N/O-linked degron and degron bodies for protein degradation

文档序号：1509442 发布日期：2020-02-07 浏览：25次中文

阅读说明：本技术 用于蛋白降解的n/o-连接的降解决定子和降解决定子体 (N/O-linked degron and degron bodies for protein degradation ) 是由 A·J·菲利普斯 C·G·纳斯维斯查克 J·A·亨德森梁焱科何敏生 M·杜普莱西斯于 2018-06-20 设计创作，主要内容包括：本发明提供了具有可连接至针对经选择进行体内降解的蛋白质的靶向配体的E3泛素连接酶靶向部分(降解决定子)的降解决定子体,及其使用方法和组合物以及它们的制备方法。本发明还提供了可用于治疗由cereblon或Ikaros家族蛋白介导的病症的降解决定子,及其使用方法和组合物以及它们的制备方法。(The present invention provides degrading ligands having an E3 ubiquitin ligase targeting moiety (degron) that can be linked to a targeting ligand for a protein selected for in vivo degradation, methods and compositions of use thereof, and methods of making the same. The invention also provides degreddeterminants useful in the treatment of conditions mediated by cereblon or Ikaros family proteins, methods of use and compositions thereof, and methods of making the same.)

1. A compound of the formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof;

wherein:

W¹is CR⁶R⁷，C═O，C═S，C═CH₂，SO₂S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)₂P (O) alkyl, P (O) OH or P (O) NH₂；

W²Is CR⁸R⁹，C═O，C═S，C═CH₂，SO₂S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)₂P (O) alkyl, P (O) OH or P (O) NH₂；

X is independently selected from NH, NR³，CH₂，CHR³，C(R³)₂O and S;

n is 0, 1,2 or 3;

is a single or double bond;

wherein when

Wherein when

R¹is selected from

R²Independently is alkyl, hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocycle;

R³in each case selected from the group consisting of alkyl, -C (O) H, -C (O) OH, -C (O) alkyl, -C (O) Oalkyl, alkene and alkyne;

R⁴in each case selected from the group consisting of alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azide, amino, -NH alkyl, -N (alkyl)₂，-NHSO₂Alkyl, -N (alkyl) SO₂Alkyl, -NHSO₂Aryl, -N (alkyl) SO₂Aryl, -NHSO₂Alkenyl, -N (alkyl) SO₂Alkenyl, -NHSO₂Alkynyl, -N (alkyl) SO₂Alkynyl and haloalkyl;

or two R⁴The substituents together with the carbon atom to which they are bonded may form a 3, 4,5 or 6 membered ring;

R¹⁴selected from the group consisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azide, amino, cyano, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl)₂，-NHSO₂(aliphatic, including alkyl), -N (aliphatic, including alkyl) SO₂Alkyl, -NHSO₂(aryl, heteroaryl or heterocycle), C (O) R⁴-N (alkyl) SO₂(aryl, heteroaryl or heterocycle) -NHSO₂Alkenyl, -N (alkyl) SO₂Alkenyl, -NHSO₂Alkynyl, -N (alkyl) SO₂Alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, and carbocyclic;

R⁶，R⁷，R⁸，R⁹，R¹⁰and R¹¹Independently selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, hydroxy, alkoxy, amine, -NH (aliphatic) and-N (aliphatic)₂；

Or R⁶And R⁷Together with the carbon to which they are bonded form a 3-, 4-, 5-or 6-membered spirocarbocyclic ring, or a 4-, 5-or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

or R⁸And R⁹Together with the carbon to which they are bonded form a 3-, 4-, 5-or 6-membered spirocarbocyclic ring, or a 4-, 5-or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

or R¹⁰And R¹¹Together with the carbon to which they are bonded form a 3-, 4-, 5-or 6-membered spirocarbocyclic ring, or a 4-, 5-or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

or R⁶And R⁸Forming a 1 or 2 carbon bridged ring;

or R⁶And R¹⁰Forming a 1 or 2 carbon bridged ring;

or R⁸And R¹⁰Forming a 1 or 2 carbon bridged ring;

or R¹⁴And R⁶Form a 3, 4,5 or 6 carbon fused ring;

or R¹⁴And R¹⁰Form a 3, 4,5 or 6 carbon fused ring;

or R¹⁴And R⁸Forming a 1 or 2 carbon bridged ring;

or R¹⁴And R⁴Form 3, 4,5 or 6 carbon condensed rings, wherein R⁴At R¹⁴On carbon α, or a 1,2, 3 or 4 carbon bridged ring of (A), wherein R is⁴Is different from R¹⁴α carbon above;

R¹²is a linker-targeting ligand;

a linker is a chemical group that links the degron to the targeting ligand; and is

A targeting ligand is a ligand that binds to a protein.

2. The compound of claim 1, wherein R¹Is that

3. The compound of claim 1, wherein R¹Is that

4. The compound of claim 1, wherein R¹Is that

5. A compound of the formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof;

wherein:

W¹is CR⁶R⁷，C═O，C═S，C═CH₂，SO₂S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)₂P (O) alkyl, P (O) OH or P (O) NH₂；

W²Is CR⁸R⁹，C═O，C═S，C═CH₂，SO₂S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)₂P (O) alkyl, P (O) OH or P (O) NH₂；

X is independently selected from NH, NR³，CH₂，CHR³，C(R³)₂O and S;

n is 0, 1,2 or 3;

wherein when

R¹is selected from

Or R¹Is selected from

Wherein each R¹Optionally substituted with one or more groups independently selected from R⁵Substituted with the substituent(s);

R²independently is alkyl, hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocycle;

R³in each case selected from the group consisting of alkyl, -C (O) H, -C (O) OH, -C (O) alkyl, -C (O) Oalkyl, alkene and alkyne;

or two R⁴The substituents together with the carbon atom to which they are bonded may form a 3, 4,5 or 6 membered ring;

R⁵and R¹⁴In each case selected from the group consisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azide, amino, cyano, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl)₂，-NHSO₂(aliphatic, including alkyl), -N (aliphatic, including alkyl) SO₂Alkyl radicals-NHSO₂(aryl, heteroaryl or heterocycle), C (O) R⁴-N (alkyl) SO₂(aryl, heteroaryl or heterocycle) -NHSO₂Alkenyl, -N (alkyl) SO₂Alkenyl, -NHSO₂Alkynyl, -N (alkyl) SO₂Alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, and carbocyclic;

each of said R⁵May be optionally substituted with one or more substituents selected from: alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azide, amino, -NH alkyl, -N (alkyl)₂Aryl, heterocycle, heteroaryl, haloalkyl and cycloalkyl;

or R⁶And R⁸Forming a 1 or 2 carbon bridged ring;

or R⁶And R¹⁰Forming a 1 or 2 carbon bridged ring;

or R⁸And R¹⁰Forming a 1 or 2 carbon bridged ring;

or R¹⁴And R⁶Form a 3, 4,5 or 6 carbon fused ring;

or R¹⁴And R¹⁰Form a 3, 4,5 or 6 carbon fused ring;

or R¹⁴And R⁸Forming a 1 or 2 carbon bridged ring;

or R¹⁴And R⁴Form 3, 4,5 or 6 carbon condensed rings, wherein R⁴At R¹⁴On carbon α, or a 1,2, 3 or 4 carbon bridged ring of (A), wherein R is⁴Is different from R¹⁴α carbon above;

R¹²is a linker-targeting ligand;

a linker is a chemical group that links the degron to the targeting ligand; and is

A targeting ligand is a ligand that binds to a protein.

6. The compound of any one of claims 1-5, wherein the linker is selected from the group consisting of

Wherein:

X¹and X²Independently selected from the group consisting of a bond, NH, NR²⁵，CH₂，CHR²⁵，C(R²⁵)₂O and S;

R²⁰，R²¹，R²²，R²³and R²⁴Independently selected from the group consisting of a bond, alkyl, - -C (O) - -, - -C (O) O- -, - -OC (O) - -, - -C (O) alkyl, - -C (O) Oalkyl, - -C (S) - -, - -SO₂-, -S (O) -, -C (S) -, -C (O) NH-, -NHC (O) -, -N (alkyl) C (O) -, -C (O) N (alkyl) -, -O-, -S-, -NH-, -N (alkyl) -, -CH (-O-R)²⁶)-，-CH(-NHR²⁵)-，-CH(-NH₂)-，-CH(-NR²⁵ ₂)-，-C(-O-R²⁶) Alkyl-, -C (-NHR)²⁵) Alkyl-, -C (-NH)₂) Alkyl-, -C (-NR)²⁵ ₂) Alkyl-, -C (R)⁴R⁴) -, -alkyl (R)²⁷) -alkyl (R)²⁸)-，-C(R²⁷R²⁸)-，-P(O)(OR²⁶)O-，-P(O)(OR²⁶)-，-NHC(O)NH-，-N(R²⁵)C(O)N(R²⁵)-，-N(H)C(O)N(R²⁵) -, polyethylene glycol, poly (lactic-co-glycolic acid), alkene, haloalkyl, alkoxy, alkyne, heteroarylalkyl, aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, carbocycle, -O- (CH)₂)_1-12-O-，-NH-(CH₂)_1-12-NH-，-NH-(CH₂)_1-12-O-，-O-(CH₂)_1-12-NH-，-S-(CH₂)_1-12-O-，-O-(CH₂)_1-12-S-，-S-(CH₂)_1-12-S-，-S-(CH₂)_1-12-NH-and-NH- (CH)₂)_1-12-S；

The R is²⁰，R²¹，R²²，R²³And R²⁴Each optionally substituted by one or more groups selected from R¹⁰¹Substituted with the substituent(s);

R¹⁰¹independently at each occurrence, is selected from the group consisting of hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COO alkyl, COOH, NO₂，F，Cl，Br，I，CF₃，NH₂NH alkyl, N (alkyl)₂Aliphatic and heteroaliphatic groups;

R²⁵in each case selected from the group consisting of alkyl, -C (O) H, -C (O) OH, -C (O) alkyl, -C (O) Oalkyl, alkenyl and alkynyl;

R²⁶is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene and alkyne; and is

R²⁷And R²⁸Independently selected from hydrogen, alkyl, amine, or together with the carbon atom to which they are attached form C (O), C (S), C ═ CH₂、C₃-C₆A spiro carbocyclic ring, or a 4-, 5-or 6-membered spiro heterocyclic ring containing 1 or 2 heteroatoms selected from N and O, or forming a 1 or 2 carbon bridged ring.

7. The compound of claim 6, wherein the linker is selected from

8. The compound of claim 6, wherein the linker is selected from

9. The compound of claim 6, wherein the linker is selected from

10. The compound of claim 6, wherein the linker is selected from

11. The compound of any one of claims 6-10, wherein:

R²⁰，R²¹，R²²，R²³and R²⁴Independently selected from the group consisting of a bond, alkyl, - -C (O) - -, - -C (O) O- -, - -OC (O) - -, - -C (O) alkyl, - -C (O) Oalkyl, - -C (O) NH- -, - -NHC (O) - -, - -N (alkyl) C (O) - -, - -C (O) N (alkyl) - -, - -O- -, - -NH- -, - -N (alkyl) - -, - -CH (- -O- -R)²⁶)-，-CH(-NHR²⁵)-，-CH(-NH₂)-，-CH(-NR²⁵ ₂)-，-C(-O-R²⁶) Alkyl-, aryl, heterocyclic, aliphatic and heteroaliphatic.

12. As claimed in claims 6 to 11The compound of any one of, wherein R²⁰，R²¹，R²²，R²³And R²⁴Is unsubstituted.

13. The compound of claim 6, wherein the linker is selected from the group consisting of:

14. the compound of claim 6, wherein the linker is selected from the group consisting of:

15. the compound of claim 6, wherein the linker is selected from the group consisting of:

16. the compound of claim 6, wherein the linker is selected from the group consisting of:

17. the compound of claim 6, wherein the linker is selected from the group consisting of:

18. the compound of any one of claims 1-17, wherein the targeting ligand is selected from the structures of figures 1A to 8PPPPP and R is the point of attachment of the linker.

19. The compound of claim 18, wherein the targeting ligand is selected from the structures of figures 1A to 1 LLL.

20. The compound of claim 18 wherein the targeting ligand is selected from the structures of figures 2A to 2 zzzzzzzz.

21. The compound of claim 18 wherein the targeting ligand is selected from the structures of figures 3A to 3 zzzzzzzz.

22. The compound of claim 18, wherein the targeting ligand is selected from the structures of figures 4A to 4 EE.

23. The compound of claim 18, wherein said targeting ligand is selected from the structures of figures 5A to 5 WW.

24. The compound of claim 18, wherein the targeting ligand is selected from the structures of figures 6A to 6 BB.

25. The compound of claim 18, wherein the targeting ligand is selected from the structures of figures 7A to 7F.

26. The compound of claim 18, wherein the targeting ligand is selected from the structures of figures 8A to 8 PPPPP.

27. A compound of the formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, prodrug thereof;

wherein:

W¹is CR⁶R⁷，C═O，C═S，C═CH₂，SO₂S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)₂P (O) alkyl, P (O) OH or P (O) NH₂；

W²Is CR⁸R⁹，C═O，C═S，C═CH₂，SO₂S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)₂P (O) alkyl, P (O) OH or P (O) NH₂；

X is independently selected from NH, NR³，CH₂，CHR³，C(R³)₂O and S;

n is 0, 1,2 or 3;

wherein when

R¹³is selected from

Wherein each R¹³Optionally substituted with one or more groups independently selected from R⁵Substituted with the substituent(s);

R²independently is alkyl, hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocycle;

R³in each case selected from the group consisting of alkyl, -C (O) H, -C (O) OH, -C (O) alkyl, -C (O) Oalkyl, alkene and alkyne;

or two R⁴The substituents together with the carbon atom to which they are bonded may form a 3, 4,5 or 6 membered ring;

R⁵and R¹⁴In each case selected from the group consisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azide, amino, cyano, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl)₂，-NHSO₂(aliphatic, including alkyl), -N (aliphatic, including alkyl) SO₂Alkyl, -NHSO₂₍Aryl, heteroaryl or heterocycle), C (O) R⁴-N (alkyl) SO₂₍Aryl, heteroaryl or heterocycle) -NHSO₂Alkenyl, -N (alkyl) SO₂Alkenyl, -NHSO₂Alkynyl, -N (alkyl) SO₂Alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, and carbocyclic;

each of said R⁵May be optionally substituted with one or more substituents selected from: alkyl, alkene, alkyneHalogen, hydroxy, alkoxy, azide, amino, -NH alkyl, -N (alkyl)₂Aryl, heterocycle, heteroaryl, haloalkyl and cycloalkyl;

or R⁶And R⁸Forming a 1 or 2 carbon bridged ring;

or R⁶And R¹⁰Forming a 1 or 2 carbon bridged ring;

or R⁸And R¹⁰Forming a 1 or 2 carbon bridged ring;

or R¹⁴And R⁶Form a 3, 4,5 or 6 carbon fused ring;

or R¹⁴And R¹⁰Form a 3, 4,5 or 6 carbon fused ring;

or R¹⁴And R⁸Forming a 1 or 2 carbon bridged ring;

or R¹⁴And R⁴Form 3, 4,5 or 6 carbon condensed rings, wherein R⁴At R¹⁴On carbon α, or a 1,2, 3 or 4 carbon bridged ring of (A), wherein R is⁴Is different from R¹⁴α carbon.

28. The compound of claim 27, wherein R¹³Selected from:

29. the compound of claim 27, wherein R¹³Selected from:

30. the compound of claim 27, wherein R¹³Selected from:

31. the compound of claim 27, wherein R¹³Selected from:

32. the compound of claim 27, wherein R¹³Selected from:

33. the compound of claim 27, wherein R¹³Selected from:

34. the compound of any one of claims 1-33, wherein W¹Is C ═ O.

35. The compound of any one of claims 1-34, wherein W²Is C ═ O.

36. The compound of any one of claims 1-35, wherein X is NH.

37. The compound of any one of claims 1-36, wherein n is 0.

38. The compound of any one of claims 1-37, wherein

39. The compound of any one of claims 1-38, wherein each R²Selected from hydrogen and alkyl.

40. The compound of any one of claims 1-38, wherein each R²Is hydrogen.

41. The compound of any one of claims 1-38, wherein each R²Is an alkyl group.

42. The method of any one of claims 1-41Compound (I) wherein R¹⁴Is hydrogen.

43. The compound of any one of claims 5-42, wherein R⁵Is unsubstituted.

44. The compound of any one of claims 5-43, wherein R¹And R¹³Not optionally selected from R⁵Is substituted with the substituent(s).

45. The compound of any one of claims 1-44, wherein R¹⁰And R¹¹Is hydrogen.

46. A pharmaceutical composition comprising a compound of any one of claims 1-45 and a pharmaceutically acceptable carrier.

47. The pharmaceutical composition of claim 46, wherein the composition is suitable for delivery to a human.

48. The pharmaceutical composition of claim 46 or 47, wherein the composition is suitable for systemic delivery.

49. The pharmaceutical composition of claim 46 or 47, wherein the composition is suitable for topical delivery.

50. The pharmaceutical composition of claim 46 or 47, wherein the composition is in a tablet dosage form.

51. The pharmaceutical composition of claim 46 or 47, wherein the composition is in a capsule dosage form.

52. The pharmaceutical composition of claim 46 or 47, wherein the composition is suitable for intravenous delivery.

53. The pharmaceutical composition of claim 46 or 47, wherein the composition is suitable for transdermal delivery.

54. The pharmaceutical composition of claim 46 or 47, wherein the composition is suitable for parenteral injection.

55. A method for treating a patient having a medical condition treatable by degradation of a target protein bound to a targeting ligand comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-26 and 34-45 or a pharmaceutical composition of any one of claims 46-54.

56. A method for treating a patient having a medical condition treatable by binding to the protein cereblon comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 27-45 or a pharmaceutical composition of any one of claims 46-54.

57. The method of claim 55 or 56, wherein the disorder is selected from abnormal cell proliferation, tumors, cancer, immune disorders, autoimmune disorders, arthritis, lupus, diabetes, cardiovascular diseases, infectious diseases, or inflammatory diseases.

58. The method of claim 55 or 56, wherein the disorder is a cancer selected from the group consisting of: squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder carcinoma, intestinal cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, lymphoma, burkitt's lymphoma, non-hodgkin's lymphoma; melanoma; myeloproliferative diseases; sarcoma, angiosarcoma, kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioma, ganglioglioma, medulloblastoma, pinealocytic tumor, meningioma, meningiosarcoma, neurofibroma, and schwannoma; breast cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma.

59. The method of claim 55, wherein the disorder is acute myeloid leukemia.

60. The method of claim 55, wherein the disorder is NUT midline carcinoma.

61. The method of claim 55, wherein the disorder is adenoid cystic carcinoma.

62. The method of claim 55, wherein the disorder is multiple myeloma.

63. The method of claim 55, wherein the disorder is lymphocytic leukemia.

64. A compound of the formula:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof;

wherein:

W¹is CR⁶R⁷，C═O，C═S，C═CH₂，SO₂S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)₂P (O) alkyl, P (O) OH or P (O) NH₂；

W²Is CR⁸R⁹，C═O，C═S，C═CH₂，SO₂S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)₂P (O) alkyl, P (O) OH or P (O) NH₂；

X is independently selected from NH, NR³，CH₂，CHR³，C(R³)₂O and S;

n is 0, 1,2 or 3;

wherein when

R¹is selected from

R¹Is selected from

Or R¹Is selected from

Wherein each R¹Optionally substituted with one or more groups independently selected from R⁵Substituted with the substituent(s);

R²independently is alkyl, hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocycle;

R³in each case selected from the group consisting of alkyl, -C (O) H, -C (O) OH, -C (O) alkyl, -C (O) Oalkyl, alkene and alkyne;

or two R⁴The substituents together with the carbon atom to which they are bonded may form a 3, 4,5 or 6 membered ring;

R⁵and R¹⁴In each case selected from the group consisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkaneOxy, azide, amino, cyano, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl)₂，-NHSO₂(aliphatic, including alkyl), -N (aliphatic, including alkyl) SO₂Alkyl, -NHSO₂(aryl, heteroaryl or heterocycle), C (O) R⁴-N (alkyl) SO₂(aryl, heteroaryl or heterocycle) -NHSO₂Alkenyl, -N (alkyl) SO₂Alkenyl, -NHSO₂Alkynyl, -N (alkyl) SO₂Alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, and carbocyclic;

or R⁶And R⁸Forming a 1 or 2 carbon bridged ring;

or R⁶And R¹⁰Forming a 1 or 2 carbon bridged ring;

or R⁸And R¹⁰Forming a 1 or 2 carbon bridged ring;

or R¹⁴And R⁶Form a 3, 4,5 or 6 carbon fused ring;

or R¹⁴And R¹⁰Form a 3, 4,5 or 6 carbon fused ring;

or R¹⁴And R⁸Forming a 1 or 2 carbon bridged ring;

or R¹⁴And R⁴Form 3, 4,5 or 6 carbon condensed rings, wherein R⁴At R¹⁴On carbon α, or a 1,2, 3 or 4 carbon bridged ring of (A), wherein R is⁴Is different from R¹⁴α carbon above;

R¹²is linker-H; and is

A linker is a chemical group that links the degron to hydrogen.

65. The compound of claim 64, wherein the linker is selected from

Wherein:

X¹and X²Independently selected from the group consisting of a bond, NH, NR²⁵，CH₂，CHR²⁵，C(R²⁵)₂O and S;

R²⁰，R²¹，R²²，R²³and R²⁴Independently selected from the group consisting of a bond, alkyl, - -C (O) - -, - -C (O) O- -, - -OC (O) - -, - -C (O) alkyl, - -C (O) Oalkyl, - -C (S) - -, - -SO₂-, -S (O) -, -C (S) -, -C (O) NH-, -NHC (O) -, -N (alkyl) C (O) -, -C (O) N (alkyl) -, -O-, -S-, -NH-, -N (alkyl) -, -CH (-O-R)²⁶)-，-CH(-NHR²⁵)-，-CH(-NH₂)-，-CH(-NR²⁵ ₂)-，-C(-O-R²⁶) Alkyl-, -C (-NHR)²⁵) Alkyl-, -C (-NH)₂) Alkyl-, -C (-NR)²⁵ ₂) Alkyl-, -C (R)⁴R⁴) -, -alkyl (R)²⁷) -alkyl (R)²⁸)-，-C(R²⁷R²⁸)-，-P(O)(OR²⁶)O-，-P(O)(OR²⁶)-，-NHC(O)NH-，-N(R²⁵)C(O)N(R²⁵)-，-N(H)C(O)N(R²⁵) -, polyethylene glycol, poly (lactic-co-glycolic acid), alkene, haloalkyl, alkoxy, alkyne, heteroarylalkyl, aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, carbocycle, -O- (CH)₂)_1-12-O-，-NH-(CH₂)_1-12-NH-，-NH-(CH₂)_1-12-O-，-O-(CH₂)_1-12-NH-，-S-(CH₂)_1-12-O-，-O-(CH2)_1-12-S-，-S-(CH₂)_1-12-S-，-S-(CH₂)_1-12-NH-and-NH- (CH)₂)_1-12-S；

The R is²⁰，R²¹，R²²，R²³And R²⁴Each optionally substituted by one or more groups selected from R¹⁰¹Substituted with the substituent(s);

R²⁵in each case selected from the group consisting of alkyl, -C (O) H, -C (O) OH, -C (O) alkyl, -C (O) Oalkyl, alkenyl and alkynyl;

R²⁶is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene and alkyne; and is

66. The compound of claim 65, wherein the linker is selected from the group consisting of

67. The compound of claim 65, wherein the linker is selected from the group consisting of

68. The compound of claim 65, wherein the linker is selected from the group consisting of

69. The compound of claim 65, wherein the linker is selected from the group consisting of

70. The compound of any one of claims 65-69, wherein:

71. The compound of any one of claims 65-70, wherein R²⁰，R²¹，R²²，R²³And R²⁴Is unsubstituted.

72. The compound of claim 65, wherein the linker is selected from the group consisting of:

73. the compound of claim 65, wherein the linker is selected from the group consisting of:

74. the compound of claim 65, wherein the linker is selected from the group consisting of:

75. the compound of claim 65, wherein the linker is selected from the group consisting of:

76. the compound of claim 65, wherein the linker is selected from the group consisting of:

Technical Field

The present invention provides degronomers having an E3 ubiquitin ligase targeting moiety (Degron) that can be linked to a targeting ligand for a protein selected for in vivo degradation, methods and compositions for their use, and methods for their preparation. The invention also provides degron determinants useful in the treatment of conditions mediated by cereblon or Ikaros family proteins.

Background

Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscular degeneration, morphogenesis of neural networks, regulation of cell surface receptors, ion channels and secretory pathways, response to stress and extracellular regulators, ribosome biogenesis, and viral infection.

Covalent attachment of multiple ubiquitin molecules to a terminal lysine residue by E3 ubiquitin ligase labels the protein for proteasomal degradation, wherein the protein is digested into small peptides and ultimately into its constituent amino acids, which serve as building blocks for new proteins. Defective proteasome degradation is associated with a variety of clinical conditions including alzheimer's disease, parkinson's disease, huntington's disease, muscular dystrophy, cardiovascular disease, and cancer, among others.

There are over 600E 3 ubiquitin ligases that promote ubiquitination of different proteins in vivo, which can be divided into four families: HECT domain E3, U-box E3, monomer RING E3 and multi-subunit E3. See generally Li et al (PLOS One,2008,3,1487) entitled "Genome-wide and functional evaluation of human E3 ubiquitin identities MULAN, a mitochondal E3 which ligands the organ's dynamics and signaling."; bernssen et al (nat. struct. mol. biol.,2014,21, 301-; desheies et al (ann.rev.biochem.,2009,78, 399-; spratt et al (biochem.2014,458,421-437), entitled "RBR E3 ubiquitin ligands: news structures, new instruments, new constraints"; and Wang et al (nat. Rev. cancer.,2014,14, 233-.

In 1995, Gosink et al (Proc. Natl. Acad. Sci. USA 1995,92,9117-9121) provided in vitro proof-of-concept that engineered peptides can selectively direct the Ubiquitination of intracellular proteins in a publication entitled "Redirecting the Specificity of Ubiquitin by Modifying Ubiquitin-Conjugating Enzymes". A publication entitled "Proteasome-Dependent Degradation of the Human Estrogen Receptor" by Nawaz et al (Proc. Natl. Acad. Sci. U.S.A.1999,96,1858-1862) describes ER Degradation using the ubiquitin-Proteasome pathway.

A patent application published as us patent 6,306,663 filed 2.1999 to Proteinex, inc, claims a method for producing a compound for activating ubiquitination of a target protein, which comprises covalently attaching a target protein binding element capable of specifically binding to the target protein via a ubiquitination recognition element. Proteinex describes that the invention can be used to control protein levels in eukaryotes. While the' 663 patent may be based on the first patent application to describe a high-level concept of how to manipulate the UPP system to degrade a selected protein in vivo, the patent does not provide sufficient detail to allow the skilled artisan to readily construct a range of proposed compounds. For example, for ubiquitination recognition elements, the skilled person is especially advised to use standard methods for drug discovery and to screen for suitable small molecules that will bind to the binding enzyme. Proteinex also emphasizes the use of peptides as ubiquitination recognition elements, which may pose significant difficulties for oral drug administration.

Since then, therapeutic intervention using the ubiquitin-proteasome pathway has attracted considerable interest in the scientific community. Zhou et al (mol. cell 2000,6,751-756) from Harvard medical college describe an engineered receptor capable of directing ubiquitination in mammalian and yeast cells in a publication entitled "Harnessing the ubiquitination Machinery to Target the differentiation of Specific cellular proteins".

Following these early publications and other publications in the late 90 th 20 th century, Craig Crews and coworkers (Yale university) identified the work of protein, i.e., molecules capable of binding to Target Proteins and ubiquitin ligases may cause Target Proteins to be degraded.their first description of such compounds is provided in U.S. Pat. No. 7,041,298 entitled "protein Targeting Pharmaceutical", filed 9.2000 and 5.2006 by Deshaies et al, which describes "PROTAC" consisting of a small molecule binding agent to MAP-AP-2 linked to a peptide capable of binding to F-Box protein β -CP. the information in the' 298 patent is also presented in Sackamoto et al (Proc. Natl.Acad.Sci.USA 2001,98,8554-8559) entitled "protein Degradation of estrogen: molecular tissue protein, Inc. USA 2001,98,8554-cell Degradation of androgen receptor (Tar-protein TAC-TAC) published under the name of protein kinase-protein, and the corresponding publication No. TAC 2003-TAC for Degradation of protein, cell-protein, TAC, US, Inc. 3, published by Ashwag et al, Inc. No. 7.

The first E3 ligase that was successfully targeted with small molecules was MDM2, its ubiquitinated tumor suppressor p 53. The targeting ligand is an HDM2/MDM 2inhibitor identified by Vassilev et al (Science 2004,303,844-848) under the heading "In Vivo Activation of the P53 Pathway by Small-molecular antibodies of MDM 2".

In 2004 (Schnekloth et al (J.Am. chem. Soc.2004,126,3748-3754), titled "Chemical Genetic Control of Protein Levels: Selective in Vivo TargetedDegradation") describe other examples of direct small molecule induced recruitment of target proteins to proteasomes for degradation when added to cultured cells. Schneekloth et al described a degradation agent (PROTAC3) that targets the FK506 binding protein (FKBP12) and showed that both PROTAC 2and PROTAC3 hit their respective targets with Green Fluorescent Protein (GFP) imaging. A publication entitled "Chemical apparatuses of controlling Intracellular Protein Degradation" by Schneekloth et al (ChemBiochem 2005,6,40-46) describes the state of the art at that time.

A publication entitled "Targeted Intracellular Protein Degradation Induced by a Small Molecule: Enroute to Chemical proteins" by Schneekloth et al (bioorg. Med. chem. Lett.2008,18,5904-5908) describes a Degradation agent consisting of two Small molecules linked by PEG that degrades androgen receptors in vivo by simultaneously binding to androgen receptors and ubiquitin E3 ligase.

WO 2013/170147 entitled "Compounds used for Promoting protein degradation and Methods of Using Same" filed by Crews et al describes Compounds comprising a protein degrading moiety covalently bound to a linker, wherein the ClogP of the compound is equal to or higher than 1.5. In particular, the specification discloses protein degrading compounds that incorporate certain small molecules that can bind to E3 ubiquitin ligase.

In an unrelated parallel study, scientists are investigating the toxicity of thalidomide. Ito et al (Science 2010,327, 1345) -1350 entitled "Identification of a Primary Target of Thialidomide Teratology" describes cereblon as a thalidomide binding protein. cereblon forms part of an E3 ubiquitin ligase protein complex, which interacts with damaged DNA binding protein 1, forming an E3 ubiquitin ligase complex with Cullin 4 and E2 binding protein ROC1 (also known as RBX1), where it selects a protein for ubiquitination as a substrate receptor. This study suggests that thalidomide-cereblon binding in vivo may be responsible for thalidomide teratogenicity. After thalidomide was found to cause teratogenicity in The mid 1960 s, The compound and related structures were still found to be useful as anti-inflammatory, anti-angiogenic and anti-cancer Agents (see Bartlett et al (nat. rev. cancer 2004,4,314-322), entitled "The Evolution of thalidomide and Its Imid Derivatives as Anticancer Agents").

The disclosure of thalidomide in combination with cereblon E3 ubiquitin ligase led to research investigations into the incorporation of thalidomide and certain derivatives into compounds to target the destruction of proteins. Two pioneering papers were published in Science 2014: lu et al, The Myeloma Drug Lenalidomide Proteins The Cerebin-dependent Deconstruction of Ikaros Proteins, Science,343, 305-; and J.Kronke et al, Lenalidomide catalysts selected Degradation of IKZF1 and IKZF 3in MultipleMyeloma Cells, Science,343, 301-.

U.S.2014/0356322 entitled "Compounds and Methods for the enhanced degradation of Target Proteins & Other Polypeptides by an E3 Ubiquitin ligand", assigned to Yale University, GlaxoSmithKline and Cambridge Enterprise Limited University of Cambridge, describes protein degrading Compounds that bind to VHL E3 Ubiquitin Ligase. See also Buckley et al (J.am. chem. Soc.2012,134,4465-4468) entitled "Targeting the VonHippel-Lindau E3 Ubiquitin lipid use Small Molecules to discard the Vhl/Hif-1alpha Interaction".

Other publications in this area include the following: lu et al (chem. biol.2015,22, 755-; bondeson et al (nat. chem. biol.2015,11, 611. sup. -) entitled "catalysis in Vivo protein knock down by Small-molecular Protacs"; gustafson et al (Angewandte Chemie, International Edition in English 2015,54, 9659) 9662) entitled "Small-Collection-Mediated Degradation of the android Receptor through Hydrophobic Tagging"; lai et al (Angewandte Chemie, International Edition in English 2016,55,807-810), entitled "modulated program Design for the interpretation of oncogene Bcr-Abl"; toure et al (Angew. chem. int. Ed.2016,55, 1966-; and Winter et al (Science 2015,348,1376-1381), entitled "Drug development. polypeptide Conjugation as a Strategy for in vivo target Protein Degradation", describe thalidomide-based target Protein Degradation techniques.

WO 2015/160845 entitled "Imide Based modules of proteins and Methods of Use" assigned to Arvinas Inc. describes protein degrading compounds incorporating thalidomide and certain derivatives that bind to cereblonE3 ligase. Additional patent applications filed by Arvinas inc. that relate to the Use of known E3 ligase ligands to direct target proteins to proteasomes for degradation to degrade the target proteins include u.s.2016/0058872 entitled "Imide Based modules of proteins and Associated Methods of Use"; U.S.2016/0045607 entitled "Estrogen-related Receptor Alpha Based Protacomplements and Associated Methods of Use"; U.S.2016/0214972 entitled "Compound Methods for the Targeted differentiation of android receiver"; U.S.2016/0272639 entitled "Compounds and Methods for the Enhanced Degradation of TargetProteins"; U.S.2017/0008904 entitled "MDM 2-Based Modulators of proteins and Methods of Use"; U.S.2017/0037004 entitled "alkaloid-Based modulated proteins and Associated Methods of Use"; U.S. Pat. No. 2017/0065719 entitled "Compounds and Methods for the Targeted Degradation of Bromodepain containment proteins"; WO2016/036036 entitled "Tank Binding Kinase-1 PROTACS and assisted Methods of Use"; WO 2016/197032 entitled "Imide-Based Modulators and Associated Methods of Use"; WO 2017/176708 entitled "Protein-Protein Interaction Inducing Technology"; WO 2018/071606 entitled "Compounds and methods for Targeted Degradation of android Receptor"; WO 2018/102067 entitled "Tau-Protein Targeting protocols and Associated Methods of Use"; and WO 2018/102725 entitled "Tetrahydroavapor and Tetrahydroisoquinoline derivatives as Estrogen Receptor gradients".

The Dana-Farber cancer institute has also filed several patent applications relating to the use of known E3 ligase ligands to direct target proteins to proteasomes for degradation to degrade the target proteins. These submissions include US2016/0176916 entitled "method to Induce Target program Degradation through functional semiconductors"; WO 2017/024318 entitled "Target Protein differentiation to attached additive T-cell therapy Associated additive Responses"; WO 2017/024317 entitled "Methods to index Target Protein Degradation through Bifunctional Molecules" and WO 2017/024319 entitled "Tunable Endogenous Protein Degradation".

C4 pharmaceutical companies have filed patent applications for target protein degradation using E3 ligase ligands to direct target proteins to proteasomes for degradation. These applications include WO 2017/197051 entitled "Amine-Linked C3-glutamide degronomers for Target Protein Degradation"; WO 2017/197036 entitled "Spirocyclic Degromers for Target Protein Degradation"; WO 2017/197055 entitled "Heterocyclic Degromers for Target Protein Degradation"; WO 2017/197056 entitled "Bromodemains Targeting Degremers for Target Protein Degradation"; WO2017/197046, entitled "C3-Carbon Linked glutathione degronomers for Targetprotein Degradation".

While advances have been made in the field of modulation of the ubiquitin proteasome pathway for protein degradation in vivo, it would be useful to have additional compounds and methods to more fully utilize the ubiquitin proteasome pathway for therapeutic treatment.

It is an object of the present invention to provide novel compounds, methods, compositions and methods of manufacture that are useful for the in vivo degradation of selected proteins.

Disclosure of Invention

In one aspect of the invention, degron is provided that causes degradation of a target protein via the Ubiquitin Proteasome Pathway (UPP). In another aspect of the invention, there is provided a degron that binds to E3 ubiquitin ligase (typically cereblon). In one embodiment, binding of the degron to cereblon results in increased interaction of cereblon with Ikaros or Aiolos, resulting in their subsequent ubiquitination and degradation in the proteasome. Decreased levels of Ikaros or Aiolos result in altered transcriptional regulation of their downstream proteins.

Selected degron, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof disclosed herein are useful for treating disorders mediated by ikros or Aiolos, for example hematopoietic malignancies such as multiple myeloma, leukemia, acute myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, or myelodysplastic syndrome. Thus, in some embodiments, there is provided a method of treating a host (typically a human) having a condition mediated by Ikaros or Aiolos, comprising administering to the host an effective amount of a degron or a pharmaceutically acceptable salt thereof, optionally as a pharmaceutically acceptable composition. The compounds may also be used to achieve immunomodulation or reduce angiogenesis.

In another aspect of the invention, the degron is a compound of formula I, formula II, formula III or formula IV comprising a "targeting ligand" that binds (typically non-covalently) to a target protein of choice, a "degron" that binds (typically non-covalently) to an E3 ligase (typically cereblon), and optionally a linker that covalently links the targeting ligand to the degron.

The disintegrin, or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable composition thereof provided herein can be used to treat a condition mediated by a selected target protein that binds to a targeting ligand. Thus, in some embodiments, there is provided a method of treating a host having a disorder mediated by a target protein, comprising administering to the host (typically a human) an effective amount of a proteosome as described herein or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition.

In certain aspects, the selected target protein is derived from a gene that undergoes an amplification, translocation, deletion, or inversion event that causes or results from a medical condition. In certain aspects, the selected target protein has been post-translationally modified by one or a combination of phosphorylation, acetylation, acylation (including propionylation and crotylation), N-linked glycosylation, amidation, hydroxylation, methylation, polymethineization, O-linked glycosylation, pyroglutamylation, myristoylation, farnesylation, geranylation, ubiquitination, or sulfation that cause or result from a medical condition. In other aspects, the target protein may be covalently modified by a targeting ligand that has been functionalized to create a covalent bond with the target protein, and the covalent bond may be irreversible or reversible.

In another aspect of the invention, there is provided a degron of formula I or formula II:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition;

wherein:

W¹is CR⁶R⁷、C═O、C═S、C═CH₂、SO₂S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)₂P (O) alkyl, P (O) OH or P (O) NH₂；

W²Is CR⁸R⁹、C═O、C═S、C═CH₂、SO₂S (O), P (O) Oalkyl, P (O) NH alkyl, P (O) N (alkyl)₂P (O) alkyl, P (O) OH or P (O) NH₂；

In an exemplary embodiment, W¹Is C ═ O;

in another exemplary embodiment, W²Is C ═ O;

x is independently selected from NH, NR³、CH₂、CHR³、C(R³)₂O and S;

n is 0,1, 2 or 3;

is a single or double bond;

wherein when

When represents a single bond, n is 0,1, 2 or 3;

wherein when

When representing a double bond, n is 0,1 or 2;

R¹is selected from

And R¹*；

Wherein each R¹Optionally substituted with one or more groups independently selected from R⁵Substituted with the substituent(s);

R²independently is alkyl, hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocycle;

in some embodiments, alkyl is C₁-C₆，C₁-C₅，C₁-C₄，C₁-C₃，C₁-C₂Or a methyl group;

R¹is selected from

Or R¹Is selected from

R³In each case selected from the group consisting of alkyl, -C (O) H, -C (O) OH, -C (O) alkyl, -C (O) Oalkyl, alkene and alkyne;

or two R⁴Substituent and otherThe carbon atoms to which they are bonded together may form a3, 4,5 or 6 membered ring;

R⁵and R¹⁴In each case selected from the group consisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azide, amino, cyano, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl)₂，-NHSO₂(aliphatic, including alkyl), -N (aliphatic, including alkyl) SO₂Alkyl, -NHSO₂(aryl, heteroaryl or heterocycle), C (O) R⁴-N (alkyl) SO₂(aryl, heteroaryl or heterocycle) -NHSO₂Alkenyl, -N (alkyl) SO₂Alkenyl, -NHSO₂Alkynyl, -N (alkyl) SO₂Alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, and carbocyclic;

each of said R⁵May be optionally substituted, for example, with one or more substituents selected from: alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azide, amino, -NH alkyl, -N (alkyl)₂Aryl, heterocycle, heteroaryl, haloalkyl, and cycloalkyl, or as otherwise described herein;

R⁶，R⁷，R⁸，R⁹，R¹⁰and R¹¹Independently selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, hydroxy, alkoxy, amine, -NH (aliphatic, including alkyl) and-N (aliphatic, including alkyl)₂；

or R⁶And R⁸Forming a1 or 2 carbon bridged ring;

or R⁶And R¹⁰Forming a1 or 2 carbon bridged ring;

or R⁸And R¹⁰Forming a1 or 2 carbon bridged ring;

or R¹⁴And R⁶Form a3, 4,5 or 6 carbon fused ring;

or R¹⁴And R¹⁰Form a3, 4,5 or 6 carbon fused ring;

or R¹⁴And R⁸Forming a1 or 2 carbon bridged ring;

or R¹⁴And R⁴Form 3,4, 5 or 6 carbon condensed rings, wherein R⁴At R¹⁴On carbon α, or a1, 2,3 or 4 carbon bridged ring of (A), wherein R is⁴Is different from R¹⁴α carbon above;

R¹²is a linker-targeting ligand;

a linker is a chemical group that links the degron to the targeting ligand; and is

The targeting ligand is a moiety that binds to the target protein.

In an alternative embodiment, R⁴Is hydrogen.

In another aspect of the invention, there is provided a compound of formula III or formula IV:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, prodrug, optionally in a pharmaceutically acceptable carrier to form a composition:

wherein:

R¹⁶is selected from

Wherein each R¹⁶Optionally one or more independently selected fromR⁵Substituted with the substituent(s);

and all other variables are as defined above in formula I and formula II.

The structure of the stator body is typically selected to have sufficient stability to sustain at least two, three, four or five months shelf life at-20 ℃. In one embodiment, the structure of the stator body is generally selected such that it has sufficient stability to maintain a shelf life of at least two, three, four, or five months under ambient conditions. To achieve this, each R group described herein must be sufficiently stable to maintain a corresponding desired shelf life of at least two, three, four, or five months under ambient conditions. One of ordinary skill in the art will be well aware of the stability of chemical moieties and can avoid those chemical moieties that are unstable or excessively reactive under the appropriate conditions.

The degrading ligand (degron, linker and targeting ligand), which includes any "R" group defined herein, may be optionally substituted as described in the following section i. Furthermore, all R groups, with or without optional substituents, should be interpreted in a manner that does not include redundancy (i.e., alkyl substituted with alkyl is redundant as is known in the art; however, alkoxy substituted with alkoxy, for example, is not redundant).

