Sik2 modulators and uses thereof

A compound of formula I-a-1 or I-b′:

• or a pharmaceutically acceptable salt thereof, wherein:
• X1 is O or NH;
• d and e are each independently 0 or 1;
• R2A and R2B are each independently selected from OH, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, —N(R4)2, and halogen;
• each R4 is independently selected from hydrogen and C1-4 alkyl;
• z is 0, 1, or 2;
• each R8 is independently selected from hydrogen, halogen, hydroxyl, —CN, C1-4 alkoxy, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic, and C1-4 alkyl;
• or two R8 groups and the carbon atom to which they are attached form oxo, a spiro 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring or a spiro 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said spiro 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring or spiro 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring is substituted with 0, 1 or 2 substituents independently selected from halogen, C1-3 alkyl, C1-3 alkoxy, and C1-3 haloalkyl;
• R5 is selected from hydrogen, —CN, OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 hydroxyalkyl, halogen, —OR, —SR, —NR2, —SO2R, —SO2NR2, —S(O)R, —S(O)NR2, —C(O)R, —CO2R, —C(O)NR2, —OC(O)R, and —OC(O)NR2, wherein C1-4 alkyl, C1-4 alkoxy or C1-4 hydroxyalkyl is optionally substituted with —CN —OH, or 1, 2, or 3 halogens, or
• R5 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring;
• or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is substituted with 0, 1, 2, or 3 RS substituents;
• each RS is independently OH, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3hydroxyalkyl, —N(R4)2, and halogen;
• a is 0, 1, 2, or 3;
• each R1A is independently halogen, —CN, oxo, C1-3 alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, —OR, —SR, —NR2, —SO2R, —SO2NR2, —S(O)R, —S(O)NR2, —C(O)R, —CO2R, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)CO2R, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)C(NR)R, —N(R)C(NR)NR2, —N(R)NR2, —N(R)SO2NR2, —N(R)SO2R, —N═S(O)R2, —S(NR)(O)R, —N(R)S(O)R, —N(R)CN, —P(O)(OR)2, —P(O)R2, or
• R1A is C0-3alkylene-Cyc and Cyc is phenyl;
• a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring;
• a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 4-12 membered saturated or partially unsaturated fused, bridged, or spiro carbocyclic ring system, and a fused, bridged or spiro 4-12 membered saturated or partially unsaturated heterocyclic ring system having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Cyc is substituted with 0, 1, 2, or 3 substituents independently selected from C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, halogen, —CN, —N(R4)2;
• and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or
• R1A and R2A combine to form a linker having a structure of —OC2-6alkylene-NH— or —C2-6alkylene-NH—, wherein the N atom forms a direct bond with the pyridine ring;
• Ring D is a carbon linked cyclic group selected from:
• a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring;
• a 5-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• and
• a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring E is a cyclic group selected from:
• a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• phenyl;
• an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic;
• and
• a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• y is 0, 1, 2, 3, or 4;
• Z is a bond, #C(R6)2—[C(R7)2]0-2—, #C(R6)2—[C(R7)2]0-2—O—, #O—[C(R7)2]0-2—, or #NR6—[C(R9)2]0-2—, wherein # is a direct bond to the pyridine ring;
• Ring C is a cyclic group selected from:
• phenyl;
• a 3-8 membered saturated or partially unsaturated carbocyclic ring;
• a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 5-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• and
• a 5-11 membered saturated or partially unsaturated bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or
• Ring C is absent and
• (i) a is 0 and R2A and Z together form —OC2-6alkylen-NH—, wherein O is the Z point of attachment to the pyridine ring;
• or
• (ii) Z is a bond to R1A, and a is 1;
• b is 0 or 1;
• R3B is halogen, oxo, C1-3 alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, —OR, —SR, —NR2, —SO2R, —SO2NR2, —S(O)R, —S(O)NR2, —C(O)R, —CO2R, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)CO2R, or
