RELATED APPLICATIONS

This application claims priority to Indian Provisional Patent Application No. 201921033255 filed on Oct. 17, 2019, the contents of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds useful as malic enzyme (ME) inhibitors, process for their preparation, and use of the compounds for the therapeutic treatment of disorders mediated by ME, such as cancer (e.g., in humans).

BACKGROUND OF THE INVENTION

One hallmark of cancer is excessive growth and uncontrolled proliferation. Cancer cells need energy and, using this energy, cell membranes, nucleotides, and proteins grow in cells and proliferate. Once cancer is initiated, alterations in key signaling pathways accumulate and lead to loss of control over metabolism as well as proliferation (Hanahan D, Weinberg R A., Hallmarks of Cancer: the next generation. Cell, 2011; 144(5): 646-74).

Metabolic alterations provide the energetic and anabolic demands of enhanced cell proliferation. In order to meet these requirements, cancer cells use various metabolic approaches, such as high aerobic glycolysis, glutaminolysis, and fatty acid synthesis. Pyruvate, NAD, and NADPH have key roles in supporting the advancement of glycolysis and fatty acid synthesis. Malic enzyme is an important enzyme in metabolism that catalyzes the conversion of malate to pyruvate with the concomitant regeneration of NADPH. Malic enzyme, by producing pyruvate and NADPH, provides abundant vital resources for glycolysis and fatty acid synthesis. Malic enzyme expression is significantly up-regulated in different types of human cancers.

Malic enzymes are oxidative decarboxylases that catalyze the conversion of L-malate to pyruvate and CO2and use NAD+ or NAD(P)+ as a cofactor. In mammals, there are three malic enzyme isoforms with different cofactor specificities: the cytosolic NADP+-dependent malic enzyme 1 (ME1), the mitochondrial NAD(P)+-dependent malic enzyme 2 (ME2), and the mitochondrial NADP+-dependent malic enzyme 3 (ME3).

Cytoplasmic ME1 decarboxylates malate to form pyruvate and ultimately NADPH. In cancer cells, pyruvate generated in this manner is utilized for lactate fermentation. It has been reported that wild-type p53 represses ME1 expression and hence ME1 overexpression is associated with cancers carrying mutated p53. Malic enzyme 1 is the link to energy metabolism, redox status, and EMT specifically in cancers of squamous cell (oral, head and neck), nasopharynx, synovium, lung, pancreas, gastric, oesophageal, liver and breast (see, e.g., Ruocen Liao et al., ME1 promotes basal-like breast cancer progression and associates with poor prognosis, Sci. Rep., 2018, 8:16743).

It has also been reported that ME2 enzyme activity increased with progression to neoplasia in a rat tracheal epithelial line and in Morris hepatomas (see, e.g., Jian-Guo Ren et al., Knockdown of Malic Enzyme 2 Suppresses Lung Tumor Growth, Induces Differentiation and Impacts PI3K/AKT Signaling, Sci. Rep., 2014, 4:5414). The first functional connection between ME2 expression and cancer was reported in ME2 knockdown (KD) in K562 cells and this led to erythroid differentiation in chronic myelogenous leukemia in K562 cells. ME2 also plays a more important role in A549 cell survival in tumor cells than in normal lung cells. ME2 depletion also induced senescence and suppressed tumor growth in the p532/2 HCT1 16 xenograft model.

Genomic deletions are a key driver of virtually all cancers. During cancer progression, many cancer cells delete tumour-suppressor genes that block tumour development. This deletion process often also removes some neighbouring genes. The partial or complete loss of these neighbouring genes can make cancer cells vulnerable to therapeutic targeting—a concept known as collateral lethality.

In mammals, there is a third malic enzyme (ME3) which is NADP+-dependent. Dey et al., (Nature, 2017 Feb. 2; 542(7639):119-123) report that silencing of ME3 when Smad4 and ME2 are co-deleted leads to collateral lethality. There could be several possible unexplored independent functions of ME3 and whence ME3 inhibitors can be useful in several cancers as well.

Pancreatic cancer is one of the leading causes of cancer deaths in western societies, with the worst prognosis. It is the third leading cause of cancer deaths in the United States (US) alone (Lancet Oncol. 2017 June; 18(6):770-778) and is projected to be the second leading cause of cancer-related deaths in US by 2030 (Endosc Ultrasound, 2017 December; 6 (Suppl 3): S58-S61). Even for early-stage disease, recurrence is high. Although recent combination therapies for metastatic pancreatic ductal adenocarcinoma (PDAC) have improved the median overall survival (mOS) by up to 5 months, the overall prognosis remains almost unchanged, and novel therapies are desperately needed. The majority of patients at diagnosis are unresectable, as the disease remains symptomatically silent during the early stages, and no effective screening test exists (Clin Cancer Res., 2017 Apr. 1; 23(7):1670-1678).

Pancreatic cancer originates from exocrine cells of the pancreas, and among all exocrine tumors, pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic neoplasm, accounting for more than 90% of pancreatic tumors (Prog. Mol. Biol. Transl. Sci., 2016; 144:241-275). In spite of intense research efforts and the development of numerous new cancer drugs and treatment strategies over the past four decades, there has been no significant improvement in overall patient survival, and death rates are almost equivalent to incidence rates.

Pancreatic cancers are accompanied by activating mutations in KRAS oncogene in >90% of cases, and subsequent loss of tumor suppressors INK4A/ARF, TP53 and SMAD4 (Genes Dev., 2003 Dec. 15; 17(24):3112-26). Oncogenic Kras (KrasG12D) is a major driver in PDAC initiation, with loss in tumor suppressor genes. Constitutive KrasG12D signaling drives uncontrolled proliferation and enhances survival of cancer cells through the activation of its downstream signaling pathways, such as the MAPK and PI3K-mTOR pathways. To meet the increased anabolic needs of enhanced proliferation, cancer cells require both sufficient energy and biosynthetic precursors as cellular building blocks to fuel cell growth. In cancer cells, metabolic pathways are rewired in order to divert nutrients, such as glucose and glutamine, into anabolic pathways to satisfy the demand for cellular building blocks. It has been reported that the reprogramming of tumor metabolism is under the control of various oncogenic signals (J. Oral Maxillofac Pathol., 2017 May-August; 21(2):244-251). The Ras oncogene in particular has been shown to promote glycolysis.

European Patent Publication No. EP 0595241 A2 discloses a method for inhibiting the growth and proliferation of mammalian tumor cells by examining the expression of specific isoforms of malic enzyme and specifically inhibiting the malate enzyme isoform which is overexpressed.

U.S. Pat. No. 9,539,323 discloses the use of a malic enzyme 2 inhibitor for treating a subject having cancer.

There is a continuing need for new compounds useful as malic enzyme (especially ME3) inhibitors.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a method of inhibiting a malic enzyme in a subject comprising administering to the subject in need thereof a compound of Formula I


or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein
X is CH or nitrogen;
R1is selected from hydrogen, CH3, —COOH, fluoro and CN;
R2is selected from hydrogen, CH3, —COOH, fluoro and CN; and
Y is selected from substituted or unsubstituted C1-5alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted 5 to 14 membered heteroaryl ring containing one, two or three heteroatoms each independently selected from nitrogen, oxygen, and sulfur, substituted or unsubstituted 5 to 14 membered heterocycloalkyl group containing one, two or three heteroatoms each independently selected from nitrogen and oxygen, substituted or unsubstituted C3-15cycloalkyl, substituted or unsubstituted C3-15cycloalkylC1-6alkyl, substituted or unsubstituted C6-14aryl, substituted or unsubstituted C6-14arylC1-6alkyl, substituted or unsubstituted C6-14arylC2-5alkenyl, substituted or unsubstituted 5 to 14 membered heteroarylC1-6alkyl, and substituted or unsubstituted 5 to 14 membered heterocycloalkylC1-6alkyl.

In another aspect, the present invention provides a compound of Formula I


or a pharmaceutically acceptable salt, stereoisomer or deuterated analog thereof, wherein
X is CH or nitrogen;
R1is selected from hydrogen, CH3, —COOH, fluoro and CN;
R2is selected from hydrogen, CH3, —COOH, fluoro and CN;
Y is selected from substituted or unsubstituted C1-5alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted 5 to 14 membered heteroaryl ring containing one, two or three heteroatoms each independently selected from nitrogen, oxygen, and sulfur, substituted or unsubstituted 5 to 14 membered heterocycloalkyl group containing one, two or three heteroatoms each independently selected from nitrogen and oxygen, substituted or unsubstituted C3-15cycloalkyl, substituted or unsubstituted C3-15cycloalkylC1-6alkyl, substituted or unsubstituted C6-14aryl, substituted or unsubstituted C6-14arylC1-6alkyl, substituted or unsubstituted C6-14arylC2-5alkenyl, substituted or unsubstituted 5 to 14 membered heteroarylC1-6alkyl, and substituted or unsubstituted 5 to 14 membered heterocycloalkylC1-6alkyl;
with the proviso that (i) when X is CH, then Y is selected from:


and (ii) when X is nitrogen, then Y is selected from:



The compounds of the present invention are potent ME inhibitors and are useful in the treatment of diseases mediated by ME such as cancer (e.g., a non-solid or a solid cancer) particularly PDAC.

