COMPOUNDS USEFUL AS RAF KINASE INHIBITORS

• US 20090036419A1
• Filed: 06/30/2008
• Published: 02/05/2009
• Est. Priority Date: 06/29/2007
• Status: Active Grant

• Current Assignee: Day One Biopharmaceuticals, Inc.
• Original Assignee: Sunesis Pharmaceuticals, Inc. (Viracta Therapeutics, Inc.)
• Inventors: Littke, Adam, Franklin, Lloyd, Xin, Zhili, Peng, Hairuo, Vessels, Jeffrey, Cossrow, Jennifer, Powell, Noel, Guan, Bing, Raimundo, Brian C., Tanaka, Hiroko, Kumaravel, Gnanasambandam, Wynn, Thomas, Jones, John Howard, Lugovskoy, Alexey, Lane, Benjamin, Chen, Weirong
• Granted Patent: US 8,293,752 B2
• Time in Patent Office: Days
• US Class Current: 514/210.200
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• 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: 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 403/12 : 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 473/00 : Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07F 9/65583 : each of the hetero rings containing nitrogen as ring hetero atom

Abstract

The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein;

Cy¹ is an optionally substituted phenyl or an optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Cy² is an optionally substituted 5-14 membered saturated, partially unsaturated, or aromatic monocyclic, bicyclic, or tricyclic ring having 0-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur;

L¹ is a direct bond or an optionally substituted, straight or branched C_1-6 alkylene chain;

L² is a direct bond, or is an optionally substituted, straight or branched C_1-6 alkylene chain wherein 1 or 2 methylene units of L² are optionally and independently replaced by —

O—

, —

S—

, —

N(R)—

, —

C(O)—

, —

C(O)N(R)—

, —

N(R)C(O)N(R)—

, —

N(R)C(O)—

, —

N(R)C(O)O—

, —

OC(O)N(R)—

, —

SO₂—

, —

SO₂N(R)—

, —

N(R)SO₂—

, —

OC(O)—

, —

C(O)O—

, or a 3-6 membered cycloalkylene;

each R is independently hydrogen or an optionally substituted C_1-6 aliphatic group;

R¹ is hydrogen or an optionally substituted C_1-6 aliphatic group;

each of R^x and R^y is independently selected from —

R², -halo, —

NO₂, —

CN, —

OR², —

SR², —

N(R²)₂, —

C(O)R², —

CO₂R², —

C(O)C(O)R², —

C(O)CH₂C(O)R², —

S(O)R², —

S(O)₂R², —

C(O)N(R²)₂, —

SO₂N(R²)₂, —

OC(O)R², —

N(R²)C(O)R², —

N(R²)N(R²)₂, —

N(R²)—

C(═

NR²)N(R²)₂, —

C(═

NR²)N(R²)₂, —

C═

NOR², —

N(R²)C(O)N(R²)₂, —

N(R²)SO₂N(R²)₂, —

N(R²)SO₂R², or —

OC(O)N(R²)₂; and

each R² is independently hydrogen or an optionally substituted group selected from C_1-6 aliphatic, a C_6-10 monocyclic or bicyclic aryl ring, or a 5-10 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or

two R² on the same nitrogen are taken together with the nitrogen to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

2. The compound according to claim 1, wherein each of R^x and R^y is independently selected from R², halo, —

OR², —

N(R²)₂, —

OC(O)R², —

N(R²)C(O)R², —

N(R²)N(R² )₂, —

N(R²)N(R²)₂, —

N(R²)C(O)N(R²)₂, —

N(R²)SO₂N(R²)₂, —

N(R²)SO₂R², or —

OC(O)N(R²)₂.

3. The compound according to claim 2, wherein R^x is hydrogen, an optionally substituted C_1-6 aliphatic group, or halo.

4. The compound according to claim 2, wherein R^y is selected from R^y, —

OR², or —

N(R²)₂.

