NZ727214B2 - Substituted chromene derivatives as selective dual inhibitors of pi3 delta and gamma protein kinases - Google Patents

Abstract

The present invention relates to a selective dual delta (?) and gamma (?) PI3K protein kinase modulator (S)-N-(5-(4-amino-1-(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-4H- chromen-2-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl) methane sulfonamide, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them. compositions containing them and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them.

Description

(12) Granted patent specificaon (19) NZ (11) 727214 (13) B2 (47) Publicaon date: 2021.12.24 (54) SUBSTITUTED CHROMENE TIVES AS SELECTIVE DUAL INHIBITORS OF PI3 DELTA AND GAMMA PROTEIN KINASES (51) Internaonal Patent Classificaon(s): C07D 487/04 A61K 31/519 A61P 35/00 A61P 37/00 (22) Filing date: (73) Owner(s): 2015.06.26 RHIZEN PHARMACEUTICALS SA (23) Complete specificaon filing date: (74) Contact: 6.26 Spruson & Ferguson Pty Ltd (30) aonal Priority Data: (72) Inventor(s): IN 3144/CHE/2014 2014.06.27 VAKKALANKA, Swaroop Kumar Venkata Sat (86) Internaonal Applicaon No.: BHAVAR, Prashant Kashinath (87) aonal aon number: WO/2015/198289 (57) Abstract: The present invenon relates to a selecve dual delta (δ) and gamma (γ) PI3K protein kinase modulator (S)-N-(5-(4-amino(1-(5-fluoro(3-fluorophenyl)oxo-4H- chromenyl)ethyl)-1H- pyrazolo[3,4-d]pyrimidinyl)methoxyphenyl) e sulfonamide, methods of preparing them, pharmaceucal composions containing them and methods of treatment, prevenon and/ or amelioraon of PI3K kinase mediated diseases or disorders with them. 727214 B2 TUTED CHROMENE DERIVATIVES AS SELECTIVE DUAL INHIBITORS OF Pl3 DELTA AND GAMMA PROTEIN KINASES The present application claims the benefit of Indian Patent Application No. 3144/CHE/2014, filed June 27, 2014 which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION The present invention provides dual delta (8) and gamma (y) PI3K protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and s of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders using them.

OUND OF THE INVENTION Phosphoinositide-3 kinase (PI3K) belongs to a class of intracellular lipid s that phosphorylate the 3-position hydroxyl group of the inositol ring of phosphoinositide lipids (PIs) generating lipid second messengers. While 0c and B isoforms of PI3K are ubiquitous in their bution, expression of 5 and y forms of PI3K is restricted to circulating haematogenous cells and endothelial cells. Unlike PIBKOL or PI3KB, mice lacking expression of PI3K5 or PI3K7 do not show any adverse phenotype ting that targeting of these specific isoforms would not result in overt toxicity.

Recently, targeted inhibitors of the PI3K y have been ted as immunomodulatory agents. This interest stems from the fact that the PI3K pathway serves multiple functions in immune cell signaling, primarily through the generation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), a membrane bound second ger.

PIP3 recruits proteins to the cytoplasmic side of the lipid bilayer, including protein kinases W0 2015/198289 and GTPases, ting a complex network of downstream ing cascades important in the regulation of immune cell on, migration, and cell-cell communication.

The four class I PI3K isoforms differ significantly in their tissue distribution. P13Ka and PI3KB are ubiquitous and ted downstream of receptor tyrosine kinases (RTK), whereas PI3K5 and PI3Ky are primarily limited to hematopoietic and endothelial cells, and are activated downstream of RTKs, and G protein coupled receptors (GPCR), respectively. Mouse genetic studies have revealed that PI3KOL and PI3KB are essential for normal development, s loss of PI3K5 and/or PI3Ky yields viable offspring with selective immune deficits.

The expression pattern and functions of PI3K8 and PI3Ky have generated much interest in developing PI3K8/y inhibitors as active agents for the treatment of many diseases, including, for e, rheumatoid arthritis, allergies, asthma, chronic obstructive pulmonary disease and le sclerosis (Hirsch et al., Pharmacol. Ther., 118, 192—205, 2008; Marone et al., Biochim. s. Acta., 1784, 159—185, 2008; Rommel et al., Nat. Rev. Immunol., 7, 191—201, 2007; Ruckle et al., Nat. Rev. Drug Discov., 5, 903— 918, 2006). Studies using both pharmacologic and genetic methods have shown these two isoforms often demonstrate synergistic ctions with each other (Konrad et al., J. Biol.

Chem, 283, 33296—33303, 2008; Laffargue et al., Immunity, 16, 441—451, 2002). In mast cells, for example, PI3K6 is essential for degranulation in response to IgE cross—linking of Fc-receptors (Ali et al., J. Immunol., 180, 2538—2544, 2008), while PI3Ky plays an important role in amplifying the response (Laffargue et al., Immunity, 16, 1, 2002).

