkyl, —CN, —NR a R b , —(NR a R b R c ) n , —SO 2 R a , —(CH 2 CH 2 O) n CH 3 , (═O), —C(═O)R a , —OC(═O)R a , —C(═O)OR a , —C(═O)NR a R b , —O—SiR a R b R c , —O-(3- to 12-membered heterocycloalkyl), phenyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of any of the R 6 , R 8 , R 11 and R 12 substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R 13 substituents independently selected from OH, halo, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, —O-haloC 1-6 alkyl, —SO 2 R c , —NR c R d , —CN, —C(═O)NR c R d , —C(═O)R c , —OC(═O)R a , —C(═O)OR c , —B(OH) 2 , a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;

wherein each R a , R b , R c , and R d is independently H, OH, —C 1-6 alkyl, —C 1-6 alkenyl, —C 2-6 alkynyl, —C 1-6 alkyl-NR 14 R 14 , NR 14 R 14 , —SO 2 R 14 , —(CH 2 CH 2 O) n CH 3 , —C(═O)R 14 , —OC(═O)R 14 , —C(═O)OR 14 , —C(═O)NR 14 R 14 , C 1-6 haloalkyl, —O-haloC 1-6 alkyl, —C 1-6 alkyl-O-C 1-6 alkyl, —C 1-6 alkyl-OH, benzyl, phenyl, a —C 1-6 alkyl-3- to 12-membered heterocycloalkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups and the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, and the heterocycloalkyl groups of the —C 1-6 alkyl-heterocycloalkyl group may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;

wherein R 14 substituents are independently selected from H, —OH, halo, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl-OC 1-6 alkyl, —C 1-6 haloalkyl, —O-haloC 1-6 alkyl, phenyl, tolyl, —C(O)C 1-6 alkyl, —C(O)OCH 3 , —SO 2 -phenyl, —SO 2 —N(CH 3 ) 2 , —N═N═N, —NH 2 , —N(C 1-6 alkyl) 2 , —NR 15 C 1-6 alkyl, —NR 15 C 1-6 alkyl-O-C 1-6 alkyl, —N(C 1-6 alkyl)C 1-6 alkyl-O-C 1-6 alkyl, —NR 15 —C 1-6 alkyl-3- to 12-membered heterocycloalkyl, a NR 15 -6- to 12-membered aryl or heteroaryl, a NR 15 -3- to 12-membered cycloalkenyl, a NR 15 -3- to 12-membered monocyclic or bicyclic cycloalkyl, or a NR 15 -3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, a —C 1-6 alkyl-3- to 12-membered heterocycloalkyl, a 6- to 12-membered aryl or heteroaryl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, and heterocycloalkyl groups and the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, heterocycloalkyl, and the heterocycloalkyl groups of the —C 1-6 alkyl-heterocycloalkyl group may include a C═O group, and further wherein the heterocycloalkyl groups may include a S═O or SO 2 ;

the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl and the heterocycloalkyl groups of the —C 1-6 alkyl-heterocycloalkyl groups of R 14 can be unsubstituted or substituted with 1, 2, 3, or 4 R 15 substituents independently selected from H, —OH, —N═N═N, halo, —C 1-6 alkyl, —OC 1-6 alkyl, C 1-6 haloalkyl, —O-haloC 1-6 alkyl, phenyl, tolyl, —C(O)C 1-6 alkyl, —C(O)OCH 3 , SO 2 -phenyl, —SO 2 —NH 2 , or —SO 2 —N(CH 3 ) 2 ; and

n is independently, in each instance, an integer of 1, 2, 3 or 4.

2. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula Ia:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof,

wherein:

R 1 is independently selected from H, —C 1-6 haloalkyl, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —(CH 2 CH 2 O) n R a , —C(═O)R a , —C(═O)OR a , —C(═O)NR a R b , —C 1-6 alkyl-O-C 1-6 alkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;

R 8 is selected from —C 1-6 haloalkyl, —C 1-6 alkyl, —O—C 1-6 alkyl, —C 2-6 alkenyl, —C 1-6 alkyl-O-C 1-6 alkyl, —(CH 2 CH 2 O) n R a , —SO 2 R a , —C(═O)R a , —C(═O)OR a , —OC(═O)R a , or —C(═O)NR a R b ;

R 8A is selected from H, OH, halo, —C 1-6 haloalkyl, —C 1-6 alkyl, —O-C 1-6 alkyl, —C 2-6 alkenyl, —C 1-6 alkyl-O-C 1-6 alkyl, —(CH 2 CH 2 O) n R a , —SO 2 R a , —C(═O)R a , —C(═O)OR a , —OC(═O)R a , or —C(═O)NR a R b ;

