MYST family histone acetyltransferase inhibitors

A compound of formula I′:

• or a pharmaceutically acceptable salt thereof, wherein:
• Z is selected from
• each of R1 and R2 is independently selected from halogen and C1-4 aliphatic;
• R3 is selected from hydrogen, halogen, —CN, —NR2, and optionally substituted C1-4 aliphatic;
• each R is independently selected from hydrogen, optionally substituted C1-4 aliphatic, and —C(O)O(C1-4 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 Ra is selected from halogen and optionally substituted C1-4 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;
• —(CH2)0-4R∘;
• —(CH2)0-4OR∘;
• —O(CH2)0-4R∘, —O—(CH2)0-4C(O)OR∘;
• —(CH2)0-4CH(OR∘)2;
• —(CH2)0-4SR∘;
• —(CH2)0-4Ph, optionally substituted with R∘;
• —(CH2)0-4O(CH2)0-1Ph optionally substituted with R∘;
• —CH═CHPh optionally substituted with R∘;
• —(CH2)0-4O(CH2)0-1-pyridyl optionally substituted with R∘;
• —NO2;
• —CN;
• —N3;
• —(CH2)0-4N(R∘)2;
• —(CH2)0-4N(R∘)C(O)R∘;
• —N(R∘)C(S)R∘;
• —(CH2)0-4N(R∘)C(O)NR∘2;
• —N(R∘)C(S)NR∘2;
• —(CH2)0-4N(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∘;
• —(CH2)0-4C(O)R∘;
• —C(S)R∘;
• —(CH2)0-4C(O)OR∘;
• —(CH2)0-4C(O)SR∘;
• —(CH2)0-4C(O)OSiR∘3;
• —(CH2)0-4OC(O)R∘;
• —OC(O)(CH2)0-4SR∘;
• —(CH2)0-4SC(O)R∘;
• —(CH2)0-4C(O)NR02;
• —C(S)NR∘2;
• —C(S)SR∘;
• —SC(S)SR∘, —(CH2)0-4OC(O)NR∘2;
• —C(O)N(OR∘)R∘;
• —C(O)C(O)R∘;
• —C(O)CH2C(O)R∘;
• —C(NOR∘)R∘;
• —(CH2)0-4SSR∘;
• —(CH2)0-4S(O)2R∘;
• —(CH2)0-4S(O)2OR∘;
• —(CH2)0-40S(O)2R∘;
• —S(O)2NR∘2;
• —(CH2)0-4S(O)R∘;
• —N(R∘)S(O)2NR∘2;
• —N(R∘)S(O)2R∘;
• —N(OR∘)R∘;
• —C(NH)NR∘2;
• —P(O)2R∘;
• —P(O)R∘2;
• —OP(O)R∘2;
• —OP(O)(OR∘)2;
• SiR∘3;
• —(C1-4 straight or branched alkylene)O—N(R∘)2;
• or —(C1-4 straight or branched alkylene)C(O)O—N(R∘)2;
• wherein each R∘ is optionally substituted and is independently hydrogen, C1-6 aliphatic, —CH2Ph, —O(CH2)0-1Ph, —CH2-(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, —(CH2)0-2R●, -(haloR●), —(CH2)0-2OH, —(CH2)0-2OR●, —(CH2)0-2CH(OR●)2, —O(haloR●), —CN, —N3, —(CH2)0-2C(O)R●, —(CH2)0-2C(O)OH, —(CH2)0-2C(O)OR●, —(CH2)0-2SR●, —(CH2)0-2SH, —(CH2)0-2NH2, —(CH2)0-2NHR●, —(CH2)0-2NR●2, —NO2, —SiR●3, —OSiR●3, —C(O)SR●, —(C1-4 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 C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, 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)2R*, ═NR*, ═NOR*, —O(C(R*2))2-3O—, or —S(C(R*2))2-3S—, or wherein a divalent substituent —O(CR*2)2-3O— is bound to vicinal substitutable carbons;
• wherein each occurrence of R* is independently selected from hydrogen, optionally substituted C1-6 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●, —NH2, —NHR●, —NR●2, or —NO2;
• wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, 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)CH2C(O)R†, —S(O)2R†, —S(O)2NR†2, —C(S)NR†2, —C(NH)NR†2, or —N(R†)S(O)2R†;
• wherein each R† is independently hydrogen, optionally substituted C1-6 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●, —NH2, —NHR●, —NR●, or —NO2,
• wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.