Innovative Targeted Therapy for Immune Regulation

Introduction

This groundbreaking targeted degradation technology offers a precise approach to managing inflammatory diseases by degrading interleukin-1 receptor-associated kinase 4 (IRAK4) polypeptides, proteins linked to immune responses that can drive inflammation. Through targeted molecular action, this technology allows for precise modulation of immune signaling pathways, helping reduce inflammation with greater specificity and fewer side effects. Companies in the biotechnology, pharmaceutical, and immunology fields can leverage this technology to develop novel treatments for autoimmune diseases and inflammatory conditions, positioning themselves as leaders in advanced, targeted therapeutics.

The Challenge: Balancing Immune Response and Inflammation

Inflammatory diseases, including autoimmune disorders and certain cancers, are often driven by overactive immune responses that damage healthy tissues. Conventional therapies can suppress immune activity, but often lack the precision to target specific signaling molecules, leading to potential side effects and a weakened immune system. Providers and patients alike need solutions that can effectively target immune pathways, specifically molecules that contribute to inflammation, without compromising overall immune health.

Precision in Action: IRAK4 Targeted Degradation

This technology provides a novel approach by directly degrading IRAK4 polypeptides, selectively inhibiting a critical pathway in inflammation. By breaking down this specific protein, it reduces the overactive immune signaling that drives inflammatory diseases, offering a targeted solution that mitigates harmful immune activity while preserving broader immune function. The precise degradation mechanism offers significant advantages over traditional immune-modulating therapies, ensuring the immune system remains responsive to actual threats while reducing unnecessary inflammation. This approach allows healthcare providers to offer patients more effective treatments with a focus on safety and targeted action.

Key Benefits for Biotech and Pharma

For biotechnology and pharmaceutical companies, this targeted degradation technology represents a significant leap forward in immune regulation and inflammation control. It enables the development of specialized therapies for autoimmune diseases, oncology, and other conditions linked to inflammation, supporting the growing trend toward precision medicine. By integrating this approach into their pipeline, companies can enhance their portfolio with a unique, patient-focused technology that meets the needs of a diverse range of inflammatory diseases. The technology aligns well with market demand for safer, more precise immunotherapies, opening new opportunities in a highly competitive field.

Invest in the Future of Inflammation Therapy

Licensing this targeted immune regulation technology positions your company as a leader in innovative inflammation therapies. By providing a safe, precise solution for immune modulation, your business can support the development of therapies that are highly specific and patient-centered. This investment offers immense potential for companies committed to advancing patient care, reducing inflammation safely, and leading in the field of immunology and targeted treatment solutions.

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Abstract
Claims

The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

1. A bifunctional compound having the chemical structure:

ULM-L-PTM,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,

wherein:

the ULM is a small molecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase;

the PTM is a small molecule comprising an Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) targeting moiety; and

the L is a bond or a chemical linking moiety connecting the ULM and the PTM.

2. The bifunctional compound according to claim 1, wherein the E3 ubiquitin ligase binding moiety that targets an E3 ubiquitin ligase selected from the group consisting of Von Hippel-Lindau (VLM), cereblon (CLM), mouse double-minute homolog2 (MLM), and IAP (ILM).

3. The compound according to claim 1, wherein PTM is represented by Formula PTM-I:

wherein:

X of PTM-I is —N═ or —CH═;

Y of PTM-I is selected from the group consisting of —NR²—, —CH₂— and —O—; or when Y is —NR²—, R²and R³together with the nitrogen to which they are attached optionally form a 4- to 6-membered heterocyclic ring, wherein the 4- to 6-membered heterocyclic ring is optionally substituted with 1 to 3 substituents independently selected from R⁷groups;

R¹of PTM-I is selected from the group consisting of: hydrogen, C_1-10alkyl, C_3-8cycloalkyl, aryl, heterocyclyl, halogen, —COOR⁷, —NR⁷, —SR⁷, —OR⁷, —SO₂R⁷, —COR⁷, —NCOR⁷, and —CONR⁷;

R²of PTM-I is selected from the group consisting of: hydrogen, C_1-10alkyl, and C_3-4cycloalkyl;

R³of PTM-I is selected from the group consisting of: hydrogen, C_1-10alkyl, C_3-4cycloalkyl, aryl, heterocyclyl, and —COOR⁷;

R⁶of PTM-I is selected from the group consisting of: C_1-10alkyl, C_3-4cycloalkyl, aryl, heterocyclyl, —COOR⁷, —SO₂R⁷, —COR⁷; and

R⁷of PTM-I is selected from the group consisting of: hydrogen, C_1-10alkyl, C_3-4cycloalkyl, aryl, and heteroaryl;

wherein each of the C_1-10alkyl, C_3-4cycloalkyl, aryl and heterocyclyl of R¹, R³, R⁶and R⁷is optionally substituted with 1-4 substituents independently selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, halogen, —SO₂R⁸and —OR⁸; and

R⁸of PTM-I is selected from the group consisting of hydrogen, and C_1-6alkyl.

4. The compound of claim 1, wherein the PTM is represented by Formula PTM-II:

wherein:

R¹of PTM-II is aryl, heteroaryl, heterocyclyl or (C_1-6alkyl)R⁶, wherein said aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or two substituents selected from the group consisting of halo, cyano, R⁴, C_1-3aminoalkyl, C_1-3hydroxyalkyl, C_3-4cycloalkyl, OR⁴, NR⁴R⁵, NR⁴COR⁶, NR⁴SO₂R⁶, SO₂NR⁴R⁵, CONR⁴R⁵;

R²of PTM-II of PTM-II is aryl, heteroaryl, C_3-8cycloalkyl, heterocyclyl or (C_1-6alkyl)R⁶, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one or two substituents selected from the group consisting of halo, cyano, oxo, hydroxyl, imino, hydroxyimino, R⁴, OR⁴, O(C_3-8cycloalkyl), (C═O)OR⁴, SO_mR⁶, SO_mR⁴, NR⁴R⁵, SO₂NR⁴R⁵and NR⁴SO₂R⁶;

R³of PTM-II is a halo, cyano, oxo, hydroxyl, imino, hydroxyimino, R⁴, OR⁴, C_3-8cycloalkyl, SO_mR⁶, SO_mR⁴NR⁴R⁵, or (C═O)NR⁴R⁵, NR⁴(CO)R⁶, SO_mNR⁴R⁵and NR⁴SO₂R⁶;

R⁴of PTM-II is independently hydrogen or C_1-6alkyl, wherein said alkyl is optionally substituted with one to three halo or hydroxyl;

R⁵of PTM-II is independently hydrogen or C_1-6alkyl, wherein said alkyl is optionally substituted with halo or hydroxyl;

R⁶of PTM-II is independently aryl, heteroaryl, C_3-8cycloalkyl or heterocyclyl; and

m of PTM-II is an integer from zero to two.

5. The compound of claim 1, wherein the PTM is represented by Formula PTM-III:

wherein:

R¹of PTM-III is an optionally substituted aromatic heterocyclic group or an optionally substituted C_6-14aryl group;

R²of PTM-III is a hydrogen atom or a substituent;

R³and R⁴of PTM-III are independently a hydrogen atom or a substituent, or R³and R⁴in combination optionally form an optionally substituted ring;

R⁵and R⁶of PTM-III are independently a hydrogen atom or a substituent, or R⁵and R⁶in combination optionally form an optionally substituted ring;

X of PTM-III is CR⁷R⁸, NR⁹, O or S;

R⁷and R⁸of PTM-III are independently a hydrogen atom or a substituent, or R⁷and R⁸in combination optionally form an optionally substituted ring; and

R⁹of PTM-III is a hydrogen atom or a substituent.

6. The compound of claim 1, wherein the PTM is represented by Formula PTM-IV:

wherein:

HET of PTM-IV is a heteroaryl selected from pyrazolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b]pyridinyl, and purinyl, wherein said heteroaryl is substituted with R_aand R_b;

R_aof PTM-IV is H, F, Cl, Br, —CN, —OH, C_1-4alkyl, C_1-4fluoroalkyl, C_1-4hydroxyalkyl, C_1-4alkoxy, —NH₂, —NH(C_1-4alkyl), —N(C_1-4alkyl)₂, —NH(C_1-4hydroxyalkyl), —NH(C_1-4fluoroalkyl), —NH(C_1-6hydroxy-fluoroalkyl), —C(O)NH₂, —CH₂NHC(O)(C_1-6alkyl), —CH₂NHC(O)(C_1-6hydroxyalkyl), —CH₂NHC(O)NH(C_1-6alkyl), CH₂NHC(O)NHCH₂(phenyl), —CH₂NHC(O)N(C_1-4alkyl)₂, —CH₂NHC(O)O(C_1-4alkyl), —CH₂NHC(O)(C_3-6cycloalkyl), —CH₂NHC(O)(tetrahydrofuranyl), CH₂NHC(O)CH₂(C_3-6cycloalkyl), —CH₂NHC(O)CH₂(tetrahydropyranyl), CH₂NHC(O)CH₂(phenyl), —NHC(O)(C_1-4alkyl), pyrrolidinyl, hydroxypyrrolidinyl, or pyridazinyl;

R_bof PTM-IV is H or —NH₂;

