PYRROLOPYRAZINE-SPIROCYCLIC PIPERIDINE AMIDES AS MODULATORS OF ION CHANNELS

• US 20120196869A1
• Filed: 02/02/2012
• Published: 08/02/2012
• Est. Priority Date: 02/02/2011
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Kallel, Edward Adam, Miller, Mark Thomas, Arumugam, Vijayalaksmi, McCartney, Jason, Anderson, Corey, Grootenhuis, Peter Diederik Jan, Hadida Ruah, Sara Sabina, Jiang, Licong
• Granted Patent: US 8,916,565 B2
• Time in Patent Office: Days
• US Class Current: 514/250
• CPC Class Codes: A61K 31/499 Spiro-condensed pyrazines or piperazines
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 27/16 : Otologicals
• 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 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 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 471/20 : Spiro-condensed systems
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention relates to pyrrolopyrazine-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, independently for each occurrence:

R¹ is H, C1-C6 alkyl, C3-C8 cycloalkyl, halo, CN, NR⁸SO₂R⁸, SO₂R⁸, SR⁸, SOR⁸, NR⁸COR⁸, NR⁸CO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂, CF₃, heterocycloalkyl, or a straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR⁸, or two R¹ taken together form an oxo group, or a 3 to 7 membered fused cycloalkyl ring, or a 3 to 7 membered spirocyclic ring;

R² is H, C1-C6 alkyl, C1-C6 haloalkyl, CN, OH, SO₂R⁸, SR⁸, SOR⁸, CO₂R⁸, CON(R⁸)₂, SO₂N(R⁸)₂, CF₃, CHF₂, or a straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, CF₂, or NR⁸;

R³ is H, C1-C6 alkyl, C3-C8 cycloalkyl, CO₂R⁸, COR^S, COH, CON(R⁸)₂, CF₃, CH₂CF₃, CH₂CHF₂, or a straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR⁸;

R⁴ is H, C1-C6 alkyl, halo, C3-C8 cycloalkyl, wherein up to two CH₂ units may be replaced by O, CO, S, SO, SO₂, or NR⁸, or 2 R⁴ taken together form a fused 3 to 7 membered cycloalkyl ring;

R⁸ is H, C1-C6 alkyl, CF₃, C3-C8 cycloalkyl, or a straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR, or 2 R⁸ taken together with the atoms to which they are attached form a ring;

R⁹ is H, CF₃, CO₂R, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R)₂, NRCOR, CON(R)₂, CN, or SO₂R;

R is H, C1-C6 alkyl, aryl, heteroaryl, C3-C8 cycloalkyl, or heterocycloalkyl;

A is an optionally substituted aryl, heteroaryl or heterocyclic;

m is an integer from 0 to 4 inclusive;

n is an integer from 0 to 3 inclusive; and

o is an integer from 0 to 4 inclusive.

3. The compound of claim 1, wherein R¹ is C1-C8 alkyl or two R¹ taken together with the atoms to which they are attached form a 3 to 7 membered fused cycloalkyl or spirocyclic ring.

4. The compound of claim 1, wherein R¹ is CH₃ or two R¹ taken together form a fused cyclohexyl ring.

5. The compound claim 1, wherein R² is H, C1-C8 alkyl, halo, CF₃, CN, COR⁸, CON(R⁸)₂, or a straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂, CF₂, or NR⁸.

6. The compound of claim 1, wherein R² is COCF₃, COtBu, Cl, COCH₃, CF₂CF₃, CH₂CF₃, CF₃, CN, Br, COCH(CH₃)₂, COCH₂CH₃, CH(OH)CF₃, SO₂CH₃,

7. The compound of claim 1, wherein R³ is H, C1-C8 alkyl, CO₂R⁸, COR⁸, COH, CON(R⁸)₂ or a straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to two CH₂ units may be replaced with O, CO, S, SO, SO₂ or NR⁸.

8. The compound of claim 1, wherein R³ is H, CH₃, CH₂CH₃, CH₂CH₂OCH₃, CH₂CH₂OH, CH₂CO₂CH₂CH₃, CH₂CON(CH₃)₂, CH₂CONH₂, CH₂CN, benzyl, cyclobutyl, CH₂CH(CH₂)₂, CH(CH₂)₂, CH₂CF₃, CH₂CHF₂, COCH₃, COCH₂CH₃, CO₂CH₃, CO₂CH₂CH₃, COH, CONH(CH₃)₂, or CONHCH₃.

