CA3050553A1 - Therapeutic modifiers of the reverse mode of atp synthase - Google Patents

Abstract

Compounds that slow the ATP-hydrolysing mode of ATP synthase are useful for treating various diseases and disorders including cancer, particularly cancers that utilise the Warburg effect.

Description

Therapeutic Modifiers of the Reverse Mode of ATP Svnthase GRACE PERIOD
The inventor/applicant is also the inventor/applicant of PCT application number PCT/EP2018/051127 (filed 17 January 2018) and PCT application number PCT/EP2018/069175 (filed 13 July 2018), which were published on 26 July 2018 and 17 January 2019 respectively, but they shoudn't be cited as prior art against the present disclosure because of the Canadian grace period.
FIELD OF THE INVENTION
This invention discloses compounds that preferentially slow the ATP-hydrolysing mode of ATP synthase, pharmaceutical compositions of these compounds, and methods of use for treating subjects known to have various diseases or disorders including cancer (e.g. diagnosed with), subjects suspected of having various diseases or disorders including cancer or subjects at risk of developing various diseases or disorders including cancer. In a particular embodiment, the subject is a human. In further embodiments, the subject is a pet, or farm or laboratory animal.
BACKGROUND OF THE INVENTION
ATP synthase ATP synthase (also known as FiFo ATP synthase, FoFi ATP synthase, FiFo-ATPase, FoFi-ATPase, FIFO ATP hydrolase) is located at the inner mitochondrial membrane (IM). It can use the proton motive force (pmf) to generate ATP from ADP and Pi [1-3]. ATP
synthase is reversible and - depending on its substrate/product concentrations, the pmf and the voltage across inner mitochondrial membrane {Tim} - it can work "forwards" (passaging protons, making ATP) or "backwards" (pumping protons, consuming ATP): its "forward" and "reverse" modes respectively, which may also be termed FIF0ATP synthesis and FiFo ATP
hydrolysis respectively.
Inhibitors of ATP synthase There are drug inhibitors of ATP synthase, reviewed in [4] (herein incorporated in its entirety). Some inhibitors disproportionally/selectively inhibit the reverse mode, as compared to the forward mode, of ATP synthase [4-13]. Macrolides are a class of polyketide. So macrolide FIFO ATP synthase inhibitors are polyketide FiFo ATP synthase inhibitors, and these terms are used interchangeably herein. Polyketide FIFO ATP synthase inhibitors (e.g.
oligomycin) inhibit the forward mode, more than the reverse mode, of ATP
synthase [Ii].
Oligomycin is well known in the art as an inhibitor of FIR' ATP synthase, and thence oxidative phosphorylation and aerobic respiration [3]. Human life relies upon aerobic respiration. Indeed, the importance of breathing (02 in, CO2 out) is widely appreciated.
Thence the danger of oligomycin is easily apparent.
IF1 is an endogenous protein, encoded by the ATPIF I gene, which selectively blocks the reverse mode of ATP synthase [4]. Its activity is pH sensitive and low, but non-zero, at normal matrix pH, and significant upon matrix acidification, caused by collapse of the proton motive force across the mitochondrial inner membrane.
Prior art teaches that compounds of this disclosure are NOT anti-cancer therapeutics Polyketide FiFo ATP synthase inhibitors (e.g. oligomycin) are poisonous to cancer [14] and normal [15] cells. Indeed, intraperitoneal injection of just 1 mg/kg oligomycin kills healthy rats (n=10) within 48 hours; LD33= 0.5 mg/kg [15]. Normal cells typically need to use F1 F0 ATP synthase in its forward mode and so blocking this mode is typically lethal. Thus, polyketide FIFO ATP synthase inhibitors are not suitable as anti-cancer therapeutics: indeed, cytovaricin, ossamycin and peliomycin don't work in xenograft mouse models of cancer (data in [16], oligomycin untested) because a therapeutic window is absent because, to repeat, polyketide FiFo ATP synthase inhibitors are highly poisonous to normal cells, whilst not even being poisonous to all cancer cells: e.g. ineffective against glycolytic cancers exhibiting the Warburg effect [14]. [17] used oligomycin in a xenograft cancer mouse model but only by applying oligomycin to the cancer cells before they were inoculated into mice, and washing the excess oligomycin off before inoculation into the mice (by culture for 2 days in drug free medium). They did the study like this (atypical, as clear to someone of the art) because oligomycin toxicity is not discriminate for cancer in a mammal. Obviously this experiment has no clinical parallel or utility. The synthesis/structure of some molecules of this disclosure has been disclosed in prior disclosures [PI, P2. P3], wherein these structures are speculated to be anti-cancer medicines merely by analogy to the anti-cancer activity of polyketide FiFo ATP synthase inhibitors in [14]. Indeed, to mirror and use the restriction of [14], these disclosures restrict their suggestion to "cancers having tumor cells that do not exhibit the Warburg effect" (in a claim of [P3], [Pl] doesn't claim for any cancer, [P2]
cancer claim

2 rejected by USPTO in correspondance on 4/11/2006). [P1, P2, P3] state in the Utility section of their Description, "inhibitors of mitochondrial FiFo-ATPase selectively kill metabolically active tumor cells that do not exhibit the Warburg effect i.e., cells that do not maintain a high level of anaerobic carbon metabolism even in the presence of oxygen". So, teaching that their compounds will not exert anti-cancer activity against cancers that exhibit the Warburg effect i.e. they restrict their suggestion to cancers using oxidative phosphorylation (OXPHOS) and ATP synthase, in its forward mode, to generate ATP. But what undermines this (postulated) approach is that this aerobic profile is what normal cells typically use also, especially on aggregate across an organism: well known to those of the art (evidence:
importance of breathing to mammalian life). By this analogy to polyketide FIFO ATP synthase inhibitors, these disclosures speculate these molecules are safe anti-cancer therapeutics.
When in fact, by this analogy, they actually teach the opposite. This is clear when [14] isn't considered in isolation, as it shouldn't be, but alongside the rest of the literature e.g.
[15], [16] and the knowledge of someone of the art (well known that normal cells need to use FiFo ATP
.. synthase in its forward mode, to generate ATP, and that oligomycin blocks this, and is potently dangerous). So, these prior disclosures [P1, P2, P3] teach someone of the art, that these compounds are, by their chosen analogy to polyketide FIFO ATP synthase inhibitors, not suitable for anti-cancer therapy. It isn't sufficient to kill cancer to be an anti-cancer therapeutic. This killing must be selective, leaving normal cells alive.
Metabolic poisons such .. as cyanide or oligomycin do not fit this criterion. By distinction, the present invention discloses selective killing of cancer cells, at compound concentrations harmless to normal cells. This couldn't have been anticipated from the prior art. Furthermore, this selective anti-cancer activity is pronounced for cancers that do exhibit the Warburg effect.
Distinctly, the present disclosure discloses experimental data. Its inventive step is to show that its compounds are safe anti-cancer therapeutics, exactly because of their distinction from polyketide FiFo ATP synthase inhibitors. There is a broad therapeutic margin for the compounds of this disclosure as a virtue of the distinctive (from oligomycin) way they work, leveraging differences between normal and cancer cells, discovered and disclosed as part of .. this invention. Indeed, the compounds of this disclosure can kill highly glycolytic cancers exhibiting the Warburg effect. These cancers tend to be the most dangerous, with the worst prognosis (numerous studies find this: representatives: [18-20]).

3 [Pl, P2, P3] do not provide any experimental evidence of any anti-cancer activity, and teach towards treating ischemia. They teach away from the present invention by suggesting, by an analogy in the unpredictable arts, that their compounds exert anti-cancer activity, like oligomycin, by inhibition of FIR' ATP synthesis, wherein oligomycin itself is unsuitable as an anti-cancer drug. [Pl, P2, P3] contains millions of compounds. The person of the art would select a subset of these for anti-cancer testing. Teaching of [P1, P2, P3] teaches the person of the art to select compounds that maximally inhibit FiFo ATP
synthesis in the submitochondrial assay they describe. Such compounds would very potently kill cancer in vitro, like oligomycin in [14], and so be excitingly entered into subsequent animal studies, wherein a lack of therapeutic margin would become evident (like polyketide Fi Fo inhibitors in [16]) and no useful cancer drugs would be found, concluding the experimentation. Indeed, none found in subsequent ¨16 years, despite long standing need. Whereas, by the present invention, compounds are selected from [Pl, P2, P3] for anti-cancer activity by the inverse.
By selection of compounds that minimally inhibit FIFO ATP synthesis (as compared to their inhibition of Fi Fo ATP hydrolysis). Indeed, by experimental evidence herein, the anti-cancer activity of such compounds is evidential. Thus, enabling the person of the art to arrive at working cancer drugs, and having the rationale to arrive at further working cancer drugs e.g.
found by a method(s) disclosed herein. These drugs can cause body temperature drop, and can have a very atypical dose-anticancer response profile, which are critical teachings, with compensatory and associated methods, of this invention. These teachings are enabling for rodent trials, and more especially mouse trials (small body, more susceptible to body temperature drop), which is a step that one of the art would use to assess compounds of this invention.
Compounds of the present invention don't just exert anti-cancer activity. They can also affect normal cells, making their metabolism more efficient, which can cause weight gain/reduce weight loss/maintain body weight, all of which combats cachexia. For example, cancer driven cachexia, which is the leading cause of death in cancer patients. By contrast, polyketide Fi Fo ATP synthase inhibitors are toxic to normal cells, denying them energy, rather than enabling them more energy, by efficiency gain, as molecules of this invention can do.
In short, [P1, P2, P3] teach that FIR ATP synthesis inhibitors only kill oxidative cancers not using Warburg metabolism, this invention experimentally shows that FIR ATP
hydrolysis

4 inhibitors do kill cancers using Warburg metabolism. The former teaching doesn't arrive at therapeutic cancer drugs, the latter does.
[P4] teaches away from the present invention. Its exemplary compound, Bz-423, inhibits the forward and reverse modes of ATP synthase equally or, in other data it discloses, the forward (EC50= 5.5 M) more than the reverse (ECK' = 8.9 M) mode of ATP synthase.
[P4]
provides arguments and evidence that Bz-423 slows cellular proliferation, and causes apoptosis, by inhibiting FIR' ATP synthesis and not by inhibiting FIFO ATP
hydrolysis. It extrapolates this feature of Bz-423 to other compounds it discloses (a point the (same) .. applicant of [P5] stresses often in examination correspondence with the USPTO). For example, in the title of Example 41 in [P4], it is written "Benzodione derivatives inhibit ATP
hydrolysis, does not affect cell synthesis properties, and does not affect cell viability", and [P4] goes on to affirm this statement with experimental data, which teaches away from the present invention, wherein compound T5 is "capable of inhibiting ATP
hydrolysis, not .. inhibiting cell synthesis, not affecting cell viability". In [P4], T5 experimental data is included to contrast with that of Bz-423, to show the lack of utility of a specific ATP
hydrolysis inhibitor such as T5, as compared to the utility of the exemplary compound, Bz-423, which inhibits ATP synthesis. In this data in [P4], Bz-423 inhibits FiFo ATP synthesis and hydrolysis and cellular viability, T5 only inhibits FIR ATP hydrolysis and not cellular viability, = Bz-423 is the exemplary compound and FIR ATP synthesis inhibition, not FiFo ATP hydrolysis inhibition, is experimentally highlighted as the responsible, exemplary mechanism. Bz-423 hyperpolarises Tim and decreases 02 consumption [21] whilst compounds of the present invention do not, as presented in experimental data of the present disclosure. Example 52 in [P4] states "For ATP synthesis (the relevant enzymatic reaction of the mitochondrial FiFo-ATPase in vivo)". Thence stating that FiFo ATP
hydrolysis is irrelevant in vivo, which the present invention discloses, with supporting experimental data, is a falsehood. This is a new fundamental biological discovery, which will surprise those of the art. [P4] teaches the use of inhibitors of the forward mode of ATP synthase, which is not teaching that arrives at the present invention; indeed, it teaches away from the present invention.
Well known to those of the art, biorxiv is a repository for documents that have not been peer reviewed. In 2015, in a document on biorxiv, the author of this present disclosure suggested the use of FIFO ATP hydrolysis inhibitors as anti-cancer therapeutics [22].
This document was

5 subsequently submitted to peer reviewed journals (elife, BMC Cancer) and was found unworthy of dissemination, let alone pursuit, by those of the art. It demonstrably wasn't considered credible by those of the art. In 2017, a paper was published by others, in a peer-reviewed journal [23], with experimental data showing that inhibiting h Fo ATP
hydrolysis assists (!), rather than harms, cancer. With this conclusion reached and emphasised by its authors. This paper is one of many experimental reports, published in leading peer reviewed journals, reaching the same conclusion, which directly opposes and teaches away from this author's suggestion in a document database well known for unreviewed/unscrutinised manuscripts. Indeed, no peer-reviewed journal publication years after a biorxiv submission would be noted very negatively by one of the art.
When selecting a path to pursue from the prior art, in the unpreditable arts, one of the art will always weigh experimental data more heavily than suggestion. Especially wherein experimental data postdates and falsifies/discredits suggestion. Experimental data in the prior art teaches away from the present invention. Indeed, it directly opposes it.
Whereas the present invention is of FiFo ATP hydrolysis inhibition conveying anti-cancer therapy, experimental data in [23] shows that FIFO ATP hydrolysis inhibition assists cancer (!), thence increasing its danger. "The ATP synthase complex does not hydrolyze ATP in either IF i-expressing or Ih-silenced osteosarcoma cells" [23]. "Even severe hypoxia could not activate the hydrolysis of ATP by the FiFo-ATPase complex" [23]. "ATP synthase does not hydrolyze ATP in cancer cells" [23]. Moreover, "in cancer cells IF) overexpression fully prevents ATP synthase hydrolytic activity" and "IF' is present at higher levels in cancer cells than in untransformed cells" (also observable in gene expression databases, also reported by many other investigators in many other journal papers, lh overexpression in cancer is a prognostic marker of poor patient outcome, IF) knockdown suppresses tumour growth in mice [241) and "lh overexpression promotes cancer cells survival" [23].
In Claim 1 of this disclosure, some compounds are excluded from the presented formula by proviso, separating all its enumerations from [P1] and [P4].
Some guidance All publications, patents and patent applications mentioned or cited in this disclosure are herein incorporated, in entirety, by reference. This disclosure uses ICso and ECso interchangeably, for a process being inhibited or reduced. Chemical structures were drawn

6 using the chemical drawing feature in [25], and if a drawing feature is unknown to the reader they are referred to its documentation, or to explore the software themselves:
all clear to those of the art. Hydrogen on structures is typically not shown, present implicitly, but it is shown for some presented structures "On Hetero and Terminal" [25] groups. Herein, the symbol D is used for deuterium (2H). For compound synthesis schemes herein, starting materials are commercially available or can be readily prepared by one of ordinary skill in the art using known methods or derived by procedures analogous to those described in the literature.
Examples and preparations herein describe the manner and process of making and using the invention. It should be understood that there will be other embodiments which fall within the spirit and scope of the invention. A phrase in the form "A/B" or in the form "A and/or B"
means (A), (B), or (A and B).
SUMMARY OF THE INVENTION
The compounds described herein, including for example almitrine dimesylate, exert anti-cancer activity because they reduce FIFO ATP hydrolysis in cancer cells. This elucidated mechanism is the core of this invention. Herein is the discovery of a cancer-specific drug target: the reverse mode of ATP synthase. Indeed, new experimental data, disclosed herein, demonstrates that molecules which specifically slow FIFO ATP hydrolysis can exert specific anti-cancer activity, at concentrations that do not harm normal cells. Any anti-cancer drug that targets/inhibits/reduces FiFo ATP hydrolysis is componentry to this invention. This disclosure discloses numerous anti-cancer drug working examples, many of which are also new compositions of matter, and discloses rationale and methods to find further working examples, which are, in turn, componentry to this invention and encompassed by this disclosure.
Almitrine dimesylate is 644-[bis(4-fluorophenyl)methyl]piperazin-1-y1]-2-N,4-N-bis(prop-2-enyl)-1,3,5-triazine-2,4-diamine methanesulfonic acid, the dimethanesulfonate salt of almitrine. Almitrine CAS number is 27469-53-0 and almitrine has the following structure:

7 N
N N

Almitrine dimesylate has been used clinically for millions of patient months to treat chronic obstructive pulmonary disease (COPD). However, after being used for decades, it is now only used sporadically. Because postmarketing surveillance has revealed it doesn't actually treat COPD, thence there is no reward to outweigh its side-effects risk, especially since there are better/working COPD treatments. Although, for example, almitrine is still in the formulary of the National Health Service (NHS) of Great Britain for its hospital/specialist doctors to prescribe for respiratory disorder. This invention repurposes almitrine for anti-cancer treatment. New experimental data herein shows that almitrine dimesylate exerts strong anti-cancer activity, greater than carboplatin in standardised NCI-60 testing at the National Cancer Institute (NCI, USA). Carboplatin is one of the most used chemotherapies today and is on the World Health Organisation (WHO) list of essential medicines, but carboplatin has a terrible side-effect profile. By contrast, the potential (don't occur in most patients) side-effects of almitrine are mild compared to present chemotherapies, and tend to only occur with chronic use, yielding the opportunity for a therapeutic window of treatment, which will treat/ameliorate/prevent/combat cancer in a subject.
An aspect of the invention is a compound, or a composition containing at least one compound, of the following formula:

8 RB
I
........-N,...õ
N/
)"----..
N - N
R )1..... ........;:i, Ai ...., N N NH
H I

or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, for use in a method of treating, ameliorating, preventing or combating cancer, or cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET
imaging (e.g. 18F-FDG PET); wherein:
RAI and le2 are each independently selected from the groups and wherein Rc and RD are each independently selected from hydrogen, deuterium, halogen and alkyl, and wherein RE is hydrogen, deuterium, or alkyl;
RB is selected from RBI, hydrogen and deuterium;
wherein RBI is selected from phenyl, benzyl, pyridyl, pyrimidyl and pyrazinyl optionally substituted with one or more substituents RB2;
wherein each RB2 is independently selected from halogen, alkyl, alkoxy, nitro, amino, methoxy and polyhalogen alkyl;
or RB is a phenylalkyl of the formula:

9 11 Gq (RG)q (RF) ¨I. )n 1 wherein le and RG are hydrogen or alkyl, G is a carbon-carbon double bond or a carbon-carbon single bond, n is 0 or 1 and q is 0 or 1 provided that where q is 0, G
is a carbon-carbon double bond and where q is 1, G is a carbon-carbon single bond, or RB is a diphenylalkyl of the formula RH
_ = P
RH
wherein RH is hydrogen or halogen, and p is 0, 1 or 2;
or RB is the group Rj RK
wherein RJ and RK each independently represent 1-5 optional substituents on each ring, and wherein each It! and each RK, when present, is independently selected from halogen, alkyl, alkoxy, nitro, amino, methoxy and polyhalogen alkyl.
In some embodiments, RB is the group:
RJ
RK
In some embodiments, RB is the group:

Rj e it RK
wherein IV and RK each independently represent 1 or 2 substituents on each ring, and wherein each RI and each RK is independently selected from halogen, alkyl, alkoxy, nitro, amino and polyhalogen alkyl.
In some embodiments, le and RK each independently represent 1 or 2 substituents on each ring, and wherein each IV and each RK is independently selected from halogen.
In some embodiments, IV and RK each independently represent I substituent on each ring, and wherein IV and RK are independently selected from halogen.
In some embodiments, RB is the group:
RL
RM

wherein le- and Rm are each independently selected from halogen, alkyl, alkoxy, nitro, amino and polyhalogen alkyl.
In some embodiments, RL and Rm are each independently selected from halogen.
In some embodiments, RL and Rm are the same.
In some embodiments, RL and Rm are each F.
In some embodiments, RAI and RA2 are each independently selected from the group RD
wherein Rc and RD are each independently selected from hydrogen, deuterium, halogen and alkyl.
In some embodiments, RAI and RA2 are the same.
In some embodiments, Rc is hydrogen. In some embodiments, RD is hydrogen. In some embodiments, Rc and RD are the same. In some embodiments, Rc and RD are both hydrogen.
In some embodiments, the compound is:
F F
"-..N./
N - N
N N N
H H
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
In some embodiments, the compound is an isotopologue(s) of:

F F
,....--N-..., \N---' NIN..- N
H2C..,=== A., 1õ ,.,-.....,,...,-. CH2 N N N
H H
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
Also described herein for prevention or treatment of cancer in a subject, particularly with cancer exhibiting the Warburg effect, is to use a pharmaceutical composition with an effective amount of one or compounds of the following formula, Z R2 R3N.N., N/s-NN= N
L H
I
(R4) R1 q or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
L is alkyl, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy, or hydroxyalkyl, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g.
(non-limiting) OH, NH2, SH, SiH3, PH2 etc.);
RI is hydrogen, cyano, ¨S02R8, ¨C(=0)R9, heteroaryl or thiazolyl;
R2 is (i) independently hydrogen, alkyl, benzyl, or substituted alkyl, or (ii) taken together with R3 forms a heterocyclo;
R3 is (i) independently alkyl, substituted alkyl, alkylthio, aminoalkyl, carbamyl, BB-aryl, BB-heterocyclo, BB-heteroaryl, or BB-cycloalkyl, or (ii) phenyl optionally substituted with Cmalkyl, halogen, trifluoromethyl, OCF3, cyano, nitro, amino, hydroxy, or methoxy, or (iii) independently selected from Ci_aalkyl, alkylthio, aminoalkyl, -BB-aryl, -BB-heterocyclo, BB-cycloalkyl, and -BB-hetaroaryl, optionally having one to three substituents selected from R3a; and/or having fused thereto a five or six membered carbocyclic ring, or (iv) taken together with R, forms a heterocyclo optionally substituted with alkyl or substituted alkyl;
BB is a bond, Ci_aalkylene, C2_4alkenylene, substituted Chaalkylene, substituted C2-4a1keny1ene, substituted Ci_aalkylene-C(=D)NH-, -C(=3)NH-, -C1.4alkylene-C(=0)NH-, -C(=0)NR19-, -C malkylene-C(=a)NR19-, or substituted C1_4alkylene-C(=0)NR19-, -(CHR14)m-(CRI5R16),- or -(CHR14)1,--C(=0)NH-;
R3a at each occurrence is selected independently from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, keto, trifluoromethyl, -NRI7R18, -SR17, -011.17, -SO2R17a, -SO2NR17R18, -NR17COR18, -0O2R17, -C(D)R17, cyoloalkyl, aryl, heterocyolo, and heteroaryl, wherein when R3a is cycloalkyl, aryl, heterocyclo or heteroaryl, said cycloalkyl, aryl, heterocyolo and heteroaryl in turn is optionally substituted with alkyl or substituted alkyl;
Z is a heteroaryl, for example an optionally-substituted bicyclic heteroaryl;
or Z is triazolyl optionally substituted with one to two R7 substituents or imidazolyl optionally substituted with one to two R7 substituents and/or having fused thereto a benzene ring in turn optionally substituted with one to two R7 substituents; and R7 is alkyl, carbamyl, or substituted alkyl;
R4 at each occurrence is selected independently of each other R4 from the group consisting of halogen, trifluoromethyl, OCF3, alkyl, substituted alkyl, haloalkyl, nitro, cyano, haloalkoxy, 0R25, SR25, NR25R26, NR25S02R27, S02R27, S02NR25R26, CO2R26, C(=0)R26, C(=0)NR25R26, OC(=0)R25, -0C(=0)NR25R26, NR25C(=D)R26, NR25CO2R26, aryl, heteroaryl, heterocyclo and cycloalkyl;
R8 is Cmalkyl or phenyl optionally substituted with alkyl, halogen, haloalkoxy, cyano, nitro, or trifluoromethyl;
R9 is -NR10R11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclo, or -0O2R12, alkyl or phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, Chaalkoxy, haloalkoxy, Ci_6alkyl, CO2alkyl, SO2alkyl, SO2NH2, amino, NH(Ci_aalkyl), N(Ci_4alky1)2, NHC(=0)alky, C(=0)alkyl, and/or Ci_aalkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl; and/or a five or six membered heteroaryl or heterocylo in turn optionally substituted with keto or having a benzene ring fused thereto or a) Ci_aalkyl optionally substituted with one to two of:
i) SR13, 0R13, NRI3aRi3b, halogen, trifluoromethyl, CO2R13a, and C(=0)NIZI3aR13b;
ii) cycloalkyl optionally substituted with one to two of C(=0)H, Cmacyl, alkenyl, carbamyl, and/or phenyl in turn optionally substituted with halogen;
iii) phenyl or napthyl optionally substituted with one to two of halogen, nitro, amino, alkyl, hydroxy, Ci_aalkoxy, or having fused thereto a five or six membered heterocyclo;
iv) pyridinyl, thiophenyl, furanyl, tetrahydrofuranyl, or azepinyl, optionally substituted with alkyl or having fused thereto a five to six membered carbocyclic ring optionally substituted with keto or Ci_aalkoxy;
b) 3 to 6 membered cycloalkyl optionally having up to four substituetits selected from alkyl, halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, phenyl in turn optionally substituted with halogen; or having an aryl fused thereto;
c) pheyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, Ci_aalkoxy, haloalkoxy, Ci_aalkyl, CO2alkyl, SO2alkyl, SO2NH2, amino NH(C3-4a1ky1), N(Ci_4alky1)2, NHC()alkyl, C(=C0)alkyl, and/or Ci_aalkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl;
and/or a five or six membejed heteroaryl or heterocyle in turn optionally substituted with keto or having a benzene ring fused thereto;
d) pyridinyl, thiazolyl, furanyl, thiophenyl, and pyrrolyl optionally substituted with one to two of halogen, alkyl, and phenyl in turn optionally substituted with halogen or trifluoromethyl;
Rio and RI I are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, heteroaryl or Ci_aalkyl optionally substituted with one to two of ¨0O2alkyl, ¨C(=0)NH(ary1), NH(ary1), cycloalkyl, phenyloxy, phenyl in turn optionally substituted with Ci_aalkyl, hydroxy, Ci_aalkoxy, halogen, amino, nitro, tetrahydrofuranyl, and/or five or six membered heterocyclo, or having a five or six membered heterocyclo fused thereto; pyrrolidinyl optionally substituted with keto;
napthyl, anthracenyl, pyridinyl, thiophenyl, furanyl, imidazolyl, benzimidazolyl, or indolyl in turn optionally substituted with Ci_aalkyl or Ci_4alkoxy; or (ii) taken together form a heteroaryl or heterocyclo selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, tetrahydropyridinyl, and imidazoilidinyl, wherein said heterocyclo formed by Rio and Ri i is optionally substituted with one to two of keto, CO2H, Ciaalkoxy, CO2alkyl, Ci_acarbamyl, benzyl; phenyl in turn optionally substituted with alkyl, halogen, or C1-4 alkoxy;
tetrahydropyridinyl in turn optionally substituted with keto and/or phenyl;
alkyl optionally substituted with amino or NHR21wherein R21 is alkyl or phenyl optionally substituted with alkyl; and/or has a benzene ring fused thereto in turn optionally substituted with one to two of alkyl, Ci_aalkoxy, CO2alkyl, and/or Ci_acarbamyl;
R12 and R19 are hydrogen or alkyl;
R13 is hydrogen or alkyl;
Ri3a and R13b are selected from hydrogen, alkyl, and aryl;
R14, R15 and R16 at each occurrence are independently selected from hydrogen, alkyl, hydroxy, hydroxyCi_aalkyl, Ci_aalkoxy, and phenyl, and/or one of R15 and one of Rio join together to form a 3 to 6 membered cycloalkyl;
R17 and R18 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, phenyl, or benzyl wherein the phenyl or benzyl is optionally substituted with alkyl, hydroxy, or hydroxyalkyl;
RI% is alkyl or substituted alkyl;
R25 and R26 are independently selected from hydrogen, alkyl, or substituted alkyl, or taken together form a heterocyclo or heteroaryl ring;
R27 is alkyl or substituted alkyl;
q is 0, 1, 2, or 3;
m and n are 0, 1 or 2; and p is 0, 1, 2, or 3.

In some embodiments, there is an enantiomeric excess of the enantiomer:

NN/
oµµµL
Id1N.'"/%N
HI
(R4)q R1 Herein, the terms "S-stereoisomer" and "S-enantiomer" refer to the arrangement of groups around the chiral centre shown in the structure above, regardless of the specific identities of the variables such as Z, L and R4 within the structure. This chiral configuration is termed S by IUPAC designation if Z is nitrogen and L is deuterium for example. But, herein, where S is written next to this configuration it is not intended to limit what atoms can be Z or L
according to IUPAC stereoisomer naming rules. For example, herein, Z can be carbon (or nitrogen or other atoms as specified herein) even when an S is written next to this chiral carbon. However, when R group type aliases, such as Z and L, are not used and all atoms are uniquely specified around a chiral carbon then IUPAC stereoisomer naming is adhered to.
In some embodiments, the S-enantiomer of the compound is in enantiomeric excess. In some embodiments, the enantiomeric excess of 5-enantiomer exceeds 70%.
In some embodiments, L is hydrogen or deuterium.
In some embodiments, L is alkyl, or deuterium, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy, or hydroxyalkyl, or any atom or isotope permitted by valence except hydrogen at natural abundance.
In some embodiments, the compound is a compound according to the formula NN/
N/k.N*. N
H H
(R4) R1 q or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof.
In some embodiments, the compound is a compound according to the formula S
Nrk'N

(R4)q or pharmaceutically-acceptable salts, solvates, hydrates and prodrugs thereof, wherein S symbolises the S stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%.
In some embodiments, the compound is a compound according to the formula R.
/j\NN
N N
D H

(R4)q or pharmaceutically-acceptable salts, solvates, hydrates and prodrugs thereof, wherein D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also).
In some embodiments, the compound is a compound according to the formula ttoDzIN
S NH N\ rii (R4)q or pharmaceutically-acceptable salts, solvates, hydrates and prodrugs thereof, wherein D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also);
S symbolises the S stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%.
In some embodiments, the compound is a compound according to the formula Z N.N, N//kNN

(R4) R1q or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof.
With a compound of this formula, in some embodiments, there is an enantiomeric excess of enantiomer. In some embodiments, the S-enantiomer of the compound is in enantiomeric excess. In other embodiments, the R-enantiomer of the compound is in enantiomeric excess.
To illustrate, for (non-limiting) example, with supporting experimental data herein, against some cancers, the S-enantiomer exerts more potent anti-cancer activity and is preferred, whilst against some other cancers, the R-enantiomer exerts more potent anti-cancer activity and is preferred, wherein in some embodiments both are independently trialled against a cancer (in vivo and/or ex vivo) to see which exerts the greater anti-cancer activity, wherein administration is subsequently delimited to the enantiomer, or sample with enantiomeric excess for that enantiomer, that is found to have greater anti-cancer activity against that particular cancer, and/or the racemate or a scalemate is administered, optionally with another compound(s) of this invention, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
In some embodiments, the compound is a compound according to the formula Z R2N. /
N
\\CH)N3 .=`
fk S N
N N
I

(R4)q or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein S
symbolises the S stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%.
In some embodiments, the compound is a compound according to the formula Z R2''=.. ,R3 N
C*
R'10/N N ilk H N
I

(R4)q or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein R
symbolises the R stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%.
In some embodiments, the compound is a compound according to the formula N/INN N
H
I

(R4)q. OH
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
In some embodiments, the compound is a compound according to the formula Z HO iN, H
I

(R4)q or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein R
symbolises the R stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%.
In some embodiments, the compound is a compound according to the formula \F
th /2' N.//s, N
HI
(R4),4 R1 or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein R
symbolises the R stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%.
In some embodiments, the compound is N
N/'=:Th..,..
,---N

CI H I
NZNNFI
H
CI
11.
CI
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.

In some embodiments, the compound is N

S NZNNH
CI
CI
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments the enantiomeric excess (ee) of the S stereoisomer exceeds 70%.
In some embodiments, the compound is N

CI D I
N/XNH
CI

or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also).
In some embodiments, the compound is ..,....' N
O .../...
N7'',.....7 .
.....--N

CI \\D A
S N NH
H
CI
411/11) ci or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also). In some embodiments the enantiomeric excess (ee) of the S stereoisomer exceeds 70%.
In some embodiments, the compound is _00-- N
110 ../...
N=/ ..:::., 1, .....--N

NZXNH
H
CI

CI
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
In some embodiments, the compound is N

CI
NH
CI
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments the enantiomeric excess (ee) of the S stereoisomer exceeds 70%.
In some embodiments, the compound is N

CI
NH
CI

or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments the enantiomeric excess (ee) of the R stereoisomer exceeds 70%.
In some embodiments, the compound is OH

CI
N/NNH
CI
CI
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
In some embodiments, the compound is N
(010 OH

CI
W'oiNZNNH
CI

or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments the enantiomeric excess (ee) of the R stereoisomer exceeds 70%.
In some embodiments, the compound is NH
CI
CI
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments the enantiomeric excess (ee) of the R stereoisomer exceeds 70%.
Compounds of this invention, which reduce FiF0 ATP hydrolysis, can also be used to treat/ameliorate/prevent/combat other diseases, disorders and conditions.
Compounds of this invention attack cancer characteristics shared with embryonic stem cells, which aren't found in the adult human body, but are in the blastocyst ¨5 days after fertilization. Thus compounds of this invention have utility as emergency contraceptives, for preventing unwanted pregnancy, with a later time window than the "morning after pill". Reducing FIFO ATP
hydrolysis reduces a futile cycle of ATP synthesis and hydrolysis, used by the body for heat generation (supporting mouse data herein). If exogenous heat replaces this reduced endogenous heat (higher room temperature, wearing more clothes, geographical relocation to the tropics etc.), this reduces energy (food) consumption and .. treats/ameliorates/prevents/combats cachexia, cancer driven cachexia and weight loss, wherein cachexia is the biggest cause of death in cancer patients. Reducing this ATP
synthesis/hydrolysis cycle means the oxidative phosphorylation rate is slower, less ROS are produced and the body accumulates less ROS damage per unit time i.e. aging slows.
Therefore, FIE) ATP hydrolysis inhibitors of this invention extend lifespan and healthspan, .. can treat/ameliorate/prevent/combat accelerated aging diseases, progeroid syndromes and the diseases of aging (e.g. Alzheimer's disease, dementia, Parkinson's disease, cancer etc.). It is noteworthy that compounds of this invention both treat cancer and slow aging, whereas many present cancer treatments accelerate aging, causing greater incidence of age related disease(s) and ailments. Also, it is noteworthy that compounds of this invention both treat and prevent cancer, whereas many present cancer treatments (e.g. radiotherapy) increase cancer risk.
Activated macrophages are distinct from resting macrophages, and other normal adult cells, because the nitric oxide they produce to kill pathogens switches off their use of oxidative phosphorylation and they rely on FIE) ATP hydrolysis to maintain LPN.
Compounds of this invention inhibit FiF0 ATP hydrolysis and so depolarise TN in activated (not resting) macrophages, which triggers their apoptosis. Compounds of this invention treat/ameliorate/prevent/combat macrophage associated diseases or disorders (e.g.
Macrophage Activation Syndrome, HIV hides safely in activated macrophages during anti-retroviral therapy {ART} and from here repopulates HIV virus in blood plasma when ART is interrupted or discontinued, virus neuroinvasion via macrophages, thence HIV-associated neurocognitive disorders). FIR ATP hydrolysis inhibitors, by increasing metabolic/bioenergetic efficiency (less heat produced), can cause energy/weight gain in a subject, which has therapeutic, aesthetic, physical/mental performance applications, and commercial applications in livestock and farming. Compounds of this invention reduce FIN
ATP hydrolysis and can reduce body temperature to a value controlled by intersection of compound dosage and ambient temperature (even at maximum possible effect, compound can't make body fall below, only to, ambient temperature; body temperature controlled by controlling ambient temperature), which can treat/ameliorate/prevent/combat a disease or disorder that causes a higher than normal body temperature (e.g. fever, infection, sepsis, malignant hyperthermia, neuroleptic malignant syndrome etc.) and a disease or disorder combated (or surgery or medical treatment helped) by hypothermia (e.g.
neuroprotection/cardioprotection/tissue protection after a stroke or ischemia, deep hypothermic circulatory arrest for surgery etc.). Disclosed herein are the first drugs to treat/ameliorate/prevent/combat emergency grade hyperthermia, wherein hyperthermia is an extremely dangerous aspect to many Emergency Room (ER) admissions e.g. in some trauma patients. This is a valuable contribution to the art. Inhibiting FIN ATP
hydrolysis reduces body temperature, which slows/reduces neural activity, wherein as regards body temperature, large reduction confers sedation (experimentally observed in mice in data herein), with applications to sleep and surgery etc., and smaller reduction confers anti-hyperactivity, anti-anxiety, anti-depression, anti-pain and treatment for premature ejaculation, epilepsy, Tourette's syndrome, Attention Deficit Hyperactivity Disorder (ADHD), Post Traumatic Stress Disorder (PTSD), homicidal/criminal/suicidal/self-harm ideation/tendency/thoughts etc. The intersection between PIP ATP hydrolysis inhibitor drug dose, and ambient temperature, dictates how much body temperature falls and thence depth of the sedation, wherein if ambient temperature equals 37 C, the drug can't reduce body temperature below this, no matter the dose, and no sedative action can occur. Drug action against a fundamental physiological parameter (body temperature), which dictates a further fundamental physiological parameter (action potential characteristic(s): firing threshold/conduction velocity/firing frequency etc.), yields incredibly broad therapeutic application. It combats any pathology/condition characterized by too much/inappropriate/undesired signals/activity/electrical activity in the nervous system. Juxtaposition of sedation with anti-aging action, which a compound of this invention confers, has applications to space travel, especially because the sedation can be turned on and off by settings of the ambient temperature.
An aspect of the invention is a pharmaceutical composition comprising at least one (optionally more than one) compound, as described herein, and a pharmaceutically-acceptable carrier or excipient or diluent.
An aspect of the invention is a compound(s) and/or composition(s) as described herein for use in a method of treatment of the human or animal body by therapy.
An aspect of the invention is a compound(s) and/or composition(s) as described herein administered to a subject topically or systemically or both.
An aspect of the invention is a compound(s), or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, and/or composition(s) as described herein, optionally a compound(s), and/or composition(s) that reduces FIE) ATP hydrolysis in a subject, for use in treating, ameliorating, preventing, reversing or combating a disease or disorder, or unwanted/undesirable physiological process or its consequences or an unwanted/undesirable aesthetic, selected from the following list;
Encompassed by this invention is a method of treating, ameliorating, preventing, reversing or combating a disease or disorder, or unwanted/undesirable physiological process or its consequences or an unwanted/undesirable aesthetic, in a subject, selected from (i) cancer, any cancer, neoplasia, metastasis, tumor formation/growth/implantation, tumorigenesis, solid tumor, blood borne tumor, cancer that is refractory or resistant to conventional chemotherapy, drug resistant tumor, multidrug resistant cancer;

(ii) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. '8F-FDG PET);
(iii) cachexia, cancer driven cachexia, cancer fatigue, weight loss, weight loss for known or unknown reason, chronic wasting disease, atrophy, brown atrophy, frailty, frailty syndrome, aging frailty, geriatric syndrome, age-related cachexia and/or sarcopenia, weakness, wasting, anorexia nervosa, bulimia nervosa, eating disorder, amenorrhea, underweight, low body mass index (BMI, e.g. <18.5), low body fat percentage, body composition change, wasting syndrome, HIV wasting syndrome, malnutrition, clinical malnutrition, starvation, kwashiorkor syndrome, marasmus syndrome, malabsorption, malabsorption due to parasitic/bacterial infection (e.g. helminthiasis, Whipple's disease, small intestine bacterial overgrowth (SIB0), giardiasis etc.), anemia, refeeding syndrome, appetite loss, catabolysis, muscle atrophy, asthenia, muscle weakness (myasthenia), sarcopenia, osteoporosis, cachexia associated with HIV, AIDS, multiple sclerosis, rheumatoid arthritis, familial amyloid polyneuropathy, chronic kidney disease, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia, Addison's disease, mercury poisoning (acrodynia), chronic pancreatitis, untreated/severe type 1 diabetes mellitus, hormonal deficiency, tuberculosis, gastroenteritis, diarrhea, dysentery, any digestive disease or disorder, any gastrointestinal disease or disorder including functional gastrointestinal disorders, coeliac disease, tropical sprue, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, short bowl syndrome, congestive heart failure, constrictive pericarditis, bradycardia, chronic obstructive pulmonary disease (COPD), altitude sickness, hyperthyroidism (subclinical hyperthyroidism, Graves' disease, multinodular goiter, toxic adenoma, inflammation of the thyroid {thyroiditis}, pituitary .. adenoma), fatigue, chronic fatigue syndrome or any disease or disorder or pathology in which a body tissue(s) is undersupplied or underutilises (vs. its need) an energetic/chemical substrate(s), including 02;
(iv) cancer associated fever, which is especially associated with, but not limited to, non Hodgkin lymphoma (NHL), Hodgkin lymphoma, acute leukaemia, kidney cancer (renal cell cancer), liver cancer (hepatocellular carcinoma), bone cancer, adrenal gland tumours such as phaeochromocytomas, tumours in the hypothalamus, solid tumours;
(v) disease or disorder or physiological process or condition that causes a higher than normal body temperature such as (without limitation) high environmental temperature, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, neutropenic sepsis, stroke, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, toxic serotonin syndrome, thyroid storm, heatstroke, surgery related, menopause ("hot flushes"), infection (non-limiting e.g. roseola, measles, enteroviral infections, parasitic, viral, fungal, Chlamydial, Rickettsial, bacterial, mycobacterial, systemic bacterial, intravascular, HIV associated, nosocomial), pyrogenic infection, thermoregulatory disorder(s), connective tissue disease(s), Kawasaki syndrome, drug overdose, drug or drug withdrawal induced hyperthermia, alcohol/drug withdrawal, idiosyncratic drug reaction, fever of known or unknown or uncertain origin (non-limiting e.g. infectious disease(s), inflammation, immunological disease(s), non-infectious inflammatory disease(s) {non-limiting eg. systemic rheumatic and autoimmune diseases, vasculitis, granulomatous diseases, autoinflammatory syndromes}, tissue destruction, reaction to incompatible blood product(s), metabolic disorder(s), inherited metabolic disorder(s), cancer, neoplasm, endogenous or exogenous pyrogen(s), injury, head injury);
(vi) disease/disorder/injury/pathology/surgery treatable/ameliorated/prevented/combated/helped by conferring hypothermia in a subject for some medical or other purpose which can include slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, slowing physiological/pathological processes (reaction rates are temperature dependent) and so "buying time" to get the subject to treatment for their emergency (e.g.
trauma/septic shock or other medical emergency), slowing the progress of sepsis until a sufficient concentration of a working antibiotic(s) can be built up in the subject (furthermore hypothermia, by slowing sepsis progression, buys time to observe which antibiotic(s) can work, yielding time to try alternative further antibiotic option(s) if required), used soon after or just before clinical/legal death to preserve the subject's organs/tissues until the subject can be frozen/cryogenically frozen or the pathology that caused clinical/legal death (e.g. wound) can be fixed and the subject resuscitated, administered to a subject when a first responder (e.g.
ambulance crew) deems the subject dead or unlikely to survive the journey to a medical facility (e.g. hospital) wherein this administration helps to preserve the subject which is helpful if hospital staff subsequently assess that they can, or might be able to, save the subject, stabilizing surgical/trauma/Emergency Room (ER) patients, deep hypothermic circulatory arrest for surgery (DHCA, non-limiting applications of DHCA include repairs of the aortic arch, repairs to head and neck great vessels, repair of large cerebral aneurysms, repair of cerebral arteriovenous malformations, pulmonary thromboendarterectomy, resection of tumors that have invaded the vena cava, brain tumor resection {wherein the anti-cancer activity of a compound(s) of this invention juxtaposes well}), Emergency Preservation and Resuscitation (EPR), hypothermia for a surgical purpose, protective hypothermia during surgery and/or surgery complication, hypothermia to slow/reduce blood loss, hypothermia for neuro- and/or cardio- and/or organ/tissue and/or life protection in a subject that has trauma/brain trauma/polytrauma/surgery/stroke/ischemic stroke/hemorrhagic stroke/cardiac arrest/myocardial infarction/hypoxia/shock (including, without limitation, low volume, cardiogenic, obstructive, and distributive shock)/sepsis/septic shock/multiple organ dysfunction syndrome/systemic inflammatory response syndrome (SIRS)/organ failure/cytokine storm/anaphylactic shock/seizure/disseminated intravascular coagulation/blocked airway/croup/rhabdomyolysis/[head/facial/spinal/chest/abdominal/ballistic/knife injury/trauma], or some other medical emergency/condition/disorder/disease/injury/operation, hypothermia for cardiac and/or cardiovascular surgery and/or open heart surgery and/or brain surgery (neurosurgery) and/or surgery using total circulatory arrest and/or surgery using cardiopulmonary bypass, Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage/transport and/or transplant, thus increasing the time window for transplantation of organs to recipients;
compound(s) of this invention is administered to organ to be transplanted [by administration to donor and/or by administration to isolated organ] and/or to organ recipient, optionally during transplant operation), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, neonatal hypoxia-ischemia, birth asphyxia, hypoxic-ischemic encephalopathy (HIE), haemorrhage, hypovolemia, exsanguination, suspended animation, decompression sickness, burn injury(s) including skin bum, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, .. hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or tourniquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (non-limiting e.g. meningitis), sepsis, septic shock, stroke, cerebrovascular disease, ischemic brain injury, ischemic stroke, traumatic injury, brain injury, spinal cord injury, cardiac arrest, heart failure, congestive heart failure, Dilated cardiomyopathy, valvular heart disease, pulmonary embolism, adrenal crisis, Addisonian crisis, hypertensive emergency, haemorrhagic (hypovolemic) shock, cardiogenic shock, neurogenic shock, hepatic encephalopathy, blood loss, ischemic brain/heart/kidney/intestinal injury, neuroprotection and/or cardioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject;
(vii) poisoning by a toxic amount of a compound(s) in a subject (non-limiting e.g.
carbon monoxide/methanol/heavy metal/ethylene glycol/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison(s), nerve agent, chemical weapon, bacterial toxin(s) (e.g. food poisoning, Salmonella poisoning), endotoxemia, eukaryote produced toxin(s) e.g. (non-limiting) brevetoxin, drug(s)/substance(s) overdose e.g. (non-limiting) heroin, ethanol, a prescription medication(s), an over the counter medication(s) such as aspirin, paracetamol etc.; hypothermia is protective to toxic insult);
(viii) hypermetabolism (optionally because of one or more of, without restriction, traumatic brain injury, injury to the body, infection, sepsis, burn, multiple trauma, fever, long-bone fracture, hyperthyroidism, prolonged steroid therapy, surgery, bone marrow transplant, recovery from anorexia/bulimia), heat intolerence, insomnia, fatal insomnia, nervousness, Luft's disease, non-thyroidal hypermetabolism, thyrotoxicosis, hyperthyroidism, overactive thyroid, subclinical hyperthyroidism, too much thyroid hormone(s) in the subject, too much triiodothyronine (T3) and/or thyroxine (T4) in the subject, hyperthyroxinemia (including, without restriction, familial dysalbuminemic hyperthyroxinemia, familial euthyroid hyperthyroxinemia, thyroid hormone resistance syndrome), thyroid storm, hyperthyroidism caused by one or more of (without restriction) Graves' disease, thyroiditis, Hashimoto's thyroiditis, subacute thyroiditis, postpartum thyroiditis, lumps (nodules) on the thyroid, enlarged thyroid gland (goitre), simple goitre, multinodular goiter, toxic multinodular goiter, toxic adenoma, toxic thyroid adenoma, inflammation of the thyroid, hyperplasia of thyroid, metastatic thyroid cancer, thyroid tumour, thyroid cancer (including, without restriction, papillary carcinoma, follicular carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma), eating too much iodine, goitrogen ingestion, consumption of ground beef contaminated with thyroid tissue ("hamburger hyperthyroidism"), too much synthetic thyroid hormone in the subject, pituitary adenoma, drug induced, Amiodarone drug induced, struma ovarii, Jod-Basedow syndrome, nonautoimmune autosomal dominant hyperthyroidism;
(ix) low or less than desired metabolic/bioenergetic efficiency in a subject, or low or less than desired physical or mental performance (e.g. memory, IQ), or low or less than desired body weight, or fatigue/tiredness/weakness/exhaustion;

(x) accelerated aging disease or progeroid syndrome including, without restriction, Werner syndrome, Bloom syndrome, De Barsy syndrome, Rothmund¨Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann¨Rautenstrauch syndrome, Hutchinson¨Gilford progeria syndrome (progeria), Ataxia telangiectasia-like disorder 2, XFE progeroid syndrome, Muscular dystrophy, Muscular Dystrophy (Becker's, Duchenne, Limb-Girdle), Yamamoto's Muscular Dystrophy, Mandibuloacral dysplasia, Dilated cardiomyopathy, GAPO syndrome, Cutis laxia, Ehlers-Danlos syndrom, Lenz-Majewski hyperostatic dwarfism, SHORT syndrome, Progressive external opthalmoplegia, .. Nester-Guillermo progeria syndrome, MDPL syndrome, Dyskeratosis congenital, Down syndrome;
(xi) disease or disorder of aging (incidence/severity increases with increased age/senescence) and/or unwanted/undesirable aspect(s) of aging and/or a disease/disorder associated with elevated reactive oxygen species including age-associated decline, aging frailty, frailty syndrome, sarcopenia, muscle weakness, osteoporosis, cognitive decline, cognitive defecit, mild cognitive impairment, degenerative diseases, neurodegenerative diseases, motor-associated neurodegenerative diseases, motor neuron disease, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, progressive supranuclear palsy, pseudobulbar palsy, hereditary spastic paraplegia, Parkinson's disease, Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), essential tremor, resting tremor, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, frontotemporal dementia, chronic traumatic encephalopathy, memory loss, aged cognition, age/aging related cognitive decline/impairment, Batten disease, polyglutamine diseases, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, heart failure with preserved ejection fraction, idiopathic pulmonary fibrosis, fibrotic disease, pulmonary disease, coronary artery disease, hypercholesterolemia, obesity, liver disease, fatty liver disease, lysosomal storage disease, amyloidosis, systemic sclerosis, kidney disease, hepatic cirrhosis, immunosenscence, clonal hematopoiesis, chronic obstructive pulmonary disease (COPD), hypertension, hypercholesterolemia, age-related thymic atrophy, arthritis, osteoarthritis, arthritis (Osteo-and Rheumatoid), Juvenile Rheumatoid Arthritis (JRA), Degenerative Disc Disease, Tendinopathy, Androgenetic Alopecia, male-pattern baldness, Idiopathic Pulmonary Fibrosis, systemic sclerosis, Chronic Obstructive Pulmonary Disease, Psoriasis, age-related loss of cardiac/pulmonary/cognitive/vision function, diabetes, type 2 diabetes, andropause, glaucoma, retinal degeneration, sarcopenia, cachexia, age-related cachexia and/or sarcopenia, age-related macular degeneration (AMD, early/intermediate/late), neovascular/wet AMD, dry AMD, Geographic atrophy (GA), wet and dry AMD in the same eye(s), Stargardt's macular degeneration, Best vitelliform macular dystrophy, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, age/aging-related eye disease, ophthalmological disease/disorder, ocular disease, vision loss, progressive vision impairment, myopia (short-sightedness), degenerative myopia, hyperopia (far-sightedness), accommodative dysfunction, glaucoma, cataract formation, retinal degeneration, progressive retinal degeneration, retinitis pigmentosa, leber hereditary optic neuropathy, Fuchs spot, Best's disease, Sorsby's fundus dystrophy, hearing loss (e.g. age-related), presbycusis, tinnitus, naive T cell shortage, movement disability, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), immunosenescence, respiratory/urinary tract infection (RTI/UTI) especially in older/aged/elderly subjects, cancer;
(xii) aging and/or one or more signs of aging, wherein one or more of these compounds slow/delay/reduce/treat/prevent/stop/reverse aging, and/or extend lifespan and/or healthspan, and/or treat or delay the onset of geriatric aging of the human/animal body, tissue(s), or organ(s), and/or treat or delay the onset of an age-associated phenotype in a cell(s)/organism(s), and/or prolong fertility e.g. female fertility, delay menopause;
(xiii) skin aging and/or damage (including sun damage) and/or scalp and/or hair aging and/or hair greying and/or hair loss;
(xiv) insomnia, fatal insomnia, sleep onset latency, delayed sleep phase disorder, exploding head syndrome, parasomnia, sleep-maintenance insomnia, sleep disorder, too much/inappropriate/undesired signals/activity/electrical activity in the nervous system, hyperactivity, hypersensitivity, Premature ejaculation, hyperreflexia, Autonomic dysreflexia (AD), Hyperventilation syndrome, brain hyperactivity, overly sensitive sensory system, pathological crying and/or laughing, Pseudobulbar affect (PBA, emotional lability), photophobia, phonophobia, temperature-sensitive, pressure-sensitive, brain hyperexcitability, overstimulation, intrusive thought(s), Perseveration, sensory overload, disorganized thinking, fantasy prone personality, malapdative daydreaming, dissociation, hyperkinetic disorder, .. agitation, Psychomotor agitation, restlessness, difficulty controlling behaviour, disruptive behaviour disorder, Emotional and behavioral disorder, pervasive developmental disorder, Overactive disorder associated with mental retardation and stereotyped movements, attention-deficit disorder, Attention Deficit Hyperactivity Disorder (ADHD), adult attention-deficit hyperactivity disorder, severe behavioral problem(s) in children (e.g., to illustrate and not restrict, combativeness and/or explosive hyperexcitable behavior {out of proportion to immediate provocation[s]}, hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of one or more of: impulsivity, difficulty sustaining attention, aggressivity, mood lability, poor frustration tolerance), Premenstrual .. dysphoric disorder (PMDD), premenstrual syndrome (PMS), impulsiveness, impulsivity, impulse control disorder, lack of self-control, hysteria, histrionic personality disorder, attention difficulty, inattention, poor attention control, anxiety, paranoid anxiety, Paranoid personality disorder, distress, dysphoria, Adjustment disorder, separation anxiety, anxiety disorder, depressive anxiety, agitated depression, treatment-resistant depression, Generalized anxiety disorder, social anxiety disorder, stranger anxiety, separation anxiety (e.g. in dogs left at home), separation anxiety disorder, Mixed anxiety-depressive disorder, depression (all forms, all severities), restlessness/apprehension/anxiety before surgery.
hypochondria, panic disorder, panic attack, emotional outburst, emotional instability, Intermittent explosive disorder, unreasonable/unwarranted anger/aggression, hyper-aggression, hostility, rage, poor temper control, self-hatred, poor attentional control, worry, irritability, neuroses, somatization disorder, somatic symptom disorder, pain disorder, psychological pain, psychogenic pain, psychogenic facial pain, Atypical odontalgia (AO), burning mouth syndrome, throbbing, toothache/pulpitis/dental pain, chronic lower back pain, negative emotion, persistent/enduring negative emotion, body dysmorphic disorder, factitious disorder, illness anxiety disorder, unwarrented fight-or-flight response, stress, emotional stress, emotional dysregulation, distress, psychological stress, acute stress, chronic stress, acute stress reaction, combat stress reaction, traumatic grief, grief, grief after death of loved one, Prolonged grief disorder (PGD), heartbreak, guilt, shame, remorse, emotional pain, Algopsychalia, psychalgia, suffering, emotional trauma, psychological trauma, broken heart, Post Traumatic Stress Disorder (PTSD), Complex post-traumatic stress disorder (C-PTSD), hypervigilance, sympathetic hyperactivity, inability or impaired ability to relax, flashbacks, dysphoric hyperarousal, agoraphobia, insomnia, fatal insomnia, mood disorder, irrational/unwarrented fear/terror, phobia, social phobia, Cancerophobia, thunderstorm/firework phobia, hypersexuality, hypersexual disorder, depression, clinical depression, unipolar depression, bipolar disorder, Bipolar I, Bipolar II, Bipolar disorder not otherwise specified (Bipolar NOS), cyclothymia, cyclothymic disorder, mixed affective state, atypical depression, melancholic depression, postpartum depression, double depression, seasonal affective disorder, mania, manic episode, hypomania, increase in energy of psychomotor activity, delirium, excited delirium, major depressive disorder, minor depressive disorder, recurrent brief depression, Depressive Disorder Not Otherwise Specified (DD-NOS), major depressive episode, persistent depressive disorder (PDD), dysthymia, dysthymic disorder, absence of euthymia, manic thoughts, racing thoughts, thought disorder, disordered thinking, reduced ability to plan and execute tasks, paranoia, hallucination (including, without limitation, visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrioceptive, nociceptive, thermoceptive, chronoceptive), Charles Bonnet syndrome, delusion, persecutory delusion, hearing voices, homicidal/criminal ideation/tendency/thoughts, suicidal ideation/tendancy/thoughts, self-injury, non-suicidal self-injury, violence, attacking others, negative mood swing, personality disorder, Borderline personality disorder, Narcissistic personality disorder, malignant narcissism, dissociative disorder, dissociative identity disorder (DID), Psychosis, acute psychosis, chronic psychosis, psychosis spectrum disorder, manifestations of psychotic disorders, behavioral complications of mental retardation, stimulant psychosis, psychotic depression, hallucinogen persisting perception disorder, Psychoactive substance-related disorder, amphetamine-induced psychosis, brief psychotic disorder, Brief reactive psychosis, Menstrual psychosis, postpartum psychosis, Psychotic disorder, Psychopathy, chronic hallucinatory psychosis, manifestation(s) of psychotic disorder, neurotic/reactive/endogenous/involutional/psychotic depression/depressive disorder (optionally accompanied by anxiety or agitation), depressive neurosis, delusional depression, psychotic aggression, psychiatric symptoms of dementia, AIDS delirium, Supersensitivity psychosis, Tardive psychosis, Tardive dysmentia, Depersonalization disorder, out-of-body experience, Sociopathy, Schizophrenia, Paranoid schizophrenia, disorganized-type schizophrenia, simple-type schizophrenia, pseudoneurotic schizophrenia, prodromal schizophrenia, schizoaffective disorder, bipolar type schizoaffective disorder, depressive type schizoaffective disorder, schizoaffective psychosis, Schizotypal personality disorder, schizophreniform disorder, Delusional parasitosis, formication, paresthesias, Acroparesthesia, tinnitus, delusional disorder, delusional jealousy, inappropriate behaviour, behavioural disorder, antisocial personality disorder, Oppositional defiant disorder (ODD), conduct disorder (CD), Disruptive mood dysregulation disorder (DMDD), sadistic personality disorder, poor inhibitory control, kleptomania, Pyromania, trichotillomania, dermatillomania, pathological/problem gambling, dyskinesia, tardive dyskinesia, paroxysmal dyskinesia, Paroxysmal kinesigenic dyskinesia, Paroxysmal nonkinesigenic dyskinesia, Paroxysmal exercise-induced dystonia, Hemiballismus, tic disorder, tremor, clonus, Tourette's syndrome, coprolalia, copropraxia, Echophenomena, Echopraxia, Echolalia, Palilalia, stuttering/stammering, stereotypy, punding, Self-stimulatory behaviour (stimming), Stereotypic movement disorder (SMD), synesthesia, obsession, Obsessive¨compulsive disorder (OCD), obsessive¨compulsive personality disorder, anankastic personality disorder, relationship obsessive¨compulsive disorder (ROCD), Scrupulosity, Primarily obsessional obsessive compulsive disorder, sexual obsession, Akathisia (including, without limitation, chronic, acute, Pseudoakathisia, Tardive akathisia, withdrawal or "rebound"
akathisia), Restless legs syndrome, motor restlessness, periodic limb movement disorder (PLMD), periodic limb movements in sleep (PLMS), Sydenham's chorea, chorea, dystonia, Hypnic jerk, twitching, spasms, Tetanus, tetanus muscle spasms, tetanized state, Myoclonus, myoclonic seizure, Action myoclonus, Palatal myoclonus, Middle ear myoclonus, Spinal myoclonus, Stimulus-sensitive myoclonus, Sleep myoclonus, Cortical reflex myoclonus, Essential myoclonus, myoclonic epilepsy, Juvenile myoclonic epilepsy, Progressive myoclonus epilepsy (PME, including, without limitation, Dentatorubral-pallidoluysian atrophy, Unverricht-Lundborg disease, MERRF syndrome, Lafora disease), Reticular reflex myoclonus, Myoclonic epilepsy, diaphragmatic flutter, automatism, status epilepticus, Epilepsia partialis continua, Complex partial status epilepticus, epilepsy, epileptic seizure, simple partial seizure, complex partial seizure, generalized epilepsy, generalized seizure (including, without limitation, tonic-clonic, tonic, clonic, myoclonic, absence (including typical absence and atypical absence), atonic seizure), focal epilepsy, focal seizure, focal/partial seizure (including, without limitation, Simple partial seizure and Complex partial seizure), focal aware seizure, focal impaired awareness seizure, generalised epilepsy, temporal lobe epilepsy (including, without restriction, mesial temporal lobe epilepsy {MTLE} and lateral temporal lobe epilepsy {LTLE}), Frontal lobe epilepsy, Rolandic epilepsy, Nocturnal epilepsy, Nocturnal frontal lobe epilepsy, Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Generalized epilepsy with febrile seizures plus (GEFS+), .. Panayiotopoulos syndrome, epileptic fit, reflex epilepsy, reflex seizure, absence seizure (including, without limitation, childhood absence epilepsy, epilepsy with myoclonic absences, juvenile absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome {eyelid myoclonia with absences}, genetic generalised epilepsy with phantom absences), complex partial seizure, atonic seizure, generalized tonic-clonic seizure, tonic¨clonic seizure, extrinsic stimulus epilepsy, intrinsic stimulus epilepsy, photosensitive epilepsy, musicogenic epilepsy, thinking epilepsy, eating epilepsy, seizure(s), Febrile seizure, nerve agent induced seizure, Dravet syndrome (sometimes modest hyperthermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals), acute symptomatic seizure, seizure-related disorder, drug related seizure, paroxysmal depolarizing shift, Ohtahara syndrome, Epilepsy in females with mental retardation, Rasmussen's encephalitis, Epilepsy syndrome, benign rolandic epilepsy, childhood absence epilepsy, absence epilepsy, juvenile myoclonic epilepsy, epileptic encephalopathies, Lennox¨Gastaut syndrome, West syndrome (Epileptic spasms), Doose syndrome (Myoclonic astatic epilepsy, MAE), Lennox-Gestaut syndrome, pseudo-Lennox Gastaut syndrome (atypical benign partial epilepsy), Benign familial neonatal epilepsy, Benign occipital epilepsy of childhood, familial neonatal convulsions, Febrile infection-related epilepsy syndrome, interictal dysphoric disorder, euphoria sclerotic, psychogenic non-epileptic seizure, non-epileptic seizure, gelastic seizure, convulsion(s), migraine, status migrainosus, tension headache, headache, Hypnic headache, hiccups, intractable hiccups, thumps in equines, Postural orthostatic tachycardia syndrome (POTS), Pheochromocytoma, agony, pain, chronic pain, acute pain, pain due to disease/injury, neuropathic pain, fibromyalgia, postherpetic neuralgia, phantom pain, referred pain, back pain, lower back pain, pelvic pain, cancer associated pain, chemotherapy associated pain, Diabetic neuropathy, small fiber peripheral neuropathy, Mononeuritis multiplex, Wartenberg's migratory sensory neuropathy, Breakthrough pain, idiopathic pain, polyneuropathy, Neuritis, Mononeuropathy, Polyradiculoneuropathy, Radial neuropathy, neuropathy, visceral pain, Burning feet syndrome, Tarsal tunnel syndrome, Carpal tunnel syndrome, Guyon's canal syndrome, Cubital Tunnel Syndrome, Repetitive strain injury, Sciatica, Neurofibromatosis, Ulnar nerve entrapment, Erythromelalgia, Paroxysmal extreme pain disorder, Proctalgia fugax, dysesthesia, scalp dysesthesia, dysesthetic burning, hyperesthesia, hyperalgesia, Opioid-induced hyperalgesia, hyperpathia, allodynia, pain response from stimuli which do not normally provoke pain, Complex regional pain syndrome (said to be most painful condition known to man), Radiculopathy, neuralgia (including, without restriction, intercostal neuralgia, trigeminal neuralgia, atypical trigeminal neuralgia, glossopharyngeal neuralgia, occipital neuralgia, postherpetic neuralgia), ciguatera poisoning, irritable bowel syndrome (IBS), interstitial cystitis (IC), temporomandibular joint disorder, acute intermittent porphyria, Porphyria, Acute porphyria (including, without limitation, acute intermittent porphyria {AIP}, variegate porphyria {VP}, aminolevulinic acid dehydratase deficiency porphyria {ALAD}, hereditary coproporphyria {HCP}, drug induced), Chronic porphyria (including, without limitation, X-linked dominant protoporphyria {XLDPP}, congenital erythropoietic porphyria {CEP}, porphyria cutanea tarda {PCT}, and erythropoietic protoporphyria {EPP}), cutaneous porphyria, Porphyria cutanea tarda, allergy, allergic reaction, anaphylaxis, anaphylactic shock, hives, asthma, allergic rhinitis, rhinitis, urticaria, contact dermatitis, cough, sore throat, esophageal reflux disease, heartburn, chest pain, Esophageal motility disorder, Nutcracker esophagus, diseases involving gastrointestinal motility, Peptic ulcer disease, esophageal spasm, angina, itchiness, Pruritus, severe pruritus, Prurigo, Pruritic skin condition, chronic itch, eczema, pruritus in eczema, neuropathic itch, neurogenic itch, itchiness due to atopic dermatitis and/or lichen simplex chronicus, peripheral sensitization, central sensitization, sensory perception of absent stimuli, too much sensory stimulation, sensory stimulation brings discomfort, Neuromyotonia, Peripheral nerve hyperexcitability, Morvan's syndrome, Benign fasciculation syndrome, Cramp fasciculation syndrome, hyperhidrosis, undifferentiated somatoform disorder, somatoform disorder, somatic symptom disorder, conversion disorder, functional neurological symptom disorder, severe nausea and/or vomiting, severe nausea/emesis, Chemotherapy-induced peripheral neuropathy, chemotherapy-induced nausea and vomiting (CINV), radiation therapy-induced nausea and vomiting (RINV), postnarcotic nausea, hyperemesis gravidarum, morning sickness, Cyclic vomiting syndrome, retching/dry heaving, Urinary incontinence, enuresis, nocturnal enuresis, tail chasing, reduce urine spraying/marking behavior, benzodiazepine withdrawal syndrome, barbituate withdrawal syndrome, Neuroleptic discontinuation syndrome, drug withdrawal discomfort/pain/symptoms, drug use disorder, alcohol use disorder, opoid use disorder, amphetamine use disorder, cocaine use disorder, alcohol withdrawal syndrome/symptoms, delirium tremens, opoid withdrawal sydrome/symptoms, drug craving, drug addiction, drug dependence, polysubstance dependence, drug overdose, smoking, tobacco (nicotine) addition, tobacco (nicotine) withdrawal symptoms, alcoholism, addiction, opoid addiction, cocaine/crack addiction, addictive behaviour, addictive personality, behavioural addiction, internet/computer/computer game/social media/media addiction, exercise addiction, compulsive behaviour (e.g. {non-limiting}
checking, counting, washing, repeating), anti-social behaviour, criminality, sexual compulsion, impulsive sexual behaviour, compulsive buying, gambling addiction, sex related addiction, sexual urge, hunger, eating desire/compulsion, eating disorder, polyphagia, overeating, binge eating disorder, compulsive overeating, insatiable/excessive appetite, bulimia nervosa, anorexia nervosa, substance abuse, substance-induced delirium, substance-induced psychosis, substance-induced mood disorder, drug overdose, vertigo, motion sickness, seasickness, mental/nervous breakdown, Autism spectrum disorder, neurological disorder, cognitive disorder, mental disorder, mental health disorder, mental health condition involving impaired or altered neural plasticity, mood disorder, mental disorder disclosed in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or a later edition, a mental/behavioural disorder disclosed by the International Classification of Diseases (ICD) in LCD-10 Chapter V: Mental and behavioural disorders (World Health Organisation, WHO); or (xv) diseases or disorders or conditions or pathologies or unwanted/undesirable effects/actions/behaviour treatable/ameliorated/prevented/combated, in totality or in part (e.g.
along with surgery), by anaesthesia, pre-anaesthesia, post-anaesthesia, hypoesthesia, hypoactivity, sedation, coma, tranquilization, behavioural submission, muscle relaxation, hibernation, artificial hibernation, torpor, synthetic torpor, suspended animation (e.g. used during spaceflight because e.g. reduces ionizing radiation damage to subject);
(xvi) hyperproliferative/hyperplasia disorder, non-cancerous proliferative disorder, hyperproliferative autoimmune disorder, hyperplasia, epidermal hyperplasia, dysplasia (e.g.
epithelial dysplasia), nodule(s), wart(s), papilloma(s), squamous cell papilloma, genital wart(s), condyloma(s), condyloma acuminatum, cyst(s), polyp(s) {including, without restriction, digestive, colorectal, endometrial, cervical, nasal, laryngeal, inflammatory fibroid polyp[s])}, inherited/hereditary (including, without restriction, Familial adenomatous polyposis, Peutz¨Jeghers syndrome, Turcot syndrome, Juvenile polyposis syndrome, Cowden disease, Bannayan¨Riley¨Ruvalcaba syndrome {Bannayan-Zonana syndrome}, Gardner's syndrome) and non-inherited (non-restrictive e.g. Cronkhite¨Canada syndrome) polyposis syndrome, benign tumour, adenoma, organ enlargement by hyperplasia, Cushing's disease (enlarged adrenal cortex by hyperplasia), congenital adrenal hyperplasia, hyperplasia of breast, atypical ductal hyperplasia, intraductal papillomatosis, fibroadenomas, fibrocystic changes, hemihyperplasia, focal epithelial hyperplasia, sebaceous hyperplasia, sebaceous adenoma, intimal hyperplasia, unwanted/undesirable smooth muscle cell proliferation, smooth muscle cell hyperplasia, intimal smooth muscle cell hyperplasia, neointimal hyperplasia, proliferative vascular disorders, stenosis, stenosis because of cellular proliferation, vaginal stenosis, stenosis in a blood vessel, lessoned patency of a blood vessel, stenosis in a blood vessel because of cellular proliferation, vascular occlusion, restenosis, restenosis in a blood vessel that has been implanted with a stent, in-stent restenosis, post-angioplasty restenosis, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g.
diabetic retinopathy and/or other retinopathy[y/ies]), cardiac hyperplasia, fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, fibromatosis, neurofibromatosis, renal interstitial fibrosis, Cowden syndrome, hamartoma(s), choristoma(s), hemangioma(s), lymphangioma(s), rhabdomyoma(s), lymphangiomatosis, cystic hygroma, trichilemmoma, sarcoidosis, neurosarcoidosis, aggressive fibromatosis, desmoid tumour(s), unwanted/undesirable skin cell proliferation, hyperproliferative skin disorder, psoriasis (including, without restriction, plaque, guttate, inverse, pustular, napkin, seborrheic-like, nail, scalp and erythrodermic psoriasis), psoriatic arthritis, dactylitis, seborrhoeic dermatitis, dandruff, eczema, atopic dermatitis, rosacea, reactive arthritis (Reiter's syndrome), pityriasis rubra pilaris, hyperproliferative variants of disorders of keratinization (e.g., without restriction, actinic keratosis, senile keratosis, keratosis pilaris, seborrheic keratosis), scleroderma, benign prostatic hyperplasia, prostate enlargement, endometrial hyperplasia, atypical endometrial hyperplasia, benign endometrial hyperplasia, adenomyosis, atypical polypoid adenomyoma, endometriosis, endometriosis of ovary (endometrioma), endometrial polyp(s), polycystic ovary syndrome, ovarian cyst(s), cervical polyp(s), uterine fibroid(s), uterine hyperplasia;
(xvii) Tumour Associated Macrophages (TAMs) or any macrophage associated disease or disorder such as, without limitation, Macrophage Activation Syndrome (MAS), HIV, AIDS, HIV-associated neurocognitive disorders (HAND), AIDS dementia, HIV
peripheral neuropathy, HIV associated cancers, AIDS-defining cancers, non-AIDS
defining cancers, any disease in which the pathogen(s) hides from the immune system in macrophages including, without limitation, Mycobacterium tuberculosis (causes tuberculosis), Leishmania parasite (causes Leishmaniasis), Chikungunya virus (causes Chikungunya), Legionella pneumophila (causes Legionnaires' disease), adenoviruses, T. whipplei (causes Whipple's Disease), Brucella spp. (causes brucellosis), Staphylococcus aureus, Ebola virus, Hepatitis B
virus, Hepatitis C virus, influenza virus strains, dengue virus and antibiotic resistant bacteria, any disease or condition in which activated macrophages are unwanted or undesirable;
(xviii) virus/pathogen neuroinvasion via macrophage(s), as used for non-limiting example by HIV, Heptatitis C virus and SARS coronavirus;
(xix) neurocognitive or neurodegenerative diseases/disorders, for non-limiting example those caused by a virus;
(xx) virus/pathogen transmission from mother to fetus/baby via macrophage(s) as used for non-limiting example by zika (via Hofbauer cells) and HIV
(macrophages in breast milk);
(xxi) acute or chronic or systemic inflammation or any inflammatory disease/disorder/syndrome or any autoinflammatory disease/disorder/syndrome or any autoimmune disease/disorder/syndrome;
(xxii) acute inflammation, chronic inflammation, systemic inflammation, inflammation because of infection or foreign bodies or injury or chemical or toxin or drug or stress or frostbite or burn or ionising radiation or surgery, inflammatory diseases/disorders/syndromes, Macrophage Activation Syndrome (MAS), autoinflammatory diseases/disorders/syndromes, age-related chronic inflammatory diseases ("inflammaging"), autoimmune diseases/disorders/syndromes, diseases/disorders of the innate immune system, sore throat, sore throat associated with cold or flu or fever, high-intensity exercise associated inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, osteoarthritis, inflammatory osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation associated depression, neuroinflammation, neuropathic pain, exercise-induced acute inflammation, atherosclerosis, allergy, hay fever, anaphylaxis, inflammatory myopathies, drug-induced inflammation, systemic inflammatory response syndrome, sepsis-related multiple organ dysfunction/multiple organ failure, microbial infection, acute brain/lung/hepatic/renal injuries, lung inflammation, acute lung injury (ARDS), acne vulgaris, celiac disease, celiac sprue, chronic prostatitis, colitis, autoimmune hemolytic anemia, diverticulitis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Mast Cell Activation Syndrome, mastocytosis, otitis, pelvic inflammatory disease (PID), endometritis, reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasitosis, eosinophilia, type III hypersensitivity, ischaemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, alcoholic hepatitis, chronic viral hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematous (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative disease, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, bronchiectasis, bronchopneumonia, obliterative bronchiolitis, appendicitis, acute appendicitis, bursitis, cystitis, dermatitis, encephalitis, HIV encephalitis, gingivitis, meningitis, infective meningitis, myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis¨associated interstitial lung disease and desquamative interstitial pneumonia, pneumonia, interstitial lung disease, Lofgren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, steatohepatitis, .. nonalcoholic steatohepatitis, silicosis, histiocytoses, Langerhans' cell histiocytosis, haemophagocytic lymphohistiocytosis, pulmonary langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudogout, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft versus host disease (GVHD), lymphadenopathy, rheumatoid arthritis (RA), osteoarthritis (OA), inflammatory osteoarthritis, lupus, multiple sclerosis (MS), myocarditis, uveitis, CNS disease(s), inflammation aspect to a CNS disease(s), hypothalamic inflammation, dementia, glaucoma, amyloid related/driven disease, lipid storage disease(s), fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, cirrhosis of the liver, alcoholic cirrhosis, nephropath(y/ies), lupus nephritis, immune nephritis, fibrotic disorder(s), cardiovascular disease, heart disease, atherosclerosis, vulnerable plaque, plaque formation, lipid containing macrophage related disease(s)/disorder(s)/malad(y/ies), macrophage foam cells, diabetes, type 1 diabetes, type 2 diabetes, insulin resistance, macrophage aspect to insulin resistance, obesity, obesity associated inflammation, macrophage accumulation/large numbers of macrophages in adipose tissue (e.g. associated with obesity), granuloma(s), granulomatous diseases, sarcoidosis (including, without limitation, Annular sarcoidosis, Erythrodermic sarcoidosis, Ichthyosiform sarcoidosis, Hypopigmented sarcoidosis, Lofgren syndrome, Lupus pernio, Morpheaform sarcoidosis, Mucosal sarcoidosis, Neurosarcoidosis, Papular sarcoid, Scar sarcoid, Subcutaneous sarcoidosis, Systemic sarcoidosis, Ulcerative sarcoidos), neurosarcoidosis, pulmonary sarcoidosis, interstitial lung disease, pulmonary fibrosis, pulmonary tuberculosis, immune reconstitution syndrome of HIV, Jarisch¨Herxheimer reaction, sepsis, Paget's disease of bone, osteolysis, monocytosis, histiocytosis, X-type histiocytoses, non-X histiocytoses, Langerhans cell histiocytosis, non-Langerhans-cell histiocytosis, malignant histiocytosis, malignant histiocytic disorders, histiocytomas, histiocytic lymphoma, hemophagocytic syndrome, hemophagocytic lymphohistiocytosis, lymphohistiocytosis, diffuse histiocytic sarcoma, Rosai¨Dorfman disease, gliosis, Bergmann gliosis, Chronic Obstructive Pulmonary Disease (COPD), chronic inflammatory lung disease, familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulinemia D with recurrent fever syndrome (HIDS), cryopyrin associated periodic syndrome (CAPS), Blau syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), mevalonate kinase deficiency, pyogenic-arthritis-pyoderma gangrenosum and acne syndrome (PAPA), periodic fever aphthous stomatitis pharyngitis adenitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, Schnitzler's syndrome, Sweet's syndrome, NLRP12-associated autoinflammatory disorders, deficiency of interleukin-1 receptor antagonist (DIRA), pyoderma gangrenosum, cystic acne, aseptic arthritis, periodic Fever Associated with mevalonate kinase deficiency (hyperimmunoglobulin D Syndrome), Pyogenic Arthritis Pyoderma Gangrenosum Acne (PAPA) syndrome, Periodic Fever Aphthous Stomatitis, Pharyngitis and Adenopathy (PFAPA) syndrome, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Chronic Recurrent Multifocal Osteomyelitis (CRMO), Synovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome, Cryopyrin associated Periodic Syndrome (CAPS), Familial cold auto inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Familial cold urticarial, Neonatal onset multisystemic inflammatory disorder (NOMID), hereditary Periodic Fever Syndromes, Periodic Fever Syndromes, systemic autoinflammatory diseases, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Bak) disease, Behcet's disease, benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Berger's disease, dermatitis herpetiformis., dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immune hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type I diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR) PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, peripheral neuropathy, perivenous encephalomyelitis, Pernicious anemia (PA), POEMS
syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type I diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)), idiopathic thrombocytopenia purpura, splenomegaly;
(xxiii) Systemic inflammatory response syndrome, cytokine release syndrome, cytokine storm, immune reaction to a drug(s) or therapy(s), immune reaction to an immune activating drug(s) or agent(s) or treatment(s) or intervention(s), immune reaction to immunotherapy and/or immune-oncology and/or immunomodulatory drug(s) and/or treatment(s), adverse reaction to adoptive T-cell therapy(s), adverse reaction to a chimeric antigen receptor T-cell therapy(s) (CAR-T cell therapy(s)), adverse reaction to a immune checkpoint inhibitor(s), adverse reaction to monoclonal antibody drug(s), tumor lysis syndrome;
(xxiv) cancer and Graft Versus Host Disease (GVHD) in transplantation therapy in a cancer patient;
(xxv) cardiovascular diseases and conditions associated with thrombosis and/or the formation of atherosclerotic plaques and/or ischemia and/or ischemic conditions and/or associated conditions including, without limitation, ischemia-reperfusion injury, myocardial ischemia, ischemic heart disease, chronic stable angina pectoris, first or recurrent myocardial infarction (MI), congestive heart failure, an acute coronary syndrome, muscle cell damage, necrosis, cardiac arrhythmia(s), non-Q wave MI, unstable angina, high blood pressure, coronary artery disease, coronary arterial thrombosis, ischemic hypoxia, cyanosis, gangrene, acute limb ischemia, stroke, ischemic stroke, brain ischemia, vascular dementia, ischemic sudden death, transient ischemic attack (TIA), thrombophlebitis, ischemic colitis, mesenteric ischemia, angina pectoris, ischemic heart disease, ischemic neuropathy, hypoxic-ischemic encephalopathy, cerebral hypoxia, brain hypoxia, ischemia resulting from vascular occlusion, cerebral infarction, stroke and related cerebral vascular diseases (including cerebrovascular accident and transient ischemic attack), muscle cell damage, necrosis, ventricular hypertrophy, ventricular enlargement (including dilated cardiac myopathy and heart failure), Prinzmetal's angina, peripheral occlusive arterial disease (e.g., peripheral arterial disease, intermittent claudication, critical leg ischemia, prevention of amputation, prevention of cardiovascular morbidity such as MI, stroke or death), pericardial effusion, constrictive pericarditis, thrombosis, thrombotic or thromboembolic conditions, circulatory disease caused by blood clot (i.e. diseases involving fibrin formation, platelet activation, and/or platelet aggregation), thrombotic or thromboembolic symptoms of thromboembolic stroke (including that resulting from atrial fibrillation or ventricular mural thrombus), arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, thromboembolic disorders in the chambers of the heart, venous thrombosis (including deep vein thrombosis), arterial thrombosis, cerebral thrombosis, cerebral arterial thrombosis, pulmonary embolism, cerebral embolism, kidney embolism, arterial embolism, thrombophilia, disseminated intravascular coagulation, restenosis, atrial fibrillation, atherosclerotic vascular disease, atherosclerotic plaque formation, atherosclerosis, atherosclerotic plaque rupture, peripheral arterial disease, coagulation syndromes, intermittent claudication, transplant atherosclerosis, vascular remodeling atherosclerosis, diabetic complications comprising retinopathy, nephropathy and neuropathy, thromboembolic consequenses of surgery, interventional cardiology or immobility, thromboembolic consequenses of medication (such as oral contraceptives, hormome replacement and heparin), thrombotic consequenses of atherosclerotic vascular disease and atherosclerotic plaque rupture leading to tissue ischemia, prevention of atherosclerotic plaque formation, transplant atherosclerosis, thrombotic or thromboembolic complications of surgery including interventional cardiology, thromboembolic complications of pregancy including fetal loss, thromboembolic consequences of thrombophilia (e.g., Factor V
Leiden, and homocystinenimia), prothrombotic consequences and/or complications of cancer, prevention of thrombosis on artificial surfaces (such as stents, blood oxygenators, shunts, vascular access ports, vascular grafts, artificial valves, etc.), coagulopathies (e.g., disseminated intravascular coagulation), coagulation syndromes, vascular remodeling atherosclerosis, restenosis and systemic infection, Kasabach-Merritt syndrome, occlusion (e.g. after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty), thromboembolic disorders resulting from conditions including but not limited to atherosclerosis, surgery or surgical complications, prolonged immobilization, arterial fibrillation, congenital thrombophilia, cancer, diabetes, effects of medications or hormones, complications of pregnancy and thrombosis resulting from prosthetic valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis, or other procedures in which blood is exposed to an artificial surface that promotes thrombosis; or (xxvi) diseases or disorders or conditions treatable/ameliorated/prevented/combated by conferring/maintaining blood vessel patency in a subject, which can be useful during interventional cardiology or vascular surgery including bypass grafting, arterial reconstruction, atherectomy, vascular graft and stent patency, organ, tissue and cell implantation and transplantation, preservation of host and/or graft tissue as related to organ transplantation, wherein the method comprises administering to the subject an effective amount of at least one compound, or a composition containing at least one compound, which reduces FiFo ATP hydrolysis in a subject, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
Another aspect is a method of treating, ameliorating, preventing or combating any such disease or disorder by administering to a subject in need thereof a therapeutically effective amount of a compound(s) and/or composition(s) as described herein.
Another aspect is the use of a compound(s) and/or composition(s) as described herein for the manufacture of a medicament for the treatment, amelioration, prevention or combating of any disease or disorder, optionally a disease or disorder mentioned or inferred herein.
In some embodiments, the subject is further/also administered with one or more compounds or compositions approved for human use, optionally for anti-cancer use, by the United States Food and Drug Administration (FDA) and/or European Medicines Agency (EMA), optionally in the same pharmaceutical composition.
In some embodiments, the mg/kg drug dose administered to the subject is comparable with or larger than the mg/kg dose which would be administered to a subject of smaller bodily size (optionally a subject of another, smaller, species), and optionally the mg/kg dosage administered to adult humans is comparable or greater than the No Observed Adverse Effects Level (NOAEL) mg/kg dosage in mice housed at 22 C. The latter would greatly surprise someone of the art because it is very distinct from most other drugs, wherein bigger species are administered much lower mg/kg doses, not comparable or larger.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1, 2, 3, 4, 5, 6, 7, 8 show anti-cancer activity of carboplatin (10 M), BTB06584 (10 M), BTB06584 (100 M), BMS-199264 (10 M), BMS-199264 (100 M), compound 31 (10 M), almitrine dimesylate (at 10 and 100 M), compounds 6a and 6b (at 10 and 100 04), respectively in the NCI one-dose assay. Figure 9 consolidates data from prior figures to show that anti-cancer activity scales with inhibition of FIR:, ATP hydrolysis.
Figure 10 shows anti-cancer activity of compounds 7a and 7b in the NCI one-dose (10 IA) assay. Figure 11 shows anti-cancer activity of compounds 8a and 8b in the NCI one-dose (10 M) assay.
Figure 12 consolidates data from prior figures to compare the anti-cancer activities of compounds 6a, 6b, 7a, 7b, 8a and 8b. Figure 13 shows anti-cancer activity of BMS-199264, Figure 14 shows anti-cancer activity of 31, Figure 15 shows anti-cancer activity of 6a and 6b, Figure 16 shows anti-cancer activity of 8a and 8b, in the NCI five-dose assay.
Figure 17 recasts data from Figures 8 & 15. Figure 18 interprets data from Figures 8, 15, and 17. Figure 19 interprets data from Figure 13. Figure 20 recasts data from Figure 16.
Figure 21 recasts data from Figure 7. Figure 22 (A) shows that different cancer cell lines of the NCI one dose assay are tested with different numbers of cancer cells and (B) presents drug aggregation data for compound 7b. Figure 23 presents in vivo mouse data for compounds 6a and 6b. Figure 24 presents experimental data showing that IF1 is a determinant of lifespan.
Figure 25 shows that, in vivo, inhibiting FIF0 ATP hydrolysis safely reduces the rate of oxidative phosphorylation and ROS generation, shown with forebrain neurons. Figure 26 shows that, in vivo, inhibiting FiFo ATP hydrolysis safely reduces the rate of oxidative phosphorylation, shown with hepatocytes. Figure 27 shows that, in vivo, inhibiting FIE) ATP
hydrolysis safely reduces the rate of oxidative phosphorylation, shown in intestine (colonic cells). Figure 28 is a diagram illustrating how decreasing [ROS] in a cell, for example by inhibiting FiFo ATP
hydrolysis which reduces the oxidative phosphorylation/ROS generation rate, can prolong/increase the information fidelity of DNA, which slows/reverses aging.
Figure 29 presents some protein sequence embodiments of the invention. Figure 30 presents experimental data on the racemization rate of 6b. Figure 31 discloses that invention compounds can reduce FIFO ATP synthesis by uncoupling the proton motive force, with supporting experimental data. Figure 32 discloses spectral data for compounds 6a and 6b.
Figure 33 discloses spectral data for compounds 7a and 7b. Figure 34 compares spectral data from Figures 32 and 33. Figure 35 discloses spectral data for compounds 8a and 8b. Figure 36 discloses spectral data for compound 31. Figure 37 discloses spectral data for the compound synthesized by Scheme IHa of this disclosure.
DETAILED DESCRIPTION OF THE INVENTION
Some definitions As used herein with reference to the utilities described, the terms "treating"
or "treatment"
encompass both responsive and prophylaxis/preventative measures designed to inhibit or delay the onset of the disease or disorder, or to cure/eradicate, alleviate, palliate, reverse, prevent, ameliorate, lessen, reduce, modulate, stabalize, delay, suppress, manage, reduce predisposition to, reduce risk of, prevent, reduce reoccurrence of, lengthen time to remission of, or slow progression/spread of the disease or disorder and/or one or more of its symptoms and/or increase quality/length of life and/or improve subject outcome/wellness. The terms "subject" and "patient" refer to organisms to be treated by the compounds/methods of the present invention and can refer to a human or animal. As used herein, the term "therapeutically effective amount" or "effective amount" refers to the amount of a compound (e.g. a compound of the present disclosure) sufficient to effect a therapeutically/cosmetically/aesthetically beneficial/desired result including, for example, mitigating (reducing frequency/duration/severity) or eliminating one or more symptoms of the disease/disorder/condition/sub-optimum, or treating at least one physiological defect or pathology or etiology that causes or contributes to the disease/disorder/condition/sub-optimum being treated. In the case of cancer, a therapeutically effective amount can be, for example that which slows/halts/stabalises/regresses cancer proliferation/spread/invasion/malignancy/danger in the subject and/or which slows/halts/stabalises/regresses cancer associated cachexia. A therapeutically effective amount accounts for treatment variables including, for example, dose, duration, timing and route of administration. An invention embodiment is to administer a compound(s) of this invention to a subject diagnosed with cancer, suspected of having cancer, exhibiting symptoms of a cancer, at risk of cancer (e.g., a human who is genetically or otherwise predisposed to developing a cancer), susceptible to cancer, recovering/recovered from cancer or free of cancer. Palliative use of a compound(s) of this invention, optionally in a subject with cancer, is contemplated by, and componentry to, this invention.

Cancer is herein used to mean any member of a class of diseases/disorders characterized by uncontrolled/undesirable/abnormal/dysregulated/unregulated, including harmful/dangerous (to health and/or lifespan), division of cells, including that independent of normal regulatory .. mechanisms (e.g. loss of contact inhibition). A "tumor" comprises one or more cancerous cells. Cancer cells, in some cases, gain the ability to invade other tissues, either by direct growth into adjacent tissue through invasion or by implantation into distant sites by metastasis. Metastasis is defined as the stage in which cancer cells are transported through the bloodstream or lymphatic system. The cancer may be, for illustrating example, a solid tumor, metastatic cancer, non-metastatic cancer, malignant cancer, benign cancer or pre-cancer. In some embodiments, the cancer may be a chemo-resistant or multidrug resistant cancer, i.e. a refractive form of cancer. It should be appreciated that a composition/compound of the invention may be used alone or in combination with one or more additional anti-cancer agents or treatments (e.g. chemotherapeutic agents, targeted therapeutic agents, pseudo-.. targeted therapeutic agents, hormones, radiation, surgery, etc., or any combination of two or more thereof), optionally a further composition(s)/compound(s) of the invention. In some embodiments, a composition(s)/compound(s) of the invention may be administered to a subject who has undergone a treatment involving one or more of surgery, radiation, chemotherapy. In certain embodiments, a composition or compound of the invention may be .. administered chronically to prevent, or reduce the risk of, a cancer recurrence. According to one embodiment, the subject to be treated is characterized by the presence of a precancerous condition, and the administering of the compound is effective to prevent development of the precancerous condition into the cancerous condition. This can occur by destroying the precancerous cell prior to or concurrent with its further development into a cancerous state.
For the purpose of this invention, beneficial or desired results in the subject include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (partial or total), disease prevention, or reducing predisposition to the disease, prolonging survival as compared to expected survival if not receiving treatment. In some embodiments, a compound(s) of the present invention is used to prevent the growth of a tumor or cancer, and/or prevent the metastasis of a tumor or cancer, and/or to shrink or destroy a cancer and/or treat complications of cancer. A
treatment using one or more of the disclosed therapeutic compounds and compositions disclosed herein may decrease the growth rate of tumor cells, decrease the cell division rate of tumor cells, decrease the extent of invasion of tumor cells into adjacent tissue or organs, decrease the extent of metastasis, decrease angiogenesis, increase apoptosis, increase tumor cell death, increase tumor cell necrosis, or all or any combination thereof. A treatment using one or more of the disclosed therapeutic compounds and compositions disclosed herein may decrease hyperplasia, decrease the growth rate of hyperproliferating cells, decrease the cell division rate of hyperproliferating cells, decrease the extent to which hyperproliferating cells becomes cancerous, decrease angiogenesis, decrease nodule formation, decrease cyst formation, increase apoptosis, increase tumor cell death and/or increase tumor cell necrosis, or all or any combination thereof.
Jurisdictions To simultaneously capture the claim format of both Europe ("use") and USA
("method") and other legal jurisdictions in a single disclosure, any place that one of the following terms (herein specified inside a ") is used, then also componentry to this disclosure is any of the other terms in this sentence, inside ", substituted in its place (including iterated substitutions): "the use of', "the method of using", "the method of using (administering an effective amount to a subject)", the method of using (administering an effective amount to a subject in need thereof)", "use of', "method of use of', "use", "method of use", "method"
"for use in", "for use in the", "for use according to", "for use in a method of', for use in a method (administering an effective amount to a subject) of', "for use in a method (administering an effective amount to a subject in need thereof) of', "for use for", "for use in a method for", "for use in a method of', "for use in", "to use", "a method of using", "a method (administering an effective amount to a subject in need thereof) of using", "used to", "used in a method of', "used in a method (administering an effective amount to a subject in need thereof) of', "in use as", "in a method of use as", "in a method (administering an effective amount to a subject) of use as", "in a method (administering an effective amount to a subject in need thereof) of use as", "for a method of use for", "for a method of use of', "for a method of', "for a method (wherein an effective amount of the compound or compounds is administered to the subject) of", "used", "used in a method", "use", "use a method of', "method of use", "a method of use", "method", "a method", "use in a method", "use in a method for", "use in a method of', "use in a method of treatment", "use in a method of treating", "to use", "a method of using", "for use in", "for a method of use in", "use for the manufacture of a medicament", "use for the manufacture of a medicament for", "use for the manufacture of a medicament to", "for use in the manufacture of a medicament", "for use in the manufacture of a medicament to", "for use in the manufacture of a medicament for", "for use in a method of manufacture of a medicament", for use in a method of manufacture of a medicament for", "for a method of manufacture of a medicament", "for manufacture of a medicament". If this simultaneous capture technically/gramatically fails in a place, places or entirity, then someone of the art will recognize my intent by this paragraph and factor in the necessary correction(s) to arrive at a technically/gramatically correct specification/interpretation for that jurisdiction. In some embodiments, where the word "method" is used in a claim or statement in this disclosure, it is substituted with "process" or "method (administering an effective amount to a subject)" or "method (administering an effective amount to a subject in need/want thereof)" or "method (administering an effective amount to a subject in need of treatment)" or "method of treatment". In some embodiments, where the word "subject" is used in a claim or statement in this disclosure, it is substituted with "subject in need of treatment" or "subject in need thereof' or "subject in need/want thereof'. In some embodiments, where the word "effective" is used in a claim or statement in this disclosure, it is substituted with "therapeutically effective". In some embodiments, where the word "manufacture" is used in a claim or statement in this disclosure, it is substituted with "preparation" or "production" or "import" or "transport" or "import across a national boundry" or "import into the country" or "sale" or "distribution" or "supply"
or "offer to supply" or "advertisment" or "handling" or "prescription" or "testing" or "trialling" or "administration" or "administer". As known by those of the art, there are 3 different claim types: method of medical treatment, Swiss-type and Product by process (purpose-limited-product format, EPC 2000) claims: in this disclosure, when a claim or statement is given in one of these forms it also incorporates by reference the same subject matter in both the other claim forms, wherein it is straightforward for one of the art to convert subject matter in one of these claim forms into both the other claim forms. Also, incorporated by reference is subject matter of this disclosure written in other claim forms that have the same intent as claim forms herein.
A pharmaceutical composition comprising at least one (optionally more than one) compound, as described herein, and a pharmaceutically-acceptable carrier or excipient or diluent. A
pharmaceutical composition comprising at least one (optionally more than one) compound, as described herein, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally a compound(s) of one or more of Formula (I), (II), (III), (IV), (V), (VI), (VII), [X], optionally a compound(s) that reduces FIFO ATP hydrolysis in a subject, and/or a composition containing at least one compound defined herein, and a pharmaceutically-acceptable carrier or excipient or diluent.
Use of a compound, specified herein, for treatment of a disease, specified herein. Use of a compound(s) defined herein, and/or use of a composition containing at least one compound defined herein, and/or use of a pharmaceutical composition defined herein, for treatment of one or more diseases or disorders specified herein. Use of a compound(s) defined herein, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, and/or use of a composition containing at least one compound defined herein, and/or use of a pharmaceutical composition defined herein, optionally a compound(s) and/or composition(s) that reduces FiFo ATP hydrolysis in a subject, optionally a compound(s) of one or more of Formula (I), (II), (III), (IV), (V), (VI), (VII), [X], for treatment/amelioration/prevention/reversal/combat of one or more diseases or disorders or unwanted/undesirable physiological processes (or consequences) or an unwanted/undesirable aesthetic specified herein.
Use of a compound(s) specified herein for the manufacture of a medicament. Use of a compound, specified herein, for manufacture of a medicament for treatment of a disease, specified herein. Use of a compound(s) defined herein, and/or use of a composition containing at least one compound defined herein, and/or use of a pharmaceutical composition defined herein, for the manufacture of a medicament for treatment of one or more diseases or disorders specified herein. Use of a compound(s) defined herein, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, and/or use of a composition containing at least one compound defined herein, and/or use of a pharmaceutical composition defined herein, optionally a compound(s) and/or composition(s) that reduces F 1 Fo ATP
hydrolysis in .. a subject, optionally a compound(s) of one or more of Formula (I), (II), (III), (IV), (V), (VI), (VII), [X], for the manufacture of a medicament for treatment/amelioration/prevention/reversal/combat of one or more diseases or disorders or unwanted/undesirable physiological processes (or consequences) or an unwanted/undesirable aesthetic specified herein.
A compound(s) and/or composition(s) described herein for use in a method of treatment of the human or animal body by therapy.

A compound(s) and/or composition(s) described herein for use in a method of treatment/improvement/enhancement of the human or animal body by therapy.
A method of treating, ameliorating, preventing or combating a disease or disorder by administering a therapeutically effective amount to the subject of at least one compound as defined herein. A method of treating, ameliorating, preventing or combating a disease or disorder by administering a therapeutically effective amount to the subject in need thereof of at least one compound defined as herein. A method of treating, ameliorating, preventing or combating a disease or disorder by administering to a subject in need of treatment an effective amount of at least one compound defined herein. A method of treating/ameliorating/preventing/reversing/combating one or more of a disease/disorder or unwanted/undesirable physiological process (or its consequences) or an unwanted/undesirable aesthetic, specified herein, in a subject wherein the method comprises administering an effective amount to the subject of at least one compound defined herein, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally a compound(s) of one or more of Formula (I), (II), (III), (IV), (V), (VI), (VII), [X], optionally a compound(s) that reduces FiFo ATP hydrolysis in a subject, and/or a composition containing at least one compound defined herein, and/or a pharmaceutical composition defined herein. A
method of treating/ameliorating/preventing/reversing/combating one or more of a disease/disorder or unwanted/undesirable physiological process (or its consequences) or an unwanted/undesirable aesthetic, specified herein, in a subject wherein the method comprises administering an effective amount to the subject in need/want thereof of at least one compound defined herein, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally a compound(s) of one or more of Formula (I), (II), (III), (IV), (V), (VI), (VII), [X], optionally a compound(s) that reduces FiFo ATP hydrolysis in a subject, and/or a composition containing at least one compound defined herein, and/or a pharmaceutical composition defined herein.
Use of a compound(s) defined herein, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, and/or use of a composition containing at least one compound defined herein, and/or use of a pharmaceutical composition defined herein, optionally a compound(s) and/or composition(s) that reduces FIR) ATP hydrolysis in a subject, optionally a compound(s) of one or more of Formula (I), (II), (III), (IV), (V), (VI), (VII), [X], for treatment/amelioration/prevention/reversal/combat of one or more diseases or disorders or unwanted/undesirable physiological processes (or consequences) or an unwanted/undesirable aesthetic specified herein, in subject, wherein the administration to the subject is topical/local (not systemic). A method of treating/ameliorating/preventing/reversing/combating one or more of a disease/disorder or unwanted/undesirable physiological process (or its consequences) or an unwanted/undesirable aesthetic, specified herein, in a subject, wherein the method comprises topically/locally (not systemically) administering an effective amount to the subject in need/want thereof of at least one compound defined herein, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally a compound(s) of one or more of Formula (I), (II), (III), (IV), (V), (VI), (VII), [X], optionally a compound(s) that reduces FiFo ATP hydrolysis in a subject, and/or a composition containing at least one compound defined herein, and/or a pharmaceutical composition defined herein,.
Use of a compound(s) defined herein, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, and/or use of a composition containing at least one compound defined herein, and/or use of a pharmaceutical composition defined herein, optionally a compound(s) and/or composition(s) that reduces FIFO ATP hydrolysis in a subject, optionally a . compound(s) of one or more of Formula (I), (II), (III), (IV), (V), (VI), (VII), [X], for treatment/amelioration/prevention/reversal/combat of one or more diseases or disorders or unwanted/undesirable physiological processes (or consequences) or an unwanted/undesirable aesthetic specified herein, in a subject, wherein the subject is also administered with one or more compounds or compositions approved for human use, optionally for anti-cancer use, by the United States Food and Drug Administration (FDA) and/or European Medicines Agency (EMA), optionally in the same pharmaceutical composition. A method of treating/ameliorating/preventing/reversing/combating one or more of a disease/disorder or unwanted/undesirable physiological process (or its consequences) or an unwanted/undesirable aesthetic, specified herein, in a subject, wherein the method comprises administering an effective amount to the subject in need/want thereof of at least one compound defined herein, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally a compound(s) of one or more of Formula (I), (II), (III), (IV), (V), (VI), (VII), [X], optionally a compound(s) that reduces FiFo ATP hydrolysis in a subject, and/or a composition containing at least one compound defined herein, and/or a pharmaceutical composition defined herein, wherein the subject is also administered with an effective amount (which can be less than when administered alone) of one or more compounds or compositions approved for human use, optionally for anti-cancer use, by the United States Food and Drug Administration (FDA) and/or European Medicines Agency (EMA), optionally in the same pharmaceutical composition.
Use of a compound(s) defined herein, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, and/or use of a composition containing at least one compound defined herein, and/or use of a pharmaceutical composition defined herein, optionally a compound(s) and/or composition(s) that reduces FIFO ATP hydrolysis in a subject, optionally a compound(s) of one or more of Formula (I), (II), (III), (IV), (V), (VI), (VII), [X], for treatment/amelioration/prevention/reversal/combat of one or more diseases or disorders or unwanted/undesirable physiological processes (or consequences) or an unwanted/undesirable aesthetic specified herein, in a subject, wherein comparable or larger mg/kg dose is used in larger subjects/animals/species, which is very distinct from most drugs, and optionally the mg/kg dosage administered to adult humans is comparable or greater than the No Observed Adverse Effects Level (NOAEL) mg/kg dosage in mice housed at 22 C. A method of treating/ameliorating/preventing/reversing/combating one or more of a disease/disorder or unwanted/undesirable physiological process (or its consequences) or an unwanted/undesirable aesthetic, specified herein, in a subject, wherein the method comprises administering an effective amount to the subject in need/want thereof of at least one compound defined herein, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally a compound(s) of one or more of Formula (I), (II), (III), (IV), (V), (VI), (VII), [X], optionally a compound(s) that reduces FIF0 ATP hydrolysis in a subject, and/or a composition containing at least one compound defined herein, and/or a pharmaceutical composition defined herein, wherein a comparable or larger mg/kg compound(s) dose is used in, or administered to, a larger subject(s)/animal(s)/species, which is very distinct from most drugs, and optionally the mg/kg dosage administered to one or more adult humans is comparable or greater than the No Observed Adverse Effects Level (NOAEL) mg/kg dosage in mice housed at 22 C.
Invention The invention of this disclosure hinges on the discovery, disclosed herein, that some cancers rely on FIFO ATP hydrolysis, even under normoxia (indeed under hyperoxia: ¨21%
02), during some or all of their cell cycle. Evidence herein: compounds of this disclosure, which specifically inhibit FIFO ATP hydrolysis, slow cancer proliferation at concentrations that they do not harm normal cells.

In some of the most dangerous cancers, refractory to present [chemo/radio]
therapies, during some or all of their cell cycle, reactive oxygen species (ROS) decrease [NADPH], because NADPH is consumed in ROS mitigation processes, and this then pulls through increased pentose phosphate pathway (PPP) and glycolytic flux. But such a pivotal increase in glycolytic/PPP flux can only occur because of FiFo ATP hydrolysis, a distinctive feature to these cancers, which stops ATP produced by glycolysis from accumulating and slowing glycolysis by negative feedback inhibition of key glycolytic enzymes. This increased PPP
flux maintains [NADPH] and ROS mitigation. In this way, these cancers can maintain a very high ROS mitigation capability, maintain very low intracellular EROS], and tend to be the most resistant to conventional [chemo/radio] therapies, which work, or often don't work (!), by increasing [ROS]. Compounds of this disclosure undermine this process/resistance. By inhibiting FIFO ATP hydrolysis, they increase the anti-cancer efficacy of any chemical or treatment that increases reactive oxygen species (ROS) in cancer cells. An embodiment of this disclosure is any such co-treatment(s). Indeed, a compound(s) of this disclosure increases the success rate of standard of care [chemo/radio] therapies and optionally permits their use at lower dosing, which reduces their horrendous side-effects. This disclosure encompasses a compound(s) of this invention, for example a compound(s) of Formula (I), (II), (III), (IV), (V), (VI), (VII) in co-therapy with one or more of surgery, chemotherapy, immunotherapy, immuno-oncology, radioimmunotherapy, biological therapy, hormone therapy, radiotherapy or any US Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) approved drug(s) or treatment, for example, a drug/treatment approved for cancer therapy. In some embodiments the anti-cancer activity of a compound(s) of this invention, for example a compound(s) of Formula (I), (II), (III), (IV), (V), (VI), (VII), synergises with (potentiates) the anti-cancer activity of an FDA and/or EMA approved anti-cancer treatment(s) e.g. one or more of chemotherapy, radiotherapy, immunotherapy, surgery etc. In other words, their combined anti-cancer effect is greater than simply being the sum of each alone. In some embodiments, a compound(s) of this invention is used as an adjuvant or neoadjuvant to another cancer treatment(s) e.g. used as an adjuvant or neoadjuvant to chemo and/or radiotherapy and/or surgery. In some embodiments a compound(s) of this invention, for example a compound(s) of Formula (I), (II), (III), (IV), (V), (VI), (VII), makes a cancer(s) more radiosensitive/less radioresistant and/or more chemosensitive/less chemoresistant i.e.
more amenable to treatment by radio- and/or chemo- therapy, acts as a radiosensitizer and/or chemosensitizer. This is very valuable for treating radio- and/or chemo-resistant cancers.

Chemotherapies are well known to those of the art, including, but not limited to, cisplatin, carboplatin, taxol, oxaliplatin etc, and tend to be (very) toxic. Encompassed herein is a method of reducing, treating and/or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, chemotherapy, radiotherapy, immunotherapy, wherein a compound(s) provided herein, e.g., a compound(s) of Formula (I), (II), (III), (IV), (V), (VI), (VII) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof, is administered to a subject prior to, during, or after the occurrence of the adverse effect associated with conventional therapy, optionally wherein the dosage/frequency/use of the conventional therapy is decreased.
In other embodiments, a compound(s) of this disclosure is used as cancer therapy alone.
Indeed, this is a much more cancer-targeted therapeutic approach. The most dangerous cancers use this distinctive metabolism, with ATP synthase distinctively in reverse, consuming glycolytic ATP, to yield high glycolytic rate, thence abundant glycolytic intermediates for biosynthesis and, crucially, to keep [ROS] low (as prior disclosed), which is necessary to cancer immortality ("limitless replicative potential", a Hallmark of cancer [26]) and thence danger. This distinction is targeted, by compound(s) of this disclosure, without significant damage to normal cells. Normal adult cells normally use a different metabolism, with ATP synthase more in forward mode, and a higher ATP yield from glucose, but at the cost of higher [ROS] and mortality.
This reliance of normal cells upon the forward mode of ATP synthase makes them exquisitely susceptible to oligomycin. The compounds of this disclosure are useful for anti-cancer treatment, unlike oligomycin, because of their distinction from oligomycin, which couldn't have been foreseen without the inventive steps of this disclosure. In normal cells that are actively respiring (known as state 3 respiration [3]), inhibitors of the forward mode of ATP synthase (e.g. oligomycin) cause a state 3 to state 4 transition, hyperpolarize decrease 02 consumption and reduce [ATP] (so called "modulators" of the forward mode of ATP synthase, e.g. Bz-423, can also cause one or more of these effects) whilst a specific inhibitor of the reverse mode of ATP synthase does not exert these effects at a working concentration ([12-13], herein incorporated in their entirety). However, at this working concentration, after inhibition of the respiratory chain (e.g. blocked by rotenone, or some other respiratory chain inhibitor, or by a reduced 02 concentration), a specific inhibitor of the reverse mode of ATP synthase will depolarise Tim. This feature distinguishes a molecule that inhibits the reverse mode of ATP synthase significantly more than it inhibits/modifies the forward mode of ATP synthase, and/or inhibits/modifies ATP synthesis. Such a molecule, put into use as an anti-cancer therapeutic, is an embodiment of this invention. A
further embodiment is the process/method of seeking new anti-cancer molecules by assaying whether a candidate molecule can depolarise Tim, when Tim is maintained by FiFo ATP
hydrolysis (e.g. when OXPHOS is blocked by a respiratory chain inhibitor or insufficient 02), but that can't hyperpolarize Tim and/or decrease 02 consumption, when Tim is maintained by proton pumping by complexes of the respiratory chain. If a candidate molecule meets these requirements, it is an anti-cancer therapeutic, as determined by the invention of this disclosure.
Some cancers intrinsically rely upon ATP synthase in reverse, as revealed by experimental data of this disclosure, and further cancers can have this reliance imposed upon them, to maintain Tim in the hypoxia of a solid tumour, which also makes them susceptible to drugs of this disclosure. Significant lactate release is correlated with the most dangerous cancers and poor patient outcomes (numerous studies find this: example: [27]). High lactate release indicates high glycolytic rate, which FIFO ATP hydrolysis enables, and which drugs of this disclosure attack. This invention confronts the most deadly cancers by discovering/disclosing a cancer-specific weakness, and the means to selectively attack it.
All the following molecules are ¨ in use as anti-cancer therapeutics -embodiments of this invention: (1) Molecules that inhibit the reverse, and not the forward, mode of ATP synthase, (2) Molecules that inhibit the reverse more than than forward mode of ATP
synthase, (3) Molecules that inhibit the reverse mode of ATP synthase, and not its forward mode, but that shuttle protons across the mitochondrial inner membrane, dissipating the pmf as heat (uncoupling [3]), which reduces FiFo ATP synthesis, and in a further embodiment:
uncoupling molecules that reduce FIR' ATP hydrolysis more than FIF0 ATP
synthesis, (4) Molecules that inhibit ATP hydrolysis more than ATP synthesis at the mitochondrial inner membrane, (5) Molecules that have a lower IC50 or ECso for FiFo ATP hydrolysis than Fi Fo ATP synthesis. This invention discloses the process/method of using one or more molecular species, each with one or more of the characteristics in the aforementioned numbered points, as an anti-cancer medicine or treatment. Some examples are presented in this disclosure. Any cancer therapy or treatment or drug that leverages, relies upon, utilises or targets that cancers employ ATP synthase in its reverse mode is an embodiment of this disclosure.

MECHANISTIC DISTINCTION FROM POLYICETIDE FiFo ATP SYNTHASE
INHIBITORS
The compounds of this invention act by a distinctly different mechanism, upon cancer cells, than oligomycin. Drugs that act against the same molecular target have a similar pattern of activity against the different cancer cell lines of the NCI-60 assay i.e. the smaller, and the larger, of their GI50 values are against the same cell lines (GI50 is compound concentration that causes 50% growth inhibition of a cell line relative to no-drug control).
The degree of (dis)similarity can be measured using the COMPARE algorithm [28-29], which employs a Pearson correlation coefficient. For example, [30] found that the COMPARE
algorithm can successfully group different FDA-approved anti-cancer drugs by their method of action using their NCI-60 GI50 data. Oligomycin A (NSC: 717694 [16]) inhibits FIFO ATP
synthase [4, 14] and so do other polyketides: cytovaricin (NSC: 349622 [16]), ossamycin (NSC: 76627 [16]) and peliomycin (NSC: 76455 [161); indeed, their NCI-60 pattern responses (GI50 values) correlate with that of oligomycin A: 0.896, 0.809 and 0.865 respectively (COMPARE
algorithm output, all significant at p <0.05). However, the NCI-60 pattern response (GI50 values) of BMS-199264 is uncorrelated to that of oligomycin A (0.009). As is that of compound 31 (-0.009). As is that of compounds 8b (0.144, not significant at p < 0.05) and 8a (0.282, p= 0.03, so actually significant at p <0.05), which have very correlated anti-cancer activity with each other (0.752, p <0.00001). As is that of compounds 6b (0.198, not significant at p < 0.05) and 6a (0.207, not significant at p <0.05), which are separated stereoisomers of racemate 19a that both epimerize towards being the 19a racemate during NCI testing, and that have very correlated anti-cancer-activity (0.754, p <0.00001). This mechanistic distinction from oligomycin is vital because polyketide FIR ATP
synthase inhibitors are poisonous to normal cells [15], which means they fail in cancer xenograft mouse experiments [16] and are without clinical utility.
Higher HIF-la (and lower pyruvate kinase (liver isoenzyme}, lower aspartate aminotransferase 2 {mitochondrial} and lower ATP synthase) gene expressions are reported to be a marker of the Warburg effect [14] and correlate (at p < 0.05) with insensitivity to the polyketide FIN ATP synthase inhibitor, cytovaricin (Table 1 of [14]). By contrast, using the same cell lines and gene expression data set used to make Table 1 of [14], BMS-sensitivity (GI50) does not correlate (at p < 0.05) with any of these gene expressions. Nor does compound 31 or 6b or 8b sensitivity (G150, at p < 0.05). Figure 5 of [14]
presents apoptolidin resistant NCI-60 cell lines, resistant because they utilise the Warburg effect [14], but the majority of these cell lines are more sensitive to BMS-19264 than the average, with a lower GI50 value than the average GI50 value (3.9 M) for BMS-199264, half of these cell lines are more sensitive to compound 31 than the average, with a lower GI50 value than the average GI50 value (13.2 j.iM) for 31, 37.5% of these cell lines are more sensitive to compound 6b than the average, with a lower G150 value than the average GI50 value (0.446 11M) for 6b.
The lower the bioenergetic cellular index (BEC) of a cancer cell [18], the more it demonstrates the Warburg effect and the more it relies on glycolytic rather than oxidative metabolism. BEC is, by one measure [19], the ratio amount of the 13 subunit of Fl ATPase (p ¨Fl-ATPase; gene: ATP5B) to that of Glyceraldehyde 3-phosphate dehydrogenase (GAPDH). I calculated BEC for the same cell lines analysed for Table 1 of [14], using the mRNA transcript amounts of ATP5B and GAPDH in each cell line, data sourced from [31-32], and then calculating the GATP5BMGAPDH] transcript ratio) for each of these cancer cell lines. Using transcript data rather than protein data is a limitation, but [33] report that a protein's cellular amount is generally well correlated (0.76) to its mRNA
transcript amount, at least for cells in the NCI-60 assay, for the protein subset they studied.
And furthermore, [14] relied on transcript data, so best comparison with [14] is made using such data.
Polyketide FiFo ATP synthase inhibitors don't work well against cancer cells exhibiting the Warburg effect [14] and, indeed, for the cell lines analysed (same ones used as for Table 1 in [14]) there is a significant (at p <0.05) negative Pearson correlation between logio(GI50) and BEC for oligomycin A (-0.9411; oligomycin A logio(GI50) values sourced from its entry [NSC: 717694] in the "Query drug data" component of the CellMiner database [32]). So, this correlation shows that the more a cancer uses Warburg metabolism, the less its danger is mitigated by oligomycin A. This significantly reduces the utility of oligomycin A as a cancer medicine because a low BEC score (indicating Warburg metabolism) is characteristic to some of the most dangerous cancers, with the worst patient outcomes [18-20]. By contrast, there is no significant (at p <0.05) Pearson correlation between cancer cell line BEC
and GI50 values for BMS-199264 (0.3639), 31 (0.4247) or 6b (0.0298) or 8b (-0.1388). This means that, distinctly from the polyketide FIFO ATP synthase inhibitors, their anti-cancer action is not restricted to those, often less dangerous, cancers that don't utilise Warburg metabolism.

Molecules of this disclosure undermine cancer by inhibiting the reverse mode of ATP
synthase. It is true that polyketide FiFo ATP synthase inhibitors also inhibit this mode, but distinctly, in addition, they also inhibit the forward mode of ATP synthase, indeed more potently [II], and whilst they can exert anti-cancer activity, because this forward mode is vital to many cancers, it is also vital to many normal cells. This makes polyketide FiFo ATP
synthase inhibitors unsuitable as clinical molecules. Molecules of this disclosure are therapeutic because of their distinction from, not their similarity to, polyketide FIN ATP
synthase inhibitors.
[14] sum up with "Many cancer cells maintain a high level of anaerobic carbon metabolism even in the presence of oxygen, a phenomenon that is historically known as the Warburg effect. From our results, we conclude that macrolide inhibitors of the mitochondrial FoFi-ATP synthase selectively kill metabolically active tumor cells that do not exhibit the Warburg effect". So, [14] find that these macrolides only kill cancers reliant upon OXPHOS, so using FIFO-ATP synthase in its forward mode to generate ATP (which unfortunately is also the metabolic profile of many key types of normal cell) and thus macrolide inhibition of the forward mode of FiFo-ATP synthase is key to this (unspecific) anti-cancer activity. By contrast, the molecules of this disclosure exert anti-cancer activity by inhibition of the reverse mode of ATP synthase. BMS-199264 [4, 7, 9, 10, 11], BTB06584 [13], 31 [8] and the stereoisomer 6b (and its racemate, 19a) [5, 6] have been described previously, as molecules that can inhibit this mode, and this invention discloses their utility as anti-cancer therapeutics, with supporting experimental data, thence identifying new cancer drugs and, more fundamentally/importantly, a new cancer specific drug target: FIFO-ATP
hydrolysis (Figure 9). The opposite stereoisomer to 6b, 6a, also exerts anti-cancer activity (Figure 8) because both 6a and 6b racemize towards being the racemate, 19a, during NCI testing.

(100 04) exerts anti-cancer activity (Figure 3), despite not inhibiting FiFo-ATP synthesis, as a function of inhibiting FiFo-ATP hydrolysis (at >100 M), and critically it isn't harmful to normal cells (mouse cortical neurons) at this concentration [13]. Its anti-cancer potency (none at 10 M, observed at 100 M; Figures 2 and 3 respectively) matches its inhibitory potency for FiFo-ATP hydrolysis (none at 10 M, requires ?100 M [13]). BMS-199264 (10 M) exerts anti-cancer activity (Figure 4). It doesn't harm normal cells (ex vivo rat heart) at this concentration [11]. In NCI five-dose testing [34-35], the mean GI50 for BMS-199264 is 3.9 M (Figure 13), which is lower/better than 62% of the 102 FDA approved cancer drugs in [30], their mean GI50 values sourced from Table 1 of [30]: all are directly comparable because they too are sourced from the NCI-60 five-dose assay. Furthermore, in NCI five-dose testing, the mean G150 for 6a and 6b is 0.666 tiM and 0.446 AM respectively (Figure 15), which, in the 6b case, is lower/better than 77% of 102 FDA approved cancer drugs in [30], including cisplatin (mean GIs() = 1.4 M), which is one of the most used, if not the most used, .. chemotherapies of today, but typically with terrible side-effects. A salt of 6b, e.g. 6b HC1, is likely to have an even lower GIso in NCI five-dose testing. At 10 M, 6b exerts greater anti-cancer activity than BMS-199264 (Figure 9), despite it having less effect on synthesis, because it inhibits the reverse mode of ATP synthase more potently than BMS-199264. Again, a vindication that the molecules of this disclosure exert anti-cancer activity .. by inhibiting the reverse mode of ATP synthase, which distinguishes them from the macrolides and, distinctly, makes them usable therapeutically. Indeed, molecules of this disclosure don't appreciably inhibit the forward mode of ATP synthase, in sharp distinction to the macrolides. The compounds that contain a protonable nitrogen atom in their imidazole reduce Fi Fo-ATP synthesis in SMPs because they shuttle protons across the mitochondrial inner membrane, dissipating the proton motive force (uncoupling). Figure 31 presents structure-activity data for such uncoupling in whole cells, using compounds that are also componentry to this invention as anti-cancer drugs. BMS-199264 (logP = 3.79, calculated [25]) uncouples more than 6b (logP =5.97, calculated [25]) because its logP is closer to the logP = 3.2 (calculated) optimum for uncoupling [36].
19a is a racemate, wherein the S stereoisomer, and not the R stereoisomer, potently inhibits FIFO-ATP hydrolysis [5-6]. I tried to test the anti-cancer activity of the separated stereoisomers. They were successfully separated by chiral supercritical fluid chromatography (SFC). But subsequently underwent racemization during the NCI-60 tests. One stereoisomer sample conveyed slightly better anti-cancer activity than the other, revealing more area under the curve for S stereoisomer exposure, and possibly a slight enduing enantiomeric excess (ee) of S stereoisomer. Both samples ultimately contained a significant proportion of S
stereoisomer and both had strong anti-cancer activity (Figure 8). The Pearson correlation coefficient (R = 0.8 at 10 AM; R = 0.9437 at 100 M) for their patterns of anti-cancer activity is significant (at p < 0.00001). Racemization of the S stereoisomer is slowed by replacing the hydrogen atom on its chiral carbon with a deuterium atom (enrichment) and this is a new composition of matter, which is componentry to this invention, as is the method/process of using it for anti-cancer therapy. With this modification, the enantiomeric excess (ee) of the eutomer endures for longer and so per-unit anti-cancer activity is better, for longer. Analogy by the macrolide inhibitors of [14], which [PI, P2, P3] teaches, would suggest that the Sand R stereoisomers have equal anti-cancer activity, and that this would be weak, because they are both comparably weak reducers of FiFo-ATP synthesis (EC50> 100 M in SMP
assays).
By contrast, by the invention of this disclosure, the S stereoisomer specifically is revealed to be a potent anti-cancer therapeutic.
STEREOISOMERISM
For some molecules of this disclosure, one of its stereoisomers has much lower 1050 than the other for inhibiting FIFO ATP hydrolysis, and so, by the invention of this disclosure, this is .. the preferred stereoisomer for anti-cancer use. Indeed, a form with high enantiomeric excess (ee) for this preferred stereoisomer is the preferred embodiment for anti-cancer therapy, e.g.
ee = >70%, ee = >95%, >99% more preferred, =100% most preferred. However, ee can be eroded by racemization. This invention discloses an improvement. Embodied by this disclosure are permutations of each of its chiral molecules, wherein the hydrogen attached to each chiral carbon is replaced with a deuterium, wherein the natural abundance of deuterium (0.015%) at this position is enhanced (non-limiting example: >3000 times greater than the natural abundance of deuterium, i.e. a >40% incorporation of deuterium). The deuterium Kinetic Isotope Effect (KIE) [37] slows racemization.
PREFERRED EMBODIMENTS
....-- N ....--N
----N --N

A
S N NH S N NH
H H
CI CI

CI CI
hydrogen (H) at chiral centre deuterium (D) at chiral centre More preferred The structure on the left has a low EC50 against FIR' ATP hydrolysis (0.018 M), its [EC50 F Fo ATP synthesis/EC50 F IF ATP hydrolysis] ratio > 5,556. In rats, this drug (administered in polyethyleneglycol:water:ethanol, 1:1:1) is orally bioavailable (47%) with good pharmacokinetics (intravenously applied drug half-life in blood = 2.1 hours, Cmax = 21 M, .. volume of distribution = 2.37 1/kg). The deuterated analogue on the right, wherein the hydrogen atom on the chiral carbon is replaced with deuterium, conferring greater stereoisomeric stability because of the kinetic isotope effect (KIE, [37]) is more preferred.
The greater the % deuterium enrichment at the chiral carbon (carbon atom number 21) and the greater the enantiomeric excess, the more preferred the embodiment. In other preferred embodiments other atoms or isotopes or groups are in place of hydrogen on the chiral carbon, blocking its racemization, ensuring enduring stereoisomeric excess. For example, a halogen e.g. fluorine or chlorine or bromine or iodine. Or carbon (methyl). Or a bigger group such as CH2OH.
The most valuable innovation of this invention is not a presented structure but a discovered, disclosed principle: the best anti-cancer compound of this invention is a molecule that inhibits PIP ATP hydrolysis as potently and specifically as possible, whilst it inhibits, by direct binding, the forward mode of the ATP synthase molecule as little as possible: most preferably not at all.
DESTROYING CANCER'S IMMORTALITY, lengthening lives Unlike normal adult cells, cancer cells are immortal e.g. Hela cancer cells have replicated >>billions of times in laboratories across the world after their originator, the person they killed, Henrietta Lacks, is sadly long since dead. Figure 18 interprets (particularly) experimental data of Figures 8, 15 and 17; interpretation expanded upon here.
The core:
Removing cancer's immortality, rendering it mortal, removes its danger without hurting normal cells, which are mortal anyhow. A hyperpolarised TN correlates with the most dangerous cancers [38-43]. I argue because this feature/mode is a function of cancer proliferation and thus, the more aggressive/dangerous the cancer, the more time they spend in this operating mode, and thus the more chance it is detected at scale by Tim imaging. In these cancer cells, Tim = around -200 rather than the -140 mV in normal adult cells.
ROS cause transient growth arrest to permanent growth arrest, to apoptosis or to necrosis, dependent on the level of ROS [44]. Constitutively activating oxidative phosphorylation (OXPHOS) in cancer cells halts their proliferation [45-46] or pushes them into apoptosis [45-49], via its inherent ROS production [47]. In cancers, a higher glycolytic rate drives greater FIN ATP
hydrolysis, greater pmf and a hyperpolarised Tim (-200 mV). This reduces the "sink" drive for electrons to enter the respiratory chain (especially when there is high lactate dehydrogenase expression (out)competing for NADH) and so decreases OXPHOS
rate, which decreases ROS production, whilst simultaneous aforementioned features of FiFo ATP
hydrolysis increase [NADPH] and ROS mitigation. Thus, cancers have decreased ROS
production and increased ROS mitigation. The outcome is that cancers have lower [ROS]
than normal cells, which is integral to their enduring information fidelity, which permits their "limitless replicative potential" (immortality), which confers their danger.
ROS sensing fluorescent probes report higher EROS] in cancer than normal cells [50], and those of the art typically think cancers do have higher EROS], but these probes are cationic and accumulate at greater concentrations in cancer cells because of their more hyperpolarised TIM (Nernst; A60 mV hyperpolarisation accumulates di-positive probe, like nitroblue tetrazolium, 100 times more). Other ROS sensing cancer studies report extracellular [ROS] [51] and some cancers overexpress NOX enzymes [52-53] at their plasma membrane, which generates greater extracellular [ROS], which reduces intracellular 02 and [ROS]. High mutation rate inextricably equals higher mutation rate, ultimately too much information lost, thence limited (not limitless) proliferative capability and mortality. Cancers have high mutational load in legacy to a higher mutation rate that excavated their lower [ROS], lower mutation rate, corrupted embryonic stem cell (ES) like phenotype from the genome, and as a legacy of cancer cells that exited this state by DNA mutation/repair, accrued mutation at higher rate, and mutated back into this state given its genomic proximity. In most cases by a different mutation route than they exited (many DNA mutation routes to a low [ROS]
destination).
Cancer is an anti-mutator phenotype, preceded and punctuated by mutator epochs, whilst normal adult bodies are in a runaway damage/mutation loop, aging and ultimately dying.
Raise the [ROS] in cancer to that of a normal adult cell and cancer danger attenuates. Indeed, raise [ROS] less than this: cancers have many embryonic stem (ES) cell characteristics [54-57], such as limitless replicative potential and hyperpolarised TIM, and ES
cells respond to ROS damage more by apoptosis than repair [57]. In cancer cells, interventional inhibition of FiFo ATP hydrolysis causes TIM depolarisation, more OXPHOS, greater [ROS], which slows cancer cell proliferation, and at greater FiF0 ATP hydrolysis inhibition, even more OXPHOS, [ROS], and the cancer cell dies by apoptosis or necrosis. However, once switched into significant OXPHOS, further FiFo ATP hydrolysis inhibition reduces OXPHOS
rate, because less ATP needs to be synthesised because less ATP is hydrolysed by FIFO ATP
hydrolysis, which reduces [ROS] and anti-cancer action. So, higher doses of an FIFo ATP
hydrolysis inhibitor can have less anti-cancer activity, seen in experimental data disclosed herein (Figures 8, 15, 17). Normal cells use OXPHOS and they benefit from this slowing of OXPHOS, less EROS], with slower aging and increased lifespan. Thus, FIE. ATP
hydrolysis inhibitors of this disclosure hurt cancer whilst simultaneously assisting normal cells. They will extend lifespan in subjects with or without cancer, especially useful for a subject(s) with an accelerated aging disease(s) or progeroid syndrome. They will extend healthspan by delaying, and reducing the incidence of, the diseases of aging (any disease/pathology whose incidence increases with age and/or in which elevated ROS is a contributory factor: numerous such diseases/pathologies known to those of the art) e.g. {non-limiting}
Alzheimer's disease, dementia, Parkinson's disease etc.). But with a caveat. This disclosure discloses a new fundamental biological discovery, supported by disclosed in vivo experimental data (Figure 23): FiFo ATP hydrolysis is not a bug but a feature, necessary for heat production and homeothermy. Thus, inhibiting FIF0 ATP hydrolysis in a subject reduces the subject's endogenous heat production, which requires substitution with exogenous heat e.g. higher ambient temperature for the subject e.g. by appropriate geographical (re)location. However, whilst this issue is very serious for smaller animals such as mice (-20 g), it is much less so for rats (-150 g), and even less for humans (¨ 62 kg). In a simulation reported in [58], a 30%
reduction in metabolic rate in man (70 kg, 170 cm, in 20 C ambient temperature), maintained for 4 hours, only decreases core body temperature by 0.18 C. By contrast, experimental data in [58] shows that 30% reduction in metabolic rate significantly decreases core body temperature in mice, and less in rats. The flip side of this is that because much more of a small animal's metabolism comprises futile cycling of ATP synthesis and hydrolysis, to generate heat, an FIFO ATP hydrolysis inhibitor can decrease their OXPHOS rate by a greater percentage, which will increase their lifespan by a greater percentage, than for a larger animal. Indeed, FIR, ATP hydrolysis inhibitors of this invention will, if ambient temperature is conducive, increase the lifespan of small animals immensely and an embodiment of this invention is to enter a compound(s) of this invention into a competition to extend a rodent's lifespan, wherein there is a financial prize or other benefit e.g. the Mprize.
FIFO ATP hydrolysis inhibitors of this invention confer greater life extension in an animal than for normal cells in culture because in culture the decrease in electron flow along the respiratory chain decreases ROS production but it also decreases 02 consumption and this raises p02, which increases ROS production, whereas in an animal, their breathing slows to keep tissue p02 (and pCO2) constant. An invention embodiment is to use an FIR, ATP
hydrolysis inhibitor of this invention in co-therapy with a respiratory stimulant (non-limiting e.g. doxapram) to elevate blood and tissue p02 to more strongly treat/ameliorate/prevent/combat cancer in a subject. Indeed, relevantly, a compound of this .. invention ¨ almitrine ¨ increases blood p02 in humans.
In an invention embodiment, one or more administered FIFO ATP hydrolysis inhibitors of this invention, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, reduces the ROS generation per unit time in a subject, which reduces their DNA
damage/aging rate, such that it becomes lower than their DNA repair rate, and so their DNA (and other) repair mechanisms are under rather than overwhelmed, and their aging is stopped (repair matches damage rate) or reverses (greater repair than damage rate) so the subject becomes biologically younger, rather than older, in chronological time.
.. In an invention embodiment, one or more FIR ATP hydrolysis inhibitors of this invention, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, are administered to a subject topically/locally rather than systemically, optionally to a cancer(s) or close to a cancer(s) or to a blood vessel perfusing a cancer(s), wherein this cancer can be a tumour, and thence the compound(s) conferred reduction in heat generation (and slower aging) is .. disproportionally applied to this localized region, wherein its lesser heat generation is offset by heat transfer from surrounding body area(s), especially given the heat distributing nature of blood flow. In a particular embodiment, the cancer is suspected rather than diagnosed. In an embodiment, a compound(s) of this invention is applied topically to the skin, optionally to a skin cancer(s).
Eukaryotes must maintain a hyperpolarised Tim or they will undergo apoptosis [59]. In cancers that cannot use OXPHOS because of deficiency(s) in their respiratory chain, or because of hypoxic/anoxic environment (tumours are often hypoxic), FIF0 ATP
hydrolysis is the only means they can maintain Tim, which an FIR ATP hydrolysis inhibitor undermines .. and the subsequent Tim depolarisation triggers cancer apoptosis.
TREATING CACHEXIA
Cancers can utilise aerobic glycolysis (Warburg effect) at one or more stages of their cell cycle. ATP yield from one glucose molecule is 2 ATP by aerobic glycolysis and ¨30 ATP by oxidative phosphorylation [1-3]. The former produces 2 molecules of lactate for each glucose consumed, which can be converted, at the cost of 6 ATP, to glucose by the Cori cycle in the liver [1]. Thence, in this case, the overall ATP yield of aerobic glycolysis is -4. Assuming equal energy use, and assuming the cancer is always rather than disproportionally using aerobic glycolysis, 1 g of cancer uses ¨34 times more (potential) energy than 1 g of normal tissue. However, this is likely an underestimate because cancers typically have higher energy use: cancer uses FiFo ATP hydrolysis, with protons returning to the mitochondrial matrix by UCP2 (overexpressed in many cancers [60-61], to burn glycolytic ATP. This releases glycolytic enzymes from ATP feedback inhibition and permits high glycolytic and PPP rate, producing glycolytic intermediates for biosynthesis and elevated [NADPH] for increased ROS mitigation, thence low [ROS], releasing significant lactate. Elevated blood [lactate]
correlates with cancer danger [27]. So, if food intake does not increase upon cancer developing, a growing cancer can deny energy to normal tissues, which atrophies them, which means even more energy is available to the cancer, which grows further and a positive .. feedback loop (cachexia) ensues which is the leading cause of death in cancer patients. By this invention, FIFO ATP hydrolysis inhibitor(s) switch cancers out of aerobic glycolysis, into OXPHOS, with its associated ROS, aging, mortality, and break this positive feedback loop, treating/ameliorating/preventing/combating cancer associated cachexia in a subject(s). FiFo ATP hydrolysis inhibitor(s) also assist cachexia sufferers by making normal cells more efficient, thence requiring less glucose, and can treat/ameliorate/prevent/combat non-cancer driven cachexia in a subject(s) too. Cachexia occurs in many end-stage illnesses such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), liver failure, kidney failure, stroke, rheumatoid arthritis, severe burn injury and HIV/AIDS. It also occurs in aging.
Embodied by this invention is a therapeutically effective amount of a compound(s) that reduces FIR) ATP hydrolysis, for example a compound(s) of Formula (I-VI), administered in co-therapy with a therapeutically effective amount of a compound(s) that inhibits UCP2, optionally incorporated in same or different pharmaceutical composition(s), to treat/ameliorate/prevent/combat cancer and/or cachexia in a subject. Genipin and cisplatin are non-limiting examples of compounds that inhibit UCP2, cisplatin acts on additional targets also.

BODY TEMPERATURE
Administered to a subject, F1 F0-ATP hydrolysis inhibitor(s) conserves ATP, so less ATP
needs to be synthesized, therefore respiration rate slows, thence metabolic heat production declines and body temperature can fall towards ambient temperature (if ambient < body temperature). Experimental evidence is disclosed in Figure 23. So, when the ambient temperature isn't arduous (not requiring significant energy consuming physiological/behavioural adaptations to maintain body temperature) and dietary intake stays constant, weight gain/maintenance can occur, which can assist cachexia, for example cancer driven cachexia. This is clinically valuable because cachexia is the leading cause of death in cancer patients. If the ambient temperature is sufficiently close to the required body temperature, then the aforementioned decrease in heat generation is safe, because the body temperature can't fall below the ambient temperature. So, for example, if the ambient temperature is 37 C, inhibiting FiFo-ATP hydrolysis could make body temperature fall to this ambient temperature, but not below it, and this is safe because ---37 C
body temperature is safe. Inhibiting FiFo-ATP hydrolysis will reduce, but not abolish, metabolic heat production. So, body metabolism will still contribute to heating the body, just less so, which will shift the thermoneutral and thermal comfort zones (terms well known to those of the art [62], temperatures vary by species, as is well known to those of the art) to higher temperature(s). If the subject is located at a higher temperature to account for this shift, for example at their updated, higher thermoneutral temperature, or make behavioural adaptations (e.g. wearing more clothes), then this shift is harmless. An embodiment of this invention is setting the dosage of a compound(s) that inhibits FIFO ATP hydrolysis with consideration of the ambient temperature, wherein higher dosages are permissible at higher ambient temperatures. The preferred ambient temperature for a dosage permits the subject to be thermoneutral, and/or thermal comfortable, without the metabolic heat (respiration) fraction driven by the FIR) ATP hydrolysis that is lost because of this dosage. This temperature management issue is more important for smaller than larger animals, because surface area scales to mass by a fractional power (e.g. refer Kleiber's law) and so larger animals retain their generated heat better, and so a given percentage drop in (per unit mass) metabolism will cause a smaller drop in body temperature in a bigger animal. The aforementioned weight gain can be of great clinical/health/nutritional value, or aesthetic value (by non-limiting example:
bodybuilders), or commercial value when applied to livestock/farm animals or any animal with a commercial value e.g. racing animals, such as horses. This invention encompasses a method/process of using a compound(s) of this disclosure for these applications, or any others wherein weight, nutritional or energetic gain is wanted in an animal or human.
An embodiment of this invention is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FiFo ATP
.. hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, to treat/ameliorate/prevent/combat cachexia, cancer-associated/driven cachexia, weight loss or a disease or disorder or physiological process or environmental temperature that causes a higher than normal body temperature (many known to those of the art, only a subset listed here to illustrate and not restrict the invention) which can include, but isn't limited to, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, neutropenic sepsis, stroke, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, toxic serotonin syndrome, thyroid storm, heatstroke, surgery related, menopause ("hot flushes"), infection (non-limiting e.g. roseola, measles, enteroviral infections, parasitic, viral, fungal, Chlamydial, Rickettsia], bacterial, mycobacterial, systemic bacterial, intravascular, HIV associated, nosocomial), pyrogenic infection, thermoregulatory disorder(s), connective tissue disease(s), Kawasaki syndrome, drug overdose, drug induced hyperthermia, alcohol/drug withdrawal, idiosyncratic drug reaction, fever of known (non-limiting e.g. infectious disease(s), inflammation, immunological disease(s), non-infectious inflammatory disease(s) {non-limiting eg. systemic rheumatic and autoimmune diseases, vasculitis, granulomatous diseases, autoinflammatory syndromes}, tissue destruction, reaction to incompatible blood product(s), metabolic disorder(s), inherited metabolic disorder(s), cancer, neoplasm, endogenous or exogenous pyrogen(s), injury, head injury) or unknown or uncertain origin, or to cause greater metabolic/bioenergetic efficiency in the subject, enhancing their physical and/or mental performance and/or causing body weight gain, and/or to confer hypothermia in a subject for some medical or other purpose which can include, but isn't limited to, any disease/disorder/pathology/injury/surgery that hypothermia has been/is shown to benefit, slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, slowing physiological/pathological processes (reaction rates are temperature dependent) and so "buying time" to get the subject to treatment for their emergency (e.g.
trauma/septic shock or other medical emergency), slowing the progress of sepsis until a sufficient concentration of a working antibiotic(s) can be built up in the subject (furthermore hypothermia, by slowing sepsis progression, buys time to observe which antibiotic(s) can work, yielding time to try alternative further antibiotic option(s) if required), used soon after or just before clinical/legal death to preserve the subject's organs/tissues until the subject can be frozen/cryogenically frozen or the pathology that caused clinical/legal death (e.g. wound) can be fixed and the subject resuscitated, administered to a subject when a first responder (e.g.
ambulance crew) deems the subject dead or unlikely to survive the journey to a medical facility (e.g. hospital) wherein this administration helps to preserve the subject which is helpful if hospital staff subsequently assess that they can, or might be able to, save the subject, stabilizing surgical/trauma/Emergency Room (ER) patients, deep hypothermic circulatory arrest for surgery (DHCA, non-limiting applications of DHCA include repairs of the aortic arch, repairs to head and neck great vessels, repair of large cerebral aneurysms, repair of cerebral arteriovenous malformations, pulmonary thromboendarterectomy, resection of tumors that have invaded the vena cava, brain tumor resection {wherein the anti-cancer activity of a compound(s) of this invention juxtaposes well)), Emergency Preservation and Resuscitation (EPR), hypothermia for a surgical purpose, protective hypothermia during surgery and/or surgery complication, hypothermia to slow/reduce blood loss, hypothermia for neuro- and/or .. cardio- and/or organ/tissue and/or life protection in a subject that has trauma/brain trauma/polytrauma/surgery/stroke/ischemic stroke/hemorrhagic stroke/cardiac arrest/myocardial infarction/hypoxia/shock (including, without limitation, low volume, cardiogenic, obstructive, and distributive shock)/sepsis/septic shock/multiple organ dysfunction syndrome/systemic inflammatory response syndrome (SIRS)/organ .. failure/cytokine storm/anaphylactic shock/seizure/disseminated intravascular coagulation/blocked airway/croup/rhabdomyolysis/[head/facial/spinal/chest/abdominal/ballistic/knife injury/trauma], or some other medical emergency/condition/disorder/disease/injury/operation, hypothermia for cardiac and/or cardiovascular surgery and/or open heart surgery and/or brain surgery (neurosurgery) and/or surgery using total circulatory arrest and/or surgery using cardiopulmonary bypass, Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage/transport and/or transplant, thus increasing the time window for transplantation of organs to recipients;
compound(s) of this invention is administered to organ to be transplanted [by administration to donor and/or by administration to isolated organ] and/or to organ recipient, optionally during transplant operation), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, neonatal hypoxia-ischemia, birth asphyxia, hypoxic-ischemic encephalopathy (HIE), haemorrhage, hypovolemia, exsanguination, suspended animation, decompression sickness, burn injury(s) including skin burn, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or tourniquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (non-limiting e.g. meningitis), sepsis, septic shock, stroke, cerebrovascular disease, ischemic brain injury, ischemic stroke, traumatic injury, brain injury, spinal cord injury, cardiac arrest, heart failure, congestive heart failure, Dilated cardiomyopathy, valvular heart disease, pulmonary embolism, adrenal crisis, Addisonian crisis, hypertensive emergency, haemorrhagic (hypovolemic) shock, cardiogenic shock, neurogenic shock, hepatic encephalopathy, blood loss, ischemic brain/heart/kidney/intestinal injury, neuroprotection and/or cardioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject, or to confer hypothermia to treat/ameliorate/prevent/combat a poisoning by a toxic amount of a compound(s) in a subject (non-limiting e.g. carbon monoxide/methanol/heavy metal/ethylene glycol/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison, nerve agent, chemical weapon, bacterial toxin(s) {food poisoning, Salmonella poisoning}, endotoxemia, eukaryote produced toxin(s) e.g. (non-limiting) brevetoxin, drug/substance overdose e.g.
(non-limiting) .. heroin, ethanol, a prescription medication(s), an over the counter medication such as aspirin, paracetamol etc.; hypothermia is protective to toxic insult), or to confer one or more of sedation, anaesthesia, hypoactivity, hibernation, torpor, suspended animation, life extension in a subject. In an embodiment, the amplitude of hypothermia is controlled by setting the ambient temperature, wherein an effective amount of administered FiFo ATP
hydrolysis inhibitor reduces subject body temperature to the ambient temperature, and so hypothermic amplitude is controlled by controlling ambient temperature. Another embodiment is that the body temperature that the body falls to, upon administration of an effective amount of FiF0 ATP hydrolysis inhibitor, is controlled by controlling feature(s) of electromagnetic radiation upon the subject, for example emergent from a radiation heater(s), optionally controlled by servocontrol, with the set point set at the desired hypothermic body temperature, used as a body heating system alone or in combination with other body warming devices and methods (many possibilites known to those of the art), which are optionally controlled by servocontrol, optionally integrated into the same control loop, optionally used by themselves alone or in combination for this body heating purporse, to "catch" and offset the hypothermic drive, of an effective amount of FIFO ATP hydrolysis inhibitor(s) in the body, at some desired hypothermic body temperature.
Many cancers cause fever in a subject. By the invention of this disclosure, FIR ATP
.. hydrolysis inhibitors exert anti-cancer activity and can reduce body temperature if [ambient <
.body temperature]. Thence an embodiment of this invention is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FIE. ATP hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or .. prodrug thereof, to treat/ameliorate/prevent/combat cancer and cancer associcated fever, especially (but without restriction) one or more of the following cancers, which are well known by those of the art to drive fever in many cases: non Hodgkin lymphoma (NHL), Hodgkin lymphoma, acute leukaemia, kidney cancer (renal cell cancer), liver cancer (hepatocellular carcinoma), bone cancer, adrenal gland tumours such as phaeochromocytomas, tumours in the hypothalamus, solid tumours.
Compounds of this invention, which inhibit FIR) ATP hydrolysis, have utility for making animals and/or humans feel more comfortable in hot weather, climates and geographies. For example, being taken by or administered to people, especially the elderly, during hot summers.
This temperature aspect to compounds of this disclosure isn't relevant to the NCI-60 tests.
Because in these studies, the ambient temperature is controlled at 37 C [35], which is optimal for cells, and so if these drugs make cellular temperature fall to ambient temperature, .. this is not detrimental. It can be an issue for laboratory animal studies though. Laboratory mice, for example, are typically kept at room temperature (e.g. 20 to 23 C) which renders them very reliant upon additional metabolic/physiological/behavioural heat production because their thermoneutral zone is much higher, at 30 to 32 C (can vary depending on strain, size, age, gender etc. [62]). An administered compound(s) of this disclosure, which inhibits FIFO ATP hydrolysis, can add to the cold stress that laboratory mice endure when kept at typical room temperature. An embodiment of this invention is the process/method of keeping laboratory animals at, or close to, their thermoneutral zone when performing animal studies with a compound(s) of this disclosure. For example, keeping mice at 30 to 32 C. And in a further embodiment, at even higher temperature to compensate for the amount that an administered compound(s) of this disclosure, by inhibiting FIB) ATP
hydrolysis, shifts the animal's thermoneutral zone to a zone of higher temperature. The amount shifted will depend on the administered dosage, so in a further embodiment, the ambient temperature is set according to the dosage used. Wherein, for a compound of this disclosure, a higher ambient temperature, within safe limits, can make a greater compound dosage safer.
An embodiment of this invention is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FiFo ATP
hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, to treat/ameliorate/prevent/combat a medical disease/disorder, wherein the subject is monitored, for example by a healthcare/research professional/worker (doctor, oncologist, nurse, vet, pharmacist, laboratory technician, scientist) or machine/artificial intelligence substitute, for any adverse signs/symptoms/non-normality after compound administration (in an embodiment for 5 minutes, in a further embodiment for 10 minutes, and in a further embodiment for longer) and in a particular embodiment for signs of reduction in body temperature (methods well known to those of the art, in a particular embodiment the subject's body temperature is monitored) and/or the dosage administered is set, and/or modified (e.g.
increased in graduations), by information from this subject wellness/normality/temperature monitoring and/or the subject is located at an ambient temperature (e.g. in a temperature controlled room/enclosure/confine/climate and/or their body temperature is modified/regulated/interdicted by heating effect of electromagnetic radiation e.g. infrared) that maintains their body temperature within safe limits whilst they have an effective amount of compound in their system. An embodiment of this invention is the process/method of considering the ambient temperature in the decision of whether to take or administer a compound(s) of this disclosure, and at what dosage. In an embodiment, a period of medical observation, by a clinical or healthcare professional (e.g. pharmacist), occurs after the subject takes or is administered a compound(s) of this disclosure for the first time, and in a further embodiment when the compound dosage is increased or decreased. In a further embodiment, during this period of medical observation, the subject stays in a location that has medical facilities and/or expertise to treat/combat hypothermia (well known to those of the art), in non-limiting example embodiments this is a hospital or clinic or pharmacy or workplace of healthcare professionals. In an embodiment, during this period of medical observation, the patient stays in a temperature controlled room or area, or at a location where one is available nearby, and if the patient displays signs or symptoms of hypothermia, feels uncomfortable, or their body temperature falls, they can be located in a higher ambient temperature. In an embodiment, while the subject takes or is administered a compound(s) of this invention, or in a monitoring period after it, they stay in a room/confinement/location at a safe ambient temperature for having a compound(s) of this disclosure (non-limiting examples: wherein the ambient temperature is close to the desired body temperature, ¨37 C, or exceeding it within safe limits) and are monitored by observation, and in a further embodiment their body temperature is monitored (methods well known to those of the art), as the controlled room/confinement/location temperature is reduced to a different temperature, in a further embodiment to, at or near, the ambient climatic temperature of that geography at that time, or colder. In a further embodiment, this process/method is iterated until the greatest dosage is found at which the subject has a safe body temperature at, or near, the ambient climatic temperature of that geography at that time or at the ambient temperature(s) at which the subject will spend their time at over their course of compound administration, or that their ambient temperature might fall to at some time over their course of compound administration, wherein the course of compound administration is the period during which the subject has an effective amount of compound in their body.
Many clinical oncology centres have equipment for body heating, for administrating hyperthermia, for anti-cancer treatment. And other clinical specialities have body heating equipment for heat therapy. An invention embodiment is to administer an effective amount of an FIFO ATP hydrolysis inhibitor(s) to a subject, who is heated by such body heating equipment/apparatus, or other body heating equipment/apparatus. An embodiment of this invention is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FIFO ATP hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, to treat/ameliorate/prevent/combat a medical disease/disorder, wherein the subject is warmed by a device(s), for example a medical device(s) (numerous examples known to those of the art e.g. refer [63-64]), to maintain their body temperature within a safe range, optionally locating in an incubator and/or in/under a radiant heater, optionally a scale up of that often used for (especially premature and/or low birth weight) babies (such scale ups, e.g.
adult radiant warmer(s), are commercially available, used for example when patients undergo general anaesthesia, which can reduce metabolic rate by 20-30% [63]; teaching of [64]
incorporated herein by reference, as applied to adult or infant), and the subject's body temperature is maintained by heating the air to a desired temperature and/or by controlled electromagnetic radiation (e.g. infrared, preferably IR-A, from 0.78 to 1.4 gm), and/or by servo-controlling the body temperature at a desired set-point, most preferably at a body temperature conducive to keeping the subject alive e.g. at or near 37 C and/or at a thermoneutral temperature for the subject (in a further embodiment the desired set-point is set at a lower temperature than a normal body temperature, to induce hypothermia in the subject for a medical purpose).
Servocontrol in this context, as well known to those of the art, refers to an electronic feedback system which maintains a constant temperature at the site of a thermistor (or other) .. probe (for non-limiting example, on the skin over the abdomen) by regulating the heat output of an incubator and/or radiant warmer and/or other body heating device.
Componentry to this invention is a servocontrol variant(s) whereby body temperature is recorded by infra-red (and/or other electromagnetic) emission from the body and/or body temperature is increased by infra-red (and/or other electromagnetic) emission towards the body, optionally where .. temperature detection and heating occurs at different wavelengths, optionally for use for heating a subject with an effective amount of a compound(s) that inhibits FIFO
ATP
hydrolysis in their body, optionally a compound(s) of Formula (I-V) or (VII).
An embodiment of this invention is a method in which a subject is administered an effective amount of a compound(s) or pharmaceutical composition(s) that inhibits FIE) ATP
hydrolysis, by intravenous injection, wherein the volume injected is heated to be at or close to normal body temperature and/or wherein any method(s), including equipment, used to treat/ameliorate/prevent/combat anaesthetic associated hypothermia (methods are well known to those of the art) is used for a subject administered with a compound(s) that inhibits FiFo ATP hydrolysis, optionally a compound(s) of Formula (I), (II), (III), (IV), (V) or (VII). An embodiment of this invention is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FIFO ATP
hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, to treat/ameliorate/prevent/combat a medical disease/disorder, wherein the subject wears one or .. more clothes, optionally a hat, to maintain body temperature within safe/comfortable limits as the FIR ATP hydrolysis inhibitor(s) reduces metabolic heat production. An embodiment of this invention is a method in which a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FiFo ATP hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, is distributed, sold and/or administered with a verbal and/or written communication, optionally in a paper insert/leaflet in a packet(s) containing the compound(s) (optionally called "instructions for use", and/or "prescribing information" and/or "patient information leaflet"), that this compound(s) can reduce body temperature and, in a further embodiment, communicating that should the subject that has taken or been administered one or more of these compounds feel cold, and/or has a reduction in body temperature, they should do one or more of: wear more clothes, wear warmer clothes, locate in a hotter environment, tell a doctor or pharmacist, go to a hospital. Each of these aforementioned communications is a separate invention embodiment and combinations of these are further embodiments. In a yet further embodiment, communicating that this is a more serious problem in children, optionally communicating that this is because children have a larger surface area to volume ratio than adults, optionally communicating that this problem is especially acute with babies and optionally communicating that this compound(s) should not be administered to babies (in a further embodiment, unless the baby is in a controlled temperature environment such as an infant incubator or radiant warmer). In another embodiment, a method in which a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FIR) ATP hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, is distributed, sold and/or administered with a verbal and/or written communication, optionally in a paper insert/leaflet in a packet(s) containing the compound(s) (optionally called "instructions for use", and/or "prescribing information" and/or "patient information leaflet"), that alcohol shouldn't be consumed in large amounts, and in another embodiment not at all, if the subject is taking or being administered such a compound(s). Optionally communicating because alcohol can corrupt thermoregulation, which can potentially, negatively interact with the thermoregulatory effect(s) of the administered compound(s). Optionally communicating the same caveat/warning/communication in reference to other drug(s) that can disrupt thermoregulation, many of which are known to those of the art (non-limiting examples:

phenothiazines {like chlorpromazine etc.), thioxanthenes etc.), in place of or in addition to the communication relating to alcohol.
BODY HEAT BALANCE EQUATION (1st Law of Thermodynamics) S = M-W-E-C-K-R;
S = storage of heat in body (=0=heat balance, i.e. no change in body temperature, positive=increased body temperature, negative=decreased body temperature);
M = metabolic heat production (always positive in living organisms);
W = work (positive = useful work accomplished, negative = mechanical work absorbed by body);
E = evaporative heat transfer (positive = transfer to environment);
, C = convective heat transfer (positive = transfer to environment);
K = conductive heat transfer (positive = transfer to environment);
R = radiant heat exchange (positive = transfer to environment);
This concept is well known ([651, herein incorporated in entirety) and numerous strategies to keep S=0, as M decreases when an FIR ATP hydrolysis inhibitor is administered to the subject, will be apparent to those of the art. For (non-limiting) example, if M decreases, use an infra-red lamp to make R negative and substantial enough to offset the decrease in M
(thence keep S=0), or increase the air temperature to make C negative and substantially negative to offset the decrease in M (thence keep S=0), or wear clothes to make positive values of one or more of E, C, K, R less positive to offset the decrease in M
(thence keep S=0).
TRANSLATING DOSAGE BETWEEN SPECIES
Larger species have lower mass specific basal metabolic rate, because this parameter scales to animal mass by a negative fractional power (e.g. refer Kleiber's law). Thence larger species metabolise drugs slower and so require, and can withstand, a lower mg/kg drug dosage, and this is factored into converting a drug dosage in one species (e.g. mouse) into one of different size (e.g. human), as is well known to those of the art (e.g. refer [66] and the FDA guidelines it refers to). However, by the invention of this disclosure, toxicity of selective FIFO ATP
hydrolysis inhibitors scales to animal mass by a negative fractional power and is less in larger animals than predicted by conventional allometric scaling methods used in the art. Because larger animals have a smaller surface area to mass ratio (animal mass is proportional to animal radius3, animal surface area is proportional to animal radius2, thence bigger animals have smaller surface area to mass ratio), they retain metabolically generated heat better and thence a given percentage drop in metabolic rate doesn't cause as big a percentage drop in body temperature i.e. they aren't as negatively affected by a drop in metabolic heat production, which FIN ATP hydrolysis inhibitors cause, which is the defining limit upon their maximally tolerated dosage (MTD), in smaller animals at least, dambient temperature is significantly below optimal body temperature e.g. when ambient temperature = ¨22 C.
Mass specific metabolic rate (MR) [62] is, assuming core body temperature stays constant (heat production=heat loss), and that ambient temperature is below the lower critical temperature, which is the lower bound of ambient temperature that an animal is thermoneutral:
MR = C(Tb-Ta);
Tb = body temperature;
Ta = ambient temperature;
C= whole body thermal conductance= heat transfer rate (by all heat transfer mechanisms) from body core to environment for temperature difference of 1 C;
1=insulation=1/C;
MR = 21.66*M" 25;
C = 4.23*M-0426;
where M = body weight (g);
MR and C decrease with increasing M; MR decrease increases drug toxicity; C
decrease decreases drug toxicity (for an FIE) ATP hydrolysis inhibitor), let us define a danger quotient for an Fi Fo ATP hydrolysis inhibitor: its danger is proportional to C and inversely proportional to MR: danger = C/MR = (4.23*M-0 426)/(21.66*M- 25). Using M=20 g for a mouse, and M=62 kg for a human, danger quotient for mouse (=0.12) and human (=0.03). So, assuming same ambient temperature for both species, which is below the thermoneutral temperature zone of both species, the mg/kg MTD will be ¨4 times more in humans than in mice, and even greater than this for a human wearing clothes (decreases C).
This is far removed from what one of the art would expect: expecting mg/kg MTD in humans to be kss than in mice: for example, calculating (21.66*20025)/(21.66*62000" 25) =
20'25/62000" 25 =
¨7.5 times less, or using the more conservative exponent of [66] (and possibly less appropriate, at least for chemotherapeutics: refer FDA guidance cited in [663) they would calculate 20033/62000033 = 14.2 times less. Any given mg/kg dose in humans will be metabolised (20-025)462000325) = ¨7.5 times slower and so because we have ascertained that the maximum permissible mg/kg dose in humans is ¨4 times more than in mice:
then the potential anti-cancer activity of an FiFo ATP hydrolysis inhibitor is 4*7.5=-30 times higher in a human than a mouse, at typical room temperature. So, elucidated by the invention of this disclosure, small animal studies at room temperature (-22 C) will dramatically underestimate the anti-cancer activity possible at room temperature in humans, and severely curtail the therapeutic benefit fconventional allometric scaling is used to set the human dose from mice studies. This invention supplies a new method to better translate the dosage of an FIFo ATP
hydrolysis inhibitor between species. However, more conventional allometric scaling methods can be used [66] ifthe smaller species studies are conducted at an ambient temperature close to optimal homeothermic body temperature, Ta;---Tb, and especially if humans will live at this same temperature. Thus, the temperature at which the smaller species study is conducted, and the temperature that the human subjects will reside at, determines the allometric scaling method applied, to find the equivalent human dose, which would not have been apparent to someone of the art without this disclosure. Furthermore, a method as disclosed herein can be used to modulate FIFO ATP hydrolysis inhibitor dosage between individuals of a single species, e.g. humans, of different sizes.
The equations and parameters used in this section illustrate the principles of the invention and are not restrictive. For example, other allometric exponents are contemplated and componentry to this invention. A method of this invention is to compare the MTD (or some other safety metric e.g. NOAEL, LD50, LD33 etc.) of an FiFo ATP hydrolysis inhibitor(s) between animal individuals and/or species of different size (e.g. mice, rats, guinea pigs, rabbits, dogs, primates etc.) to calculate more precisely what the particular allometric scaling relation is, and optionally investigate how this scaling changes with ambient temperature.
And then use this relation(s) to calculate/triangulate/estimate a safe starting dose in humans, from prior animal studies. Optionally factoring in what the ambient temperature(s) will be for the humans administered the FiFo ATP hydrolysis inhibitor(s).
ANTI-CANCER DOSAGE
Methods to gauge the anti-cancer activity of a treatment(s) in a subject(s), and/or to gauge the change in anti-cancer activity associated with a change (e.g. dosage change) in treatment(s), are well known to those of the art. They are routinely utilised in pre-clinical studies and clinical practice.

The following methods are very atypical from present dosage methods in the art of chemotherapy, wherein dosage is typically, simply just the maximum dosage that the patient can tolerate. The method of decreasing the administered dose of a compound(s) that reduces F1Fo ATP hydrolysis, for (non-limiting) example a compound of Formula (I) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, in order for it to exert greater anti-cancer activity in a subject is an embodiment of this invention.
The anti-cancer activity of a compound(s) of Formula (I) can increase or decrease in proportion to an increase in compound dosage, wherein there is an optimal anti-cancer dosage which is not, as one of the art would expect, at the maximally tolerated dose.
Decreasing or increasing (!) the dose away from this optimal dosage decreases anti-cancer activity. Herein is a method to find this optimal dosage in a subject, which is componentry to this invention, as are other methods to find the optimal dosage for a compound(s) of Formula (I) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, which leverage/utilise the extremely atypical dose vs. anti-cancer activity profile, disclosed herein (Figures 8, 15 and 17).
If increased dose = increased anti-cancer activity, increase dose further. If increased dose =
decreased anti-cancer activity, decrease dose by more than it was increased previously. Make the next increase in dose smaller than prior. Repeat. As this loop is repeated, and the increment increase in dose gets smaller, the person of the art knows that they are increasingly converging upon the optimal dosage. They can choose to exit the loop at any dosage they wish, knowing that the size of the dosage increase increment on loop exit is an indicator of how close they are to the optimal dosage. The smaller the dosage increase increment at loop exit, the closer that the dosage is to the optimum. The person of the art may choose to do the mirror image of the aforementioned loop and choose decreased, instead of increased, dose increments. There are permutations to these schemes as will be clear to someone of the art, now that this logic has been set out, which are componentry to this invention.
To help illustrate (not restrict) the invention the following R [67] programming code is disclosed, wherein the "optimal" parameter symbolises the optimal anti-cancer dosage, and the loop iterates until the administered drug dosage, "dose", equals the optimal.
Someone of the art can adjust this code, for example changing parameters and/or mathematical symbols, to explore and understand the invention further. Of course, in reality, the optimal anti-cancer dosage is unknown and is not user specified, as in the code, but the code illustrates a method to find the optimal anti-cancer dosage for a compound of Formula (I), a method componentry to this invention. All parameters are merely illustrative.
# R programming code dose = 1 # first dose to be tried reset = dose dt = 600 # step size that dose will be adjusted res = dt/100000000 # res = an accuracy parameter, larger denominator means more iterations and more accuracy x = 0 optimum = 60 # optimal anti-cancer dose, unknown in real case, following the logic herein finds it n = 10 # n = an accuracy parameter, MUST be >1, larger means more iterations and more accuracy m = n count = 0 # how many iterations are taken to converge while (dt > res) dose = dose + dt if (dose<optimum) # Increased dose = Increased anti-cancer activity, so Increase dose further dose = dose+dt x=x+1 if (dose>optimum) # Increased dose = Decreased anti-cancer activity, so Decrease dose if (dose<0){
dose=reset dt = dt/n }
dose = dose-(dt+(dt/n)) x=x-1 if (x==0){dt=dt/m }
# if dose is changed in one direction (increase or decrease) and then subsequently changed in # opposite direction, decrease step size if (abs(x)==2){x=0}
count = count + 1 # if (abs(dose-optimum)<1){break} # not used, but here for interest }
In place of, or after, the aforementioned, or other, method has converged the administered dose to be close to optimum, the dosage can be set randomly, optionally restricted within a range, by some formal/informal random number generator. It need not be perfectly random and can just be the arbitrary choice of a person(s). This formalised/informal random walk is used to find a compound(s) dosage, of Formula (I), with greater anti-cancer activity. It is distinct from conventional methods in its use of dosage reduction (not merely increase) to seek greater anti-cancer activity.
The most optimal dosage, or dosage range, for a compound of Formula (I) is that which causes cancer cell death. This is a narrow dosage range (Figure 18). Flanked at lower and higher doses by dosages that exert less anti-cancer activity. An embodiment of this invention is changing the administered dosage of a compound of Formula (I) in a subject until a dosage(s) causes cancer cell death, optionally by apoptosis. Detected, for non-limiting example, by cancer regression rather than merely slowing of cancer growth and/or by apoptosis markers, well known to those of the art (e.g. refer [68]), for example, in the blood.
Using a dosage selection method disclosed herein to find a good anti-cancer dosage for a compound of Formula (I), optionally in a xenograft/syngeneic rodent(s), optionally housing the rodent(s) at an ambient temperature >26 C (in further embodiments: >28, >30, >32, >34, .?.36 C), is componentry to this invention. As is any housing/rearing of a rodent(s) at an ambient temperature >26 C (in further embodiments: >28, >30, >32, >34, >36 C) whilst administered with a compound(s) of Formula (I), optionally to select the starting dosage(s) for human clinical trial(s).