R 10 is halo;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of the R 1 substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R 11 substituents independently selected from OH, halo, —NR c R d , —C 1-6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OC 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, —O-haloC 1-6 alkyl, SO 2 R c , SO 2 , —CN, —C(═O)NR c R d , —C(═O)R c , —OC(═O)R a , —C(═O)OR c , a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;

wherein the —C 1-6 alkyl of any of the R 1 , R 6 , R 8 , R 11 , and R 8A substituents is unsubstituted or substituted by 1, 2 or 3 R 12 substituents independently selected from OH, —OC 1-6 alkyl, —C 1-6 alkyl-O-C 1-6 alkyl, halo, —O-haloC 1-6 alkyl, —CN, —NR a R b , —(NR a R b R c ) n , —SO 2 R a , —(CH 2 CH 2 O) n CH 3 , (═O), —C(═O)R a , —OC(═O)R a , —C(═O)OR a , —C(═O)NR a R b , —O—SiR a R b R c , —O-(3- to 12-membered heterocycloakyl), phenyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;

wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of any of the R 6 , R 8 , R 11 and R 12 substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R 13 substituents independently selected from OH, halo, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, —O-haloC 1-6 alkyl, —SO 2 R c , —NR c R d , —CN, —C(═O)NR c R d , —C(═O)R c , —OC(═O)R a , —C(═O)OR c , —B(OH) 2 , a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;

wherein each R a , R b , R c , and R d is independently H, OH, —C 1-6 alkyl, —C 1-6 alkenyl, —C 2 -6alkynyl, —C 1-6 alkyl-NR 14 R 14 , NR 14 R 14 , —SO 2 R 14 , —(CH 2 CH 2 O) n CH 3 , —C(═O)R 14 , —OC(═O)R 14 , —C(═O)OR 14 , —C(═O)NR 14 R 14 , —C 1-6 haloalkyl, —O-haloC 1-6 alkyl, —C 1-6 alkyl-O-C 1-6 alkyl, —C 1-6 alkyl-OH, benzyl, phenyl, a —C 1-6 alkyl-3- to 12-membered heterocycloalkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups and the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, and the heterocycloalkyl groups of the —C 1-6 alkyl-heterocycloalkyl group may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;

wherein R 14 substituents are independently selected from H, —OH, halo, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl-OC 1-6 alkyl, —C 1-6 haloalkyl, —O-haloC 1-6 alkyl, phenyl, tolyl, —C(O)C 1-6 alkyl, —C(O)OCH 3 , SO 2 -phenyl, —SO 2 —N(CH 3 ) 2 , —N═N═N, —NH 2 , —N(C 1-6 alkyl) 2 , —NR 15 C 1-6 alkyl, —NR 15 C 1-6 alkyl-O-C 1-6 alkyl, —N(C 1-6 alkyl)C 1-6 alkyl-O-C 1-6 alkyl, —NR 15 —C 1-6 alkyl-3- to 12-membered heterocycloalkyl, a NR 15 -6- to 12-membered aryl or heteroaryl, a NR 15 -3- to 12-membered cycloalkenyl, a NR 15 -3- to 12-membered monocyclic or bicyclic cycloalkyl, or a NR 15 -3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, a —C 1-6 alkyl-3- to 12-membered heterocycloalkyl, a 6- to 12-membered aryl or heteroaryl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, and heterocycloalkyl groups and the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, heterocycloalkyl, and the heterocycloalkyl groups of the —C 1-6 alkyl-heterocycloalkyl group may include a C═O group, and further wherein the heterocycloalkyl groups may include a S═O or SO 2 ;

the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl and the heterocycloalkyl groups of the —C 1-6 alkyl-heterocycloalkyl groups of R 14 can be unsubstituted or substituted with 1, 2, 3, or 4 R 15 substituents independently selected from H, —OH, —N═N═N, halo, —C 1-6 alkyl, —OC 1-6 alkyl, C 1-6 haloalkyl, —O-haloC 1-6 alkyl, phenyl, tolyl, —C(O)C 1-6 alkyl, —C(O)OCH 3 , SO 2 -phenyl, —SO 2 —NH 2 , or —SO 2 —N(CH 3 ) 2 ; and

n is independently, in each instance, an integer of 1, 2, 3 or 4.

3. The compound of claim 1 , wherein R 10 is Cl.

4. The compound of claim 1 , wherein R 1 is selected from H, —C 1 -C 6 alkyl, or

5. The compound of claim 4 , wherein R 1 is H.

6. The compound of claim 1 , wherein R 4 is H.

7. The compound of claim 1 , wherein R 5 is H.

8. The compound of claim 1 , wherein R 6 is H.

9. The compound of claim 1 , wherein R 7 is H.

10. The compound of claim 1 , wherein R 8 is independently selected from —OH, —COOH, or

11. The compound of claim 1 , wherein R 8 is —COOH.

12. The compound of claim 1 , wherein R 8 is —OH.

13. The compound of claim 1 , wherein R 8A is —OH.

14. The compound of claim 1 , wherein the compound is selected from:

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.

15. A pharmaceutical composition comprising the compound of claim 1 , or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.