KR20200078472A - Inverse modulator of ATP synthase modulator - Google Patents

Abstract

The compounds of formula (I) below are useful for slowing down the ATP-hydrolysis mode of ATP synthase and treating a variety of diseases and disorders, including cancer, in particular cancers utilizing the Warburg effect.
(I)

Description

Inverse modulator of ATP synthase modulator

Related applications

This application is GB application number GB1711250.9 (submitted on July 13, 2017), GB1715756.1 (submitted on September 28, 2017), GB1715758.7 (submitted on September 28, 2017), GB1715938.5 (Submit on October 1, 2017), GB1716492.2 (Submit on October 9, 2017), GB1800092.7 (Submit on January 4, 2018), GB1800291.5 (Submit on January 8, 2018), GB1800581 .9 (submission on January 15, 2018), GB1801536.2 (submission on January 30, 2018), GB1806421.2 (submission on April 19, 2018), GB1808331.1 (submission on May 21, 2018) , GB1809497.9 (filed on June 8, 2018), GB1810236.8 (filed on June 21, 2018), GB1811188.0 (filed on July 8, 2018), and some of the above mentioned and additional GB applications PCT application number PCT / EP2018 / 051127 (filed January 17, 2017), GB1707945, claiming priority benefits of numbers GB1700772.5 (January 17, 2017), GB1706046.8 (April 14, 2017). 0 (filed May 17, 2017) and GB1710198.1 (filed June 27, 2017). The full teaching of these applications is incorporated herein by reference.

Field of the invention

The present invention is known to have a variety of diseases or disorders including ATP synthase preferential ATP-synthesizing enzymes, ATP-hydrolysis mode slow compounds of these compounds, and cancer (diagnosis, etc.) Patients or disorders include cancer or subjects at risk of developing various diseases or disorders, including cancer. In certain embodiments, the subject is a human.

Background of invention

ATP synthase

The ATP synthase (also known as F1F0 ATP synthetase, F0F1 ATP synthetase, F1F0-ATPase, F0F1-ATPase, F1F0 ATP hydrolase) is located in the mitochondrial lining (IM). It can use Proton Synchronous Force (PMF) to generate ATP from ADP and Pi [1-3]. ATP synthase is reversible-depending on the voltage at PMF and the mitochondrial lining at substrate/product concentration {- ΨIM} (making ATP passable ATP) or "back" (conveying ATP, proton pump) "convey" F1F0 ATP synthesis, F1F0 ATP synthesis, respectively "opposite" mode, which can also be called "forward" can work.

Inhibitors of ATP synthase

There are review ATP synthase drug inhibitors [4] (cited herein). Compared to the forward mode of the ATP synthase, some imbalance inhibitor / selectively inhibits the reverse mode [4-13]. Macrolide is a class of polytide. So, macrolide F1F0 ATP synthase inhibitors are polyketed F1F0 ATP synthase inhibitors, and these terms are used interchangeably. Polyketed F1F0 ATP is a more advanced mode inhibitor (eg oligomycin) synthase inhibitor [11] than the reverse mode of ATP synthase. Oligomycin is well known as an inhibitor of oxidative phosphorylation and aerobic respiratory F1F0 ATP synthase [3]. Human life relies on aerobic breathing. Indeed, the importance of breathing (CO2 output, O2) is widely appreciated. The risk of oligomycin is readily seen there.

IF1 is a protein encoded by the reverse mode, which selectively blocks the ATPIF1 gene ATP synthase, is endogenous [4]. Its activity is sensitive to low pH, but is important in matrix acidification by disintegration of the proton motive force across the inner membrane and the mitochondrial at the normal matrix pH.

Prior art teaches that the compounds of the present application are anticancer drugs for lower limbs

Polyketed F1F0 ATP synthase inhibitors (eg oligomycin) are toxic to cancer [14] and normal [15] cells. Indeed, only 1 milligram/kg intraperitoneal injection raises mycinine healthy rats (N = 10) within 48 hours; LD33 = 0.5 milligrams/kg[15]. Normal cells generally require use of F1F0 ATP, a synthetic enzyme so blocking this mode in forward mode is generally fatal. Therefore, polyketide F1F0 ATP synthase inhibitors are not suitable as anti-cancer drugs: true, xenograft mouse model of cytovaricin, ossamycin and peliomycin cancer (does not work in data [16], unproven oligomycin) without treatment window Because, in repetition, polyketide F1F0 ATP is an inhibitor, a highly toxic synthetase in normal cells, whereas it is not even toxic to all cancer cells: eg for sugar cancers that exert an inefficient Warburg effect [14]. [17] They were used to inoculate mice by inoculating mice with excess oligomycin before inoculation into mice (by culture for 2 days in drug-free medium), and by applying oligomycin to cancer cells only in xenograft cancer mouse models before washing. . They did not discriminate against cancer in toxic mammals and studied this same because of mycin (atypical, art people, atypical). Of course, this experiment has no clinical parallelism or utility. The synthesis/structure of some of the molecules of the present invention has been disclosed in the prior art [P1, P2, P3] Polyketide, which is believed to be an anti-cancer agent only similar to the anti-cancer activity of these structures, is an inhibitor of F1F0 ATP synthetase [14]. Indeed, using these limitations with mirrors[14], these disclosures do not make any claim for any cancer [P3], [P1] limiting their suggestions (hereinafter "tumor cells with cancer that does not exhibit the Warburg effect") in the claim, [P2] Claims rejected by the USPTO on communications on April 11, 2006). [P1, P2, P3] Utility section state of its description "Mitochondrial FIF0-ATP agonist inhibitors selectively do not exhibit the Warburg effect ie metabolically active tumor cells do not maintain high levels of anaerobic carbon metabolism even in the presence of oxygen Killing". So, that compound uses oxidative phosphorylation (OXPHOS) and ATP synthase to limit their suggestions for cancer, that is to say that the anti-cancer activity exerted against cancers that exhibit a Warburg effect in anterior mode does not produce ATP. However, if this (home) approach is compromised, this aerobic profile is what normal cells usually use, especially in aggregates across organisms, also what: (Evidence of the importance of breathing mammalian life): Is known. By this analogy, the polyketide F1F0 ATP inhibitor Syntyre speculates that this molecule is a safe anti-cancer drug. In fact, by this analogy, when they actually teach the opposite. It is clear at this time [14] that this considers separation as an eyeball, but does not come with the rest of the literature, etc. [15], [16] and the knowledge of the arts (of course the F1F0 ATP is known to be used by normal cells ATP To produce it, synthesizing enzymes and blocking oligomycin in the anterior mode, and is strongly dangerous). Therefore, these pre-published [P1, P2, P3] polyketed F1F0 ATP synthase inhibitors, which teach users in the art that there are similar compounds with their choice, are not suitable for chemotherapy. This anticancer treatment is not enough to kill cancer. This murder must be chosen, leaving the normal cells alive. Oligomycin cyanide or metabolic poisons such as these are not suitable for this standard. By distinction, the heading of the present invention is selective for killing cancer cells at concentrations of compounds harmless to normal cells. This could not be expected in the prior art. In addition, it performs pronounced anticancer activity and is pronounced for cancers exhibiting the Warburg effect.

Obviously, the present invention initiates an experiment. Its advancement is to demonstrate that its compounds are safe from anti-cancer drugs because of its distinction from polyketylated F1F0 ATP, an enzyme synthesizing inhibitor. Mycin) as a method advantage, there is a wide range of therapeutic limitations for the compounds of the invention. Indeed, the compounds of the present invention are capable of killing very sugary cancers that exhibit the Warburg effect. This cancer tends to have the worst prognosis (many researchers have found, the most dangerous: representative:[18-20]).

[P1, P2, P3] No experimental anti-cancer evidence towards ischemia treatment, and provide teaching. These are inadequate self-oligosing and mycins, which are unsuitable as anti-cancer agents, and their compounds, by suppressing the synthesis of F1F0 ATP, exhibit anti-cancer activity like oligomycins and teach by suggesting the unexpected arts of the present invention by analogy. [P1, P2, P3] Millions are included. People of the art choose a subset of these for anticancer testing. The training of [P1, P2, P3] teaches users in the industry to select the description of inhibitory F1F0 ATP synthetic compounds in the mitochondrial sub-analysis as much as possible. These compounds are very potent and evident in the lack of exciting treatment margins such as mycin, kill cancer in vitro[14] (typed in the above animal studies to be F1F0 inhibitors such as polyketides [16]) and useful anticancer drugs Signed an experiment, it will be found. In fact, no one can be found in the next ~16 years, despite standing a long need. On the other hand, by the present invention, it is selected from compounds [P1, P2, P3] and has anti-cancer activity. Minimal inhibition by F1F0 ATP synthetic compound selection (compared to inhibition of F1F0 ATP singers). Indeed, by empirical evidence herein, the anticancer activity of the compound is evidence. Therefore, the user of the art arrived at the basis of reaching the anti-cancer agent, and (S) the anti-cancer agent found by the method disclosed herein, EG said anti-cancer agent. These drugs can lower body temperature and may have a very irregular dose anticancer response profile with compensatory and related methods and critical teachings of the present invention. This experiment is made possible for rat experiments, especially in mouse experiments (small body, more vulnerable to body temperature drop),

The compounds of the present invention do not exert anti-cancer activity. It also suppresses cachexia/cause of weight gain, both/reduce weight loss, can maintain weight, make metabolism more efficient, and affect normal cells. For example, cancer-driven cachexia is the leading cause of death in some cancer patients. In contrast, polyketed F1F0 ATP increases the efficiency rather than rejecting that energy, as molecules of the present invention can, making them more energetic inhibitors synthically toxic to normal cells.

In other words, [P1, P2, P3] teaches that the F1F0 ATP synthesis inhibitor only kills oxidative cancer that does not use Warburg metabolism, and the present invention experimental F1F0 ATP hydrolysis inhibitor Warburg metabolism shows light cancer. The former professor does not arrive at therapeutic anticancer drugs, the latter does not.

[P4] Teach away from the present invention. Exemplary compounds, Bz-423, ATP forward and reverse modes, initiate different data equally inhibit the mode of (EC50 = 8.9 μM) than reverse (EC50 = 5.5 μM) of the synthase or ATP synthase anterior (EC50 = 8.9 μM). [P4 ] Provides evidence that Bz's deceleration-423 cell proliferation factor, and inhibits F1F0 ATP synthesis by inhibiting the hydrolysis of F1F0 ATP, thereby killing. It frequently highlights the examination response to the JPO (Feature A (same) Applicant Extrapolation [P5]) of Bz-423 disclosed in other compounds. For example, in the heading of Example 41 [P4] it is reported that "Benzodione derivatives do not affect cell synthesis properties, inhibit ATP hydrolysis, do not affect cell viability" and [P4] Compound T5 is "can inhibit the hydrolysis of ATP that does not affect cell survival and does not inhibit cell synthesis", and experiments obtained by teaching in the present invention continue to confirm the statement. In [P4] Example Compound Bz-423 Utility Inhibition Compared to ATP synthesis, T5 experimental data are included in contrast to that of Bz-423, indicating a lack of inhibitor-specific ATP hydrolysis utilities such as T5. In this data [P4], Bz-423 inhibition F1F0 ATP synthesis and hydrolysis and cell viability inhibit T5 only F1F0 ATP not hydrolyzed cell viability = Bz-423 exemplary compound F1F0 ATP does not inhibit synthesis F1F0 ATP hydrolysis Inhibiting, and empirically emphasizing the responsible example organization. BZ-423 ΨIM overpolarizes and reduces O2 consumption [21] whereas the compounds of the present invention do not, as presented in the experimental data of the present invention. Example 52 [P4] "ATP synthesis (relevant enzyme reaction of mitochondrial F1F0-ATPase in vivo)" state. Therefore, the indirect F1F0 ATP hydrolysis is not related to the experimental value and the false bio-in support of the present invention. This is a new fundamental biological discovery that amazes people of the arts. [P4] The teaching of the present invention does not reach the teaching of the use of inhibitors of the forward mode of ATP synthase Indeed, apart from the teaching of the present invention.

Repository for biorxiv peer unreviewed documents known to people in the art. In 2015, the authors of the present invention as seen in the document of biorxiv proposed the use of F1F0 ATP hydrolysis inhibitors as anti-cancer drugs [22]. This article was later submitted to the Review Journal (elife, BMC Cancer) peers and let alone seek by the people of the arts, found the worthy of dissemination. It was clearly not considered reliable by the people of art. In 2017, the paper was published by others, in the Peer Review Journal [23]Experimental F1F0 ATP hydrolysis assist (!) harm, cancer rather than data indicating inhibition. To reach and conclude that the author highlights. This paper is one of many experimental reports published in major peer review journals that reach the same conclusion, teaching away from this author's suggestion from a database of known documents that have not been well reviewed/unresearched manuscripts directly opposite. Indeed, after submission of biorxiv no journal publication would be mentioned very negatively as one of the years of art.

Unpredictable art, one of the arts always weighs more of the experimental data than the proposal when choosing the path pursued by the prior art. In particular, dates that distort the above experimental data and/or suggestions that degrade credit. Conventional experiments teach far away from the present invention. Indeed, direct opposition. The present invention demonstrates that F1F0 ATP hydrolysis inhibition [23]F1F0 ATP hydrolysis inhibition assist cancer (!) increases the risk there, passing experimental data in anticancer therapy. Perform hydrolysis ATP not in one of the "ATP synthase complexes"

"IF1 expresses or osteosarcoma cells IF1-silent[23]. "Severe hypoxia cannot activate ATP hydrolysis by the complexation of F1F0-ATPase" [23]. "ATP synthase ATP in cancer cells In addition, "IF1 overexpression in cancer cells completely prevents ATP from synthesizing enzymes" (also "IF1 is present at higher levels in cancer cells compared to untransformed cells" and many other Observations in the gene expression database reported by many other researchers in the journal paper and IF1 overexpression of cancer in mice are prognostic markers of patients with poor outcomes IF1 knockdown tumor growth [24]) and "IF1 overexpression leads to cancer cell survival Acceleration"[23].

Excluded from the formulas presented in all of the listed separation steps in some compounds of claim 13 of the present invention [P1] and [P4].

Some guidance

All publications, patents and patent applications mentioned or cited in this specification are incorporated herein by reference. The present invention uses a suppressed or reduced process, interchange EC50 and IC50. If a chemical structure is drawn using a feature in a chemical drawing [25] and the drawing function is mentioned in this article, or is unknown to the reader exploring the software itself: clear all to the people of art. Hydrogen in the structure is not shown, which is a typical implication, but it is marked for the structure, which is what is "on heterogeneous terminals" [25]. Here, the symbol D is used for deuterium (2H). For the method of synthesizing the compounds herein, starting materials can be prepared by those skilled in the art using commercially available or well-known methods or derivation by procedures analogous to those described in the literature. Examples and formulations illustrate the method and use of the present invention. It should be understood that there will be other embodiments within the spirit and scope of the invention.

Summary of the invention

In the first aspect of the present invention, the ㅏ compound or composition contains at least one compound of the following formula:

Or salts, solvates, hydrates, or the like, for use in methods for improving, preventing or combating cancer by pharmaceutically acceptable treatment thereof, or for use in methods of treating diseases or conditions selected from cancer of (I) Cancers in which prodrugs can be differentiated from surrounding tissues by, for example, the Warburg effect and/or PET imaging (eg 18F-FDG PET) of glucose and/or glutamine with metabolic degree; (Ii) cachexia or cancer driven cachexia; remind

Ar-shaped ^A1 and RA2 are each independently selected from the group

과

and

RC and RD are each independently selected from hydrogen, halogen and alkyl, Re is hydrogen, or alkyl;

Ar ^ratio RB1, selected from hydrogen and deuterium;

R ^B1 phenyl, benzyl, pyridyl, pyridazinyl, and optionally RB2 substituted with one or more substituents;

Each of the above R ^B2 halogen, alkyl, alkoxy, nitro, amino, methoxy and poly halogen alkyl;

Or R is phenyl of the ^non- formula:

RF and RG are hydrogen or alkyl, G is a carbon-carbon double bond or carbon-carbon single bond, where n, q is 0, or 0 or 1 with 0 or 1, q, G is double carbon- Carbon and bond, q is 1, G is carbon-carbon single bond,

Or RB is a chemical formula and diphenyl alkyl

RH is hydrogen or halogen, and p is 0, 1 or 2;

Or RB is

The RJ and RK each independently represent any 1-5 substituents on each ring, and each RJ and RK present is selected from halogen, alkyl, alkoxy, nitro, amino, methoxy and poly halogen alkyl.

In some embodiments, RB is a group:

.

In some embodiments, RB is a group:

The RJ and RK each independently represent 1 or 2 substituents on each ring, and each RJ and RK is each independently selected from halogen, alkyl, alkoxy, nitro, amino and poly halogen alkyl.

In some embodiments, each RJ and RK is each independently selected from halogen, and RJ and RK are each independently representing one or two substituents on each ring.

In some embodiments, RJ and RK are selected from halogen, and RJ and RK each independently represent a substituent on each ring.

In some embodiments, RB is a group:

RL and RM are each independently selected from halogen, alkyl, alkoxy, nitro, amino and poly halogen 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, RA1 and RA2 are each selected from independent groups

The RC and RD are each independently selected from hydrogen, halogen and alkyl.

In some embodiments, RA1 and RA2 are the same.

In some embodiments, RC is hydrogen. I N Some examples Rd is hydrogen. In some embodiments, RC and RD are the same. In some embodiments, RC and RD are both hydrogen.

In some examples, the compound is:

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In some embodiments, the compound isotopologue(s):

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

Almitrin dimesylate patients have been used clinically to treat chronic obstructive pulmonary disease (COPD) in the millions of months. However, after decades of use, it is now used sporadically. This is because post-marketing surveillance revealed that there is no better/working COPD treatment, especially in the treatment of chronic obstructive pulmonary disease, where there is no compensation to outweigh the risk of subsequent side effects. The present invention changes the use of anti-cancer treatment almitrin. The new experiments here show that the strong anti-cancer activity exerted by imitrindimesylate, than carboplatin in the standardized NCI-60 test by the National Cancer Institute (NCI, USA). Carboplatin is one of the most used chemotherapy today and is on the World Health Organization (WHO) Essential Medicines () list.

Since the compound is reduced, it exerts anti-cancer activity and hydrolyzes in F1F0 ATP cancer cells described herein, including yealmitrin dimethylate. This revealing mechanism is the heart of the invention. Here is the reverse mode of ATP synthase: the discovery of cancer-specific drug targets. Indeed, new experimental data have been disclosed herein, specifically prohibiting the molecule F1F0 ATP hydrolysis may exert certain anticancer activity, at concentrations that do not damage normal cells. Correlated anticancer agents are components of the present invention that target/inhibit F1F0 ATP hydrolysis. The present invention is also a composition of a new material, which is a working example in the present invention, which is the number of various anti-cancer agents working examples disclosed in the rationale and method, and in turn, the components are found and included in this specification.

Almitrindimesylate6-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]-2-N, N-4-bis(prop-2-enyl) -1,3 ,5-triazine 2 1,4-diamine methane sulfonic acid, dimethanesulfonate salt of almitrin. Almitrin has the following structure:

In addition, cancer, in particular, exerts a Warburg effect, using a pharmaceutical composition and an effective amount of a compound of one or the formulas described herein for the prevention or treatment of cancer in a subject,

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein

L is alkyl or substituted alkyl, or deuterated alkyl, or amino or thio alkyl or alkoxy, halogen, or halo alkyl, or halo, or any atomic isotope is valence-allowed (including attached hydrogen valences, 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) hetero3 formation with R3;

R3 is independently alkyl, substituted alkyl thio, amino alkyl, carbamyl, BB aryl, BB-hetero, BB heteroaryl, or BB cycloalkyl, or (ii) phenyl optionally C1-4 alkyl, halogen, trifluoro methyl Substituted (i), phosphorus OCF3 is cyano, nitro, amino, hydroxy or methoxy, or (iii) optionally having independently, C1-4 alkyl thio, amino, -BB aryl, hetero-BB-, BB R3a selected from cycloalkyl, and -BB heteroaryl is one selected from three substituents; And/or R2 in these fused or (IV) having a 5 or 6-membered carbocyclic ring together with an optionally substituted alkyl or substituted heteroalkyl;

BB is C1-4 alkyl, C2-4 alkenylene, substituted C1-4 alkyl, substituted C2-4 alkenylene bond, substituted C1-4 alkyl-C (= O) NH-, -C (= O) NH-, -C1-4 alkylene-C (= O) NH-, -C (= O) NR19-, -C1-4 alkylene-C (= O) NR19- or substituted C1-4 alkyl-C (= O) NR19-,-(CHR14) M- (CR15R16) N- or-(CHR14) pC (= O) NH-;

In each case R3A is independently selected from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, keto, trifluoromethyl, -NR17R18, -SR17, -OR17, -SO2R17a, -SO2NR17R18, -NR17C (= O) R18, -CO2R17 -C (= O) R17 R3a is cycloalkyl, aryl, heterocyclo or heteroaryl, cycloalkyl, arylheterocyclohetero, heteroaryl is optionally substituted with alkyl or alkyl substituted Cyclo alkyl, arylhetero cyclo, and hetero aryl;

Z is, for example, heteroaryl for an optionally substituted heterobicyclic; or

Z is optionally substituted with two R7 substituents, one substituted with R7 substituents, or imidazolyl and/or once substituted with any R7 substituents, fused to a benzene ring

R7 is alkyl, carbamill, or substituted alkyl;

In each case, R4 is independent of each other from the group consisting of halogen, trifluoromethyl, OCF3, alkyl, substituted alkyl, halo, nitro, cyano, halo, OR25, SR25, NR25R26, NR25SO2R27, SO2R27, SO2NR25R26, CO2R26, C Selection of R4 (= O) R26, C (= O) NR25R26, OC (= O) R25, -OC (= O) NR25R26, NR25C (= O) R26, NR25CO2R26, aryl, heteroaryl, heterocycloalkyl and ;

R8 is C1-4 alkyl or phenyl optionally substituted with alkyl, halogen, haloalkoxy, cyano, nitro or trifluoro methyl;

R9 is -NR10R11 is alkyl, substituted alkyl, alkoxy, alkyl thio, cycloalkyl is aryl heteroaryl, heterocyclo, or -CO2R12 is alkyl or phenyl is halogen, cyano, trifluoromethyl, nitro, nehydroxy , Substituted with C1-4 alkoxy, halo, C1-6 alkyl, CO2 alkyl, SO2 alkyl, SO2NH2, amino, NH (C1-4 alkyl), N (C1-4 alkyl) 2, NHC (= O) alkyl , C (= O) alkyl, and/or optionally substituted with one of three C1-4 alkyl trifluoro methyl, hydroxy, cyano, phenyl, pyridinyl; And/or alternating 5 or 6 membered hetero aryl or optionally heterocycloketo substitution or fusion having a benzene ring thereto or

a) C1-4 alkyl, optionally substituted with either:

Iii) SR13, OR13, NR13aR13b, halogen, trifluoromethyl, CO2R13a and C (=O) NR13aR13b;

Ii) said phenyl alkyl optionally substituted with C (=O) H, C 1-4 acyl, alkenyl, carba do one substitution, and/or halogen;

Iii) phenyl or halogen, nitro, amino, alkyl, two or one substituted naphthyl having a hydroxy number fused to a C1-4 alkoxy, or a 5 or 6-membered hetero;

Iv) having a 5-6 membered carbocyclic ring fused to a dienyl, thiophenyl, furanyl, tetrahydrofuranyl, or azepinyl, optionally substituted alkyl or optionally keto or C1-4 alkoxy

b) a 3-6 membered cycloalkyl optionally has a tetrasubstituted group in turn selected from alkyl, halogen, cyano group, alkenyl, acyl, alkyl thio, carbamyl, phenyl substituted with halogen; Or having aryl fused to it

c) Phenyl is halogen, cyano, trifluoromethyl, nitro, four substituted hydroxy, C1-4 alkoxy, halo, C1-4 alkyl, CO2 alkyl, SO2 alkyl, SO2NH2, NH (C1-4 alkyl), N (C1-4 alkyl amino) 2 NHC (= O) alkyl, C (= O) alkyl, and/or optionally substituted with one of three C1-4 alkyl trifluoro methyl, hydroxy, cyano, phenyl, pyridinyl; And/or keto or optionally a benzene ring, which in turn has a conjugation with a half-membered heteroaryl or heterocycle;

D) phenyl substituted with two of pyridinyl, thiazolyl, furanyl, thiophenyl, pyrrolyl and halogen, alkyl, in turn d) halogen or trifluoro substitution;

R10 and R11 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocycloalkyl, aryl, heteroaryl or C1-4 alkyl wherein (I) is optionally substituted with two -CO2 alkyl, -C (=O ) NH (aryl), NH (aryl) cycloalkyl, phenyl, optionally C1-4 alkyl, hydroxy, C1-4 alkoxy, halogen, amino, nitro, tetrahydro sequentially substituted phenyl, and/or 5 or 6-membered hetero Or a 5 or 6-membered heterocyclic fused to it; Keto optionally substituted pyrrolidinyl; Naphthyl, anthracenyl, pyridinyl, thiophenyl, furanyl, imidazolyl, benzimidazolyl, indolyl or turn optionally substituted with C1-4 alkyl or C1-4 alkoxy; Or (ii) formed together with hetero or hetero hetero R10 and R11 selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, tetrahydropyridinyl and imidazoilidinyl, optionally keto, CO2H, C14alkoxy, CO2alkyl, C1-4 cover mill benzyl two are substituted; Phenyl in turn is optionally substituted alkyl, halogen or C1-4 alkoxy; Tetrahydropyridinyl in turn optionally substituted with keto and/or phenyl; Alkyl is substituted with amino or NHR21 wherein R21 is an alkyl group which may be substituted with alkyl or phenyl; And/or the benzene ring is fused to C1-4 alkoxy, CO2 alkyl, and/or C1-4 carbamill, which in this case is again optionally substituted with two alkyl; Alkyl is substituted with amino or NHR21 wherein R21 is an alkyl group which may be substituted with alkyl or phenyl; And/or the benzene ring is fused to C1-4 alkoxy, CO2 alkyl, and/or C1-4 carbamill, which in this case is again optionally substituted with two alkyl; Alkyl is substituted with amino or NHR21 wherein R21 is an alkyl group which may be substituted with alkyl or phenyl; And/or the benzene ring is fused to C1-4 alkoxy, CO2 alkyl, and/or C1-4 carbamill, which in this case is again optionally substituted with two alkyl;

R12 and R19 are hydrogen or alkyl;

R13 is hydrogen or alkyl;

R13a and R13b are selected from hydrogen, alkyl and aryl;

In each case R14, R15 and R16 are independently selected from hydrogen, alkyl, hydroxy, hydroxy C, C1-4 alkoxy and phenyl, and/or one of R15 and R16 is one 3-6 membered cycloalkyl group Are joined together to form;

R17 and R18 are independently selected from phenyl or benzyl hydrogen, alkyl, substituted alkyl, aryl, phenyl or benzyl, optionally substituted with alkyl, hydroxy, or hydroxy;

R17a is alkyl or substituted alkyl;

R25 and R26 are independently taken together to form hydrogen, alkyl or substituted alkyl, or heterocyclo or heterocycle;

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:

Here, refer to the structure of the group around the chiral center shown in the above configuration, regardless of the specific identity of the variable as Z, L and R4 within the term and "- stereo S" "S is an enantiomer". This is a chiral setting, denoting S Z for nitrogen, L for deuterium, for example by IUPAC name. However, here, S does not limit what can be Z or L according to the stereoscopic IUPAC nomenclature of this atom. For example, here, Z can be carbon (or nitrogen or other atoms as defined herein), even though S is written next to this chiral carbon. The R group type alias, such as Z and L, is attached to all unused atoms, however, designated around the chiral carbon following the unique stereoscopic IUPAC name.

In some embodiments, the S enantiomer of a compound is an enantiomeric excess. In some embodiments, greater than 70% enantiomeric excess S-isomer.

In some embodiments, L is hydrogen or deuterium.

In some embodiments, L is alkyl, or deuterium, or substituted alkyl, or deuterated alkyl, or amino or thio alkyl or alkoxy, halogen, or halo alkyl, or halo, or any atomic isotope is naturally present or Hydrogen valence exclusion allowed;

In some embodiments, the compound is a compound according to the formula

Or a pharmaceutically acceptable salt, solvate, hydrate and prodrug thereof,

The D is deuterium (and, optionally, at other locations, exceeding 40% deuterium introduction at the locations shown, eg enriched).

In some embodiments, the compound is a compound according to the formula

Or a pharmaceutically acceptable salt, solvate, hydrate and prodrug thereof,

remind D is deuterium (and optionally in excess of 40% deuterium incorporation at the location shown, for example at a different location, eg enriched);

The enantiomeric excess (ee) in excess of 70% S represents, for example, the S stereoisomer.

In some embodiments, the compound is

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the enantiomeric excess (EE) of the R stereoisomer is greater than 70%.

In some embodiments, the compound is

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the enantiomeric excess (EE) of the S stereoisomer is greater than 70%.

In some embodiments, the compound is

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the enantiomeric excess (EE) of the S stereoisomer is greater than 70%.

In some embodiments, the compound is

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the enantiomeric excess (EE) of the R stereoisomer is greater than 70%.

1, 2, 3, 4, 5, 6, 7, 8, showing anti-cancer BMS-199,264 (10 μM), BMS-Gemsi activity (10 μM), BTB06584 (10 μM), BTB06584 (100 μM) 199,264 (100 μM), compound 31 (10 μM), and almitrindi mesylate (10 μM) in NCI analysis, respectively (at 10, 100 μM), FIGS. 6A and 6B. The previous figure also incorporates the data from 9 F1F0 to inhibit ATP hydrolysis to show the corresponding anticancer activity scale. In NCI five dose analysis, 11 of BMS-199264, FIG. 6A and FIG. 6B, anticancer activity, and FIG. 10 is anticancer activity. The data to be readjusted 12 from the analysis data of FIGS. 8 and 8, 11 to 11, and in vivo mouse data for compounds 6a and 6b also interpret the data of 12 to 14 as gifts of 10 to 15. Figure 16 Experimental data for racemization rate in gift (6b).

F1F0 ATP reduces hydrolysis The compounds of the present invention are also available for treatment / improvement / prevention / combat other diseases, disorders and conditions. A compound of attack cancer properties of the present invention shared with embryonic stem cells found in the adult human body but not in blastocysts ~5 days after fertilization. Thus, the compounds of the present invention have the utility of preventing unwanted pregnancy with windows later than the currently available options. Decreased F1F0 ATP hydrolysis reduces the ATP synthesis and hydrous useless cycles used in the human body for fever (supported by mouse data herein). Exogenous heat, this reduces energy (food) consumption (higher room temperature, more geographically repositioned, such as clothes, tropics) decreases when replacing endogenous heat and improves / improves / prevents / combats cachexia, cancer-driven cachexia and weight Decreased, cachexia is the leading cause of cancer patient death. If the oxidative phosphorylation rate is reduced by means of ATP synthesis/decomposition cycles, the slower and less ROS is produced and the body aging slows, i.e. accumulates less ROS damage per unit time. Thus, the F1F0 ATP hydrolysis inhibitor of the present invention and life span, CAN enlargement treatment / improvement / prevention / combat accelerated aging disease, premature aging disease and diseases of aging (eg Alzheimer's disease, dementia, Parkinson's disease, cancer, etc.). While many current cancer therapies (e.g. radiation therapy) increase the risk of cancer, this prevents cancer notable for both compounds of the present invention. Activated macrophages differentiate macrophage breaks, and of other normal adult cells Nitric oxide F1F0 ATP they hydrolyze to maintain ATP because they produce kill kills the use of pathogenic oxidative phosphorylationΨIM. Inhibition of the compounds of the present invention F1F0 ATP hydrolysis, etc. Invert ΨIM is apoptosis-inducing activity of its own (rested and omitted) macrophages. Compounds of the invention may be treated/improved/prevented/combat macrophage-related diseases or disorders (e.g., when macrophages are discontinued or when macrophages are activated, macrophages activated here during antiretroviral therapy {ART} Safely from HIV's leather, replenishes the HIV virus through viral macrophages from plasma, where HIV-related neurocognitive disorders, tumor-associated macrophages (technical account managers) are large components of the tumor mass, ) It is an essential distance for cancer pathology, correlation with the prognosis of poor patients. With increased F1F0 ATP, hydrolysis inhibitor metabolism/bio energy efficiency (less heat is generated), therapeutic, aesthetic, physical/psychiatric high performance applications, May cause energy/weight gain in subjects with commercial applications for livestock and agriculture. The compound of the present invention can reduce the F1F0 ATP hydrolysis and control the ambient temperature at room temperature (the body temperature can be reduced by the cross control value, and the compound cannot be allowed to room temperature only under the body drop) with the maximum effect on the compound administration. Treatment / Improvement / Prevention / Combat Hypothermia causes diseases or disorders higher than normal body temperature (e.g. fever, infection, sepsis, malignant hyperthermia, neuroleptic malignant syndrome, etc.) and disease or disorder combat (or surgery or treatment help) (For example, after stroke or ischemia, nerves / cardiac protection / tissue protection, surgery, etc., stop hypothermic circulation).

One aspect of the present invention is a pharmaceutical composition comprising one or more compounds described herein and a pharmaceutically acceptable carrier or diluent.

Aspects of the invention as described herein are used in a method of treating a human or animal body by compound or composition therapy.

The object of the present invention is a compound or composition as used hereinfor a method of treating, alleviating, preventing or combating a disease or condition selected from

For example, many (I) cancers (e.g. ⁽¹⁸⁾ F- ⁾ of glucose and/or glutamine metabolism with cancer lactic acid indicating cancers that can be distinguished from surrounding tissues by the Warburg effect and/or PET imaging FDG PET);

(Ii) cachexia, cancer cachexia center or weight loss;

(III) Separator intake, cause disease or disorder (e.g., 2,4-dinitrophenol), infection, sepsis, stroke, fever, fever, hyperpyrexia, high fever, malignant hyperthermia at higher ambient temperatures than normal body temperature , Neuroleptic malignant syndrome, serotonin syndrome, thyroid storm, heatstroke, thermoregulatory disorder(s), Kawasaki syndrome, fever caused by drug or drug withdrawal, unusual drug reactions, fever of unknown or uncertain origin, incompatible blood product ( Response), metabolic disorders (S), cancer, injury;

(IV) Tumor-associated phagocyte (Tech Account Manager) or macrophage activation syndrome (MAS), phagocytic disease or disorder such as HIV, AIDS, HIV-related neurocognitive disorder (hand), HIV-related cancer, AIDS-defined cancer, non-AIDS Defining cancer;

As used by phagocytic via (V) neuroinvasive virus, HIV and SARS coronavirus, for example,

(VI) neurocognitive or neurodegenerative diseases/diseases, for example by viruses;

(Iii) acute or chronic systemic inflammation or inflammatory disease / disorder / syndrome or auto-inflammatory disease / disorder / syndrome or autoimmune disease / disorder / syndrome;

(I) lower than desired metabolic abnormality/sub-bio energy efficiency, or lower or lower than desired body-body performance or lower than desired body weight;

(IX) Deep circulatory hypothermia, a disease by conferring hypothermia on the subject for several medical or other purposes, which may include slowing down the rate of chemical reaction(s) to the subject for therapeutic effect/minimizing brain and/or tissue damage Or disease treatment cardiac and/or cardiovascular surgery and/or brain surgery (neurosurgery) surgery, hypothermia for the purpose of surgery, arrest for hypothermia, emergency preservation and resuscitation (EPR), eg, limbs and/or organs (poem) Long-term storage and/or transplantation of body parts, such as separate preservation temperature management targets, protective hypothermia, therapeutic hypothermia, neonatal brain disease, birth suffocation, bleeding, hypovolemia, hypothermia for decompression sickness, skin burns, inflammation, Burn injury(s) including allergic reactions anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, oxygen deficiency, anemia, hypervolemia, altitude sickness, airway obstruction, asthma attacks, body/tissue/organ, hypoglycemia, Hypoxia (ischemia-reperfusion injury) on reperfusion injury, ligature or tourniquet at release, uremia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (e.g. For meningitis), sepsis, septic shock, ischemic brain / heart / kidney damage, nerves and / or / cardiac protection and / or tissue protection during stroke and / or ischemia and / or heart attack and / or resuscitation and / or subject Where in the flow poor blood after period(s); ligature or tourniquet, uremia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, asthma attack, body/tissue/organ, hypoglycemia, reperfusion following release of major trauma Hypoxia, (in ischemia-reperfusion injury), damage, infection, bacterial and/or viral infection(s) (e.g., meningitis) after stroke and/or ischemia / during, sepsis, septic shock, ischemic brain / heart / kidney Damage, nerves and/or Heart protection and/or tissue protection/or heart attack and/or resuscitation and/or poor blood flow to the subject where period(s); ligature or tourniquet, uremic syndrome, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major Hypoxia, asthma attacks, body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), infection, bacterial and/or viral infection(s) (e.g. meningitis) stroke and/or following trauma release Post ischemic/medium, sepsis, septic shock, ischemic brain/cardiac/kidney damage, nerve and/or heart protection and/or tissue protection/or heart attack and/or resuscitation and/or poor blood flow to the subject where period(s) ); Bacterial and/or viral infection(s) (e.g., meningitis), sepsis, septic shock, stroke and/or ischemia and/or post-cardiac ischemic brain/cardiac/kidney injury, nerve and/or heart during Protection and/or tissue protection arrest and/or resuscitation and/or poor blood flow to the subject where period(s); bacterial and/or viral infection(s) (e.g. meningitis), sepsis, septic shock, stroke and Ischemic and/or ischemic brain/cardiac/kidney damage after nerve, and/or cardiac protection and/or tissue protection during arrest and/or resuscitation and/or poor blood flow to the subject where period(s);

Subject of (x), eg carbon monoxide/methanol/heavy metal/pesticides poisoning, snake/spider/bee/insect/lizard poison metabolism poison(s), bacterial toxins (poisoned by toxic dose(s) of compounds of S) , My toxinemia drug/drug overdose, for example, heroin, ethanol, prescription drug(s) or counter drug treatment(s);

(XI) aging disease or Werner syndrome, Bloom syndrome, Rottmund-Thomson syndrome, Cockayne syndrome, dry skin pigment, trichothiodystrophy, connective scleroderma pigment-Cockayne syndrome, limited dermopathy, WIEDEMANN-Rautenstrauch syndrome, Hutchinson-Gilford's Premature ejaculation syndrome (accelerated premature ejaculation);

(XII) associated with elevated reactive oxygen species, neurodegenerative diseases, muscular atrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, including diseases or disorders of aging (increased age / increased aging) and/or degenerative diseases Diseases/diseases, Huntington's disease, spinal cerebellar ataxia, Friedrich's ataxia, dementia, fixative disease, polyglutamine disease, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, chronic obstructive pulmonary disease (COPD), hypertension, arthritis, cataracts, type 2 diabetes, male climacteric, muscular dystrophy, age-related macular degeneration (AMD), hearing loss, movement disorders, cancer;

These compounds have slow aging, prolonged life and health span, aging (XIII); or

(14 years old) skin aging.

Another aspect is a method of combating such a disease or disorder by administering an amount of a compound or composition effective for treatment, amelioration, prevention or treatment of a patient in need thereof as described herein.

Another aspect is the use of a compound or composition described herein for the manufacture of a medicament for treatment, alleviation, prevention or combating such a disease or condition.

In some embodiments, the subject is more than one compound or composition approved for human use, optionally for anti-cancer use by the U.S. Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) in the same pharmaceutical Dosage composition.

In some embodiments, a milligram/kg dose will be administered to a patient of a body size smaller than or equal to the step of administering to a patient at a dose greater than or equal to the dose administered to a patient. ) Are mice stored at 22°C with a dose of less than a milligram/kg.

Detailed description of the invention

As used herein with reference to the utility, the term "treatment" or "treatment" encompasses both designed to prohibit reactions and preventative measures or delay or mitigate, ameliorate, alleviate, reduce or reduce the onset of a disease or disorder. Description Treat a disease or disorder and/or one or more of its symptoms. The terms “subject” and “patient” refer to the organism to be treated by the compound/reference method or human or animal of the present invention.

The hinge of the present invention in search The present invention relies on some cancers, the F1F0 ATP disclosed herein also in hydrolysis normoxia (actually under high oxygen concentration: ~21% O2), during some or all of its cell cycle. Evidence is here: it is particularly inhibited Compound F1F0 ATP hydrolysis of the present invention, slow cancer proliferation at concentration does not damage normal cells.

Some of the most dangerous cancers of this refractory [Chimo/Radio] Among the treatments or reduction of all reactive oxygen species (ROS) in the cell cycle [NADPH], NADPH is consumed during the ROS alleviation process and then pulled through the phosphate pathway (PPP) Fructose increases flux pentose. However, only significant increases in sugar/PPP flux can cause F1F0 ATP hydrolysis, ATP stop The unique function of these cancers is the production of sugars that slow down sugar by inhibiting negative feedback of integrated key glycolytic enzymes. This keeps increasing PPP flux [NADPH] ROS and relaxation. In this way, these cancers tend to be the most resistant to conventional [chemotherapy/radio] treatment, or work that often does not work (maintain very low intracellular [ROS], maintaining very high ROS alleviation) Yes, by increasing ROS]. The compounds of the present invention weaken this process/resistance. By inhibiting F1F0 ATP hydrolysis, they have increased free radical species (ROS) in cancer cells to increase the anticancer efficacy of any chemical or treatment. An embodiment of the invention is such joint treatment(s). Indeed, the compound(s) of the present invention allows its use at low doses, which increases the success rate of care [Chimo/Radio] on a cautionary basis and reduces its terrible side effects. The present invention includes the compound(s) of the present invention in chemotherapy or radiation therapy or US combination therapy. The Pharmacy of Food (FDA) and/or European Medicines Agency (EMA) is for example drug(s) or treatment, cancer Approved medication/treatment approved for treatment. Chemotherapy is of course known to people in the art, including, but not limited to, cisplatin, carboplatin, taxol, oxaliplatin, etc.

In another embodiment, the compound(s) of the invention are used alone as a cancer treatment. In fact, this is a much better way to treat cancer targets. ATP consumes sugar ATP to obtain the highest risk rate for cancer, the most dangerous cancer with distinctive synthosis, and this unique metabolism is abundant sugar intermediates and crucial for biosynthesis there (ROS as previously disclosed) ROS] low maintenance cancer immortality ("infinite Replicative potential" required for proof of cancer quality [26]) so risk. This distinction is targeted, by the compound(s) herein, without serious damage to normal cells. Normal adult cells typically use ATP forward mode, higher ATP yield from glucose, more synthetic enzymes and other metabolism, but higher [ROS] and cost of mortality.

Depending on the forward mode of the ATP synthase, this dependence of normal cells is exquisitely fragile. Because of the compounds of the present application, their distinction from oligomycin, which could not have been foreseen without the inventive steps of the present application, is useful for oligomycin, anti-cancer treatment. Active breathing Normal cell (also known as [tri]) state, also called state 3 respiration, state 3, state 4 Transitional polarization ΨIM, decreased O2 consumption and reduction [ATP] Causes inhibitors of the forward mode of ATP synthase (oligomycin) (ATP synthase so-called "modulator" example Bz -423, may cause this effect at certain concentrations of ATP synthase reverse effect of certain inhibitors of these effects during one or more) ([12-13] All of the present) are included. However, after inhibition of the respiratory chain at the present concentration of concentration (e.g., at a lutein blocking or other respiratory chain enzyme inhibitor, or at a reduced O2 concentration), it will be said to inhibit the specific inhibitor ΨIM of the reverse mode of ATP synthase. The reverse mode of this function inhibits ATP is significantly greater than that of inhibiting the ATP synthetase/modified forward mode, and/or inhibiting/modifying ATP synthesis. These molecules are put into use for anticancer treatment, and are examples of the present invention. Another example is the process/method of finding a new anticancer molecule to analyze whether a candidate molecule can be ΨIM, passive, if maintained by ΨIM F1F0 ATP hydrolysis (e.g. OXPHOS is a respiratory chain enzyme inhibitor or When it is blocked by insufficient O2) but when its ΨIM hyperpolarization and/or ΨIM is maintained by the proton pump by a complex of respiratory chains, it is not possible to reduce O2 consumption. If the candidate molecule meets these requirements, it is an anti-cancer treatment, as determined by the present invention.

Some cancers revealed by the experimental data herein essentially rely on ATP synthase in reverse, and further to maintain ΨIM in hypoxia of solid tumors that make the cancer vulnerable to drugs, this trust is imposed on them You can expose. Important lactic acid data correlate with the most dangerous cancer poor patient outcomes (eg many studies find it: [27]). High lactic acid release indicates high sugar content, which is capable of F1F0 ATP hydrolysis, which is a drug of the present disclosure attack. The present invention is a means to selectively attack the most fatal cancers face to face by discovering/discovering cancer-specific weaknesses.

All of the following molecules are used as anti-cancer drugs-Examples of the present invention: Reverse Inhibition (1) Molecule, not forward ATP synthase mode, (2) Molecule (reverse inhibition more than ATP synthase forward mode 3) The reverse mode of the ATP synthase, and the anterior mode, but its shuttle proton across the inner membrane of the mitochondria, a molecule that inhibits PMF heat dissipation as heat (uncoupling [3]), which reduces F1F0 ATP synthesis and in another embodiment: uncoupling F1F0 ATP F1F0 is an ATP hydrolysis synthesis method to have a lower EC50 or IC50 band in the mitochondrial lining (5) more ATP synthesis than the ATP hydrolysis that inhibits the molecule than the additional F1F0 ATP synthesis for the reduced molecule F1F0 ATP hydrolysis see. The present invention discloses a process/method using one or more molecular species each characterized by treatment with an anticancer agent or one or more of the above numbering points. Some examples are presented herein. Leverage, ATP synthase of the employment of cancer in its reverse mode is an embodiment of the present invention is a classifier or target dependent on all cancer treatments or treatments or drugs.

