Inhibitors of serine palmitoyltransferase

Abstract

Disclosed herein are serine palmitoyltransferase inhibitors of formula (I); or a pharmaceutically acceptable salt form thereof. The variables in formula (I) are described herein. Also disclosed is a method of treating a subject with a disease characterized by elevated ceramide levels or a disease or condition that is mediated by serine palmitoyltransferase, comprising administering an effective amount of the disclosed serine palmitoyltransferase inhibitors disclosed herein.

Description

INHIBITORS OF SERINE PALMITOYLTRANSFERASEBACKGROUND OF THE INVENTION

[0001] Sphingolipids comprise a family of membrane lipids, such as sphingomyelin and glycosphingolipids and bioactive lipids, such as ceramides, sphingosines and dihydrosphingosines (sphinganines). Sphingolipids have numerous functions, including in inflammation, fibrosis and cell death. [Hannun, Y.A., and Obeid, L.M. (2018); Sphingolipids and their metabolism in physiology and disease. Nat. Rev. Mol. Cell Biol. 19, 175-191] . The first step of the cellular sphingolipid biosynthesis is normally the condensation of serine and palmitoyl-CoA, catalyzed by the serine-palmitoyltransferase (SPT). Sphingolipid metabolism has been linked to a wide variety human disorders, including muscle disorders, metabolic disorders, cardiovascular disorders and neurological disorders.

[0002] Muscle disorders are characterized by the presence of dysfunctional myocytes, often linked with loss of myocyte membrane integrity and depletion and / or exhaustion of muscle stem cells (satellite cells), leading to muscle weakness and degeneration. Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy affecting 1 in 3500 newborn boys. Patients diagnosed with the DMD often experience premature death due to cardiac or respiratory failure following protracted muscle degeneration in the heart and diaphragm (Lee, A. J., Buckingham, E.T., Kauer, A. J., and Mathews, K.D. (2018), Descriptive Phenotype of Obsessive Compulsive Symptoms in Males With Duchenne Muscular Dystrophy. J. Child Neurol. 33, 572-579). Sarcopenia can be age related or caused by extreme and chronic inactivity, such as a secondary effect from severe disease or prolonged hospital stay. The reduction of skeletal muscle mass associated with sarcopenia is one of the most important causes of functional decline and loss of independence in aged individuals in muscle disorders. Pharmacological approaches have been proposed to slow the functional impairment of skeletal muscles caused by muscle disorders, however there are currently no effective therapies.

[0003] ft has been shown that metabolic intermediates of the sphingolipid de novo synthesis pathway accumulate in mouse models of muscle diseases such sarcopenia and muscular dystrophy, accompanied by the upregulation of enzymes involved in sphingolipid de novo synthesis at both mRNA and protein level (see Turpin-Nolan, S.M., Hammerschmidt, P., Chen, W., Jais, A., Timper, K., Awazawa, M., Brodesser, S., and Bruning, J.C. (2019). CerSl-Derived C18:0 Ceramide in Skeletal Muscle Promotes Obesity -Induced Insulin Resistance. Cell. Rep. 26, l-10.e7). These metabolic intermediates also accumulate in skeletal muscle upon aging (see WO / 2021 / 058497). Pharmacological inhibition of sphingolipid de novo biosynthesis pathway counteracts DMD-related loss of muscle function in the mdx mouse model of muscular dystrophy(Pirkka-Pekka Laurilal, Peiling Luanl, Nadege Zanou, Martin Wohlwend, Tanes Imamura, de Limal, Ludger J. E. Goeminnel, Hector Gallart-Ayala, Julijana Ivanisevic, Minho Shong, Nicolas Place and Johan Auwerx (submitted for publication) Inhibition of Sphingolipid De Novo Synthesis Counteracts Muscular Dystrophy. Science Advances) and age-related loss in muscle mass and function in aged mice (WO / 2021 / 058497). Additionally, blocking sphingolipid synthesis stabilizes muscular Ca2+turnover, reverses diaphragmatic and cardiac fibrosis, and attenuates DMD -associated muscle inflammation by directing macrophage polarization towards the anti-inflammatory state (Pirkka-Pekka et al., supra , demonstrating that pharmacological sphingolipid reduction alleviated dystrophic symptoms and reversed multiple pathophysiological hallmarks of DMD. With respect to sarcopenia, genetic variants of serine palmitoyltransferase were shown to be associated with improved fitness and muscle function in elderly individuals (WO / 2021 / 058497). These results demonstrate that inhibition of sphingolipid de novo synthesis by, for example, inhibition of serine palmitoyltransferase is a viable approach for treating muscular disorder, including muscular dystrophies and sarcopenias.

[0004] Inhibition of sphingolipid de novo synthesis pathway, such as by inhibition of serine palmitoytransferase, has been proposed as a treatment for many other complex diseases, including cardiovascular disease (Havulinna, A. S. et al. Circulating Ceramides Predict Cardiovascular Outcomes in the Population-Based FINRISK 2002 Cohort. Arterioscler. Thromb. Vase. Biol. 36, 2424-2430 (2016)), diabetes (Choi, S. and Snider, A. J. Sphingolipids in High Fat Diet and Obesity-Related Diseases. Mediators Inflamm. 2015, 520618 (2015), amytropic lateral sclerosis (WO2011104298), drug induced neuropathies (WO2011104298) and Alzheimer’s disease (Filippov, V. et al. Increased ceramide in brains with Alzheimer's and other neurodegenerative diseases. J. Alzheimers Dis. 29, 537-547 (2012)), and in recent years, attention has increasingly focused on inhibiting ceramide generation in vivo to combat metabolic disease. Inhibition of serine-palmitoyl transferase (SPT) leads to reduced atherosclerosis (Hojjati, M. R. et al. Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE deficient mice. J. Biol. Chem. 280, 10284-10289 (2005)), improved glucose tolerance (Ussher, J. R. et al. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 59, 2453-2464 (2010)), and fatty liver (Zabielski, P. et al. The effect of high-fat diet and inhibition of ceramide production on insulin action in liver. J. Cell. Physiol. 234, 1851-1861 (2019)) in mouse models. Mice deficient of ceramide synthase 6 (CERS6) are protected from glucose intolerance (Turpin, S. M. et al. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell. Metab.20, 678-686 (2014) and Hammerschmidt, P. et al. CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity. Cell 111, 1536-1552. e23 (2019)) and the inhibition of dihydroceramide desaturase (DEGS1) was recently reported to improve glucosehomeostasis and liver fat accumulation (Chaurasia, B. et al. Targeting a ceramide double bond improves insulin resistance and hepatic steatosis Science 365, 386-392 (2019)).

[0005] Given the diverse cellular functions of ceramides and involvement in multiple age associated diseases, treatment of many diseases by targeting only one biological pathway presents an attractive therapeutic strategy to combat age-related multimorbidity.

[0006] Accordingly, there is a need for additional SPT inhibitors that could be developed for the treatment of the aforementioned diseases.SUMMARY OF THE INVENTION

[0007] Disclosed herein are serine palmitoyltransferase inhibitors.

[0008] One embodiment of the invention is a serine palmitoyltransferase inhibitor of formulaL3IL2

[0009] (i);

[0010] or a pharmaceutically acceptable salt form thereof, wherein:

[0011] X and Z are independently selected from C(O) and S(O)2;

[0012] Y and Y1are independently selected from a bond and NH;

[0013] Ar1is an optionally substituted 6-10 membered aromatic carbocyclylene, an optionally substituted 5-10 membered heteroarylene or an optionally substituted 3-10 membered heterocyclylene;

[0014] Ar2is an optionally substituted 6-10 membered aromatic carbocyclylene or optionally substituted 5-10 membered heteroarylene; and

[0015] R1is Ci-Cs alkyl, (QU^Cs-C? cycloalkyl, (CH2)xphenyl, (CH2)x(3-7 membered heterocyclyl) or (CH2)x(5-6 membered heteroaryl); wherein the Ci-6 alkyl, (CIU^Cs-C? cycloalkyl, (CH2)xphenyl, (CH2)x(3-7 membered heterocyclyl) and the (CH2)x(5-6 membered heteroaryl) are optionally substituted with one or more groups selected from halo, ORa, NRaRb, S(O)iRa, NRaS(O),R'. S(O)iNRaRb, C(=O)ORa, OC(=O)ORa, C(=S)ORa, O(C=S)Ra,C(=O)NRaRb, NRaC(=O)Rb, C(=S)NRaRb, NRaC(=S)Rb, NRa(C=O)ORb, O(C=O)NRaRb, NRa(C=S)ORb, O(C=S)NRaRb, NRa(C=O)NRbRc, NRa(C=S)NRbRc, C(=S)Ra, C(=O)Raand C1-C6alkyl;

[0016] L1and L3are independently selected from -0-, -N-, -S-, -SO2-, -SO3-, -SO2NH-, -NHSO2-, -(CH2)I-4, -O(CH2)I-4-, -(CH2)I-4-O-, -O(CH2)2-4O-, -NH(CH2)I-4-, -(CH2)I-4-NH-, and -NH(CH2)2-4NH-;

[0017] L2is selected from C2-C6 alkenylene, C2-C6 alkenylene oxide, Ci-Cs alkylene, C3-C7 cycloalkylene, phenylene, 3-7 membered heterocyclylene or 5-6 membered heteroarylene; wherein the Ci-Cs alkylene, C2-C6 alkenylene, C3-C7 cycloalkylene, phenylene, 3-7 membered heterocyclylene, and the 5-6 membered heteroarylene are optionally substituted with one or more groups selected from halo, ORa, NRaRb, S(O)iRa, NRaS(O)1Ra, S(O)iNRaRb, C(=O)ORa, OC(=O)ORa, C(=S)ORa, O(C=S)Ra, C(=O)NRaRb, NRaC(=O)Rb, C(=S)NRaRb, NRaC(=S)Rb, NRa(C=O)ORb, O(C=O)NRaRb, NRa(C=S)ORb, O(C=S)NRaRb, NRa(C=O)NRbRc, NRa(C=S)NRbRc, C(=S)Ra, C(=O)Raand Ci-Cs alkyl;

[0018] each Ra, Rband Rcare each independently selected from -H and C1-C3 alkyl;

[0019] each i is independently 0, 1, 2, 3 or 4 ; and

[0020] each x is independently 0 or 1.

[0021] Another embodiment of the invention is a pharmaceutical composition comprising a serine palmitoyltransferase inhibitor disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent.

[0022] Another embodiment of the invention is a method of inhibiting serine palmitoyltransferase in a subject in need thereof, comprising administering an effective amount of a serine palmitoyltransferase inhibitor disclosed herein or a pharmaceutically acceptable salt thereof to the subject.

[0023] Another embodiment of the invention is a method of reducing elevated ceramide levels in a subject in need thereof, comprising administering an effective amount of a serine palmitoyltransferase inhibitor disclosed herein or a pharmaceutically acceptable salt thereof to the subject.

[0024] Another embodiment of the invention is a serine palmitoyltransferase inhibitor disclosed herein or a pharmaceutically acceptable salt thereof for reducing elevated ceramide levels in a subject in need thereof.

[0025] Another embodiment of the invention is the use of a serine palmitoyltransferase inhibitor disclosed herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing elevated ceramide levels in a subject in need thereof.

[0026] Another embodiment of the invention is a compound disclosed herein or a pharmaceutically acceptable salt thereof for use in reducing elevated ceramide levels in a subject in need thereof.

[0027] Another embodiment of the disclosure is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing elevated ceramide levels in a subject in need thereof.

[0028] Another embodiment of the invention is a method of treating a subject with a disease or condition mediated by serine palmitoyltransferase, comprising administering an effective amount of the serine palmitoyltransferase inhibitors disclosed herein or a pharmaceutically acceptable salt thereof to the subject.

[0029] Another embodiment of the invention is a compound disclosed herein or a pharmaceutically acceptable salt thereof for use in the treatment of a subject with a disease or condition that is mediated by serine palmitoyltransferase.

[0030] Another embodiment of the disclosure is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting serine palmitoyltransferase in a subject in need thereof.DETAILED DESCRIPTION OF THE INVENTION

[0031] Disclosed herein are serine palmitoyltransferase inhibitors. The inhibitors can be used to inhibit serine palmitoyl transferase and to reduce elevated ceramide levels in a subject in need thereof, thereby treating subjects with diseases and conditions mediated by serine palmitoyltransferase. Diseases mediated by serine palmitoyltransferase include, but are not limited to, muscular dystrophies, inflammatory myopathies, metabolic myopathies, myofibrillar myopathies, sarcopenia and muscle wasting diseases.

[0032] In one embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:

[0033]

[0034] The variables in formula (I) are defined in the summary above.

[0035] In a second embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by formula (II), or a pharmaceutically acceptable salt thereof:Owherein the variables are as described above for Formula (I).

[0036] In a third embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by formula (III), or a pharmaceutically acceptable salt thereof:wherein the variables are as described above for Formula (I).

[0037] In a fourth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by formula (IV), or a pharmaceutically acceptable salt thereof:wherein the variables are as described above for Formula (I).

[0038] In a fifth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by formula (V), or a pharmaceutically acceptable salt thereof:wherein the variables are as described above for Formula (I).

[0039] In a sixth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by formula (VI), or a pharmaceutically acceptable salt thereof:Owherein the variables are as described above for Formula (I).

[0040] In a seventh embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by formula (VII), or a pharmaceutically acceptable salt thereof:(VII),wherein the variables are as described above for Formula (I).

[0041] In an eighth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by formula (VIII), or a pharmaceutically acceptable salt thereof:wherein the variables are as described above for Formula (I).

[0042] In a ninth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by any one of formulae (I)-(VIII), or a pharmaceutically acceptable salt thereof wherein:

[0043] Ar1is optionally substituted by one or more groups represented by R3;

[0044] Ar2is optionally substituted by one or more groups represented by R2;

[0045] each R2is independently halo, CN, ORd, NReRd, S(O).jRd, NReS(O).jRd, S(O).jNReRd, C(=O)ORd, OC(=O)ORd, C(=S)ORd, O(C=S)Rd, C(=O)NReRd, NReC(=O)Rd, C(=S)NReRd, NReC(=S)Rd, NRe(C=O)ORd, O(C=O)NReRd, NRe(C=S)ORd, O(C=S)NReRd, NRf(C=O)NReRd, NRf(C=S)NReRd, C(=S)Rd, C(=O)Rd, Ci-Cs alkyl, (CH2)yC3-C7cycloalkyl, (CH2)yphenyl, (CH2)y(3-7 membered heterocyclyl) or (CH2)y(5-6 membered heteroaryl), wherein the Ci.Cs alkyl, (CH2)yC3-C? cycloalkyl, (CH2)yphenyl, (CH2)y(3-7 membered heterocyclyl) and (CH2)y(5-6 membered heteroaryl) are optionally substituted with one or more groups selected from halo, Ci- Csalkyl, Ci-Csalkoxy, Ci-Cshaloalkoxy, Ci-Cshaloalkyl, cyano and SO2(Ci-C3alkyl);

[0046] each R3is independently halo, CN, ORg, NRhRg, S(O)kRg, NRhS(O)kRg, S(O)kNRhRg, C(=O)ORg, OC(=O)ORg, C(=S)ORg, O(C=S)Rg, C(=O)NRhRg, NRhC(=O)Rg, C(=S)NRhRg, NRhC(=S)Rg, NRh(C=O)ORg, O(C=O)NRhRg, NRh(C=S)ORg, O(C=S)NRhRg, NRi(C=O)NRhRg, NRi(C=S)NRhRg, C(=S)Rg, C(=O)Rg, Ci-C6alkyl, (CH2)ZC3-C7cycloalkyl, (CH2)zphenyl, (CH2)z(3-7 membered heterocyclyl) or (CH2)z(5-6 membered heteroaryl), wherein the Ci-Cs alkyl, (CH2)ZC3-C7cycloalkyl, (CH2)zphenyl, (CH2)z(3-7 membered heterocyclyl) and the (CH2)Z(5-6 membered heteroaryl) are optionally substituted with one or more groups selected from halo, Ci-Csalkyl, Ci-Csalkoxy, Ci-Cshaloalkoxy, Ci-Cshaloalkyl, cyano and SO2(Ci-C3alkyl);

[0047] each Rdand Rgis independently selected from H, Ci-Csalkyl, C2-C6alkenyl, (CH2)iPh, and SChCCi-Csalkyl), wherein said alkyl is optionally substituted with one or more R22;

[0048] each R22is independently selected from halo, CN, ORP, O(CH2)mORp, NRpRq, C(O)ORP, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more oxo;

[0049] Re, Rf, Rh, R1, Rpand Rqare each independently selected from -H, C1-C3 alkyl and Ci-C3 haloalkyl;

[0050] each j and k is independently 0, 1 or 2;

[0051] m is 2, 3, or 4;

[0052] each y and z is independently 0 or 1, and wherein the remainder of the variables are as described for Formula (I).

[0053] In a tenth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by any one of formulae (I)-(VIII), or a pharmaceutically acceptable salt thereof, wherein:

[0054] Ar1is phenylene, pyridylene, benzothienylene, quinoxalinylene, pyridazinylene, pyrazanylene, benzothiazolylene, pyrimidinylene, thienylene, thiazolylene, isothiazolylene, furanylene, naphthylene, benzofuranylene, benzothiazolylene, imdazo[l,2-a]pyridinylene, pyrazolylene, oxazolylene, isooxazolylene, quinazolinylene, imidazopyridinylene, benzimidazolylene, pyrrolylene or quinolinylene, each optionally substituted with one or more groups represented by R3;

[0055] Ar2is phenylene, pyridylene, benzothienylene, quinoxalinylene, pyridazinylene, pyrazanylene, benzothiazolylene, pyrimidinylene, thienylene, thiazolylene, isothiazolylene, furanylene, naphthylene, benzofuranylene, benzothiazolylene, imdazo[l,2-a]pyridinylene, pyrazolylene, oxazolylene, isooxazolylene, quinazolinylene, imidazopyridinylene, benzimidazolylene, pyrrolylene or quinolinylene, each optionally substituted with one or more groups represented by R2, and wherein the remainder of the variables are as described in the first or ninth embodiments.

[0056] In an eleventh embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by any one of formulae (I)-(VIII), or a pharmaceutically acceptable salt thereof, wherein Ar1is phenylene or pyridylene, each optionally substituted with one or more groups represented by R3; Ar2is phenylene or pyridylene, each optionally substituted with one or more groups represented by R2, and wherein the remainder of the variables are as described in the first or ninth embodiments.

[0057] In a twelfth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by any one of formulae (I)-(VIII), or a pharmaceutically acceptable salt thereof, wherein eachR2is independently ORd, halo, Ci-Csalkyl, CYC-cycloalkyl. CrC shaloalkyl. cyano, or SChCCi-Csalkyl); each R3is independently ORg, halo, Ci-Csalkyl, C\.C-cvcloalkvl. Ci-C shaloalkyl. cyano, or SChCCi-Csalkyl), and wherein the remainder of the variables are as described in any one of the first, ninth tenth, and eleventh embodiments.

[0058] In a thirteenth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by any one of formulae (I)-(VIII), or a pharmaceutically acceptable salt thereof, wherein:

[0059] each R2is ORd;

[0060] each Rdis independently selected from H and C1-C3 alkyl wherein alkyl is optionally substituted with one or more groups selected from CN, ORP, O(CH2)mORp, NRpRq, C(O)ORP, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more oxo;

[0061] each R3is independently selected from C 1 -C Jialoalkyl. C -Ckalkoxyl. Ci-Cshaloalkoxyl, O(CH2)n(CH=CH2), O(CH2)nPh, or OSO2(Ci-C3alkyl);

[0062] Rpand Rqare each independently selected from -H, C1-C3 alkyl and C1-C3 haloalkyl;

[0063] n is 1, 2, or 3, and wherein the remainder of the variables are as described in any one of the first, ninth tenth, eleventh, and twelfth embodiments.

[0064] In a fourteenth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by any one of formulae (I) -(VIII), or a pharmaceutically acceptable salt thereof, wherein:

[0065] R2is ORd;

[0066] Rdis C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from OMe, CN, C(O)OH, OCH2CH2OMe, -OCH2CH2OH, NEt2, imidazolyl, morpholinyl, pyrrolidinlyl, thiomorpholinyl, thiomorpholinyl 1 -oxide, and thiomorpholinyl 1,1-dioxide;

[0067] R3is C 1 -Cdialoalkyl. and wherein the remainder of the variables are as described in any one of the first, ninth tenth, eleventh, and twelfth embodiments.

[0068] In a fifteenth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by any one of formulae (I)-(VIII), or a pharmaceutically acceptable salt thereof, wherein:

[0069] R2is OMe, -OCH2CH2OMe, -OCH2CH2OH, -OCH2CH2CN, -OCH2CH2C(O)OH, - OCH2CH2OCH2CH2OMe, -OCH2CH2NEt2, or is represented by any one of the structures

[0071] R3is CF3, and wherein the remainder of the variables are as described in any one of the first, ninth tenth, eleventh, and twelfth embodiments.

[0072] In a sixteenth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by any one of formulae (I)-(VIII), or a pharmaceutically acceptable salt thereof, wherein R1is Ci-Cs alkyl, optionally substituted with one or more groups independently selected from halo, Ci-Csalkyl, C;-C -cycloalkyl. Ci-Csalkoxy, C i -C shaloalkoxy. C i -C shaloalkyl. cyano, and SChCCi-Csalkyl), and wherein the remainder of the variables are as described in any one of the first, ninth tenth, eleventh, twelfth, thirteenth, fourteenth, and fifteenth embodiments.

[0073] In a seventeenth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by any one of formulae (I)-(VIII), or a pharmaceutically acceptable salt thereof, wherein R1is Ci-Cs alkyl, and wherein the remainder of the variables are as described in any one of the first, ninth tenth, eleventh, twelfth, thirteenth, fourteenth, and fifteenth embodiments.

[0074] In an eighteenth embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by any one of formulae (I)-(VIII), or a pharmaceutically acceptable salt thereof, wherein R1is isopropyl, and wherein the remainder of the variables are as described in any one of the first, ninth tenth, eleventh, twelfth, thirteenth, fourteenth, and fifteenth embodiments.

[0075] In a nineteenth embodiment, the serine palmitoyltransferase inhibitordisclosed herein is a compound represented by any one of formulae (I)-(VIII), or a pharmaceutically acceptable salt thereof, wherein L2is selected from C2-C6 alkenylene, C2-C6 alkenylene oxide, Ci-Cs alkylene, (CH2)XC3-C? cycloalkylene, or (CH2)x(3-7 membered heterocyclylene); wherein the Ci-Cs alkylene, (CHifCs-C- cycloalkylene, and (CH2)x(3-7 membered heterocyclylene) are optionally substituted with one or more groups selected from halo, ORa, NRaRb, S(O)iRa, NRaS(O)iRa, S(O)iNRaRb, C(=O)ORa, OC(=O)ORa, C(=S)ORa, O(C=S)Ra, C(=O)NRaRb, NRaC(=O)Rb, C(=S)NRaRb, NRaC(=S)Rb, NRa(C=O)ORb, O(C=O)NRaRb, NRa(C=S)ORb, O(C=S)NRaRb, NRa(C=O)NRbRc, NRa(C=S)NRbRc, C(=S)Ra, C(=O)Raand Ci-C6alkyl, and wherein theremainder of the variables are as described in any one of the first, ninth tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, and eighteenth embodiments.

[0076] In a twentieth embodiment, the serine palmitoyltransferase inhibitors disclosed herein is a compound represented by any one of formulae (I)-(VIII), or a pharmaceutically acceptable salt thereof, wherein:

[0077] L1is -*O(CH2)I-2-, wherein “*” indicates the point of attachment to Ar2;

[0078] L2is selected from C2-C6 alkenylene, C2-C6 alkenylene oxide and Ci-Cs alkylene; wherein the Ci-Cs alkylene and C2-C6 alkenylene are optionally substituted with one or more groups selected from halo, ORa, NRaRb, S(O)iRaand Ci-Cs alkyl;

[0079] L3is -*O(CH2)I-2-, wherein “*” indicates the point of attachment to Ar1, and wherein the remainder of the variables are as described in any one of the first, ninth tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, and nineteenth embodiments.

[0080] In a twenty -first embodiment, the serine palmitoyltransferase inhibitor disclosed herein is a compound represented by any one of formulae (I)-(VIII), or a pharmaceutically acceptable salt thereof, wherein:

[0081] L1is -*O(CH2)-, wherein “*” indicates the point of attachment to Ar2;

[0082] L2is -(CH=CH)- or is represented by

[0083] \ , or XH;

[0084] L3is -*O(CH2)-, wherein “*” indicates the point of attachment to Ar1, and wherein the remainder of the variables are as described in any one of the first, ninth tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, and nineteenth embodiments.

[0085] Another embodiment of the invention is the compounds disclosed in the Exemplification, both pharmaceutically acceptable salts thereof and the free form, including the compounds shown below or pharmaceutically acceptable salts thereof:Definitions

[0086] “Alkyl”, used alone or as part of a larger moiety, such as “alkoxy”, “haloalkyl”, and the like, means saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-6 carbon atoms, i.e. (C i-Gjalkyl. A “(C -Gjalkyl" group is a radical having from 1 to 6 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like.

[0087] "Alkenyl" refers to a branched or unbranched hydrocarbon group containing at least one double bond. Unless otherwise specified, an alkenyl group comprises 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Representative examples of alkenyl include, but are not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-methypropenyl, 2-methypropenyl, 3-methypropenyl and the like.

[0088] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by -O alkyl. For example, “(Ci-C4)alkoxy” includes methoxy, ethoxy, propoxy, and butoxy.

[0089] “Carbocycle” or “carbocyclyl” means a fully saturated, partially saturated or unsaturated C3-C10 monocyclic or bicyclic ring having only carbon ring atoms. In another embodiment, the carbocyclyl is a C3-C7 cycloalkyl. “Cycloalkyl” refers to a completely saturated monocyclic or bicyclic hydrocarbon ring. The bicyclic carbocycles may be bridged, fused or spirocyclic ring systems. The C3-C10 carbocyclyl groups include fully saturated cycloalkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl rings; partially saturated carbocyclyl groups such as cyclopropene, cyclobutene, cyclopentene and cyclohexene rings; bicyclic moieties such as indene, 2,3-dihydro-indene and 1 ,2,3,4-tetrahydronaphthalene groups; bridged moieties such as bicyclo[3.1.0]hexane,bicyclo [3.2.1] octane andbicyclo[3.1.1]heptane groups; and spirocyclic carbocycles, such as spiro [2.3] hexane, spiro[2.4]hexane, spiro[3.3]heptane, spiro [3.4] octane, spiro[2.5]octane, spiro[4.5]decane and spiro[5.5]hendecane. Unsaturated carbocyclic moieties include phenyl and naphthyl groups.

[0090] The terms heterocycle or heterocyclyl used herein indicates a non-aromatic fully saturated or partially saturated 3- to 12-membered monocyclic or bicyclic ring having from 1 to 5 ring heteroatoms selected from O, S or N. In another embodiment, the heterocyclyl is a C3-C7 cyclic group with one or two heteroatoms selected from O, S or N. Bicyclic heterocycles may be bridged, fused or spirocyclic ring systems. Bicyclic heterocycles also include fused rings in whicha monocyclic heterocyclyl is fused to phenyl or to monocyclic heteroaryl. Heterocyclyl examples include, but are not limited to, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, azapanyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, oxapanyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, 3-aza-bicylco[3.2.1]octane, 2-aza-bicylco[2.2.1]heptane, octahydrocyclopentapyrrole, aza-bicyclo-nonane, indoline, dihydroindazole, isoindoline, tetrahydroindolizine, octahydro-isoindole, 4, 5,6,7-tetrahydropyrazolopyridine, 2-azaspiro[4.5]decane, 6-azaspiro[2.5]octane, 7-azaspiro[3.5]nonane, 8-azaspiro[4.5]decane, 3-asaspiro[5.5]undecane, l-oxa-7-azaspiro[4.4]nonane and l-oxa-8-azaspiro[4.5]decane.

[0091]

[0092] “Spiro”, “spirocycle” or “spirocyclic” refer to a group with two rings joined by a ring carbon atom common to both.

[0093] “Heteroaryl” refers to a 5-10 membered monocyclic or bicyclic aromatic group with 1, 2, 3 or 4 (alternatively 1 or 2) ring heteroatoms selected from N, S or O. “Heteroaryl” includes monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other aromatic or heteroaromatic rings. Examples of monocyclic 5-6 membered heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5 -pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), and thienyl (e.g., 2-thienyl, 3-thienyl). Examples of bicyclic aromatic heteroaryl groups include benzimidazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, or benzisoxazolyl.

[0094] The suffix “-ene” refers to a bivalent group, i.e. a group connected to the remainder of the molecule at two points. For example, “alkylene” refers to a fully saturated hydrocarbon group connected to the remainder of the molecule at two points. Unless otherwise specified, an alkylene has from 1-6 carbone atoms. “Alkenylene” refers to an alkenyl group connected to the remainder of the molecule at two points. Unless otherwise specified, an alkenylene has from 2-6 carbone atoms. “Heterocyclylene” refers to a heterocyclyl group connected to the remainder of themolecule at two points. “Heteroarylene” refers to a heteroaryl group connected to the remainder of the molecule at two points. “Phenylene” refers to a phenyl group connected to the remainder of the molecule at two points. “Cycloalkylene” refers to a cycloalkyl group connected to the remainder of the molecule at two points.

[0095] “Alkenylene oxide” refers to an alkenylene group in which the double bond has been replaced by an epoxide, e.g, a C2-C6 alkenylene oxide has the following structure, wherein nandm are 0, 1, 2, 3 or 4 such that n + m is less than or equal to 6:Jn L Jm Unless otherwise specified, an alkenylene oxide has from two to six carbon atoms.

[0096] “Fused” refers to two rings joined by two adjacent ring atoms common to both.

