Compounds and methods for CDK8 modulation and indications therefor

A compound of Formula II(b), II(c), or II(d):

• or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog thereof, wherein:
• R3 is —B-L-T;
• R4 is one of (a1), (a2), (b1), (b2), (c) or (d):
• (a1) saturated heterocycloalkyl substituted with 0-3 R7 groups, wherein the saturated heterocycloalkyl is further optionally substituted with one R8 group;
• (a2) heterocycloalkenyl substituted with 0-3 R7 groups, wherein the heterocycloalkenyl is further optionally substituted with one R8 group;
• (b1) saturated C3-C6 cycloalkyl substituted with 0-3 R7 groups, wherein the saturated C3-C6 cycloalkyl is further optionally substituted with one R8 group;
• (b2) C5-C6 cycloalkenyl substituted with 0-3 R7 groups, wherein the C5-C6 cycloalkenyl is further optionally substituted with one R8 group;
• (c) aryl or heteroaryl substituted with one R10 group, wherein the aryl or heteroaryl is further optionally substituted with one R1 group;
• or
• (d) —C2-C3 alkynylene substituted with R12;
• R6 is H, -C1-C6 alkyl, -C1-C6 haloalkyl, —C1-C6 alkylene-CN, —C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, or phenyl;
• each R7 is independently —C1-C6 alkyl, halogen, CN, hydroxyl, —C1-C6 haloalkyl, —C1-C6 cyanoalkyl, or —C1-C6 hydroxyalkyl optionally substituted with heteroaryl, provided that halogen and CN are not bonded to a heteroatom;
• R8 is CN, phenyl, 5-6 membered heterocycloalkyl or heteroaryl, —(CH2)0-2—C(O)—N(H)—R6, —C(O)R6, —(CH2)0-2C(O)OR6, —(CH2)0-2S(O)2R6;
• or
• or R7 and R8, when both are attached to the same carbon atom of the saturated heterocycloalkyl, join to form a heterocycloalkyl, oxoheterocycloalkyl, or dioxoheterocycloalkyl, wherein the heterocycloalkyl, oxoheterocycloalkyl, or dioxoheterocycloalkyl is optionally substituted with 1-2 —C1-C6 alkyl groups, and wherein the oxoheterocycloalkyl is optionally fused to a phenyl or 5-6 membered heteroaryl;
• B is a bond, arylene, heteroarylene, or heterocycloalkylene, wherein the arylene, heteroarylene, or heterocycloalkylene are each substituted with 0-3 G1 groups and 0-1 G2 groups;
• L is a bond, —O—, —C(O)—, —N(H)—, —N(H)S(O)2—, —S(O)2—N(H)—, —S(O)2—, —S(O)2—C1-C4 alkylene, —N(H)C(O)—C1-C4 alkylene, —N(H)C(O)O—C1-C4 alkylene, C1-C4 alkylene-N(H)—C(O)—, —N(H)—(CH2)0-4—, —C1-C6 alkylene, —O—C1-C6 alkylene, —O—C1-C6 haloalkylene, —O—C1-C6 alkylene-O—, or —O—C1-C6 hydroxyalkylene;
• T is heteroaryl, aryl, cycloalkyl, or heterocycloalkyl, wherein the heteroaryl, cycloalkyl, or heterocycloalkyl are each substituted with 0-3 G3 groups and 0-1 G4 groups;