Similar effects have been seen in other cellular functions, ing lymphocyte homing and the neutrophil respiratory burst where PI3Ky plays a critical role and PI3K5 amplifies each process. The nonredundant but related roles of PI3K5 and PI3Ky have made it difficult to determine which of the two isoforms (alone or in combination) is best targeted in a particular atory disorder.

Studies using mice that lack PI3K5 and/or PI3Ky or express kinase—dead variants of PI3K8 and PI3Ky have been valuable tools in understanding their roles. For example, PI3K5 knockout mice demonstrated diminished neutrophil chemotaxis, diminished antibody production (both T cell dependent and independent) (Jou et al., Mol.

Cell.Bi0£., 22, 8580—8591, 2002), and lower numbers of mature B cells on et al., J.

Exp. Med, 196, 753—763, 2002; Jou et al., Mal. Cell.Bi0l., 22, 8580—8591, 2002), and a decrease in their proliferation in response to anti-IgM (Jou et al., Mol. Cell.Biol., 22, 8580—8591, 2002). This ype was replicated in the PI3K5 kinase-dead t and with PI3K5 selective inhibitors along with a decreased number and proliferation of mast cells, and an attenuated allergic response. The PI3Ky knockout ned higher numbers of, but less responsive, neutrophils, lower numbers of and less responsive macrophages, and dendritic cells displayed decreased mast cell degranulation (Laffargue et al., ty, 16, 441—451, 2002), a higher ratio of CD4+ to CD8+ T cells, sed thymocyte apoptosis, diminished ion of CXCR3 on activated T cells and decreased cardiac contractility. This latter effect on cardiac tissue was a concern for chronic dosing of patients with PI3Ky tors. However, this concern was largely mitigated when the PI3Ky kinase-dead variant (which better mimics inhibition of the kinase rather than loss of the protein) showed similar immune cell phenotypes, but importantly had no cardiac defects. The cardiac effect was later shown to be due to scaffolding effects rather than the catalytic activity of PI3Ky (Olusegon et al., Chemistry & Biology, 1, 123-134, 2010, including the references cited n). The dual PI3K5/PI3Ky knockout was viable but exhibited serious defects in T cell development and thymocyte survival. The PI3Ky knockout/PI3K5 kinase—dead combination ed a similar ype suggesting that at least within the immune system, the role of PI3K8 is likely only a catalytic one.

Interpretation of studies using knockout and kinase-dead mice can be challenging because these models provide only a steady-state picture of the immune system, lack temporal and dose l, and do not permit a full understanding of how a dynamic immune response will react to reversible inhibition. Selective inhibitors with g profiles (PI3K8, P13Ky, and P13 K5/y) are necessary for studies of leukocyte signaling in order to assess the relative contributions of each PI3K to immune cell activation gon et al., supra, including the references cited therein).

Dual inhibition of Sly is ly implicated as an intervention strategy in allergic and non-allergic inflammation of the airways and other autoimmune diseases.

Scientific evidence for PI3K5 and PI3K y involvement in various cellular processes underlying asthma and chronic obstructive pulmonary disease (COPD) stems from inhibitor studies and gene-targeting approaches (William etal Chemistry & Biology, 17, 123-134, 2010 and Thompson, et (11. try & Biology, 17:101-102, 2010). Also, resistance to conventional therapies such as corticosteroids in several COPD patients has been uted to an up-regulation of the PI3K Sly pathway. Disruption of PI3K5/y signalling therefore provides a novel strategy aimed at counteracting the immuno— inflammatory response. Due to the pivotal role played by PI3K5 and PI3Ky in mediating inflammatory cell onality such as leukocyte migration and activation, and mast cell degranulation, blocking these ms may also be an effective strategy for the treatment of rheumatoid arthritis as well. Given the established criticality of these isoforms in immune surveillance, inhibitors specifically targeting the PI3K6 and PI3Ky isoforms would be expected to attenuate the progression of immune response encountered in airway inflammation and rheumatoid arthritis (William et.al Chemistry & Biology, 17, 123-134, 2010 and Thompson, et al. Chemistry & Biology, 17:101—102, 2010) Reviews and studies regarding PI3K and d n kinase pathways have been given by Liu et al., Nature Reviews Drug Discovery, 8, 627-644, 2009); Nathan et. al., Mol Cancer Ther., 8(1), 2009; Marone et al., Biochimica et Biophysica Acta, 1784, 159-185, 2008 and Markman et al., Annals of Oncology e Access, published August 2009. Similarly reviews and studies regarding role of PISKS and PI3Kv have been given by m et al., Chemistry & Biology, 17, 4, 2010 and Timothy et al. J.

Med. Chem, 55 (20), 581, 2012. All of these literature disclosures are hereby incorporated by reference in their entirety.

Compounds such as IPI—145 and CAL130 have been reported as dual inhibitors of Pi3K S/y (WO2012/008302 & WO2012/121953 respectively).IPI-145 is under clinical investigation for cancer, asthma and rheumatoid arthritis. IPI-45 has been reported to have a maximum tolerated dose (MTD) of 75 mg BID (55th ASH® Annual g. New Orleans—LA, Dec 7-10, 2013). There are no reports of CAL-130 being investigated for clinical purposes.

