COMPOUNDS AND METHODS OF TREATING CANCERS

BACKGROUND OF THE INVENTION

This disclosure relates to heterobifunctional compounds (e.g., bi-functional small molecule compounds), compositions comprising one or more of the heterobifunctional compounds, and to methods of use of the heterobifunctional compounds for the treatment of certain diseases in a subject in need thereof. The disclosure also relates to methods for identifying such heterobifunctional compounds.

SUMMARY OF THE INVENTION

According to one aspect of the present disclosure, a heterobifunctional compound disclosed herein comprises a Janus kinase (JAK) ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof.

In one embodiment JAK ligand is capable of binding to a JAK protein comprising JAK1, JAK2, JAK3, and Tyrosine Kinase 2 (TYK2), a JAK mutant, JAK deletion, or a JAK fusion protein.

In one embodiment, the JAK ligand is a JAK inhibitor or a portion of JAK inhibitor.

In another embodiment, the JAK ligand is selected from the group consisting of BSK805 (NVP-BSK805), 1-amino-[1,2,4]triazolo[1,5-a]pyridines (Cmpd 12), TG101209, CEP-33799, Ruxolitinib, Tofacitinib (CP-690550), Baricitinib, Oclacitinib, Cerdulatinib (PRT-062070), Decernotinib (VX509), Delgocitinib (JTE-052), Fedratinib, Filgotinib (GLP0634), Gandotinib (LY2784544), Ilginatinib (NS-018), Itacitinib (INCB03911), Lestauritinib, Momelotinib (CYT387), Pacritinib (SB1578), Peficitinib, Solcitinib (GSK2586184, GLG0778), Upadacitinib (ABT-494), AT9283, AZ-3, AZ960, AZD1480, BMS-986165, BMS-911543, BVB808 (NVP-BVB808), BBT594 (NVP-BBT594), CHZ868, FM381, PF-04965842, PF-06263276, PF-06651600, PF-06700841, SAR-20347, NDI-031301, NDI-31232, NVP-P830, SHR-0302, VR588, XL019, R333 and R348, 3-amido pyrrolopyrazine (Cmpd 3q), pyridone containing tetracycle (Cmpd 6), triazolo-pyrrolopyridines (Cmpd 7), pyrazolopyrimidines (Cmpd 7j), imidazolopyridines (Cmpd 19), 1-methyl-1H-imidazole derivatives (Cmpd 19a), C-2 methyl imidazopyrrolopyridines (Cmpd 20), pyrazolopyridinone (Cmpd 20a), 9H-carbazole-1-carboxamides (Cmpd 21), thianopyridines (Cmpd 23), pyrazole-4-carboxamide (Cmpd 28), imidazopyridine (Cmpd 30), hydroxyethyl imidazo-pyrrolopyridines (Cmpd 31), pyrrolopyridazines (Cmpd 35), 6-oxopyridopyrimidines (Compound 36), 2-aminopyrazolo[1,5-a]pyrimidines (Cmpd 45), cyclopropyl amides (Cmpd 46), imidazo-pyrrolopyridines (Cmpd 49), 1-amino-5H-pyrido[4,3-b]indol-4-carboxamides (Cmpd 65), Cmpd 3, Cmpd 13a, Cmpd 45a, and analogs thereof.

In another embodiment, the degradation tag binds to an ubiquitin ligase or is a hydrophobic group or a tag that leads to misfolding of the JAK proteins.

In another embodiment, the ubiquitin ligase is an E3 ligase.

In another embodiment, the E3 ligase is selected from the group consisting of a cereblon E3 ligase, a VHL E3 ligase, an IAP ligase, a MDM2 ligase, a TRIM24 ligase, a TRIM21 ligase, a KEAP1 ligase, DCAF16 ligase, RNF4 ligase, RNF114 ligase, and AhR ligase.

In another embodiment, the degradation tag is selected from the group consisting of pomalidomide, thalidomide, lenalidomide, VHL-1, adamantane, 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane, nutlin-3a, RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, CPD36, GDC-0152, CRBN-1, CRBN-2, CRBN-3, CRBN-4, CRBN-5, CRBN-6, CRBN-7, CRBN-8, CRBN-9, CRBN-10, CRBN-11, and analogs thereof.

In another embodiment, the JAK ligand is conjugated to the degradation tag via a linker moiety.

In another embodiment, the JAK ligand comprises a moiety of FORMULA 1:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

A and D are independently selected from CR⁴and N, wherein

R⁴is selected from hydrogen, halogen, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl;

B, C and G are independently selected from C and N; with the proviso that at most only one of B, C and G is N;

E and are independently selected from null, CR⁵and N, wherein

R⁵is selected from hydrogen, halogen, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl;

X and Y are independently selected from null, or a bivalent moiety selected from null, CR⁶R⁷, CO, CO₂, CONR⁶, NR⁶, NR⁶CO, NR⁶CO₂, NR⁶C(O)NR⁷, NR⁶SO, NR⁶SO₂, NR⁶SO₂NR⁷, O, OC(O), OCO₂, OCONR⁶, S, SO, SO₂, and SO₂NR⁶, wherein

R⁶and R⁷are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxy, optionally substituted C₁-C₈alkylamino, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R⁶and R⁷together with the atom or atoms to which they are connected form a 3-20 membered carbocyclyl ring or 4-20 membered heterocyclyl ring;

V and W are independently selected from null, carbocyclyl, heterocyclyl, aryl, and heteroaryl, which are optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, NR⁸R⁹, OCOR⁸, OCO₂R⁸, OCON(R⁸)R⁹, COR⁸, CO₂R⁸, CON(R⁸)R⁹, SOR⁸, SO₂R⁸, SO₂N(R⁸)R⁹, NR¹⁰CO₂R⁸, NR¹⁰COR⁸, NR¹⁰C(O)N(R⁸)R⁹, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, NR¹⁰SO₂N(R⁸)R⁹, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 4-10 membered heterocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸, R⁹, and R¹⁰are independently selected from hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxy, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclylC₁-C₈alkyl, optionally substituted 4-10 membered heterocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;

R¹is connected to the “linker” moiety of the heterobifunctional compound, and is selected from null, R′—R″, R′OR″, R′SR″, R′N(R¹¹)R″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R¹¹)R″, R′C(O)R″, R′C(O)OR″, R′CON(R¹¹)R″, R′S(O)R″, R′S(O)₂R″, R′SO₂N(R¹¹)R″, R′NR¹²C(O)OR″, R′NR¹²C(O)R″, R′NR¹²C(O)N(R¹¹)R″, R′NR¹²S(O)R″, R′NR¹²S(O)₂R″, and R′NR¹²S(O)₂NR¹¹R″, wherein

R′ and R″ are independently selected from null, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃fused carbocyclyl, optionally substituted C₄-C₁₃fused heterocyclyl, optionally substituted C₃-C₁₃bridged carbocyclyl, optionally substituted C₄-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro carbocyclyl, optionally substituted C₄-C₁₃spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R¹¹and R¹²are independently selected from optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

R′ and R″, R¹¹and R¹², R′ and R¹¹, R′ and R¹², R″ and R¹¹, R″ and R¹², together with the atom to which they are connected, form a 3-20 membered carbocyclyl or 4-20 membered heterocyclyl ring;

R²is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkenyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R³, at each occurrence, is selected from hydrogen, halogen, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl; and

n is selected from 1 or 2.

In one refinement, V is Ar².

In one refinement, the JAK ligand comprises a moiety of FORMULA 1A:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

A, B, C, D, E, F, G, X, Y, W, R¹, R², R³, and n are the same as defined in FORMULA 1; and

Ar²is selected from null, aryl and heteroaryl (preferably Ar²is selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl), each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, N(R⁸)R⁹, OCOR⁸, OCO₂R⁸, OCON(R⁸)R⁹, COR⁸, CO₂R⁸, CON(R⁸)R⁹, SOR⁸, SO₂R⁸, SO₂N(R⁸)R⁹, NR¹⁰CO₂R⁸, NR¹⁰COR⁸, NR¹⁰C(O)N(R⁸)R⁹, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, NR¹⁰SO₂N(R⁸)R⁹, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 4-10 membered heterocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-20 membered heterocyclyl ring.

In another refinement, V is Ar²; and W is Ar¹. The JAK ligand comprises a moiety of FORMULA 1B:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

A, B, C, D, E, F, G, X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1; and

Ar¹and Ar²are independently selected from null, aryl, and heteroaryl (preferably selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl), each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, N(R⁸)R⁹, OCOR⁸, OCO₂R⁸, OCON(R⁸)R⁹, COR⁸, CO₂R⁸, CON(R⁸)R⁹, SOR⁸, SO₂R⁸, SO₂N(R⁸)R⁹, NR¹⁰CO₂R⁸, NR¹⁰COR⁸, NR¹⁰C(O)N(R⁸)R⁹, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, NR¹⁰SO₂N(R⁸)R⁹, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 4-10 membered heterocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-20 membered heterocyclyl ring.

In another refinement, A is N.

In another refinement, the JAK ligand comprises a moiety of FORMULA 1C:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹; and

B, C, D, E, F, G, V, W, X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1.

In another refinement, A is N; and V is Ar².

In another refinement, the JAK ligand comprises a moiety of FORMULA 1D:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

B, C, D, E, F, G, W, X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1; and

Ar²is the same as defined in FORMULA 1A.

In another refinement, A is N; V is Ar²; and W is Ar¹.

In another refinement, the JAK ligand comprises a moiety of FORMULA 1E:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

B, C, D, E, F, G, X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1, and

Ar¹and Ar²are the same as defined in FORMULA 1B.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 1F, 1G, 1H, or 1I:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

V, W, X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1; and

R¹³and R¹⁴are selected from hydrogen, halogen, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 1J, 1K, 1L, or 1M:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

W, X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1;

Ar²is the same as defined in FORMULA 1A; and

R¹³and R¹⁴are the same as defined in FORMULAE 1F, 1G, 1H or 1I.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 1N, 1O, 1P, and 1Q:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1;

Ar¹and Ar²are the same as defined in FORMULA 1B; and

R¹³and R¹⁴are the same as defined in FORMULA 1F, 1G, 1H or 1I.

In another refinement, X is selected from null, O, and NR⁶, wherein

R⁶is selected from hydrogen, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl.

In another refinement, X is selected from null and NH.

In another refinement, Y is selected from null, CR^6′R⁷, CO, CO₂, O, SO, SO₂, and NR^6′, wherein

R^6′ and R⁷are independently selected from hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl.

In another refinement, Y is selected from null, CH₂, CO, and SO₂.