Mechanical identification from polyketide F1F0 ATP synthase inhibitors

Compound of the present invention method by a completely different mechanism in cancer cells than oligomycin. The action against the same molecular target is small, i.e. has a pattern similar to the activity for various cancer cell lines in the NCI-60 test, and inhibits its GI50 value (larger than the same cell line, 50% proliferation for GI50 cognitive drug cell lines Control occurrence compound concentration without drug ). (DIS) Similarity can be measured using a comparison algorithm [28-29], using the Pearson correlation coefficient. For example, the [30] comparison algorithm successfully found that the group's other FDA-approved anticancer drugs in their own way of action could use NCI-60 GI50 data. Oligomycin A (NSC: 717694[16]) inhibits F1F0 ATP synth[4, 14] so does other polyketides cytovaricin (NSC: 349622 [16]), NSC (ossamycin: 76627[16]) and peliomycin ( NSC: 76455 [16]); Indeed, their NCI-60 pattern responses were elevated and correlated with that of mycin (GI50 values): 0.896, 0.809 and 0.865, respectively (algorithm output, all significant comparisons at p <0.05). However, the NCI-60 pattern response of BMS-199264 (GI50 value) is elevated and non-correlated with mycin (0.009). Similarly, during the NCI test of compound (6b), i.e., the semi-ceramics during the NCI test, both of the corresponding directions were highly anti-cancer activity (0.754 correlated, as long as the stereoisomers of la semice 19A were isolated, not significant at 6A (p <0.05). , 0.198), p <0.00001). This mechanical distinction from oligomycin is important because polyketide F1F0 ATP synthase inhibitors are toxic to normal cells [15] and they are without clinical utility as a means to fail in cancer xenograft mouse experiments [16].

High HIF-1α ({2} and lower mitochondrial ATP synthase aminotransferase pyruvate kinase isoenzyme liver {}, lower aspartic acid) gene expression has been reported to be a marker of Warburg effect [14] of the polyketide F1F0 ATP synthase inhibitor correlated with cytovaricin insensitivity (p<0.05) (Table 1 [14]). In contrast, used for Table 1 using the same cell line and gene expression data set [14], there is no correlation (p<0.05) of BMS-199,264 sensitivity (GI50) of gene expression. Compound 6B of FIG. (p<0.05) is obtained. Marker correlation of the Warburg effect of high HIF-1α expression in practice (0.714, but statistically significant at p <0.05) (0.332 but statistically significant at p <0.05) High sensitivity to BMS-199,264 and 6B. Figure 5 [14] presents apoptolidin resistance NCI-60 cell line, because of resistance utilizing the Warburg effect [14], but the majority of these cell lines have a GI50 value, BMS- lower than the mean GI50 value (3.9 μM) of BMS-199264 It is more sensitive than the 19264 average.

It lowers the bioenergy cellular index (BEC) of cancer cells [18] and more it demonstrates the Warburg effect and no longer relies on sugar rather than oxidative metabolism. By measuring BEC, [19], the ratio amount of β subunits of F1 ATPase (β-F1-ATPase gene: ATP5B) row of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). I analyzed the same cell line BEC of the analysis in Table 1 [14] from each data line using the transcription amount of the mRNA of each cell line ATP5B and GAPDH [31-32] and then for each of these cancer cell lines ([ATP5B] / [GAPDH] cadavers Ratio). The use of protein data rather than transcript data is limited,[33] the amount of cells in a protein is generally well, at least for a subset of the proteins they study, at least in the NCI-60 assay, the amount of transcription of that mRNA (0.76) Report that there is a correlation. And also, [14] transcript data, too relying on the best comparison [14] are produced using these data. Polyketed F1F0 ATP synthetase inhibitors do not work well for cancer cells that show a Warburg effect [14] and, in fact, cell lines (same analysis used as in Table 1 [14]) oligomycin A (-0.9411) There is a significant (P <0.05) negative Pearson correlation between LOG10 (GI50) and BEC. So, this correlation show that uses more Ambarburg's metabolism shows less risk of low BEC scores (indicating Warburg's metabolism) and this characteristic greatly reduces the usefulness of oligomycin like cancer medicine A. Oligomycin Alleviated by the worst patient outcomes and the most dangerous of cancers [18-20]. In contrast, the BMS-199,264 and BEC (0.3639) US Pearson correlations (p<0.05) were not significant. 6B and BEC (0.0298) or. Obviously the enzyme synthesizing inhibitor from polyketide F1F0 ATP, this method is not restricted to cancer whose use of Warburg's metabolism in people, their anticancer action is often less risky.

Molecules of the invention attenuate cancer by inhibiting the reverse mode of ATP synthase. It is true that polyketide F1F0 ATP is also an enzyme that modulates inhibitors, but obviously, in addition, they also inhibit ATP synthase forward mode, more strongly true [11] This forward mode is very important for many cancers And because they exert anticancer activity, and, it is also important for many normal cells. It is not suitable as a polyke F1F0 ATP synthase inhibitor as a clinical molecule. Because of the molecule of the present disclosure, their distinction, the treatment of polyketide F1F0 ATP synthase inhibitors, not similarity.

[14]Many cancer cells retain the phenomenon known as the high-level historical Warburg effect of anaerobic carbon metabolism even in the presence of oxygen. From our results, we have shown that the mitochondrial F0F1-ATP macrolide inhibitor is selectively " Synthetic enzymes that kill metabolic active tumor cells that do not exhibit the Burgburg effect. So, [14] according to the forward mode of F1F0 so that only these macrolides are present, the cancer is performed using the forward mode F1F0-ATP synthase to generate ATP (unfortunately it is the metabolic profile of many major types of normal cells). Found to kill relying on OXPHOS -ATP synthase is the key to this (unspecified) anticancer activity. In contrast, the present invention exerts anticancer active molecules by inhibition of the reverse mode of ATP synthase. BMS-199264[4, 7, 9, 10, 11], BTB06584 [13], (31) [8] The stereoisomer 6B (and grasace, 19A) [5,6] can inhibit this mode As a molecule, the present invention, as described above, has demonstrated utility as an anti-cancer treatment, supporting experimental data to identify new anti-cancer agents targeting new cancer-specific drugs that are more fundamental/important: S1-ATP ( figure F1F0) 9 ). The stereoisomers opposite to 6B, both in FIG. 6A, and also due to anticancer activity (FIG. 8 ), both racemize towards RACEM, 19A, 6B during NCI and NCI tests. BTB06584 (100 μM) is a function that inhibits F1F0-ATP hydrolysis () at ≥100 μM anticancer activity (Volume Figure 3 ), does not inhibit F1F0-ATP synthesis, and normal cells (mouse cortical neurons) at this concentration None and very crippled [13]. Its anti-cancer efficacy (during observation at 100 μM to 10 μM, respectively 2 and 3) is inconsistent with the inhibitory efficacy for F1F0-ATP hydrolysis (no one at 10 μM needs ≥100 μM [13]). BMS-199264 (10 μM) has anti-cancer activity (Volume Figure 4 ). It does not harm normal cells (living rat heart) at this concentration [11]. In the NCI five-dose trial [34-35], the average GI50 of BMS-199264 is 3.9 μM ( Figure 10 ) Low phosphorus / 102 FDA's better 62% approved for cancer treatment [30] Their average GI50 values are in Table 1 Source of [30]: All are directly comparable because they are supplied from NCI-60 five dose analysis too. In addition, in the NCI five-dose trial, the average GI50 for Figures 6A and 6B is 0.666 μM and 0.446 μM, respectively ( Figure 11 ), which is lower/lower than 77% of FDA 102 for Figure 6B, for treating cancer Approved [30] containing cisplatin (GI50 mean = 1.4 μM) the most terrible side effects Typically, if not the chemotherapy used today, it is one of the most used. At 10 μM, 6B shows greater anticancer activity BMS-199264 ( Figure 9 ) Although it had less inhibitory synth than ATP's reverse mode BMS-199264, it had less effect on F1F0-ATP synthesis. Again, the proven anti-cancer active molecule of the present invention exerts by inhibiting the reverse mode of ATP synthase that can be used to differentiate them, and, apparently, to cure them. Indeed, the molecules of the present invention do not inhibit the forward mode of the distinct ATP synthase, which is significantly sharper in the macrolide system. Because they reduce the synthesis of SMP F1F0-ATP in compounds containing imidazole protonable nitrogen atoms, they emit a proton motif force (uncoupling), proton shuttle across the mitochondrial lining. Figure 17 Present structure activity data for this unbinding in whole cells using compounds with components of the invention as anticancer agents. BMS-199264 (Red log P = 3.79, calculated [25] calculated) is separated by more than 6b (Red log P = 5.97, [25]) is log P is closest log P = 3.2 (calculated) is optimal Because of it for uncoupling[36].

The racemate of 19, the S stereoisomer, the non-R stereoisomer, is strongly inhibited F1F0-ATP hydrolysis [5-6]. I tried to test the anticancer activity of the isolated stereoisomer. They were successfully separated by ultrafluid chromatography (SFC). However, after the NCI-60 test, the race is newly beautified. One stereoscopic sample delivers slightly better anti-cancer activity than the other, revealing more areas in the S stereoscopic exposure curve, and the possibility of the stereoisomer of S is slightly enduing enantiomeric excess (EE). (Both samples ultimately contained a significant portion of the stereoisomer of S and both had strong anticancer activity ( Figure 8 ). (R = 0.8 at 10 μM, 0.9437 at R = 100 μM) Pearson's correlation coefficient anticancer activity Their pattern (p <0.00001 AT) is important. This is a new substance composition that is a component of the present invention, as the racemization of S stereoisomers is slowed by replacing hydrogen atoms on the chiral carbon with deuterium atoms (supplementation), and conversely using them-cancer treatment. With this modification, the eutomer's perpetuate enantiomeric excess (EE) for abnormalities is longer, such as sugar unit anticancer activity is better. Analogues by inhibitors of macrolides [14] which [P1, P2, P3] teach that the S and R stereoisomers have the same anti-cancer activity and that they are relatively weak in both F1F0-ATP synthesis (EC50>100 μM in SMP Sey) It is weak because it is a reducer. In contrast, the S stereoisomers of the invention of the invention specifically manifest as potent anti-cancer treatments.

Stereoscopic reason

Some molecules of the present invention have a much lower IC50 than others to inhibit one of its stereoisomers, F1F0 ATP hydrolysis, and, by the invention of the present invention, this is the preferred stereoisomer for anticancer use. Indeed, a preferred embodiment for the treatment of anticancer in the form of such a preferred stereoscopic high enantiomeric excess (ee) is, eg, EE => 70%, EE => 95%> 99%, more preferably = 100%. However, EE can be eroded by racemicization. The present invention discloses improvements. Hydrogen attached to each chiral carbon is deuterium, deuterium, the natural abundance (substitutive chiral molecule, each substitution is specified by the present invention is 0.015%), this position is improved (AT example is not limited> 3000 hours of deuterium Above natural abundance, deuterium i.e. >40% incorporation). Deuterium Kinetic Isotope Effect (KIE)[37] Slow race beautification.

(Example)

The structure on the left has a low [EC50F1F0 ATP synthesis /EC50F1F0 ATP hydrolysis] ratio of F1F0 ATP hydrolysis (0.018 μM) against EC50> 5,556. Rat, this drug has good oral pharmacokinetics (47%) of oral bioavailability (47%) with (dose administered in polyethylene: water: ethanol 1:1: Cmax of drug half-life applied intravenously at 2.1 hours = volume distribution of 21 μM = 2.37 l / kg). Hydrogen atoms in chiral carbon are preferred to deuterated analogs on the right (KIE,[37]) because they give a large dimensional stability of the kinetic isotope effect. The greater the chiral carbon (carbon atom number 21) and the greater the excess enantiomer, the greater the concentration of deuterium, the more preferred embodiment. In other preferred embodiments, other atoms or isotopes, instead of hydrogen on chiral carbon, block racemization of sustained stereoisomer excess. For example, fluorine. Or carbon (methyl).

The most important innovation of the present invention is not the proposed structure, but the principle of discovery found: it is the best anti-cancer compound of the present invention, while inhibiting it, inhibits that strongly possible specific molecules such as F1F0 ATP hydrolysis and ATP synthetase molecules as small as possible Forward mode: Most desirable at all.

Cancer's immortality, destroying prolonged life

Unlike normal adult cells, cancer cell immortality example Hell cancer cells are the originator of the world's lab followed by a replica of time in the lab >> billions of times, they are sadly long after this killer dies lacking Henrietta. Interpretation of FIG. 13 (especially), experiments 11 and 12 of FIG. 8; Interpretation expanded here. Core: Immortality removal of cancer eliminates the risk of human rendering, normal cells in humans anyway without hurting. A is the most dangerous cancer and hyperpolarizes the correlation of ΨIM [38-43]. I insist that this function/mode is a function of cancer proliferation, and therefore more aggressive/dangerous cancer, the more time they spend in this mode of operation, thus the more chance it is detected on a scale by ΨIM imaging. In these cancer cells, ΨIM = about -200 rather than -140 mV is normal adult cells. ROS causes apoptosis, necrosis, and permanent growth arrest depending on the level of ROS [44]. Structurally activated oxidative phosphorylation (OXPHOS) in cancer cells either stops its proliferation [45-46] or pushes it to apoptosis [45-49], through intrinsic ROS production [47]. High F1F0 ATP hydrolysis, high PMF and hyperpolarizationΨIM (~ -200 mV), which drives high sugar velocity in cancer. This reduces the production of ROS while simultaneously reducing the "sink" drive for electrons entering the respiratory chain (this NADH competitive formula (outerna high lactate), especially upon), while simultaneously increasing F1F0 ATP hydrolysis, decreases ROX production and decreases OXPHOS rate [NADPH] and ROS mitigation. Therefore, cancer is increasing ROS relief, reducing ROS production. The result has lower cancer [ROS] than their normal cells at all in their constant information fidelity, allowing their "infinitely replicative potential" (immortality) to confer their risk. ROS-sensing fluorescent probes report higher [ROS] cancer than normal cells [50] and people in the art generally think that cancers do have higher [ROS], but these probes are cationic and are more hyperpolarized in ΨIM cancer cells Large concentrations (Nernst accumulation; Di-positive probes accumulating in hyperpolarization of Δ60 mV, nitro blue tetrazolium, etc. 100 times or more). Other ROS-sensing cancer studies reported extracellular [ROS] [51] and some cancer overexpressing NOX enzymes [52-53] significantly reduced intracellular O2 and [ROS] and produced extracellular [ROS] in plasma membranes. High mutation rates are inseparable, high mutation rates, loss ultimately too much information, limit there (not limitless) proliferation ability and mortality. Low damage to embryonic stem cells (ES), such as phenotype in the genome of cancer [ROS], excavate low mutation rates, high mutation rate Legacy high mutation load, terminate this state by DNA mutation/repair as a cancer cell abortion, at a higher rate The mutation that occurred, relative to its genome proximity, re-muted to this state. In most cases they are terminated by different mutant pathways (which terminate many DNA mutation pathways at low [ROS] destinations). Cancer, anti-mutator phenotype, predecessor and mutator era are culminated in normal adult bodies while ultimately dying, runaway damage/mutation in the loop. Raise [ROS] from cancer to attenuation of normal adult cell cancer risk. Indeed the impression [ROS] is smaller than this: Cancer has many embryonic stem (ES) cell characteristics [54-57] and infinite replication potential, and ΨIM over-polarization, more repairs of cells against ROS damage by cell death Reply ES[57]. F1F0 ATP hydrolysis-mediated inhibition in cancer cells ΨIM depolarization more OXPHOS greater [ROS, more OXPHOS [ROS] slows cancer cell proliferation and further inhibits F1F0 ATP hydrolysis, and cell death or necrosis caused by cancer cell die. Since ATP is less hydrolyzed by ATP hydrolysis by reducing ARO [ROS] and anticancer action, it can synthesize less ATP demands, so once switched to OXPHOS significantly reduces F1F0 ATP hydrolysis inhibition, reduces OXPHOS rate. So high doses of F1F0 ATP hydrolysis inhibitors (Figures 8, 11, 12) may have less anticancer activity seen in the experiments disclosed herein. Normal cells use OXPHOS and with slow aging and increased lifespan, this OXPHOS slows down, and can benefit less [ROS]. Therefore, F1F0 ATP simultaneously hydrolyzes inhibitors of wound cancer while revealing normal cells. They are particularly useful for disease(s) or premature aging and subject(s) accelerate, or prolong life in subjects without cancer. They extend the health span by delaying, and incidence, (their ROS increases contributing factors and/or increases the age of the disease/pathology reducing the disease of aging: numerous such diseases/pathologies known to people of art) , {Non-restriction}) Alzheimer's disease, dementia, Parkinson's disease, etc. But with caution. The present invention discloses a new basic biopsy supported by initiation in in vivo experiments (Figure 15): ATP hydrolysis F1F0 heat production and homeothermy are required bugs but are not functional. Thus, it reduces the generation of endogenous heat in patients in need of replacement with high ambient temperatures, such as self-exogenous heat by appropriate geographic (re)location, which inhibits F1F0 ATP hydrolysis of the subject. However, while this problem is very serious for small animals such as mice (~20g), much less rats (~150g), and less humans (~62kg). Simulations reported that [58] 30% reduction in human metabolic rate maintained for 4 hours (70 kg at room temperature at 20 °C, 170 cm), core body temperature drop by 0.18 °C. On the other hand, in experimental data [58] 30% of metabolism Less in the rats shown that the reduction markedly reduces mouse core body temperature. Another aspect of this is that F1F0 ATP hydrolysis inhibitors can increase their lifespan and reduce their OXPHOS rate by a large percentage, because ATP synthesis and hydrocycling generate futile heat that involves metabolic stages in smaller animals. Greater than. Indeed, if the ambient temperature is helpful, the F1F0 ATP hydrolysis inhibitor of the present invention will increase the lifespan of very small animals, and embodiments of the present invention can be used to improve the lifespan of rodents. Field), in terms of, for example, Mprize financial products or other benefits.

Due to the reduced flow of electrons along the respiratory chain, the F1F0 ATP hydrolysis inhibitor, which extends lifespan than the consultation of the present invention in animals compared to normal cells cultured in culture, reduces ROS production as well as reduces O2 consumption and increases partial pressure, which increases ROS production Ascending, in animals, on the other hand, their breathing slows down to keep the tissue oxygen partial pressure constant. Embodiments of the invention may use the F1F0 ATP hydrolysis inhibitor of the present invention in co-therapy with respiratory stimulants (non-limiting example doxapram) strongly elevated oxygen partial pressure therapy on blood and tissues / improvement / on this topic / combat cancer Prevent it. Indeed related, the compound of the invention -almitrin- increases the partial pressure of oxygen in the human body.

Eukaryotes must either maintain hyperpolarized ΨIM or will undergo cell death [59]. In cancers where OXPHOS of respiratory chain deficiency(s) is not available or because of hypoxic/oxygen-free environments (tumors are often hypoxia), F1F0 ATP hydrolysis inhibitors are the only means to maintain ΨIM, and subsequent ΨIM Sensitization triggers cancer cell death.

Treatment

Cancer can take advantage of aerobic glycolysis (Warburg effect) at one or more stages of the cell cycle. The yield of ATP in one glucose molecule is 2 ATP and ~30 ATP by aerobic glycolysis by oxidative phosphorylation [1-3]. The former produces 2 molecules for glucose and lactate, respectively, that can be converted to the cost of 6 ATP of glucose by the Cory cycle in the liver [1]. So, in this case, the overall ATP yield of aerobic glycolysis is -4. On the premise that the same energy is used, and assuming cancer, it is always unbalanced rather than using 1g to 34 times (potential) energy for aerobic sugar cancer use than normal tissue 1g. However, this cancer is generally underestimated because of its higher energy use: cancer using UCP2 mitochondrial matrix reversion protons and F1F0 ATP hydrolysis (overexpression in many cancers [60-61], can burn sugar ATP). In this release sugar ATP feedback inhibitory enzyme, high sugar and PPP rate, production of sugar biosynthetic intermediates and elevation [NADPH relief of increased ROS, where low [ROS, heterozygous lactic acid allow] significant correlation with cancer risk and blood [lactic acid] [27].When food intake does not increase with cancer development, growing cancer can use energy to normal tissue, meaning atrophy, which means it can be used for growing cancer, where more energy continues, a more positive feedback loop (cachexia) Rejectable cancer is the leading cause of patient death.By the present invention, F1F0 ATP hydrolysis inhibitor(s) among aerobic sugars with OXPHOS, switch cancer, related ROS, aging, mortality, improvement/prevention/removal cancer caused by subjects Associated cachexia therapy, this positive feedback loop break (s).F1F0 ATP hydrolysis inhibitor(s) also support cachexia patients by making them more efficient than normal cells that require less glucose, and subject(s)/improvement/prevention too / Can handle arm-driven cachexia outside of combat.

The therapeutically effective amount of the compound(s) that reduces F1F0 ATP hydrolysis is represented by the formula (I-VI), for example, the therapeutically effective amount of the compound (S administered in combination therapy) is inhibited UCP2 optionally The same or different pharmaceutical compositions (integrated into ones), subject to treatment/relief/prevention/combat cancer and/or cachexia. Non-limiting examples of compounds that inhibit Genipin and cisplatin UCP2, cisplatin acts on additional subjects.

temperature

Administered to the patient, F1F0-ATP hydrolysis inhibitor(s) (ambient <if body temperature) may fall to room temperature, and ATP, so less ATP should be synthesized, thus slowing breathing speed, thereby reducing metabolic heat generation and preserving body temperature. Experimental evidence is disclosed in Figure 15. So, the ambient temperature is not tough (to maintain a physiological/behavioral adaptive body temperature that does not require significant energy it takes) and the residence schedule of dietary intake, weight gain/maintenance Cancer may support cachexia, for example, cancer-driven cachexia. Cachexia is clinically useful because it is the leading cause of cancer patient death. If the ambient temperature is a body temperature required to be sufficiently close, the reduction in the next fever is safe because the body temperature may drop below ambient temperature. Thus, for example, if the ambient temperature is 37°C, it does not inhibit the hydrolysis of F1F0-ATP, but below, it can drop body temperature to room temperature and is safe because of ~37°C body temperature safety. Inhibiting the hydrolysis of F1F0-ATP decreases, but does not abolish metabolic heat production. Therefore, the body's metabolism is still safe because the body temperature is safe at ~37 °C, which will contribute to heating the body (less conditions that are known to the art are shifted to the thermal neutral heat pleasant zone. F1F0-ATP hydrolysis. Inhibiting decreases, but does not abolish metabolic heat production. Thus, the body's metabolism still contributes to heating the body, only less less being transferred to a comfortable zone of heat neutral heat (conditions known to the art this is ~37 °C body temperature It is safe because it is safe.Inhibiting the hydrolysis of F1F0-ATP decreases, but does not abolish metabolic heat production. Thus, the body's metabolism still shifts (the conditions known to the art to the heat-neutral comfort zone. Being less likely to contribute to heating the body [62], the temperature as well as the high temperature(s) are known by the industry and vary by species. Subjects are subject to their own updates, at high heat neutral temperatures, eg For example, if you are at a high temperature to account for these changes, or if you adapt to behavior (eg more dressed), these changes are harmless. Embodiments of the invention allow higher doses to be allowed at higher ambient temperatures Considering the compound(s) characterized by room temperature, the inhibitory F1F0 ATP hydrolysis dose is established, allowing the desired ambient temperature thermal neutralization of the administration, and/or by the F1F0 ATP hydrolysis lost due to the dose. The heat exchange is driven, comfortable heat without metabolism (breathing) fraction.The temperature management problem is smaller than the larger animals because large animals such as mass scales (eg see Kleiber's Law) maintain the heat generated better by superficial fractional power More important (because of a given percentage drop in mass per unit) Metabolism can cause a small drop in body temperature in larger animals Livestock/farm animals or commercial value eg when applied to any animal, such as a racing animal, or commercial value : Weight gain above (by non-limiting example of bodybuilding) Large clinical / health / nutritional value Chi, like a horse that may be of aesthetic value. The present invention includes methods/processes using other compounds of the present invention such that these applications or weight, nutrition or energy gains are multiples of animals or humans. Extended life of the subject. In one embodiment, the effective dose of the hypotonic dose of F1F0 ATP hydrolysis inhibitor reduces room temperature magnetic body temperature, so the hypothermic amplitude is controlled by setting the ambient temperature, which is controlled by controlling the ambient temperature. Another embodiment is that the body of the body temperature is controlled by controlling the function(s) of electromagnetic radiation to the subject upon administration of an effective amount of the F1F0 ATP hydrolysis inhibitor, for example, from a radiant heater (S) optionally desired low body temperature Controlled by set point set and servo control at body temperature

Most cancers develop fever on the subject. By the invention of the present invention, F1F0 ATP hydrolysis inhibitor exerts anticancer activity [ambient <if body temperature, can reduce body temperature. Therefore, in the embodiment of the present invention, the subject is, for example, a method of taking a compound of formula (I) or administering an effective amount of the compound(s) of the present invention, (II), (III), (IV) or (V) or another compound is selective F1F0 ATP hydrolysis, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug suppression treatment / alleviation / prevention / combat cancer and cancer associcated fever, especially (but not limited) The following cancers known by people of the art to drive fever in many cases, not more than one: Non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, acute leukemia,

The compounds of the present invention that inhibit the hydrolysis of F1F0 ATP have utility for making animals and/or humans feel more comfortable in hot weather, climate and regions. For example, during the hot summer, it is filmed or managed, especially by the elderly, people.

The temperature behavior of the compounds of the present invention is not related to the NCI-60 test . In these studies, the ambient temperature is controlled at 37 °C [35], which is optimal for cells, therefore making these drugs room temperature cellular temperature drop is not harmful. It can still be a problem for laboratory animal research. Experimental mice, e.g., usually maintain very reliably at room temperature (e.g., at 20 to 23 °C), rendering very dependent upon further metabolism / physiological / behavioral heat generation because the heat neutral region is no longer 30 ~ 32 °C (depends on strain, size, age, gender, etc. in CAN[62]). The administered compound(s) of the present invention, which inhibit the hydrolysis of F1F0 ATP, can withstand experimental mice storage at normal room temperature, adding to cold stress. An embodiment of the present invention is a process or method of maintaining or testing an animal that is close to its thermal neutral region when performing an animal experiment with the compound(s) of the invention. For example, keep mice at 30-32 °C. And in another embodiment, the compound(s) administered by inhibiting the hydrolysis of F1F0 ATP at a higher temperature of the present invention, heats the animal in the higher temperature region. Compensate for the amount of movement in the neutral region. So in other embodiments, the shift amount, which will vary depending on the dose, the ambient temperature is set according to the dose used. For the compound of the present invention,

A process/method that takes into account the ambient temperature in determining whether to take an embodiment of the invention or manage the compound(s) of the invention, and what dosage. If the subject is caught or is administered the compound(s) of the present invention for the first time, the dose is increased or decreased during the medical observation period during the medical observation period. . In another embodiment during a medical observation period, treatment/combat hypothermia in a non-limiting example (notified to the art) Subject stay in a location with medical facilities and/or expertise, this is a conducting hospital or clinic or pharmacy or medical professional Workplace. In one embodiment, medical observations may be used as near as they can, in a temperature controlled room or area, or when signs or signs of hypothermia that indicate one patient feel uncomfortable, or when their body temperature drops In the patient's accommodation can be located at high ambient temperature. In embodiments (subject to non-limiting examples), the subject needs or administers the compound(s) of the invention, or in an embodiment during a post-monitoring period, they stay in a room/restriction/place at a safe room temperature with the compound(s) of Is the target upper body temperature near the ambient temperature, and is monitored by observation) (exceeding within a safety limit of ~ 37 °C, and in other embodiments, the body temperature is monitored). Or in the vicinity, then the local weather is reduced to a different temperature, in another embodiment, at ambient temperature or cold. In another embodiment, this process/method is repeated until the maximum dose is found at the temperature of the vault body in the subject or near the ambient climate temperature of the area at that time or at ambient temperature, which repeats the subject compound administration time across them Sending them, the ambient temperature of which is the period during which the compound is administered, is the period during which the subject retains an effective amount. The temperature around the climate in the cold area at that time, or at that. In another embodiment, this process/method is repeated until the maximum dose is found at the temperature of the vault body in the subject or near the ambient climate temperature of the area at that time or at ambient temperature, which repeats the subject compound administration time across them Sending them, the ambient temperature of which is the period during which the compound is administered, is the period during which the subject retains an effective amount. The temperature around the climate in the cold area at that time, or at that. In another embodiment, this process/method is repeated until the maximum dose is found at the temperature of the vault body in the subject or near the ambient climate temperature of the area at that time or at ambient temperature, which repeats the subject compound administration time across them Sending them, the ambient temperature of which is the period during which the compound is administered, is the period during which the subject retains an effective amount.

Many clinical oncology centers have body heating, intended for administering chemotherapy, thermotherapy. And there are body heating devices in other clinical professional heat treatments. An embodiment of the invention is to administer an effective amount of F1F0 ATP hydrolysis inhibitor(s) to a subject heated by a body heating facility/device or other body heating facility/device. Embodiments of the invention are methods of taking a subject, e.g., a compound of formula (I) or administering an effective amount of a compound(s) of the invention, (II), (III), (IV) or (V) Or another compound to prevent selective F1F0 ATP hydrolysis, or their pharmaceutically acceptable salts, solvates, hydrates or prodrug suppression treatment / alleviation / silver / combat medical diseases / disorders, [63-64 ]) up to often infants) (especially for premature infants and/or underweight, randomly radiated) to maintain the body temperature arbitrarily within the safe range of constant temperature locations under heating and/or / (such scale-up, e.g. adult radiation Warm(s), commercially available patients may reduce metabolic rate by 20 to 30%, for example, not be used if undergoing general anesthesia [63]; teaching of [64]) adults or children And, if the patient's body temperature is maintained by heating the air to a desired temperature by controlled electromagnetic radiation, eg IR-A, preferably 0.78 1.4 μm) By servo control or by helping body temperature to keep the subject alive eg at 37 °C, most preferably, it is at the desired body temperature and/or thermal neutral temperature for the target (the above preferred embodiment is the desired set point). Hypothermia induction in subjects for medical purposes is set to a temperature lower than normal body temperature.In this context, servo control, as known to the art, by adjusting the calorific value of the incubator and/or radiant warm (non-limiting example of skin over the abdomen A) Thermistors (or other) refer to electronic feedback systems that maintain a constant temperature at the site of the probe and/or other body heating devices.Components of the present invention are infrared bodies that increase infrared (and/or other electrons) emission and/or Or body temperature (and/or other electrons) emitted by the servo control variant(s) F1F0 ATP hydrolysis, which interferes with the body of Formula I, where any temperature detection and heating occurs at different wavelengths, for use for heating objects with an effective amount of any compound(s), any compound(s) (IV). An embodiment of the present invention is a method corresponding to F1F0 ATP hydrolysis in which an effective amount of a compound is administered or inhibited by administering a pharmaceutical composition(s) by intravenous injection of the subject, which is injected by volume or in close heating, and is used to treat Hypothermia associated with normal body temperature and/or any of the above method(s)/improvement/prevention/combat anesthetics (methods are known to the art) (S used for compound administration) inhibit F1F0 ATP hydrolysis , Any compound(s) (I), (II), (III), (IV) or (V). In an embodiment of the present invention, the subject is stricken or an effective amount of the compound of the present invention is a method (IV) or (V) or treatment of administering the compound (I), (II), (III) of the formula (I) Clothing / hats over another compound above wearing a subject that selectively inhibits F1F0 ATP hydrolysis, or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs to prevent/mitigation/silver/combat medical illness/disorder Optionally F1F0 ATP hydrolysis inhibitor(s), reduce metabolic heat generation and maintain body temperature within safe/comfortable limits. Examples of the present invention is a compound to be treated. The present invention provides a compound of formula (I), such as compound (I), (II), (III), (IV) or (V) or other compounds that selectively inhibit F1F0 ATP Decomposition, or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, for dispersion sale and/or language and/or written administration, the insertion/shearing of the paper into any packet is such that the compound (s ) Containing (optionally referred to as "how to use", and/or "patient information leaflet" in "prescribing information" and/or)) to reduce body temperature, and also to administer one of these compounds or more taken above in the cold It should be felt that the subject communicates and/or has a decrease in body temperature, and they do one or more of the following: position in a hotter environment, wear warmer clothes, wear more clothes to the doctor or pharmacist, to the hospital Goes. Each of the above communication is an embodiment of a separate invention, and a combination of these is another embodiment. In another embodiment, the more serious problem in these children is that the communication randomly does not children, and this problem is especially acute cognitive communication in babies and optionally the compound(s) in another embodiment (which should not be administered to infants) has a bulky surface area than the adult Because these have cognitively related babies are in a temperature environment controlled by an infant incubator or warm radiant heat). In another embodiment, the compound to be methodd is a compound of the formula (I), for example, compounds (I), (II), (III), (IV) or (V), or other compounds that inhibit the selective F1F0 ATP hydrolysis, or Contains pharmaceutically acceptable salts, solvates, hydrates or prodrugs, distributed sales and/or paper and/or catalog(s) in any packet, which are administered in language and/or in writing, containing (optionally) compound(s) The method is called "and/or "patient information leaflet", "prescribe information" and/or), that is, if the subject is not taken with alcohol or administered with such compound(s), it will be conducted at all other than ingestion in large quantities. Optionally, the alcohol-damaging thermoregulatory effect(s) of the administration(s) of the negatively interacting compound(s) can potentially communicate because it can regulate the body temperature. Optionally, many known to people in the art communicate the same cautions/warnings/communications with reference to other drug(s) that may interfere with body temperature control (non-limiting example: {recommend chlorpromazine, etc.} phenoty Azine, thioxanthenes, etc.),

Body balance equation (1st law of thermodynamics)

S = MWECKR;

Heat storage in the body = S (= 0 = heat balance, change in body temperature is positive = no increase in body temperature ie cathode = decrease in body temperature);

M = metabolic heat production (always positive in living organisms);

W = day (= positive amount of useful work is achieved negative = mechanical work is absorbed by the body);

E = evaporative heat transfer (environmental positive = transmission);

C = convective heat transfer (= positive to the environment)

K = conductive heat transfer (= positive to the environment)

R radiant heat exchange (positive = environmental transcription) =;

This concept is well known ([65] cited entirely herein) and many strategies will be apparent to people in the art as M decreases when F1F0 ATP hydrolytic inhibitors are administered to patients, maintaining S = 0. (Non-limiting) For example, if M decreases, (remains = 0 S there), or increase the temperature of the air so that it minus C, so that it can substantially offset the decrease in M infrared lamps to a considerable extent except for the study Use negative M to offset the decrease (so keep S = 0), or check the amount of wear and tear on a single amount of E, C, K, R in small amounts to offset the decrease in M (Yes S = Keep 0).

Cross-dose translation

Because large species have a specific basal metabolic rate of low mass and negative partial power, the animal's mass is parameterized by scales (see, eg, Kleiber's Law). Such large species require slow drug metabolism, etc., and can withstand lower mg/kg drug administration, which is reflected in the conversion of drug administration of one species (e.g., mouse) to one of different sizes (e.g., human) and of course yes : Means reference (notice to the artist [66] and FDA guidelines). However, powered by the negative part initiates animal mass-selective F1F0 ATP hydrolysis inhibitor scale toxicity than is predicted in smaller animals by conventional relative growth scaling methods used in the art by this invention. Because larger animals have a small surface area by mass ratio (animal mass animal radius 3 proportional animal surface area animal radius 2 proportional there large animals have a small surface area by mass ratio), they keep generating more heat from them metabolism they keep negative F1F0 ATP hydrolysis like The cause of the inhibitor is not affected by the decrease in metabolic heat production, i.e. the rate drop given in the metabolic rate, the body temperature does not occur with a large rate drop

Assume the metabolic rate by mass (MR)[62], the body temperature retention constant (heat production = heat loss), and its ambient temperature is below the lower critical temperature, which is below the lower limit of room temperature to neutralize the heat of the animal:

MR = C (TB-TA);

TB = body temperature;

TA = ambient temperature;

C = systemic heat conduction from the environmental body core for a temperature difference of 1 °C = heat transfer rate (by the full heat transfer mechanism);

I = insulation = 1 / C;

MR = 21.66 * M-0.25;

C = 4.23 * M-0.426;

Where M = body weight (g);

Tb은, 특히 사람이 동일한 온도에서 살고됩니다. 따라서, 작은 종의 연구가 수행되는 온도 및 인간 대상자에 상주하는 온도는 상대 성장 스케일링 방법이없이 본 기술의 사람에게 명백하지 않았을 동등한 인간 투여를 찾기 위해인가를 판단 본 개시. 또한, 본원에 개시된 방법은, 크기가 다른 하나의 종, 예를 들면 인간의 개인간 F1F0 ATP 가수 분해 억제제의 투여 량을 조절하기 위해 사용될 수있다.Decreased as MR C and M increased; Reducing MR increases drug toxicity; C reduction reduces drug toxicity (for AN F1F0 ATP hydrolysis inhibitors) so that we can define a risk index for F1F0 ATP hydrolysis inhibitors: its risk is proportional to C and inversely proportional to MR: risk = C/MR = (4.23 * M- 0.426) / (M-21.66 * 0.25). Risk index (= 0.03) using M = 20 g for mouse (= 0.12) and M = 62 kg for human for human use. Thus, two types of milligram/kg MTD human wear clothes ~4 times less than human rats, even more than this (assuming the same ambient temperature as the two species below the reduced thermal neutral temperature zone). This is so far one of the sectors will be removed from what is expected: (* 20-0.25 21.66) / (21.66 * 62000-0 counting, for example, would be less than the expected MTG human rat less than or equal to. At least for less appropriate chemotherapy: see the FDA guidelines cited in [66]) They count less 20-0.33/62000-0.33 = 14.2 hours.The given milligram/kg dose is human metabolized (20-0.25) / (62000-0.25) = ~ 7.5 times slower and we have confirmed that the maximum /kg dose allowed humans is ~4 times more than a milligram, so mice: the potential anticancer activity of the following F1F0 ATP hydrolysis inhibitors is usually higher than that of mice at room temperature Human 4*=7.5 to 30 times, thus revealed by the invention of the present invention, exaggerated small animal studies at room temperature (~22°C, underestimated anti-cancer activity as much as possible at human room temperature, diminished severe therapeutic effect conventional relative growth Setting the human dose in mouse studies when used to scale. The present invention provides a new method of improving translational administration of F1F0 ATP hydrolysis inhibitors between species. However, more conventional relative growth scaling methods can be used [ 66] If small species studies are conducted at ambient temperatures close to optimal homeothermic body temperature, Ta

Tb, especially if a person lives at the same temperature. Thus, the present disclosure determines whether the temperature at which small species studies are performed and the temperature residing in human subjects is to find equivalent human administration that would not have been apparent to humans of the art without a relative growth scaling method. In addition, the methods disclosed herein can be used to control the dosage of F1F0 ATP hydrolysis inhibitors of one species of different size, for example, between humans.

The parameters used in this section of the equation illustrate and are not limited to the principles of the invention. For example, other relative growth indices are considered components in the present invention. The method of the present invention provides F1F0 ATP hydrolysis inhibitor (S) MTD (or other safety metrics eg NOAEL, LD50, LD33, etc.) between individual animals and/or paper of different sizes (eg, mouse, rat comparing, guinea pigs) , Rabbits, dogs, primates, etc.) to calculate the specific relative growth scaling relationship more accurately than anything, and to investigate how selective scaling changes to room temperature. And using this relationship(s) calculated/triangulated/estimated a safe starting dose for the human body in previous animal studies.

Chemotherapy

The method is, of course, to measure the anti-cancer activity of the treatment(s) in the subject(s), and/or to measure the change in anti-cancer activity associated with a change in treatment(s) (e.g., change in dosage), of course art People are known. They are routinely used in preclinical research and clinical practice.

The next method is that the dose can be tolerated by the patient, simply the maximum dose is generally very irregular, the administration of this method in the field of chemotherapy. A method to reduce the dose of compound(s) inhibits F1F0 ATP hydrolysis, (I) the compound of formula I, for example (non-limiting), in order to exert greater anti-cancer activity in the subject of the present invention Example.

As one of the techniques that can be expected to increase or decrease the anticancer activity (I) of the compound of formula (S), no optimal anticancer drug administration decreases in proportion to the increase in the dose of the compound, and the maximum allowable dose. Decreasing or increasing (!) doses reduce anticancer activity from this optimal administration step. The component here is another way of finding the optimal dosage for compound(s) of formula (I), which is how the subject finds the optimal dosage in the present invention, which utilizes / VS utilizes a very irregular dose. Anti-cancer activity profile, disclosed herein (FIGS. 8, 11, 12).

If the dose is increased = increased anticancer activity, the increased dose. If the dose is increased = decreased anticancer activity, decreased dose by more than previously increased. The next increase in capacity is smaller than before. repeat. This loop repeats, and as the increase in dose decreases, the art person knows to converge more and more to the optimal dose. They know that the magnitude of the dose increase increase at the end of the loop is an indicator of how close to the optimal dose, and they can end the loop at the desired dose. A small dose increase at the loop exit, the closer the dose is optimal. Users of the art can choose the mirror image of the loop, instead of choosing an increase in unit dose reduction. There are permutations to these schemes, which will be clearly known about the person of art, that this logic has now been undertaken, with components in the present invention. The following R invention (not limited) to help explain [67] code programming symbolizes that the "optimal" parameter symbolizes optimal anticancer drug administration, and loop iterations until start and dose drug administration, "administration" are optimally identical. Other users in the art can navigate and understand the invention, for example changing parameters and/or mathematical symbols to adjust the code. Of course, in reality, the optimal anti-cancer dose is known and not user-specified as shown in the code, the code component of the invention showing how to find the optimal anti-cancer dose for the compound of formula (I), method. All parameters are just examples.

# R programming code

Dose = 1 # try to administer first

= Reset capacity

Dose will be adjusted DT = 600 # step size

Lips = DT / 100,000,000

# = Lip precision parameter, larger denominator means more accuracy than repetition

X = 0

Optimal = 60

# Optimal anti-cancer capacity, the following logic, which is unknown in real cases, find it here

N = 10

# N = Must be an accuracy parameter> Accuracy over repeating means greater than 1

m = N

How many iterations to perform convergence = 0# calculation

Whereas (DT> resolution)

{

Dose amount = + DT

Case (dose <optimal) {

# Increased dose = increased anticancer activity, so no dose increase

Dose amount = + DT

X = X + 1

}

(Dose> optimal) {# Increased dose decreases = Decrease dose due to anticancer activity

If (dose <0) {

Dose = lee

DT = DT / N

}

Dosage Dose = (DT + (DT / N))

X = X-1

}

Case (X == 0) {DT = DT / m}

# Change in one direction (increase or decrease) after administration and then in the opposite direction to #, reduced step size

Case (ABS (X) == 2) {X = 0}

Count = + 1 count

# (ABS (capacity optimal) <1) {Relax} # If not in use, but pay attention here

}

Converging the doses to be optimal as described above, or close to other methods, or at a later location, the doses can be set arbitrarily, limited to any range, by some formal/unofficial random number generators. It can be a random choice of just the person(s) you need to do perfectly randomly. This formulated/informal random walk is used to find the formula, compound(s) dose (I), great anticancer activity. It is distinguished from conventional methods with the use of dose reduction (not just increasing) in pursuit of greater anticancer activity.

The optimal dosage or range of dosages is that it results in cancer cell death with (I) for compounds of formula (I). This is a narrow dosage range (Figure 13). Penalties to low and high doses exert less anticancer activity by dose. In the embodiment of the present invention, the formulation changes the dose of the compound of formula (I) to the subject, selectively causing death, and cancer cell death. Sensing cancer regression is, for example, blood well with only and/or apoptosis markers (see examples known in the art to slow cancer growth [68]), rather than non-limiting examples.

A method of selecting a dosage is disclosed herein to find good anticancer drug administration for compound (I) of formula (I), optionally a heterologous/winterized rodent, optionally housing rodent(s) at ambient temperature ≥26 °C (in other embodiments : ≥28 is ≥30, ≥32, ≥34, ≥36 °C) is a component of the present invention. Rearing of any housing/rodent at ambient temperature to ≥26 (S)°C (in other embodiments: ≥28, ≥30, ≥32, ≥34, ≥36°C) during administration Equation (I), optionally, selects the starting dose(s) for human clinical trial(s).

