Aminopyrimidine Derivatives as Cyclin-Dependent Kinase Inhibitors

A compound, wherein the compound is represented by Formula IA or is a pharmaceutically acceptable salt thereof:

• wherein:
• is a single bond or a double bond;
• R1 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8bicyclic alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, an oxo group, cyano, a 3-7 membered heterocyclic group, 6-10 membered aryl, and a 5-10 membered heteroaryl, wherein each of the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8bicyclic alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, 3-7 membered heterocyclic group, 6-10 membered aryl, and 5-10 membered heteroaryl is independently substituted with 0, 1, 2, or 3 R1A;
• each R1A is independently selected from halogen, hydroxyl, an oxo group, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, —C(═O)OR1B, —C(═O)N(R1B)2, —NHC(═O)OR1B, and a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, or 3 R1C;
• each R1B is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl;
• each R1C is independently selected from hydrogen, hydroxyl, halogen, an oxo group, C1-C6 alkyl, and C3-C6 cycloalkyl;
• R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cyclic haloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, C1-C6 haloalkoxy, and a 3-7 membered heterocyclic group;
• X1 and X2 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, and C3-C6 cyclic haloalkyl;
• Q is N or CRQ, wherein RQ is independently selected from hydrogen, halogen, and cyano;
• Z is C;
• W is selected from C(Rw1)2, O, S, N, and NRw2;
• wherein
• RW1 is independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, 5-8 membered bicyclic carbocyclic group, 5-8 membered bicyclic heterocyclic group, and a 3-8 membered heterocyclic group, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with 1, 2, or 3 R1D;
• Rw2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 5-8 membered bicyclic carbocyclic group, 5-8 membered bicyclic heterocyclic group, and a 3-8 membered heterocyclic group, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with 1, 2, or 3 R1D;
• and
• each R1D is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and hydroxyl;
• or
• W and R1 may be taken together with the C atom to which both are attached to form a carbocyclic ring of 5-8 atoms or a heterocyclic ring of 5-8 atoms, wherein the carbocyclic ring and heterocyclic ring is each optionally substituted with 1, 2, 3, or 4 R1E;
• or
• W, Z, R2, and the C atom to which R2 is attached may be taken together to form a carbocyclic ring of 5-8 atoms or a heterocyclic ring of 5-8 atoms, wherein each of the carbocyclic ring and heterocyclic ring is optionally substituted with 1, 2, 3, or 4 R1E;
• each R1E is independently selected from C1-C6 alkyl, hydroxyl, and an oxo group;
• Ring A i or R V
• wherein:
• R3 and R4 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, and C3-C6 cycloalkyl;
• or R3 and R4 may be taken together with the carbon atom to which both are attached to form a 3-7 membered cycloalkyl;
• R5 and R6 am independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, and aryl, wherein the C1-C6 alkyl is optionally substituted with hydroxyl;
• X is O or N—S(O)2—RX, wherein RX is selected from C1-C6 alkyl, C3-C6 cycloalkyl, a 3-7 membered heterocyclic group, aryl, and heteroaryl, and wherein each of the C3-C6 cycloalkyl, 3-7 membered heterocyclic group, aryl, and heteroaryl is optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxyl, and cyano;
• U is O or C(RU)2, wherein RU is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with hydroxyl;
• and
• V is O, C, or C(RV)2, wherein RV is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with hydroxyl;
• with the proviso that one but not both of U and V is O.

A compound, wherein the compound is represented by Formula (IB) or is a pharmaceutically acceptable salt thereof:

• wherein:
• is a single bond or a double bond;
• R1 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8bicyclic alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, an oxo group, cyano, a 3-7 membered heterocyclic group, 6-10 membered aryl, and a 5-10 membered heteroaryl, wherein each of the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8bicyclic alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, 3-7 membered heterocyclic group, 6-10 membered aryl, and 5-10 membered heteroaryl is independently substituted with 0, 1, 2, or 3 R1A;
• each R1A is independently selected from halogen, hydroxyl, an oxo group, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, —C(═O)OR1B, —C(═O)N(R1B)2, —NHC(═O)OR1B, and a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, or 3 R1C;
• each R1B is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl;
• each R1C is independently selected from hydrogen, hydroxyl, halogen, an oxo group, C1-C6 alkyl, and C3-C6 cycloalkyl;
• X1 and X2 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, and C3-C6 cyclic haloalkyl;
• Q is CRQ, N, or NRQ, wherein RQ is selected from hydrogen, halogen, C1-C4 alkyl, and an oxo group;
• Q′ is CRQ′, N, NRQ′, wherein RQ′ is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl;
• T is CRT1 or NRT2, wherein RT1 is halogen or RT2, and RT2 is hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, and hydroxyl;
• Ring A is or;
• wherein:
• R3 and R4 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, and C3-C6 cycloalkyl;
• or R3 and R4 may be taken together with the carbon atom to which both are attached to form a 3-7 membered cycloalkyl;
• R5 and R6 are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and aryl, wherein the C1-C6 alkyl is optionally substituted with hydroxyl;
• X is O or N—S(O)2—RX, wherein RX is selected from C1-C6 alkyl, C3-C6 cycloalkyl, a 3-7 membered heterocyclic group, aryl, and heteroaryl, and wherein each of the C3-C6 cycloalkyl, 3-7 membered heterocyclic group, aryl, and heteroaryl is optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxyl, and cyano;
• U is O or C(RU)2, wherein RU is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with hydroxyl;
• and
• V is O, C, or C(RV)2, wherein RV is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with hydroxyl;
• with the proviso that one but not both of U and V is O.