The degrading ligands of formula I, formula II, formula III and formula IV are bifunctional compounds having an E3 ubiquitin ligase targeting moiety (degron) linked to a protein targeting ligand (described in more detail below) that recruits the target protein to the E3 ubiquitin ligase for degradation. One non-limiting example of a condition that can be treated by such compounds is abnormal cell proliferation, such as a tumor or cancer, where the target protein is an oncogenic protein or a signaling mediator of an abnormal cell proliferation pathway, and its degradation reduces abnormal cell growth.

Based on this discovery, compounds and methods are presented for treating a patient having a disorder mediated by a protein targeted for selective degradation, comprising administering to a patient (typically a human) in need thereof an effective amount of one or a combination of compounds of formula I, formula II, formula III, or formula IV described herein, optionally in a pharmaceutically acceptable carrier. In certain embodiments, the disorder is selected from benign growth, a neoplasm (neoplasms), a tumor (tumor), a cancer, an immune disorder, an autoimmune disorder, an inflammatory disorder, graft-versus-host rejection, a viral infection, a bacterial infection, an amyloid-based protein disease, a protein disease, or a fibrotic disorder. In a typical embodiment, the patient is a human.

In one embodiment, the present invention provides a degron moiety covalently linked to a targeting ligand through a linker that may have different lengths and functions. In one embodiment, the degron moiety is directly linked to the targeting ligand (i.e., the linker is a bond). In certain embodiments, the linker may be any chemically stable group that links the degron to the targeting ligand. In typical embodiments, the linker has a chain of 2 to 14, 15,16,17, 18, or 20 or more carbon atoms, wherein one or more carbons may be replaced by a heteroatom such as O, N, S or P, as long as the resulting molecule has a stable shelf life of at least 2 months, 3 months, 6 months, or1 year as part of a pharmaceutically acceptable dosage form, and is itself pharmaceutically acceptable. In certain embodiments, the chain has 2,3,4, 5,6,7, 8, 9, 10, 11, 12,13, or 14 consecutive atoms in the chain. For example, the chain may include 1 or more ethylene glycol units, and in some embodiments, there may be at least 2,3,4, 5,6,7, 8, 9, 10, or more continuous, partially continuous, or non-continuous ethylene glycol units in the linker. In certain embodiments, the chain has at least 1,2,3,4, 5,6,7, or 8 branches, which may independently be alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl substituents, which in one embodiment, each branch has 10, 8, 6,4, 3,2 carbons, or1 carbon.

In one embodiment, the target protein is a protein that is not pharmaceutically acceptable in the classical sense, as it does not have a binding pocket or active site that can be inhibited or otherwise bound, and cannot be readily allosterically controlled. In another embodiment, the target protein is a protein that is pharmaceutically acceptable in a classical sense. Examples of target proteins are provided below.

The compounds of the present application may provide important clinical benefits to patients, particularly for the treatment of disease states and conditions modulated by a protein of interest.

In another embodiment, a degron as described herein may be used alone (i.e., not as part of a degron vector) as an in vivo binding agent for cereblon, which may be administered to a host (e.g., a human) in need thereof in an effective amount (optionally as a pharmaceutically acceptable salt, and optionally in a pharmaceutically acceptable composition) for any therapeutic indication that may be treated by modulating the function and/or activity of the cereblon-containing E3 ubiquitin ligase protein complex, including but not limited to the known uses of the cereblon binding agents thalidomide, pomalidomide, or lenalidomide. In certain alternative embodiments, the compound of formula V or VI may activate, decrease or alter the natural activity of cereblon. Non-limiting examples of disorders that can be treated with cereblon binding agents include multiple myeloma, hematologic disorders such as myelodysplastic syndrome, cancer, tumors, abnormal cell proliferation, HIV/AIDS, crohn's disease, sarcoidosis, graft versus host disease, rheumatoid arthritis, behcet's disease, tuberculosis, and myelofibrosis.

In one embodiment, the degron is a compound of formula V or formula VI. The compounds may bind to cereblon, resulting in increased interaction of cereblon with ikros or Aiolos, leading to their subsequent ubiquitination and degradation in the proteasome. Decreased levels of Ikaros or Aiolos result in altered transcriptional regulation of their downstream proteins.

In another aspect of the invention, there is provided a compound of formula V or formula VI:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, prodrug, optionally in a pharmaceutically acceptable carrier to form a composition;

wherein:

R¹³is selected from

Wherein each R¹³Optionally substituted with one or more groups independently selected from R⁵Substituted with the substituent(s);

or R¹³Is selected from

Wherein each R¹³Optionally substituted with one or more groups independently selected from R⁵Substituted with the substituent(s);

or R¹³Is selected from

R²Independently is alkyl, hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocycle;

and all other variables are as defined above in formula I and formula II.

In an alternative embodiment, R⁴Is hydrogen.

The compounds of formulas V and VI do not include a linker or targeting ligand. In certain embodiments, the compound of formula V or formula VI may activate, decrease or alter the natural activity of cereblon. When administered in an effective amount to a host, including humans, these compounds of formula V or formula VI are useful as therapeutic agents for the treatment of medical conditions including, but not limited to: abnormal cell proliferation (including tumors or cancers), or myelo-or lymphoproliferative disorders such as B-cell or T-cell lymphoma, multiple myeloma, waldenstrom's macroglobulinemia, wiskott-aldrich syndrome, or post-transplant lymphoproliferative disorder; immune disorders, including autoimmune disorders, such as Addison's disease, Celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus or type I diabetes; cardiac dysfunction diseases, including hypercholesterolemia; infectious diseases, including viral and/or bacterial infections; inflammatory disorders including asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, crohn's disease, or hepatitis.

In other embodiments, compounds and methods are presented for treating conditions treatable by thalidomide, pomalidomide or lenalidomide. Non-limiting examples of disorders that can be treated by thalidomide, pomalidomide or lenalidomide include, but are not limited to, benign growth, a neoplasm, a tumor, a cancer, abnormal cell proliferation, an immune disorder, an inflammatory disorder, graft-versus-host rejection, a viral infection, a bacterial infection, an amyloid-based protein disorder, a protein disorder or a fibrotic disorder. In addition, other conditions that may be treated with an effective amount of a compound described herein are described below.

In certain embodiments, the compounds of formula I, formula II, formula III, formula IV, formula V, or formula VI have at least one desired isotopic substitution of atoms in an amount above the natural abundance of the isotope, i.e., are enriched. In one embodiment, the compound of formula I, formula II, formula III, formula IV, formula V or formula VI comprises one deuterium atom or more deuterium atoms.

In an alternative embodiment of formula I, formula II, formula III and formula IV, R¹²Is linker-hydrogen rather than linker-targeting ligand. In this embodiment, the compounds of formula I, formula II, formula III, or formula IV may be useful synthetic intermediates, or may be useful in the treatment of disorders mediated by ereblon or Ikaros family proteins. Non-limiting examples of this embodiment include:

wherein X¹，R²¹，R²²，R²³，R²⁴And R²⁵As defined in the following connector sub-section.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the specification, the singular forms also include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed application. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the present application will be apparent from the following detailed description and claims

Thus, the invention comprises at least the following features:

(a) a prodrug of formula I, formula II, formula III, or formula IV, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof, as described herein;

(b) a degreduzer of formula I, formula II, formula III, or formula IV for use in treating a condition mediated by a target protein, wherein the compound comprises a targeting ligand for the target protein, and wherein the degreduzer is linked to the targeting ligand, optionally through a linker;

(c) a degron of formula V or formula VI as described herein or a defined analogue thereof, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivatives), or prodrug thereof;

(d) use of an effective amount of a resolviny ligand of formula I, formula II, formula III, or formula IV for treating a patient (including a human) having a disorder mediated by a target protein, including abnormal cell proliferation such as a tumor or cancer, an immune or autoimmune disorder or an inflammatory disorder, a cardiac disorder, an infectious disease, or other disorder responsive to such treatment;

(e) use of an effective amount of a compound of formula V or formula VI for treating a patient (including a human) having abnormal cell proliferation such as a tumor or cancer, an immune or autoimmune disorder or an inflammatory disorder, a cardiac disorder, an infectious disease, or other disorder responsive to such treatment;

(f) use of a compound of formula I, formula II, formula III, formula IV, formula V, or formula VI, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the manufacture of a medicament for the treatment of a medical disorder;

(g) a process for the preparation of a medicament intended for the therapeutic treatment of a disorder, characterized in that a compound of formula I, formula II, formula III, formula IV, formula V or formula VI as described herein is used in the preparation;

(h) a compound of formula I, formula II, formula III, formula IV, formula V or formula VI, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof, as described herein, which is useful for treating abnormal cell proliferation such as cancer, including any cancer described herein;

(i) use of a compound of formula I, formula II, formula III, formula IV, formula V or formula VI, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivatives), or prodrug thereof, in the manufacture of a medicament for the treatment of abnormal cell proliferation such as cancer (including any cancer described herein);

(j) a method for the manufacture of a medicament intended for therapeutic use for the treatment of abnormal cell proliferation, such as cancer (including any cancer described herein), characterised in that a compound of formula I, formula II, formula III, formula IV, formula V or formula VI as described herein is used in the manufacture;

(k) a compound of formula I, formula II, formula III, formula IV, formula V or formula VI, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof, as described herein, which is useful for treating tumors, including any tumor described herein;

(l) Use of a compound of formula I, formula II, formula III, formula IV, formula V or formula VI, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof, in the manufacture of a medicament for the treatment of a tumour (including any tumour described herein);

(m) a process for the preparation of a medicament intended for the therapeutic treatment of tumours (including any tumour described herein), characterised in that a compound of formula I, formula II, formula III, formula IV, formula V or formula VI as described herein is used in the preparation;

(n) a compound of formula I, formula II, formula III, formula IV, formula V, or formula VI, as described herein, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof, useful for treating an immune, autoimmune, or inflammatory disorder;

(o) use of a compound of formula I, formula II, formula III, formula IV, formula V or formula VI, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof, in the manufacture of a medicament for the treatment of an immune, autoimmune or inflammatory disorder;

(p) a process for the preparation of a medicament intended for the therapeutic treatment of an immune, autoimmune or inflammatory disorder, characterized in that a compound of formula I, formula II, formula III, formula IV, formula V or formula VI as described herein is used in the preparation;

(q) a compound of formula I, formula II, formula III, formula IV, formula V or formula VI as described herein, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof, which is useful for treating viral infections including, but not limited to, HIV, HBV, HCV and RSV;

(r) the use of a compound of formula I, formula II, formula III or formula IV, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof, in the manufacture of a medicament for the treatment of viral infections, including but not limited to HIV, HBV, HCV and RSV;

(s) a process for the manufacture of a medicament intended for the therapeutic treatment of viral infections (including but not limited to HIV, HBV, HCV and RSV), characterized in that a compound of formula I, formula II, formula III or formula IV as described herein is used in the manufacture;

(t) a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I, formula II, formula III, formula IV, formula V, or formula VI, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, and a pharmaceutically acceptable carrier or diluent;

(u) a compound of formula I, formula II, formula III, formula IV, formula V or formula VI as described herein, as a mixture of enantiomers or diastereomers (as relevant), including as a racemate;

(v) a compound of formula I, formula II, formula III, formula IV, formula V, or formula VI as described herein, in enantiomerically or diastereomerically (as relevant) enriched form, including as an isolated enantiomer or diastereomer (i.e., greater than 85, 90, 95, 97, or 99% pure); and

(w) a process for the preparation of a therapeutic product containing an effective amount of a compound of formula I, formula II, formula III, formula IV, formula V or formula VI as described herein.

Drawings

FIGS. 1A-1C present examples of Retinoid X Receptor (RXR) targeting ligands, where R is the point of attachment of a linker.

FIGS. 1D-1F present examples of general dihydrofolate reductase (DHFR) targeting ligands, where R is the point of attachment of a linker.

FIG. 1G presents an example of a B.anthracis dihydrofolate reductase (BaDHFR) targeting ligand, where R is the point of attachment of a linker.

FIGS. 1H-1J present examples of heat shock protein 90(HSP90) targeting ligands, wherein R is the point of attachment of a linker.

FIGS. 1K-1Q present examples of general kinase and phosphatase targeting ligands, where R is the point of attachment of a linker.

FIG. 1R-1S presents examples of tyrosine kinase targeting ligands, where R is the point of attachment of a linker.

Figure 1T presents an example of an aurora kinase targeting ligand, where R is the point of attachment of the linker.

Figure 1U presents an example of a protein tyrosine phosphatase targeting ligand, where R is the point of attachment of a linker.

Figure 1V presents an example of an ALK targeting ligand, where R is the point of attachment of the linker.

Figure 1W presents an example of an ABL targeting ligand, where R is the point of attachment of the linker.

Figure 1X shows an example of a targeting ligand for JAK2, where R is the point of attachment for the linker.

FIGS. 1Y-1Z present examples of MET targeting ligands, where R is the point of attachment of a linker.

Fig. 1AA presents examples of mTORC1 and/or mTORC2 targeting ligands, where R is the point of attachment of a linker.

FIG. 1BB-1CC presents an example of a mast/stem cell growth factor receptor (SCFR) (also known as c-KIT receptor) targeting ligand, where R is the point of attachment of a linker.

Fig. 1DD presents examples of IGF1R and/or IR targeting ligands, where R is the point of attachment of a linker.

FIG. 1EE-1FF presents examples of HDM2 and/or MDM2 targeting ligands, where R is the point of attachment of a linker.

FIGS. 1GG-1MM present examples of Bromodomain-containing (Bromodomain) BET protein targeting ligands, where R is the point of attachment of a linker.

Figure 1NN presents an example of an HDAC targeting ligand, wherein R is the point of attachment of a linker.

Fig. 1OO presents an example of a RAF receptor targeting ligand, where R is the point of attachment of a linker.

Fig. 1PP presents an example of an FKBP receptor targeting ligand, where R is the point of attachment of the linker.

FIG. 1QQ-1TT presents an example of an androgen receptor targeting ligand, where R is the point of attachment of a linker.

Fig. 1UU presents an example of an estrogen receptor targeting ligand, where R is the point of attachment of the linker.

Figure 1VV-1WW presents an example of a thyroid hormone receptor targeting ligand, where R is the point of attachment of a linker.

FIG. 1XX presents examples of HIV protease targeting ligands, where R is the point of attachment of a linker.

Fig. 1YY presents an example of an HIV integrase targeting ligand, where R is the point of attachment of the linker.

Figure 1ZZ presents an example of an HCV protease targeting ligand, where R is the point of attachment of a linker.

Fig. 1AAA presents examples of AP1 and/or AP2 targeting ligands, where R is the point of attachment of a linker.

FIG. 1BBB-1CCC presents an example of an MCL-1 targeting ligand, where R is the point of attachment of a linker.

Figure 1DDD presents an example of an IDH1 targeting ligand, where R is the point of attachment of the linker.

FIG. 1EEE-1FFF presents an example of RAS or RASK targeting ligands, where R is the point of attachment of a linker.

Figure 1GGG presents examples of merks or MER targeting ligands, where R is the point of attachment of a linker.

FIG. 1HHH-1III presents examples of EGFR-targeting ligands, where R is the point of attachment of a linker.

FIG. 1JJJ-1KKK presents an example of a targeting ligand for FLT3, where R is the point of attachment of a linker.

Fig. 1LLL presents an example of a SMRCA2 targeting ligand, where R is the point of attachment of the linker.

Figure 2A presents an example of a kinase inhibitor targeting ligand U09-CX-5279 (derivatized), where R is the point of attachment of a linker.

Figures 2B-2C present examples of kinase inhibitor targeting ligands, including kinase inhibitor compounds Y1W and Y1X (derivatized), where R is the point of attachment of a linker. For additional examples and related ligands, see, Millan et al, "Design and Synthesis of introduced P38 Inhibitors for the Treatment of chronic obstructive Disease" j.med.chem.,54:7797 (2011).

Figure 2D presents examples of kinase inhibitor targeting ligands, including kinase inhibitor compounds 6TP and 0TP (derivatized), where R is the point of attachment of the linker. For additional examples and related ligands, see, Schenkel et al, "Discovery of patent and high Selective thiopyridine Janus Kinase2Inhibitors," J.Med.chem.,54(24):8440-8450 (2011).

Figure 2E presents examples of kinase inhibitor targeting ligands (including kinase inhibitor compound 07U), where R is the point of attachment of a linker. For additional examples and related ligands, see, Van Eis et al, "26-Naphthyridines enzymes and selective inhibitors of the novel protein kinases C enzymes," Bio rg. Med. chem.Lett.,21(24):7367-72(2011) for kinase inhibitors identified.

Figure 2F presents an example of a kinase inhibitor targeting ligand (including the kinase inhibitor compound YCF), where R is the point of attachment of the linker. For additional examples and related ligands, see, Loutos et al, "structural characterization of inhibitors with Checkpoint Kinase 2(Chk2) a drug target for Cancer Therapy," J.Structure.Biol., 176:292 (2011).

Fig. 2G-2H present examples of kinase inhibitor targeting ligands, including kinase inhibitors XK9 and NXP (derivatized), where R is the point of attachment of the linker. For additional examples and related ligands, see, Loutos et al, "structural characterization of inhibitors with Checkpoint Kinase 2(Chk2) a drug target for Cancer Therapy," J.Structure.Biol., 176:292 (2011).

Figures 2I-2J present examples of kinase inhibitor targeting ligands, where R is the point of attachment of a linker.

FIGS. 2K-2M present examples of cyclin-dependent kinase 9(CDK9) targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see Baumi et al, "The Structure of P-TEFb (CDK9/cyclin T1) its complex with a flavopiridol and regulation bypass," Embo J.,27:1907-1918 (2008); bettayeb et al, "CDK InhibitorsRoscovitine and CR8 Trigger Mcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma cells," Genes Cancer,1: 369-; baumli et al, "Halogen bond form the basis for selective P-TEFb inhibition by DRB." chem.biol.17:931-936 (2010);

hole et al, "synthetic Structural and Functional students of4- (Thiazol-5-YL) -2- (Phenylamino) pyrimide-5-Carbonitrile Cdk9 inhibitor requirements for the basis for Isotype selection," J.Med.Chem.56:660(2013), "L ü king et al," Identification of the potential and reactive selection PTFb inhibitor BAY1251152for the term of the specimen of cancer-Frp.o.o.i.v. application videos, "L ü king et al U.AACR Annual Meeting, 4.2011-5 days, 7.C. Wash, USA.

FIG. 2N-2P presents examples of cyclin-dependent kinase 4/6(CDK4/6) targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see, Lu h; Schulze-Gahmen u.; "Toward sides the structural basis of cycle-dependent kinase 6specific inhibition," J.Med.chem.,49: 3826-; 4- (Pyrazol-4-yl) -pyrimidines selecting inhibitory enzymes of cycle-dependent kinase 4/6; cho et al (2010) J.Med.chem.53: 7938-7957; cho Y.S. et al, "Fragment-Based Discovery of 7-Azabenzzimidazoles as post high Selective and oraly Active CDK4/6 inhibition," ACS Med Chem Lett 3:445- "449 (2012); li Z, et al, "Discovery of AMG925a FLT3 and CDK4 dual kinase inhibitor with a pressurized activity state of FLT3," J.Med.Chem.57: 3430-; chen P. et al, "spectral development of CDK Drug Interactions precursors Clinical Performance," mol. cancer Ther.15: 2273-.

Figure 2Q presents examples of cyclin-dependent kinase 12 and/or cyclin-dependent kinase 13 targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see, Zhang t et al, "value Targeting of Remote Cysteine reagents to Develop Cdk12 and dcdk13inhibitors," nat. chem. biol.12:876 (2016).

Fig. 2R-2S presents examples of glucocorticoid receptor targeting ligands, where R is the point of attachment of a linker.

Fig. 2T-2U present examples of RasG12C targeting ligands, where R is the point of attachment of the linker.

FIG. 2V presents examples of Her3 targeting ligands, where R is the point of attachment of the linker and R' is

FIG. 2W presents examples of Bcl-2 or Bcl-XL targeting ligands, where R is the point of attachment of a linker.

Fig. 2X-2NN presents an example of a BCL2 targeting ligand, where R is the point of attachment for the linker. For additional examples and related ligands, see, cure B.B. et al, "The role of The acid of N-heterocyclic amides as inhibitors of bcl-2family proteins-proteins interactions," ACSMed Chem Lett,4:186-190 (2013); porter J. et al, "waterborne quinoline amino acids as Selective Bcl-2 Inhibitors" bioorg. Med. chem. Lett.19:230 (2009); souers A.J. et al, "ABT-199 a positional and electric BCL-2inhibitor means inhibitors or activity while spaces tables," Nature Med.19: 202-; angelo Aguilar et al, "A Power and HighlyEffercious Bcl-2/Bcl-xL Inhibitor" J Med chem.56(7): 3048-3067 (2013); LongchuanBai et al, "BM-1197: A Novel and Specific Bcl-2/Bcl-xL Inhibitor Inducing filling and Long-testing Tumor Regression In Vivo," PLoS ONE 9(6): e 99404; fariba Ne' mati1 et al, "Targeting Bcl-2/Bcl-XL indexes Activity in Uvertical Melanoma Patient-eliminated xenographs" PLoS ONE 9(1): e 80836; WO2015011396, entitled "Novelderivitives of indels and pyrole method for the production of and pharmaceutical compositions stabilizing same"; WO2008060569A1, entitled "Compound methods for inhibiting the interaction of Bcl proteins with binding partners"; "Inhibitors of the anti-apoptotic Bcl-2proteins a patent review" Expert optics. the patent documents 22(1):2008 (2012); and Porter et al, "waterborne phenyl pyrazoles as selective Bcl-2inhibitors," Bioorg Med chem Lett.,19(1):230-3 (2009).

FIG. 2OO-2UU presents examples of BCL-XL targeting ligands, where R is the point of attachment for the linker. For additional examples and related ligands, see, Zhi-Fu Tao et al, "Discovery of a patent and Selective BCL-XLINhibitor with in Vivo Activity" ACS Med. chem. Lett.,5: 1088-; leverson et al, "expanding selected BCL-2family inhibitors to dis-connected cell sources and defined improved strategies for cancer therapy" Science relative Medicine,7:279ra40 (2015); and the crystal Structure PDB 3ZK6(Guillaume Lessene et al, "Structure-defined design of a selective BCL-XL inhibitor," Natural chemical Biology 9: 390-397 (2013)).

FIG. 2VV presents an example of a PPAR-gamma targeting ligand, where R is the point of attachment of the linker.

Fig. 2WW-2YY presents examples of EGFR targeting ligands (including erlotinib, gefitinib, afatinib, lenatinib, and dactinib) targeting EGFR L858R mutant, where R is the point of attachment of the linker.

FIG. 2ZZ-2FFF presents examples of EGFR-targeting ligands (including oxitinib, lotinib, tematinib, naltretinib, azatinib, PF-06747775, erlotinib, lenatinib, elvitinib, Tarloxotinib, PF-0645998, Tesevatinib, Transtinib, WZ-3146, WZ8040, and CNX-2006) targeting the EGFR T790M mutant, where R is the point of attachment of a linker.

Fig. 2GGG presents examples of EGFR targeting ligands (including EAI045) targeting EGFR C797S mutants, where R is the point of attachment of a linker.

Fig. 2HHH presents examples of BCR-ABL targeting ligands (including nilotinib and dasatinib) targeting BCR-ABL T315I mutants, where R is the point of attachment of the linker. See, for example, the crystal structure PDB 3CS 9.

Figure 2III presents examples of targeting ligands (including nilotinib, dasatinib, ponatinib, and bosutinib) targeting BCR-ABL, where R is the point of attachment of the linker.

Figure 2JJJ-2KKK presents an example of an ALK targeting ligand (including ceritinib) targeting ALK L1196M mutant, where R is the point of attachment of the linker. See, for example, the crystal structure PDB4 MKC.

Figure 2LLL presents an example of a JAK2 targeting ligand (including lucocotinib) targeting JAK2V617F mutant, where R is the point of attachment of the linker.

Fig. 2MMM presents an example of a BRAF targeting ligand (including vemurafenib) targeting a BRAF V600E mutant, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PBD3OG 7.

Fig. 2NNN presents an example of BRAF targeting ligands (including dabrafenib), where R is the point of attachment of a linker.

Fig. 2OOO presents an example of LRRK2 targeting ligand targeting LRRK 2R 1441C mutant, where R is the point of attachment of the linker.

Figure 2PPP presents an example of LRRK2 targeting ligand targeting LRRK 2G 2019S mutant, where R is the point of attachment of the linker.

Figure 2QQQ presents an example of LRRK2 targeting ligand targeting LRRK 2I 2020T mutant, where R is the point of attachment of the linker.

Figure 2RRR-2TTT presents examples of PDGFR α targeting ligands (including AG-1478, CHEMBL94431, dorivitinib, erlotinib, gefitinib, imatinib, Janex 1, pazopanib, PD153035, sorafenib, sunitinib, and WHI-P180) targeting PDGFR α T674I mutants, where R is the point of attachment of the linker.

Fig. 2UUU presents an example of RET targeting ligands (including tazarotene) targeting RET G691S mutant, where R is the point of attachment of the linker.

Figure 2VVV presents examples of RET targeting ligands (including tazarotene) targeting the RET R749T mutant, where R is the point of attachment of the linker.

Fig. 2WWW presents an example of RET targeting ligands (including tazarotene) targeting RET E762Q mutants, where R is the point of attachment of the linker.

Fig. 2XXX presents examples of RET targeting ligands (including tazarotene) targeting RET Y791F mutants, where R is the point of attachment of the linker.

Fig. 2YYY presents examples of RET targeting ligands (including tazarotene) targeting RET V804M mutants, where R is the point of attachment of the linker.

Figure 2ZZZ presents an example of RET targeting ligands (including tazarotene) targeting RET M918T mutants, where R is the point of attachment of the linker.

Figure 2AAAA presents an example of a fatty acid binding protein targeting ligand, where R is the point of attachment of a linker.

Figure 2BBBB presents an example of a 5-lipoxygenase activating protein (FLAP) targeting ligand, where R is the point of attachment of the linker.

Fig. 2CCCC presents an example of a Kringle domain V4 BVV targeting ligand, where R is the point of attachment for a linker.

Figure 2DDDD presents an example of a lactoyl glutathione lyase targeting ligand, where R is the point of attachment of a linker.

FIG. 2EEEE-2FFFF presents an example of a mPGES-1 targeting ligand, where R is the point of attachment of a linker.

FIG. 2GGGG-2JJJJ presents examples of factor Xa targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see, Maignan S. et al, "Crystal structures of human factor Xacomplexed with potential inhibition," J.Med.chem.43:3226-3232 (2000); matsusuue T. et al, "factory Xa Specific Inhibitor which indexes the Novel Binding Model in complete with Human Fxa." (to be published); crystal structures PDB 1iqh, 1iqi, 1iqk, and 1 iqm; adler M. et al, "Crystal Structures of Two patent Nonamidine organisms Bound to factory Xa," Biochemistry 41:15514-15523 (2002); roehrigg S. et al, "Discovery of the NovelAntithroMBotic Agent5-Chloro-N- ({ (5S) -2-Oxo-3- [4- (3-Oxomorphin-4-Yl) Phenyl ] -13-Oxazolidin-5-Yl } Methyl) thiophenylene-2-Carboxamide (Bay 59-7939): anal Direct Factor Xa inhibitor," J.Med.Chem.48:5900 (2005); anselm L. et al, "Discovery of a factory Xa Inhibitor (3R 4R) -1- (22-Difluoro-Ethyl) -Pyrrolidine-34-Dicarboxylaic Acid3- [ (5-Chloro-Pyridin-2-Yl) -Amide ]4- { [2-Fluoro-4- (2-Oxo-2H-Pyridin-1-Yl) -Phenyl ] -Amide } asa Clinical ditate," cancer. Med. chem.20:5313 (2010); and Pinto D.J. et al, "Discovery of 1- (4-Methoxyphenyl) -7-oxo-6- (4- (2-oxoperidin-1-yl) phenyl) -4567-tetrahydrogen-1H-pyrozolo [ 34-c ] pyridine-3-carboxamide (Apixaban BMS-562247) a high strain selected effective and available Bioavailable Inhibitor of Blood Coagulant Xa." J.Med.chem.50:5339-5356 (2007).

FIG. 2 KKKKKKKK presents an example of a Kallikrein 7 targeting ligand, wherein R is the point of attachment of a linker. For additional examples and related ligands, see, Maibaum J et al, "Small-substrate factor D inhibition targeting the alternative pathway," nat. chem. biol.12:1105-1110 (2016).

FIG. 2LLLL-2MMMM presents an example of a Cathepsin K targeting ligand, where R is the point of attachment of a linker. For additional examples and related ligands, see, Rankovic Z, et al, "Design and optimization of diseases of novel 2-cyanos-pyrimides as cathepsin K inhibitors," bioorg. Med. chem. Lett.20: 1524-; and Cai J et al, "trifluoromethyl phenyl asP 2for ketoamide-based cathepsins S inhibitors," bioorg. Med. chem. Lett.20:6890-6894 (2010).

Figure 2NNNN presents an example of a Cathepsin L targeting ligand, where R is the point of attachment of a linker. For further examples and related ligands, see Kuhn B, et al, "progressive Evaluation of Free energy regulations for the priority of Cathepsin L inhibitors," J.Med.chem.60:2485-2497 (2017).

Fig. 2 oooooo presents an example of a Cathepsin S targeting ligand, where R is the point of attachment for a linker. For additional examples and related ligands, see Jadhav P.K. et al "Discovery of the peptide S inhibition 3000328for the Treatment of the exogenous antigenic analysis" ACS Med.chem.Lett.5: 1138-.

FIG. 2PPPP-2SSSS presents an example of a MTH1 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, e.g., "patent and Selective Inhibitors of Mth1Probe its Role in Cancer Cell surf." j.med. chem.59:2346 (2016); huber K.V.M. et al, "Stereospecific Targeting of Mth1 by (S) -Crozotinib as an anticancer Strategy," Nature 508:222 (2014); gad H, et al, "MTH 1inhibition mechanisms preservation of the dNTP port," Nature 508:215-221 (2014); NissinkJ.W.M. et al, "Mth 1Substrate Recognition- -an Example of Specific Promission." Plos One 11:51154 (2016); and Man el Ellermann et al, "Novel class of force and electric interference MTH1 as broad-specific cancer target." AACRnational Meeting Abstract 5226,2017.

Figure 2TTTT-2ZZZZ presents examples of MDM2 and/or MDM4 targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see, Popowicz g.m. et al, "Structures of low molecular weight inhibitors bound to MDMX and MDM2 novel new approaches for p53-MDMX/MDM2 anticancer drug discovery," Cell Cycle,9 (2010); miyazaki M, et al, "Synthesis evaluation of novel organic active p53-MDM2 interaction inhibitors," bioorg. Med. chem.21: 4319-; miyazaki M, et al, "Discovery of DS-5272as addressing cancer A patent and all active p53-MDM2 interactive cancer suppressor," Bioorg Med chem.23:2360-7 (2015); holzer P. et al, "Discovery of a dihydroquinonoid Derivative (NVP-CGM097): A Highly Point and selected MDM 2Inhibitor based Phase 1Clinical Trials in p53wt Tumers." J.Med.chem.58:6348-6358 (2015); Gonzalez-Lopez de Turiso F. et al, "Rational design and Binding Mode Dual of MDM2-p53 inhibition," J.Med.chem.56: 4053-; gessier F. et al, "Discovery of dihydroquinonoid derivatives as novel inhibitors of the p53-MDM2 interaction with a discrete binding mode," bioorg. Med. chem. Lett.25: 3621-; fry D.C. et al, "Deconstruction of anutlin: separating the binding reagents of a patent protein-protein inhibition," ACS Med Chem Lett 4: 660-; ding Q.et al, "Discovery of RG7388 a Point and Selective p53-MDM 2Inhibitor in clinical development," J.Med.chem.56: 5979-; wang S. et al, "SAR 405838: an optimized inhibitor of MDM2-p53interaction at anchors and durable structural tolerance" Cancer Res.74: 5855-; rew Y, et al, "Discovery of AM-7209aPotent and Selective 4-Amidobasic Acid Inhibitor of the MDM2-p53interaction," J.Med.chem.57:10499-10511 (2014); bogen S.L. et al, "Discovery of novel 33-discovered peptides as organic biological substances HDM2-p53inhibitors," ACS Med.chem.Lett.7:324-329 (2016); and Sun D, et al, "Discovery of AMG232a Point Selective and organic Bioavailable MDM2-p53Inhibitor in Clinical development," J.Med.chem.57: 1454-.

Figure 2AAAAA-2EEEEE presents examples of PARP1, PARP2, and/or PARP3 targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see, Iwashhita A. et al, "Discovery of quinazoline and quinoline derivatives as potential and selective poly (ADP-ribose) polymerase-1/2 inhibition," Febs Lett.579: 1389-; crystal structure PDB2RCW (PARP in complex with a861695, Park C.H.); crystal structure PDB 2RD6 (PARP in complex with a861696, parkc.h.); crystal structure PDB 3GN 7; miyashiro J et al, "Synthesis and SAR of novel tricyclic quinoline inhibitors of poly (ADP-ribose) polymerase-1 (PARP-1)" bioorg. Med. chem. Lett.19: 4050-; gandhi V.B. et al, "Discovery and SAR of sub-regulated 3-oxosoindoline-4-carboxamides as potential inhibitors of poly (ADP-ribose) polymerase (PARP) for the treatment of cancer," bioorg. Med. chem. Lett.20: 1023. 1026 (2010); penning T.D. et al, "Optimization of phenyl-based-pyridozizamide carboxylate poly (ADP-ribose) polymerase inhibitors: identification of (S) -2- (2-fluoro-4- (pyridolin-2-yl) phenyl) -1H-benzimidazole-4-carboxamide (A-966492) a highlylid position and efficacy inhibitors". J.Med.Chem.53:3142-3153 (2010); ye N. et al, "Design, Synthesis, and biological evaluation of a Series of benzode [17] naphthyridin-7(8H) -ones Bearing a functionalized Longger Chain application as Novel PARP1 Inhibitors." J.Med.chem.56: 2885-; patel M.R. et al, "Discovery and Structure-Activity relationship of Novel 23-dihydrobenzofurans-7-carboxamides and 23-dihydrobenzofurans-3 (2H) -one-7-carboxamides Derivaties as Poly (ADP-ribose) polymerase-1inhibitors," J.Med.chem.57: 5579-; thorsell A.G., et al, "Structural Basis for Potency and Promiscience in Poly (ADP-ribose) polymerase (PARP) and Tankyrase inhibitors," J.Med.Chem.60: 1262-; crystal structure PDB4RV6 ("Human ARTD1(PARP1) catalytic domain in complex with inhibitor Rucaparib", Karlberg t. et al); papeo G.M.E. et al, "Discovery of 2- [1- (44-Difluorocyloxyl) Piperidin-4-Yl ] -6-Fluoro-3-Oxo-23-Dihydro-1H-Isoidole-4-Carboxamide (Nms-P118): A Point Available and high choice partial-1 Inhibitor for cancer therapy," J.Med.Chem.58:6875 (2015); kinoshita T, et al, "Inhibitor-induced structural change of the active site of human poly (ADP-rib) polymerase," Febs Lett.556:43-46 (2004); and Gangloff A.R. et al, "Discovery of novel benzol [ b ] [14] oxazin-3(4H) -ones as poly (ADP-ribose) polymerase inhibitors," bioorg.Med.chem.Lett.23: 4501-.

FIG. 2FFFFF-2 GGGGGGG presents an example of a PARP14 targeting ligand, where R is the point of attachment of a linker.

Fig. 2HHHHH presents an example of a PARP15 targeting ligand, where R is the point of attachment of the linker.

Fig. 2IIIII presents an example of a PDZ domain targeting ligand, where R is the point of attachment of the linker.

Figure 2JJJJJ presents an example of a phospholipase a 2domain targeting ligand, where R is the point of attachment of the linker.

FIG. 2 KKKKKKKKKKK presents an example of a protein S100-A72 WOS targeting ligand, wherein R is the point of attachment of a linker.

FIG. 2 LLLLLLL-2 MMMMM presents an example of an activin-B targeting ligand, where R is the point of attachment of a linker.

FIG. 2 NNN-2OOOOO presents an example of a Sec7 targeting ligand, where R is the point of attachment of the linker.

FIG. 2PPPPP-2QQQQQ presents an example of the SH 2domain of a pp60 Src targeting ligand, where R is the point of attachment of the linker.

Fig. 2RRRRR presents an example of a Tank1 targeting ligand, where R is the point of attachment of the linker.

Figure 2SSSSS presents an example of Ubc9 SUMO E2 ligase SF6D targeting ligands, where R is the point of attachment of the linker.

Figure 2 ttttttt presents an example of a Src targeting ligand (including AP23464), where R is the point of attachment of the linker.

FIG. 2 UUUUUUU-2 XXXXX presents examples of Src-AS1 and/or Src AS2 targeting ligands, where R is the point of attachment of the linker.

Figure 2yyyy presents an example of a JAK3 targeting ligand (including tofacitinib), where R is the point of attachment of the linker.

Figure 2 zzzzzzz presents examples of ABL targeting ligands (including tofacitinib and ponatinib), where R is the point of attachment of the linker.

Figures 3A-3B present examples of MEK1 targeting ligands (including PD318088, trametinib, and G-573), wherein R is the point of attachment of a linker.

Fig. 3C presents an example of a KIT targeting ligand (including regorafenib), where R is the point of attachment of the linker.

Fig. 3D-3E present examples of HIV reverse transcriptase targeting ligands (including efavirenz, tenofovir, emtricitabine, ritonavir, raltegravir, and atazanavir), where R is the point of attachment of the linker.

Figures 3F-3G present examples of HIV protease targeting ligands (including ritonavir, raltegravir, and atazanavir), where R is the point of attachment of the linker.

FIGS. 3H-3I present examples of KSR1 targeting ligands, where R is the point of attachment of a linker.

Figures 3J-3L present examples of CNNTB1 targeting ligands, where R is the point of attachment of the linker.

Fig. 3M presents an example of a BCL6 targeting ligand, where R is the point of attachment for the linker.

Fig. 3N-3O presents an example of a PAK1 targeting ligand, where R is the point of attachment of the linker.

FIGS. 3P-3R present examples of PAK4 targeting ligands, where R is the point of attachment of a linker.

Figures 3S-3T present examples of TNIK targeting ligands, where R is the point of attachment of the linker.

Figure 3U presents an example of a MEN1 targeting ligand, where R is the point of attachment of the linker.

FIGS. 3V-3W present examples of ERK1 targeting ligands, where R is the point of attachment of the linker.

Fig. 3X presents an example of an IDO1 targeting ligand, where R is the point of attachment of the linker.

Fig. 3Y presents an example of a CBP targeting ligand, where R is the point of attachment of the linker.

FIGS. 3Z-3SS present examples of MCL1 targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see, Tanaka Y. et al, "Discovery of patent Mcl-1/Bcl-xL dialinihibitors by using a hybridization strategy based on structural analysis proteins," J.Med.chem.56: 9635-; friberg A. et al, "Discovery of cell of muscle cell leukemia 1(Mcl-1) inhibition-based methods and structure-based design," J.Med.chem.56:15-30 (2013); petros A.M. et al, "Fragment-based discovery of patent inhibitors of the anti-apoptotic MCL-1protein," bioorg.Med.chem.Lett.241484 + 1488 (2014); burke J.P. et al, "Discovery and circulation indexes that can be used in a patent document-1 using fragment-based methods and structure-based design," J.Med.chem.58: 3794-; pelz N.F. et al, "discovery 2-indele-acyl sulfonimide Myeloid Cell Leukamia 1(Mcl-1) inhibition Using fragment-Based methods," J.Med.Chem.59: 2054-; clifton M.C. et al, "AMaltose-Binding Protein Fusion Construct strategies years a Robust crystalline random platform for MCL 1." Plos One 10: e0125010-e0125010 (2015); kotschy A et al, "The MCL1inhibitor S63845 is soluble and effective in reverse cancer models. Nature538: 477-; EP 2886545A1, entitled "New thiopyrimide derivatives for the preparation and pharmaceutical compositions relating; jeffrey W.Johannes et al, "Structure Based Design of Non-Natural peptidic macrocycle Mcl-1Inhibitors," ACS Med.chem.Lett. (2017); DOI 10.1021/acsmedlett.6b00464; brunck M. et al, "Structure-Guided Design of a Series of MCL-1Inhibitors with High Affinity and selection," J.Med.chem.58:2180-2194 (2015); taekyu Lee et al, "Discovery and biological characterization of positional cell leukamia-1 inhibitors," FEBS Letters 591: 240-; chen L, et al, "Structure-Based Design of 3-Carboxy-subscribed 1234-Tetrahydroquinolines as Inhibitors of Myeloid Cell Leukamia-1 (Mcl-1)," org.Biomol. chem.14: 5505-; US 2016/0068545 entitled "Tetrahydroaphtaliene derivitives which at inhibit mcl-1 protein"; WO 2016207217A1, entitled "Preparation of new bicyclic derivatives as pro-apoptotic agents"; gizem

Et al "Inhibition of Mcl-1through synergistic modification of an anionic lysine side chain" Nature Chemical Biology 12: 931-936 (2016).

Fig. 3TT presents an example of an ASH1L targeting ligand, where R is the point of attachment of the linker. See, for example, the crystal structure PDB 4YNM ("Human ASH1L SET domain in complex with S-adenosyl methionine (SAM)" Rogawski D.S. et al)

Fig. 3UU-3WW presents an example of an ATAD2 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, Chaikuad A. et al, "Structure-based therapeutics for the low-throughput ATAD2 Bromodomin" Medchem Comm5:1843-1848 (2014); "confidential-monomeric mixture of flexible substrates peptide-and small molecule ligand-complexes of ATAD2" biochem. J.466:337-346 (2015); harner M.J. et al, "Fragment-based screening of the Bromodemail of ATAD2." J.Med.chem.57: 9687-; DemontE.H. et al, "Fragment-Based Discovery of Low-Micromolar Atad2 Bromodomainain inhibitors," J.Med.chem.58:5649 (2015); and Bamborough P. et al, "Structure-based optimization of Naphthidones in o Point Attad 2 Bromodomain inhibitors," J.Med.chem.58:6151 (2015).

FIGS. 3XX-3AAA present examples of BAZ2A and BAZ2B targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see, crystal structure PDB 4CUU ("Human Baz2B in Complex with fragment-6N 09645" Bradley a. et al); crystal structure PDB 5CUA ("Second Bromodeain of Bromodeain Adjacent to Finger Finger Domain Protein 2B (BAZ2B) in complex with1-Acetyl-4- (4-hydroxypropyl) piperazine". Bradley A., et al); ferguson F.M. et al, "Targeting low-throughput composites: fragment based screening and designing the BAZ2B composites". J.Med.chem.56: 10183-; marchand J.R. et al, "Derivatives of 3-Amino-2-methyl pyridine as BAZ2 BBromodipine Ligands: In silica Discovery and In Crystallo validation," J.Med.chem.59: 9919-; drouin L, et al, "Structure Enabled Design of BAZ2-ICR A Chemical Probe Targeting the Bromodeomains of BAZ2A and BAZ2B," J.Med.chem.58:2553 + 2559 (2015); chen P, et al, "Discovery and characterization of GSK2801 a selective chemical probes for the branched chemical BAZ2A and BAZ2B," J.Med.chem.59: 1410-.