Frozen coupling arm

Refers not to the meaning and characteristics of the separator, but is known to people in the technical field, for example [36]. The separator is a molecule capable of releasing proton mitochondrial matrices (S), proton mitochondrial interstitial space (S) (IMS) across the inner membrane of the mitochondria, moving, binding, and proton motif forces (S), molecules that release (PMF), then IMS Return to, and repeat this sequence repeatedly. 2,4-Di nitrophenol is an example of a separator. Many other separators are known to the art. An embodiment of the invention [administration] inhibits the amount(s) of a therapeutically effective compound corresponding to F1F0 ATP hydrolysis (e.g. the compound is of formula (I), (II), (III), (IV ) Or (V)) other compound(s) separated by the same therapeutically effective amount or proton motive force, optionally for use in a method of treatment of a human or animal body by therapy, optionally an F1F0 ATP hydrolysis inhibitor(s) and separator(s) Is a single pharmaceutical composition and/or packaging and/or distribution, and/or treatment/reduction/prevention/combat randomly sold subject(s) cancer. As described above, the dosage range of the F1F0 ATP hydrolysis inhibitor (I) of the formula kills cancer cells is very narrow. This range is amplified by the combined administration of the separator(s) to increase the OXPHOS rate [ROS] and decrease the concentration of the F1F0 ATP hydrolysis inhibitor required. Optionally, the F1F0 ATP hydrolysis inhibitor(s) (fractionation) is then administered with the method(s) described above to optimize the dosage of the separator, prior to administration of the separator, reducing the dosage of the required separator. The above co-administration, especially the optimal co-administration day, in each optimal dose single pharmaceutical composition: F1F0 ATP hydrolysis inhibitor(s) will cause metabolic inefficiency and body separators to increase metabolic inefficiency and decrease body temperature, which will each cause changes in body temperature. Can reduce; And yields synergistic effect of anticancer activity. In the present invention, the component is a compound prohibition F1F0 ATP hydrolysis, such as proton motif force (PMF) solve (non-limiting) is BMS-199264. In one embodiment of the present invention, [Management], or self-administered subjects, compound(s) are separated by a therapeutically effective amount of inhibition F1F0 ATP hydrolysis, proton motive force, separator (S) increases metabolic ineffective body temperature : Co-administration, especially optimal simultaneous administration, each optimal amount characterized by being a single pharmaceutical composition, optionally, each step to reduce changes in body temperature that would occur alone; And yields synergistic effect of anticancer activity. In the present invention, the component is a compound prohibition F1F0 ATP hydrolysis, such as proton motif force (PMF) solve (non-limiting) is BMS-199264. In one embodiment of the present invention, [Management], or self-administered subjects, compound(s) are separated by a therapeutically effective amount of inhibition F1F0 ATP hydrolysis, proton motive force, separator (S) increases metabolic ineffective body temperature : Co-administration, especially optimal simultaneous administration, each optimal amount characterized by being a single pharmaceutical composition, optionally, each step to reduce changes in body temperature that would occur alone; And yields synergistic effect of anticancer activity. In the present invention, the component is a compound prohibition F1F0 ATP hydrolysis, such as proton motif force (PMF) solve (non-limiting) is BMS-199264. In one embodiment of the present invention, by [administration] or self-administered subjects, the compound(s) are separated by a therapeutically effective amount of inhibitory F1F0 ATP hydrolysis, proton motive force, each optimal amount in a single pharmaceutical composition Can selectively reduce changes in body temperature that would each occur alone; And yields synergistic effect of anticancer activity. In the present invention, the component is a compound prohibition F1F0 ATP hydrolysis, such as proton motif force (PMF) solve (non-limiting) is BMS-199264. In one embodiment of the present invention, by [administration] or self-administered subjects, the compound(s) are separated by a therapeutically effective amount of inhibitory F1F0 ATP hydrolysis, proton motive force, each optimal amount in a single pharmaceutical composition Can selectively reduce changes in body temperature that would each occur alone; And yields synergistic effect of anticancer activity. In the present invention, the component is a compound prohibition F1F0 ATP hydrolysis, such as proton motif force (PMF) solve (non-limiting) is BMS-199264. In one embodiment of the present invention, [Management], or self-administered subjects, the compound(s) is separated by a therapeutically effective amount of inhibition F1F0 ATP hydrolysis, proton driving force, the present invention is a component prohibited F1F0 ATP The proton motif force (PMF) solve (non-limiting) such as hydrolysis is BMS-199264. In one embodiment of the present invention, [Management], or self-administered subjects, the compound(s) is separated by a therapeutically effective amount of inhibition F1F0 ATP hydrolysis, proton driving force, the present invention is a component prohibited F1F0 ATP The proton motif force (PMF) solve (non-limiting) such as hydrolysis is BMS-199264. In one embodiment of the present invention, [Management] or self-administered subjects, the compound(s) is separated by a therapeutically effective amount of inhibition F1F0 ATP hydrolysis, proton motive force, treatment method of the human or animal body by therapy For use in the treatment/reduction/prevention/combat of cancer of the subject(s) at random.

OXPHOS in the respiratory chain deficiency(s) cannot be used in cancer, or solely because of the hypoxic environment (tumors are often hypoxic), their ΨIM will erode ΨIM, relying on F1F0 ATP hydrolysis to maintain the separator(s) F1F0 ATP hydrolysis inhibitor(s) will collapse because their ΨIM causes apoptosis because it will block the only means to counteract this. Given the severity of this vulnerability, and the -enhancing effects of both drugs, lower drug use applies. Meanwhile normal cells are maintained at a faster rate of OXPHOS ΨIM.

In addition, the present invention is that the component uses a therapeutic amount of treatment/mitigation/prevention/combat separator cancer(s) in the subject. Ψ If IM is depolarized, it will continue [59]. Normal adult cells favor aerobic breathing, ΨIM hyperpolarization, which produces ATP. The aerobic glycolytic action that they prefer, some or all of the time of many cancers, consumes ATP in the hyper-polarization of ΨIM. Under the challenge of the separator compound(s), the former is more persistent than the difference because the latter of the ATP yield (~2 ATP per glucose in the 30s) is even more persistent than there, and there is a therapeutic limit. As such, some cancers can convert to aerobic breathing and convert out of aerobic sugars, but increase ROS, especially because oxidative phosphorylation (OXPHOS) components, aging, mortality and remission are likely, because the separator(s) will drive higher OXPHOS rate. Unlike other chemotherapy agents, the separator does not interact with protons and DNA encodes proteins

Frozen couple is virtuous

Imidazole containing the compounds of the present invention (proton motive force, PMF erosion, shuttle proton via mitochondrial lining (IM)) inhibits F1F0 ATP hydrolysis and decoupling. The former can exert certain anti-cancer activity, or normoxia ΨIM in hypoxic tumors (experiment shown by the data of the present invention), also uncouples compounds that can exert specific anti-cancer activity, because it undermines some cancer-retaining means Now explained. Imidazole containing a compound of ATP synthase that initiates binding at or near the IF1 binding site. In normal cells they bind sequestered from ATP unsynthesized with synthetase at the site, and ATP “save” by inhibiting the hydrolysis of F1F0 ATP, where they bind (or more) “lost” to their uncouplings to compensate for ATP Choose. However, some cancers have very high IF1 expression (numerous studies have shown this, for example, [23]). For some cancers, this inhibits the hydrolysis of F1F0 ATP to make them more efficient than their OXPHOS, which can keep [ATP] low or [O2], and survives using OXPHOS for hypoxia (his own fever) Is less but their temperature is maintained by heat conduction from surrounding tissue. These high IF1 expression blocks prevent the compounds from being seized from unbinding, tumors of the O2 requirement of this cancer that cannot be met in a hypoxic microenvironment with increased binding of the compounds to their binding sites for ATP synthase, and this uncoupling That's why cancer cells cannot sustain [ATP], their proliferation slows and/or dies. Thus, here, the disclosed anti-cancer activity of the present invention, which may provide additional specifics of the uncoupling aspect of the imidazole containing the compound of the present invention, for example, does not rely on its F1F0 ATP hydrolysis for that cancer . The present invention discloses a process/method using a compound(s) that can inhibit the hydrolysis of F1F0 ATP, and radiates PMF (uncoupled), like that can shuttle proton chemotherapy across IM. Compounds that inhibit F1F0 ATP hydrolysis by direct interaction with ATP synthase, and how F1F0 ATP synthesis is (mainly) reduced by uncoupling. Thus, the compound needs to be low and not many compounds that inhibit F1F0 ATP hydrolysis by direct interaction with ATP synthase, and how F1F0 ATP synthesis is (mainly) reduced by uncoupling. Thus, the compound needs to be low and not many compounds that inhibit F1F0 ATP hydrolysis by direct interaction with ATP synthase, and how F1F0 ATP synthesis is (mainly) reduced by uncoupling. Thus, in many SMP assays where the combined need is necessarily low, EC50 for F1F0 ATP hydrolysis rather than ATP synthesis F1F0 is a component of the present invention as an anticancer therapeutic. In fact, even the compounds with the lower F1F0 ATP synthesis than F1F0 ATP hydrolysis in SMP analysis EC50 is an anti-cancer drug, they provide, the components in the present invention may be prohibited F1F0 ATP synthesis rather than uncoupling due to ATP hydrolysis Inhibition (mainly) of ATP synthase is provided. Oligomycin, for example, does not meet the following requirements. Accordingly, the present invention discloses a method of using a compound that inhibits F1F0 ATP synthetase and does not inhibit F1F0 ATP hydrolase, and anti-cancer therapeutics, such as its proton motive force release.

Heavy water extinguishing compound of the present invention

Deuterium (D or 2H) has a stable non-radioactive isotope of hydrogen and an atomic weight of 2.0144. Mixtures of 1H (first language or hydrogen), D (2H or deuterium), and T (3H or tritium) isotopes hydrogen occur naturally, where the amount of deuterium is all percentages in molar ratios. The natural abundance of deuterium is 0.015%. One of them in the art is that the H atom(s) represents a compound, H, and a mixture of H and D of the compound, since (S) is actually about 0.015% more than D. Recognized deuterium incorporation, i.e., the concentration level of the compound has a greater abundance of D than natural abundance (>0.015%), non-natural and their non-rich counterparts and should be considered very distinct. The compound is a naturally occurring compound, or isotope It is known to be "deuterium enriched" if there is an amount of deuterium greater than the synthetic compound produced on the substrate with a naturally occurring dispersion of the elements. It can be difficult to achieve 100% heavy water digestion at any one of those compounds in laboratory-scale quantities (more than milligrams). Where 100% is shown as a deuterium term or deuterium atom specific structure, it is assumed that a small percentage of hydrogen may still be present. Deuterium enriched deuterium compounds can be synthesized or obtained from proton exchange of compounds with deuterium or starting materials that can be prepared by persons in the art using commercially available or well-known methods.

Embodiments of the present invention include compounds of formula (I), (II), (III), (IV), frequencies greater than nature (V) and one or more of their hydrogen atoms replaced with deuterium and (VI) abundance of deuterium ( 0.015%). Non-limiting example> 3000 times the natural abundance of deuterium (i.e. A> 40% deuterium incorporation at the hydrogen replacement site). Examples of deuterium rich in additional positions, or compounds of the present invention Examples 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, etc. , 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 deuterium rich, or position at position, is at least 40% of the embodiments of the compounds of the invention. In other specific embodiments, the deuterium-rich, or positional, at the above position, is at least 60% of the embodiments of the compounds of the invention. In learning and examples, deuterium rich is at least 75%. In another embodiment, deuterium rich is at least 90%. It should also be understood that deuterium-concentrated compounds can be combined with pharmaceutically acceptable carriers to form the pharmaceutical compositions described herein. Deuterium richness is at least 90%. It should also be understood that deuterium-concentrated compounds can be combined with pharmaceutically acceptable carriers to form the pharmaceutical compositions described herein. Deuterium richness is at least 90%. It should also be understood that deuterium-concentrated compounds can be combined with pharmaceutically acceptable carriers to form the pharmaceutical compositions described herein.

The location of the compound structure is due to the abundance of deuterium (D), or deuterium, or in the claims and herein described claims to be enriched for deuterium, due to its abundance at its natural deuterium value (0.015%) but more no. In general, exceed 40%. For the compound (I) of formula I, for example, the phrase "concentrated at the chiral center", ie, the molar amount of deuterium at the chiral center as a percentage of the total amount of all hydrogen isotopes at the chiral center, more than 0.015%, especially more than 1% , Preferably at least 40%, more preferably at least 45%, and in ascending order of priority, ≥52.5% deuterium enriched chiral center, ≥60% deuterium enrichment center ≥67.5% deuterium enriched chiral center ≥ 75% deuterium enriched chiral center ≥82.5% deuterium enriched chiral center ≥90% deuterium enriched chiral center ≥95% deuterium enriched center ≥97% deuterium enriched chiral center ≥99 chiral center, ≥99% deuterium Concentration 5% deuterium concentration at chiral center 100% deuterium concentration at chiral center Greater% deuterium concentration is preferred.

A further possible isotopic variant of the structure of the invention is another embodiment of the invention. (0.015%, e.g.>> 40%) for one more structure, and/or for other isotopic substitutions than for the forward mode of ATP synthase with deuterium instead of hydrogen over the reverse mode, a compound that inhibits the practice of the invention Large frequency) natural frequency eg (13C) and/or greater than 15N/concentration (concentration, 13C concentration {rich> [natural abundance = 1.109%]] I I particularly preferred chiral carbon of the compound of formula I, especially if applicable Enriched in the second half of the hydrogen {rich> [natural abundance = 0.015%] if desired, 13C enrichment of chiral carbon>40%, selective 2H enrichment in chiral carbon>40% addition}).

Synthetic pathways described in the molecule [5, 6, 7, 8, P1, P2, P3, P4, P5, P6] (internal, appropriate and all of their supplements, including references, all recited herein)-Molecular Inhibition of Synthesis F1F0 ATP F1F0 is a synthetic pathway for synthesizing or synthesizing anti-cancer molecules over ATP synthesis, and is a component of the present disclosure. In another embodiment of the present invention, [5, 6, 7, 8, P1, P2, P3, P4, P5, P6, P7, P8] starting reagents, compounds, solvents and/or It has deuterium instead of hydrogen at some position(s) used as intermediates. These compounds are commercially available (see, for example, C/D/N isotopes Enclair or CK isotopes, Desford, UK, Cambridge Isotope Institute Twicks, MA). Or you can make it at home by calling standard synthetic protocols known in the art to introduce isotope atoms into the chemical structure. (Non-limiting example) For example, a compound can be quenched with heavy water (D2O, "heavy water"), then deprotonated by LiHMDS in -78 tetrahydrofuran (THF) at -40°C for 20 min. Digested compound was obtained [37]. During this step, when the hydrogen was required over BOC deuterium to continue, the BOC protective group was removed after treatment with trifluoroacetic acid (TFA) at room temperature. Finally, the level of deuterium can be confirmed by 1H NMR. The initial deprotonation step occurs when H/D exchange occurs when quenched with the molecule D2O, and this reaction is absolutely not necessary to be catalyzed by acid, base or metal based catalysts with platinum. After quenching, D2O, if the level of deuterated compound is insufficient (observed using 1H NMR), then quenched with compound D2O, or some other deuterium containing solvent, for a long time. The compounds of the present invention may be synthesized with D2O, in one or more chemical processes, or starting compounds in version(s). So, deuterium-enriched compounds of the present invention can be prepared by deuterium-enriched reagents or solvent substitution for non-isotopically labeled reagents or solvents in synthetic schemes [5, 6, 7, 8, P1, P2 , P3, P4, P5, P6, P7, P8].

Non-limiting exemplary embodiments of the present invention enumerate heavy water digestion of Markush formulas (I), (II), (III), (IV), (V) and (VI). As these important isotopologues novel compositions, they are a component of the present invention and, in non-limiting embodiments, FDA and/or EMA, optionally in combination therapy alone or in combination with drug(s) and/or treatment(s approved), anticancer therapies, etc. For example licensed cancer treatment.

How to find the present invention in more compound components

A method for discovering compounds that lower the proliferation of examples and/or kill cancer cells, is to seek/select compounds that preferentially inhibit the reverse mode of ATP synthase, in order to find compounds of the present invention. For example, individually (total or less preferably, its component parts), ATP synthesis by ATP synthase and analysis by the effect of the compound (spatial and/or time) upon ATP hydrolysis. And compare the results of these analyzes. Inhibition of large reverse vs. forward mode, more preferred compounds are used in the present invention as selective anticancer agents. Another way is to seek screening/compounding and inhibiting ATP hydrolysis rather than synthetic compared to the Mitochondrial Subparticle Device (SMPS). ATP hydrolysis (non-limiting example) can be analyzed by spectroscopy for NADH fluorescence that pyruvate kinase and lactate dehydrogenase incubate SMPS (the assay is well known to those in the art). ATP synthesis can be analyzed by spectroscopy for NADPH fluorescence (non-limiting example) hex dehydrogenase and glucose-6-phosphate latent SMPS (well known to those in the art of analysis). This analysis is reported in either [5, 7, 8, 11, 12, 13, 70] internal references, and/or both of which are incorporated herein in their entirety. In this SMP assay, the criteria for candidate anti-cancer compounds are low EC50 for ATP hydrolysis (there is anti-cancer activity) and high EC50 for ATP synthesis (safe from normal cells there).

Cancer types are particularly subject of the invention

Compound 6b can inhibit cancer proliferation strongly at 10 μM after almost never at 100 μM. Figure 8 shows leukemia cancer cells. The lower [Figure 6B], as previously disclosed, converts cancer cells at a higher OXPHOS use/rate to exert anticancer activity, but a higher [Figure 6B] reduced OXPHOS rate that exerts the following anticancer activity. Extrapolating this data can further increase cancer assist and proliferation rates [Figure 6B]. And if the cancer has proper adaptation, and without 6B management, and using OXPHOS significantly from the beginning, then 6B can only be managed and cancer that will never interfere. Compound 6B, another F1F0 ATP compound of the present invention that inhibits hydrolysis, is administered to cancers that exhibit oxidative metabolism rather than indications of most sugars. For example, the indication one,[71].

Particularly vulnerable to the compounds of the present invention: Cancer exhibits a Warburg effect (i.e., its production ATP is primarily due to oxidative phosphorylation rather than its action in even rich O2) high sugar cancer (not metabolizing lactic acid over metabolism glucose and/or glutamine one Or both with the use of fully oxidative phosphorylation) and cancer and the power they produce ATP by primarily their action is in hypoxia. As described in the preceding section, using oxidative phosphorylation with low resident [O2] for hypoxia using its uncoupling function, imidazole containing the molecules of the present invention, and also a high IF1 formula makes cancer Can attack Since tumors are often hypoxic, many cancers are in hypoxia.

So if the cancer is either inhabited due to either hypoxia (regardless of the intrinsic sugar metabolism of [O2]) or because of its high sugar content (due to daytime, impose sugar metabolism [O2]), or use metabolism Oxidation, but in hypoxia (set by a high survival IF1 formula) is to be treated/improved/prevented/combated by the compounds of the present invention. How to identify the same cancer?

Cancers are those that exhibit the Warburg effect, or are those displayed on positron emission tomography imaging (PET) using 18F-FDG PET imposed by glycolysis (low [O2]), optionally computed tomographic integration (CT)[71 ]. FDG is a glucose analogue, and sugar is more susceptible to cancer than FDG compared to its surrounding tissues because sugar is inefficient metabolism of glucose yields ~2 ATP per sugar compared to glucose ~30 ATP produced by aerobic breathing [1-2]) And as they do with most normal cells, nearby normal cells that use oxidative metabolism, and even so, need to absorb more glucose to get the corresponding energy production. So, the cancer present in this FDG-PET diagnosis (higher glucose uptake than surround), it is vulnerable to the compounds of the present invention. High sugar cancer places a lot of lactic acid. Patients have phytate levels that are significantly higher than the normal non-pathological range, as is apparent to persons in the art, and, in some cases, their cancers are sensitive to the compounds of the present invention. For example, hydrogen nuclear magnetic resonance spectroscopy (1H-MRS) or chemical exchange saturation transmission magnetic resonance imaging can also be detected using imaging techniques (than surrounding tissue) and high lactate levels around cancer or tumors (CEST MRI)[72 ]Other imaging methods and techniques or methods. If lactate is a cancer present (surround abnormality [lactic acid]) diagnostic imaging, it is sensitive to the compounds of the present invention. Lactic acid cancer release acidifies the extracellular space and this acidification can be detected by imaging methods known to examples in the art [73-74] If cancer can distinguish surrounding tissues by this method, and it is of the present invention It is sensitive to compounds. Oxygen-sensitive chemical probes can be obtained by mapping of the oxygen partial pressure in three-dimensional tissues [75] If cancer is shown to reside in remarkable hypoxia, these two are likely to use high IF1 expression to sensitively activate oxidative metabolism with these compounds Either sugars or because, and, it is the invention sensitive to the compounds of the present invention. Imaging technology can be integrated to improve the signal with noise, etc. [75]Oxygen partial pressure and lactic acid imaging can be integrated. Such integration may provide additional information: Because it greatly utilizes the metabolism of sugars in rich O2, for example, cancer producing many lactic acids in a high oxygen partial pressure environment exerts a Warburg effect. Cancer gene expression markers and indicators of Warburg effect, known to the art examples [18-20], cancer is the genetic material of cancer can be retrieved by circulating biopsy surgery cancer cells or parts from the blood or other methods in the art Sensitive designation of the compounds of the present invention.

Cancer uses oxidized sugar metabolism rather than phosphorylation (OXPHOS), and damage to cancer is preferential F1F0 ATP singer rather than cancer, rather than oxidizing sugar metabolism and already improving its OXPHOS efficiency (see many cancer cases if not improved [23]) By inhibiting decomposition, the compounds of the present invention actually help it will confer efficiency benefits. How to identify this cancer? The IF1 gene expression in cancer, and the IF1 gene expression ratio in particular to the core ATP synthase subunit (eg ATP6) are beneficial. So when comparing gene expression corresponding to normal cells in the host tissue to detect differences in normal more. It is not wise to use the compounds of the present invention for the treatment of cancer when oxidizing glycolysis metabolism, not for cancer use, and significantly higher IF1 (or IF1/ATP6 ratio) lacks gene expression compared to the corresponding normal tissue. More simply,

The present invention preferentially uses, for example, formula (I), (II), (III), (IV) or compound(s) (compound(s) that inhibit the ATP-hydrolysis mode of the ATP synthase) Initiating methods V) or pharmaceutically acceptable/improving/preventing treatments thereof, salts, solvates, hydrates or prodrugs/combat preferential use cancer sugars that exhibit Warburg effect rather than oxidative metabolism cancer and ho methods To identify these cancers. The present invention is not described to limit the scope of the designated identification method: The present invention includes all methods for identifying sugar cancer, in order to identify the cancer with which the compound(s) of the present invention is the most obligatory for treatment.

So, innovatively useful, the compounds of the present disclosure are cancer-producing and proliferation and weakness, weakness, not weakness, but rather the general attack compound, often too often randomly admitted, how to choose anti-cancer treatment as the metabolic function of cancer to cheat Is assigned by this standard organization type. Diversity of cancer, in other tissues, will be particularly sensitive to the most dangerous compounds of the present invention: Hylactate efflux and sugar cancer often a poor prognosis [18-20, 27]. Experiments show many cancers as being effective against the compounds of the present invention.

Small cell lung cancer, Mesothelioma, Non-small cell lung cancer, Pleuropulmonary blastoma, larynx cancer, thymoma and thymic cancer, AIDS related cancer, Kaposi's sarcoma, Epithelial vascular endothelioma (EHE), connective tissue formation bovine round cell tumor, liposarcoma. It is a compound of the therapeutic cancer of the present invention, including but not limited to those occurring in the testicles, cortex, skin, fallopian tubes, parathyroid gland, small intestine, large intestine, kidney, skeletal muscle, duodenum, spleen, epididymal bone marrow, lymph nodes, adrenal glands, esophagus , Thyroid, heart muscle, tonsil, lung, prostate, rectum, anus, adipose tissue, colon, stomach, cervix, gallbladder, seminal vesicle, breast, ovary, endometrium, smooth muscle, salivary gland, pancreas, bladder, blood, brain, gum , Head, liver, nasopharynx, neck,

Cancer Imaging

F1F0 ATP hydrolysis inhibitor compounds The present invention, for example, the compounds of formula (I), (II), (III), (IV) or (V), ATP synthetase action has a greater binding affinity and is more reverse than delivery . As disclosed herein, compared to normal cells, the cancer is unbalanced, conversely, using ATP synthase, therefore, such compound(s) accumulate in unbalanced cancer cells. Therefore, the compounds can be used for imaging cancers, for example, by positron emission tomography (PET), for example by incorporation of 11C or other radionuclides if the compound is (S)-labeled. Exemplary embodiments are incorporated into the compounds of the present invention in one or more 11C 18F, 13N 150, 124I greater than the natural abundance, most preferably instead of the corresponding compound(s) (11C) for example 12C of incorporation at position(s), 13N instead of 14N, 124I, etc. are considered as substitutions of all nuclides corresponding to the atoms of the halogen-specified position (S) Formula (IV), and the components have anti-cancer imaging and/or treatment as in the present invention. For their use. Other embodiments include iodine incorporation of the halogen specified at position(s) at one or more compounds of formula (IV), and use of the compound(s) for dark iodide X-ray contrast imaging. Alternative 123I is incorporated into the halogen site(s) of one or more compounds of formula (IV), and these compound(s) are used for imaging cancer using single photon emission computed tomography (SPECT). If an abnormality shows cancer until one of the video forms (above background tissue),

Given asymmetric accumulation of compounds of formula (IV) in cancer cells, these compounds can be used for the treatment of unbalanced, damaged cancers, e. The compound(s) depicts tritium, above a natural abundance in one or more places of the compound(s) of the present invention(s), characterized in that it is used for anticancer treatment. Alternatively or additionally, 125I and/or 131I are optionally incorporated with the halogen, designated at position(s) in Formula (IV). Optionally, radionuclide imaging is performed prior to radionuclide treatment (radiation treatment) on the compounds of the present invention.

Use 10B to replace a boron compound substituted at one or more positions of the invention (S), e.g., a compound of formula (I), (II), (III), (IV) or (V), 157Gd 10B instead It is a method characterized by being used in neutron capture therapy, optionally for anticancer use, is a component of the invention.

Aging

G. Radiation) drives the cancer, which is because the compounds of the present invention are particularly preferred as a result of radiation therapy, for example, as a result of radiation therapy, a sufficient life of secondary cancer is desirable for cancer treatment in children. Radiation) Drives the above cancer, which can be a very serious problem as the compounds of the present invention are particularly useful as a result of radiation therapy, for example, as a secondary cancer leaving a sufficient lifespan for cancer treatment in children [76].

Anti aging skin cream

The F1F0 ATP hydrolysis inhibitor compound of the present invention is slow aging but can reduce body temperature. An embodiment of the invention is to selectively target the F1F0 ATP hydrolysis inhibitor compound(s) to parts/areas of the body that desire slow aging for aesthetic/cosmetic, medical/treatment needs or needs. This area or region has slow aging and less heat generation, but the allowable value of heat transfer in the rounding body region maintains the temperature of the body portion/area. Thus, temperature problems are alleviated and slow to aging that region/region. An embodiment of the invention is a method (IV) or (V) or a method of administering an effective amount of a compound of the present invention (S), for example, compounds (I), (II), (III) of formula I Selective F1F0 ATP hydrolysis, or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs to inhibit treatment / / selectively administered to the skin as combat skin / Anti-aging improvement / Another compound for skin and/or subcutaneous injection Skin cream on the side, randomly. In another embodiment, treatment/relief/prevention/combat hair and/or hair aging//loss aging is optionally administered to the scalp and/or hair of a shampoo, optionally a hair treatment. All means of applying the compound(s) of the invention to the skin and/or scalp and/or hair are contemplated by the invention and become a row component. Optional face, optionally as a skin cream, optionally by skin and/or subcutaneous injection. In another embodiment, treatment/relief/prevention/combat hair and/or hair aging//loss aging is optionally administered to the scalp and/or hair of a shampoo, optionally a hair treatment. All means of applying the compound(s) of the invention to the skin and/or scalp and/or hair are contemplated by the invention and become a row component. Optional face, optionally as a skin cream, optionally by skin and/or subcutaneous injection. In another embodiment, treatment/relief/prevention/combat hair and/or hair aging//loss aging is optionally administered to the scalp and/or hair of a shampoo, optionally a hair treatment. All means of applying the compound(s) of the invention to the skin and/or scalp and/or hair are contemplated by the invention and become a row component.

Brain aging

Neurodegenerative disease causes aging components to cause [77] to function as their onset age (oxidative stress [77]). In fact, all these diseases (prototype examples include Parkinson's disease, dementia, lateral sclerosis {ALS} muscular dystrophy, Huntington's disease, Friedrich's ataxia, genetic stiffness paraplegia Alzheimer's disease), and the brain dies more quickly and predominantly from death. It can be considered the body (the mass of the adult brain decreases with age [78]). In a rapidly aging society, these diseases are demographic time bombs. Indeed, beyond the pain of countless individuals, they stand to sustain the entire economy (medical spending is already a sustained percentage of GDP ~ 30% in the United States). For example, nearly half of Americans, who have dementia older than 85 percent of the population's growth rate will surpass, may be debilitating, which completely strains families and communities without this cure [78]. Therefore, the treatment that will make the last one brain function as the rest of the body, which will help speed up the aging of the brain, will help the "health span", which is the holy grail of modern medicine, which must be largely consistent.

Embodiments of the invention, the subject, for example, in the method of taking the compound of formula (I) or administering an effective amount of the compound (s) of the present invention, (II), (III), (IV) or ( Phosphorus V) or other compounds with selective F1F0 ATP hydrolysis, or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof / to improve/prevent treatment/degenerative disease(s) that inhibit combat brain aging. The compound(s) is delivered to an unbalanced brain or central nervous system (CNS) and optionally directed to a particular brain/CNS region(s) or cell type(s), either by the above, or by route of administration strategy or targeting. By way of example and not limitation, brain targeting was indicated as exogenous dopamine [79-80]. Preferred brain structures/cells/neurons for targets are breakdown compacta drives neurodegenerative diseases such as dopamine neurons (in black matter). There are only 7,200 in rats, some of which [81] and their number reduction by aging from 5 to 10% per decade is an enemy-induced drive to human [82] Parkinson's disease (PD). Embodiments of the invention, the subject, for example, in the method of taking the compound of formula (I) or administering an effective amount of the compound (s) of the present invention, (II), (III), (IV) or ( Phosphorus V) or other compounds, optionally characterized in that the compound(s) are optionally administered to an unbalanced dopamine neuron F1F0 ATP hydrolysis, or a pharmaceutically acceptable salt, solvate, hydrate or precursor thereof Drug/Battle Parkinson's disease, suppresses black matter. In the compounds of the present invention, when heat generation decreases, heat transfer in neighboring brain and/or body regions displaces heat.

surgery

Embodiments of the present invention (the subject II, for example, a method of taking or administering a compound of formula (I) and/or retaining an effective amount of plasma blood levels of the compound(s) of the present invention), (III), ( IV), (V) or (VI) or selective F1F0 ATP hydrolysis, or other compound, solvate, hydrate or prodrug thereof, to reduce the pharmaceutically acceptable salt thereof, the subject analgesic agent (s generally administered) And/or anti-emetic treatment agent(s) and/or anti-anxiety and/or antidepressants and/or local and/or general anesthesia (e.g. known to the art), and/or optionally other drugs optionally treated/mitigated/prevented/ As an anti-anxiety/sedative drug used before or after anesthesia (e.g. known to those in the art), such as combat cancer, a method for surgically undergoing surgery to remove tumor(s).

Emergency contraception

The adult body does not contain embryonic stem (ES) cells. ES cells exist temporarily because morphology ~ 5 days post fertilization into the inner cell mass of the blastocyst, they soon differentiate into other types of cells, without the characteristics of ES cells. So, especially when killing ES cells, the compound(s) provides utility as a window, for example, an emergency pill taken after unprotected sex, since it is effective compared to current emergency contraceptives. In addition, the scope of these terms and compositions is known and can be referred to as a feature of these combined oral contraceptives that will have utility as contraceptives, which can be administered instead or combined with other contraceptive(s) to those of the art.

The metabolism of cancer cells is similar to that of ES cells. All (without limitation, immortality) can multiply forever quickly. They share gene expression fingerprints [54]. ES cells also tend to respond to ROS damage by repairing abnormalities rather than cell death [56], where hyperpolarization ΨIM acts correspondingly to some or all of the aerobic time of employment [56].

The F1F0 ATP hydrolysis inhibitor also has anti-cancer activity, as disclosed by the present invention, by the activity of the anti-ES cells of the present invention. An embodiment of the invention is compound (S) inhibitory F1F0 ATP hydrolysis, e.g. the compound is administered in formula IV or selective CO of patient self administration to the patient for use in pregnancy/termination/prevention.eg progestin, antiprogestin Another compound(s) of a compound with multiple uses known to them, or combinations thereof (optionally pharmaceutical compositions)-managed estrogens etc. could be used after sexual intercourse for use. In other embodiments, such use is limited to the time that early ES cells are present in the embryo.

An embodiment of the invention is an F1F0 ATP hydrolysis inhibitor(s) for use in selling, distributing, and/or anti-cancer therapeutics characterized in that the compound(s) are administered verbally, or for other therapeutic uses in a subject, and/or Written warning, on the insertion of a packet of packets containing the compound(s), optionally, it should not be attempted to be pregnant and/or administered to a woman in the early and/or week of pregnancy in a woman.

The compounds of the present invention are anti-inflammatory

An embodiment of the invention is a method of using a therapeutically effective amount of at least one compound of the invention that inhibits the hydrolysis of F1F0 ATP as an immunosuppressant and/or anti-inflammatory agent. In the case of collapse in the ΨIM cell, there is a therapeutic opportunity because it will continue to die[59] and to maintain ΨIM, hydrolyze ATP and use it there, relying solely on the ATP synthase in a completely opposite mode, unlike resting phagocytes, Activate macrophages [83]. This is because activated macrophages (NO increases in the O2 complex IV km) produce their OXPHOS off/down switch nitric oxide (NO). Inhibition of F1F0 ATP hydrolysis Compounds of the present invention and selective F1F0 ATP hydrolysis inhibitors ΨIM erosion) Optionally optionally separated (S administered in combination therapy (Sim shrinking to active macrophages killing it) is the only means that activated macrophages can counteract this corrosion There ΨIM decay F1F0 ATP hydrolysis inhibitors), thus according to the present invention, according to the present invention, a therapeutically effective amount of one or more compounds of the F1F0 ATP hydrolysis inhibitors, for example compounds (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable separator thereof optionally treated/improved/prevented by co-treatment salts, solvates, hydrates or prodrugs ((S)F1F0 ATP hydrolysis and separators e.g. BMS-199264) / Attenuates inflammatory dendritic cells and attenuates other NO (inflammatory active macrophage components) that produce cells of the innate immune system and/or diseases associated with combat disease or undesirable activity or activity of macrophages and/or monocytes derived and Drugs or stress or frostbite, burns or radiation, inflammatory diseases, including/or immune or inflammatory diseases/retards/pathologies, but not limited to infections or foreign objects or injuries or chemicals or toxins or inflammations due to acute inflammation, chronic inflammation, or systemic inflammation/ Ionizing disorder/syndrome ("inflammaging") macrophage activation syndrome (MAS), auto-inflammatory disease/disorder/syndrome, senile chronic inflammatory disease, cold or flu or fever, high intensity exercise related inflammation, ulcerative colitis, inflammatory bowel Disease (IBD), irritable bowel syndrome (associated with innate immune system, sore throat, sore throat autoimmune disease/disorder/syndrome, disease/disease IBS), rheumatoid arthritis, osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic genitals Inflammation, asthma, inflammation-related depression, exercise-induced acute inflammation, atherosclerosis, allergy, pollen allergy, anaphylaxis, inflammatory myopathy, Drug-induced inflammation, systemic inflammatory response syndrome, multiple organ failure/several organ failure associated with sepsis, microbial infection, acute brain/lung liver kidney damage, acne celiac disease, celiac sprue chronic prostatitis, colitis, diverticulitis glomerulonephritis / /hidradenitis purulent, irritable, interstitial cystitis, mast cell activation syndrome, mastocytosis, otitis media, pelvic inflammatory disease (PID), reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasites, eosinophilia, III Hepatic hypersensitivity reactions, ischemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematosus (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative diseases , Cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, appendicitis, acute appendicitis, bursitis, colitis, cystitis, dermatitis, encephalitis, gingivitis, meningitis, infectious meningitis, myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, Phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendinitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis, interstitial lung disease and desquamative interstitial pneumonia, interstitial lung disease, Ropegren syndrome, Heerfordt syndrome , monocytosis, cirrhosis, fatty liver, alcoholic fatty liver, silicosis, histiocytoses, Langerhans cell histiocytosis, haemophagocytic lymphohistiocytosis lung Langerhans cell histiocytosis, obesity, diabetes, gout, pseudogout, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft versus input Host disease (GVHD), lymph node.urethritis, vasculitis, interstitial lung disease related to respiratory bronchiolitis and desquamative interstitial pneumonia, interstitial lung disease, ropegren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, fatty hepatitis, non-alcoholic fat Hepatitis, silicosis, histiocytoses, Langerhans cell histiocytosis, haemophagocytic lymphohistiocytosis, lung Langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudoplastic, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, host disease (GVHD), lymph node graft vs. Interstitial lung disease related to urethritis, vasculitis, respiratory bronchiolitis and desquamative interstitial pneumonia, interstitial lung disease, lopgren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, fatty hepatitis, non-alcoholic fatty hepatitis, silicosis, histiocytoses, Langerhans cell tissue Ataxia, haemophagocytic lymphohistiocytosis, pulmonary Langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudoplastic, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, host disease (GVHD), lymph node graft vs. histiocytoses, Langerhans cell tissue atrophy, haemophagocytic lymphohistiocytosis, pulmonary Langerhans cell histiocytosis, obesity, diabetes, gout, pseudoplastic, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft-versus-host disease (GVHD), lymph node type: histiocytosis, Langerhans cell tissue ataxia, haemophagocytic lymphohistiocytosis, Pulmonary Langerhans cell histiocytosis, obesity, diabetes, gout, pseudoplastic, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft-versus-host disease (GVHD), lymph nodes.

Clinical usefulness, anti-inflammatory activity of the compounds of the present invention juxtapose well with their ability to reduce body temperature.

The anti-inflammatory action by the compounds of the present invention has anti-cancer action. Because it can reduce the number of tumor-associated macrophages (Tech Account Manager) [84]. Their presence is often associated with poor patient prognosis, as it can constitute a large component of this tumor mass and can drive the pathology of cancer. In fact, inflammation is now considered one of the hallmarks of cancer [85]. Synergy of direct anti-cancer activity The anti-inflammatory action of these compounds, such as anti-cancer action, is disclosed herein.

Macrophages can be overturned by pathogens that hide within them for safety in the immune system. A non-limiting example of such a pathogen is HIV (which causes HIV/AIDS, the HIV virus is detected in the blood, the HIV virus is detected latent in the antiretroviral treatment process, and the antiviral therapy stops or stops the virus in the blood again) It can replicate fillable HIV into macrophages [86-87]), Mycobacterium tuberculosis (caused tuberculosis), Schumann flagella parasite (Yagi Lee Schumann flagellosis), Chikungunya virus (caused Chikungunya), Legionella pneumoniae () is Legionella syndrome The cause of the adenovirus (), the cause of the Whipple disease whipplei (T.), and Brucella species cause pink eyes. (Brushella disease occurs). Thus, by exerting anti-macrophage activity, the compounds of the present invention are capable of preventing/// improving combat and treating these disorders and diseases. Because of the selectivity for activated macrophages, the compounds of the invention are activated by administering to the patient an effective amount of a compound, protein, antibody or some other entity, e.g. pathogen, attenuated pathogen or pathogen, prior to administration of the optional compound. Are macrophages and are the components that activate macrophages. Examples include macrophages that are cytokine activators (non-limiting) and/or IL-4 and/or IL-13, and/or cytokines such as interferon-gamma (IFN-γ) and/or tumor necrosis factor (TNF). IL-10, and/or IL-2 and/or IL-12, and/or IL-6 and/or IL-18 and/or chemokines (CCL3, carbon tetrachloride, CCL5) and/or bacterial toxins such as lipopolysaccharides (LPS), or commercial agents for the activation of macrophages in biological studies (e.g. CAS 61512-20-7) or antibodies targeting receptors on the surface of macrophages or other cell types following it Activates macrophages through a mechanism. Macrophage-activated antibodies are known to those of skill in the art. And/or bacterial toxins such as IL-18 and/or chemokines (CCL3, carbon tetrachloride, CCL5) and/or lipopolysaccharide (LPS), or commercial agents for activation of macrophages in biological studies (e.g. CAS 61512 -20-7) Or antibodies target phagocytic cell activation to other cell types, surface receptors on or on the surface of phagocytes. Macrophage-activated antibodies are known to those of skill in the art. And/or bacterial toxins such as IL-18 and/or chemokines (CCL3, carbon tetrachloride, CCL5) and/or lipopolysaccharide (LPS), or commercial agents for activation of macrophages in biological studies (e.g. CAS 61512 -20-7) Or antibodies target phagocytic cell activation to other cell types, surface receptors on or on the surface of phagocytes. Macrophage-activated antibodies are known to those of skill in the art.

An embodiment of the present invention is to use an effective amount of one or more compounds of the present invention that inhibit the treatment/mitigation/prevention/combat HIV infection, F1F0 ATP hydrolysis with an effective amount of any compound, protein, antibody, macrophage ( Activating pathogens or pathogen components are not absolutely necessary because HIV activates macrophages [88-89] which are optionally co-therapy or after, anti-retroviral therapy (ART) or combination antiretroviral therapy (cart) Drives the pathological component of chronic inflammation of HIV infection. Even after HIV cartes, HIV-1 DNA and RNA can be detected in macrophages and extend to undetectable levels, they remain present, while in the shopping cart AIDS reservoir, and the virus spreads at the time of disruption or termination Can be Cart [87]: Very important for the methods and compounds herein. Additionally, these compounds are related to HIV/treatment/improvement/prevention/treatment of chronic inflammation.

Macrophages are compounds of the present invention (neural invasion by other viruses such as SARS coronavirus) HIV virus Neuroinvasive intervention is opposite and treatment is improved / silver / combat HIV related neurocognitive disorder (HAND) (and neurocognitive and degenerative neurological diseases / Prevention by other / viruses) eg Sascorona virus. Anti-HIV and anti-cancer activity of the synergistic compounds of the present invention in anti-HIV and treatment/mitigation/prevention/combat HIV-related cancers: cancer AIDS-definition (Kaposi sarcoma, aggressive B cell non-Hodgkin's lymphoma, cervical cancer.) and non-AIDS cancer Justice. The present invention includes the compound(s) of the present invention in co-therapy together with the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) approved drug(s) or treatment for HIV or AIDS. For example, but not limited to, ava kabir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, disoproxil fumarate (tenofovir DF, TDF), zidovudine (azidothymidine , AZT, ZDV), Atazanavir, Fossam Frenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Thiprana enfuvirtide, Mara though, dolutegravir, elvitegravir, raltegravir, cobicistat.

Compounds of the treatment of the present invention include, but are not limited to, recurrent fever syndrome, including/combat membranes, and improved/autonomous inflammatory diseases/diseases/syndromes that are not inherited or characterized by recurrent fever associated with or become limited hereditary A possible rash, enteritis, lymph nodes and musculoskeletal involvement. For example, familial Mediterranean fever (FMF), etc., TNF receptor associated cycle syndrome (TRAPS) Hyperimmunoglobulinemia D recurrent fever syndrome (HIDS) cryopyrin cycle syndrome (CAPS) associated Bla syndrome, Majid syndrome, interleukin-1 receptor antagonist (DIRA) , Mevalonate kinase deficiency, purulent arthritis-pyoderma gangrene and acne syndrome (Papa), periodic fever aphthous stomatitis pharyngitis deficiency (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, SCHNITZLER syndrome, sweet syndrome, NLRP12 Related auto-inflammatory disorders, deficiency of interleukin-1 receptor antagonists (DIRA), pyoderma gangrene, cystic acne, aseptic arthritis, periodic fever-related mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), purulent arthritis pyoderma gangrene and acne ( PAPA) syndrome, periodic fever aphthous stomatitis, pharyngitis and pathology (PFAPA) syndrome, adult-onset still disease (AOSD), systemic juvenile idiopathic arthritis (sJIA) chronic recurrent multiple osteomyelitis (CRMO), synoviitis acne pustular osteochondritis (Sandpaper) syndrome, Cryopyrin-related cyclic syndrome (CAPS), family cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), hives in familial cold, neonatal onset multi-inflammatory disease (NOMID), genetic cyclic fever syndrome, Periodic fever syndrome, systemic auto-inflammatory disease.