In another refinement, Ar¹and Ar²are independently selected from null, aryl, and heteroaryl (preferably selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl), each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, N(R⁸)R⁹, COR⁸, CO₂R⁸, CON(R⁸)R⁹, SOR⁸, SO₂R⁸, SO₂N(R⁸)R⁹, NR¹⁰COR⁸, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, optionally substituted C₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl, wherein

R⁸, R⁹, and R¹⁰are independently selected from hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl, or

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-10 membered heterocyclyl ring.

In another refinement, Ar¹and Ar²are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, NR⁸R⁹, NR¹⁰COR⁸, optionally substituted C₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-10 membered heterocyclyl ring.

In another refinement, R¹is selected from null, O, NH, CO, CONH, optionally substituted C₁-C₈alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

In another refinement, R¹is selected from null, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.

In another refinement, R¹is selected from null and optionally substituted 4-10 membered heterocyclyl, which contains at least one of O or N.

In another refinement, R¹is selected from null, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted azetidinyl, and optionally substituted oxetanyl.

In another refinement, R²is selected from hydrogen, halogen, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkenyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.

In another refinement, R²is selected from hydrogen, halogen, optionally substituted C₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.

In another refinement, R²is selected from CH₃, CF₃, iPr, cPr, F, Cl, Br, optionally substituted piperidinyl, optionally substituted optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted azetidinyl, and optionally substituted oxetanyl.

In another refinement, R³, at each occurrence, R¹³and R¹⁴are independently selected from hydrogen, CH₃, CF₃, iPr, cPr, tBu, CNCH₂, F, Cl, Br, OH, NH₂, CN, CH₃, and CONH₂.

In another embodiment, the JAK ligand comprises a moiety of FORMULA 2:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

A, B, and D are independently selected from CR³and N, with the proviso that not all of A, B, and D are N, wherein

R³is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, CONR⁴R⁵, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl, wherein

R⁴and R⁵are independently selected from hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl, or

R⁴and R⁵together with the atom or atoms to which they are connected form a 3-20 membered carbocyclyl ring or 4-20 membered heterocyclyl ring;

X and Y are independently selected from null, or a bivalent moiety selected from null, C(R⁶)R⁷, CO, CO₂, CONR⁶, NR⁶, NR⁶CO, NR⁶CO₂, NR⁶C(O)NR⁷, NR⁶SO, NR⁶SO₂, NR⁶SO₂NR⁷, O, OC(O), OCO₂, OCONR⁶, S, SO, SO₂, and SO₂NR⁶, wherein

R⁶and R⁷together with the atom or atoms to which they are connected form a 3-20 membered carbocyclyl ring or 4-20 membered heterocyclyl ring;

V and W are independently selected from null, carbocyclyl, heterocyclyl, aryl, and heteroaryl, which are optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, N(R⁸)R⁹, OCOR⁸, OCO₂R⁸, OCON(R⁸)R⁹, COR⁸, CO₂R⁸, CON(R⁸)R⁹, SOR⁸, SO₂R⁸, SO₂N(R⁸)R⁹, NR¹⁰CO₂R⁸, NR¹⁰COR⁸, NR¹⁰C(O)N(R⁸)R⁹, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, NR¹⁰SO₂N(R⁸)R⁹, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 4-10 membered heterocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;

When neither of V and W is null, V and W together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; When W is null and V is not null, V and R¹together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; When V is null and W is not null, W and R²together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; or When W and V are null, R¹and R²together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring;

R¹is connected to the “linker” moiety of the heterobifunctional compound, and is selected from null, R′—R″, R′OR″, R′SR″, R′NR¹¹R″, R′OC(O)R″, R′OC(O)OR″, R′OCONR¹¹R″, R′C(O)R″, R′C(O)OR″, R′CON(R¹¹)R″, R′S(O)R″, R′S(O)₂R″, R′SO₂N(R¹¹)R″, R′NR¹²C(O)OR″, R′NR¹²C(O)R″, R′NR¹²C(O)N(R¹¹)R″, R′NR¹²S(O)R″, R′NR¹²S(O)₂R″, and R′NR¹²S(O)₂N(R¹¹)R″, wherein

In another refinement, V is Ar².

In another refinement, the JAK ligand comprises a moiety of FORMULA 2A:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

A, B, D, X, Y, W, R¹, and R²are the same as defined in FORMULA 2;

Ar²is selected from null, aryl, and heteroaryl(preferably selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl), each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, NR⁸R⁹, OCOR⁸, OCO₂R⁸, OCONR⁸R⁹, COR⁸, CO₂R⁸, CONR⁸R⁹, SOR⁸, SO₂R⁸, SO₂NR⁸R⁹, NR¹⁰CO₂R⁸, NR¹⁰COR⁸, NR¹⁰C(O)NR⁸R⁹, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, NR¹⁰SO₂NR⁸R⁹, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 4-10 membered heterocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-20 membered heterocyclyl ring; and

When neither of W and Ar²is null, W and Ar²together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; When W is null and Ar²is not null, Ar²and R¹together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; When Ar²is null and W is not null, W and R²together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; or When W and Ar²are null, R¹and R²together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring.

In another refinement, V is Ar²; and W is Ar¹.

In another refinement, the JAK ligand comprises a moiety of FORMULA 2B:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

A, B, D, X, Y, R¹, and R²are the same as defined in FORMULA 2; and

Ar¹and Ar²are independently selected from null, aryl, and heteroaryl (preferably selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl), each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, N(R⁸)R⁹, OCOR⁸, OCO₂R⁸, OCONR⁸R⁹, COR⁸, CO₂R⁸, CONR⁸R⁹, SOR⁸, SO₂R⁸, SO₂NR⁸R⁹, NR¹⁰CO₂R⁸, NR¹⁰COR⁸, NR¹⁰C(O)NR⁸R⁹, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, NR¹⁰SO₂NR⁸R⁹, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 4-10 membered heterocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-20 membered heterocyclyl ring; and

When neither of Ar¹and Ar²is null, Ar¹and Ar²together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; When Ar¹is null and Ar²is not null, Ar²and R¹together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; When Ar²is null and Ar¹is not null, Ar¹and R²together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; or when Ar¹and Ar²are null, R¹and R²together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 2C, 2D, 2E or 2F:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

X, Y, Ar¹, Ar², R¹, and R²are the same as defined in FORMULA 2; and

R¹³, R¹⁴and R¹⁵are selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, CONR⁴R⁵, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl, wherein

R⁴and R⁵together with the atom or atoms to which they are connected form a 3-20 membered carbocyclyl ring or 4-20 membered heterocyclyl ring.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R or 2S:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

Y, R¹and R²are the same as defined in FORMULA 2;

Ar¹and Ar²are the same as defined in FORMULA 2B; and

R¹³, R¹⁴and R¹⁵are the same as defined in FORMULAE 2C, 2D, 2E or 2F.

In another refinement, Y is selected from null, CR⁶R⁷, CO, CO₂, CONR⁶, NR⁶CO, NR⁶C(O)NR⁷, O, SO, SO₂, SO₂NR⁶and NR⁶, wherein

R⁶and R⁷are independently selected from hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl.

In another refinement, Y is selected from null, CH₂, CO, CONH, NR⁶C(O), NR⁶C(O)NR⁷, SO₂and SO₂NH.

In another refinement, Ar¹and Ar²are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, NR⁸R⁹, COR⁸, CO₂R⁸, CONR⁸R⁹, SORB, SO₂R⁸, SO₂NR⁸R⁹, NR¹⁰COR⁸, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, optionally substituted C₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-10 membered heterocyclyl ring.

In another refinement, Ar¹and Ar²are independently selected from null, aryl, and heteroaryl (preferably selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl), each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, NR⁸R⁹, NR¹⁰COR⁸, optionally substituted C₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-10 membered heterocyclyl ring.

In another refinement, Ar¹and Ar²are independently selected from null, aryl, and heteroaryl (preferably selected from null monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl), each of which is optionally substituted with one or more substituents independently selected from H and F.

In another refinement, R¹is selected from null, O, NH, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.

In another refinement, R¹is selected from null, O, NH, and optionally substituted 4-10 membered heterocyclyl, which contains at least one of O or N.

In another refinement, R¹is selected from null, O, NH, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted azetidinyl, and optionally substituted oxetanyl.

In another refinement, R²is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₁-C₈alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

In another refinement, R²is selected from hydrogen, halogen, optionally substituted C₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

In another refinement, R²is selected from hydrogen, CH₃, CF₃, iPr, cPr, tBu, CNCH₂, F, Cl, Br, optionally substituted piperidinyl, optionally substituted optionally substituted piperazinyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydrofuranyl, optionally substituted azetidinyl, and optionally substituted oxetanyl, optionally substituted phenyl, optionally substituted triazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted triazinyl, optionally substituted fruranyl, optionally substituted oxazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted thiophenyl, optionally substituted thiazolyl, and optionally substituted thiadiazolyl.

In another refinement, R¹³, R¹⁴and R¹⁵are independently selected from H, CH₃, CF₃, iPr, cPr, tBu, CNCH₂, F, Cl, Br, OH, NH₂, CN, CH₃, and CONH₂.

In another embodiment, the JAK ligand is derived from any of the following:

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In another embodiment, the JAK ligand is derived from any of the following: NVP-BSK805, Cmpd 12, and TG101209 (preferably, NVP-BSK805 and Cmpd 12).

In another embodiment, the JAK ligand is derived from the following JAK inhibitors: NDI-031301, NDI-31232, VR588, R333 and R348.

In another embodiment, the JAK ligand is selected from the group consisting of:

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In another embodiment, the JAK ligand is selected from FORMULA 3A, FORMULA 3C, FORMULA 3D), and FORMULA 31; preferably, selected from FORMULA 3A, FORMULA 3C, and FORMULA 3D.

In some embodiments, the degradation tag is a moiety selected from the group consisting of FORMULAE 5A, 5B, 5C, and 5D:

text missing or illegible when filed

wherein

V, W, and X are independently selected from CR²and N;

Y is selected from —CO—, —CR³R⁴—, —N═CR³—, and —N═N—; preferably, Y is selected from —CO—, —CH₂—, and —N═N—;

Z is selected from null, CO, CR⁵R⁶, NR⁵, O, C≡C, optionally substituted C₁-C₁₀alkylene, optionally substituted C₂-C₁₀alkenyl, and optionally substituted C₂-C₁₀alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃fused cycloalkyl, optionally substituted C₃-C₁₃fused heterocyclyl, optionally substituted C₃-C₁₃bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro cycloalkyl, optionally substituted C₃-C₁₃spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH₂, NH, O, and C≡C;

R¹, R², R³, and R⁴are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C₁-C₆alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl, or

R³and R⁴together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and

R⁵and R⁶together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl.