[0097] “Bridged”” refers to two rings joined by three adjacent ring atoms common to both.

[0098] “Halogen” refers to fluoro, chloro, bromo, or iodo. The term “haloalkyl” refers to an alkyl group having from one halogen substituent to the maximum number of halogen substituents allowed by valence requirements. Examples include -CH2F, -CF3, -CH2-CF3, -CF2-CF3, and the like. Preferably the halogen in a haloalkyl is F.

[0099] The term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl group. To illustrate, monofluoroalkyl is an alkyl substituted with a fluoro substituent, and difluoroalkyl is an alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated).

[0100] Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.

[0101] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined bydividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0102] When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

[0103] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0104] Compounds having one or more alkene can exist in various stereoisomeric forms, i.e., each alkene can have a Z or E configuration, or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include both Z and E forms of an alkene. Z alkenes are arranged such that the highest priority functional groups (IUPAC rules) on adjacent alkene carbon atoms are on the same side of the carbon-carbon double bond. E alkenes are arranged such that the highest priority functional groups on adjacent alkene carbon atoms are on opposite sides of the carbon-carbon double bond.

[0105] When the stereochemical configuration in a compound having one or more alkene groups is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “Z” or “E”) or by its drawn structure, the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%

[0106] Included in the present disclosure are pharmaceutically acceptable salts of Compound (I). The disclosed compound has basic amine groups and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methane sulfonic, succinic, p-toluenesulfonic, and tartaric acids). Compounds of the invention with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptablebase(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates (between Compound (I) and maleic acid is 1 : 1 or 2: 1), acetates, citrates, fumarates (molar ratio of between Compound (I) and fumaric acid is 1 : 1 or 2: 1), tartrates [e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid.

[0107] The disclosed compounds can be used in a method of treating a subject with a disease characterized by elevated ceramide levels or a disease or condition that is mediated by serine palmitoyltransferase. Diseases characterized by elevated ceramide levels or diseases or conditions that are mediated by serine palmitoyltransferase include muscle disorders such as muscular dystrophies, inflammatory myopathies, metabolic myopathies, myofibrillar myopathies, sarcopenia and muscle wasting diseases.

[0108] Muscular dystrophies treatable with the disclosed compounds include Myotonic Muscular Dystrophy (also called MMD or Steinert's disease - type 1 (DM1)), Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Limb-Girdle Muscular Dystrophy, Facioscapulohumeral Dystrophy (FSHD), Congenital Muscular Dystrophy, Oculopharyngeal Muscular Dystrophy (OPMD), Distal Muscular Dystrophy and Emery-Dreifuss Muscular Dystrophy. In one particular aspect, the disclosed compounds are used to treat Duchenne Muscular Dystrophy.

[0109] Inflammatory myopathies treatable by the disclosed compounds include polymyositis, dermatomyositis, inclusion body myositis, necrotizing autoimmune myopathy and Inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB) and frontotemporal dementia (FID) (now called IBMPFD).

[0110] Mitochondrial myopathies are a group of neuromuscular diseases caused by damage to the mitochondria. Mitochondrial myopathies treatable by the disclosed compounds include Kearns-Sayre syndrome (KSS), Leigh syndrome, Mitochondrial DNA (mtDNA) depletion syndrome, Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, Mitochondrial neurogastrointestinal encephalopathy (MNGIE), Myoclonic epilepsy with ragged red fibers (MERRF), Neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome, Pearson syndrome, Progressive external ophthalmoplegia (PEO) and sarcopenia.

[0111] Sarcopenia is a condition characterized by involuntary loss of skeletal muscle mass and strength. It can be age related, which can begin as early as the 4th decade of life, with up to 50% of mass being lost by the 8th decade of life. Although sarcopenia occurs primarily as a consequence of aging, it can also occur secondary due to certain medical conditions includingchronic disease, malnutrition and inactivity. When associated with chronic and extreme inactivity caused by, for example, chronic heart failure, postoperative status after surgery, trauma, extended mechanical ventilation, longer hospital stays, and the like, this type of sarcopenia is sometimes referred to as “ICU Sarcopenia” or “ICU Associated W eakness”. The strength and functional declines associated with sarcopenia can contribute to a number of adverse health outcomes, including loss of function, disability, and frailty; it is also associated with acute and chronic disease states, increased insulin resistance, fatigue, falls, and mortality as well as physical disability, poor quality of life and death.

[0112] The disclosed compounds can be used to improved muscle morphology in a subject in need thereof or to slow or reverse age-related loss of muscle mass, strength, endurance, and coordination. As muscle dysfunction is associated with chronic comorbidities, sarcopenic patients are often managed with a number of medications. Although multiple drug usage may be necessary to obtain satisfactory treatment outcomes for chronic disease, it simultaneously predisposes patients to adverse drug reaction, interactions, and prescription cascade. The disclosed compounds have the potential to reduce age associated polypharmacy, while providing effective treatment to chronic diseases. Given the involvement of sphingolipids in a number of diseases, targeting sphingolipid metabolism with the disclosed compound could produce benefits far beyond age-related muscle dysfunction, having the potential to moderate multiple dmg prescriptions. For example, in one aspect, the disclosed compounds can be used to treat frailty characterized by i) sarcopenia and / or muscle atrophy and ii) cognitive impairment.

[0113] Myofibrillar myopathies are a group of rare genetic neuromuscular disorders that may be diagnosed in childhood but most often appear after 40 years of age. These conditions are highly variable but are characterized by a slowly progressive muscle weakness that can involve skeletal and smooth muscle. Skeletal muscle weakness can be present in the muscles close to the center of the body (proximal) as well as the distal muscles. A weakening of the heart muscle (cardiomyopathy) is common and may manifest as arrhythmia, conduction defects or congestive heart failure. Myofibrillar myopathies treatable by the disclosed compounds include plectinopathy, desminopathy, a[3-crystallinopathy, myotilinopathy, filaminopathy, BAG3 -related myofibrillar myopathy, zaspopathy, nemaline myopathy (a congenital, often hereditary neuromuscular disorder with muscle weakness, hypoventilation, swallowing dysfunction, and impaired speech ability characterized by pathologic evidence of nemaline bodies (rods) on muscle biopsy).

[0114] The disclosed compounds can also be used to treat amyloidosis, which is a group of diseases that are a consequence of abnormal amyloid protein deposits in various tissues of the body. Depending on the structure of the particular amyloid, the protein can accumulate in anisolated tissue or be widespread, affecting numerous organs and tissues. Amyloid protein can be deposited in a localized area or may be systemic.

[0115] Systemic amyloidosis has been classified into three major types that are very different from each other. The major types of systemic amyloidosis are currently categorized as primary (now AL), secondary (AA), and hereditary (ATTR, amyloid apolipoprotein Al or AApoAI, amyloid apolipoprotein A2 or AApoAII, AGel, ALys, AFib). Amyloidosis that occurs as its own entity has been called primary amyloidosis. Secondary amyloidosis is amyloidosis that occurs as a byproduct of another illness, including chronic infections (such as tuberculosis or osteomyelitis), or chronic inflammatory diseases (such as rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease). Other forms of amyloidosis include P-2 microglobulin amyloidosis from chronic kidney dialysis and Familial amyloidosis (ATTR, (a rare form of inherited amyloidosis). Localized forms of amyloidosis include Alzheimer's disease, Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Straussler-Scheinker syndrome.

[0116] In another embodiment, the disclosed compounds can be used to treat Facioscapulohumeral Dystrophy, Oculopharyngeal Muscular Dystrophy, ICU sarcopenia, amyloidosis and age-related sarcopenia. In another embodiment, the disclosed compounds can be used to treat a -crystallinopathy, VCP disease and sporadic inclusion body myositis. In yet another embodiment, the disclosed compound can be used to treat Facioscapulohumeral Dystrophy, myotonic dystrophy, Oculopharyngeal Muscular Dystrophy, VCP disease or inclusion body myositis. In yet another embodiment, the disclosed compound can be used to treat mitochondrial myopathies, ICU sarcopenia, age related sarcopenias, aP-crystallinopathy, nemaline myopathy, myofibrillar myopathies and amyloidosis.

[0117] In another embodiment, the disclosed compounds can be used to treat missense storage disorders, also referred to as lysosomal storage diseases. Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body's cells as a result of enzyme deficiencies. Examples that can be treated with the disclosed compound include Aspartylglucosaminuria, Batten Disease, Cystinosis, Fabry Disease, Gaucher Disease Types I, II, and III, Glycogen Storage Disease II (Pompe Disease), GM2-Gangliosidosis Type I (Tay Sachs Disease), GM2-Gangliosidosis Type II (Sandhoff Disease), Metachromatic Leukodystrophy, Mucolipidosis Types I, II / III and IV, Mucopolysaccharide Storage Diseases (Hurler Disease and variants, Hunter, Sanfilippo Types A,B,C,D, Morquio Types A and B, Maroteaux-Lamy and Sly diseases), Niemann-Pick Disease Types A / B, Cl and C2 and Schindler Disease Types I and II.

[0118] In another embodiment, diseases and conditions that are treatable by inhibition of serine palmitoyltransferase or are mediated by serine palmitoyltransferase include heart diseases (cardiomegaly, acute heart failure and chronic heart failure including congestive heart failure,cardiomyopathy, angina pectoris, myocarditis, arrhythmia, tachycardia, myocardial infarction, etc.), myocardial ischemia, venous insufficiency, post-myocardial infarction heart failure, hypertension, cor pulmonale, arteriosclerosis including atherosclerosis (aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular hypertrophy, vascular hypertrophy or occlusion and organ disorder after intervention (percutaneous transluminal coronary angioplasty, stent placement, coronary angioscopy, intravascular ultrasonography, intracoronary thrombolytic therapy, etc.), vascular reocclusion or restenosis after bypass surgery, respiratory diseases (acute pulmonary disorder), bone diseases (non-metabolic bone diseases such as fracture, refracture, bone deformity or osteoarthritis, osteosarcoma, myeloma, dysostosis, scoliosis and the like; bone defect, osteoporosis, osteomalacia, rachitis, osteitis fibrosa, renal osteodystrophy, Behcet's disease in bone, ankylosing spondylitis, chronic rheumatoid arthritis, osteoarthritis knees and destruction of joint tissues in similar diseases thereto, etc.), diabetic complications (retinopathy, nephropathy, neuropathy, macro angiopathy, etc.), chronic rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy, etc.), central nervous system disorders (disorders such as cerebral hemorrhage and cerebral infarction and the like, and sequelae or complications thereof, spinal cord injury, cerebral edema, encephalomyelitis, etc.), dementia, dysmnesia, impaired consciousness, amnesia, anxiety symptoms, myotonia symptoms, ischemic peripheral circulatory disturbance, deep vein thrombosis, obstructive peripheral circulatory disturbance, arteriosclerosis obliterans, thromboangiitis obliterans, diabetic complications (neuropathy, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia, diabetic hyperosmolar coma, infection, diabetic gangrene, oral dryness, decline in hearing, cerebrovascular accident, peripheral arterial disease, etc.), disturbance of metabolism or malnutrition (hyperlipidemia, hypercholesterolemia, low-HDL cholesterol, impaired glucose tolerance, etc.), insulin resistance syndrome, syndrome X, metabolic syndrome, cerebrovascular accident (asymptomatic cerebrovascular accident, transient ischemic attack, cerebral apoplexy, vascular dementia, hypertensive encephalopathy, cerebral infarction, etc.), cerebral edema, cerebral circulatory disturbance, recurrence and sequelae of cerebrovascular accident (neurological signs, mental signs, subjective symptoms, disturbance in activities of daily living, etc.), renal diseases (nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, diabetic nephropathy, nephrotic syndrome, hypertensive nephrosclerosis, complications of dialysis, organopathy including nephritis caused by radiation, etc.), eye diseases (glaucoma, ocular hypertension, etc.), thrombosis, multiple organ failure, endothelial dysfunction, hepatic diseases (hepatitis including hepatitis C, liver cirrhosis, etc.), gastrointestinal diseases (gastritis, gastric ulcer, stomach cancer, disorders after gastric surgery, esophageal ulcer, pancreatitis, colorectal polyp, cholelithiasis, inflammatory bowel disease (IBD), etc.), blood or hematopoietic diseases (polycythemia, vascular purpura, disseminatedintravascular coagulation, multiple myeloma, etc.), urological or male genital diseases (cystitis, benign prostatic hyperplasia, sexually transmitted disease, etc.), gynecological diseases (climacteric disorder, gestosis, endometriosis, ovarian disease, mammary gland disease, sexually transmitted disease, etc.), infectious diseases (viral infection caused by cytomegalovirus, influenza virus, herpes virus or the like, rickettsial infection, bacterial infection, etc.), toxemia (sepsis, septic shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, etc.), congenital diseases associated with sphingolipid accumulation (Fabry disease, Niemann-Pick disease (e.g., types A, B, C, D), Gaucher disease, Tay-Sachs disease)), skin diseases (contact dermatitis, etc.), painful affection (acute and chronic pain, persistent pain (alganesthesia, analgesia, etc.), etc.), inflammation-related diseases and immune-related diseases.

[0119] In another aspect, diseases and conditions treatable by inhibition of serine palmitoyltransferase or mediated by serine palmitoyltransferase include type 2 diabetes, type 1 diabetes, insulin resistance, the effects of obesity, metabolic syndrome (sometimes referred to as Syndrome X), impaired glucose tolerance, Cushing's disease, cardiovascular disease, prothrombotic conditions, myocardial infarction, hypertension, congestive heart failure, cardiomyopathy, atherosclerosis, dyslipidemia, sepsis, liver damage (e.g., from viral, alcohol related or reperfusion injuries), retinal degenerative disorders, cachexia, emphysema, hepatitis C infections, HIV infections and inflammatory disorders and useful in methods for raising HDL plasma levels in a mammal. The compounds of this invention can also be used to prevent damage or loss of pancreatic islet beta cells (such as in the case of pancreatic beta cell apoptosis, including those related to insulin-dependent diabetes mellitus).

[0120] In another aspect, diseases and conditions treatable by inhibition of serine palmitoyltransferase or mediated by serine palmitoyltransferase include diabetes (type 1 and type 2 diabetes), particularly diabetic neuropathy, neurodegenerative diseases such as hereditary and sensory neuropathy type I (HSAN1 ), amyotrophic lateral sclerosis (ALS), Alzheimer disease, other neurological disorders (e.g. depressive disorders, schizophrenia), medication-induced neuropathies (e.g. induced by treatment with cytostatics like paclitaxel, cis-platin compounds etc.) and other metabolic disorders such as glycogen storage disease type 1 a and asthma.

[0121] The compounds disclosed herein additionally can be used for lowering plasma lipids, elevating high density lipoprotein (HDL) particles, lowering very low density lipoprotein (VLDL) particles and low density lipoprotein (LDL) particles, lowering plasma triglyercides particles, lowering serum levels of total cholesterol, improving plasma lipid profile, inhibiting plaque formation, reducing the size of plaque, reducing the size of an atherosclerotic lesion, reducing the size of a macrophage foam cell, preventing plaque rupture and treating dyslipidemia, atherosclerosis, diabetes, metabolic syndrome and treating inflammation. In another aspect, thedisclosed compounds can be used for treating cardiovascular or cerebrovascular disease or acute clinical vascular events in a subject.

[0122] The compounds of the present invention can be used in the treatment of cancer. Included, for example, are large intestine cancer (e.g., colon cancer, rectal cancer, anus cancer, familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lung cancer (lung adenocarcinoma, etc.), small-cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., ductal pancreatic cancer, pancreatic endocrine tumor), throat cancer, voice box cancer, head and neck cancer, esophageal cancer, stomach cancer (e.g., papillary adenocarcinoma, mucous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestine cancer, breast cancer (e.g., invasive ductal breast cancer, noninvasive ductal breast cancer, inflammatory breast cancer), ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian tumor of low malignant potential), testicular tumor, prostate cancer (e.g., hormonedependent prostate cancer, hormone-independent prostate cancer, castration-resistant prostate cancer), liver cancer (e.g., hepatocellular cancer, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid cancer), kidney cancer (e.g., renal cell cancer (e.g., clear cell renal cell carcinoma), transitional cell cancer of the renal pelvis and ureter), uterine cancer (e.g., uterine cervical cancer, uterine body cancer, uterine sarcoma), gestational choriocarcinoma, brain tumor (e.g., medulloblastoma, glioma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (e.g., basalioma, malignant melanoma), sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma), malignant bone tumor, bladder cancer, blood cancer (e.g., multiple myeloma, leukemia, malignant lymphoma, Hodgkin disease, chronic myeloproliferative disease), primary unknown cancer], a cancer growth inhibitor, a cancer metastasis inhibitor, an apoptosis promoter, a therapeutic agent for premalignant lesions (e.g., myelodysplastic syndrome) or the like.

[0123] An “effective amount” means an amount which, when administered to the subject, results in beneficial or desired results, including clinical results, e.g. , inhibits, suppresses or reduces the symptoms of the disease or condition in a subject, slowing or reversing the progression of the disease or condition or ameliorating or improving a clinical symptom or indicator associated with the disease or condition.

[0124] Generally, an effective amount of a compound of the invention varies depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. An effective amount of a compound of the present invention may be readily determined by one of ordinaryskill by routine methods known in the art. In one embodiment, an effective amount of a compound of the invention ranges from about 0.01 to about 1000 mg / kg body weight per day. The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject with a disease or condition, and these factors include, but are not limited to, the severity of the disease or disorder, previous treatments, the general health and / or age of the subject and other diseases present.

[0125] “Subject” refers to a mammal in need of treatment, but is most commonly a human in need of treatment. Subjects can also include veterinary animals (horses, cows, pigs, goats, sheep and the like), companion animals (dogs, cats, and the like) and laboratory animals (rats, mice, guinea pigs and the like).

[0126] In some embodiments, the disclosure provides a pharmaceutical composition comprising a disclosed compound and / or a pharmaceutically acceptable salt thereof and at least one additional pharmaceutically acceptable excipient. The term “pharmaceutically acceptable excipient,” as used herein, refers to a pharmaceutically acceptable material, composition, and / or vehicle, such as a liquid or solid fdler, diluent, excipient, solvent, or encapsulating material. Each excipient must be “pharmaceutically acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient. Except insofar as any conventional pharmaceutically acceptable excipient is incompatible with a compound of the invention and / or pharmaceutically acceptable salts thereof, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure.

[0127] The disclosed compounds can be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The disclosed compounds may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.

[0128] The disclosed compounds can be suitably formulated into pharmaceutical compositions for administration to a subject. The pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and / or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook ofPharmaceutical Excipients (5thEd., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF 19) published in 1999. The carriers, diluents and / or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0129] Typically, for oral therapeutic administration, a disclosed compound may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0130] Typically for parenteral administration, solutions of a compound used in the disclosed methods can generally be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0131] Typically, for injectable use, sterile aqueous solutions or dispersion of, and sterile powders of, a compound used in the disclosed methods for the extemporaneous preparation of sterile injectable solutions or dispersions are appropriate.EXEMPLIFICATION

[0132] The starting material in each scheme can be prepared according to methods in US20180170874, the entire teachings of which are incorporated herein by reference. The variables in Schemes 1-8 have the same definitions as in Formula (I) above. Those skilled in the art will recognize that alternative methods are available for effecting the transformations shown in the Schemes. These include but are not limited to the substitution of Ar2NHC(O)Cl or Ar1NHC(O)Cl with Ar2N=C=O or Ar1N=C=O, respectively. Ar2N=C=O or Ar1N=C=O can be prepared by reacting Ar2NH2or Ar1NH2, respectively, with triphosgene in the presence of triethyl amine. Additionally, HATU can be replaced with carbonyl diimidazole, diphenyl carbonate, or bis(4-nitrophenyl) carbonate.