A method of decreasing the administered dose of almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally almitrine dimesylate, in order for it to exert greater anti-cancer activity in a subject is an embodiment of this invention.
Componentry to this invention is to use one or more of the aforementioned methods, disclosed in this disclosure section for a compound(s) of Formula (I), to find the optimal dosage of a compound(s) of Formula (VI) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally almitrine dimesylate, which leverages/utilises its extremely atypical dose vs. anti-cancer activity profile, disclosed herein (Figures 7 and 21).
UNCOUPLING CANCER
The meaning and characteristics of an uncoupler are well known to those of the art e.g. refer [36]. An uncoupler is a molecule that can bind a proton(s) in the mitochondrial intermembrane space (IMS), move across the mitochondrial inner membrane, and release the proton(s) in the mitochondrial matrix, which dissipates the proton motive force (pmf), and that can then return to the IMS, and repeat this sequence iteratively. 2,4 dinitrophenol is an example of an uncoupler. Many other uncouplers are known to those of the art.
An invention embodiment is to administrate a therapeutically effective amount of a compound(s) that inhibits FiFo ATP hydrolysis (e.g. a compound(s) of Formula (I), (II), (III), (IV), (V) or (VII)), with a therapeutically effective amount of the same or a different compound(s) that uncouples the proton motive force, for use in a method of treatment of the human or animal body by therapy, wherein optionally the FiFo ATP hydrolysis inhibitor(s) and uncoupler(s) are in a single pharmaceutical composition and/or are packaged, and/or distributed, and/or sold together, optionally for the treatment/amelioration/prevention/combat of cancer in a subject(s). As aforementioned, the dosage range that an F1 F0 ATP hydrolysis inhibitor of Formula (I) kills cancer cells is extremely narrow. This range is broadened by co-administration of an uncoupler(s), which increases OXPHOS rate and [ROS], and reduces the concentration of FIFO ATP hydrolysis inhibitor required. In some embodiments, the anti-cancer activity of the uncoupler(s) and FiFo ATP hydrolysis inhibitor(s) synergize (potentiate). Optionally, an FIR ATP hydrolysis inhibitor(s) is administered with an aforementioned method(s) to (fractionally) optimise its dosage, before the administration of the uncoupler, which then decreases the dosage of uncoupler required. An FiFo ATP
hydrolysis inhibitor(s) decreases metabolic inefficiency and body temperature, an uncoupler(s) increases metabolic inefficiency and body temperature: co-administration, especially optimised co-administration, optionally wherein an optimised amount of each is in a single pharmaceutical composition, can reduce the change in body temperature that each would cause alone; and there is synergy in anti-cancer activity yielded.
Componentry to this invention are compounds that inhibit FiFo ATP hydrolysis and that uncouple the proton motive force (pmf) e.g. (non-limiting) BMS-199264. An embodiment of this invention is to administrate, or for the subject to self-administer, a therapeutically effective amount of a compound(s) that inhibits FiFo ATP hydrolysis and that uncouples the proton motive force, for use in a method of treatment of the human or animal body by therapy, optionally for the treatment/amelioration/prevention/combat of cancer in a subject(s).
In cancers that cannot use OXPHOS because of deficiency(s) in their respiratory chain, or because of hypoxic environment (tumours are often hypoxic), which thence singly rely upon FiFo ATP hydrolysis to maintain TN, an uncoupler(s) will erode their Tim and an FIFO ATP
hydrolysis inhibitor(s) will block their only means to counter this, their TN
will collapse, triggering their apoptosis. Given the severity of this vulnerability, and the potentiating effect .. of the two drugs, low drug doses apply. Meanwhile, normal cells will maintain TN by greater OXPHOS rate.
Also componentry to this invention is the use of a therapeutic amount of uncoupler(s) to treat/ameliorate/prevent/combat cancer in a subject. If TIM depolarises, apoptosis ensues [59].
.. Aerobic respiration, favoured by normal adult cells, hyperpolarises TIM as it produces ATP.
Aerobic glycolysis, favoured by many cancers some or all of the time, consumes ATP to hypeipolarise 'Pm Under the challenge of an uncoupler compound(s), the former is more sustainable than the latter, even more so because of the difference in ATP
yields (-30 vs. 2 ATP per glucose), and thence there is a therapeutic margin. In response, some cancers will be able to switch out of aerobic glycolysis, and into aerobic respiration, but its oxidative phosphorylation (OXPHOS) component will increase ROS, bring aging, mortality and mitigated danger, especially because the uncoupler(s) will drive higher OXPHOS
rate. Unlike other chemotherapeutics, uncouplers only interact with protons, not DNA
encoded proteins, and so their therapy cannot be resisted by DNA mutation rendered changes in protein structure, which is the basis to present day cancer drug resistance, which kills.
UNCOUPLING IS VIRTUOUS
The imidazole containing compounds of this disclosure inhibit FIFO ATP
hydrolysis and uncouple (shuttle protons across the mitochondrial inner membrane (IM), eroding the proton motive force, pmf). The former can exert a specific anti-cancer activity, because it undermines the means some cancers maintain Tim in normoxia (experimentally shown by data of this disclosure) or in hypoxic tumours, and the compound's uncoupling can also exert specific anti-cancer activity, explained now. The imidazole containing compounds of this disclosure bind ATP synthase at or near the IFI binding site. In normal cells they bind ATP
synthase at this site and are sequestered from uncoupling, and the ATP they "save" by binding and inhibiting FIR ATP hydrolysis can (over)compensate for the ATP
"lost" to their uncoupling. But some cancers have very high IF' expression (numerous studies show this, e.g. refer [23]). And for some cancers, this is to inhibit FIR ATP hydrolysis, to make their OXPHOS more efficient, which allows them to maintain [ATP] at low [02], and thence survive using OXPHOS in hypoxia (their heat generation is less but their temperature is maintained by heat conduction from surrounding tissues). This high IF' expression blocks the binding of these compounds to their binding site on ATP synthase, so the compounds aren't sequestered from uncoupling, and this uncoupling increases the 02 requirement of this cancer which can't be met in the hypoxic microenvironment of its tumour, thence the cancer's intracellular [ATP] can't be maintained and its proliferation is slowed and/or it dies. So, herein, this invention discloses that the uncoupling aspect to the imidazole containing compounds of this disclosure can deliver additional, specific, anti-cancer activity, for example, against those cancers that don't rely upon FiFo ATP hydrolysis. This invention discloses the process/method of using a compound(s) that can inhibit FiFo ATP
hydrolysis, and that can shuttle protons across the IM to dissipate the pmf (uncouple), as an anti-cancer therapeutic. Wherein the compound inhibits FiFo ATP hydrolysis by direct interaction with ATP synthase, and reduces Fi Fo ATP synthesis (primarily) by uncoupling. So, a compound needn't necessarily have a much lower ECK' for FiFo ATP hydrolysis than FIFO
ATP
.. synthesis, in an SMP assay, to be componentry to this invention as an anti-cancer therapeutic.
Indeed, even compounds with a lower EC50 for F1F0 ATP synthesis than FIR ATP
hydrolysis in an SMP assay can be componentry to this invention, as anti-cancer therapeutics, provided they do inhibit Fi Fo ATP hydrolysis and provided their inhibition of FIR ATP
synthesis is (primarily) because of uncoupling rather than inhibiting the forward mode of ATP synthase.
Oligomycin, for example, does not fit these requisites. So, this invention discloses the method of using compounds that inhibit FiFo ATP hydrolase, that don't inhibit FIE) ATP synthase, and that uncouple the proton motive force, as anti-cancer therapeutics.

DEUTERATED COMPOUNDS OF THE INVENTION
Deuterium (D or 2H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes 1H
(hydrogen or protium), D (2H or deuterium), and T (3H or tritium). Herein, all percentages for the amount of deuterium present are mole percentages. The natural abundance of deuterium is 0.015%.
Thence one of the art recognizes that in all chemical structures containing an H atom(s), this H atom(s) actually represents a mixture of H and D in the compound, with about 0.015%
being D. Therefore compounds that have a higher level of deuterium incorporation, i.e.
compounds enriched to have a greater D incorporation than natural abundance (>0.015%), should be considered unnatural and so distinct from their non-enriched counterparts. A
compound is said to be "deuterium enriched" if it has a quantity of deuterium that is greater than in naturally occurring compounds, or synthetic compounds prepared from substrates having the naturally occurring distribution of isotopes. At a lab scale amount (milligram or greater) it can be difficult to achieve 100% deuteration at any one site of a compound. Herein, when 100% deuteration is recited or a deuterium atom is specifically shown in a structure, it is assumed that a small percentage of hydrogen may still be present. Deuterium-enrichment can be achieved either by exchanging compound protons with deuterium or by synthesizing the compound with deuterium enriched starting materials, which are commercially available or can be readily prepared by someone of the art using known methods.
Embodiments of this invention include compounds of Formula (I), (II), (III), (IV), (V), (VI) and (VII) with one or more of their hydrogen atoms replaced by deuterium, at a greater frequency than the natural abundance of deuterium (0.015%). For non-limiting example:
>3000 times greater than the natural abundance of deuterium (i.e. a >40%
incorporation of deuterium at a hydrogen replacement position). Additional examples of the abundance of deuterium at a position in, or positions of, a compound embodiment of this invention include 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 to about 100%. In certain embodiments, the abundance of deuterium at a position in, or positions of, a compound embodiment of this invention is at least 40%. In certain other embodiments, the abundance of deuterium at a position in, or positions of, a compound embodiment of this invention is at least 60%. In futher embodiments, the abundance of deuterium is at least 75%. In yet other embodiments, the abundance of deuterium is at least 90%. It is to be understood that the deuterium-enriched compounds described herein can be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition.
In the Description and Claims of this disclosure, when a position on a compound structure is designated deuterium (D), or said to have deuterium, or said to be enriched for deuterium, it is because the abundance of deuterium at that position is not at the natural value (0.015%) but greater. Typically, in excess of 40%. The phrase 'enrichment at the chiral centre' herein, for example for a compound of Formula (I), means that the molar amount of deuterium at the chiral centre, as a percentage of the total amount of all hydrogen isotopes at the chiral centre, is greater than 0.015%, especially greater than 1%, preferably greater than 40%, more preferably greater than 45%, and in ascending order of preference, >52.5%
deuterium enrichment at the chiral centre, >60% deuterium enrichment at the chiral centre, >67.5%
deuterium enrichment at the chiral centre, >75% deuterium enrichment at the chiral centre, >82.5% deuterium enrichment at the chiral centre, >90% deuterium enrichment at the chiral centre, >95% deuterium enrichment at the chiral centre, >97% deuterium enrichment at the chiral centre, >99% deuterium enrichment at the chiral centre, >99.5%
deuterium enrichment at the chiral centre, 100% deuterium enrichment at the chiral centre. Greater % deuterium enrichment is preferred.
Further possible isotopic variants of the structures of this invention are further embodiments of this invention. An invention embodiment is a compound that inhibits the reverse mode, more than the forward mode, of ATP synthase, which has deuterium in place of hydrogen (at a greater frequency than 0.015% e.g. >40%) at one or more places upon its structure, and/or any other isotopic substitution/enrichment (at a greater than natural frequency e.g. 13C and/or 15N enriched; '3C enrichment {abundance > [natural abundance=1.109%] } at the chiral carbon of compounds of Formula (I) is especially preferred, especially when, if applicable, its attached hydrogen is enriched for 2H {abundance > [natural abundance=0.015%];
preferred is when '3C enrichment at the chiral carbon >40%, optionally 2H enrichment at the chiral carbon >40% also}).
Molecule synthesis routes described in [5, 6, 7, 8, Pl, P2, P3, P4, P5, P6]
(including references cited therein, where appropriate, and in their supplementary materials, all herein incorporated in their entirety) - for synthesizing molecules that inhibit F1F0 ATP hydrolysis more than Fi Fo ATP synthesis - are componentry to this disclosure, as synthesis routes for synthesising anti-cancer molecules. In other embodiments of this invention, any given molecule synthesis route described in [5, 6, 7. 8, P1, P2, P3, P4, P5, P6, P7, P8] is used with starting reagents, compounds, solvents and/or intermediates that have deuterium in place of hydrogen at some position(s). Such compounds are commercially available (e.g.
refer C/DN
Isotopes Inc., Pointe-Claire, or CK Isotopes Ltd., Desford, UK, or Cambridge Isotope Laboratories, Tewksbury, MA). Or they can be created in house by invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.
For (non-limiting, illustrative) example, a compound can be deprotonated by LiHMDS in tetrahydrofuran (THF) at -78 to -40 C for 20 minutes, followed by quenching with deuterium oxide (D20, "heavy water"), to obtain a deuterated compound [37].
During these steps, a group upon which hydrogen is still desired over deuterium can be Boc protected and this Boc group removed subsequently using trifluoroacetic acid (TFA) treatment at room temperature. At the end, the level of deuterium can be checked by III NMR. The initial deprotonation step isn't absolutely necessary as HID exchange will occur when a molecule is quenched with D20, and this reaction can be catalysed, by acid, base or metal based catalysts such as platinum. If, after D20 quenching, the level of compound deuteration is insufficient (observed using 1H NMR) then the compound is quenched with D20, or some other deuterium containing solvent, for a longer period of time. Compounds of this disclosure can be synthesised in D20, during one or more chemical steps, or a starting compound, intermediate or final molecule of this disclosure can be incubated in D20 to produce a deuterated version(s). So, deuterium-enriched compounds of this invention can be prepared by substituting a deuterium-enriched reagent or solvent for a non-isotopically labeled reagent or solvent in the synthetic schemes reported in [5, 6, 7, 8, P1, P2, P3, P4, P5, P6, P7, P8].
Non-limiting example embodiments of the invention are deuterated enumerations of Markush Formulas (I), (II), (III), (IV), (V), (VI) and Formula (VII). These isotopologues are componentry to the present invention as new compositions of matter, and in non-limiting embodiments are used singly or in combination, optionally in co-therapy with an FDA and/or EMA approved medicine(s) and/or treatment(s), for example a licensed cancer treatment, for use in a method of treatment of the human or animal body by therapy, optionally in a method of treating/ameliorating/preventing/combating cancer in a subject.
SILICON ANALOGUES OF THE INVENTION

Encompassed by the invention is a compound or compounds of Formula (I), (II), (III), (IV), (V), (VI) and/or (VII) wherein one or more carbon atoms are substituted with silicon, and in a further embodiment wherein this compound(s) is used, or a salt, hydrate, solvate, prodrug or pharmaceutical composition thereof, optionally in co-therapy with an FDA
and/or EMA
approved medicine(s) and/or treatment(s), for example a licensed cancer treatment, optionally in the same pharmaceutical composition, for use in a method of treatment of the human or animal body by therapy, optionally in a method of treating/ameliorating/preventing/combating cancer in a subject.
METHODS TO FIND FURTHER COMPOUNDS COMPONENT TO THIS
INVENTION
A method to find a compound(s) of this invention is by screening for/seeking a compound(s) that preferentially inhibits the reverse mode of ATP synthase. For example, by separately assaying (in space and/or time) a compounds's effect upon ATP synthesis and ATP
hydrolysis by ATP synthase (in its entirety or, less preferably, a component part of it). Then comparing these assay results. The greater the inhibition of reverse vs.
forward mode, the more preferred a compound is for a use of this invention. To illustrate, by the invention of this disclosure, the greater a compound inhibits the reverse vs. forward mode of ATP
synthase, the more preferred this compound is for anti-cancer and/or anti-aging use. An invention embodiment is the process/method of seeking a new compound(s) of this invention by assaying whether a candidate molecule can depolarise Tim, when Tim is maintained by FIFO ATP hydrolysis (e.g. when OXPHOS is blocked by a respiratory chain inhibitor(s) or insufficient 02), but that can't hyperpolarize Tim and/or decrease 02 consumption, when Tim is maintained by proton pumping by complexes of the respiratory chain. Such an assay is .. described in [121. A further method is screening a number of compounds to find one or more with this activity in this assay. An invention embodiment is seeking a compound(s) of this invention by assaying whether a candidate molecule inhibits ATP hydrolysis more than ATP
synthesis in submitochondrial particles (SMPs), wherein a further method is screening a number of compounds to find one or more with this activity in this assay. ATP
hydrolysis can be assayed by (non-limiting example) a spectroscopic assay for NADH
fluorescence that incubates the SMPs with pyruvate kinase and lactate dehydrogenase enzymes (assay well-known to those of the art). ATP synthesis can be assayed by (non-limiting example) a spectroscopic assay for NADPH fluorescence that incubates the SMPs with hexokinase and glucose-6-phosphate dehydrogenase enzymes (assay well-known to those of the art). These assays are reported in in any one of [5, 7, 8, 11, 12, 13, 70], and/or as referenced therein, all of which are herein incorporated in their entirety. In these SMP assays, the criteria for a candidate anti-cancer compound is a low EC50 against ATP hydrolysis (thence anti-cancer activity) and a higher EC50 against ATP synthesis (thence safe for normal cells). These SMP
assays deliver high signal-to-noise because non-specific protein inhibiting compounds (Pan-assay interference compounds, PAINS), which are the bane of drug discovery screening assays, inhibit both ATP hydrolysis and synthesis, and thus are dismissed by the screening algorithm. So, the screening assay inherently screens out PAINS. This is distinctive and valuable.
Componentry to this invention is screening, using one or more screening assays herein described, compound(s) from one or more compound collections/libraries known to, or findable by, one of the art, optionally a proprietary compound collection(s) {optionally a collection(s) or sub-collection(s) that belongs to, or is sourced from, a major/multinational pharmaceutical company and/or a pharmaceutical company with >$50 million in annual sales and/or a Contract Research Organisation [CRO, illustrative example would be Charles River Laboratories]) and/or a publically/commercially available compound collection(s) {or a fraction thereof}, for example, without limitation, eMolecules, Zinc, MMsINCdatabase, Pubchem, Chemspider, chEMBL, Chemical Structure Lookup Service, CoCoCo, Broad Institute compound collection(s), NIH Molecular Libraries Probe Production Centers Network (MLPCN), Joint European Compound library at the European Lead factory, ScreeningPort at Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Microsource Spectrum collection (contains human approved/trialled drugs), and/or by a compound collection/library generated by "diversity-oriented synthesis" and/or by one of the art. A combinatorial library, generated by combinatorial chemistry, may be used, wherein these terms are well known in the art (e.g. EP0774464, U55798035, U55789172, US5751629; and refer to patents with the combinatorial chemistry: sub-class "C40B" in the International Patent Classification; refer GLARE software, available on sourceforge.net website, for combinatorial library design).
A method to find antibody embodiment(s) of this invention is to raise antibodies against an ATP synthase component(s), and/or the entirety of ATP synthase, and then assay each in one or more of the aforementioned assays, looking for the ability to preferentially/specifically inhibit FIE) ATP hydrolysis as compared to FIFO ATP synthesis. An invention embodiment is to administer a nucleotide sequence coding for such an antibody to a subject, optionally by gene therapy, optionally wherein this antibody coding gene is integrated into the subject's genome in one or more cells, optionally into the subject's mitochondrial DNA
(mtDNA) in one or more cells. In an embodiment, one or more antibody embodiments of this invention, and/or one or more nucleotide sequences encoding one or more of such antibodies, are administered to a subject to convey to them therapy/enhancement, optionally cancer treatment/amelioration/prevention/combat, optionally wherein one or more of said nucleotide sequences are incorporated into the subject's genome, and/or mitochondrial DNA, in one or more of their cells, optionally wherein the expression of this nucleotide sequence, to protein(s), is limited to a certain cell type/tissue type/organ/area/sub-section of the subject, optionally by the character of the promotor region incorporated with the protein(s) coding sequence and/or by where the sequence is targeted to insert into the genome and/or by where in the subject the nucleotide sequence (optionally in a vector) is introduced and/or by the nature of the vector selected. Incidentally, an invention embodiment is for an ATP synthase .. component(s)/entirety to be administered to a subject, optionally via intravenous administration, wherein this acts as an epitope in the subject, wherein the subject produces antibodies against it, which then convey therapy/enhancement to the subject.
What the terms "antibody" and "antibodies" can refer to, and how to produce them (illustrative e.g. refer US2008/0089950A1, Methods and compositions for modulating the immune system and uses thereof, Lan Bo Chen is one of the inventors, also refer to the patents and publications that it cites), is well known in the art and can include, without restriction, monoclonal antibodies, multispecific antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, single domain antibodies, single-chain FVS (ScPv), single chain antibodies, Fab fragments, F(abl) fragments, disulfide-linked FVs (sdFv), and anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above. In particular, antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen binding site.
Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGI, IgG2, IgG3, IgGa, IgAi and IgA2) or subclass.
The present invention isn't limited to a particular type of compound. In certain embodiments, a compound of the present invention can be, but isn't limited to, an inorganic molecule, organic molecule, small organic molecule, small molecule, drug compound, large molecule, nucleic acid, LNA (locked nucleic acid), polynucleotide, oligonucleotide, DNA
molecule, gene, protein coding sequence of DNA and/or RNA, plasmid, virus, morpholino, RNA
molecule, mRNA, hairpin RNA, siRNA (small interfering RNA), miRNA, antagomir, ribozyme, aptamer, amino acid, amino acid chain, peptide, cyclic peptide, bicyclic peptide, tricyclic (or higher number of cycles) peptide, peptidomimetic, polypeptide, protein, fusion protein, glycopeptide, glycoprotein, antibody, antibody fragment, antibody-drug conjugate, PNA (peptide nucleic acid), lipid, sugar, carbohydrate.
CANCER TYPES PARTICULARLY TARGETED BY THIS INVENTION
Leukemia cancer cell line examples in Figure 8 show that Compound 6b can inhibit cancer proliferation strongly at 10 M and then nearly not at all at 100 M. As disclosed earlier, lower [6b] switches cancer cells into greater OXPHOS use/rate, exerting anti-cancer activity, but higher [6b] decreases OXPHOS rate, exerting less anti-cancer activity.
Extrapolating this data, even greater [6b] may assist cancer and increase its proliferation rate.
And if a cancer has appropriate adaptations and is using OXPHOS greatly in the first place, without 6b administration, then 6b administration may only ever help and never hinder that cancer.
Compound 6b, and other FIFO ATP hydrolysis inhibiting compounds of this invention, are best administered to cancers showing signs of glycolytic rather than oxidative metabolism.
For example, those that show up, at least before treatment by this invention, in positron emission tomography (PET) imaging using fluorine-18 (18F) fluorodeoxyglucose (FDG), 18F-FDG PET [71].
Particularly vulnerable to compounds of this invention: cancers that exhibit the Warburg effect (i.e. that produce ATP primarily by glycolysis, rather than oxidative phosphorylation, even in abundant 02), highly glycolytic cancers (which metabolize glucose and/or glutamine to lactate rather than metabolizing one or both fully with the use of oxidative phosphorylation) and cancers that reside in hypoxia, which forces them to produce ATP
primarily by glycolysis. As explained in a preceding section, the imidazole containing molecules of this disclosure, with their uncoupling capability, can also attack cancers that reside in hypoxia, which use high IFI expression to enable oxidative phosphorylation at low [02]. Many cancers reside in hypoxia as tumours are often hypoxic.
So, if a cancer is highly glycolytic, either because of the Warburg effect (inherent glycolytic metabolism, regardless of [02]) or because of residing in hypoxia (imposed glycolytic metabolism, because of low [02]), or uses oxidative metabolism but resides in hypoxia (survival enabled by high IF, expression), it will be treated/ameliorated/prevented/combated by a compound of this invention. How to identify such cancers?
Cancers exhibiting the Warburg effect, or that have an imposed (by low [02]) glycolytic metabolism, are those that show up in positron emission tomography (PET) imaging using 18F-FDG PET, optionally integrated with computed tomography (CT) [71]. FDG is a glucose analogue and glycolytic cancers take up more FDG than their surrounding tissue because glycolysis is an inefficient metabolism of glucose (yielding only ¨2 ATP per glucose compared to ¨30 ATP per glucose yielded by aerobic respiration [1-21) and so they must uptake more glucose to obtain even the equivalent energy yield to nearby normal cells, which are using oxidative metabolism, as most normal cells do. So, if a cancer presents in this FDG-PET diagnostic (higher glucose uptake than surround), it is susceptible to a compound of this invention. Highly glycolytic cancers also release much lactate. So, if a patient has a high blood lactate level, noticeably above the normal non-pathological range, as clear to someone of the art, then their cancer is susceptible to a compound of this invention.
Higher lactate levels in and around the cancer or tumour (than surrounding tissue) can also be detected using imaging technologies, for example Magnetic Resonance Spectroscopy ('H-MRS) or chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) [72], or other imaging modalities and methods of the art. So, if a cancer presents (higher [lactate] than surround) in a lactate imaging diagnostic it is susceptible to a compound of this invention.
Cancer release of lactic acid acidifies its extracellular space and this acidification can be detected by imaging modalities, well known to those of the art e.g. [73-74], and if a cancer can be discriminated from its surrounding tissue by this method then it is susceptible to a compound of this invention. An oxygen-sensitive chemical probe can be used to obtain 3D
maps of tissue p02 [75], and if a cancer is shown to reside in notable hypoxia then it is susceptible to a compound of this disclosure, because it is either glycolytic or likely using high IF, expression to enable oxidative metabolism, both of which make it susceptible to a compound of this invention. Imaging technologies can be integrated to improve signal to noise e.g. [75] integrate p02 and lactate imaging. Such integration can give added information: for example, a cancer producing much lactate in a high p02 environment is exhibiting the Warburg effect because it is heavily utilising glycolytic metabolism in abundant 02. Cancer gene expression markers and indicators of the Warburg effect, well known to those of the art e.g. [18-20], specify that a cancer is susceptible to a compound of this invention, wherein the cancer's genetic material can be retrieved by biopsy, surgery, cancer cells or parts circulating in the bloodstream or some other method of the art.
If a cancer uses oxidative phosphorylation (OXPHOS) rather than glycolytic metabolism, and it does not already improve its OXPHOS efficiency by high IF' gene expression (which many cancers do e.g. refer [23]) then a compound of this invention, by preferentially inhibiting FiFo ATP hydrolysis, will confer this efficiency gain and actually assist, rather than harm, this cancer. How to identify these cancers? A cancer's IF] gene expression, and particularly its gene expression ratio of IF] to a core ATP synthase sub-unit (e.g. ATP6), is informative.
More so if compared to the corresponding gene expressions in a normal cell of its host tissue, so detecting difference from normal. If a cancer uses oxidative, rather than glycolytic, metabolism and does not have an appreciably higher IF' (or IFI/ATP6 ratio) gene expression than its corresponding normal tissue then it isn't prudent to use a compound of this invention for cancer therapy. More simply, it is best to use a compound(s) of this invention against highly glycolytic cancers and some (non-limiting) imaging methods have been described herein to identify these.
This invention discloses a method of using a compound(s) that preferentially inhibits the ATP-hydrolysing mode of ATP synthase, for example a compound(s) of Formula (I), (II), (III), (IV), (V) or (VII), or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, to treat/ameliorate/prevent/combat a cancer that preferentially uses glycolytic rather than oxidative metabolism, for example a cancer exhibiting the Warburg effect, and discloses methods to identify these cancers. Identification methods specified are to illustrate the invention and not to limit its scope: this invention encompasses all methods to identify glycolytic cancers, in order to identify cancers most amenable to treatment by a compound(s) of this invention.
So, innovatively and usefully, compounds of this disclosure are selected for anti-cancer therapy by metabolic feature of the cancer, which belie how the cancer survives and proliferates, and its weaknesses, weaknesses that compounds of this disclosure attack, rather than the typical, often too arbitrary, often unhelpful, allocation by tissue type, which is the present standard in the art. A diversity of cancers, from different tissues, will be susceptible to compounds of this invention, especially the most dangerous: glycolytic cancers, with high lactate efflux, often have the worst prognosis [18-20, 27]. Experimental data of this disclosure shows that compounds of this invention are effective against many cancers.
Compounds of the present invention treat tumour growth, treat metastasis, treat metastatic cancer, treat non-metastatic cancer, treat tumour implantation, are useful as an adjunct to chemo-/radio- therapy, treat cancers including, but not limited to, advanced malignancy, multiple brain metastase, poor prognosis malignant brain tumor, metastatic hepatocellular carcinoma, mesothelioma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, neuroendocrine tumor, amyloidosis, meningioma, hemangiopericytoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma of bone/osteosarcoma, osteosarcoma, rhabdomyosarcoma, heart cancer, brain cancer, astrocytoma, neuronal & mixed neuronal-glial tumors, glioma, brainstem glioma, pilocytic astrocytoma, ependymoma, HPV induced tumors, primitive neuroectodermal tumor, craniopharyngioma, cerebellar astrocytoma, cerebral astrocytoma, malignant glioma, recurrent malignant glioma, medulloblastoma, neuroblastoma, schwannoma, oligodendroglioma, anaplastic oligodendroglioma, pineal astrocytoma, anaplastic astrocytoma, pituitary adenoma, visual pathway and hypothalamic glioma, glioblastoma, glioblastoma multiforms, breast cancer, invasive ductal carcinoma, ductal carcinoma in situ (DCIS), invasive lobular carcinoma, tubular carcinoma, invasive cribriform carcinoma, medulloblastoma, medullary carcinoma, male breast cancer, phyllodes tumor, inflammatory breast cancer, adrenocortical carcinoma, islet cell carcinoma, multiple endocrine neoplasia syndrome, parathyroid cancer, pheochromocytoma, thyroid cancer, medullary thyroid carcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, merkel cell carcinoma, intraocular melanoma, retinoblastoma, ocular neoplasm, anal cancer, appendix cancer, cholangiocarcinoma, carcinoid tumor, colon cancer, extrahepatic bile duct cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), hepatocellular cancer, pancreatic cancer, rectal cancer, bladder cancer, cervical cancer, endometrial cancer, extragonadal germ cell tumor, ovarian cancer, ovarian epithelial cancer (surface epithelial-stromal tumor), ovarian germ cell tumor, penile cancer, renal cell carcinoma, renal pelvis and ureter, transitional cell cancer, prostate cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-refractory cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, testicular cancer, gestational trophoblastic tumor, ureter and renal pelvis, genitourinary cancer, transitional cell cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, wilms tumor, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, pharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, acute biphenotypic leukemia, acute eosinophilic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute myeloid dendritic cell leukemia, karotype acute myeloblastic leukemia, primary myelofibrosis, myelodysplastic syndromes (MDS), myeloid sarcoma, myeloproliferative neoplasms (MPNs), lymphoma, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, low grade follicular lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia, cutaneous B-Cell lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell leukemia, intravascular large B-cell lymphoma, large granular lymphocytic leukemia, lymphoplasmacytic lymphoma, lymphomatoid granulomatosis, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal large B cell lymphoma, multiple myeloma/plasma cell neoplasm, myelodysplastic syndromes, mucosa-associated lymphoid tissue lymphoma, mycosis fungoides, nodal marginal zone B cell lymphoma, non-Hodgkin lymphoma, precursor B
lymphoblastic leukemia, primary central nervous system lymphoma, primary cutaneous follicular lymphoma, primary cutaneous immunocytoma, primary effusion lymphoma, plasmablastic lymphoma, Sezary syndrome, splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, basal-cell carcinoma, melanoma, skin cancer (non-melanoma), bronchial adenomas/carcinoids, small cell lung cancer, mesothelioma, Non-Small Cell Lung Cancer (NSCLC), pleuropulmonary blastoma, adenocarcinoma, rectal adenocarcinoma, unresectable colorectal carcinoma, laryngeal cancer, thymoma and thymic carcinoma, peritoneal carcinoma, peritoneal cancer, papillary serous carcinoma, AIDS-related cancers, Kaposi sarcoma, epithelioid hemangioendothelioma (EHE), desmoplastic small round cell tumor, leiomyoma, leiomyosarcoma, Liposarcoma, fallopian tube cancer, smoldering myeloma, indolent myeloma, Waldenstrom's macroglobulinemia, fibrodysplasia ossificans progressive, breast carcinoma, non-small cell lung carcinoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, colorectal carcinoma, squamous cell carcinoma, hepatocellular carcinoma benign prostatic hyperplasia (BPH) and polycystic ovary syndrome, a neoplasm disclosed by the International Classification of Diseases (ICD) in ICD-10 Chapter II: Neoplasms (World Health Organisation, WHO) and/or the International Classification of Diseases for Oncology (WHO).
The compounds of the present invention treat cancers including, but not limited to, those that originate in the testis, cerebral cortex, skin, fallopian tube, parathyroid gland, small intestine, large intestine, kidney, skeletal muscle, duodenun, spleen, epididymis, bone, bone marrow, lymph node, adrenal gland, esophagus, thyroid gland, heart muscle, tonsil, lung, prostate, rectum, anus, adipose tissue, colon, stomach, cervix, gallbladder, seminal vesicle, breast, ovary, endometrium, smooth muscle, salivary gland, pancreas, urinary bladder, blood, brain, .. gum, mouth, throat, head, liver, nasopharynx, neck, tongue, uterus, penis, vagina, chest, eye, head, neck.
Local administration of a compound(s) of this invention, optionally for cancer treatment In some invention embodiments a compound(s) of this invention, optionally a compound(s) of Formula (I), (II), (III), (IV), (V), (VI), (VII), or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, is administered to a subject locally rather than systemically, optionally to convey therapy, optionally to treat/ameliorate/prevent/combat cancer in a subject, optionally wherein the local administration is to the cancer(s) itself. For non-limiting .. example, wherein the local administration is to a skin cancer(s) and/or pre-cancer, optionally basal-cell skin cancer (BCC), squamous-cell skin cancer (SCC), melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, keratoacanthoma, spindle cell tumor, sebaceous carcinoma, microcystic adnexal carcinoma, Paget's disease of the breast, atypical fibroxanthoma, leiomyosarcoma, angiosarcoma, hemangioma, Melanocytic nevus, Bowen's disease, Actinic keratoses, optionally administered via a liquid/solution/cream/lotion/ointment/emulsion/foam/spray/patch/transdermal patch/adhesive bandage/time release technology or some other drug administration route known to one of the art. Skin cancer is the most prevalent cancer globally. This local drug administration can locally reduce Fi Fo ATP hydrolysis, thence FIFO ATP synthesis, oxidative phosphorylation rate and metabolic heat generation, which is not detrimental when ambient temperature is 37 C, and not detrimental when ambient temperature is lower because heat transfer from the rest of the body, especially via blood flow, maintains the drug administered area at or near 37 C.

CANCER IMAGING
An FiFo ATP hydrolysis inhibitor compound(s) of this invention, for example a compound(s) of Formula (I), (II), (III), (IV), (V) or (VII), has greater binding affinity for ATP synthase operating in reverse than forwards. Thence such a compound(s) disproportionally accumulates in cancer cells because, as disclosed herein, cancers disproportionally utilise ATP synthase in reverse, as compared to normal cells. Thus, when the compound(s) is labelled, for example by "C or some other radionuclide incorporation, it can be used for cancer imaging, for example by positron emission tomography (PET). Example embodiments are one or more of 11C, 18F, 13N, 150, 124I incorporated into a compound of this invention at a greater than natural abundance, most preferably incorporated at their corresponding position(s) in the compound(s) e.g. "C in place of 12C, 13N in place of 14N, 1241 at halogen designated position(s) etc. All radionuclide substitutions of corresponding atoms in Formula (I-V, VII) are contemplated and componentry to the present invention, as is their use for anti-cancer imaging and/or therapy. Alternative embodiments include iodine incorporated at a position(s) designated halogen in one or more compounds of Formula (I-V, VII), and this compound(s) is then used for iodinated x-ray contrast imaging of cancer.
Alternatively 1231 is incorporated at halogen position(s) of one or more compounds of Formula (I-V, VII), and this compound(s) is used to image cancer using single photon emission computed tomography (SPECT). If a cancer shows up (above background tissue) in one or more of these imaging modalities, it is a good signal that this cancer will be responsive to a compound of this invention for anti-cancer therapy.
Given this asymmetric accumulation of compounds of Formula (I-V, VII) into cancer cells, radionuclides incorporated into one or more of these compound(s) can disproportionally damage cancer, and thence be used for radiotherapy. To illustrate, tritium at greater than natural abundance at one or more places on a compound(s) of this invention, wherein this compound(s) is used for anti-cancer therapy. Alternatively, or in addition, 1251 and/or 1311 , incorporated, optionally at a position(s) designated halogen in Formula (1-V, VII).
Optionally, radionuclide imaging is performed prior to radionuclide therapy (radiotherapy) with compounds of this invention.
A boronated compound(s) of this invention, for example a compound(s) of Formula (I), (II), (III), (IV), (V) or (VII), substituted at one or more positions with 1 B, for use in neutron capture therapy, optionally for an anti-cancer use, is componentry to the present invention, as is a method wherein 157Gd is used in place of ' B.
Compound(s) of this invention treat/ameliorate/prevent/combat non-cancerous .. proliferative disorders An embodiment of this invention is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound(s) of Formula (I), (II), (III), (IV), (V) or (VII) or another compound(s) that selectively inhibits FiFo ATP
hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, to treat/ameliorate/prevent/combat a non-cancerous proliferative disorder(s) including, to illustrate, without restriction, hyperproliferative autoimmune disorders, hyperplasia, epidermal hyperplasia, dysplasia (e.g. epithelial dysplasia), nodule(s), wart(s), papilloma(s), squamous cell papilloma, genital wart(s), condyloma(s), condyloma acuminatum, cyst(s), polyp(s) {including, without restriction, digestive, colorectal, endometrial, cervical, nasal, .. laryngeal, inflammatory fibroid polyp[s])}, inherited/hereditary (including, without restriction, Familial adenomatous polyposis, Peutz¨Jeghers syndrome, Turcot syndrome, Juvenile polyposis syndrome, Cowden disease, Bannayan¨Riley¨Ruvalcaba syndrome {Bannayan-Zonana syndrome}, Gardner's syndrome) and non-inherited (non-restrictive e.g.
Cronkhite¨Canada syndrome) polyposis syndromes, benign tumour, adenoma, organ enlargement by hyperplasia, Cushing's disease (enlarged adrenal cortex by hyperplasia), congenital adrenal hyperplasia, hyperplasia of breast, atypical ductal hyperplasia, intraductal papillomatosis, fibroadenomas, fibrocystic changes, hemihyperplasia, focal epithelial hyperplasia, sebaceous hyperplasia, sebaceous adenoma, intimal hyperplasia, unwanted/undesirable smooth muscle cell proliferation, smooth muscle cell hyperplasia, .. intimal smooth muscle cell hyperplasia, neointimal hyperplasia, proliferative vascular disorders, stenosis, stenosis because of cellular proliferation, vaginal stenosis, stenosis in a blood vessel, stenosis in a blood vessel because of cellular proliferation, vascular occlusion, restenosis, restenosis in a blood vessel that has been implanted with a stent, in-stent restenosis, post-angioplasty restenosis, systemic sclerosis, cirrhosis of the liver, adult .. respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g. diabetic retinopathy and/or other retinopathy[y/ies]), cardiac hyperplasia, fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, fibromatosis, neurofibromatosis, renal interstitial fibrosis, Cowden syndrome, hamartomas, choristomas, hemangiomas, lymphangiomas, rhabdomyomas, lymphangiomatosis, cystic hygroma, trichilemmoma, sarcoidosis, neurosarcoidosis, aggressive fibromatosis, desmoid tumours, unwanted/undesirable skin cell proliferation, hyperproliferative skin disorder, psoriasis (including, without restriction, plaque, guttate, inverse, pustular, napkin, seborrheic-like, nail, scalp and erythrodermic psoriasis), psoriatic arthritis, dactylitis, seborrhoeic dermatitis, dandruff, eczema, atopic dermatitis, rosacea, reactive arthritis (Reiter's syndrome), pityriasis rubra pilaris, hyperproliferative variants of disorders of keratinization (e.g., without restriction, actinic keratosis, senile keratosis, keratosis pilaris, seborrheic keratosis), scleroderma, and the like. Other examples include reproductive system-associated disorders such as benign prostatic hyperplasia, prostate enlargement, endometrial hyperplasia, atypical endometrial hyperplasia, benign endometrial hyperplasia, adenomyosis, atypical polypoid adenomyoma, endometriosis, endometriosis of ovary (endometrioma), endometrial polyp(s), polycystic ovary syndrome, ovarian cyst(s), cervical polyp(s), uterine fibroid(s), uterine hyperplasia, and the like. Moreover, proliferative smooth muscle disorders, such as intimal smooth muscle cell hyperplasia, which can lead to blockage in, for non-limiting example, the urethra, the bile duct, the airway, the bronchial airways of the lung and/or a blood vessel(s), particularly following biologically or mechanically mediated tissue injury.
One common type of non-cancerous proliferative disorder is restenosis, such as that associated with balloon angioplasty and/or insertion of a stent. In subjects with obstructive coronary artery disease, abatement of the chest pain associated with blocked blood vessels can sometimes be achieved by insertion of a stent-equipped angioplasty balloon. Inflating the balloon opens the blood vessel and installs the stent to keep the blood vessel open after removal of the balloon. The benefit is often temporary, however, because stented blood vessels can become re-blocked due to cell growth in response to tissue injury from the insertion. This process is termed restenosis. An embodiment of this invention is an angioplasty balloon and/or stent (and/or .. other medical device located inside the subject, optionally this device includes a reservoir, a coating composition, a controlled release polymer matrix, or the like which comprises the compound(s), which it can release in vivo, optionally over days or weeks or months or years, wherein optionally the device has surface contours for location of compound(s)) coated with, and/or containing ("drug-eluting balloon", "drug-eluting stent"), a compound(s) of this invention, for example a compound(s) of Formula (I), (II), (III), (IV), (V) or (VII) or another compound(s) that selectively inhibits FIFO ATP hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, and a method of implanting this stent (and/or other medical device) in a subject, optionally to maintain blood flow in a blood vessel in the subject, optionally in co-therapy with ionizing radiation, optionally wherein the medical device, e.g. stent, is bioresorbable. In one embodiment, a compound(s) of the invention is delivered locally to a treatment site by contacting the treatment site with a medical device that includes the compound(s) in a reservoir, coating composition or controlled release polymer matrix. For example, the compound(s) may be included in a coating composition or .. reservoir in a stent. Stents in all locations in a subject are componentry to this invention, including glaucoma drainage stents (reduce intraocular pressure), duodenal stents, colonic stents, pancreatic stents, biliary stents, bile duct stents, esophageal stents, gastrointestinal stents, prostatic stents, ureteral stents, urethra stents, coronary stents, peripheral stents, arterial stents, venous stents, vascular stents, pulmonary stents and the like. Componentry to this invention is any medical/aesthetic device that is coated with and/or contains a compound(s) of this invention, and a method of inserting/implanting this in a subject, wherein such medical devices include, without restriction, stents, pacemakers (e.g., including a controller implanted under the skin and an electrode extending therefrom to the heart, optionally wherein any/all parts of this device can be coated with a compound(s) of this .. invention), implantable cardioverter defibrillator (ICD), tissue augmentation implants (e.g.
breast implants), catheters, arterio-venous grafts, by-pass grafts, balloons used in the vasculature, sheaths for veins and arteries, GORE-TEX surgical prosthetics, artificial valves, artificial hearts, artificial joints, structural implants (pins, screws, plates, and the like), tooth implants, chochlear implants, osmotic pumps, and the like, any medical device wherein .. placement of the device at a treatment site in the subject can place that site at risk of pathological cell proliferation in response to tissue injury associated with placement of the device (e.g., formation of scars, lesions, adhesions, and the like). The coating composition can serve as a controlled release vehicle for the therapeutic compound(s) to be delivered at the site of a lesion, and can be selected such that the compound(s) can be released at a desired rate in vivo. The compound(s), optionally in combination with a polymer, can be applied by any conventional means such as dip coating, roll coating, spray coating, spin coating, vapour condensation, and the like. In a particular embodiment, coating polymers include silicones (poly siloxanes), polyurethanes, thermoplastic elastomers in general, ethylene vinyl acetate copolymers, polyolefin rubbers, EPDM rubbers, and combinations thereof. The coating composition can be polymeric and can further be hydrophilic, hydrophobic, biodegradable, or non-biodegradable. Example are homopolymers, co-polymers (including block copolymers and graft copolymers), dendritic polymers, crosslinked polymers and the like.
Suitable polymers include synthetic and natural polymers (e.g. polysaccharides, peptides) as well as polymers prepared by condensation, addition and ring opening polymerizations.
Also included are rubbers, fibers and plastics. Polymers can be hydrophilic, amphiphilic or hydrophobic. In one aspect, the polymers of the present invention are non-peptide polymers.
The material for the polymeric coating composition can be selected from the group consisting of polycarboxylic acids, cellulosic polymers, gelatin, polyvinylpyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, polyethylene oxides, glycosaminoglycans, polysaccharides, polyesters, polyurethanes, silicones, polyorthoesters, polyanhydrides, polycarbonates, polypropylenes, polylactic acids, polyglycolic acids, polycaprolactones, polyhydroxybutyrate valerates, polyacrylamides, polyethers, and mixtures and copolymers of the foregoing. Coating compositions prepared from polymeric dispersions such as polyurethane dispersions (BAYHYDROL, etc.) and acrylic acid latex dispersions can also be employed. Biodegradable polymers that can employed in the coating composition include polymers such as poly(L-lactic acid), poly(DL-lactic acid), polycaprolactone, poly(hydroxybutyrate), polyglycolide, poly(diaxanone), poly(hydroxyvalerate), polyorthoester, copolymers such as poly (lactide co-glycolide), polyhydroxy(butyrate-co-valerate), polyglycollide-co-trimethylene carbonate; polyanhydrides;
polyphosphoester, polyphosphoester-urethane; polyamino acids; polycyanoacrylates; biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid; and mixtures of the foregoing. Biostable materials that can be employed in the coating composition include polymers such as polyurethane, silicones, polyesters, polyolefins, polyamides, polycaprolactam, polyimide, polyvinyl chloride, polyvinylmethyl ether, polyvinyl alcohol, acrylic polymers and copolymers, polyacrylonitrile, polystyrene copolymers of vinyl monomers with olefins (such as styrene acrylonitrile copolymers, ethylene methyl methacrylate copolymers, ethylene vinyl acetate), polyethers, rayons, cellulosics (such as cellulose acetate, cellulose nitrate, cellulose propionate, etc.), parylene and derivatives thereof, and mixtures and copolymers of the foregoing. Another polymer that can be that can be employed in the coating composition is poly(MPC:LAM.:HPMAy:TSMA,) where w, x, y, and z represent the molar ratios of monomers used in the feed for preparing the polymer and MPC represents the unit 2-methacryoyloxyethylphosphorylcholine, LMA
represents the unit lauryl methacrylate, HPMA represents the unit 2-hydroxypropyl methacrylate, and TSMA represents the unit 3-trimethoxysilylpropylmethacrylate. The coated medical device, e.g., stent, can be used to maintain patency of a blood vessel, e.g. coronary artery, previously occluded by thrombus and/or atherosclerotic plaque. The delivery of a compound(s) described herein can reduce the rate of in-stent restenosis. Particular polymers can be those which are water insoluble and hydrophilic, i.e. can form hydrogels. A hydrogel is a composition which can absorb large quantities of water. Polymers which can form hydrogels are generally more biocompatible than other polymers and can be used in devices which are inserted into, for example, vascular systems. Platelets and proteins typically deposit upon insertion of polymer into a treatment, e.g., vascular site and can initiate a cascade of events .. leading to restenosis or injury. This process can be slowed or eliminated with polymers that form hydrogels, resulting in reduced risk of protein deposition and platelet activation.
Polymers which form hydrogels are typically crosslinked hydrophilic polymers.
Further descriptions and examples of hydrogels are provided in Hydrogels and Biodegradable Polymers for Bioapplications, editors Attenbrite, Huang and Park, ACS
Symposium Series, No. 627 (1996), U.S. Pat. Nos. 5,476,654, 5,498,613 and 5.487,898, the teachings of which are incorporated herein by reference. Examples of hydrogels include polyethylene hydroxides, polysaccharides and crosslinked polysaccharides. A "controlled release" polymer matrix can be a polymer combined with an active agent, such as a compound(s) of this invention, so that the active agent is released from the material in a predesigned manner. For example, the active agent may be released in a constant manner over a predetermined period of time, it may be released in a cyclic manner over a predetermined period of time, or an environmental condition or external event may trigger the release of the active agent, and the like. In one embodiment, the controlled release polymer matrix includes a polymer that is biologically degradable, chemically degradable, or both biologically and chemically .. degradable. In another embodiment, the controlled release polymer matrix includes a non-degradable polymer. Examples of suitable polymers for a controlled release polymer matrix include the polymers used for polymer coating compositions. In one embodiment, a controlled release polymer matrix is a coating. In another embodiment, the controlled release polymer matrix is solid component that forms part of the structure of the medical device. For example, a portion (e.g., about 1%, about 5%, about 10%, about 20% or about 50%) of the fibers that make up a vascular graft can be made of a controlled release polymer matrix.
Examples of synthetic biodegradable polymers include polyanhydrides, polyhydroxyacids such as polylactic acid, polyglycolic acids and copolymers thereof, polyesters, polyamides, polyorthoesters, and some polyphosphazenes. Examples of naturally occurring biodegradable polymers include proteins and polysaccharides such as collagen, hyaluronic acid, albumin and gelatin. A compound(s) of this invention can be encapsulated within, throughout, and/or on the surface of the implant/device. The compound(s) is released by diffusion, degradation of the polymer, or a combination thereof. There are two general classes of biodegradable polymers: those degrading by bulk erosion and those degrading by surface erosion. U.S.

Patents that describe the use of polyanhydrides for controlled delivery of substances include U.S. Pat. No. 4,857,311, U.S. Pat. No. 4,888,176, and U.S. Pat. No. 4,789,724 to Domb and Langer. The entire teachings of these patents are incorporated herein by reference. Non-biodegradable polymers remain intact in vivo for extended periods of time (e.g., at least about one or more years). Drug loaded into the non-biodegradable polymer matrix is released by diffusion through the polymers micropore lattice in a sustained and predictable fashion, which can be tailored to provide a rapid or a slower release rate by altering the percent drug loading, porosity of the matrix, and implant structure. Ethylene-vinyl acetate copolymer (EVAc) is an example of a nonbiodegradable polymer that has been used as a local delivery system for proteins and other micromolecules, as reported by Langer and Folkman, Nature (London) 263:797-799 (1976). Other non-biodegradable polymers include polyurethanes, polyacrylonitriles, and some polyphosphazenes.
AGING
An invention embodiment is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound of Formula (1), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits F1F0 ATP hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, to treat/ameliorate/prevent/combat an accelerated aging disease or progeroid syndrome including, but not limited to, Werner syndrome, Bloom syndrome, De Barsy syndrome, Rothmund¨Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann¨Rautenstrauch syndrome, Hutchinson¨Gilford progeria syndrome (progeria), any progeroid syndrome, Ataxia telangiectasia-like disorder 2, XFE
progeroid .. syndrome, Muscular dystrophy, Muscular Dystrophy (Becker's, Duchenne, Limb-Girdle), Yamamoto's Muscular Dystrophy, Mandibuloacral dysplasia, Dilated cardiomyopathy, GAPO syndrome, Cutis laxia, Ehlers-Danlos syndrom, Lenz-Majewski hyperostatic dwarfism, SHORT syndrome, Progressive external opthalmoplegia, Nester-Guillermo progeria syndrome, MDPL syndrome, Dyskeratosis congenital, Down syndrome and/or to treat/ameliorate/prevent/combat an aging associated disease or disease/disorder of aging (incidence increases with increased age/senescence) and/or an unwanted aspect of aging and/or a disease/disorder associated with reactive oxygen species (ROS, e.g.
elevated [ROS]) including, but not limited to, age-associated decline, degenerative diseases, neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), essential tremor, resting tremor, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, frontotemporal dementia, chronic traumatic encephalopathy, memory loss, aged cognition, age/aging related cognitive decline/impairment, hereditary .. spastic paraplegia, Batten disease, polyglutamine diseases, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, heart failure with preserved ejection fraction, idiopathic pulmonary fibrosis, fibrotic disease, pulmonary disease, coronary artery disease, hypercholesterolemia, obesity, liver disease, fatty liver disease, lysosomal storage disease, amyloidosis, systemic sclerosis, kidney disease, hepatic cirrhosis, immunosenscence, clonal hematopoiesis, chronic obstructive pulmonary disease (COPD), hypertension, hypercholesterolemia, age-related thymic atrophy, arthritis, osteoarthritis, arthritis (Osteo-and Rheumatoid), Juvenile Rheumatoid Arthritis (JRA), Degenerative Disc Disease, Tendinopathy, Androgenetic Alopecia, male-pattern baldness, Idiopathic Pulmonary Fibrosis, systemic sclerosis, Chronic Obstructive Pulmonary Disease, Psoriasis, age-related loss of cardiac/pulmonary/cognitive/vision function, diabetes, type 2 diabetes, andropause, sarcopenia, muscle weakness, cachexia, age-related cachexia and/or sarcopenia, aging frailty, frailty syndrome, osteoporosis, age-related macular degeneration (AMD, early/intermediate/late), neovascular/wet AMD, dry AMD, Geographic atrophy (GA), wet and dry AMD in the same eye(s), Stargardt's macular degeneration, Best vitelliform .. macular dystrophy, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, age/aging-related eye disease, ophthalmological disease/disorder, ocular disease, vision loss, progressive vision impairment, myopia (short-sightedness), degenerative myopia, hyperopia (far-sightedness), accommodative dysfunction, glaucoma, cataract formation, retinal degeneration, progressive retinal degeneration, retinitis pigmentosa, leber hereditary optic neuropathy, Fuchs spot, Best's disease, Sorsby's fundus dystrophy, hearing loss, age/aging-related hearing loss, presbycusis, tinnitus, naive T cell shortage, movement disability, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), immunosenescence, respiratory/urinary tract infection (RTI/UTI) especially in older/aged/elderly subjects, cancer etc., any age-related/correlated disease/disorder/condition .. including age-related/correlated cardiovascular, neurodegenerative, eye diseases, inflammatory diseases and conditions. Exemplary cardiovascular/cerebrovascular diseases and conditions include arteriosclerosis, coronary heart disease, arrhythmia, heart failure, hypertension, hypercholesterolemia, age-related thymic atrophy, orthostatic hypotension, myocardial infarction, angina pectoris, atherosclerosis, dyslipidemia, stroke, heart disease, congenital heart disease, renal artery disease or stenosis, peripheral vascular disease, chronic obstructive pulmonary disease (COPD), chronic renal disease, renal failure, and heart disease.
Exemplary neurodegenerative diseases include Parkinson's disease and Alzheimer's disease.
Exemplary eye diseases and conditions include macular degeneration, Stargardt disease, cataracts, diabetic retinopathy and glaucoma. Exemplary inflammatory diseases and conditions include arthritis, such as rheumatoid arthritis. Additional exemplary age-associated diseases and disorders include cancer, ulcers, osteopetrosis, progeria, weakness, hearing loss, celiac disease, liver spots and type 2 diabetes. It is to be understood that "age-related" refers to diseases/disorders/conditions frequently associated with aging, however, a given subject need not be of advance age, but rather the methods, compounds and compositions of this invention can be used regardless of the subject's age.
Not only does an FiFo ATP hydrolysis inhibitor compound of this invention treat/ameliorate/combat cancer in a subject, it also prevents cancer in a subject, which is distinct from many other cancer treatments (e.g. radiotherapy) which are a drive to further cancer, and so compounds of this invention are especially preferred for cancer treatment in children, who have enough lifespan left for secondary cancers, as a result of radiotherapy for example [76], to be a very severe concern. Also it is noteworthy that compounds of this invention both treat cancer and slow aging, whereas many present cancer treatments accelerate aging [77], causing greater incidence of age related disease(s) and ailments.
An anti-aging compound does one or more of slowing/reversing aging, slowing/reversing a sign(s) of aging, extending lifespan and/or healthspan, delaying/preventing/treating diseases that have an increased incidence with age, such as the neurodegenerative diseases, treating accelerated aging diseases. Any anti-aging compound that targets/inhibits FIE) ATP
hydrolysis is componentry to this invention, preferably those that preferentially inhibit FiFo ATP hydrolysis as compared to FIE) ATP synthesis, and most preferably those that don't inhibit FiFo ATP synthesis at all. This disclosure discloses numerous such working examples, many of which are also new compositions of matter, and discloses rationale and methods to find further working examples (e.g. SMP studies, looking for compounds that inhibit FiFo ATP hydrolysis more than FiFo ATP synthesis), which are, in turn, componentry to this invention and encompassed by this disclosure, for example for an anti-aging use, or for other disclosed use(s).

ANTI-AGING SKIN CREAM
FIFO ATP hydrolysis inhibitor compound(s) of this invention slow aging but can reduce body temperature. An invention embodiment is to target an FIFO ATP hydrolysis inhibitor compound(s) to a part/area of the subject/body where slower aging is desired, optionally for aesthetic/cosmetic or medical/therapeutic desire or need. This body part or area will have slower aging and lesser heat production, but heat transfer from surrounding body areas (especially via blood flow) will maintain the temperature of this body part/area at an acceptable value. So, the temperature issue is mitigated and slower aging endures in that body part/area. An invention embodiment is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FIF0 ATP
hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, to treat/ameliorate/prevent/combat skin aging, optionally administered to the skin, optionally by skin and/or subcutaneous injection/implant, optionally as a skin cream, optionally to the face.
In another embodiment, administered to the scalp and/or hair, optionally in a hair treatment, optionally in a shampoo, to treat/ameliorate/prevent/combat hair follicle and hair aging/loss/greying/baldness. All means of applying a compound(s) of this invention to the skin, and/or scalp and/or hair are contemplated by, and componentry to, this invention.
Cosmetic/aesthetic embodiments of the invention An invention embodiment is an FIFO ATP hydrolysis inhibitor compound(s), optionally at least one compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII), or a salt, solvate, hydrate, precursor, liposome or nanoparticle thereof, and/or a composition/formulation comprising one or compounds of Formula (I), (II), (III), (IV), (V), (VI) or (VII), as the entirety or a component/ingredient of a cosmetic, for example (without restriction) a product for one or more of cleansing, beautifying, promoting attractiveness and/or altering the appearance of a subject (e.g., without restriction, making a more youthful/younger appearance, reducing the appearance of lines and wrinkles, preventing/reducing the signs of aging/premature aging, making skin/hair look visibly younger), optionally wherein the product is intended to be rubbed/poured/sprinkled/sprayed on/introduced into or otherwise applied to the human body, for example (without restriction) a skin/hair care product, shampoo, antidandruff shampoo, conditioner, a product delivered by micro-needling/Dermaroller/plasma-needling/DermaPen, hair tonic, hair colour, hair dye, soap, soap substitute, shower gel, bath oil, bubble bath, toothpaste, mouthwash, moisturizer, emollient, skin/face/body/hair/moisturizing/anti-aging/wrinkle/Crow's-feet/masking/whitening/age spot/liver spot cream/oily cream/aqueous cream/lotion/powder/spray/aerosol/butter/gel/hydrogel/oil/salve/liquid/alcohol/
emulsion/anhd rous-cream/stick/wax/ointment/foam/paste/solution/drop/gum/jelly/serum/scrub/mask/ba lm, .. stretch mark/cellulite/thigh cream/treatment, varicose vein cream, chapstick, lipstick, lip gloss, lip liner, lip plumper, lip balm, lip stain, lip conditioner, lip primer, lip booster, lip butter, make-up, makeup, mascara, mascara primer, eye shadow, eye liner, eyebrow pencil/cream/wax/gel/powder, foundation, concealer, bronzer, fake tan, rouge, blush, blusher, highlighter, setting spray, cleanser, skin cleanser, foaming wash, toner, facial mask (non-.. limiting e.g. clay-based masks, e.g. using kaolin clay or fuller's earth, peel masks, sheet masks), exfoliant, perfume, cologne, aftershave, shaving foam, beard balm, fragrance, deoderant, antiperspirant, hairstyling product(s), hairspray, nail polish, massage oil, barrier cream, sunscreen/sunblock/sun cream (e.g. offering protection against UVA
and/or UVB
radiation), spot/acne cream, wherein optionally the product also contains an anti-aging/rejuvenating/moisturizing/revitalizing/exfoliating/anti-oxidant compound(s), and/or a vitamin(s), and/or one or more ingredients in a cosmetic for sale in the USA/Canada/European Union/Japan/China/Korea/Australia/Brazil, and/or one or more ingredients listed in the International Nomenclature of Cosmetic Ingredients (INCI, INCI
names are developed by the International Nomenclature Committee (INC) and published in the International Cosmetic Ingredient Dictionary and Handbook), and/or one or more ingredients listed in CosIng (the European Commission database for information on cosmetic substances and ingredients),and/or one or more anti-aging compounds/ingredients (e.g., without limitation, botulinum toxin, epidermal growth factor, Vitamin A, one or more Retinoids {e.g., without limitation, retinol, retinal, tretinoin [all-trans-retinoic acid], isotretinoin [13-cis-retinoic acid], alitretinoin [9-cis-retinoic acid], etretinate, acitretin, adapalene, bexarotene, tazarotene, seletinoid GI, one or more retinoid complexes/salts/esters/ethers {e.g., without limitation, Retinyl palmitate}, one or more Alpha Hydroxy Acids [AHAs], one or more Beta Hydroxy Acids [BHAs], Vitamin C, Vitamin E, Coenzyme Q10, one or more antioxidants, one or more peptides {e.g., without restriction, acetyl hexapeptide-3, acetyl hexapeptide-8}, one or more copper peptides e.g.
Copper peptide GHK-Cu, Matryxil, Nicotinamide adenine dinucleotide (NAD ), Nicotinamide mononucleotide [NMN], Nicotinamide riboside (NR), Nicotinamide (Nam), Nicotinic acid (NA), Nicotinic acid adenine dinucleotide (NaAD), Nicotinic acid mononucleotide (NaMN), platelet-rich plasma, rapamycin) and/or one or more compounds/ingredients to treat/ameliorate/prevent/combat hair loss (e.g., without limitation, one or more 5a-Reductase inhibitors {5-ARls, also known as dihydrotestosterone (DHT) blockers}, Finasteride, Dutasteride, Epristeride, Saw palmetto extract, Serenoa repens extract, Alfatradiol {also known as 17a-estradiol}, one or more antiandrogens (e.g., without limitation, steroidal antiandrogens and non-steroidal antiandrogens), Bicalutamide, Bimatoprost, Cyproterone acetate, Flutamide, Ketoconazole, Latanoprost, Minoxidil, MK-434, Nepidermin, Nonsteroidal antiandrogen, RU-58841, Spironolactone, Steroidal antiandrogen, Topilutamide, Kopexil, Latanoprost, bimatoprost, Pinacidil, Diazoxide, one or more corticosteroids, IGF-1 {optionally in liposomes}), and/or one or more natural product extracts, and/or one or more of Acetone, Acetyl hexapeptide-3, Allantoin, Aloe, Alpha hydroxy acid, Aluminium zirconium tetrachlorohydrex gly, Argan oil, Azulene, Behentrimonium chloride, Bimatoprost, Bisabolol, Canthaxanthin, Carnauba wax, Castor oil, Ceteareth, Cetyl alcohol, Cocamide DEA, Cocamide MEA, Cocamidopropyl betaine, Cocamidopropyl hydroxysultaine, Cocoa butter, Conditioner, Copernicia Cerifera (Carnauba) Wax, Copper peptide GHK-Cu, Decamethylcyclopentasiloxane, Dihydroxyacetone, Dioxalin, Dipropylene glycol, Disodium cocoamphodiacetate, DMDM hydantoin, Erythrulose, Ethyl macadamiate, Ethylhexyl palmitate, Film-forming agent, Glycerol, Glyceryl behenate, Glycol distearate, Guaiazulene, Guanine, Hydrogenated jojoba oil, Hydrolyzed jojoba ester, lodopropynyl butylcarbamate, Isoceteth-20, Isopropyl jojobate, Isopropyl myristate, Isopropyl palmitate, Jojoba alcohol, Jojoba ester, Jojoba oil, Jojoba Wax PEG-80 Esters, Jojoba Wax PEG-120 Esters, Lapyrium, Macadamia oil, Malic acid, Marula oil, Microbead, Microcrystalline wax, Mineral cosmetics, Mineral oil, Myristamine oxide, Oleyl alcohol, denatured alcohol, Palmitoyl pentapeptide-4, Panthenol, Paraben, PEG-10 sunflower glycerides, PEG-16 macadamia glycerides, PEG-80 Jojoba, PEG-120 Jojoba, PEG-hydrogenated jojoba, Petroleum jelly, Polyacrylic acid, Polydimethylsiloxane, Polyethylene glycol propylene glycol cocoates, Polyquaternium, Polyquaternium-7, Propylene glycol, Quaternium-15, Rice bran wax, Sculptra, Selenium disulfide, Silicone, Simmondsia Chinensis (Jojoba) Seed Oil, Simmondsia chinensis (jojoba) seed powder, Sodium laureth sulfate, Sodium lauroamphoacetate, Sodium lauroyl sarcosinate, Sodium myreth sulfate, Spermaceti, Stearalkonium chloride, Stearamidopropyl dimethylamine, Sunflower oil, Talc, 1-Tetradecanol, Tetramethyl acetyloctahydronaphthalenes, Tocopherol, 1-Tridecanol, Triethanolamine, Vitellaria, Zinc pyrithione, Zinc ricinoleate, Amiloxate, 4-Aminobenzoic acid, Avobenzone, Bemotrizinol, Benzophenone-n, Bisdisulizole disodium, Bisoctrizole, Cerium(IV) oxide, Cinoxate, Dibenzylideneacetone, Diethylamino hydroxybenzoyl hexyl benzoate, Dioxybenzone, Drometrizole trisiloxane, Ecamsule, Ensulizole, Enzacamene, Ethylhexyl triazone, Homosalate, Iscotrizinol, Menthyl anthranilate, Mexenone, Octocrylene, Octyl methoxycinnamate, Octyl salicylate, Oxybenzone, Padimate A, Padimate 0, Polysilicone-15, Sulisobenzone, Titanium dioxide, Titanium dioxide nanoparticle, Trolamine salicylate, Umbelliferone, Zinc oxide, alkyl benzoate C 12-C15, allantoin, water, ascorbyl palmitate, butane, Butyrospermum parkii, shea butter, cocoamide dea, dodecanol, egg oil, hydroxyethyl cellulose, hydroxypropyl cellulose, isobutane, isopentane, lauryl glucoside, Polysorbate 20, propane, sodium hydroxide, triethanolamine, honey, shea butter, almond oil, argan oil, rosehip oil, beeswax, stevia, glycerin, essential oil(s), benzyl alcohol, dehydroacetic acid, Glyceryl Caprilate, Potassium sorbate, Caprylhydroxamic Acid, Caprylyl Glycol, Glycerin, Xanthan Gum, EDTA, Emulsifying wax, Olive oil, Evening primrose oil, Tocopheyl Acetate, Cetearyl Alcohol, Caprylyl Glycol, Phenoxyethanol, Hexylene Glycol, Glycyrrhiza Glabra (Licorice) Root Extract, Sodium Hyaluronate.
Componentry to this invention is a compound of Formula (VII), e.g. IF1 (e.g.
from a human and/or another mammalian species), in liposomes in a fluid gel formulation (e.g., without limitation, as used in [78] for (IGF)-1) in use as a cosmetic, optionally wherein a more youthful/younger appearance is desired in a subject.
EYE AGING
Fi Fo ATP hydrolysis inhibitor compound(s) of this invention slow aging but can reduce body temperature. An invention embodiment is to target an FIR, ATP hydrolysis inhibitor compound(s) to one or both eyes of a subject, optionally by intravitreal injection(s) and/or eye drop and/or contact lens coating/solution (optionally wherein the contact lens has little to no refractive ability or wherein the contact lens is prescriptive to the refractive defect/error of the subject's eye(s)) and/or some other drug administration route/device to the eye(s), known or findable to those of the art, wherein the eye(s) then has slower aging and lesser heat production, but wherein heat transfer from surrounding body areas (especially via blood flow) maintains eye(s) temperature at acceptable value. So, the temperature issue is mitigated and slower aging in the eye(s) endures. An invention embodiment is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FiF0 ATP hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally by a local drug administration route to the eye(s) (e.g.
by an eye delivery route known or findable to those of the art e.g. an eye(s) administration route used for an FDA/EMA licensed/sanctioned drug(s) e.g. as described in the patent/scientific literature e.g. refer [79, 80, 811 and the papers they cite and the papers that cite them), to treat/ameliorate/prevent/combat eye(s) aging and/or an eye aging related disease/disorder, including any eye disease/disorder whose likelihood of onset increases with age and/or worsens with age, including, without limitation, age-related macular degeneration (AMD, early/intermediate/late), neovascular/wet AMD, dry AMD, Geographic atrophy (GA), wet and dry AMD in the same eye(s), Stargardt's macular degeneration, Best vitelliform macular dystrophy, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, vision loss, progressive vision impairment, myopia (short-sightedness), degenerative myopia, hyperopia (far-sightedness), accommodative dysfunction, glaucoma, cataract formation, retinal degeneration, progressive retinal degeneration, retinitis pigmentosa, leber hereditary optic neuropathy, Fuchs spot, Best's disease, Sorsby's fundus dystrophy. In an embodiment, one eye of the subject is treated and the other not (optionally administered drug vehicle control), optionally for a course of administrations over a period of time, and the anatomical/physiological/functional difference(s) between them is then compared after some period. Non-limiting example eye function tests are using the Snellen chart, or LogMAR
chart, for visual acuity testing and/or the Amsler grid to investigate central vision. In an embodiment, a subject genetically predispositioned to age-associated eye disease(s)/disorder(s), e.g. macular degeneration, optionally discovered by genetic testing and/or family history analysis, is administered a compound(s) of this invention prophylactically. When a compound(s) of this invention is administered by intravitreal injection(s), optionally antibiotic(s) eye drop(s) (alternatively/in addition oral antibiotic(s)) is administered one or more times on the same day and/or in the same week and/or in the same month. Given increasingly aging societies in many countries, more and more people are succumbing to macular degneration. It is noteworthy that there is presently no treatment on the market for dry AMD, which comprises 90% of macular degeneration cases, affecting millions globally. The projected number of people with age-related macular degeneration in 2020 is 196 million, increasing to 288 million in 2040 [82].
EAR AGING

FiFo ATP hydrolysis inhibitor compound(s) of this invention slow aging but can reduce body temperature. An invention embodiment is to target an FIFO ATP hydrolysis inhibitor compound(s) to one or both ears of a subject, optionally by intratympanic and/or intracochlear administration and/or trans-oval window delivery and/or by ear drops and/or some other drug administration route/device to the ear(s), known or findable to those of the art, wherein the ear(s) then has slower aging and lesser heat production, but wherein heat transfer from surrounding body areas (especially via blood flow) maintains ear(s) temperature at acceptable value. So, the temperature issue is mitigated and slower aging in the ear(s) endures. An invention embodiment is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FIE) ATP
hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally by a local drug administration route to the ear(s) (e.g. by an ear delivery route known or findable to those of the art e.g. an ear(s) administration route used for an FDA/EMA licensed/sanctioned drug(s) e.g. as described in the patent/scientific literature e.g.
refer [83, 84] and the papers they cite and the papers that cite them), to treat/ameliorate/prevent/combat ear(s) aging and/or an ear aging related disease/disorder, including any ear disease/disorder whose likelihood of onset increases with age and/or worsens with age, including, without limitation, age-related hearing loss, presbycusis, tinnitus.
BRAIN AGING
Neurodegenerative diseases have an aging component to their etiology [85] as their onset is a function of age (oxidative stress [85]). Indeed, all these diseases (prototypical examples include Parkinson's disease, dementia, Alzheimer's disease, amyotrophic lateral sclerosis {ALS}, Huntington's disease, Friedreich's ataxia, hereditary spastic paraplegia) can be thought of as the brain aging faster and dying before the rest of the body (adult brain mass decreases with age [86]). In our rapidly greying societies these diseases are a demographic time bomb. Indeed, beyond immeasurable personal suffering, they stand to decimate whole economies (healthcare spending becomes unsustainable percentage of GDP, already ¨30% in the USA). For example, nearly half of Americans, over 85, have dementia, which in time is an age that an increasing proportion of the population will surpass, it has no cure and can be completely debilitating, which strains families and communities [86]. Thus, any treatment that can slow brain aging, to make brain function last as long as the rest of the body, will greatly assist in matching "healthspan" to lifespan, which is arguably the Holy Grail in modern medicine.
An invention embodiment is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FIN
ATP hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, to treat/ameliorate/prevent/combat brain aging and neurodegenerative disease(s).
Optionally wherein the compound(s) is disproportionally delivered to the brain or central nervous system (CNS), or to specific brain/CNS area(s) or cell type(s), by administration route, strategy or targeting. Illustratively, not restrictively, brain targeting had been shown with exogenous dopamine [87-88]. Preferred brain structures/cells/neurons to target are those whose failure drives a neurodegenerative disease e.g. dopamine neurons in the pars compacta (in the substantia nigra). There are few of them, only 7,200 in rat [89], and in humans their number decline by aging at 5-10% per decade [90], which is a predisposing drive to Parkinson's disease (PD). An invention embodiment is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FIR) ATP hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, to treat/ameliorate/prevent/combat Parkinson's disease, optionally wherein the compound(s) is disproportionally administered to dopamine neurons in the substantia nigra. If a compound of this invention decreases their heat generation, heat transfer from neighbouring brain and/or body regions will substitute this heat.
LIFESPAN AND/OR HEALTHSPAN EXTENSION IN A SUBJECT BY
ADMINISTRATING A COMPOUND(S) OF THIS INVENTION
Maximal Tolerated Dose (MTD) study of a compound(s) of this invention Three mice receive an initial dose of intravenous (i.v.) 10 mg/kg of drug. If these mice survive for 72 hours, the i.v. dose for the next cohort of three different mice is increased, whereas if one or more mice die, the i.v. dose for the next cohort of three different mice is decreased. And this schema is run iteratively. To illustrate, next dose level, 72 hours after prior dose level, can be determined by the following scheme:

10 mg/kg, if no death, 30 mg/kg, if no death, 100 mg/kg 10 mg/kg if no death, 30 mg/kg, if death, 17 mg/kg mg/kg, if death, 3 mg/kg, if death, 1 mg/kg, 10 mg/kg, if death, 3 mg/kg, if no death, 5 mg/kg But other schema can be developed by one of the art, involving different doses and/or a greater number of doses and/or using a different route of administration e.g.
oral (PO), 5 -- intraperitoneal (IP), intravenous (IV), subcutaneous (SC), intramuscular (IM) or other. At each dose level, animals are observed for the presence of acute toxic symptoms (mortality, convulsions, tremors, muscle relaxation, sedation, etc.) and autonomic effects (diarrhea, salivation, lacrimation, vasodilation, piloerection, etc.) during the first 60 minutes, again at 2, 24, 48 and 72 hours. Body weights are recorded pre-dose and at 72 hours after dose.
An alternative MTD determination method that better conserves compound and minimizes the number of animals sacrificed: a single mouse is given a dose (IP, IV, SC, IM or PO) of 400 mg/kg, a second mouse receives a dose of 200 mg/kg and a third mouse receives a dose of 100 mg/kg. The mice are observed for a period of 2 weeks. They are sacrificed if they lose -- more than 20% of their body weight or if there are other signs of significant toxicity. If all 3 mice must be sacrificed or die, the next 3 dose levels (e.g. 50, 35 and 12.5 mg/kg) are tested in a similar manner, whereas if only one or two dies, or needs to be sacrificed, the next 3 dose levels are between the highest shown safe dose thus far and the lowest lethal/toxic dose shown thus far. This process is repeated until a maximal tolerated dose (MTD) is found.
A compound of this invention, a compound that preferentially inhibits FiFo ATP
hydrolysis over FiFo ATP synthesis, for example a compound(s) of Formula (I), (II), (III), (IV), (V) or (VII), or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof has the peculiarity that its MTD is higher if the animal is housed at 37 C instead of normal room temperature (-22 C). The MTD and/or LD50 and/or LD30 and/or LDio and/or No-Observed-Adverse-Effect Level (NOAEL) of a compound(s) of this invention, optionally compound 7b, is investigated and recorded at both temperatures, optionally at interim temperature(s) also.
This information is then useful for implementing other example embodiment(s) of this invention. The MTD (or other drug dose safety measure) to use, the value to use and apply in -- designing a study, depends on what temperature(s) the animal(s) is to be housed at in the study. This different MTD at different temperature aspect to a compound(s) of this invention is more pronounced the smaller the animal e.g. more pronounced/important for mice than rats.

Lifespan extension using a compound(s) of this invention An example embodiment of this invention is to use a compound(s) of this invention, a compound that preferentially inhibits F1 F0 ATP hydrolysis over FIFO ATP
synthesis, for example a compound(s) of Formula (I), (II), (III), (IV), (V) or (VII) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof in an animal (e.g. mouse) lifespan study.
Illustratively, compound 7b is used in a mouse lifespan study. For non-restrictive example, 300 six-week old female Mus Muscu/us C57BL/6 strain mice are sourced from a commercial vendor (e.g. Charles River Laboratories Inc., MA, USA). Alternatively more mice can be used to be able to statistically detect smaller percentage increases in lifespan. In an alternative embodiment male mice are used also, wherein a study with both sexes valuably permits gender difference(s) to be identified. However, males bring the additional complexity of fighting, which can lead to mice deaths (need more males than females because some males will be invariably lost to fighting). In other example embodiments another mouse strain(s) is used and/or genetically heterogeneous mice, which avoids genotype-specific effects on disease susceptibility. The mice are housed at 37 C, which is safe for mice (refer [205]), by setting the room/ambient temperature accordingly e.g. by placing their cage(s) (3-5 mice per cage) in a Plant-Growth/Veterinary or Animal Intensive Care (ICU) incubator(s) set at this temperature, wherein such incubators can be sourced from one or more of Precision Refrigerated Plant-Growth Incubators, Thermo Fisher Scientific, Darwin Chambers Inc., Powers Scientific Inc, Brinsea Products Ltd., Lyon Technologies Inc., or similar company, wherein some of these companies even make custom incubator designs. The electrical cost of this temperature maintenance is reduced by running the study in a hot geographical location/country, Singapore. Mice are kept on a 12 hour light/dark cycle, in 40-70%
humidity, with corn cob bedding and have ad libitum sterilized/irradiated chow (illustratively AIN-93G standard diet or Purina 5LG6 or Purina 5001) and water. Preferably the mice are housed in a pathogen-free barrier environment (SPF conditions). One of the art knows how to successfully look after laboratory mice and there are well known guidelines and guides publically available. Mice are randomly allocated into two groups: 100 mice are in the drug treatment group, 200 mice are in the non-drug control group (twice more mice in control than drug group). Optionally a positive control (100 mice, no drug administered, calorie restricted diet) group is added. In some example embodiments the test drug is administered to the mice through drinking water/solution (in which case fluid intake of drug treatment and control groups is recorded). Indeed, there are compounds of this invention that are orally bioavailable e.g. 6b is 47% orally bioavailable in rats when administered in polyethyleneglycol:water:ethanol (1:1:1) solution [5]. Administering 6b as a salt, e.g. 6b HC1, increases its solubility, which is advantageous for oral administration via drinking solution.
Alternatively, the drug (base and/or salt) is mixed in with previously irradiated (sterilized) chow, wherein the drug is 0.0001%, or 0.001%, or 0.01%, or 0.05% (recommended starting .. percentage for experimentation to find optimal percentage), or 1%, or 2%, or 3% or another percentage of chow weight, which is done by BioSery (Flemington, NJ, USA) or TestDiet Inc. (TestDiet, Richmond, IN, USA) or Dyets Inc. (Bethlehem, PA, USA) or a similar company/service, the drug content of chow is checked using HPLC, wherein this chow is produced every 2 months during the length of the study, and is (alongside untreated chow) stored refrigerated, is never permitted to exceed 40 C and is kept away from light whenever possible to ensure drug stability (the light/dark cycle in the mouse facility is not altered).
Preferably, water and chow are warmed to 37 C before being accessible to the mice. To calculate how many mg/kg of drug any given mg/kg of drug in chow will deliver, a 30 g mouse consumes ¨5 g food/day [911(1/6 of body weight, which is an approximate relation that can be applied to younger and lighter mice also), so illustratively, to deliver 40 mg/kg of drug to mice per day requires drug to constitute 240 mg/kg (0.024%) of chow.
Optionally, further mice can be sourced for multiple drug treatment groups, all with the same number (100) of mice, which differ in the percentage weight of chow that is the test drug. So, that mice of the different drug treatment groups are administered a different drug dosage.
Optionally, the test drug is microencapsulated e.g. by Southwest Research Institute (San Antonio, Texas) using a spinning disk atomization coating process with the enteric coating material Eudragit S100 (Rohm Pharma). This thermoplastic coating material increases the drug fraction that survives the chow preparation process. Because the coating material is water soluble only in non-acidic conditions, the encapsulated drug is released in the small intestine rather than in the stomach. It is prudent to verify that the compound retains activity after incorporation into mouse chow and that therapeutic blood levels of the drug can be achieved (blood drawn from tail vein). Method(s) to record the amount of a drug in blood is well known to those of the art e.g. using HPLC with ultraviolet detection [92]
and/or LC-MS
and/or LC-MS/MS. If eating the chow kills the mice, iteratively reduce the drug content of the chow until the mice can safely survive eating the chow. To observe if there is sufficient drug in chow to cause a physiological effect, house the mice at 22 C and record the rectal temperature of the mice every 15 minutes and observe if their body temperature falls. If so, there is a working drug concentration in the chow. Optionally, increase the drug content of chow until the body temperature drop is sufficient to kill the mice in this 22 C study. Then check that this drug content of chow doesn't kill the mice when they are housed at 37 C, if not, proceed with the study, if so, reduce the dose until finding the largest safe drug dose in chow at 37 C. Either use this largest safe dose or some fractional function (e.g. half e.g. 10%
e.g. another percentage) of it. In Figure 23 of this disclosure 40 mg/kg i.v.
of 6a was safe and 40 mg/kg i.v. of 6b wasn't safe at 22 C ambient temperature, 6b is 47% orally bioavailable in rats [5], and so the recommended oral starting dose of 6b is 40*2 = 80 mg/kg ;---; 0.05% weight of chow, wherein this recommendation is extended to compound 7b also. However, in other embodiments a different chow drug percentage is used and one of the art will be able to experiment with different chow drug percentages to explore the best positioning/compromise between drug safety and maximal drug effect, wherein preferably a Maximal Tolerated Dose (MTD) study, as described elsewhere herein, would have been performed prior to give further information to guide this assessment. Methods to derive a drug dose to be used in a drug trial, if the drug's MTD/LD5o (drug dose that kills 50%)/LDio (drug dose that kills 10%) is known, are well known in the art. In an embodiment, the No-Observed-Adverse-Effect Level (NOAEL) is found and used, or some selected fraction (e.g. 50%, 10% or other) of it, wherein most optimally the NOAEL is found for the route (e.g. oral) and method (e.g. chow) of drug administration used in the lifespan study. MTD studies are typically single dose studies whereas this will be a long term study with the drug being administered frequently over a long period and this distinction needs to be considered. Pilot studies with small numbers of mice can be very instructive for setting the parameters of larger studies with many mice. In an alternative embodiment the drug is (e.g. daily) administered intravenously (e.g. at tail vein) through a catheter wherein control mice also have a catheter fitted and are administered vehicle at the same frequency as test mice are administered [drug+vehicle]. In other embodiments the drug is administered by some other route/method of administration.
Food intake (important to record because calorie restriction extends life [93], so any difference in food intake between the drug treatment and control groups needs to be known;
food intake of drug treated mice will be less than control mice because the drug renders their metabolism more efficient requiring less food and so they will choose to eat less food) and body weight are measured on a biweekly or bimonthly basis for the duration of the study.
Healthspan assays (e.g. as set out in [94, 95, 96] and/or assaying homeostatic capacity and/or observing heart rate variability and/or rotarod assay(s) and/or grip assay and/or horizontal bar assay and/or GSSG/GSH ratio and/or NAD/NADH ratio determination and/or one or more of the healthspan/fiinctional assays listed in another example embodiment of this invention and/or another assay of the art e.g. recording one or more of body coordination, memory, learning, movement, cognitive function) can be performed at regular intervals, especially as the mice get older. During the study, the day that each mouse dies is recorded and the study ends when all mice have died. Survival curves are plotted using the Kaplan¨Meier method, which includes all available animals at each time point. Statistical analyses is performed using JMP IN (SAS, Cary, NC). The criteria for euthanasia is based on an independent assessment by a veterinarian, according to AAALAC guidelines and only cases, where the condition of the animal is considered incompatible with continued survival, are represented in the curves. Every animal found dead or euthanized is necropsied for pathology score. At study end, the mean, median and maximal lifespan is calculated separately for drug treated and control groups. Comparing the proportion of mice still alive in each group at each age when the pooled population reaches the 90% mortality point is also a useful measure. The data will show that 7b extends the lifespan of mice, especially if they are maintained at 37 C.
This temperature dependence aspect can be shown by running the experiment again, or in parallel, wherein all the mice (drug treated and control) are kept at 22 C
rather than 37 C, wherein there is a lower drug dose(s) with the drug treated group(s) at this lower ambient temperature (because the tolerated drug dose is lower at lower ambient temperature), and wherein, with lower drug dose, the lifespan extension isn't as great. In an alternative embodiment, when mice are first sourced they are older e.g. older (e.g. old) mice are sourced from the National Institute on Aging Aged Rodent Colony or from the Jackson Laboratory (USA, has 19.5 months old mice available, roughly equivalent to a 50 year old human). This means that the experiment will take less time to run, because the mice will die sooner after being received. But the increase in lifespan observed will be less. Another way to shorten the duration of the study is to use mice that undergo accelerated aging [97, 98, 99, 100] e.g., without limitation, Senescence Accelerated Mouse-Prone 8 (SAMP8) mice (approximately half the lifespan of normal laboratory mice; commercially available from Harlan Laboratories, Bicester, UK; also available from the Society for Senescence-Accelerated Mouse (SAM) Research, Japan [http://www.samrc.jp], as are further senescence accelerated mouse strains) and/or BubR1 progeroid mice [101] and/or XPD (e.g. XPDTTD
[102]) mutant mice (optionally carrying an additional mutation(s) in XPA and/or XPC) [103, 104]
(mice with a Trichothiodystrophy [TTD] mutation in XPD, with XPC knocked out, have accelerated aging and only live 4-8 weeks) and/or XPC mutant mice [105, 106]
(commercially available from The Jackson Laboratory, Stock No: 010563) and/or mutant mice (e.g. ERCC1-/- [107] e.g. ERCC1 Ai- mice carry a null mutation in one allele and a 7-amino acid truncation in the second allele, maximum lifespan is ¨6 months) [108, 109, 97] and/or Ku70 and/or Ku80 and/or Ku86 [110] and/or DNA-PKcs mutant mice [111]
and/or Caspase-2 mutant mice (commercially available from The Jackson Laboratory, Stock No: 007899) [112, 113] and/or ICE mice (Induced Changes in Epigenome) and/or some other accelerated aging mouse model of the art. Some of these accelerated aging mouse models, as are others not mentioned but that can be found by one of the art, are recognised models of human accelerated aging diseases. Alternatively, to shorten the study duration, one can use a smaller and shorter lived mammal species than mice (20 g) e.g. the Common Shrew (9 g) or the even smaller Etruscan shrew (1.8 g). An embodiment of this invention is to enter a compound(s) of this invention into the Major Mouse Testing Program (MMTP) and/or the National Institute on Aging's Interventions Testing Program (ITP) and/or use the same/similar/inspired testing protocol for a lifespan study using a compound(s) of this invention, or another lifespan study protocol in the literature or a lifespan study protocol conceived by someone of the art, optionally after their reading lifespan studies in the literature e.g., without limitation, [92, 114, 115, 116, 117, 118, 119]. An invention embodiment is to enter a compound(s) of this invention, or result(s) from using a compound(s) of this invention, into a mouse/rodent or other animal lifespan competition such as the Methuselah Mouse Prize (MPrize) and/or Palo Alto Longevity Prize and/or other/similar. A compound(s) of this invention extends lifespan by a direct anti-aging effect and also by an anti-cancer effect, reducing the incidence of, and by treating/ameliorating/preventing/combating cancer. Given the established link between age/aging and neurodegenerative disease, a compound of this invention, which slows aging as shown by this example, has utility as a therapeutic for neurodegenerative disease e.g.
(without restriction) for Alzheimer's disease and/or dementia. Illustratively, Rapamycin extends mouse lifespan [92, 117] and exerts therapy in a mouse model of Alzheimer's disease [120]. An accelerated mouse model of aging, SAMP8, is concurrently a mouse model of Alzheimer's disease [121].
Instead of, or in addition to, using mouse death as an endpoint in this study, an aging/mortality biomarker(s) can be used, e.g. one or more listed in the database:
http://mortalitypredictors.org/ [139] e.g. walking speed. In this way, compound(s) effect on aging/mortality can be assayed before death. This is especially important for human studies with a compound(s) of this invention, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally following on from mouse studies, given that humans have a long lifespan and so a surrogate endpoint (change in a biomarker(s) e.g.
walking speed) to assess the change in aging/mortality is preferable to awaiting lifespan data.
Healthspan assays show that a compound(s) of this invention slows aging, including brain aging, and treats/ameliorates/prevents/combats neurodegenerative disease(s), including Alzheimer's disease APP/swePS1AE9 mice is a mouse model of Alzheimer's disease [140], available from The Jackson Laboratory (stock no: 004462). Senescence Accelerated Mouse-Prone 8 (SAMP8) mice display a phenotype of accelerated aging, with associated cognitive decline, and is a .. mouse model of aging driving Alzheimer's disease and/or dementia [121], available from Harlan Laboratories (Bicester, UK). In an invention embodiment APP/swePS1AE9 mice (or an alternative Alzheimer's disease mouse model {to illustrate and not restrict: from the Model-AD project and/or The Jackson Laboratory have a number of different Alzheimer's disease mouse models available [typically present learning deficit, from variable age, many including spatial learning deficit], or the PDAPP (also known as hAPP(J20) transgenic mouse model of Alzheimer's disease [120]}, or a mouse model of a different neurodegenerative disease e.g. a mouse model of Parkinson's disease, optionally sourced from The Jackson Laboratory) are used for the following study. In a different invention embodiment SAMP8 mice (or an alternative accelerated aging mouse model) are used in the following study. In a .. different invention embodiment normal mice are used in the following study.
This study will now be described with SAMP8 mice. At all places that SAMP8 is referred to, in another embodiment, "APP/swePS1AE9" is substituted in its place. At all places that SAMP8 is referred to, in a further embodiment, "normal" is substituted in its place.
Six-week old male SAMP8 mice are sourced and randomly assigned to the following groups: 200 SAMP8 mice are maintained on control chow (LabDiet 5015, TestDiet, Richmond, IN) and 100 mice are maintained on chow (LabDiet 5015) that contains a compound(s) of this invention: a compound that preferentially inhibits FIFO ATP hydrolysis over FIR) ATP
synthesis, for example a compound(s) of Formula (I), (II), (III), (IV), (V) or (VII) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof. Illustratively, compound 7b of this disclosure. How to prepare such chow has been disclosed for an earlier invention example.
Food consumption and body weight are monitored during the study. In a further example embodiment there is more than one drug treated group, wherein these groups differ in drug dose given. Preferably all mice are housed at 37 C, as described for a prior invention example, and preferably the behavioural experiments are performed at 37 C
also, wherein preferably water in the water tests is also at 37 C. Mouse body weights are measured regularly. Behavioural tests are conducted every month. The study ends when all mice die.
As the mice get older, drug treated SAMP8 mice start to outperform control SAMP8 mice in one or more of these tests, and/or a test variant(s), and/or a similar test(s), and/or another test(s) of mental/cognitive faculty(s) e.g. as found in the literature or as modified by someone of the art upon reading the literature: for the following test(s) the experimenter is blinded to which mice are drug treated and non-drug treated, preferably all tests are videotaped for parallel independent confirmatory analysis by another experimenter(s), wherein automatic computer software analysis is used where available/possible to aid analysis:
(1) Activity. The open field test is performed using MED Associates hardware and Activity Monitor software according to manufacturer's protocol (MED Associates Inc, St.
Albans, VT, USA). Animals are individually placed into clear Plexiglas boxes (40.6 x 40.6 x 38.1 cm) surrounded by multiple bands of photo beams and optical sensors that measure horizontal and vertical activity. Mouse movement is detected and recorded for 30 minutes by breaks within the beam matrices. Old (e.g. 10 months) drug treated SAMP8 mice have a higher average velocity of movement, moving greater distance and a greater number of vertical movements than equally old SAMP8 control mice.
(2) Prudence. Elevated Plus maze. Young healthy mice have an aversion to open spaces.
Mental decline is associated with dis-inhibition and greater comfort/time spent in open spaces. The elevated plus maze consists of four arms (two open without walls and two enclosed by 15.25 cm high walls) 30 cm long and 5 cm wide in the shape of a plus. A video camera mounted overhead on the ceiling linked to video tracking software (Noldus Etho Vision) is used to collect behavioural data. This software detects and records when mice enter the open or closed arms of the maze and the time spent in each. Mice are habituated to the maze for 1 minute before testing by placing them in the centre of the maze and blocking their entry to the arms. Dis-inhibition is measured by comparing time spent on open arms to time spent on closed arms over a 5 minute testing period. Old (e.g. 10 months) drug treated SAMP8 mice have less dis-inhibition than equally old control SAMP8 mice.
(3) Memory, object recognition. Young healthy mice spend more time exploring a novel object than a familiar one. Mice are tested in a standard home cage. Phase 1 (Habituation):
Each mouse is placed into the apparatus (no objects present) for two 10 minute sessions separated by 1-4 hours to habituate to the testing environment. Phase 2 (Training): Two identical velcro-backed objects (object "A") are attached into designated corners of the apparatus. The mouse is placed into the apparatus opposite to the objects and recorded by a camera for 10 minutes. Phase 3 (Test): One hour after training, the test phase begins. Only one of the objects is replaced with a new object (object "B"). The mouse is placed into the apparatus opposite to the objects and recorded for 5 minutes. The apparatus is wiped and objects cleaned with 70% alcohol to remove odours between mice. "Object recognition index" is calculated by dividing the amount of time spent with (touching with nose or nose pointing at object and within 0.5 cm of object) object B by the total time spent with objects A
+ B and multiplied by 100. Old (e.g. 10 months) drug treated SAMP8 mice have a greater recognition index than equally old control SAMP8 mice.
(4) Memory, learning, re-learning. Barnes maze: The maze consists of a flat circular surface (36" diameter) with 20 equally spaced holes (2" diameter) along the outer edge. One of the holes leads to a dark hide box while the other 19 lead to boxes that are too small to be entered. The latency to enter the hide box is recorded. The test is conducted in three phases.
Phase 1 (Training): A hide box is placed under one of the holes. Animals are placed into an opaque cylinder in the centre of the maze for 30 seconds to promote spatial disorientation at the start of the test. After 30 seconds, the cylinder is removed and the animal explores the maze until it finds and enters the hide box. The number of incorrect entries (nose pokes and head deflections over any hole that did not have the hide box beneath it) is scored. If the mouse fails to enter the box within 3 minutes, it is gently led into the box.
The animal then remains in the box for an additional 20 seconds before it is removed from the box and gently placed into the home cage. Training is repeated three times a day for four days. The location of the hide box remains the same during every trial but it is shifted between subjects to reduce the potential for unintended intra-maze cues. Phase 2 (Retention): This phase measures retention of spatial memory following a delay. After a two day break from training, each animal is re-tested for a one day, three-trial session using the same hide box location as before. Phase 3 (Reversal): This phase examines memory reversal. On the day following the retention phase, a new hide box location is established 180 degrees from the original location.
The same method as before is used and trials are repeated three times a day over two consecutive days. Old (e.g. 10 months) drug treated SAMP8 mice find the hide box faster, better retain knowledge of where the hide box is and learn faster a new location of the hide box than equally old control SAMP8 mice.
(5) Spatial navigational memory. Two-day water maze. Mouse tracking is performed using SMART version 2.0 (Panlab). The water is painted milk-white with nontoxic paint. A
platform which is visible during training on Day 1 is then submerged just under the water level during testing on Day 2 and mice use spatial cues on the wall around the pool to navigate to the platform during testing. During testing on Day 2, the time it takes each mouse to find the hidden platform is measured. Old (e.g. 10 months) drug treated SAMP8 mice find the hidden platform faster than equally old control SAMP8 mice.
(6) Morris Water Maze [141]. Mouse tracking is performed using SMART version 2.0 (Panlab). The water is painted milk-white with nontoxic paint. 4 trials per day for 5 consecutive days. For each trial, mice are placed in the pool at 1 of 4 start locations. The starting locations are separated by 90 and are termed south, west, north, and east. Mice start a trial once from each of the 4 possible start locations on each day. The goal platform is positioned 45 cm from the outside wall in the south quadrant of the maze for all groups. The latency to find and mount the hidden platform is measured. Swimming speeds are also recorded to assess drug-induced motor effects. If the mice fail to find the platform before 120 seconds expires, they are placed on the platform by the experimenter. Mean daily latency to find the goal platform is calculated for each mouse. On day 6, the platform is removed and time spent in the platform quadrant determined. The water tank is surrounded by opaque dark panels with geometric designs at approximately 30 cm from the edge of the pool, to serve as distal cues. Old (e.g. 10 months) drug treated SAMP8 mice swim faster and reach the hidden platform faster, and spend longer in the platform quadrant when it is removed, than equally old control SAMP8 mice.
(7) Fear conditioning, fear memory, associative learning. A mouse freezes if it remembers and associates that environment with an aversive stimulus. Mice are trained on Day 1 to associate their environment with an aversive stimulus (a foot shock). The amount of time spent freezing in response to the environment is measured on Day 2. Fear conditioning is performed in a conditioning chamber (Med Associates) equipped with a grid floor via which the foot shock can be administered. Each mouse is placed inside the conditioning chamber for 180 seconds. A foot shock (2 seconds, 0.4 mA) is delivered 148 seconds after placement in the chamber. Twenty-four hours later, context-dependent freezing is measured during 3 minutes. Time spent freezing is measured using Any-Maze Tm software. To avoid any influence of foot shock exposure on further testing, this is the last test performed of the battery of tests and all other tests are carried out in tests rooms other than the fear conditioning test. Old (e.g. 10 months) drug treated SAMP8 mice spend more time freezing in response to the context associated with the aversive stimulus than equally old control SAMP8 mice.

(8) As measured by an assay(s) described in [142], old (10+ months) drug treated SAMP8 mice have less hearing and/or vision loss (have a lower hearing threshold and/or a greater visual contrast sensitivity) than old (10 months) control SAMP8 mice.
(9) As measured by an assay(s) described in [143], old (10+ months) drug treated SAMP8 mice have greater neuronal plasticity (e.g. greater hippocampal synaptic plasticity e.g. greater Long-Term Potentiation [LTP] with excitatory neurons), and less neuronal degeneration and reactive astrocytosis, than old (10 months) control SAMP8 mice.
(10) Social preference test (SPT). Assesses sociability and social novelty preference (i.e.
social recognition memory). The apparatus consists of 3 chambers, a central chamber (length:
9 cm, width: 18 cm, depth: 20 cm) and two outer chambers (6 cm*18 cm* 20 cm).
The dividing walls are made of clear Plexiglas, with square passages, 4 cm high and 4 cm wide.
One circular cage (i.e. mouse enclosure) is placed into each outer chamber.
The mouse enclosures are 15 cm in height with a diameter of 7 cm and bars spaced 0.5 cm apart to allow nose contact between mice but prevent fighting. The chambers and enclosures are cleaned with 30% ethanol in-between trials (inter-trial interval of 5 minutes) and fresh corn cob bedding is added prior to each test trial. Test animals are isolated for an hour prior to the start of testing. During the habituation trial, two mice are placed individually in the central chamber and allowed to freely explore the apparatus and the two empty enclosures for 5 minutes. For the sociability test an unfamiliar adult male mouse is placed in one of the two enclosures (i.e. opponent chamber) in a quasi-randomised fashion. Then the test mouse is returned to the apparatus and allowed to explore all three chambers for 10 minutes. Finally, test animals are observed in a 10 minute social recognition test. For this, a second, unfamiliar mouse is placed in the previously empty chamber so that the test mouse has the choice to explore either the familiar mouse (from the previous trial) or the novel, unfamiliar mouse.
AnyMazeTm tracking software is used to determine the time spent in the different chambers, number of entries and distance travelled by the test mice in each trial. Time spent sniffing the opponent is recorded manually (i.e. snout of test mouse within the enclosure containing the opponent mouse or <5 mm away from enclosure). Old (e.g. 10 months) drug treated SAMP8 mice spend more time with the novel individual, as compared to time spent with the familiar individual, than equally old control SAMP8 mice.

(11) Olfactory test (i.e. cookie test). Test mice are familiarised with a high carbohydrate food (Froot Loops: Kellogg Pty. Ltd., Strawberry Hills, Australia) in their home cages, 24 hours prior to the test. Consumption is observed by the experimenter to ensure the novel food is palatable for the mice. On test day, test mice are habituated for 5 minutes to a large opaque cage (47 cm*18 cm*13 cm) containing 2 cm deep bedding. The animal is removed from the cage thereafter, and one Froot Loop is buried randomly in the cage bedding. The animal is then returned to the cage and given 10 minutes to locate the buried food. The latency to find the Froot Loop is recorded. Old (e.g. 10 months) drug treated SAMP8 mice will find the Froot Loop faster than equally old control SAMP8 mice.

(12) In treadmill testing, old (e.g. 10 months) drug treated SAMP8 mice have a faster maximal running speed, and greater running endurance, than equally old control mice, whether trained or untrained at treadmill running.

(13) Old (e.g. 10 months) drug treated SAMP8 mice have one or more of better Blood Brain Barrier (BBB) homeostasis, less inflammation (e.g. in the brain), less gliosis, better vascular function (e.g. in the brain), less Amyloid beta (AO), less tau protein (and/or less hyperphosphorylation of tau protein), lower levels of Vascular Cell Adhesion Molecule 1 (VCAM-1, a protein associated with vascular endothelium inflammation), lower levels of endogenous immunoglobulin G (IgG, high levels observed in old mice as consequence of disrupted BBB permeability), less glial fibrillary acidic protein (GFAP) expression, increased brain Docosahexaenoic Acid [DHA] (possibly because of less oxidation of DHA, DHA is the primary structural fatty acid in the human brain and has been linked to cognitive performance. Low plasma levels of DHA are associated with cognitive decline in elderly and Alzheimer's disease patients, higher DHA intake and plasma levels inversely correlate with Alzheimer's disease risk, DHA supplementation in aged animals enhances learning and memory [125]), increased brain glutamate levels (brain [glutamate] decrease with age [122]
and low [glutamate] has been observed with Alzheimer's disease [123, 124]) and/or a lesser pro-oxidant status in the brain than equally old control SAMP8 mice.

(14) Old (e.g. 10 months) drug treated SAMP8 mice have less aging (are more similar to young SAMP8 mice), at one or more of the cognitive/movement/anatomical/physiological/electrophysiological/cellular (e.g. number of senescent cells [126])/biochemical/neurochemical/protein/protein modification (e.g.
carbamylation [127])/oxidation e.g. [128, 129]/metabolite/metabolic/epigenetic/histone loss/histone modification/telomere length/gene expression/DNA/DNA modification (e.g.
DNA methylation)/RNA levels, than equally old control SAMP8 mice, for example as reported using one or more of the assays described in [130, 131, 132, 133, 134, 135. 136, 137, 138] or some other aging assay(s) of the art e.g. as described in the literature e.g.
using/leveraging an aging/mortality biomarker(s) reported in the database:
http://mortalitypredictors.org/ [139].

(15) Transcriptional drift is an age-associated loss of coordination among groups of genes [144, 145]. Aging causes genes within functional groups to change expression in opposing directions, which cause a transcriptome-wide loss in mRNA stoichiometry and loss of co-expression patterns in aging animals, as compared to young animals. Observing hippocampal gene expression data, old (e.g. 10 months) drug treated SAMP8 mice have less transcriptional drift than equally old control SAMP8 mice i.e. old (e.g. 10 months) drug treated SAMP8 mice have a transcriptome (e.g. hippocampal transcriptome) more similar to young SAMP8 mice than equally old control SAMP8 mice. Metabolomic/metabolic drift is an age-associated change in the relative/absolute amounts of metabolite(s) e.g. reduced [NAD]
[146, 138], increased AMP/ATP etc. [147]. Old (e.g. 10 months) drug treated SAMP8 mice have a (e.g.
plasma and/or brain [e.g. hippocampal]) metabolome more similar to young SAMP8 mice than equally old control SAMP8 mice i.e. old (e.g. 10 months) drug treated SAMP8 mice have less (e.g. plasma and/or brain [e.g. hippocampal]) metabolomic/metabolic drift than equally old control SAMP8 mice. Optionally metabolome analysis is performed using Precision MetabolomicsTM (Metabolon Inc., Morrisville, NC, USA).
HYPERMETABOLISM
An invention embodiment is a method in which a subject takes or is administered an effective amount of a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or another compound that selectively inhibits FIR' ATP hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally in co-therapy with one or more of an anti-thyroid drug(s) (illustrating, without restriction, carbimazole, methimazole, propylthiouracil/PTU, potassium perchlorate), radioiodine, beta blocker(s) (illustrating, without restriction, propranolol, metoprolol), surgery (thyroidectomy), to treat/ameliorate/prevent/combat one or more of hypermetabolism, heat intolerance, thyroidal hypermetabolism, non-thyroidal hypermetabolism e.g.
Luft's disease.
COMPOUNDS OF THIS INVENTION ARE ANXIOLYTICS, ANTICONVULSANTS, ANTIPSYCHOTICS, ANTIDEPRESSANTS, ANTIEMETICS, ANALGESICS, SEDATIVES, HYPNOTICS AND ANTIHISTAMINES
As reported in the legend of Figure 23 of this disclosure, when mice were administered Compound 6b of this invention they exhibited hypoactivity, the duration of which correlated with their drop in rectal temperature, which correlated with the administered dosage of 6b, wherein greater 6b dose caused greater rectal temperature drop and greater hypoactivity.

Hypoactivity of mouse, after being administered compound 6b, was because 6b caused the mouse's body temperature to drop towards its ambient temperature (22 C). When ambient equals optimal body temperature (37 C), 6b doesn't/can't reduce body temperature and doesn't cause hypoactivity. In some invention embodiments, the hypoactivity/sedation aspect to a compound(s) of this invention is utilized for therapy. The intersection between drug dose and ambient temperature dictates how much the body temperature falls and thence the depth of the sedation. Larger drug dose, and/or lower ambient temperature, causes deeper sedation (e.g. useful for inducing anaesthesia, pre-anaesthesia, post-anaesthesia, hypoesthesia, sedation, coma, tranquilization, behavioural submission, muscle relaxation and/or treating/ameliorating/preventing/combating insomnia, fatal insomnia, sleep onset latency, delayed sleep phase disorder, exploding head syndrome, parasomnia, sleep-maintenance insomnia, sleep disorder etc.; repeated/continuous administration, e.g.
repeated i.v. injections or continuous i.v. infusion, of a compound(s) of this invention can sedate a subject for an extended period of time). Smaller drug dose, and/or higher ambient temperature, causes lighter sedation (e.g. useful for anti-anxiety, anti-depression, hyperactivity etc.). At ambient>optimal body temperature (37 C), no sedation occurs. Increasing sedation occurs with lower body temperature because action potential characteristics are temperature dependent. In some invention embodiments, deeper sedation is conveyed by a larger body temperature drop (body temperature<34 C) and in other invention embodiments a slight calming sedation, optionally imperceptible to the subject, is conveyed by a smaller body temperature drop, optionally less than 1 C, optionally less than 0.5 C. To repeat, the intersection between dose and ambient temperature dictates the magnitude of body temperature drop, wherein this can be zero, even at high drug dose, when ambient temperature >37 C. So many diseases/disorders are because of too much/inappropriate/undesired signals/activity/electrical activity in the nervous system, wherein a compound(s) of this invention can decrease nervous system activity by a tunable degree (reduction amplitude set by intersection of drug dose with ambient temperature) and so can treat/ameliorate/prevent/combat an incredibly large number of diseases/disorders.
Fundamental action equals broad applicability. Drug action against a fundamental physiological parameter (body temperature), which dictates a further fundamental physiological parameter (action potential characteristic(s): firing threshold/conduction velocity/firing frequency etc.), yields broad therapeutic application. For example, it raises the stimulus threshold for an epileptic seizure, which decreases the frequency of epileptic seizures in a subject. For example, it raises the stimulus threshold for ejaculation, therefore delaying ejaculation during sex, therefore assisting a subject with premature ejactulation. For example, it raises the threshold for pain perception and so any pain is reduced in magnitude.
For example, in the brain, it raises the threshold for a "behaviour suggestion signal" to be selected for action, thence reducing the occurrence of unwanted behaviour (e.g. in Tourette's syndrome).
Reduced temperature decreases action potential (AP) conduction velocity (Q10 =
¨1.7, so AP
velocity is ¨10% less at 35 than 37 C [148, 149]), decreases AP frequency (30%
decrease in spike rate with 2 C decrease in temperature [150]), increases AP firing threshold (AP firing threshold vs. temperature is U shaped because threshold increases as move away from an optimum temperature [15 I, 152]) and decreases neural circuit activity in vivo [153].
An embodiment of this invention is to administer to a subject compound 6b, and/or 7b, and/or another compound(s) of this invention, i.e. a compound that preferentially inhibits FIR, ATP
hydrolysis over FiFo ATP synthesis, for example a compound(s) of Formula (I), (II), (III), (IV), (V) or (VII) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, to treat/ameliorate/prevent/combat hyperactivity, hypersensitivity, Premature ejaculation, hyperreflexia, Autonomic dysreflexia (AD), Hyperventilation syndrome, brain hyperactivity, overly sensitive sensory system, pathological crying and/or laughing, Pseudobulbar affect (PBA, emotional lability), photophobia, phonophobia, temperature-sensitive, pressure-sensitive, brain hyperexcitability, overstimulation, intrusive thought(s), Perseveration, sensory overload, disorganized thinking, fantasy prone personality, malapdative daydreaming, dissociation, hyperkinetic disorder, agitation, Psychomotor agitation, restlessness, difficulty controlling behaviour, disruptive behaviour disorder, Emotional and .. behavioral disorder, pervasive developmental disorder, Overactive disorder associated with mental retardation and stereotyped movements, attention-deficit disorder, Attention Deficit Hyperactivity Disorder (ADHD), adult attention-deficit hyperactivity disorder, severe behavioral problem(s) in children (e.g., to illustrate and not restrict, combativeness and/or explosive hyperexcitable behavior {out of proportion to immediate provocation[s]}, hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of one or more of: impulsivity, difficulty sustaining attention, aggressivity, mood lability, poor frustration tolerance), Premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), impulsiveness, impulsivity, impulse control disorder, lack of self-control, hysteria, histrionic personality disorder, attention difficulty, inattention, poor attention control, anxiety, paranoid anxiety, Paranoid personality disorder, distress, dysphoria, Adjustment disorder, separation anxiety, anxiety disorder, depressive anxiety, agitated depression, treatment-resistant depression, Generalized anxiety disorder, social anxiety disorder, stranger anxiety, separation anxiety (e.g. in dogs left at home), separation anxiety disorder, Mixed anxiety-depressive disorder, depression (all forms, all severities), restlessness/apprehension/anxiety before surgery. hypochondria, panic disorder, panic attack, emotional outburst, emotional instability, Intermittent explosive disorder, unreasonable/unwarranted anger/aggression, hyper-aggression, hostility, rage, poor temper control, self-hatred, poor attentional control, worry, irritability, neuroses, somatization .. disorder, somatic symptom disorder, pain disorder, psychological pain, psychogenic pain, psychogenic facial pain, Atypical odontalgia (AO), burning mouth syndrome, throbbing, toothache/pulpitis/dental pain, chronic lower back pain, negative emotion, persistent/enduring negative emotion, body dysmorphic disorder, factitious disorder, illness anxiety disorder, unwarrented fight-or-flight response, stress, emotional stress, emotional dysregulation, distress, psychological stress, acute stress, chronic stress, acute stress reaction, combat stress reaction, traumatic grief, grief, grief after death of loved one, Prolonged grief disorder (PGD), heartbreak, guilt, shame, remorse, emotional pain, Algopsychalia, psychalgia, suffering, emotional trauma, psychological trauma, broken heart, Post Traumatic Stress Disorder (PTSD), Complex post-traumatic stress disorder (C-PTSD), hypervigilance, sympathetic .. hyperactivity, inability or impaired ability to relax, flashbacks, dysphoric hyperarousal, agoraphobia, insomnia, fatal insomnia, mood disorder, irrational/unwarrented fear/terror, phobia, social phobia, Cancerophobia, thunderstorm/firework phobia, hypersexuality, hypersexual disorder, depression, clinical depression, unipolar depression, bipolar disorder, Bipolar 1, Bipolar II, Bipolar disorder not otherwise specified (Bipolar NOS), cyclothymia, cyclothymic disorder, mixed affective state, atypical depression, melancholic depression, postpartum depression, double depression, seasonal affective disorder, mania, manic episode, hypomania, increase in energy of psychomotor activity, delirium, excited delirium, major depressive disorder, minor depressive disorder, recurrent brief depression, Depressive Disorder Not Otherwise Specified (DD-NOS), major depressive episode, persistent depressive disorder (PDD), dysthymia, dysthymic disorder, absence of euthymia, manic thoughts, racing thoughts, thought disorder, disordered thinking, reduced ability to plan and execute tasks, paranoia, hallucination (including, without limitation, visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrioceptive, nociceptive, thermoceptive, chronoceptive), Charles Bonnet syndrome, delusion, persecutory delusion, hearing voices, homicidal/criminal ideation/tendency/thoughts, suicidal ideation/tendancy/thoughts, self-injury, non-suicidal self-injury, violence, attacking others, negative mood swing, personality disorder, Borderline personality disorder, Narcissistic personality disorder, malignant narcissism, dissociative disorder, dissociative identity disorder (DID), Psychosis, acute psychosis, chronic psychosis, psychosis spectrum disorder, manifestations of psychotic disorders, behavioral complications of mental retardation, stimulant psychosis, psych'otic depression, hallucinogen persisting perception disorder, Psychoactive substance-related disorder, amphetamine-induced psychosis, brief psychotic disorder, Brief reactive psychosis, Menstrual psychosis, postpartum psychosis, Psychotic disorder, Psychopathy, chronic hallucinatory psychosis, manifestation(s) of psychotic disorder, neurotic/reactive/endogenous/involutional/psychotic depression/depressive disorder (optionally accompanied by anxiety or agitation), depressive neurosis, delusional depression, psychotic aggression, psychiatric symptoms of dementia, AIDS delirium, Supersensitivity psychosis, Tardive psychosis, Tardive dysmentia, Depersonalization disorder, out-of-body experience, Sociopathy, Schizophrenia, Paranoid schizophrenia, disorganized-type schizophrenia, simple-type schizophrenia, pseudoneurotic schizophrenia, prodromal schizophrenia, schizoaffective disorder, bipolar type schizoaffective disorder, depressive type schizoaffective disorder, schizoaffective psychosis, Schizotypal personality disorder, schizophreniform disorder, Delusional parasitosis, formication, paresthesias, Acroparesthesia, tinnitus, delusional disorder, delusional jealousy, inappropriate behaviour, behavioural disorder, antisocial personality disorder, Oppositional defiant disorder (ODD), conduct disorder (CD), Disruptive mood dysregulation disorder (DMDD), sadistic personality disorder, poor inhibitory control, kleptomania, Pyromania, trichotillomania, dermatillomania, pathological/problem gambling, dyskinesia, tardive dyskinesia, paroxysmal dyskinesia, Paroxysmal kinesigenic dyskinesia, Paroxysmal nonkinesigenic dyskinesia, Paroxysmal exercise-induced dystonia, Hemiballismus, tic disorder, tremor, clonus, Tourette's syndrome, coprolalia, copropraxia, Echophenomena, Echopraxia, Echolalia, Palilalia, stuttering/stammering, stereotypy, punding, Self-stimulatory behaviour (stimming), Stereotypic movement disorder (SMD), synesthesia, obsession, Obsessive¨compulsive disorder (OCD), obsessive¨compulsive personality disorder, anankastic personality disorder, relationship obsessive¨compulsive disorder (ROCD), Scrupulosity, Primarily obsessional obsessive compulsive disorder, sexual obsession, Akathisia (including, without limitation, chronic, acute, Pseudoakathisia, Tardive akathisia, withdrawal or "rebound"
akathisia), Restless legs syndrome, motor restlessness, periodic limb movement disorder (PLMD), periodic limb movements in sleep (PLMS), Sydenham's chorea, chorea, dystonia, Hypnic jerk, twitching, spasms, Tetanus, tetanus muscle spasms, tetanized state, Myoclonus, myoclonic seizure, Action myoclonus, Palatal myoclonus, Middle ear myoclonus, Spinal myoclonus, Stimulus-sensitive myoclonus, Sleep myoclonus, Cortical reflex myoclonus, Essential myoclonus, myoclonic epilepsy, Juvenile myoclonic epilepsy, Progressive myoclonus epilepsy (PME, including, without limitation, Dentatorubral-pallidoluysian atrophy, Unverricht-Lundborg disease, MERRF syndrome, Lafora disease), Reticular reflex myoclonus, Myoclonic epilepsy, diaphragmatic flutter, automatism, status epilepticus, Epilepsia partialis continua, Complex partial status epilepticus, epilepsy, epileptic seizure, simple partial seizure, complex partial seizure, generalized epilepsy, generalized seizure (including, without limitation, tonic-clonic, tonic, clonic, myoclonic, absence (including typical absence and atypical absence), atonic seizure), focal epilepsy, focal seizure, focal/partial seizure (including, without limitation, Simple partial seizure and Complex partial seizure), focal aware seizure, focal impaired awareness seizure, generalised epilepsy, temporal lobe epilepsy (including, without restriction, mesial temporal lobe epilepsy {MTLE} and lateral temporal lobe epilepsy {LTLE}), Frontal lobe epilepsy, Rolandic epilepsy, Nocturnal epilepsy, Nocturnal frontal lobe epilepsy, Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Generalized epilepsy with febrile seizures plus (GEFS+), Panayiotopoulos syndrome, epileptic fit, reflex epilepsy, reflex seizure, absence seizure (including, without limitation, childhood absence epilepsy, epilepsy with myoclonic absences, juvenile absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome {eyelid myoclonia with absences}, genetic generalised epilepsy with phantom absences), complex partial seizure, atonic seizure, generalized tonic-clonic seizure, tonic¨clonic seizure, extrinsic stimulus epilepsy, intrinsic stimulus epilepsy, photosensitive epilepsy, musicogenic epilepsy, thinking epilepsy, eating epilepsy, seizure(s), Febrile seizure, nerve agent induced seizure, Dravet syndrome (sometimes modest hyperthermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals), acute symptomatic seizure, seizure-related disorder, drug related seizure, paroxysmal depolarizing shift, Ohtahara syndrome, Epilepsy in females with mental retardation, Rasmussen's encephalitis, Epilepsy syndrome, benign rolandic epilepsy, childhood absence epilepsy, absence epilepsy, juvenile myoclonic epilepsy, epileptic encephalopathies, Lennox¨Gastaut syndrome, West syndrome (Epileptic spasms), Doose syndrome (Myoclonic astatic epilepsy, MAE), Lennox-Gestaut syndrome, pseudo-Lennox Gastaut syndrome (atypical benign partial epilepsy), Benign familial neonatal epilepsy, Benign occipital epilepsy of childhood, familial neonatal convulsions, Febrile infection-related epilepsy syndrome, interictal dysphoric disorder, euphoria sclerotic, psychogenic non-epileptic seizure, non-epileptic seizure, gelastic seizure, convulsion(s), migraine, status migrainosus, tension headache, headache, Hypnic headache, hiccups, intractable hiccups, thumps in equines, Postural orthostatic tachycardia syndrome (POTS), Pheochromocytoma, agony, pain, chronic pain, acute pain, pain due to disease/injury, neuropathic pain, fibromyalgia, postherpetic neuralgia, phantom pain, referred pain, back pain, lower back pain, pelvic pain, cancer associated pain, chemotherapy associated pain, Diabetic neuropathy, small fiber peripheral neuropathy, Mononeuritis multiplex, Wartenberg's migratory sensory neuropathy, Breakthrough pain, idiopathic pain, polyneuropathy, Neuritis, Mononeuropathy, Polyradiculoneuropathy, Radial neuropathy, neuropathy, visceral pain, Burning feet syndrome, Tarsal tunnel syndrome, Carpal tunnel syndrome, Guyon's canal syndrome, Cubital Tunnel Syndrome, Repetitive strain injury, Sciatica, Neurofibromatosis, Ulnar nerve entrapment, Erythromelalgia, Paroxysmal extreme pain disorder, Proctalgia fugax, dysesthesia, scalp dysesthesia, dysesthetic burning, hyperesthesia, hyperalgesia, Opioid-induced hyperalgesia, hyperpathia, allodynia, pain response from stimuli which do not normally provoke pain, Complex regional pain syndrome (said to be most painful condition known to man), Radiculopathy, neuralgia (including, without restriction, intercostal neuralgia, trigeminal neuralgia, atypical trigeminal neuralgia, glossopharyngeal neuralgia, occipital neuralgia, postherpetic neuralgia), ciguatera poisoning, irritable bowel syndrome (IBS), interstitial cystitis (IC), temporomandibular joint disorder, acute intermittent porphyria, Porphyria, Acute porphyria (including, without limitation, acute intermittent porphyria {AIP}, variegate porphyria {VP}, aminolevulinic acid dehydratase deficiency porphyria {ALAI)}, hereditary coproporphyria {HCP}, drug induced), Chronic porphyria (including, without limitation, X-linked dominant protoporphyria {XLDPP}, congenital erythropoietic porphyria {CEP}, porphyria cutanea tarda {PCT}, and erythropoietic protoporphyria {EPP}), cutaneous porphyria, Porphyria cutanea tarda, allergy, allergic reaction, anaphylaxis, anaphylactic shock, hives, asthma, allergic rhinitis, rhinitis, urticaria, contact dermatitis, cough, sore throat, esophageal reflux disease, heartburn, chest pain, Esophageal motility disorder, Nutcracker esophagus, diseases involving gastrointestinal motility, Peptic ulcer disease, esophageal spasm, angina, itchiness, Pruritus, severe pruritus, Prurigo, Pruritic skin condition, chronic itch, eczema, pruritus in eczema, neuropathic itch, neurogenic itch, itchiness due to atopic dermatitis and/or lichen simplex chronicus, peripheral sensitization, central sensitization, sensory perception of absent stimuli, too much sensory stimulation, sensory stimulation brings discomfort, Neuromyotonia, Peripheral nerve hyperexcitability, Morvan's syndrome, Benign fasciculation syndrome, Cramp fasciculation syndrome, hyperhidrosis, undifferentiated somatoform disorder, somatoform disorder, somatic symptom disorder, conversion disorder, functional neurological symptom disorder, severe nausea and/or vomiting, severe nausea/emesis, Chemotherapy-induced peripheral neuropathy, chemotherapy-induced nausea and vomiting (CINV), radiation therapy-induced nausea and vomiting (RINV), postnarcotic nausea, hyperemesis gravidarum, morning sickness, Cyclic vomiting syndrome, retching/dry heaving, Urinary incontinence, enuresis, nocturnal enuresis, tail chasing, reduce urine spraying/marking behavior, benzodiazepine withdrawal syndrome, barbituate withdrawal syndrome, Neuroleptic discontinuation syndrome, drug withdrawal discomfort/pain/symptoms, drug use disorder, alcohol use disorder, opoid use disorder, amphetamine use disorder, cocaine use disorder, alcohol withdrawal syndrome/symptoms, delirium tremens, opoid withdrawal sydrome/symptoms, drug craving, drug addiction, drug dependence, polysubstance dependence, drug overdose, smoking, tobacco (nicotine) addition, tobacco (nicotine) withdrawal symptoms, alcoholism, addiction, opoid addiction, cocaine/crack addiction, addictive behaviour, addictive personality, behavioural addiction, internet/computer/computer game/social media/media addiction, exercise addiction, compulsive behaviour (e.g. {non-limiting}
checking, counting, washing, repeating), anti-social behaviour, criminality, sexual compulsion, impulsive sexual behaviour, compulsive buying, gambling addiction, sex related addiction, sexual urge, hunger, eating desire/compulsion, eating disorder, polyphagia, overeating, binge eating disorder, compulsive overeating, insatiable/excessive appetite, bulimia nervosa, anorexia nervosa, substance abuse, substance-induced delirium, substance-induced psychosis, substance-induced mood disorder, drug overdose, vertigo, motion sickness, seasickness, mental/nervous breakdown, Autism spectrum disorder, neurological disorder, cognitive disorder, mental disorder, mental health disorder, mental health condition involving impaired or altered neural plasticity, mood disorder, mental disorder disclosed in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or a later edition, a mental/behavioural disorder disclosed by the International Classification of Diseases (ICD) in ICD-10 Chapter V: Mental and behavioural disorders (World Health Organisation, WHO).
Because a compound(s) of this invention can cause sedation (when ambient<optimal body temperature {37 C}) and slow aging, this juxtaposition makes a compound(s) of this invention useful for inducing hibernation/artificial hibernation/torpor/synthetic torpor/suspended animation, optionally used on a long journey, optionally during spaceflight, optionally on a journey to Mars (projected duration with present technology is ¨18 months transit time for round trip). Moreover because the compound(s) reduces food, power (e.g.
reduced lighting/heating), living space and 02 requirements in a subject, this makes the spacecraft load lighter, and the induced lower respiration rate means slower/shallower breathing, less 02 in the body, which reduces the damaging effect of ionizing radiation (significant in space), moreover permitting a lower 02 concentration outside the body, which reduces ionizing radiation damage to the outside of the body, and the smaller living space afforded by the sedation permits greater radiation shielding per unit living space and the induced hypometabolism reduces the rate of muscle and bone atrophy (reduces spaceflight osteopenia) and other negative health effects (e.g. sleep disturbance) of microgravity, and the sedation side-steps the anticipated worrying problem of interpersonal friction(s) during long confined spaceflight (Cosmonaut Valery Ryumin's autobiography: "If you want to instigate the art of manslaughter just shut two men up in a eighteen by twenty-foot cabin for a month.
Human nature won't stand it."). Optionally the drug can be administered by continuous intravenous infusion, wherein optionally respiratory substrates, nutrients, fluids etc. can be administered similarly (e.g. using parenteral nutrition). If there is a job/emergency that needs to be attended to in the spacecraft (and/or the subject is to eat/wash/administrate themselves etc.) the hibernation is paused by raising the ambient temperature of the subject to 37 C.
Afterwards, assuming the subject still has sufficient compound(s) in their system, the hibernation can be induced again by lowering the ambient temperature. During spaceflight, the use of a compound(s) of this invention combats many of the problems identified for space exploration/travel by NASA Report No. IG-16-003 ("NASA's efforts to manage health and human performance risks for space exploration", October 29 2015, audit conducted by Office of Inspector General).
An aspect of this invention is to use a compound(s) of this invention to sedate a subject undergoing treatment, and/or a course of treatment, for a pathology/disease/disorder/dysfunction/unwanted characteristic(s) of the subject. For non-limiting example, for a subject undergoing drug (e.g. opoid) withdrawal, wherein a compound(s) of this invention is used to sedate the subject during their drug withdrawal phase so they don't suffer the, typically horrific (why many drug users can't get off drugs), withdrawal symptoms such as pain, nausea, craving etc., which are worst in the first few days of withdrawal, a common time of drug relapse.

Because a compound(s) of this invention can cause sedation (when ambient<optimal body temperature{37 C}), slow aging and exert anti-cancer activity, these attributes make a compound(s) of this invention useful for a subject undergoing anti-cancer treatment, optionally during a hospital stay, wherein more than the time the subject loses sedated is returned to them by a longer [life/health]span. When the cancer patient has a visitor the sedation can be paused by raising the ambient temperature to 37 C (e.g. by transferring the patient's bed trolly into a visitors area/room maintained at this temperature). If a light sedation (small body temperature drop, cancer patient remains conscious but calmer, cancer patient can go about their normal life) is instead chosen for a cancer subject, there is a useful juxtaposition in the compound(s) anti-cancer and anxiolytic and/or antidepressant effects, because many cancer patients are anxious/depressed, and there is benefit to the compound's analgesic and/or antiemetic effects also, if radio/chemo-therapy is used in co-therapy, because radio/chemo-therapy typically causes cancer patients pain and nausea/vomiting, often extreme. Optionally a compound(s) of this invention is taken before the subject wishes to sleep, for example at night, and so any perceptible sedation, should it occur with the dose taken at that ambient temperature, is then virtuous rather than limiting to normal life.
SURGERY
An embodiment of this invention is a method in which a subject takes or is administered and/or has a plasma blood level of an effective amount of a compound(s) of this invention, for example a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or another compound that selectively reduces FIR) ATP hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, and the subject is administered an analgesic(s) and/or an anti-nausea medication(s) and/or an anxiolytic and/or antidepressant and/or a local and/or a general anaesthetic (examples well known to those of the art), and/or optionally another drug commonly used in surgery, such as an anti-anxiety/sedative drug used before general anaesthesia or after surgery (examples are well known to those of the art), optionally to treat/ameliorate/prevent/combat cancer, optionally wherein the subject undergoes surgery to remove a tumour(s).
EMERGENCY CONTRACEPTIVES
Adult bodies don't contain embryonic stem (ES) cells. ES cells are in the inner cell mass of the blastocyst, which forms ¨5 days post-fertilization, and exist temporarily because they soon differentiate into other cell types, without ES cell characteristics. So, a compound(s) that specifically kills ES cells will have utility as an emergency contraceptive, taken after unprotected sex for example, with a later window of effectiveness than present emergency contraceptives. Furthermore, it will have utility as a contraceptive, which can be administered instead of, or in combination with, another contraceptive(s) such as the combined oral contraceptive pill, wherein this term and the range of compositions it can refer to are well known to those of the art.
Cancer cell metabolism is similar to that of ES cells. Both can proliferate rapidly, forever (without limit, immortal). They share gene expression fingerprints [54]. ES
cells also have a hyperpolarised Tim [55], employ aerobic glycolysis some or all of the time [56] and tend to respond to ROS damage by apoptosis rather than repair [57].
Fi Fo ATP hydrolysis inhibitors have anti-cancer activity, as disclosed by this invention, and, also by this invention, anti-ES cell activity. An embodiment of this invention is a compound(s) that inhibits FiFo ATP hydrolysis, for example a compound(s) of Formula (I-V, VII), administered or self-administered to a subject, for use in preventing/ending their pregnancy/conception, optionally co-administered (optionally in a pharmaceutical composition) with another compound(s) or combination of compounds with this use, many of which are known to those of the art .e.g. progestin, antiprogestin, estrogen etc. This use could be after unprotected sex for example. In another embodiment, this use is restricted to the time during which ES cells exist in embryogenesis, which is early.
An embodiment of this invention is an FIR ATP hydrolysis inhibitor(s) in use as an anti-cancer medicine, or some other therapeutic use in a subject, wherein the compound(s) is distributed, sold and/or administered with a verbal and/or written warning, optionally in a paper insert in a packet containing the compound(s), that it should not be administered to a woman in the early days and/or weeks of pregnancy and/or in a woman trying to get pregnant.
COMPOUNDS OF THIS INVENTION ARE ANTI-INFLAMMATORIES
An embodiment of this invention is a method of using a therapeutically effective amount of at least one compound of this disclosure, which inhibits FIFO ATP hydrolysis, as an immunosuppressant and/or anti-inflammatory therapeutic. This therapeutic opportunity exists because if TN collapses in a cell, apoptosis ensues [59], and activated macrophages, unlike resting macrophages, singly use and thence completely rely upon ATP synthase in its reverse mode, hydrolysing ATP, to maintain Tim [154]. This is because activated macrophages produce nitric oxide (NO), which switches down/off their OXPHOS (NO increases the Km of Complex IV for 02). Compounds of the present invention inhibit FiFo ATP
hydrolysis and selectively collapse TIM in activated macrophages, selectively killing them (optionally administered in co-therapy with an uncoupler(s), to erode Tim as the FiFo ATP
hydrolysis inhibitor(s) blocks the only means activated macrophages can counter this erosion; thence Tim collapses at lower dose of FIFO ATP hydrolysis inhibitor). Thus a therapeutically effective amount of at least one compound of this invention, an FIFO ATP
hydrolysis inhibitor, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof (optionally in co-therapy with an uncoupler(s), optionally administered in the same pharmaceutical composition and/or administered/packaged/sold together; in some embodiments the therapeutic utility of the FIN ATP hydrolysis inhibitor(s) synergizes with [potentiates] that of the uncoupler(s); optionally the same compound is both an FIR ATP hydrolysis and uncoupler e.g. BMS-199264), attenuate the activated macrophage (or similar cell type) component to inflammation, and its pathologies, and treats/ameliorates/prevents/combats any disease or disorder associated with the undesirable activation and/or activity and/or number of macrophages/pancreatic islet macrophages/Langerhans cells/dendritic cells/monocytes/histiocytes/Hofbauer cells/Kupffer cells/phagocytes/microglia/epithelioid cells/osteoclasts/macrophage like cells/cells of the mononuclear phagocyte system, and/or any cell type(s) of the innate immune system and/or of the monocyte lineage, especially inducible nitric oxide synthase (iNOS) and/or iN0S2 expressing and/or NO
producing cells (e.g. monocyte-derived inflammatory dendritic cells), and/or immune or inflammation diseases/disorders/pathologies including, but not limited to, acute inflammation, chronic inflammation, systemic inflammation, inflammation because of infection or foreign bodies or injury or chemical or toxin or drug or stress or frostbite or burn or ionising radiation, inflammatory/neuroinflammatory diseases/disorders/syndromes, Macrophage Activation Syndrome (MAS), autoinflammatory diseases/disorders/syndromes, age-related chronic inflammatory diseases ("inflammaging"), autoimmune diseases/disorders/syndromes, diseases/disorders of the innate immune system, sore throat, sore throat associated with cold or flu or fever, high-intensity exercise associated inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, osteoarthritis, inflammatory osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation associated depression, neuroinflammation, neuropathic pain, exercise-induced acute inflammation, atherosclerosis, allergy, hay fever, anaphylaxis, inflammatory myopathies, drug-induced inflammation, systemic inflammatory response syndrome, sepsis-related multiple organ dysfunction/multiple organ failure, microbial infection, acute brain/lung/hepatic/renal injuries, lung inflammation, acute lung injury (ARDS), acne vulgaris, celiac disease, celiac sprue, chronic prostatitis, colitis, autoimmune hemolytic anemia, diverticulitis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Mast Cell Activation Syndrome, mastocytosis, otitis, pelvic inflammatory disease (PID), endometritis, reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasitosis, eosinophilia, type III
hypersensitivity, ischaemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, alcoholic hepatitis, chronic viral hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematous (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative disease, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, bronchiectasis, bronchopneumonia, obliterative bronchiolitis, appendicitis, acute appendicitis, bursitis, cystitis, dermatitis, encephalitis, HIV encephalitis, gingivitis, meningitis, infective meningitis, myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis¨associated interstitial lung disease and desquamative interstitial pneumonia, pneumonia, interstitial lung disease, Ltifgren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, steatohepatitis, nonalcoholic steatohepatitis, silicosis, histiocytoses, Langerhans' cell histiocytosis, haemophagocytic lymphohistiocytosis, pulmonary langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudogout, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft versus host disease (GVHD), lymphadenopathy, rheumatoid arthritis (RA), osteoarthritis (OA), inflammatory osteoarthritis, lupus, multiple sclerosis (MS), myocarditis, uveitis, CNS disease(s), inflammation aspect to a CNS disease(s), hypothalamic inflammation, dementia, glaucoma, amyloid related/driven disease, lipid storage disease(s), fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, cirrhosis of the liver, alcoholic cirrhosis, nephropath(y/ies), lupus nephritis, immune nephritis, fibrotic disorder(s), cardiovascular disease, heart disease, atherosclerosis, vulnerable plaque, plaque formation, lipid containing macrophage related disease(s)/disorder(s)/malad(y/ies), macrophage foam cells, diabetes, type 1 diabetes, type 2 diabetes, insulin resistance, macrophage aspect to insulin resistance, obesity, obesity associated inflammation, macrophage accumulation/large numbers of macrophages in adipose tissue (e.g. associated with obesity), granuloma(s), granulomatous diseases, sarcoidosis (including, without limitation, Annular sarcoidosis, Erythrodermic sarcoidosis, Ichthyosiform sarcoidosis, Hypopigmented sarcoidosis, Lofgren syndrome, Lupus pernio, Morpheaform sarcoidosis, Mucosal sarcoidosis, Neurosarcoidosis, Papular sarcoid, Scar sarcoid, Subcutaneous sarcoidosis, Systemic sarcoidosis, Ulcerative sarcoidos), neurosarcoidosis, pulmonary sarcoidosis, interstitial lung disease, pulmonary fibrosis, pulmonary tuberculosis, immune reconstitution syndrome of HIV, Jarisch¨Herxheimer reaction, sepsis, Paget's disease of bone, osteolysis, monocytosis, histiocytosis, X-type histiocytoses, non-X histiocytoses, Langerhans cell histiocytosis, non-Langerhans-cell histiocytosis, malignant histiocytosis, malignant histiocytic disorders, histiocytomas, histiocytic lymphoma, hemophagocytic syndrome, hemophagocytic lymphohistiocytosis, lymphohistiocytosis, diffuse histiocytic sarcoma, Rosai¨Dorfman disease, gliosis, Bergmann gliosis, Chronic Obstructive Pulmonary Disease (COPD), chronic inflammatory lung disease.
In clinical utility, the anti-inflammatory activity of compounds of this invention juxtaposes well with their aforementioned ability to reduce body temperature.
.. The anti-inflammatory action by a compound(s) of this invention has an anti-cancer action.
Because it reduces the number of Tumour Associated Macrophages (TAMs) [155].
These can constitute a large component of tumour mass and their presence is often associated with poor patient prognosis because they can drive cancer pathology. Indeed, inflammation is now considered one of the hallmarks of cancer [156]. The anti-inflammatory action, and thence .. anti-cancer action, of these compounds synergises with their direct anti-cancer activities disclosed herein.
Macrophages can be subverted by pathogens, which hide inside them in safety from the immune system. Examples, without limitation, of such pathogens are HIV (causes HIV/AIDS; HIV virus can lay latent in macrophages during antiretroviral therapy, wherein HIV virus becomes undetectable in blood, and then repopulate the virus in blood when antiretroviral therapy is interrupted or discontinued; HIV can replicate in macrophages [157-1581), Simian Immunodeficiency Virus (Sly), Mycobacterium tuberculosis (causes tuberculosis), Leishmania parasite (causes Leishmaniasis), Chikungunya virus (causes Chikungunya), Legionella pneumophila (causes Legionnaires' disease), adenoviruses (e.g. the adenovirus that causes pink eye), T. whipplei (causes Whipple's Disease), Brucella spp.
(causes brucellosis), Staphylococcus aureus, Ebola virus, Hepatitis B virus (HBV), Hepatitis C virus (HCV), influenza virus strains, dengue virus and antibiotic resistant bacteria. So, by exerting anti-macrophage activity, a compound(s) of this invention, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, can treat/ameliorate/prevent/combat such disorders and diseases. This is especially useful for AIDS, wherein HIV
resides in macrophages, propagating the immunocompromised character of the disease, making it more likely for intracellular opportunistic pathogens (e.g. Mycobacterium tuberculosis) to reside in macrophages also. Because the compounds of this invention are selective for activated macrophages, an option is to activate macrophages before the compound(s) administration, by administering to the patient an effective amount of a compound(s), protein(s), antibody(y/ies) or some other entit(y/ies), e.g. pathogen, attenuated pathogen or pathogen component that activates macrophages. Some examples (non-limiting) of factors that can activate macrophages are cytokines such as interferon-gamma (IFN-y) and/or tumour necrosis factor (TNF, TNF-a), and/or IL-4, and/or IL-13, and/or IL-10, and/or IL-2, and/or IL-12, and/or IL-6, and/or IL-18 and/or chemokines (CCL3, CCL4, CCL5) and/or a bacterial endotoxin such as lipopolysaccharide (LPS), or a commercially available agent for macrophage activation in biological research (e.g. CAS 61512-20-7) or an antibody targeting a receptor on the macrophage cell surface or on the surface of a different cell type, which then activates a macrophage by mechanism. Macrophage activating antibodies are well known to those of the art.
An embodiment of this invention is the use of an effective amount of at least one compound of this invention, which inhibits FIN ATP hydrolysis, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, to treat/ameliorate/prevent/combat HIV
infection/transmission/drug resistance, optionally with an effective amount of a compound(s), protein(s), antibody(s), pathogen(s) or pathogen component(s) that activates macrophages (isn't absolutely necessary because HIV activates macrophages [159-160], which drives the chronic inflammation pathology component to HIV infection; HIV stimulates nitric oxide production by human macrophages [161, 162, 163, 164]), optionally with a compound(s), protein(s), antibody(s), pathogen(s) or pathogen component(s) that polarises macrophages towards Ml type (examples, without restriction, include Granulocyte-macrophage colony-stimulating factor [GM-CSF] and/or a pharmaceutical version/analog(s)/biosimilar of GM-CSF such as, without limitation, one or more of sargramostim, molgramostim, regramostim, filgrastim, pegfilgrastim), optionally in co-therapy with, or after, Anti-Retroviral Therapy (ART), combination Anti-Retroviral Therapy (cART, Highly Active Anti Retroviral Therapy, HAART), optionally in co-therapy with L-arginine (substrate for inducible Nitric Oxide Synthase, iNOS, optionally wherein food(s) rich in this amino acid are eaten), optionally for pre- and/or post-exposure prophylaxis (PEP) e.g. after needlestick injury and/or sex with an HIV infected person(s), e.g. to reduce the probability of mother to baby HIV
transmission during pregnancy/birth/breast feeding e.g. given to a subject without HIV to decrease the risk they will acquire HIV, optionally wherein this subject is at sizeable risk of acquiring HIV, wherein this pre-exposure prophylaxis can reduce the spread of HIV within a population (for example in sub-Saharan Africa). Even after prolonged cART, which drives plasma HIV down to undetectable levels, HIV-1 DNA and RNA is detectable in macrophages: they are an HIV reservoir that remains extant, even during cART, and that the virus can spread from during any interruption or termination of cART [158].
Moreover, HIV
virus recombines and mutates in macrophages [165], which is a drive to HIV
drug resistance.
Thence the vital importance of the methods and compounds herein. By denying HIV a reservoir in which to hide (and mutate, developing drug resistance) from ART/cART/HAART therapy, a compound(s) of this invention, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, decreases the amount of HIV virus in the body, increasing the chance of HIV viral elimination from the subject, decreasing the risk the subject can transmit the HIV virus to another subject, decreasing HIV
associated symptoms/pathology, decreasing the chance of HIV developing drug resistance to one or more drugs used in ART/cART/HAART therapy, improving clinical outcome.
Notably, a compound(s) of this invention, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, treats/ameliorates/prevents/combats HIV-associated chronic inflammation and/or HIV peripheral neuropathy, wherein the latter is caused by infiltration of HIV infected monocytes/macrophages to the dorsal root ganglia (DRG) causing neuronal loss and formation of Nageotte nodules.
Macrophages mediate HIV virus neuroinvasion (and neuroinvasion by other viruses/pathogens also e.g. SARS coronavirus, Heptatitis C virus) and HIV
containing macrophages and/or microglia cause nervous system and brain patholog(y/ies) and a compound(s) of this invention, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, opposes this and treats/ameliorates/prevents/combats HIV-associated neurocognitive disorders (HAND) such as HIV-associated dementia complex (HAD) (and neurocognitive and neurodegenerative diseases/disorders caused by other viruses/bacteria/fungi/parasites/protozoa/pathgens/prions also e.g. [non-limiting] SARS
coronavirus, cytomegalovirus, herpes simplex encephalitis caused by Herpes Simplex Virus (HSV) in microglia, toxoplasmic encephalitis, Japanese encephalitis, California encephalitis, tick-borne encephalitis, viral encephalitis {non-limiting e.g. caused by one or more of rabies virus, poliovirus, measles virus, Herpesvirus 6, varicella zoster virus, Epstein-Barr, cytomegalovirus, coxsackievirus, West Nile virus}, viral or bacterial meningitis, meningoencephalitis, encephalomyelitis, refer [166] for further example CNS
pathologies, without limitation, treated/ameliorated/prevented/combated by a compound(s), or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, of this invention). The anti-HIV and anti-cancer activity of a compound(s) of this invention synergise to treat/ameliorate/prevent/combat HIV associated cancers: AIDS-defining cancers (Kaposi sarcoma, aggressive B-cell non-Hodgkin lymphoma, cervical cancer) and/or non-AIDS
defining cancers. This disclosure encompasses a compound(s) of this invention, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, in co-therapy/synergy with any Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) approved drug(s) or treatment(s) for HIV/AIDS or other/additional viral infection(s).
Examples include, but aren't limited to, abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, disoproxil fumarate (tenofovir DF, TDF), zidovudine (azidothymidine, AZT, ZDV), atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, enfuvirtide, maraviroc, dolutegravir, elvitegravir, raltegravir, cobicistat, acyclovir, vidarabine. Optionally, additionally, in co-therapy/synergy with any Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) approved drug(s) or treatment(s) for cancer.
In some invention embodiments a compound(s) of this invention, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, is used to treat/ameliorate/prevent/combat antibiotic resistant bacteria, optionally intracellular bacteria, optionally bacteria harbouring inside macrophages and/or microglia, optionally wherein this intracellular bacterial reservoir is contributory to antibiotic resistance. This disclosure encompasses a compound(s) of this invention in co-therapy/synergy with any Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) approved antibiotic(s)/antimicrobial(s).
Examples include, but aren't limited to, the following antibiotic classes with an illustrative non-limiting example(s) of each class given in subsequent brackets: Aminoglycosides (Gentamicin), Ansamycins (Rifampin), Carbapenems and other penems (Meropenem), Cephalosporins (Ceftriaxone), Phosphonic acid derivatives (Fosfomycin), Glycopeptides (Vancomycin), Glycylcyclines (Tigecycline), Lipopeptides (Daptomycin), Macrolides and ketolides (Erythromycin, telithromycin), Monobactams (Aztreonam), Oxazolidinones (Linezolid), Penicillins (Ampicillin, Oxacillin, Amoxicillin), Polymyxins (Colistin), Quinolones and Fluoroquinolones (Ciprofloxacin), drugs used solely to treat tuberculosis or other mycobacterial diseases (Isoniazid), Amidinopenicillins (Mecillinam), Amphenicols (Chloramphenicol), Cephalosporins and cephamycins (Cefazolin), Lincosamides (Clindamycin), Pleuromutilins (Retapamulin), Pseudomonic acids (Mupirocin), Riminofenazines (Clofazimine), Steroid antibacterials (Fusidic acid), Streptogramins (Quinupristin, dalfopristin), Sulfonamides, dihydrofolate reductase inhibitors, and combinations (Sulfamethoxazole, trimethoprim), Tetracyclines (Chlortetracycline), Aminocyclitols (Spectinomycin), cyclic polypeptides (Bacitracin), Nitroftirantoins (Nitrofurantoin), Nitroimidazoles (Metronidazole).
Macrophages can mediate mother-to-[fetus/baby] viral/pathogen transmission (vertically transmitted infection), for (non-limiting) example, zika virus transfers from mother to fetus by infecting placental macrophages (Hofbauer cells), HIV-1 virus transfers from mother to baby in macrophages in breast milk, and a compound(s) of this invention, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, opposes this and treats/ameliorates/prevents/combats this mother-to-[fetus/baby] viral/pathogen transmission.
Pathogens can drive macrophages/microglia to drive pathology e.g.
Streptococcus pneumonia, the most common cause of bacterial meningitis, can cause an inflammatory response, triggered by microglia, which can cause intracerebral edema, e.g.
Plasmodium falciparum, a parasite that causes malaria in humans, can cause cerebral malaria wherein microglia have been implicated in this serious malarial complication. A
compound(s) of this invention or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof will treat/ameliorate/prevent/combat a pathogen(s) that drives macrophages/microglia and/or another cell of the mononuclear phagocyte system to drive pathology.
Monocytes can be subverted by pathogens, which hide inside them in safety from the immune system, wherein this subversion can, in some cases, involve increased iNOS

expression and increased Nitric Oxide (NO) production in the monocyte.
Examples, without limitation, of such pathogens include Human Cytomegalovirus (HCMV). So, by exerting anti-monocyte activity, especially to those with high intracellular [NO], a compound(s) of this invention, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, can treat/ameliorate/prevent/combat such pathogens and their associated disorders and diseases.
Non-limiting examples of autoinflammatory diseases/disorders/syndromes that the compounds of this invention treat/ameliorate/prevent/combat include, but aren't limited to, recurrent fever syndromes, which can be hereditary or acquired, characterized by recurrent fever associated with rash, serositis, lymphadenopathy and musculoskeletal involvement.
Examples include familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulinemia D with recurrent fever syndrome (HIDS), cryopyrin associated periodic syndrome (CAPS), Blau syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), mevalonate kinase deficiency, pyogenic-arthritis-pyoderma gangrenosum and acne syndrome (PAPA), periodic fever aphthous stomatitis pharyngitis adenitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, Schnitzler's syndrome, Sweet's syndrome, NLRP12-associated autoinflammatory disorders, deficiency of interleukin-1 receptor antagonist (DIRA), pyoderma gangrenosum, cystic acne, aseptic arthritis, periodic Fever Associated with mevalonate kinase deficiency (hyperimmunoglobulin D Syndrome), Pyogenic Arthritis Pyoderma Gangrenosum Acne (PAPA) syndrome, Periodic Fever Aphthous Stomatitis, Pharyngitis and Adenopathy (PFAPA) syndrome, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Chronic Recurrent Multifocal Osteomyelitis (CRMO), Synovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome, Cryopyrin associated Periodic Syndrome (CAPS), Familial cold auto inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Familial cold urticarial, Neonatal onset multisystemic inflammatory disorder (NOMID), hereditary Periodic Fever Syndromes, Periodic Fever Syndromes, systemic autoinflammatory diseases.
Non-limiting examples of autoimmune diseases/disorders/syndromes that the compounds of this invention treat/ameliorate/prevent/combat include, but aren't limited to, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalitis, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), BalO disease, Behcet's disease, benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Berger's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immune hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type I
diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR) PANDAS, .. Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, peripheral neuropathy, perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TIP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)), idiopathic thrombocytopenia purpura, splenomegaly.
EXPERIMENTALLY DEMONSTRATING COMPOUND UTILITY AGAINST
ACTIVATED (more than non-activated, resting) MACROPHAGES
This protocol is adapted from that used in [154]. It is illustrative and not limiting. Alternative protocols, and modification(s) to this protocol, will be clear to those of the art, based on the common general knowledge, the literature, and/or the content of prior art disclosures cited herein. Cells of the murine macrophage cell line J774.A1(ATCC TIB67) are adherent. Very.
Physical (e.g. scraping/lifting) and/or chemical techniques (e.g. one or more of EDTA, EDTA
in PBS solution, trypsin, TrypLE, HyQTase, Detachin, Accutase, Versene solution, nonenzymatic cell dissociation solution from Sigma-Aldrich, Cellstripper nonenzymatic cell dissociation solution or {Dulbecco's phosphate-buffered saline [DPBS] with no calcium and no magnesium solution}) can separate them from an adhered surface but this manipulation(s) risks damaging/modifying the macrophages. Adherence is lessened by culturing macrophages in a container with a Teflon coated surface (e.g. Teflon coated (polytetrafluoroethylene) flasks or gas permeable bags that are coated with Teflon or Teflon like material made by companies such as Milteny, OriGen, Gibco, CellGenix [FEP Teflon-coated cell culture bag], Afc and others) or (less preferably) in bacterial plastic petri dishes (i.e.
non cell culture coated) or polypropylene plasticware. In the preferred protocol, adherence issues are circumnavigated because J774.A1 macrophages are grown in suspension in stirrer bottles (Techne, Burlington, NJ, USA; stirring lifts the cells into suspension, low speed [12-25 rpm]
to minimize cell shearing, soft-start/stop feature provides slow acceleration and deceleration of the stirrer, low heat production, its glass is siliconized to reduce cells adhering to it) containing cell culture medium (Dulbecco's modified Eagle's medium, DMEM) supplemented with 10% Fetal Calf Serum (FCS), 4.5 g/1D-glucose, 2 mM L-glutamine (4 mM final), 25 mM HEPES, penicillin (100 units/ml) and streptomycin (100 g/ml) {optionally L-arginine is also added, e.g. at 400 M in final medium, wherein this is a substrate that iNOS uses to produce nitric oxide [NO]}. Incubated at 37 C in a humidified atmosphere containing 5% CO2. Cell density is kept <1*106 cells/ml, which maintains cell viability at >98%. Four samples are taken from this suspension culture and each re-suspended in a separate stirrer bottle in fresh medium at a density of 0.2*106 = 200,000 cells/ml. Two of these samples additionally contain 10 U/ml murine IFN-y (e.g. sourced from Insight Biotech, .. Wembley, UK) and 10 ng/ml LPS (LPS from Salmonella typhosa 0901 e.g.
sourced from Difco, Surrey, UK), which activates J774.A1 macrophages. So, there are two samples in which the macrophages are not activated, and two samples in which the macrophages are activated. Test drug is added to a non-activated and an activated sample, wherein drug concentration in medium is 10 iM (optionally different, to illustrate, 1 or 100 M), drug vehicle is added to the two other samples. The test drug is a compound of this invention, an FIR ATP hydrolysis inhibitor, which preferentially inhibits FIFO ATP
hydrolysis over FiFo ATP synthesis, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally Compound 7b of this disclosure. Vehicle is DMSO or [12.5% solutol, 12.5% ethanol, 75%
water], or [25% solutol and 75% water], or some other vehicle selected by one of the art.
So there are four different samples, numbered as: (1) non-activated+vehicle, (2) non-activated+drug, (3) activated+vehicle, (4) activated+drug. At 3 hour time points, for 12 to 24 hours, aliquots (e.g.
of 15 ml each) are taken from each of the four samples and cell viability in each aliquot is recorded using the Trypan blue exclusion method. A further embodiment is to record for a longer period, wherein if longer than 24 hours, optionally the medium is half-changed for all samples (optionally wherein drug/vehicle is at same concentration in replacing medium than medium replaced) every 24 hours to avoid nutrient depletion and medium acidification, which can happen with activated macrophages especially because they have a high glycolytic metabolism. Optionally the study is run with replicates of each sample and/or the study is run more than once and/or the study is run again with different drug concentration(s) and/or the study is run with RAW 264.7 mouse macrophages (ATCC TIB-71; also an adherent cell line) instead of J774.Al.
During the course of the study, the macrophage number in Sample 1 increases.
The gradient of increase is less, or negative, for Sample 2 because compounds of this invention are anti-cancer therapeutics and J774.A1 is a cancer cell line. Upon activation, J774.A1 macrophages stop proliferating and so the macrophage number of Sample 3 is constant or slightly decreases during the study. Upon activation, J774.A1 macrophages produce substantial amounts of nitric oxide (NO), which reduces their OXPHOS use, and so they disproportionally rely upon F1F0 ATP hydrolysis to maintain Tim, wherein a compound of this invention selectively inhibits FIR, ATP hydrolysis, Tim collapses, apoptosis follows.
Sample 4 will have a much lower number of macrophages than the other samples.
Although the Sample 4 number is greater if S-ethyl isothiourea (SEITU, 500 NI in medium, available from Sigma-Aldrich) is administered coincident with macrophage activation, because SEITU
inhibits inducible NO synthase (iNOS). Sample 4 having a lower macrophage number than Sample 3 shows that a compound of this invention, optionally 7b, can reduce the number of activated macrophages. Sample 4 having a lower macrophage number than Sample 2 shows that a compound of this invention, optionally 7b, disproportionally affects activated rather than resting macrophages. The amplitude of this differential, between Sample 2 and Sample 4, isn't as large as it could be because J774.AI is a cancer cell line and a compound of this invention, e.g. 7b, also exerts anti-cancer activity. A bigger differential between Sample 2 and Sample 4 can be observed if primary macrophages (M1 type, iNOS expressing, nitric oxide (NO) producing) are used in this study instead of a cancer cell line.
The following protocol is adapted from that used in [167], with background detail added from [168].
Peritoneal macrophages are isolated from 8 week old pathogen free CD-1 mice.
An eliciting agent, such as 1.5 ml of sterile thioglycolate broth (Difco Laboratories) intraperitoneal injected 4 days before macrophage sourcing, which increases monocyte migration into the peritoneum, therefore increasing macrophage yield, is NOT used, because this can activate the macrophages, causing them to produce nitric oxide [167], whereas resting/unactivated macrophages are desired. So, resident rather than elicited macrophages are sourced from mice peritoneum, wherein the yield is around ¨0.5-1*106 macrophages per mouse (-1-2*106 total peritoneal exudate cells, ¨40% are macrophages). With these sourced cells, the macrophages are separated from other cell types by flow cytometry coupled with cell sorting or purification .. using magnetic beads and then cultured at a seeding density of 300,000 cells/ml, at 37 C in a humidified atmosphere containing 5% CO2, cultured in DMEM (Sigma¨Aldrich) supplemented with 10% (v/v) fetal bovine serum, 100 U/ml penicillin, 100 g/ml streptomycin and 250 ng/ml amphotericin B. Wherein these macrophages can be activated by 100 ng/ml LPS (from Escherichia coli strain 111:B4) and IFN-y (100 U/ml).
These primary macrophages can be used in place of J774.A1 cells in the aforementioned protocol. [168]
describes alternative methods to source primary macrophages from mice, wherein a preferred method is to use a method it describes but with GM-CSF instead of the M-CSF
that it specifies. Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes whereas supplementation with Macrophage colony-stimulating factor (M-CSF) promotes M2 macrophages [169]. Although activating with LPS and IFN-y favours M1 polarization of primary macrophages anyhow. It is important that the primary macrophages used produce nitric oxide (NO) when activated, wherein NO production can optionally be checked for, in a pre-experiment and/or during the test drug application and control experiments, using a method of the art e.g. using Griess reagent (1:1 v:v with culture medium, Sigma-Aldrich) and the Griess reaction wherein absorbance at 540 or 570 nm is assayed, e.g. using an ELISA
reader (Bio-Tek Instruments, Burlington, VT; standard curves of various fixed concentrations of sodium nitrite (Sigma-Aldrich) are used to calibrate a given absorbance to a given nitrite concentration) after 20 minutes of reaction time. Or, alternatively, or in addition, an NO
nanosensor (amiN0-600, Innovative Instruments, FL) can be used. Or, or in addition, Electron Paramagnetic Resonance Detection of Free NO by spin-trap method can be used [170]. An easier option is to source cryopreserved primary mouse macrophages (e.g. from C57BL/6 mice) for this experiment commercially, for (non-limiting) example from Astarte Biologics LLC (Bothell, WA, USA) or Nanobiotech (Whippany, NJ, USA).
A lesser preferred study option is to, instead of culturing the (mouse primary or mouse cancer cell line {e.g. J774.A1}) macrophages in suspension using stirrer bottles (Techne, Burlington, NJ, USA; can be expensive) as has been described, permit the macrophages to adhere to a surface, wherein their cell viability is assayed using the RealTime Glo MT
Cell Viability .. Assay (Promega, Madison, WI), which can assay the viability of adhered cells and so doesn't require prior scraping/lifting etc. that itself can negatively modulate macrophage cell number, wherein this assay reports ATP content, wherein macrophage activation itself decreases intracellular [ATP] [154], and so this must be factored into interpretation (ATP content doesn't just scale with cell viability, but can correlate with cellular processes also, and so this .. [ATP] assay isn't a direct read out of cell number, which often isn't appreciated by those of the art, however, in this case this feature of the assay doesn't change the study conclusion:
activation of macrophages decreases their ATP content without test drug applied, with test drug of this invention applied, e.g. compound 7b, the ATP content decreases even more after activation because the test drug drives activated macrophages to death, reducing the macrophage number). In this alternative study plan, commercially sourced cryopreserved bone-marrow macrophages from C57BL/6 mice are thawed, counted and plated in a 96 well flat bottom plate at 2*104 cells/well (well volume is 0.2 ml, thus macrophage density =
0.1*106 = 100,000 cells/m1) in Iscove's Modified Dulbecco's Medium (IMDM) + 2 mM
Glutamaxlm (a dipeptide: L-alanine-L-glutamine) + 10% Fetal Calf Serum (FCS) +
20 ng/ml M-CSF (or more preferably GM-CSF). The plate is transferred to a 37 C, 5% CO2 incubator for 18-24 hours. In a pre-experiment, optionally using a commercially sourced nitric oxide assay kit, it is assessed whether the sourced macrophages produce nitric oxide when activated (by LPS {100 ng/m11 and IFN-y {100 U/ml} added) in this experimental set up, wherein it is necessary that they do, and if not the source of macrophages is changed and/or the activation protocol is changed. Furthermore, it is also assessed whether the sourced macrophages produce nitric oxide when NON-activated (resting), wherein it is necessary that they do not, at least not to any major degree. There should be an observed NO production differential between the resting and activated macrophages, wherein activated should produce much more NO than resting macrophages. In the actual experiment, test drug (10 M;
experiment is run other times with 1 or 100 M, or other concentration(s)) and/or [LPS {100 ng/m11 and IFN-y {100 U/m1}} is added after the 18-24 incubation period, as shown in the table below:
LPS IFN-y Test drug 1 Non-activated+vehicle No No No 2 Non-activated+Test drug No No Yes 3 Activated+vehicle Yes Yes No 4 Activated+Test drug Yes Yes Yes After macrophage activation and/or test drug addition, macrophage cell viability (approximated by reading out [ATP]) is recorded by RealTime Glo MT Cell Viability Assay (Promega, Madison, WI) at 0, 3, 6, 9 and 24 hours. Optionally there are two more test groups, wherein SEITU drug (500 NI in medium in well), which inhibits iNOS, is added:
LPS IFN-y Test drug SEITU
5 Activated+vehicle+SEITU Yes Yes No Yes 6 Activated+vehicle+SEITU+Test drug Yes Yes Yes Yes .. EXPERIMENTALLY DEMONSTRATING COMPOUND UTILITY AGAINST HIV
INFECTED MONOCYTES/MACROPHAGES
This protocol is adapted from that used in [170]. It is illustrative and not limiting. Alternative protocols, and modification(s) to this protocol, will be clear to those of the art, based on the common general knowledge, the literature, and/or the content of prior art disclosures cited herein. Human monocytes are recovered from peripheral blood mononuclear cells (PBMCs) of an HIV- and hepatitis B- seronegative human donor after leukapheresis and purified by countercurrent centrifugal elutriation. Cell suspensions are >98% monocytes by the criteria of cell morphology on Wright-stained cytosmears, by granular peroxidase, and by nonspecific esterase. Monocytes are cultured, at 37 C in a humidified atmosphere containing 5% CO2, in Teflon coated (polytetrafluoroethylene) flasks {or gas permeable bags that are coated with Teflon or Teflon like material made by companies: Milteny, OriGen, Gibco, CellGenix [FEP
Teflon-coated cell culture bag], Afc and others} (at 2*106 cells/ml) in DMEM
(Sigma Chemical Co., St. Louis, MO) supplemented with 10% pooled human sera, 50 g/ml gentamicin, and 1,000 U/ml highly purified (<0.01 ng/ml endotoxin) recombinant human M-CSF {or alternatively GM-CSF} (Genetics Institute, Cambridge, MA) for 7 days before HIV
virus infection. HIV Infection of Monocytes: the monocyte culture is exposed to 2*105 TCID5o/m1 of a monocytotropic viral strain, HIV-1A, wherein all viral stocks are tested prior and found free of mycoplasma contamination (Gen-probe II; Gen-probe Inc., San Diego, CA). Culture medium is half-exchanged every 2 days. On the 6th day (optionally earlier or later, optionally after significant Reverse Transcriptase activity is recorded in the medium, assayed as described in [170] and references, particularly its reference 6), four samples are taken from this suspension culture and each re-suspended in a separate Teflon (or Teflon like) coated flask/bag in fresh medium at a density of 0.2*106 cells/ml. Two of these samples are administered with LPS (10 ng/ml) and TNF-a (1000 U/ml). Test drug is added to a sample with and without [LPS and TNF-a], wherein drug concentration in medium is 10 M (optionally different, to illustrate, 1 or 100 M), drug vehicle is added to the two other samples. The test drug is a compound of this invention, an FIFO ATP hydrolysis inhibitor, which preferentially inhibits FIFO ATP hydrolysis over Fi Fo ATP synthesis, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally Compound 7b of this disclosure. Vehicle is DMSO or 12.5% solutol, 12.5% ethanol, 75% water, or 25% solutol and 75% water, or some other vehicle selected by one of the art. So there are four different samples, numbered as: (1) vehicle, (2) drug, (3) [LPS and TNF-a]+vehicle, (4) [LPS and INF-a]+drug. At 3 hour time points, for 12 to 24 hours, aliquots (e.g. of 15 ml each) are taken from each of the four samples and cell viability in each aliquot is recorded using the Trypan blue exclusion method.
A further embodiment is to record for a longer period, wherein if longer than 24 hours, optionally the medium is half-changed for all samples (optionally wherein drug/vehicle is at same concentration in replacing medium than medium replaced) every 24 hours to avoid nutrient depletion and medium acidification. Optionally the study is run with replicates of each sample and/or the study is run more than once and/or the study is run again with different drug concentration(s). Importantly the study is repeated with a different monocyte donor used, wherein the study is repeated 20 times with 20 different human donors.

The monocyte number is less in Sample 2 than in Sample 1, showing that a compound of this invention kills HIV infected monocytes. HIV infected monocytes, in distinction to uninfected monocytes, produce nitric oxide, which reduces their OXPHOS use, and so they disproportionally rely upon Fi Fo ATP hydrolysis to maintain Tim, wherein a compound of this invention selectively inhibits FIFO ATP hydrolysis, Tim collapses, apoptosis follows. The monocyte number is even less in Sample 4 than Sample 2, showing that [LPS and 1NF-a]
assist the killing of HIV infected monocytes by a compound of this invention, which they do by increasing nitric oxide production by I-IIV infected monocytes further, which further reduces their OXPHOS use, further increases their reliance upon Fi Fo ATP
hydrolysis to .. maintain TN, wherein a compound of this invention selectively inhibits FiFo ATP hydrolysis, Tim collapses, apoptosis follows. There may be no difference between Sample 4 and Sample 2 if, in Sample 2, the nitric oxide production is already at maximal capacity.
Optionally, the nitric oxide dependence can be shown by running the study again but administering the test drug along with NG-methyl-L-arginine (2 mM), a competitive inhibitor of inducible Nitric .. Oxide Synthase (iNOS, competing with L-arginine), wherein the difference in monocyte number between Sample 1 and 2 will be less or absent.
Control: testing drug effect on monocytes that haven't been infected with HIV:
referring to the aforementioned protocol: just before the HIV infection step, two samples are taken from the uninfected suspension culture and each re-suspended in a separate Teflon (or Teflon like) coated flask/bag in fresh medium at a density of 0.2*1V cells/ml. Test drug in vehicle is added to one sample, wherein drug concentration in medium is 101AM (optionally different, to illustrate, 1 or 100 0/1), drug vehicle alone is added to the other sample.
At 3 hour time points, for 12 to 24 hours, aliquots (e.g. of 15 ml each) are taken from each of the four .. samples and cell viability in each aliquot is recorded using the Trypan blue exclusion method.
A further embodiment is to record for a longer period, wherein if longer than 24 hours, optionally the medium is half-changed for both samples (optionally wherein drug/vehicle is at same concentration in replacing medium than medium replaced) every 24 hours to avoid nutrient depletion and medium acidification. In this case, the monocyte number isn't .. especially different between the drug and vehicle only treated samples.
None of these monocytes are activated, and so don't produce nitric oxide substantially, and so there is no particular reliance upon Fi Fo ATP hydrolysis to maintain Tim, thence no particular sensitivity/liability to a compound of this invention.

