Proteasome inhibitors for the treatment of malaria

Abstract

Provided herein are compounds that inhibit a proteasome of a malaria parasite and methods of making the compounds. The present invention further relates to methods of treating malaria using these compounds.

Description

PROTEASOME INHIBITORS FOR THE TREATMENT OF MALARIAACKNOWLEDGMENT OF GOVERNMENT SUPPORT

[0001] This invention was made with government support under Grant Nos. AI103947 and Al 155784 awarded by the National Institutes of Health. The government has certain rights in the invention.PRIORITY

[0002] This International Application claims the benefit of U.S. Provisional Application No. 63 / 549,893, filed on February 5, 2024. This provisional application and any applicable appendices are incorporated herein by reference in their entireties for all purposes.BACKGROUND

[0003] 1 . Field

[0004] The present invention relates to compounds that inhibit the malaria parasite proteasome and methods of making the compounds. The present invention further relates to methods of treating or preventing malaria using these compounds.

[0005] 2. Discussion of Related Art

[0006] Malaria is caused by protozoan parasites of the genus Plasmodium that are transmitted by the bite of infected mosquitos, and infect and destroy red blood cells, leading to fever, severe anemia, cerebral malaria and, death in some cases. It remains endemic in 85 countries, with an exposed population of 3.2 billion. WHO reported 241 million malaria cases in 2021 and 0.63 million deaths, caused mostly by P. falciparum in sub-Saharan African children. Plasmodium falciparum is responsible for most malaria deaths, and is the dominant species in sub-Saharan Africa. The disease burden is heaviest in African children under 5 years of age and in pregnant women. Plasmodium vivax causes 25-40% of the global malaria burden, particularly in South and Southeast Asia, and Central and South America. The other three main species that are known to infect humans are Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi.

[0007] Malaria is a disease that is prevalent in many developing countries. Approximately 40% of the world’s population lives in countries where the disease is endemic; approximately 247 million people suffer from the disease every year. Various chemical agents have been developed for the treatment and prevention of malaria over the past 20 years. However, many of these medications are costly and some exhibit significant toxicity and undesirable side effects inhumans. Drugs used for treating malaria include artemisinin and its derivatives (such as artemether or dihydroartemisinin, chloroquine, quinine, mefloquine, amodiaquine, atovaquone / proguanil, doxycycline, lumefantrine, piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine, primaquine, quinacrine, ferroquine, tafenoquine, arterolane, Spiro[3H-indole-3,1’-[1 H]pyrido[3,4-b]indol]-2(1 H)-one, 5,7’-dichloro-6’-fluoro-2’,3’,4’,9’- tetrahydro-3’-methyl-,(TR,3’S)-] (CAS Registry Number: 1193314-23-6), 2-(1 ,1-difluoroethyl)-5- methyl-N-[4-(pentafluoro-A6-sulfanyl)phenyl]-[1 ,2,4]triazolo[1 ,5-a] pyrimidin-7-amine (CAS Registry Number: 1282041-94-4), Morpholine, 4-[2-(4-cis-dispiro[cyclohexane-1 ,3’- [1 ,2,4]trioxolane-5’,2”-tricyclo[3.3.1.13,7]decan]-4-ylphenoxy) ethyl]-morpholine (CAS Registry Number: 1029939-86-3).

[0008] The widespread emergence of drug resistance of malaria parasites in many tropical countries has compromised many of the current chemotherapies and there is a continued need for new chemotherapeutic approaches.

[0009] Malaria is transmitted by the bite of an infected mosquito, which injects sporozoite-stage parasites into the human host. These sporozoites migrate to the liver, invade hepatocytes, and differentiate into liver-stage schizonts. Upon rupture, parasites invade erythrocytes (red blood cells; RBCs) and divide asexually, eventually bursting from the host cell and reinvading new RBCs. Malaria symptoms are caused by these intraerythrocytic stages, and thus drugs used to treat symptomatic malaria require intraerythrocytic activity. A minority of blood-stage parasites develop into gametocytes, which reproduce sexually upon uptake via mosquito bites, enabling the spread of the infection to a new host; compounds that are active against sexual stages block transmission, and drugs that act against the liver stage are of interest for prophylaxis.

[0010] The proteasome is a well-established target for hematologic cancers. Recently it has been the focus of study for the treatment of other proliferative diseases including Leishmania and Trypanosoma brucei, and is a promising target for the development of new antimalarials with inhibitor activity shown against multiple stages, and with the potential to reverse ART resistance. Preclinical and clinical candidates targeting the proteasome have been reported for Leishmania and compounds with activity against Trypanosoma cruzi and T. brucei have also been reported. Small molecule inhibitors with activity against the malaria parasite P. falciparum in vitro and in vivo in mouse models have also been identified, and have been reported to show broad activity against multiple life cycle stages. They have also shown synergy with artemisinin and have been reported to reverse Kelchl 3-based artemisinin resistance. Thus proteasome inhibitors have the potential to be used not only for treatment of malaria, but have potential also for chemoprevention and may providing transmission blocking activity. The proteasome is a large multi-subunitmachine found in all eukaryotes that degrades damaged or unfolded proteins as part of the ubiquitin-proteasome degradation pathway. It is composed of a 20S catalytic core plus associated regulatory subunits and contains three active sites with different substrate preference: pi cleaves after acidic residues, p2 is trypsin-like cleaving after basic residues, and p5 is chymotrypsin-like cleaving after large hydrophobic or aromatic residues.

[0011] The compounds described herein are potent and reversible inhibitors of the p5 site of the Plasmodium proteasome that do not inhibit the human proteasome. They are orally active proteasome inhibitors for treatment or prevention of malaria.SUMMARY OF THE INVENTION

[0012] In some aspects, the current disclosure encompasses compounds with Formula (l)-1 , Formula (l)-T, Formula (l)-T’, Formula (l)-2, or Formula (l)-3, or a salt thereof:Formula (I)-l’ Formula (I)- 1"Formula (le)R1-R5 are each independently hydrogen, halogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, ether, ester, -C(O)CH3, - C(O)OCH3, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero cycloalkyl, optionally C3-C6substituted hetero cycloalkyl, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, - C3-C6cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, R1 and R5are interconnected to form a substituted pyrazole ring, R1 and R5 are interconnected to form an aryl ring, or absent;X1-X6 are each independently carbon or nitrogen;A, B, C, Z, and Y are each independently carbon, nitrogen, oxygen, sulfur, or absent;W is hydrogen, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-Ce hetero cycloalkyl, optionally C3-Ce substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, alkyl amine, carboxylic acid, -CH2NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, 3-methyloxazol-2(3H)-one, substituted or unsubstituted oxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzimidazole,substituted or unsubstituted benzoxazole, substituted or unsubstituted oxetane, substituted or unsubstituted triazole, thiazole, sulfonyl, or substituted sulfonyl; n is 0, 1 , or 2;Re-R? are each independently hydrogen or methyl;Rs is H, alkyl or hydroxyl; or Rs and R23 are connected to form a 3 to 6 membered cycloalkyl ring;R9-R10 are each independently H, deuterium, alkyl, or components of a ring;R11-R13 are hydrogen, deuterium, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, hetero cycloalkyl, optionally C3-C6 substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, Rn and R12 are interconnected to form a cycloalkyl ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-C6 cycloalkyl, heterocycloalkyl, or absent; wherein C1-C6substituted alkyl may be optionally substituted with one or more of halogen, hydroxy, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, hetero cycloalkyl, optionally C3-C6 substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, R1 and R5are interconnected to form a substituted pyrazole ring, R1 and R5are interconnected to form an aryl ring, Rw and Rn are interconnected to form a substituted or unsubstituted C3-C6 cycloalkyl, heterocycloalkyl, or absent;R10 is hydrogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, heteroaryl, -C(O)NHCH3, - C(O)H, -C(O)NCH3CH3, -C(O)OH, cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, Rw and Rn are interconnected to form a substituted pyrazole ring, R and R11 are interconnected to form a substituted or unsubstituted C3-C6 cycloalkyl, a substituted orunsubstituted C3-C6 cycloheteroalkyl, a substituted or unsubstituted heterocyclic aromatic, aryl ring, or heteroaryl, or absent; andR20-R28 are each independently hydrogen, alkyl, alkoxy, amine, amide, heterocycloalkyl, or alkyl amine; orR20, R22-R25, and R27-R28 are each independently hydrogen, alkyl, alkoxy, amine, amide, heterocycloalkyl, or alkyl amine R21 and R26 and are connected to form a 3 to 6 membered cycloalkyl ring. wherein halogen is F, Cl, Br, or I.

[0013] In some embodiments, the compound is an S-enantiomer.

[0014] In some embodiments, the compound comprises an S-enantiomer configuration at the carbon attached to -(CO)-E.

[0015] In some aspects, the current disclosure encompasses compounds with Formula (l)-1 , Formula (l)-T, Formula (l)-1 ”, Formula (l)-2, or Formula (l)-3, or a salt thereof:R-10 R9Formula (la)D is H, -CH2CH2OCH3, sulfonyl, substituted sulfonyl,Formula (la')Formula (le)R1-R5 are each independently hydrogen, halogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, ether, ester, -C(O)CH3, - C(O)OCH3, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero cycloalkyl, optionally C3-C6substituted hetero cycloalkyl, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, - C3-C6cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, R1 and R5 are interconnected to form a substituted pyrazole ring, R1 and R5 are interconnected to form an aryl ring, or absent;Xi-Xe are each independently carbon or nitrogen;A, B, C, Z, and Y are each independently carbon, nitrogen, oxygen, sulfur, or absent;W is hydrogen, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-Ce hetero cycloalkyl, optionally C3-Ce substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, alkyl amine, carboxylic acid, -CH2NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, 3-methyloxazol-2(3H)-one, substituted or unsubstituted oxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted oxetane, substituted or unsubstituted triazole, thiazole, sulfonyl, or substituted sulfonyl; n is 0, 1 , or 2;R6-R? are each independently hydrogen or methyl;R8is H, alkyl or hydroxyl; or Rs and R33are connected to form a 3 to 6 membered cycloalkyl ring;R9-R10 are each independently H, deuterium, alkyl, or components of a ring;RH-RI3are hydrogen, deuterium, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, hetero cycloalkyl, optionally C3-Cs substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, Rn and R12 are interconnected to form a cycloalkyl ring, R10 and R11 are interconnected to form a substituted or unsubstituted C3-Cs cycloalkyl, heterocycloalkyl, or absent; wherein C1-C6substituted alkyl may be optionally substituted with one or more of halogen, hydroxy, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, hetero cycloalkyl, optionally C3-Cs substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, R1 and Rs are interconnected to form a substituted pyrazole ring, R1 and Rs are interconnected to form an aryl ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-Cs cycloalkyl, heterocycloalkyl, or absent;R10 is hydrogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, heteroaryl, -C(O)NHCH3, - C(O)H, -C(O)NCH3CH3, -C(O)OH, cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, R10 and n are interconnected to form a substituted pyrazole ring, Rw and R11 are interconnected to form a substituted or unsubstituted C3-Ce cycloalkyl, a substituted or unsubstituted C3-Ce cycloheteroalkyl, a substituted or unsubstituted heterocyclic aromatic, aryl ring, or heteroaryl, or absent; andR20-R28 are each independently hydrogen, alkyl, alkoxy, amine, amide, heterocycloalkyl, or alkyl amine; orR20, R22-R25, and R27-R28 are each independently hydrogen, alkyl, alkoxy, amine, amide, heterocycloalkyl, or alkyl amine R21 and R26and are connected to form a 3 to 6 membered cycloalkyl ring. wherein halogen is F, Cl, Br, or I.

[0016] In some embodiments, the compound is an S-enantiomer.

[0017] In some embodiments, the compound comprises an S-enantiomer configuration at the carbon attached to -(CO)-E.

[0018] In some aspects, the current disclosure encompasses a compound of Formula (ll)-1 , Formula (I l)-2, Formula (I l)-3, or a salt thereof:whereinR1-R5 are each independently hydrogen, halogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, ether, ester, -C(O)CH3, - C(O)OCH3, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C(O)NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, - C3-Ce cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, R1 and Rs are interconnected to form a substituted pyrazole ring, R1 and Rs are interconnected to form an aryl ring, or absent;X1-X6 are each independently carbon or nitrogen;A, B, C, Z, and Y are each independently carbon, nitrogen, oxygen, sulfur, or absent;W is hydrogen, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-Ce heterocycloalkyl, optionally C3-Cs substituted heterocycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, alkyl amine, carboxylic acid, -CH2NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, 3-methyloxazol-2(3H)-one, substituted or unsubstituted oxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted oxetane, substituted or unsubstituted triazole, thiazole, sulfonyl, or substituted sulfonyl; n is 0, 1 , or 2;R6-R9 are each independently hydrogen, methyl, or absent;R11-R13 are hydrogen, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, - C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, Rn and R12 are interconnected to form a cycloalkyl ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-Ce cycloalkyl, heterocycloalkyl, or absent; wherein C1-C6substituted alkyl may be optionally substituted with one or more of halogen, hydroxy, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, R1 and R5 are interconnected to form a substituted pyrazole ring, R1 and Rs are interconnected to form an aryl ring, or absent;R10 is hydrogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, heteroaryl, -C(O)NHCH3, - C(O)H, -C(O)NCH3CH3, -C(O)OH, cycloalkyl, nitro, pyrazole, sulfonyl, R10 and Rn are interconnected to form a substituted pyrazole ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-Cs cycloalkyl or aryl ring, or absent; and wherein halogen is F, Cl, Br, or I.

[0019] In some embodiments, the compound is an S-enantiomer.

[0020] In some embodiments, Xi and X2are independently carbon or nitrogen, X3-X6are carbon, R1 is hydrogen, methyl, trifluoromethyl, cyclopropyl, methoxy, or cyano, A is sulfur; B is nitrogen, C is carbon, Z is carbon or nitrogen, R2-R10 are hydrogen, Y is oxygen, Rn is methyl, ethyl, or ethyl fluoride, R12 and RI3are absent; and n=1.

[0021] In some embodiments, the compound has Formula (ll)-1 and the compound is

[0022] In some embodiments, the compound is

[0023] In some embodiments, the compound has Formula (I l)-2 and the compound is selected from the group consisting of

[0024] In some embodiments, the compound may have the Formula (ll)-2 and the compound may be

[0025] In some embodiments, the compound may be

[0026] In some embodiments, the compound may be

[0027] In some embodiments, the compound may be

[0028] In some embodiments, the compound may have Formula (I l)-2 and the compound may be

[0029] In some embodiments, the compound may have Formula (I l)-2 and the compound may be

[0030] In some embodiments, the compound may have Formula (I l)-2 and the compound may be

[0031] In some embodiments, the compound may be

[0032] In some embodiments, the compound may have Formula (I l)-3 and the compound may be

[0033] In some aspects, the current disclosure encompasses a compound of Formula (I)- or a salt thereof:Formula (I)-l whereinR-10 R9D is H, -OMe, -CH2CH2OCH3, sulfonyl, substituted sulfonyl, Formula (la) orFormula (la')R1-R5 are each independently hydrogen, halogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, ether, ester, -C(O)CH3, - C(O)OCH3, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C(O)NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, - C3-Ce cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, R1 and R5are interconnected to form a substituted pyrazole ring, R1 and R5are interconnected to form an aryl ring, or absent;Xi-Xe are each independently carbon or nitrogen;A, B, C, Z, and Y are each independently carbon, nitrogen, oxygen, sulfur, or absent;W is hydrogen, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-Ce hetero cycloalkyl, optionally C3-Ce substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, alkyl amine, carboxylic acid, -CH2NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, 3-methyloxazol-2(3H)-one, substituted or unsubstituted oxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoimidazole,substituted or unsubstituted benzoxazole, substituted or unsubstituted oxetane, substituted or unsubstituted triazole, thiazole, sulfonyl, or substituted sulfonyl; n is 0, 1 , or 2;Re-R? are each independently hydrogen or methyl;Rs is H, alkyl or hydroxyl;R9-R10 are each independently H, deuterium, alkyl, or components of a ring;R11-R13 are hydrogen, deuterium, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-Ce hetero cycloalkyl, optionally C3-Ce substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, Rn and R12 are interconnected to form a cycloalkyl ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-Ce cycloalkyl, heterocycloalkyl, or absent; wherein C1-C6substituted alkyl may be optionally substituted with one or more of halogen, hydroxy, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-Ce hetero cycloalkyl, optionally C3-Ce substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, - C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, R1 and R5are interconnected to form a substituted pyrazole ring, R1 and R5 are interconnected to form an aryl ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-Ce cycloalkyl, heterocycloalkyl, or absent; R10 is hydrogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, heteroaryl, -C(O)NHCH3, - C(O)H, -C(O)NCH3CH3, -C(O)OH, cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, R10 and Rn are interconnected to form a substituted pyrazole ring, R10 and R11 are interconnected to form a substituted or unsubstituted C3-Ce cycloalkyl, a substituted or unsubstituted C3-Ce cycloheteroalkyl, a substituted or unsubstituted heterocyclic aromatic, aryl ring, or heteroaryl, or absent; andR20-R28 are each independently hydrogen, alkyl, alkoxy, amine, amide, heterocycloalkyl, or alkyl amine.wherein halogen is F, Cl, Br, or I.

[0034] In some embodiments, the compound is

[0035] In some aspects, the current disclosure encompasses a compound selected from the group consisting of

[0036] In some aspects, the current disclosure encompasses a pharmaceutical composition comprising one or more of the compounds described above and a pharmaceutically acceptable excipient.

[0037] In some aspects, the current disclosure encompasses a method of treating malaria in a subject in need thereof. The method comprises administering to the subject any one of the compounds described above.

[0038] In some embodiments, the compound or pharmaceutical composition may be coadministered with an artemisinin.

[0039] In some embodiments, the artemisinin may be selected from the group consisting of dihydroartemisinin (DHA), artemether, dihydroartesunate, artesunate, arteether, or artemisone.

[0040] In some embodiments, the compound or pharmaceutical composition may be coadministered with a proteasome [32 inhibitor.

[0041] In some embodiments, the proteasome 32 inhibitor may be selected from the group consisting of bortezomib, MG-132, epoximicin, and WLW-vs.

[0042] In some embodiments, the malaria may be associated with a Plasmodium falciparum infection.BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Aspects of the present inventive concept are illustrated by way of example in which like reference numerals indicate similar elements and in which:

[0044] FIGS. 1A-B present in vivo efficacy study for SW584 in humanized SCID mice infected with P. falciparum 3D7.

[0045] FIG. 1A presents SCID Mouse parasitemia data in experiments testing a compound (SW584) according to the present disclosure compared to a chloroquine (CQ) control.

[0046] FIG. 1 B presents pharmacokinetic data collected after the 1stand 6thdose showing blood levels in experiments testing a compound according to the present disclosure. SW584 was dosed at 50 mg / kg bid (0 and 10 h) for 4 days starting on Day 1 (D1). CQ was dosed daily for 2 days at 10 mg / kg. LLQ, lower limit of quantitation. Veh, vehicle - the dose formulation without drug. Data are for one mouse with exception of the vehicle control where 2 mice (ml and m2) were dosed.

[0047] The drawing figures do not limit the present inventive concept to the specific aspects disclosed and described herein.DETAILED DESCRIPTION

[0048] The inventors have discovered compounds with potent activity against malaria parasites that act by inhibiting the [35 site of the parasite proteasome. The identified compounds are reversible, and bioavailable and show selectivity towards the malarial proteosome versus the human proteasome. The compounds exhibit sustained plasma exposure after oral dosing and efficacy in a SCID mouse model of human malaria.

[0049] The following detailed description references the accompanying drawings that illustrate various aspects of the present inventive concept. The drawings and description are intended to describe aspects of the present inventive concept in sufficient detail to enable those skilled in the art to practice the present inventive concept. Other components can be utilized, and changes can be made without departing from the scope of the present inventive concept. The following description is, therefore, not to be taken in a limiting sense. The scope of the present inventive concept is defined only by the appended claims, along with the full scope of equivalents to which such claims are entitled.I. Terminology

[0050] The phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting. For example, the use of a singular term, such as, “a” is not intended as limiting of the number of items. Also, the use of relational terms such as, but not limited to, “top,” “bottom,” “left,” “right,” “upper,” “lower,” “down,” “up,” and “side,” are used in the description for clarity in specific reference to the figures and are not intended to limit the scope of the present inventive concept or the appended claims.

[0051] Further, as the present inventive concept is susceptible to aspects of many different forms, it is intended that the present disclosure be considered as an example of the principles of the present inventive concept and not intended to limit the present inventive concept to the specific aspects shown and described. Any one of the features of the present inventive concept may be used separately or in combination with any other feature. References to the terms “aspect,” “aspects,” and / or the like in the description mean that the feature and / or features being referred to are included in, at least, one aspect of the description. Separate references to the terms “aspect,” “aspects,” and / or the like in the description do not necessarily refer to the same aspect and are also not mutually exclusive unless so stated and / or except as will be readily apparent to those skilled in the art from the description. For example, a feature, structure, process, step, action, or the like described in one aspect may also be included in other aspects but is not necessarily included. Thus, the present inventive concept may include a variety of combinations and / or integrations of the aspects described herein. Additionally, all aspects of the present disclosure, as described herein, are not essential for its practice. Likewise, other systems, methods, features, and advantages of the present inventive concept will be, or become, apparent to one with skill in the art upon examination of the figures and the description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present inventive concept, and be encompassed by the claims.

[0052] The terms “comprising,” “including” and “having” are used interchangeably in this disclosure. The terms “comprising,” “including” and “having” mean to include, but not necessarily be limited to the things so described.

[0053] The terms “or” and “and / or,” as used herein, are to be interpreted as inclusive or meaning any one or any combination. Therefore, “A, B or C” or “A, B and / or C” mean any of the following: “A,” “B” or “C”; “A and B”; “A and C”; “B and C”; “A, B and C.” An exception to this definition will occur only when a combination of elements, functions, steps, or acts are in some way inherently mutually exclusive.

[0054] “Administered]” or “administration” includes a living system exposed to a compound, combination of compounds, or mixture of compounds. Such exposure can be from, but is not limited to, topical application, oral ingestion, inhalation, subcutaneous injection, intraperitoneal injection, intravenous injection, and intraarterial injection, in animals or other higher organisms.

[0055] A “subject” is a vertebrate, for example a mammal, for example a rodent, a non-human primate, or a human.

[0056] As used herein the term “therapeutically effective amount” of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of a compound. The desired reaction for a therapy of a disease or a condition may also be the retardation of the occurrence or the inhibition of the occurrence of the disease or the condition. A therapeutically effective amount of a compound according to the present invention is dependent on the condition or disease, the severity of the disease, the individual parameters of the individual, including age, physiological condition, height, and weight, the duration of the treatment, the type of an optionally accompanying therapy, the specific administration route, and similar factors.

[0057] As used herein the term “treatment” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) a disease or pathologic condition or disorder. Those in need of treatment include those who already have the disease or pathologic condition or disorder as well as those prone to have the disease or pathologic condition or disorder or those in whom the disease or pathologic condition disorder is to be prevented. Treatment may mean reducing one or more symptoms of the disease or pathologic condition or disorder.

[0058] As used herein, the term “pharmaceutically acceptable carrier” refers to a carrier medium generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, e.g., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, and dispensing agents, depending on the nature of the mode of administration and dosage forms. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., as well known to those of ordinary skill in the art.

[0059] As used herein, the term “pharmaceutically acceptable salt” refers to a salt or zwitterionic form of a compound, which is water or oil-soluble or dispersible and, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio and is effective for its intended use. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorsulfonate; hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmate, pectinate, persulfate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate. Examples of acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.

[0060] The cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.II. Compounds

[0061] In one embodiment, the present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula (l)-1 , Formula (l)-T,Formula (l)-1”, Formula (l)-2, or Formula (l)-3:Formula (I)-3 wherein:D is H, -CH2CH2OCH3, sulfonyl, substituted sulfonyl,Formula (Ic")R1-R5 are each independently hydrogen, halogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, ether, ester, -C(O)CH3, - C(O)OCH3, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero cycloalkyl, optionally C3-C6substituted hetero cycloalkyl, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, - C3-C6cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, R1 and R5are interconnected to form a substituted pyrazole ring, R1 and R5are interconnected to form an aryl ring, or absent;X1-X6 are each independently carbon or nitrogen;A, B, C, Z, and Y are each independently carbon, nitrogen, oxygen, sulfur, or absent;W is hydrogen, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl,optionally substituted heteroaryl, C3-C6 hetero cycloalkyl, optionally C3-C6 substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, alkyl amine, carboxylic acid, -CH2NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, 3-methyloxazol-2(3H)-one, substituted or unsubstituted oxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted oxetane, substituted or unsubstituted triazole, thiazole, sulfonyl, or substituted sulfonyl; n is 0, 1 , or 2;Re-R? are each independently hydrogen or methyl;Rs is H, alkyl or hydroxyl; or Rs and R23 are connected to form a 3 to 6 membered cycloalkyl ring;R9-R10 are each independently H, deuterium, alkyl, or components of a ring;R11-R13 are hydrogen, deuterium, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, hetero cycloalkyl, optionally C3-C6 substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, Rn and R12 are interconnected to form a cycloalkyl ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-Ce cycloalkyl, heterocycloalkyl, or absent; wherein C1-C6substituted alkyl may be optionally substituted with one or more of halogen, hydroxy, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, hetero cycloalkyl, optionally C3-Ce substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, R1 and R5 are interconnected to form a substituted pyrazole ring, R1 and R5 are interconnected to form an aryl ring, Rwand Rn are interconnected to form a substituted or unsubstituted C3-Ce cycloalkyl, heterocycloalkyl, or absent;R10 is hydrogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, heteroaryl, -C(O)NHCH3, - C(O)H, -C(O)NCH3CH3, -C(O)OH, cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl,substituted sulfonyl, R and Rn are interconnected to form a substituted pyrazole ring, R and R11 are interconnected to form a substituted or unsubstituted C3-C6 cycloalkyl, a substituted or unsubstituted C3-C6 cycloheteroalkyl, a substituted or unsubstituted heterocyclic aromatic, aryl ring, or heteroaryl, or absent; andR20-R28 are each independently hydrogen, alkyl, alkoxy, amine, amide, heterocycloalkyl, or alkyl amine; orR20, R22-R25, and R27-R28 are each independently hydrogen, alkyl, alkoxy, amine, amide, heterocycloalkyl, or alkyl amine R21 and R26 and are connected to form a 3 to 6 membered cycloalkyl ring. wherein halogen is F, Cl, Br, or I.

[0062] The “ * ” in the formula represents a stereogenic center.

[0063] The compound may be a tautomer, enantiomer, diastereomeric form, analog, or a pharmaceutically acceptable salt of a structure disclosed herein.

[0064] In certain embodiments, R1-R5 are each independently hydrogen, halogen, cyano, C1- Ca alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, Ci-Ce alkyl thiol, ether, ester, -C(O)CH3, -C(O)OCH3, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero cycloalkyl, optionally C3-C6 substituted hetero cycloalkyl, -C(O)NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, - C3-C6 cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, or substituted sulfonyl.

[0065] In certain embodiments, the compound is an S-enantiomer.

[0066] In certain embodiments, the compound comprises an S-enantiomer configuration at the carbon attached to -(CO)-E.

[0067] In certain embodiments, the present disclosure is directed to a compound or a pharmaceutically acceptable salt thereof, represented by Formula (l)-1 or a salt thereof:Formula (I)-l whereinR-10 Rg Formula (la)D is H, -OMe, -CH2CH2OCH3, sulfonyl, substituted sulfonyl, or;Formula (Ic') Formula (Ic")Formula (Id)orFormula (le) whereinR1-R5 are each independently hydrogen, halogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, ether, ester, -C(O)CH3, - C(O)OCH3, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C(O)NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, - C3-C6 cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, R1 and R5are interconnected to form a substituted pyrazole ring, R1 and R5are interconnected to form an aryl ring, or absent;X1-X6 are each independently carbon or nitrogen;A, B, C, Z, and Y are each independently carbon, nitrogen, oxygen, sulfur, or absent;W is hydrogen, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-C6 hetero cycloalkyl, optionally C3-C6 substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, alkyl amine, carboxylic acid, -CH2NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, 3-methyloxazol-2(3H)-one, substituted or unsubstituted oxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted oxetane, substituted or unsubstituted triazole, thiazole, sulfonyl, or substituted sulfonyl; n is 0, 1 , or 2;Re-R? are each independently hydrogen or methyl;R8is H, alkyl or hydroxyl;R9-R10 are each independently H, deuterium, alkyl, or components of a ring;R11-R13 are hydrogen, deuterium, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-C6 hetero cycloalkyl, optionally C3-C6 substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone,amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, Rn and R12 are interconnected to form a cycloalkyl ring, R10 and n are interconnected to form a substituted or unsubstituted C3-C6 cycloalkyl, heterocycloalkyl, or absent; wherein C1-C6substituted alkyl may be optionally substituted with one or more of halogen, hydroxy, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-C6 hetero cycloalkyl, optionally C3-C6 substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, - C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, R1 and R5 are interconnected to form a substituted pyrazole ring, R1 and R5 are interconnected to form an aryl ring, Rwand Rn are interconnected to form a substituted or unsubstituted C3-C6 cycloalkyl, heterocycloalkyl, or absent; R10 is hydrogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, heteroaryl, -C(O)NHCH3, - C(O)H, -C(O)NCH3CH3, -C(O)OH, cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, R10 and Rn are interconnected to form a substituted pyrazole ring, Rw and R11 are interconnected to form a substituted or unsubstituted C3-Ce cycloalkyl, a substituted or unsubstituted C3-Ce cycloheteroalkyl, a substituted or unsubstituted heterocyclic aromatic, aryl ring, or heteroaryl, or absent; andR20-R28 are each independently hydrogen, alkyl, alkoxy, amine, amide, heterocycloalkyl, or alkyl amine. wherein halogen is F, Cl, Br, or I.

[0068] In certain embodiments, the present disclosure is directed to a compound or a pharmaceutically acceptable salt thereof, represented by Formula (ll)-1, Formula (ll)-2, Formula (I l)-3, Formula (I l)-4, or a salt thereof:whereinR1-R5 are each independently hydrogen, halogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, ether, ester, -C(O)CH3, - C(O)OCH3, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C(O)NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, - C3-C6 cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, R1 and R5are interconnected to form a substituted pyrazole ring, R1 and R5are interconnected to form an aryl ring, or absent;Xi-Xe are each independently carbon or nitrogen;A, B, C, Z, and Y are each independently carbon, nitrogen, oxygen, sulfur, or absent;W is hydrogen, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-C6 heterocycloalkyl, optionally C3-C6 substituted heterocycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone,amine, amide, alkyl amine, carboxylic acid, -CH2NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, 3-methyloxazol-2(3H)-one, substituted or unsubstituted oxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted oxetane, substituted or unsubstituted triazole, thiazole, sulfonyl, or substituted sulfonyl; n is 0, 1 , or 2;R6-R9 are each independently hydrogen, methyl, or absent;R11-R13 are hydrogen, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, - C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, Rn and R12 are interconnected to form a cycloalkyl ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-C6 cycloalkyl, heterocycloalkyl, or absent; wherein C1-C6substituted alkyl may be optionally substituted with one or more of halogen, hydroxy, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, R1 and R5are interconnected to form a substituted pyrazole ring, R1 and R5are interconnected to form an aryl ring, or absent;R10 is hydrogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, heteroaryl, -C(O)NHCH3, - C(O)H, -C(O)NCH3CH3, -C(O)OH, cycloalkyl, nitro, pyrazole, sulfonyl, R10 and Rn are interconnected to form a substituted pyrazole ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-C6 cycloalkyl or aryl ring, or absent; and wherein halogen is F, Cl, Br, or I.

[0069] In certain embodiments, the compound is an S-enantiomer.

[0070] In certain embodiments, Xi and X2 are independently carbon or nitrogen.

[0071] In certain embodiments, R1 is hydrogen, methyl, trifluoromethyl, cyclopropyl, methoxy, or cyano.

[0072] In certain embodiments, A is sulfur.

[0073] In certain embodiments, B is nitrogen.

[0074] In certain embodiments, C is carbon.

[0075] In certain embodiments, Z is carbon or nitrogen.

[0076] In certain embodiments, R2-R10 are hydrogen.

[0077] In certain embodiments, Y is oxygen.

[0078] In certain embodiments, Rn is methyl, ethyl, or ethyl fluoride.

[0079] In certain embodiments, R12 and R13 are absent.

[0080] In certain embodiments, n equals 1.

[0081] In certain embodiments, Xi and X2are independently carbon or nitrogen; X3-X6 are carbon; R1 is hydrogen, methyl, trifluoromethyl, cyclopropyl, methoxy, or cyano; A is sulfur; B is nitrogen; C is carbon; Z is carbon or nitrogen; R2-RI0are hydrogen; Y is oxygen; Rn is methyl, ethyl, or ethyl fluoride; RI2and R13 are absent; and n=1.

[0082] In some embodiments, the compound has Formula (II)- 1.

[0083] In some embodiments, the compound has Formula (I l)-2.

[0084] In some embodiments, the compound has Formula (I l)-3.

[0085] In some embodiments, the compound has Formula (I l)-4.

[0086] In some embodiments, the compound is

[0087] In some embodiments, the compound is

[0088] In some embodiments, the compound is

[0089] In some embodiments, the compound is

[0090] In some embodiments, the compound is

[0091] In some embodiments, the compound is

[0092] In some embodiments, the compound is

[0093] In some embodiments, the compound is

[0095] In some embodiments, the compound is

[0096] In some embodiments, the compound is

[0097] In some embodiments, the compound is

[0098] In some embodiments, the compound is

[0099] In some embodiments, the compound is

[0100] In some embodiments, the compound is

[0101] In some embodiments, the compound is

[0102] In some embodiments, the compound is

[0103] In some embodiments, the compound is a compound in Table 1 .

[0104] Compounds in Table 1 have been shown by the inventors to exhibit biological activities. For compounds that were tested, Table 1 shows activity versus Plasmodium falciparum (Pf) 3D7 cells, cytotoxicity versus human Jurkat cells, and Table 3 shows activity at the p5 active site of the Pf20S proteasome and selectivity versus the human proteasome.Table 1. Compound structures and activity versus Plasmodium falciparum (Pf) 3D7 cells, andIII. Methods of Making the Compounds

[0105] The starting materials and reagents used in each step in the preparation are known and may be readily prepared or purchased from commercial sources.

[0106] The compound obtained in each step may also be used for the next reaction as a reaction mixture thereof or after obtaining a crude product thereof. Alternatively, the compound obtained in each step may be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography and the like according to a conventional method.

[0107] In each reaction step, while the reaction time varies depending on the reagents and solvents to be used, unless otherwise specified, it is generally 1 min. to 48 h., preferably 10 min. to 8 h. In the reaction of each step, while the reaction temperature varies depending on the reagents and solvents to be used, unless otherwise specified, it is generally -78°C to 300°C, preferably -78°C to 150°C. In the reaction of each step, unless otherwise specified, a reagent is used in 0.5 equivalent to 20 equivalents, preferably 0.8 equivalent to 5 equivalents, relative to the substrate. When a reagent is used as a catalyst, the reagent is used in 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. When the reagent is also a reaction solvent, the reagent is used in a solvent amount.

[0108] In the reaction of each step, unless otherwise specified, it is performed without solvent or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include the following. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol and the like; ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane and the like; aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like; saturated hydrocarbons: cyclohexane, hexane and the like; amides: N,N-dimethylformamide, N-methylpyrrolidone and the like; halogenated hydrocarbons: dichloromethane, carbon tetrachloride and the like; nitriles: acetonitrile and the like; sulfoxides: dimethyl sulfoxide and the like; aromatic organic bases: pyridine and the like; acid anhydrides: acetic anhydride and the like; organic acids: formic acid, acetic acid, trifluoroacetic acid and the like; inorganic acids: hydrochloric acid, sulfuric acid and the like; esters: ethyl acetate and the like; ketones: acetone, methyl ethyl ketone and the like; and water.

[0109] Two or more kinds of the above-mentioned solvents may be used by mixing at an appropriate ratio.

[0110] Unless otherwise specified, the reaction of each step is performed according to a known method, for example, the methods described in “Reactions and Syntheses: In the Organic Chemistry Laboratory 2ndEdition” (Lutz F. Tietze, Theophil Eicher, Ulf Diederichsen, AndreasSpeicher, Nina Schutzenmeister) Wiley, 2015; “Organic Syntheses Collective Volumes 1-12” (John Wiley & Sons Inc); “Comprehensive Organic Transformations, Third Edition” (Richard C. Larock) Wiley, 2018, herein incorporated by reference.

[0111] In each step, protection or deprotection of a functional group is performed by a known method, for example, the methods described in “Protective Groups in Organic Synthesis, 4thEd.” (Theodora W. Greene, Peter G.M. Wuts) Wiley-lnterscience, 2007; “Protecting Groups 3rdEd.” (P. J. Kocienski) Thieme, 2004, both of which are incorporated herein by reference.

[0112] The mass as determined by mass spectrometry of synthesized compounds is provided in Table 2.Table 2: Exact and observed mass of the synthesized compounds.IV. Pharmaceutical Composition

[0113] Provided herein is a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient. In some aspects, about 1 to 1000 mg of a compound or mixture of the one or more compounds may be compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, and so forth, in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in those compositions or preparations is such that a suitable dosage in the range indicated is obtained. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1-1000 mg, 2-800 mg, 5-500 mg, 10-400 mg, 50-200 mg, e.g., about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg of the active ingredient. The term “unit dosage from” refers to physically discrete units suitable as unitary (i.e., single) dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The concentration and / or amount of the compound in the composition will depend on absorption, inactivation, and excretion rates of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.

[0114] In some aspects, to prepare compositions, the one or more compound is mixed with a suitable pharmaceutically acceptable carrier. Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion, or the like. Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for lessening or ameliorating at least one symptom of the disease, disorder, or condition treated and may be empirically determined. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to be suitable for the particular mode of administration. In addition, the active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement thedesired action, or have another action. The compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. The concentration of the one or more compounds is effective for delivery of an amount upon administration that lessens or ameliorates at least one symptom of the disorder for which the compound is administered and / or that is effective in a prophylactic context.

[0115] In some aspects, the compounds described herein may be enclosed in multiple or single dose containers. The enclosed compounds and compositions can be provided in kits, for example, including component parts that can be assembled for use. For example, a compound in lyophilized form and a suitable diluent may be provided as separated components for combination prior to use. A kit may include a compound and a second therapeutic agent for co-administration. The compound and second therapeutic agent may be provided as separate component parts. A kit may include a plurality of containers, each container holding one or more unit dose of the one or more active agents. The containers are preferably adapted for the desired mode of administration, including, but not limited to tablets, gel capsules, sustained-release capsules, and the like for oral administration; depot products, pre-filled syringes, ampules, vials, and the like for parenteral administration; and patches, medipads, creams, and the like for topical or transdemnal administration.

[0116] The active ingredient may be administered at once or may be divided into a number of smaller doses to be administered at intervals of time. The precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. Concentrations and dosage values may also vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens can be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[0117] If oral administration is desired, the compound can be provided in a formulation that protects it from the acidic environment of the stomach. For example, the composition may be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient. Oral compositions generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules. For the purpose of oral therapeutic administration, the compound or compounds may be incorporated with excipientsand used in the form of tablets, capsules, or troches. Pharmaceutically compatible binding agents and adjuvant materials can be included as part of the composition.

[0118] In various aspects, the tablets, pills, capsules, troches, and the like may contain any of the following ingredients or equivalents thereof: a binder such as, but not limited to, gum tragacanth, acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose, starch, or lactose; a disintegrating agent such as, but not limited to, alginic acid and corn starch; a lubricant such as, but not limited to, magnesium stearate; a glidant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, or fruit flavoring.

[0119] When the dosage unit form is a capsule, it may contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials, which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds may also be administered as a component of an elixir, suspension, syrup, wafer, medicated chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors.

[0120] The compound may also be mixed with other active agents that do not impair the desired action, or with materials that supplement the desired action.

[0121] Solutions or suspensions used for parenteral, oral, intraadiposal, intraarterial, intraarticular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatical, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intravascular, intravitreal, liposomal, local, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, trans buccal, and transdermal route can include any of the following components: a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, and the like, or a synthetic fatty vehicle such as ethyl oleate, and the like, polyethylene glycol, glycerine, propylene glycol, or other synthetic solvent; antimicrobial agents such as benzyl alcohol and methyl parabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; and agents for the adjustment of tonicity such as sodium chloride and dextrose. Parenteral preparations may be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass, plastic, or other suitable material. Buffers, preservatives, antioxidants, and the like can be incorporated as required.

[0122] Suitable carriers for intravenous administration include physiological saline, phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, polypropyleneglycol, and mixtures thereof. Liposomal suspensions including tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known by those of ordinary skill in the art. Conventional formulations for inhalation typically contain carrier particles that serve to increase the fluidization of the active particles since the active particles are typically too small to be influenced by the airflow though the inhaler. These may be prepared according to methods known by those of ordinary skill in the art.

[0123] The one or more compounds or mixture of the one or more compounds may be prepared with one or more carriers that protect them against rapid elimination from the body, such as timerelease formulations or coatings. Controlled release is a mechanism of formulation to release a drug over an extended time. Use of controlled release formulation may reduce the frequency of administration, reduce fluctuations in blood concentration and protect the gastrointestinal tract from side effects. For example, the anesthetic effect of dyclonine on the mouth and sore throat, which underlies its traditional use in treating sore throats, can be reduce by use of a controlled release formulation. The active compounds may be prepared with carriers that protect the compound against rapid elimination from the body, such as time-release formulations or coating. Such carriers include controlled release formulations (also known as modified, delayed, extended or sustained release or gastric retention dosage forms, such as the Depomed GR™ system in which agents are encapsulated by polymers that swell in the stomach and are retained for about eight hours, sufficient for daily dosing of many drugs). Controlled release systems include microencapsulated delivery systems, implants and biodegradable, biocompatible polymers such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, matrix-controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be modified by varying the particle size of the active ingredient(s).V. Methods of Treatment

[0124] In some aspects, the current disclosure also encompasses a method of treating or preventing malaria in a subject, who may be in need thereof. The method may comprise administering one or more compounds or pharmaceutical compositions disclosed herein to the subject. Also provided are the one or more compounds or pharmaceutical compositions for usein treating or preventing malaria, and use of the one or more compounds or pharmaceutical compositions in the manufacture of a medicament for treating or preventing malaria. The one or more compounds may be listed in Table 1. In some aspects, a therapeutically effective amount of the one or more compounds is administered or contained in the pharmaceutical composition or medicament. The treatment may comprise reducing or ameliorating one or more symptoms of a malaria.

[0125] The malaria may be associated with a Plasmodium infection. The subject may be at a high risk of being infected by Plasmodium. The Plasmodium may be Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, or Plasmodium knowlesi.

[0126] In some aspects, the method includes co-administering an artemisinin with the compounds and pharmaceutical compositions disclosed herein. The artemisinin may be, but is not limited to, dihydroartemisinin (DHA), artemether, artesunate, dihydroartesunate, arteether, or artemisone. In one example, the artemisinin is dihydroartesunate. In another example, dihydroartesunate is administered in combination with SW394584-1 (SW584).

[0127] In some aspects, the method includes co-administering a proteasome 2 inhibitor with the compounds and pharmaceutical compositions disclosed herein. The proteasome p2 inhibitor may be but is not limited to bortezomib, MG-132, epoximicin, or WLW-vs. In one example, the proteosome 2 inhibitor is WLW-vs. In another example, WLW-sw is administered in combination with SW387996 (SW996).

[0128] In some aspects, a subject in need thereof is a mammal who is diagnosed with or suspected of having a malaria. In some aspects, a subject in need thereof is a mammal who is diagnosed with or suspected of having a malaria and the subject is co-administered the composition of the current invention and another antimalarial drug.