There still remains an unmet need for dual S/v PI3K modulators for the treatment of diseases and disorders associated with S/y PI3K kinases-mediated .

Further reference is made herein to International Publication Nos. WO 11/055215 and WO 12/151525 and US. Publication Nos. 2011/0118257 and 289496, each of which is incorporated herein by reference in its entirety.

SUMMARY OF THE INVENTION [12a] According to a first aspect, the invention relates to a compound selected from N-(5-(4- amino-l-(l-(5-fluoro(3-fluorophenyl)oxo-4H-chromenyl)ethyl)-lH-pyrazolo[3,4- d]pyrimidinyl)methoxyphenyl)methanesulfonamide and pharmaceutically acceptable salts thereof. [12b] According to a second aspect, the invention relates to a pharmaceutical composition comprising a compound ing to the ion and at least one pharmaceutically acceptable carrier. [12c] According to a third aspect, the invention relates to a use of a compound according to the invention or a pharmaceutical composition according to the ion, in the manufacture of a medicament for inhibiting a catalytic activity of a PI3δ kinase in a cell. [12d] According to a fourth aspect, the invention relates to use of a compound according to the invention or a pharmaceutical composition according to the invention, in the manufacture of a medicament for inhibiting a catalytic activity of a PI3γ kinase in a cell. [12e] According to a fifth aspect, the invention relates to use of a compound according to the invention or a pharmaceutical ition according to the ion, in the manufacture of a medicament for inhibiting a catalytic activity of a ΡΙ3δ kinase and ΡΙ3γ kinase in a cell. [12f] According to a sixth aspect, the ion relates to use of a compound of the invention or a pharmaceutical composition according to the invention, in the manufacture of a medicament for treating leukemia. [12g] According to a h aspect, the ion relates to use of a compound of the invention or a pharmaceutical composition according to the invention, in the manufacture of a medicament for ng asthma or chronic obstructive ary disease. [12h] According to an eighth aspect, the invention relates to use of a compound of the invention or a ceutical composition according to the ion, in the manufacture of a medicament for ng rheumatoid arthritis, psoriasis, lupus or experimental autoimmune encephalomyelitis (EAE). [12i] According to a ninth aspect, the invention relates to use of a compound of the invention or a pharmaceutical composition according to the invention, in the cture of a medicament for treating chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) acute myeloid leukemia (AML), multiple myeloma (MM), small lymphocytic lymphoma (SLL), or indolent non-Hodgkin's lymphoma (I-NHL) disease. [12j] ing to a tenth aspect, the ion relates to use of a compound of the invention or a pharmaceutical composition according to the invention, in the manufacture of a medicament for the treatment of a disease, disorder or condition that would benefit from inhibiting catalytic activity of a PI3δ/γ kinase. [12k] According to an eleventh aspect, the ion relates to use of a compound of the invention or a pharmaceutical composition according to the invention, in the manufacture of a medicament for the treatment of a PI3K ated e, disorder or condition. [12l] ing to a twelfth aspect, the invention relates to a compound selected from (S)(l-(4-amino(4-methoxynitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)- -fluoro(3-fluorophenyl)-4H-chromenone, (S)(l-(4-amino(3-aminomethoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidin-lyl )ethyl)fluoro(3-fluorophenyl)-4H-chromenone, and salts thereof. [12m] According to a thirteenth aspect, the invention relates to a process for the preparation of a compound of formula (I) comprising the steps of: (a) reacting 5 -bromomethoxy aniline with methane sulphonyl de to give N-(5-bromomethoxyphenyl)methanesulfonamide (Intermediate 1) Intermediate 1; (b) reacting ediate 1 with bis(pinacolato)diboron to give N-(2-methoxy(4,4,5, 5- tetramethyl- 1 ,3,2-dioxaborolanyl)phenyl)methanesulfonamide mediate 2) Intermediate 2; (c) reacting 2-(l-(4-aminoiodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)fluoro(3- fluorophenyl)-4H-chromenone with intermediate 2 in the presence of a suitable base to give a compound of formula (I). [12n] According to a fourteenth aspect, the invention relates to a process for the preparation of a compound of formula (Al) (Al) comprising the steps of: (a) reacting fluoro(3-fluorophenyl)(l-hydroxyethyl)-4H-chromenone with 3-(4-methoxynitrophenyl)- -pyrazolo[3,4-d]pyrimidinamine under Mitsunobu conditions using triphenylphosphine and dusopropylazodicarboxylate to give (S)(l-(4-amino(4-methoxynitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl) fluoro(3-fluorophenyl)-4H-chromenone (Intermediate 3) ediate 3; (b) reducing intermediate 3 to give (S)(l-(4-amino(3-aminomethoxyphenyl)- lH^yrazolo[3,4-d]pyrimidin-l-yl)ethyl)fluoro(3-fluorophenyl)-4H-chromenone (Intermediate 4) Intermediate 4; reacting Intermediate 4 with methanesulphonyl chloride to give a nd of the formula (A1). [12o] According to a fifteenth aspect, the ion relates to a compound of a (I) produced by the process of the invention. [12p] According to a sixteenth aspect, the invention relates to a compound of formula (A1) produced by the process of the invention.