EXPERIMENTALLY DEMONSTRATING COMPOUND UTILITY AGAINST HIV
INFECTED MACROPHAGES
This protocol is adapted from that used in [171]. It is illustrative and not limiting. Alternative protocols, and modification(s) to this protocol, will be clear to those of the art, based on the common general knowledge, the literature, and/or the content of prior art disclosures cited herein. The buffy coat is the fraction of an anticoagulated blood sample that contains most of the white blood cells and platelets following density gradient centrifugation of the blood.
Buffy coats from (at least 10) healthy donors are obtained. Peripheral blood mononuclear cells (PBMCs) are isolated from buffy coats by Percoll or Ficoll-Paque Plus (GE Healthcare .. Life Sciences, Pittsburgh, PA) gradient centrifugation. Monocytes are isolated from PMBCs using CD14 microbeads (Miltenyi Biotec, Auburn, CA). Monocyte purity is confirmed by fluorescence-activated cell sorter (FACS) analysis. Then, to generate macrophages, the monocytes are cultured for 7 days to allow differentiation into macrophages:
optionally cultured in 50% Myelocult (Stemcell Technologies, Vancouver, Canada), 25%
Iscove's modified Dulbecco's medium (IMDM) (containing 10% FBS), 25% H527 human fibroblast conditioned IMDM, and 1 ng/ml of macrophage colony-stimulating factor (M-CSF, or alternatively, more preferably, GM-CSF) (Sigma-Aldrich, St. Louis, MO). After 7 days culture, wherein the starting monocytes are now macrophages, the macrophages are cultured at 37 C in RPM! 1640 medium supplemented with 10% fetal bovine serum (FBS) and 1mM
sodium pyruvate at 45,000 cells/ml (9,000 cells per well) in triplicate in a 96-well plate in the presence of various concentrations (e.g. 0.1, 1, 10, 100 tiM) of test drug, wherein this drug is a compound of this invention, optionally Compound 7b. After 24 hours, the CellTiter-Glo reagent is added, resulting in cell lysis and generation of a luminescent signal proportional to the amount of ATP present in each well. The data is normalized to the average signals from the untreated (no drug added) cells. This investigation aspect shows that the drug is non-toxic to normal non-activated macrophages at a concentration(s) that, in the next step, is shown to reduce the number of macrophages infected with an HIV reporter virus. The absence of drug-associated cytotoxicity at 24 hours is also confirmed by trypan blue exclusion.
The HIV-1 reporter virus construct pSF162R3 Nef+ plasmid is replication competent, macrophage-tropic and expresses Enhanced Green Fluorescent Protein (EGFP) in conjunction with HIV nef gene expression and has been used to track HIV
expression in macrophage cultures in prior studies in the literature. Detection of GFP
protein is indicative of Tat-mediated transactivation of the HIV promoter and the expression of early viral gene products such as Nef, Tat and Rev. Therefore, GFP detection can serve as a surrogate marker for HIV DNA integration and Nef expression. The plasmid is transformed into Max Efficiency Stb12 competent cells (Life Technologies, Grand Island, NY); large-scale plasmids are prepared using the PureYield plasmid MaxiPrep system (Promega, Madison, WI). The viral stocks are generated by transient transfection into 293T/17 cells (ATCC, Manassas, VA) using SuperFect transfection reagents (Qiagen, Valencia, CA) according to the manufacturer's protocol. At 37 C, macrophages are infected with viral supernatant at 150 to 180 ng p24 per million cells (0.45 to 0.75 pg per well, 6 to 8 M cells per well) for 6 hours in the presence or absence of test drug, a compound of this invention.
Subsequently, the viral inoculate is removed, and the cells are washed and cultured in the same medium for 7 days with or without drug treatment. Medium is exchanged every 3 to 4 days. Cells are inspected for EGFP expression before harvesting using a fluorescence microscope. When examined under a fluorescence microscope, observed is a significant reduction in the proportion of EGFP-HIV+ macrophages following treatment with test drug. Macrophages are harvested by scraping and then stained using the LIVE/DEAD fixable red dead cell staining kit (Life technologies, Grand Island, NY) according to the manufacturer's manual, followed by fixation in 3% formaldehyde. The samples are analysed on a FACScan instrument and the percentage of EGFP+ cells are determined after gating out the debris by FSC/SCC and the dead cells by the LIVE/DEADstain. Observed is a significant reduction in the proportion of live EGFP-HIV+ macrophages, and/or less ELISA quantification of supernatant HIV p24 antigen, when treated with test drug.
SLOW RELEASE FORMULATIONS
An invention embodiment is to administer to a subject a therapeutic amount of at least one compound of this invention, for example a compound of Formula (I), (II), (III), (IV), (V) or (VII), in a formulation/dosage selected from modified release, extended release, long acting release, sustained release, prolonged release, controlled release, slow release or similar, as clear to someone of the art, for use in a method of treatment of the human or animal body by therapy. Such a formulation exposes the subject body to the compound(s) over a longer period of time than if the compound was applied alone. This is useful because it delivers good area under the curve for the compound, which for example exerts anti-cancer activity in the subject, without an abrupt large body temperature drop. Any body temperature drop is less in amplitude, more in duration, which is safer. Methods to make such formulations for a compound are well known to those of the art. To illustrate with some non-limiting examples:

compound is administered in an excipient/tablet/pill which takes time to dissolve/degrade/disintegrate because it is, for example, poorly soluble.
Furthermore, enteric coating, acrylics (e.g. chitin), liposomes, drug-polymer conjugate(s), microencapsulation (coating an active pharmaceutical ingredient around an inert core and layering it with insoluble substances to form a microsphere), dissolution systems (rate release is dependent on dissolution of an excipient; 2 categories: reservoir, matrix), diffusion systems (rate release is dependent on rate that drug dissolves through a barrier, usually a type of polymer; 2 categories: reservoir, matrix), osmotic systems, ion exchange resins, matrix systems (sub-categories: hydrophobic matrices, lipid matrices, hydrophilic matrices, biodegradable matrices, mineral matrices), stimuli induced release (e.g. temperature, ultrasonic, electronic etc.) and other encapsulation technologies known to those of the art.
An invention embodiment is using a dosage regime of FIFO ATP hydrolysis inhibitor that doesn't cause a significant temperature drop in a human. Optionally spreading the daily therapeutic dose over multiple pills per day so that any body temperature drop is lowered in amplitude, lengthened in duration, which is safer.
ALBUMIN AS SLOW RELEASE ASSIST
Compound 31 of this invention is a 1,4-benzodiazepine, which is a compound class known to bind albumin in blood extensively. For example, 99% of diazepam is protein bound in the blood, wherein the overwhelming majority of this protein is albumin. Albumin can bind many things non-specifically but it has high affinity binding sites with higher affinity binding to certain substances [172], for example, 1,4-benzodiazepines. Indeed, albumin has two specific high affinity binding sites, one of which is called the "benzodiazepine site", also called Site II, the diazepam site or the indole-BDZ site, which can bind a range of benzodiazepines, and so possibly Compound 31 also. Compound 31 binding albumin in blood will buffer, slow and prolong Compound 31 exposure to the tissues, which will buffer, reduce the amplitude, slow and prolong Compound 31 effect on body temperature.
In the anti-cancer data of this disclosure, Compound 31 (Figure 6) outperformed the FDA
approved, widely used, chemotherapeutic carboplatin (Figure 1). However, it underperformed by comparison to its EC50 FIFO ATP hydrolysis (Figure 9) and its sequestration by binding albumin in the 5% fetal bovine serum (FBS) added to medium used in NCI-60 testing [35] might be contributory to this underperforrnance (in addition to Compound 31 interaction with CYP2C9, as cited in Figure 9 and legend).

Reducing FBS amount to 2% and assaying if Compound 31 exerts greater anti-cancer activity vs. no drug control (also with FBS reduced to 2%) would reveal this. N.B.
carboplatin does not bind albumin with any great affinity, indeed, its protein (i.e. mainly albumin) binding in blood is very low.
An invention embodiment is to administer a compound(s) of this invention, one or more of a FiFo ATP hydrolysis modifier, optionally a compound(s) of Formula (I), (II), (III), (IV), (V), (VI) and/or (VII), in complex with albumin to a subject, optionally for use in a method of treatment of the human or animal body by therapy, optionally to treat/ameliorate/prevent/combat one or more diseases/disorders/conditions referred to in this disclosure, optionally cancer, optionally for the treatment/amelioration/prevention/combat of cancer in a subject(s), and/or for the manufacture of a medicament, optionally for treating one or more of the diseases/disorders/conditions referred to in this disclosure, optionally cancer.
TEMPERATURE CONTROLLED RELEASE
An invention embodiment is a temperature-sensitive pharmaceutical composition/vehicle that only releases a compound of this invention, for example a compound of Formula (I), (II), (III), (IV), (V), (VII) or other FIFO ATP hydrolysis inhibitor(s), when the body is at normal body temperature or higher. The latter is reached if the subject has a fever for example. Many cancers cause fever. Such a temperature-sensitive delivery composition/vehicle, releasing drug(s) at normal body temperature (37 C) for example, can effect a safety feedback loop because as FiFo ATP hydrolysis inhibitor is released, body temperature falls, thence less drug is released, body temperature can thence recover, further compound is released, and this loop iterates, implementing extended release and minimising the perturbation to body temperature from optimal. For non-limiting example, a FIFO ATP hydrolysis inhibitor(s) is loaded into a structure incorporating biocompatible thermo-sensitive polymer which shrinks at a temperature exceeding its phase/volume transition temperature, releasing the compound. This volumetric change is reversible. Should the temperature subsequently fall below the phase/volume transition temperature the structure expands and compound release doesn't occur [173]. In some embodiments the phase/volume transition temperature is tuned to be at normal body temperature, in other embodiments, at a pathologically elevated body temperature(s). Biocompatible thermosensitive polymers can be used to prepare temperature-responsive hydrogels/nanogels and thence nanoparticles, optionally with polysaccharides to modulate the drug encapsulation and release efficiency, which have a phase transition temperature, above which they release the "cargo" compound(s). Transition temperature can be readily tuned by the copolymerization conditions and by varying the content of repeating units in the copolymer. Non-limiting options for making temperature sensitive vehicles for compounds of this invention include thermosensitive hydrogels/nanogels, temperature sensitive liposomes [174-176] (these have been used in clinical trials e.g.
ThermoDox), thermosensitive micelles, polymeric micelles, core shell structures, core¨shell microgel particles, thermoresponsive composite films, smart three dimensionally ordered porous materials, thermosensitive microcontainers, nanoscale drug delivery vehicles.
Also contemplated and componentry to this invention is a compound(s) of this invention administered/released by a pharmaceutical composition/vehicle triggered by temperature in parallel with one or more other stimuli e.g. pH, and/or a pharmaceutical composition/vehicle that disproportionally delivers a compound(s) of this invention to cancer as compared to normal tissue(s) in a subject (numerous strategies available to those of the art e.g. refer [177]). For example, by the pharmaceutical composition/vehicle release being triggered by one or more cancer associated stimuli e.g. acidic pH, or one or more externally applied stimuli to the cancer/tumour e.g. heat.
COMPOUND 31, CYP2C9 Compound 31 inhibits CYP2C9 [8], which decreases Compound 31 inhibition of FIFO ATP
hydrolysis, and an invention embodiment is a method of treating, ameliorating, preventing or combating a disease or disorder, optionally cancer, by administering to a subject a therapeutically effective amount of Compound 31, and/or another F IF ATP
hydrolysis inhibitor, optionally a compound(s) of Formula (I), (II), (III), (IV), (V), (VI), (VII) and a CYP2C9 substrate(s) and/or inhibitor(s), optionally wherein these compounds are in the same pharmaceutical composition or sold/distributed together, optionally in the same packaging.
An invention embodiment is Compound 31, and/or another FIFO ATP hydrolysis inhibitor, optionally a compound(s) of Formula (I), (II), (III), (IV), (V), (VI), (VII) and a CYP2C9 substrate(s)/inhibitor(s), and/or other cytochrome P450 enzyme substrate(s)/inhibitor(s), for use in a method of treatment of the human or animal body by therapy, wherein the latter is, illustratively, not restrictively, one or more of fluorouracil (5-FU), capecitabine (prodrug of 5-FU), imatinib (gleevac), nilotinib, sorafenib, dasatinib, teniposide, tamoxifen, idarubicin, sulfaphenazole, fluconazole, miconazole, cannabis, THC, a coumarin or coumarin derivative/analogue, amentoflavone, valproic acid, valproate, apigenin, amiodarone, antihistamines, cyclizine, promethazine, chloramphenicol, fenofibrate, flavone, flavonol, fluvastatin, fluvoxamine, isoniazid, lovastatin, modafinil, phenylbutazone, probenecid, sertraline, sulfamethoxazole, voriconazole, zafirlukast, quercetin, tetrahydrocannabinol, cannabidiol, cannabinol, polyunsaturated fatty acids, nonsteroidal anti-inflammatory drug .. (NSAID), celecoxib, lornoxicam, diclofenac, ibuprofen, flubiprofen, naproxen, ketoprofen, piroxicam, meloxicam, suprofen, phenytoin, fluvastatin, sulfonylureas, glipizide, glibenclamide, glimepiride, tolbutamide, glyburide, angiotensin II receptor antagonists, irbesartan, losartan, S-warfarin, sildenafil, terbinafine, amitriptyline, fluoxetine, nateglinide, rosiglitazone, tamoxifen, torasemide, JWH-018, AM-2201, limonene, tapentadol, montelukast, ticrynafen, benzydamine N-oxide hydrogen maleate, phenprocoumon, benzbromarone, acenocoumarol, methadone, clopidogrel, delavirdine, disulfiram, doxifluridine, efavirenz (HIV/AIDS drug), leflunomide, metronidazole, sulfinpyrazole, nicardipine, gemfibrozil, floxuridine, levofloxacin, progesterone, testosterone etc.
.. A preferred method to treat/ameliorate/prevent/combat cancer in a subject is to administer Compound 31, and/or another FiFo ATP hydrolysis inhibitor, optionally a compound(s) of Formula (I), (II), (Ill), (IV), (V), (VI), (VII) for example Compound 24 from [8] (ICso CYP2C9 = 0.038 M, IC50 FiFo ATP hydrolysis = 0.008 M), and a chemotherapeutic(s) that is a substrate/inhibitor of CYP2C9 (non-limiting e.g. one or more of fluorouracil (5-FU), capecitabine (prodrug of 5-FU), imatinib (gleevac), nilotinib, sorafenib, dasatinib, teniposide, idarubicin, tamoxifen etc.); these drugs interfere with the metabolism of each other and cause greater anti-cancer activity per unit dose of each administered drug than when each drug is administered alone. Furthermore, when an anti-pain or anti-inflammatory drug(s) is prescribed, an invention embodiment is that it should be a drug that is CYP2C9 metabolised e.g. celecoxib, tapentadol, ibuprofen etc. An invention embodiment is a method wherein the subject's CYP2C9 gene sequence is obtained/read/analysed, and/or the sequence of their CYP2C9 regulatory non-coding DNA regions, and/or their CYP2C9 gene/protein expression is measured, in order to inform at what dosage, if at all, Compound 31, and/or another FiFo ATP hydrolysis inhibitor, optionally a compound(s) of Formula (I), (II), (III), (IV), (V), (VI), (VII) should be administered to a subject for use in a method of treatment of the human or animal body by therapy. Impaired CYP2C9 function in a subject, either because of gene sequence and/or expression (non-limiting e.g. human subject with rs1799853(T) and/or RS1057910(C) and/or RS9332131 (a frame shift) SNP variants of CYP2C9), permits lower Compound 31 dosage, and/or lower dosage of another FIR' ATP hydrolysis inhibitor, optionally a compound(s) of Formula (I), (II), (III), (IV), (V), (VI), (VII) to be used in a method of treatment of the subject by therapy.
An invention embodiment is to administer Compound 31 to a subject, and/or another FiFo ATP hydrolysis inhibitor, optionally a compound(s) of Formula (I), (II), (III), (IV), (V), (VI) and/or (VII), with an anti-coagulant(s) (e.g. optionally to treat/ameliorate/prevent/combat one or more of deep vein thrombosis, pulmonary embolism, systemic embolism, venous thromboembolism, acute coronary syndrome, haemorrhage, stroke, ischemic attack, thrombotic disorder, coronary artery disease, myocardial infarction, atrial fibrillation, thrombophilia etc.) that is not warfarin, especially not S-warfarin, wherein administered anti-coagulant(s) embodiments include one or more of heparin, unfractionated heparin, low-molecular-weight heparin (e.g. dalteparin, bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, tinzaparin), oligosaccharide (e.g.
fondaparinux, idraparinux), heparinoid (e.g. danaparoid, dermatan sulfate, sulodexide), dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban, darexaban, apixaban, betrixaban, darexaban, edoxaban, otamixaban, rivaroxaban, letaxaban, eribaxaban, hirudin, bivalirudin, desirudin, lepirudin, argatroban, dabigatran, efegatran, inogatran, melagatran, ximelagatran, antithrombin III, defibrotide, protein C (drotrecogin alfa), ramatroban, REG1, Vitamin E, batroxobin, hementin, direct thrombin inhibitor (e.g. hirudin), aspirin, fibrinogen receptor antagonists, streptokinase, urokinase and/or tissue plasminogen activator.
PATIENT & BUSINESS METHODS
Componentry to this invention are methods of selecting a cancer treatment regime for a subject by providing cancerous cells, obtained from this subject who has cancer, and exposing the cells, in an animal model (e.g. xenograft/syngenic mouse/rat) and/or in cell culture, to a compound(s)/composition(s) of this invention and determining if it is effective against those cancer cells (as evidenced by, for example, the ability of the invention compound(s)/composition(s) to kill the cancer cells, reduce their motility, or reduce the rate at which they grow or proliferate). This information can be utilized in choosing whether to administer this compound(s)/composition(s) to the subject and at what dosage, optionally wherein this decision is made by a clinical professional such as a doctor, vet, oncologist, pharmacist or similar. In addition, the invention encompasses methods of monitoring the growth/regression/stasis of cancer(s) in a subject wherein the subject has a compound(s)/composition(s) of this invention in their body, optionally a therapeutically effective amount, optionally wherein the cancer is monitored by blood testing and/or imaged, optionally by one or more of PET, SPECT, X-ray, CT, MRI, ultrasound, mammography or some other method known to those of the art, and optionally wherein this monitoring is performed and/or analysed by a clinical professional(s) such as a doctor, vet, oncologist, radiologist, pharmacist or similar, and optionally wherein this clinical professional(s) modifies the amount/frequency of compound(s)/composition(s) of this invention administered to the subject on the basis of this collected data. Componentry to this invention are methods of advertising/promoting/teaching/instructing/selling/distributing a compound(s)/composition(s)/method(s) of this invention (to patient(s) and/or clinical professional(s)) for a therapeutic/beneficial use(s) in a subject, optionally an anti-cancer use, optionally wherein this method is performed by a pharmaceutical company or subsidiary or employee or representative.
DETAILED DESCRIPTION OF THE DRAWINGS
For purposes of clarity, not every component is labelled in every figure, nor is every component of each embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention.
Figures 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16: Experimental evidence: molecules that specifically inhibit the reverse mode of ATP synthase: specifically exert anti-cancer activity:
representative, non-limiting examples.
Figures 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 show results from the NCI-60 one-dose in vitro assay [34-35] at the Developmental Therapeutics Program (DTP), at the National Cancer Institute (NCI, Bethesda, MD, USA). Its protocol is well known to those of the art, and it tests the effect, if any, of a test compound on the growth/survivability of a cancer cell line as compared to the no compound control. When this protocol was first developed, a compound was tested against 60 cancer cell lines, hence the name NCI-60, but more recently this has been reduced to 59 cell lines, and there is some variation over time in the cancer cell lines making up this 59 (and sometimes it drifts from being 59 also). However, a constant is that there is always representative cell lines from leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate and kidney. In a one-dose NCI compound test report, NCI
report a number for each cell line, which they call "Growth Percent", which is its growth relative to the no-compound control, and relative to the time zero number of cells. This reported parameter allows detection of both growth inhibition (values between 0 and 100) and lethality (values less than 0). For example, an NCI "Growth Percent" value of 100 means no growth inhibition. Value of 40 means 60% growth inhibition. Value of 0 means no net growth over the course of the experiment. Value of -40 means 60% lethality.
Value of -100 means all cells are dead. I don't present NCI one-dose data in this original format. Instead, if the NCI "Growth Percent" value for a cell is positive, it is manipulated: [100 minus this original NCI-60 "Growth Percent" data point], to yield the percentage "Growth Inhibition". If the original NCI "Growth Percent" value for a cell is negative, it is made positive to be the percentage of original cancer cells (at time zero) killed: "Percentage Killed"
{and in these cases, of course, all growth has been inhibited, so percentage "Growth Inhibition" is then specified to be 100% for this cancer cell line}. In my one-dose figures, "Growth Inhibition"
(0-100%) is presented on the x-axis and, if applicable, "Percentage Killed" (0-100%) further along on the x-axis. The latter is applicable when there is not just cancer growth inhibition but a reduction in the number of cancer cells from the start time i.e. when the compound is not merely slowing cancer growth, but is actively reducing the number of cancer cells from the starting number. In cases where there is only growth inhibition, only "Growth inhibition"
is presented on the x-axis. In all cases, the greater the percentage number on the x-axis, for a given cancer cell line named on the y-axis, the greater the anti-cancer activity of this compound against this cancer cell line.
NCI-60 tests are performed at a controlled temperature of 37 C [35].
To perform the anti-cancer testing reported: BMS-199264 hydrochloride was purchased from Sigma-Aldrich. BTB06584 was purchased from AdooQ Bioscience, Irvine, CA, USA.
Almitrine dimesylate was purchased from Ak Scientific, Palo Alto, CA, USA.
Compounds 19a (separated into 6a and 6b stereoisomers), 31, 7a and 7b were synthesized by reaction schemes disclosed herein. Tested compounds are available from NCI by NSC
number which are: BTB06584 (NSC: 794220), BMS-199264 HCl (NSC: 795767), almitrine dimesylate (NSC: 800450), 6h (NSC: 801828), 6a (NSC: 801827), 31 (NSC: 802605), 7b (NSC:
809247), 7a (NSC: 809248), 8a (NSC: 814041), 8b (NSC: 814040).
Figure 1: Anti-cancer activity of carboplatin in National Cancer Institute (NCI) one-dose (10 M) assay. Data retrieved from NCI Developmental Therapeutics Program (DTP) screening database [32], database entry NSC: 241240. To retrieve this data, input NSC at https://dtp.cancer.gov/dtpstandard/dwindex/index.isp. DTP database contains anti-cancer performance (or more typically lack thereof) for >800,000 compounds (NSC
numbers, wherein each NSC number represents a unique chemical entity, started at 1 and each new compound tested was assigned the next largest number as their NSC identifier [I know this by personal communication with NCI DTP] and recently assigned NSC numbers herein are >800,000) in the exact same experimental protocol. New entries become publically searchable after 3 years delay (to give time for compound submitters to secure IP protection, should they wish, before public disclosure by this database). This figure presents the anti-cancer performance of an FDA licensed cancer drug, carboplatin, one of the most used cancer drugs today, which is on the World Health Organisation (WHO) list of most Essential medicines, in exactly the same experimental protocol used for the novel cancer drugs of this disclosure, presented in later figures. This figure inclusion enables a direct like-for-like comparison between the new cancer drugs, disclosed by this disclosure, with a cancer drug in present, widespread clinical use. For carboplatin (10 M), mean and median cancer growth inhibition are 6.37% and 1.6% respectively. Maximal growth inhibition observed is with a leukemia cell line (SR) = 49.3%.
Figure 2: No anti-cancer activity of BTB06584 at 10 M (NCI one-dose assay).
Figure 3: Anti-cancer activity of BTB06584 at 100 M (NCI one-dose assay).
Mean and median cancer growth inhibition are 38.76% and 33.79% respectively. Maximal growth inhibition observed is with a leukemia cell line (MOLT-4) = 95.38%.
Figure 4: Anti-cancer activity of BMS-199264 hydrochloride at 10 M (NCI one-dose assay). Mean and median cancer growth inhibition are 22.95% and 19.71%
respectively.
Maximal growth inhibition observed is with a prostate cancer cell line (PC-3) = 85.35%.
Figure 5: Anti-cancer activity of BMS-199264 hydrochloride at 100 M (NCI one-dose assay).
Figure 6: Anti-cancer activity of compound 31 at 10 M (NCI one-dose assay).
Mean and median cancer growth inhibition are 15.17% and 13.51% respectively. Maximal growth inhibition observed is with an NSCLC cell line (HOP-92) = 66.24%.

Figure 7: Anti-cancer activity, in NCI one-dose assay, of almitrine dimesylate at (7A) 10 M
and (7B) 100 M. Mean cancer growth inhibition is 32.08% (10 M) and 35.84%
(100 M).
Median cancer growth inhibition is 30.07% (10 M) and 35.32% (100 M). Maximal growth inhibition observed at 100 tiM is with an NSCLC cell line (HOP-92) = 76.46%
growth inhibition. With some cancer cell lines, anti-cancer activity is less at 100 prVI than 10 RIVI
(7C).
Figure 8: (8A) A racemic mixture, or racemate, has equal amounts of the S and R
enantiomers of a chiral molecule. Structure 19a is a racemate and (RIS) symbolises the chiral carbon as R or S. Structure 6a is its R stereoisomer, structure 6b is its S
stereoisomer. The EC50 FiFo ATP hydrolase of the racemate (19a, 0.033 M) is approximately half as potent as that of the isolated S stereoisomer (6b, 0.018 IA) because it contains half as much of the S
stereoisomer per unit mass, because it also contains R stereoisomer (EC50 FiFo ATP
hydrolase > 100 M) in a 50:50 ratio. Chiral supercritical fluid chromatography (SFC) was used to separate 19a into its component R and S stereoisomers, which don't and do potently inhibit FiFo ATP hydrolase respectively (ECso values from SMPs in [5-6]), and two samples of opposite >97% enantiomeric excess (ee) was achieved: termed 6a and 6b respectively.
These were independently tested in NCI one-dose (10 piM) testing: their results are shown in Figures (8B) and (8C) respectively. The anti-cancer activity of 6a and 6b was similar (Pearson correlation: R = 0.8, significant at p <0.00001). This is because during the 48 hours of NCI one-dose testing, they underwent racemization and their ee eroded. Such that both samples ultimately contained a significant proportion of S stereoisomer and both exerted anti-cancer activity by inhibiting FIFO ATP hydrolysis. Racemization is not instantaneous and so one sample, 6b, conferred greater/longer S stereoisomer exposure to the cancer cells than the other sample, 6a. Racemization isn't necessarily complete at testing end.
These features explain why the 6b origin (>97% ee 6b at start) sample has greater anti-cancer activity than the 6a origin (>97% ee 6a at start) sample: 66% vs. 57% mean (67% vs. 59%
median) cancer growth inhibition, across all 59 cancer cell lines, respectively. During, and more certainly by end, of NCI one-dose testing, 6a and 6b have 97% > ee? 50% i.e. they are a racemate or scalemate. Although the fidelity of the (distinction between) 6a and 6b samples erodes during NCI testing, as they each converge (by epimerization) upon being 19a, I still use the 6a and 6b terms at times in this disclosure to refer to these samples during NCI
testing. In addition, given that during NCI testing 6a ¨> 19a, and 6b --* 19a, I use the terms 6a, 6b and 19a interchangeably at other times during this disclosure. Racemization reduces, and increases, the anti-cancer activity of 6b and 6a respectively. (8D) 6b exerts greater anti-cancer activity than 6a. 6b is the S stereoisomer, 6a the R stereoisomer. (8E) and (8F) are the anti-cancer activities of 6a and 6b respectively in the NCI one-dose (100 M) assay. In this assay, median cancer growth inhibition for both 6a and 6b >79%. Pearson correlation coefficient between 6a and 6b anti-cancer activity at 100 M = 0.9437 (p < 0.00001). With some and overwhelmingly same cancer cell lines, for both 6a (8G) or 6b (8H), anti-cancer activity is much less at 100 M than 10 M.
Figure 9: Anti-cancer potency (mean % decrease in cancer growth, as compared to no .. compound control, in NCI-60 one-dose testing) scales with inhibition of (EC50) Fi Fo ATP
hydrolase, across diverse chemical structures. Mean cancer growth inhibition values are from data in Figures 2, 3, 4, 5, 6 and S. ECso values against ATP synthase, for BMS-199264, 19a, 6a, 6b and 31 are from sub-mitochondrial (SMP) studies in [5-8], wherein these EC50 values are comparable because they are from the same research group using the same SMP assay. A
point to note, the EC50 values against ATP synthase are from bovine studies and the anti-cancer data is from human cancer cell lines, so there is a species difference, and it is assumed here that approximately the same EC50 values apply to the human case. BTB06584 potency information (is not an EC50) is from a whole cell study [13]. Compound 31 ECso for CYP2C9 is from [8]. Note that the presented EC50 for BMS-199264 is for BMS-199264, not for BMS-199264 HCI, which is the form tested for anti-cancer activity herein.
6b and 6a anti-cancer activities are similar because of their epimerization in biological systems, which erodes their enantiomeric excess (ee) during NCI testing, making them converge upon being the racemate, 19a. Thus, during NCI testing, 6b ECso FiFo ATP
hydrolase is not constant but in the range 0.033 M > EC50 FIFO ATP hydrolase < 0.018 M
because EC50 FiFo ATP hydrolase ¨> 0.033 M as 6b 19a, as racemization proceeds.
Similarly, 6a ECso FIFO ATP hydrolase 0.033 M as 6a ¨> 19a.
Mean % cancer growth inhibition for BMS-199264 at 100 M is >100% because for most cancer cell lines tested it doesn't just cause 100% cancer growth inhibition but, in addition, causes cancer regression, wherein the number of cancer cells at experiment end is less than at experiment start. BMS-199264 predominantly exerts anti-cancer activity at 10 M by inhibiting FiFo ATP hydrolase, and at 100 M, by reducing FIFO ATP synthesis.

At 10 M, 6b (and 6a) exerts more anti-cancer activity than BMS-199264, despite having less effect on F1 F0-ATP synthesis, because it inhibits FiFo-ATP hydrolysis more potently.
This shows that FiFo-ATP hydrolysis is an anti-cancer target. BTB06584 doesn't exert anti-cancer activity at 10 M, only at 100 M, wherein it has been shown only to inhibit Fi Fo-ATP hydrolysis at >100 M, and doesn't inhibit FiFo-ATP synthesis at this concentration [13]. Reaffirming that Fi Fo-ATP hydrolysis is an anti-cancer target. 31 exerts less anti-cancer activity than BMS-199264 at 10 M. Despite 31 having the lower EC50 for FiFo-ATP
hydrolysis [7-8]. However, BMS-199264 could be recruiting additional anti-cancer activity at M by reducing F1 F0-ATP synthesis also, wherein BMS-199264 has a lower EC50 for 10 FiFo-ATP synthesis than 31 ([18 9.5 M [7], so potentially 8.5 M] vs.
>30 M [8]
respectively). Furthermore [7] reports EC50 values for pure BMS-199264 whereas I test BMS-199264 HC1, which might be more soluble and thence more potent, with lower EC5ovalues for FiFo-ATP synthesis and hydrolysis than the pure form.
31 has less anti-cancer activity than its ECso FIFO ATP hydrolase value would predict because it is broken down by cytochrome P450 enzyme: CYP2C9, which it inhibits competitively (31 being consumed in the process). Average 1og2 transcript intensity of CYP2C9, across all NCI-60 cell lines, is 3.539 [31-32]. Average 10g2 transcript intensity of ATP5A1, the alpha subunit of Fi ATP synthase, across all NCI-60 lines, is 9.871 [31-32]. There are 3 alpha subunits per ATP synthase [1]. So, on average, approximately, there is a comparable amount of CYP2C9 and ATP synthase in an NCI-60 cancer cell line: 3.539:(9.871/3=3.29) 1. If we equate ECsoas some measure of binding affinity then compound 31 has a greater affinity for binding ATP synthase in its reverse mode (EC5o= 0.022 M) than for binding (ECso = 2 M) (these EC50 values come from different assays, thence this comparison isn't very robust). However, ATP synthase does not always operate in reverse, it likely has different operating propensities at different stages of the cell cycle, and compound 31 EC50 FiFo ATP synthesis is > 30 M. Thus, CYP2C9 can meaningfully reduce compound inhibition of FIFO ATP hydrolase, and thence its anti-cancer activity.
Especially because CYP2C9, a cytochrome P450 enzyme, does not merely bind and sequester compound 31, but metabolises and inactivates compound 31 at a rate set by its kcat for compound 31.
Compound 31 as substrate for an enzyme(s) of the cytochrome P450 enzyme, whilst itself having anti-cancer activity, means it can add to the anti-cancer action, for example potentiate the anti-cancer action, of one or more other anti-cancer therapeutics which are also broken down by this system e.g. fluorouracil (5-FU), capecitabine (prodrug of 5-FU), imatinib (gleevac), nilotinib, sorafenib, dasatinib, teniposide, tamoxifen, idarubicin etc. N.B. CYP2C9 inhibition does not exert anti-cancer activity. Sulfaphenazole is a specific, potent CYP2C9 inhibitor [178] and it does not exert anti-cancer activity in NCI-60 one-dose testing (NSC
757859 in DTP database [32], 10 1iM, mean cancer growth inhibition = -3.8%, negative symbol signifies growth promotion (!) rather than inhibition).
Compound 31 is a 1,4-benzodiazepine, which is a compound class known to bind albumin in blood extensively. For example, 99% of diazepam is protein bound in the blood, wherein the overwhelming majority of this protein is albumin. Albumin can bind many things non-specifically but it has high affinity binding sites with higher affinity binding to certain substances [ 1 72], for example, 1,4-benzodiazepines. Indeed, albumin has two specific high affinity binding sites, one of which is called the "benzodiazepine site", also called Site II, the diazepam site or the indole-BDZ site, which can bind a range of benzodiazepines, and so possibly compound 31 also. Compound 31 sequestration by binding albumin in the 5% Fetal Bovine Serum (FBS) component to NCI-60 testing medium [35] might be contributory to the anti-cancer underperformance of 31, less than predicted by its ECso FIR) ATP
hydrolysis.
Indeed, when 31 is tested at 10 M, there are more albumin molecules than 31 molecules in the NCI-60 test medium (200 I medium, 5% FBS [23 mg/ml albumin on average]).
Reducing FBS amount to 2% and assaying if compound 31 exerts greater anti-cancer activity vs. no drug control (also with FBS reduced to 2%) would reveal how much of a factor, if at all, albumin drug sequesteration is for compound 31 in NCI testing.
Figure 10: Chiral supercritical fluid chromatography (SFC) was used to separate the shown racemate into its component R and S stereo isomers and two samples of opposite >97%
enantiomeric excess (ee) was achieved: termed 7a and 7b respectively. 7a and 7b differ from 6a and 6b in Figure 8 because they have deuterium instead of hydrogen upon their chiral carbon. 7a and 7b were independently tested in NCI one-dose (10 M) testing:
their results are shown in Figures (10B) and (10C) respectively. The anti-cancer activity of 7a and 7b against the different cancer cell lines of the NCI-60 assay was correlated i.e. the greater, and lesser, of their anti-cancer activity was against the same cell lines (Pearson correlation: R =
0.8, significant at p < 0.00001). The anti-cancer activity of compounds 6a, 6b, 7a, 7b are correlated, which suggests that they all exert anti-cancer activity by the same mechanism, inhibition of FiFo ATP hydrolysis (refer Figure 8 and its legend), and the following table shows their pairwise Pearson correlation (R) coefficients, all significant at p < 0.00001, except 7a vs. 6b, wherein p = 0.00002, significant at p <0.00003.
6a 6h 7a 0.7693 0.5205 7b 0.6614 0.6451 The following table compares the mean and median cancer growth inhibition caused by 6a and 6b, from Figure 8, with that of 7a and 7b from the present figure:
6a 6b (6b-6a) 7a 7b (7b-7a) (7b-7a)/(6b-6a) Mean 57.3 66.15 8.85 52.35 72.81 20.46 2.3 Median 58.62 66.9 8.28 52.09 74.51 22.42 2.7 7b exerts greater anti-cancer activity than 6b, 7a exerts less anti-cancer activity than 6a.
Thence the difference between the anti-cancer activity of 7b and 7a is greater than that between 6b and 6a. This is because, whereas 6a and 6b have hydrogen attached to the chiral carbon, 7a and 7b have deuterium attached to the chiral carbon. Deuterium slows the racemization rate by a Kinetic Isotope Effect (KIE). So, 7b maintains its enantiomeric excess and anti-cancer activity better, because of a slower epimerization rate to inactive 7a. Thence 7b exerts greater anti-cancer activity than 6b. 7a maintains its enantiomeric excess and anti-cancer inactivity better, because of a slower epimerization rate to active 7b.
Thence 7a exerts less anti-cancer activity than 6a. The disparity in anti-cancer activity between 7b and 7a is 2-3 times greater than that between 6b and 6a, which is the correct order of magnitude for a KIE
(between 1 and 7 [179], can be greater if tunnelling is very mechanistically relevant [180]).
(10D) Recasts data from Figures 10B and 10C. Null hypothesis: equal (0.5) probability that x-axis value is positive (+ve) or negative (-ve): that 7a or 7b is the more powerful stereoisomer for any given cell line. Binomial probability of observed number of +ve and -ve <0.00000001. P value (one tailed) <0.000001, Significant. Conclusion: 7b has greater anti-cancer activity than 7a at 10 M. 7b is the S stereoisomer, 7a the R
stereoisomer.

Replacing hydrogen(s) with deuterium(s) on a drug structure can decrease its efficacy, for example replacing CH3 with CD3 on morphine decreases its analgesic potency (ED50) and lethality (LD50) in mice [181]. With 19 hydrogens on the structure of 6b, there are 219 (=524,288) different deuterium/hydrogen substitution combinations possible for 6a or 6b. It isn't predictable which of these will decrease, increase or be neutral to any anti-cancer activity, and/or whether a given substitution(s) will impact any anti-cancer activity of 6a and 6b in the same direction or not, at what amplitude for each, if at all. Before this experiment the anti-cancer impact, if any, of deuterating 6a and 6b on their chiral carbon, to produce 7a and 7b, couldn't have been predicted. The literature shows that KIEs can be positive [180], negative (inverse KIE) [182] or zero (neutral) [183], wherein it can't be predicted which will apply in each new case. The magnitude and direction of KlEs are unpredictable.
Moreover, the literature teaches that the epimerization of 6a and 6b is irrelevant because [Pl, P2, P3], using analogy (in the unpredictable arts) to the macrolide inhibitors of [14], teaches that FiFo ATPase inhibitors exert anti-cancer activity by inhibiting FIFO ATP synthesis, wherein 6a and 6b are both poor to non-inhibitors of this mode (EC5o> 100 M for both [5-61), and so both are taught to have poor to no anti-cancer activity, wherein this anti-cancer action, even if present, isn't cancer selective (normal cells rely upon FIR) ATP synthesis) and thus isn't clinically useful. Thus interconversion between 6a and 6b is taught irrelevant. Furthermore, the literature teaches that their epimerization rate is slow (refer Figure 30 legend herein), indeed data disclosed herein also teaches this (Figure 30), so their epimerization is taught inconsequential for this reason also. However, novel data disclosed by this invention (Figures 8 & 23) shows that 6a and 6b rapidy epimerize in biological systems.
By the invention of the present disclosure, 6b, the S stereoisomer, is discovered to selectively exert anti-cancer activity by selectively inhibiting FIFO ATP hydrolysis (reverse mode), wherein 6a, the R stereoisomer, only exerts anti-cancer activity by epimerizing to become 6b, the S
stereoisomer. That 7b has greater anti-cancer activity than 6b, and 7a has less anti-cancer activity than 6a, is further evidence (adding to that of Figure 9) that 6b exerts anti-cancer activity by inhibiting FIFO ATP hydrolysis and further teaches that, by the most fundamental invention of this disclosure, anti-cancer activity can be specifically exerted by specifically inhibiting FiFo ATP hydrolysis. A new composition of matter, 7b, is taught by the present disclosure and, furthermore, a method of its use for anti-cancer therapy. It wasn't known prior to this invention that 6b would exert greater anti-cancer activity than 6a, that 7b would exert greater anti-cancer activity than 6b, nor that 7a would exert less anti-cancer activity than 6a.

Deuteration increases and decreases the anti-cancer activity of the active, S.
and inactive, R, stereoisomers respectively. So, to acquire greater net anti-cancer activity from this effect, the S stereoisomer must be administered in enantiomeric excess to the R
stereoisomer. In some embodiments of this invention, 7b {or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof} is administered in enantiomeric excess (ee) to 7a {or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof} (non-limiting examples:
ee = >70%, ee =
>95%, >99% more preferred, =100% most preferred) for use in a method of treatment of the human or animal body by therapy, optionally to treat/ameliorate/prevent/combat one or more diseases/disorders/conditions referred to in this disclosure, optionally cancer, optionally for the treatment/amelioration/prevention/combat of cancer in a subject(s), and/or for the manufacture of a medicament, optionally for treating one or more of the diseases/disorders/conditions referred to in this disclosure, optionally cancer. The greater the % deuterium enrichment at the chiral carbon of 7b, and the greater the enantiomeric excess of 7b, the more preferred the embodiment.
Figure 11: Chiral supercritical fluid chromatography (SFC) was used to separate the shown racemate into its component Rand S stereoisomers and two samples of opposite >97%
enantiomeric excess (ee) was achieved: termed 8a and 8b respectively. 8a and 8b differ from 6a and 6b in Figure 8 because they have methyl (Me, CH3), instead of hydrogen (H), upon their chiral carbon. 8a and 8b were independently tested in NCI one-dose (10 M) testing:
their results are shown in Figures (11B) and (11C) respectively. The anti-cancer activity of 8a and 8b against the different cancer cell lines of the NCI-60 assay was correlated i.e. the greater, and lesser, of their anti-cancer activity was against the same cell lines (Pearson correlation: R = 0.5669, significant at p <0.00001). This correlation is notably less than for 6a vs. 6b (0.7991) and 7a vs. 7b (0.8049).
(11D) Recasts data from Figures 11B and 11C. Null hypothesis: equal (0.5) probability that x-axis value is positive (+ve) or negative (-ye): that 8a or 8b is the more powerful stereoisomer for any given cell line. Binomial probability of observed number of +ve (45) and ¨ve (15) {n=60} = 0.00004613852. P value (one tailed) for 45 or more +ve (n = 60) =
0.000091. Conclusion: 8b has greater anti-cancer activity than 8a at 10 M.
But one can see that there are notable exceptions, which are discussed now with 11E.

(11E) 8a and 8b NCI one-dose (10 M) test results side by side. % cancer growth inhibition > 100 means there are less cancer cells at experiment end than beginning (i.e.
cancer killing activity), = 200 = all cancer cells dead at experiment end. The observed pattern of 8a vs. 8b activity is hard to explain. One would expect one stereoisomer to have greater or equal .. activity than the other. Whereas here, 8b mostly has greater activity, and in some cases much greater (e.g. A=85.34% with MDA-MB-231/ATCC), but in some cases 8a has the much greater activity (e.g. A=38.57 with A498). Moreover, for one cancer cell line (NCI-H322M), 8a has no activity, yet 8b does. While not wishing to be bound by theory, the following model can explain these results, wherein the anti-cancer activity of 8a and 8b is set by (1) the cancer's sensitivity to a specific FIF0 ATP hydrolysis (over synthesis) inhibitor, which can vary between different cancer cell lines, and (2) the activity of an enzyme(s) that hydroxilates the methyl group (CH3) of 8a and 8b to CH2OH, which can vary between different cancer cell lines, wherein this enzyme(s) is referred to herein as CYP, but it needn't necessarily be a Cytochrome P450 enzyme(s) as other hydroxylase/monooxygenase enzymes are known to those of the art:
Hydroxylase/
=¨=N rµ__.1,1 OH
CH3N 0 monooxygenase N 0 CI
enzyme(s) CI
N NH N NH
CI CI
CI CI
Moreover, the ability to exert specific FIFO ATP hydrolysis inhibition, and thence anti-cancer activity, is ranked: R (CH20H) > S (CH2OH) S (Me) > R (Me), wherein RI S
refers to stereochemistry and the group in brackets is the group on the chiral carbon.
If CYP activity is low or non-existant, R (Me) and S (Me) are the predominant intracellular species of 6a and 6b respectively, and so, for anti-cancer activity, 6a < 6h. If CYP activity is high, R (CH2OH) and S(CH2OH) are the predominant intracellular species of 6a and 6b respectively, and so, for anti-cancer activity, 6a> 6b. Is hard to delinearate whether S (CH2OH) or S
(Me) has the greater FiFo ATP hydrolysis inhibitory, and thence anti-cancer, activity. S
(Me) does have anti-cancer activity, as observed with MDA-MB-231/ATCC, when 6a activity is much lower than 6b and so CYP activity must be low, thence S (Me) predominates. Yet S
(CH2OH) does have anti-cancer activity because 6b can still exert anti-cancer activity when 6a can. The NCI-H322M cancer cell line, against which 6a has no anti-cancer activity, may have a mutation in, and/or especially low expression of, the CYP enzyme(s), wherein this prevents it from hydroxylating the methyl of R (Me) and S (Me).
(11F) can explain this model more. 6a, R (H), and 6b, S (H), cannot and can potently inhibit FiFo ATP hydrolysis respectively [5-6]. This figure shows that S (Me) and S
(CH2OH) are likely to be very structurally similar to S (H), and thence likely to also potently inhibit FiFo ATP hydrolysis, and to exert anti-cancer activity. Crucially, R (Me) and R
(CH2OH) are not likely to be very structurally similar to R (H), nor each other, and in the case of R (CH2OH) this enables it to potently inhibit FiFo ATP hydrolysis and exert anti-cancer activity. So, in this (CH2OH) case, and in the priming CH3 on chiral carbon case, R over S
stereochemistry can, in some embodiments, be favoured/desirable.
CYP activity may also be relevant to the observed anti-cancer activity of 6a and 6b wherein the following reaction may occur inside the cell:
-;:34 N
Hydroxylase/ N
N 0 monooxygenase CI H A enzyme(s) CI
Cl N NH N NH ______________ N NH
CI ci ci ci ci ci So, 6a and 6b may converge upon the same structure inside the cell, which may explain partially how they can both inhibit FIFO ATP hydrolysis and exert anti-cancer activity, because they both converge upon a structure more similar to that of S (H) than R (H), wherein the 2"d step is likely very fast, the 1St step might be slower, set by the amount of enzyme(s) available, which could allow S (H) and R (H) to endure for a period, which could explain how S (H) can exert greater anti-cancer activity than R (H), when they both ultimately arrive at the same product. The equivalent scheme may apply for 7a and 7b but wherein the conversion is slower because the CD bond is stronger and harder to break than a CH bond (Kinetic Isotope Effect, KIE), which means S (D) and R (D) endure for longer and the anti-cancer activity disparity between 7a and 7b is greater than between 6a and 6b, wherein such disparity is experimentally observed herein.
Figure 12: The anti-cancer activity of compounds 6a, 6b, 7a, 7b, 8a and 8b are all correlated, which suggests that they all exert anti-cancer activity by the same mechanism, inhibition of F1F0 ATP hydrolysis (refer Figure 8 and its legend), and the bottom table shows their pairwise Pearson correlation (R) coefficients, all significant (p<0.05). In some invention embodiments, one or more of the compounds shown in this figure is in stereoisomeric excess such that it rotates polarized light in the levorotatory (L) direction, optionally wherein this compound(s) in stereoisomeric excess (L-rotating) is used to convey therapy in a subject, in a method of treatment of the human or animal body by therapy, optionally to treat/ameliorate/prevent/combat one or more diseases/disorders/conditions referred to in this disclosure, optionally cancer, optionally for the treatment/amelioration/prevention/combat of cancer in a subject(s), and/or for the manufacture of a medicament, optionally for treating one or more of the diseases/disorders/conditions referred to in this disclosure, optionally cancer.
Without wishing to be bound by theory, the order of anti-cancer activity can be explained if the order of inhibitory potency against F1F0 ATP hydrolysis is: R (CH2OH) > S
(CH2OH) S
(Me) > S (D) > S (H) > R (H) > R (D) > R (Me). Explaining first that 6a, R
(H), and 6b, S (H), cannot and can potently inhibit FIFO ATP hydrolysis respectively [5-6]. Then, explaining from the bottom, R (D) has greater anti-cancer activity than R (Me) because it has some chance of racemizing to S (D) or S (H). R (H) has greater anti-cancer activity than R (D) because a CH bond is weaker than a CD bond and so it has a greater chance of racemizing to S (D) or S (H). S (D) has greater anti-cancer activity than S (H) because a CD
bond is stronger than a CH bond and so it has less chance of racemizing to R (D) or R (H). S
(Me) and S
(CH2OH) have greater anti-cancer activity than S (D) and S (H) because they have no (but non-zero) chance of racemizing to R (H). R (CH2OH) has a structure very suited to inhibiting FiFo ATP hydrolysis, very distinct from the structure of R (H), more akin to S
(H), but better.
Below, the stereoisomer excess of the 6a, 6b, 7a, 7b, 8a and 8b samples used in this study, as determined by a number of different methods. For the primary data and calculations behind the numbers in this table, refer Figures 32, 33, 35 and their legends.

STEREOISOMER EXCESS
UV chromatogram Chiral SFC-MS Chiral SFC
Alternative name herein Absolute(%) ee(%) Absolute(%) ee(%) Absolute(%) ee(%) 6a Stereoisomer 2 98.83 97.66 99.64 99.28 6b Stereoisomer 1 98.23 96.46 97.9 95.8 7a Stereoisomer B 98.71 97.42 7b Stereoisomer A 100 100 8a Stereoisomer 100 100 99.57 99.14 100 100 8b Stereoisomer a 100 100 99.89 99.78 100 100 Enantiomeric excess (ee) = (Absolute excess-SO) *2 Optical rotation data:
[a]= a/(c*L) where [a] = specific rotation ( ) a = observed rotation (0) c = concentration (g/m1) L = length of polarimeter tube (in decimetres (dm)) Instrument used: RUDOLPH AUTOPOL V. Following were each performed with small amount of sample. So, whilst the direction of optical rotation is likely accurate, the magnitude of rotation is likely not. Positive rotation = Dextrorotatory (0).
6a 1 g/100m1= 0.01 g/ml, diluted with Me0H, 20 C, A = 298 nm, [a].38 rim= 438 nm/(c*L) = 0.075/(0.01*0.5) = +150 7a 0.25 g/100m1= 0.0025 g/ml, diluted with CHCI3, 25 C, = 589 nm, Optical rotation = positive (+) 7b 0.25 g/100m1= 0.0025 g/ml, diluted with CHCI3, 25 C, = 589 nm, Optical rotation = negative (-) 8a 1.0270 g/100m1= 0.01027 g/ml, diluted with Me0H, 25 C, A.= D = sodium D line = 589 nm, two trials:
[a]g= aL5/(c*L) = 0.023/(0.01027*0.5) = 4.48 = 0.024/(0.01027*0.5) = 4.67 mean = +4.58 Figure 13: Anti-cancer activity of BMS-199264 hydrochloride. Results are from the NCI-60 five-dose in vitro assay [34-35] at the Developmental Therapeutics Program (DTP), at the National Cancer Institute (NCI, Bethesda, MD, USA). In this assay, which is well known to those of the art, a compound is tested, in vitro, against 59 different cancer cell lines, sourced from 9 different tissue types, across 5 different concentrations. 9 graphs in 9 sub-figures are presented (labelled 13A to 131), one for each of the 9 tissue types. These graphs are as outputted by the NCI but changed from colour to black and white. On the y-axis of each is the aforementioned "Growth Percent" parameter used by NCI, which is growth relative to the no-compound control, and relative to the time zero number of cells. This parameter allows detection of both growth inhibition (values between 0 and 100) and lethality (values less than 0). GI50 is the compound concentration that causes 50% growth inhibition of a cell line relative to the no-compound control. Each cancer cell line has a GI50 value and the "mean GI50" of all 59 cell lines can be calculated: this mean GI50 for BMS-199264 hydrochloride is 3.9 M.
Figure 14: Anti-cancer activity of compound 31 in NCI-60 five-dose in vitro assay [34-35].
Mean GI50 is 13.2 M.
Using the COMPARE algorithm [28-29], which employs a Pearson correlation coefficient, one observes that the NCI-60 5-dose pattern response (GI50 values) of compound 31 is correlated to that of BMS-199264 (0.544, p <0.00001), which indicates that they have the same mechanism of anti-cancer action, because [30] found that the COMPARE
algorithm can successfully group different FDA-approved anti-cancer drugs by their method of action.
Using this COMPARE algorithm BMS-199264 and 31 are both uncorrelated to oligomycin A
(0.009 and -0.009 respectively), which indicates that they both have a different mechanism of anti-cancer action to oligomycin A. This is because, unlike oligomycin A which potently inhibits FIN ATP synthesis and hydrolysis, there are BMS-199264 and 31 concentrations that selectively reduce FiFo ATP hydrolysis, which exerts anti-cancer activity, whilst leaving FiF0 ATP synthesis intact.
Figure 15: Anti-cancer activity of 6a and 6b in NCI-60 five-dose in vitro assay [34-35].
Mean GI50 for 6b is 0.446 M. Mean GI50 for 6a is 0.666 M. (15J) GI50 values tend to be lower with 6b than 6a.

Using the COMPARE algorithm [28-29], the NCI-60 5-dose pattern responses of 6a and 6b are correlated (0.754, p < 0.00001). In turn, they are correlated to the pattern response of BMS-199264 (6a, 0.378, p = 0.004831) and 31 (6a, 0.303, p = 0.024535). But not too strongly. Because all these (BMS-199264, 31, 6a, 6b) potently inhibit the reverse mode of .. ATP synthase (EC5o< 1 M for all [5-8]; 6a inhibits by epimerising to 6b) but BMS-199264 and 31, distinctly from 6a and 6b, reduce FIFO ATP synthesis also with an ECso of 18 M [7]
and >30 tiN4 [8] respectively, whereas for 6a and 6b: ECso FIE) ATP synthesis > 100 M [5-6], so outside the concentration range tested. Thus, within the 5 doses tested, BMS-199264 and 31 selectively reduce FiFo ATP hydrolysis at lower test concentrations and FiF0 ATP
synthesis also at higher test concentrations (especially at 100 M, -4 on x-axis) whereas 6a and 6b selectively reduce FIFO ATP hydrolysis, without significantly affecting FiFo ATP
synthesis, at all tested concentrations. So, within the 5-dose NCI assay, BMS-199264 and 31 exert anti-cancer activity by the same mechanism as 6a and 6b at low (< 10 M) concentrations, but by a different mechanism at high concentration (100 M).
The x-axis of the graphs of Figure 15 might be incorrect. At present, the 5 doses shown are from -9 to -5. When the NCI first returned the 5-dose results back for 6a and 6b, the 5 doses shown were from -7 to -3. However, this struck me as wrong and I queried this with the NCI
and they then sent the results through a 2"d time but with different labels on the x-axis, as shown herein, wherein the 5 doses shown are from -9 to -5. However, I think this might be wrong also. I think it should be from -8 to -4, as is typical for most of the compounds tested in 5-dose testing in the DTP database [16]. In which case, the mean G150 for 6b and 6a is 4.46 and 6.66 M respectively. I have emailed the NCI for further clarification on this but no response has been forthcoming to date. But either way, this 5-dose data shows that 6a and 6b exerts good anti-cancer activity. This ambiguity in the x-axis of this figure drives ambiguity in the x-axis of figures that use this data: Figures 17 and 18.
This paragraph (alone) assumes that the x-axis of this figure is mislabelled and makes the aforementioned adjustment. The Pearson correlation coefficient between 6a activity in 1-dose (10 M) and at 10 M in 5-dose NCI-60 testing: R= 0.8943, p<0.00001. The Pearson correlation coefficient between 6b activity in 1-dose (10 M) and at 10 M in 5-dose NCI-60 testing: R= 0.8737, p<0.00001. In 5-dose NCI-60 testing, at 10 M, the anti-cancer activity of 6a and 6b is greater than at 10 M in 1-dose NCI-60 testing. Mean % cancer growth inhibition at 10 M in 1-dose testing: 6a (57.30%), 6b (66.15%); in 5-dose testing: 6a (67.61%), 6b (76.08%). Median % cancer growth inhibition at 10 M in 1-dose testing: 6a (58.62%), 6b (66.90%); in 5-dose testing: 6a (67%), 6b (77%). A compound exerting greater anti-cancer activity at 10 M in 5-dose than 1-dose NCI-60 testing is typically what is observed for compounds in the DTP database [16]. So, this isn't unexpected.
What is unexpected here, to one of the art, is that, both in 1-dose and 5-dose NCI-60 testing, anti-cancer activity is less against some cancer cell lines at 100 M than at 10 M, wherein this effect is more pronounced in 5-dose than 1-dose testing, wherein anti-cancer activity is actually greater at 10 M in 5-dose than 1-dose testing. Indeed, in 5-dose testing the mean and median cancer growth inhibition is actually less at 100 NI than at 10 M.
Mean %
cancer growth inhibition at 100 M in 1-dose testing: 6a (70.60%), 6b (74.94%); in 5-dose testing: 6a (66.22%), 6h (72.42%). Median % cancer growth inhibition at 100 M
in 1-dose testing: 6a (79.13%), 6b (82.22%); in 5-dose testing: 6a (66.22%), 6b (72%).
The Pearson correlation coefficient between 6a activity in 1-dose (100 M) and at 100 M
in 5-dose NCI-60 testing: R=0.0952, p=0.473232. The Pearson correlation coefficient between 6b activity in 1-dose (100 M) and at 100 M in 5-dose NCI-60 testing: R=0.1757, p=0.183162.
Here, the non-correlation between 5-dose and 1-dose NCI-60 results at 100 M contrasts strongly with their very strong correlation at 10 M reported prior.
Figure 16: Anti-cancer activity of 8a and 8b in NCI-60 five-dose in vitro assay [34-35].
Mean GI50 for 8b and 8a is 3.09 and 2.85 M respectively. So, 8a has the lower mean GI50 and so is the more potent. In the 8a case, this GI50 is lower/better than 65%
of 102 FDA
approved cancer drugs in [30]. A salt of 8a, e.g. 8a HC1, is likely to have an even lower GI50 in NCI five-dose testing.
Using the COMPARE algorithm [28-29], the NCI-60 5-dose pattern responses of 8a and 8b are correlated (0.752, p < 0.00001). Further correlations with other NCI-60 5-dose data, found using the COMPARE algorithm, are shown below, all significant at p<0.05 except [6b vs. 31] and [8b vs. 31].

8b 8a 6a 6b BMS-199264 31 8b 1 8a 0.752 1 0.329 0.415 1 6b 0.402 0.339 0.754 1 BMS-199264 0.438 0.503 0.378 0.302 1 31 0.139 0.389 0.303 0.245 0.544 1 8b exerts greater anti-cancer activity than 8a in 1-dose (10 M) NCI-60 testing (Figure 11).
8a exerts greater anti-cancer activity than 8b at 10 M in 5-dose NCI-60 testing. So, the 1-dose and 5-dose results contradict. However, there hasn't been a mix up of 8a and 8b samples because in 1-dose (10 M) testing, in Figures 11E and 11D, one can see that 8b exerts much greater activity against, for example, the MDA-MB-231/ATCC, 0VCAR-5, HCC-2998 and NCI-H322M cell lines than 8a. In the 5-dose testing, although most GI50s are lower with 8a, one can see that the GI50 for these cancer cell lines is greater with 8a than 8b (Figure 16J).
So, this signature carries through.
To revisit the above again, using Figure 16K: in 1-dose (10 M) NCI-60 testing, cancer growth inhibition (%) with 8b tends to be greater than with 8a, and 8b-8a is positive. By contrast, in 5-dose testing, GI50 tends to be lower for 8a than 8b, because 8a has the more potent anti-cancer activity, which makes GI50(8b-8a) positive. The exceptions to this tend to be for cancer cell lines against which 8b exerts much greater anti-cancer activity than 8a in 1-dose NCI-60 testing, so wherein 8b-8a is large, and then in 5-dose testing, GI50 tends to be lower for 8b than 8a, which makes GI50(8b-8a) negative. For these cancer cell lines, 8b has so much greater anti-cancer activity than 8a in 1-dose testing that despite the increased anti-cancer of 8a relative to 8b in 5-dose testing, it isn't sufficient to overtake that of 8b in these cases.
The Pearson correlation coefficient between 8a activity in 1-dose (10 M) and at 10 M in 5-dose NCI-60 testing: R=0.4544 p=0.00034. The Pearson correlation coefficient between 8b activity in 1-dose (10 M) and at 10 M in 5-dose NCI-60 testing: R=0.6156, p<0.00001. In 5-dose NCI-60 testing, at 10 NI, the anti-cancer activity of 8a and 8b is greater than at 10 M in 1-dose NCI-60 testing. Mean % cancer growth inhibition at 10 M in 1-dose testing: 8a (60.32%), 8b (76.51%); in 5-dose testing: 8a (102.97%), 8b (99.42%). Median %
cancer growth inhibition at 10 M in 1-dose testing: 8a (59.83%), 8b (76.99%);
in 5-dose testing: 8a (95%), 8b (93%). A compound exerting greater anti-cancer activity at 10 M in 5-dose than 1-dose NCI-60 testing is typically what is observed for compounds in the DTP
database [16]. So, this isn't unexpected. Not wishing to be bound by theory, in 5-dose NCI-60 testing, why 8a has a lower mean GI50 than 8b will now be explained. 8a does exert greater anti-cancer activity than 8b against some cancer cell lines in 1-dose (10 M) NCI-60 testing (Figures 11D and 11E). As explained in the legend of Figure 11, because it can be metabolized to a form (hydroxylated on the chiral carbon) with greater anti-cancer activity than 8b. In 5-dose NCI-60 testing, whatever the reason(s) that compounds tend to exert greater anti-cancer activity at 10 M in 5-dose than 1-dose NCI-60 testing, perhaps (to speculate) relating to greater compound availability because better care/optimization is taken over compound solubilizing, means there is more 8a, so more 8a being metabolized to the more active form (increased substrate, increased reaction rate and product), and this tips 8a into exerting greater anti-cancer activity at 10 M than 8b. Except for the cancer cell lines that 8b exerted much more activity than 8a at in 1-dose testing, wherein the increased activity of 8a can't completely make up the deficit and overtake the activity of 8b.
Figure 17: Greater anti-cancer activity occurs with greater anti-cancer drug concentration.
This is what someone of the art would expect. However, compounds 6a and 6b can, upon some (and overwhelmingly same) cancer cell lines, exert less anti-cancer activity at 100 M
than 10 M in the NCI one-dose assay (Figures 17A and 17B) and can, upon some (and overwhelmingly same) cancer cell lines, exert less anti-cancer activity at 10 M than 1 M in the NCI five-dose assay (Figure 17C). In Figures 17A and 17B, most inhibited cancer cell lines at 10 M are least inhibited at 100 M. Next most inhibited cancer cell lines at 10 M
undergo cell death at 100 M. Least inhibited cancer cell lines at 10 M are more inhibited at 100 M. Thus, to interpret, as one increases compound concentration, there are 3 zones passed, with their boundaries different for different cancer cell lines: (1) increased compound concentration increases anti-cancer activity, (2) compound causes cancer cell death, (3) increased compound concentration decreases anti-cancer activity. The anti-cancer activity of compounds 6a and 6b is highly correlated, which verifies the voracity of this data. 6b is .. stronger acting than 6a in the NCI one-dose assay and in NCI five-dose assay also (lower mean GI50), wherein 6b has more cancer cell lines with less activity at 10 M
than 1 M.
Interpretation: 6a, and 6b, [compound] increase/decrease driven increase/decrease in anti-cancer activity is by action on same target. Data in Figures 17A and 17B is from data in Figure 8. Data in Figure 17C is from data in Figure 15. Supplementary data to Figure 17C:

NCI-60 5-dose data:
Mean GI50: 6b=0.446 M, 6a=0.666 uM
% cancer growth inhibition:
by [6b]=1 M: Mean=76.08%, Median=77%
by [6a]=1 M: Mean=67.61%, Median=67%
by [6b]=10uM: Mean=72.42%, Median=72%
by [6a]=10pM: Mean=66.22%, Median=66%
Mb: Mean=-3.66%, Median=-4%
Ma: Mean=-2.17%, Median=-2%
Pearson R (Ma, Mb) = 0.78 Ip<0.000011 Number of "uptickers": 6b=40, 6a=32 Showing that greater incidence and amplitude of "upticking" (less anti-cancer activity at 10 than 1 M) occurs with 6b, the more potently (lower GI50) anti-cancer stereoisomer, which indicates that anti-cancer and upticking activity is caused by drug action upon the same molecular target, which is discussed further in the legend of Figure 18.
Figure 18: This diagram is an interpretation of experimental data in Figures 8, 15 and 17. It does not itself present real data. (18A) In Figure 15, increasing concentration of 6a or 6b (both symbolised as 19a in the present figure) slows cancer proliferation, until a concentration of maximum slowing, after which further increase in compound concentration decreases cancer growth inhibition. The present diagram incorporates Figure 15 data with an additional observation from Figure 8, wherein high 6a and 6b doses decrease the cell number of some cancer cell lines, which I suggest is due to apoptosis. This observation is incorporated by a narrow dosage range that causes cancer cell death, the boundaries of which varies by cancer cell line, and it's narrowness explains why cancer cell killing is not observed for most cancer cell lines in the broadly separated doses of NCI five-dose testing. The diagram shows that increasing compound concentration increasingly blocks FIN
ATP
hydrolysis in cancer cells, which increasingly increases their OXPHOS rate, and thence reactive oxygen species EROS]. Elevated [ROS] slows proliferation by ROS
checkpoint blockade and atrophies DNA information fidelity, which reduces the number of possible cell divisions from limitless to a value increasingly convergent upon the Hayflick limit [184] of normal cells. At the inverted peak, the OXPHOS rate is so great, and EROS] so elevated, apoptosis is triggered (by comparison, normal cells use this OXPHOS rate routinely).
However, as compound concentration is increased beyond this point, greater FIFO ATP
hydrolysis inhibition makes OXPHOS more efficient (less ATP needs to be made because less ATP is hydrolysed), which reduces the OXPHOS rate and [ROS], and anti-cancer activity is less. (18B) Upper panel shows same diagram as (A), relating to a cancer cell, above an equivalent diagram for a normal cell, with equivalent x-axis. It shows that there are concentrations of an FIR ATP hydrolysis inhibitor(s) that harm cancer and help normal cells.
Cancers have, and need, lower intracellular [ROS] than normal cells. There are concentrations of FIFO ATP hydrolysis inhibitor(s) that simultaneously raise [ROS] in cancer cells and decrease [ROS] in normal cells. In normal cells, greater FIFO ATP
hydrolysis inhibition makes OXPHOS more efficient (less ATP needs to be made because less ATP is hydrolysed), which reduces the OXPHOS rate and [ROS] and increases normal cell lifespan.
FiFo ATP hydrolysis inhibitor(s) conferred OXPHOS efficiency gain comes from, and so its maximum is dictated by, proportion of OXPHOS produced ATP hydrolysed by FIFO
ATP
hydrolysis, which is high, and so lifespan (and healthspan) extension significant, especially if it reduces EROS] sufficiently to reduce DNA mutation rate below DNA repair rate.
Especially, if this EROS] is sufficient to keep cells differentiated, maintaining tissue and organ function.
Figure 19: This diagram is an interpretation of experimental data in Figure 13. It does not itself present real data. BMS-199264 is distinct from compound 6b because, in addition to inhibiting FiFo ATP hydrolysis, it can also significantly reduce FiFo ATP
synthesis at NCI
tested concentrations. Background: BMS-199264 ECso FiFo ATP hydrolysis = 0.48 p,M, ECso FIR) ATP synthesis = 18 M. (19A) Cancer cell. At lower [BMS-199264], anti-cancer activity is predominantly by inhibition of Fi Fo ATP hydrolysis in cancer cells, which increases their OXPHOS rate, and thence reactive oxygen species [ROS].
Elevated EROS]
slows proliferation by ROS checkpoint blockade and atrophies DNA information fidelity, which reduces the number of possible cell divisions from limitless to a value, at increasing [BMS-199264], increasingly convergent upon the Hayflick limit [184] of normal cells. At higher [BMS-199264], anti-cancer activity is additionally by reduction of FIR) ATP
synthesis, principally by BMS-199264 conferred uncoupling of the proton motive force (refer Figure 27), which increases cancer OXPHOS rate and intracellular EROS]. So much that apoptosis ensues. (19B) Upper panel shows same diagram as (A), relating to a cancer cell, above equivalent diagram for a normal cell, with equivalent x-axis. It shows that lower [BMS-199264], which inhibits FiFo ATP hydrolysis, harms cancer and helps normal cells.
Thus, there is a therapeutic window. However, higher [BMS-199264], which significantly reduces F1F0 ATP synthesis, harms both cancer and normal cells. Greater EROS]
sensitivity of cancer, running an embryonic stem (ES) cell type phenotype, shown in relative positioning of plots upon equivalent x-axis.
Figure 20: This figure recasts data from Figure 16. Greater anti-cancer activity occurs with greater anti-cancer drug concentration. This is what someone of the art would expect.
However, compounds 8a and 8b can exert LESS anti-cancer activity at 100 M
than 10 M.
Looking at the mean and median % cancer growth inhibition, 8a has greater anti-cancer activity at 10 M, and much less anti-cancer activity at 100 1.04, than 8b.
This is because there is a much greater number of cancer cell lines with less activity at 100 M than 10 M
with 8a (29) than 8b (6). Indeed, whilst mean and median A8b are positive (14.70%, 11%), mean and median A8a are negative (-1.21%, -1%). In terminology developed herein:
8a has greater "upticking" than 8b. 8a is the more potent stereoisomer, with a lower mean GI50 (2.85 [04) than 8b (3.09 M). The fact that the stereoisomer with greater anti-cancer potency (lower GI50), 8a, has greater upticking (less anti-cancer activity at higher drug concentrations), and that there is a correlation (R=0.371, p=0.04755, just significant at p<0.05) between anti-cancer and upticking magnitude (Figure 20B), suggests that anti-cancer activity and its upticking might be exerted by action upon the same molecular target: reverse mode of ATP synthase, wherein the mechanisms involved have been disclosed in the legend of Figure 18. Another possible explanation for the upticking is drug aggregation at higher .. concentration (discussed in legend of Figure 23), but it isn't very likely that opposite stereoisomers could have the large difference in drug aggregation properties required to account for the upticking disparity between 8a and 8b. (P.S. to remind, if %
cancer growth inhibition > 100 = less cancer cells at experiment end than start: if = 200% =
all cancer cells dead).
Figure 21: Greater anti-cancer activity occurs with greater anti-cancer drug concentration.
This is what someone of the art would expect. However, almitrine dimesylate can, upon some (24 of 57) cancer cell lines, exert less anti-cancer activity at 100 M than 10 M in the NCI
one-dose assay. As shown in Figure 7C and this figure. Regarding ATP synthase, almitrine makes its forward mode less efficient (less ATP synthesized per protons passed) and its reverse mode more efficient (more protons pumped per ATP hydrolysed) [250-253];
expanded upon later in this disclosure. For a cancer cell currently using oxidative metabolism, almitrine makes FiFo ATP synthesis less efficient, whilst concurrently making FIF0 ATP hydrolysis more efficient, which maintains Tim and blocks a compensatory increase in OXPHOS rate to maintain [ATP], [ATP] falls, which exerts anti-cancer activity.
Almitrine decreases the maximal ATP yield available from respiratory substrates. For a cancer cell currently using glycolytic metabolism, almitrine making FIFO ATP
hydrolysis more efficient exerts anti-cancer activity because it renders less ATP
hydrolysed by FIR, ATP hydrolysis and thence, higher cytoplasmic [ATP], greater ATP feedback inhibition of key glycolytic enzyme(s), slower glycolytic rate, less glycolytic intermediates available for biosynthesis/proliferation, slower pentose phosphate pathway (PPP) rate, less NADPH
generated, less ROS mitigation, greater intracellular EROS], wherein ROS cause transient growth arrest to permanent growth arrest, to apoptosis or to necrosis, dependent on the level of ROS [44]. While not wishing to be bound by theory, almitrine may exert greater anti-cancer activity for a cancer cell predominantly and/or totally relying upon oxidative rather than glycolytic metabolism e.g. a cancer rigidly reliant upon glutaminolysis.
The lesser anti-cancer activity observed at 100 M almitrine dimesylate for some cancer cell lines might be because the greater almitrine concentration switches them to a more glycolytic metabolism, wherein the anti-cancer activity exerted by almitrine is less severe for these cancer cell lines.
Indeed, increasing inefficiency of FIFO ATP synthesis and decreasing [ATP]
should pull through increasing glycolytic rate/metabolism, assuming glucose is available (NCI-60 assay is run with 2 mM L-glutamine and glucose is available from the glucose content of the 5%
Fetal Bovine Serum (FBS) added [35], ¨0.345 mM glucose in NCI-60 asssay media by my .. calculation [not shown]). So, in clinical use of almitrine for anti-cancer therapy, a lower almitrine dose might convey greater anti-cancer therapy than a higher dose and this invention discloses methods (elsewhere herein) to converge closer to, or upon, an optimal anti-cancer dose of almitrine. Different cancer cell lines likely have different sensitivities to almitrine depending on their relative reliance upon oxidative versus glycolytic metabolism (which probably varies at different stages of their cell cycle), their malleability between these states and the respiratory substrate(s) available.
Delimiting to cell lines that almitrine dimesylate exerts less % cancer growth inhibiton at 100 than 10 M (those underneath the y = 0 line, bottom panel of this figure), the Pearson correlation coefficient between % cancer growth inhibition at 10 M and %
cancer growth inhibition ([@100]-[@10] M) is -0.281 (p = 0.183482). So, for almitrine dimesylate, there is no significant (at p < 0.05) correlation between anti-cancer activity at 10 M
and retrenchment in anti-cancer activity at 100 M. This is in distinction to 6a and 6b, wherein there is (Figure 17 and legend of Figure 22), and wherein the cancer cell lines that show retrenchment with 6a and 6b are less in number and distinct from those with almitrine dimesylate.
Figure 22A: In Figures 7, 8, 15, 16, 17, 20 and 21, less anti-cancer activity occurs with some cancer cell lines at 100 than 10 M drug concentration. This figure and legend teaches that this is not because of drug aggregation at 100 M.
In vitro, less cancer growth inhibition can occur with greater cancer drug concentration, if this greater concentration exceeds the drug's Critical Aggregation Concentration (CAC) [185, 186]. The CAC of an anti-cancer drug is higher when there are more cancer cells. Because more cancer cells sequesters more of the drug from aggregating with itself.
Thence at a CAC
exceeding drug concentration, % cancer growth inhibition is greater, as compared to no drug control, the greater the number of cancer cells. So when greater drug concentration causes less % cancer growth inhibition, one can determine if drug aggregation is the mechanism by assessing whether an increased number of cancer cells causes greater % cancer growth inhibition as compared to no drug control. If drug aggregation isn't the mechanism one would conversely observe a further reduction in % cancer growth inhibition as compared to no drug control. This methodology is componentry to this invention.
.. I couldn't do a controlled test and change the number of cancer cells tested against for any given cancer cell line. Instead I cautiously use an uncontrolled methodology.
In the NCI-60 one-dose assay, different cancer cell lines have different starting cell numbers ("innoculation densities", reported at [187]) and different cell lines have different proliferation rates ("doubling rates", reported at [187]). Thus, at the end of the NCI-60 assay, which runs for 48 .. hours, different cancer cell lines have different cell numbers when no drug is applied (no drug control) as shown in this Figure. Different cell lines have different mean cell diameters (reported at [188]) and this is represented in the figure also. The following table shows, for no drug control, the Pearson correlation coefficient (R) between starting cell numbers, starting cell numbers multiplied by mean diameters (in pm), final cell numbers, final cell numbers multiplied by mean diameters. These all correlate so highly that only one, final cell numbers multiplied by mean diameters (called [N*M] herein), is shown in the figure.

R values Innoculation density*cell diameter final cell number final cell number*cell diameter Innoculation density 0.9049 0.7838 0.8368 Innoculation density*cell diameter 0.496 0.682 final cell number 0.9282 P values Innoculation density*cell diameter final cell number final cell number*cell diameter Innoculation density p <0.00001 p < 0.00001 p < 0.00001 Innoculation density*cell diameter p = 0.000056 p <0.00001 final cell number p < 0.00001 IF (greater number of cancer cells, greater % cancer growth inhibition (vs. no drug control) =
positive correlation) then {drug aggregation relevant). IF (greater number of cancer cells, less % cancer growth inhibition (vs. no drug control) = negative correlation) then (drug aggregation IRrelevant).
For almitrine dimesylate (Figure 7), the Pearson correlation coefficient between % cancer growth inhibition (100 M) and [N*M] is 0.1119 (p = 0.39879), between % cancer growth inhibition ([@100]-[@10] M) and [N*M] is 0.1282 (p = 0.341922). Delimiting to cell lines that almitrine dimesylate exerts less % cancer growth inhibiton at 100 than 10 M, the Pearson correlation coefficient between % cancer growth inhibition ([@100]-[@101 M) and [N*M] is -0.0972 (p = 0.652062). None of these are significant at p < 0.05.
There is no statistically significant positive correlation that could indicate drug aggregation as a significant factor in this almitrine dimesylate anti-cancer activity data set.
For 6b and 6a (Figure 8), the Pearson correlation coefficient between % cancer growth inhibition (100 M) and [N*M] is -0.3811 (p = 0.002671) and -0.3784 (p =
0.002904) respectively. For 6b and 6a, the Pearson correlation coefficient between %
cancer growth inhibition ([@100]-[@10] M) and [N*M] is -0.3792 (p = 0.002824) and -0.3947 (p =
0.001841) respectively. Delimiting to cell lines that 6b exerts less % cancer growth inhibiton at 100 than 10 M, the Pearson correlation coefficient between % cancer growth inhibition ([@100]-[@10] M) and [N*M] is -0.6201 (p = 0.023764) i.e. in this data subset, the more cells a cancer cell line has with no drug control, the greater the retrenchment in % cancer growth inhibition when 6b concentration is concentration is increased from 10 to 100 M.
Delimiting to cell lines that 6a exerts less % cancer growth inhibiton at 100 than 10 M, the Pearson correlation coefficient between % cancer growth inhibition ([@100]-[@10] M) and [N*M] is -0.5355 (p = 0.072764). Leukemia cells tend to be amongst the most numerous when no drug is added (refer figure) and are the majority of the few cell lines that show retrenchment in cancer growth inhibition when 6a or 6b drug concentration is increased from to 100 M (Figure 8G and 8H).
5 To consolidate, the 6a and 6b data, with significant (at p < 0.05) negative correlations noted, suggests that the retrenchment in cancer growth inhibition observed, for some cancer cell lines, when 6a or 6b drug concentration is increased from 10 to 100 M (Figure 8) isn't because of drug aggregation. Moroever, the data suggests that this retrenchment is actually by drug action upon the same target that the drug causes cancer growth inhibition. Because 10 greatest retrenchment at 100 M occurs with cell lines most inhibited at 10 M. These are the cell lines most sensitive to this drug. For 6b and 6a, the Pearson correlation coefficient between % cancer growth inhibition at 10 M and % cancer growth inhibition ([@1001-[@10] M) is -0.5857 (p <0.00001) and -0.6643 (p <0.00001) respectively.
Delimiting to cell lines that 6b exerts less % cancer growth inhibiton at 100 than 10 04, the Pearson correlation coefficient between % cancer growth inhibition at 10 M and %
cancer growth inhibition ([@100]-[@10] M) is -0.3656 (p = 0.219275) and -0.6243 (p =
0.030015) if the outlier (not seen in 6a data) cell line data point (MDA-MB-231/ATCC) is excluded from the set. Delimiting to cell lines that 6a exerts less % cancer growth inhibiton at 100 than 10 M, the Pearson correlation coefficient between % cancer growth inhibition at 10 M and %
cancer growth inhibition ([@100]-[@10] VI) is -0.7986 (p = 0.001062). Indeed, looking at Figure 17, looking especially underneath the y = 0 line, one can visually observe the strong correlation between greater anti-cancer activity at 10 M and lesser anti-cancer activity at 100 M.
Delimiting to cell lines that 6a exerts less % cancer growth inhibiton at 100 than 10 M, the mean and median retrenchment in % cancer growth inhibiton, when concentration is increased from 10 to 100 M, is 43.52% and 53.3% respectively (Figure 8G).
Delimiting to cell lines that 6b exerts less % cancer growth inhibiton at 100 than 10 M, the mean and median retrenchment in % cancer growth inhibiton, when concentration is increased from 10 to 100 M, is 54.73% and 66.05% respectively (Figure 8H). So, greater retrenchment occurs with 6b, the stereoisomer with greater anti-cancer activity (Figure 8D), indicating that retrenchment occurs because of drug action on the same target that the drug acts upon to exert anti-cancer activity.

In Figure 17, greater incidence and amplitude of "upticking" (less anti-cancer activity at 10 than 1 M) occurs with 6b, the more potent (lower GI50) anti-cancer stereoisomer, which indicates that anti-cancer and upticking activity of 6b is caused by drug action upon the same molecular target. Comparing Figures 8 and 15, with both 6a and 6b, greater anti-cancer activity at lower dose, and greater retrenchment in anti-cancer activity at higher dose, occurs in 5-dose than 1-dose NCI-60 testing, which indicates that 6a and 6b exert both anti-cancer and upticking activity by drug action on the same molecular target, which is discussed further in the legend of Figure 18.
In Figure 20, the fact that the stereoisomer with greater anti-cancer potency (lower GI50), 8a, has greater upticking (less anti-cancer activity at higher drug concentrations), and that there is a correlation (R=0.371, p=0.04755, just significant at p<0.05) between anti-cancer and upticking magnitude (Figure 20B), suggests that anti-cancer activity and its upticking is exerted by action upon the same molecular target: reverse mode of ATP
synthase, wherein the mechanisms involved have been disclosed in the legend of Figure 18.
Another possible explanation for the upticking is drug aggregation at higher concentration, but it isn't very likely that opposite stereoisomers could have the large difference in drug aggregation properties required to account for the especially large upticking disparity observed between 8a and 8b in Figure 20.
Figure 22B: Drug aggregation assay, using methodology of [185, 186], for compound 7b. 7b starts to significantly aggregate (colloidal aggregation) at concentrations higher than its Critical Aggregation Concentration (CAC), 3.9 NI, above which it starts to scatter light, increasingly as its concentration is increased, as more and more 7b drug aggregates are formed. Drug aggregates of 7b can cause non-specific enzyme inhibition, as shown by inhibition of two very different enzymes, Malate dehydrogenase (MDH, IC50=3.1 M) and AmpC beta lactamase (IC50=13.2 M), but wherein this inhibition is lifted when Triton-X
(0.01%) detergent is added, which breaks up drug aggregates (effectively raises the CAC).
Adding cells, e.g. cancer cells, will also raise the CAC as 7b then becomes sequestered from self-aggregating by binding to its intracellular target(s) and also probably by, given its high logP value, accumulating in cell membranes.
Could drug aggregation be the reason for the "uptick" observed with many cancer cell lines in the NCI-60 5-dose data for 6a and 6b (Figure 15) and/or 8a and 8b (Figure

16)? Wherein an "uptick" is when, after a dose is found that exerts anti-cancer activity, a higher dose has lower anti-cancer activity. 7b isn't 6a or 6b. But one could tentatively suggest that the CAC
of 6b might be similar to 7b given their structural similarity. Although, a word of caution, this may well be wrong! But let us say that the CAC of 6b is ¨3.9 M. Of interest, FDA approved cancer drugs with a lower CAC value (greater propensity to aggregate), wherein all these CAC values are comparable as they are deduced from the same methodology [185, 186], have been observed to have much less, or no, "upticking" in NCI-60 5-dose tests than 6b [32]. This might be because they have a higher affinity for their intracellular target(s), and/or their intracellular target(s) are more numerous, and so they are more sequestered by the cancer cells and their free concentration is lower in relation to their CAC.
Or, especially because 6b might be expected to be the most sequestered by cancer cells (membranes) because it has the highest (computationally predicted) logP and logD values, it might be a sign that the "upticking" observed with 6b is not completely, or at all, related to 6b compound aggregation, but to a different process, for example, the process disclosed in the legend of Figure 18.
CAC ( M) Uptick observed in NCI-60 5-dose data? NSC number in DTP database logP logD (pH 7) Crizotinib 19.3 Yes (with 3 cell lines, from 109100 M) 756645 3.57 0.67 Lapatinib 0.6 Yes (with 4 cell lines, from 109100 p.M) 745750 4.64 4.19 Nilotinib 0.9 No 747599 5.36 5.33 Sorafenib 3.5 Yes (with 1 cell line, from 109100 M) 747971 4.34 4.34 Vemurafenib 1.2 No 761431 4.62 4.62 7b 3.9 ND 809247 5.97 5.89 6b ND Yes (with 40 cell lines, from 1-410 M) 801828 5.97 5.89 "Uptick" = when, after a dose is found that exerts anti-cancer activity, a higher dose has lower anti-cancer activity.
CAC values are comparable because determined by same assay.
ND = Not Determined.
6b and 7b won't be found in DTP database until 3 years after first submitted, by DTP policy.
DTP = Developmental Therapeutics Program (at National Cancer Institute, USA).
logP and logD: computationally predicted from structure using MarvinSketch software (ChemAxon).
Figure 23: In vivo study of compounds 6a and 6b, conducted at 22 C room temperature.
METHODOLOGY: 4 mice were used. Some experimental details: intravenous (IV) administration (tail vein), dosing volume = 10 l/g, solution (not suspension), sterilised (0.22 pm filter) vortexed vehicle= 12.5% solutol, 12.5% ethanol, 75% water, IV
solutions freshly prepared before injection except on days 22 and 39 when solutions prepared on previous .. dosing days were used (sub-optimal), Female Mus Muscu/us C57BL/6 strain, 6-8 weeks old at study start, mice sourced from Shanghai Lingchang Bio-Technology Co. Ltd, mice were observed/quarantined for a few days after arrival and before dosing, ad libitum Co6 irradiation sterilized dry granule food & reverse osmosis autoclaved water, corn cob bedding, polysulfone individually ventilated cage (IVC, containing up to 5 animals):
325 mm x 210 mm x 180 mm, 12 hour light/dark cycle, 40-70% humidity, 20-26 C room temperature, StudyDirectorTM software (Studylog Systems, Inc. CA, USA) used to allocate/randomize control/treatment groups, animals marked by ear coding (notch), care and use of animals in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), when recording rectal temperature: care was taken to ensure constant depth of probe insertion across different recordings, time was afforded for rectal probe temperature to equilibrate with rectal temperature, and time was afforded between recordings for probe temperature to reset. Rectal temperature recording experiments were always started between 8 and 9 am.
RESULTS: (23A) 4 mice were used, and in the presented table, "Day" refers to the number of days since the 1st drug/vehicle dose on Day 1. (23B) Statistics comparing [mouse weight vs.
day, for days 1 to 44] for Mouses 1, 2, 3, 4. Mean (Mouse 2,3,4) is significantly (at p<0.05) different from Mouse 1, the vehicle treated control. However, Mouse 4, which is the mouse administered the highest cumulative drug dose, is not significantly (at p<0.05) different from Mouse 1, the vehicle treated control. Note that naturally, any drug treatment aside, there is variation in the growth trajectories of different mice individuals. Mouses 1, 2, 3, 4 are C57BL/6 female mice. The Jackson laboratory (Jax) studied the growth trajectory of hundreds of C57BL/6 mice [189] and the mean and standard deviation (SD1) for their female C57BL/6 mice, from 7-14 weeks old, is shown in the presented graph. Only for one data point (17.47) is the Mean weight (Mouse 2,3,4) outside of the Jax standard deviation (SD!), and it is still within the 2nd standard deviation (SD2) of the Jax data (Jax mean-SD2 = 16.9) i.e. within the observed weight range of female Jax C57BL/6 mouse weight data.
However, a potential source of error in comparing with the Jax data is that Mouse 1,2,3,4 are between 6-8 weeks old, i.e. it isn't known exactly how old they are, at study start. For comparison, Jax data is presented from 7 weeks old. However, even if Jax data from 8 weeks old is used, the Mean weight (Mouse 2,3,4) = 17.47 data point is still within the 2nd standard deviation (SD2) of the Jax data (Jax mean-SD2 = 17.2). An extant disparity is that Mouse 1,2,3,4 weren't sourced from The Jackson Laboratory, but from a different supplier of C57BL/6 mice i.e. they weren't C57BL/6J mice, wherein the J refers to The Jackson Laboratory. All mice in the present study, including the no drug control mouse, Mouse 1, have decreases as well as increases in body weight during the course of observation. The administered drug (6a or 6b) confers mouse sedation when ambient temperature is 22 C (observed, refer later), and so then there is a potential margin for the drug to affect body weight if this sedation diminishes appetite/feeding.
(23C): For each animal, the l' rectal temperature recording is typically of an atypically high body temperature, which is associated with the stress of being handled, which a mouse becomes habituated to during the course of the experiment. This handling effect has been reported in other rectal thermistor studies of rodents e.g. [190-191]. Mouse 3 rectal temperature was <30 C by 45 minutes after 20 mg/kg IV injection of 6b, it died ¨210 minutes after this IV injection, whilst drinking water, "choked on water" was reported observation, water temperature was at room temperature (RT) = ¨22 C (so ingestion reduces body temperature, if it isn't already at RT). Mouse 4 rectal temperature was <30 C by 45 minutes after 40 mg/kg IV injection of 6b, survived >6 hours, found dead the next day, did not survive the night. After IV of 6b: Mouse 3 and 4 exhibited hypoactivity and tachypnea, both signs of hypothermia [192], coinciding with their rectal temperature drop (<30 C).
Mouse 2 exhibited hypoactivity but recovered after 30 minutes, matching its recovery of rectal temperature. With 6b IV administration, there is a dose-dependent drop in rectal temperature.
Before 6b dosing experiments, Mouse 1, 2 and 3 had all survived IV injections of 6a. 6a doesn't potently reduce rectal temperature like 6b: the dose-dependent rectal temperature reduction (with hypoactivity reported over same timescale that rectal temperature is reduced) that 6a can cause is because of in vivo epimerization of 6a to 6b. Similarly, when 6b is the administered compound, in vivo epimerization of 6b to 6a reduces the effective dose of 6b and chemical modifications to the 6b compound structure to prevent or slow this epimerization are componentry to this invention: for example, a non-limiting example embodiment is to replace the hydrogen on the chiral carbon of 6b with deuterium. >40 mg/kg doses of 6a weren't trialled because I ran out of 6a compound. Indeed, I only had enough 6a to dose 2 of the 3 test mice with 40 mg/kg.
Vehicle control can cause a drop in rectal temperature because of its 12.5%
ethanol content:
12.5% of 10 ul/g solution administered = 1.25 ul/g ethanol = 0.000989226 g/g =
0.99 g/kg =
1 g/kg ethanol (IV). 1.9 g/kg ethanol (intraperitoneal injection, IP) reduced rat body temperature by 1.6 C (in 24.5 to 25 C ambient temperature; raising temperature of IP
injected ethanol solution to 37 C didn't have major impact) [193]. Ideally, future studies should not use ethanol as a vehicle component. The problem is not its hypOthermia, which is safely mitigated by a higher ambient temperature [193]. But because at just a slightly higher ambient temperature than this, ethanol can cause hypERthermia [193]. And the ambient temperature that safely mitigates ethanol driven hypothermia, without causing ethanol driven hyperthermia, varies with the ethanol dose [193]. This [ethanol dose/ambient temperature/hypothermia/hyperthermia/safe rectal temperature] matrix can be mapped by experimentation, and indeed there is much in the literature already e.g. non-limiting examples: [193-199], to guide the best use of ethanol as a vehicle component in future studies. However, this experimentation can be avoided: alternative vehicle options, which are not a potent drug in and of themselves, as ethanol is, are well known to those of the art, e.g.
see [200-201]: one or more of these can be employed as an alternative. When ethanol as vehicle is used, the fraction of rectal temperature drop accountable to the test drug can be calculated by subtracting any rectal temperature drop observed just with the ethanol containing vehicle control (assumes that ethanol and drug induced rectal temperature drops are additive and not potentiating). Drug induced rectal temperature reductions in this study, when they occur, are dose-dependent and well in excess of any rectal temperature drop observed when only ethanol containing vehicle control is injected.
The presented data shows that inhibiting the reverse mode of ATP synthase reduces body temperature. 6b potently inhibits the reverse mode of ATP synthase (IC5o=
0.018 j.tM [5-6]), 6a does not (IC5o> 100 M [5-6]). 6b potently reduces rectal temperature, 6a does not (it does to a minor degree, which is evidence for in vivo epimerization of 6a to 6b, on a faster timescale than 6a clearance). A significant reduction in body temperature is lethal. Thence the maximal tolerated dose (MTD) of 6b, at room temperature = ¨22 C, is lower than the MTD
of 6a. Body temperature cannot fall below ambient temperature and so the MTD
of 6b is increased by ensuring ambient temperature is closer to the normal mouse body temperature, which ensures that mouse body temperature is maintained at an acceptable value. This brings greater alignment between the MTD of 6a and 6b, which in the case of 6a is very safe: LDso >40 mg/kg (IV). This is safer than the FDA approved anti-depressants clomipramine HCl and imipramine HC1: LD50 (mouse, IV} of 22 mg/kg and LD50 (mouse, IV} of 27 mg/kg respectively (Register of Toxic Effects of Chemical Substances, RTECS). Some patients take these drugs daily, safely, for years.

Non-limiting example embodiments to maintain mice, or some other animal, including humans, at a life permissive body temperature, whilst having a compound of this disclosure in their body, include locating them in a temperature-controlled room or confmement. For example, in small animal experiments, a plant growth (e.g. Precision Refrigerated Plant-Growth Incubators, Thermo Fisher Scientific Inc.) or egg or veterinary or animal intensive care unit (ICU) incubator or similar type device. To illustrate, and not constrain, incubators are made by Darwin Chambers Inc. Powers Scientific Inc, Brinsea Products Ltd.
(particularly favoured is its Vetario range e.g. Vetario S50 model), Lyon Technologies Inc.
An embodiment is to administer a compound of this disclosure to an animal(s), including human(s), in a hot country, geography or climate e.g. Dubai or somewhere else in the Middle East, more preferably during summer when it has high daytime and night temperatures. There are many methods in the literature to keep rodents at elevated temperature, easing the cold stress they feel at typical room temperatures [62]: e.g. partially submerging water proof mouse cages into fish tanks, in use as water baths, heated by thermostatic electric fish tank heaters [204], or by heating cages with chemical reaction hand warmers [202-203]. Such methods, or any method with equivalent intention, when employed with an animal(s)/human(s) with a compound of this invention in its body, is componentry to this invention. Adaptive heating can be employed, which adjusts the heating element output (e.g.
an infrared lamp, or any other heating element(s)) in response to the measured body temperature (e.g. by rectal temperature probe or by thermal imaging, or any other body temperature recording device(s)), to maintain a life-permissive body temperature, when a compound of this invention is in the body. With a compound of this disclosure, the need for (and amplitude of) ambient temperature intervention is more important for smaller than larger animals e.g. more so for a mouse (-20 g) than a rat (-150 g). If an experimenter has to work with a compound of this disclosure at typical room temperature (20-25 C) then the test species, and individual(s), chosen should be as large as possible. All methods of maintaining body temperature within a temperature range that permits life, whilst having a compound of this invention in the body, are componentry to this invention. For (non-limiting) example, .. wearing clothes.
In some invention embodiments, when the subject has a compound(s) of this invention in its system, for example a compound(s) of Formula (I), the subject is kept in an ambient temperature at or near 37 C i.e. at or near the optimal body temperature of a mammal. This ensures that the subject's body temperature cannot fall below this optimal body temperature.
This renders a compound(s) of this invention safer and tolerable at higher dose, which can enable the compound(s) to safely convey greater therapeutic utility e.g.
greater anti-cancer activity. To illustrate by analogous example, anaesthetic can dramatically reduce subject body temperature, but not when the body is kept at 37 C ambient temperature [205].
An ambient temperature equal to optimal body temperature can keep body temperature at its optimum when a compound(s) that reduces body heat generation and/or increases body heat dissipation is administered to the subject.
Figure (23D): diagram, prediction, not real experimental data. Compound 6b reduces FIFO
ATP hydrolysis, reduces futile cycling of ATP synthesis and hydrolysis, thence reduces metabolic heat generation. If body temperature (BT) is greater than ambient temperature (AT), 6b reduces BT to be closer to AT, but it canNOT reduce BT below AT. 6b can reduce BT to more nearly above AT (BT=AT), not completely reducing BT=AT because there are other aspects to metabolic heat production than F IF ATP hydrolysis, which 6h does not reduce, and so BT remains higher than AT (BTzAT<BT), unless the animal dies, in which case BT=AT. If AT is at or above optimal body temperature, upon 6b administration, BT will remain at this optimum because 6b canNOT reduce BT below AT.
Figure (23E): This is a diagram relating to mouse and does NOT present real data, although it is inspired by experimental data in [62] and experimental data herein. When ambient equals thermoneutral temperature, which is ¨32 C normally for a mouse [62], the mouse's basal heat production (heat production of the basal metabolic rate) is sufficient to maintain body temperature at ¨37 C. At lower ambient temperatures than this, greater metabolic rate/heat production (thermogenesis) is required, and at higher ambient temperatures than this, greater metabolic rate is required for cooling, all to maintain body temperature at ¨37 C. A specific FIF0 ATP hydrolysis inhibitor, e.g. compound 6b, reduces the mouse's basal metabolic rate and shifts its thermoneutral temperature higher, illustratively to 35 C in this figure, which makes the mouse more comfortable (lower metabolic rate) at higher ambient temperatures.
Furthermore, this figure anticipates that FIE) ATP hydrolysis is integral to thermogenic metabolic rate, in addition to basal metabolic rate, and so the gradient of the thermogenic metabolic rate increase is shallower, because of reduced FIN ATP hydrolysis, and thus the mouse is unable to maintain 37 C body temperature at lower ambient temperatures than its thermoneutral temperature. The metabolic rate at thermoneutral temperature =
35 C was selected by drawing a line from metabolic rate at thermoneutral temperature =
32 C, = 10 W/Kg, which is an experimental data point from classic Herrington albino mouse study described in [62], to 37 C on the x-axis (thermoneutral temperature = 37 C, metabolic rate =
0 W/kg) and selecting the corresponding metabolic rate for 35 C on this line.
Accordingly the basal metabolic rate was 60% lower and, in accordance, the gradient of the thermogenic plot was reduced by 60% also, anticipating that FiFo ATP hydrolysis contributes equally to basal and thermogenic metabolic rates, although it probably contributes more to the thermogenic than basal metabolic rate, in which case the ascending thermogenic metabolic gradient can be shallower, and the descending body temperature gradient steeper, than shown (although it cannot outpace the gradient of ambient temperature decline: the mouse body temperature must be higher or at {if metabolism=0 W/kg} ambient temperature). Conclusion:
mice administered with 6b compound can't survive at as low temperatures than vehicle treated mice. However, if kept at higher temperatures, at or safely greater than their thermoneutral temperature, the lower metabolic rate of 6b administered mice confers them longer lifespan.
When the connection between work (unit: joule) and time is disrupted, the simple correlation between age and time is broken. Oxidative metabolism produces damaging/aging reactive oxygen species (ROS) and a lower oxidative metabolic rate produces less ROS
per unit time, reducing the damage/aging rate, extending lifespan. An older (in time) 6b administered body can be younger (in aging/damage) than a younger (in time) vehicle administered body. Like a car, the less miles per unit time it drives, the longer it lasts, like a body metabolism, the less oxidative work (joules) it performs per unit time, the longer it lasts (P.S.
health benefit of exercise doesn't breach this: exercise provokes adaptive changes that means the body works less at rest, e.g. endurance athletes have lower resting heart rate, = net reduction in work performed by body).
Figure 24: IF! is a determinant of lifespan. Background: smaller species have a greater metabolic rate per unit mass, faster heartbeat and shorter lifespan than larger species [206].
Smaller species live fast, die young. Larger species live slower for longer.
Herein I disclose a reason/mechanism for this and how to manipulate it.
Figure: data in upper two figure panels is from [207], data in lower two panels is from the AnAge database [208]. Interpretation here is novel. There was some margin for error in marrying these two data sets because [207] uses imprecise terms such as sheep, hamster etc.
wherein there are a number of different species in [208] that can fall into these categories. But a common sense alignment was applied in each case, by estimating which species [207]
likely had easiest access to, so most likely used, and so most likely refer to. So, the 12 species that the present figure refers to are: cow (domestic cattle, Bos taurus), mouse (house mouse, Mus musculus), rat (Rattus rattus), hamster (golden hamster, Mesocricetus auratus), guinea pig (Cavia porcellus), pigeon (common wood-pigeon, Columba palumbus), chicken (red junglefowl, Gallus gallus), rabbit (European rabbit, Oryctolagus cuniculus), sheep (domestic sheep, Ovis aries), pig (wild boar, Sus scrofa), dog (Canis familiaris) and human (Homo sapiens). All warm blooded. Specific metabolic rate data wasn't available in [208] for all these species, thence the smaller number of data points in the 3rd figure panel. The maximum longevity of human from [208] (122.5 years) isn't shown in the figure because arguably this value isn't fairly comparable to the others shown, because modern medicine is disproportionally applied to humans and the verifiable longevity data set for humans is much, much bigger with so many countries recording births and deaths (the bigger the data set the greater the chance a higher maximum longevity will be found). Human could perhaps be more comparably incorporated by using a maximum longevity record from a small human data set, to mirror the small data sets for the other species, wherein this data set comes from humans living in the past e.g. from 1881 Germany where life expectancy of men and women was 35.6 and 38.5 years respectively (Statistisches Bundesamt Deutschland, www.destatis.de). However, omission was chosen instead. For domestic cattle (mass=500 kg), maximum longevity of 20 years is used in my figure, which is from [208], but [208] do caution that this value is of "questionable" quality and say in this entry's "observations"
section that the real value is likely to be higher, which if applied, would make the positive trend shown here, between body mass and lifespan, stronger.
.. The 1st figure panel shows a negative correlation between species size and mass specific FiFo ATP hydrolysis during ischemia. The 3rd figure panel shows a negative correlation between species size and mass specific metabolic rate. The 2'd figure panel shows a negative correlation between species size and heart rate, wherein bpm refers to beats per minute. The 4th 4 figure panel shows a positive correlation between species size and maximum longevity (maximal recorded lifespan). Herein disclosed, the 1st panel correlation drives the 3rd panel correlation which drives the rd panel correlation which drives the 4th panel correlation.
The following table presents the Pearson correlation coefficients, with associated p values below, for the different relationships.

Pearson R correlation Coefficient Heart rate Specific metabolic rate Maximal longevity Specific ATPase during ischemia 0.8007 0.5331 -0.7194 Heart rate 0.9034 -0.8567 Specific metabolic rate -0.7472 P value Heart rate Specific metabolic rate Maximal longevity Specific ATPase during ischemia 0.001753 0.139433 0.01265 Heart rate 0.000838 0.00075 Specific metabolic rate 0.033192 IF1 inhibits FIFO ATP hydrolysis. IF I inhibits F1F0 ATP hydrolysis more during ischemia but its inhibition of FIR ATP hydrolysis is non-zero under normal conditions.
Larger species inhibit specific FIFO ATP hydrolysis more than smaller species during ischemia (1' figure panel). This is because larger species have greater 1F1 abundance, indeed a greater IF1/F1 ratio, and/or because their IF1 has greater inhibitory potency against F iFo ATP hydrolysis [207-219]. Thence there is a positive correlation between species size and their capability to inhibit their FIFO ATP hydrolysis i.e. the bigger the species, the less FIE) ATP hydrolysis.
Animal mass is proportional to animal radius3, animal surface area is proportional to animal radius2 [220]. So, smaller animals have a larger surface area to mass ratio and so lose a greater proportion of their heat to the environment and so need to generate more heat per unit mass than larger animals, which they do by a greater metabolic rate per unit mass, which they achieve by greater specific FiF0 ATP hydrolysis, which consumes more ATP per unit mass/time, which requires more ATP be created per unit mass/time, and thence a greater metabolic rate, thence a greater specific heat production. So, smaller species have greater specific FIN ATP hydrolysis capacity than larger species (1st figure panel).
That FiF0 ATP
hydrolysis is used for heat production by animals is shown by greater FIFO ATP
hydrolysis capability, because of greater FIFO ATP synthase and lesser IF! abundance, in mitochondria sourced from cows in winter than summer, wherein such seasonal changes don't occur in laboratory rats kept at constant temperature [209]. Furthermore, in new experimental data disclosed herein, specifically inhibiting FIN ATP hydrolysis in mice reduces their heat generation and body temperature. Because smaller species have a higher specific metabolic rate than larger animals, more fuel/waste is needed/ejected per unit mass per unit time, and they require and have a faster heart rate (2nd figure panel). Smaller species have a greater specific metabolic rate (3rd panel), faster heart rate (2n(1 panel) and lower lifespan (4th panel), wherein I inventively suggest this is a function of their greater FIN ATP
hydrolysis capacity (1' panel) as a function of their lesser IF' inhibitory capacity. And thence increasing the abundance of IFI in a species, and/or expressing/administering the IF1 amino acid sequence of a larger and/or longer living species, increases the lifespan of a species, IF exogenous heat (and/or greater body insulation) substitutes for the lower endogenous heat production that will ensue. Similarly, a specific/preferential drug inhibitor(s) of FIFO ATP
hydrolysis, for non-limiting example a compound(s) of Formula (1) herein, increases the lifespan of a subject, IF
exogenous heat (and/or greater body insulation) substitutes for the lower endogenous heat production that will ensue. An invention embodiment is a method of administering a specific or preferential inhibitor(s) of FiFo ATP hydrolysis, for non-limiting example a compound(s) of Formula (I-V, VII) herein, to a subject to extend their health and/or lifespan. An invention embodiment is a method of increasing the amount of IF! in a subject to extend their health and/or lifespan. An invention embodiment is a method of administering a subject one or more of an IF1 protein, which has a greater inhibitory potency against FIFO ATP
hydrolysis than their endogenous IF1, especially at pH 8, to extend their health and/or lifespan, optionally wherein one or more of a gene or nucleotide or DNA or RNA is administered that is translated into such an IF! protein. An invention embodiment is to express/administer the IF I
of a larger species in a smaller species to increase the health and/or lifespan of the smaller species. An invention embodiment is to express/administer the IFI of a longer living species in a shorter living species to increase the health and/or lifespan of the latter.
Figure 25: In vivo, inhibiting FiFo ATP hydrolysis safely reduces the rate of oxidative phosphorylation and ROS generation (and thence the rate of aging). Shown in forebrain neurons. This figure presents re-interpreted data from [322].
[322] is an illustrative example of how an IF1 gene copy, or a mutant thereof, from the same or different species, can be transferred into an organism in order to increase its IF1 protein expression. This example shows it is safe in mouse brain (more specifically neurons in forebrain) to increase IF1 protein content by three times (300%), wherein the delta increase in [322] occurs with a mutant human IF I form with increased inhibitory potency against FIFO
ATP hydrolysis at pH 8, which reduces FIFO ATP hydrolysis capability by ¨35%, which demonstrates the safety of inhibiting FiFo ATP hydrolysis in vivo, at least specifically in forebrain neurons (mice were "normal in appearance, home-cage behaviour, reproduction, and longevity up to 1-year follow-up").
(Figure 25A) MitoSOXTM, an ROS (superoxide) reporting fluorogenic dye, accumulates more in the mitochondrial matrix than Tetramethylrhodamine Methyl Ester Perchlorate (TMRM), a fluorescent dye used to report TIM.
(Figure 25B) Experiments with mitochondria extracted from the brain of wild-type mice (wt) and double transgenic mice (H+/T+) with (1) a mutant human IF1 mutant gene (H49K), with a histidine (H) in its "pH dependence motif' {Figure 29) substituted with lysine (K), under a tetracycline-responsive promoter element (TRE) and (2) a tetracycline-controlled transactivator protein gene (tTA) under the control of the CaMKIIa promoter, wherein CaMKIIa is only expressed in forebrain neurons [323], thence tTA and thence the human H49K IF1 gene is only expressed in the mouse's forebrain neurons (in the absence of a .. tetracycline(s) e.g. doxycycline), wherein their IF1 amount (native +
mutant) is 3 times (i.e.
300%) greater than wild-type. H49K mutation renders IF1 with greater inhibitory potency against F1 F0 ATP hydrolysis at normal matrix pH (8). FiFo ATP hydrolysis is 35% less in brain mitochondria isolated from H+/T+ than wild-type mice. The reduction in hydrolysis doesn't match the increase in IF1, perhaps because an IF1 fraction is inactivated .. by phosphorylation on its "phosphorylation control switch"/serine {Figure 29), wherein in some invention embodiments, IF1 is used with this serine substituted for another residue, optionally alanine, so that it can't be phosphorylated at this position and inactivated, and in further embodiments, wherein this IF I also has a H49K substitution. H+/T+
mice have a lower respiration (02 consumption, including oligomycin sensitive 02 consumption) rate than wild-type, during State 4 (substrate [e.g. glucose, malate] stimulated) and State 3 (+ADP
stimulated) respiration. Probably as a function of their lower respiration rate, H+/T+ mice have a more hyperpolarized membrane potential across their mitochondrial inner membrane, Pm (also referred to as Tim herein), because not so much of their proton motive force (cant) is being eroded per unit time to drive ATP synthesis. However, upon FCCP/antimycin A
administration, H+/T+ mice have a more depolarized Tim than wild-type because the response to an uncoupler/respiratory chain inhibitor involves global reversal of ATP synthase and FIR, ATP hydrolysis to pump protons, partially maintaining TN, wherein hydrolysis capability is partially compromised in H+/T+ mice.

(Figure 25C) Experiments with cortical neurons in culture, after being cultured for 9-10 days, after being extracted from mouse embryos. The 1S and 2"d panel shows disparity in Tim between H+/T+ and wild-type (CRL) mice again, as in Figure 25B, but this time in cultured cortical neurons from the mice (embryos), wherein the mitochondria of H+/T+
mice have a more hyperpolarized Tim (accumulate more TMRM+) than wild-type but, as in Figure 25B, have a more depolarized TIM upon FCCP/respiratory chain inhibitor (antimycin A/rotenone) administration. A typical value for TIM in normal mitochondria is -140 mV and if we equate the 5 a.u. value for wild-type in the 2nd panel with -140 mV, then the 6 a.u.
value of H+/T+
here in the 2"d panel is -168 mV. This Tim disparity means that H+/T+
mitochondria .. accumulates more MitoSOX ROS (superoxide) reporting compound in their mitochondria]
matrix, wherein this disparity can be calculated using the equation developed in Figure 25A, and this disparity is shown here, in the 3rd panel. With this MitoSOX
accumulation disparity, one would expect a greater MitoSOX signal from H+/T+ mitochondria, to wild-type mitochondria, in the proportion shown in the 3rd panel, but what is actually experimentally .. observed is in the 4111 panel. Thence H+/T+ mitochondria must produce 66%
less ROS
(superoxide) than wild-type, which fits with their lower oxidative respiration rate observed in (Figure 25B). Thus, given that ROS are the drive to aging [325, 326], H+/T+
cells have a slower aging rate than wild-type. Indeed, the reduced ROS in the forebrain neurons of H+/T+
mice is likely underestimated by this in vitro cultured neuron assay. H+/T+
neurons have less 02 consumption, as shown in (Figure 25B), and so in neuron culture, because of this lesser 02 consumption, H+/T+ neurons experience greater p02 near their respiratory chain, which favours increased [ROS], wherein this is an experimental artefact because in vivo reduced 02 consumption doesn't increase p02, because breathing (rate, depth etc.) maintains tissue p02 within a narrow range.
[322] interpret the lesser 02 consumption of H+/T+ mitochondria as evidence that IF1 directly inhibits FIFO ATP synthesis (which suggests no clinical utility because Fi Fo ATP
synthesis is essential to aerobic life). This is incorrect. As elucidated by the invention of this disclosure, substantial FIFO ATP hydrolysis is occurring under normal conditions in mice, which sets OXPHOS at high rate, to generate heat, as disclosed by novel experimental data herein (Figure 23). Increased [IF1] inhibits FIFO ATP hydrolysis more, and so less ATP
needs to be made by FIF0 ATP synthesis, thence less OXPHOS is required, less 02 is consumed (when Fi Fo ATP hydrolysis capability is reduced by ¨35% there is ¨60% less 02 consumption during State 3 respiration), thus less ROS are generated per unit time, thence aging is slower: ¨60% slower during State 3 respiration, by the invention of this disclosure, reinterpreting data of [322]. Less heat is produced, but because in this case this effect is limited to neurons of the forebrain, heat transfer from other mouse body regions, and from astrocytes in the forebrain (which don't express CaMKIla, so don't express tTA, so don't express the transgenic IF1 gene), maintains an appropriate temperature in forebrain neurons.
By the invention of this disclosure, the H+/T+ mice are disclosed to have slower aging in forebrain neurons, wherein they have reduced [susceptibility to/progression of] brain diseases of aging e.g. neurodegenerative diseases like Alzheimer's disease, dementia, Parkinson's disease etc., and less cognitive decline with aging (e.g. as assayed by one or more of the mouse behavioural assays disclosed elsewhere herein, or another "brainspan"/cognitive assay known to one of the art). This feature can be stopped by administering tetracycline/doxycycline to these mice, which blocks IF1 transgene expression in their forebrain neurons. By contrast to the present invention, [322] claim that this mutant IF1 gene introduction increases ROS and oxidative stress in mouse forebrain neurons.
Given the linkage between oxidative stress and the development/progression of neurodegenerative diseases [85], [322] teaches that these transgenic mice have increased susceptibility to/progression of neurodegenerative disease(s) than wild-type mice.
To briefly discuss some of the data in [322], that isn't replicated in this figure, but that is also .. re-interpreted herein. The protein carbonylation assay that [322] uses can be unreliable ("numerous problems with data reproducibility or production of spurious results" [324]) and/or, furthermore is corrupted by the large difference in [tubulin] between the H+/T+ and wild-type mice (refer the western blots; [tubulin] is used as a denominator in their carbonylation calculation). Brain of H+/T+ mice has less [ATP], but less [ADP]
also, and so the ATP/ADP ratio isn't changed. There is greater [AMP]. These H+/T+ mice have less ATP
and ADP because they have less cycling of FiFo ATP synthesis (ATP generation) and FiFo ATP hydrolysis (ADP generation), so a greater proportion of their nucleotide exists as AMP.
This, greater [AMP], activates the AMP-activated protein kinase (AMPK; more phosphorylated active AMPK is observed [322]), which upregulates glycolysis, wherein the extra NADH it produces isn't very thermodynamically inclined to enter an electron into the respiratory chain because of the hyperpolarised Tim (no "sink drive"), which comes from a reduced rate of [pmf erosion (FIFO ATP synthesis) to lesser pmf creation (FIR' ATP
hydrolysis) to generate heat]. More thermodynamically favourable is for lactate dehydrogenase to use this extra NADH, switching pyruvate to lactate, which is then exported, exporting this chemical energy to be accepted by a cell more in need of energy, elsewhere in the subject.
Figure 26: In vivo, inhibiting FiFo ATP hydrolysis safely reduces the rate of oxidative phosphorylation (and thence ROS generation (by extrapolation from data of Figure 25), and thence the rate of aging). Shown in liver cells (hepatocytes). This figure presents re-interpreted data from [327].
[327] is an illustrative example of how an IF I gene copy, or a mutant thereof, from the same .. or different species, can be safely transferred into an organism in order to increase its IF1 protein expression. Shown in this figure is data from experiments with mitochondria extracted from the brain of wild-type mice (CRL) and double transgenic mice (HIT) with (i) a mutant human IF1 mutant gene (H49K), with a histidine (H) in its "pH
dependence motif' {Figure 29} substituted with lysine (K), under a tetracycline-responsive promoter element .. (TRE) and (ii) a tetracycline-controlled transactivator protein gene (tTA) under the control of the rat liver-enriched activator protein (LAP; member of Cebpb gene family) promoter, wherein LAP is only expressed in liver cells, thence tTA and thence the human gene is only expressed in the mouse's liver cells (in the absence of a tetracycline(s) e.g.
doxycycline). In perivenous hepatocytes especially. These are "Tet-off' mice, expressing the transgenic IF1 gene (h-IF1) in the absence of a tetracycline e.g. doxycycline (Dox), as shown in the 1' panel, wherein the 2" panel shows the presence of h-IF1 in the mouse liver cells using an antibody specific for human over mouse IF I , wherein this added IF1 inhibits the FiFo ATP hydrolysis capability by 25% (31d panel) and decreases State 3 respiration rate by 37%. Alternative transgenic mice were also generated, "Tet-on" mice, which have rtTA
instead of tTA under the control of the LAP promoter, which only express the IF1 transgene in the presence of a tetracycline e.g. doxycycline (Dox), wherein this added IF I inhibits the FiFo ATP hydrolysis capability by 40% (31d panel) and decreases State 3 respiration rate by 44%. These experiments demonstrate the safety of inhibiting FiFo ATP
hydrolysis in vivo, at least specifically in liver (these transgenic IF1 mice had "no differences in weight, life span and cage behavior when compared to controls after one year of follow up").
Figure 27: In vivo, inhibiting FIFO ATP hydrolysis safely reduces the rate of oxidative phosphorylation (and thence ROS generation (by extrapolation from data of Figure 25), and thence the rate of aging). Shown in intestine. This figure presents re-interpreted data from [328].
[328] is an illustrative example of how an IF1 gene copy, from the same or different species, can be safely transferred into an organism in order to increase its IF1 protein expression.
Shown in this figure is data from mitochondria extracted from the colon of wild-type mice (CL), and double transgenic mice (I/T; "Tet-on") with (i) a human IF1 (non-mutant) gene under a tetracycline-responsive promoter element (TRE) and with (ii) the intestine-specific Villin-rtTA2-M2 transactivator, thence the human IF1 gene is only expressed in the mouse's intestine cells (in the presence of a tetracycline(s) e.g. doxycycline). This extra (human) IF1 inhibits the FiFo ATP hydrolysis capability by 35% and decreases oligomycin sensitive respiration rate by 60%. This experiment demonstrates the safety of inhibiting FiFo ATP
hydrolysis in vivo, at least specifically in intestine.
Figure 28: Diagram (not real data) illustrating how reducing [ROS] in a cell, for example by inhibiting FiFo ATP hydrolysis which reduces the oxidative phosphorylation/ROS
generation rate, can prolong/increase the information fidelity of genomic/mitochondrial DNA, which slows/reverses aging. ROS = reactive oxygen species. The terms in the Michaelis-Menten equation are extremely well known to those of the art. Figure 25 shows the mechanism, (inhibiting FIFO ATP hydrolysis which reduces the oxidative phosphorylation rate) and safety of reducing ROS in vivo. Figures 26 and 27 provide further proof of mechanism and safety.
Figure 24 elucidates that a different rate of FIFO ATP hydrolysis is why different species have different maximal lifespans. Any compound(s) administered and/or method(s) that reduces/inhibits FiFo ATP hydrolysis to slow/reverse aging, and/or extend lifespan/healthspan, in a subject is componentry to this invention, optionally wherein the expression/amount/activity of one or more DNA repair enzymes is increased in the subject also. For (non-limiting) example, any such use of a compound(s) of Formula I-V
and/or VII, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, a compound(s) of this invention, a FiFo ATP hydrolysis inhibitor(s), or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, is taken/administered before/during sleep, optionally wherein the subject sleeps in a temperature controlled/heated atmosphere, and/or where the subject is heated by radiative heating, optionally wherein exogenous heat substitutes for lower endogenous heat production by the subject (lower because of a compound(s) of this invention in their system), and wherein lesser ROS

production results, thence less DNA damage per unit time, optionally wherein the rate of DNA repair thence exceeds the rate of DNA damage and so there is net DNA
repair, wherein most DNA damage can still be recognised as damage (thence the possibility of being repaired) within a 24 hour period, which is a factor that permits the restorative action of sleep -- itself, which has a metabolism slowing/body temperature dropping (ROS
reducing) component, which a compound(s) of this invention increases/improves. In this way, the subject doesn't need to live in a temperature controlled environment whilst awake, just when they are sleeping, and/or during some other time(s) of their choosing. In some embodiments the subject, with a compound(s) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof in their system, wears heat generating/retaining clothing/device(s), optionally that monitors the subject's body temperature and adjusts its heat generating/retaining ability to maintain the subject's body at or near a desired body temperature (optionally at or near 37 C).
-- Figure 29: Some protein/peptide and nucleotide sequence embodiments of the invention, one or more of which, or a precursor(s)/mutant(s)/vector(s)/"expression vector(s)"
thereof, in an aspect of the invention, are used as a medicament/in the manufacture of a medicament/in a pharmaceutical composition, optionally for treating/ameliorating/preventing/combating cancer and/or slowing aging for therapeutic (including preventative)/aesthetic utility, optionally wherein a vector can be a nucleotide sequence that contains a nucleotide sequence(s) of this invention, optionally wherein the vector is/contains a nucleotide sequence(s) of this invention and one or more of a promotor (constitutive or inducible), enhancer, inducer, termination sequence, regulatory DNA sequence, optionally wherein the vector is a virus or plasmid, capable or incapable of replication inside a host cell, preferably -- wherein the vector in a host cell leads to the expression of one or more protein sequence embodiments of the invention in this host cell, many applicable vectors are known to those of the art. Protein sequences are disclosed here using the one letter amino acid code.
Componentry to the invention, without limitation, is a mammalian IF1, mouse IF
I, rat IF I, rabbit IF1, guinea pig IF1, bovine IF1, canine IF1, feline IF1, non-human primate IF! and -- human IF I protein. (29A) These are IF1 proteins from a diversity of species, all componentry to the invention, as are their sub-sequences, aligned to show the incredible conservation of the bolded residues. The Pt bolded reside, from left to right, is the "phosphorylation control switch" [329] (when phosphorylated, IF I cannot bind and inhibit FiFo ATP
hydrolysis) and the other 4 bolded residues constitute the "pH dependence motif' [330, 332, 334]

(underlining identifies a residue that deviates from the most stereotypical consensus sequence). In other protein sequence embodiments of the invention, one or more of these bolded residues is replaced with another amino acid coded for by the genetic code. For example, a bolded serine (S) residue can be replaced with another residue that can't be phosphorylated, so that the IF1 protein cannot be inactivated by phosphorylation at this "phosphorylation control switch". For example, serine replaced by alanine (A).
The four other bolded residues constitute the "pH dependence motif' and an amino acid substitution at one or more of its positions, optionally with lysine (K) or alanine, increases IF1 inhibition of FIFO ATP hydrolysis at pH 8, the normal (non-pathological) pH of the mitochondrial matrix.
Also componentry to this invention are sub-sequences of the shown sequences (and their forms with bolded residue(s) substituted for another amino acid coded for by the genetic code) as separate stand-alone protein sequence embodiments of the invention e.g. a sub-sequence without the "mitochondrial import sequence/signal" (wherein this import sequence for human is MAVTALAARTWLGVWGVRTMQARGF [335]) or with a different mitochondrial import sequence instead. Especially a sub-sequence with greater inhibition of Fi Fo ATP hydrolysis at 8. And/or a sub-sequence that aligns and corresponds to the "minimal inhibitory sequence" of bovine IF1, which is the smallest, minimal sub-section of bovine IF I that can inhibit FIFO ATP hydrolysis [330], wherein a non-limiting candidate "minimal inhibitory sequence" is shown in the figure, corresponding to bovine IF1 residues 14-47 (corresponding human "minimal inhibitory sequence" is SIREAGGAFGKREQAEEERYFRAQSREQLAALKK [335]), wherein it may actually be shorter/longer [330] than shown (e.g. 10-47 or 16-47 or 17-47) or different [330] (e.g.
residues 42-58 or (unlikely) 22-46 of bovine IF1). Following codes are "primary accession numbers" in UniProtKB database, SV = Sequence Version: (a) Q9UII2, Homo sapiens, SV=1, (b) H2PYG9, Pan troglodytes, SV=1, (c) G3QEV8, Gorilla gorilla gorilla, SV=1, (d) F6ZXX7, Macaca mulatta,SV=1, (e) A0A2U3VIM7, Odobenus rosmarus divergens, 5V=1, (f) A0A2Y9DM04, Trichechus manatus latirostris,SV=1, (g) A9XG49, Ailuropoda melanoleuca, SV=1, (h) E2QYN4, Canis lupus familiaris,SV=1, (i) M3WI58, Felis catus, SV=2, (j) F6ZXTO, Equus caballus, SV=1, (k) A0A384CECO, Ursus maritimus, SV=1, (1) Q03344, Rattus norvegicus, SV=2, (m) A0A2Y9LD45, Delphinapterus leucas,SV=1, (n) G3SWQ8, Loxodonta afi-icana,SV=1, (o) A0A2Y9EF27, Physeter catodon,SV=1, (p) G1SEZ3, Oryctolagus cuniculus,SV=1, (q) A0A286Y43 I, Cavia porcellus, SV=1, (r) A0A2U3VOR3, Tursiops truncatus,SV=1, (s) A0A383Z6R7, Balaenoptera acutorostrata scammoni,SV=1, (t) M3YVR5, Mustela putorius furo, 5V=1, (u) Q29307, Sus scrofa, SV=2, (v) P01096, Bos taurus, SV=2, (w) Bovine "minimal inhibitory sequence" [330, 331], (x) G5AP86, Heterocephalus glaber, SV=1 , (y) 035143, Mus muscu/us, SV=2, (z) S9XNE5, Camelus ferus, SV=1, (ai) A0A1S2ZPB9, Erinaceus europaeus, SV=1, (bi) A0A1U8CVF2, Mesocricetus auratus, SV=1, (ci) G1NSN7, Myotis lucifugus, SV=1, (di) A0A151PGL2, Alligator mississippiensis,SV=1, (ei) A0A0B8RSH7, Boiga irregularis, SV=1, (fi) H2TBT1, Takifugu rubripes, SV=1, (gi) F7BK26, Xenopus tropicalis, SV=1, (hi) A0A3B4D9E6, Pygocentrus nattereri, SV=1 , (ii) A0A1D5PBD2, Gallus gallus, SV=2, (ji) A3KNL5, Danio rerio, SV =1 , (ki) A0A0E9WGC1, Anguilla anguilla, SV=1. One of the art will know how to find further IF1 sequences of other/same species, not shown here for brevity, but which are also componentry to this invention (as are their sub-sequences embodied as separate stand-alone protein embodiments of this invention, and/or are their forms with their "phosphorylation control switch" position residue, and/or one or more of the residues in their "pH dependence motif', changed to another amino acid, wherein the character of these IF I
control modules is disclosed in Figure 29B). For example, one of the art can refer to InterPro family "Mitochondrial ATPase inhibitor (IPR007648)" and/or Pfam family "IATP
(PF04568)". All protein sequences in the IPR007648 and/or PF04568 protein families, and their sub-sequences, are componentry to this invention (and their "analogs", derivatives" and "variants", as herein defined). Or, for example, one of the art can use the human IF1 protein sequence (UniProtKB: Q9U1I2, SV=1) as the query string in a "Basic Local Alignment Search Tool" (BLAST, https://blast.ncbi.nlm.nih.gov) search of a protein database (protein BLAST, BLASTp), optionally the "non-redundant protein sequences" (nr) database at the National Center for Biotechnology Information (NCBI) which is one of the database options offered with NCBI BLAST, and/or use BLAST at UniProt and search the UniProt protein database (https://www.uniprot.org/blast/), and from the results outputted select protein sequences of high BLAST score/percentage sequence similarity (in different non-limiting embodiments: >99%, >98%, >95%, >90%, >80%, >70%, >60%, >50%, >40%, >30%
percentage sequence similarity) to the query protein, wherein BLAST results are returned to the user in order of BLAST score from high to low, and/or that have one or more IF1 motif characteristics, such as the "pH dependence motif'. Especially preferred are those proteins that have been annotated in the database as an IF1 protein and/or as a protein product of an ATP5IF1 (alternatively known as ATPIF1) gene, wherein the human ATP5IF1 gene has HUGO Gene Nomenclature Committee (HGNC) ID of HGNC:871, and IF1 protein products of orthologs of this gene are componentry to the present invention. One of the art knows, and/or knows how to find, multiple online methods to find orthologs e.g. using OrthoDB

(www.orthodb.org, to illustrate refer to Group 1566610at2759 and/or Group 212481at40674 therein). All protein products of an ATP5IF1 gene are componentry to the present invention.
For example, the human ATP5IFI gene has three protein products: primary accession numbers in UniProtKB: Q9U1I2, Q9U1I2-2 and Q9UII2-3, which are all componentry to this invention. When a single species has multiple IF1 proteins/homologs, e.g.
Heterocephalus glaber has G5AP86 and A0A0P6J910 (UniProtkb primary accession numbers), e.g.
Mus muscu/us has 035143, E9PV44 and Q8BTA7, e.g. Oryctolagus cuniculus has GI
SEZ3, G1TES2 and GI U0F8, they are all componentry to the invention. IF1 protein sequences (and their "analogs", derivatives" and "variants", as herein defined), and their sub-sequences, are .. componentry to the present invention as are the gene and DNA and mRNA and cDNA
sequences that can code (and the opposite complimentary base pairing strand of the coding sequence) for these protein sequences in a cell, wherein the genetic code, with its redundant character, is well known to those of the art, and wherein further nucleotide sequences that can hybridize with one or more of these nucleotide sequence embodiments of the invention, .. "under stringent conditions" (term well understood in the art, illustrative definition included herein), are also componentry to the present invention, as are the protein sequences that they encode. Given that many species have one or more of an IF1 protein sequence, and there are many species, there are many IF1 protein embodiments of the present invention.
Although I Fl sequences can vary between species, they are typically functionally interchangeable between different species [330], wherein even a yeast IF1 sequence can inhibit bovine FIN
ATP hydrolysis [333]. All protein sequences in the IPR007648 and/or PF04568 families of proteins, and their sub-sequences, are componentry to this invention. As are their "analogs"
and "derivatives" (herein defined, refer definitions section of disclosure).
As are their variants, wherein a "variant" is a sequence of >70% sequence similarity and/or identity, more -- preferably >80% sequence similarity and/or identity, and increasingly preferred: >90%, >95%, >98%, >99% sequence similarity and/or identity. One of the art knows, optionally guided by software (e.g. DNASTAR Software, optionally DNASTAR Lasergene package [DNASTAR, Masidon Wisconsin, USA]), amino acid substitution(s) that highly conserve structural/chemical properties such as one or more of polarity, charge, solubility, hydrophobicity, hydrophilicity, amphipathic character and so can select protein sequence substituents, and/or variants with amino acid insertions/deletions, that retain biological activity, which can still inhibit FiF0 ATP hydrolysis. For protein sequence embodiments of this invention, post-translational modification at one or more amino acid residues is contemplated by, and componentry to, the invention. Illustrative post-translational modifications include, without restriction, removing the initiator methionine residue, isomerization, methylation, alkylation, phosphorylation, glycation, glycosylation, 0-linked glycosylation, N-linked glycosylation, lipidation, acylation, acetylation, amidation (for example upon the C-terminus), deamidation, formylation, sulfation, succinylation, butyrylation, carbamylation, carbonylation, oxidation, biotinylation, pegylation, gamma-carboxylation, gamma-carboxyglutamic acid hydroxylation, pyrrolidone carboxylic acid, polysialylation, malonylation, hydroxylation, iodination, nucleotide addition (e.g. ADP-ribosylation), phosphate ester (0-linked) or phosphoramidate (N-linked) formation, adenylylation, uridylylation, propionylation, pyroglutamate formation, S-glutathionylation, S-nitrosylation, S-sulfenylation, S-sulfinylation, S-sulfonylation, myristoylation, palmitoylation, isoprenylation/prenylation, farnesylation, geranilgeranilatyon, glipyatyon, glycosylphosphatidylinositol (GPI) anchor formation, lipoylation, phosphopantetheinylation, one or more flavin moietys (FMN or FAD) may be covalently attached, heme C
attachment via thioether bonds with cysteines, retinylidene Schiff base formation, ubiquitination, SUMOylation. Especially preferred is modification to one or more amino acids of a protein sequence of this invention, wherein the modification(s) is known to those of the art to increase the plasma stability of a protein/peptide, for example, wherein this has been shown with one or more protein/peptide examples in the literature. Optionally, the protein can be N"-methylated at one or more places. For protein sequence embodiments of this invention, a D-amino acid in place of the corresponding L-amino acid, at one or more places, is componentry to this invention. For protein sequence embodiments of this invention, substitution at one or more positions with a non-classical amino acid (e.g. an amino acid not ordinarily used by humans/mammals/eukaryotes/living systems) is contemplated by, and componentry to, this invention. For protein sequence embodiments of this invention, replacement of a negatively charged amino acid with a non-negatively charged amino acid at one or more positions is componentry to the invention. As is modification at the C-terminus to remove its negative charge, for example by amidation, or wherein at the C-terminus, instead of COOH, there is C(0)R or C(0)N(H)R or C(0)NR2 or R, and/or at the N
terminus instead of NH2 there is N(H)R or NR2 or H or D or R or CH3 or C(H2)R or C(H)R2 or CR3, wherein R is independently at each point of use selected from alkyl (e.g.
C(CH3)3), substituted alkyl (non-limiting examples: CF3, CC13), deuterated alkyl (non-limiting example:
CD3), aminoalkyl, thioalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, any atom or isotope permitted by valence (including any accompanying hydrogen(s)/deuterium(s) by valence e.g.
(non-limiting), H, NH2, SH, SiH3, PH2, BH2 etc.) including, without limitation, La, Ti, Ce, V, Ta, Cr, Mo, Mn, Fe, Ru, Os, Co, Pd, Pt, Cu, Ag, Au, Zn, B, Al, Go, C, Si, N, P, As, Sb, Bi, 0, S, Se, F, Cl, Br, I, Hg. In an embodiment, one or more protein sequences of this invention, and/or one or more nucleotide sequences encoding one or more of such proteins, are administered to a subject to convey to them therapy/enhancement, optionally cancer treatment/amelioration/prevention/combat, optionally wherein one or more of said nucleotide sequences are incorporated into the subject's genome, and/or mitochondrial DNA, in one or more of their cells, optionally wherein the expression of this nucleotide sequence, to protein, is limited to a certain cell type/tissue type/organ/area/sub-section of the subject, optionally by the character of the promotor region incorporated with the protein(s) coding sequence and/or -- by where the sequence is targeted to insert into the genome and/or by where in the subject the nucleotide sequence (optionally in a vector) is introduced and/or by the nature of the vector selected. (29B) The "phosphorylation control switch" and "pH dependence motif"
of an IF1 protein [330, 332, 334]. In some invention embodiments, in an IF1 protein, the amino acid at the "phosphorylation control switch" is substituted with a different amino acid coded for by the genetic code, preferably one that can't be phosphorylated, optionally alanine (A). And/or, in other embodiments, one or more histidines (H), and/or tyrosine (Y), and/or the glutamine/glutamate, of the "pH dependence motif' is replaced with another amino acid coded for by the genetic code, optionally, without restriction, tyrosine (Y), alanine (A), lysine (K), glutamate (E), glutamine (Q), valine (V), leucine (L), isoleucine (I).
Especially preferred is lysine (K) replacing the histidine (H) marked with a *, which corresponds to a I-149K
(mature protein {mitochondria' import signal sequence cleaved off} numbering) substitution in the Bos taurus IF1 sequence. Alternatively, in alternative embodiments, arginine (R) replaces histidine at this position. (29C) Some protein sequences of the invention, which are modifications of the human IF1 protein (wherein, in further protein sequence embodiments, the N-terminal mitochondrial import sequence, MAVTALAARTWLGVWGVRTMQARGF, is absent). Other IF1 protein(s), from human and/or other species, can be modified at one or more equivalent amino acid sequence positions, i.e. at their own "phosphorylation control switch" and/or in their own "pH dependence motif', by the shown rationale of this figure, wherein these modified protein sequences are also componentry to the present invention, as are nucleotide sequences that code for them by the genetic code. Any protein sequence from InterPro family "Mitochondrial ATPase inhibitor (IPRO07648)", and/or Pfam family "IATP
(PF04568)", with one or more amino acid substitutions at its "phosphorylation control switch", and/or in its "pH dependence motif', wherein these sequence elements are herein defined, is componentry to the present invention. These protein embodiments, with one or more post-translational modifications (examples disclosed prior), are further embodiments of this invention. In further embodiments of the invention, not shown in the figure, the substituted residue at one or more of the 5 bolded positions can be any amino acid coded for by the genetic code (20 standard amino acids, 21 when selenocysteine included):
215=4,084,101 protein sequences, all componentry to the present invention (as are their post-translationally modified forms), as are nucleotide sequences encoding them by the genetic code. Further componentry to the invention are IF1 protein sequences containing selenomethionine and/or N-formylmethionine, optionally in place of methionine, and/or a "non-standard amino acid(s)" and/or a "non-proteingenic amino acid(s)" (e.g.
-- hydroxyproline) and/or a non-eukaryote amino acid(s) (e.g. pyrrolysine).
(29D) Especially preferred is an IF1 protein with the histidine (H) marked with a * in its "pH
dependence motif' (Figure 29B) replaced with a lysine (K). This figure shows illustrative IF1 proteins that have been modified at this position, wherein the site of lysine (K) substitution is bolded, as is the enduring remainder of the "pH dependence motif', which is unmodified, and the -- residue at their "phosphorylation control switch", which is unmodified.
These protein sequences are componentry to the present invention as are other modified IF1 proteins, not shown, which are modified in the equivalent position of their own "pH
dependence motif', as are nucleotide sequences that code for them by the genetic code, as are sub-sequences such as those with their N-terminal mitochondrial import sequence absent. Any protein sequence from InterPro family "Mitochondrial ATPase inhibitor (IPR007648)" and/or Pfam family "IATP (PF04568)", with the starred (*) histidine (Figure 29B) of its "pH
dependence motif' replaced with a lysine (K), is componentry to this invention. Illustrative IF1 proteins modified at this position are shown in this figure (wherein the original unmodified sequences are also componentry to this invention): (a) Q9U1I2, Homo sapiens, SV=1, (b) Q5RFJ9, -- Pongo abelii,SV=1, (c) A0A2R9CQC9, Pan paniscus, SV=1, (d) A0A2J8Y5Q9, Pongo abelii, SV=1, (e) H2PYG9, Pan troglodytes, SV=1, (f) A0A213H 1 P7, Nomascus leucogenys, SV=1, (g) G3QEV8, Gorilla gorilla gorilla, SV=1, (h) A0A2K6AYV8, Macaca nemestrina, SV=1, (i) A0A2K5Y149, Mandrillus leucophaeus,SV=1, (j) A0A2K5POW3, Cercocebus atys, SV=1, (k) G7NWV6, Macaca fascicularis, SV=1 , (1) A0A096NQ00, Papio anubis, -- SV=1, (m) F6ZXX7, Macaca mulatta,SV=1, (n) A0A0D9S814, Chlorocebus sabaeus, SV=1, (o) A0A2K6N3T3, Rhinopithecus bieti,SV=1, (p) A0A2K6Q8H8, Rhinopithecus roxellana, SV=1, (q) A0A2K5SG67, Cebus capucinus imitator, SV=1, (r) A0A2K6SEK8, Saimiri boliviensis boliviensis,SV=1, (s) A0A2K5KB15, Colobus angolensis palliatus, SV=1 , (t) A0A2K5DQW7, Aotus nancymaae, SV=1 , (u) F7IA10, Callithrixjacchus, SV=1, (v) A0A0D9SDU9, Chlorocebus sabaeus,SV=1, (w) AOA1D5QRM5, Macaca mulatta, SV=1, (x) A0A1U7SXJ3, Tarsius syrichta, SV=1, (y) A0A2K6Q8J3, Rhinopithecus roxellana,SV=1, (z) A0A2K6SEL7, Saimiri boliviensis boliviensis, SV=1, (ai) A0A2K6GYY1, Propithecus coquereli, SV=1, (bi) HOX2G2, Otolemur garnettii,SV=1, (ci) A0A2Y9GJM5, Neomonachus schauinslandi, SV=1, (di) A0A2K5J921, Colobus angolensis palliatus, SV=1 , (ei) A0A2U3VIM7, Odobenus rosmarus divergens, SV=1, (fi) L8Y809, Tupaia chinensis,SV=1, (gi) L5JUTO, Pteropus alecto, SV=1, (hi) A0A2Y9DM04, Trichechus manatus latirostris,SV=1, (ii) A9XG49, Ailuropoda melanoleuca,SV=1.
(29E) Further IF1 proteins modified to have a lysine (K) at the starred (*) position of their "pH
dependence motif' (Figure 29B), wherein sub-sequences are componentry to the invention, such as those with their N-terminal mitochondrial import sequence absent, as are the unmodified native IF1 proteins: (a) E2QYN4, Canis lupus familiaris, SV=1, (b) M3WIS8, Felis catus, SV=2, (c) F6ZXTO, Equus caballus,SV=1, (d) HOXQ94, Otolemur garnettii, SV=1, (e) A0A384CECO, Ursus maritimus,SV=1, (f) D2GWK3, Ailuropoda melanoleuca, SV=1, (g) I3N8E6, ktidomys tridecemlineatus,SV=1, (h) A0A2U3YF49, Leptonychotes weddellii, SV=1, (i) Q03344, Rattus norvegicus, SV=2, (j) A0A341D6Q8, Neophocaena asiaeorientalis asiaeorientalis, SV=1, (k) A0A2Y9LD45, Delphinapterus leucas,SV=1, (1) G3SWQ8, Loxodonta africana,SV=1, (m) A0A2Y9EF27, Physeter catodon, SV=1, (n) G1SEZ3, Oryctolagus cuniculus, SV=1 , (o) A0A286Y431, Cavia porcellus, SV=1, (p) A0A340XS26, Lipotes vexillifer, SV=1, (q) A0A2U3Y890, Leptonychotes weddellii, SV=1, (r) A0A1A6FZ83, Neotoma lepida,SV=1, (s) A0A2Y9J3D1, Enhydra lutris kenyoni,SV=1, (t) A0A2U3VOR3, Tursiops truncatus,SV=1, (u) A0A383Z6R7, Balaenoptera acutorostrata scammoni, SV=1, (v) M3YVR5, Mustela putorius furo,SV=1, (w) Q29307, Sus scrofa, SV=2, (x) L8IJ24, Bos mutus,SV=1, (y) P01096, Bos taurus, SV=2, (z) A0A250Y8Y0, Castor canadensis,SV=1, (ai) G5AP86, Heterocephalus glaber, SV=1, (bi) 035143, Mus muscu/us, SV=2, (ci) G3H1Z3, Cricetulus griseus, SV=1, (di) S9XNE5, Camelus ferus, SV =1 , (ei) A0A1S2ZPB9, Erinaceus europaeus, SV=1, (fi) A0A1U8CVF2, Mesocricetus auratus, SV=1, (gi) A0A091E4M7, Fukomys damarensis, SV=1, (hi) GIU0F8, Oryctolagus cuniculus, SV=1 , (ii) G1PGS1, Myotis lucifugus, SV =1, ai) F7BE70, Monodelphis domestica, SV=1, (ki) W5NYG6, Ovis aries, SV=1. (29F) Compare and contrast this figure with Figure 29B, wherein the present figure shows a scheme for especially preferred IF1 protein sequence embodiments of this invention, which have a "phosphorylation control switch" that is locked in the "on" position, and an "attenuated pH dependence motif' in place of a "pH dependence motif'. (29G) Especially preferred is an IF1 protein with the residue in its "phosphorylation control switch" position set to alanine (A) and the starred (*) histidine (H) of its "pH dependence motif' (Figure 29B) replaced with a lysine (K). This figure shows illustrative IF1 proteins that have been modified in this way. These protein sequences are componentry to the present invention as are other modified IF1 proteins, not shown, which are modified equivalently, as are nucleotide sequences that code for them by the genetic code, as are their protein and nucleotide sub-sequences, such as those with their N-terminal mitochondrial import sequence absent. Any protein sequence from InterPro family -Mitochondria] ATPase inhibitor (IPR007648)" and/or Pfam family "IATP
(PF04568)", with the residue in its "phosphorylation control switch" position (Figure 29B) set to alanine (A) and the starred (*) histidine (Figure 29B) of its "p1-1 dependence motif' replaced with a lysine (K), is componentry to this invention. Illustrative IF1 proteins modified at these two positions are shown in this figure (wherein the original unmodified sequences are also componentry to this invention): (a) Q9U1I2, Homo sapiens, SV=1, (b) P01096, Bos taurus, SV=2, (c) 035143, Mus muscu/us, SV=2, (d) Q03344, Rattus norvegicus, SV=2, (e) G1SEZ3, Oryctolagus cuniculus, SV=1 , (f) A0A286Y431, Cavia porcellus, SV=1 , (g) E2QYN4, Canis lupus familiaris,SV=1, (h) M3WIS8, Felis catus, SV=2, (i) F6ZXTO, Equus caballus,SV=1, (j) G5AP86, Heterocephalus glaber, SV=1, (k) G3H1Z3, Cricetulus griseus, SV=1, (1) A0A1U8CVF2, Mesocricetus auratus,SV=1, (m) M3YVR5, Mustela putorius furo, SV=1, (n) A0A2Y9LD45, Delphinapterus leucas, SV=1 , (o) G3SWQ8, Loxodonta africana, SV=1, (p) A0A2Y9EF27, Physeter catodon, SV=1 , (q) Q5RFJ9, Pongo abelii, SV=1, (r) A0A2R9CQC9, Pan paniscus, SV=1, (s) A0A2J8Y5Q9, Pongo abelii, SV=1, (t) H2PYG9, Pan troglodytes, SV=1, (u) A0A213H1P7, Nomascus leucogenys, SV=1 , (v) G3QEV8, Gorilla gorilla gorilla, SV=1 , (w) A0A2K6AYV8, Macaca nemestrina, SV=1, (x) A0A2K5Y149, Mandrillus leucophaeus, SV=1, (y) A0A2K5POW3, Cercocebus atys, SV=1 , (z) G7NWV6, Macaca fascicularis, SV=1, (ai) A0A096NQ00, Papio anubis, SV=1, (bi) F6ZXX7, Macaca mulatta,SV=1, (ci) A0A0D9S814, Chlorocebus sabaeus, SV=1, (di) A0A2K6N3T3, Rhinopithecus bieti, SV=1, (ei) A0A2K6Q8H8, Rhinopithecus roxellana, SV=1, (fi) A0A2K5SG67, Cebus capucinus imitator, SV=1, (gi) A0A2K6SEK8, Saimiri boliviensis boliviensis, SV=1, (hi) A0A2K5KB15, Colobus angolensis palliatus,SV=1, (ii) A0A2K5DQW7, Aotus nancymaae, SV=1 (29H) Some preferred protein sequence embodiments of the invention, applying teaching of Figure 29F to the Human IF1 protein sequence. In further protein sequence embodiments, shown, the N-terminal mitochondrial import sequence, MAVTALAARTWLGVWGVRTMQARGF, is absent. (291) DNA and protein sequence for Human IF1 protein, and a mutant thereof, wherein two different DNA

sequences coding for this IF1 mutant protein sequence are presented, illustrating the redundancy of the genetic code. In further sequence embodiments, not shown, the N-terminal mitochondrial import sequence is absent. (29J) Consensus DNA and protein sequence for Human IF I protein, and a mutant thereof. (29K) Number of DNA sequences that code, using the genetic code, for the Human IF1 protein, and a mutant thereof. (29L) The human ATPIF I
gene, shown, with IF1 protein sequence coding and non-coding regions, is componentry to this invention, as are its sub-sequences and variants e.g. with a different codon(s) used for coding the same amino acid (or stop). (29M) Some protein and DNA sequence embodiments of the invention. The termination sequence shown is illustrative and not restrictive. Any other termination sequence (enables release of RNA polymerase during transcription) can be used in its place, wherein such sequences may comprise, without limitation, a stop codon(s), thymine rich region(s) (poly-T tail), cytosine rich region(s), palindromic region(s) etc. and wherein a termination sequence can be added at the end of any sequence of this invention to become a further sequence of this invention. Furthermore, a different mitochondrial targeting sequence than shown may be used. (29N) Some protein and DNA sequence embodiments of the invention. (290) Componentry to the invention is to locate a DNA
sequence(s) encoding an IF1 protein sequence(s) of this invention in one or more mitochondria of a subject, wherein the DNA codons used are different (AGA and AGG are not used for arginine (R), one of CGT/CGC/CGA/CGG is used independently in each case instead; this figure presents some illustrative sequence embodiments of this invention with this modification), because mitochondria use a different genetic code than the nucleus, to enable the same IF1 protein sequence to be produced. (29P) Bovine IF1 protein, and some non-limiting sub-sequence embodiments of the invention, wherein all IF1 (all species) sub-sequences, or mutant(s) thereof, and/or concatenation thereof, are componentry to this invention, as are the nucleotide sequences that code for them. IF1 1-60 fragment can't dimerize and exists as a monomer [336], 10-46 has ten-fold less activity than 10-47 showing the importance of the 47th residue, 14-47 has been termed the "minimal inhibitory sequence" [331, 330], 22-46 can inhibit F1 ATP hydrolysis [337] but not F1 F0 ATP hydrolysis [338, 331]. 42-58 is an alternative "minimal inhibitory sequence" [338-341]. It might be that 42-58 inhibits FIR) ATP
hydrolysis by a different binding/mechanism than 14-47 and entire IF I . Also shown are further non-limiting IF1 sub-sequences of this invention, which interact with the oligomerization residue(s) {e.g. H49} of IF1, therein blocking IF1 oligomerization, whilst not blocking the inhibitory sequence of IF1 (which IF1 oligomerization [>dimer]
does), thus increasing free IF1 (monomer and/or dimer) and IF1 inhibition of FIFO ATP
hydrolysis.

(29Q) Sub-sequences of an IF1 protein or mutant thereof (and nucleotide sequences that code for them) are componentry to this invention, wherein illustrative example embodiments are shown. Human IF1 protein, and some non-limiting sub-sequence embodiments of the invention, wherein all IF1 sub-sequences, or mutant(s) thereof, and/or concatenation thereof, are componentry to this invention, as are the nucleotide sequences that code for them. (29R) A sub-sequence of an IF1 protein, or mutant thereof, in either orientation (N
to C, C to N), attached to a mitochondrial import sequence, in either orientation, optionally the mitochondrial import sequence of Human IF1 (MAVTALAARTWLGVWGVRTMQARGF) or that of a different IF1 protein, optionally that of a mammal, rodent or non-human primate, -- or attached to a mitochondrial import sequence of another protein that is located to the mitochondrial matrix, is componentry to this invention (as are the nucleotide sequences that code for it), wherein illustrative example embodiments are shown. (29S) An IF1 protein or sub-sequence thereof, and/or mutant thereof, in either orientation (N to C, C
to N), attached to a cell penetrating peptide sequence, in either orientation, optionally via a connecting -- glycine (increases flexibility between domains), wherein many such cell penetrating peptide sequences are known to those of the art (>1,800; e.g. refer to [343] for CPP
sequences, e.g.
the HIV-1 Tat cell penetrating peptide sequence, YGRKKRRQRRR), is componentry to this invention (as are the nucleotide sequences that code for it), wherein illustrative example embodiments are shown. Furthermore, a sub-sequence of an IF1 protein, or mutant thereof, in either orientation, attached to a mitochondrial import sequence, in either orientation, optionally the mitochondrial import sequence of Human IF1 (or that of a different IF1 protein, optionally that of a mammal, rodent or non-human primate, or attached to a mitochondrial import sequence of another protein that is located to the mitochondrial matrix), which is itself attached to a cell penetrating peptide sequence (many known to those of the art), in either orientation, optionally via a connecting glycine, is componentry to this invention (as are the nucleotide sequences that code for it), wherein illustrative example embodiments are shown. Encompassed by the invention: the domains can be ordered differently that shown in the figure e.g. the "mitochondrial import sequence"
can instead be "upstream" (closer to N terminus) of the "cell penetrating sequence" and all possible -- orientation (N to C, C to N) combinations are contemplated by this invention. At all places in this disclosure that a cell penetrating peptide, and/or CPP, is referred to, in other invention embodiments this is replaced/substituted with mitochondria penetrating peptide (MPP), wherein many such sequences are known to those of the art. To illustrate, and not restrict, refer to [344] or a paper/patent/patent application/document that cites it (e.g. [345]), or a paper/patent/patent application/document that cites a paper that cites it, or a paper/patent/patent application/document that cites a paper that cites a paper that cites it etc., optionally found using pubmed or google scholar. Or alternatively, cell penetrating peptide, and/or CPP, can be replaced/substituted with a non-peptide mitochondria targeting moiety, to illustrate (not restrict): [346-348]. (29T) An IF1 protein or sub-sequence thereof, and/or mutant thereof, in either orientation (N to C, C to N), attached to a cell penetrating peptide sequence (many known to those of the art), in either orientation, which is attached to an epitope tag sequence (many good tags known to those of the art), in either orientation, optionally wherein the cell penetrating peptide sequence is flanked by glycines (increases -- flexibility between domains), is componentry to this invention (as are the nucleotide sequences that code for it), wherein illustrative example embodiments are shown.
Furthermore, a sub-sequence of an IF I protein, or mutant thereof, in either orientation, attached to a mitochondrial import sequence, in either orientation, optionally the mitochondrial import sequence of Human IF I (or that of a different IF1 protein, optionally that of a mammal, rodent or non-human primate, or attached to a mitochondrial import sequence of another protein that is located to the mitochondrial matrix), which is itself attached to a cell penetrating peptide sequence (many known to those of the art), in either orientation, attached to an epitope tag sequence (many good tags known to those of the art), in either orientation, optionally wherein the cell penetrating peptide sequence is flanked by -- glycines, is componentry to this invention (as are the nucleotide sequences that code for it), wherein illustrative example embodiments are shown. Encompassed by the invention: the domains can be ordered differently than shown e.g. the "mitochondrial import sequence" can instead be "upstream" (closer to N terminus) of the "cell penetrating sequence" and/or "epitope tag sequence", the "cell penetrating sequence" can be "upstream" of the "epitope tag sequence" etc. Any IF1 protein sequence or sub-sequence or concatenation of sub-sequences, optionally mutant thereof, attached to a cell penetrating peptide and/or mitochondrial import sequence and/or epitope tag sequence, wherein all orientation (N to C or C to N) combinations are contemplated, is componentry to this invention, as are their coding nucleotide sequences. (29U) Collection of non-limiting invention embodiments.
(29V) Collection of non-limiting invention embodiments. (29W) Some invention embodiments:
non-limiting peptide inhibitors of FIFO ATP hydrolysis: melittin, pre-sequence of subunit IV
of yeast cytochrome c oxidase, Syn-A2, Syn-C and A11,12 [4], bovine Fi p subunit residues 394-413, 384-403, 404-423 [337], or mutant(s) thereof, and/or concatenation thereof, are componentry to this invention, as are the nucleotide sequences that code for them.

Encompassed by the invention: the domains can be ordered differently than shown e.g. the "mitochondrial import sequence" can instead be "upstream" (closer to N
terminus) of the "cell penetrating sequence" and/or "epitope tag sequence", the "cell penetrating sequence"
can be "upstream" of the "epitope tag sequence" etc. Any FIFO ATP hydrolysis inhibitory peptide or concatenation of such sequences, optionally mutant thereof, attached to a cell penetrating peptide and/or mitochondrial import sequence and/or epitope tag sequence, wherein all orientation (N to C or C to N) combinations are contemplated, is componentry to this invention, as are their coding nucleotide sequences. (29X) A few non-limiting example embodiments are shown, wherein all IF1 protein sequences and sub-sequences from all species, or mutant(s) thereof, and/or concatenation thereof, are componentry to this invention, as are the nucleotide sequences that code for them. In some embodiments one or more of the E in the EEE sub-sequence is replaced with an amino acid whose side-chain is not negative, optionally glutamine (Q) or asparagine (N), optionally a non-proteingenic amino acid, optionally 5,6-dehydrohomoleucine (CAS: 73322-75-5; available on labnetwork.com e.g.
from Arena Chemical, La Mure, France) or (S)-2-amino-5-methylhexanoic acid (CAS:
31872-98-7; available on labnetwork.com e.g. from Astatech Inc., Bristol PA, USA). In some embodiments, in place of one or more histidines, (S)-2-amino-3-(1H-imidazol-1-yl)propanoic acid (CAS 114717-14-5; PubChem CID: 12311022; available from BOC sciences, Shirley, NY, USA, PubChem SID: 254789149) is incorporated into the protein/peptide chain instead.
Optionally, one or more of the NH are replaced with NCH3, especially preferred at one or more places on the peptide backbone i.e. one or more Nu are methylated.
Optionally, instead of N(CH3)2 as shown here, N(CH3)3 is at the N and/or C terminal ends. Or N(H)R, NR2, CH3, C(H2)R, C(H)R2, CR3, R, wherein R is independently selected at each point of use from the options for R given earlier in this figure legend. D-amino acid in place of the corresponding L-amino acid, at one or more places, is componentry to this invention.
Figure 30: The stereoisomer excess (%) of 6b (and from this, by inference, 6a) is stable in stereoisomer excess stability experiments.

STEREOISOMER EXCESS STABILITY of 6b sample After 2.5 After months 72 hours stored as in water IN PHOSPHATE SOLUTION AT 37 C
powder @RT TIME=0 TIME=24 hours TIME=48 hours 6a fib 6a 6b 6a 6b 6a 6b 6a 6b Retention Time (minutes) 1.68 1.91 1.67 1.88 1.858 2.125 absent 2.117 1.892 2.142 Area under peak 0.66 33.6 0 9.87 0.34 24.28 Absolute excess (%) 99.34 99.41 98.07 100 98.62 Enantiomeric excess (%) 98.68 98.82 96.14 100 97.24 Retention times can vary because of different chiral-SFC columns (of different lengths) used.
RT=room temperature, 6b in water assay: water was in contact with air (and so CO2), thence (by inference) water pH ¨5.6. Phosphate buffer solution, 1 M, sourced from Sigma-Aldrich (product code: P3619), its recorded pH at the 37 C temperature used = 7.41. Enantiomeric excess =
(absolute excess-50)*2.
Figure 30A: 6b sample was incubated in phosphate (1 M) buffer solution at 37 C. Via chiral SFC-MS, utilising the chiral AD-3 column (IPAJPAm_10-40_Gradient_4m1_S), the stereoisomeric excess of 6b was recorded at the start (Time=0), after 24 hours, and after 48 hours in the phosphate solution, wherein this excess wasn't observed to be eroded. However, after this incubation in phosphate solution, in the 24 and 48 hour snapshots, a new RT peak (at RT=0.325 min) was seen, containing a molecular species at m/z 450.429, not observed at Time=0 (not above the level of noise; so it is not an impurity in the 6b compound sample, nor an impurity in the phosphate solution, nor an impurity in the chiral column step), nor observed after 72 hours incubation in water (data not shown), which shows that it probably isn't a hydrolysis product of the 6b compound. The m/z 450.429 species, and the m/z 391.406 species, both observed in the RT=0.325 min peak, are not observed in the RT=2.1 peak, which contains 6b: m/z 537.08 [M+H]+. Further data for Time=0, Time=24 hours, Time=48 -- hours incubation in phosphate solution is shown in Figures 30B, 30C and 30D
respectively.
So, this emergent RT peak likely relates to 6b compound reaction with phosphate. Possibly relevantly, phosphate is well known to facilitate (some mechanisms of) racemization (e.g. "at pH 7.4 the rate of [chiral] inversion was linearly dependent on phosphate concentration"
[359]). Enantiomer self-disproportionation (SDE) [360] is the separation of a non-racemic mixture (scalemate) of enantiomers into an enantioenriched fraction and a more racemic fraction i.e. in an Achiral separation, when a compound has strong intermolecular associative forces, a racemic fraction (of predominantly hetero (R, S') oligomers e.g. R-S
dimers) can elute separately (separate) from a fraction of enantiomeric excess (of predominantly homo oligomers or monomers), especially (but not restrictively) when the number of molecules in the (most thermodynamically favored) oligomer/monomer is different. In chiral (as opposed to achiral) separation, such as conducted here by chiral SFC, for some compounds (those with significant intermolecular associative forces), there is the potential (prediction) for 3 different RT peaks to be observed, corresponding to the R stereoisomer (monomer or homo-oligomer), S stereoisomer (monomer or homo-oligomer) and racemate (hetero-oligomer). In the presented data here, peaks observed at RT=1.8 and RT=2.1 minutes likely relate to the R and S stereoisomers and, if applicable, the RT peak for the racemate is out of the observed range (i.e. at a higher unobserved RT) or it could be the emergent RT=0.325 min peak, which emerges after compound 6b incubation in phosphate solution, wherein the mono-charged -- (+1) form of a 6b-6a hetero-dimer, or higher oligomer, is out of the m/z range observed within it, wherein a multi-charged oligomer species of 6b-6a could conceivably be within the observed m/z range, possibly relating to the m/z 450.429 species observed.
Although, alternatively, this emergent RT peak, with its m/z 450.429 species, could relate to phosphate related break up of 6b. In retrospect, what would have been helpful, which wasn't done, is inject 6a-6b racemate into the column to see what RT it elutes at. Then see if this RT peak emerges after 6b incubation in phosphate solution, wherein this would then indicate if 6b racemization is occurring in this experiment or not.
As disclosed elsewhere herein, 6a and 6b significantly epimerize within 48 hours in a biological system (NCI-60 testing). This ee instability in biological media is an unexpected result. This finding is componentry to the invention of this disclosure, as are any modifications to the structure of 6a or 6b to slow their ee erosion due to epimerization/racemization. The ee instability is unexpected because it runs contrary to theory. The 2nd order rate constant (kgb) for general-base catalysed racemization can be predicted for 6a and 6b by theory from [221] (and its supplementary information, all incorporated by reference). Joined to the stereogenic carbon of 6a and 6b there is a phenyl group, alkyl and a guanidine group: IAAG(RI,R2,R3) = -19.9 +2.8 -19.1 = -36.2 kcal/mol.
The value for the guanidine group (19.1) is not from [221] but from one of its authors, Dr.
Andrew Leach, by personal communication, who sourced it by quantum mechanical calculation with the Gaussian 03 software package. The cross-conjugation correction [221]
was not applied in this case because Dr. Leach wrote "I would not expect guanidine to be a conjugating group". log(kg) = -0.11 * IAAG(RI,R2,R3) - 9.81, Kgb =
0.00000148593 M-Is-1. This is not particularly fast. Not seeking to be bound by theory, racemization might occur faster for 6a and 6b in cells than predicted by theory because their high lipophibicity concentrates them in biological membranes. 6a logP = 5.97, calculated from 6a structure using [25]. This means 6a accumulates -1,000,000 times more in model-lipid octanol than water, which means 6a disproportionally accumulates in biological membranes, which drives it to high concentration, which permits significant intermolecular racemization. The protonable nitrogen atom of the 6a imidazole group pulls a proton off the stereogenic carbon of another 6a molecule, leaving a planar carboanion, and when a proton reattaches to this carbon there is an equal probability of it doing so from either side, and so there is a 50%
chance that the stereochemistry changes. Thence, racemization proceeds at a faster rate than predicted by methodology of [221], the present state of the art in racemization theory/prediction. The same process can apply to 6b. Deuterium in place of hydrogen on the stereogenic carbon of 6b decreases the rate of this racemization, because a carbon-deuterium bond is stronger than a carbon-hydrogen bond (kinetic istope effect, KIE) and this isotopologue of 6b is componentry to this invention. The difference in %
cancer growth inhibition between 6a and 6b for each cell line at 10 04 drug dose (in NCI-60 one-dose testing) correlates with the difference in % cancer growth inhibition between 6a and 6b for each cell line at 1 1.1M drug dose (in NC1-60 five-dose testing). Pearson correlation coefficient, R = 0.7919, p-value <0.00001, significant at p <0.05. This shows that there are cellular factors, which can vary between different cancer cell lines, determining the rate of 6a and/or 6b racemization. For example, this could be membrane volume and/or the level of expression of a racemase/epimerase enzyme(s), and/or an enzyme(s) that converts the drug into a form that can undergo enzyme-catalysed epimerisation. In NCI-60 one-dose testing at 10 04, across cell lines tested, there is a positive correlation between %
cancer growth inhibition of 6b and the product [(% cancer growth inhibition due to 6b) - (%
cancer growth inhibition due to 6a)]. Pearson correlation coefficient, R = 0.4167, p =
0.000927, significant at p <0.05. Thus, when the anti-cancer performance of 6a is further behind the anti-cancer performance of 6b, anti-cancer performance of 6b is better. This suggests that for 6a to have greater anti-cancer activity, 6b needs to have less anti-cancer activity.
Conversely, for 6b to have greater anti-cancer activity, 6a needs to have less anti-cancer activity.
This is because what gives 6a its anti-cancer activity, racemization, takes away anti-cancer activity from 6b.
Thus, in cancer cell lines that enable faster epimerization of 6a and 6b, there is greater 6a vs.
6b anti-cancer activity. This explains why, for NCI-60 one-dose (10 04) assay, across the cell lines, there is a negative correlation (although not significant) between %
cancer growth inhibition of 6a and the product [(% cancer growth inhibition due to 6b) - (%
cancer growth inhibition due to 6a)]. Pearson correlation coefficient, R = -0.2136, but not significant at p <
0.05. The same phenomenon (6a and 6b compete for anti-cancer activity, because what gives to 6a, racemization, takes away from 6b) is observed in NCI60 five-dose data at 1 M.
Across cell lines tested, there is a positive correlation between % cancer growth inhibition of .. 6b and the product [(% cancer growth inhibition due to 6b) ¨ (% cancer growth inhibition due to 6a)]. Pearson correlation coefficient, R = 0.3125, p = 0.017949, significant at p <0.05.
There is a negative correlation between % cancer growth inhibition of 6a and the product [(%
cancer growth inhibition due to 6b) ¨ (% cancer growth inhibition due to 6a)].
Pearson correlation coefficient, R = -0.4211, p = 0.00111, significant at p <0.05.
Perhaps relevantly, around the chiral carbon, 6b and Econazole share 3 (of 4) of the same groups, wherein Econazole racemizes fast [361], faster than predicted by the methodology of [221].
Figure 31: Mechanistic distinction from oligomycin enables therapeutic utility. Drawn molecules of this figure (31A) have an imidazole group, with a protonable nitrogen atom that can shuttle protons across the mitochondrial inner membrane (IM), dissipating the proton motive force (pmf, uncoupling). This figure presents experimental data (31B) using the HL-1 cardiac muscle cell line (cancer derived, but now very cardiac differentiated e.g.
spontaneously contracts and beats like heart cells). Refer to the "Benchmark Drugs" first, which produce cellular effects well known to those of the art [3]. Oligomycin here refers to Oligomycin B. Oligomycin binds ATP synthase and blocks its forward, proton passing, ATP
synthesizing, mode. This means less protons pass through ATP synthase, less pmf consumed per unit time, pmf increases, Tim hyperpolarizes, electron flow along the respiratory chain slows, and 02 consumption is decreased. Carbonilcyanide p-triflouromethoxyphenylhydrazone (FCCP) is an uncoupler that shuttles protons across the IM, dissipates pmf (as heat), pmf decreases, Tim depolarizes, electron flow along the respiratory chain speeds, and 02 consumption is increased. Distinct from oligomycin, three molecules of this figure increase, rather than decrease, 02 consumption, which signifies their mechanistic distinction from oligomycin: they reduce ATP synthesis more by uncoupling than any inhibition of forward mode ATP synthase. They all contain a protonable nitrogen atom, with a basic pKa value conducive to uncoupling i.e. a pKa value reasonably close to {pH of mitochondrial intermembrane space + pH of mitochondrial matrix)/2).
Although for VG025, its most conducive pKa is on its main ring rather than its imidazole.
In a NADPH-linked sub-mitochondrial (SMP) assay of ATP synthesis, these molecules would decrease ATP production because they dissipate pmf as heat, and so there is less pmf available for ATP production. In interpretation, this uncoupling could be incorrectly attributed to inhibition of the forward mode of ATP synthase and so the full mechanistic distinction of .. these molecules from oligomycin could be missed. This has been the case with other imidazole containing compounds of this disclosure. Also with a protonable nitrogen in their imidazole, also with a pKa conducive to uncoupling, and wherein their inhibition of FIN
ATP synthesis in the NADPH-linked SMP assay has been attributed to inhibiting the forward mode of ATP synthase [5-8]. But wherein their uncoupling is likely to be the more predominant factor (extrapolated from data of this figure) and wherein they do not inhibit the forward mode of ATP synthase much, if at all, in stark distinction to oligomycin. Uncoupling capability, which decreases with increased logP (refer next paragraph), explains why different molecules of the present figure exert different effects on 02 consumption. The high logP value of VG019 means its uncoupling is minimal and its effect on 02 consumption is zero (rounded) at a concentration (100 M) it inhibits the reverse mode of ATP
synthase, in stark distinction to oligomycin (3 i.iM), which dramatically decreases 02 consumption (-40%), because, distinctly, it potently inhibits the forward mode of ATP
synthase.
LogP = ¨3.2 is the optimal compromise for best passing a membrane: its hydrophobic core (selecting for high logP) and hydrophilic boundary layer (selecting for low logP) ([36], herein incorporated in its entirety). The imidazole containing molecules presented in this figure, and in this disclosure's drawings more generally, have logP > 3.2 and present increased logP =
decreased uncoupling. The uncoupling capability/liability of a molecule actually hinges on its intersection of pKa(s) and logP [36] but for the molecules in this disclosure's drawings, wherein the imidazole pKa values are, generally, all within a fairly narrow range, the more primary determinant to each molecule's uncoupling rate, relative to the others, is the molecule's logP value relative to the others.
The drawn molecules of this figure do inhibit the reverse mode of ATP
synthase. When a respiratory chain inhibitor blocks electron flow, TIM is maintained, not by proton pumping by the respiratory complexes, but by proton pumping by ATP synthase i.e. the reverse mode of ATP synthase. In the presented data, when the respiratory chain is blocked, the presented molecules depolarise 'Pim because they block the reverse mode of ATP synthase.
They do not affect Tim by these means when the respiratory chain is operational. Because Tim is not set/maintained by the reverse mode of ATP synthase in this case. Although the molecules with stronger uncoupling capability, they can shuttle more protons across the IM (dissipate more pmf) than the respiratory chain can increase its rate to replace, and they do depolarise Tim. When the respiratory chain is blocked, a stronger uncoupler in this figure depolarises Tim more. Because not only does it inhibit the generator of Tim (reverse mode ATP
synthase), it simultaneously erodes Tim (uncoupling).
Oligomycin does inhibit the reverse mode of ATP synthase. But distinctly it inhibits its forward mode more [11]. So, using oligomycin, there is no margin to inhibit the reverse mode (anti-cancer), without adversely affecting cells using OXPHOS i.e. most normal cells.
Contrast this with molecule VG019 of this figure, for example, which can inhibit the reverse mode of ATP synthase, and yet ¨ in observed distinction to oligomycin ¨ does not affect cells using OXPHOS: it does not change their 02 consumption or Tim (at 100 M). This grants it, in distinction to oligomycin, anti-cancer selectivity. Other molecules of this disclosure have even greater cancer selectivity. For example, a preferred embodiment (refer disclosure section: "Preferred Embodiments") inhibits FIR) ATP hydrolysis >5,556 times more than FIFO ATP synthesis, in NADH-linked and NADPH-linked SMP assays [5-6], whilst oligomycin ¨ inversely - inhibits F1F0 ATP hydrolysis less than FiFo ATP
synthesis in such assays [11].
Computational calculations of logP and pKa were made using [25]. The data presented in this Figure is from [12] (herein incorporated in entirety), but the analysis/(re)interpretation is novel. As is the process/method of using these molecules as anti-cancer therapeutics, which is componentry to this invention. The imidazole of the drawn molecules is 4-yl.
Permutations, with 5-y1 instead, are also disclosed by this invention as anti-cancer therapeutics.
Figure 32. Spectra for the separated stereoisomers, Stereoisomer 1 and Stereoisomer 2, of structure 19a (shown in 32A, synthesised by Scheme 2 of this disclosure, Expected/calculated m/z {using "exact molecular weight" calculator in MarvinSketch software [Chemaxon, Budapest, Hungary, [25]], which uses the mass of the most prevalent isotope of each element in the molecule}: 537.08 [M+H], 559.06 [M+Na], 269.04 [M+2F1]2+, 575.03 [M+K]+). An invention embodiment is the use of a compound/stereoisomer(s) with chiral SFC-MS and/or LC-MS and/or NMR feature(s) as presented in this figure for use in a method of treatment of the human or animal body by therapy, optionally for cancer treatment/amelioration/prevention/combat in a subject. (32B) Chiral Supercritical Fluid Chromotography Mass Spectrum (chiral SFC-MS) for Stereoisomer 1 sample. Upper panel:
chiral-SFC annotated with Retention Time (RT, minutes) and area under peak.
Stereoisomer 1 is found in [RT=2.365] peak. Middle panel: component of mass spectrum of [RT=2.365]
peak (polarity positive; ESCiTm is multi-mode ionization {PCT/US03/16892}, which switches at very high speed between Electrospray Ionization (ESI) and Atmospheric Pressure Chemical Ionization (APCI) ionization methods, and ESCi+ refers to using ESCi in its positive ionization mode), wherein y-axis presents intensity and therein is m/z 536.839 [M+H] (0.19 removed from Expected, better concordance in subsequent spectra).
Bottom .. panel: component of mass spectrum of [RT=2.701] peak. Using this figure, Stereoisomer 1 excess (%) in this sample = (80589248/(80589248+1727802))*100 = 97.9%;
Enantiomeric excess (ee, %) = (97.9-50)*2 = 95.8%. Calculating the ee directly, rather than via the stereoisomer excess, ee = ((80589248-1727802)/(80589248+1727802))*100 = 95.8%.