[0133] The invention is illustrated by the following examples, which are not intended to be limiting in any way.Table 1: Structure, Purity and1H-NMR dataCompound Structure LCMS 1H-NMR (400 MHz) in code and Chiral DMSO-d6HPLC5 ppm: 9.08-9.02 (m, 1H), 8.02 (m, 1H), 7.80 (s, 1H), LCMS:7.33-7.11 (m, 3H), 6.84 (s, m / z:1H), 6.04-5.99 (m, 1H), 572.605.39 (m, 1H), 5.30-5.17 [M+l]+,(m, 1H), 5.10-5.06 (m, SI-001 98.11%1H), 4.79-4.75 (m, 1H), (RT: 7.054.50-4.40 (m, 3H), 4.22 min)(m, 1H), 3.74 (s, 3H), 3.56 Method A(m, 1H), 2.33-2.28 (m, 1H), 1.95 (m, 1H), 1.39- 1,34 (m, 6H). _5 ppm: 9.07 (d, J = 8.4 Hz, 1H), 8.02 (m, 1H), 7.80 (s, LCMS: 1H), 7.29 (d, J = 8.4 Hz, m / z: 1H), 7.18-7.10 (m, 2H), 572.60 6.84 (s, 1H), 6.03-5.99 (m, [M+l]+, 1H), 5.40 (m, 1H), 5.20- SI-002 97.97% 5.17 (m, 1H), 5.10-5.06(RT: 6.94 (m, 1H), 4.79-4.75 (m, min) 1H), 4.50-4.39 (m, 3H), Method A 4.21 (m, 1H), 3.74 (m,4H), 2.33-2.28 (m, 1H), 1.95 (m, 1H), 1.39-1.34 (m, 6H), _5 ppm: 9.07 (d, J = 8.4 Hz, 1H), 8.02 (m, 1H), 7.80 (s, LCMS: 1H), 7.29 (d, J = 8.8 Hz, m / z: 1H), 7.18-7.10 (m, 2H), 572.51 6.84 (s, 1H), 6.03-5.99 (m, [M+l]+, 1H), 5.40 (m, 1H), 5.20- SI-003 98.34% 5.17 (m, 1H), 5.10-5.06(RT: 6.94 (m, 1H), 4.79-4.75 (m, min) 1H), 4.50-4.39 (m, 3H), Method A 4.21 (m, 1H), 3.74 (m,4H), 2.33-2.28 (m, 1H), 1.96 (m, 1H), 1.39-1.34(m, 6H).5 ppm: 9.12-9.08 (m, 1H),7.48 (m, 1H), 7.72 (s, 1H), 0 CF3LCMS: 7.47 (t, J = 9.2 Hz, 1H), m / z: 7.35-7.29 (m, 2H), 6.76 (s, 600.39 1H), 6.07-5.94 (m, 2H), [M+l]+, 5.44-5.39 (m, 2H), 5.29 (d, SI-004 94.83% J= 10.4 Hz, 1H), 5.12 (d,N J(RT: 6.66 J = 10.4 Hz, 1H), 4.95- min) 4.70 (m, 5H), 4.47-4.44 Method A (m, 1H), 4.18-4.14 (m, N CK1H), 3.94 (m, 1H), 3.79 (m, 3H), 2.06-1.98 (m, H C HJ00 yu— 2H), 1.42-1.39 (m, 6H).LCMS: 5 ppm: 9.08 (d, J = 8.4Hz, m / z: 1H), 8.01 (m, 1H), 7.71 (s,x600.34 1H), 7.49-7.46 (m, 1H),[M+l]+, 7.30-7.28 (m, 1H), 6.76 (s, 95.96% 1H), 6.07-5.94 (m, 2H), (RT: 6.69 5.43-5.39 (m, 2H), 5.29 (d, min) J= 10.4 Hz, 1H), 5.12 (d, SI-005Method A J = 10.4 Hz, 1H), 4.95- Chiral 4.70 (m, 5H), 4.46-4.43 HPLC: (m, 1H), 4.17-4.14 (m, Method A 1H), 3.78-3.73 (m, 4H), (RT: 38.59 2.06-1.96 (m, 2H), 1.42- min) 1.38 (m, 6H).LCMS: 5 ppm: 9.08 (d, J = 8.4Hz, m / z: 1H), 8.01 (m, 1H), 7.71 (s, 600.43 1H), 7.49-7.46 (m, 1H), 0 CF3[M+l]+- 7.30-7.28 (m, 1H), 6.76 (s,94.73% 1H), 6.07-5.94 (m, 2H), (RT: 6.69 5.43-5.39 (m, 2H), 5.29 (d, min) J= 10.4 Hz, 1H), 5.12 (d, SI-006 V \X C J - Method A J = 10.4 Hz, 1H), 4.95- N Chiral 4.70 (m, 5H), 4.46-4.43HPLC: (m, 1H), 4.17-4.14 (m, Method A 1H), 3.78-3.73 (m, 4H), N C< (RT: 46.58 2.06-1.96 (m, 2H), 1.42- min) 1.38 (m, 6H).5 ppm: 9.06 (d, J = 8.0 Hz,1H), 8.00-7.95 (m, 1H), LCMS: 7.73 (s, 1H), 7.47 (d, J = m / z: 8.4 Hz, 1H), 7.28-7.25 (m, 604.37 2H), 6.72 (s, 1H), 5.40 (s, [M+l]+- 1H), 4.45 (m, 1H), 4.17- SI-007 95.54% 4.14 (m, 2H), 4.05-4.02(RT: 3.25 (m, 3H), 3.77-3.73 (m, min) 4H), 2.01-1.99 (m, 2H), Method B 1.78-1.62 (m, 4H), 1.42- 1.39 (m, 6H), 0.98 (t, J = 7.6 Hz, 3H), 0.77 (t,J= 7.2 Hz, 3H).5 ppm: 9.06 (d, J = 8.0 Hz, 1H), 8.00-7.95 (m, 1H), 7.73 (s, 1H), 7.47 (d, J = o CF3LCMS:8.4 Hz, 1H), 7.28-7.25 (m, m / z:2H), 6.72 (s, 1H), 5.41- 604.765.39 (m, 1H), 4.48-4.42 [M+l]+-N(m, 1H), 4.21-4.14 (m, SI-008 Ul 97.61%N J 1 ft A O O00- 3 \° 2H), 4.05-4.02 (m, 3H),(RT: 3.283.77-3.73 (m, 4H), 2.01- min)1.99 (m, 2H), 1.78-1.62 N^CK Method B(m, 4H), 1.42-1.39 (m, 6H), 0.98 (t, J = 7.6 Hz, Cfi • 3H), 0.77 (t, J = 7.2 Hz, / z' 3H).5 ppm: 9.06 (d, J = 8.0 Hz, 1H), 8.00-7.95 (m, 1H), 7.73 (s, 1H), 7.47 (d, J = o CF3LCMS:8.4 Hz, 1H), 7.28-7.25 (m, m / z:2H), 6.72 (s, 1H), 5.41- 604.805.39 (m, 1H), 4.48-4.42 [M+l]+- (m, 1H), 4.21-4.14 (m, SI-009 I MXL. J*- 96.78%N 2H), 4.05-4.02 (m, 3H),(RT: 3.283.77-3.73 (m, 4H), 2.01- min)^rio^ 1.99 (m, 2H), 1.78-1.62 N C< Method B(m, 4H), 1.42-1.39 (m, 6H), 0.98 (t, J = 7.6 Hz, 3H), 0.77 (t, J = 7.2 Hz,3H).5 ppm: 9.17 (d, J = 8.4Hz,1H), 7.97-7.95 (m, 1H), 0 OCF3LCMS:7.64-7.55 (m, 3H), 7.49- m / z:7.43 (m, 2H), 7.10 (s, 1H), 560.546.05-5.99 (m, 1H), 5.42 [M+l]+- (m, 1H), 5.14 (d, J= 10.8 SI-010 'vl J 95.85%N Hz, 1H), 4.99-4.93 (m,(RT: 6.083H), 4.48-4.45 (m, 1H), min)4.23-4.20 (m, 1H), 3.81- Method AN C< 3.76 (m, 4H), 2.10-1.99(m, 2H), 1.41-1.37 (m, 6H).LCMS: 5 ppm: 9.17 (d, J= 8.0 Hz, m / z: 1H), 7.98 (m, 1H), 7.64- 560.45 7.55 (m, 3H), 7.48-7.45 0 OCF3[M+l]+- (m, 2H), 7.10 (s, 1H), 6.03- 99.78% 6.02 (m, 1H), 5.42 (m, (RT: 6.08 1H), 5.14 (d, J = 9.6 Hz, min) 1H), 4.99-4.93 (m, 3H), SI-011N J Method A 4.48-4.46 (m, 1H), 4.23- Chiral 4.20 (m, 1H), 3.80-3.76 <AQ°^ HPLC: (m, 4H), 2.10-2.03 (m, N C / Method B 2H), 1.41-1.37 (m, 6H).(RT: 20.23min)LCMS: 5 ppm: 9.17 (d, J = 8.0Hz, m / z: 1H), 7.98 (m, 1H), 7.64- 560.45 7.55 (m, 3H), 7.49-7.43 0 OCF3[M+l]+- (m, 2H), 7.10 (s, 1H), 6.07- 99.43% 5.98 (m, 1H), 5.43-5.42 (RT: 6.08 (m, 1H), 5.14 (d, J= 10.0 min) Hz, 1H), 4.99-4.93 (m, SI-012NCL N J Method A 3H), 4.48-4.45 (m, 1H),Chiral 4.23-4.20 (m, 1H), 3.81- HPLC: 3.73 (m, 4H), 2.10-1.99 N^C< Method B (m, 2H), 1.41-1.37 (m,(RT: 23.96 6H).min)5 ppm: 9.21 (d, J = 8.0Hz, o CF3HRMS:1H), 8.06 (m, 1H), 7.82- TOF m / z:7.63 (m, 4H), 7.51 (d, J = 517.727.20 Hz, 1H), 7.35 (s, 1H), [M+l]+- 5.42-5.41 (m, 1H), 4.48- SI-013 \X N J 99.56%4.45 (m, 1H), 3.87 (s, 3H), (RT: 5.183.82 (s, 3H), 3.67 (m, 2H), min)2.14-2.08 (m, 1H), 2.00- Method AN O'' 1.96 (m, 1H), 1.42-1.41(m, 6H).HRMS: 5 ppm: 9.21 (d, J = 8.4Hz,TOF m / z: 1H), 8.05 (m, 1H), 7.82- 517.76 7.63 (m, 4H), 7.51 (d, J = [M+l]+- 7.60 Hz, 1H), 7.35 (s, 1H), 99.80% 5.42 (m, 1H), 4.48-4.45 (RT: 5.06 (m, 1H), 3.92 (s, 3H), 3.82 min) (s, 3H),3.67(m, 2H),2.14- SI-014Method A 2.11 (m, 1H), 2.00-1.96 Chiral (m, 1H), 1.42-1.41 (m, HPLC: 6H).Method C(RT: 22.78min)HRMS: 5 ppm: 9.21 (d, J = 8.0Hz, TOF m / z: 1H), 8.06 (m, 1H), 7.82- 0 CF3517.76 7.63 (m, 4H), 7.51 (d, J =[M+l]+- 7.60 Hz, 1H), 7.35 (s, 1H), \ / 99.91% 5.42-5.41 (m, 1H), 4.48- i ft o o — (RT: 5.07 4.45 (m, 1H), 3.92 (s, 3H), SI-015 min) 3.82 (s, 3H), 3.67 (m, 2H),N JMethod A 2.13 (m, 1H), 2.00-1.96 Chiral (m, 1H), 1.42-1.41 (m, HPLC: 6H).4? N C< Method C1 z (RT: 27.471z' min)5 ppm: 9.10 (d, J= 7.6 Hz, 1H), 8.06 (m, 1H), 7.82 (s, LCMS:1H), 7.64-7.44 (m, 1H), m / z:7.35-7.28 (m, 3H), 6.07- 574.415.98 (m, 1H), 5.43-5.39 [M+l]+- (m, 2H), 5.29 (d, J= 10.4 SI-016 99.29%Hz, 1H), 4.71-4.69 (m, (RT: 6.032H), 4.47-4.44 (m, 1H), min)3.92 (s, 3H), 3.82-3.68 (m, Method A5H), 2.13-2.08 (m, 1H), 1.98-1.95 (m, 1H), 1.41(m, 6H).LCMS: 5 ppm: 9.10 (d, J= 8.4 Hz, m / z: 1H), 8.06 (m, 1H), 7.82 (s, 574.50 1H), 7.64-7.44 (m, 1H), 0 CF, [M+l]+- 7.34-7.27 (m, 3H), 6.07- 99.99% 5.98 (m, 1H), 5.43-5.39 (RT: 6.02 (m, 2H), 5.28 (d, J= 10.8 min) Hz, 1H), 4.70-4.69 (m, SI-017N J Method A 2H), 4.45 (m, 1H), 3.92 (s,Chiral 3H), 3.82-3.68 (m, 5H), HPLC: 2.13 (m, 1H), 1.98 (m, N O^ Method D 1H), 1.41 (m, 6H).(RT: 12.44min)LCMS: 5 ppm: 9.10 (d, J= 8.4 Hz, m / z: 1H), 8.05 (m, 1H), 7.82 (s, 574.41 1H), 7.46-7.44 (m, 1H), 0 CF, [M+l]+- 7.35-7.27 (m, 3H), 6.06- 99.88% 5.99 (m, 1H), 5.43-5.38 (RT: 6.02 (m, 2H), 5.29 (d, J= 10.8 min) Hz, 1H), 4.71-4.69 (m, SI-018N J Method A 2H), 4.45 (m, 1H), 3.92 (s,Chiral 3H), 3.82-3.68 (m, 5H), HPLC: 2.12 (m, 1H), 1.98 (m, AX N' xy'"' Method D 1H), 1.41 (m, 6H).(RT: 14.28min)5 ppm: 9.00 (d, J = 8.0Hz, 1H), 8.00-7.97 (m, 1H), 7.72 (s, 1H) 7.53 (d,J= 8.8 o OCF3LCMS: Hz, 1H), 7.08-7.05 (m, m / z: 1H), 6.99 (s, 1H), 6.76 (s, 616.67 1H), 6.08-5.93 (m, 1H), [M+l]+- 5.44-5.40 (m, 2H), 5.30 (d, SI-019 \JL N J 95.01% J= 10.4 Hz, 1H), 5.12 (d,(RT: 6.82 J = 10 Hz, 1H), 4.96-4.66 min) (m, 3H), 4.68-4.67 (m, Method A 2H), 4.47-4.42 (m, 1H),4.16-4.13 (m, 1H), 3.83- 3.77 (m, 4H), 2.07-1.96 (m, 2H), 1.45-1.36 (m,6H).5 ppm: 9.00 (d, J = 8.4Hz,LCMS:1H), 7.97 (m, 1H), 7.71 (s, m / z:1H), 7.53 (d, J = 8.8 Hz, 616.530 OCF31H), 7.08-7.05 (m, 1H),[M+l]+- 6.98 (s, 1H), 6.76 (s, 1H), 98.59%6.07-5.92 (m, 1H), 5.44- (RT: 6.825.39 (m, 2H), 5.29 (d, J = min)SI-020 V JA - 10.4 Hz, 1H), 5.12 (d, J = N Method A10.4 Hz, 1H), 4.95-4.73 Chiral(m, 3H), 4.67-4.66 (m, HPLC:2H), 4.47-4.43 (m, 1H), N O^ Method E4.16-4.12 (m, 1H), 3.83- (RT: 10.923.73 (m, 4H), 2.06-1.95 min)(m, 2H), 1.40-1.35 (m, 6H).5 ppm: 9.00 (d, J = 8.4Hz, LCMS:1H), 7.97 (m, 1H), 7.71 (s, m / z:1H), 7.53 (d, J = 8.8 Hz, 616.620 OCF31H), 7.07-7.05 (m, 1H),[M+l]+- 6.98 (s, 1H), 6.75 (s, 1H), 98.18%6.07-5.92 (m, 1H), 5.43- (RT: 6.815.39 (m, 2H), 5.29 (d, J = min)SI-021 <1 J 10.4 Hz, 1H), 5.12 (d, J = N Method A10.4 Hz, 1H), 4.95-4.73 Chiral(m, 3H), 4.67-4.66 (m, HPLC:2H), 4.47-4.43 (m, 1H), N O^ Method E4.16-4.12 (m, 1H), 3.83- (RT: 13.173.73 (m, 4H), 2.09-1.95 min)(m, 2H), 1.40-1.35 (m, 6H).5 ppm: 8.99 (d, J = 8.4Hz, 1H), 7.90 (m, 1H), 7.70 (s, 0 OCF3LCMS: 1H), 7.54 (d, J = 8.0 Hz, m / z: 1H), 7.08-7.05 (m, 1H), 590.39 6.99 (s, 1H), 6.74 (s, 1H), [M+l]+, 6.06-5.99 (m, 1H), 5.43- SI-022NJO 95.37% 5.39 (m, 2H), 5.29 (d, J = N (RT: 6.37 10.4 Hz, 1H), 4.68-4.66OAQOXmin) (m, 2H), 4.49-4.43 (m,Method A 1H), 4.20-4.17 (m, 1H), N C< 3.87-3.75 (m, 7H), 2.14- 2.08 (m, 1H), 1.99-1.96(m, 1H), 1.41-1.36 (m, 6H)LCMS: 5 ppm: 8.99 (d, J = 8.4Hz, m / z: 1H), 7.90 (m, 1H), 7.70 (s, 590.35 1H), 7.54 (d, J = 8.8 Hz, 0 OCF3[M+l]+- 1H), 7.08-7.05 (m, 1H),99.94% 6.99 (s, 1H), 6.74 (s, 1H), (RT: 6.37 6.06-5.99 (m, 1H), 5.43- min) 5.39 (m, 2H), 5.29 (d, J = SI-023NJO Method A 10.4 Hz, 1H), 4.68-4.66N Chiral (m, 2H), 4.49-4.43 (m,HPLC: 1H), 4.20-4.17 (m, 1H), Method F 3.87-3.75 (m, 7H), 2.14- N O^(RT: 26.67 2.08 (m, 1H), 1.99-1.96 min) (m, 1H), 1.41-1.36 (m,6H).LCMS: 5 ppm: 8.99 (d, J = 8.4Hz, m / z: 1H), 7.90 (m, 1H), 7.70 (s, 590.55 1H), 7.54 (d, J = 8.4 Hz, 0 OCF3[M+l]+, 1H), 7.08-7.05 (m, 1H),94.22% 6.99 (s, 1H), 6.74 (s, 1H), (RT: 6.36 6.06-5.99 (m, 1H), 5.43- min) 5.39 (m, 2H), 5.29 (d, J = SI-024N J Method A 10.4 Hz, 1H), 4.68-4.66Chiral (m, 2H), 4.49-4.43 (m, 0^ -0HPLC: 1H), 4.20-4.17 (m, 1H), N O Method F 3.87-3.75 (m, 7H), 2.14- (RT: 36.08 2.08 (m, 1H), 1.99-1.96 min) (m, 1H), 1.41-1.36 (m,6H).5 ppm: 8.67 (d, J = 8.0 Hz, 0 CF31H), 7.73 (s, 1H), 7.56 (d,J = 8.8 Hz, 1H), 7.46-7.38 m / z: (m, 2H), 7.14 (s, 1H), 7.08 588.56 (s, 1H), 4.99-4.96 (m, 1H), SI-54Nvl J < [M+l]+4.76-4.65 (m, 4H), 4.57- Method A 4.53 (m, 1H), 4.16-4.12 J^ o> (m, 1H), 4.01-3.86 (m,0LX 3H), 3.72 (s, 3H), 2.32- N O^ 2.22 (m, 2H), 1.23-1.12(m, 6H).5 ppm: 8.81-8.73 (m, 1H),7.83-7.79 (m, 1H), 7.64 (s, 1H), 7.35 (dd, J = 8.4 Hz, 20.8 Hz, 1H), 7.17-7.09 m / z:(m, 2H), 6.71 (d, J = 10.8 606.73SI-56-01 Hz, 1H), 5.40 (m, 1H),[M+l]+4.83-4.75 (m, 2H), 4.50- Method D4.39 (m, 2H), 4.21-4.15 (m, 2H), 4.10-3.92 (m, S >>O2H), 3.92-3.38 (m, 6H),2.27-2.24 (m, 1H), 1.97 (m, 1H), 1.42-1.40 (m, 6H) 0 M? 5 ppm: 8.79-8.77 (m, 1H), \ O Z— 7.85 (m, 1H), 7.64 (s, 1H), o CF3o o 7.34 (d, J = 8.8 Hz, 1H),I I 7.16-7.12 (m, 2H), 6.69 m / z:(m, 1H), 5.40 (m, 1H), 606.71SI-56-02 4.96-4.95 (m, 1H), 4.71-lVX J L AOH [M+l]+4.71 (m, 1H), 4.49-4.40 Method D1 ~ o<R^; (m, 2H), 4.21-4.17 (m,0H2H), 4.05-3.85 (m, 2H),k"i\r 'c< 3.91-3.44 (m, 6H), 2.27- 2.25 (m, 1H), 1.99 (m, 1H), 1.42-1.40 (m, 6H) o CF35 ppm: 9.08 (d, J = 8.4Hz, m / z:1H), 7.69-7.34 (m, 10H), 624.416.73 (s, 1H), 5.40-5.38 (m, [M+l]+,1H), 5.24 (s, 2H), 4.47- SI-059 < T j0Y j (RT: 3.724.42 (m, 1H), 4.21-4.18 min)(m, 1H), 3.83-3.72 (m, Method A7H), 2.10-1.98 (m, 2H), N' T)"" 1.41-1.38 (m, 6H).m / z: 5 ppm: 9.08 (d, J = 8.4Hz, 624.40 1H), 7.70-7.34 (m, 10H), 0 CF3[M+l]+, 6.73 (s, 1H), 5.40-5.38 (m,(RT: 3.45 1H), 5.25 (s, 2H), 4.47- min) 4.43 (m, 1H), 4.21-4.18 SI-082 Method A (m, 1H), 3.84-3.73 (m,Chiral 7H), 2.10-1.98 (m, 2H), HPLC: 1.45-1.38 (m, 6H).N' T< Method H(RT: 8.498min)LCMS: 5 ppm: 9.07 (d, J = 8.4Hz, m / z: 1H), 7.69-7.34 (m, 10H), 624.37 6.73 (s, 1H), 5.40-5.39 (m, o CF3[M+l]+, 1H), 5.24 (s, 2H), 4.48- (RT: 3.49 4.42 (m, 1H), 4.21-4.18 min) (m, 1H), 3.92-3.72 (m, <T J Y j Method A 7H), 2.13-1.97 (m, 2H), SI-083Chiral 1.45-1.38 (m, 6H).HPLC:Yr Method HN' T / (RT:15.346min)o CF3LCMS: 5 ppm: 9.29 (d, J = 8.4Hz, m / z: 1H), 7.99-7.70 (m, 5H), 612.33 6.74 (s, 1H), 5.42-5.41 (m, XXtJl i[M+l]+, 1H), 4.48-4.45 (m, 1H), SI-061 N J J0(RT: 3.07 4.24-4.21 (m, 1H), 3.92- min) 3.78 (m, 7H), 3.50 (s, 3H), Method A 2.12-2.02 (m, 2H), 1.42- X T 1.40 (m, 6H).LCMS: 5 ppm: 9.29 (d, J = 8.0Hz, m / z: 1H), 7.79-7.69 (m, 5H), 0 CF3612.33 6.74 (s, 1H), 5.42-5.40 (m,[M+l]+, 1H), 4.48-4.44 (m, 1H), (RT: 2.96 4.24-4.20 (m, 1H), 3.82- u !XK min) 3.72 (m, 7H), 3.50 (s, 3H), SI-084NxJL J 0 Method A 2.12-2.01 (m, 2H), 1.45- Chiral 1.40 (m, 6H).^XT' HPLC:Method H(RT: 8.610min)LCMS: 5 ppm: 9.29 (d, J = 8.4Hz, m / z: 1H), 7.79-7.67 (m, 5H), 612.33 6.74 (s, 1H), 5.42-5.41 (m, 0 CF3[M+l]+- 1H), 4.48-4.45 (m, 1H),(RT: 2.87 4.24-4.20 (m, 1H), 3.81- min) 3.73 (m, 7H), 3.50 (s, 3H), Method A 2.11-2.02 (m, 2H), 1.42- SI-085 NVYO ^'0^ ''"<'Fr Chiral 1.40 (m, 6H).HPLC:Method HXTN^C< (RT: 10.82min)0 CF3LCMS: 5 ppm: 9.22 (d, J = 8.4Hz, m / z: 1H), 7.97 (m, 1H), 7.70- 584.37 7.25 (m, 5H), 6.74 (s, 1H), [M+l]+- 5.41-5.39 (m, 1H), 4.48- SI-062 "OuF(RT: 3.11 4.42 (m, 1H), 4.23-4.20 min) (m, 1H), 3.79-3.74 (m, Method A 7H), 2.15-1.99 (m, 2H), °xa N ° O^- 1.42-1.39 (m, 6H).LCMS: 5 ppm: 9.23 (d, J = 8.8Hz, m / z: 1H), 7.97 (m, 1H), 7.69- 0 CF3584.34 7.25 (m, 5H), 6.74 (s, 1H),[M+l]+- 5.41-5.39 (m, 1H), 4.48- - / HA5L I (RT: 3.18 4.42 (m, 1H), 4.23-4.20 min) (m, 1H), 3.74-3.73 (m, SI-086 ML N ) Method A 7H), 2.15-2.01 (m, 2H),Chiral 1.42-1.39 (m, 6H).HPLC:°XT Method C(RT: 12.42min)LCMS: 5 ppm: 9.22 (d, J = 8.4Hz, m / z: 1H), 7.97 (m, 1H), 7.70- 0 CF3584.34 7.25 (m, 5H), 6.74 (s, 1H),[M+l]+- 5.41-5.39 (m, 1H), 4.48- (RT: 3.19 4.42 (m, 1H), 4.23-4.20k'NV^h ''^C' F min) (m, 1H), 3.79-3.73 (m, SI-087NvX N J Method A 7H), 2.15-2.01 (m, 2H),Chiral 1.42-1.39 (m, 6H).HPLC:Method C(RT: 17.35min)5 ppm: 9.07 (d, J = 8.4Hz, 1H), 7.66 (s, 1H), 7.58- 0 OCF37.39 (m, 4H), 7.24 (s, 1H),LCMS:7.14 (s, 1H), 5.28-5.26 (m, m / z:1H), 4.38-4.30 (m, 1H), A UU 520.384.20-4.17 (m, 1H), 3.2- [M+l]+- SI-067 \X J 3.87 (m, 1H), 3.84 (s, 3H),N (RT: 2.963.73 (s, 3H), 3.67-3.63 (m, min)1H), 2.92-2.89 (m, 1H), Method AT T 2.81-2.76 (m, 1H), 2.02- N^C< 1.96 (m, 1H), 1.89-1.86(m, 1H), 1.35-1.34 (m,6H).LCMS: 5 ppm: 9.07 (d, J = 7.6Hz, m / z: 1H), 7.66 (s, 1H), 7.58- 520.40 7.40 (m, 4H), 7.24 (s, 1H), 0 OCF3[M+l]+- 7.15 (s, 1H), 5.28-5.26 (m, (RT: 1H), 4.38-4.31 (m, 1H), 3.04 4.20-4.17 (m, 1H), 3.91- min) 3.87 (m, 1H), 3.84 (s,3H), SI-068 N r JMethod A 3.76 (s, 3H), 2.92-2.89 (m, Chiral 1H), 2.81-2.75 (m, 1H), HPLC: 2.02-1.96 (m, 1H), 1.89- Y Y N C< Method I 1.86 (m, 1H), 1.35-1.33(RT: 9.61 (m, 6H).min)LCMS: 5 ppm: 9.07 (d, J = 8.0 Hz, m / z: 1H), 7.66 (s, 1H), 7.58- 0 OCF3520.40 7.40 (m, 4H), 7.24 (s, 1H),[M+l]+- 7.15 (s, 1H), 5.26 (br s, (RT: 3.05 1H), 4.38-4.31 (m, 1H), r YN^I W min) 4.20-4.17 (m, 1H), 3.91- SI-069 N jr j Method A 3.87 (m, 1H), 3.84 (s, 3H),Chiral 3.77 (s, 3H), 2.92-2.89 (m, HPLC: 1H), 2.81-2.76 (m, 1H), Y Y Method I 2.02-1.97 (m, 1H), 1.89- N^cA (RT: 15.42 1.86 (m, 1H), 1.35-1.34 min) (m, 6H).0 OCF35 ppm: 9.18 (d, J = 8.4Hz,LCMS:1H), 8.71-8.67 (m, 2H), m / z:8.10 (s, 1H), 7.90 (d, J = -r d 474.677.6 Hz, 1H), 7.61-7.43 (m, [M+l]+- SI-070NUC 5H), 5.46-5.44 (m, 1H),N J (RT: 2.294.50-4.47 (m, 1H), 3.72 min)(m, 2H), 2.15-2.14 (m, Method AoAO 1H), 1.96-1.92 (m, 1H), N 1.43-1.39 (m, 6H).LCMS: 5 ppm: 9.18 (d, J = 8.4Hz, m / z: 1H), 8.71-8.67 (m, 2H), 0 OCF3474.39 8.10 (s, 1H), 7.90 (d, J =[M+l]+- 7.6 Hz, 1H), 7.61-7.54 (m, (RT: 2.29 3H), 7.48-7.43 (m, 2H), min) 5.54-5.44 (m, 1H), 4.50- SI-071 N JT J Method-A 4.47 (m, 1H), 3.72 (br s,Chiral 2H), 2.13 (br s, 1H), 1.96- HPLC: 1.92 (m, 1H), 1.43-1.39 Method J (m, 6H).N (RT: 6.88min)LCMS: 5 ppm: 9.18 (d, J = 8.4Hz, m / z: 1H), 8.71-8.67 (m, 2H), 0 OCF3474.35 8.10 (s, 1H), 7.90 (d, J =[M+l]+- 8.0 Hz, 1H), 7.59-7.54 (m, (RT: 2.29 3H), 7.48-7.43 (m, 2H), xjCd min) 5.46-5.44 (m, 1H), 4.48- SI-072 \\JL J Method A 4.47 (m, 1H), 3.72 (br s,Chiral 2H), 2.15-2.14 (m, 1H), HPLC: 1.96-1.93 (m, 1H), 1.43- °^O Method J 1.39 (m, 6H).N (RT: 8.11min)0 5 ppm: 9.12(d, J = 7.6Hz, CF31H), 7.77-7.61 (m, 3H),LCMS:7.45 (d, J = 6.8 Hz, 1H), m / z:7.35-7.27 (m, 5H), 7.01 (s, 443.621H), 5.26 (br s, 1H), 4.36- [M+l]+- SI-073 4.31 (m, 1H), 4.25-4.22N J / IL (RT: 3.06(m, 1H), 3.94-3.90 (m, min)1H), 2.91-2.89 (m, 1H), Method ASQ 2.82-2.76 (m, 1H), 2.03- 1.88 (m, 2H), 1.37-1.35 (m, 6H).LCMS: 5 ppm: 9.12(d, J = 8.4Hz, m / z: 1H), 7.77-7.61 (m, 3H), 443.80 7.45 (d, J = 7.2 Hz, 1H), [M+l]+- 7.38-7.27 (m, 5H), 7.01 (s, (RT: 3.04 1H), 5.27-5.25 (m, 1H), min) 4.38-4.31 (m, 1H), 4.25- SI-074 Method-A 4.22 (m, 1H), 3.94-3.90Chiral (m, 1H), 2.91-2.89 (m, HPLC: 1H), 2.81-2.76 (m, 1H), Method K 2.03-1.96 (m, 1H), 1.91- (RT: 24.12 1.88 (m, 1H), 1.38-1.35 min) (m, 6H).LCMS: 5 ppm: 9.12(d, J = 8.0Hz, 0 m / z: 1H), 7.77-7.61 (m, 3H), CF3443.80 7.45 (d, J = 7.2 Hz, 1H), ^ 55 [M+l]+- 7.39-7.27 (m, 5H), 7.01 (s,(RT: 3.04 1H), 5.27-5.25 (m, 1H), min) 4.38-4.31 (m, 1H), 4.25- SI-075 N ii 1 Method A 4.22 (m, 1H), 3.94-3.90Chiral (m, 1H), 2.92-2.89 (m, HPLC: 1H), 2.82-2.76 (m, 1H), SQ Method K 2.03-1.97 (m, 1H), 1.91- (RT: 30.94 1.88 (m, 1H), 1.38-1.35 min) (m, 6H).0 OCF35 ppm: 9.07 (d, J = 8.4Hz,LCMS:1H), 7.58-7.27 (m, 9H), m / z:7.01 (s, 1H), 5.28 (br s, 459.521H), 4.38-4.33 (m, 1H), [M+l]+- SI-076 N J 4.25-4.22 (m, 1H), 3.95- (RT: 3.403.91 (m, 1H), 2.91-2.78 min)(m, 2H), 2.04-1.98 (m, Method A^0 1H), 1.90-1.87 (m, 1H),1.35-1.33 (m, 6H).LCMS: 5 ppm: 9.07 (d, J = 8.4Hz, m / z: 1H), 7.58-7.27 (m, 9H), 0 OCF3459.35 7.01 (s, 1H), 5.28 (br s,[M+l]+- 1H), 4.36-4.33 (m, 1H), (RT: 3.40 4.25-4.22 (m, 1H), 3.95- min) 3.91 (m, 1H), 2.91-2.81 SI-077Nw JL J Method A (m, 2H), 2.01-1.98 (m,Chiral 1H), 1.90-1.87 (m, 1H), HPLC: 1.35-1.33 (m, 6H).^0 Method L(RT: 7.45min)LCMS: 5 ppm: 9.08 (d, J = 8.4Hz, m / z: 1H), 7.58-7.25 (m, 9H), 0 OCF3459.36 7.01 (s, 1H), 5.29-5.27 (m,[M+l]+- 1H), 4.38-4.31 (m, 1H), w M (RT: 3.38 4.25-4.22 (m, 1H), 3.95- min) 3.91 (m, 1H), 2.91-2.88 SI-078 N JT J Method A (m, 1H), 2.83-2.78 (m,Chiral 1H), 2.01-1.98 (m, 1H), HPLC: 1.90-1.86 (m, 1H), 1.35- ^0 Method L 1.33 (m, 6H).(RT: 9.20min)5 ppm: 8.93 (d, J = 8.4Hz, LCMS: 1H), 7.90 (d, J = 6.8 Hz, m / z: 2H), 7.54-7.26 (m, 8H), W o 375.68 7.03 (s, 1H), 5.36 (br s, SI-079NUC N J [M+l]+- 1H), 4.27-4.24 (m, 2H),(RT: 2.80 3.98-3.95 (m, 1H), 2.89- min) 2.86 (m, 2H), 2.02-1.99 SQ Method A (m, 1H), 1.90-1.87 (m,1H), 1.34-1.26 (m, 6H).LCMS: 5 ppm: 8.93 (d, J = 8.0Hz, m / z: 1H), 7.90 (d, J = 7.2 Hz, 375.72 2H), 7.54-7.26 (m, 8H), [M+l]+- 7.03 (s, 1H), 5.36-5.35 (m, (RT: 2.79 1H), 4.29-4.24 (m, 2H), min) 3.98-3.95 (m, 1H), 2.88- SI-080Method A 2.83 (m, 2H), 2.08-1.99 Chiral (m, 1H), 1.90-1.87 (m, HPLC: 1H), 1.34-1.32 (m, 3H), Method L 1.27-1.26 (m, 3H).(RT: 11.25min)LCMS: 5 ppm: 8.93 (d, J = 8.4Hz, m / z: 1H), 7.90 (d, J = 6.8 Hz, 375.36 2H), 7.54-7.27 (m, 8H), [M+l]+- 7.05 (s, 1H), 5.37 (br s, (RT: 2.79 1H), 4.29-4.23 (m, 2H), min) 3.99-3.96 (m, 1H), 2.89- SI-081Method A 2.86 (m, 2H), 2.02-1.99 Chiral (m, 1H), 1.91-1.88 (m, HPLC: 1H), 1.40-1.39 (m, 3H), Method L 1.27-1.26 (m, 3H).(RT: 14.12min)o CF3o CF3o CF3k b, o % CO o CO oJNII J II J II IL <>L. _N. IL <X,0SI- 182 SI- 183 SI- 184 o CF3o CF30 CF3J >> JJNII J IINO ykkNJ C. J II IL A J SI-185 SI-186 °cQ oSI- 187Abbreviations used in experimental procedures:AcOH Acetic acidBQL Below Quantifiable LevelDtBAD Di-tert-butyl azodicarboxylateDMAP 4-DimethylaminopyridineTLC Thin layer chromatography using silica gel platesRT Room temperatureCH3CN AcetonitrileDMSO DimethylsulfoxideNa2SC>4 Sodium sulfateMeOH MethanolHATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium DMF Dimethyl formamideDIPEA V.V-Diisopropy IcthylamincK2CO3 Potassium carbonateHO Hydrochloric acidNaBH4Sodium boro hydrideNH4CI Ammonium chloridePTSA -Tolucncsulfonic acidTHF TetrahydrofuranTEA TriethylamineSynthesis of ExamplesScheme 1:Reaction conditions: a) SOCI2, MeOH, RT, 16 h b) DfBAD, PBu3, i-PrOH, THF, RT, 16 h c) 10% Pd / C, H2, MeOH, RT, 16 h d) Methyl acrylate, DMAP, DMF.100 °C, 3 days e) BnBr, K2CO3, DMF, RT, 16 h f) 1.NaHMDS, THF, 0 °C to RT then 2. NaOH aq„ 80°C, 16 h g) NH2OH.HCI, pyridine, EtOH, 90 C, 16 h h) Raney Ni, H2,MeOH, RT, 16 h i) BoczO, Et3N, DCM, RT, 4 h j) 10% Pd-C, MeOH, AcOH, RT, H2atm, 16 h k) TBTU, Et3N, DMF, THF, RT, 2 h I) 4N HCI in Dioxane, RT, 2 h m) HATU, Et3N, DMF, RT, 4 h n) Grubbs 2ndgeneration, DCM, 40°C, 16hStep-1: Preparation of methyl 4-nitro-lH-pyrazole-5 -carb oxy late (2):HN'LL OMeN02To a stirred solution of 4-nitro- 1 / / -pyrazolc-5-carboxy lie acid (1) (25 g, 0.159 mol) inMeOH (400 mL) was added SOCT (15 mL) dropwise at RT. Reaction was allowed to stir at room temperature for 16 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was evaporated under reduced pressure to get crude residue. The obtained crude residue was triturated with n-pentane (2 x 200 mL) to afford methyl 4-nitro- 1 / / -pyrazolc-5-carboxy late (2) (24 g, 88%) as off white solid, m / z: 172.09 [M+H]+, 'H-NMR (400 MHz, CDC13): 8 10.40 (br s, 1H), 8.99 (s, 1H), 3.89 (s, 3H).Rf = 0.4 (Mobile phase: 50% EtO Ac -Hexane).Step-2: Preparation of methyl l-isopropyl-4-nitro-lP[-pyrazole-5-carboxylate:N'V / IL OMeNO2To a stirred solution of methyl 4-nitro- 1 ff-pyrazole-5 -carboxy late (2) (24 g, 0.140 mol) in THF (480 mL) was added PBu3(42.4 mL, 0.168 mol), IPA (52.5 mL, 0.7 mol) and DtBAD (41.8 g, 0.182 mol) at RT. Stirred the reaction mixture at RT for 16 h. Completion of the reaction was confirmed by TLC. The reaction mixture was diluted water (1 Lit) and extracted with EtO Ac (4 x 500 mL). The combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude was purified by flash column chromatography (100-200 mesh silica gel, 15%EtOAc-Hexane as eluent) to afford methyl 1-isopropyl-4-nitro- 1 ff-pyrazole-5 -carboxylate (3) (20 g, 66%) as off white solid.1H NMR (400 MHz, CDClj): 88.42 (s, 1H), 4.76-4.69(m, 1H), 3.99 (s, 3H), 1.42 (d, J= 6.4 Hz, 6H).Rf = 0.5 (Mobile phase: 30% EtOAc-Hexane).Step-3: Preparation of methyl 4-amino-l-isopropyl-lP[-pyrazole-5-carboxylate (4):To a solution of methyl l-isopropyl-4-nitro-l / / -pyrazolc-5 -carboxylate (3) (20 g, 93.896 mmol) in MeOH (200 mL) was added 10% Pd-C (3.9 g) at RT, stirred the reaction mixture at RT under H2 atm for 16 h. Completion of the reaction was confirmed by TLC. The reaction mixture was filtered through celite bed, washed with MeOH (3 x 300 mL), volatiles was evaporated under reduced pressure to afford methyl 4-amino- 1 -isopropyl- 1 / / -pvrazolc-5-carboxylatc (4) (15 g, 87% yield) as white solid, which was used for next step without any further purification, m / z: 184.16 [M+l]+, 'H NMR (400 MHz, DMSO-de): <57.06 (s, 1H), 5.23-5.20 (m, 1H), 5.01 (brs, 2H), 3.80 (s, 3H), 1.31 (d,J= 6.4 Hz, 6H).Rf = 0.3 (Mobile phase: 30% EtOAc-Hexane).Step-4: Preparation of methyl l-isopropyl-4-((3-methoxy-3-oxopropyl) amino)-lPI-pyrazole-5-carboxylate (5):To a stirred solution of methyl 4-amino- 1 -isopropyl- 1 / / -pyrazolc-5-carboxy late (4) (15 g, 0.082 mol) in DMF (150 mL) was added DMAP (2 g, 16.393 mmol) and Methyl acrylate (74.2 mL, 0.82 mol) at RT. The reaction was heated to 100 °C and stirred for 72 h. Completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was diluted with water (1.5 Lit) and extracted with EtOAc (3 x 500 mL). The combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude was purified by flash column chromatography (100-200 mesh silica gel, 17% EtOAc-Hexane as eluent) to afford methyl l-isopropyl-4-((3-methoxy-3-oxopropyl) amino)- 1 / / -pyrazolc-5-carboxylate (5) (17 g, 77%) as colorless liquid, m / z: 270.24 [M+H]+.1H NMR (400 MHz, DMSO-de): d 7.24 (s, 1H), 5.24 (t, J= 6.4 Hz, 2H), 3.80 (s, 3H), 3.60 (s, 3H), 3.33-3.29 (m, 2H), 2.59 (t, J= 6.8 Hz, 2H), 1.32 (d, J= 6.4 Hz, 6H).Rf = 0.25 (Mobile phase: 30% EtOAc-Hexane).Step-5: Preparation of methyl4-(benzyl(3-methoxy-3-oxopropyl)amino)-l-isopropyl-lP[-pyrazole-5-carboxylate (6):To a stirred solution of methyl l-isopropyl-4-((3-methoxy-3 -oxopropyl) amino)-l / / -pyrazolc-5-carboxylate (5) (17 g, 63.197 mmol) inDMF (125 mL) was added K^COsQS.l g, 94.795 mmol) and BnBr (11.2 mL, 94.795 mmol) at RT. Completion of the reaction was confirmed by TLC after 16h. The reaction mixture was diluted with water (500 mL) and extracted with EtO Ac (3 x 500 mL). The combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude was purified by flash column chromatography (100-200 mesh silica gel, 12%EtO Ac -Hexane as eluent) to afford methyl4-(benzyl(3 -metho xy-3-oxopropyl)amino)-l -isopropyl- l / f-pyrazole-5 -carboxylate (6) (16 g, 70%) as pale-yellow liquid, m / z: 360.08 [M+H]+.1H NMR (400 MHz, DMSO-ds): d 7.42 (s, 1H), 7.38-7.20 (m, 5H), 5.20-5.15 (m, 1H), 4.14 (s, 2H), 3.80 (s, 3H), 3.50 (s, 3H), 3.22 (t, J= 6.8 Hz, 2H), 2.44 (t, J= 6.8 Hz, 2H), 1.33 (d, .7= 6.8 Hz. 6H).Rf = 0.4 (Mobile phase: 30% EtO Ac -Hexane).Step-6: Preparation of 4-benzyl-l -isopropyl- 5, 6-dihydro-lH-pyrazolo [4, 3-b] pyridin-7(4H)-one (7):BnTo a stirred solution of methyl4-(benzyl(3-methoxy-3-oxopropyl)amino)-l -isopropyl-1 H-pyrazole-5-carboxylate (6) (16 g, 44.568 mmol) in THF (160 mL) was added NaHMDS (IM in THF) (89.1 mL, 89.136 mmol) at 0°C. Stirred the reaction mixture at RT for 1 h. Then 2M NaOH (224 mL) was added at RT, heated the reaction mixture at 80°C for 16 h. Completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was diluted with water (500 mL) and extracted with EtO Ac (3 x 400 mL). The combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude was purified by flash column chromatography (100-200 silica gel, 15% EtO Ac -Hexane as eluent) to afford 4-benzyl-l-isopropyl-5, 6-dihydro-l / / -pyrazolo [4, 3-b] pyridin-7(4 / / )-onc (7) (9 g, 75%) as off white solid.m / z: 270.30 [M+H]+. 