Compounds of the treatment of the present invention include/silver/combat membranes, but are not limited to, but not limited to, Edison's disease/immune diseases/diseases/syndromes, non-restrictive Agammaglobulinemia alopecia areata, inheritance, ankylosing spondylitis, anti-GBM/anti-TBM nephritis , Antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic nerve, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axon and Neuropathy (AMAN), BALO disease, Behcet's disease, benign mucosal parenchyma, vesicular parenchyma, Castle disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating primary neuropathy (CIDP), chronic recurrent multiple Osteomyelitis (CRMO), Chuck-Strauss, Scar Cogan Syndrome, Disease, Congenital Heart Block, Coxsack Myocarditis, CREST Syndrome, Burger's Disease, Herpes Dermatitis, Dermatomyositis, Distribution Device Disease (Neuromyelomyelitis), Discoid Lupus , Wrestler syndrome, endometriosis, eosinophilic esophagitis (swallow), eosinophilic adenomyosis, fasciitis fasciitis, erythematous nodule, core hybrid cold globulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis , Multiple vasculitis granulomatosis, Goodpasture's syndrome glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immunohemolytic anemia, Henoch-Hellin's purpura (HSP), herpes gestationis or mastoid gestationis (PG) , hypogammalglobulinemia lice nephropathy, sclerosis related to IgG4, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, childhood diabetes (type 1 diabetes), juvenile myositis (JM) , Kawasaki disease, Lambert-Eton syndrome, leukocytes vasculitis, lichen planus, moss sclerosus Alveolar conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease, Chronic, Meniere's disease, Microscopic cluster (MPA), Mixed connective tissue disease (MCTD), Muren corneal ulcer, Muha-Habermann disease, Multiple Sclerosis, myasthenia gravis, myositis, narcolepsy, optic nerve myelitis, neutropenia, ocular scarring paroxysmal ulcer, optic neuritis, sold Drom rheumatism (PR) panda, adrenal biocerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH) parry Romberg syndrome Peripheral uveitis (peripheral uveitis) Parsonnage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, malignant anemia (PA) syndrome, nodular polyarteritis, glandular syndrome, type I, II, III, multiple rheumatism, multiple myositis , Myocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure erythropoiesis (PRCA), Pyoderma gangrene, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Recurrent multiple Chondritis, restless leg syndrome (RLS), posterior peritoneal fibrosis, rheumatoid fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, skin sclerosis, Sjogren's syndrome, sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac Syndrome, Sympathetic Ophthalmitis (SO), Takayasu Arteritis, Temporary Arteritis / Giant Cell Arteritis, Thrombocytopenic Purpura (TTP), Tolosa Hunt Syndrome (THS), Transverse myelitis, type 1 diabetes, ulcers ( UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo colitis, splenic hypertrophy, idiopathic thrombocytopenic purpura (red bundle (GPA) or granulation) Wegener's granulomatosis.

Slow release formulation

Embodiments of the invention include, for example, compounds (I), (II) of formula (I), (III), (IV) or (V) of the formulation of the subject, wherein the subject is administered in a therapeutic amount of at least one compound of the invention. For use by methods of treatment of the human or animal body, a choice/dose regimen from modified release, extended release, long acting release, sustained release, extended release, controlled release, slow release, or the like, which is apparent to persons of the art. This formulation exposes the workpiece to the compound(s) over a longer period of time than when the compound was applied alone. This is useful because it provides a good area under the curve for a compound that exerts anticancer activity on a subject, for example, without a large rapid body temperature drop. It is safe for periods of less amplitude than the correlated body temperature drop. The method confirms that such compound preparations are known to the art. Described with some non-limiting examples: Compounds/degrades/decomposes, so, for example, it takes time to dissolve poorly soluble excipients/tablets/pills. In addition, enteric coatings, acrylic (e.g. chitin), liposomes, drug-polymer composite(s), microencapsulation (coating active pharmaceutical ingredients around the inactive core, and laminating with water insoluble materials to form microspheres) dissolution system ( There are two types of rate release and depending on the dissolution of the excipients: reservoir matrix), replenishment system (two categories of drug dissolution through the general type of barrier polymers depending on rate release rate: reservoir matrix), osmotic system, ion exchange resin,

The embodiment of the invention does not cause a significant temperature drop in humans and uses a dosage regime of F1F0 ATP hydrolysis inhibitor. Optionally, spread the daily therapeutic dose over several pills per day, so that any body temperature drop is longer and the safety period is longer and the amplitude is reduced.

Supporting albumin slow release

Compound (31) of the present invention is a widely known compound class 1,4-benzodiazepine in albumin binding in the blood. For example, 99% of diazepam is protein, the majority of this protein is albumin and is bound to blood. Albumin can bind several things non-specifically, but the high affinity has a high affinity for binding to a site that binds to a specific substance [90], for example, 1,4-benzodiazepine. Indeed, albumin, which may bind a range of two unique high affinity binding benzodiazepines, is also referred to as a "benzodiazepine site" called a diazepam site or an indole BDZ site, and a single site capable of compound (31) also. Compound 31 albumin in the blood will slow the buffer and slow the buffer, prolong the exposure time of the compound 31 to the tissue to reduce the amplitude and buffer the compound to prolong the effect of body temperature 31. Anti-cancer data of the present invention, Compound (31) (FIG. 6) (FIG. 1) FDA is widely used, above Carbopllatin chemical approval. However, by adding albumin in 5% fetal bovine serum (FBS) by adding to the EC50 F1F0 ATP hydrolysis (FIG. 9) and RPMI 1640 medium used for the NCI-60 test, the sequestration compared to the lower [35] contributed to poorly It is possible (in addition, interaction with CYP2C9 and compound 31, as cited in Figure 9 and the legend). If the amount of 2% FBS is reduced and the large anti-cancer activity exerted by compound 31 versus drug control (such as 2% FBS reduction) is revealed, then assay. NB's carboplatin does not bind albumin, which is not a great affinity for blood binding proteins (ie mainly albumin) very low indeed.

Temperature control release

An embodiment of the invention is a temperature-sensitive pharmaceutical composition/vehicle that releases a compound of the invention to a compound of formula (I), (II), (III), (IV), (V) or other F1F0 ATP, for example only And is a phosphorylase inhibitor(s) above normal human body temperature. The latter is reached if the subject has a fever, for example. Most cancers develop fever. When the F1F0 ATP hydrolysis inhibitor is released, when the body temperature falls, there are fewer drugs there, so these temperature-sensitive delivery compositions/release the drug(s) to the vehicle general body temperature (37°C), for example, in a safety feedback loop The body temperature released can affect and recover from it, the compound is released, and this loop is repeated to minimize optimal body temperature disturbances to realize sustained release. For a non-limiting example, at the temperature of the F1F0 ATP hydrolysis inhibitor(s), the psychiatrist releases the compound and is loaded with a structure comprising a thermosensitive biocompatible polymer that exceeds its phase/volume transition temperature. This volume change is reversible. If the temperature falls below the phase/volume transition temperature where the expansion of the structure and compound separation do not occur [91]. In some embodiments, the phase/volume transition temperature is adjusted to be at elevated pathology body temperature (S), and in other embodiments, at normal body temperature. Biothermal polymers can produce temperature responsive hydrogels/nanogels and nanoparticles there, along with any polysaccharides that control the drug encapsulation and release efficiency, which have the above phase transition temperatures where they release the "carb" compound(s) have. The transition temperature can be easily adjusted by changing the copolymerization conditions and the content of the repeating unit of the copolymer. Thermally sensitive hydro/nanogel for temperature sensitive vehicles for compounds of the present invention, options including temperature sensitive liposomes are non-limiting [92-94] smart three-dimensional porous material, direct thermal micro container, direct nano drug delivery vehicle, temperature sensitive Micelles, polymeric micelles, core-shell microgel particle heat response composite films with core shell structures (these were used in clinical trials eg ThermoDox).

It is also contemplated to provide an imbalance, and the pharmaceutical composition/ vehicle and/or pharmaceutical composition/vehicle of the present invention are administered by a vehicle in which the components in this invention trigger a temperature parallel to the pH of one or more other stimuli, etc. Reference example technique and possible normal tissue (S) of the subject (compound(s) of the invention in cancer cells compared to multiple strategies [95]). For example, pharmaceutical compositions/vehicles are separated by one or more associated cancer stimuli such as acidic pH, or one or more cancers/tumors, e.g. heating, caused by external stimulation.

Drawing technology

For clarity, labeling or drawings on all drawings without all components are not required to allow those skilled in the art to understand the present invention, each element of each embodiment of the present invention shown here.

Figures 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12: Experimental Evidence: Molecules that specifically inhibit the reversal mode of ATP are syntha: a particularly non-limiting example of anticancer activity that is particularly exerted.

Figures 1, 2, 3, 4, 5, 6, 7, 8 show the results of an in vitro assay administered with NCI-60 [34-35] a developmental treatment program at the National Cancer Institute (NCI, Bethesda, MD, USA) ( DTP). If that protocol is known to the art, test the effect of the test compound on the proliferation/viability of cancer cells, as compared to the no-compound control. When this protocol was first developed, the compound was tested against 60 cancer cell lines, hence the name NCI-60 only, more recently reduced to 59 cell lines, and there may be slight fluctuations in the age of the cancer cells that make up this 59 (sometimes also being 59) Thing). However, the constant is that there are always cell lines that are representative of leukemia, melanoma and lung, colon, brain, ovary, breast cancer, prostate cancer and kidney cancer. The NCI One Compound Dosage Test Report, reporting each cell line in NCI, calls them "percent growth", which is the control over the growth furnace compound in a number of times the number of cells per hour. All of these reported parameters allow detection of growth inhibition and lethality (if the value between 0 and 100 () is less than 0). For example, NCI "growth ratio" value of growth inhibition without means 100. A value of 40 means 60% growth inhibition. 0 is the value of any net growth over the course of the Sudan experiment. -40 means 60% lethal value. A value of -100 means that all cells are dead. I do NCI one capacity data that does not exist in this original format. If the NCI "growth ratio" value for the cell is positive, manipulate it instead [100 minus this original NCI-60 "growth ratio" data point, to get the ratio "growth inhibition". If the original NCI "growth rate" value of the cell is negative, it is positive as the percentage of the original cancer cells (time zero) death: "rate death" rate "growth inhibition" is then specified as 100 {in this case, of course, All growth was inhibited.% for this cancer cell line. Application is indicated on the x-axis along the x-axis, adding "growth inhibition" (0 to 100%) in my single dose figure (in case of 0 to 100%) "death rate". The latter is applied only when there is no growth of cancer, "percentage treatment" along the x-axis (0-100%). The latter is applied only when there is no growth of cancer, "percentage treatment" along the x-axis (0-100%). The latter applies only when there is no cancer growth, but the inhibitory compound does not simply slow down cancer growth, and the active starting number is the start time to decrease the number of cancer cells, ie a decrease in the number of cancer cells. "Growth inhibition" is displayed on the x-axis only when there is only growth inhibition. In all cases, the greater the number of ratios on the X-axis to a given cancer cell line called the large y-axis, the higher the anticancer activity of the present compound against this cancer cell.

The NCI-60 test is performed at a controlled temperature of 37 °C [35].

To perform the anti-cancer test report: BMS-199264 hydrochloride was purchased from Sigma-Aldrich. BTB06584 was purchased from AdooQ Biosciences, Irvine, CA, USA. Synthesis by compound 19A (separated into 6A and 6B stereoisomers) and 31 schemes is disclosed herein. Almitrindi mesylate was purchased from AK Scientific, Palo Alto, California, USA. Ar NSC numbers are test compounds to be used by NCI: BTB06584 (NSC: 794220), BMS-199264 hydrochloric acid (NSC: 795,767) Almitrindi Mesylate (NSC: 800,450) 6B (NSC: 801,828), 6A (NSC: 801,827) 31 (NSC: 802,605).

Figure 1: Single dose (10 μM) analysis of carboplatin's anticancer activity at the National Cancer Institute (NCI). Search in the Data NCI Developmental Therapy Program (DTP) screening database [32], database entry NSC: 241240. To retrieve this data, enter the NSC at https://dtp.cancer.gov/dtpstandard/dwindex/index.jsp . The DTP database contains anticancer performance (more than that usually lacks)> 80 compounds in the same experimental protocol. New items are searched publicly after a 3-year delay (before they are published by this database, I wish, provide time for compound submitters to secure IP protection). This figure presents the FDA's anti-cancer performance licensed as one of the most used anti-cancer drugs, carboplatin, and most-used anti-cancer drugs today in the World Health Organization list of the most essential pharmaceuticals in the exact same experimental protocol used. Anti-cancer drugs, presented in subsequent drawings. This is also a recommendation for direct recommendation that may be included Compared to widely used clinical anticancer drugs and the new anticancer drugs disclosed herein.

Figure 2: No BTB06584 anti-cancer activity at 10 μM (NCI one dose analysis).

Figure 3: Anticancer activity of BTB06584 at 100 μM (NCI One Dose Assay).

Figure 4: BMS-199,264 hydrochloride anticancer at 10 μM (NCI one dose assay).

Figure 5: BMS-199,264 hydrochloride anticancer at 100 μM (NCI one dose assay).

Figure 6: Anticancer activity of compound 31 at 10 μM (NCI one dose assay).

Figure 7: Anticancer activity of almitrindimesylate at 10 μM (NCI One Dose Assay).

Figure 8 (8A) Lasemi mixture, or Lasemi body, has the same amount of S and R chiral molecules enantiomers. The structure of structural formula 19 is the S stereoisomer of Figure 6b, and the R or S structure 6A, the R stereoisomer is the same racemate and (R/S) symbolizes the chiral carbon. EC50 F1F0 ATP is also included, so it contains about half of the large amount of S stereoisomer per unit mass, so it is potentially about half the semi-isomer (19A, 0.033 μM) of that of the isolated S stereoisomer (6B, 0.018 μM). 50:50 ratio of Hydrola R stereo (EC50 F1F0 ATP hydrolysis> 100 μM). Superfluid chromatography (SFC) strongly inhibited the SMPS's F1F0 ATP hydrolase, respectively, without using separation (19A) as its R component (EC50 values performed stereoisomers, S-[5-6]) Two samples of inverse and >97 enantiomeric excess (EE) were achieved% referencing 6A and 6B respectively. They were tested for NCI (10 μM) test administered alone: the results are shown in Figures 8B and 8C, respectively. The anticancer activity of FIGS. 6A and 6B was similar (Pearson correlation: R = 0.8, note p <0.00001). At 48 hours of the NCI day dosing test, they were subjected to racemization and due to their EE erosion. Both samples contain a significant portion of the ultimate S stereoisomer and two anticancer activities that act by inhibiting the hydrolysis of F1F0 ATP. There is no moment of racemization, so one sample, Figure 6b, grants a larger/more than three-dimensional exposure of cancer cells compared to other sample 6a. S. racemization was not necessarily completed in the final test. Reasons for explaining these features 6B origin sample has greater anticancer activity than origin 6A (6B from start to >97% ee) (6A from start to >97% ee) Sample: 66% 57% vs. average cancer growth inhibition Across all 59 cancer cell lines each. While, more definitely say, in the NCI One Dosing Test (6a) they are racemic or scalemate, i.e. 97%>50% ee ≥6 degrees. Although the fidelity of the 6A and 6B sample erosion during the NCI test (between divisions) (19A) is still in use at the time of the invention referencing these samples during the NCI, the terms 6a and 6b are also used (by epimerization) respectively Test as convergence. Also, during the NCI 6A 19A → test and 6B → (19A), I was mixed using other time terms 6a, 6b and 19a given herein. The racemization reaction decreases and increases the anticancer activity of 6A and 6B, respectively. (8D) Figure 6b shows greater anticancer activity than Figure 6a. 6B is the S stereoisomer, and FIG. 6A is the R stereoisomer. However, taking into account the figure, the present invention, the sample and labeled 6B (6A) are components in the case where the R and S stereoisomers are respectively. (8E) and (8F) are NCI one dose (100 μM) assays, FIGS. 6A and 6B, respectively, for anticancer activity. In this analysis, both 6A and 6B inhibited intermediate cancer growth for >79%. Some cancer cell lines, such as both Figure 6A or Figure 6B, have less anticancer activity and less than 10 μM and 100 μM. 6A and 100 μM = 0.9437 (p<0.00001) (6B) anticancer activity and Pearson correlation coefficient. Also considered by the present invention, the sample and labeled 6B (6A) are components in the case where the R and S stereoisomers are respectively. (8E) and (8F) are NCI one dose (100 μM) assays, FIGS. 6A and 6B, respectively, for anticancer activity. In this analysis, both 6A and 6B inhibited intermediate cancer growth for >79%. Some cancer cell lines, such as both Figure 6A or Figure 6B, have less anticancer activity and less than 10 μM and 100 μM. 6A and 100 μM = 0.9437 (p<0.00001) (6B) anticancer activity and Pearson correlation coefficient. Also considered by the present invention, the sample and labeled 6B (6A) are components in the case where the R and S stereoisomers are respectively. (8E) and (8F) are NCI one dose (100 μM) assays, FIGS. 6A and 6B, respectively, for anticancer activity. In this analysis, both 6A and 6B inhibited intermediate cancer growth for >79%. Some cancer cell lines, such as both Figure 6A or Figure 6B, have less anticancer activity and less than 10 μM and 100 μM. 6A and 100 μM = 0.9437 (p<0.00001) (6B) anticancer activity and Pearson correlation coefficient. Some cancer cell lines, such as both Figure 6A or Figure 6B, have less anticancer activity and less than 10 μM and 100 μM. 6A and 100 μM = 0.9437 (p<0.00001) (6B) anticancer activity and Pearson correlation coefficient. Some cancer cell lines, such as both Figure 6A or Figure 6B, have less anticancer activity and less than 10 μM and 100 μM. 6A and 100 μM = 0.9437 (p<0.00001) (6B) anticancer activity and Pearson correlation coefficient.

Figure 9 : Anti-cancer efficacy (EC50) F1F0 inhibition of ATP hydrolase across various chemical structures (scales, compared to no compound control in NCI-60 single-dose trials as well as an average percent reduction in cancer growth), scales. EC50 values for ATP include BMS-199,264, synta (NB EC50 not pure BMS-199,264 for BMS-199,264 hydrochloric acid), Figures 19A, 6A, 6B and 31 are from sub-mitochondrial (SMP) studies [5-8], The efficacy of BTB06584 (AN50 not EC50) is from a whole cell study [13]. The EC50 for compound 31CYP2C9 is from [8].

6B and 6A are similar to those of epimers in biological systems that erode their enantiomeric excess (EE) during the NCI test, converging them to LACEMI, 19A phosphorus, because of their anticancer activity. Therefore, during the NCI test, 6B EC50 F1F0 ATP hydrolysis is constant, but not within the range: 0.033 μM ≥ EC50 F1F0 ATP hydrolase ≤ 0.018 μM EC50 F1F0 ATP is due to the hydrolytic enzyme → 0.033 6B → 19A, etc. μM. Likewise, 6A EC50 F1F0 ATP hydrolase →0.033 μM etc. → 6A 19A.

The 100% test for most cancer cells due to the average% cancer growth inhibition for 100 μM BMS-199264> is the cause of the cancer cell growth inhibition of 100%, not that it is performed, but in addition, the number of cancer cells that cause cancer regression At the end of the experiment, less than at the start of the experiment. BMS-199,264 mainly exerts anti-cancer activity at 10 μM by inhibiting F1F0 ATP hydrolysis, and at 100 μM, by reducing F1F0 ATP synthesis.

1. 우리는 다음 결합 친화도 어느 정도 화합물로서 EC50을 동일시하면 31 CYP2C9 래핑보다 그 역방향 모드 (EC50 = 0.022 μM)로 ATP 합성 효소의 결합을위한 더 큰 친 화성을 갖는다 (EC50 = 2 μM) (이 비교가 매우 강력하지 않다 거기서 이러한 EC50 값은 다른 분석에서 온). 그러나, ATP 신타 항상 역방향으로 동작하지 않고, 그것은 아마도 세포주기의 다른 단계에서 다른 운영 성향을 가지며, 화합물 31 EC50 F1F0 ATP 합성> 30 μM이다. 따라서, CYP2C9 의미심장 F1F0 ATP 가수 분해 효소의 억제 화합물 (31)을 감소시키고 그로부터의 항암 활성있다. 특히 CYP2C9, 시토크롬 P450 효소 때문에,하지 단순히 결합하여 이산화탄소 격리 화합물 31CYP2C9, it has an anticancer activity that is less than predictable for its EC50 F1F0 ATP hydrolysis because it inhibits competition (consumed in the 31 process): 31 is degraded by the cytochrome P450 enzyme. The CYP2C9 mean LOG2 carcass strength was all 3.539 across the NCI-60 cell line [31-32]. ATP5A1 average LOG2 carcass strength, F1 ATP's alpha subunit is NCI-60 9.871 across all lines [31-32]. There are three alpha subunits per ATP synthase [1]. Thus, on average approximately similar amounts of CYP2C9 and ATP synthase in NCI-60 cancer cell lines: 3.539 (9.871 / = 3.29 3)

1.We have a greater affinity for the binding of ATP synthase in its reverse mode (EC50 = 0.022 μM) than 31 CYP2C9 wrapping (EC50 = 2 μM) (if we identify EC50 as a compound to some extent then binding affinity (EC50 = 2 μM) ( These comparisons are not very strong, where these EC50 values come from different analyzes). However, ATP synth does not always work in the reverse direction, it probably has a different operating tendency at different stages of the cell cycle, and the compound 31 EC50 F1F0 ATP synthesis> 30 μM. Thus, the CYP2C9 semantic heart F1F0 ATP inhibitor inhibits the compound 31 and has anticancer activity therefrom. Especially because of the CYP2C9, cytochrome P450 enzyme, not simply by combining carbon dioxide sequestering compound 31

Although less affected by F1F0-ATP hydrolysis in anticancer activity than BMS-199264 exerted by 10 μM, 6B (6A and), it had less effect on F1F0-ATP synthesis.

Figure 10: Anticancer activity of BMS-199264 hydrochloride. The result is from an NCI-60 five-dose in vitro assay [34-35] in the Developmental Therapy Program (DTP) at the National Cancer Institute (NCI, Bethesda, MD, USA). In this assay, known to those of skill in the art, the compound is tested in vitro against 59 cancer cell lines fed from 9 different tissue types across 5 different concentrations. Shown in 10A) one is provided for each of the nine tissue types. It is output by the graph and NCI but is changed to black and white color. For each growth furnace compound control on the Y axis, it is the above "growth ratio" parameter used by NCI relative to the cell's time zero number. Both of these parameters allow the detection of growth inhibition and lethality (if the value between 0 and 100 () is less than 0). GI50 is the concentration of the compound that causes 50% inhibition of proliferation against the no-compound control cell line. Each cancer cell has a GI50 value that can be counted and "average GI50" of all cells (59) lines: BMS-199,264 hydrochloride is 3.9 μM on average GI50.

Figure 11: Anticancer activity of Figures 6a and 6b in an NCI-60 five-dose in vitro assay [34-35]. The average GI50 for FIG. 6B is 0.446 μM. The average GI50 for 6A is 0.666 μM.

Figure 12 . Large anticancer activity results in large anticancer drug concentrations. This is what art people expect. However, along with some of the cans of FIG. 6A and FIG. 6B (overwhelmingly identical), cancer cell lines may exert less than 10 μM and 100 μM of anticancer active compounds (FIGS. 12A and 12B) in one dose analysis of NCI, and in some cases (in NCI five dose analysis) 1 μM (Figure 12C) is overwhelming, such as anticancer activity, cancer cells exerted at 10 μM or less. 12A and 12B, the most inhibitory cancer cell line at 10 μM is inhibited to at least 100 μM. The next most inhibited cancer cells at 10 μM undergo cell death at 100 μM. 10 μM minimum inhibition is suppressed to 100 μM than the cancer cell line. Thus, with increasing concentrations of compounds interpreted, three regions are present for different cancer cell lines delivered, increasing the concentration of compounds at their borders (1), increasing the anticancer activity, compounds of (2), the concentration of compounds is anticancer (3) decreased activity causes cancer cell death. Compounds 6a and 6b are associated with high anti-cancer activity confirming data binge eating. Compared to FIG. 6A, FIG. 6B is a potent action sample in the NCI single dosing test and more than 1 μM because 6B has a less active cancer cell line than 10 μM and also has a low average GI50 in the NCI five dosing test. Interpretation: Increase/decrease driving increase/decrease of anticancer activity 6A and 6B [compound] acts on the same subject. The data in FIGS. 12A and 12B are data from the data in FIG. 11 to data in FIG. 12C as well. (1) anti-cancer activity, (2) compound increases the concentration of the compound that causes cancer cell death (3) increases, decreases the compound's anti-cancer activity increases. Compounds 6a and 6b are associated with high anti-cancer activity confirming data binge eating. Compared to FIG. 6A, FIG. 6B is a potent action sample in the NCI single dosing test and more than 1 μM because 6B has a less active cancer cell line than 10 μM and also has a low average GI50 in the NCI five dosing test. Interpretation: Increase/decrease driving increase/decrease of anticancer activity 6A and 6B [compound] acts on the same subject. The data in FIGS. 12A and 12B are data from the data in FIG. 11 to data in FIG. 12C as well. (1) anti-cancer activity, (2) compound increases the concentration of the compound that causes cancer cell death (3) increases, decreases the compound's anti-cancer activity increases. Compounds 6a and 6b are associated with high anti-cancer activity confirming data binge eating. Compared to FIG. 6A, FIG. 6B is a potent action sample in the NCI single dosing test and more than 1 μM because 6B has a less active cancer cell line than 10 μM and also has a low average GI50 in the NCI five dosing test. Interpretation: Increase/decrease driving increase/decrease of anticancer activity 6A and 6B [compound] acts on the same subject. The data in FIGS. 12A and 12B are data from the data in FIG. 11 to data in FIG. 12C as well. (3) Increased compound concentration decreases anticancer activity. Compounds 6a and 6b are associated with high anti-cancer activity confirming data binge eating. Compared to FIG. 6A, FIG. 6B is a potent action sample in the NCI single dosing test and more than 1 μM because 6B has a less active cancer cell line than 10 μM and also has a low average GI50 in the NCI five dosing test. Interpretation: Increase/decrease driving increase/decrease of anticancer activity 6A and 6B [compound] acts on the same subject. The data in FIGS. 12A and 12B are data from the data in FIG. 11 to data in FIG. 12C as well. (3) Increased compound concentration decreases anticancer activity. Compounds 6a and 6b are associated with high anti-cancer activity confirming data binge eating. Compared to FIG. 6A, FIG. 6B is a potent action sample in the NCI single dosing test and more than 1 μM because 6B has a less active cancer cell line than 10 μM and also has a low average GI50 in the NCI five dosing test. Interpretation: Increase/decrease driving increase/decrease of anticancer activity 6A and 6B [compound] acts on the same subject. The data in FIGS. 12A and 12B are data from the data in FIG. 11 to data in FIG. 12C as well. FIG. 6B is a potent action sample in the NCI One Dosing Test, as having a cancer cell line that is less active than 10 μM at 1 μM also has a low average GI50 in the NCI Five Dosing Test. Interpretation: Increase/decrease driving increase/decrease of anticancer activity 6A and 6B [compound] acts on the same subject. The data in FIGS. 12A and 12B are data from the data in FIG. 11 to data in FIG. 12C as well. FIG. 6B is a potent action sample in the NCI One Dosing Test, as having a cancer cell line that is less active than 10 μM at 1 μM also has a low average GI50 in the NCI Five Dosing Test. Interpretation: Increase/decrease driving increase/decrease of anticancer activity 6A and 6B [compound] acts on the same subject. The data in FIGS. 12A and 12B are data from the data in FIG. 11 to data in FIG. 12C as well.

Figure 13 . This diagram is an interpretation of the experimental results of Figures 8, 11 and 12 itself, which does not provide real data. 11 (13A), (6A) or (6B) (all symbolized in this figure (19A)) increased concentrations of decelerated cancer proliferation until further concentrations of compounds resulted in maximum deceleration concentrations after decreasing cancer growth inhibition. 6A and 6B, high dose I in this figure includes a decrease in the number of cells in some cancer cell lines suggested due to apoptosis, further observations in FIG. 8 and data from FIG. 11. These results include a narrow range of doses that cause cancer cell death with borders that change into cancer cell lines.The reason for its narrowness and why it is not observed in most cancer cell lines in the widely isolated doses of the NCI Five Dose Trial of Cancer Cell Killing Explain. The diagram program gradually increases its OXPHOS rate, thus increasing reactive oxygen species [ROS], increases cancer cell compound concentration, increases block F1F0 ATP hydrolysis. ROS blockade atrophy and DNA information fidelity rise [ROS] slowed proliferation [96] of normal cells, increasingly reducing the number of possible cell divisions from converging values to the Hayflick limit. At the inversion peak, the OXPHOS rate is too large and [ROS] is too high, triggering apoptosis (normal cells are usually compared using this OXPHOS rate). The compound concentration increases beyond this point, but reduces the OXPHOS rate [ROS] of F1F0 ATP hydrolysis inhibition (less ATP less ATP needs to be done because of hydrolysis), and less OXPHOS with anticancer activity. Equivalent diagram for normal cells with the corresponding X-axis (A) (A) and (13B) Top panel show the same drawing of cancer cells. For the F1F0 ATP hydrolysis inhibitor(s), it shows the fact that it helps concentrations in cancer and normal cells. Cancer is less [ROS] than normal cells and is needed. The concentration of F1F0 ATP hydrolysis inhibitor(s) is ie at the same time raise [ROS] cancer cell reduction [ROS] is normal cells. In normal cells, large F1F0 ATP hydrolysis reduces the inhibitory OXPHOS rate [ROS] and increases normal cell life (less ATP ATP needs to be made due to hydrolysis) makes it more efficient than OXPHOS. OXPHOS efficiency gain conferred from F1F0 ATP hydrolysis inhibitor(s), so that the ratio of OXPHOS is hydrolyzed by high ATP F1F0 ATP hydrolysis, so that it is determined by the maximum value, the production and life span (and health span) significant expansion, Especially if it is so reduced [ROS] sufficiently reduces the rate of DNA mutations below the rate of DNA repair. In particular, if this [ROS] is sufficient to maintain differentiated cells, maintaining tissue and organ function. Greater F1F0 ATP hydrolysis inhibition (hereinafter ATP less ATP needs to be achieved because of hydrolysis) increases the OXPHOS rate [ROS] and increases normal cell life, making OXPHOS more efficient. OXPHOS efficiency gain conferred from F1F0 ATP hydrolysis inhibitor(s), so that the ratio of OXPHOS is hydrolyzed by high ATP F1F0 ATP hydrolysis, so that it is determined by the maximum value, the production and life span (and health span) significant expansion, Especially if it is so reduced [ROS] sufficiently reduces the rate of DNA mutations below the rate of DNA repair. In particular, if this [ROS] is sufficient to maintain differentiated cells, maintaining tissue and organ function. Greater F1F0 ATP hydrolysis inhibition (hereinafter ATP less ATP needs to be achieved because of hydrolysis) increases the OXPHOS rate [ROS] and increases normal cell life, making OXPHOS more efficient. OXPHOS efficiency gain conferred from F1F0 ATP hydrolysis inhibitor(s), so that the ratio of OXPHOS is hydrolyzed by high ATP F1F0 ATP hydrolysis, so that it is determined by the maximum value, the production and life span (and health span) significant expansion, Especially if it is so reduced [ROS] sufficiently reduces the rate of DNA mutations below the rate of DNA repair. In particular, if this [ROS] is sufficient to maintain differentiated cells, maintaining tissue and organ function. OXPHOS efficiency gain conferred from F1F0 ATP hydrolysis inhibitor(s), so that the ratio of OXPHOS is hydrolyzed by high ATP F1F0 ATP hydrolysis, so that it is determined by the maximum value, the production and life span (and health span) significant expansion, Especially if it is so reduced [ROS] sufficiently reduces the rate of DNA mutations below the rate of DNA repair. In particular, if this [ROS] is sufficient to maintain differentiated cells, maintaining tissue and organ function. OXPHOS efficiency gain conferred from F1F0 ATP hydrolysis inhibitor(s), so that the ratio of OXPHOS is hydrolyzed by high ATP F1F0 ATP hydrolysis, so that it is determined by the maximum value, the production and life span (and health span) significant expansion, Especially if it is so reduced [ROS] sufficiently reduces the rate of DNA mutations below the rate of DNA repair. In particular, if this [ROS] is sufficient to maintain differentiated cells, maintaining tissue and organ function.

Figure 14 . This diagram is an interpretation of the experimental results in Figure 10 itself, which does not provide real data. BMS-199264 Compound 6B is distinguished because the NCI concentration can significantly reduce F1F0 ATP synthesis in addition to inhibition of F1F0 ATP hydrolysis in the test. Background: BMS-199264 ATP hydrolysis F1F0 EC50 = 0.48 μM, EC50 F1F0 ATP synthesis = 18 μM. (14A) Cancer cells. Lower [BMS-199,264], anticancer activity increases their OXPHOS rate, inhibition of cancer cell F1F0 ATP hydrolysis, thus the reactive oxygen species [ROS] is remarkable. ROS test blockade and atrophy increase DNA fidelity [ROS] slowed proliferation [BMS-199264, increasingly converging to the Hayflick limit [96] of normal cells. More than [BMS-199,264], anti-cancer activity is mainly added by reduction of F1F0 ATP synthesis, by conferring uncoupling of proton motif force (see Figure 17) to increase OXPHOS rate and cell [ROS] in BMS-199,264 cancer. So the cell apoptosis continues. (14B) Equivalent diagrams for normal cells with the X-axis and equivalents of the upper panel broadcast equivalent (A) of the stomach cancer cells. It also shows lower F1F0 ATP hydrolysis, inhibits harmful cancer and helps normal cells [BMS-199,264]. Therefore, there is a treatment window. However, it decreases F1F0 ATP synthesis of higher significance [BMS-199264, harms both cancer and normal cells. Greater [ROS] cancer sensitivity runs on the equivalent x-axis plotted embryonic stem (ES) cell type phenotype at relative locations.

Figure 15 . In an in vivo study of compounds 6a and 6b performed at room temperature of 22 °C.

Methodology 4 Mouse use Days of day 1 Some of the experimental details on the day of the presented table "Anniversary" were referred to days after the first drug/vehicle dose: volume = 10 μl administered, intravenous (IV) administered (tail vein) (0.22 μm filter) sterilization /g, solution (not suspension), vehicle = 12.5% solutol, 12.5% ethanol, 75% water solution was vortexed the prepared IV solution before injection except for freshly days 22 and 39 when prepared on the previous administration day (lane) Isolation mice were observed for several days, musculus C57BL/6 strain of female mues, 6-8 weeks before the start of the study, mice supplied from Shanghai Lingchang Bio Technology Co., Ltd./After arrival and prior to dosing Ad randomized Co60 irradiation sterilization Dry granulated food and reverse osmosis sterile water, cob bedding, polysulfone individually ventilated cage (IVC,325 mm X 210 mm, 180 mm, 12 hours / 40-70% dark cycle with humidity of 20 to 26 °C, room temperature StudyDirectorTM Software (Studylog Systems Inc., CA, USA) uses up to 5 animals to be evaluated and accredited in accordance with the Accreditation of Experimental Animal Care (AAALAC) Association/RANDOMIZE Control/Treatment Group, with animal protection indicated by ear coding (notch) When recording rectal temperature, allocating animal use: care was taken The time taken to confirm the constant depth of probe insertion across different records was obtained to rectal rectal temperature and equilibrium, and the time was obtained to record between reset probe temperatures Used to assign .StudyDirectorTM software (Studylog Systems CA, USA) / RANDOMIZE Control / Treatment Group, indicated by ear coding (notch) as assessed and accredited by the Institute of Animal Care and Animal Care (AAALAC) ), when recording rectal temperature: Carefully rectal rectal temperature and time taken to ensure constant depth of probe insertion across different recordings Probe temperature was obtained, and time was obtained between recordings for probe temperature reset. Used to assign the StudyDirectorTM software (Studylog Systems CA, USA) / RANDOMIZE Control / Treatment group, ear coding (notch), labeled and evaluated by the animal laboratory In accordance with the association's regulations, care and animal use Animal Care (AAALAC), when recording rectal temperature: Obtain rectal probe temperature to equilibrate with rectal temperature at the time taken to ensure constant depth of probe insertion across different recordings, Time was obtained between recordings for resetting the probe temperature. When recording the rectal temperature: Caution Rectal probe temperature and equilibrium with the rectal temperature were taken to ensure constant depth of probe insertion across different recordings, and time was recorded for resetting the probe temperature When recording the rectal temperature: Note that the rectal probe temperature was equilibrated with the rectal temperature at the time taken to ensure a constant depth of probe insertion across different recordings, and the time was obtained between recordings for resetting the probe temperature.

Results: (15A) and (15B) For each animal, the first rectal temperature record is an abnormally high body temperature, which is usually associated with the stress being treated which is to tame the mouse process. This treatment effect has been reported in other rectal thermistor studies, such as rodents [97-98]. The 20 mg/kg IV infusion in FIG. 6b was "water suffocation" 45 min, 30 °C, where the mouse 3 rectal temperature was reported observed after it died ~210 min after this IV infusion while drinking water, the temperature of the water was indoor temperature ( RT) = ~ 22 °C (so if ingestion is not already at RT, decrease body temperature). 4 mice rectal temperature did not survive night, 6 hours <30 min at 30 °C, survival after 45 minutes after 6B 40 mg/kg IV infusion> was found dead the next day. Post-IV of (6b): Hypothermic mice (3, 4) and exhibited hypoactivity both anemic signs[99] consistent with their rectal temperature drop (<30 °C). Mice exhibited 2 hypoactivity, but recovered after 30 minutes of matching recovery of rectal temperature. With 6B IV administration, there is a dose-dependent decrease in rectal temperature.

Before the 6B administration experiment, mice 1, 2 and 3 all survived the IV injection of 6a. 6A does not strongly reduce rectal temperature as 6B: Dose-dependent rectal temperature decreases because 6A can cause bioepimerization of 6A, even if 6A is in (as a scale report that hypoactivity is reduced as rectal temperature is over). 6b is the prevention of epimerization 6A 6B or this decreases the effective dose of 6B chemical modification of the 6B compound structure 6B to slow epimerization. Similarly, if it is a compound administered in vivo, there are components in the present invention: A non-limiting example is to replace deuterium and hydrogen on the chiral carbon of (6b). I was running a trial of 6A with a dose of >40mg/kg due to lack of 6A compound. Indeed, I was 6A as 2 doses of 3 test mice at 40 mg/kg.

Because of vehicle control, a 12.5% ethanol content may cause a drop in rectal temperature: 10 UL/g solution administered = 1.25 UL/g ethanol = 0.000989226 g/g = 0.99 g/kg = 1 g/kg ethanol (IV 12.5%). Reduced 1.9 g/kg ethanol (intraperitoneal injection, IP) rat body temperature at 1.6 °C (at 24.5 to 25 °C at room temperature, injecting the ethanol solution at 37 °C by raising the IP did not have a significant effect) [100]. Ideally, future research should not use ethanol as a vehicle component. The problem is not that hypothermia, which is safely relieved by high ambient temperatures [100]. However, at ambient temperatures only slightly higher than this, ethanol can cause high fever [100]. Safely relieves Ethanol Ethanol Driven It does not generate high heat, but it drives the body temperature, depending on the ambient temperature and the ethanol dose [100]. This [ethanol capacity / room temperature / body temperature / high fever / safe rectal temperature] matrix is mapped by experiments, and in practice there may be many non-limiting examples already in the literature: [100-106] as vehicle components in future studies We will guide you to make the most of ethanol. However, this experiment can be avoided: and other vehicle options other than their powerful drugs, ethanol can be seen well known in the art, for example, as it is [107-108] and can be used as an alternative to one or more of these. If vehicle ethanol is used, some of the liability for dropping the rectal temperature to the test drug can be calculated by subtracting a random rectal temperature drop (home control of the vehicle containing ethanol and drug-induced rectal temperature drops and containing ethanol not enhanced) just observe ). When it occurs, drug-induced rectal temperature reduction in this study is observed to be concentration dependent and exceed all well rectal temperature drops when only ethanol containing vehicle control is injected.

The proposed data shows that the inversion mode of ATP synthase reduces body temperature by inhibiting it. 6B strongly inhibits ATP synthase (IC50 = 0.018 μM inversion mode [5-6]) and does not 6A (IC50>100 μM[5-6]). 6B does not strongly reduce rectal temperature, and 6A does not (that is evidence to a minor extent, a faster timescale than the bioepimerization 6A gap 6B, even 6A). A significant decrease in body temperature is fatal. The maximum allowable dose at room temperature = ~ 22 (6b) (MTD) there ° C, lower than the MTD in Figure 6a. Body temperature is normal mouse body temperature that can not drop below ambient temperature and ensures the mouse body temperature maintained at an acceptable value near room temperature so that it is increased by checking the MTD of (6b). This results in a large orientation between the MTDs of FIGS. 6A and 6B, which is very safe in the case of FIG. 6A :LD50>40 mg/kg (IV). This is the FDA's antidepressant is safer than clomipramine approved hydrochloric acid and already pramine hydrochloride: LD50 {mouse IV} 22 mg/kg LD50 and {mouse IV} 27 mg/kg respectively (of the toxic effects of chemicals Registration, RTECS). Some patients take this medicine every day safely for years.

Temperature controlled room or confinement limiting ratios include exemplary embodiments to maintain mice, or other animals, including humans, at their body temperature, while having the compounds of the present invention in their body, in their body position. For example, in small animal experiments, plant growth or egg incubators or similar types of devices. Examples Hot countries, geography or climate, including human(s), animal(s) in the Middle East in Dubai or elsewhere, more preferably in the middle of the summer, more preferably in the summer when there is a high daylight temperature. There are many ways in the literature to keep rodents at high temperatures to alleviate the cold stress they feel at normal room temperature [62]: for example using partially heated water baths by thermostatic electric bath heaters, and watering fish tanks Evidence Mouse cage dive [111] or cage by hand warming to chemical reactions [109-110]. In that text, the same method as the compound of the present invention, or intended to be used equivalent to the animal (S), any method/person(s), is a component of the present invention. Adaptive heating can be used to adjust the output of a heating element (eg, an infrared lamp or other heating element(s)) in response to the measured body temperature (eg by a rectal temperature probe or by thermal burns, or other body temperature seen Record the device(s) when the compounds of the invention are in the body, maintain body temperature, allowing life. Larger animals are more important for mice (~ 20g) than rats (~150g), and the need for compounds of the present invention (and amplitude) is smaller and more important than for example. If the experimenter is in the rectum of the compounds of the present invention at normal room temperature (20-25 °C), the selected test species, individual(s) should be as large as possible. While having the compounds of the present invention in the text, all methods of maintaining body temperature within an acceptable temperature range for life are components of the present invention. Dress up, see for example (non-restricted).

Figure 15C also predicts, not actual experimental data.

Figure 16. The enantiomeric excess (EE) of FIGS. 6A and 6B is stable in the presented EE stability experiment. In contrast, as described elsewhere herein, FIG. 6A and 6B within 48 hours of epimerize of significance in biological systems (NCI-60 test). The instability of this EE in biological media is an unexpected result. These findings are a component of the invention of the present invention in which modifications to the composition of Figures 6A or 6B slow their EE erosion by epimerization/race. EE instability is unexpected because it runs counter to this theory. The second rate constant (KGB) of a general racemized catalyst system can be predicted for in theory 6A and 6B [112] (all of that additional information is cited for reference). ΣΔΔG (R1, R2, R3) = -19.9 2.8 -19.1 -36.2 = kilocalories/mole: stereocarbon phenyl groups of 6a and 6b, alkyl guanidine groups joined. The value of the guanidine group (19.1) is not [112] but the author of the supply by quantum mechanical calculations with the Gaussian 03 software package, one of Dr. Andrew Rich, by personal communication. The reciprocal junction correction [112] was not applied in this case because Dr. Rich wrote “I would not expect to be a group liquefying guanidine”. Log (KGB) = -0.11 * ΣΔΔG (R1, R2, R3)-9.81,∴KGB = 0.00000148593 M-1S-1. It is not particularly fast. Because racemization concentrates the high lipophibicity biological cell membranes, it can occur in cells 6A and 6B faster than predicted by theory. Figure 6a log P = 5.97 is used to calculate the 6A structure [25]. 6A of the means to drive at a high concentration, allowing significant molecular racemization, model lipid octanol than accumulates in this imbalanced biological cell membrane, more than 6A cumulative of this means. 6A imidazole group protonable nitrogen atom leaving the plane carbo anion and pulling the protons off of the other 6A molecules, so its probability on both sides is the same, and the probability that the steric changes when there is carbon proton reattachment is 50 %is. The race progresses faster than predicted by the method of doing so [112] The race beautification theory / current state of the art in anticipation. The same process can be applied to Figure 6b. Because the carbon-deuterium bond is stronger than the carbon-hydrogen bond (kinetic istope effect KIE) and the isotopologue of 6B is a component of the present invention, deuterium instead of hydrogen on 6B stereocarbon reduces the rate of the racemization reaction. Correlation with the difference in% cancer growth inhibition between each cell line 6a and 6b of 1 μM (in the NCI-60 day dosing test) The difference in% cancer cell growth inhibition between each cell line 6a and 6b at the 10 μM drug dose (NCI-60 Drug administration). Pearson's correlation coefficient R = 0.7919, a significant p-value <0.00001 at P <0.05. This shows that there are cellular elements that can vary between different cancer cell lines and this includes determining the rate of the racemization reaction in Figures 6A and/or 6B. For example, the drug in a form that can undergo catalytic epimerisation of the transmembrane, which can be the volume of the membrane and/or the expression level of semaase/epimerase enzyme(s) and/or enzyme(s). Due to (% cancer cell growth inhibition-NCI-60 across the cell line test, one dose test correlated positively between 6B% cancer cell growth inhibition and product [(caused 6B% cancer cell growth inhibition) at 10 μM) Have 6A)]. Significant Pearson's correlation coefficient at p <0.05 R = 0.4167, P = 0.000927. Therefore, the anticancer performance of 6B is better when the anticancer performance of (6a) is better behind the anticancer performance of (6b). For this 6A has great anti-cancer activity, it suggests that 6B needs less anti-cancer activity. Conversely, for 6B to have greater anticancer activity, 6A needs to have less anticancer activity. What gives its anticancer activity 6A, because racemic, takes anticancer activity away from 6B. Therefore, there is 6A 6B anti-cancer activity than in cancer cell lines using faster 6A and 6B epimerization. For the NCI-60 single dose (10 μM) analysis, through the above cell line, negative correlation% of cancer cell growth 6A was inhibited due to the product [(% between cancer growth inhibition (although not significant), explain why 6B )-(% inhibition of cancer cell growth) by (6A)]. Pearson's correlation coefficient R = -0.2136, but not significant at p <0.05. The same phenomenon (Figure 6A and 6B competition for anticancer activity, what 6A, because it gives racemization, is taken from Figure 6B) is observed in the NCI60 five dose data at 1 μM. Inhibit 6B% cancer cell growth across cell line tests, and have a positive correlation between products [(Inhibit% cancer cell growth by 6B)-(%% cancer cell growth by 6A)]. Significant Pearson's correlation coefficient R = 0.3125 at p <0.05, P = 0.017949. Fig. 6a% negative correlation between cancer cell growth inhibition and product [(% inhibition of cancer cell growth by 6B)-(% cancer cell growth inhibition by 6A)]. Significant Pearson's correlation coefficient R = -0.4211 at p <0.05, p = 0.00111. Fig. 6a% negative correlation between cancer cell growth inhibition and product [(% inhibition of cancer cell growth by 6B)-(% cancer cell growth inhibition by 6A)]. Significant Pearson's correlation coefficient R = -0.4211 at p <0.05, p = 0.00111. Fig. 6a% negative correlation between cancer cell growth inhibition and product [(% inhibition of cancer cell growth by 6B)-(% cancer cell growth inhibition by 6A)]. Significant Pearson's correlation coefficient R = -0.4211 at p <0.05, p = 0.00111.

