(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date W O 2015/068142 A2 14 May 2015 (14.05.2015) P O P C T

(51) International Patent Classification: (74) Agents: THACKER, Ankita et al; K&S Partners | Intel A61K 31/00 (2006.01) lectual Property Attorneys, 4121/B, 6th Cross, 19A Main, HAL II Stage (Extension), Bangalore 560038 (IN). (21) International Application Number: PCT/IB2014/065924 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 10 November 2014 (10.1 1.2014) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, EST, IR, IS, JP, KE, KG, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (30) Priority Data: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 5103/CHE/2013 11 November 2013 ( 11. 1 1.2013) IN PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 4949/CHE/2014 1 October 2014 (01. 10.2014) IN SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: CELLWORKS GROUP, INC. [US/US]; 2025 Gateway Place Suite 265, San Jose, CA 95 110 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors: KUMAR, Ansu; C/o Cellworks Research India GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Private Limited, 3rd floor, West Wing, Neil - Rao Tower, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 118, Road # 3, EPIP, Whitefield, Karnataka, Bangalore TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 560066 (IN). SINGH, Neeraj Kumar; C/o Cellworks Re DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, search India Private Limited, 3rd floor, West Wing, Neil - LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Rao Tower, 118, Road # 3, EPIP, Whitefield, Karnataka, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Bangalore 560066 (IN). TYAGI, Anuj; C/o Cellworks Re GW, KM, ML, MR, NE, SN, TD, TG). search India Private Limited, 3rd floor, West Wing, Neil - Rao Tower, 118, Road # 3, EPIP, Whitefield, Karnataka, Declarations under Rule 4.17 : Bangalore 560066 (IN). VALI, Shireen; C/o Cellworks — of inventorship (Rule 4.17(iv)) Research India Private Limited, 3rd floor, West Wing, Neil - Rao Tower, 118, Road # 3, EPIP, Whitefield, Karnataka, Published: Bangalore 560066 (IN). ABBASI, Taher; C/o Cellworks — without international search report and to be republished Research India Private Limited, 3rd floor, West Wing, Neil upon receipt of that report (Rule 48.2(g)) - Rao Tower, 118, Road # 3, EPIP, Whitefield, Karnataka, Bangalore 560066 (IN).

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00 (54) Title: COMPOSITIONS, PROCESS OF PREPARATION OF SAID COMPOSITIONS, USES AND METHOD OF MAN © AGEMENT OF MYELOPROLIFERATIVE DISORDER (57) Abstract: The present disclosure relates to a pharmaceutical composition and a method to manage Myeloproliferative disorder o or any associated condition, particularly, JAK2 (Janus Kinase 2) dominant (including JAK2V61 7F mutant) Myeloproliferative Dis order (MPD) and associated conditions. The disclosure provides composition comprising at least two components selected from a group comprising Phosphodiesterase Type 4 (PDE4) inhibitor, Autophagy inhibitor and AMPK agonist. The disclosure further relates to a process of preparing the said composition and a method of managing JAK2 dominant (including JAK2 V617F mutant) Myeloproliferative Disorder; existing alone or along with any other mutation. "COMPOSITIONS, PROCESS OF PREPARATION OF SAID COMPOSITIONS, USES AND METHOD OF MANAGEMENT OF MYELOPROLIFERATIVE DISORDER"

TECHNICAL FIELD The present disclosure relates to composition and method for management of Myeloproliferative disorders (MPD) or any associated condition. Specifically, it relates to management of JAK2 (Janus Kinase 2) dominant (including JAK2V617F mutant) Myeloproliferative Disorders (MPD) The disclosure provides individual compounds and combination of compounds for use in preparation of medicament for management of MPD or any associated condition. More particularly, the present disclosure employs Phosphodiesterase Type 4 inhibitor, Autophagy inhibitor and AMPK Agonist, individually and in combinations for managing said MPD or any associated condition.

BACKGROUND OF THE DISCLOSURE Myeloproliferative disorders (MPDs) are clonal hematopoietic diseases characterized by the excess production of 1 or more lineages of mature blood cells. The human myeloproliferative disorders consist of three main classes of disorders, which are Essential Thrombocythemia (ET), PolycythemiaVera (PV), and Myelofibrosis (MF). A valine to phenylalanine substitution at position 6 7 (V617F) of JAK2 in the pseudokinase domain is the most common mutation across all three classes of this disorder. JAK2V617F mutation is a subset of JA K2 dominance. Occurrence of JAK2V617F mutation isobserved in more than 95% of Polycythemia Vera cases and in approximately 50% of patients with Thrombocythemia and Myelofibrosis. Other mutations, such as K539L and T875N of JAK2 have also been identified, but in a very small subset of PolycythemiaVera patients.

Polycythemia Vera is the most common of the chronic myeloproliferative disorders. JAK2 Mutation- positive patients have multiple features resembling Polycythemia Vera, with significantly increased haemoglobin, increased neutrophil counts, increased bone marrow erythropoiesis and increased granulopoiesis. Also, more venous thrombosis, and higher rate of polycythemic transfonnation than in those without the mutation has been detected. Mutation-positive patients have lower serum erythropoietin and comparatively lower ferritin than those of mutation-negative patients.

This disorder predisposes patients to vascular diseases such as thrombosis, atherosclerosis, coronary heart disease, and cerebral ischemia. In addition, patients with MPD often have high levels of

i circulating inflammatory cytokines in their microenvironment, such as interleukin 6 (IL-6), which has been associated with symptoms such as cachexia and listlessness. MPD can also progress into Acute Myeloid Leukemia.

MPD is associated with a chronic inflammatory state due to the continuous release of inflammatory mediators in the microenvironment by other stromal cells. Chronic inflammation is characterized by persistently activated immune and stromal cells in the bone marrow microenvironment called 'inflamed bone marrow'. Chronic inflammation in the bone marrow is likely associated with increased N -kappa- beta (NF B) activity in hematopoietic and stromal cells. Furthermore, increased NFKB activity causes increased production of TNF-alpha, IL-6, IFNG and other cytokines, which in turn further increase NFKB and STAT3 and this positive feedback further worsens the myeloproliferation.

Existing standard of care for Essential Thrombocvthemia, PolycvthemiaVera. and Myelofibrosis (MPD) Conventionally, treatment of MPD disorder involves reducing the thickness of the blood and preventing bleeding and clotting. Phlebotomy is used to decrease blood thickness, wherein, one unit of blood (about 1 pint) is removed weekly until the hematocrit level is less than 45 (for males) or 42 (for females). Then therapy is continued as needed. Chemotherapy (specifically Hydroxyurea) is also given to reduce the number of red blood cells made by the bone marrow.

However, chemotherapy or phlebotomy is not curative in MPD and does not reduce the risk of clonal evolution into Myelodysplastic syndrome and Acute Leukemia. Besides the conventional approach, targeted approach for treatment of MPD is being developed. Inhibition of mutant JAK2 is considered as one of the approaches in the treatment of MPDs harboring JAK2 mutations. Various JAK2 inhibitors are currently under development and/or investigation in phase i and 2 clinical trials.

Although preliminary results show measurable clinical benefits of the targeted approach, but over time these agents become resistant. Protective microenvironment of the stromal bone marrow niche against JAK2 inhibitor therapy via stromal cell secreted humoral factors is considered to be the major cause of resistance mechanism for JAK2 inhibitors over the MPD conditions.

In summary, the existing conventional treatment of phlebotomy and chemotherapy or targeted treatment with JAK2 inhibitors, although provides measurable symptomatic relief for a subject with MPD or associated condition, but it is not able to stop disease progression. Further, the success achieved with attempted doses of single agents in the targeted approach is limited, and the obstacles to increasing the doses of the single agents include legitimate concerns about exceeding the therapeutic windows and/or concerns about the manifestation of undesirable side effects at higher doses like fluid retention, heart and blood pressure problem.In some cases, instance of drug overdose is associated with increased risk of developing Acute Leukemia.

In vie of the above mentioned limitations observed towards the treatment of MPD or its associated condition, improved or technically advanced treatment protocols for this complex disorder is needed. A safe and effective treatment and protocol that could alleviate suffering and improve outcomes would be a significant medical advance in the treatment of MPD or associated condition.

The present disclosure aims to overcome the drawbacks of the methods of the prior art by lowering the dosages of compounds and also providing synergistic efficacy by combination of compounds, wherein the compounds are Phosphodiesterase Type 4 inhibitor, Autophagy inhibitor and AMPK Agonist.

SUMMARY OF THE DISCLOSURE The shortcomings of the prior art are overcome and additional advantages are provided through the provision of a composition as described in the description.

In some embodiments, the disclosure provides, a composition comprising, at least two components selected from a group comprising:

a. a phosphodiesterase type 4 inhibitor; b. an autophagy inhibitor; and c. an AMPK Agonist; optionally along with pharmaceutically acceptable excipient.

In some embodiments, the disclosure provides, a kit comprising at least two components selected from a group comprising phosphodiesterase type 4 inhibitor, autophagy inhibitor; and AMPK Agonist; optionally along with pharmaceutically acceptable excipient; wherein the kit comprises one or plurality of dosage forms. In some embodiments, the disclosure provides, a method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of component selected from group comprising autophagy inhibitor and Phosphodiesterase type 4 inhibitor or combination thereof, optionally along with therapeutically effective amount of AMPK agonist; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient.

In some embodiments, the disclosure provides, a use of phosphodiesterase type 4 inhibitor or autophagy inhibitor or combination thereof, optionally along with AMPK Agonist, in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition.

In some embodiments, the disclosure provides, a process of preparing composition as mentioned above, said process comprising act of combining at least two components selected from a group comprising phosphodiesterase type 4 inhibitor, autophagosome inhibitor and AMPK Agonist; optionally along with pharmaceutically acceptable excipient; in any ratio, any concentration or any order thereof to obtain the composition as mentioned above.

In some embodiments, the disclosure provides, a composition comprising at least two compounds selected from a group comprising: a. a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; b. a compound of formula VI or a compound of formula VII; and c. a compound of formula VIII; optionally along with pharmaceutically acceptable excipient.

In some embodiments, the disclosure provides, a method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of compound selected from a group comprising: a. a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; and a compound of formula VI or a compound of formula VII; or a combination thereof; b. optionally along with a compound of formula VIII; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient.

In some embodiments, the disclosure provides, a use of compound selected from a group comprising: a a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; and a compound of formula VI or a compound of formula VII; or a combination thereof; b. optionally along with a compound of formula VIII; in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition.

BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES In order that the present disclosure may be readily understood and put into practical effect, reference is no made to exemplary embodiments as illustrated with reference to the accompanying figures. However, the figures are purely for the purpose of exemplifying and are non-limiting in nature. The figures together with the detailed description below, are incorporated in and form par of the specification, and serve to further illustrate the embodiments and explain various principles and advantages, in accordance with the present disclosure where:

Figures l a - I f depict the effect of autophagy inhibitor (CW170), Phosphodiesterase type 4 inhibitor (CW242) and its combination on proliferation (a), viability (b), CDK2-CCNA complex (c), CDK4- CCNDl complex (d), CDK2-CCNE complex (e) and MCLl(f) of the JAK2 mutant driven virtual disease model.

Figure 2a depicts the dose response effect of Chloroquine (CW170) and Roflumilast (CW242) alone and in combination on the proliferation index in a virtual Myelofibrosis disease model.

Figure 2b depicts the dose response effect of Chloroquine (CW170) and Roflumilast (CW242) alone and in combination on the viability index in a virtual Myelofibrosis disease model.

Figure 2c depicts the synergy plot between Chloroquine (CW170) and Roflumilast (CW242) and indicates the minimal amount of compound needed in combination to achieve about 30% inhibition of proliferation when compared to the individual compounds.

Figure 3a depicts an assay of relative growth (proliferation) in JAK2 mutant BAF3 cells to determine the effect of compounds CW170 and CW242 vs. the combination CW 170242.

Figure 3b depicts the dose response effect of adding fixed dose of CW242 to different doses of CW170 and assess relative growth (proliferation) in JAK2 mutant BAF3 cells.

Figure 3c depicts a comparison in the standard of care JAK inhibitor (Jakafi) with the combination CW 170242 in proliferation in JA 2 mutant BEL cells.

Figures 4a and 4b depict Ex-vivo clonogenic assay in JAK2 mutant patient cells with CW242, CW170, and their combination in comparison with standard of care JAK inhibitor (Jakafi).

Figure 5a and 5b depict animal in vivo data with the combination CW 170242 in presence and absence of standard of care JAK inhibitor (Jakafi).

Figures 6a to 6f depict the effect of autophagy inhibitor (CW170) on BaF3 cell line, effect of CW170 in combination with Phosphodiesterase type 4 inhibitor (CW242) on BaF3 cell line, effect of CW170 in combination with AMPK agonist (C 1 8) on BaF3 cell line, effect of CW170 in combination with CW242 and CW178 on BaF3 cell line, for assaying relative growth (a), proliferation (b), viability (c), MCLi (d), CDK4 CCNDi (e) and CDK2 CCNEl (f) respectively.

Figures 7a to 7f depict the effect of Phosphodiesterase type 4 inhibitor (CW242) on BaF3 ceil line, effect of CW242 in combination with autophagy inhibitor (CW170) on BaF3 cell line, effect of CW242 in combination with AMPK Agonist (CW178) on BaF3 cell line, effect of CW242 in combination with CW170 and CW178 on BaF3 cell line, for assaying relative growth (a), proliferation (b), viability (c), MCLI (d), CDK4 CCNDI (e) and CDK2 CCNEl (f) respectively.

Figures 8a to 8f depict the effect of AMPK agonist (CW178) on BaF3 cell line, effect of CW178 in combination with autophagy inhibitor (CW170) on BaF3 cell line, effect of CW178 in combination with Phosphodiesterase type 4 inhibitor (CW242) on BaF3 cell line, effect of CW 8 in combination with CW170 and CW242 on BaF3 ceil line for assaying relative growth (a), proliferation (b), viability (c), MCL1 (d), CDK4 CCND1 (e) and CDK2 CCNE1 (f) respectively.

Figure 9a depicts an assay of relative growth (proliferation) in JA 2 mutant BAF3 cells to determine the effect of compounds CW170, CW178 vs. the combination CW170178 (CW170:CW178).

Figure 9b depicts an assay of relative growth (proliferation) in JAK2 mutant BAF3 cells to determine the effect of compounds CW242, CW178 vs. the combination CW 78242 (CW178:CW242).

Figure 10 depicts an assay of relative growth (proliferation) in JA 2 mutant BAF3 cells to determine the effect of compounds CW242, CW178, CW 70 and their combination CW170178242 (CW 170:CWl 78:CW242).

Figure 11 depicts the dose response effect of adding fixed dose of CW170 to different doses of CW178 and assesses relative growth (proliferation) in JAK2 mutant BAF3 cells.

Figure 12 depicts the network schematic representation of mechanism of action for Autophagy inhibitor (CW170) and AMPK Agonist (CW178) on the JAK2V617F mutant driven BaF3 Cell line.

Figure 13 depicts the network schematic representation of mechanism of action for AMPK Agonist (CW178) and Phosphodiesterase type 4 inhibitor (CW242) on the JAK2V617F mutant driven BaF3 Cell line.

Figure 14 depicts the network schematic representation for mechanism of action for Autophagy inhibitor (CW170) and Phosphodiesterase type 4 inhibitor (CW242), in the JAK2 mutant driven BAF3 cell line.

Figure 15 depicts the network schematic representation of mechanism of action for Autophagy inhibitor (CW170), AMPK Agonist (CW178) and Phosphodiesterase tvpe 4 inhibitor (CW242) on the JAK2V617F mutant driven BaF3 Cell line. DETAILED DESCRIPTION OF THE DISCLOSURE The present disclosure relates to a composition comprising at least two components selected from a group comprising; a. a phosphodiesterase type 4 inhibitor; b. an autophagy inhibitor; and e. an AMPK Agonist; optionally along with pharmaceutically acceptable excipient.

In an embodiment of the present disclosure, the composition comprises a phosphodiesterase type 4 inhibitor and an autophagy inhibitor, optionally along with pharmaceutically acceptable excipient.

In another embodiment of the present disclosure, the composition comprises a phosphodiesterase type 4 inhibitor and an AMPK Agonist, optionally along with pharmaceutically acceptable excipient.

In yet another embodiment of the present disclosure, the composition comprises an autophagy inhibitor and an AMPK Agonist, optionally along with pharmaceutically acceptable excipient.

In still another embodiment of the present disclosure, the composition comprises a phosphodiesterase type 4 inhibitor; an autophagy inhibitor; and an AMPK Agonist; optionally along with pharmaceutically acceptable excipient.

In still another embodiment of the present disclosure, the phosphodiesterase type 4 inhibitor is inhibitor used for treating Chronic Obstructive Pulmonary Disease (COPD); the autophagy inhibitor is anti malarial agent an the AMPK agonist is anti-diabetic agent.

In still another embodiment of the present disclosure, the Phosphodiesterase type 4 inhibitor is selected from group comprising Roflumilast, Piclamilast, CDP 840, CP 80633, Etazolate, ICI 63197, irsogladine, (R,S)-Mesopram, RO 20-1724, Rolipram, (R)-(-)-Rolipram, S-(+)~Rolipram, CHEMBL 1232082, YM 976 and pharmaceutically-acceptable salt of any of the foregoing, or any combinations thereof. In still another embodiment of the present disclosure, the autophagy inhibitor is selected firom group comprising Chloroquine, Lucanthone, LysOl, Lys02, Lys03, Lys04, Lys05, Hydroxychloroquine, Mefloquine, Quinacrine and pharmaceutieally-acceptable salt of any of the foregoing, or any combinations thereof.

In stil another embodiment of the present disclosure, the AMPK Agonist is selected from group comprising Metformin, Phenformin, Panduratin, AICAR, B-lapachone, AMPK activator (CID 16760291), A769662 and pharmaceutieally-acceptable salt of any of the foregoing, or any combinations thereof.

In still another embodiment of the present disclosure, the Phosphodiesterase type 4 inhibitor is Roflumilast, the autophagy inhibitor is Chloroquine and the AM PK Agonist is Metformin.

In still another embodiment of the present disclosure, the pharmaceutically acceptable excipient is selected from group comprising granulating agent, binding agent, lubricating agent, disintegrating agent, sweetening agent, glidant, anti-adherent, anti-static agent, surfactant, anti-oxidant, gum, coating agent, coloring agent, flavouring agent, coating agent, plasticizer, preservative, suspending agent, emulsifying agent, plant cellulosic material, spheronization agent, immediate release agent, controlled release agent, sustained delayed release agent, or any combinations thereof.

In still another embodiment of the present disclosure, the composition is formulated into dosage form selected from group comprising feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, microgel, suppository troche, aqueous or oily suspension, ointment, patch, lotion, dentifrice, emulsion, cream, drop, dispersible powder or granule, emulsion in hard or soft gel capsule, syrup, phytoceutical, nutraceutical, or any combinations thereof.

In still another embodiment of the present disclosure, the composition is in dosage form having an immediate release, a controlled release, or a sustained delayed release mechanism.

In still another embodiment of the present disclosure, the composition is in dosage form formulated for intravenous, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, or topical administration. The present disclosure also relates to a kit comprising at least two components selected from a group comprising phosphodiesterase type 4 inhibitor, autophagy inhibitor: and AMPK Agonist; optionally along with pharmaceutically acceptable excipient; wherein the kit comprises one or plurality of dosage forms.

The present disclosure also relates to a method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of component selected from group comprising autophagy inhibitor and Phosphodiesterase type 4 inhibitor or combination thereof, optionally along with therapeutically effective amount of AMPK agonist; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient.

The present disclosure also relates to use of phosphodiesterase type 4 inhibitor or autophagy inhibitor or combination thereof, optionally along with AMPK Agonist, in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition.

The present disclosure also relates to a process of preparing composition as mentioned above, said process comprising act of combining at least two components selected from a group comprising phosphodiesterase type 4 inhibitor autophagosome inhibitor and AMPK Agonist; optionally along with pharmaceutically acceptable excipient; in any ratio, any concentration or any order thereof to obtain the composition as mentioned above.

In an embodiment of the present disclosure, the Phosphodiesterase type 4 inhibitor is inhibitor used for treating Chronic Obstructive Pulmonary Disease (COPD); the autophagy inhibitor is anti-malarial agent and the AMPK Agonist is anti-diabetic agent.

In another embodiment of the present disclosure, the Phosphodiesterase type 4 inhibitor is selected from group comprising Roflumilast, Piclamilast, CDP840, CP 80633, Etazolate, ICI 63197, irsogladine, (R,S)-Mesopram, RO 20-1724, Rolipram, (R)-(-)-Rolipram, S-(+)-Rolipram, CHEMBL 1232082, YM 976 and pharmaceutically-acceptable salt of any of the foregoing, or any combinations thereof In yet another embodiment of the present disclosure, the autophagy inhibitor is selected from group comprising Chloroquine, Lucanthone, LysOl, Lys02, Lys03, Lys04, Lys05, Hydroxychloroquine, Mefloquine, Quinacrine and pharmaceutically-acceptable salt of any of the foregoing, or any combinations thereof.

In stil another embodiment of the present disclosure, the AMPK agonist is selected from group comprising Metformin, Phenformin, Panduratin, AICAR, AMPK activator (CIDl 6760291), B- lapachone, A769662 and pharmaceutically-acceptable salt of any of the foregoing, or any combinations thereof.

In still another embodiment of the present disclosure, the Phosphodiesterase type 4 inhibitor is Roflumilast, the autophagy inhibitor is Chloroquine and the AMPK agonist is Metformin.

In still another embodiment of the present disclosure, Myeloproliferative Disorder is a condition comprising mutation in Janus kinase 2, wherein said mutation is selected from a group comprising V617F, K539L and T875N, or any combinations thereof.

In still another embodiment of the present disclosure, said Myeloproliferative Disorder or any associated condition is selected from group comprising any cancer with JAK2V617F mutation, any cancer with JAK2 dominant profile, Essential Tlirombocythemia, Polycythemia Vera, Myelofibrosis, Multiple myeloma, Acute non lymphocytic leukemia, Myelodysplasia or any combination of conditions thereof, or any condition having a mutation therein.

In still another embodiment of the present disclosure, said mutation is a JAK2V617F mutation or JAK2V617F mutation in combination with gene mutation selected from a group comprising KRAS, NRAS, TP53, CDKNIA, BRAF, EGFR, B-catenin, CDKN2A, P13KCA, APC, MYC, BCL2, S CS , SOCS3 and SMAD4 or any combinations thereof.

In still another embodiment of the present disclosure, the therapeutically effective amount of the Phosphodiesterase type 4 inhibitor is from about 10% to about 99% of a maximum tolerated dose; the therapeutically effective amount of the autophagy Inhibitor is from about 10% to about 99% of a maximum tolerated dose; and the therapeutically effective amount of the AMPK Agonist is from about

0 to about 99% of a maximum tolerated dose. In still another embodiment of the present disclosure, the therapeutically effective amount of the Phosphodiesterase type 4 inhibitor is from about 1 mg to about 2000 mg; the therapeutically effective amount of the autophagy Inhibitor is from about 1 mg to about 2000 mg; and the therapeutically effective amount of the AMPK Agonist is from about 1 mg to about 2000 mg.

The present disclosure also relates to a composition comprising at least two compounds selected from a group comprising: a. a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; b. a compound of formula VI or a compound of formula VII; and c. a compound of formula VIII; optionally along with pharmaceutically acceptable excipient.

The present disclosure also relates to a method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of compound selected from a group comprising; a. a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V: and a compound of formula VI or a compound of formula VII; or a combination thereof; b. optionally along with a compound of formula VIII; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient.

The present disclosure also relates to use of compound selected from a group comprising: a. a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V: and a compound of formula VI or a compound of formula VII; or a combination thereof; b. optionally along with a compound of formula VIII; in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition.

In an embodiment of the present disclosure, the compound of formula I, the compound of form a II, the compound of formula III, the compound of formula IV or the compound of formula V or pharmaceutically-acceptable salt of any of the foregoing, is a phosphodiesterase type 4 inhibitor.

In another embodiment of the present disclosure, the compound of formula VI or the compound of formula VII or pharmaceutically-acceptable salt of any of the foregoing, is an autophagy inhibitor.

In yet another embodiment of the present disclosure, the compound of formula VIII, or its pharmaceutically-acceptable salt is an AMPK Agonist.

In still another embodiment of the present disclosure, the compound of formula I, the compound of formula II, the compound of formula III, the compound of formula IV or the compound of formula V is used for treating Chronic Obstructive Pulmonary Disease (COPD); the compound of formula VI or the compound of formula VII is anti-malarial agent and the compound of formula VIII is anti-diabetic agent.

In still another embodiment of the present disclosure, the compound of formula I is:

q is 0, 1, 2 or 3;

A is selected from unsaturated, saturated, partially saturated, aryl and heteroaryl, each of which is optionally substituted by keto group; A4, A5, A is selected from alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted completely or partially by halogen; and

Ai, A2 are individually selected firom alkyl, alkoxy, cvcloalkylmethoxy (or cycloalkylalkoxy), eycloalkoxy, bicycloxy andaryloxy, each of which is optionally substituted completely or partially by halogen.

In still another embodiment of the present diselosure, the compound of fonnula II is:

Wherein E is selected from N and CH2; and

Ei, E2, E3 are individually selected from amino, alkyl, aryl and heteroaryl, each of which is optionally substituted.

In still another embodiment of the present disclosure, the compound of formula III is:

Wherein, E5, E , E are individually selected from N and CH2; E is selected from hydrogen and alkyl; E is N ; and E , E are individually selected from hydrogen; and , where E 2 E are individual!}' selected from oxygen and sulphur.

another embodiment of the resent disclosure, the compound of formula IV is:

Wherein,E 4, E1 are individually selected from hydrogen and alkyl; E ,E are individually selected from N and CH; and

Ei5 is selected from oxygen and sulphur.

In still another embodiment of the present disclosure, the compound of formula V is:

Wherein, P is selected from hydrogen, alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted; is selected from

, alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted; R is selected from hydrogen, alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted; and S is selected from oxygen, alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted by halogen.

In still another embodiment of the present disclosure, the compound of fonnula VI is;

Wherein, X is selected from N, N =0 and CH; L is selected from halogen, hydrogen, a halogen-containing group, alkyl and alkoxy: R is R - NH - R , and where R is a chemical bond, alkyl, cylcoalkyl, sulfonyl, carbon}'!; and

R2 is

Wherein, m is selected from 0, 1, 2, 3, 4 and 5; n is selected from 0, 1, 2 , 3, 4 and 5;

Y is selected from N-R and O ;

Z is selected from N and CH2; and R3, R4, R5, R6, R7, R7, R8, R9, R O and R is individually selected from hydrogen, alkyl, alkoxy, aryl, alkaryl, aralkyl and heteroaryl, each of which are optionally substituted.

