WO2016100184A1 - Geminal substituted quinuclidine amide compounds as agonists of alpha-7 nicotinic acetylcholine receptors - Google Patents

Geminal substituted quinuclidine amide compounds as agonists of alpha-7 nicotinic acetylcholine receptors Download PDF

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Publication number
WO2016100184A1
WO2016100184A1 PCT/US2015/065497 US2015065497W WO2016100184A1 WO 2016100184 A1 WO2016100184 A1 WO 2016100184A1 US 2015065497 W US2015065497 W US 2015065497W WO 2016100184 A1 WO2016100184 A1 WO 2016100184A1
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carboxamide
thiophene
benzo
azaspiro
bicyclo
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English (en)
French (fr)
Inventor
Raksha Acharya
Duane A. Burnett
Matthew Gregory Bursavich
Andrew Simon Cook
Bryce Alden Harrison
Gerhard Koenig
Andrew J. Mcriner
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Forum Pharmaceuticals Inc
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Forum Pharmaceuticals Inc
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Priority to JP2017533183A priority Critical patent/JP6612874B2/ja
Priority to ES15870786T priority patent/ES2764660T3/es
Priority to EP19200814.2A priority patent/EP3623371A1/en
Priority to CA2971413A priority patent/CA2971413A1/en
Priority to AU2015362790A priority patent/AU2015362790A1/en
Priority to EP15870786.9A priority patent/EP3233087B1/en
Priority to US15/536,073 priority patent/US10183938B2/en
Publication of WO2016100184A1 publication Critical patent/WO2016100184A1/en
Priority to IL252931A priority patent/IL252931A0/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—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

Definitions

  • the present invention relates to novel geminal substituted quinuclidine amide compounds, and pharmaceutical compositions of the same, that are suitable as agonists or partial agonists of a7-nAChR, and methods of preparing these compounds and compositions, and the use of these compounds and compositions in methods of maintaining, treating and/or improving cognitive function.
  • methods of administering the compound or composition to a patient in need thereof for example a patient with a cognitive deficiency and/or a desire to enhance cognitive function, that may derive a benefit therefrom.
  • acetylcholine esterase inhibitors may ameliorate the cognitive deficits in patients with cognitive disease.
  • the most widely used acetylcholine esterase inhibitor is donepezil hydrochloride (Aricept ® ).
  • Nicotinic acetylcholine receptors form a large family of ion channels which are activated by the messenger acetylcholine which is produced in the body (Galzi and Changeux, Neuropharmacol. 1995, 34, 563-582).
  • a functional nAChR consists of five subunits which may be different (certain combinations of al -9 and ⁇ 1 -4, ⁇ , ⁇ , ⁇ subunits) or identical (a7-9). This leads to the formation of a diversity of subtypes which differ in the distribution in the muscles, the nervous system l and other organs (McGehee and Role, Annu. Rev. Physiol. 1995, 57, 521-546).
  • nAChR Activation of nAChR leads to influx of cations into the cell and to stimulation of nerve cells or muscle cells. Selective activation of individual nAChR subtypes restricts this stimulation to the cell types which have a corresponding subtype and is thus able to avoid unwanted side effects such as, for example, stimulation of nAChR in the muscles.
  • Clinical experiments with nicotine and experiments in various animal models indicate that central nicotinic acetylcholine receptors are involved in learning and memory processes (e.g. Rezvani and Levin, Biol. Psychiatry 2001, 49, 258-267).
  • Nicotinic acetylcholine receptors of the alpha7 subtype have a particularly high concentration in regions of the brain which are important for learning and memory, such as the hippocampus and the cerebral cortex (Seguela et al., J. Neurosci. 1993, 13, 596-604).
  • the al nAChR has a particularly high permeability for calcium ions, modulates neurotransmission, influences the growth of axons and, in this way, modulates neuronal plasticity (Broide and Leslie, Mol. Neurobiol. 1999, 20, 1-16).
  • WO 2003/055878 describes a variety of agonists of the alpha7 nAChR said to be useful for improving cognition.
  • WO 2003/055878 suggests that certain agonists of the alpha7 nAChR are useful for improving perception, concentration, learning or memory, especially after cognitive impairments like those occurring for example in situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory loss, Alzheimer's disease, schizophrenia and certain other cognitive disorders.
