NOVEL COMPOUNDS OF Ilp-HYDROXY STEROIDS FOR USE IN
MITOCHONDRIA BIOGENESIS AND DISEASES ASSOCIATED WITH
MITOCHONDRIAL DYSFUNCTION OR DEPLETION
FIELD OF THE INVENTION
Disclosed herein are novel compounds of 1 ip-hydroxy steroids and compositions and their application as pharmaceuticals for preventing or reversing injury to mitochondria, for treating or preventing diseases relating to mitochondrial dysfunction or depletion, and for inducing regeneration or restructuring of mitochondria as a means of treating diseases relating to abnormalities in mitochondrial structure and function in a human or animal subject. Also disclosed herein are methods for diagnosing injury to mitochondria and for diagnosing the success or failure of therapeutics designed to treat, prevent, or reverse injury to or depletion of mitochondria.
BACKGROUND
Mitochondria are responsible for generating more than 90% of the energy needed by the body to sustain life and support growth. When mitochondrial function fails, less energy is generated within the cell, resulting in cell injury and ultimately cell death. Mitochondria are susceptible to degradation due to oxygen radicals produced by their own metabolic processes. Damaged mitochondria involute and are expelled by the cell. Their replacement by new mitochondria is called mitochondrial biogenesis. The proliferation of mitochondria or their hypertrophy to meet increased metabolic demand is also called mitochondrial biogenesis. It is signified by the expression of additional mitochondrial proteins, particularly those related to oxidative phosphorylation. The capacity for mitochondrial biogenesis is significantly lost with age. Thus many diseases of aging are associated with loss of mitochondria in various tissues, whose specialized function is diminished in the context of diminished mitochondrial function and/or number. Many disease states, such as those that have neuromuscular disease symptoms, sarcopenia, muscular dystrophy, diabetes mellitus, dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), obesity, hyperlipidemia, heart failure, lupus, and ocular conditions such as age-related macular degeneration (AMD), are associated with progressive mitochondrial loss in various tissues.

In addition, a number of drugs and drug classes also have an effect on mitochondrial function and biogenesis and can affect organ function and even lead to organ degeneration or other side effects which are directly related to the toxic effect of these drugs on the mitochondria.
A non-limiting list of drugs and drug classes that are associated with their mitochondria effect can be found in: Pereira et al., Current Drug Safety, 4:34-54, 2009; Gohil et al, Nature BiotechnoL, 28:249-257, 2010; and Wagner et al. Nature BiotechnoL, 26:343-351, 2008, each of which is hereby incorporated by reference in its entirety. Reflecting this understanding, the phrase "mitochondrial toxicity" as used herein refers to failure of the mitochondria resulting from the administration of chemical compositions to a subject.
Ischemic and ischemia/reperfusion injury are accompanied by decreases in mitochondrial function and number, leading to apoptotic cell death, necrosis, and functional organ deterioration in ischemic conditions such as myocardial infarction and stroke. Despite considerable advances in the diagnosis and treatment of such conditions, there remains a need for prophylactic and therapeutic approaches for the treatment of these conditions.
Mitochondria are critical to cell function and the effects of mitochondrial disease can be varied and can take on unique characteristics. The severity of the specific defect may be great or small and often affect the operation of the mitochondria and multiple tissues more severely, leading to multi-system diseases. Injury to, or dysfunction of, skeletal muscle mitochondria generally results in muscle weakness and atrophy, termed sarcopenia in severe states. In the case of generalized muscle weakness, reduction in bone density can be generalized, one of the causes of the bone disease known as osteoporosis. Depleted mitochondria in the heart can eventuate in the symptoms of congestive heart failure and eventual death. Loss of mitochondrial density in the brain is associated with neurodegeneration states such as Huntington's disease, Alzheimer's disease, and Parkinson's disease. Generalized loss of mitochondria including liver mitochondria can result in hyperlipidemia, hypertension, and insulin resistance progression to Type 2 diabetes. Liver mitochondria are injured by fructose uptake. Fructose, uric acid, and other agents injurious to liver mitochondria can cause accumulation of intracellular lipids, particularly triglycerides that contribute to the syndrome of hepatic steatosis, and increased synthesis and export of triglycerides that contributes to systemic hyperlipidemia, and ultimately obesity and insulin resistance.

Treatment options are currently limited and there remains a need for prophylactic and therapeutic approaches for the treatment of these conditions associated with chronic mitochondrial dysfunction and toxicity. Thus there is a need for treatments that stimulate mitochondrial function in response to increased metabolic demand and induce mitochondrial replication in response to agents or conditions that cause depletion of mitochondria in one or more tissues. Complicating potential therapies is the fact that the aging process is generally associated with progressive loss of the ability to support mitochondrial biogenesis, for reasons that are unknown.
DESCRIPTION
It is an object of the invention to provide compounds which are derivatives of steroids and particularly those of lip-hydroxy-steroids and other related steroids. These may find various uses as described hereinafter, in particular as pharmaceutical compounds.
Hydroxysteroids are hydroxylated compounds with a sterol structure and are known to be produced in cells when the mitochondria are exposed to high levels of endogenous H2O ^ which then acts via the mitochondrial enzyme, 1 ip-hydroxylase, to hydroxylate a variety of steroids, including cholesterol, pregnenolone, progesterone, and others. Hydroxylation can occur in numerous positions, including the 7, 16, and 11 positions. These molecules, termed hydroxysteroids, are then sulfated and secreted into the extracellular space, where in the brain they modulate GABA-receptors and calcium channels on the plasma membrane. No intracellular activity of hydroxysteroids has previously been described.
In the present invention, compounds have structural Formula I:
or a salt thereof, wherein:
a dashed line represents an optional double bond or a methylene group attached to the atoms on either side such that a fused cyclopropyl ring results, provided that cumulated double bonds (=C=) are not allowed;

n is an integer from 1 to 6;
Ai is selected from the group consisting of hydrogen, deuterium, halogen, -OH, P0 4^", -SO ^~ , -ORio, -NRigRn, -OQ, -NRJOQ, -NRnCOR j^, -OCOORj^, -NRnCOOR j^, -NRiiCONRicRii, -COR,Q, -COORio, and -CONRIQRH;
A2is selected from the group consisting of hydrogen, deuterium, halogen, P0 4^", -SO ^^-^ ^j-Ci2 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein heteroatom of the heterocylic ring or heteroaryl ring is selected from N, O or S; wherein said 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORj^, -OCORio, -NRnCORio, -OCOORio, -NRuCOORiQ -NRnCONRi QRH, -COR^Q, -COORi^, -CONRj^Rn; or A, and K^, taken together with the atom to which they are attached, may form a 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -OR^g, -OCOR,, -NRHCORIQ, -OCOOR, Q, -NRUCOORJ^, -NRuCONRio; -CORio, -COORio, and -CONR ^^Ri i; or Ai and A2, taken together, are =0;
B and C are each independently selected from the group consisting of hydrogen, -OH, -OR^^, -NRjgRii, -OQ, -NRioQ, -NRuCOR,, -OCOOR,, -NRHCOORIQ, -NRnCONRjo-CORio, -COORIO,-CONRIQRII, -NH(CH2)nNH2;, -NRiiCO(CH2)„NH2 and C,-Ci2 alkyl, wherein said Ci-Ci2 alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCORio, -NRnCORio, -OCOORio, -NRnCOORio, -NRiiCONR i^Rii, -COR^^, -COORIQ, and -CONR,QRII; or B and C, taken together with the atom to which they are attached, may form a 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein heteroatom of the heterocylic ring or heteroaryl ring is selected from N, O or S;, any of which may be optionally substituted with one or more C1-C12 alkyl; wherein said Ci-Ci2 alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORjo, -OCORi^, -NRnCORio, -OCOOR j^, -NR2COOR10, -NRuCONRioRn, -CORio, -COOR^^, and -CONRi^Rir, or B and C, taken together, are =0, -N-OH or=N-NH2;
D is selected from the group consisting of hydrogen, hydroxy 1, methyl, ethyl, propyl, isopropyl, cyclopropyl, amino, hydroxyalkyl, -CD3, -CF3, -ORio, -OCF3, phenyl, 4-6

membered heterocycloalkyl, and 5-6 membered heteroaryl; wherein heteroatom in the said heteroalkyl or heteroaryl ring is selected from the group of N, O or S; wherein said 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of C1-C4 alkyl, -Rio, -ORio, -NRioRu, fluorine, chlorine, and -CF3 or a C=0 group ; or when taken together with B or C, may represent a double bond; or B, C and D, taken together with the atom to which they are attached, may form a carbonyl group, oxime group, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; any of which may be optionally substituted with one or more substituents selected from the group consisting of -CpC 4 alkyl, -R^^, -ORio, -NRioRn, fluorine, chlorine,-C=0 and-CF3;
Ri is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -ORio, -NRioRu, -OQ, -NRioQ, -NRiiCORio, -OCOOR.o, -NRi,COOR, Q,-NRnCONRig,-CORio, -COORio, or -CONRioRn, and Ci-C g alkyl, wherein said Ci-C g alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCOR j^, -NRnCORio, -OCOOR, Q, -NRiiCOORi Q, -NRnCONRioRn, -CORio, -COORio, and -CONRioRn; or Ri and Ai or Ri and A2, taken together with the atoms to which they are attached, can form a 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORio, -OCORio, -NRnCORio, -OCOORio, -NRiiCOORi Q, -NRnCONRioRn, -CORi^, -COORio, and -CONRioRi i;
R2 is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -ORi^, -NRioRu, -OQ, -NRioQ, -NRnCORio, -OCOOR, Q, -NRiiCOORi^, -NRnCONRioRn, -CORio, -COORio, - CONRioRn, and Ci-C g alkyl, wherein said CpCs alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCORio, -NRnCORio, -OCOORio, -NRuCOOR, Q, -NRnCONR igRii, -CORio, -COORio, and -CONRioRn; or R2 and Ai or R2 and A2, taken together with the atoms to which they are attached, can form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORio, -OCORio, -NRnCORio, -OCOORio, -NRnCOORio, -NRnCONR, gRii, -CORio, -COORio, and-CONRioRn;

Rj is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and -ORig;
R4 is selected from the group consisting of hydrogen, hydroxy and Ci-Cg alkyl, wherein said Ci-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and -ORj^;
R5, Re and R^ are each independently selected from hydrogen, fluorine, chlorine, -CF3, -OH, -OR.0, -OQ, NRicRii, -NRjoQ, -NRjoQ, -NRnCORjo, -OCOORJQ, -NR„C00R JQ, -NRuCONRicRii, -COR,o, -COOR,o, -CONRjoRn, and Ci-Cg alkyl, wherein said C,-C6 alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORIQ, -OCORJO, -NRHCORJ^, -OCOOR fi, -NRUCOORIQ, -NR,iCONR jgRii, -CORIO, -COORio, and -CONRi^Ru;
Rg and Rg are each selected from hydrogen, hydroxy, methoxy, amines, alkyl or acyl.
Rig and Rii are each independently selected from the group consisting of hydrogen, C|-Ci2 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said -7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -RJQ, -ORio, -OCORj^, -NRnCOR^, OCOORIO, -NRnCOORio, -NRnCONR'^Rn, -CORi^,-COOR^^, and-CONRioRn;
R12 and Rp are each independently selected from the group consisting of hydrogen, Cj-Cg alkyl, Ci-Cg haloalkyl, amino, substituted amino, phenyl, and phenymethyl, wherein said phenyl group or the phenyl portion of the phenylmethyl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, methoxy, trifluormethoxy, and amino; and Rj4 and Rij, taken together with the atoms to which they are attached, form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of halo, methyl and methoxy;
Ri4 andRjj are each independently selected from the group consisting of hydrogen and Ci-Ce alkyl;

