Bicyclic Ketone Sulfonamide Compounds

Title:	Bicyclic ketone sulfonamide compounds
Patent Application Number:	WO2016141035	Publication date:	September 9, 2016
Priority Application:	US62127206	Priority date:	March 2, 2015
Inventors:	Weiss, Matthew; Milgram, Benajmin C.; Dineen, Thomas, Stellwagen, John; Guzman-Perez, Angel; Boezio, Alessandro; Marx, Issac E.
Assignee Company:	Amgen Inc.
Disease Area:	Pain	Biological Target:	Nav1.7

Summary:	Maintaining a specific membrane potential is a critical to various cellular functions in a variety of mammalian cells. The heart, central and peripheral nervous system, and muscle function all depend on the proper regulation and timing of changes in membrane potential. Voltage gated sodium channels play a key role in these processes. To date, nine voltage gated sodium channels, designated Nav1.1 to Nav1.9 have been identified, and improper activity can lead to a number of negative health consequences. Nav1.7, for example, has been linked to the sensation of pain. Loss of function mutations of this ion channel have been documented in humans and lead to congenital insensitivity to normally painful stimuli. Increased Nav1.7, however, has been associated with increased sensitivity to pain. These observations suggest that Nav1.7 blockade may be a viable method of treating pain, and compounds such as Raxatrigine (CNV1014802), a Nav1.7 blocker that recently completed phase II clinical trials for the treatment of lumbar radiculopathy (sciatica), appear to have validated this hypothesis. The present disclosure describes a series of compounds capable of modulating Nav1.7 activity and their use as treatment for chronic pain, acute pain, neuropathic pain, as well as pain associated with rheumatoid arthritis, osteoarthritis, cancer, or diabetes. The present disclosure also describes methods of treating cough and itch with the compounds of the disclosure.
Important Compound Classes:
Definitions:
	R1 is a 5-,6-, 7-, 8-, 9-, or 10-membered aryl or heteroaryl, or a 3-,4-,5-,6-, 7-, 8-, 9-, or 10- membered cycloalkyl or heterocycloalkyl group, wherein the heteroaryl or heterocycloalkyl group can have from 1 to 3 heteroatoms independently selected from O, N, or S, or a carbon atom in the cycloalkyl or heterocycloalkyl group can be part of a C = O group, and the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is substituted with 0, 1, 2, 3, or 4 substituents independently selected from halo, −CN, −C1–6alkyl, haloC 1–6alkyl, −OH, −O–C1–6alkyl, −O-halo C1–6alkyl, −C(=O)ORa, or -(CRbRb)nNRaRa;
	R2 is C1–6alkyl, or a 5-,6-, 7-, 8-, 9-, or 10-membered aryl or heteroaryl, or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10- membered cycloalkyl or heterocycloalkyl group, where the heteroaryl or heterocycloalkyl group can have from 1 to 3 heteroatoms independently selected from O, N or S, or a carbon atom in the cycloalkyl or heterocycloalkyl group can be part of a C=O group, and the alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group is optionally substituted with from 1 to 5 R6 substituents independently selected from halo, −CN, -C1–6alkyl, haloC1–6alkyl, −OH, −O-C1–6alkyl, −O-haloC1–6alkyl, −(CRbRb)mA, −C2–6alkenyl-A, −C2–6alkynyl-A, or −O(CRbRb)m-A;
	each R3 is independently selected from H, -C1–6alkyl, haloC1–6alkyl, or halo;
	each R4 is independently selected from H, -C1–6alkyl, haloC1–6alkyl, or halo;
	each R5 is independently selected from H, -C1–6alkyl, haloC1–6alkyl, or halo;
	A is a 4 to 9 membered aryl, heteroaryl, or heterocycloalkyl group, or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10- membered cycloalkyl group, where the heteroaryl or heterocycloalkyl group can have from 1 to 3 heteroatoms independently selected from O, N or S; and the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl group is substituted with 0, 1, 2, 3, or 4 R7 substituents independently selected from halo, -NRaRa, -C1–6alkyl, −O-C1–6alkyl, -(CRbRb)mOH, hydroxyC1–6alkyl, haloC1–6alkyl, -O-haloC1–6alkyl, −CN, -C(=O)NRaRa, -O-(CRbRb)mB or -(CRbRb)mB;
	B is a 5 to 6 membered aryl, heteroaryl, or heterocycloalkyl group, or a 3 to 5 membered cycloalkyl group, where the heteroaryl or heterocycloalkyl group can have from 1 to 3 heteroatoms independently selected from O, N or S; and the aryl, heteroaryl, cycloalkyl or heterocycloalkyl group is substituted with 0, 1, 2, 3, or 4 R8 substituents independently selected from halo, -NRaRa, -C1–6alkyl, -OC1–6alkyl, hydroxyC1–6alky1, −CF3, −CHF2, −CH2F, -OCF3, -OCHF2, -OCH2F, −CN or -C(=O)NRaRa;
	each Ra is independently H, halo, −CN, -NRcRc, −OH, -C1–6alkyl, -C1–6haloalkyl, -OC1–6haloalkyl, or -OC1–6alkyl;
	each Rb is independently H, halo, −CN, -NRcRc, −OH, -C1–6alkyl, -C1–6haloalkyl, -OC1–6haloalkyl, or -OC1–6alkyl;
	each Rc is independently H or -C1–6alkyl;
	each n is independently 0, 1, 2, 3, or 4; and
	each m is independently 0, 1, 2, 3, or 4.
Key Structures:
Recent Review Articles:	Rivara M.; Zuliani V.. Novel sodium channel antagonists in the treatment of neuropathic pain. Expert Opin. Invest. Drugs 2016, 25( (2), ), 215–226.
	Sun S.; Cohen C. J.; Dehnhardt C. M.. Inhibitors of voltage-gated sodium channel Nav1.7: patent applications since 2010. Pharm. Patent Analyst 2014, 3( (5), ), 509–521.
	King G. F.; Vetter I.. No Gain, No Pain: NaV1.7 as an Analgesic Target. ACS Chem. Neurosci.; 2014, 5( (9), ), 749–751.
Biological Assay:	Nav 1.7 In Vitro PatchXpress (PX) Assay:
	HEK293 cells stably transfected with human Nav 1. Seven were recorded in whole cell voltage clamp mode with the PatchXpress automated electrophysiology system (Molecular Devices, LLC, Sunnyvale, CA). Compound effects were measured on a partially inactivated state of the sodium channel. Cells were clamped to a holding potential yielding 20 to 50% inactivation. To elicit sodium current, channels were activated by pulsing to −10 mV for 20 ms. This voltage protocol was repeated at a rate of 0.1 Hz throughout the experiment. A single concentration of test compound was applied to cells for a duration of 3 min. Peak sodium current was measured at the end of the compound addition period to determine percent inhibition. Three to five cells were tested per concentration, and IC50 curves were fitted to percent inhibition as a function of concentration.
Biological Data:
Claims:	26 Total claims
	25 Composition of matter claims
	1 Method of use claim

The author declares no competing financial interest.