Collagen 1 translation inhibitors and methods of use thereof

Abstract

The present invention relates to novel Collagen 1 translation inhibitors, composition and methods of preparation thereof, and uses thereof for treating Fibrosis including lung, liver, kidney, cardiac and dermal fibrosis, IPF, wound healing, scarring and Gingival fibromatosis, Systemic Sclerosis, and alcoholic and non-alcoholic steatohepatitis (NASH).

Description

COLLAGEN 1 TRANSLATION INHIBITORS AND METHODS OF USE THEREOFFIELD OF THE INVENTION

[0001] The present invention relates to novel Collagen 1 translation inhibitors, composition and methods of preparation thereof, and uses thereof for treating Fibrosis including lung, liver, kidney, cardiac and dermal fibrosis, IPF, wound healing, scarring and Gingival fibromatosis, Systemic Sclerosis, and alcoholic and non-alcoholic steatohepatitis (NASH).BACKGROUND OF THE INVENTION

[0002] The formation of fibrous connective tissue is part of the normal healing process following tissue damage due to injury or inflammation. During this process, activated immune cells including macrophages stimulate the proliferation and activation of fibroblasts, which in turn deposit connective tissue. However, abnormal or excessive production of connective tissue may lead to accumulation of fibrous material such that it interferes with the normal function of the tissue. Fibrotic growth can proliferate and invade healthy surrounding tissue, even after the original injury heals. Such abnormal formation of excessive connective tissue, occurring in a reparative or reactive process, is referred to as fibrosis.

[0003] Many agents cause activation of the fibrotic process and are released in response to tissue injury, inflammation and oxidative stress. Regardless of the initiating events, a feature common to all fibrotic diseases is the conversion of tissue resident fibroblast into ECM-producing myofibroblasts that secrete collagen type I. Current programs indirectly target myofibroblast activation and collagen secretion by inhibiting a single fibrosis inducing signal.

[0004] Physiologically, fibrosis acts to deposit connective tissue, which can obliterate the architecture and function of the underlying organ or tissue. Defined by the pathological accumulation of extracellular matrix (ECM) proteins, fibrosis results in scarring and thickening of the affected tissue, which interferes with normal organ function. In various conditions, the formation of fibrotic tissue is characterized by the deposition of abnormally large amounts of collagen. The synthesis of collagen is also involved in a number of other pathological conditions. For example, clinical conditions and disorders associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus host disease (GVHD), pulmonary fibrosis and autoimmune disorders, are distinguished by excessive production of connective tissue, which results in the destruction of normal tissue architecture and function. These diseases can best be interpreted in terms of perturbations in cellular functions, a major manifestation of which, is excessive collagensynthesis and deposition. The role of collagen in fibrosis has prompted attempts to develop drugs that inhibit its accumulation.

[0005] Excessive accumulation of collagen is the major pathologic feature in a variety of clinical conditions characterized by tissue fibrosis. These conditions include localized processes, as for example, pulmonary fibrosis and liver cirrhosis, or more generalized processes, like progressive systemic sclerosis. Collagen deposition is a feature of different forms of dermal fibrosis, which in addition to scleroderma, include localized and generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenoma and connective tissue nevi of the collagen type. Recent advances in the understanding of the normal biochemistry of collagen have allowed us to define specific levels of collagen biosynthesis and degradation at which a pharmacologic intervention could lead to reduced collagen deposition in the tissues. Such compounds could potentially provide us with novel means to reduce the excessive collagen accumulation in diseases.

[0006] Fibrosis of the liver, also referred to herein as hepatic fibrosis, may be caused by various types of chronic liver injury, especially if an inflammatory component is involved. Self-limited, acute liver injury (e.g., acute viral hepatitis A), even when fulminant, does not necessarily distort the scaffolding architecture and hence does not typically cause fibrosis, despite loss of hepatocytes. However, factors such as chronic alcoholism, malnutrition, hemochromatosis, and exposure to poisons, toxins or drugs, may lead to chronic liver injury and hepatic fibrosis due to exposure to hepatotoxic chemical substances. Hepatic scarring, caused by surgery or other forms of injury associated with mechanical biliary obstruction, may also result in liver fibrosis.

[0007] Fibrosis itself is not necessarily symptomatic, however it can lead to the development of portal hypertension, in which scarring distorts blood flow through the liver, or cirrhosis, in which scarring results in disruption of normal hepatic architecture and liver dysfunction. The extent of each of these pathologies determines the clinical manifestation of hepato-fibrotic disorders. For example, congenital hepatic fibrosis affects portal vein branches, largely sparing the parenchyma. The result is portal hypertension with sparing of hepatocellular function.Treatment

[0008] Attempts to develop anti-fibrotic agents for the treatment of various disorders have been reported. However, treatment of established fibrosis, formed after months or years of chronic or repeated injury, still remains a challenge.

[0009] Treatments aimed at reversing the fibrosis are usually too toxic for long-term use ( e.g., corticosteroids, penicillamine) or have no proven efficacy ( e.g., colchicine).

[0010] Many patients do not respond to available treatments for fibrotic disorders, and long-term treatment is limited by toxicity and side effects. Therefore, a need remains for developing therapeutic modalities aimed at reducing fibrosis. The development of safe and effective treatments for established cirrhosis and portal hypertension and for attenuating fibrosis would be highly beneficial.

[0011] Attempts to treat idiopathic pulmonary fibrosis (IPF) with a combination of antiinflammatory drugs (prednisone, azathioprine and N-acetyl-l-cysteine (NAC)), failed to improve outcomes, and instead increased mortality. In 2014, two drugs, pirfenidone, a drug with poorly understood mechanisms, and nintedanib, a tyrosine kinase inhibitor, were approved for the treatment of IPF mainly on the basis of their ability to reduce the decrease in forced vital capacity (FVC) and to slow the pace of disease progression. To date, however, it is unclear whether these drugs improve symptoms such as dyspnoea and cough, or whether their beneficial effect on functional decline translates to increased survival.

[0012] The compounds of this invention target activated fibroblasts and collagen over production and can therefore be used for treating fibrosis, including primary or secondary fibrosis, such as systemic sclerosis, graft-versus host disease (GVHD), pulmonary fibrosis and autoimmune disorders, lung fibrosis and idiopathic pulmonary fibrosis (IPF), as well as localized processes, as for example, pulmonary fibrosis and liver cirrhosis, or more generalized processes, like progressive systemic sclerosis. The compounds can be further useful in the treatment of different forms of dermal fibrosis, which in addition to scleroderma, include localized and generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenoma and connective tissue nevi of the collagen type. The compounds can be further useful in the treatment of lung fibrosis and idiopathic pulmonary fibrosis (IPF), as well as hepatic fibrosis, resulting from hepatic scarring, caused by surgery or other forms of injury associated with mechanical biliary obstruction. Such fibrosis can lead to portal hypertension, in which scarring distorts blood flow through the liver, or cirrhosis as well as other hepato-fibrotic disorders including Non-alcoholic steatohepatitis (NASH), and alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD), which can be similarly be treated by compounds of the invention.SUMMARY OF THE INVENTION

[0013] This invention provides a compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, V-oxidc, reverse amide analog, prodrug, isotopic variants (e.g., deuterated analog), pharmaceutical product or any combination thereof, represented by the structure offormula I, Ka), II and / or 11(a) and by the structures listed in Table 1, as defined herein below. In various embodiments, the compound is Collagen I translation inhibitor.

[0014] This invention further provides a pharmaceutical composition comprising a compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, / V-oxidc, prodrug, isotopic variants (e.g., deuterated analog), pharmaceutical product or any combination thereof, represented by the structure of formula 1, 1(a), II and / or 11(a) and by the structures listed in Table 1, as defined herein below, and a pharmaceutically acceptable carrier.

[0015] This invention further provides a compound represented by the structure of formula 1, 1(a), II and / or 11(a) and by the structures listed in Table 1, as defined herein below for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting fibrosis in a subject. In some embodiments, the fibrosis is a systemic fibrotic disease. In some embodiments, the systemic fibrotic disease is systemic sclerosis, multifocal fibrosclerosis (IgG4-associated fibrosis), nephrogenic systemic fibrosis, sclerodermatous graft vs. host disease, or any combination thereof. In some embodiments, the fibrosis is an organ- specific fibrotic disease. In some embodiments, the organ- specific fibrotic disease is lung fibrosis, cardiac fibrosis, kidney fibrosis, pulmonary fibrosis, liver and portal vein fibrosis, radiation-induced fibrosis, bladder fibrosis, intestinal fibrosis, peritoneal sclerosis, diffuse fasciitis, wound healing, scaring, or any combination thereof. In some embodiments, the lung fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the cardiac fibrosis is hypertension-associated cardiac fibrosis, Post- myocardial infarction, Chagas disease-induced myocardial fibrosis or any combination thereof. In some embodiments, the kidney fibrosis is diabetic and hypertensive nephropathy, urinary tract obstruction-induced kidney fibrosis, inflammatory / autoimmune-induced kidney fibrosis, aristolochic acid nephropathy, polycystic kidney disease, or any combination thereof. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pneumoconiosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapeutic agent-induced pulmonary fibrosis, or any combination thereof. In some embodiments, the liver and portal vein fibrosis is alcoholic and nonalcoholic liver fibrosis, hepatitis C-induced liver fibrosis, primary biliary cirrhosis, parasite-induced liver fibrosis (schistosomiasis), or any combination thereof. In some embodiments, the diffuse fasciitis is localized scleroderma, keloids, dupuytren’s disease, peyronie’s disease, myelofibrosis, oral submucous fibrosis, or any combination thereof. In some embodiments, the fibrosis is primary or secondary fibrosis. In some embodiments, the fibrosis is a result of systemic sclerosis, graft-versus host disease (GVHD), pulmonary fibrosis, autoimmune disorder, tissue injury, inflammation, oxidative stress or any combination thereof. In some embodiments, the fibrosis is hepatic fibrosis, lung fibrosis or dermalfibrosis. In some embodiments, the subject has a liver cirrhosis. In some embodiments, the dermal fibrosis is scleroderma. In some embodiments, the dermal fibrosis is a result of a localized or generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenoma, connective tissue nevi of the collagen type, or any combination thereof. In some embodiments, the hepatic fibrosis is a result of hepatic scarring or chronic liver injury. In some embodiments, the chronic liver injury results from alcoholism, malnutrition, hemochromatosis, exposure to poisons, toxins or drugs.

[0016] This invention further provides a compound represented by the structure of formula 1, 1(a), II and / or 11(a) and by the structures listed in Table 1, as defined herein below, for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting lung fibrosis in a subject. In some embodiments, the lung fibrosis is idiopathic pulmonary fibrosis (IPF).

[0017] This invention further provides a compound represented by the structure of formula 1, 1(a), II and / or 11(a) and by the structures listed in Table 1, as defined herein below, for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting idiopathic pulmonary fibrosis (IPF) in a subject.

[0018] This invention further provides a compound represented by the structure of formula 1, 1(a), II and / or 11(a) and by the structures listed in Table 1, as defined herein below, for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting hepato-fibrotic disorder in a subject. In some embodiments, the hepato-fibrotic disorder is a portal hypertension, cirrhosis, congenital hepatic fibrosis or any combination thereof.

[0019] This invention further provides a compound represented by the structure of formula 1, 1(a), II and / or 11(a) and by the structures listed in Table 1, as defined herein below, for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting cirrhosis in a subject. In some embodiments, the cirrhosis is a result of hepatitis or alcoholism.

[0020] This invention further provides a compound represented by the structure of formula 1, 1(a), II and / or 11(a) and by the structures listed in Table 1, as defined herein below, for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting a alcoholic steatohepatitis (ASH) in a subject.

[0021] This invention further provides a compound represented by the structure of formula 1, 1(a), II and / or 11(a) and by the structures listed in Table 1, as defined herein below, for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting a non-alcoholic steatohepatitis (NASH) in a subject.

[0022] This invention further provides a compound represented by the structure of formula 1, 1(a), II and / or 11(a) and by the structures listed in Table 1, as defined herein below, for use in treating,suppressing, reducing the severity, reducing the risk of developing or inhibiting a alcoholic fatty liver disease (AFLD) in a subject.

[0023] This invention further provides a compound represented by the structure of formula 1, 1(a), II and / or 11(a) and by the structures listed in Table 1, as defined herein below, for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting a non alcoholic fatty liver disease (NAFLD) in a subject.

[0024] This invention further provides a compound represented by the structure of formula 1, 1(a), II and / or 11(a) and by the structures listed in Table 1, as defined herein below, for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting an autoimmune disease or disorder in a subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 depicts the effect of Compound 127 on expression of Collagen 1 in WI38 Human Lung Fibroblasts cells.

[0026] Figure 2 depicts the Ashcroft score across groups for Compound 127 in bleomycin lung fibrosis model vs. control. Data is presented as a scattr plot across all animals in a group (n=10 - 15), and mean, marked as a horizontal line. *p<0.05, **p<0.005 vs BLM / Vehicle; Unpaired t-test.

[0027] Figure 3 depicts Compound 127 single-dose pharmacokinetics study in Balb / C mice after PO administration at 1, 3 and 10 mg / kg and IV dose of 10 mg / kg.

[0028] Figure 4 depicts a multi-dose 5-day PK Study (Day 1 and 5) of Compound 127 in Balb / C mice after PO dosing at 10, 30 and 100 mg / kg. Compound 127 shows increased Cmax and AUC upon increasing PO dose level. No clinical abnormalities were observed in the tested mice for 10 and 30 mg / kg BID dose groups; 100 mg / kg BID group were sacrificed on Day 2 due to adverse effects. PO formulation: 1% Tween 80 in 0.5% HPMC. PK parameters for multi-dose PO administration.DETAILED DESCRIPTION OF THE INVENTION

[0029] In various embodiments, this invention is directed to a compound represented by the structure of formula (I):whereinC ring is a a single or fused C3-C10 cycloalkyl ( e.g., cyclopropyl), 5-7 membered saturated heterocyclic ring (e.g., morpholine, azetidine, piperidine, piperazine, pyrrolidine, oxetane, 1,4- diazepane), 5-7 membered unsaturated heterocyclic ring (e.g., 2-piperazinone, 2-pyrrolidone, 1,2- Dihydro-3H-l,2,4-triazol-3-one, 2-oxazolidinone, lH-l,2,4-triazol-5(4H)-one), or 5-7 membered aromatic heterocyclic ring (e.g., pyrazole, imidazole, triazole, oxadiazole, tetrazole) or a 7-12 membered fused, bridged or spiro, saturated or unsaturated carbocyclic or heterocyclic ring system (e.g., 4,7-diazaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, spiro[azetidine-3,l'-cyclobutane], 2- azaspiro [3.3 ] heptane) ;Ri is H, F, Cl, Br, I, CN, NO2, OH, SH, NH2, NHR (e.g., NH(CH3)), N(R)2, N(R10)(R11) (e.g., N(CH3)2), R8-N(RIO)(RH), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH3, CH2-CH2-CCH), C1-C5linear or branched, substituted or unsubstituted linear, branched or cyclic haloalkyl (e.g., CHF2), R8-OH (e.g., CH2-OH, CH2-CH2-OH), R8-SH, -R8-RIO (e.g., CH2- CH2-CCH), -R8-0-RIO, NHC(0)-RIO, COOH, -C(O)Ph, C(0)0-R10, R8-C(0)-R10, C(O)H, C(O)- R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(0)N(R10)(R11), SO2R, S02N(RIO)(RII), NHS02(RIO), CH(CF3)(NH-RIO), R20, C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear, branched or cyclic alkoxy, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl;R2is absent or is H, F, Cl, Br, I, CN, NO2, OH, SH, NH2, NHR (e.g., NH(CH3)), N(R)2, N(R10)(R11) (e.g., N(CH3)2), R8-N(RIO)(RII), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH3, CH2-CH2-CCH), C1-C5linear or branched, substituted or unsubstituted linear,branched or cyclic haloalkyl (e.g., CHF2), R8-OH (e.g., CH2-OH, CH2- CH2-OH), R8-SH, -R8-R10(e.g., CH2-CH2-CCH), -R8-O-R10, NHC(0)-R10, COOH, -C(O)Ph, C(0)0-R10, R8-C(0)-R10, C(O)H, C(0)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(0)N(R10)(R11), SO2R, S02N(RIO)(RH), NHS02(RIO), CH(CF3)(NH-RIO), R2Q, C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear, branched or cyclic alkoxy, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 3-8 membered heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl; or R2and Ri are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., pyridine) ring;R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5linear or branched alkoxy, -R8-O-R10(e.g., CH2- CH2-O-CH3), C1-C5linear or branched haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine), ; or two geminal R substitutions are joined together to form a 3 - 6 membered substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furane, pyrrol, pyrazole) ring;R8is [CH2]p wherein p is between 1 and 10 (e.g., 1, 2); R10and R11are each independently H, C1-C5substituted or unsubstituted, linear or branched alkyl (e.g., methyl, ethyl, CH2-CCH, CH2-CH2-CCH, CH2-CH2-O-CH3), linear or branched alkynyl (e.g., CCH), C1-C5linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)3R; or R10and R11are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine),R20 is represented by the following structure:or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, N -oxidc, prodrug, isotopic variant (e.g., deuterated analog), reverse amide, pharmaceutical product or any combination thereof.

[0030] In some embodiments, substitutions include: F, Cl, Br, I, OH, SH, C1-C5linear or branched alkyl (e.g., CHi), CH2-CH2-CCH, C2-C5linear or branched alkenyl, C2-C5linear or branched alkynyl, C1-C5linear or branched alkoxy (e.g., methoxy), C1-C5linear or branched, haloalky I (e.g., CF3,CHF2), R8-OH (e.g., CH2-OH, CH2-CH2-OH), -R8-R10 (e.g., CH2-CH2-CCH), 3-8 membered heterocyclic ring (e.g., piperidine), NH2, NHR (e.g., NH(CH3)), N(R)2, N(R10)(R11) (e.g., N(CH3)2), C(O)NHR, C(0)N(R10)(R11), R20, C3-C8cycloalkyl, CF3, aryl, phenyl, halophenyl, CN, NO2or any combination thereof.

[0031] In various embodiments, this invention is directed to a compound represented by the structure of formula 1(a):Ia) whereinC ring is a a single or fused C3-Cio cycloalkyl ( e.g., cyclopropyl), 5-7 membered saturated heterocyclic ring (e.g., morpholine, azetidine, piperidine, piperazine, pyrrolidine, oxetane, 1,4- diazepane), 5-7 membered unsaturated heterocyclic ring (e.g., 2-piperazinone, 2-pyrrolidone, 1,2- Dihydro-3H-l,2,4-triazol-3-one, 2-oxazolidinone, lH-l,2,4-triazol-5(4H)-one), or 5-7 membered aromatic heterocyclic ring (e.g., pyrazole, imidazole, triazole, oxadiazole, tetrazole) or a 7-12 membered fused, bridged or spiro, saturated or unsaturated carbocyclic or heterocyclic ring system (e.g., 4,7-diazaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, spiro[azetidine-3,l'-cyclobutane], 2- azaspiro [3.3 ] heptane) ;Ri is H, F, Cl, Br, I, CN, NO2, OH, SH, NH2, NHR (e.g., NH(CH3)), N(R)2, N(R10)(R11) (e.g., N(CH3)3), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH3, CH2-CH2- CCH), C1-C5linear or branched, substituted or unsubstituted linear, branched or cyclic haloalkyl (e.g., CHF2), R8-OH (e.g., CH2-OH, CH2-CH2-OH), -R8-R10(e.g., CH2-CH2-CCH), -C(O)NH2, C(O)NHR, C(0)N(R10)(R11), R20;R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5linear or branched alkoxy, -R8-O-R10(e.g., CH2- CH2-O-CH3), C1-C5linear or branched haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine), ; or two geminal R substitutions are joined together to form a 3 - 6 membered substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furane, pyrrol, pyrazole) ring;wherein p is between 1 and 10 (e.g., 2); R10and R11are each independently H, C1-C5substituted or unsubstituted, linear or branched alkyl (e.g., methyl, ethyl, CH2-CCH, CH2-CH2-CCH, CH2-CH2-O-CH3), linear or branched alkynyl (e.g., CCH), C1-C5linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R; or R10and R11are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine),R20 is represented by the following structure:or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, / V-oxidc, prodrug, isotopic variant (e.g., deuterated analog), reverse amide, pharmaceutical product or any combination thereof.

[0032] In various embodiments, this invention is directed to a compound represented by the structure of formula II:IIwhereinR3is H, F, Cl, Br, I, OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-0-R10(e.g., CH2-O-CH2- CCH, CH2-O-CH3, CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3, CH2-O-CH2-CCH), O-R10 (e.g., O-CH2-CH2-CCH), -0-R8-0-RIO (e.g., O-CH2-CH2-O-CH3), R6-0-R8-0-RIO (e.g., CH2-O-CH2- CH2-O-CH3), R8-(C3-C8cycloalkyl), R8-(3-8 membered heterocyclic ring), O-R20, CF3, CD3, OCD3, CN, NO2, NH2, NHR, N(R)2, N(RIO)(RII) (e.g., N(CH3)2, NH(CH3)), R8-N(R10)(R11), NHC(O)-R (e.g., NHCO-Ph, NHCO-CH3) , NHC(0)-R10(e.g., NHCO-CH3), NHCO-N(R10)(R11), COOH, -C(O)Ph, C(0)0-R10, R8-C(0)-R10, C(O)H, C(0)-R10, -C(O)NH2, C(O)NHR (e.g., C(O)NH-CH3), C(0)N(RIO)(RII) (e.g., C(O)N(CH3)2), SO2R, S02N(R10)(R11), NHS02(R10) (e.g., NHSO2CH3), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)(0H), C(CH3)2(OH), CH(CF3)(NH2), methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, substituted or unsubstituted C1-C5linear, branched or cyclic haloalkyl (e.g., CHF2, CH(OH)(CF3), CH(CF3)(NH2), CF2(OH), CHF(OH), CF2(OCH3)), C1-C5linear, branched or cyclic alkoxy ( e.g., methoxy), C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy (e.g., OCHF2), C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3- C8cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 3-8 membered single, fused, bridged or spiro, saturated, unsaturated or aromatic, heterocyclic ring (e.g., azetidine, morpholine, pyrazole, piperidine, triazole, 2-pyrrolidone, pyrrolidine, oxadiazole, tetrazole, imidazole, piperazine, oxetane, piperazinone, 1,4-diazepane, 2-oxazolidinone, lH-l,2,4-triazol-5(4H)-one, triazol-3-one, pyridine, 4,7-diazaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, spiro [azetidine- 3,l'-cyclobutane], 2-azaspiro[3.3]heptane), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl; R4and R8are each independently H, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), F, Cl, Br, I, OH, SH, CF3, CN, NO2, NH2, NHR, N(R)2, C1-C5linear, branched or cyclic haloalkyl (e.g., CHF2), C1-C5linear, branched or cyclic alkoxy ( e.g., methoxy), substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., pyrazole, thiazole, imidazole), substituted or unsubstituted aryl (e.g., phenyl); or R4and R8are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic (e.g., cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furane, pyrrol, pyrazole) ring;R is H, OH, F, Cl, Br, I, CN, CF3, NO2, C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), C1-C5linear or branched alkoxy, -R8-0-R10(e.g., CH2- CH2-O-CH3), C1-C5linear or branched haloalkyl (e.g., CF3, CF2CH3, CH2CF3, CF2CH2CH3,CH2CH2CF3, CF2CH(CH3)2,CF(CH3)-CH(CH3)2), R8-aryl (e.g., CH2-Ph), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., pyridine (2, 3, and 4-pyridine), ; or two geminal R substitutions are joined together to form a 3 - 6 membered substituted or unsubstituted, aliphatic (e.g., cyclopropyl, cyclopentene) or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., thiophene, furane, pyrrol, pyrazole) ring;Re is [CH2]Vwherein v is between 1 and 10 (e.g., 1); R8is [CHijp wherein p is between 1 and 10 (e.g., 1, 2); R10and R11are each independently H, C1-C5substituted or unsubstituted, linear or branched alkyl (e.g., methyl, ethyl, CH2-CCH, CH2-CH2-CCH, CH2-CH2-O-CH3), linear or branched alkynyl (e.g., CCH), C1-C5linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R; or R10and R11are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine),R20 is represented by the following structure:or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, / V-oxidc, prodrug, isotopic variant (e.g., deuterated analog), reverse amide, pharmaceutical product or any combination thereof.

[0033] In various embodiments, if R3 is not H. In various embodiments, if R3 is unsubstituted haloalkyl, then R4and R8are different. In various embodiments, if R3 is unsubstituted haloalkyl, then at least one of R4and R8is not alkyl. In various embodiments, if R3 is unsubstituted haloalkyl, then at least one of R4and R8is not CH3. In various embodiments, substituted haloalkyl include but not limited to haloalkyl substituted with at least one selected from: OH, NH2, alkoxy.

[0034] In various embodiments, this invention is directed to a compound represented by the structure of formula 11(a)wherein R8is substituted or unsubstituted C1-C5linear, branched or cyclic haloalkyl (e.g., CHF2, CH(OH)(CF3), CH(CF3)(NH2), CF2(OH), CHF(OH), CF2(OCH3)), R8-O-RIO (e.g., CH2-O-CH2- CCH), O-R10 (e.g., O-CH2-CH2-CCH), O-R20; R4and R8are each independently substituted or unsubstituted alkyl (e.g., methyl, ethyl), OH, NH2; Rwherein p is between 1 and 10 (e.g., 1, 2); R10is H, C1-C5substituted or unsubstituted, linear or branched alkyl (e.g., methyl, ethyl, CH2-CCH, CH2-CH2-CCH, CH2-CH2-O-CH3), linear or branched alkynyl (e.g., CCH), C1-C5linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R;R20 is represented by the following structure:wherein if R3is unsubstituted, then R4and R5 are different; or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, / V-oxidc, prodrug, isotopic variant (e.g., deuterated analog), reverse amide, pharmaceutical product or any combination thereof.

[0035] In some embodiments, C of formula I and / or 1(a), is a single or fused C3-Cio cycloalkyl. In some embodiments, C is a single cycloalkyl. In some embodiments, C is cyclopropyl. In some embodiments, C is a 3-8 membered saturated heterocyclic ring. In some embodiments, C is a 5-7 membered saturated heterocyclic ring. In some embodiments, C is morpholine, azetidine, piperidine, piperazine, pyrrolidine, oxetane, 1,4-diazepane; each represents a separate embodiment according to this invention. In some embodiments, C is 3-8 membered unsaturated heterocyclicring. In some embodiments, C is 5-7 membered unsaturated heterocyclic ring. In some embodiments, C is 2-piperazinone, 2-pyrrolidone, l,2-Dihydro-3H-l,2,4-triazol-3-one, 2- oxazolidinone, lH-l,2,4-triazol-5(4H)-one; each represents a separate embodiment according to this invention. In some embodiments, C is 3-8 membered aromatic heterocyclic ring (heteroaromatic ring). In some embodiments, C is 5-7 membered aromatic heterocyclic ring. In some embodiments, C is pyrazole, imidazole, triazole, oxadiazole, tetrazole; each represents a separate embodiment according to this invention. In some embodiments, C is a 7-12 membered fused, bridged or spiro, saturated or unsaturated carbocyclic or heterocyclic ring system; each possibility represents a separate embodiment according to this invention. In some embodiments, C is a 7-12 membered fused, bridged or spiro, saturated carbocyclic ring system; each possibility represents a separate embodiment according to this invention. In some embodiments, C is a 7-12 membered fused, bridged or spiro, saturated heterocyclic ring system; each possibility represents a separate embodiment according to this invention. In some embodiments, C is a 7-12 membered spiro, saturated heterocyclic ring system. In some embodiments, C is 4,7-diazaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, spiro[azetidine-3,l'-cyclobutane], 2-azaspiro[3.3]heptane; each possibility represents a separate embodiment according to this invention. In some embodiments, C is a 7-12 membered fused, bridged or spiro, unsaturated carbocyclic ring system; each possibility represents a separate embodiment according to this invention. In some embodiments, C is a 7-12 membered fused, bridged or spiro, unsaturated heterocyclic ring system; each possibility represents a separate embodiment according to this invention.

[0036] In some embodiments, Ri of formula I and / or 1(a) is H. In some embodiments, Ri is Ci- Cs linear or branched, substituted or unsubstituted alkyl. In other embodiments, Ri is methyl. In other embodiments, Ri is ethyl. In other embodiments, Ri is iso-propyl. In other embodiments, Ri is t-Bu. In other embodiments, Ri is iso-butyl. In other embodiments, Ri is pentyl. In other embodiments, Ri is propyl. In other embodiments, Ri is CH2-CH2-CCH. In other embodiments, Ri is benzyl. In other embodiments, Ri is F. In other embodiments, Ri is Cl. In other embodiments, Ri is Br. In other embodiments, Ri is I. In other embodiments, Ri is CN. In other embodiments, Ri is NO2. In other embodiments, Ri is OH. In other embodiments, Ri is SH. In other embodiments, Ri is NH2. In other embodiments, Ri is NHR. In other embodiments, Ri is NH(CHa). In other embodiments, Ri is N(R)2. In other embodiments, Ri is N(R10)(R11). In other embodiments, Ri is N(CHa)2. In other embodiments, Ri is R8-N(R10)(R11). In other embodiments, Ri is C1-C5linear or branched, substituted or unsubstituted alkyl. In other embodiments, Ri is CH3. In other embodiments, Ri is C1-C5linear or branched, substituted or unsubstituted linear, branched or cyclic haloalkyl. In other embodiments, Ri is CHF2. In other embodiments, Ri is CF2CH2CH3.In other embodiments, Ri is CH2CH2CF3. In other embodiments, Ri is CF2CH(CH3)2. In other embodiments, Ri is CF(CH3)-CH(CH3)2. In other embodiments, Ri is C1-C5linear, branched or cyclic alkoxy. In other embodiments, Ri is methoxy. In other embodiments, Ri is ethoxy. In other embodiments, Ri is propoxy. In other embodiments, Ri is isopropoxy. In other embodiments, Ri is 1-butoxy. In other embodiments, Ri is 2-butoxy. In other embodiments, Ri is O-tBu. In other embodiments, Ri is R8-OH. In other embodiments, Ri is CH2-OH. In other embodiments, Ri is CH2-CH2-OH. In other embodiments, Ri is -R8-R10. In other embodiments, -R8-R10is CH2-CH2- CCH. In other embodiments, Ri is R8-SH. In other embodiments, Ri is -R8-O-R10. In other embodiments, Ri is CH2-CH2-O-CH3. In other embodiments, Ri is CH2-O-CH2-CH2-O-CH3. In other embodiments, Ri is NHC(0)-R10. In other embodiments, Ri is COOH. In other embodiments, Ri is -C(O)Ph. In other embodiments, Ri is C(0)0-R10. In other embodiments, Ri is R8-C(0)-R10. In other embodiments, Ri is C(O)H. In other embodiments, Ri is C(0)-R10. In other embodiments, Ri is C1-C5linear or branched C(O)-haloalkyl. In other embodiments, Ri is - C(0)NH2. In other embodiments, Ri is C(O)NHR. In other embodiments, Ri is C(0)N(R10)(R11). In other embodiments, Ri is R20. In other embodiments, Ri is SO2R. In other embodiments, Ri is S02N(RIO)(RII) • In other embodiments, Ri is NHSChCR10). In other embodiments, Ri is C1-C5linear or branched haloalkoxy. In other embodiments, Ri is OCF3. In other embodiments, Ri is OCHF2. In other embodiments, Ri is substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, Ri is substituted or unsubstituted 3-8 membered heterocyclic ring. In other embodiments, Ri is substituted or unsubstituted aryl. In other embodiments, Ri is phenyl. In other embodiments, Ri is substituted or unsubstituted benzyl. In other embodiments, Ri may be further substituted with at least one substitution selected from: F, Cl, Br, I, OH, SH, C1-C5linear or branched alkyl, C2-C5linear or branched alkenyl, C2-C5linear or branched alkynyl (e.g., CCH), C1-C5linear or branched alkoxy (e.g., methoxy), 3-8 membered heterocyclic ring (e.g., piperidine), NH2, N(R)2, CF3, aryl, phenyl, halophenyl, CN, NO2; each is a separate embodiment according to this invention.

[0037] In some embodiments, R2 of formula I is H. In some embodiments, R2 is absent. In some embodiments, R2 is C1-C5linear or branched, substituted or unsubstituted alkyl. In other embodiments, R2 is methyl. In other embodiments, R2 is ethyl. In other embodiments, R2 is isopropyl. In other embodiments, R2 is t-Bu. In other embodiments, R2 is iso-butyl. In other embodiments, R2 is pentyl. In other embodiments, R2 is propyl. In other embodiments, R2 is benzyl. In other embodiments, R2 is F. In other embodiments, R2 is Cl. In other embodiments, R2 is Br. In other embodiments, R2 is I. In other embodiments, R2 is CN. In other embodiments, R2 is NO2. In other embodiments, R2 is OH. In other embodiments, R2 is SH. In other embodiments, R2is NH2. In other embodiments, R2 is NHR. In other embodiments, R2 is NH(CH3). In other embodiments, R2 is N(R)2. In other embodiments, R2 is N(R10)(R11). In other embodiments, R2 is N(CH3)2. In other embodiments, R2 is R8-N(R10)(R11). In other embodiments, R2 is C1-C5linear or branched, substituted or unsubstituted alkyl. In other embodiments, R2 is CH3. In other embodiments, R2 is C1-C5linear or branched, substituted or unsubstituted linear, branched or cyclic haloalkyl. In other embodiments, R2 is CHF2. In other embodiments, R2 is CF2CH2CH3. In other embodiments, R2 is CH2CH2CF3. In other embodiments, R2 is CF2CH(CH3)2. In other embodiments, R2 is CF(CH3)-CH(CH3)2. In other embodiments, R2 is C1-C5linear, branched or cyclic alkoxy. In other embodiments, R2 is methoxy. In other embodiments, R2 is ethoxy. In other embodiments, R2 is propoxy. In other embodiments, R2 is isopropoxy. In other embodiments, R2 is 1-butoxy. In other embodiments, R2 is 2-butoxy. In other embodiments, R2 is O-tBu. In other embodiments, R2 is R8-OH. In other embodiments, R2 is CH2-OH. In other embodiments, R2 is CH2-CH2-O-CH3. In other embodiments, R2 is -R8-R10. In other embodiments, -R8-R10is CH2- CH2-CCH. In other embodiments, R2 is CH2-O-CH2-CH2-O-CH3. In other embodiments, R2 is NHC(0)-R10. In other embodiments, R2 is COOH. In other embodiments, R2 is -C(O)Ph. In other embodiments, R2 is C(0)0-R10. In other embodiments, R2 is R8-C(0)-R10. In other embodiments, R2 is C(O)H. In other embodiments, R2 is C(0)-R10. In other embodiments, R2 is C1-C5linear or branched C(O)-haloalkyl. In other embodiments, R2 is -C(0)NH2. In other embodiments, R2 is C(O)NHR. In other embodiments, R2 is C(0)N(R10)(R11). In other embodiments, R2 is R20. In other embodiments, R2 is SO2R. In other embodiments, R2 is S02N(R10)(R11) • In other embodiments, R2 is NHSO2(R10). In other embodiments, R2 is C1-C5linear or branched haloalkoxy. In other embodiments, R2 is OCF3. In other embodiments, R2 is OCHF2. In other embodiments, R2 is substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl, cyclopentyl). In other embodiments, R2 is substituted or unsubstituted 3-8 membered heterocyclic ring. In other embodiments, R2 is substituted or unsubstituted aryl. In other embodiments, R2 is phenyl. In other embodiments, R2 is substituted or unsubstituted benzyl. In other embodiments, R2 may be further substituted with at least one substitution selected from: F, Cl, Br, I, OH, SH, C1-C5linear or branched alkyl, C2-C5linear or branched alkenyl, C2-C5linear or branched alkynyl (e.g., CCH), C1-C5linear or branched alkoxy (e.g., methoxy), 3-8 membered heterocyclic ring (e.g., piperidine), NH2, N(R)2, CF3, aryl, phenyl, halophenyl, CN, NO2; each is a separate embodiment according to this invention.

[0038] In some embodiments, Ri andR2of formula I are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic (e.g., benzene) or heterocyclic (e.g., pyridine) ring; each represents a separate embodiment according to this invention. In someembodiments, Ri and R2 are joined together to form a pyrrol ring. In some embodiments, Ri and R2 are joined together to form a benzene ring. In some embodiments, Ri andR2 are joined together to form a pyridine ring. In some embodiments, Ri andR2 are joined together to form a [l,3]dioxole ring. In some embodiments, Ri andR2 are joined together to form a furanone ring.

[0039] In some embodiments, R3 of formula II is H. In other embodiments, R3 is Cl. In other embodiments, R3 is I. In other embodiments, R3 is F. In other embodiments, R3 is Br. In other embodiments, R3 is OH. In other embodiments, R3 is SH. In other embodiments, R3 is R8-OH. In other embodiments, R3 is CH2OH. In other embodiments, R3 is R8-SH. In other embodiments, R3 is -R8-O-R10. In other embodiments, R8-O-R10is CH2-O-CH2-CCH, CH2-O-CH3, CH2-CH2-O- CH3, CH2-O-CH2-CH2-O-CH3; each represents a separate embodiment according to this invention. In other embodiments, R3is CH2-O-CH2-CCH, CH2-O-CH3, CH2-CH2-O-CH3, CH2-O-CH2-CH2- O-CH3; each represents a separate embodiment according to this invention. In other embodiments, R3 is O-R10. In other embodiments, O-R10 is O-CH2-CH2-CCH. In other embodiments, R3 is O- CH2-CH2-CCH. In other embodiments, R3 is -O-R8-O-R10. In other embodiments, R3 is O-CH2- CH2-O-CH3. In other embodiments, R3 is Re-O-R8-O-R10. In other embodiments, R3 is CH2-O- CH2-CH2-O-CH3. In other embodiments, R3 is R8-(C3-Cs cycloalkyl). In other embodiments, R3 is R8-(3-8 membered heterocyclic ring). In other embodiments, R3 is O-R20. In other embodiments, R3 is CF3. In other embodiments, R3 is CN. In other embodiments, R3 is NO2. In other embodiments, R3 is NH2. In other embodiments, R3 is NHR. In other embodiments, R3 is N(R)2. In other embodiments, R3 is N(R10)(R11). In other embodiments, R3 is N(CH3)2. In other embodiments, R3 is NH(CH3). In other embodiments, R3 is R8-N(R10)(R11). In other embodiments, R3 is CH2-NH2. In other embodiments, R3 is CH2-N(CH3)2. In other embodiments, R3 is NHC(O)- R. In other embodiments, R3 is NHCO-Ph. In other embodiments, R3 is NHCO-CH3. In other embodiments, R3 is NHC(0)-R10. In other embodiments, R3 is NHCO-CH3. In other embodiments, R3 is NHCO-N(R10)(R11). In other embodiments, R3 is COOH. In other embodiments, R3 is C(0)0-R10. In other embodiments, R3 is C(O)O-CH2CH3. In other embodiments, R3 is R8-C(O)- R10. In other embodiments, R3 is CH2C(O)CH3. In other embodiments, R3 is C(O)-CH2CH3. In other embodiments, R3 is C(O)H. In other embodiments, R3 is C(0)-R10. In other embodiments, R3 is C(O)-CH3. In other embodiments, R3 is -C(O)NH2. In other embodiments, R3 is C(O)NHR. In other embodiments, R3 is C(O)NH-CH3. In other embodiments, R3 is C(0)N(R10)(R11). In other embodiments, R3 is C(O)N(CH3)2. In other embodiments, R3 is SO2R. In other embodiments, R3 is S02N(RIO)(RII). In other embodiments, R3 is SChNCCHsh- In other embodiments, R3 is NHSChCR10). In other embodiments, R3 is NHSO2CH3. In other embodiments, R3 is C1-C5linear or branched, substituted or unsubstituted alkyl. In other embodiments, R3 is C1-C5linear orbranched, unsubstituted alkyl. In other embodiments, R3 is methyl. In other embodiments, R3 is ethyl. In other embodiments, R3 is propyl. In other embodiments, R3 is iso-propyl. In other embodiments, R3 is t-Bu. In other embodiments, R3 is iso-butyl. In other embodiments, R3 is pentyl. In other embodiments, R3 is C1-C5linear or branched, substituted alkyl. In some embodiments, R3 is a alkyl substituted with at least one substitution including but not limited to: C2-C5linear or branched alkenyl and C2-C5linear or branched alkynyl. In some embodiments, R3 is a alkyl substituted with C2-C5linear or branched alkynyl. In other embodiments, R3 is CH(CH3)(0H). In other embodiments, R3 is C(CH3)2(OH). In other embodiments, R3 is CH(CF3)(NH2) . In other embodiments, R3 is a C1-C5linear or branched, substituted or unsubstituted alkenyl. In other embodiments, R3 is substituted or unsubstituted C1-C5linear, branched or cyclic haloalkyl. In other embodiments, R3 is CF2CH3. In other embodiments, R3 is CF2-cyclobutyl. In other embodiments, R3 is CH2CF3. In other embodiments, R3 is CF2CH2CH3. In other embodiments, R3 is CF3. In other embodiments, R3 is CF2CH2CH3. In other embodiments, R3 is CH2CH2CF3. In other embodiments, R3 is CF2CH(CH3)2. In other embodiments, R3 is CF(CH3)-CH(CH3)2. In other embodiments, R3 is substituted C1-C5linear, branched or cyclic haloalkyl. In other embodiments, R3 is CHF2. In some embodiments, R3 is a haloalkyl substituted with at least one substitution including but not limited to: OH, NH2 or alkoxy. In other embodiments, R3 is CH(0H)(CF3). In other embodiments, R3 is CH(CF3)(NH2). In other embodiments, R3 is CF2(OH). In other embodiments, R3 is CHF(OH). In other embodiments, R3 is CF2(OCH3) . In other embodiments, R3 is C1-C5linear, branched or cyclic alkoxy. In other embodiments, R3 is methoxy. In other embodiments, R3 is isopropoxy. In other embodiments, R3 is C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy. In other embodiments, R3 is OCHF2. In other embodiments, R3 is C1-C5linear or branched alkoxyalkyl. In other embodiments, R3 is substituted or unsubstituted C3-C8cycloalkyl. In other embodiments, R3 is cyclopropyl. In other embodiments, R3 is cyclopentyl. In other embodiments, R3 is substituted or unsubstituted 3-8 membered single, fused, bridged or spiro, saturated, unsaturated or aromatic heterocyclic ring. In other embodiments, R3 is 3-8 membered saturated heterocyclic ring. In other embodiments, R3 is 5-7 membered saturated heterocyclic ring. In other embodiments, R3 is morpholine, azetidine, piperidine, piperazine, pyrrolidine, oxetane, 1,4-diazepane, 2- oxazolidinone; each represents a separate embodiment according to this invention. In other embodiments, R3 is 3-8 membered unsaturated heterocyclic ring. In other embodiments, R3 is 5-7 membered unsaturated heterocyclic ring. In other embodiments, R3 is 2-piperazinone, 2- pyrrolidone, l,2-Dihydro-3H-l,2,4-triazol-3-one, 2-oxazolidinone, lH-l,2,4-triazol-5(4H)-one; each represents a separate embodiment according to this invention. In other embodiments, R3 is 3-8 membered aromatic heterocyclic ring (i.e. heteroaromatic ring). In other embodiments, R3 is 5- 7 membered heteroaromatic ring. In other embodiments, R3 is pyrazole, imidazole, triazole, oxadiazole, tetrazole; each represents a separate embodiment according to this invention. In other embodiments, R3 is 7-12 membered fused, bridged or spiro, saturated or unsaturated carbocyclic or heterocyclic ring system. In other embodiments, R3 is 4,7-diazaspiro[2.5]octane, 3- azabicyclo[3.1.0]hexane, spiro[azetidine-3,l'-cyclobutane], 2-azaspiro[3.3]heptane; each represents a separate embodiment according to this invention. In some embodiments, the heterocyclic ring is further substituted with at least one substituent selected from: F, Cl, Br, I, CN, NO2, OH, SH, NH2, NHR (e.g., NH(CH3)), N(R)2, N(R10)(R11), R8-N(R10)(R11) (e.g., N(CH3)2), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH3, CH2-CH2-CCH), C1-C5linear or branched, substituted or unsubstituted linear, branched or cyclic haloalkyl (e.g., CHF2), and R8-OH (e.g., CH2-OH, CH2-CH2-OH), -R8-RIO (e.g., CH2-CH2-CCH), -C(O)NH2, R20, and Cs- Cs cycloalkyl; each represents a separate embodiment according to this invention. In other embodiments, R3 is morpholine. In other embodiments, R3 is azetidine. In other embodiments, R3 is pyrazole. In other embodiments, R3 is piperidine. In other embodiments, R3 is triazole. In other embodiments, R3 is 2-pyrrolidone. In other embodiments, R3 is pyrrolidine. In other embodiments, R3 is oxadiazole. In other embodiments, R3 is tetrazole. In other embodiments, R3 is imidazole. In other embodiments, R3 is piperazine. In other embodiments, R3 is oxetane. In other embodiments, R3 is 2-oxazolidinone. In other embodiments, R3 is piperazinone. In other embodiments, R3 is 1,4- diazepane. In other embodiments, R3 is l,2-Dihydro-3H-l,2,4-triazol-3-one. In other embodiments, R3 is pyridine. In other embodiments, R3 is 2-pyridine. In other embodiments, R3 is 3-pyridine. In other embodiments, R3 is 4-pyridine. In other embodiments, R3 is thiazole. In other embodiments, R3 is thiophene. In other embodiments, R3 is oxazole. In other embodiments, R3 is isoxazole. In other embodiments, R3 is furane. In other embodiments, R3 is pyrimidine. In other embodiments, R3 is pyrazine. In other embodiments, R3 is oxacyclobutane. In other embodiments, R3 is indole. In other embodiments, R3 is 3-methyl-4H-l,2,4-triazole. In other embodiments, R3 is 5-methyl-l,2,4-oxadiazole. In other embodiments, R3 is 4,7-diazaspiro[2.5]octane. In other embodiments, R3 is 3-azabicyclo[3.1.0]hexane. In other embodiments, R3 is spiro[azetidine-3,l'- cyclobutane] . In other embodiments, R3 is 2-azaspiro[3.3]heptane. In other embodiments, R3 is substituted or unsubstituted aryl. In other embodiments, R3 is phenyl. In other embodiments, R3 is substituted or unsubstituted benzyl. In some embodiments, R3 is further substituted with at least one substituent selected from: F, Cl, Br, I, CN, NO2, OH, SH, NH2, NHR, N(R)2, N(R10)(R11), R8- N(R10)(R11), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH3, CH2-CH2- CCH), C1-C5linear or branched, substituted or unsubstituted linear, branched or cyclic haloalkyl(e.g., CHF2), R8-OH (e.g., CH2-OH, CH2-CH2-OH), R8-SH, -R8-RIO (e.g., CH2-CH2-CCH), -R8- O-R10, NHC(0)-R10, COOH, -C(O)Ph, C(0)0-R10, R8-C(0)-R10, C(O)H, C(0)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(0)N(R10)(R11), SO2R, S02N(R10)(R11), NHSOiCR10), CH(CF3)(NH-RIO), R20, C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear, branched or cyclic alkoxy, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted Ca-C8cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl. In some embodiments, R3 is further substituted with at least one substituent selected from: F, Cl, Br, I, CN, NO2, OH, SH, NH2, NHR, N(R)2, N(RIO)(RII), R8-N(RIO)(RII), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH3, CH2-CH2-CCH), C1-C5linear or branched, substituted or unsubstituted linear, branched or cyclic haloalkyl (e.g., CHF2), and R8-OH (e.g., CH2-OH, CH2-CH2-OH), -R8-RIO (e.g., CH2- CH2-CCH), -C(O)NH2, R20.

[0040] In some embodiments, R3 of formula 11(a) is a substituted or unsubstituted C1-C5linear, branched or cyclic haloalkyl. In some embodiments, R3 is a substituted C1-C5linear, branched or cyclic haloalkyl. In some embodiments, R3 is a substituted C1-C5linear haloalkyl. In some embodiments, R3 is a substituted C1-C5branched haloalkyl. In some embodiments, R3 is a substituted C1-C5cyclic haloalkyl. In some embodiments, R3 is CHF2. In some embodiments, R3 is CH(OH)(CF3). In some embodiments, R3 is CH(CF3)(NH2). In some embodiments, R3 is CF2(OH). In some embodiments, R3 is CHF(OH). In some embodiments, R3 is CF2(OCH3). In some embodiments, R3 is R8-0-R10. In some embodiments, R3 is CH2-O-CH2-CCH. In some embodiments, R3 is O-R10. In some embodiments, R3 is O-CH2-CH2-CCH. In some embodiments, R3 is O-R20.

[0041] In some embodiments, R4of formula II and / or 11(a) is H. In other embodiments, R4is Ci- C5linear or branched, substituted or unsubstituted alkyl. In other embodiments, R4is methyl. In other embodiments, R4is ethyl. In other embodiments, R4is propyl. In other embodiments, R4is iso-propyl. In other embodiments, R4is t-Bu. In other embodiments, R4is iso-butyl. In other embodiments, R4is pentyl. In other embodiments, R4is F. In other embodiments, R4is Cl. In other embodiments, R4is CF3. In other embodiments, R4is CN. In some embodiments, R4of formula I-V, and / or VII-IX is H. In other embodiments, R4is Cl. In other embodiments, R4is I. In other embodiments, R4is F. In other embodiments, R4is Br. In other embodiments, R4is CF3. In other embodiments, R4is OH. In other embodiments, R4is NH2. In other embodiments, R4is NHR. In other embodiments, R4is N(R)2. In other embodiments, R4is SH. In other embodiments, R4is NO2. In other embodiments, R4is C1-C5linear, branched or cyclic haloalkyl. In otherembodiments, R4is CHF2. In other embodiments, R3 is CF2CH3. In other embodiments, R3 is CF2- cyclobutyl. In other embodiments, R4is CH2CF3. In other embodiments, R4is CF2CH2CH3. In other embodiments, R4is CF3. In other embodiments, R4is CF2CH2CH3. In other embodiments, R4is CH2CH2CF3. In other embodiments, R4is CF2CH(CH3)2. In other embodiments, R4is CF(CH3)-CH(CH3)2. In other embodiments, R4is C1-C5linear, branched or cyclic alkoxy. In other embodiments, R4is methoxy. In other embodiments, R4is isopropoxy. In other embodiments, R4is substituted or unsubstituted C3-C8cycloalkyl. In other embodiments, R4is cyclopropyl. In other embodiments, R4is cyclopentyl. In other embodiments, R4is substituted or unsubstituted 3-8 membered heterocyclic ring. In other embodiments, R4is pyrazole. In other embodiments, R4is thiazole. In other embodiments, R4is imidazole. In other embodiments, R4is thiophene. In other embodiments, R4is oxazole. In other embodiments, R4is isoxazole. In other embodiments, R4is furane. In other embodiments, R4is triazole. In other embodiments, R4is pyridine. In other embodiments, R4is 2-pyridine. In other embodiments, R4is 3-pyridine. In other embodiments, R4is 4-pyridine. In other embodiments, R4is pyrimidine. In other embodiments, R4is pyrazine. In other embodiments, R4is oxacyclobutane. In other embodiments, R4is 1 -oxacyclobutane. In other embodiments, R4is 2-oxacyclobutane. In other embodiments, R4is indole. In other embodiments, R4is 3-methyl-4H-l,2,4-triazole. In other embodiments, R4is 5-methyl-l,2,4-oxadiazole. In other embodiments, R4is substituted or unsubstituted aryl. In other embodiments, R4is phenyl. In some embodiments, R4is substituted or unsubstituted alkyl (e.g., methyl, ethyl), OH, or NH2. In some embodiments, R4is methyl, OH, or NH2.

[0042] In some embodiments, R5 of formula II and / or 11(a) is H. In other embodiments, R5 is Ci- C5linear or branched, substituted or unsubstituted alkyl. In other embodiments, R5 is methyl. In other embodiments, R5 is ethyl. In other embodiments, R5 is propyl. In other embodiments, R5 is iso-propyl. In other embodiments, R5 is t-Bu. In other embodiments, R5 is iso-butyl. In other embodiments, R5 is pentyl. In other embodiments, R5 is F. In other embodiments, R5 is Cl. In other embodiments, R5 is CF3. In other embodiments, R5 is CN. In some embodiments, R5 of formula I-V, and / or VII-IX is H. In other embodiments, R5 is Cl. In other embodiments, R5 is I. In other embodiments, R5 is F. In other embodiments, R5 is Br. In other embodiments, R5 is CF3. In other embodiments, R5 is OH. In other embodiments, R5 is NH2. In other embodiments, R5 is NHR. In other embodiments, R5 is N(R)2. In other embodiments, R5 is SH. In other embodiments, R5 is NO2. In other embodiments, R5 is C1-C5linear, branched or cyclic haloalkyl. In other embodiments, R5 is CHF2. In other embodiments, R3 is CF2CH3. In other embodiments, R5 is CF2- cyclobutyl. In other embodiments, R5 is CH2CF3. In other embodiments, R5 is CF2CH2CH3. In other embodiments, R5 is CF3. In other embodiments, R5 is CF2CH2CH3. In other embodiments,R8is CH2CH2CF3. In other embodiments, R8is CF2CH(CH3)2. In other embodiments, R8is CF(CH3)-CH(CH3)2. In other embodiments, R8is C1-C5linear, branched or cyclic alkoxy. In other embodiments, R8is methoxy. In other embodiments, R8is isopropoxy. In other embodiments, R8is substituted or unsubstituted C3-C8cycloalkyl. In other embodiments, R8is cyclopropyl. In other embodiments, R8is cyclopentyl. In other embodiments, R8is substituted or unsubstituted 3-8 membered heterocyclic ring. In other embodiments, R8is pyrazole. In other embodiments, R8is thiazole. In other embodiments, R8is imidazole. In other embodiments, R8is thiophene. In other embodiments, R8is oxazole. In other embodiments, R8is isoxazole. In other embodiments, R8is furane. In other embodiments, R8is triazole. In other embodiments, R8is pyridine. In other embodiments, R8is 2-pyridine. In other embodiments, R8is 3-pyridine. In other embodiments, R8is 4-pyridine. In other embodiments, R8is pyrimidine. In other embodiments, R8is pyrazine. In other embodiments, R8is oxacyclobutane. In other embodiments, R8is 1 -oxacyclobutane. In other embodiments, R8is 2-oxacyclobutane. In other embodiments, R8is indole. In other embodiments, R8is 3-methyl-4H-l,2,4-triazole. In other embodiments, R8is 5-methyl-l,2,4-oxadiazole. In other embodiments, R8is substituted or unsubstituted aryl. In other embodiments, R8is phenyl. In some embodiments, R8is substituted or unsubstituted alkyl (e.g., methyl, ethyl), OH, or NH2. In some embodiments, R8is methyl, OH, or NH2.

[0043] In some embodiments, R4and R8of formula II and / or 11(a) are identical. In some embodiments, R4andR8are different. In some embodiments, at least one of R4and R8is not alkyl. In some embodiments, at least one of R4and R8is not methyl.

[0044] In some embodiments, R4and R8of formula II and / or 11(a) are joined together to form a 5 or 6 membered substituted or unsubstituted, aliphatic ring. In some embodiments, R4and R8are joined together to form a cyclopentene. In some embodiments, R4and R8are joined together to form an aromatic carbocyclic ring. In some embodiments, R4and R8are joined together to form a benzene. In some embodiments, R4and R8are joined together to form an aromatic heterocyclic ring. In some embodiments, R3 and R4are joined together to form a thiophene. In some embodiments, R3 and R4are joined together to form a furane. In some embodiments, R4and R8are joined together to form a pyrrol. In some embodiments, R4and R8are joined together to form a pyrazole ring, a [l,3]dioxole ring. In some embodiments, R4and R8are joined together to form a furanone ring (e.g., furan-2(3H)-one). In some embodiments, R3 and R4are joined together to form a cyclopentene ring. In some embodiments, R4and R8are joined together to form an imidazole ring.

[0045] In some embodiments, if R3 is unsubstituted, then R4and R8are different. In some embodiments, if R3 is unsubstituted, then at least one of R4and R8is not alkyl. In someembodiments, R4and R5 are each independently substituted or unsubstituted alkyl (e.g., methyl, ethyl), OH, or NH2.

[0046] In some embodiments, R of formula 1, 1(a), II and / or 11(a) is H. In other embodiments, R is OH. In other embodiments, R is F. In other embodiments, R is Cl. In other embodiments, R is Br. In other embodiments, R is I. In other embodiments, R is CN. In other embodiments, R is CF3. In other embodiments, R is NO2. In other embodiments, R is C1-C5linear or branched, substituted or unsubstituted alkyl. In other embodiments, R is methyl. In other embodiments, R is ethyl. In other embodiments, the alkyl is substituted with linear or branched alkynyl. In other embodiments, R is CH2-CCH. In other embodiments, R is CH2-CH2-CCH. In other embodiments, R is C1-C5linear or branched alkoxy. In other embodiments, R is -R8-O-R10. In other embodiments, R is CH2-CH2-O-CH3. In other embodiments, R is C1-C5linear or branched haloalkyl. In other embodiments, R is CF3. In other embodiments, R is CF2CH3. In other embodiments, R is CH2CF3. In other embodiments, R is CF2CH2CH3. In other embodiments, R is CH2CH2CF3. In other embodiments, R is CF2CH(CH3)2. In other embodiments, R is CF(CH3)-CH(CH3)2. In other embodiments, R is R8-aryl. In other embodiments, R is CH2-Ph . In other embodiments, R is substituted or unsubstituted aryl. In other embodiments, R is phenyl. In other embodiments, R is substituted or unsubstituted heteroaryl. In other embodiments, R is pyridine. In other embodiments, R is 2, 3, or 4-pyridine. In other embodiments, two geminal R substitutions are joined together to form a 3 - 6 membered substituted or unsubstituted, aliphatic or aromatic, carbocyclic or heterocyclic ring. In other embodiments, two geminal R substitutions are joined together to form a 3 - 6 membered aliphatic ring. In other embodiments, two geminal R substitutions are joined together to form a cyclopropyl ring. In other embodiments, R may be further substituted with at least one substitution selected from: F, Cl, Br, I, OH, SH, C1-C5linear or branched alkyl, C2-C5linear or branched alkenyl, C2-C5linear or branched alkynyl, OH, alkoxy, N(R)2, CF3, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2 ; each represents a separate embodiment according to this invention.

[0047] In some embodiments, R6of formula II and / or 11(a) is CH2. In other embodiments, Re is CH2CH2. In other embodiments, Re is CH2CH2CH2. In some embodiments, Re is CH2CH2CH2CH2.

[0048] In some embodiments, v of formula II and / or 11(a) is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4. In some embodiments, v is 5. In some embodiments, v is between 1 and 3. In some embodiments, v is between 1 and 5. In some embodiments, v is between 1 and 10.

[0049] In some embodiments, R8of formula I, Ia), II and / or 11(a) is CH2. In other embodiments, R8is CH2CH2. In other embodiments, R8is CH2CH2CH2. In some embodiments, R8is CH2CH2CH2CH2.

[0050] In some embodiments, p of formula I, Ia), II and / or H(a) is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is between 1 and 3. In some embodiments, p is between 1 and 5. In some embodiments, p is between 1 and 10.

[0051] In some embodiments, R10of formula I, 1(a), II and / or 11(a) is C1-C5substituted or unsubstituted linear or branched alkyl. In other embodiments, R10is H. In other embodiments, R10is CH3. In other embodiments, R10is CH2CH3. In other embodiments, R10is CH2CH2CH3. In some embodiments, R10is isopropyl. In some embodiments, R10is butyl. In some embodiments, R10is isobutyl. In some embodiments, R10is t-butyl. In some embodiments, R10is pentyl. In some embodiments, R10is isopentyl. In some embodiments, R10is neopentyl. In some embodiments, R10is benzyl. In other embodiments, R10is CH2-CH2-O-CH3. In other embodiments, R10is CH2-CCH. In other embodiments, R10is CH2-CH2-CCH. In other embodiments, R10is C1-C5linear or branched alkoxy. In other embodiments, R10is O-CH3. In some embodiments, R10is C(O)R. In some embodiments, R10is S(O)2R. In other embodiments, R10is C2-C5linear or branched alkynyl. In other embodiments, R10is CCH.

[0052] In some embodiments, R11of formula I, 1(a), II and / or 11(a) is C1-C5substituted or unsubstituted linear or branched alkyl. In other embodiments, R11is H. In other embodiments, R11is CH3. In some embodiments, R11is ethyl. In some embodiments, R11is propyl. In some embodiments, R11is isopropyl. In some embodiments, R11is butyl. In some embodiments, R11is isobutyl. In some embodiments, R11is t-butyl. In some embodiments, R11is cyclopropyl. In some embodiments, R11is pentyl. In some embodiments, R11is isopentyl. In some embodiments, R11is neopentyl. In some embodiments, R11is benzyl. In other embodiments, R11is CH2-CH2-O-CH3. In other embodiments, R11is CH2-CCH. In other embodiments, R11is CH2-CH2-CCH. In some embodiments, R11is C(O)R. In some embodiments, R11is S(O)2R. In other embodiments, R11is C2-C5linear or branched alkynyl. In other embodiments, R11is CCH.

[0053] In some embodiments, R10and R11of formula I, Ka), II and / or 11(a) are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring. In other embodiments, R10and R11are joined to form a piperazine ring. In other embodiments, R10and R11are joined to form a piperidine ring. In some embodiments, substitutions include: F, Cl, Br, I, OH, C1-C5linear or branched alkyl, C2-C5linear or branched alkenyl, C2-C5linear or branched alkynyl, C1-C5linear or branched alkyl-OH (e.g., C(CH3)2CH2-OH, CH2CH2-OH), 3-8 membered heterocyclic ring(e.g., piperidine), alkoxy, N(R)2, CF3, aryl, phenyl, halophenyl, (benzyloxy )phenyl, CN, NO2 or any combination thereof; each represents a separate embodiment according to this invention.

[0054] In various embodiments, this invention is directed to the compounds presented in Table 1, pharmaceutical compositions and / or method of use thereof:Table 1:

[0055] It is well understood that in structures presented in this invention wherein the carbon atom has less than 4 bonds, H atoms are present to complete the valence of the carbon. It is well understood that in structures presented in this invention wherein the nitrogen atom has less than 3 bonds, H atoms are present to complete the nitrogen valence.

[0056] In some embodiments, this invention is directed to the compounds listed hereinabove, pharmaceutical compositions and / or method of use thereof, wherein the compound is pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, / V-oxidc, prodrug, isotopic variant (deuterated analog), pharmaceutical product or any combination thereof. In some embodiments, the compounds are Collagen I translation inhibitors.

[0057] In various embodiments, the C ring of formula I and / or 1(a) is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, 1 -methylimidazole, isoquinoline, pyrazolyl, pyrrolyl, furanyl, thiopheneyl, azetidinyl, isoquinolinyl, indolyl, IH-indole, isoindolyl, anthracenyl, benzimidazolyl, indazolyl, 2H-indazole, triazolyl, 4,5,6,7-tetrahydro-2H-indazole, 3H-indol-3-one, purinyl, benzoxazolyl, 1,3-benzoxazolyl, benzisoxazolyl, benzothiazolyl, 1,3-benzothiazole, 4, 5,6,7- tetrahydro-l,3-benzothiazole, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinolinyl, isoquinolinyl, 2,3-dihydroindenyl, indenyl, tetrahydronaphthyl, 3,4-dihydro-2H- benzo[b][l,4]dioxepine, benzo[d][l,3]dioxole, acridinyl, benzofuranyl, 1-benzofuran, isobenzofuranyl, benzofuran-2(3H)-one, benzothiophenyl, benzoxadiazole, benzo[c][l,2,5]oxadiazolyl, benzo [c] thiophenyl, benzodioxolyl, benzo[d][l,3]dioxole, thiadiazolyl, [l,3]oxazolo[4,5-b]pyridine, oxadiaziolyl, imidazo[2,l-b][l,3]thiazole, 4H,5H,6H- cyclopenta[d] [ 1 ,3]thiazole, 5H,6H,7H,8H-imidazo[ 1 ,2-a]pyridine, 7 -oxo-6H,7H-[l,3]thiazolo[4,5-d]pyrimidine, [l,3]thiazolo[5,4-b]pyridine, 2H,3H-imidazo[2,l-b][l,3]thiazole, thieno [3 ,2-d]pyrimidin-4(3H)-one, 4-oxo-4H-thieno [3 ,2-d] [ 1 ,3] thiazin, imidazopyridin,imidazo[l,2-a]pyridine, lH-imidazo[4,5-b]pyridine, lH-imidazo[4,5-c]pyridine, 3H-imidazo[4,5- c]pyridine, pyrazolopyridine, pyrazolo[l,5-a]pyridine, imidazo[l,2-a]pyrazine, imidazo[l,2- a]pyrimidine, lH-pyrrolo[2,3-b]pyridine, pyrido[2,3-b]pyrazine, pyrido[2,3-b]pyrazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, quinoxalin-2(lH)-one, pyrrolopyridine, lH-pyrrolo[3,2-b]pyridine, 7H- pyrrolo [2, 3-d] pyrimidine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, thieno[3,2-c]pyridine; each represents a separate embodiment according to this invention; or C is C3-Cs cycloalkyl (e.g. cyclopropyl, cyclohexyl, cyclopentyl) or 5-7 membered heterocyclic ring including but not limited to: azetidinyl, piperazinyl, pyrrolidinyl, oxetanyl, 1,4-diazepanyl, tetrahydropyranyl, piperidinyl, 1-methylpiperidinyl, tetrahydrothiophene 1,1 -dioxide, l-(piperidin-l-yl)ethenone, 2- oxazolidinone, lH-l,2,4-triazol-5(4H)-one, 4,7-diazaspiro[2.5]octane, 3- azabicyclo[3.1.0]hexane, spiro[azetidine-3,l'-cyclobutane], 2-azaspiro[3.3]heptane, or morpholinyl; each represents a separate embodiment according to this invention.

[0058] As used herein, the term “alkyl” can be any straight- or branched-chain alkyl group containing up to about 30 carbons unless otherwise specified. In various embodiments, an alkyl includes C1-C5carbons. In some embodiments, an alkyl includes Ci-Ce carbons. In some embodiments, an alkyl includes C1-C5carbons. In some embodiments, an alkyl includes C1-C10 carbons. In some embodiments, an alkyl is a C1-C12 carbons. In some embodiments, an alkyl is a C1-C20 carbons. In some embodiments, branched alkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons. In various embodiments, the alkyl group may be unsubstituted. In some embodiments, the alkyl group may be substituted by a halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C1-C5linear or branched haloalkoxy, CF3, phenyl, halophenyl, (benzyloxy)phenyl, -CH2CN, NH2, NH-alkyl, N(alkyl)2, -OC(O)CF3, -OCH2Ph, -NHCO-alkyl, - C(O)Ph, C(O)O-alkyl, C2-C5linear or branched alkenyl, C2-C5linear or branched alkynyl, C(O)H, -C(O)NH2 or any combination thereof.

[0059] The alkyl group can be a sole substituent, or it can be a component of a larger substituent, such as in an alkoxy, alkoxyalkyl, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamido, alkylurea, etc. Preferred alkyl groups are methyl, ethyl, and propyl, and thus halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylethyl, arylpropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylamido, acetamido, propylamido, halomethylamido, haloethylamido, halopropylamido, methyl-urea, ethyl-urea, propyl-urea, 2, 3, or 4-CH2-C6H4-CI, C(OH)(CH3)(Ph), etc.

[0060] As used herein, the term “aryl” refers to any aromatic ring that is directly bonded to another group and can be either substituted or unsubstituted. The aryl group can be a sole substituent, or the aryl group can be a component of a larger substituent, such as in an arylalkyl, arylamino, arylamido, etc. Exemplary aryl groups include, without limitation, phenyl, tolyl, xylyl, naphthyl, phenylmethyl, phenylethyl, phenylamino, phenylamido, etc. Substitutions include but are not limited to: F, Cl, Br, I, C1-C5linear or branched alkyl, C2-C5linear or branched alkenyl, C2-C5linear or branched alkynyl, C1-C5linear or branched haloalkyl, C1-C5linear or branched alkoxy, C1-C5linear or branched haloalkoxy, CF3, phenyl, halophenyl, (benzyloxy)phenyl, CN, NO2, - CH2CN, NH2, NH-alkyl, N(alkyl)2, hydroxyl, -OC(O)CF3, -OCH2Ph, -NHCO-alkyl, COOH, - C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH2 or any combination thereof.

[0061] As used herein, the term "alkoxy" refers to an ether group substituted by an alkyl group as defined above. Alkoxy refers both to linear and to branched alkoxy groups. Nonlimiting examples of alkoxy groups are methoxy, ethoxy, propoxy, Ao-propoxy, tert-butoxy.

[0062] As used herein, the term "aminoalkyl" refers to an amine group substituted by an alkyl group as defined above. Aminoalkyl refers to monoalkylamine, dialkylamine or trialkylamine. Nonlimiting examples of aminoalkyl groups are -N(Me)2, -NHMe, -NH3.

[0063] A “haloalkyl” group refers, in some embodiments, to an alkyl group as defined above, which is substituted by one or more halogen atoms, e.g., by F, Cl, Br or I. The term “haloalkyl” include but is not limited to fluoroalkyl, i.e., to an alkyl group bearing at least one fluorine atom. Nonlimiting examples of haloalkyl groups are CF3, CF2CF3, CF2CH3, CH2CF3, CF2CH2CH3, CH2CH2CF3, CF2CH(CH3)2and CF(CH3)-CH(CH3)2.

[0064] A “halophenyl” group refers, in some embodiments, to a phenyl substitutent which is substituted by one or more halogen atoms, e.g., by F, Cl, Br or I. In one embodiment, the halophenyl is 4-chlorophenyl.

[0065] An “alkoxyalkyl” group refers, in some embodiments, to an alkyl group as defined above, which is substituted by alkoxy group as defined above, e.g., by methoxy, ethoxy, propoxy, i-propoxy, t-butoxy etc. Nonlimiting examples of alkoxyalkyl groups are -CH2-O-CH3, -CH2-O-CH(CH3)2, - CH2-O-C(CH3)3, -CH2-CH2-O-CH3, -CH2-CH2-O-CH(CH3)2, -CH2-CH2-O-C(CH3)3.

[0066] A “cycloalkyl” or "carbocyclic" group refers, in various embodiments, to a ring structure comprising carbon atoms as ring atoms, which may be either saturated or unsaturated, substituted or unsubstituted, single or fused. In some embodiments the cycloalkyl is a 3-10 membered ring. In some embodiments the cycloalkyl is a 3-12 membered ring. In some embodiments the cycloalkyl is a 6 membered ring. In some embodiments the cycloalkyl is a 5-7 membered ring. In some embodiments the cycloalkyl is a 3-8 membered ring. In some embodiments, the cycloalkyl group may beunsubstituted or substituted by a halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C1-C5linear or branched haloalkoxy, CF3, phenyl, halophenyl, (benzyloxy)phenyl, - CH2CN, NH2, NH-alkyl, N(alkyl)2, -OC(O)CF3, -OCH2Ph, -NHCO-alkyl, -C(O)Ph, C(O)O-alkyl, C(O)H, -C(0)NH2 or any combination thereof. In some embodiments, the cycloalkyl ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring. In some embodiments, the cycloalkyl ring is a saturated ring. In some embodiments, the cycloalkyl ring is an unsaturated ring. Non limiteing examples of a cycloalkyl group comprise cyclohexyl, cyclohexenyl, cyclopropyl, cyclopropenyl, cyclopentyl, cyclopentenyl, cyclobutyl, cyclobutenyl, cycloctyl, cycloctadienyl (COD), cycloctaene (COE) etc.

[0067] A “heterocycle” or "heterocyclic" group refers, in various embodiments, to a ring structure comprising in addition to carbon atoms, sulfur, oxygen, nitrogen or any combination thereof, as part of the ring. A “heteroaromatic ring” refers in various embodiments, to an aromatic ring structure comprising in addition to carbon atoms, sulfur, oxygen, nitrogen or any combination thereof, as part of the ring. In some embodiments the heterocycle or heteroaromatic ring is a 3-10 membered ring. In some embodiments the heterocycle or heteroaromatic ring is a 3-12 membered ring. In some embodiments the heterocycle or heteroaromatic ring is a 6 membered ring. In some embodiments the heterocycle or heteroaromatic ring is a 5-7 membered ring. In some embodiments the heterocycle or heteroaromatic ring is a 3-8 membered ring. In some embodiments, the heterocycle group or heteroaromatic ring may be unsubstituted or substituted by a halogen, alkyl, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, thio, thioalkyl, C1-C5linear or branched haloalkoxy, CF3, phenyl, halophenyl, (benzyloxy)phenyl, -CH2CN, NH2, NH-alkyl, N(alkyl)2, -OC(O)CF3, -OCH2Ph, -NHCO-alkyl, - C(O)Ph, C(O)O-alkyl, C(O)H, -C(O)NH2 or any combination thereof. In some embodiments, the heterocycle ring or heteroaromatic ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring. In some embodiments, the heterocyclic ring is a saturated ring. In some embodiments, the heterocyclic ring is an unsaturated ring. In some embodiments, the heterocyclic ring is an aromatic ring. Non limiting examples of a heterocyclic ring or heteroaromatic ring systems comprise pyridine, piperidine, morpholine, piperazine, thiophene, pyrrole, benzodioxole, benzofuran-2(3H)-one, benzo[d][l,3]dioxole, indole, oxazole, isoxazole, imidazole and 1 -methylimidazole, furane, triazole, pyrimidine, pyrazine, oxacyclobutane (1 or 2- oxacyclobutane), naphthalene, tetrahydrothiophene 1,1 -dioxide, thiazole, benzimidazole, piperidine, 1 -methylpiperidine, isoquinoline, 1,3-dihydroisobenzofuran, benzofuran, 3-methyl-4H-l,2,4- triazole, 5-methyl-l,2,4-oxadiazole, or indole.

[0068] In various embodiments, this invention provides a compound of this invention or its isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, A-oxide, prodrug, isotopic variant (deuterated analog), polymorph, or crystal or combinations thereof. In various embodiments, this invention provides an isomer of the compound of this invention. In some embodiments, this invention provides a metabolite of the compound of this invention. In some embodiments, this invention provides a pharmaceutically acceptable salt of the compound of this invention. In some embodiments, this invention provides a pharmaceutical product of the compound of this invention. In some embodiments, this invention provides a tautomer of the compound of this invention. In some embodiments, this invention provides a hydrate of the compound of this invention. In some embodiments, this invention provides an A-oxidc of the compound of this invention. In some embodiments, this invention provides a prodrug of the compound of this invention. In some embodiments, this invention provides an isotopic variant (including but not limited to deuterated analog) of the compound of this invention. In some embodiments, this invention provides a PROTAC (Proteolysis targeting chimera) of the compound of this invention. In some embodiments, this invention provides a polymorph of the compound of this invention. In some embodiments, this invention provides a crystal of the compound of this invention. In some embodiments, this invention provides composition comprising a compound of this invention, as described herein, or, In some embodiments, a combination of an isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, A-oxide, prodrug, isotopic variant (deuterated analog), polymorph, or crystal of the compound of this invention.

[0069] In various embodiments, the term “isomer” includes, but is not limited to, stereoisomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like. In some embodiments, the isomer is an optical isomer. In some embodiments, the isomer is a stereoisomer.

[0070] In various embodiments, this invention encompasses the use of various stereoisomers of the compounds of the invention. It will be appreciated by those skilled in the art that the compounds of the present invention may contain at least one chiral center. Accordingly, the compounds used in the methods of the present invention may exist in, and be isolated in, optically-active or racemic forms. Accordingly, the compounds according to this invention may exist as optically-active isomers (enantiomers or diastereomers, including but not limited to: the ( / ?), (S), (R)(R), (R)(S), (S)(S), (S)(R), (R)(R)(R), (R)(R)(S), (R)(S)(R), (S)(R)(R), (R)(S)(S), (S)(R)(S), (S)(S)(R) or (S)(S)(S) isomers); as racemic mixtures, or as enantiomerically enriched mixtures. Some compounds may also exhibit polymorphism. It is to be understood that the present invention encompasses anyracemic, optically-active, polymorphic, or stereroisomeric form, or mixtures thereof, which form possesses properties useful in the treatment of the various conditions described herein.

[0071] It is well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

[0072] The compounds of the present invention can also be present in the form of a racemic mixture, containing substantially equivalent amounts of stereoisomers. In some embodiments, the compounds of the present invention can be prepared or otherwise isolated, using known procedures, to obtain a stereoisomer substantially free of its corresponding stereoisomer (i.e., substantially pure). By substantially pure, it is intended that a stereoisomer is at least about 95% pure, more preferably at least about 98% pure, most preferably at least about 99% pure. In various embodiments, the compound according to the invention comprises a substantially pure stereoisomer. In some embodiments, the substantially pure stereoisomer is at least 70%; 75%; 80%; 85%; 90%; 93%; 95%; 97%; 98%; 99%; 99.5% pure; each represents a separate embodiment according to this invention.

[0073] In various embodiments, the compound comprises a single stereoisomer in a purity of >80%; >85%; >90%; >91%; >92%; >93%; >94%; >95%; >96%; >97%; >98%; >99%; >99.5% enantiomeric excess (ee); each represents a separate embodiment according to this invention. In various embodiments, the compound comprises a single stereoisomer in a purity >80%; >85%; >90%; >91%; >92%; >93%; >94%; >95%; >96%; >97%; >98%; >99%; >99.5% enantiomeric ratio (er); each represents a separate embodiment according to this invention. In various embodiments, the compound comprises a single stereoisomer in a purity higher than 80%; 85%; 90%; 91%; 92%; 93%; 94%; 95%; 96%; 97%; 98%; 99%; 99.5%; each represents a separate embodiment according to this invention.

[0074] In various embodiments, the compound is a substantially pure single enantiomer. In various embodiments, the compound comprises a mixture of enantiomers. In various embodiments, the compound is a racemate.

[0075] In various embodiments, the compound has two chiral centers. In various embodiments, the compound comprises a mixture of stereoisomers. In various embodiments, the compound comprises a mixture of 2, 3, or 4 stereoisomers; each represents a separate embodiment according to this invention. In various embodiments, the compound is a single stereoisomer. In various embodiments, the compound is a substantially pure single stereoisomer. In various embodiments, the substantially pure stereoisomer has at least 80%, 85%, 90%, 95%, 97%, 98%, 99% purity; each represents a separate embodiment according to this invention. In various embodiments, thecompound is the substantially pure RR stereoisomer. In various embodiments, the compound is the substantially pure 55 stereoisomer. In various embodiments, the compound is the substantially pure RS stereoisomer. In various embodiments, the compound is the substantially pure SR stereoisomer.

[0076] Compounds of the present invention can also be in the form of a hydrate, which means that the compound further includes a stoichiometric or non- stoichiometric amount of water bound by non- covalent intermolecular forces.

[0077] As used herein, when some chemical functional group (e.g., alkyl or aryl) is said to be “substituted”, it is herein defined that one or more substitutions are possible. In some embodiments, the term “substituted” according to this invention, refers to but is not limited to at least one group selected from: F, Cl, Br, I, OH, CF3, CN, NO2, C1-C5linear or branched alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tertbutyl, pentyl, isopentyl, neopentyl, hexyl), C2-C5linear or branched alkenyl, C2-C5linear or branched alkynyl, C1-C5linear or branched haloalkyl, OH, C1-C5linear or branched alkoxy, cyclic alkoxy (e.g., oxetane), R8-OH (e.g., CH2- OH), OMe, amide (i.e., C(O)-NH-alkyl or NH-C(O)-alkyl), C(0)N(R10)(R11), R8- C(0)N(R10)(R11), NH(R10), N(R10)(R11), NH2, aryl, phenyl, heteroaryl, substituted or unsubstituted Ca-Cs cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic ring, which may be saturated, unsaturated, aromatic, single, fused, bridged or spiral ( e.g., pyran, oxetane, piperidine, pyrazole, methyl-pyrrazole, triazole, imidazole); each represents a separate embodiment according to this invention.

[0078] As used herein, when some chemical functional group ( e.g., alkyl or aryl) is said to be “substituted”, it is herein defined that one or more substitutions are possible.

[0079] Compounds of the present invention may exist in the form of one or more of the possible tautomers and depending on the conditions it may be possible to separate some or all of the tautomers into individual and distinct entities. It is to be understood that all of the possible tautomers, including all additional enol and keto tautomers and / or isomers are hereby covered. For example, the following tautomers, but not limited to these, are included: Tautomerization of the imidazole ring:Tautomerization of the pyrazolone ring:

[0080] The invention includes “pharmaceutically acceptable salts” of the compounds of this invention, which may be produced, by reaction of a compound of this invention with an acid or base. Certain compounds, particularly those possessing acid or basic groups, can also be in the form of a salt, preferably a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to those salts that retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N- acetylcysteine and the like. Other salts are known to those of skill in the art and can readily be adapted for use in accordance with the present invention.

[0081] Suitable pharmaceutically acceptable salts of amines of compounds the compounds of this invention may be prepared from an inorganic acid or from an organic acid. In various embodiments, examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates (hydroxy ethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates and thiocyanates.

[0082] In various embodiments, examples of organic salts of amines may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decanoates, enanthuates, ethanesulfonates, edetates, edisylates, estolates, esylates, fumarates, formates, fluorides, galacturonates gluconates, glutamates, glycolates, glucorate, glucoheptanoates, glycerophosphates, gluceptates, glycollylarsanilates, glutarates, glutamate, heptanoates, hexanoates, hydroxymaleates,hydroxycarboxlic acids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoates, hydrofluorates, lactates, lactobionates, laurates, malates, maleates, methylenebis(beta- oxynaphthoate), malonates, mandelates, mesylates, methane sulfonates, methylbromides, methylnitrates, methylsulfonates, monopotassium maleates, mucates, monocarboxylates, naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, napsylates, N- methylglucamines, oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalates, propionates, phthalates, phenylacetate, pectinates, phenylpropionates, palmitates, pantothenates, polygalacturates, pyruvates, quinates, salicylates, succinates, stearates, sulfanilate, subacetates, tartrates, theophyllineacetates, p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates, triethiodide, tricarboxylates, undecanoates and valerates.

[0083] In various embodiments, examples of inorganic salts of carboxylic acids or hydroxyls may be selected from ammonium, alkali metals to include lithium, sodium, potassium, cesium; alkaline earth metals to include calcium, magnesium, aluminium; zinc, barium, cholines, quaternary ammoniums.

[0084] In some embodiments, examples of organic salts of carboxylic acids or hydroxyl may be selected from arginine, organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, t-butylamines, benethamines (N- benzylphenethylamine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, meglamines, / V-mcthyl-D- glucamines, MA’-dibcnzylcthylcncdiamincs, nicotinamides, organic amines, ornithines, pyridines, picolies, piperazines, procain, tris(hydroxymethyl)methylamines, triethylamines, triethanolamines, trimethylamines, tromethamines and ureas.

[0085] In various embodiments, the salts may be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of a existing salt for another ion or suitable ion-exchange resin.Pharmaceutical composition

[0086] Another aspect of the present invention relates to a pharmaceutical composition including a pharmaceutically acceptable carrier and a compound according to the aspects of the present invention. The pharmaceutical composition can contain one or more of the above-identified compounds of the present invention. Typically, the pharmaceutical composition of the present invention will include acompound of the present invention or its pharmaceutically acceptable salt, as well as a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to any suitable adjuvants, carriers, excipients, or stabilizers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.

[0087] Typically, the composition will contain from about 0.01 to 99 percent, preferably from about 20 to 75 percent of active compound(s), together with the adjuvants, carriers and / or excipients. While individual needs may vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typical dosages comprise about 0.01 to about 100 mg / kg body wt. The preferred dosages comprise about 0.1 to about 100 mg / kg body wt. The most preferred dosages comprise about 1 to about 100 mg / kg body wt. Treatment regimen for the administration of the compounds of the present invention can also be determined readily by those with ordinary skill in art. That is, the frequency of administration and size of the dose can be established by routine optimization, preferably while minimizing any side effects.

[0088] The solid unit dosage forms can be of the conventional type. The solid form can be a capsule and the like, such as an ordinary gelatin type containing the compounds of the present invention and a carrier, for example, lubricants and inert fillers such as, lactose, sucrose, or cornstarch. In some embodiments, these compounds are tabulated with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin, disintegrating agents, such as cornstarch, potato starch, or alginic acid, and a lubricant, like stearic acid or magnesium stearate.

[0089] The tablets, capsules, and the like can also contain a binder such as gum tragacanth, acacia, com starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0090] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets can be coated with shellac, sugar, or both. A syrup can contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.

[0091] For oral therapeutic administration, these active compounds can be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compound in these compositions can, of course, be varied and can conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeuticallyuseful compositions is such that a suitable dosage will be obtained. Preferred compositions according to the present invention are prepared so that an oral dosage unit contains between about 1 mg and 800 mg of active compound.

[0092] The active compounds of the present invention may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they can be enclosed in hard or soft shell capsules, or they can be compressed into tablets, or they can be incorporated directly with the food of the diet.

[0093] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0094] The compounds or pharmaceutical compositions of the present invention may also be administered in injectable dosages by solution or suspension of these materials in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier or excipient. Such adjuvants, carriers and / or excipients include, but are not limited to, sterile liquids, such as water and oils, with or without the addition of a surfactant and other pharmaceutically and physiologically acceptable components. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.

[0095] These active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0096] For use as aerosols, the compounds of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example,hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The materials of the present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer.

[0097] In various embodiments, the compounds of this invention are administered in combination with an agent treating fibrosis. In some embodiment, the agent treating lung fibrosis is at least one selected from: pirfenidone and Nintedanib. Other examples of agents which can be useful in treating lung fibrosis including IPF, in combination with compound of the invention, include but are not limited to: Pioglitazone, Tralokinumab, Lebrikizumab, FG-3019, Simtuzumab, STX-100, BMS-986020, Rituximab, Carbon Monoxide, Azithromycin, and Cotrimoxazole. In various embodiments, the compounds of this invention are administered in combination with an agent treating NASH.

[0098] When administering the compounds of the present invention, they can be administered systemically or, alternatively, they can be administered directly to a specific site where fibrosis is present. Thus, administering can be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the fibrotic cells. Exemplary modes of administration include, without limitation, administering the compounds or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes.Biological Activity

[0099] In various embodiments, the invention provides compounds and compositions, including any embodiment described herein, for use in any of the methods of this invention. In various embodiments, use of a compound of this invention or a composition comprising the same, will have utility in inhibiting, suppressing, enhancing or stimulating a desired response in a subject, as will be understood by one skilled in the art. In some embodiments, the compositions may further comprise additional active ingredients, whose activity is useful for the particular application for which the compound of this invention is being administered.

[0100] The invention relates to the treatment, inhibition and reduction of fibrosis, including lung and hepatic fibrosis. More specifically, embodiments of the invention provide compositions and methods useful for the treatment and inhibition of fibrotic disorders, lung fibrosis, Idiotypic pulmonary fibrosis (IPF), hepato-fibrotic conditions associated with Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH), employing the use of a compoundaccording to this invention or a pharmaceutically acceptable salt thereof. In another embodiment, the human subject is afflicted with lung fibrosis. In another embodiment, the human subject is afflicted with Idiotypic pulmonary fibrosis (IPF). In another embodiment, the human subject is afflicted with Non-Alcoholic Fatty Liver Disease (NAFLD). In another embodiment, the human subject is afflicted with Non-Alcoholic Steatohepatitis (NASH). In another embodiment, the human subject is not afflicted with Non-Alcoholic Steatohepatitis (NASH).

[0102] In various conditions, the formation of fibrotic tissue is characterized by the deposition of abnormally large amounts of collagen. The synthesis of collagen is also involved in a number of other pathological conditions. For example, clinical conditions and disorders associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus host disease (GVHD), pulmonary fibrosis and autoimmune disorders, are distinguished by excessive production of connective tissue, which results in the destruction of normal tissue architecture and function. These diseases can best be interpreted in terms of perturbations in cellular functions, a major manifestation of which is excessive collagen synthesis and deposition. The role of collagen in fibrosis has prompted attempts to develop drugs that inhibit its accumulation.

[0103] Excessive accumulation of collagen is the major pathologic feature in a variety of clinical conditions characterized by tissue fibrosis. These conditions include localized processes, as for example, pulmonary fibrosis and liver cirrhosis, or more generalized processes, like progressive systemic sclerosis. Collagen deposition is a feature of different forms of dermal fibrosis, which in addition to scleroderma, include localized and generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenoma and connective tissue nevi of the collagen type. Recent advances in the understanding of the normal biochemistry of collagen have allowed us to define specific levels of collagen biosynthesis and degradation at which a pharmacologic intervention could lead to reduced collagen deposition in the tissues. Such compounds could potentially provide us with novel means to reduce the excessive collagen accumulation in diseases.

[0104] Accordingly, in various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting fibrosis in a subject, comprising administering a compound according to this invention, to a subject suffering from fibrosis under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit fibrosis in said subject. In some embodiments, the fibrosis is systemic. In some embodiments, the fibrosis is organ specific. In some embodiments, the fibrosis is a result of wound healing. In some embodiments, the fibrosis is a result of scarring. In some embodiments, the fibrosis is primary or secondary fibrosis. In some embodiments, the fibrosis is a result of systemic sclerosis, progressive systemic sclerosis, graft-versus host disease (GVHD), pulmonaryfibrosis, autoimmune disorders, or any combination thereof; each represents a separate embodiment according to this invention. In another embodiment, the human subject is afflicted with lung fibrosis. In another embodiment, the human subject is afflicted with Idiotypic pulmonary fibrosis (IPF). In some embodiments, the fibrosis is pulmonary fibrosis. In some embodiments, the subject has a liver cirrhosis. In some embodiments, the fibrosis is hepatic fibrosis, lung fibrosis or dermal fibrosis. In some embodiments, the dermal fibrosis is scleroderma. In some embodiments, the dermal fibrosis is a result of a localized or generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenoma, connective tissue nevi of the collagen type, or any combination thereof; each represents a separate embodiment according to this invention. In some embodiments, the fibrosis results from tissue injury, inflammation, oxidative stress or any combination thereof; each represents a separate embodiment according to this invention. In some embodiments, the fibrosis is gingival fibromatosis. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0105] Human fibrotic diseases constitute a major health problem worldwide owing to the large number of affected individuals, the incomplete knowledge of the fibrotic process pathogenesis, the marked heterogeneity in their etiology and clinical manifestations, the absence of appropriate and fully validated biomarkers, and, most importantly, the current void of effective disease-modifying therapeutic agents. The fibrotic disorders encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis (SSc), sclerodermatous graft vs. host disease, and nephrogenic systemic fibrosis, as well as numerous organ- specific disorders including radiation-induced fibrosis and cardiac, pulmonary, lung, liver, and kidney fibrosis. Although their causative mechanisms are quite diverse and, in several instances have remained elusive, these diseases share the common feature of an uncontrolled and progressive accumulation of fibrotic tissue in affected organs causing their dysfunction and ultimate failure. Despite the remarkable heterogeneity in the etiologic mechanisms responsible for the development of fibrotic diseases and in their clinical manifestations, numerous studies have identified activated myofibroblasts as the common cellular element ultimately responsible for the replacement of normal tissues with nonfunctional fibrotic tissue.

[0106] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting systemic fibrotic disease in a subject, comprising administering a compound according to this invention, to a subject suffering from a systemic fibrotic disease under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the systemic fibrotic disease in said subject. In someembodiments, the systemic fibrotic disease is systemic sclerosis. In some embodiments, the systemic fibrotic disease is multifocal fibrosclerosis (IgG4-associated fibrosis). In some embodiments, the systemic fibrotic disease is nephrogenic systemic fibrosis. In some embodiments, the systemic fibrotic disease is sclerodermatous graft vs. host disease.

[0107] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting an organ- specific fibrotic disease in a subject, comprising administering a compound according to this invention, to a subject suffering from an organ- specific fibrotic disease under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the organ- specific fibrotic disease in said subject.

[0108] In some embodiments, the organ- specific fibrotic disease is lung fibrosis. In some embodiments, the organ- specific fibrotic disease is Idiotypic pulmonary fibrosis (IPF).

[0109] In some embodiments, the organ- specific fibrotic disease is cardiac fibrosis. In some embodiments, the cardiac fibrosis is hypertension-associated cardiac fibrosis. In some embodiments, the cardiac fibrosis is post-myocardial infarction. In some embodiments, the cardiac fibrosis is chagas disease-induced myocardial fibrosis.

[0110] In some embodiments, the organ- specific fibrotic disease is kidney fibrosis. In some embodiments, the kidney fibrosis is diabetic and hypertensive nephropathy. In some embodiments, the kidney fibrosis is urinary tract obstruction-induced kidney fibrosis. In some embodiments, the kidney fibrosis is inflammatory / autoimmune-induced kidney fibrosis. In some embodiments, the kidney fibrosis is aristolochic acid nephropathy. In some embodiments, the kidney fibrosis is polycystic kidney disease.

[0111] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting cardiac fibrosis in a subject, comprising administering a compound of this invention, to a subject suffering from cardiac fibrosis under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit cardiac fibrosis in said subject. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0112] In some embodiments, the organ- specific fibrotic disease is pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is silica-induced pneumoconiosis (silicosis). In some embodiments, the pulmonary fibrosis is asbestos-induced pulmonary fibrosis (asbestosis). In some embodiments, the pulmonary fibrosis is chemotherapeutic agent-induced pulmonary fibrosis.

[0113] In some embodiments, the organ- specific fibrotic disease is liver and portal vein fibrosis. In some embodiments, the liver and portal vein fibrosis is alcoholic and nonalcoholic liver fibrosis. In some embodiments, the liver and portal vein fibrosis is hepatitis C-induced liver fibrosis. In some embodiments, the liver and portal vein fibrosis is primary biliary cirrhosis. In some embodiments, the liver and portal vein fibrosis is parasite-induced liver fibrosis (schistosomiasis).

[0114] In some embodiments, the organ- specific fibrotic disease is radiation-induced fibrosis (various organs). In some embodiments, the organ- specific fibrotic disease is bladder fibrosis. In some embodiments, the organ- specific fibrotic disease is intestinal fibrosis. In some embodiments, the organ- specific fibrotic disease is peritoneal sclerosis.

[0115] In some embodiments, the organ- specific fibrotic disease is diffuse fasciitis. In some embodiments, the diffuse fasciitis is localized scleroderma, keloids. In some embodiments, the diffuse fasciitis is dupuytren’s disease. In some embodiments, the diffuse fasciitis is peyronie’s disease. In some embodiments, the diffuse fasciitis is myelofibrosis. In some embodiments, the diffuse fasciitis is oral submucous fibrosis.

[0116] In some embodiments, the organ- specific fibrotic disease is a result of wound healing. In some embodiments, the organ- specific fibrotic disease is a result of scarring.

[0117] Fibrosis of the liver, also referred to herein as hepatic fibrosis, may be caused by various types of chronic liver injury, especially if an inflammatory component is involved. Self-limited, acute liver injury (e.g., acute viral hepatitis A), even when fulminant, does not necessarily distort the scaffolding architecture and hence does not typically cause fibrosis, despite loss of hepatocytes. However, factors such as chronic alcoholism, malnutrition, hemochromatosis, and exposure to poisons, toxins or drugs, may lead to chronic liver injury and hepatic fibrosis due to exposure to hepatotoxic chemical substances. Hepatic scarring, caused by surgery or other forms of injury associated with mechanical biliary obstruction, may also result in liver fibrosis.

[0118] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting hepatic fibrosis in a subject, comprising administering a compound of this invention, to a subject suffering from hepatic fibrosis under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit hepatic fibrosis in said subject. In some embodiments, the hepatic fibrosis results from hepatic scarring. In some embodiments, the hepatic fibrosis results from chronic liver injury. In some embodiments, the chronic liver injury results from chronic alcoholism, malnutrition, hemochromatosis, exposure to poisons, toxins or drugs; each represents a separate embodiment according to this invention. In some embodiments, the subject has a liver cirrhosis. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, thecompound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0119] Fibrosis itself is not necessarily symptomatic, however it can lead to the development of portal hypertension, in which scarring distorts blood flow through the liver, or cirrhosis, in which scarring results in disruption of normal hepatic architecture and liver dysfunction. The extent of each of these pathologies determines the clinical manifestation of hepato-fibrotic disorders. For example, congenital hepatic fibrosis affects portal vein branches, largely sparing the parenchyma. The result is portal hypertension with sparing of hepatocellular function.

[0120] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting an hepato-fibrotic disorder in a subject, comprising administering a compound of this invention, to a subject suffering from hepato-fibrotic disorder under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the hepato-fibrotic disorder in said subject. In some embodiments, the hepato-fibrotic disorder is: portal hypertension, cirrhosis, congenital hepatic fibrosis or any combination thereof; each represents a separate embodiment according to this invention. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0121] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting portal hypertension in a subject, comprising administering a compound of this invention, to a subject suffering from portal hypertension under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit portal hypertension in said subject. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0122] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting cirrhosis in a subject, comprising administering a compound of this invention, to a subject suffering from cirrhosis under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit cirrhosis in said subject. In some embodiments, the cirrhosis is a result of hepatitis. In some embodiments, the cirrhosis is a result of alcoholism. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0123] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting human alcoholism in a subject, comprising administering a compound of this invention, to a subject suffering from alcoholism under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit alcoholism in said subject. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0124] Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) have a similar pathogenesis and histopathology but a different etiology and epidemiology. NASH and ASH are advanced stages of non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive fat accumulation in the liver (steatosis), without any other evident causes of chronic liver diseases (viral, autoimmune, genetic, etc.), and with an alcohol consumption <20-30 g / day. On the contrary, AFLD is defined as the presence of steatosis and alcohol consumption >20-30 g / day.

[0125] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting Non-alcoholic steatohepatitis (NASH) in a subject, comprising administering a compound of this invention, to a subject suffering from Non-alcoholic steatohepatitis (NASH) under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit Non-alcoholic steatohepatitis (NASH) in said subject. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0126] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting alcoholic steatohepatitis (ASH) in a subject, comprising administering a compound of this invention, to a subject suffering from alcoholic steatohepatitis (ASH) under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit alcoholic steatohepatitis (ASH) in said subject. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0127] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting non-alcoholic fatty liver disease (NAFLD) in a subject, comprising administering a compound of this invention, to a subject suffering from non-alcoholic fatty liver disease (NAFLD) under conditions effective to treat,suppress, reduce the severity, reduce the risk of developing, or inhibit non-alcoholic fatty liver disease (NAFLD) in said subject. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0128] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting alcoholic fatty liver disease (AFLD) in a subject, comprising administering a compound of this invention, to a subject suffering from alcoholic fatty liver disease (AFLD) under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit alcoholic fatty liver disease (AFLD) in said subject. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0129] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting lung fibrosis in a subject, comprising administering a compound of this invention, to a subject suffering from lung fibrosis under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit lung fibrosis in said subject. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0130] Idiopathic pulmonary fibrosis (IPF) is an aging-associated recalcitrant lung disease with historically limited therapeutic options. The recent approval of two drugs, pirfenidone and nintedanib, by the United States Food and Drug Administration (FDA) in 2014 has heralded a new era in its management. Both drugs demonstrated efficacy in Phase III clinical trials by retarding the rate of progression of IPF; neither drug appears to be able to completely arrest disease progression. Advances in the understanding of IPF pathobiology have led to an unprecedented expansion in the number of potential therapeutic targets. Drugs targeting several of these are under investigation in various stages of clinical development.

[0131] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting idiopathic pulmonary fibrosis (IPF) in a subject, comprising administering a compound of this invention, to a subject suffering from idiopathic pulmonary fibrosis (IPF) under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit idiopathic pulmonary fibrosis (IPF) in said subject. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compoundrepresents a separate embodiment according to this invention. In some embodiments, the compound is administered in combination with an agent treating IPF. In some embodiments, the compound is administered in combination with pirfenidone, nintedanib, or combination thereof; each represents a separate embodiment according to this invention.

[0132] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting dermal fibrosis in a subject, comprising administering a compound of this invention, to a subject suffering from dermal fibrosis under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit dermal fibrosis in said subject. In some embodiments, the dermal fibrosis is scleroderma. In some embodiments, the dermal fibrosis is a result of a localized or generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenoma, connective tissue nevi of the collagen type, or any combination thereof; each represents a separate embodiment according to this invention. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0133] In various embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting scleroderma in a subject, comprising administering a compound of this invention, to a subject suffering from scleroderma under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit scleroderma in said subject. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0134] In various embodiments, this invention is directed to a method of inhibiting Collagen I (Col I) overproduction in a subject, comprising administering a compound of this invention, to a subject suffering from Collagen I (Col I) over production under conditions effective to inhibit Collagen I (Col I) over production in said subject. In some embodiments, the compound is a Collagen I translation inhibitor. In some embodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0135] In some embodiments, this invention is directed to a method of treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting an autoimmune disease or disorder in a subject, comprising administering a compound of this invention, to a subject suffering from an autoimmune disease or disorder under conditions effective to treat, suppress, reduce the severity, reduce the risk of developing, or inhibit the autoimmune disease or disorder in said subject. In some embodiments, the compound is a Collagen I translation inhibitor. In someembodiments, the compound is any one of the compounds listed in Table 1; each compound represents a separate embodiment according to this invention.

[0136] As used herein, subject or patient refers to any mammalian patient, including without limitation, humans and other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents. In various embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, while the methods as described herein may be useful for treating either males or females.

[0137] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention.EXAMPLESEXAMPLE 1Synthetic Details for Compounds of the Invention (Schemes 1-24)General Methods

[0138] All reagents were commercial grade and were used as received without further purification, unless otherwise specified. Reagent grade solvents were used in all cases, unless otherwise specified. Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm).1H-NMR and19F-NMR spectra were recorded on a Bruker Bruker Avance 400MHz or Avance III 400MHz spectrometer. The chemical shifts are expressed in ppm using the residual solvent as internal standard. Splitting patterns are designated as .s' (singlet), d (doublet), dd (doublet of doublets), t (triplet), dt (doublet of triplets), q (quartet), m (multiplet) and br s (broad singlet).AbbreviationsACN AcetonitrileAcOH Acetic acid amphos BA(di-tert-butyl(4-dimethylaminophenyl)phosphineBoc tert-ButyloxycarbonylBuLi 77-butyllithium t-BuLi tert-butyllithiumDAST Diethylamino sulfur trifluorideDBU l,8-Diazabicyclo[5.4.0]undec-7-ene dppb 1 ,4-B i.stdi phenyl phosph i nojbutanc dppf 1 , 1 '-B i.stdi phenyl phosph i no) ferroceneDCM DichloromethaneDIBAL-H Diisobutylaluminum hydrideDIPEA M,M-DiisopropylethylamineDMF MA- Di methyl formamideDMA DimethylacetamideDME 1,2-DimethoxyethaneDMSO DimethylsulfoxideHATU [O-(7 -Azabenzotriazol- 1 -y 1 )-N,N, N', A'-tctramcthy 1 uron i um-hexafl uorphosphat ]HPLC High performance liquid chromatographyMsCl Methanesulfonyl chlorideNBS A- Bro mo succinimideNMP A-Methyl-2-pyrrolidonePPA Polyphosphoric acid rt Room temperatureSEM 2-(Trimethylsilyl)ethoxymethylT3P Propylphosphonic anhydrideTBAF Tetrabutylammonium fluorideTBTU 2-( I / 7-Bcnzo triazole- 1 -yl)- 1 , 1 ,3, 3 -tetramethy laminium tetrafluoroborateTCFH A,A,M,M-tetramethylchloroformamidinium hexafluorophosphateTHF TetrahydrofuranTMSCF3 Trimethyl(trifluoromethyl) silaneTMS-OTf Trimethylsilyl trifluoromethanesulfonatePreparing IntermediatesSynthesis of4,5-dimethyl-6-(piperazin-l-yl)pyrimidine hydrochlorideScheme 1Synthesis of tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)piperazine-l-carboxylate

[0139] A solution of 4-chloro-5,6-dimethylpyrimidine (5.00 g, 35.07 mmol), tert-butyl piperazine-1- carboxylate (9.80 g, 52.62 mmol) and A-ethyl-A-isopropylpropan-2-amine (13.60 g, 105.22 mmol) in dioxane (100 mL) was stirred for overnight at 100°C under a nitrogen atmosphere. The resulting solution was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 25% of ethyl acetate in petroleum ether to afford tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)piperazine-l -carboxylate as a yellow solid.Yield 9.00 g (88%).JH NMR (400 MHz, CDCI ,) 6 8.54 (s, 1H), 3.57 - 3.54 (m, 4H), 3.28 - 3.24 (m, 4H), 2.42 - 2.40 (s, 3H), 2.16 (s, 3H), 1.48 (s, 9H). m / z: [ESI+] 293 (M+H)+.Synthesis of4,5-dimethyl-6-(piperazin-l-yl)pyrimidine hydrochloride

[0140] A mixture of tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)piperazine-l -carboxylate (9.00 g, 30.78 mmol) and a solution of hydrochloride (gas) in 1,4-dioxane (4 N, 30 mL) in dichloromethane (60 mL) was stirred for overnight at room temperature. The precipitated solids were collected by filtration, washed with dichloromethane (3 x 10 mL) and dried under reduced pressure to afford 4,5- dimethyl-6-(piperazin-l-yl)pyrimidine hydrochloride as an off-white solid.Yield 6.90 g (98%).1H NMR (400 MHz, DMSO) 5 9.94 (br s, 2H, NH2+), 8.79 (s, 1H), 4.01 - 3.95 (m, 4H), 3.27 - 3.20 (m, 4H), 2.52 (s, 3H), 2.20 (s, 3H). m / z: [ESI+] 193 (M+H)+.Synthesis of tert-butyl 4-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol-6- yl )piperazine-l -carboxylateScheme 2Synthesis of 6-bromo-2-( chloromethyl)benzo[d]oxazole

[0141] A solution of 2-amino-5-bromophenol (30.00 g, 159.56 mmol) in 2-chloro- 1,1,1- trimethoxyethane (50 mL) was treated for 2 h at 120°C under a nitrogen atmosphere. The resulting solution was allowed to cool down to room temperature, diluted with water (I L) and extracted with ethyl acetate (3 x 1 L). The combined organic layers were washed with brine (I L) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 9% of ethyl acetate in petroleum ether to afford 6-bromo-2-(chloromethyl)-l,3-benzoxazole as a yellow solid.Yield 25.00 g (64%).JH NMR (400 MHz, CDCh) 6 7.75 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 1.6, 8.4 Hz, 1H), 4.76 (s, 2H). m / z: [ESI+] 246, 248, 250 (M+H)+.Synthesis of 6-bromo-2-( (4-(5, 6-dimethylpyrimidin-4-yl)piperazin-l -yl )methyl)benzo[ d ] oxazole

[0142] A solution of 6-bromo-2-(chloromethyl)-l,3-benzoxazole (11.37 g, 46.13 mmol), A-ethyl-A- isopropylpropan-2-amine (27.09 g, 209.59 mmol) and 4,5-dimethyl-6-(piperazin-l-yl)pyrimidine hydrochloride (8.06 g, 35.24 mmol) in A,A-di methyl formam ide (100 mL) was stirred for 4 h at 60°C under a nitrogen atmosphere. The resulting solution was allowed to cool down to room temperature and diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 x 400 mL). The combined organic layers were washed with brine (600 mL) and dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% of ethyl acetate to afford 6-bromo-2- ((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[6noxazole as a yellow solid.Yield 10.45 g (74%).JH NMR (400 MHz, CDCI ,) 6 8.55 (s, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 1.6, 8.4 Hz, 1H), 3.95 (s, 2H), 3.49 - 3.39 (m, 4H), 2.85 - 2.75 (m, 4H), 2.44 (s, 3H), 2.16 (s, 3H). m / z: [ESI+] 402, 404 (M+H)+.Synthesis of tert-butyl 4-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol-6- yl )piperazine-l -carboxylate

[0143] 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazole (0.50 g, 1.24 mmol), tert-butyl piperazine- 1 -carboxylate (0.50 g, 2.68 mmol), sodium tert-butoxide (0.30 g, 3.12 mmol) 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.14 g, 0.24 mmol) and tris(dibenzylideneacetone)dipalladium (0.11 g, 0.12 mmol) in dioxane (10 mL) was purged with nitrogen for three times. The reaction mixture was sealed and stirred for 3 h at 90°C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature and neutralized to pH 7 with acetic acid. The resulting mixture was purified by reverse phase flash with the following conditions (330 g C18 column, Mobile Phase A: water (plus 10 mM ammonium bicarbonate), Mobile Phase B: acetonitrile; 45% - 65% B in 20 min). The fractions contained the desired product at 59% was concentrated under reduced pressure to afford tert-butyl 4-(2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[t / ]oxazol-6-yl)piperazine-l -carboxylate as a yellow solid.Yield 0.42 g (67%).1H NMR (400 MHz, CDCI ,) 6 8.54 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 2.4, 8.8 Hz, 1H), 3.92 (s, 2H), 3.63 (t, J = 5.2 Hz, 4H), 3.41 (t, J = 4.8 Hz, 4H), 3.17 (t, J = 5.2 Hz, 4H), 2.78 (t, J = 4.8 Hz, 4H), 2.42 (s, 3H), 2.14 (s, 3H), 1.51 (s, 9H). m / z: [ESI+] 508 (M+H)+.Synthesis of tert-butyl (l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol- 6-yl)piperidin-4-yl)carbamate

[0144] Compound tert-butyl (l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-yl)piperidin-4-yl)carbamate was prepared from 6-bromo-2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[( / ] oxazole (0.50 g, 1.24 mmol) and tertbutyl piperidin-4-ylcarbamate (0.50 g, 2.50 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-yl)piperazine-l-carboxylate, and was isolated as a yellow solid.Yield 0.24 g (37%).JH NMR (400 MHz, CDCI ,) 6 8.54 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 2.4, 8.8 Hz, 1H), 4.50 (br s, 1H), 3.92 (s, 2H), 3.72 - 3.57 (m, 3H), 3.55 - 3.45 (m, 4H), 2.96 - 2.86 (m, 2H), 2.84 - 2.74 (m, 4H), 2.46 (s, 3H), 2.16 (s, 3H), 2.15 - 2.05 (m, 2H), 1.67 - 1.58 (m, 2H), 1.49 (s, 9H). m / z: [ESI+] 522 (M+H)+.Synthesis of tert-butyl 4-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol-6- yl)- 1 ,4-diazepane- 1 -carboxylate

[0145] Compound tert-butyl 4-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-yl)-l,4-diazepane-l-carboxylate was prepared from 6-bromo-2-((4- (5, 6-di methyl pyihnidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|t / |oxazolc (0.50 g, 1.24 mmol) and tert- butyl 1,4-diazepane-l -carboxy late (0.37 g, 1.85 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-yl)piperazine-l-carboxylate, and was isolated as a yellow solid.Yield 0.35 g (54%).1H NMR (400 MHz, CDCI ,) 6 8.53 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 2.4, 8.8 Hz, 1H), 3.89 (s, 2H), 3.68 - 3.56 (m, 6H), 3.47 - 3.37 (m, 4H), 2.83 - 2.72 (m, 6H), 2.41 (s, 3H), 2.14 (s, 3H), 2.06 - 1.95 (m, 2H), 1.44 (s, 9H). m / z: [ESI+] 522 (M+H)+.Synthesis of (R)-N,N-dibenzyl-l -( 2-( ( 4-( 5, 6-dimethylpyrimidin-4-yl)piperazin-l -Scheme 3Synthesis of tert-butyl (R)-3-( dibenzylamino )piperidine-l -carboxylate

[0146] A solution of tert-butyl (7?)-3-aminopiperidine- 1 -carboxylate (4.00 g, 19.97 mmol), benzaldehyde (6.36 g, 59.93 mmol) and acetic acid (2 mL) in methanol (60 mL) was stirred for 2 h at room temperature. To the above solution was added sodium cyanoborohydride (3.77 g, 59.99 mmol) in portions at 0°C. The resulting solution was stirred for additional overnight at room temperature. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 17% of ethyl acetate in petroleum ether to afford tert-butyl ( / ?)-3-(dibcnzy lam ino)pipcridinc- 1 -carboxylate as a white solid.Yield 3.10 g (41%).JH NMR (400 MHz, CDCI ,) 6 7.42 - 7.36 (m, 4H), 7.36 - 7.27 (m, 4H), 7.27 - 7.20 (m, 2H), 4.41 - 4.13 (m, 1H), 4.13 - 3.91 (m, 1H), 3.79 - 3.63 (m, 4H), 2.78 - 2.48 (m, 3H), 2.05 - 1.93 (m, 1H), 1.77 - 1.66 (m, 1H), 1.59 - 1.32 (m, 2H), 1.49 (s, 9H). m / z: [ESI+] 381 (M+H)+.Synthesis of(R)-N,N-dibenzylpiperidin-3-amine dihydrochloride

[0147] Compound (R)-A,A-dibenzylpiperidin-3-amine dihydrochloride was prepared from tert-butyl (R)-3-(dibenzylamino)piperidine-l -carboxylate (3.10 g, 8.15 mmol) following a similar procedure to that described for the synthesis of 4,5-dimethyl-6-(piperazin-l-yl)pyrimidine hydrochloride, and was isolated as a light yellow solid.Yield 2.20 g (76%). ' H NMR (400 MHz, DMSO) 5 11.93 (br s, 1H, NH+), 10.25 (br s, 1H, NH+), 9.27 (br s, 1H, NH+), 7.84 - 7.56 (m, 4H), 7.49 - 7.31 (m, 6H), 4.67 - 4.40 (m, 2H), 4.37 - 4.19 (m, 1H), 4.19 - 3.94 (m, 2H), 3.72 - 3.47 (m, 1H), 3.47 - 3.27 (m, 1H), 3.23 - 3.08 (m, 1H), 2.88 - 2.68 (m, 1H), 2.46 - 2.31 (m, 1H), 2.09 - 1.86 (m, 2H), 1.62 - 1.42 (m, 1H). m / z: [ESI+] 281 (M+H)+.Synthesis of (R)-N,N-dibenzyl-l -( 2-( ( 4-( 5, 6-dimethylpyrimidin-4-yl)piperazin-l - yl)methyl)benzo[d]oxazol-6-yl)piperidin-3-amine

[0148] Comound (R)-A,A-dibenzyl-l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-yl)piperidin-3-amine was prepared from 6-bromo-2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[tf] oxazole (500 mg, 1.243 mmol) and (R)-N,N- dibenzylpiperidin-3-amine dihydrochloride (520 mg, 1.472 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-yl)piperazine-l-carboxylate, and was isolated as a light yellow solid. Yield 220 mg (29%).1H NMR (400 MHz, CDCh) 6 8.55 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.43 - 7.39 (m, 4H), 7.36 - 7.30 (m, 4H), 7.26 - 7.21 (m, 2H), 7.01 (d, J = 2.4 Hz, 1H), 6.94 (dd, J =2.4, 8.8 Hz, 1H), 3.92 (s, 2H), 3.82 - 3.67 (m, 4H), 3.63 - 3.56 (m, 1H), 3.44 - 3.38 (m, 4H), 2.99- 2.89 (m, 1H), 2.82 - 2.74 (m, 5H), 2.68 - 2.55 (m, 1H), 2.42 (s, 3H), 2.15 (s, 3H), 2.12 - 1.97 (m, 1H), 1.92 - 1.83 (m, 1H), 1.76 - 1.46 (m, 2H), 1.40 - 1.29 (m, 1H). m / z: [ESI+] 602 (M+H)+.Synthesis of (S)-6-( 3 -(benzyloxy )piperidin-l-yl)-2-( (4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l - yl )methyl)benzo[ d ]oxazoleScheme 4Synthesis of tert-butyl (S)-3 -(benzyloxy )piperidine-l -carboxylate

[0149] To a stirred solution of tert-butyl (S)-3-hydroxypipcridinc- 1 -carboxylate (5.00 g, 24.84 mmol) in N,NDmethyl formamide (100 mL) was added sodium hydride (60%, 2.00 g, 50.00 mmol) in portions at 0°C under a nitrogen atmosphere. After 1 h, to the above mixture was added benzyl bromide (5.01 g, 29.29 mmol) dropwise over 10 min at 0°C. The resulting mixture was stirred for additional 16 h at room temperature. The reaction was quenched by the addition of Ice / water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 25% of ethyl acetate in petroleum ether to afford tert-butyl (5)-3- (benzyloxy)piperidine-l -carboxylate as a yellow solid.Yield 7.00 g (97%).JH NMR (400 MHz, CDCI ,) 6 7.43 - 7.26 (m, 5H), 4.70 - 4.50 (m, 2H), 3.94 - 3.78 (m, 1H), 3.67 - 3.55 (m, 1H), 3.49 - 3.38 (m, 1H), 3.21 - 3.06 (m, 2H), 2.04 - 1.92 (m, 1H), 1.85 - 1.74 (m, 1H), 1.64 - 1.53 (m, 1H), 1.53 - 1.38 (m, 1H), 1.48 (s, 9H). m / z: [ESI+] 292 (M+H)+.Synthesis of (S)-3-(benzyloxy)piperidine hydrochloride

[0150] Compound (.S')-3-(bcnzyloxy)pipcridinc hydrochloride was prepared from tert-butyl (5)-3- (benzyloxy)piperidine-l -carboxylate (7.00 g, 24.02 mmol) following a similar procedure to that described for the synthesis of 4,5-dimethyl-6-(piperazin-l-yl)pyrimidine hydrochloride, and was isolated as a light yellow solid.Yield 4.50 g (82%).JH NMR (400 MHz, CD3OD) 5 7.52 - 7.20 (m, 5H), 4.64 (s, 2H), 3.92 - 3.80 (m, 1H), 3.38 - 3.17 (m, 3H), 3.14 - 3.02 (m, 1H), 2.21 - 1.93 (m, 2H), 1.85 - 1.65 (m, 2H). Aliphatic NH proton not observed, m / z: [ESI+] 192 (M+H)+.Synthesis of ( S)-6-( 3 -( benzyloxy )piperidin- 1 -yl)-2-( ( 4-( 5, 6-dimethylpyrimidin-4-yl)piperazin-l - yl )methyl )benzo[ d ] oxazole

[0151] Compound (S)-6-(3-(benzyloxy)piperidin-l-yl)-2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[tf] oxazole was prepared from 6-bromo-2-((4-(5,6- dimcthylpyi%nidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|<7| oxazole (500 mg, 1.243 mmol) and (5)-3- (benzyloxy)piperidine hydrochloride (357 mg, 1.568 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-yl)piperazine-l-carboxylate, and was isolated as a light yellow solid.Yield 510 mg (80%). ' H NMR (400 MHz, CDCh) 6 8.55 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.42 - 7.28 (m, 5H), 7.06 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 2.4, 8.8 Hz, 1H), 4.72 - 4.61 (m, 2H), 3.92 (s, 2H), 3.73 - 3.58 (m, 2H), 3.49 - 3.36 (m, 5H), 2.94 - 2.82 (m, 2H), 2.80 - 2.72 (m, 4H), 2.42 (s, 3H), 2.17 - 2.06 (m, 1H), 2.14 (s, 3H), 2.00 - 1.86 (m, 1H), 1.78 - 1.60 (m, 1H), 1.60 - 1.46 (m, 1H). m / z: [ESI+] 513 (M+H)+.Synthesis of (R)-6-( 3 -(benzyloxy )piperidin-l-yl)-2-( (4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -Scheme 5Synthesis of tert-butyl (R)-3-(benzyloxy)piperidine-l -carboxylate

[0152] Compound tert-butyl (R) -3 -(benzyloxy )piperidine- 1 -carboxylate was prepared from tert- butyl (R) -3 -hydroxypiperidine- 1 -carboxylate (5.00 g, 24.84 mmol) and (bromomethyl)benzene (5.01 g, 29.29 mmol) following a similar procedure to that described for the synthesis of tert-butyl (5)-3- (benzyloxy)piperidine-l -carboxylate, and was isolated as a yellow solid.Yield 7.00 g (97%).JH NMR (400 MHz, CDC1367.42 - 7.26 (m, 5H), 4.70 - 4.52 (m, 2H), 3.94 - 3.80 (m, 1H), 3.68 - 3.56 (m, 1H), 3.48 - 3.38 (m, 1H), 3.20 - 3.04 (m, 2H), 2.03 - 1.93 (m, 1H), 1.85 - 1.73 (m, 1H), 1.66 - 1.53 (m, 1H), 1.52 - 1.37 (m, 1H), 1.47 (s, 9H). m / z: [ESI+] 292 (M+H)+.Synthesis of (R)-3 -(benzyloxy )piperidine hydrochloride

[0153] Compound (R)-3-(benzyloxy)piperidine hydrochloride was prepared from tert-butyl (R)-3- (benzyloxy)piperidine-l -carboxylate (7.00 g, 24.02 mmol) following a similar procedure to that described for the synthesis of 4,5-dimethyl-6-(piperazin-l-yl)pyrimidine hydrochloride, and was isolated as a light yellow solid.Yield 4.50 g (82%).1H NMR (400 MHz, CD3OD) 5 7.45 - 7.27 (m, 5H), 4.69 - 4.59 (m, 2H), 3.90 - 3.81 (m, 1H), 3.33 - 3.28 (m, 1H), 3.27 - 3.14 (m, 2H), 3.13 - 2.99 (m, 1H), 2.17 - 1.95 (m, 2H), 1.86 - 1.68 (m, 2H). Aliphatic NH proton not observed, m / z: [ESI+] 192 (M+H)+.Synthesis of (R)-6-( 3 -(benzyloxy )piperidin-l-yl)-2-( (4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l - yl )methyl)benzo[ d ]oxazole

[0154] Compound (R)-6-(3-(benzyloxy)piperidin-l-yl)-2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[tf] oxazole was prepared from 6-bromo-2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[tf] oxazole (500 mg, 1.243 mmol) and (R)-3- (benzyloxy)piperidine hydrochloride (357 mg, 1.568 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-yl)piperazine-l-carboxylate, and was isolated as a light yellow solid.Yield 470 mg (74%).JH NMR (400 MHz, CDCh) 6 8.55 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.42 -7.28 (m, 5H), 7.06 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 2.4, 8.8 Hz, 1H), 4.72 - 4.61 (m, 2H), 3.92 (s, 2H), 3.73 - 3.58 (m, 2H), 3.49 - 3.36 (m, 5H), 2.94 - 2.82 (m, 2H), 2.80 - 2.72 (m, 4H), 2.42 (s, 3H), 2.17 - 2.06 (m, 1H), 2.14 (s, 3H), 2.00 - 1.86 (m, 1H), 1.78 - 1.60 (m, 1H), 1.60 - 1.46 (m, 1H). m / z: [ESI+] 513 (M+H)+.Synthesis of (S)-6-(3-(benzyloxy)pyrrolidin-l-yl)-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl )methyl)benzo[ d ]oxazole

[0155] Compound (S) -6-(3 -(benzyloxy )pyrrolidin- 1 -yl) -2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[tf] oxazole was prepared from 6-bromo-2-((4-(5,6- dimcthylpyi%nidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|<7| oxazole (500 mg, 1.243 mmol) and (5)-3- (benzyloxy)pyrrolidine (330 mg, 1.862 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(2-((4-(5,6-dimcthylpyrimidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|c / |oxazol- 6-yl)piperazine-l -carboxylate, and was isolated as a dark yellow solid.Yield 500 mg (81%). ' H NMR (400 MHz, CDCh) 6 8.54 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.41 -7.29 (m, 5H), 6.66 (d, J = 2.4 Hz, 1H), 6.60 (dd, J = 2.4, 8.8 Hz, 1H), 4.65 - 4.56 (m, 2H), 4.38 - 4.31 (m, 1H), 3.90 (s, 2H), 3.60 - 3.47 (m, 2H), 3.46 - 3.36 (m, 6H), 2.81 - 2.73 (m, 4H), 2.41 (s, 3H), 2.31 - 2.17 (m, 2H), 2.14 (s, 3H). m / z: [ESI+] 499 (M+H)+.Synthesis of (R)-6-( 3 -(benzyloxy )pyrrolidin-l-yl)-2-( (4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l - yl )methyl)benzo[ d ]oxazole

[0156] Compound (R)-6-(3-(benzyloxy)pyrrolidin-l-yl)-2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[tf] oxazole was prepared from 6-bromo-2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[tf] oxazole (500 mg, 1.243 mmol) and (R)-3- (benzyloxy)pyrrolidine (330 mg, 1.862 mmol) following a similar procedure to that described for thesynthesis of tert-butyl 4-(2-((4-(5,6-dimcthylpyrimidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|c / |oxazol- 6-yl)piperazine-l -carboxylate, and was isolated as a dark yellow solid.Yield 550 mg (89%).JH NMR (400 MHz, CDCh) 6 8.54 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.41 - 7.29 (m, 5H), 6.66 (d, J = 2.4 Hz, 1H), 6.60 (dd, J = 2.4, 8.8 Hz, 1H), 4.65 - 4.56 (m, 2H), 4.38 - 4.31 (m, 1H), 3.90 (s, 2H), 3.60 - 3.47 (m, 2H), 3.46 - 3.36 (m, 6H), 2.81 - 2.73 (m, 4H), 2.41 (s, 3H), 2.31 - 2.17 (m, 2H), 2.14 (s, 3H). m / z: [ESI+] 499 (M+H)+.Synthesis of tert-butyl (S)-(l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[d]oxazol-6-yl)piperidin-3-yl)carbamate

[0157] To a stirred mixture of tert-butyl (.S')-pipcridin-3-ylcarbamatc (300 mg, 1.498 mmol) and 6-bromo-2-((4-(5 ,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo | d | oxazole (300 mg, 0.746 mmol) in dioxane (20 mL) was added sodium tert-butoxide (287 mg, 2.986 mmol), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,T-biphenyl]-2-yl)phosphane (40 mg, 0.075 mmol) and BrettPhos Pd G3 (135 mg, 0.149 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90°C under a nitrogen atmosphere for 1.5 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase Llash chromatography with the following conditions: Column: WelLlash TM C18-I, 20-40 pm, 120 g; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 50% - 75% B in 25 min; Elow rate: 80 mL / min; Detector: 220 / 254 nm. Desired fractions were collected at 59% B and concentrated under reduced pressure to afford tertbutyl (S)-(l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[6?]oxazol-6- yl)piperidin-3-yl)carbamate as a brown oil.Yield 112 mg (29%). ' H NMR (400 MHz, CDCh) 6 8.54 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 7.05-6.98 (m, 1H), 4.89 (s, 1H), 3.93 (s, 2H), 3.51-3.43 (m, 5H), 3.17-3.01 (m, 3H), 2.79 (t, J = 4.8 Hz, 4H), 2.46 (s, 3H), 2.16 (s, 3H), 1.89-1.75 (m, 3H), 1.64-1.59 (m, 2H), 1.49 (s, 9H). m / z: [ESI+] 522 (M+H)+.Synthesis of2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl)-6-nitrobenzo[ d ] oxazoleScheme 6Synthesis of2-( chloromethyl)-6-nitrobenzo[d]oxazole

[0158] Compound 2-(chloromethyl)-6-nitrobenzo[t / ]oxazole was prepared from 2-amino-5- nitrophenol (6.16 g, 39.97 mmol) in 2-chloro- 1,1,1 -trimethoxy ethane (20 mL) following a similar procedure to that described for the synthesis of 6-bromo-2-(chloromethyl)-l,3-benzoxazole, and was isolated as a light yellow solid.Yield 8.20 g (97%).JH NMR (400 MHz, CDCI ,) 6 8.51 (d, J = 2.4 Hz, 1H), 8.36 (dd, J = 2.4, 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 4.82 (s, 2H). m / z: [ESI ] 211, 213 (M-H)’.Synthesis of2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl)-6-nitrobenzo[ d ]oxazole

[0159] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6- nitrobcnzo|<7| oxazole was prepared from 2-(chloromethyl)-6-nitrobenzo[t / ]oxazole (4.03 g, 18.96 mmol) and 4, 5-dimethyl-6-(piperazin-l-yl)pyrimidine hydrochloride (4.37 g, 19.11 mmol) following a similar procedure to that described for the synthesis of 6-bromo-2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[tf] oxazole, and was isolated as a yellow solid.Yield 6.30 g (90%).1H NMR (400 MHz, CDCI ,) 6 8.52 (s, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.32 (dd, J = 2.4, 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 4.01 (s, 2H), 3.43 (t, J = 4.8 Hz, 4H), 2.81 (t, J = 4.8 Hz, 4H), 2.42 (s, 3H), 2.14 (s, 3H). m / z: [ESI+] 369 (M+H)+.Synthesis of methyl 2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazole-6- carboxylateScheme 7Synthesis of methyl 2-( chloromethyl)benzo[d]oxazole-6-carboxylate

[0160] Compound methyl 2-(chloromethyl)benzo[t / ]oxazole-6-carboxylate was prepared from methyl 4-amino-3-hydroxybenzoate (20.00 g, 119.64 mmol) in 2-chloro- 1,1,1 -trimethoxyethane (40 mL) following a similar procedure to that described for the synthesis of 6-bromo-2-(chloromethyl)- 1,3-benzoxazole, and was isolated as a white solid.Yield 25.00 g (93%).JH NMR (400 MHz, CDCh) 6 8.24 (d, J = 2.0 Hz, 1H), 8.10 (dd, J = 2.0, 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 4.78 (s, 2H), 3.97 (s, 3H). m / z: [ESI+] 226, 228 (M+H)+.Synthesis of methyl 2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazole-6- carboxylate

[0161] Compound methyl 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazole-6-carboxylate was prepared from methyl 2- (chloromethyl)benzo[t / ]oxazole-6-carboxylate (1.40 g, 6.20 mmol) and 4,5-dimethyl-6-(piperazin-l- yl)pyrimidine hydrochloride (1.43 g, 6.25 mmol) following a similar procedure to that described for the synthesis of 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazole, and was isolated as a yellow solid.Yield 1.56 g (66%). 'H NMR (400 MHz, CDCh) 6 8.55 (s, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.11 (dd, J = 1.6, 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 4.00 (s, 2H), 3.99 (s, 3H), 3.47 (t, J = 4.8 Hz, 4H), 2.82 (t, J = 4.8 Hz, 4H), 2.45 (s, 3H), 2.16 (s, 3H). m / z: [ESI+] 382 (M+H)+.Synthesis of2-( chloromethyl)-6-methoxybenzo[d]oxazole

[0162] Compound 2-(chloromethyl)-6-methoxybenzo[t / ]oxazole was prepared from 2-amino-5- methoxyphenol (10.00 g, 71.86 mmol) in 2-chloro- 1,1,1 -trimethoxy ethane (60 mL) following a similar procedure to that described for the synthesis of 6-bromo-2-(chloromethyl)-l,3-benzoxazole, and was isolated as a yellow oil.Yield 6.00 g (42%).1H NMR (400 MHz, CDCh) 67.62 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 2.4, 8.8 Hz, 1H), 4.75 (s, 2H), 3.89 (s, 3H). m / z: [ESI+] 198, 200 (M+H)+.Synthesis of l-(2-((4-(5, 6-dimethylpyrimidin-4-yl)piperazin-l -yl )methyl)benzo[ d ]oxazol-6-yl)ethan- 1-oneScheme 8Synthesis of 2-((4-( 5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-N-methoxy-N- methylbenzof d ]oxazole-6-carboxamide

[0163] A solution of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazole-6- carboxylic acid (1.00 g, 2.72 mmol)(Compound 104), A,O-di methyl hydroxy lam ine hydrochloride (0.40 g, 4.10 mmol), 69-(7-azabcnzotriazol- l -yl)-MMA,A-tctramcthyluronium hcxal'luorophosphatc (1.55 g, 4.08 mmol) and A-ethyl-A-isopropylpropan-2-amine (2.11 g, 16.32 mmol) in N,N- dimethylacetamide (10 mL) was stirred for 2 h at room temperature. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 33% of ethyl acetate (plus 20% v / v methanol) in petroleum ether to afford 2-((4-(5,6- dimcthylpyrimidin-4-yl)pipcrazin- l -yl)mcthyl)-Y-mcthoxy-Y-mcthylbcnzoh / |oxazolc-6- carboxamide as a yellow solid.Yield 0.64 g (57%).JH NMR (400 MHz, CDC1) 6 8.54 (s, 1H), 7.96 (s, 1H), 7.78 - 7.73 (m, 2H), 3.99 (s, 2H), 3.59 (s, 3H), 3.48 (t, J = 4.8 Hz, 4H), 3.42 (s, 3H), 2.82 (t, J = 4.8 Hz, 4H), 2.43 (s, 3H), 2.17 (s, 3H). m / z: [ESI+] 411 (M+H)+.Synthesis of l-(2-((4-(5, 6-dimethylpyrimidin-4-yl)piperazin-l -yl )methyl)benzo[ d ]oxazol-6-yl)ethan- 1-one

[0164] Methylmagnesium bromide (1 N solution in tetrahydrofuran, 3 mL, 3.00 mmol) was added dropwise to a solution of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-A-methoxy-A- mcthylbcnzoh / |oxazolc-6-carboxamidc (640 mg, 1.559 mmol) in tetrahydrofuran (5 mL) for 5 min at room temperature under a nitrogen atmosphere. The resulting solution was stirred for 1 h at room temperature. The reaction was quenched with sat. aqueous ammonium chloride solution (10 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combinedorganic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford l-(2-((4-(5,6- dimcthylpyi%nidin-4-yl)pipcrazin- 1 -yl)mcthyl)bcnzo|t / |oxazol-6-yl)cthan- 1 -one, which was used in the next step directly without further purification.Yield 400 mg (70%).!H NMR not be ran. m / z: [ESI+] 366 (M+H)+.Synthesis of 2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazole-6- carbaldehydeCompound 120

[0165] A mixture of (2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazol-6- yl)methanol (0.50 g, 1.41 mmol)(Compound 120) and activated manganese dioxide (12.30 g, 141.48 mmol) in dioxane (15 mL) was stirred for 16 h at room temperature. The resulting mixture was filtered. The filter cake was washed with methanol (3 x 100 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 33% of ethyl acetate (plus 20% v / v methanol) in petroleum ether to afford 2-((4-(5,6- dimcthylpyrimidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|c / |oxazolc-6-carbaldchydc as an off white solid.Yield 0.41 g (82%).JH NMR (400 MHz, CDCI ,) 6 10.12 (s, 1H), 8.54 (s, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.94 (dd, J = 1.6, 8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 4.02 (s, 2H), 3.49 (t, J = 4.8 Hz, 4H), 2.83 (t, J = 4.8 Hz, 4H), 2.45 (s, 3H), 2.16 (s, 3H). m / z: [ESI+] 352 (M+H)+.Synthesis of 6-(l -azido-2, 2,2-trifluoroethyl)-2-( (4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l - yl )methyl)benzo[ d ]oxazoleScheme 9Synthesis of l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl )methyl)benzo[ d ]oxazol-6-yl)-2, 2,2- trifluoroethyl methane sulfonate

[0166] To a stirred solution of l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[7]oxazol-6-yl)-2,2,2-trifluoroethan-l-ol (736 mg, 1.746 mmol)(Compound 139) and triethylamine (530 mg, 5.238 mmol) in dichloromethane (15 mL) was added methanesulfonyl chloride (240 mg, 2.095 mmol) dropwise at 0°C. The reaction solution was stirred for 1 h at room temperature. The reaction was quenched with water (50 mL) at room temperature and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[7]oxazol-6- yl)-2,2,2-trifluoroethyl methanesulfonate as a yellow solid.Yield 800 mg (92%).JH NMR (400 MHz, CDC13δ 8.54 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.75 (d, 7 = 1.6 Hz, 1H), 7.50 (dd, J = 1.6, 8.4 Hz, 1H), 5.93 (q, J = 6.4 Hz, 1H), 3.99 (s, 2H), 3.47 (t, J = 4.8 Hz, 4H), 3.07 (s, 3H), 2.82 (t, J = 4.8 Hz, 4H), 2.45 (s, 3H), 2.16 (s, 3H). m / z: [ESI+] 500 (M+H)+.Synthesis of 6-(l -azido-2, 2,2-trifhioroethyl)-2-( (4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l - yl )methyl)benzo[ d ]oxazole

[0167] A mixture of l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[7]oxazol-6- yl)-2,2,2-trifluoroethyl methanesulfonate (800 mg, 1.602 mmol) and sodium azide (208 mg, 3.200 mmol) in A,A-dimethylformamide (10 mL) was stirred for 16 h at 90°C. The resulting mixture was cooled down to room temperature and purified by reverse phase flash chromatography with the following conditions: Column, Spherical Cl 8, 20 - 40 urn, 40; Mobile Phase A: water (plus 10 mM ammonium bicarbonate); Mobile Phase B; acetonitrile; Flow rate: 50 mL / min; Gradient:40%B-60%B in 25 min; Detector, UV 254 nm. The fractions containing desired product were collected at 50% B and concentrated under reduced pressure to afford 6-(l-azido-2,2,2-trifluoroethyl)-2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo |c / | oxazole as a yellow solid.Yield 400 mg (56%).1H NMR (400 MHz, CDCh) 6 8.55 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.69 (d, 7 = 1.6 Hz, 1H), 7.43 (dd, 7 = 1.6, 8.4 Hz, 1H), 5.08 (q, 7 = 6.8 Hz, 1H), 3.99 (s, 2H), 3.47 (t, 7 = 4.8 Hz, 4H), 2.82 (t, 7 = 4.8 Hz, 4H), 2.45 (s, 3H), 2.16 (s, 3H). m / z: [ESI+] 447 (M+H)+.Synthesis of(6-( difluoromethyl)benzo[d]oxazol-2-yl)methyl methanesulfonateScheme 10Synthesis of(6-bromobenzo[d]oxazol-2-yl)methyl acetate

[0168] A mixture of 6-bromo-2-(chloromethyl)benzo[t / ]oxazole (5.00 g, 20.28 mmol) and potassium acetate (3.00 g, 30.57 mmol) in l-methylpyrrolidin-2-one (50 mL) was stirred for 2 h at 80°C under a nitrogen atmosphere. The resulting solution was allowed to cool down to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (3 x 500 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 25% of ethyl acetate in petroleum ether to afford (6- bromobenzo[t / ]oxazol-2-yl)methyl acetate as a yellow liquid.Yield 5.10 g (93%).JH NMR (400 MHz, CDCh) 67.74 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 1.6, 8.4 Hz, 1H), 5.34 (s, 2H), 2.22 (s, 3H). m / z: [ESI+] 270, 272 (M+H)+.Synthesis of(6-vinylbenzo[d]oxazol-2-yl)methyl acetate

[0169] To a stirred mixture of (6-bromobenzo[t / ]oxazol-2-yl)methyl acetate (5.10 g, 18.88 mmol), sodium bicarbonate (4.76 g, 56.66 mmol) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (4.36 g, 28.31 mmol) in dioxane (40 mL) and water (10 mL) was added tetrakis(triphenylphosphine)palladium (2.18 g, 1.89 mmol) in portions at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 2 h at 90°C under a nitrogen atmosphere. The resulting mixture was allowed to cool down to room temperature and concentrated under reducedpressure. The residue was purified by silica gel column chromatography, eluted with 16% of ethyl acetate in petroleum ether to afford (6-vinylbenzo[t / ]oxazol-2-yl)methyl acetate as a yellow liquid. Yield 3.00 g (73%).JH NMR (400 MHz, CDCI ,) 67.69 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 1.6, 8.4 Hz, 1H), 6.83 (dd, J = 10.8, 17.6 Hz, 1H), 5.81 (d, J = 17.6 Hz, 1H), 5.36 (s, 2H), 5.34 (d, J = 10.8 Hz, 1H), 2.23 (s, 3H). m / z: [ESI+] 218 (M+H)+.Synthesis of(6-formylbenzo[d]oxazol-2-yl)methyl acetate

[0170] To a stirred mixture of (6-vinylbenzo[t / ]oxazol-2-yl)methyl acetate (3.00 g, 13.81 mmol), sodium periodate (11.82 g, 55.26 mmol) and 2,6-lutidine (2.96 g, 27.62 mmol) in ethyl acetate (30 mL) and water (30 mL) was added potassium osmate(VI) dihydrate (0.25 g, 0.69 mmol) in portions at 0°C. The reaction mixture was stirred for overnight at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 16% of ethyl acetate in petroleum ether to afford (6-formylbenzo[t / ]oxazol-2-yl)methyl acetate as a yellow oil.Yield 2.10 g (69%). 'H NMR (400 MHz, CDCI ,) 5 10.11 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.94 (dd, J = 1.6, 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 5.40 (s, 2H), 2.25 (s, 3H). m / z: [ESI+] 220 (M+H)+.Synthesis of(6-( difluoromethyl)benzo[d]oxazol-2-yl)methyl acetate

[0171] To a stirred solution of (6-formylbenzo[t / ]oxazol-2-yl)methyl acetate (2.10 g, 9.58 mmol) in dichloromethane (20 mL) was added diethylamino sulfur trifluoride (6.18 g, 38.34 mmol) dropwise at 0°C under a nitrogen atmosphere. The reaction solution was stirred for overnight at room temperature under a nitrogen atmosphere. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 25% of ethyl acetate in petroleum ether to afford (6-(difluoromethyl)benzo[t / ]oxazol-2-yl)methyl acetate as an off-white solid.Yield 1.40 g (61%). 'H NMR (400 MHz, CDCI ,) 6 7.84 (dd, J = 1.6, 8.4 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.53 (dq, J = 1.6, 8.4 Hz, 1H), 6.79 (t, J = 56.4 Hz, 1H), 5.39 (s, 2H), 2.24 (s, 3H).19E NMR (377 MHz, CDCL) 6 -108.98. m / z: [ESI+] 242 (M+H)+.Synthesis of(6-( difluoromethyl )benzo[ d ]oxazol-2-yl )methanol

[0172] A solution of (6-(difluoromethyl)benzo[t / ]oxazol-2-yl)methyl acetate (1.80 g, 7.46 mmol) and potassium carbonate (2.06 g, 14.91 mmol) in methanol (5 mL), tetrahydrofuran (5 mL) and water (5mL) was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure. The residue was diluted with methanol (10 mL) and filtered. The filter cake was washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford (6- (difluoromethyl)benzo[t / ]oxazol-2-yl)methanol as an off-white solid.Yield 1.40 g (94%).JH NMR (400 MHz, CDCh) 6 7.83 (dd, J = 1.6, 8.4 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 56.4 Hz, 1H), 4.98 (s, 2H). OH proton not observed, m / z: [ESI+] 200 (M+H)+.Synthesis of(6-( difluoromethyl)benzo[d]oxazol-2-yl)methyl methane sulfonate

[0173] Compound (6-(difluoromethyl)benzo[t / ]oxazol-2-yl)methyl methanesulfonate was prepared from (6-(difluoromethyl)benzo[t / ]oxazol-2-yl)methanol (1.40 g, 7.03 mmol) and methanesulfonic anhydride (1.84 g, 10.56 mmol) following a similar procedure to that described for the synthesis of l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[6noxazol-6-yl)-2,2,2- trifluoroethyl methanesulfonate, and was ioslated as an off-white solid.Yield 1.30 g (67%).1H NMR (400 MHz, CDCh) 67.87 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.57 (dd, J = 1.6, 8.4 Hz, 1H), 6.80 (t, J = 56.4 Hz, 1H), 5.51 (s, 2H), 3.23 (s, 3H). m / z: [ESI+] 278 (M+H)+.Synthesis of l-( 5,6-dimethylpyrimidin-4-yl)piperazin-2-one hydrochlorideScheme 11Synthesis of tert-butyl 4-( 5, 6-dimethylpyrimidin-4-yl)-3 -oxopiperazine- 1 -carboxylate

[0174] Compound tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)-3-oxopiperazine-l -carboxylate was prepared from 4-chloro-5,6-dimethylpyrimidine (1.00 g, 7.01 mmol) and tert-butyl 3-oxopiperazine- Lcarboxylate (1.69 g, 8.44 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)mcthyl)bcnzo|c / |oxazol-6- yl)piperazine-l -carboxylate, and was isolated as a yellow oil.Yield 312 mg (15%). 'H NMR (400 MHz, CDCh) 6 8.86 (s, 1H), 4.32 - 4.19 (m, 3H), 3.91 - 3.75 (m, 3H), 2.59 (s, 3H), 2.14 (s, 3H), 1.52 (s, 9H). m / z: [ESI+] 307 (M+H)+.Synthesis of l-( 5,6-dimethylpyrimidin-4-yl)piperazin-2-one hydrochloride

[0175] Compound l-(5,6-dimethylpyrimidin-4-yl)piperazin-2-one hydrochloride was prepared from tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)-3-oxopiperazine-l -carboxylate (312 mg, 1.018 mmol) following a similar procedure to that described for the synthesis of 4,5-dimethyl-6-(piperazin-l- yl)pyrimidine hydrochloride, and was isolated as a white solid.Yield 200 mg (81%).JH NMR (400 MHz, DMSO) 5 10.47 (br s, 1H, one of NH2+), 10.06 (br s, 1H, one of NH2+), 4.41 - 3.66 (m, 4H), 3.60 - 3.50 (m, 2H), 2.52 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 207 (M+H)+.Synthesis of 5-methyl-6-(piperazin- 1 -yl)pyrimidin-4(3H)-oneScheme 12Synthesis of tert-butyl 4-(5-methyl-6-oxo- 1 ,6-dihydropyrimidin-4-yl)piperazine- 1 -carboxylate

[0176] Compound tert-butyl 4-(5-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)piperazine-l- carboxylate was prepared from 6-chloro-5-methylpyrimidin-4(377)-one (1.00 g, 6.92 mmol) and tertbutyl piperazine- 1 -carboxylate (2.58 g, 13.85 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)piperazine-l -carboxylate, and was isolated as an off-white solid.Yield 1.42 g (70%). 'H NMR (400 MHz, CDCI ,) 67.95 (s, 1H), 3.63 - 3.52 (m, 4H), 3.45 - 3.35 (m, 4H), 2.06 (s, 3H), 1.50 (s, 9H). NH proton not observed, m / z: [ESI+] 295 (M+H)+.Synthesis of 5-methyl-6-(piperazin- 1 -yl)pyrimidin-4( 3H)-one hydrochloride

[0177] Compound 5-methyl-6-(piperazin-l-yl)pyrimidin-4(377)-one hydrochloride was prepared from tert-butyl 4-(5-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)piperazine-l-carboxylate (810 mg, 2.752 mmol) following a similar procedure to that described for the synthesis of 4,5-dimethyl-6- (piperazin-l-yl)pyrimidine hydrochloride, and was isolated as a yellow solid.Yield 500 mg (79%).1H NMR (400 MHz, DMSO) 5 9.52 (br s, 2H, NH2+), 7.96 (s, 1H), 3.45 (t, J = 4.8 Hz, 4H), 3.13 (t, J = 4.8 Hz, 4H), 1.86 (s, 3H). Lactam NH proton not observed, m / z: [ESI+] 195 (M+H)+.Synthesis of5-methyl-6-(piperazin-l-yl)pyrimidin-4-amine hydrochlorideScheme 13Synthesis of tert-butyl 4-( 6-amino-5-methylpyrimidin-4-yl)piperazine- 1 -carboxylate

[0178] Compound tert-butyl 4-(6-amino-5-methylpyrimidin-4-yl)piperazine-l -carboxylate was prepared from 6-chloro-5-methylpyrimidin-4-amine (2.00 g, 13.93 mmol) and tert-butyl piperazine- 1-carboxylate (3.89 g, 20.88 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)piperazine-l -carboxylate, and was isolated as an off- white solid.Yield 3.50 g (86%).JH NMR (400 MHz, CDCI ,) 6 8.22 (s, 1H), 4.74 (br s, 2H), 3.59 - 3.52 (m, 4H), 3.26 - 3.18 (m, 4H), 2.03 (s, 3H), 1.50 (s, 9H). m / z: [ESI+] 294 (M+H)+.Synthesis of 5-methyl-6-(piperazin-l-yl)pyrimidin-4-amine hydrochloride

[0179] Compound 5-methyl-6-(piperazin-l-yl)pyrimidin-4-amine hydrochloride was prepared from tert-butyl 4-(6-amino-5-methylpyrimidin-4-yl)piperazine-l -carboxylate (3.50 g, 11.93 mmol) following a similar procedure to that described for the synthesis of 4,5-dimethyl-6-(piperazin-l- yl)pyrimidine hydrochloride, and was isolated as a yellow solid.Yield 2.67 g (97%).1H NMR (400 MHz, DMSO) 5 9.62 (br s, 2H, NH2+), 8.37 (s, 1H), 7.95 (br s, 2H), 3.70 (t, J = 4.8 Hz, 4H), 3.17 (t, J = 4.8 Hz, 4H), 1.98 (s, 3H). m / z: [ESI+] 194 (M+H)+.Synthesis of4-methyl-6-(piperazin-l-yl)pyrimidin-5-amineScheme 14Synthesis of tert-butyl 4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)piperazine-l-carboxylate

[0180] Compound tert-butyl 4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)piperazine-l -carboxylate was prepared from 2,4-dichloro-6-methyl-5-nitropyrimidine (1.00 g, 4.81 mmol) and tert-butyl piperazine- 1 -carboxylate (0.98 g, 5.26 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)piperazine-l -carboxylate, and was isolated as a brown solid.Yield 1.57 g (91%).JH NMR (400 MHz, CDCI ,) 6 3.65 - 3.45 (m, 8H), 2.48 (s, 3H), 1.50 (s, 9H). m / z: [ESI+] 358, 360 (M+H)+.Synthesis of tert-butyl 4-(5-amino-6-methylpyrimidin-4-yl)piperazine- 1 -carboxylate

[0181] A mixture of tert-butyl 4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)piperazine-l -carboxylate (1.57 g, 4.39 mmol) and 10% palladium on active carbon (0.47 g) in methanol (20 mL) was stirred for overnight at room temperature under a hydrogen atmosphere (1.2 atm). The resulting mixture was filtered. The filter cake was washed with methanol (2 x 50 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-(5-amino-6-methylpyrimidin-4-yl)piperazine-l -carboxylate as a dark yellow solid.Yield 1.20 g (93%). 'H NMR (400 MHz, CDCI ,) 6 8.32 (s, 1H), 4.23 (br s, 2H), 3.70 (t, J = 4.8 Hz, 4H), 3.60 (t, J = 4.8 Hz, 4H), 2.67 (s, 3H), 1.50 (s, 9H). m / z: [ESI+] 294 (M+H)+.Synthesis o / 4-melhy l-6-( piperazin- l-yl)pyri / nidin-5-ainine hydrochloride

[0182] Compound 4-methyl-6-(piperazin-l-yl)pyrimidin-5-amine hydrochloride was prepared from tert-butyl 4-(5-amino-6-methylpyrimidin-4-yl)piperazine-l -carboxylate (1.50 g, 5.11 mmol) following a similar procedure to that described for the synthesis of 4,5-dimethyl-6-(piperazin-l- yl)pyrimidine hydrochloride, and was isolated as a yellow solid.Yield 1.10 g (94%). 'H NMR (400 MHz, CD3OD) 5 8.45 (s, 1H), 4.08 - 4.01 (m, 4H), 3.47 - 3.43 (m, 4H), 2.54 (s, 3H). All the active protons not observed, m / z: [ESI+] 194 (M+H)+.Synthesis of4-methyl-6-(piperazin-l-yl)pyrimidin-5-olScheme 15Synthesis of tert-butyl 4-( 6-chloro-5-methoxypyrimidin-4-yl)piperazine-l -carboxylate

[0183] Compound tert-butyl 4-(6-chloro-5-methoxypyrimidin-4-yl)piperazine-l -carboxylate was prepared from 4,6-dichloro-5-methoxypyrimidine (1.00 g, 5.59 mmol) and tert-butyl piperazine-1- carboxylate (1.14 g, 6.12 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(5,6-dimethylpyrimidin-4-yl)piperazine-l-carboxylate, and was isolated as a white solid. Yield 1.70 g (93%).JH NMR (400 MHz, CDCI ,) 6 8.21 (s, 1H), 3.86 - 3.79 (m, 4H), 3.77 (s, 3H),3.62 - 3.45 (m, 4H), 1.50 (s, 9H). m / z: [ESI+] 329, 331 (M+H)+.Synthesis of tert-butyl 4-( 5-methoxy-6-methylpyrimidin-4-yl)piperazine-l -carboxylate

[0184] Compound tert-butyl 4-(5-methoxy-6-methylpyrimidin-4-yl)piperazine-l -carboxylate was prepared from tert-butyl 4-(6-chloro-5-methoxypyrimidin-4-yl)piperazine-l -carboxylate (1.70 g, 5.17 mmol) and methylboronic acid (0.93 g, 15.54 mmol) following a similar procedure to that described for the synthesis of (6-vinylbenzo[t / ]oxazol-2-yl)methyl acetate, and was isolated as a brown oil.Yield 1.14 g (72%). 'H NMR (400 MHz, CDCI ,) 6 8.35 (s, 1H), 3.79 - 3.70 (m, 4H), 3.68 (s, 3H),3.63 - 3.49 (m, 4H), 2.42 (s, 3H), 1.50 (s, 9H). m / z: [ESI+] 309 (M+H)+.Synthesis of tert-butyl 4-( 5-hydroxy-6-methylpyrimidin-4-yl)piperazine-l -carboxylate

[0185] To a stirred solution of tert-butyl 4-(5-methoxy-6-methylpyrimidin-4-yl)piperazine-l- carboxylate (600 mg, 1.946 mmol) in dichloromethane (10 mL) was added boron tribromide (1 N indichloromethane, 10 mL, 10.00 mmol) dropwise at 0°C under a nitrogen atmosphere. The reaction mixture was stirred for overnight at room temperature under a nitrogen atmosphere. The mixture was acidified to pH 6 with acetic acid and purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 pm, 120 g; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 3% - 10% B in 15 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm. Desired fractions were collected at 5% B and concentrated under reduced pressure to afford a mixture of 4-methyl-6-(piperazin-l-yl)pyrimidin-5-ol and 5-methoxy-4- methyl-6-(piperazin-l-yl)pyrimidine (1:1, 350 mg) as a yellow solid, which can’t be separated by column.

[0186] A solution of 4-methyl-6-(piperazin-l-yl)pyrimidin-5-ol and 5-methoxy-4-methyl-6- (piperazin-l-yl)pyrimidine (1:1, 350 mg), triethylamine (547 mg, 5.406 mmol), di-tert-butyl dicarbonate (590 mg, 2.703 mmol) and MA-dimcthylpyridin-4-aminc (22 mg, 0.180 mmol) in dichloromethane (5 mL) was stirred for 2 h at room temperature under a nitrogen atmosphere. The resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 9% of methanol in dichloromethane to afford tert-butyl 4-(5- hydroxy-6-methylpyrimidin-4-yl)piperazine-l -carboxylate as a yellow solid.Yield 500 mg (94%). 'H NMR (400 MHz, CDC13) 6 8.22 (s, 1H), 3.88 - 3.75 (m, 4H), 3.59 - 3.54 (m, 4H), 2.52 (s, 3H), 1.44 (s, 9H). OH proton not observed, m / z: [ESI+] 295 (M+H)+.Synthesis of 4-methyl-6-(piperazin- 1 -yl)pyrimidin-5-ol hydrochloride

[0187] Compound 4-methyl-6-(piperazin-l-yl)pyrimidin-5-ol hydrochloride was prepared from tertbutyl 4-(5-hydroxy-6-methylpyrimidin-4-yl)piperazine-l -carboxylate (500 mg, 1.699 mmol) following a similar procedure to that described for the synthesis of 4,5-dimethyl-6-(piperazin-l- yl)pyrimidine hydrochloride, and was isolated as a yellow solid.Yield 350 mg (89%).1H NMR not be ran. m / z: [ESI+] 195 (M+H)+.Pd / C, H2(1 .2 atm)MeOH, rt neat, 130°CScheme 16Synthesis ofN,N-dibenzyl-2-(benzyloxy)-4-bromoaniline

[0188] To a stirred solution of 2-amino-5-bromophenol (5.00 g, 26.59 mmol) and potassium carbonate (18.00 g, 130.24 mmol) in A%V-di methyl formam ide (100 mL) was added benzyl bromide (18.01 g, 105.30 mmol) dropwise at room temperature. The resulting mixture was stirred for 16 h at 80°C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature and diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 20% of ethyl acetate in petroleum ether to afford A%V-dibenzyl-2-(benzyloxy)-4-bromoaniline as a light yellow solid.Yield 12.00 g (98%).JH NMR (400 MHz, CDCh) 6 7.50 - 7.44 (m, 2H), 7.43 - 7.33 (m, 3H), 7.28 - 7.18 (m, 10H), 7.10 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 2.0, 8.4, 1H), 6.70 (d, J = 8.4 Hz, 1H), 5.17 (s, 2H), 4.26 (s, 4H). m / z: [ESI+] 458, 460 (M+H)+.Synthesis of3-(3-(benzyloxy)-4-(dibenzylamino)phenyl)oxetan-3-ol

[0189] To a stirred solution of MAMibcnzyl-2-(bcnzyloxy)-4-bromoanilinc (1.00 g, 2.18 mmol) in tetrahydrofuran (20 mL) was added n-butyl lithium (2.5 N in tetrahydrofuran, 1 mL, 2.50 mmol) dropwise at -78°C under a nitrogen atmosphere over 2 min and stirred for 30 min at this temperature. To the above solution was added a solution of 3-oxetanone (0.80 g, 11.10 mmol) in tetrahydrofuran (3 mL) dropwise over 2 min at -78°C. The resulting solution was stirred for additional 2 h at room temperature. The reaction was quenched with sat. aqueous ammonium chloride solution (20 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combinedorganic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 30% of ethyl acetate in petroleum ether to afford 3-(3- (benzyloxy)-4-(dibenzylamino)phenyl)oxetan-3-ol as a colorless oil.Yield 0.30 g (30%).JH NMR (400 MHz, CDCI ,) 5 7.51 - 7.46 (m, 2H), 7.41 - 7.33 (m, 3H), 7.32 - 7.17 (m, 11H), 6.99 (dd, J = 2.0, 8.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.24 (s, 2H), 4.90 - 4.83 (m, 4H), 4.32 (s, 4H), 2.64 (br s, 1H). m / z: [ESI+] 452 (M+H)+.Synthesis of3-( 4-amino-3-hydroxyphenyl)oxetan-3-ol

[0190] Compound 3-(4-amino-3-hydroxyphenyl)oxetan-3-ol was prepared from 3-(3-(benzyloxy)- 4-(dibenzylamino)phenyl)oxetan-3-ol (300 mg, 0.664 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(5-amino-6-methylpyrimidin-4-yl)piperazine-l- carboxylate, and was isolated as a light yellow oil.Yield 100 mg (83%).1H NMR not be ran. m / z: [ESI+] 182 (M+H)+.Synthesis of3-( 2-( chloromethyl)benzo[d]oxazol-6-yl)oxetan-3-ol

[0191] Compound 3-(2-(chloromethyl)benzo[t / ]oxazol-6-yl)oxetan-3-ol was prepared from 3-(4- amino-3-hydroxyphenyl)oxetan-3-ol (100 mg, 0.552 mmol) in 2-chloro- 1,1,1 -trimethoxyethane (10 mL) following a similar procedure to that described for the synthesis of 6-bromo-2-(chloromethyl)- 1,3-benzoxazole, and was isolated as a light yellow oil.Yield 120 mg (91%). ' H NMR (400 MHz, CDCI ,) 6 7.86 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 1.6, 8.4 Hz, 1H), 5.02 - 4.94 (m, 4H), 4.79 (s, 2H). OH proton not observed, m / z: [ESI+] 240, 242 (M+H)+.Scheme 17Synthesis of 2-(benzyloxy)-4-fluoro-l -nitrobenzene

[0192] Compound 2-(benzyloxy)-4-fluoro- 1 -nitrobenzene was prepared from 5-fluoro-2-nitrophenol (10.00 g, 63.65 mmol) and (bromomethyl)benzene (13.06 g, 76.36mmol) following a similar procedure to that described for the synthesis of A,A-dibenzyl-2-(benzyloxy)-4-bromoaniline, and was isolated as a light yellow solid.Yield 15.00 g (95%). 'H NMR (400 MHz, CDCh) 6 8.03 - 7.95 (m, 1H), 7.51 - 7.47 (m, 2H), 7.46 - 7.41 (m, 2H), 7.40 - 7.37 (m, 1H), 6.89 - 6.83 (m, 1H), 6.80 - 6.73 (m, 1H), 5.25 (s, 2H). there is no mass signal.Synthesis of 3 -(benzyloxy )-4-nitrophenol

[0193] To a stirred solution of 2-(benzyloxy)-4-fluoro-l -nitrobenzene (5.00 g, 20.22 mmol) in water (80 mL) was added potassium hydroxide (3.40 g, 60.60 mmol) in portions. The resulting mixture was stirred for 16 h at 100°C. The mixture was allowed to cool down to room temperature and was acidified to pH 3 with 3 N hydrochloride aqueous solution. The resulting mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 30% of ethyl acetate in petroleum ether to afford 3 -(benzyloxy) -4-nitrophenol as a light yellow solid.Yield 3.00 g (60%).JH NMR (400 MHz, CDCI ,) 6 7.98 (d, J = 8.8 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.44 - 7.39 (m, 2H), 7.38 - 7.33 (m, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.47 (dd, J = 2.4, 8.8 Hz, 1H), 5.23 (s, 2H). OH proton not observed, m / z: [ESI ] 244 (M-H)’.Synthesis of2-(benzyloxy)-4-( difluoromethoxy )-l -nitrobenzene

[0194] To a stirred solution of 3 -(benzyloxy) -4-nitrophenol (1.10 g, 4.49 mmol) in acetonitrile (10 mL) were added diethyl bromodifluoromethylphosphonate (1.80 g, 6.74 mmol) and potassium hydroxide (2.52 g, 44.91 mmol) in water (10 mL) dropwise at 0°C under a nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 20% of ethyl acetate in petroleum ether to afford 2-(benzyloxy)-4-(difluoromethoxy)-l -nitrobenzene as a light yellow solid.Yield 1.10 g (83%). 'H NMR (400 MHz, CDCI ,) 6 7.98 (d, J = 8.8 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.46 - 7.40 (m, 2H), 7.40 - 7.34 (m, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 2.4, 8.8 Hz, 1H), 6.58 (t, J = 72.4 Hz, 1H), 5.25 (s, 2H).19E NMR (376 MHz, CDCI ,) 6 -82.15. m / z: [ESI ] 294 (M- H)’.Synthesis of2-amino-5-( difluoromethoxy )phenol

[0195] Compound 2-amino-5-(difluoromethoxy)phenol was prepared from 2-(benzyloxy)-4- (difluoromethoxy)-l -nitrobenzene (1.10 g, 3.73 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(5-amino-6-methylpyrimidin-4-yl)piperazine-l- carboxylate, and was isolated as a light yellow oil.Yield 0.60 g (92%).1H NMR (400 MHz, CDCI ,) 6 7.28 (s, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.40 (t, J = 74.8 Hz, 1H). All the active protons not observed, m / z: [ESI+] 176 (M+H)+.Synthesis of2-( chloromethyl)-6-(difluoromethoxy)benzo[d]oxazole

[0196] Compound 2-(chloromethyl)-6-(difluoromethoxy)benzo[t / ]oxazole was prepared from 2- amino-5-(difluoromethoxy)phenol (600 mg, 3.426 mmol) in 2-chloro- 1,1,1 -trimethoxyethane (10 mL) following a similar procedure to that described for the synthesis of 6-bromo-2-(chloromethyl)- 1,3-benzoxazole, and was isolated as a yellow oil.Yield 600 mg (75%).JH NMR (400 MHz, CDCI ,) 6 7.74 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.21 (dd, J = 2.4, 8.8 Hz, 1H), 6.57 (t, J = 73.2 Hz, 1H), 4.77 (s, 2H). m / z: [ESI+] 234, 236 (M+H)+.Synthesis of l-( 2-( chloromethyl)benzo[d]oxazol-6-yl)cyclopropane-l-carbonitrileScheme 18Synthesis of ethyl 2-cyano-2-(3-methoxy-4-nitrophenyl)acetate

[0197] To a stirred solution of ethyl 2-cyanoacetate (6.61 g, 58.43 mmol) in N,N- dimethylformamide (75 mL) was added sodium hydride (60% oil dispersion, 3.51 g, 87.75 mmol) in portions at 0°C. The resulting mixture was stirred for 30 min at room temperature under a nitrogen atmosphere. To the above mixture was added 4-fluoro-2-methoxy-l -nitrobenzene (5.00 g, 29.22 mmol) in portions at room temperature. The resulting mixture was stirred for additional 5 h at 80°C. The mixture was allowed to cool down to room temperature and quenched by the addition of sat. aqueous ammonium chloride solution (20 mL) at 0°C. To the above mixture was added ethyl acetate (500 mL). The separated organic layer was washed with brine (5 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford ethyl 2-cyano-2-(3-methoxy-4-nitrophenyl)acetate as a red oil.Yield 7.00 g (91%).1H NMR (400 MHz, CD3OD) 5 7.84 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.10 (dd, J = 2.0, 9.2 Hz, 1H), 4.85 (s, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). There is no mass signal.Synthesis of2-( 3-methoxy-4-nitrophenyl)acetonitrile

[0198] To a stirred solution of ethyl 2-cyano-2-(3-methoxy-4-nitrophenyl)acetate (6.00 g, 22.71 mmol) in 1,4-dioxane (40 mL) was added hydrochloride (6 N in water, 20 mL) dropwise at 0°C. The reaction mixture was stirred for 16 h at 50°C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL). The mixture was neutralized to pH 7 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(3-methoxy-4-nitrophenyl)acetonitrile as a yellow solid.Yield 4.00 g (92%). ' H NMR (400 MHz, CDCh) 6 7.89 (d, J = 8.4 Hz, 1H), 7.10 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H), 3.86 (s, 2H). m / z: [ESI-] 191 (M-H)’.Synthesis of l-( 3-methoxy-4-nitrophenyl)cyclopropane-l -carbonitrile

[0199] To a stirred solution of 2-(3-methoxy-4-nitrophenyl)acetonitrile (4.50 g, 23.42 mmol), 1,2- dibromoethane (8.80 g, 46.84 mmol) and tetrabutylammonium bromide (7.55 g, 23.42 mmol) in dichloromethane (50 mL) was added sodium hydroxide (10 A in water, 31 mL) dropwise at 0°C. The resulting mixture was stirred for 2h at room temperature under a nitrogen atmosphere. The mixture was acidified to pH 6 with hydrochloride (3 N in water) and filtered. The filter cake was washed with dichloromethane (3 x 20 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column, Spherical C18, 20 - 40 pm, 330; Mobile Phase A: water (plus 10 mM ammonium bicarbonate); Mobile Phase B; acetonitrile; Flow rate: 80 mL / min; Gradient:45%B - 65%B in 20 min; Detector, UV 254 nm. The fractions containing desired product were collected at 54% B and concentrated under reduced pressure to afford l-(3-methoxy-4- nitrophenyl)cyclopropane-l -carbonitrile as a yellow solid.Yield 3.38 g (66%). ' H NMR (400 MHz, CDCh) 6 7.87 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 2.0, 8.4 Hz, 1H), 4.03 (s, 3H), 1.92 - 1.86 (m, 2H), 1.57 - 1.50 (m, 2H). There is no mass signal.Synthesis of l-( 3-hydroxy-4-nitrophenyl)cyclopropane-l -carbonitrile

[0200] A solution of l-(3-methoxy-4-nitrophenyl)cyclopropane-l -carbonitrile (1.00 g, 4.58 mmol) and tribromoborane (boron tribromide) (1 A in dichloromethane, 9.2 mL, 9.20 mmol) in dichloromethane (20 mL) was stirred for 16 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified byreverse phase flash chromatography with the following conditions: Column, Spherical Cl 8, 20 - 40 urn, 330; Mobile Phase A: water (plus 10 mM ammonium bicarbonate ); Mobile Phase B; acetonitrile; Flow rate: 80 mL / min; Gradient:45%B-65%B in 20 min; Detector, UV 254 nm. The fractions containing desired product were collected at 54% B and concentrated under reduced pressure to afford l-(3-hydroxy-4-nitrophenyl)cyclopropane-l -carbonitrile as a yellow solid.Yield 0.60 g (64%).JH NMR (400 MHz, CDCh) 6 10.64 (br s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 2.0, 8.8 Hz, 1H), 1.95 - 1.89 (m, 2H), 1.59 - 1.55 (m, 2H).m / z: [ESI-] 203 (M-H)’.Synthesis of l-( 4-amino-3-hydroxyphenyl)cyclopropane-l -carbonitrile

[0201] Compound l-(4-amino-3-hydroxyphenyl)cyclopropane-l -carbonitrile was prepared from l-(3-hydroxy-4-nitrophenyl)cyclopropane-l -carbonitrile (300 mg, 1.469 mmol) in the presence of triethylamine (446 mg, 4.408 mmol) in ethyl acetate (10 mL) following a similar procedure to that described for the synthesis of tert-butyl 4-(5-amino-6-methylpyrimidin-4-yl)piperazine-l- carboxylate, and was isolated as a brown solid.Yield 220 mg (86%). ' H NMR (400 MHz, CDCh) 6 6.82 (d, J = 2.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.65 (dd, J = 2.0, 8.0 Hz, 1H), 1.66 - 1.61 (m, 2H), 1.34 - 1.29 (m, 2H). OH and NH2protons not observed, m / z: [ESI-] 173 (M-H)’.Synthesis of 1 -(2-(chloromethyl)benzo[d]oxazol-6-yl)cyclopropane-l -carbonitrile

[0202] Compound l-(2-(chloromethyl)benzo[( / ]oxazol-6-yl)cyclopropane-l -carbonitrile was prepared from l-(4-amino-3-hydroxyphenyl)cyclopropane-l -carbonitrile (220 mg, 1.263 mmol) in 2-chloro- 1,1,1 -trimethoxy ethane (1 mL) following a similar procedure to that described for the synthesis of 6-bromo-2-(chloromethyl)-l,3-benzoxazole, and was isolated as an off-white solid.Yield 260 mg (88%).1H NMR (400 MHz, CDCh) 6 7.73 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 4.78 (s, 2H), 1.92 - 1.74 (m, 2H), 1.56 - 1.39 (m, 2H). m / z: [ESI+] 233, 235 (M+H)+.Synthesis of l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[d]oxazol-6-yl)- lH-pyrazole-4-carbaldehydeScheme 19Synthesis of4-bromo-l-(3-methoxy-4-nitrophenyl)-lH-pyrazole

[0203] Compound 4-bromo- 1 -(3-mcthoxy-4-nitrophcnyl)- 177-pyrazolc was prepared from 4-fluoro- 2-methoxy-l -nitrobenzene (5.10 g, 29.80 mmol) and 4-bromopyrazole (5.69 g, 38.71 mmol) following a similar procedure to that described for the synthesis of 2V,2V-dibenzyl-2-(benzyloxy)-4- bromoaniline, and was isolated as a yellow solid.Yield 8.5 g (96%).JH NMR (400 MHz, CDCh) 6 8.06 (d, J = 8.8 Hz, 1H), 8.05 (s, 1H), 7.75 (s, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.20 (dd, J = 2.4, 8.8 Hz, 1H), 4.08 (s, 3H). m / z: [ESI+] 298, 300 (M+H)+.Synthesis of 5-(4-bromo-lH-pyrazol-l-yl)-2-nitrophenol

[0204] Compound 5-(4-bromo-177-pyrazol-l-yl)-2-nitrophenol was prepared from 4-bromo-l-(3- methoxy-4-nitrophenyl)-177-pyrazole (5.00 g, 16.77 mmol) following a similar procedure to that described for the synthesis of l-(3-hydroxy-4-nitrophenyl)cyclopropane-l -carbonitrile, and was isolated as a yellow solid.Yield 3.16 g (66%).JH NMR (400 MHz, CDCh) 6 10.85 (br s, 1H), 8.25 (d, J = 9.2 Hz, 1H), 8.05 (s, 1H), 7.77 (s, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 2.4, 9.2 Hz, 1H). m / z: [ESI+] 284 (M+H)+.Synthesis of2-amino-5-(4-bromo-lH-pyrazol-l-yl)phenol

[0205] A mixture of 5-(4-bromo-177-pyrazol-l-yl)-2-nitrophenol (2.20 g, 7.75 mmol), Zn (2.53 g, 38.70 mmol) and ammonium chloride (2.07 g, 38.70 mmol) in methanol (20 mL) and water (8 mL) was stirred for 4 h at room temperature. After filtration, the filter cake was washed with methanol (3 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 30% of ethyl acetate in petroleum ether to afford 2-amino- 5-(4-bromo-177-pyrazol-l-yl)phenol as a brown solid.Yield 1.33 g (68%). ' H NMR (400 MHz, CDCI ,) 6 7.79 (s, 1H), 7.64 (s, 1H), 7.16 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 2.4, 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H). All the active protons not observed, m / z: [ESI+] 254, 256 (M+H)+.Synthesis of 6-( 4-bromo-lH-pyrazol-l -yl)-2-( chloromethyl )benzo[ d ] oxazole

[0206] Compound 6-(4-bromo-177-pyrazol-l-yl)-2-(chloromethyl)benzo[t / ]oxazole was prepared from 2-amino-5-(4-bromo-177-pyrazol-l-yl)phenol (1.30 g, 5.12 mmol) in 2-chloro- 1,1,1 - trimethoxyethane (5 mL) following a similar procedure to that described for the synthesis of 6-bromo- 2-(chloromethyl)-l,3-benzoxazole, and was isolated as a white solid.Yield 1.25 g (78%). ' H NMR (400 MHz, CDCI ,) 6 8.00 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.67 (dd, J = 2.0, 8.8 Hz, 1H), 4.79 (s, 2H). m / z: [ESI+] 312, 314, 316 (M+H)+.Synthesis of 6-(4-bromo- IH-pyrazol- 1 -yl)-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 - yl )methyl )benzo[ d ] oxazole

[0207] Compound 6-(4-bromo- 177-pyrazol- 1 -yl)-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 - yl)methyl)benzo[tf] oxazole was prepared from 6-(4-bromo-177-pyrazol-l-yl)-2-(chloromethyl)benzo[tf] oxazole (1.20 g, 3.84 mmol) and 4,5-dimethyl-6-(piperazin-l-yl)pyrimidinehydrochloride (0.89 g, 3.89 mmol) following a similar procedure to that described for the synthesis of 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[ri]oxazole, and was isolated as a yellow solid.Yield 0.84 g (47%).JH NMR (400 MHz, CDCh) 6 8.55 (s, 1H), 7.98 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.63 (dd, J = 2.0, 8.4 Hz, 1H), 3.99 (s, 2H), 3.44 (t, J = 4.8 Hz, 4H), 2.82 (t, J = 4.8 Hz, 4H), 2.43 (s, 3H), 2.16 (s, 3H). m / z: [ESI+] 468, 470 (M+H)+.Synthesis of2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l -yl)methyl)-6-(4-vinyl-l H-pyrazol-1 - yl )benzo[ d ] oxazole

[0208] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-(4-viny 1- 1 H- pyrazol- l -yl)bcnzo|<7| oxazole was prepared from 6-(4-bromo-177-pyrazol-l-yl)-2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[ri] oxazole (0.80 g, 1.71 mmol) and 4, 4,5,5- tetramethyl-2-vinyl-l,3,2-dioxaborolane (0.79 g, 5.12 mmol) following a similar procedure to that described for the synthesis of (6-vinylbcnzo|c / |oxazol-2-yl)mcthyl acetate, and was isolated as a yellow solid.Yield 0.50 g (70%). 'H NMR (400 MHz, CDCI ,) 6 8.54 (s, 1H), 7.95 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 2.0, 8.4 Hz, 1H), 6.63 (dd, J = 10.8, 17.6 Hz, 1H), 5.61 (dd, J = 1.2, 17.6 Hz, 1H), 5.21 (dd, J = 1.2, 10.8 Hz, 1H), 3.99 (s, 2H), 3.46 (t, J = 4.8 Hz, 4H), 2.82 (t, J = 4.8 Hz, 4H), 2.44 (s, 3H), 2.16 (s, 3H). m / z: [ESI+] 416 (M+H)+.Synthesis of l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl )methyl )benzo[ d ]oxazol-6-yl)- lH-pyrazole-4-carbaldehyde

[0209] Compound 1 -(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)mcthyl)bcnzo|c / |oxazol-6- yl)-177-pyrazole-4-carbaldehyde was prepared from 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)-6-(4-vinyl-177-pyrazol-l-yl)benzo[ri]oxazole (0.50 g, 1.20 mmol) following a similar procedure to that described for the synthesis of (6-formylbenzo[ri]oxazol-2-yl)methyl acetate, and was isolated as a light yellow solid.Yield 0.29 g (58%).1H NMR (400 MHz, CDC13) 6 10.01 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 8.21 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 2.0, 8.4 Hz, 1H), 4.01 (s, 2H), 3.49 (t, J = 4.8 Hz, 4H), 2.83 (t, J = 4.8 Hz, 4H), 2.45 (s, 3H), 2.17 (s, 3H). m / z: [ESI+] 418 (M+H)+.Synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzo[ d ] oxazole

[0210] To a stirred solution of 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[tf] oxazole (8.00 g, 19.89 mmol), bis(pinacolato)diboron (7.57 g, 29.81 mmol) in dioxane (150 mL) and potassium acetate (3.90 g, 39.74 mmol) was added [1,T- bis(diphenylphosphino)ferrocene] dichloropalladium (II) (2.18 g, 2.98 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 4 h at 90°C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with l%-10% of methanol in dichloromethane to afford 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[t / ]oxazole as a black oil.Yield 8.00 g (90%).JH NMR (400 MHz, CDC13) 6 8.54 (s, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 1.6, 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 3.99 (s, 2H), 3.52 (t, J = 4.8 Hz, 4H), 2.81 (t, J = 4.8 Hz, 4H), 2.48 (s, 3H), 2.16 (s, 3H), 1.39 (s, 12H). m / z: [ESI+] 450 (M+H)+.Synthesis of 6-(l-( 2-( ( tert-butyldimethylsilyl)oxy)ethyl)-lH-pyrazol-4-yl)-2-( ( 4-( 5, 6-Scheme 20Synthesis of4-bromo-l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-lH-pyrazole

[0211] Compound 4-bromo- l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-177-pyrazole was prepared from 4-bromo- 177-pyrazole (0.50 g, 3.40 mmol) and (2-bromoethoxy)(tert-butyl)di methylsilane ( 1.22 g, 5.10 mmol) following a similar procedure to that described for the synthesis of MY-di benzyl -2- (benzyloxy)-4-bromoaniline expected that reacted at room temperature, and was isolated as a colorless oil.Yield 0.80 g (77%).JH NMR (400 MHz, CDC13) 6 7.50 (s, 1H), 7.48 (s, 1H), 4.21 (t, J = 5.2 Hz, 2H), 3.92 (t, J = 5.2 Hz, 2H), 0.87 (s, 9H), -0.03 (s, 6H). m / z: [ESI+] 305, 307 (M+H)+.Synthesis of 6-(l-( 2-( ( tert-butyldimethylsilyl)oxy)ethyl)-lH-pyrazol-4-yl)-2-( ( 4-( 5, 6- dimethylpyrimidin-4-yl)piperazin-l-yl )methyl)benzo[ d ] oxazole

[0212] Compound 6-( 1 -(2-((tert-butyldimethylsilyl)oxy)ethyl)-177-pyrazol-4-yl)-2-((4-(5,6- dimcthylpyi%nidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|<7| oxazole was prepared from 4-bromo- 1 -(2- (t / e / 7-buty Idi methyl si lyl)oxy)cthyl)- l / 7-pyrazolc (300 mg, 0.983 mmol) and 2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)benzo[tf] oxazole (662 mg, 1.473 mmol) following a similar procedure to that described for the synthesis of (6-vinylbenzo[t / ]oxazol-2-yl)methyl acetate, and was isolated as a yellow solid.Yield 180 mg (33%). m / z: [ESI+] 548 (M+H)+.!H NMR not be ran.Synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(5-methyl-4-((2-H2O, 90 CScheme 21Synthesis of 3-bromo-5-methyl-4-( ( 2-( trimethylsilyl)ethoxy)methyl)-4H-l,2,4-triazole

[0213] Compound 3-bromo-5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4 / / -l,2,4-triazole was prepared from 3-bromo-5-methyl-477-l,2,4-triazole (500 mg, 3.087 mmol) and (2- (chloromethoxy)ethyl)trimethylsilane (800 mg, 4.798 mmol) following a similar procedure to that described for the synthesis of tert-butyl CS')-3-(bcnzyloxy)pipcridinc- 1 -carboxylate, and was isolated as a colorless oil.Yield 800 mg (89%).JH NMR (400 MHz, CDCI ,) 6 5.41 (s, 2H), 3.74 - 3.43 (m, 2H), 2.54 (s, 3H), 1.05 - 0.85 (m, 2H), 0.02 (s, 9H). m / z: [ESI+] 292, 294 (M+H)+.Synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(5-methyl-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-3-yl)benzo[d]oxazole

[0214] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-(5-methyl- 1 -((2- (trimethylsilyl)ethoxy)methyl)-177-l,2,4-triazol-3-yl)benzo[t / ]oxazole was prepared from 3-bromo- 5-mcthyl-4-((2-( tri methyl silyl)cthoxy) methyl )-4 / 7- 1 ,2,4-triazolc (300 mg, 1.027 mmol) and 2-((4- (5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[tf] oxazole (400 mg, 0.890 mmol) following a similar procedure to that described for the synthesis of (6-vinylbenzo[t / ]oxazol-2-yl)methyl acetate, and was isolated as a light yellow solid. Yield 180 mg (38%).!H NMR not be ran. m / z: [ESI+] 535 (M+H)+. Synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(l-( ( 2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)benzo[d]oxazoleSynthesis of 2-bromo-l -((2-(trimethylsilyl)ethoxy)methyl)-l H-imidazole

[0215] Compound 2-bromo-l -((2-(trimethylsilyl)ethoxy)methyl)-l / / -imidazole was prepared from 2-bromo- 1 / / -imidazole (500 mg, 3.402 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (800 mg, 4.798 mmol) following a similar procedure to that described for the synthesis of tert-butyl (5)-3- (benzyloxy)piperidine-l -carboxylate, and was isolated as a colorless oil. Yield 800 mg (85%).JH NMR (400 MHz, CDCI ,) 6 7.14 (d, J = 1.6 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 5.30 (s, 2H), 3.56 (t, J = 7.6 Hz, 2H), 0.94 (t, J = 7.6 Hz, 2H), 0.02 (s, 9H). m / z: [ESI+] 277, 279 (M+H)+.Synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(l-( ( 2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)benzo[d]oxazole

[0216] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(l-((2-(trimethylsilyl)ethoxy)methyl)-177-imidazol-2-yl)benzo[t / ]oxazole was prepared from 2-bromo-l- ((2-(trimethylsilyl)ethoxy)methyl)-177-imidazole (370 mg, 1.335 mmol) and 2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)benzo[tf] oxazole (400 mg, 0.890 mmol) following a similar procedure to that described for the synthesis of (6-vinylbenzo[t / ]oxazol-2-yl)methyl acetate, and was isolated as a light yellow solid. Yield 300 mg (65%).!H NMR not be ran. m / z: [ESI+] 520 (M+H)+.Synthesis of 2-((4-( 5, 6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-( 2-( ( 2-( trimethylsilyl) ethoxy )methyl)-2H-l,2,3-triazol-4-yl)benzo[ d ] oxazoleSynthesis of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-l ,2,3-triazole

[0217] Compound 4-bromo-2-((2-( tri methyl silyl)cthoxy)mcthyl)-2 / 7- 1 ,2,3-triazole was prepared from 4-bromo-2 / 7- 1 ,2,3-triazole (500 mg, 3.379 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (800 mg, 4.798 mmol) following a similar procedure to that described for the synthesis of tert-butyl (S)-3-(bcnzyloxy)pipcridinc- 1 -carboxylate, and was isolated as a colorless oil.Yield 800 mg (85%).!H NMR not be ran. m / z: [ESI+] 278, 280 (M+H)+.Synthesis of 2-((4-( 5, 6-dimethylpyrimidin-4-yl)piperazin-l -yl)methyl)-6-( 2-( ( 2-( trimethylsilyl) ethoxy )methyl)-2H-l,2,3-triazol-4-yl)benzo[ d ] oxazole

[0218] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-(2-((2-(trimethylsilyl)ethoxy)methyl)-2 / / -l,2,3-triazol-4-yl)benzo[t / ]oxazole was prepared from 4-bromo- 2-((2-(trimethylsilyl)ethoxy)methyl)-277-l,2,3-triazole (370 mg, 1.330 mmol) and 2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)benzo[tf] oxazole (400 mg, 0.890 mmol) following a similar procedure to that described for the synthesis of (6-vinylbenzo[t / ]oxazol-2-yl)methyl acetate, and was isolated as a light yellow solid.Yield 280 mg (60%).JH NMR (400 MHz, CDCI ,) 6 8.53 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 7.84 (dd, J = 1.6, 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 5.75 (s, 2H), 4.01 (s, 2H), 3.79 - 3.67 (m, 6H), 2.90 - 2.80 (m, 4H), 2.59 (s, 3H), 2.20 (s, 3H), 1.04 - 0.94 (m, 2H), 0.02 (s, 9H). m / z: [ESI+] 521 (M+H)+.Synthesis of 6-(5-bromo-2-(difluoromethyl)-2H-l,2,3-triazol-4-yl)-2-((4-(5,6-dimethylpyrimidin-4- yl )piperazin-l -yl)methyl )benzo[ d ] oxazole ( Compound A )Synthesis of 6-(4-bromo-l-(difluoromethyl)-lH-l,2,3-triazol-5-yl)-2-((4-(5,6-dimethylpyrimidin-4-Scheme 24Synthesis of 4,5-dibromo-2-(difluoromethyl)-2H-l ,2,3-triazole and 4,5-dibromo-l -(difluoromethyl)- 1 H-l ,2, 3 -triazole (mixture)

[0219] Compounds 4,5-dibromo-2-(difluoromethyl)-277-l,2,3-triazole and 4,5-dibromo-l- (difluoromethyl)-177-l,2,3-triazole were prepared from 4,5-dibromo-2 / 7- l ,2,3-triazolc (1.00 g, 4.41 mmol) following a similar procedure to that described for the synthesis of 2-(benzyloxy)-4- (difluoromethoxy)-l -nitrobenzene, and was isolated as an off-white solid.Yield 1.00 g (82%).JH NMR (400 MHz, CDCI ,) 6 7.54 (t, J = 57.2 Hz, 1.5H), 7.24 (t, J = 57.6 Hz, 1H).19F NMR (376 MHz, CDCh) 6 -96.17 (1H), -97.41 (1.5H). m / z: [ESI+] 276, 278, 280 (M+H)+. (a mixture with the ratio about 3:2).Synthesis of 6-(5-bromo-2-(difluoromethyl)-2H-l,2,3-triazol-4-yl)-2-((4-(5,6-dimethylpyrimidin-4- yl )piperazin-l -yl)methyl )benzo[ d ] oxazole ( Compound A )Synthesis of 6-(4-bromo-l-(difluoromethyl)-lH-l,2,3-triazol-5-yl)-2-((4-(5,6-dimethylpyrimidin-4- yl )piperazin-l -yl)methyl )benzo[ d ] oxazole ( Compound B )

[0220] Compound 6-(5-bromo-2-(difluoromethyl)-277-l,2,3-triazol-4-yl)-2-((4-(5,6- dimcthylpyi%nidin-4-yl)pipcrazin- 1 -yl)mcthyl)bcnzo|<7| oxazole (Compound A) and 6-(4-bromo-l- (difluoromethyl)- 177- 1 ,2,3-triazol-5-yl)-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 - yl)methyl)benzo[tf] oxazole (Compound B) were prepared from a mixture of 4,5-dibromo-2- (difluoromethyl)-277-l,2,3-triazole and 4,5-dibromo-l-(difluoromethyl)-177-l,2,3-triazole (0.60 g, 2.17 mmol) and 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzo[t / ]oxazole (1.46 g, 3.25 mmol) following a similar procedure to that described for the synthesis of (6-vinylbenzo[t / ]oxazol-2-yl)methyl acetate, and was isolated as a yellow solid.Compound A: Yield 0.18 g (16%). ' H NMR (400 MHz, CDCh) 6 8.54 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.00 (dd, J = 1.6, 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 58.0 Hz, 1H), 4.02 (s, 2H), 3.57 -3.48 (m, 4H), 2.88 - 2.82 (m, 4H), 2.47 (s, 3H), 2.17 (s, 3H). m / z: [ESI+] 519, 521 (M+H)+.Compound B: Yield 0.15 g (13%).JH NMR (400 MHz, CDCh) 6 8.55 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.55 (t, J = 60.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.03 (s, 2H), 3.66 - 3.53 (m, 4H), 2.90 - 2.81 (m, 4H), 2.52 (s, 3H), 2.20 (s, 3H). m / z: [ESI+] 519, 521 (M+H)+.Final CompoundsSynthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(piperazin-l- yl)benzo[d] oxazole (Compound 126)Compound 126

[0221] To a stirred solution of tert-butyl 4-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-yl)piperazine-l-carboxylate (200 mg, 0.394 mmol) in dichloromethane (5 mL) was added 2,2,2-trifluoroacetic acid (1 mL) dropwise at room temperature. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (2 mL) and basified to pH 7 with 2 N aqueous ammonium bicarbonate. The resulting mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19 x 250 mm, 10 «m; Mobile Phase A: water (10 mmol / L ammonium bicarbonate), Mobile Phase B: methanol; Flow rate: 25 mL / min; Gradient: 37% B to 42% B in 8 min; Wave Length: 254 nm; RTl(min): 7.4). The fractions contained the desired product was concentrated under reduced pressure to afford 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(piperazin-l- yl)bcnzo|t / | oxazole as a yellow solid.Yield 48 mg (30%).1H NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 2.4, 8.8 Hz, 1H), 3.86 (s, 2H), 3.25 (t, J = 4.8 Hz, 4H), 3.11 - 3.04 (m, 4H), 2.87 - 2.82 (m, 4H), 2.65 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.09 (s, 3H). Aliphatic NH proton not observed, m / z: [ESI+] 408 (M+H)+. (C22H29N7O).Synthesis of l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol-6- yl)piperidin-4-amine (Compound 127)

[0222] Compound 1 -(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo[ c / |oxazol-6- yl)piperidin-4-amine was prepared from tert-butyl (l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- l-yl)methyl)benzo[t / ]oxazol-6-yl)piperidin-4-yl)carbamate (240 mg, 0.460 mmol) following a similar procedure to that described for the synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- l-yl)methyl)-6-(piperazin-l-yl)benzo[t / ]oxazole, and was isolated as a pink solid.Yield 51 mg (26%).JH NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 2.4, 8.8 Hz, 1H), 3.85 (s, 2H), 3.71 - 3.57 (m, 2H), 3.27 - 3.22 (m, 4H), 2.85 - 2.72 (m, 3H), 2.70 - 2.60 (m, 4H), 2.32 (s, 3H), 2.10 (s, 3H), 1.87 - 1.74 (m, 2H), 1.57 - 1.42 (m, 1H), 1.42 - 1.28 (m, 1H). Aliphatic NH2 protons not observed, m / z: [ESI+] 422 (M+H)+. (C23H31N7O).Synthesis of (S)-l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol-6- yl)piperidin-3 -amine (Compound 146)

[0223] Compound (S)-l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[6?]oxazol-6-yl)piperidin-3-amine was prepared from tert-butyl (S)-(l-(2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[6?]oxazol-6-yl)piperidin-3-yl)carbamate (100 mg, 0.192 mmol) following a similar procedure to that described for the synthesis of 2-((4- (5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(piperazin-l-yl)benzo[6?]oxazole, and was isolated as a light yellow solid.Yield 19 mg (24%).JH NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.8, 2.4 Hz, 1H), 3.85 (s, 2H), 3.61-3.57 (m, 2H), 3.28-3.22 (m, 4H), 2.79-2.75 (m, 1H), 2.70-2.54 (m, 5H), 2.49-2.37 (m, 1H), 2.32 (s, 3H), 2.10 (s, 3H), 1.90-1.62 (m, 2H), 1.62-1.07 (m, 2H). Aliphatic NH2 protons not observed, m / z: [ESI+] 422 (M+H)+. (C23H31N7O).Synthesis of 6-( l,4-diazepan-l-yl)-2-( ( 4-( 5, 6-dimethylpyrimidin-4-yl)piperazin-l -

[0224] Compound 6-( 1 ,4-diazepan- 1 -yl)-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 - yl)methyl)benzo[tf] oxazole was prepared from tert-butyl 4-(2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[t / ]oxazol-6-yl)-l,4-diazepane-l -carboxy late (350 mg, 0.671 mmol) following a similar procedure to that described for the synthesis of 4,5-dimethyl-6-(piperazin-l- yl)pyrimidine hydrochloride, and was isolated as an off-white solid.Yield 54 mg (19%).1H NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 2.4, 8.8 Hz, 1H), 3.82 (s, 2H), 3.62 - 3.54 (m, 2H), 3.53 - 3.45 (m, 2H), 3.28 - 3.21 (m, 4H), 2.90 - 2.82 (m, 2H), 2.68 - 2.63 (m, 4H), 2.63 - 2.58 (m, 2H), 2.32 (s, 3H), 2.09 (s, 3H), 1.84 - 1.73 (m, 2H). Aliphatic NH proton not observed, m / z: [ESI+] 422 (M+H)+. (C23H31N7O).Synthesis of 2-((4-( 5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-( lH-imidazol-2- yl)benzo[d] oxazole (Compound 118)Compound 118

[0225] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-( 1 H-i midazol-2- yl)benzo[tf] oxazole was prepared from 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6- (l-((2-(trimethylsilyl)ethoxy)methyl)-177-imidazol-2-yl)benzo[tf] oxazole (200 mg, 0.385 mmol) following a similar procedure to that described for the synthesis of 4,5-dimethyl-6-(piperazin-l- yl)pyrimidine hydrochloride, and was isolated as a white solid.Yield 18 mg (12%).JH NMR (400 MHz, DMSO) 5 12.62 (br s, 1H), 8.43 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.00 (dd, J = 1.6, 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.06 (s, 1H), 3.97 (s, 2H), 3.28 (t, J = 4.8 Hz, 4H), 2.71 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 2.11 (s, 3H). m / z: [ESI+] 390 (M+H)+. (C21H23N7O).Synthesis of 2-((4-( 5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-( 2H- 1, 2,3-1 riaz.ol-4- yl)benzo[d] oxazole (Compound 103)

[0226] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-(277- 1 ,2,3-triazol-4- yl)bcnzo|< / | oxazole was prepared from 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6- (2-((2-(trimethylsilyl)ethoxy)methyl)-277-l,2,3-triazol-4-yl)benzo[t / ]oxazole (200 mg, 0.384 mmol) following a similar procedure to that described for the synthesis of 4,5-dimethyl-6-(piperazin-l- yl)pyrimidine hydrochloride, and was isolated as a white solid.Yield 18 mg (12%). ' H NMR (400 MHz, DMSO) 5 15.10 (br s, 1H), 8.49 - 8.39 (m, 1H), 8.42 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.92 (dd, J = 1.6, 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 3.97 (s, 2H), 3.27 (t, J = 4.8 Hz, 4H), 2.70 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 391 (M+H)+. (C20H22N8O).Synthesis of 2-((4-( 5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl )methyl)-6-( 5-methyl-4H-l,2, 4-triazol- 3 -yl)benzo[d] oxazole (Compound 114)Compound 114

[0227] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(5-methyl-477- l,2,4-triazol-3-yl)benzo[6?]oxazole was prepared from 2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)-6-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-477-l,2,4-triazol-3- yl)bcnzo|<7| oxazole (180 mg, 0.337 mmol) following a similar procedure to that described for the synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-(piperazin- 1 - yl)bcnzo|<7| oxazole, and was isolated as a white solid.Yield 50 mg (37%).JH NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 8.03 (dd, J = 1.6, 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 3.96 (s, 2H), 3.27 (d, J = 4.8 Hz, 4H), 2.71 (t, J = 4.8 Hz, 4H), 2.42 (s, 3H), 2.33 (s, 3H), 2.10 (s, 3H). NH proton not observed, m / z: [ESI+] 405 (M+H)+. (C21H24N8O).Synthesis of (R)-l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl )methyl )benzo[ d ]oxazol-6-Compound 147

[0228] To a stirred solution of (7?)-AfJV-dibenzyl-l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- l -yl)mcthyl)bcnzo|d|oxazol-6-yl)pipcridin-3-aminc (220 mg, 0.366 mmol) in dichloromethane (10 mL) was added iodotrimethylsilane (366 mg, 1.829 mmol) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue waspurified by Prep-HPLC with the following conditions (Column: Xselect CSH Cl 8 OBD Column 30 x 150 mm 5 z / m; Mobile Phase A: water (10 mmol / L ammonium bicarbonate), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 20% B to 26% B in 8 min, 26% B; Wave Length: 254 nm; RTl(min): 7.6). The fractions containing the desired product was concentrated under reduced presure to afford (R)-l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)mcthyl)bcnzo|d|oxazol-6-yl)pipcridin-3-aminc as a little yellow solid.Yield 19 mg (12%).JH NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 2.4, 8.8 Hz, 1H), 3.85 (s, 2H), 3.73 - 3.59 (m, 1H), 3.59 - 3.44 (m, 1H), 3.27 - 3.21 (m, 4H), 2.83 - 2.69 (m, 1H), 2.68 - 2.61 (m, 5H), 2.48 - 2.38 (m, 1H), 2.32 (s, 3H), 2.09 (s, 3H), 1.89 - 1.78 (m, 1H), 1.77 - 1.68 (m, 1H), 1.62 - 1.49 (m, 1H), 1.22 - 1.07 (m, 1H). Aliphatic NH2 protons not observed, m / z: [ESI+] 422 (M+H)+. (C23H31N7O).Synthesis of (S)-l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol-6- yl)piperidin-3-ol (Compound 143)

[0229] Compound (S)- 1 -(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)mcthyl)bcnzo|<7|oxazol- 6-yl)piperidin-3-ol was prepared from (5')-6-(3-(benzyloxy)piperidin-l-yl)-2-((4-(5,6- dimcthylpyi%nidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|<7| oxazole (500 mg, 0.975 mmol) following a similar procedure to that described for the synthesis of (R)-l-(2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[z / ]oxazol-6-yl)piperidin-3-amine, and was isolated as an off-white solid.Yield 62 mg (15%). 'H NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 2.4, 8.8 Hz, 1H), 4.84 (d, J = 4.4 Hz, 1H), 3.85 (s, 2H), 3.69 - 3.56 (m, 2H), 3.54 - 3.43 (m, 1H), 3.25 (t, J = 4.8 Hz, 4H), 2.75 - 2.67 (m, 1H), 2.65 (t, J = 4.8 Hz, 4H), 2.61 - 2.53 (m, 1H), 2.32 (s, 3H), 2.09 (s, 3H), 1.95 - 1.84 (m, 1H), 1.82 - 1.69 (m, 1H), 1.64 - 1.46 (m, 1H), 1.37 - 1.21 (m, 1H). m / z: [ESI+] 423 (M+H)+. (C23H30N6O2).Synthesis of (R)-l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol-6- yl)piperidin-3-ol (Compound 144)

[0230] Compound (R)- 1 -(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 - yl)methyl)benzo[t / ]oxazol-6-yl)piperidin-3-ol was prepared from (7?)-6-(3-(benzyloxy)piperidin-l- yl)-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazole (500 mg, 0.975 mmol) following a similar procedure to that described for the synthesis of (7?)-l-(2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo[t / ]oxazol-6-yl)piperidin-3-am ine, and was isolated as a white solid.Yield 30 mg (7%).JH NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 2.4, 8.8 Hz, 1H), 4.84 (d, J = 4.4 Hz, 1H), 3.85 (s, 2H), 3.69 - 3.56 (m, 2H), 3.54 - 3.43 (m, 1H), 3.25 (t, J = 4.8 Hz, 4H), 2.75 - 2.67 (m, 1H), 2.65 (t, J = 4.8 Hz, 4H), 2.61 - 2.53 (m, 1H), 2.32 (s, 3H), 2.09 (s, 3H), 1.95 - 1.84 (m, 1H), 1.82 - 1.69 (m, 1H), 1.64 - 1.46 (m, 1H), 1.37 - 1.21 (m, 1H). m / z: [ESI+] 423 (M+H)+. (C23H30N6O2).Synthesis of (S)-l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol-6- yl)pyrrolidin-3-ol ( Compound 148)

[0231] Compound (S)- 1 -(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)mcthyl)bcnzo|<7|oxazol- 6-yl)pyrrolidin-3-ol was prepared from (5’)-6-(3-(benzyloxy)pyrrolidin-l-yl)-2-((4-(5,6- dimcthylpyrimidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|<7| oxazole (500 mg, 1.003 mmol) following a similar procedure to that described for the synthesis of (7?)-l-(2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[t / ]oxazol-6-yl)piperidin-3-amine, and was isolated as a purple solid.Yield 96 mg (23%).JH NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.57 (dd, J = 2.4, 8.8 Hz, 1H), 4.99 (d, J = 3.6 Hz, 1H), 4.48 - 4.36 (m, 1H), 3.83 (s,2H), 3.48 - 3.42 (m, 1H), 3.39 - 3.35 (m, 1H), 3.33 - 3.29 (m, 1H), 3.25 (t, J = 4.8 Hz, 4H), 3.13 -3.07 (m, 1H), 2.65 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.14 - 2.00 (m, 1H), 2.09 (s, 3H), 1.96 - 1.85 (m,1H). m / z: [ESI+] 409 (M+H)+. (C22H28N6O2).Synthesis of (R)-l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol-6- yl)pyrrolidin-3-ol ( Compound 149)

[0232] Compound (R)- 1 -(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 - yl)methyl)benzo[t / ]oxazol-6-yl)pyrrolidin-3-ol was prepared from (R)-6-(3-(benzyloxy)pyrrolidin-l- yl)-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazole (500 mg, 1.003 mmol) following a similar procedure to that described for the synthesis of (R)-l-(2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo[t / ]oxazol-6-yl)piperidin-3-am ine, and was isolated as a purple solid.Yield 44 mg (11%).1H NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.57 (dd, J = 2.4, 8.8 Hz, 1H), 4.99 (d, J = 3.6 Hz, 1H), 4.48 - 4.36 (m, 1H), 3.83 (s, 2H), 3.48 - 3.42 (m, 1H), 3.39 - 3.35 (m, 1H), 3.33 - 3.29 (m, 1H), 3.25 (t, J = 4.8 Hz, 4H), 3.13 - 3.07 (m, 1H), 2.65 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.14 - 2.00 (m, 1H), 2.09 (s, 3H), 1.96 - 1.85 (m, 1H). m / z: [ESI+] 409 (M+H)+. (C22H28N6O2).Synthsis of 4-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[d]oxazol-6- yl)piperazin-2-one (Compound 140)

[0233] Compound 4-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazol- 6-yl)piperazin-2-one was prepared from 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ] oxazole (500 mg, 1.243 mmol) and piperazin-2-one (250 mg, 2.497 mmol) following a similar procedure to that described for the synthesis of tert-butyl (S)-(l-(2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazol-6-yl)piperidin-3-yl)carbamate, and was isolated as a grey solid.Yield 27 mg (5%).1H NMR (400 MHz, DMSO-< / 6) 8 8.41 (s, 1H), 8.09 (br s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 2.4, 8.8 Hz, 1H), 3.86 (s, 2H), 3.77 (s, 2H), 3.48 - 3.42 (m, 2H), 3.39 - 3.31 (m, 2H), 3.25 (t, J = 4.8 Hz, 4H), 2.65 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.09 (s, 3H). m / z: [ESI+] 422 (M+H)+. (C22H27N7O2).Synthesis of l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol-6- yl)piperidin-4-ol (Compound 102)

[0234] Compound 1 -(2-((4-(5 ,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo | d I oxazol- 6-yl)piperidin-4-ol was prepared from 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)mcthyl)bcnzo|t / | oxazole (200 mg, 0.497 mmol) and piperidin-4-ol (60 mg, 0.593 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo [ d ] oxazol-6-yl)piperazine- 1 -carboxylate, and was isolated as an off-white solid.Yield 13 mg (6%).JH NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 2.4, 8.8 Hz, 1H), 4.68 (d, J = 4.4 Hz, 1H), 3.85 (s, 2H), 3.70 - 3.60 (m, 1H), 3.60 - 3.50 (m, 2H), 3.25 (t, J = 4.8 Hz, 4H), 2.96 - 2.83 (m, 2H), 2.66 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H), 1.89 - 1.79 (m, 2H), 1.58 - 1.42 (m, 2H). m / z: [ESI+] 423 (M+H)+. (C23H30N6O2).Synthesis of2-( (4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl)-6-morpholinobenzo[ d ] oxazole hemi-formate (Compound 100)

[0235] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6- morpholinobcnzo|d| oxazole hemi-formate was prepared from 6-bromo-2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[e?] oxazole (200 mg, 0.497 mmol) and morpholine (52 mg, 0.597 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo[d]oxazol-6- yl)piperazine-l -carboxylate, and was isolated as an off-white solid.Yield 14 mg (7%).JH NMR (400 MHz, DMSO) 5 8.40 (s, 1H), 8.30 (s, 0.3H, formic acid), 7.55 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 2.4, 8.8 Hz, 1H), 3.86 (s, 2H), 3.79 - 3.73 (m, 4H), 3.25 (t, J = 4.8 Hz, 4H), 3.19 - 3.10 (m, 4H), 2.65 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.09 (s, 3H). m / z: [ESI+] 409 (M+H)+. (C22H28N6O2).Synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(pyrrolidin-l- yl)benzo[d]oxazole (Compound 113)

[0236] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(pyrrolidin-l- yl)bcnzo|<7| oxazole was prepared from 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)mcthyl)bcnzo|<7| oxazole (200 mg, 0.497 mmol) and pyrrolidine (42 mg, 0.591 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo [ d ] oxazol-6-yl)piperazine- 1 -carboxylate, and was isolated as a brown solid.Yield 67 mg (34%).JH NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.60 (dd, J = 2.4, 8.8 Hz, 1H), 3.83 (s, 2H), 3.29 - 3.22 (m, 8H), 2.67 - 2.62 (m, 4H), 2.32 (s, 3H), 2.10 (s, 3H), 2.01 - 1.96 (m, 4H). m / z: [ESI+] 393 (M+H)+. (C22H28N6O).Synthesis of l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol-6- yl)pyrrolidin-2-one (Compound 107)

[0237] Compound 1 -(2-((4-(5 ,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo | d I oxazol- 6-yl)pyrrolidin-2-one was prepared from 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)mcthyl)bcnzo|t / | oxazole (200 mg, 0.497 mmol) and pyrrolidin-2-one (51 mg, 0.599 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo [ d ] oxazol-6-yl)piperazine- 1 -carboxylate, and was isolated as a light yellow solid.Yield 84 mg (42%).1H NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.66 (dd, J = 2.4, 8.8 Hz, 1H), 3.96 - 3.88 (m, 4H), 3.27 (t, J = 4.8 Hz, 4H), 2.69 (t, J = 4.8 Hz, 4H), 2.57 - 2.50 (m, 2H), 2.32 (s, 3H), 2.14 - 2.04 (m, 2H), 2.09 (s, 3H). m / z: [ESI+] 407 (M+H)+. (C22H26N6O2).Synthesis of 2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazole-6- carbonitrile ( Compound 119)Compound 119

[0238] To a stirred solution of 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[tf] oxazole (100 mg, 0.249 mmol) and zinc cyanide (35 mg, 0.298 mmol) in dioxane(2 mL) was added tetrakis(triphenylphosphine)palladium (29 mg, 0.025 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90°C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature and was filtered. The filter cake was washed with ethyl acetate (3 x 5 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: C18 Column 120 g; Mobile Phase A: water (10 mmol / L ammonium bicarbonate), Mobile Phase B: acetonitrile; Flow rate: 45 mL / min; Gradient: 30% B to 50% B in 25 min; Wave Length: 254 / 220 nm. The fractions containing the desired product were collected at 46% B and concentrated under reduced pressure. This resulted in 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazole-6-carbonitrileas a white solid.Yield 12 mg (14%).JH NMR (400 MHz, DMSO) 5 8.43 - 8.39 (m, 2H), 7.95 (d, J = 8.4 Hz, 1H), 7.84 (dd, J = 1.6, 8.4 Hz, 1H), 4.02 (s, 2H), 3.27 (t, J = 4.8 Hz, 4H), 2.71 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 349 (M+H)+. (C19H20N6O).Synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(lH-tetrazol-5- yl)benzo[d] oxazole (Compound 116)Compound 119 Compound 116

[0239] To a stirred solution of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazole-6-carbonitrile (300 mg, 0.861 mmol)(Compound 119) and azidotrimethylsilane (397 mg, 3.446 mmol) in dichloromethane (10 mL) was added dibutylstannanediyl diacetate (605 mg, 1.723 mmol) dropwise at room temperature under a nitrogen atmosphere. The reaction solution was stirred for overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash TM Cl 8- 1, 20-40 pm, 120 g; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 10% - 30% B in 25 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm. Desired fractions were collected at 20% B and concentrated under reduced pressure to afford 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(177-tetrazol-5-yl)benzo[t / ]oxazole as a white solid.Yield 109 mg (32%).JH NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.06 (dd, J = 1.6, 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.18 (br s, 1H), 3.97 (s, 2H), 3.33 - 3.24 (m, 4H), 2.73 - 2.67 (m, 4H), 2.30 (s, 3H), 2.08 (s, 3H). m / z: [ESI+] 392 (M+H)+. (C19H21N9O).Synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(3-fluorooxetan-3- yl)benzo[d] oxazole (Compound 138)

[0240] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-(3-fluorooxetan-3- yl)benzo[tf] oxazole was prepared from 3-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-yl)oxetan-3-ol (70 mg, 0.177 mmol) following a similar procedure to that described for the synthesis of (6-(difluoromethyl)benzo[t / ]oxazol-2-yl)methyl acetate, and was isolated as a yellow oil.Yield 34 mg (48%). 'H NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 1.6, 8.4 Hz, 1H), 5.04 (s, 2H), 4.98 (s, 2H), 3.97 (s, 2H), 3.26 (t, J = 4.8 Hz, 4H), 2.69 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H).19F NMR (376 MHz, DMSO) 5 -139.89. m / z: [ESI+] 398 (M+H)+. (C21H24FN5O2).Synthesis of 6-( 4-( difluoromethyl)- IH-pyrazol-l -yl)-2-( ( 4-( 5, 6-dimethylpyrimidin-4-yl)piperazin- l-yl)methyl)benzo[d] oxazole (Compound 130)

[0241] Compound 6-(4-(difluoromethyl)- 177-pyrazol- 1 -yl)-2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[tf] oxazole was prepared from l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazol-6-yl)-177-pyrazole-4-carbaldehyde (240 mg, 0.575 mmol) following a similar procedure to that described for the synthesis of (6- (difluoromethyl)benzo[t / ]oxazol-2-yl)methyl acetate, and was isolated as a light brown solid.Yield 57 mg (23%).JH NMR (400 MHz, DMSO) 5 8.93 (s, 1H), 8.42 (s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.04 (s, 1H), 7.94 (dd, J = 2.0, 8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.15 (t, J = 55.6 Hz, 1H), 3.98 (s, 2H), 3.28 (t, J = 4.8 Hz, 4H), 2.71 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 2.11 (s, 3H).19F NMR (376 MHz, DMSO) 5 -106.10. m / z: [ESI+] 440 (M+H)+. (C22H23F2N7O).Synthesis of(2-((4-(5, 6-dimethylpyrimidin-4-yl)piperazin-l -yl )methyl)benzo[ d ]oxazol-6-yl)methanol

[0242] To a stirred mixture of 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[tf] oxazole (200 mg, 0.497 mmol) and (tributylstannyl)methanol (192 mg, 0.598 mmol) in dioxane (2 mL) was added tetrakis(triphenylphosphine)palladium (57 mg, 0.049 mmol) in portions at room temperature under a nitrogen atmosphere. The mixture was stirred for 16 h at 80°C under a nitrogen atmosphere. The mixture was allowed to cool down to room temperature and purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19 x 250 mm, 5 pm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 28% B to 30% B in 12 min; Wave Length: 254 nm; RTl(min): 7.45). Desired fractions were collected and concentrated under reduced pressure to afford (2-((4-(5,6- dimcthylpyrimidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzoh / |oxazol-6-yl) methanol as a yellow solid.Yield 56 mg (32%).1H NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.33 (dd, J = 1.6, 8.0 Hz, 1H), 5.32 (t, J = 5.6 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H), 3.93 (s, 2H), 3.27 (t, J = 4.8 Hz, 4H), 2.68 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 354 (M+H)+. (C19H23N5O2).Synthesis of 2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl)-6-(methoxymethyl)benzo[d]oxazole (Compound 110)

[0243] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-(methoxymethyl)benzo[tf] oxazole was prepared from (2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- l-yl)methyl)benzo[t / ]oxazol-6-yl)methanol (150 mg, 0.424 mmol) and iodomethane (66 mg, 0.465 mmol) following a similar procedure to that described for the synthesis of tert-butyl (5)-3- (benzyloxy)piperidine-l -carboxylate, and was isolated as a yellow oil.Yield 23 mg (15%).JH NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.33 (dd, J = 1.6, 8.0 Hz, 1H), 4.53 (s, 2H), 3.93 (s, 2H), 3.31 (s, 3H), 3.26 (t, J = 4.8 Hz, 4H), 2.68 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.09 (s, 3H). m / z: [ESI+] 368 (M+H)+. (C20H25N5O2).Synthesis of 2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl)-6-( ( 2- methoxyethoxy)methyl)benzo[d]oxazole (Compound 112)

[0244] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-((2- methoxy ethoxy )methyl)benzo[tf] oxazole was prepared from (2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[t / ]oxazol-6-yl)methanol (150 mg, 0.424 mmol) and l-bromo-2- methoxyethane (118 mg, 0.849 mmol) following a similar procedure to that described for the synthesis of tert-butyl (S)-3-(benzyloxy)piperidine-l -carboxylate, and was isolated as a yellow oil. Yield 21 mg (12%). 'H NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.34 (dd, J = 1.6, 8.0 Hz, 1H), 4.61 (s, 2H), 3.94 (s, 2H), 3.61 - 3.55 (m, 2H), 3.53 - 3.46 (m, 2H), 3.28 - 3.23 (m, 4H), 3.26 (s, 3H), 2.71 - 2.65 (m, 4H), 2.32 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 412 (M+H)+. (C22H29N5O3).Synthesis of 2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl )methyl)-6-methoxybenzo[ d ] oxazole ( Compound 111)

[0245] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6- methoxybenzo[tf] oxazole was prepared from 2-(chloromcthyl)-6-mcthoxybcnzo|c / |oxazolc (100 mg, 0.506 mmol) and 4,5-dimethyl-6-(piperazin-l-yl)pyrimidine hydrochloride (127 mg, 0.555 mmol) following a similar procedure to that described for the synthesis of 6-bromo-2-((4-(5,6- dimcthylpyrimidin-4-yl)pipcrazin- 1 -yl)mcthyl)bcnzo|t / | oxazole, and was isolated as a white solid. Yield 43 mg (24%).JH NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 2.4, 8.8 Hz, 1H), 3.89 (s, 2H), 3.82 (s, 3H), 3.26 (t, J = 4.8 Hz, 4H), 2.67 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.09 (s, 3H). m / z: [ESI+] 354 (M+H)+. (C19H23N5O2).Synthesis of 6-(4-( ( 6-( difluoromethyl)benzo[d]oxazol-2-yl)methyl)piperazin-l-yl)-5- methylpyrimidin-4(3H)-one (Compound 135)

[0246] Compound 6-(4-((6-(difluoromethyl)benzo[d]oxazol-2-yl)methyl)piperazin-l-yl)-5- methylpyrimidin-4-ol was prepared from (6-(difluoromethyl)benzo[t / ]oxazol-2-yl)methyl methanesulfonate (100 mg, 0.361 mmol) and 5-methyl-6-(piperazin-l-yl)pyrimidin-4(377)-one hydrochloride (125 mg, 0.542 mmol) following a similar procedure to that described for the synthesis of 6-bromo-2-((4-(5,6-dimcthylpyi%nidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|<7|oxazolc, and was isolated as an off-white solid.Yield 76 mg (56%). 'H NMR (400 MHz, DMSO) 5 11.95 (br s, 1H), 8.01 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 55.6 Hz, 1H), 3.96 (s, 2H), 3.28 (t, J =4.8 Hz, 4H), 2.65 (t, J = 4.8 Hz, 4H), 1.84 (s, 3H).19F NMR (377 MHz, DMSO) 5 -107.18. m / z: [ESF] 376 (M+H)+. (C18H19F2N5O2).Synthesis of 6-(4-( ( 6-( difluoromethyl)benzo[d]oxazol-2-yl)methyl)piperazin-l-yl)-5- methylpyrimidin-4-amine ( Compound 132 )

[0247] Compound 6-(4-((6-(difluoromethyl)benzo[t / ]oxazol-2-yl)methyl)piperazin-l-yl)-5- methylpyrimidin-4-amine was prepared from (6-(difluoromethyl)benzo[t / ]oxazol-2-yl)methyl methanesulfonate (100 mg, 0.361 mmol) and 5-methyl-6-(piperazin-l-yl)pyrimidin-4-amine hydrochloride (124 mg, 0.540 mmol) following a similar procedure to that described for the synthesis of 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazole, and was isolated as a yellow solid.Yield 75 mg (56%). 'H NMR (400 MHz, DMSO) 5 8.01 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 1.6, 8.4 Hz, 1H), 7.17 (t, J = 55.6 Hz, 1H), 6.22 (br s, 2H), 3.97 (s, 2H), 3.13 (t, J = 4.8 Hz, 4H), 2.67 (t, J = 4.8 Hz, 4H), 1.88 (s, 3H).19F NMR (377 MHz, DMSO) 5 - 107.18. m / z: [ESF] 375 (M+H)+. (CI8H2OF2N60).Synthesis of 4-(4-( ( 6-( difluoromethyl)benzo[d]oxazol-2-yl)methyl)piperazin-l-yl)-6- methylpyrimidin-5-amine (Compound 133)

[0248] Compound 4-(4-((6-(difluoromethyl)benzo[t / ]oxazol-2-yl)methyl)piperazin- 1 -yl)-6- methylpyrimidin-5-amine was prepared from (6-(difluoromethyl)benzo[t / ]oxazol-2-yl)methyl methanesulfonate (100 mg, 0.361 mmol) and 4-methyl-6-(piperazin-l-yl)pyrimidin-5-amine hydrochloride (124 mg, 0.540 mmol) following a similar procedure to that described for the synthesisof 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazole, and was isolated as a light brown solid.Yield 30 mg (22%).JH NMR (400 MHz, DMSO) 5 8.05 (s, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 1.6, 8.4 Hz, 1H), 7.18 (t, J = 55.6 Hz, 1H), 4.52 (br s, 2H), 3.99 (s, 2H), 3.20 - 3.14 (m, 4H), 2.79 - 2.71 (m, 4H), 2.26 (s, 3H).19F NMR (377 MHz, DMSO) 5 -107.16. m / z: [ESF] 375 (M+H)+. (C18H20F2N6O).Synthesis of 4-(4-( ( 6-( difluoromethyl)benzo[d]oxazol-2-yl)methyl)piperazin-l-yl)-6- methylpyrimidin-5-ol ( Compound 136)

[0249] Compound 4-(4-((6-(difluoromethyl)benzo[t / ]oxazol-2-yl)methyl)piperazin- 1 -yl)-6- methylpyrimidin-5-ol was prepared from (6-(difluoromethyl)benzo[t / ]oxazol-2-yl)methyl methanesulfonate (150 mg, 0.541 mmol) and 4-methyl-6-(piperazin-l-yl)pyrimidin-5-ol hydrochloride (375 mg, 1.625 mmol) following a similar procedure to that described for the synthesis of 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazole but reacted at room temperature, and was isolated as an off-white solid.Yield 49 mg (24%). 'H NMR (400 MHz, DMSO) 5 8.06 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 1.6, 8.4 Hz, 1H), 7.17 (t, J = 55.6 Hz, 1H), 3.96 (s, 2H), 3.64 (t, J = 4.8 Hz, 4H), 2.66 (t, J = 4.8 Hz, 4H), 2.26 (s, 3H). OH proton not observed.19F NMR (376 MHz, DMSO) 5 -107.18. m / z: [ESF] 376 (M+H)+. (C18H19F2N5O2).Synthesis of 3-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazol-6-

[0250] Compound 3-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo[ c / |oxazol-6- yl)oxetan-3-ol was prepared from 3-(2-(chloromethyl)benzo[t / ]oxazol-6-yl)oxetan-3-ol (70 mg, 0.292 mmol) and 4,5-dimethyl-6-(piperazin-l-yl)pyrimidine hydrochloride (80 mg, 0.350 mmol) following a similar procedure to that described for the synthesis of 6-bromo-2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin- 1 -yl ) methyl )bcnzo| <7|oxazolc but reacted at room temperature, and was isolated as a light yellow solid.Yield 100 mg (87%).JH NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 1.6, 8.4 Hz, 1H), 6.52 (br s, 1H), 4.82 (d, J = 6.4 Hz, 2H), 4.75 (d, J = 6.4 Hz, 2H), 3.95 (s, 2H), 3.26 (t, J = 4.8 Hz, 4H), 2.69 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 396 (M+H)+. (C21H25N5O3).Synthesis of 6-( difluoromethoxy )-2-( (4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l - yl)methyl)benzo[d]oxazole (Compound 129)

[0251] Compound 6-(difluoromethoxy)-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 - yl)methyl)benzo[tf] oxazole was prepared from 2-(chloromethyl)-6- (difluoromethoxy)benzo[tf] oxazole (600 mg, 2.568 mmol) and 4,5-dimethyl-6-(piperazin-l- yl)pyrimidine hydrochloride (600 mg, 2.623 mmol) following a similar procedure to that described for the synthesis of 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[tf] oxazole but reacted at room temperature, and was isolated as a yellow solid.Yield 300 mg (30%).1H NMR (400 MHz, DMSO6) 6 8.42 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.28 (t, J = 73.6 Hz, 1H), 7.23 (dd, J = 2.4, 8.8 Hz, 1H), 3.94 (s, 2H), 3.26 (t, J = 4.8 Hz, 4H), 2.68 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H).19F NMR (376 MHz, DMSO) 5 - 82.14. m / z: [ESI+] 390 (M+H)+. (C19H21F2N5O2).Synthesis of l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl )methyl )benzo[ d ]oxazol-6- yl)cyclopropane-l -carbonitrile (Compound 131 )

[0252] Compound 1 -(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)mcthyl)bcnzo| c / |oxazol-6- yl)cyclopropane-l -carbonitrile was prepared from l-(2-(chloromethyl)benzo[ri]oxazol-6- yl)cyclopropane-l -carbonitrile (240 mg, 1.032 mmol) and4,5-dimethyl-6-(piperazin-l-yl)pyrimidine hydrochloride (236 mg, 1.032 mmol) following a similar procedure to that described for the synthesis of 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[ri]oxazole but reacted at room temperature, and was isolated as an off-white solid.Yield 170 mg (42%).JH NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 2.0, 8.4 Hz, 1H), 3.95 (s, 2H), 3.26 (t, J = 4.8 Hz, 4H), 2.68 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.09 (s, 3H), 1.82 - 1.74 (m, 2H), 1.61 - 1.55 (m, 2H). m / z: [ESI+] 389 (M+H)+. (C22H24N6O).Synthesis of 2-((4-(5, 6-dimethylpyrimidin-4-yl)piperazin-l -yl )methyl)benzo[ d ]oxazol-6-ol( Compound 109)

[0253] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[ri]oxazol-6-ol was prepared from 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6- mcthoxybcnzo|<7| oxazole (200 mg, 0.566 mmol)(Compound 111) following a similar procedure to that described for the synthesis of l-(3-hydroxy-4-nitrophenyl)cyclopropane-l -carbonitrile, and was isolated as a brown solidYield 107 mg (56%).JH NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 2.4, 8.8 Hz, 1H), 3.85 (s, 2H), 3.26 (t, J = 4.8 Hz, 4H), 2.66 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H). OH proton not observed, m / z: [ESI+] 340 (M+H)+. (C18H21N5O2).Synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(2- methoxy ethoxy )benzo[d] oxazole (Compound 121 )

[0254] To a stirred solution of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-ol (130 mg, 0.383 mmol)(Compound 109), 2-methoxyethan-l-ol (35 mg, 0.460 mmol) and triphenylphosphine (301 mg, 1.148 mmol) in tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (155 mg, 0.767 mmol) dropwise at 0°C under a nitrogen atmosphere. The resulting solution was stirred for overnight at room temperature. The resulting solution was concentrated under reduced pressure and purified by reverse phase Flash chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 pm, 120 g; Eluent A: water (plus 10 mmol / L ammonium bicarbonate); Eluent B: acetonitrile; Gradient: 60% - 75% B in l5 min; Flow rate: 60 mL / min; Detector: 220 / 254 nm. Desired fractions were collected at 68% B and concentrated under reduced pressure to afford 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(2- methoxy ethoxy )benzo[tf] oxazole as a yellow oil.Yield 75 mg (49%).1H NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 2.4, 8.8 Hz, 1H), 4.19 - 4.11 (m, 2H), 3.89 (s, 2H), 3.72 - 3.66 (m, 2H), 3.32 (s, 3H), 3.26 (t, J = 4.8 Hz, 4H), 2.67 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.09 (s, 3H). m / z: [ESI+] 398 (M+H)+. (C21H27N5O3).Synthesis of 2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l-yl )methyl )benzo[ d ]oxazol-6-amine

[0255] A solution of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6- nitrobenzo[rf] oxazole (100 mg, 0.271 mmol) and 10% palladium on active carbon (58 mg) in ethyl acetate (5 mL) was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with ethyl acetate (2 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19 x 250 mm, 5 z / m; Mobile Phase A: water (10 mmol / L ammonium bicarbonate), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 26% B to 36% B in 12 min, 36% B; Wave Length: 254 nm; RTl(min): 8). Desired fractions were collected and concentrated under reduced pressure to afford 2-((4-(5,6-dimethylpyrimidin-4- yl)pipcrazin- 1 -yl)mcthyl)bcnzo|z / |oxazol-6-aminc as an off-white solid.Yield 27 mg (29%).JH NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.60 (dd, J = 2.0, 8.4 Hz, 1H), 5.31 (br s, 2H), 3.79 (s, 2H), 3.25 (t, J = 4.8 Hz, 4H), 2.64 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 339 (M+H)+. (CisHiiNeO).Synthesis of l-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl )methyl)benzo[ d ]oxazol-6-yl)-2, 2,2- trifluoroethan-1- amine (Compound 128)Compound 128

[0256] Compound 1 -(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)mcthyl)bcnzo|c / |oxazol-6- yl)-2,2,2-trifluoroethan-l -amine was prepared from 6-(l-azido-2,2,2-trifluoroethyl)-2-((4-(5,6- dimcthylpyrimidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|<7| oxazole (150 mg, 0.336 mmol) following asimilar procedure to that described for the synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- l-yl)methyl)benzo[t / ]oxazol-6-amine, and was isolated as a yellow semi-solid.Yield 41 mg (29%).JH NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 1.6, 8.4 Hz, 1H), 4.74 - 4.62 (m, 1H), 3.95 (s, 2H), 3.27 (t, J = 4.8 Hz, 4H), 2.69 (t, J = 4.8 Hz, 4H), 2.62 (br s, 2H), 2.32 (s, 3H), 2.10 (s, 3H).19F NMR (376 MHz, DMSO) 5 -74.78. m / z: [ESF] 421 (M+H)+. (C20H23F3N6O).Synthesis of 6-(2-(difluoromethyl)-2H-l,2,3-triazol-4-yl)-2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[d] oxazole (Compound 141 )Compound 141

[0257] Compound 6-(2-(difluoromethyl)-277- 1 ,2,3-triazol-4-yl)-2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[tf] oxazole was prepared from 6-(5-bromo-2-(difluoromethyl)-277- 1 ,2,3-triazol-4-yl)-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -y l)mcthyl)bcnzo| <7| oxazole (150 mg, 0.289 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(5- amino-6-methylpyrimidin-4-yl)piperazine-l -carboxylate, and was isolated as a white solid.Yield: 11 mg (9%). ' H NMR (400 MHz, DMSO) 5 8.80 (s, 1H), 8.42 (s, 1H), 8.32 (d, J = 1.6 Hz, 1H), 8.21 (t, J = 57.2 Hz, 1H), 7.99 (dd, J = 1.6, 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 3.99 (s, 2H), 3.27 (d, J = 4.8 Hz, 4H), 2.72 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 2.10 (s, 3H).19F NMR (376 MHz, DMSO) 5 -95.08. m / z: [ESF] 441 (M+H)+. (C21H22F2N8O).Synthesis of 6-(l-(difluoromethyl)-lH-l,2,3-triazol-5-yl)-2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[d] oxazole (Compound 150)

[0258] Compound 6-( 1 -(difluoromethyl)- 1H- 1 ,2,3-triazol-5-yl)-2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[tf] oxazole was prepared from 6-(4-bromo-l-(difluoromethyl)-177- l,2,3-triazol-5-yl)-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazole (150 mg, 0.289 mmol) following a similar procedure to that described for the synthesis of tert-butyl 4-(5- amino-6-methylpyrimidin-4-yl)piperazine-l -carboxylate, and was isolated as an off- white solid. Yield: 7 mg (6%).JH NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 8.27 (t, J = 56.8 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 1.6, 8.4 Hz, 1H), 4.01 (s, 2H), 3.28 (t, J = 4.8 Hz, 4H), 2.72 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 2.11 (s, 3H).19F NMR (376 MHz, DMSO) 5 -95.08. m / z: [ESI+] 441 (M+H)+. (C21H22F2N8O).Synthesis of 2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl )methyl)-N-methylbenzo[ d ]oxaz.ol-6- amine ( Compound 123 )

[0259] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-7V- mcthylbcnzo|c / |oxazol-6-aminc was prepared from 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-amine (300 mg, 0.886 mmol) and polyoxymethylene (MW 90.08, 42 mg, 0.466 mmol) following a similar procedure to that described for the synthesis of tert-butyl (R)-3- (dibenzylamino)piperidine-l -carboxylate, and was isolated as a white solid.Yield 44 mg (14%).1H NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.61 (dd, J = 2.0, 8.4 Hz, 1H), 5.94 (q, J = 4.8 Hz, 1H), 3.81 (s, 2H), 3.25 (t, J = 4.8 Hz, 4H), 2.71 (d, J = 4.8 Hz, 3H), 2.65 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 353 (M+H)+. (C19H24N6O).Synthesis of 2-((4-( 5, 6-dimethylpyrimidin-4-yl)piperazin-l -yl)methyl)-N,N-dimethylbenzo[ d Joxazol-6-amine ( Compound 122)

[0260] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl) mcthyl)-M N- dimethylbenzo[t / ]oxazol-6-amine was prepared from 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazol-6-amine (200 mg, 0.591 mmol) and formaldehyde solution (37% in water, 76 mg, 0.936 mmol) following a similar procedure to that described for the synthesis of tert-butyl (R)-3-(dibenzylamino)piperidine-l -carboxylate, and was isolated as a brown solid.Yield 94 mg (43%).1H NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 2.4, 8.8 Hz, 1H), 3.84 (s, 2H), 3.25 (t, J = 4.8 Hz, 4H), 2.95 (s, 6H), 2.65 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.09 (s, 3H). m / z: [ESI+] 366 (M+H)+. (C20H26N6O).Synthesis of 2-((4-( 5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl )methyl)benzo[ d ]oxazole-6-carboxylic acid (Compound 104)

[0261] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo[ c / |oxazolc-6- carboxylic acid was prepared from methyl 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazole-6-carboxylate (100 mg, 0.262 mmol) and potassium carbonate (73 mg, 0.528 mmol) following a similar procedure to that described for the synthesis of (6- (difluoromethyl)benzo[t / ]oxazol-2-yl)methanol, and was isolated as a white solid.Yield 29 mg (30%).JH NMR (400 MHz, DMSO) 5 13.14 (br s, 1H), 8.42 (s, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.00 (dd, J = 1.6, 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 3.99 (s, 2H), 3.26 (t, J = 4.8 Hz, 4H), 2.71 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 368 (M+H)+. (C19H21N5O3).Synthesis of 2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benzo[ d ]oxazole-6- carboxamide ( Compound 105)

[0262] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo[ c / |oxazolc-6- carboxamide was prepared from 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[t / ]oxazole-6-carboxylic acid (130 mg, 0.354 mmol) and ammonium chloride (28 mg, 0.523 mmol) following a similar procedure to that described for the synthesis of 2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-iV-methoxy-iV-methylbenzo[6noxazole-6- carboxamide, and was isolated as an off-white solid.Yield 43 mg (33%).JH NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 8.08 (br s, 1H), 7.94 (dd, J = 1.6, 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.49 (br s, 1H), 3.98 (s, 2H), 3.27 (t, J = 4.8 Hz, 4H), 2.71 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 367 (M+H)+. (C19H22N6O2).Synthesis of 2-((4-(5, 6-dimethylpyrimidin-4-yl)piperazin-l -yl )melhyl)-N -methylbenzo [ d ]oxazole-6- carboxamide ( Compound 106)

[0263] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -y l)methyl)- N- mcthylbcnzoh / |oxazolc-6-carboxamidc was prepared from 2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[t / ]oxazole-6-carboxylic acid (130 mg, 0.354 mmol) and methanamine hydrochloride (35 mg, 0.518 mmol) following a similar procedure to that described for the synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-Y-methoxy-Y- methylbenzoMoxazole-6-carboxamide, and was isolated as a light yellow solid.Yield 43 mg (32%).JH NMR (400 MHz, DMSO) 5 8.54 (q, J = 4.4 Hz, 1H), 8.42 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.89 (dd, J = 1.6, 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 3.98 (s, 2H), 3.27 (t, J = 4.8 Hz, 4H), 2.83 (d, J = 4.4 Hz, 3H), 2.71 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 381 (M+H)+. (C20H24N6O2).Synthesis of 2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l-yl )methyl)-N,N- dimethylbenzo [d]oxazole-6- carboxamide (Compound 108)

[0264] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl) mcthyl)-M N- dimcthylbcnzo|c / |oxazolc-6-carboxamidc was prepared from 2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)benzo[t / ]oxazole-6-carboxylic acid (130 mg, 0.354 mmol) and dimethylamine hydrochloride (43 mg, 0.527 mmol) following a similar procedure to that described for the synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-A-methoxy-A- mcthylbcnzo|c / |oxazolc-6-carboxamidc, and was isolated as a yellow solid.Yield 57 mg (41%). 'H NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 1.6, 8.4 Hz, 1H), 3.97 (s, 2H), 3.27 (t, J = 4.8 Hz, 4H), 3.01 (s, 3H), 2.94 (s, 3H), 2.70 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 395 (M+H)+. (C21H26N6O2).Synthesis of 2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl )methyl)-6-( 5-methyl-l,3, 4-oxadiazol-2-yl)benzo[d]oxazole (Compound 115)Compound 104 Compound 115

[0265] A solution of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazole-6- carboxylic acid (20 mg, 0.054 mmol) (Compound 104), acetohydrazide (8 mg, 0.108 mmol),triethylamine (17 mg, 0.168 mmol) and T3P (50% w / w in ethyl acetate, 1 mL) in ethyl acetate (1 mL) was stirred for overnight at 70°C. The resulting solution was allowed to cool down to room temperature and was purified by reverse flash chromatography with the following conditions: Column: XBridge Shield RP18 OBD Column, 19 x 250 mm, 10(um; Mobile Phase A: water (10 mmol / L ammonium bicarbonate), Mobile Phase B: methanol; Flow rate: 25 mL / min; Gradient: 47% B to 52% B in 8 min, 52% B; Wave Length: 254 nm; RTl(min): 13. Desired fractions were collected and concentrated under reduced pressure to afford to afford 2-((4-(5,6-dimethylpyrimidin-4- yl)piperazin-l-yl)methyl)-6-(5-methyl-l,3,4-oxadiazol-2-yl)benzo[ri]oxazole as an off-white solid. Yield 5 mg (23%).JH NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.02 (dd, J = 1.6, 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 4.01 (s, 2H), 3.28 (t, J = 4.8 Hz, 4H), 2.72 (t, J = 4.8 Hz, 4H), 2.61 (s, 3H), 2.33 (s, 3H), 2.11 (s, 3H). m / z: [ESI+] 406 (M+H)+. (C21H23N7O2).Synthesis of 2-(2-((4-(5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl)methyl )benz.o[ d ]oxazol-6- yl)propan-2-ol (Compound 125)

[0266] Compound 2-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo[ c / |oxazol-6- yl)propan-2-ol was prepared from methyl 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[ri]oxazole-6-carboxylate (400 mg, 1.049 mmol) and methylmagnesium bromide (1 N in tetrahydrofuran, 2.1 mL, 2.100 mmol) following a similar procedure to that described for the synthesis of 1 -(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)benzo[ c / |oxazol-6-yl)cthan- 1-one, and was isolated as a yellow solid.Yield 23 mg (6%). 'H NMR (400 MHz, DMSO) 5 8.41 (s, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 1.6, 8.4 Hz, 1H), 5.16 (br s, 1H), 3.92 (s, 2H), 3.26 (t, J = 4.8 Hz, 4H), 2.68 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H), 1.48 (s, 6H). m / z: [ESI+] 382 (M+H)+. (C21H27N5O2).Synthesis of l-(2-((4-(5, 6-dimethylpyrimidin-4-yl)piperazin-l -yl )methyl)benzo[ d ]oxazol-6-yl)ethan- l-ol ( Compound 134)Compound 134

[0267] A solution of l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t / ]oxazol-6- yl)ethan-l-one (150 mg, 0.410 mmol) and sodium borohydride (31 mg, 0.819 mmol) in methanol (3 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30 x 150 mm 5 pm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: acenotrile; Flow rate: 60 mL / min; Gradient: 7% B to 15% B in 10 min, 15% B; Wave Length: 220 nm; RTl(min): 7.47). Desired fractions were collected and concentrated under reduced pressure to afford l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[t7]oxazol-6- yl)ethan-l-ol as a yellow semi-solid.Yield 24 mg (16%).JH NMR (400 MHz, DMSO) 5 8.40 (s, 1H), 7.68 - 7.60 (m, 2H), 7.35 (dd, J = 1.6, 8.4 Hz, 1H), 4.85 (q, J = 6.4 Hz, 1H), 3.91 (s, 2H), 3.26 (t, J = 4.8 Hz, 4H), 2.67 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.09 (s, 3H), 1.37 (d, J = 6.4 Hz, 3H). OH proton not observed, m / z: [ESI+] 368 (M+H)+. (C20H25N5O2).Synthesis of l-(2-((4-( 5, 6-dimethylpyrimidin-4-yl )piperazin-l -yl )methyl)benzo[ d ]oxazol-6-yl)-2, 2,2- trifluoroethan-l-ol (Compound 139)

[0268] To a solution of 2-((4-(5,6-dimcthylpyi%nidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|<7|oxazolc-6-carbaldehyde (200 mg, 0.569 mmol) in A,A-dimethylformamide (2 mL) was added potassiumcarbonate (236 mg, 1.708 mmol) and followed by trimethyl( trifluoromethyl) silane (243 mg, 1.709 mmol) dropwise at 0°C. The reaction mixture was stirred for 30 min at 0°C and for additional 16 h at room temperature. The reaction was quenched with water (2 mL) at 0°C. The resulting mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 «m; Mobile Phase A: water (10 mmol / L ammonium bicarbonate), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 25% B to 35% B in 8 min, 35% B; Wave Length: 254 nm; RTl(min): 7). Desired fractions were collected and concentrated under reduced pressure to afford l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[ri]oxazol-6-yl)-2,2,2- trifluoroethan-l-ol as a white solid.Yield 61 mg (25%).JH NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 1.6, 8.4 Hz, 1H), 7.00 (d, J = 5.6 Hz, 1H), 5.38 - 5.29 (m, 1H), 3.95 (s, 2H), 3.26 (d, J = 4.8 Hz, 4H), 2.70 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 2.10 (s, 3H).19F NMR (377 MHz, DMSO) 5 -76.73. m / z: [ESI+] 422 (M+H)+. (C20H22F3N5O2).Synthesis of (S)-l-(2-(( 4-( 5, 6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[ d ]oxazol-6-yl)- 2,2,2-trifluoroethan-l-ol (Compound 151) and (R)-l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl )benzo[ d ]oxazol-6-yl)-2, 2,2-trifluoroethan-l -ol ( Compound 152)Compound 151 Compound 152

[0269] l-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[ri]oxazol-6-yl)-2,2,2- trifluoroethan-l-ol (736 mg, 1.748 mmol) was applied to Prep-Chiral-SFC with the following conditions: Column: CHIRALPAK IH, 3 x 25 cm, 5 «m; Mobile Phase A: CO2, Mobile Phase B: methanol (plus 0.1% 2 M ammonia in methanol); Flow rate: 100 mL / min; Gradient: isocratic 13% B; Wave Length: UV 220 nm; RTl(min): 8.07; RT2(min): 10.15; The fractions containing desired product were collected, concentrated under reduced pressure and lyophilized to afford (R)-l-(2-((4- (5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl) methy l)benzo[ <7|oxazol-6-yl)-2,2,2-tri fluoroethan- 1 -ol, the faster eluting enantiomer as a light yellow solid.Yield 220 mg (30%).JH NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 1.6, 8.4 Hz, 1H), 7.00 (d, J = 5.6 Hz, 1H), 5.38 - 5.29 (m, 1H), 3.95 (s, 2H), 3.26 (d, J = 4.8 Hz, 4H), 2.70 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 2.10 (s, 3H).19F NMR (377 MHz, DMSO) 5 -76.73. m / z: [ESF] 422 (M+H)+. (C20H22F3N5O2).And (.S')- 1 -(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)mcthyl)bcnzo|c / |oxazol-6-yl)-2,2,2- trifluoroethan-l-ol, the slower eluting enantiomer as a light yellow solid.Yield 270 mg (37%). 'H NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 1.6, 8.4 Hz, 1H), 7.00 (d, J = 5.6 Hz, 1H), 5.38 - 5.29 (m, 1H), 3.95 (s, 2H), 3.26 (d, J = 4.8 Hz, 4H), 2.70 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 2.10 (s, 3H).19F NMR (377 MHz, DMSO) 5 -76.73. m / z: [ESF] 422 (M+H)+. (C20H22F3N5O2).Synthesis of 6-( 1 -( difluoromethyl)-! H-pyrazol-4-yl)-2-( ( 4-( 5, 6-dimethylpyrimidin-4-yl)piperazin-l - yl)methyl)benzo[d] oxazole hemi-formate ( Compound 101)

[0270] Compound 6-( 1 -(difluoromethyl)- 177-pyrazol-4-y l)-2-((4-(5,6-di methylpyri m idi n-4- yl)piperazin-l-yl)methyl)benzo[tf] oxazole hemi-formate was prepared from 6-bromo-2-((4-(5,6- dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[tf] oxazole (300 mg, 0.746 mmol) and 1- (difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-pyrazole (200 mg, 0.820 mmol) following a similar procedure to that described for the synthesis of (6-vinylbcnzo|t / |oxazol-2- yl)methyl acetate, and was isolated as a white solid.Yield 50 mg (15%). 'H NMR (400 MHz, DMSO) 5 8.82 (s, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 8.14 (s, 0.27H, formic acid), 8.13 - 8.10 (m, 1H), 7.86 (t, J = 59.2 Hz, 1H), 7.79 - 7.72 (m, 2H), 3.96 (s, 2H), 3.27 (t, J = 4.8 Hz, 4H), 2.70 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H).19F NMR (376 MHz, DMSO) 5 -94.01. m / z: [ESF] 440 (M+H)+. (C22H23F2N7O).Synthesis of 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)-6-(lH-pyrazol-3- yl)benzo[d] oxazole (Compound 117)

[0271] Compound 2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin- 1 -yl)methyl)-6-( 177-pyrazol-3- yl)bcnzo|<7| oxazole was prepared from 6-bromo-2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l- yl)methyl)benzo[tf] oxazole (200 mg, 0.497 mmol) and 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)- 177-pyrazole (91 mg, 0.469 mmol) following a similar procedure to that described for the synthesis of (6-vinylbenzo[t / ]oxazol-2-yl)methyl acetate, and was isolated as a white solid.Yield 30 mg (15%).JH NMR (400 MHz, DMSO) 5 12.97 (br s, 1H), 8.42 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 1.6, 8.4 Hz, 1H), 6.83 (d, J = 2.4 Hz, 1H), 3.96 (s, 2H), 3.27 (d, J = 4.8 Hz, 4H), 2.71 (t, J = 4.8 Hz, 4H), 2.33 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 390 (M+H)+. (C21H23N7O).Synthesis of 2-(4-(2-((4-(5,6-dimethylpyrimidin-4-yl)piperazin-l-yl)methyl)benzo[d]oxazol-6-yl)- lH-pyrazol-l-yl)ethan-l-ol (Compound 142)

[0272] To a stirred mixture of 6-(l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-177-pyrazol-4-yl)-2-((4- (5,6-dimcthylpyihnidin-4-yl)pipcrazin- l -yl)mcthyl)bcnzo|<7|oxazolc (180 mg, 0.329 mmol) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride (1 Y in tetrahydrofuran, 1 mL, 1.00 mmol) dropwise at 0°C. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with sat. aqueous ammonium chloride solution (1 mL) at room temperature and purified by reverse phase flash chromatography with the following conditions: Column, Spherical C18, 20 - 40 urn, 120 g; Mobile Phase A: water (plus 10 mM ammonium bicarbonate); Mobile Phase B; acetonitrile; Flow rate: 60 mL / min; Gradient:30%B-50%B in 25 min; Detector, UV 254 nm. Thefractions containing desired product were collected at 40% B and concentrated under reduced pressure to afford the crude product. Which was then purified by Prep-TLC (petroleum ether:ethyl acetate:methanol = 5:5:1) and followed by Prep-HPLC with the following conditions (Column: X Bridge Prep OBD C18 Column, 30 x 150 mm, 5 z / m; Mobile Phase A: water (10 mmol / L ammonium bicarbonate), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 17% B to 27% B in 8 min, 27% B; Wave Length: 254 nm; RTl(min): 7). The fractions containing desired product were collected and concentrated under reduced pressure to afford 2-(4-(2-((4-(5,6-dimethylpyrimidin-4- yl)pipcrazin- 1 -yl)mcthyl)bcnzoh / |oxazol-6-yl)- l / 7-pyrazol- 1 -yl)cthan- 1 -ol as a white solid.Yield 20 mg (14%).JH NMR (400 MHz, DMSO) 5 8.42 (s, 1H), 8.23 (d, J = 0.8 Hz, 1H), 7.97 (d, J = 0.8 Hz, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 1.6, 8.4 Hz, 1H), 4.94(t, J = 5.2 Hz, 1H), 4.17 (t, J = 5.6 Hz, 2H), 3.94 (s, 2H), 3.81 - 3.74 (m, 2H), 3.26 (d, J = 4.8 Hz, 4H), 2.70 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.10 (s, 3H). m / z: [ESI+] 434 (M+H)+. (C23H27N7O2).EXAMPLE 2 Biological Activity of Compounds of the Invention

[0273] The biological activity results of all compounds of the invention is summarized in Table 2.Table 2. Cellular ECso values of compounds of the invention in the WI-38 collagen 1 inhibition assay.EXAMPLE 3Cardiac Safety for Compounds of the Invention (hERG liability)

[0274] The hERG inhibition data of selected compounds of the invention is summarized in Table 3.Table 3. Potency in hERG channel inhibition (IC50 values) for selected compounds of the invention.

[0275] The compounds of this invention demonstrate promising cardiac safety, as evidenced by their reduced hERG inhibition.EXAMPLE 4Reduced BBB Penatration for Compounds of the Invention

[0276] The BBB profile data, as determined by permeability and efflux ratio results for selected compounds of the invention, is summarized in Table 4.Table 4. BBB penetration data as determined by (low) permeability and (high) efflux ratio results for selected compounds of the invention.

[0277] P-gp Substrate Potential*: Likely: ERa > 2, Poor or Non: ERa < 2

[0278] *ERa represents the efflux ratios of test compound without an inhibitor of efflux transporter(s).Results

[0279] Compounds 104, 116, 126, 127, 140, 145, 146 and 147 exhibit low PappA-B permeability (i.e., >2) and higher efflux ratio, indicating reduced brain exposure and a lower risk of CNS toxicity.EXAMPLE 5Effect of Compound 127 on Expression of Collagen 1 in WI38 Human Lung FibroblastsCells

[0280] Figure 1 depicts the effect of Compound 127 on expression of Collagen 1 in WI38 Human Lung Fibroblasts cells.

[0281] WI-38 cells were plated in 384- well plate and activated with fibroblast activation cocktail for 72 hours and treated with compounds in the last 48 hours. Compound 127 was tested at the indicated concentrations (0.005, 0.014, 0.12, 0.37, 1, 3, and 10 mM). Collagen 1 levels were determined by immunofluorescence microscopy using an anti-collagen 1 antibody. Relative expression of collagen was determined and normalized to control cells treated with DMSO. Normalized collagen expression is presented on the Y-axis. The EC50 of Compound 127 is 135 nM (Figure 1).EXAMPLE 6Compound 127 Efficacy in Bleomycin- Induced Lung Fibrosis Model in Mice - in vivo Study

[0282] The aim of the study was to test Compound 127 at 3, 10, and 30 mg / kg / PO / BID, starting from day (D) 7 - D21 in a 21-day mouse model of bleomycin induced pulmonary fibrosis.

[0283] Five groups of animals were enrolled in the study, each consisting of 15 male C57BL / 6 mice, except control group (group 1, no bleomycin control) which consisted of 10 mice. On DO, animals from bleomycin control and compound groups were challenged with a single intranasal (IN) administration of - 1 mg / kg of bleomycin (BLM), while no bleomycin control received a single IN challenge of 0.9% saline.

[0284] On D7 animals were harmonized based on body weight loss (%), and following randomization, treatment started for all groups and lasted daily until D21. Group 1 served as a negative control group and received 10 mL / kg / PO / QD of Vehicle (0.1% hydroxyethilcellulose (HEC)). Group 2 was a positive control and received the same Vehicle in BID regime.

[0285] Animals in groups 3-5 received test compound 127 in doses of 3, 10 or 30 mg / kg / PO / BID.

[0286] Following the challenge on DO, animals were monitored two times a day, and body weights were recorded on DO, DI, D3, D6, and from D7 every day until D21 of the study. Lungs from all animals were sampled, weighed, and stored in 10% formaldehyde until being processed for histopathological analysis.

[0287] Histopathological assessment was conducted on Crossman’s Trichrome stained slides for Ashcroft / Matsuse score and on HE stained slides for pulmonary inflammation evaluation.

[0288] The Ashcroft score across groups is depicted in Figure 2. By the end of the study on D21, a single BLM challenge has successfully induced lung fibrosis which was confirmed by increased lung weight, increase in Ashcroft score and accumulation of lymphocytes and eosinophils in the lung of BLM / Vchiclc group (group 2), in comparison to Saline / Vehicle group (group 1) (Figure 2).

[0289] Results of body weight monitoring did not show significant difference between the groups, with the exception of body weight change observed between BLM / V chicle and Saline / vehicle groups from D7-D21 (data not shown).

[0290] Treatment with Compound 127 at all tested doses showed beneficial effect as demonstrated in the significant reduction of Ashcroft score in comparison to BLM / Vchiclc. Doses of 3 and 30 mg / kg / BID showed significant reduction of lymphocytes in lung tissue, while same substance given at a dose 10 mg / kg showed trend (0.0577) of lymphocyte number decrease in comparison to BLM / V chicle group.EXAMPLE 7Safety Panel for Compound 127

[0291] Compound 127 was tested in a safety panel. Compounds concentration was lOpM. Compound binding was calculated as a % inhibition of the binding of a ligand specific for each target. Compound enzyme inhibition effect was calculated as a % inhibition of control enzyme activity. Results showing an inhibition or stimulation higher than 50% are considered to represent significant effects of the test compounds. The results of the safety panel are depicted in Table 5 below.Table 5. Compound 127 Safety Panel - Binding and enzyme and uptake assays.EXAMPLE 8Pharmacokinetics Data for Compound 127 (Figures 3 and 4) Single-dose 24h IV and PO PK study of Compound 127.

[0292] Figure 3 depicts the IV administration lOmg / kg single-dose PK study of Compound 127 and PO administration single-dose PK study of Compound 127 at PO at 3, 10, 30mg / kg.

[0293] The PK parameters for IV and PO administration of Compound 127 are summarized hereinbelow in Tables 6 and 7.Table 6. PK parameters for IV administration of Compound 127.Table 7. PK parameters for PO administration of Compound 127.

[0294] Intravenous dosing of Compound 127 shows high clearance with moderate half-life possibly compensated by high volume of distribution. Oral dosing of Compound 127 shows increased Cmax, AUC, and %F upon increasing PO dose level. No clinical abnormalities were observed in the tested mice for all dose groups (Figure 3).Multi-dose 5-day PK study of Compound 127

[0295] Figure 4 depicts the multi-dose 5-day PK Study (Day 1 and 5) of Compound 127 as plasma cone, vs time in PO dosing at 10, 30 and 100 mg / kg.

[0296] The PK parameters for PO administration of Compound 127 are summarized hereinbelow in Table 8.Table 8. Summary of Compound 127 PO plasma pharmacokinetic parameters.

[0297] Compound 127 shows an increased Cmaxand AUC upon increasing PO dose level. No clinical abnormalities were observed in the tested mice for 10 and 30 mg / kg BID dose groups; 100 mg / kg BID group were sacrificed on Day 2 due to adverse effects. PO formulation: 1% Tween 80 in 0.5% HPMC. PK parameters for multi-dose PO administration.EXAMPLE 9Experimental MethodsCell culture

[0298] WI-38 cells (ATCC® CCL-75™) were maintained in MEM EAGLE (NEAA) W. GLUT AMIN (Biological Industries, Cat. 06- 1040- 15-1 A) containing 10% fetal bovine serum (FBS) and 1% Penicillin-Streptomycin Solution. To synchronize the cells (cell cycle synchronization) prior to induction of collagen synthesis, the cells were starved using DMEM-low glucose supplemented with 0.25% FBS for two hours and then without FBS for 24 hours. To induce collagen synthesis, the cells were treated with a collagen induction cocktail for the indicated time. Compounds were added with induction.

[0299] Primary human pulmonary fibroblasts (HPF, PromoCell C- 12360) were maintained in fibroblast growth medium 2 (PromoCell C-23020) according to manufacture instruction. Collagen synthesis was inducted using the same cocktail as for the WI-38 cells.

[0300] Primary human dermal fibroblasts (HDF) (PromoCell C- 12302) were maintained in PromoCell’ s proprietary Fibroblast Growth Medium 2 (ready -to-use, Cat. C-23020). For collagen synthesis induction, cells were seeded on experimental plates for 24 hours followed by addition of collagen induction cocktail. Tested compounds were added together with induction.Collagen-I immunofluorescence assay

[0301] Cells in 96-well or 384-well plates were fixed for 20 min in 4% paraformaldehyde (PFA, ENCO, Cat. sc-281692). Following two washes with IxPBS, cells were treated with hydrogen peroxide (Acros, Cat: 7722-84-1) for 10 minutes and then washed twice with IxPBS. Cells were then incubated over-night at 4°C with Anti-Collagen I (Sigma- Aldrich, Cat: C 2456) antibody and washed three times with IxPBS. Cell were then incubated with a suitable secondary fluorescently-tagged antibody and nuclei stained with DAPI, for 1 hour, and then washed 3 times with IxPBS.

[0302] Cell images were taken with Operetta (Perkin Elmer, USA), a wide-field fluorescence microscope at 20x magnification. After acquisition, the images were transferred to Columbus software (Perkin-Elmer) for image analysis. In Columbus, cells were identified by their nucleus, using the “Find Nuceli” module and cytoplasm was detected based on the secondary antibody channel. Subsequently, the fluorescent signal was enumerated in the identified cell region. Data was exported to a data analysis and visualization software, Tibco Spotfire, USA.

Claims

1. WHAT IS CLAIMED IS:

1. A compound, represented by the structure of formula II:whereinR3is OH, SH, R8-OH (e.g., CH2OH), R8-SH, -R8-0-R10(e.g., CH2-O-CH2-CCH, CH2-O- CH3, CH2-CH2-O-CH3, CH2-O-CH2-CH2-O-CH3), O-R10 (e.g., O-CH2-CH2-CCH), -0-R8-0-RIO (e.g., O-CH2-CH2-O-CH3), R6-0-R8-0-RIO (e.g., CH2-O-CH2-CH2-O-CH3), R8-(C3-C8cycloalkyl), R8-(3-8 membered heterocyclic ring), O-R20, CN, NO2, NH2, NHR, N(R)2, N(R10)(R11) (e.g., N(CH3)2, NH(CH3)), R8-N(RIO)(RII), NHC(O)-R (e.g., NHCO-Ph, NHCO-CH3) , NHC(0)-R10(e.g., NHCO-CH3), NHCO-N(R10)(R11), COOH, -C(O)Ph, C(0)0-R10, R8-C(O)- R10, C(O)H, C(0)-R10, -C(O)NH2, C(O)NHR (e.g., C(O)NH-CH3), C(0)N(R10)(R11) (e.g., C(O)N(CH3)2), SO2R, S02N(RIO)(RH), NHS02(RIO) (e.g., NHSO2CH3), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH(CH3)(OH), C(CH3)2(OH), CH(CF3)(NH2), methyl, ethyl), C1-C5linear or branched, substituted or unsubstituted alkenyl, substituted or unsubstituted C1-C5linear, branched or cyclic haloalkyl (e.g., CHF2, CH(OH)(CF3), CH(CF3)(NH2), CF2(OH), CHF(OH), CF2(OCH3)), C1-C5linear, branched or cyclic alkoxy ( e.g., methoxy), C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy (e.g., OCHF2), C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C10 cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 3-8 membered single, fused, bridged or spiro, saturated, unsaturated or aromatic, heterocyclic ring (e.g., azetidine, morpholine, pyrazole, piperidine, triazole, 2-pyrrolidone, pyrrolidine, oxadiazole, tetrazole, imidazole, piperazine, oxetane, piperazinone, 1,4-diazepane, 2- oxazolidinone, lH-l,2,4-triazol-5(4H)-one, triazol-3-one, pyridine, 4,7-diazaspiro[2.5]octane, 3- azabicyclo[3.1.0]hexane, spiro[azetidine-3,l'-cyclobutane], 2-azaspiro[3.3]heptane), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted benzyl;R4and R5 are each independently C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl), F, Cl, Br, I, OH, SH, CF3, CN, NO2, NH2, NHR, N(R)2, C1-C5linear, branched or cyclic haloalkyl (e.g., CHF2), C1-C5linear, branched or cyclic alkoxy ( e.g., methoxy); wherein if R3 is unsubstituted haloalkyl, then R4and R5 are different;R is H, or C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl);Re is [CH2]Vwherein v is between 1 and 5 (e.g., 1); R8is [CH2]Pwherein p is between 1 and 5 (e.g., 1, 2); R10and R11are each independently H, C1-C5substituted or unsubstituted, linear or branched alkyl (e.g., methyl, ethyl, CH2-CCH, CH2-CH2-CCH, CH2-CH2-O-CH3), linear or branched alkynyl (e.g., CCH), C1-C5linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R; or R10and R11are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine),R20 is represented by the following structure:or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, 2V-oxide, isotopic variant (e.g., deuterated analog), reverse amide, or any combination thereof.

2. The compound of claim 1, wherein substitutions are selected from: F, Cl, Br, I, CN, NO2, OH, SH, NH2, NHR (e.g., NH(CH3)), N(R)2, N(R10)(R11) (e.g., N(CH3)2), R8-N(R10)(Rn), Ci-C5linear or branched alkyl (e.g., CEh), CH2-CH2-CCH, Cs-C-5 linear or branched, haloalkyl (e.g., CFs, CHF2), R8-OH (e.g., CH2-0H, CH2-CH2-OH), R«-SH, -Rg-O-R10, -R8-R10(e.g., CH2-CH2-CCH), NHC(0)-R10, COOH, -C(O)Ph, C(0)ORio, IC-GOMC;. C(O)H, C(O)-Rj0, Cr-Cs linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(0)N(Rfo)(RiO, R20, S02R, S02N(RJO)(RJ J), NHSO?.(R10), CH(CFs)(NH-R10), C1-C5linear or branched alkenyl G-C5linear, branched orcyclic alkoxy, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxy alkyl, C3-C8cycloalkyl, 3-8 membered heterocyclic ring, aryl, or benzyl.

3. The compound of claim 1 or 2, wherein R3 is substituted or unsubstituted C1-C5linear, branched or cyclic haloalkyl, R8-0-R10(e.g„ CH2-O-CH2-CCH), O-R10 (e.g., O-CH2-CH2-CCH), or O-R20.

4. The compound of claim 3, wherein the haloalkyl is: CHF2, CH(0H)(CF3), CH(CF3)(NH2), CF2(OH), CHF(OH), or CF2(OCH3).

5. The compound of any one of claims 1-4, wherein R4and R5 are each independently substituted or unsubstituted alkyl (e.g., methyl, ethyl), OH, or NH2.

6. The compound of claim 1, wherein R3 is 3-8 membered heterocyclic ring, further substituted with at least one selected from: F, Cl, Br, I, CN, NO2, OH, SH, NH2, NHR (e.g., NH(CH3)), N(R)2(e.g., N(CH3)2), N(RIO)(RII), R8-N(RIO)(RH), C1-C5linear or branched, alkyl (e.g., CH3), CH2- CH2-CCH, C1-C5linear or branched, linear, branched or cyclic haloalkyl (e.g., CF3, CHF2), R8- OH (e.g., CH2-OH, CH2-CH2-OH), R8-SH, -R8-RIO (e.g., CH2-CH2-CCH), -R8-O-R10, NHC(O)- R10, COOH, -C(O)Ph, C(0)0-R10, R8-C(0)-R10, C(O)H, C(0)-R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, R20, C(O)NHR, C(0)N(R10)(R11), SO2R, S02N(R10)(R11), NHSO2(R10), CH(CF3)(NH-RIO), C1-C5linear or branched, alkenyl, C1-C5linear, branched or cyclic alkoxy, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, C3-C8cycloalkyl, 3-8 membered heterocyclic ring, aryl, benzyl.

7. A compound represented by any one of the following structures:

8. A compound, represented by the structure of formula (I):whereinC ring is a a single or fused C3-C10 cycloalkyl ( e.g., cyclopropyl), 3-8 membered saturated heterocyclic ring (e.g., morpholine, azetidine, piperidine, piperazine, pyrrolidine, oxetane, 1,4- diazepane), 5-7 membered unsaturated heterocyclic ring (e.g., 2-piperazinone, 2-pyrrolidone, 1,2- Dihydro-3H-l,2,4-triazol-3-one, 2-oxazolidinone, lH-l,2,4-triazol-5(4H)-one), 5-7 membered aromatic heterocyclic ring (e.g., pyrazole, imidazole, triazole, oxadiazole, tetrazole), a 7-12 membered fused, bridged or spiro, saturated or unsaturated carbocyclic or heterocyclic ring system (e.g., 4,7-diazaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane, spiro[azetidine-3,l'-cyclobutane], 2- azaspiro [3.3 ] heptane) ;Ri is H, F, Cl, Br, I, CN, NO2, OH, SH, NH2, NHR (e.g., NH(CH3)), N(R)2, N(R10)(R11) (e.g., N(CH3)2), R8-N(RIO)(RH), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g.,CH3, CH2-CH2-CCH), C1-C5linear or branched, substituted or unsubstituted linear, branched or cyclic haloalkyl (e.g., CHF2), R8-OH (e.g., CH2-OH, CH2-CH2-OH), R8-SH, -R8-R10(e.g., CH2- CH2-CCH), -R8-0-RIO, NHC(0)-RIO, COOH, -C(O)Ph, C(0)0-R10, R8-C(0)-R10, C(O)H, C(O)- R10, C1-C5linear or branched C(O)-haloalkyl, -C(O)NH2, C(O)NHR, C(0)N(R10)(R11), SO2R, S02N(R10)(R11), NHS02(RIO), CH(CF3)(NH-RIO), R20, C1-C5linear or branched, substituted or unsubstituted alkenyl, C1-C5linear, branched or cyclic alkoxy, C1-C5linear or branched thioalkoxy, C1-C5linear or branched haloalkoxy, C1-C5linear or branched alkoxyalkyl, substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 3-8 membered heterocyclic ring, substituted or unsubstituted aryl, substituted or unsubstituted benzyl;R2is absent or is H, F, Cl, Br, I, CN, NO2, OH, SH, NH2, NHR (e.g., NH(CH3)), N(R)2, N(R10)(R11) (e.g., N(CH3)2), R8-N(RIO)(RII), C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., CH3, CH2-CH2-CCH), C1-C5linear or branched, substituted or unsubstituted linear, branched or cyclic haloalkyl (e.g., CHF2), R8-OH (e.g., CH2-OH, CH2-CH2-OH), -R8-RIO (e.g., CH2-CH2-CCH), C(0)NH2, R20, or substituted or unsubstituted C3-C8cycloalkyl (e.g., cyclopropyl);R is H, or C1-C5linear or branched, substituted or unsubstituted alkyl (e.g., methyl, ethyl); R8is [CH2]p wherein p is between 1 and 3 (e.g., 1, 2); R10and R11are each independently H, C1-C5substituted or unsubstituted, linear or branched alkyl (e.g., methyl, ethyl, CH2-CCH, CH2-CH2-CCH, CH2-CH2-O-CH3), linear or branched alkynyl (e.g., CCH), C1-C5linear or branched alkoxy (e.g., O-CH3), C(O)R, or S(O)2R; or R10and R11are joined to form a substituted or unsubstituted 3-8 membered heterocyclic ring (e.g., piperazine, piperidine),R20 is represented by the following structure:or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, / V-oxidc, isotopic variant (e.g., deuterated analog), reverse amide, or any combination thereof.. The compound of claim 8, selected from the following:

10. The compound according to any one of claims 1-9, wherein the compound is a collagen translation inhibitor.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

12. A compound according to any one of claims 1 to 10 for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting fibrosis in a subject.

13. The compound of claim 12, wherein said fibrosis is a systemic fibrotic disease.

14. The compound of claim 13, wherein said systemic fibrotic disease is systemic sclerosis, multifocal fibrosclerosis (IgG4-associated fibrosis), nephrogenic systemic fibrosis, sclerodermatous graft vs. host disease, or any combination thereof.

15. The compound of claim 12, wherein said fibrosis is an organ-specific fibrotic disease.

16. The compound of claim 15, wherein said organ- specific fibrotic disease is lung fibrosis, cardiac fibrosis, kidney fibrosis, pulmonary fibrosis, liver and portal vein fibrosis, radiation-induced fibrosis, bladder fibrosis, intestinal fibrosis, peritoneal sclerosis, diffuse fasciitis, wound healing, scaring, or any combination thereof.

17. The compound of claim 16, wherein said lung fibrosis is idiopathic pulmonary fibrosis (IPF).

18. The compound of claim 16, wherein said cardiac fibrosis is hypertension-associated cardiac fibrosis, Post-myocardial infarction, Chagas disease-induced myocardial fibrosis or any combination thereof.

19. The compound of claim 16, wherein said kidney fibrosis is diabetic and hypertensive nephropathy, urinary tract obstruction-induced kidney fibrosis, inflammatory / autoimmune- induced kidney fibrosis, aristolochic acid nephropathy, polycystic kidney disease, or any combination thereof.

20. The compound of claim 16, wherein said pulmonary fibrosis is idiopathic pulmonary fibrosis, silica-induced pneumoconiosis (silicosis), asbestos-induced pulmonary fibrosis (asbestosis), chemotherapeutic agent-induced pulmonary fibrosis, or any combination thereof.

21. The compound of claim 16, wherein said liver and portal vein fibrosis is alcoholic and nonalcoholic liver fibrosis, hepatitis C-induced liver fibrosis, primary biliary cirrhosis, parasite- induced liver fibrosis (schistosomiasis), or any combination thereof.

22. The compound of claim 16, wherein said diffuse fasciitis is localized scleroderma, keloids, dupuytren’s disease, peyronie’s disease, myelofibrosis, oral submucous fibrosis, or any combination thereof.

23. The compound of claim 12, wherein said fibrosis is primary or secondary fibrosis.

24. The compound of claim 12, wherein said fibrosis is a result of systemic sclerosis, graft-versus host disease (GVHD), pulmonary fibrosis, autoimmune disorder, tissue injury, inflammation, oxidative stress or any combination thereof.

25. The compound of claim 12, wherein the fibrosis is hepatic fibrosis, lung fibrosis or dermal fibrosis.

26. The compound of any one of claims 12 or 21, wherein said subject has a liver cirrhosis.

27. The compound of claim 25, wherein the dermal fibrosis is scleroderma.

28. The compound of claim 25, wherein the dermal fibrosis is a result of a localized or generalized morphea, keloids, hypertrophic scars, familial cutaneous collagenoma, connective tissue nevi of the collagen type, or any combination thereof.

29. The compound of claim 25, wherein the hepatic fibrosis is a result of hepatic scarring or chronic liver injury.

30. The compound of claim 29, wherein the chronic liver injury results from alcoholism, malnutrition, hemochromatosis, exposure to poisons, toxins or drugs.

31. A compound according to any one of claims 1 to 10 for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting lung fibrosis in a subject.

32. The compound of claim 31, wherein the lung fibrosis is idiopathic pulmonary fibrosis (IPF).

33. A compound according to any one of claims 1 to 10 for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting idiopathic pulmonary fibrosis (IPF) in a subject.

34. A compound according to any one of claims 1 to 10 for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting hepato-fibrotic disorder in a subject.

35. The compound of claim 34, wherein the hepato-fibrotic disorder is a portal hypertension, cirrhosis, congenital hepatic fibrosis or any combination thereof.

36. A compound according to any one of claims 1 to 10 for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting cirrhosis in a subject.

37. The compound of claim 36, wherein the cirrhosis is a result of hepatitis or alcoholism.

38. A compound according to any one of claims 1 to 10 for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting alcoholic steatohepatitis (ASH) in a subject.

39. A compound according to any one of claims 1 to 10 for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting non-alcoholic steatohepatitis (NASH) in a subject.

40. A compound according to any one of claims 1 to 10 for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting alcoholic fatty liver disease (AFLD) in a subject.

41. A compound according to any one of claims 1 to 10 for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting non alcoholic fatty liver disease (NAFLD) in a subject.

42. A compound according to any one of claims 1 to 10 for use in treating, suppressing, reducing the severity, reducing the risk of developing or inhibiting an autoimmune disease or disorder in a subject.

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