Figure 3BBB presents an example of a BRD1 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, Crystal Structure PDB 5AME ("the Crystal Structure of the Bromodepain of human Surface Engineered Brd1A in Complex with 3D Consortium Fragment4-Acetyl-Piperazin-2-One Pearce", N.M., et al); the crystal structure PDB 5AMF ("crystalline Structure of the Bromodeain of Human Surface Engineered Brd1A filled with complex with 3D Consortium Fragment Ethyl 4567-tetrahedron-1H-indole-5-Carboxylate", Pearl N.M. et al); the Crystal structure PDB 5FG6 ("the Crystal structure OF the branched polyamide OF human BRD1(BRPF2) in complex with OF-1chemical probe", TallantC, et al); filippakopoulos P. et al, "Histone recognition and large-scale structure analysis of the human bromodomain family," Cell,149: 214-.

FIG. 3CCC-3EEE presents an example of a BRD2 bromodomain 1 targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see crystal structure PDB2 ydw; crystal structure PDB2 yek; crystal structure PDB4a9 h; crystal structure PDB4a9 f; crystal structure PDB4a9 i; crystal structure PDB4a9 m; crystal structure PDB4 akn; crystal structure PDB 4alg and crystal structure PDB4 uyf.

Figure 3FFF-3HHH presents an example of a BRD2 bromodomain 2 targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see crystal structure PDB3 oni; filippazopoulos P. et al, "SelectiveInhibion of BET Bromodomains." Nature 468:1067-1073 (2010); crystal structure PDB4j 1 p; McLure K.G. et al "RVX-208: an indicator of ApoA-I in Humans is a BET Bromodomainantagnostist." Plos One 8: e83190-e83190 (2013); baud M.G. et al "Chemical biology. Absump-and-hole ap reach to engineering controlled selection of BET branched Chemical probes" Science 346:638-641 (2014); baud M.G. et al, "New Synthetic route Triazolo-benzodiazepine analogs: Expanding the Scope of the bulb-and-HoleAproach for selecting Bromo and Extra-terminal (BET) Bromodemian Inhibition" J.Med.chem.59:1492-1500 (2016); gosmini R. et al, "The Discovery of I-Bet726(Gsk1324726A) a patent Tetrahydroquinoline Apoa1 Up-Regulator and SelectiveBet Bromodeomain Inhibitor" J.Med.chem.57:8111 (2014); the crystal structure PDB 5EK9 ("crystalline structure of the second branched polyamide of human BRD 2in complex with hydroquinonyl inhibitor", Tallant C. et al.); crystal structure PDB 5BT 5; crystal structure PDB5 dfd; baud M.G. et al, "New Synthetic Routes to Triazolo-benzodiazepine analogs: Expanding the Scope of the bulb-and-Hole Approach for selected bromine and extract-terminal (BET) Bromodeomain Inhibition" J.Med.chem.59:1492-1500 (2016).

FIGS. 3III-3JJJ present examples of BRD4 bromodomain 1 targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see crystal structure PDB 5WUU and crystal structure PDB 5F 5Z.

FIG. 3KKK-3LLL presents an example of a BRD4 bromodomain 2 targeting ligand, wherein R is the point of attachment of a linker. For additional examples and related ligands, see Chung C.W. et al, "Discovery and characterization of Small molecules Inhibitors of the Bet Family" J.Med.Chem.54:3827(2011) and Ran X. et al, "Structure-Based Design of gamma-carbon antibodies asPotent and specificity Bromodomain Inhibitors" J.Med.Chem.58: 4927-.

Figure 3MMM presents an example of a BRDT targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 4flp and crystal structure PDB4 kcx.

FIG. 3NNN-3QQQ presents an example of a BRD9 targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see, crystal structure PDB4 nqn; crystal structure PDB4 uit; crystal structure PDB4 uiu; crystal structure PDB4 uiv; crystal structure PDB 4z6 h; crystal structure PDB 4z6 i; crystal structure PDB5e 9 v; crystal structure PDB5eu 1; crystal structure PDB 5f1 h; and the crystal structure PDB 5fp 2.

Fig. 3RRR presents examples of SMARCA4 PB1 and/or SMARCA2 targeting ligands, where R is the point of attachment of a linker, a is N or CH, and m is 0,1, 2,3,4, 5,6,7, or 8.

FIG. 3SSS-3XXX presents examples of additional bromodomain targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see Hewings et al, "35-dimylisoxazoles Act acacetinyl-lysine Bromodomain ligands," j.med.chem.546761-6770 (2011); dawson et al, "Inhibition of BET discrimination to chromaffin as an Effective Treatment for MLL-fusion Leukemia," Nature,478,529-533 (2011); US 2015/0256700; US 2015/0148342; WO 2015/074064; WO 2015/067770; WO 2015/022332; WO 2015/015318; and WO 2015/011084.

Fig. 3YYY presents an example of a PB1 targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see crystal structure PDB 3mb 4; crystal structure PDB 4q0 n; and the crystal structure PDB 5fh 6.

Figure 3ZZZ presents an example of a SMARCA4 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure 3uvd and crystal structure 5 dkd.

Figure 3AAAA presents an example of a SMARCA2 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure 5dkc and crystal structure 5 dkh.

Fig. 3BBBB presents examples of TRIM24(TIF1a) and/or BRPF1 targeting ligands, where R is the point of attachment of the linker and m is 0,1, 2,3,4, 5,6,7, or 8.

Fig. 3CCCC presents an example of a TRIM24(TIF1a) targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see Palmer W.S. et al, "Structure-Guided Design of IACS-9571: a selected High-Affinity Dual TRIM24-BRPF1 Bromodemian inhibitor," J.Med.chem.59:1440-1454 (2016).

FIG. 3DDDD-3FFFF presents an example of a BRPF1 targeting ligand, where R is the point of attachment of a linker. For further examples and related ligands, see, crystal structure PDB4 uye; crystal structure PDB 5c7 n; crystal structure PDB 5c 87; crystal structure PDB 5c 89; crystal structure PDB5d 7 x; crystal structure PDB5 dya; crystal structure PDB5 epr; crystal structure PDB5eq 1; crystal structure PDB5 etb; crystal structure PDB 5ev 9; crystal structure PDB5 eva; crystal structure PDB5 ewv; crystal structure PDB5 eww; crystal structure PDB5 ffy; crystal structure PDB 5fg 5; and the crystal structure PDB 5g4 r.

Fig. 3 gggggg presents an example of a CECR2 targeting ligand, where R is the point of attachment of a linker. For further examples and related ligands see moustackim m et al med.chem.7: 2246-; 5391-5402(2016).

Fig. 3 hhhhhh-3 OOOO presents examples of CREBBP targeting ligands, where R is the point of attachment of the linker, a is N or CH, and m is 0,1, 2,3,4, 5,6,7, or 8. For further examples and related ligands, see, crystal structure PDB 3p1 d; crystal structure PDB3 svh; crystal structure PDB 4nr 4; crystal structure PDB 4nr 5; crystal structure PDB 4ts 8; crystal structure PDB 4nr 6; crystal structure PDB 4nr 7; crystal structure PDB4 nyw; crystal structure PDB4 nyx; crystal structure PDB4 tqn; crystal structure PDB5 cgp; crystal structure PDB5 dbm; crystal structure PDB 5ep 7; crystal structure PDB5i 83; crystal structure PDB5i 86; crystal structure PDB5i 89; crystal structure PDB5i 8 g; crystal structure PDB 5j0 d; crystal structure PDB5 ktu; crystal structure PDB5 ktw; crystal structure PDB5 ktx; crystal structure PDB 5tb 6.

Fig. 3PPPP presents an example of an EP300 targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see crystal structure PDB 5BT 3.

Figure 3QQQQ presents examples of PCAF targeting ligands, where R is the point of attachment of the linker. See, e.g., M.Ghizzoni et al bioorg.Med.chem.18: 5826-.

Fig. 3RRRR presents an example of a PHIP targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see Mol Cancer ther.7(9): 2621-2632 (2008).

Fig. 3SSSS presents examples of TAF1 and TAF1L targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see Picaud S. et al Sci Adv2: e1600760-e1600760 (2016).

Fig. 3TTTT presents an example of a histone deacetylase 2(HDAC2) targeting ligand, wherein R is the point of attachment of a linker. For additional examples and related ligands, see Lauffer B.E.J.biol.chem.288: 26926-; wagner F.F.Bioorg.Med.chem.24:4008-4015 (2016); bressij.c.bioorg.med.chem.lett.20: 3142-; and Lauffer B.E.J.biol.chem.288: 26926-.

Fig. 3 uuuuu-3 VVVV presents an example of a histone deacetylase 4(HDAC4) targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see Burli r.w.j.med.chem.56:9934 (2013); luckhurst c.a.acs med.chem.lett.7:34 (2016); bottomley M.J.J.biol.chem.283: 26694-.

Figure 3 wwwwww presents an example of a histone deacetylase 6 targeting ligand, where R is the point of attachment of a linker. For additional examples and related ligands, see, Harding R.J (to be published); hai Y.Nat.chem.biol.12:741-747, (2016); and Miyake y.nat.chem.biol.12:748 (2016).

FIG. 3XXXX-3 YYYYY presents examples of histone deacetylase 7 targeting ligands, where R is the point of attachment of a linker. For further examples and related ligands see Lobera m.nat. chem.biol.9:319(2013) and Schuetz a.j.biol.chem.283:11355-11363 (2008).

FIG. 3 ZZZZZZ-3 DDDDD presents an example of a histone deacetylase 8 targeting ligand, where R is the point of attachment of a linker. For additional examples and related ligands, see Whitehead l.biol.med.chem.19:4626-4634 (2011); tabackman A.A.J.struct.biol.195:373-378 (2016); dowling d.p.biochemistry47,13554-13563 (2008); somoza J.R. biochemistry 12,1325-1334 (2004); decroos C.biochemistry 54:2126-2135 (2015); vannii A.Proc.Natl Acad.Sci.101:15064 (2004); vannii A. EMBO Rep.8:879 (2007); crystal structure PDB5 BWZ; decroos A. ACCchem. biol.9:2157-2164 (2014); somoza J.R.biochemistry 12:1325-1334 (2004); decroos C.biochemistry 54: 6501-; decroos A. ACS chem. biol.9:2157-2164 (2014); and Dowling D.P.biochemistry 47: 13554-.

Figure 3 eeeeee presents an example of a histone acetyltransferase (KAT2B) targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see Chaikuad A.J.Med.chem.59:1648-1653 (2016); crystal structure PDB1ZS 5; and Zeng L.J.Am.chem.Soc.127:2376-2377 (2005).

FIG. 3FFFFF-3GGGGG presents an example of a histone acetyltransferase (KAT2A) targeting ligand, where R is the point of attachment of a linker. For additional examples and related ligands, see ringer A.E.Actacrystallogr.D.struct.biol.72:841-848 (2016).

Fig. 3HHHHH presents an example of a histone acetyltransferase type B catalytic unit (HAT1) targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see crystal structure PDB 2P 0W.

FIG. 3IIIII presents an example of a cyclic AMP-dependent transcription factor (ATF2) targeting ligand, where R is the point of attachment of the linker.

Figure 3JJJJJ presents an example of a histone acetyltransferase (KAT5) targeting ligand, where R is the point of attachment of the linker.

FIG. 3 KKKKKKKKKKK-3 MMM presents an example of lysine-specific histone demethylase 1A (KDM1A) targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see Mimasu S.biochemistry49:6494-6503 (2010); sartori l.j.med.chem.60: 1673-; and VianelloP.J.Med.chem.60: 16993-1715 (2017).

Figure 3NNNNN presents an example of HDAC6 Zn finger domain targeting ligands, where R is the point of attachment of a linker.

Figure 3 ooooooo-3 PPPPP presents an example of a general lysine methyltransferase targeting ligand, where R is the point of attachment of a linker.

FIG. 3 QQQQ-3TTTTT presents an example of a DOT1L targeting ligand, where R is the point of attachment of the linker, A is N or CH, and m is 0,1, 2,3,4, 5,6,7, or 8. For additional examples and related ligands, see the crystal structure PDB 5MVS ("Dot 1L in complex with an adenosine and inhibitor CPD 1" Be c. et al); the crystal structure PDB5MW4 ("Dot 1L in complex inhibitor CPD 7" Be C., et al); crystal structure PDB 5DRT ("Dot 1L inludex inhibitor CPD 2" Be c. et al); be C, et al ACS Med.Lett.8: 338-; the crystal structure PDB 5JUW "(Dot 1L in complex with SS 148" Yu W. et al Structural genomics Consortium).

Fig. 3UUUUU presents an example of an EHMT1 targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see the crystal structure PDB 5TUZ ("EHMT 1in complex with inhibitor MS 0124", Babault n.

Fig. 3VVVVV presents an example of an EHMT2 targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see crystal structure PDB 5TUY ("EHMT 2in complex with inhibitor MS 0124", Babault n. et al); PDB crystal structure 5TTF ("EHMT 2in complex with inhibitor MS 012", donga et al); PDB crystal structure 3RJW (Dong a. et al, Structural Genomics Consortium); PDB crystal structure 3K 5K; liu F. et al J.Med.chem.52:7950-7953 (2009); and PDB crystal structure 4NVQ ("EHMT 2in complex with inhibitor a-366" Sweis r.f. et al).

Figure 3WWWWW presents an example of SETD2 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 5LSY ("SETD 2in complete with cyproheptadine", tisid et al); tisi D, et al ACS chem.biol.11:3093-3105 (2016); crystal structures PDB 5LSS, 5LSX, 5LSZ, 5LT6, 5LT7 and 5LT 8; PDB crystal structure 4 FMU; and Zheng W.et al J.Am.chem.Soc.134:18004-18014 (2012).

Fig. 3 xxxxxx-3 YYYYY present examples of SETD7 targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see PDB crystal structure 5AYF ("SETD 7 in complex with cyclopropeptide. PDB crystal structure 4JLG ("SETD 7 in complete with (R) -PFI-2", Dong A. et al); PDB crystal structure 4JDS (Dong A. et al Structural Genomics Consortium); PDB crystal structure 4E47(Walker J.R. et al Structural Genomics Consortium; PDB crystal structure 3VUZ ("SETD 7 in complex with AAM-1." Niwa H. et al); PDB crystal structure 3 VPO; and Niwa H et al acta crystallogra Sect.D 69:595-602 (2013)).

Figure 3 zzzzzzz presents an example of a SETD8 targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see PDB crystal structure 5TH7 ("SETD 8in complete with MS 453", Yu W. et al) and PDB crystal structure 5T5G (Yu W et al; to be published).

Fig. 4A-4B present examples of SETDB1 targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see PDB crystal structure 5KE2 ("SETDB 1in complete with inhibit xst 06472A", Iqbal a. et al); PDB crystal structure 5KE3 ("SETDB 1in complete with fragmentMRT0181 a", Iqbal A. et al); PDB crystal structure 5KH6 ("SETDB 1in complex with fragmented methyl 3- (methylsulfonylamino) benzoate", Walker J.R. et al Structural genomics Consortium); and PDB crystal structure 5KCO ("SETDB 1in complete with [ N ] - (4-chlorophenyl) methanosulfonic amide", Walker J.R. et al).

Fig. 4C-4P present examples of SMYD2 targeting ligands, where R is the point of attachment for a linker. For additional examples and related ligands, see PDB crystal structure 5KJK ("SMYD 2in complete with inhibitor AZ 13450370", Cowen s.d. et al); PDB crystal structure 5KJM ("SMYD 2in complete with AZ 931", Cowen s.d. et al); PDB crystal structure 5KJN ("SMYD 2in complex with AZ 506", Cowen s.d. et al); PDB crystal structure 5ARF ("SMYD 2in complex with N- [3- (4-chlorophenylyl) -1- { N' -cyano-N- [3- (difluoromethoxy) phenyl ] carbamimidoyl } -45-di hydro-1H-pyrazol-4-YL ] -N-ethyl-2-hydroxyacenamide", Eggert E., et al); PDB crystal structure 5ARG ("SMYD 2in complex with bay 598", Eggert e. et al); PDB crystal structure 4YND ("SMYD 2in complete with A-893", SweisR.F., et al); PDB crystal structure 4WUY ("SMYD 2in complete with LLY-507", Nguyen H. et al); and the PDB crystal structure 3S7B ("N-cyclohexenyl-N-3- [2- (34-dichlorophenyl) ethyl ] -N- (2- { [2- (5-hydroxy-3-oxo-34-dihydro-2H-14-benzoxazin-8-yl) ethyl ] amino } ethyl) -beta-alaninamide", Ferguson A.D. et al).

Fig. 4Q-4R present examples of SMYD3 targeting ligands, where R is the point of attachment for a linker. For additional examples and related ligands, see, crystal structure 5H17 ("SMYD 3in complex with 5'- { [ (3S) -3-amino-3-carboxypropyl ] [3- (dimethylamino) propyl ] amino } -5' -deoxythionine", vanallerg.s., et al); crystal structure 5CCL ("SMYD 3in complex with oxindole complex", Mitchell l.h. et al); and the Crystal structure 5CCM ("Crystal structure of SMYD3 with SAM and EPZ 030456").

FIG. 4S presents an example of a SUV4-20H1 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 5CPR ("SUV 4-20H 1in complete with inhibitor A-196", Bromberg K.D. et al).

FIGS. 4T-4AA present examples of wild-type androgen receptor targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see PDB crystal structures 5T8E and 5T8J ("android Receptor in complex with 4- (pyrolidin-1-yl) nitrile derivatives", Asano m., et al); AsanoM, et al, bioorg.Med.chem.Lett.27:1897-1901 (2017); PDB crystal structure 5JJM ("AndrogenReceptor", Nadal m. et al); PDB crystal structure 5CJ6 ("Hydrogen Receptor in complete with 2-Chloro-4- [ [ (1R2R) -2-hydroxy-2-methyl-cyclopentyl ] amino ] -3-methyl-benzoic acid derivatives", Saeed A. et al); PDB crystal structure 4QL8 ("android Receptor recomplex with 3-alkoxy-pyrolo [ 12-b ] pyrazolines derivatives", Ullrich T. et al); PDB crystal structure 4HLW ("android receiver Binding Function 3(BF3) Site of the humanandroid receiver through visual Screening", Munuganti R.S. et al); PDB crystal structure 3V49 ("android receiver lbd with activator peptide and harm inhibitor 1", Nique F. et al); nique f. et al j.med.chem.55:8225-8235 (2012); PDB crystal structure 2YHD ("Androgen Receptor in complete with AF2 small monomer inhibitor", Axero-Cilies P. et al); PDB crystal structure 3RLJ ("android receiver ligand binding domain in complex with SARM S-22", Bohl C.E., et al); bohl c.e. et al j.med.chem.54: 3973-; PDB crystal structure 3B5R ("android receiver ligand binding domain in complex with SARM C-31", Bohl C.E., et al); bohl C.E. et al bioorg.Med.chem.Lett.18:5567-5570 (2008); PDB crystal structure 2PIP ("android ligand binding domain in complex with small molecule", Estebanez-Perpina E., et al); Estebanez-Perpina.E.Proc.Natl.Acad.Sci.104:16074-16079 (2007); PDB crystal structure 2PNU ("Androgen Receptor ligand domain in complex with EM 5744", Cantin L., et al); and, PDB crystal structure 2HVC ("android binding domain in complex with LGD 2226", Wang F. et al.). For additional related ligands, see, materials P.M. et al, "Structural Basis for the glucose responsive in a Mutant Human android Receptor (Ar (ccr))," J.Med.chem.45:1439 (2002)); SackJ.S. et al, "crystalline structures of the ligand-binding domains of the hydrogen receiver and its T877A mutant complex with the natural agglomerated hydrotestosterone," Proc.Natl.Acad.Sci.98:4904-4909 (2001); HeB, et al, "Structural basis for android receivers interface and interactivity interactions activation function in nuclear receiver" mol.cell 16:425-438 (2004); "proportional of crystal structures of human and human android receivers ligand-binding domain complex with variables of microorganisms specific responses for binding". The Protein Sci.15: 987. sup. cake 999 (2006); BohlC.E., et al, "Structural Basis for evaluation of nonlinear interactions in the android receiver," MolPharmacol.63(1):211-23 (2003); "J.Med.Chem.49: 7596-7599 (2006)" Discovery of content-real and selective and gene retrieval modulators based on an N-aryl-hydroxydihydrocyclohydantion scaffold, "; nirschl A.A. et al, "N-aryl-oxoridin-2-imine muscle selective and generator modulator gene therapy orientation," J.Med.chem.52:2794-2798 (2009); bohl C.E., et al, "Effect of B-ring stabilization pattern on binding mode of propionide selective and generator modulators," bioorg.Med.chem.Lett.18: 5567-; UllrichT, et al, "3-alkoxy-pyro [ 12-b ] pyrazolines as selective android modulator with ideal physical properties for transdermal administration," J.Med.chem.57:7396-7411 (2014); saeed A. et al, "2-Chloro-4- [ [ (1R2R) -2-hydroxy-2-methyl-cyclopentyl ] amino ] -3-methyl-nitrile: A Transdermal Selective Antigen Receptor Modulator (SARM) for muscle Atrophy" J.Med.chem.59: 750-; nique et al, "Discovery of diagnostic and new selective and reliable gene modulators," J.Med.chem.55:8225-8235 (2012); and, Michael E.Jung et al, "Structure-Activity relationship for thiohydaton antigen receptors for trapping-resistance State Cancer (CRPC)," J.Med.chem.53: 2779-.

Fig. 4BB presents an example of a mutant T877A androgen receptor targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 4OGH ('android receiver T877A-AR-LBD', Hsu c.l. et al) and PDB crystal structure 2OZ7 ('android receiver T877A-AR-LBD', bohlc.e. et al).

Figure 4CC presents an example of a mutant W741L androgen receptor targeting ligand, wherein R is the point of attachment of a linker. For additional examples and related ligands, see PDB crystal structure 4OJB ("android Receptor T877A-AR-LBD", Hsu c.l. et al).

Fig. 4DD-4EE presents examples of estrogen and/or androgen targeting ligands, where R is the point of attachment of a linker.

Figure 5A presents examples of targeting ligands for afatinib, EGFR and ErbB2/4 receptors. R is the point of attachment of the linker.

Figure 5B presents examples of targeting ligands for axitinib, VEGFR1/2/3, PDGFR β and Kit receptors R is the point of attachment of the linker.

FIGS. 5C-5D present examples of targeting ligands for bosutinib, BCR-Abl, Src, Lyn, and Hck receptors. R is the point of attachment of the linker.

FIG. 5E presents examples of targeting ligands for the cabozantinib, RET, c-Met, VEGFR1/2/3, Kit, TrkB, Flt3, Axl, and Tie2 receptors. R is the point of attachment of the linker.

Figure 5F presents examples of targeting ligands for ceritinib, ALK, IGF-1R, InsR, and ROS1 receptors. R is the point of attachment of the linker.

Figure 5G presents examples of targeting ligands for crizotinib, ALK, c-Met, HGFR, ROS1, and MST1R receptors. R is the point of attachment of the linker.

Figure 5H presents examples of targeting ligands for the dabrafenib, B-Raf receptor. R is the point of attachment of the linker.

FIG. 5I presents examples of targeting ligands for the Dasatinib, BCR-Abl, Src, Lck, Lyn, Yes, Fyn, Kit, EphA 2and PDGFR β receptors R is the point of attachment of a linker.

Fig. 5J presents an example of erlotinib, a targeting ligand for the EGFR receptor. R is the point of attachment of the linker.

Fig. 5K-5M present examples of targeting ligands for everolimus, HER2 breast cancer receptor, PNET receptor, RCC receptor, RAML receptor, and SEGA receptor. R is the point of attachment of the linker.

Figure 5N presents examples of targeting ligands for gefitinib, EGFR and PDGFR receptors. R is the point of attachment of the linker.

Figure 5O presents examples of targeting ligands for ibrutinib, a BTK receptor. R is the point of attachment of the linker.

FIGS. 5P-5Q present examples of targeting ligands for imatinib, BCR-Abl, Kit and PDGFR receptors. R is the point of attachment of the linker.

Figures 5R-5S present examples of targeting ligands for the lapatinib, EGFR and ErbB2 receptors. R is the point of attachment of the linker.

Figure 5T presents examples of targeting ligands for lenvatinib, VEGFR1/2/3, FGFR1/2/3/4, PDGFR α, Kit, and RET receptors R is the point of attachment of the linker.

FIGS. 5U-5V present examples of targeting ligands for nilotinib, the BCR-Abl, PDGRF and DDR1 receptors. R is the point of attachment of the linker.

FIGS. 5W-5X present examples of targeting ligands for the Nintedanib, FGFR1/2/3, Flt3, Lck, PDGFR α/β and VEGFR1/2/3 receptors.

FIGS. 5Y-5Z present examples of targeting ligands for the Palbociclib (Palbociclib), CDK4/6 receptor. R is the point of attachment of the linker.

FIG. 5AA presents examples of targeting ligands for pazopanib, VEGFR1/2/3, PDGFR α/β, FGFR1/3, Kit, Lck, Fms, and Itk receptors.

FIGS. 5BB-5CC present examples of targeting ligands for ponatinib, BCR-Abl, T315I VEGFR, PDGFR, FGFR, EphR, Src family kinases, Kit, RET, Tie2, and Flt3 receptors. R is the point of attachment of the linker.

FIG. 5DD presents examples of targeting ligands for regorafenib, VEGFR1/2/3, BCR-Abl, B-Raf (V600E), Kit, PDGFR α/β, RET, FGFR1/2, Tie2, and Eph 2A.

Figure 5EE presents an example of a targeting ligand for the luccotinib, JAK1/2 receptor. R is the point of attachment of the linker.

FIG. 5FF-5GG presents examples of targeting ligands for the sirolimus, FKBP12/mTOR receptor. R is the point of attachment of the linker.

FIG. 5HH presents examples of targeting ligands for sorafenib, B-Raf, CDK8, Kit, Flt3, RET, VEGFR1/2/3, and PDGFR receptors. R is the point of attachment of the linker.

FIGS. 5II-5JJ present examples of targeting ligands for sunitinib, PDGFR α/β, VEGFR1/2/3, Kit, Flt3, CSF-1R, RET R is the point of attachment of the linker.

FIG. 5KK-5LL presents examples of targeting ligands for temsirolimus, FKBP 12/mTOR. R is the point of attachment of the linker.

Figure 5MM presents examples of targeting ligands for tofacitinib, JAK3 receptor. R is the point of attachment of the linker.

Figure 5NN presents examples of targeting ligands for the trametinib, MEK1/2 receptor. R is the point of attachment of the linker.

FIG. 5OO-5PP presents examples of targeting ligands for vandetanib, EGFR, VEGFR, RET, Tie2, Brk, and EphR. R is the point of attachment of the linker.

FIG. 5QQ presents examples of targeting ligands for the Vemurafenib, A/B/C-Raf, KSR1, and B-Raf (V600E) receptors. R is the point of attachment of the linker.

Figure 5RR presents an example of a targeting ligand for the Idelasib, PI3Ka receptor. R is the point of attachment of the linker.

Figure 5SS presents an example of a targeting ligand for the Buparlisib, PI3Ka receptor. R is the point of attachment of the linker.

Figure 5TT presents examples of targeting ligands for Taselisib, PI3Ka receptors. R is the point of attachment of the linker.

Fig. 5UU presents an example of a targeting ligand for Copanlisib, PI3 Ka. R is the point of attachment of the linker.

Figure 5VV presents an example of a targeting ligand for Alpelisib, PI3 Ka. R is the point of attachment of the linker.

Figure 5WW presents an example of a targeting ligand for niclosamide, CNNTB 1. R is the point of attachment of the linker.

Figures 6A-6B present examples of targeting ligands for PCAF and the BRD4 bromodomain of GCN5 receptor1, where R is the point of attachment of the linker. For further examples and related ligands, see PDB crystal structure 5tpx ("Discovery of a PCAFBromodomain Chemical Probe"); moustakim, m, et al, angew.chem.int.ed.engl.56:827 (2017); PDB crystal structure 5mlj ("Discovery of a Power, Cell Pentanent, and selected 300/CBP-Associated Factor (PCAF)/General Control nondirepressible 5(GCN5) Bromodomain Chemical Probe"); and hummphreys, p.g. et al j.med.chem.60:695 (2017).

Fig. 6C-6D present examples of G9a (EHMT2) targeting ligands, where R is the point of attachment of a linker. For further examples and related ligands, see PDB crystal structure 3k5 k; (Discovery of a2, 4-diamino-7-aminoalkoxyquinoline as a potential and selective inhibitor of hormone lysine transferase G9 a); liu, f, et al j.med.chem.52:7950 (2009); PDB crystal structure 3rjw ("intrinsic probe selective inhibitors G9a and GLP methyl transferase activity cells"); vedadi, m. et al nat. chem.biol.7:566 (2011); PDB crystal structure 4nvq ("Discovery and Discovery inhibition of ligands of hormone methyl transferase 9 a"); and Sweis, R.F. et al ACS Med Chem Lett 5:205 (2014).

Fig. 6E-6G present examples of EZH2 targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 5ij8 ("Polycomb compressed complex 2 structure with inhibitor derivatives a mechanism of activation and drug resistance"); brooun, A. et al Nat Commun 7:11384 (2016); PDB crystal structure 5ls6 ("Identification of (R) -N- ((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) -2-methyl-1- (1- (1- (2,2,2-trifluoroethyl) piperidin-4-yl) ethyl) -1H-indole-3-carboxamide (CPI-1205), aPotent and Selective Inhibitor of Histone crystal synthase EZH2, Suitable for phase I Clinical metals for B-cells"); vaswani, R.G. et al J.Med.chem.59:9928 (2016); and PDB crystal structures 5ij8 and 5ls 6.

FIGS. 6H-6I present examples of EED targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see PDB crystal structures 5h15 and 5h19 ("Discovery and Molecular Basis of a dispersive Set of Polycomb reproduction Complex 2 inhibition Recognition by EED"); li, L, et al PLoS ONE 12: e 0169845 (2017); and PDB crystal structure 5h 19.

Fig. 6J presents an example of a KMT5A (SETD8) targeting ligand, wherein R is the point of attachment of the linker. See, for example, PDB crystal structure 5t5 g.

FIGS. 6K-6L present examples of DOT1L targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see PDB crystal structure 4eki ("structural adaptation drive force, selective and durable inhibition of the human protein methyl transferase dot 1L"); basavapthluni, a. et al chem.biol.drug des.80:971 (2012); PDB crystal structure 4hra ("content inhibition of DOT1L as treatment of MLL-fusion Leukemia"); daigle, S.R. et al Blood 122:1017 (2013); PDB crystal Structure 5dry ("Discovery of Novel Dot1 lithium atoms through a Structure-Based Fragmentation application") Chen, C. et al ACSMed. chem. Lett.7:735 (2016); PDB crystal Structure 5dt2 ("Discovery of Novel Dot1 lithium atoms through a Structure-Based Fragmentation application"); and Chen, c, et al ACS med.chem.lett.7:735 (2016).

Fig. 6M-6N present examples of PRMT3 targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see PDB crystal structure 3smq ("antibiotic inhibitor of protein imaging transferase 3"); siartheyeva, a. et al Structure 20:1425 (2012); PDB crystal structure 4ryl ("A Pole, Selective and Cell-Active Allocation of protein arginine methyl transferase 3(PRMT 3)"); and Kaniska, H.U.S. et al Angew. chem.int.Ed. Engl.54:5166 (2015).

Figure 6O presents an example of a CARM1(PRMT4) targeting ligand, where R is the point of attachment of a linker. For additional examples and related ligands, see PDB crystal structures 2y1x and 2y1w and related ligands described in "Structural Basis for card 1Inhibition by index and pyrazole inhibitors," Sack, j.s. et al biochem.j.436:331 (2011).

Fig. 6P presents an example of a PRMT5 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 4x61 and related ligands described in "a selective inhibitor of PRMT5 with in vivo and in vitro in MCL models". Chan-Penebre, e.nat. chem.biol.11:432 (2015).

Fig. 6Q presents an example of a PRMT6 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 4y30 and related ligands described in "Aryl crystals as content Inhibitors of Aryl electromagnetic transmissions: Identification of the First PRMT6 Tool Compound". Mitchell, L.H., et al ACS Med.chem.Lett.6:655 (2015).

Fig. 6R presents an example of a LSD1(KDM1A) targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal Structure 5lgu and related ligands described in "Thieno [3,2-b ] pyrrole-5-carboxamides as New reverisibles electron inhibitors of Histone Lysine Demethyl KDM1A/LSD1.part 2: Structure-based drug Design and Structure-Activity Relationship shift". Vianello, P.et al J.Med.chem.60:1693 (2017).

Fig. 6S-6T present examples of KDM4 targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see PDB crystal structure 3 rvh; the PDB crystal structure 5a7p and related ligands described in "packaging and Linking of Fragments to discover Jumonji Histone depth ligands," Korczynska, M., et al J.Med.chem.59:1580 (2016); and PDB crystal structure 3f3c and related ligands described in "8-substistuted Pyridido [3,4-d ] pyrimidin-4(3H) -one Derivatives As Poten, Cell Permeable, KDM4(JMJD2) and KDM5(JARID1) Histone Lysine Demethyl inhibitors," Bavetsias, V.et al J.Med.chem.59:1388 (2016).

Fig. 6U presents an example of a KDM5 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 3fun and related ligands described in "Structural Analysis of Human Kdm5B guidelines histose 1 einhibitor Development". Johansson, c. et al nat. chem.biol.12:539(2016) and PDB crystal structure 5ceh and related ligands described in "An inhibition of Kdm5 demetalase reduction Survival of drug-tolerant cells". vinograndova, m. et al nat. chem.biol.12:531 (2016).

Fig. 6V-6W present examples of KDM6 targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 4ask and related ligands described in "a Selective Jumonji H3K27 Demethyl Inhibitor modified amino fluorescence macro Response". Kruidenier, l. et al, Nature 488:404 (2012).

Fig. 6X presents an example of an L3MBTL3 targeting ligand, where R is the point of attachment of the linker. See, for example, PDB crystal structure 4fl 6.

Figure 6Y presents an example of a Menin targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 4x5y and related ligands described In "pharmaceutical Inhibition of the Meni-MLL Interaction Block software of MLL Leukemia In Vivo" Borkin, D. et al Cancer Cell 27:589(2015) and PDB crystal structure 4g 8 and related ligands described In "High-Affinity Small-molecular Inhibition of Meni-Mixed line Leukemia MLL (L) Interaction" He, S. et al J.Med.chem.57:1543 (2014).

Fig. 6Z-6AA present examples of HDAC6 targeting ligands, wherein R is the point of attachment of the linker. See, for example, PDB crystal structures 5kh3 and 5 eei.

Fig. 6BB presents an example of an HDAC7 targeting ligand, wherein R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 3c10 and related ligands described in "Human HDAC7 classes a class ia tissue degrading enzyme-specific binding kinetic and compressive degrading enzyme activity," Schuetz, a. et al j. biol. chem.283:11355(2008) and PDB crystal structure PDB 3zns and related ligands described in "selective class IIa class ia tissue Inhibition amplification video a Non-chemical binding crystalline group". Lobera, m. et al nat. chem. biol.9:319 (2013).

FIGS. 7A-7C present examples of protein tyrosine phosphatase, non-receptor type 1, PTP1B targeting ligands, wherein R is the point of attachment for a linker. For additional examples and related ligands, see "Structural bases for inhibition of the protein type phosphorus peptide mimetics" Groves, M.R. et al Biochemistry 37: 17773. 17783(1998) for PDB crystal structure 1 bzj; "Discovery of [ (3-bromo-7-cyano-2-naphthyl) (difluoro) methyl ] phosphonic acid, apocent and organic active small molecule PTP1B inhibitor". Han Y, Bioorg MedChem Lett.18:3200-5(2008) the PDB crystal structure described in 3 cwe; PDB crystal structures 2azr and 2B07 described in "Bicyclic and tricyclic thiophenes as protein tyrosine phosphorus 1B inhibitors," Moretto, A.F., et al, bioorg.Med.chem.14:2162-2177 (2006); "Structure-Based Design of Protein Tyrosine-1B Inhibitors". Black, E.et al bioorg.Med.Chem.Lett.15:2503(2005) and "Structural Basis for Inhibition of Protein-Tyrosine-cysteine-1B by Isothiazoline Heterocyclic microorganisms". Ala., P.J. et al J.biol.Chem.281:32784(2006) "PDB crystal structures PDB 2bgd, 2bge, 2cm7, 2cm8, 2cma, 2cm B, 2cm c; PDB crystal structures 2f6t and 2f6w described in "1,2,3, 4-tetrahydroquinonyl sulfate phosphates PTP1B inhibitors". Klopfenstein, S.R. et al, bioorg.Med.chem.Lett.16:1574-1578 (2006); the crystal structures 2h4g, 2h4k, 2hb1 of PDB described in "monocarboxylic thiophenes as protein tyrosine phosphorus 1B inhibitors: Capturing interactions with Asp48." Wan, Z.K., et al, bioorg.Med.chem.Lett.16:4941-4945 (2006); the PDB crystal Structure 2zn7 described in "Structure-based optimization of protein phosphorus-1B inhibitors: capturing interactions with acquisition 24". Wan, Z.K. et al Chem Med chem.3:1525-9 (2008); PDB crystal structures 2nt7, 2nta described in "binding substitutions of thiophene PTP1B inhibitors." Wan, Z.K., et al, bioorg.Med.chem.Lett.17: 2913-; and WO2008148744A1 entitled "Thiadiazole derivatives as antimidiic agents", assigned to Novartis AG. See also, "2- (oxamido) -benzoic acid is a general, kinetic inhibitor of protein-tyrosine phosphatases". Andersen, H.S. et al J.biol.chem.275:7101-7108 (2000); "Structure-based design of a low molecular weight, nonphosphous, nonpeptide, and highly selective inhibitor of protein-type phosphinothase 1B." Iversen, L.F. et al J.biol.chem.275: 10300-; and the PDB crystal structures 1c84, 1c84, 1c85, 1c86, 1c88, 1l8g described in "semiconductor as a substrate for structure-based design of selective inhibition of protein-based phosphors". Iversen, L.F. et al Biochemistry 40:14812-14820 (2001).

Figure 7D presents an example of a tyrosine protein phosphatase non-receptor type 11, SHP2 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structures PDB 4pvg and 305x described in "Salicylic acid based small ligand for the interactive Src homology-2domain linking protein tyrosine phosphate-2 (SHP2)." Zhang, X, et al J.Med.chem.53:2482-2493 (2010); and the crystal structure PDB 5ehr and related ligands described in "Allosteric Inhibition of SHP2: Identification of a patent, Selective, and all effects phosphorus phase inhibitor," Garcia Fortantet, J. et al J.Med.chem.59: 7773-. See also the crystal structure PDB 5ehr described in "allogenic Inhibition of SHP2: Identification of a Point, Selective, and Oralytical phosphorous inhibitor," Garcia Fortanet, J.et al J.Med.chem.59:7773-7782(2016) and "allogenic Inhibition of SHP2 phosphorous Inhibition captivation by receptor type genes" Chen, Y.P. et al Nature 535:148-152 (2016).

Figure 7E presents an example of a tyrosine protein phosphatase non-receptor type 22 targeting ligand, where R is the point of attachment of a linker. For additional examples and related ligands, see the crystal structure PDB4j 51 described in "A Point and Selective Small-molecular Electron inhibitor for the lysine-Specific Tyrosine kinase (LYP), a TargetAssociation with Autoimmu diseases," He, Y, et al J.Med.chem.56:4990-5008 (2013).

Figure 7F presents an example of a scavenger mRNA decapping enzyme DcpS targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see the crystal structures PDB 3bl7, 3bl9, 3bla, 4qde, 4qdv, 4qeb and related ligands described in "Dcps a thermal target for a spectral mulgragraph," Singh, J. et al ACS chem.biol.3:711-722 (2008).