'H NMR (400 MHz, DMSO-de): <57.40-7.30 (m, 6H), 5.18-5.14 (m, 1H), 4.30 (s, 3H), 3.15 (t, J= 12 Hz, 2H), 2.50-2.47 (m, 2H), 1.33 (d, J= 6.4 Hz, 6H).Rf = 0.4 (Mobile phase: 30% EtO Ac -Hexane).Step-7 : Preparation of 4-benzyl-l -isopropyl- 5, 6-dihydro-lH-pyrazolo [4, 3-b] pyridin-7(4H)-one oxime (8):BnTo a stirred solution of 4-benzyl-l -isopropyl-5, 6 -dihydro- I / / -pyrazolo [4, 3-b] pyridin-7(4 / / )-one (7) (9 g, 33.457 mmol) inEtOH (90 mL) was added NH2OH.HC1 (11.62 g, 0.167 mol) and Pyridine (13.4 mL, 0.167 mol) at RT. Heated reaction mixture at 90 °C for 16 h. Completion of the reaction was confirmed by TLC. The reaction mixture was diluted with water (500 mL) and extracted with EtO Ac (3 x 300 mL). The combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude was purified by flash column chromatography (100-200 mesh silica gel, 20% EtOAc-Hexane as eluent) to afford 4-benzyl-l -isopropyl-5, 6-dihydro-lH-pyrazolo [4, 3-b] pyridin-7(4H)-one oxime (8) (8 g, 84%) as off white solid, m / z = 285.22 [M+H]+. 'H NMR (400 MHz, DMSO-ds): d 10.93 (s, 1H), 7.37-7.28 (m, 5H), 7.13 (s, 1H), 5.22-5.21 (m, 1H), 4.14 (s, 2H), 2.84 (t, J= 6.40 Hz, 2H), 2.69 (t, J= 6.0 Hz, 2H), 1.33 (d, J= 6.8 Hz, 6H).Rf = 0.5 (Mobile phase: 30% EtOAc-Hexane).Step-8: Preparation of 4-benzyl-l-isopropyl-4, 5, 6, 7 -tetrahydro- IPI-pyrazolo [4, 3-b] pyridin-7-amine (9):BnTo a stirred solution of 4-benzyl-l -isopropyl-5, 6-dihydro-lH-pyrazolo [4, 3-b] pyridin-7(4 / / )-one oxime (8) (8 g, 28.169 mmol) in MeOH (80 mL) was added Raney Ni (8 g, w / w%) at RT. Stirred the reaction mixture at RT under H2atm for 16 h. Completion of the reaction was confirmed by TLC. The reaction mixture was filtered through celite bed, washed with MeOH (3 x 300 mL). Volatiles was evaporated under reduced pressure to get crude compound. The obtained crude was purified by flash column chromatography (100-200 mesh silica gel, 3% MeOH-DCM as eluent) to afford 4-benzyl-l -isopropyl-4, 5, 6, 7 -tetrahydro- 1 / / -pyrazolo [4, 3-b] pyridin-7-amine (9) (6.1 g, 78%) as light brown liquid, m / z: 271.31 [M+H]+ 1H NMR (400 MHz, DMSO-de): <57.36-7.27 (m, 5H), 6.91 (s, 1H), 4.67-4.64 (m, 1H), 4.16 (d, J= 14.4 Hz, 1H), 3.93-3.90 (m, 1H), 2.79-2.70 (m, 2H), 1.92-1.85 (m, 2H), 1.37 (d, J= 6.40 Hz, 3H), 1.30 (d, J= 6.4 Hz, 3H).Rf= 0.4 (Mobile phase: 5% MeOH-DCM)Step-9: Preparation of tert-butyl(4-benzyl-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b ]pyridin- 7 -y I) carbamate (10):NNBnTo a solution of 4-benzyl-l-isopropyl-4, 5, 6, 7-tctrahydro-l / / -pyrazolo [4, 3-b] pyridin-7 -amine (9) (6.1 g, 22.592 mmol) inTHF (48 mL) was added Et-5N (6.3 mL, 45.185 mmol), Di-tert-butyldicarbonate (5.7 mL, 24.851 mmol) at RT. Stirred the reaction mixture at RT for 4 h.Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with water (250 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layer was dried over ISfeSCh, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 20% EtOAc-Hexane as eluent) to afford tert-butyl(4-benzyl-l-isopropyl-4, 5,6, 7-tctrahydro-l / / -pyrazolo|4.3-b]pyridin-7-yl)carbamate (10) (4 g, 73%) as light brown liquid, m / z: 371.49 [M+H]+ 1H NMR (400 MHz, DMSO-de): <57.43-7.26 (m, 6H), 6.95 (s, 1H), 4.81 (m, 1H), 4.35-4.32 (m, 1H), 4.18 (d, J= 14.0 Hz, 1H), 3.91 (d, J= 14.4 Hz, 1H), 2.80-2.78 (m, 2H), 1.93-1.89 (m, 1H), 1.76-1.73 (m, 1H), 1.39 (s, 9H), 1.33 (d, J= 6.40 Hz, 3H), 1.29 (d, J= 6.8 Hz, 3H).Rf = 0.4 (Mobile phase: 30% EtOAc -Hexane).Step-10: Preparation of tert-butyl(l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)carbamate (11):NTo a solution of tert-butyl(4-benzyl- 1 -isopropyl-4,5,6,7-tetrahydro- 1 / / -pyrazolo|4.3-b|pyridin-7-yl)carbamate (10) (4 g, 10.810 mmol) inMeOH (60 mL) was added 10% Pd-C (1.1 g) and AcOH (6 mL) at RT. Stirred the reaction mixture at RT under H2 atm for 16 h. Completion of the reaction was confirmed by TLC. The reaction mixture was filtered through celite bed, washed with MeOH (3 x 200 mL), volatiles was evaporated under reduced pressure to afford tert-butyl(l-isopropyl-4.5.6.7-tctrahydro-l / / -pyrazolo|4.3-b|pyridin-7-yl)carbaniatc (11) (2.7 g, 89%) as white solid, m / z: 281.28 [M+l]+Rf= 0.4 (Mobile phase: 5% MeOH-DCM).Step-11: Preparation of tert-butyl(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)carbamate (12):To a stirred solution of 5-(allyloxy)-6-methoxynicotinic acid (Int-1) (1 g, 4.784 mmol) in DMF:THF (1:1) (40 mL) was added TBTU (2.3 g, 7.177mmol), DIPEA (4.16mL, 23.92mmol) at RT. After 20 min, tert-butyl(l-isopropyl-4,5,6,7-tetrahydro-l / 7-pyrazolo[4,3-b]pyridin-7-yl)carbamate (11) (2.67 g, 9.568 mmol) was added at RT and allowed to stir 2 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with ice-cold water (250 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3% MeOH-DCM as eluent) to afford tert-butyl(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4, 5,6,7-tctrahydro-l / / -pyrazolo|4.3-b|pyridin-7-yl)carbamatc (12) (1.6 g, 71%) as off brown liquid, m / z: 472.41 [M+H]+1H-NMR (400 MHz, DMSO-de): d 8.01-7.95 (m, 1H), 7.82 (m, 1H), 7.57-7.55 (m, 1H), 7.33 (s, 1H), 6.04-6.02 (m, 1H), 5.47-5.38 (m, 1H), 5.30-5.27 (m, 1H), 4.96 (m, 1H), 4.64 (m, 2H), 4.46 (m, 1H), 4.02 (s, 3H), 3.93-3.73 (m, 2H), 2.04-1.84 (m, 2H), 1.41-1.23 (m, 15H).Rf= 0.4 (Mobile phase: 5% MeOH-DCM).Step-12: Preparation of (5-(allyloxy)-6-methoxypyridin-3-yl)(7-amino-l-isopropyl-6, 7-dihydro-lPI-pyrazolo[4,3-b]pyridin-4(5PI)-yl)methanone (13):To a stirred solution of tert-butyl(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4, 5,6,7-tctrahydro-l / / -pyrazolo|4.3-b|pyridin-7-yl)carbaniatc (12) (1.6 g, 3.397 mmol) inDCM (16 mL)was added 4N HC1 in 1,4 Dioxane (16 mL) at RT. Completion of the reaction was confirmed by TLC and LCMS after 2h. Volatiles were evaporated under reduced pressure to get crude residue The crude was triturated with Pentane (2 x 10 mL) to afford (5-(allyloxy)-6-methoxypyridin-3-yl)(7-amino-l-isopropyl-6,7-dihydro-l / f-pyrazolo[4,3-b]pyridin-4(5 / / )-yl)methanone (13) (1 g, 79%) as off black liquid, m / z: 372.40 [M+H]+Rf= 0.4 (Mobile phase: 5% MeOH-DCM).Step-13: Preparation of 4-(allyloxy)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-004):To a stirred solution of 4-(allyloxy)-2-(trifluoromethyl)benzoic acid (Int-2) (550 mg, 2.235 mmol) inDMF (6 mL) was added HATU (1.27 g, 3.353mmol), EhN (0.93 mL, 6.705mmol) at RT. Stirred the reaction mixture at RT for 20 min. Then (5-(allyloxy)-6-methoxypyridin-3-yl)(7-amino-l-isopropyl-6,7-dihydro-l / 7-pyrazolo[4,3-b]pyridin-4(5 / / )-yl)methanone (13) (1 g, 2.793mmol) was added at RT and stirred for 4 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (3 x 150 mL), the combined organic layer was dried overNa2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3% MeOH-DCM as eluent) to afford 4-(allyloxy)-A-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-l / 7-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)Benzamide (14, SI-004) (600 mg, 45% yield) as off white solid. LCMS: Method A, m / z: 600.39 [M+1]+ 1H NMR (400 MHz, DMSO-ds): d 9.12-9.08 (m, 1H), 7.48 (m, 1H), 7.72 (s, 1H), 7.47 (t, J= 9.2 Hz, 1H), 7.35-7.29 (m, 2H), 6.76 (s, 1H), 6.07-5.94 (m, 2H), 5.44-5.39 (m, 2H), 5.29 (d, J= 10.4 Hz, 1H), 5.12 (d, J= 10.4 Hz, 1H), 4.95-4.70 (m, 5H), 4.47-4.44 (m, 1H), 4.18-4.14 (m, 1H), 3.94 (m, 1H), 3.79 (m, 3H), 2.06-1.98 (m, 2H), 1.42-1.39 (m, 6H).Rf= 0.4 (Mobile phase: 5% MeOH-DCM).Step-14: Preparation of Macrocyclic compound (SI-001)To a stirred solution of 4-(allyloxy)-7V-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4, 5,6,7-tctrahydro-l / / -pyrazolo|4.3-b|pyridin-7-yl)-2-(trifluoroincthyl)Bcnzamidc (SI-004) (600 mg, 0.333 mmol) inDCM (120 mL) was added 2ndgeneration Grubbs catalyst (45 mg, 0.024 mmol) at RT. stirred the reaction mixture at 40 °C for 16 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was filtered and volatiles was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3% MeOH-DCM as eluent) to afford 150 mg of crude compound, which was further purified by Prep HPLC, pure fractions was collected and lyophilized to get SI-001 (11 mg) as white solid. 1H NMR (400 MHz, DMSO-d6): 59.08-9.02 (m, 1H), 8.02 (m, 1H), 7.80 (s, 1H), 7.33-7.11 (m, 3H), 6.84 (s, 1H), 6.04-5.99 (m, 1H), 5.39 (m, 1H), 5.30-5.17 (m, 1H), 5.10-5.06 (m, 1H), 4.79-4.75 (m, 1H), 4.50-4.40 (m, 3H), 4.22 (m, 1H), 3.74 (s, 3H), 3.56 (m, 1H), 2.33-2.28 (m, 1H), 1.95 (m, 1H), 1.39-1.34 (m, 6H). LCMS: Method Am / z: 572.60 [M+l]+, 98.11%(RT: 7.05 min)Column: KinetexEVO C18 (2.1 x 50 mm, 1.7 pm),Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN,(T / %B: 0.01 / 10, 0.5 / 10, 4 / 90, 7 / 90)Flow Rate: 0.4 mL / min.Rf= 0.4 (Mobile phase: 10% MeOH-DCM).Prep Method:Column: Zodiak C18 (150 x 21.2mm, 5 pm),Mobile Phase: A-0.1% TFA in water; B-100% ACN,(T / %B: 0 / 35, 2 / 35, 25 / 80)Flow Rate: 17 ml / min.Scheme 2:Chiral separation of (R)-4-(allyloxy)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-005) and (S)-4-(allyloxy)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-006)The racemic compound SI-004 (500 mg) was separated by chiral HPLC (CHIRALPAK IG) to afford 120 mg of the first eluted isomer SI-005 (RT = 38.59) and 140 mg of the second eluted isomer SI-006 (RT = 46.58).SI-005: H NMR (400 MHz, DMSO-d6) d: 9.08 (d, J= 8.4 Hz, 1H), 8.01 (m, 1H), 7.71 (s, 1H), 7.49-7.46 (m, 1H), 7.30-7.28 (m, 1H), 6.76 (s, 1H), 6.07-5.94 (m, 2H), 5.43-5.39 (m, 2H), 5.29 (d, J= 10.4 Hz, 1H), 5.12 (d, J= 10.4 Hz, 1H), 4.95-4.70 (m, 5H), 4.46-4.43 (m, 1H), 4.17-4.14 (m,1H), 3.78-3.73 (m, 4H), 2.06-1.96 (m, 2H), 1.42-1.38 (m, 6H). [a]D25: +110.07 (c=0.05%in MeOH); LCMS: Method A m / z: 600.34 [M+l]+SI3-006: H NMR (400 MHz, DMSO-ds) 8: 9.08 (d, J= 8.4 Hz, 1H), 8.01 (m, 1H), 7.71 (s, 1H), 7.49-7.46 (m, 1H), 7.30-7.28 (m, 1H), 6.76 (s, 1H), 6.07-5.94 (m, 2H), 5.43-5.39 (m, 2H), 5.29 (d, J= 10.4 Hz, 1H), 5.12 (d, J= 10.4 Hz, 1H), 4.95-4.70 (m, 5H), 4.46-4.43 (m, 1H), 4.17-4.14 (m, 1H), 3.78-3.73 (m, 4H), 2.06-1.96 (m, 2H), 1.42-1.38 (m, 6H). [a]D25: -72.65 (c=0.05% in MeOH); LCMS: Method A m / z: 600.43 [M+l]+Preparation of macrocyclic compound SI-002:SI-002To a stirred solution of (RJ-4-(allyloxy)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-005) (200 mg, 0.333 mmol) inDCM (40 mL) was added 2nd generation Grubbs catalyst (45 mg, 0.053 mmol) at RT. stirred the reaction mixture at 40 °C for 16 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was filtered and volatiles was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3% MeOH-DCM as eluent) to afford 150 mg of the crude compound, which was further purified by Prep HPLC, pure fractions were collected and lyophilized to get (R, E) -macrocyclic compound, SI-002 (21 mg, 10% yield) as white solid. 'H NMR (400 MHz, DMSO-ds): d 9.07 (d, J= 8.4 Hz, 1H), 8.02 (m, 1H), 7.80 (s, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.18-7.10 (m, 2H), 6.84 (s, 1H), 6.03-5.99 (m, 1H), 5.40 (m, 1H), 5.20-5.17 (m, 1H), 5.10-5.06 (m, 1H), 4.79-4.75 (m, 1H), 4.50-4.39 (m, 3H), 4.21 (m, 1H), 3.74 (m, 4H), 2.33-2.28 (m, 1H), 1.96 (m, 1H), 1.39-1.34 (m, 6H). [a]D25: +125.83 (c=0.01% inMeOH); LCMS: Method A m / z: 572.51 [M+l]+, 98.34% (RT: 6.94 min).Rf= 0.4 (Mobile phase: 10% MeOH-DCM).Prep Method:Column: XTIMATE C18 (150 x 21.2mm, 5 pm),Mobile Phase: A-0.1%FA in water; B-100% ACN,(T / %B: 0 / 20, 2 / 20, 20 / 50)Flow Rate: 17 ml / min.Preparation of macrocyclic compound SI-003 [MC-01 (S)]:SI-003To a stirred solution of (S)-4-(allyloxy)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l -isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-006) (300 mg, 0.500 mmol) in DCM (60 mL) was added 2nd generation Grubbs catalyst (50 mg, 0.08 mmol) at RT. stirred the reaction mixture at 40 °C for 16 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was filtered and volatiles was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3% MeOH-DCM as eluent) to afford 180 mg of crude compound, which was further purified by Prep HPLC, pure fractions was collected and lyophilized to get (.S', / 'j-Macrocyclic compound, SI-003 (22 mg, 8% yield) as white solid.'H NMR (400 MHz, DMSO-de): d 9.07 (d, J= 8.4 Hz, 1H), 8.02 (m, 1H), 7.80 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.18-7.10 (m, 2H), 6.84 (s, 1H), 6.03-5.99 (m, 1H), 5.40 (m, 1H), 5.20-5.17 (m, 1H), 5.10-5.06 (m, 1H), 4.79-4.75 (m, 1H), 4.50-4.39 (m, 3H), 4.21 (m, 1H), 3.74 (m, 4H), 2.33-2.28 (m, 1H), 1.95 (m, 1H), 1.39-1.34 (m, 6H). [a]D25: -124.93 (c=0.01%inMeOH); LCMS: Method A m / z: 572.60 [M+l]+, 97.97% (RT: 6.94 min).Rf= 0.4 (Mobile phase: 10% MeOH-DCM).Prep Method:Column: XTIMATE C18 (150 x 21.2mm, 5 pm),Mobile Phase: A-0.1%FA in water; B-100% ACN,(T / %B: 0 / 20, 2 / 20, 20 / 40)Flow Rate: 17 ml / min.Preparation ofN-(l-isopropyl-4-(6-methoxy-5-propoxynicotinoyl)-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-4-propoxy-2-(trifluoromethyl)Benzamide (SI-007):SI-007To a stirred solution of 4-(allyloxy)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)Benzamide (SI-004) (100 mg, 0.166 mmol) in MeOH (2 mL) was added 10% Pd-C (30 mg, w / w%) at RT, stirred the reaction mixture at RT under H2atm for 16 h. Completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was filtered through Celite bed, washed with MeOH (3 x 30 mL), volatiles was evaporated under reduced pressure to get crude compound. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3% MeOH-DCM as eluent) to afford 7V-(l-isopropyl-4-(6-methoxy-5-propoxynicotinoyl)-4, 5,6, 7-tctrahydro-l / / -pyrazolo[4,3-b]pyridin-7-yl)-4-propoxy-2-(trifluoromethyl)Benzamide (SI-007) (55 mg, 55% yield) as off white solid. LCMS: Method B ESI+m / z: 604.47 [M+1]+1H NMR (400 MHz, DMSO-de): d 9.06 (d, J= 8.0 Hz, 1H), 8.00-7.95 (m, 1H), 7.73 (s, 1H), 7.47 (d, J= 8.4 Hz, 1H), 7.28-7.25 (m, 2H), 6.72 (s, 1H), 5.40 (s, 1H), 4.45 (m, 1H), 4.17-4.14 (m, 2H), 4.05-4.02 (m, 3H), 3.77-3.73 (m, 4H), 2.01-1.99 (m, 2H), 1.78-1.62 (m, 4H), 1.42-1.39 (m, 6H), 0.98 (t, J= 7.6 Hz, 3 H), 0.77 (t, J = 7.2 Hz, 3H).Rf= 0.4 (Mobile phase: 10% MeOH-DCM).Scheme 3:Preparation of (R)-N-(l-isopropyl-4-(6-methoxy-5-propoxynicotinoyl)-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-4-propoxy-2-(trifluoromethyl)benzamide (SI-008):SI-008To a stirred solution of (R)-4-(allyloxy)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-005) (120 mg, 0.20 mmol) in MeOH (2 mL) was added 10% Pd-C (40 mg, w / w) at RT, stirred the reaction mixture at RT under H2 atm for 16 h. Completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was filtered through Celite bed, washed with MeOH (3 x 30 mL), volatiles was evaporated under reduced pressure to get crude compound. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3%MeOH-DCM as eluent) to afford (R)-N-(l-isopropyl-4-(6-methoxy-5-propoxynicotinoyl)-4,5,6,7-tetrahydro- lH-pyrazolo[4,3-b]pyridin-7-yl)-4-propoxy-2-(trifluoromethyl)benzamide (SI-008) (60 mg, 50% yield) as off white solid. LCMS: Method B m / z: 604.76 [M+1]+1H NMR (400 MHz, DMSO-de):89.06 (d, J= 8.0 Hz, 1H), 8.00-7.95 (m, 1H), 7.73 (s, 1H), 7.47 (d, J= 8.4 Hz, 1H), 7.28-7.25 (m, 2H), 6.72 (s, 1H), 5.41-5.39 (m, 1H), 4.48-4.42 (m, 1H), 4.21-4.14 (m, 2H), 4.05-4.02 (m, 3H), 3.77-3.73 (m, 4H), 2.01-1.99 (m, 2H), 1.78-1.62 (m, 4H), 1.42-1.39 (m, 6H), 0.98 (t, J= 7.6 Hz, 3H), 0.77 (t, J= 12 Hz, 3H). [a]D25: +100.62 (c=0.05% in MeOH);Rf= 0.4 (Mobile phase: 10% MeOH-DCM).Preparation of (S)-N-(l-isopropyl-4-(6-methoxy-5-propoxynicotinoyl)-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-4-propoxy-2-(trifluoromethyl)benzamide (SI-009):To a stirred solution of (S)-4-(allyloxy)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-006) (140 mg, 0.233 mmol) in MeOH (2 mL) was added 10% Pd-C (40 mg, w / w) at RT, stirred the reaction mixture at RT under H2atm for 16 h. Completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was filtered through Celite bed, washed with MeOH (3 x 30 mL), volatiles was evaporated under reduced pressure to get crude compound. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3%MeOH-DCM as eluent) to afford (S)-N-(l-isopropyl-4-(6-methoxy-5-propoxynicotinoyl)-4,5,6,7-tetrahydro- lH-pyrazolo[4,3-b]pyridin-7-yl)-4-propoxy-2-(trifluoromethyl)benzamide (SI-009) (65 mg, 46% yield) as off white solid. LCMS: Method B m / z: 604.80 [M+1]+1H-NMR (400 MHz, DMSO-ds):89.06 (d, J= 8.0 Hz, 1H), 8.00-7.95 (m, 1H), 7.73 (s, 1H), 7.47 (d, J= 8.4 Hz, 1H), 7.28-7.25 (m, 2H), 6.72 (s, 1H), 5.41-5.39 (m, 1H), 4.48-4.44 (m, 1H), 4.19-4.14 (m, 2H), 4.05-4.02 (m, 3H), 3.79-3.73 (m, 4H), 2.09-1.99 (m, 2H), 1.77-1.62 (m, 4H), 1.42-1.39 (m, 6H), 0.98 (t, J= 7.6 Hz, 3H), 0.77 (t, J= 12 Hz, 3H). [a]D25: -82.74 (c=0.05% in MeOH);Rf= 0.4 (Mobile phase: 10% MeOH-DCM).Scheme 4:HATU, DIPEA,DMF, RT,16 hStep 1 lnt-13 (Scheme 1) (SI-010) (±)(SI-011) (+) (SI-012) (-) Preparation ofN-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4, 3-b ]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-010):To a stirred solution of 2-(trifluoromethoxy)benzoic acid (500 mg, 2.426 mmol) in DMF (5 mL) was added HATU (1.38 g, 3.638 mmol), DIPEA (0.85 mL, 4.851 mmol) at RT. The reaction mixture was stirred atRT for 20 min. Then, (5-(allyloxy)-6-methoxypyridin-3-yl)(7-amino-l-isopropyl-6,7-dihydro-lH-pyrazolo[4,3-b]pyridin-4(5H)-yl)methanone (lnt-13 of Scheme 1) (1.07 g, 2.911 mmol) was added portion wise at RT. The reaction was allowed to stir for 16 h.Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (3 x 50 mL), the combined organic layer was dried over ISfeSCL, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3% MeOH-DCM as eluent) to afford racemic compound A-(4-(5-(-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-l / 7-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-010) (210 mg, 15% yield) as off white solid.1H NMR (400 MHz, DMSO-ds): 89.17 (d,J= 8.4 Hz, 1H), 7.97-7.95 (m, 1H), 7.64-7.55 (m, 3H), 7.49-7.43 (m, 2H), 7.10 (s, 1H), 6.05-5.99 (m, 1H), 5.42 (m, 1H), 5.14 (d, J= 10.8 Hz, 1H), 4.99-4.93 (m, 3H), 4.48-4.45 (m, 1H), 4.23-4.20 (m, 1H), 3.81-3.76 (m, 4H), 2.10-1.99 (m, 2H), 1.41-1.37 (m, 6H). LCMS: Method A m / z: 560.70 [M+l]+Rf= 0.4 (Mobile phase: 5% MeOH-DCM).Chiral separation of (R)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-011) and (S)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-012):SI-011 SI-012The racemic compound SI-010 (150 mg) was separated by chiral prep HPLC to afford 35 mg of compound SI-011 (RT = 20.23) and 35 mg of SI-012 (RT = 23.96).Chiral Analytical HPLC Method:CHIRALPAK IG, 250 x 4.6 mm, 5 pmMobile pahase: A: n-Hexane:EtOH:MeOH (85:10:5),F / R: 1.0 mL / min, Column Temp: 40°CChiral PrepHPLC Method: CHIRALCEL PAK IG, 250 x 30 mm, 5 pmMobile phase: n-Hexane:EtOH:MeOH (85:10:5)Flow rate: 20 mL / min.SI-011: H NMR (400 MHz, DMSO-ds) <5: 9.17 (d, J= 8.0 Hz, 1H), 7.98 (m, 1H), 7.64-7.55 (m, 3H), 7.48-7.45 (m, 2H), 7.10 (s, 1H), 6.03-6.02 (m, 1H), 5.42 (m, 1H), 5.14 (d, J= 9.6 Hz, 1H), 4.99-4.93 (m, 3H), 4.48-4.46 (m, 1H), 4.23-4.20 (m, 1H), 3.80-3.76 (m, 4H), 2.10-2.03 (m, 2H), 1.41-1.37 (m, 6H). [a]D25: +92.5 (c=0.03% inDMF); LCMS: Method A m / z: 560.40 [M+l]+SI-012: H NMR (400 MHz, DMSO-ds) <5 : 9.17 (d, J= 8.0 Hz, 1H), 7.98 (m, 1H), 7.64-7.55 (m, 3H), 7.49-7.43 (m, 2H), 7.10 (s, 1H), 6.07-5.98 (m, 1H), 5.43-5.42 (m, 1H), 5.14 (d, J= 10.0 Hz, 1H), 4.99-4.93 (m, 3H), 4.48-4.45 (m, 1H), 4.23-4.20 (m, 1H), 3.81-3.73 (m, 4H), 2.10-1.99 (m,2H), 1.41-1.37 (m, 6H). [a]D25: +80.00 (c=0.03% in DMF); LCMS: Method A m / z: 560.70 [M+l]+Example 5:Scheme 5:HATU, Et3N, DMF, RT, 16 h Step-14N HCI in 1 ,4 Dioxane, DCM, RT, 4 h HATU, Et3N, DMF,RT, 1 h Step-2 Step-3Chiral separation Step-4SI-014 (+) SI-015 (-) Step-1: Preparation of tert-butyl (4-(5 ,6-dimethoxynicotinoyl)-l-isopropyl-4,5 ,6, 7 -tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate (2):To a stirred solution of 5,6-dimethoxynicotinic acid (Int-3) (500 mg, 2.723 mmol) in DMF (5 mL) was added HATU (1.55 g, 4.004 mmol), EbN (0.8 mL, 5.446 mmol) at RT. Stirred thereaction mixture at RT for 20 min. Then tert-butyl (l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)carbamate (Int-11 of Scheme 1) (914 mg, 3.267 mmol) was added at RT. stirred the reaction mixture at RT for 16 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (3 x 150 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3% MeOH-DCM as eluent) to afford tert-butyl (4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)carbamate (2) (1 g, 83% yield) as off white solid, m / z: 446.16 [M+1]+ 1H NMR (400 MHz, DMSO-ds): d 8.11 (s, 1H), 7.81 (s, 1H), 7.57-7.55 (m, 1H), 7.33 (s, 1H), 4.97-4.96 (m, 1H), 4.47 (m, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.74 (m, 2H), 2.05 (m, 1H), 1.85-1.82 (m, 1H), 1.34-1.33 (m, 6H).Rf= 0.4 (Mobile phase: 5% MeOH-DCM).Step-2: Preparation of (7-amino-l-isopropyl-6, 7-dihydro-lH-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3-yl)methanone (3):To solution a stirred of tert-butyl (4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro- lH-pyrazolo[4,3-b]pyridin-7-yl)carbamate (1 g, 2.247 mmol) in DCM (10 mL) was added 4N HO in 1,4 Dioxane (10 mL) at 0 °C, stirred the reaction mixture at RT for 4h. Completion of the starting material was monitored by TLC. Volatiles were evaporated under reduced pressure to get crude residue, the obtained crude residue was triturated with Diethylether (10 mL) to afford (7-amino- 1 -isopropyl-6,7 -dihydro- IH-pyrazolo [4,3 -b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3 -yl)methanone (680 mg, 77% yield) as light brown solid, m / z: 346.42 [M+l]+Rf= 0.3 (Mobile phase: 5% MeOH-DCM).Step-3: Preparation ofN-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lPI-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-013):SI-013To a stirred solution of 2-(trifluoromethyl)benzoic acid (400 mg, 2.104 mmol) in DMF (8 mL) was added HATU (1.2 g, 3.155 mmol), EtsN (0.59 mL, 4.207 mmol) at RT. Stirred the reaction mixture at RT for 20 min. Then (5-(allyloxy)-6-methoxypyridin-3-yl)(7-amino-l-isopropyl-6,7-dihydro-l / / -pyrazolo|4.3-b|pyridin-4(5 / / )-yl)mcthanonc (3) (870 mg, 2.524 mmol) was added at RT. stirred the reaction mixture at RT for 30 min. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (3 x 50 mL), the combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3% MeOH-DCM as eluent) to afford the racemic compound N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-013) (65 mg, 6% yield) as white solid. LCMS: Method A m / z: 518.32 [M+1]+1H NMR (400 MHz, DMSO-de): <59.21 (d, J= 8.0 Hz, 1H), 8.06 (m, 1H), 7.82-7.63 (m, 4H), 7.51 (d, J= 7.20 Hz, 1H), 7.35 (s, 1H), 5.42-5.41 (m, 1H), 4.48-4.45 (m, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.67 (m, 2H), 2.14-2.08 (m, 1H), 2.00-1.96 (m, 1H), 1.42-1.41 (m, 6H).Rf= 0.4 (Mobile phase: 5% MeOH-DCM).Chiral separation of (R)-N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6, 7 -tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-014) and (S)-N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-015):The racemic compound SI-013 (50 mg) was separated by chiral prep HPLC to afford 13 mg of compound SI-014 (RT = 22.78) and 14 mg of SI-015 (RT = 27.47).Chiral Analytical HPLC Method:CHIRALPAK IG, 250 x 4.6 mm, 5 pmMobile phase: A: (Hexane:IPA:EtOH)(80:10:10),F / R: 1.0 mL / min, Column Temp: 40°CChiral Prep HPLC Method: CHIRALCEL PAK IG, 250 x 30 mm, 5 pmMobile phase: n-Hexane:IPA:EtOH (80:10:10)Flow rate: 20 mL / minSI-014: H NMR (400 MHz, DMSO-ds) dppm 9.21 (d, J= 8.4 Hz, 1H), 8.05 (m, 1H), 7.82-7.63 (m, 4H), 7.51 (d, J= 7.60 Hz, 1H), 7.35 (s, 1H), 5.42 (m, 1H), 4.48-4.45 (m, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.67 (m, 2H), 2.14-2.11 (m, 1H), 2.00-1.96 (m, 1H), 1.42-1.41 (m, 6H). [a]D25: +79.54 (c=0.03%inDMF); LCMS: Method A m / z: 518.32 [M+l]+SI-015: H NMR (400 MHz, DMSO-ds) dppm: 9.21 (d, J= 8.0 Hz, 1H), 8.06 (m, 1H), 7.82-7.63 (m, 4H), 7.51 (d, J= 7.60 Hz, 1H), 7.35 (s, 1H), 5.42-5.41 (m, 1H), 4.48-4.45 (m, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.67 (m, 2H), 2.13 (m, 1H), 2.00-1.96 (m, 1H), 1.42-1.41 (m, 6H). [a]D25: -81.54 (c=0.03% in DMF); LCMS: Method A m / z: 518.32 [M+l]+Scheme 6:HATU, Et3N,DMF, RT, 1 h Step 1SI-016 (±)Chiral separationStep 2SI-017 (+) SI-018 (-)Preparation of 4-(allyloxy)-N-(4-(5, 6-dimethoxynicotinoyl)-l-isopropyl-4,5, 6, 7 -tetrahydro- 1H-pyrazolo[4, 3-b ]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-016):SI-016To a stirred solution of 4-(allyloxy)-2-(trifluoromethyl)benzoic acid (Int-2) (300 mg, 1.219 mmol) in DMF (3 mL) was added HATU (695 mg, 1.829 mmol), Et-5N (0.34 mL, 2.439 mmol) at RT. Stirred the reaction mixture at RT for 20 min. Then (7 -amino- 1 -isopropyl-6,7-dihydro- 1 H-pyrazolo[4,3-b]pyridin-4(57 / )-yl)(5,6-dimethoxypyridin-3-yl)methanone (compound 3 of Scheme 5) (504 mg, 1.463 mmol) was added at RT. stirred the reaction mixture at RT for 16 h.Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (3 x 50 mL), the combined organic layer was dried over ISfeSCL, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 2% MeOH-DCM as eluent) to afford the racemic compound 4-(allyloxy)-N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-016) (120 mg, 17% yield) as white solid. 'H NMR (400 MHz, DMSO-ds): d 9.10 (d, J= 7.6 Hz,1H), 8.06 (m, 1H), 7.82 (s, 1H), 7.64-7.44 (m, 1H), 7.35-7.28 (m, 3H), 6.07-5.98 (m, 1H), 5.43- 5.39 (m, 2H), 5.29 (d, J= 10.4 Hz, 1H), 4.71-4.69 (m, 2H), 4.47-4.44 (m, 1H), 3.92 (s, 3H), 3.82-3.68 (m, 5H), 2.13-2.08 (m, 1H), 1.98-1.95 (m, 1H), 1.41 (m, 6H). LCMS: Method A m / z: 574.65 [M+l]+Rf= 0.4 (Mobile phase: 5% MeOH-DCM)Chiral separation of (R)-4-(allyloxy)-N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-017) and (S)-4-(allyloxy)-N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-018):SI-017 SI-018The racemic compound SI-016 (100 mg) was separated by chiral prep HPLC to afford 28 mg of compound SI-017 (RT = 12.44) and 29 mg of SPT-018 (RT = 14.28).Chiral Analytical HPLC Method:CHIRALPAK IG, 250 x 4.6 mm, 5 pmMobile phase:A: N-Hexane:EtOH:IPA(60:20:20),F / R: 1.0 mL / min,Column Temp: 40°CChiral Prep HPLC Method: CHIRALCEL PAK IG, 250 x 30 mm, 5 pmMobile phase: n-Hexane:IPA:EtOH (60:20:20)Flow rate: 20 mL / minSI-017: H NMR (400 MHz, DMSO-ds) dppm: 9.10 (d, J= 8.4 Hz, 1H), 8.06 (m, 1H), 7.82 (s, 1H), 7.64-7.44 (m, 1H), 7.34-7.27 (m, 3H), 6.07-5.98 (m, 1H), 5.43-5.39 (m, 2H), 5.28 (d, J= 10.8 Hz, 1H), 4.70-4.69 (m, 2H), 4.45 (m, 1H), 3.92 (s, 3H), 3.82-3.68 (m, 5H), 2.13 (m, 1H), 1.98 (m, 1H), 1.41 (m, 6H); [a]D25: +98.45 (c=0.03% inDMF); LCMS: Method A m / z: 574.41 [M+l]+SI-018: H NMR (400 MHz, DMSO-d6) 8ppm 9.10 (d, J= 8.4 Hz, 1H), 8.05 (m, 1H), 7.82 (s, 1H), 7.46-7.44 (m, 1H), 7.35-7.27 (m, 3H), 6.06-5.99 (m, 1H), 5.43-5.38 (m, 2H), 5.29 (d, J= 10.8 Hz, 1H), 4.71-4.69 (m, 2H), 4.45 (m, 1H), 3.92 (s, 3H), 3.82-3.68 (m, 5H), 2.12 (m, 1H), 1.98 (m, 1H), 1.41 (m, 6H); [a]D25: -110.25 (c=0.03% in DMF); LCMS: Method A m / z: 574.41 [M+l]+Scheme 7:HATU, EtsN, DMF, RT, 2 h Step 1SI-019 (±)Chiral separation Step 2SI-021 (-) Preparation of 4-(allyloxy)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)Benzamide (SI-019):SI-019To a stirred solution of ethyl 4-(allyloxy)-2-(trifluoromethoxy)benzoate, Int-4 (280 mg, 1.068 mmol) inDMF (2.8 mL) was added HATU (609 mg, 1.603 mmol), EtsN (0.4 mL, 2.137 mmol) at RT. Stirred the reaction mixture at RT for 20 min. Then (5-(allyloxy)-6-methoxypyridin-3-yl)(7-amino-l-isopropyl-6,7-dihydro-lH-pyrazolo[4,3-b]pyridin-4(5H)-yl)methanone (compound 13 of Scheme 1) (475 mg, 1.282 mmol) was added at RT. stirred the reaction mixture at RT for 2 h.Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (3 x 50 mL), the combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3%MeOH-DCM as eluent) to afford racemic compound 4-(allyloxy)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)Benzamide (SI-019) (150 mg, 22% yield) as white solid. 'H NMR (400 MHz, DMSO-ds): d 9.00 (d, J= 8.0 Hz, 1H), 8.00-7.97 (m, 1H), 7.72 (s, 1H) 7.53 (d, J= 8.8 Hz, 1H), 7.08-7.05 (m, 1H), 6.99 (s, 1H), 6.76 (s, 1H), 6.08-5.93 (m, 1H), 5.44-5.40 (m, 2H), 5.30 (d, J= 10.4 Hz, 1H), 5.12 (d, J = 10 Hz, 1H), 4.96-4.66 (m, 3H), 4.68-4.67 (m, 2H), 4.47-4.42 (m, 1H), 4.16-4.13 (m, 1H), 3.83-3.77 (m, 4H), 2.07-1.96 (m, 2H), 1.45-1.36 (m, 6H). LCMS: Method A m / z: 616.81 [M+l]+Rf= 0.4 (Mobile phase: 5% MeOH-DCM).Chiral separation of (R)-4-(allyloxy)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-020) and (S)-4-(allyloxy)-N-(4-(5-(allyloxy)-6-methoxynicotinoyl)-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-021):SI-020 SI-021The racemic compound SI-019 (100 mg) was separated by chiral prep HPLC to afford 35 mg of compound SI-020 (RT = 10.92) and 35 mg of SI-021 (RT = 13.17).Chiral Analytical HPLC Method:Column: CHIRALPAK V, 250 x 4.6 mm, 5 pmMobile phase: Hexane:IPA:MEOH:DEA)(85:10:05:0.1),F / R: 1.0 mL / min, Column Temp:40°CChiral Prep HPLC Method: CHIRALCEL PAK IG, 250 x 30 mm, 5 pmMobile phase: n-Hexane:IPA:MeOH (85:10:5)Flow rate: 20 mL / min.SI-020:XH-NMR (400 MHz, DMSO-d6) 3ppm: 9.00 (d, J= 8.4 Hz, 1H), 7.97 (m, 1H), 7.71 (s, 1H), 7.53 (d, J= 8.8 Hz, 1H), 7.08-7.05 (m, 1H), 6.98 (s, 1H), 6.76 (s, 1H), 6.07-5.92 (m, 1H), 5.44-5.39 (m, 2H), 5.29 (d, J= 10.4 Hz, 1H), 5.12 (d, J= 10.4 Hz, 1H), 4.95-4.73 (m, 3H), 4.67-4.66 (m, 2H), 4.47-4.43 (m, 1H), 4.16-4.12 (m, 1H), 3.83-3.73 (m, 4H), 2.06-1.95 (m, 2H), 1.40- 1.35 (m, 6H). [ot]D25: +99.77 (c=0.03% in DMF); LCMS: Method A m / z: 616.53 [M+l]+SI-021: ^-NMR (400 MHz, DMSO-d6) dppm: 9.00 (d, J= 8.4 Hz, 1H), 7.97 (m, 1H), 7.71 (s, 1H), 7.53 (d, J= 8.8 Hz, 1H), 7.07-7.05 (m, 1H), 6.98 (s, 1H), 6.75 (s, 1H), 6.07-5.92 (m, 1H), 5.43-5.39 (m, 2H), 5.29 (d, J= 10.4 Hz, 1H), 5.12 (d, J= 10.4 Hz, 1H), 4.95-4.73 (m, 3H), 4.67-4.66 (m, 2H), 4.47-4.43 (m, 1H), 4.16-4.12 (m, 1H), 3.83-3.73 (m, 4H), 2.09-1.95 (m, 2H), 1.40- 1.35 (m, 6H). [a]D25: -76.68 (c=0.03% in DMF); LCMS: Method A m / z: 616.58 [M+l]+Scheme 8:HATU, DIPEA, DMF, RT, 16 h Step 1SI-022Preparation of 4-(allyloxy)-N-(4-(5, 6-dimethoxynicotinoyl)-l-isopropyl-4,5, 6, 7 -tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-022):SI-022To a stirred solution of 4-(allyloxy)-2 -(trifluoromethoxy )benzoic acid (Int-4) (190 mg, 0.725 mmol) inDMF (1.9 mL) was added HATU (417 mg, 1.087 mmol), ELN (0.3 mL, 2.175 mmol) at RT. Stirred the reaction mixture at 0 °C for 20 min. Then (7-amino-l-isopropyl-6,7-dihydro-lH-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3-yl)methanone (compound 3 of scheme 5) (300 mg, 0.870 mmol) was added at 0 °C, stirred the reaction mixture at 0 °C for 1.5 h.Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with cold water (30 mL) and extracted with EtOAc (3 x 30 mL), the combined organic layer was dried over ISfeSCL, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 3%MeOH-DCM as eluent) to afford racemic compound 4-(allyloxy)-N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-022) (102 mg, 23% yield) as white solid. LCMS: Method A m / z: 590.39 [M+l]+ 1H NMR (400 MHz, DMSO-de): d 8.99 (d, J= 8.4 Hz, 1H), 7.90 (m, 1H), 7.70 (s, 1H), 7.54 (d, J= 8.0 Hz, 1H), 7.08-7.05 (m, 1H), 6.99 (s, 1H), 6.74 (s, 1H), 6.06-5.99 (m, 1H), 5.43-5.39 (m, 2H), 5.29 (d, J= 10.4 Hz, 1H), 4.68-4.66 (m, 2H), 4.49-4.43 (m, 1H), 4.20-4.17 (m, 1H), 3.87-3.75 (m, 7H), 2.14-2.08 (m, 1H), 1.99-1.96 (m, 1H), 1.41-1.36 (m, 6H).Rf= 0.4 (Mobile phase: 5% MeOH-DCM).Chiral separation of (R)-4-(allyloxy)-N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-023) and (S)-4-(allyloxy)-N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b ]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-024):SI-023 SI-024The racemic compound SI-022 (70 mg) was separated by chiral prep HPLC to afford 18 mg of compound SI-023 (RT = 26.67) and 19 mg of SI-024 (RT = 36.08).Chiral Analytical HPLC Method:CHIRALPAK IG, 250 x 4.6 mm, 5 gmMobile phase: (Hexane:EtOH:IPA)(70:15:15),F / R: l.OmL / min, Column Temp:40°CChiral Prep HPLC Method: CHIRALCEL PAK IG, 250 x 30 mm, 5 pmMobile phase: n-Hexane:IPA:EtOH (70:15:15)Flow rate: 20 mL / minSI-023: H-NMR (400 MHz, DMSO-d6) dppm: 8.99 (d, J= 8.4 Hz, 1H), 7.90 (m, 1H), 7.70 (s, 1H), 7.54 (d, J= 8.8 Hz, 1H), 7.08-7.05 (m, 1H), 6.99 (s, 1H), 6.74 (s, 1H), 6.06-5.99 (m, 1H), 5.43-5.39 (m, 2H), 5.29 (d, J= 10.4 Hz, 1H), 4.68-4.66 (m, 2H), 4.49-4.43 (m, 1H), 4.20-4.17 (m, 1H), 3.87-3.75 (m, 7H), 2.14-2.08 (m, 1H), 1.99-1.96 (m, 1H), 1.41-1.36 (m, 6H). [a]D25: +114.47 (c=0.03%inDMF); LCMS: Method A m / z: 590.35 [M+l]+SI-024: H-NMR (400 MHz, DMSO-d6) <5ppm: 8.99 (d, J= 8.4 Hz, 1H), 7.90 (m, 1H), 7.70 (s, 1H), 7.54 (d, J= 8.4 Hz, 1H), 7.08-7.05 (m, 1H), 6.99 (s, 1H), 6.74 (s, 1H), 6.06-5.99 (m, 1H), 5.43-5.39 (m, 2H), 5.29 (d, J= 10.4 Hz, 1H), 4.68-4.66 (m, 2H), 4.49-4.43 (m, 1H), 4.20-4.17 (m, 1H), 3.87-3.75 (m, 7H), 2.14-2.08 (m, 1H), 1.99-1.96 (m, 1H), 1.41-1.36 (m, 6H). [a]D25: -103.33 (c=0.03%inDMF); LCMS: Method A m / z: 590.38 [M+l]+Scheme 9:MC-01 -Racemic SI-054SI-001Step-1: Preparation of SI-054:To a stirred solution of SI-001 (135 mg, 0.236 mmol) in DCM (1.35 mL) was added mCPBA (162 mg, 0.944 mmol) at 0 °C, stirred the reaction mixture at RT for 16 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with sat.aq.NaHCOs solution (25 mL) and extracted with DCM (3 x 25 mL), the combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to get crude residue. The crude residue was purified by prep HPLC, pure fractions was collected and lyophilized to afford SI-054 (2 mg) as off white solid, m / z: 588.56 [M+l]+'H NMR (400 MHz, DMSO-de): d 8.67 (d, J= 8.0 Hz, 1H), 7.73 (s, 1H), 7.56 (d, J= 8.8 Hz, 1H), 7.46-7.38 (m, 2H), 7.14 (s, 1H), 7.08 (s, 1H), 4.99-4.96 (m, 1H), 4.76-4.65 (m, 4H), 4.57-4.53 (m, 1H), 4.16-4.12 (m, 1H), 4.01-3.86 (m, 3H), 3.72 (s, 3H), 2.32-2.22 (m, 2H), 1.23-1.12 (m, 6H).Rf= 0.2 (Mobile phase: 5% MeOH-DCM).Prep HPLC Method:Column: Xtimate (150 x 21.2mm, 5 pm),Mobile Phase: A-0.1%FA in water; B-100% ACN,(T / %B: 0 / 30, 2 / 30, 35 / 70)Flow Rate: 17 ml / min.LCMS Method:KinetexEVO C18 (2.1 x 50 mm, 1.7 pm),Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN,(T / %B: 0.01 / 10, 0.5 / 10, 5 / 40, 10 / 90)Flow Rate: 0.4 mL / minScheme 10OsO4, NMO, tBuOH, Acetone, H2O, 0 °C-RT, 4 h Step 1MC-01 -RacemicSI-001 Step-1: Preparation of SI-056:To a stirred solution of SI-001 (150 mg, 0.262 mmol) in t-BuOH (3 mL), Acetone (3 mL) was added NMO (31 mg, 0.262 mmol) and OsO4(0.5 mL) at 0 °C, stirred the reaction mixture at RT for 3 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with EtOAc: MeOH (1:1, 25 mL), fdtered through celitebed, filtrate was evaporated under reduced pressure to get crude residue. The crude residue was purified by prep HPLC, pure fractions was collected and lyophilized to afford SI-056-1 (11 mg, 6%) and SI-056-2 (4 mg) as off white solid.SI-056-1: 'H NMR (400 MHz, DMSO-ds): d 8.81-8.73 (m, 1H), 7.83-7.79 (m, 1H), 7.64 (s, 1H), 7.35 (dd, J= 8.4 Hz, 20.8 Hz, 1H), 7.17-7.09 (m, 2H), 6.71 (d, J= 10.8 Hz, 1H), 5.40 (m, 1H), 4.83-4.75 (m, 2H), 4.50-4.39 (m, 2H), 4.21-4.15 (m, 2H), 4.10-3.92 (m, 2H), 3.92-3.38 (m, 6H), 2.27-2.24 (m, 1H), 1.97 (m, 1H), 1.42-1.40 (m, 6H). m / z: 606.73 [M+l]+SI-056-2: 'H NMR (400 MHz, DMSO-de): d 8.79-8.77 (m, 1H), 7.85 (m, 1H), 7.64 (s, 1H), 7.34 (d, J= 8.8 Hz, 1H), 7.16-7.12 (m, 2H), 6.69 (m, 1H), 5.40 (m, 1H), 4.96-4.95 (m, 1H), 4.71-4.71 (m, 1H), 4.49-4.40 (m, 2H), 4.21-4.17 (m, 2H), 4.05-3.85 (m, 2H), 3.91-3.44 (m, 6H), 2.27-2.25 (m, 1H), 1.99 (m, 1H), 1.42-1.40 (m, 6H). m / z: 606.71 [M+l]+Rf= 0.2 (Mobile phase: 5% MeOH-DCM).Prep HPLC Method:X-TIMATE C18 (150 x 21.2mm, 5 pm),Mobile Phase: A-0.1%TFA in water; B-100% ACN,(T / %B: 0 / 30, 2 / 30, 25 / 60)Flow Rate: 17 ml / min.LCMS Method:Column: KinetexEVO C18 (2.1 x 50 mm, 1.7 gm)Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN,(T / %B: 0.01 / 10, 0.5 / 10,4 / 90, 7 / 90)Flow Rate: 0.4 mL / minTo a stirred solution of Benzyl Alcohol (0.49 mL, 4.80 mmol) in DMF (20 mL) was added NaH (926 mg, 19.7 mmol) at 0 °C, stirred reaction mixture at 0 °C for 20 min. Then was added 4-fhioro-2-(trifhioromethyl)benzoic acid (1) (1.0 g, 4.80 mmol) at 0 °C, stirred the reaction mixture at RT for 16 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (50 mL) and washed with EtOAc (2 x 50 mL), the aqueous layer was acidified by IN HO (pH= ~2) and extracted with 10% MeOH in DCM (3 x 50 mL). The combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to afford 4-(benzyloxy)-2-(trifluoromethyl)benzoic acid (2) (1.0 g, 70% yield) as an light brown liquid, m / z: 297.18 [M+l]+. 'H NMR (400 MHz, DMSO-ds): d 13.28 (br s, 1H), 7.87-7.85 (m, 1H), 7.48-7.34 (m, 7H), 5.26 (s, 2H).Rf = 0.2 (Mobile phase: 30% EtOAc-Hexane)Step-2: Preparation of 4-(benzyloxy)-N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-059):SI-059To a stirred solution of 4-(benzyloxy)-2-(trifluoromethyl)benzoic acid (2) (250 mg, 0.80 mmol) in DMF (2.5 mL) was added EhN (0.34 mL, 2.41 mmol) and HATU (459 mg, 1.20 mmol) at RT. Stirred reaction mixture at 0 °C for 5 min. Then (7-amino-l-isopropyl-6,7-dihydro-lH-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3-yl)methanone (Int-3 of SI-013) (333 mg, 0.96 mmol) was added at 0 °C, stirred the reaction mixture at RT for 2 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (25 mL) and extracted with EtOAc (3 x 25 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 60% EtOAc -Hexane as eluent) to afford 4-(benzyloxy)-N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-059) (35 mg, 7% yield ) as an off white solid, m / z: 624.41 [M+l]+. 'H NMR (400 MHz, DMSO-ds) d ppm: 9.08 (d, J= 8.4 Hz, 1H), 7.69-7.34 (m, 10H), 6.73 (s, 1H), 5.40-5.38 (m, 1H), 5.24 (s, 2H), 4.47-4.42 (m, 1H), 4.21-4.18 (m, 1H), 3.83-3.72 (m, 7H), 2.10-1.98 (m, 2H), 1.41-1.38 (m, 6H).Rf= 0.5 (Mobile phase: 5% MeOH-DCM).Chiral Separation of (R)-4-(benzyloxy) -N-(4-(5 ,6-dimethoxynicotinoyl)- 1 -isopropyl-4,5 ,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)Benzamide (SI-082) and (S)-4-(benzyloxy)-N-(4-(5,6-dimethoxynicotinoyl)-l -isopropyl-4,5, 6, 7-tetrahydro-lH-pyrazolo[4,3-b ]pyridin-7-yl)-2-(trifluoromethyl)Benzamide (SI-083):The racemic compound SI-059 (25 mg) was separated by chiral prep HPLC to afford 8 mg of compound SI-082 (RT = 8.498) and 8 mg of SI-083 (RT = 15.346).Chiral Analytical HPLC Method:CHIRALPAK U, 250 x 4.6 mm, 5 gmMobile phase: A: (HEXANE:MEOH:IPA:TFA) (50:30:20:0.1),F / R: 1.0 mL / min, Column Temp: 40°CChiral PrepHPLC Method: CHIRALPAK IJ, 250 x 4.6 mm, 5 pmMobile phase: (HEXANE:MEOH:IPA:TFA) (50:30:20:0.1),Flow rate: 25 mL / min.SI-084: H NMR (400 MHz, DMSO-d6) d ppm: 9.08 (d, J= 8.4 Hz, 1H), 7.70-7.34 (m, 10H),6.73 (s, 1H), 5.40-5.38 (m, 1H), 5.25 (s, 2H), 4.47-4.43 (m, 1H), 4.21-4.18 (m, 1H), 3.84-3.73 (m, 7H), 2.10-1.98 (m, 2H), 1.45-1.38 (m, 6H). [a]D25: +82.45 (c= 0.03% inMeOH); LCMS: Method Am / z: 624.40 [M+l]+SI-085: H NMR (400 MHz, DMSO-d6) d ppm 9.07 (d, J= 8.4 Hz, 1H), 7.69-7.34 (m, 10H),6.73 (s, 1H), 5.40-5.39 (m, 1H), 5.24 (s, 2H), 4.48-4.42 (m, 1H), 4.21-4.18 (m, 1H), 3.92-3.72 (m, 7H), 2.13-1.97 (m, 2H), 1.45-1.38 (m, 6H). [a]D25: -103.81 (c= 0.03% inMeOH); LCMS: Method Am / z: 624.37 [M+l]+Scheme 12SI-061 Step-1: Preparartion of N-(4-(5, 6-dimethoxynicotinoyl)-l-isopropyl-4,5, 6, 7 -tetrahydro- 1H-pyrazolo[ 4, 3-b ]pyridin-7-yl)-4-hydroxy-2-(trifluoromethyl)benzamide (2) :To a stirred solution of 4-hydroxy-2-(trifluoromethyl)benzoic acid (1) (300 mg, 1.45 mmol) inDMF (3 mL) was added EhN (0.61 mL, 4.36 mmol) and HATU (830 mg, 2.18 mmol) at RT. Stirred reaction mixture at 0 °C for 5 min. Then (7-amino-l-isopropyl-6,7-dihydro-lH-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3-yl)methanone (603 mg, 1.74 mmol) was added at 0 °C, stirred the reaction mixture at RT for 2 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (3 x 50 mL), the combined organic layer was dried over Na2SC>4. filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by rev-phase column chromatography (C-18 mesh silica gel, 50% ACN-0.1% FA in H2O as eluent), pure fractions was collected and lyophilized to afford N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-4-hydroxy-2-(trifluoromethyl)benzamide (2) (200 mg, 26% yield) as an off white solid, m / z: 534.38 [M+l]+'H NMR (400 MHz, DMSO-de): d 10.44 (s, 1H), 9.00 (d, J= 8.4 Hz, 1H), 8.05-7.97 (m, 1H), 7.73-7.66 (m, 1H), 7.38 (d, J= 8.4 Hz, 1H), 7.10-7.09 (m, 1H), 7.05 (d, J= 8.4 Hz, 1H), 6.74 (s, 1H), 5.39-5.38 (m, 1H), 4.474.43 (m, 1H), 4.21-4.17 (m, 1H), 3.92-3.79 (m, 1H), 3.74-3.69 (m, 6H), 2.09-2.07 (m, 1H), 1.99-1.96 (m, 1H), 1.45-1.35 (m, 6H). Rf = 0.5 (Mobile phase: 5% MeOH-DCM).Step-2: Preparartion of 4-((4-(5, 6-dimethoxynicotinoyl)-l-isopropyl-4, 5, 6, 7 -tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)carbamoyl)-3-(trifluoromethyl)phenyl methane sulfonate (SI-061)'.To a stirred solution of N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-4-hydroxy-2-(trifluoromethyl)benzamide (2) (200 mg, 0.37 mmol) in DCM (2.0 mL) was added EhN (0.06 mL, 0.45 mmol) and MsCl (0.029 mL, 0.37 mmol) at 0 °C. Stirred the reaction mixture at RT for 1 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with water (25 mL) and extracted with DCM (3 x 25 mL), the combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by rev-phase column chromatography (C-18 mesh silica gel, 70% ACN-0.1% FA in H2O as eluent) lyophilized to afford4-((4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)carbamoyl)-3-(trifluoromethyl)phenyl methanesulfonate (SI-061) (45 mg, 20% yield) as an off white solid, m / z: 612.33 [M+l]+'H NMR (400 MHz, DMSO-de) d ppm: 9.29 (d, J= 8.4 Hz, 1H), 7.99-7.70 (m, 5H), 6.74 (s, 1H), 5.42-5.41 (m, 1H), 4.48-4.45 (m, 1H), 4.24-4.21 (m, 1H), 3.92-3.78 (m, 7H), 3.50(s, 3H), 2.12-2.02 (m, 2H), 1.42-1.40 (m, 6H).Rf = 0.7 (Mobile phase: 5% MeOH-DCM).Chiral separation of (R)-4-((4-(5, 6-dimethoxynicotinoyl)-l-isopropyl-4, 5, 6, 7 -tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)carbamoyl)-3-(trifluoromethyl)phenyl methanesulfonate (SI-084) and (S)-4-((4-(5 ,6-dimethoxynicotinoyl)- 1 -isopropyl-4,5 ,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)carbamoyl)-3-(trifluoromethyl)phenyl methanesulfonate (SI-085)SI-084 SI-085The racemic compound SI-061 (35 mg) was separated by chiral prep HPLC to afford 10 mg of compound SI-084 (RT = 8.610) and 10 mg of SI-085 (RT = 10.828).Chiral Analytical HPLC Method:CHIRALPAK U, 250 x 4.6 mm, 5 pmMobile pahase: A: (HEXANE:MEOH:IPA:TFA)(50:30:20:0.1),F / R: 1.0 mL / min, Column Temp: 40°CChiral PrepHPLC Method: CHIRALPAK U, 250 x 4.6 mm, 5 pmMobile phase: (HEXANE:MEOH:IPA:TFA)(50:30:20:0.1),Flow rate: 20 mL / min.SI-084: 'H NMR (400 MHz, DMSO-de) d ppm: 9.29 (d, J= 8.0 Hz, 1H), 7.79-7.69 (m, 5H), 6.74 (s, 1H), 5.42-5.40 (m, 1H), 4.48-4.44 (m, 1H), 4.24-4.20 (m, 1H), 3.82-3.72 (m, 7H), 3.50 (s, 3H), 2.12-2.01 (m, 2H), 1.45-1.40 (m, 6H). [a]D25: + 69.56 (c=0.03%inMeOH); LCMS: Method A m / z: m / z: 612.33 [M+l]+SI-085: 'H NMR (400 MHz, DMSO-ds) d ppm: 9.29 (d, J= 8.4 Hz, 1H), 7.79-7.67 (m, 5H), 6.74 (s, 1H), 5.42-5.41 (m, 1H), 4.48-4.45 (m, 1H), 4.24-4.20 (m, 1H), 3.81-3.73 (m, 7H), 3.50 (s, 3H), 2.11-2.02 (m, 2H), 1.42-1.40 (m, 6H). [a]D25: -97.48 (c= 0.03% inMeOH); LCMS: Method Am / z: 612.33 [M+l]+Scheme 13:Step-1 : Preparation of methyl 4-hydroxy-2-(trifluoromethyl) benzoate:o CF3To a stirred solution 4-hydroxy-2-(trifluoromethyl)benzoic acid (2 g, 9.708 mmol) in MeOH (20 mL) was added Conc.EbSCb (1.55 mL, 29.124 mmol) at RT. Stirred the reaction mixture at 75 °C for 16 h. Completion of the reaction was confirmed by TLC and LCMS. Volatiles was evaporated under reduced pressure to get crude residue, which was diluted with water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was dried over IS^SCL, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 10% EtO Ac -Hexane as eluent) to afford methyl 4-hydroxy-2-(trifluoromethyl) benzoate (1.5 g, 70%) as white solid, m / z: 219.09 [M-H]+. 