In another embodiment, R¹, R², R³, R⁴, R⁵and R⁶are hydrogen.

In another embodiment, the degradation tag is a moiety selected from the group consisting of FORMULAE 5E, 5F, 5G, 5H, and 5I:

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wherein

U, V, W, and X are independently selected from CR²and N;

Y is selected from —N—, —CR³═, —CR³R⁴—, —NR³— and —O—; preferably, Y is selected from —N—, —CH₂—, —NH—, —N(CH₃)— and —O—;

Z is selected from null, CO, CR⁵R⁶, NR⁵, O, optionally substituted C₁-C₁₀alkylene, optionally substituted C₂-C₁₀alkenylene, optionally substituted C₂-C₁₀alkynylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃fused cycloalkyl, optionally substituted C₃-C₁₃fused heterocyclyl, optionally substituted C₃-C₁₃bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro cycloalkyl, optionally substituted C₃-C₁₃spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; preferably, Z is selected from null, CH₂, CH═CH, C≡C, NH and 0;

R¹, and R²are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C₁-C₆alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl;

R³, and R⁴are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C₁-C₆alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R³and R⁴together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl; and

R⁵and R⁶are independently selected from null, hydrogen, halogen, oxo, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₆alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl; or R⁵and R⁶together with the atom to which they are connected form a 3-6 membered carbocyclyl, or 4-6 membered heterocyclyl.

In another embodiment, R¹, R², R³, R⁴, R⁵and R⁶are hydrogen.

In another embodiment, when the degradation tag is a moiety of FORMULAE 5G, Y is selected from —N— and —CR³═; preferably, Y is N.

In another embodiment, when the degradation tag is a moiety of FORMULAE 5E, 5F, 5H, or 5I, Y is selected from —CR³R⁴—, —NR³—, and —O—.; preferably, Y is selected from CH₂, NH, N(CH₃) and 0.

In one embodiment, the degradation tag is a moiety selected from the group consisting of FORMULAE 5J, 5K, 5L, 5M, 5N, 5O, 5P, and 5Q:

wherein

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X′ are independently selected from CR²and N;

Y′, Y″, and Y′″ are independently selected from CR³R⁴.

U, V, W, Y, X, Z, R¹, R², R³and R⁴are defined as in FORMULAE 5E, 5F, 5G, 5H, or 5I;

R′ is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl.

In one embodiment, the degradation tag is a moiety of FORMULA 6A:

text missing or illegible when filed

wherein

R¹and R²are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, and optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈aminoalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl; and

R³is selected from hydrogen, optionally substituted C(O)C₁-C₈alkyl, optionally substituted C(O)C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C(O)C₁-C₈haloalkyl, optionally substituted C(O)C₁-C₈hydroxyalkyl, optionally substituted C(O)C₁-C₈aminoalkyl, optionally substituted C(O)C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(O)C₂-C₈alkenyl, optionally substituted C(O)C₂-C₈alkynyl, optionally substituted C(O)OC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C(O)OC₁-C₈haloalkyl, optionally substituted C(O)OC₁-C₈hydroxyalkyl, optionally substituted C(O)OC₁-C₈aminoalkyl, optionally substituted C(O)OC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C(O)O(3-10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(O)OC₂-C₈alkenyl, optionally substituted C(O)OC₂-C₈alkynyl, optionally substituted C(O)NC₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C(O)NC₁-C₈haloalkyl, optionally substituted C(O)NC₁-C₈hydroxyalkyl, optionally substituted C(O)NC₁-C₈aminoalkyl, optionally substituted C(O)NC₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(O)NC₂-C₈alkenyl, optionally substituted C(O)NC₂-C₈alkynyl, optionally substituted P(O)(OH)₂, optionally substituted P(O)(OC₁-C₈alkyl)₂, and optionally substituted P(O)(OC₁-C₈aryl)₂.

In another embodiment, the degradation tag is a moiety of FORMULAE 6B, 6C, and 6D:

text missing or illegible when filed

wherein

R¹and R²are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl; optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈aminoalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

R⁴is selected from NR⁷R⁸

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optionally substituted C₁-C₈alkoxy, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteraryl, in which

R⁷is selected from hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted C₁-C₈cycloalkyl, optionally substituted C₁-C₈alkyl-CO, optionally substituted C₁-C₈cycloalkyl-CO, optionally substituted C₁-C₈cycloalkyl-C₁-C₈alkyl-CO, optionally substituted 4-10 membered heterocyclyl-CO, optionally substituted 4-10 membered heterocyclyl-C₁-C₈alkyl-CO, optionally substituted aryl-CO, optionally substituted aryl-C₁-C₈alkyl-CO, optionally substituted heteroaryl-CO, optionally substituted heteroaryl-C₁-C₈alkyl-CO, optionally substituted aryl, and optionally substituted heteroaryl;

R⁸is selected from hydrogen, optionally substituted C₁-C₈alkyl, and optionally substituted C₁-C₈cycloalkyl;

R⁹, at each occurrence, is independently selected from hydrogen, halogen, cyano, optionally substituted C₁-C₈alkyl, optionally substituted C₁-C₈cycloalkyl, optionally substituted C₁-C₈heterocycloalkyl, optionally substituted C₁-C₈alkoxy, optionally substituted C₁-C₈cycloalkoxy, halo substituted C₁-C₈alkyl, halo substituted C₁-C₈cycloalkyl, halo substituted C₁-C₈alkoxl, halo substituted C₁-C₈cycloalkoxy, and halo substituted C₁-C₈heterocycloalkyl;

X is selected from CH and N; and

n is 0, 1, 2, 3, or 4;

R⁶is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈alkyl, optionally substituted C₁-C₈cycloalkyl, optionally substituted C₁-C₈alkoxy, and optionally substituted C₁-C₈cycloalkoxy, optionally substituted C₁-C₈heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, preferably, halogen, cyano, optionally substituted imidazole, optionally substituted pyrazole, optionally substituted oxadiazole, optionally substituted triazole, 4-methylthiazol-5-yl, or oxazol-5-yl group.

In another embodiment, the degradation tag is a moiety of FORMULA 7A:

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wherein

V, W, X, and Z are independently selected from CR⁴and N; and

R¹, R², R³, and R⁴are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, and optionally substituted C₂-C₈alkynyl; optionally substituted C₁-C₈alkoxy, optionally substituted C₁-C₈alkylamino, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.

In another embodiment, the degradation tag is a moiety of FORMULA 7B:

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wherein

R¹, R², and R³are independently selected from hydrogen, halogene, optionally substituted C₁-C₈alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₃-C₇cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted C₂-C₈alkenyl, and optionally substituted C₂-C₈alkynyl;

R⁴and R⁵are independently selected from hydrogen, COR⁶, CO₂R⁶, CONR⁶R⁷, SOR⁶, SO₂R⁶, SO₂NR⁶R⁷, optionally substituted C₁-C₈alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted aryl-C₁-C₈alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁶and R⁷are independently selected from hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R⁶and R⁷together with the atom to which they are connected form a 4-8 membered cycloalkyl or heterocyclyl ring.

In another embodiment, the degradation tag is a moiety of FORMULA 5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, and 5I.

In one embodiment, the degradation tag is a moiety selected from the group consisting of FORMULA 5B, FORMULA 5C, FORMULA 5E, and FORMULA 5F.

In one embodiment, the degradation tag is derived from any of the following:

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In another embodiment, the degradation tag is derived from any of the following: thalidomide, pomalidomide, lenalidomide, CRBN-1, CRBN-2, CRBN-3, CRBN-4, CRBN-5, CRBN-6, CRBN-7, CRBN-8, CRBN-9, CRBN-10, and CRBN-11.

In another embodiment, the degradation tag is selected from the group consisting of:

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In some embodiments, the degradation tag is selected from FORMULAE 8A, 8B, 8C, 8D, 8E, 8F, 8G, 8H, 8I, 8G, 8K, 8L, 8M, 8N, 8O, 8P, 8Q, 8R, 8AQ, 8AR, 8AS, 8AT, 8AU, 8AV, 8AW, 8AX, 8AY, 8AZ, 8BA, 8BB, 8BC, 8BD, 8BI, 8CB, 8CC, 8CD, 8CE, 8CK, 8CL, 8CR, 8CS, 8CY, 8CZ, 8GU, 8GV, 8GW, 8GX, 8GY, 8GZ, 8HA, 8HB, 8HC, 8HD, 8HE, 8HF, 8HG, 8HH, 8HI, 8HJ, 8HK, 8HL, 8HM, 8HN, 8HO, 8HP, 8HQ, 8HR, 8HS, 8HT, 8HU, 8HV, 8HW, 8HX, 8HY, 8HZ, 8IA, 8IB, 8IC, 8ID, 81E, 8IF, 8IG, 8IH, 8II, 8IJ, 8IK, 8IL, 8IM, 8IN, 8IO, 8IP, 8IQ, 8IR, 8IS, 8IT, 8IU, 8IV, 8IW, 8IX, 8IY, 8IZ, 8JA, 8JB, 8JC, 8JD, 8JE, 8JF, 8JG, 8JH, 8JI, and 8JJ.

In some embodiments, the degradation tag is selected from FORMULAE 8G, 8H, 8I, 8J, 8K, 8L, 8M, 8O, 8Q, 8AR, 8AT, 8AV, 8AX, 8AZ, 8BB, 8BC, 8BD, 8BI, 8CB, 8CC, 8CD, 8CE, 8CK, 8CL, 8CR, 8CS, 8CY, 8CZ, 8GV, 8GX, 8GZ, 8HD, 8HF, 8HH, 8HL, 8HN, 8HP, 8HT, 8HV, 8HX, 8IB, 8ID, 8IF, 8IJ, 8IL, 8IN, 8IR, 8IX, and 8JD.

In some embodiments, the linker moiety is of FORMULA 9:

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wherein

A, W, and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)N(R¹)R″, R′C(S)N(R¹)R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R¹)R″, R′SR″, R′SOR″, R′SO₂R″, R′SO₂N(R¹)R″, R′N(R¹)R″, R′N(R¹)COR″, R′N(R¹)C(O)OR″, R′N(R¹)CON(R²)R″, R′N(R¹)C(S)R″, R′N(R¹)S(O)R″, R′N(R¹)S(O)₂R″, R′N(R¹)S(O)₂N(R²)R″, optionally substituted C₁-C₈alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈alkynylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈haloalkylene, optionally substituted C₁-C₈hydroxyalkylene, optionally substituted C₃-C₁₃fused cycloalkyl, optionally substituted C₃-C₁₃fused heterocyclyl, optionally substituted C₃-C₁₃bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro cycloalkyl, optionally substituted C₃-C₁₃spiro heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R′ and R″ are independently selected from null, optionally substituted (C₁-C₈alkylene)-R^r(preferably, CH₂—R^r), optionally substituted R^r—(C₁-C₈alkylene), optionally substituted (C₁-C₈alkylene)-R^r—(C₁-C₈alkyl), or a moiety comprising of optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈alkynylene, optionally substituted C₁-C₈hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃fused cycloalkyl, optionally substituted C₃-C₁₃fused heterocyclyl, optionally substituted C₃-C₁₃bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro cycloalkyl, optionally substituted C₃-C₁₃spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^ris selected from optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃fused cycloalkyl, optionally substituted C₃-C₁₃fused heterocyclyl, optionally substituted C₃-C₁₃bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro cycloalkyl, optionally substituted C₃-C₁₃spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R¹and R²are independently selected from hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

R′ and R″, R¹and R², R′ and R¹, R′ and R², R″ and R¹, R″ and R²together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring; and

m is 0 to 15.