FIGS. 8A-8S present examples of BRD4 bromodomain 1 targeting ligands, where R is the point of attachment of a linker. For further examples and related ligands, see, Filippakopoulos, P. et al, "Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting branched molecules, Tolfriemy BET, bioorg. Med. chem.20: 1878) -1886(2012), crystal structures PDB 3u5k and 3u51 and related ligands; crystal structure PDB 3u5 l; crystal structure PDB 3zyu and related ligands described in "Inhibition of Bet retrieval of chromaffin as an Effective Treatment for Mll-Fusion Leukaemia" Nature478:529(2011) "by Dawson, M.A. et al; the crystal structure PDB 4bw1 and related ligands described in Mirguet, O. et al, "Naphthyridines asNovel Bet Family Bromodeomain inhibitors," Chemmedhem 9:589 (2014); dittmann, A. et al, "The common Used Pi3-Kinase Probe 294002is an Inhibitor of Bet Bromodomains" ACS chem.biol.9:495(2014) describe a crystal structure PDB 4cfl and related ligands; crystal structure PDB 4e96 and related ligands described in Fish, P.V. et al, "Identification of a chemical protocol for analysis and extra C-terminal analysis inhibition of fragment-derived rest," J.Med.chem.55:9831-9837 (2012); (iii) The crystal Structure PDB 4clb and related ligands described in Atkinson, S.J., et al, "The Structure Based Design of Dual Hdac/BetInhibitors as Novel epigenic probes," Medchmcomm 5:342 (2014); the crystal structure PDB4f 3i and related ligands described in Zhang, G, et al, "Down-regulation of NF- { kappa } BTdescriptive Activity in HIV-associated reagent by BRD4Inhibition," J.biol.chem.287:28840-28851 (2012); the crystal structure PDB 4hxl and related ligands described in ZHao, L. "Fragment-Based Drug Discovery of 2-Thiazolidinones as inhibitor BRD4 Bromodomain." J.Med.chem.56:3833-3851 (2013); the crystal structure PDB 4hxs and related ligands described in ZHao, L. et al, "Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain." J.Med.chem.56: 3833-; gehling, V.S. et al, "Discovery, Design, and Optimization of Isoxazole Azepane BET inhibition," ACS Med Chem Lett 4:835-840(2013) and related ligands; (iii) the crystal Structure PDB4mep and related ligands described in Vidler, L.R. "Discovery of Novel Small-Mobile Inhibitors of BRD4 Using Structure-Based visual screening", et al J.Med.chem.56:8073-8088 (2013); (iii) the crystal structures PDB 4nr8 and PDB4c 77 and related ligands described in Ember, S.W. et al, "Acetyl-lysine Binding Site of Bromodemail-contacting Protein 4(BRD4) interactions with reverse Kinase Inhibitors". ACCCHEm.biol.9: 1160-; (iii) the crystal structure PDB 4o7a and related ligands described in Ember, S.W. et al, "Acetyl-lysine Binding Site of Bromodemail-contacting Protein 4(BRD4) interactions with reverse Kinase inhibition, ACS chem.biol.9:1160-1171 (2014); "Acetyl-lysine Binding Site of Bromodein-Containing Protein 4(BRD4) interactions with reversed kinase in ligands," Ember, S.W., et al (2014) ACS chem.biol.9: 1160-; (iii) the crystal structure PDB 4o7c and related ligands described in Ember, S.W. et al, "Acetyl-lysine Binding Site of Bromodemail-contacting Protein 4(BRD4) interactions with reverse Kinase Inhibitors". ACCCHEm.biol.9: 1160-; crystal structure PDB4 gpj; theodoulou, N.H. et al, "The Discovery of I-Brd9, a Selective Cell active chemical Probe for Bromodeomain contacting Protein 9 Inhibition". J.Med.chem.59:1425(2016) describe The crystal structure PDB 4uix and related ligands; theodoulou, N.H., et al, "the discovery of I-Brd9, a Selective Cell Active Chemical Probe for Bromodemiaml containment Protein 9 Inhibition". J.Med.Chem.59:1425(2016) describe the crystal structure PDB4uiz and related ligands; crystal structure PDB 4wiv and related ligands described in McKeown, M.R. et al, "binary multicomponent reactions to novel branched ligands inhibitors," J.Med.chem.57: 9019-; crystal structure PDB4x 2i and related ligands described in Taylor, A.M. et al, "Discovery of benzothiazolo [4,3-d ] [1,4] diazepins as organic Active Inhibitors of BET Bromodomains," ACSMed. chem. Lett.7:145-150 (2016); the crystal structure PDB 4yh3 and related ligands described in Duffy, B.C. "Discovery of a new chemical series of BRD4(1) inhibition using protein-ligation and structure-defined design," bioorg.Med.chem.Lett.25:2818-2823 (2015); the crystal structure PDB 4yh4 and related ligands described in Duffy, B.C. "Discovery of a new chemical series of BRD4(1) inhibition using protein-ligand binding and structure-protected design," bioorg.Med.chem.Lett.25:2818-2823 (2015); taylor, A.M. "Discovery of benzothiazolo [4,3-d ] [1,4] diazepins as Orallyactive Inhibitors of BET Bromodomains" ACS Med. chem. Lett.7:145-150(2016) and related ligands; crystal structure PDB 4zw 1; demont, e.h. "Fragment-based discovery of Low-Micromolar Atad2 bromodeomain inhibitors.j.med.chem.58:5649(2015) and related ligands; (iii) the crystal Structure PDB5a 85 and related ligands described in Bamborough, P. "Structure-based optimization of Naphthidones Into patent Atta 2 Bromodomain Inhibitors" J.Med.chem.58:6151 (2015); the crystal structure PDB 5acy and related ligands described in Sullivan, J.M. "Austism-Like Syndrome Induced by Pharmacological prediction of BetProteins in Young Mice." J.Exp.Med.212:1771 (2015); waring, m.j. et al, "patent and Selective bivalve Inhibitors of bectromomomians". nat. chem. biol.12:1097(2016) and related ligands; (iv) the crystal structure PDB 5cfw and related ligands described in Chekler, E.L. et al, "Transmission Profiling of a Selective CREB binding protein Bromodemist Inhibitor highlighters Therapeutic opportunities," chem.biol.22:1588-1596 (2015); xue, X, et al, "Discovery of Benzo [ cd ] indole-2 (1H) -ons as post and Specific BETBromodemian Inhibitors: Structure-Based visual Screening, Optimization, and any biological Evaluation". J.Med.Chem.59:1565-1579(2016) describe the crystal Structure PDB 5cqt and related ligands; the crystal structure PDB5d 3r and related ligands described in Hugle, M. et al, "4-Acyl multirole Derivatives Young's Novel Vectors for designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4 (1)", J.Med.chem.59:1518-1530 (2016); the crystal structure PDB 5dlx and related ligands described in Milhas, S. et al, "Protein-Protein Interaction Inhibition (2P2I) -Oriented Chemical library Accelenterates high discovery." (2016) ACS chem.biol.11: 2140-; the crystal structure PDB 5dlz and related ligands described in Milhas, S. et al, "Protein-Protein Interaction Inhibition (2P2I) -organized Chemical Library acceleratees high discovery," ACS chem.biol.11: 2140-; PDB 5dw 2and related ligands in crystal structure as described in Kharenko, O.A. et al, "RVX-297-anovel BD2 selective inhibitor of BET bromodomains." biochem. Biophys. Res. Commun.477:62-67 (2016); crystal structure PDB5 dlx; albrecht, B.K., et al, "Identification of a Beizoisoxazolazoleineinhibitor (CPI-0610) of the Bromodemains and Extra-terminal (BET) Family as a Candidate for Human Clinical trials," J.Med.chem.59:1330-1339(2016) and related ligands; (iii) the crystal structure PDB 5ku3 and related ligands described in Crawford, T.D. et al, "Discovery of a patent and selected in Vivo probes (GNE-272) for the Bromodeomains of CBP/EP 300". J.Med.chem.59:10549-10563 (2016); bamborough, P. et al, "A Chemical Probe for the ATAD2 Bromodomain." Angew. chem. int. Ed. Engl.55: 11382-; wang, L. "Fragment-based, structure-enabled discovery of novel pyridines and pyridone macromycenes as pore branched and exo-tertiary domains (BET) family branched antibodies". J.Med.Chem.10.1021/acs. jmedchem.7b00017 (2017); WO 2015169962A1 entitled "Benzimidazolederivatives as BRD4 inhibitors and use for the term of cancer", assigned to Boehringer Ingelheim International GmbH, Germany; and the crystal structure PDB 5dlx and related ligands described in WO 2011143669A2 entitled "azo diazepine derivatives and their preparation, composition and methods for treating neuroplasma, inflammation and other disorders", assigned to Dana-Farber Cancer Institute, Inc, USA.

Figures 8T-8V present examples of ALK targeting ligands, where R is the point of attachment of the linker. For further examples and related ligands, see Crystal Structures PDB 2xb7 and 2xba and related ligands described in Bossi, R.T. et al, "Crystal Structures of adaptive Lymphoma kinase Kinasein Complex with ATP comparative Inhibitors" Biochemistry49: 6813-; huang, Q, et al, "Design of force and selective Inhibitors to over com Clinical nanoparticles resist to Crizotinib," J.Med.Chem.57:1170(2014) "crystal structures PDB 2yfx, 4ccb, 4ccu and 4cd0 and related ligands; johnson, T.W. et al, "Discovery of (10R) -7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16, 17-tetrahedron-2H-8, 4- (meth) Pyrazolo [4,3-H ] [2,5,11] benzoxadiazacytradetane-3-carbonitril (Pf-06463922), a multicyclic Inhibitor of Alk/Ros1 with Pre-Clinical Expo-position and Broad Spectrum dosage age alloy Alk-resist variants," J.chem.57: 4720(2014) ], crystal structures PDB4cli, 4-Amino and 4 c-related ligands; epstein, L.F., et al, "The R1275Q neuro-lastoma Mutant and Certain ATP-synergistic inhibitors stationary active Loop formulations of anaplastic lymphoma kinase," J.biol.Chem.287:37447-37457(2012), and related ligands; the crystal structure PDB 4dce and related ligands described in Bryan, M.C. et al, "Rapid displacement of piperidine amides active and selective and adaptive lymphoma kinase inhibitors," J.Med.chem.55:1698-1705 (2012); gummadi, V.R. et al, "discovery 7-azaindole based and enzymatic hydrolysis (ALK) inhibitors: with type and agent (L1196M) active compounds with unique binding mode" (2013) bioorg.Med.chem.Lett.23: 4911-; and Tu, C.H., et al, "chiral Derivatives modified with the structural Switching between Type I and Type II Binding models of Adaptive Lymphoma Kinase (ALK)," J.Med.chem.59: 3906-.

FIGS. 8W-8X present examples of BTK targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see, Marcotte, D.J. et al, "Structures of human Bruton's type kinase active and inactive formulations present a mechanism of activation for TEC family kinases," Protein Sci.19: 429-; the crystal structures PDB 3ocs, 4ot6 and related ligands described in Lou, Y, et al, "Structure-Based Drug Design of RN486, a protected selected Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis" J.Med.chem.58:512-516 (2015); liu, J. et al, "Discovery of 8-Amino-imidazole [1,5-a ] pyrazines asereversible BTK Inhibitors for the Treatment of Rheumatoid arthritis," ACSMed. chem. Lett.7:198-203(2016) describe crystal structures PDB 5fbn and 5fbo and related ligands; the crystal structure PDB 3pix and related ligands described in Kuglstat, A. et al, "instruments in the compatibility of the compliance of Bruton's styrosinase from multiple ligand and complex structures," Protein Sci.20: 428-; and the crystal structure PDB 3pij and related ligands described in Bujacz, A. et al, "crystals structures of the apo form of beta-transfuranosidase from Bifidobacterium longum and its complex with free." Febs J.278:1728-1744 (2011).

Fig. 8Y presents an example of FLT3 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, Zorn, J.A. et al, "Crystal Structure of the FLT3 Kinase Domain Boundto the Inhibitor Quizartinib (AC220)", Ploss One 10: e0121177-e0121177(2015) for Crystal structures PDB 4xuf and 4rt7 and related ligands.

Figures 8Z-8AA present examples of TNIK targeting ligands, where R is the point of attachment of the linker. For further examples and related ligands see, Masuda, m. et al, crystal structure PDB2x 7f described in "TNIK inhibition metabolites colour cancer." Nat commu 7: 12586-; crystal structures PDB5ax9 and 5d7 a; and related ligands.

Fig. 8BB-8CC presents examples of NTRK1, NTRK2, and NTRK3 targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see, Wang, T. et al, "Discovery of DisubustuteteddImidazo [4,5-B ] pyrimidines and Purines as force Trka inhibitors," ACSMed. chem. Lett.3:705(2012) for crystal structure PDB 4aoj and related ligands; the crystal structures PDB4pmm, 4pmp, 4pms and 4pmt and related ligands described in Stachel, S.J. et al, "knowledge division from a kinase, present: identification of novel and electric pan-Trk inhibitors for a cyclic pain," J.Med.chem.57:5800-5816 (2014); choi, H.S. et al "(R) -2-Phenylpyrrolidine treated Imidazolpidazines: A New Class of force and selective Pan-TRK inhibitors," ACS Med.chem.Lett.6:562-567(2015) and related ligands; crystal Structures PDB 4at5 and 4at3 and related ligands described in Bertrand, t. et al, "The Crystal Structures of Trka and dtrkb Suggest Key Regions for influencing Selective inhibition".j.mol.biol.423: 439 (2012); and the crystal structures PDB3v 5q and 4ymj and related ligands described in Albaugh, P. et al, "Discovery of GNF-5837, a selective TRK Inhibitor with efficacy in cadence analyzer models," ACS Med. Chem. Lett.3: 140-.

Fig. 8DD-8EE presents examples of FGFR1 targeting ligands, where R is the point of attachment for a linker. For additional examples and related ligands, see, Brison, Y. et al, "Functional and structural characterization of alpha- (1-2) branched from DSR-E glucose characterization," J.biol.chem.287:7915-7924(2012) and Mohammadi, M. et al, "crystalline structure of engineering inhibitor bound to the FGF receptor type domain," EMBOJ.17:5896-5904(1998), Crystal structures PDB 3tto and 2fgi and related ligands; crystal structure PDB4fb 3; harrison, C.et al, "polymeric large T organic bonds systematic repeat the biological alignment in an asymmetric manager," J.Virol.87:13751-13759(2013) describe the crystal structure PDB 4rwk and related ligands; sohl, C.D. et al, "Illuminating The molecular mechanisms of Tyrosine Kinase Inhibitor Resistance for The FGFR1 gatekeeper mutation: The acids' Heel of Targeted therapy," ACS chem. biol.10:1319-1329(2015) and related ligands; crystal structure PDB4 uwc; tucker, J.A. et al, "Structural instruments int Fgfr Kinase Isoform selection: overture binding models of Azd4547 and Ponatinib in complete with Fgfr1 and Fgfr4," Structure 22:1764(2014) describe the crystal Structure PDB 4v01 and related ligands; the crystal structure PDB5a46 and related ligands described in Klein, T. et al, "Structural and dynamic instruments Integrated the engineering of Activation Loop Rearrangement in Fgfr1 Kinase," nat. Commun.6:7877 (2015); and the crystal structure PDB 5ew8 and related ligands described in Panti, H. et al, "Landscape of activating cancer mechanisms in FGFR kinases and their differential responses to inhibitors in clinical use," Oncotarget 7:24252-24268 (2016).

Figure 8FF presents an example of an FGFR2 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, Chen, H, et al, "A molecular brake in the activity of ligand types of receptor types" mol.cell 27:717-730(2007) for the crystal structure PDB 2pvf and related ligands.

Fig. 8GG presents examples of FGFR4 targeting ligands, where R is the point of attachment of a linker. For further examples and related ligands, see the crystal structure PDB4tyi and related ligands described in Lesca, E.et al, "Structural analysis of the human fiber growth factor receptor 4 kinase." J.mol.biol.426: 3744-.

Fig. 8HH-8II present examples of MET targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see, crystal structures PDB 3qti and 3 zcl; peterson, E.A., et al, "Discovery of protected selected 8-fluorotropic ligand C-Met inhibitors," J.Med.chem.58: 2417-glass 2430(2015) and Cui, J.J. et al, "Lessons from (S) -6- (1- (6- (1-Methyl-1H-Pyrazol-4-Yl) - [1,2,4] Triazolo [4,3-B ] pyrazozin-3-Yl) Ethyl) Quinoline (Pf-04254644), and in" Receptor type ligand C-Methyl with High Protein selectivity distribution Broad ligand "crystal 9, 32, and crystal structures of ligand J.3, 19, 11, 6-and 5-gamma-3-Yl, respectively, described in Peterson, E.A. et al, in the description of ligand J.20132, J.3, and 5,2, 6-gamma.3, 2, 4; boezio, A.A. et al, "Discovery of (R) -6- (1- (8-Fluoro-6- (1-methyl-1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a ] pyridin-3-yl) ethyl) -3- (2-methoxy) -1,6-naphthyridin-5(6H) -one (AMG 337), a patent and Selectivity inhibitor of MET with High underbody Target Cover and road In vivo inhibitor activity, J.Med.Chem.59:2328-2342(2016) describe the crystal structure PDB 895 5eyd and related ligands; the crystal structure PDB 3ce3 and related ligands described in Kim, K.S. et al, "Discovery of pyrazolidine-based inhibitors of Met kinase: synthesis, X-ray crystallography analysis, and biological diagnostics," J.Med.chem.51:5330-5341 (2008); crystal structure PDB 2rfn and related ligands described in Bellon, S.F. et al, "c-Met inhibitors with novel binding mode show activity acquisition aid for vertical delivery of cells for cell specific-related ligands," J.biol.chem.283:2675-2683 (2008); and the crystal structure PDB 5dg5 and related ligands described in Smith, B.D. et al, "Altiratinib inhibitors Tumor Growth, Invasion, Angiogenesis, and Microenvironment-media Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2.

Figure 8JJ presents an example of a JAK1 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, Zak, M. et al, "Identification of C-2 Hydroxypropylimidazolium pyrazolidines as force JAK1Inhibitors with a revolute macromolecular chemical Properties and High Selectivity over JAK 2." J.Med.chem.56: 4764-; the crystal structure PDB5e 1e and related ligands described in Vasbinder, M.M. et al, "Identification of aza benzazimidozoles as potential JAK1selective inhibitors," bioorg.Med.chem.Lett.26:60-67 (2016); simov, V., et al, "Structure-based design and definition of (benz) imide pyridine as JAK1-selective kinase inhibitors," bioorg.Med.Chem.Lett.26: 1803-; caspers, N.L. et al, "Development of a high-throughput crystal structure-determination platform for JAK 1using a novel-chemical approach system". Acta Crystallogr.Sect.F 72:840-845 (2016); and key, j.g. "Discovery of the JAK1selective kinase inhibitor AZD 4205", crystal structure PDB 5hx8 and related ligands described in AACRNational Meeting, April 2017.

Figure 8KK-8LL presents an example of a JAK2 targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see, Andraos, r. et al, "Modulation of activation-phosphorylation by JAK inhibition is binding mode dependent." Cancer Discov 2:512-523(2012), crystal structure PDB 3ugc and related ligands; hart, A.C. et al, "Structure-based design of selected Janus Kinase 2Imidazo [4,5-d ] pyrrolo [2,3-b ] pyrindine inhibitors," ACS Med.Chem.Lett.6:845-849(2015) describe crystal structures PDB 5cf4, 5cf5, 5cf6 and 5cf8 and related ligands; the crystal structure PDB 5aep and related ligands described in Brasca, M.G., et al, "Novel Pyrole Carboxamide Inhibitors of Jak 2as Positive Treatment of Myelopractic reactions," bioorg.Med.chem.23:2387 (2015); farmer, L.J. et al, "Discovery of VX-509 (Decornotinib): A Point and Selective Janus Kinase3Inhibitor for the Treatment of Autoimmune diseases," J.Med.chem.58: 7195-; the crystal structures PDB4ytf, 4yth, 4yti and related ligands described in Menet, C.J., et al, "Triazolopyridiness as Selective JAK1Inhibitors: From high Identification to GLPG0634." J.Med.chem.57: 9323-; siu, M. et al, "2-Amino- [1,2,4] triazolo [1,5-a ] pyridines as JAK2inhitomers," bioorg.Med.chem.Lett.23: 5014-; and, the crystal structures PDB 3io7 and 3iok and related ligands described in Schenkel, L.B. et al, "Discovery of content and high selectivity selective catalytic Janus kinase2inhibitors," J.Med.chem.54: 8440-.

Figure 8MM presents an example of a JAK3 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, e.g., crystal structure PDB 3zc6 and related ligands described in Lynch, S.M. et al, "structural Use of structural Bias and structural Based Design to identity Point Jak3 information with improved selectivity of the Jak Family and the Kinomie," bioorg.Med.chem.Lett.23:2793 (2013); and the crystalline structures PDB 4hvd, 4i6q and 3i 3zep and related ligands described in Soth, M. et al, "3-AmidoPyrolopyrazine JAK Kinase Inhibitors: Development of a JAK 3vs JAK1selective inhibitor and Evaluation in Cellular and in Vivo models," J.Med.Chem.56:345-356(2013) and Jaime-Figuroa, S. et al, "Discovery of a series of novel 5H-pyrano [2,3-b ] pyrazine-2-phenyl ethers, as potentJAK3 Kinase Inhibitors.

FIG. 8NN-8OO presents examples of KIT targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see, Mol, C.D., et al, "Structural basis for the autoignition and STI-571inhibition of c-Kit tyrosine kinase," J.biol.chem.279: 31655-; and, the crystal structure PDB4u 0i and related ligands described in Garner, A.P. et al, "Ponatinib Inhibitspolycyclic Drug-reactive KIT Oncoproteins and show Therapeutic Potential in heaavity Pretreated structural molecular Tumor (GIST) Patents," Clin. cancer Res.20: 5745-.

FIG. 88PP-8VV presents examples of EGFR-targeting ligands where R is the point of attachment of a linker. For additional examples and related ligands, see, crystal structures PDB 5hcy, 4rj4, and 5 cav; heald, R., "non-national mutant creative Growth Factor Receptor Inhibitors: A Lead OptimizationCase Study", J.Med.chem.58, 8877-8895 (2015); hanano, E.J. "Discovery of selected and non-volatile Diaminopyrimide-Based innovations of epidemic Growth receptor Containing the T790M Resistance mutation," J.Med.chem.,57, 10176-; chan, b.k. et al, "Discovery of a noncoverent, Mutant-Selective epidemic growth Factor Receptor Inhibitor" j.med.chem.59,9080 (2016); jia, Y, et al, "Overmeeting EGFR (T790M) and EGFR (C797S) resistance with mutant-selective inhibitory organisms" Nature 534,129 (2016); (iii) the crystal Structure PDB5d 41 and related ligands described in Ward, R.A. "Structure-and-floor degree of restriction of inhibitory inhibitors of the activating and gated linker ligands for the Epidermal Growth Factor Receptor (EGFR)" J.Med.chem.56,7025-7048 (2013); "discovery of the A Point and Selective EGFR Inhibitor (AZD9291) of Both sensing and dT790M Resistance parameters targets spaces the Wild Type Form of the Receptor" J.Med.chem.,57(20),

8249-8267 (2014) and related ligands; (ii) crystal structures PDB 5em7 and related ligands described in Bryan, M.C. et al, "Pyridones as high choice Selective, non-ncovenal Inhibitors of T790M Double mutation of EGFR" ACS Med.chem.Lett.,7(1), 100-104 (2016); the crystal structure PDB 3IKA and related ligands described in Zhou, W, et al, "Novel mutant-selective EGFR kinase inhibitors against EGFRT790M," Nature 462(7276), 1070-1074 (2009); see Lelais, G., J. "Discovery of (R, E) -N- (7-Chloro-1- (1- [4- (dimethylamino) but-2-enyl ] azepan-3-yl) -1H-benzol [ d ] imidazol-2-yl) -2-methylisotinamide (EGF816), a Novel, tension, and WT spacing genetic Inhibitor of oncogeneic (L858R, ex19del) and resist (T790M) EGFR variants for the Treatment of EGFR mutation non-Cell-Lung cancer" Med. chem.,59(14), U.S.A.,

6671-6689 (2016); lee, H. -J. "Noncovent Wild-type-spacing Inhibitors of EGFR T790M" Cancer Discov.3(2): 168-; huang, W-S, et al, "Discovery of Brigatinib (AP26113), a Phosphine Oxide-containment, post, oraly Active Inhibitor of adaptive Lymphoma kinase," J.Med.chem.59:4948-4964(2016) and related ligands; the crystal Structure PDB 4v0g and related ligands described in Hennessy, E.J., et al, "inactivation of Structure-Based Design to identity Novel, Irversibleeinhibitors of EGFR Harboring the T790M mutation," ACS.Med.Chem.Lett.7: 514-; cheng, H. "Discovery of 1- { (3R,4R) -3- [ ({5-Chloro-2- [ (1-methyl-1H-pyrazol-4-yl) amino ] -7H-pyrazol [2,3-d ] pyridin-4-yl } oxy) methyl ] -4-methoxypyrolidin-1-yl } prop-2-en-1-one (PF-06459988), aPoten, WT spacing, Irversible Inhibitor bit of T790M-containment EGFR mutations," J.Med.Chem.59:2005-2024 (2016); hao, Y. "Discovery and Structural Optimization of N5-underlying 6,7-Dioxo-6,7-dihydropteridines as force and selected Epitopic Growth Factor Receptor (EGFR) Inhibitors as L858R/T790MResistance Mution," J.Med.chem.59:7111-7124(2016) crystal structure PDB 5hg7 and related ligands; planken, S. "Discovery of N- ((3R,4R) -4-Fluoro-1- (6- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) -9-methyl-9H-purin-2-yl) pyrolidin-3-yl) acrylamide (PF-06747775) through Structure-Based Drug Design, A High affinity Irregable Inhibitor Targeting immunogenic EGFR variants with selected viral over wild-Type EGFR," J.Med.chem.60: 3002-channel 3019(2017), 5ug8, 5ug9 and 5ugc and related ligands; wang, A. "Discovery of (R) -1- (3- (4-Amino-3- (3-chloro-4- (pyridine-2-yl) phenyl) -1H-pyrazolo [3,4-d ] pyridine-1-yl) peridin-1-yl) prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irversible EGFR Mutant Kinase inhibitor with a Discovery Binding model" J.Med.chem.60: 2944-; and, crystalline structure PDB 5gnk and related ligands described in Juchum, M. "trissted immidazoles with a predetermined binding motif as a single mutation of inhibitors of clinical reusable EGFR L858R/T790M and L858R/T790M/C797S mutants of target hosting. J.Med.chem.DOI. 10.1021/acs. jmedchem.7b00178 (2017).

Fig. 8WW-8XX presents examples of PAK1 targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see Rudolph, J.et al, "chemical defense Group I p21-ActivatedKinase (PAK) Inhibitors apparatus acid cardio viral susceptibility with a Narrow therapeutic Window." J.Med.Chem.59,5520-5541(2016) and Karpov AS et al ACS Med ChemLett.22; 6(7):776-81(2015).

Fig. 8YY presents an example of a PAK4 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, Staben ST, et al J Med chem.13; 57(3) (1033-45 (2014)) and Guo, C. et al, "Discovery of pyrrolopyrazoles as novel PAK inhibitors" J.Med.chem.55, 4728-4739 (2012).

FIG. 8ZZ-8AAA presents an example of an IDO targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, Yue, e.w.; "J.Med.chem.52, 7364-7367 (2009)" Discovery of reactive inhibitors of indole 2,3-dioxygenase with in vivo pharmacodynamic activity and specificity in a mouse melanoma model; tojo, s.; "Crystal structures and activity relations of imidazole derivatives as IDO1inhibitors," ACS Med. chem. Lett.5,1119-1123 (2014); mautino, m.r. et al "NLG 919, a novel indeamine-2, 3-dioxygenase (ido) -pathway inhibitor drug for cancer therapy" Abstract 491, AACR 104 by annular Meeting 2013; 6-10 days 4 months in 2013; washington, DC; and WO2012142237, entitled "fusodimidazoleditives useffels as IDO inhibitors".

FIG. 8BBB-8EEE presents examples of ERK1 and ERK2 targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see, Blake, J.F. et al, "Discovery of (S) -1- (1- (4-Chloro-3-fluorophenyl) -2-hydroxyethyl) -4- (2- ((1-methyl-1H-propyl-5-yl) amino) pyrimidin-4-yl) pyridine-2 (1H) -one (GDC-0994), an excellular Signal-regulated Kinase 1/2(ERK1/2) Inhibitor in Early Clinical Development" J.Med.chem.59: 5650-; the crystal structure PDB 5BVF and related ligands described in Bagdaoff, J.T. et al, "tetrahedrons-diazepenones as inhibitors of ERK2kinase," bioorg.Med.chem.Lett.25,3788-3792 (2015); the crystal structure PDB 4QYY and related ligands described in Deng, Y, et al, "Discovery of Novel, Dual Mechanism ERK inhibition by affinity selection Screening of an reactive Kinase" J.Med.Chem.57:8817-8826 (2014); crystal structures PDB 5HD4 and 5HD7 and related ligands described in Jha, S. et al, "separating Therapeutic Resistance to ERK Inhibition" mol.cancer ther.15: 548-; the crystal structure PDB 4XJ0 and related ligands described in Ren, L. et al, "Discovery of high level potents, selective, and effective outer molar ligands of ERK 1/2." J.Med.chem.58:1976-1991 (2015); ward, R.A. et al, "Structure-Guided Design of high hlySelective and Point compatible Inhibitors of Erk 1/2." J.Med.chem.58:4790 (2015); burrows, F. et al, "KO-947, a patent ERK inhibitor with robust predictive activity in MAPK pathway regulated tumors," Poster #5168, AACR national Meeting 2017; bhagwat, S.V. et al, "Discovery of LY3214996, a selective and novelterK 1/2inhibitor with content sensitivity or activities in cancer models with MAPkpathway identities," crystal structures PDB 4ZZM, 4ZZN, 4ZZO and related ligands described in AACR National Meeting 2017; the crystal structures PDB 3FHR and 3FXH and related ligands described in Cheng, R. et al, "High-resolution crystal structure of human Mapkapkinase 3in complex with a High affinity ligand" Protein Sci.19: 168-; ward, R.A. et al, "Structure-guided discovery of Point and Selective Inhibitors of ERK1/2from a model active and Promiscuous Chemical Start Point." J.Med.chem.60, 3438-3450 (2017) crystal structures PDB5NGU, 5NHF, 5NHH, 5NHJ, 5NHL, 5NHO, 5NHP and 5NHV and related ligands; and the crystal structures PDB 3SHE and 3R1N and related ligands described in Oubrie, A. et al, "Novel ATP reactive MK 2inhibitors with potential biochemical and cell-based reactive deep the series," bioorg.Med.chem.Lett.22: 613-.

FIG. 8FFF-8III presents an example of an ABL1 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, Schinder, T., et al, "Structural mechanism for STI-571inhibition of abelson tyrosine kinase," Science 289: 1938-; and the crystal structures PDB 1fpu and 2e2b and related ligands described in Horio, T. et al, "Structural factors distributing to the Abl/Lyn dual inhibited benzamide derivatives" bioorg. Med. chem. Lett.17:2712-2717 (2007); the crystal structures PDB2hzn and 2 high and related ligands described in Cowan-Jacob, S.W. et al, "Structural biology distributions to the discovery of drugs to treatment chronologenouses Leukaemia", Acta Crystallog.Sect.D 63:80-93(2007) and Okram, B. et al, "agricultural chemistry for culturing", chem.biol.13:779-786 (2006); weisberg, E.et al, "Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl", Cancer Cell 7:129-14(2005) describe the crystal structure PDB 3cs9 and related ligands; o' Hare, T. et al, "AP 245634, a pan-BCR-ABL inhibitor for cyclic mileoid leukemia, patent inhibitors the T315I mutant and overcom interaction-based resistance", Cancer Cell 16: 401-; the crystal structure PDB 3mss and related ligands described in Jahnke, W. et al, "Binding or Binding: differentiation of oligomeric aggregated substrates from oligomeric substrates by an NMR-based compositional assay", J.Am.chem.Soc.132:7043-7048 (2010); zhou, T.et al, "Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatini (AP 245634): letters for overlying Kinase Inhibitor Resistance", Chem.biol.drug Des.77:1-11(2011) describe the crystal structure PDB 3oy3 and related ligands; chan, W.W. et al, "formatting Control Inhibition of the BCR-ABL1 Tyrosine Kinase, incorporation of the gateway Inhibitor T315I Mutant, by the Switch-Control Inhibitor DCC-2036", Cancer Cell 19:556-568(2011) describe crystal structures PDB 3qri and 3qrk and related ligands; liu, F. et al, "Discovery and characterization of a novel position type II native and mutant BCR-ABLinhibitor (CHMFL-074) for Chronic Molecular Leukemia (CML)", Oncotarget 7:45562-45574(2016) and Young, M.A. et al, "Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680", Cancer Res.66:1007 (2006) and related ligands; tokarski, J.S. et al, "The Structure of Dasatinib (BMS-354825) Bound to ActivatedABL Kinase Domain Eluidates items inhibition Activity against inhibition ABL variants", Cancer Res.66: 5790-; and the crystal structures PDB2gqg and 2qoh and related ligands described in Zhou, T. et al, "CrystalStructure of the T315I Mutant of Abl Kinase", chem.biol.drug Des.70: 171-; tokarski, J.S. et al, "the Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Eluctates Its inhibit inhibition Activity against Imatinib-Resistant ABL Mutants", Cancer Res.66: 5790-; tokarski, J.S. et al, "The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Eluidates Its items inhibition activity against Imatinib-Resistant ABL Mutants", Cancer Res.66: 5790-; crystal structures PDB 3dk3 and 3dk8 and related ligands described in Berkholz, D.S. et al, "Catalytic cycle of human glutathione production near 1A resolution" J.mol.biol.382: 371-; levinson, N.M. et al, "Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the abl tyrosinase domain", Ploss One 7: e29828-e29828(2012), and related ligands; jensen, C.N. et al, "Structures of the Apo and Fad-Bound Forms of 2-Hydroxybiphenol 3-Monooxygenase (Hbpa) located Activity Hotspots Identified by using direct Evolution", Chemmbiochem 16:968(2015) and related ligands; the crystal structure PDB2hz 0 and related ligands described in Cowan-Jacob, S.W. et al, "Structural biology considerations to the discovery of drugs to biological bacteria leukoderma", Acta crystallogra DBiol crystallogra.63 (Pt 1):80-93 (2007); the crystal structure PDB 3pyy and related ligands described in Yang, J. et al, "Discovery and Characterization of a Cell-Permeable, Small-molecular c-Abl Kinase Activator at the Site from the branched Binding Site", chem. biol.18:177-186 (2011); and the crystal structure PDB5k5v and related ligands described in Kim, M.K., et al, "structural for dual specificity of last N-terminal amide in the N-end rulepath", Proc. Natl. Acad. Sci. U.S. A.113: 12438-.

Fig. 8JJJ presents an example of an ABL2 targeting ligand, where R is the point of attachment of the linker. For additional examples and Related ligands, see, Salah, E.et al, "Crystal Structures of Abl-Related Gene (Abl2) in Complex with Imatinib, Tozasertib (Vx-680), and a Type I Inhibitor of the Triazol Carbothioamide Class", J.Med.chem.54:2359(2011) for Crystal Structures PDB2xyn and Related ligands; ha, B.H. et al, "Structure of the ABL2/ARG kinase in complex with dadotatinib" Acta crystallogger.Sect.F 71:443 (2015) and related ligands; and Salah, e.g., "The crystal structure of human ABL 2in complex with gleevec" (to be published) with The crystal structure PDB 3gvu and related ligands.

FIG. 8KKK-8MMM presents an example of a targeting ligand for AKT1, where R is the point of attachment of a linker. For additional examples and related ligands, see Lippa, B. et al, "Synthesis and structure based optimization of novel Akt inhibition biology, Med. chem. Lett.18:3359-3363 (2008); Freeman-Cook, K.D., et al, "Design of selective, ATP-reactive inhibitors of Akt", J.Med.chem.53:4615-4622 (2010); blake, J.F. et al, "Discovery of patholytic peptides of Akt", bioorg.Med.chem.Lett.20: 5607-; kallan, N.C., et al, "Discovery and SAR of spirochromane Akt inhibitors", bioorg, Med, chem, Lett.21:2410-2414 (2011); lin, K "An ATP-Site On-Off Switch thin research of Phosphataseacessability of Akt", Sci.Signal.5: ra37-ra37 (2012); addie, M. et al, "Discoveryof 4-Amino-N- [ (1S) -1- (4-chlorophenyl) -3-hydroxypypyl ] -1- (7H-pyro [2,3-d ] pyrimid-4-yl) piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, patent Inhibitor of Akt Kinases", J.Med.chem.56: 2059-; wu, W.I., et al, "crystalline structure of human AKT1 with an alcoholic inhibitor recovery a new mode of kinase inhibition. plos One 5:12913-12913 (2010); ashwell, M.A. et al, "Discovery and optimization of a series of 3- (3-phenyl-3H-imidozo [4,5-b ] pyridine-2-yl) pyridine-2-amines: available bioavailable, selective, and post ATP-independent Akt inhibitors", J.Med.chem.55: 5291-; and Lapierre, J.M. et al, "Discovery of 3- (3- (4- (1-Aminocyclobutyl) phenyl) -5-phenyl-3H-imididazo [4,5-b ] pyridine-2-yl) pyridine-2-amine (ARQ 092): An Orally Bioavailable, Selective, and post allergy AKT Inhibitor", J.Med.chem.59: 6455-.

FIG. 8NNN-8OOO presents an example of a targeting ligand for AKT2, where R is the point of attachment for the linker. For additional examples and related ligands, see, Davies, t.g., crystal structures PDB 2jdo and 2jdr and related ligands described in "a Structural company of inhibitor binding to Pkb, Pka and Pka-Pkb chiera", j.mol.biol.367:882 (2007); crystal structure PDB 2uw9 and related ligands described in Saxty, G. et al, "Identification of Inhibitors of protein Kinase B Using Fragment-Based Lead Discovery", J.Med.chem.50: 2293-; mchar, T. et al, "Discovery of 4-Amino-1- (7H-Pyrrolo [2,3-D ] pyrimid-4-Yl) Piperidine-4-Carboxamides as selected, Oralley Active Inhibitors of Protein Kinase B (Akt)", J.Med.chem.53:2239D (2010) and related ligands; hadler, K.S. et al, "Substrate-protein formation of a catalytic component binding center and regulation of reactivity in a hydrolytic reaction from Enterobacter aeogens', J.Am.chem.Soc.130: 14129. 14138 (2008); and the crystal structures PDB3e 87, 3e8d and 3e88 and related ligands described in Rouse, M.B. et al, "Aminoureas as potential inhibitors of AKT kinase," bioorg.Med.chem.Lett.19: 1508-.

Figure 8PPP presents an example of a BMX targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, Muckelbauer, J. et al, "X-ray crystal structure of bone marrowkinase in the X chromosome: a Tec family kinase," chem.biol. drug Des.78:739-748(2011) for crystal structures PDB 3sxr and 3sxr and related ligands.

FIG. 8QQQ-8SSS presents an example of a CSF1R targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see, Schubert, C.et al, "Crystal Structure of the systematic kinase analysis of colloidal-stimulating factor-1receptor (cFMS) in complex with a fine of ligands", Crystal structures PDB 2i0v and 2i1m and related ligands described in J.biol.chem.282:4094-4101 (2007); huang, H.et al, "Design and synthesis of a pyrido [2,3-d ] pyrimidin-5-oneclass of anti-inflammatory FMS inhibitors", Bioorg.Med.chem.Lett.18: 2355-; m.t., McKay, d.b. overhead, "structure of the elastomer of Pseudomonas aeruginosa complex with phosphine" (to be published) and related ligands; "Optimization of a positional Class of aryl amide colloid-stabilizing Factor-1Receptor inhibitor Leading to anti-inflammatory mixture crystalline carbohydrate 4-Cyano-N- [2- (1-cyclic hexen-1-yl) -4- [1- [ (dimethyl) acetyl ] -4-piperidine ] phenyl ] -1H-imidazole-2-carboxylate (JNJ-28312141", crystal structures PDB3 3632 and 3D krl and related ligands described in J.Med.Chem.54:7860 7883 (CSF)), and "crystal structures PDB 2011 3D 32 and related ligands" in Tap, W.D. et al "structural Block-guide of CSF 1. synthetic protein oligomer derivative R. molecular ligand binding of N-amino ligand 3. sub.2015-5. and related ligands" in DFB-5, molecular ligand 373, molecular ligand 3D-2-5, molecular ligand 3D-373, molecular ligand 3D-5, molecular ligand J.7. molecular ligand 3D-3, molecular ligand J.7. molecular ligand J., the crystal structures PDB 3lcd and 3lcoa and related ligands described in bioorg.Med.chem.Lett.20: 1543-; zhang, C. et al, "Design and pharmacology of a high purity specific product FMS and KIT kinase inhibitor", Proc. Natl. Acad. Sci. USA 110: 5689-; and the crystal Structure PDB4r 7i and related ligands described in Tap, W.D. et al, "Structure-Guided Block of CSF1 RKnase in tenon synthetic Giant-Cell Tumor", N Engl J Med 373: 428-.

Figure 8TTT presents an example of a CSK targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see Levinson, N.M. et al, "Structural basis for the recognition of c-Srcby its inactivator Csk," Cell134: 124-.

Figure 8UUU-8YYY presents an example of a DDR1 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, Canning, P.et al, "Structural Mechanisms depletion inhibition of the Collagen Receptor Ddr1 by selected and Multi-Targeted type II Kinase Inhibitors", J.mol.biol.426:2457(2014) for crystal structures PDB 3zos and 4bkj and related ligands; crystal structure PDB 4ckr and related ligands described in Kim, H. et al, "Discovery of a patent and Selective Ddr1 ReceptorTyrosine Kinase Inhibitor", ACS chem.biol.8:2145 (2013); murray, C.W et al, "Fragment-Based Discovery of content and selected DDR1/2 Inhibitors", ACS Med. chem. Lett.6: 798-; the crystal Structure PDB 5fdp and related ligands described in Wang, Z.et al, "Structure-Based Design of Tetrahydroquinoline-7-carboxamides as Selective Discoidin Domain Receptor1(DDR1) Inhibitors", J.Med.chem.59:5911-5916 (2016); and the crystal Structure PDB 5fdx and related ligands described in Bartual, S.G. et al, "Structure of DDR1 receiver type kinase in complex with D2164 inhibitor at 2.65 inhibition resolution" (to be published).

FIG. 8ZZZ-8CCCC presents an example of an EPHA2 targeting ligand, where R is the point of attachment for the linker. For additional examples and related ligands, see, Heinzlmeir, S. et al, "Chemical protocols and structural biology definition EPHA2 Inhibition by Clinical Kinase Drug," ACS chem. biol.11: 3400-; heinzlmeir, S. et al, "Crystal Structure of Ephrin A2(EphA2) Receptor Protein Kinase with danuurtib (PHA 739358)", the Crystal Structure PDB5i9z and related ligands described in ACS Chem Biol 113400-; and the crystal structures PDB 5ia2, 5ia3, 5ia4 and 5ia5 and related ligands described in Heinzlmeir, S. et al, "Chemical protocols and structural biology Define EPHA2 Inhibition by Clinical Kinase Drug", ACS chem.biol.11: 3400-.

FIG. 8DDDD-8FFFF presents an example of an EPHA3 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, Zhao, h. et al, "Discovery of a novel chemistry of type of inhibition by fragment-based locking and molecular dynamics", acsmed.chem.lett.3:834-838(2012), crystal structure PDB4g 2f and related ligands; lafleur, K. et al, "Optimization of inhibition of the Tyrosine Kinase EphB4.2.cellular functional improvement and Binding Mode differentiation by X-ray Crystallography", crystal structures PDB 4gk 2and 4gk3 and related ligands described in J.Med.chem.56:84-96 (2013); lafleur, K. et al, "Optimization of inhibition of the Tyrosine Kinase EphB4.2.cellular patent improvements and Binding Mode differentiation by X-ray Crystallography", crystal structure PDB 4gk3 and related ligands described in J.Med.chem.56:84-96 (2013); unzue, A. et al, "Pyrrolo [3,2-b ] quinoline Derivatives as Types I1/2and II Eph tyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and in Vivo variation", J.Med.chem.57: 6834-; unzue, A. et al, "Pyrrolo [3,2-b ] quinoline Derivatives as Types I1/2and II Eph tyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and in Vivo variation", J.Med.chem.57: 6834-; dong, J.et al, "Structural Analysis of the Binding of Type I, I1/2, and II Inhibitors to EphTyrosines Kinases", ACS Med.chem.Lett.6:79-83(2015) and related ligands; walker, J.R. "Kinase Domain of Human Ephrin Type-A Receptor 3(Epha3) in complete with ALW-II-38-3" (to be published) and related ligands.

Fig. 8 gggggg presents an example of an EPHA4 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see Clifton, I.J. et al, "The Crystal Structure of Isophilin NSynthase with Delta ((L) -Alpha-amino-acyl) - (L) -cysteine- (D) -Methionine derivatives thio Coordination to Iron", Arch.biochem.Biophys.516:103(2011) for Crystal Structure PDB 2y60 and related ligands and Van Linden, O.P. et al, "Fragment Based LeadDiscoyory of Small Molecule Inhibitors for The Epha4 Receptor type Kinase", Eur.J.chem.47: 493(2012), for Crystal Structure PDB 2xyu and related ligands.

Fig. 8 hhhhhh presents an example of an EPHA7 targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 3dko and related ligands described in Walker, j.r. et al, "Kinase domain of human ephrin type-a receiver 7(epha7) in complex with ALW-II-49-7" (to be published).