[0129] In some aspect, the subject in need thereof is a mammal. In some aspects, the subject is a human. In some aspects the subject is of an age of 0-12 months. In some aspects the subject is 1 or older, or 10 or older, or 20 or older, or 30 or older, or 40 or older, or 50 or older, or 55 or older, or 60 or older, or 65 or older, or 70 or older, or 75 or older, or 80 or older, or 90 or older, or 100 or older.

[0130] In some aspects, the one or more compounds described herein may be administered orally, parenterally (IV, IM, depo-IM, SQ, and depo-SQ), sublingually, intranasally (inhalation), intraspinally, intrathecally, topically, or rectally. Dosages of agents that are known for prior use to treat or prevent a disease condition other than malaria may provide a starting point for the purpose of ameliorating the symptoms of malaria. However, lower or higher dosages of some agents may be needed for treating the disease condition than existing indications.

[0131] In various aspects, the one or more compounds described herein compound or mixture of the one or more compounds may be administered enterally or parenterally. Oral formulations include tablets and capsules as well as liquid dosage forms such as solutions, suspensions, and elixirs. When the solid dosage forms are used, it is preferred that they be of the sustained release type so that the one or more active agents need to be administered only once or twice daily (or less frequency).

[0132] The oral dosage forms may be administered to the patient 1, 2, 3, or 4 times daily or less frequently, such as on alternate days, every third day, twice a week, once a week, or once a month. In some aspects, the one or more compounds may be administered either three or fewer times, or once or twice daily. Oral dosage forms are designed so as to protect the one or more active agents from the acidic environment of the stomach, such as by enteric coated or by use of capsules filled with small spheres each coated to protect from the acidic stomach.

[0133] When administered orally, an administered amount therapeutically effective to prevent, mitigate or treat malaria are from about 0.1 mg / day to about 1000 mg / day, for example, from about 1 mg / day to about 100 mg / day, for example, from about 5 mg / day to about 50 mg / day. In some aspects, the subject is administered the one or more active agents at a dose of about 0.05 to about 0.50 mg / kg or 0.1 mg / kg-10 mg / kg or 0.5 mg / kg to 5 mg / kg, for example, about 0.05 mg / kg, 0.10 mg / kg, 0.20 mg / kg, 0.33 mg / kg, 0.50 mg / kg, 1 mg / kg, 5 mg / kg or 10 mg / kg. Although a patient may be started at one dose, that dose may be varied (increased or decreased, as appropriate) overtime as the patient’s condition changes. Depending on outcome evaluations, higher doses may be used. For example, in certain aspects, up to as much as 1000 mg / day can be administered, e.g., 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day or 1000 mg / day.

[0134] In one aspect, the one or more compounds compound or mixture of the one or more compounds can be administered parenterally, for example, by IV, IM, depo-IM, SC, or depo-SC. When administered parenterally, a therapeutically effective amount of about 0.5 to about 1000 mg / day, preferably from about 5 to about 500 or 50-200 mg daily should be delivered. In various aspects, the parenteral dosage form is a depo formulation in which case a larger amount of drug can be administered with reduced frequency.

[0135] In various aspects, the one or more compounds compound or mixture of the one or more compounds may be administered sublingually. When given sublingually, the one or more compounds or mixture of the one or more compounds can be given one to four times daily in the amounts described above for IM administration.

[0136] In various aspects, the one or more the one or more compounds compound or mixture of the one or more compounds may be administered intranasally. Appropriate formulations include a nasal spray or dry powder. The dosage of the one or more active agents and / or analogs thereof for intranasal administration is the amount described above for IM administration.

[0137] In various aspects, the one or more compounds compound or mixture of the one or more compounds may be administered intrathecally in a parenteral formulation. The dosage of the one or more active agents and / or analogs thereof for intrathecal administration is the amount described above for IM administration.

[0138] In various aspects, the one or more compounds compound or mixture of the one or more compounds may be administered topically or transdermally. When given by this route, the appropriate dosage form is a cream, ointment, or patch. When administered topically, the dosage can be from about 0.5 mg / day to about 200 mg / day. Because the amount that can be delivered by a patch is limited, two or more patches may be used. The number and size of the patch is not important, what is important is that a therapeutically effective amount of the one or more active agents and / or analogs thereof be delivered. The one or more active agents and / or analogs thereof can be administered rectally by suppository. When administered by suppository, the therapeutically effective amount can be from about 0.5 mg to about 500 mg.

[0139] In some aspects, the one or more compound or mixture of the one or more compounds may be administered by implants. When administering one or more compounds by implant, the therapeutically effective amount is the amount described above for depot administration.

[0140] The exact dosage and frequency of administration depends on the particular condition being treated (e.g., whether ataxia or other neurodegenerative disease described below), the severity of the condition being treated, the age, weight, general physical condition of the particular patient, and other medication the individual may be taking.Examples

[0141] The following examples are included to demonstrate preferred aspects of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventor to function well in the practice of the present disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific aspects which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.Example 1 : Synthesis of common intermediates (lnt.-1 & lnt.-2)

[0142] Scheme:

[0143] Experimental procedure:

[0144] Step-1 :(4-Bromothiazol-2-yl)methanol (2):

[0145] To a stirred solution of 4-bromothiazole-2-carbaldehyde (5.00 g, 26.038 mmol) in MeOH (30.0 ml_) at 0°C was added NaBH4 (1.182 g, 31.245 mmol) in portions and the reaction mixture was stirred at same temperature for 2h (TLC). On completion, reaction mixture was quenched by ice-water (5 ml_) and concentrated under reduced pressure to remove excess methanol. Water was added to the crude residue and extracted with ethyl acetate (3x). Combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get (4-bromothiazol-2-yl)methanol as brown gum (5.03 g, 99%) which was used for the next step without further purification.

[0146] 1H NMR (400 MHz, DMSO-D6): 57.75 (s, 1H), 6.19 (t, J = 6.0 Hz, 1 H), 4.72 (d, J = 6.0 Hz, 2H) ppm.

[0147] LCMS [AA: ACN]: m / z: 194.0 [M+H]+(bromo pattern), tR = 1.99 min in 5 min run.

[0148] Step-2:2-(Azidomethyl)-4-bromothiazole (3):

[0149] To a stirred solution of (4-bromothiazol-2-yl)methanol (5.00 g, 25.767 mmol) in toluene (50 mL) at 0°C were added diphenylphosphoryl azide (6.7 ml_, 30.92 mmol) and DBU (4.707 g, 30.92 mmol) respectively and the mixture was stirred for 2h at the same temperature (TLC). On completion, the reaction mixture was diluted with ethyl acetate, washed with saturated NaHCOs (aq.) solution and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (10-20% ethyl acetate in hexane) to get 2-(azidomethyl)-4-bromothiazole (4.8 g, 85%) as white solid.

[0150] 1H NMR (400 MHz, DMSO-D6): 5 7.87 (s, 1 H), 4.87 (s, 2H) ppm; (No ionization in LCMS).

[0151] Step-3:(4-Bromothiazol-2-yl)methanamine (4):

[0152] To a stirred solution of 2-(azidomethyl)-4-bromothiazole (4.90 g, 22.368 mmol) in THF: water (55 ml_, 10:1) was added triphenylphosphene (14.651 g, 55.921 mmol) and the mixture was refluxed for 3h (TLC). On completion, reaction mixture was concentrated to remove volatiles and the residue was diluted with water and extracted with ethyl acetate (3x). Combined organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (50-70% EtOAc in Hexane) to get (4-bromothiazol-2-yl)methanamine along with triphenylphosphine oxide in 7:3 ratio which was used for the next step without further purification considering quantitative conversion.

[0153] LCMS [AA: ACN]: m / z: 192.80 [M+H]+(bromo pattern), tR = 1.57 min in 5 min run.

[0154] Step-4:Tert-butyl ((4-bromothiazol-2-yl)methyl)carbamate (5):

[0155] A mixture of (4-bromothiazol-2-yl)methanamine (4.318 g, 22.367 mmol, 1.0 eq.) from previous step was dissolved in DCM (50 mL) and then triethylamine (4.67 mL, 33.549 mmol, 1.5 eq.) and boc-anhydride (6.16 mL, 26.840 mmol, 1.2 eq.) were added sequentially at 0°C. Reaction mixture was stirred at the same temperature for 3h (TLC). On completion, reactionmixture was diluted with DCM, washed with water (2x). Organic phase was dried (Na2SO4) and concentrated under reduced pressure to get a crude residue which was purified by flash column chromatography (10-20% ethyl acetate in hexane) to afford tert-butyl ((4-bromothiazol-2- yl)methyl)carbamate (4.8 g, 73% in two steps) as off-white solid.

[0156] 1H NMR (400 MHz, DMSO-D6): 57.80 (brs, 1 H), 7.72 (s, 1 H), 4.37 (d, J = 6.0 Hz, 1 H), 1.40 (s, 9H) ppm.

[0157] LCMS [AA: ACN]: m / z: 293.0 [M+H]+(bromo pattern), tR = 3.18 min in 5 min run.

[0158] Step-5:(4-Bromothiazol-2-yl)methanamine (Intermediate-1):

[0159] To a stirred solution of tert-butyl ((4-bromothiazol-2-yl)methyl)carbamate (4.5 g, 15.358 mmol) in DCM (30 mL) was added neat TFA (23.5 mL, 307.16 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for another 2 h (TLC). On completion, reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether and n-pentane (3:7) to afford (4-bromothiazol-2-yl)methanamine as TFA salt.

[0160] 1H NMR (400 MHz, DMSO-D6): 68.53 (brs, 3H), 7.94 (s, 1 H), 4.47 (s, 2H) ppm.

[0161] HPLC purity: 99.81%.

[0162] LCMS [TFA (aq.): ACN]: m / z: 192.89 [M+H]+(bromo pattern), tR = 3.01 min in 9 min run.

[0163] Step-6:

[0164] tert-butyl (S)-3-(((4-bromothiazol-2-yl)methyl)carbamoyl)piperidine-1 -carboxylate (Intermediate-2):

[0165] A solution of (4-bromothiazol-2-yl)methanamine (3.241 g, 10.55 mmol, 1.1 eq.TFA-salt) in DMF (7 mL) was neutralized by slow addition of DIPEA (1.83 mL, 10.55 mmol, 1.0 eq.) at 0°C. In a separated round bottom flask (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (2.2 g, 9.595 mmol, 1 eq.) was taken in DMF (8 mL). To this solution were added DIPEA (1.83 mL,10.55 mmol, 1.0 eq.) and HATU (4.381 g, 11.528 mmol, 1.2 eq.) under stirring and the mixture was cooled to 0°C. To this mixture was slowly added initially prepared solution of (4-bromothiazol- 2-yl)methanamine in DMF maintaining same temperature and stirred for another 1 h (TLC / LCMS). On completion, reaction mixture was diluted with ethyl acetate, washed with cold water (3x) and brine. Organic phase was separated, dried over Na2SO4 and concentrated under reduced pressure. Crude residue was purified by flash column chromatography (40%-50% EtOAc in hexane) to get tert-butyl (S)-3-(((4-bromothiazol-2-yl)methyl)carbamoyl)piperidine-1- carboxylate (2.02 g, 51%) as white solid.

[0166] 1H NMR (400 MHz, DMSO-D6, 100°C): 58.54 (brs, 1 H), 7.64 (s, 1 H), 4.54 (d, J = 5.6 Hz, 2H), 3.97 (d, J = 13.2 Hz, 1 H), 3.84 (d, J = 13.2 Hz, 1 H), 2.87 (t, J = 12.0 Hz, 1 H), 2.76 (t, J = 12.0 Hz, 1 H), 2.37-2.31 (m, 1H), 1.91-1.87 (m, 1 H), 1.69-1.55 (m, 2H), 1.42 (s, 9H), 1.40-1.37 (m, 1H) ppm.

[0167] HPLC purity: 99.71%.

[0168] LCMS (AA: ACN): m / z: 402.07 [M-H]+(bromo pattern), tR = 2.59 min in 5 min run.Example 2: Synthesis of SW394658-1

[0169] Scheme:

[0170] Step-1 :

[0171] (S)-N-((4-bromothiazol-2-yl)methyl)piperidine-3-carboxamide (2): To a stirred solution of tert-butyl (S)-3-(((4-bromothiazol-2-yl)methyl)carbamoyl)piperidine-1 -carboxylate (0.700 g, 1.731 mmol) in DCM (20 mL) was added trifluoroacetic acid (2.65 mL, 34.62 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for another 2 h (TLC). Oncompletion, reaction mixture was concentrated under reduced pressure and co-evaporated with DCM (2x) to get and (S)-N-((4-bromothiazol-2-yl)methyl)piperidine-3-carboxamide as TFA-salt which was used for the next step without further purification considering quantitative conversion.

[0172] LCMS [AA: ACN]: m / z: 304.0 [M+H]+(bromo pattern), tR = 1.71 min in 5 min run.

[0173] Step-

[0174] (S)-N-((4-bromothiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3-carboxamide (3): To a solution of (S)-N-((4-bromothiazol-2-yl)methyl)piperidine-3-carboxamide trifluoroacetic acid salt (0.200 g, 0.478 mmol, 1.0 eq.) in DCM (10 mL) was added DIPEA (0.416 mL, 2.391 mmol) at 0°C. To this mixture was added 2-methoxyacetyl chloride (0.131 mL, 1.435 mmol) dropwise at 0°C. Reaction mixture was warmed slowly to room temperature and stirred for another 4 h (TLC). On completion, reaction mixture was diluted with DCM (10 mL), washed with water (2 x 15 mL). Organic phase was dried (Na2SO4) and concentrated under reduced pressure to get a crude residue which was purified by flash column chromatography (30-40% Ethyl acetate in hexane) to afford (S)-N-((4-bromothiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3- carboxamide (0.105 g, 58%) as white solid.

[0175] 1H NMR (400 MHz, DMSO-D6, 100°C): <58.52 (brs, 1 H), 7.64 (s, 1H), 4.56-4.54 (m, 2H), 4.21-3.96 (m, 1 H), 4.07 (s, 2H), 3.95-3.79 (m, 1 H), 3.31 (s, 3H), 3.03-2.83 (m, 2H, overlapped with DMSO water residual peak), 2.47-2.35 (m, 1H), 1.94-1.90 (m, 1 H), 1.75-1.63 (m, 2H), 1.48- 1.33 (m, 1 H) ppm.

[0176] LCMS [AA: ACN]: m / z: 376.0 [M+H]+(bromo pattern), tR = 2.48 min in 5 min run.

[0177] Step-3:

[0178] (S)-1-(2-Methoxyacetyl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide [SW394658-1]: To a solution of (S)-N-((4-bromothiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3-carboxamide (0.300 g, 0.797 mmol) and 2-methyl-5-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.210 g, 0.957 mmol) in Toluene: EtOH: H2O (2:1 :2; 10.0 mL), was added Na2CO3(0.169 g, 1.595 mmol, 2.0 eq.). The reaction mixture was degassed (N2) for 10 min before the addition of Pd(PPh3)4 (0.092 g, 0.08 mmol, 0.1 eq.) and then heated at 90°C for overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (50-100% ethyl acetate in hexane) to afford (S)-1-(2-methoxyacetyl)-N-((4-(6- methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.105 g, 34%) as white solid.

[0179] 1H NMR (400 MHz, DMSO-D6, 100°C): 58.99 (d, J = 2.0 Hz, 1 H), 8.53 (brs, 1 H), 8.14 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.97 (s, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 4.64-4.61 (m, 2H), 4.15-4.05 (m, 1 H), 4.07 (s, 2H), 3.95-3.85 (m, 1 H), 3.31 (s, 3H), 2.97-2.86 (m, 2H), 2.50 (s, 3H, methyl peak overlapped with DMSO residual peak as observed in D2O exchange NMR or NMR in CD3OD), 2.44-2.38 (m, 1 H), 1.96-1.93 (m, 1 H), 1.75-1.64 (m, 2H), 1.44-1.36 (m, 1H) ppm.

[0180] HPLC purity: 92.81%.

[0181] LCMS (FA: ACN): m / z: 389.33 [M+H]+tR = 1.66 min in 5 min run.Example 3: Synthesis of SW394661-1

[0182] Scheme:

[0183] Synthesis of intermediate 4 has been prepared following literature method as described in WO2018113865A1 , which is incorporated herein by reference.

[0184] Step-1 :

[0185] 5-Bromo-2-(prop-1-en-2-yl)pyridine (2): To a solution of 2,5-dibromopyridine (1.0 g, 4.221 mmol, 1.0 eq.) in Dioxane: H2O (5:1 ; 12 mL), were added potassium trifluoro(prop-1-en-2- yl)borate (0.625 g, 4.221 mmol, 1.0 eq.) and K2CO3 (1.166 g, 8.442 mmol, 2.0 eq.). The reaction mixture was degassed (N2) for 10 min before the addition of PdCI2(dppf).DCM (0.172 g, 0.2111 mmol, 5 mol%) and then heated at 90°C for overnight (LCMS). The reaction mixture was then cooled to room temperature, diluted with water (15 mL) and extracted with EtOAc (3x). Combined organic phase was dried (Na2SC>4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (1-4% EtOAc in hexane) to afford 5- bromo-2-(prop-1-en-2-yl)pyridine (0.502 g, 61%) as colorless gum which is sufficiently pure and used for next step.

[0186] LCMS (FA: ACN): m / z: 198.2 [M+H]+(bromo pattern); tR = 2.13 min in 3 min run.

[0187] Step-2:

[0188] 2-(Prop-1-en-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3): To a stirred solution of 5-bromo-2-(prop-1-en-2-yl)pyridine (0.500 g, 2.524 mmol) in Dioxane (10 mL), were added bis(pinacolato)diboron (0.961 g, 3.787 mmol), KOAc (0.545 g, 5.554 mmol). The reaction mixture was degassed (N2) for 10 min and then PdCI2(dppf).DCM (0.144 g, 0.177 mmol) and dppf (0.140 g, 0.152 mmol) were added. The mixture was subjected to a preheated oil bath at 90°C for 16 h (LCMS). On completion, the mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure to afford crude 2-(prop-1-en-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (619 mg, -30% LCMS pure, effective yield 30%) which was used for the next step without further purification.

[0189] LCMS (AA: ACN): m / z: 246.2 [M+H]+; tR = 3.81 min in 6 min run.

[0190] Step-3:

[0191] 2-lsopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4): To a stirred solution of 2-(prop-1-en-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (crude, 0.619 g, 30% pure; effectively 0.186 g, 0.758 mmol) in MeOH (8 ml_), was added Pd / C (10% w / w, 0.081 g, 0.758 mmol, 1.0 eq.) and the mixture was stirred under Fh-ballon pressure for 2 h (LCMS). Reaction mixture was then filtered through celite, filtrate was concentrated under reduced pressure to afford crude 2-isopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine which was used for the next step without purification (-10% LCMS pure).

[0192] LCMS (AA: ACN): m / z: 248.31 [M+H]+; tR = 1.95 min in 3 min run.

[0193] Step-4:

[0194] (S)-N-((4-(6-isopropylpyridin-3-yl)thiazol-2-yl)methyl)-1-(2- methoxyacetyl)piperidine-3-carboxamide [SW394661-1]: To a solution of (S)-N-((4- bromothiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3-carboxamide (0.170 g, 0.452 mmol, 1.0 eq.) and 2-isopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (0.223 g, 0.904 mmol, 2.0 eq.) in Toluene: EtOH: H2O (2:1 :2; 10.0 mL), was added Na2COs (0.096 g, 0.904 mmol, 2.0 eq.). The reaction mixture was degassed (N2) for 10 min before the addition of Pd(PPh3)4 (0.052 g, 0.0452 mmol, 0.1 eq.) and then heated at 90°C for overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). Combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase Prep HPLC [YMC Actus Triart, ACNI 20 mM NH4HCO3 aq. Buffer] to afford (S)-N-((4-(6-isopropylpyridin-3-yl)thiazol-2-yl)methyl)-1- (2-methoxyacetyl)piperidine-3-carboxamide (0.017 g, 7%) as off-white solid.

[0195] 1H NMR (400 MHz, DMSO-D6, 100°C): 5 9.02 (s, 1 H), 8.55 (brs, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 7.97 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.65-4.60 (m, 2H), 4.08 (s, 2H), 3.99-3.86 (m, 1 H), 3.31 (s, 3H), 3.15-2.85 (m, 3H, overlapped with DMSO water peak), 2.49-2.36 (m, 2H), 1.98-1.91 (m, 1 H), 1.75-1.67 (m, 2H), 1.48-1.34 (m, 2H), 1.28 (d, J = 6.8 Hz, 6H) ppm.

[0196] HPLC purity: 99.77%.

[0197] LCMS (FA: ACN): m / z: 417.38 [M+H]+, tR = 1.98 min in 5 min run.Example 4: Synthesis of SW394591-1

[0198] Scheme:

[0199] Step-1 :(S)-N-((4-(6-cyclopropylpyridin-3-yl)thiazol-2-yl)methyl)-1 -(2- methoxyacetyl)piperidine-3-carboxamide [SW394591-1]: To a solution of (S)-N-((4- bromothiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3-carboxamide (0.300 g, 0.797 mmol) and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (0.235 g, 0.957 mmol, 1.0 eq.) in Toluene: EtOH: H2O (2:1 :2; 10.0 mL), was added Na2CC>3 (0.169 g, 1.595 mmol, 2.0 eq.). The reaction mixture was degassed (N2) for 10 min before the addition of Pd(PPh3)4 (0.092 g, 0.08 mmol, 0.1 eq.) and then heated at 90°C for overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (50-100% ethyl acetate in hexane) to afford (S)-N-((4-(6-cyclopropylpyridin-3-yl)thiazol-2-yl)methyl)-1-(2- methoxyacetyl)piperidine-3-carboxamide (0.137 g, 41%) as off-white solid.

[0200] 1H NMR (400 MHz, DMSOd6, 100°C): 68.94 (s, 1 H), 8.53 (brs, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.93 (s, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 4.64-4.61 (m, 2H), 4.08 (s, 2H), 3.99-3.80 (m, 2H), 3.31 (s, 3H), 2.97-2.85 (m, 2H), 2.45-2.36 (m, 1 H), 2.15-2.12 (m, 1 H), 1.96-1.93 (m, 1 H), 1.75- 1.68 (m, 2H), 1.43-1.36 (m, 1H), 0.98-0.96 (m, 4H); LCMS (ESI) m / z: 415.23 [M+H]+.

[0201] HPLC purity: 99.06%.

[0202] LCMS (AA: ACN): tR = 2.15 min in 5 min run.Example 5: Synthesis of SW394665-1

[0203] Scheme:

[0204] Step-1 :

[0205] (S)-N-((4-(6-fluoropyridin-3-yl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine- 3-carboxamide (3): To a stirred solution of (S)-N-((4-bromothiazol-2-yl)methyl)-1-(2- methoxyacetyl)piperidine-3-carboxamide (0.300 g, 0.797 mmol, 1.0 eq.) in Toluene: EtOH: H2O (3:1:3; 10 mL), were added (6-fluoropyridin-3-yl)boronic acid (0.135 g, 0.957 mmol, 1.2 eq.), Na2CC>3 (0.169 g, 1.594 mmol, 2.0 eq.). The reaction mixture was degassed (N2) for 10 min before the addition of Pd(PPhs)4 (0.092 g, 0.0797 mmol, 0.1 eq.) and then heated at 90°C for overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (1-3% MeOH in DCM) to afford (S)-N-((4-(6-fluoropyridin-3-yl)thiazol-2-yl)methyl)-1-(2- methoxyacetyl)piperidine-3-carboxamide (0.110 g, 35%) as off-white solid.

[0206] LCMS [AA: ACN]: m / z: 393.2 [M+H]+, tR = 2.89 min in 6 min run.

[0207] Step-2:

[0208] (S)-N-((4-(6-(cyclopropylamino)pyridin-3-yl)thiazol-2-yl)methyl)-1-(2- methoxyacetyl)piperidine-3-carboxamide [SW394665-1]: In a MW vessel, (S)-N-((4-(6- fluoropyridin-3-yl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3-carboxamide (0.050 g, 0.127 mmol, 1.0 eq.) was taken in DMSO (1.3 mL). To this solution were added triethylamine(0.138 mL, 1.016 mmol, 8.0 eq.) and cyclopropylamine (0.036 mL, 0.637 mmol, 5.0 eq.) sequentially and the mixture was subjected under MW irradiation [SEM, Discover] at 120°C for 2 h (TLC / LCMS). On completion, the mixture was cooled to room temperature, filtered and the product was directly purified by reverse phase preparative HPLC [YMC Actus Triart C-18, ACN, 20 mM NH4HCO3 aqueous buffer] to afford (S)-N-((4-(6-(cyclopropylamino)pyridin-3-yl)thiazol-2- yl)methyl)-1-(2-methoxyacetyl)piperidine-3-carboxamide (0.015 g, 27%) as off-white sticky solid.

[0209] 1H NMR (400 MHz, DMSO-D6, 100°C): 68.58 (s, 1H), 8.51 (brs, 1 H), 7.94 (d, J = 8.8 Hz, 1 H), 7.62 (s, 1 H), 6.67 (d, J = 8.8 Hz, 1 H), 6.54 (s, 1 H), 4.65-4.56 (m, 2H), 4.08 (s, 2H), 4.18-4.04 (m, 1 H, overlapped), 4.00-3.87 (m, 1 H), 3.31 (s, 3H), 3.00-2.83 (m, 2H), overlapped with DMSO water pak, 2.62-2.57 (m, 1 H), 2.47-2.36 (m, 1 H), 1.97-1.91 (m, 1 H), 1.75-1.65 (m, 2H), 1.48-1.38 (m, 1 H), 0.76-0.70 (m, 2H), 0.51-0.47 (m, 2H) ppm.

[0210] HPLC purity: 99.75%.

[0211] LCMS (FA: ACN): m / z 430.36 [M+H]+; tR = 1 .89 min in 5 min run.Example 6: Synthesis of SW394659-1

[0212] Scheme:

[0213] (S)-N-((4-(6-(cyclobutylamino)pyridin-3-yl)thiazol-2-yl)methyl)-1-(2- methoxyacetyl)piperidine-3-carboxamide [SW394659-1]: In a MW vessel, (S)-N-((4-(6- fluoropyridin-3-yl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3-carboxamide (0.100 g, 0.255 mmol, 1.0 eq.) was taken in DMSO (2.0 mL). To this solution were added triethylamine (0.277 mL, 2.038 mmol, 8.0 eq.) and cyclobutylamine (0.091 mg, 1.274 mmol, 5.0 eq.)sequentially and the mixture was subjected under MW irradiation [SEM, Discover] at 120°C for 1 .5 h (TLC I LCMS). On completion, the mixture was cooled to room temperature, filtered and the product was purified directly by reverse phase preparative HPLC [YMC Actus Triart C-18, ACN, 20 mM NH4HCO3 aqueous buffer] to afford (S)-N-((4-(6-(cyclobutylamino)pyridin-3-yl)thiazol-2- yl)methyl)-1-(2-methoxyacetyl)piperidine-3-carboxamide (0.055 g, 48%) as brown solid.

[0214] 1H NMR (400 MHz, DMSO-D6, 100°C): 68.53 (s, 1 H), 8.47 (brs, 1 H), 7.87-7.84 (m, 1 H), 7.58 (s, 1H) 6.53 (d, J = 6.8 Hz, 1 H), 6.46 (d, J = 8.8 Hz, 1 H), 4.61-4.57 (m, 2H), 4.33-4.27 (m, 1 H), 4.07 (s, 2H), 4.17-4.00 (m, 1 H), overlapped, 3.98-3.85 (m, 1 H), 3.31 (s, 3H), 2.95-2.85 (m, 1 H), 2.42-2.30 (m, 4H), 1.97-1.88 (m, 3H), 1.77-1.65 (m, 4H), 1.45-1.38 (m, 1 H).

[0215] HPLC purity: 99.51%.

[0216] LCMS (FA: ACN): m / z 444.40 [M+H]+, tR = 1 .97 min in 5 min run.Example 7: Synthesis of SW394660-1

[0217] Scheme:

[0218] (S)-N-((4-(6-(cyclopentylamino)pyridin-3-yl)thiazol-2-yl)methyl)-1-(2- methoxyacetyl)piperidine-3-carboxamide [SW394660-1]: In a MW vessel, (S)-N-((4-(6- fluoropyridin-3-yl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3-carboxamide (0.125 g, 0.319 mmol, 1.0 eq.) was taken in DMSO (2.0 mL). To this solution were added triethylamine (0.348 mL, 2.548 mmol, 8.0 eq.) and cyclopentylamine (0.136 g, 1.593 mmol, 5.0 eq.) sequentially and the mixture was subjected under MW irradiation [SEM, Discover] at 120°C for 1 .5 h (TLC). On completion, the mixture was cooled to room temperature, filtered and the product was purified directly by reverse phase preparative HPLC [YMC Actus Triart C-18, ACN, 20 mM NH4HCO3 aqueous buffer] to afford (S)-N-((4-(6-(cyclopentylamino)pyridin-3-yl)thiazol-2- yl)methyl)-1-(2-methoxyacetyl)piperidine-3-carboxamide (0.057 g, 39%) as off-white sticky solid.

[0219] 1H NMR (400 MHz, DMSO-D6, 100°C ): <5 8.54-8.49 (m, 2H), 7.84 (dd, J = 8.4 Hz, 2.0 Hz, 1 H), 7.57 (s, 1 H), 6.51 (d, J = 8.4 Hz, 1 H), 6.27 (s, 1 H), 4.62-4.54 (m, 2H), 4.20-4.11 (m, 1 H), 4.07 (s, 2H), 4.10-3.98 (m, 1 H), overlapped, 3.97-3.83 (m, 1 H), 3.31 (s, 3H), 2.97-2.85 (m, 2H), 2.45-2.35 (m, 1 H), 2.00-1.90 (m, 3H), 1.76-1.65 (m, 4H), 1.63-1.52 (m, 2H), 1.51-1.37 (m, 3H) ppm.

[0220] HPLC purity: 99.85%.

[0221] LCMS (FA: ACN): m / z 458.43 [M+H]+, tR = 2.04 min in 5 min run.Example 8: Synthesis of SW394663-1

[0222] Scheme:

[0224] tert-butyl (S)-3-(((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)carbamoyl)piperidine -1 -carboxylate (2): A mixture of tert-butyl (S)-3-(((4-bromothiazol-2- yl)methyl)carbamoyl)piperidine-1-carboxylate (2.0 g, 4.947 mmol, 1.0 eq.) and 2-methyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (1.3 g, 5.936 mmol, 1.2 eq.) in Toluene: EtOH: H2O (3:1 :3; 30.0 mL), was added Na2COs (1.049 g, 9.893 mmol, 2.0 eq.). The reaction mixture was degassed (N2) for 10 min before the addition of Pd(PPh3)4 (0.857 g, 0.742 mmol, 15 mol%) and then heated at 90°C for overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (50-70% EtOAc in hexane) to afford tert-butyl (S)-3-(((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)carbamoyl)piperidine-1 -carboxylate (1.75 g, 85%) as off- white solid.

[0225] 1H NMR (400 MHz, DMSO-D6): 69.00 (s, 1H), 8.90 (t, J = 5.2 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 8.10 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.59 (d, J = 5.2 Hz, 2H), 4.10-3.96 (m, 1 H), 3.87 (d, J = 12.8 Hz, 1H), 2.77-2.63 (m, 2H), 2.50 (s, 3H, N-methyl peak overlapped with residual DMSO peak), 2.38-2.32 (m, 1 H), 1.93-1.85 (m, 1 H), 1.69-1.53 (m, 2H), 1.40 (s, 9H), 1.38-1.29 (m, 1 H) ppm.

[0226] LCMS (AA: ACN): m / z: 417.2 [M+H]+(Boc pattern), tR = 3.14 min in 5 min run.

[0227] Step-2:

[0228] (S)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (3):To a stirred solution of tert-butyl (S)-3-(((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)carbamoyl)piperidine-1-carboxylate (0.500 g, 1.20 mmol, 1.0 eq.) in DCM (20.0 mL) at 0°C was added neat TFA (2.756 mL, 36.011 mmol, 30.0 eq.) dropwise and the reaction mixture was stirred for another 2 h at the same temperature (TLC). On completion, the mixture was concentrated under reduced pressure and co-evaporated two times with DCM to afford (S)-N-((4- (6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.020 g, 5%) as TFA-salt. The salt was neutralized using triethylamine in DCM solvent at 0°C and used for next step without further purification considering quantitative conversion.

[0229] LCMS (AA: ACN): m / z: 317.2 [M+H]+, tR = 1 .92 min in 5 min run.

[0230] Step-3:

[0231] (S)-1-cyano-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3- carboxamide (4): To a stirred solution of (S)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide (0.375 g, 1.186 mmol, 1.0 eq.) in DCM (5 mL), was added a solution of NaHCOs (0.498 g, 5.93 mmol, 5.0 eq.) in water (5 mL) at 0°C. To this mixture was added a solution of cyanogen bromide (0.151 g, 1.423 mmol, 1.2 eq.) in DCM (2 mL) dropwise at the same temperature and the mixture was allowed to warm to room temperature and stirred for1 h (TLC). On completion, water was added to the mixture and extracted with DCM (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (1-4% MeOH in DCM) to afford (S)-1- cyano-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.310 g, 76%).

[0232] 1H NMR (400 MHz, DMSO-D6): 69.00 (s, 1 H), 8.94 (t, J = 6.0 Hz, 1 H), 8.16 (dd, J = 8.0 Hz, 1.6 Hz, 1 H), 8.10 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.67-4.55 (m, 2H), 3.47-3.30 (m, 2H, overlapped with DMSO water peak), 3.14-3.08 (m, 1 H), 3.06-2.97 (m, 1 H), 2.62-2.55 (m, 1 H), 2.50 (s, 3H, N-methyl proton overlapped with DMSO residual peak), 1.93-1.87 (m, 1 H), 1.74-1.65 (m, 1 H), 1.61-1.53 (m, 2H) ppm.

[0233] LCMS (AA: ACN): m / z: 342.2 [M+H]+(Boc pattern), tR = 2.68 min in 5 min run.

[0234] Step-4:

[0235] (S)-1-(N-hydroxycarbamimidoyl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide (5): A solution of (S)-1-cyano-N-((4-(6-methylpyridin-3- yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.200 g, 0.586 mmol, 1.0 eq.) and hydroxylamine hydrochloride (0.082 g, 1.172 mmol, 1.0 eq., in 1 mL water) in ethanol (5.0 ml_) was taken in a sealed tube and heated at 60°C for overnight (LCMS). On completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to get crude (S)-1-(N-hydroxycarbamimidoyl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3- carboxamide as yellowish semi-solid which was used for the next step without further purification considering quantitative conversion.

[0236] LCMS (AA: ACN): m / z: 375.2 [M+H]+, tR = 2.06 min in 5 min run.

[0237] Step-5:

[0238] (S)-1-(5-methyl-1,2,4-oxadiazol-3-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394663-1]: To a stirred solution of (S)-1-(N- hydroxycarbamimidoyl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide(0.200 g, 0.534 mmol) in Dioxane (6 mL) was added acetic anhydride (0.5 mL, 5.34 mmol,10.0 eq.) and the reaction mixture was refluxed for overnight (LCMS). On completion, reaction mass was cooled to room temperature, concentrated under reduced pressure. The crude residue was purified by reverse phase Prep HPLC [YMC actus triart C18, (250 x 20mm, 5 pm), ACN / 20 mM NH4HCO3 aq. Buffer] to afford (S)-1-(5-methyl-1 ,2,4-oxadiazol-3-yl)-N-((4-(6-methylpyridin-3- yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.010 g, 5%) as white solid.

[0239] 1H NMR (400 MHz, DMSO-D6, 100°C): 6 8.99 (s, 1 H), 8.54 (brs, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 7.96 (s, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 4.63 (s, 2H), 3.93 (d, J = 12.8 Hz, 2H), 3.79 (d, J = 12.8 Hz, 1 H), 3.10-3.03 (m, 1 H), 2.95-2.89 (m, 1 H), overlapped with DMSO water peak, 2.43 (s, 3H), 2.04-1.95 (m, 1 H), 1.78-1.63 (m, 2H), 1.58-1.51 (m, 1 H), 3H of 2-methyl pyridine unit and 1 H corresponds to asymmetric carbon overlapped with DMSO residual peak, observed in CDCh NMR).

[0240] HPLC purity: 95.48%.

[0241] LCMS (AA: ACN): m / z: 399.34 [M+H]+, tR = 1.98 min in 5 min run.Example 9: Synthesis of SW394685-1

[0242] Scheme:

[0243] Step-1 : (S)-1-(3-methyl-1 ,2,4-oxadiazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394685-1]: To a stirred solution of (S)-1 -cyano- N-((4-(6- methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.166 g, 0.486 mmol, 1.0 eq.) in THE (8 mL) were added N-hydroxyacetamide (0.048 g, 0.632 mmol, 4.0 eq.) and ZnCh (0.132 g, 0.972 mmol, 2.0 eq.) under Ar and the mixture was heated at 70°C for 3 h (LCMS). On completion, reaction mass was cooled to room temperature, water was added and extracted with 20% MeOH in DCM (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by reverse phase Prep HPLC [YMC actus triart C18, (250 x 20mm, 5 pm), ACN / 20 mM NH4HCO3 aq. Buffer] to afford (S)-1-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.066 g, 34%) as white solid.

[0244] 1H NMR (400 MHz, DMSO-D6): 59.01 (d, J = 2.0 Hz, 1 H), 8.95 (t, J = 5.6 Hz, 1 H), 8.16 (dd, J = 8.0 Hz, 2.2 Hz, 1 H), 8.10 (s, 1H), 7.32 (d, J = 8.0 Hz, 1 H), 4.61 (d, J = 5.6 Hz, 2H), 4.01- 3.96 (m, 1 H), 3.86 (d, J = 13.6 Hz, 1 H), 3.29-3.21 (m, 1 H), 3.16-3.05 (m, 1H), 2.56-2.53 (m, 1 H),2.50 (s, 3H, methyl proton overlapped with DMSO residual peak, observed in CD3OD NMR), 2.10 (s, 3H), 1.97-1.91 (m, 1 H), 1.82-1.60 (m, 2H), 1.53-1.42 (m, 1 H).

[0245] HPLC purity: 98.33%.

[0246] LCMS (FA: ACN): m / z: 399.36 [M+H]+; tR = 1.89 min in 5 min run.Example 10: Synthesis of SW394730-1

[0247] Scheme:

[0248] Step-1 : (S)-1-(5-methyl-1 ,3,4-oxadiazol-2-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394730-1]: To a solution of (S)-N-((4-(6-methylpyridin-3- yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.200 g, 0.632 mmol) in MeOH (5 ml_) in a sealed tube were added 2-bromo-5-methyl-1 ,3,4-oxadiazole (0.205 g, 1.264 mmol, 2.0 eq.) and EtsN (0.35 ml_, 2.528 mmol, 4.0 eq.). The vessel was closed, and reaction mixture was heated with stirring at 130°C for overnight (LCMS). On completion, reaction mass was cooled to room temperature, water was added and extracted with 20% MeOH in DOM (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by flash column chromatography (3-7% MeOH in DCM) to afford (S)-1-(5-methyl-1 ,3,4- oxadiazol-2-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.080 g, 32%) as white solid.

[0249] 1H NMR (400 MHz, DMSO-D6): 69.01 (s, 1 H), 8.93 (t, J = 6.0 Hz, 1 H), 8.16 (dd, J = 8.0 Hz, 2.0 Hz, 1 H), 8.10 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.61 (d, J = 6.0 Hz, 2H), 3.85 (dd, J = 12.8 Hz, 2.4 Hz, 1 H), 3.72 (12.8 Hz, 1 H), 3.12 (t, J = 12.0 Hz, 1 H), 3.04-2.98 (m, 1 H), 2.58-2.52 (m, 1 H), 2.48 (s, 3H, overlapped with DMSO residual peak, observed in CD3OD NMR), 2.33 (s, 3H), 1.96-1.93 (m, 1 H), 1.78-1.73 (m, 1 H), 1.69-1.60 (m, 1 H), 1.56-1.49 (m, 1 H); LCMS (ESI) m / z: 399.20 [M+H]+.

[0250] HPLC purity: 99.74%.

[0251] LCMS (AA: ACN): tR = 2.04 min in 5 min run.Example 11 : Synthesis of SW394662-1

[0252] Scheme:

[0253] Ethyl (S)-2-(3-(((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)carbarnoyl)piperidin-1- yl)oxazole-4-carboxylate [SW394662-1]: To a stirred solution of (S)-N-((4-(6-methylpyridin-3- yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.300 g, 0.948 mmol) in DMF (5 ml_) were added K2CO3 (0.205 g, 1.264 mmol, 2.0 eq.) and ethyl 2-chlorooxazole-4-carboxylate (0.183 g, 1.043 mmol, 1.1 eq.) sequentially and the mixture was heated at 70°C for 2 h (TLC). On completion, reaction mass was cooled to room temperature, water was added and extracted with 20% iPrOH in DCM (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by flash column chromatography (1-3% MeOH in DCM) to afford ethyl (S)-2-(3-(((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)carbamoyl)piperidin-1-yl)oxazole-4-carboxylate (0.243 g, 56%) as off-white solid.

[0254] 1H NMR (400 MHz, DMSO-D6): <59.01 (d, J = 1.6 Hz, 1 H), 8.94 (t, J = 5.6 Hz, 1 H), 8.27 (s, 1 H), 8.16 (dd, J = 8.0 Hz, 2.0 Hz, 1 H), 8.10 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.63-4.58 (m, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.98 (dd, J = 12.8 Hz, 3.2 Hz, 1 H), 3.85 (d, J = 12.8 Hz, 1 H), 3.13 (t, J = 11.2 Hz, 1 H), 3.02 (td, J = 11.2 Hz, 2.4 Hz, 1 H), 2.56-2.52 (m, 1 H), 2.50 (s, 3H, methyl peak overlapped with DMSO residual peak, observed in CDCI3 NMR), 1.96-1.91 (m, 1 H), 1.80- 1.72 (m, 1 H), 1.71-1.61 (m, 1H), 1.57-1.45 (m, 1 H), 1.25 (t, J = 7.2 Hz, 3H).

[0255] HPLC purity: 99.62%.

[0256] LCMS (AA: ACN): m / z: 454.16 [M-H]+, tR = 2.38 min in 5 min run.Example 12: Synthesis of SW394682-1

[0257] Scheme:

[0258] Step-1 : (S)-1-(4-(hydroxymethyl)oxazol-2-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394682-1]: To a stirred solution of ethyl (S)-2-(3-(((4-(6- methylpyridin-3-yl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)oxazole-4-carboxylate (0.117 g, 0.257 mmol) in THF (5 mL) at 0°C was added a solution of UAIH4 in THF (1M, 0.642 mL, 0.642 mmol, 2.5 eq.) dropwise under Ar. The reaction mixture was warmed slowly to roomtemperature and stirred another 1 .5 h (TLC). On completion, reaction mixture was cooled to 0°C, quenched by slow addition of saturated Na2SO4 aqueous solution, room temperature, filtered through celite pad, the residue was washed with ethyl acetate (2x). Combined filtrate was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (1-5% MeOH in DCM) to afford (S)-1-(4-(hydroxymethyl)oxazol-2-yl)-N-((4-(6- methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.032 g, 30%) as white solid.

[0259] 1H NMR (400 MHz, DMSO-D6): 69.01 (d, J = 2.0 Hz, 1 H), 8.93 (t, J = 6.0 Hz, 1 H), 8.16 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 8.10 (s, 1 H), 7.35 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 5.00 (t, J = 5.6 Hz, 1 H), 4.61 (d, J = 6.0 Hz, 2H), 4.21 (d, J = 6.0 Hz, 2H), 3.99-3.95 (m, 1 H), 3.85 (d, J = 12.0 Hz, 1 H), 3.02 (t, J = 12.0 Hz, 1H), 2.91 (td, J = 12.0 Hz, 2.0 Hz, 1 H), 2.50-2.49 (m, 1 H), 2.48 (s, 3H, overlapped with DMSO residual peak, observed in D2O exchange NMR), 1.96-1.88 (m, 1 H), 1.76-1.69 (m, 1 H), 1.66-1.55 (m, 1 H), 1.51-1.41 (m, 1 H).