Working back from this ee to the stereoisomer excess: (95.8/2)+50 = 97.9%.
(32C) Using this figure, using UV Chromatogram component (more accurate), Stereoisomer 1 excess (%) in this sample = (19.93/(19.93+0.36))*100 = 98.23%; ee = (98.23-50)*2 = 96.46%.
(32D) Liquid Chromatography¨Mass Spectrometry (LC-MS) spectrum for Stereoisomer 1.
Upper panel: Liquid Chromatography (LC) Retention Time (RT) = 2.516 minutes. Lower panel:
Mass Spectrum (MS) of [RT peak=2.516]. Shows positively charged species:
"Ionization mode = API-ES" and "Polarity = Positive" wherein API is "Atmospheric Pressure Ionization"
and ES is Electrospray. Percentages are relative abundance. (32E) MS
components. Upper panel: m/z 537.1 [M+H]t 2nd panel: m/z 559.1 [M+Na]. 3rd panel: m/z 269.1 [M+2F1]2+.
Bottom panel: m/z 575.1 [M+K]. All these Observed m/z are within 0.07 of Expected. (32F) 1H NMR {NMR probe temperature = 298.15 K} for Stereoisomer 1, scaled to highest compound peak, peaks identified by "Auto peak picking" algorithm (based on Global Spectral Deconvolution, GSD) of MestReNova version 12 software (Mestrelab Research, Santiago de Compostela, Spain), with default program settings used, NO
chemical structure used/inputted to guide/constrain this peak picking. (32G) Aromatic region of previous spectrum, for Stereoisomer 1, expanded. (32H) chiral SFC-MS for Stereoisomer 2 sample.
Stereoisomer 2 is found in [RT=2.701] peak: m/z 536.839 [M+H] (0.19 removed from Expected). Stereoisomer 2 excess (%) = (435788880/(435788880+1578563))*100 =
99.64%;
ee = (99.64-50)*2 = 99.28%. (321) Using UV Chromatogram component (more accurate), Stereoisomer 2 excess (%) in this sample = (38.72/(38.72+0.46))*100 = 98.83%;
ee = (98.83-50)*2 = 97.66%. (32J) LC-MS spectrum for Stereoisomer 2. RT = 2.516 minutes.
(32K) MS

components. Upper panel: m/z 537.1 [M+H]t 2"d panel: m/z 559.1 [M+Na]t 3rd panel: m/z 269.1 [M+2H]2+. Bottom panel: m/z 575.1 [M+K]t All these Observed m/z are within 0.07 of Expected. (32L) 1H NMR {NMR probe temperature = 298.15 K} for Stereoisomer 2.
"Auto peak picking" algorithm in MestReNova v12 used to pick peaks shown. (32M) Aromatic region of previous spectrum, for Stereoisomer 2, expanded. (32N) Stereoisomer 1 in upper panel, Stereoisomer 2 in lower panel. (320) Aromatic region, Stereoisomer 1 in upper panel, Stereoisomer 2 in lower panel.
Figure 33. Spectra for the separated stereoisomers, Stereoisomer A and Stereoisomer B, of Structure 8 in Scheme 7 of this disclosure (structure shown in 33A, Expected/calculated m/z {using "exact molecular weight" calculator in MarvinSketch}: 538.08 [M+Hr, 560.06 [M+Na], 269.54 [M+2H]2+, 576.04 [M+Kr). An invention embodiment is the use of a compound/stereoisomer(s) with chiral SFC and/or chiral SFC-MS and/or LC-MS
and/or NMR feature(s) as presented in this figure for use in a method of treatment of the human or animal body by therapy, optionally for cancer treatment/amelioration/prevention/combat in a subject. (33B) Chiral Supercritical Fluid Chromotography Mass Spectrum (SFC-MS) for Stereoisomer A sample. Upper panel: chiral-SFC annotated with Retention Time (RT, minutes) and area under peak. Stereoisomer A is found in [RT=2.13] peak. Lower panel:
component of mass spectrum of [RT=2.13] peak (ESCi+ is multi-mode ionization {PCT/US03/16892} in positive ionization mode), wherein y-axis presents intensity and therein is m/z 538.215 [M+H] (0.135 removed from Expected, better concordance in subsequent spectra). (33C) Stereoisomer A excess = 100% (no other peak in the UV
chromatogram), ee = (100-50)*2 = 100%. (33D) Liquid Chromatography¨Mass Spectrometry (LC-MS) spectrum for Stereoisomer A. Upper panel: Liquid Chromatography (LC) Retention Time (RT) = 2.685 minutes. Bottom panel: Mass Spectrum (MS) of [RT=2.685 peak], shows positively charged species (API-ES positive), percentages are relative abundance. (33E) MS
components. Upper panel: m/z 538.1 [M+H]t 2"d panel: m/z 560.1 [M+Na]+. 3rd panel: m/z 269.6 [M+21-1]2 . 4th panel: m/z 576.1 [M+K]t All these Observed m/z are within 0.06 of Expected. (33F) High Resolution Mass Spectrometry (HRMS): Liquid Chromatography-Time of Flight (LC-TOF) Mass Spectrometry (MS) for Stereoisomer A. LC
Retention Time (RT) = 0.166 minutes (LC data not shown). Upper panel: OBSERVED m/z 538.0745928061 [M+H], CALCULATED from structure m/z 538.0821456 [M+Hr, so Observed mass is only 0.0075527939 Daltons (0.7% the mass of a proton) removed from calculation. The species with m/z 537.0671121449 [M+H] has hydrogen instead of deuterium on the chiral carbon, and indeed is the mass of a neutron (1.008664 Daltons) lighter (538.0745928061-537.0671121449) = 1.0074806612 Daltons mass difference (0.12% removed from being the exact mass of a neutron difference). Absolute abundance is shown on the y-axis and the molar percent deuterium incorporation for Stereoisomer A at the chiral carbon is 100% -((6180.43/710180.69)*100=0.87%) = 99.13%. 2nd panel: OBSERVED m/z 560.0600137508 [M+Na], CALCULATED from structure m/z 560.0640898 [M+Na], so Observed mass is only 0.0040760492 Daltons (0.4% the mass of a proton) removed from calculation. The species with hydrogen instead of deuterium on chiral carbon is too low abundance to be observed here. Bottom panel: OBSERVED m/z 576.0250917093 [M+Kr, CALCULATED
from structure m/z 576.0380270 [M+K], so Observed mass is only 0.0129352907 Daltons (1.3% the mass of a proton) removed from calculation. The species with hydrogen instead of deuterium on chiral carbon is too low abundance to be observed here. (33G) 11-1 NMR {NMR
probe temperature = 301 K) for Stereoisomer A, scaled to highest compound peak, peaks identified by "Auto peak picking" algorithm of MestReNova v12 software, with default program settings used, NO chemical structure used/inputted to guide/constrain this peak picking. (33H) Aromatic region of previous spectrum, for Stereoisomer A, expanded. (331) The chiral SFC-MS machine broke down and so chiral SFC was performed in its place for Stereoisomer B, wherein RT = 4.535 min. (33J) LC-MS spectrum for Stereoisomer B. RT =
2.685 minutes. (33K) MS spectrum components. Upper panel: m/z 538.1 [M+H]t 2' panel:
m/z 560.1 [M+Na]+. 3"I panel: m/z 269.6 [M+2H]2+. Bottom panel: m/z 576.0 [M+K]. All these Observed m/z are within 0.06 of Expected. (33L) HRMS: LC-TOF MS for Stereoisomer B. LC Retention Time (RT) = 0.163 minutes (LC data not shown).
Upper panel:
m/z 538.0727757864 [M+H]t The species with m/z 537.0689210144 [M+H] has hydrogen instead of deuterium on the chiral carbon. Absolute abundance is shown on the y-axis and the molar percent deuterium incorporation for Stereoisomer B at the chiral carbon is 100% -((5782.74/669735.94)*100=0.86%) = 99.14%. 2nd panel: m/z 560.0513502753 [M+Na]t Bottom panel: m/z 576.0327248583 [M+K]. (33M) 11-1 NMR {NMR probe temperature =
300.7 K} for Stereoisomer B. "Auto peak picking" algorithm in MestReNova v12 used to pick peaks shown. (33N) Aromatic region of previous spectrum, for Stereoisomer B, expanded. (330) Stereoisomer A in upper panel, Stereoisomer B in lower panel, shows integration values in this ppm region as automatically assigned by the MestReNova v12 software used. Stereoisomer A has 2H assigned (1.03+0.93=1.96, rounds to 2), Stereoisomer B has 1H assigned (1.13, rounds to 1), in this ppm region. (33P) Shown here, I
manually extended the integration line (N.B. this automatically changes the MestReNova v12 integration calculation method from "peak" to "sum") for Stereoisomer B to be the same length as that for Stereoisomer A, which changes its integration value from 1.13 (prior) to 1.52, which rounds to 2H. This improves the Stereoisomer B assignment because now it has the correct number of hydrogen nuclides (18H), whereas before it had (incorrectly) 17H. It is true that 1.52 narrowly crosses the threshold for 2H but interestingly, and perhaps relevantly, the integration value is also very low in this ppm region for the hydrogen on chiral carbon stereoisomers in Figure 32 (integration value at 7.93 ppm = 1.51 for Stereoisomer 1, 1.57 for Stereoisomer 2, as assigned by "Auto Assignment" algorithm of MestReNova v12).
(33Q) '3C NMR {NMR probe temperature = 311.9 K} for Stereoisomer B. "Auto peak picking"
algorithm in MestReNova v12 used to pick peaks shown. (33R) A region of previous 13C
NMR spectrum, for Stereoisomer B, expanded. (33S) Stereoisomer A in upper panel, Stereoisomer B in lower panel. (33T) Aromatic region, Stereoisomer A in upper panel, Stereoisomer B in lower panel.
N.B. For Stereoisomer B, its LC-MS, HRMS and NMR are not completely aligned:
to explain, LC-MS, HRMS and 'H NMR were performed and the NMR showed a high amount of impurities (spectrum not shown), further mass based purification steps were taken, and the 1H NMR was repeated (spectrum shown herein), and a 13C NMR also, all showing a much lower, acceptable level of impurity, and it is this purer form that was entered into anti-cancer testing at the National Cancer Institute (NCI). However, LC-MS and HRMS were not repeated. But the LC-MS and HRMS are clear enough to identify the [M+ion]
species needed, all be it with some additional species/impurities also observed that aren't in the LC-MS and HRMS spectra for Stereoisomer A (e.g. compare 33F and 33L).
Figure 34. Hydrogen vs. deuterium on chiral carbon. For 34A-34B: upper panel shows 1I-1 NMR spectrum for Stereoisomer 1 of compound 19a synthesized by Scheme 2 (Figure 32), lower panel shows 1H NMR spectrum for Stereoisomer B of Compound 8 synthesized by Scheme 7 (Figure 33). The former has a peak at 5.96 ppm from the hydrogen attached to its chiral carbon. The latter has this hydrogen replaced with a deuterium, and thence this 5.96 ppm peak is absent in its 1H NMR spectrum.
Figure 35. Spectra for the separated stereoisomers, Stereoisomer a and Stereoisomer p, of Structure 8 in Scheme 13 of this disclosure (structure shown in 35A, Expected/calculated m/z {using "exact molecular weight" calculator in MarvinSketch}: 551.09 [M+Hr, 573.07 [M+Na], 276.05 [M+2H]2 , 589.05 [M+K]-). Enantiomeric excess (ee) of both stereoisomer samples is >97%. An invention embodiment is the use of a compound/stereoisomer(s) with chiral SFC and/or chiral SFC-MS and/or LC-MS and/or NMR feature(s) as presented in this figure for use in a method of treatment of the human or animal body by therapy, optionally for cancer treatment/amelioration/prevention/combat in a subject. (35B) Chiral SFC (AD-3 column, 1 ILL injected volume, co-solvent Me0H [0.05% IPAm]) for Stereoisomer p sample, RT = 1.9 min. (35C) Chiral Supercritical Fluid Chromotography Mass Spectrum (SFC-MS) for Stereoisomer a sample. Upper panel: chiral-SFC annotated with Retention Time (RT, minutes) and area under peak. Stereoisomer a is found in [RT=2.47] peak.
Middle panel:
component of mass spectrum of [RT=2.47] peak (ESCi+ is multi-mode ionization {PCT/US03/16892} in positive ionization mode), wherein y-axis presents intensity and therein is m/z 551.290 [M+H] (0.2 removed from Expected, better concordance in subsequent spectra). Bottom panel: component of mass spectrum of [RT=3.44]
peak.
Stereoisomer a excess (%) = (7100000/(7100000+7535))*100 = 99.89%; ee = (99.89-50)*2 =99.78% (35D) Stereoisomer a excess = 100% (no other peak in the UV
chromatogram), ee = (100-50)*2 = 100%. (35E) Liquid Chromatography¨Mass Spectrometry (LC-MS) spectrum for Stereoisomer a. Upper panel: Liquid Chromatography (LC) Retention Time (RT) = 2.536 minutes. Bottom panel: Mass Spectrum (MS) of [RT=2.536 peak], shows positively charged species (API-ES positive), percentages are relative abundance. (35F) MS
components. Upper panel: m/z 551.0 [M+H]t 2nd panel: m/z 573.0 [M+Na]. 3rd panel: m/z 276.0 [M+2HF-. Bottom panel: m/z 588.9 [M+Kr. All these Observed m/z are within 0.15 of Expected. (35G) H NMR {NMR probe temperature = 298.2 K} for Stereoisomer a in CDC13 solvent. "Auto peak picking" algorithm in MestReNova v12 used to pick peaks shown. The peak for the methyl group is likely to be around the peak for HDO
and so this likely masks the methyl group from computational verification algorithm of Mestrelab which is why it doesn't concord that this spectrum corresponds with the structure shown in 35A.
The large peak at 3.48 ppm corresponds to the ppm shift of methanol (Me0H) in solvent [362], wherein methanol was componentry to the mobile phase with the chiral SFC, and is likely here residual from this (labelling this as a known impurity doesn't change the negative finding of the Mestrelab verification algorithm). (35H) Aromatic region of previous spectrum, for Stereoisomer a, expanded. (351) IH NMR {NMR probe temperature =
298.2 ICI for Stereoisomer a in DMSO-d6 solvent. This spectrum was taken after HPLC
purification to try and remove impurities observed in the prior presented I H
NMR spectrum for Stereoisomer a. "Auto peak picking" algorithm in MestReNova v12 used to pick peaks shown. With DMSO-d6 solvent, the peak for the methyl group is not masked/complicated by a nearby solvent related (e.g. HDO) peak and the Mestrelab verification algorithm does return concordance between this spectrum and the structure shown in 35A. The large peak at 2.08 ppm corresponds to the ppm shift of acetonitrile in DMSO-d6 solvent [362], wherein the mobile phase used for the HPLC consisted of acetonitrile and water, wherein this peak is likely residual from that process. (35J) Aromatic region of previous spectrum, for Stereoisomer a, expanded. (35K) Chiral SFC (AD-3 column, 3 IA injected volume, co-solvent Me0H [0.05% IPAm]) for Stereoisomer p sample, RT = 2.4 min. (35L) Chiral Supercritical Fluid Chromotography Mass Spectrum (SFC-MS) for Stereoisomer p sample.
Upper panel: chiral-SFC annotated with Retention Time (RT, minutes) and area under peak.
Stereoisomer 13 is found in [RT=3.44] peak. Middle panel: component of mass spectrum of [RT=3.44] peak (ESCi+ is multi-mode ionization {PCT/US03/16892) in positive ionization mode), wherein y-axis presents intensity and therein is m/z 551.290 [M+H] (0.2 removed from Expected, better concordance in subsequent spectra). Bottom panel:
component of mass spectrum of [RT=2.47] peak. Stereoisomer p excess (%) =
(4876384/(4876384+20876))*100 = 99.57%; ee = (99.57-50)*2 = 99.14%. (35M) Stereoisomer 13 excess = 100% (no other peak in the UV chromatogram), ee = (100-50)*2 = 100%. (35N) LC-MS spectrum for Stereoisomer p. Upper panel: Retention Time (RT) = 2.540 minutes. Bottom panel: Mass Spectrum (MS) of [RT= 2.540 peak], shows positively charged species (API-ES
positive), percentages are relative abundance. (350) MS components. Upper panel: m/z 551.1 [M+H].
2nd panel: m/z 573.0 [M+Na]+. 31d panel: m/z 276.1 [M+2H]2+. Bottom panel: m/z 588.9 [M+K]. All these Observed m/z are within 0.15 of Expected. (35P) 'H NMR {NMR
probe temperature = 298.2 IC) for Stereoisomer 1 in CDC13 solvent. "Auto peak picking" algorithm in MestReNova v12 used to pick peaks shown. (35Q) Aromatic region of previous spectrum, for Stereoisomer 13, expanded.
Figure 36. Spectra for Compound 31, synthesized by Scheme Ha of this disclosure (structure shown in 36A, Expected/calculated m/z {using "exact molecular weight"
calculator in MarvinSketch}: 555.14 [M+H], 577.12 [M+Na], 278.07 [M+2H]2+, 593.09 [M+K]+).
An invention embodiment is the use of a compound with LC-MS and/or NMR and/or HPLC
feature(s) as presented in this figure for use in a method of treatment of the human or animal body by therapy, optionally for cancer treatment/amelioration/prevention/combat in a subject.
High Performance Liquid Chromatography (HPLC) Retention Time (RT) for Compound = 2.117 minutes (HPLC spectrum not shown). (36B) Liquid Chromatography¨Mass Spectrometry (LC-MS) spectrum for Compound 31. Liquid Chromatography (LC) Retention Time (RT) = 0.87 minutes. Mass Spectrum (MS) of [RT=0.87 peak] shows positively charged species (API-ES positive), percentages are relative abundance. There is an intense peak at m/z 130.200 which might correspond to a N,N-Diisopropylethylamine (DIPEA) impurity ([DIPEA+H] mass is 130.16 Daltons using "exact molecular weight"
calculator in MarvinSketch), wherein an impurity with a similar m/z value is observed in other LC-MS
spectra herein for other compounds, thence this impurity might relate to the machine and/or LC-MS protocol used. (36C) MS components: Upper panel: m/z 554.90 [M+H]+. 2' panel:
m/z 576.90 [M+Na]t Bottom panel: m/z 278.90 [M+2H]2 . No peak observed in region of [M+K] (not shown). First two m/z Observed are within 0.25 of Expected, last is 0.83 removed. (36D) 'H NMR (400 MHz, Methanol-d4) for Compound 31 {NMR probe temperature = 297.9 IC}, scaled to highest compound peak, peaks identified by "Auto peak picking" algorithm of MestReNova v12 software, NO chemical structure used/inputted to guide/constrain this peak picking. (36E) Aromatic region of (36D) spectrum expanded. (36F) Downfield region of (36D) spectrum expanded. (36G) 1H NMR (400 MHz, Chloroform-d) for Compound 31 {NMR probe temperature = 298.5 K} . "Auto peak picking"
algorithm in MestReNova v12 used to pick peaks shown. (36H) Aromatic region of (36G) spectrum expanded. (361)13C NMR (101 MHz, Methanol-d4) for Compound 31 {NMR probe temperature = 298.0 K}. Firstly, "Auto peak picking" algorithm in MestReNova v12 used to pick peaks. Then, because the central Methanol-d4 solvent peak was observed at 49 instead of expected 47.60 ppm, I manually assigned this 49 ppm Methanol-d4 solvent peak as a "reference peak" in the MestReNova v12 software, which shifted all ppm values accordingly (by [49-47.60] ppm), to become as presented in this spectrum. (36J) Upfield region of (36I) spectrum expanded. (36K) Downfield region of (36I) spectrum expanded. (36L) 1H-HSQC NMR (Me0D, 400 MHz, 101 MHz, F2 (proton dimension) acquisition temperature =
299.8 K). (36M) Region of spectrum (36L) expanded. (36N) Region of spectrum (36L) expanded. (360)1H-13C HMBC NMR (Me0D, 400 MHz, 101 MI-k, F2 (proton dimension) acquisition temperature = 298.9 K). (36P) Region of spectrum (360) expanded.
(36Q) Region of spectrum (360) expanded. (36R) Assignments: atom numbers that follow are IUPAC numbers for the structure as it is shown in the figure: these assignments come from my analysis of the NMR data, especially utilising the 2D NMR spectra: 1H NMR
(400 MHz, Methanol-d4) 5 (ppm) 8.35 (s, 1H, 35), 8.10 (m, 1H, 32), 8.04 (d, J = 2.1 Hz, 1H, 17), 7.78 (m, 2H, 16, 20), 7.27 (dt, J = 22.4, 7.4 Hz, 4H, 8, 10, 26, 28), 7.16 (dd, J =
8.0, 5.6 Hz, 2H, 11,27), 7.09 (d, J = 7.5 Hz, 2H, 25, 29), 7.03 (t, J = 7.4 Hz, 1H, 9), 4.71 (d, J = 13.9 Hz, 1H, 4"), 4.37 (d, J = 14.2 Hz, 1H, 30'), 4.29 (d, J = 14.2 Hz, 1H, 30"), 3.96 (dd, J = 19.7, 13.4 Hz, 2H, 2', 4'), 3.13 (m, 1H, 3), 2.78 (d, J = 12.8 Hz, 1H, 2"), 2.69 (ddd, J =
14.5, 9.7, 5.3 Hz, 1H, 23'), 2.54 (dt, J = 13.7, 8.6 Hz, 1H, 23"), 2.11 (s, 3H, 36), 1.50 (s, 1H, 22"), 1.36 (dtd, J =
14.1, 9.1, 5.1 Hz, 1H, 22').
13C NMR (101 MHz, Methanol-d4) (ppm) 149.14, 7, 142.91 , 24, 140.73, 13, 138.20, 19, 134.62 , 5, 134.51 ,20, 132.72 , 32, 132.22, 18, 130.62, 10, 130.05, 17, 129.75 , 8, 129.50, 26, 28, 129.39, 25, 29, 129.20, 31, 128.48 ,34, 127.87, 16, 127.01 , 27, 123.78 , 9, 121.75, 11, 58.88 , 3, 53.98 , 4, 53.69 , 2,48.11 ,30, 33.55 , 23, 31.58 , 22, 9.53 , 36.
Figure 37: Spectra for compound synthesized by Scheme IIIa of this disclosure (was synthesized as an HC1salt, which dissociates in solvent, structure of most prevalent (-100%) free base tautomer is shown in 37A, Expected/calculated m/z {using "exact molecular weight" calculator in MarvinSketch}: 545.20 [M+H], 567.18 [M+Na], 273.10 [M+2H]2+, 583.15 [M+K]+). An invention embodiment is the use of a compound with LC-MS
and/or NMR feature(s) as presented in this figure for use in a method of treatment of the human or animal body by therapy, optionally for cancer treatment/amelioration/prevention/combat in a subject. (37B) LC-MS spectrum. Retention Time (RT) = 1.763 minutes. Mass Spectrum (MS) of [RT=1.763 peak] shows positively charged species (API-ES positive), percentages are relative abundance. (37C) MS components: Upper panel: m/z 545.1 [M+H]. 2nd panel:
m/z 567.1 [M+Na]+. 3rd panel: m/z 273.8 [M+2H]2+. Bottom panel: m/z 583.1 [M+K]t Three of these Observed are within 0.1 of Expected, but the [M+2H]2+ species is 0.7 removed. Only 0.12% relative abundance is BMS-199264 without the methyl added (Observed m/z 530.90 [M+1-1]+, Expected m/z 531.18 [M+H]). (37D) 1H-13C HSQC NMR (CD3CN, 400 MHz, MHz, F2 (proton dimension) acquisition temperature = 302.2 K). A potential concern using Scheme IHa is that the methyl group may attach to the 0 and not the imidazole N atom of BMS-199264. Well, in this 2D spectrum the [3.80 ppm (1H dimension) vs. 34.41 ppm (13C
dimension)] point is, with its 13C shift of 34.41 ppm, as apparent to someone of the art, much more likely to be methyl attached to the N, than the 0, atom. If the methyl was attached to the 0 atom, the 13C shift would be closer to 50 ppm.
EXAMPLE EMBODIMENTS OF THE INVENTION
The Drawings present embodiments of the invention. Further examples are enumerations of Markush Formulas (I), (II), (III), (IV), (V) and (VI), presented henceforth.
Note: none of these formulae share Markush symbols, which can be, for example, symbols of the type: Rx, wherein x is an integer and/or letter. Such symbols are well recognised by those of the art.
Markush Formulas (I), (II), (III), (IV), (V) and (VI), presented henceforth, each have their own Markush symbols, as specified for each, in their own respective sections of this disclosure. Further examples are protein embodiments of Formula (VII), including embodiments wherein one or more of a gene or nucleotide or DNA or RNA sequence is administered to the subject to administer a protein embodiment of Formula (VII) to the subject.
In this disclosure, the term "Formula [X]" is used when a statement is true for Formula (I), (II), (III), (IV), (V), (VI) and (VII), and all are being referred to independently. A compound of Formula [X] is a compound of Formula (I), or Formula (II), or Formula (III), or Formula (IV), or Formula (V), or Formula (VI), or Formula (VII), or any compound presented in this disclosure's Drawings, or any compound componentry to this invention.
This invention is described using these example embodiments but it isn't limited to these.
These merely illustrate the invention. Compounds of other structures, which are identified as therapeutic inhibitors by the rationale and methods of the present invention, are also encompassed by the present invention.
An aspect of the invention is at least one compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, and/or a pharmaceutical composition(s) comprising one or compounds of Formula (I), (II), (III), (IV), (V), (VI) or (VII), and/or an FIR ATP hydrolysis inhibitor(s) (that optionally/preferably inhibits FIFO ATP synthesis less or, more preferably, not at all), and/or a compound(s)/composition(s) that reduces FiFo ATP hydrolysis, for use in treating, ameliorating, preventing, reversing or combating a disease or disorder, or unwanted/undesirable physiological process or its consequences or an unwanted/undesirable aesthetic, selected from the following list;
Encompassed by this invention is a method of treating, ameliorating, preventing, reversing or .. combating a disease or disorder, or unwanted/undesirable physiological process or its consequences or an unwanted/undesirable aesthetic, in a subject, selected from (i) cancer, any cancer, neoplasia, metastasis, tumor formation/growth/implantation, tumorigenesis, solid tumor, blood borne tumor, cancer that is refractory or resistant to conventional chemotherapy, drug resistant tumor, multidrug resistant cancer;
(ii) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. 18F-FDG PET);
(iii) cachexia, cancer driven cachexia, cancer fatigue, weight loss, weight loss for known or unknown reason, chronic wasting disease, atrophy, brown atrophy, frailty, frailty syndrome, aging frailty, geriatric syndrome, age-related cachexia and/or sarcopenia, weakness, wasting, anorexia nervosa, bulimia nervosa, eating disorder, amenorrhea, .. underweight, low body mass index (BMI, e.g. <18.5), low body fat percentage, body composition change, wasting syndrome, HIV wasting syndrome, malnutrition, clinical malnutrition, starvation, kwashiorkor syndrome, marasmus syndrome, malabsorption, malabsorption due to parasitic/bacterial infection (e.g. helminthiasis, Whipple's disease, small intestine bacterial overgrowth (SIB0), giardiasis etc.), anemia, refeeding syndrome, appetite loss, catabolysis, muscle atrophy, asthenia, muscle weakness (myasthenia), sarcopenia, osteoporosis, cachexia associated with HIV, AIDS, multiple sclerosis, rheumatoid arthritis, familial amyloid polyneuropathy, chronic kidney disease, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia, Addison's disease, mercury poisoning (acrodynia), chronic pancreatitis, untreated/severe type 1 diabetes mellitus, hormonal .. deficiency, tuberculosis, gastroenteritis, diarrhea, dysentery, any digestive disease or disorder, any gastrointestinal disease or disorder including functional gastrointestinal disorders, coeliac disease, tropical sprue, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, short bowl syndrome, congestive heart failure, constrictive pericarditis, bradycardia, chronic obstructive pulmonary disease (COPD), .. altitude sickness, hyperthyroidism (subclinical hyperthyroidism, Graves' disease, multinodular goiter, toxic adenoma, inflammation of the thyroid {thyroiditis}, pituitary adenoma), fatigue, chronic fatigue syndrome or any disease or disorder or pathology in which a body tissue(s) is undersupplied or underutilises (vs. its need) an energetic/chemical substrate(s), including 02;
(iv) cancer associated fever, which is especially associated with, but not limited to, non Hodgkin lymphoma (NHL), Hodgkin lymphoma, acute leukaemia, kidney cancer (renal cell cancer), liver cancer (hepatocellular carcinoma), bone cancer, adrenal gland tumours such as phaeochromocytomas, tumours in the hypothalamus, solid tumours;

(v) disease or disorder or physiological process or condition that causes a higher than normal body temperature such as (without limitation) high environmental temperature, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, neutropenic sepsis, stroke, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, toxic serotonin syndrome, thyroid storm, heatstroke, surgery related, menopause ("hot flushes"), infection (non-limiting e.g. roseola, measles, enteroviral infections, parasitic, viral, fungal, Chlamydial, Rickettsial, bacterial, mycobacterial, systemic bacterial, intravascular, HIV associated, nosocomial), pyrogenic infection, thermoregulatory disorder(s), connective tissue disease(s), Kawasaki syndrome, drug overdose, drug or drug withdrawal induced hyperthermia, alcohol/drug withdrawal, idiosyncratic drug reaction, fever of known or unknown or uncertain origin (non-limiting e.g. infectious disease(s), inflammation, immunological disease(s), non-infectious inflammatory disease(s) {non-limiting eg. systemic rheumatic and autoimmune diseases, vasculitis, granulomatous diseases, autoinflammatory syndromes}, tissue destruction, reaction to incompatible blood product(s), metabolic disorder(s), inherited metabolic disorder(s), cancer, neoplasm, endogenous or exogenous pyrogen(s), injury, head injury);
(vi) disease/disorder/injury/pathology/surgery treatable/ameliorated/prevented/combated/helped by conferring hypothermia in a subject for some medical or other purpose which can include slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, slowing physiological/pathological processes (reaction rates are temperature dependent) and so "buying time" to get the subject to treatment for their emergency (e.g.
trauma/septic shock or other medical emergency), slowing the progress of sepsis until a sufficient concentration of a working antibiotic(s) can be built up in the subject (furthermore hypothermia, by slowing sepsis progression, buys time to observe which antibiotic(s) can work, yielding time to try alternative further antibiotic option(s) if required), used soon after or just before clinical/legal death to preserve the subject's organs/tissues until the subject can be frozen/cryogenically frozen or the pathology that caused clinical/legal death (e.g. wound) can be fixed and the subject resuscitated, administered to a subject when a first responder (e.g.
ambulance crew) deems the subject dead or unlikely to survive the journey to a medical facility (e.g. hospital) wherein this administration helps to preserve the subject which is helpful if hospital staff subsequently assess that they can, or might be able to, save the subject, stabilizing surgical/trauma/Emergency Room (ER) patients, deep hypothermic circulatory arrest for surgery (DHCA, non-limiting applications of DHCA include repairs of the aortic arch, repairs to head and neck great vessels, repair of large cerebral aneurysms, repair of cerebral arteriovenous malformations, pulmonary thromboendarterectomy, resection of tumors that have invaded the vena cava, brain tumor resection {wherein the anti-cancer activity of a compound(s) of this invention juxtaposes well}), Emergency Preservation and Resuscitation (EPR), hypothermia for a surgical purpose, protective hypothermia during surgery and/or surgery complication, hypothermia to slow/reduce blood loss, hypothermia for neuro- and/or cardio- and/or organ/tissue and/or life protection in a subject that has trauma/brain trauma/polytrauma/surgery/stroke/ischemic stroke/hemorrhagic stroke/cardiac arrest/myocardial infarction/hypoxia/shock (including, without limitation, low volume, cardiogenic, obstructive, and distributive shock)/sepsis/septic shock/multiple organ dysfunction syndrome/systemic inflammatory response syndrome (SIRS)/organ failure/cytokine storm/anaphylactic shock/seizure/disseminated intravascular coagulation/blocked airway/croup/rhabdomyolysis/[head/facial/spinal/chest/abdominal/ballistic/knife injury/trauma], or some other medical emergency/condition/disorder/disease/injury/operation, hypothermia for cardiac and/or cardiovascular surgery and/or open heart surgery and/or brain surgery (neurosurgery) and/or surgery using total circulatory arrest and/or surgery using cardiopulmonary bypass, Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage/transport .. and/or transplant, thus increasing the time window for transplantation of organs to recipients;
compound(s) of this invention is administered to organ to be transplanted [by administration to donor and/or by administration to isolated organ] and/or to organ recipient, optionally during transplant operation), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, neonatal hypoxia-ischemia, birth asphyxia, hypoxic-ischemic encephalopathy (HIE), haemorrhage, hypovolemia, exsanguination, suspended animation, decompression sickness, burn injury(s) including skin burn, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or tourniquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (non-limiting e.g. meningitis), sepsis, septic shock, stroke, cerebrovascular disease, ischemic brain injury, ischemic stroke, traumatic injury, brain injury, spinal cord injury, cardiac arrest, heart failure, congestive heart failure, Dilated cardiomyopathy, valvular heart disease, pulmonary embolism, adrenal crisis, Addisonian crisis, hypertensive emergency, haemorrhagic (hypovolemic) shock, cardiogenic shock, neurogenic shock, hepatic encephalopathy, blood loss, ischemic brain/heart/kidney/intestinal injury, neuroprotection and/or cardioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject;
(vii) poisoning by a toxic amount of a compound(s) in a subject (non-limiting e.g.
carbon monoxide/methanol/heavy metal/ethylene glycol/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison(s), nerve agent, chemical weapon, bacterial toxin(s) (e.g. food poisoning, Salmonella poisoning), endotoxemia, eukaryote produced toxin(s) e.g. (non-limiting) brevetoxin, drug(s)/substance(s) overdose e.g. (non-limiting) heroin, ethanol, a prescription medication(s), an over the counter medication(s) such as aspirin, paracetamol etc.; hypothermia is protective to toxic insult);
(viii) hypermetabolism (optionally because of one or more of, without restriction, traumatic brain injury, injury to the body, infection, sepsis, burn, multiple trauma, fever, long-bone fracture, hyperthyroidism, prolonged steroid therapy, surgery, bone marrow transplant, recovery from anorexia/bulimia), heat intolerence, insomnia, fatal insomnia, nervousness, Luft's disease, non-thyroidal hypermetabolism, thyrotoxicosis, hyperthyroidism, overactive thyroid, subclinical hyperthyroidism, too much thyroid hormone(s) in the subject, too much triiodothyronine (T3) and/or thyroxine (14) in the subject, hyperthyroxinemia (including, without restriction, familial dysalbuminemic hyperthyroxinemia, familial euthyroid hyperthyroxinemia, thyroid hormone resistance syndrome), thyroid storm, hyperthyroidism caused by one or more of (without restriction) Graves' disease, thyroiditis, Hashimoto's thyroiditis, subacute thyroiditis, postpartum thyroiditis, lumps (nodules) on the .. thyroid, enlarged thyroid gland (goitre), simple goitre, multinodular goiter, toxic multinodular goiter, toxic adenoma, toxic thyroid adenoma, inflammation of the thyroid, hyperplasia of thyroid, metastatic thyroid cancer, thyroid tumour, thyroid cancer (including, without restriction, papillary carcinoma, follicular carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma), eating too much iodine, goitrogen ingestion, consumption of ground beef contaminated with thyroid tissue ("hamburger hyperthyroidism"), too much synthetic thyroid hormone in the subject, pituitary adenoma, drug induced, Amiodarone drug induced, struma ovarii, Jod-Basedow syndrome, nonautoimmune autosomal dominant hyperthyroidism;

(ix) low or less than desired metabolic/bioenergetic efficiency in a subject, or low or less than desired physical or mental performance (e.g. memory, IQ), or low or less than desired body weight, or fatigue/tiredness/weakness/exhaustion;
(x) accelerated aging disease or progeroid syndrome including, without restriction, Werner syndrome, Bloom syndrome, De Barsy syndrome, Rothmund¨Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann¨Rautenstrauch syndrome, Hutchinson¨Gilford progeria syndrome (progeria), Ataxia telangiectasia-like disorder 2, XFE progeroid syndrome, Muscular dystrophy, Muscular Dystrophy (Becker's, Duchenne, Limb-Girdle), Yamamoto's Muscular Dystrophy, Mandibuloacral dysplasia, Dilated cardiomyopathy, GAPO syndrome, Cutis laxia, Ehlers-Danlos syndrom, Lenz-Majewski hyperostatic dwarfism, SHORT syndrome, Progressive external opthalmoplegia, Nester-Guillermo progeria syndrome, MDPL syndrome, Dyskeratosis congenital, Down syndrome;
(xi) disease or disorder of aging (incidence/severity increases with increased age/senescence) and/or unwanted/undesirable aspect(s) of aging and/or a disease/disorder associated with elevated reactive oxygen species including age-associated decline, aging frailty, frailty syndrome, sarcopenia, muscle weakness, osteoporosis, cognitive decline, cognitive defecit, mild cognitive impairment, degenerative diseases, neurodegenerative diseases, motor-associated neurodegenerative diseases, motor neuron disease, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, progressive supranuclear palsy, pseudobulbar palsy, hereditary spastic paraplegia, Parkinson's disease, Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), essential tremor, resting tremor, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, frontotemporal dementia, chronic traumatic encephalopathy, memory loss, aged cognition, age/aging related cognitive decline/impairment, Batten disease, polyglutamine diseases, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, heart failure with preserved ejection fraction, idiopathic pulmonary fibrosis, fibrotic disease, pulmonary disease, coronary artery disease, hypercholesterolemia, obesity, liver disease, fatty liver disease, lysosomal storage disease, amyloidosis, systemic sclerosis, kidney disease, hepatic cirrhosis, immunosenscence, clonal hematopoiesis, chronic obstructive pulmonary disease (COPD), hypertension, hypercholesterolemia, age-related thymic atrophy, arthritis, osteoarthritis, arthritis (Osteo-and Rheumatoid), Juvenile Rheumatoid Arthritis (JRA), Degenerative Disc Disease, Tendinopathy, Androgenetic Alopecia, male-pattern baldness, Idiopathic Pulmonary Fibrosis, systemic sclerosis, Chronic Obstructive Pulmonary Disease, Psoriasis, age-related loss of cardiac/pulmonary/cognitive/vision function, diabetes, type 2 diabetes, andropause, glaucoma, retinal degeneration, sarcopenia, cachexia, age-related cachexia and/or sarcopenia, age-related macular degeneration (AMD, early/intermediate/late), neovascular/wet AMD, dry AMD, Geographic atrophy (GA), wet and dry AMD in the same eye(s), Stargardt's macular degeneration, Best vitelliform macular dystrophy, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, age/aging-related eye disease, ophthalmological disease/disorder, ocular disease, vision loss, progressive vision impairment, myopia (short-sightedness), degenerative myopia, hyperopia (far-sightedness), accommodative dysfunction, glaucoma, cataract formation, retinal degeneration, progressive retinal degeneration, retinitis pigmentosa, leber hereditary optic neuropathy, Fuchs spot, Best's disease, Sorsby's fundus dystrophy, hearing loss (e.g. age-related), presbycusis, tinnitus, naive T cell shortage, movement disability, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), immunosenescence, respiratory/urinary tract infection (RTI/UTI) especially in older/aged/elderly subjects, cancer;
(xii) aging and/or one or more signs of aging, wherein one or more of these compounds slow/delay/reduce/treat/prevent/stop/reverse aging, and/or extend lifespan and/or healthspan, and/or treat or delay the onset of geriatric aging of the human/animal body, tissue(s), or organ(s), and/or treat or delay the onset of an age-associated phenotype in a cell(s)/organism(s), and/or prolong fertility e.g. female fertility, delay menopause;
(xiii) skin aging and/or damage (including sun damage) and/or scalp and/or hair aging and/or hair greying and/or hair loss;
(xiv) insomnia, fatal insomnia, sleep onset latency, delayed sleep phase disorder, exploding head syndrome, parasomnia, sleep-maintenance insomnia, sleep disorder, too much/inappropriate/undesired signals/activity/electrical activity in the nervous system, hyperactivity, hypersensitivity, Premature ejaculation, hyperreflexia, Autonomic dysreflexia (AD), Hyperventilation syndrome, brain hyperactivity, overly sensitive sensory system, pathological crying and/or laughing, Pseudobulbar affect (PBA, emotional lability), photophobia, phonophobia, temperature-sensitive, pressure-sensitive, brain hyperexcitability, overstimulation, intrusive thought(s), Perseveration, sensory overload, disorganized thinking, fantasy prone personality, malapdative daydreaming, dissociation, hyperkinetic disorder, agitation, Psychomotor agitation, restlessness, difficulty controlling behaviour, disruptive behaviour disorder, Emotional and behavioral disorder, pervasive developmental disorder, Overactive disorder associated with mental retardation and stereotyped movements, attention-deficit disorder, Attention Deficit Hyperactivity Disorder (ADHD), adult attention-deficit hyperactivity disorder, severe behavioral problem(s) in children (e.g., to illustrate and not restrict, combativeness and/or explosive hyperexcitable behavior {out of proportion to .. immediate provocation[s]}, hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of one or more of: impulsivity, difficulty sustaining attention, aggressivity, mood lability, poor frustration tolerance), Premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), impulsiveness, impulsivity, impulse control disorder, lack of self-control, hysteria, histrionic personality disorder, attention difficulty, inattention, poor attention control, anxiety, paranoid anxiety, Paranoid personality disorder, distress, dysphoria, Adjustment disorder, separation anxiety, anxiety disorder, depressive anxiety, agitated depression, treatment-resistant depression, Generalized anxiety disorder, social anxiety disorder, stranger anxiety, separation anxiety (e.g. in dogs left at home), separation anxiety disorder, Mixed anxiety-depressive disorder, depression (all forms, all severities), restlessness/apprehension/anxiety before surgery.
hypochondria, panic disorder, panic attack, emotional outburst, emotional instability, Intermittent explosive disorder, unreasonable/unwarranted anger/aggression, hyper-aggression, hostility, rage, poor temper control, self-hatred, poor attentional control, worry, irritability, neuroses, somatization disorder, somatic symptom disorder, pain disorder, psychological pain, psychogenic pain, .. psychogenic facial pain, Atypical odontalgia (AO), burning mouth syndrome, throbbing, toothache/pulpitis/dental pain, chronic lower back pain, negative emotion, persistent/enduring negative emotion, body dysmorphic disorder, factitious disorder, illness anxiety disorder, unwarrented fight-or-flight response, stress, emotional stress, emotional dysregulation, distress, psychological stress, acute stress, chronic stress, acute stress reaction, combat stress reaction, traumatic grief, grief, grief after death of loved one, Prolonged grief disorder (PGD), heartbreak, guilt, shame, remorse, emotional pain, Algopsychalia, psychalgia, suffering, emotional trauma, psychological trauma, broken heart, Post Traumatic Stress Disorder (PTSD), Complex post-traumatic stress disorder (C-PTSD), hypervigilance, sympathetic hyperactivity, inability or impaired ability to relax, flashbacks, dysphoric hyperarousal, agoraphobia, insomnia, fatal insomnia, mood disorder, irrational/unwarrented fear/terror, phobia, social phobia, Cancerophobia, thunderstorm/firework phobia, hypersexuality, hypersexual disorder, depression, clinical depression, unipolar depression, bipolar disorder, Bipolar I, Bipolar II, Bipolar disorder not otherwise specified (Bipolar NOS), cyclothymia, cyclothymic disorder, mixed affective state, atypical depression, melancholic depression, postpartum depression, double depression, seasonal affective disorder, mania, manic episode, hypomania, increase in energy of psychomotor activity, delirium, excited delirium, major depressive disorder, minor depressive disorder, recurrent brief depression, Depressive Disorder Not Otherwise Specified (DD-NOS), major depressive episode, persistent .. depressive disorder (PDD), dysthymia, dysthymic disorder, absence of euthymia, manic thoughts, racing thoughts, thought disorder, disordered thinking, reduced ability to plan and execute tasks, paranoia, hallucination (including, without limitation, visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrioceptive, nociceptive, thermoceptive, chronoceptive), Charles Bonnet syndrome, delusion, persecutory delusion, hearing voices, .. homicidal/criminal ideation/tendency/thoughts, suicidal ideation/tendancy/thoughts, self-injury, non-suicidal self-injury, violence, attacking others, negative mood swing, personality disorder, Borderline personality disorder, Narcissistic personality disorder, malignant narcissism, dissociative disorder, dissociative identity disorder (DID), Psychosis, acute psychosis, chronic psychosis, psychosis spectrum disorder, manifestations of psychotic disorders, behavioral complications of mental retardation, stimulant psychosis, psychotic depression, hallucinogen persisting perception disorder, Psychoactive substance-related disorder, amphetamine-induced psychosis, brief psychotic disorder, Brief reactive psychosis, Menstrual psychosis, postpartum psychosis, Psychotic disorder, Psychopathy, chronic hallucinatory psychosis, manifestation(s) of psychotic disorder, neurotic/reactive/endogenous/involutional/psychotic depression/depressive disorder (optionally accompanied by anxiety or agitation), depressive neurosis, delusional depression, psychotic aggression, psychiatric symptoms of dementia, AIDS delirium, Supersensitivity psychosis, Tardive psychosis, Tardive dysmentia, Depersonalization disorder, out-of-body experience, Sociopathy, Schizophrenia, Paranoid schizophrenia, disorganized-type .. schizophrenia, simple-type schizophrenia, pseudoneurotic schizophrenia, prodromal schizophrenia, schizoaffective disorder, bipolar type schizoaffective disorder, depressive type schizoaffective disorder, schizoaffective psychosis, Schizotypal personality disorder, schizophreniform disorder, Delusional parasitosis, formication, paresthesias, Acroparesthesia, tinnitus, delusional disorder, delusional jealousy, inappropriate behaviour, behavioural disorder, antisocial personality disorder, Oppositional defiant disorder (ODD), conduct disorder (CD), Disruptive mood dysregulation disorder (DMDD), sadistic personality disorder, poor inhibitory control, kleptomania, Pyromania, trichotillomania, dermatillomania, pathological/problem gambling, dyskinesia, tardive dyskinesia, paroxysmal dyskinesia, Paroxysmal kinesigenic dyskinesia, Paroxysmal nonkinesigenic dyskinesia, Paroxysmal exercise-induced dystonia, Hemiballismus, tic disorder, tremor, clonus, Tourette's syndrome, coprolalia, copropraxia, Echophenomena, Echopraxia, Echolalia, Palilalia, stuttering/stammering, stereotypy, punding, Self-stimulatory behaviour (stimming), Stereotypic movement disorder (SMD), synesthesia, obsession, Obsessive¨compulsive disorder (OCD), obsessive¨compulsive personality disorder, anankastic personality disorder, relationship obsessive¨compulsive disorder (ROCD), Scrupulosity, Primarily obsessional obsessive compulsive disorder, sexual obsession, Akathisia (including, without limitation, chronic, acute, Pseudoakathisia, Tardive akathisia, withdrawal or "rebound"
akathisia), Restless legs syndrome, motor restlessness, periodic limb movement disorder (PLMD), periodic limb movements in sleep (PLMS), Sydenham's chorea, chorea, dystonia, Hypnic jerk, twitching, spasms, Tetanus, tetanus muscle spasms, tetanized state, Myoclonus, myoclonic seizure, Action myoclonus, Palatal myoclonus, Middle ear myoclonus, Spinal myoclonus, Stimulus-sensitive myoclonus, Sleep myoclonus, Cortical reflex myoclonus, Essential myoclonus, myoclonic epilepsy, Juvenile myoclonic epilepsy, Progressive myoclonus epilepsy (PME, including, without limitation, Dentatorubral-pallidoluysian atrophy, Unverricht-Lundborg disease, MERRF syndrome, Lafora disease), Reticular reflex myoclonus, Myoclonic epilepsy, diaphragmatic flutter, automatism, status epilepticus, Epilepsia partialis continua, Complex partial status epilepticus, epilepsy, epileptic seizure, simple partial seizure, complex partial seizure, generalized epilepsy, generalized seizure (including, without limitation, tonic-clonic, tonic, clonic, myoclonic, absence (including typical absence and atypical absence), atonic seizure), focal epilepsy, focal seizure, focal/partial seizure (including, without limitation, Simple partial seizure and Complex partial seizure), focal aware seizure, focal impaired awareness seizure, generalised epilepsy, temporal lobe epilepsy (including, without restriction, mesial temporal lobe epilepsy {MTLE} and lateral temporal lobe epilepsy ILTLEI), Frontal lobe epilepsy, Rolandic epilepsy, Nocturnal epilepsy, Nocturnal frontal lobe epilepsy, Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Generalized epilepsy with febrile seizures plus (GEFS+), Panayiotopoulos syndrome, epileptic fit, reflex epilepsy, reflex seizure, absence seizure (including, without limitation, childhood absence epilepsy, epilepsy with myoclonic absences, juvenile absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome {eyelid myoclonia with absences}, genetic generalised epilepsy with phantom absences), complex partial seizure, atonic seizure, generalized tonic-clonic seizure, tonic¨clonic seizure, extrinsic stimulus epilepsy, intrinsic stimulus epilepsy, photosensitive epilepsy, musicogenic epilepsy, thinking epilepsy, eating epilepsy, seizure(s), Febrile seizure, nerve agent induced seizure, Dravet syndrome (sometimes modest hyperthermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals), acute symptomatic seizure, seizure-related disorder, drug related seizure, paroxysmal depolarizing shift, Ohtahara syndrome, Epilepsy in females with mental retardation, Rasmussen's encephalitis, Epilepsy syndrome, benign rolandic epilepsy, childhood absence epilepsy, absence epilepsy, juvenile myoclonic epilepsy, epileptic encephalopathies, Lennox¨Gastaut syndrome, West syndrome (Epileptic spasms), Doose syndrome (Myoclonic astatic epilepsy, MAE), Lennox-Gestaut syndrome, pseudo-Lennox Gastaut syndrome (atypical benign partial epilepsy), Benign familial neonatal epilepsy, Benign occipital epilepsy of childhood, familial neonatal convulsions, Febrile infection-related epilepsy syndrome, interictal dysphoric disorder, euphoria sclerotic, psychogenic non-epileptic seizure, non-epileptic seizure, gelastic seizure, convulsion(s), migraine, status migrainosus, tension headache, headache, Hypnic headache, hiccups, intractable hiccups, thumps in equines, Postural orthostatic tachycardia syndrome (POTS), Pheochromocytoma, agony, pain, chronic pain, acute pain, pain due to disease/injury, neuropathic pain, fibromyalgia, postherpetic neuralgia, phantom pain, referred pain, back pain, lower back pain, pelvic pain, cancer associated pain, chemotherapy associated pain, Diabetic neuropathy, small fiber peripheral neuropathy, Mononeuritis multiplex, Wartenberg's migratory sensory neuropathy, Breakthrough pain, idiopathic pain, polyneuropathy, Neuritis, Mononeuropathy, Polyradiculoneuropathy, Radial neuropathy, neuropathy, visceral pain, Burning feet syndrome, Tarsal tunnel syndrome, Carpal tunnel syndrome, Guyon's canal syndrome, Cubital Tunnel Syndrome, Repetitive strain injury, Sciatica, Neurofibromatosis, Ulnar nerve entrapment, Erythromelalgia, Paroxysmal extreme pain disorder, Proctalgia fugax, dysesthesia, scalp dysesthesia, dysesthetic burning, hyperesthesia, hyperalgesia, Opioid-induced hyperalgesia, hyperpathia, allodynia, pain response from stimuli which do not normally provoke pain, Complex regional pain syndrome (said to be most painful condition known to man), Radiculopathy, neuralgia (including, without restriction, intercostal neuralgia, trigeminal neuralgia, atypical trigeminal neuralgia, glossopharyngeal neuralgia, occipital neuralgia, postherpetic neuralgia), ciguatera poisoning, irritable bowel syndrome (IBS), interstitial cystitis (IC), temporomandibular joint disorder, acute intermittent porphyria, Porphyria, Acute porphyria (including, without limitation, acute intermittent porphyria {AIP}, variegate porphyria {VP}, aminolevulinic acid dehydratase deficiency porphyria {ALAD}, hereditary coproporphyria {HCP}, drug induced), Chronic porphyria (including, without limitation, X-linked dominant protoporphyria {XLDPP}, congenital erythropoietic porphyria {CEP}, porphyria cutanea tarda {PCT}, and erythropoietic protoporphyria {EPP}), cutaneous porphyria, Porphyria cutanea tarda, allergy, allergic reaction, anaphylaxis, anaphylactic shock, hives, asthma, allergic rhinitis, rhinitis, urticaria, contact dermatitis, cough, sore throat, esophageal reflux disease, heartburn, chest pain, Esophageal motility disorder, Nutcracker esophagus, diseases involving gastrointestinal motility, Peptic ulcer disease, esophageal spasm, angina, itchiness, Pruritus, severe pruritus, Prurigo, Pruritic skin condition, chronic itch, eczema, pruritus in eczema, neuropathic itch, neurogenic itch, itchiness due to atopic dermatitis and/or lichen simplex chronicus, peripheral sensitization, central sensitization, sensory perception of absent stimuli, too much sensory stimulation, sensory stimulation brings discomfort, Neuromyotonia, Peripheral nerve hyperexcitability, Morvan's syndrome, Benign fasciculation syndrome, Cramp fasciculation syndrome, hyperhidrosis, undifferentiated somatoform disorder, somatoform disorder, somatic symptom disorder, conversion disorder, functional neurological symptom disorder, severe nausea and/or vomiting, severe nausea/emesis, Chemotherapy-induced peripheral neuropathy, chemotherapy-induced nausea and vomiting (CINV), radiation therapy-induced nausea and vomiting (RINV), postnarcotic nausea, hyperemesis gravidarum, morning sickness, Cyclic vomiting syndrome, retching/dry heaving, Urinary incontinence, enuresis, nocturnal enuresis, tail chasing, reduce urine spraying/marking behavior, benzodiazepine withdrawal syndrome, barbituate withdrawal syndrome, Neuroleptic discontinuation syndrome, drug withdrawal discomfort/pain/symptoms, drug use disorder, alcohol use disorder, opoid use disorder, amphetamine use disorder, cocaine use disorder, alcohol withdrawal syndrome/symptoms, delirium tremens, opoid withdrawal sydrome/symptoms, drug craving, drug addiction, drug dependence, polysubstance dependence, drug overdose, smoking, tobacco (nicotine) addition, tobacco (nicotine) withdrawal symptoms, alcoholism, addiction, opoid addiction, cocaine/crack addiction, addictive behaviour, addictive personality, behavioural addiction, internet/computer/computer game/social media/media addiction, exercise addiction, compulsive behaviour (e.g. {non-limiting}
checking, counting, washing, repeating), anti-social behaviour, criminality, sexual compulsion, impulsive sexual behaviour, compulsive buying, gambling addiction, sex related addiction, sexual urge, hunger, eating desire/compulsion, eating disorder, polyphagia, overeating, binge eating disorder, compulsive overeating, insatiable/excessive appetite, bulimia nervosa, anorexia nervosa, substance abuse, substance-induced delirium, substance-induced psychosis, substance-induced mood disorder, drug overdose, vertigo, motion sickness, seasickness, mentaUnervous breakdown, Autism spectrum disorder, neurological disorder, cognitive disorder, mental disorder, mental health disorder, mental health condition involving impaired or altered neural plasticity, mood disorder, mental disorder disclosed in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or a later edition, a mental/behavioural disorder disclosed by the International Classification of Diseases (LCD) in LCD-I 0 Chapter V: Mental and behavioural disorders (World Health Organisation, WHO); or (xv) diseases or disorders or conditions or pathologies or unwanted/undesirable effects/actions/behaviour treatable/ameliorated/prevented/combated, in totality or in part (e.g.
along with surgery), by anaesthesia, pre-anaesthesia, post-anaesthesia, hypoesthesia, hypoactivity, sedation, coma, tranquilization, behavioural submission, muscle relaxation, hibernation, artificial hibernation, torpor, synthetic torpor, suspended animation (e.g. used during spaceflight because e.g. reduces ionizing radiation damage to subject);
(xvi) hyperproliferative/hyperplasia disorder, non-cancerous proliferative disorder, hyperproliferative autoimmune disorder, hyperplasia, epidermal hyperplasia, dysplasia (e.g.
epithelial dysplasia), nodule(s), wart(s), papilloma(s), squamous cell papilloma, genital wart(s), condyloma(s), condyloma acuminatum, cyst(s), polyp(s) {including, without restriction, digestive, colorectal, endometrial, cervical, nasal, laryngeal, inflammatory fibroid polyp[s])}, inherited/hereditary (including, without restriction, Familial adenomatous polyposis, Peutz¨Jeghers syndrome, Turcot syndrome, Juvenile polyposis syndrome, Cowden disease, Bannayan¨Riley¨Ruvalcaba syndrome {Bannayan-Zonana syndrome}, Gardner's syndrome) and non-inherited (non-restrictive e.g. Cronkhite¨Canada syndrome) polyposis syndrome, benign tumour, adenoma, organ enlargement by hyperplasia, Cushing's disease (enlarged adrenal cortex by hyperplasia), congenital adrenal hyperplasia, hyperplasia of breast, atypical ductal hyperplasia, intraductal papillomatosis, fibroadenomas, fibrocystic changes, hemihyperplasia, focal epithelial hyperplasia, sebaceous hyperplasia, sebaceous adenoma, intimal hyperplasia, unwanted/undesirable smooth muscle cell proliferation, smooth muscle cell hyperplasia, intimal smooth muscle cell hyperplasia, neointimal hyperplasia, proliferative vascular disorders, stenosis, stenosis because of cellular proliferation, vaginal stenosis, stenosis in a blood vessel, lessoned patency of a blood vessel, stenosis in a blood vessel because of cellular proliferation, vascular occlusion, restenosis, restenosis in a blood vessel that has been implanted with a stent, in-stent restenosis, post-angioplasty restenosis, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g.
diabetic retinopathy and/or other retinopathy[y/ies]), cardiac hyperplasia, fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, fibromatosis, neurofibromatosis, renal interstitial fibrosis, Cowden syndrome, hamartoma(s), choristoma(s), hemangioma(s), lymphangioma(s), rhabdomyoma(s), lymphangiomatosis, cystic hygroma, trichilemmoma, sarcoidosis, neurosarcoidosis, aggressive fibromatosis, desmoid tumour(s), unwanted/undesirable skin cell proliferation, hyperproliferative skin disorder, psoriasis (including, without restriction, plaque, guttate, inverse, pustular, napkin, seborrheic-like, nail, scalp and erythrodermic psoriasis), psoriatic arthritis, dactylitis, seborrhoeic dermatitis, dandruff, eczema, atopic dermatitis, rosacea, reactive arthritis (Reiter's syndrome), pityriasis rubra pilaris, hyperproliferative variants of disorders of keratinization (e.g., without restriction, actinic keratosis, senile keratosis, keratosis pilaris, seborrheic keratosis), scleroderma, benign prostatic hyperplasia, prostate enlargement, endometrial hyperplasia, atypical endometrial hyperplasia, benign endometrial hyperplasia, adenomyosis, atypical polypoid adenomyoma, endometriosis, endometriosis of ovary (endometrioma), endometrial polyp(s), polycystic ovary syndrome, ovarian cyst(s), cervical polyp(s), uterine fibroid(s), uterine hyperplasia;
(xvii) Tumour Associated Macrophages (TAMs) or any macrophage associated disease or disorder such as, without limitation, Macrophage Activation Syndrome (MAS), HIV, AIDS, HIV-associated neurocognitive disorders (HAND), AIDS dementia, HIV
peripheral neuropathy, HIV associated cancers, AIDS-defining cancers, non-AIDS
defining cancers, any disease in which the pathogen(s) hides from the immune system in macrophages including, without limitation, Mycobacterium tuberculosis (causes tuberculosis), Leishmania parasite (causes Leishmaniasis), Chikungunya virus (causes Chikungunya), Legionella pneumophila (causes Legionnaires' disease), adenoviruses, T. whipplei (causes Whipple's Disease), Brucella spp. (causes brucellosis), Staphylococcus aureus, Ebola virus, Hepatitis B
virus, Hepatitis C virus, influenza virus strains, dengue virus and antibiotic resistant bacteria, any disease or condition in which activated macrophages are unwanted or undesirable;
(xviii) virus/pathogen neuroinvasion via macrophage(s), as used for non-limiting example by HIV, Heptatitis C virus and SARS coronavirus;
(xix) neurocognitive or neurodegenerative diseases/disorders, for non-limiting example those caused by a virus;
(xx) virus/pathogen transmission from mother to fetus/baby via macrophage(s) as used for non-limiting example by zika (via Hofbauer cells) and HIV
(macrophages in breast .. milk);
(xxi) acute or chronic or systemic inflammation or any inflammatory disease/disorder/syndrome or any autoinflammatory disease/disorder/syndrome or any autoimmune disease/disorder/syndrome;

(xxii) acute inflammation, chronic inflammation, systemic inflammation, inflammation because of infection or foreign bodies or injury or chemical or toxin or drug or stress or frostbite or burn or ionising radiation or surgery, inflammatory diseases/disorders/syndromes, Macrophage Activation Syndrome (MAS), autoinflammatory .. diseases/disorders/syndromes, age-related chronic inflammatory diseases ("inflammaging"), autoimmune diseases/disorders/syndromes, diseases/disorders of the innate immune system, sore throat, sore throat associated with cold or flu or fever, high-intensity exercise associated inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, osteoarthritis, inflammatory osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation associated depression, neuroinflammation, neuropathic pain, exercise-induced acute inflammation, atherosclerosis, allergy, hay fever, anaphylaxis, inflammatory myopathies, drug-induced inflammation, systemic inflammatory response syndrome, sepsis-related multiple organ dysfunction/multiple organ failure, microbial infection, acute brain/lung/hepatic/renal injuries, lung inflammation, acute lung injury (ARDS), acne vulgaris, celiac disease, celiac sprue, chronic prostatitis, colitis, autoimmune hemolytic anemia, diverticulitis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Mast Cell Activation Syndrome, mastocytosis, otitis, pelvic inflammatory disease (PID), .. endometritis, reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasitosis, eosinophilia, type III hypersensitivity, ischaemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, alcoholic hepatitis, chronic viral hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematous (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative disease, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, bronchiectasis, bronchopneumonia, obliterative bronchiolitis, appendicitis, acute appendicitis, bursitis, cystitis, dermatitis, encephalitis, HIV encephalitis, gingivitis, meningitis, infective meningitis, myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendonitis, .. testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis¨associated interstitial lung disease and desquamative interstitial pneumonia, pneumonia, interstitial lung disease, LOfgren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, steatohepatitis, nonalcoholic steatohepatitis, silicosis, histiocytoses, Langerhans' cell histiocytosis, haemophagocytic lymphohistiocytosis, pulmonary langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudogout, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft versus host disease (GVHD), lymphadenopathy, rheumatoid arthritis (RA), osteoarthritis (OA), inflammatory osteoarthritis, lupus, multiple sclerosis (MS), myocarditis, uveitis, CNS disease(s), inflammation aspect to a CNS disease(s), hypothalamic inflammation, dementia, glaucoma, amyloid related/driven disease, lipid storage disease(s), fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, cirrhosis of the liver, alcoholic cirrhosis, nephropath(y/ies), lupus nephritis, immune nephritis, fibrotic disorder(s), cardiovascular disease, heart disease, atherosclerosis, vulnerable plaque, plaque formation, lipid containing macrophage related disease(s)/disorder(s)/malad(y/ies), macrophage foam cells, diabetes, type 1 diabetes, type 2 diabetes, insulin resistance, macrophage aspect to insulin resistance, obesity, obesity associated inflammation, macrophage accumulation/large numbers of macrophages in adipose tissue (e.g. associated with obesity), granuloma(s), granulomatous diseases, sarcoidosis (including, without limitation, Annular sarcoidosis, Erythrodermic sarcoidosis, Ichthyosiform sarcoidosis, Hypopigmented sarcoidosis, LOfgren syndrome, Lupus pernio, Morpheaform sarcoidosis, Mucosal sarcoidosis, Neurosarcoidosis, Papular sarcoid, Scar sarcoid, Subcutaneous sarcoidosis, Systemic sarcoidosis, Ulcerative sarcoidos), neurosarcoidosis, pulmonary sarcoidosis, interstitial lung disease, pulmonary fibrosis, pulmonary tuberculosis, immune reconstitution syndrome of HIV, Jarisch¨Hencheimer reaction, sepsis, Paget's disease of bone, osteolysis, monocytosis, histiocytosis, X-type histiocytoses, non-X histiocytoses, Langerhans cell histiocytosis, non-Langerhans-cell histiocytosis, malignant histiocytosis, malignant histiocytic disorders, histiocytomas, histiocytic lymphoma, hemophagocytic syndrome, hemophagocytic lymphohistiocytosis, lymphohistiocytosis, diffuse histiocytic sarcoma, Rosai¨Dorfman disease, gliosis, Bergmann gliosis, Chronic Obstructive Pulmonary Disease (COPD), chronic inflammatory lung disease, familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulinemia D with recurrent fever syndrome (HIDS), cryopyrin associated periodic syndrome (CAPS), Blau syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist (D1RA), mevalonate kinase deficiency, pyogenic-arthritis-pyoderma gangrenosum and acne syndrome (PAPA), periodic fever aphthous stomatitis pharyngitis adenitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, Schnitzler's syndrome, Sweet's syndrome, NLRP12-associated autoinflammatory disorders, deficiency of interleukin-1 receptor antagonist (DIRA), pyoderma gangrenosum, cystic acne, aseptic arthritis, periodic Fever Associated with mevalonate kinase deficiency (hyperimmunoglobulin D Syndrome), Pyogenic Arthritis Pyoderma Gangrenosum Acne (PAPA) syndrome, Periodic Fever Aphthous Stomatitis, Pharyngitis and Adenopathy (PFAPA) syndrome, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Chronic Recurrent Multifocal Osteomyelitis (CRMO), Synovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome, Cryopyrin associated Periodic Syndrome (CAPS), Familial cold auto inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Familial cold urticarial, Neonatal onset multisystemic inflammatory disorder (NOMID), hereditary Periodic Fever Syndromes, Periodic Fever Syndromes, systemic autoinflammatory diseases, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), BalO disease, Behcet's disease, benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Berger's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immune hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR) PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, peripheral neuropathy, perivenous encephalomyelitis, Pernicious anemia (PA), POEMS
syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type I diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)), idiopathic thrombocytopenia purpura, splenomegaly;
(xxiii) Systemic inflammatory response syndrome, cytokine release syndrome, cytokine storm, immune reaction to a drug(s) or therapy(s), immune reaction to an immune activating drug(s) or agent(s) or treatment(s) or intervention(s), immune reaction to immunotherapy and/or immune-oncology and/or immunomodulatory drug(s) and/or treatment(s), adverse reaction to adoptive T-cell therapy(s), adverse reaction to a chimeric antigen receptor T-cell therapy(s) (CAR-T cell therapy(s)), adverse reaction to a immune checkpoint inhibitor(s), adverse reaction to monoclonal antibody drug(s), tumor lysis syndrome;
(xxiv) cancer and Graft Versus Host Disease (GVHD) in transplantation therapy in a cancer patient;
(xxv) cardiovascular diseases and conditions associated with thrombosis and/or the formation of atherosclerotic plaques and/or ischemia and/or ischemic conditions and/or associated conditions including, without limitation, ischemia-reperfusion injury, myocardial ischemia, ischemic heart disease, chronic stable angina pectoris, first or recurrent myocardial infarction (MI), congestive heart failure, an acute coronary syndrome, muscle cell damage, necrosis, cardiac arrhythmia(s), non-Q wave MI, unstable angina, high blood pressure, coronary artery disease, coronary arterial thrombosis, ischemic hypoxia, cyanosis, gangrene, acute limb ischemia, stroke, ischemic stroke, brain ischemia, vascular dementia, ischemic sudden death, transient ischemic attack (TIA), thrombophlebitis, ischemic colitis, mesenteric ischemia, angina pectoris, ischemic heart disease, ischemic neuropathy, hypoxic-ischemic encephalopathy, cerebral hypoxia, brain hypoxia, ischemia resulting from vascular occlusion, cerebral infarction, stroke and related cerebral vascular diseases (including cerebrovascular accident and transient ischemic attack), muscle cell damage, necrosis, ventricular hypertrophy, ventricular enlargement (including dilated cardiac myopathy and heart failure), Prinzmetal's angina, peripheral occlusive arterial disease (e.g., peripheral arterial disease, intermittent claudication, critical leg ischemia, prevention of amputation, prevention of cardiovascular morbidity such as MI, stroke or death), pericardial effusion, constrictive pericarditis, thrombosis, thrombotic or thromboembolic conditions, circulatory disease caused by blood clot (i.e. diseases involving fibrin formation, platelet activation, and/or platelet aggregation), thrombotic or thromboembolic symptoms of thromboembolic stroke (including that resulting from atrial fibrillation or ventricular mural thrombus), arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, thromboembolic disorders in the chambers of the heart, venous thrombosis (including deep vein thrombosis), arterial thrombosis, cerebral thrombosis, cerebral arterial thrombosis, pulmonary embolism, cerebral embolism, kidney embolism, arterial embolism, thrombophilia, disseminated intravascular coagulation, restenosis, atrial fibrillation, atherosclerotic vascular disease, atherosclerotic plaque formation, atherosclerosis, atherosclerotic plaque rupture, peripheral arterial disease, coagulation syndromes, intermittent claudication, transplant atherosclerosis, vascular remodeling atherosclerosis, diabetic complications comprising retinopathy, nephropathy and neuropathy, thromboembolic consequenses of surgery, interventional cardiology or immobility, thromboembolic consequenses of medication (such as oral contraceptives, hormome replacement and heparin), thrombotic consequenses of atherosclerotic vascular disease and atherosclerotic plaque rupture leading to tissue ischemia, prevention of atherosclerotic plaque formation, transplant atherosclerosis, thrombotic or thromboembolic complications of surgery including interventional cardiology, thromboembolic complications of pregancy including fetal loss, thromboembolic consequences of thrombophilia (e.g., Factor V
Leiden, and homocystinenimia), prothrombotic consequences and/or complications of cancer, prevention of thrombosis on artificial surfaces (such as stents, blood oxygenators, shunts, vascular access ports, vascular grafts, artificial valves, etc.), coagulopathies (e.g., disseminated intravascular coagulation), coagulation syndromes, vascular remodeling atherosclerosis, restenosis and systemic infection, Kasabach-Merritt syndrome, occlusion (e.g. after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty), thromboembolic disorders resulting from conditions including but not limited to atherosclerosis, surgery or surgical complications, prolonged immobilization, arterial fibrillation, congenital thrombophilia, cancer, diabetes, effects of medications or hormones, complications of pregnancy and thrombosis resulting from prosthetic valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis, or other procedures in which blood is exposed to an artificial surface that promotes thrombosis; or (xxvi) diseases or disorders or conditions treatable/ameliorated/prevented/combated by conferring/maintaining blood vessel patency in a subject, which can be useful during interventional cardiology or vascular surgery including bypass grafting, arterial reconstruction, atherectomy, vascular graft and stent patency, organ, tissue and cell implantation and transplantation, preservation of host and/or graft tissue as related to organ transplantation;
wherein the method comprises administering to the subject an effective amount of at least one compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, and/or a pharmaceutical composition(s) comprising one or compounds of Formula (I), (II), (III), (IV), (V), (VI) or (VII), and/or an FiFo ATP hydrolysis inhibitor(s) (that optionally/preferably inhibits FIFO ATP
synthesis less or, more preferably, not at all), and/or a compound(s)/composition(s) that reduces FIE) ATP
hydrolysis.
The invention further includes the use of one or more of a compound/composition disclosed herein for the manufacture of a medicament, optionally for treating one or more of the diseases/disorders/conditions listed in the list immediately above/aforementioned.
The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof. In an embodiment, the present invention provides a composition comprising at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof. In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate, thereof. In another embodiment, the present invention provides a pharmaceutical composition, comprising: a pharmaceutically acceptable .. carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof. In another embodiment, the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s).
The compound(s)/composition(s) of the present invention can be used in therapy. In another embodiment, the present invention provides a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, for use in therapy. The compound(s)/composition(s) of the invention can be used in the treatment and/or prophylaxis of cancer. In another embodiment, the present invention provides a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, for use in therapy for the treatment and/or prophylaxis of cancer. In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of cancer comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof. The compound(s)/composition(s) of the present invention can be used for the manufacture of a medicament, optionally a medicament for the treatment and/or prophylaxis of cancer. In another embodiment, the present invention provides the use of a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a .. solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer. The compounds/compositions of the invention can be used alone, in combination with other compounds/compositions of the present invention, or in combination with one or more, preferably one to two, other agent(s). In another embodiment, the present invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy. In another embodiment, the present invention provides a combined pharmaceutical preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in treatment and/or prophylaxis of cancer. In a preferred embodiment, the additional therapeutic agent(s) is an anti-cancer agent or combination thereof.

In an embodiment, the present invention provides a process for making a compound of the present invention. In another embodiment, the present invention provides an intermediate for making a compound of the present invention. The present invention provides processes and .. intermediates for making the compounds of the present invention. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein.
Different methods to prepare the compounds of the present invention will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence in order to give the desired compound or compounds. The reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
Example compounds are typically prepared as racemic mixtures. Preparation of homochiral .. examples may be carried out by techniques known to one skilled in the art.
For example, homochiral compounds may be prepared by separation of racemic products by chiral phase preparative HPLC. Alternatively, the example compounds may be prepared by methods known to give enantiomerically enriched products. These include, but are not limited to, the incorporation of chiral auxiliary functionalities into racemic intermediates which serve to control the diastereoselectivity of transformations, providing enantio-enriched products upon cleavage of the chiral auxiliary.
It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group(s) used for protection of the reactive functional group(s) present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene et al. (Protective Groups in Organic Synthesis, 3rd Ed., Wiley-Interscience (1999)). One of the art is familiar with orthogonal protecting groups, orthogonality, wherein different groups are protected by different protecting groups, removable by different conditions, and so a protecting group(s) can be removed without removing another protecting group(s).
EXAMPLE (I) Summary of Formula (I) This invention embodiment relates to compounds having the following formula:
Formula (I) Z LM)rn X / (LN)1 '"=(LTh G2 (LU)u w .õ,õG1 G3 ZZ (L c (L.-)r ¨R1 OR

(LM)m (LN)n Z N
(_1")t G2 (LU G1 ZN'' G3 )u ZZ (LR)r ¨R1 OR

(LõN)m, ,,(LN)n (LT)t G2*.
(LU)u4G3 I (LP)p ZZ L (I-1r ¨R1 including I
(LlmN (LN)n (LT)t G2 (LU)u4 G3 I L
I
ZZ (Llr ¨R1 including u (LN)n zs=
(LlmI
(LTh NN I
(LU)u N G3 I
(L¨R1 =L H
(R4),4 including N/

L H

(R4)q or a pharmaceutically-acceptable salt, solvate, hydrate, or prodrug thereof, wherein:
G1 is N or CH;
G4 is NH or Cl-I2;
G2 is N or CH;
G3 is sulphur (S) or oxygen (0) or selenium (Se) or CH2 and R1 is absent and r is 0; or G3 is nitrogen (N), or CH or phosphorus (P) and R1 is present;
example embodiments include Z R2N.NrR3 L L
4110 N/%S
L H
(R4)q , Z R2NN"R3 L L
N X N
L H I

(R4),4 ;
Lm, LN, Lu, . T, L LW, LP and LR are each independently selected from a single bond, 0, S, Se, NRv, pRv, Be, c¨vs (IC )2 or Si(Rv)2, wherein each Rv is independently selected from hydrogen, deuterium, halogen (e.g. F), alkyl, or substituted alkyl (non-limiting examples:
CF3, CC13), or deuterated alkyl (non-limiting example: CD3), or aminoalkyl, or thioalkyl, or alkoxy, or 0, or OH (hydroxyl), or halogen, or haloalkyl, or haloalkoxy;
m, n, u, t, w, p and r are each independently selected from 0, 1, 2, 3 and 4;
L is independently at each point of its use alkyl, or substituted alkyl (non-limiting examples:
CF3, CC13), or deuterated alkyl (non-limiting example: CD3), or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy, or hydroxyalkyl or any atom or isotope permitted by valence (including any accompanying hydrogen(s)/deuterium(s) by valence e.g.
(non-limiting) OH, NH2, SH, S1H3, PH2, BH2 etc.) including, without limitation, La, Ti, Ce, V, Ta, Cr, Mo, Mn, Fe, Ru, Os, Co, Pd, Pt, Cu, Ag, Au, Zn, B, Al, Ga, C, Si, N, P, As, Sb, Bi, 0, S, Se, F, CI, Br, I, Hg;

R1 is absent, R.
- R3, hydrogen, deuterium, cyano, aryl, heteroaryl, ¨S02R8, ¨C(=0)R9, ¨C(=CH2)R9, ¨C(-0H)R9, ¨C(-SH)R9, ¨C(-SeH)R9, ¨C(-0L)R9 (wherein L defined earlier), ¨C(=S)R9, ¨C(=Se)R9, ¨C(=NH)R9, C(=PH)R9, ¨S(=0)R9, ¨C(=N-OH)R9, ¨
C(-N=0)R9, ¨C(-P=0)R9, ¨C(=N-0-CH3)R9, --C(=RD)-(0-R9, C(=RD)-R9, or ic\z/R9 0 Se 0= s=
or or or or or Se=
RD is 0, S, Se, NH or PH;
1.-1 is selected from a single bond, 0, S, NW or C(102, wherein each RJ is independently selected from hydrogen, deuterium, halogen (e.g. F), alkyl, or substituted alkyl (non-limiting examples: CF3, CCI3), or deuterated alkyl (non-limiting example: CD3), or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy;
j is 0, 1, 2 or 3;
Rextra is selected from L (defined earlier), aryl, heteroaryl, cycloalkyl, heterocyclo, arylalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkylene, substituted alkylene, alkynyl, substituted alkynyl, alkoxy, thioalkyl, aminoalkyl, carbamyl, sulfonyl, sulfonamide, cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, morpholinylalkyl, acyl, alkoxycarbonyl, substituted amino;
R2 is (i) independently hydrogen, L (defined earlier), alkyl, or substituted alkyl, or (ii) taken together with R3 forms a heterocyclo;
R3 is (i) independently RI, alkyl, substituted alkyl, L (defined earlier), alkylthio, aminoalkyl, carbamyl, BB-aryl, BB-heterocyclo, BB-heteroaryl, or BB-cycloalkyl, or (ii) taken together with R2 forms a heterocyclo;
Z is heteroaryl;
Zz is aryl, heteroaryl, cycloalkyl or heterocyclo;

BB is a bond, Ci_aalkylene, C2_4alkenylene, substituted Ci_aalkylene, substituted C2-4alkenylene, ¨C(=0)NR 9¨, ¨C _aalkylene-C(=0)NRI 9¨, or substituted C
1_4alkylene-C(=-0)NR19¨;
114 at each occurrence is selected independently of each other R4 from the group consisting of PH2,0H, SH, halogen, alkyl, substituted alkyl, haloalkyl, nitro, cyano, haloalkoxy, 0R25, SR25, NR25R26, NR25S02R27, S02R27, S02NR25R26, CO2R26, C(=0)R26, CHNR25R26, OC(=0)R25, ¨0C(=0)NR25R26, NR25C(=0)R26, NR25CO2R26, aryl, heteroaryl, heterocyclo and cycloalkyl;
R8 is alkyl, substituted alkyl, aryl, or heteroaryl;
R9 is ¨NR1ORII, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocycle, heterocyclo or ¨CO2R12;
Rio and Rii, are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, and heteroaryl; or (ii) taken together form a hetero cyclo or heteroaryl;
Ri2 and R19 are hydrogen or alkyl;
R25 and R26 are independently selected from hydrogen, alkyl, or substituted alkyl, or taken together form a heterocyclo or heteroaryl ring;
R27 is alkyl or substituted alkyl, and q is 0, I, 2, or 3.
Preferred compounds of Formula (I) Preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, L
(R4),4 R1 further preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, oxµµH
S
N/kµN

(R4)q and even more preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, S _ N X N

(R4)q =
other preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, R2'`=N/R3 N/IN.\

(R4)q H
further preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, tik \CH
s eix S
N N N
H' (R4 )q other preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, CH ) Sk x eiiiN
li H N N
I
(R4)q R1 other preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, \,\F tik N
R N NN
HI

(R4 )q in which, in the preceding 7 structures shown:
L is hydrogen, or methyl, or alkyl, or hydroxyalkyl, or CF3, or CD3, or deuterium (D);
D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also);
S symbolises the S stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%;
R symbolises the R stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%
(following IUPAC naming rules the chiral carbon of the fluorine (F) analogue is labelled R
rather than S, but note that the arrangement of which bond is up, bold wedge, and down, dashed, around the stereogenic carbon is the same as the preceeding structures labelled S at their chiral carbon, it is this molecule arrangement that is salient, and that is disclosed, rather than a mere label in a naming convention. This clarification won't be repeated at every place to which it applies in this disclosure, at every point at which there is an F
in place of an I-I on the chiral carbon, or any other higher order of priority atom (by IUPAC
rules), e.g. (non-limiting) any other halogen, because this clarification here itself is likely superfluous: all this is very clear to someone of the art. So, when there is said to be an enantiomeric excess (ee) in this disclosure in relation to this example embodiment, Formula (I), it applies to this molecular configuration, this arrangement of solid/dashed wedges, about the chiral carbon, whether this be S or R by IUPAC naming rules);
Z is triazolyl optionally substituted with one to two R7 or imidazolyl optionally substituted with one to two R7 and/or having fused thereto a benzene ring in turn optionally substituted with one to two R7;
Ri is cyano or ¨C(=0)R9;
R2 is hydrogen, alkyl, or benzyl;
R3 is aryl or arylalkyl optionally substituted with alkyl, halogen, trifluoromethyl, OCF3, cyano, nitro, amino, hydroxy, or methoxy;
R4 is halogen, alkyl, trifluoromethyl, or OCF3;
R7 is alkyl, carbamyl or carbamylCi_aalkyl;
R9 is ¨NRioRli, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocycle, heterocyclo or ¨0O2R12;
Rio and Ri i are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, and heteroaryl; or (ii) taken together form a heterocyclo or heteroaryl;
R12 is hydrogen or alkyl; and q is 0, 1, 2, or 3.
More preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, (R24)y (CHR23)x N
*)k`
O (R4)q L N

other preferred compounds are those with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, (R24)y Z NNV R2 (CHR23)x Osoµ\H
lik S
N/kµN
I
(R4)q H R1 and even more preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, = (R24)y Z R2NN," .õ(CHR23)x *AD/ IN
jjk S N Ns= N
I

(R4)q other preferred compounds are those with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, (11110 (R24)y Z NNV R2 (CHR23)x N -(R4)q R1 other preferred compounds are those with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, 1110 (R24)y Z R2N Z(CHR23)x N
ACH;IN
.01 ak S ti,ii N N
I

(R4 )q other preferred compounds are those with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, 11110 (R24)y Z R2NNZ(CHR23)x O R's1/4N//%N
I
(R4) (1H

(1 other preferred compounds are those with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, (R24)y Z \NV R2 (CHR23)x ox\F /IN
ik 12*
N X N
H
I

(R4)q in which, for the preceding 7 structures shown:
E
(R7a)0_3 I
Z is %
%
Y¨N
and more preferably , R7c R7a A syR7b R7a Z iS or Y ¨A ---- E A __ R7c R7aNR7b R7a or or Y ¨N
+
R7a Nkr.R7b or /7- or Y¨N+ Y ¨N
L is hydrogen, or methyl, hydroxyalkyl, or CF3, or CD3, or deuterium (D);
D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also);
S symbolises the S stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%;
A is nitrogen (N), or N+, or carbon;
E is absent, or alkyl, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2 etc.), for example hydrogen, deuterium or fluorine;
Y is N, CH or CR7c;
RI is cyano or ¨q=0)R9;
R2 is hydrogen or Cmalkyl;
R4 is halogen, Ci_zialkyl, trifluoromethyl; or OCF3;
R7a, R7b, and It7c are independently E (defined earlier), hydrogen, alkyl, carbamyl or carbamylCi_aalkyl, or R7a and R7c join to form an optionally substituted fused phenyl ring;
R9 is ¨NR1ORII, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocycle, heterocyclo or ¨0O21Z12;

Rio and Rii are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, and heteroaryl; or (ii) taken together form a heterocyclo or heteroaryl;
R12 is hydrogen or alkyl;
R23 is hydrogen, alkyl, hydroxyalkyl, or phenyl;
R24 is alkyl, substituted alkyl, haloalkyl, halogen, trifluoromethyl, cyano, hydroxy, OCF3, methoxy, phenyloxy, benzyloxy, cyano, or acyl, or two R24 groups join to form a fused cycloalkyl or benzene ring;
el is 1 or 2;
x is 0, 1, or 2; and y is 0, 1, 2, or 3.
More preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, IP (R24)y Z z(CHR23)x HN
ilk N N N
L H I

(R4),1 other preferred compounds are those with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, IP (R24)y Z "(CHR23)x HN
.0 \\ H

(R4 )q and even more preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, e(R24)y Z "(CHR23)x HN
AD
O Ss NZN
I

(R4)q H
other preferred compounds are those with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, (R24)y Z y(CHR23)x HN
SIPN/NN N
CH3 " I
(R4)q R1 other preferred compounds are those with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, (R24)y =
Z z(CHR23)x HN

O S' N/\\\N
I
(R4)4 H R1 other preferred compounds are those with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, (R24)y Z y(CHR23)x HN
IcaCH3",,IN
eft/ X
N N
H' (R4 )q other preferred compounds are those with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, (R24)y Z z(CHR23)x HN
F\N
l io .0 R N/N
I
(R4)q in which, for the preceding 7 structures shown:

R7c R7a N=y.. R7b R7a Z iS or R7c R7a N + R7b R7a or '5Y or \
N+
R7c R7c L is hydrogen, or methyl, or hydroxyalkyl, or deuterium;
D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also);
S symbolises the S stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%;
RI is cyano or ¨C(=0)R9;
R4 is halogen, Ci_aalkyl, trifluoromethyl, or OCF3;
R7c is hydrogen or R7 and R7c join to form a fused benzene ring optionally substituted with C _4a1ky1 or ¨(CH2)1.2¨NHC(=0)Ci_4a1ky1, R7b is hydrogen, C1_4alkyl, or ¨(CH2)i_2¨NHC(=0)Ci_4alkyl;
R9 is a) ¨NRIoRi b) Ci_salkyl optionally substituted with one to two of:
i) SR13, OR13, NRi3aRi3b, halogen, trifluoromethyl, CO2Ri3a, and C(=0)NRi3aR13b, ii) cycloalkyl optionally substituted with one to two of C(=0)H, alkenyl, carbamyl, and/or phenyl in turn optionally substituted with halogen;
iii) phenyl or napthyl optionally substituted with one to two of halogen, nitro, amino, alkyl, hydroxy, Ci_aalkoxy, or having fused thereto a five or six membered heterocyclo;
iv) pyridinyl, thiophenyl, furanyl, tetrahydrofuranyl, or azepinyl, optionally substituted with alkyl or having fused thereto a five to six membered carbocyclic ring optionally substituted with keto or Ci_aalkoxy;
c) C i_aalkoxy;
d) Ci_4alkylthio;
e) CO2alkyl;

f) 3 to 6 membered cycloalkyl optionally having up to four substituents selected from alkyl, halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, and/or phenyl in turn optionally substituted with halogen; or having an aryl fused thereto;
g) phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, .. hydroxy, Cmalkoxy, haloalkoxy, Ci_6alkyl, CO2alkyl, SO2alkyl, SO2NH2, amino, NH(Ci-4alkyl), N(Cmalky1)2, NHC(=0)alkyl, C(=0)alkyl, and/or C14 alkyl in turn optionally substituted with one to three of trifluoromethyl; hydroxy, cyano, phenyl, pyridinyl; and/or a five or six membered heteroaryl or heterocyle in turn optionally substituted with keto or having a benzene ring fused thereto;
.. h) pyridinyl, thiazolyl, furanyl, thiophenyl, and pyrrolyl optionally substituted with one to two of halogen, alkyl, and phenyl in turn optionally substituted with halogen or trifluoromethyl;
Rio is hydrogen, alkyl, or alkoxy;
Rii is alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, or heteroaryl;
or Rio and Rii, taken together form a heterocyclo or heteroaryl;
R23 is hydrogen, alkyl, hydroxyalkyl, or phenyl;
R24 is alkyl, halogen, trifluoromethyl, cyano, halogen, hydroxy, OCF3, methoxy, phenyloxy, benzyloxy, cyano, or acyl, or two R24 groups join to form a fused cycloalkyl or benzene ring;
q is 0, 1, or 2;
xis 0 or 1; and y is 0, 1, or 2.
Most preferred are compounds as immediately defined above wherein, Ri is cyano or -C(=0)R9; R9 is optionally substituted phenyl or phenyl Cmalkyl; x is 0 or 1;
and q and y are 1 or 2. For this preferred structure, its S stereoisomer is preferred. And further preferred is for its L group to be deuterium.
Example embodiments of Formula (I) Compounds from [5-6], selected as specific anti-cancer therapeutics by the invention of this disclosure, selected because they inhibit the reverse, more than the forward, mode of ATP
synthase. EC50 and ICso used interchangeably. ECso values for FiFo ATP
hydrolysis, and FiFo ATP synthesis, in NADH-linked and NADPH-linked sub-mitochondrial (SMP) assays respectively, sourced from [5-6], are presented. [5-6] refer to these ECso values as IC50 values for inhibiting FIFO ATP hydrolase (reverse mode) and Fi Fo ATP synthase (forward mode).
However, this in incorrect. Because, as identified by the invention of this disclosure, explained herein, although these molecules inhibit FIFO ATP hydrolase, their reducing of FiFo ATP synthesis is not (predominantly) because of inhibiting FM ATP synthase, but by uncoupling. More preferred molecules of this invention have a low ECK' for FiFo ATP
hydrolysis, and a higher ECK' for FiFo ATP synthesis, and their ratio difference is large.
N
t_ I

CI
N NH
CI
SOD
Racemate CI
EC so FIFO ATP hydrolase = 0.033 0.02 (pM) EC so RIF ATP synthesis > 100 (pM) EC50 Ratio >3,030 N N
I

CI , HA CI .0õH
NH S N NH
CI
CI

R stereoisomer Cl S stereoisomer Preferred CI
EC50FiFo ATP hydrolase > 100 (pM) EC so FiFo ATP hydrolase = 0.018 0.016 (pM) EC50 FiFo ATP synthesis > 100 (pM) ECso F1F0 ATP synthesis > 100 (pM) ECso Ratio >5,556 In rat: orally bioavailable (47%), iv. half-life (2.1 hours), C = 21 pM, volume of distribution Vss = 2.37 Ukg Further example embodiments of Formula (I), with SMP data, reinterpreted (as aforementioned, these molecules don't significantly inhibit FIR) ATP synthase but do reduce FIFO ATP synthesis by uncoupling), from [5], CI

CI CI
CI N//11\ NH
N).\ NH
ci 1.1 CI 41 CI CI
Ec50 Fi Fo ATP hydrolase = 0.082 t 0.03 (pM) EC50 FiF0 ATP hydrolase = 2.41 (pM) EC50 F1F0 ATP synthesis > 100 (pM) EC50 F1F0 ATP synthesis > 100 (pM) EC Ratio >1,220 EC Ratio >41.5 F N
FJJJci N NH N NH

CI
41i CI CI
EC FiFo ATP hydrolase = 0.71 t 0.34 (pM) EC F1F0 ATP hydrolase = 0.60 t 0.16 (pM) EC F1 F0 ATP synthesis > 100 (pM) EC50 FiFo ATP synthesis > 100 (pM) EC50 Ratio >141 EC Ratio >167 Further examples [5]:

For all: EC50 F1F0 ATP synthesis > 100 OA
R1 R2 EC50F0 ATP hydrolase ( M) 4-CI CN 8.8 2-CI CN 2.23 /R2 2,3-Cl2 CN 2.49 0.72 3-CL CN 9.17 4-CI C(=0)4-CN-Ph 0.28 CI
4-CI C(=0)Et 2.27 NH
Ri = H
CI
Further example, with synthesis step, effectively without a protonable element in its imidazole, which diminishes the molecule's ability to uncouple the proton motive force:

N NH N NH
CI CI is 401 CI
Further example embodiment:
/NH
ci N NH
CI
Further example embodiments:

N11', N1/''' \µ--N CI CICI .--N

CI I I
N NH NH
H

CI CI
, GENERAL COMPOUND SYNTHESIS
A general synthetic route applicable to some compounds of the invention is set out in Scheme / below.
Scheme 1 Z
Z (a) Z-,, (b) L
3,H20 -,-'' 0 H DMF =-...4-----.'"----"--"-1N3 THE
1 (R4)q X'', (R4)4 (R4 )(1 (C) CH3CN

Z R,,, 3 KO Hil""' H NI" L
H ACN, NH3, H20 (R4)q (R4)q I Rg-COOH
(e) CDI, THF
Z, ,R3 --- HN" Rg Z

L
(n Lõ,, I H
NNO
SEC s'µ
H
(R44' 0 (R4),:i The person skilled in the art is able to make modifications to this general synthetic route, based on the common general knowledge, the chemical reaction literature, and/or the content of prior art disclosures cited herein, in order to synthesise compounds of the invention where necessary.
SPECIFIC COMPOUND SYNTHESIS
Racemate 19a [5] was synthesised by the following synthesis route, Scheme 2, and separated into component stereoisomers using chiral supercritical fluid chromatography (SFC). Starting reagents for this synthesis were sourced commercially using the LabNetwork (www.labnetwork.com), which is a website that permits one to search for chemical suppliers for inputted structures/chemical names. There are numerous suppliers listed on LabNetwork for the starting compound, Compound 1 (e.g. Apollo Scientific Ltd., Stockport, UK), and for Compound 3-A (e.g. Astatech Inc., Bristol PA, USA) and Compound 5-A (e.g.
Atlantic Research Chemicals Ltd., Bude, UK). Scheme 2 N
DPPA, DBU PPh3, H20 OH
DMF THF

417% CI 77 4%
CI CI CI

CI

CIJII' NCS IBX
CH3CN NANH ACN, NH3 H20 i 89 8% a 4 a 40 c Nr":z1 CI
NH
N
NANH C(9 ci 5 SFC
N NH
COI, THF
CI 4024 2% 19a CI
N CI N
N

NH(NNH
S
CI CI Ci ci 6a 6b CI CI

Products of Scheme 2:
Stereoisomer ("Stereoisomer 1", enantiomeric excess >97%): Liquid Chromatography-Mass Spectrometry (LC-MS): Liquid chromatography (LC) retention time (RT) = 2.516 minutes, Mass spectrometry (MS; electrospray ionization, positive mode): m/z 537.1 [M+Hr, 559.1 [M+Na], 269.1 [M+2H]2 .
1H NMR (400 MHz, DMSO-d6) (ppm) 11.43 (s, 1H), 8.30 (s, 1H), 8.21 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.68 ¨ 7.56 (m, 3H), 7.56¨ 7.46 (m, 4H), 7.20 (s, 1H), 7.09 (d, J =
8.1 Hz, 2H), 6.97 (s, 1H), 5.96 (s, 1H), 4.33 (s, 1H), 4.19 (s, 1H). {NMR
probe temperature =
298.15 .
Opposite stereoisomer ("Stereoisomer 2", enantiomeric excess >97%): LC-MS:
Liquid Chromatography RT = 2.516 minutes, Mass spectrometry (MS; electrospray ionization, positive mode): m/z 537.1 [M+H], 559.1 [M+Na], 269.1 [M+2H]2+.
1H NMR (400 MHz, DMSO-d6) 5 (ppm) 11.43 (s, 1H), 8.30 (s, 1H), 8.21 (d, J =
7.9 Hz, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.67 ¨ 7.56 (m, 3H), 7.50 (t, J = 6.5 Hz, 4H), 7.20 (s, 1H), 7.09 (d, J
= 8.2 Hz, 2H), 6.97 (s, 1H), 5.96 (s, 1H), 4.34 (s, 1H), 4.19 (s, 1H). {NMR
probe temperature = 298.15 K} .
Presented NMR peaks are from using the "Auto Assignment" algorithm in MestReNova version 12 software (Mestrelab Research, Santiago de Compostela, Spain), which picks peaks in an inputted NMR spectrum, influenced by an inputted structure, which was structure 19a in Scheme 2. An invention embodiment is the use of a compound with LCMS and/or NMR
features as presented above, for use in a method of treatment of the human or animal body by therapy, optionally for cancer treatment/amelioration/prevention/combat in a subject. The actual LCMS and NMR spectra are presented in Figure 32 herein, with further information in its legend.
The reaction scheme below, Scheme 3, is the same as Scheme 2 up until Compound 5. This shared component isn't shown, just the point of divergence from Compound 5, which comes from using a different Compound 5-A, which is available from multiple suppliers on labnetwork.com (e.g. HE Chemical, Changzhou, Jiangsu, China).
Scheme 3 CN
NH

1110 N)LNH
CI ci HO 0 N 0 COI, THF
N NH
CI CI CI *
CI
The reaction scheme below, Scheme 4, is the same as Scheme 2 up until Compound 5. This shared component isn't shown, just the point of divergence from Compound 5, which comes from using a different Compound 5-A, which is available from multiple suppliers on 5 labnetwork.com (e.g. HE Chemical, Changzhou, Jiangsu, China).
Scheme 4 CN
N
NH

5 =COI, THF
ao N NH
CI CI c, is CI
The reaction schemes below, Scheme 5 and Scheme 6, show only starting material and product because they use the same internal steps as Scheme 2 (not shown), but with a different starting material, a different Compound 1 than Scheme 2 and each other, as shown below, and thence different products produced, as shown. Compound 1 of Scheme 5 and Scheme 6 are available from suppliers listed on labnetwork.com (e.g. Toronto Research Chemicals, Ontario, Canada).
Scheme 5 D
D D
OH D CI DI
N NH
CI

CI
ci CI
Scheme 6 -;-,N
p L/D
rs ts1 D N
OH
N NH
CI CI

CI
The reaction scheme below, Scheme 7, is modified from Scheme 2, in order to produce a deuterated analogue, with deuterium in place of hydrogen on the chiral carbon.
The scheme is provided for the purpose of illustrating the invention, and should not be regarded in any manner as limiting the scope or the spirit of the invention. This illustrating, not limiting, feature applies to all the compound synthesis schemes of this disclosure. The starting compound in the scheme below, Compound 1, is available from multiple suppliers listed on LabNetwork (e.g. Apollo Scientific Ltd., Stockport, UK). The 2nd compound, Compound 2, is also available from multiple suppliers listed on LabNetwork (e.g. Manchester Organics Ltd., UK). So, one of the art can choose between these two starting options depending on their preference. Compound 2 tends to be more expensive than Compound 1 to buy and the Compound 1 to Compound 2 reaction shown gives high yield, and imidazole (Compound 1A) can be purchased cheaply (e.g. from Apollo Scientific Ltd., Stockport, UK), thus starting from Compound 1 as opposed to Compound 2 can be cheaper. In an alternative embodiment (not shown), Compound lA is replaced with Imidazole-13C,15N2 (CAS no: 1173018-62-6;
available from suppliers on Labnetwork.com e.g. Meihezhiku(Wuhan) Biotechnology Co., Ltd, China) in Scheme 7 to produce an alternative product of this invention, isotopically enriched for '3C and '5Ix1 at equivalent positions in the final product.
Scheme 7 Br /---:-.-.1 iz--. -. -....1 r---NH N.......,N N 1 \`\..,.....N
?IA NaBD4 D DPPA, DBU
0 N ____... ________________ ==
DMF
K2CO3, DMF 0 OH
CI CI

Nn CI 2 ci ci 3 CI
_õ...N NCS
C
Of 5A
D PPh3, H20 I _____ ...,..N

THF
D =

CI CI

7:-.-...1 ----N
N..õ,..N 5 N 1 ...,,....N
S NH hiJ7A
DA D...1, ,cI
N NH IBX
= N NH
H ACN, NH3 H20 6 7 a H HO 'LO
_________________________________________________________ =
CI CI 01 Cl 40 CD, THF
a tsl a ":õN ..:5,1=1 liz =.,õ..N r---1- -/----- 1._ N.....-N N 0 N
D..,.. SFC I, N 0 N 0 D), .õ.u).., H 40 Fe/N NH 40 s N NH
H H
ci N)NH 8 c, 401 c, ci 40, c, ci 0, CI CI CI
Products of Scheme 7:
Stereoisomer ("Stereoisomer A", enantiomeric excess >97%): LC-MS: LC retention time (RT) = 2.685 minutes, MS (electrospray ionization, positive mode): m/z 538.1 [M+H], 560.1 [M+Na], 269.6 [M+2F1]2+. High Resolution Mass Spectrometry (HRMS): Liquid Chromatography-Time of Flight (LC-TOF) MS (electrospray ionization, positive mode): LC
Retention Time (RT) = 0.166 minutes, m/z 538.0745928061 [M+H], m/z 560.0600137508 [M+Na], m/z 576.0250917093 [M+K], molar percent deuterium incorporation at chiral carbon = 99.13%.
IHNMR (400 MHz, DMSO-d6) a 11.48 (s, 1H), 8.33 (s, 1H), 8.25 (dt, J = 7.8, 1.5 Hz, 1H), 7.96 (dt, J = 7.7, 1.5 Hz, 1H), 7.92 (s, 1H), 7.71 ¨7.60 (m, 3H), 7.60¨ 7.49 (m, 4H), 7.23 (s, 1H), 7.14 (s, 2H), 7.00 (s, 1H), 4.38 (d, J = 14.1 Hz, 1H), 4.23 (s, 1H). {NMR probe temperature = 301 K).
Opposite stereoisomer ("Stereoisomer B", enantiomeric excess >97%): LC-MS: LC
retention time (RT) = 2.685 minutes, MS (electrospray ionization, positive mode): m/z 538.1 [M+H]+, 560.1 [M+Na], 269.6 [M+2H]2+. HRMS: LC-TOF MS (electrospray ionization, positive mode): LC RT = 0.163 minutes, m/z 538.0727757864 [M+H], m/z 560.0513502753 [M+Na], m/z 576.0327248583 [M+K]+, molar percent deuterium incorporation at chiral carbon = 99.14%.
'H NMR (400 MHz, DMSO-d6) 5 11.46 (s, 1H), 8.32 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), .. 7.95 (d, J = 7.7 Hz, 2H), 7.70 - 7.59 (m, 3H), 7.59 - 7.49 (m, 4H), 7.21 (s, 1H), 7.12 (d, J =
7.9 Hz, 2H), 6.99 (s, 1H), 4.36 (d, J = 13.9 Hz, 1H), 4.22 (s, 1H). {NMR probe temperature =
300.7K}.
Presented NMR peaks come from using the "Auto Assignment" algorithm in MestReNova version 12 software (Mestrelab Research, Santiago de Compostela, Spain), which picks peaks in an inputted NMR spectrum, influenced by an inputted structure, which was structure 8 in Scheme 7. However, after automatic assignment, I manually made a single change for the 2"d stereoisomer: I changed the number of hydrogens at 7.95 ppm from 1H to 2H. I
executed this change by manually extending the integration line (this manipulation automatically changes the MestReNova program's integration calculation method from "peak" to "sum") in this 7.95 ppm region for the 2nd stereoisomer, making it the same length as the integration line in the same region for the 1st stereoisomer, which then rendered/integrated this region with 2H
as compared to 1H, the same as for the 1st stereoisomer in this region (by "Auto Assignment"
algorithm: 1st stereoisomer has peaks at 7.96 [1H] and 7.92 [1H] = 2H in 7.95 ppm region).
.. This change in integration increases the nuclide count to the correct number for the structure (18H). This manipulation is best explained in pictures and so please refer to Figures 33L and 33M, which both show the 1st stereoisomer in upper panel, 2nd stereoisomer in lower panel, wherein Figure 33L shows how this region was automatically integrated and Figure 33M
shows how I manually extended the integration line of the 2"d stereoisomer to match the .. length of the 1St stereoisomer, so that both now integrate to 2H in this region.
On another issue, please note that for the 2nd stereoisomer, its LC-MS, HRMS
and NMR are not completely aligned: to explain, LC-MS, FIRMS and 1H NMR were performed and the NMR showed a high amount of impurities (spectrum not shown), further purification steps were taken, and the 1H NMR was repeated (spectrum shown herein), and a 13C NMR
also, all showing a much lower, acceptable level of impurity. However, LC-MS and HRMS
were not repeated. But the LC-MS and HRMS are clear enough to identify the [M+ion]
species needed, all be it with some additional species/impurities also observed that aren't in the LC-MS and HRMS spectra for the lst stereoisomer.
An invention embodiment is the use of a compound with LC-MS and/or NMR
features as presented above, for use in a method of treatment of the human or animal body by therapy, optionally for cancer treatment/amelioration/prevention/combat in a subject.
The actual LC-MS and NMR spectra are presented in Figure 29 herein, with further information in its legend.
The separated stereoisomers of structure 19a in Scheme 2 have a 'H NMR peak at 5.96 ppm = from the hydrogen attached to their chiral carbon. The present stereoisomers, those produced by Scheme 7, have this hydrogen replaced with a deuterium and thence this 5.96 ppm peak is observed absent in their 'H NMR spectra. Indeed, aside from this absence all these stereoisomers have an incredibly similar 1H NMR spectra. The 1H NMR spectra of hydrogen vs. deuterium on chiral carbon stereoisomers are compared in Figure 34.
Compound 5 in Scheme 7 is of the form of Compound 1, the starting compound, in the molecule synthesis embodiments of [Pl] (presented in its "Process of Preparation" section), BUT with the exception that is deuterated on its chiral carbon. This deuterated form can be substituted into the synthesis schemes described in [Pl] to produce deuterated molecules, with deuterium on their chiral carbon, which are componentry to the present invention, and in a non-limiting embodiment, one of more of these new compositions of matter are used as anti-cancer medicines. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or can be readily prepared by one of ordinary skill in the art using known methods.
Further methods to synthesize Compound 5, of Scheme 7 above, are given below in Scheme 8.
Scheme 8 DPPA, DBU PPh H20, =
DMF THF

CI CI CI CI CI CI
IH/D exchange H/D exchange NO NO NO
D DPPA, DBU, D PPh H20 D Further OH
DMF N3 THF " synthesis ci cs CI
(deuterium can be incorporated at other positions also, not shown, depending on the particular deuteration reaction used) Compound 1 in Scheme 8 is available from multiple suppliers listed on LabNetwork (e.g.
Apollo Scientific Ltd., Stockport, UK). Conducting Scheme 8, the aim is to obtain a higher degree of deuterium incorporation on the chiral carbon than natural abundance:
for Compound 4 ultimately, and for Compound 1 first if the lower arm of the synthesis route is used. In both cases, the greater the deuterium incorporation, the better.
Deuterium incorporation at other positions of each molecule is permissible and within the scope of the invention, as is elevated deuterium incorporation only at the chiral carbon.
Reactions described in [L, H, G, K, M, .11, J2, J3, I, F, S] deuterate (herein defined as replace hydrogen with deuterium) the a-carbon to a secondary alcohol and so the chiral carbon of Compound 1.
Reactions described in [A, B, P, El, E2, F] deuterate the a-carbon to primary amines, thence can deuterate the chiral carbon of Compound 4. Reactions described in [N]
deuterate sp3 carbons, thence can deuterate the chiral carbon of Compounds 1 and 4.
Reactions described in [01, 021 can deuterate the I3-carbon to phenyl groups and so can deuterate the chiral carbon of Compounds 1 and 4. Reactions described in [R1, R2, Q I, Q2] can deuterate widely, upon aromatic and alkyl molecular components, and thence can deuterate the chiral carbon of Compounds 1 and 4. Reactions described in [D] deuterate the 13-carbon to tertiary amines, thence can deuterate the chiral carbon of Compounds 1 and 4. The teaching of [D] is .. especially preferred for use in the present context. Whichever option(s) is chosen, solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. The level of deuteration can be modulated by modulating the reaction time: greater deuterium incorporation by longer reaction time. One can do multiple cycles of one or more of these reactions until the desired level of deuterium incorporation occurs, monitored by 1H and/or 2H NMR (e.g. deuterium incorporation quantified by decrease of 1H
NMR integral intensity at specified position(s) compared to starting material) and/or mass spectrometry. Some of the reactions cited herein use commercially available catalysts e.g.
10% Pd/C catalyst [01, 02, Q I, R1, R2], and/or Pt/C catalyst [R1, R2, Ql, Q2], or shvo catalyst [D], or RuC12(P(Ph)3)3 (CAS no: 15529-49-4) [A], or 5% Ru/C catalyst [K], or Ru-macho catalyst [G, M], all available from Sigma-Aldrich. Others teach, or cite literature teaching, how to prepare the catalyst to use. The aforementioned list of synthesis options, to make Compound 4 in Scheme 8, is not exhaustive. A person skilled in the art will know how to find further options. For example using computational tools, including artificial intelligence (AI, non-limiting e.g. [222, 223, 224]), to search the chemical reaction literature/databases, e.g. (non-limiting) the Reaxys or CAS databases, and their own skill in the art to find, plan and prioritise synthesis routes. 2-(1H-imidazol-1-y1)-1-phenylethanamine is commercially available on LabNetwork and can be deuterated at its chiral carbon (and optionally at other positions also) by one or more of the aforementioned methods disclosed herein for deuterating the chiral carbon of 1-(2,4-dichloropheny1)-2-(imidazol-yl)ethanamine. Before or after deuteration, its phenyl group can be (non-limiting) alkylated, halogenated, or CF3 added (non-limiting example: at the 1UPAC 2,5 positions), at desired position(s) by methods well known to those of the art. Then it can be a starting compound in the synthesis schemes of [Pl] and used to produce deuterated compositions of matter that are componentry to this invention, which in non-limiting embodiments, are used singly or in a combination in anti-cancer therapy, in an animal or human. Alternatively, the final products, rather than starting materials, of the synthesis schemes of [Pl] can be deuterated, to produce deuterated compositions of matter that are componentry to this invention, which in non-limiting embodiments, are used singly or in a combination in anti-cancer therapy, in an animal or human. Reactions described in [A, B, El, E2, F] can deuterate the a-carbon to secondary amines, and thence the chiral carbon of Compound 19a, in Scheme 2 presented previously, and the chiral carbon of other molecules with the scaffold of [P1], as presented in the abstract of [P1]. These compounds can also be deuterated at their chiral carbon, and in further embodiments at further or other position(s), by reactions described in [N], which deuterate sp3 carbons. And/or by reactions described in [01, 02], which can deuterate the 3-carbon to phenyl groups. And/or by reactions described in [R1, R2. Q1, Q2], which deuterate aromatic and alkyl molecular components. And/or by reactions described in [D], which can deuterate the 13-carbon to tertiary amines. Some of these reactions are stereoretentive [F, N.
El, E2] and thus can be used, optionally, after stereoisomer enrichment.
Others are not, e.g.
[Q1, Q2], and so should be used before any enantiomeric excess (ee) enrichment step. All patents and papers cited by the present disclosure, and their supplementary materials, are herein incorporated by reference, and are componentry, to the present disclosure.
The reaction scheme below, Scheme 9, is the same as Scheme 7 up until Compound 7. This shared component isn't shown, just the point of divergence from Compound 7, which comes from using a different Compound 7A, which is available from multiple suppliers on labnetwork.com (e.g. HE Chemical, Changzhou, Jiangsu, China).
Scheme 9 CN
I
NH

r 1- cHDOI THO NN F. 0 IX<N NH
CI CI CI
CI
The reaction scheme below, Scheme 10, is the same as Scheme 7 up until Compound 7. This shared component isn't shown, just the point of divergence from Compound 7, which comes from using a different Compound 7A, wherein three different options of Compound 7A are shown and the three resultant products, wherein Compound 7A(i), 7A(ii) and 7A(iii) are all available from multiple suppliers on labnetwork.com (e.g. all available from Fluorochem, Hadfield, Derbyshire, UK).
Scheme 10 Br Br 7A(i) HO
THF NNH

CI
N 07A(ii) NH
X*lZN NH Ho CDI, THF N) NH
CI CI

CI CI
CI
CI
7A(Iii) HO
D.)t, COI, THFµ N NH
CI CI
CI
The reaction scheme below, Scheme 11, shows only starting material and product because it uses the same internal steps as Scheme 7, but with a different starting compound, as shown below (available from suppliers listed on labnetwork.com e.g. Matrix Scientific, Columbia, SC, USA), and thence a different product is produced, as shown.
Scheme 11 N
k D)L.

CI
CI
The reaction scheme below, Scheme 12, shows only starting material and product because it uses the same internal steps as Scheme 7(starting from its Compound 2), but with a different starting compound, as shown below (available from suppliers listed on labnetwork.com e.g.
Vitas-M Laboratory, Champaign, IL, USA), and thence a different product is produced, as shown. Product shown is the (predicted, MarvinSketch software [Chemaxon, Hungary]) predominant tautomer.
Scheme 12 ,-N
H C
3 ¨N+
HaC¨tri N N

CI CI

CI
The reaction scheme below, Scheme 13, differs from Scheme 2 in order to produce methylated analogues, with methyl in place of hydrogen on the chiral carbon.
The starting compound and imidazole are both available from Apollo Scientific Ltd., Stockport, UK and other suppliers listed on labnetvvork.com. In an alternative embodiment (not shown), Compound IA is replaced with Imidazole-13C,15N2 (CAS no: 1173018-62-6;
available from suppliers on Labnetwork.com e.g. Meihezhiku(Wuhan) Biotechnology Co., Ltd, China) in Scheme 13 to produce an alternative product of this invention, isotopically enriched for 13C
and 'Nat equivalent positions in the final product.
Scheme 13 Br fz"-----1 r----1 f N N
N 11"\
N.=,. NH CH3 HnSO4 MeMgBr K2CO3, DMF 0 = OH DH3CN
THF
CI i CI
CI CI CI CI

/---:----1 NCS
N
CH3 ,,, HCI
--=- CH3 a N--e CN
N.õ....,N Isk\,,...,N` so --11-,õ,õ IBX
a 1,,i4 .,.. ACN, NH3 -H2 6 a H N.11...NH HO 0 CI CI a c,= ci a CD, THF

CI CI
--- --- ---CH.31 SFC . cH3N 0 ),, H, 0 N NH 40 s N., NH 0 Fi NH
H F I
CI 8 CI (110 CI CI 100 CI CI ao Products of Scheme 13:
Stereoisomer ("Stereoisomer a", enantiomeric excess >97%): LC retention time (RT) =
2.536 minutes, MS (electrospray ionization, positive mode): m/z 551.0 [M+Hr, 573.0 [M+Na], 276.0 [M+2H]2+.
1H NMR (400 MHz, DMSO-d6) 8 (ppm) 11.37 (s, 1H), 7.89 (dt, J = 7.6, 1.5 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.65 -7.56 (m, 3H), 7.55 -7.47 (m, 2H), 7.47 - 7.37 (m, 3H), 7.22 (d, J =
8.4 Hz, 2H), 7.05 (s, 1H), 6.95 (s, 1H), 6.91 (s, 1H), 4.88 (d, J = 13.6 Hz, 1H), 4.76 (d, J =
13.7 Hz, 1H), 1.70 (s, 3H). {NMR probe temperature = 298.2 K}
Opposite Stereoisomer ("Stereoisomer p", enantiomeric excess >97%): LC
retention time (RT) = 2.540 minutes, MS (electrospray ionization, positive mode): m/z 551.1 [M+H], 573.0 [M+Na], 276.1 [M+2H]2+;

Presented NMR peaks come from using the "Auto Assignment" algorithm in MestReNova version 12 software (Mestrelab Research, Santiago de Compostela, Spain), which picks peaks in an inputted NMR spectrum, influenced by an inputted structure, which was structure 8 in Scheme 13. However, after automatic assignment, I manually made a single change: I
changed the number of hydrogens at 7.05 ppm from OH to 1H by manually changing its integration value from 0.41 to 0.5 (which is rounded to 1). This change in integration increases the nuclide count to the correct number for the structure (21H).
On another issue, please note that the presented LC-MS and NMR are not completely aligned: the LC-MS was conducted before, and the shown NMR after, HPLC
purification.
Prior NMR, before the HPLC purification, showed many impurities present, and so the NMR
was repeated after HPLC purification (from which peaks are shown). This rd NMR
was only performed for one of the stereoisomers.
An invention embodiment is the use of a compound with LC-MS and/or NMR
features as presented above, for use in a method of treatment of the human or animal body by therapy, optionally for cancer treatment/amelioration/prevention/combat in a subject.
The actual LC-MS and NMR spectra are presented in Figure 35 herein, with further information in its legend.

Compound 5 in Scheme 13 is of the form of Compound 1, the starting compound, in the molecule synthesis embodiments of [P11 (presented in its "Process of Preparation" section), BUT with the exception that is methylated on its chiral carbon. This methylated form can be substituted into the synthesis schemes described in [Pl] to produce methylated molecules, with methyl on their chiral carbon, that are componentry to the present invention, and in a non-limiting embodiment, one of more of these new compositions of matter are used as anti-cancer medicines. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or can be readily prepared by one of ordinary skill in the art using known methods.
In some embodiments, Scheme 13 is implemented with each intermediate purified by HPLC, especially the last 3 intermediates, wherein this yields a lower fraction of impurit[y/ies] in the final product. Two alternatives for a step in Scheme 13:
CN

N NH

CI ci T3P,THF

ci CI 8 CI io OR CI
CN
CI CI
CH3aNH
NNH N
HO 0 cH3N
o HATU,THF..

ci CI 8 CI
CI
The reaction scheme below, Scheme 14, differs from Scheme 2 in order to produce fluorinated analogues, with fluorine in place of hydrogen on the chiral carbon.
Scheme 14 f--z-.1 r-----t- Cl A /--,=-1 -N
N N.,...-N Nr.--1 03- N...-....-N S
DPPA, DBU. PPh3, H20 NCS IBX
DMF .
OH th THF
NH2 CH3CN NANH ACN, NH3=1120 H

CI CI CI 4 CI io Selectfluor, K2S208, cl MeCN/H20, heat (e.g. 80 C) OR
Selectfluor, Fe(acac)2 catalyst MeCN
NH OR
5-A 1-:"---1 0 NANH HO __ 0 N\,.......N Selectfluor, H .
N 0 9-fluorenone catalyst CI 5 CI 0 CDI, THF .
__11 MeCN, visable light (light bulb) N¨NH OR
a H Selectfluor, Cl 6 Cl 40 xanathone catalyst MeCN, blacklight (360 nm) CI OR
Selectfluor, 1,2,4,5-tetracyanobenzene (TCB) catalyst,.
MeCN, UV (302 nm) light OR
TREAT=HF (+ optionally AgF) [Mn(salen)Cl] catalyst PhI0, MeCN, heat (e.g. 50 C) OR
N-fluorobenzenesulfonimide (NFSI) tetrabutylammonium decatungstate (TBDAT) catalyst N NaHCO3, MeCN, hf (A = 365 nm) v .- ,--U fliIP
Iµ1\,___N
N

F.,..4._ SFC N 0 N 0 N NH
H '`N H H"---NH 40 R N NH
CI 7 ci 40 c, ci 0 ci a a ci ci ci Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available (e.g. refer www.labnetwork.com) or can be readily prepared by one of ordinary skill in the art using known methods. In alternative invention embodiments the fluorination step is implemented with an earlier or later intermediate than that shown in Scheme 14. A method to fluorinate a benzylic carbon in a structure of Scheme 14 using a Fe(acac)2 [225-226], or 9-fluorenone [227], or xanathone [228], or 1,2,4,5-tetracyanobenzene (TCB) [229] or [Mn(salen)C1] [230], or tetrabutylammonium decatungstate (TBDAT) [231], or no [232] catalyst is componentry to this invention, optionally with the judicious (to someone of the art) addition of a protecting group(s) before, and removal after, the fluorination step e.g. (non-limiting) protecting the OH
group, optionally with TMS, if fluorinating Compound 1. Alternative fluorination methods can be found in the literature, e.g. (non-limiting) refer [233] or [234].
Compound 3 (compound with the NH2 group) in Scheme 14 is of the form of Compound 1, the starting compound, in the molecule synthesis embodiments of [Pl] (presented in its "Process of Preparation" section). Its fluorinated form, fluorinated on its chiral carbon, optionally by a benzylic carbon fluorination reaction disclosed herein, can be substituted into the synthesis schemes described in [P1] to produce fluorinated molecules, with fluorine on their chiral carbon, that are componentry to the present invention, and in a further non-limiting embodiment, one of more of these new compositions of matter are used as anti-cancer medicines.
The following scheme can be substituted into Scheme 14 to produce alternatively halogenated invention embodiments. In other invention embodiments a halogenation step is implemented with an earlier or later intermediate of Scheme 14 than that shown below.
NBS
MeCN, fluorescent lamp OR <,1=1 N-bromosuccinimide (NBS) SePPh3 40 Na0C1 Mn5(salen)C1 OR
N 0 N 0 TBACI, DCM, N2 N 0 Br_x, BBr4 OR

OR DBDMH Cl6 ClH Cu(OAc)2=1120 CI CI a CI CI

NHPI, CH7C1, ZrCI4 .CH2C12, ambient light CI CI Cl DIH or 3-ITMH catalyst N
o-NO2C6H4CO2H
NHPI, CH2Cl2 NN

I
N NH
CI CI
c, A method to chlorinate [235-236], or brominate [237-240], or iodinate [241] a benzylic carbon in a structure of Scheme 14 is componentry to this invention, optionally with the judicious (to someone of the art) addition of a protecting group(s) before, and removal after, the halogenation step.
Scheme 15 CI rt., I-% N"-- NH (NH
(NH
..., '-I
CI C
lb 1)TEA N.--I . -1 2) AcOH, HCI NaBD4N-- D DPPA, DBU.

T-NH

\fµr D PPh3, H20 c NH CI 5b , N
D NC.S

DA
eNH
CI CIeNH N-- S
N NH IBX N.--- NH I. 7b J1ICkH ACN, NH3.H2 N--0.. D u CI 6 CI al -'NH
H HO 0 , CI ci a CDI, THF

7N --_õ,=N
T-NH
e \µNr N 0 NH (NH
isr N 0 0).., _S_FS li-.,... . D).LN
N NH rNNH i N NH
H H10 CI OH, tio CI 8 CI 0 CI a a ci ci ci Scheme 16 a cH3 eNH (NH
NI-- N--a CI CI
H2S0,4, lb 1) TEA 0 MeM9Br. OH CH3CN

2) AcOH, Ha a3 rNli 2 (NH NCS
\N--CH3 NCI N--- i 0 +. r .......4 3 (10 5b =11¨f CH3 NH2 CI 4 CI CI ' (NH CIS 5 CI CH3CN
N-- CH
3 õ eml , la CN
N--11.-, NH IBX N CH NH

NH N..
ACN, NH3 .H2O )L, H
CI CI ao H HO 0 .

CI 7 CI a CDI, THF
CI õN ,- N "N
...- --.
CI
NH
eNH H r (-NH
N"--- C N 0 \N--SFC __________________ . PH3 N 3,...tL.
N NH S N NH N.-- C., F1N 0 R ''N NH
H H H
CI 8 CI ao ci ci a ci ci 40 CI CI CI
For Scheme 15 and Scheme 16, starting materials are available from suppliers listed on labnetwork.com. For example: Compound 1 (e.g. Apollo Scientific Ltd., Stockport, UK), Compound lb (e.g. ChemScene, Monmouth Junction, NJ, USA), Compound 5b (e.g.
Astatech Inc., Bristol PA, USA) and Compound 7b (e.g. Atlantic Research Chemicals Ltd., Bude, UK). For Scheme 17 below, starting materials are available from suppliers listed on labnetwork.com: e.g. Compound lb from ChemScene, Monmouth Junction, NJ, USA;
e.g.
Compound 5b from HE Chemical, Changzhou, Jiangsu, China.

Scheme 17 CI ¨CH3 (NH
rl N-.";''= NH N¨

..., NH20H
lb 1)TEA
CI CI . 0 Zn, HCI
1 2) AcOH, HCI
CI

r NH NH
411D _... r N¨ Li N-- NCS S. NH3, HgOs H
CI CI CI 4 CI ao rNH CN
CI
N¨

NH 5b ("NH

N ANH N¨

HO 0 II SFC, H
CDI THF
CI 5 CI * ' - N---"NH
H
CI 6 CI Op CI
CI
(¨NH
eNNH
N¨ N 0 N¨ N 0 H Ji õM., ji.s.
$ N NH
H H

CI CI
For Scheme 18, starting materials are commerically available from suppliers listed on labnetwork.com: Compound 1 (Toronto Research Chemicals, Ontario, Canada), Compound 4 and Compound 7 (Astatech Inc., Bristol PA, USA).
Scheme 18 NJ

7--:--1- /----N.---N D N....-N D N.....-N1 D
D D DPPA DBU D D PPh3, H20. D D
OH DMFJJJ(N3 THF

CI i CI CI 2 CI CI 3 CI
,-N
.,-- -->N Nr-L-1 ....-N D
D D
CS2, Mel ________________ = NH2 H3C¨S 5 S¨CH3 r----1- r=1¨

D D 1 7 CI, D D I
N S¨CH3 N NH

CI
For Scheme 19, starting materials are commerically available from suppliers listed on labnetwork.com: Compounds 1, 3, 9, 11 (Toronto Research Chemicals, Ontario, Canada).
Scheme 19 -NJr-,----1 o o /--,--1 N...¨N D Nt,,,N D Et01,1{, 1µ1,,,..N D
D D Mn 2 D Et0 3 0E,t D 0 '..
OH 0 4 OEt N/------1 r---1 N,..-NI
Pd/C, H2 D 0 NH4OH D D 0 TFAA
5 OEt 6 NH2 :=N
CI CI CI CI
=/=----1 P-------1 µ....N D 9 Et0H D D NH CI 0 __ .
=N
7 8 OEt =N
CI CI =N CI .. CI
NH2 Nr'---/¨

D

D 1 _ CI 12 NH
OEt CI CI 0 ci ci cl Reaction Scheme 2 in more detail In this section, numbers in square brackets are CAS numbers.
Nr-- N17----...,N1 DPPA, DBU Isl ______________________ D.

CI CI CI CI

I. Charge Compound 1 [24155-42-8] (10.0 g, 1.00 X by weight) and DPPA [26386-88-9]
(10.7 g, 1.07 X by weight) in DMF [68-12-2] (50 mL, 5.00 X by volume).
2. Charge DBU [6674-22-2] (5.90 g, 0.59 X by weight) into the mixture under nitrogen atmosphere at 0 C, then stir for about 15 min.
3. After that, take the reaction mixture to 20-30 C and stir for 24 h.
4. TLC (DCM/Me0H = 10/1, Rf = 0.6) show raw material remains, LC-MS (SM: RT =
0.729 min, Product: RT = 0.822 min) indicates reaction mixture has desired product.
5. The reaction mixture is extracted with Et0Ac (100 mL x 3).
6. The combined organic phase is washed with aq.NaC1 (100 mL), dried with Na2SO4, filtered and concentrated in vacuum to get the residue.
7. The residue is purified by column chromatography (DCM/Me0H = 1/0 to 100/1).
8. Compound 2 (4.82 g, 41.7%, 95% purity) is obtained as yellow oil, which is confirmed by HNMR and HPLC (Retention Time = 1.919 min).
Compound 2: 1H NMR (CDC13, 400 MHz) 6 (ppm) 7.47 (d, J = 2.2 Hz, 1H), 7.41 (s, 1H), 7.33 - 7.28 (m, 1H), 7.26 - 7.23 (m, 1H), 7.06 (s, 1H), 6.92 (s, 1H), 5.26 (m,1H), 4.23 (m, 1H), 4.02 (m, 1H).
Ni---- hill ,.,,Isl \,_..,...N
PPh3, H20 CI CI CI CI

1. Charge Compound 2 (3.00 g, 1.00 X by weight) and PPh3 [603-35-0] (8.40 g, 2.80 X by weight) in H20 (1 mL, 0.33 X by volume) and THF [109-99-9] (10 mL, 3.33 X by volume).
2. Stir at 70 C for 24 h.
3. Check the reaction by LC-MS (SM: RT = 0.822 min, Product: RT = 0.299 min), it shows Compound 2 is consumed completely and desired mass is detected.

4. The reaction mixture is concentrated under reduced pressure to remove TI-IF.
5. The reaction mixture is added with H20 (30 mL), adjust pH to 3 with con.HC1 and washed with Et0Ac (30 mL).
6. After that collect water phase, adjust pH to 13 with IN aq.Na0H, then exact with Et0Ac (30 mL x 2).
7. The combined organic phase is washed with aq.NaC1 (30 mL), dried with Na2SO4, filtered and concentrated in vacuum to obtain the product.
8. Compound 3 (2.23 g, 77.4%, 94.5% purity) is obtained as a yellow liquid, which is confirmed by HNMR and HPLC (Retention Time = 0.658 min).
Compound 3: 1H NMR (CDC13, 400 MHz) 5 (ppm) 7.48 - 7.37 (m, 3H), 7.30 - 7.26 (m, 1H), 7.06 (s, 1H), 6.91 (s, 1H), 4.72 (m, 1H), 4.21 (m, 1H), 3.91 (m, 1H).
rsirs CI
3-A Mi Ncs N )L NH

CI c, CI

1. Charge compound 3 (2.00 g, 1.00 X by weight) and compound 3-A [2131-55-7]
(1.30 g, 0.65 X by weight) in CH3CN [75-05-8] (30 mL, 15.00 X by volume).
2. Stir at 20-30 C for 12 h.
3. Check the reaction by TLC (DCM/Me0H = 10/1, Rf = 0.7) and LC-MS (SM: RT =
0.299 min, Product: RT = 0.949 min), desired product is detected, TLC indicated Compound 3 is consumed completely.
4. The reaction mixture is concentrated under reduced pressure to remove CH3CN
to obtain the residue.
5. The residue is purified by column chromatography (DCM/Me0H = 1/0 to 50/1).
6. Compound 4 (2.95 g, 89.8%, 99.7% purity) is obtained as a white solid, which is confirmed by HNMR and HPLC (Retention Time = 2.521 min).
Compound 4: 1H NMR (DMSO-d6, 400 MHz) 5 (ppm) 9.81 (s, 1H), 8.54 (d, J = 7.5 Hz, 1H), 7.64 (s, 1H), 7.55 (s, 1H), 7.53 - 7.48 (m, 1H), 7.45 - 7.41 (m, 114), 7.38 (d, J = 8.6 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.11 (s, 1H), 6.94 (s, 1H), 6.03 (s, 1H), 4.46 - 4.34 (m, 1H), 4.31 -4.22 (m, 1H).

NH
NANH IBX NA NH
CI CI C H 3C N, NH3 H20 CI CI
*
CI CI

1. Charge Compound 4(1.63 g, 1.00 X by weight) and IBX [61717-82-6] (1.18 g, 0.75 X by weight) in CH3CN [75-05-8] (16 mL, 10.00 X by volume) and NH3.H20 [1336-21-6]
(8 mL, 5.00 X by volume).
2. Stir at 20-30 C for 18 h.
3. Check the reaction by LC-MS (SM: RT = 0.949 min, Product: RT = 1.050 min) and HPLC
(SM: RT = 2.535 min, Product: RT = 1.757 min), desired product is detected.
4. The reaction mixture is extracted with Et0Ac (20 mL x 3).
5. The combined organic phase is washed with aq.NaC1(20 mL), dried with Na2SO4, filtered and concentrated in vacuo to obtain the crude product (1.0 g, white solid), which is used into next step directly.
N

NH

N NH
CI 5 ci 40 COI, THF
CI
19a io ci CI
1. Charge Compound 5-A [1877-72-1] (0.36 g, 0.36 X by weight) and CDI [530-62-1] (0.40 g, 0.36 X by weight) in THF [109-99-9] (20 mL, 20.00 X by volume), stir at 20-30 C for 3 h.
2. Charge Compound 5 into the reaction mixture, stir at 20-30 C for 14 h.
3. Check the reaction by LC-MS (SM: RT = 1.050 min, Product: RT = 1.347 min) and TLC
(DCM/Me0H = 10/1, Rf = 0.75), desired mass is detected. TLC indicates the raw material is consumed completely.
4. The reaction mixture is concentrated under reduced pressure to remove THF.
5. The reaction mixture is extracted with Et0Ac (20 mL x 3) 6. The combined organic phase is washed with aq.NaC1(20 mL), dried with Na2SO4, filtered and concentrated in vacuo to obtain the residue.

7. The residue is purified by column chromatography (DCM/Me0H = I/O to 100/1) and chiral SFC {column: AD (250 mm*50 mm, 10 gm); mobile phase: [0.1%NH3H20 IPA];
B%:
28%-28%, 3.5 min} separating the stereoisomers of Compound 19a: Stereoisomer 1(0.17 g, SFC RT = 2.35 min) is obtained as a white solid. Stereoisomer 2 (0.15 g, SFC
RT = 2.69 min) is obtained as a white solid.
Reaction Scheme 7 in more detail In this section, numbers in square brackets are CAS numbers.
Br 1 1A ,õN1 K2CO3, DMF
CI CI CI CI

1. Charged Compound 1 [170894-53-8] (15.0 g, 55.9 mmol) and DMF [68-12-2] (150 mL) into the reactor at 25 C under N2.
2. Charged K2CO3 [584-08-7] (23.2 g, 167 mmol) into the reactor at 25 C.
3. Charged imidazole [288-32-4] (11.4 g, 167 mmol) into the reactor at 25 C.
4. The mixture was stirred at 25 C for 3 h.
5. TLC (petroleum ether:ethyl acetate = 5:1, Rf = 0.0) showed raw material was consumed.
6. The mixture was quenched with water (100 mL).
7. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
8. The residue was purified by silica gel chromatography (column height: 250 mm, diameter:
100 mm, 100-200 mesh silica gel, petroleum ether/ethyl acetate=20/1, 3/1) to give Compound 2 (13.0 g, 38.8 mmol, 69.3% yield, 76.1% purity) as yellow solid.
Compound 2: 1H NMR (CDC13, 400 MHz) Es (ppm) 7.55 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.35-7.37 (dd, J = 8.0 Hz, 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 111), 6.93 (s, 1H), 5.32 (s, 2H).

NaBD4 CI CI CI CI

1. Charged Compound 2 (8.00 g, 31.3 mmol) and Me0H (40 mL) into the reactor at under N2.
2. Charged NaBDa [15681-89-7] (1.31 g, 34.5 mmol) to the solution.
3. The mixture was stirred at 50 C for 3 h.
4. LCMS (product: RT= 0.914 min) showed raw material was consumed.
5. The reaction was quenched with water (100 mL).
6. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
7. The residue was purified by silica gel chromatography (column height: 250 mm, diameter:
100 mm, 100-200 mesh silica gel, petroleum ether/ethyl acetate=10/1, 0/1) to give Compound 3 (5.50 g, 21.3 mmol, 67.9% yield) as white solid.
Compound 3: 1HNMR (CDCI3, 400 MHz) 5 (ppm) 7.57 (d, J = 8.0 Hz, 1H), 7.39 (m, 1H), .. 7.28-7.30 (dd, J = 8.0 Hz, 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 2H), 4.20 (d, J = 12 Hz, 1H), 3.84-3.88 (d, J = 16 Hz, 1H).
DPPA, DBU

Ci CI Ci CI

1. Set up a reactor R-1. (Note: R-1 is a 100 mL three-necked bottle) 2. Charged Compound 3 (4.50 g, 17.4 mmol) and DPPA [26386-88-9] (4.80 g, 17.4 mmol, 3.78 mL), DMF (22.5 mL) into the reactor R-1 at 25-30 C.
3. Charged DBU [6674-22-2] (2.65 g, 17.4 mmol, 2.63 mL) into the mixture under nitrogen atmosphere at 0-5 C, then the mixture was stirred for about 15 min.
4. After that, the reaction mixture was stirred for 24 h at 20-30 C.

5. TLC (DCM/Me0H = 10/1, SM Rf = 0.55, product Rf = 0.72) showed raw material was consumed, LCMS (product: RT = 0.764 min) and HPLC (product: RT = 1.893 min) indicated reaction mixture has desired product.
6. The reaction mixture was extracted with Et0Ac (40 mL x 3).
7. The combined organic phase was washed with brine (40 mL), dried with Na2SO4, filtered and concentrated in vacuum to get the residue.
8. The residue was purified by column chromatography (SiO2, dichloromethane:
methanol =
1/0 to 100/1) to give Compound 4 (3.80 g, crude) as yellow oil.
Compound 4: 1H NMR (CDCI3, 400 MHz) 8 (ppm) 7.50 (s, 1H), 7.44 (s, 1H), 7.35 (d, J =
2.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.29-7.30 (m, 1H), 6.94-7.10 (m, 1H), 4.25 (d, J = 14.4 Hz, 1H), 4.04 (d, J = 14.4 Hz, 1H).
Nf="---1-- 1::----1 PPh3, H20 CI CI CI CI

1. Set up a reactor R-1. (Note: R-1 is a 100 mL three-necked bottle) 2. Charged Compound 4 (3.80 g, 13.4 mmol), PPh3 [603-35-0] (10.5 g, 40.2 mmol), THF
[109-99-9] (12.6 mL) and H20 (1.26 mL) into the reactor R-1 at 25-30 C.
3. Stirred at 65-70 C for 16 h.
4. Checked the reaction mixture by TLC (dichloromethane: methano1=10:1, SM: Rf = 0.54, product: Rf= 0.45) and LCMS (product: RT = 1.253min) showed that reactant was consumed completed.
5. The reaction mixture was concentrated under reduced pressure to remove THF.
6. The reaction mixture was added with H20 (38 mL), adjusted pH to 3 with con.
HC1 and washed with Et0Ac (38 mL).
7. The water phase was adjusted pH to 13 with IN aq. NaOH, then exacted with Et0Ac (38 mL x 2).
8. The combined organic phase was washed with brine (38 mL), dried with Na2SO4, filtered and concentrated in vacuum to give Compound 5 (2.60 g, crude) as a yellow liquid.
Compound 5: 1H NMR (CDC13, 400 MHz) 8 (ppm) 7.44 (d, J = 14 Hz, 1H), 7.41 (s, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 1.2 Hz, 1H), 7.07 (s, 1H), 6.92 (s, 1H), 4.21 (d, J = 14 Hz, 1H), 3.92 (d, J = 14 Hz, 1H).

CI a 5A
NCS
N NH

CI CI (10 CI
1. Charged Compound 5(2.50 g, 9.72 mmol), Compound 5A [2131-55-7] (1.65 g, 9.72 mmol) and MeCN (37.5 mL) into the reactor at 25 C.
5 2. The mixture was stirred at 25 C for 12 h.
3. TLC (dichloromethane: methano1=10:1, SM: Re= 0.5, product: Re= 0.2) showed raw material was consumed completed.
4. The mixture was concentrated in vacuum.
5. The residue was purified by silica gel chromatography (column height: 250 mm, diameter:
100 mm, 100-200 mesh silica gel, petroleum ether/ethyl acetate=3/1, 0/1) to give Compound 6 (3.60 g, 8.44 mmol, 86.7% yield) as white solid.
Compound 6: 1H NMR (CDC13, 400 MHz) ö (ppm) 9.08 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, I H), 7.25-7.28 (m, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.00 (s, 1H), 6.88 (d, J =
8.0 Hz, 1H), 6.72 (s, 1H), 4.46 (dd, J = 14.4 Hz, 14 Hz, 1H), 1.84 (s, 1H).
NH
DA DA
N NH __ IBX N NH
ACN, NH3 H20 ci CI CI CI

CI CI
1. Charged Compound 6 (3.00 g, 7.03 mmol) and MeCN (30 mL) into the reactor at 25 C.
2. Charged IBX [61717-82-6] (2.17 g, 7.73 mmol) into the reactor at 25 C.
3. Charged NH3.H20 [1336-21-6] (13.6 g, 116 mmol, 15 mL, 30% purity) into the reactor at 25 C.
4. The mixture was stirred at 25 C for 12 h.
5. LCMS (product: RT = 0.717 min) showed raw material was consumed completed.
6. The mixture was filtered and the filter cake was concentrated in vacuum to give Compound 7 (2.50 g, 6.10 mmol, 86.8% yield) as white solid.

Compound 7: 1H NMR (CDC13, 400 MHz) 5 (ppm) 7.87 (d, J = 8.0 Hz, 11-1), 7.67 (s, 1H), 7.55-7.60 (m, 2H), 7.37-7.41 (m, 2H), 7.23 (s, 1H), 7.07-7.09 (m, 1H), 6.92 (s, 1H), 4.33 (dd, J = 14.4 Hz, 14 Hz, 1H).
N
, N /
Ni----- IW
NH 7A r---D)1 N
, HO 0 s\N

H D
CM, THF

H
CI CI io CI
CI
1. Charged Compound 7 (538 mg, 3.66 mmol), CDI [530-62-1] (593 mg, 3.66 mmol) and THF [109-99-9] (30 mL) into the reactor at 25 C.
2. The solution was stirred at 25 C for 3 h.
3. Charged compound 7A [1877-72-1] (1.50 g, 3.66 mmol) into the reactor at 25 C.
4. The mixture was stirred at 25 C for 12 h.
5. LCMS (SM: RT = 0.730 min, product: RT = 1.030 min) showed the raw material was consumed/completed.
6. The mixture was concentrated in vacuum.
7. Seperating stereoisomers of Compound 8: the residue was purified with Prep-HPLC
(column: DAICEL CHIRALPAKAD-H (250 mm*30 mm, 5 pm); mobile phase: [0.1%
NH3H20 IPA]; B%: 44%-44%, 6.45 min) to give Stereoisomer A (0.025 g, 45.8 ttmol, 1.25%
yield, 98.8% purity) as white solid and Stereoisomer 13 (0.025 g, 45.5 mot, 1.24% yield, 98.1% purity) as white solid.
Reaction Scheme 13 in more detail In this section, numbers in square brackets are CAS numbers.
r ____________________ B Nr------1 _..NH
0 b.
K2003,DMF 0 1. Compound 1 (10.0 g, 37.3 mmol) was added in DMF (100 mL) at 25 C under N2.
2. K2CO3 [584-08-7] (15.4 g, 111 mmol) was added to the solution.

3. Imidazole [288-32-4] (7.62 g, 111 mmol) was added.
4. The mixture was stirred at 25 C for 3 h.
5. TLC (petroleum ether: ethyl acetate = 5:1, Rf = 0.35) showed raw material was completed.
6. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mLx 2).
7. The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
8. The residue was purified by silica gel chromatography (100-200 mesh silica gel, Petroleum ether/Ethyl acetate = 20/1, 3/1).
9. Compound 2 (7.20 g, 14.4 mmol, 38.7% yield, 51.2% purity) was obtained as a yellow solid.
Compound 2: 1H NMR (CDC13, 400 MHz) 8 (ppm) 7.55 (d, J = 8.00 Hz, 1 H), 7.48-7.49 (m, 2 H), 7.34-7.36 (m, 1 H), 7.09 (s, 1 H), 6.90 (s, 1 H), 5.31 (s, 2 H).
LC-MS: RT = 1.02 min, m/z 254.9 [M+H].
MeMgBr CI CI CI CI

1. MeMgBr (3.0 M, 91.4 mL, 274 mmol) was added to the reactor and cooled to 0 C
under N2.
2. A solution of Compound 2 (7.00 g, 27.4 mmol) in THF (70 mL) was added.
3. The mixture was stirred at 25 C for 12 h.
4. TLC (petroleum ether: ethyl acetate = 5:1, Rf = 0) showed raw material was completed.
5. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 2).
6. The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
7. Compound 3 (9.70 g, crude) was obtained as a yellow solid.
Compound 3: 1H NMR (CDC13, 400 MHz) 8 (ppm) 7.63 (d, J = 6.36 Hz, 1 H), 7.31-7.44 (m, 3 H), 7.10 (d, J = 5.50 Hz, 1 H), 6.70 (s, 1 H), 4.34-4.52 (m, 2 H), 1.62 (s, 3 H).

LC-MS: RT = 1.05 min, m/z 270.9 [M+H]t Nrn, CI CI CI CI

1. To a mixture of Compound 3 (3.00 g, 11.0 mmol) in CH3CN (40 mL) was added H2SO4 [7664-93-9] (15 mL, 281mm01) in one portion at 20 C under N2.
2. The mixture was stirred at 40 C for 10 h.
3. LC-MS (product: RT = 0.63 min; SM: RT = 0.72 min) showed the reaction was completed.
4. The mixture was poured into ice-water (w/w = 1/1) (200 mL) and adjust to pH = 7 with 10% aq.Na0H.
5. The aqueous phase was extracted with DCM (100 mL x 2).
6. The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
7. Compound 4 (3.00 g, crude) was obtained as a yellow solid.
1H NMR (CDCI3, 400 MHz) 6 (ppm) 7.32-7.35 (m, 2 H), 7.18 (m, 2 H), 6.94 (s, 1 H), 6.72 (s, 1 H), 5.99 (s, 1 H), 5.09 (d, J = 13.7 I-1z, 1 H), 4.53 (d, J = 13.7 Hz, 1 H), 1.57 (s, 3 H).
dTh 0 Con HCI

CI CI CI CI

1. A mixture of Compound 4(2.70 g, 8.65 mmol) in Con.HC1 (12 M, 50 mL, 600 mmol) was stirred at 100 C for 40 h.
2. LC-MS (product: RT = 0.32 min; SM: RT = 0.67 min) showed the reaction was completed.
3. The mixture was adjusted to PH = 7 with 10% aq.Na0H.
4. The aqueous phase was extracted with ethyl acetate (100 mL x 2).
5. The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
6. The residue was used into next step without purification.

7. Compound 5 (3.00 g, crude) was obtained as a yellow solid.
CI At "PP NCS
1IIitN

11.=

CI CI
CI

1. A mixture of compound 5 (3.00 g, 11.1 mmol) and compound 5A [2131-55-7]
(1.88 5 g, 11.1 mmol) in CH3CN (30 mL) was stirred at 20 C for 12 h.
2. LC-MS (product: RT = 0.95 min; SM: RT = 0.32 min) showed the reaction was completed.
3. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 2).
4. The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
5. The residue was purified by silica gel chromatography (100-200 mesh silica gel, CH2C12/Me0H = 200/1, 50/1).
6. Compound 6 (1.80 g, 4.09 mmol, 36.8% yield) was obtained as a yellow solid.
Compound 6: 1H NMR (CDC13, 400 MHz) 8 (ppm) 7.50 (s, 1 H), 7.34 (s, 1 H), 7.19-7.26 (m, 4 H), 6.94-7.06 (m, 4 H), 6.23 (s, 1 H), 6.58-6.59 (m, 1 H), 4.35 (d, J = 13.0 Hz, 1 H), 1.50 (s, 3H).
NH
NANH _______________________________________ N A NH
IBX
CI CI 40 CH3CN, NH3=1120 CI CI 410 CI CI

1. To a mixture of compound 6(1.80 g, 4.09 mmol) in CH3CN (20 mL) was added IBX
[61717-82-6] (1.26 g, 4.50 mmol) and NH3.H20 (9.0 mL, 70.1 mmol) in one portion at 20 C
under Nz.
2. The mixture was stirred at 20 C for 3 h.

3. LC-MS (product: RT = 0.73 min; SM: RT = 0.95 min) showed the reaction was completed.
4. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 2).
5. The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
6. The residue was used into next step without purification.
7. Compound 7 (1.50 g, crude) was obtained as a yellow oil.
7.N

NNH TA

40 COI, THF
CI CI

CI CI C ao CI I
R stereoisomer/ R stereoisomer/
S stereoisomer_A CI S stereoisomer_B CI
1. To a mixture of compound 7A [1877-72-1] (278 mg, 1.89 mmol) in CH3CN (20 mL) was added CDI [530-62-1] (306 mg, 1.89 mmol) in one portion at 25 C under N2.
2. The mixture was stirred at 25 C for 3 h.
3. Then Compound 7 (800 mg, 1.89 mmol) was added into the mixture, and stirred at 25 C for 12 h.
4. LC-MS (product: RT = 0.73 min; SM: RT = 1.03 min) showed the reaction was completed.
5. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 2).
6. The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
7. The residue was purified by silica gel chromatography (100-200 mesh silica gel, CH2C12/Me0H = 200/1, 50/1) to give 400 mg compound R stereoisomer / S
stereoisomer, and further purified by SFC (SFC condition: column: DAICEL CHIRALPAK AD-H
(250mm*30mm, 5 pm); mobile phase: [Neu-Me0H]; B%: 60%-60%, 5 min).
8. Compound R stereoisomer / S stereoisomer_A (80.0 mg, 144 pmol, 15.3%
yield, 100% e.e.) was obtained as an off-white solid.

9. Compound R stereoisomer / S stereoisomer_B (80.0 mg, 144 1.1mol, 15.3% yield, 98.9% e.e.) was obtained as an off-white solid.
EXAMPLE (H) Summary of Formula (II) This invention embodiment relates to compounds having the formula:
Formula (H) (R1)m \Aa/ (R7)d $k (Cvv)w Zõ
Rr x / v `.(C')g / , (Cf)f/<
including (R1)m Aa (R7)d k Nh )s (Cw)w µz n Rr v k / ' x ________ L
G.(Cf)fi including (R1)m (R7)d Aa, N "
Z
ik (Cg)g ,4)w Rr,T tõY X
Gi Gi (Cf)f L
including (Rilm A/(R7)d a, %
N(h)h A
E\ ---1 4N........f___EA \ (cg)g I
,,I, ik L
R3N2 -..,... L
R4 (Cf)f L
Bb \
(R5)n including (R1)m ( R7 )q E\
ifsit .....*Rr=-..Tt.....-Y-..,N
N¨Z=

---¨Bb \
(R5),, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, wherein:

GI is, independently at each point of use, aryl or heteroaryl;
G2 is, independently at each point of use, N or CH;
L is independently at each point of use alkyl, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy, or hydroxyalkyl, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2 etc.), for example hydrogen, or deuterium, or fluorine;
A is nitrogen (N), or N , or carbon;
E is absent, or alkyl, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2 etc.), for example hydrogen, or deuterium or fluorine;
Cf, Cg, Ch and C"' are each independently selected from a single bond, 0, S, Se, Nle, PRv, BRv, C(Rv)2 or Si(Rv)2, wherein each le is independently selected from a constituent group of L (defined earlier);
x, w, f, g, h are independently selected to be 0, 1, 2 or 3;
d is a selected integer between 0 and 7;
k, s and sk are independently selected to be 0, 1, 2, or 3;
The 5-sided ring structure is attached by any one of its available ring atoms, and none, one or two of its bonds can be a double bond, for example at locations shown by the "single or double bond" symbol;
RI and R5 are attached to any available carbon atom of phenyl rings A and Bb, respectively, and at each occurrence are independently selected from PH2, OH, SH, hydrogen, deuterium, alkyl, substituted alkyl, trifluoromethoxy, halogen, haloalkyl, cyano, nitro, OR8, NR8R9, C(=0)R8, CO2R8, C(=0)NR8R9, NR8C(=0)R9, NR8C(=0)0R9, S(0)0R9, NR8S02R9, S02NR8R9, cycloalkyl, heterocycle, heterocyclo, aryl, and heteroaryl, and/or two of RI and/or two of R5 join together to form a fused benzo Ting;
R2, R3 and R4 are independently selected from E (defined earlier), hydrogen, or deuterium, or alkyl, or deuterated alkyl, and substituted alkyl, or one of R2, R3 and R4 is a bond to R, T or Y
and the other of R2, R3 and R4 are independently selected from hydrogen, alkyl, and substituted alkyl;
Z and Y are independently selected from C(=0),-0O2-, -SO2---, -CH2-, -CH2C(=0)-, and -C(=0)C(=0)-, or Z may be absent;

R and T are selected from ¨CH2--, ¨C(=0)¨, and ¨CH RCH2)p(Q)]¨, wherein Q is NRioRti, 0R10 or CN;
R6 is selected from thienyl, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, heterocyclo, heteroaryl and aryl optionally substituted with a lower aliphatic group or one or more functional groups selected independently from the group consisting of¨NH2, -OH, phenyl, halogen, (Cl-C4)alkoxy or -NHCOCH3;
R7 is selected from L (defined earlier), PH2, OH, SH, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aminoalkyl, halogen, haloalkyl, cyano, nitro, keto (=0), hydroxy, alkoxy, alkylthio, C(=0)H, acyl, CO2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamidyl, cycloalkyl, heterocycle, heterocyclo, aryl, and heteroaryl;
R8 and R9 are independently selected from hydrogen, alkyl, substituted alkyl, C2-4 alkenyl optionally substituted, cycloalkyl, heterocycle, heterocyclo, aryl, and heteroaryl, or R8 and R9 taken together to form a heterocycle or heterocyclo or heteroaryl, except R9 is not hydrogen when attached to a sulfonyl group as in S02R9;
R10 and RI I are independently selected from hydrogen, alkyl, and substituted alkyl;
m and n are independently selected from 0, 1, 2 and 3 o, p and q are independently 0, 1 or 2; and r and t are 0 or 1.
Preferred compounds of Formula (H) Preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, (R1),, R2 Aka, (R7)q E\
A N¨Z
' t N
R3-'5 NZ R6 (R5),, including (R1),, (R7)q R2 AaZ
N¨Z
t R6 ¨13-b (R5)õ
wherein:
L is hydrogen, or deuterium, or methyl, or hydroxyalkyl, or fluorine;
A is nitrogen (N), or N+, or carbon;

E is absent, or alkyl, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2 etc.), for example hydrogen or deuterium;
R1 and R5 are attached to any available carbon atom of phenyl ring Aa and phenyl ring Bb, respectively, and at each occurrence are independently selected from hydrogen, deuterium, alkyl, aralkyl, aminoalkyl, halogen, cyano, nitro, hydroxy, alkoxy, trifluoromethoxy, alkylthio, NH2, NH(alkyl), N(alkyl)2, C(=0)H, acyl, CO2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, cycloalkyl, heterocycle, heterocyclo, aryl, and heteroaryl, and/or two .. of RI and/or two of R5 join together to form a fused benzo ring;
R2, R3 and R4 are independently selected from hydrogen and alkyl;
Z is ¨0O2¨, ¨S02¨, or is absent;
Y, R and T are selected from ¨CH2¨ and ¨C(=0) ¨, R6 is selected from:
Cmalkyl or Ci_aalkenyl optionally substituted with up to three of halogen, aryl and CO2Ci-6a1ky1;
phenyl optionally substituted with up to three R12 and/or having fused thereto a benzo-ring or a five to six membered heteroaryl;
heteroaryl selected from thiophenyl, imidazolyl, pyrazolyl, and isoxazolyl wherein said heteroaryl is optionally substituted with up to two Ri2, R7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aminoalkyl, halogen, cyano, nitro, keto (=0), hydroxy, alkoxy, alkylthio, C(=0)H, acyl, CO2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, cycloalkyl, heterocycle, heterocyclo, aryl, and heteroaryl;
R12 at each occurrence is independently selected from each other R12 from the group consisting of Ci_6alkyl, halogen, nitro, cyano, hydroxy, alkoxy, NHC(=0)alkyl, ¨0O2alky1, ¨S02phenyl, aryl, five to six membered monocyclic heteroaryl, and phenyloxy or benzyloxy in turn optionally substituted with halogen, hydroxyl, Ci_aalkyl, and/or 0(Ci_4a1ky1);
m and n are independently selected from 0, 1, 2 or 3; and q is 0, 1 or 2; and r and t are 0 or 1.
More preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, (R1),, \ N N-Z
\

H L
11 (R5),, wherein RI and R5 are attached to any available carbon atom of phenyl ring Aa and phenyl ring Bb, respectively, and at each occurrence are independently selected from alkyl, halogen, cyano, hydroxy, alkoxy, NH2, NH(alkyl), N(alkyl)2, C(0)H, acyl, CO2H, , alkoxycarbonyl, and/or two of Ri and/or two of R5 join together to form a fused benzo ring;
R2, R3 and R4 are independently selected from hydrogen and lower alkyl;
Z is ¨0O2¨, ¨S02¨, or is absent;
R6 is selected from:
C i_aalkyl or Ci_aalkenyl optionally substituted with up to three of halogen, aryl and CO2C i_ 6alkyl;
phenyl optionally substituted with up to three R12 and/or having fused thereto a benzo ring or a five to six membered heteroaryl;
heteroaryl selected from thiophenyl, imidazolyl, pyrazolyl, and isoxazolyl, wherein said heteroaryl is optionally substituted with up to two RI2, RI2 at each occurrence is independently selected from each other R12 from the group consisting of Ci_6 alkyl, halogen, nitro, cyano, hydroxy, alkoxy, NHC(=0)alkyl, ¨0O2alkyl, ¨S02phenyl, aryl, five to six membered monocyclic heteroaryl, and phenyloxy or benzyloxy in turn optionally substituted with halogen, hydroxyl, C1-4 alkyl, and/or 0(C1-4 alkyl); and m and n are independently selected from 0, 1, or 2.
Even more preferred are compounds as immediately defined above wherein R6 is selected from Ci_aalkyl, trifluoromethyl, benzyl, C2_3alkenyl substituted with phenyl, (R15),, (R17), (R17), 411 R16 , __ et, , ________ (R17)v (R17)v N
wherein:
RI5 is halogen, alkyl, nitro, cyano, hydroxy, alkoxy, NHC(=0)alkyl, and/or two RI5 groups are taken together to form a fused benzo ring or a five to six membered heteroaryl;
RI6 is selected from hydrogen, deuterium, halogen, alkyl, nitro, cyano, hydroxy, alkoxy, NHC(=0)alkyl, and phenyloxy or benzyloxy in turn optionally substituted with 1 to 3 of hydrogen, deuterium, halogen, cyano, and Ci_aalkoxy;
RI7 is selected from alkyl, alkoxy, CO2C1_6alkyl, and SO2phenyl;
and u and v are independently 0, 1 or 2.
Most preferred compounds of Formula (II) are those having the formula:

N N ¨Z \

NH
=

wherein L is deuterium;
R2 is hydrogen or CH3;
Z is ¨0O2¨, ¨S02¨, or is absent; and R6 is selected from the groups recited immediately above, most preferably (R15)u Example embodiments of Formula (II) Compounds from [8, 12], selected as specific anti-cancer therapeutics by the invention of this disclosure, selected because they inhibit the reverse, more than the forward, mode of ATP
synthase. EC50 and IC50 used interchangeably. EC50 values for FIFO ATP
hydrolysis, and FiFo ATP synthesis, in NADH-linked and NADPH-linked sub-mitochondrial (SMP) assays respectively, sourced from [8], are presented. [8] refer to these ECso values as IC50 values for inhibiting FIFO ATP hydrolase (reverse mode) and FIF0 ATP synthase (forward mode).
However, this in incorrect. Because, as identified by the invention of this disclosure, explained herein, although these molecules inhibit FiFo ATP hydrolase, their reducing of FiFo ATP synthesis is not (predominantly) because of inhibiting FiFo ATP synthase, but by uncoupling.
4y\

N\__ N-- N--S
./

=
CI
CI

EC50 FiFo ATP hydrolase = 0.022 (pM) EC5c, F1F0 ATP hydrolase = 0.077 (pM) EC, F1F0 ATP synthesis > 30 (pM) EC50FiFo ATP synthesis > 30 (pM) EC 50 Ratio >1,364 EC Ratio >390 5o For all compounds: EC50 F1F0 ATP synthesis > 30 pAl R6 RS imidazole ECK, FiFo ATP hydrolase ( M) 4-F-Ph SO2 5-y1 0.221 Ph SO2 5-y1 0.282 4-0H-Ph SO2 5-y1 0.667 4-0Me-Ph SO2 5-y1 0.077 2,5-di-CI-Ph SO2 5-y1 0.158 4-(AcNH)-Ph SO2 5-y1 2.981 4-CN-Ph SO2 5-y1 0.255 .4 IN1-.....R5 2-CI-4-CN-Ph 502 5-y1 0.939 -44 , . ' N
., 3-NO2-Ph 502 5-y1 0.423 \
Naphth-1-y1 SO2 5-y1 0.338 R6 Thiophen-2-y1 SO2 5-y1 0.636 Benzofurazan-7-y1 SO2 5-y1 1.777 Quinolin-8-y1 SO2 5-y1 2.935 Bn SO2 5-y1 2.405 CF3 SO2 5-y1 0.077 4-t-Bu-Ph SO2 5-y1 0.008 4-t-8u-Ph CH2 5-y1 2.138 4-t-Bu-Ph CH2 4-Me-5-y1 2.352 4-t-Bu-Ph SO2 2-y1 >10 4-F-Ph 502 2-Me-5-y1 9.623 4-F-Ph SO2 4-Me-5-y1 0.151 Further examples [12], /-=--N 0 ,0 /-=---N 1110 , 0 ,=N 0 HN õ- NITS, H ,..IN N N-S' HN, N 041h 0 N -,S' CH3 WIP- 1 . H3C
F Cl CH3 Further, N., õN N N¨,-,S
"---CI
CI
=
Scheme Ha is a route for synthesizing Compound 31 [8], starting reagents are commercially available from multiple suppliers listing on the LabNetwork (www.labnetwork.com) e.g.
Compounds 1, 7 and 9 are available from Astatech Inc., Bristol PA, USA, Compound 2 from Stru Chem, Wujiang city, China.
Scheme Ha COOEt ., H COOEt is NH 4 N
TFA, Et3Sill o.
NH2 toluene, 130 C, 18 h NH DCE, 0-25 C, 2 h IIP

N LiAIH4 1N NaOH 0 4 .
NH2 HN 0 C, 18 h 0 THF, 25 C, 1Erh COOEt NH
0 CI,.. //0 5 /IS Is a ON Cl N
TEA, DCM, 25 C, 3 h.-NH

ii--NH 5 0 H N--r---- \ I/
SI H3C.--L
N ...N.,1H Ny,)\__ N¨S

--, HC N 0//
Ni= ,0 0 , NaBH(0/1/403, DCE, 25 C 1. Cl 8 . CI Ci it, 31 Cl Product of Scheme Ha, Compound 31:
LC retention time (RT) = 0.87 minutes, MS (electrospray ionisation, positive mode): m/z 554.90 [M+Hr, 576.90 [M+Na], 278.90 [M+2H]2+, (all Observed m/z are within 0.3 Daltons of Expected: 555.14 [M+11] , 577.12 [M+Na] , 278.07 [M+211_72");
1H NMR (400 MHz, Methanol-d4) 8 (ppm) 8.35 (s, 1H), 8.14 - 8.06 (m, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.84 - 7.71 (m, 2H), 7.27 (dt, J = 22.4, 7.4 Hz, 4H), 7.16 (dd, J =
8.0, 5.6 Hz, 2H), 7.09 (d, J = 7.5 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 4.71 (d, J = 13.9 Hz, 1H), 4.37 (d, J = 14.2 Hz, 1H), 4.29(d, J = 14.2 Hz, 1H), 3.96 (dd, J = 19.7, 13.4 Hz, 2H), 3.17 -3.10 (m, 1H), 2.78 (d, J = 12.8 Hz, 1H), 2.69 (ddd, J = 14.5, 9.7, 5.3 Hz, 11-1), 2.54 (dt, J = 13.7, 8.6 Hz, 1H), 2.11 (s, 3H), 1.50 (s, 1H), 1.36 (dtd, J = 14.1, 9.1, 5.1 Hz, 1H) {NMR
probe temperature = 297.9K).
1H NMR (400 MHz, Chloroform-d) 8 (ppm) 8.21 (s, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.82 (s, 1H), 7.65 (dd, J = 8.4, 2.1 Hz, 1H), 7.58 (d, J = 8.4 Hz, 11-1), 7.30 (s, OH), 7.26 (s, 2H), 7.20 (t, J = 7.3 Hz, 1H), 7.10 (d, J = 7.4 Hz, 2H), 7.07 - 6.98 (m, 2H), 4.60 (d, J
= 13.8 Hz, 1H), 4.32 (d, J = 14.1 Hz, 1H), 4.12 (dd, J = 24.1, 14.0 Hz, 2H), 3.82 (d, J = 12.8 Hz, 1H), 3.08 (s, 2H), 2.91 (d, J = 13.0 Hz, 1H), 2.76 - 2.64 (m, 1H), 2.49 (dt, J = 14.8, 8.2 Hz, 1H), 2.11 (s, 3H), 1.58 - 1.43 (m, 1H) {NMR probe temperature = 298.5 .
"C NMR (101 MHz, Methanol-d4) 8 (ppm) 149.14, 142.91, 140.73, 138.20, 134.62, 134.51, 132.72, 132.22, 130.62, 130.05, 129.75, 129.50, 129.39, 129.20, 128.48, 127.87, 127.01, 123.78, 121.75, 58.88, 53.98, 53.69, 48.11, 33.55, 31.58, 9.53 {NMR probe temperature =
298.0 K1.
Presented NMR peaks come from using the "Auto Assignment" algorithm in MestReNova version 12 software (Mestrelab Research, Santiago de Compostela, Spain), which picks peaks in an inputted NMR spectrum, influenced by an inputted structure, which was Compound 31 in Scheme Ha. However, for the 13C NMR spectrum, after automatic assignment, I
manually intervened because the central Methanol-d4 solvent peak was observed at 49 instead of expected 47.60 ppm. By my intervention, this 49 ppm Methanol-d4 solvent peak was then used/set as a "reference peak" in MestReNova which shifted all ppm values accordingly (by [49-47.60] ppm).
An invention embodiment is the use of a compound with LCMS and/or NMR features as presented above, for use in a method of treatment of the human or animal body by therapy, optionally for cancer treatment/amelioration/prevention/combat in a subject.
The actual LCMS and NMR spectra are presented in Figure 32 herein, with further information in its legend.
Compound 31, in Scheme Ha, can be deuterated at its chiral carbon, and in further embodiments at further or other position(s), by reactions described in [N], which deuterate sp3 carbons. And/or by reactions described in [R1, R2, Ql, Q2], which deuterate aromatic and alkyl molecular components. And/or by reactions described in [D], which deuterate a and 13-carbons to tertiary amines. And/or by reactions described in [F, El, E2, Exl], which deuterate a carbons to tertiary amines. Alternatively, to produce a Compound isotopologue, deuterated on its chiral carbon, and in further embodiments at further or other position(s), an intermediate in Compound 31 synthesis, presented in Scheme Ha, can be deuterated. For (non-limiting) example, Compound 6 in Scheme Ha can be deuterated by reactions described in [A, B, El, E2, F], which can deuterate the a-carbon to secondary amines. And/or by reactions described in [N], which deuterate sp3 carbons.
And/or by reactions described in [R1, R2, Q I, Q2], which deuterate aromatic and alkyl molecular components. A deuterated Compound 6 can be inputted into synthesis schemes of [P2], in place of Compound 10 in Scheme III in the "Process of Preparation" section of [P2], to make deuterated isotopologues with the scaffold of [P2]. These are componentry to the present invention as new compositions of matter, and in non-limiting embodiments are used singly or in combination, optionally in co-therapy with an FDA and/or EMA approved medicine(s) and/or treatment(s), for example a licensed cancer treatment, as anti-cancer therapeutics.
Throughout this disclosure, deuteration methods conveyed are illustrative rather than limiting. All stereoisomers of all the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form.
Scheme Jib o COOEt ., H COOEt NH2NH2 toluene, 130 C, 18 hi 0 Ill NH TFA, Et3SiH
DCE, 0-25 C, 2 SO H
IN NaOH N
0 Boc20 4 = =
NH2 HN 0 C, 18 h 0 DMAP, TEA, THF
NH
COOEt 11, 5 111P Boc I Boc N I
Mel = N CH3 HCI, Me0H
1110 N......Bo0c t-BuOK, DMF
11101 o 6 N--õBoc IP, 7 0 H 410, N CH3 LiAl H4 c,,0 NH 0 THF, 25 C, 18 h H
N 0 01 S Cl //

1110 cH3 CI
TEA, DCM, 25 C, 3 hi.

r---NH 1110 0 H N.=-- \ ../y\\__ N¨S
N //
N
SI CH3 H3c .., --,12 NH N ,**/

r/
Rt.,- 0 0 0. CH3 ...,,o- NaBH(OAc)3, DCE, 25 C Cl U.-11 c c, , c, .
The reaction schemes below, Scheme Ilc, Scheme lid, Scheme Ile and Scheme Ill, show only starting material(s) and product because they use the same internal steps as Scheme Ha 5 (not shown), but with a different starting material, a different Compound 1 in the case of Scheme Hc, Scheme lid, Scheme He, or a different Compound 2 in the case of Scheme Ilf, and thence different products are produced as shown. Starting compounds are available from suppliers listed on labnetwork.com: e.g. Compound 1 of Scheme lk and Scheme Ile from Fluorochem, Hadfield, Derbyshire, UK, e.g. Compound 1 of Scheme lid from J&W
Pharmlab LLC, Levittown, PA, USA, e.g. Compound 2 of Scheme Ilf from Arena Chemical, .. La Mure, France, Compound 1 of Scheme Ilf from Astatech Inc., Bristol PA, USA.
Scheme lk 0' CI
Scheme lid NH2 b¨NH
NS' H3C ç 4110 ci Scheme Ile 40 NH2 ,0 N N-S

CI
CI
Scheme Ilf 1110 , io NH2 COOEt 0 NH2 toluene, 130 C, 18h H3C

CI

The reaction schemes below, Scheme Hg and Scheme Hit are the same as Scheme Ha up until Compound 6. This shared component isn't shown, just the point of divergence from Compound 6, which comes from using a different Compound 7, wherein the Compound 7 options shown in Scheme Hg and Scheme Ms are available from multiple suppliers on labnetwork.com (e.g. available from Fluorochem, Hadfield, Derbyshire, UK).
Scheme lig ci =
o=s=0 W.:7A 110 --(;) N
NH TEA. DCM, 25 C, 3ChI.