Ri6 is selected from the group consisting of hydrogen and Ci-C g alkyl, wherein said Ci-C g alkyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, methoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(C j-Cg alkyl), -CONH2, and phenyl, wherein said phenyl may be optionally substituted with one or more substituents selected from the group consisting of halo and hydroxyl; Q is selected from the group consisting of:
X and Y are each independently selected from the group consisting of hydrogen and Cj-CE alkyl, wherein said Ci-C ^ alkyl that may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCORio, -NRiiCORjo, -OQ, -NR,oQ, -OCOORJQ, -NRHCOORJ^, -NRuCONRioRn, -CORIO, -COORIO, and-CONRlORll.
Certain compounds disclosed herein may possess useful mitochondrial biogenesis modulating activity, and may be used in the treatment or prophylaxis of a disease or condition in which mitochondrial biogenesis plays an active role. Thus, in broad aspect, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments provide methods for modulating mitochondrial biogenesis. Other embodiments provide methods for treating a

mitochondrial biogenesis-mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition according to the present invention. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the modulation of mitochondrial biogenesis.
In the present invention, compounds have structural Formula II:
or a salt thereof, wherein:
a dashed line represents an optional double bond or a methylene group attached to the atoms on either side such that a fused cyclopropyl ring results, provided that cumulated double bonds (=C=) are not allowed;
n is an integer from 1 to 6;
m is an integer from 1 to 6;
A i is selected from the group consisting of hydrogen, -OH, deuterium, halogen, PO^-^',-SO 42--ORio, -NRioRn, -OQ, -NRj^Q, -NRnCOR^o, -OCOOR j^,-NRnCOORio, -NRnCONRj^Rii, -COR,o, -COORio, and -CONRj^Rn;
A2 is selected from the group consisting of hydrogen, deuterium, halogen, ¥0 4^' , -SO ^^-^ Ci-ty^ alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein heteroatom in the said heteroalkyl or heteroaryl ring is selected from the group ofN, O or S; wherein said 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORJO, -OCORio, -NRuCORio, -OCOOR,o, -NRnCOORio, -NRnCONRioRn, -CORio, -COORio, -CONR, QRU; or A, and A2, taken together with the atom to which they are attached, may form a 3-7 membered

cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -RIQ, -OR^Q, -OCORi, -NRnCORio, -OCOOR j^, -NRHCOORIQ, -NRnCONRio; -CORi^, -COORio, and -CONRioRn; or Ai and A^, taken together, are =0;
R) is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -ORIQ, -NRlORll, -OQ, -NRlOQ, -NRnCORio, -OCOORi^, -NR„COOR,o, -NRnCONR^^, -COR^^, -COORio, or -CONRioRn, and Ci-Ce alkyl, wherein said Ci-C g alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR^o, -OCOR, Q, -NRnCORig, -OCOORIO, -NR^^ COOR, Q, -NRnCONR ^^Rn, -CORjO, -COORio, and -CONR^QRH; orRi and Ai orRi and A2, taken together with the atoms to which they are attached, can form a 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORIO, -OCORIO, -NRiiCORjQ, -OCOORIQ, -NR„ COORio, -NR11 CONRioRii, -CORj^, -COORio, and -CONR, QRU;
R2 is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -OR^o, -NRioRii, -OQ, -NRIOQ, -NRnCOR ^^, -OCOORIO, -NR,iCOOR ^^, -NRIICONRIQRU, -CORIO, -COORio, - CONRioRn, and C]-C6 alkyl, wherein said Ci-C g alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR^^, -OCOR, Q, -NRiiCORig, -OCOORio, -NRnCOOR, Q, -NRi,CONRi QRH, -CORIO, -COORio, and -CONRioRn; or R2 and Ai or R2 and A2, taken together with the atoms to which they are attached, can form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -OR,o, -OCORig, -NRnCORio, -OCOORio, -NRuCOORig, -NRuCONR j^Rii, -CORi^, -COORio, and -CONRioRn;
R3 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and -OR^O;
R4 is selected from the group consisting of hydrogen, hydroxy and CpCg alkyl, wherein said CpCg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and -ORIQ;

R5, Rg and R^ are each independently selected from hydrogen, fluorine, chlorine, -CF3, -OH, -ORIO, -OQ, NRlORll, -NRioQ, -NRj^Q, -NRIICORIQ, -OCOORIQ, -NRuCOORiQ, -NRiiCONRioRn, -CORlO, -COOR ^^, -CONR j^Rn, and Ci-Cg alkyl, wherein said CpCg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR^g,-OCORig,-NRiiCOR,o, -OCOOR j^,-NRuCOORio, -NRuCONRioRn, -COR ^^, -COOR, Q, and -CONR,oR 11;
Rg and Rg are each selected from hydrogen, hydroxy, methoxy, amines, alkyl or acyl. R^o and Ru are each independently selected from the group consisting of hydrogen, Ci-C ]2 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said -7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORi^, -OCORio, -NRnCORio, -OCOOR|o, -NRnCOOR ^^, -NRuCONRioRn, -COR, Q, -COOR ^^, and -CONR, oR,i;
Ri2 and Rig are each independently selected from the group consisting of hydrogen, Ci-Cg alkyl, Ci-C g haloalkyl, amino, substituted amino, phenyl, and phenymethyl, wherein said phenyl group or the phenyl portion of the phenylmethyl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, methoxy, trifluormethoxy, and amino; and R14 and R15, taken together with the atoms to which they are attached, form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of halo, methyl and methoxy;
Ri4 and R15 are each independently selected from the group consisting of hydrogen and Ci-C^ alkyl;
Rie is selected from the group consisting of hydrogen and Ci-C 5 alkyl, wherein said Ci-C 5 alkyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, methoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(Ci-C3 alkyl), -CONH2, and phenyl, wherein said phenyl may be optionally substituted with one or more substituents selected from the group consisting of halo and hydroxyl;

Q is selected from the group consisting of:
X and Y are each independently selected from the group consisting of hydrogen and Ci-Ci 2 alkyl, wherein said CpC^ alkyl that may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCORj^, -NRuCORio, -OQ, -NRIQQ, -OCOORJ^, -NRUCOORIQ, -NRI,CONRI QRH, -COR^^, -COORio, and -CONRioRu.
R^ may be hydrogen.
In the present invention, compounds have structural Formula III:
or a salt thereof, wherein:

a dashed line represents an optional double bond or a methylene group attached to the atoms on either side such that a fused cyclopropyl ring results, provided that cumulated double bonds (=C=) are not allowed;
n is an integer from 1 to 6;
Ai is selected from the group consisting of hydrogen, deuterium, halogen, -OH, FO 4^', -SO 4^' , -OR,o, -NRioRh, -OQ, -NRj^Q, -NRnCOR ^o, -OCOORIQ, -NRnCOORio, -NRiiCONRicRn, -CORi^, -COORIQ, and -CONRj^Rn;
A2is selected from the group consisting of hydrogen, deuterium, halogen, PO^^", -SO 4^', Cp C[2 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein heteroatom in the said heteroalkyl or heteroaryl ring is selected from the group of N, O or S; wherein said 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORio, -OCORio, -NRuCORio, -OCOORio, -NRuCOORjQ, -NRHCONRIQRU, -COR,Q, -COORIQ, -CONRoRn; or Ai and A2, taken together with the atom to which they are attached, may form a 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORio, -OCORi, -NRuCORio, -OCOORio, -NRHCOORIQ, -NRhCONR, Q; -CORIQ, -COORio, and -CONRIQRH; or Ai and A2, taken together, are =0; Ri is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -ORio, -NRioRh, -OQ, -NRioQ, -NRHCORIQ, -OCOORIO, -NRHCOORIQ, -NRUCONRIQ, -COR^^, -COORio, or -CONRioRii, and Ci-Cg alkyl, wherein said Ci-Ce alkyk may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR^^, -OCOR^^, -NRuCORio, -OCOOR^^, -NRuCOOR ^^, -NRnCONRioRn, -CORio, -COORio, and -CONRioRn; or Ri and A| or Ri and A2, taken together with the atoms to which they are attached, can form a 4-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein heteroatom in the said heteroalkyl or heteroaryl ring is selected from the group of N, O or S; any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -RIQ, -ORio, -OCOR^^, -NRuCORio, -OCOORio, -NRi,COORi Q, -NRI,CONR,ORII, -CORio, -COORIQ, and -CONR, pRii;

R2 is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -ORio, -NRioRn, -OQ, -NRj^Q, -NRnCORig, -OCOORig, -NRnCOORjO, -NRnCONR'^Rn, CORio, -COORjg, - CONRioRn, and CpCe alkyl, wherein said Ci-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCORig, -NRuCORi^, -OCOOR,o, -NRHCOORIQ, -NRnCONR j^Rn, -CORjg, -COOR jg, and -CONR j^Rii; or R2 and Ai or R2 and A2, taken together with the atoms to which they are attached, can form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -RIQ, -ORio, -OCORig, -NRnCORc -OCOORi^, -NRUCOORIQ, -NRnCONR'^Ru, -COR^^, -COORjQ, and -CONR^^Rn;
R3 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and -ORio;
R4 is selected from the group consisting of hydrogen , hydroxy and Ci-Cg alkyl, wherein said Ci-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and -OR]Q;
R5, R(, and R7 are each independently selected from hydrogen, fluorine, chlorine, -CF3, -OH, -OR,o, -OQ, NRioRn, -NRi^Q, -NRi^Q, -NR„COR i^, -OCOOR^^, -NRnCOORj^, -NRnCONRioRn, -CORIO, -COOR^^, -CONRj^Rn, and Cj-Cg alkyl, wherein said Ci-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCORJQ, -NRHCORIQ, -OCOOR^^, -NRnCOORio, -NRnCONRioRn, -CORIO, -COORIO, and -CONRioRn;
Rg and R9 are each selected from hydrogen, hydroxy, methoxy, amines, alkyl or acyl.
Rio and Rn are each independently selected from the group consisting of hydrogen, Ci-Cia alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said -7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORio, -OCOR fi, -NRnCORio, -OCOORIO,-NRnCOORio, -NRnCONRioRn, -COR, Q,-COOR] g, and-CONRioRn;
RI2 and R13 are each independently selected from the group consisting of hydrogen, Ci-Cg alkyl, Ci-C6 haloalkyl, phenyl, and phenymethyl, wherein said phenyl group or the phenyl

portion of the phenylmethyl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, methoxy, trifluormethoxy, and amino; and R^^ and Rj5, taken together with the atoms to which they are attached, form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of halo, methyl and methoxy;
s
Ri and R are each independently selected from the group consisting of hydrogen and Ci-Cg
alkyl;
Rjg is selected from the group consisting of hydrogen and C\-C(, alkyl, wherein said C1-C6 alkyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, methoxy, amino, thio, methylthio, -C(0 )0H, -C(0)0 -(Ci-Cs alkyl), -CONH2, and phenyl, wherein said phenyl may be optionally substituted with one or more substituents selected from the group consisting of halo and hydroxyl; Q is selected from the group consisting of:
X and Y are each independently selected from the group consisting of hydrogen and C1-C12 alkyl, wherein said Ci-Cj2 alkyl that may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCORio, -

wo 2014/115167

PCT/IN2014/000048

10'
NRnCORio, -OQ, -NR0Q, -OCOORio, -NRiiCOOR,„, -NRnCONR^Rn, -COR COORio, and -CONRioRn.
R^ may be hydrogen.
The compound of the present invention, compounds have structural Formula IV:
Wi'W2
/
Ai I R
R2 Rs
(IV)
or a salt thereof, wherein:

a dashed line represents an optional double bond or a methylene group attached to the atoms on either side such that a fused cyclopropyl ring results, provided that cumulated double bonds (=C=) are not allowed;
n is an integer from 1 to 6;

2" ■
Ai is selected from the group consisting of hydrogen, deuterium, halogen, -OH, P043", -S04

-OR,0, -NRi0Rii, -OQ, -NRT^IQ, -NRnCOR,„, -OCOORTP,, -NR„COOR
, 'U' '0 ' ^' I0^' " 10' I0' ^'
NRi iCONR,„Rii, -CORio, -COOR,„, and -CONRioRn,;
10 ' ' 10' "