[0260] HPLC purity: 98.88%.

[0261] LCMS (AA: ACN): m / z: 414.14 [M+H]+; tR = 2.17 min in 5 min run.Example 13: Synthesis of SW394664-1

[0262] Scheme:

[0263] Step-1 : Ethyl (S)-2-(3-(((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)carbamoyl)piperidin-1-yl)oxazole-5-carboxylate [SW394664-1]: To a stirred solution of (S)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.300 g,0.948 mmol) in DMF (5 mL) were added K2CC>3 (0.262 g, 1.896 mmol, 2.0 eq.) and ethyl 2- chlorooxazole-5-carboxylate (0.183 g, 1.043 mmol, 1.1 eq.) sequentially and the mixture was heated at 70°C for 2 h (TLC). On completion, reaction mass was cooled to room temperature, water was added and extracted with 20% iPrOH in DCM (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by flash column chromatography (1-3% MeOH in DCM) to afford ethyl (S)-2-(3-(((4-(6-methylpyridin-3- yl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)oxazole-5-carboxylate (0.231 g, 53%) as off white solid.

[0264] 1H NMR (400 MHz, DMSO-D6): 69.01 (d, J = 2.0 Hz, 1 H), 8.98 (t, J = 6.0 Hz, 1 H), 8.16 (dd, J = 8.0 Hz, 2.4 Hz, 1 H), 8.11 (s, 1 H), 7.70 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.62 (d, J = 6.4 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 4.06 (dd, J = 12.8 Hz, 4.0 Hz, 1 H), 3.93 (d, J = 12.8 Hz, 1 H), 3.30-3.19 (m, 1 H), 3.14-3.08 (m, 1 H), 2.57-2.52 (m, 1 H), 2.50 (s, 3H, methyl peak overlapped with DMSO residual peak, observed in CDCI3NMR), 1.99-1.94 (m, 1 H), 1.82-1.76 (m, 1 H), 1.72- 1.61 (m, 1 H), 1.58-1.46 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H)

[0265] HPLC purity: 98.82%.

[0266] LCMS (AA: ACN): m / z: 456.17 [M+H]+; tR = 2.36 min in 5 min run.Example 14: Synthesis of SW394683-1

[0267] Scheme:

[0268] Step-1 : (S)-1-(5-(hydroxymethyl)oxazol-2-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394683-1]: To a stirred solution of ethyl (S)-2-(3-(((4-(6- methylpyridin-3-yl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)oxazole-5-carboxylate (0.130 g, 0.285 mmol) in THF (6 mL) at 0°C was added a solution of UAIH4 in THF (1M, 0.856 mL, 0.856 mmol, 3.0 eq.) dropwise under Ar. The reaction mixture was warmed slowly to room temperature and stirred for another 2 h (TLC). On completion, reaction mixture was cooled to 0°C, quenched by slow addition of saturated Na2SO4 aqueous solution, room temperature, filtered through celite pad, the residue was washed with ethyl acetate (2x). Combined filtrate was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (1-5% MeOH in DCM) to afford (S)-1-(5-(hydroxymethyl)oxazol-2-yl)-N-((4-(6- methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.041 g, 35%) as white solid.

[0269] 1H NMR (400 MHz, DMSO-D6): 69.01 (d, J = 2.0 Hz, 1 H), 8.94 (t, J = 6.0 Hz, 1 H), 8.16 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 8.10 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 6.65 (s, 1 H), 5.12 (t, J = 5.6 Hz, 1 H), 4.61 (d, J = 6.0 Hz, 2H), 4.29 (d, J = 5.6 Hz, 2H), 3.98 (dd, 12.0 Hz, 3.2 Hz, 1H), 3.86 (d, J = 12.0 Hz, 1 H), 3.02 (t, J = 12.0 Hz, 1 H), 2.94-2.88 (m, 1 H), 2.53-2.50 (m, 1 H), 2.49 (s, 3H, overlapped with DMSO residual peak, observed in D2O exchange NMR), 1.95-1.91 (m, 1 H), 1.78- 1.72 (m, 1 H), 1.69-1.55 (m, 1H), 1.54-1.42 (m, 1 H).

[0270] HPLC purity: 99.08%.

[0271] LCMS (AA: ACN): m / z: 414.2 [M+H]+; tR = 2.04 min in 5 min run.Example 15: Synthesis of SW394727-1

[0272] Scheme:

[0273] Step-1 : (S)-1-(5-methyloxazol-2-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394727-1]: To a stirred solution of (S)-1-(5- (hydroxymethyl)oxazol-2-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3- carboxamide (0.100 g, 0.242 mmol) in DCM (5 mL) were added TFA (0.205 g, 1.264 mmol, 2.0 eq.) and Et3SiH (0.35 mL, 2.528 mmol, 4.0 eq.) sequentially at 0°C. The reaction mixture was warmed to room temperature and stirred for overnight (LCMS). On completion, reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous NaHCO3solution at 0°C and with 20% MeOH in DCM (3x). Combined organic phase was dried (Na3SO4), filtered and concentrated under reduced pressure. Crude residue was purified by reverse phase Prep HPLC [YMC actus triart C18, (250 x 20mm, 5 pm), ACN 120 mM NH4HCO3aq. Buffer] to afford (S)-1-(5-methyloxazol-2-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3- carboxamide (0.011 g, 11%) as white solid.

[0274] 1H NMR (400 MHz, DMSO-D6): <59.01 (d, J = 2.0 Hz, 1 H), 8.92 (t, J = 6.0 Hz, 1 H), 8.16 (dd, J = 8.0 Hz, 2.0 Hz, 1 H), 8.10 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 6.42 (s, 1 H), 4.60 (d, J = 6.0 Hz, 2H), 3.93 (dd, J = 12.4 Hz, 3.0 Hz, 1 H), 3.80 (d, J = 12.8 Hz, 1 H), 2.98 (t, J = 12.0 Hz, 1 H), 2.90-2.84 (m, 1 H), 2.49 (s, 3H, overlapped with DMSO residual peak, observed in CD3OD NMR), 2.47-2.42 (m, 1 H), 2.16 (s, 3H), 1.95-1.89 (m, 1 H), 1.78-1.70 (m, 1 H), 1.68-1.56 (m, 1 H), 1.55- 1.43 (m, 1 H).

[0275] HPLC purity: 97.11%

[0276] LCMS (TFA: ACN): m / z: 398.45 [M+H]+, tR = 4.00 min in 8 min run.Example 16: Synthesis of SW394687-1

[0277] Scheme:

[0278] Step-1 :

[0279] Ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (3):To a stirred solution of ethyl (Z)- 2-chloro-2-(hydroxyimino)acetate (0.200 g, 1.32 mmol, 1.0 eq.) in dry diethyl ether (5 mL) was added tributyl(ethynyl)tin (0.300 g, 0.797 mmol, 1.0 eq.) under Ar. To this mixture was added Et3N (0.169 g, 1.595 mmol, 2.0 eq.) dropwise over 10 in maintaining ice-cold conditions. Cold bath was removed and the reaction mixture was stirred at room temperature for 3 h. The solution was filtered to remove the precipitate, the filtrate was concentrated under reduced pressure and purified by flash column chromatography (10-15% EtOAc in Hexane) to afford ethyl 5- (tributylstannyl)isoxazole-3-carboxylate (0.220 g, 39%) as yellowish oil.

[0280] Step-2:

[0281] Ethyl 5-bromoisoxazole-3-carboxylate (3): To a stirred solution of ethyl 5- (tributylstannyl)isoxazole-3-carboxylate (0.700 g, 1.627 mmol, 1.0 eq.) in DCM (10 mL) was added Na2CC>3 (0.259 g, 2.441 mmol, 1.5 eq.) at 0°C. To this mixture was added bromine (0.167 mL, 3.254 mmol, 2.0 eq.) dropwise. Cooling batch was removed and the reaction mixturewas stirred at room temperature for overnight (TLC). On completion, the mixture was quenched with 10% aqueous sodium thiosulfate solution and then extracted with DCM (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by flash column chromatography (5-10% EtOAc in hexane) to afford ethyl 5- bromoisoxazole-3-carboxylate (0.307 g, 86%, impure) as colorless oil.

[0282] 1H NMR (400 MHz, DMSO-D6): 67.23 (s, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); [Note: Ethyl peak overlapped with other impurities],

[0283] GCMS: m / z: 219.1 [M]+; (bromo pattern), tR = 8.81 min in 15 min run.

[0284] Step-3:

[0285] Ethyl (S)-5-(3-(((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)carbamoyl)piperidin-1- yl)isoxazole-3-carboxylate SW394687-1]: To a stirred solution of (S)-N-((4-(6-methylpyridin-3- yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.200 g, 0.632 mmol) in DMF (6 mL) were added K2CO3 (0.175 g, 1.264 mmol, 2.0 eq.) and ethyl 5-bromoisoxazole-3-carboxylate (0.167 g, 0.758 mmol, 1.2 eq.) sequentially and the mixture was heated at 80°C for 6 h (TLC). On completion, reaction mixture was cooled to room temperature, water was added and extracted with 25% iPrOH in DCM (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by flash column chromatography (1-4% MeOH in DCM) to afford ethyl (S)-5-(3-(((4-(6-methylpyridin-3-yl)thiazol- 2-yl)methyl)carbamoyl)piperidin-1-yl)isoxazole-3-carboxylate (0.145 g, 50%) as white solid.

[0286] 1H NMR (400 MHz, DMSO-D6): 69.01 (d, J = 2.0 Hz, 1 H), 8.96 (t, J = 6.0 Hz, 1 H), 8.16 (dd, J = 8.0 Hz, 2.4 Hz, 1 H), 8.11 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1H), 5.75 (s, 1 H), 4.68-4.56 (m, 2H), 4.28 (q, J = 7.2 Hz, 2H), 3.82 (dd, J = 12.8 Hz, 3.6 Hz, 1 H), 3.72 (d, J = 12.8 Hz, 1 H), 3.18- 3.12 (m, 1 H), 3.03 (td, J = 12.8 Hz, 2.4 Hz, 1H), 2.57-2.52 (m, 1H), 2.50 (s, 3H, methyl peak overlapped with DMSO residual peak, observed in CD3OD NMR), 1.97-1.91 (m, 1 H), 1.77-1.70 (m, 1 H), 1.69-1.59 (m, 1H), 1.57-1.42 (m, 1 H), 1.25 (t, J = 7.2 Hz, 3H),

[0287] HPLC purity: 97.75%.

[0288] LCMS (FA: ACN): m / z: 456.36 [M+H]+; tR = 2.26 min in 5 min run.Example 17: Synthesis of SW394724-1

[0289] Scheme:

[0290] Step-1 : (S)-1-(3-(hydroxymethyl)isoxazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394724-1]: To a stirred solution of ethyl (S)-5-(3-(((4-(6- methylpyridin-3-yl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)isoxazole-3-carboxylate (0.050 g, 0.110 mmol) in THF (5 mL) at 0°C was added a solution of LiAIH4in THF (1M, 0.33 mL, 0.330 mmol, 3.0 eq.) dropwise under Ar. The reaction mixture was warmed slowly to room temperature and stirred for another 2 h (TLC). On completion, reaction mixture was cooled to 0°C, quenched by slow addition of saturated NazSO4aqueous solution, room temperature, filtered through celite pad, the residue was washed with ethyl acetate (2x). Combined filtrate was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (1-5% MeOH in DCM) to afford (S)-1-(3-(hydroxymethyl)isoxazol-5-yl)-N-((4-(6- methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.025 g, 55%) as white solid.

[0291] 1H NMR (400 MHz, DMSO-D6): 69.01 (d, J = 2.0 Hz, 1 H), 8.96 (t, J = 6.0 Hz, 1 H), 8.16 (dd, J = 8.0 Hz, 2.4 Hz, 1 H), 8.10 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1H), 5.30 (t, J = 6.0 Hz, 1 H), 5.29 (s, 1 H), 4.63-4.59 (m, 2H), 4.31 (d, J = 6.0 Hz, 2H), 3.73 (dd, 12.0 Hz, 3.2 Hz, 1 H), 3.63 (d, J = 12.0 Hz, 1 H), 3.04 (t, J = 12.0 Hz, 1 H), 2.95 (td, 12.0 Hz, 2.4 Hz, 1 H), 2.54-2.51 (m, 1H), 2.49 (s, 3H, overlapped with DMSO residual peak, observed in NMR in CD3OD), 1.94-1.90 (m, 1 H), 1.76- 1.72 (m, 1 H), 1.69-1.60 (m, 1H), 1.57-1.45 (m, 1 H).

[0292] HPLC purity: 99.35%.

[0293] LCMS (FA: ACN): m / z: 414.37 [M+H]+; tR = 1.85 min in 5 min run.Example 18: Synthesis of SW394809-1

[0294] Scheme:

[0295] Step-1 :

[0296] (S)-1-(3-(bromomethyl)isoxazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide (1): To a stirred solution of (S)-1-(3- (hydroxymethyl)isoxazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3- carboxamide (0.250 g, 0.605 mmol, 1.0 eq.) in DCM (7 mL) at 0°C were added PPha (0.270 g, 1.028 mmol, 1.7 eq.), 2,6-lutidine (0.028 mL, 0.242 mmol, 0.4 eq.) and CBr4(0.341 g, 1.028 mmol, 1.7 eq.) in sequence. Cold bath was removed, and the mixture was stirred at room temperature for overnight (LCMS). On completion, saturated NaHCOa solution (aq.) was added to the mixture and then extracted with DCM (3x). Combined organic phase was dried (NaaSO^, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (1-4% MeOH in DCM) to afford (S)-1-(3-(bromomethyl)isoxazol-5-yl)-N-((4-(6- methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.105 g, 36%) as light brown gum.

[0297] 1H NMR (400 MHz, DMSO-D6): 69.01 (s, 1H), 8.94 (brs, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.10 (s, 1H), 7.32 (d, J = 8.0 Hz, 1 H), 5.33 (s, 1H), 4.66-4.56 (m, 2H), 4.44 (s, 2H), 3.77-3.73 (m, 1 H), 3.66-3.62 (m, 1 H), 3.08 (t, J = 12.0 Hz, 1 H), 2.95 (t, 12.0 Hz, 1 H), 2.56-2.52 (m, 1 H), 2.49 (s, 3H), both peaks overlapped with DMSO residual peak, 1.96-1.90 (m, 1 H), 1.76-1.72 (m, 1 H), 1.70-1.58 (m, 1 H), 1.57-1.45 (m, 1 H).

[0298] LCMS (AA: ACN): m / z: 476.0 [M+H]+(bromo pattern); tR = 3.45 min in 5 min run.

[0299] Step-2:

[0300] (S)-1-(3-(methoxymethyl)isoxazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394809-1]: To a stirred solution of (S)-1-(3- (bromomethyl)isoxazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3- carboxamide (0.100 g, 0.21 mmol) in MeOH (5 mL) was added a solution of NaOMe (25% w / v, 0.136 mL, 0.63 mmol, 3.0 eq.) at room temperature and the mixture was then refluxed for 3 h (LCMS). On completion, reaction mixture was cooled to room temperature, quenched with few drops of water and concentrated under reduced pressure. Crude residue was purified by reverse phase Prep HPLC [Column: YMC actus Triart C18 (250 x 20mm, 5 pm), ACN / 20 mM aq. NH4HCO3-buffer] flash column chromatography (3-7% MeOH in DCM) to afford (S)-1-(3- (methoxymethyl)isoxazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3- carboxamide (0.030 g, 33%) as white solid.

[0301] 1H NMR (400 MHz, DMSO-D6): 69.01 (s, 1H), 8.94 (brs, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 8.10 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 5.33 (s, 1 H), 4.66-4.56 (m, 2H), 4.28 (s, 2H), 3.75 (d, 12.0 Hz, 1 H), 3.64 (d, J = 12.0 Hz, 1 H), 3.27 (s, 3H), 3.07 (t, J = 12.0 Hz, 1 H), 2.94 (t, 12.0 Hz, 1 H), 2.60-2.54 (m, 1 H), 2.49 (s, 3H), both peaks overlapped with DMSO residual peak, observed in NMR in CD3OD), 1.96-1.90 (m, 1H), 1.76-1.72 (m, 1 H), 1.70-1.58 (m, 1 H), 1.57-1.45 (m, 1 H).

[0302] HPLC purity: 99.54%.

[0303] LCMS (AA: ACN): m / z: 426.1 [M-H]+; tR = 2.21 min in 5 min run.Example 19: Synthesis of SW394686-1

[0304] Scheme:

[0306] Ethyl 5-(trichloromethyl)-1,2,4-oxadiazole-3-carboxylate (3): To a stirred suspension of ethyl 2-(hydroxyamino)-2-iminoacetate (0.200 g, 1.514 mmol, 1.0 eq.) in toluene (5 ml_) was added perchloroacetic anhydride (0.277 mL, 1.514 mmol, 1.0 eq.) and the mixture was refluxed for overnight. The reaction mixture was cooled to room temperature and concentrated under vacuo. Crude residue was diluted ethyl acetate, washed with saturated NaHCCh (aq.) solution (2x), brine, dried (Na2SC>4) and concentrated under reduced pressure to get ethyl 5-(trichloromethyl)-1,2,4-oxadiazole-3-carboxylate (0.330 g, 84%) as colorless oil which was used for the next step without further purification.

[0307] 1H NMR (400 MHz, CDCI3): 54.53 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H).

[0308] GCMS: m / z: 257.9 [M]+(trichloro pattern); tR = 9.75 min in 15 min run.Step-2:

[0309] Ethyl (S)-5-(3-(((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)- 1 ,2,4-oxadiazole-3-carboxylate [SW394686-1]: To a stirred solution of (S)-N-((4-(6-methylpyridin- 3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.200 g, 0.632 mmol) in DMF (5 ml_) was added ethyl 5-(trichloromethyl)-1 ,2,4-oxadiazole-3-carboxylate (0.164 g, 0.632 mmol, 1.0 eq.) and the mixture was heated at 60°C under argon for 4 h (TLC / LCMS). On completion, reaction mixture was cooled to room temperature, diluted with 20% iPrOH in DCM, washed with cold water (2x). Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. Crude residue was purified by reverse phase Prep HPLC [Column: YMC actus Triart C18 (250 x 20 mm, 5 pm), ACN / 20 mM aq. NF HCOa-buffer] to afford ethyl (S)-5-(3-(((4-(6-methylpyridin- 3-yl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)-1 ,2,4-oxadiazole-3-carboxylate (0.020 g, 7%) as white solid.

[0310] 1H NMR (400 MHz, DMSO-D6): 69.01 (s, 1H), 8.98 (t, J = 6.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.10 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 5.75 (s, 1 H), 4.65-4.56 (m, 2H), 4.34 (q, J = 7.2 Hz, 2H), 4.01 (d, J = 10.0 Hz, 1 H), 3.88 (d, J = 12.8 Hz, 1 H), 3.38 (t, J = 12.8 Hz, 1 H), 3.29-3.22 (m, 1 H), 2.57-2.52 (m, 1 H), 2.60-2.53 (m, 1H), 2.49 (s, 3H, methyl peak overlapped with DMSO residual peak, observed in CD3OD NMR), 1.98-1.93 (m, 1 H), 1.82-1.76 (m, 1 H), 1.74-1.66 (m, 1 H), 1.51-1.50 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H).

[0311] HPLC purity: 95.16%.

[0312] LCMS (FA: ACN): m / z: 457.37 [M+H]+; tR = 2.09 min in 5 min run.Example 20: Synthesis of SW394726-1

[0313] Scheme:

[0314] Step-1 : (S)-1-(3-(hydroxymethyl)-1 ,2,4-oxadiazol-5-yl)-N-((4-(6-methylpyridin-3- yl)thiazol-2-yl)methyl)piperidine-3-carboxamide [SW394726-1]: To a stirred solution of ethyl (S)- 5-(3-(((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)-1 ,2,4-oxadiazole-3- carboxylate (0.150 g, 0.329 mmol) in THF (4 mL) at 0°C was added a solution of UAIH4 in THF (1 M, 0.987 mL, 0.987 mmol, 3.0 eq.) dropwise under Ar. The reaction mixture was warmed slowly to room temperature and stirred for another 2 h (TLC). On completion, reaction mixture was cooled to 0°C, quenched by slow addition of saturated Na2SO4 aqueous solution, room temperature, filtered through celite pad, the residue was washed with ethyl acetate (2x).Combined filtrate was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (1-5% MeOH in DCM) to afford (S)-1-(3-(hydroxymethyl)-1 ,2,4- oxadiazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.019 g, 14%) as white solid.

[0315] 1H NMR (400 MHz, DMSO-D6): <59.01 (d, J = 2.0 Hz, 1 H), 8.99 (t, J = 6.0 Hz, 1 H), 8.16 (dd, J = 8.0 Hz, 2.0 Hz, 1 H), 8.11 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1H), 5.49 (t, J = 6.0 Hz, 1 H), 4.61 (d, J = 6.0 Hz, 2H), 4.30 (d, J = 6.0 Hz, 2H), 4.01 (dd, 12.8 Hz, 3.6 Hz, 1 H), 3.88 (d, J = 12.8 Hz, 1 H), 3.26 (t, J = 12.0 Hz, 1 H), 3.19-3.12 (m, 1H), 2.55-2.52 (m, 1 H), 2.49 (s, 3H, overlapped with DMSO residual peak, observed in NMR in CD3OD), 1.96-1.92 (m, 1 H), 1.81-1.72 (m, 1 H), 1.71- 1.60 (m, 1 H), 1.58-1.45 (m, 1H).

[0316] HPLC purity: 95.78%.

[0317] LCMS (FA: ACN): m / z: 415.19 [M+H]+; tR = 1.71 min in 5 min run.Example 21 : Synthesis of SW394857

[0318] Scheme:

[0320] (S)-1-(3-(chloromethyl)-1,2,4-oxadiazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide (1): To a stirred solution of (S)-1-(3-(hydroxymethyl)-1 ,2,4- oxadiazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.150 g, 0.363 mmol, 1.0 eq.) in DCM (5 ml_), was added SOCI2 (0.26 ml_, 3.63 mmol, 10.0 eq.) at 0°C. The mixture was warmed to room temperature and stirred for another 3 h (TLC). On completion, the mixture was concentrated under reduced pressure and DCM was added to the residue, washed with water and brine. Organic layer was separated, dried (Na2SO4) and concentratedunder reduced pressure and the residue was purified by flash column chromatography to afford (S)-1-(3-(chloromethyl)-1 ,2,4-oxadiazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide (0.030 g, 19%) which was sufficiently pure and used for the next step without further purification.

[0321] LCMS (AA: ACN): m / z: 433.0 [M+H]+; tR = 3.0 min in 5 min run.

[0322] Step-2:

[0323] (S)-1-(3-(methoxymethyl)-1 ,2,4-oxadiazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394857]: To a stirred solution of (S)-1-(3-(chloromethyl)- 1 ,2,4-oxadiazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.060 g, 0.126 mmol) in MeOH (5 mL) was added a solution of NaOMe (25% w / v, 0.082 mL, 0.378 mmol, 3.0 eq.) at room temperature and the mixture was then refluxed for overnight (LCMS). On completion, reaction mixture was cooled to room temperature, quenched with few drops of water and concentrated under reduced pressure. Crude residue was purified by reverse phase Prep HPLC [Column: YMC actus Triart C18 (250 x 20mm, 5 pm), ACN I 20 mM aq. NH4HCO3-buffer] flash column chromatography (3-7% MeOH in DCM) to afford (S)-1-(3- (methoxymethyl)-1 ,2,4-oxadiazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2-yl)methyl)piperidine- 3-carboxamide (0.005 g, 9%) as white solid.

[0324] 1H NMR (400 MHz, DMSO-D6): 69.01 (s, 1H), 8.96 (t, J = 6.0 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 8.10 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 5.33 (s, 1 H), 4.61 (d, J = 6.0 Hz, 2H), 4.29 (s, 2H), 4.01 (d, 12.8 Hz, 1H), 3.88 (d, J = 12.8 Hz, 1 H), 3.27 (s, 3H), overlapped with DMSO water peak observed in D2O exchange NMR, 3.18 (t, J = 11.2 Hz, 1 H), 3.10-2.75 (m, 1H), 2.57-2.53 (m, 1 H), 2.49 (s, 3H), both peaks overlapped with DMSO residual peak, observed in D2O exchange NM ), 1.98-1.91 (m, 1 H), 1.781-1.76 (m, 1 H), 1.75-1.63 (m, 1H), 1.59-1.45 (m, 1 H).

[0325] HPLC purity: 99.68%.

[0326] LCMS (AA: ACN): m / z: 429.2 [M+H]+; tR = 2.23 min in 5 min run.Example 22: Synthesis of SW394776

[0327] Scheme:

[0328] Step-1 : tert-butyl 5-(((4-bromothiazol-2-yl)methyl)carbamoyl)-2,2- dimethylpiperidine-1-carboxylate (2): 1-(tert-butoxycarbonyl)-6,6-dimethylpiperidine-3- carboxylic acid (1) was prepared following literature described reported method [W02011026904A1] starting from benzylamine. To a stirred solution of l-(tert-butoxycarbonyl)- 6,6-dimethylpiperidine-3-carboxylic acid (0.100 g, 0.389 mmol, 1 eq.) in DMF (5 ml_) was added DIPEA (0.135 mL, 0777 mmol, 2.0 eq.) followed by HATU (0.177 g, 0.446 mmol, 1.2 eq.) at 0°C and the mixture was stirred for 5 min. To this mixture was added (4-bromothiazol-2- yl)methanamine. Reaction mixture was warmed to room temperature and stirred for another 2 h (TLC). On completion, the reaction mixture was diluted with ethyl acetate, washed with cold water (3x) and brine. Organic phase was separated, dried over Na2SO4 and concentrated under reduced pressure. Crude residue was purified by flash column chromatography (30%-40% EtOAc in hexane) to get tert-butyl 5-(((4-bromothiazol-2-yl)methyl)carbamoyl)-2,2-dimethylpiperidine-1- carboxylate (0.106 g, 63%) as off-white solid.

[0329] 1H NMR (400 MHz, DMSO-D6): 5 8.85 (t, J = 5.6 Hz, 1 H), 7.74 (s, 1 H), 4.56-4.48 (m, 2H), 3.84 (dd, J = 13.2 Hz, 4.8 Hz, 1 H), 3.05 (t, J = 13.2 Hz, 1H), 2.69-2.65 (m, 1 H), 1.73-1.62 (m, 3H), 1.49-1.42 (m, 1H), 1.41-1.33 (m, 12H), 1.26 (s, 3H) ppm.

[0330] LCMS [AA: ACN]: m / z: 432.0 [M+H]+(bromo pattern), tR = 3.88 min in 6 min run.

[0331] Step-2: tert-butyl 5-(((4-(4-cyanophenyl)thiazol-2-yl)methyl)carbamoyl)-2,2- dimethylpiperidine-1-carboxylate (3): A mixture of tert-butyl 5-(((4-bromothiazol-2- yl)methyl)carbamoyl)-2,2-dimethylpiperidine-1 -carboxylate (0.100 g, 0.231 mmol, 1.0 eq.) and (4- cyanophenyl)boronic acid (0.041 g, 0.278 mmol, 1.2 eq.) in Toluene: EtOH: H2O (3: 1 : 3, 7 ml_), was added Na2CO3 (0.049 g, 0.463 mmol, 2.0 eq.). The reaction mixture was degassed (N2) for 10 min before the addition of Pd(PPh3)4 (0.027 g, 0.023 mmol, 10 mol%) and then heated at 90°Cfor overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (1-5% MeOH in DCM) to afford tert-butyl 5-(((4-(4-cyanophenyl)thiazol-2- yl)methyl)carbamoyl)-2,2-dimethylpiperidine-1 -carboxylate (0.080 g, 76%) as light yellow solid.

[0332] 1H NMR (400 MHz, DMSO-D6): 68.89 (t, J = 6.0 Hz, 1 H), 8.31 (s, 1 H), 8.13 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 4.64-4.53 (m, 2H), 3.87 (dd, J = 13.2 Hz, 4.8 Hz, 1 H), 3.10-3.04 (m, 1 H), 2.69-2.62 (m, 1 H), 1.80-1.65 (m, 3H), 1.52-1.46 (m, 1 H), 1.42-1.39 (m, 12H), 1.27 (s, 3H) ppm [TPPO and other impurities present in NMR).

[0333] LCMS (AA: ACN): m / z: 455.2 [M+H]+(Boc pattern), tR = 4.00 min in 5 min run.

[0334] Step-3: N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-6,6-dimethylpiperidine-3- carboxamide (4): To a stirred solution of tert-butyl 5-(((4-(4-cyanophenyl)thiazol-2- yl)methyl)carbamoyl)-2,2-dimethylpiperidine-1 -carboxylate (0.380 g, 0.835 mmol, 1.0 eq.) in DCM (10.0 mL) at 0°C was added TFA (1.92 mL, 25.055 mmol, 30.0 eq.) dropwise and the reaction mixture was stirred for another 2 h at the same temperature (TLC). On completion, the mixture was concentrated under reduced pressure and co-evaporated two times with DCM. Crude residue was diluted with DCM, neutralized by slow addition of DIPEA dropwise. The mixture was again concentrated under reduced pressure to afford N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)- 6,6-dimethylpiperidine-3-carboxamide as brown gum which was used directly for the next step without further purification considering quantitative conversion.

[0335] LCMS (AA: ACN): m / z: 355.0 [M+H]+; tR = 2.93 min in 5 min run.

[0336] Step-4: N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2-(2-fluoroethoxy)acetyl)-6,6- dimethylpiperidine-3-carboxamide [SW394776]: To a stirred solution of 2-(2-fluoroethoxy)acetic acid (0.041 g, 0.337 mmol, 1.1 eq.) in DMF (4 mL) was added DIPEA (0.16 mL, 0.918 mmol, 3.0 eq.) followed by HATU (0.140 g, 0.367 mmol, 1.2 eq.) at 0°C and the mixture was stirred for 5 min. To this mixture was added a solution N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-6,6- dimethylpiperidine-3-carboxamide (0.100 g, 0.306 mmol, 1 eq.) in DMF. Reaction mixture was warmed to room temperature and stirred for another 2 h (TLC). On completion, the reaction mixture was diluted with ethyl acetate, washed with cold water (3x) and brine. Organic phase was separated, dried over Na2SO4 and concentrated under reduced pressure. Crude residue was purified by reverse phase Prep HPLC [YMC Actus Triart, ACN I 20 mM NH4HCO3 aq. buffer] to afford N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2-(2-fluoroethoxy)acetyl)-6,6- dimethylpiperidine-3-carboxamide (0.015 g, 11%) as white solid.

[0337] 1H NMR (400 MHz, DMSO-D6): 68.85 (m, 1 H), 8.31 (s, 1 H), 8.13 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 4.69-4.52 (m, 3H), 4.46 (t, J = 4.0 Hz, 1 H), 4.21 (d, J = 14.0 Hz, 1 H), 4.05 (d, J = 14.0 Hz, 1 H), 3.71-3.65 (m, 1 H), 3.62-3.56 (m, 1 H), 3.48-3.39 (m, 1 H), 2.71-2.60 (m, 1 H), 1.89-1.60 (m, 3H), 1.59-1.48 (m, 1 H), 1.43 (s, 3H), 1.36 (s, 3H). Ppm.

[0338] HPLC purity: 98.56%.

[0339] LCMS [FA: ACN]: m / z: 459.32 [M+H]+, tR = 4.79 min in 12 min run.Example 23: Synthesis of SW394806-1

[0340] Scheme:

[0341] N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2-ethoxyacetyl)-6,6- dimethylpiperidine-3-carboxamide [SW394806-1]: To a solution of N-((4-(6-cyanopyridin-3- yl)thiazol-2-yl)methyl)-6,6-dimethylpiperidine-3-carboxamide (0.080 g, 0.225 mmol, 1.0 eq.) in DCM (5 mL) was added Et3N (0.094 ml_, 0.675 mmol, 3.0 eq) at 0°C. To this mixture was added 2-methoxyacetyl chloride (0.041g, 0.338 mmol, 1.5 eq.) maintaining 0°C. Reaction mixture was warmed slowly to room temperature and stirred for another 3 h (TLC). On completion, reaction mixture was diluted with DCM (10 mL), washed with water (2x) and brine. Organic phase was dried (Na2SO4) and concentrated under reduced pressure to get a crude residue which was purified by reverse phase Prep HPLC [YMC Triart C18, ACN, 20mm NH4HCO3 (aq.) buffer] to afford N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2-ethoxyacetyl)-6,6-dimethylpiperidine-3- carboxamide (0.015 g, 15%) as white solid.

[0342] 1H NMR (400 MHz, DMSO-D6): 68.87 (t, J = 5.6 Hz, 1 H), 8.31 (s, 1 H), 8.13 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 4.67-4.56 (m, 2H), 4.10 (d, J = 13.6 Hz, 1H), 3.92 (d, J = 13.6 Hz, 1 H), 3.51 (dd, J = 13.6 Hz, 4.8 Hz, 1 H), 3.40 (q, J = 6.8 Hz, 2H), 3.31-3.25 (m, 2H), 2.69-2.61 (m, 1 H), 1.84-1.71 (m, 2H), 1.70-1.61 (m, 1 H), 1.53-1.46 (m, 1 H), 1.43 (s, 3H), 1.35 (s, 3H), 1.09 (t, J = 6.8 Hz, 3H) ppm.

[0343] HPLC purity: 99.53%.

[0344] LCMS (FA: ACN): m / z: 441.27 [M+H]+tR = 2.73 min in 5 min run.Example 24: Synthesis of SW394772-1

[0345] Scheme:

[0346] N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-6,6-dimethyl-1-(oxazole-5- carbonyl)piperidine-3-carboxamide [SW394772-1]: To a stirred solution of oxazole-5- carboxylic acid (0.070 g, 0.62 mmol, 1.1 eq.) in DMF (5 ml_), were added DIPEA (0.29 mL, 1.69 mmol, 3.0 eq.) and HATU (0.321 g, 0.845 mmol, 1.5 eq.) at 0°C. After 5 min, N-((4-(4- cyanophenyl)thiazol-2-yl)methyl)-6,6-dimethylpiperidine-3-carboxamide (0.200 g, 0.563 mmol, 1 .0 eq.) was added and the reaction mixture was warmed to room temperature and stirred for 15 h (TLC). The mixture was then diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by reverse phase Prep HPLC [YMC Triart C18, ACN, 20mm NH4HCO3 (aq.) buffer] to afford N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-6,6-dimethyl-1 -(oxazole- 5- carbonyl)piperidine-3-carboxamide (0.043 g, 17%) as white solid.

[0347] 1H NMR (400 MHz, DMSO-D6): 58.94 (t, J = 6.0 Hz, 1 H), 8.49 (s, 1 H), 8.30 (s, 1 H), 8.12 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.64 (s, 1 H), 4.67-4.55 (m, 2H), 3.74 (dd, J = 14.0 Hz, 4.8 Hz, 1H), 3.45-3.39 (m, 1 H), 2.81-2.77 (m, 1 H), 1.85-1.74 (m, 3H), 1.62-1.55 (m, 1 H), 1.50 (s, 3H), 1.41 (s, 3H) ppm.

[0348] HPLC purity: 99.77%.

[0349] LCMS (FA: ACN): m / z: 450.25 [M+H]+, tR = 2.71 min in 5 min run.Example 25: Synthesis of SW394729-1

[0350] Scheme:

[0351] (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(isoxazolidine-2- carbonyl)piperidine-3-carboxamide [SW394729-1]: To a stirred solution of (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.125 g, 0.383 mmol, 1.0 eq.) in DCM (5.0 mL) at O°C, triphosgene (0.045 g, 0.153 mmol, 0.4 eq.) was added and the mixture was warmed to room temperature over 20 min and stirred for another 3 h. The mixture was added to another round bottom flask containing isoxazolidine hydrochloride (0.050 g, 0.46 mmol, 1.2 eq.) and triethylamine (0.267 mL, 1.915 mmol, 5.0 eq.) in DCM (5 mL) and the reaction mixture was stirred at room temperature for overnight (LCMS). On completion, the mixture was diluted with DCM, washed with water (2x) and brine. Organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. Crude residue was purified by reverse phase Prep HPLC [YMC Actus Triart C-18, ACN, 20 mM NH4HCO3 aqueous buffer] to afford (S)-N-((4-(4- cyanophenyl)thiazol-2-yl)methyl)-1-(isoxazolidine-2-carbonyl)piperidine-3-carboxamide (0.022 g, 13%) as white solid.

[0352] 1H NMR (400 MHz, DMSO-D6): 68.92 (t, J = 6.0 Hz, 1 H), 8.31 (s, 1 H), 8.13 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 4.59 (d, J = 6.0 Hz, 2H), 4.08 (d, J = 11.2 Hz, 1 H), 3.98 (d, J = 12.8 Hz, 1 H), 3.78 (t, J = 7.2 Hz, 2H), 3.40 (t, J = 7.2 Hz, 1 H), 2.92 (t, J = 12.0 Hz, 1 H), 2.82 (t, J = 12.0 Hz, 1 H), 2.47-2.35 (m, 1 H), 2.11 (quint, J = 7.2 Hz, 2H), 1.94-1.87 (m, 1 H), 1.73-1.55 (m, 2H), 1.46-1.32 (m, 1H) ppm.

[0353] HPLC purity: 99.95%.

[0354] LCMS (FA: ACN): m / z 426.24 [M+H]+; tR = 2.60 min in 5 min run.Example 26: Synthesis of SW394773-1

[0355] Scheme:

[0356] Step-1 : tert-butyl (S)-3-(((4-(4-(trifluoromethyl)phenyl)thiazol-2- yl)methyl)carbamoyl)piperidine-1 -carboxylate (3): A mixture of tert-butyl (S)-3-(((4- bromothiazol-2-yl)methyl)carbamoyl)piperidine-1 -carboxylate (2.4 g, 7.809 mmol, 1.0 eq.) and (4-(trifluoromethyl)phenyl)boronic acid (1.78 g, 9.371 mmol, 1.2 eq.) in Toluene: EtOH: H2O (3: 1 : 3, 105 mL), was added Na2CO3(1.655 g, 15.619 mmol, 2.0 eq.). The reaction mixture was degassed (N2) for 15 min before the addition of Pd(PPh3)4(0.902 g, 0.781 mmol, 10 mol%) and then heated at 90°C for overnight (LCMS). On completion, the mixture was cooled to room temperature, water was added to the mixture and extracted with ethyl acetate (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (1-5% MeOH in DCM) to afford tert-butyl (S)-3-(((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl)carbamoyl)piperidine-1-carboxylate (2.4 g, 65%) as light brown solid.

[0357] 1H NMR (400 MHz, DMSO-D6): 58.92 (m, 1 H), 8.25 (s, 1 H), 8.16 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 4.66-4.53 (m, 2H), 4.11-3.92 (m, 1 H), 3.87 (d, J = 12.8 Hz, 1 H), 2.91- 3.62 (m, 2H), 2.38-2.27 (m, 1 H), 1.89 (d, J = 12.8 Hz, 1 H), 1.69-1.50 (m, 2H), 1.40 (s, 9H), 1.41- 1.28 (m, 1 H, overlapped) ppm.

[0358] LCMS (AA: ACN): m / z: 470.3 [M+H]+(Boc pattern), tR = 3.65 min in 5 min run.

[0359] Step-2: (S)-N-((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (4): To a stirred solution of tert-butyl (S)-3-(((4-(4-(trifluoromethyl)phenyl)thiazol-2- yl)methyl)carbamoyl)piperidine-1-carboxylate (2.4 g, 5.09 mmol, 1.0 eq.) in DCM (40.0 mL) at 0°C was added TEA (7.79 mL, 101.794 mmol, 20.0 eq.) dropwise and the reaction mixture was stirred for another 3 h at the same temperature (TLC). On completion, the mixture was concentrated under reduced pressure and co-evaporated three times with DCM. Crude residue was diluted with DCM, neutralized by slow addition of DIPEA dropwise. The mixture was again concentrated under reduced pressure to afford (S)-N-((4-(4-(trifluoromethyl)phenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide as brown gum which was used directly for the next step without further purification considering quantitative conversion.

[0360] LCMS (AA: ACN): m / z: 370.0 [M+H]+; tR = 3.26 min in 6 min run.

[0361] Step-3: tert-butyl (S)-(2-(2-oxo-2-(3-(((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl) carbamoyl)piperidin-1-yl)ethoxy)ethyl)carbamate (3): To a stirred solution of 2-(2-((tert- butoxycarbonyl)amino)ethoxy)acetic acid (0.087 g, 0.767 mmol, 1.0 eq.) in DMF (4 mL), were added DIPEA (0.267 mL, 1.535 mmol, 2.0 eq.) and HATU (0.350 g, 0.921 mmol, 1.2 eq.) at 0°C. After 5 min, (S)-N-((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (0.300 g, 0.767 mmol, 1.0 eq) was added and the reaction mixture was warmed to room temperature and stirred overnight (LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash columnchromatography (20-35% EtOAc in hexane) to afford tert-butyl (S)-(2-(2-oxo-2-(3-(((4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)methyl) carbamoyl)piperidin-1-yl)ethoxy)ethyl)carbamate (0.250 g, 57%).

[0362] LCMS (AA: ACN): m / z: 571 .0 [M+H]+(Boc pattern); tR = 3.81 min in 5 min run.

[0363] Step-4: (S)-1-(2-(2-aminoethoxy)acetyl)-N-((4-(4-(trifluoromethyl)phenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394773-1]: To a stirred solution of tert-butyl (S)-(2-(2- oxo-2-(3-(((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl) carbamoyl)piperidin-1- yl)ethoxy)ethyl)carbamate (0.250 g, 0.438 mmol, 1.0 eq.) in DCM (10.0 mL) at 0°C was added TFA (1.00 mL, 13.143 mmol, 30.0 eq.) dropwise and the reaction mixture was stirred for another 2 h at the same temperature (TLC). On completion, the mixture was concentrated under reduced pressure and co-evaporated two times with DCM. Crude residue was purified by reverse phase preparative HPLC [ATLANTIS C-18, ACN, 0.1% TFA aqueous buffer] to afford (S)-1-(2-(2- aminoethoxy)acetyl)-N-((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (0.090 g, 35%) as TFA salt, white solid.

[0364] 1H NMR (400 MHz, DMSO-D6, 100°C): 5 8.57 (brs, 1 H), 8.17-8.08 (m, 3H), 7.89-7.61 (m, 4H), 4.72-4.56 (m, 2H) 4.31 (s, 2H), 3.95-3.70 (m, 1 H), 3.68 (t, J = 5.2 Hz, 2H), 3.63-3.49 (m, 2H), 3.33-3.12 (m, 2H), overlapped with DMSO water peak), 3.05-2.95 (m, 3H), 2.01-1.93 (m, 1 H), 1.80-1.69 (m, 2H), 1.51-1.38 (m, 1 H).

[0365] HPLC purity: 99.95%.

[0366] LCMS (FA: ACN): m / z 471.2 [M+H]+, tR = 2.28 min in 5 min run.Example 27: Synthesis of SW394775

[0367] (S)-1-(2-(2-aminoethoxy)acetyl)-N-((4-(4-cyclopropylphenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide. (SW394775)

[0368] Prepared following similar synthetic protocol as described for SW394773-1 above.

[0369] Isolated as TFA salt.1H NMR (400 MHz, DMSO-D6, 100°C ): 58.53 (brs, 1H), 7.99-7.58 (m, 5H), 7.14 (d, J = 8.0 Hz, 2H), 4.70-4.55 (m, 2H), 4.31 (s, 2H), 3.95-3.70 (m, 2H, overlapped with DMSO water peak), 3.15-2.95 (m, 4H), 2.49-2.40 (m, 1 H, overlapped with DMSO residual peak), 2.00-1.92 (m, 2H), 1.77-1.65 (m, 2H), 1.51-1.38 (m, 1 H), 1.00-0.94 (m, 2H), 0.74-0.67 (m, 2H).