The present invention is directed to selective dual inhibitors of PI3K delta () and gamma (γ) protein kinases. These compounds are suitable for use in a pharmaceutical composition for the treatment of PI3K ated diseases, disorders or conditions, e.g., a proliferative disease such as 5d ed by page 6 cancer. Inhibition of both PI3Kδ and PI3Kγ protein s may provide cial effects in the treatment of certain diseases and disorders.

The selective dual inhibitors of the present ion include N-(5-(4-amino(1-(5-fluoro- 3-(3-fluorophenyl)oxo-4H-chromenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidinyl) methoxyphenyl)methanesulfonamide, pharmaceutically acceptable salts thereof, and prodrugs thereof. For example, the selective dual inhibitor may be selected from the following compounds, pharmaceutically acceptable salts thereof, and prodrugs thereof: (RS)-N-(5-(4-amino(1-(5-fluoro(3-fluorophenyl)oxo-4H-chromenyl) ethyl)- 1H-pyrazolo[3,4-d]pyrimidinyl)methoxyphenyl)methanesulfonamide (Compound A); and (5-(4-amino(1-(5-fluoro(3-fluorophenyl)oxo-4H-chromenyl) ethyl)-1H- pyrazolo[3,4-d]pyrimidinyl)methoxyphenyl)methanesulfonamide (Compound A1).

In one embodiment, the compound (S)-N-(5-(4-amino(1-(5-fluoro(3-fluorophenyl) oxo-4H-chromenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidinyl) methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof is ntially free (e.g., contains less than about 10%, such as less than about 5%, less than about 2.5%, less than about 1%, less than about 0.1% by weight) or is free of (5-(4-amino(1-(5-fluoro(3- fluorophenyl)oxo-4H-chromenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidinyl) methoxyphenyl)methanesulfonamide and pharmaceutically acceptable salts thereof.

In another embodiment, the compound (S)-N-(5-(4-amino(1-(5-fluoro(3- fluorophenyl)oxo-4H-chromenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidinyl) methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof has an enantiomeric excess of greater than about 90%, such as greater than about 91%, greater than about 92%, greater than about 93%, greater than about 94%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.5%, r than about 99.9%, or greater than about 99.99%.

In one preferred embodiment, the present invention relates to the compound (S)-N—(5-(4-amino- l -( l -(5-fluoro(3-fluorophenyl)oxo-4H-chromen—2-yl) ethyl)- l H— pyrazolo[3,4-d]pyrimidinyl)—2-methoxyphenyl)methanesulfonamide (Compound Al).

In another embodiment, the present invention s to the compound (S)— N—(S—(4-amino- l -( l -(5—fluoro-3—(3-fluorophenyl)oxo—4H-chromenyl)ethyl)— 1H- pyrazolo [3,4-d]pyrimidin—3-yl)methoxyphenyl)methanesulfonamide or a pharmaceutically acceptable salt thereof.

Another ment of the present invention is (R)-N—(5-(4-amino(1-(5- fluoro(3-fluorophenyl)oxo-4H-chromenyl) -lH-pyrazolo[3,4-d]pyrimidin-3— yl)-2—methoxyphenyl)methanesulfonamide (Compound A2), a pharmaceutically acceptable salt thereof, or prodrug thereof. Compound A2 is an inhibitor of PI3K delta (5) n kinase. These compounds are le for use in a pharmaceutical composition for the treatment of PI3K associated diseases, disorders or conditions, e.g., a proliferative disease such as cancer.

The chemical structures of N-(S-(4-amino-l-(1-(5-flu0ro(3— fluorophenyl)oxo-4H-chromen-2—yl) ethyl)- l H-pyrazolo[3 ,4-d]pyrimidinyl) methoxyphenyl)methanesulfonamide, compound A1, and nd A2 are shown below.

M50 HN‘SOZMe MeO HN‘SOZMe (A1) (A2) The present invention further provides a pharmaceutical composition comprising one or more compounds of the present invention (such as compound A1) together with a pharmaceutically acceptable carrier. The pharmaceutical composition may further comprise one or more of additional active agents (such as anti-cancer agents and the active agents discussed below). In one embodiment, the pharmaceutical ition includes a eutically effective amount of one or more compounds of the t invention.