10

A2is selected from the group consisting of hydrogen, deuterium, halogen, P04^', -S04 , d-C12 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein heteroatom of the heterocylic ring or heteroaryl ring is selected from N, O or S; wherein said 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Ri0, -OR|0, -OCORio, -NRnCORio, -OCOORio, -NRnCOORio, -NR| 1 CONRioRii, -COR10, -COOR,0, -CONR10RU; or A\ and A2, taken together with the atom to which they are attached, may form a 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may
15

wo 2014/115167 PCT/IN2014/000048
be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORio, -OCORi, -NRnCOR10, -OCOORi0, -NRiiCOORi0, -NRnCONR i„; -CORir,, -COORio, and -CONR, 0Rn; or Ai and A^, taken together, are =0;
'0' '0' ' ' U^ ' ' 2' o 5 5
Ri is selected from the group consisting of hydrogen, fluorine, chlorine, -CFo, -ORi0, -
1 Of o J o ^ ■> ' . 3' U'
NRipRii, -OQ, -NRioQ, -NRiiCOR,„, -OCOOR,„, -NRnCOOR,„, -NRiiCONR,„, -COR,0, -
r- •> ^<.? ^<.? »i 10' 10' 10' *^ 10' ' U'
COORio, or -CONRioRu, and Ci-Cg alkyl, wherein said C-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCORio, -NRnCORio, -OCOORi„, -NRnCOORi0, -NRnCONRi0Rii, -
' ' ' ' '0' '' U' '' U^ '
CORio, -COORio, and -CONRioRu; or Rj and Ai or Ri and A2, taken together with the atoms to which they are attached, can form a 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORio, -OCORio, -NRnCORio, -OCOOR,o, -NR,iCOOR 10, -NRiiCONR10Rii, -COR10, -
COORio, and -CONR,„Rii;
' 10 '
R2 is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -ORio, -NRioRii, -OQ, -NRioQ, -NR„COR, 0, -OCOOR1, -NRnCOOR ,„, -NR,iCONR ,„Rii, -
' ^' ^' ,, ' \r 1 ' 10' ' 10 ''
COR,„, -COORio, - CONRioRu, and Ci-Ce alkyl, wherein said Ci-C6 alkyl may be optionally
10' ' ' u J 5 I {^ J J f J
substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCOR,„, -NRnCORio, -OCOORio, -NRnCOORi0, -NRnCONRioRu, -
' ' 10' ' 5 H (J5 I I ■>
CORio, -COORio, and -CONRiou; or R^ and Ai or Ri and A^, taken together with the atoms
' ' " ' 2 ^2' °
to which they are attached, can form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORio, -OCOR,„, -NRnCORio, -OCOORio, -NRnCOORir,, -NRiiCONRi0Ru, -CORio, -
'10' ' ' ' -0' '0 ' '
COORio, and -CONRioRu;
R3 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and -ORio;
i- Of o J o ^ ■> 5 J 5 ■>
R. is selected from the group consisting of hydrogen , hydroxy and Ci-C^ alkyl, wherein said
4 Of O J O ^ J J 10^5
Ci-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and -ORj 0;
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R5, R6 and R7are each independently selected from hydrogen, fluorine, chlorine, -CF3, -OH, -ORio, -OQ, NRioRn, -NR10Q, -NRI0Q, -NRIICORi0, -OCOORI0, -NRIICOOR,o, -NRnCONR10Rii, -COR10, -COOR10, -CONR,oRn, and C|-Ce alkyl, wherein said Ci-C6 alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORi 0 , -OCOR, 0 , -NRIICORi 0 , -OCOOR10, -NRHCOORi 0 , -NRnCONRioRii, -COR, 0, -COOR 10, and -CONRioRi,;
Rg and R9 are each selected from hydrogen, hydroxy, methoxy, amines, alkyl or acyl. Rio and Rn are each independently selected from the group consisting of hydrogen, C1-C12 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said -7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -RI0, -ORi0, -OCORJO, -NRnCORio, -OCOOR10, -NRnCOORio, -NRnCONRioRii, -COR10, -COOR 10 , and-CONRioRn;
R12 and Ri3 are each independently selected from the group consisting of hydrogen, Ci-C6 alkyl, Ci-C 6 haloalkyl, phenyl, and phenymethyl, wherein said phenyl group or the phenyl portion of the phenylmethyl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, methoxy, trifluormethoxy, and amino; and R14 and R15, taken together with the atoms to which they are attached, form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of halo, methyl and methoxy;
Ri4 and R15 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl;
R16 is selected from the group consisting of hydrogen and Ci-Ce alkyl, wherein said Ci-C6 alkyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, methoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(Ci-C 3 alkyl), -CONH2, and phenyl, wherein said phenyl may be optionally substituted with one or more substituents selected from the group consisting of halo and hydroxyl;
17

wo 2014/115167

PCT/IN2014/000048

Q is selected from the group consisting of:




R
O

12

O Ri2
n ^^13

o
\ 0-Ri3

O D

o

.R

12

N'Ri2 I Rl3

O Ri2
R
Rl3
16
R14R159 R12

O O
12
,R
R14R15 9 p
" 0-R13

o.
R12 n
R14R15O V^0^R,3
R14R159
RuRisO^.P

R14R15O
R16 R12
o
V*°Y" ^«o... V-A,:- ^■A.o^^,;.
12
o
O
°^
6 , and
°^,
O •

Wi, Wo and Wo are each independently selected from the group consisting of CH,, CH, C,
3
2,
' 2 .-> f J Of 0 7'''
NH, N, NR,o, NQ, and O; and

X and Y are each independently selected from the group consisting of hydrogen and Ci-C)2 alkyl, wherein said C]-Ci2 alkyl that may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR10, -OCOR10, -NRnCORio, -OQ, -NR^Q, -OCOOR,„, -NRiiCOORio, -NRnCONR ,„Rii, -COR10, -
' ^-' '0^' 10' 11 ? 10 ' '
COOR10, and -CONRioRn-
The present invention further provides compounds have structural Formula V:

18
or a salt thereof, wherein:

wo 2014/115167 PCT/IN2014/000048
a dashed line represents an optional double bond or a methylene group attached to the atoms on either side such that a fused cyclopropyl ring results, provided that cumulated double bonds (=C=) are not allowed; and it is understood by a person skilled in the art that the atoms are placed inside the molecule such that their valency is suitably satisfied;
Aiand A2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C3 alkyl, hydroxy, C,-C3 alkoxy, -NH2, P0 43'or -S0 2';
or Ai and A2, taken together, is selected from the group consisting of carbonyl or Oxime; or Ai and A~, taken together with the atom to which they are attached, may form a 3-7
' 2' ° J ^ J
membered cycloalkyl, 4-7 membered heterocycloalkyl comprising 1-3 heteroatoms selected from O or N, or 5-6 membered heteroaryl comprising 1-3 hereoatoms; wherein the heteroatom is selected from the group consisting of O,N and S.
Ri and R,, are each independently selected from the group consisting of hydrogen, deuterium,
2 f J Of o J o ^ ■>
halogens, hydroxy, C1-C3 alkyl, Ci-C3 alkoxy or -NHo; or Ri and R? taken together may be selected from an oxo group or an oxime group.
Ro is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and -OR10;
3 Of o J o ^ ■> 5J5 ■>
R4 is selected from the group consisting of hydrogen , hydroxy and Ci-C 6 alkyl, wherein said
Of O J O ^ J J (j J ^
Ci-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and -ORir,;
Of O 5 5 0;
Bi and Bo are each independently selected from the group consisting of hydrogen, deuterium,
2 f J Of 0J05 5
an -NHT, a carbonyl, a Cr 5 alkoxy, -OH, -ORo, -CORo, -CONR^R., -CONH(CH2) NH,, -
Z5 J 5 1-5 J 5 5 35 35 34 ' ^ 2''n 2'
C(R3)=N-OH or -C(R3)=N-NH2; or a Ci 5 alkyl optionally substituted with one or more substituents selected from the group consisting of an alkyl, amino, a hydroxyalkyl, a carbonyl group, a C1 5 alkoxy, -OH, -OR3, -COR3, -CONR3R4, -CONH(CH2) NH2, -C(R3)=N-OH or -NHCOCH-NH,; or Bi is a 3-7 membered cycloalkyl or 4-7 membered heterocycloalkyl or
22 ' -' . -' -' -'
heterocycloalkenyl group comprising 1-3 heteroatoms selected from O or N, or 5-6 membered heteroaryl comprising 1-3 hereoatoms selected from the group consisting of O, N and S; any of which may be optionally substituted with one or more C1-C3 alkyl or a carbonyl group; or Bi and B,, taken together, is an oxo or an oxime group; or Bi and BT, taken together
O J-5 2' O 5 O J-5 ^ Z5 O
with the atom to which they are attached, may form a 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally
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wo 2014/115167 PCT/IN2014/000048
substituted with one or more substituents selected from the group consisting of hydrogen, -NH2, hydroxyl, carbonyl, Ci5 alkyl or a Ci 5 alkoxy group;
Rg and R9 are each selected from hydrogen, hydroxy, methoxy, amines, alkyl or acyl. With the proviso that the 11th position is [3 in configuration.
The compound of the present invention is selected from the group consisting of Examples 1 to 70.
In certain embodiments, disclosed herein is a method of treatment of a mitochondrial biogenesis-mediated disease comprising the administration of a therapeutically effective amount of a compound as disclosed herein to a patient in need thereof.
The mitochondrial biogenesis-mediated disease is selected from the group consisting of skeletal or cardiac muscle diseases associated with ischemia, or impaired or inadequate blood flow, diseases associated with genetic disorders that directly or indirectly affect the number, structure, or function of mitochondria, diseases associated with impaired neurological function associated with decreased mitochondrial number or function, diseases associated with loss of number, loss of function, or loss of correct, optimally efficient internal organization of skeletal muscle cells or cardiac muscle cells, metabolic diseases, and conditions associated with liver cell injury and altered fatty acid metabolism.
The mitochondrial biogenesis-mediated disease is selected from the group consisting of acute coronary syndrome, myocardial infarction, angina, renal injury, renal ischemia, diseases of the aorta and its branches, injuries arising from medical interventions, atherosclerosis, trauma, diabetes, hyperlipidemia, vascular stenosis, peripheral arterial disease, vasculopathy, and vasculitis.
The mitochondrial biogenesis-mediated disease is selected from the group consisting of Friedreich's ataxia, muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy, limb girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, spinal muscular atrophy, and Emery-Dreifuss muscular dystrophy.
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The mitochondrial biogenesis-mediated disease is selected from the group consisting of Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.
The mitochondrial biogenesis-mediated disease is selected from the group consisting of sarcopenia.
The mitochondrial biogenesis-mediated disease is selected from the group consisting of congestive heart failure, aging, myocarditis, myositis, polymyalgia rheumatic, polymyositis, HIV, cancer and/or the side effects of chemotherapy targeting the cancer, malnutrition, aging, inborn errors of metabolism, trauma, and stroke or other types of neurological impairment.
The mitochondrial biogenesis-mediated disease is selected from the group consisting of hepatic steatosis, hepatic fibrosis, cirrhosis, and hepatocyte or stellate cell injury.
In further embodiments, said method further comprises the administration of another therapeutic agent.
The said agent is selected from the group consisting of hormones which stimulate muscle cell growth, y-amino butyric acid or its derivatives, dietary protein supplements, anabolic steroids, biological factors known to enhance the growth, strength, endurance, or metabolism of skeletal or cardiac muscle, or recovery of skeletal muscle or cardiac muscle from injury or weakness, compounds known to be associated with increased nitric oxide production which promotes blood flow through muscles, extracts of natural products known to promote muscle strength or endurance, inhibitors of myostatin, stimulators of folistatin expression, compounds known to promote or facilitate mitochochondrial function or biogenesis, a tetracycline antibiotic, glycoprotein Ilb/IIIa inhibitor, ADP receptor/P2Y12 inhibitor, prostaglandin analog, COX inhibitor, antiplatelet drug, anticoagulant, heparin, direct factor Xa inhibitor, direct thrombin (II) inhibitor, vasodilator.
The said agent is doxycycline.
The said agent is niacin or allopurinol.
In certain embodiments, disclosed herein are methods of treating or preventing the adverse effects of administration of compounds which exhibit mitochondrial toxicity comprising the
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administration of a therapeutically effective amount of a compound as disclosed herein to a patient in need thereof.
The adverse effect is selected from the group consisting of abnormal mitochondrial respiration, abnormal oxygen consumption, abnormal extracellular acidification rate, abnormal mitochondrial number, abnormal lactate accumulation, and abnormal ATP levels.
In certain embodiments, disclosed herein are methods of improving muscle structure or function; improving mitochondrial effects associated with exercise; enhancing the capacity for exercise in those limited by age, inactivity, diet, or diseases; enhancing muscle health and function in response to exercise; enhancing muscle health and function in the clinical setting of restricted capacity for exercise; enhancing recovery of muscles from vigorous activity or from injury associated with vigorous or sustained activity, comprising the administration of a therapeutically effective amount of a compound as disclosed herein to a patient in need thereof.
In certain embodiments, disclosed herein are methods of enhancing sports performance and endurance, building muscle shape and strength, or facilitating recovery from the muscle related side effects of training or competition comprising the administration of a therapeutically effective amount of a compound as disclosed herein to a patient in need thereof.
In certain embodiments, disclosed herein are methods of stimulating increased number or function of skeletal muscle cells or contractile muscle cells comprising the administration of a therapeutically effective amount of a compound as disclosed herein to a patient in need thereof.
The said stimulation of muscle cells comprises stimulation of cell division, muscle cell regeneration, activation of muscle satellite cells and their differentiation into adult muscle cells, recovery from injury, increased number or function of mitochondria or processes serving mitochondrial function, increased expression of proteins contributing to contractility, regulation of biochemical or translational processes, mitoses, or transduction of mechanical energy via dystrophin or other attachment processes.
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In certain embodiments, disclosed herein is a method of modulation of mitochondrial biogenesis comprising contacting mitochondria with a compound as disclosed herein.
The mitochondrial biogenesis-mediated diseases include sarcopenia, muscular dystrophy, neurodegenerative diseases, liver disease, acute or chronic kidney failure, congestive heart failure, chronic obstructive pulmonary disorder (COPD), peripheral vascular disease, pulmonary hypertension, hyperlipidemia, hypertension, and diabetes.
The present invention comprises administering a compound or composition disclosed herein in an amount effective to stimulate the function, recovery, or regeneration of mitochondria or mitochondrial proteins or function. In further embodiments, the present invention provides methods for preventing or treating adverse events or diseases associated with impaired mitochondrial number or function.
The term "about," as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.
The term "acyl," as used herein, alone or in combination, refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon. An "acetyl" group refers to a -C(0)CH 3 group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.
The term "alkenyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene [(-CH=CH-),(-C::C-)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwise specified, the term "alkenyl" may include "alkenylene" groups.
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The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
The term "alkyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will comprise from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like. The term "alkylene," as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term "alkyl" may include "alkylene" groups.
The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like.
The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.
The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether (R-S-) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.
The term "alkynyl," as used herein, alone or in combination, refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term
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wo 2014/115167 PCT/IN2014/000048
"alkynylene" refers to a carbon-carbon triple bond attached at two positions such as
ethynylene (-C:::C-, -C=C-). Examples of alkynyl radicals include ethynyl, propynyl,
hydroxypropynyl, butyn-l-yl, butyn-2-yl, pentyn-l-yl, 3-methylbutyn-l-yl, hexyn-2-yl, and
the like. Unless otherwise specified, the term "alkynyl" may include "alkynylene" groups.
The terms "amido" and "carbamoyl,"as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa. The term "C-amido" as used herein, alone or in combination, refers to a -C(0)N(RR') group with R and R' as defined herein or as defined by the specifically enumerated "R" groups designated. The term "N-amido" as used herein, alone or in combination, refers to a RC(0)N(R')- group, with R and R' as defined herein or as defined by the specifically enumerated "R" groups designated. The term "acylamino" as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CH3C(0)NH-).
The term "amino," as used herein, alone or in combination, refers to —NRR , wherein R and R are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may combine to form heterocycloalkyl, either of which may be optionally substituted.
The term "aryl," as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.
The term "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
The term "arylalkyl" or "aralkyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
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wo 2014/115167 PCT/IN2014/000048
The term "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
The term "arylalkanoyl" or "aralkanoyl" or "aroyl,"as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.
The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.
The terms "benzo" and "benz," as used herein, alone or in combination, refer to the divalent radical C6H4= derived from benzene. Examples include benzothiophene and benzimidazole.
The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.
The term "0-carbamyr as used herein, alone or in combination, refers to a -OC(0)NRR\ group-with R and R' as defined herein.
The term "N-carbamyl" as used herein, alone or in combination, refers to a ROC(0)NR'-group, with R and R' as defined herein.
The term "carbonyl," as used herein, when alone includes formyl [-C(0)H] and in combination is a -C(O)- group.
The term "carboxyl" or "carboxy," as used herein, refers to -C(0)OH or the corresponding "carboxylate" anion, such as is in a carboxylic acid salt. An "O-carboxy" group refers to a RC(0)0- group, where R is as defined herein. A "C-carboxy" group refers to a -C(0)OR groups where R is as defined herein.
The term "cyano," as used herein, alone or in combination, refers to -CN.
The term "cycloalkyl," or, alternatively, "carbocycle," as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and
26