'H NMR (400 MHz, DMSO-de): d 10.87 (br s, 1H), 7.79 (d, J= 8.8 Hz, 1H), 7.19-7.18 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H).Rf = 0.4 (Mobile phase: 20% EtO Ac -Hexane).Step-2: Preparation of methyl 4-(difluoromethoxy)-2-(trifluoromethyl)benzoate (5):To a stirred solution of methyl 4-hydroxy-2-(trifluoromethyl)benzoate (3) (500 mg, 2.272 mmol) inDMF (5 mL) was added K2CO3 (940 mg, 6.818 mmol) and methyl 2-chloro-2,2-difluoroacetate (4) (1.1 mL, 11.363 mmol) at RT. Heated the reaction mixture at 60 °C for 16 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (25 mL) and extracted withEtOAc (3 x 25 mL), the combined organic layer was dried over ISfeSCL, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 10% EtO Ac -Hexane as eluent) to afford methyl 4-(difhioromethoxy)-2-(trifluoromethyl)benzoate (3) (400 mg, 65% yield) as a light greenish liquid.'H NMR (400 MHz, DMSO-ds): d 7.97 (d, J= 8.4 Hz, 1H), 7.63-7.31 (m, 3H), 3.87 (s, 3H). TLC: Rf = 0.6 (Mobile phase: 20% EtO Ac -Hexane).Step-3: Preparation of 4-(difluoromethoxy)-2-(trifluoromethyl)benzoic acid (6):To a stirred solution of methyl 4-(difluoromethoxy)-2-(trifluoromethyl)benzoate (5) (400 mg, 1.481 mmol) in MeOH:THF:H2O (1:1:1, 6 mL) was added LiOHH2O (62 mg, 1.481 mmol) atRT. Stirred the reaction mixture at RT for 16 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (20 mL) and washed with Diethylether (2 x 10 mL), the aqueous layer was acidified by IN HC1 (pH = ~4) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to afford 4-(difluoromethoxy)-2-(trifluoromethyl)benzoic acid (6) (280 mg, 73% yield) as a greenish liquid, m / z: 255.18 [M-l]+- 'H NMR (400 MHz, DMSO-de): d 13.65 (br s, 1H), 7.94 (d, J= 8.8 Hz, 1H), 7.65-7.28 (m, 3H).Rf = 0.2 (Mobile phase: 10% MeOH-DCM).Step-4: Preparation of 4-(difluoromethoxy)-N-(4-(5, 6-dimethoxynicotinoyl)-l-isopropyl-4,5,6, 7-tetrahydro-lP[-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-062)'.To a stirred solution of 4-(difluoromethoxy)-2-(trifluoromethyl)benzoic acid (6) (210 mg, 0.82 mmol) in DMF (2.1 mL) was added EhN (0.34 mL, 2.46 mmol) and HATU (467 mg, 1.23 mmol) at 0°C. stirred the reaction mixture at RT for 15 min. Then was added (7-amino-l-isopropyl-6,7-dihydro-lH-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3-yl)methanone (Int-3 of SI-013) (283 mg, 0.82 mmol) at RT. Stirred the reaction mixture at RT for 2 h. Completion of thereaction was confirmed by TLC. Reaction mixture was diluted with cold water (40 mL) and extracted withEtOAc (3 x 50 mL), the combined organic layer was dried over IS^SCL, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by combi column chromatography (100-200 mesh silica gel, 50% EtOAc-Hexane as eluent) to afford 4-(difluoromethoxy)-N-(4-(5,6-dimethoxynicotinoyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-062) (102 mg, 21%yield) as an off white solid, m / z: 584.37 [M+l]+ 1H NMR (400 MHz, DMSO-ds) d ppm: 9.22 (d, J= 8.4 Hz, 1H), 7.97 (m, 1H), 7.70-7.25 (m, 5H), 6.74 (s, 1H), 5.41-5.39 (m, 1H), 4.48-4.42 (m, 1H), 4.23-4.20 (m, 1H), 3.79-3.74 (m, 7H), 2.15-1.99 (m, 2H), 1.42-1.39 (m, 6H).Rf = 0.6 (Mobile phase: 5% MeOH-DCM)Chiral separation of (R)-4-(difluoromethoxy)-N-(4-(5 , 6-dimethoxynicotinoyl)-l-isopropyl-4, 5, 6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)Benzamide (SI-086) and (S)-4- (difluoromethoxy)-N-(4-(5 , 6-dimethoxynicotinoyl)-l-isopropyl-4,5, 6, 7 -tetrahydro- 1H-pyrazolo[ 4, 3-b ]pyridin-7-yl)-2-(trifluoromethyl)Benzamide (SI-087)The racemic compound SI-062 (90 mg) was separated by chiral prep HPLC to afford 25 mg of compound SI-086 (RT = 12.420) and 25 mg of SI-087 (RT = 17.356).Chiral Analytical HPLC Method:CHIRALPAK U, 250 x 4.6 mm, 5 pmMobile pahase: A: (HEXANE:IPA:MEOH)(80:10:10),F / R: 1.0 mL / min, Column Temp: 40°CChiral PrepHPLC Method: CHIRALPAK U, 250 x 4.6 mm, 5 pmMobile phase: (HEXANE:IPA:MEOH)(80:10:10),Flow rate: 25 mL / min.SI-086: 'H NMR (400 MHz, DMSO-ds) d ppm: 9.23 (d, J= 8.8 Hz, 1H), 7.97 (m, 1H), 7.69-7.25 (m, 5H), 6.74 (s, 1H), 5.41-5.39 (m, 1H), 4.48-4.42 (m, 1H), 4.23-4.20 (m, 1H), 3.74-3.73 (m, 7H), 2.15-2.01 (m, 2H), 1.42-1.39 (m, 6H). [a]D25: +88.78 (c= 0.05%inMeOH); LCMS: Method Am / z: 584.57 [M+l]+SI-087: 'H NMR (400 MHz, DMSO-ds) d ppm: 9.22 (d, J= 8.4 Hz, 1H), 7.97 (m, 1H), 7.70-7.25 (m, 5H), 6.74 (s, 1H), 5.41-5.39 (m, 1H), 4.48-4.42 (m, 1H), 4.23-4.20 (m, 1H), 3.79-3.73 (m, 7H), 2.15-2.01 (m, 2H), 1.42-1.39 (m, 6H). [a]D25: -50.7 (c= 0.05% inMeOH); LCMS: Method A m / z:584.57 [M+l]+Scheme-14SI-067 Step-1: Preparation of N-(4-benzyl-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (2) :Bn To a stirred solution of 2-(trifluoromethoxy)benzoic acid (1) (300 mg, 1.45 mmol) in DMF: THF (3:3 mL) was added EhN (1.02 mL, 7.28 mmol), TBTU (701 mg, 2.18 mmol) at RT, stirred the reaction mixture atRT for 15 min. Then4-benzyl-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-amine (Int-9 of SI-001) (707 mg, 2.62 mmol) was added at RT, stirred the reaction mixture at RT for 2 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (3 x 50 mL), the combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to get cmde residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 3%MeOH-DCM as eluent) to afford N-(4-benzyl-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (2) (400 mg, 60% yield) as off white solid, m / z:459.52 [M+l]+'H NMR (400 MHz, DMSO-ds) d ppm: 9.07 (d, J= 8.4 Hz, 1H), 7.58-7.27 (m, 9H), 7.01 (s, 1H), 5.28 (brs, 1H), 4.38-4.31 (m, 1H), 4.25-4.22 (m, 1H), 3.95-3.91 (m, 1H), 2.91-2.78 (m, 2H), 2.04-1.98 (m, 1H), 1.90-1.87 (m, 1H), 1.35-1.33 (m, 6H).Rf = 0.3 (Mobile phase: 5% MeOH-DCM).Step-2: Preparation of N-(l-isopropyl-4,5, 6, 7 -tetrahydro- lH-pyrazolo[ 4, 3-b ]pyridin-7-yl)-2- (trifluoromethoxy)benzamide (3):To a stirred solution of N-(4-benzyl-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (2) (300 mg, 0.65 mmol) in MeOH (6 mL) was added 10% Pd / C (60 mg, 20% w / w) at RT. Stirred the reaction mixture at RT for 2 h under H2(gas) atmosphere. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was filtered through celite bed and washed with MeOH, filtrate was evaporated under reduced pressure to afford 7V-(l-isopropyl-4,5,6,7-tetrahydro-l.H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (3) (250 mg, 92% yield) as a light brown liquid, m / z: 369.25 [M+l]+Rf = 0.1 (Mobile phase: 5% MeOH-DCM).Step-3: Preparation of N-(4-((5,6-dimethoxypyridin-3-yl)methyl)-l-isopropyl-4,5,6, 7-tetrahydro-lPI-pyrazolo[ 4, 3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-067):To a stirred solution of N-(l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (3) (200 mg, 0.543 mmol) in DMF (2 mL) was added K2CO3 (112 mg, 0.815 mmol) and 5-(bromomethyl)-2,3-dimethoxypyridine (Int-6) (190 mg, 0.815 mmol) at RT. Stirred the reaction mixture at RT for 2 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with cold water (25 mL) and extracted with EtOAc (3 x 25 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get cmde residue. The obtained cmde residue was purified by column chromatography(100-200 mesh silica gel, 30%EtO Ac -Hexane as eluent) to afford N-(4-((5,6-dimethoxypyridin-3-yl)methyl)-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethoxy)benzamide (SI-067) (120 mg, 42% yield) as off white solid, m / z: 520.35 [M+l]+, 'H NMR (400 MHz, DMSO-de) d ppm: 9.07 (d, J= 8.4 Hz, 1H), 7.66 (s, 1H), 7.58-7.39 (m, 4H), 7.24 (s, 1H), 7.14 (s, 1H), 5.28-5.26 (m, 1H), 4.38-4.30 (m, 1H), 4.20-4.17 (m, 1H), 3.2-3.87 (m, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.67-3.63 (m, 1H), 2.92-2.89 (m, 1H), 2.81-2.76 (m, 1H), 2.02-1.96 (m, 1H), 1.89-1.86 (m, 1H), 1.35-1.34 (m, 6H).Rf = 0.4 (Mobile phase: 5% MeOH-DCM)Chiral separation of (R)-N-(4-((5,6-dimethoxypyridin-3-yl)methyl)-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-068) and (S)-N-(4-((5,6-dimethoxypyridin-3-yl)methyl)-l-isopropyl-4, 5, 6, 7-tetrahydro-lH-pyrazolo[4, 3-b ]pyridin-7-yl)-2-(trifluoromethoxy)Benzamide (SI-069)The racemic compound SI-067 (80 mg) was separated by chiral prep HPLC to afford 25 mg of compound SI-068 (RT = 9.619) and 22 mg of SI-069 (RT = 15.429).Chiral Analytical HPLC Method:CHIRALPAK IG, 250 x 4.6 mm, 5 pmMobile pahase: A: (HEXANE:IPA:MEOH)(80:10:10),F / R: 1.0 mL / min, Column Temp: 40°CChiral PrepHPLC Method: CHIRALPAK IG, 250 x 4.6 mm, 5 pmMobile phase: (HEXANE:IPA:MEOH)(80:10:10),Flow rate: 20 mL / min.SI-068: 'H NMR (400 MHz, DMSO-ds) d ppm: 9.07 (d, J= 7.6 Hz, 1H), 7.66 (s, 1H), 7.58-7.40 (m, 4H), 7.24 (s, 1H), 7.15 (s, 1H), 5.28-5.26 (m, 1H), 4.38-4.31 (m, 1H), 4.20-4.17 (m, 1H), 3.91-3.87 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 2.92-2.89 (m, 1H), 2.81-2.75 (m, 1H), 2.02-1.96 (m, 1H), 1.89-1.86 (m, 1H), 1.35-1.33 (m, 6H). [a]D25: + 48.54 (c= 0.05% in MeOH); LCMS: Method A m / z: 520.40 [M+l]+SI-069: 'H NMR (400 MHz, DMSO-ds) d ppm: 9.07 (d, J= 8.0 Hz, 1H), 7.66 (s, 1H), 7.58-7.40 (m, 4H), 7.24 (s, 1H), 7.15 (s, 1H), 5.26 (brs, 1H), 4.38-4.31 (m, 1H), 4.20-4.17 (m, 1H), 3.91-3.87 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 2.92-2.89 (m, 1H), 2.81-2.76 (m, 1H), 2.02-1.97 (m, 1H), 1.89-1.86 (m, 1H), 1.35-1.34 (m, 6H). [a]D25: -62.83 (c= 0.05% in MeOH); LCMS: Method A m / z:520.40 [M+l]+Scheme-15:Step-1: Preparation of tert-butyl (l-isopropyl-4-nicotinoyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)carbamate (2):To a stirred solution of nicotinic acid (1) (150 mg, 1.21 mmol) in THF:DMF (3:3 mL) was added DIPEA (1.07 mL, 6.09 mmol) and TBTU (587 mg, 1.82 mmol) at RT, stirred the reaction mixture at RT for 15 min. Then tert-butyl (l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)carbamate (Int-11 of SI-001) (614 mg, 2.19 mmol) was added at RT, stirred the reaction mixture at RT for 2 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (3 x 50 mL), the combined organic layer was dried over Na2SO«, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 40% EtOAc -Hexane as eluent) to afford tert-butyl (l-isopropyl-4-nicotinoyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)carbamate (2) (300 mg, 77% yield) as a light brown solid, m / z: 386.37 [M+l]+Rf = 0.4 (Mobile phase: 5% MeOH-DCM).Step-2: Preparation of (7-amino- 1 -isopropyl -6, 7-dihydro-lH-pyrazolo[4,3-b]pyridin-4(5H)-yl) (pyri din- 3 -yl) methanone (3):To a stirred solution of tert-butyl (l-isopropyl-4-nicotinoyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)carbamate (2) (300 mg, 0.77 mmol) in DCM (6 mL) was added 4M HO in dioxane (1.5 mL) at 0 °C, stirred the reaction mixture at RT for 2 h. Completion of the reaction was confirmed by TLC. Reaction mixture was evaporated under reduced pressure to get crude residue. The obtained crude residue was triturated in diethyl ether (5 mL) and dried to afford (7-amino-l-isopropyl-6,7-dihydro-lH-pyrazolo[4,3-b]pyridin-4(5H)-yl)(pyridin-3-yl)methanone (3) (230 mg, Quantitative) as an off white solid, m / z: 286.31 [M+l]+Rf = 0.1 (Mobile phase: 05% MeOH-DCM).Step-3: Preparation of N-(l-isopropyl-4-nicotinoyl-4, 5, 6, 7-tetrahydro- lH-pyrazolo[ 4, 3-b]pyridin- 7-yl)-2-(trifluoromethoxy)benzamide (SI-070):To a stirred solution of 2-(trifluoromethoxy)benzoic acid (4) (200 mg, 0.97 mmol) inDMF (2.1 mL) was added EDC.HC1 (292 mg, 1.52 mmol), DIPEA (0.54 mL, 3.05 mmol) andHOBt (206 mg, 1.52 mmol) at RT. stirred the reaction mixture at RT for 15 min. Then was added (7-amino-l-isopropyl-6,7-dihydro-lH-pyrazolo[4,3-b]pyridin-4(5H)-yl)(pyridin-3-yl)methanone (3) (220 mg, 0.776 mmol) at RT, stirred the reaction mixture at RT for 2 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (25 mL) and extracted with EtOAc (3 x 25 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get cmde residue. The obtained cmde residue was purified by column chromatography (100-200 mesh silica gel, 60% EtOAc -Hexane as eluent) to afford N-(l-isopropyl-4-nicotinoyl-4.5.6.7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2 -(trifluoromethoxy )benzamide SI-070 (60 mg, 13%yield) as an off white solid, m / z: 474.67 [M+l]+'H NMR (400 MHz, DMSO-ds) d ppm: 9.18 (d, J= 8.4 Hz, 1H), 8.71-8.67 (m, 2H), 8.10 (s, 1H), 7.90 (d, J= 7.6 Hz, 1H), 7.61-7.43 (m, 5H), 5.46-5.44 (m, 1H), 4.50-4.47 (m, 1H), 3.72 (m, 2H), 2.15-2.14 (m, 1H), 1.96-1.92 (m, 1H), 1.43-1.39 (m, 6H).Rf = 0.3 (Mobile phase: 05% MeOH-DCM).Chiral separation of (R)-N-(l-isopropyl-4-nicotinoyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)Benzamide (SI-071) and (S)-N-(l-isopropyl-4-nicotinoyl- 4.5.6.7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)Benzamide (SI- 072)The racemic compound SI-070 (50 mg) was separated by chiral prep HPLC to afford 20 mg of compound SI-071 (RT = 6.887) and 15 mg of SI-072 (RT = 8.110).Chiral Analytical HPLC Method:CH IRALPAK IH, 250 x 4.6 mm, 5 pmMobile pahase: A: (HEXANE:IPA:MEOH)(80:10:10),F / R: 1.0 mL / min, Column Temp: 40°CChiral PrepHPLC Method: CHIRALPAK IH, 250 x 4.6 mm, 5 pmMobile phase: (HEXANE:IPA:MEOH)(80:10:10),Flow rate: 25 mL / min.SI-071: 'H NMR (400 MHz, DMSO-de) dppm: 9.18 (d, .7= 8.4 Hz, IH), 8.71-8.67 (m, 2H), 8.10 (s, IH), 7.90 (d, J= 7.6 Hz, IH), 7.61-7.54 (m, 3H), 7.48-7.43 (m, 2H), 5.54-5.44 (m, IH), 4.50-4.47 (m, IH), 3.72 (br s, 2H), 2.13 (br s, IH), 1.96-1.92 (m, IH), 1.43-1.39 (m, 6H). [a]D25: +46.9 (c= 0.03% in MeOH); LCMS: Method A m / z: 474.39 [M+l]+SI-072: 'H NMR (400 MHz, DMSO-ds) dppm: 9.18 (d, .7= 8.4 Hz, IH), 8.71-8.67 (m, 2H), 8.10 (s, IH), 7.90 (d, J= 8.0 Hz, IH), 7.59-7.54 (m, 3H), 7.48-7.43 (m, 2H), 5.46-5.44 (m, IH), 4.48-4.47 (m, IH), 3.72 (br s, 2H), 2.15-2.14 (m, IH), 1.96-1.93 (m, IH), 1.43-1.39 (m, 6H). [a]D25: -97.56 (c= 0.03% in MeOH); LCMS: Method A m / z: 474.35 [M+l]+Scheme-16:Step-1 : Preparation of N-(4-benzyl-l-isopropyl-4, 5, 6, 7-tetrahydro-lH-pyrazolo [ 4, 3-b ] pyridin-7-yl)-2-(trifluoromethyl)benzamide (SI-073):To a stirred solution of 2-(trifluoromethyl)benzoic acid (100 mg, 0.52 mmol) in DMF (1.0 mL) was added EDC.HC1 (151 mg, 0.78 mmol), DIPEA (0.28 mL, 1.57 mmol) and HOBt (106 mg, 0.78 mmol) at RT. stirred the reaction mixture at RT for 15 min. Then was added 4-benzyl-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-amine (Int-9 of SPT-001) (170 mg, 0.63 mmol) at RT. Stirred the reaction mixture at RT for 2 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (25 mL) and extracted with EtOAc (3 x 25 mL), the combined organic layer was dried over Na2SO«, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 40% EtOAc-Hexane as eluent) to afford N-(4-benzyl-l-isopropyl-4, 5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide SI-073 (70 mg, 43% yield) as a light brown solid, m / z: 443.62 [M+1]+1H NMR (400 MHz, DMSO-de) <5 ppm: 9.12 (d, J= 7.6 Hz, 1H), 7.77-7.61 (m, 3H), 7.45 (d, J= 6.8 Hz, 1H), 7.35-7.27 (m, 5H), 7.01 (s, 1H), 5.26 (brs, 1H), 4.36-4.31 (m, 1H), 4.25-4.22 (m, 1H), 3.94-3.90 (m, 1H), 2.91-2.89 (m, 1H), 2.82-2.76 (m, 1H), 2.03-1.88 (m, 2H), 1.37-1.35 (m, 6H).Rf = 0.4 (Mobile phase: 5% MeOH-DCM).Chiral separation of (R)-N-(4-benzyl-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)Benzamide (SI-074) and (S)-N-(4-benzyl-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[ 4, 3-b]pyridin-7-yl)-2-(trifluoromethyl)Benzamide (SI-075)SI-074The racemic compound SI-073 (60 mg) was separated by chiral prep HPLC to afford 20 mg of compound SI-074 (RT = 24.121) and 20 mg of SI-075 (RT = 30.945).Chiral Analytical HPLC Method:CHIRALPAK IG, 250 x 4.6 mm, 5 pmMobile pahase: A: (n-HEXANE:EtOH)(92:8),F / R: 1.0 mL / min, Column Temp: 40°CChiral PrepHPLC Method: CHIRALPAK IG, 250 x 4.6 mm, 5 pmMobile phase: (n-HEXANE:ETOH)(92:8),Flow rate: 25 mL / min.SI-074: 'H NMR (400 MHz, DMSO-ds) d ppm: 9.12 (d, J= 8.4 Hz, 1H), 7.77-7.61 (m, 3H), 7.45 (d, J= 7.2 Hz, 1H), 7.38-7.27 (m, 5H), 7.01 (s, 1H), 5.27-5.25 (m, 1H), 4.38-4.31 (m, 1H), 4.25-4.22 (m, 1H), 3.94-3.90 (m, 1H), 2.91-2.89 (m, 1H), 2.81-2.76 (m, 1H), 2.03-1.96 (m, 1H), 1.91- 1.88 (m, 1H), 1.38-1.35 (m, 6H). [a]D25: + 65.00 (c= 0.05% in MeOH); LCMS: Method A m / z: 443.80 [M+l]+SI-075: 'H NMR (400 MHz, DMSO-ds) d ppm: 9.12 (d, J= 8.0 Hz, 1H), 7.77-7.61 (m, 3H), 7.45 (d, J= 7.2 Hz, 1H), 7.39-7.27 (m, 5H), 7.01 (s, 1H), 5.27-5.25 (m, 1H), 4.38-4.31 (m, 1H), 4.25-4.22 (m, 1H), 3.94-3.90 (m, 1H), 2.92-2.89 (m, 1H), 2.82-2.76 (m, 1H), 2.03-1.97 (m, 1H), 1.91- 1.88 (m, 1H), 1.38-1.35 (m, 6H). [a]D25: -41.81 (c= 0.05% in MeOH); LCMS: Method A m / z: 443.80 [M+l]+Scheme-17:Step-1: Preparation ofN-(4-benzyl-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-076):To a stirred solution of 2-(trifluoromethoxy)benzoic acid (300 mg, 1.45 mmol) in DMF (3.0 mL) was added Et3N (1.0 mL, 7.28 mmol) and TBTU (701 mg, 2.18 mmol) at RT. stirred the reaction mixture at RT for 15 min. Then was added 4-benzyl-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-amine (Int-9 of SI-001) (707 mg, 2.62 mmol) atRT. The reaction mixture was allow to stirred at RT for 2 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (25 mL) and extracted with EtOAc (3 x 25 mL), the combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 40% EtOAc -Hexane as eluent) to afford N-(4-benzyl-l-isopropyl-4, 5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide (SI-076) (400 mg, 60% yield) as a light brown solid, m / z: 459.52 [M+l]+'H NMR (400 MHz, DMSO-de) d ppm: 9.07 (d, J= 8.4 Hz, 1H), 7.58-7.27 (m, 9H), 7.01 (s, 1H), 5.28 (br s, 1H), 4.38-4.33 (m, 1H), 4.25-4.22 (m, 1H), 3.95-3.91 (m, 1H), 2.91-2.78 (m, 2H), 2.04-1.98 (m, 1H), 1.90-1.87 (m, 1H), 1.35-1.33 (m, 6H). Rf = 0.3 (Mobile phase: 5% MeOH-DCM).Chiral separation of (R)-N-(4-benzyl-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin- 7-yl)-2-(trifluoromethoxy)Benzamide (SI-077) and (S)-N-(4-benzyl-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)Benzamide (SI-078)The racemic compound SI-076 (40 mg) was separated by chiral prep HPLC to afford 8 mg of compound SI-077 (RT = 7.455) and 10 mg of SI-078 (RT = 9.207).Chiral Analytical HPLC Method:CHIRALPAK U, 250 x 4.6 mm, 5 pmMobile pahase: A: (HEXANE:IPA:MEOH)(90:05:05),F / R: 1.0 mL / min, Column Temp: 40°CChiral PrepHPLC Method: CHIRALPAK U, 250 x 4.6 mm, 5 pmMobile phase: (HEXANE:IPA:MEOH)(90:05:05),Flow rate: 25 mL / min.SI-077: 'H NMR (400 MHz, DMSO-de) d ppm: 9.07 (d, J= 8.4 Hz, 1H), 7.58-7.27 (m, 9H), 7.01 (s, 1H), 5.28 (br s, 1H), 4.36-4.33 (m, 1H), 4.25-4.22 (m, 1H), 3.95-3.91 (m, 1H), 2.91-2.81 (m, 2H), 2.01-1.98 (m, 1H), 1.90-1.87 (m, 1H), 1.35-1.33 (m, 6H). [a]D25: -67.74 (c= 0.05% inMeOH); LCMS: Method A m / z: 459.35 [M+l]+SI-078: 'H NMR (400 MHz, DMSO-de) d ppm: 9.08 (d, J= 8.4 Hz, 1H), 7.58-7.25 (m, 9H), 7.01 (s, 1H), 5.29-5.27 (m, 1H), 4.38-4.31 (m, 1H), 4.25-4.22 (m, 1H), 3.95-3.91 (m, 1H), 2.91-2.88 (m, 1H), 2.83-2.78 (m, 1H), 2.01-1.98 (m, 1H), 1.90-1.86 (m, 1H), 1.35-1.33 (m, 6H). [a]D25: +30.125 (c= 0.05% in MeOH); LCMS: Method A m / z: m / z: 459.36 [M+l]+Scheme-18:Step-1: Preparation ofN-(4-benzyl-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)benzamide (SI-079):To a stirred solution of benzoic acid (100 mg, 0.81 mmol) in DMF (1.0 mL) was added EDC.HC1 (235 mg, 1.22 mmol), DIPEA (0.43 mL, 2.45 mmol) and HOBt (166 mg, 1.22 mmol) at RT. stirred the reaction mixture at RT for 15 min. Then was added 4-benzyl-l-isopropyl-4,5,6,7-tetrahydro- lH-pyrazolo[4,3-b]pyridin-7-amine (Int-9 of MC-01) (264 mg, 0.98 mmol) at RT. The reaction mixture was allow to stirred at RT for 2 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (25 mL) and extracted with EtOAc (3 x 25 mL), the combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200mesh silica gel, 40% EtOAc-Hexane as eluent) to afford N-(4-benzyl-l-isopropyl-4, 5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)benzamide (SI-079) (110 mg, 84% yield) as a light brown solid, m / z: 375.50 [M+l]+'H NMR (400 MHz, DMSO-de) d ppm: 8.93 (d, J= 8.4 Hz, 1H), 7.90 (d, J= 6.8 Hz, 2H), 7.54-7.26 (m, 8H), 7.03 (s, 1H), 5.36 (br s, 1H), 4.27-4.24 (m, 2H), 3.98-3.95 (m, 1H), 2.89-2.86 (m, 2H), 2.02-1.99 (m, 1H), 1.90-1.87 (m, 1H), 1.34-1.26 (m, 6H).Rf = 0.4 (Mobile phase: 5% MeOH-DCM).Chiral separation of (R)-N-(4-benzyl-l-isopropyl-4,5,6, 7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)Benzamide (SI-080) and (S)-N-(4-benzyl-l-isopropyl-4,5,6,7-tetrahydro-lH-pyrazolo[4,3-b]pyridin-7-yl)Benzamide (SI-081 )HN HNNSI-080 SI-081The racemic compound SI-079 (100 mg) was separated by chiral prep HPLC to afford 28 mg of compound SI-080 (RT = 11.250) and 26 mg of SI-081 (RT = 14.128).Chiral Analytical HPLC Method:CHIRALPAK U, 250 x 4.6 mm, 5 pmMobile pahase: A: (HEXANE:IPA:MeOH)(90:05:05),F / R: 1.0 mL / min, Column Temp: 40°CChiral PrepHPLC Method: CHIRALPAK U, 250 x 4.6 mm, 5 pmMobile phase: (HEXANE:IPA:MeOH)(90:05:05),Flow rate: 25 mL / min.SI-080: 'H NMR (400 MHz, DMSO-de) d ppm: 8.93 (d, J= 8.0 Hz, 1H), 7.90 (d, J= 7.2 Hz, 2H), 7.54-7.26 (m, 8H), 7.03 (s, 1H), 5.36-5.35 (m, 1H), 4.29-4.24 (m, 2H), 3.98-3.95 (m, 1H), 2.88-2.83 (m, 2H), 2.08-1.99 (m, 1H), 1.90-1.87 (m, 1H), 1.34-1.32 (m, 3H), 1.27-1.26 (m, 3H). [a]D25: -96.43 (c= 0.05% inMeOH); LCMS: Method A m / z: 375.72 [M+l]+SI-081: 'H NMR (400 MHz, DMSO-de) d ppm: 8.93 (d, J= 8.4 Hz, 1H), 7.90 (d, J= 6.8 Hz, 2H), 7.54-7.27 (m, 8H), 7.05 (s, 1H), 5.37 (br s, 1H), 4.29-4.23 (m, 2H), 3.99-3.96 (m, 1H), 2.89-2.86 (m, 2H), 2.02-1.99 (m, 1H), 1.91-1.88 (m, 1H), 1.40-1.39 (m, 3H), 1.27-1.26 (m, 3H). [a]D25: +83.05 (c= 0.05% in MeOH); LCMS: Method A m / z: 375.36 [M+l]+Intermediate Synthesis:Reaction conditions: a) Et3N, MeOH, RT, 16 h b) 10% Pd-C, EtOH, H2atm, RT, 16 h c) NaNO2, H2SO4, 100 °C, 2 h d) allyl bromide, Cs2CO3, KI, DMF, 80 °C, 6 h e) LIOH.H2O, MeOH, THF, H2O, RT, 2 h Step-1: Preparation of methyl 6-methoxy-5-nitronicotinate:To a stirred solution of methyl 6-chloro-5-nitronicotinate (10 g, 46.172 mmol) inMeOH (150 mL) was added EhN (6.4 mL, 46.172 mmol) at RT. Stirred the reaction mixture at RT for 16 h. Completion of the reaction was confirmed by TLC and LCMS. Volatiles was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 15% EtOAc-Hexane as eluent) to afford methyl 6-methoxy -5 -nitronicotinate (9 g, 91%) as pale-yellow solid, m / z: 213.18 [M+H]+Rf = 0.5 (Mobile phase: 20% EtOAc-Hexane).Step-2: Preparation of methyl 5-amino-6-methoxynicotinate:NH2N O'To a stirred solution of methyl 6-methoxy-5-nitronicotinate (9 g, 42.452 mmol) inMeOH (90 mL) was added 10% Pd-C (2.26 g, 21.226mmol) at RT, stirred the reaction mixture at RT under H2atm for 16 h. completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was filtered through celitebed, washed with MeOH (3 x 300 mL), volatiles was evaporated under reduced pressure to afford methyl 5-amino-6-methoxynicotinate (4 g, 51%) as yellow solid, which was used for next step without any further purification, m / z: 183.12 [M+H]+Rf = 0.4 (Mobile phase: 30% EtOAc-Hexane).Step-3: Preparation of methyl 5-hydroxy-6-methoxynicotinate:.OHTo a stirred solution of methyl 5-amino-6-methoxynicotinate (4 g, 21.978 mmol) in H2O (66 mL) was added NaNO2(1.51 g, 21.978 mmol) inH2O (5 mL) followed by Conc.H2SO4(4 mL) at 0°C, stirred the reaction mixture at 100 °C for 2 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with cold water (300 mL) and extracted with DCM (3 x 200 mL), the combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to get crude residue to afford methyl 5 -hydroxy-6 -methoxynicotinate (2 g, 59%) as light brown liquid, which was used for next step without any further purification, m / z: 184.15 [M+H]+1H NMR (400 MHz, DMSO-ds): d 10.09(s, 1H), 8.22-8.21 (m, 1H), 7.50-7.49 (m, 1H), 3.94 (s, 3H), 3.82 (s, 3H).Rf = 0.35 (Mobile phase: 30% EtO Ac -Hexane).Step-4: Preparation of methyl 5-(allyloxy)-6-methoxynicotinate:OTo a stirred solution of methyl 5-hydroxy-6-methoxynicotinate (2 g, 10.928 mmol) inDMF (20 mL) was added Cs2CO3 (10.65 g, 32.786mmol), KI (540 mg, 3.278mmol) and 3 -bromoprop- 1-ene (1.4 mL, 16.392 mmol) at RT. Stirred the reaction mixture at 80 °C for 6 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with water (150 mL) and extracted with EtO Ac (2 x 100 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 8% EtOAc-Hexane as eluent)to afford methyl 5-(allyloxy)-6-methoxynicotinate (1.2 g, 49%) as pale-yellow liquid, m / z: 224.17 [M+H]+Rf = 0.5 (Mobile phase: 20% EtOAc-Hexane).Step-5: Preparation of 5-(allyloxy)-6-methoxynicotinic acid:Olnt-1To a stirred solution methyl 5-(allyloxy)-6-methoxynicotinate (1.2 g, 5.381 mmol) in MeOH:THF: H2O (1:1:1) (15 mL) was added LiOH.tLO (678 mg, 16.143 mmol) at RT. Stirred the reaction mixture at RT for 2 h. Completion of the reaction was confirmed by TLC and LCMS.Volatiles was evaporated under reduced pressure to get crude residue, which was diluted with water (30 mL) and acidified with 2N HO (pH 2-3) and extracted with DCM (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to afford 5-(allyloxy)-6-methoxynicotinic acid, Int-1 (800 mg, 71%) as white solid, m / z: 210.13 [M+l]+. 