In still another embodiment of the present disclosure, the compound of formula VII is: Wherein, V, W is individually selected from oxygen and sulphur; t is selected from 0, 1, 2, 3, 4 and 5; and R14, R , R 6 and R 7 is individually selected from hydrogen, alkyl, alkoxy, aryl, alkaryl, aralkyl and heteroaryl, each of which are optionally substituted.

In still another embodiment of the present disclosure, the compound of formula VIII is:

Wherein, R is selected from hydrogen and alkyl;

R2 is selected from hydrogen, alkyl wherein; n is an integer ranging between 1to 4.

In an embodiment of the present disclosure, the terra "managing" or "management" or "manage" includes therapeutic and prophylactic activities. It includes treatment and healing of a disease or disorder, or ill effects or side effects of the disease or the disorder. The term also includes prevention of further progress of the disease or disorder, or ill effects or side effects of the disease or the disorder. It further includes maintenance of the optimum state in an individual.

Throughout the present disclosure, the terms "aberration", "anomaly", "mutation" and "abnormality" have the same scope and meaning and are used interchangeably. An aberration or anomaly or mutation or abnormality includes numerical, sequence as well as structural aberration.

In some embodiments, the present disclosure provides individual agent, two-drug combinations and three drug combinations, which provides multi-targeted combination therapeutic approach to suppress and cure symptoms associated with Myeloproliferative Disorders and associated conditions. The drug combinations are designed using virtual computational simulations.

Further, the biological material employed in the present disclosure is obtained from Florida, USA. The present disclosure relates to a composition comprising at least two components selected from a group comprising: a a Phosphodiesterase Type 4 inhibitor; b. an Autophagy inhibitor; and c. an AMPK Agonist; optionally along with pharmaceutically acceptable excipient.

In an embodiment, the composition comprises Phosphodiesterase type 4 inhibitor and Autophagy inhibitor. In an embodiment, the composition comprises Phosphodiesterase type 4 inhibitor, Autophagy inhibitor and pharmaceutically acceptable excipient.

In an embodiment, the composition comprises Phosphodiesterase type 4 inhibitor and AMPK Agonist. In an embodiment, the composition comprises Phosphodiesterase type 4 inhibitor, AMPK Agonist and pharmaceutically acceptable excipient.

In an embodiment, the composition comprises Autophagy inhibitor and AMPK Agonist. In an embodiment, the composition comprises Autophagy inhibitor, AMPK Agonist and pharmaceutically acceptable excipient.

In an embodiment, the composition comprises Phosphodiesterase type 4 inhibitor, AMPK Agonist and Autophagy inhibitor. In an embodiment, the composition comprises Phosphodiesterase type 4 inhibitor, AMPK Agonist, Autophagy inhibitor and pharmaceutically acceptable excipient.

The present disclosure further relates to a kit comprising at least two components selected from a group comprising phosphodiesterase type 4 inhibitor, autophagy inhibitor, and AMPK Agonist; optionally along with pharmaceutically acceptable excipient; wherein the kit comprises one or plurality of dosage forms.

In some embodiments, the present disclosure relates to a kit comprising: a) a phosphodiesterase type 4 inhibitor; b) an autophagy inhibitor; and c) an AMPK Agonist; and optionally along with pharmaceutically acceptable excipient, wherein the kit comprises one or plurality of dosage forms.

In some embodiments, the present disclosure relates to a kit comprising: a) a phosphodiesterase type 4 inhibitor; b) an autophagy inhibitor; and optionally along with pharmaceutically acceptable excipient, wherein the kit comprises one or plurality of dosage forms.

In some embodiments, the present disclosure relates to a kit comprising: a) a phosphodiesterase type 4 inhibitor; and b) an AMPK Agonist; and optionally along with pharmaceutically acceptable excipient, wherein the kit comprises one or plurality of dosage forms.

In some embodiments, the present disclosure relates to a kit comprising: a) an autophagy inhibitor; and b) an AMPK Agonist; and optionally along with pharmaceutically acceptable excipient, wherein the kit comprises one or plurality of dosage forms.

The present disclosure further relates to a method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of component selected from group comprising autophagy inhibitor and Phosphodiesterase type 4 inhibitor or combination thereof, optionally along with therapeutically effective amount of AMPK agonist; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient. In some embodiments, the present disclosure further relates to a method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of autophagy inhibitor, optionally along with therapeutically effective amount of AMPK agonist; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient.

In some embodiments, the present disclosure further relates to a method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of Phosphodiesterase type 4 inhibitor, optionally along with therapeutically effective amount of AMPK agonist; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient

In some embodiments, the present disclosure further relates to a method for managing Myeloproliferanve Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of autophagy inhibitor and Phosphodiesterase type 4 inhibitor, optionally along with therapeutically effective amount of AMPK agonist; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient

The present disclosure further relates to use of autophagy inhibitor or Phosphodiesterase type 4inhibitor or combination thereof, optionally along with AMPK agonist in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition.

In some embodiments, the present disclosure relates to use of autophagy inhibitor, optionally along with AMPK agonist in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition.

In some embodiments, the present disclosure relates to use of Phosphodiesterase type 4 inhibitor, optionally along with AMPK agonist in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition. In some embodiments, the present disclosure relates to use of autophagy inhibitor and Phosphodiesterase type 4 inhibitor optionally along with AMPK agonist in preparation of a medicament for management of Myeloprol iferative Disorder or any associated condition.

In embodiments of the present disclosure, AMPK or AMP activated Protein Kinase includes AMPK gene or protein or combination thereof.

In embodiments of the present disclosure, Phosphodiesterase type 4 includes Phosphodiesterase type 4 gene or protein or combination thereof.

In embodiments of the present disclosure, autophagy includes gene involved in lysosome formation ar d function, formation of autophagsome or Autophagosome structure or combination thereof.

In embodiments of the present disclosure, the Janus Kinase 2 mutation is selected from a group comprising V6 F, K539L and T875N or a y combinations thereof.

The mutations are described below:

V617F = Valine (V) at position 6 17 is replaced by a Phenylalanine (F) K539L = Lysine (K) at position 539 is replaced by a Leucine (L)

T875N = Threonine (T) at position 875 is replaced by a Asparagine (N)

The drug combinations are designed using virtual computational simulations.

The two-drug combinations and three drug combinations of the present disclosure provide synergistic efficacy on the end-point markers, while dosing as low as about 20-100% of the recommended therapeutic dose of the drag in humans. Using a lower dose of the individual drug also provides an advantage in terms of minimizing the intensity of side-effects or toxicities associated with the drags. Also, the drug combination works by inhibiting multiple targets minimally, so that an amplified effect is observed on all of the primary end-point markers and at the same time ensuring that all the targets have primary response ability, so as to negate the possibility of immune suppression and secondary infections.

e of smaller doses of individual drugs also lowers the cost of manufacture and formulation, providing an improved effect at lower price to the subject. Smaller doses also mitigate against wasteful administration of a drug to a physiological system that has been saturated or has reached a peak therapeutic response from smaller, synergistic doses.

Thus, some of the important advantages provided by the compounds, compositions, methods and uses of the present disclosure are: ) reduction of dosages of drugs/compounds being used in the treatment of Myeloproliferative disorders; ) synergistic efficacy of the combination of compounds provided for management of Myeloproliferative disorders; and ) minimizing the intensity of side-effects or toxicities associated with the drugs used in the treatment of Myeioprol iterative disorders.

Phosphodiesterase type 4 inhibitor compound (CW242) As used herein, the term, "CW242" refers to any Phosphodiesterase type 4 inhibitor compound. In embodiments of the present disclosure, the phosphodiesterase type 4 inhibitor compound is selected from a group comprising, but is not limited to Roflumilast, Piclamilast, CDP 840, CP 80633, Etazolate, C 63197, Isrogladine, (R,S)-Mesopram, RO 20-1724, Rolipram, (R)-(-)-Rolipram, S-(+)-Rolipram, CHEMBL1 232082, YM 976 or pharmaceutically-acceptabie salt of any of the foregoing, or any combinations thereof.

The CW242 class of drug is a PDE4 (Phosphodiesterase type 4) inhibitorcompound. In profiles with JAK2 dominance or harboring JAK2V617F mutations; JAK-STATs, SHC-RAF-ERK, PI3K-AKT signaling is hyper-activated through constitutive activation or over-activation via signaling inputs of JAK2. Inhibition of PDE4 by CW242 brings about a reduction in this dominant signaling pathway of the JAK2V617F mutant or JAK2 dominant profiles.

Inhibition of PDE4 by CW242 results in an increase in cAMP and in turn an increase in PRKACA (eAMP-dependent protein kinase catalytic subunit alpha) and CREBl(cAMP response element- binding protein 1).CREB1 mediated NFKB reduction by CW242 causes reduction in viability and proliferation of the tumor cell. PRKACA mediated inhibition of RAF, further reduces dominance of this pathway in JAK2V637F or JAK2 dominant mutant profiles. PRKACA mediated activation of RUNX2 that transcribes CDKNIA and CDK B helpsin reducing proliferation by inhibiting key cell cycle kinases CDK4 and CDK2. RUNX2 also causes induction of BAX which is pro-apoptotic. CW242 is a selective PDE4 inhibitor having potent inhibition activity against PDE4.In a biochemical assay of CWG242,dose response effect on theinhibition of PDE4 activity is plotted as a curve generated by non-linear regression analysis .wherein the concentration of CWG242 required for 50% activity inhibition of PDE4 is as follows:

Cmax values are calculated from maximum drug concentration in human plasma after oral drug dose.Cmax level concentration of CW242 is found in the range of about 6.9 , which is equivalent to about 1.71 1 nM and inhibition constant is about 0.08 M.CW242 inhibits as a non-competitive inhibitor and in such cases, IC50 is equivalent to Inhibition Constant. Lesser the inhibition constant, higher is the efficacy of the drug. C ax value greater than IC50 indicates that more than IC50 target inhibition takes place with that drag.

Therefore in summary, in a JAK2V617F or JAK2 mutant profile, inhibition of PDE4 by CW242 mediates reduction of proliferation and viability through inhibition of RAF by PRKACA, inhibition of NFKB by CREB and activation of RU 2 by PRKACA that in turn induces cell cycle inhibitors and BAX.

Autophagy inhibitor compound (CW170) As used herein, the term, "CW170" refers to any autophagy inhibitor compound. n embodiments of the present disclosure, the autophagy inhibitor compound is selected from a group comprising, but is not limited to Chloroquine, Lucanthone, LysOl, Lys02, Lys03, Lys04, Lys05, Hydroxychloroquine, Mefloquine, Quinacrine or pharmaceutically-acceptable salt of any of the foregoing, or any combinations thereof.

The CW170 class of compound is an inhibitor of Autophagy, which inhibits autophagosome mediated proteosomal degradation and results in accumulation of protein aggregates. Accumulated protein aggregates cause increase in ROS (Reactive Oxygen Species). High level of ROS triggers Endoplasmic Reticulurn(ER) stress, which activates the DNA repair machinery and induces TP53. increase in ROS and induction of TP53 make the cell vulnerable to apoptosis and leads to reduction of viability and proliferation in JAK2 dominant or mutant profiles.

CW170 is a selective autophagy inhibitor having potent inhibition activity against Autophagosomal Vacuole.In an embodiment, in vitro IC50 value of CW170 across various cel lines such as MDAMB- 231, SKBR-3JHCC1954, MDAMB-43 1, HCC 1937 and BT20 are as follows:

Bioavailability of CW170 is about 89% and Cmax is about 2-4µΜ, which are calculated from maximum drug concentration in human plasma after oral drug dose. In humans, the reported Cmax value is about M ar d in rat it is about 308 µΜ Cmax value for CW1 70 is reported as high as about 700µ.Μ in patients.

AMPK Agonist compound (CW178) As used herein, the term, "CW178" refers to any AMPK agonist compound n embodiments of the present disclosure, the AMPK agonist compound is selected from a group comprising but is not limited to Metformin, Phenformin, Panduratin, AICAR, B-lapachone, AMPK activator (CID16760291), A769662 or pharmaceutically-acceptable salt of any of the foregoing, or any combinations thereof.

CW178 class of drug is an activator or agonist of AMPK. AMPK or AMP activated protein kinase is an energy sensor enzyme which is activated in cells under metabolic stress. Activated AMPK helps the cells to survive under nutrient deprived conditions by inhibiting ceil proliferation. AMPK is known to phosphorylate and activate TSC1-TSC2 complex which is an endogenous inhibitor of mTOR or mechanistic target of rapamycin (serine/threonine kinase). AMPK also causes an inhibitory phosphorylation of IRS1 (Insulin receptor substrate I) at ser-789 position. So in a cancer profile having highly-activated PBK/AKT/mTQR signaling axis, such as those with PTEN (Phosphatase and tensin homolog) mutation/loss or activated IRS, the activation of AMPK will result in inhibition of the constitutive!y active mTORCl, thereby reducing cell proliferation.

The combination of the two inhibitors through very different mechanisms of actions and pathway impacts converge on reducing proliferation and viability in JAK2 dominant or mutant patient profiles.

The combination of any CW242 compound,any CW170 compound and any CW178 compound, in any amount, ratio, concentration, volume or order thereof inhibits JAK2V6 17F or JAK2 dominant mutant patient profiles which have hyper-activated JAK2, STAT3 and STATS. CW242 reduces the dominance ofERK pathway, NFKB Pathway, SHH pathway and it inducesCDKNlA and CDKN1B which are cell cycle inhibitors and suppress the activity of key cel cycle kinases CDK4 and CDK2 in JAK2 dominant patient profiles. C 70 induces ROS, ER Stress, TP53, Ceramide biosynthesis and cell cycle inhibitor.CW178 is an AMPK agonist which reduces the dominance of mTOR pathway and ER pathway by reducing prenylation of RHEB and RAS through inhibition of HMGCR. It inhibits AKT pathway through inhibitor}' phosphorylation of IRS1 and induces BBC3, BAX and CDKN A expression by inducing TP53 activation.

The present disclosure further relates to a composition comprising at least two compounds selected from;

a) a compound of formula I, acompound of formula 11, a compound of formula III, a compound of formula IV or a compound of formula V; b) a compound of formula VI or a compound of formula VII; and

c) a compound of formula VIII; optionally along with pharmaceutically acceptable excipient.

In some embodiments, a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V is a phosphodiesterase type 4 inhibitor.

In some embodiments, a compound of formula VI or a compound of formula VII is an autophagy inhibitor.

In some embodiments, a compound of formula VIII is an AMPK Agonist.

In some embodiments, the compound of formula I is: is O, 1, 2 or 3;

A3 is selected from unsaturated, saturated, partially saturated, aryl and heteroaryl, each of which is optionally substituted by keto group;

A , A5, A is selected from alkyl, alkylheteroarvl, alkarvl, aralkyi, aryl and heteroaryl, each of which is optionally substituted completely or partially by halogen; and

A , A2 are individually seiected from alkyl, alkoxy, cycioalkylmethoxy (or cycioaikylalkoxy), cycloalkoxy, bicycloxv and aryloxv, each of which is optionally substituted completely or partially by halogen.

In some embodiments, the compound of formula II is:

Wherein E is selected from N and CH2; and

Ei, E2, E are individually selected from amino, alkyl, aryl and heteroaryl, each of which is optionally substituted.

In some embodiments, the compound of formula III is:

Wherein, E5, E , are individually selected from N and CH2; E is selected from hydrogen and alkyl;

E is NH; and ally selected from hydrogen; and

, where E 2 ,E 3 are individually selected from oxygen and sulphur.

In some embodiments, the compound of formula IV is:

Wherein,Ej 4 , E are individually selected from hydrogen and

E 17 ,E are individually selected from N and CH; and E is selected from oxygen and sulphur.

In some embodiments, the compound of formula V is: Wherein, P is selected from hydrogen, alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted; is seiected from

, alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted: R is selected from hydrogen, alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted; and S is selected from oxygen, alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted by halogen;

In some embodiments, the compound of formula VI is:

Wherein, X is selected from N, N =0 and CH; L is selected from halogen, hydrogen, a halogen-containing group, alkyl andalkoxy; R is Ri -NH R , and where R is a chemical bond, alkyl, cylcoalkyl, sulfonyl, earbonyl; and R is Wherein, m is selected from 0, 1, 2 ,3, 4 and 5; n is selected from 0, 1, 2 , 3, 4 and 5; Y is selected from N~R and O;

Z is selected from N and CH2; and R3, R4, R5, R6, R7, R7, R8, R9, RIO and Rl is individually selected from hydrogen, alkyl, alkoxy, aryl, alkaryl, aralkyl and heteroaryl, each of which are optionally substituted.

In some embodiments, the compound of formula VII is;

Wherein, W is individually selected from oxygen and sulphur; t is selected from 0, 1, 2, 3, 4 and 5: and R14, R15, R16 and R17is individually selected from hydrogen, alkyl, alkoxy, aryl, alkaryl, aralkyl and heteroaryl, each of which are optionally substituted.

In some embodiments, the compound of formula VIII is:

Wherein, Rl is selected from hydrogen and alkyl; between 1 to 4.

In some embodiments, the present disclosure relates to a composition comprising: a) a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; b) a compound of formula VI or a compound of formula VII; and c) a compound of formula VIII; optionally along with pharmaceutically acceptable excipient.

In some embodiments, the present disclosure relates to a composition comprising: a) a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula V or a compound of formula V; and b) a compound of formula VI or a compound of formula VII; and optionally along with pharmaceutically acceptable excipient.

In some embodiments, the present disclosure relates to a composition comprising: a) a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; and b) a compound of formula VIII; and optionally along with pharmaceutically acceptable excipient.

In some embodiments, the present disclosure relates to a composition comprising: a) a compound of formula VI or a compound of formula VII; and b) a compound of formula VIII; and optionally along with pharmaceutically acceptable excipient.

The present disclosure further relates to a kit comprising at least two compounds selected from a group comprising: a) a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; b) a compound of formula VI or a compound of formula VII; and c) a compound of formula VIII; optionally along with pharmaceutically acceptable excipient, wherein the kit comprises one or plurality of dosage forms.

In some embodiments, the present disclosure relates to a kit comprising: a) a compound of formula I, a compound of formula II, a compound of form a III, a compound of formula IV or a compound of formula V; b) a compound of formula VI or a compound of formula VII; and c) a compound of formula VIII; and optionally along with pharmaceutically acceptable excipient, wherein the kit comprises one or plurality of dosage forms.

In some embodiments, the present disclosure relates to a kit comprising: d) a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; and e) a compound of formula VI or a compound of formula VII; and optionally along with pharmaceutically acceptable excipient, wherein the kit comprises one or plurality of dosage forms.

In some embodiments, the present disclosure relates to a kit comprising: a) a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; and b) a compound of formula VIII; and optionally along with pharmaceutically acceptable excipient, wherein the kit comprises one or plurality of dosage forms.

In some embodiments, the present disclosure relates to a kit comprising: a) a compound of formula VI or a compound of formula VII; and b) a compound of formula VIII; and optionally along with pharmaceutically acceptable excipient, wherein the kit comprises one or plurality of dosage forms. The present disclosure further relates to a method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of compound selected from a group comprising; a) a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; and a compound of formula VI or a compound of formula VII; or a combination thereof; b) optionally along with a compound of formula VIII; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient.

In some embodiments, the present disclosure relates to a method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of:

a) a compound of formula I, a compound of formula II, a compound of formula III, a compound

of formula TV or a compound of"formula V; b) optionally along with a compound of formula VIII; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient.

In some embodiments, the present disclosure relates to a method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of: a) a compound of formula VI or a compound of formula VII; b) optionally along with a compound of formula VIII; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient.

In some embodiments, the present disclosure relates to a method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of: a) a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; and b) a compound of formula VI or a compound of formula VII; c) optionally along with a compound of formula VIII; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient.

The present disclosure further re tes to use of compound selected from a group comprising: a) a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; and a compound of formula VI or a compound of formula VII; or a combination thereof; b) optionally along with a compound of formula VIII; in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition.

In some embodiments, the present disclosure relates to use of: a) a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula V or a compound of formula V; b) optionally along with a compound of formula VIII; in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition.

In some embodiments, the present disclosure relates to use of: a) a compound of formula VI or a compound of formula VII; b) optionally along with a compound of formula VIII; in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition.

In some embodiments, the present disclosure relates to use of: a) a compound of formula I, a compound of Formula II, a compound of formula III, a compound of formula IV or a compound of formula V; and b) a compound of formula VI or a compound of formula VII; c) optionally along with a compound of formula VIII; in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition.

The combination of the two compounds and three compounds in the present disclosure, through very different mechanisms of actions and pathway impacts converge on reducing proliferation and viability in JAK2 dominant or mutant patient profiles.

As used herein, the term, "CW 170 178," refers to a combination of any CW170 compound, and any CW178 compound in any amount, ratio, concentration, or order thereof.

As used herein, the term, "CW 170242," refers to a combination of any CW170 compound, and any CW242 compound i any amount, ratio, concentration, or order thereof.

As used herein, the term, "CW 178242," refers to a combination of any CWI78 compound, and any CW242 compound in any amount, ratio, concentration, or order thereof.

As used herein, the term, "CW1 70 178242," refers to a combination of any CW170 compound, any CW178 and any CW242 compound in any amount, ratio, concentration, or order thereof.

Further, throughout the present disclosure and accompanying figures, in terms of representation, CW242 may be used interchangeably with a Phosphodiesterase type 4 inhibitor and has the same scope, CW170 may be used interchangeably with an Autophagy inhibitor and has the same scope and CW178 may be used interchangeably with an AMPK Agonist and has the same scope.

Also, though CW242, a Phosphodiesterase type 4 inhibitor may be represented by Roflumilast, any other Phosphodiesterase type 4 inhibitor, being similar in biological and functional features, gives results similar to Roflumilast. Though CW170, an Autophagy inhibitor may be represented by Chioroquine, any other Autophagy inhibitor, being similar in biological and functional features, gives results similar to Chioroquine. Though CW178, an AMPK Agonist may be represented by Metformin, any other AMPK Agonist, being similar in biological and functional features, gives results similar to Metformin. Furthermore, throughout the present disclosure and accompanying figures, in terms of representation, CW242 3µΜ or CW170 1 µΜ indicates the concentration of the particular compound used, expressed in Micromolars (µΜ). For instance, CW242 3 µΜ indicates a phosphodiesterate type 4 inhibitor compound such as Rofiumilast present at a concentration of 3 µΜ

The present disclosure is further described with reference to the following examples, which are only illustrative in nature and should not be construed to limit the scope of the present disclosure in any manner.

Figure l a of the present disclosure depicts the effect of Autophagy Inhibitor (CW1 70) Phosphodiesterase type 4 inhibitor (CW242) and its combination on proliferation phenotype in JAK2 driven virtual disease model.

Figure l b of the present disclosure depicts the effect of C 70, CW242 and its combination on viability phenotype in JAK2 driven virtual disease model.

Figure l c of the present disclosure depicts the effect of CW170, CW242 and its combination on CDK2-CCNA complex, a proliferation biomarker, in the JA 2 driven virtual disease model.

CD 2 is a cyciin dependent kinase. Cyclin A (CCNA) binds to one side of CDK2's catalytic cleft, inducing large conformational changes and transform CDK2 CCNA complex into active state that plays a key role in ceil proliferation. CW242 and CW170 converge on CDK2 CCNA complex through various pathways. CW242 activates PRKACA which inhibits RAF->ERK pathway. ERK activates S , which is transcription factor of CDK2.PRKACA also activates R NX2 which is transcription factor of CDKN1A a d CDKN1B, a cell cycle inhibitor which inhibits CDK2 CCNA Complex. CW170 which inhibits autophagy suppress CDK2 CCNA Complex by activation of cell cycle inhibitors through ROS - > TP53~>CDKN I A and TP53--> MYC ->CDKN1 A pathway.

gure of the present disclosure depicts the effect of CW170, CW242 and its combination CDK4-CCND1 complex, a proliferation biomarker, in the JAK2 driven virtual disease model. CD 4 is also a cycliii dependent kinase, which converts into active state after binding with Cyclin D (CCNDl). This CDK4-CCND1 complex is the G to S cell cycle checkpoint marker. CW242 and CW170 converge on CD 4 CCNDl complex through various pathways. CW242 activates PRKACA which inhibits RAF-> ERK pathway. ERK activates SPl, which is transcription factor of CDK4. PRKACA also activates RUNX2 which is transcription factor of CDKNl A and CDKNIB, a cell cycle inhibitor which inhibits CDK4 CCNDl Complex. PRKACA activates CREB which in turns inhibits NFKB. NFKB is transcription factor of CCNDl. CW170 which inhibits autophagy inhibits CDK4_CCND1 Complex by activation of cell cycle inhibitors through ROS --> TP53->CDKN3 A and TP53--> MYC >CDKN A Pathway.

Figure l e of the present disclosure depicts the effect of CW170, CW242 and its combination on CDK2-CCNE comp ex a proliferation biomarker, in the JAK2 driven virtual disease model.

CyclinE (CCNE) binds to one side of CDK2's catalytic cleft, inducing large conformational changes and transform CDK2 CCNE Complex into active state that plays a key role in cell proliferation CW242 and CW170 converge on CDK2 CCNE complex through various pathways. C 242 activates PRKACA which inhibits RAF-> ERK pathway. ERK activates S which is transcription factor of CDK2. PRKACA also activates RUNX2 which is transcription factor of CDKNl A and CDKNIB, a cell cycle inhibitor which inhibits CDK2 CCNE Complex. CW170 which inhibits autophagy, inhibits

CDK2 CCNE complex by activation of cell cycle inhibitors through ROS — > TP53—>CDKN1A and TP53-> MYC ~>CDKNT A Pathway.

Figure f of the present disclosure depicts the effect of CW170, CW242 and its combination on MCLi, a survival biomarker, in the JAK2 driven virtual disease model.

MCL1 is anti-apoptotic protein, which is a member of the Bcl-2 family of proteins. CW242 mainly acts on MCLI by PRKACA~>CREB— >NFKB pathway. NFKB is transcription factor of MCLI. CW170 also inhibits MCL through Caspase 3 and BIRC5 pathway.