Another aspect of the present invention relates to a process for the preparation of N-(5-(4—amino—1—(1-(5-fluoro-3—(3-fluor0phenyl)—4-oxo-4H-chromenyl) ethyl)—lH-pyrazolo[3,4—d]pyrimidinyl)methoxyphenyl)methanesulfonamide: The process ses the steps of: (a) reacting 5-bromomethoxyaniline with methane sulphonyl chloride to give N-(5-bromo-2— methoxyphenyl)methanesulfonamide (Intermediate 1): Intermediate 1; (b) ng Intermediate 1 with bis(pinacolato)diboron, for example in the presence of potassium acetate, to give N-(2-methoxy(4,4,5,5-tetramethyl-l,3,2- dioxaborolan—2-yl)phenyl)methanesulfonamide (Intermediate 2): O\B/O \S/IO // \N 0 H Intermediate 2; and (c) reacting 4—amino—3—iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-5— fluoro—3-(3-fluorophenyl)-4H-chromenone with intermediate 2 in the presence of a base (such as, for example, sodium carbonate) to give the desired compound N-(S-(4-amino(l-(5-fluoro(3-fluorophenyl)oxo-4H- chromenyl) -lH-pyrazolo[3,4-d]pyrimidinyl)—2— methoxyphenyl)methanesulfonamide; (d) optionally converting 4-amino-l-(l—(5-fluoro(3-fluorophenyl) oxo—4H—chromenyl) ethyl)— l H-pyrazolo[3 ,4—d]pyrimidinyl)—2- methoxyphenyl)methanesulfonamide to a pharmaceutically acceptable salt thereof or prodrug thereof.

Yet another embodiment relates to a process for preparation of a compound of formula (A1): (A1).

The process comprises the steps of: (a) ting (R)—5—fluoro—3-(3-fluorophenyl)(l—hydroxyethyl)-4H— chromenone: to a Mitsunobu reaction with 3-(4-methoxy-3—nitrophenyl)-lH—pyrazolo[3,4-d]pyrimidin— ,N N N | \ \ N (for example, in the presence of triphenylphosphine and diisopropylazodicarboxylate) to give (S)-2—( l -(4-amino(4-methoxynitropheny1)- l H-pyrazolo[3,4—d]pyrimidin- l- yl)ethyl)fluoro(3—fluorophenyl)—4H-chromenone (Intermediate 3): Intermediate 3; (b) reducing Intermediate 3, for example with a ng agent such as Raney Ni, to give (S)—2-(l-(4—amino-3—(3-aminomethoxyphenyl)-lH—pyrazolo[3,4- d]pyrimidin-l—yl)ethyl)—5-fluoro(3-fluorophenyl)-4H-chromen—4-one (Intermediate 4): Intermediate 4; (c) treating Intermediate 4 with methanesulphonyl chloride to give the desired compound of the formula (A1); and (d) optionally converting compound (Al) to a pharmaceutically acceptable salt thereof or prodrug thereof.

Yet another ment are intermediates useful for preparing the compounds of the present invention such as (S)(l-(4-amino-3—(4—methoxy henyl)-1H-pyrazolo[3,4-d]pyrimidiny1)ethyl)fluoro(3-fluoropheny1)-4H— chromenone, (S)(l-(4-amino(3-amino-4—methoxyphenyl)-lH-pyrazolo[3,4— d]pyrimidin—1—yl)ethyl)—5-fluoro(3—fluorophenyl)-4H—chromenone, and salts thereof.

Yet another embodiment of the present invention is a method of inhibiting PI3K5 and PI3Ky in a t comprising administering to the patient an effective amount of at least one compound of the present invention.

Yet another embodiment of the present invention is a method of inhibiting PI3K5 in a patient comprising administering to the patient an effective amount of at least one of (R)-N-(5-(4-amino—l-(l-(5-fluoro-3—(3-fluorophenyl)—4-oxo-4H-chromenyl) ethyl)—1H-pyrazolo[3,4—d]pyrimidinyl)—2-methoxyphenyl)methanesulfonamide und A2), a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Yet r embodiment of the present invention is a method of treating, preventing, and/or inhibiting a PI3K protein kinase mediated disease, disorder or condition (such a proliferative disease or disorder, e.g., cancer) in a patient comprising administering to the patient an effective amount of at least one compound of the present invention.

Yet another embodiment of the present invention is a method for inhibiting PI3K, in particular P13K5 and PI3Ky, in a patient comprising administering to the patient an effective amount of at least one compound of the present invention.

Yet another embodiment of the present invention is a method for treating an inflammatory, mune or proliferative disease Via modulation of a protein kinase (such as P13K5 and P13Ky) comprising administering to a patient in need of such treatment an ive amount of at least one compound of the present invention. In one ment, the compound of the t invention ts both PI3K5 and PI3Ky.

Yet another embodiment of the t invention is a method for treating an inflammatory, autoimmune or proliferative disease via modulation of a protein kinase (such as PI3K8 and PI3Ky) by administering to a patient in need of such ent an effective amount of at least one compound of the present invention, in combination (simultaneously or sequentially) with at least one other anti-inflammatory, modulator or ancer agent, or a combination thereof. In one embodiment, the compound of the present invention inhibits both PI3K5 and PI3Ky.

