Protein Kinase Conjugates and Inhibitors

• US 20110117073A1
• Filed: 09/15/2010
• Published: 05/19/2011
• Est. Priority Date: 09/16/2009
• Status: Active Grant

• Current Assignee: Celgene Car LLC (Bristol-Myers Squibb Company)
• Original Assignee: Avila Therapeutics Inc. (Bristol-Myers Squibb Company)
• Inventors: Petter, Russell Colyn, Niu, Deqiang, Singh, Juswinder, Lobb, Roy, Zhu, Zhendong, Qiao, Lixin, Kluge, Arthur, Ghosh, Shomir
• Granted Patent: US 9,556,426 B2
• Time in Patent Office: Days
• US Class Current: 424/94.5
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 213/72 Nitrogen atoms nitro radicals C07D213/61
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 215/22 attached in position 2 or 4
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 333/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems
• CPC Class Codes: C12N 9/1205 : Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases
• CPC Class Codes: C12N 9/96 : Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates

Abstract

The invention relates to protein conjugates that contain a protein kinase containg a cysteine residue in the ATP binding site and an inhibitor that is covalently and irreversibly bonded to said cysteine residue, such that the activity of the protein kinase is irreversibly inhibited. The invention also relates to compounds that irreversibly inhibit protein kinases.

Claims

1. A protein kinase conjugate that has the formula,

X-M-S—

CH₂-Prot

wherein, Prot is a protein kinase or portion thereof that contains a cysteine residue selected from the group consisting of CYS1, CYS5, CYS6, CYS7, CYS8, CYS9, CYS10, CYS11, CYS12 and CYS13;

S—

CH₂ is the sulfur atom and methylene group from the side chain of said cysteine residue;

M is a modifier moiety that is formed by the covalent bonding of a warhead group with the side chain of said cysteine residue; and

X is a chemical moiety that binds in or near the ATP binding site of the protein kinase.

2. The conjugate of claim 1, wherein the warhead group is -L-Y, wherein

L is a covalent bond or a bivalent C_1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —

NR—

, —

N(R)C(O)—

, —

C(O)N(R)—

, —

N(R)SO₂—

, —

SO₂N(R)—

, —

O—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

S—

, —

SO—

, —

SO₂—

, —

C(═

S)—

, —

C(═

NR)—

, —

N═

N—

, or —

C(═

N₂)—

;

Y is hydrogen, nitrile, C_1-6 aliphatic optionally substituted with one or more OH, NRxRy, oxo, halogen, NO₂, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R^e groups; and

Rx and Ry are independently hydrogen, lower alkyl, lower haloalkyl, or lower cycloalkyl;

each R^e is independently selected from -Q-Z, OH, oxo, NO₂, halogen, CN, a suitable leaving group, or a C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN, wherein;

Q is a covalent bond or a bivalent C_1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —

N(R)—

, —

S—

, —

O—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

SO—

, or —

SO₂—

, —

N(R)C(O)—

, —

C(O)N(R)—

, —

N(R)SO₂—

, or —

SO₂N(R)—

; and

Z is hydroen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

3. The conjugate of claim 1, wherein the warhead group is

4. The conjugate of claim 1, wherein the modifier moiety taken together with the side chain Sulfur and methylene of the cysteine have a formula selected from the group consisting of

5. The conjugate of claim 1, wherein Prot is a kinase or portion of a kinase comprising CYS1, and is selected from the group consisting of JAK3, FGFR1, FGFR2, FGFR3, FGFR4, CKIT, CSFR1, PDGFR-A, FAK2, FLT3, FER, FES, CDKL1, CDKL4, FLT4, KDR, FLT1, PDGFR-B, and a portion of any one of the foregoing that comprises CYS1.

6. The conjugate of claim 5, wherein Prot comprises an amino acid sequence selected from the group consisting of RC*VHRDL, KC*IHRDL, NC*IHRDL, NC*IHRDV, NC*VIIRDL, NC*VHRDI, SC*VHRDL, CC*IHRDL, or NC*IHRDI, wherein C* is CYS1.

7. The conjugate of claim 1, wherein Prot is a kinase or portion of a kinase comprising CYS5, and is selected from the group consisting of PFTAIRE1, JNK1, JNK2, JNK3 BMPR2, and a portion of any one of the foregoing that comprises CYS5.

8. The conjugate of claim 7, wherein Prot comprises an amino acid sequence selected from the group consisting of DLC*QYMD, NLC*QVIH, NLC*QVIQ, and SLC*KYLSL, wherein C* is CYS5.

9. The conjugate of claim 1, wherein Prot is a kinase or portion of a kinase comprising CYS6, and is selected from the group consisting of TNK1, YES, FGR, SRC, LIMK1, FGFR1, FGFR2, FGFR3, FGFR4, and a portion of any one of the foregoing that comprises CYS6.

10. The conjugate of claim 9, wherein Prot comprises an amino acid sequence selected from the group consisting of SGC*FGV, QGC*FGE, TGC*FGD, KGC*FGQ, and EGC*FGQ, wherein C* is CYS6.