In one embodiment, the linker moiety is of FORMULA 9A:

embedded image

wherein

R¹, R², R³and R⁴, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxy, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkylamino, and optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R¹and R², R³and R⁴together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

A, W, and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)N(R¹)R″, R′C(S)N(R⁵)R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R⁵)R″, R′SR″, R′SOR″, R′SO₂R″, R′SO₂N(R⁵)R″, R′N(R⁵)R″, R′N(R⁵)COR″, R′N(R⁵)C(O)OR″, R′N(R⁵)CON(R⁶)R″, R′N(R⁵)C(S)R″, R′N(R⁵)S(O)R″, R′N(R⁵)S(O)₂R″, R′N(R⁵)S(O)₂N(R⁶)R″, optionally substituted C₁-C₈alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈alkynylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈haloalkylene, optionally substituted C₁-C₈hydroxyalkylene, optionally substituted C₃-C₁₃fused cycloalkyl, optionally substituted C₃-C₁₃fused heterocyclyl, optionally substituted C₃-C₁₃bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro cycloalkyl, optionally substituted C₃-C₁₃spiro heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R′ and R″ are independently selected from null, optionally substituted (C₁-C₈alkylene)-R^r(preferably, CH₂—R^r), optionally substituted R^r—(C₁-C₈alkylene), optionally substituted (C₁-C₈alkylene)-R^r—(C₁-C₈alkylene), or a moiety comprising of optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈alkynylene, optionally substituted C₁-C₈hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃fused cycloalkyl, optionally substituted C₃-C₁₃fused heterocyclyl, optionally substituted C₃-C₁₃bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro cycloalkyl, optionally substituted C₃-C₁₃spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁵and R⁶are independently selected from hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

R′ and R″, R⁵and R⁶, R′ and R⁵, R′ and R⁶, R″ and R⁵, R″ and R⁶together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

m is 0 to 15;

n, at each occurrence, is 0 to 15; and

o is 0 to 15.

In another embodiment, the linker moiety is of FORMULA 9B:

embedded image

wherein

R¹and R², at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C₁-C₈alkyl, optionally substituted C₁-C₈alkoxy, optionally substituted C₁-C₈alkoxy C₁-C₈alkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkylamino, C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R¹and R²together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

A and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)N(R³)R″, R′C(S)N(R³)R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R³)R″, R′SR″, R′SOR″, R′SO₂R″, R′SO₂NR″R³, R′N(R³)R″, R′N(R³)COR″, R′N(R³)C(O)OR″, R′N(R³)CON(R⁴)R″, R′N(R³)C(S)R″, R′N(R³)S(O)R″, R′N(R³)S(O)₂R″, R′N(R³)S(O)₂N(R⁴)R″, optionally substituted C₁-C₈alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈alkynylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈haloalkylene, optionally substituted C₁-C₈hydroxyalkylene, optionally substituted C₃-C₁₃fused cycloalkyl, optionally substituted C₃-C₁₃fused heterocyclyl, optionally substituted C₃-C₁₃bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro cycloalkyl, optionally substituted C₃-C₁₃spiro heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R′ and R″ are independently selected from null, optionally substituted (C₁-C₈alkylene)-R^r(preferably, CH₂—R^r), optionally substituted R^r—(C₁-C₈alkylene), optionally substituted (C₁—C₈alkylene)-R^r—(C₁-C₈alkylene), or a moiety comprising of optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈alkynylene, optionally substituted C₁-C₈hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃fused cycloalkyl, optionally substituted C₃-C₁₃fused heterocyclyl, optionally substituted C₃-C₁₃bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro cycloalkyl, optionally substituted C₃-C₁₃spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R³and R⁴are independently selected from hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

R′ and R″, R³and R⁴, R′ and R³, R′ and R⁴, R″ and R³, R″ and R⁴together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

each m is 0 to 15; and

n is 0 to 15.

In another embodiment, the linker moiety is of FORMULA 9C:

embedded image

wherein

X is selected from O, NH, and NR⁷;

R¹, R², R³, R⁴, R⁵, and R⁶, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxy, optionally substituted C₁-C₈alkoxy C₁-C₈alkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkylamino, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

A and B are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO₂R″, R′C(O)N(R⁸)R″, R′C(S)N(R⁸)R″, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R⁸)R″, R′SR″, R′SOR″, R′SO₂R″, R′SO₂N(R′)R″, R′N(R⁸)R″, R′N(R⁸)COR″, R′N(R⁸)C(O)OR″, R′N(R⁸)CON(R⁹)R″, R′N(R⁸)C(S)R″, R′N(R⁸)S(O)R″, R′N(R⁸)S(O)₂R″, R′N(R⁸)S(O)₂N(R⁹)R″, optionally substituted C₁-C₈alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈alkynylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈haloalkylene, optionally substituted C₁-C₈hydroxyalkylene, optionally substituted C₃-C₁₃fused cycloalkyl, optionally substituted C₃-C₁₃fused heterocyclyl, optionally substituted C₃-C₁₃bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro cycloalkyl, optionally substituted C₃-C₁₃spiro heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R′ and R″ are independently selected from null, optionally substituted (C₁-C₈alkylene)-R^r(preferably, CH₂—R^r), optionally substituted R^r—(C₁-C₈alkylene), optionally substituted (C₁-C₈alkylene)-R^r—(C₁-C₈alkylene), or a moiety comprising of optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈alkylene, optionally substituted C₂-C₈alkenylene, optionally substituted C₂-C₈alkynylene, optionally substituted C₁-C₈hydroxyalkylene, optionally substituted C₁-C₈alkoxyC₁-C₈alkylene, optionally substituted C₁-C₈alkylaminoC₁-C₈alkylene, optionally substituted C₁-C₈haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C₃-C₁₃fused cycloalkyl, optionally substituted C₃-C₁₃fused heterocyclyl, optionally substituted C₃-C₁₃bridged cycloalkyl, optionally substituted C₃-C₁₃bridged heterocyclyl, optionally substituted C₃-C₁₃spiro cycloalkyl, optionally substituted C₃-C₁₃spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R⁷, R⁸and R⁹are independently selected from hydrogen, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or

R′ and R″, R⁸and R⁹, R′ and R⁸, R′ and R⁹, R″ and R⁸, R″ and R⁹together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;

m, at each occurrence, is 0 to 15;

n, at each occurrence, is 0 to 15;

o is 0 to 15; and

p is 0 to 15.

In another refinement, A and B, at each occurrence, are independently selected from null, CO, NH, NH—CO, CO—NH, CH₂—NH—CO, CH₂—CO—NH, NH—CO—CH₂, CO—NH—CH₂, CH₂—NH—CH₂—CO—NH, CH₂—NH—CH₂—NH—CO, —CO—NH, CO—NH— CH₂—NH—CH₂, CH₂—NH—CH₂.

In another refinement, o is 0 to 5.

In another refinement, the linker moiety comprises a ring selected from the group consisting of a 3 to 13 membered ring, a 3 to 13 membered fused ring, a 3 to 13 membered bridged ring, and a 3 to 13 membered spiro ring.

In another embodiment, the linker moiety comprises one or more rings selected from the group consisting of FORMULAE C1a, C2a, C3a, C4a and C5a

embedded image

wherein

X′ and Y′ are independently selected from N, CR^b;

A¹, B¹, C¹and D¹, at each occurrence, are independently selected from null, O, CO, SO, SO₂, NR^b, and CR^bR^c;

A², B², C², and D², at each occurrence, are independently selected from N, and CR^b;

A³, B³, C³, D³, and E³, at each occurrence, are independently selected from N, O, S, NR^b, and CR^b;

R^band R^c, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxy, optionally substituted C₁-C₈alkoxyalkyl, optionally substituted C₁-C₈haloalkyl, optionally substituted C₁-C₈hydroxyalkyl, optionally substituted C₁-C₈alkylamino, and optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

m¹, n¹, o¹and p¹are independently selected from 0, 1, 2, 3, 4 and 5.

In another refinement, the linker moiety comprises one or more rings selected from the group consisting of FORMULAE C1, C2, C3, C4 and C5:

embedded image

In another refinement, the linker moiety comprises one or more rings selected from Group R, and Group R consists of:

embedded image

In another refinement, the length of the linker is 0 to 40 chain atoms.

In another refinement, the length of the linker is 1 to 20 chain atoms.

In another refinement, the length of the linker is 2 to 12 chain atoms.

In another refinement, the linker is selected from —(CO)—(CH₂)_1-8—, —(CH₂)_1-9—, —(CH₂)_1-2—(CO)—NH—(CH₂)_2-9—, —(CH₂)_1-2—(CO)—NH—(CH₂)_1-3—(OCH₂CH₂)_1-7, and —(CH₂)_0-1—(CO)—(CH₂)_1-3—(OCH₂CH₂)_1-7.

In another refinement, the linker is —(CO)—(CH₂)_1-8—, —(CH₂)_1-9—, —(CH₂)_1-2(CO)—NH—(CH₂)_2-9—, or —(CH₂)_1-2—(CO)—NH—(CH₂)_1-3—(OCH₂CH₂)_1-7—.

In another embodiment, R^ris selected from FORMULA C1a, C2a, C3a, C4a, C5a, C1, C2, C3, C4, and C5 as defined above.

In another embodiment, R^ris selected from Group R.

In some embodiments, the heterobifunctional compound is selected from the group consisting of JA-001 to JA-295 or a pharmaceutically acceptable salt or analog thereof.

In some embodiments, the heterobifunctional compound is selected from the group consisting of JA-093, JA-094, JA-179, JA-180, JA-182, JA-187, JA-188, JA-189, JA-196, JA-198, JA-199, JA-202, JA-203, JA-213, JA-214, JA-224, JA-225, JA-231, JA-252, JA-261, JA-263, JA-264, JA-268, JA-269, JA-273 and a pharmaceutically acceptable salt or analog thereof.