  • An aspect of the invention provides a geminal substituted quinuclidine amide compound represented by Formula (I):
  • Z , Z , Z , Z , and Z independently represent N or CR ; with the proviso that no more than two of Z ⁇ Z 2 , Z 3 , Z 4 , and Z 5 are N;
  • R 5 and R 6 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • R 5 and R 6 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical;
  • Z 6 , Z 7 , Z 8 , and Z 9 independently represent N or CR 7 ; with the proviso that no more than two of Z 6 , Z 7 , Z 8 , and Z 9 are N;
  • R 7 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 8 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the carbonyl moiety; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)- heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, - Br, -I, -CN, -N0 2j -OR 8 ,
  • R 8 and R 9 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • R 8 and R 9 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical;
  • X 1 independently represents N or C
  • a 1 , A 2 , A 3 and A 4 independently represent N; NR 10 ; N(CH 2 ) m R 10 ; O; S; or CR 11 ; with the
  • R 10 independently represents -H; -D; -S0 2 (CH 2 ) m R 12 ; -(CO)(CH 2 ) m R 12 ; -
  • R 11 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 12 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 - cycloalkyl radical; a (3-6 membered) -heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: - D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 12 ; -(CH 2 ) m OR 12
  • R 12 and R 13 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • R 12 and R 13 taken together represent a C 2 -C 6 -alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • X 2 independently represents N or C
  • a 5 , A 6 , and A 7 independently represent N; NR 14 ; N(CH 2 ) m R 14 ; O; S; or CR 15 ; with the proviso that only one A 5 , A 6 , and A 7 is NR 14 , O, or S; with the further proviso that when X 2 is N, then A 5 , A 6 , and A 7 independently represent N or CR 15 ;
  • R 14 independently represents -H; -D; -(CH 2 ) m N(R 16 )(R 17 ); -S0 2 (CH 2 ) m R 16 ; -
  • R 15 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 16 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 - cycloalkyl radical; a (3-6 membered) -heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the carbonyl moiety; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: - D; -F; -CI; -Br; -I; -CN; -N0 2 ;
  • R 16 and R 17 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • R 16 and R 17 taken together represent a C 2 -C 6 -alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • G 1 , G 2 , G 3 , and G 4 independently represent C(R 18 )(R 18 ); N(R 19 ); -N(CH 2 ) m R 18 ; O; S; S0 2 ; or
  • R 18 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 19 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 - cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: - D, -F, -CI, -Br, -I, -CN, -NO 3 ⁇ 4 -OR 19 , -(CH 2 ) m OR 19 ,
  • R 19 and R 20 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • n independently represents an integer from 1 to 6;
  • Z , Z , Z , Z , and Z independently represent N or CR ; with the proviso that no more than two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are N;
  • R 4 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 5 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; a (3-6 membered) -heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)- heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, - Br, -I, -CN, -N0 2, -OR 5 , -(CH 2 ) m OR 5 , -N(R
  • R 5 and R 6 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical;
  • Z 6 , Z 7 , Z 8 , and Z 9 independently represent N or CR 7 ; with the proviso that no more than two of Z 6 , Z 7 , Z 8 , and Z 9 are N;
  • R 7 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 8 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the carbonyl moiety; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)- heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, - Br, -I, -CN, -N0 2j -OR 8 ,
  • R 8 and R 9 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • R 8 and R 9 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical;
  • X 1 independently represents N or C
  • a 1 , A 2 , A 3 and A 4 independently represent N; NR 10 ; N(CH 2 ) m R 10 ; O; S; or CR 11 ; with the
  • R 10 independently represents -H; -D; -S0 2 (CH 2 ) m R 12 ; -(CO)(CH 2 ) m R 12 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 - cycloalkyl radical; a (3-6 membered) -heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: - D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 12 ; -(CH 2 ) m OR 12
  • R 12 and R 13 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • R 12 and R 13 taken together represent a C 2 -C 6 -alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • X 2 independently represents N or C
  • a 5 , A 6 , and A 7 independently represent N; NR 14 ; N(CH 2 ) m R 14 ; O; S; or CR 15 ; with the proviso that only one A 5 , A 6 , and A 7 is NR 14 , O, or S; with the further proviso that when X 2 is N, then A 5 , A 6 , and A 7 independently represent N or CR 15 ;
  • R 14 independently represents -H; -D; -(CH 2 ) m N(R 16 )(R 17 ); -S0 2 (CH 2 ) m R 16 ; -
  • R 15 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 16 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 - cycloalkyl radical; a (3-6 membered) -heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the carbonyl moiety; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: - D; -F; -CI; -Br; -I; -CN; -N0 2 ;
  • R 16 and R 17 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • R 16 and R 17 taken together represent a C 2 -C 6 -alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • G 1 , G 2 , G 3 , and G 4 independently represent C(R 18 )(R 18 ); N(R 19 ); -N(CH 2 ) m R 18 ; O; S; S0 2 ; or
  • R 18 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 19 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 - cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: - D, -F, -CI, -Br, -I, -CN, -NO 3 ⁇ 4 -OR 19 , -(CH 2 ) m OR 19 ,
  • R 19 and R 20 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • n independently represents an integer from 1 to 6;
  • An aspect of the invention relates to the amide compound represented by Formula (I), wherein R 1 and R 2 independently represent an unbranched Ci-alkyl radical and said compound is represented by Formula (II):
  • An aspect of the invention relates to an amide compound represented by Formula (I), wherein R 1 and R 2 taken together represent a C 2 -alkyl di-radical and said compound is represented by Formula (III):
  • An aspect of the invention relates to a single stereoisomer of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof.
  • An aspect of the invention relates to a single enantiomer or a single diastereomer of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof.
  • An aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier, excipient or diluent.
  • An aspect of the invention relates to a method comprising administering to a patient in need thereof an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient a pharmaceutical composition comprising an effective dose of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent.
  • Another aspect of the invention provides a method of treating a patient in need thereof, comprising: administering to the patient an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient a pharmaceutical composition comprising an effective dose of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent.
  • Another aspect of the invention provides a method of maintaining, treating, curing and/or improving at least one cognitive function in a patient in need thereof, comprising: administering to the patient an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient a pharmaceutical composition comprising an effective dose of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent.
  • Another aspect of the invention provides a method of maintaining, treating, curing and/or improving at least one cognitive function in a patient in need thereof, comprising: administering to the patient an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient a pharmaceutical composition comprising an effective dose of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent.
  • Another aspect of the invention provides a method of treating a patient diagnosed as having a cognitive impairment, comprising: administering to the an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient an effective dose of a pharmaceutical composition comprising the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent.
  • Another aspect of the invention provides a method of treating a patient in need thereof, comprising: administering to the patient, for example, a patient diagnosed with having a cognitive impairment, Limited Cognitive Impairment, Mild Cognitive Impairment, Alzheimer's disease, and/or schizophrenia, an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient a pharmaceutical composition comprising an effective dose of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent; such that the patient may derive a benefit therefrom.
