Morpholine-spirocyclic piperidine amides as modulators of ion channels

• US 8,828,996 B2
• Filed: 03/13/2012
• Issued: 09/09/2014
• Est. Priority Date: 03/14/2011
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Hadida-Ruah, Sara Sabina, Binch, Hayley Marie, DeNinno, Michael Paul, Fanning, Lev Tyler Dewey, Frieman, Bryan A., Grootenhuis, Peter Diederik Jan, Hilgraf, Nicole, Joshi, Pramod, Kallel, Edward Adam, Miller, Mark Thomas, Pontillo, Joseph, Silina, Alina, Sheth, Urvi Jagdishbhai, Hurley, Dennis James, Arumugam, Vijayalaksmi
• Primary Examiner(s): Habte, Kahsay
• Application Number:
  US13/418,737
• Publication Number:
  US 20120264749A1
• Time in Patent Office: 910 Days
• Field of Search: 544/71, 514/232.2, 514/235.8, 514/235.5
• US Class Current: 514/232.2
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/04 Antipruritics
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 498/10 : Spiro-condensed systems

Abstract

The invention relates to morpholine spirocyclic piperidine amide compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein R¹ is optionally substituted aryl, heteroaryl, C1-C6 alkyl, C1-C6 fluoroalkyl, a straight chain, branched, or cyclic-(C3-C8)—

R⁹ wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, N, or NR⁸.

3. The compound of claim 1, wherein R¹ is F, or optionally substituted phenyl, pyridyl, oxazole, thiazole, pyrazole, oxadiazole, CH₂OCH₃, CH₂F, CH₂OCH(CH₃)₂, CH₂OCHF₂, CH₃, CH₂CH₃, CH₂OH, C(CH₃)₂OH, CH₂CH₂OH, CH₂OCH₂CH₃, CH(CH₂)₂,

4. The compound of claim 1, wherein R² is H, C1-C6 alkyl, C1-C6 fluoroalkyl, CF₃, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or a straight chain, branched, or cyclic-(C3-C8)—

R⁹ wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, N, or NR⁸.

5. The compound of claim 1, wherein R² is H, CH₂CHF₂, CH₂CF₃, CH(CH₃)CH₂F, CH₂CH(CH₃)₂, CH₃, CH₂CH₃, tBu, CH₂CN, CH(CH₃)₂, CH₂C(CH₃)₂OH, CH₂CH₂CH(CH₃)₂, CH₂CH₂OH, C(O)CH₂CH₃, C(O)CH(CH₃)₂, CH(CH₃)CH₂F, CH₂CH(CH₃)₂, CH(CH₂CH₃)₂, CH₂C(CH₃)₂OH, CH₂CH₂CH(CH₃)₂, CH₂CH₂OH, C(O)CH₃, C(O)CH₂CH₃, C(O)CH(CH₃)₂, CH₂CF₂CH₃, CH₂CCCH₃, CH₂C(O)tBu, CH₂CH₂OCH₃, CH₂OCH₃, CH₂C(O)CH₃, CH₂C(O)OCH₃, CH₂CH₂OCH₂CH₂CH₃, CH₂CCCH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂CH₂SCH₃, CH₂CH₂CH₂OCH₃, CH₂CH(CH₂CH₃)₂, n-butyl, n-propyl,

6. The compound of claim 1, wherein n is 0, 1, 2, or 3.

7. The compound of claim 1, wherein n is 1 or 2.

8. The compound of claim 1, wherein n is 1.

9. The compound of claim 1, wherein o is 0 or 1.

10. The compound of claim 1, wherein o is 0.

11. The compound of claim 1, wherein A is

12. The compound of claim 11, wherein R⁴ is H, C1-C6 alkyl, halo, or OCHF₂.

13. The compound of claim 11, wherein R⁴ is H, F, CH₃, or OCHF₂.

14. The compound of claim 11, wherein R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CF₃, CN, or a straight chain, branched, or cyclic-(C3-C8)—

R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, N, or NR⁸.