In one embodiment, the heterobifunctional compound is 2-(4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)acetamide (JA-093).

In one embodiment, the heterobifunctional compound is 2-(4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)acetamide (JA-094).

In one embodiment, the heterobifunctional compound is 2-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptyl)acetamide (JA-179).

In one embodiment, the heterobifunctional compound is 2-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)acetamide (JA-180).

In one embodiment, the heterobifunctional compound is 5-((5-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-182).

In one embodiment, the heterobifunctional compound is 5-((8-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-8-oxooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-187).

In one embodiment, the heterobifunctional compound is 5-((7-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-7-oxoheptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-188).

In one embodiment, the heterobifunctional compound is 5-((6-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-189).

In one embodiment, the heterobifunctional compound is 2-(2,6-dioxopiperidin-3-yl)-5-((5-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperazin-1-yl)-5-oxopentyl)amino)isoindoline-1,3-dione (JA-196).

In one embodiment, the heterobifunctional compound is 2-(2,6-dioxopiperidin-3-yl)-5-((6-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperazin-1-yl)-6-oxohexyl)amino)isoindoline-1,3-dione (JA-198).

In one embodiment, the heterobifunctional compound is 2-(2,6-dioxopiperidin-3-yl)-5-((7-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperazin-1-yl)-7-oxoheptyl)amino)isoindoline-1,3-dione (JA-199).

In one embodiment, the heterobifunctional compound is 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperidin-1-yl)-3-oxopropyl)amino)isoindoline-1,3-dione (JA-202).

In one embodiment, the heterobifunctional compound is 2-(2,6-dioxopiperidin-3-yl)-5-((8-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperidin-1-yl)-8-oxooctyl)amino)isoindoline-1,3-dione (JA-203).

In one embodiment, the heterobifunctional compound is N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)-2-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperidin-1-yl)acetamide (JA-213).

In one embodiment, the heterobifunctional compound is N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptyl)-2-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperidin-1-yl)acetamide (JA-214).

In one embodiment, the heterobifunctional compound is 2-(4-(4-((4-((3-(N-(tert-butyl)sulfamoyl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)piperazin-1-yl)-N-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaheptadecyl)acetamide (JA-224).

In one embodiment, the heterobifunctional compound is N-(tert-butyl)-3-((2-((4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperazin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)benzenesulfonamide (JA-225).

In one embodiment, the heterobifunctional compound is N-(tert-butyl)-3-((2-((4-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoyl)piperazin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)benzenesulfonamide (JA-231).

In one embodiment, the heterobifunctional compound is 2-(2,6-dioxopiperidin-3-yl)-5-(7-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperazin-1-yl)hept-1-yn-1-yl)isoindoline-1,3-dione (JA-252).

In one embodiment, the heterobifunctional compound is 3-(5-((6-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperazin-1-yl)-6-oxohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (JA-261).

In one embodiment, the heterobifunctional compound is 3-(5-((6-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (JA-263).

In one embodiment, the heterobifunctional compound is 5-(7-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)hept-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (JA-264).

In one embodiment, the heterobifunctional compound is 3-(6-(7-(4-(4-((5-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)phenyl)piperazin-1-yl)-7-oxoheptyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (JA-268).

In one embodiment, the heterobifunctional compound is 3-(6-(7-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-7-oxoheptyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (JA-269).

In one embodiment, the heterobifunctional compound is 3-(5-((6-(4-(4-(8-(3,5-difluoro-4-(morpholinomethyl)phenyl)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-6-oxohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (JA-273),

According to one aspect of the present disclosure, a composition disclosed herein comprises the heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof.

According to one aspect of the present disclosure, a method of treating a JAK-mediated disease disclosed herein comprises administering to a subject with a JAK-mediated disease the heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof.

In one embodiment, the JAK-mediated disease results from JAK expression, mutation, deletion, or fusion.

In one embodiment, the subject with the JAK-mediated disease has an elevated JAK function relative to a healthy subject without the JAK-mediated disease.

In one embodiment, the heterobifunctional compound is selected from the group consisting of JA-001 to JA-295, or analogs thereof.

In one embodiment, the heterobifunctional compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.

In one embodiment, the method further comprises administering to the subject an additional therapeutic regimen for treating cancer, inflammatory disorders, or autoimmune diseases.

In one embodiment, the additional therapeutic regimen is selected from the group consisting of surgery, chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy.

In one embodiment, the JAK-mediated cancer is selected from the group consisting of brain cancer, stomach cancer, gastrointestinal tract cancer, liver cancer, biliary passage cancer, breast cancer, ovary cancer, cervix cancer, prostate cancer, testis cancer, penile cancer, genitourinary tract cancer, esophagus cancer, larynx cancer, skin cancer, lung cancer, pancreas cancer, thyroid cancer, gland cancer, bladder cancer, kidney cancer, muscle cancer, bone cancer, cancers of the hematopoietic system, myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin's lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, and myeloma.

In one embodiment, the JAK-mediated inflammatory disorders are selected from the group consisting of ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, and ischemia reperfusion injuries.

In one embodiment, the JAK-mediated auto-immune diseases are selected from the group consisting of multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, myasthenia gravis, type I diabetes, systemic lupus erythematosus, IgA nephropathy, autoimmune thyroid disorders, alopecia areata, and bullous pemphigoid.

In one embodiment, the JAK-mediated dermatological disorders are selected from the group consisting of atopic dermatitis, pruritus, alopecia areata, psoriasis, skin rash, skin irritation, skin sensitization, chronic mucocutaneous candidiasis, dermatomyositis, erythema multiforme, palmoplantar pustulosis, vitiligo, polyarteritis nodosa, and STING vasculopathy.

In one embodiment, the JAK-mediated viral infections are selected from the group consisting of infections of Hepatitis B, Hepatitis C, Human Immunodeficiency Virus (HIV), Human T-lymphotropic Virus (HTLV1), Epstein Barr Virus (EBV), Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV).

In one embodiment, the JAK-mediated dry eye disorders are selected from the group consisting of dry eye syndrome (DES) and keratoconjunctivitis sicca (KCS).

In one embodiment, the JAK-mediated bone remodeling disorders are selected from the group consisting of osteoporosis and osteoarthritis.

In one embodiment, the JAK-mediated organ transplant associated immunological complications are selected from the group consisting of graft-versus-host diseases.

In one embodiment, the JAK-mediated disease is a relapsed cancer.

In one embodiment, the JAK-mediated disease is refractory to one or more previous treatments.

According to one aspect of the present disclosure, a method for identifying a heterobifunctional compound which mediates degradation or reduction of JAK is disclosed. The method comprises:

providing a heterobifunctional test compound comprising an JAK ligand conjugated to a degradation tag through a linker;

contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and JAK;

determining whether JAK level is decreased in the cell; and

identifying the heterobifunctional test compound as a heterobifunctional compound which mediates degradation or reduction of JAK.

In one embodiment, the cell is a cancer cell.

In one embodiment, the cancer cell is a JAK-mediated cancer cell.

According to one aspect of the present disclosure, a method of treating a GSTP1-mediated disease disclosed herein comprises administering to a subject with a GSTP1-mediated disease the heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof.

According to one aspect of the present disclosure, a method of treating a JAK- and GSTP1-mediated disease disclosed herein comprises administering to a subject with a JAK- and GSTP1-mediated disease the heterobifunctional compound or a pharmaceutically acceptable salt or analog thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

FIG. 1 shows an immunoblot of JAK1/2/3 proteins expressed in HEL cells after treatment with a dose range of heterobifunctional compounds JA-189 or JA-213 or a single dose of NVP-BSK805.

FIG. 2 shows an immunoblot of JAK1/3 proteins expressed in RS4;11 cells after treatment with a dose range of compounds JA-189, JA-213, NVP-BSK805 or TG101209.

FIG. 3 shows graphs of MV4;11, RS4;11, Kasumi-1 and HEL cell viability vs. concentration of JA-189, JA-213, NVP-BSK805 and TG101209.

FIG. 4 shows graphs of MV4;11, RS4;11, Kasumi-1 and HEL cell viability vs. concentration of JA-189, JA-213, NVP-BSK805 and TG101209 in the presence or absence of pomalidomide at 10 μM.

FIG. 5 shows an immunoblot of GSPT1 and tubulin expressed in RS4:11 cells treated with JA-189, JA-213, or CC-885 at indicated concentrations for 16 hours.

FIG. 6 shows graphs of immortalized human lung fibroblast IMR-90 and keratinocyte HACAT cell viability vs. concentration of JA-189, and JA-213.

DETAILED DESCRIPTION OF THE INVENTION

The human Janus kinase (JAK) family comprises four nonreceptor tyrosine kinases, JAK1, JAK2, JAK3 and TYK2. JAK kinases play a central role in the hematopoietic system through transducing cytokine-mediated signals (O'Shea, Schwartz et al. 2015). These intracellular kinases bound to type I and II cytokine receptors, which lack catalytic domains and reply on the kinase activities of JAKs for transducing signals to downstream molecules. Cytokine binding triggers conformational changes of their respective receptors and subsequently induces autophosphorylation and activation of JAK kinases bound to the receptors. JAK kinases then recruit and phosphorylate downstream signaling molecules, most importantly the signal transducer and activator of transcription (STAT) family transcription factors. Phosphorylated STATs are subsequently translocated into nucleus and activate transcription of genes implicated in hematopoiesis and immune response. Different cytokine receptors recruit distinct combinations of JAK kinases, which transduce signals to a wide range of downstream targets, modulating complex and lineage-dependent signaling networks (Schwartz, Kanno et al. 2017).

Acting downstream of a variety of cytokine receptors, JAK kinases are crucially implicated in proliferation, survival, activation, and differentiation of hematopoietic cells (Villarino, Kanno et al. 2015). Furthermore, there is no known pathways that may adequately compensate the JAK/STAT signaling in the hematopoietic system. Hence, the activities of JAK kinases are essential to hematopoiesis and immunity. As a consequence, aberrations of JAK kinases are known to drive the pathogenesis of many diseases, most significantly inflammation, autoimmune diseases, and cancer (O'Shea, Schwartz et al. 2015). For many of these indications, JAK family kinases are well documented as important therapeutic targets.