wo 2014/115167 PCT/IN2014/000048
which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In certain embodiments, said cycloalkyl will comprise from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-lH-indenyl, adamantyl and the like. "Bicyclic" and "tricyclic" as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[l,l,l]pentane, camphor, adamantane, and bicyclo[3,2,1] octane.
The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms.
The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms.
The term "halo," or "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
The term "haloalkyl," as used herein, alone or in combination, refers to an alkyl radical
having the meaning as defined above wherein one or more hydrogens are replaced with a
halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A
monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom
within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo
atoms or a combination of different halo radicals. Examples of haloalkyl radicals include
fiuoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHC1-) and the like.
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The term "heteroalkyl," as used herein, alone or in combination, refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3.
The term "heteroaryl," as used herein, alone or in combination, refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom selected from the group consisting of O, S, and N. In certain embodiments, said heteroaryl will comprise from 5 to 7 carbon atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The terms "heterocycloalkyl" and, interchangeably, "heterocycle," as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur In certain embodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said hetercycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said
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hetercycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said hetercycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said hetercycloalkyl will comprise from 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrdcinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-bjpyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.
The term "hydrazinyl" as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.
The term "hydroxy," as used herein, alone or in combination, refers to -OH.
The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
The term "imino," as used herein, alone or in combination, refers to =N-.
The term "iminohydroxy," as used herein, alone or in combination, refers to =N(OH) and =N- C.
The phrase "in the main chain" refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein.
The term "isocyanato" refers to a -NCO group.
The term "isothiocyanato" refers to a -NCS group.
The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
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The term "lower," as used herein, alone or in a combination, where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms.
The term "lower aryl," as used herein, alone or in combination, means phenyl or naphthyl, either of which may be optionally substituted as provided.
The term "lower heteroaryl," as used herein, alone or in combination, means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four said members may be heteroatoms selected from the group consisting of O, S, and N, or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms selected from the group consisting of O, S, and N.
The term "lower cycloalkyl," as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "lower heterocycloalkyl," as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms selected from the group consisting of O, S, and N. Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls may be unsaturated.
The term "lower amino," as used herein, alone or in combination, refers to —NRR , wherein R and R are independently selected from the group consisting of hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and R' of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, either of which may be optionally substituted.
The term "mercaptyl" as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.
The term "nitro," as used herein, alone or in combination, refers to -N0 2. The terms "oxy" or "oxa," as used herein, alone or in combination, refer to -0-.
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The term "oxo," as used herein, alone or in combination, refers to =0.
The term "perhaloalkoxy" refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
The term "perhaloalkyl" as used herein, alone or in combination, refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
The terms "sulfonate," "sulfonic acid," and "sulfonic," as used herein, alone or in combination, refer the -S0 3H group and its anion as the sulfonic acid is used in salt formation.
The term "sulfanyl," as used herein, alone or in combination, refers to -S-.
The term "sulfinyl," as used herein, alone or in combination, refers to -S(0>-.
The term "sulfonyl," as used herein, alone or in combination, refers to -S(0) 2-.
The term "N-sulfonamido" refers to a RS(=0) 2NR'- group with R and R' as defined herein.
The term "S-sulfonamido" refers to a -S(=0 )2NRR', group, with R and R' as defined herein.
The terms "thia" and "thio," as used herein, alone or in combination, refer to a -S- group or an ether wherein the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.
The term "thiol," as used herein, alone or in combination, refers to an -SH group.
The term "thiocarbonyl," as used herein, when alone includes thioformyl -C(S)H and in combination is a -C(S)- group.
The term "N-thiocarbamyl" refers to an ROC(S)NR'- group, with R and Ras defined herein.
The term "O-thiocarbamyl" refers to a -OC(S)NRR', group with R and Ras defined herein.
The term "thiocyanato" refers to a -CNS group.
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The term "trihalomethanesulfonamido" refers to a X3CS(0) iNR- group with X is a halogen and R as defined herein.
The term "trihalomethanesulfonyl" refers to a X3CS(0) 2- group where X is a halogen.
The term "trihalomethoxy" refers to a X3CO- group where X is a halogen.
The term "trisubstituted silyl," as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.
"Deuterated compounds" encompassed within the scope of this invention are the compounds which have selective incorporation of deuterium in place of hydrogen.
Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
When a group is defined to be "null," what is meant is that said group is absent.
The term "optionally substituted" means the anteceding group may be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(0)CH 3, C0 2CH3, C02H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may
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be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, "optionally substituted with."
The term R or the term R', appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether an R group has a number designation or not, every R group, including R, R' and R" where n=(l, 2, 3, ...n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as -C(0)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen;
Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms as well as d-isomers and 1-isomers, and mixtures thereof Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic
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columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.
The term "bond" refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
The term "disease" as used herein is intended to be generally synonymous, and is used interchangeably with, the terms "disorder," "syndrome," and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
The term "muscular diseases" refers to diseases associated with impaired skeletal muscle or cardiac muscle cell number or function.
The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. In certain embodiments, a combination of compounds is administered such that the clearance half-life of each compound from the body overlaps at least partially with one another. For example, a first pharmaceutical has a
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clearance half-life of 1 hour and is administered at time=0, and a second pharmaceutical has a clearance half-life of 1 hour and is administered at time=45 minutes.
The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.
The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
As used herein, reference to "treatment" of a patient is intended to include prophylaxis. Treatment may also be preemptive in nature, i.e., it may include prevention of disease. Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen, or may involve prevention of disease progression. For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable level. Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease.
The term "patient" is generally synonymous with the term "subject" and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.
The term "pregnenolone and other related steroids" as used herein refers to any compound which retains the ring structure and the 11-oxo moiety of 11-hydroxy-pregnenolone itself, but which contains one or more substituent groups relative to 11-oxo-pregenolone. The term also includes prodrugs which release 11-hydroxy-pregnenolone when administered to a subject. The term also includes active metabolites of 11p-hydroxypregnenolone such as 11(3-hydroxypro gesterone.
The term " 1 1p-hydroxypregnenolone" as used herein refers to a compound having the structural formula:
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The term "li b-hydroxyprogesterone" as used herein refers to a compound having the structural formula:


The term "derivative" as used herein to modify the term "Ii b-hydroxypregnenolone" or "Iip-hydroxysreoid" the term " 1 1 b-hydroxyprogesterone" refers to any compound which retains the ring structure and stereochemistry of 1 1 b-hydroxypregnenolone or 11 b-hydroxyprogesterone, "Ii b-hydroxysreoid" itself, but which contains one or more substituent groups relative to 1 1 b-hydroxypregnenolone or 1 1 b-hydroxyprogesterone. The term also includes combination molecules or prodrugs that release 1 1 b-hydroxypregnenolone when administered to a subject. Such a combination molecule may include, for example, 11 b-hydroxypregnenolone and an agent joined by a hydrolysable linker group.
The term "HCAEC" as used herein refer to Human corniary Artery endothelial cells; the term "BCAEC" refers to bovine corniary Artery endothelial cells; and the term "GAPDH" refers to glyceraldehyde-3-phosphate dehydrogenase.
The term "prodrug" refers to a compound that is made more active in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs
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are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
The compounds disclosed herein can exist as therapeutically acceptable salts. The present invention includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and f/se (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).
The term "therapeutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and

undecanoate. Also, basic groups in the compounds disclosed herein can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group, with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, tri ethyl amine, diethylamine, ethylamine, tributylamine, pyridine, iV, iV^dimethylaniline, iV-methylpiperidine, iV-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, iV iV-dibenzylphenethylamine, 1-ephenamine, and iV,jV-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piped dine, and piperazine.
A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
While it may be possible for the compounds of the subject invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and

excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

We Claim:
1. A compound of structural Formula I:
or a salt thereof, wherein:
a dashed line represents an optional double bond or a methylene group attached to the atoms on either side such that a fused cyclopropyl ring results, provided that cumulated double bonds (=C=) are riot allowed; n is an integer from 1 to 6;
A) is selected from the group consisting of hydrogen, deuterium, halogen, -OH, PO ^3" , -S042", -OR,o, -NRigRii, -OQ, -NR,QQ, -NR„C0R, Q, -OCOORO, -NR„C00R ^^, -NRnCONRioRh, -CORi^, -COORio, and -CONRipRn;
A2 is selected from the group consisting of hydrogen, deuterium, halogen, PO^^' ^ -S04 ', C1-C12 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein heteroatom of the heterocylic ring or heteroaryl ring is selected from N, O or S; wherein said 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORig, -OCORIO, -NRnCORio, -OCOORIQ, -NRHCOORIQ, -NRnCONR ^oRn, -CORIO, -COORio, -CONRlORll; or Ai and A^, taken together with the atom to which they are attached, may form a 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -RIQ, -OR,Q, -OCORi, -NRnCORio, -OCOORIO, -NRuCOOR^o, -NRIICONRIO; -COR,Q, -COORIQ, and -CONRi^R^ ; or Ai and A^, taken together, are =0;

B and C are each independently selected from the group consisting of hydrogen, -OH, -ORio, -NRioRn, -OQ, -NR^^Q, -NRnCORi, -OCOORj, -NRnCOORig, -NRnCONRi Q'-CORIO, -COORIO,-CONR|ORII, ,-NH(CH2)„NH2. ,-NRiiCO(CH2)nNH2
and Ci-Ci 2 alkyl, wherein said Ci-Ci 2 alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR^^, -OCORio, -NRnCORio, -OCOORIQ, -NRHCOORIQ, -NRUCONR i^Rn, -COR^^, -COORio, and -CONRioRn; or B and C, taken together with the atom to which they are attached, may form a 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, wherein heteroatom of the heterocylic ring or heteroaryl ring is selected from N, O or S;, any of which may be optionally substituted with one or more Cj-Cj^ alkyl; wherein said Ci-Ci2 alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCOR,o, -NRnCORio, -OCOOR^^, -NR2COOR, Q, -NRnCONRjoRii, -CORj^, -COORio, and -CONRioRn; or B and C, taken together, are =0, =N-OH or =N-NH2; D is selected from the group consisting of hydrogen, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, amino, hydroxyalkyl, -CD3, -CF3, -OR^^, -OCF3, phenyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; wherein heteroatom in the said heteroalkyl or heteroaryl ring is selected from the group of N, O or S; wherein said 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of Ci-C4 alkyl, -Rig, -ORio, -NRioRn, fluorine, chlorine, and -CF3 or a C=0 group ; or when taken together with B or C, may represent a double bond; or B, C and D, taken together with the atom to which they are attached, may form a carbonyl group, oxime group, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; any of which may be optionally substituted with one or more substituents selected from the group consisting of-Ci-C4 alkyl, -Rio, -ORio, -NRioRn, fluorine, chlorine, -C=0 and -CF3;
Ri is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -ORio, -NRioRn, -OQ, -NRIOQ, -NRnCORio, -OCOORIO, -NRnCOORio, -NRHCONRIQ, -CORjO, -COORio, or -CONRioRn, and C,-C6 alkyl, wherein said Ci-Ce alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCORio, -NRnCORio, -OCOOR, Q, -NRuCOORio, -NRnCONRioRn, -COR, 0, -COORio, and -CONRioRn; or R, and Ai

or Ri and A^^ taken together with the atoms to which they are attached, can form a 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORIQ, -OCORio, -NRnCORio, -OCOOR,o,-NRnCOORio, -NR,iCONR i^Rn, -COR,Q, -COORJ^, and -CONR,QRII; R2 is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -OR^g, -NR,oRii, -OQ, -NRioQ, -NR„ CORio, -OCOORio, -NRuCOORj^, -NRuCONR'^Rn, -CORjQ, -COORjQ, - CONRioRii, and Ci-Cg alkyl, wherein said d-C g alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORIQ, -OCORIO, -NRHCORIQ, -OCOORJQ, -NRiiCOOR,o, -NRhCONRioRn, -COR^^, -COORio, and -CONR^^Rn; or R2 and Ai or R2 and A2, taken together with the atoms to which they are attached, can form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORio, -OCOR^^, -NRu CORio, -OCOORJQ, -NRhCOORig, -NRuCONR i^Ru, -CORio, -COORio, and -CONRIQRU; R3 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and -ORio;
R4 is selected from the group consisting of hydrogen, hydroxy and Ci-Ce alkyl, wherein said Ci -Ce alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and -ORIQ; Rj, Rg and R7 are each independently selected from hydrogen, fluorine, chlorine, -CF3, -OH, -ORio, -OQ, NR,QRII, -NRJ^Q, -NRJQQ, -NRnCORio, -OCOOR^^, -NRnCOORio, -NRhCONRioRn, -COR,o, -COORio, -CONRigRn, and C,-C6 alkyl, wherein said Ci-Ce alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR^^, -OCORio, -NRnCORio, -OCOOR,o, -NR„ COORio, -NRnCONR'^Rn, -CORio, -COORio, and -CONR,oRii;
Rg and R 9 are each selected from hydrogen, hydroxy, methoxy, amines, alkyl or acyl. Rio and Rii are each independently selected from the group consisting of hydrogen, Ci-Ci2 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said -7 membered cycloalkyl, 4-7 membered

heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -
ORio, -OCORio, -NRnCORio, -OCOORJQ, -NRHCOORIQ, -NRiiCONRjoRii, -CORio, -COORio, and -CONRj^R,,;
R12 and R13 are each independently selected from the group consisting of hydrogen, Ci-Cg alkyl, Ci-C^ haloalkyl, amino, substituted amino, phenyl, and phenymethyl, wherein said phenyl group or the phenyl portion of the phenylm ethyl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, methoxy, trifiuormethoxy, and amino; and R^^ and R]5, taken together with the atoms to which they are attached, form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of halo, methyl and methoxy;
Ri4 and Rj5 are each independently selected from the group consisting of hydrogen and Ci-Cg alkyl;
R16 is selected from the group consisting of hydrogen and Ci-Cg alkyl, wherein said Ci-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, methoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(C i-Cg alkyl), -CONH2, and phenyl, wherein said phenyl may be optionally substituted with one or more substituents selected from the group consisting of halo and hydroxyl; Q is selected from the group consisting of:

X and Y are each independently selected from the group consisting of hydrogen and C]-Ci2 alkyl, wherein said Ci-Ci2 alkyl that may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR^Q, -OCORig, -NRnCORio, -OQ, -NRIOQ, -OCOORio, -NRuCOORio, -NRuCONRioRn, -CORK,-COORio, and-CONR,„Rii.
2. The compound as claimed in claim 1, having structural Formula II:
or a salt thereof, wherein:
a dashed line represents an optional double bond or a methylene group attached to the
atoms on either side such that a fused cyclopropyl ring results, provided that
cumulated double bonds (=C=) are not allowed;
n is an integer from 1 to 6;
m is an integer from 1 to 6;
Ai is selected from the group consisting of hydrogen, -OH, deuterium, halogen, PO43"
, -SO42., -ORio, -NRioRu, -OQ, -NRj^Q, -NR„CORio, -OCOOR^^, -NRUCOOR^Q, -
NRnCONR j^Rii, -CORj^, -COOR^^, and -CONRioRii;
A2 is selected from the group consisting of hydrogen, deuterium, halogen, PO ^' , -
so 4 ", C1-C12 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-
6 membered heteroaryl, wherein heteroatom in the said heteroalkyl or heteroaryl ring
is selected from the group of N, O or S; wherein said'3-7 membered cycloalkyl, 4-7
membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally

substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Ri^, -ORio, -OCORio, -NRiiCORio, -OCOOR i^, -NR„ COORIQ, -NRnCONR mRii, -CORio, -COORJO, -CONR mRn; or Ai and Aj, taken together with the atom to which they are attached, may form a 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rj^, -ORio, -OCORi, -NRnCOR i^, -OCOORio, -NRnCOORio, -NRnCONR^; -CORio, -COORj^, and -CONRmRn; or Ai and Aj, taken together, are =0;
Ri is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -ORj^, -NRioRii, -OQ, -NRioQ, -NRnCORio, -OCOOR i^, -NRnCOORio, -NRnCONR i^, -CORjo, -COORjo, or -CONRi QRU, and Ci-Cg alkyl, wherein said CpCg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR^, -OCORio, -NRnCOR m, -OCOORi^, -NRnCOORio, -NRnCONRioRii, -COR^, -COORio, and -CONRioRn; or R, and A1 or Ri and Aj, taken together with the atoms to which they are attached, can form a 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rj^, -ORi^, -OCORio, -NRnCORio, -OCOOR,o, -NRnCOORio, -NRnCONRioRn, -CORio,-COOR^, and-CONR ^Rn; R2 is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -ORio, -NRjoRii, -OQ, -NRioQ, -NRnCORio, -OCOOR m, -NRnCOORio, -NR „ CONRioRn, -CORio, -COORio, - CONRioRn, and Ci-Cg alkyl, wherein said Ci-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCOR^, -NR^CORjo, -OCOORio, -NRnCOORio, -NRn CONRioRn, -CORio, -COORio, and -CONR ^Rn; or Rj and Ai or R2 and Aj, taken together with the atoms to which they are attached, can form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -OR^, -OCORio, -NRnCORio, -OCOORio, -NRnCOOR,o, -NRiiCONR, QRH, -CORio, -COORio, and -CONRioRn; R3 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and -ORio;