The compounds of the t invention are useful in the treatment of a variety of cancers, including, but not limited to: carcinoma, including, but not limited to, that of the bladder, breast, colon, , liver, lung, including small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including, but not limited to, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B—cell ma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin’s lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including, but not limited to, acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of hymal origin, including, but not limited to, fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including, but not limited to, ytoma, neuroblastoma, glioma and schwannomas; and other tumors, including, but not d to, melanoma, ma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.

In one ment, an effective amount of a compound of the t invention is stered to treat a leukemia, acute lymphocytic leukemia, acute lymphoblastic ia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non— Hodgkin’s lymphoma, hairy cell lymphoma, Burkett's ma, acute and chronic myelogenous leukemias, myelodysplastic syndrome or promyelocytic leukemia.

Due to the key role of protein kinases in the regulation of cellular proliferation in general, the compounds of the present invention may act as reversible cytostatic agents, and may therefore be useful in the treatment of any disease process which features abnormal cellular proliferation, such as, e. g., benign prostatic hyperplasia, familial adenomatosis polyposis, fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following lasty or vascular surgery, hypertrophic scar formation, atory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.

The compounds of the present invention as modulators of apoptosis are useful in the treatment of cancer (including, but not limited to, those types mentioned herein , Viral infections (including, but not d to, herpes Virus, poxvirus, Epstein-Barr virus, Sindbis Virus and adenovirus), autoimmune diseases (including, but not limited to, systemic lupus, erythematosus, mune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, AIDS—related dementia, Parkinson's disease, ophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar ration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol d liver diseases, haematological diseases (including, but not limited to, c anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including, but not limited to, osteoporosis and arthritis) n-sensitive rhinosinusitis, cystic fibrosis, multiple sis, kidney diseases and cancer pain. The compounds of the present invention are also useful in the prevention, inhibition, or suppression of AIDS development in HIV-infected individuals.

The compounds of the present invention may modulate the level of cellular RNA and DNA synthesis. The nds of the present invention are therefore useful in the treatment of Viral infections, including, but not limited to, HIV, human papilloma Virus, herpes virus, poxvirus, Epstein-Barr Virus, Sindbis Virus and adenovirus.

The compounds of the present invention are useful in the Chemoprevention of cancer. Chemoprevention is defined herein as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already ed an insult or inhibiting tumor relapse. The compounds of the present invention are also useful in inhibiting tumor angiogenesis and metastasis. One embodiment of the present invention is a method of inhibiting tumor angiogenesis or metastasis in a patient in need f by administering an ive amount of one or more compounds of the present invention.

Another embodiment of the present invention is a method of treating an immune system-related e or immune disorder (e.g., an autoimmune disease), a disease or disorder involving inflammation (e.g., , chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis and disorders of the immune system), cancer or other proliferative disease, a hepatic disease or disorder, a renal disease or disorder. The method includes administering an effective amount of one or more compounds of the present invention.

Examples of immune disorders include, but are not d to, psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, , inflammatory muscle disease, allergic rhinitis, vaginitis, titial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic lantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus matosus, inflammatory disease, type I diabetes, ary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune haemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, ic conjunctivitis and atopic dermatitis.

In one ment, the compounds described herein are useful as immunosuppresants to prevent transplant graft rejections, allogeneic or xenogeneic transplantation ion (organ, bone marrow, stem cells, other cells and s), and graft - versus - host disease. In one particular embodiment, transplant graft rejections result from tissue or organ transplants. In further embodiments, the graft-versus-host disease results from bone marrow or stem cell transplantation. One embodiment of the present ion is a method of preventing or decreasing the risk of transplant graft rejection, allogeneic or xenogeneic transplantation rejection (organ, bone marrow, stem cells, other cells and tissues) or graft - versus - host disease comprising administering an effective amount of one or more nds of the present invention.

The compounds of the present invention are also useful in ation istered together or tially) with known anti-cancer treatments, such as, for example, radiation therapy or with cytostatic or cytotoxic or anticancer agents, such as, for example, DNA ctive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT—ll or topotecan; tubulin interacting agents, such as paclitaxel, xel or the epothilones (for example ixabepilone), either naturally occurring or synthetic; hormonal agents, such as tamoxifen; 2015/054844 thymidilate synthase inhibitors, such as 5-fluorouracil; and anti-metabolites, such as methotrexate, other tyrosine kinase inhibitors, such as Iressa and 081-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; CDK inhibitors; SRC inhibitors; c-Kit inhibitors; Her1/2 inhibitors and onal antibodies directed against growth factor receptors such as erbitux (EGF) and herceptin (Her2); BTK inhibitor, such as ibrutinib; and other protein kinase modulators, and any combination f.

The compounds of the present invention are also useful in combination (administered together or sequentially) with one or more steroidal anti-inflammatory drugs, eroidal anti-inflammatory drugs (NSAIDs) and immune selective anti— inflammatory derivatives (ImSAIDs), and any combination thereof.

The present invention further provides a ceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition may further comprise one or more of the active ingredients identified above, such as other anti—cancer .