Figure 17 : Mechanical separation from oligomycin may be a therapeutic utility. The green molecule of the ear canal (17A) already has a doze, with a protonable nitrogen atom shedding the can shuttle proton (uncoupling, PMF) proton motive force across the mitochondrial inner membrane (IM). This figure presents experimental data using HL-1 cardiac muscle cell lines (17B) (cancer-derived, but now very cardiac differentiation, such as spontaneous contraction and cardiac cell beat). See "Benchmark drugs" [3]. Oligomycin Excitation Oligomycin B. Oligomycin Attribution ATP synth block Anterior proton delivery, ATP synthesis mode. This method, as the proton electron breathing chain slows down, flows ATP synthase, PMF consumption per unit time, PMF increase ΨIM hyperpolarization passes, and O2 consumption decreases. Carbonilcyanide P-triflouromethoxyphenylhydrazone (FCCP) is a separator that crosses the IM, dissipative PMF (heat) and reduces the PMF of the shuttle proton ΨIM flows along the respiratory chain speed of depolarization, increasing O2 consumption. They further reduce ATP synthesis by uncoupling than the inhibition of mod ATP synthase: Oligomycin, which means a difference in their mechanism: oligomycin, a decrease in oxygen levels, rather than three molecules of increased levels. They all contain protonable nitrogen atoms with fairly close {mitochondrial interstitial spatial acidity mitochondrial matrix acidity +)/2}, i.e. basic pKa values that help with pKa values of uncoupling. Although in VG025, the most helpful pKa is already in dazol rather than the main ring. In the NADPH-linked sub-mitochondrial (SMP) analysis of ATP synthesis, this molecule reduces ATP production due to the resolved PMF heat, so there will be as little PMF as possible in ATP production. Interpretation, this uncoupling can be attributed to the incorrect inhibition of the forward mode of ATP synthase and the oligomycin so that the entire mechanical distinction of these molecules can be missing. This was the case with other compounds of the invention and already imidazole. Also, protonable nitrogen from imidazole, [5-8]. But their uncoupling is likely to be a more dominant factor, with many synthesizing enzymes in a distinct distinction to oligomycin, characterized by (inferred from the data in this figure) and no case inhibiting the mode of progression of ATP at all. . Increasing log P (see next paragraph) decreased uncoupling function, explained why different molecules of different effects exerted as seen in O2 consumption. The high log P value of VG019 minimizes uncoupling, the effect on O2 consumption is dramatically increased, and the concentration at a distinct difference between mycin (3 μM) (100 μM) is 0 (rounded up) in inhibiting the reverse mode of ATP synthase. Significantly, it strongly reduces the O2 consumption (-40%), because it inhibits the forward mode of the ATP synthase.

LOGP = ˜3.2 is the best compromise for passing through the membrane, including hydrophobic cores (for high selective log P) and hydrophilic boundary layers (for low selective log P) ([36]). The following figure shows the imidazole containing the molecule presented in this figure, and more generally the figure of the present invention has a log P>3.2 and decreases the log p=uncoupling present. The unbinding function/responsibility of a molecule actually depends on its pKa(s) and its intersection of log P[36] The pKa value of the imidazole is above, but for the molecules in the figures herein, generally, all within a relatively narrow range In, the more primary determination of the uncoupling ratio of each molecule to another relative is relative to the log P value of the molecule relative to the other.

The withdrawal molecule in this figure inhibits the opposite mode of ATP synthase. When the respiratory chain enzyme inhibitor block flow electrons ΨIM not remain as a proton pump by the respiratory complex, but both are pumped by ATP, the opposite mode of the synthase ATP synthase. In the data showing that the respiratory chain is blocked, it is passive to ΨIM the molecules presented because they block the reverse mode of the ATP synthase. When the respiratory chain is working they do not affect ΨIM in this way. Because ΨIM is not set/in this case, it was kept in the opposite mode of the ATP synthase. Molecules with strong uncoupling function can increase the rate to replace the proton shuttle across the IM (more evaporation and more PMF) than the respiratory chain, and they are not passive in ΨIM. When the respiratory chain is blocked, the strong separator in this figure de-polarizes ΨIM. At the same time, ΨIM (uncoupled) erodes because it does not inhibit the occurrence of ΨIM (reverse mode ATP synthase).

Oligomycin inhibits the opposite mode of ATP synthase. But apparently it further suppressed the mod [11]. So, using oligomycin, the margin to suppress reverse mode (anti-cancer) does not exist without OXPHOS, ie most normal cells, without negatively affecting cells. 100 does not affect cells using OXPHOS (does not change their O2 consumption or ΨIM-in the observed differences in oligomycin-inhibits the opposite mode of ATP synthase, yet can, for example, this figure Molecular VG019 of the contrast is μM). Separated by oligomycin and anti-cancer selection, it confers. Other molecules in this specification have greater cancer selectivity. Inhibition of ATP hydrolysis F1F0> Analysis in SMP linked with NADH and NADPH F1F0 ATP synthesis more than 5,556 times, e.g., preferred embodiment (see "Preferred practice" starting part) [5-6], whereas oligomycin-reverse-inhibition F1F0 ATP hydrolysis than ATP synthesis F1F0 in the following analysis [11].

It was created using computational calculation of pKa with log P [25]. Although the data presented in this figure are [12] (cited entirely in this application), the analysis/(re)interpretation is novel. Likewise, it is an anti-cancer drug that is a component of the present invention, and a process/method using these molecules. The stretch molecule is imidazole-4-yl. Day 5 and not permutation, also disclosed by the present invention as an anti-cancer treatment.

Exemplary implementation of the invention

The drawings show this embodiment of the present invention. Further examples are the Markush formulas (I), (II), (III), (IV), (V) and (VI), hereinafter, an enumeration of indications. Note: Receive, X is an integer known to the art: Markush among these formulas, for example, does not share the number of symbols, type of symbols. They each have their own as specified in each, in a separate section of this specification.

In this specification, the term "formula [X]" is used where applicable for formula (I), and (II) refers to all of (III), (IV), (V) and (VI) Be independent. The compound of formula [X] is a drawing of the present specification, which is a given compound (I) or formula (II) or formula (III) or formula (IV) or formula (V) or formula (VI) or compound.

The present invention is described using these exemplary embodiments, but is not limited to them. These merely illustrate the invention. Compounds of other structures based and identified as treatment inhibitors by the methods of the invention are also included in the invention.

A method of treating a patient suffering from a medical disease or disorder by administering an effective amount of formulas (I), (II), (III), (IV), (V) or at least one compound (this invention is encompassed comprehensively VI) or Pharmaceutically acceptable) III () salts, solvates, hydrates or prodrugs or pharmaceutical compositions thereof include one or more compounds of formula (I), (II), (IV), (V) or (VI) , Especially for use in methods of treatment of the human or animal body by therapy for use in methods of treating, alleviating, preventing or combating a disease or disorder selected from

(Iii) cancer;

(Ii) cancer metabolism of glucose and/or glutamine with cancer lactic acid, indicating cancer that can be distinguished from surrounding tissues, for example by the Warburg effect and/or PET imaging (eg 18F-FDG PET);

(Iii) cachexia, cancer cachexia or weight loss driven;

(Ⅳ) (e.g., 2,4-dinitrophenol), infection, sepsis, stroke, fever, fever, hyperpyrexia, high fever, malignant high fever, nerve intake, high environmental temperature is higher than normal body temperature Or disorders, serotonin syndrome, thyroid storms, heatstroke, thermoregulatory disorder(s), Kawasaki syndrome, hyperthermia due to drug or withdrawal symptoms, unusual drug reactions, fever of unknown or uncertain origin, incompatible blood agent(s) Response to, metabolic disorder(s) cancer, injury;

(V) Tumor-related macrophages (technical account manager) or macrophage-activating syndrome (MAS), HIV, AIDS, or other phagocytic diseases or disorders HIV-related neurocognitive disorders (hands), HIV-related cancer, AIDS-defined cancer, non-AIDS Definition cancer;

(VI) Neuroinvasive virus through macrophages, as used by HIV and SARS coronavirus, for example,

(Iii) neurocognitive or neurodegenerative diseases/diseases, for example by viruses;

(VIII) acute or chronic systemic inflammation or inflammatory disease / disorder / syndrome or auto-inflammatory disease / disorder / syndrome or autoimmune disease / disorder / syndrome;

(IX) lower or more desirable metabolic / bio-energy efficiency of the subject, or lower than the desired physical or mental performance or lower or lower than desired body weight;

(X) Imparting hypothermia to the subject for some medical or other purposes, which may include slowing down the rate of chemical reaction(s) to the subject for disease or disease deep circulation hypothermia, therapeutic effect/minimizing brain and/or tissue damage Treatment by cardiac and/or cardiovascular surgery and/or brain surgery (neurosurgery) surgery, hypothermia for the purpose of surgery, arrest for hypothermia, emergency preservation and resuscitation (EPR), eg, limbs and/or organs Long-term storage and/or transplantation for separate preservation temperature management of the same body part), protective hypothermia, therapeutic hypothermia, neonatal brain disease, suffocation, bleeding, hypovolemia, hypothermia for decompression sickness, skin burns, inflammation, allergies Burn injury(s) including reaction anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, oxygen deficiency, anemia, hypervolemia, altitude sickness, airway obstruction, asthma attacks, body/tissue/organ, hypoglycemia, reperfusion Hypoxia to damage (ischemia-reperfusion injury), ligature or tourniquet at release, uremia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (e.g. , Meningitis), sepsis, septic shock, ischemic brain / heart / kidney damage, nerve and / or / cardioprotection and / or tissue protection during stroke and / or ischemia and / or heart attack and / or resuscitation and / or subject Where after the period(s) of poor blood flow; ligature or tourniquet, uremia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, asthma attack, body/tissue/organ, hypoglycemia, reperfusion injury following major trauma release Hypoxia, (ischemia-reperfusion injury), infection, bacterial and/or viral infection(s) (e.g., meningitis) after stroke and/or ischemia / during, sepsis, septic shock, ischemic brain / heart / kidney damage , Nerves and/or heart Protection and/or tissue protection/or heart failure and/or resuscitation and/or poor blood flow to the subject where period(s); ligature or tourniquet, uremia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma Hypoxia, asthma attacks, body/tissue/organ, hypoglycemia, and reperfusion injury (ischemia-reperfusion injury), depending on the release of, infection, bacterial and/or viral infection(s) (eg meningitis) stroke and/or ischemia Post/medium, sepsis, septic shock, ischemic brain/cardiac/kidney damage, nerve and/or cardiac protection and/or tissue protection/or heart attack and/or resuscitation and/or poor blood flow to the subject where period(s) ;Protection of the heart during bacterial and/or viral infection(s) (e.g. meningitis), sepsis, septic shock, stroke and/or ischemia and/or ischemic brain/cardiac/kidney damage after nerve, and/or heart And/or tissue protection arrest and/or resuscitation and/or poor blood flow to the subject period(s); bacterial and/or viral infection(s) (e.g. meningitis), sepsis, septic shock, stroke and/or Or ischemic and/or post-ischemic brain/cardiac/kidney damage, nerve and/or/or cardiac protection and/or tissue protection during arrest and/or resuscitation and/or poor blood flow to the subject where period(s);

Subjects, such as carbon monoxide / methanol / heavy metals / pesticide poisoning, snake / spider / bee / insect / lizard poison metabolism poison(s), bacterial toxin (poisoned by the toxic amount(s) of the compound of S(XI)), Endotoxin drug/drug overdose eg heroin, ethanol, prescription drug(s) or counter drug treatment(s);

(XII) aging disease or Werner syndrome, Bloom syndrome, Rottmund-Thomson syndrome, Cockayne syndrome, dry skin pigment, trichothiodystrophy, connective scleroderma pigment-Cockayne syndrome, limited dermopathy, WIEDEMANN-Rautenstrauch syndrome, Hutchinson-Gilford's Premature ejaculation syndrome (accelerated premature ejaculation);

(XIII) associated with elevated free radicals, neurodegenerative diseases, muscular atrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, including diseases or disorders of aging (increased age / increased aging) and/or degenerative diseases Diseases/diseases, Huntington's disease, spinal cerebellar ataxia, Friedrich's ataxia, dementia, fixative disease, polyglutamine disease, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, chronic obstructive pulmonary disease (COPD), hypertension, arthritis, cataracts, type 2 diabetes, male climacteric, muscular dystrophy, age-related macular degeneration (AMD), hearing loss, movement disorders, cancer;

Formula XIV compound Slow aging, long life and health span anti-aging;

Aging (XV) skin;

(XVI) Cardiovascular diseases and symptoms associated with associated ischemic conditions including, without limitation, ischemic reperfusion injury, myocardial ischemia, ischemic heart disease, chronic stable angina angina, myocardial infarction, congestive heart failure, acute coronary syndrome, muscle cell damage, necrosis , Cardiac arrhythmia, non-Q wave myocardial infarction, unstable angina, hypertension, coronary artery disease, ischemic hypoxia, cyanosis, gangrene, acute limb ischemia, stroke, ischemic stroke, cerebral ischemia, vascular dementia, transient ischemic attack (TIA), ischemic colitis , Mesenteric ischemia, angina, ischemic heart disease, muscle cell damage, necrosis (including cerebrovascular accident and transient ischemic attack) ischemic neuropathy, hypoxic ischemic encephalopathy, cerebral hypoxia, cerebral hypoxia, vascular occlusion, cerebral infarction, stroke and related cerebrovascular disease Ischemia caused by; or

(XVII) Inflammation or burn or radiation of infection or foreign body or injury or chemical or toxin or drug or stress or frostbite due to acute inflammation, chronic inflammation, systemic inflammation, inflammatory disease / disorder / syndrome ionization, macrophage activation syndrome (MAS) , Auto-inflammatory disease/disorder/syndrome, senile chronic inflammatory disease associated with cold or flu or fever, high congenital immune system, sore throat, sore throat autoimmune disease/disorder/syndrome, disease/disease ("inflammaging")- Intense exercise-related inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation-related depression, exercise-induced acute inflammation , Atherosclerosis, allergy, pollen allergy, anaphylaxis, inflammatory myopathy, drug-induced inflammation, systemic inflammatory response syndrome, multiple organ failure associated with sepsis, multiple organ failure, microbial infection, acute brain/lung/liver/kidney wound, acne, Celiac disease, celiac sprue, chronic prostatitis, colitis, diverticulitis, glomerulonephritis, hidradenitis purulent, hypersensitivity, interstitial cystitis, mast cell activation syndrome, mastocytosis, otitis media, pelvic inflammatory disease (PID), reperfusion injury, rheumatic fever, Rhinitis, sarcoidosis, transplant rejection, parasites, eosinophilia, type III hypersensitivity reactions, ischemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic erythema Reflex (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative disease, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, appendicitis, acute appendicitis, bursitis, colitis, cystitis, dermatitis, encephalitis, gingivitis, meningitis, infectious meningitis, Myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis related interstitial lung disease and desquamative interstitial pneumonia, interstitial lung disease, ropegren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, fatty hepatitis, non-alcoholic fatty hepatitis, silicosis, histiocytoses, Langerhans cell histiocytosis, haemophagocytic lymphohistiocytosis, lung Langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudoplastic, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, host disease (GVHD), lymph node graft vs. familial Mediterranean fever ( FMF), TNF's cycle syndrome (Trap) receptor-associated Hyperimmunoglobulinemia D recurrent fever syndrome (HIDS) cryopyrin associated cycle syndrome (CAPS), Bla syndrome Majid syndrome, interleukin-1 receptor antagonist deficiency (DIRA), mevalonate Kinase deficiency purulent arthritis-pyoderma gangrene and acne syndrome (Papa), periodic fever aphthous stomatitis pharyngitis ointitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, SCHNITZLER syndrome, sweet syndrome, autoinflammatory disorders, interleukin-1 receptor NLRP12 deficiency of antagonist (DIRA) is related, pyoderma gangrene, cystic acne, aseptic arthritis, periodic fever-related mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), purulent arthritis pneumococcal necrotic acne (PAPA) syndrome, periodic With fever aphthous stomatitis, pharyngitis and pathology (PFAPA) syndrome, adult-onset is still a disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), chronic relapsing multiple osteomyelitis (CRMO), synoviitis acne pustulitis osteoarthritis (sandpaper) Syndrome, Cryopyrin Related Periodic Syndrome (CAPS), Family Cold Automatic Inflammation Syndrome (FCAS), Muckle-Wells Syndrome (MWS), Family Lack of sex colds develops neonatal multi-inflammatory disease (NOMID) Interleukin-1 receptor antagonist deficiency (DIRA), pyoderma gangrene, cystic acne, aseptic arthritis, periodic fever-related mevalonate kinase deficiency (hyperimmunoglobulin D syndrome) A), purulent arthritis pyoderma necrotic acne (PAPA) syndrome, periodic fever aphthous stomatitis, pharyngitis and pathology (PFAPA) syndrome, adult-onset still, familial disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), Chronic recurrent polymyelitis (CRMO), synovitis acne pustular osteochondrosis (sandal) syndrome, Cryopyrin-related periodic syndrome (CAPS), cold automatic inflammation syndrome (FCAS), Muckle-Wells syndrome (MWS), hives in familial cold Endemic neonatal multi-inflammatory disease (NOMID) deficiency of interleukin-1 receptor antagonist (DIRA), pyoderma gangrene, cystic acne, aseptic arthritis, periodic fever-related mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), purulent Arthritis pyoderma necrotic acne (PAPA) syndrome, periodic fever aphthous stomatitis, pharyngitis and pathology (PFAPA) syndrome, adult-onset still, familial disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), chronic recurrent multiple Osteomyelitis (CRMO), synoviitis acne pustular osteochondritis (sandpaper) syndrome, Cryopyrin-related cyclic syndrome (CAPS), cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), is a neonatal family with hives in family cold Inflammatory disease (NOMID) is associated with periodic fever associated with mebalonate kinase deficiency (hyperimmunoglobulin D syndrome), purulent arthritis pneumococcal necrotic acne (Papa) syndrome, periodic fever aphthous stomatitis, pharyngitis and pathology (PFAPA) syndrome , Adult-onset is still a disease (AOSD), Systemic juvenile idiopathic arthritis (sJIA), chronic recurrent polymyelitis (CRMO), synoviitis acne pustular osteochondritis (sandal) syndrome, Cryopyrin-related periodic syndrome (CAPS), family cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome ( MWS), familial cold hives, neonatal multipathy inflammatory disease (NOMID), and associated with periodic fever associated with mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), purulent arthritis pyoderma necrotic acne (Papa) syndrome, periodic Fever aphthous stomatitis, pharyngitis and pathology (PFAPA) syndrome, adult-onset is still a disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), chronic recurrent polymyelitis (CRMO), synoviitis acne pustular osteochondrosis osteoarthritis (sandal) syndrome Cryopyrin-related cyclic syndrome (CAPS), family cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), hives in familial cold, neonatal polyinflammatory disease (NOMID), pharyngitis and pathology (PFAPA) syndrome, Adult-onset is still a disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), chronic recurrent multiple osteomyelitis (CRMO), synovial acne pustular osteochondrosis (sandpaper) syndrome, Cryopyrin-related periodic syndrome (CAPS), family cold automatic inflammation Syndrome (FCAS), Muckle-Wells Syndrome (MWS) is a neonatal multi-inflammatory disease (NOMID) that is prominent in familial colds Pharyngitis and Pain (PFAPA) Syndrome, adult-onset is still a disease (AOSD), generalized adolescent idiopathic Arthritis (sJIA), Chronic Recurrent Multiple Osteomyelitis (CRMO), Synoviitis Acne Pustulosis Osteoarthritis (Sandulitis) Syndrome, Cryopyrin Related Periodic Syndrome (CAPS), Family Cold Automatic Inflammation Syndrome (FCAS) is Muckle-Wells Syndrome (MWS) Hives in family sex colds are multi-inflammatory Diseases (NOMID) onset angiogenesis inflammatory disease (NOMID) Diseases onset inflammatory disease (NOMID) Genetic periodic fever syndrome, periodic fever syndrome, systemic auto-inflammatory disease, Addison's disease, Agammaglobulinemia, alopecia areata, Amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome, autoimmune autoimmune angioedema, autoimmune autonomic nerve, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, pancreatitis , Autoimmune retinopathy, autoimmune urticaria, axonal and neuropathy (AMAN), BALO disease, Behcet's disease, benign mucosal parenchyma, vesicular parenchyma, Castle disease (CD), celiac disease, Chagas disease, chronic inflammatory Demyelinating Neuropathy (CIDP), Chronic Recurrent Multiple Osteomyelitis (CRMO) Chuck-Strauss, Scar Cogan, Syndrome, Cold Disease, Congenital Heart Block, Coxsack Myocarditis, CREST Syndrome, Burger's Disease Aggregate, Herpes zoster dermatitis, giant dermatomyositis, disease of the distribution apparatus (optic nerve myelitis), discoid lupus, wrestler syndrome, endometriosis, eosinophilic esophagitis (swallow), eosinophilic fasciitis, erythematous nodules, core hybrid cold globulinemia, Evans syndrome, fibromyalgia , Fibrosing alveolitis, giant cell arteritis (temporal arteritis) cell myocarditis, multiple vasculitis granulomatosis, Goodpasture's syndrome glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immune hemolytic anemia, Henoch-Chen line Purpura (HSP), herpes gestationis or pylori gestationis (PG), hypogammalglobulinemia, IgA nephropathy, sclerosis related to IgG4, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), Juvenile arthritis, childhood diabetes (type 1 diabetes), juvenile myositis (JM) Kawasaki disease, Lambert-Eton Syndrome, leukocyte vasculitis, lichen planus, lichen sclerosus, xylem conjunctivitis, linear IgA disease (LAD), lupus, Lyme disease, chronic, Meniere's disease, microscopic red bundles (MPA), mixed connective tissue disease (MCTD) muren cornea Ulcers, Muha-Habermann's disease, multiple sclerosis, severe myositis, narcolepsy, optic neuritis, neutropenia, ocular scarring vesicular, optic neuritis, homologous rheumatism (PR) panda, adrenal biocerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH) ), Myasthenia, Parry Romberg syndrome, Peri-peripheral uveitis (peripheral uveitis) Parsonnage-Turner syndrome, pemphigus peripheral neuropathy, perivenous encephalomyelitis, malignant anemia (PA), POEMS syndrome, nodular polyarteritis glandular syndrome, II, III I Multiple myalgia rheumatism, multiple myositis, myocardial infarction syndrome, Postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone, psoriasis, psoriatic arthritis, pure erythropoiesis (PRCA), pyoderma necrosis, Raynaud's phenomenon, reactive arthritis, reflexes Sympathetic dystrophy, recurrent dermatitis chondritis, silver anxiety leg syndrome (RLS), peritoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, skin sclerosis, Sjogren's syndrome, sperm and testicular autoimmunity, Stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmitis (SO), Takayasu arteritis, temporary arteritis/giant cell arteritis, thrombocytopenic purpura (TTP) is Tolosahunt syndrome (THS) Transverse myelitis, type 1 diabetic ulcerative colitis (UC), splenic hypertrophic undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo (red bundle (GPA) or granulation), vitiligo, Wegener's granulomatosis, idiopathic thrombocytopenic purpura.

Yes (I)

Summary Formula (I)

Embodiments of the invention relate to compounds having the following formula:

Formula (I)

include

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein

or

Or deuterated alkyl (non: LM, LN, LU, LT and LR are each independently each RV independently selected from hydrogen, alkyl or substituted alkyl (CF3, CCl3 non-limiting examples) Or CRV2—limiting example: CD3), or amino alkyl, or thio alkyl, alkoxy, halogen, or halo alkyl, or halo;

m is N, U, t and R are each independently 1, 2, 3 and 4 selected from 0;

L is independently at each point of the alkyl or substituted alkyl used (non-limiting example: CF3, CCl3) or deuterated alkyl (non-limiting example: CD3), or amino alkyl, or thio alkyl, alkoxy, or halogen, or Halo alkyl, or halo alkoxy or atomic isotopes are valence permissible (eg the valence () is a non-limiting attachment including hydrogen by OH, NH2, SH, SiH3, PH2, etc.);

R1 is Rextra hydrogen, cyano, -SO2R8, -C (= O) R9, or heteroaryl;

Rextra (defined earlier) L, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyl, substituted alkyl, alkynyl, substituted alkynyl, alkoxy, thio alkyl, amino alkyl, carbamyl, sulfonyl, sulfonamide, Selected from cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxy, morpholinyl, aryl, arylalkyl, heterocyclo, heteroaryl, (hetero)alkyl, acyl, alkoxycarbonyl, substitution Amino;

R2 is (i) independently hydrogen, L, alkyl or substituted alkyl (as previously defined)

Or hetero-forming with R3 of (II);

R3 is (i) independently alkyl, substituted alkyl, L is alkyl thio is alkyl, amino alkyl, carbamyl, BB-aryl, BB-hetero, BB heteroaryl, or BB cycloalkyl, or (ii) with R2 Form a hetero;

Z is hetero aryl;

BB is C1-4 alkyl, C2-4 alkenylene, substituted C1-4 alkyl, substituted C2-4 alkenylene, -C bond (= O) NR19-, -C1-4 alkylene-C (= O) NR19- or substituted C1-4 alkyl -C (= O) NR19-;

In each case, R4 is different from the group consisting of halogen, alkyl, halo, nitro, cyano, halo alkoxy, OR25, SR25, NR25R26, NR25SO2R27, SO2R27, SO2NR25R26, CO2R26, C (= O) R26, C And independently selected from (=) NR25R26, OC (=O) R25, -OC (=O) NR25R26, NR25C (=O) R26, NR25CO2R26, aryl, heteroaryl, heterocycloalkyl;

R8 is alkyl, substituted alkyl, aryl, or heteroaryl;

R9 is -NR10Rll, alkyl, substituted alkyl, alkoxy, alkyl thio, cycloalkyl, aryl, heteroaryl, heterocycle, or -CO2R12;

R10 and R11 are (I) independently of each other selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocycloalkyl, aryl, and heteroaryl; Or (ii) together with hetero formation

Cyclo or heteroaryl;

R12 and R19 are hydrogen or alkyl;

R25 and R26 are independently taken together to form hydrogen, alkyl or substituted alkyl, or heterocyclo or heterocycle;

R27 is alkyl or substituted alkyl

q is 0, 1, 2 or 3.

Preferred compounds of formula I (I)

Then, a compound having a chemical formula or a pharmaceutically acceptable salt, solvate, hydrate or prodrug is used. Preferred compounds are

And compounds having the formula: or pharmaceutically acceptable salts, solvates, hydrates or prodrugs, using more preferred methods thereof, preferred compounds being

Then a compound having the formula or other preferred method of a pharmaceutically acceptable salt, solvate, hydrate or prodrug is used, the preferred compound being

Shown in the preceding three structures:

L is hydrogen, or methyl, or CF3, or CD3 or deuterium (D);

D is deuterium (and optionally in excess of 40% deuterium incorporation at the location shown, for example at a different location, eg enriched);

In excess of 70% of the S enantiomer excess (ee), for example symbolizing the S stereoisomer;

Ar is very evident to all art people. When it is known, whether this example has formula (I), for chiral carbon, this molecular composition will be a solid/dotted wedge in relation to the application of these compositions to the enantiomeric excess (ee) of the present invention, iUPAC) S or R days by naming convention;

Z has a benzene ring fused to it once with a triazole optionally substituted with imidazolyl 2 or R7 optionally substituted with one optionally R7 and/or optionally substituted with R7

R1 is cyano or -C (=0) R9;

R2 is hydrogen, alkyl or benzyl;

R3 is OCF3, cyano, nitro, amino, hydroxy or methoxy, substituted with aryl or optionally aryl alkyl, halogen, trifluoromethyl;

R4 is halogen, alkyl, trifluoro methyl, or OCF3;

R7 is alkyl, cover mill or cover mill C1-4 alkyl;

R9 is -NR1OR11, alkyl, substituted alkyl, alkoxy, alkyl thio, cycloalkyl, aryl, heteroaryl, heterocycle, or -CO2R12;

R10 and R11 are each independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocycloalkyl, aryl, and heteroaryl; Or (ii) together forming a heterocyclo or heteroaryl;

R12 is hydrogen or alkyl; and

q is 0, 1, 2 or 3.

In addition, a compound having the following formula is preferable, or a salt, solvate, hydrate or prodrug thereof is pharmaceutically acceptable.

More preferably, a compound having the formula: or a salt, solvate, hydrate or prodrug thereof is pharmaceutically acceptable

Other preferred compounds are those having the following formula, or their salts, solvates, hydrates or prodrugs:

The preceding three structure cities:

More desirable

L is hydrogen, or methyl, or CF3, or CD3 or deuterium (D);

D is deuterium (and optionally in excess of 40% deuterium incorporation at the location shown, for example at a different location, eg enriched);

In excess of 70% of the S enantiomer excess (ee), for example symbolizing the S stereoisomer;

A is nitrogen (N), or N + or carbon;

E is absent, or alkyl, or substituted alkyl, or deuterated alkyl, or amino alkyl, or thio alkyl, alkoxy, or atomic isotopes are valence-acceptable (e.g., the valence () is non-limiting OH, Attachments including hydrogen by NH2, SH, SiH3, PH2, etc.) such as hydrogen, deuterium or fluorine;

Y is N, CH or CR7c;

R1 is cyano or -C (=0) R9;

R2 is hydrogen or C1-4 alkyl;

R4 is halogen, C1-4 alkyl, trifluoro methyl; Or optionally substituted with OCF;

In addition, R7a, R7b, R7c are independent of E (defined previously) hydrogenalkyl, carbamill or carbamillC1-4alkyl, or, also, R7a and R7c are joined to form this optionally substituted fused phenyl ring

R9 is -NR1OR11, alkyl, substituted alkyl, alkoxy, alkyl thio, cycloalkyl, aryl, heteroaryl, heterocycle, or -CO2R12;

R10 and R11 are each independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocycloalkyl, aryl, and heteroaryl; Or (ii) together forming a heterocyclo or heteroaryl;

R12 is hydrogen or alkyl;

R23 is hydrogen, alkyl, hydroxy alkyl, or phenyl;

R24 is alkyl, halogen, trifluoromethyl, cyano, halogen, hydroxy, OCF3, methoxy, phenyl oxy, benzyl oxy, cyano or acyl, or two R24 groups form a fused cycloalkyl or benzene ring Join

q is 1 or 2;

X 0, 1 or 2; and

Y is 0, 1, 2 or 3.

More preferably, a compound having the following formula, or a salt, solvate, hydrate or prodrug thereof is pharmaceutically acceptable

More preferably, a compound having the formula: or a salt, solvate, hydrate or prodrug thereof is pharmaceutically acceptable

Other preferred compounds are those having the following formula, or their salts, solvates, hydrates or prodrugs:

The preceding three structure cities:

L is hydrogen, or methyl or deuterium;

D is deuterium (and optionally in excess of 40% deuterium incorporation at the location shown, for example at a different location, eg enriched);

In excess of 70% of the S enantiomer excess (ee), for example symbolizing the S stereoisomer;

R1 is cyano or -C (=0) R9;

R4 is halogen, C1-4 alkyl, trifluoro methyl, or OCF3;

R7c is hydrogen or (CH2) 1-2-NHC (= O) C1-4 alkyl-R7 and R7c form C1-4 alkyl or an optionally substituted fused benzene ring

R7b is hydrogen, C1-4 alkyl, or-(CH2) 1-2-NHC (= O) C1-4 alkyl;

R9 is -NR10R11

b) C1-8 alkyl, optionally substituted with either:

Iii) SR13, OR13, NR13aR13b, halogen, trifluoromethyl, CO2R13a and C (=O) NR13aR13b;

Ii) phenyl in turn substituted with any two C (one substituted cyclo=O) H, C1-4 acyl, alkenyl, carbamyl and/or halogen;

Iii) phenyl or halogen, nitro, amino, alkyl, two or one substituted naphthyl having a hydroxy number fused to a C1-4 alkoxy, or a 5 or 6-membered hetero;

Iv) having a 5-6 membered carbocyclic ring fused to a dienyl, thiophenyl, furanyl, tetrahydrofuranyl, or azepinyl, optionally substituted alkyl or optionally keto or C1-4 alkoxy

c) C1-4 alkoxy;

d) C1-4 alkyl thio;

E) CO2 alkyl;

F) 3-6 membered cycloalkyl having four substituents selected from alkyl, halogen, cyano group, alkenyl, acyl, alkyl thio, carbamill and/or phenyl in turn substituted with halogen; Or having aryl fused to it

g) Phenyl is halogen, cyano, trifluoromethyl, nitro, hydroxy, net, C1-4 alkoxy, halo, C1-6 alkyl, CO2alkyl, SO2alkyl, SO2NH2, amino, NH (C1-4 alkyl) , N (substituted with C1-4 alkyl) 2 NHC (= O) alkyl, C (= O) alkyl, and/or C1-4 alkyl, optionally substituted with one of three fluoro; Hydroxy, cyano, phenyl, pyridinyl; And/or keto or optionally a benzene ring having a substituted alternating 5 or 6 membered heteroaryl or heterocycle having a bond to it;

H in turn, phenyl substituted with one of dinil, thiazolyl, furanyl, thiophenyl, pyrrolyl and halogen, alkyl, halogen or trifluoro;

R10 is hydrogen, alkyl or alkoxy;

R11 is alkyl, substituted alkyl, alkoxy, heterocycloalkyl, aryl or heteroaryl;

Or R10 and R11 together form a heterocyclo or heteroaryl;

R23 is hydrogen, alkyl, hydroxy alkyl, or phenyl;

R24 is alkyl, halogen, trifluoromethyl, cyano, halogen, hydroxy, OCF3, methoxy, phenyl oxy, benzyl oxy, cyano or acyl, or two R24 groups form a fused cycloalkyl or benzene ring Join

q is 0, 1 or 2;

X is 0 or 1; and

Y is 0, 1 or 2.

Immediately as most compounds, R1 is cyano or preferred as defined above

-C (=0) R9; R9 is optionally C1-4 alkyl phenyl, or substituted; X is 0 or 1; Q and Y are 1 or 2. In the case of such a preferred structure, the S stereoisomer is preferable. The L group is more preferable to be deuterated.

Illustrative Example (I) of Formula I

In compound [5-6] more selected as a specific anti-cancer treatment of the invention of the present invention selected because they inhibit reverse rather than the forward mode of ATP synthase. Used in the same way as EC50 and IC50. EC50 values and F1F0 ATP synthesis for F1F0 ATP hydrolysis in NADH-linked sub-mitochondrial NADPH-linked (SMP) assays, supplied from each [5-6], hello. [5-6] IC50 values for inhibiting F1F0 ATP hydrolase (reverse mode) and F1F0 ATP synthase (forward mode) See these EC50 values. But this is wrong. As confirmed by the invention of the present invention, these molecules are described herein (mainly) not synergistically by F1F0 ATP, but not by F1F0 ATP synthetase, because F1F0 ATP inhibits F1F0 ATP synthesis, decreases in hydrolytic enzymes, but by uncoupling. The lower EC50 for the more preferred molecule of the present invention, the higher the EC50 of F1F0 ATP hydrolysis and the higher the F1F0 ATP synthesis, the greater the difference in proportion.

In another exemplary embodiment (I) of formula (I), with reinterpretation SMP data (as described above, these molecules do not significantly inhibit F1F0 ATP synthase but decrease F1F0 ATP synthesis by uncoupling) [5 ],

Another example [5]:

Proton motif forces the ability of the uncoupled molecule to reduce the ability of the imidazole protonable element effectively without synthesis steps and further examples:

Synthesis of general compounds

General synthetic routes that can be applied to several compounds of the present invention are shown in Scheme 1 below.

Scheme 1

Those of ordinary skill in the art may be able to modify this general synthetic route, based on the literature in general common sense, chemical reactions, and/or disclosure of prior art needs, cited herein, in order to have compounds synthesized with the present invention positions.

Synthesis of specific compounds

19A [5] of racemate is synthesized by the following synthetic route, and separated into three-dimensional components using Scheme 2 and ultrafluid chromatography (SFC). Starting this synthetic reagent has been commercially supplied using LabNetwork ( www.labnetwork.com )/ Chemical Name 1 Starting compound for compounds Multiple compounds listed in LabNetwork enable search for entered chemical structure dealers, eg presence It is a website.

Scheme 2

The reaction scheme below, scheme (3), is modified from what is presented above to produce deuterium, deuterated analogs instead of hydrogen on chiral carbon. The plan is provided to illustrate the invention and should not be regarded as limiting the scope or spirit of the invention. This shows that the features are not limited, and all compounds herein are applied in a synthetic manner. Compound (1) Starting compounds in the following manner are provided by several companies listed in LabNetwork (eg Manchester Organics, UK).

Scheme 3

In the molecular synthesis example of compound 4 in scheme 3, compound 1, in the form of the starting compound [P1], but with a chiral carbon deuterated exception (as presented in the section "Methods for the preparation of the process"). It can be substituted in the synthetic manner described in deuterated digestion mode [P1], which is a component of the present invention, and is used as an anti-cancer agent in the composition of deuterium molecules, newer substances of chiral carbon and deuterium production in non-limiting examples. will be. Solvent, temperature, pressure and other reaction conditions can be selected by one skilled in the art. Starting materials are either commercially available or can be prepared by a person skilled in the art using methods known immediately. The method of Synthetic Compound 4 is also described in Reaction Schemes 3 and 4 above.

Scheme 4

In Scheme 4, compounds 1 are provided by several companies listed in LabNetwork (eg Apollo Science, Inc., Stockport, UK). The objective of carrying out Scheme 4 is to obtain a high level of deuterium incorporation at chiral carbon above its natural abundance: finally, if the lower arm of the synthetic pathway of compound 4 and compound 1 is used. In both cases, larger deuterium integration, better. Elevated deuterium incorporation is within the scope of the present invention, where deuterium introduction at different positions of each molecule is allowed, as in chiral carbon only. Described in the reaction [L, H, G, K, M, J1, J2, J3, I, F, S] deuterate is described in α carbon in secondary alcohols and in the chiral carbon of the compound (1) reaction (main deuterium and hydrogen Defined as an alternative) [A, B, P, E1, E2, F] deuterate α carbon of the secondary amine compound (4) chiral carbon number of the reaction described there (4) deuterate [en] deuterate SP3 carbon, so described Deuterate the carbon and reactant of the chiral compound (1) [O1, O2] deuterate the β carbon for the phenyl group, etc. deuterate the carbon and the reactant of the chiral compound (1) deuterate [R1, R2, Q1 , Q2] can be widely deuterate to aromatic and alkyl molecular weight components, and thus deuterate the carbon and the reactant of the chiral compound (1) described [di] β-carbon deuterate of the tertiary amine, where there is the chiral carbon of compound 1 and my teaching Deuterate [D] is particularly preferred for use in this context. Either option(s), solvent, temperature, pressure, and other reaction conditions can be selected by those skilled in the art. Deuterium incorporation over longer reaction times: Deuterium digestion levels can be controlled by controlling the reaction time. Deuterium incorporation of 1H and/or 2H NMR (e.g. deuterium incorporation) by reduction of 1H NMR integral intensity at the specified position(s) compared to the start of the occurrence or to perform multiple cycles of one of these reactions further to the desired level of deuterium incorporation Material monitored by quantification) and/or mass spectrometer. Some of the reactions are cited here using 10% Pd/C catalysts in commercial catalyst examples [O1, O2, Q1, R1, R2] and/or platinum/C catalysts [R1, R2, Q1, Q2] or shvo Catalyst [D] or RuCl2 (P (PH) 3) 3 (CAS number: 15529-49-4) [ㅏ] or 5% Ru/C catalyst [K] or RU-forage catalyst [G, M] sigma- All available in Aldrich. Others cite teachings in literature, how to prepare by teaching or using catalysts. The above list of synthetic options is not exhaustive to make compound (4) in Scheme 4. Those of ordinary skill in the art will know how to find additional options. Using a computational tool, including artificial intelligence (for example, AI, non-restrictive example [AI1, AI2, AI3]) to find their skills in the Reaxys or CAS database and technical field (non-restrictive planning) And can search the chemical reaction literature/database for synthetic routes to priorities 2-(1H-imidazole-1-yl)--1-phenylethanamine is commercially available on LabNetwork and deuterating chirals among the above mentioned methods Deuterated from chiral carbon disclosed by one (or optionally at another location, etc.) can be deuterated 1-(2,4-dichlorophenyl)-2-(imidazole-1-yl) ethane amine carbon. After digestion, that phenyl group may be (non-limiting) alkyl, halogenated or CF3 added: at any position(s) by methods known to me (non-limiting example IUPAC 2,5-position) art. It can then be a starting compound in a synthetic fashion [P1] and used to generate, in a non-limiting embodiment, in animals or humans, alone or in combination with an anticancer therapy, deuterate a composition of matter with components of the invention. Starting material, not the final product of the comprehensive plan of [P1] in a non-limiting embodiment where production is non-deuterated, deuterated, in animals or humans, alone or in combination with anti-cancer therapy, in the composition of the material with the components of the present invention Description of the reaction [A, B, E1, E2, F] deuterate α carbon for secondary amines, the chiral carbon of the compound (19A) of Scheme 2 previously presented, and the chiral carbon number of the skeleton and other molecules There as an abstract presentation of [P1][P1].These compounds can also be described by deuteration in chiral carbon, the reaction in the above example, in another position (S) [yen], the carbon of SP3 deuterate and/or by descriptive reaction [O1, O2], which is the β-carbon deuterate of the phenyl group. [R1, R2, Q1, Q2] aromatic and alkyl molecular weight components are deuterate by high/or explanatory reactions. And/or by descriptive reaction [di] which is the β-carbon deuterate of the tertiary amine. Some of these reactions are stereoretentive [F, N, E1, E2] and therefore can be used selectively after stereoconcentration. Others are not, for example, [Q1, Q2] etc. Any enantiomeric excess (ee) should be used before the concentration step. All patents and papers cited in this specification and their supplements are the components cited herein as references herein.

Scheme 5 is different from Scheme 2 in order to prepare methyl and methylated analogs instead of hydrogen on chiral carbon.

Plan (5)

In the synthetic examples of compound 5 in Scheme 5, [P1] in the form of molecule, compound 1, starting compound, but excluding chiral carbon methylation (however, it is presented in the section "Methods for Process Preparation"). It can be substituted in the synthetic manner described in the methylation format [P1], which is a component of the present invention, and in a non-limiting example, one or more of the composition of this new material is used as an anti-cancer agent, its chiral carbon and methyl production methylation molecule It is about. Solvent, temperature, pressure and other reaction conditions can be selected by one skilled in the art. Starting materials are either commercially available or can be prepared by a person skilled in the art using methods known immediately.

Scheme 6 is followed by Scheme 2 to produce fluorine, fluorinated analogues instead of hydrogen on chiral carbon.

Plan (6)

In a synthetic molecular embodiment of compound 6 of scheme 6, compound 1, in the form of the starting compound [P1], but with the exception of chiral carbon fluorination (as presented in its "Methods for Process Preparation" section). It can be substituted in the synthetic manner described in the fluorination modality [P1] to produce components of the present invention with fluorine on their chiral carbon, molecular fluorine, and, in a non-limiting example, with one or more of the compositions of these new materials. Used as an anticancer agent. Solvent, temperature, pressure and other reaction conditions can be selected by one skilled in the art. Starting materials are either commercially available or can be prepared by a person skilled in the art using methods known immediately.

