HETEROARYL COMPOUNDS AND USES THEREOF

• US 20090137588A1
• Filed: 10/17/2008
• Published: 05/28/2009
• Est. Priority Date: 10/19/2007
• Status: Active Grant

• Current Assignee: Celgene Avilomics Research Inc. (Bristol-Myers Squibb Company)
• Original Assignee: Avila Therapeutics Inc. (Bristol-Myers Squibb Company)
• Inventors: Ghosh, Shomir, Tester, Richland W., Kluge, Arthur F., Singh, Juswinder, Petter, Russell C.
• Granted Patent: US 7,982,036 B2
• Time in Patent Office: Days
• US Class Current: 514/235.800
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07B 2200/05 : Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 59/002 : Heterocyclic compounds
• CPC Class Codes: C07D 239/47 : One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/48 : Two nitrogen atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : 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 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C12N 9/12 : transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: C12Y 207/10 : Protein-tyrosine kinases (2.7.10)

Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein the compound is of formula II:

3. The compound according to claim 2, wherein Ring A is selected from:

4. The compound according to claim 1, wherein Ring B is selected from:

5. The compound according to claim 2, wherein m is 1, 2, 3, or 4.

6. The compound according to claim 1, wherein said compound is of formula I-i, I-ii, or I-iii:

7. The compound according to claim 1, wherein said compound is of formula II-i, II-ii, or II-iii:

8. The compound according to claim 1, wherein R¹ is -L-Y, wherein:

L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —

NRC(O)—

, —

C(O)NR—

, —

N(R)SO₂—

, —

SO₂N(R)—

, —

S—

, —

S(O)—

, —

SO₂—

, —

OC(O)—

, —

C(O)O—

, cyclopropylene, —

O—

, —

N(R)—

, or —

C(O)—

;

Y is hydrogen, C_1-6 aliphatic optionally substituted with 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

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

9. The compound according to claim 8, wherein:

L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —

C(O)—

, —

NRC(O)—

, —

C(O)NR—

, —

N(R)SO₂—

, —

SO₂N(R)—

, —

S—

, —

S(O)—

, —

SO₂—

, —

OC(O)—

, or —

C(O)O—

, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —

O—

, —

N(R)—

, or —

C(O)—

; and

Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

10. The compound according to claim 9, wherein L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —

C(O)—

, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —

O—

, —

N(R)—

, or —

C(O)—

.

11. The compound according to claims 9, wherein L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —

OC(O)—

.

12. The compound according to claim 9, wherein L is —

NRC(O)CH═

CH—

, —

NRC(O)CH═

CHCH₂N(CH₃)—

, —

NRC(O)CH═

CHCH₂O—

, —

CH₂NRC(O)CH═

CH—

, —

NRSO₂CH═

CH—

, —

NRSO₂CH═

CHCH₂—

, —

NRC(O)(C═

N₂)—

, —

NRC(O)(C═

N₂)C(O)—

, —

NRC(O)CH═

CHCH₂N(CH₃)—

, —

NRSO₂CH═

CH—

, —

NRSO₂CH═

CHCH₂—

, —

NRC(O)CH═

CHCH₂O—

, —

NRC(O)C(═

CH₂)CH₂—

, —

CH₂NRC(O)—

, —

CH₂NRC(O)CH═

CH—

, —

CH₂CH₂NRC(O)—

, or —

CH₂NRC(O)cyclopropylene-;

wherein R is H or optionally substituted C_1-6 aliphatic; and

Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

13. The compound according to claim 12, wherein L is —

NHC(O)CH═

CH—

, —

NHC(O)CH═

CHCH₂N(CH₃)—

, —

NHC(O)CH═

CHCH₂O—

, —

CH₂NHC(O)CH═

CH—

, —

NHSO₂CH═

CH—

, —

NHSO₂CH═

CHCH₂—

, —

NHC(O)(C═

N₂)—

, —

NHC(O)(C═

N₂)C(O)—

, —

NHC(O)CH═

CHCH₂N(CH₃)—

, —

NHSO₂CH═

CH—

, —

NHSO₂CH═

CHCH₂—

, —

NHC(O)CH═

CHCH₂O—

, —

NHC(O)C(═

CH₂)CH₂—

, —

CH₂NHC(O)—

, —

CH₂NHC(O)CH═

CH—

, —

CH₂CH₂NHC(O)—

, or —

CH₂NHC(O)cyclopropylene-.

14. The compound according to claim 9, wherein L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —

C(O)—

, —

NRC(O)—

, —

C(O)NR—

, —

N(R)SO₂—

, —

SO₂N(R)—

, —

S—

, —

S(O)—

, —

SO₂—

, —

OC(O)—

, or —

C(O)O—

, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —

O—

, —

N(R)—

, or —

C(O)—

.

15. The compound according to claim 1, wherein R¹ is -L-Y, wherein:

L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two additional methylene units of L are optionally and independently replaced by —

NRC(O)—

, —

C(O)NR—

, —

N(R)SO₂—

, —

SO₂N(R)—

, —

S—

, —

S(O)—

, —

SO₂—

, —

OC(O)—

, or —

C(O)O—

,

Y is hydrogen, C_1-6 aliphatic optionally substituted with 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

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

16. The compound according to claim 15, wherein Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

17. The compound according to claim 16, wherein L is —

C≡

C—

, —

C≡

CCH₂N(isopropyl)-, —

NHC(O)C≡

CCH₂CH₂—

, —

CH₂—

C≡

C—

CH₂—

, —

C≡

CCH₂O—

, —

CH₂C(O)C≡

C—

, —

C(O)C≡

C—

, or —

CH₂C(═

O)C≡

C—

.