9. The compound of claim 1, wherein R⁴ is H, halo, or C1-C8 alkyl.

10. The compound of claim 1, wherein R⁴ is H, F, or CH₃.

11. The compound of claim 1, wherein m is 0, 1, or 2.

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

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

14. The compound of claim 1, wherein A is

15. The compound of claim 14, wherein R⁵ is H, C1-C8 alkyl, C1-C8 alkoxy, halo, OCF₃, OCHF₂, R⁹, or a straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁷.

16. The compound of claim 14, wherein R⁵ is H, CH₃, OCH₃, OCF₃, OPh, Ph, OCHF₂, or F.

17. The compound of claim 14, wherein R⁶ is H, C1-C8 alkyl, C1-C8 alkoxy, halo, R⁹, or a straight chain, branched, or cyclic (C1-C8)-R⁹ wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁸.

18. The compound of claim 14, wherein R⁶ is H, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, CF₃, CN, Ph, SO₂CH₃, OH, CH(CH₃)₂, OCH₂CH₂CH₂CH₃, F, Cl, or CH₂OH.

19. The compound of claim 14, wherein R⁷ is H, C1-C8 alkyl, C1-C8 alkoxy, SO₂R⁸, OSO₂R⁸, SO₂N(R⁸)₂, R⁹, OCHF₂, OCF₃, or a straight chain, branched, or cyclic (C1-C8)-(R⁹)_p, wherein p is 1 or 2 and wherein up to three CH₂ units may be replaced with O, CO, S, SO, SO₂, or NR⁸.

20. The compound of claim 14, wherein R⁷ is H, CH₃, CH₂CH₃, tBu, Cl, F, OH, C(═

CH₂)CH₃, OC(═

CH₂)CH₃, OCH₃, OCH₂CH₂CH₂CH₃, CH₂OH, OCH₂CH₂OH, OCH₂CH₂CH₂OH, OtBu, OCH(CH₃)(CH₂CH₃), OCH₂C(CH₃)₂OH, C(CH₃)₂OH, CH₂C(CH₃)₂OH, CH(OH)CH(CH₃)₂, C(CH₃)₂CH₂OH, OCH₂CH₂CH(CH₃)₂, OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂OCH₃,

21. The compound of claim 14, wherein

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

23. The compound of claim 22, wherein A is a monocyclic heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O, or S.

24. The compound of claim 22, wherein A is selected from a bicyclic heteroaryl comprising from 1 to 3 heteroatoms independently selected from N, O, or S.

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

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

27. The compound of claim 26, wherein R² is H, COCF₃, COtBu, Cl, COCH₃, CF₂CF₃, CH₂CF₃, CF₃, CN, Br, COCH(CH₃)₂, COCH₂CH₃, CH(OH)CF₃, SO₂CH₃,

28. The compound of claim 26, wherein R³ is H, CH₃, CH₂CH₃, CH₂CH₂OCH₃, CH₂CH₂OH, CH₂CO₂CH₂CH₃, CH₂CON(CH₃)₂, CH₂CONH₂, CH₂CN, benzyl, cyclobutyl, CH₂CH(CH₂)₂, CH(CH₂)₂, CH₂CF₃, CH₂CHF₂, COCH₃, COCH₂CH₃, CO₂CH₃, CO₂CH₂CH₃, COH, CONH(CH₃)₂, or CONHCH₃.

29. The compound of claim 26, wherein R⁶ is H, CH₃, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, CF₃, CN, Ph, SO₂CH₃, OH, CH(CH₃)₂, OCH₂CH₂CH₂CH₃, F, Cl, or CH₂OH.

30. The compound of claim 26, wherein R⁷ is H, CH₃, CH₂CH₃, tBu, Cl, F, OH, C(═

CH₂)CH₃, OC(═

CH₂)CH₃, OCH₃, OCH₂CH₂CH₂CH₃, CH₂OH, OCH₂CH₂OH, OCH₂CH₂CH₂OH, OtBu, OCH(CH₃)(CH₂CH₃), OCH₂C(CH₃)₂OH, C(CH₃)₂OH, CH₂C(CH₃)₂OH, CH(OH)CH(CH₃)₂, C(CH₃)₂CH₂OH, OCH₂CH₂CH(CH₃)₂, OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂OCH₃,

31. The compound of claim 26, wherein the

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

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

34. 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 of claim 1.

35. The method of claim 34, wherein the voltage-gated sodium ion channel is NaV 1.7.

36. 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 abnormal gastro-intestinal motility, comprising administering an effective amount of a compound of claim 1.

37. The method of claim 36, 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, pruritis, tinnitis, or angina-induced pain.