• or B-L is ethynylene and T is heteroaryl substituted with 0-3 G3 or G4 groups;
• each G1 is independently halogen, —C1-C4 alkyl, alkoxy, —C1-C4haloalkyl, hydroxyl, or —C1-C4 hydroxyalkyl;
• G2 is —C0-C4 alkylene-S(O)2—C1-C4alkyl, —C0-C4 alkylene-C(O)—NH2, or —N(H)C(O)—C1-C4 alkyl;
• each G3 is independently halogen, —C1-C6alkyl, —C1-C6 alkoxy, —C1-C6 haloalkyl, hydroxyl, C1-C6 hydroxyalkyl, or —C0-C6 alkylene-CN;
• G4, when attached to a carbon atom, is halogen, —C1-C6alkyl, —C1-C6 alkoxy, —C1-C6 haloalkyl, hydroxyl, —C1-C6 hydroxyalkyl, —C0-C6 alkylene-CN, —C0-C4 alkylene-S(O)2—C1-C6 alkyl, —C0-C4 alkylene-N(H)—S(O)2—C1-C4 alkyl, —C0-C4 alkylene-C(O)—NH2, —C0-C4 alkylene-C(O)—N(H)—C1-C4 alkyl, —N(H)—C(O)—C1-C4 alkyl, —C0-C4 alkylene-C(O)—N(C1-C4 alkyl)2, —C1-C6 alkylene-N—(C1-C4 alkyl)2, —C1-C6 alkylene-N(H)—(C1-C4 alkyl), —C1-C6 alkylene-NH2, —C0-C4 alkylene-heterocycloalkyl, —C0-C4 alkylene-C(O)O—C1-C6 alkyl, or —C0-C6 alkylene-cycloalkyl optionally substituted with CN, OH, —C1-C4alkyl, —C(O)O—C1-C4 alkyl, —C(O)OH, or halogen;
• or G4, when attached to a nitrogen atom, is —C1-C6alkyl, —C1-C6alkylene-C1-C6 alkoxy, —C1-C6 haloalkyl, —C1-C6 hydroxyalkyl, —C1-C6 alkylene-CN, —C1-C4 alkylene-S(O)2—C1-C6 alkyl, —C1-C3 alkylene-N(H)—S(O)2—C1-C4 alkyl, —C1-C4 alkylene-C(O)—NH2, —C1-C4 alkylene-C(O)—N(H)—C1-C4 alkyl, —C1-C4 alkylene-C(O)—N(C1-C4 alkyl)2, —C1-C6 alkylene-N—(C1-C4 alkyl)2, —C1-C6 alkylene-N(H)—(C1-C4 alkyl), —C1-C6 alkylene-NH2, —C0-C4 alkylene-heterocycloalkyl, —C0-C4 alkylene-C(O)O—C1-C6 alkyl, —C0-C4 alkylene-C(O)OH, or —C1-C6 alkylene-cycloalkyl optionally substituted with CN, OH, C1-C4 alkyl, —C(O)O—C1-C4 alkyl, —C(O)OH, or halogen;
• R10 is —NHS(O)2—C1-C5 alkyl, —S(O)2—C1-C5 alkyl, —S(O)2-5-6 membered heterocycloalkyl, —S(O)2—N(H) C1-C5alkyl, —(CH2)0-1—C(O)NH2, —(CH2)0-1—O-phenyl, —(CH2)0-1—O-(5-6 membered)heteroaryl, —(CH2)0-1—NHC(O)O—C1-C2-alkylene-phenyl, —(CH2)0-1—NHC(O)-5-6 membered heteroaryl, —(CH2)0-1—NHC(O)-phenyl, —C1-C5 alkylene-(5-6 membered)heterocycloalkyl, —C2-C4alkenyl, or CN;
• R11 is H, C3-C7 cycloalkyl, C5-C6 cycloalkenyl or 5-6 membered heterocycloalkyl;
• R12 is 3-6 membered cycloalkylene-R13a, —C(O)NHR6, —Z1—(CH2)1-2—Z2, —Z1—(C1-C2)haloalkylene-Z2, or —Z1—(C1-C2)hydroxyalkylene-Z2;
• each R13a is halogen, hydroxyl, —C1-C3 alkyl, —C1-C3 hydroxyalkyl, —C1-C3 haloalkyl or CN;
• Z1 is absent, —C1-C3 alkylene, or —C1-C3 haloalkylene;
• and
• Z2 is —C1-C3 alkoxyl optionally substituted with hydroxyl, —N(H)—S(O)2—C1-C3 alkyl, —N(H)—C(O)—C1-C3 alkyl, —N(H)—C(O)—C1-C3 haloalkyl, —C(O)—N(H)—C1-C3 alkyl, —C(O)—N(H)—C1-C3 haloalkyl or phenyl.