FIGS. 8IIII-8LLLL present examples of EPHB4 targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see, Bardelle, C. et al, "Inhibitors of the Tyrosine kinase Ephb4.part 2: Structure-Based Discovery and optimization of 3,5-bis Substistured antibiotic", bioorg.Med.chem.Lett.18:5717(2008), crystal Structure PDB 2vx1 and related ligands; bardelle, C. et al, "Inhibitors of the Tyrosine KinaseEphb4.part 3: Identification of Non-Benzodioxole-Based Kinase Inhibitors", bioorg. Med. chem. Lett.20:6242-6245(2010) and related ligands; crystal structures PDB 2xvd and related ligands described in Barlaam, B. et al, "inhibition of the Tyrosine Kinase Ephb4.part 4: Discovery and optimization of a cubic Alcohol Series", bioorg. Med. chem. Lett.21:2207 (2011); (iii) the crystal structure PDB 3zew and related ligands described in Overman, R.C. et al, "Completing the structural family portal of the Human Ephb Tyrosine Kinase Domains", Protein Sci.23:627 (2014); crystal structure PDB 4aw5 and related ligands described in Kim, m.h. et al, "The Design, Synthesis, and Biological Evaluation of patent receiver type Kinase Inhibitors", bioorg.med.chem.lett.22:4979 (2012); the crystal structure PDB 4bb4 and related ligands described in Vasbinder, M.M. et al, "Discovery and Optimization of a Novel Series of Point mutation B-Raf V600E Selective Kinase Inhibitors" J.Med.chem.56:1996 ", (2013); bardelle, C. et al, "inhibition of the tyrosine kinase Ephb4.part 1: Structure-Based Design and Optimization of a Series of 2, 4-Bis-Anilinopylimides", the crystal structures PDB 2vwu, 2vwv and 2vww and related ligands described in bioorg. Med. chem. Lett.18: 2776-; bardelle, C. et al, "inhibition of the tyrosine kinase Ephb4.part 2: Structure-Based Discovery and optimization of 3,5-bis Substisted anilorphyrinoids", Crystal structures PDB 2vwx, 2vwy and 2vwz and related ligands described in bioorg. Med. chem. Lett.18:5717 (2008); and Welin, M. et al, "Substrate Specificity and oligomerization of Human Gmp synthitas", J.mol.biol.425:4323(2013), with the crystal structure PDB 2vxo and related ligands.

Fig. 8MMMM presents an example of ERBB2 targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see, e.g., Aetgeerts, K. et al, "Structural Analysis of the Mechanism of inhibition and Activation of the Kinase Domain of HER2 Protein", J.biol.chem.286: 18756-.

Fig. 8NNNN presents an example of ERBB3 targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see, Littlefield, P.et al, "An ATP-reactive Inhibitor modules the analog Function of the HER3 pseudo-kinase," chem.biol.21:453-458 (2014).

Fig. 8 oooooo presents an example of ERBB4 targeting ligands, where R is the point of attachment for the linker. For additional examples and related ligands, see, Qiu, C. et al, "mechanisms of Activation and Inhibition of the HER4/ErbB4 Kinase", Structure 16: 460-.

FIG. 8PPPP-8QQQQ presents an example of an FES targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see Filippakoulolos, P. et al, "Structural Coupling of SH2-KinaseDomains Links Fes and Abl Substrate Recognition and KinaseAction," Cell134: 793-.

Fig. 8RRRR presents an example of a FYN targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see Kinoshita, T. et al, "Structure of human Fyn kinase domain complex with stable carbohydrate", biochem. Biophys. Res. Commun.346:840-844 (2006).

Figure 8SSSS-8 vvvvvv presents an example of a GSG2(Haspin) targeting ligand, where R is the point of attachment of the linker. For additional examples and related ligands, see, e.g., Filippakopoulos, P. et al, "Crystal Structure of human Haspin with a pyrazolo-pyrimidine ligand" (to be published) describing the Crystal Structure PDB3e7v, PDB 3f2n, 3fmd and related ligands; ewaran, J. et al, "Structure and function characterization of the antigenic human kinase heparin", Proc. Natl. Acad. Sci. USA106: 20198-; and Chaikuad, A. et al, "Aunique inhibitor binding site in ERK1/2is associated with slow binding kinetics", Nat. chem. biol.10: 853-.

Figure 8 wwwwww-8 AAAAA presents an example of an HCK targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see, Schinder, T. et al, "Crystal Structure of Hck in complex with a Src family-selective type kinase inhibitor", mol. cell 3: 639-; burcha, A. et al, "Discovery of A-770041, a Src-Family selected organic Active Lck Inhibitor which present s organic affinity Rejection", bioorg.Med.chem.Lett.16:118(2006) and related ligands; sabat, M. et al, "The deterioration of 2-benzamidozolylated pyridine based inhibitors of lysine specific kinase (Lck)", bioorg. Med. chem. Lett.16:5973-5977(2006) and related ligands; saito, Y. et al, "A Pyrolo-Pyrimidine Derivative Targets Human Primary AML StemCells in Vivo", Sci Transl Med 5:181ra52-181ra52(2013) describe the crystal structures PDB3vry, 3vs3, 3vs6 and 3vs7 and related ligands; and Parker, L.J., et al, "Kinase crystallization and ATP-reactive inhibition using the fluorescent localized SKF 86002",. Acta crystalloger, Sect.D. 70: 392-.

FIG. 8BBBBB-8FFFFF presents an example of an IGF1R targeting ligand, where R is the point of attachment of the linker. For further examples and related ligands, see, Velaparathi, U.S. et al, "Discovery and initiation SAR of 3- (1H-benzene [ d ] imidazole-2-yl) pyridine-2 (1H) -ones as inhibitors of insulin-producing factor 1-receptor (IGF-1R)", bioorg.Med.chem.Lett.17:2317-2321(2007) for crystal structure PDB 2oj9 and related ligands; wittman, M.D. et al, "Discovery of a2, 4-disubstuted pyronol [1,2-f ] [1,2,4] triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical details", J.Med.chem.52:7360-7363(2009) and related ligands; sampognaro, A.J. et al, "Proline isosteres in a series of 2, 4-disubstitated pyrolo [1,2-f ] [1,2,4] triazine inhibitors of IGF-1R kinase and IR kinase," Crystal Structure PDB 3nw5 and related ligands described in bioorg.Med.chem.Lett.20: 5027-; (ii) the crystal structure PDB 3qqu and related ligands described in Buchanan, J.L. et al, "Discovery of 2,4-bis-arylamino-1, 3-pyridines as insulin-like growth factor-1 receptors (IGF-1R) inhibitors", bioorg.Med.chem.Lett.21: 2394-; the crystal structure PDB 4d2r and related ligands described in Kettle, J.G. et al, "Discovery and optimization of a Novel Series of Dyrk1B Kinase Inhibitors to Explore a MekResistence Hypothesis". J.Med.chem.58:2834 (2015); monferer, D. et al, "Structural studios on the full-length lysR-typeguided TsAR from Comamonas testosteroni T-2 novel a novel optical transformation of the quaternary LTTR fold", mol. Microbiol.75:1199-1214(2010) and related ligands; PDB 5fxs and related ligands in crystal structure as described in Degorce, S. et al, "Discovery of Azd9362, a lattice selected organic Bioavailable and efficacy Novel Inhibitor of Igf-R1" (to be published); mayer, S.C. et al, "Lead identification generation isocyanate inhibitor of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment", bioorg.Med.chem.Lett.18: 3641-; the crystal structure PDB 3f5p and related ligands described in "Lead identification to generator 3-cyanoquinoline inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment" bioorg.Med.chem.Lett.19:62-66 (2009); the crystal structure PDB 3lvp and related ligands described in Nemecek, C. et al, "Design of patent IGF1-R inhibition coated to Bis-azaindoles," chem. biol. drug Des.76:100-106 (2010); the crystal structure PDB 3o23 and related ligands described in Lesuise, D.et al, "Discovery of the first non-ATP reactive IGF-1R kinase inhibitors: Advantages in compositions with reactive inhibitors", bioorg. Med. chem. Lett.21:2224 + 2228 (2011); wu, J.et al, "Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor", Embo J.27: 1985-; and Stauffer, F.et al, "Identification of a5- [3-phenyl- (2-cyclic-ether) -methyl-4-aminopyrrolo [2,3-d ] pyridine series of IGF-1 Rinhibitors", bioorg.Med.chem.Lett.26: 2065-2062067 (2016), crystal structure PDB 5hzn and related ligands.

FIG. 8GGGGG-8JJJJ presents examples of INSR targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see, Katayama, N.et al, "Identification of a key element for hydrogen-binding patterns between protein Proteins and the same inhibitors", Proteins 73:795-801(2008), crystal structure PDB 2z8c and related ligands; chamberland, S.D. et al, "Discovery of4, 6-bis-anilo-1H-pyrrolo [2,3-d ] pyrimidines," Potenitinibitors of the IGF-1R receptor tyrosine kinase "(2009), bioorg.Med.chem.Lett.19: 469-473; chamberland, S.D. et al, "Optimization of4, 6-bis-anilino-1H-pyrrolo [2,3-d ] pyrimidine IGF-1R type kinase inhibitors towards JNK selection", the crystal structure PDB 3ekn and related ligands described in bioorg.Med.chem.Lett.19:360-364 (2009); sanderson, M.P. et al, "BI 885578, a Novel IGF1R/INSR Tyrosine Kinase inhibitor with pharmacological Properties That resist activity and Perturbation of Glucose Homeostasis" mol. cancer ther.14: 2762. sup. 2772 ", (2015) crystal structure PDB5e 1s and related ligands; patnaik, S. et al, "Discovery of 3, 5-disubstuted-1H-pyrolo [2,3-b ] pyridines as potential inhibitors of the insulin-like growth factor-1receptor (IGF-1R) tyrosine kinase", bioorg.Med.chem.Lett.19: 3136-; stauffer, F. et al, "Identification of a5- [3-phenyl- (2-cyclic-ether) -methyl ] -4-aminopyrrolo [2,3-d ] pyrimidasieres of IGF-1R inhibitors", crystal structure PDB 5hhw and related ligands described in bioorg.Med.chem.Lett.26:2065-2067 (2016); and the crystal structure PDB 4ibm and related ligands described in Antassiadis, T. et al, "A high selectivity driven kinase (IR)/insulin-like growth factor 1receptor (IGF-1R) inhibited from an extracellular-regulated kinase (ERK) inhibitor", J.biol.chem.288: 28068-.

Figure 8 kkkkkkkkk-8 PPPPP presents an example of an HBV targeting ligand where R is the point of attachment of a linker, Y is methyl or isopropyl, and X is N or C. For additional examples and related ligands, see Weber, o.; "Artificial Res.54,69-78 (2002)" by a novel non-nuclear magnetic compound in an innovative mouse model ", et al; deres, K. et al, "inhibition of hepatitis B virus reproduction by drug-induced duplication of nucleic applications," Science,299, 893-; stray, s.j.; zlotnick, a. "BAY 41-4109has multiple effects on Hepatitis B virus capsule assembly." j.mol.recognit.19,542-548 (2006); "Proc.Natl.Acad.Sci.U.S. A.,102, 8138-; guian, H.et al, "The novel compound Z060228 inhibitors assembly of The HBVcappsid." Life Sci.133,1-7 (2015); wang, X.Y. et al, "In vitro inhibition of HBVplayback by a novel compound, GLS4, and its effectiveness against infection-Dipivoxil-resistant HBV events," antibiotic ther.17,793-803 (2012); klumpp, K. et al, "High-resolution crystal structure of a hepatitis B virus regenerative bottom to the viral core protein," 112, 15196-; qiu, Z. et al, "Design and synthesis of organic bioavailable 4-methylheteroaryldihydropyrimide based Hepatitis B Viruses (HBV) capsid inhibitors," J.Med.chem.59,7651-7666 (2016); zhu, X. et al, "2, 4-Diaryl-4,6,7,8-tetrahydroquinazolin-5(1H) -one derivatives as anti-HBV agents targeting tcapsid assembly," bioorg.Med.chem.Lett.20,299-301 (2010); campagna, M.R. et al, "leather benzizamide derivatives inhibition of the assembly of hepatitis B viro-subsequent applications," J.Virol.87,6931-6942 (2013); campagna, M.R. et al, "leather benzizamide derivatives inhibition of the assembly of hepatitis B viro-subsequent applications," J.Virol.87,6931-6942 (2013); WO 2013096744A 1 entitled "Patitis Bantiial agents"; WO 2015138895, entitled "heparis B core protein aggregates"; wang, Y.J. et al, "A novel pyridine derivative inhibitors ligation by introduction genome-free cap formation," anti-microbiobs Agents Chemother.59,7061-7072 (2015); WO 2014033167 entitled "functional surface derivatives for the treatment of hepatitis"; U.S.20150132258 entitled "Azepane derivatives and methods of treating hepatitis B infections"; and WO 2015057945 "Hepatitis B visual assembly effect".

Figure 9 is a dendrogram of a human bromodomain family of proteins organized into eight subfamilies, which is involved in epigenetic signaling and chromatin biology. Any protein of the bromodomain family in figure 9 can be selected as a target protein according to the present invention.

FIG. 10 depicts six general formulas of the present invention. Formula I, formula II, formula III and formula IV depict the reduced solution stator body of the present invention. Formulae V and VI depict the degradation determinants of the present invention. The variables used are defined herein.

Detailed Description

I. Definition of

Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The compounds of any of the formulae described herein may be in the form of racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, isomers; e.g., rotamers, as if each were explicitly recited, unless explicitly excluded by context.

The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and/or". Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are inclusive of the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

The present invention includes compounds of formula I, formula II, formula III, formula IV, formula V, and formula VI having at least one desired isotopic substitution, in an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e. atoms of the same proton number but different neutron numbers.

Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I. in one non-limiting embodiment, isotopically-labeled compounds can be used for metabolic studies (using, for example¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including drug or substrate tissue distribution assays, or in the radiotherapy of patients. In particular, it is possible to use, for example,¹⁸f-labelled compounds may be particularly desirable for PET or SPECT studies. Isotopically-labelled compounds of the present invention and prodrugs thereof can generally be prepared by substituting a readily available isotopically-labelled reagent for a non-isotopically-labelled reagentBy carrying out the procedures and preparations disclosed in the schemes or in the examples below.

Isotopic substitution, for example deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is 90, 95, or 99% or more isotopically enriched at any position of interest. In one non-limiting embodiment, deuterium is 90, 95, or 99% enriched at the desired position.

In one non-limiting embodiment, the substituted hydrogen atom may be provided as a deuterium atom in any compound of formula I, formula II, formula III, formula IV, formula V, or formula VI. In one non-limiting embodiment, replacement of a hydrogen atom as a deuterium atom occurs within one or more groups selected from any R or variable described herein. For example, when any group is or contains (e.g., by substitution) a methyl, ethyl, or methoxy group, the alkyl residue may be deuterated (in a non-limiting embodiment, CDH₂、CD₂H、CD₃、CH₂CD₃、CD₂CD₃、CHDCH₂D、CH₂CD₃、CHDCHD₂、OCDH₂、OCD₂H or OCD₃Etc.). In certain other embodiments, when two substituents combine to form a ring, the unsubstituted carbon may be deuterated.

The compounds of the present invention may form solvates with solvents, including water. Thus, in one non-limiting embodiment, the present invention includes solvated forms of the compounds. The term "solvate" refers to a molecular complex of a compound of the invention (including salts thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the present invention and water. Pharmaceutically acceptable solvates according to the invention include those wherein the solvent may be isotopically substituted (e.g., D)₂O、d₆-acetone, d₆-DMSO). The solvate may be in liquid or solid form.

Is not twoA connection number ("-") between letters or symbols is used to indicate the point of attachment of a substituent. For example, - (C ═ O) NH₂Is a carbon linkage through a carbonyl (C ═ O) group.

"alkyl" is a branched or straight chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, alkyl is C₁-C₂、C₁-C₃、C₁-C₄、C₁-C₅Or C₁-C₆. The specified ranges as used herein denote alkyl groups having each member of the ranges described as independent species (species). For example, the term C as used herein₁-C₆Alkyl represents straight or branched chain alkyl groups having 1,2,3,4, 5 or 6 carbon atoms, and is intended to mean that each of these is described as a separate species, and thus each subset is considered to be separately disclosed. For example, the term C as used herein₁-C₄Alkyl represents straight or branched chain alkyl groups having 1,2,3 or 4 carbon atoms and is intended to mean that each of these is described as an independent species. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2-dimethylbutane, and 2, 3-dimethylbutane. In an alternative embodiment, the alkyl group is optionally substituted. The term "alkyl" also includes cycloalkyl or carbocyclyl. For example, when a term is used that includes "alk (alk)", then "cycloalkyl" or "carbocyclyl" may be considered part of the definition unless explicitly excluded by context. For example, and without limitation, the terms alkyl, alkoxy, haloalkyl, and the like can be considered to include cyclic forms of alkyl unless specifically excluded by the context.

An "alkenyl group" is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may exist along the point of stabilization of the chain. The specified ranges as used herein represent alkenyl groups having each member of the ranges described as independent species, as described above for the alkyl moiety. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also includes "cis" and "trans" alkenyl geometries, or "E" and "Z" alkenyl geometries. In an alternative embodiment, the alkenyl is optionally substituted. The term "alkenyl" also includes cycloalkyl or carbocyclyl groups having at least one point of unsaturation.

An "alkynyl group" is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain. The specified ranges as used herein represent alkynyl groups having each member of the ranges described as independent species, as described above for the alkyl moiety. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. In an alternative embodiment, the alkynyl group is optionally substituted. The term "alkynyl" also includes cycloalkyl or carbocyclyl having at least one triple bond.

An "alkylene" is a divalent saturated hydrocarbon. For example, alkylene can be a1, 2,3,4, 5,6,7 to 8 carbon moiety, a1 to 6 carbon moiety, or a specified number of carbon atoms, such as C₁-C₂Alkylene radical, C₁-C₃Alkylene radical, C₁-C₄Alkylene radical, C₁-C₅Alkylene or C₁-C₆An alkylene group.

An "alkenylene" is a divalent hydrocarbon having at least one carbon-carbon double bond. For example, alkenylene may be a2 to 8 carbon moiety, a2 to 6 carbon moiety, or the indicated number of carbon atoms, such as C₂-C₄An alkenylene group.

"alkynylene" is a divalent hydrocarbon having at least one carbon-carbon triple bond. For example, an alkynylene group can be a2 to 8 carbon moiety, a2 to 6 carbon moiety, or the specified number of carbon atoms, e.g., C₂-C₄AlkynyleneAnd (4) a base.

"Halo (Halo)" or "halogen" refers to fluorine, chlorine, bromine or iodine.

"haloalkyl" is a branched or straight-chain alkyl group substituted with1 or more of the above-described halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "perhaloalkyl" means an alkyl group having all hydrogen atoms replaced with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

By "chain" is meant that all other chains (long or short or both) can be considered to be straight chains flanked thereon. When two or more chains can also be considered as backbones, "chain" refers to the chain that results in the simplest representation of a molecule.

"haloalkoxy" refers to a haloalkyl group as defined herein attached through an oxygen bridge (the oxygen of an alcohol group).

"heterocycloalkyl" is an alkyl group, as defined herein, substituted with a heterocyclyl group, as defined herein.

An "arylalkyl" group is an alkyl group, as defined herein, substituted with an aryl group, as defined herein.

"heteroarylalkyl" is an alkyl group as defined herein substituted with a heteroaryl group as defined herein.

As used herein, "aryl" refers to a compound having an aromatic ring system ("C)_6–14Aryl ") and zero heteroatoms (e.g., bicyclic or tricyclic) 4n +2 aromatic ring systems (e.g., having 6, 10, or 14 pi electrons shared in the ring array). In some embodiments, an aryl group has 6 ring carbon atoms ("C)₆Aryl "; for example, phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C)₁₀Aryl "; for example, naphthyl groups such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C)₁₄Aryl "; for example, an anthracene group). "Aryl "also includes the following ring systems: wherein an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups wherein the linking group or point of attachment is on the aryl ring and in such cases the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The one or more fused carbocyclic or heterocyclic groups may be a4 to 7 or 5 to 7 membered saturated or partially unsaturated carbocyclic or heterocyclic group optionally containing 1,2 or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulphur, silicon and boron to form, for example, a3, 4-methylenedioxyphenyl group. In one non-limiting embodiment, the aryl group is a pendant group. An example of a pendant ring is phenyl substituted with phenyl. In an alternative embodiment, the aryl group is optionally substituted as described above. In certain embodiments, aryl is unsubstituted C_6–14And (4) an aryl group. In certain embodiments, aryl is substituted C_6–14And (4) an aryl group. The aryl group may be optionally substituted with one or more functional groups including, but not limited to, halogen, hydroxyl, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocycle.

The term "heterocyclyl" (or "heterocycle") includes saturated and partially saturated heteroatom-containing ring groups in which the heteroatoms may be selected from nitrogen, sulfur and oxygen. Heterocyclyl rings include 3-8 membered monocyclic rings, as well as 5-16 membered bicyclic ring systems (which may include bridged fused and spiro fused bicyclic ring systems). It does not include rings containing-O-, -O-S-or-S-moieties. The "heterocyclyl" group may be optionally substituted, for example, with1, 2,3,4, or more substituents including, but not limited to, hydroxy, Boc, halogen, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino. Examples of saturated heterocyclic groups include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [ e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl ]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [ e.g., morpholinyl ]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [ e.g., thiazolidinyl ]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclyl groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2, 3-dihydro-benzo [1,4] dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, isochromanyl, chromanyl, 1, 2-dihydroquinolinyl, 1,2,3, 4-tetrahydro-isoquinolinyl, 1,2,3, 4-tetrahydro-quinolinyl, 2,3,4,4a,9,9 a-hexahydro-1H-3-aza-fluorenyl, 5,6, 7-trihydro-1, 2, 4-triazolo [3,4-a ] isoquinolinyl, 3, 4-dihydro-2H-benzo [1,4] oxazinyl, benzo [1,4] dioxanyl, 2, 3-dihydro-1H-1 λ' -benzo [ d ] isothiazol-6-yl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl.

Heterocyclic groups also include groups in which the heterocyclic group is fused/condensed with an aryl or heteroaryl group: for example, unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms (e.g., indoline, isoindoline), unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.

The term "heteroaryl" denotes an aryl ring system containing one or more heteroatoms selected from O, N and S, wherein the ring nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. Examples include, but are not limited to, unsaturated 5-to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [ e.g., 4H-1,2, 4-triazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl ]; unsaturated 5-to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl and the like; unsaturated 5-to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [ e.g., 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl ]; unsaturated 5-to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [ e.g., 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl ].

The term "optionally substituted" means that the group is substituted herein with a moiety (motif) including, but not limited to, C₁-C₁₀Alkyl radical, C₂-C₁₀Alkenyl radical, C₂-C₁₀Alkynyl, C₃-C₁₂Cycloalkyl radical, C₃-C₁₂Cycloalkenyl radical, C₁–C₁₂Heterocycloalkyl radical, C₃-C₁₂Heterocycloalkenyl, C₁-C₁₀Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C₁-C₁₀Alkylamino radical, C₁-C₁₀Dialkylamino, arylamino, diarylamino, C₁-C₁₀Alkylsulfonylamino, arylsulfonylamino, C₁-C₁₀Alkylimino, arylimino, C₁-C₁₀Alkylsulfonylimide, arylsulfonylimide, hydroxy, halogen, thio, C₁-C₁₀Alkylthio, arylthio, C₁-C₁₀Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidino, ureido, cyano, nitro, azido, acyl, thioacyl, acyloxy, carboxyl and carboxylic acid ester.

In an alternative embodiment, any suitable group may be present in a "substituted" or "optionally substituted" position if indicated to form a stable molecule and meet the desired objectives of the present invention, and includes, but is not limited to, for example, halogen (which may independently be F, Cl, Br, or I); a cyano group; a hydroxyl group; a nitro group; an azide group; alkanoyl (such as C)₂-C₆Alkanoyl); formamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl groups including those having one or more thioether linkages; an alkylsulfinyl group; alkylsulfonyl including those having one or more sulfonyl linkages; aminoalkyl, bagsIncluding groups having more than one N atom; aryl (e.g., phenyl, biphenyl, naphthyl, and the like, each ring substituted or unsubstituted); arylalkyl having, for example, 1 to 3 separate or fused rings and 6 to about 14 or 18 ring carbon atoms, wherein benzyl is an exemplary arylalkyl; for example, an arylalkoxy group having 1 to 3 separate or fused rings, wherein benzyloxy is an exemplary arylalkoxy group; or a saturated or partially unsaturated heterocycle having 1 to 3 independent or fused rings having one or more N, O or S atoms, or a heteroaryl group having 1 to 3 independent or fused rings having one or more N, O or S atoms, such as coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such groups may be further substituted, for example, with hydroxy, alkyl, alkoxy, halo, and amino groups. In certain embodiments, "optionally substituted" includes one or more substituents independently selected from the group consisting of: halogen, hydroxy, amino, cyano, -CHO, -COOH, -CONH₂Alkyl (including C)₁-C₆Alkyl), alkenyl (including C)₂-C₆Alkenyl), alkynyl (including C)₂-C₆Alkynyl), -C₁-C₆Alkoxy, alkanoyl (including C)₂-C₆Alkanoyl) C₁-C₆Alkyl esters, (mono-and di-C)₁-C₆Alkylamino) C₀-C₂Alkyl, haloalkyl (including C)₁-C₆Haloalkyl), hydroxy C₁-C₆Alkyl, ester, carbamate, urea, sulfonamide, -C₁-C₆Alkyl (heterocyclyl), C₁-C₆Alkyl (heteroaryl), -C₁-C₆Alkyl radical (C)₃-C₇Cycloalkyl), O-C₁-C₆Alkyl radical (C)₃-C₇Cycloalkyl), B (OH)₂Phosphate esters, phosphonate esters and haloalkoxy groups (including C)₁-C₆Alkyl halidesOxy) group.

"aliphatic group" means a saturated or unsaturated, straight-chain, branched, or cyclic hydrocarbon. "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, thus incorporating each of these definitions. In one embodiment, "aliphatic group" is used to denote those aliphatic groups having 1 to 20 carbon atoms. The aliphatic chain may be, for example, monounsaturated, diunsaturated, triunsaturated, or polyunsaturated, or alkynyl. The unsaturated aliphatic group may be in the cis or trans configuration. In one embodiment, the aliphatic group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C₁-C₂、C₁-C₃、C₁-C₄、C₁-C₅Or C₁-C₆. The specified ranges as used herein represent aliphatic groups having each member of the ranges described as separate species. For example, the term C as used herein₁-C₆Aliphatic groups represent straight-chain or branched alkyl, alkenyl or alkynyl groups having 1,2,3,4, 5 or 6 carbon atoms, and are intended to mean that each of these is described as an independent species. For example, the term C as used herein₁-C₄Aliphatic groups represent straight-chain or branched alkyl, alkenyl or alkynyl groups having 1,2,3 or 4 carbon atoms, and are intended to mean that each of these is described as an independent species. In one embodiment, the aliphatic group is substituted with one or more functional groups that result in the formation of a stabilizing moiety.

The term "heteroaliphatic" refers to an aliphatic moiety containing at least one heteroatom in the chain, such as an amine, carbonyl, carboxyl, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon or boron atom in place of a carbon atom. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. "Heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, "heteroaliphatic" is used to denote a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1 to 20 carbon atoms. In one embodiment, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Non-limiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amides, polyamides, polylactides, polyglycolides, thioethers, ethers, alkyl-heterocycle-alkyl, -O-alkyl, alkyl-O-haloalkyl, and the like.

By "dosage form" is meant an administration unit of the active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, spheroids, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal agents, sublingual agents, topical agents, gels, mucoadhesives and the like. "dosage form" may also include implants, such as optical implants.

An "effective amount" as used herein means an amount that provides a therapeutic or prophylactic benefit.

As used herein, "endogenous" refers to any substance that is derived from or produced within an organism, cell, tissue, or system.

As used herein, the term "exogenous" refers to any substance introduced from or produced externally to an organism, cell, tissue or system.

The term "modulate" as used herein means to mediate a detectable increase or decrease in the level of a response in a subject compared to the level of a response in a subject in the absence of the treatment or compound, and/or compared to the level of a response in an otherwise identical but untreated subject. The term includes disrupting and/or affecting the natural signal or response, thereby mediating a beneficial therapeutic response in a subject (preferably a human).

"parenteral" administration of an immunogenic composition includes, for example, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection, or infusion techniques.

As used herein, the terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to a compound consisting of amino acid residues covalently linked by peptide bonds. The protein or peptide must contain at least two amino acids, and there is no limit to the maximum number of amino acids that can comprise the protein or peptide sequence. Polypeptides include any peptide or protein comprising two or more amino acids linked to each other by peptide bonds. As used herein, the term refers to short chains, which are also commonly referred to in the art, for example, as peptides, oligopeptides, and oligomers; and longer chains, commonly referred to in the art as proteins, which are of many types. "polypeptide" includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, and the like. The polypeptide includes a natural peptide, a recombinant peptide, a synthetic peptide, or a combination thereof.

"treating" a disease, as the term is used herein, means reducing the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject.

The range is as follows: throughout this disclosure, various aspects of the invention may be presented in a range format. It is to be understood that the description of the range format is merely for convenience and should not be construed as limiting the scope of the invention. It is to be understood that the description of a range has specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, it is contemplated that the description of a range such as1 to 6 has specifically disclosed sub-ranges such as1 to 3,1 to 4,1 to 5,2 to 4,2 to 6,3 to 6, etc., as well as individual numerical values within that range, e.g., 1,2, 2.7, 3,4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

As used herein, a "pharmaceutical composition" is a composition comprising at least one active agent, and at least one other material, such as a carrier. A "pharmaceutical combination" is a combination of at least two active agents that can be provided together in a single dosage form or in separate dosage forms, with instructions for the co-use of the active agents to treat any of the conditions described herein.

As used herein, "pharmaceutically acceptable salts" are derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. Salts of the compounds of the present invention may be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are generally carried out in water or in an organic solvent or in a mixture of the two. Generally, nonaqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical where feasible. Salts of the compounds of the present invention also include solvates of the compounds and salts of the compounds.

Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; basic or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC- (CH)₂)_n-COOH (where n is 0-4), etc., or salts prepared using different acids yielding the same counter ion. A further list of suitable salts can be found, for example, in Remington's pharmaceutical Sciences, 17 th edition, Mack Publishing Company, Easton, Pa., p.1418 (1985).

The term "carrier" as applied to the pharmaceutical compositions/combinations of the present invention refers to the diluent, excipient or vehicle with which the active compound is provided.

By "pharmaceutically acceptable excipient" is meant an excipient that can be used to prepare a pharmaceutical composition/combination that is generally safe, non-toxic, and neither biologically nor otherwise suitable for administration to a host (typically a human). In one embodiment, a veterinarily acceptable excipient is used.

A "patient" or "host" or "subject" is a human or non-human animal in need of treatment or prevention of any condition as explicitly described herein (e.g., a condition that is modulated by a native (wild-type) or modified (non-wild-type) protein that can be degraded according to the invention, thereby producing a therapeutic effect). Typically, the host is a human. Alternatively, "host" may also refer to, for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.

A "therapeutically effective amount" of a pharmaceutical composition/combination of the invention refers to an amount effective to provide a therapeutic benefit such as an improvement in symptoms or a reduction or decrease in the disease itself when administered to a host.

II. Compound

Formula I and formula II

In one aspect of the invention, there is provided a compound of formula I or formula II:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, prodrug, optionally in a pharmaceutically acceptable carrier to form a composition; the variables are as defined above.

The term degreddeterminant as used in formula I, formula II, formula III and formula IV refers to R¹²A linked molecular moiety. For example, if the compound of the formula I is

The degron moiety of the compound is

Non-limiting examples of compounds of formula I include:

additional non-limiting examples of compounds of formula I include:

R¹embodiments of (1)

R¹Non-limiting examples of (a) include:

formula III and formula IV

In one aspect of the invention, there is provided a compound of formula III or formula IV:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, prodrug, optionally in a pharmaceutically acceptable carrier to form a composition; the variables are as defined above.

Formula V and formula VI

In another aspect of the invention, there is provided a compound of formula V or formula VI:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, prodrug, optionally in a pharmaceutically acceptable composition; the variables are as defined above.

Non-limiting examples of compounds of formula V include:

non-limiting examples of compounds of formula V include:

R¹³non-limiting examples of (a) include:

connector

Linkers are included in the reduced solution stators of formula I, formula II, formula III, and formula IV. Linkers are bonds or chemically stable groups that link the degron to the targeting ligand.

Any of the linkers described herein can be used in either orientation, i.e., left-hand linked to the degron and right-hand linked to the targeting linker, or left-hand linked to the targeting linker and right-hand linked to the degron. Any desired linker may be used according to the invention, as long as the resulting compound has a stable shelf life of at least 2 months, 3 months, 6 months or1 year as part of a pharmaceutically acceptable dosage form, and is itself pharmaceutically acceptable.

In typical embodiments, the linker has a chain of 2 to 14, 15, 16, 17, 18, or 20 or more carbon atoms, wherein one or more carbons may be replaced by a heteroatom such as O, N, S or P. In certain embodiments, the chain has 2,3,4, 5,6,7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive atoms in the chain. For example, the chain may include one or more ethylene glycol units, which may be continuous, partially continuous, or discontinuous (e.g., 2,3,4, 5,6,7, 8,9, 10, 11, or 12 ethylene glycol units). In certain embodiments, the chain has at least 1,2,3, 4,5,6,7, or 8 continuous chains, which may have branches that may independently be alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl, aliphatic, heteroaliphatic, cycloalkyl, or heterocyclyl substituents.

In other embodiments, the linker may comprise or consist of one or more of ethylene glycol, propylene glycol, lactic acid and/or glycolic acid. Generally, propylene glycol increases hydrophobicity, while propylene glycol increases hydrophilicity. Lactic acid segments tend to have longer half-lives than glycolic acid segments. It is known in the art that both block and random lactic acid-co-glycolic acid moieties as well as ethylene glycol and propylene glycol are pharmaceutically acceptable and can be modified or arranged to achieve the desired half-life and hydrophilicity. In certain aspects, the units may be flanked or interspersed with other moieties, such as aliphatic groups (including alkyl groups), heteroaliphatic groups, aryl groups, heteroaryl groups, heterocycles, cycloalkyls, and the like, as desired, to achieve appropriate pharmaceutical properties.

In one embodiment, the linker is a moiety selected from formula LI, formula LII, formula LIII, formula LIV, formula LV, formula LVI and formula LVII:

wherein:

X¹and X²Independently selected from the group consisting of a bond, NH, NR²⁵、CH₂、CHR²⁵、C(R²⁵)₂O and S;

R²⁰、R²¹、R²²、R²³and R²⁴Independently selected from the group consisting of a bond, alkyl, -C (O) -, -C (O) O-, -OC (O) -, -C (O) alkyl, -C (O) Oalkyl, -C (S) -, -SO₂-, -S (O) -, -C (S) -, -C (O) NH-, -NHC (O) -, -N (alkyl) C (O) -, -C (O) N (alkyl) -, -O-, -S-, -NH-, -N (alkyl) -, -CH (-O-R)²⁶)-、-CH(-NHR²⁵)-、-CH(-NH₂)-、-CH(-NR²⁵ ₂)-、-C(-O-R²⁶) Alkyl-, -C (-NHR)²⁵) Alkyl-, -C (-NH)₂) Alkyl-, -C (-NR)²⁵ ₂) Alkyl-, -C (R)⁴R⁴) -, -alkyl (R)²⁷) -alkyl (R)²⁸)-、-C(R²⁷R²⁸)-、-P(O)(OR²⁶)O-、-P(O)(OR²⁶)-、-NHC(O)NH-、-N(R²⁵)C(O)N(R²⁵)-、-N(H)C(O)N(R²⁵) -, polyethylene glycol, poly (lactic-co-glycolic acid), olefin, alkyl halideAlkyl, alkoxy and alkyne;

or R²⁰、R²¹、R²²、R²³And R²⁴May be independently selected from heteroarylalkyl, aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, carbocyclic, or-O- (CH) in addition to those described above₂)_1-12-O-、-NH-(CH₂)_1-12-NH-、-NH-(CH₂)_1-12-O-or-O- (CH)₂)_1-12-NH-、-S-(CH₂)_1-12-O-、-O-(CH₂)₁-12-S-、-S-(CH₂)₁-12-S-、-S-(CH₂)₁-12-NH-、-NH-(CH₂)₁-12-S-, (and wherein said 1-12 may independently be 1,2,3, 4,5,6,7, 8,9, 10, 11 or 12, and wherein one or more CH are₂Or NH may be modified by replacing H with methyl, ethyl, cyclopropyl, F (if on carbon), etc., as described herein), and optionally, a heteroatom, heteroalkyl, aryl, heteroaryl, or cycloaliphatic group interspersed in the chain). Some non-limiting examples include-O-CH (CH)₃)-CH(CH₃)CH-O-、-O-CH₂-CH(CH₃)CH-O-、-O-CH(CH₃)-CH₂CH-O-, and the like.

R²⁰、R²¹、R²²、R²³And R²⁴Each of which is optionally substituted with one or more groups selected from R¹⁰¹Or alternatively as described in definition section 1;

R¹⁰¹independently at each occurrence, is selected from the group consisting of hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO₂、F、Cl、Br、I、CF₃、NH₂NH alkyl, N (alkyl)₂Aliphatic and heteroaliphatic groups; and is

R²⁵In each case selected from: alkyl, -C (O) H, -C (O) OH, -C (O) alkyl, -C (O) Oalkyl, alkenyl, and alkynyl;

R²⁶is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, and alkyne; and is

R²⁷And R²⁸Independently selected from hydrogen, alkyl, amine, or together with the carbon atom to which they are attached form C (O), C (S), C ═ CH₂、C₃-C₆A spiro carbocyclic ring, or a 4-, 5-or 6-membered spiro heterocyclic ring containing 1 or2 heteroatoms selected from N and O, or forming a1 or2 carbon bridged ring.

In further embodiments, the linker is a moiety selected from formulas LVIII, LIX and LX:

wherein each variable is as defined in formula LI. In alternative embodiments of LVIII, LIX and LX, a carbocyclic ring is used instead of a heterocyclic ring.

The following are non-limiting examples of linkers that can be used in the present invention. Based on this description, the skilled person will understand how to use all the linkers that will achieve the object of the invention.

As certain non-limiting examples, formula LI, formula LII, formula LIII, formula LIV, formula LV, formula LVI, or formula LVII include:

in another linker embodiment, R²¹、R²²、R²³Or R²⁴Selected from:

in further embodiments, the linker is selected from:

in one embodiment, X¹Linked to a targeting ligand. In another embodiment, X²Linked to a targeting ligand.

R²⁰、R²¹、R²²、R²³And R²⁴Non-limiting examples of moieties of (a) include:

R²⁰、R²¹、R²²、R²³and R²⁴Additional non-limiting examples of moieties include:

in further embodiments, the linker group is an optionally substituted (poly) ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 ethylene glycol units, or optionally substituted alkyl groups interspersed with optionally substituted O, N, S, P or Si atoms. In certain embodiments, the linker is flanked, substituted or interspersed with aryl, phenyl, benzyl, alkyl, alkylene or heterocyclyl groups. In certain embodiments, the linker may be asymmetric or symmetric. In some embodiments, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, between about 2 to about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units. In any embodiment of the compounds described herein, the linker group may be any suitable moiety as described herein.

In further embodiments, the linker is selected from:

-NR⁶¹(CH₂)_n1- (lower alkyl) -, -NR⁶¹(CH₂)_n1- (lower alkoxy) -, -NR⁶¹(CH₂)_n1- (lower alkoxy) -OCH₂-，-NR⁶¹(CH₂)_n1- (lower alkoxy) - (lower alkyl) -OCH₂-，-NR⁶¹(CH₂)_n1- (cycloalkyl) - (lower alkyl) -OCH₂-，-NR⁶¹(CH₂)_n1- (heterocycloalkyl) -, -NR⁶¹(CH₂CH₂O)_n1- (lower alkyl) -O-CH₂-，-NR⁶¹(CH₂CH₂O)_n1- (Heterocycloalkyl) -O-CH₂-，-NR⁶¹(CH₂CH₂O)_n1-aryl-O-CH₂-，-NR⁶¹(CH₂CH₂O)_n1- (heteroaryl) -O-CH₂-，-NR⁶¹(CH₂CH₂O)_n1- (cycloalkyl) -O- (heteroaryl) -O-CH₂-，-NR⁶¹(CH₂CH₂O)_n1- (cycloalkyl) -O-aryl-O-CH₂-，-NR⁶¹(CH₂CH₂O)_n1- (lower alkyl) -NH-aryl-O-CH₂-，-NR⁶¹(CH₂CH₂O)_n1- (lower alkyl) -O-aryl-CH₂，-NR⁶¹(CH₂CH₂O)_n1-cycloalkyl-O-aryl-, -NR⁶¹(CH₂CH₂O)_n1-cycloalkyl-O-heteroaryl-, -NR⁶¹(CH₂CH₂)_n1- (cycloalkyl) -O- (heterocyclic) -CH₂，-NR⁶¹(CH₂CH₂)_n1- (heterocycle) -CH₂and-NR⁶¹- (heterocycles) -CH₂(ii) a Wherein n1 is 0,1, 2,3,4, 5,6,7, 8,9, or 10; and R is⁶¹Is H, methyl or ethyl.

In further embodiments, the linker is selected from:

-N(R⁶¹)-(CH₂)_m1-O(CH₂)_n2-O(CH₂)_o1-O(CH₂)_p1-O(CH₂)_q1-O(CH₂)_r1-OCH₂-，

-O-(CH₂)_m1-O(CH₂)_n2-O(CH₂)_o1-O(CH₂)_p1-O(CH₂)_q1-O(CH₂)_r1-OCH₂-，

-O-(CH₂)_m1-O(CH₂)_n2-O(CH₂)_o1-O(CH₂)_p1-O(CH₂)_q1-O(CH₂)_r1-O-；

-N(R⁶¹)-(CH₂)_m1-O(CH₂)_n2-O(CH₂)_o1-O(CH₂)_p1-O(CH₂)_q1-O(CH₂)_r1-O-；

-(CH₂)_m1-O(CH₂)_n2-O(CH₂)_o1-O(CH₂)_p1-O(CH₂)_q1-O(CH₂)_r1-O-；

-(CH₂)_m1-O(CH₂)_n2-O(CH₂)_o1-O(CH₂)_p1-O(CH₂)_q1-O(CH₂)_r1-OCH₂-；

-O(CH₂)_m1O(CH₂)_n2O(CH₂)_p1O(CH₂)_q1OCH₂-；

-O(CH₂)_m1O(CH₂)_n2O(CH₂)_p1O(CH₂)_q1OCH₂-; wherein

m1, n2, o1, p1, q1 and r1 are independently 1,2,3, 4 or 5; and R is⁶¹Is H, methyl or ethyl.

In further embodiments, the linker is selected from:

m1, n2, o1, p1, q2 and r1 are independently 1,2,3, 4 or 5.

In further embodiments, the linker is selected from:

in further embodiments, the linker is selected from:

wherein R is⁷¹is-O-, -NH, N-alkyl, heteroaliphatic, aliphatic or-NMe.

In further embodiments, the linker is selected from:

in further embodiments, the linker is selected from:

in certain embodiments, the linker is selected from:

in the above-described structure, the first and second electrodes,

represents

In certain embodiments, the linker may be a straight chain of 4 to 24 carbon atoms, wherein one or more carbon atoms in the straight chain may be replaced or substituted with oxygen, nitrogen, amide, fluorinated carbon, and the like, such as the following:

in certain embodiments, the linker may be a non-linear chain and may be or include an aliphatic or aromatic or heteroaromatic cyclic moiety.