'H NMR (400 MHz, DMSO-de): d 12.61 (brs, 1H), 7.60 (s, 1H), 7.11 (s, 1H), 6.04-5.97 (m, 1H), 5.39 (d, J= 16.4 Hz, 1H), 5.26 (d, J= 10.8 Hz, 1H), 4.75-4.74 (m, 2H), 3.73 (s, 3H).Rf= 0.2 (Mobile phase: 10% MeOH-DCM).Scheme for Int-2:lnt-2Reaction conditions: a) Conc.H2SO4, MeOH, Reflux, 16 h b) allyl bromide, Cs2CO3, DMF, 80 °C, 4 h c) MeOH, THF, H2O, RT, 2 h Step-1: Preparation of methyl 4-hydroxy-2-(trifluoromethyl) benzoate:To a stirred solution 4-hydroxy-2-(trifluoromethyl)benzoic acid (2 g, 9.708 mmol) in MeOH (20 mL) was added Conc.H2SO4 (1.55 mL, 29.124 mmol) at RT. Stirred the reaction mixture at 75 °C for 16 h. Completion of the reaction was confirmed by TLC and LCMS. Volatiles was evaporated under reduced pressure to get crude residue, which was diluted with water (50 mL) and extractedwith DCM (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 10% EtOAc-Hexane as eluent) to afford methyl 4-hydroxy-2-(trifluoromethyl) benzoate (1.5 g, 70%) as white solid, m / z: 219.09 [M-H]+.'H NMR (400 MHz, DMSO-de): d 10.87 (br s, 1H), 7.79 (d, J= 8.8 Hz, 1H), 7.19-7.18 (m, 1H), 7.10 (d, J= 8.4 Hz, 1H), 3.87 (s, 3H).Rf = 0.4 (Mobile phase: 20% EtOAc-Hexane).Step-2: Preparation of methyl 4-(allyloxy)-2-(trifluoromethyl)benzoate):To a stirred solution of methyl 4-hydroxy-2-(trifluoromethyl) benzoate (1.5 g, 6.818 mmol) in DMF (15 mL) at RT was added Cs2CO2(6.64 g, 20.454 mmol), 3 -bromoprop- 1-ene (0.7 mL, 8.181 mmol) at RT. Stirred the reaction mixture at 80 °C for 4 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (2 x 100 mL), the combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 15% EtOAc -Hexane as eluent) to afford methyl 4-(allyloxy)-2-(trifluoromethyl)benzoate) (1.2 g, 67%) as pale-yellow liquid, m / z: 242.08 [M-18]+Rf = 0.3 (Mobile phase: 40% EtOAc -Hexane).Step-3: Preparation of 4-(allyloxy)-2-(trifluoromethyl) benzoic acid:o CF3lnt-2To a stirred solution methyl 4-(allyloxy)-2-(trifluoromethyl)benzoate) (1.2 g, 4.615 mmol) in MeOH: THF: H20 (1:1:1) (15 mL) was added LiOH.H2O (582 mg, 13.845 mmol) atRT. Stirred the reaction mixture at RT for 2 h. Completion of the reaction was confirmed by TLC and LCMS. Volatiles was evaporated under reduced pressure to get crude residue, which was diluted with water (30 mL) and acidified with 2N HO (pH 2-3) and extracted with DCM (2 x 100 mL). Thecombined organic layer was dried over Na2S0j. filtrate was evaporated under reduced pressure to afford 4-(allyloxy)-2 -(trifluoromethyl) benzoic acid, Int-2 (700 mg, 62%) as white solid, m / z: 245.29 [M-H]+. 'H NMR (400 MHz, DMSO-ds): dppm: 13.25 (br s, 1H), 7.86 (d, J= 8.4 Hz, 1H), 7.32-7.30 (m, 2H), 6.10-6.00 (m, 1H), 5.45 (d, J= 12.0 Hz, 1H), 5.31 (d, J= 10.4 Hz, 1H), 4.74-4.73 (m, 2H).Rf= 0.2 (Mobile phase: 10% MeOH-DCM).Scheme for Int-3:Reaction conditions: a) Et3N, MeOH, RT, 16 h b) 10% Pd-C, EtOH, H2atm, RT c) NaNO2, H2SO4, 70 °C, 8 h d) Mel, K2CO3, DMF, 60 °C, 6 h e) LiOH.H2O, MeOH, THF, H2OStep-1: Preparation of methyl 6-methoxy-5-nitronicotinate:OTo a stirred solution of methyl 6-chloro-5-nitronicotinate (10 g, 46.172 mmol) in MeOH (150 mL) was added EhN (6.4 mL, 46.172 mmol) at RT. Stirred the reaction mixture at RT for 16 h. Completion of the reaction was confirmed by TLC and LCMS. Volatiles was evaporated underreduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 15% EtOAc-Hexane as eluent) to afford methyl 6-methoxy -5 -nitronicotinate (9 g, 91%) as pale-yellow solid, m / z: 213.18 [M+H]+Rf = 0.5 (Mobile phase: 20% EtOAc-Hexane).Step-2: Preparation of methyl 5-amino-6-methoxynicotinate:OTo a stirred solution of methyl 6-methoxy-5-nitronicotinate (9 g, 42.452 mmol) inMeOH (90 mL) was added 10% Pd-C (2.26 g, 21.226mmol) at RT, stirred the reaction mixture at RT under H2 atm for 16 h. completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was filtered through celite bed, washed with MeOH (3 x 300 mL), volatiles was evaporated under reduced pressure to afford methyl 5-amino-6-methoxynicotinate (4 g, 51%) as yellow solid, which was used for next step without any further purification, m / z: 183.12 [M+H]+Rf = 0.4 (Mobile phase: 30% EtOAc-Hexane).Step-3: Preparation of methyl 5-hydroxy-6-methoxynicotinate :OTo a stirred solution of methyl 5-amino-6-methoxynicotinate (4 g, 21.978 mmol) inH2O (66 mL) was added NaNTCL (1.51 g, 21.978 mmol) inH2O (5 mL) followed by Conc.H2SO4(4 mL) at 0°C, stirred the reaction mixture at 100 °C for 2 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with cold water (300 mL) and extracted with DCM (3 x 200 mL), the combined organic layer was dried over NaiSOf. filtrate was evaporated under reduced pressure to get crude residue to afford methyl 5 -hydroxy-6 -methoxynicotinate (2 g, 59%) as light brown liquid, which was used for next step without any further purification, m / z: 184.15 [M+H]+1H NMR (400 MHz, DMSO-ds): d 10.09 (s, 1H), 8.22-8.21 (m, 1H), 7.50-7.49 (m, 1H), 3.94 (s, 3H), 3.82 (s, 3H).Rf = 0.35 (Mobile phase: 30% EtOAc-Hexane).Step-4: Preparation of methyl 5 f -dimethoxynicotinate:To a stirred solution of methyl 5-hydroxy-6-methoxynicotinate (3 g, 16.393 mmol) inDMF (30 mL) was added K2CO3 (10.65 g, 49.180 mmol) and Methyl iodide (1.5 mL, 24.589 mmol) at RT. Stirred the reaction mixture at 60 °C for 6 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2 x 100 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 10% EtOAc-Hexane as eluent) to afford methyl 5,6-dimethoxynicotinate (1.5 g, 46%) as pale-yellow liquid, m / z: 198.17 [M+H]+Rf = 0.4 (Mobile phase: 30% EtOAc-Hexane).Step-5: Preparation of 5, 6-dimethoxynicotinic acid:lnt-3To a stirred solution methyl 5,6-dimethoxynicotinate (1.5 g, 7.614 mmol) inMeOH: THF: H2O (1:1:1) (22.5 mL) was added LiOH.tLO (630 mg, 15.228 mmol) at RT. Stirred the reaction mixture at RT for 2 h. Completion of the reaction was confirmed by TLC and LCMS. Volatiles was evaporated under reduced pressure to get crude residue, which was diluted with water (30 mL) and acidified with 2N HO (pH 2-3) and extracted with DCM (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to afford 5, 6-dimethoxynicotinic acid, Int-3 (1 g, 71%) as white solid, m / z: 184.16 [M+l]+.Rf= 0.2 (Mobile phase: 10% MeOH-DCM).Scheme for Int-4:Reaction conditions: a)TBS-CI, Imidazole, DMF, RT, 16 h b) TMEDA, sec-BuLi, Cyclohexane, THF, -78 ° C, -40 °C, 0 °C, 4 h c) Conc.H2S04, EtOH, 90 °C, 24 h d) allyl bromide, Cs2CO3, DMF, 80 °C, 4 h e) LiOH.H2O, MeOH:THF:H2O, RT, 4 h Step-1: Preparation of triisopropyl(3-(trifluoromethoxy)phenoxy)silane:To a stirred solution of 3 -(trifluoro metho xy)phenol (5 g, 28.072 mmol) in DMF (15 mL) was added Imidazole (5.73 g, 84.217 mmol) at RT, stirred the reaction mixture at RT for 20 min. Then chlorotriisopropylsilane (12 mL, 56.145 mmol) was added at RT. stirred the reaction mixture at RT for 16 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (250 mL) and extracted with EtOAc (3 x 250 mL), the combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 10%EtO Ac -Hexane as eluent) to afford triisopropy 1(3 -(trifluoromethoxy )phenoxy)silane (7 g, 74% yield) as colorless oil. 'H NMR (400 MHz, DMSO-ds): d 7.26-7.19 (m, 1H), 6.81-6.74 (m, 3H), 1.30-1.22 (m, 3H), 1.11-1.09 (m, 18H).Rf = 0.5 (Mobile phase: 20% EtOAc-Hexane).Step-2: Preparation of2-(trifluoromethoxy)-4-((triisopropylsilyl)oxy)benzoic acid :To a stirred solution of triisopropyl(3-(trifluoromethoxy)phenoxy)silane (5 g, 0.0149 mol) in THF (100 mL) was added N,N,N',N'-Tetramethylethylene diamine (2.2 mL, 0.0149 mol) at RT, cooled the reaction mixture to -78 °C then Sec.BuLi (1.4M in Cyclohexane, 7.5 mL, 0.0223 mol) was added dropwise, warmed the reaction mixture to -40 °C, stirred at -40 °C for 1 h. Cooled the reaction mixture to -78 °C, reaction mixture was purge the CO2 gas over 2 h. Reaction mixture was stirred at 0 °C for 1 h. Completion of the reaction was confirmed by TLC. Reaction mixture was quenched with saturate aq.NH4Cl (100 mL) and extracted with EtOAc (3 x 250 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 5%EtOAc-Hexane as eluent) to afford 2-(trifluoromethoxy)-4-((triisopropylsilyl)oxy)benzoic acid (2.5 g, 44% yield) as colorless oil.1H NMR (400 MHz, DMSO-de): d 13.08 (s, 1H), 7.86 (d, J= 8.8 Hz, 1H), 6.99-6.97 (m, 1H), 6.81 (s, 1H), 1.25-1.20 (m, 3H), 1.14-1.02 (m, 18H).Rf = 0.5 (Mobile phase: 10% EtOAc-Hexane).Step-3: Preparation of ethyl 4-hydroxy-2-(trifluoromethoxy)benzoate:To a stirred solution of 2-(trifluoromethoxy)-4-((triisopropylsilyl)oxy)benzoic acid (810 mg, 2.140 mmol) inEtOH (8 mL) was added Conc.H2SO4(0.8 mL) at 0 °C, heated the reaction mixture at 90 °C for 24 h. Completion of the reaction was confirmed by TLC and LCMS.Volatiles was evaporated under reduced pressure to get crude compound, which Reaction mixture was quenched with sat.aq.NaHCO3 (50 mL) and extracted with EtOAc (3 x 150 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 10%EtO Ac -Hexane as eluent) to afford ethyl 4-hydroxy-2-(trifluoromethoxy)benzoate (210 mg, 39% yield) as off white solid, m / z: 251.15 [M+1]+ 1H NMR (400 MHz, DMSO-de): d 10.92 (s, 1H), 7.84 (d, J= 8.8 Hz, 1H), 6.91-6.88 (m, 1H), 6.79 (s, 1H), 4.25 (q, J= 6.8 Hz, 2H), 1.33-1.26 (m, 3H).Rf = 0.4 (Mobile phase: 20% EtOAc -Hexane).Step-4: Preparation of ethyl 4-(allyloxy)-2-(trifluoromethoxy)benzoate:To a stirred solution of ethyl 4-hydroxy-2-(trifluoromethoxy)benzoate (280 mg, 1.12 mmol) in DMF (5 mL) was added CS2CO3 (1 g, 3.36 mmol), Allyl bromide (271 mg, 2.24 mmol) at RT, heated the reaction mixture at 80 °C for 4 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (3 x 50 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by flash column chromatography (100-200 mesh silica gel, 10% EtOAc-Hexane as eluent) to afford ethyl 4-(allyloxy)-2-(trifluoromethoxy)benzoate (200 mg, 61% yield) as Light brown oil. m / z: 291.24 [M+1]+ 1H NMR (400 MHz, DMSO-de): <57.93 (d, .7= 8.8 Hz, 1H), 7.14-7.12 (m, 1H), 7.04 (s, 1H), 6.04-6.00 (m, 1H), 5.43 (d, J= 16.8 Hz, 1H), 5.31 (d, J= 10.4 Hz, 1H), 4.72-4.70 (m, 2H), 4.28 (q, J= 22 Hz, 2H), 1.29 (t, J= 6.8 Hz, 3H).Rf = 0.4 (Mobile phase: 15% EtOAc-Hexane).Step-5: Preparation of 4-(allyloxy)-2-(trifluoromethoxy)benzoic acid:Int-4To a stirred solution of ethyl 4-(allyloxy)-2-(trifluoromethoxy)benzoate (290 mg, 1 mmol) in THF:MeOH:H2O (1:1:1, 9 mL) was added LiOH.H2O (126 mg, 3 mmol) atRT, stirred the reaction mixture at RT for 4 h. Completion of the reaction was confirmed by TLC. Volatiles were evaporated under reduced pressure to get crude residue, which was acidified with 1H HO (pH = 2) and extracted with EtOAc (3 x 50 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to afford 4-(allyloxy)-2-(trifluoromethoxy)benzoic acid, Int-4 (200 mg, 76% yield) as white solid, m / z: 263.19 [M+l]+ 1H NMR (400 MHz, DMSO-de): d 11.02 (s, 1H), 7.92 (d, J= 8.4 Hz, 1H), 7.11-7.09 (m, 1H), 7.00 (s, 1H), 6.07-5.99 (m, 1H), 5.42 (d, J= 17.2 Hz, 1H), 5.30 (d, J= 10.4 Hz, 1H), 4.71-4.69 (m, 2H).Rf= 0.4 (Mobile phase: 5% MeOH-DCM).Reaction conditions: a) b) 10% Pd-C, EtOH, H2atm, RT c) NaNO2, H2SO4, 70 °C, 8 h d) Mel, K2CO3, DMF, 100 °C, 4 h e) LiAIH4, THF, 0 °C, 1 h f) PBr3, DCM, 0 °C-RT, 2 h Step-1: Preparation of methyl 6-methoxy-5-nitronicotinate (2):OTo a stirred solution of methyl 6-chloro-5-nitronicotinate (1) (10 g, 46.172 mmol) in MeOH (150 mL) was added Et-5N (6.4 mL, 46.172 mmol) at RT. Stirred the reaction mixture at RT for 16 h. Completion of the reaction was confirmed by TLC and LCMS. Volatiles was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 15% EtOAc -Hexane as eluent) to afford methyl 6-methoxy -5 -nitronicotinate (2) (9 g, 91%) as pale-yellow solid, m / z: 213.18 [M+H]+Rf = 0.5 (Mobile phase: 20% EtOAc -Hexane).Step-2: Preparation of methyl 5-amino-6-methoxynicotinate (3):OTo a stirred solution of methyl 6-methoxy-5-nitronicotinate (2) (9 g, 42.452 mmol) in MeOH (90 mL) was added 10% Pd-C (2.26 g, 21.226mmol) at RT, stirred the reaction mixture at RT under H2 atm for 16 h. completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was filtered through celite bed, washed with MeOH (3 x 300 mL), volatiles was evaporated underreduced pressure to afford methyl 5-amino-6-methoxynicotinate (3) (4 g, 51%) as yellow solid, which was used for next step without any further purification, m / z: 183.12 [M+H]+Rf = 0.4 (Mobile phase: 30% EtO Ac -Hexane).Step-3: Preparation of methyl 5-hydroxy-6-methoxynicotinate (4):OTo a stirred solution of methyl 5-amino-6-methoxynicotinate (3) (4 g, 21.978 mmol) in H2O (66 mL) was added NaNCh (1.51 g, 21.978 mmol) in H2O (5 mL) followed by Conc.H2SO4(4 mL) at 0°C, stirred the reaction mixture at 100 °C for 2 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with cold water (300 mL) and extracted with DCM (3 x 200 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue to afford methyl 5-hydroxy-6-methoxynicotinate (4) (2 g, 59%) as light brown liquid, which was used for next step without any further purification, m / z: 184.15 [M+H]+1H NMR (400 MHz, DMSO-ds): d 10.09 (s, 1H), 8.22-8.21 (m, 1H), 7.50-7.49 (m, 1H), 3.94 (s, 3H), 3.82 (s, 3H).Rf = 0.35 (Mobile phase: 30% EtOAc -Hexane).Step-4: Preparation of methyl 5 f -dimethoxynicotinate (5):OTo a stirred solution of methyl 5-hydroxy-6-methoxynicotinate (4) (3 g, 16.393 mmol) in DMF (30 mL) was added K2CO3 (10.65 g, 49.180 mmol) and Methyl iodide (1.5 mL, 24.589 mmol) at RT. Stirred the reaction mixture at 60 °C for 6 h. Completion of the reaction was confirmed by TLC and LCMS. Reaction mixture was diluted with water (150 mL) and extracted with EtO Ac (2 x 100 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure to get crude residue. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel, 10% EtO Ac -Hexane as eluent) to afford methyl 5,6-dimethoxynicotinate (5) (1.5 g, 46%) as pale-yellow liquid, m / z: 198.17 [M+H]+Rf = 0.4 (Mobile phase: 30% EtO Ac -Hexane).Step-5: Preparation of (5,6-dimethoxypyridin-3-yl)methanol (6):To a stirred solution of methyl 5,6-dimethoxynicotinate (5) (1.0 g, 5.07 mmol) in THF (20 mL) was added LiAlH4(1.0 M in THF) (2.53 mL, 2.53 mmol) at 0°C. Stirred the reaction mixture at0°C for 1 h. Completion of the reaction was confirmed by TLC. Reaction mixture was quenched with sat NH4CI solution (50 mL) and extracted with EtOAc (3 x 50 mL), the combined organic layer was dried over Na2SC>4, filtrate was evaporated under reduced pressure to afford (5,6-dimethoxypyridin-3-yl)methanol (6) (380 mg, 44% yield) as a light brown liquid, m / z: 170.19 [M+l]+Rf = 0.2 (Mobile phase: 20% EtOAc -Hexane).Step-6: Preparation of of 5-(bromomethyl)-2,3-dimethoxypyridine (Int-6):To a stirred solution of (5,6-dimethoxypyridin-3-yl)methanol (6) (380 mg, 2.24 mmol) in DCM (3.8 mL) was added PBr3(0.1 mL, 1.12 mmol) at 0 °C. Stirred the reaction mixture at RT for 2 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with cold water (30 mL) and extracted with DCM (3 x 30 mL), the combined organic layer was dried over Na2SO4, filtrate was evaporated under reduced pressure afford 5-(bromomethyl)-2,3-dimethoxypyridine (Int-6) (230 mg, 44% yield) as a light brown liquid, m / z: 232.07 [M]+, 234.04 [M+2]+Rf = 0.2 (Mobile phase: 20% EtOAc -Hexane).Method write-up for LCMS and Chiral HPLCMethods for LCMS:Method-A:Column: KinetexEVO C18 (2.1 x 50 mm, 1.7 pm),Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN,(T / %B: 0.01 / 10, 0.5 / 10, 5 / 40, 10 / 90)Flow Rate: 0.4 mL / min.Method-B:KinetexEVO C18 (2.1 x 50 mm, 1.7 pm)Mobile Phase: A-0.01% FA in water; B-0.01% FA in ACN,(T / %B: 0.01 / 10, 0.5 / 10,4 / 90, 7 / 90)Flow Rate: 0.4 mL / min.Chiral HPLC methods:Method A:Column: CHIRALPAK IG, 250 x 4.6 mm, 5 gmMobile phase: (HEXANE: ETOH: IP A) (85:10:05),F / R: l.OmL / min, Column Temp: 40°CMethod B:Column: CHIRALPAK IG, 250 x 4.6 mm, 5 pmMobile phase: HEXANE: ETOH: MEOH; (85:10:5), F / R: 1.0 mL / min, Column Temp:40°CMethod C:Column: CHIRALPAK IG, 250 x 4.6 mm, 5 pmMobile phase: (HEXANE: IPA: EtOH) (80:10:10),F / R: l.OmL / min, Column Temp: 40°CMethod D:Column: CHIRALPAK IG, 250 x 4.6 mm, 5 pmMobile phase: (HEXANE: ETOH: IPA) (60:20:20),F / R: l.OmL / min, Column Temp: 40°CMethod E:Column: CHIRALPAK V, 250 x 4.6 mm, 5 pmMobile phase: (HEXANE: IPA: MeOH: DEA) (85:10:05:0.1), F / R: l.OmL / min, Column Temp: 40°CMethod F:Column: CHIRALPAK IG, 250 x 4.6 mm, 5 pmMobile phase: (HEXANE: ETOH: IP A) (70:15:15),F / R: l.OmL / min, Column Temp: 40°CMethod G:Column: CHIRALPAK IG, 250 x 4.6 mm, 5 pmMobile phase: HEXANE: ETOH: IPA: MEOH: TFA (50:10:15:25:0.1),F / R: 1.0 mL / min, Column Temp:40°CBiological characterisationCeramide Inhibition ProtocolCell culture and treatment:The C2C12 mouse myoblast cell line was obtained from the American Type Culture Collection (CRL-1772TM). C2C12 cells were cultured in growth medium consisting of Dulbecco’s modified Eagle’s medium (DMEM; Gibco, 41966-029), 10% fetal bovine serum (FBS; Gibco, 10270-106), and penicillin (100 U / ml) and streptomycin (100 U / ml) (Gibco, 15140- 122). Cells were tested for mycoplasma contamination. No contamination was observed. C2C12 Cells were seeded in a 6-well tissue culture plate for 24 hours, DMSO or test compound, at varying concentration, was added and incubated again for 20 hours. Trypsin-EDTA solution (Gibco, 25200072) was used to detach the cells and the cell pellets were stored at -80°C.Reference compound, IRL-007 was synthesized as reported in the patent #US2019062274Al. Measurements of ceramides:Cell pellets were lysed by the addition of 400 pl Ethyl acetate + Propan-2 -ol (85 % + 15%), spiked with myriocin and kept on shaking (600RPM) at room temperature for 90 minutes.Samples were centrifuged at 12,000 g for 10 minutes and organic phase was transferred into new vials. Organic phase was evaporated and 200 pl of Methanol (100%) were added and LC-MS / MS quantification was performed. LC-MS / MS was used to quantify sphingolipids in positive ionization mode with a Sciex 4500 Q Trap system interfaced with an Exion-high performance liquid chromatography (HPLC) system (Sciex). In brief, the chromatographic separation was performed in a ZORBAX Eclipse Plus C8 column (Agilent) (1.8 pm, 100 mm x 2.1 mm inner diameter). Mobile phase A consisted of 5 mM ammonium formate and 0.2% formic acid in H2Owhile mobile phase B consisted of 5 m ammonium formate and 0.2% formic acid in methanol, and a flow rate of 400 pl min-1 was used. The injection volume of the sample was 2 pl, and the column temperature was 40 °C. A linear gradient was applied and held until minute 14, with elution starting from 80% to 100% of B in 8 min and held until 16 minutes. The column was then equilibrated to initial conditions. ESI source conditions were used as follows: Ion source: Turbo spray, Temperature (TEM):-500 °C, Curtain gas (CUR):35, collision gas (CAD):10, Ion spray voltage (IS):5000, Ion source gas-1 (GS1):5O Ion source gas-2 (GS2):55. Multiple reaction monitoring was used as the acquisition mode with a total cycle time of 359 ms. Optimized collision energies for each ceramide were used. Raw LC-MS / MS data were processed applying Analyst software (version 1.7.1). For absolute quantification, calibration curves and the IS were used to determine the response factor. For each ceramide, linearity of the standard curves was evaluated using a 6-point range. Protein was estimated from the remaining pellet after organic phase separation by BCA method.Table 2: Estimation of ceramide levels (ng / mg of protein) in C2C12 cells treated with test compoundsN-C16- N-C24:l- N-C24:l- N-C16- DH- DH- Deoxys Sample Cone. C18 C24 Deoxysph Deoxysphi Deoxysphi C18 C24 phingos ingosine nganine nganine ineDMSO - 15.4 8.7 641 30.1 39.5 2.19 0.33 0.67 lOpM 1.4 4.6 63 3 2.7 0.15 0 0 SI-001 3pM 2.8 6.5 75 4 3.5 0.25 0.01 0.03 IpM 6.2 7.3 110 7 5.6 0.46 0.13 0.2 lOpM 3.1 6.9 166 4.7 5.9 0.33 0.01 0.04 SI-002 3pM 5 7.8 237 12.7 12.9 0.87 0 0 IpM 9.5 6.1 197 19.3 10.7 0.63 0.07 0.11 lOpM 1.2 6.1 56 2 2.6 0.15 0 0 SI-003 3pM 1.3 6.1 55 2 2.5 0.13 0 0 IpM 4.9 6.3 116 6 5.5 0.37 0.06 0.08 lOpM 1 1.1 16 1.4 1.6 0.95 0 0 SI-004 3pM 1.8 3.5 13 1.6 1.8 0.72 0 0 IpM 3.4 5.6 29 3 2.4 1.59 0 0 lOpM 1.2 1.8 19 7.7 3.2 1.02 0 0 SI-005 3pM 2 2.7 10 12.1 4.5 1.29 0 0 IpM 2.7 10 19 12.4 6.9 3.7 0 0.96 lOpM 0.6 7.5 19 1.3 1.5 0.91 0 0 SI-006 3pM 1.1 9.3 21 1.1 1.3 0.51 0 0IpM 2 10.5 25 1.8 1.2 1.02 0 0N-C16- N-C24:l- N-C24:l- N-C16- DH- DH- C18 C24 Deoxysph Deoxysphi Deoxys Sample Cone. Deoxysphi C18 C24 phingos ingosine nganine nganine inelOpM 1.3 1.2 92 1.9 0.3 1 0 0 3pM 0.9 1.5 80 2.6 0.6 0.9 0 0 SI-0076.7 3.6 86 3.2 1.6 0 0 IpM 1.1lOpM 4.4 1.9 204 39 3.9 1.8 0 0 3pM 8.7 9.3 271 44 7.2 2.9 0.17 0.24 SI-00822 19 426 35 11.4 5.6 0.5 0.68 IpMlOpM 1.8 45 0.9 0.6 0.5 0 0 1.13pM 2.3 2.1 53 1.3 0.8 0.6 0.05 0 SI-0097.9 3.5 68 1.6 1.8 0.7 0.25 0 IpM- - lOpM 2.3 4 93 1.7 2.1 0.7- - 3pM 2.2 4.1 84 2.4 1.9 0.7 SI-010- - 5.9 4.9 99 3 3 IpM 1.1- lOpM 12.6 9 530 44 13 2.6 0.04 11.8- 3pM 9.2 549 33 14.5 3.8 0.08 SI-0111- 24.9 11.7 716 17 18.6 9.5 0.26 IpM- - lOpM 5.18 3.9 90 1.6 1.8 1- - 3pM 4.1 4.9 108 2.6 2.5 1 SI-012- 10 3.9 103 2.6 3.1 1.2 0.01 IpM- - lOpM 2.1 2.9 107 1.9 1.6 0.8- - 3pM 3.9 3.2 106 2.1 2.6 0.7 SI-013- - 4.8 2.2 105 2.4 2.8 0.5 IpM- lOpM 16.1 5.1 428 48.6 10.3 2.3 0.1 - 3pM 22 9.6 802 76.9 20.3 7.8 0.8 SI-014- 23 7.9 785 63.3 15.3 9.5 0.8 IpM- - lOpM 1.2 2.7 97 1.5 1.6 0.5- - 3pM 1.8 1.6 73 1.5 0.3 SI-015 1.1- - 2 2.3 102 1.7 2.3 0.4 IpMlOpM 1.4 1.9 71 0.9 0.9 0.6 0 0 3pM 2.5 2.3 52 0.6 0.6 0.5 0.04 0 SI-0165.8 3.2 59 0.9 1 0.7 0.16 0 IpMlOpM 10.9 6.7 301 27 4.5 3.5 0.15 0.32 3pM 3.2 3.9 149 20 1.8 1.2 0.2 0.02 SI-0173 3 99 11 2 0.8 0.3 0 IpMlOpM 0.7 0.6 77 0.9 0.7 0.17 0 1.13pM 1 1.2 61 0.7 0.8 0.6 0.21 0 SI-0184.6 1.7 74 1 1.2 0.8 0.25 0 IpM- - lOpM 2.2 1.8 106 1.8 2.3 0.48 SI-019N-C16- N-C24:l- N-C24:l- N-C16- DH- DH- C18 C24 Deoxysph Deoxysphi Deoxys Sample Cone. Deoxysphi C18 C24 phingos ingosine nganine nganine ine3pM 4.9 2.2 137 3 3.3 0.94 - - - - 6.1 1.8 177 5.2 4.5 1.17 IpM- - lOpM 4.7 3 311 34.8 6 1.33- - 3pM 20.2 6.7 637 82.1 13.5 2.47 SI-020- 25.4 4.8 669 50.1 15.2 3.8 0.24 IpM- - lOpM 0.9 1.6 106 1.9 2 0.68- - 3pM 6.6 2 87 1.5 1.8 0.39 SI-021- - 7 3.9 163 3.4 4.2 1.08 IpM- - lOpM 14 4.8 168 3.2 2.3 1.4- - 3pM 21 3.9 175 3.5 3.1 1.6 SI-022- - 24 2.7 201 3.9 4.1 1.2 IpM- - lOpM 14 5.3 510 52.1 8.4 1.5- 3pM 24 4.8 544 30.2 12.2 1.5 0 SI-023- 22 5.8 774 25.4 17 5.4 0.5 IpM- - lOpM 13 3.8 130 2.3 2.4 1- - 3pM 13 2.1 125 2 2.1 0.7 SI-024- - 24 2.5 262 4.2 5.4 1.8 IpMlOpM 15 7 108 17 17 4.6 BQL BQL SI-056-01 3pM 14 7 114 19 20 5.5 BQL BQL 22 6 101 12 20 8.1 BQL BQL IpMlOpM 19 7 136 17 19 5.3 BQL BQL 3pM 15 7 124 16 14 4.7 BQL BQL SI-056-0215 7 111 13 11 4.6 BQL BQL IpM14 7 104 24 6 4.1 BQL BQL SI-054 IpM9 8 54 6 4 3 BQL BQL IpM SI-05972 22 572 67 50 5 0.02 2.28 IpM SI-08214.2 7.7 65.4 5.8 7.1 3.9 BQL BQL IpM SI-08317 13 213 192 21 5 BQL 0.8 SI-061 IpM20 11 366 116 36 8 BQL 1.4 SI-084 IpM19 12 122 78 16 7 BQL 0.8 IpM SI-085SI-062 6 14 230 14 8 BQL BQL 0.18 IpMSI-086 13 17 326 30 19 BQL BQL 0.48 IpM25 16 219 9 14 BQL 0.05 0.23 SI-087 IpMSI-067 27 13 436 124 32 7 BQL 1.5 IpMSI-068 26 14 450 115 39 8 BQL 1.3 IpMSI-069 39 16 420 81 32 12 BQL 2.9 IpMSI-070 42 34 635 178 44 5 0.09 1.85 IpMSI-071 43 30 630 121 60 7 0.14 1.93 IpMSI-072 87 42 637 156 56 9 0.17 2.59 IpMSI-073 36 31 487 66 46 6 0.11 1.61 IpMSI-074 35 29 569 59 53 6 0.03 1.62 IpMN-C16- N-C24:l- N-C24:l- N-C16- DH- DH- C18 C24 Deoxysph Deoxysphi Deoxys Sample Cone. Deoxysphi C18 C24 phingos ingosine nganine nganine ineSI-075 IpM 70 27 591 29 58 7 0.11 2.1628 16 481 105 37 10 BQL 2.3 SI-076 IpMSI-077 23 12 462 89 42 9 BQL 1.8 IpM32 14 451 62 49 14 BQL 2.7 IpM SI-07832 22 493 111 47 5 0.03 1.50 IpM SI-07937 27 535 108 67 6 0.05 1.76 IpM SI-08072 22 572 67 50 5 0.02 2.28 SI-081 IpMSolubility (pg / mL) and Chrome LogD data for the MC analogues:Sample Solubility Chrome Sample Solubility Chrome (pg / mL) (pg / mL) LogD LogD (cLogD?.4) (cLogD?.4)- SI-003 8 4.5 SI-056- 1702SI-006 BQL 4.6 SI-069 38SI-009 49 SI-072 47SI-012 30 SI-075 41SI-015 4 SI-078 6SI-018 9 SI-081 7SI-021 3 SI-083 1SI-024 4 SI-085 11SI-054 0.8 SI-087 2SI-056-01 27 2.5