The simulation experiments and analyses, as depicted in Figures la-f of the present disciosureareperformed using the predictive tumor model, a comprehensive and dynamic representation of signaling and metabolic pathways in the context of cancer physiology. The simulation model includes representation of important signaling pathways implicated in cancer such as growth factor pathways; cytokines and chemokmes such as ILl, IL4, IL6, ILl , TNF; GPCR mediated signaling pathways; mTOR signaling; cell cycle regulations, tumor metabolism, oxidative and ER stress, representation of autophagy and proteosomal degradation, DNA damage repair, p53 signaling and apoptotic cascade.

The referenced version of the cancer model includes more than 4700 intracellular biological entities and about 6500 reactions representing their interactions regulated by about 25000 kinetic parameters. This comprises a comprehensive and extensive coverage of the kinorne, transcriptome, proteome and the metabolome. There are 142 kinases and 102 transcription factors modelled in the system.Disease phenotype indices are defined in the tumor model as functions of biomarkers that are involved in regulating these aspects of the tumor cell.

The proliferation index is an average function of the active CDK-Cyclin complexes that define cell cycle check points and are a key factor for regulating overall tumor proliferation potential. The biomarkers include; CDK4-CCND1, CDK2-CCNE, CDK2-CCNA and CDKl-CCNBl.The biomarkers are given a certain weightage in the index definition.

The viability index is a ratio of two sub-indices: Survival over Apoptosis. The components for each of the sub-indices are selected based on their regulation and convergence towards these endpoints. The biomarkers constituting the survival index include: A T1, BCL2, MCLl, BIRC5, BIRC2 and XIAP. All these biomarkers are well reported to supporting tumor survival. The apoptosis index comprises of: BAX, CASP3, NOXA and CASP8. The overall cell viability index is then calculated as a ratio of survival index/apoptosis index. The weightage of each biomarker is decided to achieve a maximum correlation with experimental trends for the end points.

In order to correlate the results from experiments such as MTT Assay, which are a measure of metabolically active cells, 'Relative Growth' index is provided, that is, an average of the survival and proliferation indices.

In summary, since mutations in cell signaling pathways and associated components.form some of the contributory factors to cancerous conditions, the effects of compounds of the present disclosure on cell signaling pathways and associated components, in a virtual model has been provided above in the present disclosure. The result of such experimentation provides an analysis on how the compounds of the present disclosure are beneficial and efficaciousin a cancerous condition. For example, a compound of the present disclosure that indirectly impacts MCL1, a survival marker, affects the role played by MCL1 in a cel signaling pathway in a cancerous condition, and thus has an effect on the disease condition.

Figure 2a depicts the dose response effect of Autophagy inhibitor CW170 (represented by Chloroquine) and Phosphodiesterase Type 4 inhibitor CW242 (represented by Roflumilast) alone and in combination on the proliferation index in a virtual Myelofibrosis (MF) disease model. Furthermore, ' C refers to IC25 based on proliferation.

This dose response effect of CW170 and CW242 alone and in combination is done on the virtual MF disease model and the proliferation index is assayed. At all doses, the combination of the two compounds is more enhanced over the individual compound effects, in reduction of % proliferation. CW242 has a higher contribution to reducing proliferation and the combination shows a synergistic reduction in proliferation. Any other Phosphodiesterase compound (CW242) and any other Autophagy Inhibitor compound (CW170) yields similar result in reduction of proliferation % in the virtual Myelofibrosis model.

Figure 2b depicts the dose response effect of CW170 (represented by Chloroquine) and CW242 (represented by Roflumilast) alone and in combination on the viability index in a virtual Myelofibrosis (MF) disease model. Furthermore, " refers to IC25 based on proliferation.

This dose response effect of CW170 and CW242 alone and in combination is done on the virtual MF disease model and the viability index is assayed. At all doses, the combination of the two compounds is more enhanced over the individual compound/drag effects. CW170 has a higher contribution to reducing viability index, when compared to CW242, and the combination of the two has further enhanced effect on reduction of viability. Any other Phosphodiesterase compound (CW242) and any other Autophagy Inhibitor compound (CW170) yields similar result in reduction of viability index in the virtual Myelofibrosis model. Figure 2c depicts the synergy plot between CW170 (represented by Chloroquine) and CW242 (represented by Roflumilast) and indicates the minimal amount of compound needed in combination to achieve about 30% inhibition of proliferation when compared to the individual compounds.

This synergy plot has concentration of CW170 (represented by Chloroquine) on the x-axis and CW242 (represented by Roflumilast) on the y-axis and it indicates the minimal amount of compound needed in combination to achieve about 30% inhibition of proliferation when compared to the individual compounds. The black dot below the line indicates that only less than about l/4 of CW170 and about ½ of CW242 is needed in combination to achieve about 30% inhibition of proliferation when compared to the individual compounds. All concentrations of the compounds are micromolar concentrations.

This plot is an indication of the reduction of dosage of the individual compounds required in a disease condition, wherein the reduction is brought about by the compositions of the present disclosure, in embodiments where the composition comprises 2 or more compounds. Any other Phosphodiesterase compound (CW242) and any other Autophagy Inhibitor compound (CW170) yields similar result in reduction of proliferation %.

EXAMPLE 3 - Example 3. - Figure 3a depicts an assay of relative growth (proliferation) in JA 2 mutant BAF3 cells to determine the effect of compounds CW170 (represented by Chloroquine), CW242 (represented by Roflumilast) vs. the combination CW 170242 (Chloroquine: Roflumiiast/CW170:CW242).

Assay of relative growth (proliferation) in JAK2 mutant BAF3 cells The aim of this experiment is to determine the effect of single compounds CW170 (represented by Chloroquine) and CW242 (represented by Roflumilast) vs. the combination CW 170242 (Chloroquine:Roflumilast) on relative growth in JA 2 mutant BAF3 cells.

Experimental system : BaF3 mouse hematopoietic pro-B cells are cultured in RPMI 1640 medium (Invitrogen) complemented with 10% Fetal calf serum, 10% of WEHI-3B cell supernatant as a source of IL-3 and 1% penicillin/streptomycin. JAK2v617F mutant construct is transfected into the BAF3 cells that triggers the transformation of these cells into tumorigenic cells. The JAK2 mutant BAF3 cells are incubated with different concentrations of the compounds CW242, CW170 and the combination of the two, along with Jakafi (a JAK2 inhibitor) as a positive control. The relative growth is assayed using the MTT assay.

es lt : Individual compounds CW242 at 3µΜ and CW170 at 10 µΜ reduce proliferation of cells by about 30% while in combination there is about 55% reduction in proliferation of cells, indicating an enhanced effect with the combination. Similarly, CW242 at 30 µΜ reduces proliferation of cells by about 45% and CW170 at 10 µΜ by about 30%, but in combination there is synergistic reduction in proliferation of greater than about 70%.

The synergistic efficacy of the combination of compounds is to be analyzed by the parameter that two or more mutually exclusive compounds, which are different in functions and characteristics and that activates different pathways, work in combination with each other and provide a reduction in the proliferation of cells which is higher than the reduction brought about by the compounds individually. Thus, the compositions of the present disclosure provide a surprising advantage over the individual compounds, and obtaining such compositions is useful and unobvious.

EXAMPLE 3.2 - Figure 3b depicts the dose response effect of adding fixed dose of Phosphodiesterase type 4 Inhibitor CW242 (represented by Roflumilast) to different doses of autophagy inhibitor CW170 (represented by Chioroquine).

The same experiment as described for figure 3A is plotted to show the dose response effect of adding fixed dose of Roflumilast (ΟµΜ or 3µΜ or 30µΜ) to different doses of Chioroquine (ΟµΜ, 3µΜ ,

10µΜ and 30µΜ) . The concentration of Chioroquine (in micromoles) is on x-axis and y-axis is % change from control. The dashed ( ¥242_3 µ.Μ and dotted 242_30µΜ lines indicate an enhancement of Chioroquine effect in combination with Roflumilast

The synergistic efficacy of the combination of compounds is to be analyzed by the parameter that two or more mutually exclusive compounds, which are different in functions and characteristics and that activate different pathways, wor in combination with each other and provide a reduction in the proliferation of cells which is higher than the reduction brought about by the compounds individually. Thus, the compositions of the present disclosure provide a surprising advantage over the individual compounds, and obtaining such compositions is useful and unobvious.

EXAMPLE 3.3 - Figure 3c depicts a comparison in the standard of care JAK inhibitor (Jakafi) wit the combination of Phosphodiesterase type 4 inhibitor and Autophagy Inhibitor - CW 170242 (represented by Chloroquine: Roflumilast) in proliferation in JAK2 mutant HEL cells.

Method : HEL is a human erythroleukaemic cell line with complex genome rearrangements and has multiple copies of the JAKV2617F mutation. HEL cell line is established from a patient with a therapy related Acute Myeloid Leukaemia (AML), that is the final progression of MPD. It is extensively used a model for myeloid malignancies.

HEL cells are cultured in PM1 1640 medium containing 10% FBS, glutamine, penicillin and streptomycin in 5% C0 2. The cells are treated with different concentrations of CW170 (represented by Chloroquine, 5µΜ and 10µΜ ) and CW242 (represented by Roflumilast 5µΜ and 10µΜ ) individually and in combination for about 72 hours. 150 M JAK2 inhibitor Jakafi is used as positive control. Proliferation is assessed by MTT assay.

The aim of the experiment is to compare the standard of care JAK inhibitor (Jakafi) with the combination of compounds of the present disclosure, in JAK2 mutant HEL cells.

Results : Combination of CW170 10 µΜ and CW242 5µΜ shows an equivalent effect to high dose Jakafi in HEL cells indicating that this combination is comparable or has better efficacy than standard of care. Standard of care is known to be effective initially, but leads to resistance in due time. The reduction in proliferation of cells seen in both cases is about 30%. HEL cells have many other mutations besides JAK2 and therefore the effects seen may appear slightly less than in BAF3 cells. However, the combination of compounds of the present disclosure, at different doses, shows an enhanced reduction over the individual compounds.

The synergistic efficacy of the combination of compounds is to be analyzed by the parameter that two or more mutually exclusive compounds, which are different in functions and characteristics and that activate different pathways, work in combination with each other and provide a reduction in the proliferation of cells which is higher than the reduction brought about by the compounds individually. Thus, the compositions of the present disclosure provide a surprising advantage over the individual compounds, and obtaining such compositions is useful and unobvious.

EXAMPLE 4 - Figures 4a and 4b depict Ex-vivo clonogenic assay in JAK2 mutant patient cells with Phosphodiesterase type 4 inhibitor CW242 (represented by Roflumilast), autophagy inhibitor CW1 70 (represented by Chloroquine), and their combination in comparison with standard of care JAK inhibitor (Jakafi).

A clonogenic assay is a microbiology technique for studying the effectiveness of specific agents on the survival and proliferation of cells. t is used in cancer research laboratories to determine the effect of drugs or radiation on proliferating tumor cells.

The experiment involves three major steps: . The treatment is applied to a sample of cells. 2. The cells are "plated" in a tissue culture vessel and allowed to grow. 3. The colonies produced are fixed, stained, and counted.

At the conclusion of the experiment, the percentage of cells that survived the treatment is measured.

Patient bone marrow cells are treated with different concentrations of Phosphodiesterase type 4 inhibitor, represented by Roflumilast (ΙΟµΜ), Autophagy inhibitor represented by Chloroquine (ΙΟµΜ) and combination in comparison with high dose jakafi (500 nM), low dose Jakafi (100 nM), and the combination is tested in the absence and presence of low dose Jakafi.

Method : Patient bone marrow aspirate is obtained. Bone marrow mononuclear cells are isolated from the aspirate by Density Gradient Centrifugation, resuspended in Dulbecco's modified Eagle's medium containing Penicillin G (lOOU/ml) and Streptomycin (lOOug/ml) and supplemented with 15% (weight/volume) Fetal Bovine Semm (FBS) and cultured at 37°C in a humidified atmosphere of 5%

C0 2. A colony formation assay is performed by seeding cells in a six well plate ( 00 cells/well) in MesenCult medium (Stem Cell Technologies). The untreated cells are the controls and the remaining wells are treated with the different concentrations of thecompounds of the present disclosure. After 2 weeks, cells are washed twice, fixed with 70% ethanol for about 15 minutes and stained with 0.5% crystal violet at room temperature. Colonies containing 50 cells or more are counted and colony efficiency is calculated.

Res lts: There is an enhanced reduction of clonogenic survival with the low dose combination of CW242J0 µΜ : : 170_10 µΜ of about 25% when compared to no effect with CW242_1(^M alone and about 15% with CW170 10 µΜ alone. In the presence of low dose Jakafi, the effect of the CW242 10 µΜ : \ 70 10 µΜ combination shows a synergistic decrease of the clonogenic survival of about 80%, that is equivalent to the high dose Jakafi (500nM) also showing about 80% reduction.

The synergistic efficacy of the combination of compounds is to be analyzed by the parameter that two or more mutually exclusive compounds, which are different in functions and characteristics and that activate different pathways, work in combination wit each other and provide a reduction in the proliferation of cells which is higher than the reduction brought about by the compounds individually. Thus, the compositions of the present disclosure provide a surprising advantage over the individual compounds, and obtaining such compositions is useful and unobvious.

Implications: High dose Jakafi has many adverse effects.Therefore, combining the low dose Jakafi with low dose combination of CW170 and CW242 gives the desired effect with much lowered toxicity.

Experiment 4B: Patient bone marrow cells are treated with different concentrations of Autophagy inhibitor, represented by Chloroquine (20 µΜ ), Phosphodiesterase type 4 inhibitor, represented by Roflumilast (20µΜ ), and combination of both, in comparison with high dose akafi (500 nM), low dose Jakafi (100 nM), and the combination is tested in the absence and presence of low dose Jakafi.

Results : The reduction with CW242 (20 µΜ ) is about 35 to 40%, with CW170 (20 µΜ ) is about 60% while with the combination, the reduction in survival is enhanced to around 75%, almost similar to the 80% reduction with high dose Jakafi. Further, 20 µΜ CW1 70:20 µΜ CW242 combination with low dose Jakafi (!OOnM) shows an improved and more enhanced effect when compared to high dose Jakafi with a reduction of greater than 90%.

The synergistic efficacy of the combination of compounds is to be analyzed by the parameter that two or more mutually exclusive compounds, which are different in functions and characteristics and that activate different pathways, work in combination with each other and provide a reduction in the proliferation of cells which is higher than the reduction brought about by the compounds individually. Thus, the compositions of the present disclosure provide a surprising advantage over the individual compounds, and obtaining such compositions is useful and unobvious.

Implications: High dose Jakafi has many adverse effects. Therefore, combining the low dose Jakafi with low dose combination of CW170 and CW242 gives the desired effect with much lowered toxicity.CW170 and CW242 are compounds/drugs approved for extended use in man and a have lower toxicity when compared to the approved dose of Jakafi. Therefore combining these compounds/drugs with low dose Jakafi gives an improved and enhanced efficacy with lower toxicity.

EXAMPLE 5 - Figure 5a and 5b depict animal in vivo data with the combination of C 170242 (represented by Chioroquine: Roflumilast) in presence and absence of standard of care JAK inhibitor (Jakafi).

Experiment : C57BL/6 background strain of nude mice are injected with BaF3/Jak2-V617F cells described earlier in the present disclosure. Baseline blood samples are obtained (50 ul) through submandibular bleeding in tubes containing EDTA. Complete blood cell counts are obtained using a HESKA Vet ABC-Diff Hematology analyzer (Heska, Loveland, CO). The mice then receive vehicle (n=6) or treated with Phosphodiesterase type 4 inhibitor CW242 at 5mg/kg BID (twice a day) oral dosing and Autophagy inhibitor CW170 at 30 mg/kg BID oral dosing (n=6) or the combination of CW242 and CW170 at the aforementioned dosing BID along with Jakafi at 30 mg/kg BID oral dosing. Samples from Spleen and bone marrow tissues are obtained at the study termination. Spleen weight and body weight of the animals are assessed.

Resisits : Figure 5a provides the percentage reduction in the ratio of spleen weight to body weight, of mice administered with BaF3/Jak2-V617F cells in presence or absence of compounds. Spleen size reduction is a clinical endpoint indicating drug action and effectiveness and about 20% reduction in the ratio of spleen weight to bod}' weight is seen in presence of combination of CW170 at 30 mg/kg BID and CW242 at 5 mg/kg BID and combination of (CW170 (30mg/kg BID) +CW242 (5mg/kg BID) with low dose Jakafi at 30 mg/kg BID.

Figure 5b is the plot of the spleen weight of mice in grams, in presence of combination of CW242 and CW170, and with combination with low dose Jakafi. The reduction in spleen weight of the mice is enhanced by the combination and Jakafi, when compared to the combination alone. In both cohorts, about a 20-30% reduction in spleen weight is observed, indicating efficacy of the combination of CW242 and CW170.

The synergistic efficacy of the combination of compounds is to be analyzed by the parameter that two or more mutually exclusive compounds, which are different in functions and characteristics and that activate different pathways, work in combination with each other and provide a reduction in the proliferation of cells which is higher than the reduction brought about by the compounds individually. Thus, the compositions of the present disclosure provide a surprising advantage over the individual compounds, and obtaining such compositions is useful and unobvious

EXAMPLE 6 - Figiire 6a of the present disclosure depicts the effect of CW170 on BaF3 ceil line, effect of CW170 in combination with CW242 on BaF3 cell line, effect of CW170 in combination with CW178 on BaF3 cel line, effect of CW170 in combination with CW242 and CW178 on BaF3 cel line respectively. In the given plot, phenotype marker of relative growth is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 cell line used here is the virtual prototype of the JAK2V617F mutation incorporated cell line.

Figure 6b of the present disclosure depicts the effect of CW170 on BaF3 cell line, effect of CW170 in combination with CW242 on BaF3 cell line, effect of CW170 in combination with CW178 on BaF3 cell line, effect of CW170 in combination with CW242 and CW178 on BaF3 cell line respectively. In the given plot, phenotype marker of proliferation is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 cell line used here is the virtual prototype of JAK2V617F mutation incorporated cell line. Figure 6c of the present disclosure depicts the effect of CW170 on BaF3 cell line, effect of CW170 in combination with CW242 on BaF3 cel line, effect of CW 70 in combination with CW178 on BaF3 cell line, effect of CW170 in combination with CW242 and CW178 on BaF3 cell line respectively. In the given plot, phenotype marker of viability is assayed. "C" of each individual drug is IC20 on the basis of relative growth BaF3 cell line used here is the virtual prototype of JAK2V617F mutation incorporated cell line.

Figure 6 of the present disclosure depicts the effect of CW170 o BaF3 cell li e, effect of CW170 in combination with CW242 on BaF3 cell line, effect of CW170 in combination with CW178 on BaF3 cell line, effect of CW170 in combination with CW242 and CW 78 on BaF3 cell line respectively. In the given plot, biomarker of MCL1 is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 cell line used here is the virtual prototype of JAK2V617F mutation incorporated cell line.

MCL1 is anti-apoptotic protein, which is a member of the Bcl-2 family of proteins. CW178 mainly acts on MCL1 by AMPK-»TP53-» BBC3. BBC3 inhibits MCL1 pathway. CW170 also inhibits MCL1 through Caspase 3 and BIRC5 pathway. CW242 mainly acts on MCL1 by PRKACA~>CREB~ >NFKB pathway. NFKB is a transcription factor of MCL1.

Figure 6e of the present disclosure depicts the effect of CW170 on BaF3 ce l line, effect of CW170 in combination with CW242 on BaF3 cell line, effect of CW170 in combination with CW178 on BaF3 cel line, effect of CW170 in combination with CW242 and CW178 on BaF3 cel line respectively. In the given plot, biomarker of CDK4 CCNDl is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 ce l line used here is the virtual prototype of JAK2V6 7F mutation incorporated cell line.

CDK4 is also a cyclin dependent kinase, which converts into active state after binding with Cyclin D l (CCNDl). This CDK4-CCND1 complex is the Gl to S cell cycle checkpoint marker. CW178, CW242 and CW170 converge on CDK4 CCNDl complex through various pathways. CW178 inhibits HMGCR which inhibits RAF->ERK pathway via isoprenylation. ERK activates SP1 and API, which is the transcription factor of CDK4 and CCNDl respectively. CW170 which inhibits autophagy, inhibits CDK4 CCND1 complex by activation of cell cycle inhibitors through OS --> TP53-->CDKN1A and TP53-> MYC ->CDKN1A Pathways. CW242 activates PRKACA, which inhibits RAF-> ERK pathway. ERK activates SP1, which is transcription factor of CDK4. PRKACA also activates RUNX2, which is transcription factor of CDKNIA and CDKNIB, a cell cycle inhibitor which inhibits CDK4 CCND1 Complex. PRKACA activates CREB which in turns inhibits NFKB. NFKB is transcription factor of CCNDl.

Figure 6f of the present disclosure depicts the effect of CW170 (Chloroqume) on BaF3 cell line, effect of CW170 in combination with CW242 on BaF3 cell line, effect of CW170 in combination with CW178 on BaF3 cell line, effect of CW170 in combination with CW242 and CW178 on BaF3 cell line respectively. In the given plot, biomarker of CDK2_CCNE1 is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 cell line used here is the virtual prototype of the JAK2V617F mutation incorporated cell line.

CyclinE (CCNE) binds to one side of CDK2's catalytic cleft, inducing large conformational changes and transforms CDK2 CCNE complex into active state that plays a key role in cell proliferation. CW178, CW170 and CW242 converge on CDK2 CCNE complex through various pathways. CW178 inhibits HMGCR, which inhibits RAF->ERK pathway isoprenylation. ERK activates SP1, which is transcription factor of CDK2. CW178 also inhibits translation of proteins through inhibition of mTOR pathway. CW242 activates PRKACA , which inhibits RAF-> ERK pathway. ERK activates S , which is transcription factor of CDK2. PRKACA also activates RUNX2, which is transcription factor of CDK A and CDKNIB, a cell cycle inhibitor which inhibits CDK2 CCNE Complex. CW170 which inhibits autophagy, inhibits CDK2 CCNE complex by activation of cell cycle inhibitors through ROS - -> TP53-->CDKN1A and TP53-> MYC - >CDK 1A pathways.

EXAMPLE 7 - Figure 7a of the present disclosure depicts the effect of CW242 on BaF3 cell line, effect of CW242 in combination with CW170 on BaF3 cel line, effect of CW242 in combination with CW178 on BaF3 cell line, effect of CW242 in combination with CW170 and CW178 on BaF3 cell line respectively. In the given plot, phenotype marker of relative growth is assayed. "C" of each individual drug is IC20 on the basis of relative growth BaF3 cell line used here is the virtual prototype of the JAK2V617F mutation incorporated cell line. Figure 7b of the present disclosure depicts the effect of CW242 on BaF3 cell line, effect of CW242 in combination with CW170 on BaF3 cel line, effect of CW242 in combination with CW178 on BaF3 cell line, effect of CW242 in combination with CW170 and CW178 on BaF3 cell line respectively. In the given plot, phenotype marker of proliferation is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 cell line used here is the virtual prototype of the JA 2V6 7F mutation incorporated cell line.

Figure 7c of the present disclosure depicts the effect of CW242 on BaF3 cell line, effect of CW242 in combination with CW 0 on BaF3 cell line, effect of CW242 in combination with CW 78 on BaF3 cell line, effect of CW242 in combination with CW 0 and CW 78 on BaF3 cell line respectively. In the given plot, phenotype marker of viability is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 cell line used here is the virtual prototype of JA 2V6 7F mutation incorporated ceil line.

Figure 7 of the present disclosure depicts the effect of CW242 on BaF3 cell line, effect of CW242 in combination with CW170 on BaF3 cell line, effect of CW242 in combination with CW178 on BaF3 cell line, effect of CW242 in combination with CW170 and CW178 on BaF3 cell line respectively. In the given plot, biomarker of MCL1 is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 ce l ine used here is the virtual prototype of JA 2V6 7F mutation incorporated cel line.

Figure 7e of the present disclosure depicts the effect of CW242 on BaF3 ce l line, effect of CW242 in combination with CW170 on BaF3 cell line, effect of CW242 in combination with CW178 on BaF3 cel ine, effect of CW242 in combination with CW170 and CW178 on BaF3 cel ine respectively. In the given plot, biomarker of CDK4 CCND1 is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 cell line used here is the virtual prototype of JAK2V617F mutation incorporated cell line.

Figure 7f of the present disclosure depicts the effect of CW242 on BaF3 cell line, effect of CW242 in combination with CW170 on BaF3 cell line, effect of CW242 in combination with CW178 on BaF3 cell line, effect of CW242 in combination with CW 0 and CW1 78 on BaF3 cell line respectively. In the given plot, biomarker of CDK2 CCNE1 is assayed. "C" of each individual drug is IC20 on the basis of relative growth BaF3 cell line used here is the virtual prototype of JAK2V617F mutation incorporated cell line.

EXAMPLE 8 - Figure 8a of the present disclosure depicts the effect of CW178 on BaFB cell line, effect of CW178 in combination with CW170 on BaF3 cel line, effect of CW178 in combination with CW242 on BaF3 cell line, effect of CW178 in combination with CW170 and CW242 on BaF3 cell line respectively. In the given plot, phenotype marker of relative growth is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 cell line used here is the virtual prototype of JAK2V617F mutation incorporated cell line.

Figure 8b of the present disclosure depicts the effect of CW178 on BaF3 cell line, effect of CW178 in combination with CW170 on BaF3 cell line, effect of CW178 in combination with CW242 on BaF3 cell line, effect of CW178 in combination with CW170 and CW242 on BaF3 cell line respectively. In the given plot, phenotype marker of proliferation is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 cell line used here is the virtual prototype of JAK2V617F mutation incorporated ceil line.

Figure 8c of the present disclosuredepicts the effect of CW178 on BaF3 ceil line, effect of CW178 in combination with CW170 on BaF3 cell line, effect of CW178 in combination with CW242 on BaF3 cel ine, effect of CW178 in combination with CW170 and CW242 on BaF3 cel ine respectively. In the given plot, phenotype marker of viability is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 ceil line used here is the virtual prototype of JAK2V617F mutation incorporated ceil line.

Figure 8 of the present disclosure depicts the effect of CW178 on BaF3 cell line, effect of CW178 in combination with CW170 on BaF3 cel line, effect of CW178 in combination with CW242 on BaF3 cell line, effect of CW178 in combination with CW170 and CW242 on BaF3 cell line respectively. In the given plot, biomarker MCL1 is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 cell line used here is the virtual prototype of JAK2V617F mutation incorporated cell line. Figure 8e of the present disclosure depicts the effect of CW178 on BaF3 cell line, effect of CW178 in combination with CW170 on BaF3 cell line, effect of CW178 in combination with CW242 on BaF3 cell line, effect of CW178 in combination with CW170 and CW242 on BaF3 cell line respectively. In the given plot, biomarker CDK4 CCNDl is assayed. "C" of each individual drug is IC20 on the basis of relative growth. BaF3 cell line used here is the virtual prototype of JAK2V617F mutation incorporated cell line.