R₁of PTM-IV is: (i) C_1-6alkyl, C_1-6fluoroalkyl, C_1-6hydroxyalkyl, C_1-8hydroxy-fluoroalkyl, —(C_1-6alkylenyl)O(C_1-4alkyl), —(C_1-6alkylenyl)O(C_1-4fluoroalkyl), —(C_1-6fluoroalkylenyl)O(C_1-4alkyl), —(C_1-6fluoroalkylenyl)O(C_1-4deuteroalkyl), —(C_1-6fluoroalkylenyl)O(C_1-4fluoroalkyl), —(C_1-4fluoroalkylenyl)C(C_3-6cycloalkyl)₂(OH), (C_1-4alkylenyl)NHC(O)(C_1-4alkylenyl)OC(O)(C_1-3alkyl), —(C_1-6alkylenyl)NHS(O)₂(C_1-4alkyl), —(C_1-6alkylenyl)_P(O)(C_1-4alkoxy)₂, —(C_1-6fluoroalkylenyl)NH(C_1-4alkyl), —(C_1-6alkylenyl)C(O)NH(C_1-4alkyl), —(C_1-6fluoroalkylenyl)C(O)NH(C_1-4alkyl), —(C_1-6fluoroalkylenyl)C(O)NH(C_1-4hydroxyalkyl), or —(C_1-6fluoroalkylenyl)OP(O)(OH)₂; (ii) —(C_1-3alkylenyl)R_x, —(C_1-3fluoroalkylenyl)R_x, —(C_1-3alkylenyl)C(O)R_x, —(C_1-3alkylenyl)C(O)NHR_x, —(C_1-3fluoroalkylenyl)C(O)R_x, or —CH₂CF=(tetrahydropyranyl), wherein R_xis a cyclic group selected from C_3-6cycloalkyl, tetrazolyl, 1,1-dioxidotetrahydrothiophenyl, 1,1-dioxidothiomorpholinyl, oxadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, imidazolyl, morpholinyl, phenyl, and triazinyl, wherein each cyclic group is substituted with zero to 3 substituents independently selected from F, —OH, —CH₃, —C(CH₂)₂OH, —OCH₃, —C(O)CH₂CN, —S(O)₂CH₃, —S(O)₂NH₂, —NHC(O)CH₃, —N(S(O)₂CH₃)₂, —CH₂CH₂(acetamidophenyl), —CH₂CH₂(methoxyphenyl), —CH₂CH₂(sulfamoylphenyl), oxetanyl, benzyl, and morpholinyl; (iii) C3-6 cycloalkyl or C4-6 cycloalkenyl, each substituted with zero to 3 substituents independently selected from F, —OH, —CN, C1-3 alkyl, C1-3 alkoxy, —S(C1-3 alkyl), —NO2, —S(O)2(C1-3 alkyl), C1-4 hydroxyalkyl, —C(C1-3 alkyl)(OH)(C3-6 cycloalkyl), —CH2C(O)NH(C1-3 alkyl), —NHC(O)(C1-3 alkyl), —NHC(O)(C1-4 hydroxyalkyl), —C(O)NH(C1-3 alkyl), C(O)NH(C1-3 deuteroalkyl), —C(O)NH(C3-6 cycloalkyl), —NHC(O)O(C1-3 alkyl), NHS(O)2(C1-3 alkyl), pyridinyl, imidazolyl, pyrazolyl, methylimidazolyl, methylpyrazolyl, and thiazolyl; (iv) tetrahydropyranyl, piperidinyl, pyrazolyl, phenyl, pyridinyl, or pyrimidinyl, each substituted with zero to 1 substituent selected from —OH, C1-3 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkoxy, —C(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), —S(O)2NH(C1-4 alkyl), —NH(C1-3 alkyl), —N(C1-3 alkyl)2, O(C1-3 alkylenyl)N(C1-3 alkyl)2, —CH2(morpholinyl), azetidinyl, oxetanyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, methylpiperazinyl, methoxypiperidinyl, pyridinyl, pyrimidinyl, methylsulfonyl azetidinyl, and C(O)(methylsulfonyl azetidinyl); or (v) pyrrolo[2,3-c]pyridinyl, bicyclo[2.2.1]heptan-1-ol, tetrahydrobenzo[d]thiazol-2-amine, or 1,3-diazaspiro[4.5]decane-2,4-dione; and

R₂is: (i) C_1-7alkyl or C_2-6alkenyl, each substituted with zero to three substituents independently selected from F, —OH, and —CN; —(C_1-4alkylenyl)O(C_1-4alkyl), —(C_1-4alkylenyl)O(C_1-4fluoroalkyl), —(C_1-6alkylenyl)NH2, —(C_1-6alkylenyl)S(O)₂(C_1-3alkyl), —(C_1-6fluoroalkylenyl)NH(C_1-3alkyl), or —(C_1-6alkylenyl)NHC(O)(C_1-4fluoroalkyl); (ii) —(C₁-4 alkylenyl)R_ywherein R_yis C_3-6cycloalkyl, azetidinyl, oxetanyl, oxazolyl, pyridinyl, tetrahydropyranyl, or morpholinyl, each substituted with zero to 2 substituents independently selected from F, —OH, and C_1-3alkyl; (iii) C_3-6cycloalkyl, azetidinyl, oxetanyl, furanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, or tetrahydropyranyl, each substituted with zero to 3 substituents independently selected from F, —OH, C_1-3alkyl, C₁-3 hydroxyalkyl, —C(O)(C_1-3alkyl), —C(O)(C_1-3fluoroalkyl), —C(O)(C_1-3cyanoalkyl), C(O)O(C_1-3alkyl), —C(O)NH₂, —C(O)NH(C_1-3alkyl), —C(O)(difluorophenyl), —NH₂, —NH(C_1-3alkyl), —NH(C_1-3fluoroalkyl), —NH(oxetanyl), —NHC(O)(C_1-3alkyl), NHC(O)(C_1-3fluoroalkyl), —NHC(O)(C_3-6cycloalkyl), —NHC(O)(fluorophenyl), S(O)₂(C_1-3alkyl), imidazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, and methoxypyrimidinyl; (iv) adamantanyl, hydroxyadamantanyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]triazolyl, benzothiazolyl, bicyclo[1.1.1]pentanyl, or hydroxybicyclo[2.2.1]heptanyl; or (v) phenyl, pyrazolyl, thiazolyl, thiadiazolyl, or indazolyl, each substituted with 0 to 2 substituents independently selected from F, Cl, —OH, —CN, C_1-4alkyl, C_1-4hydroxyalkyl, C_1-4fluoroalkyl, C_1-4cyanoalkyl, C_1-3alkoxy, C_3-6cycloalkyl, —(C_1-3alkylenyl)O(C_1-3alkyl), —(C_1-3alkylenyl)O(C_1-3fluoroalkyl), —C(O)NH₂, —C(O)NH(C_1-3alkyl), —NHC(O)(C_1-3alkyl), —NHC(O)S(O)₂(C_1-3alkyl), —S(O)₂NH₂, S(O)₂(C_1-3alkyl), pyrazolyl, methyl pyrazolyl, imidazolyl, triazolyl, methyl tetrazolyl, ethyl tetrazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl, and tetrahydropyranyl.

7. The compound of claim 1, wherein the PTM is represented by Formula PTM-Va or PTM-Vb:

wherein:

X₁and X₃of PTM-Va or PTM-Vb independently are CH or N; X₂of PTM-V is CR₂or N; provided one and not more than one of X₁, X₂or X₃is N;

Y of PTM-Va or PTM-Vb is —CH₂— or O;

Ring Z of PTM-Va or PTM-Vb is aryl, heteroaryl, or heterocyclyl;

A of PTM-Va or PTM-Vb is O, S, or NH;

R₁of PTM-Va or PTM-Vb at each occurrence, is independently hydrogen, cyano, halo, hydroxy, —NO2, —NR₅R₆, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the substituent, in each occurrence, is independently selected from alkyl, alkoxy, haloalkyl, cyano, aminoalkyl, halo, hydroxyl, hydroxyalkyl, —NR⁷R⁸, or COOR⁹;

R₂of PTM-Va or PTM-Vb is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or —NR_aR_b; wherein the substituent is alkyl, amino, halo or hydroxyl;

R₃of PTM-V, at each occurrence, is independently selected from hydrogen, carboxy, cyano, hydroxy, hydroxyalkyl, alkyl, aryl, heteroaryl, —SO₂R⁷, hydroxyl or oxo;

R₄of PTM-Va or PTM-Vb at each occurence is independently selected from hydrogen, halogen, alkyl, aryl, heterocycloalkyi, heterocycloalkylalkyl, heteroaryl, Y-arylalkyl or —Y-cycloalkyl; wherein cycloalkyl, aryl, heterocycloalkyi, heterocycloalkylalkyl, heteroaryl and arylalkyl can be optionally substituted with hydroxy, alkyl, haloalkyl, cyano or halo;

Y₁of PTM-Va or PTM-Vb is selected from direct bond, O, —C(O)— or NR⁹;

R₅and R₆of PTM-Va or PTM-Vb are independently selected from hydrogen, hydroxyalkyl, aminoalkyl, acyl, optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted aryl; wherein the optional substituent, in each occurrence, is independently selected from halo, haloalkyl or —COOR₉;

R₇and R₈of PTM-Va or PTM-Vb are independently hydrogen, alkyl, acyl, heterocyclyl, —COR₉or —COOR₉;

R₉of PTM-V or PTM-Vb at each occurence is independently selected from hydrogen or alkyl;

R_9aof PTM-Vb is selected from hydrogen, halo, optionally substituted alkoxy (e.g., optionally substituted C1-C4 alkoxy), optionally substituted alkyl (e.g., C1-C4 alkyl optionally substituted with halo or hydroxy), hydroxyalkyl (e.g. C1-C4 hydroxyalkyl), or haloalkyl (e.g., C1-C4 haloalkyl);

“m”, “n” and “q” of PTM-Va or PTM-Vb are independently selected from 0, 1, 2, or 3; and

“p” of PTM-Va or PTM-Vb is 0 or 1.