Claims

CLAIMSWhat is claimed is:

1. A compound of the formula:or a pharmaceutically acceptable salt form thereof, wherein:X and Z are independently selected from C(0) and S(0)2;Y and Y1are independently selected from a bond and NH;Ar1is an optionally substituted 6-10 membered aromatic carbocyclylene, an optionally substituted 5-10 membered heteroarylene or an optionally substituted 3-10 membered heterocyclylene;Ar2is an optionally substituted 6-10 membered aromatic carbocyclylene or optionally substituted 5-10 membered heteroarylene; andR1is Ci-Cs alkyl, (QDxCs-C? cycloalkyl, (CH2)xphenyl, (CH2)x(3-7 membered heterocyclyl) or (CH2)x(5-6 membered heteroaryl); wherein the Ci-6 alkyl, (CH2)XC3-C? cycloalkyl, (CH2)xphenyl, (CH2)x(3-7 membered heterocyclyl) and the (CH2)x(5-6 membered heteroaryl) are optionally substituted with one or more groups selected from halo, ORa, NRaRb, S(O)iRa, NRaS(O),R'. S(O)iNRaRb, C(=O)ORa, OC(=O)ORa, C(=S)ORa, O(C=S)Ra, C(=O)NRaRb, NRaC(=O)Rb, C(=S)NRaRb, NRaC(=S)Rb, NRa(C=O)ORb, O(C=O)NRaRb, NRa(C=S)ORb, O(C=S)NRaRb, NRa(C=O)NRbRc, NRa(C=S)NRbRc, C(=S)Ra, C(=O)Raand C1-C6alkyl;L1and L3are independently selected from -O-, -N-, -S-, -SO2-, -SO3-, -SO2NH-, -NHSO2-, -(CH2)I-4, -O(CH2)I-4-, -(CH2)I-4-O-, -O(CH2)2-4O-, -NH(CH2)I-4-, -(CH2)I-4-NH-, and -NH(CH2)2-4NH-;L2is is selected from C2-C6 alkenylene, C2-C6 alkenylene oxide, Ci-Cs alkylene, C3-C7 cycloalkylene, phenylene, 3-7 membered heterocyclylene or 5-6 membered heteroarylene; wherein the Ci-Cs alkylene, C2-C6 alkenylene, C3-C7 cycloalkylene, phenylene, 3-7 membered heterocyclylene, and the 5-6 membered heteroarylene are optionally substituted with one or more groups selected from halo, 0Ra, NRaRb, S(O)iRa, NRaS(O)iRa, S(O)iNRaRb, C(=O)ORa, OC(=O)ORa, C(=S)ORa, O(C=S)Ra, C(=O)NRaRb, NRaC(=O)Rb, C(=S)NRaRb, NRaC(=S)Rb, NRa(C=O)ORb, O(C=O)NRaRb, NRa(C=S)ORb, O(C=S)NRaRb, NRa(C=O)NRbRc, NRa(C=S)NRbRc, C(=S)Ra, C(=O)Raand Ci-Cs alkyl;each Ra, Rband Rcare each independently selected from -H and C1-C3 alkyl; each i is independently 0, 1, 2, 3 or 4 ; andeach x is independently 0 or 1.

2. The compound of claim 1, wherein the compound is represented by the following structural formula:Oor a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound is represented by the following structural formula:or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound is represented by the following structural formula:Oor a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound is represented by the following structural formula:or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound is represented by the following structural formula:Oor a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound is represented by the following structural formula:or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, wherein the compound is represented by the following structural formula:or a pharmaceutically acceptable salt thereof.

9. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein:Ar1is optionally substituted by one or more groups represented by R3;Ar2is optionally substituted by one or more groups represented by R2;eachR2is independently halo, CN, 0Rd, NReRd, S(O)jRd, NReS(O)jRd, S(O)jNReRd, C(=O)ORd, OC(=O)ORd, C(=S)ORd, O(C=S)Rd, C(=O)NReRd, NReC(=O)Rd, C(=S)NReRd, NReC(=S)Rd, NRe(C=O)ORd, O(C=O)NReRd, NRe(C=S)ORd, O(C=S)NReRd, NRf(C=O)NReRd, NRf(C=S)NReRd, C(=S)Rd, C(=O)Rd, Ci-Cs alkyl, (CH2)yC3-C7cycloalkyl, (CH2)yphenyl, (CH2)y(3-7 membered heterocyclyl) or (CH2)y(5-6 membered heteroaryl), wherein the Ci.Cs alkyl, (CH2)yC3-C? cycloalkyl, (CH2)yphenyl, (CH2)y(3-7 membered heterocyclyl) and (CH2)y(5-6membered heteroaryl) are optionally substituted with one or more groups selected from halo, Ci- Galkyl. Ci-Csalkoxy, Ci-Cshaloalkoxy, Ci-Cshaloalkyl, cyano and SChCCi-Csalkyl);each R3is independently halo, CN, 0Rg, NRhRg, S(O)kRg, NRhS(O)kRg, S(O)kNRhRg, C(=O)ORg, OC(=O)ORg, C(=S)ORg, O(C=S)Rg, C(=O)NRhRg, NRhC(=O)Rg, C(=S)NRhRg, NRhC(=S)Rg, NRh(C=O)ORg, O(C=O)NRhRg, NRh(C=S)ORg, O(C=S)NRhRg, NR‘(C=O)NRhRg, NR‘(C=S)NRhRg, C(=S)Rg, C(=O)Rg, Ci-Cs alkyl, (CH2)ZC3-C7 cycloalkyl, (CH2)zphenyl, (CH2)z(3-7 membered heterocyclyl) or (CH2)z(5-6 membered heteroaryl), wherein the Ci-Cs alkyl, (CH2)ZC3-C? cycloalkyl, (CH2)zphenyl, (CH2)Z(3-7 membered heterocyclyl) and the (CH2)z(5-6 membered heteroaryl) are optionally substituted with one or more groups selected from halo, CVC salkyl. Ci -C salkoxy. Ci-Cdialoalkoxy. C’i-C;haloalkyl. cyano and SO2(Ci-C3alkyl);each Rdand Rgis independently selected from H, Ci-Csalkyl, CVG, alkenyl. (CH2)iPh, and SO2(Ci-C3alkyl), wherein said alkyl is optionally substituted with one or more R22;each R22is independently selected from halo, CN, ORP, O(CH2)mORp, NRpRq, C(O)ORP, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more oxo;Re, Rf, Rh, R1, Rpand Rqare each independently selected from -H, C1-C3 alkyl and Ci-C3 haloalkyl;each j and k is independently 0, 1 or 2;m is 2, 3, or 4; andeach y and z is independently 0 or 1.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein:Ar1is phenylene, pyridylene, benzothienylene, quinoxalinylene, pyridazinylene, pyrazanylene, benzothiazolylene, pyrimidinylene, thienylene, thiazolylene, isothiazolylene, furanylene, naphthylene, benzofuranylene, benzothiazolylene, imdazo[l,2-a]pyridinylene, pyrazolylene, oxazolylene, isooxazolylene, quinazolinylene, imidazopyridinylene, benzimidazolylene, pyrrolylene or quinolinylene, each optionally substituted with one or more groups represented by R3; andAr2is phenylene, pyridylene, benzothienylene, quinoxalinylene, pyridazinylene, pyrazanylene, benzothiazolylene, pyrimidinylene, thienylene, thiazolylene, isothiazolylene, furanylene, naphthylene, benzofuranylene, benzothiazolylene, imdazo[l,2-a]pyridinylene, pyrazolylene, oxazolylene, isooxazolylene, quinazolinylene, imidazopyridinylene, benzimidazolylene, pyrrolylene or quinolinylene, each optionally substituted with one or more groups represented by R2.

11. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein: Ar1is phenylene or pyridylene, each optionally substituted with one or more groups represented by R3;Ar2is phenylene or pyridylene, each optionally substituted with one or more groups represented by R2.

12. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-11, wherein:eachR2is independently 0Rd, halo, Ci.Csalkyl, C\.C-cycloalkyl. CVCThaloalkyl. cyano, or SChCCi-Csalkyl); andeachR3is independently 0Rg, halo, Ci.Csalkyl, C\.C-cycloalkyl. C’i-C;haloalkyl. cyano, or SChCCi-Csalkyl).

13. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-12, wherein:eachR2is 0Rd;each Rdis independently selected from H and C1-C3 alkyl wherein alkyl is optionally substituted with one or more groups selected from CN, ORP, O(CH2)mORp, NRpRq, C(O)ORP, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more oxo;eachR3is independently selected from Ci-Cshaloalkyl, Ci-Csalkoxyl, Ci-C3haloalkoxyl, O(CH2)„(CH=CH2), O(CH2)„Ph, or OSO2(Ci-C3alkyl);Rpand Rqare each independently selected from -H, C1-C3 alkyl and C1-C3 haloalkyl; andn is 1, 2, or 3.

14. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-12, wherein R2is 0Rd;Rdis C1-C3 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from OMe, CN, C(O)OH, OCH2CH2OMe, -OCH2CH2OH, NEt2, imidazolyl, morpholinyl, pyrrolidinlyl, thiomorpholinyl, thiomorpholinyl 1 -oxide, and thiomorpholinyl 1,1-dioxide; andR3is Ci-Cshaloalkyl.

15. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-12, wherein R2is OMe, -OCH2CH2OMe, -OCH2CH2OH, -OCH2CH2CN, -OCH2CH2C(O)OH, -OCH2CH2OCH2CH2OMe, -OCH2CH2NEt2, or is represented by any one of the structures16. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-15, wherein R1is Ci-Cs alkyl, optionally substituted with one or more groups independently selected from halo, Ci-Csalkyl, Cs-Cvcycloalkyl, Ci-Csalkoxy, Ci-Cshaloalkoxy, Ci-Cshaloalkyl, cyano, and SO2(Ci-C3alkyl).

17. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-15, wherein R1is Ci-Cs alkyl.

18. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-15, wherein R1is isopropyl.

19. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-18, wherein L2is selected from C2-C6 alkenylene, C2-C6 alkenylene oxide, Ci-Cs alkylene, (CH2)XC3-C7 cycloalkylene, or (CH2)x(3-7 membered heterocyclylene); wherein the Ci-Cs alkylene, (CH2 C3-C7 cycloalkylene, and (CH2)x(3-7 membered heterocyclylene) are optionally substituted with one or more groups selected from halo, 0Ra, NRaRb, S(O)iRa, NRaS(O)iRa, S(O)iNRaRb, C(=O)ORa, OC(=O)ORa, C(=S)ORa, O(C=S)Ra, C(=O)NRaRb, NRaC(=O)Rb, C(=S)NRaRb, NRaC(=S)Rb, NRa(C=O)ORb, O(C=O)NRaRb, NRa(C=S)ORb, O(C=S)NRaRb, NRa(C=O)NRbRc, NRa(C=S)NRbRc, C(=S)Ra, C(=O)Raand Ci-Cs alkyl.

20. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-19, wherein:L1is -*O(CH2)I-2-, wherein “*” indicates the point of attachment to Ar2; L2is selected from C2-C6 alkenylene, C2-C6 alkenylene oxide and Ci-Cs alkylene; wherein the Ci-Cs alkylene and C2-C6 alkenylene are optionally substituted with one or more groups selected from halo, ORa, NRaRb, S(O)iRaand Ci-Cs alkyl; andL3is -*O(CH2)I-2-, wherein “*” indicates the point of attachment to Ar1.

21. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-19, wherein:L1is -*O(CH2)-, wherein “*” indicates the point of attachment to Ar2;L2is -(CH=CH)- or is represented byA^-OH<, / 0H, or ; andL3is -*O(CH2)-, wherein “*” indicates the point of attachment to Ar1.

22. A pharmaceutical composition comprising the compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or diluent.

23. A method of inhibiting serine palmitoyltransferase in a subject in need thereof, comprising administering an effective amount of the compound of any one of claims 1-21 to the subject.

24. A method of reducing elevated ceramide levels in a subject in need thereof, comprising administering an effective amount of the compound of any one of claims 1-21 to the subject.

25. A method of treating a subject with a disease characterized by elevated ceramide levels, or a disease or condition mediated by serine palmitoyltransferase, comprising administering an effective amount of the compound of any one of claims 1-21 to the subject.

26. The method of claim 25, wherein the disease or condition is a muscular dystrophy, an inflammatory myopathy, a metabolic myopathy or a myofibrillar myopathy.

27. The method of claim 26, wherein:the muscular dystrophy is myotonic muscular dystrophy (also called MMD or Steinert's disease), Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Limb-Girdle Muscular Dystrophy, Facioscapulohumeral Dystrophy, Congenital Muscular Dystrophy, Oculopharyngeal Muscular Dystrophy, Distal Muscular Dystrophy or Emery-Dreifuss Muscular Dystrophy;the inflammatory myopathy is polymyositis, dermatomyositis, inclusion body myositis, necrotizing autoimmune myopathy and inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB) or frontotemporal dementia (FTD) (also referred to as “IBMPFD”);the metabolic myopathy is Kearns-Sayre syndrome (KSS), Leigh syndrome, Mitochondrial DNA (mtDNA) depletion syndrome, Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, Mitochondrial neurogastrointestinal encephalopathy (MNGIE), Myoclonic epilepsy with ragged red fibers (MERRF), Neuropathy,ataxia and retinitis pigmentosa (NARP) syndrome, Pearson syndrome, Progressive external ophthalmoplegia (PEO) or sarcopenia; andthe myofibrillar myopathy is plectinopathy, desminopathy, aP-crystallinopathy, myotilinopathy, filaminopathy, BAG3 -related myofibrillar myopathy, zaspopathy or nemaline myopathy.

28. The method of claim 25, wherein the disease or condition is amyloidosis.

29. The method of claim 25, wherein the disease or condition is Facioscapulohumeral Dystrophy, myotonic dystrophy, Oculopharyngeal Muscular Dystrophy, VCP disease or inclusion body myositis.

30. The method of claim 25, wherein the disease or condition is a mitochondrial myopathy, ICU sarcopenia, age related sarcopenia, aP-crystallinopathy, nemaline myopathy, a myofibrillar myopathy and amyloidosis.

31. The method of claim 24 the disease or condition or sarcopenia, such as ICU sarcopenia, age related sarcopenia.

32. The method of claim 24 wherein the disease or condition is a lysosomal storage disease.

33. The method of claim 31, wherein the lysosomal storage disease is Aspartylglucosaminuria, Batten Disease, Cystinosis, Fabry Disease, Gaucher Disease Types I, II, or III, Glycogen Storage Disease II (Pompe Disease), GM2 -Gangliosidosis Type I (Tay Sachs Disease), GM2-Gangliosidosis Type II (Sandhoff Disease), Metachromatic Leukodystrophy, Mucolipidosis Types I, II / III or IV, Mucopolysaccharide Storage Diseases (Hurler Disease and variants, Hunter, Sanfilippo Types A,B,C orD, Morquio Types A orB, Maroteaux-Lamy or Sly diseases), Niemann-Pick Disease Types A / B, Cl or C2 or Schindler Disease Types I or II.

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