Figure 8f of the present disclosure depicts the effect of CW 78 on BaF3 cell line, effect of CW178 in combination with CW370 on BaF3 cell line, effect of CW 78 in combination with CW242 on BaF3 cell line, effect of CW178 in combination with CW370 and CW242 on BaF3 cell line respectively. In the given plot, biomarker CD 2 CCNE is assayed."C" of each individual drug is IC20 on the basis of relative growth. BaF3 cell line used here is the virtual prototype of JAK2V61 7F mutation incorporated cell line.

EXAMPLE 9- Figure 9a depicts an assay of relative growth (proliferation) in JA K2 mutant BAF3 cells to determine the effect of compounds CW170 (represented by Chloroquine), CW178 (represented by Metformin) vs. the combination CW170178 (CW170:CW178).

Experimental system : BaF3 mouse hematopoietic pro-B ceils are cultured in RPMI 1640 medium (Invitrogen) complemented with 10% Fetal calf serum, 0% of WEHI-3B cell supernatant as a source of IL-3 and 1% penicillin/streptomycin. JAK2v617F mutant construct is transfected into the BAF3 cells that triggers the transformation of these ceils into tumorigenic cells. The JA 2 mutant BAF3 cells are incubated with different concentrations of the compounds CW170, CW178 and the combination of the two. The relative growth is assayed using the MTT assay.

It is observed that for individual compound CW170 at 5 µΜ , there is no reduction is proliferation of cells and CW178 at 0.5 mM reduced proliferation of cells by about 50% while in combination of both there is about 60% reduction in proliferation of cells, indicating an enhanced effect with the combination. The synergistic efficacy of the combination of compounds is to be analyzed by the parameter that two or more mutually exclusive compounds, which are different in functions and characteristics and that activate different pathways, work in combination with each other and provide a reduction in the proliferation of cells which is higher than the reduction brought about by the compounds individually. Thus, the compositions of the present disclosure provide a surprising advantage over the individual eompoundsand obtaining such compositions is useful and unobvious.

Figure 9b depicts an assay of relative growth (proliferation) in JA 2 mutant BAF3 cells to determine the effect of compounds CW242 (represented by Roflumilast), CW 8 (represented by Metformin) vs. the combination CW 78242 (CW578:CW242).

Experimental system : BaF3 mouse hematopoietic pro-B cells are cultured in RPMI 1640 medium (Invitrogen) complemented with 10% Fetal calf serum, 0% of WEHI-3B cell supernatant as a source of IL-3 and 1% penicillin/streptomycin. JAK2v617F mutant construct is transfected into the BAF3 cells that triggers the transformation of these ceils into tumorigenic ceils. The AK2 mutant BAF3 cells are incubated with different concentrations of the compounds CW242, CW178 and the combination of the two. The reiative growth is assayed using the MTT assay.

It is observed that for individual compound CW242 at 3 µΜ, there is no reduction is proliferation of cells and CW178 at 0.5 mM reduced proliferation of cells by about 50%, while in combination of both there is about 58% reduction in proliferation of cells indicating an enhanced effect with the combination.

The synergistic efficacy of the combination of compounds is to be analyzed by the parameter that two or more mutually exclusive compounds, which are different in functions and characteristics and that activate different pathways, work in combination with each other and provide a reduction in the proliferation of cells which is higher than the reduction brought about by the compounds individually. Thus, the compositions of the present disclosure provide a surprising advantage over the individual compounds and obtaining such compositions is useful and unobvious.

Figure 10 depicts an assay of relative growth (proliferation) in A 2 mutant BAF3 cells to determine the effect of compounds CW242 (represented by Roflumilast), CW178 (represented by Metformin), CW170 (represented by Chloroquine) and their combination CW 70 178242 (CW1 70:CW178:CW242).

Experimental system ; BaF3 mouse hematopoietic pro-B cells are cultured in RPMI 1640 medium (Invitrogen) complemented with 10% Fetal calf serum, 10% of WEHI-3B cell supernatant as a source of L-3 and 1% penicillin/streptomycin. JAK2v617F mutant construct is transfected into the BAF3 cells that triggers the transformation of these cells into tumorigenic cells. The JAK2 mutant BAF3 cells are incubated with different concentrations of the compounds CW242, CW1 70, CW178 and the combination of the three. The relative growth is assayed using the MTT assay.

It is observed that for individual compounds CW242 at 3 µΜ and CW 0 at 5 µΜ, there is no reduction is proliferation of cells and CW 78 at 0.5 mM reduced proliferation of cells by about 50% while in combination of CW242, CW170 and CW178 there is about 62% reduction in proliferation of cells, indicating an enhanced effect with the combination.

The synergistic efficacy of the combination of compounds is to be analyzed by the parameter that two or more mutually exclusive compounds, which are different in functions and characteristics and that activate different pathways, work in combination with each other and provide a reduction in the proliferation of cells which is higher than the reduction brought about by the compounds individually. Thus, the compositions of the present disclosure provide a surprising advantage over the individual compounds, and obtaining such compositions is useful and unobvious.

EXAMPLE 11 - Figure 11 depicts the dose response effect of adding fixed dose of CW170 (represented by Chloroquine) to different doses of CW178 (represented by Metformin) and assess relative growth (proliferation) in JAK2 mutant BAF3 cells.

Experimental system : BaF3 mouse hematopoietic pro-B cells are cultured in RPMI 1640 medium (Invitrogen) complemented with 10% Fetal Calf Serum, 0% of WEHI-3B cell supernatant as a source of IL-3 and 1% penicillin/streptomycin. JAK2v617F mutant construct is transfected into the BAF3 cells that triggers the transformation of these cells into tumorigenic cells. The JAK2 mutant BAF3 cells are incubated with different concentrations of the compounds CW178 individually or in combination with a fixed dose of CW170. The relative growth is assayed using the MTT assay.

The same experiment as described for figure 9A is plotted to show the dose response effect of adding fixed dose of CW170 to different doses of CW178. The concentration of CW178 in millimoles is on x ~ axis and y-axis is % change from control. The 1 µΜ CW170 and 5 µΜ CW170 lines indicate an enhancement of CW178 effect in combination with CW170.

The synergistic efficacy of the combination of compounds is to be analyzed by the parameter that two or more mutually exclusive compounds, which are different in functions and characteristics and that activate different pathways, work in combination with each other and provide a reduction in the proliferation of cells which is higher than the reduction brought about by the compounds individually. Thus, the compositions of the present disclosure provide a surprising advantage over the individual compounds, and obtaining such compositions is useful and unobvious.

Figure 12 of the present disclosure depicts the network schematic representation for mechanism of action for Autophagy inhibitor (CW170) and AMPK Agonist (CW178), on the JAK2V617F mutant driven BaF3 ceil line.

In a JAK2V617F mutant profi le there is an up-regulation of the RAF-ERK pathway via SHC1; activation of the PI3K-AKT pathway and a significant activation of STAT3, STAT5 and STA i transcription factors. This is a highly proliferative condition with the ER and NFkB activations resulting in increased expression of the CD s (cyclin-dependent kinases) and cyclins, the key regulators of cell cycle and proliferation. CW170, the autophagy inhibitor increases protein aggregates in the system that are cleared through the autophagy process. Increased protein aggregates lead to increased production of reactive species (ROS) and increase ER stress. This in turn leads to activation of P53 and other key pathways that make the cell more vulnerable to apoptosis. There is also an increase in cell cycle inhibitors CDKN2A and CDKNIA that further help in inhibiting proliferation.

CW178, which is an AMPK agonist inhibits TO pathway and hence causes reduction of translation of the proteins. CW178 also activates TP53 through AMPK Increase in TP53 causes increase in various tumor suppressor genes like BAX, AP.AFI, PTEN and CDKNIA. Thus the two inhibitors CW178 and CW170 through very different mechanisms of actions converge on reducing cell proliferation and viability in a JAK2 driven profile.

Figure 13 of the present disclosure depicts the network schematic representation for mechanism of action for Phosphodiesterase type 4 inhibitor (CW242) and AMPK Agonist (CW178), on the JAK2V617F mutant driven BaF3 cell line.

In a JAK2V617F mutant BaF3 profile, there is an up-regulation of the RAF-ERK pathway via SHC1; activation of the PI3K-AKT pathway and a significant activation of STAT3, STATS and STATl transcription factors. This is a highly proliferative disease with the ERK and NFkB activations resulting in increased expressions of the CDKs (cycli -dependent kinases) and cyclins, the key regulators of cell cycle and proliferation.

CW242, the PDE4 inhibitor class of compounds, causes an increase in cAMP by inhibiting the phosphodiesterase and thereby inducing PKA (PRKACA). PKA inhibits RAF and via CREB inhibits NFkB, thereby impacting the two key transcription factors driving proliferation gene expression. PKA also inhibits the hedgehog pathway mediators GL1 isoforms and activates the transcription factor RUNX2 that in turn up-regulates the cell cycle inhibitors CDK 1A and CDKN1B. The overall impact of the PDE4 inhibitor leads to reduction in the proliferation endpoint.

CW178, which is an AMPK agonist, inhibits mTOR pathway and hence causes reduction of translation of the proteins. CW178 also activates TP53 through AMPK. Increase in TP53 causes increase in various tumor suppressor genes like BAX, APAF1, PTEN and CDKN IA.

Figure 14 of the present disclosure depicts the network schematic representation for mechanism of action for Autophagy Inhibitor (CW170) and Phosphodiseterase type 4 inhibitor (CW242).

In a JAK2V617F mutant profile, there is an up-regulation of the RAF-ERK pathway via SHC1; activation of the PI3K-AKT pathway and a significant activation of STAT3, STAT5 and STATl transcription factors. This is a highly proliferative disease with the ERK and NFkB activations resulting in increased expressions of the CDKs (cyclin-dependent kinases) and cyclins, thekey regulators of cell cycle and proliferation. CW242, the PDE4 inhibitor class ofcompounds, causes an increase in cAMP by inhibiting the phosphodiesterase and thereby inducing PKA (PRKACA). PKA inhibits RAF and via CREB inhibits NFkB, thereby impacting the two key transcriptionfactors driving proliferation gene expression. PKA also inhibitsthe hedgehog pathway mediators GLI isoforms and activates the transcription factor RU X2 that in turn up-regulates the cell cycle inhibitors CDKNlAand CDKNIB. The overall impact of the PDE4 inhibitor leads to reduction in the proliferation endpoint.

CW170, the autophagy inhibitor, increases protein aggregates in thesystem that are cleared through the autophagy process. Increased protein aggregates lead to increased production of reactive species (ROS) ar d increase ER stress. This in turn leads to activation of P53 and other key pathways that make the cell more vulnerable to apoptosis. There is also an increase in cell cycle inhibitors CDKN2A and CDK 1A thai further help in inhibiting proliferation. Thus the two inhibitors CW242 and CW170 through very different mechanisms of actions converge on reducing cell proliferation and viability in a JAK2 driven profile.

Figure 15 of the present disclosure depicts the network schematic representation for mechanism of action for Autophagy inhibitor (CW170), AMPK Agonist (CW178) and Phosphodiesterase type 4 inhibitor (CW242), on the JAK2V617F mutant driven BaF3 Cell line.

In a JAK2V617F mutant profile, there is an up-regulation of the RAF-ERK pathway via SHC1; activation of the PI3K-AKT pathway and a significant activation of STAT3, STATS and STAT1 transcription factors. This is a highly proliferative condition with the ERK and NFkB activations resulting in increased expressions of the CDKs (cyclin-dependent kinases) an cyciins, the key regulators of cel cycle an proliferation. CW242, the PDE4 inhibitor class of drugs, causes an increase in cAMP by inhibiting the phosphodiesterase and thereby induces PKA (PRKACA). PKA inhibits RAF and via CREB inhibits NFkB, thereby impacting the two key transcription factors driving proliferation gene expression. PKA also inhibits the hedgehog pathway mediators GLI isoforms and activates the transcription factor R NX2 that in turn up-regulates the cell cycle inhibitors CDKNlAand CDKNIB.

The overall impact of the PDE4 inhibitor leads to reduction in the proliferation endpoint

CW170, the autophagy inhibitor, increases protein aggregates in the system that are cleared through the autophagy process. Increased protein aggregates lead to increased production of reactive species (ROS) and increase ER stress. This in turn leads to activation of P53 and other key pathways that make the cell more vulnerable to apoptosis. There is also an increase in cell cycle inhibitors CDKN2A and CDKNIAthat further help in inhibiting proliferation.

CW178, which is an AMPK agonist, inhibits mTOR pathway and hence causes reduction of translation of the proteins. CW178 also activates TP53 through AMPK. Increase in TPS3 causes increase in various tumor suppressor genes like BAX, APAFl, PTEN and CDKN1A.

The present disclosure proposes that a lower dose of CW242 along with a lower dose of CW170 has an enhanced impact on JAK2 dominant or mutant patient profiles by inhibiting all the key driver pathways downstream of JAK2 activation. This combination through very different mechanisms of action CW242 via inhibition of JAK2 downstream signaling, CW170 via increasing vulnerability of cell to stress and apoptosis, and C 78 via decreasing mTOR, AKT1 and increasing apoptosis via TP53 has an enhanced effect on effectively inhibiting proliferation and viability in JAK2 driven patient profiles.

Non-limiting examples of Phosphodiesterase Type 4 Inhibitor (C 242) include:- Rofiumiiast or Daiiresp or DAXAS or 162401-32-3 or 3-(CYCLOPROPYLMETHOXY)-N-(3,5- DICHLOROPYRIDfN-4-YL)-4-(DIFLUOROMETHOXY)BENZAMIDE or BY217 or Ixmu or Ixoq or BYK20869 or Rofiumiiast [USAN] or S21 3 1 Selleck or CHEBL47657 or UNII-0P6C6ZOP5U or AC1L9MU7 or B9302-107 or Rofiumiiast (JAN/USAN/INN) or CHEMBL193240 or APTA-2217 or Rofiumiiast, Daxas or BY-217 or ZINC00592419 or Benzamide, 3-(cyclopropylmethoxy)-N-(3,5- dicMoro-4-pyridinyl)-4-(difluoromethoxy)-or AKOS005 146309 or LS-26272 or 3-

Cyclopropyimethoxy-N-(3 ,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamideor DOS 744 or ROF or roflumilastum or Libertek or or Daiiresp (TN) or CID449193 or NERI IV or SureCN19158 or Rofiumiiast [USAN;INN] or C424423 or cc-305 or BENS30 or CTK8E9183 or DCL000580 or DCL000896 or DCL000964 or FC0016 or 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-di- chloropyrid-4-yl)benzamide or AK1 10425 or HY- 15455 or Roflumilast-(Supplied by Selleck Chemicals) or BCP0726000146 or AB1008459 or X4421 or A24672 or 114-15194 or 3- (Cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)benzamide or a pharmaceutically acceptable salt. b) Piclamilast or Cpodpmb or RP 73401 or RP 73-401 or 144035-83-6 or 3~(Cyclopentyloxy)~N-(3,5~ dichloropyridin-4-yl)-4-methoxybenzamide or RP-73401 or RPR 73401 or 3-(Cyclopentyloxy)-N-(3,5- dichloro-4-pyridyl)-4-methoxybenzamide or 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridinyl)-4- methoxybenzamide or 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-p-anisamide or Benzamide, 3- (cyclopentyloxy)-N-(3,5-dichloro-4-pyridinyl)-4-methoxy- or PIL or lxon or lxm4 or RP-73-401 or AC1L4CKF or SureCN26573 o Piclamilast (USAN IN ) or Piclamilast [USAN:INN] or UNII- WM58D7C3ZT or CHEMBL42126 or C18H18C12N203 o CCRIS 8304 or CHEBL47619 or CTK8G9663 or PDSPi 001283 or PDSP2 001267 or RPR-73401 or DB01791 or LS-26265 or RP- 73041 or D05474 or 3-cyclopentyloxy-N-(3,5-dichloropyridin-4-yl)-4-methoxybenzamideor 3- (Cyclopentyloxy)-N-(3,5-di-chloro-4-pyridyl)-4-methoxy-benzamideor a pharmaceutically acceptable salt

c)Cdp 840 or CDP840 or Cdp-840or 4-(2-(3-(Cyclopentyloxy)-4-methoxyphenyl)-2- phenyletliyl)pyridine or (R)-4-(2-(3-(Cyclopentyloxy)-4-methoxyphenyl)-2-phenylethyl)pyridine or Pyridine, 4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-phenylethyl)-, (R)- or SureCN84490 or AC1L2SW5 or CHEMBL32442 or C25H27N02 or CHEB1:148019 or DNC003665 or PDSPI 001288 or PDSP2 001272 or LS-131122 or 4-[(2R)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2- phenylethyl]pyridine or a pharmaceutically acceptable salt.

) 135637-46-6 or ACMC-20ekqr or SureCN450388 or 5-{3-[(2s)-bicyclo[2.2.1]hept-2-yloxy]-4- methoxyphenyl} tetrahydropyrimidin-2( 1h)~one or 2(1 H)-Pyrimidinone,5 -[3-[( 1S,2S,4R)- bicyclo[2.2.1]hept-2-yloxy]-4-metlioxyphenyl]tetrahydro- or CP 80633 or a pharmaceutically acceptable salt.

;) Etazolate or SQ-20009 or Etazolatum [INN-Latin] or Etazoiato [ΓΝΝ-Spanish] or SQ 20009 or 51022- 77-6 or 1H-Pyrazolo(3 ,4-b)pyridine-5-carboxylic acid, 1-ethyl-4-(( 1-methylethylidene)hydrazino)-, ethy ester or ethy l-ethyl-4-(2-isopropylidenehydrazino)~lh~pyrazok>[3,4~b]pvTidine-5-carboxylate or NSC16361 1 or 35838-58-5 or SQ 20,009 or Etazolate [INN] or Tocris-0438 or AC1L1FKK or 1H- Pyrazolo[3,4-b]pyridine-5-carboxylic acid, 1-ethyl-4-[(l -methylethylidene)hydrazino]-, ethyl ester, monohydrochloride or Lopac-E-1896 or AC1Q64CH or LopacO 000440 or Etazolate hydrochloride(USAN) or CHEMBL356388 or UNII-I89Y79062L or CTK4H5430 or EHT-202 or CHEBI:352174 or C14H19N502 or HMS2090J08 or EHT-0202 or AR-1I7928 or HSCIl 000299 or ZINC00001379 or AG-J-53671 or CCG-204532 or NCGC00015403-01 or NCGCOOOl 5403-02 or NCGCOOOl 5403-03 or NCGC00015403-04 or NCGC00024590-01 or NCGC00024590-02 or LS- 175214 or BRD-K64755930-003-01-6 o ethyl l-el3iyl-4-(2-r^opan-2-ylidenehydrazinyl)pyrazolo[3,4- b]pyridine-5-carboxylate or lH-Pyrazolo[3,4-b]pyridine-5-carboxylicacid, ethy -4- [(1- methylethylidene)hydrazino]-, ethyl ester,monohydrochloride (9CI) or Etazolate hydrochloride or SQ 20009 or lH-Pyrazolo[3,4-b]pyridine-5-carboxylicacid, l-ethyl-4-[2-(l-methylethylidene)hydrazinyl]-, ethyl ester, hydrochloride^ :1) or a pharmaceutically acceptable salt.

Caswell No. 033E or 27277-00-5 or 2-Amino-6-methyl-4-propyl-[l,2,4]triazolo[l,5-alpyrimidin-5(4H)- one or Ici 63197 or EINECS 248-383-5 or PP 769 or ICI 63,197 or 2-amino-6-raethyl-4-propyl- [1,2,4]triazolo[ 1,5-a]pyrimidin-5-one or 2-Arnino-6-methyl-5-oxo-4n-propyl-4,5-dihydro-s- triazolo(l ,5-a)pyrimidine or (l ,2,4)Triazolo( ,5-a)pyrimidin-5(4H)-one, 2-amino-6-methyl-4-propyl- or 2-Amino-4,5-dihydro-6-methyl-4-propyl-5-triazolo-(l,5-c)-pyrarnidin-5-one or 2-Amino-4,5- dihydro-6-methyl-4-propyl-s-triazolo-(l,5-A)-pyrimidin-5-one or 33406-42-7 or Tocris-1816 or AC1L1XUP or SureCN3056576 or 18283 SIGMA or CTK1C4212 or MolPort-003-983-770 or HMS3263L18 or HMS3268114 or ANW-73005 or ICI-63197 or PDSPl 001286 or PDSP2 001270 or ZINCOl 849697 or ICI 63,137 or LP01258 or ICI 63, 197 or NCGC00025306-01 or NCGC00025306- 02 or AK109179 or U754 or LS-184726 or A818988 or BRD-K52219182-001-01-6 or 2-azanyl-6- methyi-4-propyl-j l,2,4]triazolo[l,5-a]pyrimidin-5-one or a pharmaceutically acceptable salt.

) Irsogladine or 57381-26-7 or Irsog adin m [Latin] or Irsogladina [Spanish] or Irsogiadine (INN) or Irsogladine [INN] or 2,4-Diamino-6-(2,5-dichlorophenyl)-l,3,5-triazine or 6-(2,5-Dichlorophenyl)- l,3,5-triazine-2,4-diamine or l,3,5-Triazine-2,4-diamine, 6-(2,5-dichlorophenyl)- or DCPDAT or MN 1695 or PubCheml4375 or ACILIGMT or AC1Q3LMI or UNII-QBX79NZC1D or SureCN62215 or 2',5'-dichlorobenzoguanamine or 6-(2 5-dichlorophenyi)-2,4-diamino-L3,5- riazine or CHEMBL1 36497 or 84504-69-8 (maleate) or MolPort-005-935-612 or HMS2090J12 or Pharmakonl600-01502352 or AR-1J1156 or NSC759836 or ZINC00002645 or AKOSO 15962234 or NSC-759836 or NCGC00 160397-02 or NCGC00 160397-03 or AC- 16088 or Irsogladine-fSirpplied by Selleck Chemicals) or AB2000380 or LS-155251 or D08087 or 2,4-Diammo-6-(2,5-dichlorophenyl)-s- triazine or BRD-K74195 153-050-03-0 or a phannaceutically acceptable salt.

) (R,S)-Mesopram or SureCN450824 or Mesopram or 5-(4-methoxy-3-propoxyphenyl)-5-rnethyl-l,3- oxazolidin-2-one or a pharmaceutically acceptable salt. i) RO 20-1724 or 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone or 4~(3~Butoxy~4~ methoxybenzyl)imidazolidin-2-one or Ro 201724 or 29925-17-5 or ro-20-1724 or 4-[(3-butoxy-4- methoxyphenyl)methyl]imidazolidin-2-one or 2-Imidazolidinone, 4-((3-butoxy-4- methoxyphenyl)methyl)- or ST044509 or 2-Imidazolidinone, 4-((3-butoxy-4-methoxyphenyl)methyl)-, (+-)- or 34185-37-0 or Naphthoquinone analogs or Ro 20 1724 or Spectrum 001840 or AC1L1 J X o AC 1Q6GVZ or Spectrum3 001826 or SureCN1022716 or LopacO 000204 or BSPBio 001358 or BSPBio_002560 or BSPBio_003471 or KBioGR_000078 or KBioSS_000078 or KBioSS_002345 or MLS000859915 or B8279_SIGMA or CHEMBL18701 or SPECTRUM2300287 or BCBcMAP01_000185 or CT C5272 or KBio2_000078 or KBio2_002342 or KBio2_002646 or ! 2 004 or KBio2_005214 or KBio2_007478 or KBio3_000155 or Bio3_000 56 or KBio3_002975 or MolPort-003-666-578 or Bio2_000078 or Bio2_000558 or HMS1361D20 or HMS1791D20 or HMS1989D20 or HMS2231019 or HMS3260J09 or HMS3266M13 or AR-1F6066 or DNC000990 or DNC001219 or DNC004221 or INI 119 or AG-J-66621 or AG-L-66735 or CCG-

204299 or LP00204 or IDI1 033828 or NCGC00015166-03 or NCGC000 15 166-04 or

NCGCOOOl 5166-05 or NCGC000 15 166-06 or NCGC00015 166-07 or NCGCOOOl 5166-08 or NCGCOOOl 5166-09 or NCGC00024577-02 or NCGC00024577-03 or NCGC00024577-04 or NCGC00024577-05 or NCGC00024577-06 or NCGC00024577-07 or SMR000326776 or LS-183352 or LS- 187049 or LS- 187661 or RO-201724 or EU-0 100204 or B 8279 or BRD-A07207424-00 1-04-1 or 4-[(3-Butoxy-4-methoxyphenyl)methyl]-2-imidazolidione or (+-)-4-((3-butoxy-4- methoxyphenyl)methyl)-2-imidazolidinone or a pharmaceutically acceptable salt.