8. The compound of claim 1, wherein the PTM is represented by Formula PTM-VIa, PTM-VIb, or PTM-VIc:

wherein:

X of PTM-VIa-c is CH or N;

a of PTM-VIa-c is 0 or 1;

b of PTM-VIa-c is 0 or 1;

m of PTM-VIa-c is 0, 1 or 2;

Ring A of PTM-VIa-c is (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl, aryl or heterocycle optionally substituted with one to three substituents independently selected from R₁;

R₁of PTM-VIa-c is selected from: H, oxo, (C═O)_aO_b(C₁-C₁₀)alkyl, (C═O)_aO_b-aryl, (C═O)_aO_b(C₂-C₁₀)alkenyl, (C═O)_aO_b(C₂-C₁₀)alkynyl, CO₂H, halo, OH, O_b(C₁-C₆)fluoroalkyl, (C═O)_aNR₅R⁶, CN, (C═O)_aO_b(C₃-C₈)cycloalkyl, S(O)_mNR₅R₆, SH, S(O)_m—(C₁-C₁₀)alkyl and (C═O)_aO_b-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from R_a;

R₂and R₃of PTM-VIa-c are independently selected from: H, (C═O)_aO_bC₁-C₁₀alkyl, (C═O)_aO_baryl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, (C═O)_aO_bheterocyclyl, CO₂H, CN, O_bC1-C₆fluoroalkyl, O_a(C═O)_bNR₅R₆, CHO, (N═O)R₅R⁶, S(O)_mNR₅R₆, SH, S(O)_m(C₁-C₁₀)alkyl, (C═O)_aO_bC₃-C₈cycloalkyl, optionally substituted with one or more substituents selected from R₁; or R₂and R₃can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R₁;

R₄of PTM-VIa-c is selected from: (C₁-C₆)alkyl and (C₃-C₆)cycloalkyl, optionally substituted with R_a;

R₅and R₆of PTM-VIa-c are independently selected from: H, oxo, (C═O)_aO_b(C₁-C₁₀)alkyl, (C═O)_aO_b-aryl, (C═O)_aO_b(C₂-C₁₀)alkenyl, (C═O)_aO_b(C₂-C₁₀)alkynyl, CO₂H, O_b(C₁-C₆)fluoroalkyl, (C═O)_aN(R_a)₂, CN, (C═O)_aO_b(C₃-C₈)cycloalkyl, S(O)_mN(R_a)₂, SH, S(O)_m—(C₁-C₁₀)alkyl and (C═O)_aO_b-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from R_a;

R_aof PTM-VIa-c is independently selected from R_b, OH, (C₁-C₆)alkoxy, halogen, cyclopropyl, CO₂H, CN, O_a(C═O)_b(C₁-C₆)alkyl, oxo, and N(R^b)₂; and

R_bof PTM-VIa-c is independently selected from H and (C₁-C₆)alkyl.

9. The compound of claim 1, wherein the PTM is represented by Formula PTM-VIIa, PTM-VIIb, PTM-VIIc, PTM-VIId, PTM-VIIe, PTM-VIIf, PTM-VIIg, PTM-VIIh, PTM-VIIi, PTM-VIIj, PTM-VIIk, or PTM-VIIm:

wherein:

X and X′ of PTM-VIIa-k or PTM-VIIm are each independently CR⁸, N or —N⁺—O—; Y is independently N, —N⁺—O⁻or CR^8′; provided that at least one of X, X′ or Y is neither N nor —N⁺—O⁻and that no more than one of X, X′ or Y is —N⁺—O—;

R¹of PTM-VIIa-k or PTM-VIIm is C₁-C₆alkyl; C₂-C₆alkenyl; C₂-C₆alkynyl; —(CR^3aR^3b)_m-(3-to 7-membered cycloalkyl); —(CR^3aR^3b)_m-(3- to 7-membered heterocycloalkyl) having one to three heteroatoms; —(CR^3aR^3b)_m-(5- to 10-membered heteroaryl), having one to three heteroatoms; or —(CR^3aR^3b)_m—C₆-C₁₂aryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to five halogen, deuterium, —OR⁵, —SR⁵, —NR^11aR^11b, cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl or —C₁-C₆alkoxy;

R²of PTM-VIIa-k or PTM-VIIm is —(CR^3aR^3b)_m-(3- to 10-membered cycloalkyl); (CR^3aR^3b)_m-(3- to 10-membered heterocycloalkyl) having one to three heteroatoms; —(CR^3aR^3b)_m-(5- to 10 membered heteroaryl) having one to three heteroatoms; or —(CR^3aR^3b)_m—C₆-C₁₂aryl; wherein said cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to five R⁴; and wherein, if the heteroatom on said heterocycloalkyl and heteroaryl is N, said N is optionally substituted with R^4′; or R²is C₁-C₆alkyl, wherein said alkyl is optionally substituted with NH₂, OH or cyano;

R^3aand R^3bof PTM-VIIa-k or PTM-VIIm for each occurrence are independently hydrogen or C₁-C₃alkyl;

R⁴of PTM-VIIa-k or PTM-VIIm for each occurrence is independently a bond, deuterium, halogen, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, oxo, —OR⁵, —SR⁵, —S(O)R⁹, —S(O)₂R⁹, NR^11aR^11b, —C(O)R¹⁰, —(CR^3aR^3b)_n-(3- to 7-membered cycloalkyl), —(CR^3aR^3b)_n-(4- to 10-membered heterocycloalkyl), having one to three heteroatoms, —(CR^3aR^3b)_n-(5- to 10 membered heteroaryl), having one to three heteroatoms, or —(CR^3aR^3b)_n-C₆-C₁₂aryl wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is each optionally and independently substituted with one to five deuterium, halogen, OR⁵, —SR⁵, —NR^11aR^11bcyano, C₁-C₆alkyl, C₃-C₆cycloalkyl or C₁-C₆alkoxy; or two R⁴taken together with the respective carbons to which each are bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR⁵, —SR⁵, —NR^11aR^1lb, cyano or C₁-C₆alkyl or C₁-C₆alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, —OR⁵, —SR⁵, —NR^11aR^11bor cyano; and wherein, if a heteroatom on said heterocycloalkyl is N, said N is optionally substituted with R^4′;

R^4′ of PTM-VIIa-k or PTM-VIIm is independently C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R¹⁰, —S(O)₂R⁹, —(CR^3aR^3b)_n-(3- to 7-membered cycloalkyl), —(CR^3aR^3b)_n-(4- to 10-membered heterocycloalkyl) or C(O)(CH₂)_tCN; wherein said alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is each optionally and independently substituted with one to five deuterium, halogen, OH, cyano or C₁-C₆alkoxy; or R⁴and R^4′ taken together with the respective atoms to which each are bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR⁵, —SR⁵, cyano, C₁-C₆alkyl or C₁-C₆alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, —OR⁵, —SR⁵, —NR^11aR^11b, or cyano;

R^4aand R^4bof PTM-VIIa-k or PTM-VIIm are each independently hydrogen, deuterium, fluoro, OH, —OR⁵, methyl, ethyl, vinyl, cyclopropyl or propyl, optionally substituted with one to five deuterium, fluoro, methoxy or OH;

R^4cand R^4dof PTM-VIIa-k or PTM-VIIm for each occurrence are independently and optionally halogen, OH, deuterium, C₁-C₆alkyl, C₂-C₆alkenyl, —OR⁵, —(CR^3aR^3b)_n-(3- to 6-membered cycloalkyl), or —(CR^3aR^3b)_n-(4- to 6-membered heterocycloalkyl) wherein said alkyl, cycloalkyl and heterocycloalkyl are each optionally and independently substituted with one to five deuterium, halogen, OH, cyano, or C₁-C₆alkoxy; NH₂; or R^4cand R^4dtaken together with the carbons to which they are bonded form a 4- to 7-membered heterocycloalkyl or a 3- to 7-membered cycloalkyl, wherein said heterocycloalkyl or cycloalkyl is optionally substituted with one to three fluoro, C₁-C₃alkyl or C₁-C₃fluoroalkyl;

or R^4aand R^4cof PTM-VIIa-k or PTM-VIIm taken together with the carbon to which they are bonded form a 4- to 7-membered heterocycloalkyl or a 3- to 7-membered cycloalkyl, wherein said heterocycloalkyl or cycloalkyl is optionally substituted with one to three fluoro, C₁-C₃alkyl or C₁-C₃fluoroalkyl;

R⁵of PTM-VIIa-k or PTM-VIIm is independently hydrogen or C₁-C₆alkyl, wherein said alkyl is optionally substituted with halogen, deuterium, C₁-C₆alkoxy, C₁-C₆alkylthiolyl, —NR^11aR^11b, cyano, C₁-C₆alkyl or C₃-C₆cycloalkyl; or two R⁵taken together with the oxygen atoms to which they are bonded form a 5- or 6-membered heterocycloalkyl;

R⁶of PTM-VIIa-k or PTM-VIIm is —C(O)NHR⁷, CO₂R⁷or cyano;

R⁷of PTM-VIIa-k or PTM-VIIm is hydrogen or C₁-C₆alkyl;

each R⁸of PTM-VIIa-k or PTM-VIIm is independently hydrogen, halogen, cyano, —OR⁵, SR⁵, —C₁-C₆alkyl, C₃-C₆cycloalkyl, 3- to 10-membered heterocycloalkyl or 5- to 6-membered heteroaryl or aryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to three halogen, —NR^11aR^11b, OR⁵, —SR⁵, cyano, C₁-C₃alkyl, —C(O)R¹⁰or oxo;

R^8′ of PTM-VIIa-k or PTM-VIIm is hydrogen, deuterium, halogen, cyano, —OR⁵, —SR⁵or —NR^11aNR_11b;

R⁹of PTM-VIIa-k or PTM-VIIm is —(CR^3aR^3b)_p(C₁-C₃alkyl), —(CR^3aR^3b)_p(4- to 6-membered cycloalkyl), —(CR^3aR^3b)_p(4- to 6-membered heterocycloalkyl) or —(CR^3aR^3b)_p(C₅-C₉aryl), wherein said alkyl, cycloalkyl, heterocycloalkyl or aryl is each optionally substituted with fluoro or C₁-C₃alkyl;

R¹⁰of PTM-VIIa-k or PTM-VIIm is C₁-C₆alkyl, wherein said alkyl is optionally substituted with deuterium, halogen, OH, C₁-C₆alkoxy or cyano;

R^11aand R^11bof PTM-VIIa-k or PTM-VIIm are each independently hydrogen or C₁-C₆alkyl, wherein said alkyl is optionally substituted with deuterium, C₁-C₆alkoxy or cyano; and if C₂-C₆alkyl, said alkyl is optionally substituted with deuterium, C₁-C₆alkoxy, cyano, halogen or OH;

m of PTM-VIIa-k or PTM-VIIm is independently 0, 1, 2 or 3;

n of PTM-VIIa-k or PTM-VIIm is independently 0, 1, 2 or 3;

p of PTM-VIIa-k or PTM-VIIm is independently 0 or 1; and

t of PTM-VIIa-k or PTM-VIIm is 1, 2 or 3.