11. The conjugate of claim 1, wherein Prot is a kinase or portion of a kinase comprising CYS7, and is selected from the group consisting of FAK, ALK1, ALK2, and a portion of any one of the foregoing that comprises CYS7.

12. The conjugate of claim 11, wherein Prot comprises an amino acid sequence selected from the group consisting of GRC*IGEGQFGD, VEC*VGKGRYG, and LEC*VGKGRYG, wherein C* is CYS7.

13. The conjugate of claim 1, wherein Prot is a kinase or portion of a kinase comprising CYS8, and is selected from the group consisting of ZAP70, CRIK, ERK3, CK1g1, CK1g2, CK1g3, and a portion of any one of the foregoing that comprises CYS8.

14. The conjugate of claim 13, wherein Prot comprises an amino acid sequence selected from the group consisting of GC*GNF, GC*GHF, and GC*GGN, wherein C* is CYS8.

15. The conjugate of claim 1, wherein Prot is a kinase or portion of a kinase comprising CYS9, and is ROR1 or a portion thereof that comprises CYS9.

16. The conjugate of claim 1, wherein Prot is a kinase or portion of a kinase comprising CYS10, and is MELK or a portion thereof that comprises CYS10.

17. The conjugate of claim 1, wherein Prot is a kinase or portion of a kinase comprising CYS11, and is selected from the group consisting of c-KIT, FMS, RON, FLT3, FGR, and a portion of any one of the foregoing that comprises CYS11.

18. The conjugate of claim 17, wherein Prot comprises an amino acid sequence selected from the group consisting of YCC*YG, TMC*HG, and FMC*HG, wherein C* is CYS11.

19. The conjugate of claim 1, wherein Prot is a kinase or portion of a kinase comprising CYS12, and is ALK or a portion thereof that comprises CYS12.

20. The conjugate of claim 19, wherein Prot comprises the amino acid sequence AARNCLLTC*PGPGRVAKIGD, wherein C* is CYS12.

21. The conjugate of claim 1, wherein Prot is a kinase or portion of a kinase comprising CYS13, and is B-RAF or a portion thereof that comprises CYS13.

22. The conjugate of claim 21, wherein Prot comprises the amino acid sequence TKPQLAIVTQWC*EGSSLYHH, wherein C* is CYS13.

23. A protein kinase conjugate comprising C-KIT or a portion thereof comprising CYS1 (Cys788), and a compound of formula XVIII, XIX, XIX-a, XIX-b, XIX-c, XX or XX-a that is covalently and irreversible bonded to CYS1.

24. A protein kinase conjugate comprising KDR or a portion thereof comprising CYS2 (Cys1045), and a compound of formula XVIII, XIX, XIX-a, XIX-b, XIX-c, XX or XX-a that is covalently and irreversible bonded to CYS2.

25. A protein kinase conjugate comprising B-RAF or a portion thereof comprising CYS13 (Cys532), and a compound of formula XVIII, XIX, XIX-a, XIX-b, XIX-c, XX or XX-a that is covalently and irreversible bonded to CYS13.

26. A protein kinase conjugate comprising FLT3 or a portion thereof comprising CYS2 (Cys828), and a compound of formula II-a, II-b, II-c or II-d that is covalently and irreversible bonded to CYS2.

27. A protein kinase conjugate comprising MEK1 or a portion thereof comprising CYS2 (Cys207), and a compound of formula II-a, II-b, II-c or II-d that is covalently and irreversible bonded to CYS2.

28. A protein kinase conjugate comprising JAK3 or a portion thereof comprising CYS3 (Cys909), and a compound of formula V that is covalently and irreversible bonded to CYS3.

29. A protein kinase conjugate comprising PLK1 or a portion thereof comprising CYS4 (Cys67), and a compound of formula III that is covalently and irreversible bonded to CYS4.

30. A protein kinase conjugate comprising FAK or a portion thereof comprising CYS7 (Cys427), and a compound of formula IV, IVa or IVb that is covalently and irreversible bonded to CYS7.

31. A protein kinase conjugate comprising JNK1 or a portion thereof comprising CYS5 (Cys116), and a compound of formula V1, VII, VIII, IX, IX-a, X, X-a XI, XII or XII-a that is covalently and irreversible bonded to CYS5.

32. A protein kinase conjugate comprising ZAP70 or a portion thereof comprising CYS8 (Cys346), and a compound of formula I-a, I-b, I-c, I-d, I-e, and I-f that is covalently and irreversible bonded to CYS8.

33. A protein kinase conjugate comprising RON or a portion thereof comprising CYS11 (Cys1165), and a compound of formula XIII-a, XIII-b, XIII-c, XIII-d, XIV, XV, XVI, or XVII that is covalently and irreversible bonded to CYS11.

34-44. -44. (canceled)

45. A compound of formula XIII-a or XIII-b:

56. A pharmaceutical composition comprising a compound of any one of claims 45-52 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

46. A compound of formula XIV:

47. A compound of formula XV:

48. A compound of formula XVI or XVI-a:

49. A compound of formula XVII:

50. A compound of formula XVIII:

51. A compound of formula XIX:

52. A compound of formula XX:

53-55. -55. (canceled)

57-59. -59. (canceled)