Benzothiazole and benzoimidazole derivatives for the treatment of a disease or disorder

Abstract

The disclosure relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein A, Ra, Rb, R1, and p, are as described herein, as well as compositions and methods of using such compounds.

Description

[0001] BENZOTHIAZOLE AND BENZOIMIDAZOLE DERIVATIVES FOR THE TREATMENT OF A DISEASE OR DISORDER

[0002] RELATED APPLICATIONS

[0003]

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 714,962, filed November 1, 2024, and U.S. Provisional Application No. 63 / 900,308, filed October 16, 2025, the entire contents of each of which are hereby incorporated by refference in their entireties.

[0004] BACKGROUND

[0005]

[0002] Heart failure is a major public health problem concerning more than 20 million patients around the world and is associated with high morbidity. Natriuretic Peptide Receptor 1 (NPR1; also known as NPRA) is a receptor guanylate cyclase, which is activated by Atrial Natriuretic Peptide (ANP) resulting in lowering of blood pressure and blood volume. ANP binding induces dimerization and twisting of the receptor that induces activation of the guanylate cyclase domain and conversion of GTP into cGMP. ANP is cleared by NPR3, a natriuretic peptide receptor that lacks the guanylate cyclase domain, and degraded by Neutral Endopeptidase (NEP).

[0006]

[0003] It has been shown that an increase in ANP via infusions may be beneficial for patients with chronic heart failure with reduced ejection fraction (outbound pumping of blood by heart). However, there is a need for oral agents that are able to supplement or replace existing therapies.

[0007] SUMMARY

[0008]

[0004] In a first aspect, the disclosure relates to a compound of Formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof wherein:

[0011]

[0012] R2and R3are each independently selected from H, (C1-C6)alkyl, and (Ci-Ce)alkoxy; or

[0013] R2and R3together with the carbon to which they are bound combine to form a (C3-C6)cycloalkyl or a 3- to 10-membered heterocycle containing 0;

[0014] Rais independently for each occurrence selected from halo, (C1-C6)alkyl, (Ci-C6)haloalkyl, (C3- C6)cycloalkyl, (Ci-Ce)alkoxy, or (Ci-C6)haloalkoxy;

[0015] Rbis H or (C1-C6)alkyl; Rd1is H, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, 6 membered heterocycle containing N, 0, or S, or heteroaryl, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (C1-C6)alkyl, the (C1-C6)alkyl, the (C3- C6)cycloalkyl, and the 6 membered heterocycle are optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from halo, -OH, -COOH, (C1-C6)haloalkoxy, (C1-C6)alkoxy, and a 5 or 6 membered heterocycle containing O; Rd2is H, aryl or heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (C1-C6)alkyl; Rd3is H or (C1-C6)alkyl; Rd4is H, (C1-C6)alkyl, C3-C6)cycloalkyl, or aryl, wherein the aryl is optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from halo and (C1-C6)alkyl;

[0016] Reis (Ci-C6)alkyl, (C3-C6)cycloalkyl, 5 or 6 membered heterocycle containing N, 0, or S, and heteroaryl, wherein the (C1-C6)alkyl, (C3-C6)cycloalkyl, 5 or 6 membered heterocycle containing N, 0, or S,

[0017] / J- and heteroaryl are each independently substituted with (Ci-C6)alkyl, -CN, -C00H, O,

[0018]

[0019] W is N or S; and

[0020] p is an integer selected from 1, 2, 3, and 4.

[0005] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0021]

[0006] In another aspect, the present disclosure relates to a combination comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutical agents.

[0022]

[0007] In another aspect, the present disclosure relates to a method for treating a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or disorder is a cardiovascular disease or disorder. In some embodiments, the cardiovascular disease or disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, cardiac dysrhythmia, atrial fibrillation (AF), new onset of atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, and myocardial infarction (MI). In some embodiments, the disease or disorder is disorder is a disorder or disease associated with natriuretic peptide receptor activity

[0023]

[0008] In another aspect, the present disclosure relates to a compound of Formula I or a pharmaceutically acceptable salt thereof for use as a medicament.

[0024]

[0009] In another aspect, the present disclosure relates to a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder.

[0025]

[0010] In yet another aspect, the present disclosure relates to a compound of Formula I for use in the manufacture of a medicament for treating a disease or disorder.

[0026] [OH] In still another aspect, the present disclosure relates to use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the treatment of a disease or disorder.

[0027]

[0012] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.

[0028] DETAILED DESCRIPTION

[0029]

[0013] In certain aspects, the disclosure provides substituted hydroquinazoline derivatives compounds, and pharmaceutical compositions thereof. In particular, such substituted compounds are useful as activators of NPR1 and thus can be used to treat or prevent a disease or condition.

[0030]

[0014] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

[0031] Compounds

[0032]

[0015] In one aspect, the disclosure therefore provides a compound of Formula (I):

[0033]

[0034] or a pharmaceutically acceptable salt thereof wherein:

[0035]

[0036] R2and R3are each independently selected from H, (C1-C6)alkyl, and (Ci-Ce)alkoxy; or

[0037] R2and R3together with the carbon to which they are bound combine to form a (C3-C6)cycloalkyl or a 3- to 10-membered heterocycle containing 0;

[0038] Rais independently for each occurrence selected from halo, (C1-C6)alkyl, (Ci-C6)haloalkyl, (C3- C6)cycloalkyl, (Ci-Ce)alkoxy, or (Ci-C6)haloalkoxy;

[0039] Rbis H or (C1-C6)alkyl; Rd1is H, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, 6 membered heterocycle containing N, O, or S, or heteroaryl, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (C1-C6)alkyl, the (C1-C6)alkyl, the (C3-C6)cycloalkyl, and the 6 membered heterocycle are optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from halo, -OH, -COOH, (C1-C6)haloalkoxy, (C1-C6)alkoxy, and a 5 or 6 membered heterocycle containing O; Rd2is H, aryl or heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (C1-C6)alkyl; Rd3is H or (C1-C6)alkyl; Rd4is H, (C1-C6)alkyl, C3-C6)cycloalkyl, or aryl, wherein the aryl is optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from halo and (C1-C6)alkyl; Reis (C1-C6)alkyl, (C3-C6)cycloalkyl, 5 or 6 membered heterocycle containing N, O, or S, and heteroaryl, wherein the (C1-C6)alkyl, (C3-C6)cycloalkyl, 5 or 6 membered heterocycle and heteroaryl are each independently substituted with (C1-C6)alkyl, -CN, -

[0040]

[0041]

[0042] W is N or S; and

[0043] p is an integer selected from 1, 2, 3, and 4.

[0044]

[0016] In some embodiments,

[0045]

[0046] R2and R3are each independently selected from H, (C1-C6)alkyl, and (Ci-Ce)alkoxy; or

[0047] R2and R3together with the carbon to which they are bound combine to form a (C3-C6)cycloalkyl or a 3- to 10-membered heterocycle containing 0;

[0048] Rais independently for each occurrence selected from halo, (C1-C6)alkyl, (Ci-Ce)alkoxy, or (Ci- C6)haloalkoxy;

[0049] Rbis H or (C1-C6)alkyl; Rd1is H, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, 6 membered heterocycle containing N, 0, or S, or heteroaryl, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (C1-C6)alkyl, the (C1-C6)alkyl is optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (Ci-Ce)alkoxy;

[0050] Rd2is H, aryl or heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (Ci-C6)alkyl; Reis (C1-C6)alkyl, (C3-C6)cycloalkyl, 5 or 6 membered heterocycle containing N, O, or S, and heteroaryl, wherein the (C3-C6)cycloalkyl, 5 or 6 membered heterocycle containing N, O, or S, and heteroaryl are each independently substituted with (C1-C6)alkyl, -COOH, and O

[0051] W is N or S; and

[0052] p is an integer selected from 1, 2, 3, and 4.

[0053]

[0017] In some embodiements, W is S. In some embodiments, W is N.

[0054]

[0018] In some embodiemnts, the compound or a pharmaceutically acceptable salt thereof is of formula

[0055]

[0056]

[0057] some embodiments, the compound or a pharmaceutically acceptable salt thereof is of formula

[0058]

[0059] embodiments, the compound is of formula

[0060]

[0061]

[0062]

[0019] In some embodiments, Rais independently for each occurrence selected from halo, (C1-C3)alkyl and (C1-C3)alkoxy, and (C1-C3)haloalkoxy. In some embodiments, Rais independently for each occurrence selected from fluoro, chloro, bromo, -OCH3, -OCF3, and cyclopropyl. In some embodiments, Rais independently for each occurrence selected from fluoro, chloro, -OCH3, and -OCF3. In some embodiments, Rais independently for each occurrence fluoro.

[0063]

[0020] In some embodiments,

[0064]

[0065] some embodiments,

[0066]

[0067] some embodiments,

[0068]

[0069] In some embodiments,

[0070]

[0071] ky!)

[0072]

[0021] In some embodiments, R1is [structure image]; and R2and R3are each independently selected from H, (C1-C6)alkyl, and (Ci-Ce)alkoxy; or R2and R3together with the carbon to which they are bound combine to form a (C3-C6)cycloalkyl or a 6-membered heterocycle containing 0. In some embodiments, R1is

[0073]

[0074] together with the carbon to which they are bound combine to form a (C4- C6)cycloalkyl.

[0075]

[0022] In some embodiments, R1is selected from

[0076]

[0077]

[0078] some embodiments, R1is selected from

[0079]

[0080]

[0023] In some embodiments, Rxis [structure]; and Rd1is (C1-C6)alkyl, (C3-C6)cycloalkyl, C6aryl, 6 membered heterocycle containing O, or heteroaryl, wherein the C6 aryl and heteroaryl are each optionally substituted with one or two substituents selected from (C1-C2)alkyl, the (C1-C6)alkyl is optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (C1-C2)alkoxy. In some embodiments, Rxis [structure]; and Rd1is (C1-C6)alkyl, (C3-C6)cycloalkyl, C6aryl, 6 membered heterocycle containing O, or a 5 membered heteroaryl containing N, wherein the C6 aryl is optionally substituted with one or two substituents selected from (C1-C2)alkyl, the 5 membered heteroaryl containing N is optionally substituted with one or two substituents (e.g., 1, 2, 3, or 4) selected from (C1-C2)alkyl, and the (C1-C6)alkyl is optionally substituted with one or two substituents selected from (C1-C2)alkoxy. In some embodiments, Rxis [structure]; and Rd2is H, C6 aryl or 5 or 6 membered heteroaryl containing N or S, wherein the heteroaryl is optionally substituted with one or two substituents selected from (Ci-C6)alkyl.

[0081]

[0024] In some embodiments, Rd1is (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, 6 membered heterocycle containing N, O, or S, or heteroaryl, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (C1-C6)alkyl, the (C1-C6)alkyl, the (C3-C6)cycloalkyl, and the 6 membered heterocycle are optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from halo, -OH, -COOH, (C1-C6)haloalkoxy, (C1-C6)alkoxy, and a 5 or 6 membered heterocycle containing O. In some embodiments, Rd1is (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, 6 membered heterocycle containing O, or heteroaryl, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (C1-C6)alkyl, the (C1-C6)alkyl, the (C3-C6)cycloalkyl, and the 6 membered heterocycle are optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from halo, -OH, -COOH, (C1-C6)haloalkoxy, (C1-C6)alkoxy, and a 5 or 6 membered heterocycle containing O. In some embodiments, Rd1is (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, 6 membered heterocycle containing O, or heteroaryl, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (C1-C6)alkyl, the (C1-C6)alkyl, the (C3-C6)cycloalkyl, and the 6 membered heterocycle are optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from halo, -OH, -COOH, (C1-C6)haloalkoxy, (C1-C6)alkoxy, and a 6 membered heterocycle containing O.

[0082]

[0025] In some embodiments, Rd1is (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, 6 membered heterocycle containing N, O, or S, or heteroaryl, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (C1-C6)alkyl, the (C1-C6)alkyl, the (C3-C6)cycloalkyl, and the 6 membered heterocycle are optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from halo, -OH, -COOH, (C1-C6)haloalkoxy, (C1-C6)alkoxy, and a 5 or 6 membered heterocycle containing O. In some embodiments, Rd1is (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, 6 membered heterocycle containing N, O, or S, or heteroaryl, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (C1-C6)alkyl, the (C1-C6)alkyl, the (C3-C6)cycloalkyl, and the 6 membered heterocycle are optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from halo, -OH, -COOH, -CF3, -OCH3, and a 6 membered heterocycle containing O.

[0083]

[0026] In some embodiments, Rd2is H, phenyl, imidazolyl, pyrazolyl, pyridyl, or thiophenyl, wherein the imidazolyl, pyrazolyl, pyridyl, or thiophenyl are each optionally substituted with one or two substituents selected from -CH3 and -CH2CH3. In some embodiments, Rd2is H, phenyl, imidazolyl, pyrazolyl, pyridyl, or thiophenyl, wherein the imidazolyl, pyrazolyl, pyridyl, or thiophenyl are each optionally substituted with one substituent selected from -CH3. In some embodiments, Rd2is H, phenyl, imidazolyl, pyrazolyl, pyridyl, or thiophenyl, wherein the imidazolyl and pyrazolyl are each optionally substituted with one substituent selected from -CH3.

[0084]

[0027] In some embodiments, Rd3is H, CH3 or -CH2CH3. In some embodiments, Rd3is H or -CH3. In some embodiments, Rd3is H.

[0085]

[0028] In some embodiments, Rd4is H, (C1-C6)alkyl, C3-C6)cycloalkyl, or aryl, wherein the aryl is optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from halo and (C1-C6)alkyl. In some embodiments, Rd4is H, (C1-C6)alkyl, C3-C6)cycloalkyl, or phenyl, wherein the phenyl is optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from fluoro and (C1-C6)alkyl. In some embodiments, Rd4is H, methyl, cyclohexyl, or phenyl, wherein the phenyl is optionally substituted with one or two substituents selected from fluoro. In some embodiments, Rd4is H, methyl, cyclohexyl, or phenyl, wherein the phenyl is optionally substituted with fluoro. In some embodiments, Rd4is H, cyclohexyl, or phenyl, wherein the phenyl is optionally substituted with one substituent selected fluoro. In some embodiments, Rd4is H.