6 o--=s=o NaBH(OAc)3, DCE, 25 C 40 c, c, Scheme Hh \ /
IS 7 -NH WI= \ ir 1110 = H3c N=Nr.AN
TEA, DCM, 25 C, 3 h 110). LçJ 9 H3c 6 NaBH(OAc)3, DCE, 25 C
The reaction schemes below, Scheme Hi, Scheme II j, Scheme Ilk and Scheme III
are the same as Scheme Ha up until Compound 8. This shared component isn't shown, just the point of divergence from Compound 8, which comes from using a different Compound 9, wherein the Compound 9 options shown in Scheme Hi, Scheme I lj, Scheme Ilk and Scheme III are all available from multiple suppliers on labnetwork.com (e.g. all, except that for Scheme Ill, available from Fluorochem, Hadfield, Derbyshire, UK, Compound 9 from Scheme III
available from Matrix Scientifjc, Columbia, SC, USA).
Scheme Ili H 14,---\ Tr-NH 110 ,P
Br-Cc, Nõ\i,,,,,-õ.1.\\_, 11-7S

,.. Br N O'Ar N _____________________ 0, _0 -OS aBH(0A03. DCE, 25 C
' 8 . CI CI
CI
Scheme Hj * H3C, 110 .
H N-:-"\ ,CH3 fi¨N ,0 =N--cs Br--4 9 Ny-,\\___N
Br o'at N0. o .
-S - NaBH(OAc), DCE, 25 C
O' CI
11 a Cl Scheme Ilk HA .H N--=\- ,CH3 F-N ,0 1.-1:;k<4 N.,?,\._ 1110 N 9 N O'Aia I
N0, O W ci -S - NaBH(OAc),, DCE 25`C
O' CI

CI
Scheme III
H

N
N(;;;"--\:=,,,o N ¨
\ ,..ti . di CI
*S NaBH(00s,03, DCE, 25 C

CI
8 11 ci a Reaction Scheme Ha in more detail In this section, numbers in square brackets are CAS numbers.

2 COOEt H COOEt NH2 toluene, 130 C, 18 II-7.
NH

A mixture of 2-(aminomethyl)aniline (2 g, 16.37 mmol, 1 eq) and ethyl 2-oxo-4-phenyl-butanoate (3.38 g, 16.37 mmol, 3.10 mL, 1 eq) in toluene (100 mL) was stirred at 130 C for 18 h. TLC(PE:Et0Ac=1:1, rf=0.6) showed the starting material was consumed and a new .. spot was generated. The mixture was concentrated to the desired material (4.8 g, yield:
94.5%) as a brown oil, which was used for next step without further purification.
Compound 3: ill NMR (CDC13, 400 MHz) 6 (ppm) 7.25 - 7.16 (m, 3 H), 7.16 - 7.07 (m, 3 H), 6.96 (t, J=7.2 Hz, 1H), 6.83 (d, J=7.3 Hz, 1 H), 6.63 (dt, J=0.7, 7.4 Hz, 1 H), 6.52 (d, J=7.9 Hz, 1 H), 4.22 - 4.08 (m, 2 H), 4.04 - 3.81 (m, 2 H), 2.83 - 2.66 (m, 1 H), 2.66 - 2.50 (m, 1 H), 2.13 -2.01 (m, 2 H), 1.21 (t, J=7.1 Hz, 3 H).
H COOEt TFA, Et3S1H
N
NH DCE, 0-25*C, 2 h .. NH2HN
COOEt To a solution of ethyl 2-(2-phenylethyl)-3,4-dihydro-1H-quinazoline-2-carboxylate (3.3 g, 10.63 mmol, 1 eq) in DCE (30 mL) at 0 C was added TFA (11.86 g, 104.00 mmol, 7.70 mL, 9.78 eq) and Et3SiH (2.08 g, 17.91 mmol, 2.86 mL, 1.68 eq). The resultant solution was stirred at 25 C for 2 h. The mixture was concentrated to dryness, the residue was used for next step without further purification. Compound 4: LC-MS: RT= 1.057 min, m/z 296.2 (M-NH2)+.
1N NaOH
NH2HN 0 C, 18 h COOEt NH

Ethyl 2[2-(aminomethypanilino]-4-phenyl-butanoate (4.5 g, 10.55 mmol, 1 eq, TFA) was dissolved in Me0H (50 mL), then the solution was adjusted pH=12-13 with IN
NaOH. The resultant solution was stirred at 25 C for 16 h. The mixture was filtered to give the desired material, which was used for next step directly. Compound 5: LC-MS: RT= 0.879 min, m/z 289.1 (M+Na).
Compound 4: 1H NMR (CDC13, 400 MHz) 8 (ppm) 7.39 - 7.28 (m, 2 H), 7.26 - 7.18 (m, 3 H), 7.08 (t, J=7.8 Hz, 1 H), 6.91 (d, J=7.4 Hz, 1 H), 6.68 (t, J=7.4 Hz, 1 H), 6.54 (d, J=8.0 Hz, 1 H), 6.15 (br s, 1 H), 4.90 (dd, J=5.9, 16.2 Hz, 1 H), 4.36 (br t, J=6.5 Hz, 1 H), 3.89 (dd, J=7.1, 16.3 Hz, 1 H), 3.52 (br s, 1 H), 2.98 - 2.84 (m, 1 H), 2.84 - 2.71 (m, 1 H), 2.44 - 2.24 (m, 1 H), 1.95 (m, 1 H).
LiAIH4 N
NH 0 THF, 25 C, 18 h NH
To a solution of LiA1H4 (313.51 mg, 8.26 mmol, 1.1 eq) in THF (20 mL) was added a solution of 2-(2-phenylethyl)-1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one (2.0 g, 7.51 mmol, 1 eq) in THF (20 mL). The resultant solution was stirred at 25 C for 18 h. The reaction was quenched with 1 mL water, and filtered. The filtrate was concentrated to dryness. The residue was purified by reverse chromatography (TFA) to give 2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (1.2 g, 4.13 mmol, 55.03% yield, 86.9% purity) was obtained as a brown oil.
LC-MS: RT= 0.668 min, m/z 253.3 (M+H)+.
NMR (CDC13, 400 MHz) 8 (ppm) 7.37 - 7.30 (m, 2H), 7.26 - 7.13 (m, 5H), 6.97 -6.89 (m, 1H), 6.64 (d, J=7.8 Hz, 1H), 4.30 (d, J=14.1 Hz, 1H), 4.14 - 4.00 (m, 1H), 3.45 (br d, J=11.7 Hz, 2H), 3.32 - 3.21 (m, 1H), 3.12 - 3.01 (m, 1H), 2.90 - 2.72 (m, 2H), 2.02- 1.89 (m, 2H).
CI, S
7 op NH TEA, DCM, 25 C, 3 h C?'S/' CI
6 8 a To a solution of Compound 6 (220 mg, 871.79 mol, 1 eq) in DCM (5 mL) at 25 C
was added TEA (363.50 mg, 3.59 mmol, 0.5 mL, 4.12 eq) and Compound 7 (214.04 mg, 871.79 mol, 1 eq). The resultant solution was stirred at 25 C for 2 h. LCMS showed the starting material was consumed and the desired MS was found. The mixture was concentrated to dryness, and the residue was purified by reverse chromatography (HCOOH) to give Compound 8 (170 mg, 362.36 gmol, 41.57% yield, 98.35% purity) as a colorless oil.
Compound 8: LC-MS: RT= 1.058 min, m/z 461.1 (M-FH)+.
Compound 8: ill NMR (CDC13, 400 MHz) 7.72 (d, J=2.1 Hz, 1H), 7.46 - 7.41 (m, 1H), 7.40 - 7.36 (m, 1H), 7.34- 7.28 (m, 2H), 7.26- 7.21 (m, 1H), 7.20- 7.13 (m, 3H), 7.09 (dt, J=1.5, 7.6 Hz, 1H), 6.92- 6.84 (m, 1H), 6.50 (d, J=7.7 Hz, 1H), 4.59 -4.44 (m, 1H), 4.41 -4.26 (m, 1H), 3.61 (dd, J=2.1, 13.3 Hz, 1H), 3.33 (dd, J=8.6, 13.3 Hz, 1H), 3.10 - 2.97 (m, 1H), 2.78 -2.67 (m, 2H), 1.86- 1.71 (m, 2H).
fi-NH 1 c-ç9NH Nj,S' dab RP _______________________ H3C=-o a -s' NaBH(OAc), DCE. 25'C
8 r"-- 31 CI
A mixture solution of Compound 8 (100 mg, 216.73 gmol, 1 eq) and Compound 9 (30 mg, 272.44 gmol, 1.26 eq) in CH3COOH (0.5 mL) and DCE (1 mL) was stirred at 25 C
for 30 min. Then NaBH(OAc)3 (150 mg, 707.74 gmol, 3.27 eq) was added into the mixture solution, the resultant solution was stirred at 25 C for 1.5 h. LCMS showed the starting material was consumed and the desired MS was generated. The mixture was diluted with water (50 mL) and extracted with Et0Ac (50 mL*2). The organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness, the residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150*25*10 gm; mobile phase: [water (0.225%
FA)-ACN];B%: 40%-51%, 4 min) to Compound 31 (46 mg, 66.30 gmol, 30.59% yield, 99.7% purity) was obtained as a white solid.
EXAMPLE (III) Summary of Formula (III) This invention embodiment relates to compounds having the following formula:

Formula (III) w I
(Xlw I aµ
¨GI¨ (kW.
(Xic)k including w I
(XII&
N¨(.)(9)9 including /3¨Th 0 1%

X
R.12 (R8)q N
N

including %1 N,¨ Rl2x N (R8)q including R12,_ (R8)q including (L), 147.41µ
NH
(L)õ, 0 o )c soµ H
(L), including (Om (L), N NH

\OH
oµµ
(L)m (1-)m or their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, wherein:
Optionally, one or more places have deuterium in place of hydrogen, at an artificially high level of deuterium incorporation, in excess of the naturally occuring abundance;
Optionally, one or more places have fluorine, or other halogen, or methyl, or alkyl, or substituted alkyl, in place of hydrogen;
Z is heteroaryl;
g, w and k are independently selected from 0, 1, 2, 3, 4;
.. L is independently at each point of its use hydrogen, alkyl, or substituted alkyl (non-limiting example: CF3), or deuterated alkyl (non-limiting example: CD3), or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy, or hydroxyalkyl, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g.
(non-limiting) OH, NH2, SH, S1H3, PH2etc.);
Xg, X' and Xk are independently selected from a single bond, 0, S. Se, Nle, PRv, BRv, C(Rv)2 or Si(Rv)2, wherein each Rv is independently selected from a constituent group of L
(defined earlier);
GI is, independently at each point of use, N or CH;
c is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9;
m is independently at each point of use selected from 0, 1, 2, 3, 4, 5, 6, as valence permits;
R2 is hydrogen, L (defined earlier), hydroxyl (-OH), SH, NH2, methyl, alkoxy, substituted alkoxy, haloalkoxy, ether, halogen or ¨0C(0)R14;
R14 is hydrogen, alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl or (cycloalkyl)alkyl;

R3 and R4 are each independently hydrogen, or L (defined earlier), or CF3, or NH2, or OH, or chlorine or other halogen, or alkyl, or substituted alkyl, or deuterated alkyl, or arylalkyl, or R3 and R4 taken together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic ring;
R5 is independently at each point of use hydrogen, L (defined earlier), PH2, OH, SH, alkyl, substituted alkyl, halogen, nitrile, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclo;
R12 is selected from hydrogen, deuterium, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclo;
X is alkyl;
Y is a single bond, ¨CH2¨, ¨C(0)¨, ¨0¨, ¨S¨, ¨N(R14) ¨ or (Xf)f where Xf is selected from a single bond, 0, S, Nle or C(Rv)2, wherein each Itv is independently selected from a constituent group of L (defined earlier);
f is 0, 1, 2 or 3;
A is nitrogen (N), or N , or carbon;
E is absent, or alkyl, or substituted alkyl (non-limiting example: CF3), or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2etc.), for example hydrogen, or deuterium, or fluorine;
R8 is independently selected at each point of use from E (defined earlier), hydrogen, alkyl, halogen, carbamyl, carbamylChaalkyl, substituted alkyl or two R8 groups join to form an optionally substituted fused phenyl ring;
q is 0, 1, 2, 3 or 4.
R1 is selected from L (defined earlier), hydrogen, deuterium, CN, 502-piperidine, S02-piperidine substituted with 0-10 of R5, R9, cyano, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkylene, substituted alkylene, alkynyl, substituted alkynyl, alkoxy, thioalkyl, aminoalkyl, carbamyl, sulfonyl, sulfonamide, cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, morpholinylalkyl, aryl, arylalkyl, heterocyclo, heteroaryl, (heterocyclo)alkyl, (heteroaryl)alkyl, acyl, alkoxycarbonyl, substituted amino;
Most preferably R1 is smaller than 300 Daltons;
R9 is I I

"

=
, R6 and R7 are independently hydrogen, L (defined earlier), R1 (provided R1 is not R9), alkyl, aryl, heteroaryl, cycloalkyl, heterocyclo, arylalkyl, (heteroaryl)alkyl, haloalkyl, hydroxyalkyl, hydroxyalkyl substituted with a carboxylic ester or carboxylic acid, alkoxyalkyl, thioalkyl, (cycloalkyl)alkyl, morpholinylalkyl, heterocyclo or (heterocyclo)alkyl; or R6 and R7 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered mono or bicyclic ring including fused rings such as 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-motpholinyl, 4-thiamorpholinyl, 4-thiamorpholine dioxide, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalky1-1-piperazinyl; or 1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl or 1-azepinyl substituted with one or more L (defined earlier), alkyl, alkoxy, alkylthio, halo, trifluoromethyl, hydroxy, aryl, arylalkyl, ¨000R14 or ¨CO-substituted amino;
or R5 and R6 taken together with the atoms to which they are attached form a 5-to 7-membered ring optionally substituted with aryl;
Encompassed by this invention are methods of administering a therapeutically effective amount of any compound(s) of [P6], or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally in a pharmaceutical composition(s), optionally in co-therapy with another anti-cancer treatment(s), to treat/ameliorate/prevent/combat cancer in a subject.
Especially preferred for this use are compounds of [P6] with 3S, 4R
stereochemistry.
Preferred compounds of Formula (III) Preferred methods are to use, and preferred compounds are, compounds of Formula (III), their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, in which:
Z is triazolyl optionally substituted with one to two R8 or imidazolyl optionally substituted with one to two R8 and/or having fused thereto a benzene ring in turn optionally substituted with one to two R8;
Y is oxygen;

R2 is hydroxyl;
R3 and R4 are methyl or chlorine;
R1 is R9;
GI is nitrogen;
R6 and R7 are alkyl; or R6 and R7 taken together with the nitrogen atom to which they are attached (GI = N) form a 6-membered ring;
X is alkyl;
R12 is aryl or heterocyclo;
A is N;
E is absent, or deuterium, or hydrogen;
R5 and R8 are hydrogen;
Stereochemistry is 3S, 4R;
Example embodiments of Formula (III) .. Immediately below, compounds from [7], selected as specific anti-cancer therapeutics by the invention of this disclosure. EC50values for FIFO ATP hydrolysis, and FIFO ATP
synthesis, in NADH-linked and NADPH-linked sub-mitochondrial (SMP) assays respectively. [7]
refers to these EC50 values as ICsovalues for inhibiting FiFo ATP hydrolase (reverse mode) and FIF0 ATP synthase (forward mode). However, this in incorrect. Because, as identified by the invention of this disclosure, explained herein, although these molecules inhibit FIFO ATP
hydrolase, their reducing of FIN ATP synthesis is not (predominantly) because of inhibiting FiFo ATP synthase, but by uncoupling. The structure on the left is BMS-199264.
It does not harm ex vivo rat heart at a concentration (10 t.tM [11]) that it exerts anti-cancer activity (discovery of this disclosure).

/-----i--''¨I--\
Cl N
0 Ny-NH Cl 0 y NH
N

' R
OH

=,.' aCH3 CH3 CH3 3S,4R CH3 EC50F 1 Fo ATP hydrolase = 0.48 i 0.23 (pM) EC50F1F0 ATP hydrolase = 0.24 t 0.13 (pM) EC50F1F0 ATP synthesis = 18 t 9.5 (pM) EC50F1F0 ATP synthesis = 3.8 2.1 (pM) EC50 Ratio = 38 3R,4S
pM doesn't harm ex vivo rat heart EC50 F1F0 ATP hydrolase = 0.48 0.23 (pM) EC FiFo ATP synthesis = 4 i 0.45 (pM) For the following example embodiment, with synthesis scheme (as 2 possible salts shown, Scheme IHa), the starting material is BMS-199264, which is available commercially. For 5 example from Sigma-Aldrich, a chemical and reagents vender well known to those of the art.
Scheme Illa /....:-.1 41111 õ... ..-NH CI 011) --N
CI ,CH3 --I
N I-13C N"
0õ ,0 R
K2CO3, DMF .õ,-----.N.:-S" R. OH
---...--) s s CH3 ."....) CH3 0 ,..,,, 0 a...1_1 %A-13 t...1-13 -r CIz--1-.
HN t Me0H ' CI 0N"

F`F
F\_-õ-F CI N/---1 * Hy.N.t.
...-b N
CH3 0, ,0 N ..---,N;S' 0 R
0\õ0 s "....--) 0 s CH3 CH3 Further example embodiment:

CI *

PI

The following example embodiment does not uncouple the proton motive force (pmf) because its imidazole group, unlike BMS-199264, for example, does not have a protonable element.
H3C-1\14.1"1¨

CI yr\I¨CH3 ,0 The following example embodiment (logP=3.79, calculated from structure [31]) uncouples the proton motive force (pmf) less than BMS-199264 (logP=4.35, calculated from structure [31]) because its logP is further removed from the logP=-3,2 optimum for uncoupling [32].
CI

, HO
.0µ
CI

CI
Further example embodiment, CI
0õ0 OH

Further example embodiment, CI N \ NH
0, ,0 OH

BMS-199264, and/or its analogues, can be deuterated by reactions described in [R1, R2. Ql , Q2], which deuterate aromatic and alkyl molecular components. Furthermore, there is a great wealth of reactions available to deuterate their aromatic rings, and those skilled in the art will know these. For (non-limiting) example, refer [Ex2]. Carbon 1 of BMS-199264, a chiral centre, can be deuterated by reactions described in [D, F, El, E2, Exl], which deuterate a carbons to tertiary amines, and/or by reactions described in [N], which deuterate sp3 carbons, and/or by reactions described in [I, M, G. H], which deuterate a and 0-carbons to an OH
group. Carbon 6 of BMS-199264, a chiral centre, can be deuterated by reactions described in [L, H, G, A, K, M, J1,12, J3, I, F, S], which deuterate the a-carbon to an OH
group, and/or by reactions described in [D], which deuterate a and 0-carbons to tertiary amines, and/or by reactions described in [N], which deuterate sp3 carbons. The scaffold of [P6]
is presented in its abstract. Deuterated isotopologues of this [P6] scaffold, for (non-limiting) example deuterated BMS-199264, are componentry to the present invention as new compositions of matter, and in non-limiting embodiments are used singly or in combination, optionally in co-therapy with an FDA and/or EMA approved medicine(s) and/or treatment(s), for example a licensed cancer treatment, as anti-cancer therapeutics.
EXAMPLE (IV) Background Well known to those of the art: amino acids have the following structure, wherein the R
group is different in different amino acids.
R
H
"N/ <0 H OH
H
Summary of Formula (IV) This invention embodiment relates to compounds having the following formula:
Formula (IV) .. j...........G1. i,..,...,,,.s,.0 lik G1 (R1)u R4 R5 ( n )m Z
including R3 . N7."*Isr"....'......... (R1 )u R4 R5 ( n )m Z
including (R8)0.4 NN
\t*

gN m or their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, wherein:
GI is, independently at each point of use, N or CH;
u is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;
X is selected from 0 or S;
A is selected from hydrogen, deuterium, alkyl, substituted alkyl, cycloalkyl, heterocycle, heterocyclo, aryl, heteroaryl, aminoalkyl, thioalkyl, alkoxy and an R group of a proteogenic amino acid, or other amino acid synthesized or used by a living system (non-limiting example of such a system: a human), which is optionally isotopically enriched, and/or substituted by alkyl, substituted alkyl, deuterated alkyl, halogen, cycloalkyl, heterocycle, heterocyclo, aryl, heteroaryl, aminoalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g.
(non-limiting) OH, NH2, SH, SiH3, PH2etc.);
n and m are 0, 1, or 2;
RI through R5 are independently selected from hydrogen, halogen, NO2, PH2, OH, SH, CN, Chsalkyl, substituted Ci_salkyl, C3_8cycloalkyl, aryl, heterocyclo, heteroaryl, 0R9, SR9, CORI], CO2R11, CONR9R10 or NR9R10;
R6 and R7 are independently hydrogen, alkyl or substituted alkyl;
R8 is hydrogen, deuterium, Ci_salkyl, substituted Ci_aalkyl, deuterated Ci_8alkyl, aryl, heterocyclo, heteroaryl, aminoalkyl, thioalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2 etc.);
Z is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, CORii, CO2R1i, S02R11, S(0)R1 or CONR9R10;
R9 and Rio are independently hydrogen, C1.8alkyl, substituted Ci_salkyl, C3_10cycloalkyl, aryl, heterocyclo, heteroaryl, COR13, S02R13 or S(0)R13; and R11, R12 and R13 are independently hydrogen, Ci_salkyl, substituted Ci_aalkyl, Cflocycloalkyl, aryl, heterocyclo or heteroaryl;
wherein each occurrence of R9-R13 is chosen independently.
Preferred compounds of Formula (IV) Preferred methods are to use, and preferred compounds are, compounds of Formula (IV), their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, in which:
R2, R3 and R4 are all hydrogen; and/or R6 and R7 are both hydrogen; and/or n and mare both 1; and/or RI and R5 are both C1-8 alkyl, preferably both Ri and R5 are isopropyl groups.
Other preferred methods use, and preferred compounds are, compounds of Formula (IV), their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, in which:
Z is Ci_salkyl, C2_8alkeny1, Ci_shaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl ¨CORI 1, ¨0O2R11, ¨SO2R1i, ¨S(0)Ri or ¨CONR9Rio; especially preferable is benzyl, ¨C(0)2H or ¨C(0)2Ci_salkyl;
R9 is hydrogen;
Rio is Ci_salkyl or C3_10cycloalkyl; aryl or arylalkyl; and Ri is hydrogen, C _salkyl, C3-locycloalkyl, C3-loheterocycloalkyl, C3.10aryl or C3-io arylalkyl.
Other preferred methods use, and preferred compounds are, compounds of Formula (IV), their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, in which:

A is hydrogen, deuterium, Ci_aalkyl, aminoalkyl, heteroaryl, aryl, or alkyl substituted with heterocyclo, aryl, OH, SH, ST'. ¨C(0), H, T3-NT5T6, -T8-C(0)tT9-NT5T6 or T3-N(T2)T4NT5T6, TI is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl;
T2 and T3 are each independently a single bond, -T8-S(0)t-T9-, -18-C(0)-T9-, -T18-C(S)-T9, _ T8-S-T9-, -T8-0¨C(0)-T9-, -T8-C(0)tT9-, -T8-C(=NT10)-T9- or ¨T8-C(0) ¨C(0)-T9-;
T5, T6, T7, T8 and T9 are independently hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alky, each group optionally substituted where valence allows by one to three groups selected from halo, cyano, nitro, OH, oxo, ¨SH, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, ¨STI I, ¨C(0)tH, ¨C(0)tTI I, ¨0¨C(0)T11, T8c(0) )1tN(T12,-.-11, ¨S03H, ¨S(0)JI I, S(0)tN(1-12)T1 I, ¨T'3-NT" T'2, T12, _ T'3¨N(T12)-T4-NTI T22, _T13_N(T11,--.-) 1 12-TH and 3-N(T18)-Tm-H; or T8 and T9 are each independently a single bond, alkylene, alkenylene or alkynylene;
TI I is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl;
TI2 is halo, cyano, nitro, OH, oxo, ¨SH, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl, ¨C(0)tH or ¨S03H;
TI3 and TI4 are each independently a single bond, ¨S(0)t¨, ¨C(0)¨, ¨C(S)--, ¨0--, ¨S¨, ¨0¨C(0)--, ¨C(0)t¨, ¨C(=NTI3)-- or ¨C(0)--C(0)--;
wherein each occurrence of T1-T14 is chosen independently; and t is 1 or 2.
Preferred compounds of the foregoing section are those in which A is hydrogen, deuterium, Ci_salkyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, heteroaryl alkyl, aryl, arylalkyl, or alkyl substituted with a group selected from SH, ST4, ¨C(0)H, T6-NT8T9, -III-C(0)J12-NT8T9 and T6-N(T5)T7NT8T9.

More preferred are those compounds in which A is hydrogen, deuterium, methyl, ¨
CH2(CH3)2, ¨(CH2)2(CH3)2, ¨CH(CH3)CH2(CH3), ¨(CH2)0H, hydroxyethyl, ¨
(CH2)2SCH3, ¨CH2SH, phenyl, ¨CH2(phenyl), ¨CH2(p-hydroxyphenyl), ¨CH2(indole), ¨(CH2)C(0)NH2, ¨(CH2)2C(0)NH2, ¨(CH2)2C(0)0H, ¨CH2C(0)0H, ¨(CH2)4NF12, ¨
(CH2)3(=NH)CNH2, or ¨CH2(imidazole). Especially preferred A groups are ¨
CH(CH3)CH2(CH3), phenyl, phenyl alkyl or ¨CH2(2-indole).
Alternatively preferred methods use, and preferred compounds are, compounds of Formula (IVb), their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, in which:
Formula (IVb) ii õ----õN

gN

Z
including (R8)04 N\--\

=

7 11 R8 \
(RN

wherein:
A is selected from hydrogen, deuterium, Ci_salkyl, aminoalkyl, substituted alkyl, deuterated alkyl, aryl, heteroaryl, or alkyl substituted with heterocyclo, aryl, heteroaryl, OH, SH, ST', ¨
C(0)H, T3-NT5T6, -T8-C(0)tT9-NT5T6 or T3-N(12)T4NT5T6;
RI and R5 are independently Ci_salkyl optionally substituted where valence allows;
R6 and R7 are independently hydrogen or Ci_salkyl;
R8 is hydrogen, halogen, deuterium, C1.8alkyl or substituted Ci_salkyl;
Z is hydrogen, Ci_8alkyl, C2_8alkenyl, Ci_shaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl ¨CORI ¨0O21211, ¨SO2RI I, ¨S(0)R11 or ¨CONR9RI ;
R9 is hydrogen, R'' is Ci_8a1ky1 or C3_10cycloalkyl; aryl or arylalkyl;
RH is hydrogen, Ci_8a1ky1, C3_10cycloalkyl, C3_10heterocycloalkyl, C3_10aryl or C3_10arylalkyl.
TI is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl;
T2 and T3 are each independently a single bond, -T8-S(0)t-T9-, -T8-C(0)-T9-, -T8-S-T9-, -T8 -O ______ C(0)-T9-, -T8-C(0)tT9-, -T8-C(=NTI )-T9 or -T8-C(0) C(0)-T9-;
.. T5, T6, T7, T8 and T9 are independently hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alky, each group optionally substituted where valence allows by one to three groups selected from halo, cyano, nitro, OH, oxo, ¨SH, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, ¨OTII, ¨ST, ¨C(0)tH, ¨C(0)1T11, ¨0¨C(0)TI I, T8C(0)tN(T12)TI I, ¨S03H, ¨S(0)1TI I, S(0)1N(T12)TI I, -T'3-NT' 'T'2, -T13-N(T12)-T4-NTIIT22, -T13-N(Tl I)-T12 -Viand -T13-N(T18)-T14-H; or T8 and T9 are each independently a single bond, alkylene, alkenylene or alkynylene;
T" is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, .. heteroaryl or (heteroaryl)alkyl;
T12 is halo, cyano, nitro, OH, oxo, ¨SH, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, ¨C(0)111 or ¨S03H;
T13 and TI4 are each independently a single bond, ¨S(0)r¨, ¨C(0)--, ¨C(S)--, ¨0¨, ¨S¨, ¨C(0)1¨, ¨C(=NT13)- or ¨C(0)--C(0)¨; and t is 1 or 2.
More preferred methods/compounds use/are:
A is hydrogen, deuterium, methyl, ¨CH2(CH3)2, --(CH2)2(CH3)2, --CH(CH3)CH2(CH3), ¨
(CH2)0H, hydroxyethyl, ¨(CH2)2SCH3, ¨CH2SH, phenyl, ¨CH2(phenyl), ¨CH2(p-hydroxyphenyl), ¨CH2(indole), ¨(CH2)C(0)NH2, ¨(CH2)2C(0)NH2, ¨(CH2)2C(0)0H, ¨CH2C(0)0H, ¨(CH2)4NH2, ¨(CH2)3(=NH)CNH2 or ¨CH2(imidazole).
Especially preferred methods/compounds use/are:
A is ¨CH(CH3)CH2(CH3), phenyl, CH2(phenyl) or ¨CH2(2-indole).
Also, especially preferred methods/compounds use/are:
R8 is hydrogen and the configuration about the carbon marked with the * is S, provided A is not H. Also preferred: R8 is deuterium and the configuration about the carbon marked with the * is S, provided A is not H or deuterium.
Other preferred methods/compounds use/are:
RI and R5 are both isopropyl; and/or R6R7and R9 are all hydrogen; and/or Z is CH2(phenyl), ¨C(0)2H or ¨C(0)2C1_8alkyl.

Example embodiments of Formula (IV) In the following scheme, Scheme X, all reactants are commercially available e.g. Compound 1 from Matrix Scientific, Columbia, SC, USA, Compound 2 from Oxchem Corporation, IL, USA, Compound 4A from Astatech Inc., Bristol PA, USA, Compound 4B from Apollo Scientific Ltd., Stockport, UK.
Scheme X

C.) N
CH3 ..- -...
N NaOH3C CH3 N
N=c=0 4. Fi2N av v. 0 õ.4 , 4B
T
NANO
H3//N. CH3 HO 0 HF H H OH 0 0___/

2 Fi O

1 HC "'CH B = ED
CI
i CH2Cl2 (r¨N A H 1 ) N N
H3C CH3 N H3C CH3 * r N) 0 v,?0 ...

H H i_N., EDCI
4 f,u r H3C 'CH3 CH3 112%-.1i 2 I

, Using Scheme X, above, with different amino acids as the Compound 2 input, gives different Compound 5 products. Non-limiting illustration follows: Compound 2b is available from Aurora Fine Chemicals LLC, San Diego, USA, Compound 2c and 2d from Sigma-Aldrich:
N--,---A N--=\

-,, NH
N¨\ H3C CH3 . NH H3C

.,.
Nr., NH
.,A 0 NAN 0 H2N Scheme X . 11.1 11 F N 142N Scheme H H ' N
F (arm A) F (arm B) HO 0 , 2b 2b H3C'NOT
. 0 ;

N---=-- \
H3C CH3 ''' N¨CH3 H3C CH3 ,.., N--CH3 N=.-\
-N. N--CH3 I 0 N. N--CH3 0 H2N Scheme X N H2N Scheme X.
(arm A) -- (arm B) H H N H H
, HO 0 HO 0 ---------------- ,--Fi3C CH3 H3C CH3 2c 2c ..---\

. 0 .

¨
HN F HN \ z F
HN H3C CH3 '''' HN H3C CH3 '' N N

arm B) Scheme ______________________________________ X 411 ,k 0 H2N Scheme )c. (1 N)ls'N H2N N N
H H N
(arm A) ( 2d 2d H3C o_n In preferred embodiments, the S stereoisomer product of Scheme X is in enantiomeric excess, optionally because the Compound 2 input into Scheme X has enantiomeric excess of S
stereoisomer. To illustrate, with histidine (available from Sigma-Aldrich) as Compound 2 input, N=--\ N--.--\
NH -..H

N---,A N.=-1 .tts:H
A 0 4:,,,C1H

õNH2 Scheme X. 414 N N S NH2 Scheme )c 4110 N NI
H H N
S ' (arm A) S (arm B) 2e 2e "

=

, ;
Where the amino acid side chain contains an NH group it can optionally be protected as a first step, preferably using a protecting group with some degree of specificity for an amine over an alcohol group, and for a secondary (NH) over primary (NH2) amine, wherein greater specificity is more favoured. Or using an amine protecting group (or chemical reaction/modification e.g. [non-limiting] refer [242-243]) with some degree of specificity for a primary over seconday amine, then protecting the secondary amine with a different protecting group, then removing the first protecting group (or reversing the chemical reaction/modification of primary amine) with conditions that don't remove the second protecting group. Thence a protection group on the NH group of the amino acid side chain, and not on the NH2 and OH of the amino acid, is extant. This judicious use of protecting groups is inherent to one of the art e.g. refer Greene et al., Protective Groups in Organic Synthesis, 3rd Ed., Wiley-Interscience, 1999 (or later edition). Alternatively one can use an amino acid starting material with desirable protections incorporated, for example the starting material, a protected form of L-histidine (CAS: 274927-61-6), in the scheme below is available from multiple suppliers on Labnetwork.com e.g. Astatech Inc., Bristol PA, USA

Bn 1) NaOH H
CH KII N N---=\
..--,,,,,, 2)CJJ Bn N=C=O H3C CH3 ,,.,. 1.,,,,,N H3C

N--\\ 0 HCI crN
c.
CH3 0 "e CH3 N)INN4' t:NF12 Et3N H H 0-CH3 3) H2, Pd/CQr N--11,,N .H H
N
0 9 H3c CH3 An illustrating, non-limiting, judicious use of protecting groups is shown below, wherein Compound 1 is available from Sigma-Aldrich (609226) and the remaining starting compounds from suppliers listed on labnetwork.com: Compound 2 (Fluorochem, Hadfield, Derbyshire, UK), Compound 5 (Astatech Inc., Bristol PA, USA), Compound 9 (Matrix Scientific, Columbia, SC, USA) and Compound 12 (Alfa Aesar, Shanghai, China).

N=A 0 N=\ N=\
NH CrNH
15"
µr:H 142N-5 2 0¨ N - 0 1 SOCI 10¨
Ji 0 * --.õ _21.
.===

N=-\ N=-\ N=\
Cc Selectfluor C 1.;
NH l HN
S-Quinuclidin-3-ol 1 ---. -------------.
Cu(OAc)2, Ag2CO3 F-.15.,)-- 7 2) LiOH F b_ 8 6 0¨

AN
N
I ll N--=\ .1...,,,J N=\
N=\ sCCH CH3 1,5 CH3 0¨

fe NCO =N)15N4 15N N2H4o. F
'>=` '.' H HFN
0 ll 2 Cits,1 13 CH LJ
1..

JJ

10 Other example embodiments:

.)1. N N S 0 N N 0 H H N H H (N., H3C CH3 H3C CH3 1`,.../

a 0 N N =-= lik --NAN 0 H H N H H rN., Other embodiments:
H3C CH3 0 ...r4;;7,ii H3c CH3 0 ¨ )1..
F
O
i-HN)Nli ,...N., ( / HN HN S N

H3C".\041'' N ;...,.:.

-NH

NAN74.0 A 0 N N
H H N H H

H3C..\oi cl Further embodiments:

H3C CH3 rsd H3C CH3 (rN) } 9 _ - N N
H H

H3C\ 0 T1 () ()) H3C CH3 N) H3C CH3 H H N H H
H3C CH3 H3C CH3 c.,""

Following is Structure IV, from Scheme I, in the "Process of Preparation"
section of [P3], symbol definitions are as in [P3]. Scheme I in [P3] is a more general form of Scheme X
above.

A

OH
IV
This Structure IV can be deuterated, as can final compounds of the scaffold of [P3] (scaffold presented in its abstract), at its chiral carbon, and in further embodiments at further or other position(s), by reactions described in [A, B, El, E2, F], which can deuterate the a-carbon to .. secondary amines. And/or by reactions described in [Ex3], which can deuterate the a-carbon to a carbonyl, using pyrrolidine (available from Sigma-Aldrich) as catalyst, and/or by reactions described in [Ex4], which deuterate ketones. And/or by reactions described in [N], which deuterate sp3 carbons. And/or by reactions described in [RI, R2, Ql, Q2], which deuterate aromatic and alkyl molecular components. Deuterated Compound IV
structure(s) can be inputted into the synthesis Scheme I of [P3], in place of an undeuterated Compound IV form compound(s), to make deuterated isotopologue(s) with the scaffold of [P3], its scaffold is shown in its abstract. Alternatively, to achieve this aim, a compound(s) of Structure III form in Scheme I of [P3] can be deuterated at its chiral carbon, and in further embodiments at further or other position(s), by reactions described in [A, B, P, El, E2, F], which deuterate the a-carbon to primary amines. And/or by a methodology used to deuterate amino acids, of which many are known to those of the art (non-limiting e.g.
[244-249, B]), because Structure III (of [P3]) is of the amino acid form. Indeed, deuterated (and/or other isotopically enriched e.g. 13C and/or 15N) amino acids can be sourced commercially, e.g.
(non-limiting) from Sigma-Aldrich or Cambridge Isotope Laboratories Inc., e.g.
look in their catalogues for options/contact them for further options (e.g. for custom synthesis), and used in Scheme I of [P3] to produce isotopically enriched compound embodiments of the present invention. For (illustrative, non-limiting) example, Cambridge Isotope Laboratories Inc. sell L-histidine enriched (97-99%) for 13C, 15N, 2H at the respective positions of C, N and H in histidine (item number: CDNLM-6806-PK). Sigma-aldrich sell this also (item number:
750158 ALDRICH) and L-tryptophan (749931), L-lysine (749907) and L-phenylalanine (749885) enriched for these isotopes also, and L-histidine (791318) and L-phenylalanine (CAS: 17942-32-4) enriched for 2H, at multiple positions, only. Cambridge Isotope Laboratories sell L-lysine enriched for 2H at multiple positions (DLM-570-PK).
Deuterated (and other isotopically enriched) compound embodiments of the scaffold of [P3]
(scaffold presented in its abstract), most preferably deuterated at their chiral carbon (which in an embodiment is 13C at enriched, non-natural abundance, e.g. {non-limiting}
>70%13C
incorporation), are componentry to the present invention as new compositions of matter. And in non-limiting embodiments, these are used singly or in combination, optionally in co-therapy with an FDA and/or EMA approved medicine(s) and/or treatment(s), for example a licensed cancer treatment, as anti-cancer and/or anti-aging therapeutics.
To further illustrate by example, without restriction, Compounds 2f (CAS
number: 54793-54-3), 2g (CAS: 136056-01-4), 2i (L-lysine), 2j (CAS Number: 169524-86-1), 2k (607665 ALDRICH) are available from Sigma-Aldrich, Compound 2h (CAS: 91037-48-8) from Cambridge Isotope Laboratories:
H3c cH3 Fi3c cH3 S
,,,NH2 Scheme )c NH Scheme X., N
H H
S D (arm A) S D (arm B) 2f 2f H3e\DP
0 .

1101 H3C CH3 *

A 13c 0 1110 A 13c 0 N N'S'"
13CiNH2 S(cahemAe H H N 13,,,,NH2 Scheme ----, '-, S (arm B) ===-. H H .õ14..., 2g 2g H3C 0_11 0 ;
N---:---\ N---:--- \
N--=\ I-13C CH3 N, N-CD3 N-=\ H3C CH3 N N-CD3 ..c.N-CD3 0 c.,N-CD3 0 Sche 0 ..,kN0 =-. 0 1NH2 me NN X 4110' A S
S (arm A) H H N .5,,,N H Scheme2(arm B)X 10 N
H H N
--- N
0 OH H3C CH3 0"0H H3C CH-4-2h 2h n,_, ,..õ---\
3k,,, 0T
= 0 , .N, 0 0 NH2 ,....1 .H2 H2NI, H3C CH3 I H2NN HC CI-43 Scheme X. 40' NAN'ACI
Nej:NH2 H H N
s (arm B) ,AH2 ScheITI-12-4.
H H N
(arm A) c 21 21 Iv"o_ri = 0 .

H2NN H3C CH3 <NH2 H2N <NH2 'IN 0 mu Scheme X, 411 NAN11`e '113,, ,,..I l'f H H N õõ.., Scheme X 41 XS ' (arm A) 13cs='"' .2 (arm B) H H N
C
0 OH H3C CH3 -)N

2j 2j =
5 0 ;
15,NH2 isc 1,qH2 1,11.i2 13c H3C CH3 13015NNõ. 13C
' --z H3C CH3 l'N 0 cheme X NAN0 Scheme X S N N

H H N NH., _ S
S (arm A) I'-` (arm B) H H .õN...,, ...; , 0 OH H3C CH3 0 OH H3C CH3 "N.---2k S 2k "

5 0 ;

EXAMPLE (V) Formula (V) 11 (R110.4 R2 = 0, S, Se R3 = 0, C, S, Se, Si R3 0_3 R4 = S, Se L....._hi R2=R4=R2 R5 = N, C
R6 = R3, X

(R1)0_3 I/

1-3 \
(R1)0_4 R6 I
X

X

R1 = H X I ___________ X
II

AN<C:-0¨ X
0¨ X f---o o-x x \_N-x X
¨X
N¨ XI II
___________________________________________ X X
N=N
X X

I I E-s-x F-s-x r---s-x 13 1--X I x I I I I X

X = absent, H, Deuterium, OH (hydroxyl), SH (thiol), =0 (keto), CN (cyano), halogen, CH3 (methyl), methoxy (OCH3), trifluoromethyl, OCF3, NH2(amino), NOOH (nitro), =N-OH, COOH
(carboxyl), COH (formyl), N=0 (nitroso), 0-N=0 (nitrosooxy), alkyl(C1.4), alkoxy(C1_4), haloalkyl(C1_4), alkylthio(C14), hydroxyalkyl(C1_4), aminoalkyl(C1.4), cycloalkyl (C14), haloalkoxy(C1.4), alkenyl(C14), alkynyl(C14), alkoxycarbonyl(C14), substituted alkyl(C1_4) (which is an alkyl with between 1 and 4 carbons and one or more independent substituents of X) Molecular permutations of BTB06584. Enumerations of this Markush structure, and their pharmaceutically-acceptable salts, solvates, hydrates and prodrugs thereof, are disclosed as anti-cancer molecules: the process/method of their use as anti-cancer molecules is disclosed by this invention. As valence permits: RI is selected from the options of RI
(independently in each case of RI), X is selected from the options of X (independently in each case of X), R2 is selected from the options of R2 (independently in each case of R2), R3 is selected from the options of R3 (independently in each case of R3), R4 is selected from the options of R4 (independently in each case of R4). In other embodiments one or more phenyl groups has one or more of its double bonds replaced with a single bond. In other embodiments, one or more phenyl groups is replaced with cyclohexane, each with the same possible substitutions as the .. phenyl it replaces. Hydrogen atoms aren't shown in this figure, but in further embodiments one or more hydrogen atoms is replaced with deuterium. In further embodiments:
any possible isotopic substitution at one or more places.

Example embodiments of Formula (V) BTB06584 o=s=o =
- N+

0=s=0 0=s=0 (10 0 /10 0 -Nt CI cy-N--to CI ,0 '0 , B1B06584, and/or its analogues, can be deuterated by reactions described in [RI, R2, Ql, Q2], which deuterate aromatic and alkyl molecular components. Furthermore, there is a great wealth of reactions available to deuterate their aromatic rings, and those skilled in the art will know these. For (non-limiting) example, refer [Ex2]. Deuterated isotopologues of Formula (V), for (non-limiting) example deuterated BTB06584, are componentry to the present invention as new compositions of matter, and in non-limiting embodiments are used singly or in combination, optionally in co-therapy with an FDA and/or EMA approved medicine(s) and/or treatment(s), for example a licensed cancer treatment, as anti-cancer therapeutics.
EXAMPLE (VI) Encompassed by this embodiment are methods of treating a subject suffering from cancer by administering an effective amount of at least one compound of Formula (VI) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising one or compounds of Formula (VI).
Summary of Formula (VI) This invention embodiment relates to compounds having the following formula:
Formula (VI) RB
b( M I LA
X
Q
xa(4) Qr = )xa .0)%...\\
RA1 cr N
b( QB QB
b( LY-RA2 X
including RB
N N
NH

or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
each QA is independently selected from N and CH;
each QB is independently selected from 0, S, Se, NH, CH2, NRw, PRw, BRw, C(Rw)2 and Si(Rw)2;

each M is independently selected from 0, S. Se, NH, CH2, NRw, PRw, BRw, C(R)2 and Si(Rw)2;
each Rw is independently selected from hydrogen, deuterium, halogen (e.g. F), alkyl, or substituted alkyl (non-limiting examples: CF3, CC13), or deuterated alkyl (non-limiting example: CD3), or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy;
xa is independently at each point of use selected from 1, 2, 3, 4, or 5; xb is independently at each point of use selected from 0, 1, 2, 3, 4, or 5; LA represents 0-5 optional substituents on the ring independently selected from alkyl, substituted alkyl, deuterated alkyl, aminoalkyl, thioalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2 etc.);
RAI and RA2 are each independently selected from the groups R C
RD " _________________________________________________ RE
and wherein Rc and RD are each independently selected from hydrogen, deuterium, halogen and alkyl, and wherein RE is hydrogen, deuterium, halogen or alkyl;
le is selected from RBI, hydrogen and deuterium;
wherein RBI is selected from phenyl, benzyl, heteroaryl, pyridyl, pyrimidyl and pyrazinyl optionally substituted with one or more substituents RB2;
wherein each RB2 is independently selected from halogen, alkyl, substituted alkyl, deuterated alkyl, alkoxy, nitro, amino, methoxy, haloalkyl, polyhalogen alkyl, aminoalkyl, thioalkyl, alkoxy, haloalkoxy, and any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2 etc.);
or le is a phenylalkyl of the formula:

. G _______________________________________ (RG)q (RF)q wherein RF and RG are hydrogen or alkyl, G is a carbon-carbon double bond or a carbon-carbon single bond, n is 0 or 1 and q is 0 or 1 provided that where q is 0, G
is a carbon-carbon double bond and where q is 1, G is a carbon-carbon single bond, or RH is a diphenylalkyl of the formula _ it P

wherein RH' and RH2 each independently represent 1-5 optional substituents on each ring, and wherein each RHI and RH2, when present, is independently selected at each point of use from hydrogen, deuterium, halogen, alkyl, substituted alkyl, deuterated alkyl, alkoxy, nitro, amino, .. methoxy, haloalkyl, polyhalogen alkyl, aminoalkyl, thioalkyl, alkoxy, haloalkoxy, and any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2 etc.), and p is 0, 1,2 or 3;
or RH is the group RJ
.
(GTA\ IL
,QH
(Gu)u"

RK
including Rj e .
RK
including Fe RK
Wherein GT and Gu are each independently selected from a single bond, 0, S, Ne or C(Rv)2, wherein each le is independently selected from hydrogen, deuterium, alkyl, or substituted alkyl (non-limiting examples: CF3, CC13), or deuterated alkyl (non-limiting example: CD3), or aminoalkyl, or thioalkyl, or alkoxy, or halogen (e.g. F), or haloalkyl, or haloalkoxy;
u and t are each independently selected from 0, 1, 2, 3 and 4;
Q is C, CH or N, Wand RK each independently represent 1-5 optional substituents on each ring, and wherein each IV and each RK, when present, is independently selected from deuterium, halogen, alkyl, substituted alkyl, deuterated alkyl, alkoxy, haloalkoxy, methoxy, nitro, amino, aminoalkyl, thioalkyl, haloalkyl, polyhalogen alkyl, and any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g.
(non-limiting) OH, NH2, SH, Sift, PH2 etc.);
L is absent (when Q is N), alkyl, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy, or hydroxyalkyl, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2 etc.).
In some embodiments, when one or both of R3 and RK is alkoxy, this alkoxy group may be methoxy.
It is to be understood that in the compounds of general Formula (VI), wherein RA' and/or RA2 are alkenyl moieties having different substituents at the position Rc and RD, that compound may exist in cis or trans isomeric forms both of which are considered to be within the scope of the present invention. All isotopic, including radionuclide, forms of Formula (VI) are within the scope of the present invention.
Preferred embodiments of Formula (VI) For Formula (VI), the symbols Rc and le, as defined in subgroups RAI and RA2, may be hydrogen, halogen (suitably fluorine, chlorine or bromine), alkyl, suitably "lower alkyl"
(herein now defined) having from 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl and the like, most preferably methyl;
and the moiety RE may be hydrogen, or lower alkyl having from 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, or pentyl, most suitably methyl.
The subgroup RB may be hydrogen; phenyl; or substituted phenyl. The substituted phenyl group may include one or more of the preferred substituents in any of the available positions for substitution, however, mono substitution in the 4-position of the phenyl nucleus is .. especially preferred. Suitable substituents for the phenyl nucleus include halogen, preferably fluorine, chlorine or bromine; lower alkyl, lower alkoxy, and poly halogen lower alkyl (i.e.
substituted alkyl) wherein the alkyl moiety contains from 1 to 5 carbon atoms, especially preferred however are methyl, methoxy, and trifluoromethyl; and nitro and amino.
Where the subgroup RB represents substituted pyridyl, substituted pyrimidyl, or substituted pyrazinyl, the substituting group may be located on one or more of the available carbon atoms in the nucleus, and may be the same or different. Preferred among the substituting groups are lower alkyl or lower alkoxy having from 1 to 5 carbon atoms such as methyl, ethyl, butyl or penty; or methoxy, propoxy, butoxy or pentoxy.
Where the moiety le represents substituted benzyl, the benzyl moiety may be substituted in one or more of the available positions on the phenyl nucleus thereof. Among the preferred substituents are halogen (suitably fluorine, chlorine or bromine), lower alkoxy having from 1 to 5 carbon atoms, especially preferred is methoxy and most preferred being di-and tri-methoxy; or alkylenedioxy suitably lower alkylenedioxy such as methylenedioxy, ethylenedioxy, propylenedioxy and the like, most suitably, the alkylenedioxy moiety is attached across the 3- and 4-positions of the phenyl nucleus, although the bridging of other carbon atoms in the phenyl nucleus is to be considered within the scope of the present invention.
The moieties RF and RG may be hydrogen, or lower alkyl of 1 to 5 carbon atoms, most preferred however being methyl.

The groups RBI and RIL2 may be independently hydrogen, or halogen suitably fluorine, chlorine or bromine.
Preferred embodiments of Formula (VI) include wherein Rc and RD are methyl, RE
is methyl and RB is selected from chlorophenyl, methylphenyl, methoxyphenyl, trifluorophenyl, chlorophenyl, dimethoxybenzyl, trimethoxybenzyl, methylenedioxybenzyl and ethylenedioxybenzyl.
In some embodiments RB is the group RK
In some embodiments, RB is the group RL
RM
wherein RL and Rm are each independently selected from halogen, alkyl, alkoxy, nitro, amino = and polyhalogen alkyl.

Synthesis of structures of Formula (VI) Synthesis routes for example embodiments of Formula (VI) are in [P7], which is herein incorporated in entirety by reference. One or more chemical enumerations/structures from [P7], in use as an anti-cancer therapeutic, is componentry to the present invention. Indeed, encompassed by this embodiment are methods of treating a subject suffering from cancer by administering an effective amount of at least one compound from [P7] or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising one or compounds from [P7].
Example embodiments of Formula (VI) Invention embodiments include compounds of Formula (VI), whether a decoupler or not, and any compound(s) of any formula, which has decoupling activity (changes FIFO
ATP synthase stoichiometry), in use for anti-cancer therapy.
Decoupler drugs as anti-cancer medicines Enumerations of Formulas I-V exert anti-cancer activity by inhibiting, and so reducing, FiFo ATP hydrolysis. The present embodiment also exerts anti-cancer activity by reducing FIE.
ATP hydrolysis. However, not by inhibition of FIR) ATP hydrolysis, but by making FiFo ATP hydrolysis more efficient! Such that less ATP is hydrolysed per unit proton motive force (pmf) generated i.e. FIFO ATP hydrolysis is reduced. The shared feature of these embodiments is that cancer function is impaired, and cancer danger reduced, by reducing FiFo ATP hydrolysis in cancer cells. The present embodiment relates to and discloses the method/use of a "decoupler" drug(s) as an anti-cancer therapeutic e.g. (non-limiting) almitrine, which is a compound of Formula (VI). Disclosed experimental data shows that almitrine exerts anti-cancer activity (Figure 7).

A A
I A A I
A., õGõ, I I G,, A
G G
II I A II
A¨Gõ I õ..Gõ
G
A A
.¨A
A¨G
G:ZA
A A i5N
13c N N A A E E N
H2C NH Pk õ/ G IA E N N NH
I
A A
Almitnne GA11 G = 12C,13C (enriched, >NA) I I
CH2 A¨G¨A CH2 E 14N, 15N (enriched, >NA) A = 1H, 2H (enriched, >NA), F, 32CI (enriched, >NA), halogen, alkyl, substituted alkyl, CF3, deuterated alkyl NA = natural abundance Decoupler drugs modify the Fr/ATP stoichiometry of ATP synthase, so modifying the ATP/0 ratio, without significantly changing Tim [250-253]. Such drugs symmetrically modify the forward and reverse modes of ATP synthase: they make the forward mode less efficient (less ATP synthesized per protons passed) and the reverse mode more efficient (more protons pumped per ATP hydrolysed). In other words, they reduce the (fractional) ATP yield/cost of a proton passing through ATP synthase energetically "downhill"/"uphill", in relation to the direction of the proton motive force (pmf). In isolated mitochondria, the almitrine conferred decrease in FiFo ATP synthesis and hydrolysis is maximal at 40%, no matter how great the almitrine concentration [251]. Almitrine can double the stoichiometry:
double the number of protons required/pumped for/by ATP synthesis/hydrolysis.
Almitrine reduces the amount of ATP that FiFo ATP synthase synthesizes, but it also reduces the amount of ATP that FIFO ATP synthase hydrolyses, which is normally, without almitrine, significant. Indeed, this disclosure discloses a new fundamental biological discovery, with supporting in vivo experimental data (Figure 23): FiFo ATP hydrolysis isn't a bug but a feature, substantial and essential to heat generation and homeothermy.
Almitrine reduces ATP synthesis and hydrolysis and these aspects largely offset and intracellular [ATP] remains within survivable limits. Almitrine reduces inefficiency (heat generation) but simultaneously increases inefficiency (heat generation). Making the forward mode of ATP
synthase less efficient might be bad for normal cells, as it might be for cancer cells that use OXPHOS, but this decoupler action disproportionally affects cells with a higher respiratory rate [251], which could disproportionally affect cancer cells. Although decouplers make the reverse mode of ATP synthase more efficient, this action still exerts anti-cancer activity on cancers using ATP synthase in reverse. Because these cancers use this mode for its inefficiency: to consume ATP, to permit high glycolytic and PPP flux, to enable high [NADPH]
and low [ROS]. So, slowing/reducing this FIFO ATP hydrolysis exerts anti-cancer activity. The same cancer can be disrupted by both almitrine actions, upon the forward and reverse modes of ATP synthase, at different stages of the cell cycle.
In normal cells, almitrine decreases ATP synthesis, but decreases ATP
hydrolysis also, and so [ATP] is maintained. In cancer cells residing in hypoxia, thence forced to survive with a lower OXPHOS rate, which already rely upon high IFI expression (many cancers overexpress [23-24]) to block ATP hydrolysis and buoy [ATP], almitrine conferred decrease in ATP
synthesis strikes them disproportionally.
Comparing Figure 1 and 7A, one observes that in standardized NCI one-dose testing [16-17], almitrine dismesylate (10 M) exerts greater anti-cancer activity than carboplatin (10 M), which is an FDA approved chemotherapeutic, one of the most used chemotherapies today, and is on the World Health Organisation (WHO) list of essential medicines.
Furthermore, almitrine dismesylate is less toxic to normal cells than carboplatin. In mice, intraperitoneal injection (IP) LD5o (dosage at which 50% of test mice die) = 118 mg/kg for carboplatin [254]
and = 370 mg/kg for almitrine dismesylate [255].
In humans, 200 mg per day of oral almitrine dimesylate has been trialled for sleep apnea, which is a drive to snoring [256]. In humans, oral almitrine dimesylate has been used for decades, totalling millions of patient months of almitrine administration, for chronic obstructive pulmonary disease (COPD), often at 200 mg oral almitrine dimesylate per day [257, 258], wherein 400 mg per day has been shown safe in humans [259]. In humans, a single 200 mg oral almitrine dimesylate dose (>85% orally bioavailable [260]) renders a mean Cmax plasma concentration of 286 ng/ml = 0.6 M, AUC(0-72 hours) = 3943.2 (ng*h)/ml, AUC(0.03) = 6248 (ng*h)/m1 [258]. Using [Css= AUC(0.00/dosing interval] [261], wherein Css is drug plasma concentration at steady state, wherein 200 mg is administered per day (thence dosing interval = 24 hours), Cs, = 6248/24 = 260.3 ng/ml = 0.55 M. Because almitrine volume of distribution (VD) = 17 1/kg [258], and human volume = 1/kg [262], corresponding almitrine tissue concentration (assuming uniform) at steady state = (0.55*17) = --10 M, which is an almitrine concentration that exerts anti-cancer activity in NCI testing (Figure 7A). Almitrine has a long half-life in the body, so daily doses fractionally compound and drive higher and higher almitrine plasma concentrations and, indeed, in humans, oral 50 mg almitrine dimesylate, twice per day, for 1 year produced an average steady state almitrine plasma concentration on the 3651h day of 432.8 ng/ml (daily peak plasma concentration in some patients exceeded 1000 ng/ml); almitrine plasma levels didn't stop increasing and stabilize until a point between day 90 and day 180 [263]. Extrapolating from [263], oral 200 mg per day almitrine dimesylate (a dosage used in human therapy [257, 258]) produces average steady state almitrine plasma concentration on the 365th day of 865.6 ng/ml = 1.81 M, (1.81*17) = 30.8 M tissue concentration of almitrine, which is 3 times greater than an almitrine concentration, 10 M, that exerts significant anti-cancer activity in NCI testing (Figure 7A). A different human study [264] recorded a higher almitrine volume of distribution (39.23 1/kg), which translates to a greater tissue concentration of almitrine:
(1.81*39.23) = 71 M. In clinical use for COPD, a plasma concentration of 300 ng/ml almitrine is the directive [257], which corresponds to an anti-cancer tissue concentration (-10 M to >10 M) of almitrine. Non-limiting anti-cancer embodiments of this invention are almitrine dosages/formulations/compositions/salts/patterns of administration (e.g. sequential administration scheme) already used in humans (for example, as reported in the literature).
Furthermore, higher or lower almitrine doses for anti-cancer therapy, optionally administered intravenously and/or with layoff periods (no drug administered), are further embodiments of .. this invention.
Five minutes after i.v. bolus administration of radioactively labelled "C-almitrine to anesthetized rats, almitrine in plasma is 0.69% dose/g and almitrine has disproportionally distributed to the lungs [12.26% dose/g = 17.77 times the plasma concentration, this disparity rises to 75.3 times at 15 minutes because plasma falls faster than lung concentration] (bronchi [10.62% dose/g]), adrenal glands [10.66% dose/g], liver [2.55% dose/g]
(although a significant amount of radioactivity detected in liver isn't because of intact almitrine but because of one or more of its metabolite [s] ; if accumulated by the liver, almitrine is significantly broken down), kidney [1.58% dose/g], heart [2.73% dose/g], carotid body .. [2.66% dose/g] and superior cervical ganglion (SCG) [0.26% dose/g, but increases to 1.81%
dose/g by 2 hours] [266]. The same experiment was performed without the rats being anesthetized, with the Pt recording time point two hours after i.v. bolus, wherein this was the last recording time point for the prior experiment with anesthetized rats, and so at this shared time point, differences in almitrine tissue distribution between anesthetized and unanesthetized rats can be identified. There was no notable difference for any of the aforementioned tissues, except for (anesthetized vs. unanesthetized) the caratoid body (1.18 vs. 0.58 % dose/g), SCG (1.81 vs. 0.22 % dose/g), which both had less almitrine, and the liver (0.88 vs. 2.51 % dose/g), which had more. Relating the tissue types that disproportionally accumulate almitrine in rats to the case of humans administered with almitrine: the almitrine concentration in one or more of these human tissues, most especially the lung (especially the bronchi), might exceed the human tissue calculation disclosed earlier, which treated the entirety of the tissues as a single uniform compartment (in the case of lungs, it at least matches it on the basis of the rat data, wherein lung has

17.77 times greater than plasma concentration of almitrine, 5 minutes after i.v. bolus of almitrine, which is close to the multiplicative constant, 17, that I used in my earlier calculation).
Therefore, in invention embodiments, almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is especially suited, without limitation, to treating a cancer in one or more of these regions in a subject. For example, treating/ameliorating/preventing/combating a lung cancer(s) such as, without limitation, small-cell lung carcinoma (SCLC), non-small-cell lung carcinoma (NSCLC, including, without limitation, adenocarcinoma of the lung, bronchioloalveolar lung cancer, bronchioloalveolar carcinoma, squamous-cell carcinoma of the lung, large-cell lung carcinoma, pleomorphic, carcinoid tumor, salivary gland-like carcinoma, unclassified carcinoma, rhabdoid carcinoma, sarcomatoid carcinoma, adenosquamous carcinoma, papillary adenocarcinoma, giant-cell carcinoma, an admix of NSCLC types, "not otherwise specified" type), combined small-cell lung carcinoma (c-SCLC), pancoast tumors, carcinoid tumors, bronchial gland carcinomas, sarcomatoid carcinomas and non-carcinomas (such as, without limitation, sarcoma, lymphoma, immature teratoma, melanoma), a cancer(s) listed in [267], cancer(s) in a bronchus/bronchi, bronchial adenoma. Almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is particularly suited to treat/ameliorate/prevent/combat Non-Small Cell Lung Cancer (NSCLC) because in vitro data shows almitrine dimesylate to exert anti-cancer activity against NSCLC cell lines (Figure 7, 31.6% mean growth inhibition for NSCLC
cell lines when administered at 10 uM). At 10 M, almitrine dimesylate exerts greater anti-cancer activity than carboplatin (Figure 1, 6.3% mean growth inhibition for NSCLC
cell lines when administered at 10 p,M), a drug in present clinical use for NSCLC. At 100 M, the maximum growth inhibition that almitrine dimesylate exerts against an NSCLC cell line, = 76.46%
growth inhibition (Figure 7B). Moreover, the way almitrine exerts anti-cancer activity, disclosed elsewhere herein, it is suited to treat chemoresistant and/or radioresistant lung cancer(s) because it undermines a mechanism by which these cancers have radio-and/or chemo- resistance, as disclosed elsewhere herein. Futhermore, almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is especially suited, without limitation, to treat/ameliorate/prevent/combat a cancer(s) of the caratoid body, such .. as carotid paraganglioma (carotid body tumor), and/or a liver cancer(s) such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma and/or a kidney cancer(s) such as renal cell carcinoma (RCC), renal oncocytoma, transitional cell carcinoma (TCC), squamous cell carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma, metanephric adenoma, cystic nephroma, Wilms' tumor, mixed epithelial stromal tumor and/or a heart cancer(s) (primary and/or secondary) such as papillary fibroelastoma, rhabdomyoma, angiosarcoma, teratoma, cystic tumour of the atrioventricular nodal region and/or a cancer of the adrenal gland such as adrenocortical adenoma, adrenocortical carcinoma, neuroblastoma, pheochromocytoma, and paraganglioma.
An embodiment of the invention is administering almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof to a subject with cancer, optionally lung cancer and/or mesothelioma of the lung, wherein this subject has difficulty breathing and/or has low blood p02 and/or high blood pCO2 and/or Chronic Obstructive Pulmonary Disease (COPD) and/or Acute Respiratory Distress Syndrome and/or is undergoing (or will undergo or has undergone) surgery including anti-cancer surgery including surgery to remove lung cancer including surgery to remove part or the entirety of a lung (pneumonectomy) including open-chest thoracic surgery (thoracotomy) including open-chest one lung ventillation, optionally in co-administration with (e.g. inhalation of) Nitric Oxide, NO (illustratively, not restrictively, NO at 10 parts per million [p.p.m]) and/or hyperbaric 02 therapy. Almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is especially suited to treating lung cancer because it exerts anti-cancer activity, thence fundamentally treating the symptoms of lung cancer, and concurrently directly treats the shortness of breath/beathlessness symptom of lung cancer. Without limitation to any mechanism(s), the former action is by almitrine effect upon ATP synthase in cancer cells, the latter action is by almitrine effect upon BK potassium channels in the caratoid bodies, wherein this latter action also exerts anti-cancer activity, adding/potentiating with the first, because it increases tissue p02 and thence ROS production. Elegantly, almitrine both increases ROS (by increasing blood and tissue p02) and decreases ROS mitigation, especially in cancer cells (by slowing FIR) ATP hydrolysis).
Almitrine acts upon BK potassium channels in chemoreceptors, within the caratoid bodies, and acts as a respiratory stimulant, which increases blood and tissue oxygenation, decreasing their [CO2] [268, 269]. This respiratory stimulation should exert an additional anti-cancer effect in vivo because increasing [02] in blood and tissues increases their [ROS], especially in combination with ROS inducing [chemo/radio] therapies (permitting their use at lower doses, reducing their side effects). This synergises with the almitrine conferred reduction in Fi Fo ATP hydrolysis in cancer cells, which corrupts the system cancers use to maintain low intracellular [ROS] at key stage(s) of the cell cycle, which is paramount to their "limitless replicative potential" (Hallmark of cancer [26]) and thence danger. Almitrine will be especially valuable against cancers (e.g. lung, breast) that can disrupt breathing and/or reduce 02 delivery to tissues. Embodiments of this invention are to use almitrine, or any other drug(s) that modifies ATP synthase stoichiometry (a decoupler), as an anti-cancer medicine, optionally in co-therapy with one or more FDA and/or EMA approved drug(s), e.g. a cancer drug(s), and/or in co-therapy with any other compound(s) embodiments of the present invention e.g. a compound(s) of Formula (I-V) herein. Almitrine dimesylate is also known as almitrine bismesylate or almitrine dimethanesulfonate. All pharmaceutical salts of almitrine are contemplated as anti-cancer therapeutics, as is almitrine in complex with another drug(s) e.g. almitrine-raubasine.
When used chronically, almitrine dimesylate can have side effects [257]. A 30 year national pharmacovigilance survey in France, representing several million patient months of oral .. almitrine dimesylate treatment [265], showed that upon multi-year use (mean onset of adverse reactions = 11 months), some patients receiving oral almitrine dimesylate for COPD
exhibited weight loss (795 cases) and peripheral neuropathy (2,304 cases) [257]. Although these side effects only presented in a minority of patients and only in a sub-minority (<10%) of these were they categorised as serious [257]. In most cases, these side-effects were .. reversible. Almitrine has never been submitted for FDA approval (doxapram is a drug alternative to almitrine, also a respiratory stimulant, which is FDA approved, wherein doxapram was found first, which may, to speculate, have been a factor in dissuading an {expensive} FDA application for almitrine). Oral almitrine dimesylate has now been withdrawn from use in France, Portugal and Poland, where it was previously approved to treat chronic obstructive pulmonary disease (COPD). This withdrawal was because of the aforementioned two side effects and because "available efficacy data, including data which became available since the initial marketing authorisation, showed only very limited clinical efficacy of oral almitrine in its approved indications" [257]. Although oral almitrine does increase arterial p02, this does not translate to significant clinical benefit for COPD sufferers [257]. Injectable almitrine dimesylate was reviewed separately, in a review of its use to treat its own indications, distinct from the review in 2013 of oral almitrine dimesylate for COPD
[257]. It was reviewed in France by the Haute Autorite De Sante in 2013 [270].
After this review, injected almitrine dimesylate is still used in France ("Special status, List II, medicinal product for hospital use only") wherein "the [review] Committee recommends the continued inclusion of VECTARION [brand name for almitrine dimesylate in France, where it is made by Servier], lyophilisate and solution for preparation for injection, in the list of medicines approved for hospital use in hypoxaemia and hypercapnia associated with alveolar hypoventilation when weaning patients off artificial ventilatory support and at the dosages indicated in the Marketing Authorisation". From this report, "the adverse effects observed with injectable almitrine are paradoxical breathing difficulties and possible digestive disturbances such as nausea, heartburn and bloating...these effects do not routinely entail the discontinuation of treatment". Up to 25/11/2011, the number of treatment days with injectable almitrine in France was estimated at 9,453 patient-months and from 26/11/2006 to 25/11/2011 (5 years) there were only two pharmacovigilance reports: "one case of a non-serious increase in lactic acidaemia with a plausible causal link to VECTARION
for injection, and one case of Stevens-Johnson syndrome in a polymedicated female patient under treatment with injectable VECTARION". Injectable almitrine is also available/used in some other jurisdictions, e.g. for "specialist and hospital prescribing" by the British National Health Service (NHS) [271]. Why does oral almitrine dimesylate for COPD
treatment produce side-effects in a small number of cases [265], whereas injected almitrine dimesylate produces less side-effects [270]? Probably because oral almitrine dimesylate for COPD
treatment tends to be used chronically, over months to years, whereas injectable almitrine dimesylate tends to be used acutely, over day(s). And it is chronic almitrine use (mean onset of adverse reactions = 11 months [265]) that can cause, typically non-serious and reversible, side effects in a minority of patients. Acute almitrine administration is even safer. Thence there is a therapeutic window for using almitrine, very safely, for acute anti-cancer treatment.
Moreover, I argue later in this disclosure that the side-effects observed with chronic almitrine use for COPD are very tied to the COPD pathology itself, and won't be seen so prevelantly with chronic almitrine use for anti-cancer treatment. But anyhow, chronic administration won't be needed/chosen in many cases. Significant cancer treatment will come from using almitrine acutely or non-continuously, with breaks in almitrine treatment.
Indeed, present radio- and chemo- therapies are extremely toxic and so can only be administered infrequently (e.g. by FDA label: a cisplatin dose [100 mg/m2] should not be administered more frequently than every 3 to 4 weeks, e.g. a carboplatin dose [360 mg/m2] should not be administered more frequently than every 4 weeks; this instruction is not because these drugs stay in the body for an especially long time, they don't, but because they are just so toxic that the body needs time to recover inbetween doses) and typically for a capped number of times, or regularly (e.g. daily) for a short period, or for cycles of a short period of administration alternating with periods of non-administration inbetween them. Alm itrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof can be administered exactly or approximately matching, or some function of, the pattern of administration of one or more of chemo- and/or radio- therapy given to the subject, wherein almitrine will synergize with their anti-cancer effects by a mechanism that will be disclosed later in this disclosure. To illustrate, an invention embodiment is to administer almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof (oral and/or injected) every day that radiotherapy is administered, wherein illustrative (not restictive) courses of radiotherapy are to administer it every week day (one or more times) for a period that can vary between 3 to 9 weeks, or 3 times per day for 12 days (continuous hyperfractionated accelerated radiotherapy, CHART) or (especially with stereotactic radiotherapy) 3 to 8 times over 2 to 3 weeks, or accelerated fractionation, or hyperfractionation, or hypofractionation radiotherapy administration schemes. In further embodiments, almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is also administered (oral and/or injected) at weekends during a weekday radiotherapy course, and/or during pauses in radiotherapy treatment and/or is administered (oral and/or injected) for a further period of administration flanking one or both sides of a radiotherapy treatment period. In some embodiments, almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is administered during a period before and/or during and/or after anti-cancer surgery.
Oral almitrine dimesylate (100-200 mg) was administered to human COPD patients daily for a year [266]. In a minority, peripheral neuropathy started to manifest (5 times higher incidence in almitrine than control group) by 7 months on average. Subjects with greatest plasma [almitrine] were most at risk. Averaged, those presenting peripheral neuropathy in the study year had plasma [almitrine] of 344 and 617 ng/ml at 3 and 12 months respectively, those that didn't had plasma [almitrine] of 249 and 387 ng/ml at 3 and 12 months respectively. The suggested optimal long term mean (not peak) plasma [almitrine] for treating COPD, without inducing neuropathy, is in the 200-300 ng/ml range [266, 272].
Almitrine has a long half-life in the human body. When daily almitrine intake exceeds daily almitrine elimination from the body, as it does with 2100 mg oral almitrine dimesylate dosed per day [263], there is fractional compounding of daily doses, which drives higher plasma [almitrine]
over time, until an eventual point (between day 90 and day 180 with the 100 mg administered in [263]) when plasma [almitrine] stops increasing and stabilizes. If the almitrine dimesylate daily dose is sufficiently high (2100 mg and more surely 2200 mg), peripheral neuropathy can occur in the minority of COPD subjects that eliminate almitrine most poorly, who have greatest compounding of almitrine daily doses, and in which the greatest mean and trough plasma [almitrine] occurs (trough refers to the lowest drug concentration inbetween two doses). Wherein it still typically takes months, on 100-200 mg almitrine dimesylate daily, for this fraction of COPD subjects to accumulate enough almitrine in their body to cause peripheral neuropathy [272]. The majority of COPD subjects don't accumulate such an amount with clinically used almitrine doses (50 to 200 mg oral almitrine dimesylate per day), at least for the length of periods that have been studied, which is months to years. So peripheral neuropathy is a dose-dependent side-effect, wherein the overwhelming majority of COPD subjects administered, even with 200 mg oral almitrine dimesylate daily, don't accumulate sufficient [almitrine] in their body for it to occur. Almitrine administered subjects suffering paraesthesiae/peripheral neuropathy must already have a high almitrine concentration in their body, which is enough to exert significant anti-cancer activity in subjects with cancer. For these subjects, the solution is just to stop/reduce their almitrine daily dosage. The almitrine concentration in their body will then decrease, and the paraesthesiae/peripheral neuropathy with it. Afterwards, optionally, their almitrine dosing can be restarted, optionally at a lower (e.g. daily) dosage. This is a reactionary dosage regime.
Alternatively a "proactive dosage regime" can be used. Wherein the administered daily dosage of almitrine, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, is decreased over the treatment course, by some function of time since treatment start (non-limiting e.g. 200 mg almitrine dimesylate administered per day for 1s1 month, 100 mg per day in subsequent month(s)), and/or the course of administration has pauses or rest periods, wherein less or no almitrine is administered (non-limiting example: a repeating cycle of [2 months almitrine administration, 1 month none]). Optionally the almitrine administration dosage/regime can be individually tailored to the almitrine elimination parameters of each individual subject. When deciding the almitrine dosage/regime to administer, the duration of the administration course should be a principal consideration.
Wherein if the course is short, e.g. for days to weeks, it is probable that constantly high daily almitrine concentrations (e.g. 200 mg oral almitrine dimesylate per day) will not produce significant side-effects in most to all subjects. Indeed, 400 mg oral almitrine dimesylate per day is safe, in healthy subjects at least [259], at least over the short term.
For longer courses of almitrine administration (non-limiting e.g. >3 months), to protect the minority of subjects susceptible to associated peripheral neuropathy, a "proactive dosage regime", as prior defined, can be used, and/or a lower almitrine dose. Illustratively, in human COPD patients, [273] 75 mg oral almitrine dimesylate administered daily for 6 months produced no adverse effects in any of the study subjects, wherein at study end, the average of the trough (lowest inbetween doses) plasma [almitrine] in the subjects was 302 ng/ml. In human COPD patients, [274] administered 100 mg oral almitrine dimesylate daily for 2 months, then 1 month with no administration, and this cycle was repeated for I year, at the end of which the mean plasma [almitrine] was 285 ng/ml, and the authors mention that "there is a close relationship between the almitrine [mean or trough I would specify] plasma level and the occurrence of side-effects such as peripheral neuropathies", concluding that their regime is safe. In human COPD patients, [275] administered 50 mg almitrine dimesylate twice daily (i.e.
100 mg per day) for 8 weeks and, before the morning dose, plasma [almitrine] was on average across the subjects: 93, 134, 148, 171 ng/ml on days 14, 28, 42, 56 respectively, and 104 ng/ml 2 weeks after the study. In different human COPD patients, [275] administered 100 mg almitrine dimesylate twice daily (i.e. 200 mg per day) for 8 weeks and, before the morning dose, plasma [almitrine] was on average across the subjects: 268, 409, 442, 572 ng/ml on days 14, 28, 42, 56 respectively, and 311 ng/ml 2 weeks after the study. In human COPD
patients, over long term, two 50 mg doses of oral almitrine dimesylate per day results in plasma [almitrine] that is 2 to 3 times higher than a single 100 mg oral dose [276], so dividing the daily dose can make a big difference. In human COPD patients, [263]
administered 100 mg .. oral almitrine dimesylate daily for 1 year and at year end mean plasma [almitrine] was 409.35 ng/ml, trough plasma [almitrine] was 301.8 ng/ml (doesn't comment on any side-effects observed or lack thereof, was a purely pharmacokinetic study). In human COPD
patients [277], 100 mg oral almitrine dimesylate daily for I year increased the occurrence, compared to placebo control, of a nervous system disorder by 4%, paraesthesia by 5% and polyneuropathy by 3.6%. Anyhow, I will now discuss how almitrine associated peripheral neuropathy is probably more prevelant in COPD than cancer patients, thence is less of a concern in cancer patients.
Greater incidence of peripheral neuropathy is observed in almitrine than placebo administered COPD patients [265]: 9% greater chance of peripheral neuropathy in COPD
patients administered almitrine than placebo [278]. However, a complicating issue is that COPD itself is associated with sub-clinical (93.8% [279], 60-87% [280], 58-95%
[281] 87%
[283], 58% [284], 4% [285] incidence in COPD patents), and even clinically evidential (40%
[280], 7-88% [281], 87.5% [282], 17% [283], 7% [284], 20% [285] incidence in COPD
patents), peripheral neuropathy. Plus, there is wider evidence to suggest that hypoxia, which is of course symptomatic of COPD, can cause peripheral neuropathy [286, 287].
So, it might be that almitrine doesn't cause peripheral neuropathy per se, but that it unmasks/increases COPD driven peripheral neuropathy, perhaps in some cases elevating it from sub-clinically evident (e.g. in electrophysiological recordings, reduced nerve conduction velocities etc.) to clinically evident (patient complains of neuropathic pain etc.). Thus, I
anticipate that almitrine used for a different disease, e.g. cancer, which isn't characterised by poor 02 delivery to normal body tissues, will have a lower incidence of peripheral neuropathy than its use for COPD: much lower frequency of incidence, and much longer duration of use (therapeutic window), before any neuropathic onset. Thus, the risk-reward benefit for almitrine cancer treatment might be even greater than the present data would at first glance suggest.
Many COPD patients are or were smokers, often heavy. Indeed, in many patients smoking is the drive to their COPD. Moreover, smoking constricts blood vessels, driving hypoxia, and contains many harmful chemicals, and smoking and peripheral neuropathy are correlated in COPD patients [283] and a wider patient set (smokers reporting to the hospital for any reason were investigated) [288]. Few of the clinical studies, used by [257] to appraise almitrine use for COPD, wherein [257] recommended almitrine withdrawal, control for smoking, past or present, which is an oversight, and merits re-appraisal, which can't be done in most cases because the constituent clinical studies didn't document the smoking frequency/history of their particpants (at least this isn't reported in their publications).
Moreover, because the almitrine group is larger than the placebo group in most of these studies/pooled studies [278], if a given percentage of trial participants smoke or have smoked (likely to be high in COPD

patients), there will be a higher percentage of trial smokers in the almitrine than placebo group. Nor do these almitrine clinical studies control for alcohol intake, which also predisposes to peripheral neuropathy (alcoholic polyneuropathy), wherein a COPD patient set is likely to have a disproportionate number of heavy drinkers than general population because smoking is a strong drive to COPD and smokers are disproportionally alcohol drinkers e.g.
refer [289]. Nor do they control for diabetes, which correlates with COPD
(COPD patients have higher diabetes prevelance than general population [290]), wherein diabetes is associated with neuropathy [286, 287].
Peripheral neuropathy incidence in almitrine dimesylate administered COPD
patients is low (and might be even lower, as explained prior), only occurs after prolonged administration (mean onset = 11 months into the almitrine administration [257], therapeutic window) and in most cases is reversible, in the minority of cases that it occurs. Plus, it might be even less frequent/serious in cancer than COPD patients (as prior explained). So, almitrine conferred peripheral neuropathy is much less prevelant/serious than Chemotherapy Induced Peripheral Neuropathy (CIPN), which occurs in 71-96% [291]/52.7% [292]/68.6% [293] of patients who receive chemotherapy, 68.1% have it from the 1st month of chemotherapy treatment [294], wherein CIPN is irreversible in many cases [292], greatly diminishing the quality of life of cancer survivors (cancer patients rank CIPN near the most intense pain imaginable, 8 or 9 on a 10-point scale, "like walking on shards of glass or hot coals"
[295]). Carboplatin produces peripheral neuropathy in 49% of cancer patients [292], whereas almitrine dimesylate produces a much lower incidence of peripheral neuropathy (reversible, only after prolonged use), wherein almitrine dimesylate exerts greater anti-cancer activity in standardised testing (at 10 NI) than carboplatin (compare Figures 1 and 7A):
almitrine =
less side-effects + more potent anti-cancer activity = better anti-cancer drug. Furthermore, chemotherapies deliver many further, horrific side-effects, which almitrine doesn't. Indeed, in some cases chemotherapy, rather than cancer, kills cancer patients [296]. That is how toxic chemotherapies in present use are. Almitrine dimesylate, with its anti-cancer activity and low side-effect profile vs. chemotherapy, will help many cancer patients. For example, firstly, the many that withdraw from chemotherapy because of its horrific side-effects and whose present prognosis is stark. With the widespread problem of cancer resistance to present chemotherapies, which kills many, any new cancer drug is a blessing, especially one so structurally distinct, and targeting a target so different, from other cancer drugs, as is the case with almitrine.

For the minority of almitrine administered patients that do present peripheral neuropathy, and for those that don't (i.e. proactive treatment), an invention embodiment is to administer a treatment(s) sanctioned for treating peripheral neuropathy. For (non-limiting) example, a .. treatment(s) that is, or has been, used for CIPN and/or diabetic neuropathy e.g. (non-limiting) one or more of duloxetine (a preferred embodiment, [297]), a tricyclic antidepressant(s), pregabalin, venlafaxine, carbamazepine, oxcarbazepine, amifostine, Org 2766, zonisamide, gabapentin, lamotrigine, prednisone, baclofen, am itriptyline, ketamine, intravenous calcium and/or magnesium, glutathione, amifostine, glutamine, acetyl-L-carnitine, alpha-lipoic acid, acetylcysteine, diethyldithiocarbamate, vitamin E, vitamin B6, valproate, interleukin-6, capsaicin cream, tapentadol, lidocaine patches, topical menthol, a topical analgesic(s), an alpha-2-delta antagonist(s), an antiepileptic/anticonvulsant drug(s) (AEDs), a serotonin-norepinephrine reuptake inhibitor(s) (SNRIs), a tricyclic antidepressant(s) (TCAs), an opoid(s), morphine sulfate, oxycodone, botulinum toxin, acupuncture, scrambler therapy, cannabis, THC, transcutaneous electrical nerve stimulation (TENS), interferential current (IFC), medical device(s).
Almitrine's anti-cancer activity was unknown prior to my work, despite almitrine being around since the early 1970s, approaching 50 years ago. Its anti-cancer activity is unexpected to a person of the art. Especially because another respiratory stimulant, doxapram, has been publically shown by others to have no anti-cancer activity in the same one-dose (10 M) NCI-60 test in which, disclosed herein, almitrine dimesylate (10 M) exerts anti-cancer activity. Doxapram in NCI-60 (10 pM) testing: mean % cancer growth inhibition = -3.7%
(median = -2.3%) i.e. negative numbers show cancer growth promotion (!) rather inhibition, as compared to no drug control, NSC: 760347 in [16]. Thence, the discovery of almitrine conferred anticancer activity, disclosed herein, is unforeseen by a person of the art, novel and componentry to the invention of this disclosure. The risk-reward axis for almitrine is sufficient, indeed it is excellent, for an anti-cancer drug. Especially when used acutely, because most of almitrine's side-effects only occur with chronic use. Acute almitrine use for .. cancer treatment has a different risk-reward axis than chronic almitrine use for COPD
treatment (for which it is ineffective [257]), especially because almitrine's side-effects are mostly associated with chronic use, and because cancer can be an immediately life-threatening disease for too many patients, with too few life-saving options, wherein present treatments typically have absolutely horrendous side-effects ("after a few courses, Tim only needed to see the drip coming towards him down the corridor to trigger aggressive and relentless vomiting", Cancer Research UK article on "Our milestones:
Cisplatin" [298], one of, if not the most, widely used cancer drug today). Indeed, the merit of anti-cancer treatment merits the risk of higher almitrine dosages than 200 mg per day.
Intravenous delivery of 459 155 mg almitrine dimesylate, infused within 24 hours, caused reversible lactic acidosis and hepatic dysfunction in 30% of 25 patients [299]. The other 70%
of patients had no ill effects, and unaltered plasma [lactate]. The side-affected minority correlated with an impaired liver function parameter, increased plasma [bilirubin], prior to almitrine administration. Thus, this side-affected cohort is largely predictable. Most side-affected were women, but not all women were affected (N.B. women can have a smaller liver relative to body size e.g. refer [300]). The liver converts lactate to glucose by the Cori cycle [1] and an impaired/overwhelmed liver cannot process the elevated plasma lactate that almitrine administration can cause [252], which renders lactate acidosis. An embodiment of this invention is to select a cancer patient's almitrine dosage dependent upon their liver function. That is, in a further (non-limiting) embodiment, assessed by measuring plasma [bilirubin]. For non-limiting example: if (plasma [bilirubin] > 17 M) {the patient should not be administered high almitrine dosage(s)}. Patients with better liver function are at less risk of almitrine driven lactic acidosis [299] and can endure higher almitrine dosages. Another embodiment is to record plasma [lactate], and/or a liver function assay chemical(s) (non-limiting e.g. bilirubin), whilst a cancer patient is administered with almitrine, or a course of almitrine administrations, and to lower the administered almitrine dosage/frequency if these plasma concentrations become abnormal. An invention embodiment is to use almitrine, and a drug(s)/treatment(s) treating/mitigating lactic acidosis (e.g. sodium dichloroacetate, DCA, which also has reported anti-cancer activity [47]), in anti-cancer therapy.
Another embodiment is almitrine for anti-cancer therapy, given with a dosage adjustment dependent upon initial body weight, before treatment, and optionally reducing the dosage if significant weight loss occurs. Almitrine in co-therapy with a high(er) calorie diet, as an anti-cancer treatment, is another embodiment. Almitrine in co-therapy with a drug to treat or mitigate peripheral neuropathy (e.g. {non-limiting} gabapentin, duloxetine, pregabalin etc.), as an anti-cancer treatment, is an embodiment of this invention. An embodiment is to use almitrine for anti-cancer therapy and to monitor the almitrine recipient, or for the almitrine recipient to self-monitor, for weight loss and/or signs of neuropathy, and/or odd neurological sensations, especially in the body periphery e.g. the limbs. An embodiment is to use almitrine for anti-cancer therapy under medical supervision. Wherein, in animal or human, almitrine dosage, frequency, route and duration of administration is directed/recommended, and/or almitrine is administered, by a medically qualified professional(s) e.g. a doctor or vet or nurse or pharmacist. In an embodiment, an oncologist or other cancer specialist or a medically qualified professional that has undergone additional training and/or qualification and/or residency in oncology beyond a degree in human and/or veterinary medicine. And optionally wherein one or more of the dosage, frequency, route and duration of almitrine administration is modulated in the light of cancer progression/regression/stasis during the course of almitrine administration.
Mechanistic studies in animals [301-302] have identified that it might not be almitrine itself that causes almitrine associated neuropathy but instead difluorobenzhydrylpiperadine (DFBP), which is the major almitrine metabolite formed in humans. DFBP also causes weight loss in [301] and so DFBP could also be the basis to almitrine associated weight loss (reported in [257]), or this could just be a function of altered feeding behaviour as a function of the DFBP generated neuropathy. To render DFBP from almitrine, the bond between almitrine's nitrogen, at atom number 11, and carbon, at atom number 9, must be broken. An embodiment of this invention is almitrine isotopically enriched (greater than natural abundance, e.g. {non-limiting} >70%) for 15N at Atom Number 11, and/or isotopically enriched for '3C at Atom Number 9 (can be done, to illustrate and not limit, by substituting cyanuric chloride-'3C3 {CAS: 286013-07-8; available from Sigma-Aldrich} for cyanuric chloride in almitrine synthesis, to give almitrine enriched at three carbon positions with '3C, including at Atom Number 9), which will make this bond stronger by the kinetic isotope effect (KIE), which will reduce the rate of DFBP formation, and reduce neuropathy (Atom Numbers as labelled by [25]). Kinetic isotope effect (KIE) is the change in the rate of a chemical reaction when one (or more) of the atoms in the reactants is replaced with its isotope. Heavier isotopes form stronger bonds that require higher energy to break them, which ultimately slows down the chemical reaction rate. Other atom(s) of almitrine enriched (greater than natural abundance, e.g. {non-limiting} >70%) with their heavier, stable respective isotope(s) (e.g. {non-limiting} 2H replacements of 'H) is also componentry to the present invention. As is one or more hydrogen atom(s) upon almitrine, or an aforementioned almitrine isotopologue, replaced by fluorine (or other halogen), especially near the N11-C9 bond that breaks to release DFBP, preferably upon the piperazine ring. The use of one or more of the new compositions of matter of this disclosure, to treat a condition for which almitrine has been used in humans, for (non-limiting) example, chronic obstructive pulmonary disease (COPD), is componentry to this invention. As is their use as an anti-cancer treatment.
Following reactions are illustrative, not restrictive: almitrine could be deuterated, upon its piperazine ring and/or other loci, by reactions described in [N], which deuterate sp3 carbons.
And/or by reactions described in [RI, R2, Q1, Q2] which deuterate widely, upon aromatic and alkyl molecular components. And/or by reactions described in [01, 02], which deuterate a- and 0-carbons to phenyl groups. And/or by reactions described in [D], which deuterate a-and 0-carbons to tertiary amines. And/or by reactions described in [F, El, E2, Exl], which deuterate a-carbons to tertiary amines. And/or by reactions described in [A, B, El, E2, F], which deuterate a-carbons to secondary amines. Whichever option(s) is chosen, solvents, temperatures, pressures, and other reaction conditions can be selected by one of ordinary skill in the art. Deuteration can be modulated by modulating reaction time: greater deuterium incorporation by longer reaction time. One can do multiple cycles of one or more of these reactions until the desired level of deuterium incorporation occurs, monitored by 1H and/or 2H NMR and/or mass spectrometry.
Encompassed by this invention are methods of administering an effective amount of almitrine (and/or one or more of its metabolites or derivatives), or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising almitrine (and/or one or more of its metabolites or derivatives), optionally in co-therapy with another anti-cancer treatment(s) including radiotherapy, to treat/ameliorate/prevent/combat cancer in a subject. Encompassed by this invention are methods of administering an effective amount of GAL021 [268-269] and/or any compound(s) of [P8-12], or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising GAL021 [268-269] and/or any compound(s) of [P8-12], optionally in co-therapy with another anti-cancer treatment(s) including radiotherapy, to treat/ameliorate/prevent/combat cancer in a subject. Encompassed by this invention are methods of administering an effective amount of doxapram, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising doxapram, optionally in co-therapy with another anti-cancer treatment(s) including radiotherapy, to treat/ameliorate/prevent/combat cancer in a subject. Encompassed by this invention are methods of administering an effective amount of a (e.g. chemoreceptor) respiratory stimulant(s), or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising a respiratory stimulant(s), optionally in co-therapy with another anti-cancer treatment(s) including radiotherapy, to treat/ameliorate/prevent/combat cancer in a subject. Encompassed by this invention are methods of administering an effective amount of a compound(s) that increases p02 in the subject's blood, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising a compound(s) that increases p02 in the subject's blood, optionally in co-therapy with another anti-cancer treatment(s) including radiotherapy, to treat/ameliorate/prevent/combat cancer in the subject.
A method of treating, ameliorating, preventing or combating cancer in a subject wherein the method comprises the subject taking, or being administered, a therapeutically effective amount of almitrine and/or other compound(s) of Formula VI (and/or a pharmaceutical composition(s) containing a therapeutically effective amount of almitrine and/or other compound(s) of Formula VI herein). Almitrine and/or other compound(s) of Formula VI, .. (and/or a pharmaceutical composition(s) containing almitrine and/or other compound(s) of Formula VI) for use in the treatment/amelioration/prevention/combat of cancer in a subject.
The use of almitrine, and/or other compound(s) of Formula VI, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of cancer, optionally in a ready-to-use drug form, optionally in a package together with instructions for its anti-cancer use.
Almitrine, and/or other compound(s) of Formula VI, for use in a method for the treatment/amelioration/prevention/combat of cancer and/or ischemia and/or stroke (reduces ATP hydrolysis and maintains intracellular [ATP] when 02 and glucose is in short supply because of a vascular occlusion or similar) in a subject.
An invention embodiment is a pharmaceutical composition comprising a therapeutically effective amount of almitrine and a fatty acid(s), wherein the scope of what is a fatty acid is well known to those of the art. For non-limiting example, wherein almitrine and a fatty acid are in a 1:2 ratio. Other stoichiometries/ratios are also componentry to the present invention.
For example, a 1:1 almitrine to fatty acid ratio. Some fatty acid(s) can exert anti-cancer activity (illustrative literature: [303, 304]) and in preferred embodiments almitrine is combined in a composition(s) with a fatty acid(s) that exerts anti-cancer activity, and in more preferred embodiments the anti-cancer activity of almitrine and fatty acid(s) synergise. The greater the anti-cancer activity of the fatty acid(s) the more preferred the embodiment of its formulation with almitrine. In a further embodiment, an almitrine and fatty acid(s) containing composition(s) is used in a method of treatment of the human or animal body by therapy, for (non-limiting) example to treat/ameliorate/prevent/combat cancer in a subject.
In another embodiment, an almitrine and fatty acid(s) containing composition is used for the manufacture of a medicament for the treatment/amelioration/prevention/combat of cancer. An invention embodiment is almitrine in a 1:2 stoichiometry with 9Z,1 1E
conjugated linoleic acid (Rumenic Acid), which is an example of a fatty acid with anti-cancer activity [lips2]. In other illustrative example embodiments almitrine is in a 1:2 stoichiometry with Eicosapentaenoic Acid, or Docosahexaenoic Acid, or Erucic acid. Example embodiment:
FJF
H30,, 01-i3 N N
o N N N
OH
HO

In some embodiments, almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is used as an adjuvant or neoadjuvant to another cancer treatment(s) e.g. used as an adjuvant to chemo and/or radiotherapy e.g. used as a chemosensitizer and/or radiosensitizer/radioenhancer. Many conventional [chemo/radio] therapies act against cancer, wholly or in part, by increasing [ROS]. Indeed, radiotherapy [305] and chemotherapy [306, 307, 308] increase [ROS] in cancer cells. A mechanism that cancers use to mitigate and counteract this [ROS] increase is greater FiFo ATP hydrolysis, consuming ATP, which releases glycolysis from ATP feedback inhibition, permitting higher glycolytic and pentose phosphate pathway rate, more NADPH produced and thence greater ROS mitigation.
Almitrine slows Fi Fo ATP hydrolysis, reducing ROS mitigation and this assists the anti-cancer activity of chemo/radio therapy. Almitrine also increases blood and tissue p02, increasing ROS production. So, almitrine combats tumor hypoxia, wherein this hypoxia can be a drive to radio- [305] and chemo- [sens5, sens6] resistance of cancer. In some embodiments the anti-cancer activity of almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof, synergises with (potentiates) the anti-cancer activity of an FDA and/or EMA approved anti-cancer treatment(s) e.g. one or more of chemotherapy, radiotherapy, immunotherapy, surgery, immune-oncology, radioimmunotherapy, biological therapy, hormone therapy etc. In other words, in some embodiments, the combined anti-cancer effect of almitrine and another cancer treatment(s) is greater than the sum of each alone. In some embodiments, almitrine administration enables the same or greater anti-cancer activity to be exerted by another anti-cancer treatment(s) but with lower radiative (e.g. x-ray, y ray, electromagnetic radiation, radioactivity etc.) and/or drug(s) exposure, e.g. lower radio-and/or chemo- therapeutic(s) dose, most preferably enabling a lower side-effect profile.
Encompassed herein is a method of reducing, treating and/or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, chemotherapy, radiotherapy, immunotherapy, wherein almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof, is administered to a subject prior to, during, or after the occurrence of the adverse effect associated with conventional therapy, optionally wherein the dosage/frequency/use of the conventional therapy is decreased. In some embodiments, almitrine is used in co-therapy with cisplatin and/or carboplatin and/or some other platinum based therapeutic(s) for anti-cancer treatment in a subject, and in further embodiments their anti-cancer activities synergize. In some embodiments, almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is used in co-therapy with radiotherapy for anti-cancer treatment in a subject, and in further embodiments their anti-cancer activities synergize. In some embodiments, almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is administered alongside radiotherapy to treat radioresistant cancer(s) and/or alongside chemotherapy to treat chemoresistant cancer(s).
In some embodiments, almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is administered/prescribed for anti-cancer therapy in a subject(s) at King's College Hospital, London, and/or another National Health Service (NHS) hospital/location and/or by an NHS employee(s) and/or in a country where almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is, or is not, available for prescription/administration by a medical practitioner(s). The i.v. dose of almitrine used in clinical practice at King's College Hospital (London, UK) is 8 tig/kg/min for COPD and 4-16 tig/kg/min for Acute Respiratory Distress Syndrome (ARDS) [271]. Intravenous, as opposed to oral, administration of almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof can be advantageous for anti-cancer therapy in a subject, especially in clinical trialing, because subject variability in oral bioavailability of almitrine is rendered irrelevant. An aspect to this is that, unlike oral administration, i.v.
dosing, if sufficiently large, permits one to know precisely when peak plasma [almitrine] occurs in each subject. It being at the final time point of i.v. administration. This is useful when almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is administered with radio- and/or chemo- therapy and maximal therapeutic synergy is desired. For example, if radiotherapy can't be administered during, it should be administered as soon as possible after, the i.v. administration of almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof. The shorter the delay between the end of i.v. almitrine administration and the start of radiotherapy, the more preferred the embodiment. Most preferred is the delay is zero and they are concurrent. During concurrent administration, radiotherapy preferably starts after the start of i.v. almitrine administration, to permit a build up of [almitrine] in the tissues .. before radiotherapy commences.
In humans, [266] infused ¨7.47 g/kg/min for 2 hours, delivering 60 mg almitrine dimesylate, wherein the mean almitrine plasma level in the subjects was 327 ng/ml at the end of the infusion period (lowest observed = 242 ng/ml), which then fell to to 157, 154, 105, 67, 55 ng/ml, at 15, 30, 60, 120, 600 minutes afterwards respectively. In humans, [312] infused 8 g/kg/min for 20 minutes during which the mean plasma concentration of almitrine was 325 ng/ml. In humans, [313] infused 8.3 g/kg/min for 30 minutes, wherein "no adverse side-effect was observed during or after the administration of almitrine". In humans, [314] infused 16 g/kg/min for 1 hour, during which plasma almitrine concentration rose to be greater than 600 ng/ml in all subjects, much greater in some subjects (-1,600 ng/ml highest observed), and by 2 hours after the infusion stopped, this had fallen to below 400 ng/ml in all subjects but one, and by 12 hours was below 200 ng/ml in all. In humans, [315] infused 16.7 g/kg/min for 1 hour "without deleterious effects". In humans, [316] infused 16 g/kg/min = and 20 minutes into this infusion the mean plasma concentration of almitrine was 659 ng/ml, wherein "plasma lactate concentrations remained within the normal range in all patients".
There are many more human studies in the literature wherein ¨16 or 16 g/kg/min is infused, and many more wherein less is infused. Someone of the art will know how to find all these. A
fraction, but by no means all, are listed and usefully compared in a table in [270]. In humans, [3 1 7] infuses a higher rate than ¨16 g/kg/min, = 25 g/kg/min for 1 hour.
[270], a French regulatory review document for injectable almitrine, states "maximum recommended flow-rate: 15 mg/minute", which corresponds to a flow rate of 242 g/kg/min for a 62 kg human.
In humans, [318] gave a rapid intravenous (bolus) injection of 0.5 mg/kg, followed by infusing 2 mg/kg (corresponds to 16.7 g/kg/min for a 62 kg human) for 2 hours, giving 2.5 mg/kg (corresponds to 155 mg for a 62 kg human) in just ¨2 hours. 200 mg (=3.23 mg/kg for a 62 kg human) almitrine dimesylate orally per day has clinical precedent [257], as does an i.v. infusion rate of 16 g/kg/min [271]. Combining these, one arrives at a daily i.v. infusion of 16 g/kg/min for 202 minutes (3 hours and 22 minutes) to deliver 200 mg to a 62 kg human. Because, on average across subjects, only 85% [260] of the oral dose is bioavailable, .. this oral dose can actually be approximated (in a 62 kg human) by a daily i.v. infusion of 16 g/kg/min for 171 minutes (2 hours and 51 minutes). To illustrate, and not restrict, to deliver this same dose (to a 62 kg human) of almitrine dimesylate by continuous i.v., with an infusion rate of 8, 32, 64 g/kg/min would take 5.7, 1.43 and 0.71 hours respectively.
Optionally, infusion time can be shortened by injecting a proportion of the daily dose as i.v.
bolus, optionally preceding the steady infusion. So, to illustrate, if 15 mg was administered by a preceding i.v. bolus (permissible by "maximum recommended flow-rate"
instruction of [2701) then the duration required (in a 62 kg human) to replicate a 200 mg oral dose (factoring in bioavailability issue) would be 159 minutes of 16 g/kg/min continuous i.v.
infusion. In some invention embodiments, almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is administered orally and by i.v. in combination to treat/ameliorate/prevent/combat cancer in a subject. So, to illustrate (not restrict), per day, 100 mg is administered orally and 100 mg is administered intravenously by 16 g/kg/min for (in a 62 kg human) 101 minutes, 86 minutes if 15 mg of the i.v. dose is given by bolus.
Optionally, the oral and i.v. administrations are timed so that as the i.v.
administration finishes, and as plasma [almitrine] from the i.v. dose declines, almitrine from the oral dose enters the bloodstream to buoy/increase plasma [almitrine]. Figure 3.3. in [266] shows (data normalised to a 1 mg/kg dose) that the gradient of increase in plasma [almitrine] in the first 3 hours after an oral almitrine dose is similar to the gradient of decrease in plasma [almitrine]
in the first 3 hours after an i.v. dose of almitrine terminates. So, administering oral almitrine .. as i.v. almitrine administration finishes can act to buoy/increase plasma [almitrine] for a longer period of time. This is very useful if the subject is to undergo radio-and/or chemo-therapy afterwards, wherein a high plasma [almitrine] is desired to gain the maximal additive/synergistic anti-cancer effect. All aforementioned dosages, routes/patterns of administration and infusion rates of almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, in use for anti-cancer therapy/treatment in a subject, are componentry to the present invention. As are others, which are also contemplated by the scope of this invention. For example, the administered daily dosage could be greater than 200 mg. Indeed, relevantly, 400 mg oral almitrine dimesylate per day has been shown safe in healthy subjects, at least for the duration of that study [259]. Or the administered dosage could be less.
Intravenous infusion of 5.5 ( 1.7) g/kg/min almitrine dimesylate, in co-therapy with inhalation of nitric oxide (5 p.p.m.), increased arterial p02 by >30% across all subjects [311].
There are many similar papers in the literature, describing co-administration of almitrine and NO, which can be found readily by someone of the art. In some invention embodiments, almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof is administered, optionally intravenously, in co-therapy with nitric oxide (NO), optionally breathed, to treat/ameliorate/prevent/combat cancer in a subject, optionally in co-therapy with .. radio- and/or chemo- therapy, wherein the almitine and NO combination increases the subject's blood and tissue p02, which makes radio- and/or chemo- therapy more effective, adding to/synergising with the inherent anti-cancer activity of almitrine. At any point that almitrine administration is referred to in the disclosure, in further embodiments of this invention, NO is administered also.
Componentry to this invention is administering an i.v. bolus dose of almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof for anti-cancer therapy in a subject, optionally wherein the subject has lung cancer, and optionally wherein the almitrine concentration in the body is subsequently increased/prolonged by a subsequent period(s) of continuous i.v. infusion (optionally where the infusion rate equals/approximates the almitrine elmination rate) and/or one or more oral administrations of almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof (non-limiting e.g. tablet and/or solution). Optionally, wherein a foundational concentration of almitrine in subject plasma has been built up, prior to the i.v. dose of almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, by one or more oral and/or i.v.
doses of almitrine or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally administered on the same day and/or at some regular/irregular frequency, e.g.
daily, in the day(s)/week(s)/month(s) before. Faster almitrine build up in the body can be achieved by dividing the daily dose up into multiple smaller doses, e.g. (non-limiting) 200 mg per day is administered by 100 mg administered twice per day, which means the build up period can be shorter.
At every point that radiotherapy is referred to in this disclosure, it encompasses all that a person of the art would expect it to. Including, without limitation, external (including, without limitation, one or more of external beam radiation therapy {e.g. using photons/electrons/hadrons/protons/neutrons/ions/nuclei etc.}, stereotactic body radiation therapy [SBRT], radiosurgery, 3-dimensional conformal radiation therapy, image-guided radiation therapy, intensity-modulated radiation therapy, tomotherapy, volumetric modulated arc therapy, particle therapy, proton therapy, neutron capture therapy, auger therapy) and/or internal (including, without limitation, one or more of brachytherapy, unsealed source radiotherapy, intraoperative radiotherapy, deep inspiration breath-hold, selective internal radiation therapy) radiotherapy. Moreover, when radiotherapy is referred to in this disclosure it encompasses radiotherapy with or without the co-administration of excess oxygen, wherein the subject breathes gas with a greater 02 fraction than normal air at that altitude, optionally pure 02, optionally the subject is administered hyperbaric 02 therapy. An embodiment of this invention is to administer almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof to a subject with cancer, optionally lung cancer, either orally and/or by i.v.
(bolus and/or continuous) and/or by some other administration route, prior (on the same day and/or on prior day[s]) and/or during and/or after radiotherapy and/or chemotherapy. In some embodiments, almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof is i.v. administered (bolus and/or continuous) before, during and after the subject undergoes radiotherapy and/or chemotherapy (optionally administered by i.v.
also, bolus and/or continuous, in a separate or same infusion line to the subject), alternatively only before, or only during or only after, alternatively only before and after, alternatively only before and during, alternatively only during and after. In some embodiments, the administered almitrine enables a lower radiative/ionizing/chemotherapeutic(s) dose to be used to convey therapy. Optionally, it permits the same radiative dose to be used but over a longer timeframe, so the radiative intensity (per unit time) is less.
Alternatively, the same radio- and/or chemo- therapy dose is used and greater therapeutic effect ensues. In a further embodiment, the subject has cancer and in more particular embodiments, the subject has lung cancer. In some invention embodiments a high g/kg/min i.v. infusion rate, e.g. >8 g/kg/min or ?16 g/kg/min or _>_64 mg/kg/min, of almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof is delivered to a subject, optionally that has cancer, optionally lung cancer, prior and/or during and/or after radiotherapy and/or chemotherapy. A
high infusion rate (by bolus only, or bolus+continuous, or continuous only) optimizes for all, or a significant proportion of, the daily almitrine dose, which in an embodiment is 200 mg but in other embodiments is higher or lower, being inside the subject at or around the time that radiotherapy and/or chemotherapy is administered, which gives the best opportunity for therapeutic synergy to occur. In some embodiments, i.v. (bolus and/or continuous) almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof is administered preceding radio- and/or chemo- therapy and when this i.v. administration is stopped an oral dose of almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof is administered so that the amount of almitrine entering the bloodstream from the oral dose partially/completely/exceeds the amount of i.v. dose almitrine eliminated from the body, which buoys the plasma almitrine concentration, which gives greater opportunity for anti-cancer therapeutic synergy between almitrine and radio- and/or chemo- therapy.
In some embodiments, on days that the subject is administered radio- and/or chemo-therapy, all or some of the daily dose of almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof is administered by i.v. (bolus and/or continuous), preferably near in time to the radio- and/or chemo- therapy, the nearer in time the better, most preferably coincident in time (for continuous i.v. infusion) or just before (for i.v. bolus only) or starting just before (for i.v. bolus followed my continuous i.v. infusion and/or oral administration), and, optionally, on days that the subject is not administered radio- and/or chemo-therapy, the daily dose of almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof is absent or administered/taken orally, which the subject can do easily outside of a medical facility e.g. at home. So, for non-limiting example, during a daily course of radiotherapy and/or chemotherapy the subject receives almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof by i.v. (bolus and/or continuous) and when this course of radiotherapy and/or chemotherapy pauses or finishes, and/or before it starts, the subject receives almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof, optionally daily, orally, for a duration decided by a medical practitioner(s) and/or the subject.
For i.v. administering almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof, and/or one or more chemotherapeutics (e.g. cisplatin, carboplatin etc.), during radiotherapy an uncharacteristically long i.v tube is preferable to keep the bulk of the i.v. equipment further away from the radiotherapy beam, most preferably wherein it is located behind some shielding. Optionally its radioactivity, or lack thereof, is regularly checked (e.g.
using a Geiger counter and/or using some radioactivity sensor that stays on the equipment always {e.g. similar to that worn by workers that work in radioactive risk settings e.g. a dosimeter)), in an embodiment, before each use, and if too high, it is replaced with new equipment. In some embodiments, radioactive/electromagnetic/ionizing shielding is incorporated into the equipment itself. Preferably, the i.v. administration site(s) upon the subject shouldn't be directly under the radiotherapy beam and should be appropriately shielded as much as possible. In some embodiments, multiple i.v. lines are incident upon the subject undergoing radiotherapy, optionally wherein different chemotherapeutics are adminstered by the different lines, optionally wherein one or more i.v. lines administer almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof.
In some embodiments, almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof is i.v. administered (bolus and/or continuous), optionally in the same i.v, infusion, with one or more chemotherapies to a subject with cancer, optionally a lung cancer patient. In some embodiments, the timing of administering almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof (e.g. oral or i.v. [bolus and/or continuous]), and the timing of administering one or more chemotherapies (e.g. oral or i.v.
[bolus and/or continuous]), is coordinated so that peak plasma almitrine concentration occurs at the same time as the peak plasma concentration of chemotherapeutic(s), whereupon optionally, at this peak time, radiotherapy is administered.
In some embodiments, almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof is orally administered before and/or during and/or after the subject, who in a further embodiment has cancer, optionally lung cancer, undergoes radiotherapy and/or chemotherapy; most preferably this oral almitrine is administrated before radiotherapy and/or chemotherapy and in further embodiments the timing of this oral almitrine administration vs.
timing of radiotherapy and/or chemotherapy is co-ordinated so that the peak plasma concentration of almitrine occurs during or near in time to the radiotherapy and/or chemotherapy (N.B. in human, peak plasma concentration of almitrine occurs 3.5 0.7 hours after consuming almitrine dimesylate, absorption is improved by eating food [266]). In further embodiments, an oral course (e.g. daily, or other frequency) of almitrine administration, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof, is started days/weeks/months before a course of radiotherapy and/or chemotherapy starts, to build up a foundational level of almitrine inside the subject, and in further embodiments oral almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof continues to be administered during the course of of radiotherapy and/or chemotherapy and, in further embodiments, afterwards also. Before radio- and/or chemo- therapy, the number of days and the timing/frequency/dose of almitrine administered, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof, is optimized so that the plasma concentration of almitrine in the subject is suitably high (in some embodiments, to illustrate and not restrict, >300 ng/ml and/or >200 ng/ml) before radio- and/or chemo- therapy starts, wherein in a further embodiment the plasma concentration of almitrine in the subject is recorded to make sure. If not, the same or increased dose of almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof is administered/taken to/by the subject, optionally more frequently, for a further time period before radio- and/or chemo- therapy commences.
In some invention embodiments, a therapeutically effective amount of almitrine or a pharmaceutically acceptable salt, solvate, hydrate, prodrug thereof, and/or an almitrine containing pharmaceutical composition, is administered to treat/ameliorate/prevent/combat cancer in a subject, optionally lung cancer, optionally Non-Small Cell Lung Cancer (NSCLC), optionally lung adenocarcinoma, optionally a PET positive cancer, optionally in co-therapy with radiotherapy, optionally wherein almitrine makes the cancer more radiosensitive/less radioresistant and/or the anti-cancer activities of almitrine and radiotherapy add/synergize, optionally in co-therapy with one or more chemotherapies, optionally wherein almitrine makes the cancer more chemosensitive/less chemoresistant and/or the anti-cancer activities of almitrine and chemotherap[y/ies]
add/synergize, optionally in co-therapy with (without limitation) one or more of cisplatin, carboplatin, etoposide, gemcitabine, vincristine, vinblastine, paclitaxel, albumin-bound paclitaxel, vinorelbine, topotecan, irinotecan, temozolomide, docetaxel, pemetrexed, erlotinib, brigatinib, gefitinib, lorlatinib, afatinib, alectinib, denosumab, ipilimumab, pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentriq), durvalumab, dacomitinib, osimertinib, tivantinib, onartuzumab, sorafenib, crizotinib, ceritinib, trametinib, dabrafenib, bevacizumab (avastin), exisulind, bexarotene, cetuximab, squalamine, necitumumab, cyclophosphamide, ramucirumab, doxorubicin, porfimer, methotrexate, an FDA and/or EMA approved drug(s) or treatment(s) for lung cancer (including, without limitation, radiofrequency ablation, microwave ablation, cryoablation, thermal ablation, chemoembolization), optionally with plasma [almitrine] and/or [lactate] and/or [bilirubin] recording(s) before and/or during the course of almitrine administration, wherein if these are abnormally/too high, almitrine administration is reduced/stopped/not commenced. Almitrine greatly assists the treatment/amelioration/prevention/combat of NSCLC, which can be very radio-(e.g. refer radioresistance of NCI-H460 cell line in [319]) and chemo- resistant, wherein almitrine undermines this resistance, enabling greater radio- and chemo- therapy to occur, improving the clinical outcome of the subject and/or their quality of life. It especially, without =
limitation, helps subjects with NSCLC that can't/won't undergo surgery, or whose cancer is inoperable, and who must completely rely on radio- and/or chemo- therapy for cancer treatment, wherein some NSCLC cancers are very radio- [319] and chemo-resistant and thence incredibly dangerous.
Almitrine is mentioned, in combination with a plant extracted compound, in the Simplified Chinese to English machine translation of CN105693806A [P13]. The "First Office Action"
from The State Intellectual Property Office of People's Republic of China for CN105693806A identifies that CN105693806A is not a teaching document because it presents exactly the same extraction protocol as another Chinese filing (CN201610258319) but wherein a very different compound is extracted, which is highly improbable, to the point of incredulity, as reported by the Chinese Examiner. Furthermore the anti-cancer data points (and even error bars) in CN105693806A are identical to that of CN201610258319, despite different compounds being tested, which is an extremely improbable result, again, to the point of incredulity, again, as identified by the Chinese Examiner, wherein and CN201610258319 were both filed on the same day (23/04/2016) by different inventors.
Furthermore, perversely, there are many other Chinese patent applications, from same and different inventors, many submitted on the same or within days of one another, that report the exact same protocol as CN105693806A for extracting very different compounds, which is extremely strange and improbable, again to the point of incredulity, as highlighted by the Chinese examiner of CN105693806A in their First Office Action report, wherein some of these other applications are listed. But there are many further such applications findable by one of the art (>100), and their examination reports typically identify fabrication in each case, while further identifying that this fabrication is componentry to a wider fabrication of multiple patent filings, with shared characterizing features (e.g. same extraction protocol used in every case). So there are many legal documents teaching one of the art about this iterated fabrication scheme, of which CN105693806A is apart. Refer, for non-limiting example, to the following filings and (especially) their Chinese Intellectual Property Office examination reports: CN201610111060 (CN105622711), CN201610157201 (CN105585609), CN201610167771 (CN105663143A), CN201610167879 (CN105837393A), CN201610168492 (CN I05777682A), CN201610172606 (CN105646642), CN201610203075 (CN105837656), CN201610263608 (CN 1 05884773A), CN201610331470 (CN I06008539A), CN201610331596 (CN106008542A), CN201610333811 (CN105906647A), CN201610334869 (CN105924339A), CN201610335078 (CN I 05859535A), CN201610335171 (CN105884792A), CN201610335324 (CN105906683A), CN201610338448 (CN105924413A), CN201610340391 (CN105949216A), CN201610343221 (CN 1 06008248A), CN201610473707 (CN106083988A), CN201610493013 (CN106046112A), CN201610580967 (CN106220702A). So, to recap, the Chinese examiner of CN105693806A concluded that CN105693806A is not a teaching document. CN105693806A is, or at least would be surmised by one of the art, to be a fabricated filing. There are motivations for fabricating a patent filing(s), for example in China, some of which are disclosed in this Economist magazine article [320]. In China "workers and students who file patents are more likely to earn a hukou (residence permit) to live in a desirable city", "for some patents the government pays cash bonuses", "corporate income tax can be cut from 25% to 15% for firms that file many patents" and "they are also more likely to win lucrative government contracts", "many companies therefore offer incentives to their employees to come up with patentable ideas", "the generosity of China's incentives for patent-filing may make it worthwhile for companies and individuals to patent even worthless ideas", "most of these patents are probably filed with the expectation that they will be ignored" [320]. Refer also to this Bloomberg article [321]. In short, the official Chinese Intellectual Property Office examination report (First Office Action) of CN105693806A, reporting that CN105693806A is not a teaching document, teaches away from CN105693806A.
EXAMPLE (VII) Formula (VII): Any amino acid sequence/protein/peptide/polypeptide/antibody, either naturally occurring or produced by engineering or fortuity, that preferentially/disproportionally/selectively inhibits the "reverse" ATP
hydrolysing mode as compared to the "forward" ATP synthesising mode of ATP synthase. Note that selectively inhibiting FIFO ATP hydrolysis can seemingly inhibit FiFo ATP synthesis because less ATP is made, but this is because less ATP is hydrolysed and so less ATP needs to be made, rather than any actual direction inhibition upon FIFO ATP synthesis. Preferred embodiments are those that inhibit the reverse mode of ATP synthase potently and the forward mode of ATP
synthase less potently, and most preferably not at all. If FiFo ATP synthesis falls because of inhibited FiFo ATP hydrolysis, and not primarily because of direct inhibition of FIFO ATP
synthesis, then this compound is still within the scope of this invention.
Componentry to Formula (VII) is one or more of melittin, the presequence of yeast cytochrome oxidase subunit IV and each synthetic derivative of this presequence ([4], incorporated in its entirety). Also componentry to Formula (VII) is one or more IF1 proteins from any eukaryote, and/or one or more of any IF1 subsequence e.g. any minimal inhibitory IF I sequence, which, for example, for bovine IF I is amino acid residues 14 to 47 [330, 331], and/or any IF1 protein variant especially wherein this variant has greater inhibitory potency against FIFO ATP hydrolysis, and/or one or more of any gene or nucleotide or DNA or RNA
that translates to one or more of any IF1 protein, IF1 protein variant, IF1 subsequence and IF1 subsequence variant. These examples just given, and further examples herein, for Formula (VII) are illustrative and not restrictive.
IF1 proteins are highly conserved and typically interchangeable between species [330]. An invention embodiment is an increased amount of IF1 protein in a subject, beyond normally occurring IF1 levels in a subject, and/or expression of an IF1 protein from a different species and/or an IF1 protein variant(s), and/or subsequence variant(s), most preferably one that has greater inhibitory action against FIR) ATP hydrolysis at normal matrix pH (-8) e.g. the H49K
(mature {mitochondrial import signal sequence cleaved off} IF1 protein numbering) mutant of bovine IF1 [330, 332], wherein methods of introducing genes and/or gene copies and/or DNA and/or RNA and/or proteins into a subject are well known to those of the art e.g. refer [322], which expresses H49K mutant human [Fl in mice (this amino acid substitution makes IF1 constitutively active at normal matrix pH {-8}). An invention embodiment is bovine IF I
expressed in a subject, wherein this IF1 has one or more of its histidine residues at positions His-48, 49, 55 changed to another amino acid, for example alanine or lysine.
In another embodiment, IF1 from a non-bovine species is expressed in a subject, wherein this 1F1 is changed at the equivalent histidine positions to those aforementioned in the bovine IF I
sequence (highly conserved across species, but not always with same amino acid numbering), which renders the IF1 with greater inhibitory potency against FIFO ATP
hydrolysis at normal matrix pH (-8) [330, 332]. A further invention embodiment is the expression of IF1 in a subject (a native IF1 sequence to a species or an altered [Fl sequence herein described) that has one or more amino acid changes that don't significantly alter its inhibitory potency against FIF0 ATP hydrolysis (could be termed neutral changes), and more preferably that increases its inhibitory potency against FiFo ATP hydrolysis.
Larger species have more IFI [330], and/or use an IF I variant that has greater inhibitory potency for FIR' ATP hydrolysis, a lower specific metabolic rate, less metabolic heat production per unit mass, and longer lifespan (Figure 24). Increasing the amount of IF1, and/or expressing an IF I variant that has greater inhibitory potency for FiFo ATP hydrolysis, decreases metabolic rate and extends lifespan, so long as exogenous heat substitutes for the lesser endogenous heat production, or greater body insulation (e.g. wearing more clothes) renders same body temperature for a lessor metabolic rate. An invention embodiment is to use an animal(s), whose quantity and/or nature of its IF1 is manipulated, in a lifespan and/or healthspan study, optionally entering it into a competition with a financial or other reward e.g. the M prize. To extend the lifespan of a subject, for example a mouse or human, increase the amount of its own IF1 sequence and/or express one or more of the IF1 sequence of a bigger and/or longer living species. The naked mole rat (Heterocephalus glaber) expresses ATPIF I five times more than the mouse [342], and lives ten times longer. An invention embodiment is to express the IF1 (National Center for Biotechnology Information [NCBI]
Gene ID: 101712500), and/or its further IF1 like gene (NCBI Gene ID:
110349814), of the naked mole rat in a homeothermic species to slow its metabolism and extend its lifespan, with the caveat that this species will now acquire some or all of the thermoconformer character of the naked mole rat and now must be kept at higher ambient temperature: naked mole rats can survive without homeothermy because they live in hot East African countries, permanently underground in burrows (wherein heat is maintained at night), even eating underground (tubers), and can behaviourally thermoregulate by choosing their depth in the burrow.
Any method wherein a compound(s), including protein and/or antibody compounds, that inhibits FIFO ATP hydrolysis is administered to a subject to increase/improve the subject's health, healthspan and/or lifespan, and/or to reduce/slow the signs/damage/maladies/diseases of aging, is componentry to the present invention.
For reference, human IF1 amino acid sequence, with pre-sequence (using one letter amino acid code; NCBI Gene ID: 93974):

MAVTALAARTWLGVWGVRTMQARGFGSDQSENVDRGAGSIREAGGAFGKREQAE
EERYFRAQSREQLAALKKHHEEEIVHHKKEIERLQKEIERHKQKIKMLKHDD
Human IF1 amino acid sequence, with less pH dependency (has a histidine changed to another amino acid, in this case a lysine):
MAVTALAARTWLGVWGVRTMQARGFGSDQSENVDRGAGSIREAGGAFGKREQAE
EERYFRAQSREQLAALKKHKEEEIVHHKKEIERLQKEIERHKQKIKMLKHDD
Another human IF1 amino acid sequence, with less pH dependency (key histidines changed to another amino acid, alanine in each case here to illustrate):
MAVTALAARTWLGVWGVRTMQARGFGSDQSENVDRGAGSIREAGGAFGKREQAE
EERYFRAQSREQLAALKKAAEEEIVAHKKEIERLQKEIERHKQKIKMLKHDD
Naked mole rat IF1 sequence (NCBI Gene ID: 101712500):
MAGTALASRARLGVWGVRAMQTRGFSSDKDHESSSGSIRDAGGAFGKREQAEEERF
FRQKTKEQLEALKKHHEDEIYHHKKAIEHMEKEIERHKQKIKQLKHDD
Naked mole rat IF1 like sequence (NCBI Gene ID: 110349814):
QDHESSSGSIRDAGGAFGKREQAEEEPFFQQKTKEQLEALKKHHEDEIYHHKKAIEC
MEKEIERHKQKIKQLKHDD
Melittin sequence: GIGAVLKVLTTGLPALISWIKRKRQQ-NH2 Presequence of yeast cytochrome oxidase subunit IV:

Synthetic derivatives of yeast cytochrome oxidase subunit IV presequence:

Some protein sequence embodiments of the invention are presented in Figure 29 and in the SEQUENCE LISTING componentry to this disclosure.
Cyclic peptide embodiments of the invention Componentry to this invention is any IF1 sub-sequence(s)/FIFo ATP hydrolysis inhibitory peptide(s), or mutant thereof, optionally with one or more non-proteingenic (e.g. D-) amino acids (increases plasma stability), optionally lipidated (fatty acid(s) attached), optionally with one or more Na-methylated, optionally with a cell penetrating peptide (CPP) sequence(s), in a cyclic form (optionally monocyclic, bicyclic, tricyclic, or higher cycle number), wherein a CPP sequence(s) for cyclic forms is preferred e.g. (non-limiting) as disclosed in US20170190743A1, US20170355730A1, W02015/179691A2, [349-350]. In a bicyclic form, in some invention embodiments, an IF1 sub-sequence(s)/Fi Fo ATP hydrolysis inhibitory peptide(s) sequence is in one cycle and a CPP sequence(s) in the other cycle.
So, the target binding and CPP sequences are in different cycles of a bicyclic form, wherein, to illustrate (not restrict), this division (for a different target) was used in [351]. In some embodiments, an IF1 sub-sequence(s)/FIF0 ATP hydrolysis inhibitory peptide(s) sequence, with a CPP
sequence, is incorporated into a reversible bicycle structure which becomes linear in the reducing intracellular environment, to illustrate (not restrict), as used in [352], wherein 3,5-bis(mercaptomethyl)benzoyl [BMB] and two cysteine residues are incorporated into the sequence judiciously, optionally with sequence order: BMB ¨ CPP ¨ cysteine ¨
[IF1 sub-sequence] ¨ cysteine. In alternative embodiments, the CPP is in an intracellular labile cycle and the IF1 sub-sequence is linear, optionally implemented by using 3-mercaptopropionyl (MP) and sequence order: MP ¨ CPP ¨ cysteine ¨ [IF1 sub-sequence], following teaching of [352]. In some embodiments, an IF1 sub-sequence(s)/FIF0 ATP hydrolysis inhibitory peptide(s) sequence, or mutant thereof, optionally with one or more non-proteingenic amino acids, is incorporated into a bicycle structure, optionally with the same sequence in both cycles, optionally with a different IF1 sub-sequence/FIF0 ATP hydrolysis inhibitory sequence in each cycle, optionally with a CPP sequence also in both or just one of the cycles, optionally wherein a CPP sequence occupies one of the cycles and an IF1 sub-sequence(s)/FiFo ATP hydrolysis inhibitory sequence(s) occupies the other cycle, optionally wherein the bicycle structure is made according to a teaching of the art e.g.
[353-358] , e.g. as exemplified by the publication/patent/drug output of Bicycle Therapeutics Ltd., (Babraham Research Campus, Cambridge, U.K) and/or its subsidiaries/affiliates/founders/investors/acquirer(s).
An IF! sub-sequence(s)/FIF0 ATP hydrolysis inhibitory peptide(s), or mutant thereof, optionally with a cell penetrating peptide (CPP) sequence(s), in a cyclic form (optionally monocyclic, bicyclic, tricyclic, or higher cycle number) is componentry to this invention.
Some non-limiting invention embodiments, disclosed using one-letter amino acid code and further symbols designated herein: Cyclo(F(DRRRRx); Cyclo(xFORRRR);
Cyclo(RRFRORx); Cyclo(xRRFROR); Cyclo(FORRRx); Cyclo(xFORRR);
Cyclo(FORRRRRx); Cyclo(xFORRRRR); Cyclo(FFORRRRx); Cyclo(xFFORRRR);
Cyclo(RFRFRORx); Cyclo(xRFRFROR); Cyclo(fORrRrx); Cyclo(xfORrRr);
Cyclo(fearRrRx); Cyclo(xfORrRrR); Cyclo(FfelltrRrx); Cyclo(xFfORrRr);

Cyclo(F9rRrRx); Cyclo(xF(prRrR); Cyclo(FWRRRRx); Cyclo(xFWRRRR);
Cyclo(YORRRRx); Cyclo(xYORRRR); Cyclo(gORRRRx); Cyclo(xgORRRR);
Cyclo(F9rRrRx); Cyclo(xF9rRrR);
wherein,O= L-2-naphthylalanine, 9 = D-2-naphthylalanine, f= D-phenylalanine, r = D-arginine, g = L-phenylglycine, x = IF1 sub-sequence(s)/F 1F0 ATP hydrolysis inhibitory peptide(s) {in either orientation}, optionally one of following sequences (or one of these reversed): H, HH, HHH, HHHH, HHHHH, HHHHHH, HHHHHHH, HHHHHHHH, HHE, HHEE, HHEEE, HHEEE1, HHEEEIV, HHEEEIVH, HHEEEIVHH.
In further embodiments, (ANyN /(AA)r, (AA)v (AA) y z(NA)n (AA)m (AA)v Cys Cys Cys Cys Cys S--I Ls Loop 1 z3 Loop 2 zi Monocyclic z2 zi bicyclic z2 AA = amino acid (proteingenic or non-proteingenic);
Cys = cysteine;
y and v are independently selected from 0 and an integer between 1-100;
n and m are independently selected from an integer between 1-20;
zl, z2, z3 are independently selected from an integer between 1-5;
(AA)n = IF1 sub-sequence(s)/FIF0 ATP hydrolysis inhibitory peptide(s)/histidine(s);
(AA)m = IF1 sub-sequence(s)/FiFo ATP hydrolysis inhibitory peptide(s)/cell penetrating peptide (CPP) sequence;
Optionally, (AA)m is selected from one of FORRRR, RRRROF, RRFROR, RORFRR, =
FORRR, RRROF, FORRRRR, RRRRROF, FFORRRR, RRRROFF, RFRFROR, RORFRFR, fORrRr, rRritil)f, filarRrR, RrRrRilf, FfetRrRr, rRrRoDfF, F9rRIR, RrRr9F, FWRRRR, RRRRWF, YORRRR, RRRROY, gilaRRR, RRRROg, F9rRrR, RrRr9F;

Optionally, (AA)n is selected from one of H, HH, HHH, HHHH, HHHI-IH, HHHHHH, HHHHHHH, HHHHHHHH, HHE, HHEE, HHEEE, HHEEE1, HHEEEIV, HHEEEIVH, HHEEEIVHH.
Gene therapy embodiments of the invention Componentry to this invention are the nucleic acid sequences that code for the protein sequences of the invention. In a specific embodiment, a nucleic acid sequence encoding one or more protein embodiments of the invention is administered to a subject, optionally to treat and/or enhance the subject, by way of gene therapy. Any method for gene therapy available in the art can be used according to the present invention. For general reviews of the methods of gene therapy, refer Goldspiel et al., 1993, Clinical Pharmacy 12:488-505;
Wu and Wu, 1991, Biotherapy 3:87-95; Tolstoshev, 1993, Ann. Rev. Pharmacol. Toxicol.
32:573-596;
Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, 1993, Ann. Rev.

Biochem. 62:191-217; May, 1993, TIBTECH 11(5): 155-215. Methods known in the art of recombinant DNA technology can be used, some of which are described in Ausubel et al.
(eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993);
and Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990).
In a preferred aspect, a composition of the invention comprises a nucleic acid sequence, encoding a protein sequence embodiment of the invention, in an expression vector that expresses the nucleic acid sequence into a protein sequence of the invention.
Such a nucleic acid sequence has a promoter, optionally a heterologous promoter, operably linked to the protein coding region. Said promoter is inducible or constitutive, and, optionally, tissue-specific. With an inducible promoter, expression of the nucleic acid is controllable by controlling the presence or absence of the appropriate inducer of transcription (non-limiting .. e.g. "Tet-Off' {transcription is inactive in presence of tetracycline or doxycycline or similar}
and "Tet-On" {transcription is only active in presence of tetracycline or doxycycline or similar} expression systems). In a particular embodiment, the nucleic acid sequence used has the sequence coding for the therapeutic protein embodiment, and optionally its regulatory region(s) {promoter(s) etc.}, flanked by regions that promote homologous recombination at a desired site in the genome, thus providing for intrachromosomal expression of the protein encoding nucleic acid sequence (Koller and Smithies, 1372718-2 72 1989, Proc.
Natl. Acad.
Sci. USA 86:8932-8935; Zijlstra et al., 1989, Nature 342:435 438). Delivery of the nucleic acid into a subject may be direct, by directly exposing the subject to the nucleic acid or nucleic acid-carrying vector, or indirect, wherein cells are transformed with the nucleic acid in vitro, then transplanted into the subject: termed in vivo and ex vivo gene therapy respectively. In a specific embodiment, a nucleic acid sequence of this invention is incorporated into a nucleic acid expression vector and administered to the subject such that it becomes intracellular e.g. by infection using a defective or attenuated retroviral or other viral vector (see U.S. Pat. No. 4,980.286), or by direct injection of naked DNA, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or by a matrix with in situ scaffolding in which the nucleic acid Sequence is contained (See, e.g., European Patent No.
EP 0 741 785 BI and U.S. Pat. No. 5,962,427), or coating with lipids or cell-surface receptors or transfecting agents, encapsulation in liposomes, microparticles, or microcapsules, or by administering in linkage to a peptide which is known to enter the nucleus, by administering it in linkage to a ligand subject to receptor-mediated endocytosis (see, e.g., Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432) (which can be used to target cell types specifically expressing the receptors), etc. In another embodiment, nucleic acid-ligand complexes can be formed in which the ligand comprises a fusogenic viral peptide to disrupt endosomes, allowing the nucleic acid to avoid lysosomal degradation. In yet another embodiment, the nucleic acid can be targeted in vivo for cell specific uptake and expression, by targeting a specific receptor (See, e.g., PCT Publication Nos. WO 92/06180, WO 92/22635, WO 92/20316, WO
93/14188, and WO 93/20221). Alternatively, the nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination (Koller and Smithies, 1989, Proc. Nat). Acad. Sci. USA 86:8932-8935; and Zijlstra et al., 1989, Nature 342:435-438). In a specific embodiment, a viral vector that contains a nucleic acid sequence of this invention is used. For example, a retroviral vector can be used (see, e.g., Miller etal., 1993, Meth. Enzymol. 217:581 599). These retroviral vectors contain the components necessary for the correct packaging of the viral genome and integration into the host cell DNA. More detail about retroviral vectors can be found in Boesen et al., 1994, Biotherapy 6:291-302, which describes the use of a retroviral vector to deliver the MDR I gene to hematopoietic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are: Clowes et al., 1994, J. Clin. Invest. 93:644-651; Klein et al., 1994, Blood 83:1467-1473; Salmons and Gunzberg, 1993, Human Gene Therapy 4:129-141; and Grossman and Wilson, 1993, Curr. Opin. in Genetics and Devel. 3:110-114.
Adenoviruses are other viral vectors that can be used in gene therapy. Adenoviruses are especially attractive vehicles for delivering genes to respiratory epithelia. Adenoviruses naturally infect respiratory epithelia where they cause a mild disease. Other targets for adenovirus-based delivery systems are liver, the central nervous system, endothelial cells, and muscle.
Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson, 1993, Current Opinion in Genetics and Development 3:499-503 present a review of adenovirus based gene therapy. Bout et al., 1994, Human Gene Therapy 5:3-10 demonstrated the use of adenovirus vectors to transfer genes to the respiratory epithelia of rhesus monkeys. Other instances of the use of adenoviruses in gene therapy can be found in Rosenfeld et al., 1991, Science 252:431-434; Rosenfeld et al., 1992, Cell 68:143-155;
Mastrangeli et al., 1993, J. Clin. Invest. 91:225-234, PCT Publication W094/12649; and Wang et al., 1995, Gene Therapy 2:775-783. Adeno-associated virus (AAV) is another option for use in gene therapy (Walsh et al., 1993, Proc. Soc. Exp. Biol. Med.
204:289-300; and U.S.
Pat. No. 5,436,146). Another option is to use an ancestral AAV such as Anc80 (Zinn et al.
2015, Cell Reports, 12(6):1056-68). Another approach to gene therapy involves transferring a gene to cells in vitro, in tissue culture, by such methods as electroporation, lipofection, calcium phosphate mediated transfection, or viral infection. Usually, the method of transfer includes the transfer of a selectable marker to the cells. The cells are then placed under selection to isolate those cells that have taken up and are expressing the transferred gene.
Those cells are then delivered to a subject. In an embodiment, the nucleic acid is introduced into a cell prior to administration in vivo of the resulting recombinant cell.
Such introduction can be carried out by any method known in the art, including but not limited to transfection, electroporation, microinjection, infection with a viral or bacteriophage vector containing the nucleic acid sequence(s), cell fusion, chromosome-mediated gene transfer, microcellmediated gene transfer, spheroplast 1372718-2 74 fusion, etc. Numerous techniques are known in the art for the introduction of foreign genes into cells (see, e.g., Loeffler and Behr, 1993, Meth.
Enzymol. 217:599-618; Cohen et al., 1993, Meth. Enzymol. 217:618-644; Clin.
Pharma.
Ther. 29:69-92 (1985)) and may be used in accordance with the present invention. The technique should provide for the stable transfer of the nucleic acid to the cell, so that the nucleic acid is expressible by the cell and, optionally, heritable and expressible by its cell progeny. The resulting recombinant cells can be delivered to a subject by various methods known in the art. Recombinant blood cells (e.g., hematopoietic stem or progenitor cells) are preferably administered intravenously. The amount of cells envisioned for use depends on the desired effect, patient state, etc., and can be determined by one skilled in the art. Cells into which a nucleic acid can be introduced for purposes of gene therapy encompass any desired, available cell type, and include but are not limited to epithelial cells, endothelial cells, keratinocytes, fibroblasts, muscle cells, hepatocytes, blood cells Such as T
lymphocytes, B

lymphocytes, natural killer (NK) cells, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes, granulocytes, various stem or progenitor cells, in particular hematopoietic stem or progenitor cells, e.g., as obtained from bone marrow, umbilical cord blood, peripheral blood, fetel liver, etc. In a preferred embodiment, the cell used for gene therapy is autologous to the subject. In a specific embodiment, stem or progenitor cells are used.
Any stem and/or progenitor cells which can be isolated and maintained in vitro can potentially be used in accordance with this embodiment of the present invention (see e.g., PCT
Publication No.
W094/08598; Stemple and Anderson, 1992, Cell 7 1:973-985; Rheinwald, 1980, Meth. Cell Bio. 21A:229; and Pittelkow and Scott, 1986, Mayo Clinic Proc. 61:771).
"Tet-Off" and "Tet-On" inducible gene expression embodiments of the invention In a "Tet-Off' system, gene expression is under the control of a tetracycline-responsive promoter element (TRE), which permits gene expression if the tetracycline-controlled transactivator protein (tTA) binds, wherein tTA binding is blocked by the presence of tetracycline or doxycycline or similar compound structure. In a "Tet-On"
system, gene expression is under the control of a tetracycline-responsive promoter element (TRE), which permits gene expression if the reverse tetracycline-controlled transactivator (rtTA) binds, wherein rtTA binding is enabled and conditional upon the presence of tetracycline or doxycycline or similar compound structure. So, one can transfer a gene into an organism under the control of a TRE promoter, and then control this gene's expression, spatially and/or temporally, by (1) controlling whether tTA or rtTA is expressed (which is set by which of these genes is also gene transferred into the organism) and (2) whether a tetracycline type compound structure is present or absent (set by compound administration or lack thereof).
For example, [322] generated transgenic mice with a human IF1 mutant gene (a histidine in the "pH dependence motif' {refer Figure 29} substituted with lysine) under a TRE promotor.
Furthermore, these mice had another exogenous gene present, for tTA protein expression, but only expressed in its forebrain neurons, and thence the mutant human IF I gene was only expressed in forebrain neurons (wherein this expression is dependent on absence of tetracycline or similar structure). [322] doesn't specify the ambient temperature these mice .. were housed at. With this omission, I presume normal room temperature, which is typically in the range 20-25 C. [322] is an illustrative example of how an IF1 gene copy, or a mutant thereof, from the same or different species, can be transferred into an organism in order to increase its IF1 protein expression. This example shows it is safe in mouse brain (more specifically neurons in forebrain [323], [322] is incorrect to refer to whole brain as it does) to increase IF1 protein content by three times, wherein the delta increase in [IPI] occurs with a mutant human IF1 form with increased inhibitory potency against FIF0 ATP
hydrolysis at pH
8, which reduces FIFO ATP hydrolysis capability by ¨35%, which demonstrates the safety of inhibiting FIFO ATP hydrolysis in vivo, at least specifically in forebrain neurons (mice were "normal in appearance, home-cage behavior, reproduction, and longevity up to 1-year follow-up"). For more data and analysis on this herein, refer Figure 25 and legend, and then Figures 26 and 27 and their legends. In alternative embodiments, tTA is expressed in all the tissues of the mouse, not just the brain (or part(s) thereof), and this mouse, and others like it, are entered into a lifespan study. These mice will have a longer health- and life ¨span than control mice (control mice optionally have the transgene for tTA but not the transgene for IF1 or IF I mutant, or are the same genetically but are administered doxycycline, or other tetracycline, so that they don't express the extra IF1 gene), especially if the mice are kept at 37 C.
Further "Tet-Off' embodiments of the invention An invention embodiment is for an IF1 protein coding gene (herein referred to as an IF1 gene), optionally a mutant thereof, optionally with a nucleotide change(s) that causes an amino acid residue change(s) at the "phosphorylation control switch" and/or the "pH
dependence motif' in the IF! protein coded for (these IF I elements are defined in Figure 29), to be expressed only, or only substantially, or disproportionally, or more, in a specific cell type/tissue/organ/area of a subject, optionally wherein this selective IF1 expression reduces Fi Fo ATP hydrolysis and slows the metabolic/aging rate in this sub-section(s) of the subject, wherein this sub-section(s) generates less metabolic heat, but this is substituted for by heat transfer from surrounding body areas. For illustrative example, by making a transgenic mouse that expresses tTA specifically in a certain mouse body tissue, by putting tTA
expression under the control of a tissue specific promoter, wherein this tissue specific expression of tTA
then drives tissue specific expression of an introduced IF1 gene, optionally a mutant thereof, whose expression is under the control of a tetracycline-responsive promoter element (TRE).
For non-limiting example, putting tTA expression under the control of a dopamine neuron specific promoter such as that for tyrosine hydroxylase (the first and rate-limiting enzyme for dopamine synthesis) [363], or the dopamine transporter (DAT, required for dopamine re-uptake into dopaminergic neurons) [364, 365], or Pitx3 (transcription factor involved in dopaminergic neuron differentiation), or DIA dopamine receptor subtype, which then drives specific expression of an IF I gene, or mutant thereof, in dopaminergic neurons, wherein this IF1 gene is under the control of a tetracycline-responsive promoter element (TRE). Greater IF1 protein expression in dopaminergic neurons reduces their F IF ATP
hydrolysis, especially if the extra IF1 protein has an amino acid residue that can't be phosphorylated (optionally alanine) at its "phosphorylation control switch" position and/or a substitution (position 49 using mature {mitochondria' import signal sequence cleaved oft) human IF1 protein numbering) in its "pH dependence motif', which slows the metabolic/aging rate in dopaminergic neurons, which reduces the subject's risk/progression of Parkinson's disease, wherein these dopaminergic neurons generate less metabolic heat, but this is substituted for by heat transfer from surrounding body areas, such that the .. dopaminergic neurons are maintained at normal body temperature. A useful control is that this subject, when administered (e.g. in drinking water) with tetracycline, has the same risk/progression of Parkinson's disease as control subject without these genetic manipulations (which are, to recap, addition of tTA gene, under dopaminergic neuron specific promoter, and addition of IF1 gene, or mutant thereof, under control of a tetracycline-responsive promoter element, TRE). In another invention embodiment, tTA expression is put under the control of a photoreceptor specific promoter, such as that for rhodopsin (or other opsin), which then drives specific expression of an IF1 gene, or mutant thereof, in photoreceptors, wherein this IF1 gene is under the control of a tetracycline-responsive promoter element (TRE). Greater IF1 protein expression in photoreceptors reduces their FIFO ATP hydrolysis, especially if the extra IF1 protein has an amino acid residue that can't be phosphorylated (optionally alanine) at its "phosphorylation control switch" position and/or a H49K substitution (position 49 using mature {mitochondria' import signal sequence cleaved off) human IF I protein numbering) in its "pH dependence motif', which slows the metabolic/aging rate in photoreceptors, which reduces the subject's risk/progression of aging related/correlated eye disease(s), optionally age-related macular degeneration (AMD), wherein these photoreceptors generate less metabolic heat, but this is substituted for by heat transfer from surrounding body areas, such that the photoreceptors are maintained at normal body temperature.
In an invention embodiment, the experiment of [322] is repeated but with the mutant IF1 transgene expressed in a different part of the mouse. So, instead of using B16-Tg(Camk2a-tTa)1Mmay/J mice, which express tTA in forebrain neurons, as [322] used, a different transgenic mouse type can be used, which expresses tTA in a different part of the mouse body, which drives mutant IF1 expression in that different part of the mouse body.
Illustratively, a variety of transgenic mice that express tTA in different body areas/tissues/organs are available to those of the art, e.g. refer to a database of such mice at [366], and a number are commercially available, for illustrative example from The Jackson Laboratory (USA). Wherein (stock numbers given are for The Jackson Laboratory), for non-limiting example, B6.Cg-Tg(GFAP-tTA)110Pop/.1 mouse (stock No: 005964) has tTA
expression driven by the human glial fibrillary acidic protein (GFAP) promoter and expresses tTA in astrocytes, B6.Cg-Tg(Sirpa-tTA)AUmri/J mouse (stock No: 023970) has tTA

expression driven by mouse signal-regulatory protein alpha (Sirpa) promoter and expresses tTA in dentate granule cells of the hippocampus, B6.Cg-Tg(Scg2-tTA)1Jta mouse (stock No:
008284) has tTA expression driven by mouse secretogranin II promoter and expresses tTA in the brain, especially the suprachiasmatic nucleus, B6.Cg-Tg(Eno2tTA)5030Nes/J
mouse (stock No: 003763) has tTA expression driven by rat neuron-specific enolase (Eno2) promoter and expresses tTA at high levels in the striatum and to a lesser extent in the cerebral cortex and hippocampus, B6;C3-Tg(NEFH-tTA)8V1e/J mouse (stock No: 025397) has tTA
expression driven by human neurofilament heavy polypeptide (NEFH) promoter and expresses tTA in neurons and large-caliber axons of the brain and spinal cord, B6;129S-51c6a3tm4.1(tTA)Xza mouse (stock No: 027178) has tTA expression driven by mouse Slc6a3 (solute carrier family 6, neurotransmitter transporter, dopamine, DAT) promoter and expresses tTA in dopamine neurons, NOD.Cg-Tg(Ins2-tTA)1Doi/DoiJ mouse (stock No:
004937) has tTA expression driven by rat insulin promoter (Ins2, commonly designated RIP) and expresses tTA in pancreatic beta cells, FVB.Cg-Tg(Myh6-tTA)6Smbf/J mouse (stock No: 003170) has tTA driven by rat alpha myosin heavy chain promoter and expresses tTA in cardiac myocytes. Many other such mice are commercially available, and/or are known to those of the art (e.g. from the literature) and other such mice, with tTA
(and/or rtTA) specifically expressed in other cell type(s)/tissue(s)/organ(s), can be generated using techniques of the art, wherein how to apply these techniques to other mammal species is known to those of the art.
An invention embodiment is for an IF1 gene, optionally a mutant thereof, optionally with a nucleotide change(s) that causes an amino acid residue change(s) at the "phosphorylation control switch" and/or the "pH dependence motif' (these IF1 elements are defined in Figure 29) in the IF1 protein coded for, to be expressed ubiquitously in a subject, in every tissue. For illustrative example, by making a transgenic mouse that expresses tTA
ubiquitously, by putting tTA expression under the control of a ubiquitous (e.g. promoter for actin gene) or synthetic (e.g. CAG promoter [367]) promoter, wherein this ubiquitous expression of tTA can then drive ubiquitous expression of an introduced IF! gene, optionally a mutant thereof, whose expression is under the control of a tetracycline-responsive promoter element (TRE).
More direct IF1 genetic manipulations of this invention An invention embodiment is to render localized or ubiquitous expression of an extra IFI
gene(s) in a subject, optionally a mutant thereof, directly, without using tTA
or rtTA and TRE. So, to illustrate, and not restrict, to render tissue specific IF1 expression in a subject by administering the IF1 gene(s), or mutant thereof, locally (rather than systemically) and/or under the control of a tissue specific promoter or, alternatively, rendering ubiquitous IF!
expression in a subject by introducing the IF1 gene(s), or mutant thereof, under the control of a ubiquitous promoter, optionally a synthetic promoter. Without restriction, there are two possible options: (1) the introduced IF1 gene(s), or mutant thereof, under the control of an introduced promoter (and/or enhancer and/or other regulatory element(s)), is introduced to the subject or (2) the IF1 gene(s) only, or mutant thereof, is introduced to the subject, wherein it inserts into the genome at a place that renders its expression under the control of a cell/tissue/organ specific or ubiquitous promoter already in the genome. The IF1 gene(s), or mutant thereof, can be introduced into one or more cells of the subject, a somatic or germline cell(s), in vivo or ex vivo (wherein cell(s) are removed from the subject, the IF1 gene(s) and/or mutant thereof is introduced into the cell(s), and the cell(s) are returned back into the subject afterwards), wherein optionally the introduced nucleotide sequence, including the IF1 gene(s) (or mutant thereof) and/or regulatory sequence(s), is introduced as naked nucleotide material (optionally, without restriction, by one or more of heat shock, cell squeezing, using calcium phosphate to bind the DNA, electroporation, gene gun, sonoporation, photoporation, magnetofection, magnet assisted transfection, lipofection, impalefection, optical transfection, nucleofection, protofection, hydroporation, hydrodynamic delivery, microinjection {DNA is injected through the cell's nuclear envelope directly into the nucleus}, pronuclear injection {after the sperm enters the egg, but before the genetic material of the sperm and egg fuse, genetic material is injected into the pronucleus of either the sperm or egg, when these pronuclei become visible, which is the first sign of successful fertilization;
this oocyte is then .. implanted in the oviduct of a pseudopregnant female [e.g. induced when female is bred by an infertile male], the offspring thence carry the genetic modification}, embryonic Stem Cell-Mediated Gene Transfer {gene is transfected into an embryonic stem cell(s) that is then inserted into a subject blastocyst(s), which is then implanted into foster mother, resulting offspring is/are chimeric, further mating can produce mice fully transgenic subject(s) with the gene of interest}) or in a vector, wherein the vector can be, without restriction, one or more of a plasmid, episome, lipoplex (optionally with cationic lipids), liposome, cationic liposome, liposome coated in a polymer called polyethylene glycol, polymersome (synthetic liposome, made of amphiphilic block copolymers; copolymer is a polymer derived from more than one species of monomer), polyplex (complex of polymer with DNA), dendrimer (highly branched macromolecule with a spherical shape), inorganic nanoparticle (e.g. gold, silica, iron oxide, calcium phosphate etc.), organic nanoparticle, fugene, cell-penetrating peptide, virosome (viral envelope {phospholipid membrane and surface glycoproteins} of a virus that, instead of viral genetic material, contains therapeutic agent(s) of this invention e.g. nucleotide sequence(s) of the invention), virus (replication-competent, or replication-defective/attenuated {coding region(s) for gene(s) necessary for virion replication/packaging is replaced with other gene(s), corrupted or deleted}), retrovirus (has a single stranded RNA
genome that codes for a reverse transcriptase enzyme that produces a double stranded DNA
sequence that is inserted into host genome by viral enzyme integrase; most retroviruses can only insert into actively dividing cells, which makes them appropriate for delivering IF1 gene(s), or mutant thereof, for anti-cancer therapy; however, they tend to insert into the genome unpredictably, so "insertional mutagenesis" is a concern, however, in an embodiment, sequence(s) is incorporated that directs a retroviral coded DNA
sequence(s) to be inserted at a specific locus or loci in the genome e.g. utilizing the beta-globin locus control region and/or by inserting a sequence for a Zinc finger nuclease which cuts the genome at a place that the viral DNA is desired to be inserted; retroviral vector particles with tropism for various target cells have been designed in the art), lentivirus (a genus of retrovirus; can insert into non-dividing cells; HIV is an example; enhancers can be used to improve transduction efficiency such as, without limitation, polybrene, protamine sulfate, retronectin, and DEAE
Dextran), gammaretrovirus (a genus of retrovirus; non-limiting e.g. moloney retrovirus), adenovirus (doesn't integrate into genome, not replicated during cell division), adeno-associated virus (AAV; single stranded DNA virus {becomes double stranded in the cell};
can be integrated into genome, mostly at a known site in humans {designated AAVS1, in human chromosome 19}, but is more likely to remain episomal {replicating without incorporation into the chromosome}; useful for dividing and non-dividing cells; has been used in clinical trials e.g. for retinal gene therapy by subretinal and/or intravitreal injection {e.g. Voretigene neparvovec (Luxturna)}, wherein an invention embodiment is to deliver an IF I gene(s), or mutant thereof, similarly to treat/ameliorate/prevent/combat an aging-related/linked/correlated eye(s) disease/condition, optionally age-related macular degeneration, AMD; all AAV serotypes are [contemplated by/ componentry to] the present invention), self-complementary adeno-associated virus (scAAV; viral vector engineered from the naturally occurring adeno-associated virus (AAV); double stranded DNA
virus), pseudotyped viruses (in which the endogenous viral envelope proteins have been replaced by either envelope proteins from other viruses, or by chimeric proteins, e.g. to alter the cell type(s) that the virus infects), hybrid vector (=genetically engineered virus, to have desired vector characteristics), recombinant virus, replication-deficient Herpes simplex virus (human neurotropic virus, infects neurons), cell penetrating peptide (e.g. protein transduction domain of Tat protein of HIV-1 virus) etc. This list is not exhaustive, other methods of introducing new genetic material to a subject are known to those of the art. Including using an ancestral or ancestral like AAV, such as Anc80 [368], which has significant merit because it doesn't stimulate immune reactions, because modern organisms haven't encountered this virus for generations.
Componentry to this invention is to use genome editing with engineered nuclease(s) and/or CRISPR/Cas9 and/or CRISPR/Cpfl and/or Zinc finger nuclease(s) and/or Zinc-finger nickase(s) and/or Transcription activator-like effector nuclease(s) (TALEN) and/or meganuclease(s) and/or megaTAL(s) and/or homing endonuclease(s) and/or restriction enzyme(s) and/or endonuclease and/or nuclease(s) and/or "gene targeting" (in particular "gene knock-in", replacement strategy based on homologous recombination) and/or Recombinant AAV mediated genome engineering (rAAV) and/or Multiplex Automated Genomic Engineering (MAGE) and/or Cre-Lox system(s) and/or Flp-FRT system(s) and/or similar and/or other genetic editing/engineering technology to edit a native IF I gene in a subject to become a different IF I gene of this invention, optionally with a nucleotide change(s) that causes an amino acid residue change(s) at the "phosphorylation control switch" (optionally serine to alanine substitution) and/or the "pH dependence motif' (optionally a H49K substitution at position 49, using mature {mitochondrial import signal sequence cleaved off) human IF1 protein numbering) in the IF1 protein coded for (these IF I
elements are defined in Figure 29), and/or to insert a nucleotide sequence(s) of this invention, which is a nucleotide sequence(s) that codes for one or more of the IF1 protein sequence embodiments of this invention, into a genome, optionally in one or more cells of a subject, optionally one or more of a somatic cell(s), germline cell(s), gamete(s) (e.g. sperm(s) or egg(s)), gametocyte(s), spermatocyte(s), oocyte(s), fertilized egg(s), pronuclear fertilized egg(s), embryonic stem cell(s), induced pluripotent stem cell (IPSC), or other(s).