  • a pharmaceutical composition comprising an effective dose of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent; such that the patient may derive a benefit therefrom.
  • Another aspect of the invention provides a method of treating one or more symptoms associated with a cognitive impairment, comprising administering to a patient an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient a pharmaceutical composition comprising an effective dose of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent; wherein the patient suffers from, or has been diagnosed as having, a cognitive impairment.
  • Another aspect of the invention provides a method of improving cognition of a patient in need thereof, comprising: administering to the patient an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient a pharmaceutical composition comprising an effective dose of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent.
  • Another aspect of the invention provides a method of improving cognition in a patient suffering from a cognitive impairment, such as a cognitive impairment associated with either schizophrenia or Alzheimer's disease, for example mild Alzheimer's disease, moderate Alzheimer's disease, severe Alzheimer's disease, or mild-to-moderate Alzheimer's disease, comprising
  • Another aspect of the invention provides a method of treating a patient suffering from, diagnosed with having, or suffers from one or more symptoms associated with, a cognitive impairment, for example, Alzheimer's disease, dementia of an Alzheimer's type, MCI, LCI, or schizophrenia, comprising: administering to the patient an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient a pharmaceutical composition comprising an effective dose of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent.
  • a cognitive impairment for example, Alzheimer's disease, dementia of an Alzheimer's type, MCI, LCI, or schizophrenia
  • the method of treating a patient suffering from, diagnosed with having, or suffers from one or more symptoms associated with, a cognitive impairment may provide said patient at least one of the following: (i) treats, minimizes progression of, prevents the deterioration of, or reduces the rate of detioraration of, one or more symptoms associated with the cognitive impairment; (ii) treats the cognitive impairment; (iii) improves cognition in said cognitively impaired patient; (iv) improves one or more behavioral symptoms associated with the cognitive impairment; (v) provides a pro-cognitive effect; (vi) provides a pro-cognitive effect in at least one of the following: visual motor, learning, delayed memory, or executive function, or (vii) provides a positive effect on clinical function in said cognitively impaired patient.
  • Another aspect of the invention provides a method of treating a patient previously treated, or currently being treated, with an AChEI, that is suffering from, or has been diagnosed with having, a cognitive impairment, for example, Alzheimer's disease, dementia of an Alzheimer's type, MCI, LCI, or schizophrenia, comprising: administering to the patient an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient a pharmaceutical composition comprising an effective dose of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluents; wherein the method improves one or more symptoms associated with the cognitive impairment in the previously, or currently, AChEI treated patient.
  • a cognitive impairment for example, Alzheimer's disease, dementia of an Alzheimer's type, MCI, LCI, or schizophrenia
  • Another aspect of the invention provides a method of treating a patient suffering from, or diagnosed with having a cognitive impairment, comprising: administering to the patient an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient a pharmaceutical composition comprising an effective dose of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent; wherein the method provides a positive effect on cognition or a positive effect on clinical function in said cognitively impaired patient, and wherein said patient has been previously treated or is currently being treated with an AChEI.
  • Another aspect of the invention provides a method of improving cognition in a patient diagnosed as having a probable cognitive disease, comprising: administering to the patient an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient an effective dose of a pharmaceutical composition comprising the amide compound represented by Formula (I), Formula (III), Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient an effective dose of a pharmaceutical composition comprising the amide compound represented by Formula (I), Formula
  • Another aspect of the invention provides a method of improving or substantially improving one or more symptoms in a cognitve disease patient, comprising: administering to the patient an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula
  • Another aspect of the invention provides a method of slowing the rate of deterioration of at least one symptom in a cognitve disease patient, comprising: administering to the patient an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient the pharmaceutical composition comprising the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent.
  • Another aspect of the invention provides a method of treating one or more symptoms associated with a cognitive disease in a patient suffering therefrom, comprising: administering to the patient an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient an effective dose of a pharmaceutical composition comprising the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent
  • Another aspect provides a method of minimizing or substantially halting the rate of progression of one or more cognitive diseases in a patient suffering from a cognitive disease, comprising: administering to the patient an effective dose of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient an effective dose of a pharmaceutical composition comprising the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent.
  • Another aspect of the invention provides a method of substantially stopping or reversing progression of one or more cognitive diseases, in a patient suffering therefrom, comprising:
  • Another aspect of the invention provides a method of treating dementia, comprising: administering to a patient in need thereof an effective amount of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient an effective dose of a pharmaceutical composition comprising the effective amount of the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent; wherein said effective amount is administered in an effective dose.
  • Another aspect of the invention provides a method of treating dementia, comprising: administering to a patient in need thereof an effective amount of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient an effective dose of a pharmaceutical composition comprising the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent.
  • Another aspect of the invention provides a method of treating dementia, comprising: administering to a patient in need thereof an effective amount of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, wherein the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, is administered in the form of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, excipient or diluent.
  • Another aspect of the invention provides a method of treating dementia, comprising: administering to a patient in need thereof an effective amount of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient an effective dose of a pharmaceutical composition comprising the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent; wherein the pharmaceutical composition is in the form of a tablet.
  • Another aspect of the invention provides a method of treating a patient having a cognitive disease and being administered an acetylcholine esterase inhibitor, comprising: administering to a patient in need thereof an effective amount of an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof; or administering to the patient an effective dose of a pharmaceutical composition comprising an amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent; wherein the treatment comprises halting the administration of the acetylcholine esterase inhibitor prior to treating with the amide compound represented by Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof.
  • Figure 1 Illustrates a 3-D representation of the formed crystal of (i?)-2,2-dimethyl-N- ((R)- 1 -phenylethyl)quinuclidin-3 -amine fumarate .