R4 is selected from the group consisting of hydrogen, hydroxy and Ci-Ce alkyl, wherein said Ci-Ce alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and -OR^^; R5, Rg and R^ are each independently selected from hydrogen, fluorine, chlorine, -CF3, -OH, -ORIO, -OQ, NRigRn, -NR^^Q, -NRioQ, -NRnCORj^, -OCOOR j^, -NRIICOORIO, -NRnCONRioRj,, -CORIO, -COORj^, -CONRj^Rn, and Ci-Ce alkyl, wherein said Ci-C g alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR^Q, -OCOR^Q, -NRuCORio, -OCOORjQ, -NRnCOORj^, -NRnCONR i^Rn, -CORj^, -COORJQ, and -CONRoRu;
Rg and Rg are each selected from hydrogen, hydroxy, methoxy, amines, alkyl or acyl.Rio and Rn are each independently selected from the group consisting of hydrogen, C)-Ci2 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said -7 membered cycloalkyl, 4-7 membered ■heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORIO, -OCORIO, -NRuCORio, -OCOORvo, -NRuCOORi Q, -NRiiCONRi oRn, -CORl 0, -COOR JO, and -CONRioRn;
R12 and Rj3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, Ci-Cg haloalkyl, amino, substituted amino, phenyl, and phenymethyl, wherein said phenyl group or the phenyl portion of the phenylmethyl group may be Optionally substituted with one or more substituents selected from the group consisting of halogen, methoxy, trifluormethoxy, and amino; and Ri4 and R15, taken together with the atoms to which they are attached, form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of halo, methyl and methoxy;
Ri4 and Rj5 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl;
Rie is selected from the group consisting of hydrogen and Ci-C g alkyl, wherein said Ci-C g alkyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, methoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(Ci-C3 alkyl), -CONH2, and phenyl, wherein said phenyl may be optionally

substituted with one or more substituents selected from the group consisting of halo
and hydroxyl;
Q is selected from the group consisting of:
X and Y are each independently selected from the group consisting of hydrogen and C]-Ci2 alkyl, wherein said Ci-C j2 alkyl that may be Optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORJo, -OCOR,o, -NRnCORio, -OQ, -NRIOQ, -OCOORjo, -NRuCOORio, -NRnCONR'^R,,, -CORIO, -COORIO, and -CONRjoRii.
3. The compound as claimed in claim 1, having structural Formula III:
or a salt thereof, wherein:

a dashed hne represents an optional double bond or a methylene group attached to the atoms on either side such that a fused cyclopropyl ring results, provided that cumulated double bonds (=C=) are not allowed; n is an integer from 1 to 6;
A] is selected from the group consisting of hydrogen, deuterium, halogen, -OH, PO4 " , -SO42", -OR,o, -NR,oRn, -OQ, -NR^^Q, -NR„COR ^o, -OCOOR^^, -NRIICOOR^Q, -NRnCONR1dR.11,-CORIO,-COORio, and-CONRj^Ru;
A2 is selected from the group consisting of hydrogen, deuterium, halogen, PO ^' , -SO4 , C1-C12 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein heteroatom in the said heteroalkyl or heteroaryl ring is selected from the group of N, O or S; wherein said 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -R^^, -OR^g, -OCORic -NRiiCORj^, -OCOOR^^, -NRnCOOR^^, -NRnCONRioRn, -COR^^, -COORio, -CONRioRn; or A1 and A^, taken together with the atom to which they are attached, inay form a 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -R^^, -ORIQ, -OCORi, -NRuCORio, -OCOORIQ, -NRiiCOORio, -NRiiCONR ^o; -CORio, -COOR^^, and -CONRj^Rn; or Ai and A^, taken together, are =0;
R) is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -ORio, -NRioRii, -OQ, -NRIOQ, -NRUCORIQ, -OCOORIO, -NRnCOOR 10, -NRiiCONRio, -CORiO, -COORio, or -CONRioRn, and C,-C6 alkyl, wherein said C1-C6 alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORIQ, -OCOR^^, -NRHCOR^Q, -OCOOR JO, -NR)iCOOR,o, -NRnCONR igRii, -CORIO, -COORio, and -CONRioRn; or Ri and A, or Ri and A2, taken together with the atoms to which they are attached, can form a 4-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein heteroatom in the said heteroalkyl or heteroaryl ring is selected from the group of N, O or S; any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -RIQ' "ORJO, -OCOR,o, -NRuCORio, -OCOORIO, -NRiiCOORj^, -NRnCONRioRii, -COR, Q, -COOR,o, and -CONRioRn;

wo 2014/115167 PCT/IN2014/000048
R2 is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -OR/o, -NRioRii, -OQ, -NR10Q, -NRiiCORi„, -OCOORio, -NRuCOOR, 0, -NRnCONRi ^Rn,
5 -<5 ^' " '0' ' ' ' ' U' 0 '
-CORio, -COOR10, - CONRi0Rii, and Ci-Cg alkyl, wherein said Ct-C^ alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR10, -OCOR10, -NRnCORio, -OCOOR10, -NRnCOORio, -NR,iCONR,oRii, -COR1, -COOR, 0, and -CONR 1Ri 1; or R2 and A, or R2 and A2, taken together with the atoms to which they are attached, can form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORi 0 , -OCOR ,0, -NRnCORio, -
Of o 5 ' ' U' 1 ' '
OCOORJO , -NRijCOOR,o, -NRIjCONR )oRi), -CORjo? -COORio, and -CONR, oR,);
R3 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and -
OR10;
R4 is selected from the group consisting of hydrogen, hydroxy and Cj-Cg alkyl, wherein said Ci-C ^ alkyl may b e optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and -ORi0; R5, R6 and R7 are each independently selected from hydrogen, fluorine, chlorine, -CF3, -OH, -OR,o, -OQ, NRi0Rii, -NRl0Q, -NR10Q, -NRnCORio, -OCOORio, -NRnCOORio, -NRnCONR 10Rii, -CORio, -COOR10, -CONRl0RU, and Ci-C6 alkyl, wherein said Ci-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR10, -OCORio, -NRnCORio, -OCOOR,o, -NRnCOORio, -NRnCONRi 0Ru, -COR, 0, -COOR10, and -
' ' ' ' U '" ^ U' '
CONRioRii;
Rgand R9 are each selected from hydrogen, hydroxy, methoxy, amines, alkyl or acyl. Rio and Ri i are each independently selected from the group consisting of hydrogen, Ci-Ci2 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein said -7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -RiQ, -OR,o, -OCORio, -NRnCORio, -OCOORio, -NRHCOOR,o, -NRnCONRi0Rii, -CORio, -COOR,o, and -CONRioRn; R,2and R13 are each independently selected from the group consisting of hydrogen,
1 f J Of o J o ^
Ci-C 6 alkyl, Ci-C (, haloalkyl, phenyl, and phenymethyi, wherein said phenyl group or the phenyl portion of the phenylmethyl group may be optionally substituted with one
136

or more substituents selected from the group consisting of halogen, methoxy, trifluormethoxy, and amino; and Ri^ and Rj^, taken together with the atoms to which they are attached, form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of halo, methyl and methoxy; R]4 and Ri^ are each independently selected from the group consisting of hydrogen and q-Cg alkyl;
Rj6 is selected from the group consisting of hydrogen and Ci-C^ alkyl, wherein said C]-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, methoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(Ci-C3 alkyl), -CONH2, and phenyl, wherein said phenyl may be optionally substituted with one or more substituents selected from the group consisting of halo and hydroxyl; Q is selected from the group consisting of
X and Y are each independently selected from the group consisting of hydrogen and C j-C j2 alkyl, wherein said Ci-Ci ^ alkyl that may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCORio, -NR, iCOR,o, -OQ, -NRIQQ, -OCOORio, -NRnCOOR i^, -NRnCONRioRii, -COR,o, -COOR,o, and -CONR igRii.

4. The compound as claimed in claim 1, having structural Formula IV:
or a salt thereof, wherein:
a dashed line represents an optional double bond or a methylene group attached to the
atoms on either side such that a fused cyclopropyl ring results, provided that
cumulated double bonds (=C=) are not allowed;
n is an integer from 1 to 6;
Ai is selected from the group consisting of hydrogen, deuterium, halogen, -OH, FO 4^'
, -so/", -ORjo, -NR.0R11, -OQ, -NRjoQ, -NRnCOR j^, -OCOORo, -NRnCOORig, -
NRnCONRioRn, -CORio, -COORio, and -CONRIQRII,;
A2 is selected from the group consisting of hydrogen, deuterium, halogen, PO 4^' , -
SO42', C1-C12 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-
6 membered heteroaryl, wherein heteroatom of the heterocylic ring or heteroaryl ring
is selected from N, O or S; wherein said 3-7 membered cycloalkyl, 4-7 membered
heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one
or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -
ORjo, -OCORIO, -NRIICORIO, -OCOORi^, -NR,iCOOR j^, -NRnCONRioRn, -
CORIO, -COORio, -CONRioRif, or Ai and A2, taken together with the atom to which
they are attached, may form a 3-7 membered cycloalkyl, 4-7 membered
heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally
substituted with one or more substituents selected from the group consisting of
fluorine, chlorine, -R,o, -ORIQ, -OCORi, -NRnCORj^, -OCOOR^Q, -NRUCOORJ^, -
NR,iCONR j^; -CORj^, -COORio, and -CONRicR,,; or Ai and A2, taken together, are
=0;
R) is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -OR jg, -
NRlORll, -OQ, -NRIOQ, -NRnCORig, -OCOOR, 0, -NRnCOORig, -NRi,CONRi 0, -
CORIO, -COORjo, or -CONR, pRn, and Ci-Cg alkyl, wherein said Ci-Cg alkyl may be

optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORIQ, -OCORio, -NRnCORio, -OCOORio, -NRnCOORio, -NRnCONRioRn, -CORi^, -COORio, and -CONRioRn; or VA and Ai or Ri and A2, taken together with the atoms to which they are attached, can form a 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rio, -ORio, -OCORio, -NRuCOR[ Q, -OCOORio, -NRnCOOR j^, -NRn CONRioRn, -COR^^, -COOR^^, and -CONR, QR„; R2 is selected from the group consisting of hydrogen, fluorine, chlorine, -CF3, -ORIQ, -NRioRn, -OQ, -NRioQ, -NRnCOR ^^, -OCOOR^^, -NRUCOORIQ, -NR,, CONRioRn, -CORjQ, -COORio, - CONRioRn, and Ci-Cg alkyl, wherein said d-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCORio, -NRnCORio, -OCOORio, -NRnCOORio, -NRnCONRioRn, -CORi Q, -COOR, Q, and -CONRioRn; or R2 and Ai or R2 and A2, taken together with the atoms to which they are attached, can form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rig, -ORio, -OCOR^^, -NRnCORio, -OCOORio, -NRiiCOOR,o, -NRnCONR ^oRii, -CORIQ, -COORIQ, and -CONRioRn; R3 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and -ORio;
R4 is selected from the group consisting of hydrogen , hydroxy and Ci-Cg alkyl, wherein said Ci-Ce alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and -ORIQ; R5, Rg and Ryare each independently selected from hydrogen, fluorine, chlorine, -CF3, -OH, -ORio, -OQ, NRioRn, -NRjOQ, -NRIQQ, -NRnCORio, -OCOORio, -NRiiCOOR,Q, -NR,iCONR,oRib -COR,Q, -COOR,Q, -CONRioRn, and C,-Cg alkyl, wherein said Ci-Cg alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -ORio, -OCORio, -NRnCORio, -OCOOR,o, -NRHCOORIQ, -NR„CONRI QRU, -COR^^, -COORIO, and -
CONRioRn;
Rg and R 9 are each selected from hydrogen, hydroxy, methoxy, amines, alkyl or acyl. Rio and Rn are each independently selected from the group consisting of hydrogen, Ci-Ci2 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, and 5-6

membered heteroaryl, wherein said -7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -Rjg, -ORio, -OCORio, -NRuCORo, -OCOORio, -NRnCOORio, -NRnCONRioRn, -COR JO, -COORio, and -CONRioRn;
Ri2 and R13 are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, CpCehaloalkyl, phenyl, and phenymethyl, wherein said phenyl group or the phenyl portion of the phenylmethyl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, methoxy, trifluormethoxy, and amino; and R14 and RjS, taken together with the atoms to which they are attached, form 5-7 membered cycloalkyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of halo, methyl and methoxy; Ri^ and R15 are each independently selected from the group consisting of hydrogen and Ci-Cg alkyl;
Rjg is selected from the group consisting of hydrogen and Ci-Cg alkyl, wherein said Ci-Cealkyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, methoxy, amino, thio, methylthio, -C(0)OH, -C(0)0-(Ci-C 3 alkyl), -CONH2, and phenyl, wherein said phenyl may be optionally substituted with one or more substituents selected from the group consisting of halo and hydroxyl;
Q is selected from the group consisting of:

Wi, W2 and W3 are each independently selected from the group consisting of C%, CH, C, NH, N, NRio, NQ, and O; and
X and Y are each independently selected from the group consisting of hydrogen and Cj-Ci2 alkyl, wherein said Cj-C^^ alkyl that may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, -OR^Q, -OCOR,o, -NRnCORo, -OQ, -NRj^Q, -OCOOR, Q, -NR,ICOOR, Q, -NRnCONR jgR,,, -CORIO, -COORIO, and -CONR, QRH.
The compound as claimed in claim 1, having structural Formula V:
or a salt thereof, wherein
a dashed line represents an optional double bond or a methylene group attached to the atoms on either side such that a fused cyclopropyl ring results, provided that cumulated double bonds (=C=) are not allowed; and it is understood by a person skilled in the art that the atoms are placed inside the molecule such that their valency is suitably satisfied;
Ai and A2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, Cj-C3 alkyl, hydroxy, C^-Cg alkoxy, -N%, P0 4^'or -SO42';
or Ai and A2, taken together, is selected from the group consisting of carbonyl or Oxime; or Ai and A2, taken together with the atom to which they are attached, may form a 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl comprising 1-3 heteroatoms selected from O or N, or 5-6 membered heteroaryl comprising 1-3

wo 2014/115167 PCT/IN2014/000048
hereoatoms; wherein the heteroatom is selected from the group consisting of O, N and S.
Ri and R2 are each independently selected from the group consisting of hydrogen, deuterium, halogens, hydroxy, Ci-C3 alkyl, C 1-C3 alkoxy or -NH2; or RI and R2 taken together may be selected from an oxo group or an oxime group.
R3 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and -OR10;
R4 is selected from the group consisting of hydrogen , hydroxy and Ci-C6 alkyl, wherein said Ci-C^ alkyl may be optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, and -OR 10;
Bi and B2 are each independently selected from the group consisting of hydrogen, deuterium, an -NH2, a carbonyl, a Cis alkoxy, -OH, -OR3, -COR3, -CONR3R4, -CONH(CH2)nNH2, -C(R3)=N-OH or -C(R3)=N-NH2; or a C1-5 alkyl optionally substituted with one or more substituents selected from the group consisting of an alkyl, amino, a hydroxyalkyl, a carbonyl group, a C1-5 alkoxy, -OH, -OR3, -COR3, -CONR3R1, -CONH(CH2)nNH2, -C(R3)=N-OH or -NHCOCH2NH2; or Bi is a 3-7 membered cycloalkyl or 4-7 membered heterocycloalkyl or heterocycloalkenyl group comprising 1-3 heteroatoms selected from O or N, or 5-6 membered heteroaryl comprising 1-3 hereoatoms selected from the group consisting of O, N and S; any of which may be optionally substituted with one or more Ci-C3 alkyl or a carbonyl group; or Bi and B2, taken together, is an oxo or an oxime group; or Bi and B2, taken together with the atom to which they are attached, may form a 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 5-6 membered heteroaryl, any of which may be optionally substituted with one or more substituents selected from the group consisting of hydrogen, -NH2, hydroxyl, carbonyl, Ci 5 alkyl or a Ci 5 alkoxy group;
Rg and R 9 are each selected from hydrogen, hydroxy, methoxy, amines, alkyl or acyl. With the proviso that the 11th position is [3 in configuration.
6. The compound as claimed in claim 1, wherein the compound is selected from the
group consisting of
142

i. (3S,8S,9S,10R,1 lS,13S,14S,17S)-10,13-dimethyl-17-(2-methyl-l,3-dioxolan-
2-yl)-2,3,4,7,8,9,10,11, 12,13,14,15,16,17-tetradecahydro-lH-
cyclopenta[a]phenanthrene-3,l 1-diol;
ii. 1-((3S,8S,9S,10R,1 1S,13S,14S,17S)-3,1 l-dihydroxy-10,13-dimethyl-
2,3,4,7,8,9,10,1 1,12,13,14,15,16,17-tetradecahydro-lH-
cyclopenta[a]phenanthren- 17-yl)ethanone
iii. (3S,8S,9S, 10R,llS,13S,14S,17S)-17-(l-hydroxyethyl)- 10,13-dimethyl-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro- IH-
cyclopenta[a]phenanthrene-3 ,11-diol
iv. (3S,8S,9S,10R,1 1S,13S,14S,1 7S)-methyl 3,1 1-dihydroxy- 10,13-dimethyl-
2,3,4,7,8,9,10,1 1,12,13,14,15,16,1 7-tetradecahydro- IH-
cyclopenta[a]phenanthrene- 17-carboxylate
V. (8S,9S, lOR, 1 IS, 13S,14S, 17S)-methyl 11-hydroxy- 10,13-dimethyl-3-oxo-
2,3,6,7,8,9, 10,1 1,12,13,14,15,16,1 7-tetradecahydro- IH-
cyclopenta[a]phenanthrene- 17-carboxylate
vi. 1-((3S,8S,9S, lOR, lis, 13S,14S,17S)-3,11-dihydroxy- 10,13-dimethyl-
2,3,6,7,8,9,10,1 1,12,13,14,15,16,17-tetradecahydro-lH-
cyclopenta[a]phenanthren- 17-yl)ethanone
vii. (8S,9S,10R,11S,13S,14S, 17S)-17-acetyl- U-hydroxy- 10,13-dimethyl-
6,7,8,9, 10,1 1,12,13,14,15,16,1 7-dodecahydro- lH-cyclopenta[a]phenanthren-
3(2H)-one
viii. 1-((3S,8S,9S,10S,1 1S,13S,14S,17S)-3,1 l-dihydroxy-10,13-
dimethylhexadecahydro- lH-cyclopenta[a]phenanthren- 17-yl)ethanone
ix. (3S,8S,9S, lOR, 11S,13R,14S, 17S)- 17-ethyl- 10,13-dimethyl-
2,3,4,7,8,9, 10,11,12,13,14,15,16,17-tetradecahydro- IH-
cyclopenta[a]phenanthrene-3 ,11-diol
X. (8S,9S, lOR, 1 IS, 13S, 14S, 17R)- 17-((R)- 1,2-dihydroxyethyl)- 11,1 7-dihydroxy-
10,13-dimethyl-6,7,8,9, 10,11,12,13,14,15,16,1 7-dodecahydro- IH-
cyclopenta[a]phenanthren-3(2H)-one
xi. (8S,9S, lOR, 1 IS, 13S, 14S)-11 -hydroxy- 10,13-dimethyl-
7,8,9,10,1 1,12,13,14,15,1 6-decahydro- lH-cyclopenta[a]phenanthrene-
3,17(2H,6H)-dione

xii. (8S,9S,10R,1 1S,13S,14S,17S)-1 l-hydroxy-10,13-dimethyl-17-(3-methyl-
l,2,4-oxadiazol-5-yl)-6,7,8,9,10,l 1,12,13,14,15,16,17-dodecahy dro-lH-
cy clopenta[a]phenanthren-3 (2H)-one;
xiii. Trimethylammomum (3S,8S,9S,10R,1 lS,13S,14S,17S)-17-acetyl-l 1-
hydroxy- 10,13-dimethyl-2,3 ,4,7,8,9,10,1 1,12,13,14,15,16,1 7-tetradecahydro-
lH-cyclopenta[a]phenanthren-3 -yl sulfate;
xiv. (8S,9S,10R,1 1S,13S,14S,17S)-1 1-hydroxy- 17-(2-hydroxyacetyl)- 10,13-
dimethyl-6,7,8,9, 10,11,12,13,14,15,16,17-dodecahydro- IH-
cy clopenta[a]phenanthren-3 (2H)-one;
XV. (8S,9S,10R,1 1S,13S,14S,17R)-1 l,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-
dimethyl-6,7,8,9,10,ll,12,13,14,15,16,17-dodecahydro-lH-
cy clopenta[a]phenanthren-3 (2H)-one;
XVI. 1-((3S,10R,HS,13S,17S)-3,1 1-dihy droxy-10,13-dimethyl-
2,3,4,7,8,9, 10,1 1,12,13,14,15,16,1 7-tetradecahydro- IH-
cyclopenta[a]phenanthren- 17-yl)ethan- 1-one;
xvii. (3S,lOR,llS,13S,17S)-10,13-dimethyl-2,3 ,4,7,8,9, 10,1 1,12,13,14,15,16,17-
tetradecahydro- lH-cyclopenta[a]phenanthrene-3, 11,17-triol;
xviii. (10R,1 1S,13S,17S)-1 1,17-dihy droxy-10,13-dimethyl-
1,2,6,7,8,9, 10,11,1.2,13,14,15,16,17-tetradecahydro-3H-
cy clopenta[a]phenanthren-3-one;
XIX. (10R,11S,13S)-1 1-hydroxy- 10,13-dimethyl- 1,6,7,8,9,10,1 1,12,13,14,15,16-
dodecahydro-3H-cyclopenta[a]phenanthrene-3, 17(2H)-dione;
XX. (10R,1 1S,13S)-1 1-hy droxy-10,13-dimethyl-3-0X0-
2,3,6,7,8,9, 10,1 1,12,13,14,15,16,1 7-tetradecahydro- IH-
cyclopenta[a]phenanthrene- 17-carboxylic acid;
XXI. (10R,1 lS,13S)-17-(l-hydroxyethyl)-10,13-dimethyl-
1,2,4,7,8,9,10,1 1,12,13,14,15,16,17-
tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[ l,3]dioxblan]- 1 l-ol;
xxh. (3Z,10R,1 1S,13S,17E)-1 1-hydroxy-10,13-dimethyl-
1,6,7,8,9, 10,11,12,13,14,1 5,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione dioxime;

xxiii. (10R,11S,13S,17R)-1 l,17-dihydroxy-10,13-dimethyl-3-oxo-
2,3,6,7,8,9,10,1 1,12,13, 14,15,16,17-tetradecahydro-lH-
cyclopenta[a]phenanthrene-l 7-carboxylic acid;
xxiv. (10R,1 1S,13S,E)-1 l-hydroxy-17-(hydroxyimino)-10,13-dimethyl-
1,2,6,7,8,9, 10,ll,12,13,l4,15,16,17-tetradecahydro-3H-
cyclopenta[a]phenanthren-3-one;
XXV. (10R,llS,13S,17S)-17-acetyl- 11-hydroxy- 10,13-dimethyl-
1,2,6,7,8,9, 10,ll,12,13,14,15,16,17-tetradecahydro-3H-
cyclopenta[a]phenanthren-3 -one;
xxvi. (lOS, 11 S, 13 S, 17S)-17-acetyl- 11-hydroxy- 10,13-dimethylhexadecahydro-3H-
cyclopenta[a]phenanthren-3-one;
xxvii. (3S,10R,1 lS,13S,17S)-10,13-dimethyl-2,3,6,7,8,9,10,l 1,12,13,14,15,16,17-
tetradecahydro- lH-cyclopenta[a]phenanthrene-3, 11,17-triol;
xxviii. (lOR, 1 IS, 13 S, 17R)-11-hydroxy- 10,13-dimethyl-
1,6,7,8,9, 10,1 1,12,13,14,15,1 6-dodecahydrospiro[cyclopenta[a]phenanthrene-
17,2'-oxetane] -3,3'(2H)-dione;
xxix. 1-((10R,HS,13S)-1 l-hydroxy-10,13-dimethyl-
1,2,4,7,8,9,10,1 1,12,13,14,15,16,17-
tetradecahydrospiro[cyclopenta[a]phenanthrene-3 ,2'-[ l,3]dioxolan]- 17-
yl)ethan-l-one;
XXX. (10R,11S,13S)-1 l-hydroxy-N,N,10,13-tetramethyl-3-oxo-
2,3,6,7,8,9,10,1 1,12,13,14,15,16,17-tetradecahydro-lH-
cyclopentajajphenanthrene- 17-carboxamide;
xxxi. (10R,1 1S,13S, 17S,Z)-1 1-hydroxy- 17-((Z)-1-(hydroxyimino)ethyl)- 10,13-
dimethyl- 1,2,6,7,8,9,10,1 1,12,13,14,15,16, 17-tetradecahydro-3H-
cyclopenta[a]phenanthren-3-one oxime;
xxxii. (lOR, 11S,13S)-1 1-hydroxy- 17-( 1-hydroxy ethyl)- 10,13 -dimethyl-
1,2,6,7,8,9, 10,11,12,13,14,15,16,17-tetradecahydro-3H-
cyclopenta[a]phenanthren-3 -one;
xxxiii. (10S,1 1S,13S)-1 l-hydroxy-N,N, 10,1 3-tetramethyl-3 -oxohexadecahydro- IH-
cyclopenta[a]phenanthrene- 17-carboxamide;
xxxiv. (10S,1 1S,13S)-1 1-hydroxy- 10,1 3-dimethyltetradecahydro-3H-
cyclopenta[a]phenanthrene-3, 17(2H)-dione;