Yes (II)

Summary Formula (II)

Embodiments of the invention relate to compounds having the formula:

Formula (II)

include

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein

L is the alkyl used, or substituted alkyl, or deuterated alkyl, or amino alkyl, or thio alkyl, alkoxy, halogen, or halo alkyl, or independently at each point of halo alkoxy or any atomic isotope is valence Allowed (for example, the valence () is non-limiting, including hydrogen by OH, NH2, SH, SiH3, PH2, etc.) such as 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 amino alkyl, or thio alkyl, alkoxy, or atomic isotopes are valence-acceptable (e.g., the valence () is non-limiting OH, Attachments including hydrogen by NH2, SH, SiH3, PH2, etc.) such as hydrogen or deuterium or fluorine;

C is carbon;

X is F, w is g is independently selected from 0, 1, 2 or 3;

D is an integer selected between 0 and 7;

K and s are independently selected from 1, 2 or 3;

The five-sided ring structure is linked by one of the available ring atoms and none, one or two of its bonds, at positions shown by two "single or double bond" symbols, for example, can be a double bond;

R1 and R5 attached to any available carbon atom of the phenyl group are A and B, respectively, and in each case independently hydrogen, deuterium, alkyl, substituted alkyl, trifluoromethoxy, halogen, cyano, Nitro, OR8, NR8R9, C (selected from = O) R8, CO2R8, C (= O) NR8R9, NR8C (= O) R9, NR8C (= O) OR9,

So) _zero-type R9, NR8SO2R9, SO2NR8R9, cycloalkyl, heterocycle, aryl and heteroaryl, and/or two R1 and/or R5 join together to form benzo fused two rings

R2, R3 and R4 are independently (as previously defined) E, hydrogen, deuterium, or alkyl, or alkyl deuterated and substituted with alkyl, or one of R2, R3 and R4 is a bond to R, T or Y and The other of the R2, R3 and R4 are independently hydrogen, alkyl, substituted alkyl;

Z and Y are independently selected from C (= O), -CO2-, -SO2-, -CH2-,

-CH2C (= O)-and -C (= O) C (= O) -, or Z may not be present;

R and T are selected from -CH2-, -C (= O) -, and -CH [(CH2) p (Q)] -, wherein Q is NR10Rll, OR10 or CN;

A lower aliphatic group independently selected from the group R6 is optionally selected from thienyl, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, heterocyclo, heteroaryl, or one of lower aliphatic groups Aryl substituted with the above functional groups, -OH, phenyl, halogen, (C1-C4) alkoxy or -NHCOCH3;

R7 is (as previously defined) L, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, amino, halogen, cyano, nitro, keto (= O), hydroxy, alkoxy, alkyl thio, C (= O ) H, acyl, CO2H, alkoxy, carbasulfonyl, sulfonamidyl, cycloalkyl, heterocycle, aryl and heteroaryl;

When attached, R8 and R9 are independently hydrogen, alkyl, substituted alkyl, C2-4 alkenyl, optionally substituted cycloalkyl, heteroaryl and heteroaryl, or R8 together to form a heterocycle or heteroaryl except R9 is not hydrogen And a sulfonyl group selected from R9 and SO2R9;

R10 and R11 are independently hydrogen, alkyl, 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 compound of formula I (II)

Then, a compound having a chemical formula or a pharmaceutically acceptable salt, solvate, hydrate or prodrug is used. Preferred compounds are

include

remind

L is hydrogen, deuterium, or methyl or fluorine;

A is nitrogen (N), or N + or carbon;

E is absent, or alkyl, or substituted alkyl, or deuterated alkyl, or amino alkyl, or thio alkyl, alkoxy, or atomic isotopes are valence-acceptable (e.g., the valence () is non-limiting OH, Attachments including hydrogen by NH2, SH, SiH3, PH2, etc.) such as for hydrogen or deuterium;

R1 and R5 are each attached to any available carbon atom of phenyl ring A and phenyl ring B, and in each case independently hydrogen, alkyl, aralkyl, amino alkyl, halogen, cyano, nitro, hydroxy, alkoxy , Trifluoromethoxy and selected from thio, NH2, NH (alkyl), N (alkyl) 2, C (= O) H, acyl, CO2H, alkoxy carbonyl, carbamyl, sulfonyl, sulfonamide,

Cycloalkyl, heteroaryl, heteroaryl, and/or two R1 and/or R5 join together to form a fused benzo with two rings

R2, R3 and R4 are independently selected from hydrogen and alkyl;

Z is -CO2-, -SO2-, or absent;

Y, R and T are selected from -CH2- and -C (= O)-

Select from R6:

C1-4 alkyl or halogen C1-4alkenyl is up to three, aryl and substituted CO2C1-6alkyl;

Phenyl three optionally substituted up to R12 and/or a benzo ring fused to it or a 5-6 membered heteroaryl or de;

Thiophenyl, imidazolyl, pyrazolyl, and isoxazolyl heteroaryl, heteroaryl optionally substituted with up to 2 R12

R7 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, amino, halogen, cyano, nitro, keto (= O), hydroxy, alkoxy, alkyl thio, C (= O) H, acyl, CO2H, Alkoxy carbonyl, carba, and is selected from sulfonyl, sulfonamide, cycloalkyl, heterocycle, aryl and heteroaryl;

R12 in each case is independently a 6-membered monocyclic group from the group consisting of C1-6 alkyl, halogen, nitro, cyano, hydroxy, alkoxy, NHC (= O) alkyl, -CO2 alkyl, -SO2phenyl, aryl, five Halogen, hydroxyl, C1-4 alkyl, and/or O (C1-4 alkyl) selected from R12 and optionally substituted with phenyl or benzyl in turn;

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 preferably, a compound having the following formula, or a salt, solvate, hydrate or prodrug thereof is pharmaceutically acceptable

remind

R1 and R5 are independently selected from alkyl, each, and in each case possible linked to the carbon atom of the phenyl ring A and the phenyl ring B

Halogen, cyano, hydroxy, alkoxy, NH2, NH (alkyl), N (alkyl) 2, and/or 2 R1 of C (= O) H, acyl, CO2H, alkoxy and /R5 or both together to form Join A is a benzo fused ring;

R2, R3 and R4 are independently selected from hydrogen and lower alkyl;

Z is -CO2-, -SO2-, or absent;

Select from R6:

C1-4 alkyl or halogen C1-4alkenyl is up to three, aryl and substituted CO2C1-6alkyl;

Phenyl three optionally substituted up to R12 and these fused or 5-membered hetero six having a /benzo ring;

Heteroaryl is a heteroaryl selected from thiophenyl, imidazolyl, pyrazolyl and isoxazolyl, characterized in that it is optionally substituted with R12 up to 2,

R12 in each case is independently selected from R12 from each other from the group consisting of C1-6 alkyl, halogen, nitro, cyano, hydroxy, alkoxy, NHC (= O) alkyl,

-CO2alkyl, -SO2phenyl, aryl, 5-6 is monocyclic heteroaryl, in turn phenyl oxy or benzyl oxy is substituted with halogen, hydroxyl, C1-4 alkyl, and/or O (C1-4 alkyl); and

m and n are independently selected from 0, 1 or 2.

R6 is more preferably the same compound as defined above, selected from C1-4 alkyl, trifluoromethyl, benzyl, C2-3alkenyl substituted with phenyl

remind

R15 is NHC (= O) alkyl, and/or two R15 groups are halogen, alkyl, nitro, cyano, hydroxy, alkoxy together to form five heteroaryl on the ring benzo fused 6;

R16 is selected from hydrogen, halogen, alkyl, nitro, cyano, hydroxy, alkoxy, NHC (= O) optionally 1 to 3 substitutions of hydrogen, halogen, cyano, alkyl and phenyl oxy or benzyl oxy, and C1 -4alkoxy;

R17 is selected from alkyl, alkoxy, CO2C1-6alkyl and SO2phenyl;

U and V are independently 0, 1 or 2.

The most preferred compound (II) of formula I has its formula:

remind

L is deuterium;

R2 is hydrogen or CH3;

Z is -CO2-, -SO2-, or absent; and

R6 is most preferably selected from the group described immediately above

Illustrative Example (II) of Formula I

In compounds [8, 12] more selected as specific anti-cancer therapeutics of the invention of the invention selected because they inhibit reverse rather than the forward mode of the ATP synthase. Used in the same way as EC50 and IC50. EC50 values and F1F0 ATP synthesis for F1F0 ATP hydrolysis in NADH-linked sub-mitochondrial NADPH-linked (SMP) assays, supplied from each [8], hello. [8] IC50 values for inhibiting F1F0 ATP hydrolase (reverse mode) and F1F0 ATP synthase (forward mode) See these EC50 values. But this is wrong. As confirmed by the invention of the present invention, these molecules are described herein (mainly) not synergistically by F1F0 ATP, but because of inhibition of F1F0 ATP synthesis, decrease of F1F0 ATP synthesis, hydrolytic enzyme inhibition, but by uncoupling. .

Another example [12],

The scheme IIA pathway was used for synthetic compounds (8) [8], starting reagents were commercially supplied using LabNetwork ( www.labnetwork.com ).

Plan IIA

Compound 31 may deuterate the carbon of SP3, by the reaction described in the IIA scheme, deuteration at chiral carbon, and may be in another example at another position(s). And/or deuterate the aromatic and alkyl molecular weight components [R1, R2, Q1, Q2] by explanatory reactions. And/or α and β-carbon number of any diamine amine deuterate by descriptive reaction. And/or deuterate the higher amine α carbon number by [F, E1, E2, EX1] by explanatory reactions. Alternatively, that chiral carbon deuterated compound 31 isotopologue can be generated, and in the above examples, in the middle in the synthesis of compound 31 of the additional or different position(s) presented in the IIA scheme, deuterated digestion is possible. (Non-limiting) For example, the compound of Scheme 6 IIA can be deuterated by describing it in the reaction [A, B, E1, E2, F] which deuterate α carbon for secondary amines. And/or by descriptive reaction [yen], the carbon of SP3 is deuterate. And/or deuterate the aromatic and alkyl molecular weight components [R1, R2, Q1, Q2] by explanatory reactions. The synthesis method of deuterated compound 6 can be entered [P2] in section "Method of preparation of the process" in order to make deuterium isotopologues with scaffolds of [P2] instead of compound 10 of scheme III [P2]. As a novel composition of such a substance, it is a component of the present invention, and in a non-limiting embodiment, the drug(s) is approved by FDA and/or EMA, optionally used alone or in combination in co-therapy and/or treated (S) For cancer treatment licensed as an anti-cancer drug. Throughout this specification, the method of transferring heavy water is an example, not a limitation. All stereoisomers of all compounds of the invention are also contemplated as mixtures or pure or substantially pure forms.

Example (III)

Summary Formula (III)

Embodiments of the invention relate to compounds having the following formula:

Formula (III)

include

include

include

include

include

Or their enantiomers, diastereomers, pharmaceutically acceptable salts, solvates, hydrates or prodrugs, above

Optionally, one or more sites have deuterium in place of hydrogen, at an artificially high level of deuterium establishment, which is a naturally occurring abundant excess;

Optionally, have fluorine or other halogen, or methyl, or alkyl, or substituted alkyl in place of hydrogen at one or more sites;

Z is hetero aryl;

g is selected from 4 3, 2, 1, 0;

Or deuterated alkyl (non-limiting example: CD3), or amino alkyl, or thio alkyl, alkoxy, halogen, or: L at each point of the hydrogen, alkyl, or substituted alkyl used (CF3 non-limiting example) Independent halo alkyl, or halo alkoxy or atomic isotopes are valence permissible (eg the valence () is non-limiting, including hydrogen by OH, NH2, SH, SiH3, PH2, etc.);

G1 is N or C;

C is selected from 9 8, 7, 6, 5, 4, 3, 2, 1;

m is independent at each point of use, selected from singer permission, 6, 5, 4, 3, 2, 1, 0;

R2 is hydrogen, (as previously defined) L, hydroxy, or -OC(O) R14;

R14 is hydrogen, alkyl, halo alkyl, aryl, aryl alkyl, cyclo alkyl or (cyclo alkyl) alkyl;

R3 and R4 are each independently hydrogen or (as previously defined) L, or CF3, or chlorine or other halogen, or alkyl, or substituted alkyl, or deuterated alkyl, or aryl, or R3 and R4 are carbon atoms and Together they are attached forming a 3- to 7-membered carbocyclic ring;

R5 is independent of L, alkyl, halogen, heteronitrile, haloaryl or at each point, using hydrogen;

R12 is selected from hydrogen, aryl, heteroaryl, heterocyclo;

X is alkyl;

Y is a single bond, -CH2-, -C (O) -, -O-, -S- or -N (R14) -;

A is nitrogen (N), or N + or carbon;

E is absent, or alkyl, or substituted alkyl (non-limiting example: CF3), or deuterated alkyl, or amino alkyl, or thio alkyl, alkoxy, or atomic isotopes are allowed to have a valence (e.g. ) Is non-limiting including hydrogen by OH, NH2, SH, SiH3, PH2, etc.) such as hydrogen or deuterium or fluorine;

R8 is independently E (defined earlier), hydrogen, alkyl, halogen, carbacover mill C1-4 alkyl, substituted alkyl or two R8 groups each selected at the point of use in a join forming an optionally substituted fused phenyl ring Become;

q is 0, 1, 2, 3 or 4.

R1 is hydrogen, deuterium, CN, SO2 is piperidine, piperidine SO2-R5 substitution 0-10 (defined earlier) L is selected from R9, Cyano, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyl, substituted alkyl, alkynyl, substituted alkynyl, alkoxy, thio alkyl, amino alkyl, carbamyl, sulfonyl, sulfonamide, cycloalkyl, ( Cycloalkyl) alkyl, hydroxy alkyl, halo, halo alkoxy, alkoxy, morpholinyl, aryl, aryl alkyl, hetero cyclo, hetero aryl, (hetero) alkyl, acyl, alkoxy carbonyl, substituted amino;

Most preferably R1 is less than 300 daltons;

R9 is

;

;

R6 and R7 are independently hydrogen, L (defined above), R1 (R1 is provided without R9), alkyl, cycloalkyl, aryl, aryl alkyl, halo alkyl, hydroxy alkyl, carboxylic ester or carboxylic acid, Alkoxy, thio alkyl, (which is hydroxy alkyl substituted with cycloalkyl) alkyl, morpholinyl, or hetero (hetero) alkyl; Or R6 and R7 together with a nitrogen atom bonded in the form of a bicyclic ring containing fused rings such as 5- to 7-membered mono

1-pyrrolidinyl, 1-piperidinyl, 1-azepynyl, 4-morpholinyl, 4-thiamorpholinyl 4-thiamorpholine -1-piperazinyl dioxide, 4-alkyl-1-piperazinyl, 4- Aryl alkyl-1-piperazinyl, 4-diaryl alkyl-1-piperazinyl; Or 1-piperazinyl, 1-pyrrolidinyl is 1-piperidinyl or 1-azepynyl is one or more (as previously defined) L, alkyl, alkoxy, alkyl thio, halo, trifluoromethyl, hydroxy , Aryl, aryl alkyl, -COOR14 or -CO substituted substituted amino acids;

Or R5 and R6 together with the atoms to form a 5 to 7 membered ring, optionally substituted with aryl;

Methods for administering a therapeutically effective amount of any compound(s) are included in the present invention [P6] or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, optionally pharmaceutical composition(s), optionally Subject to co-therapy treatment/mitigation/prevention/combat cancer, along with other anticancer treatment(s). The use of compounds is particularly preferred [P6] with 3S, 4R stereochemistry.

Preferred compound of formula I (III)

The preferred method is used, and the preferred compound is compound (III) of formula (I), its enantiomer, diastereomer, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof:

Z is fused to a benzene ring in turn, which in turn is imidazolyl R8 2 or optionally substituted with tria optionally 1 R8 and/or optionally substituted with one R8

Y is oxygen;

R2 is hydroxyl;

R3 and R4 are methyl or chlorine;

R1 is R9;

G1 is nitrogen;

R6 and R7 are alkyl; Or R6 and R7 together with the nitrogen atom to which they are attached (N = G1) form a 6-membered ring;

X is alkyl;

R12 is aryl or heterocyclo;

A is N;

E is absent, deuterium, or hydrogen;

R5 and R8 are hydrogen;

Stereoscopic 3S, 4R;

Illustrative Example (III) of Formula I

Directly below compound [7] selected as a specific anti-cancer therapeutic agent of the present invention. EC50 values for F1F0 ATP hydrolysis and F1F0 ATP synthesis each NADH linked NADPH linkage analysis. [7] F1F0 ATP hydrolase (reverse mode) and F1F0 ATP synthase (forward mode). IC50 values for suppression These are EC50 values. But this is wrong. As confirmed by the invention of the present invention, these molecules are described herein (mainly) not synergistically by F1F0 ATP, but because of inhibition of F1F0 ATP synthesis, decrease of F1F0 ATP synthesis, hydrolytic enzyme inhibition, but by uncoupling. . The structure on the left is BMS-199264; it does not mind the rats in vivo at concentrations (10 μM [11]), which indicates the (discovered) anticancer activity of this specification.

The following exemplary embodiment in the synthetic manner of (Scheme scope IIIa as possible salt 2), starting material is BMS-199264, commercially available. Aldrich, an example of a manufacturing company chemistry and reagents known to the art.

On plan IIIa

Also an example:

Unlike BMS-199264, the imidazole group, for example, does not have a protonable element, so the following example does not solve the quantum motive force (PMF).

The following exemplary embodiment (= 3.79 log P is the structural calculation [31]), the structural calculation, BMS-199264 (log P = 4.35 or more) proton motif force (separated by PMF [31]) is the log P Is also removed from the log P = ~3,2 optimal for uncoupling [32].

BMS-199264, and/or analogs thereof, deuterate heavy water [R1, R2, Q1, Q2] aromatic and alkyl molecular weight components that can be explained by reaction. In addition, there is a great wealth of reactions that can deuterate their aromatic rings, and those of ordinary skill in the art will know the following. (Non-limiting) See, eg, [EX2]. BMS-199264, can be deuterated by the reaction described in chiral carbon center 1 [D, F, E1, E2, EX1] which deuterate α is a carbon amine and/or described by reaction [yen] which deuterate SP3 By carbon and/or by reaction [I, M, G, H] which OH group deuterate α and β are carbon -. BMS-199264, deuterated by the reaction described in chiral carbon center 6 [L, H, G, A, K, M, J1, J2, J3, I, F, S] to which and/or reaction By explaining, deuterate [carbon] of the OH group, deuterate α and β-class amine-carbon, and/or by reaction [en], SP3 carbon deuterate. The scaffolding of [P6] is provided abstractly. Its heavy water digestion isotopologues [P6] (non-limiting) For example, the support is a novel composition of the material, BMS-199264, which is a component of the present invention and, in a non-limiting embodiment, optionally co-worked with FDA and/or Deuterated EMA, used alone or in combination in therapy, has approved medical treatment(s) and/or treatment(s), for example, cancer treatment licensed as an anti-cancer treatment.

Example (IV)

background

Known to the art: R groups of acids are amino acids that have the following structure and other characteristics of different amino acids.

Summary Formula (IV)

Embodiments of the invention relate to compounds having the following formula:

Formula (IV)

include

Or their enantiomers, diastereomers, pharmaceutically acceptable salts, solvates, hydrates or prodrugs, above

X is selected from O or S;

(A) is selected from the R group of hydrogen, alkyl, substituted alkyl, cycloalkyl, heteroaryl, heteroaryl, amino, thio, alkoxy and proteogenic amino acids or other amino acids used for biosynthesis or other (non-limiting and limiting examples of such systems Human, optionally substituted with isotopic enrichment and/or alkyl), substituted alkyl, deuterated alkyl, halogen, cycloalkyl, heteroaryl, heteroaryl, aminoalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, or any Atomic isotopes (including, for example, hydrogen (non-limiting) accompanied by hydrogen by OH, NH2, SH, SiH3, PH2, etc.) valence allowed;

n and m are 0, 1 or 2;

R1 to R5 are independently hydrogen, halogen, NO2, CN, C1-8 alkyl, substituted C1-8 alkyl, C3-8 cycloalkyl, aryl, heterocyclo, heteroaryl, OR9, SR9, COR11, CO2R11, CONR9R10 or NR9R10;

R6 and R7 are independently hydrogen, alkyl or substituted alkyl;

R8 is hydrogen, C1-8 alkyl, substituted C1-8 alkyl, deuterated C1-8 alkyl, aryl, heterocyclo, heteroaryl, amino, thio, alkoxy, halogen, haloalkyl, haloalkoxy or any atomic iso Elements are allowed to have valences (including, but not limited to, OH, NH2, SH, SiH3, PH2, etc.)

Z is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, COR11, CO2R11, independently of the following groups: S(O) R11 or CONR9R1O;

R9 and R10 are independently hydrogen, C1-8 alkyl, substituted C1-8 alkyl, C3-10 cycloalkyl, aryl, heterocyclo, heteroaryl, COR13, SO2R13 or S(O) R13; and

R11, R12 and R13 are independently hydrogen, C1-8 alkyl, substituted C1-8 alkyl, C3-10 cycloalkyl, aryl, heterocyclo or heteroaryl;

Each case of R9-R13 is independently selected.

Preferred compounds of formula I (IV)

Preferred compounds are used, and the preferred compounds are of compound (IV) of formula (I), their isomers, stereoisomers thereof, pharmaceutically acceptable salts, solvates, hydrates or prodrugs:

R2, R3 and R4 are all hydrogen; And/or

R6 and R7 are both hydrogen; And/or

n and m are both 1; And/or

R1 and R5 are preferably two C1-8 alkyl, wherein both R1 and R5 are isopropyl groups.

Preferred compounds using other preferred methods are those of formula (IV), their enantiomers, diastereomers, pharmaceutically acceptable salts, solvates, hydrates or prodrugs:

Z is C1-8 alkyl, C alkenyl, C1-8 halo alkyl, cycloalkyl, aryl, aryl alkyl, heteroaryl, hetero-COR11, -CO2R11, -SO2R11, -S (O) R11 or -CONR9R10; Particularly preferred is benzyl, -C (O) 2H or -C (O) 2C1-8 alkyl;

R9 is hydrogen;

R10 is C1-8 alkyl or C3-10 cycloalkyl; Aryl or aryl; and

R11 is hydrogen, C1-8 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C3-10 aryl or C3-10 aryl.

Preferred compounds using other preferred methods are those of formula (IV), their enantiomers, diastereomers, pharmaceutically acceptable salts, solvates, hydrates or prodrugs:

A is hydrogen, deuterium, C1-8 alkyl is heteroaryl, or aryl or alkyl, aryl, OH, SH, ST1, -C (O) H, T3-NT5T6, -T8-C (O) tT9-NT5T6 hetero Substituted or N-T3 (T2) T4NT5T6,

T1 is alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, aryl (aryl) alkyl, heterocyclo ( Hetero) alkyl, hetero aryl or (hetero aryl) alkyl;

T2 and T3 are each independently a single bond, -T8-S (O) t-T9-, -T8-C (O) -T9-, -T18-C (S) -T9, -T8-S- T9 -, -T8-OC (O) -T9-, -T8-C (O) tT9-, -T8-C (= NT10) -T9- or -T8-C (O) -C (O) -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 and hetero (hetero) alkyl, or heteroaryl (heteroaryl) alkyl, valence halo, cyano, nitro, OH, oxo, -SH, alkyl, (hydroxy) alkyl, (from alkoxy Each group) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, aryl (aryl) alkyl, heterocyclo ( Heterocyclo) alkyl, or heteroaryl (heteroaryl) alkyl, -OT11, -ST11, -C (O) (TH) -C (O) tT11, -OC (O) T11, T8C (O) Tennessee (T12) T11, -SO3H, -S (O) tT11, S (O) Tennessee (T12) T11, -T13 -NT11T12, -T13-N (T12) -T4-NT11T22, -T13-N (T11) -T12-T11 And -T13-N (T18) -T14-H; or

T8 and T9 are each independently a single bond, alkylene, alkenylene or alkynylene;

T11 is alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, aryl (aryl) alkyl, heterocyclo ( Hetero) alkyl, hetero aryl or (hetero aryl) alkyl;

T12 is halo, cyano, nitro, phosphorus OH, oxo, -SH, alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, ( Cycloalkenyl) alkyl, aryl (aryl) alkyl, heterocyclo (hetero) alkyl, or heteroaryl (heteroaryl) alkyl, -C (O) tH or -SO3H;

T13 and T14 are each independently a single bond, and -S (O) T -, -C (O) -, -C (S) -, -O-, -S-, -OC (O) -,-C (O) T- -C (=NT13)-or -C (O) -C (O) -;

Each case of T1-T14 is independently selected; and

t is 1 or 2.

Preferred compounds in this zone are those being hydrogen, deuterium, C1-8 alkyl, hydroxy alkyl, heterocycloalkyl, heteroalkyl, aryl, arylalkyl, or alkyl substituted with a group selected from SH, ST4, -C( O) th T6-NT8T9, -T11-C (O)-tT12 NT8T9 and T6-N (T5) T7NT8T9.

Compounds that are further hydrogen are preferably deuterium methyl, -CH2 (CH3) 2,-(CH2) 2 (CH3) 2, -CH (CH3) CH2 (CH3),-(CH2) OH, hydroxy,-(CH2) 2SCH3, -CH2SH, -phenyl, -CH2 (phenyl) -, -CH2 (p-hydroxy), -CH2 (indole),-(CH2) C (O) NH2,-(CH2) 2C (O) NH2, -(CH2) 2C (O) OH,-CH2C (O) OH,-(CH2) 4NH2,-(CH2) 3 (=NH) CNH2 or -CH2 (imidazole). Particularly preferred groups are -CH (CH3) CH2 (CH3), phenyl, phenyl alkyl or -CH2 (2-indole).

Alternative preferred methods and preferred compounds are among the compounds of the formula mob, its enantiomers, stereoisomers, pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof:

Chemical formula

include

remind

A is hydrogen, deuterium, C1-8 alkyl is heteroaryl, or aryl or alkyl heterosubstituted aryl, OH, SH, ST1, -C (O) th T3-NT5T6, -T8-C (O) tT9-NT5T6 or T3-N (T2) T4NT5T6;

R1 and R5 are independently C1-8 alkyl optionally substituted if valence permits;

R6 and R7 are independently hydrogen or C1-8 alkyl;

R8 is hydrogen, halogen, deuterium, C1-8 alkyl or C1-8 alkyl substitution;

Z is hydrogen, C1-8 alkyl, C alkenyl, C1-8 halo alkyl, cycloalkyl, aryl, aryl alkyl, heteroaryl, hetero-COR11, -CO2R11, -SO2R11, -S(O) R11 or -CONR9R10;

R9 is hydrogen,

R10 is C1-8 alkyl or C3-10 cycloalkyl; Aryl or aryl;

R11 is hydrogen, C1-8 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C3-10 aryl or C3-10 aryl alkyl.

T1 is alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, aryl (aryl) alkyl, heterocyclo ( Hetero) alkyl, hetero aryl or (hetero aryl) alkyl;

T2 and T3 are each independently a single bond, -T8-S (O) t-T9-, -T8-C (O) -T9-, -T18-C (S) -T9-, -T8-O-T9 Yes--T8-S-T9-, -T8-OC (O) -T9-, -T8-C (O) tT9-, -T8-C (=NT10) -T9- or -T8-C (O) -C (O) -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 and hetero (hetero) alkyl, or heteroaryl (heteroaryl) alkyl, valence halo, cyano, nitro, OH, oxo, -SH, alkyl, (hydroxy) alkyl, (from alkoxy Each group) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, aryl (aryl) alkyl, heterocyclo ( Heterocyclo) alkyl, or heteroaryl (heteroaryl) alkyl, -OT11, -ST11, -C (O) (TH) -C (O) tT11, -OC (O) T11, T8C (O) Tennessee (T12) T11, -SO3H, -S (O) tT11, S (O) Tennessee (T12) T11, -T13-NT11T12, -T13-N (T12) -T4-NT11T22, -T13-N (T11) -T12-T11 And -T13-N (T18) -T14-H; or

T8 and T9 are each independently a single bond, alkylene, alkenylene or alkynylene;

T11 is alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, (cycloalkenyl) alkyl, aryl (aryl) alkyl, heterocyclo ( Hetero) alkyl, hetero aryl or (hetero aryl) alkyl;

T12 is halo, cyano, nitro, phosphorus OH, oxo, -SH, alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkenyl, ( Cycloalkenyl) alkyl, aryl (aryl) alkyl, hetero (hetero cyclo) alkyl, or heteroaryl (heteroaryl) alkyl, -C (O) tH or -SO3H;

T13 and T14 are each independently a single bond, and -S (O) T -, -C (O) -, -C (S) -, -O-, -S-, -OC (O) -,-C (O) T- -C (=NT13)-or -C (O) -C (O) -; and

t is 1 or 2.

The more preferred method is / the compound is used /

A is hydrogen, deuterium methyl, -CH2 (CH3) 2,-(CH2) 2 (CH3) 2, -CH (CH3) CH2 (CH3),-(CH2) OH, hydroxy,-(CH2) 2SCH3,- CH2SH, -phenyl, -CH2 (phenyl) -, -CH2 (p-hydroxy), -CH2 (indole),-(CH2) C (O) NH2,-(CH2) 2C (O) NH2,-(CH2 ) 2C (O) OH,-CH2C (O) OH,-(CH2) 4NH2,-(CH2) 3 (=NH) CNH2 or -CH2 (imidazole).

A particularly preferred method is / the compound is used /

A is -CH (CH3) CH2 (CH3), phenyl, CH2 (phenyl) or -CH2 (2-indole).

Also, a particularly preferred method is / the compound is used /

R8 is S, and A is not provided. H. Hydrogen and the structure for carbons marked with *. Also preferred: R8 is provided for the deuterium and carbons marked with *, and is not H or deuterium S.

Another preferred method is / the compound is used /

R1 and R5 are both isopropyl; And/or R6R7and R9 are all hydrogen; And/or Z is CH2 (phenyl), -C (O) 2H or -C (O) 2C1-8 alkyl.

Illustrative Example (IV) of Formula I

All reactants can be used in commercially available, eg Compound 2 Oxchem Corporation, Illinois, USA in the following scheme X.

Plan X

Plan of Use X, 5 different products available for complex 2C and 2D from Aurora Fine Chemicals LLC, San Diego, USA, Sigma to different complexes, with different amino acids as inputs for Compound 2 above (for example, all reactants are commercially available Complex 2B is provided by Aldrich).

,

,

,

,

Structure IV in Scheme I, in section "Preparing Process", has the following [P3] symbol definitions [P3]: In Scheme I [P3] is a more general form of Scheme X above.

This structure is the final compound of the support can of IV, deuterated [P3] in chiral carbon (supports are shown abstractly), and in another example (S) in the above example, described by reaction [A, B , E1, E2, F] which have deuterate α carbon for secondary amines. And/or deuterate the α carbon number of carbonyl [EX4] ketone, using a pyrrolidine catalyst (available from Sigma-Aldrich) which is described by the reaction [Ex3-] and/or by the reaction do. And/or by descriptive reaction [yen], the carbon of SP3 is deuterate. And/or deuterate the aromatic and alkyl molecular weight components [R1, R2, Q1, Q2] by explanatory reactions. The deuterated compound IV structure(s) can be entered into the synthetic scheme I[P3], to create a deuterated isotopologue(s) with a support at the position of the undeuterated compound IV form compound(s) [P3] Is shown in the abstract. Alternatively, this objective can be explained by reaction, in the above-described embodiment, in deuteration to chiral carbon, in another position (S), to achieve the compound(s) in the form of structure III in scheme I [P3] [ A, B, P, E1, E2, F] deuterate α carbon for any secondary amine. And// structure III (of [P3]) is in the form of an amino acid due to the use of deuterate (non-limiting examples [AA1-AA6, B]) or by the methodology used to deuterate amino acids known to many technical fields. Amino acids Aldrich Cambridge isotope laboratory (eg, non-limiting), commercial sources, and facts available in Scheme I, deuterium digestion (and/or other isotopes, eg 13C and/or concentrated 15N) [P3] Example compounds of the present invention in isotopic production enriched. CDNLM-6806- (example non-limiting), for example, histidine from Cambridge Isotope Laboratories Inc. (13C, 15N, 2H cases (97-99%) incubation at each position of C, N and H in part number histidine) PK). Sigma-Aldrich Sales Channel (item number: 750158 Aldrich). Conduct a compound of the skeleton of heavy water digestion (concentration of other isotopes) [P3] (supports are shown in abstract), most preferably (>> 70% (13C) incorporation in the example {non-limiting} yes concentration non-natural abundance In 13C) there is a component in the present invention AS deuterium, that is from chiral carbon relates to a new composition in question. And in a non-limiting embodiment, they can be used in half, e.g., optionally, alone or in combination with a FDA and/or EMA-approved medicine(s) and/or treatment(s) in combination therapy or a combination licensed cancer treatment. remedy.

Yes (V)

Formula (V)

Molecular permutation of BTB06584. Listed by Markush structure and disclosed as pharmaceutically acceptable salts, solvates, hydrates and prodrugs, anticancer molecules thereof: Process/method of use as anticancer molecule is by the present invention Is disclosed. Singer permission: R1 is selected from the options of R1 (independently in each case of R1), X is selected from the options of X (independently in each case of X), and R2 is each independently (of the options of R2 For selected R2), R3 is selected from the options of R3 (R3 independently for each case), R4 is independently) for R4 for each instance of R4 (selected. Other embodiments, one or more phenyl groups One or more double bonds having are replaced by a single bond.In another embodiment, one or more phenyl groups are replaced each by substitutable substitutions such as phenyl, which is replaced by cyclohexane.Hydrogen atoms are not shown in this figure, but in other embodiments , Wherein one or more hydrogen atoms are replaced with deuterium In the above embodiment, isotopes that are replaceable at one or more sites.

Illustrative Example (V) of Formula I

BTB06584, and/or its analogs, deuterate heavy water [R1, R2, Q1, Q2] aromatic and alkyl molecular weight components, which can be explained by reaction. In addition, there is a great wealth of reactions that can deuterate their aromatic rings, and those of ordinary skill in the art will know the following. (Non-limiting) See, eg, [EX2]. (Non-limiting) For example, deuterated isotopologues (V) of formula (I) is a novel composition of this substance BTB06584, which is a component of the present invention, and in a non-limiting embodiment, optionally used alone or in combination in co-therapy Being deuterated by FDA and/or EMA approved cancer treatment, for example, as an anti-cancer treatment, medical(s) and/or approved treatment(s).

Yes (VI)

A method of treating a patient suffering from cancer by administration comprising these general formula (VI) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug comprising at least one effective amount of a compound or pharmaceutical composition(s) It is in the form of one or more compounds of formula (I) (VI).

Summary Formula (VI)

Embodiments of the invention relate to compounds having the following formula:

Formula (VI)

include

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein

Each QA is independently selected from N and CH;

QB are each independently selected from CH2 and NH;

M is independently selected from O, NH and CH2;

XA is independent at each point of use selected from 1, 2, 3, 4 or 5; XB is 3, 2, 1, 0 to 4 or 5, independent of each point of use of choice; L represents an independently selected 0-5 ring optionally substituted alkyl, substituted alkyl, deuterated alkyl, amino, thio, alkoxy, halogen, halo alkyl, halo alkoxy, or any atomic isotope (e.g., a singer ( Non-limiting) including hydrogen with OH, NH2, SH, SiH3, PH2, etc.) valence tolerance;

RA1 and RA2 are each independently selected from the group

과

and

RC and RD are each independently selected from hydrogen, halogen and alkyl, Re is hydrogen, or alkyl;

Ar ^ratio RB1, selected from hydrogen and deuterium;

The R ^B1 phenyl, benzyl, heteroaryl, pyridyl, pyridazinyl and optionally RB2 substituted with one or more substituents;

Each of the above R ^B2 halogen, alkyl, alkoxy, nitro, amino, methoxy and poly halogen alkyl;

Or R is phenyl of the ^non- formula:

RF and RG are hydrogen or alkyl, G is a carbon-carbon double bond or carbon-carbon single bond, where n, q is 0, or 0 or 1 with 0 or 1, q, G is double carbon- Carbon and bond, q is 1, G is carbon-carbon single bond,

Or RB is a chemical formula and diphenyl alkyl

The anti-RH1 and RH2 each independently represent each ring 1-5 optional substituent, and when each RH1 and RH2 are present, are independently selected at each point of time with hydrogen, L (defined previously) or halogen, p is 0 and 1 Or 2;

Or RB is

Wherein Q is CH or N, RJ and RK each independently represent any 1-5 substituents on each ring, and each of the above RJ and RK is independently (as previously defined) selected from L, a halogen, alkyl, Alkoxy, nitro amino alkyl and poly halogen.

In some embodiments, one or both RJ and RK are alkoxy, and this alkoxy group can be methoxy.

It will be understood that RA1 and/or RA2 are alkenyl residues with different substituents at positions RC and RD. Compounds of formula (VI) above, i.e., compounds will be understood that both cis or deemed can exist in trans isomer form. It is included in the scope. All isotopic forms (VI) of formula (I) are within the scope of the present invention.

Preferred embodiments of formula I (VI)

In the case of formula (VI), the symbols RC and RD described in subgroups RA1 and RA2 are hydrogen, halogen (preferably fluorine, chlorine or bromine) alkyl having 1 to 5, suitable "lower alkyl (currently defined herein)" Can be, for example, carbon atoms, such as methyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl groups, tert-butyl, pentyl, most preferably;

The residue RE can be lowered to hydrogen, or 1 to methyl, ethyl, propyl, butyl, pentyl, most preferably methyl, alkyl with 5 carbon atoms.

Subgroup RB may be hydrogen; Phenyl; Or substituted phenyl. Substituted phenyl groups may contain one or more of the preferred substituents at any position that is replaceable, but substituted mono at the 4-position of the phenyl nucleus is particularly preferred. Suitable substituents for the phenyl nucleus include halogen, preferably fluorine, chlorine or bromine; Containing alkyl, lower alkoxy lower and poly halogen, lower alkyl (eg substituted alkyl) alkyl moieties are 1 to 5 carbon atoms, particularly preferred, but methyl, methoxy and trifluoromethyl; With nitro and amino.

If the subgroup RB represents substituted pyridyl, substituted pyrimidyl, pyrazinyl or substitution, it may be located at one of the carbon atoms available in the nucleus of the assignment group or more, and may be the same or different. Substituents are preferred from lower alkyl or alkoxy (1), such as methyl, ethyl, butyl or low having 5 carbon atoms such as penty; Or methoxy, propoxy, butoxy or pentoxy.

Residues of RB represent substituted benzyl, and benzyl and phenyl residues can be substituted at one or more of the possible positions in its nucleus. Among the preferred substituents are halogens (preferably fluorine, chlorine or bromine), particularly preferably methoxy, the preferred alkoxy being most di- and tri-methoxy having 1 to 5 carbon atoms; Or, alkylenedioxy is appropriately crosslinked with other carbon atoms in the phenyl nucleus, such as lowering alkylenedioxy, such as methylene, ethylene, propylenedioxy, etc. Most preferably, the alkylenedioxy moiety is in the 3- and 4-positions of the phenyl nucleus. It is attached across and can be considered within the scope of the present invention.

Residues RF and RG are hydrogen, or 1 to 5 carbon atoms, most preferred, but can lower methyl group alkyl.

Independently of the group RH1 RH2 can be hydrogen or halogen, preferably fluorine, chlorine or bromine.

Preferred embodiments of formula (VI) are RC and RD methyl, RE is methyl, and RB is selected from chlorophenyl, methylphenyl, methoxyphenyl, trifluorophenyl, chlorophenyl, dimethoxybenzyl, trimethoxybenzyl, methylenedioxybenzyl and ethylenedioxybenzyl It is becoming.

In some embodiments, RB is a group

.

.

In some embodiments, RB is a group

RL and RM are each independently selected from halogen, alkyl, alkoxy, nitro, amino and poly halogen alkyl.

Synthesis of Structure of Formula I (VI)

To the synthetic route (VI) for an exemplary embodiment of Formula I, [P7] is incorporated herein by reference in its entirety. In one or more chemical enumerations/structures [P7], it is a component of the invention for use as an anti-cancer agent. Indeed, the method of treating a patient suffering from cancer by administering an effective amount of at least one compound from [P7] is surrounded by this example or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, or Contains one or more compounds from pharmaceutical composition(s) [P7].

Illustrative Example (VI) of Formula I

This example includes the use of a compound of formula (VI), the presence of a decoupler, and any compound(s) of any formula decoupling activity (F1F0 ATP synthometric change), for use in anticancer therapy.

Coupler drugs such as anticancer drugs

Enumeration of Formula IV exerts anticancer activity by reducing F1F0 ATP hydrolysis, such as inhibition. This example also exhibits anticancer activity by reducing F1F0 ATP hydrolysis. However, by suppression of F1F0 ATP hydrolysis, but F1F0 ATP hydrolysis is more efficient! F1F0 ATP hydrolysis, i.e. less ATP production, is hydrolyzed per proton motive force (PMF) is reduced. A common feature of these embodiments is that the function of cancer is impaired, and cancer risk is reduced by reducing F1F0 ATP hydrolysis. It relates to this example and discloses a method/use of a "coupler" drug(s) such as an anti-cancer treatment example (non-limiting) almitrin, which is a compound of formula (VI). Experimental data broadcast initiation Almitlin anti-cancer activity ( Fig . 7 to emit light).

Coupler drug modifies the ATP/O ratio without significantly changing the ΨIM, modifying the H+/ATP stoichiometry of the ATP synthase [113-116]. These drugs modify the forward and reverse modes of the symmetric ATP synthase: they make the forward and reverse modes less efficient (passing less synthetic ATP per proton) and more efficiently (more protons pumping per ATP). In other words, they reduce the (partial) ATP yield/cost of protons that pass ATP relative to the direction of the proton motive force (PMF) / energetically "downhill" or "uphill" synthase. In sequestering mitochondria, almitrin confers a reduction in F1F0 ATP synthesis and hydrolyzates up to 60% irrespective of how high the almitrin concentration is [114]. Almitrin can be doubled as required by ATP synthesis / hydrolysis / pumping / stoichiometric stoichiometry. F1F0 Almitrin reduces the amount of ATP that ATP synthically synthesizes, as well as the normally important F1F0 ATP synthase without Almitrin reduces the amount of ATP that hydrolyzes. Indeed, the present invention (in support of in vivo experiments, initiates new basic biological discovery, Figure 15 ): F1F0 ATP hydrolysis is not a practical and important bug, but not a function, for fever and homeothermy. Almitrin reduces ATP synthesis and hydrolysis, and these aspects remain largely within the cell [ATP] within offset and persistence limits. Almitrin inefficiency (fever) increases, but at the same time decreases inefficiency (fever). ATP's advancing mode may be good for normal cells, making less efficient synthetase [114], as this coupler action may be cancer cells, although this coupler action may affect cells with unbalanced high respiration [114], which is unbalanced cancer cells May affect. Although the separator makes the opposite mode of ATP more efficient synthetase, this task still shows anti-cancer activity against cancer using ATP synthase in reverse. The reason these cancers use this mode of inefficiency, allow high sugars to consume ATP, and PPP activate high flux [NADPH] low [ROS]. So, slowing down/reducing the hydrolysis of this F1F0 ATP shows anti-cancer activity. The same cancer can be disrupted by almitlin action in both forward and reverse modes of ATP synthase at different stages of the cell cycle.

In normal cells, almitrin reduces ATP synthesis, but ATP hydrolysis decreases, and so [ATP] remains. In cancer cells residing in hypoxia, there are already low OXPHOS rates that rely on high IF1 expression (many cancer overexpression IF1 and forced to survive [23-24]) and disproportionate ATP synthesis attacks ATP hydrolysis and drift [ATP] eggs It prevents the reduction of mithrination.

Comparative Figure 1 and (7) One observed it in a standardized NCI day dosing trial [16-17], almitrindimesylate (10 μM) chemistry, one of the most used chemotherapy in the Carboplatin FDA The therapy is approved, and the World Health Organization (WHO) essential medicines (in the list) exhibit more anticancer activity (10 μM). In addition, carbople latinalmitrindimesylate is less toxic than normal cells. In mice, carbopllatin = 118 mg/kg [117] and = 370 mg/kg of dimethylate for almitrin [118] for intraperitoneal injection (IP) LD50 (50% of mouse die tested).

In humans, oral almitrindimesylate has been tested for street sleep apnea in snoring at 200 mg per day [119]. Human oral almitrin dimesylate is often used for decades, reaching months to millions of patients with almitrin management for chronic obstructive pulmonary disease (COPD), from oral almitrin dimesylate to 200 mg per day Came [120, 121]. A dose of 200 mg single oral almitrin dimesylate renders an average plasma concentration of 286 ng/ml = 0.6 μM Cmax (70% oral bioavailability) [121]. Volumetric distribution of the distribution (VD) of aluminine 17 L = Because / kg[121] and human volume = 1 to L / kg[122] Corresponding aluminin tissue concentration (assuming uniformity) = (17 * 0.6) = exerted in NCI To test for anticancer activity, the concentration of almitrin is ~10 μM ( Figure 7 ). Almitrin is 50 ~ NG / ㎖ still has a long body life and 200 mg oral almitrin dimesylate, plasma almitrin] is retained after 24 hours [121] followed by a daily dose of 200 mg almitrindi mesylate compound Almitrin tissue concentration will drive >10 μM. Other studies [123] recorded Cmax as a mean plasma concentration, NG 379/mL, and posted a dose of 150 mg single oral almitrin dimesylate and a higher volume than the almitrin distribution. In clinical use of COPD, the plasma concentration of 300 ng/mL almitrin is directional [120], corresponding to the cancerous tissue concentration (μM ~ 10) of almitrin. An anti-cancer embodiment of the present invention is a non-limiting almitrin dose/formulation/composition/administration salt/pattern already used in humans (e.g., sequential mode of administration) (e.g., as reported in the literature). In addition, higher or lower dosages for anti-cancer treatment are altrim selective (no drug at all) and/or intravenous administration during the dismissal period is another embodiment of the invention. An embodiment of the invention is a method for performing an almitrin test as an anticancer agent in a human cancer patient without performing an almitrin phase I test or without testing almitrin in a healthy human subject.