  • Figure 2 Illustrates a 3-D representation of the formed crystal of (i?)-N-((i?)-l - phenylethyl)-r-azaspiro[cyclopropane-l,2'-bicyclo[2.2.2]octan]-3'-amine bis(4- methylbenzenesulfonate) .
  • An embodiment of the present invention provides a geminal substituted quinuclidine amide compound represented by Formula (I):
  • R 1 and R 2 independently represent a branched or unbranched Ci-C 4 -alkyl radical; or the C(R : )(R 2 ) moiety forms a (3-4 membered)-carbocycle, wherein R 1 and R 2 taken together represent a C 2 -C 3 -alkyl di-radical; wherein the Ci- C 4 -alkyl radical and the C 2 -C 3 -alkyl di-radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, CH 3 ,
  • Z , Z , Z , Z , and Z independently represent N or CR ; with the proviso that no more than two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are N;
  • R 4 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 5 ; -
  • R 5 and R 6 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • R 5 and R 6 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical;
  • Z 6 , Z 7 , Z 8 , and Z 9 independently represent N or CR 7 ; with the proviso that no more than two of Z 6 , Z 7 , Z 8 , and Z 9 are N;
  • R 7 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 8 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the carbonyl moiety; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)- heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, - Br, -I, -CN, -N0 2j -OR 8 ,
  • R 8 and R 9 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • R 8 and R 9 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical;
  • X 1 independently represents N or C
  • a 1 , A 2 , A 3 and A 4 independently represent N; NR 10 ; N(CH 2 ) m R 10 ; O; S; or CR 11 ; with the
  • R 10 independently represents -H; -D; -S0 2 (CH 2 ) m R 12 ; -(CO)(CH 2 ) m R 12 ; -
  • R 11 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 12 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 - cycloalkyl radical; a (3-6 membered) -heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: - D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 12 ; -(CH 2 ) m OR 12
  • R 12 and R 13 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • R 12 and R 13 taken together represent a C 2 -C 6 -alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • X 2 independently represents N or C
  • a 5 , A 6 , and A 7 independently represent N; NR 14 ; N(CH 2 ) m R 14 ; O; S; or CR 15 ; with the proviso that only one A 5 , A 6 , and A 7 is NR 14 , O, or S; with the further proviso that when X 2 is N, then A 5 , A 6 , and A 7 independently represent N or CR 15 ;
  • R 14 independently represents -H; -D; -(CH 2 ) m N(R 16 )(R 17 ); -S0 2 (CH 2 ) m R 16 ; -
  • R 15 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 16 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 - cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the carbonyl moiety; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: - D; -F; -CI; -Br; -I; -CN; -N0 2 ; -
  • R 16 and R 17 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • R 16 and R 17 taken together represent a C 2 -C 6 -alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • G 1 , G 2 , G 3 , and G 4 independently represent C(R 18 )(R 18 ); N(R 19 ); -N(CH 2 ) m R 18 ; O; S; S0 2 ; or
  • R 18 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 19 ; -
  • Ci-C 6 -alkyl radical a Ci-C 6 -haloalkyl radical; a C 3 -C 6 - cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: - D, -F, -CI, -Br, -I, -CN, -NO 3 ⁇ 4 -OR 19 , -(CH 2 ) m OR 19 ,
  • R 19 and R 20 independently represent -H; a branched or unbranched Ci-C 6 -alkyl
  • n independently represents an integer from 1 to 6;
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-I.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-I, wherein, for example, the Z 1 represents N, and Z 2 , Z 3 , Z 4 , and Z 5 each independently represent CR 4 ;
  • Z 2 represents N, and Z 1 , Z 3 , Z 4 , and Z 5 each independently represent CR 4 ;
  • Z 3 represents N, and Z 1 , Z2 , Z 4 , and Z 5 each independently represent
  • CR 4 ; Z 1 and Z2 each represent N, and Z 3 , Z4 , and Z5 each independently represent CR 4 ;
  • Z1 and Z3 each represent N, and Z 2 , Z 4 , and Z 5 each independently represent CR 4 ;
  • Z 1 and Z 4 each represent N, and Z 2 ,
  • Z 3 , and Z5 each independently represent CR 4 ;
  • Z1 and Z5 each represent N, and Z 2 , Z3 , and Z4 each independently represent CR 4 ;
  • Z 2 and Z 3 each represent N, and Z 1 , Z 4 , and Z 5 each independently represent CR 4 ; or
  • Z 2 and Z 4 each represent N, and Z 1 , Z 3 , and Z 5 each independently represent CR 4 .
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-I, wherein at least one or two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , represent CR 4 with said R 4 representing -D; -F; -CI; -Br; -I; -CN; - N0 2 ; -OR 5 ; -N(R 5 )(R 6 ); -S0 2 (CH 2 ) m R 5 ; -(CO)(CH 2 ) m R 5 ; -(CO)N(R 5 )(R 6 ); -OCF 3 ; a Ci-C 6 -alkyl radical; a Ci-C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; or a (3-6 membered)-heterocycloalkyl radical; where
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-I, wherein the at least one or two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , represent CR 4 with said R 4 representing -F; -CI; -Br; -I; or -CN.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-I, wherein the at least one or two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , represent CR 4 with said R 4 representing an aryl radical or a heteroaryl radical; wherein the aryl radical and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N0 2> -OR 5 , -(CH 2 ) m OR 5 , -N(R 5 )(R 6 ), - (CH 2 ) m N(R 5 )(R 6 ), -S0 2 (CH 2 ) m R 5 , -(CO)(CH 2 ) m R 5 , -(CO)N(R 5 )(R 6 ), -(CO)N(
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-I, wherein Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , each independently represent CR 4 with said R 4 representing -H; -D; -F; -CI; -Br; -I; - OCH 3 ; -OCF 3 ; a Ci-C 3 -alkyl radical; -CF 3 ; or a C 3 -C 4 -cycloalkyl radical; wherein the Ci-C 3 -alkyl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, a branched or unbranched Ci-C 3 -alkyl radical, a C 3 -C 4 -cycloalkyl radical, or a Ci-C 3 -haloalkyl radical.
