MYST family histone acetyltransferase inhibitors

1. A compound of formula I′:

or a pharmaceutically acceptable salt thereof, wherein:

Z is selected from

each of R 1 and R 2 is independently selected from halogen and C 1-4 aliphatic;

R 3 is selected from hydrogen, halogen, —CN, —NR 2 , and optionally substituted C 1-4 aliphatic;

each R is independently selected from hydrogen, optionally substituted C 1-4 aliphatic, and —C(O)O(C 1-4 aliphatic);

Ring A is an optionally substituted 5- or 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

each R a is selected from halogen and optionally substituted C 1-4 aliphatic; and

x is 0-3;

wherein optional substituents are independently selected from monovalent and divalent substituents,

each optional monovalent substituent on a substitutable carbon atom is independently selected from halogen; —(CH 2 ) 0-4 R ∘ ; —(CH 2 ) 0-4 OR ∘ ; —O(CH 2 ) 0-4 R ∘ , —O—(CH 2 ) 0-4 C(O)OR ∘ ; —(CH 2 ) 0-4 CH(OR ∘ ) 2 ; —(CH 2 ) 0-4 SR ∘ ; —(CH 2 ) 0-4 Ph, optionally substituted with R ∘ ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph optionally substituted with R ∘ ; —CH═CHPh optionally substituted with R ∘ ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl optionally substituted with R ∘ ; —NO 2 ; —CN; —N 3 ; —(CH 2 ) 0-4 N(R ∘ ) 2 ; —(CH 2 ) 0-4 N(R ∘ )C(O)R ∘ ; —N(R ∘ )C(S)R ∘ ; —(CH 2 ) 0-4 N(R ∘ )C(O)NR ∘ 2 ; —N(R ∘ )C(S)NR ∘ 2 ; —(CH 2 ) 0-4 N(R ∘ )C(O)OR ∘ ; —N(R ∘ )N(R ∘ )C(O)R ∘ ; —N(R ∘ )N(R ∘ )C(O)NR ∘ 2 ; —N(R ∘ )N(R ∘ )C(O)OR ∘ ; —(CH 2 ) 0-4 C(O)R ∘ ; —C(S)R ∘ ; —(CH 2 ) 0-4 C(O)OR ∘ ; —(CH 2 ) 0-4 C(O)SR ∘ ; —(CH 2 ) 0-4 C(O)OSiR ∘ 3 ; —(CH 2 ) 0-4 OC(O)R ∘ ; —OC(O)(CH 2 ) 0-4 SR ∘ ; —(CH 2 ) 0-4 SC(O)R ∘ ; —(CH 2 ) 0-4 C(O)NR 02 ; —C(S)NR ∘ 2 ; —C(S)SR ∘ ; —SC(S)SR ∘ , —(CH 2 ) 0-4 OC(O)NR ∘ 2 ; —C(O)N(OR ∘ )R ∘ ; —C(O)C(O)R ∘ ; —C(O)CH 2 C(O)R ∘ ; —C(NOR ∘ )R ∘ ; —(CH 2 ) 0-4 SSR ∘ ; —(CH 2 ) 0-4 S(O) 2 R ∘ ; —(CH 2 ) 0-4 S(O) 2 OR ∘ ; —(CH 2 ) 0-40 S(O) 2 R ∘ ; —S(O) 2 NR ∘ 2 ; —(CH 2 ) 0-4 S(O)R ∘ ; —N(R ∘ )S(O) 2 NR ∘ 2 ; —N(R ∘ )S(O) 2 R ∘ ; —N(OR ∘ )R ∘ ; —C(NH)NR ∘ 2 ; —P(O) 2 R ∘ ; —P(O)R ∘ 2 ; —OP(O)R ∘ 2 ; —OP(O)(OR ∘ ) 2 ; SiR ∘ 3 ; —(C 1-4 straight or branched alkylene)O—N(R ∘ ) 2 ; or —(C 1-4 straight or branched alkylene)C(O)O—N(R ∘ ) 2 ;