Componentry to this invention is to "knock-in", wherein this term is well understood in the art (e.g. one of the art is very familiar with "knock-out" and "knock in"
mice, and protocols used), an IF1 protein coding nucleotide DNA sequence of this invention, optionally with a nucleotide change(s) that causes an amino acid residue change(s) at the "phosphorylation control switch" (optionally serine to alanine substitution) and/or the "pH
dependence motif"
(optionally a H49K substitution at position 49, using mature {mitochondrial import signal sequence cleaved off} human IF1 protein numbering) in the IF1 protein coded for (these IF1 elements are defined in Figure 29), in place of the native IF1 gene of the subject.
Manipulating IF1 gene expression An invention embodiment is to manipulate/change the promoter/enhancer/repressor/regulatory sequence(s) of an IF1 gene(s), to increase the expression of IF1 protein, in somatic and/or germline cell(s) of a subject, optionally wherein a new promoter/enhancer/regulatory sequence(s) is added, optionally wherein this increased IF1 expression reduces FiFo ATP hydrolysis and slows the metabolic/aging rate in this cell(s) of the subject, optionally wherein exogenous/ambient heat is administered to the subject to substitute for this lesser heat generation and/or greater body insulation (e.g. clothing) is administered to the subject to reduce heat loss per unit time, which correspondingly keeps the subject warm despite lesser heat generation.
Summary/overview/recap of IF1 genetic manipulations of the invention An embodiment of the invention is to change the sequence of a subject's IF1 gene, optionally conferring a greater inhibitory potency against FIR) ATP hydrolysis at normal mitochondrial matrix pH 8, and/or increase the amount of IF1 protein in a cell(s) of a subject, optionally in all or the majority of cells in the subject or a subset of cell type(s) and/or cell(s) in certain tissue(s)/area(s) of the subject, optionally wherein change in the amount of IF1 protein is effected by (1) altering the regulatory sequence(s) of the subject's IF1 gene to effect greater IF1 gene expression, by greater transcription and/or translation, and/or (2) by adding another IF1 gene(s) to the subject's cell(s) genome, optionally wherein one or more of the added IF!
gene(s) are from a different (larger and/or longer living {greater maximal lifespan}) species and/or is a mutant IF1 gene, optionally with a greater inhibitory potency against FiFo ATP
hydrolysis at normal mitochondrial matrix pH 8, optionally with a nucleotide change(s) that causes an amino acid residue change(s) at the "phosphorylation control switch"
(optionally serine to alanine substitution) and/or the "pH dependence motif' (optionally a substitution at position 49, using mature {mitochondria] import signal sequence cleaved off}
human IF1 protein numbering) in the IF1 protein coded for (these IF1 elements are defined in Figure 29), optionally, especially if many/all of the subject's cells have been manipulated in this way, greater exogenous/ambient heat is administered to the subject to substitute for lesser endogenous heat generation and/or greater body insulation (e.g. clothing) is administered to the subject to reduce heat loss per unit time, which correspondingly keeps the subject warm despite lesser metabolic rate/body heat generation.
Example embodiment: IF1 gene therapy for Parkinson's disease Firstly, gene therapy is now well established in the clinic, with thousands of clinical trials having taken place, with more being conducted, across dozens of countries for many indications, with notable approvals [369]. Secondly, for closer context, there are numerous reviews of gene therapy for Parkinson's disease in the literature e.g. [370, 371, 372, 373]. An invention embodiment is to locally deliver, optionally bilaterally, optionally by injection into the subject's putamen (as used in [374]) and/or into the subject's basal ganglia/substantia nigra (SN)/substantia nigra pars compacta (SNpc), an IF1 gene(s) {optionally another gene(s) also, optionally one or more genes coding for an enzyme in dopamine synthesis e.g. for tyrosine hydroxylase, this enzyme catalyses the rate-limiting step of dopamine synthesis, e.g.
for aromatic L-amino acid decarboxylase (AADC)}, optionally in a viral vector, optionally in a lentiviral viral vector (optionally ProSavin [374]) and/or an adeno-associated viral vector (optionally AAV2 [375]), to dopaminergic neurons, which reduces their FiFo ATP

hydrolysis, especially if the resulting extra IF I protein has an amino acid residue that can't be phosphorylated (optionally alanine) at its "phosphorylation control switch"
position and/or a H49K substitution (position 49 using mature {mitochondrial import signal sequence cleaved off} human IF1 protein numbering) in its "pH dependence motif', which slows the metabolic/aging rate in dopaminergic neurons, which reduces the subject's risk/progression of Parkinson's disease, wherein these dopaminergic neurons generate less metabolic heat, but this is substituted for by heat transfer from surrounding body areas, such that the dopaminergic neurons are maintained at normal body temperature, optionally wherein this therapy is administered alongside one or more other therapies for Parkinson's disease known to those of the art e.g. L-DOPA administration, deep brain stimulation etc. In other embodiments, additionally or instead of, an IF I gene(s) is administered to another brain region(s), optionally a brain region(s) (whose dysfunction is) implicated in Parkinson's disease e.g. optionally by infusion directly into the subject's subthalamic nucleus (as used in [374]).
Example embodiment: IF1 gene therapy for Osteoarthritis Example embodiment: IF1 gene therapy extends mouse lifespan An IF1 gene(s), optionally with a nucleotide change(s) that causes an amino acid residue change(s) at the "phosphorylation control switch" and/or the "pH dependence motif' in the IF1 protein coded for (these IF1 protein elements are defined in Figure 29), with a promoter that can drive its expression, optionally the CMV enhancer element and a chicken 13-actin promoter containing its first intron (regulatory element used in [376];
alternatively IF1 gene is flanked by -actin promoter and terminator), is delivered to a nascent B6(B6C3F1) mouse embryo by pronuclear microinjection, wherein the resulting mouse has this extra IF1 gene(s) (with regulatory element(s) for expression) in all its cells (checked by PCR
for a number of different cells from different tissues isolated from the mouse, amount of IF1 protein is also assayed, wherein the genetically modified mouse should have more IF1 protein in its cells).
This protocol is repeated to generate a number of such genetically modified mice and their lifespans, and/or those of their progeny as they are mated with each other and/or backcrossed with C57BL/6J mice one or more times, are monitored as compared to control mice (no genetic modification), wherein the genetically modified mice live longer:
longer health- and life- (median and maximal) span. Food intake and body weight is monitored for all mice over their lifespan. Mice are kept in specific pathogen free conditions. Optionally the study is repeated or run in parallel with mice of a different genetic background. More details on the protocol to follow (e.g. number of mice and statistics to be used, healthspan assays that can be used {e.g. cardiac pathology, cataract development, oxidative damage, mitochondrial deletions etc.) etc.) can be sourced from emulating the protocol of [376]. A
protocol of a different study of genetic manipulation and lifespan in the literature can be used instead e.g.
[377]. But crucially, distinctly, all mice in the present study are housed at 37 C. The genetically modified mice have more IF1 protein in their cells, less FiFo ATP
hydrolysis per unit time, less oxidative phosphorylation per unit time, less heat generation per unit time (not detrimental when ambient temperature is 37 C), less ROS production per unit time, less oxidative damage per unit time, slower aging and longer lifespan.

Instead of the 'IF1 transgene(s) adding an extra IF1 gene copy or copies to the mouse genome, as above, in an alternative invention embodiment, the IF1 transgene replaces the native IF1 gene by a "genetic knock-in" (replacement strategy based on homologous recombination), optionally wherein the IF1 transgene has a nucleotide change(s) that causes an amino acid residue change(s) at the "phosphorylation control switch" and/or the "pH
dependence motif' in the IF1 protein coded for (these IF I protein elements are defined in Figure 29). These mice also have slower aging and longer lifespan.
Example embodiment: IF1 gene therapy, restricted to brain, extends "brainspan"
Transgenic mice are made via pronuclear microinjection of mouse embryos with an IF I
transgene(s), optionally with a nucleotide change(s) that causes an amino acid residue change(s) at the "phosphorylation control switch" and/or the "pH dependence motif' in the IF1 protein coded for (these IF1 protein elements are defined in Figure 29), under the control of human neurofilament heavy polypeptide (NEFH) promoter, or other brain/neuron/astrocyte specific promoter of the art, some (non-limiting) examples of which have been mentioned herein, optionally using multiple IF I gene copies with different promoters to ensure IF1 transgene expression in both neurons and astrocytes. The mice are housed at an ambient temperature between 21 and 37 C. These genetically modified mice have more IF1 protein in their brain, wherein there is less FIFO ATP hydrolysis per unit time, less oxidative phosphorylation per unit time, less heat generation per unit time (not detrimental when ambient temperature is 37 C, and not detrimental when ambient temperature is lower because heat transfer from the rest of the body, especially via blood flow, maintains the brain at 37 C), less ROS production per unit time, less oxidative damage per unit time, slower brain aging and longer "brainspan" i.e. less cognitive decline with age, lower risk/later onset/slower progression of age-related/correlated brain disease(s) e.g.
Alzheimer's disease, dementia etc.
CONSOLIDATORY FORMULA/MECHANISM
This Formula consolidates prior formulas to present some preferred embodiments of the invention. These structures share the common motif:

(X3) NsN
(x2xx)xx especially.
N' NH
N7:21 Or NNNN.N
X1 Xi Wherein each X3 is, independently at each point of use, absent, or hydrogen, or alkyl, or substituted alkyl (non-limiting example: CF3), or deuterated alkyl (non-limiting example:
CD3), or aminoalkyl, or thioalkyl, or alkoxy, or haloalkyl, or haloalkoxy, or hydroxyalkyl, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2 etc.), for example deuterium, or halogen, or fluorine;
Each X2" is, independently at each point of use, selected from a single bond, 0, S. Se, NXP, PXP, BXP, C(XP)2 or Si(XP)2, wherein each XP is, independently at each point of use, selected from a constituent group of X3 (defined earlier);
xx and xy are each independently selected from 0, 1, 2, 3, 4, 5;
X 1 is /INN.
N
(R4)q R1 wherein Markush symbols are as defined previously for Formula (I), or (R1),õ
(R7)q \ Aa, N¨Z
1-- N \

L
Bb \
(R5)õ
wherein Markush symbols are as defined previously for Formula (II), or I
(Xk)k L
L

Y

wherein Markush symbols are as defined previously for Formula (III), or R2 R1 X NOM*
R3 fi (R1),, R4 R5 ( n )m Z
wherein Markush symbols are as defined previously for Formula (IV), or 0 ......Ar 0 AAA ¨Nly\ /yNH AAA
N
H

wherein each AAR is, independently at each point of use, an amino acid side chain, optionally (but not restrictively) the side chain of an amino acid coded for by the genetic code, each AAA is, independently at each point of use, an amino acid (proteingenic or non-proteingenic) or a chain of amino acids (proteingenic, or non-proteingenic or a combination) linked by peptide bonds, not exceeding 300 amino acid residues, optionally an amino acid sequence coded for by a component of a genome, optionally an amino acid chain sub-sequence of an IF I protein sequence, preferably an amino acid sequence falling under Formula (VII) and/or presented in Figure 29, optionally wherein one or more of the amino acids have a post-translational modification(s), and/or a modification/manipulation to increase plasma stability, wherein such strategies are well known to those of the art e.g.
swopping stereochemistry (D instead of L) of one or more amino acids, optionally with a modification at their N and/or C terminal ends as disclosed elsewhere herein.
Whilst it is true that compounds of Formula (V) don't have this imidazole structural motif, it is also true that they aren't particularly potent inhibitors of FIR ATP
hydrolysis.
IF I monomers and [Fl dimers can inhibit FIR ATP hydrolysis because their FiFo ATP
hydrolysis domain is exposed. Higher IF I oligmers (>dimer) cannot inhibit FIR) ATP

hydrolysis because their FIFO ATP hydrolysis domain is buried in the IF1 oligomer, thence higher oligomerization (>dimer) sequesters IF I from inhibiting FiFo ATP
hydrolysis, and this is the basis to the pH dependence of IF1 inhibition of F1 F0 ATP hydrolysis:
higher pH = IF1 higher (>dimer) oligomerization and low FIR ATP hydrolysis inhibition, lower pH = higher (>dimer) IF1 oligomers break up and high FIR ATP hydrolysis inhibition.
Without wishing to be restricted by theory, how this imidazole motif enables a compound to inhibit FiFo ATP
hydrolysis is that it interacts with, and locates the compound to, one or more histidines in the pH dependence motif of IF I (Figure 29B) and its location here blocks the higher oligomerization (>dimer) of IF1, without blocking the FIFO ATP hydrolysis domain of IFI, and so there are more free IF1 monomers and dimers, thence more inhibition of FiFo ATP
hydrolysis. So, the compound interacts with, and exerts its action through, IF
I rather than ATP synthase. The compound can reduce FIFO ATP synthesis, but this is by uncoupling (Figure 31) rather than by interaction with ATP synthase and direct inhibition of FIFO ATP
synthesis. Componentry to this invention is any compound(s) that interacts with IF1, optionally the pH dependence motif of IF I (Figure 29B), optionally wherein the compound(s) has an imidazole motif, to reduce/prevent/stop the higher (>dimer) oligomerization of IF1, optionally to treat/prevent/ ameliorate/combat one or more of the diseases or disorders or physiological processes or sub-optimalities mentioned herein, optionally cancer and/or aging.
With a compound(s) of this invention bound, IF I should still be able to inhibit FiFo ATP
hydrolysis, but with the compound bound, IF I can't higher (>dimer) oligomerize and so there is more free IF] monomer/dimer and so greater inhibition of FiFo ATP
hydrolysis. Thence the size/shape of the compound is paramount, such that is blocks/interferes with the higher (>dimer) oligomerization, and not the inhibitory domain, of IFI. The higher (>dimer) oligomerization domain (or part thereof, or modified form thereof) of IF!, without the inhibitory domain of IF I attached, is componentry to this invention (Figure 29).
A method to find a compound of this invention is to assess whether a compound reduces/prevents/stops the higher (>dimer) oligomerization of IF1 at pH 8. If so, in an optional but preferable rd step, it is assessed whether the compound doesn't (necessary) block IF1 inhibition of FIFO ATP hydrolysis in a sub-mitochondrial particle (SMP) assay, optionally conducted at pH 6.7. In a 3rd step, or as an alternative rd step, it is assessed whether the compound enhances (preferable) IF I inhibition of FiFo ATP
hydrolysis in a sub-mitochondrial particle (SMP) assay, optionally conducted at pH 8, optionally wherein action through IF I, rather than direct action upon ATP synthase, can be assayed by observing the effect of removing IF I from the SMP assay. At pH 8, if there is much less FIR
ATP
hydrolysis inhibition with much less IF1 in the assay, then the compound is acting upon FIFO
ATP hydrolysis via interaction with IF1 rather than directly upon ATP
synthase. If a compound hits criterion/criteria in one or more of these steps, and most preferably in all 3 of these steps, then it is a compound of this invention. In some embodiments a screening method is employed using one or more of these steps, wherein a number of compounds are tested in this method to find one or more compounds that reduces/prevents/stops the higher (>dimer) oligomerization of IF I at pH 8 and increases IF I inhibition of F IF ATP
hydrolysis at pH 8.
The 1st step of this method is especially suited to high throughput screening, and only those compounds that pass the 1st step need be entered into the more technically/time demanding 2' and/or 3' steps. In some embodiments one or more of these steps is perfomed at the European Lead Factory.
Definitions used to specify Formulas (I), (H), (III), (IV), (V), (VI) and (VII) The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
The term "alkyl" refers to straight or branched chain hydrocarbon groups having 1 to 21 carbon atoms, preferably 1 to 8 carbon atoms. Lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, are most preferred.
The term "substituted alkyl" refers to an alkyl group as defined above having one, two, three, or four substituents selected from the group consisting of PH2, deuterium, halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, CH, keto (=0), ORa, SRa, NRaRb, NRaS02, NRaSO2Rc, SO2Rc, SO2NRaRb, CO2Ra, C(=0)Ra, C(=0)NRaRb, OC(=0)Ra, ¨
OC(=0)NRaRb, NRaC(=0)Rb, NRaCO2Rb, =N¨OH, =N-0-alkyl, aryl, heteroaryl, heterocyclo and cycloalkyl, wherein Ra and Rb are selected from hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclo, aryl, and heteroaryl, and Rc is selected from hydrogen, alkyl, cycloalkyl, heterocyclo aryl and heteroaryl. When a substituted alkyl includes an aryl, heterocyclo, heteroaryl, or cycloalkyl substituent, said ringed systems are as defined below and thus may in turn have zero to four substituents (preferably 0-2 substituents), also as defined below. When either Ra, Rb or fic is an alkyl, said alkyl may optionally be substituted with 1-2 of PH2, deuterium, halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, CH, keto (=0), OH, 0(alkyl), phenyloxy, benzyloxy, SH, S(alkyl), NH2, NH(alkyl), N(alkyl)2, NHS02, NHS02(alkyl), S02(alkyl), SO2NH2, SO2NH(alkyl), CO2H, CO2(alkyl), C(0)H, C(0)alkyl, C(=0)NH2, C(=0)NH(alkyl), C(=0)N(alky1)2, OC(=0)alkyl, ¨0C(=0)NH2,¨
OC(=0)NH(alkyl), NHC(=0)alkyl, and/or NHCO2(alkyl).
"Alkyl" when used in conjunction with another group such as in arylalkyl refers to a substituted alkyl in which at least one of the substituents is the specifically named group. For example, the term arylalkyl includes benzyl, or any other straight or branched chain alkyl having at least one aryl group attached at any point of the alkyl chain. As a further example, the term carbamylalkyl includes the group ¨(CH2)n¨NH¨C(=0)alkyl, Wherein n is 1 to 12.
The term "alkenyl" refers to straight or branched chain hydrocarbon groups having 2 to 21 carbon atoms and at least one double bond. Alkenyl groups of 2 to 6 carbon atoms and having one double bond are most preferred.
The term "alkynyl" refers to straight or branched chain hydrocarbon groups having 2 to 21 carbon atoms and at least one triple bond. Alkynyl groups of 2 to 6 carbon atoms and having one triple bond are most preferred.
The term "alkylene" refers to bivalent straight or branched chain hydrocarbon groups having 1 to 21 carbon atoms, preferably 1 to 8 carbon atoms, e.g., {¨CH2¨}n, Wherein n is 1 to 12, preferably 1-8. Lower alkylene groups, that is, alkylene groups of 1 to 4 carbon atoms, are most preferred. The terms "alkenylene" and "alkynylene" refer to bivalent radicals of alkenyl and alknyl groups, respectively, as defined above.
When reference is made to a substituted alkylene, alkenylene, or alkynylene group, these groups are substituted with one to four substituents as defined above for alkyl groups. A
substituted alkylene, alkenylene, or alkynylene may have a ringed substituent attached in a spiro fashion as in `,..,...%5L 7 %.**=,..57=....s.7....
f and so forth.
The term "alkoxy" refers to an alkyl or substituted alkyl group as defined above having one, two or three oxygen atoms (-0¨) in the alkyl chain. For example, the term "alkoxy"
includes the groups ¨0¨CI-12alkyl, ¨C1_6alkylene-O¨C1.6alkyl, ¨C1_4alkylene-0-phenyl, and so forth.
The term "thioalkyl" or "alkylthio" refers to an alkyl or substituted alkyl group as defined above having one or more sulphur (¨S¨) atoms in the alkyl chain. For example, the term "thioalkyl" or "alkylthio" includes the groups ¨(CH2), ¨S¨CH2aryl, ¨(CH2)n¨S¨aryl, etc. etc.
The term "aminoalkyl" or "alkylamino" refers to an alkyl or substituted alkyl group as .. defined above having one or more nitrogen (¨N11.`¨) atoms in the alkyl chain. For example, the term "aminoalkyl" includes the groups ¨NR`¨C1..12alkyl and ¨CH2¨NR`-aryl, etc.
(where R' is hydrogen, alkyl or substituted alkyl as defined above.) "Amino"
refers to the group ¨N H2.
When a subscript is used as in Ci_salkyl, the subscript refers to the number of carbon atoms the group may contain. Zero when used in a subscript denotes a bond, e.g., CO-4 alkyl refers to a bond or an alkyl of 1 to 4 carbon atoms. When used with alkoxy, thioalkyl or aminoalkyl, a subscript refers to the number of carbon atoms that the group may contain in addition to heteroatoms. Thus, for example, monovalent. C1_2aminoalkyl includes the groups ¨CH2-__________________________________________________ NH2, ¨NH¨C H3, ¨(C H2)2¨N
H2, ¨NH¨C H2¨C H3, ¨CH2¨NH2 CH3, and ¨N¨

(CH3)2. A lower aminoalkyl comprises an aminoalkyl having one to four carbon atoms.
The alkoxy, thioalkyl, or aminoalkyl groups may be monovalent or bivalent. By "monovalent" it is meant that the group has a valency (i.e., power to combine with another group), of one, and by "bivalent" it is meant that the group has a valency of two. For example, a monovalent alkoxy includes groups such as ¨0¨C1-12alkyl, ¨Ci_6alkylene¨
C1.6alkyl, etc., whereas a bivalent alkoxy includes groups such as ¨0¨C1_2alkylene-, ¨
C _6alky lene-O¨C 1_6alkylene-, etc.
The term "acyl" refers to a carbonyl (ii) linked to an organic group i.e.

I I
Rd wherein Rd may be selected from alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, .. heterocyclo, cycloalkyl, or heteroaryl, as defined herein.
The term "alkoxycarbonyl" refers to a group having a carboxy or ester group ii 0¨

linked to an organic radical, i.e., Rd Wherein Rd is as defined above for acyl.
The term "carbamyl" refers to a functional group in which a nitrogen atom is directly bonded to a carbonyl, i.e., as in ¨NReC(=0)Rf or ¨C(=0)NReRe, wherein Re and Re can be hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, cycloalkyl, aryl, heterocyclo, or heteroaryl, or they may join to form a ring.
The term "sulfonyl" refers to a sulphoxide group (i.e.,¨S(0)1_2) linked to an organic radical Re, as defined above.

The term "sulfonamide" or "sulfonamido" refers to the group -S(0)2NReRf, wherein Re and Rf are as defined above. Preferably when one of Re and Rf is optionally substituted heteroaryl or heterocycle (as defined below), the other of Re and Rf is hydrogen or alkyl.
The term "cycloalkyl" refers to fully saturated and partially unsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7 carbon atoms. The term "cycloalkyl" includes such rings having zero to four substituents (preferably 0-2 substituents), selected from the group consisting of OH, SH, PH2, deuterium, halogen, alkyl, substituted alkyl (e.g., trifluoromethyl), alkenyl, substituted alkenyl, alkynyl, nitro, cyano, CH, keto, ORd, SRd NRafte NRcS02, NReS02Re, C(=0)H, acyl, -CO2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, -0C(=0)Rd, =N-OH, =N-0-alkyl, aryl, heteroaryl, heterocyclo, a 4 to 7 membered carbocyclic ring, and a five or six membered ketal, e.g., 1,3-dioxolane or 1,3-dioxane, wherein Re, Rd and Re are defined as above. The term "cycloalkyl" also includes such rings having a phenyl ring fused thereto or having a carbon-carbon bridge of 3 to 4 carbon atoms.
Additionally, when a cycloalkyl is substituted with a further ring, i.e., aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo, heterocycloalkyl, cycloalkylalkyl, or a further cycloalkyl ring, such ring in turn may be substituted with one to two of Co_aalkyl optionally substituted with OH, SH, PH2, halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, CH, keto (=0), OH, 0(alkyl), phenyloxy, benzyloxy, SH, S(alkyl), NH2, NH(alkyl), N(alkyl)2, NHS02, NHS02(alkyl), S02(alkyl), SO2NH2, SO2NH(alkyl), CO2H, CO2(alkyl), C(=0)H, C(=0)alkyl, C(=0)NH2, C(=0)NH(alkyl), C(0)N(alkyl)2, OC(=0)alkyl, -0C(=0)NH2, -0C(=0)NH(alkyl), NHC(=0)alkyl, and NHCO2(alkyl).
The term "halo" or "halogen" refers to chloro, bromo, fluoro and iodo.
The term "haloalkyl" means a substituted alkyl having one or more halo substituents. For example, `taloallcyl" includes mono, bi, and trifluoromethyl.
The term "haloallcoxy" means an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF3.
The term "aryl" refers to phenyl, biphenyl, I-naphthyl, 2-naphthyl, and anthracenyl, with phenyl being preferred. The term "aryl" includes such rings having zero to four substituents (preferably 0-2 substituents), selected from the group consisting of deuterium, OH, SH, PH2, halo, alkyl, substituted alkyl (e.g., trifluoromethyl), alkenyl, substituted alkenyl, alkynyl, nitro, cyano, CH, ORd, SRd, NRdRe, NRdS02, NRdS02Re, C(0)H, acyl, -CO2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, -0C(=0)Rd, heteroaryl, heterocyclo, cycloalkyl, phenyl, benzyl, napthyl, including phenylethyl, phenyloxy, and phenylthio, wherein Re, Rd and Re are defined as above. Additionally, two substituents attached to an aryl, particularly a phenyl group, may join to form a further ring such as a fused or spiro-ring, e.g., cyclopentyl or cyclohexyl or fused heterocycle or heteroaryl. When an aryl is substituted with a further ring, such ring in turn may be substituted with one to two of Co-aalkyl optionally substituted with deuterium, SH, PH2, halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, CH, keto (=0), OH, 0(alkyl), phenyloxy, benzyloxy, SH, S(alkyl), NH2, NH(alkyl), N(alkyl)2, NHS02, NHS02(alkyl), S02(alkyl), SO2NH2, SO2NH(alkyl), CO2H, CO2(alkyl), C(=0)H, C(=0)alkyl, C(=0)NH2, C(=0)NH(alkyl), C(=0)N(alky1)2, OC(=0)alkyl, -0C(=0)NH2, -0C(=0)NH(alkyl), NHC(=0)alkyl, and NHCO2(alkyl).
The term "heterocyclo" refers to substituted and unsubstituted non-aromatic 3 to 7 membered monocyclic groups, 7 to 11 membered bicyclic groups, and 10 to 15 membered tricyclic groups, in which at least one of the rings has at least one heteroatom selected from 0, S and N. Each ring of the heterocyclo group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The fused rings completing bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The heterocyclo group may be attached at any available nitrogen or carbon atom. The heterocyclo ring may contain zero to four substituents (preferably 0-substituents), selected from the group consisting of deuterium, OH, SH, PH2, halo, alkyl, substituted alkyl (e.g., trifluoromethyl), alkenyl, substituted alkenyl, alkynyl, nitro, cyano, CH, keto, ORd, SRd, NRdRe, NRdS02, NReiSO2Rc, SO2Rd, C(0)H, acyl, -CO2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, -0C(0)Rd, =N-OH, =N-0-alkyl, aryl, heteroaryl, cycloalkyl, a five or six membered ketal, e.g., 1,3-dioxolane or 1,3-dioxane, or a monocyclic 4 to 7 membered non aromatic ring having one to four heteroatoms, wherein Re, Rd and Re are defined as above. The term "heterocyclo" also includes such rings having a phenyl ring fused thereto or having a carbon-carbon bridge of 3 to 4 carbon atoms.

Additionally, when a heterocyclo is substituted with a further ring, i.e., aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or a further heterocyclo ring, such ring in turn may be substituted with one to two of Co_aalkyl optionally substituted with deuterium, SH, PH2, halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, CH, keto (=0), OH, 0(alkyl), phenyloxy, benzyloxy, SH, S(alkyl), NH2, NH(alkyl), N(alkyl)2, NHS02, NHS02(alkyl), S02(alkyl), SO2NH2, SO2NH(alkyl), CO2H, CO2(alkyl), C(=0)H, C(0)alkyl, C(=0)NH2, C(=0)NH(alkyl), C(=0)N(alky1)2, OC(=0)alkyl, -OC(=0)NH2, -0C(=0)NH(alkyl), NHC(=0)alkyl, and NHCO2(alkyl).
Exemplary monocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like.
Exemplary bicyclic heterocyclo groups include quinuclidinyl.
The term "heteroaryl" refers to substituted and unsubstituted aromatic 5 to 7 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom selected from 0, S and N in at least one of the rings. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized.
Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. The heteroaryl ring system may contain zero to four substituents (preferably 0-2 substituents), selected from the group consisting of deuterium, OH, SH, PH2, halo, alkyl, substituted alkyl (e.g., trifluoromethyl), alkenyl, substituted alkenyl, alkynyl, nitro, cyano, CH, ORd, SRd, NRdRe, NRdS02, NRdS02Re, SO2Rd, C(=0)H, acyl, -CO2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, -0C(=0)Rd, heterocyclo, cycloalkyl, aryl, or a monocyclic 4 to 7 membered aromatic ring having one to four heteroatoms, including phenylethyl, phenyloxy, and phenylthio, wherein Itc, Rd and R, are defined as above. Additionally, when a heteroaryl is substituted with a further ring, i.e., aryl, arylalkyl, heterocyclo, heterocycloalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or a further heteroaryl ring, such ring in turn may be substituted with one to two of C0-4 alkyl optionally substituted with deuterium, PH2, halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, CH, keto (=0), OH, 0(alkyl), phenyloxy, benzyloxy, SH, S(alkyl), NH2, NH(alkyl), N(alkyl)2, NHS02, NHS02(alkyl)n, S02(alkyl), SO2NH2, SO2NH(alkyl), CO2H, CO2(alkyl), C(0)H, C(0)alkyl, C(=0)NH2, C(=0)NH(alkyl), C(=0)N(alky1)2, OC(=0)alkyl,-0C(=0)NH2, ¨0C(=0)NH(alkyl), NHC(=0)alkyl, and NHCO2(alkyl).
Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl (Le <;-), thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.
Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
When the term "unsaturated" is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.
The phrase "optionally substituted" is intended to include substituted or unsubstituted possibilities. Accordingly, the phrase "each group of which may be optionally substituted means that each group includes both substituted and unsubstituted groups.

The use of the phrase "Where valence allows" means that the groups may be substituted only to the degree and nature allowed by valency of the group. This is commonly understood by those of skill in the art. For example, a hydrogen substituent cannot be further substituted nor can a phenyl group be directly substituted by an oxo group due to limits on valency.
The term "substituted amino" refers to a group of the formula -NZ2Z3 wherein Z2 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, (cycloalkyl)alkyl, morpholinylalkyl, heterocyclo or (heterocyclo)alkyl and Z3 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, (cycloalkyl)alkyl or hydroxyalkyl further substituted with a carboxylic ester or carboxylic acid, with the proviso that when Z2 is hydrogen, then Z3 is other than hydrogen; or Z2 and Z3 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl; or 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
Hydroxy, hydroxyl and ¨OH are used interchangeably herein.
The term "heterocyclo" or "hetero" also includes such monocyclic and bicyclic rings wherein an available carbon atom is substituted with a (Cl-C4)-alkyl, aryl, (CI-C4)-alkylthio, (Ci-C4)-alkoxy, halo, nitro, keto, cyano, CH, hydroxy, azo, thiazo, amino, -NH-(Cl-C4)-alkyl, -N((Ci-C4)-alky1)2, -CF3, (aminoester)alkyl, carboxylic acid, carboxylic ester, -OCHF2 or (Ci-C4)-alkoxy further substituted with a carboxylic acid or such monocyclic and bicyclic rings wherein two or three available carbons have substituents selected from methyl, methoxy, methylthio, halo, -CF3, nitro, hydroxy, amino and -OCHF2.
Herein, when "carboxyl" or "carboxylic acid" is used, this can mean ¨C(0)0H
but can also refer to carboxylic ester or ester, which encompasses -0C(0)0Rester and -C(0)0R.
- -,ster wherein Rester is selected from hydrogen, deuterium, alkyl, alkenyl, alkoxy, thioalkyl, aminoalkyl, cycloalkyl, haloalkyl, haloalkoxy, aryl, heteroaryl or heterocyclo, each of which may be optionally substituted, as defined herein.
Use of "aryl" herein encompasses "aryloxy", which refers to ¨0-aryl, wherein aryl is selected from prior definition of aryl specified herein. Use of "heteroaryl" herein encompasses "heteroaryloxy", which refers to ¨0-heteroaryl, wherein heteroaryl is selected from prior definition of heteroaryl specified herein. Use of "heterocyclo" herein encompasses "hetereocyclooxy", which refers to ¨0-heterocyclo, wherein heterocyclo is selected from prior definition of heterocyclo specified herein.
Use of "ether" herein encompasses --0.,,R-ther wherein Rether is selected from hydrogen, deuterium, alkyl, alkenyl, alkoxy, thioalkyl, aminoalkyl, cycloalkyl, haloalkyl, haloalkoxy, aryl, heteroaryl or heterocyclo, each of which may be optionally substituted, as defined herein.
At various places herein, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual sub-combination of the members of such groups and ranges. For example, the term "Ci_3allcyl" is intended to include Cialkyl (methyl), C2alkyl (ethyl), C3alkyl.
As used herein, the terms "nucleic acid(s)" and "nucleotide sequence(s)" and "polynucleotide(s)" include DNA molecules (e.g. cDNA or genomic DNA), RNA
molecules (e.g. mRNA), combinations of DNA and RNA molecules or hybrid DNA/RNA
molecules, and analogs, derivatives and modifications (e.g. methylation) of DNA or RNA
molecules.
Analogs can be generated using, for example, nucleotide analogs, which include, but are not limited to, inosine or tritylated bases. Such analogs can also comprise DNA or RNA
molecules comprising modified backbones that lend beneficial attributes to the molecules such as, for example, nuclease resistance or an increased ability to cross cellular membranes.
The nucleic acids or nucleotide sequences can be single-stranded (the sense or antisense strand), double-stranded, may contain both single-stranded and double-stranded portions, and may contain triple-stranded portions.
As used herein, the term "hybridizes under stringent conditions" describes conditions for hybridization and washing under which nucleotide sequences at least 30%
(preferably, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%) identical to each other typically remain hybridized to each other. Such stringent conditions are known to those skilled in the art and can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989). In one, non-limiting example stringent hybridization conditions are hybridization at 6*Sodium chloride/sodium citrate (SSC) at about 45 C, followed by one or more washes in 0.1*SSC, 0.2% SDS at about 68 C. In a preferred, non-limiting example stringent hybridization conditions are hybridization in 6xSSC at about 45 C, followed by one or more washes in 0.2*SSC, 0.1% SDS at 50-65 C (i.e. one or more washes at 50 C, 55 C, 60 C. or 65 C). It is understood that the nucleic acids of the invention do not include nucleic acid molecules that hybridize under these conditions solely to a nucleotide sequence consisting of only A or T nucleotides.
As used herein, the term "proteinaceous agent" is a peptide, polypeptide, protein, fusion protein or antibody. Wherein "analog" refers to a proteinaceous agent that possesses a similar/identical function to a second proteinaceous agent, which does, or does not, comprise a similar/identical amino acid sequence. Two proteinaceous agents have a similar amino acid sequence, and/or 3D structure, if at least one of the following is satisfied:
(a) a proteinaceous agent having an amino acid sequence that is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to the amino acid sequence of a second proteinaceous agent; (b) a proteinaceous agent encoded by a nucleotide sequence that hybridizes under stringent conditions to a nucleotide sequence encoding a second proteinaceous agent of at least 5 contiguous amino acid residues, at least 10 contiguous amino acid residues, at least 15 contiguous amino acid residues, at least 20 contiguous amino acid residues, at least 25 contiguous amino acid residues, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues, at least 60 contiguous amino residues, at least 70 contiguous amino acid residues, at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, at least 100 contiguous amino acid residues, at least 125 contiguous amino acid residues, or at least 150 contiguous amino acid residues; (c) a proteinaceous agent encoded by a nucleotide sequence that is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% identical to the nucleotide sequence encoding a second proteinaceous agent; (d) a proteinaceous agent with similar structure to a second proteinaceous agent refers to a proteinaceous agent that has a similar secondary, tertiary or quaternary structure to the second proteinaceous agent. The structure of a proteinaceous agent can be determined by one or more methods known to those skilled in the art, including but not limited to x-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, circular dichroism, crystallographic electron microscopy, cryogenic electron microscopy (cryo-EM).
To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid, or nucleic acid, sequence for optimal alignment with a second amino acid, or nucleic acid, sequence). The amino acid/nucleotide residues at corresponding amino acid/nucleotide positions are then compared.
When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences {i.e. % identity = (number of identical overlapping positions/total number of positions)*100}. The determination of percent identity between two sequences can also be accomplished using a mathematical algorithm.
A
preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad.
Sci. U.S.A.
87:2264-2268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci.
U.S.A.
90:5873-5877. Such an algorithm is incorporated into the NBLAST and XBLAST
programs of Altschulet al., 1990, J. Mol. Biol. 215:403. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set e.g. for score=100, word1ength=12 to obtain nucleotide sequences homologous to a nucleic acid molecules of the present invention.
BLAST protein searches can be performed with the XBLAST program parameters set e.g. to Score=50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule of the present invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402. Alternatively, PSI-BLAST can be used to perform an iterated search which detects distant relationships between molecules. When utilizing BLAST, Gapped BLAST
and/or PSI-Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see e.g. the NCBI website). Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17. Such an algorithm is incorporated in the ALIGN
program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.
The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.
As used herein, the term "derivative" in the context of a proteinaceous agent refers to a proteinaceous agent that comprises an amino acid sequence which has been altered by the introduction of amino acid residue substitutions, deletions or additions. The term "derivative' as used herein also refers to a proteinaceous agent which, has been modified, i.e. by the covalent attachment of any type of molecule to the proteinaceous agent. For example, but not by way of limitation, a protein/antibody may be modified, e.g., by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. A
derivative of a proteinaceous agent may be produced by chemical modifications using techniques known to those of skill in the art, including, but not limited to specific chemical cleavage, acetylation, formylation, etc. Further, a derivative of a proteinaceous agent may contain one or more non-classical amino acids. In a preferred embodiment, a proteinaceous derivative possesses a similar or identical function as the proteinaceous agent from which it was derived.
Stereoisomers All stereoisomers of Formula [X], such as those, for example, which may exist due to asymmetric carbons, including enantiomeric forms (which may exist even in the absence of asymmetric carbons) and diastereomeric forms, are contemplated and within the scope of this invention. Individual stereoisomers of the compounds of this invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
This disclosure encompasses the use of stereomerically pure forms of a compound(s) of this invention, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a compound(s) of Formula [X], for example a compound(s) of Formula (I), may be used in methods and compositions disclosed herein.
These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p.
268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).
For the molecules presented in this invention's Description and Drawings: the present invention contemplates all polymorphs, crystals, co-crystals, metabolites, isotopologues, geometric/conformational isomers, rotamers, atropisomers, atropenantiomers, stereoisomers, optically active forms, racemates, scalemates, tautomers, keto-enol tautomers, cis- and trans-isomers, E and Z isomers, R- and S-enantiomers, diastereomers, isomers, (D)-isomers, (L)-.. isomers, the racemic mixtures thereof, other mixtures thereof and isotopic variants (e.g.
deuterium in place of hydrogen in some or all places upon the molecule {s}) as falling within the scope of the invention. All such isomers, as well as mixtures thereof, are intended to be included in this invention. As well as analogues and pharmaceutically/physiologically acceptable salts/ethers/esters/solvates/hydrates/solvates of salts/chelates/complexes/metal complexes/mixtures/prodrugs/particles/radionuclides/derivatives/carriers/crysta lline forms/isomorphic crystalline forms/crystals/co-crystals/clathrates/liposomes/nanoparticles/micronized forms/polymer matrices/microspheres/vesicles/micelles/compositions/formulations/doses/combina tionsN-oxides/acid salt hydrates thereof. Unless indicated otherwise, chemical structures and graphical representations of compounds herein encompass all stereoisomers, racemates, scalemates, relative proportions/combinations of R and S stereoisomers and optically active or inactive forms. Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of CC double bonds, C=N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention.
Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E"
configuration wherein the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z"
isomers.
Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention. The present invention is not limited to any particular mechanism, nor to any understanding of the action of the agents being administered.

The invention also embraces isotopically labelled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31p, 32p, 35s, 18F, and ui respectively. Isotopically labelled compounds of the present disclosure can generally be prepared by following proceedures analogous to those disclosed herein by substituting an isotopically labelled reagent for a non-isotopically labelled reagent. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of subjects (e.g. humans). Substitution with positron emitting isotopes, such as 'IC, r '50 and can be useful in PET studies for examining substrate receptor occupancy. These radiolabelled compounds can be useful to further determine or measure the effectiveness of the compounds, by characterizing, for example, the site/mode of action, or binding affinity to pharmacologically important site of action. Substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Also provided for isotopically labeled compounds described herein are any pharmaceutically acceptable salts, solvates, hydrates or .. prodrugs, as the case may be.
In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to afford other compounds of this invention.
Thus, shown/claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N¨*0) derivative.
Any metabolite of a compound of this invention is a compound of this invention.
Componentry to the invention is any compound of this invention, optionally a compound of Formula [X], (I), (II), (III), (IV), (V), (VI), (VII) herein, with one or more of its H
atoms/isotopes replaced with OH (hydroxyl), for example catalysed/enabled by an enzyme e.g. one or more of a Cytochorome P450 enzyme(s), monoxygenase enzyme(s), hydroxylase enzyme(s) and/or by other relevant enzyme(s) known to those of the art.
Optionally, but not restrictively, such a compound(s) of the invention can be produced by incubating a compound(s) of the invention with microsomes, optionally liver microsomes, wherein this technique is well known to those of the art.
Reference to a compound(s) of Formula [X], (I), (II), (III), (IV), (V), (VI), (VII) herein is understood to include reference to every tautomer, enantiomer, mixture of enantiomers, salt, solvate, hydrate, prodrug, chemically protected form, ester, N-oxide, metabolite, crystal, polymorph, co-crystal, clathrate thereof, unless otherwise indicated.
Salts & solvates Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds.
The compounds of Formula [X] form salts which are also within the scope of this invention.
Reference to a compound of the Formula [X] herein is understood to include reference to salts thereof, unless otherwise indicated. For illustrating, not restricting, example: quaternary ammonium salts of compounds of Formula [X] are componentry to the present invention.
Generally speaking, salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of ordinary skill in the art, "salts" of the compounds of the present invention may be derived from inorganic or organic acids and bases. For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable). However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation, isolation or purification of a pharmaceutically acceptable compound. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, Pa. (1990) and Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002) and refer Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19, all hereby incorporated by reference.
The term "salt(s)", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of Formula [X]
contains both a basic moiety, such as, but not limited to an amine or a pyridine or imidazole ring, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein.
Salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Salts of the compounds of the Formula [X] may be formed, for example, by reacting a compound of the Formula [X] with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
The compounds of Formula [X] which contain a basic moiety, such as, but not limited to an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihalo acetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methane-sulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
The compounds of Formula [X] which contain an acidic moiety, such as, but not limited to a carboxylic acid, may form salts with a variety of organic and inorganic bases.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines [formed with N,N-bis(dehydro-abietyl)ethylenediamine], N-methyl D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e. g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
Compounds of Formula [X], and salts thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
It should be understood that solvates (e.g., hydrates) of a compound(s) of Formula [X] are also within the scope of the present invention. Herein, the term "solvate"
means a compound provided herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of solvent (organic or inorganic) bound by non-covalent intermolecular forces (e.g.
hydrogen bonding). Where the solvent is water, the solvate is a hydrate. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
"Solvate" encompasses both soluiion-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates.
Methods of solvation are known in the art.
Chelates, metal complexes (metal complexes include calcium, zinc, iron and the like), mixtures, radionuclides and liposomes of Formula [X] are within the scope of this invention.
In some embodiments, a compound(s) of Formula [X] is anhydrous.
Fatty acids In an embodiment, a therapeutic compound(s) componentry to the present invention, for example a compound(s) of Formula [X], is formulated with a pharmaceutically-acceptable fatty acid(s). In an embodiment, the stoichiometry of a compound of Formula [X] to a fatty acid is 1:1, in another embodiment it is 1:2, and in other embodiments it is other stoichiometries/ratios. What constitutes a fatty acid is well known to those of the art, and isn't necessarily limited to the brief specification given herein. A fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated (no C=C double bonds; in some cases with a formula CH3(CH2)nCOOH where n is a positive integer) or unsaturated (with one or more C=C double bonds, each of which can be in a cis or trans configuration;
monounsaturated fatty acids have a single C=C double bond, polyunsaturated fatty acids (PUFA) have more than one C=C double bond, methylene-interrupted polyenes have two or more cis double bonds separated from each other by a single methylene bridge (-CH2-) (i.e. C=C-C-C=C), conjugated fatty acids have at least one pair of double bonds separated by only a single bond (i.e. C=C-C=C)), which is either branched or (more typically) unbranched, which is optionally substituted. This arrangement confers a fatty acid with a polar, hydrophilic end, and a nonpolar, hydrophobic end that is insoluble in water. Most naturally occurring fatty acids have an unbranched hydrocarbon chain of an even number of carbon atoms, typically between 4 and 28 carbons, and may be attached to functional groups containing oxygen, halogens, nitrogen, and sulfur. Synthetic or non-natural fatty acids may have a hydrocarbon chain of any number of carbon atoms from between 3 and 40 carbons. Where a double bond exists, there is the possibility of either cis or trans geometric isomerism (=
EIZ isomerism in IUPAC nomenclature), which significantly affects the molecule's molecular configuration.
Cis-double bonds cause the fatty acid chain to bend, an effect that is more pronounced the more cis double bonds there are in a chain. Most naturally occurring fatty acids are of the cis configuration, although the trans form does exist in some natural and partially hydrogenated fats and oils, wherein trans fats have been associated with increased risk of coronary heart disease. Omega (co) is the name for the methyl end of a fatty acid and, starting from the omega end, omega-3 (co-3 or n-3) fatty acids have their first (in some cases only) double bond between the 3rd and zith carbon atoms from the methyl end, omega-6 (co-6 or n-6) fatty acids have their first (in some cases only) double bond between the 6th and 7th carbon atoms from .. the methyl end, omega-7 (co-7 or n-7) fatty acids have their first (in some cases only) double bond between the 71h and 8th carbon atoms from the methyl end, omega-9 (co-9 or n-9) fatty acids have their first (in some cases only) double bond between the 9th and 10th carbon atoms from the methyl end. In naming fatty acids a form used is, to illustrate with an example, (18:3, n-3), wherein this fatty acid has 18 carbons in its aliphatic chain, 3 double bonds, the first of which emanates from the 3rd carbon from the methyl (omega, o)) end of the chain (i.e.
this is an omega-3 fatty acid). To give a further example, (20:5, n-3), wherein this fatty acid has 20 carbons in its aliphatic chain, 5 double bonds, the first of which emanates from the 3' carbon from the methyl (omega, co) end of the chain (i.e. this is an omega-3 fatty acid). To give yet a further example, (20:3, n-9), wherein this fatty acid has 20 carbons in its aliphatic chain, 3 double bonds, the first of which emanates from the 9th carbon from the methyl (omega, co) end of the chain (i.e. this is an omega-9 fatty acid). Note that these examples haven't been fully specified using this notation because the cis/trans (EIZ) isomerism of their double bond(s) hasn't been specified. Also, note that this naming system is not what is specified by IUPAC, where for one thing, carbons are counted from the carboxyl rather than the methyl end of the aliphatic chain. a-Linolenic acid (ALA) is (18:3, n-3) and in IUPAC
nomenclature: (9Z,12Z,15Z)-9,12,15-Octadecatrienoic acid, wherein this fatty acid has 3 double bonds, all Z configuration, at carbons 9, 12, 15 from the carboxyl end, wherein (to revert back away from IUPAC) its first double bond emanates from the 3rd carbon atom from the methyl end.
Examples of fatty acids include, without limitation, Capryllic acid, Caprylic acid, pelargonic acid, Capric acid. Undecylic acid, Lauric acid, Tridecylic acid, Myristic acid, Myristoleic acid, Pentadecyclic acid, Palmitic acid, Palmitoleic acid, Sapienic acid, Margaric acid, Stearic acid, Oleic acid, Elaidic acid, Vaccenic acid, Linoleic acid, Linoelaidic acid, a -Linolenic acid, y -Linolenic acid, Stearidonic acid, Nonadecylic acid, Arachidic acid, Eicosenoic acid, 11-Eicosenoic acid, Dihomo-y-linolenic acid, Mead acid, Arachidonic acid, Eicosapentaenoic acid, Heneicosylic acid, Behenic acid, Erucic acid, Docosahexaenoic acid, Tricosylic acid, Lignoceric acid, Nervonic acid, Pentacosylic acid, Cerotic acid, Heptacosylic acid, Montanic acid, Nonacosylic acid, Melissic acid, Henatriacontylic acid, Lacceroic acid, Psyllic acid, Geddic acid, Ceroplastic acid, and Hexatriacontylic acid, a-Linolenic acid, y-Linolenic acid, omega 3 fatty acid (ALA), omega 3 fatty acid (DHA), omega 3 fatty acid (EPA), omega 6 fatty acid (AA), omega 7 fatty acid (CLA), omega 9 fatty acid (OA), omega 9 hydroxylated fatty acid (RA), Arachidonic acid, [9Z, 11E conjugated Linoleic acid], conjugated linoleic acid, conjugated (9Z,11E)-Linoleic acid (CAS Number 2540-56-9), Docosahexaenoic acid, Eicosapentaenoic acid, Oleic acid, Ricinoleic acid, butyric acid, hexanoic acid, decanoic acid, valeric acid, pentadecan acid, heptanoic acid, docosatetraenoic acid, heptadecanoic acid, paullinic acid, alpha-parinaric acid, calendic acid, docosapentaenoic acid, linolelaidic acid, gadoleic acid, alpha-Eleostearic acid, petroselinic acid, punicic acid, pinolenic acid, rumenic acid, eicosatetraenoic acid, tuberculostearic acid, vernolic acid, prostanoic acid, catalpic acid, jacaric acid, malvalic acid, aleuritic acid, lesquerolic acid, bosseopentaenoic acid, hydnocarpic acid.
In aspects of this embodiment, a saturated or unsaturated fatty acid comprises, e.g., at least 8, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 22, at least 24, at least 26, at least 28, or at least 30 carbon atoms. In other aspects of this embodiment, a saturated or unsaturated fatty acid comprises, e.g., between 4 and 24 carbon atoms, between 6 and 24 carbon atoms, between 8 and 24 carbon atoms, between 10 and 24 carbon atoms, between 12 and 24 carbon atoms, between 14 and 24 carbon atoms, or between 16 and 24 carbonatoms, between 4 and 22 carbonatoms, between 6 and 22 carbon atoms, between 8 and 22 carbon atoms, between 10 and 22 carbon atoms, between 12 and 22 carbon atoms, between 14 and 22 carbon atoms, or between 16 and 22 carbonatoms, between 4 and 20 carbon atoms, between 6 and 20 carbon atoms, between 8 and 20 carbon atoms, between 10 and 20 carbon atoms, between 12 and 20 carbon atoms, between 14 and 20 carbon atoms, or between 16 and 20 carbon atoms. If unsaturated, the fatty acid may have, e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more double bonds.
In another embodiment, an adjuvant may comprise one kind of pharmaceutically-acceptable fatty acid. In another embodiment, an adjuvant may comprise a plurality of different .. pharmaceutically-acceptable fatty acids. In aspects of this embodiment, an adjuvant may comprise, e.g., two or more different fatty acids, three or more different fatty acids, four or more different fatty acids, five or more different fatty acids, or six or more different fatty acids.

A pharmaceutically-acceptable fatty acid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically-acceptable omega fatty acid. Non-limiting examples of an omega fatty acid include an omega-3 fatty acid, an omega-6 fatty acid, an omega-7 fatty acid, an omega-9 fatty acid.
Omega-3 fatty acids (also known as n-3 fatty acids or a)-3 fatty acids) are a family of unsaturated fatty acids that have in common a final carbon-carbon double bond in the n-3 position, that is, the third bond, counting from the methyl end of the fatty acid. Omega-3 fatty acids are "essential" fatty acids because they are vital for normal metabolism and cannot be synthesized by the human body. An omega-3 fatty acid includes, without limitation, Hexadecatrienoic acid (16:3), a-Linolenic acid (18:3), Stearidonic acid (18:4), Eicosatrienoic acid (20:3), Eicosatetraenoic acid (20:4), Eicosapentaenoic acid (20:5), Heneicosapentaenoic acid (21:5), Docosapentaenoic acid (Clupanodonic acid) (22:5), Docosahexaenoic acid (22:6), Tetracosapentaenoic acid (24:5), Tetracosahexaenoic acid (Nisinic acid) (24:6).
Omega-6 fatty acids (also known as n-6 fatty acids or co-6 fatty acids) are a family of unsaturated fatty acids that have in common a final carbon-carbon double bond in the n-6 position, that is, the sixth bond, counting from the methyl end of the fatty acid. An omega-6 fatty acid includes, without limitation, Linoleic acid (18:2), y-linolenic acid (18:3), Calendic acid (18:3), Eicosadienoic acid (20:2), Dihomo-y-linolenic acid (20:3), Arachidonic acid (20:4), Docosadienoic acid (22:2), Adrenic acid (22:4). Docosapentaenoic acid (22:5), Tetracosatetraenoic acid (24:4), and Tetracosapentaenoic acid (24:5).
Omega-7 fatty acids (also known as n-7 fatty acids or a)-7 fatty acids) are a family of unsaturated fatty acids that have in common a final carbon-carbon double bond in the n-7 position, that is, the seventh bond, counting from the methyl end of the fatty acid. An omega-7 fatty acid includes, without limitation, 5-Dodecenoic acid (12:1), 7-Tetradecenoic acid (14:1), 9-1-lexadecenoic acid (Palmitoleic acid) (16:1), 11-Decenoic acid (Vaccenic acid) (18:1), 9Z, 11E conjugated Linoleic acid (Rumenic acid) (18:2), 13-Eicosenoic acid (Paullinic acid) (20:1), 15-Docosenoic acid (22:1), and 17-Tetracosenoic acid (24:1).
Omega-9 fatty acids (also known as n-9 fatty acids or 6)-9 fatty acids) are a family of unsaturated fatty acids that have in common a final carbon-carbon double bond in the n-9 position, that is, the ninth bond, counting from the methyl end of the fatty acid. An omega-9 fatty acid includes, without limitation, Oleic acid (18:1), Elaidic acid (18:1), Eicosenoic acid (20:1), Mead acid (20:3), Erucic acid (22:1), Nervonic acid (24:1), Ricinoleic acid, ximenic acid (26:1).
A pharmaceutically-acceptable fatty acid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically-acceptable conjugated fatty acid. Conjugated fatty acids are positional and geometric isomers of polyunsaturated fatty acids in which at least one pair of double bonds are separated by only one single bond. In one aspect of this embodiment, a pharmaceutically-acceptable conjugated fatty acid is, e.g., a C16 conjugated fatty acid, a C18 conjugated fatty acid, a C20 conjugated fatty acid, a C22 conjugated fatty acid, a C24 conjugated fatty acid, a C26 conjugated fatty acid, a C28 conjugated fatty acid or a C30 conjugated fatty acid. In one aspect of this embodiment, pharmaceutically-acceptable conjugated fatty acid is, e.g., a C16-C18 conjugated fatty acid, a C 16-C20 conjugated fatty acid, a C16-C22 conjugated fatty acid, a C16-C24 conjugated fatty acid, a C16-conjugated fatty acid, a C16-C28 conjugated fatty acid, a C16-C30 conjugated fatty acid, a C18-C20 conjugated fatty acid, a C18-C22 conjugated fatty acid, a C 18-C24 conjugated fatty acid, a C18-C26 conjugated fatty acid, a C18-C28 conjugated fatty acid, a C18-conjugated fatty acid, a C20-C22 conjugated fatty acid, a C20-C24 conjugated fatty acid, a C20-C26 conjugated fatty acid, a C20-C28 conjugated fatty acid, a C20-C30 conjugated fatty acid, a C22-C24 conjugated fatty acid, a C22-C26 conjugated fatty acid, a C22-conjugated fatty acid, a C22-C30 conjugated fatty acid, a C24-C26 conjugated fatty acid, a C24-C28 conjugated fatty acid, a C24-C30 conjugated fatty acid, a C26-C28 conjugated fatty acid, a C26-C30 conjugated fatty acid, or C28-C30 conjugated fatty acid.
In another aspect of this embodiment, a pharmaceutically acceptable conjugated fatty acid includes, e.g., a conjugated Linoleic acid, a conjugated Linoelaidic acid, a conjugated a-Linolenic acid, a conjugated y-Linolenic acid, a conjugated Calendic acid, a conjugated Eicosadienoic acid, a conjugated Stearidonic acid, a conjugated Nonadecylic acid, a conjugated Arachidic acid, a conjugated Dihomo-y-linolenic acid, a conjugated DocoSadienoic, a conjugated Mead acid, a conjugated Arachidonic acid, a conjugated Eicosapentaenoic acid, a conjugated Adrenic acid, a conjugated Docosapentaenoic acid, a conjugated Heneicosylic acid, a conjugated Tetracosatetraenoic acid, a conjugated Tetracosapentaenoic acid, a conjugated Behenic acid, a conjugated Docosahexaenoic acid, a conjugated Tricosylic acid, a conjugated Lignoceric acid, a conjugated Pentacosylic acid, a conjugated Cerotic acid, a conjugated Heptacosylic acid, a conjugated Montanic acid, a conjugated Nonacosylic acid, a conjugated Melissic acid, a conjugated Henatriacontylic acid, a conjugated Lacceroic acid, a conjugated Psyllic acid, a conjugated Geddic acid, a conjugated Ceroplastic acid, a conjugated Hexatriacontylic acid, or any combination thereof.
A pharmaceutically-acceptable fatty acid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically-acceptable conjugated linoleic acid (CLA).
Conjugated linoleic acid (CLA) refers to a group of at least 28 positional and geometric isomers of the omega-6 essential fatty acid linoleic acid (cis-9, cis-12, octadecadienoic acid). The double bonds of CLAS are conjugated, with only one single bond between them.
Virtually all cis-and trans-isomeric combinations of CLA have been identified. A CLA includes, without limitation, cis-9, trans-11, octadecadienoic acid (c-9, t-11 CLA), cis-9, cis-11, octadecadienoic acid (c-9, c-11 CLA), trans-9, trans-11, octadecadienoic acid (t-9, t-11 CLA), and trans-9, cis-11, octadecadienoic acid (t-9, c-11 CLA), cis-9, trans-11, conjugated linoleic acid (c-9, t-11 CLA), cis-9, cis 11, conjugated linoleic acid (c-9, c-11 CLA), trans-9, trans 11, conjugated linoleic acid (t-9, t-11 CLA), and trans-9, cis-11, conjugated linoleic acid (t-9, c-11 CLA), cis-10, trans 12, conjugated linoleic acid (c-10, t-12 CLA), cis-10, cis-12, conjugated linoleic acid (c-10, c-12 CLA), trans-10, trans-12, conjugated linoleic acid (t-10, t-12 CLA), and trans-i0, cis 12, conjugated linoleic acid (t-10, c-12 CLA), and any combination thereof.
In an aspect of this embodiment, a pharmaceutical composition comprises a compound(s) of Formula [X] and an Omega-3 fatty acid(s). In another aspect of this embodiment, a pharmaceutical composition comprises a compound(s) of Formula [X] and an Omega-6 fatty acid(s). In yet another aspect of this embodiment, a pharmaceutical composition comprises a compound(s) of Formula [X] and an Omega-7 fatty acid(s). In still another aspect of this embodiment, a pharmaceutical composition comprises a compound(s) of Formula [X] and an Omega-9 fatty acid(s). In other aspects, a pharmaceutical composition comprises a compound(s) of Formula [X] and an Omega-3 fatty acid, an Omega-6 fatty acid, an Omega-7 fatty acid, an Omega-9 fatty acid, or any combination thereof. In yet other aspects, a pharmaceutical composition comprises a compound(s) of Formula [X] and C-Linolenic acid, Arachidonic acid, Docosahexaenoic acid, Rumenic acid, or any combination thereof.

In an embodiment, a pharmaceutical composition comprises one or more compounds of Formula [X] and one or more of a fatty acid(s), wherein the fatty acid is an omega-3 fatty acid, an omega-6 fatty acid, an omega-7 fatty acid, an omega-9 fatty acid, or any combination thereof, wherein (if present) the omega-3 fatty acid is Hexadecatrienoic acid (16:3), C-Linolenic acid (18:3), Stearidonic acid (18:4), Eicosa trienoic acid (20:3), Eicosatetraenoic acid (20:4), Eicosa pentaenoic acid (20:5), Heneicosapentaenoic acid (21:5), Docosapentaenoic acid (Clupanodonic acid) (22:5), Docosahexaenoic acid (22:6), Tetracosapentaenoic acid (24:5), Tetracosahexaenoic acid (Nisinic acid) (24:6), or any combination thereof, wherein (if present) the omega-6 fatty acid is Linoleic acid (18:2), Y-linolenic acid (18:3), Calendic acid (18:3), Eicosadienoic acid (20:2), Dihomo-y-linolenic acid (20:3), Arachidonic acid (20:4), Docosadienoic acid (22:2), Adrenic acid (22:4).Docosapentaenoic acid (22:5), Tetracosatetraenoic acid (24:4), and Tetracosapentaenoic acid (24:5), or any combination thereof, wherein (if present) the omega-7 fatty acid is 5-Dodecenoic acid, 7-Tetradecenoic acid, 9-Hexadecenoic acid (Palmitoleic acid), 11-Decenoic acid (Vaccenic acid), 13-Eicosenoic acid (Paullinic acid), 15-Docosenoic acid, 17-Tetracosenoic acid, and 9Z, 11E
conjugated Linoleic acid (Rumenic acid), or any combination thereof, wherein (if present) the omega-9 fatty acid Oleic acid, Elaidic acid, Eicosenoic acid, Meadacid, Erucic acid, Nervonic acid, and Ricinoleic acid, or any combination thereof.
In an embodiment, a pharmaceutical composition comprises one or more compounds of Formula [X] and one or more of a fatty acid, plus optionally a chemotherapeutic and/or anti-proliferative agent(s) and/or one or more compounds approved for human use, optionally for anti-cancer use, by the United States Food and Drug Administration (FDA) and/or European Medicines Agency (EMA). Optionally, further/alternative constituent(s) are componentry to this composition, wherein the range of options is clear to someone of the art, some of which are disclosed elsewhere herein, and include (without limitation) pharmaceutically-acceptable carriers include vehicles, stabilizers, diluents, additives, auxiliarys or excipients, including buffers, preservatives, tonicity adjusters, salts, demulcents, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, flavoring agents, or coloring agents, a therapeutically effective amount of a chemotherapeutic or anti-proliferative agent(s), wherein the chemotherapeutic or anti-proliferative agent(s) is selected from the group consisting of an alkylating agent, a platinum agent, an antimetabolite, a topoisomerase inhibitor, an antitumor antibiotic, an aromatase inhibitor, a thymidylate synthase inhibitor, a DNA antagonist, farnesyltransferase inhibitor, a pump inhibitor, a metalloproteinase inhibitor, a ribonucleoside reductase inhibitor, a TNFC, agonist, an endothelin A receptor antagonist, a retinoic acid receptoragonist, an immuno-modulator, a hormonal and antihormonal agent, a photodynamic agent, a tyrosine kinase inhibitor, and any combination thereof.
An aspect of the invention is to use a composition(s) componentry to this disclosure, for (non-limiting) example a composition containing a compound(s) of Formula [X]
and a fatty acid(s), in a method of treatment of the human or animal body by therapy, for (non-limiting) example to treat/ameliorate/prevent/combat one or more of the diseases/disorders/pathologies/damages/processes mentioned herein, including (non-limiting) aging, signs of aging, diseases of aging, cancer and cachexia. A yet further aspect is to use a composition componentry to this disclosure, for (non-limiting) example a composition containing a compound(s) of Formula [X] and a fatty acid(s), for the manufacture of a medicament for the treatment/amelioration/prevention/combat of body damage, aging and/or a disease/disorder/pathology and/or to enhance/improve body/brain function, optionally for one or more of the therapeutic/beneficial/desirable applications mentioned herein, optionally cancer.
Fatty acids can have anti-cancer activity (e.g. refer [303, 304]). In an embodiment, when formulating a composition of a compound(s) of Formula [X] and a fatty acid(s), if this composition is to be used for an anti-cancer use, the fatty acid(s) selected should, in a preferred embodiment, be a fatty acid(s) with the greatest anti-cancer activity, especially the fatty acid(s) with the greatest anti-cancer activity at the dosage used. In especially preferred composition embodiments the anti-cancer activity of a compound(s) of Formula [X] and a fatty acid(s) synergise.
An invention embodiment is a pharmaceutical composition comprising a therapeutically effective amount of a compound(s) of Formula [X] and 9Z,I1E conjugated linoleic acid, optionally in a 1:1 ratio.
Prod rugs In addition, compounds of the Formulas [X] may have prodrug forms. Any compound that will be converted or react under biological conditions, e.g. in vivo, to provide the bioactive agent (i.e., a compound of Formula [X]) is a prodrug within the scope and spirit of the invention. For example, a derivative of a compound of Formula [X] that can hydrolyze, oxidize, or otherwise react under biological conditions to provide a compound of Formula [X]. For example, prodrug compounds of Formula [X] may be carboxylate ester moieties. A
carboxylate ester may be conveniently formed by esterifying any of the carboxylic acid functionalities found on the disclosed structure(s). For example, prodrug compounds of Formula [X] comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of a compound of Formula [X] that comprise ¨NO, ¨NO2, ¨
ONO, or ¨0NO2 moieties. Various forms of prodrugs are well known in the art.
For examples of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985), and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et. al. (Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H.
Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H. Bundgaard, p. 113-191 (1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p. 1-38 (1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, Vol. 77, p. 285 (1988); and e) N. Kakeya, et. al., Chem Phar Bull, Vol. 32, p. 692 (1984).
0 Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff .. ed., 5th ed. 1995) g) Medicinal Chemistry: Principles and Practice, King, F. D., ed. The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); The Practice of Medicinal Chemistry, Wermuth, C. G., ed., Academic Press, San Diego, Calif. (1999); Pro-drugs as Novel Delivery Systems, Vol. 14, ACS
Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate fimctionalities present in the compounds of Formula [X] with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985), or in Prodrugs: Challenges and Reward, 2007 edition, edited by Valentino Stella, Ronald Borchardt, Michael Hageman, Reza Oliyai, Hans Maag, Jefferson Tilley, pages 134-175 (Springer, 2007).
Moreover, certain compounds of Formula [X] may themselves act as prodrugs of other compounds of Formula (I).
Also included within the scope of the invention are metabolites of compounds of Formula [X], that is, compounds formed in vivo upon administration of the drug.
As used herein and unless otherwise indicated, the terms "biohydrolyzable amide,"
"biohydrolyzable ester," "biohydrolyzable carbamate," "biohydrolyzable carbonate,"
"biohydrolyzable ureide," and "biohydrolyzable phosphate" mean an amide, ester, carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (such as acetoxylmethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyl-oxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylamino alkyl esters (such as acetamidomethyl esters). Examples of .. biohydrolyzable amides include, but are not limited to, lower alkyl amides, a-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the invention and the like.
Dosage As used herein, the term "therapeutically effective amount" or "effective amount" refers to the amount of an administered compound sufficient to effect a beneficial or desired result(s) in the subject, e.g. prevents, reduces or eliminates a cause and/or symptom(s) of a disease/disorder, optionally in combination with other active compound(s). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
The effective amount of a compound of the present invention may be determined and by one of ordinary skill in the art. The specific dose level and frequency of dosage for any particular subject may vary and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the pharmacokinetics of the compound, the formulation of compound used, the species, age, body weight, general health, medical condition, medical history, resilience, sex and diet of the subject, the mode/route and frequency of administration, rate of excretion, renal and hepatic function of patient, drug combination, concurrent treatment and type and severity/extent of the particular condition, nature/type/extent of presenting symptoms, the desired effect/outcome and/or the responsiveness/reaction of the subject. In an embodiment, a physician or veterinarian determines and prescribes the effective amount of the drug required.
Broadly, small dosages may be used initially and, if necessary, increased by small increments until the desired effect under the circumstances is reached.
An exemplary effective amount of compounds of Formula [X] may be within the dosage range of about 0.001 to about 300 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) on a regimen in single or 2 to 6 (or more) divided daily doses. But more exactly it depends upon the compound used, the condition and its advancement/severity (e.g. the type and grade of cancer), the route of administration, type of dosing (e.g. pulse or consistent etc.), what other treatments are undertaken alongside or previously (e.g.
chemotherapeutics, surgery, radiotherapy, immunotherapy etc.), the age, sex, condition, previous/other diseases of the patient, pharmacokinetics of compound in that patient, response to treatment and exceptions to this dosage range are contemplated by the present invention, and can be changed during treatment to find the optimum. Optimal dosage to be administered to a subject can be determined by those skilled in the art.
Clinical trials may be used to optimize the dose and dosing frequency for any particular compound, with subsequent further optimization for each particular subject by the direction of one of ordinary skill of the art e.g. a medical/veterinary practitioner. When the compounds described herein are co-administered with another agent, the effective amount may be less than when the agent is used alone.
Once improvement of the subject's disease/disorder/condition has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Subject may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
Subjects may also require chronic treatment on a long-term basis.
Pharmaceutical composition While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation/composition. The compound(s) of Formula [X], or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, co-crystal, clathrate, or polymorph thereof, may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.
The term "pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier, , inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo. Disclosed is a pharmaceutical composition of a therapeutically effective amount of a compound(s) of Formula [X] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, additives and/or diluents. This can be manufactured by a method of the art including, but not restricted to, mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, melt-spinning, spray-drying, or lyophilizing processes. Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient, e.g. a compound(s) of Formula [X], per unit dose.
A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including (without limitation), i.e., adjuvant, excipient, carrier or vehicle, such as diluents, preserving agents, preservatives, stabalizers, fillers, flow regulating agents, disintegrating agents, encapsulating materials, coating agents, release agents, wetting agents, emulsifying agents, water, phosphate buffered saline solution, emulsions (e.g., such as an oil/water or water/oil emulsions), suspending agents, anti-oxidants, buffers, pH buffers, tonicity adjusters, osmolality adjusting agents, physiological substances, pharmacological substances, sweetening agents, flavoring agents, coloring agents, perfuming agents, bulking agents, antibacterial agents, antifungal agents, surfactants, humectants, absorbents, precipitation inhibitors, adsorbants, solution retarding agents, solvents, anti-foaming agents, salivary stimulating agents, absorption accelerators, cooling agents, lubricating agents, viscosity enhancing agents, dispensing agents, and the like, depending on the nature of the mode of administration and dosage forms. Most preferably, but not restrictively, the chosen pharmaceutically acceptable vehicle(s) (e.g., carrier(s), adjuvant(s), and/or other excipient(s)) has met the required standards of toxicological and manufacturing testing and/or is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990) or Remington: The Science and Practice of Pharmacy, 22n1 Ed., Pharmaceutical Press (2013) or Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985) or Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA
Publications, 4th edition 2003) or Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G.
Hardman etal., eds., McGraw Hill Professional, 10th ed. 2001, or 13th ed.
2017) or Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed. 1999). Suitable pharmaceutical compositions may be formulated by means known in the art, or that become available to those skilled in the art, and their mode of administration and dose determined by the skilled practitioner. These protocols are routine proceedures and any modifications are well within the scope of one skilled in the art and from the teaching herein. In preferred embodiments, pharmaceutical compositions according to the invention are sterile compositions.
A therapeutic compound disclosed herein may be formulated by itself in a pharmaceutical composition, or may be formulated together with one or more other therapeutic compounds disclosed herein in a single pharmaceutical composition. Depending upon the particular condition, or disease, to be treated, additional therapeutic agent(s) that are normally administered to treat that condition may also be present in the compositions disclosed herein.
Some examples of materials which can serve as pharmaceutically acceptable carriers include:
.. (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its analogs, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt, (6) gelatin; (7) talc.; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil: (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar, (14) buffering agents, such as magnesium hydroide and aluminum hydroxide; (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
Buffers include, without limitation, acetate buffers, citrate buffers, phosphate buffers, neutral buffered saline, phosphate buffered saline and borate buffers. It is understood that acids or bases can be used to adjust the pH of a composition as needed.
Pharmaceutically acceptable antioxidants include, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene, (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
Useful preservatives include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxychloro composition and chelants, such as, e.g., DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjustors useful in a pharmaceutical composition include, without limitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjustor.
In certain embodiments, the pharmaceutical preparation is non-pyrogenic i.e.
does not substantially elevate the body temperature of a subject.
The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of bringing into association a compound(s) of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Administration The compounds of Formula [X] may be administered by any means suitable for the condition to be treated e.g. parenteral administration e.g. by intramuscular, intradermal, epicutaneous, intraperitoneal, intravenous or intra-arterial (infusion or bolus, dose given continuously or intermittently), intracardiac, intracistemal, epidural, intrastemal, intramedullary, intravesical injection or infusion, via the cerebrospinal fluid, instillation, subcutaneous injection/implant, transdermal (e.g. by skin patch, controlled release patch), transmucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal) or oral routes, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. For further example: oral, parenteral, enteral (e.g. oral, buccal, sublabial, lingual, sublingual), infusion, injection, transdermal, topical, paste applied to tongue, intravaginal (e.g. pessaries, tampons), rectal (e.g. by suppository, retention enema, enema, Murphy drip), transcutaneous, intracutaneous, subcutaneous, sublabial, subcuticular, intramuscular, intraarticular, intracapsular, subcapsular, subarachnoid, ocular/intraocular/ophthalmic (e.g. by eye drops {optionally using a measured dose eyedropper}, eye lotion), intraorbital, intravitreal, retrobulbar, aural, ear drops, intrathecal, intraventricular, intracardiac, intrasynovial, intracerebral, intracerebroventricular (optionally using a Ommaya reservoir), intraduodenal, intradermal, transdermal, intrapleural, intraspinal, intrastemal, intrathecal, intralesional, intratumoral, intracavemous (base of penis), extra-amniotic administration/infusion, perivascular administration, intravesicular, intraosseously (e.g. intraosseous infusion), endotracheally, transtracheal, intravaginal, nasally, by inhalation, insufflation (snorting), by skin patch, by dermal patch, by transdermal patch (e.g., without restriction, matrix type patch, reservoir type patch, monolithic drug-in-adhesive type patch, multilaminate drug-in-adhesive type patch, and the like, refer Ghosh TK, Pfister WR, Yum SI, Transdermal and Topical Drug Delivery Systems, Interpharm Press, Inc., one of ordinary skill in the art can determine other patches which can be employed in the present invention), by adhesive bandage, transdermal spray, transdermal implant, nanocell injection, patient controlled pump, peripherally inserted central catheter (PIC line), delivery by catheter, indwelling catheter, gastric/duodenal feeding tube, gastrostomy, enteral nutrition, balloon (drug-eluting balloon), stent (drug-eluting stent), vaginal ring, vaginal sponge, vaginal douche, intrauterine device, cervical ring and the like, local injection into a body part(s) that is affected by a cancer(s). The compound may be delivered by pill/tablet/capsule/pastille/time release technology/modified release dosage/osmotic delivery system/orally disintegrating tablet/film/lollipop/sublingual drops/lozenges/effervescent buccal tablet/chewing gum/smoking device/dry-powder inhaler/vaporizer/nebulizer/metered-dose inhaler/gas mask/nasal cannula/nasal spray/mucoadhesive microdisc/pessary/suppository/electuary/emulsion/extended-release syrup/effervescent [powder/tablet]/hydrogel/molecular =
encapsulation/powder/softgel/solution/suspension/syrup/syrup concentrate for dilution and/or addition of carbonated water/tincture/moutwash/toothpaste/ointment/oral spray/nasal spray/liniment/electrophoretic dermal delivery system/liposomes/transfersome vesicles/lip balm/shampoo/jet injector/vapor/solid/decoction/ointment/cream/salve/oil/rinse/alcohol/spray/aer osol/foam/past e/lotion/tincture/shake lotion/gel/implant/dressing/sponge/tape/drop/powder/patch/transdermal patch/electroporation/iontophoresis/phonophoresis/sonophoresis, penetration enhancers may be incorporated e.g. see Finnin and Morgan, J. Pharm. Sci. 1999, 88, 955-958).
In other embodiments, local administration may be accomplished by implanting a sustained-release device such as a pump or a micropump, or sustained-release implant, such as a bead or gel that contains the compound(s), e.g. anti-cancer agent, and slowly releases the drug into the desired area over time. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. The compound may be delivered orally, such as in the form of tablets(optionally chewable)/caplets/capsules/pills/lozenges(including liquid filled)/pastilles/electuary/paste/oral films/[buccal/mucoadhesive] patches (each of which also includes sustained release or timed release formulations), granules, pastilles (e.g. using an inert base, such as gelatin and glycerin, or sucrose and acacia), lozenges (e.g. using a flavored basis, usually sucrose and acacia or tragacanth), lyophilisates, dragees, cachets, troches, microgranules, pellets, soft-gels, powders, powders for reconstitution, dispersions, tinctures, or liquid formulations including syrups, liquids, solutions, elixirs, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), emulsions, microemulsions, solutions, mouthwashes, elixirs and the like, each containing a predetermined amount of a compound(s) of the present invention as an active ingredient; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration;
emulsions or magmas;
sublingually; bucally; transdermally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions; sterile solids {e.g., crystalline or amorphous solids} that can be reconstituted to provide liquid dosage forms suitable for parenteral administration);
nasally such as by inhalation spray (aerosol, nasal spray, inhaler, nebuliser etc.); rectally such as in the form of suppositories; or liposomally; each containing a predetermined amount of a compound(s) of the present invention as an active ingredient. A compound(s) of the present invention may also be administered as a bolus, electuary or paste. A
compound(s) of this invention can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release.
Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.
To illustrate, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) .. wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared' using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystal line cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavouring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, sugar(s), dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents, granulating agents and lubricants such as those known in the art. The inventive compounds may be orally delivered by sublingual and/or buccal administration, e.g., with molded, compressed, or freeze-dried tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL0) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g., GANTREZ0); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 9340). Lubricants, glidants, flavours, colouring agents and stabilizers may also be added for ease of fabrication and use.
Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain:
pharmaceutically-acceptable excipients such as preservatives, buffers, propellants, suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents. Indeed, liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
Oily Suspensions may be formulated by suspending a therapeutic compound disclosed herein in admixture with (a) Vegetable oils, such as, e.g., almond oil, arachis oil, avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed oil, olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, walnut oil, wheat germ oil, or a combination thereof, (b) a saturated fatty acid, an unsaturated fatty acid, or a combination thereof.
Such as, e.g., palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a combination thereof, (c) mineral oil such as, e.g., liquid paraffin, (d) Surfactants or detergents.
The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
A therapeutic compound disclosed herein may be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil as disclosed herein or a mineral oil as disclosed herein or mixtures thereof. Suitable emulsifying agents may be naturally occurring gums, such as, e.g., gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Inhibition of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
.. Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide.
Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
Exemplary compositions for parenteral administration include injectable solutions or suspensions, preferably sterile and preferably buffered to an appropriate pH
and isotonicity, and/or which may contain, for example, suitable non-toxic, parenterally acceptable diluents, oils or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, ethyl alcohol, polyethylene glycol, polypropylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms provided herein. For example, cyclodextrin and/or its derivatives can be used to increase the solubility of a compound provided herein.
Sterile compositions of compound(s) of this invention are contemplated by the invention, indeed preferred, including compositions that are in accord with national and local regulations governing such compositions.
Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active ingredient.
Exemplary compositions for rectal/vaginal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal/vaginal cavity to release the drug. Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose analogs, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Ophthalmic formulations, eye ointments, powders, solutions, drops and the like, are also contemplated as being within the scope of this invention.
Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the composition in the proper medium. Absorption enhancers can also be used to increase the flux of the composition across the skin. The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.
In some embodiments, a compound or pharmaceutical formulation in accordance may be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent etc. Implants may be devised which are intended to contain and release such compounds or compositions. An example would be an implant made of a polymeric material adapted to release the compound over a period of time.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compounds described herein, when in liposome form can contain, in addition to the compounds described herein, stabilizers, preservatives, excipients, and the like. Methods to form liposomes are known in the art. (See, e.g., Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., (1976), P33 et seq.).
Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
The composition, shape, and type of dosage forms provided herein may vary depending on their use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients than an oral dosage form used to treat the same disease. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).
Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form provided herein depends on a variety of factors, including, but not limited to, the route of administration. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition.
Consequently, encompassed herein are pharmaceutical compositions and dosage forms that contain little, if any, lactose. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
Lactose-free compositions provided herein can comprise excipients that are listed, for example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In certain embodiments, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. In certain embodiments, lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
Further encompassed herein are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time.
See, e.g., Jens T.
Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, in certain embodiments, provided herein are anhydrous compositions packaged using materials to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
Encompassed herein are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
Examples of pharmaceutically-acceptable antioxidants include, but are not limited to: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
The pH of a pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent.
Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound(s) of Formula [X], a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.
Alternatively, the compound(s) of Formula [X] may be in the form of multiparticulate beads.
The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %. Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
The compounds of the invention (including pharmaceutically acceptable salts thereof) can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone; as a mixture, for example, in a dry blend with lactose; or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurized container, pump, spray, atomizer (for example an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns).
This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
In inhaled dosage forms, the therapeutic compound(s) may be prepared for delivery as an aerosol in a liquid propellant for use in a pressurised (PD!) or other metered dose inhaler (MDI). Propellants suitable for use in a PD! or MDI include, without limitation, CFC-12, HFA-134a, HFA-227, HCFC-22 (difluorochloromethane), HFA-152 (difluoroethane and isobutane). A therapeutic compound may also be delivered using a nebulisers or other aerosol delivery system. A therapeutic compound may be prepared for delivery as a dry powder for use in a dry powder inhaler (DPI). A dry powder for use in the inhalers will usually have a mass median aerodynamic diameter of less than 30 pm, preferably less than 20 pm and more preferably less than 10 pm. Microparticles having aerodynamic diameters in the range of about 5 pm to about 0.5 pm will generally be deposited in the respiratory bronchioles, whereas smaller particles, having aerodynamic diameters in the range of about 2 pm to about 0.05 pm, are likely to be deposited in the alveoli. A DPI may be a passive delivery mechanism, which relies on the individual's inspiration to introduce the particles into the lungs, or an active delivery mechanism, requiring a mechanism for delivering the powder to the individual. In inhalatory formulations, a therapeutically effective amount of a therapeutic compound disclosed herein for an inhaled formulation may be between about 0.0001% (w/v) to about 60% (w/v), about 0.001% (w/v) to about 40.0% (w/v), or about 0.01%
(w/v) to about 20.0% (w/v). In inhalatory formulations, a therapeutically effective amount of a therapeutic compound disclosed herein for an inhaled formulation may also be between about 0.0001% (w/w) to about 60% (w/w), about 0.001% (w/w) to about 40.0% (w/w), or about 0.01% (w/w) to about 20.0% (w/w).
Tablets Tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms may be prepared by some known methods of pharmacy. In certain embodiments, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
In certain embodiments, a tablet is prepared by compression or molding. In certain embodiments, compressed tablets are be prepared by compressing in a suitable machine the active ingredients in a free-flowing form, e.g., powder or granules, optionally mixed with an excipient. In certain embodiments, molded tablets are made by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent.
Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
Suitable forms of microcrystalline cellulose include, but are not limited to, AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (e.g., AVICEL

RC-581). Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103Tm and Starch 1500 LM.
Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. In certain embodiments, the binder or filler in pharmaceutical compositions provided herein is present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
Disintegrants are used in the compositions provided herein to provide tablets the ability to disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms provided herein. The amount of disintegrant used varies based upon the type of formulation. In certain embodiments, the pharmaceutical compositions provided herein comprise from about 0.5 to about 15 weight percent or from about 1 to about 5 weight percent of disintegrant.
Disintegrants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
Lubricants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, but are not limited to, a syloid silica gel (AEROSIL200, W.R. Grace Co., Baltimore, Md.), a coagulated aerosol of synthetic silica (Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide, Cabot Co. of Boston, Mass.), and mixtures thereof. In certain embodiments, if used at all, lubricants are used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

In certain embodiments, provided herein is a solid oral dosage form, comprising a compound(s) of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, co-crystal, clathrate, or polymorph thereof; and one or more excipients selected from anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
If required, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art.
One method includes the use of lipid excipients in the formulation. See "Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences)," David J. Hauss, ed. Informa Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed. Wiley-Interscience, 2006. Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROLTm and PLURONICTM (BASF
Corporation), or block copolymers of ethylene oxide and propylene oxide.
Controlled release Administration of compounds in controlled release formulations is useful where the compound of the present invention has (i) a narrow "therapeutic index" e.g. the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; generally, the therapeutic index (TI) is defined as the ratio of median lethal dose (LD50), or median toxic dose (TD50), to median effective dose (ED50);
(ii) a narrow absorption window in the gastro-intenstinal tract; or (iii) a short biological half-life, such that frequent dosing during a day is required in order to sustain the plasma concentration at a therapeutic level.
Many strategies can be pursued to obtain controlled release in which the rate of release outweighs the rate of metabolism of the therapeutic compound. For example, controlled release can be obtained by the appropriate selection of formulation parameters and ingredients, including e.g. appropriate controlled release compositions and coatings.
Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticle formulations, patches, and liposomes.
In certain embodiments, the active ingredients provided herein are administered by controlled .. release means or by delivery devices. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;
4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference in its entirety. In certain embodiments, such dosage forms are be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Encompassed herein are single unit dosage forms suitable for oral administration, including, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
Controlled release II

Compound(s) herein may also be formulated so as to provide slow or controlled release of this compound(s) using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes, microemulsions and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include aluminum monostearate, gelatin, polymeric substances and waxes.
The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the excipients herein or known to those of the art.
Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release formulations for the purposes of the invention are described in U.S. Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. Compounds of the invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(DL-lactic-coglycolic acid) (PLGA) microspheres.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of an administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle or by forming and using microencapsuled matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled.
Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.

A therapeutic compound(s) disclosed herein, or a composition comprising such a therapeutic compound(s), may be incorporated into a drug delivery platform in order to achieve a controlled release profile over time. Such a drug delivery platform comprises a therapeutic compound(s) disclosed herein dispersed within a polymer matrix, typically a biodegradable, bioerodible, and/or bioresorbable polymer matrix. As used herein, the term "polymer" refers to synthetic homo- or copolymers, naturally occurring homo- or copolymers, as well as synthetic modifications or derivatives thereof having a linear, branched or star structure.
Copolymers can be arranged in any form, such as, e.g., random, block, segmented, tapered blocks, graft, or triblock. Polymers are generally condensation polymers.
Polymers can be further modified to enhance their mechanical or degradation properties by introducing cross-linking agents or changing the hydrophobicity of the side residues. If crosslinked, polymers are usually less than 5% crosslinked, usually less than 1% crosslinked.
Suitable polymers include, without limitation, alginates, aliphatic polyesters, polyalkylene oxalates, polyamides, polyamidoesters, polyanhydrides, polycarbonates, polyesters, polyethylene glycol, polyhydroxyaliphatic carboxylic acids, polyorthoesters, polyoxaesters, polypeptides, polyphosphazenes, polysaccharides, and polyurethanes. The polymer usually comprises at least about 10% (w/w), at least about 20% (w/w), at least about 30% (w/w), at .. least about 40% (w/w), at least about 50% (w/w), at least about 60% (w/w), at least about 70% (w/w), at least about 80% (w/w), or at least about 90% (w/w) of the drug delivery platform. Examples of biodegradable, bioerodible, and/or bioresorbable polymers and methods useful to make a drug delivery platform are described in, e.g., Drost, et. al., Controlled Release Formulation, U.S. Pat. No. 4,756,911; Smith, et. al., Sustained Release Drug Delivery Devices, U.S. Pat. No. 5,378.475; Wong and Kochinke. Formulation for Controlled Release of Drugs by Combining Hyrophilic and Hydrophobic Agents, U.S. Pat.
No. 7,048,946; Hughes, et. al., Compositions and Methods for Localized Therapy of the Eye, U.S. Patent Publication 2005/0181017: Hughes, Hypotensive Lipid-Containing Biodegradable Intraocular Implants and Related Methods, U.S. Patent Publication 2005/0244464; Altman, et al., Silk Fibroin Hydrogels and Uses Thereof, U.S.
Patent Publication 2011/0008437; each of which is incorporated by reference in its entirety.
In aspects of this embodiment, a polymer composing the matrix is a polypeptide such as, e.g., silk fibroin, keratin, or collagen. In other aspects of this embodiment, a polymer composing the matrix is a polysaccharide such as, e.g., cellulose, agarose, elastin, chitosan, chitin, or a glycosaminoglycan like chondroitin sulfate, dermatan sulfate, keratan sulfate, or hyaluronic acid. In yet other aspects of this embodiment, a polymer composing the matrix is a polyester such as, e.g., D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, caprolactone, and combinations thereof.
One of ordinary skill in the art appreciates that the selection of a suitable polymer for forming a suitable disclosed drug delivery platform depends on several factors. The more relevant factors in the selection of the appropriate polymer(s), include, without limitation, compatibility of polymer with drug, desired release kinetics of drug, desired biodegradation kinetics of platform at implantation site, desired bioerodible kinetics of platform at implantation site, desired bioresorbable kinetics of platform at implantation site, in vivo mechanical performance of platform, processing temperatures, biocompatibility of platform, and patient tolerance. Other relevant factors that, to some extent, dictate the in vitro and in vivo behavior of the polymer include the chemical composition, spatial distribution of the constituents, the molecular weight of the polymer and the degree of crystallinity.
A drug delivery platform includes both a sustained release drug delivery platform and an extended release drug delivery platform. "Sustained release" can refer to the release of a therapeutic compound disclosed herein over a period of about seven days or more.
"Extended release" can refer to the release of a therapeutic compound disclosed herein over a period of time of less than about seven days. In aspects of this embodiment, a drug delivery platform (e.g. sustained/extended release drug delivery platform) releases a therapeutic compound(s) disclosed herein with substantially zero or first order release kinetics over an illustrative (not restrictive) period of, e.g., about 1 day after administration, about 2 days after administration, about 3 days after administration, about 4 days after administration, about 5 days after administration, about 6 days after administration, about 7 days after administration, about 15 days after administration, about 30 days after administration, about 45 days after administration, about 60 days after administration, about 75 days after administration, or about 90 days after administration. In other aspects of this embodiment, a drug delivery platform (e.g. sustained/extended release drug delivery platform) releases a therapeutic compound(s) disclosed herein with substantially zero or first order release kinetics over an illustrative (not restrictive) period of, e.g., at most 1 day after administration, at most 2 days after administration, at most 3 days after administration, at most 4 days after administration, at most 5 days after administration, or at most 6 days after administration, at least 7 days after administration, at least 15 days after administration, at least 30 days after administration, at least 45 days after administration, at least 60 days after administration, at least 75 days after administration, or at least 90 days after administration.
Micronization An invention embodiment is a micronized form of a compound(s) and/or composition(s) and/or formulation(s) of Formula [X], wherein the meaning of micronization is well understood by those of the art. A pharmaceutical composition comprising a micronized compound(s) of Formula [X] or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein the compound/composition particles have an average diameter of less than 30 microns.
Smaller particles have increased surface area to volume ratio, which can deliver greater water solubility in the gastrointestinal tract and thence increased bioavailability, especially useful for compounds with poor water solubility, wherein many compounds of Formula [X] have poor water solubility.
Micronization is the process of reducing the average diameter of a material's particles. It usually refers to the reduction of average particle diameters to the micrometer range, but can also describe further reduction to the nanometer scale (nanonization). Many micronization techniques are based on friction to reduce particle size. Such methods include one or more of milling, bashing, grinding, crushing, cutting of larger particles into smaller particles. More modern methods use supercritical fluids and fluid energy, to accelerate and collide particles, in the micronization process. The most widely applied techniques of this category include the RESS process (Rapid Expansion of Supercritical Solutions), the SAS method (Supercritical Anti-Solvent) and the PGSS method (Particles from Gas Saturated Solutions).
Preferably micronized means to reduce to particles that possess an average diameter of less than about 30 microns in diameter, preferably less than about 20 microns, more preferably less than about 10 microns, and still more preferably less than about 5 microns. The average diameter (e.g., volume diameter) of the particles is typically at least about 400 nm, preferably at least about 500 nm, more preferably at least about 700 nm, such as at least about 800 nm or even at least about 1000 nm. An exemplary preferred formulation of the invention includes particles having an average diameter of about 0.8 (or 1.0) to about 5.0 microns, such as about 0.8 (or 1.0) to about 2 microns. A micronized drug form promotes better and more uniform absorption than forms having a larger average size and a wider distribution of particle sizes.
In certain embodiments, a large proportion of the particles have diameters within a defined range. For example, 80% of the particles have a diameter of from about 0.1 microns to about 20 microns, such as about 0.2 microns to about 10 microns, particularly about 0.2 microns to about 5 microns or even about 0.2 microns to about 2 microns.
Drugs according to the invention can be micronized using conventional micronization equipment, such as the Micron-Master line of micronizers available from The Jet Pulverizer Company (Moorestown, N.J.), or processed by a third-party micronization processor such as Micron Technologies (Exton, Pa.).
Many drug manufacturing, milling and micronizing machines pulverize substances into extremely fine particles, and thus reduce bulk chemicals to the required size for pharmaceutical formulation. Particles may also be micronized by chemical or temperature controlled processes. The primary benefit to micronizing is the increase in solubility/bioavailability due to the increase in surface area. These finished chemicals are combined and processed further in mixing machines. The mixed ingredients may then be mechanically capsulated, pressed into tablets, or made into solutions.
"Micronizing" can be considered to refer to the processes of making uniform particle size of a drug, wherein the size desired may be 10 microns or less, and wherein said process may be mechanical, chemical, temperature or pH controlled, or any other process known to those of the art.
Optimization and control of micronizing processes, particularly relating to particle size, are becoming ever more important in the development of pharmaceuticals. Air jet micronization is a well proven technique that consistently produces particles in the 1-30 micron range.
Micron Technologies and Jet Pharma are contract micronizers. The primary advantages of air jet micronizers are that particle reduction occurs via particle to particle collisions, with limited reduction from metal to product contact, and no generation of heat.
Other advantages include no moving parts and easy to clean surfaces.

The original principles of jet milling are simple. The powder particles are fed into the flat cylindrical milling chamber tangentially through a venturi system by pressurized air or nitrogen. The particles are accelerated in a spiral movement inside the milling chamber by a number of nozzles placed around the periphery of the chamber. The micronizing effect takes place by the collision between the incoming particles and those already accelerated into the spiral path. While centrifugal force retains the larger particles at the periphery of the milling chamber, the smaller particles exit with the exhaust air from the centre of the chamber. The particle size distribution is controlled by adjusting a number of parameters, two of the main ones being pressure and feed rate.
In general, there are two types of air jet micronizers or tangential fluid energy mills, pancake and loop. The primary difference between the two is in overall distribution.
Loop mills are excellent choices for cleaning up the tails of the distribution. An additional advantage is that both mill types generate no heat. The mills are available in numerous sizes ranging from 1", 4", 6", 8", 12", and 15" to 20" and provide flexibility in engineering the desired particle size in ranges of 1-30 micons.
U.S. Pat. Nos. 6,645,466, 6,623,760, 6,555,135, hereby incorporated by reference, describe other micronization procedures.
As used herein, particle size of micronized drug dispersions refers to an average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, disk centrifugation, and dynamic and static light scattering (e.g., laser diffraction such as Mie scattering).
Typically, micronized active compounds are formulated as a freely flowing liquid (e.g., not a gel, paste or gum) or as a solid dosage form (e.g., a tablet or capsule). Such formulations are preferably safe for internal use (e.g., ingestion, injection). Powders comprising micronized drug can be made by spray-drying aqueous dispersions of a micronized drug to form a dry powder which consists of aggregated drug particles. Alternatively, the aqueous dispersion of drug can contain a dissolved diluent, such as lactose or mannitol, which when spray dried forms diluent particles, each of which contains at least one embedded drug particle.
Micronized drug dispersions can also be freeze dried to obtain powders suitable for formulation into solid dose forms. Such powders comprise aggregated micronized drug particles. Freeze dried powders can also be obtained by freeze drying aqueous dispersions of drug, which additionally contain a dissolved diluent such as lactose or mannitol. In these instances the freeze dried powders consist of particles of diluent, each of which contains at least one embedded drug particle.
Other known methods of processing liquid dispersions, and which can be employed in the present invention, include granulation, including but not limited to high shear granulation, fluid bed granulation, roto granulation, and melt granulation. Additional methods such as spray coating and extrusion spherization can also be used. Any other conventional method for drying or otherwise processing a liquid dispersion can also be used in the invention.
The particles are preferably reduced in size at a temperature which does not significantly degrade the drug substance. Processing temperatures of less than about 30 degrees to about 40 degrees Centigrade are ordinarily preferred. If desired, the processing equipment can be cooled with conventional cooling equipment. The method is conveniently carried out under conditions of ambient temperature and at processing pressures which are safe and effective for the milling process.
Typically, micronized drug dispersions contain a discrete phase of a drug substance as described above having a surface modifier adsorbed on the surface thereof.
Useful surface modifiers are believed to include those which physiccally adhere to the surface of the drug substance but do not chemically bond to the drug. Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants, such as nonionic and anionic surfactants. Representative examples of excipients include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, Stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available Tweens (Tween 80), polyethylene glycols, polyoxyethylene stearates, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylm ethycellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most of these excipients are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986, the disclosure of which is hereby incorporated by reference in its entirety. The surface modifiers are commercially available and/or can be prepared by techniques known in the art.
Nanoparticles An aspect of the present invention provides a composition that includes nanoparticles comprising a compound(s) of Formula [X], or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. Such particles can, for example, have a mean diameter of 50 nm to 500 nm, such as 100 nm to 200 nm.
Nanoparticles are particles with a diameter from about 5 nm to up to about 1000 nm. The term "nanoparticles" can refer to particles formed by a polymeric matrix in which the active compound is dispersed, also known as "nanospheres, and also refers to nanoparticles which are composed of a core containing the active compound which is surrounded by a polymeric membrane, also known as "nanocapsules.
Nanoparticles can be prepared by in situ polymerization of dispersed monomers or by using preformed polymers. Since polymers prepared in situ are often not biodegradable and/or contain toxicological byproducts, nanoparticles from preformed polymers are preferred.
Nanoparticles from preformed polymers can be prepared by different techniques, e.g., by emulsion evaporation, solvent displacement, salting-out and by emulsification diffusion.
Emulsion evaporation is the classical technique for preparation of nanoparticles from preformed polymers. According to this technique, the polymer and the active compounds are dissolved in a water-immiscible organic solvent, which is emulsified in an aqueous solution.
The crude emulsion is then exposed to a high-energy source such as ultrasonic devices or passed through high pressure homogenizers or microfluidizers to reduce the particle size.
Subsequently the organic solvent is removed by heat and/or vacuum resulting in formation of the nanoparticles with a diameter of about 100 nm to about 300 nm. Usually, methylene chloride and chloroform are used as organic solvent because of their water insolubility, good solubilizing properties, easy emulsification and high volatility. These solvents are, however, critical in view of their physiological tolerability. Moreover, the high shear force needed for particle size reduction can lead to damage of polymer and/or the active compound.
The solvent displacement process is described in EPO 274.961 Al. In this process the active compound and the polymer are dissolved in an organic solvent which is miscible with water in all proportions. This solution is introduced in an aqueous solution containing a stabilizer under gentle agitation resulting in spontaneous formation of nanoparticles.
Examples for suitable organic solvents and stabilizer are acetone or ethanol.
Advantageously chlorinated solvents and shear stress can be avoided. The mechanism of formation of nanoparticles has been explained by interfacial turbulence generated during solvent displacement (Fessi et al., Int. J. Pharm. 55:R1-R4 (1989)). A solvent displacement technique was disclosed by WO 97/03657A1, in which the organic solvent containing the active compound and the polymer is introduced into the aqueous solution without agitation.
The salting-out technique is firstly in WO 88/08011A1. In this technique a solution of a water-in soluble polymer and an active compound in a water-miscible organic solvent. Such as acetone, is mixed with a concentrated aqueous viscous solution or gel containing a colloidal stabilizer and a salting-out agent. To the resulting oil-in water emulsion water is added in a quantity sufficient to diffuse into the aqueous phase and to induce rapid diffusion of the organic solvent into the aqueous phase leading to interfacial turbulence and formation of nanoparticles. The organic solvent and the salting-out agent remaining in the suspension of nanoparticles are subsequently eliminated by repeated washing with water.
Alternatively, the solvent and salting-out agent can be eliminated by cross-flow filtration.
In emulsification-diffusion process the polymer is dissolved in a water-saturated partially water-soluble organic solvent. This solution is mixed with an aqueous solution containing a stabilizer resulting in an oil-in-water emulsion. To this emulsion water is added causing the solvent to diffuse into the aqueous external phase accompanied with formation of nanoparticles. During particle formation each emulsion droplet leads to several nanoparticles.
As this phenomenon cannot be fully explained by convection effect caused by interfacial turbulence, it has been proposed that diffusion of organic solvent from the droplets of the crude emulsion carries molecules of active compound and polymer phase into the aqueous phase resulting in supersaturated local regions, from which the polymer aggregates in the form of nanoparticles (Quintanar-Guerrero et al., Colloid. Polym. Sci. 275:640-647 (1997)).
Advantageously, pharmaceutically acceptable solvents like propylene carbonate or ethyl acetate are used as organic solvents.
With the methods described above, nanoparticles can be formed with various types of polymers. For use in the method of the present invention, nanoparticles made from biocompatible polymers are preferred. The term "biocompatible" refers to material that after introduction into a biological environment has no serious effects to the biological environment. From biocompatible polymers those polymers are especially preferred which are also biodegradable. The term "biodegradable' refers to material that after introduction into a biological environment is enzymatically or chemically degraded into smaller molecules, which can be eliminated subsequently. Examples are polyesters from hydroxycarboxylic acids such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polycaprolactone (PCL), copolymers of lactic acid and glycolic acid (PLGA), copolymers of lactic acid and caprolactone, polyepsilon caprolactone, polyhyroxy butyric acid and poly(ortho)esters, polyurethanes, polyanhydrides, polyacetals, polydihydropyrians, polycyanoacrylates, natural polymers such as alginate and other polysaccharides including dextran and cellulose, collagen and albumin.
Additional methods of preparing nanoparticles include the steps of dispersing a therapeutic or diagnostic agent in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the therapeutic or diagnostic agent to an effective average particle size of less than about 400 nm. The particles can be reduced in size in the presence of a surface modifier. Alternatively, the particles can be contacted with a surface modifier after attrition.
It is preferred, but not essential, that the particle size of the compound/composition of Formula [X] be less than about 10 mm as determined by sieve analysis. If the coarse particle size is greater than about 100 mm, then it is preferred that the particles be reduced in size to less than 100 mm using a conventional milling method such as airjet or fragmentation milling.
The compound(s) of Formula [X] can then be added to a liquid medium in which it is essentially insoluble to form a premix. The concentration of the therapeutic or diagnostic agent in the liquid medium can vary from about 0.1-99%, and preferably is from 5-30%
(w/w). It is preferred, but not essential, that the surface modifier be present in the premix.
The concentration of the surface modifier can vary from about 0.1 to about 90%, and preferably is 1-75%, more preferably 20-60%, by weight based on the total combined weight of the compound(s) of Formula [X] and surface modifier. The apparent viscosity of the premix suspension is preferably less than about 1000 centipoise.
The premix can be used directly by subjecting it to mechanical means to reduce the average particle size in the dispersion to less than 1000 nm. It is preferred that the premix be used directly when a ball mill is used for attrition. Alternatively, the therapeutic or diagnostic agent and, optionally, the surface modifier, can be dispersed in the liquid medium using suitable agitation, e.g., a roller mill or a Cowles type mixer, until a homogeneous dispersion is observed in which there are no large agglomerates visible to the naked eye.
It is preferred that the premix be subjected to such a premilling dispersion step when a recirculating media mill is used for attrition.
The mechanical means applied to reduce the particle size of compound(s)/composition(s) of Formula [X] conveniently can take the form of a dispersion mill. Suitable dispersion mills include a ball mill, an attritor mill, a vibratory mill, and media mills such as a sand mill and a bead mill. A media mill is preferred due to the relatively shorter milling time required to provide the intended result, desired reduction in particle size. For media milling, the apparent viscosity of the premix preferably is from about 100 to about 1000 centipoise.
For ball milling, the apparent viscosity of the premix preferably is from about 1 to about 100 centipoise. Such ranges tend to afford an optimal balance between efficient particle fragmentation and media erosion.
The attrition time can vary widely and depends primarily upon the particular mechanical means and processing conditions selected. For ball mills, processing times of up to five days or longer may be required. On the other hand, processing times of less than 1 day (residence times of one minute up to several hours) have provided the desired results using a high shear media mill.
The particles must be reduced in size at a temperature which does not significantly degrade the compound(s) of Formula [X]. Processing temperatures of less than about 30-40 C are ordinarily preferred. If desired, the processing equipment can be cooled with conventional cooling equipment. The method is conveniently carried out under conditions of ambient temperature and at processing pressures which are safe and effective for the milling process.
For example, ambient processing pressures are typical of ball mills, attritor mills and vibratory mills. Control of the temperature, e.g., by jacketing or immersion of the milling chamber in ice water are contemplated. Processing pressures from about 1 psi (0.07 kg/cm2) up to about 50 psi (3.5 kg/cm2) are contemplated. Processing pressures from about 10 psi (0.7 kg/cm2) to about 20 psi (1.4 kg/cm2).
The surface modifier, if it was not present in the premix, must be added to the dispersion after attrition in an amount as described for the premix above. Thereafter, the dispersion can be mixed, e.g., by shaking vigorously. Optionally, the dispersion can be subjected to a sonication step, e.g., using an ultrasonic power supply. For example, the dispersion can be subjected to ultrasonic energy having a frequency of 20-80 kHz for a time of about 1 to 120 seconds.
After attrition is completed, the grinding media is separated from the milled particulate product (in either a dry or liquid dispersion form) using conventional separation techniques, such as by filtration, sieving through a mesh screen, and the like.
In a particular method, a compound(s) of Formula [X] is prepared in the form of submicron particles by grinding the agent in the presence of a grinding media having a mean particle size of less than about 75 microns.
Another method of forming a nanoparticle dispersion is by microprecipitation.
This is a method of preparing stable dispersions of a compound(s) of Formula [X] in the presence of a surface modifying and colloid stability enhancing surface active agent free of any toxic solvents or solubilized heavy metal inpurities by the following procedural steps:
I. Dissolving the therapeutic or diagnostic agent in aqueous base with stirring, 2. Adding above #1 formulation with stirring to a surface active surfactant (or surface modifiers) solution to form a clear solution, and 3. Neutralizing above formulation #2 with stirring with an appropriate acid solution. The procedure can be followed by:
4. Removal of formed salt by dialysis or diafiltration and 5. Concentration of dispersion by conventional means.
This microprecipitation process produces a dispersion of a compound(s) of Formula [X] with Z-average particle diameter less than 400 nm (as measured by photon correlation spectroscopy) that is stable in particle size upon keeping under room temperature or refrigerated conditions. Such dispersions also demonstrate limited particle size growth upon autoclave-decontamination conditions used for standard blood-pool pharmaceutical agents.
In one embodiment, the above procedure is followed with step 4 which comprises removing the formed salts by diafiltration or dialysis. This is done in the case of dialysis by standard dialysis equipment and by diafiltration using standard diafiltration equipment known in the art. Preferably, the final step is concentration to a desired concentration of the agent dispersion. This is done either by diafiltration or evaporation using standard equipment known in this art.
In another embodiment of the microprecipitation process, a crystal growth modifier is used.
A crystal growth modifier is defined as a compound that in the co-precipitation process incorporates into the crystal structure of the microprecipitated crystals of the pharmaceutical agent, thereby hindering growth or enlargement of the microcrystalline precipitate, by the so called Ostwald ripening process. A crystal growth modifier (or a CGM) is a chemical that is at least 75% identical in chemical structure to the pharmaceutical agent. By "identical' is meant that the structures are identical atom for atom and their connectivity.
Structural identity is charactarized as having 75% of the chemical structure, on a molecular weight basis, identical to the therapeutic or diagnostic agent. The remaining 25% of the structure may be absent or replaced by different chemical structure in the CGM. The crystal growth modifier is dissolved in step #1 above with the therapeutic or diagnostic agent.
Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight .. oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and ionic surfactants. Representative examples of surface modifiers include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, Stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available TweensTm, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxy propylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most of these surface modifiers are known pharmaceutical excipients and are describedin detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986.
Particular surface modifiers include polyvinylpyrrolidone, tyloxapol, poloxamers such as PluronicsTM F68 and F108, which are block copolymers of ethylene oxide and propylene oxide, and polyxamines such as TetronicsTm 908 (also known as Poloxamine 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, available from BASF, dextran, lecithin, dialkylesters of sodium sulfosuccinic acid, such as Aerosol OTsTm, which is a dioctylester of sodium sulfosuccinic acid, available from American Cyanimid, DuponolsTM P. which is a sodium lauryl sulfate, available from DuPont, Tritons Tm X-200, which is an alkylaryl polyether sulfonate, available from Rohn and Haas, TweenTm 20 and TweenTm 80, which are polyoxyethylene sorbitan fatty acid esters, available from ICI Specialty Chemicals;
CarbowaxsTM 3550 and 934, which are polyethylene glycols available from Union Carbide:
CrodestasTM F-110, which is a mixture of sucrose stearate and sucrose distearate, available from Croda Inc., CrodestasTm SL-40, which is available from Croda, Inc., and SA9OHCO, which is C181-137CH2(CON(CH3)CH2(CHOH)4(CH2OH)2. Surface modifiers which have been found to be particularly useful include TetronicTm 908, the TweensTm, PluronicsTM F-68 and polyvinylpyrrolidone. Other useful surface modifiers include: decanoyl-N-methylglucamide;
n-decyl-beta-D-glucopyranoside; n-decyl-beta-D-maltopyranoside; n-dodecyl beta-D-glucopyranoside; n-dodecyl-beta-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-beta-Dglucopyranoside; n-heptyl-beta-D-thioglucoside; n-hexyl beta-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl-beta-D-glucopyranoside; octanoyl-N-methylglucam ide; n-octyl-beta-D-glucopyranoside; octyl beta-D-thioglucopyranoside; and the like.

Another useful surface modifier is tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type; also known as superinone or triton). Another Surface modifier is p-isononylphenoxypoly(glycidol) also known as Olin-10GTm or Surfactant 10-G, commercially available as lOGIm from Olin Chemicals, Stamford, Conn.
Two-or more surface modifiers can be used in combination.
Auxiliary surface modifiers can be used to impart resistance to particle aggregation during sterilization and include dioctylsulfosuccinate (DOSS), polyethylene glycol, glycerol, sodium dodecyl sulfate, dodecyl trimethyl ammonium bromide and a charged phospholipid such as dimyristoyl phophatidyl glycerol. Two or more auxiliary surface modifiers can be used in combination.
Further description on preparing nanoparticles can be found, for example, in U.S. Pat. No.
6,264,922, the contents of which are incorporated herein by reference.
Liposomes Liposomes are a further drug delivery system. Accordingly, in the method of invention the active compound(s) can also be administered in the form of a liposome delivery system.
Liposomes are well-known by a person skilled in the art. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine of phosphatidylcholines.
Liposomes being usable for the method of invention encompass all types of liposomes including, but not limited to, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
= 25 Liposomes are used for a variety of therapeutic purposes, and in particular, for carrying therapeutic agents to target cells. Advantageously, liposome-drug formulations offer the potential of improved drug-delivery properties, which include, for example, controlled drug release. An extended circulation time is often needed for liposomes to reach a target region, cell or site. In particular, this is necessary where the target region, cell or site is not located near the site of administration. For example, when liposomes are administered systemically, it is desirable to coat the liposomes with a hydrophilic agent, for example, a coating of hydrophilic polymer chains such as polyethyleneglycol (PEG) to extend the blood circulation lifetime of the liposomes. Such surface-modified liposomes are commonly referred to as "long circulating or "sterically stabilized" liposomes.
One surface modification to a liposome is the attachment of PEG chains, typically having a molecular weight from about 1000 daltons (Da) to about 5000 Da, and to about 5 mole percent (%) of the lipids making up the liposomes (see, for example, Stealth Liposomes, CRC
Press, Lasic. D. and Martin, F., eds., Boca Raton, Fla., (1995)), and the cited references therein. The pharmacokinetics exhibited by such liposomes are characterized by a dose-independent reduction in uptake of liposomes by the liver and spleen via the mononuclear phagocyte system (MPS), and significantly prolonged blood circulation time, as compared to non surface-modified liposomes, which tend to be rapidly removed from the blood and accumulated in the liver and spleen.
The PEG moiety can have a molecular weight of for example, 750-20,000 Daltons, such as 1000-10,000 Daltons, in particular 2000-5000 Daltons. In one embodiment, the complex may comprise more than one type of PEG moiety (for example, PEG molecular weight 5K and PEG molecular weight 2K). The PEG moiety may further comprise a suitable functional group, such as, for example, methoxy, N-hydroxyl succinimide (NHS), carbodimide, etc., for ease of conjugating PEG to the lipid or to the targeting factor.
Table 2 of Harasym et al. Advanced Drug Delivery Reviews 32:99-118 (1998) provides examples of suitable functional groups. Functionalized PEG moieties can be purchased from, for example, Shearwater Polymer Inc. (Huntsville, Ala.) and Avanti Polar Lipid Inc.
(Alabaster, Ala.). In an exemplary embodiment, the PEG moiety is N-[methoxy(polyethylene glycol)-5K] (PEG5k). Other types of hydrophilic polymers may be substituted for the PEG moiety, including, for example, poloxamer and poloxamine, as described in Feldman et al. (1997) Gene Therapy 4(3):189-198: Lemieux et al. (2000) Gene Therapy 7(11):986-91;
Moghimi et al. (2000) Trends. In Biotechnology 18:412-420; Torchilin (1998) Journal of Microencapsulation 15(1): 1-19; and Claesson et al. (1996) Colloids &
Surfaces A-Physicochemical & Engineering Aspects 112(2):-3, 131-139.
The PEG moiety may be conjugated to a suitable lipid to form a "pegylated lipid'. Preferably, the PEG moiety is covalently attached to the lipid. Suitable lipids include dioleoylphosphatidyl-ethanolamine (DOPE), cholesterol, and ceramides. Lipids comprising a polar end (such as, e.g., phosphatidylethanolamines, including DOPE, DPPE and DSPE), which may be utilized for conjugating to PEG, are preferred for ease of synthesis of pegylated lipids. See Harasym et al., Advanced Drug Delivery Reviews 32:99-118 (1998) for non-limiting examples of suitable functionalized lipids. In a particular embodiment, the lipid is 1,2-distearoyl-sn-glycero-3-phosphotidylethanolamine (DSPE) or dimyristoyl phophatidylethanolamine (DMPE). In a particular embodiment, the pegylated lipid comprises 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[methoxy(polyethylene glycol)-51{] (DSPE-PEG5k) or dimyristoyl phosphatidylethanolamine-N-[methoxy(polyethylene glycol)-5K] (DSPE-PEG5k).
The PEG moiety can be conjugated to the lipid by methods known in the art.
See, for example, Woodle (1998) Adv. Drug Delivery Reviews 32:139-152 and references cited therein; Haselgruber et al. (1995) Bioconjug Chem 6:242-248: Shahinian et al.
(1995) Biochim Biophys Acta 1239:157-167; Zalipsky etal. (1994) FEBS Lett. 353:71-74;

Zalipsky et al. (1997) Bioconjug Chem. 8(2):111-118: Zalipsky et al. (1995) Bioconjug Chem. 6:705-708; Hansen et al. (1995) Biochim Biophys Acta. 1239(2):133-44;
Allen et al.
(1995) Biochim Biophys Acta 1237(2): 99-108; Zalipsky (1995) Bioconjug Chem 6(2): 150-65; Zalipsky (1993) Bioconjug Chem 4(4): 296-9; and Zalipsky (1995) in Stealth Liposomes.
(Eds: Lasic, D., et al.) CRC Press, Boca Raton, Fla., p. 93-102. Pegylated lipids are also available commercially from, for example, Shearwater Polymer Inc. (Huntsville, Ala.).
It is to be understood that compounds other than lipids, such as, for example, peptides, hydrophobic anchors or polymers, carbohydrates, metals or other ions can be used for conjugating with PEG, provided the compounds anchor PEG to the lipid complex, and allow PEG to be displayed on the surface of the lipid complex.
While not wishing to be bound by theory, the charge shielding effect provided by PEG may enhance the circulatory half-life of the complexes. Shielding may also increase the resistance (decrease the sensitivity) of nucleic acid to degradation, for example by nucleases or other species present in vitro or in vivo (e.g., hyuralonic acid, poly(Asp)) and/or decrease or prevent interactions between individual complex particles or interactions with other species present in vitro or in vivo that may lead to increased complex particle size or aggregation of complex particles. Accordingly, in a preferred embodiment, the complex comprises a neutral surface. In another preferred embodiment, the complex is charge shielded.

As used herein, the term "shielding, and its cognates such as "shielded, refers to the ability of "shielding moieties" to reduce the non-specific interaction of the complexes described herein with serum complement or with other species present in serum in vitro or in vivo. Shielding moieties may decrease the complex interaction with or binding to these species through one or more mechanisms, including, for example, non-specific steric or non-specific electronic interactions. Examples of such interactions include non-specific electrostatic interactions, charge inter actions, Van der Waals interactions, steric-hindrance and the like. For a moiety to act as a shielding moiety, the mechanism or mechanisms by which it may reduce interaction with, association with or binding to the serum complement or other species does not have to be identified. One can determine whether a moiety can act as a shielding moiety by determining whether or to what extent a complex binds serum species.
Other moieties that will act as shielding moieties can be identified by their ability to block binding of serum complement or the serum complement pathway, such as the C3A
or C5 proteins of the complement pathway. If a moiety is not recognized by (e.g., does not bind) at least one of the components of serum complement or the serum complement pathway, then the moiety likely acts as a shielding moiety. In particular examples, if a moiety does not bind to or interact with at least one of the C3A or C5 proteins, then the moiety likely is not bound by or does not interact with serum complement.
Incorporation of a moiety which does not bind, associate with, or interact with serum complement or other serum species on the surface of the complexes described herein results in the shielding of the complex. In other words, the components (e.g., lipids) of the complex that would be recognized by or would interact with components of serum are instead shielded from the serum components (e.g., serum proteins, for example, albumin, serum complement, hormones, vitamins, co-factors and others) and therefore are not accessible to serum components and thus are not bound by, associated with, or interacting with these components, including serum complement. The complex therefore can be described as "shielded. A moiety capable of providing shielding can be termed a 'shielding moiety'.
Shielding, as described above, can also be measured by the level of complement opsonization, as described herein. In particular embodiments, the shielding moiety will reduce complement opsonization by approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, or approximately 80%. In other embodiments, the shielding moiety will reduce complement opsonisation by at least 40%, at least 50%, at least 55% or at least 60%.
It should be noted that "shielding moieties' can be multifunctional. For example, a shielding moiety may also function as, for example, a targeting factor. A shielding moiety may also be referred to as multifunctional with respect to the mechanism(s) by which it shields the complex. While not wishing to be limited by proposed mechanism or theory, examples of such a multifunctional shielding moiety are pH sensitive endosomal membrane-disruptive synthetic polymers, such as PPAA or PEAA. Certain poly(alkylacrylic acids) have been shown to disrupt endosomal membranes while leaving the outer cell surface membrane intact (Stayton et al. (2000).J. Controll. Release 65:203-220; Murthy et al. (1999) J. Control!.
Release 61:137-143: W099/34831), thereby increasing cellular bioavailability and functioning as a targeting factor. However, PPAA reduces binding of serum complement to complexes in which it is incorporated, thus functioning as a shielding moiety.
As will be understood by those of skill in the art, it is important that incorporation of a shielding moiety does not eliminate the complex's ability to be delivered to cells. Therefore, in some embodiments, complexes incorporating a shielding moiety will further comprise a targeting factor. For example, a complex may comprise a cell surface receptor ligand (e.g., folate, an RGD peptide, an LHRH peptide, etc.) that may, for example, be conjugated to a lipid or pegylated lipid and optionally also incorporate PPAA. In certain embodiments, the lipid-targeting factor conjugate is DSPE-PEG5k-RGD or DSPE-PEG5k-Folate.
The amount or ratio of shielding moiety incorporated in a complex formulation can be limited, so as not to eliminate the complex's delivery to cells. Thus in particular examples, the complexes comprise less than about 15%, less than about 12%, less than about 10%, less than about 8%, less than about 7%, less than about 5%, less than about 4%, less than about 3%, or less than about 2% shielding moiety. In particular embodiments, the amount of shielding moiety is about 10%, about 8%, about 5% or about 2%. A complex may also incorporate more than one shielding moiety. In certain embodiments, the amount of shielding moiety is at least 2%, at least 5% or at least 8% or at least 10%.
In certain embodiments, the shielding moiety may be conjugated to another component of the complex, for example a lipid or pegylated lipid. In certain examples, the shielding moiety may be conjugated to a co-lipid or pegylated co-lipid. In other embodiments, the shielding moiety is not conjugated to any other component of the complex.
In particular embodiments, the complex is shielded by incorporation of compounds .. comprising polyethylene glycol moieties (PEG) or by the incorporation of synthetic polymers. In particular examples of the complexes described herein, the shielded complex may comprise one or more synthetic polymers, including for example, membrane disruptive synthetic polymers, pH sensitive membrane-disruptive synthetic polymers, pH
sensitive endosomal membrane disruptive synthetic polymers, or poly(alkylacrylic acid) polymers.
Particular examples of membrane disruptive polymers include poly(alkylacrylic acid) polymers such as poly(ethyl acrylic acid) (PEAA) and poly(propyl acrylic acid) (PPAA).
It is also possible that shielding the complexes may reduce the toxicity of the complexes.
The pegylated lipid and/or targeting factor-pegylated lipid conjugate and/or targeting factor-lipid conjugate may comprise, for example, from about 0.01 to about 30 mol percent of the total lipids, more preferably, from about 1 to about 30 mol percent of the total lipids. The pegylated lipid and/or targeting factor-pegylated lipid conjugate and/or targeting factor-lipid conjugate may comprise, for example, from about 1 to about 20 mol percent, from about 1 to about 10 mol percent of the total lipids, from about 2 to about 5 mol percent, about 1 mol percent, about 2 mol percent, about 3 mol percent, about 4 mol percent, about 5 mol percent, about 10 mol percent, about 15 mol percent or about 20 mol percent of the total lipids. The complex may comprise a pegylated lipid without conjugated targeting factor as well as a targeting factor-pegylated lipid conjugate. The complex may also comprise a targeting factor-pegylated lipid conjugate and a targeting factor-lipid conjugate. The complex may comprise more than one targeting factor-pegylated lipid conjugate or targeting factor-lipid conjugate.
The PEG moiety may be the same or different when more than one pegylated lipid is present in the complex. In one non limiting example, the targeting factor-pegylated lipid conjugate may comprise PEG of 5 KDa molecular weight, and the pegylated lipid without conjugated targeting factor may comprise PEG of 750 Da -2 KDa molecular weight. The complex may also comprise a pegylated lipid and a targeting factor conjugated to a lipid.
In one embodiment, the complex comprises a targeting factor-pegylated lipid conjugate and a targeting factor-lipid conjugate. Alternatively, in other embodiments, the complex comprises a targeting factor that is not conjugated to lipid or pegylated lipid, and comprises a pegylated lipid.
Cyclodextrin A composition comprising a cyclodextrin(s) and a compound(s) of Formula [X], or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, optionally wherein the composition is a liquid that comprises at least 30 mM of a compound of Formula [X], optionally wherein the cyclodextrin is a substituted cyclodextrin, optionally wherein the cyclodextrin is substituted on the 2-, 3- or 6- hydroxyl group of a glycopyranose moiety, optionally wherein the cyclodextrin is amorphous, optionally wherein the cyclodextrin is one or more of 2-hydroxypropyl-p-cyclodextrin (or derivative thereof)/hydroxypropyl-P-cyclodextrin (or derivative thereof)/-cyclodextrin (or derivative thereof)/a-cyclodextrin (or derivative thereof)/y-cyclodextrin (or derivative thereof), optionally wherein the composition is a lyophilized (e.g. water soluble), optionally wherein the cyclodextrin(s) is of the structure:
OR (R1)m OR

0 0 (R1)m OR RO

(R1)m OR OR OR (R1)m (R1)m OR
RO _n or a pharmaceutically acceptable salt, ester, solvate, or hydrate thereof.
Wherein, each R is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; or C(0)ORB, -0C(0)RB, -C(0)1e, or C(0)NRARB;
each R1 is selected independently from H, D, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halogen, hydroxy, amino, CN, CF3, N3, NO2, ORB, SRB, SORB, S02R8, -N(RB)S(02), RB, -N(RB)S(02)NRARB, NRARB, -C(0)ORB, OC(0)RB, C(0)RB, C(0)NRARB, or N(RB)C(0)RB; each of which is optionally substituted;
wherein each RA is independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
wherein each RB is independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
wherein n is 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , or 10;
wherein each m is independently 0, 1 , 2 , 3 , 4, or 5.
A way to produce a formulation, particularly a solution, of a compound(s) of Formula [X] or a derivative thereof, is through the use of cyclodextrin. By cyclodextrin, it is meant a-,13 or '-cyclodextrin. Cyclodextrins are described in detail in Pitha et al., U.S. Pat.
No. 4,727,064, which is incorporated herein by reference. Cyclodextrins are cyclic oligomers of glucose;
these compounds form inclusion complexes with any drug whose molecule can fit into the lipophile-seeking cavities of the cyclodextrin molecule.
By amorphous cyclodextrin, it is meant non-crystalline mixtures of cyclodextrins wherein the mixture is prepared from a-,13-, or y-cyclodextrin. In general the amorphous cyclodextrin is prepared by non-selective additions, especially alkylation of the desired cyclodextrin species.
Reactions are carried out to yield mixtures containing a plurality of components thereby preventing crystallization of the cyclodextrin. Various alkylated and hydroxyalkyl cyclodextrins can be made and of course will vary, depending upon the starting species of cyclodextrin and the addition agent used. Among the amorphous cyclodextrins suitable for compositions according to the invention are hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of 13-cyclodextrin, carboxyamidomethyl-P-cyclodextrin, carboxymethy1-13-cyclodextrin, hydroxypropyl-13-cyclodextrin and diethylamino-P-cyclodextrin. The substituted y-cyclodextrins may also be suitable, including hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of y-cyclodextrin.

The cyclodextrin of the compositions according to the invention may be a-, p-, or y-cyclodextrin. a-cyclodextrin contains six glucopyranose units; P-cyclodextrin contains seven glucopyranose units; and 'y-cyclodextrin contains eight glucopyranose units.
The molecule is believed to form a truncated cone having a core opening of 4.7-5.3 angstroms, 6.0-6.5 angstroms, and 7.5-8.3 angstroms in a-, 0-, or y-cyclodextrin respectively.
The composition according to the invention may comprise a mixture of two or more of the a-, 0-, or y-cyclodextrins. Typically, however, the composition according to the invention will comprise only one of the a-, 0-, or y-cyclodextrins.
The unmodified a-, 0-, or y-cyclodextrins are less preferred in the compositions according to the invention because the unmodified forms tend to crystallize and are relatively less soluble in aqueous solutions. More preferred for the compositions according to the invention are the a-, 0-, and 'y-cyclodextrins that are chemically modified or substituted.
Chemical substitution at the 2, 3 and 6 hydroxyl groups of the glucopyranose units of the cyclodextrin rings yields increases in solubility of the cyclodextrin compound.
Most preferred cyclodextrins in the compositions according to the invention are amorphous cyclodextrin compounds. By amorphous cyclodextrin is meant non-crystalline mixtures of cyclodextrins wherein the mixture is prepared from a-, 0-, or y-cyclodextrin.
In general, the amorphous cyclodextrin is prepared by non-selective alkylation of the desired cyclodextrin species. Suitable alkylation agents for this purpose include but are not limited to propylene oxide, glycidol, iodoacetamide, chloroacetate, and 2-diethylaminoethlychloride. Reactions are carried out to yield mixtures containing a plurality of components thereby preventing crystallization of the cyclodextrin. Various alkylated cyclodextrins can be made and of course will vary, depending upon the starting species of cyclodextrin and the alkylating agent used.
Among the amorphous cyclodextrins suitable for compositions according to the invention are hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of 1-cyclodextrin, carboxyamidom ethyl-0-cyclodextrin, carboxymethyl-P-cyclodextrin, hydroxypropyl-P-cyclodextrin and diethylamino-P-cyclodextrin.
Importantly, if the aqueous solution comprising the therapeutic compound(s) and a cyclodextrin is to be administered parenterally, especially via the intravenous route, a cyclodextrin will be substantially free of pyrogenic contaminants. Various forms of cyclodextrin, such as forms of amorphous cyclodextrin, may be purchased from a number of vendors including Sigma-Aldrich, Inc. (St. Louis, Mo., USA). A method for the production of hydroxypropy1-13-cyclodextrin is disclosed in Pitha et al., U.S. Pat. No.
4,727,064 which is incorporated herein by reference.
To produce the formulations according to the invention, a pre-weighed amount of a cyclodextrin compound, which is substantially pyrogen free is placed in a suitable depyrogenated sterile container. Methods for depyrogenation of containers and closure components are well known to those skilled in the art and are fully described in the United States Pharmacopeia 23 (United States Pharmacopeial Convention, Rockville, Md.
USA).
Generally, depyrogenation is accomplished by exposing the objects to be depyrogenated to temperatures above 400 degrees Centigrade for a period of time sufficient to fully incinerate any organic matter. As measured in U.S.P. Bacterial Endotoxin Units, the formulation will contain no more than 10 Bacterial Endotoxin Units per gram of amorphous cyclodextrin. By substantially pyrogen free is meant that the cyclodextrin con tains less than 10 U.S.P.
bacterial endotoxin units per gram using the U.S.P. method. Preferably, the cyclodextrin will contain between 0.1 and 5 U.S.P. bacterial endotoxin units per mg, under conditions specified in the United States Pharmacopeia 23.
Sufficient sterile water for injection is added to the substantially pyrogen free amorphous cyclodextrin until the desired concentration of the cyclodextrin is in solution. To this solution a pre-weighed amount of the therapeutic compound(s), optionally a compound(s) of Formula [X], is added with agitation and with additional standing if necessary until it dissolves.
The solution is then filtered through a sterile 0.22 micron filter into a sterile holding vessel and is subsequently filled in sterile depyrogenated vials and is capped. For products that will be stored for long periods of time, a pharmaceutically acceptable preservative may be added to the solution of therapeutic compound(s) and cyclodextrin prior to filtration, filling and capping or alternatively, may be added sterilely after filtration.
As discussed above, the present invention provides improved water soluble formulations of compound(s) of Formula [X] and methods of preparing and employing such formulations.

The advantages of these water soluble formulations are that a drug is entrapped in cyclodextrin in dissolved form. These compositions can be delivered in the form by slow infusions or by bolus injection or by other parenteral or oral delivery routes.
Additional description of the use of cyclodextrin for solubilizing compounds can be found in US 2005/0026849, the contents of which are incorporated herein by reference.
In an embodiment, the therapeutic action of a cyclodextrin(s), or derivative(s) thereof, synergises with the therapeutic action of one or more compounds of Formula [X], or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. For non-limiting example, cyclodextrin(s) can slow aging (delay the onset of an age associated phenotype in a cell) and a compound of Formula [X] can slow aging (delay the onset of an age associated phenotype in a cell) and when co-administered, optionally in a pharmaceutical composition, these anti-aging properties add/synergise. A method of treating or delaying the onset of geriatric aging of the human or animal body, tissue, or organ comprising administering a composition that includes one or more cyclodextrins and one or more compounds of Formula [X] to a subject. A method of preventing, treating or delaying the onset of a disease/condition associated with aging, and/or a lipofuscin associated disorder, by administering a composition that includes one or more of cyclodextrins and one or more compounds of Formula [X] to a subject.
Implants Implantable devices containing a compound(s) of Formula [X] are also included in the invention, optionally a bioerodable implant comprising an the active agent dispersed within a biodegradable polymer matrix, optionally wherein 75% of the particles of the active agent have a diameter of less than about 10 um. The invention provides implantable (optionally rechargeable or biodegradable) devices that contain a compound(s) of Formula [X], or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a drug at a particular target site.
The biodegradable polymer can be, for example, a poly(lactic-co-glycolic)acid (PLGA) copolymer. The ratio of lactic to glycolic acid monomers in the polymer can be about 50/50 , weight percentage. Additionally, the PLGA copolymer can be about 20 to about 90 weight percent of the bioerodible implant. Alternately, the PLGA copolymer can be about 40 percent by weight of the bioerodible implant.
In another example, a drug delivery device is formed, in whole or in part, by co-extruding a drug core and an outer tube. The outer tube may be permeable, semi-permeable, or impermeable to the drug. The drug core may include a polymer matrix which does not significantly affect the release rate of the drug. The outer tube, the polymer matrix of the drug core, or both may be bioerodible. The co-extruded product can be segmented into drug delivery devices. The devices may be left uncoated so that their respective ends are open, or the devices may be coated with, for example, a layer that is permeable to the drug, semi-permeable to the drug, or bioerodible.
In a further example, a surgically implanted device has a reservoir container having a diffusible wall of polyvinyl alcohol or polyvinyl acetate and containing milligram quantities of a compound(s) of Formula [X]. As another example, milligram quantities of agent(s) may be incorporated into a polymeric matrix, optionally having dimensions of about 2 mm by 4 mm, and made of a polymer such as polycaprolactone, poly(glycolic) acid, poly(lactic) acid, or a polyanhydride, or a lipid such as sebacic acid. This is usually accomplished with the patient receiving either a topical or local anesthetic and using a small 3-4 mm incision to enter the implant. The matrix, containing the agent(s), is then inserted through the incision and sutured to the sclera using 9-0 nylon.
Additional description of implantable devices can be found, for example, in U.S. Publication Nos. 2004/0009222, 2004/0180075, 2005/0048099, 2005/0064010 and 2005/0025810, the contents of which are incorporated herein by reference.
Fast melt formulations Rapid disintegration facilitates delivery of the active material. Rapidly disintegrating or dissolving dosage forms are useful for the rapid absorption, particularly buccal and sublingual absorption, of pharmaceutically active agents. Fast melt dosage forms are beneficial to patients, such as aged and pediatric patients, who have difficulty in swallowing typical solid dosage forms, such as caplets and tablets. Additionally, fast melt dosage forms circumvent drawbacks associated with, for example, chewable dosage forms, wherein the length of time an active agent remains in a patient's mouth plays an important role in determining the amount of taste masking and the extent to which a patient may object to throat grittiness of the active agent.
To overcome such problems manufacturers have developed a number of fast melt solid dose oral formulations. These are available from manufacturers including Cima Labs, Fuisz Technologies Ltd., Prographarmn, R. P. Scherer, Yamanouchi-Shaklee, and McNeil-PPC, Inc. All of these manufacturers market different types of rapidly dissolving solid oral dosage forms.
Cima Labs markets OraSolTM, which is an effervescent direct compression tablet having an oral dissolution time of five to thirty seconds, and DuraSolTM, which is a direct compression tablet having a taste-masked active agent and an oral dissolution time of 15 to 45 seconds.
Cima's U.S. Pat. No. 5,607,697, for "Taste Masking Microparticles for Oral Dosage Forms,"
the contents of which are incorporated herein by reference, describes a solid dosage form consisting of coated microparticles that disintegrate in the mouth. The microparticle core of Cima's patented oral dosage form has a pharmaceutical agent and one or more sweet-tasting compounds having a negative heat of solution wherein the sweet-tasting compound can be mannitol, sorbitol, a mixture of an artificial sweetener and menthol, a mixture of sugar and menthol, or methyl salicylate. The microparticle core is coated, at least partially, with a material that retards dissolution in the mouth and masks the taste of the pharmaceutical agent.
The microparticles are then compressed to form a tablet. Cima's patent discloses that other excipients can also be added to the tablet formulation.
WO 98/46215 for "Rapidly Dissolving Robust Dosage Form," the contents of which are incorporated herein by reference, is directed to a hard, compressed, fast melt formulation having an active ingredient and a matrix of at least a non-direct compression filler and lubricant. A non-direct compression filler is typically not free-flowing, in contrast to a direct compression (DC grade) filler, and usually requires additionally processing to form free-flowing granules.
Cima also has U.S. patents and international patent applications directed to effervescent dosage forms (U.S. Pat. Nos. 5,503,846, 5,223,264, and 5,178,878, the contents of each are incorporated herein by reference) and tableting aids for rapidly dissolving dosage forms (U.S.

Pat. Nos. 5,401,513 and 5,219,574, the contents of both are incorporated herein by reference), and rapidly dissolving dosage forms for water soluble drugs (WO 98/14179 for "Taste-Masked Microcapsule Composition and Methods of Manufacture", the contents of which are incorporated herein by reference).
Fuisz Technologies, now part of BioVail, markets Flash DoseTM, which is a direct compression tablet containing a processed excipient called ShearformTM.
ShearformTM is a cotton candy-like substance of mixed polysaccharides converted to amorphous fibers. U.S.
patents describing this technology include U.S. Pat. No. 5,871,781 for "Apparatus for Making Rapidly Dissolving Dosage Units;" U.S. Pat. No. 5,869,098 for "Fast-Dissolving Comestible Units Formed Under High-Speed/High-Pressure Conditions;" U.S. Pat. Nos.
5,866,163, 5,851,553, and 5,622,719, all for "Process and Apparatus for Making Rapidly Dissolving Dosage Units and Product Therefrom;" U.S. Pat. No. 5,567,439 for "Delivery of Controlled-Release Systems;" and U.S. Pat. No. 5,587,172 for "Process for Forming Quickly Dispersing Comestible Unit and Product Therefrom," each of which is incorporated herein by reference.
Prographarm markets FlashtabTM, which is a fast melt tablet having a disintegrating agent such as carboxymethyl cellulose, a swelling agent such as a modified starch, and a taste-masked active agent. The tablets have an oral disintegration time of under one minute (U.S.
Pat. No. 5,464,632, the contents of which are incorporated herein by reference).
R. P. Scherer markets ZydisTM, which is a freeze-dried tablet having an oral dissolution time of 2 to 5 seconds. Lyophilized tablets are costly to manufacture and difficult to package because of the tablets sensitivity to moisture and temperature. U.S. Pat. No.
4,642,903 (R. P.
Scherer Corp.), the contents of which are incorporated herein by reference, refers to a fast melt dosage formulation prepared by dispersing a gas throughout a solution or suspension to be freeze-dried. U.S. Pat. No. 5,188,825 (R. P. Scherer Corp.), the contents of which are incorporated herein by reference, refers to freeze-dried dosage forms prepared by bonding or complexing a water-soluble active agent to or with an ion exchange resin to form a substantially water insoluble complex, which is then mixed with an appropriate carrier and freeze dried. U.S. Pat. No. 5,631,023 (R. P. Scherer Corp.), the contents of which are incorporated herein by reference, refers to freeze-dried drug dosage forms made by adding xanthan gum to a suspension of gelatin and active agent. Finally, U.S. Pat.
No. 5,827,541 (R.
P. Scherer Corp.), the contents of which are incorporated herein by reference, discloses a process for preparing solid pharmaceutical dosage forms of hydrophobic substances. The process involves freeze-drying a dispersion containing a hydrophobic active ingredient and a surfactant, in a non-aqueous phase; and a carrier material, in an aqueous phase.
Yamanouchi-Shaklee markets WowtabTM, which is a tablet having a combination of a low moldability and a high moldability saccharide. U.S. patents covering this technology include U.S. Pat. No. 5,576,014 for "Intrabuccally Dissolving Compressed Moldings and Production Process Thereof," and U.S. Pat. No. 5,446,464 for "Intrabuccally Disintegrating Preparation and Production Thereof," both of which are incorporated herein by reference.
Other companies owning rapidly dissolving technology include Janssen Pharmaceutica. U.S.
patents assigned to Janssen describe rapidly dissolving tablets having two polypeptide (or gelatin) components and a bulking agent, wherein the two components-have a net charge of the same sign, and the first component is more soluble in aqueous solution than the second component. See U.S. Pat. No. 5,807,576 for "Rapidly Dissolving Tablet;" U.S.
Pat. No.
5,635,210 for "Method of Making a Rapidly Dissolving Tablet;" U.S. Pat. No.
5,595,761 for "Particulate Support Matrix for Making a Rapidly Dissolving Tablet;" U.S. Pat.
No.
5,587,180 for "Process for Making a Particulate Support Matrix for Making a Rapidly Dissolving Tablet;" and U.S. Pat. No. 5,776,491 for "Rapidly Dissolving Dosage Form,"
each of which is incorporated herein by reference.
Eurand America, Inc. has U.S. patents directed to a rapidly dissolving effervescent composition having a mixture of sodium bicarbonate, citric acid, and ethylcellulose (U.S. Pat.
Nos. 5,639,475 and 5,709,886, the contents of which are incorporated herein by reference).
L.A.B. Pharmaceutical Research owns U.S. patents directed to effervescent-based rapidly dissolving formulations having a pharmaceutically active ingredient and an effervescent couple comprising an effervescent acid and an effervescent base (U.S. Pat.
Nos. 5,807,578 and 5,807,577, each of which is incorporated herein by reference).
Schering Corporation has technology relating to buccal tablets having an active agent, an excipient (which can be a surfactant) or at least one of sucrose, lactose, or sorbitol, and either magnesium stearate or sodium dodecyl sulfate (U.S. Pat. Nos. 5,112,616 and 5,073,374, each of which is incorporated herein by reference).

Laboratoire L. LaFon owns technology directed to conventional dosage forms made by lyophilization of an oil-in-water emulsion in which at least one of the two phases contains a surfactant (U.S. Pat. No. 4,616,047, the contents of which are incorporated herein by reference). For this type of formulation, the active ingredient is maintained in a frozen suspension state and is tableted without micronization or compression, as such processes could damage the active agent.
Takeda Chemicals Inc., Ltd. owns technology directed to a method of making a fast dissolving tablet in which an active agent and a moistened, soluble carbohydrate are compression molded into a tablet, followed by drying of the tablets (U.S. Pat.
No. 5,501,861, which is incorporated herein by reference).
Finally, Elan's U.S. Pat. No. 6,316,029, for "Rapidly Disintegrating Oral Dosage Form," the contents of which are incorporated by reference, discloses fast melt dosage forms comprising nanoparticulate active agents.
In one example of fast melt tablet preparation, granules for fast melt tablets made by either the spray drying or pre-compacting processes are mixed with excipients and compressed into tablets using conventional tablet making machinery. The granules can be combined with a variety of carriers including low density, high moldability saccharides, low moldability saccharides, polyol combinations, and then directly compressed into a tablet that exhibits an improved dissolution and disintegration profile.
The granules used to make the tablets can be, for example, mixtures of low density alkali earth metal salts or carbohydrates. For example, a mixture of alkali earth metal salts includes a combination of calcium carbonate and magnesium hydroxide. Similarly, a fast melt tablet can be prepared according to the methods of the present invention that incorporates the use of A) spray dried extra light calcium carbonate/maltodextrin, B) magnesium hydroxide and C) a eutectic polyol combination including sorbitol instant, xylitol and mannitol.
These materials can be combined to produce a low density tablet that dissolves very readily and promotes the fast disintegration of the active ingredient. Additionally, the pre-compacted and spray dried granules can be combined in the same tablet.

For fast melt tablet preparation, a compound(s) useful in the present invention can be in a form such as solid, particulate, granular, crystalline, oily or solution. The compound(s) for use in the present invention may be a spray dried product or an adsorbate that has been pre-compacted to a harder granular form that reduces the medicament taste. A
pharmaceutical active ingredient for use in the present invention may be spray dried with a carrier that prevents the active ingredient from being easily extracted from the tablet when chewed.
In addition to being directly added to the tablets of the present invention, the medicament drug itself can be processed by the pre-compaction process to achieve an increased density prior to being incorporated into the formulation.
The pre-compaction process used in the present invention can be used to deliver poorly soluble pharmaceutical materials so as to improve the release of such pharmaceutical materials over traditional dosage forms. This could allow for the use of lower dosage levels to deliver equivalent bioavailable levels of drug and thereby lower toxicity levels. Poorly soluble pharmaceutical materials can be used in the form of nanoparticles, which are nanometer-sized particles.
In addition to the active ingredient and the granules prepared from low density alkali earth metal salts and/or water soluble carbohydrates, the fast melt tablets can be formulated using conventional carriers or excipients and well established pharmaceutical techniques.
Conventional carriers or excipients include, but are not limited to, diluents, binders, adhesives (i.e., cellulose derivatives and acrylic derivatives), lubricants (i.e., magnesium or calcium stearate, vegetable oils, polyethylene glycols, talc, sodium lauryl sulphate, polyoxy ethylene monostearate), disintegrants, colorants, flavorings, preservatives, sweeteners and miscellaneous materials such as buffers and adsorbents.
Additional description of the preparation of fast melt tablets can be found, for example, in U.S. Pat. No. 5,939,091, the contents of which are incorporated herein by reference.
Animal feed Componentry to this invention is to add a compound(s) of Formula [X] to animal feed and/or drinking water/fluid.

The addition of the active compound of the invention to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration.
Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as "Applied Animal Nutrition", W.H.
Freedman and CO., San Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding"
0 and B
books, Corvallis, Oreg., U.S.A., 1977).
Cycling Therapy In certain embodiments, the prophylactic/therapeutic agents provided herein are cyclically administered to a subject. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, wherein the rest period equals a day, days, weeks, or months without the compound(s) being administered, before the administration period starts again, and this cycle is repeated over a period of time, optionally wherein the length (and dosage) of the administration and/or rest periods can be modulated, optionally to find the best cycle for the subject. A variant is wherein the rest period isn't complete rest, but the compound(s) is administered at lower dosage. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid, or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment. In an embodiment, a cycle of administration with one or more compounds of Formula [X] is implemented completely out of phase, or with a degree of overlap, with a cycle of administration of one or more other compounds of Formula [X], or another drug approved for human use by the regulatory body applicable to the country that the subject resides e.g. the FDA applies for a subject in the USA.
Optimising for brain/CNS administration Delivery approaches can be used to deliver therapeutic agents to the brain whilst circumventing the blood-brain barrier. Such approaches utilize intrathecal injections, surgical implants (Ommaya, Cancer Drug Delivery, 1: 169-178 (1984) and U.S. Pat. No.
5,222,982), interstitial infusion (Bobo et al., Proc. Natl. Acad. Sci. U.S.A., 91: 2076-2080 (1994)), and the like. These strategies deliver an agent to the CNS by direct administration into the cerebrospinal fluid (CSF) or into the brain parenchyma (ECF).

Drug delivery to the central nervous system through the cerebrospinal fluid can be achieved, for example, by means of a subdurally implantable device the "Ommaya reservoir". The drug is injected into the device and subsequently released into the cerebrospinal fluid surrounding the brain. It can be directed toward specific areas of exposed brain tissue which then adsorb the drug. This adsorption is limited since the drug does not travel freely. A
modified device, whereby the reservoir is implanted in the abdominal cavity and the injected drug is transported by cerebrospinal fluid (taken from and returned to the spine) to the ventricular space of the brain, is used for agent administration. Through omega-3 derivatization, site-specific biomolecular complexes can overcome the limited adsorption and movement of therapeutic agents through brain tissue.
Another strategy to improve agent delivery to the CNS is by increasing the agent absorption (adsorption and transport) through the blood-brain barrier and the uptake of therapeutic agent by the cells (Broadwell, Acta Neuropathol., 79: 117-128 (1989); Pardridge etal., J.
Pharmacol. Experim. Therapeutics, 255: 893-899 (1990); Banks et al., Progress in Brain Research, 91: 139-148 (1992); Pardridge, Fuel Homeostasis and the Nervous System, ed.:
Vranic et al., Plenum Press, New York, 43-53 (1991)). The passage of agents through the blood-brain barrier to the brain can be enhanced by improving either the permeability of the agent itself or by altering the characteristics of the blood-brain barrier.
Thus, the passage of the agent can be facilitated by increasing its lipid solubility through chemical modification, and/or by its coupling to a cationic carrier, or by its covalent coupling to a peptide vector capable of transporting the agent through the blood-brain barrier. Peptide transport vectors are also known as blood-brain barrier perrneabilizer compounds (U.S. Pat. No.
5,268,164).
Site specific macromolecules with lipophilic characteristics useful for delivery to the brain are described in U.S. Pat. No. 6,005,004. Other examples (U.S. Pat. No.
4,701,521, and U.S.
Pat. No. 4,847,240) describe a method of covalently bonding an agent to a cationic macromolecular carrier which enters into the cells at relatively higher rates.
These patents teach enhancement in cellular uptake of bio-molecules into the cells when covalently bonded to cationic resins. U.S. Pat. No. 4,046,722 discloses anti-cancer drugs covalently bonded to cationic polymers for the purpose of directing them to cells bearing specific antigens. The polymeric carriers have molecular weights of about 5,000 to 500,000. Such polymeric carriers can be employed to deliver compounds described herein in a targeted manner.
Further work involving covalent bonding of an agent to a cationic polymer through an acid-sensitive intermediate (also known as a spacer) molecule, is described in U.S.

Pat. No. 4,631,190 and U.S. Pat. No. 5,144,011. Various spacer molecules, such as cis-aconitic acid, are covalently linked to the agent and to the polymeric carrier. They control the release of the agent from the macromolecular carrier when subjected to a mild increase in acidity, such as probably occurs within a lysosome of the cell. The drug can be selectively hydrolyzed from the molecular conjugate and released in the cell in its unmodified and active form. Molecular conjugates are transported to lysosomes, where they are metabolized under the action of lysosomal enzymes at a substantially more acidic pH than other compartments or fluids within a cell or body. The pH of a lysosome is shown to be about 4.8, while during the initial stage of the conjugate digestion, the pH is possibly as low as 3.8.
Kits The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages.
The kit may comprise multiple internal containers to keep components separate. An article of manufacture of the present invention, comprises: (a) a first container (most preferably sterilised, sterilization methodology well known to those skilled in the art, and packaged/sealed to maintain sterilization; optionally it is a blister pack, wherein this term and its meaning is well known in the art); (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of a specified disease(s)/disorder(s)/condition(s) in a subject, optionally stating the treatment of a disease(s)/disorder(s)/condition(s) refered to herein, optionally stating the treatment of cancer. In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent(s) to treat the same specified disease(s)/disorder(s) in a subject, optionally wherein this is cancer. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries.
The first container is a receptacle used to hold a pharmaceutical composition.
This container can be for manufacturing, storing, shipping, and/or individual/bulk selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.
The second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.
The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container.
Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.
The package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).
Information may be provided by reference to a website(s).
Herein disclosed are articles of manufacture that include a compound(s) and/or pharmaceutical composition(s) described herein in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, intravenous bag or other used for containing a drug for human or veterinary use. Disclosed herein are kits that include a compound(s) of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and suitable packaging, optionally with a package insert, optionally a paper package insert. In some embodiments, a kit further includes instructions for use, which can be upon a package insert. In some embodiments, a kit includes a compound(s) of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, packaging and a label and/or instructions for use of the compound(s)/composition(s) in the treatment/amelioration/prevention/combating of indications, optionally including one or more diseases/disorders/conditions described herein. Pharmaceutical compound(s)/composition(s) of this invention can be inside one or more embodiments of a container/pack/package/dispenser, optionally together with instructions for administration, optionally with drug information such as, for example, disease(s)/disorder(s)/condition(s) treated/ameliorated/prevented/combated, possible side-effects, desirable or undesirable/dangerous drug interactions possible in the subject, information related to what to do upon overdose, and any information specified for inclusion according to the relevant regulatory authority e.g. the FDA in the USA, and optionally wherein each dose (e.g. daily) of compound(s)/composition(s) is compartmentalized in its own compartment or discrete storage within a bigger package, optionally labelled (e.g. with day of week).
For example, a packaged product may comprise a container; an effective amount of a compound(s) of the invention; and an insert associated with the container, indicating administering the compound(s) for treating a disorder(s), optionally cancer. The composition(s) of the kit may be provided as any suitable form. The kits may contain instructions for mixing, diluting, and/or administrating the compounds. In certain embodiments, the kit provided herein further comprises a device that is used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
The kits also can include other container(s) with pharmaceutically acceptable vehicle(s) that can be used to administer one or more active ingredients, such as one or more solvents, surfactants, preservatives, and/or diluents (e.g., normal saline (0.9% NaCI), or 5%
dextrose) as well as containers for mixing, diluting or administering the components to the subject in need of such treatment. When the composition provided is a dry powder, the powder may be reconstituted by the addition of a suitable solvent, which may also be provided. In embodiments where liquid forms of the composition are sued, the liquid form may be concentrated or ready to use. The solvent will depend on the compound and the mode of use or administration.
Suitable solvents for drug compositions are well known and are available in the literature. In a particular embodiment, the solution for administering the compound is sterilised. In some embodiments, the package insert instructs a user of the kit to administer the compound or pharmaceutical composition to a subject. In some embodiments, the package insert instructs a user of the kit to mix the compound or pharmaceutical composition with an aqueous solution.
In some embodiments, the package insert instructs a user of the kit to orally administer the compound to the subject. The kits may further comprise conventional pharmaceutical kit components which will be readily apparent to those skilled in the art.
Optionally the kit contains a compound(s) of Formula [X] and a further compound or compounds approved for human use by the FDA and/or EMA, for example an anti-cancer drug(s), and optionally instructions for administrating the compounds contained therein to a subject, optionally with materials to perform or assist said administration.
An article of manufacture embodiment of this invention is almitrine dimesylate in a kit for cancer treatment wherein almitrine dimesylate, or some other composition of almitrine, is in a package associated with instructions for, and/or information pertaining to, its use as an anti-cancer treatment in a subject. These instructions can be inside the package, optionally in an insert, or outside the package and distributed with the package, most preferably physically attached to the package, for example being on a label adhered to the package.
Promotion; business methods of the invention The invention encompasses methods of promoting the treatment/amelioration/prevention/combating of a disease/disorder/condition/etiology/unwanted body feature or aspect by a subject taking or being administered a compound(s) and/or pharmaceutical composition(s) of the present invention. The invention encompasses a method of promoting the treatment/amelioration/prevention/combating of cancer/tumor/abnormal cell proliferation according to any of the methods/compounds/compositions/kits/combinations described herein e.g. promoting the administration of a therapeutically effective amount of a compound(s) of this invention to the subject in need thereof, optionally where the subject has, or is suspected of having, or could, have cancer. As used herein, "promoted" or "promoting"
includes all methods of doing business including methods of education, hospital and other clinical instruction, pharmaceutical industry activity including pharmaceutical sales/licensing, and any advertising/marketing or other promotional activity (directed at patient(s) and/or clinical professional(s)) including written, oral and electronic communication of any form, associated with compounds/compositions/methods/kits of the invention optionally in connection with treatment of cell proliferation, cancers or tumors. "Instructions" can define a component of promotion, and typically involve written instructions on or associated with packaging of compounds/compositions of the invention. Instructions also can include any oral or electronic instructions provided in any manner. The "kit" typically defines a package including any one or a combination of the compounds/compositions of the invention and the instructions, but can also include the composition of the invention and instructions of any form that are provided in connection with the composition in a manner such that a clinical professional will clearly recognize that the instructions are to be associated with the specific compound(s)/composition(s).
An invention embodiment is the promotion of almitrine dimesylate, or some composition(s) of almitrine, for treatment/amelioration/prevention/combat of cancer in a subject. A method of this invention is wherein almitrine or almitrine dimesylate, or some other composition(s) of almitrine, is exchanged between people, either directly or by exchange(s) via further proxy person(s), for example between physician and patient, or physician and almitrine distributor, or pharmaceutical company representative and patient via almitrine distributor and physician, and associated with this physical exchange of almitrine/almitrine composition between people, information is also transmitted between these people, optionally orally or written, pertaining to the use of almitrine and/or almitrine composition(s) for anti-cancer use in a subject.
An invention embodiment is a business method wherein the subject pays for an insurance product from a company (e.g. an insurance company/medical insurance company), optionally paying a daily, weekly, monthly or yearly fee, and when the subject is need of a compound(s) of this invention, optionally as directed by a physician or medical/clinical practitioner, the insurance company pays for all or some of its cost, or the subject and/or the medical practice (a place of one or more working clinical professionals) pays for it and this cost to the subject and/or medical practice is then reimbursed to the subject and/or medical practice, either in part or in total, by the insurance company, optionally wherein the insurance covers the cost of other medical treatment also. Put another way, the cost of the compound(s) of this invention is not met by the subject to be treated directly but through one or more intermediates which can include a hospital or clinical establishment and an insurance company or companies, wherein the subject pays an insurance company for a promise/agreement/contact that the company will pay directly or ultimately for a compound(s) of this invention should the subject require it for their treatment.
Clinical Trials Embodied by this invention are methods of testing/assessing/verifying the safety and/or therapeutic/beneficial activity of a compound(s) and/or pharmaceutical composition(s) of this invention in a subject, optionally in human subjects using a clinical trial methodology or methodologies, many variants of which are known to, and could be conceived by, those of ordinary skill of the art, optionally wherein the human subjects have cancer, optionally wherein this clinical trial(s) is to obtain regulatory approval for a human use(s) from a regulatory body(s), optionally a national or supranational regulator, optionally the FDA in USA, optionally wherein the clinical trial is for a compound(s)/composition(s) of this invention in use for anti-cancer treatment/amelioration/prevention/combat in a subject(s), optionally administered with another drug(s)/treatment(s), optionally wherein this other drug(s)/treatment(s) is also for anti-cancer treatment, optionally wherein it already has regulatory approval (e.g. by FDA) for this use or other. Possible clinical trial endpoints include, illustratively, not restrictively, disease free survival (DFS), objective response rate (ORR), time to progression (TTP), progression-free survival (PFS), and time-to-treatment failure (TTF), where these terms are well known in the art. Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or Mill scan and other commonly accepted evaluation modalities.
Solvents The reactions of the synthetic methods described herein can be carried out in suitable solvents which can be readily selected by one skilled in the art of organic synthesis.
Generally, suitable Solvents are solvents which are substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvents freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, suitable solvents for a particular work-up following the reaction can be selected. Suitable solvents, as used herein can include, by way of example and without limitation, chlorinated solvents, hydrocarbon solvents, aromatic solvents, ether solvents, protic solvents, polar aprotic solvents, and mixtures thereof.
Suitable halogenated solvents include, but are not limited to, carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, 0-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane, chlorotrifluoromethane, bromotrifluoromethane, carbon tetrafluoride, dichlorofluoromethane, chlorodifluoromethane, trifluoromethane, 1,2-dichlorotetrafluorethane and hexafluoroethane.
Suitable hydrocarbon solvents include, but are not limited to, alkane or aromatic solvents such as cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-Xylene, octane, indane, nonane, benzene, ethylbenzene, and m-, o-, or p-xylene.
Suitable ether solvents include, but are not limited to dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethylether, diethylene glycol diethyl ether, triethylene glycol diisopropyl ether, anisole, or t-butyl methyl ether.
Suitable protic solvents include, but are not limited to water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2.2.2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, 1-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, and glycerol.
Suitable aprotic solvents include, but are not limited todimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethy1-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethy1-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide,N-methylformamide, acetonitrile (ACN), dimethylsulfoxide (DMSO), propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, isopropyl acetate, t-butyl acetate, Sulfolane, N,Ndimethylpropionamide,nitromethane, nitrobenzene, and hexamethylphosphoramide.
Polymorphs In certain embodiments, a compound(s) of Formula [X] is a solid. In certain embodiments, a solid compound(s) of Formula [X] is amorphous (lacks long-range order at the molecular level). In certain embodiments, a solid compound(s) of Formula [X] is crystalline. The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Compounds of the present invention may exist as polymorphs. As used herein "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, and/or ions forming the crystal. Co-crystals are typically defined as crystalline complexes of neutral molecular constituents that are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together; see 0. Almarsson and M. J.
Zaworotko, Chem. Commun. 2004, 17, 1889-1896. For a general review of multi-component complexes, see J. K. Haleblian, J. Pharm. Sci. 1975, 64, 1269-1288. Reference to a .. compound of the Formula [X] herein is understood to include reference to amorphous/crystal/polymorph/co-crystal/clathrate form thereof, unless specified otherwise or otherwise clear from context. A polymorph(s) of a compound(s), or a polymorph of a salt/solvate/hydrate/prodrug of a compound(s), of Formula (I), (II), (III), (IV), (V), (VI) or (VII), or a polymorph(s) of another compound(s) that reduces F IF ATP
hydrolysis, is .. componentry to this invention, as is its incorporation, optionally of a therapeutically effective amount, into a pharmaceutically acceptable composition, optionally with a further polymorph(s) and/or compound(s) of this invention, optionally with an FDA
and/or EMA
approved therapeutic(s). An invention embodiment is the use of a polymorph(s) of this invention for the manufacture of a medicament for the treatment, amelioration, prevention or combating of a disease or disorder, optionally one or more diseases/disorders/conditions referred to herein. An invention embodiment is the use of one or more of these polymorph(s)/composition(s) for use in a method of treatment of the human or animal body by therapy, optionally to treat/ameliorate/prevent/combat one or more diseases/disorders/conditions referred to herein, optionally cancer. In some embodiments, the subject is further administered with one or more compounds or compositions approved for human use, optionally for anti-cancer use, by the United States Food and Drug Administration (FDA) and/or European Medicines Agency (EMA), optionally in the same pharmaceutical composition. The present invention provides pharmaceutically acceptable crystalline forms. An aspect of the invention is a pharmaceutical composition comprising at least one polymorph of a compound as described herein and a pharmaceutically-acceptable carrier or diluent.
In one embodiment, a compound of the present invention is in substantially pure form. The term "substantially pure", as used herein, means a compound having a purity greater than about 90% including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight % of the compound, based on the weight of the compound. The remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation. For example, a .. crystalline form of a compound may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of material comprises other form(s) of the compound and/or reaction impurities and/or processing impurities.
.. Samples of the crystalline forms may be provided with substantially pure phase homogeneity, indicating the presence of a dominant amount of a single crystalline form and optionally minor amounts of one or more other crystalline forms. The presence of more than one crystalline form in a sample may be determined by techniques such as powder X-ray diffraction (PXRD) or solid state nuclear magnetic resonance spectroscopy (SSNMR). For example, the presence of extra peaks in the comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern may indicate more than one crystalline form in the sample. The simulated PXRD may be calculated from single crystal X-ray data. see Smith, D. K., A FORTRAN Program for Calculating X- Ray Powder Diffraction Patterns,"
Lawrence Radiation Laboratory, Livermore, Calif, UCRL-7196, April 1963.
Preferably, the crystalline form has substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5%, and more preferably less than 2% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated XRPD pattern. Most preferred is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD
pattern arising from the extra peaks that are absent from the simulated PXRD
pattern.
The crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture. High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs.
Crystals of drugs, including polymorphs, methods of preparation, and characterization of .. drug crystals are discussed in Solid- State Chemistry of Drugs, S. R. Bym, R. R. Pfeiffer, and J. G. Stowell, 2"d Edition, SSCI, West Lafayette, Ind., 1999.
For crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, .. crystallization technique, and vapor pressure of the solvent. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals. An antisolvent is a solvent in which the compound has low solubility. Suitable solvents for preparing crystals include .. polar and nonpolar solvents.
In one method to prepare crystals, the compound of the present invention is suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to promote dissolution.
The term "slurry", as used herein, means a saturated solution of the compound and a solvent at a given temperature. Suitable solvents in this regard include, for example, polar aprotic solvents, and polar protic solvents, and nonpolar solvents, and mixtures of two or more of these.
Suitable polar aprotic solvents include, for example, dicholomethane (CH 2CI 2 or DCM), tetrahydrofuran (THF), acetone, methyl ethyl ketone (MEK), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethy1-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethy1-2-imidazolidinone (DM I), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile (ACN or MeCN), dimethylsulfoxide (DMSO), propionitrile, ethyl formate, methyl acetate (Me0Ac), ethyl acetate (Et0Ac), isopropyl acetate (Ip0Ac), butyl acetate (BuOAc), t-butyl acetate, hexachloroacetone, dioxane, sulfolane, N,N-dimethylpropionamide, nitromethane, nitrobenzene and hexamethylphosphoramide.

Suitable polar protic solvents include, for example, alcohols and glycols, such as H 20, methanol, ethanol, 1-propanol, 2-propanol, isopropanol (IPA), 1-butanol (1-BuOH), 2-butanol (2-BuOH), i-butyl alcohol, t-butyl alcohol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol and methyl t-butyl ether (MTBE).
Preferred solvents include, for example, acetone, H 20, CH 2C12, methanol, ethanol, MEK, IPA, and Et0Ac. Other solvents suitable for the preparation of slurries, in addition to those exemplified above, would be apparent to one skilled in the art, based on the present disclosure.
Seed crystals may be added to any crystallization mixture to promote crystallization. As will be clear to the skilled artisan, seeding is used as a means of controlling growth of a particular crystalline form or as a means of controlling the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in "Programmed cooling of batch crystallizers," J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. In general, seeds of small size are needed to effectively control the growth of crystals in the batch. Seeds of small size may be generated by sieving, milling, or micronizing of larger crystals, or by micro-crystallization of solutions.
Care should be taken that milling or micronizing of crystals does not result in any change in crystallinity of the desired crystal form or form conversions (i.e. change to amorphous or to another polymorph).
A cooled mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form. The isolated solids may be analyzed by a suitable spectroscopic or analytical technique, such as SSNMR, DSC, PXRD, or the like, to assure formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, but preferably greater than 90 weight % based on the weight of the compound originally employed in the crystallization procedure. The product may be comilled or passed through a mesh screen to delump the product, if necessary.
Crystalline forms may be prepared directly from the reaction medium of the final process step for preparing the compound of the present invention. This may be achieved, for example, by employing in the final process step a solvent or mixture of solvents from which the compound may be crystallized. Alternatively, crystalline forms may be obtained by distillation or solvent addition techniques. Suitable solvents for this purpose include any of those solvents described herein, including protic polar solvents such as alcohols, and aprotic polar solvents such as ketones.
By way of general guidance, the reaction mixture may be filtered to remove any undesired impurities, inorganic salts, and the like, followed by washing with reaction or crystallization solvent. The resulting solution may be concentrated to remove excess solvent or gaseous constituents. If distillation is employed, the ultimate amount of distillate collected may vary, depending on process factors including, for example, vessel size, stirring capability, and the like, by way of general guidance, the reaction solution may be distilled to about 1/10 the original volume before solvent replacement is carried out. The reaction may be sampled and assayed to determine the extent of the reaction and the wt % product in accordance with standard process techniques. If desired, additional reaction solvent may be added or removed to optimize reaction concentration. Preferably, the final concentration is adjusted to about 50 wt % at which point a slurry typically results.
It may be preferable to add solvents directly to the reaction vessel without distilling the reaction mixture. Preferred solvents for this purpose are those which may ultimately participate in the crystalline lattice as discussed above in connection with solvent exchange.
Although the final concentration may vary depending on desired purity, recovery and the like, the final concentration of the in solution is preferably about 4% to about 7%. The reaction mixture may be stirred following solvent addition and simultaneously warmed. By way of illustration, the reaction mixture may be stirred for about 1 hour while warming to about 70 C. The reaction is preferably filtered hot and washed with either the reaction solvent, the solvent added or a combination thereof. Seed crystals may be added to any crystallization solution to initiate crystallization.