XXXV. (10R,11 S,l 3S,1 7S)- 17-acetyl- 11-hydroxy- 10,1 1,13-trimethyl-
1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-
cy clopenta[a]phenanthren-3-one;
xxxvi. (3S, lOR,llS,13S)-17-( 1-hydroxyethyl)- 10,13-dimethyl-
2,3,4,7,8,9, 10,11,12,13,14,15,16,17-tetradecahydro- IH-
cyclopenta[a]phenanthrene-3 ,11-diol;
xxxvii. (3S,8S,9S,10R,1 lS,13S,14S,17S)-17-(l-hydroxyethyl)-10,13-dimethyl-
2,3,6,7,8,9, 10,11,12,13,14,15,16,17-tetradecahydro- IH-
cyclopenta[a]phenanthrene-3,l 1-diol;
xxxviii. I-((3 S, lOR, 1 IS, 13S, 17S)- li-hydroxy-3 -methoxy- 10,13-dimethyl-
2,3,4,7,8,9,10,1 1,12,13,14,15,16,17-tetradecahydro- IH-
cyclopenta[a]phenanthren- 17-yl)ethan- 1-one;
xxxix. (10S,1 IS, 13 S)-17-(l-hy droxy ethyl)-10,13-
dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[l,3]dioxolan]-
ll-ol;
xl. (3 S, lOS, IIS, 13 S, 17S)-17-( 1-hydroxyethyl)- 10,13-dimethylhexadecahydro-
lH-cyclopenta[a]phenanthrene-3 ,11-diol;
xli. (3S, lOR, 1 IS, 13R, 17S)- 17-ethyl- 10,13-dimethyl-
2,3,4,7,8,9,10,1 1,12,13,14,15,16,17-tetradecahydro-lH-
cyclopenta[a]phenanthrene-3 ,11-diol;
xlii. 1-((3S, 10S,1 lS,13S,17S)-3,11-dihydroxy- 10,13-dimethylhexadecahydro- IH-
cyclopenta[a]phenanthren-17-yl)ethan-l-one;
xliii. (3S,10R,1 1S,13S,17S)-3,1 l-dihydroxy-N,N,10,13-tetramethyl-
2,3,4,7,8,9,10,1 1,12,13,14,15,16,17-tetradecahydro-lH-
cyclopenta[a]phenanthrene-17-carboxamide;
xliv. 1-((8S,9S, 10R,11S, 13S, 14S, 17S)-1 1-hydroxy-10,13-dimethyl-
2,7,8,9,10,1 1,12,13,14,15,16,1 7-dodecahydro- lH-cyclopenta[a]phenanthren-
17-yl)ethan-l-one;
xlv. l-((3 S, lOR, 1 IS, 13S,17S)-3,11-dihydroxy- 10,13-dimethyl-
2,3,4,7,8,9,10,1 1,12,13,14,15,16,1 7-tetradecahydro- IH-
cyclopenta[a]phenanthren-17-yl-3-d)ethan-l-one;
xlvi. (3S,10R,1 1S,13S,17S)-3,1 l-dihydroxy-N,N,10,13-tetramethyl-
2,3,6,7,8,9,10,1 1,12,13,14,15,16,1 7-tetradecahydro- IH-cyclopenta[a]phenanthrene- 17-carboxamide;

xlvii. l-((3 S, lOR, 1 IS, 13S, 17S)-3,11-dihydroxy- 10,1 1,13 -trimethyl-
2,3,4,7,8,9, 10,11,12,13, l4,15, l6,17-tetradecahydro- IH-
cyclopenta[a]phenanthren- 17-yl)ethan- 1-one;
xlviii. (10R,1 1S,13S)-1 l-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-
1,2,6,7,8,9,10,11, 12,13,14,15,16,17-tetradecahydro-3H-
cy clopenta[a] phenanthren-3-one;
xlix. (lOR, 11 S, 13S, 17S)-11-hydroxy- 17-(2-hydroxypropan-2-yl)- 10,13 -dimethyl •
1,2,6,7,8,9,10,1 1,12,13,14,15,16,1 7-tetradecahydro-3H-
cyclopenta[a] phenanthren-3-one;
1. (E)-1-((3S,10R,1 1S,13S)-3,1 1-dihydroxy- 10,1 3-dimethyl-
2,3,4,7,8,9, 10,11,12,13,14,15,16,17-tetradecahydro- IH-
cyclopenta[a]phenanthren- 17-yl)ethan- 1-one oxime;
li. 1-((3S, lOR, 11 S,l 3S, 17S)-3,11 -dihydroxy- 10,1 3-dimethyl-
2,3,4,7,8,9, 10,11,12,13,14,15,16,17-tetradecahydro- IH-
cyclopenta[a]phenanthren- 17-yl-1 l-d)ethan- 1-one;
lii. (3 S, lOR, 1 IS, 13 S, 17S)- 17-((E)- 1-hydrazonoethyl)- 10,13-dimethyl-
2,3,4,7,8,9,10,1 1,12,13, 14,15,16,17-tetradecahydro-lH-
cyclopenta[a]phenanthrene-3,l 1-diol;
liii. l-(( 10S,1 IS, 13 S,17S)-11-hydroxy-10,13-dimethylhexadecahydro- IH-
cyclopenta[a]phenanthren- 17-yl)ethan- 1-one;
liv. (3S, lOS, 1 IS, 13S)-1 7-(l -aminoethyi)- 10,13-dimethylhexadecahydro- IH-
cyclopenta[a]phenanthrene-:3 ,11-diol;
Iv. 1-((3R,1 0R,1 lS,13S,17S)-3-fluoro-l 1-hydroxy- 10,13-dimethyl-
i 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro- IH-
cyclopenta[a]phenanthren- 17-yl)ethan- 1-one;
Ivi. (3S,lOS,llS,13S)-17-amino-10,13-dimethylhexadecahydro-l H-
cyclopenta[a]phenanthrene-3, 11-diol;
Ivii. (lOR, 11S, 13 S)-11 -hydroxy- 10,13 -dimethyl- 17-(piperazine- 1 -carbonyl)-
1,2,6,7,8,9, 10,1 1,12,13,14,15,16,1 7-tetradecahydro-3H-cyclopenta[a] phenanthren-3-one;
Iviii. (8S,9S,10R,1 lS,13S,14S,17S)-17-acetyl-l l-hydroxy-10,1 1,13-trimethyl-
1,2,6,7,8,9, 10,1 1,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a] phenanthren-3-one;

hx. (8S,9S,10R,1 lS,13S,14S,17S)-N-(2-aminoethyl)-l l-hydroxy-10,13-dimethyl-
3-0X0-2,3,6,7,8,9,10,1 1,12,13,14,15,1 6-tetradecahydro- IH-
cyclopenta[a]phenanthrene- 17-carboxamide;
Ix. 1-((3S,10R,1 1S,13S,17S)-3,1 l-dihydroxy-10,13-dimethyl-
2,3,4,7,8,9,10,1 1,12,13,14,15,16,17-tetradecahydro-lH-
cyclopenta[a]phenanthren-17-yl-3,l l-d2)ethan-l-one;
Ixi. (3S,8S,9S,10S,1 1S,13S,14S,17S)-3,1 l-dihydroxy-N,10,13-
trimethylhexadecahydro- lH-cyclopenta[a]phenanthrene- 17-carboxamide;
Ixii. (3S,10R,1 1S,13S,17S)-2,3,6,7,8,9,10,1 1,12,13,14,15,16,17-tetradecahydro-
10,13-dimethyl- lH-cyclopenta[a]phenanthrene-3, 11,17-triol;
1x111. (3S,8S,9S, lOS, 1 IS, 13S, 14S, 17S)-N-(2-aminoethyl)-3, 1 1-dihydroxy- 10,13-
dimethylhexadecahydro- lH-cyclopenta[a]phenanthrene- 17-carboxamide;
Ixiv. (3S, lOR, 1 IS, 13S, 17S)-5-methoxy-10,13-dimethyl-17-(2-methyl- 1,3-dioxolan-
2-yl)hexadecahydro- lH-cyclopenta[a]phenanthrene-3 ,6,11 -triol;
Ixv. 1-((3S,5R,6R,10R,1 1S,13S,17S)-3,5,1 l-trihydroxy-6-methoxy-10,13-
dimethylhexadecahydro- lH-cyclopenta[a]phenanthren- 17-yl)ethan- 1-one;
Ixvi. 1-((3S,5R,6R,10R,1 1S,13S,17S)-3,5,1 l-trihydroxy-6-merhoxy-10,13-
dimethylhexadecahydro- lH-cyclopenta[a]phenanthren- 17-yl)ethan- 1-one;
Ixvh. 1-((3S,5R,6R, lOR, 1 IS, 13S, 17S)-3,5,6, 11-tetrahydroxy- 10,13-
dimethylhexadecahydro- lH-cyclopenta[a]phenanthren- 17-yl)ethan-1 -one;
Ixvih. 3S,10R,1 lS,13S,17S)-17-(l-hydroxyethyl)-10,13-dimethyl-
2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro- IH-cyclopentafa]phenanthrene-3, 11-diol;
7. A pharmaceutical composition comprising a compound as claimed in Claim 1 together with a pharmaceutically acceptable carrier.
8. Use of the compounds as claimed in claims 1 to 6 for the activation AMPK.
9. Use of the compounds as claimed in claims 1 to 6 for the subsequent activation transcription factors such as PCG-1 alpha associated with mitochondrial biogenisis.
10. Use of the compounds as claimed in claims 1 to 6 for the activation mitochondrial biogenisis and functions.

11. Use of the compounds as claimed in claims 1 to 6 for treatment of diseases associated with mitochondrial depletion and/ or dysfunctionselected, but not limited to, the group consisting of skeletal muscle diseases, cardiac muscle diseases associated with ischemia, or impaired or inadequate blood flow, diseases associated with genetic disorders that directly or indirectly affect the number, structure, or function of mitochondria, diseases associated with impaired neurological function associated with decreased mitochondrial number or function, diseases associated with loss of number, loss of function, or loss of correct, optimally efficient internal organization of skeletal muscle cells or cardiac muscle cells, metabolic diseases, and conditions associated with liver cell injury and altered fatty acid metabolism.
12. Use of the compounds as claimed in claims 1 to 6 for mitochondrial biogenesis-mediated disease is selected from the group consisting of acute coronary syndrome, myocardial infarction, angina, renal injury, renal ischemia, diseases of the aorta and its branches, injuries arising from medical interventions, atherosclerosis, trauma, diabetes, hyperlipidemia, vascular stenosis, peripheral arterial disease, vasculopathy, and vasculitis, Friedreich's ataxia, muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy, limb girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, spinal muscular atrophy, Emery-Dreifuss muscular dystrophy, Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, sarcopenia, congestive heart failure, aging, myocarditis, myositis, polymyalgia rheumatic, polymyositis, HIV, cancer and/or the side effects of chemotherapy targeting the cancer, malnutrition, aging, inborn errors of metabolism, trauma, and stroke or other types of neurological impairment, hepatic steatosis, hepatic fibrosis, cirrhosis, and hepatocyte or stellate cell injury.
13. Use of the compounds as claimed in claims 1 to 6 in a dosage in the range of 0.01 to lOOmg/Kg.
14. The compounds as claimed in claims 1 to 6 when administered as orally or parenterally.
15. A method of manufacturing the compound as claimed in claim 1, as described herein.