[0086]

[0029] In some embodiments, R1is selected from

[0087]

[0088]

[0089]

[0090]

[0030] In some embodiments, R1is selected from

[0091]

[0092]

[0031] In some embodiments, R1is selected from

[0093]

[0094]

[0032] In some embodiments, R1is selected from

[0095]

[0096]

[0097]

[0033] In some embodiments, R1is selected from

[0098]

[0099]

[0034] In some embodiments, R1is selected from

[0100]

[0101]

[0037] In some embodiments,

[0102]

[0103] 6)cycloalkyl, 5 or 6 membered heterocycle containing N, or heteroaryl, wherein the (C3-C6)cycloalkyl, 5 or 6 membered heterocycle containing N, and heteroaryl are each independently substituted with (C1-C6)alkyl, -COOH, and

[0104]

[0105]

[0038] In some embodiments, R1is selected from

[0106]

[0107]

[0108]

[0039] In some embodiments, R1is selected from

[0109]

[0110]

[0040] In some embodiments, Rbis H or -CH3. In some embodiments, wherein Rbis H.

[0111]

[0041] In some embodiments, p is an integer selected from 1 and 2. In some embodiments, p is an integer selected from 1.

[0112]

[0042] Unless specified otherwise, the term “compounds of the present disclosure” or “compound of the present disclosure” refers to compounds of Formula (I) thereof, and exemplified compounds, and salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), as well as inherently formed moieties.

[0113]

[0043] Various embodiments of the disclosure are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features of other embodiments to provide further embodiments.

[0114]

[0044] In certain embodiments, the compound is a compound or a pharmaceutically acceptable salt thereof selected from Table 1.

[0115] Table 1

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0045] As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the present disclosure. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this disclosure and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. When both a basic group and an acid group are present in the same molecule, the compounds of the present disclosure may also form internal salts, e.g., zwitterionic molecules.

[0152]

[0046] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

[0153]

[0047] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0154]

[0048] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0155]

[0049] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0156]

[0050] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

[0157]

[0051] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0158]

[0052] In another aspect, the present disclosure provides compounds of the present disclosure in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form.

[0159]

[0053] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into compounds of the disclosure include, for example, isotopes of hydrogen.

[0160]

[0054] Further, incorporation of certain isotopes, particularly deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index or tolerability. It is understood that deuterium in this context is regarded as a substituent of a compound of the present disclosure. The concentration of deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this disclosure is denoted as being deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term “isotopic enrichment factor” can be applied to any isotope in the same manner as described for deuterium.

[0161]

[0055] Other examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as3H,11C,13C,14C,15N,18F31P,32P,35S,36Cl,123I,124I,125I respectively. Accordingly it should be understood that the disclosure includes compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as3H and14C, or those into which non-radio active isotopes, such as2H and13C are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

[0162]

[0056] Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present disclosure can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.

[0163]

[0057] Accordingly, as used herein a compound of the present disclosure can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

[0164]

[0058] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0165]

[0059] Any resulting racemates of compounds of the present disclosure or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present disclosure into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-. '- -toluoyl tartaric acid, mandelic acid, malic acid or camphor- 10-sulfonic acid. Racemic compounds of the present disclosure or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent. Pharmaceutical Compositions

[0166]

[0060] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein.

[0167]

[0061] In some embodiments, a pharmaceutical composition further comprises at least one additional pharmaceutically active agent. In some embodiments, the additional pharmaceutically active agent is selected from an ACE (angiotensin-converting-enzyme) inhibitor, an angiotensin receptor blocker (ARB), a neprilysin inhibitor, a beta blocker, a diuretic, a calcium channel blocker, a cardiac glycoside, a sodiumglucose co-transporter 2 inhibitor (SGLT2i), or combinations thereof.

[0168]

[0062] The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration (e.g. by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also pertain to inhalation or intranasal application. The pharmaceutical compositions of the present disclosure can be made up in a solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including, without limitation, solutions, suspensions or emulsions). Tablets may be either film coated or enteric coated according to methods known in the art. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of:

[0169] a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0170] b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethyleneglycol; for tablets also

[0171] c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired

[0172] d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.

[0173]

[0063] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0174]

[0064] The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

[0065] Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

[0175]

[0066] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

[0176]

[0067] The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0177]

[0068] The pharmaceutical composition or combination of the present disclosure may, for example, be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg. In one embodiment, the compositions are in the form of a tablet that can be scored. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated.

[0178] Methods of Use

[0179]

[0069] In yet another aspect, the present disclosure is directed to a method of treating or preventing a disease or disorder comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0180]

[0070] In another aspect, the present disclosure relates to a method for treating a disease or disorder comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the disease or disorder is a cardiovascular disease or disorder.

[0181]

[0071] In certain embodiments, the cardiovascular disease or disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, cardiac dysrhythmia, atrial fibrillation (AF), new onset of atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, and myocardial infarction (MI). In some embodiments, the heart failure is selected from a heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute decompensated heart failure. In some embodiments, the hypertrophic cardiomyopathy is ventricular hypertrophy. In some embodiments, the hypertension is selected from resistant hypertension, hypertensive heart disease, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, resistant hypertension, and pulmonary arterial hypertension. In some embodiments, the hypertension is selected from resistant hypertension and hypertensive heart disease.

[0182]

[0072] In some embodiments, the disease or disorder is preeclampsia, asthma, glaucoma, a kidney disorder, and / or cytokine release syndrome in a subject in need of such treatment. In some embodiments, the kidney disorder is selected from: diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute renal injury, contrast induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, renal vascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis, and polycystic kidney disease (PKD).

[0183]

[0073] In some embodiments, the disease or disorder is a disorder or disease associated with natriuretic peptide receptor activity.

[0184]

[0074] In another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for the manufacture of a medicament for use to treat a disease or disorder disclosed herein.

[0185]

[0075] In another aspect, the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for use as a medicament.

[0186]

[0076] Another aspect of the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for use in the in the treatment of a disease or disorder disclosed herein. In some embodiments, the disease or disorder is a cardiovascular disease or disorder (e.g., a cardiovascular disease or disorder as disclosed herein).

[0187]

[0077] In another aspect, the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein in the treatment of a disease or disorder disclosed herein.

[0188]

[0078] The disclosed compounds of the disclosure can be administered in effective amounts to treat or prevent a disorder and / or prevent the development thereof in subjects. Combination Therapy

[0189]

[0079] The compounds of the disclosure can be administered in therapeutically effective amounts in a combinational therapy with one or more pharmaceutically active agents (pharmaceutical combinations) or modalities, e.g., non-drug therapies. The compounds of the present disclosure may be administered either simultaneously with, or before or after, one or more other pharmaceutically active agent. The compound of the present disclosure may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents. A pharmaceutically active agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the present disclosure.

[0190]

[0080] In one embodiment, the disclosure provides a product comprising a compound of the present disclosure and at least one other pharmaceutically active agent as a combined preparation for simultaneous, separate or sequential use as disclosed herein. Products provided as a combined preparation include a composition comprising the compound of the present disclosure and the other pharmaceutically active agent(s) together in the same pharmaceutical composition as described herein, or the compound of the present disclosure and the other pharmaceutically active agent (s) in separate form, e.g. in the form of a kit.

[0191]

[0081] In another aspect, the disclosure includes a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in a combination therapy.

[0192]

[0082] Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more pharmaceutically active agent. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0193]

[0083] Combination therapy includes the administration of the subject compounds in further combination with other biologically active ingredients. For instance, the compounds of the application can be used in combination with other pharmaceutically active agents, preferably compounds that are able to enhance the effect of the compounds of the application. The compounds of the application can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy or treatment modality. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.

[0194]

[0084] Exemplary additional pharmaceutically active agents that may be used in combination with the compounds of the disclosure, include, but are not limited to an ACE (angiotensin-converting-enzyme) inhibitor, an angiotensin receptor blocker (ARB), a neprilysin inhibitor, a beta blocker, a diuretic, a calcium channel blocker, a cardiac glycoside, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), or combinations thereof. As a non-limiting set of examples, a compound or a pharmaceutically acceptable salt thereof described herein may be combined with an additional pharmaceutically active agent selected from enalapril, benazepril, captopril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, valsartan, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, sacubitril, bisoprolol, carvedilol, propanolol, metoprolol, metoprolol tartrate, metoprolol succinate, thiazide diuretics, loop diuretics, potassium-sparing diuretics, amlodipine, clevidipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, a digitalis glycoside, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and combinations thereof. Exemplary diuretics and digitalis glycosides include, but are not limited to, chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, eplerenone, spironolactonem, triamterene, digoxin, and combinations thereof. In some embodiments, a compound or a pharmaceutically acceptable salt thereof described herein may be combined with an angiotensin receptor-neprilysin inhibitor (ARNi) such as a combination of sacubitril and valsartan (e.g., Entresto®). In some embodiments, a compound or a pharmaceutically acceptable salt thereof described herein can be combined with one or more of a corticosteroid (e.g., an inhaled corticosteroid such as fluticasone, budesonide, mometasone, beclomethasone, ciclesonide, or fluticasone furoate; or an oral or intravenous corticosteroid such as prednisone or methylprednisolone), a leukotriene modifier (e.g., montelukast, zafirlukast, or zileuton), a bronchodilator (e.g., a long-acting beta agonist (e.g., salmeterol or formoterol), a short-acting beta agonist (e.g., albuterol or lev albuterol), theophylline or ipratropium), or combinations thereof (e.g., a combination of fluticasone and salmeterol, a combination of budesonide and formoterol, or a combination of formoterol and mometasone). In some embodiments, a compound or a pharmaceutically acceptable salt thereof described herein can be combined with one or more of a beta-adrenoceptor antagonist (e.g., timolol, levobunolol, metipranolol, carteolol, or betaxolol), a carbonic anhydrase inhibitor (e.g., acetazolamide, dorzolamide, brinzolamide, or methazolamide), an alpha 2-adrenoceptor agonist (e.g., brimonidine or apraclonidine), a parasympathomimetic (e.g., cholinomimetics like pilocarpine), a prostaglandin analog (e.g., latanoprost, latanoprostene bunod, travoprost, bimatoprost, or tafluprost), a rho kinase inhibitor (e.g., netarsudil or ripasudil), or combinations thereof (e.g., a combination of rho kinase inhibitor and latanoprost).

[0195]

[0085] ‘ ‘Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time and in any order, or in alternation and in any order, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical.

[0196] Method of Synthesizing the Compounds

[0197]

[0086] The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

[0198]

[0087] The compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of Formula (I).

[0199]

[0088] Those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0200]

[0089] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0201] Definitions

[0090] Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. For purposes of interpreting this specification, the following definitions will apply unless specified otherwise and whenever appropriate, terms used in the singular will also include the plural and vice versa.

[0202]

[0091] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “the pharmaceutical formulation” includes reference to one or more pharmaceutical formulations; and so forth.

[0203]

[0092] The term “alkoxy”, as used herein, refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto, e.g., -O(alkyl). Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy and the like. Representative substituted alkoxy groups include, but are not limited to, — OCF3 and the like.

[0204]

[0093] An “alkyl” group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C1-C6straight chained or branched alkyl group is also referred to as a “lower alkyl” group.

[0205]

[0094] The term “aryl”, as used herein, include single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0206]

[0095] The term “Cx. Cy” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx-Cyalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms “Cz-Cyalkenyl” and “Cz-Cyalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0096] The terms “carbocycle”, and “carbocyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond. “Carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic

[0207]

[0097] A “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated. “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.

[0208]

[0098] The term “cycloalkyl-alkyl”, as used herein, refers to an alkyl group substituted with a cycloalkyl group.

[0209]

[0099] The term “alkyl-cycloalkyl”, as used herein, refers to an cycloalkyl group substituted with an alkyl group.

[0210]

[0100] The terms “halo” and “halogen”, as used herein, means halogen and includes chloro, fluoro, bromo, and iodo.

[0211]

[0101] “Haloalkyl”, as used herein, refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. “Fluoroalkyl”, as used herein, refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) fluoro groups.

[0212]

[0102] The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyridyl N-oxide, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][l,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazo lo[l, 5 -a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[l,2-a]pyrimidinyl, tetrahydropyrrolo[l,2-a]pyrimidinyl, 3,4-dihydro-2H-lA2-pyrrolo[2,l-b]pyrimidine, dibenzo [b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][l,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo[l,2,3]triazolyl, imidazo[l,2-a]pyrimidinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][l,2,5]thiadiazolyl, benzo[c][l,2,5]oxadiazole, 1,3 -dihydro-2H-benzo [d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo [ 1,5 -b] [ 1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridinyl, thiazolo[5,4 d]thiazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.

[0213]

[0103] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0214]

[0104] The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. The polycyclic ring systems may be fused or bridged. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, azaadamantane and the like. Heterocyclyl groups can also be substituted by oxo groups. For example, “heterocyclyl” encompasses both pyrrolidine and pyrrolidinone.

[0215]

[0105] As used herein, the term “oxo” refers to a carbonyl group. When an oxo substituent occurs on an otherwise saturated group, such as with an oxo-substituted cycloalkyl group (e.g., 3-oxo-cyclobutyl), the substituted group is still intended to be a saturated group. When a group is referred to as being substituted by an “oxo” group, this can mean that a carbonyl moiety (i.e., — C(=O) — ) replaces a methylene unit (i.e., — CH2— ).

[0216]

[0106] The term “optionally substituted” means that a given chemical moiety (e.g., an alky 1 group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen, wherein the substituents are as defined herein. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0217]

[0107] The term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0218]

[0108] The term “unsubstituted” means that the specified group bears no substituents.

[0219]

[0109] A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or nonhuman primate, such as a monkey, chimpanzee, baboon or, rhesus. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0220] [HO] The terms “pharmaceutically effective amount” or “therapeutically effective amount” or “effective amount” means an amount of a compound according to the disclosure which, when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue, system, or patient that is sought by a researcher or clinician. The amount of a compound according to the disclosure which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the disclosure, and the age, body weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure. [Hl] As used herein, the term “pharmaceutical composition” refers to a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0221]

[0112] ‘ ‘Carrier” encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0222]

[0113] A subject is “in need of’ a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably, a human).