  • Z 1 , Z 2 , Z 4 , and Z 5 independently represent CR 4 with said R 4 representing -H or -D; and Z 3 independently represents CR 4 with said R 4 representing -H; -D; -F; -CI; -Br; -I; - OCH 3 ; -OCF 3 ; a Ci-C 3 -alkyl radical; -CF 3 ; or a C 3 -C 4 -cycloalkyl radical; wherein the Ci-C 3 -alkyl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, a branched or unbranched Ci-C 3 -alkyl radical, a C 3 -C 4 -cycloalkyl radical, or a Ci-C 3 -haloalkyl radical.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-I, wherein Z 1 , Z 2 , Z 4 , and Z 5 independently represent CR 4 with said R 4 representing -H or -D; and Z 3 independently represents CR 4 with said R 4 representing -CI; -OCH 3 ; -OCF 3 ; a Ci-C 3 -alkyl radical; -CF 3 ; or a C 3 - C 4 -cycloalkyl radical.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II, wherein X 1 represents C.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II, wherein M-II represents a moiety represented by one of the fo
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II, wherein either Z 6 or Z 7 represents CR 7 with said R 7 representing the bond directly attaching the W moiety with the carbonyl moiety, or wherein either Z 8 or Z 9 represents CR 7 with said R 7 representing the bond directly attaching the W moiety with the carbonyl moiety.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II with X 1 representing C, wherein M-II represents a moiety represented by:
  • (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-1 with X 1 representing C, said R 7 of Z 7 represents the bond directly attaching the W moiety with the carbonyl moiety:
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-1, wherein A 1 and A 2 independently represent CR 11 , and A 3 represents NR 10 , O, or S, such as wherein A 1 and A 2 independently represent CR 11 , for example A 1 and A 2 independently represent wherein R 11 independently represents -H, -F, -CI, a Ci-C 4 -alkyl radical, -CF 3 , or a C 3 -C 4 -cycloalkyl radical, and A 3 represents O; or wherein A 1 represents N and A 2 represents CR 11 , and A 3 represents NR 10 , O, or S.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-2 with X 1 representing C, said R 7 of Z 8 represents the bond directly attaching the W moiety with the carbonyl moiety:
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-2, wherein A 1 and A 2 independently represent CR 11 , and A 3 represents NR 10 , O, or S, such as wherein A 1 and A 2 independently represent CR 11 , for example A 1 and A 2 independently represent wherein R 11 independently represents -H, -F, -CI, -Br, -CN, -OR 12 , -OCF 3 , a Ci-C 4 -alkyl radical, -CF 3 , or a C 3 -C 4 -cycloalkyl radical, and A 3 represents NR 10 , O, or S; or
  • A represents N and A represents CR , and A represents NR , O, or S.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II with X 1 representing C, wherein M-II represents a moiety represented by: wherein A 1 and A2 independently represent N or CR 11 ; A3 independently represents NR 10 , O, or S; and
  • Z 7 , Z 8 , and Z 9 independently represent CR 7 , with one of said R 7 of Z7 , Z8 , and Z9 representing the bond directly attaching the W moiety with the carbonyl moiety.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-3 with X 1 representing C, said R 7 of Z 7 represents the bond directly attaching the W moiety with the carbonyl moiety:
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-3, wherein A 1 and A2 independently represent CR 11 , and A3 represents NR 10 , O, or S; or wherein A 1 represents N and A 2 represents CR 11 , and A3 represents NR 10 , O, or S.
  • (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-4 with
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-4, wherein A 1 and A 2 independently represent CR 11 , and A 3 represents NR 10 , O, or S; or wherein A 1 represents N and A 2 represents CR 11 , and A 3 represents NR 10 , O, or S.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II with X 1 representing C, wherein M-II represents a moiety represented by:
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-5 with X 1 representing C, said R 7 of Z 8 represents the bond directly attaching the W moiety with the carbonyl moiety:
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-5, wherein A 1 and A2 independently represent CR 11 , and A3 represents NR 10 , O, or S; or wherein A 1 represents N and A 2 represents CR 11 , and A3 represents NR 10 , O, or S.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II with X 1 representing C, wherein M-II represents a moiety represented by:
  • a 1 and A 2 independently represent N or CR 11 ;
  • a 3 independently represents NR 10 , O, or S; and
  • Z 6 , Z 7 , and Z 9 independently represent CR 7 , with one of said R 7 of Z 6 , Z 7 , and Z 9 representing the bond directly attaching the W moiety with the carbonyl moiety.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-6 with X 1 representing C, said R 7 of Z 7 represents the bond directly attaching the W moiety with the carbonyl moiety:
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-6, wherein A 1 and A 2 independently represent CR 11 , for example, wherein R 11 independently represents -H, -F, -CI, -OCF 3 , a Ci-C 4 -alkyl radical, -CF 3 , or a C 3 -C 4 -cycloalkyl radical, such as wherein R 11 independently represents -H, and A 3 represents NR 10 , O, or S, for example, wherein A 3 represents O; or wherein A 1 represents N and A 2 represents CR 11 , and A 3 represents NR 10 , O, or S.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II with X 1 representing C, wherein M-II represents a moiety represented by:
  • a 1 and A 2 independently represent N or CR 11 ;
  • a 3 independently represents NR 10 , O, or S; and
  • Z 6 , Z 7 , and Z 8 independently represent CR 7 , with one of said R 7 of Z 6 , Z 7 , and Z 8 representing the bond directly attaching the W moiety with the carbonyl moiety.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-7 with X 1 representing C, said R 7 of Z 7 represents the bond directly attaching the W moiety with the carbonyl moiety:
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-7, wherein A 1 and A2 independently represent CR 11 , and A3 represents NR 10 , O, or S; or wherein A 1 represents N and A 2 represents CR 11 , and A3 represents NR 10 , O, or S.