) Rolipram or Rolipramum [Latin] or ZK 62711 or 61413-54-5 or Adeo or 4-[3-(Cyclopentyloxy)-4- methoxyphenyl]-2 -pyrrolidinone or ZK-62711 or 4-[3-(cyclopentyioxy)-4-methoxyphenyi]pyrrolidin- 2-one or CHEBI: 104872 or EINECS 262-771-1 or ME-3167 or BRN 1588548 or SB 95952 or (S)~ ROLIPRAM or ST50405218 or 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone or 4-(3- cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-oneor 4-(3-(Cyclopentyloxy)-4-methoxyphenyl)-2- pyrrolidinone or 2-Pyrrolidinone, 4-(3-(cyclopentyloxy)-4-methoxyphenyl)- or ZK 62711, SB 95952,

ME-3167, Adeo, 61413-54-5 or CPD000058510 or SMR000058510 or Z 6271 1, SB 95952, ME- 3167, Adeo, Rolipram oror NCGC00016899-01 or CAS-61413-54-5 or S1430 Selleck or (+/-)- Rolipram or Rolipram [USAN:INN] or AC IL LC or CHEMBL63 or Prestwick0_000924 or Prestwickl 000924 or Prestwick2 000924 or Prestwick3 000924 or SureCN27930 or UPCMLD- DP110 or AC1Q6O0R or DSSTox C D 24124 or DSSTox RID 80104 or DSSTox GSID 44124 or LopacO 001072 or BSPBio 000828 or BSPBio 001356 or KBioGR 000076 or BioSS 000076 or Rolipram (JAN/USAN/INN) or MLS000069691 or MLS000758273 or MLS000759531 o MLSOOl 146912 or MLS001424084 or R6520 SIGMA or UNII-K676NL63N7 or SPBio 003007 or BPBiol 000912 or Pyrrolidone, 4-(3-cyclopentyloxy-4-methoxyphenyl)-2- or (4S)-4-[3- (CYCLOPENTYLOXY)-4-METHOXYPHENYL]PYRROLIDIN-2-ONE or UPCMLD-DP110:001 or UPCMLD-DP1 10:002 or CTK5F4996 or KBio2 000076 or KBio2 002644 or KBio2 005212 or KBio3_000151 or KBio3_000152 or MolPort-000-860-686 or Bio2_000076 or Bio2_000556 or

HMS1361D18 or HMS 570. 0 or HMS 79 D 8 or HMS1989D18 or HMS2051N15 or HMS2090J16 or HMS2097J10 or HMS2232F06 or HMS3263G06 or HMS3267A05 or HMS3393N15 or Pharmakonl 600-01505683 or Tox21_l 10672 or AR-1F9691 or DNC000014 or DNC000017 or DNC003593 or INI 123 or NSC760125 or AKOS015959793 or Rolipram-(Supplied by Selieck Chemicals) or AG-J-77375 or CCG-1 00965 or CCG-205149 or LP01072 or NSC-760125 or ID11 033826 or NCGC00015898-03 or NCGC00015898-04 or NCGC00015898-05 or NCGC00015898-06 or NCGC00015898-07 or NCGC00015898-08 or NCGC00015898-09 or NCGCOOOl 5898-11 or NCGCOOOl 5898-12 or NCGC00089796-02 or NCGC00089796-04 or NCGC00089796-05 or NCGC00089796-06 or NCGC00089796-07 or NCGC00089796-08 or SAM001246766 or SAM001246998 or Z -6277 or LS-138709 or ZK 62 711 or Z - 627 or AB00513966 or EU-0101072 or D01783 or R 6520 or BRD-A34255068-001-04-8 or 4-(3- (cyclopentyloxy)-4-methoxyphenyl)-2-pyrrolidinon or 4-[4-Methoxy-3-(cyclopentyloxy)phenyl]-2- pyrrolidinone or (4R)-4-[3-(Cyclopentyloxy)-4 Methoxyphenyl)pyrrolidin-2-one or 2-Pyrrolidinone, 4- [3-(cyclopentyloxy)-4-methoxyphenyl]- (9CI) or a pharmaceutically acceptable salt.

) (R)-(-)-Rolipram or (R)- ! R or CHEBL40133 or 85416-75-7 or (-)-ROLIPRAM or (R)-4-(3- (cyclopentyk>xy)-4-methoxyphenyl)pyrrolidin-2-one or (S)-ROLIPRAM or (4R)-4~[3~ (CYCLOPENTYLOXY)-4-METHOXYPHENYL]PYRROLIDIN-2-ONE or NCGC000 6899-0 1 or

CAS-6 4 3-54-5 or PubCheml8284 or Tocris-0905 or Toeris-1349 or Tocris-1350 or lq9m or iro6 or AC 1L9LJS or Lopac-R-6520 or SureCN576805 or JNII-DPX5 UP08 or CHEMBL430893 or MolPort-003-983-801 or HMS3267P19 or ANW-64684 or DNC004059 or ZINC00004982 or AKOS015891287 or DB01954 or DB03606 or DB04149 or NCGC00015898-01 or NCGC00015898- 02 or NCGC00015898-10 or NCGCOOOl 6899-02 or NCGC00016899-03 or NCGCOOOl 6899-04 or NCGCOOOl 6899-05 or NCGC00024862-01 or NCGC00024862-02 or NCGC00024862-03 or

AK103559 or P623 or 101-8873 or BRD-K755 6 18-001 -01-7 or (4R)-4-(3-cyclopentyloxy-4- methoxyphenyl)pyrrolidin-2-one or 2-Pyrrolidinone, 4-(3-(cyclopentyloxy)-4-methoxyphenyl)-, (R)- or 4RR or 4SR or a pharmaceutically acceptable salt.

) S-(+)-Rolipram or 85416-73-5 or CHEBL59540 or (S)-ROLIPRAM or (4S)-4-[3- (CYCLOPENTYLOXY)-4-METHOXYPHENYL]PYRROLIDIN-2-ONE or oy or · Rolipram or S2 127 Seileck or (S)-(+)-rolipramor IxnO or (S)-( )-Rolipram or AC1L4KJV or SureCN5321568 or CHEMBL325795 or CTK8G3018 or CHEBI:282163 or MolPort-003-983-800 or HMS3267P21 or ZINC02000919 or AG-H-43654 or BCP0726000229 or X5034 or S-(+)-Ro1ipram-Supplied by Seileck Chemicals or BRD-K6585671 1-001-01-0 or (4S)-4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2- one or 2-Pyrrolidinone, 4-(3-(cyclopentyloxy)-4-methoxyphenyl)-, (4S)- or a pharmaceutically acceptable salt.

OCHEMBLl 232082 or Pyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione,l-(3-nitrophenyl)-3-(4- pyridinylmethyl)- or 152814-89-6 or D71 or ACMC-20n6je or SureCN2469373 or CTK4C7578 or AG-E-00222 or RS 25344 or RS 25344-000 orl-(3-nitrophenyl)-3-(pyridin-4-ylmethyl)pyrido[2 ,3- d]pyrimidine-2,4-dione or a pharmaceutically acceptable salt.

) YM 976 or 4-(3-Chlorophenyl)-l J-diethylpyrido[2,3-d]pyrimidin-2(lH)-one or 191219-80-4 or Tocris- 1821 or SureCN157252 or AC107H1W or Y4877 SIGMA or CHEMBL1358525 or CTK4E0609 or MolPorf-003 -960-224 or HMS3260C13 or HMS3268I18 or AG-E-39611 or LP00016 or NCGC00025308-01 or NCGC00025308-02 or LS-134167 or BRD-K12932420-001-01-5 or 4-(3- chlorophenyl)-l,7-diethylpyrido[2,3-d]pyrimidin-2-one or Pyrido[2,3-d]pyrimidin-2(lH)-one,4-(3- chlorophenyl)-l,7-diethyl- or a pharmaceutically acceptable salt.

) Chloroquine or CHLOROQUINE or chloroqume or Aralen or Artrichin or Chlorochin or Chemochm or Chingamin or Reumachlor or Capquin or Chloroquinium or Arthrochin or Bemaphate or Bemasulph or Benaquin or Bipiquin or Chloraquine or Chloroquina or Chlorquin or Cidanehin or Clorochina or Cocartrit or Dichinalex or Gontoehin or Heliopar or Iroquine or Klorokin or Lapaquin or Malaquin or Mesylith or Nivaquine or Pfizerquine or Quinachlor or Quinercyl or Quinilon or Quinoscan or Resoquine or Sanoquin or Silbesan or Solprina or Sopaquin or Tresochin or Amokin or Bemaco or Elestol or Imagon or Malaren or Malarex or Neochin or Roquine or Siragaii or Tanakan or Trochin or Nivaquine B or Quingamine or Arechin or Avloclor or Delagil or Khingamin or Resochin or Avlochlor or Chlorochine or Nivaehine or Quinagamin or Qumagamme or Resochen or Resoquina or Reumaquin or Chlorochinum or Chloroquinum or Arechine or Arequin or Cloroquina or Ronaquine or Aral en HC1 or 54-05-7 or Chloroqiiine phosphate or Chloroquine (VAN) or Clorochina [DCIT] or 3377 RP opalate or Chloroquin or Chloroin or Rivoqiiine or Arolen or WIN 244 or ST 2 1 (pharmaceutical) or Chloroquinum [ΓΝΝ-Latin] or Cloroquina [INN-Spanish] or Chloroqiiine, D- or (+)-Chloroquine or (-)- Chloroquine or Miniquine or Tanakene or RP 3377 or CCRIS 3439 or CHEBI:3638 or 1,4- Pentanediamine, N4-(7-chloro-4-quinolmyl)-N1 ,N -diethyl- or HSDB 3029 or Spectrum_000 32 or

ST 2 1 or Gontochin phosphate or (R)-(-)-Chloroquine or CHEMBL76 or Chloroquine (USP/INN) or Prestwick0_000548 or Prestwickl 000548 or Prestwick2_000548 or Prestwick3_000548 or Spectram2_000127 or Spectrum3_000341 or Spectrura4_000279 or Spectrani5_000707 or ETNECS 200-191-2 or NSC187208 or W 7618 or Malaquin (*Diphosphate*) or MolMap 000009 or NSC 187208 or AC1L1EB8 or AC1Q2ZA7 or AC1Q2ZA8 or BRN 0482809 or LopacO 000296 or UNII- 886U3H6UFF or BSPBio 000595 or BSPBio 002001 or C18H26C1N3 or KBioGR 000778 or KBioSS 000592 or DivKlc 000404 or Ipsen 225 or SPBio 000174 or SPBio 002516 or Chloroquine [USA :IN :BAN] or GNF-Pf-4216 or BPBiol 000655 or Chloroquine Bis-Phosphoric Acid or KBiol 000404 or KBio2 000592 or KBio2 003160 or KBio2 005728 or KBio3 001221 or CID2719 or NINDS 000404 or HMS2090O03 or NSC' 4050 or NSC-187208 or DB00608 or RP-3377 or SN 6718 or SN-7618 or nchembio.215-comp4 or nchembio.368-comp8 or nchembio.87-compl7 or IDI1 000404 or Ro 01-6014/N2 or SMP2 000034 or NCGC00015256-04 or NCGC00162120-01 or 7- Chloro-4-((4-(diethylamino)-l-methylbutyl)ainino)quinoline or NCI60 000894 or WLN: T66 BNJ EMY1&3N2&2 IG or N4-(7-Chloro-4-quinolinyI)-Nl,Nl -diethyl- 1,4-pentanediamine or N4-(7- chloroquinolin-4-yl)-Nl,Nl-diethylpentane-l,4-diamine or LS-141726 or AB00053436 or C07625 or D02366 or 58175-86-3 or CQ or BRD-A91 69965 1-065-01-1 or Chloroquine hydrochloride or CU- 01000012392-2 or {4-[(7-chloroquinolin-4-yl)amino]pentyl}die%lamine or MolPort-001-783-623 or 7-Chloro-4-[[4-(diethylamino)-l-methylbutyl]amino]quinoline or Quinoline, 7-chloro-4-((4- (diethylamino)-l-methylbutyl)amino)- or ,4-Pentanediamine, N(4)-(7-chloro-4-quinolinyl)-N(l),N(l)- diethyl- or ,4-Pentanediamine, N4-(7-chloro-4-quinolinyl)-Nl,Nl -diethyl-, (+)- or ,4- Pentanediamine, N(sup 4)-(7-chloro-4-quinolinyl)-N(sup l),N(sup l)-diethyl- or N(sup 4)-(7-Chloro-4- quinolinyl)-N(sup l),N(sup l)-diethyl-l,4-pentanediamine or 56598-66-4 or 58175-87-4 or 3545-67-3 or {4-[(7-chloro(4-quinolyl))amino]pentyl} diethylamine or Quinoline, 7-chloro-4-(4-diethylamino- 1- methyl-butylamino)- or Quinoline, 7-chloro-4-[[4-(diethylamino)-l-methylbutyl]amino]- or (+-)- Chloroquine or Chloroquine + Proveblue or SureCN8933 or Chloroquine [USP:INN:BAN] or 1,4- Pentanedi ine, N4-(7-chloro-4-quinolinyl)-Nl,N 1-diethyl-, (4R)~ or CTK1H1520 or DAP000165 or DAP001357 or SBB072644 or AKOS015935106 or CCG-204391 or NCGCOOO 15256-02 or NCGC000 15256-03 or NCGCOOO 15256-05 or NCGCOOO 15256-06 or NCGCOOO 15256-07 or NCGCOOO 5256-08 or NCGC00015256-09 or NCGC00015256-10 or AK1 16457 or ST45028748 or MLS-0466768.0001 or 1, N4-(7-chloro-4-quinolinyl)-Nl,Nl-diethyl- or n(sup4)-(7-chloro-4- quinol inyl)-n(sup 1),4-pentanediamine or 7-chloro-4- {[4-(diethylamino)- - methylhutyi]ammo}quinolimura or N4-(7-chloro-4-quinolyl)-Nl,Nl-diethyl-pentane-l,4-diamine or (+)-N4-(7-Chloro-4-quinolinyl)-Nl,Nl -diethyl- 1,4-peritanedi amine or 4-N-(7-chloroquinolin-4-yl)-l- N ,1-N-diethylpentane- ,4-diamine or (+-)-N4-(7-Chloro-4-quinolinyl)-N I ,N I -diethyl- 1,4- pentanedi mine or ,4-Pentanedi amine, N4-(7-chloro-4-quinolinyl)-Nl,Nl -diethyl-, (+-)- or 1,4- Pentanedi amine, N4-(7-chioro-4-qiiinolinyi)-Nl,Nl -diethyl-, (-)- or 1,4-Pentanediamine, N4-(7-chloro- 4-quinolinyl)-N 1,N 1-diethyl-, (R)- or N(4)-(7-chloro-4-quinolinyl)-N( 1),N( 1)-diethyl- ,4- pentanediamine or N(4)-(7-chloroquinolin-4-yl)-N(l),N(l)-diethylpentaiie-l,4-diamine or N*4*-(7- Chloro-quinolin-4-yl)-N* 1*,N* 1*-diethyl-pentane- ,4-diamine or ,4-Pentanediamine, N4-(7-chloro- 4-quinolinyl)-Nl,Nl -diethyl- or Quinoline, 7-chloro-4-(4-diethylamino-l -methyl-butylamino)- or a pharmaceutically acceptable salt.

>) LUCANTHONE or Lucanthon or Tixantone or Miracil D or Lucanthonum [INN-Latin] or Lucantona [INN-Spanish] or Lucanthonum or Miracoi or Nilodin or Scapuren or LUCANTHONE HYDROCHLORIDE or Lucantlione [INN;BAN] or 479-50-5 or l-((2-(Diethylamino)ethyl)amino)-4- methylthioxanthen-9-one or CCRJS 1106 or CHEBL51052 or Lucantlione monohydrochloride or ACILIUNW or EINECS 207-532-4 or NCTMech 000830 or l-{[2-(Diethylamino)ethyl]amino}-4- methyl-9H-thioxanthen-9-one or BRN 0312369 or AI3-16160 or CHEMBL279014 or l-[[2- (Diethylamino)ethyl]amino]-4-methylthioxanthone or DB04967 or NCI60 000988 or Thioxanthen-9-

one, l-((2-(diethylamino)ethyl)amino)-4-methyl- or LS- 153695 or 9H-Thioxanthen-9-one, 1~((2~ (diethylamino)ethyl)amino)-4-methyl- or CI 1715 or 5-18-11-00503 (Beilstein Handbook Reference) or

1~(2~diethylaminoethylamino)-4-methylthioxanthen~9-one or 9H-Thioxanthen-9-one, 1~((2~ (diethylamino)ethyl)amino)-4-methyl- (9CI) or SC 4574 or 548-57-2 or l-{[2- (diethylammo)ethyl]amino}-4-methylthioxanthen-9-one or CID 0 80 or SureCN9156 or UNII- FC6D57000M or CCG-35817 or DAP001003 or 1-diethyl aminoethylethylamino-4-met yl- thioxanthenone or a pharmaceutically acceptable salt. c) LysO 1 or 1-N-(7-chloroqumolm-4-yl)-2-N-(2-((7-cM 1,2-diamine or a pharmaceutically acceptable salt.

1) Lys02 or 1-N-(2-aminoethyl)-2-N-(7-chloroquinolm-4-yl)- 1-N-methylethane- 1,2-diamine or a pharmaceutically acceptable salt.

;) Lys03 or l-N-(7-methoxyquinolin-4-yl)-2-N-(2-((7-methoxyquinolin-4-yl)amino)ethyl)-2-N- methylethane-1 ,2-diamine or a pharmaceutically acceptable salt.

') Lys04 or N,N'-((ethane-l,2-diylbis(oxy))bis(emane-2,l-diyl))bis(7-chloroquinolin-4-amine) or a pharmaceutically acceptable salt.

) Lys05 or l-N-(7-chloroquinolin-4-yl)-2-N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-2-N-metliylethane- ,2-diamine trihydrochloride or a pharmaceutically acceptable salt.

) Hydroxychloroquine or hydroxychloroquine or Plaquenil or Oxichlorochinum or Oxychlorochin or Oxychloroquine or Idrossiclorochina [DOT] or Oxichloroquine or Quensyl or Hydroxychlorochin or Hydroxychloroguine or Hidroxicloroquma [INN-Spanish] or Hydroxychloroquinum [INN-Latin] or 118-42-3 or Hidroxicloroquma or Idrossiclorochina or WIN 1258 or Polirreumin (TN) or Ercoquin or AC1L1GEW or Hydroxychloroquine (INN) or Spectrum2 001238 or SpectrumS 001697 or EINECS 204-249-8 or UNII-4Q WG6N8 QKH or 2-((4-((7-ChIoro-4-quinolyl)amino)pentyl)ethylamiiio)ethanoI or Gen-Hydroxychloroquine 200mg Tablets or Hydroxychloroquine Sulfate (1:1) Salt or BRN 0253894 or C18H26CIN30 or CHEMBL1535 or ST072188 or Div c 000942 or Hydroxychloroquine [INN:BAN] or SPBio 001116 or HCQ or HMS502P04 or Bio 000942 or NINDS 000942 or NSC4375 or Ethanol, 2-((4-((7-chloro-4-quinolinyl)amino)pentyl)ethylamino)- or Ethanol, 2-[[4-[(7-

chloro-4-quinolinyl)amino]pentyl]ethylamino]- or DB01611 or S ) !! 000942 or NCGCOOi 59483-02 or 747-36-4 (sulfate (1:1) salt) or LS-66614 or Ethanol, 2-((4-((7-chloro-4- quinolyl)amino)pentyl)ethylamino)- or 2-(N-(4-(7-Chlor-4-chinolylamino)-4- methylbutyl)ethylamino)ethanol or 7-Chloro-4-(4-(ethyl(2-hydroxyethyl)amino)- 1- methylbutylamino)quinoline or 7-Chloro-4-(5-(N-ethyl-N-2-hydroxyethylamino)-2- pentyl)aminoquinoline or 7-Chloro-4-(4-(N-ethyl-N-beta-hydroxyethylamino)- - methylbutylamino)quinoline or C07043 or D08050 or 5-22-10-00280 or 2-[4-[(7-chloroquinolin-4- yl)amino]pentyl-ethylamino]ethanol or2-[{4-[(7-chloroquinolin-4- yl)amino]pentyl}(ethyl)amino]ethanol or Polirreumin or 2-({4-[(7-chloro(4- quinolyl))amino]pentyl}ethylamino)ethan-l-ol or CID3652 or SureCN8170 or MolPort-003-847-792 or DAP000878 or SBB0 12559 or M566 or a pharmaceutically acceptable salt.

) Mefloquine or (-)-Mefloquine or Racemic mefloquine or Mefloquinum [IN -Latin] or Mefloquina [INN-Spanish]or Mephloquine or Mefloquine [USAN: INN:BAN]or CHEBI:63687 or HSDB 6853 or

(-)-(llS,2'R)-erythro-Mefloquine or Ro 215998 or RT 189-1 - 1 or Ro 21-5998 or RO 13-7225 or 4- Quinolinemethanol, alpha-2-piperidinyl-2,8-bis(trifluoromethyl)-, (R*,S*)-(+-)- or WR 142490 or 53230-10-7 or (DL-erythro-alpha-2-Piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol or (S)- [2,8-bis(trifluoromethyl)quinolin-4-yl][(2R)-piperidin-2-yllmethanol or 4-Quinolinemethanol, alpha- (2R)-2-piperidinyl-2,8-bis(trifluoiomethyl)-, (alphaS)-rel- or a pharmaceutically acceptable salt.

) Acrichine or Atabrine or Atebrin or Dihvdrochloride, Quinacrine or Dimesylate, Quinacrine or Hydrochloride, Quinacrine or Mepacrine or Monoacetate, Quinacrine or Monohydrochloride, Quinacrine or Monomesylate, Quinacrine or Quinacrine or Quinacrine Dihydrochloride or Quinacrine Dihvdrochloride, Dihydrate or Quinacrine Dihyrochloride, (R)-Isomer or Quinacrine Dihyrochloride, (S)-Isomer or Quinacrine Dimesylate or Quinacrine Hydrochloride or Quinacrine Monoacetate or Quinacrine Monohydrochloride or Quinacrine Monomesylate or Quinacrine, (+-)-Isomer or Quinacrine, (R)-Isomer or Quinacrine, (S)-Isomer or a pharmaceutically acceptable salt.

Non-limiting examples of AMPK Agonist (CW178) include: ) Metformin or Metformin HCL, metformin hydrochloride or l-carbamimidamido-N,N- dimeth ylmeth anirnidamide. ) Phenformin or PhenethylbiguanideFenformin or l-carbamimidamido-N-(2- phen y1ethyl)methani idamide. ) Panduratiii or ACI05G2Z, CHEMBL3791 0, CHEBI:4499I1 or 2,6-dihydroxy-4-methoxyphenyl)- [(lR 2S,6R)-3-methyl-2-(3-methylbut-2-enyl)-6-phenylcyclohex-3-en-l-yl]methanone. ) AICAR or Imidazole-4-carboxamide, 5'-(dihydrogen phosphate), lH-Imidazole-4-carboxamide, 5-

amino- -(5-0-phosphono-.beta.-D-ribofuranosyl)-, AC L SPA[5 -(5-amino-4-carbamoylimidazol- - yl)-3,4-dihydroxyoxolan-2-yl]methyldihydrogen phosphate e) AMPK activator (CID16760291) or IN1531, )942. 5-(3-(4-(2-(4- Fluorophenyl)ethoxy)phenyl)propyl)furan-2-carboxylic acid 5-[3-[4-[2-(4- fluorophenyl)ethoxy]phenyl]propyl]furan-2-carboxylic acid. B-lapachone or beta.-Lapaehone, or A-lapachone or Lapachoneorbeta-, 4707-32-8, NSC 26326, NSC26326, NSC629749, NSC 629749, BRN 0181499 or 2,2-dimethyl-3,4-dihydrobenzo[h]chromene- 5,6-dione. ) A769662 or A-769662, 844499-71-4, 4-Hydroxy-3-(2'-hydroxy-l,l'-biphenyl-4~yl)-6-oxo-6,7- dihydrothieno[2,3 -bjpyri dine-5-carbonitrile, PubChem 16663 or 4-hydroxy-3 -[4-(2- hydroxyphenyl)phenyll-6-oxo-7H-thieno[2,3-b]pyridine-5-carbonitrile.

Non-limiting examples of CW242 include the compounds of Table 1.

CW242 Compound Names and Chemical Structures

General Name

Roflumilast or Daliresp or DAXAS or 3- 162401-32-3 or 3- (cyclopropylmethoxy) (CYCLOPROP YLMETHOXY) -N-(3, -N-(3,5-DICHLOROPYR!DIN- 5-dichloropyri din-4- 4-YL)-4- y])-4- (DIFLUOROMETHOXY)BEN ( ifluorometh oxy)ben ZAMIDE or BY217 or l mu or zamide lxoq or BYK20869 or :i7H14C12F2N20: Roflumilast [USAN] or S2 3 Selieck or CHEB1:47657 or UN11-0P6C6ZOP5U or AC1L9MU7 or B9302-107 or Roflumilast (JAN/USAN/INN) or CHEMBL193240 or APTA- 2217 or Roflumilast, Daxas or BY-217 or Z1NC00592419 or Benzamide, 3- (cyclopropylmethoxy)-N-(3,5- dichloro-4-pyridinyl)-4- (difluoromethoxy)- or AKOS005 146309 or LS-26272 or 3-Cycl opropylmeth oxy-N- (3,5-dichloropyridin-4-yl)-4- (difluoromethoxy)benzamide or D05744 or ROF or roflumilastuin or Libertek or or Daliresp (TN) or CTD449193 or NERI IV or SureCN19158 or Roflurailast [USAN:INN] or C424423 or cc-305 or BEN530 or CT 8E9 83 or DCL000580 or DCL000896 or DCL000964 or FC0016 or 3- cyclopropylmethoxy-4- difluoromethoxy-N-(3 ,5-di- chloropyrid-4-yl)benzamide or A 0425 or HY- 15455 o Roflumilast-(Supplied by Selleck Chemicals) or BCP0726000146 or AB 1008459 or X4421 or A24672 or 114- 15194 or 3- (Cyclopropylmethoxy)-N-(3,5- dichloro-4-pyridinyl)-4- (difluoromethoxy)benzarnide dichloropyridin-4-yl)-4-

68 methoxybenzamide or 3- (Cyclopentyloxy)-N-(3,5-di- chloro-4-pyridyl)-4-methoxy- benzaraide.

CDP840 Cdp 840 or CDP840 or Cdp-840 4-[(2R)-2-(3- or 4-(2-(3-(Cyclopentyloxy)-4- cyclopentyloxy-4- methoxyphenyl)-2- methoxyphenyl)-2- phenylethyl)pyridine or (R)-4- phenylethyljpyridine (2-(3-(Cyclopentyloxy) -4- methoxyphenyl)-2- C25H27NO; phenylethyl)pyridine or Pyridine, 4-(2-(3- (cyclopentyloxy)-4- methoxyphenyl)-2-phenylethyl)- , (R)~ or SureCN84490 o AC5L2SW5 or CHEMBL32442 or C25H27N02 o CHEBI; 148019 or DNC003665 or PDSP1 001288 or PDSP2_001272 or LS-131122 or 4-[(2R)-2-(3-cycl pe tyloxy- 4-metlioxyphenyl) -2- phenylethyi jpyridine. CP 80633 135637-46-6 or ACMC- 20ekqr or SureCN450388 o bicyclo[2.2. 1jlieptanylo 5-{3-[(2s)- xy)-4-methoxyphenyl] - bicyclo[ 2. ]hept-2-yloxy] - ,3-diazinan-2-one 4- methoxyphenyl }tetrahvdrop yrirnidin-2(lh)-one or C18H24N203 2(1H)-Pyrimidinone,5 -[3- [(1S,2S,4R)- bicycio [ .2 . ]hept-2-yloxy] - 4-

methoxypheny 1] tetrahydro- or CP 80633.