10. The compound of claim 1, wherein the PTM is represented by Formula PTM-VIIIa, PTM-VIIIb, PTM-VIIIc, PTM-VIIId, PTM-VIIIe, or PTM-VIIIf:

wherein:

Ring A of PTM-VIIIa-f is phenylene or 5- to 6-membered heteroarylene containing 1-3 heteroatoms chosen from O, S, and N, wherein ring A is optionally substituted with lower alkyl that is further optionally substituted;

Ring B of PTM-VIIIa-f is phenylene, 5- to 6-membered heterocycloalkylene containing 1-3 heteroatoms chosen from O, S, and N, or 5- to 6-membered heteroarylene containing 1-3 heteroatoms chosen from O, S, and N, wherein ring B is optionally substituted with lower alkyl or lower alkyloxyalkyl, either of which is is further optionally substituted;

R²of PTM-VIIIa-f is chosen from hydrogen and lower alkyl;

R³of PTM-VIIIa-f is chosen from hydrogen, lower alkyl optionally substituted with alkoxy, amino, N-(alkyl)amino, N,N-(dialkyl)amino, or phenyl, heterocycloalkyl, and heteroaryl, wherein phenyl, heterocycloalkyl, and heteroaryl are optionally substituted with one or two groups independently chosen from lower alkyl and wherein alkoxy is optionally substituted with tri(alkyl)silyl;

R⁴of PTM-VIIIa-f is chosen from heteroarylene and arylene, each of which is optionally substituted, or R⁴and R³of PTM-VIIIa-f taken together with the nitrogen to which they are bound, form an optionally substituted 3- to 7-membered heterocycloalkyl ring, or R⁴of PTM-VIIIa-f is an alkylene chain having 1-3 carbon atoms that is optionally substituted with one or two groups independently chosen from lower alkyl and cycloalkyl, each of which groups is optionally substituted with hydroxyl or alkoxy, or R⁴of PTM-VIIIa-f is absent;

R⁵of PTM-VIIIa-f is chosen from C(O)NR⁵¹, NR⁵², and O, or R⁵is absent, provided that if R⁴is absent, then R⁵is absent;

R⁶of PTM-VIIIa-f is an alkylene or alkenylene chain having one or two double bonds, wherein the alkylene or alkenylene chain has 2 to 10 carbon atoms, the alkylene or alkenylene chain is optionally substituted with one or two groups independently chosen from lower alkyl, cycloalkyl and phenyl, each of which groups is optionally substituted with hydroxyl, alkoxy, —C(O)OR⁸⁵, —C(O)NR⁸²R⁸³, benzoyl, and benzyl, further wherein one or two of the carbon atoms in the alkylene or alkenylene chain is optionally replaced by an O, S, SO, SO₂, C(O)NR⁵¹, or NR⁶¹, and wherein one of the carbon atoms in the alkylene or alkenylene chain, is optionally connected by the nitrogen atom of C(O)NR⁵¹or NR⁶¹to form a 5- to 7-membered ring, which may further be substituted with oxo, wherein two of the carbon atoms in the alkylene or alkenylene chain, are optionally connected by a two or three carbon atom alkylene or alkenylene chain to form a 5- to 7-membered ring;

R⁷of PTM-VIIIa-f is chosen from NR⁷¹and O, or R⁷is absent;

R²¹of PTM-VIIIa-f is chosen from hydrogen and lower alkyl optionally substituted with lower alkoxy, wherein lower alkoxy is optionally substituted with tri(alkyl)silyl;

R⁴¹of PTM-VIIIa-f is independently chosen from heterocycloalkyl, lower alkyl optionally substituted with —C(O)OR⁹, amino, N-(alkyl)amino, N,N-(dialkyl)amino, cycloalkyl, or heterocycloalkyl, —C(O)OR⁹, hydroxyl, and —C(O)NR¹⁰R¹¹, wherein R⁹is chosen from hydrogen and lower alkyl, R¹⁰and R¹¹are independently hydrogen and lower alkyl, or R¹⁰and R¹¹, together with the nitrogen to which they are bound form a heterocycloalkyl, and each lower alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one, two, or three groups independently chosen from —C(O)OR⁹, lower alkyl, lower alkoxy, hydroxyl, halogen, amino, N-(alkyl)amino, N,N-(dialkyl)amino, and heterocycloalkyl;

R⁵¹of PTM-VIIIa-f is chosen from hydrogen and lower alkyl;

R⁵²of PTM-VIIIa-f is chosen from hydrogen, lower alkyl, and —C(O)OR⁸¹;

R⁶¹of PTM-VIIIa-f is chosen from hydrogen, lower alkyl, —(CH₂)_nC(O)OR⁸¹, (CH₂)_nC(O)NR⁸²R⁸³, —C(O)R⁸⁴, —C(O)(CH₂)_pNR⁸²C(O)OR⁸¹, —C(O)(CH₂)_pNR⁸²R⁸³;

R⁷¹of PTM-VIIIa-f is chosen from hydrogen, lower alkyl, and —C(O)OR⁸¹;

R⁸¹of PTM-VIIIa-f is hydrogen or lower alkyl;

R⁸²of PTM-VIIIa-f is hydrogen or lower alkyl,

R⁸³of PTM-VIIIa-f is hydrogen or lower alkyl,

R⁸⁴of PTM-VIIIa-f is hydrogen, lower alkyl, C₃-C₆cycloalkyl or tetrahydropyran, wherein the lower alkyl is optionally substituted with hydroxy or —C(O)OR⁸¹;

R⁸⁵of PTM-VIIIa-f is hydrogen, lower alkyl, or benzyl,

n of PTM-VIIIa-f is 0, 1, 2, or 3;

p of PTM-VIIIa-f is 1 or 2; and

Z of PTM-VIIIa-f is chosen from O, S, and NR²¹.

11. The compound of claim 1, wherein PTM is represented by Formula PTM-IXa, PTM-IXb, PTM-IXc, PTM-IXd, PTM-IXe, PTM-IXf, PTM-IXg, PTM-IXh, PTM-IXi, PTM-IXj, PTM-IXk, PTM-IXl, or PTM-IXm:

wherein:

Ring A of PTM-IXa-m is selected from phenyl and 5- or 6-membered heteroaryl;

Ring B of PTM-IXa-m is selected from phenyl and 5- or 6-membered heteroaryl;

Ring C of PTM-IXa-m is selected from a 5- or 6-membered cycloalkyl or cycloheteroalkyl;

Rind D of PTM-IXa-m selected from phenyl, 5-membered aryl or heteroaryl, 6-member aryl or heteroaryl, 5-membered cycloalkyl or cycloheteroalkyl, or 6-membered cycloalkyl or cycloheteroalkyl;

n of PTM-IXa-m is 0, 1, or 2;

p of PTM-IXa-m is 0, 1, or 2;

one of W and X of PTM-IXa-m is N, and the other of W and X is C;

Y of PTM-IXa-m is N or C—R²;

R¹of PTM-IXa-m is selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3-to 6-membered saturated heterocyclyl, halo, —CN, —C(R^1a)═NR(OR^1a), —C(R^1a)═N(R^1a), —C(O)R^1a, C(O)₂R^1a, —C(O)N(R^1a)₂, —NO₂, —N(R^1a)₂, —N(R^1a)C(O)R^1a, —N(R^1a)C(O)₂R^1a, N(R^1a)C(O)N(R^1a)₂, —N(R^1a)S(O)₂R^1a, —OR^1a, —OC(O)R^1a, —OC(O)N(R^1a)₂, —SR^1a, —S(O)R^1a, S(O)₂R^1a, —S(O)N(R^1a)₂, and —S(O)₂N(R^1a)₂, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, and 3-to 6-membered saturated heterocyclyl are optionally substituted with one or more R¹⁰; or two R¹substituents, together with their intervening atoms, form a C_5-7cycloalkyl or a saturated 5- to 7-membered heterocyclic ring, wherein said C_5-7cycloalkyl or a saturated 5- to 7-membered heterocyclic ring are optionally substituted with one or more R¹⁵;

R^1aof PTM-IXa-m in each occurrence is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 3- to 6-membered monocyclic heterocyclyl wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 3- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R¹⁰;

R¹⁰of PTM-IXa-m in each occurrence is independently selected from ĈaUcyl, C_2-6alkenyl, C_2-6alkynyl, 3- to 6-membered carbocyclyl, 3-to 6-membered heterocyclyl, halo, —CN, —C(R^10a)═NR(OR^10a), —C(R^10a)═N(R^11a), —C(O)R^10a, —C(O)₂R^10a, —C(O)N(R^10a)₂, —NO₂, N(R^10a)₂, —N(R^10a)C((O)R^10a, —N(R^10a)C(O)₂R^10a, —N(R^10a)C(O)N(R^10a)₂, —N(R^10a)S(O)₂R^10a, —OR¹⁰, —OC(O)R^10a—OC(O)N(R^10a)₂, —SR^10a, —S(O)R^10a, —S(O)₂R^10a, —S(O)N(R^10a)₂, and —S(O)₂N(R^10a)₂—;

R^10aof PTM-IXa-m in each occurrence is independently selected from H and C_1-6alkyl, wherein said C_1-6alkyl is optionally substituted with one or more halo;

R¹⁵of PTM-IXa-m in each occurrence is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, 3- to 6-membered carbocyclyl, 3-to 6-membered heterocyclyl, halo, —CN, —C(R^15a)═NR(OR^15a), —C(R^15a)═N(R^15a), —C(O)R^15a, —C(O)₂R^15a, —C(O)N(R^15a)₂, —NO₂, —N(R^15a)₂, —N(R^15a)C(O)R^15a, —N(R^15a)C(O)₂R^15a, —N(R^15a)C(O)N(R^15a)₂, —N(R^15a)S(O)₂R^15a, —OR^15a, —OC(O)R^15a, —OC(O)N(R^15a)₂, —SR^15a, —S(O)R^15a, —S(O)₂R^15a, —S(O)N(R^15a)₂, and —S(O)₂N(R^15a)₂;