In certain embodiments, the linker may comprise a continuous, partially continuous, or discontinuous group of ethylene glycol units ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, between about 2 to about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units, for example, 1,2,3, 4,6,7, 8,9, 10, 11, or 12 ethylene glycol units.

In certain embodiments, the linker may have 1,2,3, 4,5,6,7, 8,9, 10, 11, 12, 13, 14, or 15 fluorine substituents. In another embodiment, the linker is perfluorinated. In yet another embodiment, the linking group is a partially or fully fluorinated polyether. Non-limiting examples of fluorinated linkers include:

in certain embodiments, when a targeting ligand binds more than one protein (i.e., is not fully selective), selectivity can be enhanced by varying the linker length, where the ligand binds some of its targets in different binding pockets, e.g., deeper or shallower than others. Thus, the length can be adjusted as desired.

In certain embodiments, the present application relates to a degron-linker (DL) having the structure:

wherein each variable is as described above for formula I and formula LI, and the targeting ligand is employed next to X²Is/are as follows

Covalently bonded to DL.

Target protein

Cellular homeostasis and normal cellular functions such as proliferation, differentiation, and cell death require degradation of cellular proteins. When the system becomes dysfunctional or unable to recognize and reduce abnormal protein behavior in vivo, a disease state may arise in a host, such as a human. As is well known to those skilled in the art, published in the literature and patent applications, and presented in scientific reports, a large number of proteins can cause, modulate, or amplify diseases in vivo.

Thus, in one embodiment, a selected degron compound of the invention may be administered in vivo to a host in need thereof in an amount effective to degrade a selected protein mediating the condition to be treated. The protein target of choice may modulate a condition in humans through mechanisms of action such as modification of biological pathways, pathogen signaling, or modulation of signaling cascades or cellular entry. In one embodiment, the target protein is a protein that is not pharmaceutically acceptable in the classical sense, as it does not have a binding pocket or active site that can be inhibited or otherwise bound, and cannot be readily allosterically controlled. In another embodiment, the target protein is a protein that is pharmaceutically acceptable in the classical sense, but for therapeutic purposes, degradation of the protein is preferred over inhibition.

The target protein is recruited using a targeting ligand that is a ligand for the target protein. Typically, the targeting ligand binds the target protein in a non-covalent manner. In an alternative embodiment, the target protein is covalently bound to the degradation determinant in a manner that may be irreversible or reversible.

In one embodiment, the selected target protein is expressed from a gene that undergoes an amplification, translocation, deletion or inversion event that causes or is caused by a medical condition. In certain aspects, the selected target protein has been post-translationally modified by one or a combination of phosphorylation, acetylation, acylation (including propionylation and crotylation), N-linked glycosylation, amidation, hydroxylation, methylation and polymethylation, O-linked glycosylation, pyroglutamylation, myristoylation, farnesylation, geranylgeranylation, ubiquitination, or sulfation that cause or result from a medical condition.

As contemplated herein, the invention includes an elevator ligand having a targeting ligand that binds to a target protein of interest. A target protein is any amino acid sequence that can bind to a degradation subunit, causing a beneficial therapeutic effect in vivo by degrading it. In one embodiment, the target protein is a non-endogenous peptide, such as a peptide from a pathogen or toxin. In another embodiment, the target protein may be an endogenous protein that mediates a disorder. The endogenous protein may be a normal or abnormal form of the protein. For example, the target protein may be a mutein found in cancer cells, or a protein encoded by a nucleotide polymorphism, for example, in which part or all of the function is obtained or lost. In some embodiments, the degradation determinant targets an abnormal form of the protein rather than a normal form of the protein. In another embodiment, the target protein may mediate an inflammatory or immune disorder, including an autoimmune disorder.

In one embodiment, the target protein is a non-endogenous protein from a virus, by way of non-limiting example, HIV, HBV, HCV, RSV, HPV, CMV, flavivirus, pestivirus, coronavirus, norovirus, and the like. In one embodiment, the target protein is a non-endogenous protein from a bacterium, which may be, for example, a gram-positive bacterium, a gram-negative bacterium, or other bacterium, and may be a drug-resistant form of the bacterium. In one embodiment, the target protein is a non-endogenous protein from a fungus. In one embodiment, the target protein is a non-endogenous protein from a prion. In one embodiment, the target protein is a protein derived from a eukaryotic pathogen, such as protists, helminths (helminths), and the like.

In one aspect, the target protein mediates chromatin structure and function. The target protein may mediate epigenetic effects such as DNA methylation or covalent modification of histones. One example is histone deacetylase ( HDAC 1,2,3, 4,5,6,7, 8,9, 10 or 11). Alternatively, the target protein may be a bromodomain, which is a reader of lysine acetylation (e.g., BRD1, 2,3,4, 5,6,7, 8,9, and T). Figure 9 illustrates a bromodomain family protein, which for example may serve as a target protein according to the present invention.

Other non-limiting examples of target proteins are structural proteins, receptors, enzymes, cell surface proteins, proteins involved in apoptosis signaling, aromatase, helicase, mediators of metabolic processes (anabolic or catabolic), antioxidant factors, proteases, kinases, oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases, enzyme regulators, signal transducers, structural molecules, binding activities (proteins, lipid carbohydrates), cellular motor proteins, membrane fusion proteins, cell communication media, modulators of biological processes, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter, channel transporter, carrier activity, permease, secretase or secretion media, electron transporter, chaperone regulator, protein, Nucleic acid binding, transcriptional regulators, extracellular tissue and biogenesis regulators, and translational regulators).

In one embodiment, the target protein is a modulator of a signaling cascade associated with a known disease state. In another embodiment, the target protein mediates a condition by a mechanism other than modulating a signaling cascade. As further described herein, any protein in eukaryotic or microbial systems (including viruses, bacteria, or fungi) is a target for proteasome degradation using the present invention. The target protein may be a eukaryotic protein, and in some embodiments, a human protein.

In one embodiment, the target protein is RXR, DHFR, Hsp90, kinase, HDM2, MDM2, bromodomain-containing BET protein, HDAC, IDH1, Mcl-1, human lysine methyltransferase, nuclear hormone receptor, arene receptor (AHR), RAS, RAF, FLT, SMARC, KSR, NF2L, CTNB, CBLB, BCL.

In one embodiment, the bromodomain-containing protein has histone acetyltransferase activity.

In one embodiment, the bromodomain-containing protein is BRD2, BRD3, BRD4, BRDT, or ASH 1L.

In one embodiment, the bromodomain-containing protein is a non-BET protein.

In one embodiment, the non-BET protein is BRD7 or BRD 9.

In one embodiment, the FLT is not FLT 3. In one embodiment, the RAS is not RASK. In one embodiment, the RAF is not RAF 1. In one embodiment, the SMARC is not SMARC 2. In one embodiment, the KSR is not KSR 1. In one embodiment, NF2L is not NF2L 2. In one embodiment, the CTNB is not CTNB 1. In one embodiment, the BCL is not BCL 6.

In one embodiment, the target protein is selected from the group consisting of: EGFR, FLT3, RAF1, SMRCA2, KSR1, NF2L2, CTNB1, CBLB, BCL6, and RASK.

In another embodiment, the target protein is not selected from the group consisting of: EGFR, FLT3, RAF1, SMRCA2, KSR1, NF2L2, CTNB1, CBLB, BCL6, and RASK.

In one embodiment, the targeting ligand is an EGFR ligand, FLT3 ligand, RAF1 ligand, SMRCA2 ligand, KSR1 ligand, NF2L2 ligand, CTNB1 ligand, CBLB ligand, BCL6 ligand, or RASK ligand.

In one embodiment, the targeting ligand is not an EGFR ligand, FLT3 ligand, RAF1 ligand, SMRCA2 ligand, KSR1 ligand, NF2L2 ligand, CTNB1 ligand, CBLB ligand, BCL6 ligand, or RASK ligand.

The present invention is useful for treating a variety of disease states and/or conditions, including any disease state and/or condition in which protein imbalance and the patient would benefit from protein degradation.

For example, target proteins known as targets of human therapeutics may be selected, and when incorporated into the homeostatic receptor according to the present invention, such therapeutics may be used as targeting ligands such as proteins useful for restoring polygenic disease function, including e.g. B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl2/Bax and other partners in the apoptotic pathway (partner), C5a receptor, HMG-CoA reductase, PDE V phosphodiester type, PDE IV phosphodiesterase type 4, PDEI, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, Nitric Oxide (NO) synthase, cyclo-1, cyclo-oxygenase 2, 5HT receptor, dopamine receptor, G proteins such as Gq, histamine receptor, 5-lipoxygenase, trypsin-like protease serine synthetase, purine nucleoside kinase, GAGAGAP, trypsinokinase, glycogen synthase, luciferase receptor, tyrosine kinase, serine kinase, tyrosine kinase, serine kinase, tyrosine kinase, serine kinase, tyrosine kinase, serine kinase, tyrosine kinase.

In certain embodiments, the target protein is derived from a kinase that targets the ability of the ligand to bind or bind, including, but not limited to, tyrosine kinases (e.g., AATK, ABL, ALK, AXL, BLK, BMX, BTK, CSF1, CSK, DDR, EGFR, EPHA, EPHB, ERBB, FER, FES, FGFR, FLT, FRK, FYN, GSG, HCK, IGF1, ILK, INSRR, IRAK, ITK, JAK, KDR, KIT, KSR, LCK, LMTK, LTK, LYN, mat, mnk, metk, MLTK, mstk, mut, mtk, mut, NPR, tnrk, tprk.

In certain embodiments, the target protein is derived from a kinase to which a targeting ligand is capable of binding or binding, including, but not limited to, serine/threonine kinase (e.g., casein kinase 2, protein kinase a, protein kinase B, protein kinase, CaM kinase, AKT, ALK, Aurora a, Aurora B, Aurora C, CHK, CLK, DAPK, DMPK, ERK, GCK, GSK, HIPK, KHS, LKB, LOK, MAPKAPK, kamappk, MNK, PIM, MST, NDR, NEK, PAK, PIM, PLK, RIP, RSK, RIP, tsk, sgsk, tsuk, tsuko, or tako).

In certain embodiments, the target protein is derived from a kinase to which the targeting ligand is capable of binding or binding, including, but not limited to, cyclin dependent kinases such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK 13.

In certain embodiments, the target protein is derived from a kinase to which the targeting ligand is capable of binding or binding, including but not limited to leucine-rich repeat kinase (e.g., LRRK 2).

In certain embodiments, the target protein is derived from a kinase to which the targeting ligand is capable of binding or binding, including but not limited to a lipid kinase (e.g., PIK3CA, PIK3CB) or a sphingosine kinase (e.g., S1P).

In certain embodiments, the target protein is derived from a bromodomain-containing BET protein capable of binding or binding to a targeting ligand, including, but not limited to, ASH1, ATAD, BAZ1, BAZ2, BRD, BRDT, BRPF, BRWD, CECR, CREBBP, EP300, FALZ, GCN5L, KIAA1240, LOC93349, MLL, PB, PCAF, PHIP, PRKCBP, SMARCA, SP100, SP110, SP140, TAF1, TIF1, TRIM, wdynd, and MLL. In certain embodiments, the bromodomain-containing BET protein is BRD 4.

In certain embodiments, the target protein is derived from a nuclear protein to which the targeting ligand is capable of binding or binding, including, but not limited to, BRD2, BRD3, BRD4, antennapedia homeodomain protein, BRCA1, BRCA2, CCAAT enhanced binding protein, histone proteins, polycomb family proteins, high mobility family proteins, telomere binding protein, FANCA, FANCD2, FANCE, FANCF, hepatocyte nuclear factor, Mad2, NF- κ B, nuclear receptor co-activator, CREB binding protein, p55, p107, p130, Rb protein, p53, c-fos, c-jun, c-mdm2, c-myc, and c-rel.

In certain embodiments, the target protein is a member of the Retinoid X Receptor (RXR) family, and the disorder treated is a neuropsychiatric or neurodegenerative disorder. In certain embodiments, the target protein is a member of the Retinoid X Receptor (RXR) family and the disorder treated is schizophrenia.

In certain embodiments, the target protein is dihydrofolate reductase (DHFR) and the disorder treated is cancer. In certain embodiments, the target protein is dihydrofolate reductase (DHFR) and the condition being treated is microbial.

In certain embodiments, the target protein is dihydrofolate reductase (BaDHFR) from Bacillus anthracis, and the disorder being treated is anthrax.

In certain embodiments, the target protein is heat shock protein 90(HSP90), and the disorder being treated is cancer.

In certain embodiments, the target protein is a kinase or phosphatase, and the disorder treated is cancer.

In certain embodiments, the target protein is HDM2 and or MDM2, and the disorder being treated is cancer.

In certain embodiments, the target protein is a bromodomain-containing BET protein, and the disorder treated is cancer.

In certain embodiments, the target protein is lysine methyltransferase, and the disorder treated is cancer.

In certain embodiments, the target protein belongs to the RAF family and the disorder treated is cancer.

In certain embodiments, the target protein belongs to the FKBP family and the disorder treated is an autoimmune disorder. In certain embodiments, the target protein belongs to the FKBP family and the disorder treated is organ rejection. In certain embodiments, the target protein belongs to the FKBP family and the compound is administered prophylactically to prevent organ failure.

In certain embodiments, the target protein is an androgen receptor and the condition being treated is cancer.

In certain embodiments, the target protein is an estrogen receptor and the condition being treated is cancer.

In certain embodiments, the target protein is a viral protein and the condition being treated is a viral infection. In certain embodiments, the target protein is a viral protein and the disorder treated is HIV, HPV, or HCV.

In certain embodiments, the target protein is an AP-1 or AP-2 transcription factor, and the disorder treated is cancer.

In certain embodiments, the target protein is HIV protease and the condition being treated is HIV infection. In certain embodiments, the target protein is HIV integrase and the disorder treated is HIV infection. In certain embodiments, the target protein is HCV protease and the disorder treated is HCV infection. In certain embodiments, the treatment is prophylactic and the target protein is a viral protein.

In certain embodiments, the target protein is a member of the Histone Deacetylase (HDAC) family, and the disorder is a neurodegenerative disorder. In certain embodiments, the target protein is a member of the Histone Deacetylase (HDAC) family, and the disorder is huntington's disease, parkinson's disease, kennedy's disease, amyotrophic lateral sclerosis, rubinstein-tebi syndrome, or stroke.

In certain embodiments, a target protein as referred to herein is named by the gene that expresses it. One skilled in the art will recognize that when a gene is referred to as a target protein, the protein encoded by the gene is the target protein. For example, the ligand of protein SMCA2 encoded by SMRCA2 is referred to as a SMRCA2 targeting ligand.

Targeting ligands

In certain aspects, the targeting ligand is a ligand that binds, covalently or non-covalently, a target protein that has been selected for proteasomal degradation by a selected degrading determinant. A targeting ligand is a small molecule or moiety (e.g., a peptide, nucleotide, antibody fragment, aptamer, biomolecule, or other chemical structure) that binds to a target protein, and wherein the target protein is a disease mediator in a host as described in detail below. Exemplary targeting ligands are provided in figures 1A-8 PPPPP.

In one embodiment, the targeting ligand binds to an endogenous protein that has been selected for degradation as a means of achieving a therapeutic effect in the host. Illustrative targeting ligands include: RXR ligands, DHFR ligands, Hsp90 inhibitors, kinase inhibitors, HDM2 and MDM 2inhibitors, compounds targeting bromodomain-containing human BET proteins, HDAC inhibitors, ligands for MerTK, ligands for IDH1, ligands for Mcl-1, ligands for SMRCA2, ligands for EGFR, ligands for RAF, ligands for cRAF, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds and compounds targeting Aryl Hydrocarbon Receptors (AHR), and the like. Targeting ligands are also contemplated to include pharmaceutically acceptable salts, prodrugs, and isotopic derivatives thereof.

In certain aspects, the targeting ligand binds to a dehalogenase in a patient or subject or diagnostic assay and is an alkyl halide (preferably C)₁-C₁₀An alkyl group substituted with at least one halo group, preferably a halo group distal (i.e., distal to the linker) to the alkyl group. In other embodiments, the targeting ligand is a haloalkyl group, wherein the alkyl group typically ranges in size from about 1 or2 carbons in length to about 12 carbons, typically from about 2 to 10 carbons in length, typically from about 3 carbons to about 8 carbons in length, more typically from about 4 carbons to about 6 carbons in length. Haloalkyl groups are typically linear alkyl groups (although it is also possible to useBranched alkyl) and terminated with at least one halogen group (preferably a single halogen group, typically a single chlorine group). The haloalkyl PT group useful in the present invention preferably consists of the chemical structure- (CH)₂)_v-halogen represents, wherein v is any integer from 2 to about 12, typically from about 3 to about 8, more typically from about 4 to about 6. The halogen may be any halogen, but is preferably Cl or Br, more typically Cl.

In certain embodiments, the targeting ligand is a Retinoid X Receptor (RXR) agonist or antagonist. Non-limiting examples include retinol, retinoic acid, bexarotene, docosahexaenoic acid, WO 9929324, Canan Koch et al, a publication entitled "Identification of the First reliable X Receptor Homodimer Antagonst" (J.Med.chem.1996,39,3229-3234), WO 9712853, EP 0947496a1, compounds disclosed in WO 2016002968, and analogs thereof.

In certain embodiments, the targeting ligand is a DHFR agonist or antagonist. Non-limiting examples include folic acid, methotrexate, 8,10-dideaza tetrahydrofolic acid (8,10-dideaza tetrahydrofolate), Tian et al (chem. biol. drug Des.2016,87,444-454), compounds disclosed under the title "Synthesis, Inhibitors and Inhibitors Activities of N5-Substructured 8, 10-diazatetrahydro antigens", Kaur et al (Bio. Merg. chem. Lett.2016,26,1936-1940), compounds prepared under the title "Modification of the Lead Molecule: engineering in the antibiotic modified DNA Modification, International publication No. 2016022890, expression J. expression (inhibition et al, growth in the antibiotic modified DNA Modification of nucleotides, Modification of the amino acids of the antibiotic molecules, Modification of the amino acids of the genes, Modification of the amino acids of the derivatives of the amino acids of the genes, Modification of the amino acids of the genes, Modification of the amino acids of the genes, Modification of the genes of the amino acids of the genes of the strains, the derivatives of the amino acids of the genes, the derivatives of the amino acids of the genes, the amino acids of the derivatives of the genes, the amino acids of the genes, the derivatives of the amino acids of the genes of interest of the genes of interest of the genes of interest of the genes of interest of.

In certain embodiments, the targeting ligand is derived from an estrogen, an estrogen analog, a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of a partial or complete estrogen antagonist or agonist. Examples are the partial antiestrogens raloxifene and tamoxifen and the complete antiestrogen fulvestrant. Non-limiting examples of antiestrogenic compounds are provided in WO2014/19176, WO2013/090921, WO2014/203129, WO 2014/203132, assigned to Astra Zeneca, and US2013/0178445, assigned to olema pharmaceuticals, and U.S. patent numbers 9,078,871, 8,853,423 and 8,703,810, and US 2015/0005286, WO 2014/205136 and WO 2014/205138. Additional non-limiting examples of anti-estrogenic compounds include: SERMS such as norgestimate (anordrin), bazedoxifene, bronarestrol, clorenyl (chlorotrianisene), cromiphene citrate, cyclofenib, lasofoxifene, oxybimexifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane and letrozole; anti-gonadotrophins such as leuprorelin, cetrorelix, allylestrenol, chlormadinone acetate, cyproterone acetate, demegestone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethindrone acetate, progesterone, and spironolactone. Other estrogen ligands that may be used according to the present invention are described in U.S. Pat. nos. 4,418,068; 5,478,847, respectively; 5,393,763, respectively; and 5,457,117, WO2011/156518, U.S. patent nos. 8,455,534 and 8,299,112, U.S. patent No. 9,078,871; 8,853,423, respectively; 8,703,810, respectively; US 2015/0005286; and WO 2014/205138, US2016/0175289, US2015/0258080, WO 2014/191726, WO 2012/084711; WO 2002/013802; WO 2002/004418; WO 2002/003992; WO 2002/003991; WO 2002/003990; WO 2002/003989; WO 2002/003988; WO 2002/003986; WO 2002/003977; WO 2002/003976; WO 2002/003975; WO 2006/078834; US 6821989; US 2002/0128276; US 6777424; US 2002/0016340; US 6326392; US 6756401; US 2002/0013327; US 6512002; US 6632834; US 2001/0056099; US 6583170; US 6479535; WO 1999/024027; US 6005102; EP 0802184; US 5998402; US 5780497, US5880137, WO 2012/048058 and WO 2007/087684.

In certain embodiments, the targeting ligand is Vallee et al (J.Med.chem.2011,54,7206-7219), HSP90 Inhibitors identified in "Tricyclic Series of Heat Shock Protein 90(Hsp90) Inhibitors Part I: Discovery of Tricyclic Imidazo [4,5-C ] pyridine as Protein Inhibitors of the Hsp90 Molecular conduit", including YKB (N- [4- (3H-Imidazo [4,5-C ] pyridin-2-yl) -9H-fluoren-9-yl ] -succinamide), Brough et al (J.Med.chem.2008,51, 196-succinamide), H.Med.4, 5-Diarylimidazole Hsp 36 molecules: proteins modified peptides Inhibitors of the HSP90 Molecular conduit ", HSP90 Inhibitors identified in" 4, 5-Diarylimidazole Hsp 36: proteins Inhibitors, including 3H-ethyl-2-5-ethyl-5-phenyl-2-ethyl-2-5-dimethyl-2-ethyl-2-ethyl-5-morpholine-3-5-3-ethyl-5-3-ethyl-2-5-ethyl-2-one, 4-2-one, and 5-2-one, including the HSP-4- -4-ylmethyl) phenyl ] isoxazole-3-carboxamide), the HSP90 inhibitor geldanamycin ((4E,6Z,8S,9S,10E,12S,13R,14S,16R) -13-hydroxy-8, 14, 19-trimethoxy-4, 10,12, 16-tetramethyl-3, 20, 22-trioxo-2-azabicyclo [16.3.1] (derivatized) or any derivative thereof (e.g. 17-alkylamino-17-demethoxygeldanamycin ("17-AAG") or 17- (2-dimethylaminoethyl) amino-17-demethoxygeldanamycin ("17-DMAG")), or Wright et al (HSP. Chem. biol.2004,11, 775. 785) entitled "modified inhibitors of Structure-Activity Relationships in pure-basic inhibition Hsp90 binding of diabetes 90" (modified inhibitors), including the HSP90 inhibitor PU 3. Non-limiting examples of other Hsp90 targeting ligands include SNX5422, Reddy et al (clin. lymphoma myloma leuk.2013,13,385-391), titled "Phase I triple of the Hsp90 Inhibitor Pf-04929113(SNX5422) in additive substrates with recovery, reflective hematology malignanes", or NVP-AUY922, currently in Phase I clinical trials, whose anticancer Activity is assessed by Jensen et al (break Cancer Research: BCR 2008,10, R33-R33), titled "Nvp-Auy922: a moll milk 90 Inhibitor with Cancer Inhibitor in Preclinical Cancer model".

In certain embodiments, the targeting ligand is Millan et al (J.Med.chem.2011,54,7797-7814), the Kinase Inhibitors identified in "Design and Synthesis of introduced P38 Inhibitors for the Treatment of viral infection purification Disease", including Kinase Inhibitors Y1W and Y1X, Schenkel et al (J.Med.chem.2011,54,8440-8450), the Kinase Inhibitors identified in "Discovery of Point and high selectivity sensitive Kinase Janus 2Inhibitors", including compounds 6 and 0, van Eis et al (Bio.chem.3, 21, 2011 2. Kinase Inhibitors, the Kinase Inhibitors identified in "protein Inhibitors for the Treatment of protein Kinase", including compounds 6 and 0, the Kinase Inhibitors identified in "tissue Inhibitors J.C.7.chem.7367, 2011.2011.2011, the gene Inhibitors identified in" protein Inhibitors for the Treatment of protein Kinase, the Kinase Inhibitors identified in "protein Inhibitors for the Treatment of protein Kinase, the enzyme Inhibitors identified in" protein Inhibitors for the Treatment of protein Kinase, including protein Inhibitors of protein Kinase, III Inhibitors, III Inhibitors identified in U.C. 2, protein Inhibitors identified in No. 7, protein Inhibitors for the enzyme Inhibitors identified in No. 7, protein Inhibitors for the enzyme Inhibitors identified in No. 12, III, protein Inhibitors identified in No. 7, III, protein Inhibitors identified in No. 7, protein Inhibitors for protein Inhibitors, including the kinase inhibitors XK9 and NXP, afatinib, fostamatinib, gefitinib, lenvatinib, vandetanib, Gleevec, pazopanib, AT-9283, TAE684, nilotanib, NVP-BSK805, crizotinib, JNJ FMS, foretinib, OSI-027, OSI-930, or OSI-906.

In certain embodiments, the targeting ligand is Vassilev et al (Science 2004,303,844- & 848), entitled "In Vivo Activation of the P53 Pathway by Small-molecular anchors of Mdm2" and Schnekloth et al (bioorg. Med. chem. Lett.2008,18,5904- & 5908), entitled "Targeted Intracellular Protein Degradation Induced by a Small molecular inhibitor: Enroute to Chemical Proteomics" including the compounds nutlin-3, nutlin-2 and nutlin-1.

In certain embodiments, the targeting ligand is a human BET bromodomain targeting ligand identified in the title "Selective Inhibition of Bet Bromodomains," Filipakopoulos et al (Nature 2010,468,1067-1073), e.g., JQ 1; nicode et al (Nature 2010,468, 1119-; chung et al (J.Med.chem.2011,54, 3827-; hewings et al (J.Med.chem.2011,54,6761-6770) entitled "3,5-Dimethylisoxazoles Act as Acetyl-Lysine-maleic Bromodimom ligands"; dawson et al (Nature 2011,478, 529-plus 533) titled ligand identified in "inhibition of Bet retrieval to chromosome as an Effective Treatment for MLL-fusion Leukaemia"; or the ligands identified in the following patent applications US 2015/0256700, US 2015/0148342, WO2015/074064, WO 2015/067770, WO 2015/022332, WO 2015/015318 and WO 2015/011084.

In certain embodiments, the targeting ligand is Finnin et al (Nature 1999,401,188-193), entitled HDAC targeting ligand identified in "Structure of a Histone deacylase Homologue Bound to the Tsa and Sahainhibitors" or the ligand identified as formula (I) in PCT WO 0222577.

In certain embodiments, the targeting ligand is Chang et al (Nat Structure Mol Biol 2009,16,312-317), a human Lysine Methyltransferase ligand identified in entitled "Structure Bass for G9a-Like Protein Lysine methyl transferase enzyme inhibition by Bix-01294", Liu et al (J Med Chem2009,52,7950-7953), a ligand identified in entitled "Discovery of a2, 4-Diamino-7-amino koxquinalina force and Selective Inhibitor of Histone Lysine methyl transferase G9a", azacitidine, decitabine, or an analog thereof.

In certain embodiments, the targeting ligand is an angiogenesis inhibitor. Non-limiting examples of angiogenesis inhibitors include: GA-1, estradiol, testosterone, Oldhamitocystin, fumagillin, and the like.

In certain embodiments, the targeting ligand is an immunosuppressive compound. Non-limiting examples of immunosuppressive compounds include: AP21998, hydrocortisone, prednisone, prednisolone, methylprednisolone, beclomethasone dipropionate, methotrexate, cyclosporine, tacrolimus, actinomycin, and the like.

In certain embodiments, the targeting ligand is an Aryl Hydrocarbon Receptor (AHR) ligand. Non-limiting examples of AHR ligands include: apigenin, SR1, LGC006 and analogs thereof.

In certain embodiments, the targeting ligand is a MerTK or Mer targeting ligand. Non-limiting examples of MerTK targeting ligands are included in WO2013/177168 and WO2014/085225, both entitled "Pyrimidine Compounds for the Treatment of cancer" filed by Wang et al.

In certain embodiments, the targeting ligand is an EGFR ligand. In certain embodiments, the targeting ligand is an EGRF ligand selected from afatinib, dactinib, neratinib, bositinib, and canatinib or derivatives thereof.

In certain embodiments, the targeting ligand is FLT3 ligand. In certain embodiments, the targeting ligand is an FLT3 ligand selected from tandutinib, lestaurtinib, sorafenib, midostaurin, quinatinib, and criranib (Crenolanib).

In certain embodiments, the targeting ligand is a RAF inhibitor. In certain embodiments, the targeting ligand is a RAF inhibitor selected from dabrafenib, regorafenib, and vemurafenib. In certain embodiments, the targeting ligand is a cRAF inhibitor.

In some embodiments, the targeting ligand is an Ubc9 SUMO E2 ligase 5F6D targeting ligand, including but not limited to those described in "Insights Into the alkaline Inhibition of the SUMO E2 Enzyme Ubc 9." Hewitt, W.M., et al (2016) Angew. chem. int. ed. Engl.55: 5703-.

In another embodiment, the targeting ligand is a Tank1 targeting ligand, including but not limited to "Structure of human tankyrase 1in complex with small-molecule inhibitors PJ34 and XAV939." Kirby, C.A., Cheung, A., Fazal, A., Shultz, M.D., stamps, T, (2012) Actalystallogr, Sect.F 68: 115-118; and "Structure-Efficiency Relationship of [1,2,4] Triazol-3-ylamines as Novel Nicotinamide Isosperms that is not the inhibitor Tankyrases," Shultz, M.D. et al (2013) J.Med.Chem.56: 7049-.

In another embodiment, the targeting ligand is a SH2 Domain targeting ligand of pp60Src, including but not limited to Those described in "requisitions for specificity Binding of Low Affinity Inhibitors Fragments to the SH2 Domain of pp60Src identity to the same for High Affinity Binding of full Length Inhibitors," Gudran Lange et al, J.Med.chem.2003,46, 5184-.

In another embodiment, the targeting ligand is a Sec7 domain targeting ligand, including but not limited to those described in "the lysosol Protein Saponin B bonds chloroquinone," Huta, B.P. et al (2016) Chemmedchem11: 277.

In another embodiment, the targeting ligand is an activin-B targeting ligand, which includes, but is not limited to, those described in "the structure of cytomegavirus immune modulator UL141 high hlights structure Ig-fold versatility for receptor binding" I.Nemcovicova and D.M.Zajonc Actacryst. (2014). D70,851- "862.

IN another embodiment, the targeting ligand is a protein S100-A72 OWS targeting ligand, including but not limited to "2 WOS STRUCTURE OF HUMAN S100A7 IN COMPLEX WITH 2,6 ANS" DOI:10.2210/pdb2 WOS/pdb; and those described in "Identification and Characterization of Binding Sites on S100A7, aParticipation in Cancer and infection Pathways," Leon, R., Murray et al (2009) Biochemistry 48: 10591-.

In another embodiment, the targeting ligand is a phospholipase A2 targeting ligand, including but not limited to those described in "Structure-based design of the first site and selective inhibitor of human-systemic phospholipases A2" Schevitz, R.W. et al, Nat.Structure.biol.1995, 2, 458-465.

In another embodiment, the targeting ligand is a PHIP targeting ligand, including but not limited to "A PoissedFragmentLibrary enzymes Rapid Synthesis expanding stabilizing the first transported Inhibitors of PHIP (2), an exemplary Bromodeomain" Krojer, T.; those described in chem.sci.2016,7, 2322-2330, et al.

In another embodiment, the targeting ligand is a PDZ targeting ligand, including but not limited to those described in "Discovery of Low-Molecular-Weight Ligands for the AF6 PDZ Domain" Man esh Joshi et al, Angew.chem.int.Ed.2006,45, 3790-3795.

In another embodiment, the targeting ligand is a PARP15 targeting ligand, including but not limited to those described in "structural basis for Lock of ADP-ribosyltransferase Activity in Poly (ADP-ribose) Polymerase-13/Zinc Finger antibiotic protein." Karlberg, T. et al, (2015) J.biol.chem.290: 7336-7344.

In another embodiment, the targeting ligand is a PARP14 targeting ligand, including but not limited to "discovery Ligands for ADP-Ribosyl transfer via Docking-Based visual screening," Andersson, C.D. et al, (2012) J.Med.chem.55: 7706-; "Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors," Wahlberg, E.et al (2012) Nat. Biotechnol.30: 283-; "Discovery of Ligands for ADP-Ribosyl transfer glasses vision gating-Based visual screening", Andersson, C.D. et al (2012) J.Med.chem.55: 7706-.

In another embodiment, the targeting ligand is an MTH1 targeting ligand, including but not limited to those described in "MTH 1inhibition domains by prevention of the dNTP spot" HelgeGad et al Nature,2014,508, 215-221.

In another embodiment, the targeting ligand is an mPGES-1 targeting ligand, including but not limited to those described in "CrystalStructure of mPGES-1Inhibitor Complexes Form a Basis for the Rational design of the design Point antigen and Anti-inflammation therapeutics," Luz, J.G. et al, (2015) J.Med.chem.58: 4727-.

In another embodiment, the targeting ligand is a FLAP-5-lipoxygenase activating protein targeting ligand including, but not limited to, those described in "Crystal Structure of inhibitor-bound human 5-lipoxygenase-activating protein," Ferguson, A.D., McKeever, B.M., Xu, S., Wisniewski, D.D., Miller, D.K., Yamin, T.T., Spencer, R.H., Chu, L., Ujjainwala, F., Cunningham, B.R., Evans, J.F., Becker, J.W (2007) Science 317:510 one 512.

In another embodiment, the targeting ligand is a FA binding protein targeting ligand, including but not limited to those described in "AReal-World functional on Molecular design," Kuhn, B. et al J.Med.chem.2016,59, 4087-.

In another embodiment, the targeting ligand is a BCL2 targeting ligand, including but not limited to those described in "ABT-199, apotent and selective BCL-2inhibitor, achieves inhibitor activity while sparing tables," Souers, A.J. et al (2013) NAT.MED. (N.Y.)19: 202-.

In another embodiment, the targeting ligand is a NF2L2 targeting ligand.

In another embodiment, the targeting ligand is a CTNNB1 targeting ligand.

In another embodiment, the targeting ligand is a CBLB targeting ligand.

In another embodiment, the targeting ligand is a BCL6 targeting ligand.

In another embodiment, the targeting ligand is a RASK targeting ligand.

In another embodiment, the targeting ligand is a TNIK targeting ligand.

In another embodiment, the targeting ligand is a MEN1 targeting ligand.

In another embodiment, the targeting ligand is a PI3Ka targeting ligand.

In another embodiment, the targeting ligand is an IDO1 targeting ligand.

In another embodiment, the targeting ligand is an MCL1 targeting ligand.

In another embodiment, the targeting ligand is a PTPN2 targeting ligand.

In another embodiment, the targeting ligand is a HER2 targeting ligand.

In another embodiment, the targeting ligand is an EGFR targeting ligand. In one embodiment, the targeting ligand is selected from erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), lotterib (CO-1686), oxitinib (Tagrisso), oxitinib (Olita), naltretinib (ASP8273), naltretinib (EGF816), PF-06747775(Pfizer), erlotinib (BPI-2009), lenatinib (HKI-272; PB 272); avertinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988(Pfizer), tesevitinib (XL 647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006 and dacomitinib (PF-00299804; Pfizer). Linkers can be placed on these targeting ligands at any position that does not interfere with ligand binding to EGFR. Non-limiting examples of linker binding sites are provided in the following table. In one embodiment, the EGFR-targeting ligand binds to the L858R mutant of EGFR. In another embodiment, the EGFR-targeting ligand binds to a T790M mutant of EGFR. In another embodiment, the EGFR-targeting ligand binds a C797G or C797S mutant of EGFR. In one embodiment, the EGFR-targeting ligand is selected from erlotinib, gefitinib, afatinib, neratinib and dacatinib, and binds to the L858R mutant of EGFR. In another embodiment, the EGFR-targeting ligand is selected from the group consisting of oxitinib, lotinib, temotinib, naltretinib, PF-06747775, icotinib, neratinib, elvitinib, tarloxtinib, PF-0645998, Tesevatinib, Transtinib, WZ-3146, WZ8040, and CNX-2006, and binds to the T790M mutant of EGFR. In another embodiment, the EGFR-targeting ligand is EAI045 and binds to a C797G or C797S mutant of EGFR.

In one embodiment, the protein target and targeting ligand pair are selected by screening a library of ligands. Such screening is described in Duong-Ly et al, "Kinase Inhibitor Profile improvements unknown amplified mutation-Associated Mutant genes"; cell Reports 14, 772-.

In one embodiment, the protein target and targeting ligand pair is discovered by screening for background-specific degraded promiscuous kinase binding ligands. Non-limiting examples of targeting ligands are shown below and found in "Optimized chemical proteins Assay for Kinase Inhibitor Profiling" Guillame M dark ard, Fiona Pachl, Benjamin Ruprecht, Susan Klaeger, Stephanie Heinzlmier, Dominic Helm, HuichaoQiao, Xin Ku, Mathias Wilhelm, Thomas Kuehne, Zhixiang Wu, Antje Dittmann, CarstenHopf, Karl amer and Bernhard Kuster J. proteome Res, 2015,14(3), pp 1574 1586:

these ligands may be linked to a linker as shown below:

wherein:

r is the point of attachment of the linker.

According to the present invention, the targeting ligand is covalently bound to the linker in any manner that achieves the desired result of degrading the determinant for therapeutic use. In certain non-limiting embodiments, the targeting ligand is bound to a linker having a functional group that does not adversely affect binding of the ligand to the target protein. The following connection points are exemplary in nature and one of ordinary skill in the art will be able to determine different suitable connection points.

The non-limiting compounds described below exemplify some of these types of small molecule targeting ligands. In the table below, R is the point of attachment of the linker to the targeting ligand.

In certain embodiments, the targeting ligand is a compound of formula TL-I:

or a pharmaceutically acceptable salt thereof, wherein:

is composed of

A¹Is S or C ═ C;

A²is NRa⁵Or O;

nn1 is 0,1 or 2;

each Ra¹Independently is C₁-C₃Alkyl group, (CH)₂)_0-3-CN、(CH₂)_0-3-halogen, (CH)₂)_0-3-OH、(CH₂)_0-3-C₁-C₃Alkoxy or R;

Ra²is H, C₁-C₆Alkyl group, (CH)₂)_0-3-heterocyclyl (CH)₂)_0-3-phenyl or R, wherein heterocyclyl comprises one saturated 5-or 6-membered ring and 1-2 heteroatoms selected from N, O and S, and is optionally substituted by C₁-C₃Alkyl substituted, and wherein phenyl is optionally substituted by C₁-C₃Alkyl, CN, halogen, OH, C₁-C₃Alkoxy substitution;

nn2 is 0,1, 2 or 3;

each Ra³Independently is C₁-C₃Alkyl group, (CH)₂)_0-3-CN、(CH₂)_0-3-halogen or R;

Ra⁴is C₁-C₃An alkyl group;

Ra⁵is H or C₁-C₃An alkyl group; and is

R is the point of attachment of the linker.

Wherein the compound of formula TL-I is substituted with only one R.

In certain embodiments, the targeting ligand is a compound of formula TL-VIII or formula TL-IX:

wherein the compounds of formula TL-VIII or TL-IX are substituted with only one R.

In some embodiments of the present invention, the substrate is,

is composed of

In some embodiments of the present invention, the substrate is,

is composed of

In certain embodiments, A¹Is S.

In certain embodiments, A¹Is C ═ C.

In certain embodiments, A²Is NRa⁵. In further embodiments, Ra⁵Is H. In other embodiments, Ra⁵Is C₁-C₃Alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In further embodiments, Ra⁵Is methyl.

In certain embodiments, A²Is O.

In certain embodiments, nn1 is 0.

In certain embodiments, nn1 is 1.

In certain embodiments, nn1 is 2.

In certain embodiments, at least one Ra¹Is C₁-C₃Alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In a further embodiment, at least one Ra¹Is methyl. In a further embodiment, two Ra¹Is methyl.

In certain embodiments, at least one Ra¹Is CN, (CH)₂)-CN、(CH₂)₂-CN or (CH)₂)₃-CN. In a further embodiment, at least one Ra¹Is (CH)₂)-CN。

In certain embodiments, at least one Ra¹Is halogen (e.g., F, Cl or Br), (CH)₂) -halogen, (CH)₂)₂-halogen or (CH)₂)₃-a halogen. In a further embodiment, at least one Ra¹Is Cl, (CH)₂)-Cl、(CH₂)₂-Cl or (CH)₂)₃-Cl。

In certain embodiments, at least one Ra¹Is OH, (CH)₂)-OH、(CH₂)₂-OH or (CH)₂)₃-OH。

In certain embodiments, at least one Ra¹Is C₁-C₃Alkoxy (e.g., methoxy, ethoxy or propoxy), (CH)₂)-C₁-C₃Alkoxy group, (CH)₂)₂-C₁-C₃Alkoxy or (CH)₂)₃-C₁-C₃An alkoxy group. In certain embodiments, at least one Ra¹Is methoxy.

In further embodiments, Ra⁵Is H. In other embodiments, Ra⁵Is C₁-C₃Alkyl (e.g., methyl, ethyl, propyl, or isopropyl).

In further embodiments, Ra⁵Is H. In other embodiments, Ra⁵Is C₁-C₃Alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In other embodiments, Ra⁵Is methyl.

In certain embodiments, one Ra¹Is R.

In certain embodiments, Ra²Is H.

In certain embodiments, Ra²Is straight chain C₁-C₆Or branched C₃-C₆Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl)Pentyl or hexyl). In further embodiments, Ra²Is methyl, ethyl or tert-butyl.

In certain embodiments, Ra²Is heterocyclic radical, (CH)₂) -heterocyclyl (CH)₂)₂-heterocyclyl or (CH)₂)₃-a heterocyclic group. In further embodiments, Ra²Is (CH)₂)₃-a heterocyclic group. In other embodiments, heterocyclyl is selected from pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, and thiomorpholinyl. In other embodiments, the heterocycle is piperazinyl.

In certain embodiments, the heterocyclyl is substituted with C₁-C₃Alkyl (e.g., methyl, ethyl, propyl, or isopropyl) substituted.

In certain embodiments, Ra²Is phenyl, (CH)₂) -phenyl, (CH)₂)₂-phenyl or (CH)₂)₃-phenyl. In further embodiments, Ra²Is phenyl.

In certain embodiments, the phenyl group is substituted with C₁-C₃Alkyl (e.g., methyl, ethyl, propyl, or isopropyl) substituted. In certain embodiments, the phenyl is substituted with CN. In certain embodiments, the phenyl is substituted with a halogen (e.g., F, Cl or Br). In certain embodiments, the phenyl is substituted with OH. In certain embodiments, the phenyl group is substituted with C₁-C₃Alkoxy (e.g., methoxy, ethoxy, or propoxy) substituted.

In certain embodiments, Ra²Is R.

In certain embodiments, nn2 is 0.

In certain embodiments, nn2 is 1.

In certain embodiments, nn2 is 2.

In certain embodiments, nn2 is 3.

In certain embodiments, at least one Ra³Is C₁-C₃Alkyl (e.g. methyl)Alkyl, ethyl, propyl or isopropyl). In a further embodiment, at least one Ra³Is methyl.