Etazolate etazolate or SQ-20009 or ethyl Etazolatum [INN-Latin] or 1-ethyl-4-(2-propan-2-

Etazolato [INN-Spanish] or yli den ehydrazinyl)pyraz SQ 20009 or 51022-77-6 o olo[3, 1H-Pyrazolo(3,4- 4-b]pyridine-5- b)pyridine-5-carboxylic carboxylate acid, l-ethyl-4-((l- methylethylidene)hydrazino )-, ethyl ester or ethyl 1- ethyl-4-(2- isopropylidenehydrazino)- 1h-pyrazolof 3,4-b]pyridine- 5-carboxyiate or NSC163611 or 35838-58-5 or SQ 20,009 Etazolate [INN] or Tocris-0438 or AC1L1FKK or 1H- Pyrazolo[3,4-b]pyridine-5- carboxylic acid, l-ethyl-4- [(i- methylethylidene)hydrazino ]-, ethyl ester, monohydrochloride or Lopac-E-1 896 or AC1Q64CH or Lopac0_000440 or Etazolate hydrochloride(USAN) or CHEMBL356388 or UNII- I89Y79062L or CTK4H5430 or EHT-202 or CHEBI:352174 or C14H19N502 or HMS2090J08 or EHT-0202 or AR- 117928 or HSCI1 000299 or ZINC00001379 or AG-J- 53671 or CCG-204532 or NCGC000 15403-01 or NCGC000 15403-02 or NCGC000 15403-03 or NCGC000 15403-04 or NCGC00024590-01 or NCGC00024590-02 o LS- 175214 or BRD- K64755930-003-01-6 or ethyl I -ethyl-4-(2-propan-2- y idenehydraziny1)pyrazol o[ 3,4-b]pyridine-5- carboxylate or H- Pyrazolo [3 ,4-b]pyridine-5 - carboxylicacid, 1-ethyl-4- [(1- methylethylidene)hydrazino ]-, ethyl ester,monohydrochloride (9CI) or Etazolate hydrochloride or SQ 20009 or lH-Pyrazolo[3,4- b]pyridine-5- carboxylicacid, l-ethyl-4- [2-(l- methylethylidene)hydraziny

1 - , ethyl ester,

hydrochloride(l :1)

ICI 63197 Caswell No. 033E or 2-amino-6-methyl- 27277-00-5 or 2-Amino-6- propyl- methyl-4-propyl- [l,2,4]triazolo[l,5-

[ 1,2,4]triazolo[l,5- a]pyrirnidin-5-one a]pyrimidin-5(4H)-one or Ici 63197 or EINECS 248- 383-5 or PP 769 or ICI 63,197 or 2-amino-6- methyl-4-propyl- ,2 4 jtriazoiof 1,5- a]pyrimidin-5-one or 2- Amino-6-methyl-5-oxo-4n- propyl-4,5-dihydro-s- triazolo(l,5-a)pyrimidine or (l,2,4)Triazolo(l,5- a)pyrimidin-5(4H)-one, 2- ainino-6-methyl-4-propyl- or 2-Amino-4,5-dihydro-6- a pyrimidin-5-one.

AB2000380 or LS-155251 or D08087 or 2,4-Diamino- 6-(2,5-dichlorophenyl)-s- triazine or BRD- K74195153-050-03-0

General Structure IUPAC Name

(R,S)-Mesopram SureCN450824 or Mesopram 5-(4-methoxy-3- propoxyphenyl) -5- methyl- 1,3- oxazolidin-2-one

C14H19N04

RO 204724 R 20-1724 or 4-(3-Butoxy-4- 4-[(3-butoxy-4- methoxybenzyl)-2- methoxyphenyl)metli imidazolidinone or 4-(3-Butoxy- yl]imidazolidin-2- 4-methoxybenzyl)imidazolidin-2- one one or Ro 201724 or 29925-17-5 or ro-20-1724 or 4-[(3-butoxy-4-

methoxyphenyl)methyl]imidazoli C15H22N203 din-2-one or 2-Imidazolidinone, 4-((3-butoxy-4- methoxyphenyl)m eth )- or ST044509 or 2-Imidazolidinone, 4-((3-butoxy-4- methoxyphenyl)methyl)-, (+-)- or 34 85-37-0 or Naphthoquinone analogs or Ro 20 1724 or Spectrum_001 840 or AC1L1JKX

or AC1Q6GVZ or Spectrum3 001826 o SureCN 10227 16 or Lopac0_000204 or BSPBio 001358 or BSPBio 002560 or BSPBio 003471 or BioGR 000078 or KBioSS 000078 or KBioSS 002345 or MLS000859915 or B8279 SIGMA or CHEMBL 18701 or SPECTRUM2300287 or BCBcMAPOl 000185 or CTK1C5272 or KBio2 000078 or KBio2 002342 or KBio2 002646 or Bio2 004910 or KBio2 005214 or KBio2 007478 or KBio3 000155 or KBio3 000156 or Bio3 002975 or MolPort-003-666-578 or Bio2 000078 or Bio2 000558 or HMSI361D20 or HMS1791D20 or HMS1989D20 or HMS2231019 or HMS3260J09 or HMS3266M13 or AR-1F6066 or DNC000990 or DNC001219 or

DNC004221 or ΓΝ 1 1 19 or AG-J- 6662 or AG-L-66735 or CCG- 204299 or LP00204 or IDI1 033828 or NCGC00015 66- 03 or NCGCOOOl 5166-04 or

(3-Cyclopentyl oxy-4- methoxyphenyl)-2-pyrrolidone or 4-(3 -cyclopentyl oxy-4- methoxyphenyl)pyrroli din-2-one or 4-(3-(Cyclopentyloxy)-4- methoxyphenyl)-2-pyrrolidinone or 2-Pyrrolidmone, 4-(3- (eye1opentyloxy)-4- methoxyphenyl)- or ZK 627 , SB 95952, ME-3167, Adeo, 61413-54-5 or CPD000058510 or SMR000058510 or ZK 62711, SB 95952, ME-3167, Adeo, Rolipram or NCGC000 16899-01 or CAS- 61413-54-5 or S1430 Selleck or (+/-)-Rolipram or Rolipram [USAN:INN] or AC1L1JLC or CHEMBL63 or PrestwickO 000924 or Prestwickl 000924 or Prestwiek2 000924 or Prestwick3 000924 o SureCN27930 or UPCMLD- DP 0 or AC1Q6O0R or DSSTox CID 24124 or DSSTox_RID_80104 or DSSTox GSID 44124 or Lopac0_001072 or BSPBio_000828 or BSPBio_001356 or KBioGR_000076 or KBioSS 000076 or Rolipram (JAN USAN/IN ) o MLS000069691 or MLS000758273 or MLS000759531 or MLS001 146912 or MLS00 1424084 or R6520 3IG A or UNII- K676NL63N7 or SPBio 003007 or BPBiol 000912 or Pyrrolidone, 4-(3 -cyclopenty loxy- 4-methoxyphenyl)-2- or (4S)-4- [3-(CYCLOPENTYLOXY)-4- METHOX YPHENYL]PYRROLI DIN-2-QNE or UPCMLD- DP110:001 or UPCMLD- DPI 10:002 or CTK5F4996 or Bio2 000076 or Bio2 002644 or KBio2 005212 or Bio3 000151 or Bio3 000152 or MolPort-000-860-686 o Bio2 000076 or Bio2 000556 or HMS1361D18 or HMS1570J10 or HMS1791D18 or HMS1989D18 or HMS2051N15 or HMS2090J16 or HMS2097J10 or HMS2232F06 or HMS3263G06 or HMS3267A05 or HMS3393N15 or Pharmakon 1600-01505683 or Tox21_l 10672 or AR-1F9691 or DNC000014 or DNC000017 or DNC003593 or INI 123 or

(cyclopentyloxy)-4- methoxyphenyl)-, (4S)-

CHEMBL 123208 CHEMBL1232082 or Pyrido[2,3- 1-(3-nitrophenyl)-3- 2 d]pyrimidine-2,4( 1H,3H)-dione, 1- (pyridin-4- (3-nitrophenyl)-3 -(4- ylmethyl)pyrido[2,3 - pyridinylmethyl)- or 152814-89-6 d]pyrimidine-2, or D71 or ACMC-20n6je or 4-dione SureCN2469373 or CTK4C7578 or AG-E-00222 or RS 25344 or C19H13N504 RS 25344

YM 976 YM 976 or 4-(3-Chloropheny1)- 4-(3-chlorophenyl)- ί ,7-diethylpyrido[2,3- 1,7- d]pyrimidin-2( 1H)-one or diethylpyrido[2,3- 191219-80-4 or Tocris-1821 or d]pyrimidin-2-one SureCNl 57252 or AC107H1 W or Y4877 SIGMA or

CHEMBL 135 8525 or C17H16C1N30 CTK4E0609 or MolPort-003-960- 224 or HMS3260C13 or HMS3268I18 or AG-E-39611 or LP00016 or NCGC00025308-01 or NCGC00025308-02 or LS- 134167 or BRD- 12932420-00 1- 01-5 or 4-(3-chlorophenyl)-l,7- diethylpyrido[2 ,3-d]pyrimidin-2- one or Pyrido[2,3-d]pyrimidin- 2(lH)-one,4-(3-chlorophenyl)- 1.7-diethvl-

In some embodiments, CW242 is a Phosphodiesterase Type 4 Inhibitor represented by compound of formula I or II or III or IV or V. In some embodiments, the compound of formula I is:

Wherein. A is selected from

-C(0)NH - A4, S(0) 2NH - A ,

And where q is 0, 1, 2 or 3;

A is selected from unsaturated, saturated, partially saturated, aryland heteroaryl, each of which is optionally substituted by keto group;

A4, A5, A is selected from alkyl, alkylheteroaryi, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted completely or partially by halogen; and

A\, A2 are individually selected from alkyl, alkoxy, cycloalkylmethoxy (or cycfoaikylalkoxy), cycloalkoxy, bicycloxy and aryloxy, each of which is optionally substituted completely or partially by halogen.

In some embodiments, the compound of formula II is: Wherein E is selected from N and CH2; and

Ej, E2, E are individually selected from amino, alkyl, ary and heteroaryl, each of which isoptionally substituted.

e compound of formula is:

Wherein, E5, E , E are individually selected from N and CH2; E is selected from hydrogen and alkyl; E is NH; and lly selected from hydrogen; and

where E 2 ,E 3 are individually selected from oxygen and sulhur.

In some embodiments, the compound of formula IV is: Wherein,Ei4 , E are individually selected from hydrogen and alkyl; E , are individually selected from N and CH; and

E is selected from oxygen and sulphur.

In some embodiments, the compound of formula V is;

Wherein, P is selected firom hydrogen, alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted; is selected from

, alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl a d heteroaryl, each of which is optionally substituted; R is selected from hydrogen, alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted; and S is selected from oxygen, alkyl, alkylheteroaryL alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted by halogen.

In some embodiments, the compound of formula I is: Non-limiting examples of CWl /0 include the compounds of Table 2.

Table 2: CW170 C Names Chemical Structures

General Name Synonyms Structure IUPAC Name Chioroquine chioroquine or Aralen or 4-N-(7-chloroquinolin- Artrichin or Chlorochin or II 4-yl)-l -N,l -N- Chemochin or Chingamin or diethylpentane- ,4- Reumaclilor or Capquin or diamine Chloroquinium or Arthrociiin or Bemaphate or Bemasulph or Benaquin or C 8H26CiN3 Bipiquin or Chloraquine or Chloroquina or Chlorquin or Cidanchin or Clorochina or Cocartrit or Dichinalex or Gontochin or Heliopar or Iroquine or Klorokin or Lapaquin or Malaquin or Mesylith or Nivaquine or Pfizerquine or Quinachlor or Quinercyl or Quinilon or Quinoscan or Resoquine or Sanoquin or Silbesan or Solprina or Sopaquin or Tresochin or Amokin or Bemaco or Elestol or Imagon or Malaren or Malarex or Neochin or Roquine or Siragan or Tanakan or Trochin or Nivaquine B or Quingamine or Arechin or Avloclor or Delagil or Khingamin or Resochin or Avlochlor or Chlorochine or Nivachine or Quinagamin or Quinagamine or Resochen or Resoquma or Reumaquin or Chlorochinum or Chloroquinum or Arechine or Arequiii or Cloroquina or Ronaquine or Aralen HC1 or 54-05-7 or Chloroquine phosphate or Chloroquine (VAN) or Clorochina [DCfT] or 3377 RP opa!ate or Chloroquin or Chloroin or Rivoquine or Arolen or WIN 244 or ST 2 1 (pharmaceutical) or Chloroquinum fINN-Latin] or Cloroquina [INN- Spanish] or Chloroquine, D- or (+)-Chloroquine or (-)- Chloroquine or Miniquine or Tanakene or ( -)- Chloroquine or RP 3377 or CCRLS 3439 or CHEBL3638 or 1,4- Pentanediamine, N4-(7- chloiO-4-quinolinyl)-N 1, I- diethyl- or HSDB 3029 or Spectrum 000132 or ST or Gontochin phosphate or (R)-(-)-Chloroquine or CHEMBL76 or Chloroquine USP/ ) or Pres i kO 000548 or Prestwickl 000548 or Prestwick2_000548 or PrestwickS 000548 or Spectrum2 000127 or Spectrum3_00034 or Spectnim4_000279 or SpectTuiri5_000707 or EINECS 200-191-2 or NSC 187208 or W 76 8 or Malaquin (*Diphosphate *) or MoiMap 000009 or NSC 187208 or AC1L1EB8 or AC1Q2ZA7 or AC1Q2ZA8 or BR 0482809 or LopacO 000296 or U - 886U3H6UFF or

89 BSPBio 000595 or BSPBio_002001 or C18H26C1N3 or BioGR 000778 or BioSS 000592 or DivKlc 000404 or Ipsen 225 or SPBio 000 74 or SPBio 002516 or Chloroquine [USA ;INN :BAN] or GNF- Pf-4216 or BPBiol 000655 or Chloroquine Bis- Phosphoric Acid or Biol 000404 or KBio2 000592 or KBio2 003160 or KBio2 005728 or KBio3 001221 or CID2719 or NINDS 000404 or HMS2090O03 o NSC14050 or NSC- 187208 or DB00608 or RP-3377 or SN 671 8 or SN-7618 or nchembio.215- comp4 or nchembio.368- comp8 or nchembio.87- compl7 or IDI1 000404 or Ro 01-6014/N2 or SMP2 000034 or NCGCOOO 15256-04 or NCGC00 162 120-01 or 7- Chloro-4-((4- (diethylamino)- 1- methylbutyl)amino)quinolin

e or 6 000894 or WLN: T66 BNJ

EMY1&3N2&2 1G or 4~ (7-Chloro-4-quinolinyl)- N 1,N1 -diethyl- 1,4- pentanediamine or N4-(7- chloroquinolin-4-yl)-N 1,N 1- diethylpentane- ,4-diamine or LS-141726 or AB00053436 or C07625 or D02366 or 58175-86-3 or CQ or BRD-A9 1699651- 065-01-1 or Chloroquine hydrochloride or CU- 01000012392-2 or {4-[(7- chloroquinol in-4- yl)amino]pentyl}diethylamin e or MolPort-001-783-623 or 7-ChloTo-4-[[4- (diethylamino)- - methylbutyl] amino] quinolin e or Quinoline, 7-chloro-4- ((4-(dietliylamino)- - methylbutyl)amino)- or 1,4- Pentanediamine, N(4)-(7- chloro-4-quinolinyl)- N(l),N(l)-diethyl- or 1,4- Pentanediamine, N4-(7- chioro-4-qiiinolinyi)-Nl ,N1- diethyl-, (+)- or 1,4- Pentanediamine, N(sup 4)- (7-chloro-4-quinolinyl)- N(sup l),N(sup l)-diethyl- or N(sup 4)-(7-Chloro-4- quinolinyl)-N(sup 1),N(sup l)-diethyl-l,4- pentanediamine or 56598- 66-4 or 58175-87-4 or 3545- 67-3 or {4-[(7-chloro(4- quinolyl))amino]pentyl}diet hylamine or Quinoline, 7- chloro-4-(4-diethylamino- - methyl-butylamino)- or Quinoline, 7-chioro-4-[[4- (diethylamino)- - methylbutyl] amino]- or (+-)- Chloroqume or Chloroquine + Proveblue or SureCN8933 or Chloroquine [USP:INN:BAN] or 1,4- Pentanediamine, N4-(7~ chloro-4-quinol inyl)-N 1,N 1- diethyl-, (4 )- or CTK 1H 520 or DAP000165 or DAP001357 or SBB072644 or AKOS0 15935 06 or CCG- 204391 or NCGC000 15256- 02 or NCGC00015256-03 or NCGC000 1525 6-05 or NCGC000 15256-06 or NCGC000 15256-07 or

NCGC000 15256-08 or NCGC000 15256-09 or

NCGC000 15256- 10 or AK 116457 or ST45028748 or MLS-0466768.0001 or 1, N4-(7-chloro-4-quinolinyl)- , -diethyl- or n(sup4)- (7-chloro-4-quinolinyl)- n(supl ),4-pentanediamine or 7-chloro-4-{[4- (diethylamino)- - methylbutyl] amino} quinolin ium or N4-(7-chloro-4- quinolyl)-Nl,Nl-diethyl- pentane-l,4-diamine or (+)- N4-(7-Chloro-4-quinolinyl)- N 1,N1 -diethyl- 1,4- pentanediamine or 4~N~(7- chloroquinolin-4-yl)- 1-N, 1- N-diethylpentane- ,4- diamine or (+-)-N4-(7- Chloro-4-quinolinyl)- N 1,N1 -diethyl- 1,4- pentanediamine or ,4- Pentanediamine, N4-(7- chloro-4-quinol inyl)-N i N 1- diethyl-, (+-)- or 1,4- Pentanediamine, N4-(7- chloro-4-quinolinyl)-Nl,Nl- diethyl-, (-)- or 1,4- Pentanediamine, N4-(7- chloro-4-quinolinyl)-N 1,N 1- diethyl-, (R)- or N(4)-(7- chforo-4-quinolinyl)- N(l),N(l)-diethyl-l,4- pentanedi amine or N(4)-(7- chloroquinolin-4-yl)- N(1),N( 1)-diethylpentane- 1,4-diamine or N*4*-(7- Chloro-quinolin-4-yl)- N*ί *,N* ί *-diethyl-pentane- 4-diamine or ,4- Pentanediamine, N4-(7- chloro-4-quinolinyl)-N 1,N 1- diethyl- or Quinoline, 7- chloro-4-(4-diethylamino- - methyl-butylamino)-.

Lucanthone L CANTHO E or l-[2- Lucanthon or Tixantone or (diethylamino)ethylami

Miracil D or Lucanthonum no -4 - fINN-Latin] or Lucantona niethylthioxanthen-9- [INN-Spanish] or one Lucanthonum or Miracol or C20H24N2OS Nilodin or Scapuren or LUCANTHONE HYDROCHLORIDE or Lucanthone [INN:BAN] or 479-50-5 or l-((2- (Diethylamino)ethyl)amino)- 4-methylthioxanthen-9-one or CCRIS 1106 or CHEBL51052 or Lucanthone monohydrochloride or AC1L1UNW or E1 ECS 207-532-4 or

NCIMech 000830 or ί - | 2 - (Diethylamino)ethyl] amino } -4-methyl-9H-thioxanthen- 9-one or BRN 0312369 or AI3-16160 or CHEMBL279014 or l-[[2- (Diethylamino)ethyl] amino] - 4-methylthioxanthone or DB04967 or NCI6Q 000988 or Thioxanthen-9-one, l-((2- (diethylamino)ethyl)amino)- 4-methyl- or LS 53695 or

9H-Thioxanthen-9-one, 1- ((2- (diethylamino)ethyl)amino)- 4-methyl- or C 1715 or 5- 18-11-00503 (Beilstein Handbook Reference) or 1- (2-diethylaminoethylamino)- 4-methylthioxanthen-9-one

or 9H-Thioxanthen-9-one, 1- ((2- (diethyl amino)ethyl )amino)- 4-methyl- (9C1) or

NSC14574 or 548-57-2 or 1-

{[2- (diethylamino)ethyl] amino} - 4-methylthioxanthen-9-one or CID10180 or SureCN9156 or N -

9.5 FC6D57000M or CCG-

35817 or DAP001003 or 1- diethylaininoethylethylamin o-4-methyl-thioxanthenone LysOl l-N-(7-chloroquinolin-4-yl)- 1-N-(7-chloroquinolin- 2-N-(2-((7-chloroquinolin-4- 4-yl)-2-N-(2-((7- y])amino)etbyl)~ chloroquinolin-4- 2-N-methylethane- ,2- yl)amino)ethyl)- diamine. 2-N-methylethane-l ,2- diamine. Lys02 1-N-(2-aminoethyl)-2-N-(7- i -N-(2-aminoethyl)-2- chloroquinolin-4-yl)- -N- N-(7-chloroquinolin-4- methylethane- ,2-diamine. yl)- 1-N-methylethane- 1,2-diamine

1-N-(7-methoxyquinolin-4- * Lys03 \ l-N-(7- yl)-2-N-(2-((7- methoxyquinol in-4-yl)- methoxyquinolin-4- rrS 2-N-(2-((7- yl)amino)ethyl)- methoxyquinolin-4- 2-N-methylethane- ,2- yl)amino)ethyl)- diamine. 2-N-methylethane- ,2- diamine. Lys04 Ν,Ν '-((ethane- 1,2- Ν,Ν'-((ethane- 1,2- diylbis(oxy))bis(ethane-2, 1- diylbis(oxy))bis(ethane diyl))bis(7-chloroquinolin-4- -2,l-diyl))bis(7- amine). chloroquinolin-4- amine). Lys05 l-N-(7-chloroquinolin-4-yl)- 1-N-(7-chloroquinolin- 2-N-(2-((7-chloroquinolin-4- 4-yl)-2-N-(2-((7- yl)amino)ethyl)- chloroquinolin-4- 2-N-methylethane- ,2- yl)amino)ethyl)- diamine trihydrochloride . 2-N-methylethane- ,2- diamine trihydrochloride. Hydroxychloroqui hydroxychloroquine or 2-[4-[(7- ne Plaquenil or chloroquinolin-4-

Oxichlorochinum or y )amino]pentyl- Oxychlorochin or ethylamino] ethanol Oxychloroquine or Idrossiclorochina [DCIT] or Oxichloroquine or Quensyl c 8H 6C1N30 or Hydroxychlorochin or Hydroxychloroguine or Hidroxicloroquina [INN- Spanish] or Hydroxychloroquinum [INN-Latin] or 8-42-3 or Hidroxicloroquina or Idrossiclorochina or or WIN 1258 or Polirreumin (TN) or Ercoquin or AC1L1GEW or Hydroxychloroquine (INN) or Spectrum! 001238 or Spectrum5 001697 or EINECS 204-249-8 or UNII- 4QWG6N8QKH or 2-((4- ((7-Chloro-4- quinolyl)amino)pentyl)ethyl amino)ethanol or Gen- Hydroxychloroquine 200mg Tablets or Hydroxychloroquine Sulfate

( 1:1) Salt or BRN 0253894 or C18H26C1N30 or CHEMBL1535 o ST072188 or DivKlc 000942 or Hydroxychloroquine [INN:BAN] or SPBio 001 116 or HCQ or HMS502P04 or KBiol 000942 or NINDS 000942 or NSC4375 or Ethanol, 2-((4- ((7-chloro-4- quinolinyl)amino)pentyl)eth ylamino)- or Ethanol, 2-[[4- [(7-chloro-4- quinolinyl)amino]pentyl]eth ylamino]- or DB01611 or IDI1 000942 or NCGC00 159483 -02 or 747-

36-4 (sulfate ( 1:1) salt) or LS-66614 or Ethanol, 2-((4- ((7-chloro-4- quinolyl)amino)pentyl)ethyl amino)- or 2-(N-(4-(7-Chlor- 4-chinolylamino)-4- methylbutyl)ethylammo)etha no or 7-Chloro-4-(4- (ethyl(2- hydroxyethyl)amino )- 1- methylbutylamino)quinoline or 7-Chloro-4-(5 -(N-ethyl- N-2-hydroxyethylamino)-2- pentyl)aminoquinoline or 7- Chloro-4-(4-(N-ethyl-N- beta-hydroxyethylamino)- -

9'8 methylbutylamino)quinoline or C07043 or D08050 or 5- 22-10-00280 or 2-[4-[(7- chloroquinolin-4- yl)amino]pentyl-

ethylamino]ethanol or 2-f {4- [(7-chloroquinolin-4- yl)amino Ipentyl }(ethyl)amin ojethanol or Polirreumin or 2-({4-[(7-chloro(4- quinolyl))amino]pentyl}ethy lamino)ethan- -ol or CID3652 or SureCN8170 or MolPort-003 -847-792 or DAP000878 or SBB0 12559 or M566. Mefloquine Mefloquine or (-)- (S)-[2,8- Mefloquine or Racemic bis(trifluoromethyl)qui mefloquine or Mefloquinum nolin-4-yl]-[(2R)- [INN-Latin]or Mefloquina piperidin-2- [INN-Spanish]or yl]methanol Mephloquine or Mefloquine [USA ;INN :BAN]or CHEBL63687 or HSDB

6853 or (··)··( ! !S.2'R)- erythro-Mefloquine or Ro 215998 o RTI1189-l-l or Ro 21-5998 or RO 13-7225 or 4-Quinolinemethanol alpha-2-piperidinyl-2,8- bis(trifluoromethyl)-, (R*,S*)-(+-)- or WR 142490 or 53230-10-7 or (DL- erythro-alpha-2-Piperidyl- 2,8-bis(trifluoromethyl)-4- quinolinemethanol or (S)-[2,8- bis(trifluoromethyl)quinolin- 4-yl][(2R)-piperidin-2- yl]methanol or 4- Quinolinemethanol, alpha- (2R)-2-piperidinyl-2,8- bis(trifliioromethyl)-, (alphaS)-rel-. macrine Acrichine or Atabrine or 4-N-(6-chloro-2- methoxyacridin-9-yl)- Atebrin or Dihydrochloride, - . - - Quinacrine or Dimesylate, diethylpentane- 1,4- diamine Quinacrine or Hydrochloride, Quinacrine C23 3 C O or Mepacrine or Monoacetate, Quinacrine or Monohydrochloride, Quinacrine or Monomesylate, Quinacrine or Quinacrine or Quinacrine Dihydrochloride or Quinacrine Dihydrochloride, Dihydrate or Quinacrine Dihyrochloride, (R)-Isomer or Quinacrine Dihyrochloride, (S)-Isomer or Quinacrine Diraesylate or Quinacrine Hydrochloride or Quinacrine Monoacetate or Quinacrine Monohydrochloride or Quinacrine Monomesylate or Quinacrine, (+-)-Isomer or Quinacrine, (R)-Isomer or Quinacrine, (S)-lsomer.