R^15aof PTM-IXa-m in each occurrence is independently selected from H and C_1-6alkyl, wherein said C_1-6alkyl is optionally substituted with one or more halo;

R²of PTM-IXa-m is selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, 3- to 7-membered carbocyclyl, 3-to 7-membered heterocyclyl, halo, —CN, —C(R^2a)═NR(OR^2a), C(R^2a)═N(R^2a), —C(O)R^2a, —C(O)₂R^2a, —C(O)N(R^2a)₂, —NO₂, —N(R^2a)₂, —N(R^2a)C(O)R^2a, —N(R^2a)C(O)₂R^2a, —N(R^2a)C(O)N(R^2a)₂, —N(R^2a)S(O)₂R^2a, —OR^2a, —OC(O)R^2a, OC(O)N(R^2a)₂, —SR^2a, —S(O)R^2a, —S(O)₂R^2a, —S(O)N(R^2a)₂, and —S(O)₂N(R^2a)₂, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, 3-to 7-membered carbocyclyl, and 3-7 membered heterocyclyl are optionally substituted with one or more R²⁰;

R^2aof PTM-IXa-m in each occurrence is independently selected from H and C_1-6alkyl, wherein said C_1-6alkyl in each occurrence is optionally and independently substituted with one or more R²⁰;

R²⁰of PTM-IXa-m in each occurrence is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, 3-to 7-membered saturated heterocyclyl, halo, —CN, —C(R^20a)═NR(OR^20a), —C(R^20a)═N(R^20a), —C(O)R^20a, —C(O)₂R^20a, —C(O)N(R^20a)₂, —NO₂, —N(R^20a)₂, —N(R^20a)C(O)R^20a, —N(R^20a)C(O)₂R^20a, —N(R^20a)C(O)N(R^20a)₂, —N(R^20a)S(O)₂R^20a, —OR^20a, —OC(O)R^20a, —OC(O)N(R^20a)₂, —SR^20a, —S(O)R^20a, —S(O)₂R^20a, —S(O)N(R^20a)₂, and —S(O)₂N(R^20a)₂, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, and 3-7 membered saturated heterocyclyl in each occurrence are optionally and independently substituted with one or more R²⁵;

R^20aof PTM-IXa-m in each occurrence is independently selected from H and C_1-6alkyl, wherein said C_1-6alkyl is optionally substituted with R²⁵;

R²⁵of PTM-IXa-m is selected from halo and —OR^25a;

R^25aof PTM-IXa-m is selected from H and C_1-6alkyl;

R³of PTM-IXa-m is selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3-to 6-membered saturated heterocyclyl, halo, —CN, —C(R^3a)═NR(OR^3a), —C(R^3a)═N(R^3a), C(O)R^3a, —C(O)₂R^3a, —C(O)N(R^3a)₂, —NO₂, —N(R^3a)₂, —N(R^3a)C(O)R^3a, —N(R^3a)C(O)₂R^3a, N(R^3a)C(O)N(R^3a)₂, —N(R^3a)S(O)₂R^3a, —OR^3a, —OC(O)R^3a, —OC(O)N(R^3a)₂, —SR^3a, —S(O)R^3a, —S(O)₂R^3a, —S(O)N(R^3a)₂, and —S(O)₂N(R^3a)₂, wherein said C_1-6alkyl, C_2-6alkenyl, C₂-6alkynyl, C_3-6cycloalkyl, and 3-to 6-membered saturated heterocyclyl are optionally substituted with one or more R³⁰;

R^3aof PTM-IXa-m in each occurrence is independently selected from H, C_1-6alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl, wherein said C_1-6alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R³⁰;

R³⁰of PTM-IXa-m in each occurrence is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, 3- to 6-membered carbocyclyl, 3-to 6-membered heterocyclyl, halo, —CN, —C(R^30a)═NR(OR^30a), —C(R^30a)═N(R^30a), —C(O)R^30a, —C(O)₂R^30a, —C(O)N(R^30a)₂, —NO₂, —N(R^30a)₂, —N(R^30a)C(O)R^30a, —N(R^30a)C(O)₂R^30a, —N(R^30a)C(O)N(R^30a)₂, —N(R^30a)S(O)₂R^30a, —OR^30a, —OC(O)R^30a, —OC(O)N(R^30a)₂, —SR^30a, —S(O)R^30a, —S(O)₂R^30a, —S(O)N(R^30a)₂, and —S(O)₂N(R^30a)₂, wherein said C_1-3alkyl, C_2-6alkenyl, C_2-6alkynyl, 3-6 membered carboyclyl, 3- to 6-membered heterocyclyl in each occurence are optionally and independently substituted with one or more R³⁵;

R^30aof PTM-IXa-m in each occurrence is independently selected from H and C_1-6alkyl, wherein said C_1-6alkyl is optionally substituted with one or more R³⁵;

R³⁵of PTM-IXa-m in each occurrence is independently selected from halo and —OR^35a;

R^35aof PTM-IXa-m in each occurrence is independently selected from H and C_1-6alkyl;

R^35bof PTM-IXa-m in each occurrence is independently selected from H, halo, optionally substituted alkoxy (e.g., optionally substituted C1-C4 alkoxy), optionally substituted alkyl (e.g., C1-C4 alkyl optionally substituted with halo or hydroxy), hydroxyalkyl (e.g. C1-C4 hydroxyalkyl), or haloalkyl (e.g., C1-C4 haloalkyl);

R^35cof PTM-IXa-m in each occurrence is independently selected from halo or haloalkyl (e.g., C1-C4 haloalkyl);

R⁴of PTM-IXa-m is selected from H, halo, C_1-6alkyl, N(R^4a)₂, and —OR^4a; and

R^4aof PTM-IXa-m in each occurrence is independently selected from H and C_1-6alkyl.

12. The compound of claim 1, wherein the PTM is represented by Formula PTM-Xa, PTM-Xb, PTM-Xc, PTM-Xd, PTM-Xe, PTM-Xf, or PTM-Xg:

wherein:

A of PTM-Xa-g is

or A of PTM-X is a triazole optionally substituted by 0-2 R

X of PTM-Xa-g is N or C—R⁷;

R of PTM-Xa-g is hydrogen, R¹, halogen, cyano, nitro, —OR¹, —C(═O)—R¹, —C(═O)O—R¹, —C(═O)NR¹¹—R¹, —S(═O)₂—R¹, —NR¹¹C(═O)—R, —NR¹¹C(═O)NR¹¹R¹¹, —NR¹¹C(═O)NR¹¹R¹, —NR¹¹C(═O)O—R¹, —NR¹¹S(═O)₂R¹, —NR¹¹R¹¹, or NR¹¹R¹;

R¹of PTM-Xa-g is C_1-6alkyl substituted with 0-4 R^1a, C_1-6haloalkyl, C_2-6alkenyl substituted with 0-3 R^1a, C_2-6alkynyl substituted with 0-3 R^1a, C_3-10cycloalkyl substituted with 0-3 R^1aC_6-10aryl substituted with 0-3 R^1a, a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^1a, or a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^1a;

R^1aof PTM-Xa-g is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_rOR^b, —(CH₂)_rSR^b, (CH₂)_rC(O)R^b, —(CH₂)_rC(O)OR^b, —(CH₂)_rOC(O)R^b, —(CH₂)_rNR¹¹R¹¹, (CH₂)_rC(O)NR¹¹R¹¹, —(CH₂)_rNR^bC(O)R^c, —(CH₂)_rNR^bC(O)OR^c, NR^bC(O)NR¹¹R¹¹, S(O)_pNR¹¹R¹¹, NR^bS(O)_pR^c, —S(O)R^c, —S(O)₂R^c, C_1-6alkyl substituted with 0-2 R^a, C_1-6haloalkyl, —(CH₂)_r-3-14 membered carbocycle substituted with 0-3 R^a, or —(CH₂)_r-5-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_psubstituted with 0-3 R^a;

R²of PTM-Xa-g is C_6-10aryl substituted with 0-4 R^2a, a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 1-4 R^2a, or a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R^2a;

R^2aof PTM-Xa-g at each occurrence is independently selected from hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CH₂)_rOR^b, —(CH₂)_rSR^b, —(CH₂)_rC(O)R^b, —(CH₂)_rC(O)OR^b, (CH₂)_rOC(O)R^b, —(CH₂)_rNR¹¹R¹¹, —(CH₂)_rC(O)NR¹¹R¹¹, —(CH₂)_rNR^bC(O)R^c, (CH₂)_rNR^bC(O)OR^c, —NR^bC(O)NR¹R¹, —S(O)_pNR¹¹R¹¹, —NR^bS(O)_pR^c, —S(O)R^c, S(O)₂R^c, C_1-6alkyl substituted with 0-2 R^a, C_1-6haloalkyl, —(CH₂)_r-3-14 membered carbocycle substituted with 0-1 R^a, or —(CH₂)_r-5-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_psubstituted with 0-2 R^a;

R³of PTM-Xa-g is C_1-6alkyl substituted with 0-3 R^3a, C_1-6haloalkyl, C_2-6alkenyl substituted with 0-3 R^3a, C_2-6alkynyl substituted with 0-3 R^3a, C_3-10cycloalkyl substituted with 0-3 R^3aC_6-10aryl substituted with 0-3 R^3a, a 5-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^3aor a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^3a;

R^3aof PTM-Xa-g is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_rOR^b, —(CH₂)_rSR^b, (CH₂)_rC(O)R^b, —(CH₂)_rC(O)OR^b, —(CH₂)_rOC(O)R^b, —(CH₂)_rNR¹¹R¹¹, (CH₂)_rC(O)NR¹¹R¹¹, —(CH₂)_rNR^bC(O)R^c, —(CH₂)_rNR^bC(O)OR^c, NR^bC(O)NR¹¹R¹¹, —S(O)_pNR¹¹R¹¹, NR^bS(O)_pR^c, —S(O)R^c, —S(O)₂R^c, C_1-6alkyl substituted with 0-2 R^a, C_1-6haloalkyl, —(CH₂)_r-3-14 membered carbocycle substituted with 0-1 R^a, or —(CH₂)_r-5-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_psubstituted with 0-1 R^a;