  • (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-8 with
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II-8, wherein A 1 and A 2 independently represent CR 11 , and A 3 represents NR 10 , O, or S; or wherein A 1 represents N and A 2 represents CR 11 , and A3 represents NR 10 , O, or S.
  • (II), or (III) may comprise the W representing the moiety represented by any one of ring systems M- II-l to M-II-8, wherein R 7 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -OR 8 ; -OCF 3 ; a Ci-C 6 -alkyl radical; a Ci-C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; wherein the Ci-C 6 -alkyl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, - N0 2j -OR 8 , -(CH 2 ) m OR 8 , a branched or unbranched Ci-C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, a Ci-C 6 -hydroxyal
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by any one of ring systems M- II-l to M-II-8, wherein R 11 independently represents -H; -F; -CI; -Br; -I; -CN; -OR 12 ; - (CH 2 ) m OR 12 ; -OCF 3 ; a Ci-C 6 -alkyl radical; a Ci-C 6 -haloalkyl radical; or a C 3 -C 6 -cycloalkyl radical; for example, wherein R 11 independently represents -H; -F; -CI; -Br; -I; -CN; -OR 12 ; -(CH 2 ) m OR 12 ; -OCF 3 ; a Ci-C 4 -alkyl radical; or a Ci-C 2 -haloalkyl radical; for example, wherein
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by any one of ring systems M- II- 1 to M-II-8, wherein R 12 independently represents -H, a branched or unbranched Ci-C 4 -alkyl radical, or a C 3 -C 6 -cycloalkyl radical.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II. In certain embodiments, the amide compound represented by Formula (I), (II), or (III), may comprise the W representing the moiety represented by the ring system M-II, wherein X 1 represents N. For example, the amide compound represented by Formula (I), (II), or (III), may comprise the W representing the moiety represented by the ring system M-II, wherein M-II represents a moiety represented by one of the
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II, wherein A 1 independently represents CR 11 ; and A 2 and A 3 independently represent N or CR 11 ; for example, wherein A 2 independently represents CR 11 ; and
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-II, wherein either Z 6 or Z 7 represents CR 7 with said R 7 representing the bond directly attaching the W moiety with the carbonyl moiety, or wherein either Z 8 or Z 9 represents CR 7 with said R 7 representing the bond directly attaching the W moiety with the carbonyl moiety.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-III.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-III, wherein M-III represents a moiety represented by one of the following ring systems:
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-III, wherein M-III represents a moiety represented by one of the following:
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-III, wherein M-III represents
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-III, wherein M-III re
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein X 2 represents C.
  • the amide compound represented by Formula (I), (II), or (III), comprising W representing the moiety represented by the ring system M-IV may comprise a moiety represented by one of the following:
  • a 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A represents NR , N(CH 2 ) m R , O, or S, preferably A represents O or S.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein M-IV represents a moiety represented by ring system M-IV-1 :
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV-1, wherein A 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 , N(CH 2 ) m R 14 , O, or S, preferably A 7 represents O or S; and wherein R 4 independently represents -H; -D; -F; -CI; -Br; -I; - CN; -N0 2 ; -OR 5 ; -N(R 5 )(R 6 ); -S0 2 (CH 2 ) m R 5 ; -OCF 3 ; a d-d-alkyl radical; a d-C 6 -haloalkyl radical; a C 3
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV-1, wherein R 5 and R 6 independently represent -H; a branched or unbranched Ci-C 3 -alkyl radical; or a C 3 -C 6 -cycloalkyl radical.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein M-IV represents a moiety represented by ring system M-IV-1, wherein A 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 , N(CH 2 ) m R 14 , O, or S, preferably A 7 represents O or S; and wherein Z 1 and Z 2 independently represent CH; and Z 3 and Z 4 independently represent CR 4 , wherein R 4 independently represents -H; -D; -F; -CI; -Br; -CN; -OR 5 ; -N(R 5 )(R 6 ); -S0 2 (CH 2 ) m R 5 ; -OCF 3 ; a Ci-C 4 -alkyl radical; -CF 3 ; a C 3
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein M-IV represents a moiety represented by ring system M-IV-1, wherein A 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 , N(CH 2 ) m R 14 , O, or S, preferably A 7 represents O or S; and wherein Z 1 , Z 2 , and Z 4 independently represent CH; and Z 3 independently represent CR 4 , wherein R 4 independently represents -H; -D; -F; -CI; -Br; -CN; -OR 5 ; -N(R 5 )(R 6 ); -S0 2 (CH 2 ) m R 5 ; -OCF 3 ; a C C 4 -alkyl radical; -CF 3 ; a C
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein M-IV represents a moiety represented by ring system M-IV-1, wherein A 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 , N(CH 2 ) m R 14 , O, or S, preferably A 7 represents O or S; and wherein Z 1 , Z 2 , and Z 4 independently represent CH; and Z 3 independently represent CR 4 , wherein R 4 independently represents -H; -D; -F; -CI; -Br; -OR 5 ; - N(R 5 )(R 6 ); -OCF 3 ; a Ci-C 4 -alkyl radical; -CF 3 ; or a C 3 -C 4 -cycloalkyl radical; wherein the Ci
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein M-IV represents a moiety represented by ring system M-IV-1, wherein A 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 , N(CH 2 ) m R 14 , O, or S, preferably A 7 represents O or S, for example, A 7 represents S; and wherein Z 1 , Z 2 , and Z 4 independently represent CH; and Z 3 independently represent CR 4 , wherein R 4 independently represents -H; -D; -F; -CI; -Br; -OCH 3 ; -NH 2 ; -CH 3 ; -CF 3 ; or a cyclopropyl radical, for example, wherein R 4 independently represents -H, -D, -F, -