In some embodiments, CW170 is an Autophagy inhibitor represented by compound of formula VI or VII. in some embodiments, the compound of formula VI is:

Wherein, X is selected from N, N =0 and CH; L is selected from halogen, hydrogen, a halogen-containing group, alkyl andalkoxy;

R is i NH R2, and where is a chemical bond, alkyl, cylcoalkyl, sulfonyl, carbonyl; and R s

Wherein, m is selected from 0, 1, 2 ,3, 4 and 5; n is selected from 0, 1, 2 , 3, 4 and 5; Y is selected from N-R and O

Z is selected from N and CH2; and R3, R4, R5, R6, R7, R7, R8, R9, RIO and Rl is individually selected from hydrogen, alkyl, alkoxy, aryl, alkaryl, aralkyl and heteroaryl, each of which are optionally substituted.

In some embodiments, the compound of formula VII is:

Wherein,V, W is individually selected from oxygen and sulphur; t is selected from 0, 1, 2, 3, 4 and 5; and R14, R15, R16 and R17is individually selected from hydrogen, alkyl, alkoxy, aryl, alkaryl, aralkyl heteroaryl,each of which are optionally substituted.

In some embodiments, the compound of formula VI is; INon-limitrag examples of CW178 include the compounds of Table 3.

Table 3: CW178 Compound Names and Chemical Structures,

A-769662, 844499-71-4, 4- Hydroxy-3-(2'-hydroxy- , - 4-hydroxy-3-[4-(2- biphenyl-4-yl)-6-oxo-6,7- A769662 hydroxyphenyl )phenyl]-6- dihydrothieno[2,3-b]pyridine- oxo-7H-thieno[2, 5-carbonitrile, 3-b]pyridine-5-carbonitrile PubChem 16661 n some embodiments, CWl 78 is an AMPK Agonist represented by compound of formula VIII.

In some embodiments, the compound of formula VIII is;

Wherein, Rl is selected from hydrogen and alkyl;

R2 is selected from hydrogen, alkyl wherein: n is an integer ranging between 1 to 4. In some embodiments, the com ound of formula VIII is:

The present disclosure provides the use of pharmaceutically-acceptable salts of any compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base- addition salts. The acid that is added to the compound to form an acid-addition salt is an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt is an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-acceptable salt is an ammonium salt.

Metal salts arise from the addition of an inorganic base to a compound of the present disclosure. The inorganic base consists of a meta cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal is an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminium, copper, cadmium, or zinc.

In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

Ammonium salts arise from the addition of ammonia or an organic amine to a compound of the present disclosure. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol aammiinnee,, ddiieetthhaannooll aammiinnee,, mtrieetthhaannooll aammiinnee,, mmoorrpphhoolliinnee,, NN--mmeetthhyyllmmoorrpphhoolliinnee,, ppiippeerriiddiinnee,, NN~~ mmeetthhyyiippiippeerriiddiinnee,, NN--eetthhyyllppiippeerriiddiinnee,, ddiibbeennzzyyllaammiinnee,, ppiippeerraazziinnee,, ppyyrriiddiinnee,, ppyyrrrraazzoollee,, ppiippyyrrrraazzoollee,, iimmiiddaazzoollee,, ppyyrraazziinnee,, oorr ppiippyyrraazziinnee..

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A pharmaceutical composition o f the present disclosure i s a combination o f any pharmaceutical compounds described herein with other chemical components, such a s carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration o f the compound t o a organism. Pharmaceutical compositions are administered in therapeutically-effective amounts as pharmaceutical compositions by any fo n and route known in the art including, for example, intravenous, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, and topical administration.

A pharmaceutical composition is administered in a local or systemic manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation. Pharmaceutical compositions are provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the fonn of an intermediate release formulation. A rapid release form provides an immediate release. An extended release formulation provides a controlled release or a sustained delayed release.

For oral administration, pharmaceutical compositions are formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients well known in the art. Such carriers are used to formulate tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a subject.

Pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Cores are provided with suitable coatings. For this purpose, concentrated sugar solutions are used, which optionally contain an excipient such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments are added to the tablets or dragee coatings, for example, for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations which are used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In some embodiments, the capsule comprises a hard gelatin capsule comprising one or more of pharmaceutical, bovine, and plant gelatins.A gelatin may be alkaline processed. The push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers are added. All formulations for oral administration are provided in dosages suitable for such administration.

For buccal or sublingual administration, the compositions are tablets, lozenges, or gels.

Parenteral injections are formulated for bolus injection or continuous infusion. The pharmaceutical compositions are in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and contain forrnulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds are prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may also contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

In an embodiment the active compounds are administered topically and formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, ge s, pastes, medicated sticks, balms, creams, and ointments.Such pharmaceutical compositions contain soiubiiizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

In another embodiment, formulations suitable for transdermal administration of the active compounds may employ transdermal delivery devices and transdermal delivery patches, and may be lipophilic emulsions or buffered aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical compounds. Transdemial delivery may be accomplished by means of lontophoretic patches and the like. Additionally, transdermal patches provide controlled delivery. The rate of absorption may be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers are used to increase absorption. An absorption enhancer or carrier includes absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing compounds and carriers, a rate controlling barrier to deliver the compounds to the skin of the subject at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

For administration by inhalation, the active compounds are in the form of an aerosol, a mist, or a powder. Pharmaceutical compositions are conveniently delivered in the form of an aerosol spray from pressurized packs or a nebuliser, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit is determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compounds and a suitable powder base such as lactose or starch.

The compounds are also formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.

In practicing the methods of management or use provided herein, therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease, disorder or condition to be treated or prevented. In some embodiments, the subject is a mammal such as a human. A therapeutically-effective amount varies widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. The compounds are used singly or in combination with one or more therapeutic agents as components of mixtures. Pharmaceutical compositions may be formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that are used pharmaceutically. Formulation is modified depending upon the route of administration chosen. Pharmaceutical compositions comprising compounds described herein are manufactured in a conventional manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

The pharmaceutical compositions may include at least one pharmaceutically acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically-acceptable salt form. The methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs), and active metabolites of these corapounds having the same type of activity.

Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include, for example, solutions in whic a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi solid compositions include, for example, gels, suspensions and creams. The compositions may be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions may also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, p buffering agents, and other pharmaceutically- acceptable additives.

Compounds may also be delivered via liposomal technology. The use of liposomes as drug carriers increases the therapeutic index of the compounds. Liposomes are composed of natural phospholipids, and may contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine). A liposome design employs surface ligands for attaching to unhealthy tissue. Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV). Liposomal physicochemical properties are modulated to optimize penetration through biological barriers and retention at the site of administration, and to prevent premature degradation and toxicity to non-target tissues.

Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting PEGylation reduces the uptake of the liposomes by liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally, liposomal surfaces are modified to achieve selective delivery of the encapsulated drug to specific target cells. Non-limiting examples of targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease.

The compounds of the present disclosure, in a composition, can be delivered via Antibody-Drug Conjugates (ADCs) technology. Here, drags/compounds are conjugated/fused to tumor-specific antibodies so as to deliver the drug/compound to the site of tumor and increase their therapeutic efficacy. ADCs have been developed for targeted delivery of anti-cancer drugs to tumor in the body of the subject, with the aim of bypassing the morbidity common to conventional drug delivery.

Non-limiting examples of dosage forms suitable for use in the disclosure include feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticie, microgel, suppository troches, aqueous or oily suspensions, ointment, patch, lotion, dentifrice, emulsion, creams, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups, phyfoeeuticais, nutraceuticals, and any combination thereof.

Non-limiting examples of pharmaceuticaliy-acceptabie excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti-adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavouring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof.

A composition of the present disclosure may be, for example, an immediate release form or a controlled release formulation. An immediate release formulation is formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release fonnulations include readily dissolvable formulations. A controlled release formulation is a pharmaceutical formulation that has been adapted such that drug release rates and drug release profiles are matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of a drug at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, granular masses, and the like.

In embodiments, compositions of the present disclosure are delivered via a time-controlled delivery system. An example of a suitable time-controlled delivery system is the PULSINCAP® system, or a variant thereof. The time-controlled delivery system further comprises pH-dependent systems, microbially-triggered delivery systems, or a combination thereof. The time-controlled system comprises a water insoluble capsule body enclosing a drag reservoir.The capsule body is closed at one end with a hydrogel plug. The hydrogel plug may comprise sweliable polymers, erodible compressed polymers, congealed melted polymers, enzymatically-controlled erodible polymers, or a combination thereof.

The sweliable polymers include poiymethacrylates. Non-limiting examples of erodible compressed polymers include hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, and combinations thereof.Non-iimitiiig examples of congealed melted polymers include saturated polyglycolated glycerides, glyceryl monooleate, and combinations thereof. Non-limiting examples of enzymatically-controlled erodible polymers include polysaccharides; amylose; guar gum; pectin; chitosan; inulin; cyclodextrin; chondroitin sulphate; dextrans; locust bean gum; arabinogalactan; chondroitin sulfate; xylan; calcium pectinate; peetin/chitosan mixtures; amidated pectin; and combinations thereof.

The time-controlled delivery system comprises a capsule, which further comprises an organic acid. The organic acid is filled into the body of a hard gelatin capsule. The capsule is coated with multiple layers of polymers. The capsule is coated first with an acid soluble polymer, such as EUDRAGIT® E, then with a hydrophilic polymer, such as hydroxypropyl methylcellulose, and finally with an enteric coating, such as EUDRAGIT® L.

An additional example of a suitable time-controlled delivery system is the CHRONOTROPIC® system, or a variant thereof, which comprises a drug core that is coated with hydroxypropyl methylcellulose and a outer enteric film.

An additional example of a suitable time-controlled delivery system is the CODES™ system, or a variant thereof. The time-controlled delivery system comprises a capsule body, which houses, for example, a drug-containing tablet, an erodible tablet, a swelling expulsion excipient, or any combination thereof. The capsule comprises an ethyl cellulose coat. The time-controlled delivery system comprises two different sized capsules; o e inside the other. The space between the capsules comprises a hydrophilic polymer. The drug-containing core is housed within the inner capsule. The drag delivery system comprises an impermeable shell, a drag-containing core, and erodible outer layers at each open end. When the outer layers erode, the drag is released.

Examples of suitable multiparticulate drug delivery systems include DIFFUCAPS®, DIFFUTAB®, ORBEXA®, EURAND MINITABS®, MICROCAPS®, and variants thereof. The drag delivery system comprises multiparticulate beads, which are comprised of multiple layers of the drug compound, excipients, and release-controlling poiymers.The multiparticulate beads comprise an organic acid or alkaline buffer.The multiparticulate beads comprise a solid solution of the drug compound and crystallization inhibitor. The drug delivery system comprises a matrix tablet containing water-soluble particles and the drug compound. The matrix tablet further comprises hydrophilic and hydrophobic polymers. In some multiparticulate delivery systems, particles in the micron size range are used. In some multiparticulate delivery systems nanoparticle colloidal carriers composed of natural or synthetic polymers are used.

In some embodiments, a controlled release formulation is a delayed release form. A delayed release form is formulated to delay a compound's action for an extended period of time. A delayed release form is formulated to delay the release of a effective dose of one or more compounds, for example, for about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours.

A controlled release formulation may be a sustained release form. A sustained release form is formulated to sustain, for example, the compound's action over an extended period of time. A sustained release form is formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours.

A tablet providing a sustained or controlled release comprises a first layer containing one or two of the compounds described herein, and a tablet core containing one or two other compounds. The core may have a delayed or sustained dissolution rate. Other exemplary embodiments include a barrier between the first layer and core, to limit drug release from the surface of the core. Barriers prevent dissolution of the core when the pharmaceutical formulation is first exposed to gastric fluid. For example, a barrier comprises a disintegrant, a dissolution-retarding coating (e.g., a polymeric material, for example, an enteric polymer such as a Eudragit polymer), or a hydrophobic coating or film, and may be selectively soluble in either the stomach or intestinal fluids. Such barriers permit the compounds to leach out slowly. The barriers cover substantially the whole surface of the core.

Non-limiting examples of pharmaceutically-acceptable excipients are found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton Pa.; Mack Publishing Company, 1995); Hoover, John E. Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drag Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), each of which is incorporated by reference in its entirety.

Pharmaceutical compositions described herein are in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage is in the form of a package containing discrete quantities of the fonnulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions are packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers are used, for example, in combination with a preservative. Formulations for parenteral injection are presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.

Each of the compounds of the present disclosure, belonging to the class of drugs, Autophagy Inhibitor (CW170), AMPK Agonist (CW178) and Phosphodiesterase type 4 inhibitor (CW242) are present in the compositions of the present disclosure in an amount that does not exceed the maximum tolerated dosage of each of the compounds individually.

A compound described herein is present in a composition in a range of from about I mg to about 2000 rag; from about 5 rag to about 000 mg, from about 1 mg to about 500 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 50 mg, from about 50 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1000 mg.

A compound described herein is present in a composition in an amount of about 1 mg, about 5 mg, about 0 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 00 mg, about 50 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 100 mg, about 1200 mg, about 300 mg, about 1400 mg, about 1500 mg, about 600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg.

In some embodiments, a dose is expressed in terms of an amount of the drug divided by the mass of the subject, for example, milligrams of drug per kilograms of subject body mass. In some embodiments, a compound described herein is present in a composition in an amount that is a fraction or percentage of the maximum tolerated amount. The maximum tolerated amount is as determined in a subject, such as a mouse or human. The fraction is expressed as a ratio of the amount present in the composition divided by the maximum tolerated dose. The ratio is from about 1/20 to about 1/1. The ratio is about 1/20, about 1/19, about 1/18, about 1/17, about 1/16, about 1/15, about

1/14, about 1/13, about / 12, about 1/1 1, about 1/10, about 1/9, about 1/8, about 1/7, about 1/6, about 1/5, about 1/4, about /3, about 1/2, or about 1/1. The ratio is 1/20, 1/19, 1/18, 1/17, / 16, / 15, 1/14,

1/13, 1/12, 1/1 1, 1/10, 1/9, 1/8, 1/7, 1/6, 1/5, 1/4, 1/3, 1/2, or 1/1.

The ratio, expressed as percentage, is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. The ratio is in a range f om about 5% to about 100%, from about 0% to about 100%, from about 5% to about 80%, from about 0% to about 80%, from about 5% to about 60%, from about 0% to about 60%, from about 5% to about 50%, from about 10% to about 50%, from about 5% to about 40%, from about 10% to about 40%, from about 5% to about 20%, or from about 0% to about 20%.

The foregoing ranges are merely suggestive. Dosages are altered depending on a number of variables, including, for example, the activity of the compound used, the disease, disorder or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease,disorder or condition being treated, and the judgment of the practitioner.

A dose is modulated to achieve a desired pharmacokinetic or pharmacodynamics profile, such as a desired or effective blood profile, as described herein.

Pharmacokinetic an Pharmacodynamic Measurements Pharmacokinetic and Pharmacodynamic data is obtained by techniques known in the art. Appropriate pharmacokinetic and pharmacodynamic profile components describing a particular composition vary due to the inherent variation in pharmacokinetic and pharmacodynamic parameters of drug metabolism in human subjects. Pharmacokinetic and Pharmacodynamic profiles are based on the determination of the mean parameters of a group of subjects. The group of subjects includes any reasonable number of subjects suitable for determining a representative mean. The mean is determined by calculating the average of all subject's measurements for each parameter measured.

a The Cma , AUC, and bioavailability values for CWl 70 (represented by Chloroquine), CWl 78 (represented by Metformin) and CW242 (represented by Roflumilast) compounds are provided in the table below. AUC ( ng*hr/mL) About 26,81 ± 7055 (ng hr/mL)

Tmax (h) About 6 (ranging from 3-10) T i 2(h) About 6.2 hours. Duration of action is 8-12 hours. Bioavailability About 80%

The pharmacodynamic parameters are any parameters suitable for describing compositions of the present disclosure. For example, the pharmacodynamic profile exhibits decreases in viability phenotype for the tumor cells or tumor size reduction in tumor cell lines or xenograft studies, for example, in about 24 hours, about 48 hours, about 72 hours, about 1 week or about 1 month.

In an alternate embodiment, the pharmacodynamic parametres of the composition of the present disclosure, can be obtained at a time after dosing of, for example, about zero minutes, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 20 minutes, about 2 1 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 3 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 rnmutes, about 40 minutes, about 4 minutes, about 42 rnmutes, about 43 minutes, about 44 minutes, about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 rnmutes, about 5 minutes, about 52 minutes, about 53 rnmutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about zero hours, about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 0 hours, about

0.5 hours, about hours, about 11.5 hours, about 2 hours, about 12.5 hours, about 13 hours, about

13.5 hours, about 14 hours, about 14.5 hours, about 15 hours, about 15.5 hours, about 16 hours, about 16.5 hours, about 17 hours, about 17.5 hours, about 8 hours, about 18.5 hours, about 19 hours, about 19.5 hours, about 20 hours, about 20.5 hours, about 2 1 hours, about 21.5 hours, about 22 hours, about 22.5 hours, about 23 hours, about 23.5 hours or about 24 hours. The pharmacokinetic parameters can be any parameters suitable for describing a compound. The Cmax can be, for example, not less than about 1 ng/mL; not less than about 5 ng/mL; not less than about 10 ng mL; not less than about 15 ng/mL; not less than about 20 ng/mL; not less than about 25 ng/mL; not less than about 50 ng/mL; not less than about 75 ng/mL; not less than about 100 ng/mL; not less than about 200 ng/mL; not less than about 300 ng mL; not less than about 400 ng/mL; not less than about 500 ng/mL; not less than about 600 ng/mL; not less than about 700 ng/mL; not less than about 800 ng mL; not less than about 900 ng/mL; not less than about 1000 ng/mL; not less than about 1250 ng/mL; not less than about 1500 ng/mL; not less than about 1750 ng/mL; not less than about 2000 ng mL; or any other Cmax appropriate for describing a pharmacokinetic profile of a compound described herein. The Cmax can be, for example, about 1 ng mL to about 5,000 ng mL; about 1 ng mL to about 4,500 ng/mL; about ng/mL to about 4,000 ng/mL; about 1 ng/mL to about 3,500 ng/mL; about I ng mL to about 3,000 ng/mL; about 1 ng mL to about 2,500 ng mL; about ng/mL to about 2,000 ng/mL; about 1 ng/mL to about 1,500 ng/mL; about 1 ng/mL to about 1,000 ng/mL; about 1 ng/mL to about 900 ng/mL; about 1 ng mL to about 800 ng/mL; about 1 ng/mL to about 700 ng/mL; about 1 ng/mL to about 600 ng/mL; about 1 ng/mL to about 500 ng/mL; about 1 ng/mL to about 450 ng/mL; about 1 ng/mL to about 400 ng/mL; about 1 ng/mL to about 350 ng/mL; about 1 ng/mL to about 300 ng/mL; about 1 ng/mL to about 250 ng/mL; about 1 ng mL to about 200 ng/mL; about 1 ng/mL to about 150 ng/mL; about 1 ng/mL to about 125 ng/mL; about 1 ng/mL to about 100 ng/mL; about 1 ng/mL to about 90 ng/mL; about 1 ng/mL to about 80 ng/mL; about ng/mL to about 70 ng/mL; about 1 ng/mL to about 60 ng/mL; about i ng/mL to about 50 ng/mL; about 1 ng/mL to about 40 ng/mL; about 1 ng/mL to about 30 ng/mL; about 1 ng/mL to about 20 ng/mL; about 1 ng/mL to about 10 ng/mL; about 1 ng/mL to about 5 ng/mL; about 10 ng/mL to about 4,000 ng/mL; about 10 ng/mL to about 3,000 ng/mL; about 10 ng/mL to about 2 000 ng/mL; about 10 ng/mL to about 1,500 ng/mL; about 10 ng/mL to about 1,000 ng/mL; about 10 ng/mL to about 900 ng/mL; about 10 ng/mL to about 800 ng/mL; about 10 ng/mL to about 700 ng mL; about 10 ng/mL to about 600 ng/mL; about 10 ng mL to about 500 ng/mL; about 10 ng/mL to about 400 ng/mL; about 10 ng/mL to about 300 ng/mL; about 0 ng mL to about 200 ng/mL; about 10 ng mL to about 100 ng mL; about 10 ng/mL to about 50 ng/mL; about 25 ng/mL to about 500 ng mL; about 25 ng/mL to about 100 ng/mL; about 50 ng/mL to about 500 ng/mL; about 50 ng/mL to about 100 ng/mL; about 100 ng/mL to about 500 ng/mL; about 100 ng/mL to about 400 ng/mL; about 00 ng/mL to about 300 ng/mL; or about 100 ng/mL to about 200 ng/mL. The Tmax of a compound described herein can be, for example, not greater than about 0.5 hours, not greater than about 1 hours, not greater than about .5 hours, not greater than about 2 hours, not greater than about 2.5 hours, not greater than about 3 hours, not greater than about 3.5 hours, not greater than about 4 hours, not greater than about 4.5 hours, not greater than about 5 hours, or any other Tmax appropriate for describing a pharmacokinetic profile of a compound described herein. The Tmax can be, for example, about 0 1 hours to about 24 hours; about 0.1 hours to about 0.5 hours; about 0 5 hours to about 1 hour; about 1 hour to about 1.5 hours; about 1.5 hours to about 2 hour; about 2 hours to about 2.5 hours; about 2.5 hours to about 3 hours; about 3 hours to about 3.5 hours; about 3.5 hours to about 4 hours; about 4 hours to about 4.5 hours; about 4.5 hours to about 5 hours; about 5 hours to about 5.5 hours; about 5.5 hours to about 6 hours; about 6 hours to about 6.5 hours; about 6.5 hours to about 7 hours; about 7 hours to about 7.5 hours; about 7.5 hours to about 8 hours; about 8 hours to about 8.5 hours; about 8.5 hours to about 9 hours; about 9 hours to about 9.5 hours; about 9.5 hours to about 10 hours; about 10 hours to about 10.5 hours; about 10.5 hours to about 11 hours; about hours to about .5 hours; about .5 hours to about 1 hours; about 12 hours to about 12.5 hours; about 12.5 hours to about 3 hours; about 13 hours to about 3.5 hours; about 13.5 hours to about 14 hours; about

14 hours to about 14.5 hours; about 14.5 hours to about 5 hours; about 15 hours to about 15.5 hours; about 1 .5 hours to about 16 hours; about 16 hours to about 16.5 hours; about 16.5 hours to about 17 hours; about 17 hours to about 7.5 hours; about 17.5 hours to about 18 hours; about 8 hours to about 18.5 hours; about 18.5 hours to about 19 hours; about 19 hours to about 19.5 hours; about 19.5 hours to about 20 hours; about 20 hours to about 20.5 hours; about 20.5 hours to about 2 1 hours; about 2 1 hours to about 2 .5 hours; about 21.5 hours to about 22 hours; about 22 hours to about 22 5 hours; about 22.5 hours to about 23 hours; about 23 hours to about 23.5 hours; or about 23.5 hours to about 24 hours.

The AUC(O-inf) of a compound described herein can be, for example, not less than about 1 ng hr/mL, not less than about 5 ng»hr/mL, not less than about 0 ng»hr/mL, not less than about 20 ng»hr/mL, not less than about 30 ng hr/mL, not less than about 40 ng hr/mL, not less than about 50 ng hr/mL, not less than about 00 ng hr/mL, not less than about 150 ng»hr/mL, not less than about 200 ng*hr/niL, not less than about 250 ng»hr/mL, not less than about 300 ng hr/mL, not less than about 350 ng»hr/mL, not less than about 400 ng hr/mL, not less than about 450 ng»hr/mL, not less than about 500 ng*hr/niL, not less than about 600 ng»hr/mL, not less than about 700 ng hr/mL, not less than about 800 ng»hr/mL, not less than about 900 ng*hr/rnL, not less than about 1000 ng'hr/mL, not less than about 1250 ng»hr/niL, not less than about 1500 ng m7mL, not less than about 750 ng»hr/mL, not less than about 2000 ng hr/mL, not less than about 2500 ng hr/mL, not less than about 3000 ng hr/mL not less than about 3500 ng hr/mL, not less than about 4000 ng hr/mL, not less than about 5000 ng»hr/mL, not less than about 6000 ng»hr/mL, not less than about 7000 ng»hr/mL, not less than about 8000 ng»hr/mL, not less than about 9000 ng hr/mL, not less than about 10,000 ng hr/mL, or any other AUC(O-inf) appropriate for describing a pharmacokinetic profile of a compound described herein.

The AUC(O-inf) of a compound can be, for example, about 1 ng hr/mL to about 10,000 ng»hr/mL; about I ng hr/mL to about 0 ng»hr/niL; about 0 ng*hr/mL to about 25 ng hr/mL; about 25 ng»hr/mL to about 50 ng'hr/mL; about 50 ng*hr/mL to about 00 ng hr/mL; about 100 ng hr/mL to about 200 ng*hr/mL; about 200 ng*hr/mL to about 300 ng»hr/niL; about 300 ng hr/mL to about 400 ngHhr/mL; about 400 ng hr/mL to about 500 ng*hr/mL; about 500 ng hr/mL to about 600 ng»hr/niL; about 600 ng hr/mL to about 700 ng hr/mL; about 700 ng*hr/mL to about 800 ng'hr/mL; about 800 ng hr/mL to about 900 ng*hr/mL; about 900 ng»hr/mL to about 1,000 ng hi m L; about 1,000 ng hr/mL to about 1,250 ng hr/mL; about 1,250 ng»hr/mL to about 1,500 ng»hr/mL; about 1,500 ng*hr/mL to about 1,750 ng hr/mL; about 1,750 ng hr/mL to about 2,000 ng hr/mL; about 2,000 ng'hr/mL to about 2,500 ng'hr/ 'mL; about 2,500 ng*hr/mL to about 3,000 ng hr/mL; about 3,000 ng hr/mL to about 3,500 ng hr/mL; about 3,500 ng hr/mL to about 4,000 ng hr/mL; about 4,000 ng'hr/mL to about 4,500 ng'hr/ 'mL; about 4,500 ng*hr/mL to about 5,000 ng hr/mL; about 5,000 ng hr/mL to about 5,500 ng'hr/mL; about 5,500 ng»hi7mL to about 6,000 ng hr/mL; about 6,000 ng hr/mL to about 6,500 ng hr./mL; about 6,500 ng hr/mL to about 7 000 ng'hr/mL; about 7,000 ng»hr,½L to about 7,500 ng'hr/mL; about 7,500 ng»hi7mL to about 8,000 ng hr/mL; about 8,000 ng hr/mL to about 8,500 ng hr/mL; about 8,500 ng hr/mL to about 9 000 ng»hr/mL; about 9,000 ng»hr/mL to about 9,500 ng'hr/mL; or about 9,500 ng hr/mL to about 10,000 ng»hi7mL.

