Compounds and methods for EP300 or CBP modulation and indications therefor

A compound of Formula I:

• or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof, wherein:
• A1 is R6, A2 is R7, A3 is -L-R1, A4 is R5, X1 is CH, X2 is C, and X3 is N;
• or
• A1 is R6, A2 is absent, A3 is -L1-R1, A4 is R5, X1 is CH, X2 is N, and X3 is CH;
• or
• A1 is R7, A2 is R6, A3 is -L-R1, A4 is R5, X1 is N, X2 is C, and X3 is CH;
• or
• A1 is R7, A2 is R6, A3 is R5, A4 is -L-R1, X1 is N, X2 is C, and X3 is CH;
• L is a bond, —CH2—CH2—, —(CH2)1-2—CH═CH—(CH2)0-1—, —CR2R3—, or —C(O)—;
• provided that when A1 is R7, A2 is R6, A3 is A4 is R5, X1 is N, X2 is C, and X3 is C, then L is a bond;
• L2 is a bond or —C(R13)2—;
• R1 is phenyl, 5-9 membered heteroaryl, C3-C6cycloalkyl, C5-C6cycloalkenyl, 4-9 membered heterocycloalkyl, or 5-6 membered heterocycloalkenyl, wherein R1 is optionally substituted with 1 G1 group and 1-3 G2 groups;
• R2 is H, C1-C6alkyl, or OH;
• R3 is H, C1-C6alkyl, C1-C6cyanoalkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 5-6 membered heteroaryl;
• R4 is H, OH, C1-C6alkyl, or C1-C6haloalkyl;
• R5, when attached to carbon, is 4-6 membered cycloalkyl, 5-6 membered cycloalkenyl, phenyl, 5-9 membered heteroaryl, 5-6-membered heterocycloalkyl,
• wherein the 4-6 membered cycloalkyl, 5-6 membered cycloalkenyl, phenyl, or 5-9-membered heteroaryl are each optionally substituted with one -L2-J1 group and 0-4 J2 groups, provided that J1 is directly bonded to a carbon atom;
• or R5, when attached to nitrogen, is 4-6 membered cycloalkyl, 5-6 membered cycloalkenyl, phenyl, or 5-9 membered heteroaryl, wherein the 4-6 membered cycloalkyl, 5-6 membered cycloalkenyl, phenyl, or 5-9-membered heteroaryl are each optionally substituted with 1-L2-J1 group and 1-4 J2 groups, provided that J1 is directly bonded to a carbon atom;
• R6 is a five membered heteroaryl containing at least one nitrogen atom, wherein the 5-membered heteroaryl is optionally substituted with 0-2 R8 groups;
• R7 is H, halo, or C1-C6alkyl;
• R8 is C1-C6alkyl or C1-C3alkoxyC1-C3alkylene;
• each R10 is independently H, C1-C6alkyl, C1-C6haloalkyl, or cyclopropyl;
• each R11 is independently H, C1-C6alkyl, or C1-C6haloalkyl, or two R11 groups, together with the carbon atom to which both R11 groups are attached, join to form a cyclopropyl group;
• each R12 is independently H, C1-C6alkyl, C1-C6hydroxyalkyl, or C1-C6haloalkyl;
• each R13 is independently H, CH3, or F, or each R13 join, together with the carbon atom to which they are both attached, to form a C3-C6 cycloalkyl group;
• R14 is H, C1-C6alkyl, or C1-C3alkoxyC1-C3alkylene;
• G1 is CN, C2-C6 alkenyl, C1-C6cyanoalkyl, C1-C6cyanoalkylethynylene, C2-C6alkenylC1-C6alkylene, C1-C6alkylsulfonyl, C1-C6alkylsulfonylC1-C6alkylene, —N(R10)2, di-C1-C6alkylaminoC1-C6alkylene, C1-C6alkylaminoC1-C6alkylene, aminoC1-C6alkylene, —C(O)—C1-C6alkyl, —C(O)—C1-C6hydroxyalkyl, —C(O)—C1-C6haloalkyl, —C(O)OR12, —C1-C3alkylene-C(O)OR12, —C(O)—N(H)—C3-C6cycloalkyl, C3-C6cycloalkyl, C3-C6cycloalkylC1-C6alkylene, C3-C6cycloalkylC2-C6alkynylene, 4-6 membered heterocycloalkyl, —C(O)—N(R10)2, —C1-C6alkylene-C(O)—N(R10)2 or phenyl-C1-C6alkoxy, provided that when G1 is attached to a nitrogen atom, G1 is not CN;
• each G2 is independently CN, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, OH, oxo, C1-C6hydroxyalkyl, provided that when G2 is attached to a nitrogen atom, G2 is not CN, halo, C1-C6alkoxy, C1-C6haloalkoxy, or OH;
• J1 is —C(R11)2—C(O)OH, —C(O)OH, —C(O)O—C1-C6alkyl, —CH2—C(O)O—C1-C6alkyl, —C(O)N(R10)2, —C(O)N(H)—CN, —C(O)N(H)OH, —C(O)N(H)—SO2—C1-C6alkyl, —N(H)—SO2—C1-C6alkyl, C1-C6alkylsulfonyl, tetrazolyl, or)-S(O)2—N(R10)2;
• and
• each J2 is independently 4-6 membered heterocycloalkyl, —O-(4-6 membered heterocycloalkyl), —O—C3-C6cycloalkyl, C3-C6cycloalkylalkoxy, phenyl-C1-C6alkoxy, C1-C6alkyl, C1-C6alkoxy, halo, C1-C6haloalkyl, C1-C6haloalkoxy, OH, C1-C6hydroxyalkyl, CN, C1-C6cyanoalkyl, C2-C6alkynyl, C3-C6cycloalkylethynylene, C3-C6cycloalkyl, 4-6 membered heterocycloalkyl, NO2, or —N(R10)2, provided that when J2 is attached to nitrogen, J2 is not —O-(4-6 membered heterocycloalkyl), —O—C3-C6cycloalkyl, C3-C6cycloalkylalkoxy, phenyl-C1-C6alkoxy, C1-C6alkoxy, halo, C1-C6haloalkoxy, OH, CN, C2-C6alkynyl, C3-C6cycloalkylethynylene, or —N(R10)2.