wherein each R ∘ is optionally substituted and is independently hydrogen, C 1-6 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, —CH 2 -(5-6 membered heteroaryl ring), or a 3-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

or two independent occurrences of R ∘ are taken together with their intervening atom(s) form an optionally substituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein each optional monovalent substituent bound to R ∘ is independently halogen, —(CH 2 ) 0-2 R ● , -(haloR ● ), —(CH 2 ) 0-2 OH, —(CH 2 ) 0-2 OR ● , —(CH 2 ) 0-2 CH(OR ● ) 2 , —O(haloR ● ), —CN, —N 3 , —(CH 2 ) 0-2 C(O)R ● , —(CH 2 ) 0-2 C(O)OH, —(CH 2 ) 0-2 C(O)OR ● , —(CH 2 ) 0-2 SR ● , —(CH 2 ) 0-2 SH, —(CH 2 ) 0-2 NH 2 , —(CH 2 ) 0-2 NHR ● , —(CH 2 )0-2NR ● 2 , —NO 2 , —SiR ● 3 , —OSiR ● 3 , —C(O)SR ● , —(C 1-4 straight or branched alkylene)C(O)OR ● , —SSR ● , or -Ph optionally substituted with R ● ;

wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, ═O, or ═S;

wherein each optional divalent substituent on a saturated carbon atom is ═O, ═S, ═NNR*2, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O) 2 R*, ═NR*, ═NOR*, —O(C(R* 2 )) 2-3 O—, or —S(C(R* 2 )) 2-3 S—, or wherein a divalent substituent —O(CR* 2 ) 2-3 O— is bound to vicinal substitutable carbons;

wherein each occurrence of R* is independently selected from hydrogen, optionally substituted C 1-6 aliphatic, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein each occurrence of R* is optionally substituted with halogen, —R ● , -(haloR ● ), —OH, —OR ● , —O(haloR ● ), —CN, —C(O)OH, —C(O)OR ● , —NH 2 , —NHR ● , —NR ● 2 , or —NO 2 ;

wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein each optional substituent on a substitutable nitrogen atom is independently —R † , —NR † 2 ,

—C(O)R † , —C(O)OR † , —C(O)NR † 2 , —C(O)C(O)R † , —C(O)CH 2 C(O)R † , —S(O) 2 R † , —S(O) 2 NR † 2 , —C(S)NR † 2 , —C(NH)NR † 2 , or —N(R † )S(O) 2 R † ;

wherein each R † is independently hydrogen, optionally substituted C 1-6 aliphatic, unsubstituted —OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,

two independent occurrences of R † are taken together with their intervening atom(s) to form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein each optional substituent on R † is independently halogen, —R ● , -(haloR ● ), —OH, —OR ● , —O(haloR ● ), —CN, —C(O)OH, —C(O)OR ● , —NH 2 , —NHR ● , —NR ● , or —NO 2 ,

wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

2. The compound claim 1 , wherein Ring A is an optionally substituted 5-membered heteroaryl ring.

3. The compound or pharmaceutically acceptable salt of claim 1 , wherein Ring A is selected from

4. The compound or pharmaceutically acceptable salt of claim 1 , wherein Ring A is selected from

5. The compound of claim 1 , wherein the compound is of formula II:

or a pharmaceutically acceptable salt thereof, wherein:

each of R 1 and R 2 is independently selected from halogen and C 1-4 aliphatic;

R x is optionally substituted C 1-4 aliphatic; and

each of R a and R a′ is independently selected from hydrogen, halogen and optionally substituted C 1-4 aliphatic.

6. The compound of claim 1 , wherein the compound is of formula III:

or a pharmaceutically acceptable salt thereof, wherein:

each of R 1 and R 2 is independently selected from halogen and C 1-4 aliphatic; and

R x is optionally substituted C 1-4 aliphatic.

7. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.