[0370] HPLC purity: 99.44%.

[0371] LCMS (AA: ACN): m / z 443.2 [M+H]+, tR = 2.29 min in 5 min run.Example 28: Synthesis of SW394853

[0372] Scheme:

[0373] (S)-6-methylmorpholin-3-one (2) was prepared from (S)-1-aminopropan-2-ol following the synthetic procedure as described in Synthesis 2015, 47, 712-720.Step-2:

[0374] (S)-2-((1-aminopropan-2-yl)oxy)acetic acid, hydrochloride (4): A mixture of (S)-6- methylmorpholin-3-one (0.100 g, 0.87 mmol) and 6N HCI (5 ml_) was heated at 100°C for 3 h.Reaction mixture was cooled to room temperature and concentrated under reduced pressure and dried (azeotrope, toluene, two times) to get the desired compound as colorless gum which was used for the next step without further purification considering quantitative conversion.

[0375] Step-3: (S)-2-((1-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)acetic acid (5): To a stirred solution of (S)-2-((1-aminopropan-2-yl)oxy)acetic acid, hydrochloride (0.200 g, 1 .52 mmol) in dioxane and water (8 mL, 3:1) at 0°C was added 1M NaOH (aq.) solution to adjust the pH 9. To this solution was added Boc-anhydride (0.698 mL, 3.04 mmol, 2.0 eq.) and warmed to room temperature and stirred for another 3 h. The reaction mixture was concentrated under vacuo, water was added and washed with diethyl ether. The aqueous layer was acidified with 10% citric acid (aq.) solution and extracted with ethyl acetate (3x). Organic phase was dried (Na2SO4) and concentrated under reduced pressure to afford (S)-2-((1-((tert-butoxycarbonyl)amino)propan-2- yl)oxy)acetic acid (0.302 g, 85%).

[0376] 1H NMR (400 MHz, DMSO-D6): 5 12.4 (brs, 1 H), 6.69-6.64 (m, 1H), 3.99 (s, 2H), 3.63- 3.55 (m,1 H), 2.71-2.57 (m, 2H), 1.37 (s, 9H), 1.01 (d, J = 6.4 Hz, 3H) ppm.

[0377] Step-4: tert-butyl ((S)-2-(2-((S)-3-(((4-(4-cyanophenyl)thiazol-2-yl)methyl)carbamoyl) piperidin-1-yl)-2-oxoethoxy)propyl)carbamate (6): To a stirred solution of (S)-2-((1-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)acetic acid (0.300 g, 0.767 mmol, 1.0 eq) in DMF (3 ml_) were added DIPEA (0.267 mL, 1.53 mmol, 2.0 eq.) and HATU (0.349 g, 0.917 mmol, 1.2 eq.) at 0°C. After 10 min, (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.250 g, 0.765 mmol, 1.0 eq.) in DMF (1 mL) was added and the reaction mixture was warmed to room temperature and stirred overnight (LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl (S)-(2-(2-oxo-2-(3-(((4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)ethoxy)ethyl)carbamate (0.294 g, 72%) which was used for the next step without further purification.

[0378] LCMS (AA: ACN): m / z: 542.2 [M+H]+(Boc pattern); tR = 3.57 min in 5 min run.

[0379] Step-5:(S)-1-(2-(((S)-1-aminopropan-2-yl)oxy)acetyl)-N-((4-(4-cyanophenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394853)]: To a stirred solution of tert-butyl (S)-(2-(2-oxo- 2-(3-(((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl) carbamoyl)piperidin-1- yl)ethoxy)ethyl)carbamate (0.294 g, 0.543 mmol, 1.0 eq.) in DCM (7.0 mL) at 0°C was added TFA (1.24 mL, 10.868 mmol, 20.0 eq.) dropwise and the reaction mixture was stirred for another 2 h at the same temperature (TLC). On completion, the mixture was concentrated under reduced pressure and co-evaporated two times with DCM. Crude residue was purified by reverse phase preparative HPLC [YMC Actus Triart C-18, ACN, 20 mM NH4HCO3 aqueous buffer] to afford (S)- 1-(2-(((S)-1-aminopropan-2-yl)oxy)acetyl)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (0.030 g, 13%) as white solid.

[0380] 1H NMR (400 MHz, DMSO-D6, 100°C ): 5 8.65 (brs, 1H), 8.19 (s, 1 H), 8.12 (d, J = 7.6 Hz, 2H), 7.86 (d, J = 7.6 Hz, 2H), 4.67-4.58 (m, 3H), 4.40-4.08 (m, 3H), 4.07-3.85 (m, 1 H), 3.49- 3.86 (m, 1 H), 2.62-2.55 (m, 1 H), 1.99-1.91 (m, 1H), 1.76-1.62 (m, 2H), 1.48-1.32 (m, 1 H), 1.10- 1.01 (m, 3H) ppm [NH2 protons are not observed clearly],

[0381] HPLC purity: 93.13%.

[0382] LCMS (FA: ACN): m / z 442.29 [M+H]+, tR = 2.20 min in 5 min run.Example 29: Synthesis of SW394881-1

[0383] (S)-1-(2-(((R)-1-aminopropan-2-yl)oxy)acetyl)-N-((4-(4-cyanophenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide. Synthesized in analogy to SW394853.

[0384] 1H NMR (400 MHz, DMSO-D6, 100°C ): 5 8.56 (brs, 1H), 8.21 (s, 1 H), 8.12 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 4.63 (s, 2H), 4.21-4.08 (m, 2H), 4.01-3.88 (m, 2H), 3.45-3.37 (m, 1 H), 2.95-2.82 (m, 2H, overlapped with DMSO-water peak), 2.62-2.56 (m, 2H), 2.49-2.40 (m, 1 H, overlapped with DMSO residual peak), 2.00-1.91 (m, 1H), 1.77-1.65 (m, 2H), 1.49-1.38 (m, 1 H), 1.09 (d, J - 6.0 Hz, 3H) [NH2-peak was not observed] clearly].

[0385] HPLC purity: 95.55%.

[0386] LCMS (FA: ACN): m / z 442.29 [M+H]+, tR = 2.24 min in 5 min run.Example 30: Synthesis of SW394854

[0387] (S)-1-(2-((S)-2-aminopropoxy)acetyl)-N-((4-(4-cyanophenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide. Synthesized in analogy to SW394853.

[0388] 1H NMR (400 MHz, DMSO-D6, 100°C ): 68.68 (m, 1 H), 8.19 (s, 1 H), 8.12 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 4.61-4.59 (m, 2H), 4.19-4.14 (m, 2H), 4.08-3.81 (m, 2H), 3.34-3.10 (m, 2H), 2.95-2.85 (m, 3H) overlapped with DMSO water peak, 2.51-2.49 (m, 1 H) overlapped with DMSO residual peak, 2.02-1.92 (m, 1 H), 1.81-1.59 (m, 2H), 1.51-1.39 (m, 1 H), 0.95-0.87 (m, 3H) [NH2 peak was not observed clearly],

[0389] HPLC purity: 98.12%.

[0390] LCMS (FA: ACN): m / z 442.29 [M+H]+, tR = 2.20 min in 5 min run.Example 31 : Synthesis of SW394856

[0391] (S)-1-(2-((R)-2-aminopropoxy)acetyl)-N-((4-(4-cyanophenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide. Synthesized in analogy to SW394853.

[0392] Isolated as TFA salt.1H NMR (400 MHz, DMSO-D6, 100°C ): 5 8.65 (brs, 1 H), 8.21 (s, 1 H), 8.12 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.81 (brs, 3H) overlapped, 4.72-4.57 (m, 2H), 4.39-4.25 (m, 2H), 3.92-3.65 (m, 4H), 3.50-3.35 (m, 2H, overlapped with DMSO water peak), 3.08-2.98 (m, 1 H), 2.50-2.48 (m, 1H, overlapped with DMSO residual peak), 2.01-1.94 (m, 1 H), 1.81-1.65 (m, 2H), 1.50-1.34 (m, 1 H), 1.17 (d, J = 4.8 Hz, 3H).

[0393] HPLC purity: 99.38%.

[0394] LCMS (FA: ACN): m / z 442.29 [M+H]+, tR = 2.32 min in 5 min run.Example 32: Synthesis of SW394860

[0395] (S)-1-(2-(2-amino-2-methylpropoxy)acetyl)-N-((4-(4-cyanophenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide. Synthesized in analogy to SW394853.

[0396] 1H NMR (400 MHz, DMSO-D6, 100°C ): 6 8.57 (brs, 1H), 8.17 (s, 1 H), 8.11 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 4.63 (d, J = 5.6 Hz, 2H), 4.16 (s, 2H), 4.10-3.85 (m, 2H), 3.17 (s, 2H), 2.51-2.42 (m, 3H, overlapped with DMSO residual peak), 1.99-1.89 (m, 1 H), 1.78-1.62 (m, 2H), 1.50-1.35 (m, 1H), 1.01 (m, 6H).

[0397] HPLC purity: 97.24%

[0398] LCMS (FA: ACN): m / z 456.31 [M+H]+, tR = 2.24 min in 5 min run.Example 33: Synthesis of SW394887-1

[0399] Scheme:

[0400] Step-1 : Ethyl 2-((1-((tert-butoxycarbonyl)amino)-2-methylpropan-2-yl)oxy)acetate(2): To a stirred solution of tert-butyl (2-hydroxy-2-methylpropyl)carbamate (0.350 g, 1.849 mmol, 1.0 eq.) in DCM ( 6 mL) was added Rh(ll) acetate dimer (0.082 g, 0.018 mmol, 0.01 eq.) followed by ethyl diazoacetate (0.195 mL, 1.849 mmol, 1.0 eq.) dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 6 h (LCMS). The reaction mixture was then diluted with DCM, filtered through celite pad. The filtrate was concentrated under reduced pressure to afford crude ethyl 2-((1-((tert-butoxycarbonyl)amino)-2-methylpropan-2-yl)oxy)acetate which was used for the next step without further purification [~70% LCMS pure, crude weight was greater than 100% conversion],

[0401] LCMS (AA: ACN): m / z: 276.2 [M+H]+(Boc pattern), tR = 3.33 min in 5 min run.

[0402] Step-2: 2-((1-((tert-butoxycarbonyl)amino)-2-methylpropan-2-yl)oxy)acetic acid(3): To a stirred solution of ethyl 2-((1-((tert-butoxycarbonyl)amino)-2-methylpropan-2- yl)oxy)acetate (0.200 g, 0.722 mmol, 1.0 eq.) in MeOH and H2O (5 mL, 3:2) was added LiOH.H2O (0.152 g, 3.61 mmol, 5.0 eq.) and the resulting mixture was stirred at room temperature for 16 h (TLC, KMnC>4 marker). On completion, the mixture was concentrated under reduced pressure and again diluted with water, acidified 10% with citric acid solution (aq.) and extracted with ethyl acetate (3x). Organic fractions were combined, dried over by sodium sulphate and concentrated under reduced pressure to get crude 2-((1-((tert-butoxycarbonyl)amino)-2-methylpropan-2- yl)oxy)acetic acid which was used for the next step without further purification considering quantitative conversion.

[0403] LCMS (AA: ACN): m / z: 248.0 [M+H]+(Boc pattern), tR = 2.01 min in 5 min run [very poor UV response],

[0404] Step-3 & 4: tert-butyl (S)-(2-(2-(3-(((4-(4-cyanophenyl)thiazol-2-yl)methyl) carbamoyl)piperidin-1-yl)-2-oxoethoxy)-2-methylpropyl)carbamate (5): To a stirred solution of 2-((1-((tert-butoxycarbonyl)amino)-2-methylpropan-2-yl)oxy)acetic acid (0.083 g, 0.336 mmol, 1.1 eq) in DMF (2 mL) were added DIPEA (0.106 mL, 0.612 mmol, 2.0 eq.) and HATU (0.139 g, 0.367 mmol, 1.2 eq.) at 0°C. After 10 min, (S)-N-((4-(4-cyanophenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide (0.100 g, 0.306 mmol, 1.0 eq.) was added and the reaction mixture was warmed to room temperature and stirred overnight (LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure to afford crude tert-butyl (S)-(2-(2-(3-(((4-(4-cyanophenyl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)-2-oxoethoxy)-2- methylpropyl)carbamate (43 mg, 25% based on LCMS purity) which was used for the next step N-Boc deprotection without further purification. [Crude weight of product was higher than 100% conversion as DMF contaminated with the product after workup],

[0405] Final step deprotection reaction was done using the combined product from two batches (100 mg + 200 mg scale with respect to amine 4).

[0406] LCMS (AA: ACN): m / z: 342.2 [M+H]+(Boc pattern), tR = 2.68 min in 5 min run.

[0407] (S)-1-(2-((1-amino-2-methylpropan-2-yl)oxy)acetyl)-N-((4-(4-cyanophenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394887-1]: To a stirred solution of tert-butyl (S)-(2-(2-(3- (((4-(4-cyanophenyl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)-2-oxoethoxy)-2- methylpropyl)carbamate (0.130 g, 0.234 mmol, 1.0 eq.) in DCM (5.0 mL) at 0°C was added TFA (0.54 mL, 7.027 mmol, 30.0 eq.) dropwise and the reaction mixture was stirred for another 2 h at the same temperature (TLC). On completion, the mixture was concentrated under reduced pressure and co-evaporated two times with DCM. Crude residue was purified by reverse phase preparative HPLC [KINETEX, EVO C-18, ACN, 0.1% TFA aqueous buffer] to afford (S)-1-(2-((1- amino-2-methylpropan-2-yl)oxy)acetyl)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (0.017 g, 13%) as TFA salt, white solid.

[0408] 1H NMR (400 MHz, DMSO-D6, 100°C): <58.93-8.86 (m, 1 H), 8.31 (s, 1 H), 8.13 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 8.02-7.85 (brs, 2H, overlapped with aromatic proton), 4.75-4.49 (m, 3H), 4.42-4.23 (m, 3H), 4.01-3.92 (m, 1 H), 3.73-3.61 (m, 1H), 3.02-2.70 (m, 5H), 2.49-2.41 (m, 1 H), 2.01-1.90 (m, 1H), 1.79-1.58 (m, 2H), 1.53-1.30 (m, 1 H), 1.20 (s, 6H).

[0409] HPLC purity: 99.28%.

[0410] LCMS (FA: ACN): m / z 456.35 [M+H]+, tR = 2.21 min in 5 min run.Example 34: Synthesis of SW394805-1

[0411] Scheme:

[0412] Step-1 : 2-(3-((tert-butoxycarbonyl)amino)propoxy)acetic acid (2): Prepared following slightly modified literature reported procedure [PCT Int. Appl., 2012004005], To a stirred solution of tert-butyl (3-hydroxypropyl)carbamate (0.500 g, 2.85 mmol) in THF (10 ml_) was added bromoacetic acid (0.196 g, 1.43 mmol, 0.5 eq.) and the solution was cooled to 0°C. To this solution was added NaH (60% in mineral oil, 0.171 g, 4.27 mmol, 1.5 eq.) in portions. Ice-bath was removed, and the mixture was stirred at room temperature for 4 h. The reaction mixture was then quenched with ice-water, acidified with 10% aq. citric acid solution and extracted with ethyl acetate to get 2-(3-((tert-butoxycarbonyl)amino)propoxy)acetic acid (0.380 g, 47%) as colorless gum which was used for the next step without further purification.

[0413] 1H NMR (400 MHz, CDCI3): 54.93 (brs, 1 H,), 4.10 (s, 2H); 3.60 (t, J = 6.0 Hz, 2H); 3.35- 3.16 (m, 2H); 1.83-1.69 (m, 2H); 1.43 (s, 9H).

[0414] Step-2: tert-butyl (S)-(3-(2-(3-(((4-(4-cyclopropylphenyl)thiazol-2- yl)methyl)carbamoyl) piperidin-1-yl)-2-oxoethoxy)propyl)carbamate (4): To a stirred solution of 2-(3-((tert-butoxycarbonyl)amino)propoxy)acetic acid (0.376 g, 1.611 mmol, 1.1 eq.) in DMF (6 ml_), were added DIPEA (0.64 mL, 3.661 mmol, 2.5 eq.) and HATU (0.668 g, 1.757 mmol, 1.2 eq.) at 0°C. After 10 min, (S)-N-((4-(4-cyclopropylphenyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (0.500 g, 0.612 mmol, 1.0 eq.) was added. The reaction mixture was warmed to room temperature and stirred for 16 h (LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. Crude residue was purified by flash column chromatography to afford tert-butyl (S)-(3-(2-(3-(((4-(4-cyclopropylphenyl)thiazol-2- yl)methyl)carbamoyl)piperidin-1-yl)-2-oxoethoxy)propyl) carbamate (0.302 g, 37%) as brown sticky oil.

[0415] LCMS (AA: ACN): m / z: 557.0 [M+H]+; tR = 3.40 min in 5 min run (Boc-pattern).

[0416] Step-3: (S)-1-(2-(3-aminopropoxy)acetyl)-N-((4-(4-cyclopropylphenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394805-1]: To a stirred solution of tert-butyl (S)-(3-(2- (3-(((4-(4-cyclopropylphenyl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)-2-oxoethoxy)propyl) carbamate (0.300 g, 0.538 mmol, 1.0 eq.) in DCM (10.0 ml_) at 0°C was added TFA (1.23 ml_, 16.17 mmol, 30.0 eq.) dropwise and the reaction mixture was stirred for another 2 h at the same temperature (TLC). On completion, the mixture was concentrated under reduced pressure and co-evaporated two times with DCM. Crude residue was purified by reverse phase preparative HPLC [SUNFIRE C-18, ACN, 0.1 % TFA aqueous buffer] to afford (S)-1-(2-(3- aminopropoxy)acetyl)-N-((4-(4-cyclopropylphenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.106 g, 35%) as TFA salt, colorless sticky gum.

[0417] 1H NMR (400 MHz, DMSO-D6, 100°C): 58.56 (brs, 1 H), 7.95-7.55 (m, 6H), 7.14 (d, J = 8.0 Hz, 2H), 4.70-4.53 (m, 2H), 4.25 (s, 2H), 4.02-3.66 (m, 2H), 3.57 (s, 2H), 3.40-3.05 (m, 1 H), 2.97 (s, 2H), 2.53 (s, 1H), 2.00-1.91 (m, 2H), 1.90-1.80 (m, 2H), 1.79-1.65 (m, 2H), 1.51-1.38 (m, 1 H), 1.00-0.93 (m, 2H), 0.72-0.67 (m, 2H) ppm, [mixture of rotamers observed at room temperature],

[0418] HPLC purity: 98.64%.

[0419] LCMS (AA: ACN): m / z: 457.2 [M+H]+; tR = 2.31 min in 5 min run.Example 35: Synthesis of SW394808-1

[0420] Scheme:

[0421] Step-1 8> 2: 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)acetic acid (3): This compound was prepared following the literature reported method [Org. Biomol. Chem., 2016,14, 3950-3955], A solution of NaOH pellets (1.07 g, 26.628 mmol, 1 eq.) in water (25 mL) was added to a solution of 2-methylaminoethanol (2.0 g, 26.628 mmol, 1.0 eq.) in DCM (25 mL). To this mixture, a solution of chloroacetyl chloride (2.12 mL, 26.628 mmol, 1.0 eq.) in dry DCM (40 mL)was added dropwise over the course of 30 min. The reaction mixture was warmed to room temperature and stirred for 20 h. The biphasic mixture was separated, and the organic layer was concentrated to get a colorless oil which was subsequently re-dissolved in EtOH (35 mL). KOH powder (1.5 g, 26.733 mmol) was added to the mixture and the reaction was stirred at 45°C for 10 h. A second portion of KOH (1.5 g, 26.733 mmol) was added to the mixture and the reaction mixture was heated at 90°C under a reflux condenser for 15 h. The mixture was cooled to room temperature, diluted with EtOH (35 mL). To this mixture Boc-anhydride (12.24 mL, 53.255 mmol, 1.0 eq.) was added dropwise and stirred at room temperature for 5 h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was acidified with 1(N) HCI at 0°C and extracted with ethyl acetate (3x). The combined organic phase was dried over Na2SO4, concentrated to get 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)acetic acid (1.3 g, 21%) as colorless oil which was used for the next step without further purification.

[0422] 1H NMR (400 MHz, CDCI3): 54.11 (s, 2H), 3.71-3.66 (m, 2H), 3.48-3.39 (m, 2H), 2.91 (s, 3H), 1.44 (s, 9H).

[0423] Step-3: tert-butyl (S)-(2-(2-(3-(((4-(4-cyanophenyl)thiazol-2-yl)methyl) carbamoyl)piperidin-1-yl)-2-oxoethoxy)ethyl)(methyl)carbamate (5): To a stirred solution of 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)acetic acid (0.236 g, 1.011 mmol, 1.1 eq) in DMF (3 mL) were added DIPEA (0.32 mL, 1.838 mmol, 2.0 eq.) and HATU (0.419 g, 1.103 mmol, 1.2 eq.) at 0°C. After 10 min, a solution of (S)-N-((4-(4-cyanophenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide (0.300 g, 0.919 mmol, 1.0 eq.) in DMF (2 mL) was added and the reaction mixture was warmed to room temperature and stirred overnight (LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. Crude residue was purified by flash column chromatography (5% MeOH in DCM) to afford tert-butyl (S)- (2-(2-(3-(((4-(4-cyanophenyl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)-2-oxoethoxy)ethyl) (methyl)carbamate (0.150 g, 30%) brown semisolid.

[0424] LCMS (AA: ACN): m / z: 542.0 [M+H]+(Boc pattern); tR = 3.59 min in 5 min run.

[0425] Step-4:(S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2-(2-(methylamino)ethoxy)acetyl)piperidine-3-carboxamide [SW394808-1]: To a stirred solution of tert-butyl (S)-(2-(2-(3-(((4-(4-cyanophenyl)thiazol-2-yl)methyl)carbamoyl)piperidin-1-yl)-2- oxoethoxy)ethyl)(methyl)carbamate (0.150 g, 0.277 mmol, 1.0 eq.) in DCM (5.0 mL) at 0°C was added TFA (0.64 mL, 8.307 mmol, 30.0 eq.) dropwise and the reaction mixture was stirred for another 2 h at the same temperature (TLC). On completion, the mixture was concentrated under reduced pressure and co-evaporated two times with DCM. Crude residue was purified by reversephase preparative HPLC [YMC Actus Triart C-18, ACN, 20 mM NH4HCO3 aqueous buffer] to afford (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2-(2-(methylamino)ethoxy)acetyl) piperidine-3-carboxamide (0.022 g, 18%) as white solid.

[0426] 1H NMR (400 MHz, DMSO-D6, 100°C ): 5 8.57 (brs, 1H), 8.17 (s, 1 H), 8.12 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 4.65-4.59 (m, 2H), 4.18-4.05 (m, 3H), 3.99-3.90 (m, 2H), 3.51 (t, J = 5.6 Hz, 2H), 2.91-2.85 (m, 1 H, overlapped with DMSO water peak), 2.66 (t, J = 5.6 Hz, 2H), 2.49-2.48 (m, 1 H, overlapped with DMSO residual peak) 2.31 (s, 3H), 1.96-1.91 (m, 1 H), 1.75- 1.66 (m, 2H), 1.46-1.37 (m, 1H) ppm.

[0427] HPLC purity: 99.45%.

[0428] LCMS (AA: ACN): m / z 442.2 [M+H]+, tR = 1 .95 min in 5 min run.Example 36: Synthesis of SW394859

[0429] Scheme:

[0430] Step-1 :

[0431] (S)-1-(2-(2-chloroethoxy)acetyl)-N-((4-(4-cyanophenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide (3): To a stirred solution of 2-(2-chloroethoxy)acetic acid (0.093 g, 0.673 mmol, 1.1 eq.) in DMF (4 mL), were added DIPEA (0.21 mL, 1.223 mmol, 2.0 eq.) and HATU (0.279 g, 0.734 mmol, 1.2 eq.) at 0°C. After 5 min, (S)-N-((4-(4-cyanophenyl)thiazol- 2-yl)methyl)piperidine-3-carboxamide (0.200 g, 0.612 mmol, 1.0 eq.) was added. The reaction mixture was warmed to room temperature and stirred overnight (TLC / LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure to afford crude (S)-1-(2-(2-chloroethoxy)acetyl)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)piperidine- 3- carboxamide (0.245 g, 89%) as brown gum which was used for next step without further purification.

[0432] LCMS (AA: ACN): m / z: 447.0 [M+H]+; tR = 3.07 min in 5 min run.

[0433] Step-2: (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2-(2-(pyrrolidin-1- yl)ethoxy)acetyl)piperidine-3-carboxamide [SW394859)]: To a stirred solution of pyrrolidine (0.041 mL, 0.492 mmol, 1.0 eq.) in acetonitrile (8 mL) were added K2CO3 (0.204 g, 1.477 mmol, 2.0 eq.) and Nal (0.015 g, 0.098 mmol, 0.2 eq.) ethyl 5-bromoisoxazole-3-carboxylate (0.167 g, 0.758 mmol, 1.2 eq.) and (S)-1-(2-(2-chloroethoxy)acetyl)-N-((4-(4-cyanophenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide (0.242 g, 0.541 mmol, 1.1 eq.) sequentially and the mixture was heated at 80°C for 6 h (TLC / LCMS). On completion, the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by reverse phase Prep HPLC [(X-Bridge C-18, MeOH, 20 mM NH4HCO3 aqueous buffer] to afford (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2-(2-(pyrrolidin-1-yl)ethoxy)acetyl) piperidine-3-carboxamide (0.037 g, 10%) as white solid.

[0434] 1H NMR (400 MHz, DMSO-D6100°C): 8.56 (brs, 1 H), 8.22 (s, 1 H), 8.17 (s, 1H), 8.12 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 4.63 (s, 2H), 4.13 (s, 2H), 4.11-3.84 (m, 2H), 3.55 (t, J = 6.0 Hz, 2H), 2.95-2.82 (m, 2H) overlapped with DMSO water peak, 2.61 (t, J = 6.0 Hz, 2H), 2.50-2.36 (m, 5H) overlapped with DMSO residual peak, 2.01-1.91 (m, 2H), 1.78-1.61 (m, 6H), 1.49-1.36 (m, 1 H).

[0435] HPLC purity: 99.16%.

[0436] LCMS (FA: ACN): m / z: 482.36 [M+H]+; tR = 2.23 min in 5 min run.Example 37: Synthesis of SW394803-1

[0437] Scheme:

[0438] (S)-1-(2-Aminooxazole-5-carbonyl)-N-((4-(4-(trifluoromethyl)phenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394803-1]: To a stirred solution of 2-aminooxazole-5- carboxylic acid (0.035 g, 0.271 mmol, 1.0 eq.) in DMF (3 mL) at O°C, were added NMM (0.075 mL, 0.677 mmol, 2.5 eq.) and TBTU (0.130 g, 0.407 mmol, 1.5 eq.). After 5 min, (S)-N-((4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.100 g, 0.271 mmol,1 .0 eq.) was added, the reaction mixture was warmed to room temperature and stirred overnight (TLC I LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was dried (Na2SO4) and concentrated under reduced pressure. Crude residue was purified by reverse phase Prep HPLC [YMC Actus Triart C18, AON, 20mM NH4HCO3 (aq.) buffer] to afford (S)-1-(2-aminooxazole-5-carbonyl)-N-((4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.043 g, 33%).

[0439] 1H NMR (400 MHz, DMSO-D6): 58.95 (t, J = 5.8 Hz, 1 H), 8.25 (s, 1 H), 8.16 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.30 (s, 1 H), 7.22 (brs, 2H), 4.62 (d, J = 5.8 Hz, 2H), 4.32 (d, J = 11.6 Hz, 1 H), 4.19 (d, J = 12.4 Hz, 1 H), 3.09-2.91 (m, 2H), 2.48-2.39 (m, 1H), 1.95 (d, J = 11.6 Hz, 1 H), 1.78-1.65 (m, 2H), 1.49-1.36 (m, 1 H).

[0440] HPLC purity: 99.66%.

[0441] LCMS (AA: ACN): m / z: 478.0 [M-H]+; tR = 2.41 min in 5 min run.Example 38: Synthesis of SW394804-1

[0442] Scheme:

[0443] (S)-1-(2-Aminooxazole-5-carbonyl)-N-((4-(4-cyclopropylphenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394804-1]: To a stirred solution of 2-aminooxazole-5- carboxylic acid (0.094 g, 0.732 mmol, 1.0 eq.) in D F (4 mL) at O°C, were added NMM (0.201 mL, 1.83 mmol, 2.5 eq.) and TBTU (0.352 g, 1.1 mmol, 1.5 eq.). After 5 min, (S)-N-((4-(4- cyclopropylphenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.250 g, 0.732 mmol, 1.0 eq) was added, the reaction mixture was warmed to room temperature and stirred overnight (TLC / LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by reverse phase Prep HPLC [KINETEX C18, MeOH, 10mM NH4OAC (aq.) buffer] to afford (S)-1-(2-aminooxazole-5-carbonyl)-N-((4-(4-cyclopropylphenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide (0.040 g, 12%).

[0444] 1H NMR (400 MHz, DMSO-D6): 58.89 (t, 1 H, J = 5.5 Hz), 7.87 (s, 1 H), 7.78 (d, 2H, J = 8.0 Hz, 2H), 7.27 (s, 1H), 7.20 (s, 2H ), 7.10 (d, J = 8.0 Hz, 2H), 4.56 (d, J = 5.2 Hz, 2H), 4.30 (d, J = 12.0 Hz, 1 H), 4.17 (d, J = 12.6 Hz, 1 H), 3.07-2.87 (m, 2H), 2.45-2.32 (m, 1 H), 1.96-1.86 (m, 2H), 1.75-1.62 (m, 2H), 1.45-1.33 (m, 1 H), 0.94 (d, J = 8.0 Hz, 2H), 0.68 (d, J = 4.8 Hz, 2H).

[0445] HPLC purity: 96.37%.

[0446] LCMS (AA: ACN): m / z: 452.1 [M+H]+; tR = 2.37 min in 5 min run.Example 39: Synthesis of SW394855

[0447] Scheme:

[0448] Step-1 : 2-Amino-4-methyloxazole-5-carboxylic acid (2): To a stirred solution of ethyl 2-amino-4-methyloxazole-5-carboxylate (0.200 g, 1.271 mmol, 1.0 eq.) in water (5 mL) was added 10% aq. NaOH (3 mL) and the mixture was stirred at room temperature for overnight (LCMS). On completion, the mixture was cooled to 0°C, acidified with 2N HCI. Solid precipitate formed, which was collected by filtration, dried under vacuum to get 2-amino-4-methyloxazole-5- carboxylic acid (0.100 g, 55%) as white solid.

[0449] 1H NMR (400 MHz, DMSO-D6): 5 12.35 (brs, 1 H), 7.29 (s, 2H), 2.20 (s, 3H) ppm.

[0450] Step-2: (S)-1-(2-amino-4-methyloxazole-5-carbonyl)-N-((4-(4-cyanophenyl)thiazol- 2-yl)methyl)piperidine-3-carboxamide [SW394855]: To a stirred solution of 2-amino-4- methyloxazole-5-carboxylic acid (0.096 g, 0.673 mmol, 1.0 eq.) in DMF (4 mL), were added N- Methylmorpholine (0.185 mL, 1.68 mmol, 2.5 eq.) and TBTU (0.346 g, 1.077 mmol, 1.6 eq.) at 0°C. After 5 min, (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.220 g, 0.673 mmol, 1.0 eq) was added and the reaction mixture was warmed to room temperature and stirred for overnight (LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by reverse phase Prep HPLC YMC Actus Triart C18, ACN, 20mm NH4HCO3 (aq.) buffer] to afford (S)-1-(2-amino-4-methyloxazole-5-carbonyl)-N-((4- (4-cyanophenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.030 g, 10%).

[0451] 1H NMR (400 MHz, DMSO-D6): 58.94-8.89 (m, 1 H), 8.29 (s, 1 H), 8.13 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.05 (s, 2H), 4.60 (d, J = 6.0 Hz, 2H), 4.26 (d, J = 12.8 Hz, 1 H), 4.14 (d, J = 12.8 Hz, 1 H), 3.02-2.90 (m, 2H), 2.49-2.48 (m, 1 H), 2.12 (s, 3H), 1.99-1.88 (m, 1 H), 1.78- 1.61 (m, 2H), 1.49-1.35 (m, 1H) ppm.

[0452] HPLC purity: 99.79%.

[0453] LCMS (FA: ACN): m / z: 451.26 [M+H]+; tR = 2.190 min in 5 min run.Example 40: Synthesis of SW394810-1

[0454] Scheme:

[0455] Step-1 : Ethyl 2-(methylamino)oxazole-5-carboxylate (2): To a stirred solution of ethyl 2-chlorooxazole-5-carboxylate (0.400 g, 2.278 mmol, 1.0 eq.) in THF (6 mL), was added a solution of methylamine in THF (2M, 4.56 mL, 9.112 mmol, 4.0 eq.) and the mixture was stirred to room temperature for overnight (TLC). On completion, the mixture was concentrated under reduced pressure and triturated with diethyl ether and pentane (3:7) to get ethyl 2- (methylamino)oxazole-5-carboxylate (0.280 g, 72%).

[0456] 1H NMR (400 MHz, DMSO-D6): <58.03-7.93 (m, 1 H), 7.62 (s, 1 H), 4.20 (q, J = 7.2 Hz, 2H), 2.83 (d, J = 4.4 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H) ppm.

[0457] LCMS (FA: ACN): m / z: 171.12 [M+H]+; tR = 1.48 min in 3 min run.

[0458] Step-2: 2-(Methylamino)oxazole-5-carboxylic acid (3): To a stirred solution of ethyl 2-(methylamino)oxazole-5-carboxylate (0.260 g, 1.529 mmol, 1.0 eq.) in MeOH and water (5:2, 7 mL) was added UOH.H2O (0.321 g, 7.645 mmol, 5.0 eq.) in portions at 0°C. The mixture was warmed to room temperature and stirred overnight (LCMS). On completion, the mixture was concentrated under reduced pressure and again diluted with water, acidified with 2N HCI and extracted with EtOAc (3x). The combined organic phase was dried (Na2SO4) and concentrated under vacuum to afford 2-(methylamino)oxazole-5-carboxylic acid (0.170 g, 78%) which was used for the next step without further purification.

[0459] LCMS (AA: ACN): m / z: 142.2 [M]+; tR = 0.56 min in 5 min run.

[0460] Step-3: (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2-(methylamino)oxazole- 5-carbonyl)piperidine-3-carboxamide [SW394810-1]: To a stirred solution of 2- (methylamino)oxazole-5-carboxylic acid (0.143 g, 1.00 mmol, 1.1 eq.) in DMF (3 mL), were added DIPEA (0.32 mL, 1.835 mmol, 2.0 eq.) and HATU (0.418 g, 1.101 mmol, 1.2 eq.) at 0°C. After 10min, (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.300 g, 0.917 mmol, 1.0 eq) was added and the reaction mixture was warmed to room temperature and stirred for overnight (TLC I LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by reverse phase Prep HPLC [YMC Triart C18, AON, 20 mm NH4HCO3 (aq.) buffer] to afford (S)-N-((4-(4-cyanophenyl)thiazol- 2-yl)methyl)-1-(2-(methylamino)oxazole-5-carbonyl)piperidine-3-carboxamide (0.040 g, 10%).

[0461] 1H NMR (400 MHz, DMSO-D6): 68.60 (brs, 1 H), 8.17 (s, 1 H), 8.12 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.29 (brs, 1 H), 4.67-4.62 (m, 2H), 4.32 (d, J = 12.8 Hz, 1 H), 4.17 (d, J = 12.8 Hz, 1 H), 4.09-3.70 (m, 1 H), 3.21-3.09 (m, 1 H), 2.83 (d, J = 4.0 Hz, 3H), 2.48-2.37 (m, 1 H), 2.01-1.90 (m, 1 H), 1.80-1.57 (m, 2H), 1.52-1.38 (m, 1 H) ppm.

[0462] HPLC purity: 99.74%.

[0463] LCMS (FA: AON): m / z: 451.29 [M+H]+; tR = 2.21 min in 5 min run.Example 41 : Synthesis of SW394807-1

[0464] Scheme:

[0465] Step-1 : Ethyl 2-(dimethylamino)oxazole-5-carboxylate (2): To a stirred solution of ethyl 2-chlorooxazole-5-carboxylate (0.550 g, 3.133 mmol, 1.0 eq.) in THF (8 mL), was added a solution of dimethylamine in THF (2M, 6.26 mL, 12.531 mmol, 4.0 eq.) and the mixture was stirred to room temperature for overnight (TLC). On completion, the mixture was concentrated under reduced pressure and triturated with diethyl ether and pentane (3:7) to get ethyl 2- (dimethylamino)oxazole-5-carboxylate (0.200 g, 35%) which was used for the next step without further purification.

[0466] 1H NMR (400 MHz, DMSO-D6): 6 7.67 (s, 1 H), 4.22 (q, J = 7.2 Hz, 2H), 3.05 (s, 6H), 1.25 (t, J = 7.2 Hz, 3H) ppm.

[0467] LCMS (AA: ACN): m / z: 185.1 [M+H]+; tR = 2.64 min in 5 min run.

[0468] Step-2: 2-(Dimethylamino)oxazole-5-carboxylic acid (3): To a stirred solution of (S)- 1-(3-(hydroxymethyl)-1 ,2,4-oxadiazol-5-yl)-N-((4-(6-methylpyridin-3-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide (0.260 g, 1.413 mmol, 1.0 eq.) in MeOH and water (5:2, 10 mL) was added LiOH (0.297 g, 7.065 mmol, 5.0 eq.) in portions at 0°C. The mixture was warmed to room temperature and stirred for overnight (LCMS). On completion, the mixture was concentrated under reduced pressure and again diluted with water, acidified with 2N HCI and extracted with EtOAc (3x). Combined organic phase was dried (Na2SO4) and concentrated under vacuum to afford 2-(dimethylamino)oxazole-5-carboxylic acid (0.100 g, 45%) which was used for the next step without further purification.

[0469] LCMS (AA: ACN): m / z: 156.0 [M]+; tR = 1.35 min in 5.5 min run.

[0470] Step-3: (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2-(dirnethylamino) oxazole-5-carbonyl)piperidine-3-carboxamide [SW394807-1]: To a stirred solution of 2- (dimethylamino)oxazole-5-carboxylic acid (0.078 g, 0.336 mmol, 1.1 eq.) in DMF (4 mL), were added DIPEA (0.133 mL, 0.765 mmol, 2.5 eq.) and HATU (0.140 g, 0.367 mmol, 1.2 eq.) at 0°C. After 5 min, (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.100 g, 0.306 mmol, 1.0 eq) was added and the reaction mixture was warmed to room temperature and stirred for overnight (TLC I LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by reverse phase Prep HPLC YMC Triart C18, ACN, 20mm NH4HCO3 (aq.) buffer] to afford (S)-N-((4-(4-cyanophenyl)thiazol-2- yl)methyl)-1-(2-(dimethylamino)oxazole-5-carbonyl)piperidine-3-carboxamide (0.016 g, 11 %).

[0471] 1H NMR (400 MHz, DMSO-D6): 68.94 (t, J = 6.0 Hz, 1 H), 8.31 (s, 1 H), 8.13 (d, J = 8.4 Hz, 1 H), 7.90 (d, J = 8.4 Hz, 2H), 7.39 (s, 1 H), 4.61 (d, J = 6.0 Hz, 2H), 4.55-4.37 (m, 1 H), 4.24- 4.16 (m, 1 H), 3.15-2.90 (m, 8H overlapped with N-Methyl peaks), 2.51-2.41 (m, 1 H), 2.04-1.88 (m, 1 H), 1.79-1.65 (m, 2H), 1.48-1.32 (m, 1 H) ppm.

[0472] HPLC purity: 95.62.

[0473] LCMS (FA: ACN): m / z: 465.25 [M+H]+; tR = 2.53 min in 5 min run.Example 42: Synthesis of SW394851

[0474] Scheme:

[0475] Step-1 : 2-Aminooxazole-4-carboxylic acid (2): To a stirred solution of ethyl 2- aminooxazole-4-carboxylate (0.200 g, 1.281 mmol, 1.0 eq.) in water (5 mL) was added 10% aq. NaOH (5 mL) and the mixture was stirred at room temperature for overnight (LCMS). On completion, the mixture was cooled to 0°C, acidified with 2N HCI. Solid precipitate formed, which was collected by filtration, dried under vacuum to get 2-aminooxazole-4-carboxylic acid (0.100 g, 61%) as white solid.

[0476] 1H NMR (400 MHz, DMSO-D6): 6 12.48 (s, 1 H), 10.53 (s, 1 H), 10.41 (s, 1 H) ppm.

[0477] LCMS (AA: ACN): m / z: 126.8 [M-H]+; tR = 0.45 min in 6 min run.

[0478] Step-2: (S)-1-(2-aminooxazole-4-carbonyl)-N-((4-(4-cyanophenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394851]: To a stirred solution of 2-aminooxazole-4- carboxylic acid (0.039 g, 0.306 mmol, 1.0 eq.) in D F (2 mL) at O°C, were added NMM (0.095 mL, 0.734 mmol, 2.4 eq.) and TBTU (0.157 g, 0.489 mmol, 1.6 eq.). After 5 min, a solution of (S)-N- ((4-(4-cyanophenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.100 g, 0.306 mmol, 1.0 eq.) in DMF (1.0 mL) was added, the reaction mixture was warmed to room temperature and stirred overnight (TLC I LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was dried (Na2SO4) and concentrated under reduced pressure. Crude residue was purified by reverse phase Prep HPLC [YMC Actus Triart C18, ACN, 20 mM NH4HCO3 (aq.) buffer] to afford (S)-1-(2-aminooxazole-4-carbonyl)-N-((4-(4- cyanophenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.010 g, 8%).

[0479] 1H NMR (400 MHz, DMSO-D6): 5 10.35 (s, 1 H), 10.19 (s, 1 H), 8.95 (t, J = 6.0 Hz, 1 H), 8.30 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 1.6 Hz, 1H), 4.66-4.59 (m, 2H), 4.26 (d, J = 12.0 Hz, 1 H), 4.12 (d, J = 12.0 Hz, 1 H), 3.14-2.88 (m, 2H), 2.49-2.38 (m, 1 H), 1.99-1.89 (m, 1H), 1.76-1.63 (m, 2H), 1.51-1.33 (m, 1 H).

[0480] HPLC purity: 99.78%.

[0481] LCMS (FA: ACN): m / z: 437.23 [M+H]+; tR = 2.34 min in 5 min run.Example 43: Synthesis of SW394777-1

[0482] Scheme:

[0483] Step-1 : Ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)oxazole-5-carboxylate (2): To a stirred solution of tert-butyl piperazine-1 -carboxylate (0.250 g, 1.342 mmol 1.0 eq.) in DMF (5 mL) was added potassium carbonate (0.278 g, 2.013 mmol, 1.5 eq.) followed by ethyl 2- chlorooxazole-5-carboxylate (0.237 g, 1.342 mmol, 1.0 eq.) and the mixture was heated at 60°C for 2 h (TLC). On completion, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with cold water (3x) and brine. The organic phase was dried over anhydrous NasSOzi and concentrated under reduced pressure. Crude residue was purified by flash column chromatography (20-30% EtOAc in hexane) to get ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1- yl)oxazole-5-carboxylate (0.275 g, 63%).

[0484] 1H NMR (400 MHz, DMSO-D6): 57.71 (s, 1 H), 4.23 (q, J = 7.0 Hz, 2H), 3.59-3.37 (m, 8H), 1.42 (s, 9H), 1.25 (t, J = 7.0 Hz, 3H) ppm.

[0485] LCMS (AA: ACN): m / z: 326.2 [M+H]+(Boc-pattern), tR = 3.67 min in 6 min run.