The various forms described herein may be distinguishable from one another through the use of various analytical techniques known to one of ordinary skill in the art.
Such techniques include, but are not limited to, solid state nuclear magnetic resonance (SSNMR) spectroscopy, X-ray powder diffraction (PXRD), differential scanning calorimetry (DSC), and/or thermogravimetric analysis (TGA).
The crystalline forms of the compound of the present invention may be formulated into pharmaceutical compositions and/or employed in therapeutic and/or prophylactic methods.
These methods include, but are not limited to, the administration of the crystalline compound, alone or in combination with one or more other pharmaceutically active agents, including agents that may be useful in the treatment of the disorders mentioned herein.
The methods preferably comprise administering to a patient a pharmaceutically effective amount of the novel crystals of the present invention, preferably in combination with one or more pharmaceutically acceptable carriers and/or excipients. The relative proportions of active ingredient and carrier and/or excipient may be determined, for example, by the solubility and chemical nature of the materials, chosen route of administration and standard pharmaceutical practice.
The crystalline forms of the compound may be administered to a patient in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They may be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage regimen for the crystalline forms of the compound will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular .. agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms;
the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the disease/disorder/condition. Obviously, several unit dosage forms may be administered at about the same time. The dosage of the crystalline form of the compound that will be most suitable for prophylaxis or treatment may vary with the form of administration, the particular crystalline form of the compound chosen and the physiological characteristics of the particular patient under treatment. Broadly, small dosages may be used initially and, if necessary, increased by small increments until the desired effect under the circumstances is reached.
By way of general guidance, in the adult, suitable doses may range from about 0.001 to about 1000 mg/Kg body weight, and all combinations and subcombinations of ranges and specific doses therein. Preferred doses may be from about 0.01 to about 100 mg/kg body weight per day by inhalation, preferably 0.1 to 70, more preferably 0.5 to 20 mg/Kg body weight per day by oral administration, and from about 0.01 to about 50, preferably 0.01 to 10 mg/Kg body weight per day by intravenous administration. In each particular case, the doses may be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product. The crystalline forms of the compound may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
For oral administration in solid form such as a tablet or capsule, the crystalline forms of the compound can be combined with a non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Preferably, in addition to the active ingredient, solid dosage forms may contain a number of additional ingredients referred to herein as "excipients". These excipients include among others diluents, binders, lubricants, glidants and disintegrants. Coloring agents may also be incorporated.
"Diluents", as used herein, are agents which impart bulk to the formulation to make a tablet a practical size for compression. Examples of diluents are lactose and cellulose. "Binders", as used herein, are agents used to impart cohesive qualities to the powered material to help ensure the tablet will remain intact after compression, as well as improving the free-flowing qualities of the powder. Examples of typical binders are lactose, starch and various sugars.
"Lubricants", as used herein, have several functions including preventing the adhesion of the tablets to the compression equipment and improving the flow of the granulation prior to compression or encapsulation. Lubricants are in most cases hydrophobic materials. Excessive use of lubricants is undesired, however, as it may result in a formulation with reduced disintegration and/or delayed dissolution of the drug substance. "Glidants", as used herein, refer to substances which may improve the flow characteristics of the granulation material. Examples of glidants include talc and colloidal silicon dioxide. "Disintegrants", as used herein, are substances or a mixture of substances added to a formulation to facilitate the breakup or disintegration of the solid dosage form after administration. Materials that may serve as disintegrants include starches, clays, celluloses, algins, gums and cross-linked polymers. A
group of disintegrants referred to as "super-disintegrants" generally are used at a low level in the solid dosage form, typically 1% to 10% by weight relative to the total weight of the dosage unit. Croscarmelose, crospovidone and sodium starch glycolate represent examples of a cross-linked cellulose, a cross-linked polymer and a cross-linked starch, respectively.
Sodium starch glycolate swells seven- to twelve-fold in less than 30 seconds effectively disintegrating the granulations that contain it.
The disintegrant preferably used in the present invention is selected from the group comprising modified starches, croscarmallose sodium, carboxymethylcellulose calcium and crospovidone. A more preferred disintegrant in the present invention is a modified starch such as sodium starch glycolate.
Preferred carriers include capsules or compressed tablets which contain the solid pharmaceutical dosage forms described herein. Preferred capsule or compressed tablet forms generally comprise a therapeutically effective amount of the crystalline forms of the compound and one or more disintegrants in an amount greater than about 10% by weight relative to the total weight of the contents of the capsule or the total weight of the tablet.
Preferred capsule formulations may contain the crystalline forms of the compound in an amount from about 5 to about 1000 mg per capsule. Preferred compressed tablet formulations contain the crystalline forms of the compound in an amount from about 5 mg to about 800 mg per tablet. More preferred formulations contain about 50 to about 200 mg per capsule or compressed tablet. Preferably, the capsule or compressed tablet pharmaceutical dosage form comprises a therapeutically effective amount of the crystalline forms; a surfactant; a disintegrant; a binder; a lubricant; and optionally additional pharmaceutically acceptable excipients such as diluents, glidants and the like; wherein the disintegrant is selected from modified starches; croscarmallose sodium, carboxymethylcellulose calcium and crospovidone.
For oral administration in liquid form, the crystalline forms of the compound can be combined with any oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. The liquid composition may contain a sweetening agent which to make the compositions more palatable. The sweetening agent can be selected from a sugar such as sucrose, mannitol, sorbitol, xylitol, lactose, etc. or a sugar substitute such as cyclamate, saccaharin, aspartame, etc. If sugar substitutes are selected as the sweetening agent the amount employed in the compositions of the invention will be substantially less than if sugars are employed. Taking this into account, the amount of sweetening agent may range from about 0.1 to about 50% by weight, and all combinations and subcombinations of ranges and specific amounts therein. Preferred amounts range from about 0.5 to about 30%
by weight. The more preferred sweetening agents are the sugars and particularly sucrose. The particle size of the powdered sucrose used has been found to have a significant influence in the physical appearance of the finished composition and its ultimate acceptance for taste. The preferred particle size of the sucrose component when used is in the range of from 200 to less than 325 mesh US Standard Screen, and all combinations and subcombinations of ranges and specific particle sizes therein.
Sterile injectable solutions may be prepared by incorporating the crystalline forms of the compound in the required amounts, in the appropriate solvent, with various of the other ingredients enumerated herein, as required, followed by filtered sterilization. Generally, dispersions may be prepared by incorporating the sterilized active ingredient into a sterile vehicle which contains the dispersion medium and any other required ingredients. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation may include vacuum drying and the freeze drying technique which may yield a powder of the active ingredient, plus any additional desired ingredient from the previously sterile-filtered solution thereof.
As would be apparent to a person of ordinary skill in the art, once armed with the teachings of the present disclosure, when dissolved, a crystalline compound loses its crystalline structure, and is therefore considered to be a solution of the compound. All forms of the present invention, however, may be used for the preparation of liquid formulations in which the compound may be, for example, dissolved or suspended. In addition, the crystalline forms of the compound may be incorporated into solid formulations.
The liquid compositions may also contain other components routinely utilized in formulating pharmaceutical compositions. One example of such components is lecithin. Its use in compositions of the invention as an emulsifying agent in the range of from 0.05 to 1% by weight, and all combinations and subcombinations of ranges and specific amounts therein.
More preferably, emulsifying agents may be employed in an amount of from about 0.1 to about 0.5% by weight. Other examples of components that may be used are antimicrobial preservatives, such as benzoic acid or parabens; suspending agents, such as colloidal silicon dioxide; antioxidants; topical oral anesthetics; flavoring agents; and colorants.
The selection of such optional components and their level of use in the compositions of the invention is within the level of skill in the art and will be even better appreciated from the working examples provided hereinafter.
The crystalline forms of the compound may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidine pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamidephenol or polyethylene oxide-polylysine substituted with palmitolyl residues.
Furthermore, the crystalline compound may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
Gelatin capsules of the crystalline forms of the compound may contain the crystalline compound and the liquid or solid compositions described herein. Gelatin capsules may also contain powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Tablets can be sugar coated or film coated to mask any unpleasant taste and to protect the tablet from the atmosphere or enteric coated for selective disintegration in the gastrointestinal track.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral solutions are prepared by dissolving the crystalline compound in the carrier and, if necessary, adding buffering substances. Anti-oxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA may also be employed. Parenteral solutions may also contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., the disclosures of which are hereby incorporated herein by reference, in their entireties.
The crystalline forms of the compound of the present invention and pharmaceutical composition thereof may be administered to treat/ameliorate/prevent/combat cancer in a subject. Accordingly, the present invention provides methods for the treatment and/or prevention of cancer in mammals. Crystalline forms of the compound may be used alone or in combination with other anti-cancer agent(s). The preferred crystalline form of the compound may serve as component (a) of this invention and can independently be in any dosage form, such as those described above, and can also be administered in various combinations, as described above. In the following description component (b) is to be understood to represent one or more agents as described herein suitable for combination therapy. Accordingly, components (a) and (b) of the present invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product. When component (a) and (b) are not formulated together in a single dosage unit, the component (a) may be administered at the same time as component (b) or in any order; for example component (a) of this invention may be administered first, followed by administration of component (b), or they may be administered in the reverse order. If component (b) contains more than one agent, these agents may be administered together or in any order. When not administered at the same time, preferably the administration of component (a) and (b) occurs less than about one hour apart.
Preferably, the route of administration of component (a) and (b) is oral. Although it may be preferable that component (a) and component (b) both be administered by the same route (that is, for example, both orally) or dosage form, if desired, they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or dosage forms.
Co-administration A compound(s) of Formula [X] can be combined with one or more other pharmacologically active compounds ("second active agents") in methods and compositions provided herein. As used herein, the term "co-administration" refers to the administration of at least two agent(s)/therapies, one or more of which is a compound or composition of the present invention. In some embodiments, the co-administration of two or more agents/therapies is concurrent. In other embodiments, a first agent/therapy is administered prior to a second agent/therapy. Those of skill in the art understand that the formulations and/or routes of administration of the various agents/therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when agents/therapies are co-administered, the respective agents/therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents/therapies lowers the requisite dosage of a known potentially harmful (e.g., toxic) agent(s). The use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.
The compounds of the present disclosure may be administered individually, in combination with each other, and/or in combination with other pharmaceuticals/treatments useful for treating the disease or condition of interest. It is understood that the component medications of a combination therapy may be administered to the patient simultaneously or at different times, and may be administered on the same or different dosing schedules, as appropriate.
When administered in combination, each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect, in a way that the therapeutical effects of the first administered one is not entirely dissipated when the subsequent is administered. The dosage of each component medication need not be the same and are expected to be different in most cases. Furthermore, the routes of administration may be the same or different. In one embodiment, the component medications are coformulated for convenience (e.g. in the same injectable or ingestible composition). In an alternative embodiment, the component medications are packaged/distributed/sold/promoted/advertised together.
Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of the present invention and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.
For cancer indications, additional such agents include, but are not limited to, kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), ALK inhibitors (e.g., crizotinib) standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatories such as NSAIDs. The pharmaceutical compositions of the invention may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.
Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present invention or may be included with a compound of the present invention in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present invention.
Provided herein are methods of treating patients who have been previously treated for cancer but are non-responsive to standard therapies, as well as those who have not previously been treated. The invention further encompasses methods of treating patients who have undergone surgery in an attempt to treat the disease or condition at issue, as well as those who have not.
Because patients with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his/her prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy to administer to a patient administered with a compound(s) of Formula [X], which can be effectively used to treat an individual subject with cancer.
A compound(s) provided herein, e.g. a compound(s) of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, can be combined with one or more other pharmacologically active compounds ("second active agents") in methods and compositions provided herein. It is believed that certain combinations work synergistically in the treatment of particular types of cancer. The compound(s) of Formula [X] provided herein can also work to alleviate adverse effects associated with certain second active agents. One or more second active ingredients or agents can be used in the methods and compositions provided herein with the compound(s) of Formula [X] provided herein. Administration of a compound(s) of Formula [X] and one or more second active agents to a subject can occur simultaneously or sequentially by the same or different routes of administration. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules). Examples of small molecule second active agents include, but are not .. limited to, anti-cancer agents, anti-neoplastic agents, anti-proliferation agents, chemotherapeutics, antibiotics, painkillers, anti-depressants, anti-anxiety drugs, anti-nausea drugs, antihistamines, immunosuppressive agents, steroids, anti-angiogenic agents, anti-fibrotic agents, anti-inflammatory agents, immune modulating agents, immunotherapeutic agents, therapeutic antibodies, radiotherapeutic agents, (i) antimetabolites;
(ii) DNA-.. fragmenting agents, (iii) DNA-crosslinking agents, (iv) intercalating agents (v) protein synthesis inhibitors, (vi) topoisomerase I poisons, such as camptothecin or topotecan; (vii) topoisomerase II poisons, (viii) microtubule-directed agents, (ix) kinase inhibitors (x) miscellaneous investigational agents (xi) hormones and (xii) hormone antagonists.
Examples of large molecule active agents include, but are not limited to, immunotherapies, immuno-oncology agents, hematopoietic growth factors, cytokines, monoclonal and polyclonal antibodies e.g. antagonistic antibodies to one or more of PD-L1, CD27, CD137, CD25, CD40, OX4OL, IDO, GITR, LAG-3, CTLA-4. In certain embodiments, large molecule active agents are biological molecules, such as naturally occurring or artificially made proteins. Proteins that are particularly useful in this disclosure .. include proteins that stimulate the survival and/or proliferation of hematopoietic precursor cells and immunologically active poietic cells in vitro or in vivo. Others stimulate the division and differentiation of committed erythroid progenitors in cells in vitro or in vivo. Particular proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II ("rIL2") and canarypox 1L-2), IL-10, IL-12, and IL-18; interferons, such as interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO.
Particular proteins that can be used in the methods and compositions of the disclosure include, but are not limited to: filgrastim, which is sold in the United States under the trade name NEUPOGEN (Amgen, Thousand Oaks, Calif.); sargramostim, which is sold in the United States under the trade name LEUKINE (Immunex, Seattle, Wash.); and recombinant EPO, which is sold in the United States under the trade name EPGEN (Amgen, Thousand Oaks, Calif.).
Inhibitors of ActRII receptors or activin-ActRII inhibitors may be used in the methods and compositions provided herein. ActRII receptors include ActRIIA inhibitors and ActRIIB

inhibitors. Inhibitors of ActRII receptors can be polypeptides comprising activin-binding domains of ActRII. In certain embodiments, the activin-binding domain comprising polypeptides are linked to an Fc portion of an antibody (i.e., a conjugate comprising an activin-binding domain comprising polypeptide of an ActRII receptor and an Fe portion of an antibody is generated). In certain embodiments, the activin-binding domain is linked to an Fe portion of an antibody via a linker, e.g., a peptide linker. Examples of such non-antibody proteins selected for activin or ActRIIA binding and methods for design and selection of the same are found in WO/2002/088171, WO/2006/055689, WO/2002/032925, WO/2005/037989, US 2003/0133939, and US 2005/0238646, each of which is incorporated herein by reference in its entirety.
Recombinant and mutated forms of GM-CSF can be prepared as described in U.S.
Pat.
Nos. 5,391,485; 5,393,870; and 5,229,496; the disclosure of each of which is incorporated herein by reference in its entirety. Recombinant and mutated forms of G-CSF
can be prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755;
the disclosure of each of which is incorporated herein by reference in its entirety.
This disclosure encompasses the use of native, naturally occurring, and recombinant proteins. The disclosure further encompasses mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit, in vivo, at least some of the pharmacological activity of the proteins upon which they are based. Examples of mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the proteins. Also encompassed by the term "mutants" are proteins that lack carbohydrate moieties normally present in their naturally occurring forms (e.g., nonglycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to the protein or active portion of the protein of interest. See, e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. Methods 248:91-101 (2001).
One or more antibodies (or antibody fragments) and/or antibody-drug conjugates can be used in combination(s) with a compound(s) of Formula [X] including, but not limited to, monoclonal, polyclonal, multi-specific, murine, chimeric, humanized and human antibodies.
Examples of antibodies include, but are not limited to, immune checkpoint inhibitors, including an antibody that targets one or more of PD-1 (CD279), PDL-1 (CD274), PDL-2, CTLA4, TIM3, 0X40, GITR, LAG3, CD137, 4-1BB, B7-H3, B7-H4, KIR, PARP, CD27, ICOS, TIGIT, BTLA, VISTA, A2AR, CD80, CD86, CD-47, GD2, CSF1R, or antibodies that target cancer expressed antigens, which may or not be also expressed by normal cells, such as, to illustrate, (on B cells) CD20, CD22, CD52, CD23, ROR-1. Exemplary antibodies include, but are not limited to, pembrolizumab (Keytruda), nivolumab (Opdivo), durvalumab, avelumab, atezolizumab (Tecentriq), ipilimumab (Yervoy), pidilizumab, AMP-224, AMP-514, PDR001, cemiplimab, BMS-936559, CK-301, pexidartinib, PLX7486, ARRY-382, JNJ-40346527, BLZ945, emactuzumab, AMG820, IMC-CS4, MCS110, cabiralizumab, abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab, narnatumab, naptumomab, necitumumab, nimotuzumab, nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, CC49 and 3F8.
trastuzumab (HERCEPTINg), rituximab (RITUXANt), bevacizumab (AVASTINTm), pertuzumab (OMNITARGTm), tositumomab (BEXXARO), edrecolomab (PANOREXg), panitumumab and G250. The exemplified therapeutic antibodies may be further labeled or combined with a radioisotope particle, such as indium In-111, yttrium Y-90, iodine 1-131 (radioimmunotherapy). A compound(s) of Formula [X], or salt(s)/hydrate(s)/solvate(s)/prodrug(s) thereof, can be combined with or used in combination with one or more of cytokine(s) therapy, such as interferon(s) and/or interleukin(s) administration, oncolytic virus therapy or therapies, cancer vaccine(s) administration, antigen(s)/tumour antigen(s)/neoantigen(s) administration, CpG
oligodeoxynucleotide(s), immunostimulant(s), dendritic cell therapy, adoptive cell transfer, CAR-T cell therapy, antibody therapy, anti-TNF-a antibody(ies), combination immunotherapy, immunotherapy, cancer immunotherapy, immuno-oncology therapy or any treatment(s), most preferably FDA

approved, that utilises/leverages a subject's immune system or an immune system component(s) or mimetic(s) to treat cancer in a subject, optionally in further combination with one or more other cancer treatment(s) including, but not limited to, chemotherapy, targeted agent(s), radiation etc.
Examples of anti-cancer agents include, but are not limited to: abraxane; ace-11; acivicin;
aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;
altretamine;
ambomycin; ametantrone acetate; amrubicin; amsacrine; anastrozole;
anthramycin;
asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;
benzodepa;
bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;
bleomycin sulfate;
brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;
caracemide; carbetimer;
carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol;
celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;
cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride;
decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone;
docetaxel;
doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate;
dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin;
enloplatin;
enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate;
etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine;
fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;
gemcitabine;
gemcitabine hydrochloride; herceptin; hydroxyurea; idarubicin hydrochloride;
ifosfamide;
ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; lapatinib;
letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium;
lomustine;
losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride;
megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;
methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;
mitocarcin;
mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane;
mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin;
oxisuran;
paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;
perfosfamide;
pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane;
porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;
puromycin hydrochloride; pyrazofurin; riboprine; romidepsin; safingol; safingol hydrochloride;
semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride;
spiromustine; spiroplatin; stem cell treatments such as PDA-001;
streptonigrin; streptozocin;

sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone hydrochloride;
temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine;
thiotepa;
tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate;
trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride;
uracil mustard;
uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;
vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate;
vinorelbine tartrate;
vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin;
and zorubicin hydrochloride.
Other anti-cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3;
5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;
adozelesin; aldesleukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid;
amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;
antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;
.. aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;
apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1;
axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III
derivatives; balanol;
batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; b-FGF inhibitor;
bicalutamide;
bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin;
breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives;
capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3;
CARN 700;
cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS);
castanospermine;
cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;
cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B;
combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol;
cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam;
cypemycin;
cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine;
dehydrodidemnin B;
deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone;
didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-;
dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron;
doxifluridine;
doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;
edelfosine;
edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;
estramustine analogue;
estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate;
exemestane;

fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;
flezelastine;
fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;
formestane;
fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine;
ganirelix;
gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;
heregulin;
hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;
idramantone;
ilmofosine; ilomastat; imatinib (e.g., GLEEVECO), imiquimod; immunostimulant peptides;
insulin-like growth factor-1 receptor inhibitor; interferon agonists;
interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole;
isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N
triacetate;
lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin;
letrozole; leukemia inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin;
levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol;
lonidamine;
losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;
maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim;
mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin;
mitoxantrone; mofarotene; molgramostim; Erbitux, human chorionic gonadotrophin;
.. monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;
mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;
naphterpin;
nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin;
nitric oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen (GENASENSE0); 0 6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;
ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;
oxaliplatin; oxaunomycin;
paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine;
palmitoylrhizoxin;
pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine;
pentosan polysulfate sodium; pentostatin; pentrozole; perflubron;
perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;
pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex;
porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor;
protein kinase C

inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide;
roquinimex;
rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides;
signal transduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate;
solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D;
spiromustine; splenopentin; spongistatin 1; squalamine; stipiamide;
stromelysin inhibitors;
sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista;
suramin;
swainsonine; tallimustine; tamoxifen methiodide; tauromustine; tazarotene;
tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;
teniposide;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;
thrombopoietin;
thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist;
thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin;
toremifene; translation inhibitors; tretinoin; triacetyluridine; triciribine;
trimetrexate;
triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors;
tyrphostins; UBC inhibitors;
ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists;
vapreotide; variolin B; velaresol; veramine; verdins; verteporfin;
vinorelbine; vinxaltine;
vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
Specific second active agents include, but are not limited to, oblimersen (GENASENSE , remicade, docetaxel, celecoxib, melphalan, dexamethasone (DECADRONO), steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, ARISA , taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (DOXILO), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (EMCYTO), sulindac, and etoposide.
In one embodiment, the compound or combination described herein may be used or combined with one or more additional therapeutic agents. The one or more therapeutic agents include, but are not limited to, an enzyme inhibitor, an inhibitor of Abl, activated CDC kinase (ACK), adenosine A2B receptor (A2B), apoptosis signal-regulating kinase (ASK), Auroa kinase, Bruton's tyrosine kinase (BTK), BET-bromodomain (BRD) such as BRD4, c-Kit, c-Met, CDK-activating kinase (CAK), calmodulin-dependent protein kinase (CaMK), cyclin-.. dependent kinase (CDK), casein kinase (CK), discoidin domain receptor (DDR), epidermal growth factor receptors (EGFR), focal adhesion kinase (FAK), Flt-3, FYN, glycogen synthase kinase (GSK), HCK, histone deacetylase (HDAC), IKK such as IKK3c, isocitrate dehydrogenase (IDH) such as IDH1, Janus kinase (JAK), KDR, lymphocyte-specific protein tyrosine kinase (LCK), lysyl oxidase protein, lysyl oxidase-like protein (LOXL), LYN, matrix metalloprotease (MMP), MEK, mitogen-activated protein kinase (MAPK), NEK9, NPM-ALK, p38 kinase, platelet-derived growth factor (PDGF), phosphorylase kinase (PK), polo-like kinase (PLK), phosphatidylinositol 3-kinase (PI3K), protein kinase (PK) such as protein kinase A, B, and/or C, PYK, spleen tyrosine kinase (SYK), serine/threonine kinase TPL2, serine/threonine kinase STK, signal transduction and transcription (STAT), SRC, serine/threonine-protein kinase (TBK) such as TBKI, TIE, tyrosine kinase (TK), vascular endothelial growth factor receptor (VEGFR), or any combination thereof.
Many experimental strategies for vaccination against cancers/tumors have been devised (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis, C, 2000, ASCO Educational Book Spring: 300-302; Khayat, D.
2000, ASCO
Educational Book Spring: 414-428; Foon, K. 2000, ASCO Educational Book Spring:

738; see also Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita, V. et al. (eds.), 1997, Cancer: Principles and Practice of Oncology. Fifth Edition). The study of gene expression and large scale gene expression patterns in various tumors has led to the definition of so called tumor specific antigens (Rosenberg, S A (1999) Immunity 10: 281-7).
In many cases, these tumor specific antigens are differentiation antigens expressed in the tumors and in the cell from which the tumor arose, for example melanocyte antigens gp100, MAGE antigens, and Trp-2.
In certain embodiments, a compound(s) of Formula [X] or a salt(s) thereof can be combined with one or more anti-cancer or anti-tumor vaccine, antigen, immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J. Immunol. 173:4919-28). Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF. Or for example, vaccines that secrete, or cause the secretion of, cytokines such as IL-2, SCF, CXC14 (platelet factor 4), G-CSF, and GM-CSF
can be used in the methods, pharmaceutical compositions, and kits of the disclosure. See, e.g., Emens, L.
A., et at., Curr. Opinion Mol. Ther. 3(1):77-84 (2001). The administered tumor antigen may also include the protein telomerase, which is required for the synthesis of telomeres of chromosomes and which is expressed in more than 85% of human cancers and in only a limited number of somatic tissues (Kim, Net al. (1994) Science 266: 2011-2013).
Administered tumor antigen may also be "neo-antigens" expressed in cancer cells because of somatic mutations that alter protein sequence or create fusion proteins between two unrelated sequences (ie. bcr-abl in the Philadelphia chromosome), or idiotype from B
cell tumors.
Other tumor vaccines may include the proteins from viruses implicated in human cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV, HDV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). Administered antigen may be purified heat shock .. proteins (HSP) isolated from the tumor tissue itself. These heat shock proteins contain fragments of proteins from the tumor cells (Suot, R & Srivastava, P (1995) Science 269:
1585-1588; Tamura, Y. et at. (1997) Science 278: 117-120). Dendritic cells (DC) are potent antigen presenting cells that can be used to prime antigen-specific responses in a subject upon administration. DCs can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et at. (1998) Nature Medicine 4: 328-332).
DCs may also be transduced by genetic means to express these tumor antigens as well. DCs have also been fused directly to tumor cells for the purposes of immunization (Kugler, A. et al. (2000) Nature Medicine 6:332-336).
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with specific agents such as heparin, aspirin, coumadin, or G-CSF to avoid adverse effects that are associated with anti-cancer drugs such as but not limited to neutropenia or thrombocytopenia.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with melphalan and dexamethasone to patients with amyloidosis. In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and steroids can be administered to patients with amyloidosis.
In certain embodiments, a compound provided herein, e.g., the compound of Formula = [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with gemcitabine and cisplatinum to patients with locally advanced or metastatic transitional cell bladder cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with a second active ingredient as follows: temozolomide to pediatric patients with relapsed or progressive brain tumors or recurrent neuroblastoma;
celecoxib, etoposide and cyclophosphamide for relapsed or progressive CNS cancer; temodar to patients with recurrent or progressive meningioma, malignant meningioma, hemangiopericytoma, multiple brain metastases, relapsed brain tumors, or newly diagnosed glioblastoma multiforms;
irinotecan to patients with recurrent glioblastoma; carboplatin to pediatric patients with brain stem glioma; procarbazine to pediatric patients with progressive malignant gliomas;
cyclophosphamide to patients with poor prognosis malignant brain tumors, newly diagnosed or recurrent glioblastoma multiforms; Gliadel for high grade recurrent malignant gliomas;
temozolomide and tamoxifen for anaplastic astrocytoma; or topotecan for gliomas, glioblastoma, anaplastic astrocytoma or anaplastic oligodendroglioma.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with methotrexate, cyclophosphamide, taxane, abraxane, lapatinib, herceptin, aromatase inhibitors, selective estrogen modulators, estrogen receptor antagonists, and/or PLX3397 (Plexxikon) to patients with metastatic breast cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with temozolomide to patients with neuroendocrine tumors.

In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with gemcitabine to patients with recurrent or metastatic head or neck cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with gemcitabine to patients with pancreatic cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with colon cancer in combination with ARISAS, avastatin, taxol, and/or taxotere.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with capecitabine and/or PLX4032 (Plexxikon) to patients with refractory colorectal cancer or patients who fail first line therapy or have poor performance in colon or rectal adenocarcinoma.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with fluorouracil, leucovorin, and irinotecan to patients with Dukes C & D
colorectal cancer or to patients who have been previously treated for metastatic colorectal cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with refractory colorectal cancer in combination with capecitabine, xeloda, and/or CPT-11.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with capecitabine and irinotecan to patients with refractory colorectal cancer or to patients with unresectable or metastatic colorectal carcinoma.

In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered alone or in combination with interferon alpha or capecitabine to patients with unresectable or metastatic hepatocellular carcinoma; or with cisplatin and thiotepa to patients with primary or metastatic liver cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with pegylated interferon alpha to patients with Kaposi's sarcoma.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with fludarabine, carboplatin, and/or topotecan to patients with refractory or relapsed or high-risk acuted myelogenous leukemia.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with liposomal daunorubicin, topotecan and/or cytarabine to patients with unfavorable karotype acute myeloblastic leukemia.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with gemcitabine, abraxane, erlotinib, geftinib, and/or irinotecan to patients with non-small cell lung cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with carboplatin and irinotecan to patients with non-small cell lung cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with doxetaxol to patients with non-small cell lung cancer who have been previously treated with carboNP 16 and radiotherapy.

In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with carboplatin and/or taxotere, or in combination with carboplatin, pacilitaxel and/or thoracic radiotherapy to patients with non-small cell lung cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with taxotere to patients with stage IIIB or IV non-small cell lung cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with oblimersen (Genasensee) to patients with small cell lung cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with ABT-737 (Abbott Laboratories) and/or obatoclax (GX15-070) to patients with lymphoma and other blood cancers.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered alone or in combination with a second active ingredient such as vinblastine or fludarabine to patients with various types of lymphoma, including, but not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low grade follicular lymphoma.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with taxotere, IL-2, IFN, GM-CSF, PLX4032 (Plexxikon) and/or dacarbazine to patients with various types or stages of melanoma.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered alone or in combination with vinorelbine to patients with malignant mesothelioma, or stage IIIB non-small cell lung cancer with pleural implants or malignant pleural effusion mesothelioma syndrome.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of multiple myeloma in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan, cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, or a combination thereof.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with relapsed or refractory multiple myeloma in combination with doxorubicin (Doxile), vincristine and/or dexamethasone (Decadrone).
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of ovarian cancer such as peritoneal carcinoma, papillary serous carcinoma, refractory ovarian cancer or recurrent ovarian cancer, in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or a combination thereof.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of prostate cancer, in combination with xeloda, 5 FU/LV, gemcitabine, irinotecan plus gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, denderon or a combination thereof.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of renal cell cancer, in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex , or a combination thereof.

In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of gynecologic, uterus or soft tissue sarcoma cancer in combination with IFN, a COX-2 inhibitor such as Celebrex , and/or sulindac.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of solid tumors in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
In certain embodiments, a compound provided herein, e.g., the compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients .. with scleroderma or cutaneous vasculitis in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
The above "other" therapeutic agents, when employed in combination with a compound(s) of the present disclosure, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present disclosure, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds.
Use with transplantation therapy The abovementioned therapies can be supplemented or combined with stem cell transplantation or treatment, including peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, and nonmyeloablative allogeneic hematopoietic stem cell transplantation.

The compound(s) of Formula [X] provided herein can be used to reduce the risk of Graft Versus Host Disease (GVHD). Therefore, encompassed herein is a method of treating, preventing and/or managing cancer, which comprises administering one or more of these compounds, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in conjunction with transplantation therapy.
As those of ordinary skill in the art are aware, the treatment of cancer is often based on the stages and mechanism of the disease. For example, as inevitable leukemic transformation develops in certain stages of cancer, transplantation of peripheral blood stem cells, hematopoietic stem cell preparation or bone marrow may be necessary. The combined use of a compound provided herein and transplantation therapy provides a unique and unexpected synergism. In particular, the compound exhibits immunomodulatory activity that may provide additive or synergistic effects when given concurrently with transplantation therapy in patients with cancer.
The compound(s) of Formula [X] can work in combination with transplantation therapy reducing complications associated with the invasive procedure of transplantation and risk of GVHD. Encompassed herein is a method of treating, preventing and/or managing cancer which comprises administering to a subject at least one compound of Formula [X], or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, before, during, or after the transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation, or bone marrow. Some examples of stem cells suitable for use in the methods provided herein are disclosed in U.S. Pat. No.
7,498,171, the disclosure of which is incorporated herein by reference in its entirety.
In one embodiment, at least one compound of Formula [X] is administered to patients with multiple myeloma before, during, or after the transplantation of autologous peripheral blood progenitor cell.
In another embodiment, at least one compound of Formula [X] is administered to patients with relapsing multiple myeloma after the stem cell transplantation.
In yet another embodiment, at least one compound of Formula [X] and prednisone are administered as maintenance therapy to patients with multiple myeloma following the transplantation of autologous stem cell.

In yet another embodiment, at least one compound of Formula [X] and dexamethasone are administered as salvage therapy for low risk post transplantation to patients with multiple myeloma.
In yet another embodiment, at least one compound of Formula [X] and dexamethasone are administered as maintenance therapy to patients with multiple myeloma following the transplantation of autologous bone marrow.
In yet another embodiment, at least one compound of Formula [X] is administered following the administration of high dose of melphalan and the transplantation of autologous stem cell to patients with chemotherapy responsive multiple myeloma.
In yet another embodiment, at least one compound of Formula [X] and PEG INTRO-A
are administered as maintenance therapy to patients with multiple myeloma following the transplantation of autologous CD34-selected peripheral stem cell.
In yet another embodiment, at least one compound of Formula [X] is administered with post transplant consolidation chemotherapy to patients with newly diagnosed multiple myeloma to evaluate anti-angiogenesis.
In still another embodiment, at least one compound of Formula [X] and dexamethasone are administered as maintenance therapy after DCEP consolidation, following the treatment with high dose of melphalan and the transplantation of peripheral blood stem cell to 65 years of age or older patients with multiple myeloma.
In one embodiment at least one compound of Formula [X] is administered to patients with NHL (e.g., DLBCL) before, during, or after the transplantation of autologous peripheral blood progenitor cell.
In another embodiment, at least one compound of Formula [X] is administered to patients with NHL (e.g., DLBCL) after a stem cell transplantation.
Scope The examples of this invention are provided to better illustrate the claimed invention and are not to be interpreted in any way as limiting the scope of the invention. These specific compounds, compositions, materials, methods and kits are not intended to limit the invention, but merely to illustrate specific embodiments falling within the scope of the invention. One skilled in the art may develop equivalent compounds, compositions, materials, and methods without the exercise of inventive capacity and without departing from the scope of the invention. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. It will be understood that many variations can be made in the procedures herein described while still remaining within the bounds of the invention. It is the intention of the inventor that such variations are included within the scope of the invention. The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment. Feature(s) described in connection with one embodiment of the invention may be used in conjunction with another embodiment(s), even if not explicitly stated.
Abbreviations All abbreviations used in this disclosure are standard/used in the art, familiar/discernable to a person of the art, especially in their context, to illustrate:
Ph=phenyl Bn=benzyl Me=methyl Et=ethyl Me0H=methanol Et0H=ethanol Pr=propyl Bu=butyl PE=petroleum ether COOEt=ethoxycarbonyl CO2Et=ethoxycarbonyl Et3SiH=triethylsilane LiA1H4=lithium aluminium hydride ACN=acetonitrile=CH3CN
AcOH=acetic acid MeI=CH3I
Boc=tert-butyloxycarbonyl protecting group CDI=1,1'-carbonyldiimidazole DCE=1,2-Dichloroethane DCM=dichloromethane DBU=1,8-diazabicyclo[5,4,0]undec-7-ene DMAP=4-Dimethylaminopyridine DMF=N,N-dimethylformamide DPPA=Diphenylphosphoryl azide EDCI=N-(3-dimethylaminopropy1)-N'-ethylcarbodiimide hydrochloride Et0Ac=ethyl acetate HEPES= 4-(2-hydroxyethyl)- 1 -piperazineethanesulfonic acid IBX=2-iodoxybenzoic acid IPA=isopropanol MEI=methyl iodide Tf20=triflic anhydride NaBH(OAc)3=sodium triacetoxyborohydride NCS= N=C=S
Rf=retention value t-BuOK=potassium tert-butoxide TEA=triethylamine=Et3N
THF=tetrahydrofuran TFA=trifluoroacetic acid T3P=Propanephosphonic acid anhydride HATU=Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium TLC=thin-layer chromatography SFC=supercritical fluid chromatography or chiral supercritical fluid chromatography IPAm=isopropylamine SM=starting material min=minute(s) h or hr=hour(s) aq. or aq=aqueous PATENTS, OR PATENT APPLICATIONS, CITED
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DESCRIPTION claims (Method of use format) [1] A compound, or a composition containing at least one compound, of the following formula:

=N
L
HI
(R4)q R1 or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
L is alkyl, or deuterium, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy, or hydroxyalkyl, or any atom or isotope permitted by valence except hydrogen at natural abundance;
RI is hydrogen, cyano, ¨SO2R8, ¨C(3)R9, heteroaryl or thiazolyl;
R2 is (i) independently hydrogen, alkyl, benzyl, or substituted alkyl, or (ii) taken together with R3 forms a heterocyclo;
R3 is (i) independently alkyl, substituted alkyl, alkylthio, aminoalkyl, carbamyl, BB-aryl, BB-heterocyclo, BB-heteroaryl, or BB-cycloalkyl, or (ii) phenyl optionally substituted with Ci..4alkyl, halogen, trifluoromethyl, OCF3, cyano, nitro, amino, hydroxy, or methoxy, or (iii) independently selected from Ci_aalkyl, alkylthio, aminoalkyl, -BB-aryl, -BB-heterocyclo, BB-cycloalkyl, and -BB-hetaroaryl, optionally having one to three substituents selected from R3a; and/or having fused thereto a five or six membered carbocyclic ring, or (iv) taken together with R2 forms a heterocyclo optionally substituted with alkyl or substituted alkyl;
BB is a bond, Chaalkylene, C2_4alkenylene, substituted Ci_aalkylene, substituted C2-4a1keny1ene, substituted Ci_4alkylene-C(=0)NH¨, ¨Ci_4alkylene-C(=0)NH¨, ¨C(I)NRI ¨C
malkylene-C()NRI9¨, or substituted C 4alkylene-C(=0)NRI9¨, ¨(CHR14)m¨(CRI5R16),¨ or ¨(CHR14)p¨C(=0)NH¨;
R3a at each occurrence is selected independently from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, keto, trifluoromethyl, ¨NRI7R18, ¨SR17, ¨0R17, ¨
-- SO2R17a, ¨S02NRI7R18, ¨Nit17g=a)R18, --0O2R17, --C(D)R17, cyoloalkyl, aryl, heterocyolo, and heteroaryl, wherein when R3a is cycloalkyl, aryl, heterocyclo or heteroaryl, said cycloalkyl, aryl, heterocyolo and heteroaryl in turn is optionally substituted with alkyl or substituted alkyl;

Z is a heteroaryl, for example an optionally-substituted bicyclic heteroaryl;
or Z is triazolyl optionally substituted with one to two R7 substituents or imidazolyl optionally substituted with one to two R7 substituents and/or having fused thereto a benzene ring in turn optionally substituted with one to two R7 substituents; and R7 is alkyl, carbamyl, or substituted alkyl;
R4 at each occurrence is selected independently of each other R4 from the group consisting of halogen, trifluoromethyl, OCF3, alkyl, substituted alkyl, haloalkyl, nitro, cyano, haloalkoxy, OR25, SR25, NR25R26, NR25S02R27, S02R27, S02NR25R26, CO2R26, C(=0)R26, C(=0)NR25R26, OC(=C))R25, -0C(=0)NR25R26, NR25C(:))R26, NR25CO2R26, aryl, heteroaryl, heterocyclo and cycloalkyl;
R8 is Ci_aalkyl or phenyl optionally substituted with alkyl, halogen, haloalkoxy, cyano, nitro, or trifluoromethyl;
R9 is -NRIORII, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclo, or -0O2R12, alkyl or phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, Ci_aalkoxy, haloalkoxy, C1_6alkyl, CO2alkyl, SO2alkyl, SO2NH2, amino, NH(C1-4alkyl), N(Ci_4alky1)2, NHC(=0)alkY, C(=0)alkyl, and/or Ci_aalkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl; and/or a five or six membered heteroaryl or heterocylo in turn optionally substituted with keto or having a benzene ring fused thereto or a) Ci_aalkyl optionally substituted with one to two of:
i) SR13, 0R13, NR13aRi3b, halogen, trifluoromethyl, CO2R13a, and C(=0)NR13aRi3b;
ii) cycloalkyl optionally substituted with one to two of C(=0)H, Ci_aacyl, alkenyl, carbamyl, and/or phenyl in turn optionally substituted with halogen;
iii) phenyl or napthyl optionally substituted with one to two of halogen, nitro, amino, alkyl, hydroxy, Ci_aalkoxy, or having fused thereto a five or six membered heterocyclo;
iv) pyridinyl, thiophenyl, fiiranyl, tetrahydrofuranyl, or azepinyl, optionally substituted with alkyl or having fused thereto a five to six membered carbocyclic ring optionally substituted with keto or Ci_4a1k0xy;
b) 3 to 6 membered cycloalkyl optionally having up to four substituetits selected from alkyl, -- halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, phenyl in turn optionally substituted with halogen; or having an aryl fused thereto;
c) pheyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, Ci_aalkoxy, haloalkoxy, Ci_aalkyl, CO2alkyl, SO2alkyl, SO2NH2, amino NH(Ci_ 4a1ky1), N(Ci_4alky1)2, NHC(=3)alkyl, C(=;30)alkyl, and/or Chaalkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl;
and/or a five or six membejed heteroaryl or heterocyle in turn optionally substituted with keto or having a benzene ring fused thereto;
d) pyridinyl, thiazolyl, furanyl, thiophenyl, and pyrrolyl optionally substituted with one to two of halogen, alkyl, and phenyl in turn optionally substituted with halogen or trifluoromethyl;
Rio and Ri I are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, heteroaryl or Ci_4alkyl optionally substituted with one to two of ¨0O2alkyl, ¨C(C)NH(ary1), NH(ary1), cycloalkyl, phenyloxy, phenyl in turn optionally substituted with Ci_aalkyl, hydroxy, Ci_aalkoxy, halogen, amino, nitro, tetrahydrofuranyl, and/or five or six membered heterocyclo, or having a five or six membered heterocyclo fused thereto; pyrrolidinyl optionally substituted with keto;
napthyl, anthracenyl, pyridinyl, thiophenyl, furanyl, imidazolyl, benzimidazolyl, or indolyl in turn optionally substituted with Ci_4alkyl or Ci_aalkoxy; or (ii) taken together form a heteroaryl or heterocyclo selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, tetrahydropyridinyl, and imidazoilidinyl, wherein said heterocyclo formed by Rio and RH is optionally substituted with one to two of keto, CO2H, Ciaalkoxy, CO2alky1, Ci_acarbamyl, benzyl; phenyl in turn optionally substituted with alkyl, halogen, or CI-4 alkoxy;
tetrahydropyridinyl in turn optionally substituted with keto and/or phenyl;
alkyl optionally substituted with amino or NHR21wherein R21 is alkyl or phenyl optionally substituted with alkyl; and/or has a benzene ring fused thereto in turn optionally substituted with one to two of alkyl, Ci_aalkoxy, CO2alkyl, and/or Ci_acarbamyl;
R12 and R19 are hydrogen or alkyl;
Ri3 is hydrogen or alkyl;
Ri3a and Ri3b are selected from hydrogen, alkyl, and aryl;
RI4, RI5 and RI6 at each occurrence are independently selected from hydrogen, alkyl, hydroxy, hydroxyCi_aalkyl, Cmalkoxy, and phenyl, and/or one of R15 and one of Ri6 join together to form a 3 to 6 membered cycloalkyl;
R17 and R18 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, phenyl, or benzyl wherein the phenyl or benzyl is optionally substituted with alkyl, hydroxy, or hydroxyalkyl;
RIM is alkyl or substituted alkyl;
R25 and R26 are independently selected from hydrogen, alkyl, or substituted alkyl, or taken together form a heterocyclo or heteroaryl ring;

R27 is alkyl or substituted alkyl;
q is 0, 1, 2, or 3;
m and n are 0, 1 or 2; and p is 0, 1, 2, or 3.
[2] A compound according to Claim 1, of the formula, 0,s\L

(R4),14*
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
there is an enantiomeric excess (cc) of the particular stereoisomer shown in the formula.
[3] A compound according to Claim 1, of the formula, NN./
N/L
N
D

(R4)q or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
D is deuterium (enrichment, for (non-limiting) example, exceeding 40%
deuterium incorporation at position shown, optionally deuterium enrichment at other locations also), 141 A compound according to Claim 1, of the formula, Z R2N r N
,oxµD
Slik S
H
I
(R4)q R1 or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at position shown);
the enantiomeric excess (ee) of the S stereoisomer exceeds 70%;
[5] A compound according to Claim 1, of the formula, Z R2N. ..,R3 N
ZIN\
jjkN " N

(R4)q or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
[6] A compound according to Claim 1, of the formula, N
NV
ACH>IN
ss"
N X N
I

(R4)q or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
the enantiomeric excess (ee) of the S stereoisomer exceeds 70%;
[7] A compound according to Claim 1, of the formula, Z X N ./.
CI*
(R4)q RD'f// N ga N N
I
H

or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
the enantiomeric excess (ee) of the R stereoisomer exceeds 70%;
-- 181 A compound according to Claim 1, wherein, R7c R7a .............c,N,R7b R7a ...,.......\,k,N
or \
Y ¨N N
c Y is CH, N or CIZ7c;
RI is cyano, ¨S02R8, ¨C(=D)R9, or heteroaryl;
R2 is (i) independently hydrogen, alkyl, or substituted alkyl, or (ii) taken together with R3 forms a heterocyclo;
R3 is (i) independently selected from (a) alkyl optionally substituted with one to two of hydroxy and alkoxy;
(b) alkylthio or aminoalkyl optionally substituted with hydroxy or alkoxy;
(c) -At-aryl, wherein the aryl is optionally substituted with up to four substituents selected from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, ¨NRI7R18, ¨SR17, ¨0R17, ¨S021Zi7a, ¨S02NRI7R18, ¨NRi7C(=a)R18, ¨0O2R17, ¨C(=0)R17, cycloalkyl, aryl, heterocyclo, and heteroaryl, and/or has fused thereto a five or six membered cycloalkyl ring;
(d) -A2-heteroaryl wherein the heteroaryl is a five or six membered monocyclic ring having 1 to 3 heteroatoms selected from N, 0, and S, or an eight or nine membered bicyclic ringed system having at least one aromatic ring and 1 to 4 heteroatoms selected from N, 0, and S in at least one of the rings, said heteroaryl being optionally substituted with halogen. alkyl, alkoxycarbonyl, sulfonamide, nitro, cyano, trifluoromethyl, alkylthio, alkoxy, keto, ¨

C(=0)H, acyl, benzyloxy, hydroxy, hydroxyalkyl, or phenyl optionally substituted with alkyl or substituted alkyl;
(e) -A2-heterocyclo wherein the heterocyclo is optionally substituted with one to two groups selected from alkyl, keto, hydroxy, hydroxyalkyl, ¨C(=0)H, acyl, CO2H, alkoxycarbonyl, phenyl, and/or benzyl, and/or has a bridged carbon¨carbon chain or fused benzene ring joined thereto;
(0 -A2-cycloalkyl wherein the cycloalkyl is optionally substituted with one to two groups selected from alkyl, keto, ¨C(=0)H, acyl, CO2H, alkoxycarbonyl, and/or benzyl, and/or has a bridged carbon¨carbon chain or fused benzene ring joined thereto; or (ii) taken together with R2 forms a heterocyclo;
R4 at each occurrence is selected independently of each other R4 from the group consisting of halogen, alkyl, haloalkyl, cyano, and haloalkoxy;
R7a, R7b and R7c are independently selected from hydrogen, alkyl, carbamyl, or carbamylalkyl, or R7a and R7c join to form an aryl or heteoraryl;
R8 is alkyl, arylalkyl, or aryl;
R9 is ¨NRIORI I, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclo, CO2R12, or phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, Ci_aalkoxy, haloalkoxy, Ci_6alkyl, CO2alkyl, SO2alkyl, SO2NH2, amino, NH(C1.4alkyl), N(Ci_4alky1)2, NHC(=0)alkyl, C(=0)alkyl, and/or Ci_aalkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl;
and/or a five or six membered heteroaryl or heterocyclo in turn optionally substituted with keto or having a benzene ring fused thereto;
Rio is independently hydrogen, alkyl, or alkoxy; and Ri is independently hydrogen, alkyl, substituted alkyl, alkoxy heterocyclo cycloalkyl, aryl, or heteroaryl; or Rio and Ru1 taken together form a heterocyclo or heteroaryl optionally substituted with alkyl, keto, CO2H, alkoxycarbonyl, hydroxy, alkoxy, alkyl, carbamyl, aryl, or substituted alkyl, wherein when the RIO and Ri group comprises a phenyl ring, said phenyl ring is optionally substituted with one to two of alkyl, halogen, and alkoxy;
Ri2 is hydrogen or alkyl;
Au is ¨(CHRia)m¨V¨(CRI5R16)n¨ or ¨(CHR14)p¨(C=D)NH¨;
A2 IS ¨(CHR14)m¨V¨(CRI5R16)n;
V is a bond, S, or ¨NR22¨;

Ri4, RI5 and R16 at each occurrence are independently selected from hydrogen, alkyl, hydroxy, hydroxyCi-aalkyl, Ci_aalkoxy, and phenyl, and/or one of R15 and one of Ri6join together to form a three to six membered cycloalkyl;
R17 and Riaare independently selected from hydrogen, alkyl, phenyl, and benzyl, wherein the phenyl and benzyl is optionally substituted with alkyl, hydroxy, or hydroxyalkyl;
R17a is alkyl or substituted alkyl;
R22 is hydrogen or alkyl;
m and n are 0, 1, 2, or 3;
p is 0, 1, 2, or 3; and q is 0, 1, 2, or 3.
191 A compound according to Claim 8 having the formula, (R24)y Z NNZ R2 (CHR23)x L
NrkN
H
I
(R4) R1 or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
R7a, R7b and R7c are independently selected from hydrogen, alkyl, carbamyl or carbamylCi_aalkyl, or R7a and R7, join to form a fused phenyl ring;
R23 is selected from hydrogen, alkyl, hydroxyalkyl, or phenyl;
R24 is selected from alkyl, halogen, trifluoromethyl, cyano, halogen, hydroxy, OCF3, methoxy, phenyloxy, benzyloxy, cyano, acyl, or two R24 groups join to form a fused cycloalkyl or benzene ring; and x is 0, 1, or 2; and y is 0, 1, 2, or 3.
1101 A compound according to Claim 1, having the structure:

N

N/

CI
=

HZNNH

CI
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
deuterium (D) enrichment at the chiral centre, and optionally at other locations, exceeds 40% deuterium incorporation the enantiomeric excess (ee) of the S stereoisomer exceeds 70%.
1111 A compound according to Claim 1, having the structure:

......==" N
N'('7%' t¨N

CI * N
H NH

Ci or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
1121 A compound according to Claim 1, having the structure:
<21 1.1 NiZZL--1 N

el s ....................
N NH
H
CI

CI
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
the enantiomeric excess (ee) of the S stereoisomer exceeds 70%.

1131 A compound according to Claim 1, having the structure:
N
11/\
NO

Rs"//N NH
CI

CI
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
the enantiomeric excess (ee) of the R stereoisomer exceeds 70%.
[14] A pharmaceutical composition comprising at least one compound as defined in Claim 1 and a pharmaceutically-acceptable carrier or excipient or diluent.
[15] At least one compound, or a composition containing at least one compound, according to Claim 1 for use in a method of treatment of the human or animal body by therapy.
[16] A method of treating, ameliorating, preventing, reversing or combating a disease or disorder, or unwanted/undesirable physiological process or its consequences or an unwanted/undesirable aesthetic, in a subject, selected from (i) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. 18F-FDG PET);
(ii) cachexia, cancer driven cachexia, cancer fatigue, weight loss, weight loss for known or unknown reason, chronic wasting disease, atrophy, brown atrophy, frailty, frailty syndrome, aging frailty, geriatric syndrome, age-related cachexia and/or sarcopenia, weakness, wasting, anorexia nervosa, bulimia nervosa, eating disorder, amenorrhea, underweight, low body mass index (BMI, e.g. <18.5), low body fat percentage, body composition change, wasting syndrome, HIV wasting syndrome, malnutrition, clinical .. malnutrition, starvation, kwashiorkor syndrome, marasmus syndrome, malabsorption, malabsorption due to parasitic/bacterial infection (e.g. helminthiasis, Whipple's disease, small intestine bacterial overgrowth (SIB0), giardiasis etc.), anemia, refeeding syndrome, appetite loss, catabolysis, muscle atrophy, asthenia, muscle weakness (myasthenia), sarcopenia, osteoporosis, cachexia associated with HIV, AIDS, multiple sclerosis, rheumatoid arthritis, familial amyloid polyneuropathy, chronic kidney disease, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia, Addison's disease, mercury poisoning (acrodynia), chronic pancreatitis, untreated/severe type 1 diabetes mellitus, hormonal deficiency, tuberculosis, gastroenteritis, diarrhea, dysentery, any digestive disease or disorder, any gastrointestinal disease or disorder including functional gastrointestinal disorders, coeliac disease, tropical sprue, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, short bowl syndrome, congestive heart failure, constrictive pericarditis, bradycardia, chronic obstructive pulmonary disease (COPD), altitude sickness, hyperthyroidism (subclinical hyperthyroidism, Graves' disease, multinodular goiter, toxic adenoma, inflammation of the thyroid {thyroiditis}, pituitary adenoma), fatigue, chronic fatigue syndrome or any disease or disorder or pathology in which a body tissue(s) is undersupplied or underutilises (vs. its need) an energetic/chemical substrate(s), including 02;
(iii) cancer associated fever, which is especially associated with, but not limited to, non Hodgkin lymphoma (NHL), Hodgkin lymphoma, acute leukaemia, kidney cancer (renal cell cancer), liver cancer (hepatocellular carcinoma), bone cancer, adrenal gland tumours such as phaeochromocytomas, tumours in the hypothalamus, solid tumours;
(iv) disease or disorder or physiological process or condition that causes a higher than normal body temperature such as (without limitation) high environmental temperature, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, neutropenic sepsis, stroke, .. fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, toxic serotonin syndrome, thyroid storm, heatstroke, surgery related, menopause ("hot flushes"), infection (non-limiting e.g. roseola, measles, enteroviral infections, parasitic, viral, fungal, Chlamydial, Rickettsial, bacterial, mycobacterial, systemic bacterial, intravascular, 1-11V associated, nosocomial), pyrogenic infection, thermoregulatory disorder(s), connective tissue disease(s), Kawasaki syndrome, drug overdose, drug or drug withdrawal induced hyperthermia, alcohol/drug withdrawal, idiosyncratic drug reaction, fever of known or unknown or uncertain origin (non-limiting e.g. infectious disease(s), inflammation, immunological disease(s), non-infectious inflammatory disease(s) {non-limiting eg. systemic rheumatic and autoimmune diseases, vasculitis, granulomatous diseases, autoinflammatory syndromes}, tissue destruction, reaction to incompatible blood product(s), metabolic disorder(s), inherited metabolic disorder(s), cancer, neoplasm, endogenous or exogenous pyrogen(s), injury, head injury);
(v) disease/disorder/injury/pathology/surgery treatable/ameliorated/prevented/combated/helped by conferring hypothermia in a subject for some medical or other purpose which can include slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, slowing physiological/pathological processes (reaction rates are temperature dependent) and so "buying time" to get the subject to treatment for their emergency (e.g.
trauma/septic shock or .. other medical emergency), slowing the progress of sepsis until a sufficient concentration of a working antibiotic(s) can be built up in the subject (furthermore hypothermia, by slowing sepsis progression, buys time to observe which antibiotic(s) can work, yielding time to try alternative further antibiotic option(s) if required), used soon after or just before clinical/legal death to preserve the subject's organs/tissues until the subject can be frozen/cryogenically frozen or the pathology that caused clinical/legal death (e.g. wound) can be fixed and the subject resuscitated, administered to a subject when a first responder (e.g.
ambulance crew) deems the subject dead or unlikely to survive the journey to a medical facility (e.g. hospital) wherein this administration helps to preserve the subject which is helpful if hospital staff subsequently assess that they can, or might be able to, save the subject, stabilizing .. surgical/trauma/Emergency Room (ER) patients, deep hypothermic circulatory arrest for surgery (DHCA, non-limiting applications of DHCA include repairs of the aortic arch, repairs to head and neck great vessels, repair of large cerebral aneurysms, repair of cerebral arteriovenous malformations, pulmonary thromboendarterectomy, resection of tumors that have invaded the vena cava, brain tumor resection {wherein the anti-cancer activity of a compound(s) of this invention juxtaposes well}), Emergency Preservation and Resuscitation (EPR), hypothermia for a surgical purpose, protective hypothermia during surgery and/or surgery complication, hypothermia to slow/reduce blood loss, hypothermia for neuro- and/or cardio- and/or organ/tissue and/or life protection in a subject that has trauma/brain trauma/polytrauma/surgery/stroke/ischemic stroke/hemorrhagic stroke/cardiac arrest/myocardial infarction/hypoxia/shock (including, without limitation, low volume, cardiogenic, obstructive, and distributive shock)/sepsis/septic shock/multiple organ dysfunction syndrome/systemic inflammatory response syndrome (SIRS)/organ failure/cytokine storm/anaphylactic shock/seizure/disseminated intravascular .. coagulation/blocked airway/croup/rhabdomyolysis/[head/facial/spinal/chest/abdominal/ballistic/knife injury/trauma], or some other medical emergency/condition/disorder/disease/injury/operation, hypothermia for cardiac and/or cardiovascular surgery and/or open heart surgery and/or brain surgery (neurosurgery) and/or surgery using total circulatory arrest and/or surgery using cardiopulmonary bypass, Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage/transport and/or transplant, thus increasing the time window for transplantation of organs to recipients;
compound(s) of this invention is administered to organ to be transplanted [by administration to donor and/or by administration to isolated organ] and/or to organ recipient, optionally during transplant operation), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, neonatal hypoxia-ischemia, birth asphyxia, hypoxic-ischemic encephalopathy (HIE), haemorrhage, hypovolemia, exsanguination, suspended animation, decompression sickness, burn injury(s) including skin burn, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or tourniquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (non-limiting e.g. meningitis), sepsis, septic shock, stroke, cerebrovascular disease, ischemic brain injury, ischemic stroke, traumatic injury, brain injury, spinal cord injury, cardiac arrest, heart failure, congestive heart failure, Dilated cardiomyopathy, valvular heart disease, pulmonary embolism, adrenal crisis, Addisonian crisis, hypertensive emergency, haemorrhagic (hypovolemic) shock, cardiogenic shock, neurogenic shock, hepatic encephalopathy, blood loss, ischemic brain/heart/kidney/intestinal injury, neuroprotection and/or cardioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject;
(vi) poisoning by a toxic amount of a compound(s) in a subject (non-limiting e.g.
carbon monoxide/methanol/heavy metal/ethylene glycol/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison(s), nerve agent, chemical weapon, bacterial toxin(s) (e.g. food poisoning, Salmonella poisoning), endotoxemia, eukaryote produced toxin(s) e.g. (non-limiting) brevetoxin, drug(s)/substance(s) overdose e.g. (non-limiting) heroin, ethanol, a prescription medication(s), an over the counter medication(s) such as aspirin, paracetamol etc.; hypothermia is protective to toxic insult);
(vii) hypermetabolism (optionally because of one or more of, without restriction, traumatic brain injury, injury to the body, infection, sepsis, burn, multiple trauma, fever, long-bone fracture, hyperthyroidism, prolonged steroid therapy, surgery, bone marrow transplant, recovery from anorexia/bulimia), heat intolerence, insomnia, fatal insomnia, nervousness, Luft's disease, non-thyroidal hypermetabolism, thyrotoxicosis, hyperthyroidism, overactive thyroid, subclinical hyperthyroidism, too much thyroid hormone(s) in the subject, too much triiodothyronine (T3) and/or thyroxine (T4) in the subject, hyperthyroxinemia (including, without restriction, familial dysalbuminemic hyperthyroxinemia, familial euthyroid hyperthyroxinemia, thyroid hormone resistance syndrome), thyroid storm, hyperthyroidism caused by one or more of (without restriction) Graves' disease, thyroiditis, Hashimoto's thyroiditis, subacute thyroiditis, postpartum thyroiditis, lumps (nodules) on the thyroid, enlarged thyroid gland (goitre), simple goitre, multinodular goiter, toxic multinodular goiter, toxic adenoma, toxic thyroid adenoma, inflammation of the thyroid, hyperplasia of thyroid, metastatic thyroid cancer, thyroid tumour, thyroid cancer (including, without restriction, papillary carcinoma, follicular carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma), eating too much iodine, goitrogen ingestion, consumption of ground beef contaminated with thyroid tissue ("hamburger hyperthyroidism"), too much synthetic thyroid hormone in the subject, pituitary adenoma, drug induced, Amiodarone drug induced, struma ovarii, Jod-Basedow syndrome, nonautoimmune autosomal dominant hyperthyroidism;
(viii) low or less than desired metabolic/bioenergetic efficiency in a subject, or low or less than desired physical or mental performance (e.g. memory, IQ), or low or less than desired body weight, or fatigue/tiredness/weakness/exhaustion;
(ix) accelerated aging disease or progeroid syndrome including, without restriction, Werner syndrome, Bloom syndrome, De Barsy syndrome, Rothmund¨Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann¨Rautenstrauch syndrome, Hutchinson¨Gilford progeria syndrome (progeria), Ataxia telangiectasia-like disorder 2, XFE progeroid syndrome, Muscular dystrophy, Muscular Dystrophy (Becker's, Duchenne, Limb-Girdle), Yamamoto's Muscular Dystrophy, Mandibuloacral dysplasia, Dilated cardiomyopathy, GAPO syndrome, Cutis laxia, Ehlers-Danlos syndrom, Lenz-Majewski hyperostatic dwarfism, SHORT syndrome, Progressive external opthalmoplegia, Nester-Guillermo progeria syndrome, MDPL syndrome, Dyskeratosis congenital, Down syndrome;
(x) disease or disorder of aging (incidence/severity increases with increased age/senescence) and/or unwanted/undesirable aspect(s) of aging and/or a disease/disorder associated with elevated reactive oxygen species including age-associated decline, aging frailty, frailty syndrome, sarcopenia, muscle weakness, osteoporosis, cognitive decline, cognitive defecit, mild cognitive impairment, degenerative diseases, neurodegenerative diseases, motor-associated neurodegenerative diseases, motor neuron disease, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, progressive supranuclear palsy, pseudobulbar palsy, hereditary spastic paraplegia, Parkinson's disease, Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), essential tremor, resting tremor, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, frontotemporal dementia, chronic traumatic encephalopathy, memory loss, aged cognition, age/aging related cognitive decline/impairment, Batten disease, polyglutamine diseases, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, heart failure with preserved ejection fraction, idiopathic pulmonary fibrosis, fibrotic disease, pulmonary disease, coronary artery disease, hypercholesterolemia, obesity, liver disease, fatty liver disease, lysosomal storage disease, amyloidosis, systemic sclerosis, kidney disease, hepatic cirrhosis, immunosenscence, clonal hematopoiesis, chronic obstructive pulmonary disease (COPD), hypertension, hypercholesterolemia, age-related thymic atrophy, arthritis, osteoarthritis, arthritis (Osteo-and Rheumatoid), Juvenile Rheumatoid Arthritis (JRA), Degenerative Disc Disease, Tendinopathy, Androgenetic Alopecia, male-pattern baldness, Idiopathic Pulmonary Fibrosis, systemic sclerosis, Chronic Obstructive Pulmonary Disease, Psoriasis, age-related loss of cardiac/pulmonary/cognitive/vision function, diabetes, type 2 diabetes, andropause, glaucoma, retinal degeneration, sarcopenia, cachexia, age-related cachexia and/or sarcopenia, age-related macular degeneration (AMD, early/intermediate/late), neovascular/wet AMD, dry AMD, Geographic atrophy (GA), wet and dry AMD in the same eye(s), Stargardt's macular degeneration, Best vitelliform macular dystrophy, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, age/aging-related eye disease, ophthalmological disease/disorder, ocular disease, vision loss, progressive vision impairment, myopia (short-sightedness), degenerative myopia, hyperopia (far-sightedness), accommodative dysfunction, glaucoma, cataract formation, retinal degeneration, progressive retinal degeneration, retinitis pigmentosa, leber hereditary optic neuropathy, Fuchs spot, Best's disease, Sorsby's fundus dystrophy, hearing loss (e.g. age-related), presbycusis, tinnitus, naive T cell shortage, movement disability, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), immunosenescence, respiratory/urinary tract infection (RTI/UTI) especially in older/aged/elderly subjects, cancer;
(xi) aging and/or one or more signs of aging, wherein one or more of these compounds slow/delay/reduce/treat/prevent/stop/reverse aging, and/or extend lifespan and/or .. healthspan, and/or treat or delay the onset of geriatric aging of the human/animal body, tissue(s), or organ(s), and/or treat or delay the onset of an age-associated phenotype in a cell(s)/organism(s), and/or prolong fertility e.g. female fertility, delay menopause;
(xii) skin aging and/or damage (including sun damage) and/or scalp and/or hair aging and/or hair greying and/or hair loss;
(xiii) insomnia, fatal insomnia, sleep onset latency, delayed sleep phase disorder, exploding head syndrome, parasomnia, sleep-maintenance insomnia, sleep disorder, too much/inappropriate/undesired signals/activity/electrical activity in the nervous system, hyperactivity, hypersensitivity, Premature ejaculation, hyperreflexia, Autonomic dysreflexia (AD), Hyperventilation syndrome, brain hyperactivity, overly sensitive sensory system, pathological crying and/or laughing, Pseudobulbar affect (PBA, emotional lability), photophobia, phonophobia, temperature-sensitive, pressure-sensitive, brain hyperexcitability, overstimulation, intrusive thought(s), Perseveration, sensory overload, disorganized thinking, fantasy prone personality, malapdative daydreaming, dissociation, hyperkinetic disorder, agitation, Psychomotor agitation, restlessness, difficulty controlling behaviour, disruptive behaviour disorder, Emotional and behavioral disorder, pervasive developmental disorder, Overactive disorder associated with mental retardation and stereotyped movements, attention-deficit disorder, Attention Deficit Hyperactivity Disorder (ADHD), adult attention-deficit hyperactivity disorder, severe behavioral problem(s) in children (e.g., to illustrate and not restrict, combativeness and/or explosive hyperexcitable behavior {out of proportion to immediate provocation[s]}, hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of one or more of: impulsivity, difficulty sustaining attention, aggressivity, mood lability, poor frustration tolerance), Premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), impulsiveness, impulsivity, impulse control disorder, lack of self-control, hysteria, histrionic personality disorder, attention difficulty, inattention, poor attention control, anxiety, paranoid anxiety, Paranoid personality disorder, distress, dysphoria, Adjustment disorder, separation anxiety, anxiety disorder, depressive anxiety, agitated depression, treatment-resistant depression, Generalized anxiety disorder, social anxiety disorder, stranger anxiety, separation anxiety (e.g. in dogs left at home), separation anxiety disorder, Mixed anxiety-depressive disorder, depression (all forms, all severities), restlessness/apprehension/anxiety before surgery.
hypochondria, panic disorder, panic attack, emotional outburst, emotional instability, Intermittent explosive disorder, unreasonable/unwarranted anger/aggression, hyper-aggression, hostility, rage, poor temper control, self-hatred, poor attentional control, worry, irritability, neuroses, somatization disorder, somatic symptom disorder, pain disorder, psychological pain, psychogenic pain, psychogenic facial pain, Atypical odontalgia (AO), burning mouth syndrome, throbbing, toothache/pulpitis/dental pain, chronic lower back pain, negative emotion, persistent/enduring negative emotion, body dysmorphic disorder, factitious disorder, illness anxiety disorder, unwarrented fight-or-flight response, stress, emotional stress, emotional dysregulation, distress, psychological stress, acute stress, chronic stress, acute stress reaction, combat stress reaction, traumatic grief, grief, grief after death of loved one, Prolonged grief disorder (PGD), heartbreak, guilt, shame, remorse, emotional pain, Algopsychalia, psychalgia, suffering, emotional trauma, psychological trauma, broken heart, Post Traumatic Stress Disorder (PTSD), Complex post-traumatic stress disorder (C-PTSD), hypervigilance, sympathetic hyperactivity, inability or impaired ability to relax, flashbacks, dysphoric hyperarousal, agoraphobia, insomnia, fatal insomnia, mood disorder, irrational/unwarrented fear/terror, phobia, social phobia, Cancerophobia, thunderstorm/firework phobia, hypersexuality, hypersexual disorder, depression, clinical depression, unipolar depression, bipolar disorder, Bipolar I, Bipolar II, Bipolar disorder not otherwise specified (Bipolar NOS), cyclothymia, cyclothymic disorder, mixed affective state, atypical depression, melancholic depression, postpartum depression, double depression, seasonal affective disorder, mania, manic episode, hypomania, increase in energy of psychomotor activity, delirium, excited delirium, major depressive disorder, minor depressive disorder, recurrent brief depression, Depressive Disorder Not Otherwise Specified (DD-NOS), major depressive episode, persistent depressive disorder (PDD), dysthymia, dysthymic disorder, absence of euthymia, manic thoughts, racing thoughts, thought disorder, disordered thinking, reduced ability to plan and execute tasks, paranoia, hallucination (including, without limitation, visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrioceptive, nociceptive, thermoceptive, chronoceptive), Charles Bonnet syndrome, delusion, persecutory delusion, hearing voices, homicidal/criminal ideation/tendency/thoughts, suicidal ideation/tendancy/thoughts, self-injury, non-suicidal self-injury, violence, attacking others, negative mood swing, personality disorder, Borderline personality disorder, Narcissistic personality disorder, malignant narcissism, dissociative disorder, dissociative identity disorder (DID), Psychosis, acute psychosis, chronic psychosis, psychosis spectrum disorder, manifestations of psychotic disorders, behavioral complications of mental retardation, stimulant psychosis, psychotic depression, hallucinogen persisting perception disorder, Psychoactive substance-related disorder, amphetamine-induced psychosis, brief psychotic disorder, Brief reactive psychosis, Menstrual psychosis, postpartum psychosis, Psychotic disorder, Psychopathy, chronic hallucinatory psychosis, manifestation(s) of psychotic disorder, neurotic/reactive/endogenous/involutional/psychotic depression/depressive disorder (optionally accompanied by anxiety or agitation), depressive neurosis, delusional depression, psychotic aggression, psychiatric symptoms of dementia, AIDS delirium, Supersensitivity psychosis, Tardive psychosis, Tardive dysmentia, Depersonalization disorder, out-of-body experience, Sociopathy, Schizophrenia, Paranoid schizophrenia, disorganized-type schizophrenia, simple-type schizophrenia, pseudoneurotic schizophrenia, prodromal schizophrenia, schizoaffective disorder, bipolar type schizoaffective disorder, depressive type schizoaffective disorder, schizoaffective psychosis, Schizotypal personality disorder, schizophreniform disorder, Delusional parasitosis, formication, paresthesias, Acroparesthesia, tinnitus, delusional disorder, delusional jealousy, inappropriate behaviour, behavioural disorder, antisocial personality disorder, Oppositional defiant disorder (ODD), conduct disorder (CD), Disruptive mood dysregulation disorder (DMDD), sadistic personality disorder, poor inhibitory control, kleptomania, Pyromania, trichotillomania, dermatillomania, pathological/problem gambling, dyskinesia, tardive dyskinesia, paroxysmal dyskinesia, Paroxysmal kinesigenic dyskinesia, Paroxysmal nonkinesigenic dyskinesia, Paroxysmal exercise-induced dystonia, Hemiballismus, tic disorder, tremor, clonus, Tourette's syndrome, coprolalia, copropraxia, Echophenomena, Echopraxia, Echolalia, Palilalia, stuttering/stammering, stereotypy, punding, Self-stimulatory behaviour (stimming), Stereotypic movement disorder (SMD), synesthesia, obsession, Obsessive¨compulsive disorder (OCD), obsessive¨compulsive personality disorder, anankastic personality disorder, relationship obsessive¨compulsive disorder (ROCD), Scrupulosity, Primarily obsessional obsessive compulsive disorder, sexual obsession, Akathisia (including, without limitation, chronic, acute, Pseudoakathisia, Tardive akathisia, withdrawal or "rebound"
akathisia), Restless legs syndrome, motor restlessness, periodic limb movement disorder (PLMD), periodic limb movements in sleep (PLMS), Sydenham's chorea, chorea, dystonia, Hypnic jerk, twitching, spasms, Tetanus, tetanus muscle spasms, tetanized state, Myoclonus, myoclonic seizure, Action myoclonus, Palatal myoclonus, Middle ear myoclonus, Spinal myoclonus, Stimulus-sensitive myoclonus, Sleep myoclonus, Cortical reflex myoclonus, Essential myoclonus, myoclonic epilepsy, Juvenile myoclonic epilepsy, Progressive myoclonus epilepsy (PME, including, without limitation, Dentatorubral-pallidoluysian atrophy, Unverricht-Lundborg disease, MERRF syndrome, Lafora disease), Reticular reflex myoclonus, Myoclonic epilepsy, diaphragmatic flutter, automatism, status epilepticus, Epilepsia partialis continua, Complex partial status epilepticus, epilepsy, epileptic seizure, simple partial seizure, complex partial seizure, generalized epilepsy, generalized seizure (including, without limitation, tonic-clonic, tonic, clonic, myoclonic, absence (including typical absence and atypical absence), atonic seizure), focal epilepsy, focal seizure, focal/partial seizure (including, without limitation, Simple partial seizure and Complex partial seizure), focal aware seizure, focal impaired awareness seizure, generalised epilepsy, temporal lobe epilepsy (including, without restriction, mesial temporal lobe epilepsy {MTLE} and lateral temporal lobe epilepsy ILTLED, Frontal lobe epilepsy, Rolandic epilepsy, Nocturnal epilepsy, Nocturnal frontal lobe epilepsy, Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Generalized epilepsy with febrile seizures plus (GEFS+), Panayiotopoulos syndrome, epileptic fit, reflex epilepsy, reflex seizure, absence seizure (including, without limitation, childhood absence epilepsy, epilepsy with myoclonic absences, juvenile absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome {eyelid myoclonia with absences), genetic generalised epilepsy with phantom absences), complex partial seizure, atonic seizure, generalized tonic-clonic seizure, tonic¨clonic seizure, extrinsic stimulus epilepsy, intrinsic stimulus epilepsy, photosensitive epilepsy, musicogenic epilepsy, thinking epilepsy, eating epilepsy, seizure(s), Febrile seizure, nerve agent induced seizure, Dravet syndrome (sometimes modest hyperthermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals), acute symptomatic seizure, seizure-related disorder, drug related seizure, paroxysmal depolarizing shift, Ohtahara syndrome, Epilepsy in females with mental retardation, Rasmussen's encephalitis, Epilepsy syndrome, benign rolandic epilepsy, childhood absence epilepsy, absence epilepsy, juvenile myoclonic epilepsy, epileptic encephalopathies, Lennox¨Gastaut syndrome, West syndrome (Epileptic spasms), Doose syndrome (Myoclonic astatic epilepsy, MAE), Lennox-Gestaut syndrome, pseudo-Lennox Gastaut syndrome (atypical benign partial epilepsy), Benign familial neonatal epilepsy, Benign occipital epilepsy of childhood, familial neonatal convulsions, Febrile infection-related epilepsy syndrome, interictal dysphoric disorder, euphoria sclerotic, psychogenic non-epileptic seizure, non-epileptic seizure, gelastic seizure, convulsion(s), migraine, status migrainosus, tension headache, headache, Hypnic headache, hiccups, intractable hiccups, thumps in equines, Postural orthostatic tachycardia syndrome (POTS), Pheochromocytoma, agony, pain, chronic pain, acute pain, pain due to disease/injury, neuropathic pain, fibromyalgia, postherpetic neuralgia, phantom pain, referred pain, back pain, lower back pain, pelvic pain, cancer associated pain, chemotherapy associated pain, Diabetic neuropathy, small fiber peripheral neuropathy, Mononeuritis multiplex, Wartenberg's migratory sensory neuropathy, Breakthrough pain, idiopathic pain, polyneuropathy, Neuritis, Mononeuropathy, Polyradiculoneuropathy, Radial neuropathy, neuropathy, visceral pain, Burning feet syndrome, Tarsal tunnel syndrome, Carpal tunnel syndrome, Guyon's canal syndrome, Cubital Tunnel Syndrome, Repetitive strain injury, Sciatica, Neurofibromatosis, Ulnar nerve entrapment, Erythromelalgia, Paroxysmal extreme pain disorder, Proctalgia fugax, dysesthesia, scalp dysesthesia, dysesthetic burning, hyperesthesia, hyperalgesia, Opioid-induced hyperalgesia, hyperpathia, allodynia, pain response from stimuli which do not normally provoke pain, Complex regional pain syndrome (said to be most painful condition known to man), Radiculopathy, neuralgia (including, without restriction, intercostal neuralgia, trigeminal neuralgia, atypical trigeminal neuralgia, glossopharyngeal neuralgia, occipital neuralgia, postherpetic neuralgia), ciguatera poisoning, irritable bowel syndrome (IBS), interstitial cystitis (IC), temporomandibular joint disorder, acute intermittent porphyria, Porphyria, Acute porphyria (including, without limitation, acute intermittent porphyria {AIP}, variegate porphyria {VP}, aminolevulinic acid dehydratase deficiency porphyria {ALAD}, hereditary coproporphyria {HCP}, drug induced), Chronic porphyria (including, without limitation, X-linked dominant protoporphyria {XLDPP}, congenital erythropoietic porphyria {CEP}, porphyria cutanea tarda {PCT}, and erythropoietic protoporphyria {EPP}), cutaneous porphyria, Porphyria cutanea tarda, allergy, allergic reaction, anaphylaxis, anaphylactic shock, hives, asthma, allergic rhinitis, rhinitis, urticaria, contact dermatitis, cough, sore throat, esophageal reflux disease, heartburn, chest pain, Esophageal motility disorder, Nutcracker esophagus, diseases involving gastrointestinal motility, Peptic ulcer disease, esophageal spasm, angina, itchiness, Pruritus, severe pruritus, Prurigo, Pruritic skin condition, chronic itch, eczema, pruritus in eczema, neuropathic itch, neurogenic itch, itchiness due to atopic dermatitis and/or lichen simplex chronicus, peripheral sensitization, central sensitization, sensory perception of absent stimuli, too much sensory stimulation, sensory stimulation brings discomfort, Neuromyotonia, Peripheral nerve hyperexcitability, Morvan's syndrome, Benign fasciculation syndrome, Cramp fasciculation syndrome, hyperhidrosis, undifferentiated somatoform disorder, somatoform disorder, somatic symptom disorder, conversion disorder, functional neurological symptom disorder, severe nausea and/or vomiting, severe nausea/emesis, Chemotherapy-induced peripheral neuropathy, chemotherapy-induced nausea and vomiting (CINV), radiation therapy-induced nausea and vomiting (RINV), postnarcotic nausea, hyperemesis gravidarum, morning sickness, Cyclic vomiting syndrome, retching/dry heaving, Urinary incontinence, enuresis, nocturnal enuresis, tail chasing, reduce urine spraying/marking behavior, benzodiazepine withdrawal syndrome, barbituate withdrawal syndrome, Neuroleptic discontinuation syndrome, drug withdrawal discomfort/pain/symptoms, drug use disorder, alcohol use disorder, opoid use disorder, amphetamine use disorder, cocaine use disorder, alcohol withdrawal syndrome/symptoms, delirium tremens, opoid withdrawal sydrome/symptoms, drug craving, drug addiction, drug dependence, polysubstance dependence, drug overdose, smoking, tobacco (nicotine) addition, tobacco (nicotine) withdrawal symptoms, alcoholism, addiction, opoid addiction, cocaine/crack addiction, addictive behaviour, addictive personality, behavioural addiction, internet/computer/computer game/social media/media addiction, exercise addiction, compulsive behaviour (e.g. {non-limiting}
checking, counting, washing, repeating), anti-social behaviour, criminality, sexual compulsion, impulsive sexual behaviour, compulsive buying, gambling addiction, sex related addiction, sexual urge, hunger, eating desire/compulsion, eating disorder, polyphagia, overeating, binge eating disorder, compulsive overeating, insatiable/excessive appetite, bulimia nervosa, anorexia nervosa, substance abuse, substance-induced delirium, substance-induced psychosis, substance-induced mood disorder, drug overdose, vertigo, motion sickness, seasickness, mental/nervous breakdown, Autism spectrum disorder, neurological disorder, cognitive disorder, mental disorder, mental health disorder, mental health condition involving impaired or altered neural plasticity, mood disorder, mental disorder disclosed in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or a later edition, a mental/behavioural disorder disclosed by the International Classification of Diseases (LCD) in ICD-10 Chapter V: Mental and behavioural disorders (World Health Organisation, WHO); or (xiv) diseases or disorders or conditions or pathologies or unwanted/undesirable effects/actions/behaviour treatable/ameliorated/prevented/combated, in totality or in part (e.g.
along with surgery), by anaesthesia, pre-anaesthesia, post-anaesthesia, hypoesthesia, hypoactivity, sedation, coma, tranquilization, behavioural submission, muscle relaxation, hibernation, artificial hibernation, torpor, synthetic torpor, suspended animation (e.g. used during spaceflight because e.g. reduces ionizing radiation damage to subject);
(xv) hyperproliferative/hyperplasia disorder, non-cancerous proliferative disorder, hyperproliferative autoimmune disorder, hyperplasia, epidermal hyperplasia, dysplasia (e.g.
epithelial dysplasia), nodule(s), wart(s), papilloma(s), squamous cell papilloma, genital wart(s), condyloma(s), condyloma acuminatum, cyst(s), polyp(s) {including, without restriction, digestive, colorectal, endometrial, cervical, nasal, laryngeal, inflammatory fibroid polyp[s])}, inherited/hereditary (including, without restriction, Familial adenomatous polyposis, Peutz¨Jeghers syndrome, Turcot syndrome, Juvenile polyposis syndrome, Cowden disease, Bannayan¨Riley¨Ruvalcaba syndrome {Bannayan-Zonana syndrome}, Gardner's syndrome) and non-inherited (non-restrictive e.g. Cronkhite¨Canada syndrome) polyposis syndrome, benign tumour, adenoma, organ enlargement by hyperplasia, Cushing's disease (enlarged adrenal cortex by hyperplasia), congenital adrenal hyperplasia, hyperplasia of breast, atypical ductal hyperplasia, intraductal papillomatosis, fibroadenomas, fibrocystic changes, hemihyperplasia, focal epithelial hyperplasia, sebaceous hyperplasia, sebaceous adenoma, intimal hyperplasia, unwanted/undesirable smooth muscle cell proliferation, smooth muscle cell hyperplasia, intimal smooth muscle cell hyperplasia, neointimal hyperplasia, proliferative vascular disorders, stenosis, stenosis because of cellular proliferation, vaginal stenosis, stenosis in a blood vessel, lessoned patency of a blood vessel, stenosis in a blood vessel because of cellular proliferation, vascular occlusion, restenosis, restenosis in a blood vessel that has been implanted with a stent, in-stent restenosis, post-angioplasty restenosis, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g.
diabetic retinopathy and/or other retinopathy[y/ies]), cardiac hyperplasia, fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, fibromatosis, neurofibromatosis, renal interstitial fibrosis, Cowden syndrome, hamartoma(s), choristoma(s), hemangioma(s), lymphangioma(s), rhabdomyoma(s), lymphangiomatosis, cystic hygroma, trichilemmoma, sarcoidosis, neurosarcoidosis, aggressive fibromatosis, desmoid tumour(s), unwanted/undesirable skin cell proliferation, hyperproliferative skin disorder, psoriasis (including, without restriction, plaque, guttate, inverse, pustular, napkin, seborrheic-like, nail, scalp and erythrodermic psoriasis), psoriatic arthritis, dactylitis, seborrhoeic dermatitis, dandruff, eczema, atopic dermatitis, rosacea, reactive arthritis (Reiter's syndrome), pityriasis rubra pilaris, hyperproliferative variants of disorders of keratinization (e.g., without restriction, actinic keratosis, senile keratosis, keratosis pilaris, seborrheic keratosis), scleroderma, benign prostatic hyperplasia, prostate enlargement, endometrial hyperplasia, atypical endometrial hyperplasia, benign endometrial hyperplasia, adenomyosis, atypical polypoid adenomyoma, endometriosis, endometriosis of ovary (endometrioma), endometrial polyp(s), polycystic ovary syndrome, ovarian cyst(s), cervical polyp(s), uterine fibroid(s), uterine hyperplasia;
(xvi) Tumour Associated Macrophages (TAMs) or any macrophage associated disease or disorder such as, without limitation, Macrophage Activation Syndrome (MAS), HIV, AIDS, HIV-associated neurocognitive disorders (HAND), AIDS dementia, HIV
peripheral neuropathy, HIV associated cancers, AIDS-defining cancers, non-AIDS
defining cancers, any disease in which the pathogen(s) hides from the immune system in macrophages including, without limitation, Mycobacterium tuberculosis (causes tuberculosis), Leishmania parasite (causes Leishmaniasis), Chikungunya virus (causes Chikungunya), Legionella pneumophila (causes Legionnaires' disease), adenoviruses, T. whipplei (causes Whipple's Disease), Brucella spp. (causes brucellosis), Staphylococcus aureus, Ebola virus, Hepatitis B
virus, Hepatitis C virus, influenza virus strains, dengue virus and antibiotic resistant bacteria, any disease or condition in which activated macrophages are unwanted or undesirable;
(xvii) virus/pathogen neuroinvasion via macrophage(s), as used for non-limiting example by HIV, Heptatitis C virus and SARS coronavirus;
(xviii) neurocognitive or neurodegenerative diseases/disorders, for non-limiting example those caused by a virus;
(xix) virus/pathogen transmission from mother to fetus/baby via macrophage(s) as used for non-limiting example by zika (via Hofbauer cells) and HIV
(macrophages in breast milk);
(xx) acute or chronic or systemic inflammation or any inflammatory disease/disorder/syndrome or any autoinflammatory disease/disorder/syndrome or any autoimmune disease/disorder/syndrome;
(xxi) acute inflammation, chronic inflammation, systemic inflammation, inflammation because of infection or foreign bodies or injury or chemical or toxin or drug or stress or frostbite or burn or ionising radiation or surgery, inflammatory diseases/disorders/syndromes, Macrophage Activation Syndrome (MAS), autoinflammatory diseases/disorders/syndromes, age-related chronic inflammatory diseases ("inflammaging"), autoimmune diseases/disorders/syndromes, diseases/disorders of the innate immune system, sore throat, sore throat associated with cold or flu or fever, high-intensity exercise associated inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, osteoarthritis, inflammatory osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation associated depression, neuroinflammation, neuropathic pain, exercise-induced acute inflammation, atherosclerosis, allergy, hay fever, anaphylaxis, inflammatory myopathies, drug-induced inflammation, systemic inflammatory response syndrome, sepsis-related multiple organ dysfunction/multiple organ failure, microbial infection, acute brain/lung/hepatic/renal injuries, lung inflammation, acute lung injury (ARDS), acne vulgaris, celiac disease, celiac sprue, chronic prostatitis, colitis, autoimmune hemolytic anemia, diverticulitis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Mast Cell Activation Syndrome, mastocytosis, otitis, pelvic inflammatory disease (PID), endometritis, reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasitosis, eosinophilia, type III hypersensitivity, ischaemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, alcoholic hepatitis, chronic viral hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematous (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative disease, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, bronchiectasis, bronchopneumonia, obliterative bronchiolitis, appendicitis, acute appendicitis, bursitis, cystitis, dermatitis, encephalitis, HIV encephalitis, gingivitis, meningitis, infective meningitis, myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis¨associated interstitial lung disease and desquamative interstitial pneumonia, pneumonia, interstitial lung disease, Lofgren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, steatohepatitis, nonalcoholic steatohepatitis, silicosis, histiocytoses, Langerhans' cell histiocytosis, haemophagocytic lymphohistiocytosis, pulmonary langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudogout, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft versus host disease (GVHD), lymphadenopathy, rheumatoid arthritis (RA), osteoarthritis (OA), inflammatory osteoarthritis, lupus, multiple sclerosis (MS), myocarditis, uveitis, CNS disease(s), inflammation aspect to a CNS disease(s), hypothalamic inflammation, dementia, glaucoma, amyloid related/driven disease, lipid storage disease(s), fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, cirrhosis of the liver, alcoholic cirrhosis, nephropath(y/ies), lupus nephritis, immune nephritis, fibrotic disorder(s), cardiovascular disease, heart disease, atherosclerosis, vulnerable plaque, plaque formation, lipid containing macrophage related disease(s)/disorder(s)/malad(y/ies), macrophage foam cells, diabetes, type I
diabetes, type 2 diabetes, insulin resistance, macrophage aspect to insulin resistance, obesity, obesity associated inflammation, macrophage accumulation/large numbers of macrophages in adipose tissue (e.g. associated with obesity), granuloma(s), granulomatous diseases, sarcoidosis (including, without limitation, Annular sarcoidosis, Erythrodermic sarcoidosis, Ichthyosiform sarcoidosis, Hypopigmented sarcoidosis, Lofgren syndrome, Lupus pernio, Morpheaform sarcoidosis, Mucosal sarcoidosis, Neurosarcoidosis, Papular sarcoid, Scar sarcoid, Subcutaneous sarcoidosis, Systemic sarcoidosis, Ulcerative sarcoidos), neurosarcoidosis, pulmonary sarcoidosis, interstitial lung disease, pulmonary fibrosis, pulmonary tuberculosis, immune reconstitution syndrome of HIV, Jarisch¨Herxheimer reaction, sepsis, Paget's disease of bone, osteolysis, monocytosis, histiocytosis, X-type histiocytoses, non-X histiocytoses, Langerhans cell histiocytosis, non-Langerhans-cell histiocytosis, malignant histiocytosis, malignant histiocytic disorders, histiocytomas, histiocytic lymphoma, hemophagocytic syndrome, hemophagocytic lymphohistiocytosis, lymphohistiocytosis, diffuse histiocytic sarcoma, Rosai¨Dorfman disease, gliosis, Bergmann gliosis, Chronic Obstructive Pulmonary Disease (COPD), chronic inflammatory lung disease, familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulinemia D with recurrent fever syndrome (HIDS), cryopyrin associated periodic syndrome (CAPS), Blau syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), mevalonate kinase deficiency, pyogenic-arthritis-pyoderma gangrenosum and acne syndrome (PAPA), periodic fever aphthous stomatitis pharyngitis adenitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, Schnitzler's syndrome, Sweet's syndrome, NLRP12-associated autoinflammatory disorders, deficiency of interleukin-1 receptor antagonist (DIRA), pyoderma gangrenosum, cystic acne, aseptic .. arthritis, periodic Fever Associated with mevalonate kinase deficiency (hyperimmunoglobulin D Syndrome), Pyogenic Arthritis Pyoderma Gangrenosum Acne (PAPA) syndrome, Periodic Fever Aphthous Stomatitis, Pharyngitis and Adenopathy (PFAPA) syndrome, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Chronic Recurrent Multifocal Osteomyelitis (CRMO), Synovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome, Cryopyrin associated Periodic Syndrome (CAPS), Familial cold auto inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Familial cold urticarial, Neonatal onset multisystemic inflammatory disorder (NOMID), hereditary Periodic Fever Syndromes, Periodic Fever Syndromes, systemic autoinflammatory diseases, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Balo disease, Behcet's disease, benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Berger's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immune hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type I diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR) PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Tumer syndrome, Pemphigus, peripheral neuropathy, perivenous encephalomyelitis, Pernicious anemia (PA), POEMS
syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)), idiopathic thrombocytopenia .. purpura, splenomegaly;
(xxii) Systemic inflammatory response syndrome, cytokine release syndrome, cytokine storm, immune reaction to a drug(s) or therapy(s), immune reaction to an immune activating drug(s) or agent(s) or treatment(s) or intervention(s), immune reaction to immunotherapy and/or immune-oncology and/or immunomodulatory drug(s) and/or treatment(s), adverse reaction to adoptive T-cell therapy(s), adverse reaction to a chimeric antigen receptor T-cell therapy(s) (CAR-T cell therapy(s)), adverse reaction to a immune checkpoint inhibitor(s), adverse reaction to monoclonal antibody drug(s), tumor lysis syndrome; or (xxiii) cancer and Graft Versus Host Disease (GVHD) in transplantation therapy in a cancer patient;
wherein the method comprises administering to the subject an effective amount of at least one compound or composition from Claim 1.
1171 A method of treating, ameliorating, preventing, reversing or combating a disease or disorder, or unwanted/undesirable physiological process or its consequences or an unwanted/undesirable aesthetic, in a subject, selected from (i) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. 18F-FDG PET);
(ii) cachexia, cancer driven cachexia, cancer fatigue, weight loss, weight loss for known or unknown reason, chronic wasting disease, atrophy, brown atrophy, frailty, frailty syndrome, aging frailty, geriatric syndrome, age-related cachexia and/or sarcopenia, weakness, wasting, anorexia nervosa, bulimia nervosa, eating disorder, amenorrhea, underweight, low body mass index (BMI, e.g. <18.5), low body fat percentage, body composition change, wasting syndrome, HIV wasting syndrome, malnutrition, clinical malnutrition, starvation, kwashiorkor syndrome, marasmus syndrome, malabsorption, malabsorption due to parasitic/bacterial infection (e.g. helminthiasis, Whipple's disease, small intestine bacterial overgrowth (SIB0), giardiasis etc.), anemia, refeeding syndrome, appetite loss, catabolysis, muscle atrophy, asthenia, muscle weakness (myasthenia), sarcopenia, osteoporosis, cachexia associated with HIV, AIDS, multiple sclerosis, rheumatoid arthritis, familial amyloid polyneuropathy, chronic kidney disease, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia, Addison's disease, mercury poisoning (acrodynia), chronic pancreatitis, untreated/severe type I diabetes mellitus, hormonal deficiency, tuberculosis, gastroenteritis, diarrhea, dysentery, any digestive disease or disorder, any gastrointestinal disease or disorder including functional gastrointestinal disorders, coeliac disease, tropical sprue, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, short bowl syndrome, congestive heart failure, constrictive pericarditis, bradycardia, chronic obstructive pulmonary disease (COPD), altitude sickness, hyperthyroidism (subclinical hyperthyroidism, Graves' disease, multinodular goiter, toxic adenoma, inflammation of the thyroid {thyroiditis}, pituitary adenoma), fatigue, chronic fatigue syndrome or any disease or disorder or pathology in which a body tissue(s) is undersupplied or underutilises (vs. its need) an energetic/chemical substrate(s), including 02;
(iii) cancer associated fever, which is especially associated with, but not limited to, non Hodgkin lymphoma (NHL), Hodgkin lymphoma, acute leukaemia, kidney cancer (renal cell cancer), liver cancer (hepatocellular carcinoma), bone cancer, adrenal gland tumours such as phaeochromocytomas, tumours in the hypothalamus, solid tumours;
(iv) disease or disorder or physiological process or condition that causes a higher than .. normal body temperature such as (without limitation) high environmental temperature, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, neutropenic sepsis, stroke, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, toxic serotonin syndrome, thyroid storm, heatstroke, surgery related, menopause ("hot flushes"), infection (non-limiting e.g. roseola, measles, enteroviral .. infections, parasitic, viral, fungal, Chlamydial, Rickettsial, bacterial, mycobacterial, systemic bacterial, intravascular, FIIV associated, nosocomial), pyrogenic infection, thermoregulatory disorder(s), connective tissue disease(s), Kawasaki syndrome, drug overdose, drug or drug withdrawal induced hyperthermia, alcohol/drug withdrawal, idiosyncratic drug reaction, fever of known or unknown or uncertain origin (non-limiting e.g. infectious disease(s), inflammation, immunological disease(s), non-infectious inflammatory disease(s) {non-limiting eg. systemic rheumatic and autoimmune diseases, vasculitis, granulomatous diseases, autoinflammatory syndromes), tissue destruction, reaction to incompatible blood product(s), metabolic disorder(s), inherited metabolic disorder(s), cancer, neoplasm, endogenous or exogenous pyrogen(s), injury, head injury);
(v) disease/disorder/injury/pathology/surgery treatable/ameliorated/prevented/combated/helped by conferring hypothermia in a subject for some medical or other purpose which can include slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, slowing physiological/pathological processes (reaction rates are temperature dependent) and so "buying time" to get the subject to treatment for their emergency (e.g.
trauma/septic shock or other medical emergency), slowing the progress of sepsis until a sufficient concentration of a working antibiotic(s) can be built up in the subject (furthermore hypothermia, by slowing sepsis progression, buys time to observe which antibiotic(s) can work, yielding time to try .. alternative further antibiotic option(s) if required), used soon after or just before clinical/legal death to preserve the subject's organs/tissues until the subject can be frozen/cryogenically frozen or the pathology that caused clinical/legal death (e.g. wound) can be fixed and the subject resuscitated, administered to a subject when a first responder (e.g.
ambulance crew) deems the subject dead or unlikely to survive the journey to a medical facility (e.g. hospital) wherein this administration helps to preserve the subject which is helpful if hospital staff subsequently assess that they can, or might be able to, save the subject, stabilizing surgical/trauma/Emergency Room (ER) patients, deep hypothermic circulatory arrest for surgery (DHCA, non-limiting applications of DHCA include repairs of the aortic arch, repairs to head and neck great vessels, repair of large cerebral aneurysms, repair of cerebral arteriovenous malformations, pulmonary thromboendarterectomy, resection of tumors that have invaded the vena cava, brain tumor resection {wherein the anti-cancer activity of a compound(s) of this invention juxtaposes well)), Emergency Preservation and Resuscitation (EPR), hypothermia for a surgical purpose, protective hypothermia during surgery and/or surgery complication, hypothermia to slow/reduce blood loss, hypothermia for neuro- and/or cardio- and/or organ/tissue and/or life protection in a subject that has trauma/brain trauma/polytrauma/surgery/stroke/ischemic stroke/hemorrhagic stroke/cardiac arrest/myocardial infarction/hypoxia/shock (including, without limitation, low volume, cardiogenic, obstructive, and distributive shock)/sepsis/septic shock/multiple organ dysfunction syndrome/systemic inflammatory response syndrome (SIRS)/organ failure/cytokine storm/anaphylactic shock/seizure/disseminated intravascular coagulation/blocked airway/croup/rhabdomyolysis/[head/facial/spinal/chest/abdominal/ballistic/knife injury/trauma], or some other medical emergency/condition/disorder/disease/injury/operation, .. hypothermia for cardiac and/or cardiovascular surgery and/or open heart surgery and/or brain surgery (neurosurgery) and/or surgery using total circulatory arrest and/or surgery using cardiopulmonary bypass, Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage/transport and/or transplant, thus increasing the time window for transplantation of organs to recipients;
compound(s) of this invention is administered to organ to be transplanted [by administration to donor and/or by administration to isolated organ] and/or to organ recipient, optionally during transplant operation), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, neonatal hypoxia-ischemia, birth asphyxia, hypoxic-ischemic encephalopathy (I-11E), haemorrhage, hypovolemia, exsanguination, suspended animation, decompression sickness, burn injury(s) including skin burn, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or tourniquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (non-limiting e.g. meningitis), sepsis, septic shock, stroke, cerebrovascular disease, ischemic brain injury, ischemic stroke, traumatic injury, brain injury, spinal cord injury, cardiac arrest, heart failure, congestive heart failure, Dilated cardiomyopathy, valvular heart disease, pulmonary embolism, adrenal crisis, Addisonian crisis, hypertensive emergency, haemorrhagic (hypovolemic) shock, cardiogenic shock, neurogenic shock, hepatic encephalopathy, blood loss, ischemic brain/heart/kidney/intestinal injury, neuroprotection and/or cardioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject;
(vi) poisoning by a toxic amount of a compound(s) in a subject (non-limiting e.g.
carbon monoxide/methanol/heavy metal/ethylene glycol/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison(s), nerve agent, chemical weapon, bacterial toxin(s) (e.g. food poisoning, Salmonella poisoning), endotoxemia, eukaryote produced toxin(s) e.g. (non-limiting) brevetoxin, drug(s)/substance(s) overdose e.g. (non-limiting) heroin, ethanol, a prescription medication(s), an over the counter medication(s) such as aspirin, paracetamol etc.; hypothermia is protective to toxic insult);
(vii) hypermetabolism (optionally because of one or more of, without restriction, traumatic brain injury, injury to the body, infection, sepsis, burn, multiple trauma, fever, long-bone fracture, hyperthyroidism, prolonged steroid therapy, surgery, bone marrow transplant, recovery from anorexia/bulimia), heat intolerence, insomnia, fatal insomnia, nervousness, Luft's disease, non-thyroidal hypermetabolism, thyrotoxicosis, hyperthyroidism, overactive thyroid, subclinical hyperthyroidism, too much thyroid hormone(s) in the subject, too much triiodothyronine (T3) and/or thyroxine (T4) in the subject, hyperthyroxinemia (including, without restriction, familial dysalbuminemic hyperthyroxinemia, familial euthyroid hyperthyroxinemia, thyroid hormone resistance syndrome), thyroid storm, hyperthyroidism caused by one or more of (without restriction) Graves' disease, thyroiditis, Hashimoto's thyroiditis, subacute thyroiditis, postpartum thyroiditis, lumps (nodules) on the thyroid, enlarged thyroid gland (goitre), simple goitre, multinodular goiter, toxic multinodular goiter, toxic adenoma, toxic thyroid adenoma, inflammation of the thyroid, hyperplasia of thyroid, metastatic thyroid cancer, thyroid tumour, thyroid cancer (including, without restriction, papillary carcinoma, follicular carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma), eating too much iodine, goitrogen ingestion, consumption of ground beef contaminated with thyroid tissue ("hamburger hyperthyroidism"), too much synthetic thyroid hormone in the subject, pituitary adenoma, drug induced, Amiodarone drug induced, struma ovarii, Jod-Basedow syndrome, nonautoimmune autosomal dominant hyperthyroidism;
(viii) low or less than desired metabolic/bioenergetic efficiency in a subject, or low or less than desired physical or mental performance (e.g. memory, IQ), or low or less than desired body weight, or fatigue/tiredness/weakness/exhaustion;
(ix) accelerated aging disease or progeroid syndrome including, without restriction, Werner syndrome, Bloom syndrome, De Barsy syndrome, Rothmund¨Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann¨Rautenstrauch syndrome, Hutchinson¨Gilford progeria syndrome (progeria), Ataxia telangiectasia-like disorder 2, XFE progeroid syndrome, Muscular dystrophy, Muscular Dystrophy (Becker's, Duchenne, Limb-Girdle), Yamamoto's Muscular Dystrophy, Mandibuloacral dysplasia, Dilated cardiomyopathy, GAPO syndrome, Cutis laxia, Ehlers-Danlos syndrom, Lenz-Majewski hyperostatic dwarfism, SHORT syndrome, Progressive external opthalmoplegia, Nester-Guillermo progeria syndrome, MDPL syndrome, Dyskeratosis congenital, Down syndrome;
(x) disease or disorder of aging (incidence/severity increases with increased age/senescence) and/or unwanted/undesirable aspect(s) of aging and/or a disease/disorder associated with elevated reactive oxygen species including age-associated decline, aging frailty, frailty syndrome, sarcopenia, muscle weakness, osteoporosis, cognitive decline, cognitive defecit, mild cognitive impairment, degenerative diseases, neurodegenerative diseases, motor-associated neurodegenerative diseases, motor neuron disease, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, progressive supranuclear palsy, pseudobulbar palsy, hereditary spastic paraplegia, Parkinson's disease, Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), essential tremor, resting tremor, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, frontotemporal dementia, chronic traumatic encephalopathy, memory loss, aged cognition, age/aging related cognitive decline/impairment, Batten disease, polyglutamine diseases, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, heart failure with preserved ejection fraction, idiopathic pulmonary fibrosis, fibrotic disease, pulmonary disease, coronary artery disease, hypercholesterolemia, obesity, liver disease, fatty liver disease, lysosomal storage disease, amyloidosis, systemic sclerosis, kidney disease, hepatic cirrhosis, immunosenscence, clonal hematopoiesis, chronic obstructive pulmonary disease (COPD), hypertension, hypercholesterolemia, age-related thymic atrophy, arthritis, osteoarthritis, arthritis (Osteo-and Rheumatoid), Juvenile Rheumatoid Arthritis (JRA), Degenerative Disc Disease, Tendinopathy, Androgenetic Alopecia, male-pattern baldness, Idiopathic Pulmonary Fibrosis, systemic sclerosis, Chronic Obstructive Pulmonary Disease, Psoriasis, age-related loss of cardiac/pulmonary/cognitive/vision function, diabetes, type 2 diabetes, andropause, glaucoma, retinal degeneration, sarcopenia, cachexia, age-related cachexia and/or sarcopenia, age-related macular degeneration (AMD, early/intermediate/late), neovascular/wet AMD, dry AMD, Geographic atrophy (GA), wet and dry AMD in the same eye(s), Stargardt's macular degeneration, Best vitelliform macular dystrophy, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, age/aging-related eye disease, ophthalmological disease/disorder, ocular disease, vision loss, progressive vision impairment, myopia (short-sightedness), degenerative myopia, hyperopia (far-sightedness), accommodative dysfunction, glaucoma, cataract formation, retinal degeneration, progressive retinal degeneration, retinitis pigmentosa, leber hereditary optic neuropathy, Fuchs spot, Best's disease, Sorsby's fundus dystrophy, hearing loss (e.g. age-related), presbycusis, tinnitus, naive T cell shortage, movement disability, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), immunosenescence, respiratory/urinary tract infection (Rh/UT!) especially in older/aged/elderly subjects, cancer;
(xi) aging and/or one or more signs of aging, wherein one or more of these compounds slow/delay/reduce/treat/prevent/stop/reverse aging, and/or extend lifespan and/or healthspan, and/or treat or delay the onset of geriatric aging of the human/animal body, tissue(s), or organ(s), and/or treat or delay the onset of an age-associated phenotype in a cell(s)/organism(s), and/or prolong fertility e.g. female fertility, delay menopause;
(xii) skin aging and/or damage (including sun damage) and/or scalp and/or hair aging and/or hair greying and/or hair loss;
(xiii) insomnia, fatal insomnia, sleep onset latency, delayed sleep phase disorder, exploding head syndrome, parasomnia, sleep-maintenance insomnia, sleep disorder, too much/inappropriate/undesired signals/activity/electrical activity in the nervous system, hyperactivity, hypersensitivity, Premature ejaculation, hyperreflexia, Autonomic dysreflexia (AD), Hyperventilation syndrome, brain hyperactivity, overly sensitive sensory system, pathological crying and/or laughing, Pseudobulbar affect (PBA, emotional lability), photophobia, phonophobia, temperature-sensitive, pressure-sensitive, brain hyperexcitability, overstimulation, intrusive thought(s), Perseveration, sensory overload, disorganized thinking, .. fantasy prone personality, malapdative daydreaming, dissociation, hyperkinetic disorder, agitation, Psychomotor agitation, restlessness, difficulty controlling behaviour, disruptive behaviour disorder, Emotional and behavioral disorder, pervasive developmental disorder, Overactive disorder associated with mental retardation and stereotyped movements, attention-deficit disorder, Attention Deficit Hyperactivity Disorder (ADHD), adult attention-deficit .. hyperactivity disorder, severe behavioral problem(s) in children (e.g., to illustrate and not restrict, combativeness and/or explosive hyperexcitable behavior {out of proportion to immediate provocation[s]}, hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of one or more of: impulsivity, difficulty sustaining attention, aggressivity, mood lability, poor frustration tolerance), Premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), impulsiveness, impulsivity, impulse control disorder, lack of self-control, hysteria, histrionic personality disorder, attention difficulty, inattention, poor attention control, anxiety, paranoid anxiety, Paranoid personality disorder, distress, dysphoria, Adjustment disorder, separation anxiety, anxiety disorder, depressive anxiety, agitated depression, treatment-resistant depression, Generalized anxiety disorder, social anxiety disorder, stranger anxiety, separation anxiety (e.g. in dogs left at home), separation anxiety disorder, Mixed anxiety-depressive disorder, depression (all forms, all severities), restlessness/apprehension/anxiety before surgery.
hypochondria, panic disorder, panic attack, emotional outburst, emotional instability, Intermittent explosive disorder, unreasonable/unwarranted anger/aggression, hyper-aggression, hostility, rage, poor temper control, self-hatred, poor attentional control, worry, irritability, neuroses, somatization disorder, somatic symptom disorder, pain disorder, psychological pain, psychogenic pain, psychogenic facial pain, Atypical odontalgia (AO), burning mouth syndrome, throbbing, toothache/pulpitis/dental pain, chronic lower back pain, negative emotion, persistent/enduring negative emotion, body dysmorphic disorder, factitious disorder, illness anxiety disorder, unwarrented fight-or-flight response, stress, emotional stress, emotional dysregulation, distress, psychological stress, acute stress, chronic stress, acute stress reaction, combat stress reaction, traumatic grief, grief, grief after death of loved one, Prolonged grief disorder (PGD), heartbreak, guilt, shame, remorse, emotional pain, Algopsychalia, psychalgia, suffering, emotional trauma, psychological trauma, broken heart, Post Traumatic Stress Disorder (PTSD), Complex post-traumatic stress disorder (C-PTSD), hypervigilance, sympathetic hyperactivity, inability or impaired ability to relax, flashbacks, dysphoric hyperarousal, agoraphobia, insomnia, fatal insomnia, mood disorder, irrational/unwarrented fear/terror, phobia, social phobia, Cancerophobia, thunderstorm/firework phobia, hypersexuality, hypersexual disorder, depression, clinical depression, unipolar depression, bipolar disorder, Bipolar I, Bipolar II, Bipolar disorder not otherwise specified (Bipolar NOS), cyclothymia, cyclothymic disorder, mixed affective state, atypical depression, melancholic depression, postpartum depression, double depression, seasonal affective disorder, mania, manic episode, hypomania, increase in energy of psychomotor activity, delirium, excited delirium, major depressive disorder, minor depressive disorder, recurrent brief depression, Depressive Disorder Not Otherwise Specified (DD-NOS), major depressive episode, persistent depressive disorder (PDD), dysthymia, dysthymic disorder, absence of euthymia, manic thoughts, racing thoughts, thought disorder, disordered thinking, reduced ability to plan and execute tasks, paranoia, hallucination (including, without limitation, visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrioceptive, nociceptive, thermoceptive, chronoceptive), Charles Bonnet syndrome, delusion, persecutory delusion, hearing voices, homicidal/criminal ideation/tendency/thoughts, suicidal ideation/tendancy/thoughts, self-injury, non-suicidal self-injury, violence, attacking others, negative mood swing, personality disorder, Borderline personality disorder, Narcissistic personality disorder, malignant narcissism, dissociative disorder, dissociative identity disorder (DID), Psychosis, acute psychosis, chronic psychosis, psychosis spectrum disorder, manifestations of psychotic disorders, behavioral complications of mental retardation, stimulant psychosis, psychotic depression, hallucinogen persisting perception disorder, Psychoactive substance-related disorder, amphetamine-induced psychosis, brief psychotic disorder, Brief reactive psychosis, Menstrual psychosis, postpartum psychosis, Psychotic disorder, Psychopathy, chronic hallucinatory psychosis, manifestation(s) of psychotic disorder, neurotic/reactive/endogenous/involutional/psychotic depression/depressive disorder (optionally accompanied by anxiety or agitation), depressive neurosis, delusional depression, psychotic aggression, psychiatric symptoms of dementia, AIDS delirium, Supersensitivity psychosis, Tardive psychosis, Tardive dysmentia, Depersonalization disorder, out-of-body experience, Sociopathy, Schizophrenia, Paranoid schizophrenia, disorganized-type schizophrenia, simple-type schizophrenia, pseudoneurotic schizophrenia, prodromal schizophrenia, schizoaffective disorder, bipolar type schizoaffective disorder, depressive type schizoaffective disorder, schizoaffective psychosis, Schizotypal personality disorder, schizophreniform disorder, Delusional parasitosis, formication, paresthesias, Acroparesthesia, tinnitus, delusional disorder, delusional jealousy, inappropriate behaviour, behavioural disorder, antisocial personality disorder, Oppositional defiant disorder (ODD), conduct disorder (CD), Disruptive mood dysregulation disorder (DMDD), sadistic personality disorder, poor inhibitory control, kleptomania, Pyromania, trichotillomania, dermatillomania, pathological/problem gambling, dyskinesia, tardive dyskinesia, paroxysmal dyskinesia, Paroxysmal kinesigenic dyskinesia, Paroxysmal nonkinesigenic dyskinesia, Paroxysmal exercise-induced dystonia, Hemiballismus, tic disorder, tremor, clonus, Tourette's syndrome, coprolalia, copropraxia, Echophenomena, Echopraxia, Echolalia, Palilalia, stuttering/stammering, stereotypy, punding, Self-stimulatory behaviour (stimming), Stereotypic movement disorder (SMD), synesthesia, obsession, Obsessive¨compulsive disorder (OCD), obsessive¨compulsive personality disorder, anankastic personality disorder, relationship obsessive¨compulsive disorder (ROCD), Scrupulosity, Primarily obsessional obsessive compulsive disorder, sexual obsession, Akathisia (including, without limitation, chronic, acute, Pseudoakathisia, Tardive akathisia, withdrawal or "rebound"
akathisia), Restless legs syndrome, motor restlessness, periodic limb movement disorder (PLMD), periodic limb movements in sleep (PLMS), Sydenham's chorea, chorea, dystonia, Hypnic jerk, twitching, spasms, Tetanus, tetanus muscle spasms, tetanized state, Myoclonus, myoclonic seizure, Action myoclonus, Palatal myoclonus, Middle ear myoclonus, Spinal myoclonus, Stimulus-sensitive myoclonus, Sleep myoclonus, Cortical reflex myoclonus, Essential myoclonus, myoclonic epilepsy, Juvenile myoclonic epilepsy, Progressive myoclonus epilepsy (PME, including, without limitation, Dentatorubral-pallidoluysian atrophy, Unverricht-Lundborg disease, MERRF syndrome, Lafora disease), Reticular reflex myoclonus, Myoclonic epilepsy, diaphragmatic flutter, automatism, status epilepticus, Epilepsia partialis continua, Complex partial status epilepticus, epilepsy, epileptic seizure, simple partial seizure, complex partial seizure, generalized epilepsy, generalized seizure (including, without limitation, tonic-clonic, tonic, clonic, myoclonic, absence (including typical absence and atypical absence), atonic seizure), focal epilepsy, focal seizure, focal/partial seizure (including, without limitation, Simple partial seizure and Complex partial seizure), focal aware seizure, focal impaired awareness seizure, generalised epilepsy, temporal lobe epilepsy (including, without restriction, mesial temporal lobe epilepsy {MTLE} and lateral temporal lobe epilepsy {LTLE}), Frontal lobe epilepsy, Rolandic epilepsy, Nocturnal epilepsy, Nocturnal frontal lobe epilepsy, Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Generalized epilepsy with febrile seizures plus (GEFS+), Panayiotopoulos syndrome, epileptic fit, reflex epilepsy, reflex seizure, absence seizure (including, without limitation, childhood absence epilepsy, epilepsy with myoclonic absences, juvenile absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome {eyelid myoclonia with absences}, genetic generalised epilepsy with phantom absences), complex partial seizure, atonic seizure, generalized tonic-clonic seizure, tonic¨clonic seizure, extrinsic stimulus epilepsy, intrinsic stimulus epilepsy, photosensitive epilepsy, musicogenic epilepsy, thinking epilepsy, eating epilepsy, seizure(s), Febrile seizure, nerve agent induced seizure, Dravet syndrome (sometimes modest hyperthermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals), acute symptomatic seizure, seizure-related .. disorder, drug related seizure, paroxysmal depolarizing shift, Ohtahara syndrome, Epilepsy in females with mental retardation, Rasmussen's encephalitis, Epilepsy syndrome, benign rolandic epilepsy, childhood absence epilepsy, absence epilepsy, juvenile myoclonic epilepsy, epileptic encephalopathies, Lennox¨Gastaut syndrome, West syndrome (Epileptic spasms), Doose syndrome (Myoclonic astatic epilepsy, MAE), Lennox-Gestaut syndrome, pseudo-Lennox Gastaut syndrome (atypical benign partial epilepsy), Benign familial neonatal epilepsy, Benign occipital epilepsy of childhood, familial neonatal convulsions, Febrile infection-related epilepsy syndrome, interictal dysphoric disorder, euphoria sclerotic, psychogenic non-epileptic seizure, non-epileptic seizure, gelastic seizure, convulsion(s), migraine, status migrainosus, tension headache, headache, Hypnic headache, hiccups, intractable hiccups, thumps in equines, Postural orthostatic tachycardia syndrome (POTS), Pheochromocytoma, agony, pain, chronic pain, acute pain, pain due to disease/injury, neuropathic pain, fibromyalgia, postherpetic neuralgia, phantom pain, referred pain, back pain, lower back pain, pelvic pain, cancer associated pain, chemotherapy associated pain, Diabetic neuropathy, small fiber peripheral neuropathy, Mononeuritis multiplex, Wartenberg's migratory sensory neuropathy, Breakthrough pain, idiopathic pain, polyneuropathy, Neuritis, Mononeuropathy, Polyradiculoneuropathy, Radial neuropathy, neuropathy, visceral pain, Burning feet syndrome, Tarsal tunnel syndrome, Carpal tunnel syndrome, Guyon's canal syndrome, Cubital Tunnel Syndrome, Repetitive strain injury, Sciatica, Neurofibromatosis, Ulnar nerve entrapment, Erythromelalgia, Paroxysmal extreme pain disorder, Proctalgia fugax, dysesthesia, scalp dysesthesia, dysesthetic burning, hyperesthesia, hyperalgesia, Opioid-induced hyperalgesia, hyperpathia, allodynia, pain response from stimuli which do not normally provoke pain, Complex regional pain syndrome (said to be most painful condition known to man), Radiculopathy, neuralgia (including, without restriction, intercostal neuralgia, trigeminal neuralgia, atypical trigeminal neuralgia, glossopharyngeal neuralgia, occipital neuralgia, postherpetic neuralgia), ciguatera poisoning, irritable bowel syndrome (IBS), interstitial cystitis (IC), temporomandibular joint disorder, acute intermittent porphyria, Porphyria, Acute porphyria (including, without limitation, acute intermittent porphyria {AIP}, variegate porphyria {VP}, aminolevulinic acid dehydratase deficiency porphyria {ALAD}, hereditary coproporphyria {HCP}, drug induced), Chronic porphyria (including, without limitation, X-linked dominant protoporphyria {XLDPP}, congenital erythropoietic porphyria {CEP}, porphyria cutanea tarda {PCT}, and erythropoietic protoporphyria {EPP}), cutaneous porphyria, Porphyria cutanea tarda, allergy, allergic reaction, anaphylaxis, anaphylactic shock, hives, asthma, allergic rhinitis, rhinitis, urticaria, contact dermatitis, cough, sore throat, esophageal reflux disease, heartburn, chest pain, Esophageal motility disorder, Nutcracker esophagus, diseases involving gastrointestinal motility, Peptic ulcer disease, esophageal spasm, angina, itchiness, Pruritus, severe pruritus, Prurigo, Pruritic skin condition, chronic itch, eczema, pruritus in eczema, neuropathic itch, neurogenic itch, itchiness due to atopic dermatitis and/or lichen simplex chronicus, peripheral sensitization, central sensitization, sensory perception of absent stimuli, too much sensory stimulation, sensory stimulation brings discomfort, Neuromyotonia, Peripheral nerve hyperexcitability, Morvan's syndrome, Benign fasciculation syndrome, Cramp fasciculation syndrome, hyperhidrosis, undifferentiated somatoform disorder, somatoform disorder, somatic symptom disorder, conversion disorder, functional neurological symptom disorder, severe nausea and/or vomiting, severe nausea/emesis, Chemotherapy-induced peripheral neuropathy, chemotherapy-induced nausea and vomiting (CINV), radiation therapy-induced nausea and vomiting (RINV), postnarcotic nausea, hyperemesis gravidarum, morning sickness, Cyclic vomiting syndrome, retching/dry heaving, Urinary incontinence, enuresis, nocturnal enuresis, tail chasing, reduce urine spraying/marking behavior, benzodiazepine withdrawal syndrome, barbituate withdrawal syndrome, Neuroleptic discontinuation syndrome, drug withdrawal discomfort/pain/symptoms, drug use disorder, alcohol use disorder, opoid use disorder, amphetamine use disorder, cocaine use disorder, alcohol withdrawal syndrome/symptoms, delirium tremens, opoid withdrawal sydrome/symptoms, drug craving, drug addiction, drug dependence, polysubstance dependence, drug overdose, smoking, tobacco (nicotine) addition, tobacco (nicotine) withdrawal symptoms, alcoholism, addiction, opoid addiction, cocaine/crack addiction, addictive behaviour, addictive personality, behavioural addiction, intemet/computer/computer game/social media/media addiction, exercise addiction, compulsive behaviour (e.g. {non-limiting}
checking, counting, washing, repeating), anti-social behaviour, criminality, sexual compulsion, impulsive sexual behaviour, compulsive buying, gambling addiction, sex related addiction, sexual urge, hunger, eating desire/compulsion, eating disorder, polyphagia, overeating, binge eating disorder, compulsive overeating, insatiable/excessive appetite, bulimia nervosa, anorexia nervosa, substance abuse, substance-induced delirium, substance-induced psychosis, substance-induced mood disorder, drug overdose, vertigo, motion sickness, seasickness, mental/nervous breakdown, Autism spectrum disorder, neurological disorder, cognitive disorder, mental disorder, mental health disorder, mental health condition involving impaired or altered neural plasticity, mood disorder, mental disorder disclosed in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or a later edition, a mental/behavioural disorder disclosed by the International Classification of Diseases (ICD) in ICD-10 Chapter V: Mental and behavioural disorders (World Health Organisation, WHO); or (xiv) diseases or disorders or conditions or pathologies or unwanted/undesirable effects/actions/behaviour treatable/ameliorated/prevented/combated, in totality or in part (e.g.
along with surgery), by anaesthesia, pre-anaesthesia, post-anaesthesia, hypoesthesia, hypoactivity, sedation, coma, tranquilization, behavioural submission, muscle relaxation, hibernation, artificial hibernation, torpor, synthetic torpor, suspended animation (e.g. used during spaceflight because e.g. reduces ionizing radiation damage to subject);
(xv) hyperproliferative/hyperplasia disorder, non-cancerous proliferative disorder, hyperproliferative autoimmune disorder, hyperplasia, epidermal hyperplasia, dysplasia (e.g.

epithelial dysplasia), nodule(s), wart(s), papilloma(s), squamous cell papilloma, genital wart(s), condyloma(s), condyloma acuminatum, cyst(s), polyp(s) {including, without restriction, digestive, colorectal, endometrial, cervical, nasal, laryngeal, inflammatory fibroid polyp[s])}, inherited/hereditary (including, without restriction, Familial adenomatous polyposis, Peutz¨Jeghers syndrome, Turcot syndrome, Juvenile polyposis syndrome, Cowden disease, Bannayan¨Riley¨Ruvalcaba syndrome {Bannayan-Zonana syndrome}, Gardner's syndrome) and non-inherited (non-restrictive e.g. Cronkhite¨Canada syndrome) polyposis syndrome, benign tumour, adenoma, organ enlargement by hyperplasia, Cushing's disease (enlarged adrenal cortex by hyperplasia), congenital adrenal hyperplasia, hyperplasia of breast, atypical ductal hyperplasia, intraductal papillomatosis, fibroadenomas, fibrocystic changes, hemihyperplasia, focal epithelial hyperplasia, sebaceous hyperplasia, sebaceous adenoma, intimal hyperplasia, unwanted/undesirable smooth muscle cell proliferation, smooth muscle cell hyperplasia, intimal smooth muscle cell hyperplasia, neointimal hyperplasia, proliferative vascular disorders, stenosis, stenosis because of cellular proliferation, vaginal stenosis, stenosis in a blood vessel, lessoned patency of a blood vessel, stenosis in a blood vessel because of cellular proliferation, vascular occlusion, restenosis, restenosis in a blood vessel that has been implanted with a stent, in-stent restenosis, post-angioplasty restenosis, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g.
diabetic retinopathy and/or other retinopathy[y/ies]), cardiac hyperplasia, fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, fibromatosis, neurofibromatosis, renal interstitial fibrosis, Cowden syndrome, hamartoma(s), choristoma(s), hemangioma(s), lymphangioma(s), rhabdomyoma(s), lymphangiomatosis, cystic hygroma, trichilemmoma, sarcoidosis, neurosarcoidosis, aggressive fibromatosis, desmoid tumour(s), unwanted/undesirable skin cell proliferation, hyperproliferative skin disorder, psoriasis (including, without restriction, plaque, guttate, inverse, pustular, napkin, seborrheic-like, nail, scalp and erythrodermic psoriasis), psoriatic arthritis, dactylitis, seborrhoeic dermatitis, dandruff, eczema, atopic dermatitis, rosacea, reactive arthritis (Reiter's syndrome), pityriasis rubra pilaris, hyperproliferative variants of disorders of keratinization (e.g., without restriction, actinic keratosis, senile keratosis, keratosis pilaris, seborrheic keratosis), scleroderma, benign prostatic hyperplasia, prostate enlargement, endometrial hyperplasia, atypical endometrial hyperplasia, benign endometrial hyperplasia, adenomyosis, atypical polypoid adenomyoma, endometriosis, endometriosis of ovary (endometrioma), endometrial polyp(s), polycystic ovary syndrome, ovarian cyst(s), cervical polyp(s), uterine fibroid(s), uterine hyperplasia;

(xvi) Tumour Associated Macrophages (TAMs) or any macrophage associated disease or disorder such as, without limitation, Macrophage Activation Syndrome (MAS), HIV, AIDS, HIV-associated neurocognitive disorders (HAND), AIDS dementia, HIV
peripheral neuropathy, HIV associated cancers, AIDS-defining cancers, non-AIDS
defining cancers, any disease in which the pathogen(s) hides from the immune system in macrophages including, without limitation, Mycobacterium tuberculosis (causes tuberculosis), Leishmania parasite (causes Leishmaniasis), Chikungunya virus (causes Chikungunya), Legionella pneumophila (causes Legionnaires' disease), adenoviruses, T. whipplei (causes Whipple's Disease), Brucella spp. (causes brucellosis), Staphylococcus aureus, Ebola virus, Hepatitis B
virus, Hepatitis C virus, influenza virus strains, dengue virus and antibiotic resistant bacteria, any disease or condition in which activated macrophages are unwanted or undesirable;
(xvii) virus/pathogen neuroinvasion via macrophage(s), as used for non-limiting example by HIV, Heptatitis C virus and SARS coronavirus;
(xviii) neurocognitive or neurodegenerative diseases/disorders, for non-limiting example those caused by a virus;
(xix) virus/pathogen transmission from mother to fetus/baby via macrophage(s) as used for non-limiting example by zika (via Hofbauer cells) and HIV
(macrophages in breast milk);
(xx) acute or chronic or systemic inflammation or any inflammatory disease/disorder/syndrome or any autoinflammatory disease/disorder/syndrome or any autoimmune disease/disorder/syndrome;
(xxi) acute inflammation, chronic inflammation, systemic inflammation, inflammation because of infection or foreign bodies or injury or chemical or toxin or drug or stress or frostbite or burn or ionising radiation or surgery, inflammatory diseases/disorders/syndromes, Macrophage Activation Syndrome (MAS), autoinflammatory diseases/disorders/syndromes, age-related chronic inflammatory diseases ("inflammaging"), autoimmune diseases/disorders/syndromes, diseases/disorders of the innate immune system, sore throat, sore throat associated with cold or flu or fever, high-intensity exercise associated inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, osteoarthritis, inflammatory osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation associated depression, neuroinflammation, neuropathic pain, exercise-induced acute inflammation, atherosclerosis, allergy, hay fever, anaphylaxis, inflammatory myopathies, drug-induced inflammation, systemic inflammatory response syndrome, sepsis-related multiple organ dysfunction/multiple organ failure, microbial infection, acute brain/lung/hepatic/renal injuries, lung inflammation, acute lung injury (ARDS), acne vulgaris, celiac disease, celiac sprue, chronic prostatitis, colitis, autoimmune hemolytic anemia, diverticulitis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Mast Cell Activation Syndrome, mastocytosis, otitis, pelvic inflammatory disease (PID), endometritis, reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasitosis, eosinophilia, type III hypersensitivity, ischaemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, alcoholic hepatitis, chronic viral hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematous (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative disease, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, bronchiectasis, bronchopneumonia, obliterative bronchiolitis, appendicitis, acute appendicitis, bursitis, cystitis, dermatitis, encephalitis, HIV encephalitis, gingivitis, meningitis, infective meningitis, myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis¨associated interstitial lung disease and desquamative interstitial pneumonia, pneumonia, interstitial lung disease, Liifgren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, steatohepatitis, nonalcoholic steatohepatitis, silicosis, histiocytoses, Langerhans' cell histiocytosis, haemophagocytic lymphohistiocytosis, pulmonary langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudogout, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft versus host disease (GVHD), lymphadenopathy, rheumatoid arthritis (RA), osteoarthritis (OA), inflammatory osteoarthritis, lupus, multiple sclerosis (MS), myocarditis, uveitis, CNS disease(s), inflammation aspect to a CNS disease(s), hypothalamic inflammation, dementia, glaucoma, amyloid related/driven disease, lipid storage disease(s), fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, cirrhosis of the liver, alcoholic cirrhosis, nephropath(y/ies), lupus nephritis, immune nephritis, fibrotic disorder(s), cardiovascular disease, heart disease, atherosclerosis, vulnerable plaque, plaque formation, lipid containing macrophage related disease(s)/disorder(s)/malad(y/ies), macrophage foam cells, diabetes, type 1 diabetes, type 2 diabetes, insulin resistance, macrophage aspect to insulin resistance, obesity, obesity associated inflammation, macrophage accumulation/large numbers of macrophages in adipose tissue (e.g. associated with obesity), granuloma(s), granulomatous diseases, sarcoidosis (including, without limitation, Annular sarcoidosis, Erythrodermic sarcoidosis, Ichthyosiform sarcoidosis, Hypopigmented sarcoidosis, Lofgren syndrome, Lupus pernio, Morpheaform sarcoidosis, Mucosal sarcoidosis, Neurosarcoidosis, Papular sarcoid, Scar sarcoid, Subcutaneous sarcoidosis, Systemic sarcoidosis, Ulcerative sarcoidos), neurosarcoidosis, pulmonary sarcoidosis, interstitial lung disease, pulmonary fibrosis, pulmonary tuberculosis, immune reconstitution syndrome of HIV, Jarisch¨Herxheimer reaction, sepsis, Paget's disease of bone, osteolysis, monocytosis, histiocytosis, X-type histiocytoses, non-X histiocytoses, Langerhans cell histiocytosis, non-Langerhans-cell histiocytosis, malignant histiocytosis, malignant histiocytic disorders, histiocytomas, histiocytic lymphoma, hemophagocytic syndrome, hemophagocytic lymphohistiocytosis, lymphohistiocytosis, diffuse histiocytic sarcoma, Rosai¨Dorfman disease, gliosis, Bergmann gliosis, Chronic Obstructive Pulmonary Disease (COPD), chronic inflammatory lung disease, familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulinemia D with recurrent fever syndrome (HIDS), cryopyrin associated periodic syndrome (CAPS), Blau syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), mevalonate kinase deficiency, pyogenic-arthritis-pyoderma gangrenosum and acne syndrome (PAPA), periodic fever aphthous stomatitis pharyngitis adenitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, Schnitzler's syndrome, Sweet's syndrome, NLRP12-associated autoinflammatory disorders, deficiency of interleukin-1 receptor antagonist (DIRA), pyoderma gangrenosum, cystic acne, aseptic arthritis, periodic Fever Associated with mevalonate kinase deficiency (hyperimmunoglobulin D Syndrome), Pyogenic Arthritis Pyoderma Gangrenosum Acne (PAPA) syndrome, Periodic Fever Aphthous Stomatitis, Pharyngitis and Adenopathy (PFAPA) syndrome, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Chronic Recurrent Multifocal Osteomyelitis (CRMO), Synovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome, Cryopyrin associated Periodic Syndrome (CAPS), Familial cold auto inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Familial cold urticarial, Neonatal onset multisystemic inflammatory disorder (NOMID), hereditary Periodic Fever Syndromes, Periodic Fever Syndromes, systemic autoinflammatory diseases, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Balo disease, Behcet's disease, benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid, .. Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Berger's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immune hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, =
Optic neuritis, Palindromic rheumatism (PR) PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Tumer syndrome, Pemphigus, peripheral neuropathy, perivenous encephalomyelitis, Pernicious anemia (PA), POEMS
syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type I diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)), idiopathic thrombocytopenia purpura, splenomegaly;
(xxii) Systemic inflammatory response syndrome, cytokine release syndrome, cytokine storm, immune reaction to a drug(s) or therapy(s), immune reaction to an immune activating drug(s) or agent(s) or treatment(s) or intervention(s), immune reaction to immunotherapy and/or immune-oncology and/or immunomodulatory drug(s) and/or treatment(s), adverse reaction to adoptive 1-cell therapy(s), adverse reaction to a chimeric antigen receptor T-cell therapy(s) (CAR-T cell therapy(s)), adverse reaction to a immune checkpoint inhibitor(s), adverse reaction to monoclonal antibody drug(s), tumor lysis syndrome; or (xxiii) cancer and Graft Versus Host Disease (GVHD) in transplantation therapy in a cancer patient;
wherein the method comprises administering to the subject an effective amount of at least one compound, or a composition containing at least one compound, of the following formula:

\N"
N/INN
L

(4 (R4) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
L is selected from alkyl, substituted alkyl, deuterated alkyl, aminoalkyl, thioalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2 etc.);
RI is hydrogen, cyano, ¨SO2R8, ¨C(=0)R9, heteroaryl or thiazolyl;
R2 is (i) independently hydrogen, alkyl, benzyl, or substituted alkyl, or (ii) taken together with R3 forms a heterocyclo;

R3 is (i) independently alkyl, substituted alkyl, alkylthio, aminoalkyl, carbamyl, BB-aryl, BB-heterocyclo, BB-heteroaryl, or BB-cycloalkyl, or (ii) phenyl optionally substituted with Ci_4alkyl, halogen, trifluoromethyl, OCF3, cyano, nitro, amino, hydroxy, or methoxy, or (iii) independently selected from C1_4alkyl, alkylthio, aminoalkyl, -BB-aryl, -BB-heterocyclo, BB-cycloalkyl, and -BB-hetaroaryl, optionally having one to three substituents selected from R3a; and/or having fused thereto a five or six membered carbocyclic ring, or (iv) taken together with R2 forms a heterocyclo optionally substituted with alkyl or substituted alkyl;
BB is a bond, Ci_aalkylene, C2_4alkenylene, substituted Ci_aalkylene, substituted C2-4alkenylene, substituted C1_4alkylene-C(=9)NH-, -C(=3)NH-, -C1,4alkylene-C(=0)NH-, -C(=0)NR19-, -C1_4alkylene-C(=3)NR19-, or substituted C1_4alkylene-C(=0)NR19-, -(CHR14)6,-(CRI5R16)6- or -(CHRI4)p-C(=0)NH-;
R3a at each occurrence is selected independently from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, keto, trifluoromethyl, -NRI7Ri 8, -S1217, -0R17, -SO2R17a, -SO2NR17R18, -NR17C(=0)R18, -0O2R17, --C(=0)R17, cyoloalkyl, aryl, heterocyolo, and heteroaryl, wherein when R3a is cycloalkyl, aryl, heterocyclo or heteroaryl, said cycloalkyl, aryl, heterocyolo and heteroaryl in turn is optionally substituted with alkyl or substituted alkyl;
Z is a heteroaryl, for example an optionally-substituted bicyclic heteroaryl;
or Z is triazolyl optionally substituted with one to two R7 substituents or imidazolyl optionally substituted with one to two R7 substituents and/or having fused thereto a benzene ring in turn optionally substituted with one to two R7 substituents; and R7 is alkyl, carbamyl, or substituted alkyl;
R4 at each occurrence is selected independently of each other R4 from the group consisting of halogen, trifluoromethyl, OCF3, alkyl, substituted alkyl, haloalkyl, nitro, cyano, haloalkoxy, OR25, SR25, NR25R26, NR25S02R27, S02R27, S02NR25R26, CO2R26, C(=0)R26, C(=0)NR25R26, OC(=0)R25, -0C(=0)NR25R26, NR25C()R26, NR25CO2R26, aryl, heteroaryl, heterocyclo and cycloalkyl;
R8 is Ci_aalkyl or phenyl optionally substituted with alkyl, halogen, haloalkoxy, cyano, nitro, or trifluoromethyl;
R9 is -NRioRii, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclo, or -0O2R12, alkyl or phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, Ci_aalkoxy, haloalkoxy, Ci_6alkyl, CO2alkyl, SO2alkyl, SO2NH2, amino, NH(Ci_aalkyl), N(Ci_4alky1)2, NHC(=0)alky, C(=0)alkyl, and/or Ci_aalkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl; and/or a five or six membered heteroaryl or heterocylo in turn optionally substituted with keto or having a benzene ring fused thereto or a) Ci_aalkyl optionally substituted with one to two of:
i) SIZ13, 0R13, NRi3aRi3b, halogen, trifluoromethyl, CO2Ri3a, and C(=34)NR13aRi3b;
ii) cycloalkyl optionally substituted with one to two of C(=C0)H, Ci4acyl, alkenyl, carbamyl, and/or phenyl in turn optionally substituted with halogen;
iii) phenyl or napthyl optionally substituted with one to two of halogen, nitro, amino, alkyl, hydroxy, Ci_aalkoxy, or having fused thereto a five or six membered heterocyclo;
iv) pyridinyl, thiophenyl, furanyl, tetrahydrofuranyl, or azepinyl, optionally substituted with alkyl or having fused thereto a five to six membered carbocyclic ring optionally substituted with keto or Ci_4alkoxy;
b) 3 to 6 membered cycloalkyl optionally having up to four substituetits selected from alkyl, halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, phenyl in turn optionally substituted with halogen; or having an aryl fused thereto;
c) pheyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, Ci-aalkoxy, haloalkoxy, CI-4alkyl, CO2alkyl, SO2alkyl, SO2NH2, amino NH(Ci-4alkyl), N(Ci_4alky1)2, NHC(=3)alkyl, C(=0)alkyl, and/or Ci_aalkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl;
and/or a five or six membejed heteroaryl or heterocyle in turn optionally substituted with keto or having a benzene ring fused thereto;
d) pyridinyl, thiazolyl, furanyl, thiophenyl, and pyrrolyl optionally substituted with one to two of halogen, alkyl, and phenyl in turn optionally substituted with halogen or trifluoromethyl;
Rio and R11 are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, heteroaryl or Ci_aalkyl optionally substituted with one to two of¨0O2alkyl, ¨C(=3)NH(ary1), NH(ary1), cycloalkyl, phenyloxy, phenyl in turn optionally substituted with Ci_4alkyl, hydroxy, Ci_aalkoxy, halogen, amino, nitro, tetrahydrofuranyl, and/or five or six membered heterocyclo, or having a five or six membered heterocyclo fused thereto; pyrrolidinyl optionally substituted with keto;
napthyl, anthracenyl, pyridinyl, thiophenyl, furanyl, imidazolyl, benzimidazolyl, or indolyl in turn optionally substituted with Ci_aalkyl or Ci_aalkoxy; or (ii) taken together form a heteroaryl or heterocyclo selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, tetrahydropyridinyl, and imidazoilidinyl, wherein said heterocyclo formed by Rio and R11 is optionally substituted with one to two of keto, CO2H, Ciaalkoxy, CO2alkyl, Ci_acarbamyl, benzyl; phenyl in turn optionally substituted with alkyl, halogen, or C14 alkoxy; tetrahydropyridinyl in turn optionally substituted with keto and/or phenyl; alkyl optionally substituted with amino or NHR21 wherein R21 is alkyl or phenyl optionally substituted with alkyl; and/or has a benzene ring fused thereto in turn optionally substituted with one to two of alkyl, Ci_4alkoxy, CO2alkyl, and/or C1.4carbamyl;
R12and R19 are hydrogen or alkyl;
R13 is hydrogen or alkyl;
R13a and R13b are selected from hydrogen, alkyl, and aryl;
R14, R15 and R16 at each occurrence are independently selected from hydrogen, alkyl, hydroxy, hydroxyCi_aalkyl, Ci_aalkoxy, and phenyl, and/or one of R15 and one of Ri6join together to form a 3 to 6 membered cycloalkyl;
Ri7and Risare independently selected from hydrogen, alkyl, substituted alkyl, aryl, phenyl, or benzyl wherein the phenyl or benzyl is optionally substituted with alkyl, hydroxy, or hydroxyalkyl;
Ri7a is alkyl or substituted alkyl;
R25 and R26 are independently selected from hydrogen, alkyl, or substituted alkyl, or taken together form a heterocyclo or heteroaryl ring;
R27 is alkyl or substituted alkyl;
q is 0, 1, 2, or 3;
m and n are 0, 1 or 2; and p is 0, 1, 2, or 3.
[18] A method according to Claim 17, wherein L is hydrogen.
[19] A method according to Claim 17, wherein the S-enantiomer is in enantiomeric excess.
[20] A method according to Claim 19, wherein the enantiomeric excess of S-enantiomer exceeds 70%.
[21] A method according to Claim 17, using the structure ...../ N
N/'''....
.¨..--N

CI s µµµ11 A
S N NH
H
CI

Cl or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
the enantiomeric excess (ee) of the S stereoisomer exceeds 70%.
[22] A method of treating, ameliorating, preventing, reversing or combating a disease or disorder, or unwanted/undesirable physiological process or its consequences or an unwanted/undesirable aesthetic, in a subject, selected from (i) cancer, any cancer, neoplasia, metastasis, tumor formation/growth/implantation, tumorigenesis, solid tumor, blood borne tumor, cancer that is refractory or resistant to conventional chemotherapy, drug resistant tumor, multidrug resistant cancer;
(ii) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. '8F-FDG PET);
(iii) cachexia or cancer driven cachexia;
wherein the method comprises administering to the subject an effective amount of at least one compound, or a composition containing at least one compound, of the following formula:

RB
I
...,õ-N-..,...
N/
NN
).., ....õ,..
RAi .., N NL.. NH
H I

or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
RAI and RA2 are each independently selected from the groups RD le' ___________ __________________________________________________ and wherein Rc and RD are each independently selected from hydrogen, deuterium, halogen and alkyl, and wherein RE is hydrogen, deuterium, or alkyl;
RB is selected from RBI, hydrogen and deuterium;
wherein RBI is selected from phenyl, benzyl, pyridyl, pyrimidyl and pyrazinyl optionally substituted with one or more substituents RB2;
wherein each RB2 is independently selected from halogen, alkyl, alkoxy, nitro, amino, methoxy and polyhalogen alkyl;
or RB is a phenylalkyl of the formula:
11 G (RG)q (RF)q ----(C )n 1 wherein RF and RG are hydrogen or alkyl, G is a carbon-carbon double bond or a carbon-carbon single bond, n is 0 or 1 and q is 0 or 1 provided that where q is 0, G
is a carbon-carbon double bond and where q is 1, G is a carbon-carbon single bond, or RB is a diphenylalkyl of the formula RH
RH
wherein RH is hydrogen or halogen, and p is 0, 1 or 2;
or RB is the group Rj RK
wherein R and RK each independently represent 1-5 optional substituents on each ring, and wherein each fe and each RK, when present, is independently selected from halogen, alkyl, alkoxy, nitro, amino and polyhalogen alkyl.
1231 A method according to Claim 22, wherein RB is the group:

11) RK
[24] A compound or composition for use according to Claim 22, wherein RB is the group:
RL, RM
wherein RL and Rm are each independently selected from halogen, alkyl, alkoxy, nitro, amino and polyhalogen alkyl.
[25] A method according to Claim 24, wherein RL and Rm are each independently selected from halogen.
[26] A method according to Claim 24, wherein RL and Rm are the same.
[27] A method according to Claim 24, wherein RL and Rm are each F.

[28] A method according to Claim 22, wherein RAI and RA2 are each independently selected from the group .r\ ______________________________________ R C
RD
wherein Rc and RD are each independently selected from hydrogen, deuterium, halogen and alkyl.
[29] A method according to Claim 28, wherein RAI and RA2 are the same.
[30] A method according to Claim 28, wherein Rc is hydrogen.
[31] A method according to Claim 28, wherein RD is hydrogen.
[32] A method according to Claim 22, wherein the compound is:
FUF
N N
I I

or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
[33] A method according to Claim 22, wherein the compound is an isotopologue(s) of:

N
N N

or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
[34] A method of treating, ameliorating, preventing, reversing or combating a disease or disorder, or unwanted/undesirable physiological process or its consequences or an unwanted/undesirable aesthetic, in a subject, selected from (i) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. 18F-FDG PET);
(ii) cachexia, cancer driven cachexia, cancer fatigue, weight loss, weight loss for known or unknown reason, chronic wasting disease, atrophy, brown atrophy, frailty, frailty syndrome, aging frailty, geriatric syndrome, age-related cachexia and/or sarcopenia, weakness, wasting, anorexia nervosa, bulimia nervosa, eating disorder, amenorrhea, underweight, low body mass index (BMI, e.g. <18.5), low body fat percentage, body composition change, wasting syndrome, HIV wasting syndrome, malnutrition, clinical malnutrition, starvation, kwashiorkor syndrome, marasmus syndrome, malabsorption, malabsorption due to parasitic/bacterial infection (e.g. helminthiasis, Whipple's disease, small intestine bacterial overgrowth (SIB0), giardiasis etc.), anemia, refeeding syndrome, appetite loss, catabolysis, muscle atrophy, asthenia, muscle weakness (myasthenia), sarcopenia, osteoporosis, cachexia associated with HIV, AIDS, multiple sclerosis, rheumatoid arthritis, familial amyloid polyneuropathy, chronic kidney disease, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia, Addison's disease, mercury poisoning (acrodynia), chronic pancreatitis, untreated/severe type 1 diabetes mellitus, hormonal deficiency, tuberculosis, gastroenteritis, diarrhea, dysentery, any digestive disease or disorder, any gastrointestinal disease or disorder including functional gastrointestinal disorders, coeliac disease, tropical sprue, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, short bowl syndrome, congestive heart failure, constrictive pericarditis, bradycardia, chronic obstructive pulmonary disease (COPD), altitude sickness, hyperthyroidism (subclinical hyperthyroidism, Graves' disease, multinodular goiter, toxic adenoma, inflammation of the thyroid {thyroiditis}, pituitary adenoma), fatigue, chronic fatigue syndrome or any disease or disorder or pathology in which a body tissue(s) is undersupplied or underutilises (vs. its need) an energetic/chemical substrate(s), including 02;
(iii) cancer associated fever, which is especially associated with, but not limited to, non Hodgkin lymphoma (NHL), Hodgkin lymphoma, acute leukaemia, kidney cancer (renal cell cancer), liver cancer (hepatocellular carcinoma), bone cancer, adrenal gland tumours such as phaeochromocytomas, tumours in the hypothalamus, solid tumours;
(iv) disease or disorder or physiological process or condition that causes a higher than normal body temperature such as (without limitation) high environmental temperature, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, neutropenic sepsis, stroke, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, toxic serotonin syndrome, thyroid storm, heatstroke, surgery related, menopause ("hot flushes"), infection (non-limiting e.g. roseola, measles, enteroviral infections, parasitic, viral, fungal, Chlamydial, Rickettsia', bacterial, mycobacterial, systemic bacterial, intravascular, HIV associated, nosocomial), pyrogenic infection, thermoregulatory disorder(s), connective tissue disease(s), Kawasaki syndrome, drug overdose, drug or drug withdrawal induced hyperthermia, alcohol/drug withdrawal, idiosyncratic drug reaction, fever of known or unknown or uncertain origin (non-limiting e.g. infectious disease(s), inflammation, immunological disease(s), non-infectious inflammatory disease(s) {non-limiting eg. systemic rheumatic and autoimmune diseases, vasculitis, granulomatous diseases, autoinflammatory syndromes}, tissue destruction, reaction to incompatible blood product(s), metabolic disorder(s), inherited metabolic disorder(s), cancer, neoplasm, endogenous or exogenous pyrogen(s), injury, head injury);
(v) disease/disorder/injury/pathology/surgery treatable/ameliorated/prevented/combated/helped by conferring hypothermia in a subject for some medical or other purpose which can include slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, slowing physiological/pathological processes (reaction rates are temperature dependent) and so "buying time" to get the subject to treatment for their emergency (e.g.
trauma/septic shock or other medical emergency), slowing the progress of sepsis until a sufficient concentration of a working antibiotic(s) can be built up in the subject (furthermore hypothermia, by slowing sepsis progression, buys time to observe which antibiotic(s) can work, yielding time to try alternative further antibiotic option(s) if required), used soon after or just before clinical/legal death to preserve the subject's organs/tissues until the subject can be frozen/cryogenically frozen or the pathology that caused clinical/legal death (e.g. wound) can be fixed and the subject resuscitated, administered to a subject when a first responder (e.g.
ambulance crew) deems the subject dead or unlikely to survive the journey to a medical facility (e.g. hospital) wherein this administration helps to preserve the subject which is helpful if hospital staff subsequently assess that they can, or might be able to, save the subject, stabilizing surgical/trauma/Emergency Room (ER) patients, deep hypothermic circulatory arrest for surgery (DHCA, non-limiting applications of DHCA include repairs of the aortic arch, repairs to head and neck great vessels, repair of large cerebral aneurysms, repair of cerebral arteriovenous malformations, pulmonary thromboendarterectomy, resection of tumors that have invaded the vena cava, brain tumor resection {wherein the anti-cancer activity of a compound(s) of this invention juxtaposes well}), Emergency Preservation and Resuscitation (EPR), hypothermia for a surgical purpose, protective hypothermia during surgery and/or surgery complication, hypothermia to slow/reduce blood loss, hypothermia for neuro- and/or cardio- and/or organ/tissue and/or life protection in a subject that has trauma/brain trauma/polytrauma/surgery/stroke/ischemic stroke/hemorrhagic stroke/cardiac arrest/myocardial infarction/hypoxia/shock (including, without limitation, low volume, cardiogenic, obstructive, and distributive shock)/sepsis/septic shock/multiple organ dysfunction syndrome/systemic inflammatory response syndrome (SIRS)/organ failure/cytokine storm/anaphylactic shock/seizure/disseminated intravascular .. coagulation/blocked airway/croup/rhabdomyolysis/[head/facial/spinal/chest/abdominal/ballistic/knife injury/trauma], or some other medical emergency/condition/disorder/disease/injury/operation, hypothermia for cardiac and/or cardiovascular surgery and/or open heart surgery and/or brain surgery (neurosurgery) and/or surgery using total circulatory arrest and/or surgery using cardiopulmonary bypass, Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage/transport and/or transplant, thus increasing the time window for transplantation of organs to recipients;
compound(s) of this invention is administered to organ to be transplanted [by administration to donor and/or by administration to isolated organ] and/or to organ recipient, optionally during transplant operation), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, neonatal hypoxia-ischemia, birth asphyxia, hypoxic-ischemic encephalopathy (HIE), haemorrhage, hypovolemia, exsanguination, suspended animation, decompression sickness, burn injury(s) including skin burn, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or tourniquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (non-limiting e.g. meningitis), sepsis, septic shock, stroke, cerebrovascular disease, ischemic brain injury, ischemic stroke, traumatic injury, brain injury, spinal cord injury, cardiac arrest, heart failure, congestive heart failure, Dilated cardiomyopathy, valvular heart disease, pulmonary embolism, adrenal crisis, Addisonian crisis, hypertensive emergency, haemorrhagic (hypovolemic) shock, cardiogenic shock, neurogenic shock, hepatic encephalopathy, blood loss, ischemic brain/heart/kidney/intestinal injury, neuroprotection and/or card ioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject;
(vi) poisoning by a toxic amount of a compound(s) in a subject (non-limiting e.g.
carbon monoxide/methanol/heavy metal/ethylene glycol/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison(s), nerve agent, chemical weapon, bacterial toxin(s) (e.g. food poisoning, Salmonella poisoning), endotoxemia, eukaryote produced toxin(s) e.g. (non-limiting) brevetoxin, drug(s)/substance(s) overdose e.g. (non-limiting) heroin, ethanol, a prescription medication(s), an over the counter medication(s) such as aspirin, paracetamol etc.; hypothermia is protective to toxic insult);
(vii) hypermetabolism (optionally because of one or more of, without restriction, traumatic brain injury, injury to the body, infection, sepsis, burn, multiple trauma, fever, long-bone fracture, hyperthyroidism, prolonged steroid therapy, surgery, bone marrow transplant, recovery from anorexia/bulimia), heat intolerence, insomnia, fatal insomnia, nervousness, Luft's disease, non-thyroidal hypermetabolism, thyrotoxicosis, hyperthyroidism, overactive thyroid, subclinical hyperthyroidism, too much thyroid hormone(s) in the subject, too much triiodothyronine (T3) and/or thyroxine (T4) in the subject, hyperthyroxinemia (including, without restriction, familial dysalbuminemic hyperthyroxinemia, familial euthyroid hyperthyroxinemia, thyroid hormone resistance syndrome), thyroid storm, hyperthyroidism caused by one or more of (without restriction) Graves' disease, thyroiditis, Hashimoto's thyroiditis, subacute thyroiditis, postpartum thyroiditis, lumps (nodules) on the thyroid, enlarged thyroid gland (goitre), simple goitre, multinodular goiter, toxic multinodular goiter, toxic adenoma, toxic thyroid adenoma, inflammation of the thyroid, hyperplasia of thyroid, metastatic thyroid cancer, thyroid tumour, thyroid cancer (including, without restriction, papillary carcinoma, follicular carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma), eating too much iodine, goitrogen ingestion, consumption of ground beef contaminated with thyroid tissue ("hamburger hyperthyroidism"), too much synthetic thyroid hormone in the subject, pituitary adenoma, drug induced, Amiodarone drug induced, struma ovarii, Jod-Basedow syndrome, nonautoimmune autosomal dominant hyperthyroidism;
(viii) low or less than desired metabolic/bioenergetic efficiency in a subject, or low or less than desired physical or mental performance (e.g. memory, IQ), or low or less than .. desired body weight, or fatigue/tiredness/weakness/exhaustion;
(ix) accelerated aging disease or progeroid syndrome including, without restriction, Werner syndrome, Bloom syndrome, De Barsy syndrome, Rothmund¨Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann¨Rautenstrauch syndrome, Hutchinson¨Gilford progeria syndrome (progeria), Ataxia telangiectasia-like disorder 2, XFE progeroid syndrome, Muscular dystrophy, Muscular Dystrophy (Becker's, Duchenne, Limb-Girdle), Yamamoto's Muscular Dystrophy, Mandibuloacral dysplasia, Dilated cardiomyopathy, GAPO syndrome, Cutis laxia, Ehlers-Danlos syndrom, Lenz-Majewski hyperostatic dwarfism, SHORT syndrome, Progressive external opthalmoplegia, Nester-Guillermo progeria syndrome, MDPL syndrome, Dyskeratosis congenital, Down syndrome;
(x) disease or disorder of aging (incidence/severity increases with increased age/senescence) and/or unwanted/undesirable aspect(s) of aging and/or a disease/disorder associated with elevated reactive oxygen species including age-associated decline, aging frailty, frailty syndrome, sarcopenia, muscle weakness, osteoporosis, cognitive decline, cognitive defecit, mild cognitive impairment, degenerative diseases, neurodegenerative diseases, motor-associated neurodegenerative diseases, motor neuron disease, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, progressive supranuclear palsy, pseudobulbar palsy, hereditary spastic paraplegia, Parkinson's disease, Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), essential tremor, resting tremor, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, frontotemporal dementia, chronic traumatic encephalopathy, memory loss, aged cognition, age/aging related cognitive decline/impairment, Batten disease, polyglutamine diseases, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, heart failure with preserved ejection fraction, idiopathic pulmonary fibrosis, fibrotic disease, pulmonary disease, coronary artery disease, hypercholesterolemia, obesity, liver disease, fatty liver disease, lysosomal storage disease, amyloidosis, systemic sclerosis, kidney disease, hepatic cirrhosis, immunosenscence, clonal hematopoiesis, chronic obstructive pulmonary disease (COPD), hypertension, hypercholesterolemia, age-related thymic atrophy, arthritis, osteoarthritis, arthritis (Osteo-and Rheumatoid), Juvenile Rheumatoid Arthritis (JRA), Degenerative Disc Disease, Tendinopathy, Androgenetic Alopecia, male-pattern baldness, Idiopathic Pulmonary Fibrosis, systemic sclerosis, Chronic Obstructive Pulmonary Disease, Psoriasis, age-related loss of cardiac/pulmonary/cognitive/vision function, diabetes, type 2 diabetes, andropause, glaucoma, retinal degeneration, sarcopenia, cachexia, age-related cachexia and/or sarcopenia, age-related macular degeneration (AMD, early/intermediate/late), neovascular/wet AMD, dry AMD, Geographic atrophy (GA), wet and dry AMD in the same eye(s), Stargardt's macular degeneration, Best vitelliform macular dystrophy, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, age/aging-related eye disease, ophthalmological disease/disorder, ocular disease, vision loss, progressive vision impairment, myopia (short-sightedness), degenerative myopia, hyperopia (far-sightedness), accommodative dysfunction, glaucoma, cataract formation, retinal degeneration, progressive retinal degeneration, retinitis pigmentosa, leber hereditary optic neuropathy, Fuchs spot, Best's disease, Sorsby's fundus dystrophy, hearing loss (e.g. age-related), presbycusis, tinnitus, naive T cell shortage, movement disability, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), immunosenescence, respiratory/urinary tract infection (RTI/UTI) especially in older/aged/elderly subjects, cancer;
(xi) aging and/or one or more signs of aging, wherein one or more of these compounds slow/delay/reduce/treat/prevent/stop/reverse aging, and/or extend lifespan and/or healthspan, and/or treat or delay the onset of geriatric aging of the human/animal body, tissue(s), or organ(s), and/or treat or delay the onset of an age-associated phenotype in a cell(s)/organism(s), and/or prolong fertility e.g. female fertility, delay menopause;

(xii) skin aging and/or damage (including sun damage) and/or scalp and/or hair aging and/or hair greying and/or hair loss;
(xiii) insomnia, fatal insomnia, sleep onset latency, delayed sleep phase disorder, exploding head syndrome, parasomnia, sleep-maintenance insomnia, sleep disorder, too much/inappropriate/undesired signals/activity/electrical activity in the nervous system, hyperactivity, hypersensitivity, Premature ejaculation, hyperreflexia, Autonomic dysreflexia (AD), Hyperventilation syndrome, brain hyperactivity, overly sensitive sensory system, pathological crying and/or laughing, Pseudobulbar affect (PBA, emotional lability), photophobia, phonophobia, temperature-sensitive, pressure-sensitive, brain hyperexcitability, overstimulation, intrusive thought(s), Perseveration, sensory overload, disorganized thinking, fantasy prone personality, malapdative daydreaming, dissociation, hyperkinetic disorder, agitation, Psychomotor agitation, restlessness, difficulty controlling behaviour, disruptive behaviour disorder, Emotional and behavioral disorder, pervasive developmental disorder, Overactive disorder associated with mental retardation and stereotyped movements, attention-deficit disorder, Attention Deficit Hyperactivity Disorder (ADHD), adult attention-deficit hyperactivity disorder, severe behavioral problem(s) in children (e.g., to illustrate and not restrict, combativeness and/or explosive hyperexcitable behavior {out of proportion to immediate provocation[s] }, hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of one or more of: impulsivity, difficulty sustaining attention, aggressivity, mood lability, poor frustration tolerance), Premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), impulsiveness, impulsivity, impulse control disorder, lack of self-control, hysteria, histrionic personality disorder, attention difficulty, inattention, poor attention control, anxiety, paranoid anxiety, Paranoid personality disorder, distress, dysphoria, Adjustment disorder, separation anxiety, anxiety disorder, depressive anxiety, agitated depression, treatment-resistant depression, Generalized anxiety disorder, social anxiety disorder, stranger anxiety, separation anxiety (e.g. in dogs left at home), separation anxiety disorder, Mixed anxiety-depressive disorder, depression (all forms, all severities), restlessness/apprehension/anxiety before surgery.
hypochondria, panic disorder, panic attack, emotional outburst, emotional instability, Intermittent explosive disorder, unreasonable/unwarranted anger/aggression, hyper-aggression, hostility, rage, poor temper control, self-hatred, poor attentional control, worry, irritability, neuroses, somatization disorder, somatic symptom disorder, pain disorder, psychological pain, psychogenic pain, psychogenic facial pain, Atypical odontalgia (AO), burning mouth syndrome, throbbing, toothache/pulpitis/dental pain, chronic lower back pain, negative emotion, persistent/enduring negative emotion, body dysmorphic disorder, factitious disorder, illness anxiety disorder, unwarrented fight-or-flight response, stress, emotional stress, emotional dysregulation, distress, psychological stress, acute stress, chronic stress, acute stress reaction, combat stress reaction, traumatic grief, grief, grief after death of loved one, Prolonged grief disorder (PGD), heartbreak, guilt, shame, remorse, emotional pain, Algopsychalia, psychalgia, suffering, emotional trauma, psychological trauma, broken heart, Post Traumatic Stress Disorder (PTSD), Complex post-traumatic stress disorder (C-PTSD), hypervigilance, sympathetic hyperactivity, inability or impaired ability to relax, flashbacks, dysphoric hyperarousal, agoraphobia, insomnia, fatal insomnia, mood disorder, irrational/unwarrented fear/terror, phobia, social phobia, Cancerophobia, thunderstorm/firework phobia, hypersexuality, hypersexual disorder, depression, clinical depression, unipolar depression, bipolar disorder, Bipolar I, Bipolar II, Bipolar disorder not otherwise specified (Bipolar NOS), cyclothymia, cyclothymic disorder, mixed affective state, atypical depression, melancholic depression, postpartum depression, double depression, seasonal affective disorder, mania, manic episode, hypomania, increase in energy of psychomotor activity, delirium, excited delirium, major depressive disorder, minor depressive disorder, recurrent brief depression, Depressive Disorder Not Otherwise Specified (DD-NOS), major depressive episode, persistent depressive disorder (PDD), dysthymia, dysthymic disorder, absence of euthymia, manic thoughts, racing thoughts, thought disorder, disordered thinking, reduced ability to plan and .. execute tasks, paranoia, hallucination (including, without limitation, visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrioceptive, nociceptive, thermoceptive, chronoceptive), Charles Bonnet syndrome, delusion, persecutory delusion, hearing voices, homicidal/criminal ideation/tendency/thoughts, suicidal ideation/tendancy/thoughts, self-injury, non-suicidal self-injury, violence, attacking others, negative mood swing, personality disorder, Borderline personality disorder, Narcissistic personality disorder, malignant narcissism, dissociative disorder, dissociative identity disorder (DID), Psychosis, acute psychosis, chronic psychosis, psychosis spectrum disorder, manifestations of psychotic disorders, behavioral complications of mental retardation, stimulant psychosis, psychotic depression, hallucinogen persisting perception disorder, Psychoactive substance-related disorder, amphetamine-induced psychosis, brief psychotic disorder, Brief reactive psychosis, Menstrual psychosis, postpartum psychosis, Psychotic disorder, Psychopathy, chronic hallucinatory psychosis, manifestation(s) of psychotic disorder, neurotic/reactive/endogenous/involutional/psychotic depression/depressive disorder (optionally accompanied by anxiety or agitation), depressive neurosis, delusional depression, psychotic aggression, psychiatric symptoms of dementia, AIDS delirium, Supersensitivity psychosis, Tardive psychosis, Tardive dysmentia, Depersonalization disorder, out-of-body experience, Sociopathy, Schizophrenia, Paranoid schizophrenia, disorganized-type schizophrenia, simple-type schizophrenia, pseudoneurotic schizophrenia, prodromal schizophrenia, schizoaffective disorder, bipolar type schizoaffective disorder, depressive type schizoaffective disorder, schizoaffective psychosis, Schizotypal personality disorder, schizophreniform disorder, Delusional parasitosis, formication, paresthesias, Acroparesthesia, tinnitus, delusional disorder, delusional jealousy, inappropriate behaviour, behavioural disorder, antisocial personality disorder, Oppositional defiant disorder (ODD), conduct disorder (CD), Disruptive mood dysregulation disorder (DMDD), sadistic personality disorder, poor inhibitory control, kleptomania, Pyromania, trichotillomania, dermatillomania, pathological/problem gambling, dyskinesia, tardive dyskinesia, paroxysmal dyskinesia, Paroxysmal kinesigenic dyskinesia, Paroxysmal nonkinesigenic dyskinesia, Paroxysmal exercise-induced dystonia, Hemiballismus, tic disorder, tremor, clonus, Tourette's syndrome, coprolalia, copropraxia, Echophenomena, Echopraxia, Echolalia, Palilalia, stuttering/stammering, stereotypy, punding, Self-stimulatory behaviour (stimming), Stereotypic movement disorder (SMD), synesthesia, obsession, Obsessive¨compulsive disorder (OCD), obsessive¨compulsive personality disorder, anankastic personality disorder, relationship obsessive¨compulsive disorder (ROCD), Scrupulosity, Primarily obsessional obsessive compulsive disorder, sexual obsession, Akathisia (including, without limitation, chronic, acute, Pseudoakathisia, Tardive akathisia, withdrawal or "rebound"
akathisia), Restless legs syndrome, motor restlessness, periodic limb movement disorder (PLMD), periodic limb movements in sleep (PLMS), Sydenham's chorea, chorea, dystonia, Hypnic jerk, twitching, spasms, Tetanus, tetanus muscle spasms, tetanized state, Myoclonus, myoclonic seizure, Action myoclonus, Palatal myoclonus, Middle ear myoclonus, Spinal myoclonus, Stimulus-sensitive myoclonus, Sleep myoclonus, Cortical reflex myoclonus, Essential myoclonus, myoclonic epilepsy, Juvenile myoclonic epilepsy, Progressive myoclonus epilepsy (PME, including, without limitation, Dentatorubral-pallidoluysian atrophy, Unverricht-Lundborg disease, MERRF syndrome, Lafora disease), Reticular reflex myoclonus, Myoclonic epilepsy, diaphragmatic flutter, automatism, status epilepticus, Epilepsia partialis continua, Complex partial status epilepticus, epilepsy, epileptic seizure, simple partial seizure, complex partial seizure, generalized epilepsy, generalized seizure (including, without limitation, tonic-clonic, tonic, clonic, myoclonic, absence (including typical absence and atypical absence), atonic seizure), focal epilepsy, focal seizure, focal/partial seizure (including, without limitation, Simple partial seizure and Complex partial seizure), focal aware seizure, focal impaired awareness seizure, generalised epilepsy, temporal lobe epilepsy (including, without restriction, mesial temporal lobe epilepsy {MTLE} and lateral temporal lobe epilepsy ILTLED, Frontal lobe epilepsy, Rolandic epilepsy, Nocturnal epilepsy, Nocturnal frontal lobe epilepsy, Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Generalized epilepsy with febrile seizures plus (GEFS+), Panayiotopoulos syndrome, epileptic fit, reflex epilepsy, reflex seizure, absence seizure (including, without limitation, childhood absence epilepsy, epilepsy with myoclonic absences, juvenile absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome {eyelid myoclonia with absences}, genetic generalised epilepsy with phantom absences), complex partial seizure, atonic seizure, generalized tonic-clonic seizure, tonic¨clonic seizure, extrinsic stimulus epilepsy, intrinsic stimulus epilepsy, photosensitive epilepsy, musicogenic epilepsy, thinking epilepsy, eating epilepsy, seizure(s), Febrile seizure, nerve agent induced seizure, Dravet syndrome (sometimes modest hyperthermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals), acute symptomatic seizure, seizure-related disorder, drug related seizure, paroxysmal depolarizing shift, Ohtahara syndrome, Epilepsy in females with mental retardation, Rasmussen's encephalitis, Epilepsy syndrome, benign rolandic epilepsy, childhood absence epilepsy, absence epilepsy, juvenile myoclonic epilepsy, epileptic encephalopathies, Lennox¨Gastaut syndrome, West syndrome (Epileptic .. spasms), Doose syndrome (Myoclonic astatic epilepsy, MAE), Lennox-Gestaut syndrome, pseudo-Lennox Gastaut syndrome (atypical benign partial epilepsy), Benign familial neonatal epilepsy, Benign occipital epilepsy of childhood, familial neonatal convulsions, Febrile infection-related epilepsy syndrome, interictal dysphoric disorder, euphoria sclerotic, psychogenic non-epileptic seizure, non-epileptic seizure, gelastic seizure, convulsion(s), migraine, status migrainosus, tension headache, headache, Hypnic headache, hiccups, intractable hiccups, thumps in equines, Postural orthostatic tachycardia syndrome (POTS), Pheochromocytoma, agony, pain, chronic pain, acute pain, pain due to disease/injury, neuropathic pain, fibromyalgia, postherpetic neuralgia, phantom pain, referred pain, back pain, lower back pain, pelvic pain, cancer associated pain, chemotherapy associated pain, .. Diabetic neuropathy, small fiber peripheral neuropathy, Mononeuritis multiplex, Wartenberg's migratory sensory neuropathy, Breakthrough pain, idiopathic pain, polyneuropathy, Neuritis, Mononeuropathy, Polyradiculoneuropathy, Radial neuropathy, neuropathy, visceral pain, Burning feet syndrome, Tarsal tunnel syndrome, Carpal tunnel syndrome, Guyon's canal syndrome, Cubital Tunnel Syndrome, Repetitive strain injury, Sciatica, Neurofibromatosis, Ulnar nerve entrapment, Erythromelalgia, Paroxysmal extreme pain disorder, Proctalgia fugax, dysesthesia, scalp dysesthesia, dysesthetic burning, hyperesthesia, hyperalgesia, Opioid-induced hyperalgesia, hyperpathia, allodynia, pain response from stimuli which do not normally provoke pain, Complex regional pain syndrome (said to be most painful condition known to man), Radiculopathy, neuralgia (including, without restriction, intercostal neuralgia, trigeminal neuralgia, atypical trigeminal neuralgia, glossopharyngeal neuralgia, occipital neuralgia, postherpetic neuralgia), ciguatera poisoning, irritable bowel syndrome (IBS), interstitial cystitis (IC), temporomandibular joint disorder, acute intermittent porphyria, Porphyria, Acute porphyria (including, without limitation, acute intermittent porphyria {AIP}, variegate porphyria {VP}, aminolevulinic acid dehydratase deficiency porphyria {ALA)}, hereditary coproporphyria {HCP}, drug induced), Chronic porphyria (including, without limitation, X-linked dominant protoporphyria {XLDPP}, congenital erythropoietic porphyria {CEP}, porphyria cutanea tarda {PCT}, and erythropoietic protoporphyria {EPP}), cutaneous porphyria, Porphyria cutanea tarda, allergy, allergic reaction, anaphylaxis, anaphylactic shock, hives, asthma, allergic rhinitis, rhinitis, urticaria, contact dermatitis, cough, sore throat, esophageal reflux disease, heartburn, chest pain, Esophageal motility disorder, Nutcracker esophagus, diseases involving gastrointestinal motility, Peptic ulcer disease, esophageal spasm, angina, itchiness, Pruritus, severe pruritus, Prurigo, Pruritic skin condition, chronic itch, eczema, pruritus in eczema, neuropathic itch, neurogenic itch, itchiness due to atopic dermatitis and/or lichen simplex chronicus, peripheral sensitization, central sensitization, sensory perception of absent stimuli, too much sensory stimulation, sensory stimulation brings discomfort, Neuromyotonia, Peripheral nerve hyperexcitability, Morvan's syndrome, Benign fasciculation syndrome, Cramp fasciculation syndrome, hyperhidrosis, undifferentiated somatoform disorder, somatoform disorder, somatic symptom disorder, conversion disorder, functional neurological symptom disorder, severe nausea and/or vomiting, severe nausea/emesis, Chemotherapy-induced peripheral neuropathy, chemotherapy-induced nausea and vomiting (CINV), radiation therapy-induced nausea and vomiting (RINV), postnarcotic nausea, hyperemesis gravidarum, morning sickness, Cyclic vomiting syndrome, retching/dry heaving, Urinary incontinence, enuresis, nocturnal enuresis, tail chasing, reduce urine spraying/marking behavior, benzodiazepine withdrawal syndrome, barbituate withdrawal syndrome, Neuroleptic discontinuation syndrome, drug withdrawal discomfort/pain/symptoms, drug use disorder, alcohol use disorder, opoid use disorder, amphetamine use disorder, cocaine use disorder, alcohol withdrawal syndrome/symptoms, delirium tremens, opoid withdrawal sydrome/symptoms, drug craving, drug addiction, drug dependence, polysubstance dependence, drug overdose, smoking, tobacco (nicotine) addition, tobacco (nicotine) withdrawal symptoms, alcoholism, addiction, opoid addiction, cocaine/crack addiction, addictive behaviour, addictive personality, behavioural addiction, internet/computer/computer game/social media/media addiction, exercise addiction, compulsive behaviour (e.g. {non-limiting}
checking, counting, washing, repeating), anti-social behaviour, criminality, sexual compulsion, impulsive sexual behaviour, compulsive buying, gambling addiction, sex related addiction, sexual urge, hunger, eating desire/compulsion, eating disorder, polyphagia, overeating, binge eating disorder, compulsive overeating, insatiable/excessive appetite, bulimia nervosa, anorexia nervosa, substance abuse, substance-induced delirium, substance-induced psychosis, substance-induced mood disorder, drug overdose, vertigo, motion sickness, seasickness, mental/nervous breakdown, Autism spectrum disorder, neurological disorder, cognitive disorder, mental disorder, mental health disorder, mental health condition involving impaired or altered neural plasticity, mood disorder, mental disorder disclosed in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or a later edition, a mental/behavioural disorder disclosed by the International Classification of Diseases (ICD) in LCD-10 Chapter V: Mental and behavioural disorders (World Health Organisation, WHO); or (xiv) diseases or disorders or conditions or pathologies or unwanted/undesirable effects/actions/behaviour treatable/ameliorated/prevented/combated, in totality or in part (e.g.
along with surgery), by anaesthesia, pre-anaesthesia, post-anaesthesia, hypoesthesia, hypoactivity, sedation, coma, tranquilization, behavioural submission, muscle relaxation, hibernation, artificial hibernation, torpor, synthetic torpor, suspended animation (e.g. used during spaceflight because e.g. reduces ionizing radiation damage to subject);
(xv) hyperproliferative/hyperplasia disorder, non-cancerous proliferative disorder, hyperproliferative autoimmune disorder, hyperplasia, epidermal hyperplasia, dysplasia (e.g.
epithelial dysplasia), nodule(s), wart(s), papilloma(s), squamous cell papilloma, genital wart(s), condyloma(s), condyloma acuminatum, cyst(s), polyp(s) {including, without restriction, digestive, colorectal, endometrial, cervical, nasal, laryngeal, inflammatory fibroid polyp[s])}, inherited/hereditary (including, without restriction, Familial adenomatous polyposis, Peutz¨Jeghers syndrome, Turcot syndrome, Juvenile polyposis syndrome, Cowden disease, Bannayan¨Riley¨Ruvalcaba syndrome {Bannayan-Zonana syndrome}, Gardner's syndrome) and non-inherited (non-restrictive e.g. Cronkhite¨Canada syndrome) polyposis syndrome, benign tumour, adenoma, organ enlargement by hyperplasia, Cushing's disease (enlarged adrenal cortex by hyperplasia), congenital adrenal hyperplasia, hyperplasia of breast, atypical ductal hyperplasia, intraductal papillomatosis, fibroadenomas, fibrocystic changes, hemihyperplasia, focal epithelial hyperplasia, sebaceous hyperplasia, sebaceous adenoma, intimal hyperplasia, unwanted/undesirable smooth muscle cell proliferation, smooth muscle cell hyperplasia, intimal smooth muscle cell hyperplasia, neointimal hyperplasia, proliferative vascular disorders, stenosis, stenosis because of cellular proliferation, vaginal stenosis, stenosis in a blood vessel, lessoned patency of a blood vessel, stenosis in a blood vessel because of cellular proliferation, vascular occlusion, restenosis, restenosis in a blood vessel that has been implanted with a stent, in-stent restenosis, post-angioplasty restenosis, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g.
diabetic retinopathy and/or other retinopathy[y/ies]), cardiac hyperplasia, fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, fibromatosis, neurofibromatosis, renal interstitial fibrosis, Cowden syndrome, hamartoma(s), choristoma(s), hemangioma(s), lymphangioma(s), rhabdomyoma(s), lymphangiomatosis, cystic hygroma, trichilemmoma, sarcoidosis, neurosarcoidosis, aggressive fibromatosis, desmoid tumour(s), unwanted/undesirable skin cell proliferation, hyperproliferative skin disorder, psoriasis (including, without restriction, plaque, guttate, inverse, pustular, napkin, seborrheic-like, nail, scalp and erythrodermic psoriasis), psoriatic arthritis, dactylitis, seborrhoeic dermatitis, dandruff, eczema, atopic dermatitis, rosacea, reactive arthritis (Reiter's syndrome), pityriasis rubra pilaris, hyperproliferative variants of disorders of keratinization (e.g., without restriction, actinic keratosis, senile keratosis, keratosis pilaris, seborrheic keratosis), scleroderma, benign prostatic hyperplasia, prostate enlargement, endometrial hyperplasia, atypical endometrial hyperplasia, benign endometrial hyperplasia, adenomyosis, atypical polypoid adenomyoma, endometriosis, endometriosis of ovary (endometrioma), endometrial polyp(s), polycystic ovary syndrome, ovarian cyst(s), cervical polyp(s), uterine fibroid(s), uterine hyperplasia;
(xvi) Tumour Associated Macrophages (TAMs) or any macrophage associated disease or disorder such as, without limitation, Macrophage Activation Syndrome (MAS), HIV, AIDS, HIV-associated neurocognitive disorders (HAND), AIDS dementia, HIV
peripheral neuropathy, HIV associated cancers, AIDS-defining cancers, non-AIDS
defining cancers, any disease in which the pathogen(s) hides from the immune system in macrophages including, without limitation, Mycobacterium tuberculosis (causes tuberculosis), Leishmania parasite (causes Leishmaniasis), Chikungunya virus (causes Chikungunya), Legionella pneumophila (causes Legionnaires' disease), adenoviruses, T. whipplei (causes Whipple's Disease), Brucella spp. (causes brucellosis), Staphylococcus aureus, Ebola virus, Hepatitis B

virus, Hepatitis C virus, influenza virus strains, dengue virus and antibiotic resistant bacteria, any disease or condition in which activated macrophages are unwanted or undesirable;
(xvii) virus/pathogen neuroinvasion via macrophage(s), as used for non-limiting example by HIV, Heptatitis C virus and SARS coronavirus;
(xviii) neurocognitive or neurodegenerative diseases/disorders, for non-limiting example those caused by a virus;
(xix) virus/pathogen transmission from mother to fetus/baby via macrophage(s) as used for non-limiting example by zika (via Hofbauer cells) and HIV
(macrophages in breast milk);
(xx) acute or chronic or systemic inflammation or any inflammatory disease/disorder/syndrome or any autoinflammatory disease/disorder/syndrome or any autoimmune disease/disorder/syndrome;
(xxi) acute inflammation, chronic inflammation, systemic inflammation, inflammation because of infection or foreign bodies or injury or chemical or toxin or drug or stress or frostbite or burn or ionising radiation or surgery, inflammatory diseases/disorders/syndromes, Macrophage Activation Syndrome (MAS), autoinflammatory diseases/disorders/syndromes, age-related chronic inflammatory diseases ("inflammaging"), autoimmune diseases/disorders/syndromes, diseases/disorders of the innate immune system, sore throat, sore throat associated with cold or flu or fever, high-intensity exercise associated inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, osteoarthritis, inflammatory osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation associated depression, neuroinflammation, neuropathic pain, exercise-induced acute inflammation, atherosclerosis, allergy, hay fever, anaphylaxis, inflammatory myopathies, drug-induced inflammation, systemic inflammatory response syndrome, sepsis-related multiple organ dysfunction/multiple organ failure, microbial infection, acute brain/lung/hepatic/renal injuries, lung inflammation, acute lung injury (ARDS), acne vulgaris, celiac disease, celiac sprue, chronic prostatitis, colitis, autoimmune hemolytic anemia, diverticulitis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Mast Cell Activation Syndrome, mastocytosis, otitis, pelvic inflammatory disease (PID), endometritis, reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasitosis, eosinophilia, type III hypersensitivity, ischaemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, alcoholic hepatitis, chronic viral hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematous (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative disease, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, bronchiectasis, bronchopneumonia, obliterative bronchiolitis, appendicitis, acute appendicitis, bursitis, cystitis, dermatitis, encephalitis, HIV encephalitis, gingivitis, meningitis, infective meningitis, myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis¨associated interstitial lung disease and desquamative interstitial pneumonia, pneumonia, interstitial lung disease, Lofgren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, steatohepatitis, nonalcoholic steatohepatitis, silicosis, histiocytoses, Langerhans' cell histiocytosis, haemophagocytic lymphohistiocytosis, pulmonary langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudogout, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft versus host disease (GVHD), lymphadenopathy, rheumatoid arthritis (RA), osteoarthritis (OA), inflammatory osteoarthritis, lupus, multiple sclerosis (MS), myocarditis, uveitis, CNS disease(s), inflammation aspect to a CNS disease(s), hypothalamic inflammation, dementia, glaucoma, amyloid related/driven disease, lipid storage disease(s), fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, cirrhosis of the liver, alcoholic cirrhosis, nephropath(y/ies), lupus nephritis, immune nephritis, fibrotic disorder(s), cardiovascular disease, heart disease, atherosclerosis, vulnerable plaque, plaque formation, lipid containing macrophage related disease(s)/disorder(s)/malad(y/ies), macrophage foam cells, diabetes, type I
diabetes, type 2 diabetes, insulin resistance, macrophage aspect to insulin resistance, obesity, obesity associated inflammation, macrophage accumulation/large numbers of macrophages in adipose tissue (e.g. associated with obesity), granuloma(s), granulomatous diseases, sarcoidosis (including, without limitation, Annular sarcoidosis, Erythrodermic sarcoidosis, Ichthyosiform sarcoidosis, Hypopigmented sarcoidosis, Lofgren syndrome, Lupus pemio, Morpheaform sarcoidosis, Mucosal sarcoidosis, Neurosarcoidosis, Papular sarcoid, Scar sarcoid, Subcutaneous sarcoidosis, Systemic sarcoidosis, Ulcerative sarcoidos), neurosarcoidosis, pulmonary sarcoidosis, interstitial lung disease, pulmonary fibrosis, pulmonary tuberculosis, immune reconstitution syndrome of HIV, Jarisch¨Herxheimer reaction, sepsis, Paget's disease of bone, osteolysis, monocytosis, histiocytosis, X-type histiocytoses, non-X histiocytoses, Langerhans cell histiocytosis, non-Langerhans-cell histiocytosis, malignant histiocytosis, malignant histiocytic disorders, histiocytomas, histiocytic lymphoma, hemophagocytic syndrome, hemophagocytic lymphohistiocytosis, lymphohistiocytosis, diffuse histiocytic sarcoma, Rosai¨Dorfman disease, gliosis, Bergmann gliosis, Chronic Obstructive Pulmonary Disease (COPD), chronic inflammatory lung disease, familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulinemia D with recurrent fever syndrome (HIDS), cryopyrin associated periodic syndrome (CAPS), Blau syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), mevalonate kinase deficiency, pyogenic-arthritis-pyoderma gangrenosum and acne syndrome (PAPA), periodic fever aphthous stomatitis pharyngitis adenitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, Schnitzler's syndrome, Sweet's syndrome, NLRP12-associated autoinflammatory disorders, deficiency of interleukin-1 receptor antagonist (DIRA), pyoderma gangrenosum, cystic acne, aseptic arthritis, periodic Fever Associated with mevalonate kinase deficiency (hyperimmunoglobulin D Syndrome), Pyogenic Arthritis Pyoderma Gangrenosum Acne (PAPA) syndrome, Periodic Fever Aphthous Stomatitis, Pharyngitis and Adenopathy (PFAPA) syndrome, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Chronic Recurrent Multifocal Osteomyelitis (CRMO), Synovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome, Cryopyrin associated Periodic Syndrome (CAPS), Familial cold auto inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Familial cold urticarial, Neonatal onset multisystemic inflammatory disorder (NOMID), hereditary Periodic Fever Syndromes, Periodic Fever Syndromes, systemic autoinflammatory diseases, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Bak) disease, Behcet's disease, benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Berger's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immune hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type I diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR) PANDAS, Paraneoplastic cerebellar .. degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Tumer syndrome, Pemphigus, peripheral neuropathy, perivenous encephalomyelitis, Pernicious anemia (PA), POEMS
syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type I diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)), idiopathic thrombocytopenia purpura, splenomegaly;
(xxii) Systemic inflammatory response syndrome, cytokine release syndrome, cytokine storm, immune reaction to a drug(s) or therapy(s), immune reaction to an immune activating drug(s) or agent(s) or treatment(s) or intervention(s), immune reaction to immunotherapy and/or immune-oncology and/or immunomodulatory drug(s) and/or treatment(s), adverse reaction to adoptive T-cell therapy(s), adverse reaction to a chimeric antigen receptor T-cell therapy(s) (CAR-T cell therapy(s)), adverse reaction to a immune checkpoint inhibitor(s), adverse reaction to monoclonal antibody drug(s), tumor lysis syndrome; or (xxiii) cancer and Graft Versus Host Disease (GVHD) in transplantation therapy in a cancer patient, wherein the method comprises administering to the subject an effective amount of at least one compound, or a composition containing at least one compound, which reduces F1 Fo ATP hydrolysis in a subject, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
[35] A method according to Claim 16, wherein the subject is also administered with an effective amount of one or more compounds or compositions approved for human use, optionally for anti-cancer use, by the United States Food and Drug Administration (FDA) and/or European Medicines Agency (EMA), optionally in the same pharmaceutical composition.
[36] A method according to Claim 17, wherein the subject is also administered with an effective amount of one or more compounds or compositions approved for human use, optionally for anti-cancer use, by the United States Food and Drug Administration (FDA) and/or European Medicines Agency (EMA), optionally in the same pharmaceutical composition.
[37] A method according to Claim 16, wherein comparable or larger mg/kg compound(s) , dose is used in, or administered to, a larger subject(s)/animal(s)/species, which is very distinct from most drugs, and optionally the mg/kg dosage administered to one or more adult humans is comparable or greater than the No Observed Adverse Effects Level (NOAEL) mg/kg dosage in mice housed at 22 C.
[38] A method according to Claim 17, wherein comparable or larger mg/kg compound(s) dose is used in, or administered to, a larger subject(s)/animal(s)/species, which is very distinct from most drugs, and optionally the mg/kg dosage administered to one or more adult humans is comparable or greater than the No Observed Adverse Effects Level (NOAEL) mg/kg dosage in mice housed at 22 C.