R⁴and R⁵of PTM-Xa-g are independently selected from hydrogen, C_1-4alkyl substituted with 0-1 R^f, (CH₂)-phenyl substituted with 0-3 R^d, and a —(CH₂)-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_p;

R⁶and R⁷of PTM-Xa-g are independently at each occurrence is selected from hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_rOR^b, —(CH₂)_rSR^b, —(CH₂)_rC(O)R^b, (CH₂)_rC(O)OR^b, —(CH₂)_rOC(O)R^b, —(CH₂)_rNR¹¹R¹¹, —(CH₂)_rC(O)NR¹¹R¹¹, (CH₂)_rNR^bC(O)R^c, —(CH₂)_rNR^bC(O)OR^c, —NR^bC(O)NR¹⁰R¹¹, —S(O)_pNR¹¹R¹¹, NR^bS(O)_pR^c, —S(O)R^c, —S(O)₂R^c, C_1-6alkyl substituted with 0-2 R^a, C_1-6haloalkyl, (CH₂)_r-3-14 membered carbocycle substituted with 0-3 R^a, or —(CH₂)_r-5-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_psubstituted with 0-3 R^a, provided R⁶and R⁷are not both hydrogen;

R¹¹of PTM-Xa-g at each occurrence is independently hydrogen, R^e, C_1-4alkyl substituted with 0-1 R^f, CH₂-phenyl substituted with 0-3 R^d, or —(CH₂)-5-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_psubstituted with 0-3 R^d; or R¹¹and along with another R¹¹, R¹, or R²on the same nitrogen atom may join to form an optionally substituted heterocycle;

R^aof PTM-Xa-g is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, —(CH₂)_rOR^b, (CH₂)_rSR^b, —(CH₂)_rC(O)R^b, —(CH₂)_rC(O)OR^b, —(CH₂)_rOC(O)R^b, —(CH₂)_rNR¹¹R¹¹, (CH₂)_rC(O)NR¹¹R¹¹, —(CH₂)_rNR^bC(O)R^c, —(CH₂)_rNR^bC(O)OR^c, —NR^bC(O)NR¹¹R¹¹, —S(O)_pNR¹¹R¹¹, NR^bS(O)_pR^c, —S(O)R^c, —S(O)₂R^c, C_1-6alkyl substituted with 0-1 R^f, C_1-6haloalkyl, —(CH₂)_r-3-14 membered carbocycle, or —(CH₂)_r-5-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_p; or two R^aon adjacent or the same carbon atom form a cyclic acetal of the formula —O—(CH₂)_n—O—, or —O—CF₂—O—, wherein n is selected from 1 or 2;

R^bof PTM-Xa-g is hydrogen, R^eof PTM-X, C_1-6alkyl substituted with 0-2 R^d, C_1-6haloalkyl, C_3-6cycloalkyl substituted with 0-2 R^d, or (CH₂)_r-phenyl substituted with 0-3 R^d; R^eis C₁-6 alkyl substituted with 0-1 R^f, C_3-6cycloalkyl, or (CH₂)_r-phenyl substituted with 0-3 R^f;

R^cof PTM-Xa-g is C_1-6alkyl, C_3-6cycloalkyl, or (CH₂)_r-phenyl substituted with 0-3 R^f;

R^dof PTM-Xa-g is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^e, —(CH₂)_rC(O)R^e, NR^eR^e, —NR^eC(O)OR^c, C_1-6alkyl, or (CH₂)_r-phenyl substituted with 0-3 R^f;

R^eof PTM-Xa-g is selected from hydrogen, C_1-6alkyl, C_3-6cycloalkyl, and (CH₂)_r-phenyl substituted with 0-3 R^f;

R^fof PTM-Xa-g is hydrogen, halo, NH₂, OH, or O(C_1-6alkyl);

p of PTM-Xa-g is 0, 1, or 2;

r of PTM-Xa-g is 0, 1, 2, 3, or 4; and

m of PTM-Xa-g is 0, 1, or 2.

13. The compound of claim 1, wherein the PTM is represented by Formula PTM-XIa, PTM-XIb, or PTM-XIc:

wherein:

X of PTM-XIa-c is NH or O;

b of PTM-XIa-c is 0 or 1;

n of PTM-XIa-c is 0, 1, 2, 3 or 4;

R₁and R₂of PTM-XIa-c are independently H, (C₁-C₄)alkyl and heterocyclyl, or R₁and R₂can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic (fused, bridged or spirocyclic) heterocycle containing 3-8 carbon atoms optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said alkyl and heterocycle are optionally substituted with one or more substituents selected from R_a;

R³of PTM-XIa-c is (C₁-C₄)alkyl wherein two adjacent alkyl groups can join together and form a bridged moiety of 3-6 carbon atoms;

R₄of PTM-XIa-c is absent, halo or O_b(C₁-C₄)alkyl;

R₅of PTM-XIa-c is selected from halo, CN, O(C₁-C₄)alkyl, C₁-C₄alkyl and C₂-C₄alkenyl which are optionally substituted with one or more substituents selected from R_bor R₅is aryl or heteroaryl each optionally substituted with one or more substitutents selected from R_b;

R₆of PTM-XIa-c is absent, halo, or O(C₁-C₄)alkyl;

R_aof PTM-XIa-c is halo, oxo, OH, O_b(C₁-C₄)alkyl, C(O)O_b(C₁-C₆)alkyl, (C═O)_bheterocyclyl, CF₃, SO₂H, SO₂(C₁-C₄)alkyl, C(O)C₁-C₄alkyl, or heterocyclyl, wherein said alkyl can come together with another alkyl to form a bridged moiety and said alkyl and heterocyclyl are optionally substituted with one or more substituents independently selected from F and (C₁-C₄)alkyl; and

R_bof PTM-XIa-c is independently selected from OH, halo, CHF₂, CF₃, COOH, SO₂(C₁-C₄)alkyl, C(O)C₁-C₄alkyl, (C═O)NH₂, O_b(C₁-C₄)alkyl, aryl, heterocyclyl, CN, C(O)N(R^c)₂, N(R^c)₂, wherein the R^cand alkyl are optionally substituted with OH, O(C₁-C₄)alkyl and heterocyclyl; and

R^cof PTM-XIa-c is independently selected from H, SO₂(C₁-C₄)alkyl, or C₁-C₄alkyl.

14. The compound of claim 1, wherein the PTM is represented by Formula PTM-XIIa, PTM-XIIb, PTM-XIIc, PTM-XIId, PTM-XIIe, or PTM-XIIf:

wherein:

B of PTM-XIIa-f is CH, N or S; D of PTM-XII is CH or N; E of PTM-XII is CH or N; F of PTM-XII is CH or N; G of PTM-XII is CH or N; and J of PTM-XII is C or N, wherein when B is S then D is CH, E is N, F is CH, G is N and J is C;

X of PTM-XIIa-f is O, S, CH₂or N;

m of PTM-XIIa-f is 0 or 1;

n of PTM-XIIa-f is 0, 1, 2, 3 or 4;

Ring A of PTM-XIIa-f is aryl, heterocyclyl, pyridinyl, pyrazolyl, thiophenyl, furanyl or phenyl;

R₁of PTM-XIIa-f is independently selected from (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, heterocyclyl, CF₃, CHF₂, CN, halo, pyrimidine, piperidine and phenyl, each optionally substituted with (C₁-C₄)alkyl, OH, CH₃, OCH₃, halo, O(C₁-C₄)alkyl, methyl-piperidine, S(O)₂R^c, C(O)N(R^b)₂, or C(O)O(C₁-C₄)alkyl;

R₂of PTM-XIIa-f is absent or H and R₃is independently selected from: (C₁-C₄)alkyl, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, heterocyclyl, pyranyl, cyclopentyl, cyclohexyl, cycloheptyl, thiopyranyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, each optionally substituted with one or more substituents independently selected from halo, OH, oxo, N(R_b)₂, oxopyrrolidinyl, or morpholinyl, or R₂and R₃can be taken together with the nitrogen to which they are attached to form a heterocyclyl, piperazine or morpholine, each optionally substituted with one or more substituents selected from oxo and R_a;

R₄of PTM-XIIa-f is independently H or methyl;

R_aof PTM-XIIa-f is independently selected from (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, cyclopropyl, CF₃, F, CHF₂, OH, halo and NH₂, said alkyl optionally substituted with (C₃-C₆)cycloalkyl and CF₃; and

R_bof PTM-XIIa-f is independently selected from H and (C₁-C₄)alkyl; and

R_cof PTM-XIIa-f is methyl.

15. The compound of claim 1, wherein the PTM is represented by Formula PTM-XIIIa, PTM-XIIIb, PTM-XIIIc, PTM-XIIId, PTM-XIIIe, PTM-XIIIf, PTM-XIIIg, PTM-XIIIh, PTM-XIIIi, or PTM-XIIIj:

wherein:

Ring Z₁of PTM-XIIIa-j is an optionally substituted heteroaryl;

Ring Z₂of PTM-XIIIa-j is a optionally substituted heterocycloalkyl, optionally substituted heteroaryl or a direct bond;

R₁of PTM-XIIIa-j is optionally substituted alkyl, optionally substituted hydroxyalkyl, cyano, —NR_aR_b, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl; wherein the substituent, at each occurrence, independently is alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, —OCO—CH₂—O-alkyl, —OP(O)(O-alkyl)₂or —CH₂—OP(O)(O-alkyl)₂;

R₂of PTM-XIIIa-j, at each occurrence, independently is an optionally substituted group selected from alkyl, cycloalkyl, or cycloheteroalkyl; wherein the substituent, at each occurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy;

R_2aof PTM-XIIIa-j is an H or optionally substituted alkyl (e.g., optionally substituted C₁-C₄alkyl);

R₃of PTM-XIIIa-j, at each occurrence, independently is hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, —NR_aR_b, hydroxyl or hydroxyalkyl;

R₄of PTM-XIIIa-j at each occurrence is independently is halogen, cyano, an unsubstituted or a singly or multiply, identically or differently substituted C1-C5-alkyl or an unsubstituted or a singly or multiply, identically or differently substituted C3-C6-cycloalkyl (e.g., the substituents of the alkyl or cycloalkyl may be selected from the group of halogen and hydroxyl);