Almitrin acts on the chemical receptor BK potassium channel in the body of the caratoid, reduces these [CO2], increases oxygenation of blood and tissues, and acts as a respiratory stimulant [125, 126]. Allows use at low doses of respiratory stimulation ROS ([Chimo/Radio] induces [O2] increases their [ROS] in blood and tissues, especially in combination with their reduction inducing the induction of additional anti-cancer effects in vivo Exerts side effects). Used to keep cells low in cancer cells Injured cancer cells F1F0 ATP hydrolysis Reduces amitrin [ROS] Synergy at the major stage(s) of the cell cycle, the highest priority in their "infinite replication potential" (hole mark of cancer [26 ]) That's dangerous. Almitrin may stop breathing and/or reduce oxygen supply to tissues (eg, lungs, breasts), which will be especially helpful for cancer. Embodiments of the invention use anti-cancer drugs in co-treatment with one or more FDA and/or EMA-approved drugs, fertilization stoichiometry (decoupler) that uses the synthetase ATP to almitrin, or other drug(s) In S), e.g., anti-cancer agent(s) and/or (IV) e.g. compound(s) of formula (I) herein, the invention is co-treated with other compounds in the Examples. Almitrindimesylate is also known as almitrin bismesylate or almitrin dimethanesulfonate. All pharmaceutical salts of almitrin are other drug(s) such as almitrin-raubasine complex aalmetrin, and are considered anti-cancer treatments.

When used chronically, it may have almitrin side effects [120]. A thirty-year national drug surveillance survey in France, representing millions of months of patients with almitrin therapy,[124], showed multiple years of use (average onset of adverse events = 11 months), weight loss during oral almitrin relapse (795) Case) and peripheral neuropathy (2,304 cases) [120]. These side effects were present in all patients and only a few of them were present, although they were classified as severe (<10%) [120]. Almitrin has never been FDA approved. Almitrin is now excluded from use in France, Portugal and Poland, which has been previously approved for treatment chronic obstructive pulmonary disease (COPD). Because of the withdrawal of these two side effects were possible because of the withdrawal of alternative treatments, because of the "approval efficacy data, including data that became available after the initial marketing authorization, which showed very limited clinical efficacy of almitrin in its approved indications" [ 120]. Although almitrin increases arterial oxygen partial pressure, this does not translate into significant clinical benefits for patients with chronic obstructive pulmonary disease [120].

Almitrin's anti-cancer activityAlmitrin, despite its surroundings since the early 1970s, was previously unknown to the present disclosure. Its anti-cancer activity is unexpected for people of art. The anti-cancer activity exerted by almitrindi mesylate (10 μM), shown herein by others, which has no anti-cancer activity in the same one dose in the public (10 μM) NCI-60 trial, especially because of another respiratory stimulant, doxapram. (!) Average% Cancer Growth Inhibition = -3.7% (Average = -2.3%), ie negative number showed cancer growth promotion, rather inhibition, no drug control, NSC: NCI-60 (10 μM) test From Doxapram 760347 to [16]. The discovery of almitrin confers anti-cancer activity, the technology for the invention of the present invention disclosed in the specification, and new components can be predicted by the user. The risk compensation axis for almitrin is sufficient for anticancer drugs. Most of the side effects of almitrin are caused by chronic use, especially when used heavily. The use of acute almitrin for the treatment of cancer is a risk other than the use of chronic almitrin for the treatment of chronic obstructive pulmonary disease, which is effective-compensation axis (2[120]), side effects of almitrin are mainly chronic This is because cancer can be an immediate life-threatening disease for too many patients, especially because cancer is an option that saves too little life. In fact, the benefits of the benefits of anti-cancer treatment are the risk of an almitrin dose of over 200 milligrams per day.

Almitrin intravenous delivery of 459 ± 155 mg within 24 hours after injection causes reversible lactic acidosis and liver dysfunction in 30% of 25 patients [127]. 70% of patients had other adverse and constant plasma lactic acid]. Side effects that correlate with poor liver function parameters are increased by increasing plasma bilirubin, prior to almitrin administration. Therefore, the impact cohort of this aspect is largely expected. NB female example: may have a small liver relative to the reference body size (most lateral effects were female, but all women were affected [128]). Liver transformation renders lactate [1] and lactate [1] which is unable to process plasma lactic acid, which may result in lactate[1] and damaged/overwhelming liver meatlin administration to glucose by the Cory cycle. An embodiment of the present invention selects the dose of almitrin in cancer patients dependent on liver function. That is, in other (non-limiting) examples, [Byrubin was evaluated by measuring plasma. For a non-limiting example (plasma bilirubin)> 17 μM) {patient should not be administered almitrin high dose (S)}. Patients with better liver function are less exposed to the risk of almitrin-driven lactic acidosis [127] and can withstand high almitrin doses. Another embodiment is recorded plasma lactic acid], and/or is administered in the course of administration of almitrin or almitrin in cancer patients, and low nigan function assay chemical(s) (non-limiting example bilirubin) Lean administration/frequency once these plasma concentrations are above. An embodiment of the invention is almitrin used, drug(s) / treatment (S) / treatment, anti-cancer treatment, relieve lactic acidosis. Another embodiment is an anti-cancer almitrin given by adjusting the dose dependent on the initial weight prior to treatment, and optionally reducing the dose if significant weight loss occurs. A high (ER) calorie diet and co-therapy Almitrin is another example such as chemotherapy. Drugs to be treated with anti-cancer drugs or co-therapy with relieving peripheral neuropathy (for example, non-limiting {} gabapentin, duloxetine, such as pregabalin) and almitrin are one embodiment of the present invention. Examples are examples of using almitrin for anticancer treatment and receiving almitrin on magnetic monitors, or for self-monitoring, especially for body weight, for weight loss and/or neuropathy signs and/or odd nerve sensations. For buy it. An example is the use of almitrin for chemotherapy under medical supervision. In the above formula, / supervised recommendation and/or the animal or human being administered by the medically qualified professional(s), or the amitrin dose, frequency, route of administration and duration, e.g. doctor or veterinarian or nurse Or pharmacist. In one embodiment, the oncologist is another oncologist or a medically qualified specialist with additional education and/or qualifications and/or permanent residency received in oncology with a human and/or veterinary degree or higher. Optionally, the one or more doses, frequencies, routes, and durations of the almrin administration are modulated by cancer progression/regression/congestion light during the almrin administration process.

Mechanical studies of animals [129-130] confirmed that the cause may not be self-almitrin itself, which is related to neuropathy but difluorobenzhydrylpiperadine (DFBP), which is a major metabolite of human amitrin in human formation. DFBP can also be a cause of weight loss [129] DFBP can also be a reference to aluminine related weight loss (report [120]) or it can be a function of strain feeding behavior only as a function of DFBP-producing pathology. To render DFBP from the bond between Almitrin and Almitrin nitrogen at atomic number 9, atomic number 11, carbon must be broken. In the embodiment of the present invention, the concentration of the altrin isotope is stronger, and the enrichment for the isotope atomic number 11 (15N) for atomic isotopes 9 to 13C (exceeds the natural abundance such as {non-limiting}, >70%) And/or as shown by reducing the rate of DFBP formation (by reducing kinetic isotope kinetic isotope effect (KIE) [25]). One (or more) of the atoms of a reactant is a change in the rate of a kinetic isotope effect (KIE) chemical reaction when substituted with its isotope. Heavy isotopes form strong bonds that require high energy to break them, ultimately slowing down the chemical reaction. Other atom(s) of their heavy and stable isotopic almitrin enrichment (S) (e.g., natural abundance exceeded, {non-limited}> 70%) (e.g., {non-limited} replaced by 1H in the second half) The present invention is a component. Dividing the DFBP, preferably on a piperazine ring, is especially because the above-mentioned isotopologue of Almitrin is replaced by one or more Almitlina, hydrogen atom(s), or fluorine (or other halogen) near the N11-C9 bond. . At least one of the compositions of the novel substance of the present invention, almitrin is a component of the present invention, for use in (e.g., non-limiting), e.g., humans for chronic obstructive pulmonary disease (COPD) and treating a corresponding condition. . It is used as an anti-cancer treatment.

The following reaction is not described as limiting, almitrin has deuterate the carbon of SP3, as described in deuterium number, by its reaction to the piperazine ring and/or other trajectories. And/or by explanatory reactions [R1, R2, Q1, Q2] which are widely deuterate to aromatic and alkyl molecular weight components. And/or by descriptive reactions [O1, O2] deuterate to a phenyl group is α- and β-carbon number. And/or by descriptive reactions [di]any amine deuterate is α- and β-carbon number. And/or by descriptive reaction [F, E1, E2, EX1] which deuterate grade amine α-carbon number. And/or by descriptive reaction [A, B, E1, E2, F] which deuterate secondary amine α-carbon number. Either option(s), solvent, temperature, pressure and other reaction conditions can and will be selected by those skilled in the art. Reaction time over large deuterium establishment: deuterium can be modulated by modulating the reaction time. One can perform multiple cycles of one or more of these reactions up to the desired level of deuterium incorporation, which is monitored by 1H and/or 2H NMR and/or mass spectroscopy.

A method for administering an effective amount of almitrin (and/or one of its metabolites), or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, or pharmaceutical composition(s) Included are inventions (and/or one or more metabolites), optionally co-treatment/combat cancer with other anti-cancer treatment(s) to treatment/improvement/prevention on the subject. Methods for administering an effective amount of GAL021 are included in the present invention [125-126] and/or [P8] of any compound(s) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, or GAL021 [125 to 126] and/or [P8] of any compound(s), including pharmaceutical composition(s), optionally is a co-treatment/combat cancer with other anti-cancer treatment(s) for treatment/improvement/prevention on the subject. Method of administering an effective amount of a respiratory stimulant(s) comprising a respiratory stimulant (e.g. a chemical receptor) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug or pharmaceutical composition(s) thereof (s invention) Lay siege), optionally with other anti-cancer treatment(s) on treatment/improvement/prevention on the subject/co-treatment/combat cancer. A pharmaceutical composition(s) comprising a method for administering an effective amount of a compound of (S) to increase the partial pressure of blood in a subject to be covered, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug or compound thereof (Increased oxygen partial pressure in the subject's blood)

The method comprises taking a subject, or is administered in a therapeutically effective amount of almitrin and/or other compound(s) of Formula VI, and treating, alleviating, preventing or combating cancer in the subject (and/or pharmaceutical Composition (S) comprising a therapeutically effective amount of almitrin and/or other compound(s) of Formula VI. Almitrin and/or other compound(s) of Formula VI (and/or pharmaceutical compositions contain almitrin and/or other compounds containing Formula VI) are used for cancer treatment/mitigation/prevention/combat. Almitrin, and/or other compounds in the manufacture of a medicament for the treatment and/or prophylactic treatment of cancer in the form of a selective ready-to-use pharmaceutical form, with the use of formula (S) of formula VI, optionally with a package of instructions for the use of anti-cancer agents do. Almitrin, and/or other compounds for use in methods of treatment/reduction/prevention/combating (S) of formula VI (S), cancer and/or ischemia and/or stroke (to reduce ATP hydrolysis and intracellular [ATP] O2 is a deficiency of blood vessel occlusion or similar in subjects due to glucose.

Definition (II) Used to specify formulas (I), (III), (IV), (V) and (VI)

The initial definition provided for a group or term applies to that group or term herein, individually or as part of another group not otherwise mentioned herein.

The term "alkyl" means a straight or branched chain hydrocarbon group having 1 to 21 carbon atoms, preferably 1 to 8 carbon atoms. The alkyl group is lowered, that is, the alkyl group having 1 to 4 carbon atoms is most preferable.

"Alkyl substituted as defined above having one, two, three, or four substituents selected from the group consisting of halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, keto (= 0) ORd The term "SRA, NRaRb, NRaSO2, NRaSO2Rc, SO2Rc, SO2NRaRb, CO2Ra, C (= O) Ra, C (= O) NRaRb, OC (= O) Ra, -OC (= O) NRaRb, NRaC (= O) Rb, NRaCO2Rb, = N-OH, = NO alkyl, aryl, heteroaryl, hetero and Ra and Rb are selected from hydrogen, alkyl, alkenyl, cycloalkyl, heteroaryl, and heteroaryl And Rc is selected from hydrogen, said alkyl, alkyl, cycloalkyl, heteroaryl and heteroaryl. When including substituted alkyl aryl, heterocyclo, heteroaryl, or cycloalkyl substituents, as defined below, as defined below, can eventually have zero four substituents (preferably 0 to 2 substituents), so the ring There is a system.

At least one of the substituents of substituted alkyl, meaning "alkyl" used with other groups, such as aryl alkyl, is a group specifically named. For example, the term aryl includes benzyl, or another straight or branched chain of alkyl having at least one aryl group linked to any point in the alkyl chain. As another example, the term kava wheat alcohol group containing-(CH2) N-NH-C (= O) alkyl, wherein N is 1 to 12.

The term "alkenyl" means a straight or branched chain hydrocarbon group having 2 to 21 carbon atoms and at least one double bond. Alkenyl groups having 2 to 6 carbon atoms and one double bond are most preferred.

The term "alkynyl" means a straight or branched chain hydrocarbon group having 2 to 21 carbon atoms and one or more triple bonds. Most preferred are alkynyl groups having 2 to 6 carbon atoms and 1 triple bond.

The term “alkylene” refers to a divalent hydrocarbon group having 1 to 21 carbon atoms, preferably 1 to 8 carbon atoms, for example {-CH2-} N, having a straight or branched chain hydrocarbon group having the above n is 1 to 12 , Preferably 1-8. Phosphorus alkylene group, lowering the alkylene group having 1 to 4 carbon atoms, is most preferred. The terms "alkenylene" and "alkynylene" as defined above refer to the divalent radical of the alkenyl group alknyl, respectively.

If the criteria consist of substituted alkyl, alkenyl or alkynyl groups, as defined above for alkyl groups, these groups are substituted with 1 to 4 substituents. Substituted alkylene, alkenylene or alkynylene may have a substituent of a ring attached in a spiro manner as in

Etc.

The term "alkoxy" as defined above having 1, 2 or 3 oxygen atoms (-O-) in the alkyl chain refers to an alkyl or substituted alkyl group. For example, the term "alkoxy" includes -O and -C1-6 alkylene-O-C1-6 alkyl, -C1-4 alkylene-O-C1-12 alkyl phenyl in groups and the like.

The term "thio" or "alkyl thio" means alkyl or substituted with an alkyl group as defined above having one or more sulfur (-S-) atoms in the alkyl chain. (CH2) -S-N CH2aryl--(CH2) N-S-aryl, etc. For example the term "thio" or "alkyl thio" includes groups

The term "amino alkyl" or "alkyl amino" as defined above having one or more nitrogen (-NR'-) atoms in the alkyl chain refers to an alkyl or substituted alkyl group. For example, the term "amino" includes groups such as -NR'-C1-12 alkyl and -CH2-NR' aryl (R' is hydrogen, alkyl or substituted alkyl and as defined above.") Amino" means group -NH2.

When used as in C1-8 alkyl, subscripts indicate the number of carbon atoms in which the group can be included. The use of a subscript is a bond, for example zero means a C0-4 alkyl bond or alkyl having 1 to 4 carbon atoms. When used with alkoxy, or amino thio refers to the number of carbon atoms that subscript groups may further include in the hetero atom. Thus, for example, 1 is. (CH2) 2-NH2, -NH-CH2-CH3, -CH2-CH3-NH2 and -N- (CH3) 2 -C1-2 amino alkyl include groups -CH2-NH2, -NH-CH3. The lower portion includes amino amino acids having 1 to 4 carbon atoms.

The alkoxy can be a thio alkyl, or an amino group monovalent or bivalent. By "pseudo" it means that this group has a valence, but that means that the group has two valences (ie, the power source combines with other groups) and "bivalent". A pseudo alkoxy includes groups such as -O-C1-2 alkylene-, whereas monovalent alkoxy, such as -O-C1-12 alkyl, -C1-6 alkylene-O-C1-6 alkyl Contains -C1-6 alkylene-O-C1-6 alkylene- etc.

The term "acyl" means carbonyl

Example of linking to an organic group

RD can be selected from alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, heterocyclo or heteroaryl, as defined herein above.

The term "alkoxy" means a group having a carboxy or ester group

That connects to radical organic,

In the above definition for acyl, it is RD.

The term "carbyl mill" refers to a functional group that is directly attached to a carbonyl, such as -NReC, to a nitrogen atom (= O) RF or Re and Rf can be hydrogen, -C (= O) NReRf, alkyl, Substituted alkyl, alkenyl, substituted alkenyl, alkoxy, cycloalkyl, aryl, heterocyclo or heteroaryl, or they may combine to form a ring.

The term "sulfo" refers to a sulfoxide side group (ie, -S(O) 1-2) linking the organic radical Rc as defined above.

The term "sulfone amide" or "sulfone" refers to the group -S(O) 2NReRf ash and RF as defined above. Preferred ashes and RFs are optionally heteroaryl or (as defined below) substituted heterosic ashes and the other of the RFs is hydrogen or alkyl.

The term "cycloalkyl" preferably means 3 to 7 carbon atoms, 9 (3) fully saturated and partially unsaturated hydrocarbon rings. The term “cycloalkyl” is such a ring (eg trifluoromethyl), alkenyl having 0 to 4 substituents (preferably 0 to 2 substituents) selected from the group consisting of halogen, alkyl, substituted alkyl. Keto, ORd, including substituted alkenyl, alkynyl, nitro, cyano, SRD NRdRe NRcSO2, NRcSO2Re, C (= O) H, acyl, -CO2H, alkoxy carbonyl, carbamil, sulfonyl, sulfonamide, -OC (=O) RD = N-OH, = NO alkyl, aryl, heteroaryl, heterocyclo, 4- to 7-membered carbocyclic ring and 5 or 6-membered ketal, for example Rc, RD and R6 Is the above definition and the 1,3-dioxolane 1,3-dioxane. The term “alkyl” also includes fused rings having a phenyl ring or having carbon to carbon bridges of 3 to 4 carbon atoms.

The terms "halo" or "halogen" mean chloro, bromo, fluoro and iodo.

The term "halo alkyl" means substituted alkyl having one or more halogen substituents. For example, "halo alkyl" includes mono, BI, and trifluoro methyl.

The term "halo alkoxy" means an alkoxy group having one or more halogen substituents. For example, "halo" contains OCF3.

The term "aryl" refers to phenyl, preferably phenyl, biphenyl, 1-naphthyl, 2-naphthyl, and anthracenyl. The term "aryl" is such a ring (eg, trifluoro methyl), alkenyl having 0 to 4 substituents (preferably 0 to 2 substituents) selected from the group consisting of halo, alkyl, substituted alkyl, ORd containing substituted alkenyl, alkynyl, nitro, cyano, SRD, NRdRe, NRdSO2, NRdSO2Rc, C (= O) H, acyl, -CO2H, alkoxy carbonyl, carbamil, sulfonyl, sulfonamide,- OC (=O) (RD), heteroaryl, heterocyclo, cycloalkyl, phenyl, benzyl, naphthyl, Rc, RD and R6 include the above definitions and the phenyl, phenyl oxy and phenyl thio. In addition, aryl, especially the two substituents attached to the phenyl group, is a joining fused or spiro ring capable of forming such a ring, for example, pentyl or hexyl or fused heterocycle or heteroaryl.

The term "heterocyclo" means a substituted or unsubstituted 7 to 11 membered bicyclic group having 7 to 11 membered bicyclic groups, and a 10 to 15 membered tricyclic group having at least one hetero atom selected from at least one of three non-aromatic rings. Rings O, S and N. The total number of heteroatoms in each ring is 4 or less, and may also include heteroatoms that may contain one or two oxygen or sulfur atoms of four nitrogen atoms provided by cognition and/or one. Each circular ring of a containing hetero group contains at least one carbon atom. The fused rings that complete the bicyclic and tricyclic groups can contain only carbon atoms, and can be partially saturated, unsaturated or saturated. Nitrogen and sulfur atoms can be oxidized arbitrarily and nitrogen atoms can be quaternized arbitrarily. Hetero groups can be attached to any available nitrogen atom or carbon atom. Heterocycles may contain 0 to 4 substituents (preferably 0 to 2 substituents) selected from halo, alkyl, substituted alkyl groups (e.g. trifluoromethyl), alkenyl, substituted alkenyl, alky Neil, nitro, cyano, keto, ORd, SRD,

NRdRe, NRdSO2, NRdSO2Rc, SO2Rd, C (= O) H, acyl, -CO2H, alkoxy carbonyl, carbamill, sulfonyl, sulfonamide, -OC (= O) RD = N-OH, = NO alkyl, aryl , 5 or 6 membered ketals to heterocyclo, for example 1,3-dioxolane 1,3-dioxane, or monocyclic 7 4 Rc, non-aromatic having 1 to 4 heteroatoms defined as Rd and ash Above the ring circle. The term “heterocyclo” also includes fused groups having phenyl rings or rings having carbon to carbon bridges of 3 to 4 carbon atoms, and the like. In addition, at this time, the hetero substituted with another ring, that is, aryl, aryl alkyl, hetero aryl, hetero aryl alkyl,

Cycloalkyl, cycloalkyl, hetero silver, or another hetero ring, these rings in turn, can be two substituted on one of the C0-4-alkyl substituted with halogen

Trifluoro methyl, alkenyl, alkynyl, nitro, cyano, keto (= 0), OH, O (alkyl), phenyl, benzyl oxy, SH, S (alkyl), NH2, NH (alkyl), N ( Alkyl) 2, NHSO2, NHSO2 (alkyl), SO2 (alkyl),

SO2NH2, SO2NH (alkyl), CO2H, CO2 (alkyl), C (= O) H, C (= O) alkyl, C (= O) NH2, C (= O) NH (alkyl), C (= O) N (alkyl) 2, OC (= O) alkyl, -OC (= O) NH2, -OC (= O) NH

(Alkyl), NHC (=0) alkyl, and NHCO2 (alkyl).

Exemplary monocyclic groups are azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl 2-oxopiperazinyl 2-oxopiperidinyl 2-oxopyrrolodinyl 2-oxoazepinyl, azepinyl, 4-piperidonyl, polyphenyl containing tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide,

thiamorpholinyl sulfone, etc. 1,3-dioxolan and tetrahydro-1,1-dioxothienyl. Exemplary bicyclic hetero groups include quinuclidinyl.

The term "heteroaryl" means aromatic 5 to 7 membered monocyclic group, 9 or 10 membered bicyclic group and 11 to 14 membered tricyclic group having at least one hetero atom selected from O, S and N Substituted or unsubstituted rings. Each ring of a heteroaryl group containing a hetero atom may contain a total of 4 or less hetero atoms in each ring and/or contain one or two nitrogen atoms or two oxygen or sulfur atoms provided in one And each ring has at least one carbon atom. Fused rings that complete bicyclic and tricyclic groups may contain only carbon atoms, and may be partially saturated, unsaturated or saturated. Nitrogen and sulfur atoms can be oxidized arbitrarily and nitrogen atoms can be quaternized arbitrarily. Heteroaryl groups that are bicyclic or tricyclic are one or more aromatic rings, but must contain completely different fused rings or the rings can be aromatic or non-aromatic. Heteroaryl groups can be attached to any available nitrogen or carbon atom of any ring. Heteroaryl ring systems may include halo, alkyl, substituted alkyl (e.g., trifluoromethyl), alkenyl, substituted alkenyl, alkynyl, nitro, cyano, ORd, four selected from the group consisting of SRD 4 substituents (preferably 0 to 2 substituents), zero, NRdRe is NRdSO2, NRdSO2Rc is SO2Rd, C is (= O) H, acyl, -CO2H, alkoxy carbonyl, carbamil, sulfonyl, sulfonamide is- OC is (= O) RD is heterocyclo, cycloalkyl, aryl or monocyclic 4 7-membered aromatic ring Rc, RD and R6 are the above definitions, and 4 heteroatoms such as phenyl, phenyloxy and phenylthio , Having one. Also,

Exemplary mono-cyclic heteroaryl groups include pyrrolyl, thiazolyl isoxazolyl, pyrazolyl, pyrazolyl, imidazolyl, oxazolyl

These are jolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, pyridazinyl, tria, etc.

Exemplary bicyclic heteroaryl groups, indolyl benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzoindolizinyl, pyrindinyl, benzofura Like Neil, chromonyl, coumarinyl, benzo, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, tetrahydro and include.

Exemplary cyclic heteroaryl groups include recommended zolyl, benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl families.

The term "unsaturated" is used when referring to a ring or group, or the ring group can be fully unsaturated or partially unsaturated.

The phrase “optionally substituted” is intended to include substituted or unsubstituted possibilities. Thus, the phrase “each group may be substituted for any group in which each group includes all substituted or unsubstituted groups.

The use of the phrase "atoms allowed" means that the group can be substituted with the degree and properties allowed by the valence of the group alone. This is generally understood by those skilled in the art. For example, the hydrogen substituent can not be further substituted, and the phenyl group can be directly substituted by the valence limit oxo group.

The term "amino acid substitution" means a group of the following formula: -NZ2Z3 Z2 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, (cycloalkyl) alkyl, morpholinyl, hetero or (hetero)alkyl, Z3 is hydrogen, When alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, alkoxy, thioalkyl, (cycloalkyl)alkyl or Z2 is hydrogen, Z3 is other than hydrogen, except that it is a carboxyl ester or carboxyl Hydroxy substituted with acid; Or Z2 and Z3 are pyrrolidinyl, 1-piperidinyl, 1-azepynyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-taken with the nitrogen atom to which they are attached 1-piperazinyl, 4-aryl alkyl-1-piperazinyl, 4-diaryl alkyl-1-piperazinyl; Or 1-pyrrolidinyl, 1-pigepi is alkoxy substituted with alkyl, alkyl thio, halo,

Available carbon atoms of the term "heterocyclo" or "hetero" are substituted with (C1-C4)-alkyl, aryl, (C1-C4) alkyl thio, (C1-C4)-alkoxy, monocyclic as above And bicyclic rings include halo, nitro, keto, cyano, hydroxy, azo, thia, amino, -NH- (C1-C4) alkyl, -N ((C1-C4) alkyl) 2, -CF3, ( aminoester) alkyl carboxylic acid, carboxylic ester, -OCHF2 or (C1-C4) is a substituent in which the two or three possible carbons substituted by the alkoxy carboxylic acid or mono cyclic and bicyclic ring are selected from methyl, Methoxy, methyl thio, halo, -CF3, nitro, hydroxy, amino and -OCHF2.

solid

These are contemplated (even may exist in the absence of asymmetric carbons) and those that may exist due to asymmetric carbons, including enantiomeric forms and diastereomeric forms, for example all stereoisomers of formula [X] within this range , invent. Individual stereoisomers of the compounds of the present invention may be substantially free of other isomers, for example, or as racemates or all other selections or other stereoisomers, for example, mixed. The chiral center of the present invention, as defined by the IUPAC 1974 recommendation, may have an S or R configuration.

Molecules presented in the detailed description and drawings of the present invention: all polymorphs, metabolic isotopologues geometric/stereoisomers, rotational isomers, rotational isomers, stereoisomers, optically active forms, tautomers, keto-enol tautomers, cis and Consider trans isomers, E and Z isomers, R- and S- enantiomers, diastereomers, (D)-isomers, (L)-isomers, their racemic mixtures, other mixtures and isotopic variants thereof (e.g. For example, any place in the molecule {S}) instead of hydrogen in some deuterium or within the scope of the present invention. It is intended that all such isomers as well as mixtures thereof are included in the present invention. As well as analogs and pharmacological/physiologically acceptable salts/ethers/esters/solvents/hydrates/chelates/complexes/metal complexes/mixtures/prodrugs/particles these/nuclides/derivatives/carriers/crystalline/liposomes. Unless otherwise specified, graphical representations of chemical structures and compounds include all stereoisomers herein. The substituent terms "Z" and "E" around the carbon-carbon double bond are designated to be the constituents of the above "Z" or "E" used in accordance with IUPAC standards. Structures showing double bonds include both "E" and "Z" isomers, unless otherwise specified. The present invention is not limited to any particular mechanism, but is administered to the understanding of the action of the agent.

In addition, the present invention is the isotope labeling compound of the present invention identical to those recited herein except for one or more atoms substituted by atoms having atomic mass or mass number and atomic mass or mass number different from those commonly found in nature. It includes. Examples of isotopes that can be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P Contains elements, 35S, 18F and 36Cl, respectively.

Salt, solvate, prodrug

Throughout the specification, their groups and substituents can be selected by those skilled in the art to provide stable residues and compounds.

Compounds of formula (I) are within the scope of the present invention [X] to form a salt. References to compounds of formula (I) are understood to include references to salts thereof [X], unless otherwise specified herein.

The term “pharmaceutically acceptable salt” as used herein refers to a compound (eg, acid or base) of the invention of a subject upon administration of a pharmaceutically acceptable salt to provide a compound of the invention or There are active metabolites or residues thereof. As known to those skilled in the art, “salts” of the compounds of the present invention can be derived from inorganic or organic acids and bases. For therapeutic use, salts of the compounds of the invention (physiologically acceptable, ie non-toxic) are considered pharmaceutically acceptable. However, amino acids and non-pharmaceutically acceptable base salts can also find use in the preparation, isolation or purification of pharmaceutically acceptable compounds, for example.

The term "salt(s)", as used herein, refers to acidic and/or basic salts formed with inorganic and/or organic acids and bases. Not only when both amphoteric ions contain all of the basic moieties of the compound [X] of the formula below, but not limited to amine or pyridine or imidazole rings, acidic residues, etc., but not limited to carboxylic acids ("internal salts") It can be formed and is included within the term "salt(s)" as used herein.

The salt of the compound of formula [X] can be formed, for example, by reacting the compound of general formula [X] with a medium such as one, for example in the amount of an acid or a base, in a salt precipitate or in an aqueous medium. Freeze dried.

It can form various salts of organic and inorganic acids that are not compounds of formula [X] containing basic moieties such as, and are limited to amine or pyridine or imidazole rings. Exemplary acid addition salts, adipates, alginate, ascorbate, aspartate, benzoate, sulfonate, bisulfates, borate, butyrate, citrate, camphorates, camphores (e.g. acetic acid or trihaloacetic acid, Cyclopentanepropionates, digluconates, dodecylsulfates, ethane, fumarate, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochloride, bromide (forming hydrogen bromide), maleate iodide , 2-hydroxyethanesulfonates, lactates (formed with hydrochloric acid) (formed with maleic acid),

It can form various salts of organic and inorganic bases that are not compounds of formula [X] containing the same acidic residues, limited to carboxylic acids. Exemplary basic salts include benzathines, dicyclohexylamines, hydrabamines [alkali metal salts such as ammonium salts, sodium and lithium, alkaline earth metal salts such as potassium salts, calcium and magnesium salts, salts with organic bases (eg organic amines) Recommended amino acids such as arginine, lysine and N, N-bis (dehydroabiethyl) ethylene diamine, N methyl D-glucamines, N-methyl-D-glucamide, t-butyl amine salts. Basic nitrogen-containing groups can be quaternized with lower alkyl halides (e.g. methyl, ethyl, propyl and butyl chloride, bromide and iodide), dialkyl formulations

Sulfates (eg dimethyl, diethyl, dibutyl and diamyl sulfate), long chain halides (eg decyl, lauryl, myristyl and stearyl chloride, bromide and iodide), aralkyl halides (eg benzyl and phen Netyl bromide) and the like.

Compounds of formula [X] and salts thereof, (as amides or imino ethers, for example) may exist in their tautomeric forms. All these tautomeric forms are contemplated herein as part of the invention.

In addition, the compound of formula [X] may have a prodrug form. Providing a bioactive agent of any compound to be converted in vivo (ie, a compound of Formula [X]) is a prodrug within the scope and spirit of the invention.

For example, the prodrug compound of formula [X] can be a carboxyl ester residue. Carboxylate esters can be conveniently formed by any esterification of carboxylic acid functional groups in the initiating ring structure(s).

Various forms of prodrugs are well known in the art. For examples of these prodrug derivatives, see:

H. Bundgaard from Enzyme Science, (Elsevier, 1985)] and methods, editorial volume) design of prodrugs. 42, P. et al. K. Aries, edited 309-396. egg. (Academic burden,

1985);

b) Krosgaard-Lassen and H. Bundgaard, Chapter 5 Textbook of Drug Design and Development, “Design and Application of Prodrugs” by H. Bundgaard, (P). 113-191 (1991);

C) H. Bundgaard, Advanced Drug Delivery Review, Vol. 8, P. 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmacy. (77), P. 285 (1988); and

E) N. Kakeya, et al. Etc., Phar Fire of Chemistry. 32, P. 692 (1984).

It should be understood that solvates (eg hydrates) of the compounds of formula [X] are also within the scope of the present invention. Methods of plum blossom are generally known in the art.

[X] Chelate metal complexes, mixtures thereof, radionuclides and formula liposomes are within the scope of the present invention.

dosage

As used herein, the term “effective amount” refers to the amount of a compound that favors a sufficient effect or results in a desired result. An effective amount can be administered in one or more dosage applications or dosages, and is not limited to a particular formulation or route of administration.

The effective amount of the compound of the present invention can be determined by one skilled in the art. The specific dosage level and frequency of administration for any particular subject may vary and will depend on various factors including the activity of the particular compound used, the metabolic stability and length of action of this compound, species, age, weight, and general health , Gender, subject, mode and administration time, excretion rate, diet of drug combinations, and severity of certain conditions.

Exemplary effective amounts of the compound of Formula [X] are milligrams/kg, preferably in the range of about 300 to about 0.001, preferably about 0.2 to 25 mg/kg (or about 50 mg/kg, more preferably about 0.5 to About 2000 milligrams, preferably about 5 1 to about 2500 mg, or about 2 to 4 divided daily doses on a single prescription per month. However, the compound used more accurately, depending on what conditions and their development/severity, route of administration (e.g. pulse or consistency, etc.) administered prior to other treatments or depending on the type of administration (e.g. chemotherapy, surgery, radiation therapy) Age, gender, condition, patient's previous/other diseases, i.e., the pharmacokinetics of the patient's compounds can be considered by the present invention in response to dose ranges and exception treatments, as they find the optimum and be changed during treatment can. The optimal dosage to be administered to a patient can be determined by the skilled artisan. If the compounds described herein are other co-administered agents, the effective amount may be less than if I was used alone.

Pharmaceutical composition

As used herein, the term “pharmaceutical composition” refers to a combination of active ingredients in which the composition for diagnostic or therapeutic uses in vivo has a particularly suitable carrier inert or active. Compound (s) of formula [X] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, additives and/or diluents.

As used herein, the term “pharmaceutically acceptable carrier” means phosphate buffered saline solution, water, emulsion, in a standard pharmaceutical carrier (eg, such as oil/water or water/oil emulsion), and various forms Wetting agent. The composition may also contain stabilizers and preservatives. For examples of airlines, stabilizers and supplements, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mac PUBL. Co., Eastern, Pennsylvania,. [1975].

management

The compound of formula [X] can be administered by any suitable means by which the conditions are treated. Oral, parenteral, enteral, infusion, injection, sublingual, topical, rectal, transdermal, intramuscular and inhalation eg. The compound can be delivered orally, in the form of tablets, capsules, granules, fine granules, pellets, softgels, powders, or liquid formulations including syrups, liquids, solutions, elixirs, suspensions, emulsions or magma; Sublingual; Narrowly; Transdermal; Such as sterile injectable aqueous or non-aqueous solutions or suspensions, eg subcutaneously, intravenously, intramuscularly or intrasternalally by injection or infusion; Nasal phase by inhalation spray; Rectal, etc. in the form of suppositories; Or liposomes. Non-toxic containing unit dosage forms, phosphorus pharmaceutically acceptable excipients or diluents can be administered. The compound can be immediately released or administered in a form suitable for sustained release. Rapid release or sustained release can be achieved by subcutaneous implants or devices, especially in the case of sustained release, by an appropriate pharmaceutical composition or by an osmotic pump.

Examples of compositions for oral administration include suspensions, such as bulk, alginic acid or sodium alginate suspensions, as viscosity enhancers, which may impart methyl microcrystalline ad cellulose sweeteners or flavoring agents such as those known in the art; Antimicrobial tablets that may contain microbial cellulose, dicalcium phosphate, starch, magnesium stearate and/or other known agents in the art, such as, for example, microcrystalline cellulose, dicalcium phosphate, and/or other excipients, binders, extenders, disintegrants, diluents and lubricants. Compounds of the invention can be delivered orally sublingually

Cosmetic examples and/or oral administration, compressed, or lyophilized tablets. Examples of compositions may include fast dissolution diluents such as mannitol, lactose, sucrose, and/or cyclodextrin. It can also be a high molecular weight excipient such as cellulose (AVICEL®) or polyethylene glycol (PEG). Excipients included in these formulations are hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC) ), and/or maleic anhydride copolymers (eg GANTREZ®) to aid mucosal adhesion; Controlled release agents such as polyacrylic copolymers (e.g. CARBOPOL 934®). Lubricants, lubricants, fragrances, colorants and stabilizers can be added for ease of manufacture and use.

Examples of compositions for nasal aerosol or inhalation administration may include, for example, benzyl alcohol or other suitable preservatives, solutions, absorption to improve absorption and/or bioavailability and/or other solubilizers or dispersants as known in the art. Contains accelerators.

Examples of compositions for parenteral administration may contain mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or suitable non-toxic injection solutions or suspensions, e.g. parenterally acceptable diluents or solvents Other suitable dispersants or wetting agents include the synthesis of mono- or diglycerides and topical agents, including fatty acids, including oleic acid.

Examples of compositions for rectal administration are solids at room temperature but may contain liquefied and/or released soluble in the rectal cavity, for example suppositories, including suitable non-polar excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycol drugs.

Joint management

The term “co-administration” as used herein refers to the administration of at least two agent(s) to a subject (eg, a compound of the invention) or a therapeutic agent. In some embodiments, co-administration of two or more agents/therapies is simultaneous. In another embodiment, the first agent/treatment is administered prior to 2 agents/treatment. Those skilled in the art understand that the formulation and/or route of administration of the various formulations may vary. The appropriate dosage for simultaneous administration can be readily determined by one skilled in the art. When the agent/treatment is administered simultaneously, in some embodiments, each agent/treatment alone is administered at a lower dosage suitable for that administration. therefore,

Citing a patent or patent application

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[P2] Ding C, Hamann L, Stein P, Pudzianowski A, inventors; Ding Charles Z., Hamann Lawrence G., Stein Philip D., Pudzianowski Andrew T., assignee. Benzodiazepine inhibitors of mitochondial F1F0 ATP hydrolase and methods of inhibiting F1F0 ATP hydrolase. US patent application US 10/461,736. 2003 June 13.

[P3] Hamann LG, Pudzianowski AT, inventors; Bristol-Myers Squibb Company, assignee. N-substituted phenylurea inhibitors of mitochondrial F1F0 ATP hydrolase. U.S. Patent US 6,846,836. January 25, 2005.

[P4] Glick GD, inventor; University of Michigan, assignee. Methods and compositions for treating diseases and conditions associated with mitochondrial function. US patent application US 11/726,219. November 2009 5.

[P5] Glick G, inventor; University of Michigan, assignee. Methods and compositions for treating diseases and conditions associated with mitochondrial function. US patent application US 11/110,228. 2005 December 8.

[P6] Ding CZ, Atwal KS, inventors; Bristol-Myers Squibb Company, assignee. Sulfonamido substituted benzopyran derivatives. United States patent US 5,869,478. 1999 February 9.

[P7] Regnier G, Canevari R, Laubie M, inventors; En Nom Collectif Science Union, Medicale Rech France, assignee. S-triazine compounds. U.S. Patent US 3,647,794. 1972 March 7.

[P8] Dax SL, Woodward R, Peng S, inventors; Galleon Pharmaceuticals Inc, assignee. Compounds as respiratory stimulants for treatment of breathing control disorders or diseases. U.S. Patent US 9,351,972. 2016 May 31.

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Claims (33)

ㅏ A compound or composition contains at least one compound of the following formula:

Or a salt, solvate, hydrate or prodrug for use in, or for use in, a method for improving, preventing, or combating cancer by treatment in a method of treating a disease or condition selected from a pharmaceutically acceptable thereof.
(I) many cancers of glucose and/or glutamine metabolism with cancer lactic acid, for example cancers that can be distinguished from surrounding tissues by, for example, the Warburg effect and/or PET imaging (eg 18F-FDG PET);
(Ii) cachexia or cancer driven cachexia; remind
Ar-shaped ^A1 and RA2 are each independently selected from the group

and

RC and RD are each independently selected from hydrogen, halogen and alkyl, Re is hydrogen, or alkyl;
Ar ^ratio RB1, selected from hydrogen and deuterium;
R ^B1 phenyl, benzyl, pyridyl, pyridazinyl, and optionally RB2 substituted with one or more substituents;
Each of the above R ^B2 halogen, alkyl, alkoxy, nitro, amino, methoxy and poly halogen alkyl;
Or R is phenyl of the ^non- formula:

RF and RG are hydrogen or alkyl, G is a carbon-carbon double bond or carbon-carbon single bond, where n, q is 0, or 0 or 1 with 0 or 1, q, G is double carbon- Carbon and bond, q is 1, G is carbon-carbon single bond,
Or RB is a chemical formula and diphenyl alkyl

RH is hydrogen or halogen, and p is 0, 1 or 2;
Or RB is

The RJ and RK each independently represent any 1-5 substituents on each ring, and each of the RJ and RK angles currently selected from halogen, alkyl, alkoxy, nitro, amino and poly halogen alkyl.
RB is a compound according to group 1 or a composition for use:

RB is a compound according to Group 2 or a composition for use:

RL and RM are each independently selected from halogen, alkyl, alkoxy, nitro, amino and poly halogen alkyl.
The compound or composition according to claim 3, wherein RL and RM are each independently selected from halogen.
In use, the compound or composition has the same RL and RM as in claim 3 or 4.
RL and RM are respectively F. for the use of a compound or composition according to claim 3 above,
The compound or composition according to any one of claims 1 to 6, wherein RA1 and RA2 are each selected from an independent group.