15. The compound of claim 11, wherein R⁵ is H, CH₃, OCH₃, OCH₂CH₃, OCH(CH₃)₂, F, Cl, CF₃, CN, or CH₂OH.

16. The compound of claim 11, wherein R⁶ is H, C1-C6 alkyl, C1-C6 alkoxy, SO₂R⁸, SO₂N(R⁸)₂, R⁹, or a straight chain, branched, or cyclic (C3-C8)—

R⁹, wherein up to three CH₂ units may be replaced with O, S, SO, SO₂, N, or NR⁸.

17. The compound of claim 11, wherein R⁶ is H, CH₂OH, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH₂CH₂CH(CH₃)₂, OtBu, tBu, OCH(CH₃)₂, OCH₂C(CH₃)₂OCH₃, CH(OH)CH(CH₃)₂, C(OH)(CH₂CH₃)₂, OCH₂C(CH₃)₂OH, C(CH₃)₂OH, OCH₂CH₂OCH₃, OCH₂CH₂OH, OCH₂CH₂CH₂OH, CCCH₂OCH₃, SO₂CH₃, SO₂CH₂CH(CH₃)₂, SO₂CH(CH₃)₂, SO₂CH₂CH₃, SO₂C(CH₃)₃, CON(CH₂CH₃)₂, C(CH₃)₂CO₂CH₃,

18. The compound of claim 11, wherein

19. The compound of claim 1, wherein A is heteroaryl or heterocyclic.

20. The compound of claim 19, wherein A is a monocyclic heteroaryl comprising 1 to 3 heteroatoms, wherein said heteroatoms are independently N, O, or S.

21. The compound of claim 19, wherein A is a bicyclic heteroaryl comprising from 1 to 3 heteoratoms, wherein said heteroatoms are independently N, O, or S.

22. The compound of claim 19, wherein A is

23. The compound of claim 22, wherein R⁴ is H or C1-C6 alkyl.

24. The compound of claim 22, wherein R⁴ is H.

25. The compound of claim 22, wherein R⁵ is H, C1-C6 alkyl, or C1-C6 alkoxy.

26. The compound of claim 22, wherein R⁵ is H, CH₃, or OCH₃.

27. The compound of claim 22, wherein R⁶ is H, CN, C1-C6 alkoxy, or CF₃.

28. The compound of claim 22, wherein R⁶ is H, CN, OCH₃, or CF₃.

29. The compound of claim 22, wherein A is:

30. The compound of claim 1, wherein the compound has formula IA:

31. The compound of claim 30, wherein R² is C1-C6 alkyl, C1-C6 fluoroalkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or a straight chain, branched, or cyclic-(C3-C8)—

R⁹ wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸.

32. The compound of claim 30, wherein R² is CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH₂CHF₂, CH₂CF₃, CH(CH₃)CH₂F, CH₂CN, CH₂CH₂OH, CH₂C(CH₃)₂OH, COCH₂CH₃, or COCH(CH₃)₂.

33. The compound of claim 30, wherein R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluroroalkyl, halo, or a straight chain, branched, or cyclic (C3-C8)—

R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸.

34. The compound of claim 30, wherein R⁵ is H, CH₃, OCH₃, OCH₂CH₃, CF₃, Cl, F, or CH₂OH.

35. The compound of claim 30, wherein R⁶ is H, C1-C6 alkoxy, or a straight chain, branched, or cyclic-(C3-C8)—

R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸.