[0223]

[0114] As used herein, the term “inhibit”, “inhibition”, or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0224]

[0115] As used herein, the term “treat”, “treating", or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.

[0225]

[0116] As used herein, the term “prevent”, “preventing", or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0226]

[0117] “Pharmaceutically acceptable” means that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0227]

[0118] ‘ ‘Disorder” means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0228]

[0119] ‘ ‘Administer”, “administering”, or “administration” means to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body.

[0229]

[0120] “Compounds of the present disclosure”, “Compounds of Formula (I)”, “compounds of the disclosure”, and equivalent expressions (unless specifically identified otherwise) refer to compounds of Formula (I) as herein described including the salts particularly the pharmaceutically acceptable salts thereof, where the context so permits thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labelled compounds (including deuterium (“D”) substitutions).

[0230]

[0121] In a specific embodiment, the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0231] Examples

[0232]

[0122] The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims.

[0233]

[0123] Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.

[0234]

[0124] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker Avance spectrometer or Varian Oxford 400 MHz spectrometer unless otherwise noted. NMR spectra are given in ppm (8) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (82.50), methanol (83.31), chloroform (87.26) or other solvent as indicated in NMR spectral data. A small amount of dry sample (2-5 mg) is dissolved in an appropriate deuterated solvent (1 mL). Mass spectra (ESI-MS) were collected using a Waters System (Acquity UPLC and a Micromass ZQ mass spectrometer) or Agilent-1260 Infinity (6120 Quadrupole); all masses reported are the m / z of the protonated parent ions unless recorded otherwise. The chemical names were generated using ChemBioDraw Ultra vl4 from CambridgeSoft.

[0235]

[0125] Temperatures are given in degrees Celsius. As used herein, unless specified otherwise, the term "room temperature" or "ambient temperature" means a temperature of from 15 degrees centigrade to 30 degrees centigrade, such as of from 20 degrees centigrade to 30 degrees centigrade, such as of from 20 degrees centigrade to 25 degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

[0236]

[0126] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present disclosure are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art.

[0237]

[0127] Abbreviations used are those conventional in the art.

[0238]

[0128] Methods Employed in the Purification of the Examples

[0239]

[0129] Purification of intermediates and final products was carried out via either normal, reverse phase chromatography or supercritical fluid chromatography (SFC). Normal phase chromatography was carried out using prepacked SiO2cartridges (e.g., RediSep® Rf columns from Teledyne Isco, Inc.) eluting with gradients of appropriate solvent systems (e.g., heptane and ethyl acetate; DCM and MeOH; or unless otherwise indicated). Reverse phase preparative HPLC was carried out using the methods described below or unless otherwise indicated in the experimental section:

[0240]

[0130] (1) Basic method: XBridge 5pm column, 5 mM NH4OH in acetonitrile and Water.

[0241]

[0131] (2) TFA method: Sunfire 5pm column, 0.1% TFA in acetonitrile and Water.

[0242]

[0132] (3) Formic acid method: XBridge 5pm column; 0.1% formic acid in acetonitrile and Water.

[0243]

[0133] Analytical Methods, Materials, and Instrumentation

[0244]

[0134] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker Avance spectrometer or Varian Oxford 400 MHz spectrometer unless otherwise noted. Spectra are given in ppm (8) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (82.50), methanol (83.31), chloroform (87.26) or other solvent as indicated in NMR spectral data. A small amount of the dry sample (2-5 mg) is dissolved in an appropriate deuterated solvent (1 mL). The chemical names were generated using ChemBioDraw Ultra vl2 from CambridgeSoft.

[0245]

[0135] Mass spectra (ESI-MS) were collected using a Waters System (Acquity UPLC and a Micromass ZQ mass spectrometer) or Agilent- 1260 Infinity (6120 Quadrupole); all masses reported are the m / z of the protonated parent ions unless recorded otherwise. The sample was dissolved in a suitable solvent such as MeCN, DMSO, or MeOH and was injected directly into the column using an automated sample handler. The analysis is performed on Waters Acquity UPLC system (Column: Waters Acquity UPLC BEH C18 1.7pm, 2.1 x 30mm; Flow rate: 1 mL / min; 55°C (column temperature); Solvent A: 0.05% formic acid in water, Solvent B: 0.04% formic acid in MeOH; gradient 95% Solvent A from 0 to 0.10 min; 95% Solvent A to 20% Solvent A from 0.10 to 0.50 min; 20% Solvent A to 5% Solvent A from 0.50 to 0.60 min; hold at 5% Solvent A from 0.6 min to 0.8 min; 5% Solvent A to 95% Solvent A from 0.80 to 0.90 min; and hold 95% Solvent A from 0.90 to 1.15 min.

[0246]

[0136] Analytical HPLC Method Information

[0247]

[0137] The analytical HPLC of final compounds is carried out using columns and specific conditions as described below. The analytical equipment (Waters, Agilent, Shimadzu) is also equipped with a mass detector in each case.

[0248]

[0138] Method of synthesizing the compounds of the invention

[0249]

[0139] Table 2: LCMS Methods

[0250]

[0251]

[0252]

[0253]

[0140] Table 3: Prep-HPLC Methods

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0141] Table 4: Chiral-HPLC / SFC Methods

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0142] General reaction scheme and summary of the synthetic route towards compounds

[0271] (I) according to the invention

[0272]

[0143] Compounds (I) according to the invention can be prepared stepwise starting with a synthesis depicted in general reaction scheme 1 - 6.

[0273]

[0144] In addition to the routes described below, also other routes may be used to synthesize the target compounds, in accordance with common general knowledge of a skilled person in the art of organic synthesis. The order of transformations exemplified in the following six schemes is therefore not intended to be limited, and suitable synthesis steps from various schemes can be combined to form additional synthesis sequences.

[0274]

[0145] General Reaction Scheme 1:

[0275]

[0276] intermedaite - (Ia ~ Id) a ~ j )

[0277]

[0146] Scheme 1 outlines the synthesis towards the examples la - Id via amide coupling between Intermediate la - Id and corresponding carboxylic acid with appropriate R1 substituents.

[0278]

[0147] General Reaction Scheme 2:

[0279]

[0280] Examples le - Ig can be prepared using Intermediates le - Ig and respective carboxylic acids through amide coupling.

[0281]

[0148] General Reaction Scheme 3:

[0282]

[0283] Step 1 Step 2 Intermedaite - (Ia - Id) Intermedaite - (IIx)

[0284]

[0285] (II) (IIa)

[0286]

[0149] Compounds in formula (II) according to the invention can be prepared stepwise starting with a synthesis depicted in general reaction scheme 3. Key Intermediate (IIx) can be prepared via amide coupling with Intermediate la - Id and 5-methoxy-2-methylene-5-oxopentanoic acid under peptide coupling reagent TFFH. Example (II) can be prepared via Aza-Michael addition between respective amine with appropriate R2 substituents and Intermediate (IIx) under basic conditions.

[0287]

[0150] General Reaction Scheme 4:

[0288]

[0289] Intermedalte - (le - lg) Intermedaite ~ (IIIx)

[0290]

[0291] (III) (IIIa)

[0292]

[0151] Compounds in formula (III) according to the invention can be prepared stepwise starting with a synthesis depicted in general reaction scheme 3. Key Intermediate (IIIx) can be prepared via amide coupling with Intermediate le - Ig and 5 -methoxy-2-m ethylene-5 -oxopentanoic acid under peptide coupling reagent TFFH. Example (III) can be prepared via Aza-Michael addition between respective amine with appropriate R2 substituents and Intermediate (IIIx) under basic conditions.

[0293]

[0152] General Reaction Scheme 5: Boc

[0294] i

[0295]

[0296] Step 1 Step 2 Intermedaite - (le - Ig) Intermedaite - (IVa)

[0297]

[0298] Intermedaite - (IVb) (IV)

[0299]

[0153] Compounds in formula (IV) according to the invention can be prepared stepwise starting with a synthesis depicted in general reaction scheme 5. Key Intermediate (IVa) can be prepared via amide coupling (Step 1) with Intermediate le - Ig and l-(tert-butoxycarbonyl)piperidine-3 -carboxylic acid under amide coupling reagent HATU. Removal of Boc group from key Intermediate (IVa) with catalytical amount of TFA resulted in Intermediate (IVb). Example (IV) can be prepared through another amide coupling between respective carboxylic acid which are either commercially available or synthesized and Intermediate (IVb) under HATU conditions.

[0300]

[0154] General Reaction Scheme 6:

[0301]

[0302] Step 1 Intermedaite - (IVb) Intermedaite - (Vc)

[0303]

[0304]

[0155] Example (V) can be prepared via reductive amination between Intermediate (IVb) and corresponding aldehyde followed by hydrolysis under basic conditions resulted in examples (V).

[0305]

[0156] Synthetic procedures for Key intermediates:

[0157] Example 1: Synthesis of intermediate!: 4-chloro-6-fluorobenzo[dlthiazol-2-amine

[0306]

[0158]

[0307]

[0308]

[0159] Step 1: l-(2-chloro-4-fluorophenyl) (IM1-1)

[0309]

[0160] To a stirred solution of 2-chloro-4-fluoroaniline (CAS # 2106-02-7) (15.00 g, 103.1 mmol) in water (150.0 mL) was added concentrated HC1 (7.514 g, 206.1 mmol) at room temperature and heated to 50 °C, Potassium thiocyanate (40.06 g, 412.2 mmol) was added portion wise at 50 °C, and the resulting reaction mixture was heated at 110 °C for 6 h. The progress of reaction was monitored by TLC and LCMS. After completion of starting material, reaction mixture was cooled to room temperature, then the solid precipitated, filtrated and washed with diethyl ether to afford IM1-1 (19.00 g, 71.24 mmol, 69.13 % yield, 76.73% Purity) as a white solid. MS (m / z) [M+H]+= 205.1, Rt = 1.147 min.

[0310]

[0161] Step 2: 4-chloro-6-fluorobenzo[d]thiazol-2-amine (Intermediate 1)

[0311]

[0162] To a stirred solution of IM1-1 (15.00 g, 73.30 mmol) in H2SO4 (45.00 mL) was added ammonium bromide (7.89 g, 80.63 mmol) portion wise over a period of 40 mins. Then the reaction mixture was heated at 100 °C for 6 h. The progress of reaction was monitored by TLC and LCMS. After the completion of reaction, reaction mixture was cooled to room temperature and then poured into ice cold water (100 mL), neutralized with saturated solution of NaHCO3 (pH ~8) and solid was precipitated. The solid was filtered, washed with n-pentane and dried under reduced pressure to afford Intermediate 1 (13.00 g, 59.77 mmol, 81.54 %yield, 93.16% Purity) as a white solid. MS (m / z) [M+H]+= 202.9, Rt = 1.535 min. [Method-L7], ’H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 2H), 7.62 (dd, J= 8.4, 2.4 Hz, 1H), 7.27 (dd, J= 9.2, 2.4 Hz, 1H).

[0312]

[0163] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0313]

[0164] Table 5:

[0314]

[0315]

[0316]

[0165] Example 2: Synthesis of Intermediate 5 (5-chloro-6-fluorobenzo[d]thiazol-2-amine) & Intermediate 6 (7-chloro-6-fluorobenzo[d]thiazol-2-amine):

[0317]

[0318] Intermediate 5 intermediate 6

[0319] Step 2

[0320]

[0166] Step 7: l-(3-chloro-4-fluorophenyl)thiourea (IM5-1)

[0321]

[0167] To a stirred solution of 3-chloro-4-fluoroaniline (CAS # 367-21-5) (10.00 g, 68.70 mmol) in water (150.0 mL) was added Cone HC1 (5.46 mL, 137.4 mmol). The reaction mixture was heated to 50 °C and potassium thiocyanate (26.71 g, 274.8 mmol) was added. The resulting reaction mixture was stirred at 110 °C for 12 h. Progress of the reaction was monitored by TLC. After completion of the starting material, reaction mixture was cooled to room temperature. The solid separated was filtered and washed with diethyl ether to obtain IM5-1 (9.400 g, 41.0 mmol, 59.6 % yield, 89.2% Purity) as a white solid. MS (m / z) [M+H]+= 205.1, Rt = 1.375 min. 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 7.77-7.74 (m, 1H), 7.54 (bs, 1H), 7.38-7.29 (m, 2H).

[0322]

[0168] Step 2: 5-chloro-6-fluorobenzo[d]thiazol-2-amine (Intermediate 5) & 7-chloro-6-fluorobenzo[d]thiazol-2-amine (Intermediate 6)

[0323]

[0169] To a stirred solution of IM5-1 (9.400 g, 45.93 mmol) in H2SO4 (28.00 mL) was added ammonium bromide (5.39 g, 55.12 mmol) portion-wise over a period of 10 min, then the reaction was refluxed at 100 °C for 16 h. The progress of reaction was monitored by TLC. The reaction mixture was then cooled to room temperature and then poured into ice water (100 mL). The mixture was basified (pH ~8) using saturated sodium bicarbonate solution, solid was precipitated which was filtered, washed with water followed by w-pentane and dried under reduced pressure to afford a mixture of isomers (7.0 g). The isomers were separated by prep HPLC purification using Method-Hl. Two fractions were evaporated separately and lyophilized to get Intermediate 5 (Peak-1) (3.000 g, 15 mmol, 32 %, 99% Purity) and Intermediate 6 (Peak-2) (450.0 mg, 2.2 mmol, 4.8 %, 99% Purity) as white solids.

[0324]

[0170] Analytical characterization of Intermediate 5 (Peak-1):

[0325]

[0171] MS (m / z) [M+H]+= 203.0, Rt = 4.513 min. [Method-L30], ’H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 12 Hz, 1H), 7.67 (s, 2H), 7.45 (d, J = 4.0 Hz, 1H).

[0326]

[0172] Analytical characterization of Intermediate 6 (Peak -2):

[0327]

[0173] MS (m / z) [M+H]+= 203.0, Rt = 4.716 min. [Method-L30], ’H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 2H), 7.31-7.24 (m, 2H).