[0486] Step-2: 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)oxazole-5-carboxylic acid (3): To a stirred solution of ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)oxazole-5-carboxylate (0.370 g, 1.137 mmol) in MeOH (4 ml_) was added LiOH.H2O (0.913 g, 21.739 mmol, dissolved in 2 ml_ water) at 0°C. Cold bath was removed, the reaction mixture was stirred at room temperature for overnight. After completion, the reaction mixture was concentrated under vacuo, water was added to the residue and acidified 10% aq. citric acid solution and extracted with EtOAc (4 x). Organic extracts were combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to get 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)oxazole-5-carboxylic acid (0.210 g, 62%) as off-white gum.

[0487] 1H NMR (400 MHz, DMSO-D6): 6 12.7 (brs, 1 H), 7.61 (s, 1H), 3.51-3.39 (m, 8H), 1.42 (s, 9H) ppm.

[0488] LCMS [AA: ACN]: m / z: 296.0 [M-H]+(Boc-pattern), tR = 2.26 min in 5 min run.

[0489] Step-3: tert-butyl (S)-4-(5-(3-(((4-(4-cyanophenyl)thiazol-2- yl)methyl)carbamoyl)piperidine-1-carbonyl)oxazol-2-yl)piperazine-1-carboxylate (5): To a stirred solution of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)oxazole-5-carboxylic acid (0.220 g, 0.741 mmol, 1.1 eq.) in DMF (4 mL), were added DIPEA (0.23 mL, 1.35 mmol, 2.0 eq.) and HATU (0.308 g, 0.809 mmol, 1.2 eq.) at 0°C. After 10 min, a solution of (S)-N-((4-(4-cyanophenyl)thiazol- 2-yl)methyl)piperidine-3-carboxamide (0.220 g, 0.674 mmol, 1.0 eq) in DMF (1 mL), the reaction mixture was warmed to room temperature and stirred overnight (LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (1-4% MeOH in DCM) to afford tert-butyl (S)-4-(5-(3- (((4-(4-cyanophenyl)thiazol-2-yl)methyl)carbamoyl) piperidine-1-carbonyl)oxazol-2-yl)piperazine- 1-carboxylate (0.122 g, 30%) as brown gum.

[0490] LCMS (AA: ACN): m / z: 606.0 [M+H]+; tR = 3.49 min in 6 min run.

[0491] Step-4: (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2-(piperazin-1-yl)oxazole-5- carbonyl)piperidine-3-carboxamide [SW394777-1]: To a stirred solution of tert-butyl (S)-4-(5-(3- (((4-(4-cyanophenyl)thiazol-2-yl)methyl) carbamoyl)piperidine-1-carbonyl)oxazol-2-yl)piperazine-1-carboxylate (0.120 g, 0.198 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.46 mL, 5.94 mmol) at 0°C and the reaction mixture was stirred at the same temperature for another 2 h (LCMS). On completion, reaction mixture was concentrated under reduced pressure and coevaporated with DCM (two times) to remove excess TFA. Crude residue was purified by reverse phase PREP HPLC [ATLANTIS C18, ACN, 0.1% TFA in water] to afford (S)-N-((4-bromothiazol-2-yl)methyl)piperidine-3-carboxamide as TFA-salt (0.030 g, 24%, white solid).

[0492] 1H NMR (400 MHz, DMSO-D6): 58.94 (t, J = 6.0 Hz, 1 H), 8.16 (brs, 1H), 8.31 (s, 1 H), 8.13 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.47 (s, 1 H), 4.65-4.56 (m, 2H), 4.29 (d, J = 12.4 Hz, 1 H), 4.16 (d, J = 12.8 Hz, 1 H), 3.70-3.64 (m, 4H), 3.29-3.15 (m, 4H), 3.13-2.95 (m, 2H), 2.50- 2.38 (m, 1 H), 2.01-1.89 (m, 1H), 1.80-1.67 (m, 2H), 1.50-1.35 (m, 1H) ppm.

[0493] HPLC purity: 97.68%.

[0494] LCMS (FA: ACN): m / z: 506.34 [M+H]+; tR = 3.49 min in 5 min run.Example 44: Synthesis of SW394774-1

[0495] Scheme:

[0496] Step-1 : tert-butyl (S)-4-(2-oxo-2-(3-(((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl) carbamoyl)piperidin-1-yl)ethoxy)piperidine-1-carboxylate (4): To a stirred solution of 2-((1-(tert- butoxycarbonyl)piperidin-4-yl)oxy)acetic acid (0.232 g, 0.893 mmol, 1.1 eq.) in DMF (4 mL), were added DIPEA (0.283 mL, 1 .624 mmol, 2.0 eq.) and HATU (0.371 g, 0.975 mmol, 1 .2 eq.) at 0°C. After 10 min, a solution of (S)-N-((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (0.300 g, 0.917 mmol, 1.0 eq) in DMF (1 mL) was added and the reaction mixture was warmed to room temperature and stirred overnight (TLC I LCMS). On completion, the mixture was diluted with 20% isopropanol in DCM, washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. Crude residue was purified by flash column chromatography (1-4% MeOH in DCM) to afford tert-butyl (S)-4-(2-oxo- 2-(3-(((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl) carbamoyl)piperidin-1-yl)ethoxy) piperidine- 1 -carboxylate (0.250 g, 50%) as brown gum.

[0497] LCMS (AA: ACN): m / z: 611.0 [M+H]+; tR = 3.91 min in 5 min run.

[0498] Step-2: (S)-1-(2-(piperidin-4-yloxy)acetyl)-N-((4-(4-(trifluoromethyl)phenyl)thiazol-2- yl)methyl) piperidine-3-carboxamide [SW394774-1]: To a stirred solution of tert-butyl (S)-4-(2- oxo-2-(3-(((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl) carbamoyl)piperidin-1-yl)ethoxy) piperidine- 1 -carboxylate (0.400 g, 0.655 mmol, 1.0 eq.) in DCM (20 mL) was added trifluoroacetic acid (1.50 mL, 19.65 mmol, 30.0 eq.) at 0°C. The reaction mixture was stirred at the same temperature for another 2h (TLC). On completion, reaction mixture was concentrated under reduced pressure and co-evaporated with DCM (two times) to remove excess TFA. Crude residue was purified by reverse phase PREP HPLC [ATLANTIS C18, Mobile phase: Acetonitrile and 0.1% TFA in water] to afford (S)-1-(2-(piperidin-4-yloxy)acetyl)-N-((4-(4-(trifluoromethyl)phenyl)thiazol- 2-yl)methyl) piperidine-3-carboxamide as TFA-salt (0.130 g, 32%).

[0499] 1H NMR (400 MHz, DMSO-D6, 100°C): <58.57 (brs, 1 H), 8.43-8.17 (brs, 2H), 8.16-8.12 (m, 3H), 7.77 (d, J = 8.0 Hz, 2H), 4.71-4.58 (m, 2H), 4.22 (s, 2H), 3.75-3.65 (m, 2H), 3.24-3.16 (m, 2H), 3.05-2.86 (m, 4H), 2.49-2.35 (m, 1 H), 2.02-1.92 (m, 3H), 1.80-1.69 (m, 4H), 1.51-1.38 (m, 1 H) ppm.

[0500] HPLC purity: 99.85%.

[0501] LCMS (AA: ACN): m / z: 511 .2 [M+H]+; tR = 2.25 min in 5 min run.Example 45: Synthesis of SW394852

[0502] Scheme:>

[0503] Step-1 : 2-(2-Fluoroethoxy)acetic acid (2): To a stirred solution of sodium choro acetate (0.500 g, 2.85 mmol) in DMF (10 mL) was added 2-fluoroethanol (0.196 g, 1.43 mmol, 0.5 eq.) followed by sodium hydroxide (0.196 g, 1.43 mmol, 0.5 eq.) and the resulting mixture was heated at 60°C for overnight. Reaction mixture was cooled to room temperature, concentrated under reduced pressure. Crude mass was diluted with water, acidified with 1 N HCI (aq.) at 0°C and then extracted with ethyl acetate (3x). Combined organic phase was dried over anhydrous sodium sulphate to get 2-(2-fluoroethoxy)acetic acid (0.520 g, 33%) as colorless oil which was used for the next step without further purification.

[0504] 1H NMR (400 MHz, DMSO-D6): 6 12.61 (brs, 1 H), 4.59 (t, J = 4.0 Hz, 1H), 4.47 (t, J = 4.0 Hz, 1 H), 4.06 (s, 2H), 3.75 (t, J = 4.0 Hz, 1 H), 3.67 (t, J = 4.0 Hz, 1 H), ppm.

[0505] Step-2: (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1 -(2-(2-fluoroethoxy)acetyl) piperidine-3-carboxamide [SW394852]: To a stirred solution of 2-(2-fluoroethoxy)acetic acid (0.082 g, 0.673 mmol, 1.1 eq.) in DMF (3 mL), were added DIPEA (0.213 mL, 1.223 mmol, 2.0 eq.) and HATU (0.279 g, 0.734 mmol, 1.2 eq.) at O°C.After 10 min, (S)-N-((4-(4- cyanophenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.200 g, 0.612 mmol, 1.0 eq) was added and the reaction mixture was warmed to room temperature and stirred overnight (TLC I LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by reverse phase Prep HPLC [YMC Triart C18, ACN, 20 mm NH4HCO3(aq.) buffer] to afford (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2-(2- fluoroethoxy)acetyl)piperidine-3-carboxamide (0.043 g, 18%).

[0506] 1H NMR (400 MHz, DMS0-D6): 68.52 (brs, 1 H), 8.16 (s, 1 H), 8.11 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 4.68-4.61 (m, 2H), 4.59 (t, J = 4.0 Hz, 1 H), 4.47 (t, J = 4.0 Hz, 1 H), 4.21 (s, 2H), 4.17-3.99 (m, 1H), 3.95-3.85 (m, 1 H), 3.76 (t, J = 4.0 Hz, 1 H), 3.68 (t, J = 4.0 Hz, 1 H), 2.46-2.39 (m, 1 H), 1.99-1.91 (m, 1 H), 1.78-1.65 (m, 2H), 1.50-1.38 (m, 1H) ppm.

[0507] HPLC purity: 99.95%.

[0508] LCMS (FA: ACN): m / z: 431.27 [M+H]+; tR = 4.24 min in 12 min run.Example 46: Synthesis of SW394930-1

[0509] Scheme:

[0510] Step-1 : (6-(4-fluorophenoxy)pyridin-3-yl)boronic acid (3): To a stirred solution of 5- bromo-2-(4-fluorophenoxy)pyridine (1.2 g, 4.461 mmol, 1.0 eq.) in 1,4-dioxane (15 mL) were added bis(pinacolato)diboron (1.7 g, 6.691 mmol, 1.5 eq.) and potassium acetate (0.963 g, 9.814 mmol, 2.2 eq.). The reaction mixture was degassed (N2) for 10 min and then PdCh(dppf) (0.255 g, 0.312 mmol, 7 mol%) was added and the resulting mixture was heated at 80°C overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with ethyl acetate, insoluble materials were removed by filtration. The filtrate was washed with water and brine. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by reverse phase PREP HPLC [YMC Actus Triart C18, ACN, NH4HCO3 (aq.) buffer] to get (6-(4-fluorophenoxy)pyridin-3-yl)boronic acid (0.430 g, 41%) as white solid.

[0511] 1H NMR (400 MHz, DMSOd6): 6 8.45 (s, 1 H), 8.22 (d, J = 8.4 Hz, 1 H), 8.17-8.13 (m, 2H), 7.30-7.13 (m, 4H), 6.97 (d, J = 8.4 Hz, 1 H).

[0512] LCMS (FA: ACN): 234.14 [M+H]+; tR = 1.70 min in 5 min run.

[0513] Step-2: (S)-N-((4-bromothiazol-2-yl)methyl)-1-(2-(2-fluoroethoxy)acetyl)piperidine -3-carboxamide (6): To a stirred solution of 2-(2-fluoroethoxy)acetic acid (1.019 g, 8.35 mmol, 1.1 eq.) in DMF (15 mL), were added DIPEA (2.65 mL, 15.182 mmol, 2.0 eq.) and HATU (3.46 g, 9.109 mmol, 1.2 eq.) at 0°C. After 10 min, (S)-N-((4-bromothiazol-2-yl)methyl)piperidine-3- carboxamide (2.3 g, 7.59 mmol, 1.0 eq) in DMF (5 mL) was added and the reaction mixture was warmed to room temperature and stirred for overnight (TLC I LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified flash column chromatography (1-3% MeOH in DCM) to afford (S)-N-((4-bromothiazol-2-yl)methyl)-1-(2-(2- fluoroethoxy)acetyl)piperidine-3-carboxamide (1.1 g, 34%) as brown gum.

[0514] LCMS (AA: ACN): m / z: 408.2 [M+H]+(bromo pattern); tR = 2.39 min in 5 min run.

[0515] Step-3: (S)-1-(2-(2-fluoroethoxy)acetyl)-N-((4-(6-(4-fluorophenoxy)pyridin-3- yl)thiazol-2-yl)methyl)piperidine-3-carboxamide [SW394930-1]: To a stirred solution of (S)-N- ((4-bromothiazol-2-yl)methyl)-1-(2-(2-fluoroethoxy)acetyl) piperidine-3-carboxamide (0.100 g, 0.245 mmol, 1.0 eq.) in Toluene: EtOH: H2O (2: 1 : 2; 5 mL), were added and 2-cyclopropyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (0.068 g, 0.294 mmol, 1.2 eq.) and Na2COs (0.064 g, 0.612 mmol, 2.5 eq.). The reaction mixture was degassed (N2) for 10 min and Pd(PPh3)4 (0.019 g, 0.017 mmol, 7 mol%) was added and then heated at 90°C for overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by reverse phase preparative HPLC [KINETEX C18, MeOH and 20 mM NH4HCO3 aq. Buffer] to afford (S)-1-(2-(2-fluoroethoxy)acetyl)- N-((4-(6-(4-fluorophenoxy)pyridin-3-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.008 g, 10%) as white solid.

[0516] 1H NMR (400 MHz, DMSOd6, 100°C): 58.70 (s, 1 H), 8.51 (brs, 1 H), 8.31 (d, J = 8.4 Hz, 1 H), 7.93 (s, 1 H), 7.26-7.15 (m, 4H), 7.06 (d, J = 8.4 Hz, 1 H), 4.64-4.55 (m, 3H), 4.50-4.43 (m, 1 H), 4.20 (s, 2H), 4.18-4.03 (m, 1H), 3.95-3.85 (m, 1 H), 3.79-3.72 (m, 1 H), 3.71-3.67 (m, 1 H), 2.45-2.36 (m, 1 H), 1.99-1.92 (m, 1 H), 1.75-1.65 (m, 2H), 1.50-1.37 (m, 1H).

[0517] HPLC purity: 98.51%.

[0518] LCMS (FA: ACN): m / z: 517.37 [M+H]+,tR = 3.13 min in 5 min run.Example 47: Synthesis of SW394885-1

[0519] Scheme:

[0520] Step-1 : 5-Bromo-6’-methyl-2,3’-bipyridine (2):To a stirred solution of 5-bromo-2- iodopyridine (0.500 g, 1.767 mmol, 1.0 eq.) in mixture of Toluene and methanol (2:1 , 10 ml_), were added 2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (0.464 g, 2.12 mmol, 1.2 eq.) and K2CO3 (0.488 g, 3.534 mmol, 2.0 eq.). The reaction mixture was degassed (N2) for 10 min and then Pd(PPh3)2Cl2 (0.124 g, 0.177 mmol, 0.1 eq.) and then heated at 80°C for 2 h (LCMS). On completion, the mixture was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate (3x). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (10-35% EtOAc in hexane) to afford 5-Bromo-6’-methyl-2,3’-bipyridine (0.250 g, 57%) as brown sticky oil which was used for the next step [pure product was not obtained even after column chromatography],

[0521] LCMS [AA: ACN]: m / z: 248.8 [M+H]+, tR = 3.28 min in 5 min run.

[0522] Step-2: 6’-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3’-bipyridine (3): To a stirred solution of 5-bromo-6’-methyl-2,3’-bipyridine (0.250 g, 1.323 mmol, 1.0 eq.) in 1 ,4-dioxane (10 mL) were added bis(pinacolato)diboron (0.504 g, 1.984 mmol, 1.5 eq.) and potassium acetate (0.286 g, 2.91 mmol, 2.2 eq.). The reaction mixture was degassed (N2) for 10 min and then PdCI2(dppf) (0.076 g, 0.093 mmol, 7 mol%) was added and the resulting mixture was heated at 80°C overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with ethyl acetate, insoluble materials were removed by filtration. The filtrate was washed with water and brine. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by flash columnchromatography (30-40% EtOAc in hexane) to get crude 6’-Methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2,3’-bipyridine (0.158 g, 40%) as light-yellow gum.

[0523] LCMS [AA: ACN]: m / z: 297.0 [M+H]+, tR = 3.79 min in 5 min run.

[0524] Step-3: (S)-1-(2-(2-fluoroethoxy)acetyl)-N-((4-(6’-methyl-[2,3’-bipyridin]-5-yl) thiazol-2-yl)methyl)piperidine-3-carboxamide [SW394885-1]: To a stirred solution of (S)-N- ((4-bromothiazol-2-yl)methyl)-1-(2-(2-fluoroethoxy)acetyl) piperidine-3-carboxamide (0.100 g, 0.245 mmol, 1.0 eq.) in Toluene: EtOH: H2O (3: 1 : 3; 7 mL), were added 6’-methyl-5-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3’-bipyridine (0.114 g, 0.49 mmol, 2.0 eq.), Na2CC>3 (0.051 g, 0.49 mmol, 2.0 eq.). The reaction mixture was degassed (N2) for 10 min and Pd(PPh3)4(0.092 g, 0.0797 mmol, 0.1 eq.) was added and then heated at 90°C for overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by reverse phase PREP HPLC [SUN Fl RE C18, ACN, 0.1% formic acid (aq.) buffer] to afford (S)-1-(2-(2-fluoroethoxy)acetyl)-N-((4-(6’- methyl-[2,3’-bipyridin]-5-yl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.010 g, 8%) as white solid.

[0525] 1H NMR (400 MHz, D SO-D6, 100°C): <59.23 (s, 1 H), 9.16 (s, 1H), 8.58 (brs, 1 H), 8.38- 8.31 (m, 2H), 8.13 (s, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1H), 4.73-4.55 (m, 3H), 4.51-4.45 (m, 1 H), 4.21 (s, 2H), 3.99-3.86 (m, 2H), 3.78-3.73 (m, 1H), 3.72- 3.67 (m, 1 H), 3.15- 3.00 (m, 2H, overlapped with DMSO water peak), 2.55 (s, 3H), 2.01-1.93 (m, 1 H), 1.77-1.64 (m, 2H), 1.47-1.36 (m, 1H) ppm.

[0526] HPLC purity: 99.93%.

[0527] LCMS (FA: ACN): m / z 498.34 [M+H]+; tR = 2.05 min in 5 min run.is of SW394925-1

[0528] Scheme:

[0529] Step-1 : 5-(4-Bromophenyl)pyrimidine (2):To a stirred solution of 1-bromo-4- iodobenzene (2.0 g, 7.069 mmol, 1.0 eq.) in mixture of Toluene and methanol (2:1 , 15 mL), were added 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (1.748 g, 8.483 mmol, 1.2 eq.) and K2CO3 (1.954 g, 14.139 mmol, 2.0 eq.). The reaction mixture was degassed by nitrogen for 10 min and then Pd(PPh3)2Cl2 (0.496 g, 0.707 mmol, 0.1 eq.) and then heated at 80°C for 2 h (LCMS). On completion, the mixture was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate (3x). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (10-25% EtOAc in hexane) to afford 5- (4-Bromophenyl)pyrimidine (0.850 g, 51%) as off-white solid.

[0530] 1H NMR (400 MHz, DMSO-D6): 5 9.21 (s, 1 H), 9.16 (s, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1 H).

[0531] Step-2: (4-(pyrimidin-5-yl)phenyl)boronic acid (3): To a stirred solution of 5-(4- Bromophenyl)pyrimidine (0.400 g, 1.702 mmol, 1.0 eq.) in 1 ,4-dioxane (10 mL) were added bis(pinacolato)diboron (0.864 g, 3.404 mmol, 2.0 eq.) and potassium acetate (0.501 g, 5.106 mmol, 3.0 eq.). The reaction mixture was degassed (N2) for 10 min and then PdCh(dppf) (0.060 g, 0.085 mmol, 5 mol%) was added and the resulting mixture was heated at 80°C for overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with ethyl acetate, insoluble materials were removed by filtration. The filtrate was washed with water and brine. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reducedpressure. Crude residue was purified by reverse phase PREP HPLC [YMC Actus Triart C18, ACN, NH4HCO3 (aq.) buffer] to get (4-(pyrimidin-5-yl)phenyl)boronic acid (0.060 g, 13%) as white solid.

[0532] 1H NMR (400 MHz, DMSO-D6): 59.19 (s, 1H), 9.17 (s, 2H), 8.17 (brs, 2H), 7.94 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H).

[0533] LCMS [AA: ACN]: m / z: 199.2 [M-H]+, tR = 1 .88 min in 5 min run.

[0534] Step-3: (S)-1 -(2-(2-fluoroethoxy)acetyl)-N-((4-(4-(pyrimidin-5-yl)phenyl)thiazol-2- yl)methyl) piperidine-3-carboxamide [SW394925-1]: To a stirred solution of (S)-N-((4- bromothiazol-2-yl)methyl)-1-(2-(2-fluoroethoxy)acetyl) piperidine-3-carboxamide (0.200 g, 0.488 mmol, 1.0 eq.) in 1 ,4-dioxane and water (10 mL, 9:1) were added (4-(pyrimidin-5- yl)phenyl)boronic acid (0.133 g, 0.537 mmol, 1.1 eq.) and K3PO4 (0.280 g, 1.224 mmol, 2.5 eq.). The reaction mixture was degassed (N2) for 10 min before the addition of Pd-118 (0.180 g, 0.024 mmol, 5 mol%) and then heated at 90°C for 5 h (LCMS). On completion, the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (2-5% MeOH in DCM) to afford tert-butyl (S)-5-(2-((1-(2-(2-fluoroethoxy)acetyl)piperidine-3-carboxamido)methyl) thiazol-4-yl)-2,3-dihydro- 1 H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.042 g, 18%) as off-white solid.

[0535] 1H NMR (400 MHz, DMSO-D6, 100°C): 69.16 (s, 1 H), 9.14 (s, 2H), 8.58 (brs,1 H), 8.09 (d, 8.0 Hz, 2H), 8.02 (s, 1 H), 7.87 (d, J = 8.0 Hz, 2H), 4.69-4.56 (m, 3H), 4.50-4.46 (m, 1 H), 4.21 (s, 2H), 3.99-3.83 (m, 1 H), 3.78-3.71 (m, 2H), 3.70-3.65 (m, 1 H), 3.23-3.15 (m, 1 H), 2.94-2.83 (m, 1 H) overlapped with DMSO water peak, 2.49-2.47 (m, 1 H), 2.00-1.92 (m, 1H), 1.78-1.67 (m, 2H), 1.50-1.38 (m, 1 H) ppm.

[0536] HPLC purity: 94.84%.

[0537] LCMS (FA: ACN): m / z 484.4 [M+H]+; tR = 8.26 min in 18 min run.Example 49: Synthesis of SW394858

[0538] Scheme:

[0539] Step-1 : (S)-N-((4-(3,4-dichlorophenyl)thiazol-2-yl)methyl)-1-(2-(2- fluoroethoxy)acetyl) piperidine-3-carboxamide [SW394858)]: To a stirred solution of (S)-N- ((4-bromothiazol-2-yl)methyl)-1-(2-(2-fluoroethoxy)acetyl) piperidine-3-carboxamide (0.100 g,0.245 mmol, 1.0 eq.) in Toluene: EtOH: H2O (3: 1 : 3; 7 mL), were added (3,4- dichlorophenyl)boronic acid (0.056 g, 0.294 mmol, 1.2 eq.) and Na2CC>3 (0.053 g, 0.49 mmol, 2.0 eq.). The reaction mixture was degassed (N2) for 10 min before the addition of Pd(PPh3)4(0.028 g, 0.024 mmol, 10 mol%) and then heated at 90°C overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). The combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by reverse phase preparative HPLC [YMC Actus Triart C18, ACN, 20 mm NI- HCO3 (aq.) buffer] to afford (S)-N-((4-(3,4-dichlorophenyl)thiazol-2-yl)methyl)-1- (2-(2-fluoroethoxy)acetyl)piperidine-3-carboxamide (0.030 g, 26%) as off-white solid.

[0540] 1H NMR (400 MHz, DMSO-D6, 100°C): 5 8.54 (brs, 1 H), 8.14 (d, J = 2.0 Hz, 1 H), 8.09 (s, 1 H), 7.91 (dd, J = 8.4 Hz, 2.0 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 4.63-4.58 (m, 3H), 4.47 (t, J = 4.0 Hz, 1 H), 4.21 (s, 2H), 3.96-3.85 (m, 2H), 3.75 (t, J = 4.0 Hz, 1 H), 3.68 (t, J = 4.0 Hz, 1 H), 2.92- 2.86 (m, 2H) overlapped with DMSO water peak, 2.48-2.38 (m, 1 H), 1.96-1.93 (m, 1 H), 1.75-1.68 (m, 2H), 1.48-1.38 (m, 1H) ppm.

[0541] HPLC purity: 98.58%.

[0542] LCMS (FA: ACN): m / z 474.18 [M+H]+; tR = 2.87 min in 5 min run.Example 50: Synthesis of SW394884-1

[0543] Scheme:

[0544] (S)-N-((4-(3-chloro-4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl)-1-(2-(2- fluoroethoxy)acetyl)piperidine-3-carboxamide [SW394884-1]: SW394884-1 was prepared following similar synthetic protocol as described for SW394858 above.

[0545] 1H NMR (400 MHz, DMSO-D6, 100°C ): 58.56 (brs, 1 H), 8.27 (s, 1 H), 8.22 (s, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 4.67-4.57 (m, 3H), 4.48 (t, J = 4.0 Hz, 1 H), 4.21 (s, 2H), 4.17-3.96 (m, 1 H), 3.95-3.85 (m, 1 H), 3.76 (t, J = 4.0 Hz, 1H), 3.68 (t, J = 3.6 Hz, 1 H), 2.99- 2.87 (m, 2H) overlapped with DMSO water peak, 2.49-2.38 (m, 1 H), 1.98-1.91 (m, 1 H), 1.75-1.66 (m, 2H), 1.45-1.41 (m, 1H) ppm.

[0546] HPLC purity: 98.93%.

[0547] LCMS (FA: ACN): m / z 508.23 [M+H]+, tR = 2.97 min in 5 min run.Example 51 : Synthesis of SW394926-1

[0548] Scheme:

[0549] Step-1 : tert-butyl 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1 -carboxylate (2): To a stirred solution of 5-bromo-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine (0.500 g, 2.513 mmol,I .0 eq.) in DMF (5.0 mL) were added DIPEA (0.65 mL, 3.77 mmol, 1.5 eq.) and di-tert-butyl dicarbonate (1.15 mL, 5.025 mmol, 2.0 eq.) under argon. The reaction mixture was warmed to room temperature and stirred for 2 h (TLC / LCMS). On completion, the mixture was diluted with ethyl acetate, washed with cold water (3x) and brine. Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-1% MeOH in DCM) to afford tert-butyl 5-bromo-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-1-carboxylate (0.180 g, 24%) as light-yellow gum.

[0550] 1H NMR (400 MHz, DMSO-D6): 68.13 (s, 1 H), 7.76 (s, 1 H), 3.93 (t, J = 8.4 Hz, 1 H), 3.02 (t, J = 8.4 Hz, 1 H), 1.48 (s, 9H) ppm.

[0551] LCMS (AA: ACN): m / z: 299.0 [M+H]+, tR = 3.52 min in 5 min run.

[0552] Step-2: tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-1-carboxylate (3): To a stirred solution of t-butyl 5-bromo-2,3-dihydro- 1 H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.0 g, 5.051 mmol, 1.0 eq.) in 1 ,4-dioxane (15 mL) were added bis(pinacolato)diboron (1.923 g, 7.576 mmol, 1.5 eq.) and potassium acetate (1.09 g,I I.11 mmol, 2.2 eq.). The reaction mixture was degassed (N2) for 10 min and then PdCI2(dppf) (0.289 g, 0.354 mmol, 7 mol%) was added and the resulting mixture was heated at 90°C for 2 h (LCMS). On completion, the mixture was cooled to room temperature, diluted with ethyl acetate,insoluble materials were removed by filtration. The filtrate was washed with water and brine. The organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. Crude residue was purified by flash column chromatography (40-60% EtOAc in hexane) to get tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-1- carboxylate as brown oil (0.505 g, 29%) which was pure enough and taken for the next step without further purification.

[0553] LCMS (AA: ACN): m / z: 347.0 [M+H]+, tR = 3.74 min in 5 min run.

[0554] Step-3: tert-butyl (S)-5-(2-((1-(2-(2-fluoroethoxy)acetyl)piperidine-3- carboxamido)methyl) thiazol-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1 -carboxylate (5): To a stirred solution of (S)-N-((4-bromothiazol-2-yl)methyl)-1-(2-(2-fluoroethoxy)acetyl) piperidine-3-carboxamide (0.200 g, 0.49 mmol, 1.0 eq.) in 1 ,4-dioxane and water (8 mL, 3:1) were added tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 H-pyrrolo[2,3- b]pyridine-1 -carboxylate (0.203 g, 0.588 mmol, 1.2 eq.) and K3PO4 (0.260 g, 1.224 mmol, 2.5 eq.). The reaction mixture was degassed (N2) for 10 min before the addition of Pd-118 (0.016 g, 0.024 mmol, 5 mol%) and then heated at 90°C for overnight (LCMS). On completion, the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). Combined organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (2-5% MeOH in DCM) to afford tertbutyl (S)-5-(2-((1-(2-(2-fluoroethoxy)acetyl)piperidine-3-carboxamido)methyl) thiazol-4-yl)-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.152 g, 56%) as brown semisolid.

[0555] LCMS (AA: ACN): m / z: 546.0 [M+H]+, tR = 3.37 min in 5 min run.

[0556] Step-4: (S)-N-((4-(2,3-dihydro-1 H-pyrrolo[2,3-b]pyridin-5-yl)thiazol-2-yl)methyl)-1- (2-(2-fluoroethoxy)acetyl)piperidine-3-carboxamide [SW394926-1]: To a stirred solution of tert-butyl (S)-5-(2-((1-(2-(2-fluoroethoxy)acetyl)piperidine-3-carboxamido)methyl) thiazol-4-yl)- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.200 g, 0.426 mmol, 1.0 eq.) in DCM (10.0 mL) at 0°C was added trifluoroacetic acid (0.977 mL, 12.766 mmol, 30.0 eq.) dropwise and the reaction mixture was stirred for another 1 h at the same temperature (TLC). On completion, the mixture was concentrated under reduced pressure and co-evaporated two times with DCM to remove excess TFA. Crude residue was purified by reverse phase preparative HPLC [YMC Actus Triart C18, ACN, 20 mm NH4HCO3 (aq.) buffer] to afford (S)-N-((4-(2,3-dihydro-1 H-pyrrolo[2,3- b]pyridin-5-yl)thiazol-2-yl)methyl)-1-(2-(2-fluoroethoxy) acetyl)piperidine-3-carboxamide (0.012 g, 6%) as brown gum.

[0557] 1H NMR (400 MHz, DMSO-D6, 100°C): 58.48 (brs, 1 H), 8.31 (s, 1 H), 7.73 (s, 1 H), 7.57 (s, 1 H), 6.21 (brs, 1 H), 4.64-4.53 (m, 3H), 4.50-4.45 (m, 1 H), 4.21 (s, 2H), 4.19-3.99 (m, 1 H),3.96-3.85 (m, 1 H), 3.78-3.73 (m, 1 H), 3.72-3.65 (m, 1 H), 3.58-3.51 (m, 2H), 3.10-2.98 (m, 2H, overlapped with DMSO-water peak), 2.55-2.50 (m, 2H, overlapped with DMSO-residual peak), 2.47-2.37 (m, 1 H), 1.99-1.91 (m, 1 H), 1.85-1.74 (m, 2H), 1.48-1.37 (m, 1 H), ppm.

[0558] HPLC purity: 97.77%.

[0559] LCMS (FA: ACN): m / z: 448.35 [M+H]+, tR = 1.96 min in 5 min run.Example 52: Synthesis of SW394890-1

[0560] Scheme:

[0561] Step-1 : tert-butyl (S)-3-(([1,1’-biphenyl]-4-ylmethyl)carbamoyl)piperidine-1- carboxylate (2): To a stirred solution of (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (0.500 g, 2.172 mmol, 1.0 eq.) in DMF (10 ml_), were added DIPEA (0.755 mL, 4.343 mmol, 2.0 eq.) and HATU (0.990 g, 2.606 mmol, 1.2 eq.) at 0°C. After 10 min, [1,1’-biphenyl]-4- ylmethanamine (0.438 g, 2.389 mmol, 1.1 eq) was added and the reaction mixture was warmed to room temperature and stirred for another 3 h (TLC I LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash column chromatography to get tert-butyl (S)-3-(([1,1’-biphenyl]-4- ylmethyl)carbamoyl)piperidine-1 -carboxylate (0.770 g, 89%).

[0562] 1H NMR (400 MHz, DMSO-D6): 58.46 (m, 1 H), 7.67-7.59 (m, 4H), 7.46 (t, J = 7.6 Hz, 2H), 7.38-7.31 (m, 3H), 4.30 (s, 3H), 4.07-3.90 (m, 1 H), 3.87 (d, J = 13.2 Hz, 1 H), 2.72-2.54 (m, 1 H), 2.33-2.27 (m, 1 H), 1.92-1.82 (m, 1 H), 1.70-1.49 (m, 2H), 1.40 (s, 9H), 1.35-1.25 (m, 1 H) ppm.

[0563] LCMS (FA: ACN): m / z: 395.2 [M+H]+; tR = 3.70 min in 5 min run.

[0564] Step-2: (S)-N-([1,1’-biphenyl]-4-ylmethyl)piperidine-3-carboxamide (3): To a stirred solution of tert-butyl (S)-3-(([1 ,T-biphenyl]-4-ylmethyl)carbamoyl)piperidine-1 -carboxylate (0.400 g, 1.014 mmol, 1.0 eq.) in DCM (10.0 mL) at 0°C was added trifluoroacetic acid (2.33 mL,30.417 mmol, 30.0 eq.) dropwise and the reaction mixture was stirred for another 2 h at the same temperature (TLC I LCMS). On completion, the mixture was concentrated under reduced pressure and co-evaporated two times with DCM to afford (S)-N-([1 ,1’-biphenyl]-4-ylmethyl)piperidine-3- carboxamide as TFA-salt. The salt was dissolved in DCM, neutralized by slow addition of DIPEA at 0°C and again concentrated under reduced pressure to get the free amine which was used for next step without further purification considering quantitative conversion.

[0565] LCMS (AA: ACN): m / z: 295.0 [M+H]+, tR = 3.20 min in 5 min run.

[0566] Step-3: (S)-N-([1,T-biphenyl]-4-ylmethyl)-1-(2-(2-fluoroethoxy)acetyl)piperidine-3- carboxamide [SW394890-1]: To a stirred solution of 2-(2-fluoroethoxy)acetic acid (0.091 g, 0.747 mmol, 1.1 eq.) in DMF (4 mL), were added DIPEA (0.24 mL, 1.359 mmol, 2.0 eq.) and HATU (0.310 g, 0.815 mmol, 1.2 eq.) at 0°C.After 10 min, (S)-N-([1,1’-biphenyl]-4- ylmethyl)piperidine-3-carboxamide (0.200 g, 0.679 mmol, 1.0 eq) was added and the reaction mixture was warmed to room temperature and stirred for another 2 h (TLC I LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by reverse phase Prep HPLC [YMC Triart C18, ACN, 20mm NH4HCO3 (aq.) buffer] to afford (S)-N-([1 ,T-biphenyl]-4-ylmethyl)-1-(2-(2-fluoroethoxy)acetyl)piperidine-3- carboxamide (0.035 g, 13%).

[0567] 1H NMR (400 MHz, DMSO-D6,100°C): 5 8.11 (brs, 1 H), 7.67-7.57 (m, 4H), 7.45 (t, J = 7.6 Hz, 2H), 7.38-7.31 (m, 3H), 4.61-4.57 (m, 1 H), 4.50-4.47 (m, 1 H), 4.36-4.28 (m, 2H), 4.20 (s, 2H), 4.16-3.82 (m, 2H), 3.79-3.72 (m, 1H), 3.70-3.65 (m, 1 H), 2.99-2.75 (m, 2H), 2.45-2.30 (m, 1 H), 1.97-1.80 (m, 1H), 1.75-1.53 (m, 2H), 1.49-1.33 (m, 1 H) ppm.

[0568] HPLC purity: 99.26%.

[0569] LCMS (AA: ACN): m / z: 399.2 [M+H]+, tR = 2.50 min in 5 min run.Example 53: Synthesis of SW394924-1

[0570] (S)-N-([1,T-biphenyl]-3-ylmethyl)-1-(2-(2-fluoroethoxy)acetyl)piperidine-3- carboxamide [SW394924-1]: SW394924-1 was prepared following similar synthetic protocol as described for SW394890-1 above.

[0571] 1H NMR (400 MHz, DMSO-D6, 100°C ): 58.12 (brs, 1 H), 7.63 (d, J = 8.0 Hz, 2H), 7.54- 7.50 (m, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.41-7.33 (m, 2H), 7.25 (d, J = 7.2 Hz, 1 H), 4.58 (t, J = 4.0 Hz, 1 H), 4.46 (t, J = 4.0 Hz, 1 H), 4.37-4.31 (m, 2H), 4.19 (s, 2H), 4.08-3.82 (m, 2H), 3.74 (t, J = 4.0 Hz, 1 H), 3.67 (t, J = 4.0 Hz, 1 H), 2.45-2.36 (m, 1 H), 1.95-1.89 (m, 1 H), 1.73-1.64 (m, 2H), 1.45-1.36 (m, 1 H) ppm.

[0572] HPLC purity: 99.88%.

[0573] LCMS (FA: ACN): m / z 399.42 [M+H]+, tR = 2.81 min in 5 min run.Example 54: Synthesis of SW394888-1

[0574] Scheme:

[0575] (S)-1-(2-(piperazin-1-yl)oxazole-5-carbonyl)-N-((4-(4-(trifluoromethyl)phenyl) thiazol-2-yl)methyl)piperidine-3-carboxamide [SW394888-1]: SW394888-1 was prepared following similar synthetic protocol as described for SW394777-1 above.

[0576] 1H NMR (400 MHz, DMSO-D6): 58.98-8.91 (m, 1 H), 8.83 (brs, 2H), 8.25 (s, 1 H), 8.16 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.47(s, 1 H), 4.64-4.61 (m, 2H), 4.30 (d, J = 11 .6 Hz), 4.16 (d, J = 14.4 Hz, 1 H), 3.69-3.66 (m, 4H), 3.32-3.22 (m, 4H), 3.19-2.98 (m, 2H), 2.50-2.38 (m, 1 H), 2.05-1.93 (m, 1H), 1.81-1.65 (m, 2H), 1.51-1.35 (m, 1 H).

[0577] HPLC purity: 99.18%.

[0578] LCMS (FA: ACN): m / z: 549.35 [M+H]+; tR = 2.37 min in 5 min run.Example 55: Synthesis of SW394883-1

[0579] Scheme:

[0580] (S)-1-(2-((3S,5R)-3,5-dimethylpiperazin-1-yl)oxazole-5-carbonyl)-N-((4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide [SW394883-1]: SW394883-1 was prepared following similar synthetic protocol as described for SW394777-1 above.

[0581] 1H NMR (400 MHz, DMSO-D6): 5 9.20-9.11 (m, 1 H), 8.89-8.82 (m, 1 H), 8.68-8.47 (m, 1 H), 8.25 (s, 1 H), 8.16 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.47 (s, 1 H), 4.68-4.56 (m, 2H), 4.31 (d, J = 12.4 Hz, 1 H), 4.20-4.08 (m, 3H), 3.49-3.39 (m, 2H), 3.19-3.08 (m , 1 H), 3.05-2.93 (m, 3H), 2.49-2.48 (m, 1 H, overlapped with DMSO residual peak), 2.05-1.93 (m, 1 H), 1.82-1.68 (m, 2H), 1.45-1.42 (m, 1H), 1.24 (d, J = 6.2 Hz, 6H).

[0582] HPLC purity: 99.41%.

[0583] LCMS (AA: ACN): m / z: 577.1 [M+H]+; tR = 2.43 min in 5 min run.Example 56: Synthesis of SW394889-1

[0584] Scheme:

[0585] Step-1 : (S)-2-((1-(tert-butoxycarbonyl)piperidin-3-yl)oxy)acetic acid (2): To a stirred solution of tert-butyl (S)-3-hydroxypiperidine-1-carboxylate (0.200 g, 0.994 mmol, 1.0 eq.) in THF (4 mL) was added NaH (60% in mineral oil, 0.120 g, 2.981 mmol, 3.0 eq.) in portions at 0°C under argon. Reaction mixture was stirred for 30 min at the same temperature and a solution of bromoacetic acid (0.276 g, 1.987 mmol, 2.0 eq.) in THF (1 mL) was added. Reaction mixture was allowed to warm to room temperature slowly and stirring was continued for overnight. The mixture was then quenched with ice-water, acidified with 10% citric acid solution (aq.), and extracted with ethyl acetate (3x) to get crude (S)-2-((1-(tert-butoxycarbonyl)piperidin-3-yl)oxy)acetic acid as colorless gum (0.200 g, 77%) which was used for the next step without further purification.

[0586] Step-2: tert-butyl (S)-3-(2-oxo-2-((S)-3-(((4-(4-(trifluoromethyl)phenyl)thiazol-2- yl)methyl) carbamoyl)piperidin-1-yl)ethoxy)piperidine-1 -carboxylate (4): To a stirred solution of (S)-2-((1-(tert-butoxycarbonyl)piperidin-3-yl)oxy)acetic acid (0.281 g, 1.083 mmol, 1.0 eq.) in DMF (6 mL), were added DIPEA (0.57 mL, 3.248 mmol, 3.0 eq.) and HATU (0.453 g, 1.191 mmol, 1.2 eq.) at 0°C. After 10 min, a solution of (S)-N-((4-(4-(trifluoromethyl) phenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide (0.400 g, 1.083 mmol, 1.0 eq.) in DMF (2 mL) was added. Cold-bath was removed, and the reaction mixture was stirred at room temperature for overnight (LCMS). On completion, the mixture was diluted with cold water and extracted with 30% isopropanol in DCM (3x) and brine. Combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated under reduced pressure. Crude residue was purified by flash column chromatography (5-10% MeOH in DCM) to afford tert-butyl (S)-3-(2-oxo-2-((S)-3-(((4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)methyl) carbamoyl)piperidin-1-yl)ethoxy)piperidine-1- carboxylate (0.300 g, 45%) as brown oil.

[0587] LCMS [AA: ACN]: m / z: 610.8 [M-H]+(Boc-pattern), tR = 3.94 min in 6 min run.

[0588] Step-3: (S)-1-(2-(((S)-piperidin-3-yl)oxy)acetyl)-N-((4-(4-(trifluoromethyl)phenyl) thiazol-2-yl)methyl)piperidine-3-carboxamide [SW394889-1]: To a stirred solution of tert-butyl (S)-3-(2-oxo-2-((S)-3-(((4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)methyl)carbamoyl)piperidin-1- yl)ethoxy)piperidine-1-carboxylate (0.300 g, 0.491 mmol, 1.0 eq.) in DCM (10 mL) was added trifluoroacetic acid (1.13 mL, 14.737 mmol, 30 eq.) at 0°C and the reaction mixture was stirred at the same temperature for another 1 h (LCMS). On completion, reaction mixture was concentrated under reduced pressure and co-evaporated with DCM (two times) to remove excess TFA. Crude residue was purified by reverse phase PREP HPLC [ATLANTIS C18, ACN, 0.1% TFA in water] to afford (S)-1-(2-(((S)-piperidin-3-yl)oxy)acetyl)-N-((4-(4-(trifluoromethyl)phenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide as TFA-salt (0.015 g, 6%, white solid).