Yet another embodiment is a method of treating leukemia in a patient in need thereof comprising administering a eutically effective amount of a compound of the present invention. In one embodiment, the leukemia is ed from chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), n lymphoma (HL), acute myeloid leukemia (AML), le myeloma (MM), small lymphocytic lymphoma (SLL), and indolent non-Hodgkin’s lymphoma (I-NHL).

Yet another embodiment of the t invention is a method of treating an autoimmune disorder in a patient in need thereof comprising administering a therapeutically effective amount of a compound of the present invention. In one embodiment, the autoimmune disorder is selected from asthma, COPD, rheumatoid arthritis, psoriasis, lupus and experimental autoimmune encephalomyelitis (EAE).

Yet another embodiment of the present invention is a method of treating allergic rhinitis in a patient in need thereof comprising stering to the patient a therapeutically effective amount of a compound of the present invention.

In any of the aforementioned methods, the compound(s) of the present invention and optional additional active agents can be administered in the form of a pharmaceutical ition as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts a bar graph of the neutrophil count in bronchoalveolar lavage fluid (BALF) from female Wistar rats treated with 10 mg/kg of Compound Al (po) according to the lipopolysaccharide induced pulmonary neutrophilia model described in Assay 7.

Figure 2 depicts a bar graph of the neutrophil count in peritoneal lavage fluid from Wistar rats treated with l, 3, and 10 mg/kg of Compound Al (po) according to the lipopolysaccharide-induced rat air pouch inflammation model described in Assay 8.

Figures 3A and 3B depict the line and bar graphs of individual clinical scores for hind and fore paws and AUC for al score, respectively, in Wistar rats with collagen induced arthritis treated with a l or 10 mg/kg/QD of Compound A1 ing to the procedure in Assay ll.

Figures 3C and 3D depict line and bar graphs of individual al scores for hind and fore paws, respectively, in Wistar rats with collagen induced arthritis treated with e or 10 mg/kg/QD of Compound A1 according to the procedure in Assay ll.

Figures 4A and 4B depict the line and bar graphs of volume for hind paws and AUC of paw volume, respectively, in Wistar rats with collagen induced arthritis treated with vehicle or 10 mg/kg/QD of Compound Al according to the ure in Assay ll.

Figures 4C and 4D depict line and bar graphs of ankle diameter for hind paws and AUC of ankle diameter, respectively, in Wistar rats with en induced arthritis treated with vehicle or 10 mg/kg/QD of Compound Al according to the procedure in Assay 11.

Figures 4E to 4G depict bar graphs of histopathological score for inhibition of inflammation, age and pannus, respectively, of all the hind and fore paws in Wistar rats with collagen d arthritis treated with vehicle or 10 mg/kg/QD of Compound Al ing to the procedure in Assay 11.

Figure 4H depicts a bar graph of total histopathological score of all the hind and fore paws in Wistar rats with collagen induced arthritis treated with vehicle or 10 mg/kg/QD of nd A1 according to the ure in Assay 11.

Figure 5 depicts a bar graph of the percentage incidence of arthritis in Wistar rats with collagen induced arthritis treated with vehicle or 10 mg/kg/QD of Compound A1 according to the ure in Assay 11.

Figures 6A and 6B depict bar graphs g the oratic effect of Compound A1 (3, 10, 30 mg/kg) on imiquimod induced psoriasis in Balb/c mice ing to the procedure in Assay 13.

DETAILED DESCRIPTION OF THE INVENTION As used herein the following definitions shall apply unless otherwise indicated. Further many of the groups defined herein can be optionally substituted. The listing of substituents in the definition is exemplary and is not to be construed to limit the substituents defined elsewhere in the ication.

Certain of the compounds bed herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be d, in terms of absolute stereochemistry, as (R)— or (S)—. Unless otherwise specified, the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. For the instance, non-limiting example of intermediate mixtures include a mixture of R: S or S: R isomers in a ratio of 10:90, 13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or ed using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

The term "tautomers" refers to compounds, which are characterized by relatively easy interconversion of isomeric forms in equilibrium. These isomers are ed to be covered by this invention. "Tautomers" are urally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol erization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypentenone tautomers. Another example of tautomerization is -keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin—4-ol and pyridin— 4(1H)—one tautomers.

The term "prodrug" refers to a compound, which is an inactive precursor of a compound that is converted into its active form in the body by normal metabolic processes. Prodrug design is discussed generally in Hardma, et al. (Eds), Goodman and Gilman's The cological Basis of Therapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion is provided in Higuchi, et a1., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). To illustrate, gs can be converted into a pharmacologically active form through hydrolysis of, for example, an ester or amide linkage, thereby introducing or ng a onal group on the resultant product. The prodrugs can be ed to react with an endogenous compound to form a water-soluble conjugate that r enhances the pharmacological ties of the compound, for example, increased circulatory half-life. Alternatively, prodrugs can be designed to undergo nt modification on a functional group with, for example, glucuronic acid, sulphate, hione, amino acids, or acetate. The resulting conjugate can be vated and excreted in the urine, or rendered more potent than the parent nd. High molecular weight conjugates also can be excreted into the bile, subjected to enzymatic cleavage, and released back into the circulation, thereby effectively increasing the biological half-life of the originally administered compound. 2015/054844 The term "ester" refers to a compound, which is formed by reaction between an acid and an alcohol with ation of water. An ester can be represented by the general formula RCOOR' (where R is a drug and R’ is a chemical group).

These prodrugs and esters are intended to be covered within the scope of this invention.

Additionally the instant invention also includes the compounds which differ only in the presence of one or more ically enriched atoms for example replacement of hydrogen with deuterium or tritium, or the replacement of a carbon by 13C— or 14C— enriched carbon.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.

For example, the nds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (1251) or carbon-l4 (14C). All isotopic ions of the compounds of the t invention, whether radioactive or not, are encompassed within the scope of the present invention.

Pharmaceutically acceptable salts forming part of this ion include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine; chiral bases such as alkylphenylamine, glycinol, and phenyl glycinol; salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, ine, omithine, lysine, arginine, and serine; quaternary ammonium salts of the nds of ion with alkyl halides, alkyl sulphates such as Mel and (Me)zSO4; non-natural amino acids such as D- isomers or substituted amino acids; guanidine; and substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted um salts and aluminum salts. Salts may include acid addition salts where appropriate which may be sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, tes, methanesulphonates, tes, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.

When ranges are used herein for al ties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments n are intended to be included.

The term "about" when ing to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental , and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes those embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, that "consist of” or "consist essentially of” the described features.

The following abbreviations and terms have the indicated meanings hout: PI3-K = Phosphoinositide 3-kinase; PI = phosphatidylinositol; AIDS = Acquired Immuno Deficiency Syndrome; HIV = Human Immunodeficiency Virus; MeI = Methyl Iodide; ND: Not determined.

Abbreviations used herein have their conventional meaning within the chemical and biological arts.

The term "cell proliferation" refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.

The terms "co-administration, II II administered in combination with," and their tical equivalents, as used herein, encompass stration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. inistration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to effect the intended application ing but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the ed application (in vitro or in vivo), or the subject and disease condition being treated, e. g., the weight and age of the subject, the severity of the disease ion, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g. reduction of platelet adhesion and/or cell migration. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is d.

As used herein, "treatment," "treating," or orating" are used interchangeably. These terms refers to an approach for obtaining beneficial or d results including but, not limited to, therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying er being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the ying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a sis of this disease may not have been made.

A "therapeutic effect," as that term is used herein, encompasses a eutic benefit and/or a prophylactic t as described above. A prophylactic effect includes delaying or eliminating the ance of a disease or condition, ng or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination f.

The term "subject" or “patient” refers to an animal (e.g., a dog, cat, horse, or pig), such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the patient is a mammal. In a preferred embodiment, the patient is human. tion therapy" means exposing a patient, using routine methods and compositions known to the practitioner, to radiation emitters such as particle emitting radionuclides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters (i.e. beta emitters), conversion electron emitters (e.g. strontium-89 and samarium- 153-EDTMP), or high-energy ion, including, without limitation, X-rays, gamma rays, and neutrons.

"Signal transduction" is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response. A modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator may augment (agonist) or suppress onist) the activity of a signalling molecule.

The term "selective inhibition" or "selectively inhibit" as applied to a biologically active agent refers to the agent's ability to selectively reduce the target signalling activity as compared to off—target signalling activity, via direct or indirect interaction with the target.

The term aceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes, but is not limited to, any and all solvents, dispersion media, gs, antibacterial and antifungal agents, isotonic and absorption delaying , one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorantsfflavouring, rs, excipients, buffers, stabilizers, solubilizers, and combinations thereof. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the ion is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

In other embodiments, the compounds of the t invention selectively t one or more members of type I or class I atidylinositol 3-kinases (PI3— kinase) with an IC50 value of about 100 nM or less, about 50 nM or less, about 10 nM or less, about 5 nM or less, about 100 pM or less, about 10 pM or less, or about 1 pM or less as ed in an in vitro kinase assay.

In yet another aspect, an inhibitor that selectively inhibits one or more members of type I PI3-kinases, or an inhibitor that selectively inhibits one or more type I PI3-kinase mediated ling pathways, alternatively can be understood to refer to a compound that ts a 50% inhibitory concentration (ICso) with respect to a given type I PI3-kinase, that is at least 10-fold lower, at least 20-fold lower, at least 50-fold lower, at least 100-fold lower, or at least 1000-fold lower than the inhibitor's ICso with respect to the rest of the other type I P13 -kinases.

As used herein, the term “dual PI3-kinase 5 / y inhibitor" and “dual P13— kinase 5 / y selective tor” refers to a compound that inhibits the activity of both the PI3-kinase 5 and y e more effectively than other isozymes of the PI3K family. A dual nase