In certain embodiments, at least one Ra³Is CN, (CH)₂)-CN、(CH₂)₂-CN or (CH)₂)₃-CN. In a further embodiment, at least one Ra³Is CN.

In certain embodiments, at least one Ra³Is halogen (e.g., F, Cl or Br), (CH)₂) -halogen, (CH)₂)₂-halogen or (CH)₂)₃-a halogen. In a further embodiment, at least one Ra³Is Cl, (CH)₂)-Cl、(CH₂)₂-Cl or (CH)₂)₃-Cl. In a further embodiment, at least one Ra³Is Cl.

In certain embodiments, one Ra³Is R.

In other embodiments, Ra⁵Is H. In other embodiments, Ra⁵Is C₁-C₃Alkyl (e.g., methyl, ethyl, propyl, or isopropyl).

In certain embodiments, Ra⁴Is C₁-C₃Alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In further embodiments, Ra⁴Is methyl.

In certain embodiments, Ra⁵Is H.

In certain embodiments, Ra⁵Is C₁-C₃Alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In further embodiments, Ra⁵Is methyl.

In some embodiments of the present invention, the substrate is,

is composed of

And A is¹Is S.

In some embodimentsIn (1),

is composed of

And A is¹Is C ═ C.

In some embodiments of the present invention, the substrate is,

is composed of

And A is¹Is C ═ C.

In certain embodiments, A²Is NH, and Ra²Is (CH)₂)_0-3-a heterocyclic group. In further embodiments, Ra²Is (CH)₂)₃-a heterocyclic group.

In certain embodiments, A²Is NH, and Ra²Is (CH)₂)_0-3-phenyl. In further embodiments, Ra²Is phenyl. In a further embodiment, the phenyl is substituted with OH.

In certain embodiments, A²Is NH, and Ra²Is R.

In certain embodiments, A²Is NH, and Ra²Is H or C₁-C₆An alkyl group. In further embodiments, Ra²Is C₁-C₄An alkyl group.

In certain embodiments, A²Is O, and Ra²Is H or C₁-C₆An alkyl group. In further embodiments, Ra²Is C₁-C₄An alkyl group.

Methods of treatment

The compounds of formula I, formula II, formula III, formula IV, formula V and formula VI are used in an effective amount to treat a host (including a human) in need thereof, optionally in a pharmaceutically acceptable carrier, to treat any of the conditions described herein.

As used herein, the terms "treatment", "treating" and "treatment" and the like are intended to refer to any effect that provides a benefit to a patient to whom a compound of the present invention may be administered, including the treatment of any disease state or condition modulated by the protein to which the compound of the present invention binds. Illustrative non-limiting disease states or conditions, including cancer, that can be treated using compounds according to the present invention are set forth herein.

The degreddeterminants of formula I, formula II, formula III and formula IV as described herein are useful for degrading a target protein that is a mediator of a disorder affecting a patient (e.g., a human). Control of the protein level obtained by the degron of formula I, formula II, formula III or formula IV provides treatment of a disease state or condition that is modulated by a target protein by reducing the level of the target protein in a cell (e.g., a patient cell). In certain embodiments, the method comprises administering an effective amount of a compound as described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, i.e., a pharmaceutically acceptable composition, optionally in combination with another biologically active agent or combination of agents.

The term "disease state or condition" when used in conjunction with a degron of formula I, formula II, formula III, or formula IV is intended to refer to any disease state or condition in which dysregulation of a protein occurs via a target protein (i.e., an increased amount of protein expressed in a patient), and in which degradation of such a protein in a patient can provide beneficial treatment or symptomatic relief to a patient in need thereof. In some cases, the disease state or condition may be cured. When administered in an effective amount to a host (including a human), the compounds of formula I, formula II, formula III and formula IV may, for example, be used as therapeutic agents to treat myeloproliferative or lymphoproliferative disorders such as B-cell or T-cell lymphoma, multiple myeloma, waldenstrom's macroglobulinemia, wiskott-aldrich syndrome or post-transplant lymphoproliferative disorder; immune disorders including autoimmune disorders such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus or type I diabetes; cardiac dysfunction diseases, including hypercholesterolemia; infectious diseases, including viral and/or bacterial infections; inflammatory disorders including asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, crohn's disease, or hepatitis.

The term "disease state or condition," for example when used in conjunction with a compound of formula V or formula VI, refers to any therapeutic indication that may be treated by modulating the activity of cereblon or a cereblon-containing E3 ligase, including but not limited to the known uses of the cereblon binders thalidomide, pomalidomide or lenalidomide. Non-limiting examples of the use of cereblon binding agents are multiple myeloma, hematologic disorders such as myelodysplastic syndrome, cancer, tumor, abnormal cell proliferation, HIV/AIDS, HBV, HCV, hepatitis, crohn's disease, sarcoidosis, graft versus host disease, rheumatoid arthritis, behcet's disease, tuberculosis, and myelofibrosis. Other indications include myeloproliferative or lymphoproliferative disorders such as B-cell or T-cell lymphoma, Waldants macroglobulinemia, Wisktt-Aldrich syndrome, or post-transplant lymphoproliferative disorder; immune disorders including autoimmune disorders such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, arthritis (particularly rheumatoid arthritis), lupus or type I diabetes; cardiac dysfunction diseases, including hypercholesterolemia; infectious diseases, including viral and/or bacterial infections, as generally described herein; inflammatory conditions including asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis and ulcerative colitis.

In another embodiment, the term "disease state or condition" refers to any disease state or condition mediated by Ikaros or Aiolos, such as cell proliferation, or any disease state or condition mediated by proteins downstream of Ikaros or Aiolos, and wherein degradation of such proteins in a patient can provide beneficial treatment or symptomatic relief to a patient in need thereof. In some cases, the disease state or condition may be cured. In an alternative embodiment, the "disease state" or "condition" refers to a disorder for which lenalidomide, pomalidomide or thalidomide is used for treatment.

In one embodiment, a compound as described herein, or a corresponding pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, can be used in an effective amount to treat a host, e.g., a human, suffering from a lymphoma or a lymphocytic or myelocytic proliferative disease or disorder. For example, a compound as described herein may be administered to a host having hodgkin's lymphoma or non-hodgkin's lymphoma. For example, the host may have a non-hodgkin lymphoma such as, but not limited to: AIDS-associated lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; recrystallizing NK cell lymphoma; burkitt's lymphoma; burkitt's lymphoma (small non-dividing cell lymphoma); diffuse small-cell lymphoma (DSCCL); chronic lymphocytic leukemia/small lymphocytic lymphoma; cutaneous T cell lymphoma; diffuse large B cell lymphoma; enteropathy-type T cell lymphoma; follicular lymphoma; hepatosplenic gamma-delta T cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; pediatric lymphoma; peripheral T cell lymphoma; primary central nervous system lymphoma; t cell leukemia; a transformed lymphoma; t cell lymphoma associated with therapy; langerhans cell histiocytosis; or wollaston macroglobulinemia.

In another embodiment, a compound as described herein, or a corresponding pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, can be used in an effective amount to treat a host, e.g., a human, suffering from hodgkin's lymphoma, such as, but not limited to: tuberous sclerosis Classical Hodgkin Lymphoma (CHL); mixed cell type CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; hodgkin lymphoma, predominantly lymphocytic; or HL with nodular lymphocytes as the main component.

In certain embodiments, the present invention provides for administering a compound of formula I, formula II, formula III, formula IV, formula V, or formula VI to a patient, e.g., a human, having an infectious disease, wherein the therapy targets a protein of the infectious agent, optionally in combination with another bioactive agent. The disease state or condition may be a disease caused by: the microbial agent or other exogenous agent such as a virus (as non-limiting examples, HIV, HBV, HCV, HSV, HPV, RSV, CMV, ebola virus, flavivirus, pestivirus, rotavirus, influenza, coronavirus, EBV, viral pneumonia, drug-resistant virus, avian influenza, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, or hepadnavirus), bacteria (gram negative, gram positive), fungus, protozoan, helminth, worm, prion, parasite, or other microorganism, or may be a disease state caused by the overexpression of a protein that results in a disease state and/or condition.

In certain embodiments, the condition treated with a compound of the invention is a disorder associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, can be induced by a variety of factors, including gene mutations, infection, exposure to toxins, autoimmune disorders, and benign or malignant tumors.

There are many skin conditions associated with cellular hyperproliferation. For example, psoriasis is a benign disease of human skin, often characterized by plaques covered with thickened scales. The disease is caused by an increase in epidermal cell proliferation of unknown cause. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.

Other hyperproliferative cellular disorders include vascular proliferative disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancers.

Angiogenic disorders include angiogenic and angiogenic disorders. The proliferation of smooth muscle cells during plaque development in vascular tissue leads to, for example, restenosis, retinopathy and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

Fibrotic conditions are often due to abnormal formation of extracellular matrix. Examples of fibrotic disorders include cirrhosis of the liver and mesangial proliferative cell disorders. Cirrhosis is characterized by an increase in extracellular matrix components, leading to the formation of hepatic scarring. Liver cirrhosis can cause diseases such as cirrhosis of the liver. An increase in extracellular matrix leading to hepatic scarring may also be caused by viral infections such as hepatitis. Adipocytes appear to play a major role in cirrhosis.

Mesangial disorders are caused by abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell disorders include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies.

Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered to be an autoimmune disease, which is thought to be associated with the activity of autoreactive T cells, and is caused by autoantibodies produced against collagen and IgE.

Other diseases that may include abnormal cell proliferation components include Behcet's syndrome, Acute Respiratory Distress Syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid tissue cell proliferation, septic shock and general inflammation.

Skin contact hypersensitivity and asthma are just two examples of immune responses that can be associated with significant morbidity. Other examples include atopic dermatitis, eczema, sjogren's syndrome (including keratoconjunctivitis sicca secondary to sjogren's syndrome), alopecia areata, allergic reactions due to arthropod bite reactions, crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may result in any one or more of the following symptoms or signs: itching, swelling, redness, blisters, scabbing, ulceration, pain, desquamation, cracking, hair loss, scarring or exudation of fluids involving the skin, eyes or mucous membranes.

In atopic dermatitis and eczema in general, immune-mediated infiltration of leukocytes (particularly infiltration of monocytes, lymphocytes, neutrophils and eosinophils) into the skin plays an important role in the pathogenesis of these diseases. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Immune-mediated leukocyte infiltration also occurs in sites other than the skin, such as the asthmatic airways and tear-producing ocular glands of keratoconjunctivitis sicca.

In one non-limiting embodiment, the compounds of the present invention are useful as topical agents for the treatment of: contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, sjogren's syndrome (including keratoconjunctivitis sicca secondary to sjogren's syndrome), alopecia areata, allergic reactions due to arthropod bite reactions, crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruption. The novel methods are also useful for reducing skin infiltration by malignant leukocytes in diseases such as mycosis fungoides. These compounds are also useful in treating aqueous deficient dry eye states (e.g., immune-mediated keratoconjunctivitis) in patients suffering therefrom by topically applying the compounds to the eye.

Disease states treatable with compounds according to the invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliated diseases, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, ametropia, infertility, Angelman's syndrome, canavan disease, celiac disease, charcot-marie-tooth disease, cystic fibrosis, duchenne muscular dystrophy, hemochromatosis, hemophilia, kleiniart syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease 1(PKD1) or 2(PKD2), pan-weidi's syndrome, sickle cell disease, tay-saxophone disease, turner's syndrome.

Other disease states or conditions that may be treated by the compounds according to the invention include alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, guillain-barre syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive compulsive disorders, panic disorders, parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, tourette syndrome, vasculitis.

Other disease states or conditions which may be treated by the compounds according to the invention also include ceruloplasmin deficiency, chondroplast insufficiency type II, achondroplasia, ichthyosis cuspidata, gaucher disease type 2, acute intermittent porphyria, canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, homogentisate urine, alexander disease, uraemia nigra urine brown yellow disease, α -antitrypsin deficiency, α -1 protease inhibitors, emphysema, amyotrophic lateral sclerosis, alexander-tourette syndrome, alexander disease, amelogenia, ALA dehydratase deficiency, anderson-fabry disease, androgen-insensitive syndrome, anemia, diffuse angiokeratoma, retinoblastoma (von peller-schin-schiff-gehler syndrome), alper-von willebrand syndrome, spidrome syndrome (spidrome syndrome), spider-like von willebrand-von willebrand syndrome, von willebrand's-willebrand syndrome, neuroleptical disorder (borneovascular disorder), tourette-type II), tourette-type neuroleptosis syndrome, tourette-type II, idiopathic nodular brunettle syndrome, leptinemia-type neuroleptinemia, neuroleptinemia-type II, neuroleptinomatosis-type II, leptinomatosis-type macroleprospinal syndrome, leptinomatosis-type neuroleptinomatosis, leptinomatosis-type neuroleptinomatosis, leptinomatosis-type 2-type neuroleptinomatosis, leptinomatosis, neuroleptinomatosis) Prion diseases, Bert-Hogger-Duobu syndrome, osteopathia (osteogenesis imperfecta), Broadthumb syndrome (BroadThumb-Hallux syndrome) (robustan-Tiber syndrome), bronze diabetes/bronze cirrhosis (hemochromatosis), bulbar muscular atrophy (Kennedy's disease), Berger-Groutz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatosis, torticollis dysplasia, biotin enzyme deficiency, cardiomyopathy (Nuonan syndrome), Cat syndrome, CAVD (congenital seminal duct deficiency), Caylor heart-surface syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, hypothyroidism, chondrotrophic disorder syndrome (dysplasia), otospondyloepiphyseal epiphyseal dysepiphyseal, Lestigmatosis-Nicothan syndrome, galactosemia, Ehryss-Duchenopodium syndrome, lethal dysplasia-koehne syndrome, Kernea-Leptorin syndrome, (Ginkrin-Tourethrophymatosis syndrome), Graptophytin syndrome, Graptophymatosis, Graptophytin syndrome, Grapton-Graptophytin syndrome, Grapton-Grapton syndrome, Grapto,Friedreich's ataxia-familial paroxysmal uveitis, delayed skin porphyria, familial pressure sensitive neuropathy, Primary Pulmonary Hypertension (PPH), pancreatic fibrocystic disease, fragile X syndrome, galactosemia, hereditary brain disorders, giant cell hepatitis (neonatal hemochromatosis), grenburg-strandberg syndrome (pseudoxanthoma elasticum), radiculopathy (congenital erythropoietic porphyria), hemochromatosis, hallux syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), von hippel-lindau disease (von hippel-lindau disease), huntington's disease, hahnsen-gilford's premature senility syndrome (premature senility), hyperandrogenism, chondrodynoplasia, hypopigmentation anemia, immune system disorders (including X-linked severe combined immunodeficiency), Inflixie-astley syndrome, jackson-westh syndrome, burbert syndrome, lesch-niemann syndrome, jackson-westh syndrome, nephropathy (including hyperoxaluria), kleinefelter syndrome, knighter dysplasia, interstitial dementia, langer-saldino chondroproliferation insufficiency, ataxia telangiectasia, lingci syndrome, lysyl hydroxylase deficiency, machado-joseph disease, metabolic disorders (including knight dysplasia), mavan syndrome, dyskinesia, muert-wilson syndrome, cystic fibrosis, minck syndrome, neurofibromatosis, southern-insteine syndrome, southern-snelvir dysplasia, niemann-pick disease, nokia-nevrich syndrome (faffir syndrome), Osler-Weber-Landskin's disease, Piez-Jagges syndrome, polycystic kidney disease, bony fibrous dysplasia (McJohn-Orlbilt syndrome), Piez-Jagges syndrome, Prider-Labard-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Leishmanian-Nihan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, premature senility (Hazarn Gilford's premature senility syndrome), progressive chorea, chronic hereditary (Huntington) (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyrinopathy, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthoma elasticum)Rb (retinoblastoma), rekinnhausen disease (neurofibromatosis type I), recurrent polyhedrosis, retinal disorders, retinoblastoma, reiter syndrome, RFALS type 3, rekins syndrome, lyre-wear syndrome, luxi-livid syndrome, severe achondroplasia with delayed development and acanthosis nigricans (sadda), li-fluminella syndrome, mammary sarcoma, leukemia and adrenal (SBLA) syndrome, nodular sclerosis (tuberous sclerosis), SDAT, congenital SED (congenital spondyloepiphyseal dysplasia), stredwelksweck SED (sterd-verwack type spondyloepiphyseal dysplasia), SEDc (congenital spondyloepiphyseal dysplasia), SEMD, stredwelkuck-schwang dysgenesis, stringpakus syndrome, nonphagia (stredwelkus-schwang type epiphyseal dysgenesis syndrome), stringynia syndrome, stringynia-lepsy syndrome, trephine-schwang syndrome, trephine-voporphin syndrome, trephine-vophilia (trephine-schwann-voxil syndrome), trephine syndrome, trephine-type neuropsyis syndrome, trephine-type isopsytosis syndrome, trephine-type isopsytosis, trephine syndrome, trephine-type isopsytosis syndrome, trephine-induced neuropsyis, trephine syndrome, trephine-induced neuropsyis, trephine-induced neuropsychiasis, trephine syndrome, trephine-

Syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo fleelius syndrome, weissenbach-zwey ü ller syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disease, weissenbach-zwey ü ller syndrome, xeroderma pigmentosum and the like.

The term "tumor" or "cancer" is used throughout the present specification to denote the following pathological process: it leads to the formation and growth of cancerous or malignant tumors (i.e., abnormal tissue that grows generally more rapidly than normal by cellular proliferation and continues to grow after stimulation to initiate new growth ceases). Malignant tumors exhibit a partial or complete lack of structural architecture and functional coordination in the case of normal tissue, and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and cause death of the patient unless adequately treated. As used herein, the term tumor is used to describe all cancer disease states and includes or encompasses pathological processes associated with malignant hematogenous, ascites and solid tumors. Exemplary cancers that can be treated by the compounds of the invention, alone or in combination with at least one other anticancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer; leukemia; benign and malignant lymphomas, especially burkitt's lymphoma and non-hodgkin's lymphoma; benign and malignant melanoma; a myeloproliferative disease; sarcomas, including ewing's sarcoma, angiosarcoma, kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelial tumors, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pinealocytic tumor, meningioma, meningiosarcoma, neurofibroma, and schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratoma. Additional cancers that may be treated using compounds according to the invention include, for example, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, burkitt lymphoma, B-cell ALL, philadelphia chromosome positive ALL, and philadelphia chromosome positive CML.

The term "biologically active agent" is used to describe an agent other than a compound according to the present invention, which is used as a biologically active agent in combination with a compound of the present invention to help achieve the intended therapeutic, inhibitory and/or prophylactic/preventative treatment for which the compound of the present invention is used. The biologically active agents preferably used herein include those having pharmacological activity similar to that of the compound of the present invention used or administered, and include, for example, anticancer agents, antiviral agents (including especially anti-HIV agents and anti-HCV agents), antibacterial agents, antifungal agents and the like.

Combination therapy

The compounds of formula I, formula II, formula III, formula IV, formula V, and formula VI may be used alone or in combination in effective amounts to treat a host (e.g., a human) suffering from a disorder as described herein.

The disclosed compounds described herein can be used in an effective amount, alone or in combination with another compound of the invention or another biologically active agent, to treat a host (e.g., a human) suffering from a condition described herein.

The term "bioactive agent" is used to describe an agent other than a selected compound according to the present invention, which may be used in combination or alternation with a compound of the present invention to achieve a desired therapeutic result. In one embodiment, the compound of the invention and the biologically active agent are administered within overlapping time periods in such a manner that they are active in vivo, e.g., time periods with overlapping Cmax, Tmax, AUC, or other pharmacokinetic parameters. In another embodiment, the compound of the invention and the biologically active agent are administered to a host in need thereof that does not have overlapping pharmacokinetic parameters, however, one has a therapeutic effect on the therapeutic effect of the other.

In one aspect of this embodiment, the biologically active agent is an immunomodulatory agent including, but not limited to, checkpoint inhibitors, including, as non-limiting examples, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V-domain Ig suppressor of T cell activation (VISTA) inhibitors, small molecules, peptides, nucleotides, or other inhibitors. In certain aspects, the immunomodulatory agent is an antibody, e.g., a monoclonal antibody.

PD-1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor and thereby inhibit immunosuppression include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224(AstraZeneca and Medamene), PF-06801591(Pfizer), MEDI0680(AstraZeneca), PDR001(Novartis), REGN2810(Regeneron), SHR-12-1(Jiangsu Hengrui medicinal Company and Incyte Corporation), TSR-042(Tesaro) and PD-L1/VISTA inhibitor CA-170(Curis Inc.). PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor and thereby inhibit immunosuppression include, for example, Attributumab (Teventriq), Duvacizumab (AstraZeneca and MedImmune), KN035(Alphamab), and BMS-936559(Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and Medmelimune), AGEN1884, and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016(Bristol-Myers Squibb), GSK2831781(GlaxoSmithKline), IMP321(Prima BioMed), LAG525(Novartis), and the dual PD-1 and LAG-3 inhibitors MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

In yet another embodiment, one of the active compounds described herein may be used in combination or alternation in an effective amount with an effective amount of an estrogen inhibitor, including but not limited to a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader or another form of a partial or complete estrogen antagonist or agonist, for the treatment of abnormal tissue of the female reproductive system, such as breast, ovarian, endometrial or uterine cancer. Some antiestrogens such as raloxifene and tamoxifen retain some estrogen-like effects, including estrogen-like stimulation of uterine growth, and also in some cases, retain estrogen-like effects during breast cancer progression, which actually stimulate tumor growth. In contrast, fulvestrant, a complete antiestrogen, has no estrogen-like effect on the uterus and is effective against tamoxifen resistant tumors. Non-limiting examples of anti-estrogen compounds are provided in WO2014/19176 assigned to Astra Zeneca; WO2013/090921, WO2014/203129, WO 2014/313232; and US2013/0178445 assigned to olema pharmaceuticals; and U.S. patent nos. 9,078,871, 8,853,423, and 8,703,810; and US 2015/0005286, WO 2014/205136 and WO 2014/205138. Additional non-limiting examples of anti-estrogenic compounds include: SERS such as dicarballyl carbonate, bazedoxifene, bromphenestriol (broparestrol), clorenyl, clomiphene citrate, cyclofenib, lasofoxifene, or meloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane and letrozole; and gonadotrophins such as leuprorelin, cetrorelix, allylestrenol, chlormadinone acetate, cyproterone acetate, demegestone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethindrone acetate, progesterone, and spironolactone. Other estrogen ligands that may be used according to the present invention are described in U.S. Pat. nos. 4,418,068; 5,478,847, respectively; 5,393,763, respectively; and 5,457,117, WO2011/156518, U.S. patent nos. 8,455,534 and 8,299,112, U.S. patent No. 9,078,871; 8,853,423, respectively; 8,703,810, respectively; US 2015/0005286; and WO 2014/205138, US2016/0175289, US2015/0258080, WO 2014/191726, WO 2012/084711; WO 2002/013802; WO 2002/004418; WO 2002/003992; WO 2002/003991; WO 2002/003990; WO 2002/003989; WO 2002/003988; WO 2002/003986; WO 2002/003977; WO 2002/003976; WO 2002/003975; WO 2006/078834; US 6821989; US 2002/0128276; US 6777424; US 2002/0016340; US 6326392; US 6756401; US 2002/0013327; US 6512002; US 6632834; US 2001/0056099; US 6583170; US 6479535; WO 1999/024027; US 6005102; EP 0802184; US 5998402; US 5780497, US5880137, WO 2012/048058 and WO 2007/087684.

In another embodiment, the active compounds described herein may be administered in an effective amount in combination or alternation with an effective amount of an androgen (e.g., testosterone) inhibitor, including but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of a partial or complete androgen antagonist, for the treatment of abnormal tissue of the male reproductive system, such as prostate cancer or testicular cancer. In one embodiment, the prostate cancer or testicular cancer is androgen resistant. Non-limiting examples of antiandrogen compounds are provided in WO2011/156518 and U.S. patent nos. 8,455,534 and 8,299,112. Additional non-limiting examples of antiandrogen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

In one embodiment, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, aragoninib, ceritinib, TAE684(NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entritinib (RXDX-101), and AP 26113.

In one embodiment, the biologically active agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rockitinib (CO-1686), oxitinib (Tagrisso), oitinib (Olita), naltretinib (ASP8273), nanozatinib (EGF816), PF-06747775(Pfizer), erlotinib (BPI-2009), lenatinib (HKI-272; PB 272); afatinib (AC0010), EAI045, tarloxotinib (TH-400; PR-610), PF-06459988(Pfizer), tesevatinib (XL 647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006 and dacomitinib (PF-00299804; Pfizer).

In one embodiment, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

In one embodiment, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab tiuxetan, tositumomab, and ocrelizumab.

In one embodiment, the biologically active agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tofacitinib.

In one embodiment, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199(4- [4- [ [2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-en-1-yl ] methyl ] piperazin-l-yl ] -N- [ [ 3-nitro-4- [ [ (tetrahydro-2H-pyran-4-yl) methyl ] amino ] phenyl ] sulfonyl ] -2- [ (lH-pyrrolo [2,3-b ] pyridin-5-yl) oxy ] benzamide), ABT-737(4- [4- [ [2- (4-chlorophenyl) phenyl ] methyl ] piperazin-1-yl ] -N- [4- [ [ (2R) -4- (dimethylamino) -1-phenylsulfonylbutazone- 2-yl ] amino ] -3-nitrophenyl ] sulfonylbenzamide) (navitoclax), ABT-263((R) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [ l, l' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((4-morpholino-1- (phenylthio) but-2-yl) amino) -3 ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide), GX15-070(obatoclax methanesulfonate, (2Z) -2- [ (5Z) -5- [ (3, 5-dimethyl-lH-pyrrol-2-yl) methylene ] -4-methoxypyrrole-2- Subunit ] indole; methanesulfonic acid))), 2-methoxy-antimycin a3, YC137(4- (4, 9-dioxo-4, 9-dihydronaphtho [2,3-d ] thiazol-2-ylamino) -phenyl ester), pogosin, 2-amino-6-bromo-4- (1-cyano-2-ethoxy-2-oxoethyl) -4H-chromene-3-carboxylic acid ethyl ester, nilotinib-d 3, TW-37(N- [4- [ [2- (1, 1-dimethylethyl) phenyl ] sulfonyl ] phenyl ] -2,3, 4-trihydroxy-5- [ [2- (1-methylethyl) phenyl ] methyl ] benzamide), gossypolone (ApoG2), HA14-1, AT101, sabutocrax, gambogic acid or G3139 (Obblimers).

In one embodiment, the bioactive agent is a kinase inhibitor. In one embodiment, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's Tyrosine Kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.

Examples of PI3 kinase inhibitors include, but are not limited to, wortmannin, chloronorviridin, perifosine, Idelalisib, Picclisib, Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032(Taselisib) (2- [4- [2- (2-isopropyl-5-methyl-1, 2, 4-triazol-3-yl) -5, 6-dihydroimidazo [1,2-d ] [1,4] benzoxazin-9-yl ] pyrazol-1-yl ] -2-methylpropanamide), MLN-1117((2R) -1-phenoxy-2-butylhydro (S) -methylphosphonate, or methyl (oxo) { [ (2R) -l-phenoxy-2-butyl ] oxy } phosphonium)), (2, BYL-719((2S) -N1- [ 4-methyl-5- [2- (2,2, 2-trifluoro-1, 1-dimethylethyl) -4-pyridinyl ] -2-thiazolyl ] -1, 2-pyrrolidinedicarboxamide), GSK2126458(2, 4-difluoro-N- {2- (methyloxy) -5- [4- (4-pyridazinyl) -6-quinolinyl ] -3-pyridinyl } benzenesulfonamide) (omipalisib), TGX-221 ((+ -) -7-methyl-2- (morpholin-4-yl) -9- (l-phenylaminoethyl) -pyrido [ l,2-a ] -pyrimidin-4-one); and methods of making and using the same, GSK2636771 (2-methyl-1- (2-methyl-3- (trifluoromethyl) benzyl) -6-morpholino-lH-benzo [ d ] imidazole-4-carboxylic acid dihydrochloride), KIN-193((R) -2- ((l- (7-methyl-2-morpholino-4-oxo-4H-pyrido [1,2-a ] pyrimidin-9-yl) ethyl) amino) benzoic acid), TGR-1202/RP5264, GS-9820((S) -l- (4- ((2- (2-aminopyrimidin-5-yl) -7-methyl-4-hydroxypropan-1-one), GS-1101 (5-fluoro-3-phenyl-2- ([ S) ] -1- [ 9H-purin-6-ylamino ] -propyl) -3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR 24409 (N- (4- (N- (3- ((3, 5-dimethoxyphenyl) amino) quinoxalin-2-yl) sulfamoyl) phenyl) -3-methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N- (7-methoxy-8- (3-morpholinopropoxy) -2, 3-dihydroimidazo [ l,2-c ] quinazolinone), AS 252424(5- [ l- [5- (4-fluoro-2-hydroxy-phenyl) -furan-2-yl ] -methyl- (Z) -ylidene ] -thiazolidine -2, 4-dione), CZ 24832(5- (2-amino-8-fluoro- [ l,2,4] triazolo [ l,5-a ] pyridin-6-yl) -N-tert-butylpyridine-3-sulfonamide), Buparlisib (5- [2, 6-bis (4-morpholinyl) -4-pyrimidinyl ] -4- (trifluoromethyl) -2-pyridylamine), GDC-0941(2- (lH-indazol-4-yl) -6- [ [4- (methylsulfonyl) -l-piperazinyl ] methyl ] -4- (4-morpholinyl) thieno [3,2-d ] pyrimidine), GDC-0980((S) -1- (4- ((2- (2-aminopyrimidin-5-yl) -7-methyl-4-morpholinothieno [3,2-d ] pyrimidin-6 yl) methyl) piperazin-l-yl) -2-hydroxypropan-l-one (also known as RG7422)), SF1126((8S,14S,17S) -14- (carboxymethyl) -8- (3-guanidinopropyl) -17- (hydroxymethyl) -3,6,9,12, 15-pentaoxo-1- (4- (4-oxo-8-phenyl-4H-chromen-2-yl) morpholino-4-ium) -2-oxa-7, 10,13, 16-tetraazaoctadeca-18-oate), PF-05212384(N- [4- [ [4- (dimethylamino) -1-piperidinyl ] carbonyl Yl ] phenyl ] -N' - [4- (4, 6-di-4-morpholinyl-l, 3, 5-triazin-2-yl) phenyl ] urea) (gedatolisib), LY3023414, BEZ235 (2-methyl-2- {4- [ 3-methyl-2-oxo-8- (quinolin-3-yl) -2, 3-dihydro-lH-imidazo [4,5-c ] quinolin-l-yl ] phenyl } propionitrile) (dapoxib), XL-765(N- (3- (N- (3, 5-dimethoxyphenylamino) quinoxalin-2-yl) sulfamoyl) phenyl) -3-methoxy-4-methylbenzamide), And GSK1059615(5- [ [4- (4-pyridyl) -6-quinolinyl ] methylene ] -2, 4-thiazolidinedione), PX886([ (3aR,6E,9S,9aR,10R,11aS) -6- [ [ bis (prop-2-enyl) amino ] methylene ] -5-hydroxy-9- (methoxymethyl) -9a,11 a-dimethyl-l, 4, 7-trioxo-2, 3,3a,9,10, ll-hexahydroindeno [4,5h ] isochromen-10-yl ] acetate (also known aS sonolisib)), LY294002, D8186, PF-4989216, pilalasib, GNE-317, PI-3065, PI-103, NU7441(KU-57788), HS 173, VS-5584(SB2343) CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226(NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; 7422), and the structures described in WO 2014/071109.

Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (ibruvica)^TM) (1- [ (3R) -3- [ 4-amino-3- (4-phenoxy-phenyl) pyrazolo [3,4-d]Pyrimidin-1-yl]Piperidin-1-yl radical]Prop-2-en-1-one), inhibitors of dianilinopyrimidinyl such as AVL-101 and AVL-291/292(N- (3- ((5-fluoro-2- ((4- (2-methoxyethoxy) phenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide) (Avila Therapeutics) (see U.S. patent publication No. 2011/0117073, incorporated herein in its entirety), dasatinib ([ N- (2-chloro-6-methylphenyl) -2- (6- (4- (2-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide)]LFM-A13(α -cyano- β -hydroxy- β -methyl-N- (2, 5-dibromophenyl) acrylamide), GDC-0834([ R-N- (3- (6- (4- (1, 4-dimethyl-3-oxopiperazin-2-yl) phenylamino) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -2-methylphenyl) -4,5,6, 7-tetrahydrobenzo [ b]Thiophene-2-carboxamides]CGI-5604- (tert-butyl) -N- (3- (8- (phenylamino) imidazo [1, 2-a)]Pyrazin-6-yl) phenyl) benzamide, CGI-1746(4- (tert-butyl) -N- (2-methyl-3- (4-methyl-6- ((4- (morpholine-4-carbonyl) phenyl) amino) -5-oxo-4, 5-dihydropyrazin-2-yl) phenyl) benzamide), CNX-774(4- (4- ((4- ((3-acrylamidophenyl) amino) -5-fluoropyrimidin-2-yl) amino) phenoxy) -N-methylpyridinamide), CTA056 (7-benzyl-1- (3- (piperidin-1-yl) propyl) -2- (4).- (pyridin-4-yl) phenyl) -1H-imidazo [4,5-g]Quinoxalin-6 (5H) -one), GDC-0834((R) -N- (3- (6- ((4- (1, 4-dimethyl-3-oxopiperazin-2-yl) phenyl) amino) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -2-methylphenyl) -4,5,6, 7-tetrahydrobenzo [ b]Thiophene-2-carboxamide), GDC-0837((R) -N- (3- (6- ((4- (1, 4-dimethyl-3-oxopiperazin-2-yl) phenyl) amino) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -2-methylphenyl) -4,5,6, 7-tetrahydrobenzo [ b ] a]Thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059(ONO Pharmaceuticals), PRT062607(4- ((3- (2H-1,2, 3-triazol-2-yl) phenyl) amino) -2- (((1R,2S) -2-aminocyclohexyl) amino) pyrimidine-5-carboxamide hydrochloride), QL-47(1- (1-acryloylindolin-6-yl) -9- (1-methyl-1H-pyrazol-4-yl) benzo [ H ] H][1,6]Naphthyridin-2 (1H) -one), and RN486 (6-cyclopropyl-8-fluoro-2- (2-hydroxymethyl-3- { 1-methyl-5- [5- (4-methyl-piperazin-1-yl) -pyridin-2-ylamino)]-6-oxo-1, 6-dihydro-pyridin-3-yl } -phenyl) -2H-isoquinolin-1-one), and other molecules capable of inhibiting BTK activity, such as akinley et al, Journal of Hematology&Those BTK inhibitors disclosed in Oncology,2013,6:59, the entire contents of which are incorporated herein by reference.

Syk inhibitors include, for example, Cerdulatinib (4- (cyclopropylamino) -2- ((4- (4- (ethylsulfonyl) piperazin-1-yl) phenyl) amino) pyrimidine-5-carboxamide), entospletinib (6- (1H-indazol-6-yl) -N- (4-morpholinophenyl) imidazo [1,2-a ] pyrazin-8-amine), fostamitinib ([6- ({ 5-fluoro-2- [ (3,4, 5-trimethoxyphenyl) amino ] -4-pyrimidinyl } amino) -2, 2-dimethyl-3-oxo-2, 3-dihydro-4H-pyrido [3,2-b ] [1,4] oxazin-4-yl ] methyl dihydrogen phosphate), fostamatinib disodium salt ((6- ((5-fluoro-2- ((3,4, 5-trimethoxyphenyl) amino) pyrimidin-4-yl) amino) -2, 2-dimethyl-3-oxo-2H-pyrido [3,2-b ] [1,4] oxazin-4 (3H) -yl) sodium methyl phosphate), BAY 61-3606(2- (7- (3, 4-dimethoxyphenyl) -imidazo [1,2-c ] pyrimidin-5-ylamino) -nicotinamide HCl), RO9021(6- [ (1R,2S) -2-amino-cyclohexylamino ] -4- (5, 6-dimethyl-pyridin-2-ylamino) -pyridazine-3-carboxylic acid amide), Imatinib (gleevec; 4- [ (4-methylpiperazin-1-yl) methyl ] -N- (4-methyl-3- { [4- (pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl) benzamide), staurosporine, GSK143(2- (((3R,4R) -3-aminotetrahydro-2H-pyran-4-yl) amino) -4- (p-tolylamino) pyrimidine-5-carboxamide), PP2(1- (tert-butyl) -3- (4-chlorophenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine), PRT-060318(2- (((1R,2S) -2-aminocyclohexyl) amino) -4- (m-tolylamino) pyrimidine Pyridine-5-carboxamide), PRT-062607(4- ((3- (2H-1,2, 3-triazol-2-yl) phenyl) amino) -2- (((1R,2S) -2-aminocyclohexyl) amino) pyrimidine-5-carboxamide hydrochloride), R112(3,3' - ((5-fluoropyrimidin-2, 4-diyl) bis (azanediyl)) diphenol), R348 (3-ethyl-4-methylpyridine), R406(6- ((5-fluoro-2- ((3,4, 5-trimethoxyphenyl) amino) pyrimidin-4-yl) amino) -2, 2-dimethyl-2H-pyrido [3,2-b ] [1,4] oxazin-3 (4H) -one, piceatannol (3-hydroxyresveratrol), YM193306 (see Singh et al Discovery and Development of spread type Kinase (SYK) inhibitor, J.Med.chem.2012,55,3614-, med. chem.2012,55, 3614-.

In one embodiment, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known and include, for example, trametinib/GSKl 120212(N- (3- { 3-cyclopropyl-5- [ (2-fluoro-4-iodophenyl) amino ] -6, 8-dimethyl-2, 4, 7-trioxo-3, 4,6, 7-tetrahydropyrido [4,3-d ] pyrimidin-l (2H-yl } phenyl) acetamide), semetinib (6- (4-bromo-2-chloroanilino) -7-fluoro-N- (2-hydroxyethoxy) -3-methylbenzimidazole-5-carboxamide), pimasetib/AS 703026/MSC1935369((S) -N- (2, 3-dihydroxypropyl) -3- ((2-fluoro-4-iodophenyl) amino) isonicotinic acid Amide), XL-518/GDC-0973(l- ({3, 4-difluoro-2- [ (2-fluoro-4-iodophenyl) amino ] phenyl } carbonyl) -3- [ (2S) -piperidin-2-yl ] azetidin-3-ol), refametinib/BAY869766/RDEAl19(N- (3, 4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide), PD-0325901(N- [ (2R) -2, 3-dihydroxypropoxy ] -3, 4-difluoro-2- [ (2-fluoro-4-iodophenyl) amino ] -benzamide), TAK733((R) -3- (2, 3-dihydroxypropyl) -6-fluoro-5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3-d ] pyrimidine-4, 7(3H,8H) -dione), MEK162/ARRY438162(5- [ (4-bromo-2-fluorophenyl) amino ] -4-fluoro-N- (2-hydroxyethoxy) -1-methyl-1H-benzimidazole-6-carboxamide), R05126766(3- [ [ 3-fluoro-2- (methylsulfamoylamino) -4-pyridyl ] methyl ] -4-methyl-7-pyrimidin-2-yloxyen-2-one), WX-554, R04987655/CH4987655(3, 4-difluoro-2- ((2-fluoro-4-iodophenyl) amino) -N- (2-hydroxyethoxy) -5- ((3-oxo-l, 2-oxazacyclohex-2-yl) methyl) benzamide), or AZD8330(2- ((2-fluoro-4-iodophenyl) amino) -N- (2 hydroxyethoxy) -1, 5-dimethyl-6-oxo-l, 6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352(CI-1040), GDC-0623, BI-847325, cobicistinib, PD98059, BIX 02189, BIX 02188, biimetiniib, SL-327, TAK-733, PD 318088.

In one embodiment, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, Vemurafinib (N- [3- [ [5- (4-chlorophenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] carbonyl ] -2, 4-difluorophenyl ] -1-propanesulfonamide), sorafenib tosylate (4- [4- [ [ 4-chloro-3- (trifluoromethyl) phenyl ] carbamoylamino ] phenoxy ] -N-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628(3- (2-cyanoprop-2-yl) -N- (4-methyl-3- (3-methyl-4-oxo-3, 4-dihydroquinazolin-6-ylamino) phenyl) benzamide), NVP-BHG712 (4-methyl-3- (1-methyl-6- (pyridin-3-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-ylamino) -N- (3- (trifluoromethyl) phenyl) benzamide), RAF-265 (1-methyl-5- [2- [5- (trifluoromethyl) -1H-imidazol-2-yl ] pyridin-4-yl ] oxy-N- [4- (trifluoromethyl) phenyl ] benzimidazol-2-amine), 2-bromodisine (2-bromo-6, 7-dihydro-1H, 5H-pyrrolo [2,3-c ] azepine-4, 8-dione), Raf kinase inhibitor IV (2-chloro-5- (2-phenyl-5- (pyridin-4-yl) -1H-imidazol-4-yl) phenol), sorafenib N-oxide (4- [4- [ [ [ [ 4-chloro-3 (trifluoromethyl) phenyl ] amino ] carbonyl ] amino ] phenoxy ] -N-methyl-2 pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, Raf265, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (Encorafenib).

In one embodiment, the bioactive agent is an AKT inhibitor, including but not limited to MK-2206, GSK690693, piperacillin, (KRX-0401), GDC-0068, triciribine, AZD5363, Honokiol (Honokiol), PF-04691502, and miltefosine, FLT-3 inhibitors, including but not limited to P406, polyvirtinib, quinzatinib (AC220), Amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076, and KW-2449, or a combination thereof.

In one embodiment, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and desphospholimus (deforolimus). Examples of MEK inhibitors include, but are not limited to, trametinib/GSKl 120212(N- (3- { 3-cyclopropyl-5- [ (2-fluoro-4-iodophenyl) amino ] -6, 8-dimethyl-2, 4, 7-trioxo-3, 4,6, 7-tetrahydropyrido [4,3-d ] pyrimidin-l (2H-yl } phenyl) acetamide), semetinib (6- (4-bromo-2-chloroanilino) -7-fluoro-N- (2-hydroxyethoxy) -3-methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC1935369((S) -N- (2, 3-dihydroxypropyl) -3- ((2-fluoro-4-iodophenyl) amino) isonicotinamide), XL-518/GDC-0973(l- ({3, 4-difluoro-2- [ (2-fluoro-4-iodophenyl) amino ] phenyl } carbonyl) -3- [ (2S) -piperidin-2-yl ] azetidin-3-ol) (cobimetinib), refametininib/BAY 869766/RDEAl19(N- (3, 4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide), PD-0325901(N- [ (2R) -2, 3-dihydroxypropoxy ] -3, 4-difluoro-2- [ (2-fluoro-4-iodophenyl) amino ] -benzamide), TAK733((R) -3- (2, 3-dihydroxypropyl) -6-fluoro-5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3d ] pyrimidine-4, 7(3H,8H) -dione), MEK162/ARRY438162(5- [ (4-bromo-2-fluorophenyl) amino ] -4-fluoro-N- (2-hydroxyethoxy) -1-methyl-1H-benzimidazole-6-carboxamide), R05126766(3- [ [ 3-fluoro-2- (methylsulfamoylamino) -4-pyridyl ] methyl ] -4-methyl-7-pyrimidin-2-yloxyen-2-one), WX-554, R04987655/CH4987655(3, 4-difluoro-2- ((2-fluoro-4-iodophenyl) amino) -N- (2-hydroxyethoxy) -5- ((3-oxo-l, 2-oxazacyclohex-2-yl) methyl) benzamide) or AZD8330(2- ((2-fluoro-4-iodophenyl) amino) -N- (2-hydroxyethoxy) -1, 5-dimethyl-6-oxo-l, 6-dihydropyridine-3-carboxamide).