36. The compound of claim 30, wherein R⁶ is H, CH₂OH, OCH₂CH₃, OtBu, OCH(CH₃)₂, OCH₂C(CH₃)₂OCH₃, CH(OH)CH(CH₃)₂, OCH₂C(CH₃)₂OH, C(CH₃)₂OH, OCH₂CH₂OCH₃, OCH₂CH₂OH, OCH₂CH₂CH₂OH, CCCH₂OCH₃, SO₂CH₃, SO₂CH₂CH(CH₃)₂, SO₂CH(CH₃)₂, SO₂CH₂CH₃, SO₂C(CH₃)₃, CON(CH₂CH₃)₂, C(CH₃)₂CO₂CH₃,

37. The compound of claim 30, wherein R⁷ is halo.

38. The compound of claim 30, wherein R⁷ is F.

39. The compound of claim 30, wherein the

40. The compound of claim 30, wherein the compound has formula IB:

41. The compound of claim 40, wherein R² is C1-C6 alkyl, C1-C6 fluoroalkyl, or a straight chain, branched, or cyclic-(C3-C8)—

R⁹ wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR8.

42. The compound of claim 40, wherein R² is CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH₂CHF₂, CH₂CF₃, CH(CH₃)CH₂F, CH₂CN, CH₂CH₂OH, CH₂C(CH₃)₂OH, COCH₂CH₃, or COCH(CH₃)₂.

43. The compound of claim 40, wherein R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluroroalkyl, halo, or a straight chain, branched, or cyclic (C3-C8)—

R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸.

44. The compound of claim 40, wherein R⁵ is H, CH₃, OCH₃, OCH₂CH₃, CF₃, Cl, F, or CH₂OH.

45. The compound of claim 40, wherein R⁶ is H, C1-C6 alkoxy, or a straight chain, branched, or cyclic-(C3-C8)—

R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸.

46. The compound of claim 40, wherein R⁶ is H, CH₂OH, OCH₂CH₃, OtBu, OCH(CH₃)₂, OCH₂C(CH₃)₂OCH₃, CH(OH)CH(CH₃)₂, OCH₂C(CH₃)₂OH, C(CH₃)₂OH, OCH₂CH₂OCH₃, OCH₂CH₂OH, OCH₂CH₂CH₂OH, CCCH₂OCH₃, SO₂CH₃, SO₂CH₂CH(CH₃)₂, SO₂CH(CH₃)₂, SO₂CH₂CH₃, SO₂C(CH₃)₃, CON(CH₂CH₃)₂, C(CH₃)₂CO₂CH₃,

47. The compound of claim 40, wherein R⁷ is halo.

48. The compound of claim 40, wherein R⁷ is F.

49. The compound of claim 40, wherein the

50. The compound of claim 1, wherein the compound has formula IC:

51. The compound of claim 50, wherein the Het ring is an optionally substituted thiazole, pyridine, pyrazole, oxazole, or oxadiazole.

52. The compound of claim 50, wherein p is 0 or 1.

53. The compound of claim 50, wherein, R⁷ is C1-C6 alkyl.

54. The compound of claim 50, wherein, R⁷ is CH₃, CH₂CH₃, CH(CH₃)₂, or tBu.

55. The compound of claim 50, wherein the Het ring is

56. The compound of claim 50, wherein R² is C1-C6 alkyl or a straight chain, branched, or cyclic-(C3-C8)—

R⁹ wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸.

57. The compound of claim 50, wherein R² is CH₂CH₃, tBu, CH₂CHF₂, CH₂CF₃, or

58. The compound of claim 50, wherein R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, or halo.

59. The compound of claim 50, wherein R⁵ is H, CH₃, OCH₃, F, or Cl.

60. The compound of claim 50, wherein R⁶ is H, C1-C6 alkoxy, or a straight chain, branched, or cyclic-(C3-C8)—

R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸.

61. The compound of claim 50, wherein R⁶ is OCH(CH₃)₂, C(CH₃)₂OH, OCH₂CH₂OH, OCH₂CH₂CH₂OH,

62. The compound of claim 1, wherein the compound has formula ID:

63. The compound of claim 62, wherein the Het ring is an optionally substituted thiazole, pyridine, pyrazole, oxazole, or oxadiazole.