A compound, wherein the compound is represented by Formula (IC) or is a pharmaceutically acceptable salt thereof:

• wherein:
• is a single bond or a double bond;
• R1 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8bicyclic alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, an oxo group, cyano, a 3-7 membered heterocyclic group, 6-10 membered aryl, and a 5-10 membered heteroaryl, wherein each of the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8bicyclic alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, 3-7 membered heterocyclic group, 6-10 membered aryl, and 5-10 membered heteroaryl is independently substituted with 0, 1, 2, or 3 R1A;
• each R1A is independently selected from halogen, hydroxyl, an oxo group, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, —C(═O)OR1B, —C(═O)N(R1B)2, —NHC(═O)OR1B, and a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, or 3 R1C;
• each R1B is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl;
• each R1C is independently selected from hydrogen, hydroxyl, halogen, an oxo group, C1-C6 alkyl, and C3-C6 cycloalkyl;
• R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cyclic haloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, C1-C6 haloalkoxy, and a 3-7 membered heterocyclic group;
• X1 and X2 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, and C3-C6 cyclic haloalkyl;
• Q is N, O, or CRQ, wherein RQ is selected from hydrogen, halogen, and an oxo group;
• Q′ is CH, CH2, CRQ′, N, or NR″, wherein RQ′ is halogen or R″, and R1A is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, and a 3-8 membered heterocyclic group, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, and hydroxyl;
• Z is C;
• W is CRW1, N, or NRW2;
• wherein
• Rw1 is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, and a 3-8 membered heterocyclic group, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with 1, 2, or 3 R1D,
• RW2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and a 3-8 membered heterocyclic group, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with 1, 2, or 3 R1D, and
• each R1D is independently selected from halogen, C1-C6 alkyl, and hydroxyl;
• or
• W, Z, R2, and the C atom to which R2 is attached may be taken together to form a carbocyclic ring of 5-8 atoms or a heterocyclic ring of 5-8 atoms, wherein each of the carbocyclic ring and heterocyclic ring is optionally substituted with 1, 2, 3, or 4 R1E, and wherein each R1E is independently selected from C1-C6 alkyl, hydroxyl, and an oxo group;
• Ring A is
• wherein:
• R3 and R4 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, and C3-C6 cycloalkyl;
• or R3 and R4 may be taken together with the carbon atom to which both are attached to form a 3-7 membered cycloalkyl;
• R5 and R6 am independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and aryl, wherein the C1-C6 alkyl is optionally substituted with hydroxyl;
• X is O or N—S(O)2—RX, wherein RX is selected from C1-C6 alkyl, C3-C6 cycloalkyl, a 3-7 membered heterocyclic group, aryl, and heteroaryl, and wherein each of the C3-C6 cycloalkyl, 3-7 membered heterocyclic group, aryl, and heteroaryl is optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxyl, and cyano;
• U is O or C(RU)2, wherein RU is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with hydroxyl;
• and
• V is O, C, or C(RV)2, wherein RV is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with hydroxyl;
• with the proviso that one but not both of U and V is O.

A compound, wherein the compound is represented by Formula (ID) or is a pharmaceutically acceptable salt thereof:

• wherein:
• is a single bond or a double bond;
• R1 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8bicyclic alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, an oxo group, cyano, a 3-7 membered heterocyclic group, 6-10 membered aryl, and a 5-10 membered heteroaryl, wherein each of the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 cyclic haloalkyl, C5-C8bicyclic alkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, 3-7 membered heterocyclic group, 6-10 membered aryl, and 5-10 membered heteroaryl is independently substituted with 0, 1, 2, or 3 R1A;
• each R1A is independently selected from halogen, hydroxyl, an oxo group, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, —C(═O)OR1B, —C(═O)N(R1B)2, -NHC(═O)OR1B, and a 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group is optionally substituted with 1, 2, or 3 R1C;
• each R1B is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl;
• each R1C is independently selected from hydrogen, hydroxyl, halogen, an oxo group, C1-C6 alkyl, and C3-C6 cycloalkyl;
• R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C3-C6 cyclic alkoxy, C1-C6 haloalkoxy, and a 3-7 membered heterocyclic group;
• X1 and X2 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, and C3-C6 cyclic haloalkyl;
• Q is N or CRQ, wherein RQ is independently selected from hydrogen, halogen, and cyano;
• D and E together with the carbon atom to which they are both attached form a carbocyclic ring of 5-8 atoms or a heterocyclic ring of 5-8 atoms containing 1 to 2 heteroatoms selected from O, S, and N, wherein any carbon ring may be optionally substituted with halogen, C1-C4 alkyl, or hydroxyl;
• Ring A is
• wherein:
• R3 and R4 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, and C3-C6 cycloalkyl;
• or R3 and R4 may be taken together with the carbon atom to which both are attached to form a 3-7 membered cycloalkyl;
• R5 and R6 am independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and aryl, wherein the C1-C6 alkyl is optionally substituted with hydroxyl;
• X is O or N—S(O)2—RX, wherein RX is selected from C1-C6 alkyl, C3-C6 cycloalkyl, a 3-7 membered heterocyclic group, aryl, and heteroaryl, and wherein each of the C3-C6 cycloalkyl, 3-7 membered heterocyclic group, aryl, and heteroaryl is optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxyl, and cyano;
• U is O or C(RU)2, wherein RU is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with hydroxyl;
• and
• V is O, C, or C(RV)2, wherein RV is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, and C3-C6 cycloalkyl, wherein each of the C1-C6 alkyl and C3-C6 cycloalkyl is optionally substituted with hydroxyl;
• with the proviso that one but not both of U and V is O.