18. The compound according to claim 1, wherein R¹ is -L-Y, wherein:

L is a bivalent C_2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —

NRC(O)—

, —

C(O)NR—

, —

N(R)SO₂—

, —

SO₂N(R)—

, —

S—

, —

S(O)—

, —

SO₂—

, —

OC(O)—

, or —

C(O)O—

;

Y is hydrogen, C_1-6 aliphatic optionally substituted with 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

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

19. The compound according to claim 18, wherein Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

20. The compound according to claim 1, wherein R¹ is -L-Y, wherein:

L is a covalent bond, —

C(O)—

, —

N(R)C(O)—

, or a bivalent C_1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and

Y is selected from the following (i) through (xvii);

(i) C_1-6 alkyl substituted with oxo, halogen, NO₂, or CN;

(ii) C_2-6 alkenyl optionally substituted with oxo, halogen, NO₂, or CN;

or

(iii) C_2-6 alkynyl optionally substituted with oxo, halogen, NO₂, or CN;

or

(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R^e groups;

or

(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R^e groups;

or

(vi)

21. The compound according to claim 20, wherein L is a covalent bond, —

CH₂—

, —

NH—

, —

C(O)—

, —

CH₂NH—

, —

NHCH₂—

, —

NHC(O)—

, —

NHC(O)CH₂OC(O)—

, —

CH₂NHC(O)—

, —

NHSO₂—

, —

NHSO₂CH₂—

, —

NHC(O)CH₂OC(O)—

, or —

SO₂NH—

.

22. The compound according to claim 21, wherein L is a covalent bond.

23. The compound according to claim 20, wherein Y is selected from:

24. The compound according to claim 1, wherein R¹ is selected from:

27. A composition comprising a compound according to claim 1, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

28. The composition according to claim 27, in combination with an additional therapeutic agent.

29. The composition according to claim 28, wherein the additional therapeutic agent is a chemotherapeutic agent.

30. A method for inhibiting one or more of ErbB1, ErbB2, ErbB3, or ErbB4, or a mutant thereof, activity in a patient or in a biological sample comprising the step of administering to said patient or contacting said biological sample with a compound according to claim 1.

31. The method according to claim 30, wherein the one or more of ErbB1, ErbB2, or ErbB4, or a mutant thereof, activity is inhibited irreversibly.

32. The method according to claim 30, wherein the one or more of ErbB1, ErbB2, or ErbB4, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys797 of ErbB1, Cys805 of ErbB2 or Cys803 of ErbB4.

33. A method for treating an ErbB1-, ErbB2-, ErbB3-, or ErbB4-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to claim 1.

34. The method according to claim 33, wherein the disorder is a carcinoma selected from breast cancer, glioblastoma, lung cancer, cancer of the head and neck, colorectal cancer, bladder cancer, non-small cell lung cancer, squamous cell carcinoma, salivary gland carcinoma, ovarian carcinoma, or pancreatic cancer.

35. The method according to claim 34, wherein the disorder is selected from neurofibromatosis type I (NF1), neurofibromatosis type II (NF2) Schwann cell neoplasms (e.g. MPNST'"'"'s), or a Schwannoma.

36. A method for inhibiting one or more TEC-kinases, or a mutant thereof, activity in a patient or in a biological sample comprising the step of administering to said patient or contacting said biological sample with a compound according to claim 1.

37. The method according to claim 36, wherein the TEC-kinase, or a mutant thereof, activity is inhibited irreversibly.

38. The method according to claim 37 wherein the TEC-kinase is selected from one or more of TEC, ITK or BMX.

39. The method according to claim 38, where the one or more of TEC, ITK or BMX activity is inhibited irreversibly by colvalently modifying Cys 449 of TEC, Cys 442 of ITK or Cys 496 of BMX.

40. A method for treating a TEC-kinase-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to claim 1.

41. The method according to claim 40, wherein the disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, a hyperproliferative disease, an immunological-mediated diseases a disease of the respiratory tract, a disease of the bone and joints, a skin disorder, a gastrointestinal disorder, a systemic disease, or allograft rejection.

42. A method for inhibiting BTK, or a mutant thereof, activity in a patient or in a biological sample comprising the step of administering to said patient or contacting said biological sample with a compound according to claim 1.

43. The method according to claim 42, wherein the BTK, or a mutant thereof, activity is inhibited irreversibly.

44. The method according to claim 43, wherein the BTK, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys 481 of BTK.

45. A method for treating a BTK-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to claim 1.

46. The method according to claim 45, wherein the disorder is an autoimmune disease, a heteroimmune disease, an inflammatory disease, a cancer, or a thromboembolic disorder.

47. The method according to claim 46, wherein the disorder is selected from rheumatoid arthritis, multiple sclerosis, B-cell chronic lymphocytic leukemia, hairy cell leukemia, non-Hodgkin'"'"'s lymphoma, irritable bowel syndrome, Crohn'"'"'s disease, lupus or disorders associated with renal transplant.

48. A method for inhibiting JAK3, or a mutant thereof, activity in a patient or in a biological sample comprising the step of administering to said patient or contacting said biological sample with a compound according to claim 1.

49. The method according to claim 48, wherein the JAK3, or a mutant thereof, activity is inhibited irreversibly.

50. The method according to claim 49, wherein the JAK3, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys 909 of JAK3.

51. A method for treating a JAK3-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound according to claim 1.

52. The method according to claim 51, wherein the disorder is selected from an autoimmune disorder, an inflammatory disorder, a neurodegenerative disorder, or a solid or hematologic malignancy.

25. A compound selected from the group consisting of:

26. A compound selected from the group consisting of: