Heterocycles as potassium channel modulators
Compounds, compositions and methods are provided which are useful in the treatment of diseases through the modulation of potassium ion flux through voltage-dependent potassium channels. More particularly, the invention provides heterocycles, compositions and methods that are useful in the treatment of central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorders, trigeminal neuralgia, spasticity, mood disorders, brain tumors, psychotic disorders, myokymia, seizures, epilepsy, seizure, retinal degeneration, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning deficiencies, anxiety, neuronal degeneration and motor neuron diseases, maintaining bladder control or treating urinary incontinence) and as neuroprotective agents (e.g., to prevent stroke and the like) by modulating potassium channels associated with the onset or recurrence of the indicated conditions.
1. A compound of Formula (IX):
or a pharmaceutically acceptable salt thereof, wherein:
R 11 and R 12 are each independently selected from the group consisting of —H, halogen, C 1-8 haloalkyl, —CN, C 1-8 alkyl, C 1-8 alkoxy, aryloxy and aryl-C 1-8 alkoxy;
R 13 is selected from the group consisting of aryl, C 3-8 cycloalkyl, aryl-C 1-6 alkyl, C 3-8 cycloalkyl-C 1-8 alkyl, heteroaryl and heteroaryl-C 1-6 alkyl, wherein the aromatic portion of the R 13 group is optionally substituted with from 1-3 R a substituents, each R a is independently selected from the group consisting of halogen, C 1-8 haloalkoxy, C 1-8 alkoxy, C 1-8 haloalkyl, —CN and R b , wherein R b is C 1-8 alkyl optionally substituted with from 1-2 substituents selected from halogen, —CN, —OH, C 1-8 haloalkoxy or C 1-8 alkoxy; or any two adjacent R a substituents together with the atoms to which they are attached form a 5- or 6-membered carbocyclic ring, optionally substituted with a C 1-8 alkyl;
R 14 is selected from the group consisting of C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-8 alkyl, aryl, aryl-C 1-8 alkyl, wherein the aromatic portion of the R 14 group is optionally substituted with from 1-3 R e substituents independently selected from the group consisting of halogen, C 1-8 haloalkyl, C 1-8 alkyl, C 1-8 alkoxy, —CN or haloalkoxy, —OH, —OC(O)O—R f , —OC(O)R f , —OC(O)NHR f , —OC(O)N(R f ) 2 , —S(O)R f , —S(O) 2 R f , —SO 2 NH 2 , —S(O) 2 NHR f , —S(O) 2 N(R) 2 , —NHS(O) 2 R f , —NR f S(O) 2 R f , —C(O)NH 2 , —C(O)NHR f , —C(O)N(R f ) 2 , —C(O)R f , —C(O)H, wherein each R f is independently a C 1-8 alkyl; and the cycloalkyl portion of the R 14 group is optionally substituted with from 1-3 substituents selected from halogen, C 1-8 alkyl or optionally fused with a 5- or 6 membered aromatic ring having from 0-2 heteroatoms as ring members selected from N, O or S;
R 15 is —H;
Z 1 is ═C(R 16 )— and Z 2 is ═C(R 17 )—, wherein R 16 and R 17 are each independently —H, C 1-8 alkyl, halogen, —CN, C 1-8 haloalkyl, C 1-8 haloalkoxy, —OR 9 or —N(R 9 ) 2 , wherein R 9 is independently —H, C 1-8 alkyl or aryl-C 1-8 alkyl;
at each occurrence, “alkyl” by itself or as part of another substituent, is an unsubstituted, fully saturated, straight or branched chain hydrocarbon radical;
at each occurrence, “cycloalkyl” by itself or as part of another substituent is an unsubstituted, fully saturated, cyclic hydrocarbon radical; and
at each occurrence, “aryl” by itself or as part of another substituent is a monovalent monocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbon radical.
2. The compound of claim 1 , represented by Formula (IXa):
or a pharmaceutically acceptable salt thereof; wherein R 16 and R 17 are each independently —H, C 1-8 alkyl, halogen, —CN, C 1-8 haloalkyl, C 1-8 haloalkoxy, —OR 9 or —N(R 9 ) 2 , wherein R 9 is independently —H, C 1-8 alkyl or aryl-C 1-8 alkyl.
3. A compound represented by a Formula selected from the group consisting of:
or a pharmaceutically acceptable salt thereof; wherein:
R 11 and R 12 are each independently selected from the group consisting of —H, halogen, C 1-8 haloalkyl, —CN, C 1-8 alkyl, C 1-8 alkoxy, aryloxy and aryl-C 1-8 alkoxy;
R 16 and R 17 are each independently —H, C 1-8 alkyl, halogen, CN, C 1-8 haloalkyl, C 1-8 haloalkoxy, —OR 9 or —N(R 9 ) 2 , wherein R 9 is independently —H, C 1-8 alkyl or aryl-C 1-8 alkyl;
the subscripts m and n are each independently an integer of 0-3;
R 13 is selected from the group consisting of aryl, C 3-8 cycloalkyl, aryl-C 1-8 alkyl, C 3-8 cycloalkyl-C 1-8 alkyl, heteroaryl and heteroaryl-C 1-8 alkyl, wherein the aromatic portion of the R 13 group is optionally substituted with from 1-3 R a substituents, each R a is independently selected from the group consisting of halogen, C 1-8 haloalkoxy, C 1-8 alkoxy, C 1-8 haloalkyl, —CN and R b , wherein R b is C 1-8 alkyl optionally substituted with from 1-2 substituents selected from halogen, —CN, —OH, C 1-8 haloalkoxy or C 1-8 alkoxy; or any two adjacent R a
substituents together with the atoms to which they are attached form a 5- or 6-membered carbocyclic ring, optionally substituted with a C 1-8 alkyl;
R 13a is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
R 14 is selected from the group consisting of C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-8 alkyl, aryl, aryl-C 1-8 alkyl, C 4-5 heterocycloalkyl, and C 4-5 heterocycloalkyl-C 1-8 alkyl, wherein the aromatic portion of the R 14 group is optionally substituted with from 1-3 R e substituents independently selected from the group consisting of halogen, C 1-8 haloalkyl, C 1-8 alkyl, C 1-8 alkoxy, —CN or haloalkoxy, —OH, —OC(O)O—R f , —OC(O)R f , —OC(O)NHR f , —OC(O)N(R f ) 2 , —S(O)R f , —S(O) 2 R f , —SO 2 NH 2 , —S(O) 2 NHR f , —S(O) 2 N(R) 2 , —NHS(O) 2 R f , —NR f S(O) 2 R f , —C(O)NH 2 , —C(O)NHR f , —C(O)N(R f ) 2 , —C(O)R f , —C(O)H, wherein each R f is independently a C 1-8 alkyl; and the cycloalkyl portion of the R 14 group is optionally substituted with from 1-3 substituents selected from halogen, C 1-8 alkyl or optionally fused with a 5- or 6 membered aromatic ring having from 0-2 heteroatoms as ring members selected from N, O or S;
R 15 is —H;
R 18 and R 19 are each independently selected from the group consisting of halogen, C 1-8 haloalkoxy, C 1-8 alkoxy, C 1-8 haloalkyl, —CN and R b ; and
R 23 and R 24 are each independently —H, C 1-8 alkyl, halogen, C 1-8 haloalkyl, —CN, —NH 2 , —NHC 1-8 alkyl, —N(C 1-8 alkyl) 2 or R e .
4. The compound of claim 1 , represented by the Formula:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 12 is F or CF 3 .
6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 13 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, and 4-trifluoromethyl-2-pyridyl.
7. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 14 is 3,4-difluorophenyl.
8. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
9. A method of treating, represented by inhibiting or ameliorating a disorder or condition through modulation of a potassium ion channel, said method comprising:
administering to a subject in need of such treatment an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said disorder or condition is selected from migraine, pain, and anxiety.
10. The method of claim 9 , wherein said pain is a member selected from neuropathic pain, diabetic pain, somatic pain, cutaneous pain, visceral pain, inflammatory pain, cancer pain, migraine pain, or musculoskeletal pain.
11. The method of claim 9 , wherein said condition or disorder is pain or anxiety.
12. A compound of the formula:
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound of the formula:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.