The plasma concentration of a compound described herein can be, for example, not less than about 1 ng 'mL, not less than about 5 ng/mL, not less than about 10 ng/mL, not less than about 5 ng/mL, not less than about 20 ng/mL, not less than about 25 ng/mL, not less than about 50 ng/mL, not less than about 75 ng/mL, not less than about 100 ng/mL, not less than about 150 ng/mL, not less than about 200 ng/mL, not less than about 300 ng/mL, not less than about 400 ng/mL, not less than about 500 ng/mL, not less than about 600 ng/mL, not less than about 700 ng mL, not less than about 800 ng/mL, not less than about 900 ng/mL, not less than about 1000 ng/mL, not less than about 1200 ng/mL, or any other plasma concentration of a compound described herein. The plasma concentration can be, for example, about 1 ng/mL to about 2,000 ng/mL; about 1 ng/mL to about 5 ng/mL; about 5 ng/mL to about 10 ng mL; about 10 ng/mL to about 25 ng/mL; about 25 ng/mL to about 50 ng mL; about 50 ng/mL to about 75 ng/mL; about 75 ng/mL to about 100 ng/mL; about 100 ng/mL to about 150 ng/mL; about 150 ng/mL to about 200 ng/mL; about 200 ng/mL to about 250 ng/mL; about 250 ng/mL to about 300 ng/mL; about 300 ng/mL to about 350 ng/mL; about 350 ng/mL to about 400 ng/mL; about 400 ng/mL to about 450 ng/mL; about 450 ng/mL to about 500 ng/mL; about 500 ng/mL to about 600 ng/mL; about 600 ng/mL to about 700 ng/mL; about 700 ng/m L to about 800 ng/mL; about 800 ng/mL to about 900 ng/mL; about 900 ng/mL to about 1,000 ng/mL; about 1,000 ng/mL to about 3,100 ng/mL; about 1,100 ng/mL to about 1,200 ng/mL; about 1,200 ng/mL to about 1,300 ng/mL; about 1,300 ng/mL to about 1,400 ng/mL; about 1,400 ng/mL to about 1,500 ng/mL; about 1,500 ng/mL to about 1,600 ng/mL; about 1,600 ng/mL to about 1,700 ng/mL; about 1,700 ng/mL to about 1,800 ng/mL; about ,800 ng/mL to about 1,900 ng/mL; or about 1,900 ng/mL to about 2,000 ng/mL.

Cancer Associated Conditions and Methods of Management In some embodiments, the present disclosure provides a process for preparing a composition, the composition comprising two or more compounds, wherein the compounds are Phosphodiesterase type 4 Inhibitor, Autophagy Inhibitor and AMPK Agonist.

The disclosure described herein provides therapeutic methods for the treatment of cancer and prophylactic methods for prevention of cancer, wherein the cancer condition is Myeioproliferativedisorder or any associated condition, or combinations thereof.

In one embodiment of the present disclosure, the disclosure provides a method for treating a subject either suspected of having or having a Myeloproliferative disorder or any associated condition or mutation or a combination thereof, selected from group comprising any cancer with JAK2V617F mutation OR JAK2 dominant profile, myeloproliferative disease (MPD) or myeloproliferative neoplasm (MPN), multiple myeloma, acute non lymphocytic leukemia or myelodysplasia or any combination of conditions thereof, or wherein said mutation is in genes selected from a group comprising JAK2V617F mutation, KRAS, NRAS, TP53, CDKN1A, BRAF, EGFR, B-catenin, CDKN2A, P13KCA, APC, MYC, BCL2, SOCS1, SOCS3 and SMAD4 or any combination of mutations thereof, said raethod comprising act of administering to the subject therapeutically effective amount of component selected from group comprising Autophagy inhibitor and Phosphodiesterase type 4 inhibitor or combination thereof, optionally along with therapeutically effective amount of AMPK agonist.

In some embodiments the disclosure provides a use of compounds or a combination of compounds in the preparation of a medicament for the treatment/management of myeloproliferative disorder or any associated condition, the compounds comprising Phosphodiesterase type 4 Inhibitor, Autophagy Inhibitor and AMPK Agonist.

In some embodiments the disclosure provides a use of compounds or a combination of compounds in the preparation of a kit for the treatment of myeloproliferative disorder or any associated condition, the compounds comprising Phosphodiesterase type 4 Inhibitor, Autophagy Inhibitor and AMPK Agonist.

Pharmaceutical compositions containing compounds described herein are administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compounds/compositions are administered to a subject already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition, or to cure, heal, improve, or ameliorate the condition itself. In prophylactic applications, the compounds/compositions are administered to a subject to avoid occurrence of disease/disorder, to increase resistance to disease/disorder, to detect and address an existing disease/disorder prior to the appearance of symptoms or to reduce negative impact of symptomatic disease.

Amounts effective for this use vary based on the severity and course of the disease or condition, previous therapy, the subject's health status, weight, and response to the drugs, and the judgment of the treating physician. Pharmaceutically-acceptable amounts are determined by routine experimentation, for example, by a dose escalation clinical trial.

Multiple therapeutic agents are administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents are provided in a single, unified form, or in multiple forms, for example, as multiple separate pills. The compounds are packed together or separately, in a single package or in a plurality of packages. One or all of the therapeutic agents are given in multiple doses. If not simultaneous, the timing between the multiple doses may vary to as much as about a month. In some embodiments compounds of the disclosure are administered sequentially at a time interval. The time interval ranges from about60seconds to about 720 minutes.

In embodiments, compounds and compositions of the present disclosure are packaged as a kit. In some embodiments, a kit includes written instructions on the use of the compounds and compositions. The instructions provide information on the identity of the therapeutic agent(s), modes of administration, or the indications for which the therapeutic agent(s) are used.

In some embodiments, therapeutics is combined with genetic or genomic testing to determine whether an individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions. A personalized medicine approach is used to provide companion diagnostic tests to discover a subject's predisposition to certain conditions and susceptibility to therapy. The companion diagnostic test is performed on a tissue sample of the subject, such as blood, hair, or skin. Instructions on the use of a companion diagnostic test are provided on written material packaged with a compound, composition, or kit of the present disclosure. The written material is, for example, a label. The written material suggests conditions or genetic features relevant to inflammation or the therapeutic compounds of the present disclosure. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy.

In an embodiment of the present disclosure, JA 2 mutation diagnostics is used for patient selection with the inclusion criteria being JAK2 mutant positive. JAK2:p.V617F mutation is detected using a specific quantitative real time PGR assay in bone marrow aspirates or plasma samples.

Compounds described herein are administered before during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound may vary. For example, the compounds are used as a prophylactic and are administered continuously to subjects with a propensity to conditions or diseases in order to prevent the occurrence of the disease or condition. The compounds and compositions may be administered to a subject during or as soon as possible after the onset of the symptoms. The initial administration is via any route practical, such as by any route described herein using any formulation described herein. A compound is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. The length of treatment varies for each subject, and the length is determined using the known criteria. Roflumilast is an example of a Phosphodiesterase type 4 inhibitor which is approved by the FDA and utilized in the composition, kit and method of the present disclosure. The present disclosure also provides other approved Phosphodiesterase tvpe 4 inhibitors such as Pielamilast, CDP 840, CP 80633, Etazolate, ICI 63197, Irsogladme, (R,S)-Mesopram, RO 20-1724, Rolipram, (R)-(-)-Rolipram, S-(+)~ Rolipram, CHEMBL1232082, YM 976 etc. However, the present disclosure also envisages the use of: » a compound not yet approved by the FDA as a Phosphodiesterase type 4 inhibitor, a compound that may be approved by the FDA at a later stage as a Phosphodiesterase type 4 inhibitor, a compound known in the art to be a Phosphodiesterase type 4 inhibitor but not approved by the FDA as a Phosphodiesterase type 4 inhibitor, and • a compound that might be proven at a later stage to be a Phosphodiesterase type 4 inhibitor, without approval by the FDA for the same.

Physicochemical properties & Mechanism of Action - C 70 - Autophagy Inhibitor -

The group/class of compounds it belongs to Chloroquine

Members of the group Chloraquine; Chlorochine; Chloroquina; Chloroquinium ; Chiorquin ; Clorochina

IUPAC name {4-[(7-chloroquinolin-4- yl)amino]pentyl }diethylamine

Other names Amokin ; Aralen ; Arechin ; Arthrochin Artrichin ; Avlochlor ; Avioclor ; Bemaco Bemaphate ; Bemasulph ; Benaquin ; Bipiquin Capquin ; Chemochin ; Chingamin Chiorochin Cidanchin ; Cocartrit ; Dawaquin : Delagii Dichinalex ; Elestol ; Gontochin ; Heliopar Imagon ; Iroquine ; Klorokin ; Lapaquin Malaquin ; Malaren ; Malarex Mesylith Neochin : Nivachine Nivaquine : Nivaquine B Quinachlor ; Quinagamin ; Quinagamine Quinercyl ; Quingamine ; Quinilon ; Quinoscan Resochen ; Resochin ; Resoquina ; Resoquine Reumachlor ; Reumaquin ; Roquine ; Sanoquin

2

chloroquine] which leads to cell lysis.

Absorption Completely absorbed from gasfrointestinai tract

Metabolism Hepatic (partially)

Half-life About 1-2 months

Route of elimination Urine

Chloroquine is an example of an Autophagy inhibitor which is approved by the FDA and utilized in the composition, kit and method of the present disclosure. The present disclosure also provides other approved Autophagy inhibitors such as Lueanthorie, LysOl , Lys02, Lys03, Lys04, Lys05, Hydroxychloroquine, Mefloquine, Quraacrme etc. However, the present disclosure also envisages the use of: a compound not yet approved by the FDA as an Autophagy inhibitor, a compound that may be approved by the FDA at a later stage as an Autophagy inhibitor, a compound known in the art to be an Autophagy inhibitor but not approved by the FDA as an Autophagy inhibitor, and a compound that might be proven at a later stage to be an Autophagy inhibitor, without approval by the FDA for the same.

Phvsicochemical properties & Mechanism of Acttion - CW178 - AMPK Agonist - represented by Metformin

Group/class of compounds it belongs to Metformin

Members of the group Metformin, Metformin HCL, metformin hydrochloride

IUPAC name 1-carbamimidamido-N ,N- dimethylmethanimidamide

Other names Apo-Metformin, Fortamet, Gen-Metformin, Glucophage, Glucophage XR, GlumetzaGlycon, Mylan-Metformin, Novo-Metformin, Nu~ Metformin, PMS-Metforrnin, Ran-Metformm, ora antihyperglycemic agents. Unlike sulfonylureas, Metformin does not produce hypoglycemia in either patients with N DDM or healthy subjects and does not cause hyperinsulinemia. Metformin does not affect insulin secretion.

Metformin's mechanisms of action differ from other classes of oral anti-hyperglycemic agents. Metformin decreases blood glucose levels by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization. These effects are mediated by the initial activation by Metformin of AMP- activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats. Activation of AMPK is required for Metformin's inhibitory effect o the production of glucose by liver cells. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors. Metformin administration also increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. The rare side effect, lactic acidosis, is thought to be caused by decreased liver uptake of serum lactate, one of the substrates of gluconeogenesis. In those with health}' renal function, the slight excess is simply cleared. However, those with severe renal impairment may accumulate clinically significant serum lactic acid levels. Other conditions that may precipitate lactic acidosis include severe hepatic disease and acute/decompensated heart failure.

Absorption Absorbed over 6 hours, bioavailability is 50 to 60% under fasting conditions. Administration with food decreases and delays absorption. Some evidence indicates that the level of absorption is not dose-related, suggesting that absorption occurs through a saturable process. Limited data from animal and human cell cultures indicate that absorption occurs through a passive, non-saturable process, possibly involving a paracellular route. Peak action occurs 3 hours after oral administration.

Metabolism Metformin is not metabolized.

Half-life 6.2 hours. Duration of action is 8- hours

Route of elimination Intravenous single-dose studies in normal subjects demonstrate that Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Approximately 90% of the drug is eliminated in 24 hours in those with healthy renal function. Renal clearance of Metformin is approximately 3.5 times that of creatinine clearance, indicating the tubular secretion is the primary mode of metformin elimination.

Metformin is a example of an AMPK Agonist which is approved by the FDA and utilized in the composition, kit and method of the present disclosure. The present disclosure also provides other approved AMPK Agonists such as Phenformin, Panduratin, AICAR, B-lapaehone, AMPK activator (CID16760291), A769662 etc. However, the present disclosure also envisages the use of: » a compound not yet approved by the FDA as an AMPK Agonist, a compound that may be approved by the FDA at a later stage as an AMPK Agonist, a compound known in the art to be an AMPK Agonist but not approved by the FDA as an AMPK Agonist, and a compound that might be proven at a later stage to be an AMPK Agonist, without approval by the FDA for the same. e claim:

1) A composition comprising at least two components selected from a group comprising: a.a phosphodiesterase type 4 inhibitor; b.an autophagy inhibitor; and n AMPK Agonist; optionally along with pharmaceutically acceptable excipient

2) The composition as claimed in claim 1, wherein the composition comprises a phosphodiesterase type 4 inhibitor and an autophagy inhibitor, optionally along with pharmaceutically acceptable excipient

3) The composition as claimed in claim 1, wherein the composition comprises a phosphodiesterase type 4 inhibitor and an AMPK Agonist, optionally along with pharmaceutically acceptable excipient.

4) The composition as claimed in claim 1, wherein the composition comprises an autophagy inhibitor and an AMPK Agonist, optionally along with pharmaceutically acceptable excipient.

5) The composition as claimed in claim 1 wherein, the composition comprises a phosphodiesterase type 4 inhibitor; an autophagy inhibitor; and an AMPK Agonist; optionally along with pharmaceutically acceptable excipient.

6) The composition as claimed in claim 1, wherein the phosphodiesterase type 4 inhibitor is inhibitor used for treating Chronic Obstructive Pulmonary Disease (COPD); the autophagy inhibitor is anti-malarial agent and the AMPK agonist is anti-diabetic agent.

7) The composition as claimed in claim I, wherein the Phosphodiesterase type 4 inhibitor is selected from group comprising Roflumilast, Piclainilast, CDP 840, CP 80633, Etazolate, ICI 63197, irsogladine, (R,S)~Mesopram, RO 20-1724, Rolipram, (R)-(-)-Rolipram, S-(+)~ Rolipram, CHEMBL1 232082, YM 976 and pharmaceutically-acceptable salt of any of the foregoing, or any combinations thereof. 8) The composition as claimed in claim , wherein the autophagy inhibitor is selected from group comprising Chloroquine, Lucanthone, LysOl, Lys02, LysG3, Lys04, Lys05, Hydroxychloroquine, Mefloquine, Quinacrine and pharmaceutically-acceptable salt of any of the foregoing, or any combinations thereof.

9) The composition as claimed in claim 1, wherein the AMPK Agonist is selected from group comprising Metformin, Phenformin, Panduratin, A CA , B-lapachone, AMPK activator (C D 6760291), A769662 and pharmaceutically-acceptable salt of any of the foregoing, or any combinations thereof.

10) The composition as claimed in claim 1, wherein the Phosphodiesterase type 4 inhibitor is Roflumilast, the autophagy inhibitor is Chloroquine and the AMPK Agonist is Metformin.

) The composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient is selected from group comprising granulating agent, binding agent, lubricating agent, disintegrating agent, sweetening agent, glidant, anti-adherent, anti-static agent, surfactant, anti oxidant, gum, coating agent, coloring agent, flavouring agent, coating agent, plasticizer, preservative, suspending agent, emulsifying agent, plant cellulosic material, spheronization agent, immediate release agent, controlled release agent, sustained delayed release agent, or any combinations thereof.

2) The composition as claimed in claim , wherein the composition is formulated into dosage form selected from group comprising feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, microgel, suppository troche, aqueous or oily suspension, ointment, patch, lotion, dentifrice, emulsion, cream, drop, dispersible powder or granule, emulsion in hard or soft gel capsule, syrup, phytoceutical, nutraceutical, or any combinations thereof.

13) The composition as claimed in claim 1, wherein the composition is in dosage form having an immediate release, a controlled release, or a sustained delayed release mechanism. 4) The composition as claimed in claim 1, wherein the composition is in dosage form formulated for intravenous, subcutaneous intramuscular, oral, rectal, aerosol parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, or topical administration.

15) A kit comprising at least two components selected from a group comprising phosphodiesterase type 4 inhibitor, autophagy inhibitor; and AMPK Agonist; optionally along with pharmaceutically acceptable excipient; wherein the kit comprises one or plurality of dosage forms

16) A method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of component selected from group comprising autophagy inhibitor and Phosphodiesterase type 4 inhibitor or combination thereof, optionally along with therapeutically effective amount of AMPK agonist; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient.

17) Use of phosphodiesterase type 4 inhibitor or autophagy inhibitor or combination thereof, optionally along with AMPK Agonist, in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition.

18) A process of preparing composition as claimed in claim 1, said process comprising act of combining at least two components selected from a group comprising phosphodiesterase type 4 inhibitor autophagosome inhibitor and AMPK Agonist: optionally along with pharmaceutically acceptable excipient; in any ratio, any concentration or any order thereof to obtain the composition as claimed in claim .

9) The kit, the method, the use and the process as claimed in any of the claims 15 to 18, wherein the Phosphodiesterase type 4 inhibitor is inhibitor used for treating Chronic Obstructive Pulmonary Disease (COPD); the autophagy inhibitor is anti-malarial agent and the AMPK Agonist is anti-diabetic agent.

20) The kit, the method, the use and the process as claimed in any of the claims 15 to 18, wherein the Phosphodiesterase type 4 inhibitor is selected from group comprising Roflumilast, Piclamilast, CDP840, CP 80633, Etazolate, C 63197, irsogladine, (R,S)-Mesopram, RO 20- 1724, Rolipram, (R)-(-)~Rolipram, S-(+)-Rolipram, CHEMBL1 232082, YM 976 and pharmaceutical! y-acceptable salt of any of the foregoing, or any combinations thereof.

21) The kit, the method, the use and the process as claimed in any of the claims 15 to 18, wherein the autophagy inhibitor is selected from group comprising Chloroquine, Lucanthone, LysOl, Lys02, Lys03, Lys04, LysOS, Hydroxychloroquine, Mefloquine, Quinacrine and pharmaceutically-acceptable salt of any of the foregoing, or any combinations thereof

22) The kit, the method, the use and the process as claimed in any of the claims 5 to 8, wherein the AMPK agonist is selected from group comprising Metformin, Phenforaiin, Panduratin, AICAR, AMPK activator (C1D16760291), B-lapachone, A769662 and pharmaceutically- acceptable salt of any of the foregoing, or any combinations thereof.

23) The kit, the method, the use and the process as claimed in any of the claims 15 to 18, wherein the Phosphodiesterase type 4 inhibitor is Roflumilast, the autophagy inhibitor is Chloroquine and the AMPK agonist is Metformin.

24) The method and the use as claimed in any of the claims 6 to 17, wherein Myeloproliferative Disorder is a condition comprising mutation in Janus kinase 2, wherein said mutation is selected from a group comprising V617F, K539L and T875N, or any combinations thereof.

25) The method and the use as claimed in any of the claims 16 to 17, wherein said Myeloproliferative Disorder or any associated condition is selected from group comprising any cancer with JAK2V617F mutation, any cancer with JAK2 dominant profile, Essential Thrombocythemia, Polycythemia Vera, Myelofibrosis, Multiple myeloma, Acute non lymphocytic leukemia, Myelodysplasia or any combination of conditions thereof, or any condition having a mutation therein.

26) The method and the use as claimed in claim 25, wherein said mutation is a JAK2V617F mutation or JAK2V617F mutation in combination with gene mutation selected from a group comprising KRAS, NRAS, TP53, CDKNI A, BRAF, EGFR, B-catenin, CDKN2A, P33KCA, APC. MYC, BCL2, SOCS1 , SOCS3 and SMAD4 or any combinations thereof.

27) The method as claimed in claim 16, wherein the therapeutically effective amount of the Phosphodiesterase type 4 inhibitor is from about 10% to about 99% of a maximum tolerated dose; the therapeutically effective amount of the autophagy Inhibitor is from about 10% to about 99% of a maximum tolerated dose; and the therapeutically effective amount of the AMPK Agonist is from about 10% to about 99% of a maximum tolerated dose.

28) The method as claimed in claim 16, wherein the therapeutically effective amount of the Phosphodiesterase type 4 inhibitor is from about I mg to about 2000 mg; the therapeutically effective amount of the autophagy Inhibitor is from about mg to about 2000 mg; and the therapeutically effective amount of the AMPK Agonist is from about 1 mg to about 2000 mg.

29) A composition comprising at least two compounds selected from a group comprising:

a. a compound of formula I, a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V; b. a compound of formula VI or a compound of formula VII; and c. a compound of formula VIII; optionally along with pharmaceutically acceptable excipient.

30) A method for managing Myeloproliferative Disorder or any associated condition in a subject, said method comprising act of administering to the subject, therapeutically effective amount of compound selected from a group comprising;

a. a compound of formula I, a compound of formula II, a compound of formula III a compound of formula IV or a compound of formula V; and a compound of formula VI or a compound of form a VII; or a combination thereof; b. optionally along with a compound of formula VIII; wherein the administration is using one or plurality of dosage forms, each dosage form comprising one or more components, and wherein each dosage form optionally further comprises pharmaceutically acceptable excipient.

31) Use of compound selected from a group comprising: a. a compound of formula I, a compound of formula II, a compound of fonnula III, a compound of formula IV or a compound of formula V; and a compound of formula VI or a compound of form a VII; or a combination thereof; b. optionally along with a compound of formula VIII; in preparation of a medicament for management of Myeloproliferative Disorder or any associated condition.

32) The composition, the method and the use as claimed in any of the claims 29 to 3 , wherein the compound of formula I, the compound of Formula II, the compound of formula III, the compound of formula IV or the compound of formula V or pharmaceutically-acceptable salt of any of the foregoing, is a phosphodiesterase type 4 inhibitor.

33) The composition, the method and the use as claimed in any of the claims 29 to 31, wherein the compound of fonnula VI or the compound of formula VII or pharraaceutically-acceptable salt of any of the foregoing, is an autophagy inhibitor.

34) The composition, the method and the use as claimed in any of the claims 29 to 31, wherein the compound of formula VIII, or its pharmaceutically-acceptable salt is an AMPK Agonist.

35) The composition, the method and the use as claimed in any of the claims 29 to 31, wherein the compound of formula I, the compound of formula II, the compound of formula III, the compound of formula IV or the compound of formula V is used for treating Chronic Obstructive Pulmonary Disease (COPD); the compound of formula VI or the compound of formula VII is anti-malarial agent and the compound of formula VIII is anti-diabetic agent.

36) The composition the method and the use as claimed in any of the claims 29 to 31, wherein the compound of formula I is: Wherein, A is selected fromj

C(0)NH -A4, S(0) 2 And where

q is 0, 1, 2 or 3;

A 3 is selected from unsaturated, saturated, partially saturated, aryl and heteroaryl, each of which is optionally substituted by keto group;

A4, A5, A is selected frora alkyl, alkylheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted completely or partially by halogen; and

Ai, A are individually selected from alkyl, aikoxy, cycloalkylmethoxy (or cycioaikylalkoxy), cycioalkoxy, bicycloxy andaryloxy, each of which is optionally substituted completely or partially by halogen.

37) The composition, the method and the use as claimed in any of the claims 29 to 31, wherein the compound of formula II is:

Wherein E is selected from N and C¾; and

E , E , E 3 are individually selected from amino, alkyl, aryi and heteroaryl, each of which is optionally substituted.

38) The composition, the method and the use as claimed in any of the claims 29 to 31, wherein the compound of formula III is:

Wherein, E , E , E are individually selected from N and CH ; E is selected from hydrogen and alkyl; E is NH; and ally selected from hydrogen; and

, where E ,E are individually selected from oxygen and sulphur.

39) The composition, the method and the use as claimed in any of the claims 29 to 31, wherein the com ound of formula IV is:

Wherein,E 14, E16 are individually selected from hydrogen and alkyl; E ,E are individual!}' selected from N and CH; and

E is selected from oxygen and sulphur.

40) The composition, the method and the use as claimed in any of the claims 29 to 31, wherein the compound of formu

Wherein, P is selected from hydrogen, alky], alkvlheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted; is selected from

, alkyl, alkvlheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted; R is selected from hydrogen alkyl, alkvlheteroaryl, alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted; and S is selected from oxygen alkyl, alkylheteroarvl alkaryl, aralkyl, aryl and heteroaryl, each of which is optionally substituted by halogen.

41) The composition, the method and the use as claimed in any of the claims 29 to 31, wherein the com oun of formula VI is:

Wherein, X is selected from N N =0 and CH; L is selected from halogen, hydrogen, a halogen-containing group, alkyl and alkoxy;

is R -NH 2, an where R is a chemical bond, alkyl, cylcoalkyl, sulfonyl, carbonyl; and

I S Wherein, m is selected from 0, 1, 2, 3, 4 and 5;

n is selected from 0, 1, 2 , 3, 4 and 5; Y is selected from -R and O;

Z is selected from N and CH2; and R3, R4, R5, R6, R7, R7, R8, R9, R O and R l is individually selected from hydrogen, a ky , alkoxy, aryl, alkarvl, aralkvl and heteroaryl, each of which are optionally substituted.

42) The composition the method and the use as claimed in any of the claims 29 to 31, wherein the compound of formula VII is:

Wherein, V, W is individually selected from oxygen and sulphur; t is selected from 0, , 2, 3, 4 and 5; and R14, R15, R16 and R17 is individually selected from hydrogen, alkyl, alkoxy, aryl, alkaryl, araikyl and heteroaryl, each of which are optionally substituted.

43) The composition, the method and the use as claimed in any of the claims 29 to 31, wherein the compound of formula VIII is: wherein: n is an inte ranging between1 to 4.