[0589] 1H NMR (400 MHz, DMSO-D6, 100°C): 6 8.58 (brs, 2H), 8.31 (brs, 1 H), 8.17-8.13 (m, 3H), 7.77 (d, J = 8.0 Hz, 2H), 4.72-4.57 (m, 2H), 4.37 (d, 1 H, J = 14.4 Hz), 4.28 (d, J = 14.4 Hz, 1 H), 3.91-3.80 (m, 1 H), 3.79-3.72 (m, 2H), 3.18-3.08 (m, 4H), 3.06-2.95 (m, 2H), 2.48-2.40 (m, 1 H, overlapped with DMSO residual peak), 2.02-1.85 (m, 2H), 1.81-1.69 (m, 4H), 1.63-1.57 (m, 1 H), 1.50-1.39 (m, 1H) ppm.

[0590] HPLC purity: 96.33%.

[0591] LCMS (AA: ACN): m / z: 511.1 [M+H]+, tR = 4.59 min in 12 min run.Example 57: Synthesis of SW394886-1

[0592] Scheme:

[0593] (S)-1-(2-(((R)-piperidin-3-yl)oxy)acetyl)-N-((4-(4-(trifluoromethyl)phenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide [SW394886-1]: SW394886-1 was prepared following similar synthetic protocol as described forSW394889-1 above.

[0594] 1H NMR (400 MHz, DMSO-D6, 100°C): 58.57 (brs, 1 H), 8.16-8.10 (m, 3H), 7.77 (d, J = 7.6 Hz, 2H), 4.71-4.58 (m, 2H), 4.28-4.17 (m, 2H), 4.16-3.85 (m, 2H), 3.50-3.42 (m, 1 H), 3.08- 3.02 (m, 3H, overlapped with DMSO water peak), 2.85-2.77 (m, 1 H), 2.72-2.62 (m, 2H), 2.49-2.39 (m, 1 H), 2.01-1.82 (m, 2H), 1.77-1.65 (m, 3H), 1.59-1.39 (m, 3H) ppm.

[0595] HPLC purity: 95.85%.

[0596] LCMS (AA: ACN): m / z: 511 .2 [M+H]+; tR = 2.37 min in 5 min run.Example 58: Synthesis of SW394882-1

[0597] Scheme:

[0598] Step-1 : 2-Hydroxyoxazole-5-carboxylic acid (2): To a stirred suspension of ethyl 2- chlorooxazole-5-carboxylate (0.200 g, 1.142 mmol, 1.0 eq.) in water (5 mL) was added 10% aq. NaOH (5 mL) and the mixture was stirred at room temperature for overnight (LCMS). On completion, the mixture was cooled to 0°C, acidified with 2N HCI. Solid precipitate formed, which was collected by filtration, dried under vacuum to get 2-hydroxyoxazole-5-carboxylic acid (0.120 g, 81%) as white solid.

[0599] 1H NMR (400 MHz, DMSO-D6): <5 13.15 (brs, 1 H), 11.40 (s, 1 H), 7.79 (s, 1H) ppm.

[0600] Step-2: (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1 -(2-hydroxyoxazole-5- carbonyl)piperidine-3-carboxamide [SW394882-1]: To a stirred solution of 2-hydroxyoxazole- 5-carboxylic acid (0.059 g, 0.459 mmol, 1.0 eq.) in DMF (4 mL) at 0°C, were added NMM (0.14 mL, 1.101 mmol, 2.4 eq.) and TBTU (0.236 g, 0.734 mmol, 1.6 eq.).After 5 min, a solution of (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide (0.150 g, 0.459 mmol, 1 .0 eq.) in DMF (1 .0 mL) was added, the reaction mixture was warmed to room temperature and stirred overnight (LCMS). On completion, the mixture was diluted with EtOAc and washed with cold water (3x) and brine. Organic phase was dried (Na2SO4) and concentrated under reduced pressure. Crude residue was purified by reverse phase Prep HPLC [GEMINI C18, ACN, 20mM NH4HCO3 (aq.) buffer] to afford (S)-N-((4-(4-cyanophenyl)thiazol-2-yl)methyl)-1-(2- hydroxyoxazole-5-carbonyl) piperidine-3-carboxamide (0.026 g, 13%, white solid).

[0601] 1H NMR (400 MHz, DMSO-D6): <5 11.27 (brs, 1 H), 8.95 (t, J = 6.0 Hz, 1 H), 8.30 (s, 1 H), 8.13 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.58 (s, 1 H), 4.68-4.55 (m, 2H), 4.30 (d, J = 12.8Hz, 1 H), 4.15 (d, J = 12.8 Hz, 1 H), 3.21-2.88 (m, 2H), 2.49-2.41 (m, 1 H), 1.98-1.90 (m, 1 H), 1.80-1.65 (m, 2H), 1.50-1.36 (m, 1H) ppm.

[0602] HPLC purity: 98.40%

[0603] LCMS (FA: ACN): m / z: 438.22 [M+H]+, tR = 2.46 min in 5 min run.Example 59: General Procedure A

[0604] Synthesis of tert-butyl (S)-3-(((4-phenylthiazol-2-yl)methyl)carbamoyl)piperidine- 1 -carboxylate (3) To a solution of (4-phenylthiazol-2-yl)methanamine 1 (1.00 g, 5.26 mmol, 1.00 equiv) and (S)-1-(te / t-butoxycarbonyl)piperidine-3-carboxylic acid 2 (1.20 g, 5.26 mmol, 1.00 equiv) in DMF (30 mL) at 0°C were added HATU (2.19 g, 5.78 mmol, 1.10 equiv) and DIPEA (1.80 mL, 10.5 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature for 30 min. On completion (checked by LCMS), the reaction mixture was diluted with ethyl acetate and washed with water (2 x 30 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by ISCO automated flash column chromatography (7:3 Hexane: EtOAc v / v) to get the product 3 (1.72 g, 82%) as a colorless liquid.

[0605] 1H NMR (400 MHz, MeOD-c / 4) 67.91 - 7.88 (m, 2H), 7.72 (s, 1H), 7.43 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1 H), 4.71 - 4.59 (m, 2H), 4.17 - 4.10 (m, 1 H), 4.02 - 3.98 (m, 1H), 3.09 - 2.70 (m, 2H), 2.46 - 2.33 (m, 1 H), 2.02 - 1.97 (m, 1H), 1.78 - 1.67 (m, 2H), 1.53 - 1.45 (m, 10H).

[0606] ESI MS. C21H28N3O3S m / z [M+H]+ calc. 402.2, found 402.1.

[0607] Synthesis of (S)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3-carboxamide (4) To a solution of the thiazole derivative 3 (1.50 g, 3.74 mmol, 1.00 equiv) in CH2CI2 (20 mL) was added TFA (1.40 mL, 18.7 mmol, 5.00 equiv) at 0°C. After stirring at room temperature for 12 h, the solvent was removed under vacuum. The resulting mixture was basified with saturated aqueous solution of NaHCCh and extracted with CH2CI2 (3 x 30 mL). The combined organic layers were dried over Na2SC>4, the solvent was evaporated, and the crude product was used for the next reaction without any further purification.

[0608] ESI MS. C16H20N3OS m / z [M+H]+ calc. 302.1 , found 302.1.

[0609] Synthesis of (S)-1-(2-alkoxyacetyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (5).

[0610] HATU (692 mg, 1.82 mmol, 1.10 equiv) and DIPEA (0.60 mL, 3.32 mmol, 2.00 equiv) were added to a solution of the piperidine derivative 4 (500 mg, 1.66 mmol, 1.00 equiv) and acid derivative (1.66 mmol, 1.00 equiv) in DMF (15 mL) at 0°C. The resulting suspension was stirred for 30 min at room temperature before water was added to the reaction mixture. The aqueous phase was extracted with EtOAc (3 x 30 mL), the combined organic extracts were washed with water and dried over Na2SO4. The solvent was evaporated, and the crude product was purified by ISCO flash column chromatography (97:3 CH2CI2: MeOH v / v) to get the product 5.Example 60: Synthesis of (S)-SW2930042

[0611] (S)-1-(2-Methoxyacetyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide

[0612] Synthesized by general procedure A.

[0613] Yield: 81%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:l\ / leOH v / v).

[0614] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 57.91 - 7.88 (m, 2H), 7.72 (s, 1 H), 7.43 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1H), 4.78 - 4.66 (m, 2H), 4.55 - 4.50 (m, 0.5H), 4.25 - 4.10 (m, 2.5H), 3.87 - 3.78 (m, 1 H), 3.39 (brs, 3H), 3.35 - 3.32 (m, 0.5 H), 3.11 - 3.04 (m, 0.5H), 2.93 - 2.86 (m, 1 H), 2.57 - 2.41 (m, 1 H), 2.07 - 2.01 (m, 1 H), 1.89 - 1.75 (m, 2H), 1.61 - 1.45 (m, 1 H).

[0615] 13C NMR (151 MHz, MeOH-d4) mixture of rotamers: 175.9, 170.8, 170.2, 170.1, 156.5, 135.7, 129.8, 129.2, 127.3, 114.6, 72.0, 114.6, 71.9, 59.4, 48.1 , 46.3, 45.3, 44.3, 44.0, 43.3, 41.8, 28.9, 28.8, 26.1 , 25.2.

[0616] ESI MS. Ci9H24N3O3S m / z [M+H]+ calc. 374.2, found 374.1.

[0617] [a]25D+20.74 (c 0.13, CHCI3).Example 61 : Synthesis of (R)-SW2930042

[0618] (R)-1-(2-Methoxyacetyl)-W-((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide ((R)-SW293042)

[0619] Synthesized by general procedure A starting from the enantiomeric piperidine.

[0620] Yield: 79%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0621] ESI MS. C19H24N3O3S m / z [M+H]+ calc. 374.2, found 374.1.Example 62: Synthesis of (rac)-SW2930042

[0622] (rac)-1-(2-Methoxyacetyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide ((rac)-

[0623] Synthesized by general procedure A starting from the racemic piperidine.

[0624] Yield: 82%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0625] ESI MS. C19H24N3O3S m / z [M+H]+ calc. 374.2, found 374.1.Example 63: General Procedure B

[0626] (S)- / V-((4-Bromothiazol-2-yl)methyl)piperidine-3-carboxamide (11) To a solution of the Boc protected amine Common Intermediate-2 (2.50 g, 6.17 mmol) in CH2Cl2 (25 mL) at 0°C was added TFA (9.50 mL, 120 mmol, 20.0 equiv). The reaction mixture was stirred at room temperature for 2 h (progress of the reaction was monitored by LCMS). After the starting material was consumed, the solvent was evaporated and the crude TFA salt 11 was used for the next reaction.

[0627] ESI MS. CioHi5BrN3OS m / z [M+H]+ calc. 304.0, found 303.9.

[0628] (S)-A / -((4-Bromothiazol-2-yl)methyl)-1-(2-alkoxyacetyl)piperidine-3-carboxamide(12) T3P (1.1 mL, 1.79 mmol, 1.5 equiv) was added to a solution of the piperidine derivative 11 (500 mg, 1.19 mmol, 1.00 equiv), required carboxylic acid (1.19 mmol, 1.00 equiv) and Et3N (0.8 mL, 5.95 mmol, 5.00 equiv) in DMF (5 mL) at 0°C. The resulting suspension was stirred for 30 min at room temperature. Then water was added to the reaction mixture. The aqueous phase was extracted with EtOAc (3 x 30 mL), and the combined organic extracts were washed with water and dried over Na2SC>4. The solvent was evaporated and the crude product was purified by ISCO flash column chromatography (97:3 / 95:5 CH2Cl2:MeOH v / v) to get the product 12.

[0629] (S)- / V-((4-Bromothiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3- carboxamide (12a).

[0630] ESI MS. Ci3Hi9BrN3O3S m / z [M+H]+ calc. 376.0, found 375.9.

[0631] (S)-A / -((4-Bromothiazol-2-yl)methyl)-1-(2-ethoxyacetyl)piperidine-3-carboxamide (12b).

[0632] ESI MS. Ci4H2iBrN3O3S m / z [M+H]+ calc. 390.0, found 390.0.Example 64: Suzuki Coupling procedure C

[0633] Under nitrogen atmosphere, K2CO3(17.0 mg, 0.12 mmol, 1.20 equiv) and boronic acid 13 (0.12 mmol, 1.20 equiv) were added to a solution of the 4-bromothiazole derivative 12 (0.10 mmol, 1.00 equiv) in 1,2 DME (1.0 mL). The resulting solution was purged with N2for 5 min. Then Pd(PPh3)4 (11.0 mg, 0.01 mmol 0.10 equiv) was added to the reaction mixture under N2atmosphere, and the solution was stirred at 90 °Cfor 12 h (progress of reaction was monitored by LCMS). Upon completion of the reaction, the solvent was evaporated under reduced pressure. The crude mixture was diluted with CH2CI2and water. The aqueous layer was extracted with CH2CI2(3 * 10). The combined organic layer was dried over Na2SO4, concentrated, and purified by ISCO flash chromatography.Example 65: Suzuki Coupling procedure D

[0634] Under nitrogen atmosphere, to a solution of the 4-bromothiazole derivative 12 (0.10 mmol, 1.00 equiv) and boronic acid 13 (0.12 mmol, 1.20 equiv) in 1 ,2 DME / EtOH (1 :0.3 ml_, v / v 3 / 1) was added 2N aqueous Na2CO3solution (0.12 mL, 0.12 mmol, 1.10 equiv). The resulting solution was purged with N2for 5 min. Then Pd(dppf)CI2- CH2CI2(16.0 mg, 0.02 mmol, 0.20 equiv) was added to the reaction mixture under N2atmosphere and stirred at 90 °Cfor 6-12 h (progressof reaction was monitored by LCMS). Upon completion of the reaction, solvent was evaporated under reduced pressure. The crude mixture was diluted with CH2CI2 and water. The aqueous layer was extracted with CH2CI2 (3 x 10). The organic layers were dried over Na2SC>4, concentrated, and purified by ISCO flash column chromatography.Example 66: Synthesis of SW389000

[0635] (S)- / V-((4-(4-Cyanophenyl)thiazol-2-yl)methyl)piperidine-3-carboxamide

[0636] Synthesized by general procedure B and Suzuki coupling procedure C.

[0637] Yield: 62% (over two steps).

[0638] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 68.11 - 8.08 (m, 2H), 7.99 (s, 1 H),7.79 - 7.66 (m, 2H), 4.80 (s, 1 H), 4.68 (d, J = 16.2 Hz, 1 H), 3.35 - 3.32 (m, 1 H), 3.30 - 3.28 (m,1 H), 3.25 - 3.19 (m, 1 H), 3.15 - 3.08 (m, 1 H), 2.90 - 2.84 (m, 1H), 2.12 - 2.06 (m, 1 H), 2.01 - 1.78 (m, 3H).

[0639] ESI MS. C17H19N4OS m / z [M+H]+ calc. 327.1, found 327.1.Example 67: Synthesis of SW389999

[0640] Synthesis of (S)-1-(2-methoxyacetyl)piperidine-3-carboxylic acid (SW388999).

[0641] Methyl (S)-1-(2-methoxyacetyl)piperidine-3-carboxylate (19) Compound 19 was synthesized from 17 analogous to general procedure B.

[0642] Yield: 49% (over two steps).

[0643] ESI MS. CIOHI8N04m / z [M+H]+ calc. 216.1, found 216.1.

[0644] (S)-1-(2-Methoxyacetyl)piperidine-3-carboxylic acid (SW388999) A mixture of methyl ester 19 (30.0 mg, 0.14 mmol, 1.00 equiv), lithium hydroxide (63.0 mg, 0.42 mmol, 3.00 equiv), THF (1.0 mL), H2O (0.3 mL) and CH3OH (0.3 mL) were stirred at room temperature for 2 h. The organic solvent was removed under reduced pressure, and the residue obtained was then acidified to pH 2 with 1 N HCI, and the mixture was extracted with EtOAc (3 * 20 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the acid which was purified by washing with hexane.

[0645] Yield: 65%.

[0646] 1H NMR (400 MHz, MeOD-ck) 54.43 - 4.09 (m, 2.5H), 3.80 - 3.63 (m, 1 ,5H), 3.53 - 3.46 (m, 0.5H), 3.39 (s, 3H), 3.37 - 3.33 (m, 0.5H), 3.18 - 2.99 (m, 1H), 2.66 - 2.41 (m, 1 H), 2.16 - 1.95 (m, 1 H), 1.95 - 1.61 (m, 2H), 1.61 - 1.43 (m, 1 H).

[0647] ESI MS. C9H16NO4 m / z [M+H]+ calc. 202.1 , found 202.1.Example 68: Synthesis of SW337760

[0648] (S)-1-(Dimethylglycyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3-carboxamide (SW337760).

[0649] Synthesized by general procedure A.

[0650] Yield: 62%. Purified by ISCO flash column chromatography (95:5 CH2Cl2:MeOH v / v).

[0651] 1H NMR (500 MHz, MeOD-cL) mixture of rotamers: <57.91 - 7.88 (m, 2H), 7.73 (d, 1 H), 7.43 - 7.39 (m, 2H), 7.36 - 7.29 (m, 1 H), 4.81 - 4.64 (m, 2H), 4.47 - 4.43 (m, 0.5H), 4.20 (d, J = 15.6 Hz, 0.5H), 4.07 - 3.97 (m, 1 H), 3.79 - 3.54 (m, 2.0H), 3.48 - 3.43 (m, 0.5H), 3.35 - 3.33 (m, 0.5H), 3.18 - 3.12 (m, 0.5H), 3.08 - 3.03 (m, 0.5H), 2.79 (d, J = 1.4 Hz, 6H), 2.65 - 2.60 (m, 0.5H), 2.52 - 2.46 (m, 0.5H), 2.10 - 2.04 (m, 1 H), 2.01 - 1.72 (m, 2H), 1.64 - 1.54 (m, 1 H).

[0652] ESI MS. C20H27N4O2S m / z [M+H]+ calc. 387.2, found 387.1.Example 69: Synthesis of SW337761

[0653] (S)-1-Butyryl- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3-carboxamide (SW337761).xvm?7$$

[0654] Synthesized by general procedure A.

[0655] Yield: 74%. Purified by ISCO flash column chromatography (98:2 CH2Cl2:MeOH v / v).

[0656] 1H NMR (500 MHz, MeOD-d4) mixture of rotamers: 57.91 - 7.88 (m, 2H), 7.72 (d, J =4.7 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.35 - 7.31 (m, 1H), 4.77 - 4.67 (m, 2H), 4.57 - 4.53 (m, 0.5H), 4.34-4.30 (m, 0.5H) 3.99-3.88 (m, 1H), 3.36-3.33 (m, 0.5H), 3.14-3.09 (m, 0.5H), 2.89-2.76 (m, 1H) 2.55-2.33 (m, 3H), 2.07- 2.00 (m, 1H), 1.86- 1.76 (m, 2H), 1.65- 1.40 (m, 3H), 0.98- 0.94 (m, 3H).

[0657] ESI MS. C20H26N3O2S m / z [M+H]+ calc.372.2, found 372.1.Example 70: Synthesis of SW337762

[0658] (S)-1-Acetyl-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3-carboxamide (SW337762).

[0659] Synthesized by general procedure A.

[0660] Yield: 82%. Purified by ISCO flash column chromatography (98:2 CH2Cl2: eOH v / v).

[0661] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 57.91 - 7.88 (m, 2H), 7.72 (d, J =2.8 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.36 - 7.30 (m, 1H), 4.78 - 4.70 (m, 2H), 4.57 - 4.52 (m, 0.5H), 4.27-4.21 (m, 0.5H), 3.93-3.83 (m, 1H), 3.41 -3.34 (m, 0.5H), 3.16-3.09 (m, 0.5H), 2.89-2.81 (m, 1H), 2.56 - 2.38 (m, 1H), 2.11 (d, J = 9.4 Hz, 3H), 2.06- 1.99 (m, 1H), 1.87 - 1.74 (m, 2H), 1.60-1.41 (m, 1H).

[0662] ESI MS. C18H22N3O2S m / z [M+H]+ calc.344.1, found 344.1.Example 71 : Synthesis of SW337763

[0663] (S)-1-(Methylsulfonyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3-carboxamide (SW337763).

[0664] Synthesized by general procedure A.

[0665] Yield: 60%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0666] 1H NMR (400 MHz, MeOD-ck) mixture of rotamers: 67.91 - 7.88 (m, 2H), 7.72 (s, 1 H), 7.46 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1 H), 4.72 (d, J = 0.9 Hz, 2H), 3.85 - 3.81 (m, 1 H), 3.71 - 3.66 (m, 1 H), 2.92 - 2.85 (m, 4H), 2.78 - 2.70 (m, 1 H), 2.65 - 2.57 (m, 1 H), 2.05 - 1.99 (m, 1H), 1.92 - 1.83 (m, 1 H), 1.72 - 1.63 (m, 2H).

[0667] ESI MS. C17H22N3O3S2 m / z [M+H]+ calc. 380.1 , found 380.2.Example 72: Synthesis of SW337764

[0668] (S)-1-(Cyclopropanecarbonyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW337764).

[0669] Synthesized by general procedure A.

[0670] Yield: 60%. Purified by ISCO flash column chromatography (97:3 CH2Cl2: eOH v / v).

[0671] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 6 7.87 - 7.84 (m, 2H), 7.63 (d, J = 2.3 Hz, 1 H), 7.42 - 7.37 (m, 2H), 7.34 - 7.29 (m, 1 H), 4.78 - 4.66 (m, 2H), 4.52 - 4.49 (m, 0.5H), 4.36 - 4.30 (m, 1H), 4.22 (d, J = 13.7 Hz, 0.5H), 3.44 - 3.34 (m, 0.5H), 3.25 - 3.19 (m, 0.5H) 2.96 - 2.90 (m, 0.5H), 2.80 - 2.74 (m, 0.5H), 2.56 - 2.39 (m, 1 H), 2.10 - 2.06 (m, 1 H), 1.97 - 1.73 (m, 3H), 1.62 - 1.43 (m, 1 H), 0.91 - 0.72 (m, 4H).

[0672] ESI MS. C20H24N3O2S m / z [M+H]+ calc. 370.2, found 370.1.Example 73: Synthesis of SW337765

[0673] (S)-1-(Cyclopentanecarbonyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW337765).

[0674] Synthesized by general procedure A.

[0675] Yield: 61%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0676] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 8.01 - 7.77 (m, 2H), 7.72 (d, J = 4.1 Hz, 1 H), 7.43 - 7.39 (m, 2H), 7.37 - 7.23 (m, 1 H), 4.80 - 4.62 (m, 2H), 4.55 - 4.50 (m, 0.5H), 4.41 - 4.36 (m, 0.5H), 4.15 - 4.05 (m, 0.5H), 4.03 - 3.99 (m, 0.5H), 3.35 - 3.32 (m, 0.5H), 3.21 - 2.97 (m, 1.5H), 2.93 - 2.87(m, 0.5H), 2.78 - 2.71 (m, 0.5H), 2.52 - 2.37 (m, 1 H), 2.12 - 2.01 (m, 1 H), 1.96 - 1.33 (m, 11 H).

[0677] ESI MS. C22H28N3O2S m / z [M+H]+ calc. 398.2, found 398.1.Example 74: Synthesis of SW337766

[0678] Methyl(S)-3-(((4-phenylthiazol-2-yl)methyl)carbamoyl)piperidine-1 -carboxylate (SW337766).

[0679] Synthesized by general procedure A.

[0680] Yield: 63%. Purified by ISCO flash column chromatography (97:3 CHhC^MeOH v / v).

[0681] 1H NMR (400 MHz, MeOD-cU) mixture of rotamers: 57.88 - 7.85 (m, 2H), 7.64 - 7.63 (m, 1 H), 7.42 - 7.38 (m, 2H), 7.34 - 7.29 (m, 1 H), 4.71 (s, 2H), 4.19 - 4.12 (m, 1 H), 4.07 - 4.01 (m, 1 H), 3.68 (s, 3H), 3.01 - 2.85 (m, 2H), 2.47 - 2.40 (m, 1H), 2.04 - 1.98 (m, 1 H), 1.80 - 1.68 (m, 2H), 1.55 - 1.43 (m, 1 H).

[0682] ESI MS. C18H22N3O3S m / z [M+H]+ calc. 360.1 , found 360.1.Example 75: Synthesis of SW337767

[0683] (S)-1-(3-Methylbutanoyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW337767).

[0684] Synthesized by general procedure A.

[0685] Yield: 48%. Purified by ISCO flash column chromatography (98:2 CH2Ch:MeOH v / v).

[0686] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.99 - 7.88 (m, 2H), 7.72 (d, J = 3.8 Hz, 1 H), 7.44 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1 H), 4.79 - 4.63 (m, 2H), 4.61 - 4.54 (m, 0.5H), 4.38 - 4.34 (m, 0.5H), 4.02 - 3.92 (m, 1 H), 3.36 - 3.32 (m, 0.5H), 3.17 - 3.10 (m, 0.5H), 2.91 - 2.75 (m, 1 H), 2.53 - 2.38 (m, 1 H), 2.32 - 2.28 (m, 2H), 2.11 - 1.99 (m, 2H), 1.88 - 1.77 (m, 2H), 1.53 - 1.43 (m, 1 H), 0.98 - 0.95 (m, 6H).

[0687] ESI MS. C21H28N3O2S m / z [M+H]+ calc. 386.2, found 386.1.Example 76: Synthesis of SW337768

[0688] (S)-1-lsobutyryl-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3-carboxamide (SW337768).

[0689] Synthesized by general procedure A.

[0690] Yield: 62%. Purified by ISCO flash column chromatography (98:2 CH2Cl2:MeOH v / v).

[0691] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.91 - 7.88 (m, 2H), 7.72 (d, J = 3.0 Hz, 1 H), 7.45 - 7.38 (m, 2H), 7.36 - 7.29 (m, 1 H), 4.78 - 4.66 (m, 2H), 4.59 - 4.53 (m, 0.5H), 4.38 - 4.35 (m, 0.5H), 4.09 - 3.98 (m, 1 H), 3.38 - 3.32 (m, 0.5H), 3.18 - 3.11 (m, 0.5H), 3.05 - 2.70 (m, 2H), 2.54 - 2.38 (m, 1 H), 2.09 - 1.99 (m, 1 H), 1.90 - 1.77 (m, 2H), 1.60 - 1.41 (m, 1H), 1.13 - 1.07 (m, 6H).

[0692] ESI MS. C20H26N3O2S m / z [M+H]+ calc. 372.2, found 372.1.Example 77: Synthesis of SW337769

[0693] (S)-A / -((4-Phenylthiazol-2-yl)methyl)-1-propionylpiperidine-3-carboxamide (SW337769).

[0694] Synthesized by general procedure A.

[0695] Yield: 75%. Purified by ISCO flash column chromatography (98:2 CH2Cl2: eOH v / v).

[0696] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 57.91 - 7.88 (m, 2H), 7.72 - 7.71 (m, 1 H), 7.43 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1 H), 4.78 - 4.66 (m, 2H), 4.58 - 4.52 (m, 0.5H), 4.32 - 4.27 (m, 0.5H), 3.98 - 3.85 (m, 1 H), 3.37 - 3.31 (m, 0.5H), 3.14 - 3.06 (m, 0.5H), 2.90 - 2.76 (m, 1 H), 2.54 - 2.37 (m, 3H), 2.07 - 1.98 (m, 1 H), 1.87 - 1.74 (m, 2H), 1.57 - 1.41 (m, 1 H), 1.12 - 1.08 (m, 3H).

[0697] ESI MS. C19H24N3O2S m / z [M+H]+ calc. 358.2, found 358.1.Example 78: Synthesis of SW337851

[0698] (S)-1-Benzoyl-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3-carboxamide (SW337851).

[0699] Synthesized by general procedure A.

[0700] Yield: 67%. Purified by ISCO flash column chromatography (98:2 CH2Cl2:MeOH v / v).

[0701] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.91 - 7.86 (m, 2H), 7.70 (d, J = 19.2 Hz, 1 H), 7.50 - 7.30 (m, 8H), 4.75 - 4.61 (m, 3H), 3.81 - 3.65 (m, 1 H), 3.34 - 3.32 (m, 0.5H),3.20 - 3.13 (m, 1 H), 3.01 - 2.95 (m, 0.5H), 2.60 - 2.50 (m, 1 H), 2.16 - 2.04 (m, 1 H), 1.94 - 1.50 (m, 3H).

[0702] ESI MS. C23H24N3O2S m / z [M+H]+ calc. 406.2, found 406.2.Example 79: Synthesis of SW337852

[0703] (S)-1-(2-Hydroxyacetyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3-carboxamide (SW337852).

[0704] Synthesized by general procedure A.

[0705] Yield: 42%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0706] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 67.91 - 7.88 (m, 2H), 7.72 (s, 1 H),7.43 - 7.38 (m, 2H), 7.36 - 7.30 (m, 1H), 4.78 - 4.65 (m, 2H), 4.56 - 4.51 (m, 0.5H), 4.27 - 4.19 (m, 2.5H), 3.77 - 3.65 (m, 1 H), 3.30 - 3.27 (m, 0.5H), 3.08 - 3.01 (m, 0.5H), 2.96 - 2.88 (m, 1 H), 2.56 - 2.42 (m, 1 H), 2.08 - 2.01 (m, 1 H), 1.88 - 1.75 (m, 2H), 1.60 - 1.46 (m, 1H).

[0707] ESI MS. C18H22N3O3S m / z [M+H]+ calc. 360.1 , found 360.0.Example 80: Synthesis of SW337853

[0708] (S)-A / 1-Ethyl- / V3-((4-phenylthiazol-2-yl)methyl)piperidine-1,3-dicarboxamide (SW337853).

[0709] Synthesized by general procedure A.

[0710] Yield: 45%. Purified by ISCO flash column chromatography (97:3 CH2Cl2: eOH v / v).

[0711] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 67.91 - 7.88 (m, 2H), 7.72 (s, 1 H),7.44 - 7.39 (m, 2H), 7.35 - 7.31 (m, 1 H), 4.72 (d, J = 1.6 Hz, 2H), 4.12 - 4.07 (m, 1 H), 3.92 - 3.88 (m, 1 H), 3.17 (q, J = 7.2 Hz, 2H), 2.98 (dd, J = 13.4, 10.7 Hz, 1 H), 2.85 (ddd, J = 13.5, 11.9, 2.8 Hz, 1 H), 2.44 (tt, J = 10.9, 3.9 Hz, 1H), 2.04 - 2.00 (m, 1 H), 1.83 - 1.71 (m, 2H), 1.56 - 1.44 (m, 1 H), 1.10 (t, J = 7.2 Hz, 3H).

[0712] ESI MS. C19H25N4O2S m / z [M+H]+ calc. 373.2, found 373.1.Example 81 : Synthesis of SW337854

[0713] (S)- / V-((4-Phenylthiazol-2-yl)methyl)-1-picolinoylpiperidine-3-carboxamide (SW337854).

[0714] Synthesized by general procedure A.

[0715] Yield: 42%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0716] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 68.60 - 8.57 (m, 1 H), 7.96 - 7.85 (m, 3H), 7.71 (d, J = 18.0 Hz, 1H), 7.62 - 7.56 (m, 1 H), 7.52 - 7.45 (m, 1 H), 7.43 - 7.39 (m, 2H), 7.35- 7.31 (m, 1 H), 4.75 - 4.61 (m, 2.5H), 4.42 - 4.36 (m, 0.5H) 3.79 - 3.75 (m, 0.5H), 3.67 - 3.62 (m, 0.5H), 3.43 - 3.37 (m, 0.5H), 3.18 - 3.09 (m, 1.5H), 2.67 - 2.59 (m, 1 H), 2.13 - 2.06 (m, 1 H), 1.94- 1.56 (m, 3H).

[0717] ESI MS. C22H23N4O2S m / z [M+H]+ calc. 407.1 , found 407.0.Example 82: Synthesis of SW337855

[0718] (S)-1-(Methylglycyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3-carboxamide

[0719] Synthesized by general procedure A.

[0720] Yield: 92%. Purified by ISCO flash column chromatography (19:1 CH2Cl2:MeOH v / v).

[0721] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.91 - 7.88 (m, 2H), 7.72 (d, J = 1.7 Hz, 1 H), 7.43 - 7.38 (m, 2H), 7.35 - 7.30 (m, 1 H), 4.79 - 4.66 (m, 2H), 4.57 - 4.51 (m, 0.5H), 4.19 - 4.14 (m, 0.5H), 3.81 - 3.74 (m, 1 H), 3.50 - 3.43 (m, 2H), 3.39 - 3.33 (m, 0.5H), 3.12 - 2.86 (m, 1.5H), 2.55 - 2.33 (m, 4H), 2.07 - 2.01 (m, 1H), 1.90 - 1.73 (m, 2H), 1.58 - 1.44 (m, 1 H).

[0722] ESI MS. Ci9H25N4O2S m / z [M+H]+ calc. 373.2, found 373.2.Example 83: Synthesis of SW337856

[0723] (3S)-1-(2-Methoxypropanoyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW337856).

[0724] Synthesized by general procedure A.

[0725] Yield: 35%. Purified by ISCO flash column chromatography (97:3 CH2Ch:MeOH v / v).

[0726] 1H NMR (400 MHz, MeOD-ck) mixture of rotamers: 67.92 - 7.90 (m, 2H), 7.73 (s, 1 H), 7.44 - 7.40 (m, 2H), 7.35 -7.32 (m, 1 H), 4.80 - 4.68 (m, 2H), 4.58 - 4.53 (m, 0.5H), 4.46 - 4.03 (m, 2.5H), 3.42 - 3.36 (m, 0.5H), 3.32 - 3.24 (m, 3H), 3.19 - 3.11 (m, 0.5H), 3.02 - 2.70 (m, 1 H), 2.58 - 2.41 (m, 1 H), 2.12 - 2.03(m, 1H), 1.91 - 1.77 (m, 2H), 1.62 - 1.46 (m, 1 H), 1.34 - 1.30 (m, 3H).

[0727] ESI MS. C20H26N3O3S m / z [M+H]+ calc. 388.2, found 388.1.Example 84: Synthesis of SW337857

[0728] (S)-1-(2-Methoxy-2-methylpropanoyl)-W-((4-phenylthiazol-2-yl)methyl)piperidine- 3-carboxamide (SW337857).

[0729] Synthesized by general procedure A.

[0730] Yield: 45%. Purified by ISCO flash column chromatography (97:3 CH2Cl2: eOH v / v).

[0731] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 67.91 - 7.88 (m, 2H), 7.73 (s, 1 H), 7.43 - 7.39 (m, 2H), 7.35 - 7.31 (m, 1 H), 5.07 - 4.96 (m, 0.5H) 4.72 - 4.50 (m, 3.5H), 3.26 - 3.13 (s, 3.5H), 3.05 - 2.87 (m, 0.5H), 2.81 (s, 0.5H), 2.68 - 2.41 (m, 1.5H), 2.09 - 1.99 (m, 1H), 1.87 - 1.80 (m, 2H), 1.60 - 1.37 (m, 7H).

[0732] ESI MS. C21 H28N3O3S m / z [M+H]+ calc. 402.2, found 402.1.Example 85: Synthesis of SW337858

[0733] (S)-1-(2-Ethoxyacetyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3-carboxamide (SW337858).

[0734] Synthesized by general procedure A.

[0735] Yield: 84%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0736] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 6 7.91 - 7.88 (m, 2H), 7.71 (d, J = 4.0 Hz, 1 H), 7.43 - 7.39 (m, 2H), 7.34 - 7.30 (m, 1 H), 4.77 - 4.67 (m, 2H), 4.55 - 4.49 (m, 0.5H), 4.27 - 4.07 (m, 2.5H), 3.93 - 3.81 (m, 1 H), 3.58 - 3.50 (m, 2H), 3.35 - 3.32 (m, 0.5 H), 3.11 - 3.04 (m, 0.5H), 2.92 - 2.81 (m, 1 H), 2.57 - 2.41 (m, 1 H), 2.07 - 2.01 (m, 1 H), 1.89 - 1.75 (m, 2H), 1.60 - 1.44 (m, 1 H), 1.24 - 1.18 (m, 3H).

[0737] ESI MS. C20H26N3O3S m / z [M+H]+ calc. 388.2, found 388.1.

[0738] [a]256D+25.44 (c 0.55, CHCI3).Example 86: Synthesis of SW337859

[0739] (3S)-A / -((4-Phenylthiazol-2-yl)methyl)-1-(tetrahydro-2H-pyran-2- carbonyl)piperidine-3-carboxamide (SW337859).

[0740] Synthesized by general procedure A.

[0741] Yield: 58%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0742] 1H NMR (500 MHz, MeOH-d4) mixture of rotamers: 57.93 - 7.87 (m, 2H), 7.74 - 7.71 (m, 1 H), 7.43 - 7.38 (m, 2H), 7.35 - 7.30 (m, 1 H), 4.74 - 4.69 (m, 2H), 4.56 - 4.48 (m, 0.5H), 4.36 - 4.30 (m, 0.5H), 4.29 - 4.18 (m, 1 H), 4.17 - 3.93 (m, 2H), 3.60 - 3.49 (m, 1 H), 3.29 - 3.25 (m, 0.5H), 3.18 - 3.00 (m, 0.5H), 2.93 - 2.73 (m, 1 H), 2.60 - 2.39 (m, 1H), 2.09 - 2.02 (m, 1H), 1.95 - 1.75 (m, 3H), 1.74 - 1.41 (m, 6H).

[0743] ESI MS. C22H28N3O3S m / z [M+H]+ calc. 414.2, found 414.1.Example 87: Synthesis of SW337860

[0744] (S)-1-(2-Methoxybenzoyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW337860).

[0745] Synthesized by general procedure A.

[0746] Yield: 61%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0747] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 57.95 - 7.82 (m, 2H), 7.76 - 7.65 (m, 1 H), 7.45 - 7.39 (m, 3H), 7.37 - 7.30 (m, 1 H), 7.28 - 7.13 (m, 1H), 7.10 - 6.97 (m, 2H), 4.75 - 4.53 (m, 3H), 3.89 - 3.84 (m, 3H), 3.59 - 3.51 (m, 0.5H), 3.45 - 3.42 (m, 0.5H), 3.28 - 2.85 (m, 2H), 2.67 - 2.28 (m, 1 H), 2.17 - 2.02 (m, 1 H), 1.97 - 1.53 (m, 3H).

[0748] ESI MS. C24H26N3O3S m / z [M+H]+ calc. 436.2, found 436.2.Example 88: Synthesis of SW337861

[0749] (S)-A / -((4-Phenylthiazol-2-yl)methyl)-1-(®-tetrahydrofuran-2-carbonyl)piperidine- 3-carboxamide (SW337861).

[0750] Synthesized by general procedure A.

[0751] Yield: 63%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0752] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.91 - 7.88 (m, 2H), 7.72 (d, J = 1 .9 Hz, 1 H), 7.43 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1 H), 4.79 - 4.66 (m, 3H), 4.56 - 4.46 (m, 0.5H), 4.38 - 4.26 (m, 0.5H), 4.11 - 3.81 (m, 3H), 3.39 - 3.31 (m, 0.5H), 3.16 - 3.08 (m, 0.5H), 2.98 - 2.76 (m, 1 H), 2.58 - 2.39 (m, 1H), 2.30 - 1.73 (m, 7H). 1.65 - 1.43 (m, 1 H).

[0753] ESI MS. C2IH26N3O3S m / z [M+H]+ calc. 400.2, found 400.1.Example 89: Synthesis of SW337862

[0754] (S)-A / -((4-Phenylthiazol-2-yl)methyl)-1-((S)-tetrahydrofuran-2-carbonyl)piperidine- 3-carboxamide (SW337862).

[0755] Synthesized by general procedure A.

[0756] Yield: 61%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0757] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.91 - 7.88 (m, 2H), 7.72 (d, J = 2.6 Hz, 1 H), 7.43 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1 H), 4.78 - 4.70 (m, 3H), 4.57 - 4.52 (m, 0.5H), 4.38 - 4.33 (m, 0.5H), 4.12 - 3.80 (m, 3H), 3.30 - 3.25 (m, 0.5H), 3.16 - 3.09 (m, 0.5H), 2.96 - 2.86 (m, 0.5H), 2.79 - 2.72 (m, 0.5H), 2.60 - 2.39 (m, 1 H), 2.29 - 1.74 (m, 7H), 1.58 - 1.43 (m, 1 H).

[0758] ESI MS. C2IH26N3O3S m / z [M+H]+ calc. 400.2, found 400.1.Example 90: Synthesis of SW337863

[0759] (S)-1-(2-Phenoxyacetyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW337863).

[0760] Synthesized by general procedure A.

[0761] Yield: 67%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0762] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.90 - 7.88 (m, 2H), 7.70 (d, J = 6.9 Hz, 1 H), 7.43 - 7.38 (m, 2H), 7.37 - 7.20 (m, 3H), 6.98 - 6.91 (m, 3H), 4.87 - 4.67 (m, 4H), 4.56 - 4.52 (m, 0.5H), 4.18 - 4.12 (m, 0.5H), 3.96 - 3.93 (m, 1 H), 3.49 - 3.43 (m, 0.5H), 3.20 - 3.13 (m, 0.5H), 3.06 - 2.91 (m, 1 H), 2.62 - 2.42 (m, 1 H), 2.09 - 2.02 (m, 1 H), 1.92 - 1 .77 (m, 2H), 1.66 - 1.48 (m, 1 H).

[0763] ESI MS. C24H26N3O3S m / z [M+H]+ calc. 436.2, found 436.0.Example 91 : Synthesis of SW337880

[0764] (S)-A / -Benzyl-1-(2-methoxyacetyl)piperidine-3-carboxamide (SW337880).

[0765] Synthesized by general procedure A.

[0766] Yield: 39%. Purified by ISCO flash column chromatography (EtOAc).

[0767] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 67.34 - 7.22 (m, 5H), 4.99 - 4.09 (m, 5H), 3.84 - 3.77 (m, 1 H), 3.38 (d, J = 2.9 Hz, 3H), 3.27 - 3.24 (m, 0.5H), 3.09 - 3.02 (m, 0.5H), 2.89 - 2.79 (m, 1 H), 2.49 -2.34 (m, 1 H), 2.01 - 1.95 (m, 1 H), 1.84 - 1.73 (m, 2H), 1.58 - 1.42 (m, 1 H).

[0768] ESI MS. CI6H23N2O3 m / z [M+H]+ calc. 291 .2, found 291.1.Example 92: Synthesis of SW337881

[0769] (S)-1-(2-(2-Methoxyethoxy)acetyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW337881).

[0770] Synthesized by general procedure A.

[0771] Yield: 43%. Purified by ISCO flash column chromatography (19:1 CH2CI2:MeOH v / v).

[0772] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.91 - 7.89 (m, 2H), 7.72 (d, J = 2.8 Hz, 1 H), 7.43 - 7.39 (m, 2H), 7.35 - 7.31 (m, 1 H), 4.78 - 4.61 (m, 2H), 4.54 - 4.49 (m, 0.5H), 4.35 - 4.17 (m, 2.5H), 3.96 - 3.82 (m, 1 H), 3.68 - 3.54 (m, 4H), 3.36 - 3.31 (m, 3.5H), 3.15 - 3.05 (m, 0.5H), 2.93 - 2.82 (m, 1 H), 2.59 - 2.41 (m, 1 H), 2.09 - 1.99 (m, 1 H), 1.88 - 1.75 (m, 2H), 1.63 - 1.48 (m, 1 H).

[0773] ESI MS. C2iH28N3O4S m / z [M+H]+ calc. 418.2, found 418.2.Example 93: Synthesis of SW337882

[0774] 1-(2-Methoxyacetyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-4-carboxamide (SW337882).

[0775] Synthesized by procedure analogous to general procedure A.