R₅of PTM-XIIIa-j at each occurrence is independently is hydrogen, halogen or an unsubstituted or poly-halogen-substituted C1-C5-alkyl;

R₆of PTM-XIIIa-j at each occurrence is independently optionally substituted C1-C6-alkyl (e.g., C1-C6-alkyl radical unsubstituted, monobustituted or polysubstituted identically or differently by halogen, hydroxyl, an unsubstituted or mono- or poly-halogen-substituted C3-C6-cycloalkyl, or an R⁹, R¹⁰SO₂, R¹⁰SO or R¹¹O radical, or a group selected from:

wherein * represents the bonding site of the group to the rest of the molecule);

R₇and R₈of PTM-XIIIa-j at each occurrence is independently selected from hydrogen or C1-C6-alkyl (e.g., both may be H or a C1-C6 alkyl, including the same C1-C6 alkyl);

R₉of PTM-XIIIa-j is an unsubstituted or mono- or di-methyl-substituted monocyclic saturated heterocycle having 4 to 6 ring atoms, which contains a heteroatom or a heterogroup from the group of O, S, SO and SO₂;

R₁₀of PTM-XIIIa-j is a C1-C6-alkyl, where the C1-C5-alkyl radical is unsubstituted or mono- or polysubstituted identically or differently by halogen, hydroxyl or C3-C5-cycloalkyl; or

R₁₀is C3-C6-cycloalkyl

R₁₁of PTM-XIIIa-j is an optionally substituted C1-C6-alkyl (e.g., a C1-C6-alkyl radical is unsubstituted or mono- or polysubstituted identically or differently by, e.g., halogen);

R_aof PTM-XIIIa-j is hydrogen or alkyl;

R_bof PTM-XIIIa-j is hydrogen, alkyl, acyl, hydroxyalkyl, —SO₂-alkyl or optionally substituted cycloalkyl;

R₁₂of PTM-XIIIa-j is optionally substituted C1-C5 alkyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted cyloalky, or

R₁₃of PTM-XIIIa-j is H or methyl;

R₁₄of PTM-XIIIa-j is an optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-C8 alkyl), optionally substituted amide, carboxylic group, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted heteroaryl (e.g., optionally substituted C5-C7 heteroaryl), —SO₂-alkyl, —SO2H, —O-alkyl, —O-aryl, —O-heteroaryl, optionally substituted urea group;

W and Y of PTM-XIIIa-j are selected from C and N with the proviso that one is N and one is C;

X of PTM-XIIIa-j is CH or N;

“m” of PTM-XIIIa-j is 1 or 2; and

“n” of PTM-XIIIa-j is 1 or 2.

16. The compound according to claim 1, wherein ULM is a Von Hippel-Lindau (VHL) ligase-binding moiety (VLM) with a chemical structure represented by:

wherein:

X¹, X²are each independently selected from the group of a bond, O, NR^Y3, CR^Y3R^Y4, C═O, C═S, SO, and SO₂;

R^Y3, R^Y4are each independently selected from the group of H, linear or branched C_1-6alkyl, optionally substituted by 1 or more halo, optionally substituted C_1-6alkoxyl (e.g., optionally substituted by 0-3 R^pgroups);

R^Pis 0, 1, 2, or 3 groups, each independently selected from the group H, halo, —OH, C_1-3alkyl, C═O;

W³is selected from the group of an optionally substituted T, an optionally substituted -T-N(R^1aR^1b)X³, optionally substituted -T-N(R^1aR^1b), optionally substituted -T-Aryl, an optionally substituted -T-Heteroaryl, an optionally substituted T-biheteroaryl, an optionally substituted -T-Heterocycle, an optionally substituted -T-biheterocycle, an optionally substituted —NR¹-T-Aryl, an optionally substituted —NR¹-T-Heteroaryl or an optionally substituted —NR¹-T-Heterocycle;

X³is C═O, R¹, R^1a, R^1b;

each of R¹, R^1a, R^1bis independently selected from the group consisting of H, linear or branched C₁-C₆alkyl group optionally substituted by 1 or more halo or —OH groups, R^Y3C═O, R^Y3C═S, R^Y3SO, R^Y3SO₂, N(R^Y3R^Y4)C═O, N(R^Y3R^Y4)C═S, N(R^Y3R^Y4)SO, and N(R^Y3R^Y4)SO₂;

T is selected from the group of an optionally substituted alkyl, —(CH₂)_n— group, wherein each one of the methylene groups is optionally substituted with one or two substituents selected from the group of halogen, methyl, optionally substituted alkoxy, a linear or branched C₁-C₆alkyl group optionally substituted by 1 or more halogen, C(O) NR₁R^1a, or NR¹R^1aor R¹and R^1aare joined to form an optionally substituted heterocycle, or —OH groups or an amino acid side chain optionally substituted; and

n is 0 to 6,

W⁴is

R_14a, R_14b, are each independently selected from the group of H, haloalkyl, or optionally substituted alkyl;

W⁵is selected from the group of a phenyl or a 5-10 membered heteroaryl,

R₁₅is selected from the group of H, halogen, CN, OH, NO₂, N R_14aR_14b, OR^14a, CONR_14aR_14b, NR_14aCOR_14b, SO₂NR_14aR_14b, NR_14aSO₂R_14b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;

and wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM′) or a chemical linker moiety coupling at least one PTM or a ULM′ or both to ULM.

17. The compound according to claim 1, wherein ULM is a Von Hippel-Lindau (VHL) ligase-binding moiety (VLM) with a chemical structure represented by:

wherein:

W³is selected from the group of an optionally substituted aryl, optionally substituted heteroaryl, or

R₉and R₁₀are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R₉, R₁₀, and the carbon atom to which they are attached form an optionally substituted cycloalkyl;

R₁₁is selected from the group of an optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

R₁₂is selected from the group of H or optionally substituted alkyl;

R₁₃is selected from the group of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;

R_14a, R_14b, are each independently selected from the group of H, haloalkyl, or optionally substituted alkyl;

W⁵is selected from the group of a phenyl or a 5-10 membered heteroaryl,

R₁₅is selected from the group of H, halogen, CN, OH, NO₂, N R_14aR_14b, OR^14a, CONR_14aR_14b, NR_14aCOR_14b, SO₂NR_14aR_14b, NR_14aSO₂R_14b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;

R₁₆is independently selected from the group of halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;

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

R₁₈is independently selected from the group of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker; and

p is 0, 1, 2, 3, or 4, and wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM′) or a chemical linker moiety coupling at least one PTM or a ULM′ or both to ULM.

18. The compound according to claim 1, wherein the ULM has a chemical structure selected from the group of:

wherein:

R₁is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl;

R_14ais H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;

R₁₅is selected from the group consisting of H, halogen, CN, OH, NO₂, optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;

X is C, CH₂, or C═O

R₃is absent or an optionally substituted 5 or 6 membered heteroaryl; and

wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM′) or a chemical linker moiety coupling at least one PTM or a ULM′ or both to the ULM.

19. The compound according to claim 1, wherein the ULM comprises a group according to the chemical structure:

wherein:

R_14ais H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;

R9 is H;

R10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

R11 is

optionally substituted heteroaryl,

p is 0, 1, 2, 3, or 4; and

each R₁₈is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker;

R12 is H, C═O;

R13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;

R₁₅is selected from the group consisting of H, halogen, Cl, CN, OH, NO₂, optionally substituted heteroaryl, optionally substituted aryl;

and

wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM′) or a chemical linker moiety coupling at least one PTM or a ULM′ or both to the ULM.

20. The compound according to claim 1, wherein the ULM is a cereblon E3 ligase-binding moiety (CLM) selected from the group consisting of a thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.

21. The compound according to claim 20, wherein the CLM has a chemical structure represented by:

wherein:

W is selected from the group consisting of CH₂, CHR, C═O, SO₂, NH, and N-alkyl;

each X is independently selected from the group consisting of O, S, and H₂;

Y is selected from the group consisting of CH₂, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S;

Z is selected from the group consisting of O, S, and H₂;

G and G′ are independently selected from the group consisting of H, optionally substituted linear or branched alkyl, OH, R′OCOOR, R′OCONRR″, CH₂-heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′;

Q₁, Q₂, Q₃, and Q₄represent a carbon C substituted with a group independently selected from R′, N or N-oxide;

A is independently selected from the group H, optionally substituted linear or branched alkyl, cycloalkyl, C₁and F;

R comprises —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″, —CR′R″—, —CR′NR′R″—, (—CR′O)_n′R″, -aryl, -hetaryl, optionally substituted linear or branched -alkyl, -cycloalkyl, -heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F, —Br, —I, —CF₃, —CN, —NR′SO₂NR′R″, —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″, —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′, —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅and —OCF₃;

R′ and R″ are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, —C(═O)R, heterocyclyl, each of which is optionally substituted;

represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and

R_ncomprises from 1 to 4 independently selected functional groups or atoms, for example, O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., an -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy,

n′ is an integer from 1-10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and wherein

when n is 1, R_nis modified to be covalently joined to the linker group (L), and

when n is 2, 3, or 4, then one R_nis modified to be covalently joined to the linker group (L), and any other R_nis optionally modified to be covalently joined to a PTM, a CLM, a second CLM having the same chemical structure as the CLM, a CLM′, a second linker, or any multiple or combination thereof.

22. The compound according to claim 20, wherein the CLM has a chemical structure represented by:

wherein:

W is independently selected from the group CH2, C═O, NH, and N-alkyl;

R is independently selected from a H, methyl, or optionally substituted linear or branched C1-C6 alkyl;

represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and

Rn comprises from 1 to 4 independently selected functional groups or atoms, for example, O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., an -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy, and optionally, one of which is modified to be covalently joined to a PTM, a chemical linker group (L), a CLM (or CLM′) or combination thereof.