[0328]

[0174] Example 3: Synthesis of intermediate 7: 7-cvclopropyl-4-fluorobenzo[d1thiazol-2-amine

[0329]

[0330] Step 2 SM7-2 intermediate 7

[0331]

[0175] Step 1: tert-butyl (7-bromo-4-fluorobenzo[d]thiazol-2-yl)carbamate (IM7-1)

[0332]

[0176] To a stirred solution of Intermediate 4 (13.00 g, 52.61 mmol) in DCM (130.0 mL) at room temperature were added TEA (22.0 mL, 157.84 mmol), 4-Dimethylaminopyridine (1.285 g, 10.522 mmol) and di-tert-butyl dicarbonate (14.1 mL, 63.135 mmol) in sequence. The reaction mixture was stirred at 25 °C for 16 h. Progress of the reaction was monitored by TLC. After completion of rection, the reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (2 x 150 mL). Combined organic extract was dried over sodium sulphate and evaporated under reduced pressure to get a pale yellow liquid (crude). The crude compound was purified by flash column chromatography on silica gel where the product was eluted with 30 to 40% ethyl acetate in heptane to afford IM7-1 (10.50 g, 25.86 mmol, 49.16 yield %, 85.52% Purity) as a white solid. MS (m / z) [M+H]+= 346.9, Rt = 1.991 min.

[0333]

[0177] Step 2: 7-cyclopropyl-4-fluorobenzo[d]thiazol-2-amine (Intermediate 7)

[0334]

[0178] To a stirred solution of IM7-1 (1.00 g, 1 Eq, 2.88 mmol) and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (296.9 mg, 1.2 Eq, 3.45 mmol) in 1,4-Dioxane (15.00 mL) and Water (5.000 mL)was added K2CO3 (1.194 g, 3 Eq, 8.641 mmol). Reaction mixture was purged for 5 min with Nitrogen gas. Then [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)Complex.DCM (235.2 mg, 0.1 Eq, 288.0 pmol) was added. The reaction mixture was heated to 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After 16 h, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 20 mL). Combined organic extract was dried over sodium sulphate and evaporated under reduced pressure to get a pale yellow viscous liquid (crude). The obtained crude compound was dissolved in THF (10 ml) and added Quadrasil AP (1000 mg), stirred at room temperature for 1 h. Then the mixture was filtered through celite bed, and the filtrate was concentrated under reduced pressure to get the crude. The crude compound was purified by flash column chromatography on silica gel using 0-30% ethyl acetate in heptane to afford IM7-2 (590.0 mg, 1.366 mmol, 47.43% yield, 71.40% Purity) as a yellow liquid and Intermediate 7 (120.0 mg, 497.2 pmol, 17.26 % yield, 86.28% Purity) as an off-white solid. MS (m / z) [M+H]+= 209.0, Rt = 1.588 min. [Method-L7]

[0335]

[0179] Example 4: Synthesis of intermediate 8: methyl 4-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)pent-4-enoate

[0336]

[0337]

[0181] Step 7: 2 -methylenepentanedioic acid (IM8-1)

[0338]

[0182] To a stirred solution of dimethyl 2-methylenepentanedioate (CAS # 5621-44-3) (30.00 g, 1 Eq., 174.2 mmol) in MeOH (180.0 mL) and water (90.00 mL), NaOH (20.91 g, 3 Eq, 522.7 mmol) was added and allowed to stir for 16 h at 70 °C. Progress of the reaction was monitored by TLC LCMS (Showed the complete consumption of starting material). Reaction mixture was cooled to room temperature and concentrated to remove methanol. The remaining water solution was acidified ~ 2 pH using 6N HC1 solution. The compound was observed to be precipitated; the precipitate was filtered using Buchner funnel and dried in vacuum to afford IM8-1 (25.00 g, 166 mmol, yield 99.27 %, Purity 99.72%) as white solid. MS (m / z) [M+H]+= 148.1, Rt = 0.37 min. ‘H NMR (400 MHz, DMSO-d6) δ 12.09 (bs, 2H), 6.05 (s, 1H), 5.60 (s, 1H), 2.51-2.36 (m, 4H).

[0339]

[0183] Step 2: 5 -methoxy -2 -m ethylene-5 -oxopentanoic acid (IM8-2)

[0340]

[0184] To a stirred solution of IM8-1 (25.00 g, 1 Eq., 173.5 mmol) in MeOH (200.0 mL), PTSA (1.493 g, 0.05 Eq., 8.673 mmol) was added and allowed to stir for 16 h at 25 °C. Progress of the

[0341] reaction monitored by TLC and LCMS (Showed the complete consumption of starting material). The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 100:0 to 85:15; 80 g Redisep Silver column via liquid injection) to give IM8-2 (14.00 g, 86.87 mmol, yield 50.08 %, Purity 98.13%) as a colourless oil. MS (m / z) [M+H]+= 159.10, Rt = 1.01 min.

[0185] ’H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 6.05 (s, 1H), 5.61 (s, 1H), 3.59 (s, 3H), 2.51-2.48 (m, 4H).

[0342]

[0186] Step 3: methyl 4-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)pent-4-enoate (Intermediate 8)

[0343]

[0187] To a stirred solution of Intermediate 3 (2.500 g, 1 Eq, 12.34 mmol) and 5-methoxy-2-methylene-5 -oxopentanoic acid (CAS # 5621-44-3) (2.927 g, 1.5 Eq, 18.51 mmol) in DMF (25.00 mL) were added TFFH (4.888 g, 1.5 Eq, 18.51 mmol) and DIPEA (4.784 g, 6.45 mL, 3 Eq, 37.01 mmol), then the reaction was stirred for 6 h at 100 °C. The progress of reaction was monitored by TLC and LCMS. Reaction mixture was diluted with ice-cold water (100 mL) where solid was precipitate out and filtered, given diethyl ether wash to afford Intermediate 8 (2.90 g, 7.894 mmol, 63.99 % yield, 93.31% Purity) as an off-white solid. MS (m / z) [M+H]+= 343.1. Rt = 1.497 min. [Method-L2], ’H NMR (400 MHz, DMSO-de) 8 12.96 (s, 1H), 7.44-7.35 (m, 2H), 6.29 (s, 1H), 5.81 (s, 1H), 3.60 (m, 3H), 2.66-2.63 (m, 2H), 2.56-2.50 (m, 2H)

[0344]

[0188] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0345]

[0189] Table 6

[0346]

[0347]

[0348]

[0190] Example 5: Synthesis of intermediate 9: 7-chloro-4-fluoro-lH-benzo[d1imidazol-2-amine

[0349]

[0350]

[0191] Step 1 IM9-1 Step 2! M9-2 Step 3 intermediate 9

[0351]

[0192] Step 1: 6-chloro-3-fluoro-2 -nitroaniline (IM9-1)

[0352]

[0193] To a stirred solution of 3-fluoro-2-nitroaniline (CAS # 567-63-5) (20.0 g, 1 Eq, 128.11 mmol) in DMF (300.0 mL) at -5 °C was added slowly N-Chlorosuccinimide (17.11 g, 10.61 mL, 1 Eq, 128.11 mmol, dissolved in 20 mL of DMF). The reaction mixture was allowed to stir at -5 °C for 5 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction. The reaction was quenched with ice cold water (100 mL) and extracted with ethyl acetate (3 X 300mL). Combined organic layer was dried over sodium sulfate and concentrated under reduced pressure using rotavapor to afford crude residue. The crude residue was purified by combi flash column chromatography on silica gel (eluent: heptane / EtOAc = 95:5 to 90:10; a 80 g NCC column via 100-200 mesh silica) to give IM9-1 (7.40 g, 38.83 mmol, 30.31 %yield, 89% Purity) as orange needle solid. MS (m / z) [M-H]+= 189.1, Rt = 1.33 min.

[0353]

[0194] 'HNMR (400 MHz, DMSO-6) 57.42-7.39 (m, 1H), 6.49 (dd, J= 8.80, 10.80 Hz, 1H).

[0354]

[0195] Step 2: 3-chloro-6-fluorobenzene-l,2-diamine (IM9-2)

[0355]

[0196] To a stirred solution of IM9-1 (7.40 g, 1 Eq, 38.83 mmol) in ethanol (20.0 mL) and water (20.0 mL) at 25 °C were added zinc dust (12.69 g, 5 Eq, 194.2 mmol) and ammonium chloride (10.39 g, 7.07 mL, 5 Eq, 194.2 mmol). The reaction mixture was allowed to stir at 65 °C for 8 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction. The reaction mixture was filtered through celite bed and the celite bed washed with ethanol (20 mL). The filtrate was concentrated under reduced pressure using rotavapor. The crude diluted with water (100 mL) and extracted with 10% MeOH in DCM (3 X lOOmL). Combined organic layer was dried over sodium sulphate and concentrated under reduced pressure using rotavapor to afford crude residue. The residue was purified by combi flash column chromatography on silica gel (eluent: heptane / EtOAc = 85: 15 to 80:20; a 40 g NCC column via 100-200 mesh silica) to give 3-chloro-6-fluorobenzene-l,2-diamine (IM9-2) (5.80 g, 34 mmol, 88 % yield, 95% Purity) as a white solid. MS (m / z) [M-H]+= 161.1, Rt = 1.210 min.1HNMR(400 MHz, DMSO-O 86.49-6.56 (m, 1H), 6.36-6.43 (m, 1H), 4.97 (s, 2H), 4.76 (s, 2H).

[0356]

[0197] Step 3: 4-chloro-7-fluoro-lH-benzo[d]imidazol-2-amine (Intermediate 9)

[0357]

[0198] To a stirred solution of IM9-2 (5.80 g, 1 Eq, 36.12 mmol) in methanol (50.0 mL) at 25 °C was added cyanogen bromide (3.83 g, 2.19 mL, 1 Eq, 36.12 mmol). The reaction mixture was allowed to stir at 25 °C for 12 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction. Reaction mixture was concentrated under reduced pressure and the obtained crude diluted with saturated sodium carbonate solution (100 mL) then extracted with 10% MeOH in DCM (3 X lOOmL). Combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure using rotavapor to yield 4-chloro-7-fluoro-lH-benzo[d]imidazol-2-amine (Intermediate 9) (4.80 g, 26 mmol, 71 % yield, 99% Purity) as a white solid. MS (m / z) [M-H]+= 185.9. Rt = 0.455 min. [Method-L2],1HNMR (400 MHz, DMSO-6) 8 11.56 (s, 1H), 7.10-7.08 (m, 1H), 6.88 (t, J= 4.00 Hz, 1H), 6.40 (s, 2H).

[0358]

[0199] Example 6: Synthesis of intermediate 10: 5-chloro-7-fluoro-lH-benzo[d1imidazol-2-amine

[0359]

[0360] Step 1 Intermediate 10

[0361]

[0200] Step 1: 5-chloro-7-fluoro-lH-benzo[d]imidazol-2-amine (Intermediate 10)

[0362]

[0201] To the mixture of 5 -chloro-3 -fluorobenzene- 1,2-diamine (CAS # 1106717-48-9) (500.0 mg, 1 Eq, 3.114 mmol) in Methanol (20.00 mL) at 25 °C were added cyanogen bromide (824.5 mg, 472.0 pL. 2.5 Eq, 7.784 mmol). After stirring for 10 min, the reaction mixture was allowed to stir at 25 °C for 10 h. Desired mass of the product observed as indicated in TLC and LCMS. Reaction mixture was concentrated under reduced pressure which further quenched with saturated sodium carbonate solution then filtered and dried in vacuum to obtain Intermediate 10 (420.0 mg, 2.26 mmol, 72.7 %, 100% Purity). MS (m / z) [M+H]+= 185.9. Rt = 2.27 min. [Method-L29], *HNMR (400 MHz, DMSO-O 8 11.29 (s, 1H), 7.01 (s, 1H), 6.83 (d, J= 12.0 Hz, 1H), 6.48 (s, 2H).

[0363]

[0202] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0364]

[0203] Table 7:

[0365]

[0366]

[0367]

[0204] Example 7: Synthesis of intermediate 12: 5-oxaspiro[3.51nonane-8-carboxylic acid

[0368]

[0369] Step 3 M12-3 Step 4 intermediate 12

[0370]

[0205] Step 7: 5-oxaspiro[3.5]nonan-8-ol (IM12-1)

[0371]

[0206] To a stirred solution of but-3-en-l-ol (CAS # 627-27-0) (5.00 g, 6.0 mL, 1 Eq, 69.34 mmol) in H2SO4(15.00 mL) and water (60.00 mL) at 0 °C was added cyclobutanone (4.86 g, 5.2 mL, 1 Eq, 69.34 mmol) and stirred for 5 min at 0 °C. The reaction mixture was stirred for 16 h at 80 °C. Progress of the reaction monitored by TLC and LCMS. TLC indicated product formation and completion of

[0372] SM. Reaction mixture quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (2 X 50 ml), combined organic layers was dried over sodium sulfate and concentrated using reduced vacuum to afford crude. The crude was purified using MPLC (10-15 % ethyl acetate in heptane) to afford IM12-1 (7.20 g, 50.63 mmol, 73.02 % yield, 99% Purity) as a colourless liquid compound. MS (m / z) [M+H]+= 143.1. Rt = 0.531 min. ‘H NMR (DMSO-<fc) 83.85-3.77 (m, 2H), 3.46-3.39 (td, J = 12.0, 2.4 Hz, 1H), 2.19-2.11 (m, 2H), 2.01-1.95 (m, 3H), 1.86-1.81(m, 2H), 1.80-1.74 (m, 1H), 1.53-1.36 (m, 3H).