[0776] Yield: 62%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0777] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 57.90 - 7.87 (m, 2H), 7.71 (s, 1 H), 7.43 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1 H), 4.71 (s, 2H), 4.54 - 4.47 (m, 1H), 4.21 - 4.10 (m, 2H), 3.95 - 3.89 (m, 1 H), 3.40 (s, 3H), 3.15 - 3.08 (m, 1 H), 2.80 - 2.73 (m, 1H), 2.63 - 2.55 (m, 1 H), 1.93 - 1.87 (m, 2H), 1.76 - 1.59 (m, 2H).

[0778] ESI MS. C19H24N3O4S m / z [M+H]+ calc. 374.1 , found 374.2.Example 94: Synthesis of SW337874

[0779] (S)-A / -((4-Phenylthiazol-2-yl)methyl)-1-(2-propoxyacetyl)piperidine-3-carboxamide (SW337874).

[0780] Synthesized by general procedure A.

[0781] Yield: 53%. Purified by ISCO flash column chromatography (97:3 CH2Ch:MeOH v / v).

[0782] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.99 - 7.88 (m, 2H), 7.73 (d, J = 1.7 Hz, 1 H), 7.43 - 7.37 (m, 2H), 7.35 - 7.30 (m, 1 H), 4.77 - 4.67 (m, 2H), 4.55 - 4.49 (m, 0.5H), 4.27 - 4.13 (m, 2.5H), 3.96 - 3.86 (m, 1 H), 3.49 - 3.41 (m, 2H), 3.36 - 3.31(m, 0.5H), 3.13 - 3.06 (m, 0.5H), 2.93 - 2.84 (m, 1 H), 2.59 - 2.42 (m, 1 H), 2.09 - 1.99 (m, 1 H), 1.86 - 1 .76 (m, 2H), 1.67- 1.49 (m, 3H), 0.98 - 0.89 (m, 3H).

[0783] ESI MS. C21H28N3O3S m / z [M+H]+ calc. 402.2, found 402.1.Example 95: Synthesis of SW337875

[0784] (S)-1-(2-Butoxyacetyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3-carboxamide(SW337875).

[0785] Synthesized by general procedure A.

[0786] Yield: 53%. Purified by ISCO flash column chromatography (49:1 CH2Cl2:MeOH v / v).

[0787] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.91 - 7.88 (m, 2H), 7.72 (d, J = 2.2 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.32 (t, J = 7.4 Hz, 1 H), 4.77 - 4.67 (m, 2H), 4.54 - 4.49 (m, 0.5H), 4.25 - 4.12 (m, 2.5H), 3.95 - 3.83 (m, 1H), 3.53 - 3.42 (m, 2H), 3.35 - 3.33 (m, 0.5H), 3.11- 3.04 (m, 0.5H), 2.92 - 2.81 (m, 1 H), 2.56 - 2.41 (m, 1 H), 2.09 - 1.98 (m, 1 H), 1.86 - 1.75 (m, 2H), 1.62 - 1.29 (m, 5H), 0.95 - 0.88 (m, 3H).

[0788] ESI MS. C22H3ON303S m / z [M+H]+ calc. 416.2, found 416.1.Example 96: Synthesis of SW337876

[0789] (S)-1-(2-lsobutoxyacetyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW337876).

[0790] Synthesized by general procedure A.

[0791] Yield: 59%. Purified by ISCO flash column chromatography (49:1 CH2Cl2:MeOH v / v).

[0792] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.91 - 7.88 (m, 2H), 7.72 (d, J =1.8 Hz, 1 H), 7.43 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1 H), 4.76 - 4.67 (m, 2H), 4.54 - 4.49 (m, 0.5H), 4.26 - 4.09 (m, 2.5H), 3.99 - 3.88 (m, 1 H), 3.36 - 3.33 (m, 0.5H), 3.29 - 3.20 (m, 2H), 3.13 - 3.06 (m, 0.5H), 2.93 - 2.81 (m, 1 H), 2.57 - 2.42 (m, 1 H), 2.09 - 1.99 (m, 1 H), 1.94 - 1.76 (m, 3H), 1.63 - 1.46 (m, 1 H), 0.93 - 0.87 (m, 6H).

[0793] ESI MS. C22H3ON303S m / z [M+H]+ calc. 416.2, found 416.1.Example 97: Synthesis of SW337877

[0794] (S)-1-(2-(Cyclopropylmethoxy)acetyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine- 3-carboxamide (SW337877).

[0795] Synthesized by general procedure A.

[0796] Yield: 53%. Purified by ISCO flash column chromatography (49:1 CH2Cl2: eOH v / v).

[0797] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 6 7.91 - 7.88 (m, 2H), 7.71 (d, J =1.9 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.32 (t, J = 7.4 Hz, 1 H), 4.78 - 4.65 (m, 2H), 4.54 - 4.49 (m, 0.5H), 4.29 - 4.15 (m, 2.5H), 3.95 - 3.82 (m, 1H), 3.41 - 3.33 (m, 2H), 3.29 - 3.27 (m, 0.5H), 3.12 - 3.04 (m, 0.5H), 2.92 - 2.84 (m, 1 H), 2.58 - 2.41 (m, 1 H), 2.09 - 1 .99 (m, 1 H), 1.87 - 1.75 (m, 2H), 1.62 - 1.44 (m, 1 H), 1.11 - 1.02 (m, 1 H), 0.57 - 0.43 (m, 2H), 0.28 - 0.17 (m, 2H).

[0798] ESI MS. C22H28N3O3S m / z [M+H]+ calc. 414.2, found 414.1.Example 98: Synthesis of SW337878

[0799] (S)-1-(2-Methoxyacetyl)- / V-(thiazol-2-ylmethyl)piperidine-3-carboxamide (SW337878).

[0800] Synthesized by general procedure A.

[0801] Yield: 41%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0802] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.44 - 7.42 (m, 1 H), 7.11 (d, J = 3.6 Hz, 1 H), 4.89 (s, 2H), 4.52 - 4.47 (m, 0.5H), 4.27 - 4.13 (m, 2.5H), 3.91 - 3.77 (m, 1H), 3.43 - 3.37 (m, 3.5H), 3.17 - 3.10 (m, 0.5H), 3.04 - 2.92 (m, 1 H), 2.75 - 2.61 (m, 1 H), 2.11 - 2.04 (m, 1 H), 1.90 - 1.78 (m, 2H), 1.64 - 1.47 (m, 1H).

[0803] ESI MS. C13H20N3O3S m / z [M+H]+ calc. 298.1 , found 298.0.Example 99: Synthesis of SW337879

[0804] (S)-1-(2-Methoxyacetyl)-A / -phenylpiperidine-3-carboxamide (SW337879).

[0805] Synthesized by procedure analogous to general procedure A.

[0806] Yield: 58%. Purified by ISCO flash column chromatography (EtOAc).

[0807] 1H NMR (400 MHz, MeOD-c / 4) mixture of rotamers: 57.56 - 7.53 (m, 2H), 7.32 - 7.28 (m, 2H), 7.11 - 7.07 (m, 1 H), 4.56 - 4.51 (m, 0.5H), 4.34 - 4.12 (m, 2.5H), 3.92 - 3.78 (m, 1 H), 3.40 (d, J = 3.3 Hz, 3H), 3.35 -3.32 (m, 0.5H), 3.14 - 3.05 (m, 0.5H), 2.95 - 2.80 (m, 1H), 2.62 - 2.48 (m, 1 H), 2.10 - 2.03 (m, 1 H), 1.90 - 1.78 (m, 2H), 1.63 - 1.47 (m, 1 H).

[0808] ESI MS. C15H21N2O3 m / z [M+H]+ calc. 277.1 , found 277.0.Example 100: Synthesis of SW337887

[0809] (S)-1-(2-lsopropoxyacetyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW337887).

[0810] Synthesized by general procedure A.

[0811] Yield: 58%. Purified by ISCO flash column chromatography (49:1 CH2CI2:MeOH v / v).

[0812] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 57.91 - 7.88 (m, 2H), 7.71 (d, J = 2.7 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.34 - 7.30 (m, 1H), 4.76 - 4.67 (m, 2H), 4.54 - 4.49 (m, 0.5H), 4.27 - 4.10 (m, 2.5H), 4.00- 3.87 (m, 1 H), 3.70 - 3.59 (m, 1H), 3.34- 3.28 (m, 0.5H), 3.11 -3.04 (m, 0.5H), 2.91 -2.81 (m, 1H), 2.58-2.41 (m, 1H), 2.09-1.99 (m, 1H), 1.86- 1.75 (m, 2H), 1.62 - 1.44 (m, 1H), 1.19- 1.15 (m,6H).

[0813] ESI MS. C2IH28N3O3S m / z [M+H]+ calc.402.2, found 402.2.Example 101: Synthesis of SW337888

[0814] (S)-1-(2-(tert-Butoxy)acetyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW337888).

[0815] Synthesized by general procedure A.

[0816] Yield: 68%. Purified by ISCO flash column chromatography (49:1 CH2CI2:MeOH v / v).

[0817] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 57.91 - 7.88 (m, 2H), 7.72 (d, J = 3.1 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1H), 4.75 - 4.69 (m, 2H), 4.55 - 4.50 (m, 0.5H), 4.30-4.26 (m, 0.5H), 4.21 -3.95 (m, 3H), 3.30-3.26 (m, 0.5H), 3.11 -3.04 (m, 0.5H), 2.89-2.77 (m, 1H), 2.61 -2.41 (m, 1H), 2.09-2.02 (m, 1H), 1.87- 1.75 (m, 2H), 1.64- 1.46 (m, 1H), 1.25- 1.21 (m, 9H).

[0818] ESI MS. C22H3ON303S m / z [M+H]+ calc.416.2, found 416.1.Example 102: Synthesis of SW387912

[0819] (S)-1-(2-Methoxyacetyl)-A / -((4-phenylthiazol-2-yl)methyl)pyrrolidine-3- carboxamide (SW387912).

[0820] Synthesized by procedure analogous to general procedure A.

[0821] Yield: 65%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0822] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 57.91 - 7.88 (m, 2H), 7.72 (d, J = 2.3 Hz, 1H), 7.43-7.39 (m, 2H), 7.35-7.30 (m, 1H), 4.78-4.69 (m, 2H), 4.09 (d, J= 1.9 Hz, 2H), 3.77 - 3.61 (m, 3H), 3.54 - 3.44 (m, 1 H), 3.40 (d, J = 1.2 Hz, 3H), 3.24 - 3.07 (m, 1 H), 2.30 - 2.07 (m, 2H).

[0823] ESI MS. CI8H22N3O3S m / z [M+H]+ calc. 360.1 , found 360.0.Example 103: Synthesis of SW387915

[0824] (S)-1-(2-Methoxyacetyl)-A / -((4-phenyl-1H-imidazol-2-yl)methyl)piperidine-3- carboxamide (SW387915).

[0825] Synthesized by general procedure A.

[0826] Yield: 59%. Purified by ISCO flash column chromatography (19:1 CH2CI2:MeOH v / v).

[0827] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.67 (d, J = 7.6 Hz, 2H), 7.37 - 7.33 (m, 3H), 7.22 (t, J = 7.4 Hz, 1 H), 4.56 - 4.40 (m, 2.5H), 4.28 - 4.10 (m, 2.5H), 3.87 - 3.74 (m, 1 H), 3.38 (s, 3H), 3.29 - 3.24 (m, 0.5H), 3.14 - 3.07 (m, 0.5H), 3.01 - 2.95 ( m, 0.5H), 2.86 - 2.79 (m, 0.5H), 2.50 - 2.39 (m, 1H), 2.03 - 1.97 (m, 1H), 1.86 - 1.74 (m, 2H), 1.58 - 1.42 (m, 1 H).

[0828] ESI MS. CI9H25N4O3m / z [M+H]+ calc. 357.2, found 357.1.Example 104: Synthesis of SW387916

[0829] (S)-1-(2-Methoxyacetyl)-N-(4-phenylthiazol-2-yl)piperidine-3-carboxamide (SW387916).

[0830] Synthesized by procedure analogous to general procedure A.

[0831] Yield: 55%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0832] 1H NMR (400 MHz, MeOD-cU) mixture of rotamers: <57.90 - 7.88 (m, 2H), 7.39 - 7.35 (m, 3H), 7.28 (t, J = 7.4 Hz, 1 H), 4.56 - 4.41 (m, 0.5H), 4.27 - 4.12 (m, 2.5H), 3.92 - 3.76 (m, 1 H), 3.40 (d, J = 2.1 Hz, 3H), 3.16 - 2.91 (m, 2H), 2.74 - 2.61 (m, 1 H), 2.13 - 2.07 (m, 1 H), 1.91 - 1.78 (m, 2H), 1.64 - 1.48 (m, 1 H).

[0833] ESI MS. CI8H22N3O3S m / z [M+H]+ calc. 360.1 , found 360.2.Example 105: Synthesis of SW387920

[0834] (S)-1-(2-Methoxyacetyl)- / V-methyl- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW387920).

[0835] To a solution of (S)-SW2930042 (20.0 mg, 0.05 mmol, 1.00 equiv) in THF (0.5 mL) was added NaH (10 mg, 0.16 mmol, 3.00 equiv) at 0°C, stirred for 5 min followed by addition of Mel (15.0 mg, 0.11 mmol, 2.00 equiv). The resulting reaction mixture was stirred overnight at room temperature. Then the reaction mixture was quenched by addition of ice cold water, extracted with EtOAc (3 x 10 mL) and dried over anhydrous Na2SC>4. The combined organic layer was then concentrated in vacuo and purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v) to furnish SW387920 (12.0 mg, 60% yield).

[0836] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 57.95 - 7.86 (m, 2H), 7.76 (s, 1 H), 7.45 - 7.40 (m, 2H), 7.36 - 7.31 (m, 1H), 5.18 - 4.95 (m, 2H), 4.86 - 4.80 (m, 0.5H), 4.61 - 4.54 (m, 0.5H), 4.43 - 4.36 (m, 0.5H), 4.28 - 4.09 (m, 1.5H), 3.94 - 3.83 (m, 1 H), 3.44 - 3.34 (m, 3H), 3.27 (s, 2H), 3.13 (s, 1 H), 3.10 - 2.95 (m, 2H), 2.90 - 2.76 (m, 1 H), 2.04 - 1.97 (m, 1 H), 1.86 - 1.71 (m, 2H), 1.66 - 1.47 (m, 1 H).

[0837] ESI MS. C20H26N3O3S m / z [M+H]+ calc. 388.2, found 388.1.Example 106: Synthesis of SW393111

[0838] (S)-1-(2-Methoxyacetyl)- / V-(2-(4-phenylthiazol-2-yl)ethyl)piperidine-3- carboxamide (SW393111).

[0839] Synthesized by general procedure A.

[0840] Yield: 67%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0841] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 5 7.92 - 7.86 (m, 2H), 7.68 (d, J = 6.6 Hz, 1 H), 7.45 - 7.25 (m, 3H), 4.47 - 4.42 (m, 0.5H), 4.31 - 4.00 (m, 2.5H), 3.80 - 3.68 (m, 1 H), 3.65 - 3.58 (m, 2H), 3.35 (d, J = 17.4 Hz, 3H), 3.30 - 3.24 (m, 2H), 3.21 - 3.15 (m, 0.5H), 3.05 - 2.98 (m, 0.5H), 2.83 - 2.73 (m, 1 H), 2.40 - 2.27 (m, 1H), 2.00 - 1 .84 (m, 1 H), 1.80 - 1.65 (m, 2H), 1.55 - 1.35 (m, 1 H).

[0842] ESI MS. C2OH26N303S m / z [M+H]+ calc. 388.2, found 388.1.Example 107: Synthesis of SW387923

[0843] (S)-1-(2-Methoxyacetyl)- / V-((4-(4-methoxyphenyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (SW387923).

[0844] Synthesized by general procedure B and Suzuki coupling procedure C.

[0845] Yield: 72%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0846] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 67.84 - 7.80 (m, 2H), 7.55 (s, 1 H), 6.98 - 6.95 (m, 2H), 4.77 - 4.64 (m, 2H), 4.54 - 4.50 (m, 0.5H), 4.25 - 4.10 (m, 2.5H), 3.87 - 3.78 (m, 4H), 3.38 (brs, 3H), 3.35 - 3.34 (m, 0.4H), 3.11 - 3.03 (m, 0.6H), 2.92 - 2.86 (m, 1 H), 2.55 - 2.41 (m, 1 H), 2.07 -1.96 (m, 1 H), 1.88 - 1.75 (m, 2H), 1.57 - 1.49 (m, 1 H).

[0847] 13C NMR (101 MHz, MeOH-d4) mixture of rotamers: 5175.9, 175.7, 170.5, 170.4, 170.1 , 170.1 , 161.3, 156.4, 128.7, 128.5, 115.1 , 112.71, 72.0, 71.9, 59.4, 55.8, 46.3, 45.4, 44.3, 44.0, 43.3, 41.8, 28.9, 28.8, 26.1 , 25.2.

[0848] ESI MS. C2OH26N304S m / z [M+H]+ calc. 404.2, found 404.

[0849] [a]256D+ 17.45 (c 0.27, CHCh).Example 108: Synthesis of SW387924

[0850] (S)-1-(2-Methoxyacetyl)-N-((4-(2-methoxyphenyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (SW387924).

[0851] Synthesized by general procedure B and Suzuki coupling procedure C.

[0852] Yield: 65%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0853] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: <58.09 (dd, J = 7.7, 1.8 Hz, 1 H), 7.90 (s, 1H), 7.34 - 7.29 (m, 1 H), 7.10 (d, J = 8.3 Hz, 1 H), 7.04 - 7.00 (m, 1 H), 4.77 - 4.66 (m, 2H), 4.57- 4.50 (m, 0.5H), 4.25 - 4.10 (m, 2.5H), 3.94 (s, 3H), 3.88 - 3.76 (m, 1 H), 3.39 (s, 3H), 3.37 - 3.33 (m, 0.5H), 3.12 - 3.04 (m, 0.5H), 2.93 - 2.87 (m, 1 H), 2.55 - 2.41 (m, 1 H), 2.10 - 1.99 (m, 1 H), 1.89- 1.76 (m, 2H), 1.61 - 1.46 (m, 1 H).

[0854] ESI MS. C20H26N3O4S m / z [M+H]+ calc. 404.2, found 404.Example 109: Synthesis of SW387925

[0855] (S)-1-(2-Methoxyacetyl)- / V-((4-(3-methoxyphenyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (SW387925).

[0856] Synthesized by general procedure B and Suzuki coupling procedure C.

[0857] Yield: 69%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0858] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.73 (d, J = 1.5 Hz, 1 H), 7.48 - 7.45 (m, 2H), 7.32 (t, J = 7.9 Hz, 1 H), 6.92 - 6.88 (m, 1H), 4.78 - 4.66 (m, 2H), 4.54 - 4.50 (m, 0.5H), 4.26 - 4.11 (m, 2.5H), 3.86 - 3.76 (m, 4H), 3.39 (d, 3H), 3.37 - 3.33 (m, 0.5H), 3.12 - 3.04 (m, 0.5H), 2.93 - 2.87 (m, 1 H), 2.57 - 2.41 (m, 1 H), 2.05 - 2.00 (m, 1 H), 1.89 - 1.76 (m, 2H), 1.61 - 1.46 (m, 1 H).

[0859] ESI MS. C2OH26N304S m / z [M+H]+ calc. 404.2, found 404.Example 110: Synthesis of SW387926

[0860] (S)-A / -((4-(2-Fluorophenyl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3- carboxamide (SW387926).

[0861] Synthesized by general procedure B and Suzuki coupling procedure C.

[0862] Yield: 62%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0863] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 8.15 - 8.11 (m, 1 H), 7.79 (d, J = 2.2 Hz, 1 H), 7.39 - 7.33 (m, 1 H), 7.28 - 7.18 (m, 2H), 4.79 - 4.67 (m, 2H), 4.55 - 4.51 (m, 0.5H), 4.26 - 4.11 (m, 2.5H), 3.88 - 3.79 (m, 1 H), 3.39 (d, J = 1.6 Hz, 3H), 3.35 - 3.33 (m, 0.5H), 3.13 - 3.05 (m, 0.5H), 2.94 - 2.87 (m, 1 H), 2.57 - 2.42 (m, 1H), 2.07 - 2.02 (m, 1 H), 1.89 - 1.76 (m, 2H), 1.60 - 1.46 (m, 1 H).

[0864] ESI MS. C19H23FN3O3S m / z [M+H]+ calc. 392.1 , found 392.2.Example 111 : Synthesis of SW387927

[0865] (S)- / V-((4-(3-Fluorophenyl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3- carboxamide (SW387927).

[0866] Synthesized by general procedure B and Suzuki coupling procedure C.

[0867] Yield: 61%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0868] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 6 7.82 (d, J = 1.5 Hz, 1 H), 7.74 - 7.72 (m, 1 H), 7.68 - 7.65 (m, 1H), 7.45 - 7.40 (m, 1 H), 7.09 - 7.04 (m, 1 H), 4.78 - 4.66 (m, 2H), 4.54 - 4.50 (m, 0.5H), 4.26 - 4.11 (m, 2.5H), 3.88 - 3.79 (m, 1 H), 3.39 (d, J = 1.6 Hz, 3H), 3.36 - 3.33 (m, 0.5H), 3.14 - 3.05 (m, 0.5H), 2.94 - 2.86 (m, 1 H), 2.57 - 2.42 (m, 1 H), 2.07 - 2.02 (m, 1 H), 1.89 - 1.75 (m, 2H), 1.58 - 1.50 (m, 1H).

[0869] ESI MS. C19H23FN3O3S m / z [M+H]+ calc. 392.1 , found 392.2.Example 112: Synthesis of SW387928

[0870] (S)- / V-((4-(4-Fluorophenyl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3- carboxamide (SW387928).

[0871] Synthesized by general procedure B and Suzuki coupling procedure C.

[0872] Yield: 63%. Purified by ISCO flash column chromatography (97:3 CH2Cl2: eOH v / v).

[0873] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.95 - 7.85 (m, 2H), 7.69 (d, J = 4.1 Hz, 1 H), 7.18 - 7.11 (m, 2H), 4.77 - 4.64 (m, 2H), 4.58 - 4.50 (m, 0.5H), 4.25 - 4.10 (m, 2.5H), 3.88 - 3.78 (m, 1H), 3.42 - 3.35 (m, 3.5H), 3.12 - 3.03 (m, 0.5H), 2.94 - 2.86 (m, 1 H), 2.56 - 2.42 (m, 1 H), 2.07 - 2.02 (m, 1 H), 1.88 - 1.75 (m, 2H), 1.60 - 1.49 (m, 1 H).

[0874] ESI MS. C19H23FN3O3S m / z [M+H]+ calc. 392.1 , found 392.2.Example 113: Synthesis of SW387929

[0875] (S)-1-(2-Methoxyacetyl)- / V-((4-(o-tolyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (SW387929)

[0876] Synthesized by general procedure B and Suzuki coupling procedure C.

[0877] Yield: 71%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0878] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 57.49 - 7.47 (m, 1H), 7.42 (s, 1H), 7.33 - 7.18 (m, 3H), 4.77 - 4.66 (m, 2H), 4.57 - 4.50 (m, 0.5H), 4.25 - 4.11 (m, 2.5H), 3.88 - 3.79 (m, 1H), 3.39-3.32 (m, 3.5H), 3.11-3.04 (m, 0.5H), 2.93-2.86 (m, 1H), 2.56 - 2.36 (m, 4H), 2.09 -2.01 (m, 1H), 1.88- 1.75 (m, 2H), 1.60- 1.45 (m, 1H).

[0879] ESI MS. C20H26N3O3S m / z [M+H]+ calc.388.2, found 388.1.Example 114: Synthesis of SW387930

[0880] (S)-1-(2-Methoxyacetyl)- / V-((4-(m-tolyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (SW387930).

[0881] Synthesized by general procedure B and Suzuki coupling procedure C.

[0882] Yield: 67%. Purified by ISCO flash column chromatography (97:3 CH2Cl2: eOH v / v).

[0883] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 57.73 - 7.66 (m, 3H), 7.31 - 7.27 (t, J= 7.7 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 4.77 - 4.66 (m, 2H), 4.55 - 4.50 (m, 0.5H), 4.25-4.11 (m, 2.5H), 3.88 - 3.76 (m, 1H), 3.39 - 3.32 (m, 3.5H), 3.13 - 3.04 (m, 0.5H), 2.93 - 2.86 (m, 1H), 2.56-2.36 (m,4H), 2.07 -2.01 (m, 1H), 1.88- 1.75 (m, 2H), 1.61 - 1.45 (m, 1H).

[0884] ESI MS. C20H26N3O3S m / z [M+H]+ calc.388.2, found 388.1.Example 115: Synthesis of SW387931

[0885] (S)-1-(2-Methoxyacetyl)-A / -((4-(p-tolyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (SW387931).

[0886] Synthesized by general procedure B and Suzuki coupling procedure C.

[0887] Yield: 69%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0888] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 57.78 - 7.76 (m, 2H), 7.63 (s, 1H), 7.24 - 7.22 (m, 2H), 4.77 - 4.65 (m, 2H), 4.54 - 4.50 (m, 0.5H), 4.25 - 4.09 (m, 2.5H), 3.87 - 3.78 (m, 1H), 3.39 (s, 3H), 3.35-3.32 (m, 0.5H), 3.11 -3.03 (m, 0.5H), 2.93-2.87 (m, 1H), 2.56-2.41 (m, 1H), 2.36 (s, 3H), 2.13 - 2.01 (m, 1H), 1.87- 1.76 (m, 2H), 1.60- 1.45 (m, 1H).

[0889] ESI MS. C2OH26N303S m / z [M+H]+ calc.388.2, found 388.1.

[0890] [a]256D+21.32 (c 0.15, CHCI3).Example 116: Synthesis of SW387988

[0891] (S)- / V-((4-Phenylthiazol-2-yl)methyl)-1-(2-(prop-2-yn-1-yloxy)acetyl)piperidine-3- carboxamide (SW387988).

[0892] Synthesized by general procedure A.

[0893] Yield: 62%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0894] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 6 7.91 - 7.88 (m, 2H), 7.71 (d, J = 2.1 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.34 - 7.30 (m, 1 H), 4.78 - 4.66 (m, 2H), 4.54 - 4.49 (m, 0.5H), 4.38 - 4.19 (m, 4.5H), 3.90 - 3.78 (m, 1 H), 3.36 - 3.32 (m, 0.5H), 3.13 - 3.04 (m, 0.5H), 2.95 - 2.81 (m, 2H), 2.58 - 2.42 (m, 1 H), 2.08 - 2.00 (m, 1 H), 1.87 - 1.81 (m, 2H), 1.62 - 1.44 (m, 1 H). ESI MS. C21H24N3O3S m / z [M+H]+ calc. 398.1 , found 398.0.Example 117: Synthesis of SW387989

[0895] (S)-1-((R)-oxirane-2-carbonyl)-M-((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide(SW387989).

[0896] Synthesized by general procedure A.

[0897] Yield: 64%. Purified by ISCO flash column chromatography (97:3 CH2Cl2: eOH v / v).

[0898] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 67.90 - 7.87 (m, 2H), 7.71 (s, 1 H), 7.43 - 7.38 (m, 2H), 7.34 - 7.30 (m, 1H), 4.80 - 4.66 (m, 2H), 4.52 - 4.46 (m, 0.5H), 4.17 - 4.09 (m, 1.5H), 3.90 (dd, J = 4.5, 2.6 Hz, 0.5H), 3.84 (dd, J = 4.4, 2.6 Hz, 0.5H), 3.56 (dd, J = 13.7, 9.7 Hz, 0.5H), 3.24 - 3.17 (m, 0.5H), 3.05 - 2.94 (m, 2H), 2.90 - 2.77 (m, 1 H), 2.57 - 2.45 (m, 1 H), 2.10 - 2.03 (m, 1 H), 1.94 - 1.74 (m, 2H), 1.70 - 1.44 (m, 1 H).

[0899] ESI MS. C19H22N3O3S m / z [M+H]+ calc. 372.1 , found 372.2.Example 118: Synthesis of SW387990

[0900] (S)-1-((S)-Oxirane-2-carbonyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW387990).

[0901] Synthesized by general procedure A.

[0902] Yield: 61%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0903] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 57.91 - 7.88 (m, 2H), 7.71 (s, 1 H), 7.43 - 7.38 (m, 2H), 7.35 - 7.30 (m, 1H), 4.80 - 4.65 (m, 2H), 4.54 - 4.48 (m, 0.5H), 4.16 - 4.11 (m, 1.5H), 3.87 (dd, J = 4.5, 2.6 Hz, 0.5H), 3.83 (dd, J= 4.4, 2.6 Hz, 0.5H), 3.52 (dd, = 13.7, 9.7 Hz, 0.5H), 3.29 - 3.21 (m, 0.5H), 3.05 - 2.94 (m, 2H), 2.81 - 2.77 (m, 1 H), 2.66 - 2.59 (m, 0.5H), 2.48 - 2.41 (m, 0.5H), 2.12 - 2.01 (m, 1 H), 1.93 - 1.78 (m, 2H), 1.60 - 1.48 (m, 1H).

[0904] ESI MS. C19H22N3O3S m / z [M+H]+ calc. 372.1 , found 372.2.Example 119

[0905] General procedure E.

[0906] (R,E)-2-methyl- / V-((4-phenylthiazol-2-yl)methylene)propane-2-sulfinamide (22): To a stirred suspension of (S)-p-toluenesulfinamide 21 (320 mg, 2.64 mmol, 1.00 equiv) and CS2CO3 (1.29 g, 3.16 mmol, 1.50 equiv) in CH2CI2 (35 mL) was added 2-formylthiazole 20 (500 mg, 2.64 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 12 h. Then, the mixture was passed through a pad of celite. The celite pad was washed with CH2CI2, and the filtrate was concentrated in vacuo. Purification of the residue by ISCO flash column chromatography (Hexane: EtOAc, 4:1 to 1:1 v / v) gave 22 (3.58 g, 90%) as a yellow solid.

[0907] ESI MS. C14H17N2OS2 m / z [M+H]+ calc. 293.1 , found 293.0.

[0908] (R)-2-methyl-A / -(®-1-(4-phenylthiazol-2-yl)ethyl)propane-2-sulfinamide (23): Methylmagnesium bromide (3M in Et20, 1.36 mL, 4.10 mmol, 2.00 equiv) was added dropwise to a solution of sulfinamide 22 (600 mg, 2.05 mmol, 1.00 equiv) in dry CH2CI2 (12 mL) at -78°C. The mixture was stirred at -78°C for 2 h. The reaction was quenched with saturated aqueous NH4CI. The aqueous phase was extracted with CH2CI2. The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure on a rotary evaporator to afford the crude sulfinamine 23, which was submitted to the next step without further purification.

[0909] ESI MS. C15H21N2OS2 m / z [M+H]+ calc.309.1, found 309.0.

[0910] (R)-1-(4-phenylthiazol-2-yl)ethan-1 -amine: To a solution of the crude sulfinamide 23 (1.00 equiv) in dry diethyl ether (5.0 mL) was added HCI (4 M in dioxane, 1.47 mL, 6.00 mmol, 3.00 equiv) at 0°C. The resulting mixture was warmed to room temperature and stirred for 1 h. The residue was basified by 1 M aqueous sodium hydroxide and extracted with CH2CI2. The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure on a rotary evaporator. Purification of the crude material by ISCO flash column chromatography. (10:1 CH2Cl2:MeOH v / v) yielded the pure amine 24 (348 mg, 83% over 2 steps).

[0911] ESI MS. C11H13N2S m / z [M+H]+ calc.205.1, found 205.1.Example 120: Synthesis of SW387991

[0912] (S)-1-(2-Methoxyacetyl)- / V-((R)-1-(4-phenylthiazol-2-yl)ethyl)piperidine-3- carboxamide (SW387991).

[0913] Synthesized by general procedure E and A.

[0914] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 57.92 - 7.89 (m, 2H), 7.68 (s, 1H), 7.42- 7.39 (m,2H), 7.34-7.30 (m, 1H), 5.37-5.32 (m, 1H), 4.57 - 4.46 (m, 0.5H), 4.26 - 4.04 (m, 2.5H), 3.85-3.78 (m, 1H), 3.43-3.33 (m, 3.5H), 3.13-3.04 (m, 0.5H), 2.94-2.80 (m, 1H), 2.55 -2.43 (m, 1H), 2.15- 1.98 (m, 1H), 1.87- 1.74 (m, 2H), 1.67- 1.50 (m, 4H).

[0915] ESI MS. C20H26N3O3S m / z [M+H]+ calc.388.2, found 388.1.Example 121: Synthesis of SW387992

[0916] (S)-1-(2-Methoxyacetyl)- / V-((S)-1-(4-phenylthiazol-2-yl)ethyl)piperidine-3- carboxamide (SW387992).

[0917] Synthesized by general procedure E and A.

[0918] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 57.92 - 7.89 (m, 2H), 7.68 (s, 1H), 7.42- 7.39 (m,2H), 7.34-7.30 (m, 1H), 5.37-5.32 (m, 1H), 4.49 - 4.46 (m, 0.5H), 4.26 - 4.11 (m, 2.5H), 3.85-3.78 (m, 1H), 3.40-3.33 (m, 3.5H), 3.13-3.04 (m, 0.5H), 2.95-2.84 (m, 1H), 2.55 -2.43 (m, 1H), 2.15- 1.98 (m, 1H), 1.87- 1.74 (m, 2H), 1.67- 1.45 (m, 4H).

[0919] ESI MS. C20H26N3O3S m / z [M+H]+ calc.388.2, found 388.1.Example 122: Synthesis of SW387993

[0920] (S)- / V-((1-(2-Methoxyacetyl)piperidin-3-yl)methyl)-4-phenylthiazole-2- carboxamide (SW387993).

[0921] Synthesized by general procedure A.

[0922] Yield: 62%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0923]

[0786] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: <5 8.07 (d, J = 6.0 Hz, 1 H), 8.03 - 8.01 (m, 2H), 7.46 - 7.42 (m, 2H), 7.39 - 7.32 (m, 1 H), 4.35 - 4.21 (m, 1H), 4.18 - 4.04 (m, 2H), 3.86 - 3.81 (m, 0.5H), 3.72 - 3.66 (m, 0.5H), 3.42 - 3.28 (m, 5H), 3.13 - 3.07 (m, 0.5H), 2.92 - 2.69 (m, 1.5H), 1.98 - 1.73 (m, 3H), 1.57 - 1.25 (m, 2H).

[0924] ESI MS. C19H24N3O3S m / z [M+H]+ calc. 374.1 , found 374.1.Example 123: Synthesis of SW387994

[0925] (S)- / V-((4-Phenylthiazol-2-yl)methyl)-1-(2-(2,2,2-trifluoroethoxy)acetyl)piperidine- 3-carboxamide (SW387994).

[0926] Synthesized by general procedure A.

[0927] Yield: 51%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0928] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 67.90 - 7.87 (m, 2H), 7.71 (s, 1 H), 7.43 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1H), 4.81 - 4.65 (m, 2H), 4.53 - 4.35 (m, 2.5H), 4.15 - 3.95 (m, 2.5H), 3.76 - 3.70 (m, 1 H), 3.39 - 3.33 (m, 0.5H), 3.12 - 2.89 (m, 1.5H), 2.57 - 2.42 (m, 1 H), 2.09 - 2.01 (m, 1 H), 1.89 - 1.75 (m, 2H), 1.62 - 1.46 (m, 1 H).

[0929] ESI MS. C2OH23F3N303S m / z [M+H]+ calc. 442.1 , found 442.0.Example 124: Synthesis of SW387995

[0930] (S)-1-(2-Methoxyacetyl)-A / -((4-(4-(trifluoromethyl)phenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide (SW387995).

[0931] Synthesized by general procedure B and Suzuki coupling procedure C.

[0932] Yield: 59%. Purified by ISCO flash column chromatography (97:3 CHhC^MeOH v / v).

[0933] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 58.11 (d, J = 8.1 Hz, 2H), 7.93 (s, 1 H), 7.72 (d, J = 8.2 Hz, 2H), 4.80 - 4.66 (m, 2H), 4.55 - 4.50 (m, 0.5H), 4.26 - 4.11 (m, 2.5H), 3.88 - 3.79 (m, 1H), 3.39 - 3.33 (m, 3.5H), 3.12 - 3.05 (m, 0.5H), 2.95 - 2.85 (m, 1 H), 2.57 - 2.42 (m, 1 H), 2.08 - 2.01 (m, 1 H), 1.89 - 1.76 (m, 2H), 1.60 - 1.49 (m, 1 H).

[0934] ESI MS. C20H23F3N3O3S m / z [M+H]+ calc. 442.1 , found 442.1.Example 125: Synthesis of SW387996

[0935] (S)-A / -((4-(4-Cyanophenyl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3- carboxamide (SW387996).

[0936] Synthesized by general procedure B and Suzuki coupling procedure C.

[0937] Yield: 63%. Purified by ISCO flash column chromatography (97:3 CH2Cl2: eOH v / v).

[0938] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 58.09 - 8.06 (m, 2H), 7.90 (s, 1 H), 7.76 - 7.73 (m, 2H), 4.75 - 4.65 (m, 2H), 4.54 - 4.50 (m, 0.5H), 4.23 - 4.09 (m, 2.5H), 3.86 - 3.77 (m, 1 H), 3.39 (s, 3H), 3.35 - 3.32 (m, 0.4H), 3.14 - 3.04 (m, 0.6H), 2.93 - 2.87 (m, 1 H), 2.54 - 2.41 (m, 1 H), 2.12 - 1.99 (m, 1 H), 1.88 - 1.76 (m, 2H), 1.60 - 1.46 (m, 1 H).

[0939] 13C NMR (151 MHz, MeOH-d4) mixture of rotamers: 175.5, 175.3, 170.9, 170.8, 169.6, 169.5, 154.0, 139.6, 139.5, 133.5, 127.7, 119.5, 117.5, 111.9, 73.2, 71.8, 71.7, 62.0, 59.4, 47.8, 46.1 , 45.2, 43.9, 43.6, 43.1 , 41.7, 28.7, 28.4, 25.8, 24.9.

[0940] ESI MS. C2OH23N403S m / z [M+H]+ calc. 399.1 , found 399.0.

[0941] [a]25D+23.63 (c 0.33, CHCI3).Example 126: Synthesis of SW387997

[0942] (S)- / V-((4-(4-Ethoxyphenyl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3- carboxamide (SW387997).

[0943] Synthesized by general procedure B and Suzuki coupling procedure C.

[0944] Yield: 67%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0945] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.82 - 7.78 (m, 2H), 7.54 (d, J = 1 .5 Hz, 1 H), 6.95 - 6.93 (m, 2H), 4.76 - 4.65 (m, 2H), 4.54 - 4.50 (m, 0.5H), 4.24 - 4.10 (m, 2.5H),4.07 (q, J = 7.0 Hz, 2H), 3.87 - 3.77 (m, 1H), 3.39 (s, 3H), 3.35 - 3.32 (m, 0.5H), 3.10 - 3.03 (m, 0.5H), 2.93 - 2.86 (m, 1H), 2.55 - 2.41 (m, 1 H), 2.05 - 2.00 (m, 1 H), 1.88 - 1.75 (m, 2H), 1.60 - 1 .44 (m, 1 H), 1.40 (t, J = 7.0 Hz, 3H).

[0946] ESI MS. C2iH28N3O4S m / z [M+H]+ calc. 418.2, found 418.1.Example 127: Synthesis of SW387998

[0947] (S)-1-(2-Methoxyacetyl)- / V-((4-(4-(methylthio)phenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide (SW387998).

[0948] Synthesized by general procedure B and Suzuki coupling procedure C.

[0949] Yield: 61%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0950] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 67.84 - 7.81 (m, 2H), 7.67 (s, 1 H), 7.32 - 7.29 (m, 2H), 4.77 - 4.65 (m, 2H), 4.54 - 4.50 (m, 0.5H), 4.26 - 4.05 (m, 2.5H), 3.87 - 3.78 (m, 1 H), 3.39 - 3.36 (m, 3.5H), 3.12 - 3.05 (m, 0.5H), 2.93 - 2.87 (m, 1 H), 2.53 - 2.44 (m, 4H), 2.09 - 1.98 (m, 1 H), 1.88 - 1.75 (m, 2H), 1.63 - 1.44 (m, 1 H).

[0951] ESI MS. C20H26N3O3S2 m / z [M+H]+ calc. 420.1 , found 420.1.Example 128: Synthesis of SW387999

[0952] (S)-A / -((4-(4-Chlorophenyl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3- carboxamide (SW387999).

[0953] Synthesized by general procedure B and Suzuki coupling procedure C.

[0954] Yield: 60%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0955] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 67.90 - 7.87 (m, 2H), 7.74 (s, 1 H), 7.42 - 7.39 (m, 2H), 4.77 - 4.65 (m, 2H), 4.54 - 4.50 (m, 0.5H), 4.25 - 4.07 (m, 2.5H), 3.87 - 3.78 (m, 1 H), 3.39 (s, 3H), 3.35 - 3.33 (m, 0.5), 3.11 - 3.04 (m, 0.5H), 2.93 - 2.87 (m, 1 H), 2.56 - 2.41 (m, 1 H), 2.07 - 2.00 (m, 1 H), 1.88 - 1.75 (m, 2H), 1.61 - 1.46 (m, 1 H).

[0956] ESI MS. C19H23CI N3O3S m / z [M+H]+ calc. 408.1 , found 408.0.Example 129: Synthesis of SW388000

[0957] (S)-1-(2-Methoxyacetyl)- / V-((4-(4-(trifluoromethoxy)phenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide (SW388000).

[0958] Synthesized by general procedure B and Suzuki coupling procedure C.

[0959] Yield: 64%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0960] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 58.03 - 7.99 (m, 2H), 7.79 (s, 1 H), 7.33 - 7.31 (m, 2H), 4.78 - 4.66 (m, 2H), 4.55 - 4.50 (m, 0.5H), 4.25 - 4.11 (m, 2.5H), 3.88 - 3.79 (m, 1 H), 3.39 (s, 3H), 3.36 - 3.32 (m, 0.5H), 3.13 - 3.05 (m, 0.5H), 2.95 - 2.87 (m, 1 H), 2.57 - 2.42 (m, 1 H), 2.07 - 2.02 (m, 1 H), 1.89 - 1.75 (m, 2H), 1.60 - 1.46 (m, 1 H).

[0961] ESI MS. C2OH23F3N304S m / z [M+H]+ calc. 458.1 , found 458.1.Example 130: Synthesis of SW388631

[0962] (S)-A / -((4-(4-Formylphenyl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3- carboxamide (SW388631).

[0963] Synthesized by general procedure B and Suzuki coupling procedure C.

[0964] Yield: 49%. Purified by ISCO flash column chromatography (97:3 CH2CI2: eOH v / v).

[0965] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 10.00 (s, 1 H), 8.15 - 8.13 (m, 2H),7.99 - 7.95 (m, 3H), 4.80 - 4.68 (m, 2H), 4.56 - 4.51 (m, 0.5H), 4.26 - 4.11 (m, 2.5H), 3.87 - 3.78 (m, 1 H), 3.39 (d, J = 1 .9 Hz, 3H), 3.36 - 3.32 (m, 0.5H), 3.13 - 3.04 (m, 0.5H), 2.95 - 2.87 (m, 1 H), 2.57 - 2.42 (m, 1 H), 2.08 - 2.01 (m, 1 H), 1.88 - 1.75 (m, 2H), 1.61 - 1.45 (m, 1 H).

[0966] ESI MS. C20H24N3O4S m / z [M+H]+ calc. 402.1 , found 402.0.Example 131 : Synthesis of SW388632

[0967] (S)-A / -((4-(4-(Dimethylcarbamoyl)phenyl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl) pi peri di ne-3-carboxam ide (SW388632).

[0968] Synthesized by general procedure B and Suzuki coupling procedure C.

[0969] Yield: 58%. Purified by ISCO flash column chromatography (19:1 CH2Cl2:MeOH v / v).