23. The compound of any of claims 1-15, wherein the ULM is a (MDM2) binding moiety (MLM) with a chemical moiety selected from the group consisting of a substituted imidazolines, a substituted spiro-indolinones, a substituted pyrrolidines, a substituted piperidinones, a substituted morpholinones, a substituted pyrrolopyrimidines, a substituted imidazolopyridines, a substituted thiazoloimidazoline, a substituted pyrrolopyrrolidinones, and a substituted isoquinolinones.

24. The compound according to claim 1, wherein the ULM is a IAP E3 ubiquitin ligase binding moiety (ILM) comprising the amino acids alanine (A), valine (V), proline (P), and isoleucine (I) or their unnatural mimetics.

25. The compound according to claim 24, wherein the ULM is a IAP E3 ubiquitin ligase binding moiety (ILM) comprising a AVPI tetrapeptide fragment or derivative thereof.

26. The compound according to claim 1, wherein the linker (L) comprises a chemical structural unit represented by the formula:

-(A^L)_q-,

wherein:

(A^L)_qis a group which is connected to at least one of ULM moiety, PTM moiety, or a combination thereof; and

q is an integer greater than or equal to 1,

each A is independently selected from the group consisting of, a bond, CR^L1R^L2, O, S, SO, SO₂, NR^L3, SO₂NR^L3, SONR^L3, CONR^L3, NR^L3CONR^L4, NR^L3SO₂NR^L4, CO, CR^L1═CR^L2, C≡C, SiR^L1R^L2, P(O)R^L1, P(O)OR^L1, NR^L3C(═NCN)NR^L4, NR^L3C(═NCN), NR^L3C(═CNO₂)NR^L4, C_3-11cycloalkyl optionally substituted with 0-6 R^L1and/or R^L2groups, C_3-11heteocyclyl optionally substituted with 0-6 R^L1and/or R^L2groups, aryl optionally substituted with 0-6 R^L1and/or R^L2groups, heteroaryl optionally substituted with 0-6 R^L1and/or R^L2groups, where R^L1or R^L2, each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R^L5groups; and

R^L1, R^L2, R^L3, R^L4and R^L5are, each independently, H, halo, C_1-8alkyl, OC_1-8alkyl, SC_1-8alkyl, NHC_1-8alkyl, N(C_1-8alkyl)₂, C_3-11cycloalkyl, aryl, heteroaryl, C_3-11heterocyclyl, OC_1-8cycloalkyl, SC_1-8cycloalkyl, NHC_1-8cycloalkyl, N(C_1-8cycloalkyl)₂, N(C_1-8cycloalkyl)(C_1-8alkyl), OH, NH₂, SH, SO₂C_1-8alkyl, P(O)(OC_1-8alkyl)(C_1-8alkyl), P(O)(OC_1-8alkyl)₂, CC—C_1-8alkyl, CCH, CH═CH(C_1-8alkyl), C(C_1-8alkyl)═CH(C_1-8alkyl), C(C_1-8alkyl)═C(C_1-8alkyl)₂, Si(OH)₃, Si(C_1-8alkyl)₃, Si(OH)(C_1-8alkyl)₂, COC_1-8alkyl, CO₂H, halogen, CN, CF₃, CHF₂, CH₂F, NO₂, SF₅, SO₂NHC_1-8alkyl, SO₂N(C_1-8alkyl)₂, SONHC_1-8alkyl, SON(C_1-8alkyl)₂, CONHC_1-8alkyl, CON(C_1-8alkyl)₂, N(C_1-8alkyl)CONH(C_1-8alkyl), N(C_1-8alkyl)CON(C_1-8alkyl)₂, NHCONH(C_1-8alkyl), NHCON(C_1-8alkyl)₂, NHCONH₂, N(C_1-8alkyl)SO₂NH(C_1-8alkyl), N(C_1-8alkyl) SO₂N(C_1-8alkyl)₂, NH SO₂NH(C_1-8alkyl), NH SO₂N(C_1-8alkyl)₂, NH SO₂NH₂.

27. The compound according to claim 26, wherein the linker (L) comprises a group represented by a general structure selected from the group consisting of:

—N(R)—(CH2)_m—O(CH2)_n—O(CH2)_o—O(CH2)_p—O(CH2)_q—O(CH2)_r-OCH2-,

—O—(CH2)_mO(CH2)_n—O(CH2)_o—O(CH2)_p—O(CH2)_q—O(CH2)_r-OCH2-,

—O(CH2)_mO(CH2)_n—O(CH2)_o—O(CH2)_p—O(CH2)_q—O(CH2)_r—O—;

—N(R)—(CH2)_mO(CH2)_nO(CH2)_oO(CH2)_pO(CH2)_qO(CH2)_rO—;

—(CH2)_mO(CH2)_nO(CH2)_oO(CH2)_p—O(CH2)_q—O(CH2)_r—O—;

—(CH2)_mO(CH2)_nO(CH2)_oO(CH2)_p—O(CH2)_q—O(CH2)_r-OCH2-;

wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6, with the proviso that when the number is zero, there is no N—O or O—O bond, R is selected from the group H, methyl and ethyl, and X is selected from the group H and F;

28. The compound according to claim 26, wherein the linker (L) is selected from the group consisting of:

29. The compound according to claim 26, wherein the linker (L) is selected from the group consisting of:

wherein each m, n, o, p, q, r, and s is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

30. The compound according to claim 26, wherein the linker is selected from:

31. The compound according to claim 1, wherein the linker (L) comprises the following chemical structure:

wherein:

W^L1and W^L2are each independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with RQ, each RQ is independently a H, halo, OH, CN, CF3, C1-C6 alkyl (linear, branched, optionally substituted), C1-C6 alkoxy (linear, branched, optionally substituted), or 2 RQ groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;

Y^L1is each independently a bond, C1-C6 alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are replaced with O; or C1-C6 alkoxy (linear, branched, optionally substituted);

n is 0-10; and

a dashed line indicates the attachment point to the PTM or ULM moieties.

32. The compound according to claim 1, wherein the linker (L) comprises the following chemical structure:

wherein:

W^L1and W^L2are each independently aryl, heteroaryl, cyclic, heterocyclic, C_1-6alkyl, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each optionally substituted with R^Q, each R^Qis independently a H, halo, OH, CN, CF₃, hydroxyl, nitro, C≡CH, C_2-6alkenyl, C_2-6alkynyl, C₁-C₆alkyl (linear, branched, optionally substituted), C₁-C₆alkoxy (linear, branched, optionally substituted), OC_1-3alkyl (optionally substituted by 1 or more —F), OH, NH₂, NR^Y1R^Y2, CN, or 2 R^Qgroups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;

Y^L1is each independently a bond, NR^YL1, O, S, NR^YL2, CR^YL1R^YL2, C═O, C═S, SO, SO₂, C₁-C₆alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are replaced with O; C₁-C₆alkoxy (linear, branched, optionally substituted);

Q^Lis a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 R^Q, each R^Qis independently H, C_1-6alkyl (linear, branched, optionally substituted by 1 or more halo, C_1-6alkoxyl), or 2 R^Qgroups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms);

R^YL1, R^YL2are each independently H, OH, C_1-6alkyl (linear, branched, optionally substituted by 1 or more halo, C_1-6alkoxyl), or R¹, R²together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms);

n is 0-10; and

a dashed line indicates the attachment point to the PTM or ULM moieties.

33. The compound according to claim 31, wherein the linker (L) is selected from the group consisting of:

34. The compound according to claim 1, wherein the linker (L) is a polyethylenoxy group optionally substituted with aryl or phenyl comprising from 1 to 10 ethylene glycol units.

35. The compound according to claim 1, wherein the compound is selected from Table 4, including salts, prodrugs, polymorphs, analogs, derivatives, and deuterated forms thereof.

36. The compound according to claim 1, wherein at least one of: the PTM is selected from Table 6, the linker is selected from Table 7, the ULM is selected from Table 8, or a combination thereof.

37. The compound according to claim 1, wherein the PTM is selected from:

38. A composition comprising an effective amount of a bifunctional compound of claim 1, and a pharmaceutically acceptable carrier.

39. The composition of claim 38, wherein the composition further comprises at least one of additional bioactive agent or another bifunctional compound of claim 1.

40. The composition of claim 39, wherein the additional bioactive agent is anti-neurodegenerative agent, an anti-inflammatory agent, and/or an anti-cancer agent.

41. A method for treating a disease or disorder in a subject, the method comprising administering a composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound of claim 1 to a subject in need thereof, wherein the compound is effective in treating or ameliorating at least one symptom of the disease or disorder.

42. The method of claim 41, wherein the disease or disorder is associated with tau accumulation and aggregation.

43. The method of claim 41, wherein the disease or disorder is a neurodegenerative disease or disorder, an inflammatory disease or disorder and/or a cancer associated with IRAK-4 accumulation and aggregation.

44. The method of claim 43, wherein the cancer is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt’s lymphoma and Non-Hodgkin’s lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing’s sarcoma, hemangiosarcoma, Kaposi’s sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin’s disease, Wilms’ tumor and teratocarcinomas. Additional cancers which may be treated using compounds according to the present disclosure include, for example, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.

45. The method of claim 44, wherein the inflammatory disease or disorder is selected from the group consisting of ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn’s disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave’s disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren’s syndrome, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (e.g. including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis renal disease, glaucoma, retinal disease, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, fibrositis, gastritis, gastroenteritis, nasal sinusitis, ocular allergy, silica induced diseases, chronic obstructive pulmonary disease (COPD), cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison’s disease, lichen planus, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, juvenile rheumatoid arthritis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, vasculitis, vulvitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Cryopyrin Associated Periodic Syndrome (CAPS) and osteoarthritis.

Title

Compounds and methods for the targeted degradation of interleukin-1 receptor-associated kinase 4 polypeptides

Inventor(s)

Andrew P. Crew, Keith R. Hornberger, Kurt Zimmermann, Erika Araujo

Assignee(s)

Arvinas Inc, Arvinas Operations Inc

Patent #

20190151295

Patent Date

May 23, 2019

Innovative Targeted Therapy for Immune Regulation

Introduction

The Challenge: Balancing Immune Response and Inflammation

Precision in Action: IRAK4 Targeted Degradation

Key Benefits for Biotech and Pharma

Invest in the Future of Inflammation Therapy

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