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein M-IV represents a moiety represented by ring system M-IV-1, wherein A 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 , N(CH 2 ) m R 14 , O, or S, preferably A 7 represents O or S; and wherein Z 1 , Z 2 , and Z 3 independently represent CH; and Z 4 independently represent CR 4 , wherein R 4 independently represents -H; -D; -F; -CI; -Br; -CN; -OR 5 ; -N(R 5 )(R 6 ); -S0 2 (CH 2 ) m R 5 ; -OCF 3 ; a C C 4 -alkyl radical; -CF 3 ; a C
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein M-IV represents a moiety represented by ring system M-IV-1, wherein A 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 , N(CH 2 ) m R 14 , O, or S, preferably A 7 represents O or S; and wherein Z 1 , Z 2 , and Z 3 independently represent CH; and Z 4 independently represent CR 4 , wherein R 4 independently represents -H; -D; -F; -CI; -Br; -OR 5 ; - N(R 5 )(R 6 ); -OCF 3 ; a Ci-C 4 -alkyl radical; -CF 3 ; or a C 3 -C -cycloalkyl radical; wherein the Ci-
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein M-IV represents a moiety represented by ring system M-IV-1, wherein A 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 , N(CH 2 ) m R 14 , O, or S, preferably A 7 represents O or S; and wherein Z 1 , Z 2 , and Z 3 independently represent CH; and Z 4 independently represent CR 4 , wherein R 4 independently represents -H; -D; -F; -CI; -Br; -OCH 3 ; - NH 2 ; -CH 3 ; -CF 3 ; or a cyclopropyl radical.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein M-IV represents a moiety represented by ring system M-IV-1, wherein A 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 , N(CH 2 ) m R 14 , O, or S, preferably A 7 represents O or S; and wherein Z 1 , Z 2 , and Z 3 independently represent CH; and Z 4 independently represent CR 4 , wherein R 4 independently represents -F; -CI; -OCH 3 ; -CH 3 ; -CF 3 ; or a cyclopropyl radical.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein M-IV represents a moiety represented by ring system M-IV-1, wherein A 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 , N(CH 2 ) m R 14 , O, or S, preferably A 7 represents O or S; and wherein Z 1 , Z 2 , and Z 3 independently represent CH; and Z 4 independently represent CR 4 , wherein R 4 independently represents -H; -F; -CI; -CN; -OCH 3 ; - OCH 2 CH 3 ; -OCF 3 ; or a cyclopropyl radical, for example, wherein R 4 independently represents -H; - F; -CN; -OCH 2 CH 3 ; -OCF 3 ; or a cyclopropyl
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein M-IV represents a moiety represented by ring system M-IV-1, wherein A 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 , N(CH 2 ) m R 14 , O, or S, preferably A 7 represents O or S; and wherein Z 1 independently represents CH; Z 2 independently represents CR 4 , wherein R 4 independently represents -H or -F; Z 3 independently represents CR 4 , wherein R 4 independently represents -H; -D; -CI; -Br; -OCH 3 ; -CH 3 ; or a cyclopropyl radical; and Z 4 independently represents CR 4 , wherein R 4 independently represents -H; -D; -F; -CI; -
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein X 2 represents C.
  • the amide compound represented by Formula (I), (II), or (III), comprising W representing the moiety represented by the ring system M-IV may comprise a moiety represented by one of the following:
  • a 5 represents NR 14 ; O; or S, preferably A 5 represents O or S.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein X 2 represents N.
  • the amide compound represented by Formula (I), (II), or (III), comprising W representing the moiety represented by the ring system M-IV may comprise a moiety represented by one of the following:
  • a 5 and A 6 independently represent N or CR 15 , preferably A 5 and A 6 represents CR 15 , wherein R 15 preferably represents -H.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein X 2 represents N.
  • the amide compound represented by Formula (I), (II), or (III), comprising W representing the moiety represented by the ring system M-IV may comprise a moiety represented by one of the following:
  • a 5 and A 7 independently represent N or CR 15 .
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV, wherein X 2 represents N.
  • the amide compound represented by Formula (I), (II), or (III), comprising W representing the moiety represented by the ring system M-IV may comprise a moiety represented by one of the following:
  • a 6 and A 7 independently represent N or CR 15 .
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-IV-22:
  • Z 1 , Z 2 , and Z 3 independently represent CR 4 ;
  • a 6 represents CR 15 ; and
  • a 7 represents N.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-V.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-V, wherein M-V represents a moiety re
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-VI.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-VI, wherein M-VI represents a moiety represented by one of the following:
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-VI, wherein M-VI represents a moiety represented by one of the following:
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-VI, wherein M-VI represents a moiety represented by ring system M-VI-1 :
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-VI-1, wherein G 1 and G 4 independently represent -NH or O; and G 2 and G 3 independently represent C(R 18 )(R 18 ); for example, wherein G 1 and G 4 independently represent O; and G 2 and G 3 independently represent C(R 18 )(R 18 ), wherein R 18 independently represents -H.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-VI, wherein M-VI represents a moiety represented by ring system M-VI-3 :
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-VI-1, wherein G 1 and G 4 independently represent -NH or O; and G 2 and G 3 independently represent C(R 18 )(R 18 ); for example, wherein G 1 and G 4 independently represent O; and G 2 and G 3 independently represent C(R 18 )(R 18 ), wherein R 18 independently represents -H.