[0373]

[0207] Step 2: 5-oxaspiro[3.5]nonan-8-one (IM12-2)

[0374] To a stirred solution of IM12-1 (7.15 g, 1 Eq, 50.28 mmol) in DCM (100.0 mL) at 0 °C was added PCC (16.26 g, 1.5 Eq, 75.42 mmol) lot wise for 5 min. The reaction was allowed to stir at 25 °C for 16 h. Progress of the reaction monitored by TLC and LCMS. TLC indicated that new non polar product was formed. Reaction mixture was filtered using celite bed and washed with ethyl acetate (50 mL). Filtrate was concentrated under reduced pressure to afford crude product, which was purified using combi flash column chromatography on silica gel (eluent: heptane / EtOAc = 85: 15 to 80:20; a 40 g NCC column via 100-200 mesh silica) to afford IM12-2 (5.60 g, 39.95 mmol, 79.45 % yield, 98% Purity) as yellow liquid compound. MS (m / z) [M+H]+= 141.1. Rt = 1.094 min.

[0375]

[0208] Step 3: 5-oxaspiro[3.5]nonane-8-carbonitrile (IM12-3)

[0376]

[0209] To a stirred solution of IM12-2 (5.00 g, 1 Eq, 35.67 mmol) in DME (200.0 mL) were added tosylmethyl isocyanide (9.05 g, 1.3 Eq, 46.37 mmol) and 2-methylpropan-2-olate potassium (10.01 g, 10 mL, 2.5 Eq, 89.17 mmol) lot wise 0 °C for 5minutes. The reaction mixture allowed to stir for 16 h at room temperature. Progress of the reaction monitored by TLC and LCMS. After completion the reaction, reaction mixture quenched with ice cold water (100 ml) and extracted with ethyl acetate twice (2 X 100 ml), combined organic layer dried using sodium sulfate and concentrated using reduced vacuum, to afford crude, crude was purified under MPLC chromatography to afford IM12-3 (1.5 g, 9.92 mmol, 27.81 % yield, 98% Purity) as pale-yellow liquid compound. MS (m / z) [M+H]+= 152.2. Rt = 1.390 min. ’H NMR (DMSO-t / e) 83.63-3.58 (m, 1H), 3.37-3.34 (m,lH), 3.06-2.98 (m,lH), 2.08-1.90 (m,4H), 1.86-1.69 (m, 2H), 1.67-1.56 (m, 4H).

[0377]

[0210] Step 4: 5-oxaspiro[3.5]nonane-8-carboxylic acid (Intermediate 12)

[0378]

[0211] To a stirred solution of IM12-3 (1.45 g, 1 Eq, 9.589 mmol) in methanol (30.00 mL) and water (10.00 mL) was added NaOH (767.1 mg, 2 Eq, 19.18 mmol). The reaction mixture stirred a 90 °C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to remove methanol. The residue was acidified by 2N HC1 (20 ml) to pH ~ 7 and extracted with ethyl acetate (2 X 50 mL). The organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to afford Intermediate 12 (1.50 g, 8.81 mmol, 91.90 % Yield, 99.96% Purity) as brown gummy compound. MS (m / z) [M+H]+= 171.1. Rt = 1.318 min.

[0379] [Method-L3], *HNMR (DMSO-t / 6): 8 12.18 (s, 1H), 3.64-3.60 (m, 1H), 3.34-3.28 (m,lH), 2.45-2.41 (m, 1H), 2.32-1.90 (m, 3H), 1.83-1.81 (m,2H), 1.73-1.64 (m, 3H), 1.52-1.40 (m, 2H).

[0212] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0380]

[0213] Table 8:

[0381]

[0382]

[0383]

[0384]

[0214] Example 8: Synthesis of intermediate 16: 6-oxo-l-(pyridin-3-yl)piperidine-3-carboxylic acid

[0385]

[0386]

[0215] Step 1: Methyl 2-oxo-2H-[l,3'-bipyridine]-5-carboxylate (IM16-1)

[0387]

[0216] To a stirred solution of methyl 2-oxo-2H-pyran-5 -carboxylate (CAS # 6018-41-3) (10.00 g, 1 Eq, 64.88 mmol) and pyridin-3 -amine (CAS # 462-08-8) (7.32 g, 1.2 Eq, 77.861 mmol) in water (30.00 mL) was added 15% aq. Na2CO3(6.881 g, 30.00 mL, 15% Wt, 1 Eq, 64.85 mmol) at 25 °C to get clear solution. Reaction mixture was stirred at 25 °C for 20 minutes. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the precipitated solid formed was filtered, solid was washed with o- Pentane (2 X 40 mL) and dried under vacuum to afford IM16-1 (12.80 g, 55.60 mmol, 85.69 % purity) as an off white solid.

[0388]

[0217] MS (m / z) [M+H]+= 231.1. Rt = 0.279 min.

[0389]

[0218] Step 2: methyl 6-oxo-l-(pyridin-3-yl)piperidine-3-carboxylate (IM16-2):

[0390]

[0219] To a stirred solution of IM16-1 (6.00 g, 1 Eq, 26.06 mmol) in methanol (30.00 mL) and THF (30.00 mL), was added to 10% palladium on carbon (50% wet) (2.774 g) at 25 °C. Reaction mixture was stirred at 25 °C with 80 psi of hydrogen pressure for 16 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, reaction mixture was filtered through celite, washed with methanol (40 mL) and filtrate was evaporated under vacuum to get crude. Crude was dissolved in THF (50 mL), was added quadrasil (2.0 g). Reaction mixture was stirred for 1 h and filtered through celite and filtrate was evaporated under vacuum to get the IM16-2 (5.00 g, 21.34 mmol, 81.9 % purity) as a colourless viscous liquid. MS (m / z) [M+H]+= 235.1, Rt = 0.991 min.

[0391]

[0220] Step 3: 6-oxo-l-(pyridin-3-yl)piperidine-3 -carboxylic acid (Intermediate 16)

[0392]

[0221] To a stirred solution of IM16-2 (3.8 g, 1 Eq, 16.22 pmol) in THF (10.00 mL) and Water (5 mL), was added LiOH (1.165 g, 719.0 pL, 3 Eq, 48.66 mmol) at room temperature. Reaction mixture was stirred at 50 °C for 1 h. The reaction was monitored by TLC and LCMS. After completion of starting, reaction mixture was evaporated under vacuum (Keep water bath temp, less than 40 °C) to get the crude. The crude was diluted with water & acidified to pH ~ 4 by using 0.1N HC1 and concentrated under reduced pressure concentrated under reduced pressure to get Intermediate 16 (1.5 g, 16.22 mmol, 41.99% yield) along with lithium chloride salt as a white solid. The Intermediate was taken further without purification. MS (m / z) [M+H]+= 238.9. Rt = 0.277 min. [Method-L24], ’H NMR (400 MHz, DMSO-O 8 ppm: 12.97 (s, 1H), 7.45-7.36 (m, 2H), 6.30 (s, 1H), 5.83 (s, 1H), 3.60 (s, 3H), 2.73-2.63 (m, 2H), 2.56-2.48 (m, 2H).

[0393]

[0222] Example 9: Synthesis of intermediate 17: 6-oxo-l-(pyridin-3-yl)piperidine-3-carboxylic acid

[0394]

[0395]

[0223] Step 1: methyl 6-oxo-l-(tetrahydro-2H-pyran-4-yl)-l,6-dihydropyridine-3 -carboxylate (IM17-1)

[0396]

[0224] To a stirring solution of methyl 2-oxo-2H-pyran-5 -carboxylate (CAS # 6018-41-3) (4.00 g, 1 Eq, 25.95 mmol) and tetrahydro-2H-pyran-4-amine (CAS # 38041-19-9) (3.938 g, 1.5 Eq, 38.93 mmol) in methanol (50.00 mL) was heated at 70 °C for 1 h. Progress of the reaction was monitored by TLC (50% ethyl acetate in n-heptane) and LCMS. After completion of starting material, methanol was evaporated under vacuum. The residue obtained was purified by flash column chromatography on silica gel using 0%-100% ethyl acetate in n-Heptane as eluent. Pure fractions were collected and concentrated under vacuum to obtain IM17-1 (2.80 g, 11.80 mmol, 45.47 % yield) as orange solid. MS (m / z) [M+H]+= 238.1. Rt = 1.268 min.

[0397]

[0225] Step 2: methyl 6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxylate (IM17-2)

[0226] To a solution of IM17-1 (2.800 g, 1 Eq, 11.80 mmol) in methanol (30.00 mL) was added Pd / C (1.256 g, 50% Wt, 0.5 Eq, 5.901 mmol) and stirred at 60 °C for 16 h at 80 psi hydrogen pressure.

[0398] Progress of the reaction was monitored by TLC (50% ethyl acetate in n-heptane, UV inactive and KMnO4active) and LCMS. After complete consumption of starting material, reaction mixture was filtered through celite pad, filtrate was evaporated under vacuum to obtain IM17-2 (2.000 g, 6.712 mmol, 56.88 % yield, 80.98% Purity) as crude. Crude was taken as such to the next step without any purification. MS (m / z) [M+H]+= 242.2. Rt = 1.136 min.

[0399]

[0227] Step 3: 6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxylic acid (Intermediate 17)

[0400]

[0228] To a stirred solution of IM17-2 (2.00 g, 1 Eq, 8.289 mmol) in tetrahydrofuran (10.00 mL), methanol (10.00 mL) and water (10.00 mL) was added Lithium Hydroxide (992.6 mg, 5 Eq, 41.44 mmol) at 0 °C and stirred at 25 °C for 1 h. Progress of the reaction was monitored by TLC (70% Ethyl acetate in n-heptane) and LCMS. After completion of starting material, reaction mixture was evaporated under vacuum. The residue obtained was diluted with water (20 mL) and washed with ethyl acetate (2 x 20 mL) to remove non-polar impurity. Aqueous layer was acidified with IN HC1 solution to get pH~4 and extracted with 20% methanol in dichloromethane (5 x 20 mL). Combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under vacuum. The solid obtained was washed with diethyl ether (2 x 20 mL) to obtain Intermediate 17 (1.500 g, 4.664 mmol, 56.27 % yield, 70.66% Purity) as white solid. The intermediate was taken further without purification. MS (m / z) [M+H]+= 228.2, Rt = 0.442 min. [Method-L4],

[0401]

[0229] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0402]

[0230] Table 9:

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0231] Example 10: Synthesis of intermediate 27: l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6- oxopiperidine-3 -carboxylic acid

[0411]

[0412]

[0232] Step 1: methyl l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-oxopiperidine-3-carboxylate (IM27-1)

[0413]

[0233] In a sealed tube, to a stirred solution of dimethyl 2-methylenepentanedioate (CAS # 5621-44-3) (4.000 g, 1 Eq, 23.23 mmol) in methanol (20.000 mL), was added 2-((tert-butyldimethylsilyl)oxy)ethan- 1-amine ( CAS # 101711-55-1) (12.22 g, 3 Eq, 69.69 mmol) at 25 °C and stirred the solution at 70 °C for 48 h. Progress of the reaction was monitored by TLC and LCMS. After completion of starting material, reaction mixture was concentrated under reduce pressure to get crude. The crude was purified by column chromatography column using combi flash. The compound eluted at 50% ethyl acetate in n-Heptane. Pure fractions were collected and concentrated to give IM27-1 (5.800 g, 18.38 mmol, 79.14 %) as brown liquid. MS (m / z) [M+H]+= 316.2, Rt = 1.81 min.

[0414]

[0234] Step 2: l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-oxopiperidine-3-carboxylic acid (Intermediate 27)

[0415]

[0235] To a stirred solution of IM27-1 (3.500 g, 1 Eq, 11.09 mmol) in methanol (12.000 mL) and THF (12.000 mL) was added LiOH (531.4 mg, 2 Eq, 22.19 mmol) in water (12.000 mL) solution at 0 °C and stirred the solution at 25 °C for 1.5 h. Reaction was monitored by TLC and LCMS. Reaction mixture was concentrated, and the residue was acidified with citric acid solution (PH~5), the solid formed was filtered washed with water (10 mL) to give Intermediate 27 (2.500 g, 8.293 mmol, 74.75 %) as a white solid. MS (m / z) [M+H]+= 302.2, Rt = 1.727 min. [Method-L7], ’H NMR (400 MHz, DMSO-d₆) δ 12.53 (s, 1H), 3.63 (t, J= 6.4 Hz, 2H), 3.49-3.44 (m, 2H), 3.33 -3.29 (m, 2H), 2.75 -2.71 (m, 1H), 2.23-2.21 (m, 2H), 1.94 -1.93 (m, 1H), 1.76 -1.75 (m, 1H), 0.82 (s, 6H)

[0416]

[0236] Example 11: Synthesis of intermediate 28: l-(1.3-dimethoxypropan-2-yl)-6-oxopiperidine-3-carboxylic acid

[0417]

[0418] Step 2 SM28-2 Step 3 intermediate 28

[0419]

[0237] Step 1: dimethyl 2-(((l,3-dimethoxypropan-2-yl)amino)methyl)pentanedioate (IM28-1)

[0420]

[0238] To a mixture of dimethyl 2-methylenepentanedioate (CAS # 5621-44-3) (5.00 g, 1 Eq, 29.04 mmol), 1,3 -dim ethoxypropan -2-amine (10.38 g, 3 Eq, 87.12 mmol) in methanol (50.00 mL) was added Boron trifluoride etherate (8.243 g, 7.275 mL, 2 Eq, 58.08 mmol) at 70 °C and stirred at 70 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. Reaction mixture was evaporated completely to give crude as pale brown liquid. The crude was purified by flash column chromatography on silica gel eluted with 80 % ethyl acetate in n-Heptane to 5% MeOH in DCM to give IM28-1 (3.50 g, 10 mmol, 35% purity, 85% Purity) as a pale-yellow liquid. MS (m / z) [M+H]+= 292.2, Rt = 0.363 min.

[0421]

[0239] Step 2: methyl 1-(1, 3 -dimethoxypropan-2-yl)-6-oxopiperidine-3 -carboxylate (IM28-2)

[0422]

[0240] To a mixture of IM28-1 (2.500 g, 1 Eq, 8.581 mmol) in toluene (30.00 mL) was added 2-Hydroxypyridine (2.448 g, 3 Eq, 25.74 mmol) and stirred at 110 °C for 14 h. Progress of the reaction was monitored by TLC and LCMS. After completion of starting material, reaction mixture was diluted with water and extracted with ethyl acetate twice. Combined organic layers were dried over sodium sulphate and evaporated under reduced pressure to give IM28-2 (1.0 g, 3.857 mmol, 44.94 %) as a yellow liquid. MS (m / z) [M+H]+= 260.1, Rt = 1.130 min.