[0970] 1H NMR (400 MHz, MeOD-d) mixture of rotamers: 68.02 - 8.00 (m, 2H), 7.86 (d, J = 1.4 Hz, 1 H), 7.50 - 7.48 (m, 2H), 4.79 - 4.67 (m, 2H), 4.56 - 4.50 (m, 0.5H), 4.26 - 4.11 (m, 2.5H), 3.87- 3.78 (m, 1H), 3.39 (d, J= 1.9 Hz, 3H), 3.36- 3.33 (m, 0.5H), 3.12 (s, 3H), 3.09- 3.06 (m, 0.5H), 3.04 (s, 3H), 2.94-2.86 (m, 1H), 2.57-2.42 (m, 1H), 2.07-2.02 (m, 1H), 1.89- 1.75 (m, 2H), 1.61 - 1.43 (m, 1H).

[0971] ESI MS. C22H29N4O4S m / z [M+H]+ calc.445.2, found 445.2.Example 132: Synthesis of SW388633

[0972] (S)-1-(2-Methoxyacetyl)-N-((4-(naphthalen-2-yl)thiazol-2-yl)methyl)piperidine-3- carboxamide (SW388633).

[0973] Synthesized by general procedure B and Suzuki coupling procedure C.

[0974] Yield: 63%. Purified by ISCO flash column chromatography (49:1 CH2Cl2: eOH v / v).

[0975] 1H NMR (400 MHz, MeOD-d) mixture of rotamers: <58.43 (s, 1H), 8.00 (dd, J = 8.6, 1.7 Hz, 1 H), 7.92 - 7.85 (m, 4H), 7.52 - 7.45 (m, 2H), 4.82 - 4.70 (m, 2H), 4.57 - 4.52 (m, 0.5H), 4.27 - 4.11 (m, 2.5H), 3.88-3.78 (m, 1H), 3.39 (d, J= 3.1 Hz, 3H), 3.36-3.33 (m, 0.5H), 3.11 - 3.04 (m, 0.5H), 2.94 - 2.88 (m, 1 H), 2.58 - 2.43 (m, 1 H), 2.09 - 2.04 (m, 1 H), 1.90 - 1.74 (m, 2H), 1.62 -1.46 (m, 1H).

[0976] ESI MS. C23H26N3O3S m / z [M+H]+ calc.424.2, found 424.0.Example 133: Synthesis of SW388634

[0977] (S)-1-(2-Methoxyacetyl)- / V-((4-(1-methyl-1H-indazol-5-yl)thiazol-2- yl)methyl)piperidine-3-carboxamide (SW388634).

[0978] Synthesized by general procedure B and Suzuki coupling procedure C.

[0979] Yield: 51%. Purified by ISCO flash column chromatography (19:1 CH2Cl2:MeOH v / v).

[0980] 1H NMR (400 MHz, MeOD-d) mixture of rotamers: 68.31 (s, 1H), 8.05 (s, 1H), 7.99 (dd, J= 8.8, 1.6 Hz, 1H), 7.70 (d, J= 1.7 Hz, 1H), 7.59 (d, J= 8.8 Hz, 1H), 4.80-4.68 (m, 2H), 4.56- 4.52 (m, 0.5H), 4.28 - 4.06 (m, 5.5H), 3.90 - 3.78 (m, 1 H), 3.39 (d, J = 2.7 Hz, 3H), 3.34 - 3.32 (m, 0.5H), 3.11 - 3.04 (m, 0.5H), 2.94-2.87 (m, 1H), 2.59-2.42 (m, 1H), 2.08-2.01 (m, 1H), 1.90- 1.76 (m, 2H), 1.62- 1.43 (m, 1H).

[0981] ESI MS. C2IH26N5O3S m / z [M+H]+ calc. 428.2, found 428.0.Example 134: Synthesis of SW388635

[0982] Methyl(S)-4-(2-((1-(2-methoxyacetyl)piperidine-3-carboxamido)methyl)thiazol-4- yl)benzoate (SW388635).

[0983] Synthesized by general procedure B and Suzuki coupling procedure C.

[0984] Yield: 56%. Purified by ISCO flash column chromatography (24:1 CH2CI2:MeOH v / v).

[0985] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: <58.07 - 8.00 (m, 4H), 7.09 - 7.88 (m, 1 H), 4.79 - 4.67 (m, 2H), 4.56 - 4.50 (m, 0.5H), 4.25 - 4.10 (m, 2.5H), 3.92 (s, 3H), 3.88 - 3.74 (m, 1 H), 3.39 (s, 3H), 3.35 - 3.33 (m, 0.5H), 3.11 - 3.04 (m, 0.5H), 2.92 - 2.86 (m, 1H), 2.57 - 2.40 (m, 1 H), 2.07 - 1.98 (m, 1 H), 1.90 - 1.75 (m, 2H), 1.61 - 1.46 (m, 1 H).

[0986] ESI MS. C2IH26N3O5S m / z [M+H]+ calc. 432.2, found 432.0.Example 135: Synthesis of SW388636

[0987] (S)- / V-((4-(4-Acetylphenyl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine-3- carboxamide (SW388636).

[0988] Synthesized by general procedure B and Suzuki coupling procedure C.

[0989] Yield: 53%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[0990] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 58.04 (s, 4H), 7.93 (d, J = 1.7 Hz, 1 H), 4.79 - 4.67 (m, 2H), 4.56 - 4.50 (m, 0.5H), 4.25 - 4.10 (m, 2.5H), 3.88 - 3.77 (m, 1 H), 3.39 (d, J = 2.2 Hz, 3H), 3.35 - 3.33 (m, 0.5H), 3.11 - 3.04 (m, 0.5H), 2.94 - 2.86 (m, 1H), 2.62 (s, 3H), 2.57 - 2.40 (m, 1 H), 2.07 - 2.01 (m, 1 H), 1.90 - 1.75 (m, 2H), 1.61 - 1.46 (m, 1 H).

[0991] ESI MS. C2iH26N3O4S m / z [M+H]+ calc. 416.2, found 416.0.Example 136: Synthesis of SW388637

[0992] (S)- / V-((4-([1,T-Biphenyl]-4-yl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine- 3-carboxamide (SW388637).

[0993] Synthesized by general procedure B and Suzuki coupling procedure C.

[0994] Yield: 69 %. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[0995] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 57.99 - 7.96 (m, 2H), 7.74 - 7.63 (m, 5H), 7.46 - 7.42 (m, 2H), 7.36 - 7.32 (m, 1 H), 4.79 - 4.68 (m, 2H), 4.56 - 4.52 (m, 0.5H), 4.25 - 4.10 (m, 2.5H), 3.87 - 3.78 (m, 1 H), 3.39 (s, 3H), 3.36 - 3.32 (m, 0.5H), 3.11 - 3.04 (m, 0.5H), 2.93 - 2.86 (m, 1 H), 2.57 - 2.42 (m, 1 H), 2.08 - 2.02 (m, 1 H), 1.86 - 1.76 (m, 2H), 1.61 - 1.46 (m, 1 H).

[0996] ESI MS. C25H28N3O3S m / z [M+H]+ calc. 450.2, found 450.0.Example 137: Synthesis of SW388638

[0997] (S)-A / -((4-(4-lsopropoxyphenyl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl)piperidine- 3-carboxamide

[0998] Synthesized by general procedure B and Suzuki coupling procedure C.

[0999] Yield: 58 %. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[1000] 1H NMR (400 MHz, MeOD-d4) mixture of rotamers: 5 7.83 - 7.76 (m, 2H), 7.55 (d, J = 1 .6 Hz, 1 H), 7.00 - 6.91 (m, 2H), 4.76 - 4.61 (m, 3H), 4.56 - 4.50 (m, 0.5H), 4.25 - 4.14 (m, 2.5H), 3.87 - 3.78 (m, 1 H), 3.39 (d, J = 1.6 Hz, 3H), 3.36 - 3.32 (m, 0.5H), 3.10 - 3.03 (m, 0.5H), 2.93 - 2.86 (m, 1 H), 2.57 - 2.42 (m, 1H), 2.08 - 2.02 (m, 1 H), 1.86 - 1.76 (m, 2H), 1.61 - 1.46 (m, 1 H), 1.33 (s, 3H), 1.32 (s, 3H).

[1001] ESI MS. C22H30N3O4S m / z [M+H]+ calc. 432.2, found 432.2.Example 138: Synthesis of SW388721

[1002] (S)-1-(2-Methoxyacetyl)-A / -((4-(4-(pyridin-2-yl)phenyl)thiazol-2- yl)methyl)piperidine-3-car

[1003] Synthesized by general procedure B and Suzuki coupling procedure C.

[1004] Yield: 52%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[1005] 1H NMR (400 MHz, MeOD-c ) mixture of rotamers: 5 8.90 - 8.87 (m, 1H), 8.64 - 8.62 (m, 1 H), 8.07 - 7.89 (m, 5H), 7.85 (s, 1 H), 7.42 - 7.39 (m, 1 H), 4.77 - 4.70 (m, 2H), 4.55 - 4.50 (m, 0.5H), 4.26 - 4.11 (m, 2.5H), 3.87 - 3.78 (m, 1 H), 3.39 (s, 3H), 3.37 - 3.32 (m, 0.5H), 3.13 - 3.03(m, 0.5H), 2.94 - 2.86 (m, 1 H), 2.57 - 2.42 (m, 1 H), 2.08 - 2.02 (m, 1 H), 1.90 - 1.76 (m, 2H), 1.61- 1.50 (m, 1 H).

[1006] ESI MS. C24H27N4O3S m / z [M+H]+ calc. 451 .2, found 451.0.Example 139: Synthesis of SW388722

[1007] (S)-1-(2-Methoxyacetyl)-A / -((4-(4-(pyridin-3-yl)phenyl)thiazol-2-yl)methyl) piperidine-3-carboxamide

[1008] Synthesized by general procedure B and Suzuki coupling procedure C.

[1009] Yield: 51 %. Purified by ISCO flash column chromatography (97:3 CH2Ch:MeOH v / v).

[1010] 1H NMR (400 MHz, MeOD-cM) mixture of rotamers: 58.85 (s, 1 H), 8.53 (d, J = 4.8 Hz, 1 H), 8.16 - 8.13 (m, 1 H), 8.07 - 8.00 (m, 2H), 7.82 (s, 1 H), 7.77 - 7.70 (m, 2H), 7.53 (dd, J = 8.1, 4.9 Hz, 1 H), 4.76 - 4.72 (m, 2H), 4.55 - 4.50 (m, 0.5H), 4.26 - 4.11 (m, 2.5H), 3.87 - 3.78 (m, 1 H), 3.39 (s, 3H), 3.37 - 3.32 (m, 0.5H), 3.13 - 3.03 (m, 0.5H), 2.94 - 2.86 (m, 1 H), 2.57 - 2.42 (m, 1 H), 2.08 - 2.02 (m, 1 H), 1.90 - 1.76 (m, 2H), 1.61 - 1.50 (m, 1 H).

[1011] ESI MS. C24H27N4O3S m / z [M+H]+ calc. 451 .2, found 451.0.Example 140: Synthesis of SW388723

[1012] (S)-1-(2-Methoxyacetyl)-A / -((4-(pyridin-3-yl)thiazol-2-yl)methyl)piperidine-3- carboxamide (SW388723).

[1013] Synthesized by general procedure B and Suzuki coupling procedure C.

[1014] Yield: 56%. Purified by ISCO flash column chromatography (97:3 CH2Cl2: eOH v / v).

[1015] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 59.11 (s, 1 H), 8.49 (d, J = 4.0 Hz, 1 H), 8.35 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.50 (dd, J = 8.0, 4.0 Hz, 1 H), 4.81 - 4.67 (m, 2H), 4.54 - 4.40 (m, 0.5H), 4.25 - 4.14 (m, 2.5H), 3.88 - 3.78 (m, 1 H), 3.39 (s, 3H), 3.34 - 3.33 (m, 0.5H), 3.12 - 3.05 (m, 0.5H), 2.95 - 2.87 (m, 1 H), 2.57 - 2.42 (m, 1H), 2.06 - 1.99 (m, 1H), 1.89 - 1.75 (m, 2H), 1.61 - 1.43 (m, 1 H).

[1016] ESI MS. C18H23N4O3S m / z [M+H]+ calc. 375.1 , found 375.1.

[1017] [a]2S'6D+22.99 (c 0.2, CHCI3).Example 141 : Synthesis of SW388724

[1018] (S)-1-(2-Methoxyacetyl)- / V-((4-(pyrimidin-5-yl)thiazol-2-yl)methyl)piperidine-3- carboxamide (SW388724).

[1019] Synthesized by general procedure B and Suzuki coupling procedure C.

[1020] Yield: 53%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[1021] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 59.30 (s, 2H), 9.10 (s, 1 H), 8.10 (d, J = 1.2 Hz, 1H), 4.81 - 4.67 (m, 2H), 4.58 - 4.49 (m, 0.5H), 4.25 - 4.10 (m, 2.5H), 3.88 - 3.78 (m, 1 H), 3.39 (s, 3H), 3.36 - 3.33 (m, 0.5H), 3.12 - 3.05 (m, 0.5H), 2.95 - 2.87 (m, 1H), 2.57 - 2.42 (m, 1 H), 2.08 - 2.01 (m, 1 H), 1.89 - 1.75 (m, 2H), 1.61 - 1.48 (m, 1 H).

[1022] ESI MS. C17H22N5O3S m / z [M+H]+ calc. 376.1 , found 376.0.Example 142: Synthesis of SW388725

[1023] (S)- / V-((4-(4-Cyclopropylphenyl)thiazol-2-yl)methyl)-1-(2-methoxyacetyl) piperidine-3-carboxamide

[1024] Synthesized by general procedure B and Suzuki coupling procedure C.

[1025] Yield: 68%. Purified by ISCO flash column chromatography (97:3 CH2Cl2: eOH v / v).

[1026] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: <57.76 (d, J = 8.0 Hz, 2H), 7.62 (s, 1 H), 7.11 (d, J = 8.0 Hz, 2H), 4.76 - 4.65 (m, 2H), 4.54 - 4.49 (m, 0.5H), 4.25 - 4.10 (m, 2.5H), 3.88 - 3.78 (m, 1 H), 3.39 (s, 3H), 3.36 - 3.33 (m, 0.5H), 3.10 - 3.03 (m, 0.5H), 2.92 - 2.87 (m, 1 H), 2.57 - 2.42 (m, 1 H), 2.07 - 2.01 (m, 1 H), 1.96 - 1.89 (m, 1 H), 1.85 - 1.74 (m, 2H), 1.59 - 1.45 (m, 1 H), 1.04 -0.92 (m, 2H), 0.73 - 0.66 (m, 2H).

[1027] ESI MS. C22H28N3O3S m / z [M+H]+ calc. 414.2, found 414.1.Example 143: Synthesis of SW388726

[1028] (S)- / V-((4-(4-Cyanophenyl)thiazol-2-yl)methyl)-1-(2-ethoxyacetyl)piperidine-3- carboxamide (SW388726).

[1029] Synthesized by general procedure B and Suzuki coupling procedure C.

[1030] Yield: 65%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[1031] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 58.12 - 8.10 (m, 2H), 7.99 (s, 1 H), 7.79 - 7.76 (m, 2H), 4.78 - 4.67 (m, 2H), 4.54 - 4.49 (m, 0.5H), 4.28 - 4.14 (m, 2.5H), 3.92 - 3.84 (m, 1 H), 3.59 - 3.48 (m, 2H), 3.37 - 3.33 (m, 0.5H), 3.14 - 3.06 (m, 0.5H), 2.93 - 2.87 (m, 1 H), 2.57 - 2.42 (m, 1 H), 2.08 - 2.02 (m, 1 H), 1.89 - 1.76 (m, 2H), 1.61 - 1.47 (m, 1H), 1.23 - 1.19 (m, 3H).

[1032] ESI MS. C2IH25N4O3S m / z [M+H]+ calc. 413.2, found 413.2.

[1033] [a]256D+42.65 (c 0.15, CHCI3).Example 144: Synthesis of SW388727

[1034] (S)- / V-((4-(4-Chlorophenyl)thiazol-2-yl)methyl)-1 -(2-ethoxyacetyl)piperidine-3- carboxamide (SW388727)

[1035] Synthesized by general procedure B and Suzuki coupling procedure C.

[1036] Yield: 62%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[1037] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 57.92 - 7.88 (m, 2H), 7.99 (s, 1 H),7.46 - 7.36 (m, 2H), 4.76 - 4.67 (m, 2H), 4.54 - 4.49 (m, 0.5H), 4.28 - 4.14 (m, 2.5H), 3.92 - 3.84 (m, 1 H), 3.59 - 3.50 (m, 2H), 3.37 - 3.33 (m, 0.5H), 3.14 - 3.06 (m, 0.5H), 2.93 - 2.87 (m, 1 H), 2.55 - 2.42 (m, 1 H), 2.10 - 1.99 (m, 1 H), 1.89 - 1.76 (m, 2H), 1.61 - 1.47 (m, 1H), 1.23 - 1.19 (m, 3H).

[1038] ESI MS. C20H25CIN3O3S m / z [M+H]+ calc. 422.1 , found 422.2.Example 145: Synthesis of SW388728

[1039] (S)-1-(2-Ethoxyacetyl)- / V-((4-(4-ethoxyphenyl)thiazol-2-yl)methyl)piperidine-3- carboxamide (SW388728)

[1040] Synthesized by general procedure B and Suzuki coupling procedure C.

[1041] Yield: 71%. Purified by ISCO flash column chromatography (97:3 CH2Cl2: eOH v / v).

[1042] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 67.82 - 7.78 (m, 2H), 7.55 (s, 1 H),6.97 - 6.93 (m, 2H), 4.75 - 4.66 (m, 2H), 4.54 - 4.49 (m, 0.5H), 4.28 - 4.14 (m, 2.5H), 4.07 (q, J = 7.0 Hz, 2H), 3.92 - 3.84 (m, 1H), 3.59 - 3.50 (m, 2H), 3.37 - 3.33 (m, 0.5H), 3.14 - 3.06 (m, 0.5H),2.93 - 2.87 (m, 1 H), 2.55 - 2.42 (m, 1 H), 2.10 - 1.99 (m, 1 H), 1.87 - 1.76 (m, 2H), 1.61 - 1.47 (m, 1 H), 1.40 (t, J = 7.0 Hz, 3H), 1.23 - 1.19 (m, 3H).

[1043] ESI MS. C22H3ON304S m / z [M+H]+ calc. 432.2, found 432.2.Example 146: Synthesis of SW388729

[1044] (S)-4-(2-((1-(2-Methoxyacetyl)piperidine-3-carboxamido)methyl)thiazol-4- yl)benzoic acid (SW388729)

[1045] To a solution of methyl ester SW387998 (20.0 mg, 0.05 mmol, 1.00 equiv) in THE (1.0 mL), H2O (0.3 mL) and CH3OH (0.3 mL) was added lithium hydroxide (10.0 mg, 0.23 mmol, 5.00 equiv) and stirred at room temperature for 2 h. The organic solvent was removed under reduced pressure, and the residue obtained was then acidified to pH 2 with 1 N HCI, and the mixture was extracted with EtOAc (3 x 20 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the acid which was purified by washing with a mixture of hexane and EtOAc.

[1046] Yield: 72%

[1047] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 58.09 - 8.05 (m, 2H), 7.97 - 7.94 (m, 2H), 7.75 (d, = 1.8 Hz, 1 H), 4.78 - 4.67 (m, 2H), 4.54 - 4.49 (m, 0.5H), 4.27 - 4.08 (m, 2.5H), 3.85 - 3.75 (m, 1 H), 3.39 (s, 3H), 3.34 - 3.33 (m, 0.5H), 3.14 - 3.05 (m, 0.5H), 2.93 - 2.81 (m, 1 H), 2.53 - 2.40 (m, 1 H), 2.10 - 1.99 (m, 1 H), 1.89 - 1.75 (m, 2H), 1.61 - 1.43 (m, 1 H).

[1048] ESI MS. C2oH24N304S m / z [M+H]+ calc. 418.1 , found 418.0.Example 147: Synthesis of SW388730

[1049] (S)-N-((4-(4-(1 H-Pyrazol-1-yl)phenyl)thiazol-2-yl)methyl)-1-(2- methoxyacetyl)piperidine-3-carboxamide (SW388730)

[1050] Synthesized by general procedure B and Suzuki coupling procedure C.

[1051] Yield: 61%. Purified by ISCO flash column chromatography (19:1 CH2Cl2:MeOH v / v).

[1052] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 5 8.22 (d, J = 2.6 Hz, 1 H), 8.06 - 8.00 (m, 2H), 7.83 - 7.73 (m, 4H), 6.53 (t, J = 2.2 Hz, 1 H), 4.78 - 4.67 (m, 2H), 4.55 - 4.49 (m, 0.5H), 4.24 - 4.08 (m, 2.5H), 3.87 - 3.77 (m, 1 H), 3.39 (s, 3H), 3.36 - 3.33 (m, 0.5H), 3.11 - 3.04(m, 0.5H), 2.93 - 2.83 (m, 1 H), 2.56 - 2.42 (m, 1 H), 2.10 - 1.99 (m, 1 H), 1.89 - 1.75 (m, 2H), 1.61- 1.43 (m, 1 H).

[1053] ESI MS. C22H26N5O3S m / z [M+H]+ calc. 440.2, found 440.1.Example 148: Synthesis of SW388786

[1054] (S)-1-(2-Methoxyacetyl)-A / -((4-(4-(methylsulfonyl)phenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide (SW388786)

[1055] Synthesized by general procedure B and Suzuki coupling procedure C.

[1056] Yield: 41%. Purified by ISCO flash column chromatography (19:1 CH2Cl2:MeOH v / v).

[1057] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 58.20 - 8.18 (m, 2H), 8.01 - 7.98 (m, 3H), 4.80 - 4.67 (m, 2H), 4.57 - 4.49 (m, 0.5H), 4.27 - 4.08 (m, 2.5H), 3.88 - 3.79 (m, 1 H), 3.39 - 3.33 (m, 3.5H), 3.14 - 3.05 (m, 3.5H), 2.98 - 2.87 (m, 1 H), 2.53 - 2.42 (m, 1 H), 2.10 - 1.99 (m, 1 H), 1.89 - 1.75 (m, 2H), 1.61 - 1.46 (m, 1H).

[1058] ESI MS. C20H26N3O5S2 m / z [M+H]+ calc. 452.1 , found 452.0.Example 149: Synthesis of SW388767

[1059] (S)-1-(5-Methylisoxazole-3-carbonyl)- / V-((4-phenylthiazol-2-yl)methyl)piperidine- 3-carboxamide (SW388767)

[1060] Synthesized by general procedure A

[1061] Yield: 56%. Purified by ISCO flash column chromatography (19:1 CH2Cl2: eOH v / v).

[1062] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 5 7.87 - 7.83 (m, 2H), 7.72 (d, J = 5.4 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.35 - 7.30 (m, 1 H), 6.29 (d, J = 8.2 Hz, 1 H), 4.75 - 4.59 (m, 2.5H), 4.48 - 4.40 (m, 0.5H), 4.26 - 4.11 (m, 1H), 3.81 - 3.74 (m, 1 H), 3.44 - 3.35 (m, 0.5H), 3.23 - 2.97 (m, 1.5H), 2.62 - 2.53 (m, 1 H), 2.46 (d, J = 6.1 Hz, 3H), 2.15 - 2.01 (m, 1H), 1.90 - 1.78 (m, 2H), 1.66 - 1.56 (m, 1 H).

[1063] ESI MS. C2iH23N4O3S m / z [M+H]+ calc. 411.1 , found 411.0.Example 150: Synthesis of SW388768

[1064] (S)-1-(2-Methoxyacetyl)-A / -((4-(4-morpholinophenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide (SW388768)

[1065] Synthesized by general procedure B and Suzuki coupling procedure C.

[1066] Yield: 66%. Purified by ISCO flash column chromatography (19:1 CH2Cl2:MeOH v / v).

[1067] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 5 7.78 - 7.71 (m, 2H), 7.41 (d, J = 2.5 Hz, 1 H), 6.99 - 6.95 (m, 2H), 4.76 - 4.64 (m, 2H), 4.55 - 4.50 (m, 0.5H), 4.28 - 4.08 (m, 2.5H), 3.86 - 3.73 (m, 5H), 3.39 (s, 3H), 3.30 - 3.24 (m, 0.5H), 3.23 - 3.15 (m, 4H), 3.09 - 3.02 (m, 0.5H), 2.92 - 2.78 (m, 1 H), 2.51 - 2.37 (m, 1 H), 2.07 - 1.99 (m, 1 H), 1.86 - 1.75 (m, 2H), 1.58 - 1.45 (m, 1 H).

[1068] ESI MS. C23H3IN4O4S m / z [M+H]+ calc. 459.2, found 459.2.Example 151 : Synthesis of SW388770

[1069] (S)-1-(2-Methoxyacetyl)-A / -((4-(1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)methyl) piperidine-3-carboxamide (SW388770)

[1070] Synthesized by general procedure B and Suzuki coupling procedure C.

[1071] Yield: 54%. Purified by ISCO flash column chromatography (19:1 CH2Ch:MeOH v / v).

[1072] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 57.96 (s, 1 H), 7.84 (s, 1 H), 7.42 (s, 1 H), 4.76 - 4.64 (m, 2H), 4.55 - 4.49 (m, 0.5H), 4.28 - 4.04 (m, 2.5H), 3.92 (s, 3H), 3.87 - 3.78 (m, 1 H), 3.39 (s, 3H), 3.35 - 3.32 (m, 0.5H), 3.11 - 3.02 (m, 0.5H), 2.94 - 2.81 (m, 1H), 2.54 - 2.41 (m, 1 H), 2.07 - 1.99 (m, 1 H), 1.86 - 1.75 (m, 2H), 1.61 - 1.45 (m, 1 H).

[1073] ESI MS. CI7H24N5O3S m / z [M+H]+ calc. 378.2, found 378.1.Example 152: Synthesis of SW388771

[1074] (S)- / V-((4-Phenylthiazol-2-yl)methyl)-1-(pyrazine-2-carbonyl)piperidine-3- carboxamide (SW388771)

[1075] Synthesized by general procedure A

[1076] Yield: 64%. Purified by ISCO flash column chromatography (19:1 CH2Cl2:MeOH v / v).

[1077] 1H NMR (400 MHz, MeOH-ck) mixture of rotamers: 5 8.84 (dd, J = 13.9, 1.5 Hz, 1 H), 8.69 - 8.61 (m, 2H), 7.93 - 7.83 (m, 2H), 7.71 (d, J = 14.5 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.35 - 7.30 (m, 1 H), 4.77 - 4.59 (m, 2.5H), 4.40 - 4.35 (m, 0.5H), 3.96 - 3.75 (m, 1 H), 3.48 - 342 (m, 0.5H), 3.22 - 3.12 (m, 1.5H), 2.71 - 2.60 (m, 1 H), 2.17 - 2.07 (m, 1H), 1.98 - 1.74 (m, 2H), 1.73 - 1.61 (m, 1 H).

[1078] ESI MS. C21 H22N5O2S m / z [M+H]+ calc. 408.1 , found 408.2.Example 153: Synthesis of SW388772

[1079] (S)-1-(2-(Methylthio)acetyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW388772)

[1080] Synthesized by general procedure B and Suzuki coupling procedure C.

[1081] Yield: 73%. Purified by ISCO flash column chromatography (97:3 CH2Cl2: eOH v / v).

[1082] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: <5 7.90 - 7.85 (m, 2H), 7.66 (d, J = 2.0 Hz, 1 H), 7.43 - 7.39 (m, 2H), 7.35 - 7.31 (m, 1 H), 4.76 - 4.67 (m, 2H), 4.57 - 4.49 (m, 0.5H), 4.34 - 4.29 (m, 0.5H), 4.00 - 3.85 (m, 1 H), 3.50 - 3.32 (m, 2.5H), 3.19 - 3.10 (m, 0.5H), 2.93 - 2.76 (m, 1 H), 2.67 - 2.42 (m, 1 H), 2.16 (d, J = 1.6 Hz, 3H), 2.10 - 1.99 (m, 1 H), 1.86 - 1.75 (m, 2H), 1.70 - 1.44 (m, 1 H).

[1083] ESI MS. C19H24N3O2S2 m / z [M+H]+ calc. 390.1 , found 390.0.Example 154: Synthesis of SW388769

[1084] (S)-1 -(2-Methoxyacetyl)-A / -((4-(4-(methylcarbamoyl)phenyl)thiazol-2- yl)methyl)piperidine-3-carboxamide (SW388769)

[1085] Synthesized by general procedure B and Suzuki coupling procedure C.

[1086] Yield: 55%. Purified by ISCO flash column chromatography (19:1 CH2Cl2:MeOH v / v).

[1087] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 58.03 - 7.96 (m, 2H), 7.89 - 7.84 (m, 3H), 4.79 - 4.67 (m, 2H), 4.56 - 4.50 (m, 0.5H), 4.26 - 4.07 (m, 2.5H), 3.87 - 3.78 (m, 1 H), 3.39 - 3.33 (m, 3.5H), 3.12 - 3.06 (m, 0.5H), 2.94 - 2.86 (m, 4H), 2.57 - 2.42 (m, 1 H), 2.07 - 2.02 (m, 1 H), 1.89 - 1.75 (m, 2H), 1.61 - 1.43 (m, 1H).

[1088] ESI MS. C2IH27N4O4S m / z [M+H]+ calc. 431.2, found 431.2.Example 155: Synthesis of SW388773

[1089] (S)-1-(2-(Methylsulfonyl)acetyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW388773)

[1090] To a solution of above thiol SW388772 (30.0 mg, 0.075 mmol, 1.00 equiv) in CH2CI2 (2.0 mL) at 0°C was added 3-chloroperoxybenzoic acid (45.0 mg, 0.18 mmol, 2.40 equiv). The resulting mixture was allowed to warm to room temperature after addition and stirred at room temperature for 1 h. The reaction was quenched with saturated solution of sodium sulfite (5.0 mL) and extracted with CH2CI2. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified using ISCO flash column chromatography.

[1091] Yield: 71%. Purified by ISCO flash column chromatography (19:1 CH2Cl2: eOH v / v).

[1092] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 57.88 - 7.85 (m, 2H), 7.62 (s, 1 H), 7.43 - 7.37 (m, 2H), 7.33 - 7.30 (m, 1 H), 4.76 - 4.64 (m, 2H), 4.59 - 4.49 (m, 1H), 4.41 - 4.20 (m, 2H), 4.01 - 3.94 (m, 1 H), 3.50 - 3.44 (m, 0.5H), 3.23 - 3.16 (m, 0.5H), 3.11 (s, 3H), 3.03 - 2.93j (m, 1 H), 2.67 - 2.60 (m, 0.5H), 2.50 - 2.42 (m, 0.5H), 2.10 - 1.99 (m, 1 H), 1.90 - 1.75 (m, 2H), 1.73 - 1.48 (m, 1 H).

[1093] ESI MS. CI9H24N3O4S2 m / z [M+H]+ calc. 422.1 , found 422.0.Example 156: Synthesis of SW388776

[1094] (S)- / V-((4-Phenylthiazol-2-yl)methyl)-1-(thiophene-2-carbonyl)piperidine-3- carboxamide (SW388776)

[1095] Synthesized by general procedure A

[1096] Yield: 73%. Purified by ISCO flash column chromatography (97:3 CH2Cl2:MeOH v / v).

[1097] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 57.940 - 7.87 (m, 2H), 7.71 (s, 1 H), 7.63 (dd, J = 5.0, 1.1 Hz, 1 H), 7.47 - 7.36 (m, 3H), 7.36 - 7.30 (m, 1 H), 7.11 (dd, = 5.0, 3.6 Hz, 1 H), 4.71 (s, 2H), 4.53 - 4.28 (m, 2H), 3.24 - 3.04 (m, 1 H), 2.81 (s, 1 H), 2.64 - 2.55 (m, 1 H), 2.13 - 2.04 (m, 1 H), 1.94 - 1.80 (m, 2H), 1.67 - 1.52 (m, 1 H).

[1098] ESI MS. C21H22N3O2S2 m / z [M+H]+ calc. 412.1 , found 412.1.Example 157: Synthesis of SW388775

[1099] (S)-1-(Furan-2-carbonyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW388775)

[1100] Synthesized by general procedure A

[1101] Yield: 68%. Purified by ISCO flash column chromatography (97:3 CH2CI2:MeOH v / v).

[1102] 1H NMR (400 MHz, MeOH-d4) mixture of rotamers: 57.93- 7.87 (m, 2H), 7.71 (s, 1H), 7.67-7.66 (m, 1H), 7.46- 7.36 (m, 2H), 7.35-7.30 (m, 1H), 7.02 (dd, J= 3.5, 0.8 Hz, 1H), 6.57 (dd, J =3.5, 1.8 Hz, 1H), 4.72 (s, 2H), 4.53 (d, J= 13.2 Hz, 1H), 4.39 (d, = 13.3 Hz, 1H), 3.28- 2.86 (m, 2H), 2.62-2.54 (m, 1H), 2.15- 2.04 (m, 1H), 1.94- 1.83 (m, 2H), 1.68- 1.56 (m, 1H).

[1103] ESI MS. C2IH22N3O3S m / z [M+H]+ calc.396.1, found 396.2.Example 158: Synthesis of SW388777

[1104] (S)-1-(lsoxazole-5-carbonyl)-A / -((4-phenylthiazol-2-yl)methyl)piperidine-3- carboxamide (SW388777)

[1105] Synthesized by general procedure A

[1106] Yield: 67%. Purifi...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (l)-1 , Formula (l)-T, Formula (l)-1”, Formula (l)-2, or Formula (I)-3, or a salt thereof:Formula (I)-l'Formula (I)-3 whereinR-io R9Formula (la)D is H, -CH2CH2OCH3, sulfonyl, substituted sulfonyl, orFormula (Ic'")R1-R5 are each independently hydrogen, halogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, ether, ester, -C(O)CH3, -C(O)OCH3, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero cycloalkyl, optionally C3-C6 substituted hetero cycloalkyl, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, - C(O)OH, - C3-C6 cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl,Ri and Rs are interconnected to form a substituted pyrazole ring, Ri and Rs are interconnected to form an aryl ring, or absent;X-i-Xs are each independently carbon or nitrogen;A, B, C, Z, and Y are each independently carbon, nitrogen, oxygen, sulfur, or absent;W is hydrogen, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-C6 hetero cycloalkyl, optionally C3-C6 substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, alkyl amine, carboxylic acid, -CH2NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, 3-methyloxazol-2(3H)-one, substituted or unsubstituted oxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted oxetane, substituted or unsubstituted triazole, thiazole, sulfonyl, or substituted sulfonyl; n is 0, 1 , or 2;Re-R? are each independently hydrogen or methyl;Rs is H, alkyl or hydroxyl; or Rs and R23 are connected to form a 3 to 6 membered cycloalkyl ring;R9-R10 are each independently H, deuterium, alkyl, or components of a ring;R11-R13 are hydrogen, deuterium, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, Ci-Ce substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, hetero cycloalkyl, optionally C3- Cs substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, - C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, Rn and R12 are interconnected to form a cycloalkyl ring, R10 and n are interconnected to form a substituted or unsubstituted C3-C6 cycloalkyl, heterocycloalkyl, or absent; wherein C1-C6substituted alkyl may be optionally substituted with one or more of halogen, hydroxy, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, hetero cycloalkyl, optionally C3- Ce substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, Ri and Rs are interconnected to form a substituted pyrazole ring, Ri and R5are interconnected to form an aryl ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-C6 cycloalkyl, heterocycloalkyl, or absent;R10 is hydrogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, heteroaryl, - C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, R and Rn are interconnected to form a substituted pyrazole ring, Rw and Rn are interconnected to form a substituted or unsubstituted Cs-Ce cycloalkyl, a substituted or unsubstituted C3-C6 cycloheteroalkyl, a substituted or unsubstituted heterocyclic aromatic, aryl ring, or heteroaryl, or absent; andR20-R28 are each independently hydrogen, alkyl, alkoxy, amine, amide, heterocycloalkyl, or alkyl amine; orR20, R22-R25, and R27-R28 are each independently hydrogen, alkyl, alkoxy, amine, amide, heterocycloalkyl, or alkyl amine R21 and R26 and are connected to form a 3 to 6 membered cycloalkyl ring. wherein halogen is F, Cl, Br, or I.

2. The compound of claim 1, wherein the compound is an S-enantiomer.

3. The compound of claim 1, wherein the compound comprises an S-enantiomer configuration at the carbon attached to -(CO)-E.

4. A compound of Formula (ll)-1 , Formula (ll)-2, Formula (ll)-3, or a salt thereof:whereinR1-R5 are each independently hydrogen, halogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, ether, ester, -C(O)CH3, -C(O)OCH3, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C(O)NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, - C3-Ce cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, R1 and Rs are interconnected to form a substituted pyrazole ring, R1 and Rs are interconnected to form an aryl ring, or absent;X-i-Xe are each independently carbon or nitrogen;A, B, C, Z, and Y are each independently carbon, nitrogen, oxygen, sulfur, or absent;W is hydrogen, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-Cs heterocycloalkyl, optionally C3-Ce substituted heterocycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, alkyl amine, carboxylic acid, -CH2NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, 3-methyloxazol-2(3H)-one, substituted or unsubstituted oxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted oxetane, substituted or unsubstituted triazole, thiazole, sulfonyl, or substituted sulfonyl; n is 0, 1 , or 2;R6-R9 are each independently hydrogen, methyl, or absent;Rn-Ri3 are hydrogen, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C-i-Ce alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, Rn and R12 are interconnected to form a cycloalkyl ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-Cs cycloalkyl, heterocycloalkyl, or absent; wherein C1-C6substituted alkyl may be optionally substituted with one or more of halogen, hydroxy, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, - C(O)H, -C(O)NCH3CH3, -C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, R1 and Rs are interconnected to form a substituted pyrazole ring, R1 and Rs are interconnected to form an aryl ring, or absent;R10 is hydrogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, heteroaryl, - C(O)NHCH3, -C(O)H, -C(O)NCH3CH3I-C(O)OH, cycloalkyl, nitro, pyrazole, sulfonyl, Rwand R11 are interconnected to form a substituted pyrazole ring, R« and Rn are interconnected to form a substituted or unsubstituted C3-C6cycloalkyl or aryl ring, or absent; and wherein halogen is F, Cl, Br, or I.

5. The compound of claim 4, wherein the compound is an S-enantiomer.

6. The compound of claim 4, whereinXi and X2 are independently carbon or nitrogen;X3-Xe are carbon;R1 is hydrogen, methyl, trifluoromethyl, cyclopropyl, methoxy, or cyano;A is sulfur;B is nitrogen;C is carbon;Z is carbon or nitrogen;R2-R10 are hydrogen;Y is oxygen;R11 is methyl, ethyl, or ethyl fluoride;R12 and R13 are absent; and n=1.

7. The compound of claim 4, wherein the compound has Formula (ll)-1 ; and wherein the compound is8. The compound of claim 7, wherein the compound is9. The compound of claim 4, wherein the compound has Formula (ll)-2; and wherein the compound is selected from the group consisting of10. The compound of claim 4, wherein the compound has Formula (ll)-2; and wherein the compound is wherein the compound is11. The compound of claim 3, wherein the compound is12. The compound of claim 3, wherein the compound is13. The compound of claim 3, wherein the compound is14. The compound of claim 4, wherein the compound has Formula (ll)-2; and wherein the compound is15. The compound of claim 4, wherein the compound has Formula (ll)-2; and wherein the compound is16. The compound of claim 4, wherein the compound has Formula (ll)-2; and wherein the compound is17. The compound of claim 4, wherein the compound is18. The compound of claim 4, wherein the compound has Formula (ll)-3; and wherein the compound is19. A compound of Formula (l)-1 or a salt thereof:Formula (I)-l whereinD is H, -OMe, -CH2CH2OCH3, sulfonyl, substituted sulfonyl, Formula (la) orFormula (Ic") Formula (Ic'")R1-R5 are each independently hydrogen, halogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, ether, ester, -C(O)CH3, -C(O)OCH3, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C(O)NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, - C3-Ce cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, R1 and R5 are interconnected to form a substituted pyrazole ring, R1 and Rs are interconnected to form an aryl ring, or absent;Xi-Xe are each independently carbon or nitrogen;A, B, C, Z, and Y are each independently carbon, nitrogen, oxygen, sulfur, or absent;W is hydrogen, halogen, cyano, hydroxy, alkoxy, C-i-Ce alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-Ce hetero cycloalkyl, optionally C3-Ce substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, alkyl amine, carboxylic acid, -CFhNHCHs, -C(O)H, - C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, 3-methyloxazol-2(3H)-one, substituted or unsubstituted oxazole, substituted or unsubstituted benzothiazole, substituted or unsubstituted benzoimidazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted oxetane, substituted or unsubstituted triazole, thiazole, sulfonyl, or substituted sulfonyl; n is 0, 1 , or 2;Re-R? are each independently hydrogen or methyl;Rs is H, alkyl or hydroxyl;R9-R10 are each independently H, deuterium, alkyl, or components of a ring;R11-R13 are hydrogen, deuterium, halogen, cyano, hydroxy, alkoxy, C1-C6alkyl, C1-C6substituted alkyl, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-Ce hetero cycloalkyl, optionally C3-Ce substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, R11 and R12 are interconnected to form a cycloalkyl ring, R and Rn are interconnected to form a substituted or unsubstituted C3-Ce cycloalkyl, heterocycloalkyl, or absent; wherein C1-C6substituted alkyl may be optionally substituted with one or more of halogen, hydroxy, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C3-Ce hetero cycloalkyl, optionally C3-Ce substituted hetero cycloalkyl, cycloalkyl, optionally substituted cycloalkyl, ether, ester, aldehyde, ketone, amine, amide, carboxylic acid, -C(O)NHCH3, -C(O)H, - C(O)NCH3CH3, -C(O)OH, nitro, pyrazole, sulfonyl, substituted sulfonyl, R1 and R5are interconnected to form a substituted pyrazole ring, R1 and R5are interconnected to form anaryl ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-C6 cycloalkyl, heterocycloalkyl, or absent;R10 is hydrogen, cyano, C1-C6alkyl optionally substituted with one or more halogen, alkoxy, substituted alkoxy, C1-C6alkyl thiol, -C(O)CH3, -C(O)OCH3, aryl, heteroaryl, - C(O)NHCH3, -C(O)H, -C(O)NCH3CH3, -C(O)OH, cycloalkyl, nitro, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, sulfonyl, substituted sulfonyl, R10 and Rn are interconnected to form a substituted pyrazole ring, R10 and Rn are interconnected to form a substituted or unsubstituted C3-Ce cycloalkyl, a substituted or unsubstituted C3-Ce cycloheteroalkyl, a substituted or unsubstituted heterocyclic aromatic, aryl ring, or heteroaryl, or absent; andR20-R28 are each independently hydrogen, alkyl, alkoxy, amine, amide, heterocycloalkyl, or alkyl amine. wherein halogen is F, Cl, Br, or I.

20. The compound of claim 19 with Formula (l)-1 , wherein the compound is21. The compound of claim 19 with Formula (l)-1 , wherein the compound is22. The compound of claim 19 with Formula (l)-1 , wherein the compound is23. A compound selected from the group consisting of24. A pharmaceutical composition comprising the compound of claim 23 and a pharmaceutically acceptable excipient.

25. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

26. A method of treating malaria in a subject in need thereof, comprising administering to the subject the compound of any one of claims 1-25 or pharmaceutical composition of any one of claims 22-23.

27. The method of claim 26, wherein the compound or pharmaceutical composition is coadministered with an artemisinin.

28. The method of claim 27, wherein the artemisinin is selected from the group consisting of dihydroartemisinin (DHA), artemether, dihydroartesunate, artesunate, arteether, or artemisone.

29. The method of claim 28, wherein the compound or pharmaceutical composition is coadministered with a proteasome 02 inhibitor.

30. The method of claim 29, wherein the proteasome 2 inhibitor is selected from the group consisting of bortezomib, MG-132, epoximicin, and WLW-vs.

31. The method of any one of claims 26-30, wherein the malaria is associated with a Plasmodium falciparum infection.

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