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-I, M-IV, or M-V, wherein adjacent members of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , is (CR 4 )(CR 4 ), and the (CR 4 )(CR 4 ) forms a cycle such that the adjacent R 4 substitutents taken together represents a (3-6 membered)-heteroalkyl di- radical with at least one ring atom of the (3-6 membered)-heteroalkyl di-radical selected from the group consisting of oxygen, nitrogen, and sulfur, with the proviso that when the at least one ring atom is nitrogen, the nitrogen is unsubstituted (specifically is -N(H)-) or is substituted with a branched or unbranched Ci-C 4 -alkyl radical, a C 3 -C 4 -cyclo
  • the amide compound represented by Formula (I), (II), or (III) may comprise the W representing the moiety represented by the ring system M-I, M-IV, or M-V, wherein adjacent members of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , is (CR 4 )(CR 4 ), such as adjacent members Z 1 and Z 2 is (CR 4 )(CR 4 ), adjacent members Z 2 and Z 3 is (CR 4 )(CR 4 ), adjacent members Z 3 and Z 4 is (CR 4 )(CR 4 ), or adjacent members Z 4 and Z 5 is (CR 4 )(CR 4 ), and the (CR 4 )(CR 4 ) forms a cycle such that the adjacent R 4 substitutents taken together represents a (3-6 membered)-heteroalkyl di-radical with at least one ring atom of the (3-6 membered)-heteroalkyl di-radical selected from the group consisting of oxygen, nitrogen, and sulfur, for
  • adjacent members of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is (CR 4 )(CR 4 ), and the (CR 4 )(CR 4 ) forms a cycle such that the adjacent R 4 substitutents taken together represents a (3-6 membered)-heteroalkyl di-radical, and the (3-6 membered)-heteroalkyl di-radical comprises: -OCH 2 CH 2 CH 2 - -OCH 2 CH 2 N(H)-, -OCH 2 CH 2 N(Ci-C 4 -alkyl)-, such as - OCH 2 CH 2 N(Me)-; - CH 2 CH 2 CH 2 N(CO)(C 1 -C 4 -alkyl)-, -N(H)CH 2 CH 2 0-, -N(d-C 4 - alkyl)CH 2 CH 2 0-, such as -N(Me)CH 2 CH 2 0-; -OC
  • the (3-6 membered)-heteroalkyl di-radical when specified, it is both referenced and attached on the ring system M-I, M-IV, or M-V, in order from lowest to highest of adjacent members of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 .
  • the resulting ring system of W representing the moiety represented by the ring system M-IV-1, wherein A 7 is S, and the adjacent members Z 1 and Z 2 is (CR 4 )(CR 4 ), and the (CR 4 )(CR 4 ) forms a cycle such that the adjacent R 4 substitutents taken together represents a (3-6 membered)-heteroalkyl di-radical, and the (3-6 membered)-heteroalkyl di-radical is: (i) -OCH 2 CH 2 CH 2 - (ii) -OCH 2 CH 2 N(H)-; (iii) - N(H)CH 2 CH 2 0-; (iv) -OCH 2 CH 2 0-; (v) -OCF 2 0-; or (vi) -CH 2 CH 2 CH 2 0- would be represented by the following structures:
  • the amide compound represented by Formula (I), (II), or (III), for example, may comprise the W representing the moiety represented by the ring system M-I to M-VI, wherein R 1 and R 2 independently represent an unbranched Ci-alkyl radical, and said compound is represented by Formula (II):
  • the amide compound represented by Formula (I), (II), or (III), for example, may comprise the W representing the moiety represented by the ring system M-I to M-VI, wherein R 1 and R 2 taken together represent a C 2 -alkyl di-radical and said compound is represented by Formula (III):
  • the amide compound represented by Formula (I), (II), or (III) may comprise racemic mixture of enantiomers, a mixture of diastereomers, a single enantiomer, or a single diastereomer, of the compound, or a pharmaceutically acceptable salt thereof.
  • the amide compound represented by Formula (I), (II), or (III) may comprise a mixture of tautomers, substantially a single tautomer form, or a single tautomer form, such as a tautomer contained within W, for example, a tautomer may be contained within a W containing a heteroaryl ring nitrogen adjacent to a heteroaryl ring carbon substituted with a hydroxyl group.
  • amide compound represented by Formula (I) may include, collectively or individually, the compounds listed below, and single enantiomers and pharmaceutically acceptable salts thereof:
  • amide compound represented by Formula (I) may include, collectively or individually, the compounds listed below, and single enantiomers and pharmaceutically acceptable salts thereof:
  • amide compound represented by Formula (I) may include, collectively or individually, the single enantiomers listed below, and pharmaceutically acceptable salts thereof:
  • amide compound represented by Formula (I) may include, collectively or individually, the compounds listed below, and single enantiomers and pharmaceutically acceptable salts thereof:
  • amide compound represented by Formula (I) may include, collectively or individually, the single enantiomers listed below, and pharmaceutically acceptable salts thereof:
  • amide compound represented by Formula (I) may include, collectively or individually, the single enantiomers listed below, and pharmaceutically acceptable salts thereof:

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US20170369486A1 (en) 2017-12-28
EP3233087B1 (en) 2019-10-02
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CA2971413A1 (en) 2016-06-23
AU2015362790A1 (en) 2017-07-20
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