5. The compound according to claim 4, wherein R^y is —

NH₂, —

NHCH₃, —

NHCH₂CH₃, —

NHCH₂CH₂CH₃, —

NHCH(CH₃)₂, —

NH(C₃H₅), —

NHCH₂CH₂CH₂OH, —

N(CH₂CH₂)₂O, or —

NHCH₂CH₂CH₂NH(CH₃)₂.

6. The compound according to claim 4, wherein R^y is an optionally substituted C_1-6 aliphatic group.

7. The compound according to claim 6, wherein R^y is an optionally substituted group selected from C_2-6 alkenyl or C_2-6 alkynyl.

8. The compound according to claim 4, wherein R^y is an optionally substituted 5-10 membered saturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

9. The compound according to claim 8, wherein R^y is an optionally substituted group selected from:

(a) a 5-6 membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

(b) a 5-6 membered aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

or

(c) an 8-10 membered saturated, partially unsaturated or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

10. The compound according to claim 8, wherein R^y is an optionally substituted group selected from phenyl, octahydroazocinyl, thiocyclopentanyl, thiocyclohexanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, thioxanyl, morpholinyl, oxathiolanyl, imidazolidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiaziolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrahydropyridinyl, benzofuranyl, thianaphthenyl, pyrolizinyl, indolyl, quinolinyl, isoquinolinyl, benximidazolyl, imidazopyridinyl, purinyl, indazolyl, pyrrolopyridinyl, cinnolinyl, quinazolinyl, phthalazinyl, napthyridinyl, or quinoxalinyl.

11. The compound according to claim 1, wherein R¹ is hydrogen and L¹ is an optionally substituted, straight or branched C_1-4 alkylene chain.

12. The compound according to claim 11, wherein L¹ is an optionally substituted, branched C_1-4 alkylene chain.

13. The compound according to claim 1, wherein Cy¹ is an optionally substituted 5-membered saturated, partially unsaturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

14. The compound according claim 13, wherein Cy¹ is an optionally substituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, or oxadiaziolyl group.

15. The compound according to claim 1, wherein L² is a direct bond or an optionally substituted, straight or branched C_1-4 alkylene chain wherein 1 or 2 methylene units of L² are replaced by —

O—

, —

S—

, —

N(R)—

, —

C(O)—

, —

C(O)N(R)—

, —

N(R)C(O)N(R)—

, —

N(R)C(O)—

, —

N(R)C(O)O—

, —

OC(O)N(R)—

, —

SO₂—

, —

SO₂N(R)—

, —

N(R)SO₂—

, —

OC(O)—

, or —

C(O)O—

.

16. The compound according to claim 15, wherein L² is —

C(O)N(R)—

, —

N(R)C(O)—

, —

SO₂N(R)—

, —

N(R)SO₂—

, —

OC(O)—

, or —

C(O)O—

.

17. The compound according to claim 16, wherein L² is —

C(O)N(H)—

or —

N(H)C(O)—

.

18. The compound according to claim 1, wherein Cy² is an optionally substituted group selected from:

(a) a 5-membered saturated, partially unsaturated, or aromatic monocyclic ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur;

(b) phenyl or a 6-membered saturated, partially unsaturated, or aromatic monocyclic ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur;

or

(c) a 5-10 membered saturated, partially unsaturated, or aromatic bicyclic ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.

19. The compound according to claim 18, wherein Cy² is an optionally substituted group selected from:

(a) a 5-membered heteroaryl ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur;

(b) phenyl or a 6-membered heteroaryl ring having 1-3 nitrogen atoms;

or

(c) a 5,6-fused bicyclic heteroaryl ring having 1-4 heteroatoms selected from oxygen, sulfur or nitrogen.

20. The compound according to claim 19, wherein Cy² is an optionally substituted group selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiaziolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyyrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, imidazopyridinyl, indazolyl, purinyl, cinnolinyl, quinazolinyl, phthalazinyl, naphthridinyl, quinoxalinyl, thianaphtheneyl, or benzofuranyl.

21. The compound according to claim 1, wherein said compound is of formula II:

or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 1, wherein said compound is selected from those depicted in Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof.