[39] A method according to Claim 16, wherein the compound(s) and/or composition(s) is administered to the subject topically/locally and not systemically.
[40] A method according to Claim 17, wherein the compound(s) and/or composition(s) is administered to the subject topically/locally and not systemically.
[41] A compound(s) and/or composition(s) for use and/or method according to any one of Claims 1 to 33 or Claims 35 to 40, wherein the claim is made (e.g. written to be/ammended to be) a dependent claim of Claim 34.

Claims

Claims [1] A compound, or a composition containing at least one compound, of the following formula:
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
L is alkyl, or deuterium, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy, or hydroxyalkyl, or any atom or isotope permitted by valence except hydrogen at natural abundance;
R1 is hydrogen, cyano, ¨SO2R8, ¨C(=O)R9, heteroaryl or thiazolyl;
R2 is (i) independently hydrogen, alkyl, benzyl, or substituted alkyl, or (ii) taken together with R3 forms a heterocyclo;
R3 is (i) independently alkyl, substituted alkyl, alkylthio, aminoalkyl, carbamyl, B B-aryl, B B-heterocyclo, B B-heteroaryl, or B B-cycloalkyl, or (ii) phenyl optionally substituted with C1-4alkyl, halogen, trifluoromethyl, OCF3, cyano, nitro, amino, hydroxy, or methoxy, or (iii) independently selected from C1-4alkyl, alkylthio, aminoalkyl, -B B-aryl, -B B-heterocyclo, B B-cycloalkyl, and -B B-hetaroaryl, optionally having one to three substituents selected from R3a; and/or having fused thereto a five or six membered carbocyclic ring, or (iv) taken together with R2 forms a heterocyclo optionally substituted with alkyl or substituted alkyl;
B B is a bond, C1-4alkylene, C2-4alkenylene, substituted C1-4alkylene, substituted C2-4alkenylene, substituted C1-4alkylene-C(=O)NH¨, ¨C(=O)NH¨, ¨C1-4alkylene-C(=O)NH¨, ¨C(=O)NR19---, ¨C1-4alkylene-C(=O)NR19¨, or substituted C1-4alkylene-C(=O)NR19¨, ¨(CHR14)m¨(CR15R16)n¨ or ¨(CHR14)p¨C(=O)NH¨;
R3a at each occurrence is selected independently from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, keto, trifluoromethyl, ¨NR17R18, ¨SR17, ¨OR17, ¨
SO2R17a, ¨SO2NR17R18, ¨NR17C(=O)R18, ¨CO2R17, ¨C(=O)R17, cyoloalkyl, aryl, heterocyolo, and heteroaryl, wherein when R3a is cycloalkyl, aryl, heterocyclo or heteroaryl, said cycloalkyl, aryl, heterocyolo and heteroaryl in turn is optionally substituted with alkyl or substituted alkyl;

Z is a heteroaryl, for example an optionally-substituted bicyclic heteroaryl;
or Z is triazolyl optionally substituted with one to two R7 substituents or imidazolyl optionally substituted with one to two R7 substituents and/or having fused thereto a benzene ring in turn optionally substituted with one to two R7 substituents; and R7 is alkyl, carbamyl, or substituted alkyl;
R4 at each occurrence is selected independently of each other R4 from the group consisting of halogen, trifluoromethyl, OCF3, alkyl, substituted alkyl, haloalkyl, nitro, cyano, haloalkoxy, OR25, SR25, NR25R26, NR25SO2R27, SO2R27, SO2NR25R26, CO2R26, C(=O)R26, C(=O)NR25R26, OC(=O)R25, -OC(=O)NR25R26, NR25C(=3)R26, NR25CO2R26, aryl, heteroaryl, heterocyclo and cycloalkyl;
R8 is C1-4alkyl or phenyl optionally substituted with alkyl, halogen, haloalkoxy, cyano, nitro, or trifluoromethyl;
R9 is -NR10R11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclo, or -CO2R12, alkyl or phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, C1-4alkoxy, haloalkoxy, CO2alkyl, SO2alkyl, SO2NH2, amino, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(=O)alky, C(=O)alkyl, and/or C1-4alkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl; and/or a five or six membered heteroaryl or heterocylo in turn optionally substituted with keto or having a benzene ring fused thereto or a) C1-4alkyl optionally substituted with one to two of:
i) SR13, OR13, NR13a R13b, halogen, trifluoromethyl, CO2R13a, and C(=O)NR13a R13b;
ii) cycloalkyl optionally substituted with one to two of C(=3)H, C1-4acyl, alkenyl, carbamyl, and/or phenyl in turn optionally substituted with halogen;
iii) phenyl or napthyl optionally substituted with one to two of halogen, nitro, amino, alkyl, hydroxy, C1-4alkoxy, or having fused thereto a five or six membered heterocyclo;
iv) pyridinyl, thiophenyl, furanyl, tetrahydrofuranyl, or azepinyl, optionally substituted with alkyl or having fused thereto a five to six membered carbocyclic ring optionally substituted with keto or C1-4alkoxy;
b) 3 to 6 membered cycloalkyl optionally having up to four substituetits selected from alkyl, halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, phenyl in turn optionally substituted with halogen; or having an aryl fused thereto;
c) pheyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, C1-4alkoxy, haloalkoxy, C1-4alkyl, CO2alkyl, SO2alkyl, SO2NH2, amino NH(C1-4alkyl), N(C1-4alkyl)2, NHC(=O)alkyl, C(=3)alkyl, and/or C1-4alkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl;
and/or a five or six membejed heteroaryl or heterocyle in turn optionally substituted with keto or having a benzene ring fused thereto;
d) pyridinyl, thiazolyl, furanyl, thiophenyl, and pyrrolyl optionally substituted with one to two of halogen, alkyl, and phenyl in turn optionally substituted with halogen or trifluoromethyl;
R10 and R11 are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, heteroaryl or C1-4alkyl optionally substituted with one to two of ¨CO2alkyl, ¨C(=C)NH(aryl), NH(aryl), cycloalkyl, phenyloxy, phenyl in turn optionally substituted with C1-4alkyl, hydroxy, C1-4alkoxy, halogen, amino, nitro, tetrahydrofuranyl, and/or five or six membered heterocyclo, or having a five or six membered heterocyclo fused thereto; pyrrolidinyl optionally substituted with keto;
napthyl, anthracenyl, pyridinyl, thiophenyl, furanyl, imidazolyl, benzimidazolyl, or indolyl in turn optionally substituted with C1-4alkyl or C1-4alkoxy; or (ii) taken together form a heteroaryl or heterocyclo selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, tetrahydropyridinyl, and imidazoilidinyl, wherein said heterocyclo formed by R10 and R11 is optionally substituted with one to two of keto, CO2H, C14alkoxy, CO2alkyl, C1-4carbamyl, benzyl; phenyl in turn optionally substituted with alkyl, halogen, or C1-4 alkoxy;
tetrahydropyridinyl in turn optionally substituted with keto and/or phenyl;
alkyl optionally substituted with amino or NHR21wherein R21 is alkyl or phenyl optionally substituted with alkyl; and/or has a benzene ring fused thereto in turn optionally substituted with one to two of alkyl, C1-4alkoxy, CO2alkyl, and/or C1-4carbamyl;
R12 and R19 are hydrogen or alkyl;
R13 is hydrogen or alkyl;
R13a and R13b are selected from hydrogen, alkyl, and aryl;
R14, R15 and R16 at each occurrence are independently selected from hydrogen, alkyl, hydroxy, hydroxyC1-4alkyl, C1-4alkoxy, and phenyl, and/or one of R15 and one of R16 join together to form a 3 to 6 membered cycloalkyl;
R17 and R18 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, phenyl, or benzyl wherein the phenyl or benzyl is optionally substituted with alkyl, hydroxy, or hydroxyalkyl;
R17a is alkyl or substituted alkyl;
R25 and R26 are independently selected from hydrogen, alkyl, or substituted alkyl, or taken together form a heterocyclo or heteroaryl ring;

R27 is alkyl or substituted alkyl;
q is 0, 1, 2, or 3;
m and n are 0, 1 or 2; and p is 0, 1, 2, or 3.
[2] A compound according to Claim 1, of the formula, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
there is an enantiomeric excess (ee) of the particular stereoisomer shown in the formula.
[3] A compound according to Claim 1, of the formula, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
D is deuterium (enrichment, for (non-limiting) example, exceeding 40%
deuterium incorporation at position shown, optionally deuterium enrichment at other locations also), [4] A compound according to Claim 1, of the formula, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at position shown);
the enantiomeric excess (ee) of the S stereoisomer exceeds 70%;
[5] A compound according to Claim 1, of the formula, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
[6] A compound according to Claim 1, of the formula, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
the enantiomeric excess (ee) of the S stereoisomer exceeds 70%;
[7] A compound according to Claim 1, of the formula, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
the enantiomeric excess (ee) of the R stereoisomer exceeds 70%;
181 A compound according to any one of Claims 1 to 7, wherein, Y is CH, N or CR7c;
R1 is cyano, ¨SO2R8, ¨C(O)R9, or heteroaryl;
R2 is (i) independently hydrogen, alkyl, or substituted alkyl, or (ii) taken together with R3 forms a heterocyclo;
R3 is (i) independently selected from (a) alkyl optionally substituted with one to two of hydroxy and alkoxy;
(b) alkylthio or aminoalkyl optionally substituted with hydroxy or alkoxy;
(c) -A1aryl, wherein the aryl is optionally substituted with up to four substituents selected from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, ¨NR17R18, ¨SR17, ¨OR17, ¨SO2R17a, ¨SO2NR17R18, ¨NR17C(=O)R18, ¨CO2R17, ¨C(=O)R17, cycloalkyl, aryl, heterocyclo, and heteroaryl, and/or has fused thereto a five or six membered cycloalkyl ring;
(d) -A2-heteroaryl wherein the heteroaryl is a five or six membered monocyclic ring having 1 to 3 heteroatoms selected from N, O, and S, or an eight or nine membered bicyclic ringed system having at least one aromatic ring and 1 to 4 heteroatoms selected from N, O, and S in at least one of the rings, said heteroaryl being optionally substituted with halogen. alkyl, alkoxycarbonyl, sulfonamide, nitro, cyano, trifluoromethyl, alkylthio, alkoxy, keto, ¨

C(=O)H, acyl, benzyloxy, hydroxy, hydroxyalkyl, or phenyl optionally substituted with alkyl or substituted alkyl;
(e) -A2-heterocyclo wherein the heterocyclo is optionally substituted with one to two groups selected from alkyl, keto, hydroxy, hydroxyalkyl, ¨C(=O)H, acyl, CO2H, alkoxycarbonyl, phenyl, and/or benzyl, and/or has a bridged carbon¨carbon chain or fused benzene ring joined thereto;
(f) -A2-cycloalkyl wherein the cycloalkyl is optionally substituted with one to two groups selected from alkyl, keto, ¨C(O)H, acyl, CO2H, alkoxycarbonyl, and/or benzyl, and/or has a bridged carbon¨carbon chain or fused benzene ring joined thereto; or (ii) taken together with R2 forms a heterocyclo;
R4 at each occurrence is selected independently of each other R4 from the group consisting of halogen, alkyl, haloalkyl, cyano, and haloalkoxy;
R2a, R7b and R2c are independently selected from hydrogen, alkyl, carbamyl, or carbamylalkyl, or R7a and R7c join to form an aryl or heteoraryl;
R8 is alkyl, arylalkyl, or aryl;
R9 is ¨NR10R11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclo, CO2R12, or phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, C1-aalkoxy, haloalkoxy, C1-6alkyl, CO2alkyl, SO2alkyl, SO2NH2, amino, NH(Ci4alkyl), N(C1-4alkyl)2, NHC(=O)alkyl, C(=O)alkyl, and/or C1-4alkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl;
and/or a five or six membered heteroaryl or heterocyclo in turn optionally substituted with keto or having a benzene ring fused thereto;
R10 is independently hydrogen, alkyl, or alkoxy; and R11 is independently hydrogen, alkyl, substituted alkyl, alkoxy heterocyclo cycloalkyl, aryl, or heteroaryl; or R10 and R11 taken together form a heterocyclo or heteroaryl optionally substituted with alkyl, keto, CO2H, alkoxycarbonyl, hydroxy, alkoxy, alkyl, carbamyl, aryl, or substituted alkyl, wherein when the R10 and R11 group comprises a phenyl ring, said phenyl ring is optionally substituted with one to two of alkyl, halogen, and alkoxy;
R12 is hydrogen or alkyl;
A12 is ¨(CHR14)m¨V¨(CR15R16)n¨ or ¨(CHR14)p¨(C)NH¨;
A2 is ¨(CHR14)m¨V--(CR15R16)n;
V is a bond, S, or ¨NR22¨;

R14, R15 and R16 at each occurrence are independently selected from hydrogen, alkyl, hydroxy, hydroxyC1-4alkyl, C1-4alkoxy, and phenyl, and/or one of R15 and one of R16 join together to form a three to six membered cycloalkyl;
R17 and R18 are independently selected from hydrogen, alkyl, phenyl, and benzyl, wherein the phenyl and benzyl is optionally substituted with alkyl, hydroxy, or hydroxyalkyl;
R17a is alkyl or substituted alkyl;
R22 is hydrogen or alkyl;
m and n are 0, 1, 2, or 3;
p is 0, 1, 2, or 3; and q is 0, 1, 2, or 3.
[9] A compound according to Claim 8 having the formula, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
R7a, R7b and R7c are independently selected from hydrogen, alkyl, carbamyl or carbamyl C1-4alkyl, or R7a and R7c join to form a fused phenyl ring;
R23 is selected from hydrogen, alkyl, hydroxyalkyl, or phenyl;
R24 is selected from alkyl, halogen, trifluoromethyl, cyano, halogen, hydroxy, OCF3, methoxy, phenyloxy, benzyloxy, cyano, acyl, or two R24 groups join to form a fused cycloalkyl or benzene ring; and x is 0, 1, or 2; and y is 0, 1, 2, or 3.
[10] A compound according to Claim 1, having the structure:

or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
deuterium (D) enrichment at the chiral centre, and optionally at other locations, exceeds 40% deuterium incorporation the enantiomeric excess (ee) of the S stereoisomer exceeds 70%.
[11] A compound according to Claim 1, having the structure:

or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
[12] A compound according to Claim 1, having the structure:
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
the enantiomeric excess (ee) of the S stereoisomer exceeds 70%.

[13] A compound according to Claim 1, having the structure:
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
the enantiomeric excess (ee) of the R stereoisomer exceeds 70%.
[14] A pharmaceutical composition comprising at least one compound as defined in any one of Claims 1 to 13 and a pharmaceutically-acceptable carrier or excipient or diluent.
[15] A compound according to any one of Claims 1 to 13, or a pharmaceutical composition according to Claim 14, for use in a method of treatment of the human or animal body by therapy.
[16] A compound according to any one of Claims 1 to 13, or a pharmaceutical composition according to Claim 14, for use in treating, ameliorating, preventing, reversing or combating a disease or disorder or unwanted/undesirable physiological process or its consequences or an unwanted/undesirable aesthetic selected from (i) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. 18F-FDG PET);

(ii) cachexia, cancer driven cachexia, cancer fatigue, weight loss, weight loss for known or unknown reason, chronic wasting disease, atrophy, brown atrophy, frailty, frailty syndrome, aging frailty, geriatric syndrome, age-related cachexia and/or sarcopenia, weakness, wasting, anorexia nervosa, bulimia nervosa, eating disorder, amenorrhea, underweight, low body mass index (BMI, e.g. (18.5), low body fat percentage, body composition change, wasting syndrome, HIV wasting syndrome, malnutrition, clinical malnutrition, starvation, kwashiorkor syndrome, marasmus syndrome, malabsorption, malabsorption due to parasitic/bacterial infection (e.g. helminthiasis, Whipple's disease, small intestine bacterial overgrowth (SIBO), giardiasis etc.), anemia, refeeding syndrome, appetite loss, catabolysis, muscle atrophy, asthenia, muscle weakness (myasthenia), sarcopenia, osteoporosis, cachexia associated with HIV, AIDS, multiple sclerosis, rheumatoid arthritis, familial amyloid polyneuropathy, chronic kidney disease, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia, Addison's disease, mercury poisoning (acrodynia), chronic pancreatitis, untreated/severe type 1 diabetes mellitus, hormonal deficiency, tuberculosis, gastroenteritis, diarrhea, dysentery, any digestive disease or disorder, any gastrointestinal disease or disorder including functional gastrointestinal disorders, coeliac disease, tropical sprue, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, short bowl syndrome, congestive heart failure, constrictive pericarditis, bradycardia, chronic obstructive pulmonary disease (COPD), altitude sickness, hyperthyroidism (subclinical hyperthyroidism, Graves' disease, multinodular goiter, toxic adenoma, inflammation of the thyroid {thyroiditis}, pituitary adenoma), fatigue, chronic fatigue syndrome or any disease or disorder or pathology in which a body tissue(s) is undersupplied or underutilises (vs. its need) an energetic/chemical substrate(s), including 02;
(iii) cancer associated fever, which is especially associated with, but not limited to, non Hodgkin lymphoma (NHL), Hodgkin lymphoma, acute leukaemia, kidney cancer (renal cell cancer), liver cancer (hepatocellular carcinoma), bone cancer, adrenal gland tumours such as phaeochromocytomas, tumours in the hypothalamus, solid tumours;
(iv) disease or disorder or physiological process or condition that causes a higher than normal body temperature such as (without limitation) high environmental temperature, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, neutropenic sepsis, stroke, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, toxic serotonin syndrome, thyroid storm, heatstroke, surgery related, menopause ("hot flushes"), infection (non-limiting e.g. roseola, measles, enteroviral infections, parasitic, viral, ftmgal, Chlamydial, Rickettsial, bacterial, mycobacterial, systemic bacterial, intravascular, HIV associated, nosocomial), pyrogenic infection, thermoregulatory disorder(s), connective tissue disease(s), Kawasaki syndrome, drug overdose, drug or drug withdrawal induced hyperthermia, alcohol/drug withdrawal, idiosyncratic drug reaction, fever of known or unknown or uncertain origin (non-limiting e.g. infectious disease(s), inflammation, immunological disease(s), non-infectious inflammatory disease(s) {non-limiting eg. systemic rheumatic and autoimmune diseases, vasculitis, granulomatous diseases, autoinflammatory syndromes}, tissue destruction, reaction to incompatible blood product(s), metabolic disorder(s), inherited metabolic disorder(s), cancer, neoplasm, endogenous or exogenous pyrogen(s), injury, head injury);
(v) disease/disorder/injury/pathology/surgery treatable/ameliorated/prevented/combated/helped by conferring hypothermia in a subject for some medical or other purpose which can include slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, slowing physiological/pathological processes (reaction rates are temperature dependent) and so "buying time" to get the subject to treatment for their emergency (e.g.
trauma/septic shock or other medical emergency), slowing the progress of sepsis until a sufficient concentration of a working antibiotic(s) can be built up in the subject (furthermore hypothermia, by slowing sepsis progression, buys time to observe which antibiotic(s) can work, yielding time to try alternative further antibiotic option(s) if required), used soon after or just before clinical/legal death to preserve the subject's organs/tissues until the subject can be frozen/cryogenically frozen or the pathology that caused clinical/legal death (e.g. wound) can be fixed and the subject resuscitated, administered to a subject when a first responder (e.g.
ambulance crew) deems the subject dead or unlikely to survive the journey to a medical facility (e.g. hospital) wherein this administration helps to preserve the subject which is helpful if hospital staff subsequently assess that they can, or might be able to, save the subject, stabilizing surgical/trauma/Emergency Room (ER) patients, deep hypothermic circulatory arrest for surgery (DHCA, non-limiting applications of DHCA include repairs of the aortic arch, repairs to head and neck great vessels, repair of large cerebral aneurysms, repair of cerebral arteriovenous malformations, pulmonary thromboendarterectomy, resection of tumors that have invaded the vena cava, brain tumor resection {wherein the anti-cancer activity of a compound(s) of this invention juxtaposes well}), Emergency Preservation and Resuscitation (EPR), hypothermia for a surgical purpose, protective hypothermia during surgery and/or surgery complication, hypothermia to slow/reduce blood loss, hypothermia for neuro- and/or cardio- and/or organ/tissue and/or life protection in a subject that has trauma/brain trauma/polytrauma/surgery/stroke/ischemic stroke/hemorrhagic stroke/cardiac arrest/myocardial infarction/hypoxia/shock (including, without limitation, low volume, cardiogenic, obstructive, and distributive shock)/sepsis/septic shock/multiple organ dysfunction syndrome/systemic inflammatory response syndrome (SIRS)/organ failure/cytokine storm/anaphylactic shock/seizure/disseminated intravascular coagulation/blocked airway/croup/rhabdomyolysis/[head/facial/spinal/chest/abdominal/ballistic/knife injury/trauma], or some other medical emergency/condition/disorder/disease/injury/operation, hypothermia for cardiac and/or cardiovascular surgery and/or open heart surgery and/or brain surgery (neurosurgery) and/or surgery using total circulatory arrest and/or surgery using cardiopulmonary bypass, Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage/transport and/or transplant, thus increasing the time window for transplantation of organs to recipients;
compound(s) of this invention is administered to organ to be transplanted [by administration to donor and/or by administration to isolated organ] and/or to organ recipient, optionally during transplant operation), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, neonatal hypoxia-ischemia, birth asphyxia, hypoxic-ischemic encephalopathy (HIE), haemorrhage, hypovolemia, exsanguination, suspended animation, decompression sickness, burn injury(s) including skin burn, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or tourniquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (non-limiting e.g. meningitis), sepsis, septic shock, stroke, cerebrovascular disease, ischemic brain injury, ischemic stroke, traumatic injury, brain injury, spinal cord injury, cardiac arrest, heart failure, congestive heart failure, Dilated cardiomyopathy, valvular heart disease, pulmonary embolism, adrenal crisis, Addisonian crisis, hypertensive emergency, haemorrhagic (hypovolemic) shock, cardiogenic shock, neurogenic shock, hepatic encephalopathy, blood loss, ischemic brain/heart/kidney/intestinal injury, neuroprotection and/or cardioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject;

(vi) poisoning by a toxic amount of a compound(s) in a subject (non-limiting e.g.
carbon monoxide/methanol/heavy metal/ethylene glycol/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison(s), nerve agent, chemical weapon, bacterial toxin(s) (e.g. food poisoning, Salmonella poisoning), endotoxemia, eukaryote produced toxin(s) e.g. (non-limiting) brevetoxin, drug(s)/substance(s) overdose e.g. (non-limiting) heroin, ethanol, a prescription medication(s), an over the counter medication(s) such as aspirin, paracetamol etc.; hypothermia is protective to toxic insult);
(vii) hypermetabolism (optionally because of one or more of, without restriction, traumatic brain injury, injury to the body, infection, sepsis, bum, multiple trauma, fever, long-bone fracture, hyperthyroidism, prolonged steroid therapy, surgery, bone marrow transplant, recovery from anorexia/bulimia), heat intolerence, insomnia, fatal insomnia, nervousness, Luft's disease, non-thyroidal hypermetabolism, thyrotoxicosis, hyperthyroidism, overactive thyroid, subclinical hyperthyroidism, too much thyroid hormone(s) in the subject, too much triiodothyronine (T3) and/or thyroxine (T4) in the subject, hyperthyroxinemia (including, without restriction, familial dysalbuminemic hyperthyroxinemia, familial euthyroid hyperthyroxinemia, thyroid hormone resistance syndrome), thyroid storm, hyperthyroidism caused by one or more of (without restriction) Graves' disease, thyroiditis, Hashimoto's thyroiditis, subacute thyroiditis, postpartum thyroiditis, lumps (nodules) on the thyroid, enlarged thyroid gland (goitre), simple goitre, multinodular goiter, toxic multinodular goiter, toxic adenoma, toxic thyroid adenoma, inflammation of the thyroid, hyperplasia of thyroid, metastatic thyroid cancer, thyroid tumour, thyroid cancer (including, without restriction, papillary carcinoma, follicular carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma), eating too much iodine, goitrogen ingestion, consumption of ground beef contaminated with thyroid tissue ("hamburger hyperthyroidism"), too much synthetic thyroid hormone in the subject, pituitary adenoma, drug induced, Amiodarone drug induced, struma ovarii, Jod-Basedow syndrome, nonautoimmune autosomal dominant hyperthyroidism;
(viii) low or less than desired metabolic/bioenergetic efficiency in a subject, or low or less than desired physical or mental performance (e.g. memory, IQ), or low or less than desired body weight, or fatigue/tiredness/weakness/exhaustion;
(ix) accelerated aging disease or progeroid syndrome including, without restriction, Wemer syndrome, Bloom syndrome, De Barsy syndrome, Rothmund¨Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann¨Rautenstrauch syndrome, Hutchinson¨Gilford progeria syndrome (progeria), Ataxia telangiectasia-like disorder 2, XFE progeroid syndrome, Muscular dystrophy, Muscular Dystrophy (Becker's, Duchenne, Limb-Girdle), Yamamoto's Muscular Dystrophy, Mandibuloacral dysplasia, Dilated cardiomyopathy, GAPO syndrome, Cutis laxia, Ehlers-Danlos syndrom, Lenz-Majewski hyperostatic dwarfism, SHORT syndrome, Progressive extemal opthalmoplegia, Nester-Guillermo progeria syndrome, MDPL syndrome, Dyskeratosis congenital, Down syndrome;
(x) disease or disorder of aging (incidence/severity increases with increased age/senescence) and/or unwanted/undesirable aspect(s) of aging and/or a disease/disorder associated with elevated reactive oxygen species including age-associated decline, aging frailty, frailty syndrome, sarcopenia, muscle weakness, osteoporosis, cognitive decline, cognitive defecit, mild cognitive impairment, degenerative diseases, neurodegenerative diseases, motor-associated neurodegenerative diseases, motor neuron disease, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, progressive supranuclear palsy, pseudobulbar palsy, hereditary spastic paraplegia, Parkinson's disease, Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), essential tremor, resting tremor, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, frontotemporal dementia, chronic traumatic encephalopathy, memory loss, aged cognition, age/aging related cognitive decline/impairment, Batten disease, polyglutamine diseases, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, heart failure with preserved ejection fraction, idiopathic pulmonary fibrosis, fibrotic disease, pulmonary disease, coronary artery disease, hypercholesterolemia, obesity, liver disease, fatty liver disease, lysosomal storage disease, amyloidosis, systemic sclerosis, kidney disease, hepatic cirrhosis, immunosenscence, clonal hematopoiesis, chronic obstructive pulmonary disease (COPD), hypertension, hypercholesterolemia, age-related thymic atrophy, arthritis, osteoarthritis, arthritis (Osteo-and Rheumatoid), Juvenile Rheumatoid Arthritis (JRA), Degenerative Disc Disease, Tendinopathy, Androgenetic Alopecia, male-pattem baldness, Idiopathic Pulmonary Fibrosis, systemic sclerosis, Chronic Obstructive Pulmonary Disease, Psoriasis, age-related loss of cardiac/pulmonary/cognitive/vision function, diabetes, type 2 diabetes, andropause, glaucoma, retinal degeneration, sarcopenia, cachexia, age-related cachexia and/or sarcopenia, age-related macular degeneration (AMD, early/intermediate/late), neovascular/wet AMD, dry AMD, Geographic atrophy (GA), wet and dry AMD in the same eye(s), Stargardt's macular degeneration, Best vitelliform macular dystrophy, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, age/aging-related eye disease, ophthalmological disease/disorder, ocular disease, vision loss, progressive vision impairment, myopia (short-sightedness), degenerative myopia, hyperopia (far-sightedness), accommodative dysfunction, glaucoma, cataract formation, retinal degeneration, progressive retinal degeneration, retinitis pigmentosa, leber hereditary optic neuropathy, Fuchs spot, Best's disease, Sorsby's fundus dystrophy, hearing loss (e.g. age-related), presbycusis, tinnitus, naive T cell shortage, movement disability, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), immunosenescence, respiratory/urinary tract infection (RTI/UTI) especially in older/aged/elderly subjects, cancer;
(xi) aging and/or one or more signs of aging, wherein one or more of these compounds slow/delay/reduce/treat/prevent/stop/reverse aging, and/or extend lifespan and/or healthspan, and/or treat or delay the onset of geriatric aging of the human/animal body, tissue(s), or organ(s), and/or treat or delay the onset of an age-associated phenotype in a cell(s)/organism(s), and/or prolong fertility e.g. female fertility, delay menopause;
(xii) skin aging and/or damage (including sun damage) and/or scalp and/or hair aging and/or hair greying and/or hair loss;
(xiii) insomnia, fatal insomnia, sleep onset latency, delayed sleep phase disorder, exploding head syndrome, parasomnia, sleep-maintenance insomnia, sleep disorder, too much/inappropriate/undesired signals/activity/electrical activity in the nervous system, hyperactivity, hypersensitivity, Premature ejaculation, hyperreflexia, Autonomic dysreflexia (AD), Flyperventilation syndrome, brain hyperactivity, overly sensitive sensory system, pathological crying and/or laughing, Pseudobulbar affect (PBA, emotional lability), photophobia, phonophobia, temperature-sensitive, pressure-sensitive, brain hyperexcitability, overstimulation, intrusive thought(s), Perseveration, sensory overload, disorganized thinking, fantasy prone personality, malapdative daydreaming, dissociation, hyperkinetic disorder, agitation, Psychomotor agitation, restlessness, difficulty controlling behaviour, disruptive behaviour disorder, Emotional and behavioral disorder, pervasive developmental disorder, Overactive disorder associated with mental retardation and stereotyped movements, attention-deficit disorder, Attention Deficit Hyperactivity Disorder (ADHD), adult attention-deficit hyperactivity disorder, severe behavioral problem(s) in children (e.g., to illustrate and not restrict, combativeness and/or explosive hyperexcitable behavior {out of proportion to immediate provocation[s]}, hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of one or more of: impulsivity, difficulty sustaining attention, aggressivity, mood lability, poor frustration tolerance), Premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), impulsiveness, impulsivity, impulse control disorder, lack of self-control, hysteria, histrionic personality disorder, attention difficulty, inattention, poor attention control, anxiety, paranoid anxiety, Paranoid personality disorder, distress, dysphoria, Adjustment disorder, separation anxiety, anxiety disorder, depressive anxiety, agitated depression, treatment-resistant depression, Generalized anxiety disorder, social anxiety disorder, stranger anxiety, separation anxiety (e.g. in dogs left at home), separation anxiety disorder, Mixed anxiety-depressive disorder, depression (all forms, all severities), restlessness/apprehension/anxiety before surgery.
hypochondria, panic disorder, panic attack, emotional outburst, emotional instability, Intermittent explosive disorder, unreasonable/unwarranted anger/aggression, hyper-aggression, hostility, rage, poor temper control, self-hatred, poor attentional control, worry, irritability, neuroses, somatization disorder, somatic symptom disorder, pain disorder, psychological pain, psychogenic pain, psychogenic facial pain, Atypical odontalgia (AO), burning mouth syndrome, throbbing, toothache/pulpitis/dental pain, chronic lower back pain, negative emotion, persistent/enduring negative emotion, body dysmorphic disorder, factitious disorder, illness anxiety disorder, unwarrented fight-or-flight response, stress, emotional stress, emotional dysregulation, distress, psychological stress, acute stress, chronic stress, acute stress reaction, combat stress reaction, traumatic grief, grief, grief after death of loved one, Prolonged grief disorder (PGD), heartbreak, guilt, shame, remorse, emotional pain, Algopsychalia, psychalgia, suffering, emotional trauma, psychological trauma, broken heart, Post Traumatic Stress Disorder (PTSD), Complex post-traumatic stress disorder (C-PTSD), hypervigilance, sympathetic hyperactivity, inability or impaired ability to relax, flashbacks, dysphoric hyperarousal, agoraphobia, insomnia, fatal insomnia, mood disorder, irrational/unwarrented fear/terror, phobia, social phobia, Cancerophobia, thunderstorm/firework phobia, hypersexuality, hypersexual disorder, depression, clinical depression, unipolar depression, bipolar disorder, Bipolar I, Bipolar II, Bipolar disorder not otherwise specified (Bipolar NOS), cyclothymia, cyclothymic disorder, mixed affective state, atypical depression, melancholic depression, postpartum depression, double depression, seasonal affective disorder, mania, manic episode, hypomania, increase in energy of psychomotor activity, delirium, excited delirium, major depressive disorder, minor depressive disorder, recurrent brief depression, Depressive Disorder Not Otherwise Specified (DD-NOS), major depressive episode, persistent depressive disorder (PDD), dysthymia, dysthymic disorder, absence of euthymia, manic thoughts, racing thoughts, thought disorder, disordered thinking, reduced ability to plan and execute tasks, paranoia, hallucination (including, without limitation, visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrioceptive, nociceptive, thermoceptive, chronoceptive), Charles Bonnet syndrome, delusion, persecutory delusion, hearing voices, homicidal/criminal ideation/tendency/thoughts, suicidal ideation/tendancy/thoughts, self-injury, non-suicidal self-injury, violence, attacking others, negative mood swing, personality disorder, Borderline personality disorder, Narcissistic personality disorder, malignant narcissism, dissociative disorder, dissociative identity disorder (DID), Psychosis, acute psychosis, chronic psychosis, psychosis spectrum disorder, manifestations of psychotic disorders, behavioral complications of mental retardation, stimulant psychosis, psychotic depression, hallucinogen persisting perception disorder, Psychoactive substance-related disorder, amphetamine-induced psychosis, brief psychotic disorder, Brief reactive psychosis, Menstrual psychosis, postpartum psychosis, Psychotic disorder, Psychopathy, chronic hallucinatory psychosis, manifestation(s) of psychotic disorder, neurotic/reactive/endogenous/involutional/psychotic depression/depressive disorder (optionally accompanied by anxiety or agitation), depressive neurosis, delusional depression, psychotic aggression, psychiatric symptoms of dementia, AIDS delirium, Supersensitivity psychosis, Tardive psychosis, Tardive dysmentia, Depersonalization disorder, out-of-body experience, Sociopathy, Schizophrenia, Paranoid schizophrenia, disorganized-type schizophrenia, simple-type schizophrenia, pseudoneurotic schizophrenia, prodromal schizophrenia, schizoaffective disorder, bipolar type schizoaffective disorder, depressive type schizoaffective disorder, schizoaffective psychosis, Schizotypal personality disorder, schizophreniform disorder, Delusional parasitosis, formication, paresthesias, Acroparesthesia, tinnitus, delusional disorder, delusional jealousy, inappropriate behaviour, behavioural disorder, antisocial personality disorder, Oppositional defiant disorder (ODD), conduct disorder (CD), Disruptive mood dysregulation disorder (DMDD), sadistic personality disorder, poor inhibitory control, kleptomania, Pyromania, trichotillomania, dermatillomania, pathological/problem gambling, dyskinesia, tardive dyskinesia, paroxysmal dyskinesia, Paroxysmal kinesigenic dyskinesia, Paroxysmal nonkinesigenic dyskinesia, Paroxysmal exercise-induced dystonia, Hemiballismus, tic disorder, tremor, clonus, Tourette's syndrome, coprolalia, copropraxia, Echophenomena, Echopraxia, Echolalia, Palilalia, stuttering/stammering, stereotypy, punding, Self-stimulatory behaviour (stimming), Stereotypic movement disorder (SMD), synesthesia, obsession, Obsessive¨compulsive disorder (OCD), obsessive¨compulsive personality disorder, anankastic personality disorder, relationship obsessive¨compulsive disorder (ROCD), Scrupulosity, Primarily obsessional obsessive compulsive disorder, sexual obsession, Akathisia (including, without limitation, chronic, acute, Pseudoakathisia, Tardive akathisia, withdrawal or "rebound"
akathisia), Restless legs syndrome, motor restlessness, periodic limb movement disorder (PLMD), periodic limb movements in sleep (PLMS), Sydenham's chorea, chorea, dystonia, Hypnic jerk, twitching, spasms, Tetanus, tetanus muscle spasms, tetanized state, Myoclonus, myoclonic seizure, Action myoclonus, Palatal myoclonus, Middle ear myoclonus, Spinal myoclonus, Stimulus-sensitive myoclonus, Sleep myoclonus, Cortical reflex myoclonus, Essential myoclonus, myoclonic epilepsy, Juvenile myoclonic epilepsy, Progressive myoclonus epilepsy (PME, including, without limitation, Dentatorubral-pallidoluysian atrophy, Unverricht-Lundborg disease, MERRF syndrome, Lafora disease), Reticular reflex myoclonus, Myoclonic epilepsy, diaphragmatic flutter, automatism, status epilepticus, Epilepsia partialis continua, Complex partial status epilepticus, epilepsy, epileptic seizure, simple partial seizure, complex partial seizure, generalized epilepsy, generalized seizure (including, without limitation, tonic-clonic, tonic, clonic, myoclonic, absence (including typical absence and atypical absence), atonic seizure), focal epilepsy, focal seizure, focal/partial seizure (including, without limitation, Simple partial seizure and Complex partial seizure), focal aware seizure, focal impaired awareness seizure, generalised epilepsy, temporal lobe epilepsy (including, without restriction, mesial temporal lobe epilepsy {MTLE} and lateral temporal lobe epilepsy {LTLE}), Frontal lobe epilepsy, Rolandic epilepsy, Noctumal epilepsy, Noctumal frontal lobe epilepsy, Autosomal dominant noctumal frontal lobe epilepsy (ADNFLE), Generalized epilepsy with febrile seizures plus (GEFS+), Panayiotopoulos syndrome, epileptic fit, reflex epilepsy, reflex seizure, absence seizure (including, without limitation, childhood absence epilepsy, epilepsy with myoclonic absences, juvenile absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome {eyelid myoclonia with absences}, genetic generalised epilepsy with phantom absences), complex partial seizure, atonic seizure, generalized tonic-clonic seizure, tonic¨clonic seizure, extrinsic stimulus epilepsy, intrinsic stimulus epilepsy, photosensitive epilepsy, musicogenic epilepsy, thinking epilepsy, eating epilepsy, seizure(s), Febrile seizure, nerve agent induced seizure, Dravet syndrome (sometimes modest hyperthermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals), acute symptomatic seizure, seizure-related disorder, drug related seizure, paroxysmal depolarizing shift, Ohtahara syndrome, Epilepsy in females with mental retardation, Rasmussen's encephalitis, Epilepsy syndrome, benign rolandic epilepsy, childhood absence epilepsy, absence epilepsy, juvenile myoclonic epilepsy, epileptic encephalopathies, Lennox¨Gastaut syndrome, West syndrome (Epileptic spasms), Doose syndrome (Myoclonic astatic epilepsy, MAE), Lennox-Gestaut syndrome, pseudo-Lennox Gastaut syndrome (atypical benign partial epilepsy), Benign familial neonatal epilepsy, Benign occipital epilepsy of childhood, familial neonatal convulsions, Febrile infection-related epilepsy syndrome, interictal dysphoric disorder, euphoria sclerotic, psychogenic non-epileptic seizure, non-epileptic seizure, gelastic seizure, convulsion(s), migraine, status migrainosus, tension headache, headache, Hypnic headache, hiccups, intractable hiccups, thumps in equines, Postural orthostatic tachycardia syndrome (POTS), Pheochromocytoma, agony, pain, chronic pain, acute pain, pain due to disease/injury, neuropathic pain, fibromyalgia, postherpetic neuralgia, phantom pain, referred pain, back pain, lower back pain, pelvic pain, cancer associated pain, chemotherapy associated pain, Diabetic neuropathy, small fiber peripheral neuropathy, Mononeuritis multiplex, Wartenberg's migratory sensory neuropathy, Breakthrough pain, idiopathic pain, polyneuropathy, Neuritis, Mononeuropathy, Polyradiculoneuropathy, Radial neuropathy, neuropathy, visceral pain, Buming feet syndrome, Tarsal tunnel syndrome, Carpal tunnel syndrome, Guyon's canal syndrome, Cubital Tunnel Syndrome, Repetitive strain injury, Sciatica, Neurofibromatosis, Ulnar nerve entrapment, Erythromelalgia, Paroxysmal extreme pain disorder, Proctalgia fugax, dysesthesia, scalp dysesthesia, dysesthetic burning, hyperesthesia, hyperalgesia, Opioid-induced hyperalgesia, hyperpathia, allodynia, pain response from stimuli which do not normally provoke pain, Complex regional pain syndrome (said to be most painful condition known to man), Radiculopathy, neuralgia (including, without restriction, intercostal neuralgia, trigeminal neuralgia, atypical trigeminal neuralgia, glossopharyngeal neuralgia, occipital neuralgia, postherpetic neuralgia), ciguatera poisoning, irritable bowel syndrome (IBS), interstitial cystitis (IC), temporomandibular joint disorder, acute intermittent porphyria, Porphyria, Acute porphyria (including, without limitation, acute intermittent porphyria {All)), variegate porphyria {VP}, aminolevulinic acid dehydratase deficiency porphyria {ALAD}, hereditary coproporphyria {HCP}, drug induced), Chronic porphyria (including, without limitation, X-linked dominant protoporphyria {XLDP13}, congenital erythropoietic porphyria {CEP}, porphyria cutanea tarda {PCT}, and erythropoietic protoporphyria {EPP}), cutaneous porphyria, Porphyria cutanea tarda, allergy, allergic reaction, anaphylaxis, anaphylactic shock, hives, asthma, allergic rhinitis, rhinitis, urticaria, contact dermatitis, cough, sore throat, esophageal reflux disease, heartburn, chest pain, Esophageal motility disorder, Nutcracker esophagus, diseases involving gastrointestinal motility, Peptic ulcer disease, esophageal spasm, angina, itchiness, Pruritus, severe pruritus, Prurigo, Pruritic skin condition, chronic itch, eczema, pruritus in eczema, neuropathic itch, neurogenic itch, itchiness due to atopic dermatitis and/or lichen simplex chronicus, peripheral sensitization, central sensitization, sensory perception of absent stimuli, too much sensory stimulation, sensory stimulation brings discomfort, Neuromyotonia, Peripheral nerve hyperexcitability, Morvan's syndrome, Benign fasciculation syndrome, Cramp fasciculation syndrome, hyperhidrosis, undifferentiated somatoform disorder, somatoform disorder, somatic symptom disorder, conversion disorder, functional neurological symptom disorder, severe nausea and/or vomiting, severe nausea/emesis, Chemotherapy-induced peripheral neuropathy, chemotherapy-induced nausea and vomiting (CINV), radiation therapy-induced nausea and vomiting (RINV), postnarcotic nausea, hyperemesis gravidarum, morning sickness, Cyclic vomiting syndrome, retching/dry heaving, Urinary incontinence, enuresis, nocturnal enuresis, tail chasing, reduce urine spraying/marking behavior, benzodiazepine withdrawal syndrome, barbituate withdrawal syndrome, Neuroleptic discontinuation syndrome, drug withdrawal discomfort/pain/symptoms, drug use disorder, alcohol use disorder, opoid use disorder, amphetamine use disorder, cocaine use disorder, alcohol withdrawal syndrome/symptoms, delirium tremens, opoid withdrawal sydrome/symptoms, drug craving, drug addiction, drug dependence, polysubstance dependence, drug overdose, smoking, tobacco (nicotine) addition, tobacco (nicotine) withdrawal symptoms, alcoholism, addiction, opoid addiction, cocaine/crack addiction, addictive behaviour, addictive personality, behavioural addiction, internet/computer/computer game/social media/media addiction, exercise addiction, compulsive behaviour (e.g. {non-limiting}
checking, counting, washing, repeating), anti-social behaviour, criminality, sexual compulsion, impulsive sexual behaviour, compulsive buying, gambling addiction, sex related addiction, sexual urge, hunger, eating desire/compulsion, eating disorder, polyphagia, overeating, binge eating disorder, compulsive overeating, insatiable/excessive appetite, bulimia nervosa, anorexia nervosa, substance abuse, substance-induced delirium, substance-induced psychosis, substance-induced mood disorder, drug overdose, vertigo, motion sickness, seasickness, mental/nervous breakdown, Autism spectrum disorder, neurological disorder, cognitive disorder, mental disorder, mental health disorder, mental health condition involving impaired or altered neural plasticity, mood disorder, mental disorder disclosed in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or a later edition, a mental/behavioural disorder disclosed by the International Classification of Diseases (ICD) in ICD-10 Chapter V: Mental and behavioural disorders (World Health Organisation, WHO); or (xiv) diseases or disorders or conditions or pathologies or unwanted/undesirable effects/actions/behaviour treatable/ameliorated/prevented/combated, in totality or in part (e.g.
along with surgery), by anaesthesia, pre-anaesthesia, post-anaesthesia, hypoesthesia, hypoactivity, sedation, coma, tranquilization, behavioural submission, muscle relaxation, hibernation, artificial hibernation, torpor, synthetic torpor, suspended animation (e.g. used during spaceflight because e.g. reduces ionizing radiation damage to subject);
(xv) hyperproliferative/hyperplasia disorder, non-cancerous proliferative disorder, hyperproliferative autoimmune disorder, hyperplasia, epidermal hyperplasia, dysplasia (e.g.
epithelial dysplasia), nodule(s), wart(s), papilloma(s), squamous cell papilloma, genital wart(s), condyloma(s), condyloma acuminatum, cyst(s), polyp(s) {including, without restriction, digestive, colorectal, endometrial, cervical, nasal, laryngeal, inflammatory fibroid polyp[s])}, inherited/hereditary (including, without restriction, Familial adenomatous polyposis, Peutz¨Jeghers syndrome, Turcot syndrome, Juvenile polyposis syndrome, Cowden disease, Bannayan¨Riley¨Ruvalcaba syndrome {Bannayan-Zonana syndrome}, Gardner's syndrome) and non-inherited (non-restrictive e.g. Cronkhite¨Canada syndrome) polyposis syndrome, benign tumour, adenoma, organ enlargement by hyperplasia, Cushing's disease (enlarged adrenal cortex by hyperplasia), congenital adrenal hyperplasia, hyperplasia of breast, atypical ductal hyperplasia, intraductal papillomatosis, fibroadenomas, fibrocystic changes, hemihyperplasia, focal epithelial hyperplasia, sebaceous hyperplasia, sebaceous adenoma, intimal hyperplasia, unwanted/undesirable smooth muscle cell proliferation, smooth muscle cell hyperplasia, intimal smooth muscle cell hyperplasia, neointimal hyperplasia, proliferative vascular disorders, stenosis, stenosis because of cellular proliferation, vaginal stenosis, stenosis in a blood vessel, lessoned patency of a blood vessel, stenosis in a blood vessel because of cellular proliferation, vascular occlusion, restenosis, restenosis in a blood vessel that has been implanted with a stent, in-stent restenosis, post-angioplasty restenosis, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g.
diabetic retinopathy and/or other retinopathy[y/ies]), cardiac hyperplasia, fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, fibromatosis, neurofibromatosis, renal interstitial fibrosis, Cowden syndrome, hamartoma(s), choristoma(s), hemangioma(s), lymphangioma(s), rhabdomyoma(s), lymphangiomatosis, cystic hygroma, trichilemmoma, sarcoidosis, neurosarcoidosis, aggressive fibromatosis, desmoid tumour(s), unwanted/undesirable skin cell proliferation, hyperproliferative skin disorder, psoriasis (including, without restriction, plaque, guttate, inverse, pustular, napkin, seborrheic-like, nail, scalp and erythrodermic psoriasis), psoriatic arthritis, dactylitis, seborrhoeic dermatitis, dandruff, eczema, atopic dermatitis, rosacea, reactive arthritis (Reiter's syndrome), pityriasis rubra pilaris, hyperproliferative variants of disorders of keratinization (e.g., without restriction, actinic keratosis, senile keratosis, keratosis pilaris, seborrheic keratosis), scleroderma, benign prostatic hyperplasia, prostate enlargement, endometrial hyperplasia, atypical endometrial hyperplasia, benign endometrial hyperplasia, adenomyosis, atypical polypoid adenomyoma, endometriosis, endometriosis of ovary (endometrioma), endometrial polyp(s), polycystic ovary syndrome, ovarian cyst(s), cervical polyp(s), uterine fibroid(s), uterine hyperplasia;
(xvi) Tumour Associated Macrophages (TAMs) or any macrophage associated disease or disorder such as, without limitation, Macrophage Activation Syndrome (MAS), HIV, AIDS, HIV-associated neurocognitive disorders (HAND), AIDS dementia, HIV
peripheral neuropathy, HIV associated cancers, AIDS-defining cancers, non-AIDS
defining cancers, any disease in which the pathogen(s) hides from the immune system in macrophages including, without limitation, Mycobacterium tuberculosis (causes tuberculosis), Leishmania parasite (causes Leishmaniasis), Chikungunya virus (causes Chikungunya), Legionella pneumophila (causes Legionnaires' disease), adenoviruses, T whipplei (causes Whipple's Disease), Brucella spp. (causes brucellosis), Staphylococcus aureus, Ebola virus, Hepatitis B
virus, Hepatitis C virus, influenza virus strains, dengue virus and antibiotic resistant bacteria, any disease or condition in which activated macrophages are unwanted or undesirable;
(xvii) virus/pathogen neuroinvasion via macrophage(s), as used for non-limiting example by HIV, Heptatitis C virus and SARS coronavirus;
(xviii) neurocognitive or neurodegenerative diseases/disorders, for non-limiting example those caused by a virus;
(xix) virus/pathogen transmission from mother to fetus/baby via macrophage(s) as used for non-limiting example by zika (via Hofbauer cells) and HIV
(macrophages in breast milk);
(xx) acute or chronic or systemic inflammation or any inflammatory disease/disorder/syndrome or any autoinflammatory disease/disorder/syndrome or any autoimmune disease/disorder/syndrome;
(xxi) acute inflammation, chronic inflammation, systemic inflammation, inflammation because of infection or foreign bodies or injury or chemical or toxin or drug or stress or frostbite or burn or ionising radiation or surgery, inflammatory diseases/disorders/syndromes, Macrophage Activation Syndrome (MAS), autoinflammatory diseases/disorders/syndromes, age-related chronic inflammatory diseases ("inflammaging"), autoimmune diseases/disorders/syndromes, diseases/disorders of the innate immune system, sore throat, sore throat associated with cold or flu or fever, high-intensity exercise associated inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, osteoarthritis, inflammatory osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation associated depression, neuroinflammation, neuropathic pain, exercise-induced acute inflammation, atherosclerosis, allergy, hay fever, anaphylaxis, inflammatory myopathies, drug-induced inflammation, systemic inflammatory response syndrome, sepsis-related multiple organ dysfunction/multiple organ failure, microbial infection, acute brain/lung/hepatic/renal injuries, lung inflammation, acute lung injury (ARDS), acne vulgaris, celiac disease, celiac sprue, chronic prostatitis, colitis, autoimmune hemolytic anemia, diverticulitis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Mast Cell Activation Syndrome, mastocytosis, otitis, pelvic inflammatory disease (PID), endometritis, reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasitosis, eosinophilia, type III hypersensitivity, ischaemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, alcoholic hepatitis, chronic viral hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematous (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative disease, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, bronchiectasis, bronchopneumonia, obliterative bronchiolitis, appendicitis, acute appendicitis, bursitis, cystitis, dermatitis, encephalitis, HIV encephalitis, gingivitis, meningitis, infective meningitis, myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis¨associated interstitial lung disease and desquamative interstitial pneumonia, pneumonia, interstitial lung disease, Löfgren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, steatohepatitis, nonalcoholic steatohepatitis, silicosis, histiocytoses, Langerhans' cell histiocytosis, haemophagocytic lymphohistiocytosis, pulmonary langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudogout, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft versus host disease (GVHD), lymphadenopathy, rheumatoid arthritis (RA), osteoarthritis (OA), inflammatory osteoarthritis, lupus, multiple sclerosis (MS), myocarditis, uveitis, CNS disease(s), inflammation aspect to a CNS disease(s), hypothalamic inflammation, dementia, glaucoma, amyloid related/driven disease, lipid storage disease(s), fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, cirrhosis of the liver, alcoholic cirrhosis, nephropath(y/ies), lupus nephritis, immune nephritis, fibrotic disorder(s), cardiovascular disease, heart disease, atherosclerosis, vulnerable plaque, plaque formation, lipid containing macrophage related disease(s)/disorder(s)/malad(y/ies), macrophage foam cells, diabetes, type 1 diabetes, type 2 diabetes, insulin resistance, macrophage aspect to insulin resistance, obesity, obesity associated inflammation, macrophage accumulation/large numbers of macrophages in adipose tissue (e.g. associated with obesity), granuloma(s), granulomatous diseases, sarcoidosis (including, without limitation, Annular sarcoidosis, Erythrodermic sarcoidosis, Ichthyosiform sarcoidosis, Hypopigmented sarcoidosis, Löfgren syndrome, Lupus pernio, Morpheaform sarcoidosis, Mucosal sarcoidosis, Neurosarcoidosis, Papular sarcoid, Scar sarcoid, Subcutaneous sarcoidosis, Systemic sarcoidosis, Ulcerative sarcoidos), neurosarcoidosis, pulmonary sarcoidosis, interstitial lung disease, pulmonary fibrosis, pulmonary tuberculosis, immune reconstitution syndrome of HIV, Jarisch¨Herxheimer reaction, sepsis, Paget's disease of bone, osteolysis, monocytosis, histiocytosis, X-type histiocytoses, non-X histiocytoses, Langerhans cell histiocytosis, non-Langerhans-cell histiocytosis, malignant histiocytosis, malignant histiocytic disorders, histiocytomas, histiocytic lymphoma, hemophagocytic syndrome, hemophagocytic lymphohistiocytosis, lymphohistiocytosis, diffuse histiocytic sarcoma, Rosai¨Dorfman disease, gliosis, Bergmann gliosis, Chronic Obstructive Pulmonary Disease (COPD), chronic inflammatory lung disease, familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome ( TRAPS), Hyperimmunoglobulinemia D with recurrent fever syndrome (HIDS), cryopyrin associated periodic syndrome (CAPS), Blau syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), mevalonate kinase deficiency, pyogenic-arthritis-pyoderma gangrenosum and acne syndrome (PAPA), periodic fever aphthous stomatitis pharyngitis adenitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, Schnitzler's syndrome, Sweet's syndrome, NLRP12-associated autoinflammatory disorders, deficiency of interleukin-1 receptor antagonist (DIRA), pyoderma gangrenosum, cystic acne, aseptic arthritis, periodic Fever Associated with mevalonate kinase deficiency (hyperimmunoglobulin D Syndrome), Pyogenic Arthritis Pyoderma Gangrenosum Acne (PAPA) syndrome, Periodic Fever Aphthous Stomatitis, Pharyngitis and Adenopathy (PFAPA) syndrome, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Chronic Recurrent Multifocal Osteomyelitis (CRMO), Synovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome, Cryopyrin associated Periodic Syndrome (CAPS), Familial cold auto inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Familial cold urticarial, Neonatal onset multisystemic inflammatory disorder (NOMID), hereditary Periodic Fever Syndromes, Periodic Fever Syndromes, systemic autoinflammatory diseases, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Baló disease, Behcet's disease, benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Berger's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immune hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR) PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, peripheral neuropathy, perivenous encephalomyelitis, Pernicious anemia (PA), POEMS
syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)), idiopathic thrombocytopenia purpura, splenomegaly;
(xxii) Systemic inflammatory response syndrome, cytokine release syndrome, cytokine storm, immune reaction to a drug(s) or therapy(s), immune reaction to an immune activating drug(s) or agent(s) or treatment(s) or intervention(s), immune reaction to immunotherapy and/or immune-oncology and/or immunomodulatory drug(s) and/or treatment(s), adverse reaction to adoptive T-cell therapy(s), adverse reaction to a chimeric antigen receptor T-cell therapy(s) (CAR-T cell therapy(s)), adverse reaction to a immune checkpoint inhibitor(s), adverse reaction to monoclonal antibody drug(s), tumor lysis syndrome; or (xxiii) cancer and Graft Versus Host Disease (GVHD) in transplantation therapy in a cancer patient.
[17] A compound, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a composition containing at least one compound, of the following formula:
for use in the treatment, amelioration, prevention, reversal or combat of a disease or disorder or unwanted/undesirable physiological process or its consequences or an unwanted/undesirable aesthetic selected from:

(i) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. 18F-FDG PET);
(ii) cachexia, cancer driven cachexia, cancer fatigue, weight loss, weight loss for known or unknown reason, chronic wasting disease, atrophy, brown atrophy, frailty, frailty syndrome, aging frailty, geriatric syndrome, age-related cachexia and/or sarcopenia, weakness, wasting, anorexia nervosa, bulimia nervosa, eating disorder, amenorrhea, underweight, low body mass index (BMI, e.g. <18.5), low body fat percentage, body composition change, wasting syndrome, HIV wasting syndrome, malnutrition, clinical malnutrition, starvation, kwashiorkor syndrome, marasmus syndrome, malabsorption, malabsorption due to parasitic/bacterial infection (e.g. helminthiasis, Whipple's disease, small intestine bacterial overgrowth (SIBO), giardiasis etc.), anemia, refeeding syndrome, appetite loss, catabolysis, muscle atrophy, asthenia, muscle weakness (myasthenia), sarcopenia, osteoporosis, cachexia associated with HIV, AIDS, multiple sclerosis, rheumatoid arthritis, familial amyloid polyneuropathy, chronic kidney disease, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia, Addison's disease, mercury poisoning (acrodynia), chronic pancreatitis, untreated/severe type 1 diabetes mellitus, hormonal deficiency, tuberculosis, gastroenteritis, diarrhea, dysentery, any digestive disease or disorder, any gastrointestinal disease or disorder including functional gastrointestinal disorders, coeliac disease, tropical sprue, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, short bowl syndrome, congestive heart failure, constrictive pericarditis, bradycardia, chronic obstructive pulmonary disease (COPD), altitude sickness, hyperthyroidism (subclinical hyperthyroidism, Graves' disease, multinodular goiter, toxic adenoma, inflammation of the thyroid {thyroiditis}, pituitary adenoma), fatigue, chronic fatigue syndrome or any disease or disorder or pathology in which a body tissue(s) is undersupplied or underutilises (vs. its need) an energetic/chemical substrate(s), including O2;
(iii) cancer associated fever, which is especially associated with, but not limited to, non Hodgkin lymphoma (NHL), Hodgkin lymphoma, acute leukaemia, kidney cancer (renal cell cancer), liver cancer (hepatocellular carcinoma), bone cancer, adrenal gland tumours such as phaeochromocytomas, tumours in the hypothalamus, solid tumours;
(iv) disease or disorder or physiological process or condition that causes a higher than normal body temperature such as (without limitation) high environmental temperature, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, neutropenic sepsis, stroke, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, toxic serotonin syndrome, thyroid storm, heatstroke, surgery related, menopause ("hot flushes"), infection (non-limiting e.g. roseola, measles, enteroviral infections, parasitic, viral, fungal, Chlamydial, Rickettsial, bacterial, mycobacterial, systemic bacterial, intravascular, HIV associated, nosocomial), pyrogenic infection, thermoregulatory disorder(s), connective tissue disease(s), Kawasaki syndrome, drug overdose, drug or drug withdrawal induced hyperthermia, alcohol/drug withdrawal, idiosyncratic drug reaction, fever of known or unknown or uncertain origin (non-limiting e.g. infectious disease(s), inflammation, immunological disease(s), non-infectious inflammatory disease(s) {non-limiting eg. systemic rheumatic and autoimmune diseases, vasculitis, granulomatous diseases, autoinflammatory syndromes}, tissue destruction, reaction to incompatible blood product(s), metabolic disorder(s), inherited metabolic disorder(s), cancer, neoplasm, endogenous or exogenous pyrogen(s), injury, head injury);
(v) disease/disorder/injury/pathology/surgery treatable/ameliorated/prevented/combated/helped by conferring hypothermia in a subject for some medical or other purpose which can include slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, slowing physiological/pathological processes (reaction rates are temperature dependent) and so "buying time" to get the subject to treatment for their emergency (e.g.
trauma/septic shock or other medical emergency), slowing the progress of sepsis until a sufficient concentration of a working antibiotic(s) can be built up in the subject (furthermore hypothermia, by slowing sepsis progression, buys time to observe which antibiotic(s) can work, yielding time to try alternative further antibiotic option(s) if required), used soon after or just before clinical/legal death to preserve the subject's organs/tissues until the subject can be frozen/cryogenically frozen or the pathology that caused clinical/legal death (e.g. wound) can be fixed and the subject resuscitated, administered to a subject when a first responder (e.g.
ambulance crew) deems the subject dead or unlikely to survive the journey to a medical facility (e.g. hospital) wherein this administration helps to preserve the subject which is helpful if hospital staff subsequently assess that they can, or might be able to, save the subject, stabilizing surgical/trauma/Emergency Room (ER) patients, deep hypothermic circulatory arrest for surgery (DHCA, non-limiting applications of DHCA include repairs of the aortic arch, repairs to head and neck great vessels, repair of large cerebral aneurysms, repair of cerebral arteriovenous malformations, pulmonary thromboendarterectomy, resection of tumors that have invaded the vena cava, brain tumor resection {wherein the anti-cancer activity of a compound(s) of this invention juxtaposes well}), Emergency Preservation and Resuscitation (EPR), hypothermia for a surgical purpose, protective hypothermia during surgery and/or surgery complication, hypothermia to slow/reduce blood loss, hypothermia for neuro- and/or cardio- and/or organ/tissue and/or life protection in a subject that has trauma/brain trauma/polytrauma/surgery/stroke/ischemic stroke/hemorrhagic stroke/cardiac arrest/myocardial infarction/hypoxia/shock (including, without limitation, low volume, cardiogenic, obstructive, and distributive shock)/sepsis/septic shock/multiple organ dysfunction syndrome/systemic inflammatory response syndrome (SIRS)/organ failure/cytokine storm/anaphylactic shock/seizure/disseminated intravascular coagulation/blocked airway/croup/rhabdomyolysis/[head/facial/spinal/chest/abdominal/ballistic/knife injury/trauma], or some other medical emergency/condition/disorder/disease/injury/operation, hypothermia for cardiac and/or cardiovascular surgery and/or open heart surgery and/or brain surgery (neurosurgery) and/or surgery using total circulatory arrest and/or surgery using cardiopulmonary bypass, Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage/transport and/or transplant, thus increasing the time window for transplantation of organs to recipients;
compound(s) of this invention is administered to organ to be transplanted [by administration to donor and/or by administration to isolated organ] and/or to organ recipient, optionally during transplant operation), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, neonatal hypoxia-ischemia, birth asphyxia, hypoxic-ischemic encephalopathy (HIE), haemorrhage, hypovolemia, exsanguination, suspended animation, decompression sickness, bum injury(s) including skin burn, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or toumiquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (non-limiting e.g. meningitis), sepsis, septic shock, stroke, cerebrovascular disease, ischemic brain injury, ischemic stroke, traumatic injury, brain injury, spinal cord injury, cardiac arrest, heart failure, congestive heart failure, Dilated cardiomyopathy, valvular heart disease, pulmonary embolism, adrenal crisis, Addisonian crisis, hypertensive emergency, haemorrhagic (hypovolemic) shock, cardiogenic shock, neurogenic shock, hepatic encephalopathy, blood loss, ischemic brain/heart/kidney/intestinal injury, neuroprotection and/or cardioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject;
(vi) poisoning by a toxic amount of a compound(s) in a subject (non-limiting e.g.
carbon monoxide/methanol/heavy metal/ethylene glycol/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison(s), nerve agent, chemical weapon, bacterial toxin(s) (e.g. food poisoning, Salmonella poisoning), endotoxemia, eukaryote produced toxin(s) e.g. (non-limiting) brevetoxin, drug(s)/substance(s) overdose e.g. (non-limiting) heroin, ethanol, a prescription medication(s), an over the counter medication(s) such as aspirin, paracetamol etc.; hypothermia is protective to toxic insult);
(vii) hypermetabolism (optionally because of one or more of, without restriction, traumatic brain injury, injury to the body, infection, sepsis, burn, multiple trauma, fever, long-bone fracture, hyperthyroidism, prolonged steroid therapy, surgery, bone marrow transplant, recovery from anorexia/bulimia), heat intolerence, insomnia, fatal insomnia, nervousness, Luft's disease, non-thyroidal hypermetabolism, thyrotoxicosis, hyperthyroidism, overactive thyroid, subclinical hyperthyroidism, too much thyroid hormone(s) in the subject, too much triiodothyronine (T3) and/or thyroxine (T4) in the subject, hyperthyroxinemia (including, without restriction, familial dysalbuminemic hyperthyroxinemia, familial euthyroid hyperthyroxinemia, thyroid hormone resistance syndrome), thyroid storm, hyperthyroidism caused by one or more of (without restriction) Graves' disease, thyroiditis, Hashimoto's thyroiditis, subacute thyroiditis, postpartum thyroiditis, lumps (nodules) on the thyroid, enlarged thyroid gland (goitre), simple goitre, multinodular goiter, toxic multinodular goiter, toxic adenoma, toxic thyroid adenoma, inflammation of the thyroid, hyperplasia of thyroid, metastatic thyroid cancer, thyroid tumour, thyroid cancer (including, without restriction, papillary carcinoma, follicular carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma), eating too much iodine, goitrogen ingestion, consumption of ground beef contaminated with thyroid tissue ("hamburger hyperthyroidism"), too much synthetic thyroid hormone in the subject, pituitary adenoma, drug induced, Amiodarone drug induced, struma ovarii, Jod-Basedow syndrome, nonautoimmune autosomal dominant hyperthyroidism;
(viii) low or less than desired metabolic/bioenergetic efficiency in a subject, or low or less than desired physical or mental performance (e.g. memory, IQ), or low or less than desired body weight, or fatigue/tiredness/weakness/exhaustion;

(ix) accelerated aging disease or progeroid syndrome including, without restriction, Werner syndrome, Bloom syndrome, De Barsy syndrome, Rothmund¨Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann¨Rautenstrauch syndrome, Hutchinson¨Gilford progeria syndrome (progeria), Ataxia telangiectasia-like disorder 2, XFE progeroid syndrome, Muscular dystrophy, Muscular Dystrophy (Becker's, Duchenne, Limb-Girdle), Yamamoto's Muscular Dystrophy, Mandibuloacral dysplasia, Dilated cardiomyopathy, GAPO syndrome, Cutis laxia, Ehlers-Danlos syndrom, Lenz-Majewski hyperostatic dwarfism, SHORT syndrome, Progressive external opthalmoplegia, Nester-Guillermo progeria syndrome, MDPL syndrome, Dyskeratosis congenital, Down syndrome;
(x) disease or disorder of aging (incidence/severity increases with increased age/senescence) and/or unwanted/undesirable aspect(s) of aging and/or a disease/disorder associated with elevated reactive oxygen species including age-associated decline, aging frailty, frailty syndrome, sarcopenia, muscle weakness, osteoporosis, cognitive decline, cognitive defecit, mild cognitive impairment, degenerative diseases, neurodegenerative diseases, motor-associated neurodegenerative diseases, motor neuron disease, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, progressive supranuclear palsy, pseudobulbar palsy, hereditary spastic paraplegia, Parkinson's disease, Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), essential tremor, resting tremor, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, frontotemporal dementia, chronic traumatic encephalopathy, memory loss, aged cognition, age/aging related cognitive decline/impairment, Batten disease, polyglutamine diseases, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, heart failure with preserved ejection fraction, idiopathic pulmonary fibrosis, fibrotic disease, pulmonary disease, coronary artery disease, hypercholesterolemia, obesity, liver disease, fatty liver disease, lysosomal storage disease, amyloidosis, systemic sclerosis, kidney disease, hepatic cirrhosis, immunosenscence, clonal hematopoiesis, chronic obstructive pulmonary disease (COPD), hypertension, hypercholesterolemia, age-related thymic atrophy, arthritis, osteoarthritis, arthritis (Osteo-and Rheumatoid), Juvenile Rheumatoid Arthritis (JRA), Degenerative Disc Disease, Tendinopathy, Androgenetic Alopecia, male-pattern baldness, Idiopathic Pulmonary Fibrosis, systemic sclerosis, Chronic Obstructive Pulmonary Disease, Psoriasis, age-related loss of cardiac/pulmonary/cognitive/vision function, diabetes, type 2 diabetes, andropause, glaucoma, retinal degeneration, sarcopenia, cachexia, age-related cachexia and/or sarcopenia, age-related macular degeneration (AMD, early/intermediate/late), neovascular/wet AMD, dry AMD, Geographic atrophy (GA), wet and dry AMD in the same eye(s), Stargardt's macular degeneration, Best vitelliform macular dystrophy, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, age/aging-related eye disease, ophthalmological disease/disorder, ocular disease, vision loss, progressive vision impairment, myopia (short-sightedness), degenerative myopia, hyperopia (far-sightedness), accommodative dysfunction, glaucoma, cataract formation, retinal degeneration, progressive retinal degeneration, retinitis pigmentosa, leber hereditary optic neuropathy, Fuchs spot, Best's disease, Sorsby's fundus dystrophy, hearing loss (e.g. age-related), presbycusis, tinnitus, naive T cell shortage, movement disability, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), immunosenescence, respiratory/urinary tract infection (RTI/UTI) especially in older/aged/elderly subjects, cancer;
(xi) aging and/or one or more signs of aging, wherein one or more of these compounds slow/delay/reduce/treat/prevent/stop/reverse aging, and/or extend lifespan and/or healthspan, and/or treat or delay the onset of geriatric aging of the human/animal body, tissue(s), or organ(s), and/or treat or delay the onset of an age-associated phenotype in a cell(s)/organism(s), and/or prolong fertility e.g. female fertility, delay menopause;
(xii) skin aging and/or damage (including sun damage) and/or scalp and/or hair aging and/or hair greying and/or hair loss;
(xiii) insomnia, fatal insomnia, sleep onset latency, delayed sleep phase disorder, exploding head syndrome, parasomnia, sleep-maintenance insomnia, sleep disorder, too much/inappropriate/undesired signals/activity/electrical activity in the nervous system, hyperactivity, hypersensitivity, Premature ejaculation, hyperreflexia, Autonomic dysreflexia (AD), Hyperventilation syndrome, brain hyperactivity, overly sensitive sensory system, pathological crying and/or laughing, Pseudobulbar affect (PBA, emotional lability), photophobia, phonophobia, temperature-sensitive, pressure-sensitive, brain hyperexcitability, overstimulation, intrusive thought(s), Perseveration, sensory overload, disorganized thinking, fantasy prone personality, malapdative daydreaming, dissociation, hyperkinetic disorder, agitation, Psychomotor agitation, restlessness, difficulty controlling behaviour, disruptive behaviour disorder, Emotional and behavioral disorder, pervasive developmental disorder, Overactive disorder associated with mental retardation and stereotyped movements, attention-deficit disorder, Attention Deficit Hyperactivity Disorder (ADHD), adult attention-deficit hyperactivity disorder, severe behavioral problem(s) in children (e.g., to illustrate and not restrict, combativeness and/or explosive hyperexcitable behavior {out of proportion to immediate provocation[s]}, hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of one or more of: impulsivity, difficulty sustaining attention, aggressivity, mood lability, poor frustration tolerance), Premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), impulsiveness, impulsivity, impulse control disorder, lack of self-control, hysteria, histrionic personality disorder, attention difficulty, inattention, poor attention control, anxiety, paranoid anxiety, Paranoid personality disorder, distress, dysphoria, Adjustment disorder, separation anxiety, anxiety disorder, depressive anxiety, agitated depression, treatment-resistant depression, Generalized anxiety disorder, social anxiety disorder, stranger anxiety, separation anxiety (e.g. in dogs left at home), separation anxiety disorder, Mixed anxiety-depressive disorder, depression (all forms, all severities), restlessness/apprehension/anxiety before surgery.
hypochondria, panic disorder, panic attack, emotional outburst, emotional instability, Intermittent explosive disorder, unreasonable/unwarranted anger/aggression, hyper-aggression, hostility, rage, poor temper control, self-hatred, poor attentional control, worry, irritability, neuroses, somatization disorder, somatic symptom disorder, pain disorder, psychological pain, psychogenic pain, psychogenic facial pain, Atypical odontalgia (AO), burning mouth syndrome, throbbing, toothache/pulpitis/dental pain, chronic lower back pain, negative emotion, persistent/enduring negative emotion, body dysmorphic disorder, factitious disorder, illness anxiety disorder, unwarrented fight-or-flight response, stress, emotional stress, emotional dysregulation, distress, psychological stress, acute stress, chronic stress, acute stress reaction, combat stress reaction, traumatic grief, grief, grief after death of loved one, Prolonged grief disorder (PGD), heartbreak, guilt, shame, remorse, emotional pain, Algopsychalia, psychalgia, suffering, emotional trauma, psychological trauma, broken heart, Post Traumatic Stress Disorder (PTSD), Complex post-traumatic stress disorder (C-PTSD), hypervigilance, sympathetic hyperactivity, inability or impaired ability to relax, flashbacks, dysphoric hyperarousal, agoraphobia, insomnia, fatal insomnia, mood disorder, irrational/unwarrented fear/terror, phobia, social phobia, Cancerophobia, thunderstorm/firework phobia, hypersexuality, hypersexual disorder, depression, clinical depression, unipolar depression, bipolar disorder, Bipolar I, Bipolar II, Bipolar disorder not otherwise specified (Bipolar NOS), cyclothymia, cyclothymic disorder, mixed affective state, atypical depression, melancholic depression, postpartum depression, double depression, seasonal affective disorder, mania, manic episode, hypomania, increase in energy of psychomotor activity, delirium, excited delirium, major depressive disorder, minor depressive disorder, recurrent brief depression, Depressive Disorder Not Otherwise Specified (DD-NOS), major depressive episode, persistent depressive disorder (PDD), dysthymia, dysthymic disorder, absence of euthymia, manic thoughts, racing thoughts, thought disorder, disordered thinking, reduced ability to plan and execute tasks, paranoia, hallucination (including, without limitation, visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrioceptive, nociceptive, thermoceptive, chronoceptive), Charles Bonnet syndrome, delusion, persecutory delusion, hearing voices, homicidal/criminal ideation/tendency/thoughts, suicidal ideation/tendancy/thoughts, self-injury, non-suicidal self-injury, violence, attacking others, negative mood swing, personality disorder, Borderline personality disorder, Narcissistic personality disorder, malignant narcissism, dissociative disorder, dissociative identity disorder (DID), Psychosis, acute psychosis, chronic psychosis, psychosis spectrum disorder, manifestations of psychotic disorders, behavioral complications of mental retardation, stimulant psychosis, psychotic depression, hallucinogen persisting perception disorder, Psychoactive substance-related disorder, amphetamine-induced psychosis, brief psychotic disorder, Brief reactive psychosis, Menstrual psychosis, postpartum psychosis, Psychotic disorder, Psychopathy, chronic hallucinatory psychosis, manifestation(s) of psychotic disorder, neurotic/reactive/endogenous/involutional/psychotic depression/depressive disorder (optionally accompanied by anxiety or agitation), depressive neurosis, delusional depression, psychotic aggression, psychiatric symptoms of dementia, AIDS delirium, Supersensitivity psychosis, Tardive psychosis, Tardive dysmentia, Depersonalization disorder, out-of-body experience, Sociopathy, Schizophrenia, Paranoid schizophrenia, disorganized-type schizophrenia, simple-type schizophrenia, pseudoneurotic schizophrenia, prodromal schizophrenia, schizoaffective disorder, bipolar type schizoaffective disorder, depressive type schizoaffective disorder, schizoaffective psychosis, Schizotypal personality disorder, schizophreniform disorder, Delusional parasitosis, formication, paresthesias, Acroparesthesia, tinnitus, delusional disorder, delusional jealousy, inappropriate behaviour, behavioural disorder, antisocial personality disorder, Oppositional defiant disorder (ODD), conduct disorder (CD), Disruptive mood dysregulation disorder (DMDD), sadistic personality disorder, poor inhibitory control, kleptomania, Pyromania, trichotillomania, dermatillomania, pathological/problem gambling, dyskinesia, tardive dyskinesia, paroxysmal dyskinesia, Paroxysmal kinesigenic dyskinesia, Paroxysmal nonkinesigenic dyskinesia, Paroxysmal exercise-induced dystonia, Hemiballismus, tic disorder, tremor, clonus, Tourette's syndrome, coprolalia, copropraxia, Echophenomena, Echopraxia, Echolalia, Palilalia, stuttering/stammering, stereotypy, punding, Self-stimulatory behaviour (stimming), Stereotypic movement disorder (SMD), synesthesia, obsession, Obsessive¨compulsive disorder (OCD), obsessive¨compulsive personality disorder, anankastic personality disorder, relationship obsessive¨compulsive disorder (ROCD), Scrupulosity, Primarily obsessional obsessive compulsive disorder, sexual obsession, Akathisia (including, without limitation, chronic, acute, Pseudoakathisia, Tardive akathisia, withdrawal or "rebound"
akathisia), Restless legs syndrome, motor restlessness, periodic limb movement disorder (PLMD), periodic limb movements in sleep (PLMS), Sydenham's chorea, chorea, dystonia, Hypnic jerk, twitching, spasms, Tetanus, tetanus muscle spasms, tetanized state, Myoclonus, myoclonic seizure, Action myoclonus, Palatal myoclonus, Middle ear myoclonus, Spinal myoclonus, Stimulus-sensitive myoclonus, Sleep myoclonus, Cortical reflex myoclonus, Essential myoclonus, myoclonic epilepsy, Juvenile myoclonic epilepsy, Progressive myoclonus epilepsy (PME, including, without limitation, Dentatorubral-pallidoluysian atrophy, Unverricht-Lundborg disease, MERRF syndrome, Lafora disease), Reticular reflex myoclonus, Myoclonic epilepsy, diaphragmatic flutter, automatism, status epilepticus, Epilepsia partialis continua, Complex partial status epilepticus, epilepsy, epileptic seizure, simple partial seizure, complex partial seizure, generalized epilepsy, generalized seizure (including, without limitation, tonic-clonic, tonic, clonic, myoclonic, absence (including typical absence and atypical absence), atonic seizure), focal epilepsy, focal seizure, focal/partial seizure (including, without limitation, Simple partial seizure and Complex partial seizure), focal aware seizure, focal impaired awareness seizure, generalised epilepsy, temporal lobe epilepsy (including, without restriction, mesial temporal lobe epilepsy {MTLE} and lateral temporal lobe epilepsy {LTLE}), Frontal lobe epilepsy, Rolandic epilepsy, Nocturnal epilepsy, Nocturnal frontal lobe epilepsy, Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Generalized epilepsy with febrile seizures plus (GEFS+), Panayiotopoulos syndrome, epileptic fit, reflex epilepsy, reflex seizure, absence seizure (including, without limitation, childhood absence epilepsy, epilepsy with myoclonic absences, juvenile absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome {eyelid myoclonia with absences}, genetic generalised epilepsy with phantom absences), complex partial seizure, atonic seizure, generalized tonic-clonic seizure, tonic¨clonic seizure, extrinsic stimulus epilepsy, intrinsic stimulus epilepsy, photosensitive epilepsy, musicogenic epilepsy, thinking epilepsy, eating epilepsy, seizure(s), Febrile seizure, nerve agent induced seizure, Dravet syndrome (sometimes modest hyperthermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals), acute symptomatic seizure, seizure-related disorder, drug related seizure, paroxysmal depolarizing shift, Ohtahara syndrome, Epilepsy in females with mental retardation, Rasmussen's encephalitis, Epilepsy syndrome, benign rolandic epilepsy, childhood absence epilepsy, absence epilepsy, juvenile myoclonic epilepsy, epileptic encephalopathies, Lennox¨Gastaut syndrome, West syndrome (Epileptic spasms), Doose syndrome (Myoclonic astatic epilepsy, MAE), Lennox-Gestaut syndrome, pseudo-Lennox Gastaut syndrome (atypical benign partial epilepsy), Benign familial neonatal epilepsy, Benign occipital epilepsy of childhood, familial neonatal convulsions, Febrile infection-related epilepsy syndrome, interictal dysphoric disorder, euphoria sclerotic, psychogenic non-epileptic seizure, non-epileptic seizure, gelastic seizure, convulsion(s), migraine, status migrainosus, tension headache, headache, Hypnic headache, hiccups, intractable hiccups, thumps in equines, Postural orthostatic tachycardia syndrome (POTS), Pheochromocytoma, agony, pain, chronic pain, acute pain, pain due to disease/injury, neuropathic pain, fibromyalgia, postherpetic neuralgia, phantom pain, referred pain, back pain, lower back pain, pelvic pain, cancer associated pain, chemotherapy associated pain, Diabetic neuropathy, small fiber peripheral neuropathy, Mononeuritis multiplex, Wartenberg's migratory sensory neuropathy, Breakthrough pain, idiopathic pain, polyneuropathy, Neuritis, Mononeuropathy, Polyradiculoneuropathy, Radial neuropathy, neuropathy, visceral pain, Burning feet syndrome, Tarsal tunnel syndrome, Carpal tunnel syndrome, Guyon's canal syndrome, Cubital Tunnel Syndrome, Repetitive strain injury, Sciatica, Neurofibromatosis, Ulnar nerve entrapment, Erythromelalgia, Paroxysmal extreme pain disorder, Proctalgia fugax, dysesthesia, scalp dysesthesia, dysesthetic burning, hyperesthesia, hyperalgesia, Opioid-induced hyperalgesia, hyperpathia, allodynia, pain response from stimuli which do not normally provoke pain, Complex regional pain syndrome (said to be most painful condition known to man), Radiculopathy, neuralgia (including, without restriction, intercostal neuralgia, trigeminal neuralgia, atypical trigeminal neuralgia, glossopharyngeal neuralgia, occipital neuralgia, postherpetic neuralgia), ciguatera poisoning, irritable bowel syndrome (IBS), interstitial cystitis (IC), temporomandibular joint disorder, acute intermittent porphyria, Porphyria, Acute porphyria (including, without limitation, acute intermittent porphyria {AIP}, variegate porphyria {VP}, aminolevulinic acid dehydratase deficiency porphyria {ALAD}, hereditary coproporphyria {HCP}, drug induced), Chronic porphyria (including, without limitation, X-linked dominant protoporphyria {XLDPP}, congenital erythropoietic porphyria {CEP}, porphyria cutanea tarda {PCT}, and erythropoietic protoporphyria {EPP}), cutaneous porphyria, Porphyria cutanea tarda, allergy, allergic reaction, anaphylaxis, anaphylactic shock, hives, asthma, allergic rhinitis, rhinitis, urticaria, contact dermatitis, cough, sore throat, esophageal reflux disease, heartburn, chest pain, Esophageal motility disorder, Nutcracker esophagus, diseases involving gastrointestinal motility, Peptic ulcer disease, esophageal spasm, angina, itchiness, Pruritus, severe pruritus, Prurigo, Pruritic skin condition, chronic itch, eczema, pruritus in eczema, neuropathic itch, neurogenic itch, itchiness due to atopic dermatitis and/or lichen simplex chronicus, peripheral sensitization, central sensitization, sensory perception of absent stimuli, too much sensory stimulation, sensory stimulation brings discomfort, Neuromyotonia. Peripheral nerve hyperexcitability, Morvan's syndrome, Benign fasciculation syndrome, Cramp fasciculation syndrome, hyperhidrosis, undifferentiated somatoform disorder, somatoform disorder, somatic symptom disorder, conversion disorder, functional neurological symptom disorder, severe nausea and/or vomiting, severe nausea/emesis, Chemotherapy-induced peripheral neuropathy, chemotherapy-induced nausea and vomiting (CINV), radiation therapy-induced nausea and vomiting (RINV), postnarcotic nausea, hyperemesis gravidarum, morning sickness, Cyclic vomiting syndrome, retching/dry heaving, Urinary incontinence, enuresis, nocturnal enuresis, tail chasing, reduce urine spraying/marking behavior, benzodiazepine withdrawal syndrome, barbituate withdrawal syndrome, Neuroleptic discontinuation syndrome, drug withdrawal discomfort/pain/symptoms, drug use disorder, alcohol use disorder, opoid use disorder, amphetamine use disorder, cocaine use disorder, alcohol withdrawal syndrome/symptoms, delirium tremens, opoid withdrawal sydrome/symptoms, drug craving, drug addiction, drug dependence, polysubstance dependence, drug overdose, smoking, tobacco (nicotine) addition, tobacco (nicotine) withdrawal symptoms, alcoholism, addiction, opoid addiction, cocaine/crack addiction, addictive behaviour, addictive personality, behavioural addiction, internet/computer/computer game/social media/media addiction, exercise addiction, compulsive behaviour (e.g. {non-limiting}
checking, counting, washing, repeating), anti-social behaviour, criminality, sexual compulsion, impulsive sexual behaviour, compulsive buying, gambling addiction, sex related addiction, sexual urge, hunger, eating desire/compulsion, eating disorder, polyphagia, overeating, binge eating disorder, compulsive overeating, insatiable/excessive appetite, bulimia nervosa, anorexia nervosa, substance abuse, substance-induced delirium, substance-induced psychosis, substance-induced mood disorder, drug overdose, vertigo, motion sickness, seasickness, mental/nervous breakdown, Autism spectrum disorder, neurological disorder, cognitive disorder, mental disorder, mental health disorder, mental health condition involving impaired or altered neural plasticity, mood disorder, mental disorder disclosed in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or a later edition, a mental/behavioural disorder disclosed by the International Classification of Diseases (ICD) in ICD-10 Chapter V: Mental and behavioural disorders (World Health Organisation, WHO); or (xiv) diseases or disorders or conditions or pathologies or unwanted/undesirable effects/actions/behaviour treatable/ameliorated/prevented/combated, in totality or in part (e.g.
along with surgery), by anaesthesia, pre-anaesthesia, post-anaesthesia, hypoesthesia, hypoactivity, sedation, coma, tranquilization, behavioural submission, muscle relaxation, hibernation, artificial hibernation, torpor, synthetic torpor, suspended animation (e.g. used during spaceflight because e.g. reduces ionizing radiation damage to subject);
(xv) hyperproliferative/hyperplasia disorder, non-cancerous proliferative disorder, hyperproliferative autoimmune disorder, hyperplasia, epidermal hyperplasia, dysplasia (e.g.
epithelial dysplasia), nodule(s), wart(s), papilloma(s), squamous cell papilloma, genital wart(s), condyloma(s), condyloma acuminatum, cyst(s), polyp(s) {including, without restriction, digestive, colorectal, endometrial, cervical, nasal, laryngeal, inflammatory fibroid polyp[s])}, inherited/hereditary (including, without restriction, Familial adenomatous polyposis, Peutz¨Jeghers syndrome, Turcot syndrome, Juvenile polyposis syndrome, Cowden disease, Bannayan¨Riley¨Ruvalcaba syndrome {Bannayan-Zonana syndrome}, Gardner's syndrome) and non-inherited (non-restrictive e.g. Cronkhite¨Canada syndrome) polyposis syndrome, benign tumour, adenoma, organ enlargement by hyperplasia, Cushing's disease (enlarged adrenal cortex by hyperplasia), congenital adrenal hyperplasia, hyperplasia of breast, atypical ductal hyperplasia, intraductal papillomatosis, fibroadenomas, fibrocystic changes, hemihyperplasia, focal epithelial hyperplasia, sebaceous hyperplasia, sebaceous adenoma, intimal hyperplasia, unwanted/undesirable smooth muscle cell proliferation, smooth muscle cell hyperplasia, intimal smooth muscle cell hyperplasia, neointimal hyperplasia, proliferative vascular disorders, stenosis, stenosis because of cellular proliferation, vaginal stenosis, stenosis in a blood vessel, lessoned patency of a blood vessel, stenosis in a blood vessel because of cellular proliferation, vascular occlusion, restenosis, restenosis in a blood vessel that has been implanted with a stent, in-stent restenosis, post-angioplasty restenosis, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g.
diabetic retinopathy and/or other retinopathy[y/ies]), cardiac hyperplasia, fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, fibromatosis, neurofibromatosis, renal interstitial fibrosis, Cowden syndrome, hamartoma(s), choristoma(s), hemangioma(s), lymphangioma(s), rhabdomyoma(s), lymphangiomatosis, cystic hygroma, trichilemmoma, sarcoidosis, neurosarcoidosis, aggressive fibromatosis, desmoid tumour(s), unwanted/undesirable skin cell proliferation, hyperproliferative skin disorder, psoriasis (including, without restriction, plaque, guttate, inverse, pustular, napkin, seborrheic-like, nail, scalp and erythrodermic psoriasis), psoriatic arthritis, dactylitis, seborrhoeic dermatitis, dandruff, eczema, atopic dermatitis, rosacea, reactive arthritis (Reiter's syndrome), pityriasis rubra pilaris, hyperproliferative variants of disorders of keratinization (e.g., without restriction, actinic keratosis, senile keratosis, keratosis pilaris, seborrheic keratosis), scleroderma, benign prostatic hyperplasia, prostate enlargement, endometrial hyperplasia, atypical endometrial hyperplasia, benign endometrial hyperplasia, adenomyosis, atypical polypoid adenomyoma, endometriosis, endometriosis of ovary (endometrioma), endometrial polyp(s), polycystic ovary syndrome, ovarian cyst(s), cervical polyp(s), uterine fibroid(s), uterine hyperplasia;
(xvi) Tumour Associated Macrophages (TAMs) or any macrophage associated disease or disorder such as, without limitation, Macrophage Activation Syndrome (MAS), HIV, AIDS, HIV-associated neurocognitive disorders (HAND), AIDS dementia, HIV
peripheral neuropathy, HIV associated cancers, AIDS-defining cancers, non-AIDS
defining cancers, any disease in which the pathogen(s) hides from the immune system in macrophages including, without limitation, Mycobacterium tuberculosis (causes tuberculosis), Leishmania parasite (causes Leishmaniasis), Chikungunya virus (causes Chikungunya), Legionella pneumophila (causes Legionnaires' disease), adenoviruses, T. whipplei (causes Whipple's Disease), Brucella spp. (causes brucellosis), Staphylococcus aureus, Ebola virus, Hepatitis B
virus, Hepatitis C virus, influenza virus strains, dengue virus and antibiotic resistant bacteria, any disease or condition in which activated macrophages are unwanted or undesirable;
(xvii) virus/pathogen neuroinvasion via macrophage(s), as used for non-limiting example by HIV, Heptatitis C virus and SARS coronavirus;
(xviii) neurocognitive or neurodegenerative diseases/disorders, for non-limiting example those caused by a virus;
(xix) virus/pathogen transmission from mother to fetus/baby via macrophage(s) as used for non-limiting example by zika (via Hofbauer cells) and HIV
(macrophages in breast milk);
(xx) acute or chronic or systemic inflammation or any inflammatory disease/disorder/syndrome or any autoinflammatory disease/disorder/syndrome or any autoimmune disease/disorder/syndrome;
(xxi) acute inflammation, chronic inflammation, systemic inflammation, inflammation because of infection or foreign bodies or injury or chemical or toxin or drug or stress or frostbite or burn or ionising radiation or surgery, inflammatory diseases/disorders/syndromes, Macrophage Activation Syndrome (MAS), autoinflammatory diseases/disorders/syndromes, age-related chronic inflammatory diseases ("inflammaging"), autoimmune diseases/disorders/syndromes, diseases/disorders of the innate immune system, sore throat, sore throat associated with cold or flu or fever, high-intensity exercise associated inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, osteoarthritis, inflammatory osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation associated depression, neuroinflammation, neuropathic pain, exercise-induced acute inflammation, atherosclerosis, allergy, hay fever, anaphylaxis, inflammatory myopathies, drug-induced inflammation, systemic inflammatory response syndrome, sepsis-related multiple organ dysfunction/multiple organ failure, microbial infection, acute brain/lung/hepatic/renal injuries, lung inflammation, acute lung injury (ARDS), acne vulgaris, celiac disease, celiac sprue, chronic prostatitis, colitis, autoimmune hemolytic anemia, diverticulitis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Mast Cell Activation Syndrome, mastocytosis, otitis, pelvic inflammatory disease (PID), endometritis, reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasitosis, eosinophilia, type III hypersensitivity, ischaemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, alcoholic hepatitis, chronic viral hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematous (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative disease, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, bronchiectasis, bronchopneumonia, obliterative bronchiolitis, appendicitis, acute appendicitis, bursitis, cystitis, dermatitis, encephalitis, HIV encephalitis, gingivitis, meningitis, infective meningitis, myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis¨associated interstitial lung disease and desquamative interstitial pneumonia, pneumonia, interstitial lung disease, Löfgren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, steatohepatitis, nonalcoholic steatohepatitis, silicosis, histiocytoses, Langerhans' cell histiocytosis, haemophagocytic lymphohistiocytosis, pulmonary langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudogout, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft versus host disease (GVHD), lymphadenopathy, rheumatoid arthritis (RA), osteoarthritis (OA), inflammatory osteoarthritis, lupus, multiple sclerosis (MS), myocarditis, uveitis, CNS disease(s), inflammation aspect to a CNS disease(s), hypothalamic inflammation, dementia, glaucoma, amyloid related/driven disease, lipid storage disease(s), fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, cirrhosis of the liver, alcoholic cirrhosis, nephropath(y/ies), lupus nephritis, immune nephritis, fibrotic disorder(s), cardiovascular disease, heart disease, atherosclerosis, vulnerable plaque, plaque formation, lipid containing macrophage related disease(s)/disorder(s)/malad(y/ies), macrophage foam cells, diabetes, type 1 diabetes, type 2 diabetes, insulin resistance, macrophage aspect to insulin resistance, obesity, obesity associated inflammation, macrophage accumulation/large numbers of macrophages in adipose tissue (e.g. associated with obesity), granuloma(s), granulomatous diseases, sarcoidosis (including, without limitation, Annular sarcoidosis, Erythrodermic sarcoidosis, Ichthyosiform sarcoidosis, Hypopigmented sarcoidosis, Löfgren syndrome, Lupus pernio, Morpheaform sarcoidosis, Mucosal sarcoidosis, Neurosarcoidosis, Papular sarcoid, Scar sarcoid, Subcutaneous sarcoidosis, Systemic sarcoidosis, Ulcerative sarcoidos), neurosarcoidosis, pulmonary sarcoidosis, interstitial lung disease, pulmonary fibrosis, pulmonary tuberculosis, immune reconstitution syndrome of HIV, Jarisch¨Herxheimer reaction, sepsis, Paget's disease of bone, osteolysis, monocytosis, histiocytosis, X-type histiocytoses, non-X histiocytoses, Langerhans cell histiocytosis, non-Langerhans-cell histiocytosis, malignant histiocytosis, malignant histiocytic disorders, histiocytomas, histiocytic lymphoma, hemophagocytic syndrome, hemophagocytic lymphohistiocytosis, lymphohistiocytosis, diffuse histiocytic sarcoma, Rosai¨Dorfman disease, gliosis, Bergmann gliosis, Chronic Obstructive Pulmonary Disease (COPD), chronic inflammatory lung disease, familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulinemia D with recurrent fever syndrome (HIDS), cryopyrin associated periodic syndrome (CAPS), Blau syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), mevalonate kinase deficiency, pyogenic-arthritis-pyoderma gangrenosum and acne syndrome (PAPA), periodic fever aphthous stomatitis pharyngitis adenitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, Schnitzler's syndrome, Sweet's syndrome, NLRP12-associated autoinflammatory disorders, deficiency of interleukin-1 receptor antagonist (DIRA), pyoderma gangrenosum, cystic acne, aseptic arthritis, periodic Fever Associated with mevalonate kinase deficiency (hyperimmunoglobulin D Syndrome), Pyogenic Arthritis Pyoderma Gangrenosum Acne (PAPA) syndrome, Periodic Fever Aphthous Stomatitis, Pharyngitis and Adenopathy (PFAPA) syndrome, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Chronic Recurrent Multifocal Osteomyelitis (CRMO), Synovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome, Cryopyrin associated Periodic Syndrome (CAPS), Familial cold auto inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Familial cold urticarial, Neonatal onset multisystemic inflammatory disorder (NOMID), hereditary Periodic Fever Syndromes, Periodic Fever Syndromes, systemic autoinflammatory diseases, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Baló disease, Behcet's disease, benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Berger's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immune hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type I diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gyavis, Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR) PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, peripheral neuropathy, perivenous encephalomyelitis, Pernicious anemia (PA), POEMS
syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)), idiopathic thrombocytopenia purpura, splenomegaly;
(xxii) Systemic inflammatory response syndrome, cytokine release syndrome, cytokine storm, immune reaction to a drug(s) or therapy(s), immune reaction to an immune activating drug(s) or agent(s) or treatment(s) or intervention(s), immune reaction to immunotherapy and/or immune-oncology and/or immunomodulatory drug(s) and/or treatment(s), adverse reaction to adoptive T-cell therapy(s), adverse reaction to a chimeric antigen receptor T-cell therapy(s) (CAR-T cell therapy(s)), adverse reaction to a immune checkpoint inhibitor(s), adverse reaction to monoclonal antibody drug(s), tumor lysis syndrome; or (xxiii) cancer and Graft Versus Host Disease (GVHD) in transplantation therapy in a cancer patient;
wherein L is selected from alkyl, substituted alkyl, deuterated alkyl, aminoalkyl, thioalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH2, SH, SiH3, PH2 etc.);
R1 is hydrogen, cyano, ¨SO2R8, ¨C(=O)R9, heteroaryl or thiazolyl;
R2 is (i) independently hydrogen, alkyl, benzyl, or substituted alkyl, or (ii) taken together with R3 forms a heterocyclo;

R3 is (i) independently alkyl, substituted alkyl, alkylthio, aminoalkyl, carbamyl, B B-aryl, B B-heterocyclo, B B-heteroaryl, or B B-cycloalkyl, or (ii) phenyl optionally substituted with C1-4alkyl, halogen, trifluoromethyl, OCF3, cyano, nitro, amino, hydroxy, or methoxy, or (iii) independently selected from C1-4alkyl, alkylthio, aminoalkyl, -B B-aryl, -B B-heterocyclo, B B-cycloalkyl, and -B B-hetaroaryl, optionally having one to three substituents selected from R3a; and/or having fused thereto a five or six membered carbocyclic ring, or (iv) taken together with R2 forms a heterocyclo optionally substituted with alkyl or substituted alkyl;
B B is a bond, C1-4alkylene, C2-4alkenylene, substituted C1-4alkylene, substituted C2-4alkenylene, substituted C1-4alkylene-C(O)NH-, -C(=O)NH-, -C1-alkylene-C(=O)NH-, -C(=O)NR19-, -C1-4alkylene-C()NR19-, or substituted C1-4alkylene-C(=0)NR19--, -(CHR14)m-(CR15R16)n- or -(CHR14)p-C(=0)NH-;
R3a at each occurrence is selected independently from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, keto, trifluoromethyl, -NR17R18, -SR17, -OR17, -SO2R17a, -SO2NR17R18, -NR17C(=D)R18, -CO2R17, -C(=O)R17, cyoloalkyl, aryl, heterocyolo, and heteroaryl, wherein when R3a is cycloalkyl, aryl, heterocyclo or heteroaryl, said cycloalkyl, aryl, heterocyolo and heteroaryl in turn is optionally substituted with alkyl or substituted alkyl;
Z is a heteroaryl, for example an optionally-substituted bicyclic heteroaryl;
or Z is triazolyl optionally substituted with one to two R7 substituents or imidazolyl optionally substituted with one to two R7 substituents and/or having fused thereto a benzene ring in turn optionally substituted with one to two R7 substituents; and R7 is alkyl, carbamyl, or substituted alkyl;
R4 at each occurrence is selected independently of each other R4 from the group consisting of halogen, trifluoromethyl, OCF3, alkyl, substituted alkyl, haloalkyl, nitro, cyano, haloalkoxy, OR25, SR25, NR25R26, NR25SO2R27, SO2R27, SO2NR25R26, CO2R26, C(=O)R26, C(=O)NR25R26, OC(=O)R25, -OC(=O)NR25R26, NR25C(=O)R26, NR25CO2R26, aryl, heteroaryl, heterocyclo and cycloalkyl;
R8 is C1-4alkyl or phenyl optionally substituted with alkyl, halogen, haloalkoxy, cyano, nitro, or trifluoromethyl;
R9 is -NR10R11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclo, or -CO2R12, alkyl or phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, C1-4alkoxy, haloalkoxy, C1-6alkyl, CO2alkyl, SO2alkyl, SO2NH2, amino, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(=O)alky, C(=O)alkyl, and/or C1-4alkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl; and/or a five or six membered heteroaryl or heterocylo in turn optionally substituted with keto or having a benzene ring fused thereto or a) C1-4alkyl optionally substituted with one to two of:
i) SR13, OR13, NR13a R13b, halogen, trifluoromethyl, CO2R13a, and C(=O)NR13a R13b;
ii) cycloalkyl optionally substituted with one to two of C(=O)H, C1-4acyl, alkenyl, carbamyl, and/or phenyl in turn optionally substituted with halogen;
iii) phenyl or napthyl optionally substituted with one to two of halogen, nitro, amino, alkyl, hydroxy, C1-4alkoxy, or having fused thereto a five or six membered heterocyclo;
iv) pyridinyl, thiophenyl, furanyl, tetrahydrofuranyl, or azepinyl, optionally substituted with alkyl or having fused thereto a five to six membered carbocyclic ring optionally substituted with keto or C1-4alkoxy;
b) 3 to 6 membered cycloalkyl optionally having up to four substituetits selected from alkyl, halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, phenyl in turn optionally substituted with halogen; or having an aryl fused thereto;
c) pheyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, C1-4alkoxy, haloalkoxy, C1-4alkyl, CO2alkyl, SO2alkyl, SO2NH2, amino NH(C1-4alkyl), N(C1-4alkyl)2, NHC(=O)alkyl, C(=3)alkyl, and/or C1-4alkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl;
and/or a five or six membejed heteroaryl or heterocyle in turn optionally substituted with keto or having a benzene ring fused thereto;
d) pyridinyl, thiazolyl, furanyl, thiophenyl, and pyrrolyl optionally substituted with one to two of halogen, alkyl, and phenyl in turn optionally substituted with halogen or trifluoromethyl;
R10 and R11 are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, heteroaryl or C1-4alkyl optionally substituted with one to two of ¨CO2alkyl, ¨C(=O)NH(aryl), NH(aryl), cycloalkyl, phenyloxy, phenyl in turn optionally substituted with C1-4alkyl, hydroxy, C1-4alkoxy, halogen, amino, nitro, tetrahydrofuranyl, and/or five or six membered heterocyclo, or having a five or six membered heterocyclo fused thereto; pyrrolidinyl optionally substituted with keto;
napthyl, anthracenyl, pyridinyl, thiophenyl, furanyl, imidazolyl, benzimidazolyl, or indolyl in turn optionally substituted with C1-4alkyl or C1-4alkoxy; or (ii) taken together form a heteroaryl or heterocyclo selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, tetrahydropyridinyl, and imidazoilidinyl, wherein said heterocyclo formed by R10 and R11 is optionally substituted with one to two of keto, CO2H, C1-4alkoxy, CO2alkyl, C1-4carbamyl, benzyl; phenyl in turn optionally substituted with alkyl, halogen, or C1-4 alkoxy; tetrahydropyridinyl in turn optionally substituted with keto and/or phenyl; alkyl optionally substituted with amino or NHR21wherein R21 is alkyl or phenyl optionally substituted with alkyl; and/or has a benzene ring fused thereto in turn optionally substituted with one to two of alkyl, C1-4alkoxy, CO2alkyl, and/or C1-4carbamyl;
R12 and R19 are hydrogen or alkyl;
R13 is hydrogen or alkyl;
R13a and R13b are selected from hydrogen, alkyl, and aryl;
R14, R15 and R16 at each occurrence are independently selected from hydrogen, alkyl, hydroxy, hydroxyC1-4alkyl, C1-4alkoxy, and phenyl, and/or one of R15 and one of R16 join together to form a 3 to 6 membered cycloalkyl;
R17 and R18 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, phenyl, or benzyl wherein the phenyl or benzyl is optionally substituted with alkyl, hydroxy, or hydroxyalkyl;
R17a is alkyl or substituted alkyl;
R25 and R26 are independently selected from hydrogen, alkyl, or substituted alkyl, or taken together form a heterocyclo or heteroaryl ring;
R27 is alkyl or substituted alkyl;
q is 0, 1, 2, or 3;
m and n are 0, 1 or 2; and p is 0, 1, 2, or 3.
[18] A compound for use according to Claim 17, wherein L is hydrogen.
[19] A compound for use according to Claim 17 or 18, wherein the S-enantiomer is in enantiomeric excess.
[20] A compound for use according to Claim 19, wherein the enantiomeric excess of S-enantiomer exceeds 70%.
[21] A compound for use according to Claim 17, having the structure or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
the enantiomeric excess (ee) of the S stereoisomer exceeds 70%.
1221 A compound, or a composition containing at least one compound, of the following formula:
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, for use in treating, ameliorating, preventing or combating cancer, or for use in treating a disease or disorder selected from (i) cancer, any cancer, neoplasia, metastasis, tumor formation/growth/implantation, tumorigenesis, solid tumor, blood borne tumor, cancer that is refractory or resistant to conventional chemotherapy, drug resistant tumor, multidrug resistant cancer;

(ii) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. 18F-FDG PET);
(iii) cachexia or cancer driven cachexia;
wherein R A1 and R A2 are each independently selected from the groups wherein R C and R D are each independently selected from hydrogen, deuterium, halogen and alkyl, and wherein R E is hydrogen, deuterium, or alkyl;
R B is selected from R B1, hydrogen and deuterium;
wherein R B1 is selected from phenyl, benzyl, pyridyl, pyrimidyl and pyrazinyl optionally substituted with one or more substituents R B2;
wherein each R B2 is independently selected from halogen, alkyl, alkoxy, nitro, amino, methoxy and polyhalogen alkyl;
or le is a phenylalkyl of the formula:
wherein R F and R G are hydrogen or alkyl, G is a carbon-carbon double bond or a carbon-carbon single bond, n is 0 or 1 and q is 0 or 1 provided that where q is 0, G
is a carbon-carbon double bond and where q is 1, G is a carbon-carbon single bond, or R B is a diphenylalkyl of the formula wherein R H is hydrogen or halogen, and p is 0, 1 or 2;
or R H is the group wherein R J and R K each independently represent 1-5 optional substituents on each ring, and wherein each R J and each R K, when present, is independently selected from halogen, alkyl, alkoxy, nitro, amino and polyhalogen alkyl.
[23] A compound or composition for use according to Claim 22, wherein R B is the group:

[24] A compound or composition for use according to Claim 22, wherein R B is the group:
wherein R L and R M are each independently selected from halogen, alkyl, alkoxy, nitro, amino and polyhalogen alkyl.
[25] A compound or composition for use according to Claim 24, wherein R L and R M are each independently selected from halogen.
[26] A compound or composition for use according to Claim 24 or 25, wherein R
L and R M
are the same.

[27] A compound or composition for use according to Claim 24, wherein R L and R M are each F.
[28] A compound or composition for use according to any one of Claims 22 to 27, wherein R A1 and R A2 are each independently selected from the group wherein R C and R D are each independently selected from hydrogen, deuterium, halogen and alkyl.
[29] A compound or composition for use according to Claim 28, wherein R A1 and R A2 are the same.
[30] A compound or composition for use according to Claim 28 or 29, wherein R
C is hydrogen.
[31] A compound or composition for use according to any one of Claims 28 to 30, wherein R D is hydrogen.
[32] A compound or composition for use according to Claim 22, wherein the compound is or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.

[33] A compound or composition for use according to Claim 22, wherein the compound is an isotopologue(s) of:
or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
[34] At least one compound and/or composition, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, that reduces F1F0 ATP hydrolysis in a subject, for use in treating, ameliorating, preventing or combating a disease or disorder selected from:
(i) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. 18F-FDG PET);
(ii) cachexia, cancer driven cachexia, cancer fatigue, weight loss, weight loss for known or unknown reason, chronic wasting disease, atrophy, brown atrophy, frailty, frailty syndrome, aging frailty, geriatric syndrome, age-related cachexia and/or sarcopenia, weakness, wasting, anorexia nervosa, bulimia nervosa, eating disorder, amenorrhea, underweight, low body mass index (BMI, e.g. <18.5), low body fat percentage, body composition change, wasting syndrome, HIV wasting syndrome, malnutrition, clinical malnutrition, starvation, kwashiorkor syndrome, marasmus syndrome, malabsorption, malabsorption due to parasitic/bacterial infection (e.g. helminthiasis, Whipple's disease, small intestine bacterial overgrowth (SIBO), giardiasis etc.), anemia, refeeding syndrome, appetite loss, catabolysis, muscle atrophy, asthenia, muscle weakness (myasthenia), sarcopenia, osteoporosis, cachexia associated with HIV, AIDS, multiple sclerosis, rheumatoid arthritis, familial amyloid polyneuropathy, chronic kidney disease, cystic fibrosis, multiple sclerosis, motor neuron disease, Parkinson's disease, dementia, Addison's disease, mercury poisoning (acrodynia), chronic pancreatitis, untreated/severe type 1 diabetes mellitus, hormonal deficiency, tuberculosis, gastroenteritis, diarrhea, dysentery, any digestive disease or disorder, any gastrointestinal disease or disorder including functional gastrointestinal disorders, coeliac disease, tropical sprue, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, short bowl syndrome, congestive heart failure, constrictive pericarditis, bradycardia, chronic obstructive pulmonary disease (COPD), altitude sickness, hyperthyroidism (subclinical hyperthyroidism, Graves' disease, multinodular goiter, toxic adenoma, inflammation of the thyroid {thyroiditis), pituitary adenoma), fatigue, chronic fatigue syndrome or any disease or disorder or pathology in which a body tissue(s) is undersupplied or underutilises (vs. its need) an energetic/chemical substrate(s), including O2;
(iii) cancer associated fever, which is especially associated with, but not limited to, non Hodgkin lymphoma (NHL), Hodgkin lymphoma, acute leukaemia, kidney cancer (renal cell cancer), liver cancer (hepatocellular carcinoma), bone cancer, adrenal gland tumours such as phaeochromocytomas, tumours in the hypothalamus, solid tumours;
(iv) disease or disorder or physiological process or condition that causes a higher than normal body temperature such as (without limitation) high environmental temperature, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, neutropenic sepsis, stroke, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, toxic serotonin syndrome, thyroid storm, heatstroke, surgery related, menopause ("hot flushes"), infection (non-limiting e.g. roseola, measles, enteroviral infections, parasitic, viral, fungal, Chlamydial, Rickettsial, bacterial, mycobacterial, systemic bacterial, intravascular, HIV associated, nosocomial), pyrogenic infection, thermoregulatory disorder(s), connective tissue disease(s), Kawasaki syndrome, drug overdose, drug or drug withdrawal induced hyperthermia, alcohol/drug withdrawal, idiosyncratic drug reaction, fever of known or unknown or uncertain origin (non-limiting e.g. infectious disease(s), inflammation, immunological disease(s), non-infectious inflammatory disease(s) {non-limiting eg. systemic rheumatic and autoimmune diseases, vasculitis, granulomatous diseases, autoinflammatory syndromes), tissue destruction, reaction to incompatible blood product(s), metabolic disorder(s), inherited metabolic disorder(s), cancer, neoplasm, endogenous or exogenous pyrogen(s), injury, head injury);
(v) disease/disorder/injury/pathology/surgery treatable/ameliorated/prevented/combated/helped by conferring hypothermia in a subject for some medical or other purpose which can include slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, slowing physiological/pathological processes (reaction rates are temperature dependent) and so "buying time" to get the subject to treatment for their emergency (e.g.
trauma/septic shock or other medical emergency), slowing the progress of sepsis until a sufficient concentration of a working antibiotic(s) can be built up in the subject (furthermore hypothermia, by slowing sepsis progression, buys time to observe which antibiotic(s) can work, yielding time to try alternative further antibiotic option(s) if required), used soon after or just before clinical/legal death to preserve the subject's organs/tissues until the subject can be frozen/cryogenically frozen or the pathology that caused clinical/legal death (e.g. wound) can be fixed and the subject resuscitated, administered to a subject when a first responder (e.g.
ambulance crew) deems the subject dead or unlikely to survive the journey to a medical facility (e.g. hospital) wherein this administration helps to preserve the subject which is helpful if hospital staff subsequently assess that they can, or might be able to, save the subject, stabilizing surgical/trauma/Emergency Room (ER) patients, deep hypothermic circulatory arrest for surgery (DHCA, non-limiting applications of DHCA include repairs of the aortic arch, repairs to head and neck great vessels, repair of large cerebral aneurysms, repair of cerebral arteriovenous malformations, pulmonary thromboendarterectomy, resection of tumors that have invaded the vena cava, brain tumor resection {wherein the anti-cancer activity of a compound(s) of this invention juxtaposes well}), Emergency Preservation and Resuscitation (EPR), hypothermia for a surgical purpose, protective hypothermia during surgery and/or surgery complication, hypothermia to slow/reduce blood loss, hypothermia for neuro- and/or cardio- and/or organ/tissue and/or life protection in a subject that has trauma/brain trauma/polytrauma/surgery/stroke/ischemic stroke/hemorrhagic stroke/cardiac arrest/myocardial infarction/hypoxia/shock (including, without limitation, low volume, cardiogenic, obstructive, and distributive shock)/sepsis/septic shock/multiple organ dysfunction syndrome/systemic inflammatory response syndrome (SIRS)/organ failure/cytokine storm/anaphylactic shock/seizure/disseminated intravascular coagulation/blocked airway/croup/rhabdomyolysis/[head/facial/spinal/chest/abdominal/ballistic/knife injury/trauma], or some other medical emergency/condition/disorder/disease/injury/operation, hypothermia for cardiac and/or cardiovascular surgery and/or open heart surgery and/or brain surgery (neurosurgery) and/or surgery using total circulatory arrest and/or surgery using cardiopulmonary bypass, Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage/transport and/or transplant, thus increasing the time window for transplantation of organs to recipients;

compound(s) of this invention is administered to organ to be transplanted [by administration to donor and/or by administration to isolated organ] and/or to organ recipient, optionally during transplant operation), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, neonatal hypoxia-ischemia, birth asphyxia, hypoxic-ischemic encephalopathy (HIE), haemorrhage, hypovolemia, exsanguination, suspended animation, decompression sickness, burn injury(s) including skin burn, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or tourniquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (non-limiting e.g. meningitis), sepsis, septic shock, stroke, cerebrovascular disease, ischemic brain injury, ischemic stroke, traumatic injury, brain injury, spinal cord injury, cardiac arrest, heart failure, congestive heart failure, Dilated cardiomyopathy, valvular heart disease, pulmonary embolism, adrenal crisis, Addisonian crisis, hypertensive emergency, haemorrhagic (hypovolemic) shock, cardiogenic shock, neurogenic shock, hepatic encephalopathy, blood loss, ischemic brain/heart/kidney/intestinal injury, neuroprotection and/or cardioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject;
(vi) poisoning by a toxic amount of a compound(s) in a subject (non-limiting e.g.
carbon monoxide/methanol/heavy metal/ethylene glycol/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison(s), nerve agent, chemical weapon, bacterial toxin(s) (e.g. food poisoning, Salmonella poisoning), endotoxemia, eukaryote produced toxin(s) e.g. (non-limiting) brevetoxin, drug(s)/substance(s) overdose e.g. (non-limiting) heroin, ethanol, a prescription medication(s), an over the counter medication(s) such as aspirin, paracetamol etc.; hypothermia is protective to toxic insult);
(vii) hypermetabolism (optionally because of one or more of, without restriction, traumatic brain injury, injury to the body, infection, sepsis, burn, multiple trauma, fever, long-bone fracture, hyperthyroidism, prolonged steroid therapy, surgery, bone marrow transplant, recovery from anorexia/bulimia), heat intolerence, insomnia, fatal insomnia, nervousness, Luft's disease, non-thyroidal hypermetabolism, thyrotoxicosis, hyperthyroidism, overactive thyroid, subclinical hyperthyroidism, too much thyroid hormone(s) in the subject, too much triiodothyronine (T3) and/or thyroxine (T4) in the subject, hyperthyroxinemia (including, without restriction, familial dysalbuminemic hyperthyroxinemia, familial euthyroid hyperthyroxinemia, thyroid hormone resistance syndrome), thyroid storm, hyperthyroidism caused by one or more of (without restriction) Graves' disease, thyroiditis, Hashimoto's thyroiditis, subacute thyroiditis, postpartum thyroiditis, lumps (nodules) on the thyroid, enlarged thyroid gland (goitre), simple goitre, multinodular goiter, toxic multinodular goiter, toxic adenoma, toxic thyroid adenoma, inflammation of the thyroid, hyperplasia of thyroid, metastatic thyroid cancer, thyroid tumour, thyroid cancer (including, without restriction, papillary carcinoma, follicular carcinoma, medullary thyroid carcinoma, anaplastic thyroid carcinoma), eating too much iodine, goitrogen ingestion, consumption of ground beef contaminated with thyroid tissue ("hamburger hyperthyroidism"), too much synthetic thyroid hormone in the subject, pituitary adenoma, drug induced, Amiodarone drug induced, struma ovarii, Jod-Basedow syndrome, nonautoimmune autosomal dominant hyperthyroidism;
(viii) low or less than desired metabolic/bioenergetic efficiency in a subject, or low or less than desired physical or mental performance (e.g. memory, IQ), or low or less than desired body weight, or fatigue/tiredness/weakness/exhaustion;
(ix) accelerated aging disease or progeroid syndrome including, without restriction, Werner syndrome, Bloom syndrome, De Barsy syndrome, Rothmund-Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann-Rautenstrauch syndrome, Hutchinson-Gilford progeria syndrome (progeria), Ataxia telangiectasia-like disorder 2, XFE progeroid syndrome, Muscular dystrophy, Muscular Dystrophy (Becker's, Duchenne, Limb-Girdle), Yamamoto's Muscular Dystrophy, Mandibuloacral dysplasia, Dilated cardiomyopathy, GAPO syndrome, Cutis laxia, Ehlers-Danlos syndrom, Lenz-Majewski hyperostatic dwarfism, SHORT syndrome, Progessive external opthalmoplegia, Nester-Guillermo progeria syndrome, MDPL syndrome, Dyskeratosis congenital, Down syndrome;
(x) disease or disorder of aging (incidence/severity increases with increased age/senescence) and/or unwanted/undesirable aspect(s) of aging and/or a disease/disorder associated with elevated reactive oxygen species including age-associated decline, aging frailty, frailty syndrome, sarcopenia, muscle weakness, osteoporosis, cognitive decline, cognitive defecit, mild cognitive impairment, degenerative diseases, neurodegenerative diseases, motor-associated neurodegenerative diseases, motor neuron disease, amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, progressive supranuclear palsy, pseudobulbar palsy, hereditary spastic paraplegia, Parkinson's disease, Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), essential tremor, resting tremor, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, frontotemporal dementia, chronic traumatic encephalopathy, memory loss, aged cognition, age/aging related cognitive decline/impairment, Batten disease, polyglutamine diseases, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, heart failure with preserved ejection fraction, idiopathic pulmonary fibrosis, fibrotic disease, pulmonary disease, coronary artery disease, hypercholesterolemia, obesity, liver disease, fatty liver disease, lysosomal storage disease, amyloidosis, systemic sclerosis, kidney disease, hepatic cirrhosis, immunosenscence, clonal hematopoiesis, chronic obstructive pulmonary disease (COPD), hypertension, hypercholesterolemia, age-related thymic atrophy, arthritis, osteoarthritis, arthritis (Osteo-and Rheumatoid), Juvenile Rheumatoid Arthritis (JRA), Degenerative Disc Disease, Tendinopathy, Androgenetic Alopecia, male-pattern baldness, Idiopathic Pulmonary Fibrosis, systemic sclerosis, Chronic Obstructive Pulmonary Disease, Psoriasis, age-related loss of cardiac/pulmonary/cognitive/vision function, diabetes, type 2 diabetes, andropause, glaucoma, retinal degeneration, sarcopenia, cachexia, age-related cachexia and/or sarcopenia, age-related macular degeneration (AMD, early/intermediate/late), neovascular/wet AMD, dry AMD, Geographic atrophy (GA), wet and dry AMD in the same eye(s), Stargardt's macular degeneration, Best vitelliform macular dystrophy, diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, age/aging-related eye disease, ophthalmological disease/disorder, ocular disease, vision loss, progressive vision impairment, myopia (short-sightedness), degenerative myopia, hyperopia (far-sightedness), accommodative dysfunction, glaucoma, cataract formation, retinal degeneration, progressive retinal degeneration, retinitis pigmentosa, leber hereditary optic neuropathy, Fuchs spot, Best's disease, Sorsby's fundus dystrophy, hearing loss (e.g. age-related), presbycusis, tinnitus, naive T cell shortage, movement disability, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), immunosenescence, respiratory/urinary tract infection (RTI/UTI) especially in older/aged/elderly subjects, cancer;
(xi) aging and/or one or more signs of aging, wherein one or more of these compounds slow/delay/reduce/treat/prevent/stop/reverse aging, and/or extend lifespan and/or healthspan, and/or treat or delay the onset of geriatric aging of the human/animal body, tissue(s), or organ(s), and/or treat or delay the onset of an age-associated phenotype in a cell(s)/organism(s), and/or prolong fertility e.g. female fertility, delay menopause;
(xii) skin aging and/or damage (including sun damage) and/or scalp and/or hair aging and/or hair greying and/or hair loss;
(xiii) insomnia, fatal insomnia, sleep onset latency, delayed sleep phase disorder, exploding head syndrome, parasomnia, sleep-maintenance insomnia, sleep disorder, too much/inappropriate/undesired signals/activity/electrical activity in the nervous system, hyperactivity, hypersensitivity, Premature ejaculation, hyperreflexia, Autonomic dysreflexia (AD), Hyperventilation syndrome, brain hyperactivity, overly sensitive sensory system, pathological crying and/or laughing, Pseudobulbar affect (PBA, emotional lability), photophobia, phonophobia, temperature-sensitive, pressure-sensitive, brain hyperexcitability, overstimulation, intrusive thought(s), Perseveration, sensory overload, disorganized thinking, fantasy prone personality, malapdative daydreaming, dissociation, hyperkinetic disorder, agitation, Psychomotor agitation, restlessness, difficulty controlling behaviour, disruptive behaviour disorder, Emotional and behavioral disorder, pervasive developmental disorder, Overactive disorder associated with mental retardation and stereotyped movements, attention-deficit disorder, Attention Deficit Hyperactivity Disorder (ADHD), adult attention-deficit hyperactivity disorder, severe behavioral problem(s) in children (e.g., to illustrate and not restrict, combativeness and/or explosive hyperexcitable behavior {out of proportion to immediate provocation[s]}, hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of one or more of: impulsivity, difficulty sustaining attention, aggressivity, mood lability, poor frustration tolerance), Premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), impulsiveness, impulsivity, impulse control disorder, lack of self-control, hysteria, histrionic personality disorder, attention difficulty, inattention, poor attention control, anxiety, paranoid anxiety, Paranoid personality disorder, distress, dysphoria, Adjustment disorder, separation anxiety, anxiety disorder, depressive anxiety, agitated depression, treatment-resistant depression, Generalized anxiety disorder, social anxiety disorder, stranger anxiety, separation anxiety (e.g. in dogs left at home), separation anxiety disorder, Mixed anxiety-depressive disorder, depression (all forms, all severities), restlessness/apprehension/anxiety before surgery.
hypochondria, panic disorder, panic attack, emotional outburst, emotional instability, Intermittent explosive disorder, unreasonable/unwarranted anger/aggression, hyper-aggression, hostility, rage, poor temper control, self-hatred, poor attentional control, worry, irritability, neuroses, somatization disorder, somatic symptom disorder, pain disorder, psychological pain, psychogenic pain, psychogenic facial pain, Atypical odontalgia (AO), burning mouth syndrome, throbbing, toothache/pulpitis/dental pain, chronic lower back pain, negative emotion, persistent/enduring negative emotion, body dysmorphic disorder, factitious disorder, illness anxiety disorder, unwarrented fight-or-flight response, stress, emotional stress, emotional dysregulation, distress, psychological stress, acute stress, chronic stress, acute stress reaction, combat stress reaction, traumatic grief, grief, grief after death of loved one, Prolonged grief disorder (PGD), heartbreak, guilt, shame, remorse, emotional pain, Algopsychalia, psychalgia, suffering, emotional trauma, psychological trauma, broken heart, Post Traumatic Stress Disorder (PTSD), Complex post-traumatic stress disorder (C-PTSD), hypervigilance, sympathetic hyperactivity, inability or impaired ability to relax, flashbacks, dysphoric hyperarousal, agoraphobia, insomnia, fatal insomnia, mood disorder, irrational/unwarrented fear/terror, phobia, social phobia, Cancerophobia, thunderstorm/firework phobia, hypersexuality, hypersexual disorder, depression, clinical depression, unipolar depression, bipolar disorder, Bipolar I, Bipolar II, Bipolar disorder not otherwise specified (Bipolar NOS), cyclothymia, cyclothymic disorder, mixed affective state, atypical depression, melancholic depression, postpartum depression, double depression, seasonal affective disorder, mania, manic episode, hypomania, increase in energy of psychomotor activity, delirium, excited delirium, major depressive disorder, minor depressive disorder, recurrent brief depression, Depressive Disorder Not Otherwise Specified (DD-NOS), major depressive episode, persistent depressive disorder (PDD), dysthymia, dysthymic disorder, absence of euthymia, manic thoughts, racing thoughts, thought disorder, disordered thinking, reduced ability to plan and execute tasks, paranoia, hallucination (including, without limitation, visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrioceptive, nociceptive, thermoceptive, chronoceptive), Charles Bonnet syndrome, delusion, persecutory delusion, hearing voices, homicidal/criminal ideation/tendency/thoughts, suicidal ideation/tendancy/thoughts, self-injury, non-suicidal self-injury, violence, attacking others, negative mood swing, personality disorder, Borderline personality disorder, Narcissistic personality disorder, malignant narcissism, dissociative disorder, dissociative identity disorder (DID), Psychosis, acute psychosis, chronic psychosis, psychosis spectrum disorder, manifestations of psychotic disorders, behavioral complications of mental retardation, stimulant psychosis, psychotic depression, hallucinogen persisting perception disorder, Psychoactive substance-related disorder, amphetamine-induced psychosis, brief psychotic disorder, Brief reactive psychosis, Menstrual psychosis, postpartum psychosis, Psychotic disorder, Psychopathy, chronic hallucinatory psychosis, manifestation(s) of psychotic disorder, neurotic/reactive/endogenous/involutional/psychotic depression/depressive disorder (optionally accompanied by anxiety or agitation), depressive neurosis, delusional depression, psychotic aggression, psychiatric symptoms of dementia, AIDS delirium, Supersensitivity psychosis, Tardive psychosis, Tardive dysmentia, Depersonalization disorder, out-of-body experience, Sociopathy, Schizophrenia, Paranoid schizophrenia, disorganized-type schizophrenia, simple-type schizophrenia, pseudoneurotic schizophrenia, prodromal schizophrenia, schizoaffective disorder, bipolar type schizoaffective disorder, depressive type schizoaffective disorder, schizoaffective psychosis, Schizotypal personality disorder, schizophreniform disorder, Delusional parasitosis, formication, paresthesias, Acroparesthesia, tinnitus, delusional disorder, delusional jealousy, inappropriate behaviour, behavioural disorder, antisocial personality disorder, Oppositional defiant disorder (ODD), conduct disorder (CD), Disruptive mood dysregulation disorder (DMDD), sadistic personality disorder, poor inhibitory control, kleptomania, Pyromania, trichotillomania, dermatillomania, pathological/problem gambling, dyskinesia, tardive dyskinesia, paroxysmal dyskinesia, Paroxysmal kinesigenic dyskinesia, Paroxysmal nonkinesigenic dyskinesia, Paroxysmal exercise-induced dystonia, Hemiballismus, tic disorder, tremor, clonus, Tourette's syndrome, coprolalia, copropraxia, Echophenomena, Echopraxia, Echolalia, Palilalia, stuttering/stammering, stereotypy, punding, Self-stimulatory behaviour (stimming), Stereotypic movement disorder (SMD), synesthesia, obsession, Obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder, anankastic personality disorder, relationship obsessive-compulsive disorder (ROCD), Scrupulosity, Primarily obsessional obsessive compulsive disorder, sexual obsession, Akathisia (including, without limitation, chronic, acute, Pseudoakathisia, Tardive akathisia, withdrawal or "rebound"
akathisia), Restless legs syndrome, motor restlessness, periodic limb movement disorder (PLMD), periodic limb movements in sleep (PLMS), Sydenham's chorea, chorea, dystonia, Hypnic jerk, twitching, spasms, Tetanus, tetanus muscle spasms, tetanized state, Myoclonus, myoclonic seizure, Action myoclonus, Palatal myoclonus, Middle ear myoclonus, Spinal myoclonus, Stimulus-sensitive myoclonus, Sleep myoclonus, Cortical reflex myoclonus, Essential myoclonus, myoclonic epilepsy, Juvenile myoclonic epilepsy, Progressive myoclonus epilepsy (PME, including, without limitation, Dentatorubral-pallidoluysian atrophy, Unverricht-Lundborg disease, MERRF syndrome, Lafora disease), Reticular reflex myoclonus, Myoclonic epilepsy, diaphragmatic flutter, automatism, status epilepticus, Epilepsia partialis continua, Complex partial status epilepticus, epilepsy, epileptic seizure, simple partial seizure, complex partial seizure, generalized epilepsy, generalized seizure (including, without limitation, tonic-clonic, tonic, clonic, myoclonic, absence (including typical absence and atypical absence), atonic seizure), focal epilepsy, focal seizure, focal/partial seizure (including, without limitation, Simple partial seizure and Complex partial seizure), focal aware seizure, focal impaired awareness seizure, generalised epilepsy, temporal lobe epilepsy (including, without restriction, mesial temporal lobe epilepsy {MTLE} and lateral temporal lobe epilepsy {LTLE}), Frontal lobe epilepsy, Rolandic epilepsy, Nocturnal epilepsy, Nocturnal frontal lobe epilepsy, Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Generalized epilepsy with febrile seizures plus (GEFS+), Panayiotopoulos syndrome, epileptic fit, reflex epilepsy, reflex seizure, absence seizure (including, without limitation, childhood absence epilepsy, epilepsy with myoclonic absences, juvenile absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome {eyelid myoclonia with absences}, genetic generalised epilepsy with phantom absences), complex partial seizure, atonic seizure, generalized tonic-clonic seizure, tonic-clonic seizure, extrinsic stimulus epilepsy, intrinsic stimulus epilepsy, photosensitive epilepsy, musicogenic epilepsy, thinking epilepsy, eating epilepsy, seizure(s), Febrile seizure, nerve agent induced seizure, Dravet syndrome (sometimes modest hyperthermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals), acute symptomatic seizure, seizure-related disorder, drug related seizure, paroxysmal depolarizing shift, Ohtahara syndrome, Epilepsy in females with mental retardation, Rasmussen's encephalitis, Epilepsy syndrome, benign rolandic epilepsy, childhood absence epilepsy, absence epilepsy, juvenile myoclonic epilepsy, epileptic encephalopathies, Lennox-Gastaut syndrome, West syndrome (Epileptic spasms), Doose syndrome (Myoclonic astatic epilepsy, MAE), Lennox-Gestaut syndrome, pseudo-Lennox Gastaut syndrome (atypical benign partial epilepsy), Benign familial neonatal epilepsy, Benign occipital epilepsy of childhood, familial neonatal convulsions, Febrile infection-related epilepsy syndrome, interictal dysphoric disorder, euphoria sclerotic, psychogenic non-epileptic seizure, non-epileptic seizure, gelastic seizure, convulsion(s), migraine, status migrainosus, tension headache, headache, Hypnic headache, hiccups, intractable hiccups, thumps in equines, Postural orthostatic tachycardia syndrome (POTS), Pheochromocytoma, agony, pain, chronic pain, acute pain, pain due to disease/injury, neuropathic pain, fibromyalgia, postherpetic neuralgia, phantom pain, referred pain, back pain, lower back pain, pelvic pain, cancer associated pain, chemotherapy associated pain, Diabetic neuropathy, small fiber peripheral neuropathy, Mononeuritis multiplex, Wartenberg's migratory sensory neuropathy, Breakthrough pain, idiopathic pain, polyneuropathy, Neuritis, Mononeuropathy, Polyradiculoneuropathy, Radial neuropathy, neuropathy, visceral pain, Burning feet syndrome, Tarsal tunnel syndrome, Carpal tunnel syndrome, Guyon's canal syndrome, Cubital Tunnel Syndrome, Repetitive strain injury, Sciatica, Neurofibromatosis, Ulnar nerve entrapment, Erythromelalgia, Paroxysmal extreme pain disorder, Proctalgia fugax, dysesthesia, scalp dysesthesia, dysesthetic burning, hyperesthesia, hyperalgesia, Opioid-induced hyperalgesia, hyperpathia, allodynia, pain response from stimuli which do not normally provoke pain, Complex regional pain syndrome (said to be most painful condition known to man), Radiculopathy, neuralgia (including, without restriction, intercostal neuralgia, trigeminal neuralgia, atypical trigeminal neuralgia, glossopharyngeal neuralgia, occipital neuralgia, postherpetic neuralgia), ciguatera poisoning, irritable bowel syndrome (IBS), interstitial cystitis (IC), temporomandibular joint disorder, acute intermittent porphyria, Porphyria, Acute porphyria (including, without limitation, acute intermittent porphyria {AIP}, variegate porphyria {VP}, aminolevulinic acid dehydratase deficiency porphyria {ALAD}, hereditary coproporphyria {HCP}, drug induced), Chronic porphyria (including, without limitation, X-linked dominant protoporphyria {XLDPP}, congenital erythropoietic porphyria {CEP}, porphyria cutanea tarda {PCT}, and erythropoietic protoporphyria {EPP}), cutaneous porphyria, Porphyria cutanea tarda, allergy, allergic reaction, anaphylaxis, anaphylactic shock, hives, asthma, allergic rhinitis, rhinitis, urticaria, contact dermatitis, cough, sore throat, esophageal reflux disease, heartburn, chest pain, Esophageal motility disorder, Nutcracker esophagus, diseases involving gastrointestinal motility, Peptic ulcer disease, esophageal spasm, angina, itchiness, Pruritus, severe pruritus, Prurigo, Pruritic skin condition, chronic itch, eczema, pruritus in eczema, neuropathic itch, neurogenic itch, itchiness due to atopic dermatitis and/or lichen simplex chronicus, peripheral sensitization, central sensitization, sensory perception of absent stimuli, too much sensory stimulation, sensory stimulation brings discomfort, Neuromyotonia, Peripheral nerve hyperexcitability, Morvan's syndrome, Benign fasciculation syndrome, Cramp fasciculation syndrome, hyperhidrosis, undifferentiated somatoform disorder, somatoform disorder, somatic symptom disorder, conversion disorder, functional neurological symptom disorder, severe nausea and/or vomiting, severe nausea/emesis, Chemotherapy-induced peripheral neuropathy, chemotherapy-induced nausea and vomiting (CINV), radiation therapy-induced nausea and vomiting (RINV), postnarcotic nausea, hyperemesis gravidarum, morning sickness, Cyclic vomiting syndrome, retching/dry heaving, Urinary incontinence, enuresis, nocturnal enuresis, tail chasing, reduce urine spraying/marking behavior, benzodiazepine withdrawal syndrome, barbituate withdrawal syndrome, Neuroleptic discontinuation syndrome, drug withdrawal discomfort/pain/symptoms, drug use disorder, alcohol use disorder, opoid use disorder, amphetamine use disorder, cocaine use disorder, alcohol withdrawal syndrome/symptoms, delirium tremens, opoid withdrawal sydrome/symptoms, drug craving, drug addiction, drug dependence, polysubstance dependence, drug overdose, smoking, tobacco (nicotine) addition, tobacco (nicotine) withdrawal symptoms, alcoholism, addiction, opoid addiction, cocaine/crack addiction, addictive behaviour, addictive personality, behavioural addiction, internet/computer/computer game/social media/media addiction, exercise addiction, compulsive behaviour (e.g. {non-limiting}
checking, counting, washing, repeating), anti-social behaviour, criminality, sexual compulsion, impulsive sexual behaviour, compulsive buying, gambling addiction, sex related addiction, sexual urge, hunger, eating desire/compulsion, eating disorder, polyphagia, overeating, binge eating disorder, compulsive overeating, insatiable/excessive appetite, bulimia nervosa, anorexia nervosa, substance abuse, substance-induced delirium, substance-induced psychosis, substance-induced mood disorder, drug overdose, vertigo, motion sickness, seasickness, mental/nervous breakdown, Autism spectrum disorder, neurological disorder, cognitive disorder, mental disorder, mental health disorder, mental health condition involving impaired or altered neural plasticity, mood disorder, mental disorder disclosed in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or a later edition, a mental/behavioural disorder disclosed by the International Classification of Diseases (ICD) in ICD-10 Chapter V: Mental and behavioural disorders (World Health Organisation, WHO); or (xiv) diseases or disorders or conditions or pathologies or unwanted/undesirable effects/actions/behaviour treatable/ameliorated/prevented/combated, in totality or in part (e.g.
along with surgery), by anaesthesia, pre-anaesthesia, post-anaesthesia, hypoesthesia, hypoactivity, sedation, coma, tranquilization, behavioural submission, muscle relaxation, hibernation, artificial hibernation, torpor, synthetic torpor, suspended animation (e.g. used during spaceflight because e.g. reduces ionizing radiation damage to subject);
(xv) hyperproliferative/hyperplasia disorder, non-cancerous proliferative disorder, hyperproliferative autoimmune disorder, hyperplasia, epidermal hyperplasia, dysplasia (e.g.
epithelial dysplasia), nodule(s), wart(s), papilloma(s), squamous cell papilloma, genital wart(s), condyloma(s), condyloma acuminatum, cyst(s), polyp(s) {including, without restriction, digestive, colorectal, endometrial, cervical, nasal, laryngeal, inflammatory fibroid polyp[s])}, inherited/hereditary (including, without restriction, Familial adenomatous polyposis, Peutz-Jeghers syndrome, Turcot syndrome, Juvenile polyposis syndrome, Cowden disease, Bannayan-Riley-Ruvalcaba syndrome {Bannayan-Zonana syndrome}, Gardner's syndrome) and non-inherited (non-restrictive e.g. Cronkhite-Canada syndrome) polyposis syndrome, benign tumour, adenoma, organ enlargement by hyperplasia, Cushing's disease (enlarged adrenal cortex by hyperplasia), congenital adrenal hyperplasia, hyperplasia of breast, atypical ductal hyperplasia, intraductal papillomatosis, fibroadenomas, fibrocystic changes, hemihyperplasia, focal epithelial hyperplasia, sebaceous hyperplasia, sebaceous adenoma, intimal hyperplasia, unwanted/undesirable smooth muscle cell proliferation, smooth muscle cell hyperplasia, intimal smooth muscle cell hyperplasia, neointimal hyperplasia, proliferative vascular disorders, stenosis, stenosis because of cellular proliferation, vaginal stenosis, stenosis in a blood vessel, lessoned patency of a blood vessel, stenosis in a blood vessel because of cellular proliferation, vascular occlusion, restenosis, restenosis in a blood vessel that has been implanted with a stent, in-stent restenosis, post-angioplasty restenosis, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g.
diabetic retinopathy and/or other retinopathy[y/ies]), cardiac hyperplasia, fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, fibromatosis, neurofibromatosis, renal interstitial fibrosis, Cowden syndrome, hamartoma(s), choristoma(s), hemangioma(s), lymphangioma(s), rhabdomyoma(s), lymphangiomatosis, cystic hygroma, trichilemmoma, sarcoidosis, neurosarcoidosis, aggressive fibromatosis, desmoid tumour(s), unwanted/undesirable skin cell proliferation, hyperproliferative skin disorder, psoriasis (including, without restriction, plaque, guttate, inverse, pustular, napkin, seborrheic-like, nail, scalp and erythrodermic psoriasis), psoriatic arthritis, dactylitis, seborrhoeic dermatitis, dandruff, eczema, atopic dermatitis, rosacea, reactive arthritis (Reiter's syndrome), pityriasis rubra pilaris, hyperproliferative variants of disorders of keratinization (e.g., without restriction, actinic keratosis, senile keratosis, keratosis pilaris, seborrheic keratosis), scleroderma, benign prostatic hyperplasia, prostate enlargement, endometrial hyperplasia, atypical endometrial hyperplasia, benign endometrial hyperplasia, adenomyosis, atypical polypoid adenomyoma, endometriosis, endometriosis of ovary (endometrioma), endometrial polyp(s), polycystic ovary syndrome, ovarian cyst(s), cervical polyp(s), uterine fibroid(s), uterine hyperplasia;
(xvi) Tumour Associated Macrophages (TAMs) or any macrophage associated disease or disorder such as, without limitation, Macrophage Activation Syndrome (MAS), HIV, AIDS, HIV-associated neurocognitive disorders (HAND), AIDS dementia, HIV
peripheral neuropathy, HIV associated cancers, AIDS-defining cancers, non-AIDS
defining cancers, any disease in which the pathogen(s) hides from the immune system in macrophages including, without limitation, Mycobacterium tuberculosis (causes tuberculosis), Leishmania parasite (causes Leishmaniasis), Chikungunya virus (causes Chikungunya), Legionella pneumophila (causes Legionnaires' disease), adenoviruses, T. whipplei (causes Whipple's Disease), Brucella spp. (causes brucellosis), Staphylococcus aureus, Ebola virus, Hepatitis B
virus, Hepatitis C virus, influenza virus strains, dengue virus and antibiotic resistant bacteria, any disease or condition in which activated macrophages are unwanted or undesirable;
(xvii) virus/pathogen neuroinvasion via macrophage(s), as used for non-limiting example by HIV, Heptatitis C virus and SARS coronavirus;
(xviii) neurocognitive or neurodegenerative diseases/disorders, for non-limiting example those caused by a virus;
(xix) virus/pathogen transmission from mother to fetus/baby via macrophage(s) as used for non-limiting example by zika (via Hofbauer cells) and HIV
(macrophages in breast milk);
(xx) acute or chronic or systemic inflammation or any inflammatory disease/disorder/syndrome or any autoinflammatory disease/disorder/syndrome or any autoimmune disease/disorder/syndrome;
(xxi) acute inflammation, chronic inflammation, systemic inflammation, inflammation because of infection or foreign bodies or injury or chemical or toxin or drug or stress or frostbite or burn or ionising radiation or surgery, inflammatory diseases/disorders/syndromes, Macrophage Activation Syndrome (MAS), autoinflammatory diseases/disorders/syndromes, age-related chronic inflammatory diseases ("inflammaging"), autoimmune diseases/disorders/syndromes, diseases/disorders of the innate immune system, sore throat, sore throat associated with cold or flu or fever, high-intensity exercise associated inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, osteoarthritis, inflammatory osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation associated depression, neuroinflammation, neuropathic pain, exercise-induced acute inflammation, atherosclerosis, allergy, hay fever, anaphylaxis, inflammatory myopathies, drug-induced inflammation, systemic inflammatory response syndrome, sepsis-related multiple organ dysfunction/multiple organ failure, microbial infection, acute brain/lung/hepatic/renal injuries, lung inflammation, acute lung injury (ARDS), acne vulgaris, celiac disease, celiac sprue, chronic prostatitis, colitis, autoimmune hemolytic anemia, diverticulitis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Mast Cell Activation Syndrome, mastocytosis, otitis, pelvic inflammatory disease (PID), endometritis, reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasitosis, eosinophilia, type III hypersensitivity, ischaemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, alcoholic hepatitis, chronic viral hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematous (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative disease, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, bronchiectasis, bronchopneumonia, obliterative bronchiolitis, appendicitis, acute appendicitis, bursitis, cystitis, dermatitis, encephalitis, HIV encephalitis, gingivitis, meningitis, infective meningitis, myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis¨associated interstitial lung disease and desquamative interstitial pneumonia, pneumonia, interstitial lung disease, Löfgren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, steatohepatitis, nonalcoholic steatohepatitis, silicosis, histiocytoses, Langerhans' cell histiocytosis, haemophagocytic lymphohistiocytosis, pulmonary langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudogout, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft versus host disease (GVHD), lymphadenopathy, rheumatoid arthritis (RA), osteoarthritis (OA), inflammatory osteoarthritis, lupus, multiple sclerosis (MS), myocarditis, uveitis, CNS disease(s), inflammation aspect to a CNS disease(s), hypothalamic inflammation, dementia, glaucoma, amyloid related/driven disease, lipid storage disease(s), fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, cirrhosis of the liver, alcoholic cirrhosis, nephropath(y/ies), lupus nephritis, immune nephritis, fibrotic disorder(s), cardiovascular disease, heart disease, atherosclerosis, vulnerable plaque, plaque formation, lipid containing macrophage related disease(s)/disorder(s)/malad(y/ies), macrophage foam cells, diabetes, type I
diabetes, type 2 diabetes, insulin resistance, macrophage aspect to insulin resistance, obesity, obesity associated inflammation, macrophage accumulation/large numbers of macrophages in adipose tissue (e.g. associated with obesity), granuloma(s), granulomatous diseases, sarcoidosis (including, without limitation, Annular sarcoidosis, Erythrodermic sarcoidosis, Ichthyosiform sarcoidosis, Hypopigmented sarcoidosis, Löfgren syndrome, Lupus pernio, Morpheaform sarcoidosis, Mucosal sarcoidosis, Neurosarcoidosis, Papular sarcoid, Scar sarcoid, Subcutaneous sarcoidosis, Systemic sarcoidosis, Ulcerative sarcoidos), neurosarcoidosis, pulmonary sarcoidosis, interstitial lung disease, pulmonary fibrosis, pulmonary tuberculosis, immune reconstitution syndrome of HIV, Jarisch¨Herxheimer reaction, sepsis, Paget's disease of bone, osteolysis, monocytosis, histiocytosis, X-type histiocytoses, non-X histiocytoses, Langerhans cell histiocytosis, non-Langerhans-cell histiocytosis, malignant histiocytosis, malignant histiocytic disorders, histiocytomas, histiocytic lymphoma, hemophagocytic syndrome, hemophagocytic lymphohistiocytosis, lymphohistiocytosis, diffuse histiocytic sarcoma, Rosai¨Dorfman disease, gliosis, Bergrnann gliosis, Chronic Obstructive Pulmonary Disease (COPD), chronic inflammatory lung disease, familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulinemia D with recurrent fever syndrome (HIDS), cryopyrin associated periodic syndrome (CAPS), Blau syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), mevalonate kinase deficiency, pyogenic-arthritis-pyoderma gangrenosum and acne syndrome (PAPA), periodic fever aphthous stomatitis pharyngitis adenitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, Schnitzler's syndrome, Sweet's syndrome, NLRP12-associated autoinflammatory disorders, deficiency of interleukin-1 receptor antagonist (DIRA), pyoderma gangenosum, cystic acne, aseptic arthritis, periodic Fever Associated with mevalonate kinase deficiency (hyperimmunoglobulin D Syndrome), Pyogenic Arthritis Pyoderma Gangrenosum Acne (PAPA) syndrome, Periodic Fever Aphthous Stomatitis, Pharyngitis and Adenopathy (PFAPA) syndrome, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Chronic Recurrent Multifocal Osteomyelitis (CRMO), Synovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome, Cryopyrin associated Periodic Syndrome (CAPS), Familial cold auto inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Familial cold urticarial, Neonatal onset multisystemic inflammatory disorder (NOMID), hereditary Periodic Fever Syndromes, Periodic Fever Syndromes, systemic autoinflammatory diseases, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Baló disease, Behcet's disease, benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Berger's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, proliferative glomerulonephritis, membranous nephropathy, minimal change nephrotic syndrome, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immune hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR) PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, peripheral neuropathy, perivenous encephalomyelitis, Pernicious anemia (PA), POEMS
syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)), idiopathic thrombocytopenia purpura, splenomegaly;

(xxii) Systemic inflammatory response syndrome, cytokine release syndrome, cytokine storm, immune reaction to a drug(s) or therapy(s), immune reaction to an immune activating drug(s) or agent(s) or treatment(s) or intervention(s), immune reaction to immunotherapy and/or immune-oncology and/or immunomodulatory drug(s) and/or treatment(s), adverse reaction to adoptive T-cell therapy(s), adverse reaction to a chimeric antigen receptor T-cell therapy(s) (CAR-T cell therapy(s)), adverse reaction to a immune checkpoint inhibitor(s), adverse reacflon to monoclonal antibody drug(s), tumor lysis syndrome; or (xxiii) cancer and Graft Versus Host Disease (GVHD) in transplantation therapy in a cancer patient.
[35] A compound(s) and/or composition(s) for use according to any one of Claim 16, Claims 17 to 21, Claims 22 to 33 or Claim 34, wherein the subject is also administered with one or more compounds or compositions approved for human use, optionally for anti-cancer use, by the United States Food and Drug Administration (FDA) and/or European Medicines Agency (EMA), optionally in the same pharmaceutical composition.
[36] A compound(s) and/or composition(s) for use according to any one of Claim 16 or Claims 17 to 21 or Claim 34, wherein comparable or larger mg/kg doses are used in larger subjects/animals/species, which is very distinct from most drugs, and optionally the mg/kg dosage administered to adult humans is comparable or greater than the No Observed Adverse Effects Level (NOAEL) mg/kg dosage in mice housed at 22 C.
[37] A compound(s) and/or composition(s) for use according to any one of Claim 16, Claims 17 to 21 or Claim 34, wherein the compound(s) and/or composition(s) is administered to the subject topically/locally and not systemically [38] A compound(s) and/or composition(s) for use and/or method according to any one of Claims 1 to 33 or Claims 35 to 38, wherein the claim is made (e.g. written to be/ammended to be) a dependent claim of Claim 34.