[0423]

[0241] Step 3: l-(l,3-dimethoxypropan-2-yl)-6-oxopiperidine-3-carboxylic acid (Intermediate 28)

[0424]

[0242] To a mixture of IM28-2 (1.000 g, 1 Eq, 3.857 mmol) in tetrahydrofuran (10.00 mL) and Water (5.000 mL) was added lithium hydroxide (138.5 mg, 1.5 Eq, 5.785 mmol) and stirred at 25 °C for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion of starting material, reaction mixture was concentrated to remove organic solvent and aqueous layer was acidified with HC1 solution to pH (~2 to 3). The compound was extracted from aqueous layer with DCM twice. The combined organic layers were separated, dried over anhydrous sodium sulphate, evaporated under reduced pressure to give Intermediate 28 (450.0 mg, 1.7 mmol, 43 %, 90% Purity) as orange liquid. MS (m / z) [M+H]+= 246.1, Rt = 0.258 min. [Method-L7]

[0425]

[0243] Example 12: Synthesis of intermediate 29: l-isopropyl-6-oxo-5-phenylpiperidine-3 -carboxylic acid

[0426]

[0427] IM29-2 Step 3 IM29-3 Step 4 Intermediate 29

[0428]

[0244] Step 1: ethyl 5-bromo-l-isopropyl-6-oxo-l,6-dihydropyridine-3-carboxylate (IM29-1)

[0429]

[0245] To a stirred compound ethyl 5 -bromo-6-oxo-l,6-dihydropyridine-3 -carboxylate (CAS # 169773-94-8) (5.5 g, 1 Eq, 22.35 mmol) and 2-iodopropane (CAS # 75-30-9) (3.8 g, 1 Eq, 22.35 mmol) in DMF (20.0 mL) was added Potassium carbonate (4.63 g, 1.96 mL, 1.5 Eq, 33.53 mmol) stirred to 100°C for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of starting material, the reaction mixture was diluted with ice-cold water (50 mL) and extracted with ethyl acetate (200 mL X 2). The organic layer was washed with brine solution (50 mL), dried over anhydrous sodium sulphate and evaporated under vacuum to get crude. The crude was purified by flash column chromatography on silica gel using 20% EA in Heptane as eluent. Pure fractions were collected and concentrated under vacuum to obtain IM29-1 (3.4 g, 22.35 pmol, 52.79 %, 93.41% Purity). MS (m / z) [M+H]+= 290.1, Rt = 1.38 min.

[0430]

[0246] Step 2: ethyl l-isopropyl-6-oxo-5-phenylpiperidine-3 -carboxylate (IM29-2)

[0431]

[0247] To a stirred solution of IM29-1 (2.000 g, 1 Eq, 6.941 mmol) and phenylboronic acid (846.3 mg, 1 Eq, 6.941 mmol) in 1,4-dioxane (15.000 mL) and water (5.000 mL) was added Cesium carbonate (4.523 g, 1.111 mL, 2 Eq, 13.88 mmol) and purged with nitrogen gas for 10 mins followed by the addition of l, T-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (253.9 mg, 0.05 Eq, 347.1 pmol). The resulting mixture was stirred at 100 °C for 16 h. Progress of the reaction was monitored by TLC. After completion of starting material, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine solution (10 mL). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to obtain crude. The obtained crude compound was dissolved in THF (10 ml) and added Quadrasil AP (250 mg) was added. The resulting mixture was stirred at room temperature for 1 h. Then the mixture was filtered through celite bed and the filtrate was concentrated to get the crude compound. The crude was purified by flash column chromatography on silica gel using 20% EA in Heptane as eluent. Pure fractions were collected and concentrated under vacuum to obtain IM29-2 (1.9 g, 6.94 pmol, 95.93 % yield, 99.24% Purity). MS (m / z) [M+H]+= 286.1. Rt = 1.836 min.

[0432]

[0248] Step 3: ethyl l-isopropyl-6-oxo-5-phenylpiperidine-3 -carboxylate (IM29-3)

[0433]

[0249] To a solution of IM29-2 (1.200 g, 1 Eq, 4.206 mmol) in methanol (5.00 mL) was added 10% Pd / C (358.0 mg, 0.8 Eq, 3.364 mmol) at room temperature and reaction mixture stirred under 80 psi hydrogen pressure at 60 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of starting material, reaction mixture was filtered through celite bed, filtrate was evaporated under vacuum to obtain crude. The crude was purified by flash column chromatography on silica gel using 20% EA in Heptane as eluent. Pure fractions were collected and concentrated under vacuum to obtain IM29-3 (1.8 g, 6.94 pmol, 95.93 % yield, 72% Purity). MS (m / z) [M+H]+= 290.2, Rt = 1.375 min.

[0434]

[0250] Step 4: l-isopropyl-6-oxo-5-phenylpiperidine-3-carboxylic acid (Intermediate 29)

[0435]

[0251] To a stirred solution of IM29-3 (1.600 g, 1 Eq, 5.811 mmol) in MeOH (5.000 mL), THF (5.000 mL) and water (5.000 mL) was added Lithium hydroxide (695.8 mg, 429.3 pL, 5 Eq, 29.05 mmol) to room temperature, The reaction mixture stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After 16 h, the reaction mixture was evaporated to get crude. The crude washed with ethyl acetate to remove non polar impurities. The crude was diluted with water (10 mL) and acidified to pH=2 using IN HC1 solution to obtain solid. The solid filtered and then washed with diethyl ether and dried under vacuum to afford Intermediate 29 (1.200 g, 4.592 mmol, 79.03 % yield, 56.31% purity). MS (m / z) [M+H]+= 262.1. Rt = 1.408 min. [Method-L7]. ’H NMR (400 MHz, DMSO-t / 6) 8 12.67 (s, 1H), 7.33-7.15 (m, 5H), 4.76-4.62 (m, 1H), 3.67-3.60 (m, 1H), 3.50-3.36 (m, 2H), 2.90-2.77 (m, 1H), 2.30-2.21 (m, 1H), 2.06-1.89 (m, 1H), 1.14-1.01 (m, 6H).

[0436]

[0252] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0437]

[0253] Table 10:

[0438]

[0439]

[0440]

[0254] Example 13: Synthesis of intermediate 31: 5-(4-fluorophenyl)-6-oxo-l-(tetrahvdro-2H-pyran-4-yl)piperidine-3 -carboxylic acid

[0441]

[0442]

[0255] Step 1: methyl 6-oxo-l-(tetrahydro-2H-pyran-4-yl)-l,6-dihydropyridine-3-carboxylate (IM31-1)

[0443]

[0256] To a stirred solution methyl 2-oxo-2H-pyran-5 -carboxylate (CAS # 6018-41-3) (10.00 g, 1 Eq, 64.88 mmol) in methanol (100.0 mL) at room temperature was added tetrahydro-2H-pyran-4-amine (6.563 g, 1 Eq, 64.88 mmol). The reaction mixture stirred at 80 °C for 1 h. The progress of the reaction was monitored by TLC and LCMS. After the completion of starting material, the reaction mixture was cooled to room temperature and quenched with ice-cold water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get crude. The crude was purified using flash chromatographic technique using 0%-100% ethyl acetate in n-heptane as eluent. Compound eluted at 70% n-Heptane in ethyl acetate. Pure fractions were collected and evaporated under vacuum to obtain IM31-1 (4.50 g, 11.6 mmol, 17.9 %yield, 61.4% Purity). MS (m / z) [M+H]+= 238.1, Rt = 1.173 min.

[0444]

[0257] Step 2: methyl 5-bromo-6-oxo-l-(tetrahydro-2H-pyran-4-yl)-l,6-dihydropyridine-3-carboxylate (IM31-2)

[0445]

[0258] To a stirred solution of IM31-1 (4.10 g, 1 Eq, 17.28 mmol) in acetonitrile (40.00 mL) was added NBS (3.076 g, 1 Eq, 17.28 mmol) at 0 °C. Then reaction mixture stirred at 70 °C for 1 h. The progress of the reaction was monitored by TLC. After the completion of starting material, the reaction mixture was cooled to room temperature and quenched with ice-cold water (100 mL) and extracted with ethyl acetate (2 x lOOmL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get crude. The crude was purified by Combi-Flash column chromatography (using gradient elution of 0-70% of ethyl acetate in heptane) to afford IM31-2 (1.23 g, 3.5 mmol, 20 % yield, 89% Purity) as a pale-yellow solid. MS (m / z) [M+H]+= 318.1, Rt = 1.224 min.

[0446]

[0259] Step 3: methyl 5-(4-fluorophenyl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)-l,6-dihydropyridine-3-carboxylate (IM31-3)

[0447]

[0260] To a mixture of IM31-2 (2.500 g, 1 Eq, 7.908 mmol), (4-fluorophenyl)boronic acid (1.549 g, 1.4 Eq, 11.07 mmol) in 1,4-Dioxane (20.00 mL) and water (5 mL) at room temperature was added CS2CO3 (6.441 g, 2.5 Eq, 19.77 mmol) under N2 gas was purged for

[0448] 15 mins. [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)ComplexWithDichloromethane (129.2 mg, 0.02 Eq, 158.2 pmol) was then added and the reaction mixture to stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of starting material. The reaction mixture was filtered through celite bed using ethyl acetate. The filtrate was concentrated to get

[0449] crude residue. The crude residue was purified by flash column chromatography on silica gel (eluent: heptane / [EtOAc / EtOH (3:1)] = 70:30 to 60:40; a 24 g) to afford IM31-3 (2.200 g, 4.3 mmol, 55 % yield, 65% Purity) as a brown solid. MS (m / z) [M+H]+= 333.3, Rt = 1.379 min.

[0450]

[0261] Step 4: methyl 5 -(4-fluorophenyl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3 -carboxylate (IM31-4):

[0451]

[0262] To a mixture of IM31-3 (2.200 g, 1 Eq, 6.640 mmol) in

[0452] methanol (20.00 mL) was added Pd / C (3.533 g, 10% Wt, 0.5 Eq, 3.320 mmol) and allowed to stir at 60 °C and 80 Psi pressure under hydrogen atmosphere. Progress of reaction monitored by TLC. After

[0453] Ill completion of starting material, reaction mixture was filtered through celite bed and the filtrate was concentrated to get crude. The crude was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 70:30 to 50:50; a 24 g Redisep Silver column) to afford IM31-4 (1.400 g, 4.10 mmol, 61.8 % yield, 98.3% Purity) as a colorless liquid. MS (m / z) [M+H]+= 336.1, Rt = 1.655 min.

[0454]

[0263] Step 5: 5-(4-fluorophenyl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxylic acid (Intermediate 31)

[0455]

[0264] To a mixture of IM31-4 (1.200 g, 1 Eq, 3.578 mmol) in MeOH (5.00 mL), THF (5.000 mL) and water (5.000 mL) was added LiOH (428.5 mg, 5 Eq, 17.89 mmol) at room temperature and allowed to stir for 5 h at room temperature. Progress of reaction was monitored by TLC. The reaction mixture was concentrated, and the crude diluted with water and extracted with ethyl acetate. The organic layers were separated. Then the aqueous layer was acidify using 2N HC1 pH~4 and extracted with DCM (2 x 50 mL). The combined organic layers were separated, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to obtain Intermediate 31 (900.0 mg, 2.75 mmol, 76.9 % yield, 98.3% Purity) as white solid. MS (m / z) [M+H]+= 322.2. Rt = 1.094 min. [Method-L2], ’H NMR (400 MHz, DMSO-d6) 8 12.66 (s, 1H), 7.22-7.19 (m, 2H), 7.14-7.07 (m, 2H), 4.53-4.42 (m, 1H), 3.92-3.90 (m, 2H), 3.70-3.67 (m, 1H), 3.50-3.36 (m,4H), 2.93-2.80 (m, 1H), 2.26-2.21 (m, 1H), 2.03-1.93 (m, 1H), 1.77-1.73 (m, 2H), 1.53-1.44 (m, 2H).

[0456]

[0265] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0457]

[0266] Table 11

[0458]

[0459]

[0460]

[0267] Example 14: Synthesis of intermediate 32: lithium 6-oxo-l-(pyridin-4-yl)piperidine-3-carboxylate

[0461]

[0462]

[0268] Step 7: methyl 6-oxopiperidine-3-carboxylate (IM32-1)

[0269] To a solution of methyl 6-oxo-l,6-dihydropyridine-3-carboxylate ((CAS # 6018-41-3) (2.500 g, 1 Eq, 16.32 mmol) in Methanol (25.00 mL) (taken in a hydrogenation vessel) was added 10% Pd / C (1.000 g, 0.1 Eq) and the reaction was stirred at 50 °C under H₂ atmosphere of 80 psi for 16 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed, the celite bed was washed with additional MeOH and the combined filtrate was concentrated under reduced pressure to afford IM32-1 (2.000 g, yield 76 %, purity 98%) as an off white solid. The compound was used for the next step without further purification. MS (m / z) [M+H]+= 158.1, Rt = 0.249 min.1H NMR (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 3.63 (s, 3H), 3.33-3.23 (m, 2H), 2.85-2.79 (m, 1H), 2.25-2.10 (m, 1H), 2.01-1.94 (m, 2H), 1.89-1.79 (m, 1H).