Mutations leading to constitutive JAK2 activation are found in the majority of BCR-ABL-negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) (Levine, Wadleigh et al. 2005, Griesshammer and Sadjadian 2017). Within these indications, JAK2-V617F is the most common mutation. JAK2 mutations have also been described in chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin's lymphoma, and other hematologic malignancies. In addition to JAK2 point mutations, fusions of JAK2, and mutations of JAK1 and JAK3 have also been identified as mechanisms activating the JAK pathway, albeit to less extent (O'Shea, Holland et al. 2013). Alternative mechanisms to activate JAK kinases include mutations of JAK regulators, such as CSFR3 (Maxson, Gotlib et al. 2013), MPL (Kilpivaara and Levine 2008), and CALR (Rumi, Pietra et al. 2014). Activation of JAK2 is also implicated in non-malignant hematopoietic indications, such as hereditary thrombocythemia (Langabeer 2014). Importantly, a wide range of immunological disorders involves aberrant activation of JAK kinases, such as rheumatoid arthritis, atopic dermatitis, psoriasis, pruritus, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriatic arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, alopecia areata, systemic lupus erythematosus, and graft-versus-host disease (Schwartz, Kanno et al. 2017).

Three JAK inhibitors have been approved for use in human for treatment of rheumatoid arthritis including Ruxolitinib (Mesa, et al., 2012), Tofacitinib (CP-690550) (Traynor, 2012; Lee, et al., 2014; Dhillon, 2017; Strand, et al., 2019), and Baricitinib (Taylor, et al., 2017; Markham, 2017), and the JAK inhibitor Oclacitinib (Gonzales, et al., 2014) has been approved for treatment of canine allergic dermatitis. Multiple JAK kinase inhibitors are currently undergoing clinical or pre-clinical development, including but are not limited to Cerdulatinib (PRT-062070) (Hamlin, et al., 2019), Decemotinib (VX509) (Farmer, et al., 2015), Delgocitinib (JTE-052) (Nakagawa, et al., 2018), Fedratinib (Wernig, et al., 2008; Harrison, et al., 2017), Filgotinib (GLP0634) (Menet, et al., 2014; Van Rompaey, et al., 2013), Gandotinib (LY2784544) (Berdeja, et al., 2018), Ilginatinib (NS-018) (Nakaya, et al., 2011; Verstovsek, et al., 2016), Itacitinib (INCB03911) (Beatty, et al., 2018), Lestauritinib (Mascarenhas, et al., 2019; Pinto, et al., 2018), Momelotinib (CYT387) (Pardanani, et al., 2018), Pacritinib (SB1578) (Tremblay, et al., 2018; William, et al., 2012), Peficitinib (Takeuchi, et al., 2016; Hamaguchi, et al., 2018), Solcitinib (GSK2586184, GLG0778) (Kahl, et al., 2016), Upadacitinib (ABT-494) (Serhal, et al., 2018; Genovese, et al., 2018), AT9283 (Howard, et al., 2009), AZ-3 (Grimster, et al., 2018), AZ960 (Gozgit, et al., 2008), AZD1480 (Verstovsek, et al., 2015; Ioannidis, et al., 2011), BMS-986165 (Papp, et al., 2018), BMS-911543 (Wan, et al., 2015), BSK805 (NVP-BSK805) and BVB808 (NVP-BVB808) (Ringel, et al., 2014; Andraos, et al., 2012), BBT594 (NVP-BBT594) (Koppikar, et al., 2012; Andraos, et al., 2012), CEP-33799 (Dugan, et al., 2012), CHZ868 (Wu, et al., 2015), FM381 (Forster, et al., 2016; Forster, et al., 2018), PF-04965842 (Vazquez, et al., 2018), PF-06263276 (Jones, et al., 2017), PF-06651600 (Thorarensen, et al., 2017; Telliez, et al., 2016), PF-06700841 (Fensome, et al., 2018), SAR-20347 (Works, et al., 2014), NDI-031301 (Akahane, et al., 2017), NDI-31232 (Masse, et al., 2015), NVP-P830 (Brasca, et al., 2015) SHR-0302 (Wu, et al., 2016), VR588 (Wiegman, et al., 2015), XL019 (Forsyth, et al., 2012), TG101209 (Demyanets, et al., 2018; Pardanani, et al., 2007), R333 and R348 (Deuse, et al., 2008), 3-amido pyrrolopyrazine (Cmpd 3q) (Soth, et al., 2013), pyridone containing tetracycle (Cmpd 6) (Thompson, et al., 2001; Williams, et al., 2009), triazolo-pyrrolopyridines (Cmpd 7) (Hurley, et al., 2013), pyrazolopyrimidines (Cmpd 7j) (Hanan, et al., 2012), 1-amino-[1,2,4]triazolo[1,5-a]pyridines (Cmpd 12) (Siu, et al., 2013), imidazolopyridines (Cmpd 19) (Simov, et al., 2016), 1-methyl-1H-imidazole derivatives (Cmpd 19a) (Su, et al., 2014), C-2 methyl imidazopyrrolopyridines (Cmpd 20) (Zak, et al., 2012), pyrazolopyridinone (Cmpd 20a) (Yogo, et al., 2016), 9H-carbazole-1-carboxamides (Cmpd 21) (Zimmermann, et al., 2015), thianopyridines (Cmpd 23) (Schenkel, et al., 2011), pyrazole-4-carboxamide (Cmpd 28) (Siu, et al., 2017), imidazopyridine (Cmpd 30) (Liang, et al., 2017), hydroxyethyl imidazo-pyrrolopyridines (Cmpd 31) (Zak, et al., 2013), pyrrolopyridazines (Cmpd 35) (Hynes, et al., 2017), 6-oxopyridopyrimidines (Compound 36) (Labadie, et al., 2013), 2-aminopyrazolo[1,5-a]pyrimidines (Cmpd 45) (Ledeboer, et al., 2009), cyclopropyl amides (Cmpd 46) (Liang, et al., 2013; Liang, et al., 2013), imidazo-pyrrolopyridines (Cmpd 49) (Kulagowski, et al., 2012), 1-amino-5H-pyrido[4,3-b]indol-4-carboxamides (Cmpd 65) (Lim, et al., 2011), and covalent selective inhibitors of JAK3 (Cmpd 3) (Goedken, et al., 2015), (Cmpd 13a) (Kempson, et al., 2017), and (Cmpd 45a) (Tan, et al., 2015).

Despite the approval of JAK2 kinase inhibitors for the treatment of MPNs, the efficacy of these drugs is generally modest and short-lived (Tefferi 2012). A key mechanism of resistance to JAK2 kinase inhibitors is the kinase-independent functions of JAK2. Knockout of JAK2 in mouse models results in embryonic lethality due to a complete loss of EpoR signaling and a lack of erythropoiesis (Neubauer, Cumano et al. 1998). JAK2-knockout mice also show deficient interferon γ signaling. The tyrosine residues 1007/1008 of JAK2 within the kinase activation loop are essential for its kinase activity. Using a genetically engineered mouse model that expresses a kinase-dead mutant (YY1007/1008FF) of JAK2, Keil and colleagues demonstrate that kinase-dead JAK2 partially sustains the interferon γ signaling, possibly through acting as a scaffolding protein at the heteromeric interferon γ receptor (Keil, Finkenstadt et al. 2014). It is also well documented that JAK2 kinase inhibitors stimulate the activation loop phosphorylation, leading to reactivation of JAK signaling through dimerization of JAK2 with other JAK kinases, and consequently promoting resistance to JAK2 kinase inhibitors in MPNs (Koppikar, Bhagwat et al. 2012). Most importantly, cells resistant to JAK2 kinase inhibitors remain sensitive to depletion of JAK2 expressions (Koppikar, Bhagwat et al. 2012). Therefore, depleting JAK2 protein is an appealing strategy to improve outcomes of patients with JAK2-driven MPNs.

Without wishing to be bound by any theory, the present disclosure is believed to be based, at least in part, on the discovery that novel heterobifunctional small molecules which degrade JAK (e.g. JAK1, JAK2, JAK3, and TYK2), JAK fusion proteins, JAK deletion proteins, and/or JAK mutant proteins are useful in the treatment of JAK-mediated diseases: such as cancer (e.g. cancers of brain, stomach, gastrointestinal tracts, liver, biliary passage, breast, ovary, cervix, prostate, testis, penile, genitourinary tract, esophagus, larynx, skin, lung, pancreas, thyroid, glands, bladder, kidney, muscle, bone, and cancers of the hematopoietic system, such as myeloproliferative neoplasms, including essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic neutrophilic leukemia, acute lymphoblastic leukemia, Hodgkin's lymphoma, chronic myelomonocytic leukemia, systemic mast cell disease, hypereosinophilic syndrome, cutaneous T-cell lymphoma, B-cell lymphoma, myeloma, and other hematologic malignancies, particularly cancers that involve inflammation, mutations or other aberrations that activate the JAK pathway) (LaFave and Levine 2012, O'Shea, Holland et al. 2013); inflammation (e.g. ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, and ischemia reperfusion injuries, which are conditions related to inflammatory ischemic events such as stroke or cardiac arrest) (Schwartz, Kanno et al. 2017); auto-immune diseases (e.g. multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, myasthenia gravis, type I diabetes, systemic lupus erythematosus, IgA nephropathy, autoimmune thyroid disorders, alopecia areata, and bullous pemphigoid) (O'Shea, Kontzias et al. 2013); dermatological disorders (e.g. atopic dermatitis, pruritus, alopecia areata, psoriasis, skin rash, skin irritation, skin sensitization, chronic mucocutaneous candidiasis, dermatomyositis, erythema multiforme, palmoplantar pustulosis, vitiligo, polyarteritis nodosa, and STING-associated vasculopathy) (Damsky and King 2017); viral infections (e.g. viral infections and consequent complications, such as infections of Hepatitis B, Hepatitis C, Human Immunodeficiency Virus (HIV), Human T-lymphotropic Virus (HTLV1), Epstein Barr Virus (EBV), Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV)) (Fleming 2016); dry eye disorder, also known as dry eye syndrome (DES) or keratoconjunctivitis sicca (KCS) (Colligris, Alkozi et al. 2014); bone remodeling disorders (e.g. osteoporosis and osteoarthritis) (Li 2013); organ transplant associated immunological complications (e.g. graft-versus-host diseases) (Moore, Iasella et al. 2017).

Termination of translation is a GTP-dependent process that is regulated by two key proteins eRF1 and eRF3. The translation termination factor eRF3a (also known as GSPT1) is a GTPase that interacts with eRF1 to promote stop codon recognition and release of nascent peptide from ribosome (Chauvin, Salhi et al. 2005). GSPT1 activates eRF1 in a GTP-dependent manner and its GTPase activity requires complexing with eRF1 and ribosomes (Frolova, Le Goff et al. 1996). The GTP-bound GSPT1 and eRF1 together with ribosomes form the functional translation termination complexes (Zhouravleva, Frolova et al. 1995). Through regulation of translation, GSPT1 has diverse and important roles in cell physiology. Increased expression of GSPT1 has been reported in human malignancies, including lung cancer and gastric cancer (Malta-Vacas, Aires et al. 2005, Tian, Tian et al. 2018, Sun, Zhang et al. 2019, Zhang, Zou et al. 2019). Hence, GSPT1 is thought to be a novel cancer target through which may compromise active translation that contributes to malignant phenotypes of cancer cells. Recently, Matyskiela and colleagues have reported that a phthalimide-derived molecule CC-885 led to cereblon-dependent degradation of GSPT1 and other targets, such as IKZF1 and IKZF3 (Matyskiela, Lu et al. 2016). Ishoey et al. also reported that GSPT1 was degraded by a subset of heterobiofunctional compounds derived from phthalimide (Ishoey, Chorn et al. 2018). CC-885 induced significant toxicity in the vast majority of tested cell lines, presumably due to degrading GSTP1 and many other proteins (Matyskiela, Lu et al. 2016). Therefore, despite the broad and potent anti-cancer activity, CC-885 exhibits unacceptable toxicity that prevents further development (Hansen, Correa et al. 2020).

Selective degradation of a target protein induced by a small molecule may be achieved by recruiting an E3 ubiquitin ligase and mimicking protein misfolding with a hydrophobic tag (Buckley and Crews 2014). Additionally, protein degraders are heterobifunctional compounds having one moiety that binds to an E3 ubiquitin ligase and another moiety that binds the protein target of interest (Buckley and Crews 2014). The induced proximity leads to ubiquitination of the target followed by its degradation via proteasome-mediated proteolysis. Several types of high affinity small-molecule E3 ligase ligands have been identified or developed. They include (1) immunomodulatory drugs (IMiDs) such as thalidomide and pomalidomide, which bind cereblon (CRBN or CRL4CRBN), a component of a cullin-RING ubiquitin ligase (CRL) complex (Ito, Ando et al. 2010, Chamberlain, Lopez-Girona et al. 2014, Fischer, Bohm et al. 2014, Bondeson, Mares et al. 2015, Winter, Buckley et al. 2015); (2) VHL-1, a hydroxyproline-containing ligand, which binds van Hippel-Lindau protein (VHL or CRL2VHL), a component of another CRL complex (Buckley, Gustafson et al. 2012, Buckley, Van Molle et al. 2012, Galdeano, Gadd et al. 2014, Bondeson, Mares et al. 2015, Zengerle, Chan et al. 2015); (3) compound 7, which selectively binds KEAP1, a component of a CRL3 complex (Davies, Wixted et al. 2016); (4) AMG232, which selectively binds MDM2, a heterodimeric RING E3 ligase (Sun, Li et al. 2014); and (5) LCL161, which selectively binds IAP, a homodimeric RING E3 ligase (Okuhira, Ohoka et al. 2011, Ohoka, Okuhira et al. 2017, Shibata, Miyamoto et al. 2017). The PROTAC technology has been applied to degradation of several protein targets (Bondeson, Mares et al. 2015, Buckley, Raina et al. 2015, Lu, Qian et al. 2015, Winter, Buckley et al. 2015, Zengerle, Chan et al. 2015, Lai, Toure et al. 2016). In addition, a hydrophobic tagging approach, which utilizes a bulky and hydrophobic adamantyl group, has been developed to mimic protein misfolding, leading to the degradation of the target protein (Buckley and Crews 2014). This approach has been applied to selective degradation of the pseudokinase HER3 (Xie, Lim et al. 2014). The inventors have not yet seen any efforts applying any of these approaches to degradation of JAK (e.g. JAK1, JAK2, JAK3, and TYK2), JAK mutant, JAK deletion, or JAK fusion proteins.

Currently available small molecules targeting JAK (e.g. JAK1, JAK2, JAK3, and TYK2) focus on inhibition of JAK kinase activities.

In the present disclosure, a novel approach is taken: to develop compounds that directly and selectively modulate not only the kianse activity of JAK (e.g. JAK1, JAK2, JAK3, and TYK2), but also their protein level. Strategies for inducing protein degradation include recruiting E3 ubiquitin ligases, mimicking protein misfolding with hydrophobic tags, and inhibiting chaperones. Such an approach, based on the use of heterobifunctional small molecule compounds, permits more flexible regulation of protein levels in vitro and in vivo compared with techniques such as genetic knockout or knockdown. Unlike genetic knockout or knockdown, a small molecule approach further provides an opportunity to study dose and time dependency in a disease model through modulating the administration routes, concentrations and frequencies of administration of the corresponding small molecule.

This disclosure includes all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted and compounds named herein. This disclosure also includes compounds described herein, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.

This disclosure includes pharmaceutically acceptable salts of the structures depicted and compounds named herein.

One or more constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of the hydrogen atoms in a compound can be replaced or substituted by deuterium atoms. In some embodiments, the compound includes at least one fluorine atom. In some embodiments, the compound includes two or more fluorine atoms. In some embodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 fluorine atoms. In some embodiments, all of the hydrogen atoms in a compound can be replaced or substituted by fluorine atoms.

Heterobifunctional Compounds

As used herein, the term “heterobifunctional compound(s)” and “bivalent compound(s)” can be used interchangeably.

In some aspects, the present disclosure provides heterobifunctional compounds including a JAK ligand conjugated to a degradation tag, or a pharmaceutically acceptable salt or analog thereof. The JAK ligand may be conjugated to the degradation tag directly or via a linker moiety. In certain embodiments, the JAK ligand may be conjugated to the degradation tag directly. In certain embodiments, the JAK ligand may be conjugated to the degradation tag via a linker moiety.

As used herein, the terms “Janus kinase ligand” and “JAK ligand”, or “JAK targeting moiety” are to be construed to encompass any molecules ranging from small molecules to large proteins that associate with or bind to any of JAK1, JAK2, JAK3, or TYK2 proteins. In certain embodiments, the JAK ligand is capable of binding to a JAK protein comprising JAK (e.g. JAK1, JAK2, JAK3, and TYK2), a JAK mutant, a JAK deletion, or a JAK fusion protein. The JAK ligand can be, for example but not limited to, a small molecule compound (i.e., a molecule of molecular weight less than about 1.5 kilodaltons (kDa)), a peptide or polypeptide, nucleic acid or oligonucleotide, carbohydrate such as oligosaccharides, or an antibody or fragment thereof.

JAK Ligand

The JAK ligand or targeting moiety can be a JAK inhibitor or a portion of JAK inhibitor. In certain embodiments, the JAK inhibitor comprises one or more of (e.g., Ruxolitinib, Tofacitinib (CP-690550), Baricitinib, Oclacitinib, Cerdulatinib (PRT-062070), Decernotinib (VX509), Delgocitinib (JTE-052), Fedratinib, Filgotinib (GLP0634), Gandotinib (LY2784544), Ilginatinib (NS-018), Itacitinib (INCB03911), Lestauritinib, Momelotinib (CYT387), Pacritinib (SB1578), Peficitinib, Solcitinib (GSK2586184, GLG0778), Upadacitinib (ABT-494), AT9283, AZ-3, AZ960, AZD1480, BMS-986165, BMS-911543, BSK805 (NVP-BSK805) and BVB808 (NVP-BVB808), BBT594 (NVP-BBT594), CEP-33799, CHZ868, FM381, PF-04965842, PF-06263276, PF-06651600, PF-06700841, SAR-20347, NDI-031301 (Akahane, Li, & Etchin, 2017), NDI-31232 (Masse, Miao, Greenwood, Shelley, & Kapeller, 2015), NVP-P830, SHR-0302, VR588 (Wiegman, Adcock, Rothaul, Main, & Morgan, 2015), XL019, TG101209, R333 and R348 (Deuse, et al., 2008), 3-amido pyrrolopyrazine (Cmpd 3q), pyridone containing tetracycle (Cmpd 6), triazolo-pyrrolopyridines (Cmpd 7), pyrazolopyrimidines (Cmpd 7j), 1-amino-[1,2,4]triazolo[1,5-a]pyridines (Cmpd 12), imidazolopyridines (Cmpd 19), 1-methyl-1H-imidazole derivatives (Cmpd 19a), C-2 methyl imidazopyrrolopyridines (Cmpd 20), pyrazolopyridinone (Cmpd 20a), 9H-carbazole-1-carboxamides (Cmpd 21), thianopyridines (Cmpd 23), pyrazole-4-carboxamide (Cmpd 28), imidazopyridine (Cmpd 30), hydroxyethyl imidazo-pyrrolopyridines (Cmpd 31), pyrrolopyridazines (Cmpd 35), 6-oxopyridopyrimidines (Compound 36), 2-aminopyrazolo[1,5-a]pyrimidines (Cmpd 45), cyclopropyl amides (Cmpd 46), imidazo-pyrrolopyridines (Cmpd 49), 1-amino-5H-pyrido[4,3-b]indol-4-carboxamides (Cmpd 65), Cmpd 3, Cmpd 13a, Cmpd 45a, and analogs thereof), which is capable of inhibiting the protein-protein interaction or acetyltransferase activity of JAK. As used herein, a “JAK inhibitor” refers to an agent that restrains, retards, or otherwise causes inhibition of a physiological, chemical or enzymatic action or function and causes a decrease in binding of at least 5%. An inhibitor can also or alternately refer to a drug, compound, or agent that prevents or reduces the expression, transcription, or translation of a gene or protein. An inhibitor can reduce or prevent the function of a protein, e.g., by binding to or activating/inactivating another protein or receptor.