The RC and RD are each independently selected from hydrogen, halogen and alkyl.
RA1 and RA2 are the same according to claim 7, wherein the compound or composition used.
The compound or composition for use characterized in that RC is hydrogen, according to claim 7 or 8.
RD is hydrogen and the compound or composition according to any one of claims 7 to 9, which is used.
The compound is a compound according to claim 1 or a composition for use:

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
The compound isotopologue(s) using the compound or composition according to claim 1:

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
Compounds having the formula,

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein
L is alkyl, or deuterium, or substituted alkyl, or deuterated alkyl, or amino or thio alkyl or alkoxy, halogen, or halo alkyl, or halo, or any atomic isotope is allowed to exclude natural abundance or hydrogen atoms;
R1 is hydrogen, cyano, -SO2R8, -C (= O) R9, heteroaryl or thiazolyl;
R2 is (i) independently hydrogen, alkyl, benzyl or substituted alkyl, or (ii) hetero3 formation with R3;
R3 is independently alkyl, substituted alkyl thio, amino alkyl, carbamyl, BB aryl, BB-hetero, BB heteroaryl, or BB cycloalkyl, or (ii) phenyl optionally C1-4 alkyl, halogen, trifluoro methyl Substituted (i), phosphorus OCF3 is cyano, nitro, amino, hydroxy or methoxy, or (iii) optionally having independently, C1-4 alkyl thio, amino, -BB aryl, hetero-BB-, BB R3a selected from cycloalkyl, and -BB heteroaryl is one selected from three substituents; And/or R2 in these fused or (IV) having a 5 or 6-membered carbocyclic ring together with an optionally substituted alkyl or substituted heteroalkyl;
BB is C1-4 alkyl, C2-4 alkenylene, substituted C1-4 alkyl, substituted C2-4 alkenylene bond, substituted C1-4 alkyl-C (= O) NH-, -C (= O) NH-, -C1-4 alkylene-C (= O) NH-, -C (= O) NR19-, -C1-4 alkylene-C (= O) NR19- or substituted C1-4 alkyl-C (= O) NR19-,-(CHR14) M- (CR15R16) N- or-(CHR14) pC (= O) NH-;
In each case R3A is independently selected from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, keto, trifluoromethyl, -NR17R18, -SR17, -OR17, -SO2R17a, -SO2NR17R18, -NR17C (= O) R18, -CO2R17 -C (= O) R17 R3a is cycloalkyl, aryl, heterocyclo or heteroaryl, cycloalkyl, arylheterocyclohetero, heteroaryl is optionally substituted with alkyl or alkyl substituted Cyclo alkyl, arylhetero cyclo, and hetero aryl;
Z is, for example, heteroaryl for an optionally substituted heterobicyclic; or
Z is optionally substituted with two R7 substituents, one substituted with R7 substituents, or imidazolyl and/or once substituted with any R7 substituents, fused to a benzene ring
R7 is alkyl, carbamill, or substituted alkyl;
In each case, R4 is independent of each other from the group consisting of halogen, trifluoromethyl, OCF3, alkyl, substituted alkyl, halo, nitro, cyano, halo, OR25, SR25, NR25R26, NR25SO2R27, SO2R27, SO2NR25R26, CO2R26, C Selection of R4 (= O) R26, C (= O) NR25R26, OC (= O) R25, -OC (= O) NR25R26, NR25C (= O) R26, NR25CO2R26, aryl, heteroaryl, heterocycloalkyl and ;
R8 is C1-4 alkyl or phenyl optionally substituted with alkyl, halogen, haloalkoxy, cyano, nitro or trifluoro methyl;
R9 is -NR10R11 is alkyl, substituted alkyl, alkoxy, alkyl thio, cycloalkyl is aryl heteroaryl, heterocyclo, or -CO2R12 is alkyl or phenyl is halogen, cyano, trifluoromethyl, nitro, nehydroxy , Substituted with C1-4 alkoxy, halo, C1-6 alkyl, CO2 alkyl, SO2 alkyl, SO2NH2, amino, NH (C1-4 alkyl), N (C1-4 alkyl) 2, NHC (= O) alkyl , C (= O) alkyl, and/or optionally substituted with one of three C1-4 alkyl trifluoro methyl, hydroxy, cyano, phenyl, pyridinyl; And/or alternating 5 or 6 membered hetero aryl or optionally heterocycloketo substitution or fusion having a benzene ring thereto or
a) C1-4 alkyl, optionally substituted with either:
Iii) SR13, OR13, NR13aR13b, halogen, trifluoromethyl, CO2R13a and C (=O) NR13aR13b;
Ii) said phenyl alkyl optionally substituted with C (=O) H, C 1-4 acyl, alkenyl, carba do one substitution, and/or halogen;
Iii) phenyl or halogen, nitro, amino, alkyl, two or one substituted naphthyl having a hydroxy number fused to a C1-4 alkoxy, or a 5 or 6-membered hetero;
Iv) having a 5-6 membered carbocyclic ring fused to a dienyl, thiophenyl, furanyl, tetrahydrofuranyl, or azepinyl, optionally substituted alkyl or optionally keto or C1-4 alkoxy
b) a 3-6 membered cycloalkyl optionally has a tetrasubstituted group in turn selected from alkyl, halogen, cyano group, alkenyl, acyl, alkyl thio, carbamyl, phenyl substituted with halogen; Or having aryl fused to it
c) Phenyl is halogen, cyano, trifluoromethyl, nitro, four substituted hydroxy, C1-4 alkoxy, halo, C1-4 alkyl, CO2 alkyl, SO2 alkyl, SO2NH2, NH (C1-4 alkyl), N (C1-4 alkyl amino) 2 NHC (= O) alkyl, C (= O) alkyl, and/or optionally substituted with one of three C1-4 alkyl trifluoro methyl, hydroxy, cyano, phenyl, pyridinyl; And/or keto or optionally a benzene ring, which in turn has a conjugation with a half-membered heteroaryl or heterocycle;
D) phenyl substituted with two of pyridinyl, thiazolyl, furanyl, thiophenyl, pyrrolyl and halogen, alkyl, in turn d) halogen or trifluoro substitution;
R10 and R11 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocycloalkyl, aryl, heteroaryl or C1-4 alkyl wherein (I) is optionally substituted with two -CO2 alkyl, -C (=O ) NH (aryl), NH (aryl) cycloalkyl, phenyl, optionally C1-4 alkyl, hydroxy, C1-4 alkoxy, halogen, amino, nitro, tetrahydro sequentially substituted phenyl, and/or 5 or 6-membered hetero Or a 5 or 6-membered heterocyclic fused to it; Keto optionally substituted pyrrolidinyl; Naphthyl, anthracenyl, pyridinyl, thiophenyl, furanyl, imidazolyl, benzimidazolyl, indolyl or turn optionally substituted with C1-4 alkyl or C1-4 alkoxy; Or (ii) formed together with hetero or hetero hetero R10 and R11 selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, tetrahydropyridinyl and imidazoilidinyl, optionally keto, CO2H, C14alkoxy, CO2alkyl, C1-4 cover mill benzyl two are substituted; Phenyl in turn is optionally substituted alkyl, halogen or C1-4 alkoxy; Tetrahydropyridinyl in turn optionally substituted with keto and/or phenyl; Alkyl is substituted with amino or NHR21 wherein R21 is an alkyl group which may be substituted with alkyl or phenyl; And/or the benzene ring is fused to C1-4 alkoxy, CO2 alkyl, and/or C1-4 carbamill, which in this case is again optionally substituted with two alkyl; Alkyl is substituted with amino or NHR21 wherein R21 is an alkyl group which may be substituted with alkyl or phenyl; And/or the benzene ring is fused to C1-4 alkoxy, CO2 alkyl, and/or C1-4 carbamill, which in this case is again optionally substituted with two alkyl; Alkyl is substituted with amino or NHR21 wherein R21 is an alkyl group which may be substituted with alkyl or phenyl; And/or the benzene ring is fused to C1-4 alkoxy, CO2 alkyl, and/or C1-4 carbamill, which in this case is again optionally substituted with two alkyl;
R12 and R19 are hydrogen or alkyl;
R13 is hydrogen or alkyl;
R13a and R13b are selected from hydrogen, alkyl and aryl;
In each case R14, R15 and R16 are independently selected from hydrogen, alkyl, hydroxy, hydroxy C, C1-4 alkoxy and phenyl, and/or one of R15 and R16 is one 3-6 membered cycloalkyl group Are joined together to form;
R17 and R18 are independently selected from phenyl or benzyl hydrogen, alkyl, substituted alkyl, aryl, phenyl or benzyl, optionally substituted with alkyl, hydroxy, or hydroxy;
R17a is alkyl or substituted alkyl;
R25 and R26 are independently taken together to form hydrogen, alkyl or substituted alkyl, or heterocyclo or heterocycle;
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.
The compound according to the formula 13

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 above.
The compound according to the formula 13

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein
The enantiomeric excess (EE) of the silver R stereoisomer is greater than 70%;
The compound according to the formula 13

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein
The enantiomeric excess (EE) of the S stereoisomers is greater than 70%;
The compound according to any one of 13 to 16 above,

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) hetero3 formation with R3;
R3 (ⅰ) independently selected
One substitution for both hydroxy alkyl and alkoxy (a);
(b) substitution with alkyl thio, amino alkyl or hydroxy or alkoxy;
(C) -A1 aryl, characterized in that aryl is optionally substituted with up to four alkyl substituents, substituted alkyl, halogen, haloalkoxy, cyano, nitro, -NR17R18, -SR17, -OR17, -SO2R17a, -SO2NR17R18 -NR17C (= O) R18, -CO2R17, -C (= O) R17, having alkyl, aryl, heterocyclo, heteroaryl, and/or 5 or 6-membered cycloalkyl rings fused to it
(d) Heteroaryl is N, O, and S, or a 5 or 6 membered monocyclic ring having 1 to 3 heteroatoms selected from 8-9 membered bicyclic ring systems having one or more aromatic rings and 1- Four hetero atoms selected from N, O and S of at least one of the A2 hetero rings may be heteroaryl substituted with halogen. Alkyl, alkoxy carbonyl, sulfonamide, nitro, cyano, trifluoromethyl, alkyl thio, alkoxy, keto, -C (= O) H, acyl oxy, hydroxy, hydroxy alkyl, phenyl or optionally substituted Alkyl or substituted alkyl;
(e) a hetero-A2-and/or benzyl and/or crosslinked group wherein said hetero is optionally substituted with one group selected from alkyl, keto, hydroxy, hydroxy alkyl, -C (= O) H, acyl, CO2H, alkoxy phenyl groups Carbon chain or fused benzene ring joins it;
(f) the alkyl is substituted with one or two groups selected from substituted alkyl, keto, -C (=O) H, acyl, CO2H, alkoxycarbonyl, and/or having benzyl and/or crosslinked carbon Features-A2 cyclo alpha carbon ring or fused benzene ring is bonded to it; or
(II) together with R2 form hetero;
In each case, R4 is independently R4 selected from the group consisting of halogen, alkyl, halo alkyl, cyano and halo;
Further, R7a, R7b and R7c are independently selected from hydrogen, alkyl, carba mill, or carba mill alcohol, or, in addition, R7a and R7c form this aryl or heteroaryl silver,
R8 is alkyl, aryl, or aryl;
R9 is -NR10R11 is alkyl, substituted alkyl, alkoxy, alkyl thio, cycloalkyl is aryl heteroaryl, heterocyclo, CO2R12, or phenyl is halogen, cyano, trifluoromethyl, nitro, hydroxy, C1-4 Alkoxy, haloalkoxy, C1 four one substituted -6alkyl, CO2alkyl, SO2alkyl, SO2NH2, amino, NH (C1-4 alkyl), N (C1-4 alkyl) 2, NHC (= O) alkyl, C (= O) alkyl, and/or any trifluoro methyl, hydroxy, cyano, phenyl, pyridinyl 3 substituted with C1-4 alkyl; And/or keto or optionally a benzene ring having a substituted alternating 5 or 6 membered heteroaryl or heterozygote;
R10 is independently hydrogen, alkyl or alkoxy; and
R11 is independently hydrogen, alkyl, substituted alkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl; or
R10 and R11 optionally R10 and R11 groups form an alkyl, keto, CO2H, alkoxycarbonyl, hydroxy, alkoxy, alkyl, carbamill, aryl, or substituted alkyl, substituted heterocyclo or heteroaryl containing a phenyl ring Together the phenyl ring is optionally substituted with alkyl, halogen, and alkoxy 12:58;
R12 is hydrogen or alkyl;
A1 is-(CHR14) mV- (CR15R16) N- or-(CHR14) P- (C = O) NH-;
A2 is-(CHR14) mV- (CR15R16) N;
V is an S or -NR22- bond;
In each case R14, R15 and R16 are independently selected from hydrogen, alkyl, hydroxy, hydroxy C, C1-4 alkoxy and phenyl, and/or one of the R16join of R15 together with 3 to 6 membered cycloalkyl Form;
R17 and R18 are independently selected from hydrogen, alkyl, phenyl and benzyl, where phenyl and benzyl are optionally substituted with alkyl, hydroxy, or hydroxy;
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.
In the compound having the 17th formula,

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein
Further, R7a, R7b and R7c are independently hydrogen, alkyl, carbamill or carbamill C1-4 alkyl forming a fused phenyl ring, or, R7a and R7c are also selected to participate;
R23 is selected from hydrogen, alkyl, hydroxy alkyl, or phenyl;
R24 is selected from alkyl, halogen, trifluoromethyl, cyano, halogen, hydroxy, OCF3, methoxy, phenyl oxy, benzyl oxy, cyano, acyl, and 2 R24 groups form fused cycloalkyl or benzene rings Being and
X 0, 1 or 2; and
Y is 0, 1, 2 or 3.
Compound with structure

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein
The enantiomeric excess (EE) of the S stereoisomers exceeds 70%.
Compound with structure

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein
The enantiomeric excess (EE) of the silver R stereoisomer exceeds 70%.
Pharmaceutical composition comprising one or more of the compounds of any one of 13-20 pharmaceutically acceptable carrier or diluent.
A compound according to any one of claims 13 to 20, or according to claim 21 for use in a method of treatment of a human or animal body by treatment.
Compound according to any one of claims 13-20, or according to the pharmaceutical composition according to claim 21, for use in the method, relieve treatment, prevent or combat the disease or disorder selected from claim 21
(I) many cancers of glucose and/or glutamine metabolism with cancer lactic acid, for example cancers that can be distinguished from surrounding tissues by, for example, the Warburg effect and/or PET imaging (eg 18F-FDG PET);
(Ii) cachexia, cancer cachexia or weight loss driven;
(Ⅲ) (e.g., 2,4-dinitrophenol), infection, sepsis, stroke, fever, fever, hyperpyrexia, high fever, malignant high fever, nerve intake, high environmental temperature is higher than normal body temperature Or disorders, serotonin syndrome, thyroid storms, heatstroke, thermoregulatory disorder(s), Kawasaki syndrome, hyperthermia due to drug or withdrawal symptoms, unusual drug reactions, fever of unknown or uncertain origin, incompatible blood agent(s) Response to, metabolic disorder(s) cancer, injury;
(IV) Tumor-associated phagocyte (Tech Account Manager) or macrophage activation syndrome (MAS), phagocytic disease or disorder such as HIV, AIDS, HIV-related neurocognitive disorder (hand), HIV-related cancer, AIDS-defined cancer, non-AIDS Defining cancer;
(V) Neuroinvasive virus through macrophages, as used by HIV and SARS coronavirus, for example,
(VI) neurocognitive or neurodegenerative diseases/diseases, for example, for those caused by viruses;
(VII) Acute or chronic systemic inflammation or inflammatory disease / disorder / syndrome or autoinflammatory disease / disorder / syndrome or autoimmune disease / disorder / syndrome;
(Iv) lower or more desirable metabolic/bio-energy efficiency of the subject, or lower or lower physical or mental performance or lower or lower than desired weight compared to desired;
(IX) Deep circulatory hypothermia, a disease by conferring hypothermia on the subject for several medical or other purposes, which may include slowing down the rate of chemical reaction(s) to the subject for therapeutic effect/minimizing brain and/or tissue damage Or disease treatment cardiac and/or cardiovascular surgery and/or brain surgery (neurosurgery) surgery, hypothermia for the purpose of surgery, arrest for hypothermia, emergency preservation and resuscitation (EPR), eg, limbs and/or organs (poem) Long-term storage and/or transplantation of body parts, such as separate preservation temperature management targets, protective hypothermia, therapeutic hypothermia, neonatal brain disease, birth suffocation, bleeding, hypovolemia, hypothermia for decompression sickness, skin burns, inflammation, Burn injury(s) including allergic reactions anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, oxygen deficiency, anemia, hypervolemia, altitude sickness, airway obstruction, asthma attacks, body/tissue/organ, hypoglycemia, Hypoxia (ischemia-reperfusion injury) on reperfusion injury, ligature or tourniquet at release, uremia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (e.g. For meningitis), sepsis, septic shock, ischemic brain / heart / kidney damage, nerves and / or / cardiac protection and / or tissue protection during stroke and / or ischemia and / or heart attack and / or resuscitation and / or subject Where in the flow poor blood after period(s); ligature or tourniquet, uremia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, asthma attack, body/tissue/organ, hypoglycemia, reperfusion following release of major trauma Hypoxia, (in ischemia-reperfusion injury), injuries, infections, bacterial and/or viral infection(s) (e.g. meningitis) after stroke and/or ischemia / during, sepsis, septic shock, ischemic brain / heart / kidney Damage, nerves and/or Heart protection and/or tissue protection/or heart attack and/or resuscitation and/or poor blood flow to the subject where period(s); ligature or tourniquet, uremic syndrome, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major Hypoxia, asthma attacks, body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), infection, bacterial and/or viral infection(s) (e.g. meningitis) stroke and/or following trauma release Post ischemic/medium, sepsis, septic shock, ischemic brain/cardiac/kidney damage, nerve and/or heart protection and/or tissue protection/or heart attack and/or resuscitation and/or poor blood flow to the subject where period(s) ); Bacterial and/or viral infection(s) (e.g., meningitis), sepsis, septic shock, stroke and/or ischemia and/or post-cardiac ischemic brain/cardiac/kidney injury, nerve and/or heart during Protection and/or tissue protection arrest and/or resuscitation and/or poor blood flow to the subject where period(s); bacterial and/or viral infection(s) (e.g. meningitis), sepsis, septic shock, stroke and Ischemic and/or ischemic brain/cardiac/kidney damage after nerve, and/or cardiac protection and/or tissue protection during arrest and/or resuscitation and/or poor blood flow to the subject where period(s);
Subject of (x), eg carbon monoxide/methanol/heavy metal/pesticides poisoning, snake/spider/bee/insect/lizard poison metabolism poison(s), bacterial toxins (poisoned by toxic dose(s) of compounds of S) , My toxinemia drug/drug overdose, for example, heroin, ethanol, prescription drug(s) or counter drug treatment(s);
(XI) aging disease or Werner syndrome, Bloom syndrome, Rottmund-Thomson syndrome, Cockayne syndrome, dry skin pigment, trichothiodystrophy, connective scleroderma pigment-Cockayne syndrome, limited dermopathy, WIEDEMANN-Rautenstrauch syndrome, Hutchinson-Gilford's Premature ejaculation syndrome (accelerated premature ejaculation);
(XII) associated with elevated reactive oxygen species, neurodegenerative diseases, muscular atrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, including diseases or disorders of aging (increased age / increased aging) and/or degenerative diseases Diseases/diseases, Huntington's disease, spinal cerebellar ataxia, Friedrich's ataxia, dementia, fixative disease, polyglutamine disease, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, chronic obstructive pulmonary disease (COPD), hypertension, arthritis, cataracts, type 2 diabetes, male climacteric, muscular dystrophy, age-related macular degeneration (AMD), hearing loss, movement disorders, cancer;
These compounds have slow aging, prolonged life and health span, aging (XIII); or
(14 years old) skin aging .
A compound or composition for use according to any one of claims 12 or 23 to 37 wherein the subject is administered with at least one compound or composition approved for human use for said selective anti-cancer by said U.S. food. The Agency for Drug Administration (FDA) and/or the European Agency for Medicine (EMA), optionally the same pharmaceutical composition.
The method of claim 23, wherein the compound used in the above is administered to patients with a dose of milligrams/kg, which is comparable or will be administered to patients of small body size with a dose of milligrams/kg, arbitrarily greater than Mg/kg doses comparable to adult humans Mice stored at 22°C at a dose of milligram/kg at a dose adverse effect level (NOAEL) greater than or equal to this observed.
In use, according to compound 23, the anti-inflammatory / auto-inflammatory / autoimmune disease / disease / syndrome selected from acute inflammation, chronic inflammation, systemic inflammation, infection or foreign body or injury or chemical or toxin or drug or stress Or ionization of frostbite inflammation or burns or radiation, inflammatory diseases/disorders/syndrome, macrophage activation syndrome (MAS), auto-inflammatory diseases associated with colds, flu or fever, intense exercise ("inflammaging")/disorders/syndrome, Senile chronic inflammatory disease, autoimmune disease/disorder/syndrome, disease/disease of the innate immune system, sore throat, sore throat related inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, Osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation-related depression, exercise-induced acute inflammation, atherosclerosis, allergies, pollen allergy, anaphylaxis, inflammatory myopathy, drug-induced inflammation, systemic inflammatory reaction syndrome, sepsis and Multiple organ dysfunction associated / multiple organ failure, microbial infection, acute brain / lung / liver / kidney wound, acne, celiac disease, celiac sprue, chronic prostatitis, colitis, diverticulitis, glomerulonephritis, hidradenitis purulent, hypersensitivity, interstitial cystitis , Mast cell activation syndrome, mastocytosis, otitis media, pelvic inflammatory disease (PID), reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasites, eosinophilia, type III hypersensitivity reactions, ischemia, chronic peptic ulcer, Tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematosus (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative diseases, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute Bronchitis, appendicitis, acute appendicitis, bursitis, colitis, cystitis, dermatitis, encephalitis, gingivitis, meningitis, infectious meningitis, myelitis, nephritis, neuritis, periodontal Interstitial pulmonary disease related to inflammatory, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendinitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis and desquamative interstitial pneumonia, interstitial lung disease, rope Gren's syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, fatty hepatitis, non-alcoholic steatohepatitis, silicosis, histiocytoses, Langerhans cell histiocytosis, haemophagocytic lymphohistiocytosis, lung Langerhans cell tissue anorexia, obesity, type II diabetes, gout, pseudo, organ transplant rejection , Epidermal hyperplasia, chronic fatigue syndrome, host disease (GVHD), lymph node graft vs. familial Mediterranean fever (FMF), cycle syndrome (trap) receptor of TNF-associated Hyperimmunoglobulinemia D recurrent fever syndrome (HIDS) cryopyrin associated cycle syndrome ( CAPS), Blar syndrome Majid syndrome, interleukin-1 receptor antagonist deficiency (DIRA), mevalonate kinase deficiency purulent arthritis-pyoderma gangrene and acne syndrome (papapa), periodic fever aphthous stomatitis pharyngitis ointitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, SCHNITZLER syndrome, Sweet syndrome, autoinflammatory disorder, deficiency of interleukin-1 receptor antagonist (DIRA), NLRP12 related, pyoderma gangrene, cystic acne, aseptic arthritis, periodic fever related me Valonate kinase deficiency (hyperimmunoglobulin D syndrome), purulent arthritis pneumococcal acne (PAPA) syndrome, periodic fever aphthous stomatitis, pharyngitis and pathology (PFAPA) syndrome, adult-onset is still a disease (AOSD), systemic adolescent idiopathic Arthritis (sJIA), Chronic Recurrent Multiple Osteomyelitis (CRMO), Synoviitis Acne Pustular Osteoarthritis Osteoarthritis (SAND) Syndrome, Cryopyrin Related Regular Syndrome (CA) PS), Family Cold Automatic Inflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) is a prominent neonatal multi-inflammatory disease (NOMID) that is prominent in familial cold Interleukin-1 receptor antagonist deficiency (DIRA), pustular gangrene , Cystic acne, aseptic arthritis, periodic fever-related mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), purulent arthritis pneumococcal necrotic acne (PAPA) syndrome, periodic fever aphthous stomatitis, pharyngitis and pathology (PFAPA) Syndrome, adult-onset still, familial disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), chronic recurrent multiple osteomyelitis (CRMO), synoviitis acne pustuitis osteomyelitis (sandal) syndrome, Cryopyrin-related cyclic syndrome (CAPS) Cold Auto-inflammatory Syndrome (FCAS) of Muckle-Wells Syndrome (MWS) is a neonatal multiplicative inflammatory disease (NOMID) that is prominent in familial cold Interleukin-1 receptor antagonist deficiency (DIRA), pyoderma gangrene, cystic acne , Aseptic arthritis, periodic fever-related mevalonate kinase deficiency (hyperimmunoglobulin D syndrome), purulent arthritis pyoderma necrotic acne (PAPA) syndrome, periodic fever aphthous stomatitis, pharyngitis and pathology (PFAPA) syndrome, adult- Onset still, cold automatic inflammation of familial disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), chronic recurrent multiple osteomyelitis (CRMO), synovitis acne pustular osteochondrosis (sandpaper) syndrome, Cryopyrin-related periodic syndrome (CAPS) Syndrome (FCAS), Muckle-Wells Syndrome (MWS) is a neonatal multipathy disease (NOMID) that is prominent in familial colds.Mevalonate kinase deficiency (hyperimmunoglobulin D syndrome) and periodic fever-related, purulent arthritis Necrotic acne (Papa) syndrome, periodic fever ah Phthalamic stomatitis, pharyngitis and pathology (PFAPA) syndrome, adult-onset is still a disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), chronic recurrent polymyelitis (CRMO), synoviitis acne pustular osteochondrosis osteoarthritis (sandal) syndrome, Cryopyrin-related periodic syndrome (CAPS), family cold automatic inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), hives in familial colds, neonatal multi-inflammatory disease (NOMID), and metabolic kinase deficiency (hyperimmunoglobulin D syndrome) ) And periodic fever-related, purulent arthritis pneumococcal necrotic acne (Papa) syndrome, periodic fever aphthous stomatitis, pharyngitis and pathology (PFAPA) syndrome, adult-onset is still a disease (AOSD), systemic juvenile idiopathic arthritis ( sJIA), chronic recurrent multiple osteomyelitis (CRMO), synoviitis acne pustular osteomyelitis (sandal) syndrome, Cryopyrin-related cyclic syndrome (CAPS), family cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), familial Hives in colds, neonatal polymyelitis (NOMID), pharyngitis and pathology (PFAPA) syndrome, adult-onset disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), chronic recurrent polymyelitis (CRMO), synoviitis Acne Pustular Osteoarthritis (Sandulitis) Syndrome, Cryopyrin Related Periodic Syndrome (CAPS), Family Cold Automatic Inflammation Syndrome (FCAS), Muckle-Wells Syndrome (MWS) is a neonatal multi-inflammatory disease (NOMID) that is prominent in familial colds Onset pharyngitis and pathology (PFAPA) syndrome, adult-onset is still a disease (AOSD), systemic juvenile idiopathic arthritis (sJIA), chronic recurrent multiple osteomyelitis (CRMO), synovitis acne pustular osteoarthritis (sandpaper) syndrome, periodicity related to Cryopyrin Syndrome (CAPS), family cold auto-inflammatory syndrome (FCAS) Muckle-Wells Syndrome (MWS) is an onset of neonatal multi-inflammatory disease (NOMID), which is prominent in the familial cold. Onset of a pro-inflammatory disease (NOMID). Fever Syndrome, Cyclic Fever Syndrome, Systemic Autoinflammatory Disease, Addison's Disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing Spondylitis, Anti-GBM / Anti-TBM Nephritis, Antiphospholipid Syndrome, Autoimmune Autoimmune Angioedema, Autoimmune Autonomic Neuro , Autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, pancreatitis, autoimmune retinopathy, autoimmune urticaria, axon and neuropathy (AMAN), BALO disease, Behcet's disease, benign mucosal vesicle Chronic vesicular vesicles, Castle disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating neuropathy (CIDP), chronic recurrent polymyelitis (CRMO) veneer-Strauss, scarring Cogan syndrome Ulceration, cold disease, congenital heart block, coxsack myocarditis, CREST syndrome, Burger's disease agglomerates, follicular dermatitis giant dermatomyositis, diseases of the distribution device (optic nerve myelitis), discoid lupus, wrestler syndrome, endometriosis, eosinophilic esophagitis (Swallow), eosinophilic fasciitis, erythematous nodules, core hybrid cold globulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis) cell myocarditis, multiple vasculitis granulomatosis, Goodpasture syndrome glomerulonephritis, Graves Disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immunohemolytic anemia, Henoch-Schlein purpura (HSP), herpes gestationis or vesicular gestationis (PG), hypogammalglobulinemia, IgA nephropathy, sclerosis-related diseases, IgG4, Immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), Juvenile arthritis, childhood diabetes (type 1 diabetes), juvenile myositis (JM) Kawasaki disease, Lambert-Eton syndrome, leukocytosis, lichen planus, moss sclerosus, conjunctivitis, linear IgA disease (LAD), lupus, Lyme disease, chronic , Meniere's disease, microscopic red bundles (MPA), mixed connective tissue disease (MCTD), Muren corneal ulcer, Muha-Habermann disease, multiple sclerosis is myositis, narcolepsy, optic nerve myelitis, neutropenia, ocular scarring vesicular vesicles, optic neuritis , Homologous rheumatism (PR) panda, adrenal biocerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis, Parry Romberg syndrome, pars peripheral uveitis (peripheral uveitis) Parsonnage-Turner syndrome, vesicular peripheral neuropathy, perivenous encephalomyelitis Silver malignant anemia (PA), POEMS syndrome, nodular polyarteritis glands syndrome, II, III I input multiple myalgia rheumatism, multiple myositis, myocardial infarction syndrome, Postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone, psoriasis , Psoriatic arthritis, pure erythropoiesis (PRCA), pyoderma gangrene, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, recurrent dermatitis chondritis, silver anxiety leg syndrome (RLS), peritoneal fibrosis, rheumatic fever, rheumatism Arthritis, sarcoidosis, Schmidt syndrome, scleritis, sclerosis, Sjogren's syndrome, sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmitis (SO), Takaya arteritis , Temporary arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), transverse myelitis syndrome (THS), type 1 diabetic ulcerative colitis (UC), splenic hypertrophic undifferentiated connective tissue disease (UCTD), uveitis, vasculitis Vitiligo, Wegener's granulomatosis, idiopathic blood (red bundle (GPA) or granulation) Decreased purpura.
Compounds according to the formula:

Choose from use in prevention or treatment of diseases or disorders:
Glucose and/or cancer with lactic acid, for example, indicating cancer that can be distinguished from surrounding tissues by the Warburg effect and/or, for example, the Warburg effect and/or PET imaging (e.g. 18F-FDG PET) Glutamine metabolism cancer;
(Ii) cachexia, cancer cachexia or weight loss driven;
(Ⅲ) (e.g., 2,4-dinitrophenol), infection, sepsis, stroke, fever, fever, hyperpyrexia, high fever, malignant high fever, nerve intake, high environmental temperature is higher than normal body temperature Or disorders, serotonin syndrome, thyroid storms, heatstroke, thermoregulatory disorder(s), Kawasaki syndrome, hyperthermia due to drug or withdrawal symptoms, unusual drug reactions, fever of unknown or uncertain origin, incompatible blood agent(s) Response to, metabolic disorder(s) cancer, injury;
(IV) Tumor-associated phagocyte (Tech Account Manager) or macrophage activation syndrome (MAS), AIDS, phagocyte-related disease or disorder HIV-related neurocognitive disorder (hand), HIV-related cancer, AIDS-defined cancer or non-AIDS-defined cancer ;
(V) Neuroinvasive virus through macrophages, as used by HIV and SARS coronavirus, for example,
(VI) neurocognitive or neurodegenerative diseases/diseases, for example, for those caused by viruses;
(VII) Acute or chronic systemic inflammation or inflammatory disease / disorder / syndrome or autoinflammatory disease / disorder / syndrome or autoimmune disease / disorder / syndrome;
(VIII) lower than desired metabolic abnormality/sub-bio energy efficiency, or lower or lower than desired body and body performance or lower than desired body weight;
(IX) Deep circulatory hypothermia, a disease by conferring hypothermia on the subject for several medical or other purposes, which may include slowing down the rate of chemical reaction(s) to the subject for therapeutic effect/minimizing brain and/or tissue damage Or disease treatment cardiac and/or cardiovascular surgery and/or brain surgery (neurosurgery) surgery, hypothermia for the purpose of surgery, arrest for hypothermia, emergency preservation and resuscitation (EPR), eg, limbs and/or organs (poem) Long-term storage and/or transplantation of body parts, such as separate preservation temperature management targets, protective hypothermia, therapeutic hypothermia, neonatal brain disease, birth suffocation, bleeding, hypovolemia, hypothermia for decompression sickness, skin burns, inflammation, Burn injury(s) including allergic reactions anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, oxygen deficiency, anemia, hypervolemia, altitude sickness, airway obstruction, asthma attacks, body/tissue/organ, hypoglycemia, Hypoxia (ischemia-reperfusion injury) on reperfusion injury, ligature or tourniquet at release, uremia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (e.g. For meningitis), sepsis, septic shock, ischemic brain / heart / kidney damage, nerves and / or / cardiac protection and / or tissue protection during stroke and / or ischemia and / or heart attack and / or resuscitation and / or subject Where in the flow poor blood after period(s); ligature or tourniquet, uremia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, asthma attack, body/tissue/organ, hypoglycemia, reperfusion following release of major trauma Hypoxia, (in ischemia-reperfusion injury), injuries, infections, bacterial and/or viral infection(s) (e.g. meningitis) after stroke and/or ischemia / during, sepsis, septic shock, ischemic brain / heart / kidney Damage, nerves and/or Heart protection and/or tissue protection/or heart attack and/or resuscitation and/or poor blood flow to the subject where period(s); ligature or tourniquet, uremic syndrome, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major Hypoxia, asthma attacks, body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), infection, bacterial and/or viral infection(s) (e.g. meningitis) stroke and/or following trauma release Post ischemic/medium, sepsis, septic shock, ischemic brain/cardiac/kidney damage, nerve and/or heart protection and/or tissue protection/or heart attack and/or resuscitation and/or poor blood flow to the subject where period(s) ); Bacterial and/or viral infection(s) (e.g., meningitis), sepsis, septic shock, stroke and/or ischemia and/or post-cardiac ischemic brain/cardiac/kidney injury, nerve and/or heart during Protection and/or tissue protection arrest and/or resuscitation and/or poor blood flow to the subject where period(s); bacterial and/or viral infection(s) (e.g. meningitis), sepsis, septic shock, stroke and Ischemic and/or ischemic brain/cardiac/kidney damage after nerve, and/or cardiac protection and/or tissue protection during arrest and/or resuscitation and/or poor blood flow to the subject where period(s);
Subject of (x), eg carbon monoxide/methanol/heavy metal/pesticides poisoning, snake/spider/bee/insect/lizard poison metabolism poison(s), bacterial toxins (poisoned by toxic dose(s) of compounds of S) , My toxinemia drug/drug overdose, for example, heroin, ethanol, prescription drug(s) or counter drug treatment(s);
(XI) aging disease or Werner syndrome, Bloom syndrome, Rottmund-Thomson syndrome, Cockayne syndrome, dry skin pigment, trichothiodystrophy, connective scleroderma pigment-Cockayne syndrome, limited dermopathy, WIEDEMANN-Rautenstrauch syndrome, Hutchinson-Gilford's Premature ejaculation syndrome (accelerated premature ejaculation);
(XII) associated with elevated reactive oxygen species, neurodegenerative diseases, muscular atrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, including diseases or disorders of aging (increased age / increased aging) and/or degenerative diseases Diseases/diseases, Huntington's disease, spinal cerebellar ataxia, Friedrich's ataxia, dementia, fixative disease, polyglutamine disease, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, chronic obstructive pulmonary disease (COPD), hypertension, arthritis, cataracts, type 2 diabetes, male climacteric, muscular dystrophy, age-related macular degeneration (AMD), hearing loss, movement disorders, cancer;
These compounds have slow aging, prolonged life and health span, aging (XIII); or
Age (14 years old) skin;
remind
L is selected from alkyl, substituted alkyl, deuterated alkyl, amino, thio alkyl, alkoxy, halogen, halo alkyl, halo alkoxy, or any atomic isotope is valence-allowed (including accompanying hydrogen valences, 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) hetero3 formation with R3;
R3 is independently alkyl, substituted alkyl thio, amino alkyl, carbamyl, BB aryl, BB-hetero, BB heteroaryl, or BB cycloalkyl, or (ii) phenyl optionally C1-4 alkyl, halogen, trifluoro methyl Substituted (i), phosphorus OCF3 is cyano, nitro, amino, hydroxy or methoxy, or (iii) optionally having independently, C1-4 alkyl thio, amino, -BB aryl, hetero-BB-, BB R3a selected from cycloalkyl, and -BB heteroaryl is one selected from three substituents; And/or R2 in these fused or (IV) having a 5 or 6-membered carbocyclic ring together with an optionally substituted alkyl or substituted heteroalkyl;
BB is C1-4 alkyl, C2-4 alkenylene, substituted C1-4 alkyl, substituted C2-4 alkenylene bond, substituted C1-4 alkyl-C (= O) NH-, -C (= O) NH-, -C1-4 alkylene-C (= O) NH-, -C (= O) NR19-, -C1-4 alkylene-C (= O) NR19- or substituted C1-4 alkyl-C (= O) NR19-,-(CHR14) M- (CR15R16) N- or-(CHR14) pC (= O) NH-;
In each case R3A is independently selected from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, keto, trifluoromethyl, -NR17R18, -SR17, -OR17, -SO2R17a, -SO2NR17R18, -NR17C (= O) R18, -CO2R17 -C (= O) R17 R3a is cycloalkyl, aryl, heterocyclo or heteroaryl, cycloalkyl, arylheterocyclohetero, heteroaryl is optionally substituted with alkyl or alkyl substituted Cyclo alkyl, arylhetero cyclo, and hetero aryl;
Z is, for example, heteroaryl for an optionally substituted heterobicyclic; or
Z is optionally substituted with two R7 substituents, one substituted with R7 substituents, or imidazolyl and/or once substituted with any R7 substituents, fused to a benzene ring
R7 is alkyl, carbamill, or substituted alkyl;
In each case, R4 is independent of each other from the group consisting of halogen, trifluoromethyl, OCF3, alkyl, substituted alkyl, halo, nitro, cyano, halo, OR25, SR25, NR25R26, NR25SO2R27, SO2R27, SO2NR25R26, CO2R26, C Selection of R4 (= O) R26, C (= O) NR25R26, OC (= O) R25, -OC (= O) NR25R26, NR25C (= O) R26, NR25CO2R26, aryl, heteroaryl, heterocycloalkyl and ;
R8 is C1-4 alkyl or phenyl optionally substituted with alkyl, halogen, haloalkoxy, cyano, nitro or trifluoro methyl;
R9 is -NR10R11 is alkyl, substituted alkyl, alkoxy, alkyl thio, cycloalkyl is aryl heteroaryl, heterocyclo, or -CO2R12 is alkyl or phenyl is halogen, cyano, trifluoromethyl, nitro, nehydroxy , Substituted with C1-4 alkoxy, halo, C1-6 alkyl, CO2 alkyl, SO2 alkyl, SO2NH2, amino, NH (C1-4 alkyl), N (C1-4 alkyl) 2, NHC (= O) alkyl , C (= O) alkyl, and/or optionally substituted with one of three C1-4 alkyl trifluoro methyl, hydroxy, cyano, phenyl, pyridinyl; And/or alternating 5 or 6 membered hetero aryl or optionally heterocycloketo substitution or fusion having a benzene ring thereto or
a) C1-4 alkyl, optionally substituted with either:
Iii) SR13, OR13, NR13aR13b, halogen, trifluoromethyl, CO2R13a and C (=O) NR13aR13b;
Ii) said phenyl alkyl optionally substituted with C (=O) H, C 1-4 acyl, alkenyl, carba do one substitution, and/or halogen;
Iii) phenyl or halogen, nitro, amino, alkyl, two or one substituted naphthyl having a hydroxy number fused to a C1-4 alkoxy, or a 5 or 6-membered hetero;
Iv) having a 5-6 membered carbocyclic ring fused to a dienyl, thiophenyl, furanyl, tetrahydrofuranyl, or azepinyl, optionally substituted alkyl or optionally keto or C1-4 alkoxy
b) a 3-6 membered cycloalkyl optionally has a tetrasubstituted group in turn selected from alkyl, halogen, cyano group, alkenyl, acyl, alkyl thio, carbamyl, phenyl substituted with halogen; Or having aryl fused to it
c) Phenyl is halogen, cyano, trifluoromethyl, nitro, four substituted hydroxy, C1-4 alkoxy, halo, C1-4 alkyl, CO2 alkyl, SO2 alkyl, SO2NH2, NH (C1-4 alkyl), N (C1-4 alkyl amino) 2 NHC (= O) alkyl, C (= O) alkyl, and/or optionally substituted with one of three C1-4 alkyl trifluoro methyl, hydroxy, cyano, phenyl, pyridinyl; And/or keto or optionally a benzene ring, which in turn has a conjugation with a half-membered heteroaryl or heterocycle;
D) phenyl substituted with two of pyridinyl, thiazolyl, furanyl, thiophenyl, pyrrolyl and halogen, alkyl, in turn d) halogen or trifluoro substitution;
R10 and R11 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocycloalkyl, aryl, heteroaryl or C1-4 alkyl wherein (I) is optionally substituted with two -CO2 alkyl, -C (=O ) NH (aryl), NH (aryl) cycloalkyl, phenyl, optionally C1-4 alkyl, hydroxy, C1-4 alkoxy, halogen, amino, nitro, tetrahydro sequentially substituted phenyl, and/or 5 or 6-membered hetero Or a 5 or 6-membered heterocyclic fused to it; Keto optionally substituted pyrrolidinyl; Naphthyl, anthracenyl, pyridinyl, thiophenyl, furanyl, imidazolyl, benzimidazolyl, indolyl or turn optionally substituted with C1-4 alkyl or C1-4 alkoxy; or
(Ii) together with the formation of heteroaryl or pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, tetrahydropyridinyl and imidazoilidinyl, the R11 formed by the hetero R10 is optionally ketodu, CO2H, C14alkoxy, CO2alkyl, C1 Hetero benzyl-4 cover mill selected from one substitution; Phenyl in turn is optionally substituted alkyl, halogen or C1-4 alkoxy; Tetrahydropyridinyl in turn optionally substituted with keto and/or phenyl; Alkyl is substituted with amino or NHR21 wherein R21 is an alkyl group which may be substituted with alkyl or phenyl; And/or the benzene ring is fused to C1-4 alkoxy, CO2 alkyl, and/or C1-4 carbamill, which in this case is again optionally substituted with two alkyl;
R12 and R19 are hydrogen or alkyl;
R13 is hydrogen or alkyl;
R13a and R13b are selected from hydrogen, alkyl and aryl;
In each case R14, R15 and R16 are independently selected from hydrogen, alkyl, hydroxy, hydroxy C, C1-4 alkoxy and phenyl, and/or one of R15 and R16 is one 3-6 membered cycloalkyl group Are joined together to form;
R17 and R18 are independently selected from phenyl or benzyl hydrogen, alkyl, substituted alkyl, aryl, phenyl or benzyl, optionally substituted with alkyl, hydroxy, or hydroxy;
R17a is alkyl or substituted alkyl;
R25 and R26 are independently taken together to form hydrogen, alkyl or substituted alkyl, or heterocyclo or heterocycle;
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.
L is hydrogen and is a compound for use according to claim 27.
In the enantiomeric excess of the S-enantiomer, the compound used above is according to clause 27 or 28.
30. The method of claim 29, wherein the compound for use according to the excess enantiomer - S-isomer in excess of 70%.
Compounds used according to claim 27 having a structure

Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, wherein
The enantiomeric excess (EE) of the S stereoisomers exceeds 70%.
The compound of any one of claims 27 to 31 wherein, for the compound used, the drug administered at a mg/kg greater than or equal to comparison is mostly used in very large distinct animals, and the Mg/kg administered is greater than or equal to observed in adult humans. Dosage adverse effects levels (NOAEL) are mice stored at a 22 mg/kg dose.
ㅏ Compounds that reduce F1F0 ATP hydrolysis in subjects, for treatment, alleviation, prevention or for combating a disease or disorder selected from:
(I) cachexia, cancer cachexia or weight loss driven;
(Ii) (e.g., 2,4-dinitrophenol), infection, sepsis, stroke, fever, fever, hyperpyrexia, high fever, malignant high fever, neuronal completion of the separator, causes of high environmental temperature higher than normal body temperature Or disorders, serotonin syndrome, thyroid storms, heatstroke, thermoregulatory disorder(s), Kawasaki syndrome, hyperthermia due to drug or withdrawal symptoms, unusual drug reactions, fever of unknown or uncertain origin, incompatible blood agent(s) Response to, metabolic disorder(s) cancer, injury;
(Ⅲ) Macrophage-related macrophages (technical account managers) or macrophage-activated syndrome (MAS), AIDS, phagocytic-related diseases or disorders HIV-related neurocognitive disorders (hands), HIV-related cancer, AIDS-defined cancer or non-AIDS-defined cancer ;
(Iv) by neuronal invasion via macrophages, HIV and SARS coronavirus, as used, for example,
(V) neurocognitive or neurodegenerative diseases/diseases, for example, for those caused by viruses;
(VI) lower than desired metabolic abnormality / subject bio energy efficiency, or lower or lower than desired body and body performance or lower than desired body weight;
(Ⅶ) Consultation on the subject for some medical or other purposes may include slowing down the rate of chemical reaction(s) on the subject for therapeutic effect/surgical brain and/or tissue damage, minimizing hypothermic circulatory arrest. Hypothermia for surgical purposes, hypothermia for cardiac and/or cardiovascular surgery and/or brain surgery (neurological surgery), emergency preservation and resuscitation (EPR), such as long-term storage and upon, for example, limbs and/or organs ( Keep separate body parts such as/or transplantation), including protective hypothermia, target temperature management, therapeutic hypothermia, neonatal brain disease, childbirth suffocation, bleeding, hypovolemia, hypothermia therapy for decompression sickness, skin burns, inflammation, and allergic reactions Anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, oxygen deficiency, anemia, hypervolemia, altitude sickness, airway obstruction, asthma attack, hypoxia (ischemia) to body/tissue/organ, hypoglycemia, reperfusion injury -Reperfusion injury), ligature or tourniquet, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (e.g. meningitis) upon release of uremia Sepsis, septic shock, ischemic brain/cardiac/kidney damage, neurology/or stroke and/or ischemia and/or heart attack and/or resuscitation and/or poor blood flow to the subject where/after period(s) of cardiac protection And/or tissue protection; reperfusion injury (ischemia-reperfusion injury), ligature or tourniquet, uremia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) Depending on release (e.g. meningitis), sepsis, septic shock, stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or ischemic brain/cardiac/kidney damage after periods, nerves and/or/or Heart protection and/or tissue protection Where poor blood flow to the subject(s); reperfusion injury (ischemia-reperfusion injury), ligature or tourniquet, uremia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacteria and/or viruses Depending on the release of the infection(s) (e.g. meningitis), sepsis, septic shock, stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or ischemic brain/cardiac/kidney damage after the period, nerves And/or where cardiac protection and/or tissue protection(s) of poor blood flow to the subject(s); stroke and/or ischemia and/or heart attack and/or resuscitation and/or subject to poor blood flow to the period(s) Neuroprotection and/or cardiac protection and/or tissue protection during and/or ischemic and/or cardiac arrest and/or resuscitation and/or poor blood flow to the subject after period(s) of neuroprotection and/or/ During heart protection and/or tissue protection;
(Ⅷ) / Hypothermia consulted for improvement / preventive treatment / Poisoning by toxic amounts (S) of combat targets, e.g. carbon monoxide, poisoning / methanol / heavy metal / pesticide poisoning, snake / spider / bee / insect / lizard poison metabolism Heroin, ethanol, prescription drug(s) or prescription drug(s), such as poison(s), bacterial toxin(s), my toxins or drug/drug overdose;
(IX) aging disease or Werner syndrome, Bloom syndrome, Rottmund-Thomson syndrome, Cockayne syndrome, dry skin pigment, trichothiodystrophy, connective scleroderma pigment-Cockayne syndrome, limited dermopathy, WIEDEMANN-Rautenstrauch syndrome, Hutchinson-Gilford's Premature ejaculation syndrome (accelerated premature ejaculation);
(x) is associated with elevated free radicals, neurodegenerative diseases, muscular atrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, including diseases or disorders of aging (increased age/increased ageing) and/or degenerative diseases Related diseases/diseases, Huntington's disease, spinal cerebellar ataxia, Friedrich's ataxia, dementia, fixative disease, polyglutamine disease, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, chronic obstructive lung Disease (COPD), hypertension, arthritis, cataracts, type 2 diabetes, male climacteric, muscular dystrophy, age-related macular degeneration (AMD), hearing loss, movement disorders, cancer;
(XI) This compound has slow aging, long life and health span anti-aging; or
(XII) Skin aging.

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