• R3B is a 3-7 membered saturated or partially unsaturated monocyclic or bridged carbocyclic ring;
• a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is substituted with 0, 1, or 2 RS substituents;
• c is 0 or 1;
• R3A is a C0-6alkylene-cyclic group;
• wherein the cyclic group is selected from:
• a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• phenyl;
• an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 7-12 membered saturated or partially unsaturated bicyclic or tricyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic;
• and
• a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• wherein R3A is substituted with 0,1, 2, 3, or 4 RA;
• each RA is independently selected from halogen;
• C1-3 alkyl;
• C2-6 alkenyl;
• C2-4 alkynyl;
• C1-3 alkoxy;
• C1-3 haloalkyl;
• C1-3 hydroxyalkyl;
• —CN;
• —OR;
• —SR;
• —SF6;
• —C0-3alkylene-NR2;
• —SO2R;
• —SO2NR2;
• —S(O)R;
• —S(O)NR2;
• —C(O)R;
• —CO2R;
• —C(O)NR2;
• —C(O)N(R)OR;
• —OC(O)R;
• —OC(O)NR2;
• —N(R)CO2R;
• a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, —CN, —NR2, and —OR;
• a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a fused, bridged, or spiro 4-12 membered saturated or partially unsaturated carbocyclic ring, and a fused, bridged, or spiro 4-12 membered saturated or partially unsaturated heterocyclic ring system having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said carbocyclic ring, heterocyclic ring, or heteroaryl ring is substituted with 0, 1, 2 or 3 substituents independently selected from C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, halogen, —CN, —OR, and —NR2;
• or
• two RA on the same carbon atom together form oxo or a spiro cyclic group selected from:
• 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring;
• and
• 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• wherein the cyclic group formed by two RA on the same carbon atom is substituted with 0,1, 2, or 3 groups independently selected from a C1-6alkyl, C1-6haloalkyl, C1-6alkylene-CN, C1-6alkylene-NR2, C1-6alkylene-OR;
• halogen;
• —CN;
• —NO2;
• —OR;
• SR;
• —NR2;
• —S(O)2R;
• —S(O)2NR2;
• —S(O)R;
• —S(O)NR2;
• —C(O)R;
• —C(O)OR;
• —C(O)NR2;
• —C(O)N(R)OR;
• —OC(O)R;
• —OC(O)NR2;
• —N(R)C(O)OR;
• —N(R)C(O)R;
• —N(R)C(O)NR2;
• —N(R)C(NR)NR2;
• —N(R)S(O)2NR2;
• and —N(R)S(O)2R;
• or
• two RA on adjacent atoms form a fused cyclic group selected from:
• 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring;
• a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• phenyl;
• and
• a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• wherein the fused cyclic group formed by two RA on adjacent atoms is substituted with 0,1, 2, or 3 groups independently selected from a C1-6 alkyl, C1-6haloalkyl, C1-6alkylene-CN, C1-6 alkylene-NR2, C1-6alkylene-OR;
• halogen;
• —CN;
• —NO2;
• —OR;
• —SR;
• —NR2;
• —S(O)2R;
• —S(O)2NR2;
• —S(O)R;
• —S(O)NR2;
• —C(O)R;
• —C(O)OR;
• —C(O)NR2;
• —C(O)N(R)OR;
• —OC(O)R;
• —OC(O)NR2;
• —N(R)C(O)OR;
• —N(R)C(O)R;
• —N(R)C(O)NR2;
• —N(R)C(NR)NR2;
• —N(R)S(O)2NR2;
• and —N(R)S(O)2R;
• each R6 is independently selected from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl, or two R6 combine to form oxo;
• each R7 is independently selected from hydrogen, halogen, and C1-4 alkyl, or two R7 combine to form oxo;
• each R9 is independently selected from hydrogen and C1-4 alkyl;
• each R is independently hydrogen, C1-3 alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, —C(O)N(CH3)2, —C(O)2CH3, —C(O)2C(CH3)3, —C(O)2CH(CH3)2, —S(O)2CH3, and C0-6 alkylene-cyclic group, wherein the cyclic group is selected from:
• phenyl;
• a 3-7 membered saturated or partially unsaturated carbocyclic ring;
• a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• and 6-11 membered saturated or partially unsaturated bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• wherein the cyclic group is substituted with 0, 1, 2, or 3 RS;
• or
• two R on the same atom together with the atom on which they are attached form a cyclic group selected from:
• a 4-7 membered saturated or partially unsaturated carbocycyl;
• a 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• and
• a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,
• and the cyclic group is substituted with 0, 1, 2, or 3 RS.