In certain embodiments, the JAK ligand is derived from a JAK inhibitor comprising:

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In certain embodiments, the JAK ligand include, but are not limited to Ruxolitinib, Tofacitinib (CP-690550), Baricitinib, Oclacitinib, Cerdulatinib (PRT-062070), Decernotinib (VX509), Delgocitinib (JTE-052), Fedratinib, Filgotinib (GLP0634), Gandotinib (LY2784544), Ilginatinib (NS-018), Itacitinib (INCB03911), Lestauritinib, Momelotinib (CYT387), Pacritinib (SB1578), Peficitinib, Solcitinib (GSK2586184, GLG0778), Upadacitinib (ABT-494), AT9283, AZ-3, AZ960, AZD1480, BMS-986165, BMS-911543, BSK805 (NVP-BSK805) and BVB808 (NVP-BVB808), BBT594 (NVP-BBT594), CEP-33799, CHZ868, FM381, PF-04965842, PF-06263276, PF-06651600, PF-06700841, SAR-20347, NDI-031301 (Akahane, Li, & Etchin, 2017), NDI-31232 (Masse, Miao, Greenwood, Shelley, & Kapeller, 2015), NVP-P830, SHR-0302, VR588 (Wiegman, Adcock, Rothaul, Main, & Morgan, 2015), XL019, TG101209, R333 and R348 (Deuse, et al., 2008), 3-amido pyrrolopyrazine (Cmpd 3q), pyridone containing tetracycle (Cmpd 6), triazolo-pyrrolopyridines (Cmpd 7), pyrazolopyrimidines (Cmpd 7j), 1-amino-[1,2,4]triazolo[1,5-a]pyridines (Cmpd 12), imidazolopyridines (Cmpd 19), 1-methyl-1H-imidazole derivatives (Cmpd 19a), C-2 methyl imidazopyrrolopyridines (Cmpd 20), pyrazolopyridinone (Cmpd 20a), 9H-carbazole-1-carboxamides (Cmpd 21), thianopyridines (Cmpd 23), pyrazole-4-carboxamide (Cmpd 28), imidazopyridine (Cmpd 30), hydroxyethyl imidazo-pyrrolopyridines (Cmpd 31), pyrrolopyridazines (Cmpd 35), 6-oxopyridopyrimidines (Compound 36), 2-aminopyrazolo[1,5-a]pyrimidines (Cmpd 45), cyclopropyl amides (Cmpd 46), imidazo-pyrrolopyridines (Cmpd 49), 1-amino-5H-pyrido[4,3-b]indol-4-carboxamides (Cmpd 65), Cmpd 3, Cmpd 13a, and Cmpd 45a.

In one embodiment, the JAK ligand comprises a moiety of FORMULA 1:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

A and D are independently selected from CR⁴and N, wherein

R⁴is selected from hydrogen, halogen, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl;

B, C, and G are independently selected from C and N; with the proviso that at most only one of B, C, and G is N;

E and F are independently selected from null, CR⁵and N, wherein

R⁵is selected from hydrogen, halogen, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl;

R⁶and R⁷together with the atom or atoms to which they are connected form a 3-20 membered carbocyclyl ring or 4-20 membered heterocyclyl ring;

V and W are independently selected from null, carbocyclyl, heterocyclyl, aryl, and heteroaryl, which are optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, NR⁸R⁹, OCOR⁸, OCO₂R⁸, OCONR⁸R⁹, COR⁸, CO₂R⁸, CONR⁸R⁹, SOR⁸, SO₂R⁸, SO₂NR⁸R⁹, NR¹⁰CO₂R⁸, NR¹⁰COR⁸, NR¹⁰C(O)NR⁸R⁹, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, NR¹⁰SO₂NR⁸R⁹, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 4-10 membered heterocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;

R³, at each occurrence, is selected from hydrogen, halogen, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl; and

n is selected from 1 or 2.

In one refinement, V is Ar².

In one refinement, the JAK ligand comprises a moiety of FORMULA 1A:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

A, B, C, D, E, F, G, X, Y, W, R¹, R², R³, and n are the same as defined in FORMULA 1; and

Ar²is selected from null, aryl, and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, NR⁸R⁹, OCOR⁸, OCO₂R⁸, OCONR⁸R⁹, COR⁸, CO₂R⁸, CONR⁸R⁹, SOR⁸, SO₂R⁸, SO₂NR⁸R⁹, NR¹⁰CO₂R⁸, NR¹⁰COR⁸, NR¹⁰C(O)NR⁸R⁹, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, NR¹⁰SO₂NR⁸R⁹, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 4-10 membered heterocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-20 membered heterocyclyl ring.

In another refinement, V is Ar²; and W is Ar¹. The JAK ligand comprises a moiety of FORMULA 1B:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

A, B, C, D, E, F, G, X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1; and

Ar¹and Ar²are independently selected from null, aryl, and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, NR⁸R⁹, OCOR⁸, OCO₂R⁸, OCONR⁸R⁹, COR⁸, CO₂R⁸, CONR⁸R⁹, SOR⁸, SO₂R⁸, SO₂NR⁸R⁹, NR¹⁰CO₂R⁸, NR¹⁰COR⁸, NR¹⁰C(O)NR⁸R⁹, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, NR¹⁰SO₂NR⁸R⁹, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 4-10 membered heterocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-20 membered heterocyclyl ring.

In another refinement, A is N. The JAK ligand comprises a moiety of FORMULA 1C:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹; and

B, C, D, E, F, G, V, W, X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1.

In another refinement, A is N; and V is Ar². The JAK ligand comprises a moiety of FORMULA 1D:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

B, C, D, E, F, G, W, X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1; and

Ar²is the same as defined in FORMULA 1A.

In another refinement, A is N; V is Ar²; and W is Ar¹.

In another refinement, the JAK ligand comprises a moiety of FORMULA 1E:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

B, C, D, E, F, G, X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1, and

Ar¹and Ar²are the same as defined in FORMULA 1B.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 1F, 1G, 1H, or 1I:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

V, W, X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1; and

R¹³and R¹⁴are selected from hydrogen, halogen, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 1J, 1K, 1L, or 1M:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

W, X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1;

Ar²is the same as defined in FORMULA 1A; and

R¹³and R¹⁴are the same as defined in FORMULAE 1F, 1G, 1H or 1I.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 1N, 1O, 1P, and 1Q:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

X, Y, R¹, R², R³, and n are the same as defined in FORMULA 1;

Ar¹and Ar²are the same as defined in FORMULA 1B; and

R¹³and R¹⁴are the same as defined in FORMULAE 1F, 1G, 1H, or 1I.

In another refinement, X is selected from null, O, and NR⁶, wherein

R⁶is selected from hydrogen, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl.

In another refinement, X is selected from null and NH.

In another refinement, Y is selected from null, CR^6′R⁷, CO, CO₂, O, SO, SO₂, and NR^6′, wherein

In another refinement, Y is selected from null, CH₂, CO, and SO₂.

In another refinement, Ar¹and Ar²are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is substituted with R²and optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, NR⁸R⁹, COR⁸, CO₂R⁸, CONR⁸R⁹, SOR⁸, SO₂R⁸, SO₂NR⁸R⁹, NR¹⁰COR⁸, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, optionally substituted C₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-10 membered heterocyclyl ring.

In another refinement, Ar¹and Ar²are independently selected from null, monocyclic aryl, monocyclic heteroaryl, bicyclic aryl, bicyclic heteroaryl, tricyclic aryl, and tricyclic heteroaryl, each of which is substituted with R²and optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, NR⁸R⁹, NR¹⁰COR⁸, optionally substituted C₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-10 membered heterocyclyl ring.

In another refinement, R¹is selected from null, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.

In another refinement, R¹is selected from null and optionally substituted 4-10 membered heterocyclyl, which contains at least one of O or N.

In another refinement, R³, at each occurrence, R¹³and R¹⁴are selected from hydrogen, CH₃, CF₃, iPr, cPr, tBu, CNCH₂, F, Cl, Br, OH, NH₂, CN, CH₃, and CONH₂.

In another embodiment, the JAK ligand comprises a moiety of FORMULA 2:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

A, B, and D are independently selected from CR³and N, with the proviso that not all of A, B, and D are N, wherein

R³is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, CONR⁴R⁵, optionally substituted C₁-C₈alkyl, and optionally substituted 3-10 membered carbocyclyl, wherein

R⁴and R⁵together with the atom or atoms to which they are connected form a 3-20 membered carbocyclyl ring or 4-20 membered heterocyclyl ring;

R⁶and R⁷together with the atom or atoms to which they are connected form a 3-20 membered carbocyclyl ring or 4-20 membered heterocyclyl ring;

V and W are independently selected from null, carbocyclyl, heterocyclyl, aryl, and heteroaryl, which are optionally substituted with one or more substituents independently selected from hydrogen, halogen, oxo, CN, NO₂, OR⁸, SR⁸, NR⁸R⁹, OCOR⁸, OCO₂R⁸, OCONR⁸R⁹, COR⁸, CO₂R⁸, CONR⁸R⁹, SOR⁸, SO₂R⁸, SO₂NR⁸R⁹, NR¹⁰CO₂R⁸, NR¹⁰COR⁸, NR¹⁰C(O)NR⁸R⁹, NR¹⁰SOR⁸, NR¹⁰SO₂R⁸, NR¹⁰SO₂NR⁸R⁹, optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈alkynyl, optionally substituted C₁-C₈alkoxyC₁-C₈alkyl, optionally substituted C₁-C₈alkylaminoC₁-C₈alkyl, optionally substituted 4-10 membered heterocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclylC₁-C₈alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, wherein

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;

R¹is connected to the “linker” moiety of the heterobifunctional compound, and is selected from null, R′—R″, R′OR″, R′SR″, R′NR¹¹R″, R′OC(O)R″, R′OC(O)OR″, R′OCON(R¹¹)R″, R′C(O)R″, R′C(O)OR″, R′CON(R¹¹)R″, R′S(O)R″, R′S(O)₂R″, R′SO₂N(R¹¹)R″, R′NR¹²C(O)OR″, R′NR¹²C(O)R″, R′NR¹²C(O)N(R¹¹)R″, R′NR¹²S(O)R″, R′NR¹²S(O)₂R″, and R′NR¹²S(O)₂N(R¹¹)R″, wherein

In another refinement, V is Ar².

In another refinement, the JAK ligand comprises a moiety of FORMULA 2A:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

A, B, D, X, Y, W, R¹, and R²are the same as defined in FORMULA 2;

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-20 membered heterocyclyl ring; and

In another refinement, V is Ar²; and W is Ar¹. The JAK ligand comprises a moiety of FORMULA 2B:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

A, B, D, X, Y, R¹, and R²are the same as defined in FORMULA 2; and

R⁸and R⁹, R⁸and R¹⁰together with the atom to which they are connected form a 4-20 membered heterocyclyl ring; and

When neither of Ar¹and Ar²is null, Ar¹and Ar²together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; When Ar¹is null and Ar²is not null, Ar²and R¹together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; When Ar²is null and Ar¹is not null, Ar¹and R²together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring; or When Ar¹and Ar²are null, R¹and R²together with the substituents to which they are connected optionally form a 10-30 membered macrocyclic ring.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 2C, 2D, 2E or 2F:

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wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

X, Y, Ar¹, Ar², R¹, and R²are the same as defined in FORMULA 2; and

R⁴and R⁵together with the atom or atoms to which they are connected form a 3-20 membered carbocyclyl ring or 4-20 membered heterocyclyl ring.

In another refinement, the JAK ligand comprises a moiety of FORMULAE 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R or 2S:

embedded image

wherein

the linker moiety of the heterobifunctional compound is attached to R¹;

Y, R¹and R²are the same as defined in FORMULA 2;

Ar¹and Ar²are the same as FORMULA 2B; and

R¹³, R¹⁴and R¹⁵are the same as FORMULAE 2C, 2D, 2E or 2F.