[0463]

[0270] Step 2: methyl 6-oxo-l-(pyridin-4-yl)piperidine-3-carboxylate (IM32-2)

[0464]

[0271] To a stirred solution of IM32-1 (500.0 mg, 1 Eq, 3.181 mmol) in 1,4-Dioxane (10.00 mL) was added 4-Bromopyridine Hydrobromide (618.6 mg, 1 Eq, 3.181 mmol) followed by CS2CO3 (3.11 g, 3 Eq, 9.544 mmol), reaction mixture was degassed with nitrogen for 10 min. then added Methyl[2-(methylamino)ethyl] amine (280.4 mg, 342 pL, 1 Eq, 3.181 mmol) and Cuprous iodide (363.5 mg, 64.7 pL, 0.6 Eq, 1.909 mmol). The reaction mixture was stirred at 100 °C for 16 h. The progress of reaction was monitored by TLC and LCMS. Reaction mixture was quenched with water (20 mL) and extracted with Ethyl Acetate (2 x 50 mL), organic layer was washed with brine solution (50 mL), dried over Na2SO4, concentrated under reduced pressure to get crude compound. The crude compound was purified by flash column chromatography on silica gel [eluent: heptane: EtOAc = 90:10 to 80:20; using a 24 g column pre-packed with silica (60A)] to give IM32-2 (300.0 mg, yield 36 %, LCMS purity 90%) as paleyellow liquid. MS (m / z) [M+H]+= 235.1, Rt = 0.631 min.XH NMR (400 MHz, DMSO-d6) δ 8.57-8.52 (m, 2H), 7.39-7.38 (m, 2H), 3.93-3.83 (m, 2H), 3.65 (m, 3H), 3.16-3.11 (m, 1H), 2.67-2.57 (m, 1H), 2.47-2.41 (m, 1H), 2.28-2.11 (m, 1H), 2.18-2.02 (m, 1H).

[0465]

[0272] Step 3: lithium 6-oxo-l-(pyridin-4-yl)piperidine-3-carboxylate (Intermediate 32)

[0466]

[0273] To a mixture of IM32-2 (400.0 mg, 1 Eq, 1.708 mmol) in MeOH (2.000 mL), THF (5 mL) and Water (2.000 mL) was added Lithium hydroxide monohydrate (214.9 mg, 142 pL. 3 Eq, 5.123 mmol). Reaction mixture was stirred at rt for 2 h. The progress of the reaction was monitored by TLC. Reaction mixture was evaporated under reduced pressure and dried completely using Lyophilization to yield Intermediate 32 (250.0 mg, yield 66.48 %) as an off white solid. MS (m / z) [M+H]+= Not ionized. Crude material was used and characterized at the next step.

[0467]

[0274] Example 15: Synthesis of intermediate 33: lithium 6-oxo-l-(pyridin-2-yl)piperidine-3-carboxylate

[0468]

[0469] Step 1 M33-1 Step 2 intermediate 33

[0470]

[0275] Step 1: methyl 6-oxo-l-(pyridin-2-yl) piperidine-3 -carboxylate (IM33-1)

[0471]

[0276] To a mixture of 2-bromopyridine (CAS # 109-04-6) (500.00 mg, 3.1646 mmol) and IM32- 1(497.37 mg, 3.1646 mmol) in Dioxane (15.00 mL) was added cesium carbonate (3.0932 g, 3 Eq, 9.4937 mmol) and the reaction was purged with N2 for 15 min. Methyl [2-(m ethylamino) ethyl] amine (CAS # 958991-06-5) (279.0 mg, 340 pL, 3.1646 mmol) and Cuprous iodide (361.61 mg, 64.3 pL, 0.6 Eq, 1.8987 mmol) were then added to the reaction mixture and stirred at 100 °C for 16 h. The reaction was monitored using TLC and LCMS. The reaction mixture was diluted with water (40 mL) and extracted using ethyl acetate (2 x 45 mL). The combined organic extracts were washed with water (25 mL), dried over sodium sulphate, filtered and concentrated in vacuo to obtain IM33-1 (520.0 mg, 1.4 mmol, Yield: 44 %, Purity: 63%) as yellow liquid. Crude only taken forward to next step. MS (m / z) [M+H]+= 235.1, Rt = 0.885 min.

[0472]

[0277] Step 2: lithium 6-oxo-l-(pyridin-2-yl) piperidine-3 -carboxylate (Intermediate 33)

[0473]

[0278] To a mixture of IM33-1 (400.0 mg, 1 Eq, 1.708 mmol) in THF (6.000 mL) and MeOH (2.500 mL) was added Lithium hydroxide monohydrate (286.6 mg, 190 pL, 4 Eq, 6.830 mmol) in Water (2.500 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to furnish its crude form. Crude was directly kept under lyophilization to obtain Intermediate 33 (380.0 mg, 1.680 mmol, Yield: 98.40 %) as a white solid. Crude only taken forward to next step. 'H NMR (400 MHz, DMSO-d6) δ 7.87 (dd, J= 4.00, 1.6 Hz,1H), 7.46-7.42 (m, 1H), 6.57- 6.52 (m, 2H), 3.34-3.04 (m, 2H), 2.58-2.51 (m, 1H), 2.34-2.20 (m, 2H), 2.18-1.84 (m, 2H).

[0474]

[0279] Synthesis of Intermediate 37: N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)piperidine-3-carboxamide hydrochloride

[0475] Boc

[0476]

[0477] intermediate 3 Step 1 iM37-1 Step 3 intermediate 37

[0478]

[0280] Step 1: tert-butyl 3-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carboxylate (IM37-1)

[0281] In a 250 mL RBF, to a mixture of Intermediate 3 (5.000 g, 1 Eq., 24.68 mmol), l-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (CAS # 84358-12-3) (5.658 g, 1 Eq., 24.68 mmol) in pyridine (40.000 mL) at 0 °C were added POCl₃ (11.35 g, 6.900 mL, 3 Eq., 74.03 mmol). The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with NaHCO3 (100 mL) and then extracted with ethyl acetate (100 mL). The separated organic layer was concentrated to afford crude. The residue was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 85:15 to 70:30; a 80 g Redisep Silver column via liquid injection) to give IM37-1 (6.500 g, 54 % yield, 85% Purity) as orange solid. MS (m / z) [M+H]+= 414.2, Rt = 1.683 min.

[0479]

[0282] Step 2: N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)piperidine-3-carboxamide hydrochloride (Intermediate 37)

[0480]

[0283] In a 250 mL round bottom flask, to a mixture of IM37-1 (6.0 g, 1 Eq., 14 mmol) in 1,4-dioxane (20.00 mL) at 25 °C were added 4.0M HC1 in dioxane (2.1 g, 14 mL, 4.000 molar, 4 Eq., 58 mmol). After stirring for 10 min, added concentrated HC1 (1.6 g, 1.2 mL, 36.00 molar, 3 Eq., 43 mmol). The reaction mixture was stirred at 25 °C for 16 hours. After 16 hours, the reaction mixture was concentrated to afford crude. The crude was further washed with n-Pentane (60 mL) and diethyl ether (50 mL) and dried in vacuum to give Intermediate 32 (4.500 g, 89 % yield, 81% purity) as a brown solid. The Intermediate was taken further without purification. MS (m / z) [M+H]+= 314.1, Rt = 1.06 min. [Method-L3],

[0481]

[0284] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0482]

[0285] Table 12:

[0483]

[0484]

[0485]

[0286] Example 16: Synthesis of intermediate 42: (S)-N-(7-chloro-4-fluoro-lH-benzo[d1imidazol-2-yl)piperidine-3 -carboxamide hydrochloride (Intermediate 42)

[0486]

[0487] rt, 16 h

[0488] Intermediate 9 Step 1

[0489]

[0490] Step 2 Intermediate 42

[0491]

[0287] Step 1: tert-butyl (S)-3-((4-chloro-7-fluoro-lH-benzo[d]imidazol-2-yl)carbamoyl)piperidine-l-carboxylate (IM42-1)

[0492]

[0288] In a 500 mL sealed tube, to a mixture of 1 (1.5 g, 1 Eq., 8.0823 mmol) in DMF (10.000 mL) at rt were added HATU (4.6098 g, 1.5 Eq., 12.123 mmol), DIPEA (3.1339 g, 4.22 mL, 3 Eq., 24.247 mmol) and (S)-l-(tert-butoxycarbonyl)piperidine-3 -carboxylic acid (2.7797 g, 1.5 Eq, 12.123 mmol). After stirring for 10 min, the reaction mixture was heated to 110 °C for 16 hours. After 16 hours, the reaction mixture was diluted with NaHCO3 solution (20 mL) and then extracted with EtOAc (10 mL). The separated organic layer was concentrated to afford crude. The residue was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 80:20 to 70:30; a 40 g Redisep Silver column via liquid injection) to give IM42-1 (1.900 g, 57 % yield, 97% Purity) as orange solid. MS (m / z) [M+H]+= 397.2, Rt = 1.497 min.

[0289] Step 2: (S)-N-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)piperidine-3-carboxamide hydrochloride (Intermediate 42)

[0493]

[0290] In a 500 mL round bottom flask, to a mixture of IM42-1 (1.900 g, 1 Eq., 4.788 mmol) in Dioxane (20.00 mL) at 25 °C were added Hydrogen chloride (698.2 mg, 4.788 mL, 4.000 molar, 4 Eq., 19.15 mmol) (4M solution in dioxane). After stirring for 10 min, the reaction mixture was heated to 25 °C for 12 h. The reaction mixture was concentrated to afford crude. The crude was further washed with n- Pentane (60 mL) and ether (50 mL) and dried in vacuum to give Intermediate 42 (1.300 g, 80 % yield, 70% Purity) as a white solid. The Intermediate was taken further without purification. MS (m / z) [M+H]+= 297.1, Rt = 1.354 min. [Method-L26],

[0494]

[0291] Example 17: Synthesis of intermediate 43: (S)-N-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)- l-((R)-pyrrolidine-3-carbonyl)piperidine-3 -carboxamide hydrochloride

[0495]

[0496]

[0292] Step 1: tert-butyl (R)-3-((S)-3-((7-chloro-4-fluoro-lH-benzo[d]imidazol-2- yl)carbamoyl)piperidine- 1 -carbonyl)pyrrolidine- 1 -carboxylate (IM43 - 1 )

[0497]

[0293] In a 500 mL sealed tube, to a mixture of Intermediate 42 (1100.0 mg, 1 Eq., 3.3014 mmol) in DMF (20.000 mL) at room temperature were added HATU (1.8830 g, 1.5 Eq., 4.9521 mmol), DIPEA (1.2801 g, 1.73 mL, 3 Eq., 9.9043 mmol) and (R)-l-(tert-butoxycarbonyl)pyrrolidine-3 -carboxylic acid (CAS # 72925-16-7) (1.0659 g, 1.5 Eq., 4.9521 mmol). The reaction mixture was heated to 110 °C for 16 hours. After 16 hours, the reaction mixture was diluted with NaHCO3 (20 mL) and then extracted with ethyl acetate (2 x 10 mL). The separated organic layer was concentrated to afford crude. The residue was purified by flash column chromatography on silica gel (eluent: DCM / MeOH = 90: 10 to 85:15; a 40 g Redisep Silver column via liquid injection) to give IM43-1 (1.600 g, 83 % yield, 85% Purity) as a brown oil.

[0498] MS (m / z) [M+H]+= 494.3, Rt = 1.39 min.

[0499]

[0294] Step 2: (S)-N-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-l-((R)-pyrrolidine-3- carbonyl)piperidine-3-carboxamide hydrochloride (Intermediate 43)

[0500]

[0295] In a 500 mL round bottom flask, to a mixture of IM43-1 (1.600 g, 1 Eq., 3.239 mmol) in 1,4- dioxane (8.000 mL) at 25 °C was added 4M HC1 in dioxane (472.4 mg, 3.239 mL, 4.000 molar, 4 Eq., 12.96 mmol) and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated to afford crude. The crude was further washed with n-Pentane (60 mL) and diethyl ether (50 mL) and dried in vacuum to give crude. The crude was diluted with water and basified to pH =12 using sat NaHCOs solution (30 mL) and extracted with 20% MeOH / DCM solution (30 mL). The separated organic layer was dried over anhydrous Na2SO4, concentrated under vacuum to afford Intermediate 43 (700.0 mg, 28 % yield, 55% Purity) as brown solid. The Intermediate was taken further without purification. MS (m / z) [M+H]+= 394.0, Rt = 1.31 min. [Method-L3],

[0501]

[0296] Example 18: Synthesis of 7-(trifluoromethyl)benzo[d1thiazol-2-amine (Intermediate 49)

[0502]

[0503] Ammonia in MeOH

[0504] 16 h, 50 °C

[0505] CAS# 1175277-66-3 Step 1 intermediate 49

[0506]

[0297] To a stirred solution of 2-chloro-7-(trifluoromethyl)benzo[d]thiazole (CAS # 1175277-66-3) (3.0 g, 97% wt, 1 Eq., 12.25 mmol) in MeOH (30.00 mL), ammonia (2.086 g, 2.65 mL, 10 Eq., 122.5 mmol) was purged for 10 mins at 0 °C. Then the reaction mixture was stirred at 50 °C for 16 h. Progress of reaction was monitored by TLC and LCMS. After 16 h, the reaction mixture was concentrated, and the crude was dissolved in 5 mL ACN and stirred for 2 mins. Then added n- Pentane (50 ml) and stirred for another 10 mins. The solution was brought to room temperature and w-pentane layer was descended to wash-off remaining starting material in the reaction mixture. The residual compound in the ACN layer was dried using high vacuum to afford Intermediate 49 (2.00 g, 74.85 % yield) as a pale-yellow solid. MS (m / z) [M+H]+= 219.0, Rt = 0.92 min. [Method-L7],

[0507]

[0298] Example 19: Synthesis of 1.4-dimethyl-6-oxopiperidine-3 -carboxylic acid (intermediate 50)

[0508]

[0509] I 80 psi, 80 °C, 48 h

[0510] IM50-2 Step 3 Intermediate 50

[0511]

[0299] Step 7: methyl l,4-dimethyl-6-oxo-l,6-dihydropyridine-3-carboxylate (IM50-1)

[0512]

[0300] To a stirred solution of methyl 4-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (CAS # 1224465-02-4) (10.000 g, 1 Eq, 59.823 mmol) in DMF (75.000 mL) was added cesium carbonate (29.237 g, 7.180 mL, 1.5 Eq, 89.734 mmol) followed by methyl iodide (10.190 g, 4.644 mL, 1.2 Eq, 71.788 mmol) dropwise at room temperature under argon atmosphere. Then the reaction was stirred for 1 h. The reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was quenched with ice-cold water and extracted with 5% methanol in DCM (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford a crude compound and it was purified by column chromatography with 5% methanol in DCM to give methyl IM50-1 (9.000 g, 83% yield, 83.03% purity) as a brown solid. MS (m / z) [M+H]+= 182.1, Rt = 1.31 min.