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

26. The composition of claim 25, in combination with a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

27. A method of inhibiting Raf kinase activity in a patient;

or a biological sample, which method comprises administering to said patient, or contacting said biological sample with a compound according to claim 1, or a pharmaceutical composition thereof;

28. A method of treating or lessening the severity of a Raf-mediated disorder in a mammal suffering such disorder, wherein the disorder is selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically-mediated disorder, a viral disease, or a bone disorder, the method comprising the step of administering to said patient a compound according to claim 1, or a pharmaceutical composition thereof.

29. The method according to claim 28, wherein the disorder is selected from melanoma, leukemia, colon cancer, breast cancer, gastric cancer, ovarian cancer, lung cancer, brain cancer, laryngeal cancer, cervical cancer, renal cancer, cancer of the lymphatic system, cancer of the genitourinary tract (including bladder cancer and prostate cancer), stomach cancer, bone cancer, lymphoma, glioma, papillary thyroid cancer, neuroblastoma, and pancreatic cancer.

30. The method according to claim 29, comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein:

said additional therapeutic agent is appropriate for the disease being treated; and

said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

22. The compound according to claim 22, wherein said compound is of formula II-a or II-b:

23. The compound according to claim 22, wherein Cy¹ is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

31. A method for preparing a compound of formula II-a′

;

or a pharmaceutically acceptable salt thereof, wherein;

Cy¹ is an optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Cy² is an optionally substituted 5-10 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur;

each of R^x and R^y is independently selected from —

R², -halo, —

NO₂, —

CN, —

OR², —

SR², —

N(R²)₂, —

C(O)R², —

CO₂R², —

C(O)C(O)R², —

C(O)CH₂C(O)R², —

S(O)R², —

S(O)₂R², —

C(O)N(R²)₂, —

SO₂N(R²)₂, —

OC(O)R², —

N(R²)C(O)R², —

N(R²)N(R²)₂, —

N(R²)—

C(═

NR²)N(R²)₂, —

C(═

NR²)N(R²)₂, —

C═

NOR², —

N(R²)C(O)N(R²)₂, —

N(R²)SO₂N(R²)₂, —

N(R²)SO₂R², or —

OC(O)N(R²)₂;

each R² is independently hydrogen or an optionally substituted group selected from C_1-6 aliphatic, a C_6-10 monocyclic or bicyclic aryl ring, or a 5-10 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or

two R² on the same nitrogen are taken together with the nitrogen to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,

comprising the step of coupling a compound of formula II-viii;

with a compound of formula II-vii;

to form the compound of formula II-a′

.

32. The method according to claim 31, wherein the compound of formula II-vii is prepared from a compound of formula II-vi-b:

wherein A⁻

is a suitable chiral anion,

comprising the step of treating the compound of formula II-vi-b with a suitable base to form a compound of formula II-vii.

33. The method according to claim 32, wherein the compound of formula II-vi-b is prepared from a compound of formula II-v:

comprising the steps of;

(a) treating the compound of formula II-v with a chiral agent to form a compound of formula II-vi-a;

and

(b) separating the resulting diastereomers by suitable physical means to obtain a compound of formula II-vi-b.

34. The method according to claim 33, wherein the compound of formula II-v:

is prepared from a compound of formula II-iv;

comprising the step of converting the oxime moiety of formula II-iv to the amine group of formula II-v.

35. The method according to claim 34, wherein the compound of formula II-iv is prepared from a compound of formula II-iii:

comprising the step of treating the conpound of formula II-iii with hydroxylamine to form the compound of formula II-iv.

36. The method according to claim 35, wherein the compound of formula II-iii is prepared by coupling a compound of formula II-i:

with a compound of formula II-ii;

37. A compound of formula II-vi-a or II-vi-b:

wherein;

A⁻

is a suitable chiral anion;

Cy¹ is an optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

Cy² is an optionally substituted 5-10 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.

38. A compound of formula II-iv:

wherein

Cy¹ is an optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

Cy² is an optionally substituted 5-10 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.