64. The compound of claim 62, wherein p is 0 or 1.

65. The compound of claim 62, wherein R⁷ is C1-C6 alkyl.

66. The compound of claim 62, wherein R⁷ is CH₃, CH₂CH₃, CH(CH₃)₂, or tBu.

67. The compound of claim 62, wherein the Het ring is

68. The compound of claim 62, wherein R² is C1-C6 alkyl or a straight chain, branched, or cyclic-(C3-C8)—

R⁹ wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸.

69. The compound of claim 62, wherein R² is CH₂CH₃, tBu, CH₂CHF₂, CH₂CF₃, or

70. The compound of claim 62, wherein R⁵ is H, C1-C6 alkyl, C1-C6 alkoxy, or halo.

71. The compound of claim 62, wherein R⁵ is H, CH₃, OCH₃, F, or Cl.

72. The compound of claim 62, wherein R⁶ is H, C1-C6 alkoxy, or a straight chain, branched, or cyclic-(C3-C8)—

R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, N, CF₂, or NR⁸.

73. The compound of claim 62, wherein R⁶ is OCH(CH₃)₂, C(CH₃)₂OH, OCH₂CH₂OH, OCH₂CH₂CH₂OH,

74. The compound of claim 1, wherein the compound is selected from the following table:

75. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

76. A method of inhibiting a voltage-gated sodium ion channel in:

a patient;

or

a biological sample;

comprising administering to the patient, or contacting the biological sample, with the compound or composition of claim 1.

77. The method of claim 76, wherein the voltage-gated sodium ion channel is NaV 1.7.

78. A method of treating or lessening the severity in a subject of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpatic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise induced angina, palpitations, hypertension, migraine, or abormal gastro-intestinal motility, comprising administering an effective amount of a compound of claim 1.

79. The method of claim 78, wherein said method is used for treating or lessening the severity of femur cancer pain;

non-malignant chronic bone pain;

rheumatoid arthritis;

osteoarthritis;

spinal stenosis;

neuropathic low back pain;

neuropathic low back pain;

myofascial pain syndrome;

fibromyalgia;

temporomandibular joint pain;

chronic visceral pain, abdominal pain;

pancreatic;

IBS pain;

chronic and acute headache pain;

migraine;

tension headache, including, cluster headaches;

chronic and acute neuropathic pain, post-herpatic neuralgia;

diabetic neuropathy;

HIV-associated neuropathy;

trigeminal neuralgia;

Charcot-Marie Tooth neuropathy;

hereditary sensory neuropathies;

peripheral nerve injury;

painful neuromas;

ectopic proximal and distal discharges;

radiculopathy;

chemotherapy induced neuropathic pain;

radiotherapy-induced neuropathic pain;

post-mastectomy pain;

central pain;

spinal cord injury pain;

post-stroke pain;

thalamic pain;

complex regional pain syndrome;

phantom pain;

intractable pain;

acute pain, acute post-operative pain;

acute musculoskeletal pain;

joint pain;

mechanical low back pain;

neck pain;

tendonitis;

injury/exercise pain;

acute visceral pain, abdominal pain;

pyelonephritis;

appendicitis;

cholecystitis;

intestinal obstruction;

hernias;

chest pain, cardiac pain;

pelvic pain, renal colic pain, acute obstetric pain, labor pain;

cesarean section pain;

acute inflammatory, burn and trauma pain;

acute intermittent pain, endometriosis;

acute herpes zoster pain;

sickle cell anemia;

acute pancreatitis;

breakthrough pain;

orofacial pain including sinusitis pain, dental pain;

multiple sclerosis (MS) pain;

pain in depression;

leprosy pain;

Behcet'"'"'s disease pain;

adiposis dolorosa;

phlebitic pain;

Guillain-Barre pain;

painful legs and moving toes;

Haglund syndrome;

erythromelalgia pain;

Fabry'"'"'s disease pain;

bladder and urogenital disease, including, urinary incontinence;

hyperactivity bladder;

painful bladder syndrome;

interstitial cyctitis (IC);

prostatitis;

complex regional pain syndrome (CRPS), type I and type II;

widespread pain, paroxysmal extreme pain, pruritic, tinnitis, or angina-induced pain.