In one embodiment, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

In one embodiment, the bioactive agent is an HSP inhibitor. HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol.

Additional biologically active compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, palopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244(ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, aurora kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, adhesion plaque kinase inhibitors, Map kinase (mek) inhibitors, VEGF trap antibodies, metrexarubicin, panitumumab, amcinolone, agoutiv, Lep-leutu, perunit, peimin-897Latrexed, azd2171, barbitulin, ofatumumab, zamumab, idocamarin (edotecarin), tetrandrine, rubitecan, timifene, orimerson, tiximumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cetrimantan, gemmacetan, IL13-PE38QQR, INO1001, IPdR₁KRX-0402, Canadian, LY317615, neuradiab, WEITESPEN (vitespan), Rta 744, Sdx102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5' -deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, celecoxib (seliciclib); PD0325901, AZD-6244, capecitabine, N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2,3-d ]]Pyrimidin-5-yl) ethyl]Benzoyl radical]-disodium L-glutamate heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3- [5- (methylsulfonylpiperazinylmethyl) -indolyl-quinolone, vatalanib (vatalanib), AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canatinib, ABX-EGF antibody, Erbitux (Erbitux), EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine (arnsacrine), anagrelide (anagrelide), L-asparaginase, BCG vaccine, doxorubicin, bleomycin, buserelin, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, actinomycin D, daunorubicin (daunorubicin), hexeneEstrenol, epirubicin, fludarabine, fludrocortisone, flumethosterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprorelin, levamisole, lomustine, mechlorethamine (mechlorethamine), melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronic acid, pentostatin, plicamycin, porfimer sodium (porfimer), procarbazine, raltitrexendine, rituximab, streptozotocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoformate, 13-cis-retinoic acid, melphalan, estramustine, altretamine, flutamide, fludarabine, fludroxyfotemozide, fludroxyfotemustine, fludroxydoline, fludroxyverine, fludroxyfotemozide, fludroxyverine, doxycycline, meglumine-3379-2, doxycycline, doxycα -2b interferon α -2b azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulins, nitrogen mustard (nitrogen mustard), methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethamidine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casipiptan, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, loxapigenin, lorazepam, alopotam, fluazurol, dolichol, dolichlorosetron, dolichloropectin, dolichthasone, dolichloropectin, dexdolasel, pentostatin, megestrone, pentostatin, meglumine, pentostatin, megestrone, pentostatin, and mixtures thereof.

In one embodiment, the bioactive agent is selected from, but not limited to, imatinib mesylate

Dasatinib

NilotinibBosutinib

Trastuzumab

trastuzumab-DM 1, pertuzumab (Perjeta TM), lapatinib

Gefitinib

ErlotinibCetuximab

Panitumumab

Vandetanib

Verofini

Vorinostat

Romidepsin

BexaroteneAliretin A acidRetinoic acid

Carfilzomib (Kyprolis), pralatrexate

Bevacizumab

Ziv-aflibercept

Sorafenib

Sunitinib

Pazopanib

Regorafenib

And cabozantinib (CometriqTM).

In certain aspects, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressive agent.

Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, toxins (also known as cytotoxins or cytotoxic agents, which include any agent that is detrimental to cell viability), and liposomes or other vesicles containing chemotherapeutic compounds. Typical anti-cancer agents include: vincristine

Or liposomal vincristine

Daunorubicin (daunomycin) or

) Or doxorubicinCytarabine (cytosine arabinoside), ara-C or

) L-asparaginase

Or PEG-L-asparaginase (polyethylene glycol asparaginase or

) Etoposide (VP-16) and teniposide

6-mercaptopurine (6-MP or

) Methotrexate, cyclophosphamide

Prednisone, dexamethasone (Decadron), imatinib

Dasatinib

Nilotinib

Bosutinib

And ponatinib (Iucig)^TM). Additional examples of suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin (adriamycin), aldesleukin (aldesleukin), alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, Anthranilamycin (AMC), antimitotics, cis-dichlorodiamine platinum (II) (DDP) (cisplatin), diamidodichloroplatinum (diamorph), anthracycline (anthacyline), antibiotics, BCG, asparaginase, active intravesical (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucovorin (calceium leucharoirin), calicheamicin (calicheamicin), loplatin, lopeptide (CCC), Carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, and mixtures thereof,Conjugated estrogens, cyclophosphamide, cyclamate, cytarabine, cytochalasin B, cyclophosphamide (Cytoxan), dacarbazine, actinomycin D (formerly actinomycin), daunorubicin hydrochloride (dauuniubicin HCL), daunorubicin citrate (daunorubicin citrate), dinebin (diferukin difitox), Dexrazoxane (Dexrazoxane), Dibromomannitol (dibromanonnitol), dihydroxyanthracenedione (dihydanthrindione), docetaxel, dolasetron mesylate, doxorubicin hydrochloride, dronabinol, E.coli L-asparaginase, emetine (emetine), epoetin- α (epoetinin- α), Wenyu L-asparaginase (Witinase L-paragua), esterified estrogen, tolethyne, oxyphospholidine, medroxyprogesterone hydrochloride, medroxypChlorambucil (chlorambucil), thioguanine (thioguanine), thiotepa (thiotepa), topotecan hydrochloride, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

Additional therapeutic agents that may be administered in combination with the degradation determinants disclosed herein may include bevacizumab, sunitinib, sorafenib, 2-methoxyestradiol or 2ME2, finasteride, vatalanib, vandetanib, afixatet, valacyclovir, eptatuzumab (MEDI-522), cilengitide (cillengitide), erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, doviranib, figitumumab, asexipt (atacicept), rituximab, alemtuzumab, aldesleukin (aldesleukine), alelizumab (atlizumab), tositumumab, temsirolimus, everolimus, lucuzumab, dactuzumab (dacetuzumab), dacetuzumab (dacetuzumab), hnu 1, huN-901-1, atexpiruril (atipamirkins), bortezomib, tezomib, bevacizumab, tasamivir, quinavir (quinavir), quinavir, and a, Ritonavir, nelfinavir mesylate, indinavir sulfate, brinestat, panobinostat, mapatumab (mapatmumab), lexamuron (lexatumumab), dolamin (dulanermin), ABT-737, oblimersen (oblimersen), cortidaxin (plipidepsin), tapernimod (talmapimod), P276-00, enzapine (enzastaurin), tipifarnib (tipifarnib), perimidin, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rituximab, oxaliplatin (oxeletin), PD 2991, ribiciclib (LEE011), beaconiclib (PIM 3528219), HDM201, fulvestrant (fevericin), rituximab (bge 398), rituximab (PIM ii), rituximab (bge-g (ibozetimacy), rituximab (bgm 201, valsartan (398), rituximab (PIM (ibc), rituximab (bgm) and valtuzumab (ibc).

In one aspect of the invention, the disclosed compounds are administered in combination with an anti-infective agent such as, but not limited to, an anti-HIV agent, an anti-HCV agent, an anti-HBV agent, or other antiviral or antibacterial agents. In one embodiment, the anti-HIV agent may be, but is not limited to, for example, Nucleoside Reverse Transcriptase Inhibitors (NRTI), other non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, and the like. nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI) include, but are not limited to, abacavir or ABC (Zigen), didanosine or ddl (Videx), emtricitabine or FTC (Emtriva), lamivudine or 3TC (Epivir), ddC (zalcitabine), stavudine or D4T (Zerit), tenofovir (Tenofovir) TDF (Viread), D-D4FC (Reverseset) and zidovudine or AZT or ZDV (Retrovir). Non-nucleoside reverse transcriptase inhibitors (NNRTIs) include, but are not limited to, delavirdine (recriprtor), efavirenz (Sustiva), etravirine (Intelence), nevirapine (Viramune), and rilpivirine (Edurant). anti-HIV Protease Inhibitors (PI) include, but are not limited to, atazanavir or ATV (Reyataz), darunavir or DRV (Prezista), fosamprenavir or FPV (Lexiva), indinavir or IDV (Crixivan), lopinavir + ritonavir or LPV/r (Kaletra), nelfinavir or NFV (Viracept), ritonavir or RTV (Norvir), saquinavir or SQV (Invirase), tipinavir or TPV Aptivus, Coxstar (Tybost), atazanavir + Kobitaor ATV/COBI (Evoz), darunavir + Kobitaor DRV/COBI (Prezcox). anti-HIV fusion inhibitors include, but are not limited to, enfuvirdine or ENF or T-20 (Fuzeon). anti-HIV agents also include, but are not limited to, maraviroc or mvc (selzentry). anti-HIV integrase inhibitors include, but are not limited to, dolutegravir (Tivicay), etiravir (Vitekta), raltegravir (isentres). The anti-HIV combination agent comprises abacavir + dolutegravir + lamivudine or ABC/DTG/3TC (Triumeq), abacavir + lamivudine or ABC/3TC (Epzicom), abacavir + lamivudine + zidovudine or ABC/3TC/ZDV (Trizivir), efavirenz + emtricitabine + tenofovir or EFV/FTC/TDF (Atriplast, Tribuss), ezetimivir, costatat, emtricitabine, tenofovir alafenamide or EVG/TDFIDI/FTC/TAF or ECF/TAF (Genvoya; (Stribild), emtricitabine + ribavirin + tenofovir/TAF or FTC/RPV/TAF (COBcFTtavudine), tenofovir + Pifuvirin + Tevovudine or Combivudine/Tvudine, and other anti-HIV combination agent(s), and other anti-HIV combination agent Including but not limited to Racivir, L-FddC, L-FD4C, SQVM (saquinavir mesylate), IDV (indinavir), SQV (saquinavir), APV (amprenavir), LPV (lopinavir), fusion inhibitors such as T20 and the like, fuseon and mixtures thereof, including anti-HIV compounds currently in clinical trial or development.

Other anti-HIV agents may be used for co-administration with the disclosed compounds according to the present invention. NNRTI can be selected from nevirapine (BI-R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781(N- [ 4-chloro-3- (3-methyl-2-butenyloxy) phenyl ] -2-methyl-3-furanthioamide), etravirine (TMC125), travirine (Ly300046.HCl), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, baicalin (TJN-151) ADAM-II (3 ', 3' -dichloro-4 ', 4 "-dimethoxy-5', 5" -BIs (methoxycarbonyl) -6, 6-diphenylhexenoic acid methyl ester), 3-bromo-5- (1-5-bromo-4-methoxy-) 3- (methoxycarbonyl) phenyl) hept-1-enyl) -2-methoxybenzoic acid methyl ester (alkenyldiarylmethane analogue, Adam analogue), (5-chloro-3- (phenylsulfinyl) -2' -indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), carpivirine (AG-1549, S-1153), atenervidine (U-87201E), aurintricarboxylic acid (SD-095345), 1- [ (6-cyano-2-indolyl) carbonyl ] -4- [3- (isopropylamino) -2-pyridyl ] piperazine, 1- [5- [ [ N- (methyl) methylsulfonylamino ] -2-indolcarbonyl-4- [3- (isopropylamino) -2-pyridyl ] piperazine, 1- [5- [ [ N- (methyl) methylsulfonylamino ] -2-indolylcarbonyl-4- [3- (isopropylamino) -2-pyridyl ] piperazine, 1- [3- (ethylamino) -2- [ pyridinyl ] -4- [ (5-hydroxy-2-indolyl) carbonyl ] piperazine, 1- [ (6-formyl-2-indolyl) carbonyl ] -4- [3- (isopropylamino) -2-pyridinyl ] piperazine, 1- [ [5- (methylsulfonyloxy) -2-indolyl) carbonyl ] -4- [3- (isopropylamino) -2-pyridinyl ] piperazine, U88204E, bis (2-nitrophenyl) sulfone (NSC 633001), calanolide A (NSC675451), calanolide B, 6-benzyl-5-methyl-2- (cyclohexyloxy) pyrimidin-4-one (DABO-546), DPC 961, E-EBU-dm, E-EPSeU, E-EPU, foscamet (Foscavir), HEPT (1- [ (2-hydroxyethoxy) methyl ] -6- (phenylthio) thymine), HEPT-M (1- [ (2-hydroxyethoxy) methyl ] -6- (3-methylphenyl) thio) thymine), HEPT-S (1- [ (2-hydroxyethoxy) methyl ] -6- (phenylthio) -2-thiothymine), begonia simplicin P, L-737,126, Michellamine A (NSC650898), Michellamine B (NSC649324), Michellamine F, 6- (3, 5-dimethylbenzyl) -1- [ (2-hydroxyethoxy) methyl ] -5-isopropyluracil, 6- (3, 5-dimethylbenzyl) -1- (ethoxymethyl) -5-isopropyluracil, NPPS, E-BPTU (NSC 648400), oltipraz (4-methyl-5- (pyrazinyl) -3H-1, 2-dithienyl-3-thione), N- {2- (2-chloro-6-fluorophenethyl ] -N ' - (2-thiazolyl) thiourea (PETT Cl, F derivatives), N- {2- (2, 6-difluorophenethyl ] -N ' - [2- (5-bromopyridyl) ] thiourea { PETT derivatives), N- {2- (2, 6-difluorophenethyl ] -N ' - [2- (5-methylpyridyl ] thiourea { PETT pyridyl derivatives) N- [2- (3-fluorofuranyl) ethyl ] -N ' - [2- (5-chloropyridyl) ] thiourea, N- [2- (2-fluoro-6-ethoxyphenethyl) ] -N ' - [2- (5-bromopyridyl) ] thiourea, N- (2-phenethyl) -N ' - (2-thiazolyl) thiourea (LY-73497), L-697,639, L-697,593, L-697,661, 342- (4, 7-difluorobenzoxazol-2-yl) ethyl } -5-ethyl-6-methyl (pyridine-2 (1H) -thione (2-pyridone derivative), 3- [ [ (2-methoxy-5), 6-dimethyl-3-pyridyl) methyl ] amine ] -5-ethyl-6-methyl (pyridine-2 (1H) -thione, R82150, R82913, R87232, R88703, R89439 (loweinamine), R90385, S-2720, suramin sodium, TBZ (thiazolobenzoimidazole, NSC 625487), thiazoloisoindol-5-one, (+) (R) -9b- (3, 5-dimethylphenyl-2, 3-dihydrothiazolo [2,3-a ] isoindol-5 (9bH) -one, tevirapine (R86183), UC-38, UC-84, and the like.

In one aspect of the invention, when used to treat HCV infection, the disclosed compounds can be administered in combination with another anti-HCV agent. anti-HCV agents are known in the art. To date, a number of fixed dose drug combinations have been approved for the treatment of HCV.

(Gilead Sciences, Inc.) contains the NS5A inhibitor ledipasvir and the NS5B inhibitor sofosbuvir. TechnivieTM (AbbVie, Inc.) is a fixed dose combination containing orbetavir, an NS5A inhibitor; palivir, an NS3/4A protease inhibitor; and ritonavir, an inhibitor of CYP 3A. Daklinza (Daklindavir, Bristol-Myers Squibb) is a fabric suitable for use with sofosclothThe viruse together are useful as HCV NS5A inhibitors for the treatment of chronic genotype 3 infection. Zepatiert (Merck)&Co.) was recently approved for the treatment of chronic HCV genotypes 1 and 4. ZepatierTM is a fixed dose combination comprising elbasvir, an HCV NS5A inhibitor; and Gezoprevir, an HCV NS3/4A protease inhibitor. ZepatiertM is useful with or without ribavirin.

(Gilead Sciences, Inc.) is a fixed-dose combination tablet containing sofosbuvir and vipatavir. Additional anti-HCV agents and combinations thereof include those described in: U.S. patent nos.: 9,382,218, respectively; 9,321,753, respectively; 9,249,176, respectively; 9,233,974, respectively; 9,221,833, respectively; 9,211,315, respectively; 9,194,873, respectively; 9,186,369, respectively; 9,180,193, respectively; 9,156,823, respectively; 9,138,442, respectively; 9,133,170, respectively; 9,108,999, respectively; 9,090,559, respectively; 9,079,887, respectively; 9,073,943, respectively; 9,073,942, respectively; 9,056,090, respectively; 9,051,340, respectively; 9,034,863, respectively; 9,029,413, respectively; 9,011,938, respectively; 8,987,302, respectively; 8,945,584, respectively; 8,940,718, respectively; 8,927,484, respectively; 8,921,341, respectively; 8,884,030, respectively; 8,841,278, respectively; 8,822,430, respectively; 8,772,022, respectively; 8,765,722, respectively; 8,742,101, respectively; 8,741,946, respectively; 8,674,085, respectively; 8,673,288, respectively; 8,669,234, respectively; 8,663,648, respectively; 8,618,275, respectively; 8,580,252, respectively; 8,575,195, respectively; 8,575,135, respectively; 8,575,118, respectively; 8,569,302, respectively; 8,524,764, respectively; 8,513,298, respectively; 8,501,714, respectively; 8,404,651, respectively; 8,273,341, respectively; 8,257,699, respectively; 8,197,861, respectively; 8,158,677, respectively; 8,105,586, respectively; 8,093,353, respectively; 8,088,368, respectively; 7,897,565, respectively; 7,871,607, respectively; 7,846,431, respectively; 7,829,081, respectively; 7,829,077, respectively; 7,824,851, respectively; 7,572,621, respectively; and 7,326,536; patents assigned to Alios: U.S. patent nos.: 9,365,605, respectively; 9,346,848, respectively; 9,328,119, respectively; 9,278,990, respectively; 9,249,174, respectively; 9,243,022, respectively; 9,073,960, respectively; 9,012,427, respectively; 8,980,865, respectively; 8,895,723, respectively; 8,877,731, respectively; 8,871,737, respectively; 8,846,896 and 8,772,474; patent 9,273,082 assigned to Achillion; 9,233,136, respectively; 9,227,952, respectively; 9,133,115, respectively; 9,125,904, respectively; 9,115,175, respectively; 9,085,607, respectively; 9,006,423, respectively; 8,946,422, respectively; 8,835,456, respectively; 8,809,313, respectively; 8,785,378, respectively; 8,614,180, respectively; 8,445,430, respectively; 8,435,984, respectively; 8,183,263, respectively; 8,173,636, respectively; 8,163,693, respectively; 8,138,346, respectively; 8,114,888, respectively; 8,106,209, respectively; 8,088,806, respectively; 8,044,204, respectively; 7,985,541, respectively; 7,906,619, respectively; 7,902,365, respectively; 7,767,706, respectively; 7,741,334, respectively; 7,718,671, respectively; 7,659,399, respectively; 7,476,686, respectively; 7,439,374, respectively; 7,365,068, respectively; 7,199,128; and 7,094,807; patent 9,181,227 assigned to Crystal Pharma Inc.; 9,173,893, respectively; 9,040,479 and 8,771,665; patent 9,353,423 assigned to Gilead Sciences; 9,346,841, respectively; 9,321,800, respectively; 9,296,782, respectively; 9,296,777, respectively; 9,284,342, respectively; 9,238,039, respectively; 9,216,996, respectively; 9,206,217, respectively; 9,161,934, respectively; 9,145,441, respectively; 9,139,604, respectively; 9,090,653, respectively; 9,090,642, respectively; 9,085,573, respectively; 9,062,092, respectively; 9,056,860, respectively; 9,045,520, respectively; 9,045,462, respectively; 9,029,534, respectively; 8,980,878, respectively; 8,969,588, respectively; 8,962,652, respectively; 8,957,046, respectively; 8,957,045, respectively; 8,946,238, respectively; 8,933,015, respectively; 8,927,741, respectively; 8,906,880, respectively; 8,889,159, respectively; 8,871,785, respectively; 8,841,275, respectively; 8,815,858, respectively; 8,809,330, respectively; 8,809,267, respectively; 8,809,266, respectively; 8,779,141, respectively; 8,765,710, respectively; 8,759,544, respectively; 8,759,510, respectively; 8,735,569, respectively; 8,735,372, respectively; 8,729,089, respectively; 8,722,677, respectively; 8,716,264, respectively; 8,716,263, respectively; 8,716,262, respectively; 8,697,861, respectively; 8,664,386, respectively; 8,642,756, respectively; 8,637,531, respectively; 8,633,309, respectively; 8,629,263, respectively; 8,618,076, respectively; 8,592,397, respectively; 8,580,765, respectively; 8,569,478, respectively; 8,563,530, respectively; 8,551,973, respectively; 8,536,187, respectively; 8,513,186, respectively; 8,513,184, respectively; 8,492,539, respectively; 8,486,938, respectively; 8,481,713, respectively; 8,476,225, respectively; 8,420,597, respectively; 8,415,322, respectively; 8,338,435, respectively; 8,334,270, respectively; 8,329,926, respectively; 8,329,727, respectively; 8,324,179, respectively; 8,283,442, respectively; 8,263,612, respectively; 8,232,278, respectively; 8,178,491, respectively; 8,173,621, respectively; 8,163,718, respectively; 8,143,394, respectively; patents assigned to Idenix, obtained by Merck, including U.S. patent nos.: 9,353,100, respectively; 9,309,275, respectively; 9,296,778, respectively; 9,284,307, respectively; 9,249,173, respectively; 9,243,025, respectively; 9,211,300, respectively; 9,187,515, respectively; 9,187,496, 9,109,001; 8,993,595, respectively; 8,951,985, respectively; 8,691,788, respectively; 8,680,071, respectively; 8,637,475, respectively; 8,507,460, respectively; 8,377,962, respectively; 8,362,068, respectively; 8,343,937, respectively; 8,299,038, respectively; 8,193,372, respectively; 8,093,379, respectively; 7,951,789, respectively; 7,932,240, respectively; 7,902,202, respectively; 7,662,798, respectively; 7,635,689, respectively; 7,625,875, respectively; 7,608,600, respectively; 7,608,597, respectively; 7,582,618, respectively; 7,547,704, respectively; 7,456,155, respectively; 7,384,924, respectively; 7,365,057, respectively; 7,192,936, respectively; 7,169,766, respectively; 7,163,929, respectively; 7,157,441, respectively; 7,148,206, respectively; 7,138,376, respectively; 7,105,493, respectively; 6,914,054 and 6,812,219; patents assigned to Merck, including U.S. patent nos.: 9,364,482, respectively; 9,339,541, respectively; 9,328,138, respectively; 9,265,773, respectively; 9,254,292, respectively; 9,243,002, respectively; 9,242,998, respectively; 9,242,988, respectively; 9,242,917, respectively; 9,238,604, respectively; 9,156,872, respectively; 9,150,603, respectively; 9,139,569, respectively; 9,120,818, respectively; 9,090,661, respectively; 9,073,825, respectively; 9,061,041, respectively; 8,987,195, respectively; 8,980,920, respectively; 8,927,569, respectively; 8,871,759, respectively; 8,828,930, respectively; 8,772,505, respectively; 8,715,638, respectively; 8,697,694, respectively; 8,637,449, respectively; 8,609,635, respectively; 8,557,848, respectively; 8,546,420, respectively; 8,541,434, respectively; 8,481,712, respectively; 8,470,834, respectively; 8,461,107, respectively; 8,404,845, respectively; 8,377,874, respectively; 8,377,873, respectively; 8,354,518, respectively; 8,309,540, respectively; 8,278,322, respectively; 8,216,999, respectively; 8,148,349, respectively; 8,138,164, respectively; 8,080,654, respectively; 8,071,568, respectively; 7,973,040, respectively; 7,935,812, respectively; 7,915,400, respectively; 7,879,815, respectively; 7,879,797, respectively; 7,632,821, respectively; 7,569,374, respectively; 7,534,767, respectively; 7,470,664 and 7,329,732; U.S. patent application publications US2013/0029904 assigned to Boehringer Ingelheim GMBH and US 2014/0113958 assigned to Stella Aps.

In one embodiment, the additional therapy is a monoclonal antibody (MAb). Some mabs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these mabs can "coat" the surface of cancer cells, thereby triggering their destruction by the immune system. For example, bevacizumab targets Vascular Endothelial Growth Factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment that promotes tumor vascular development. When bound to bevacizumab, VEGF is unable to interact with its cellular receptors, thereby preventing signaling leading to new blood vessel growth. Similarly, cetuximab and panitumumab target Epidermal Growth Factor Receptor (EGFR), and trastuzumab targets human epidermal growth factor receptor 2 (HER-2). Mabs that bind to cell surface growth factor receptors prevent the targeted receptor from sending its normal growth promoting signal. They can also trigger apoptosis and activate the immune system to destroy tumor cells.

In one aspect of the invention, the bioactive agent is an immunosuppressive agent. The immunosuppressant may be a calcineurin inhibitor, e.g. cyclosporin or an ascomycin, e.g. cyclosporin AFK506 (tacrolimus), pimecrolimus; mTOR inhibitors, e.g. rapamycin or derivatives thereof, e.g. sirolimusEverolimus

Temsirolimus, zotarolimus, tioxalimus-7, tioxalimus-9; rapamycin analogues (rapalogs), such as ridaforolimus, azathioprine, alemtuzumab 1H (campath 1H); S1P receptor modulators, such as fingolimod or an analog thereof; anti-IL-8 antibodies, mycophenolic acid or salts thereof, e.g. sodium salts or prodrugs thereof, e.g. mycophenolateOKT3(ORTHOCLONE

) Prednisone, prednisone,

Brequinar sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tripterygium and leflunomide

CTLAI-Ig, anti-CD 25, anti-IL 2R, basiliximabDalizumab

Mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus,

) CTLA4lg (arbirayp), Belacian, LFA3lg, etanercept (by Immunex and/or Epsilon)

Sale), adalimumabInfliximabResist against

anti-LFA-1 antibody, natalizumab

Emomab, gavilimomab, anti-thymocyte immunoglobulins, siplizumab, alefacelizumab, bordeaux, mesalazine, asacol, codeine phosphate, benorilate, fenbufen, naproxen, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.

V. pharmaceutical composition

The compounds of formula I, formula II, formula III, formula IV, formula V and formula VI as disclosed herein may be administered as pure chemicals, but more typically are administered as pharmaceutical compositions comprising an effective amount for a host (typically a human) in need of treatment for any of the conditions described herein. Accordingly, the present disclosure provides a pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition may contain the compound or salt as the only active agent or, in an alternative embodiment, the compound and at least one additional active agent.

In certain embodiments, the pharmaceutical composition is in a dosage form containing from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg, or from about 200mg to about 600mg of the active compound and optionally from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg, or from about 200mg to about 600mg of additional active agent in a unit dosage form. Examples are dosage forms having at least 0.1, 1,5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700 or 750mg of the active compound or a salt thereof. The pharmaceutical composition may also comprise the active compound and the additional active agent in molar proportions. For example, the pharmaceutical composition may comprise about 0.5: 1, about 1: 1, about 2: 1, about 3: 1 or about 1.5: 1 to about 4: 1 of an anti-inflammatory agent or an immunosuppressive agent. The compounds disclosed herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implants (including ocular implants), transdermally, via buccal administration, rectally, as ophthalmic solutions, injections (including ophthalmic injections), intravenously, intraarterially, intracranially, subdermally (subdermal), intraperitoneally, subcutaneously (subeutaneous), nasally, sublingually, or rectally (recal), or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For ocular delivery, the compounds may be administered in an immediate or controlled release manner or by ocular devices, as desired, e.g., by intravitreal, intrastromal, intracameral, subcortical, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, scleral, periocular, transscleral, retrobulbar, posterior juxtascleral, pericorneal, or lacrimal injection, or by mucus, mucin, or mucosal barrier.

The pharmaceutical composition may be formulated in any pharmaceutically useful form, for example, in an aerosol, cream, gel, pill, injection or infusion solution, capsule, tablet, syrup, transdermal patch, subcutaneous patch, dry powder, inhalation formulation, medical device, suppository, buccal or sublingual formulation, parenteral formulation or ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing appropriate quantities of the active ingredient, e.g., an effective amount to achieve the desired purpose.

Carriers include excipients and diluents, and must be of sufficiently high purity and low toxicity to render them suitable for administration to the patient being treated. The carrier may be inert or it may have its own pharmaceutical benefits. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound.

Classes of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one category, for example vegetable oils may be used as lubricants in some formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered gum tragacanth, malt, gelatin; talc and vegetable oils. Optional active agents may be included in the pharmaceutical composition that do not substantially interfere with the activity of the compounds of the present invention.

The pharmaceutical composition/composition may be formulated for oral administration. These compositions may contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight percent (wt.%), and typically at least about 5 wt.% of the compound. Some embodiments contain from about 25 wt.% to about 50 wt.% or from about 5 wt.% to about 75 wt.% of the compound.

Formulations suitable for rectal administration are generally presented as unit dose suppositories. These can be prepared by mixing the active compound with one or more conventional solid carriers, for example cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferably take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Carriers that may be used include petrolatum, lanolin, polyethylene glycols, alcohols, dermal penetration enhancers, and combinations of two or more thereof.

Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for an extended period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3(6):318(1986)), and typically take the form of an aqueous solution of the active compound, optionally buffered. In one embodiment, a microneedle patch or device is provided for delivering a drug through or into a biological tissue, particularly skin. Microneedle patches or devices allow drug delivery through or into the skin or other tissue barrier at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

Formulations suitable for administration to the lung can be delivered by a variety of passive breath-actuated and active power-actuated single/multi-dose Dry Powder Inhalers (DPIs). The most commonly used devices for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of atomizers are available, including jet atomizers, ultrasonic atomizers, and vibrating screen atomizers. The choice of a suitable pulmonary delivery device depends on parameters such as the nature of the drug and its formulation, the site of action and the pathophysiology of the lung.

Many methods and devices for drug delivery are known in the art. Non-limiting examples are described in the following patents and patent applications (incorporated herein by reference in their entirety). Examples are US8,192,408 entitled "Oculartrocar assembly" (Psivida US, Inc.); US 7,585,517, entitled "Transcleral delivery" (Macusight, Inc.); US5,710,182 and US5,795,913 entitled "opthalmic composition" (Santen OY); US8,663,639 entitled "Formulations for treating associated diseases" US8,486,960 entitled "Formulations and methods for treating related diseases or conditions", US8,367,097 and US8,927,005 entitled "liquids for treating of diseases or conditions", US 7,455,855 entitled "treating substtate and drive delivery system using the same" (attention pharmaceutical co., Ltd.); WO/2011/050365 entitled "compatible Therapeutic Shield for Vision and Pain" and WO/2009/145842 entitled "Therapeutic Device for Panel management and Vision" (design Labs, LLC); US 9,066,779 and US8,623,395 entitled "printable thermal Devices", WO/2014/160884 entitled "optical imaging for rendering thermal subsystems", US8,399,006, US8,277,830, US8,795,712, US8,808,727, US8,298,578 and WO/2010/088548 entitled "spatial segment driver", WO/2014/152959 and US20140276482 entitled "System for summary architectural Delivery of Low solvent computing from Port Delivery System", US8,905,963 and US 9,033,911 entitled "interior coating and metallic Delivery device", WO/36/formulation for modeling and computing device for rendering "for mapping and computing device for rendering" WO/9638 entitled "for mapping and computing device for rendering", WO/9638 entitled "mapping and computing device for rendering" for mapping and computing device for rendering ", WO/2015/057554 entitled" mapping and computing device for rendering ", WO/9638 entitled" computing and computing device for rendering ", WO/9638 for mapping and computing device for rendering" for rendering and computing device for rendering ", WO/9638 entitled" mapping and computing device for rendering "and computing device for rendering", WO/3638 for rendering "for rendering and rendering" for rendering by rendering and implementing Systems for rendering "for rendering and rendering" for rendering and for rendering "for rendering Devices for rendering, WO/2015/085234 and WO/2012/019176, entitled "printable Therapeutic Device", WO/2012/065006, entitled "Methods and Apparatus to define layers Structures for drive", WO/2010/141729, entitled "antioxidant Segment drive", WO/2011/050327, entitled "scientific depletion for Treatment of objective Panel", WO/2013/022801, entitled "Small molecular Delivery with Implantable Therapeutic Device", WO/2012/019047, entitled "Subconjunctional Apparatus for spatial Segment drive", WO/2012/068549, entitled "cosmetic Agent for display Apparatus for use", WO/493 for use "method and Apparatus for use", and entitled "method for application 2", and "method for use" for application 3 ", WO/2012/068549, entitled" method for use of additive Device for use ", WO/493 Device for use" and method for use "for use of additive Delivery, WO/493 Devices for use" and method for use "for use of application 2", and method for use "for use of application 2013/040426, and method for use" for use of application and Apparatus for use of "Devices for use, WO/2013/040247 entitled "Fluid Exchange Apparatus and methods" (ForSight Vision4, Inc.); US/2014/0352690 entitled "incubation Device with feedback System", US8,910,625 and US/2015/0165137 entitled "incubation Device for use in Aerosol Therapy" (Vectra GmbH); US6,948,496, entitled "inputs", US/2005/0152849, entitled "Power comprising anti-adaptive materials for Use in drypower inputs", US6,582,678, US8,137,657, US/2003/0202944 and US/2010/0330188, entitled "Carrier Devices for Use in drive power inputs", US6,221,338, entitled "Method of generating Devices for Use in drive power inputs", US6,989,155, entitled "Power derivatives", US/2007/0043030, entitled "Pharmaceutical Compositions for formatting by public power inputs", US 7,845,349, entitled "Inhalers 462" and US8,101,160, entitled "Formulations for formatting by public power inputs", US 7,845,349, entitled "Formulations for Use in drive inputs", US/2012/0114709 and US 7384, entitled "Formulations for Use in development Devices", US 3884, and US 3884 for Use in parallel, US/2015/0174343 entitled "Mixing Channel for an incubation Device", US 7,744,855 and US/2010/0285142 entitled "Method of creating features for use in adaptive computing", US 7,541,022, US/2009/0269412 and US/2015/0050350 entitled "Pharmaceutical formulations for dry powder applicators" (vectrula Limited).

Other non-limiting examples of how to deliver the active compound are provided in the following: WO/2015/085251, entitled "Intra camera image for Treatment of an Ocular Conditioning" (Envisia therapeutics, Inc.); WO/2011/008737, entitled "Engineered Aerosol composites, and associated Methods", WO/2013/082111, entitled "geographic Engineered composites Methods for modulated macromolecular or animal Responses", WO/2009/132265, entitled "Degradable composites and Methods of using thermal Methods", WO/2008/100304, entitled "polymeric composite viscosity instruments, and associated Methods", WO/2010/099321, entitled "Interactive driver and associated Methods", WO/2008/100304, entitled "polymeric composite viscosity instruments, and associated Methods", and associated Methods, entitled "polymeric composite viscosity instruments, size, and shape, and associated Methods", WO/2007/024323, entitled "nanoparticles viscosity Methods, and associated Technologies" (identification of interest, quality of technology); WO/2010/009087, entitled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye", (Liquiria Technologies, Inc. and Eyegate pharmaceuticals, Inc.) and WO/2009/132206, entitled "Compositions and Methods for intracellular Delivery and Release of Cargo", WO/2007/133808, entitled "Nano-particles for biological applications", WO/2007/056561, entitled "Medical devices, materials, and Methods", WO/2010/065748, entitled "Method for manufacturing substrates", WO/2007/081876, entitled "Nano-structured substrates for biological applications", and "biological applications" are disclosed.

Additional non-limiting examples Of drug delivery devices and methods include, For example, US20090203709 entitled "Pharmaceutical Dosage Form For Oral Administration Of Tyrosine KinaseInhibitor" (Abbott Laboratories); US20050009910 entitled "Delivery of an active to the spatial device part of the eye vision sub-section or temporal Delivery of a driver", US 20130071349 entitled "Biodegradable polymers For accessing the interactive systems", US8,481,069 entitled "type kinematic systems", US8,465,778 entitled "Method of mapping the systematic kinematic systems", US8,409,607 entitled "stabilized interactive modeling of the interactive modeling and related Methods", US8,512,738 and US2014/0031408 entitled "Biodegradable molecular modeling of the interactive modeling and related Methods", US8,512,738 and US2014/0031408 entitled "Delivery of the interactive modeling and mapping US 0294986", US8,911,768 entitled "retrieval System For describing the interactive modeling of the interactive modeling System", US8,911,768 entitled "retrieval System". US6,495,164 entitled "Preparation of injectable suspensions having improved injectable availability" (Alkermes Controlled Therapeutics, Inc.); WO 2014/047439, entitled "BiodegradableMicrocapsules Containing Filling Material" (Akina, Inc.); WO 2010/132664 entitled Compositions And Methods For Drug Delivery (Baxter International Inc. Baxter healthcare SA); US20120052041 entitled "Polymeric nanoparticles with enhanced ruggedness and methods of use of thermoof" (The Brigham and Women's Hospital, Inc.); US20140178475, US20140248358 and US20140249158, entitled "Therapeutic nanoparticles Comprising a Therapeutic Agent and Methods of Making and using same" (bond Therapeutics, Inc.); US5,869,103, entitled "Polymer microparticles for drug delivery" (danbiosystem UK Ltd.); US 8628801 entitled "Pegylated nanoparticules" (Universal de Navarra); US2014/0107025 entitled "Ocular drug delivery system" (Jade Therapeutics, LLC); US6,287,588 entitled "active delivery system comprising of microparticles and biodegradable delivery profiles and of methods of use thermally", US6,589,549 entitled "active delivery system comprising of microparticles and biodegradable delivery to implantable delivery profiles" (Macromed, Inc.); US6,007,845 and US5,578,325 entitled "Nanoparticles and pharmaceutical compositions of non-linear hydrophyllic multiblock polymers" (Mass of Technology); US20040234611, US20080305172, US 20120269874 and US20130122064, entitled "ocular depot formulations for personal or subenjunctival administration (Novartis Ag); US6,413,539, entitled "Block polymer" (Poly-Med, Inc.); US 20070071756 entitled "Delivery of an agent toamylimate translation" (Peyman); US 20080166411 entitled "Injectable Depo formulations And Methods For Providing stabilized Release Of Poorly solubles compositions Nanoparticles" (Pfizer, Inc.); US6,706,289 entitled "Methods and compositions for enhanced delivery of biological molecules" (PRpharmaceuticals, Inc.); and US8,663,674 entitled "Microparticle containing information for drug delivery" (submitics).

General Synthesis

The compounds described herein are prepared by methods known to those skilled in the art. In one non-limiting example, the disclosed compounds are prepared using the following scheme.

For convenience, compounds of the present invention having a stereocenter may be drawn without stereochemistry. One skilled in the art will recognize that pure enantiomers and diastereomers are prepared by methods known in the art. Examples of the method for obtaining an optically active substance include at least the following.

i) Physical separation of crystals-a technique whereby visually visible crystals of individual enantiomers are separated manually. This technique is used if there is a crystallization of the individual enantiomers, i.e. the substance is an aggregate and the crystallization is visually different;

ii) simultaneous crystallization-a technique whereby individual enantiomers are crystallized separately from a solution of the racemate, is only possible when the latter is a solid aggregate;

iii) enzymatic resolution-a technique whereby racemates are partially or completely separated by the different reaction rates of enantiomers with enzymes;

iv) enzymatic asymmetric synthesis-a synthetic technique whereby at least one synthetic step uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;

v) chemical asymmetric synthesis-a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries;

vi) diastereoisomeric separation-a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) which converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization, by virtue of their now more pronounced structural differences, after which the chiral auxiliary is removed to obtain the desired enantiomer;

vii) first and second order asymmetric transformations-a technique whereby the diastereoisomers from the racemate are either balanced so that they have an advantage over the desired enantiomer in solution, or the preferential crystallization of the diastereoisomers over the desired enantiomer disturbs the balance so that ultimately in principle all the material is converted from the desired enantiomer to the crystalline diastereoisomer. Then releasing the desired enantiomer from the diastereomer;

viii) kinetic resolution-this technique refers to the partial or complete resolution of the racemate (or the further resolution of the partially resolved compound) by virtue of unequal reaction rates of the enantiomers with chiral non-racemic reagents or catalysts under kinetic conditions;

ix) enantiospecific synthesis from non-racemic precursors-a synthetic technique whereby the desired enantiomer is obtained from a non-chiral starting material and wherein the stereochemical integrity is not compromised or is only minimally compromised during the synthesis;

x) chiral liquid chromatography-a technique whereby enantiomers of a racemate are separated in a liquid mobile phase by virtue of their different interactions with a stationary phase (including by chiral HPLC). The stationary phase may be made of chiral material, or the mobile phase may contain additional chiral material to cause different interactions;

xi) chiral gas chromatography-a technique whereby the racemate is evaporated and the enantiomers are separated by means of different interactions in a gaseous mobile phase using a column containing a fixed, non-racemic chiral adsorption phase;

xii) extraction with a chiral solvent-a technique whereby enantiomers are separated by preferentially dissolving one enantiomer in a particular chiral solvent;

xiii) transport across chiral membranes-a technique whereby the racemate is placed in contact with a thin membrane barrier. Barriers typically separate two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential results in preferential transport across the membrane barrier. Separation occurs due to the non-racemic chiral nature of the membrane which allows only one enantiomer of the racemate to pass through.

xiv) simulated moving bed chromatography is used in one embodiment. Various chiral stationary phases are commercially available.

Scheme 1

Scheme 2

As shown in scheme 1, compounds useful in the present invention can be prepared by chemically binding a degredating determinant and a linker, followed by addition of a targeting ligand. Similarly, in scheme 2, the compounds for use in the present invention are prepared by first chemically binding the targeting ligand and linker, followed by the addition of the degron. As described above and in the following schemes, the compounds useful in the present invention can be readily synthesized by those skilled in the art in a variety of methods and chemical reactions.

Scheme 3

Scheme 3: in step 1, the nucleophilic degron replaces a leaving group on the linker to produce a degron linker fragment. In step 2, the protecting group is removed by methods known in the art to release the nucleophilic site on the linker. In step 3, the nucleophilic degron linker fragment displaces a leaving group on the targeting ligand to form a compound for use in the present invention. In an alternative embodiment, step 1 and/or step 2 is accomplished by a coupling reaction rather than nucleophilic attack.

Scheme 4

Scheme 4: in step 1, a nucleophilic targeting ligand replaces a leaving group on the linker to produce a targeting ligand linker fragment. In step 2, the protecting group is removed by methods known in the art to release the nucleophilic site on the linker. In step 3, the nucleophilic targeting ligand linker fragment replaces the leaving group on the degron to form the compound for use in the present invention. In an alternative embodiment, step 1 and/or step 2 is accomplished by a coupling reaction rather than nucleophilic attack.

Scheme 5

Scheme 5 and scheme 6: in step 1, a nucleophilic linker replaces a leaving group on the degron to produce a degron linker fragment. In step 2, the protecting group is removed by methods known in the art to release the nucleophilic site on the linker. In step 3, the nucleophilic degron linker fragment displaces a leaving group on the targeting ligand to form the compound of formula I or formula II. In an alternative embodiment, step 1 and/or step 2 is accomplished by a coupling reaction rather than nucleophilic attack.

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