[0513]

[0301] Step 2: l,4-dimethyl-6-oxo-l,6-dihydropyridine-3 -carboxylic acid (IM50-2)

[0514]

[0302] To a stirred solution of IM50-1 (4.000 g, 1 Eq., 22.08 mmol) in THF (10.000 mL), MeOH (10.000 mL) and Water (10.000 mL), Lithium hydroxide monohydrate (1.112 g, 736 pL. 1.2 Eq, 26.49 mmol) was added at room temperature and the reaction mixture was stirred at 25 °C for 1 h. Progress of the reaction was monitored by TLC; after complete consumption of starting material, the reaction mixture was concentrated. The crude was acidified with IM HC1 solution (pH~5). The obtained precipitated solid was filtered, washed with water and w-pentane (2 x 100 mL). The solid was dried under vacuum to get IM50-2 (3.00 g, 18 mmol, 80 % yield, 98% Purity) as an off white solid. MS (m / z) [M+H]+= 168.1, Rt = 0.26 min.

[0303] Step-3'. l,4-dimethyl-6-oxopiperidine-3 -carboxylic acid (Intermediate 50)

[0515]

[0304] To a stirred solution of IM50-2 (3.00 g, 1 Eq., 17.95 mmol) in methanol (100.00 mL) was added 10% of Pd / C (2.122 g, 1 Eq, 17.95 mmol). Reaction mixture was stirred at 80°C for 36 h. Progress of the reaction was monitored by LCMS. The reaction mixture was filtered through celite pad and the filtrate obtained was concentrated under vacuum to give Intermediate 50 (1.400 g, 45.57% yield) as a white solid. MS (m / z) [M+H]+= 172.1, Rt = 0.42 mins. [Method-7],

[0516]

[0305] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0517]

[0306] Table 13:

[0518]

[0519]

[0520]

[0307] Example 20: Synthesis of l-isopropyl-6-oxo-2-(pyridin-3-yl)piperidine-3 -carboxylic acid (Intermediate 52)

[0521]

[0522]

[0308] Step 1 (E)-N-isopropyl-l-(pyridin-3-yl)methanimine (IM52-1)

[0523]

[0309] A mixture of pyridine-3 -aldehyde (CAS # 500-22-1) (10.00 g, 1 Eq., 93.36 mmol) and isopropylamine (CAS # 75-31-0) (8.278 g, 12 mL, 1.5 Eq., 140.0 mmol) in MeOH (50.00 mL) was stirred at 25 °C for 1 h. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was concentrated to get IM52-1 (13.50 g, 97.56 % yield, 97% purity) as a brown liquid. MS (m / z) [M+H]+= 149.2, Rt = 0.245 min.

[0524]

[0310] Step 2: l-isopropyl-6-oxo-2-(pyridin-3-yl)piperidine-3-carboxylic acid (Intermediate 52)

[0525]

[0311] To a stirred solution of IM52-1 (1.000 g, 1 Eq., 6.747 mmol) in toluene (10.0 mL) was added dihydro-2H-pyran-2,6(3H)-dione (CAS # 108-55-4) (769.9 mg, 1 Eq., 6.747 mmol). The reaction was stirred at 110°C for 16 h. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was concentrated under reduced pressure to get the crude. The crude was purified by silica gel column chromatography using 10-15% MeOH in DCM to yield Intermediate 52 (0.280 g, 12 % yield, 79% purity) as a yellow solid. MS (m / z) [M+H]+= 263.1, Rt = 0.359 min. [Method L7],

[0312] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0526]

[0313] Table 14

[0527]

[0528]

[0314] Example 21: Synthesis of Methyl 5-(tetrahvdro-2H-pyran-4-yl)-2-oxa-5-azaspirononane-7-

[0529]

[0530] carboxylate (Intermediate 60)

[0531]

[0532] 60

[0315] Step 7: N-(3-allyloxetan-3-yl)tetrahydro-2H-pyran-4-amine (IM60-1)

[0533]

[0316] To a stirred solution of oxetan-3-one (CAS # 6704-31-0) (5 g, 69.39 mmol) in toluene (100 mL) was added tetrahydro-2H-pyran-4-amine (CAS # 38041-19-9) (7.018 g, 69.39 mmol) at room temperature. The reaction mixture was stirred for 30 min and 2-allyl-4, 4, 5, 5 -tetramethyl- 1,3,2-dioxaborolane (CAS # 72824-04-5) (14.57 g 86.73 mmol) was added. The resulting reaction mixture was stirred at 40 °C for 16 h. Progress of the reaction was monitored by LCMS. The reaction mixture was cooled to room temperature and washed with 0.1 M aqueous NaOH (30 mL) and diluted with water (100 mL) and extracted using ethyl acetate (2x150 mL). Combined organic layer was washed with water (50 mL) followed by brine solution (30 mL), dried over sodium sulphate and evaporated under reduced pressure to yield crude. The crude was purified by flash column chromatography on silica gel where the product was eluted with 30 to 40% ethyl acetate in w-heptane to afford IM60-1 (6.2 g, 45.3 % yield) as a pale-yellow liquid. 1HNMR (400 MHz, DMSO-6) 85.88-5.75 (m, 1H), 5.2-5.1 (m, 1H), 5.10-5.07 (m, 1H), 4.30 (d, J= 8.8 Hz, 2H), 4.22 (d, J= 6 Hz, 2H), 3.78 (d, J= 10.8 Hz, 2H), 3.31-3.23 (m, 2H), 2.75-2.68 (m, 1H), 2.53-2.50 (m, 2H), 2.27 (bs, 1H), 1.51 (dd, J= 1.6, 12.4 Hz, 2H), 1.30-1.20 (m, 2H).

[0534]

[0317] Step 2: methyl 2-(((3-allyloxetan-3-yl)(tetrahydro-2H-pyran-4-yl)amino)methyl)acrylate (IM60-2)

[0535]

[0318] To a stirred solution of IM60-1 (6.20 g, 31.43 mmol) in ACN (100 mL) at room temperature were added K2CO3 (6.51 g, 47.14 mmol) and followed by dropwise addition of methyl 2-(bromomethyl)acrylate (CAS # 4224-69-5) (6.188 g, 34.57 mmol). The reaction mixture was heated to 80 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted using water (100 mL) and extracted using ethyl acetate (2 x 200 mL). The combined organic extracts were washed with water (100 mL), dried over sodium sulphate and evaporated under reduced pressure to get crude. The crude was purified by flash column chromatography on silica gel where the product was eluted with 5 to 10% ethyl acetate in w-heptane to afford IM60-2 (8.00 g, 86.18% yield) as a colourless gummy material. MS (m / z) [M+H]+= 296.1. Rt = 1.558 min. [Method-L7],1H NMR (400 MHz, DMSO-r / r,) 86.21-6.13 (m, 2H), 6.06-5.96 (m, 1H), 5.26 (d, J= 16.4 Hz, 1H), 5.15 (dd, J= 1.6, 10 Hz, 1H), 4.41 (d, J= 6 Hz, 2H), 4.21 (d, J= 6 Hz, 2H), 3.78 (d, J= 10.4 Hz, 2H), 3.69 (s, 3H), 3.26-3.20 (m, 2H), 2.83-2.78 (m, 1H), 2.61 (d, J= 6.8 Hz, 2H), 2.50 (s, 1H), 1.41-1.24 (m, 5H).

[0536]

[0319] Step 3: methyl 5-(tetrahydro-2H-pyran-4-yl)-2-oxa-5-azaspiro[3.5]non-7-ene-7-carboxylate (IM60-3)

[0537]

[0320] To a stirred solution of IM60-2 (8.00 g, 27.08 mmol) in DCE (800 mL) at room temperature was added p-toluene sulfonic acid monohydrate (5.152 g, 27.08 mmol). The reaction mixture was purged with nitrogen for 10 min followed by addition of Grubbs Catalyst 2 (CAS # 246047-72-3) (2.29 g, 2.70 mmol) and the reaction mixture was stirred at 80 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to reduce the volume of solvent. The resulting reaction mixture was quenched using 10% aqueous K2CO3 (250 mL) and extracted using dichloromethane (2 x 300 mL). The combined organic layer was washed with water (100 mL), dried over sodium sulphate and evaporated under reduced pressure to obtain the crude. The crude was purified by flash column chromatography on silica gel where the product was eluted with 20 to 25% ethyl acetate in w-heptane to afford IM60-3 (1.90 g, 26.2 % yield, 99.9% purity) as a brown solid. MS (m / z) [M+H]+= 268.1. Rt = 0.395 min [Method-L7], 'H NMR (400 MHz, DMSO-d6) 86.92 (s, 1H), 4.51 (d, J= 8 Hz, 2H), 4.12 (d, J= 4 Hz, 2H), 3.85-3.75 (m, 2H), 3.69 (s, 3H), 3.47-3.19 (m, 3H), 2.63 (s, 2H), 2.53-2.48 (s, 2H), 1.49-1.31 (m, 4H).

[0538]

[0321] Step 4'. methyl 5-(tetrahydro-2H-pyran-4-yl)-2-oxa-5-azaspiro[3.5]nonane-7-carboxylate (Intermediate 60)

[0539]

[0322] To a stirred solution of methyl IM60-3 (1.90 g, 7.10 mmol) in methanol (60 mL) was added 10% Pd / C (278.7 mg) at room temperature. The reaction was kept under 80 psi hydrogen pressure at 25 °C in parr shaker for 16 h. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtered through celite bed and washed with MeOH (1 L). The filtrate was evaporated under reduced pressure to obtain the crude. The crude was purified by flash column chromatography on silica gel where the product eluted with 15 to 20% ethyl acetate in w-heptane to afford Intermediate 60 (500.0 mg, 18 % yield, crude) as a colourless gummy compound. The compound was used without further purification. MS (m / z) [M+H]+= 270.1. Rt = 0.565 min. [Method-L7],

[0323] Example 22: Synthesis of 4-ethyl-l-methyl-6-oxopiperidine-3-carboxylic acid (Intermediate 65),

[0540]

[0541] 100 °C, 16 h parr shaker, 72 h CAS # 821791-58-6

[0542]

[0543] Step 1 Step 2

[0544] LiOH,

[0545]

[0546] rt, 5 h

[0547]

[0548] Step 3

[0549]

[0550]

[0324] Step 1: ethyl l-methyl-6-oxo-4-vinyl-l,6-dihydropyridine-3-carboxylate (IM65-1)

[0551]

[0325] To a stirred solution of ethyl 4-chloro-l-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (CAS # 821791-58-6) (3.00 g, 13.91 mmol) in 1,4- dioxane (30 mL) / water (10 mL) were added vinyl boronic acid pinacol ester (CAS # 75927-49-0) (6.429 g, 7.08 mL, 41.74 mmol) added CS2CO3 (9.973 g, 30.61 mmol). The resulting reaction mixture was purged with nitrogen for 10 min followed by addition of tetrakis(triphenylphosphine)palladium (1.608 g, 1.391 mmol). The reaction was stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, it was diluted with water (25 mL), extracted with ethyl acetate (100 mL). Collected organic layers, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude. The crude was purified by flash column chromatography on silica gel where the product was eluted with 80 to 85% ethyl acetate in w-heptane to afford IM65-1 (1.00 g, 34.68% yield) as a yellow solid. MS (m / z) [M+H]+= 208.3. Rt = 1.452 min. [Method-L7],

[0552]

[0326] Step 2: 4-ethyl-l-methyl-6-oxopiperidine-3 -carboxylate (IM65-2).

[0553]

[0327] IM65-1 (0.800 g, 3.82 mmol) was taken in Parr shaker (SS bottle) and dissolved in mixture of Methanol (5.00 mL), Ethanol (5.00 mL) and Acetic Acid (5.00 mL). The resulting reaction mixture was degassed under N2 for 5 min followed by addition of 10% Pd / C (1.02 g, 10% wt, 0.956 mmol). After that reaction mixture was degassed with H2 gas (2 times) and then stirred at 25 °C for 72 h under H2 / 120 psi. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite bed, washed with MeOH and dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield IM65-2 (0.700 g, 82 % yield, 95% Purity) as a brown solid. MS (m / z) [M+H]+= 214.2. Rt = 1.435 min. [Method-L7],

[0554]

[0328] Step 3: 4-ethyl-l-methyl-6-oxopiperidine-3-carboxylic acid (Intermediate 65)

[0555]

[0329] To a stirred solution of IM65-2 (0.700 g, 3.28 mmol) in THF (3.00 mL) / Water (2.00 mL) was added lithium hydroxide monohydrate (689 mg, 16.4 mmol) and stirred at 25 °C for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced vacuo, acidified with IM HC1 solution, and extracted with ethyl acetate. Collected organic layers and dried over anhydrous sodium sulphate, concentrated under vacuo to afford Intermediate 65 (500 mg, 76 % yield, 92% Purity) as a white solid. MS (m / z) [M+H]+= 186.2. Rt = 0.968 min. [Method-L7], *HNMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 3.41-3.35 (m, 2H), 2.96-2.91 (m, 1H), 2.79 (s, 3H), 2.38-2.31 (m, 1H), 2.17-2.11 (m, 1H), 2.04-2.02 (m, 1H), 1.38-1.30 (m, 1H), 1.27-1.19 (m, 1H), 0.88 (t, J =7.2 Hz, 3H).

[0556]

[0330] Example 23: Synthesis of 5-chloro-8-fluoroquinolin-2-amine (Intermediate 72)

[0557] CA

[0558]

[0559]

[0560]

[0331] Step 7: 7V-(5-chloro-2-fluorophenyl)-3, 3 dimethoxypropanamide (IM72-1)

[0561]

[0332] To a stirring solution of 5-Chloro-2-fluoroaniline (CAS # 2106-05-0) (5.00 g, 34.35 mmol) in THF (100 mL) at 0°C were added methyl 3,3-dimethoxypropanoate (CAS #7424-91-1) (6.10 g, 41.22 mmol) and NaHMDS (2M in THF, 12.60 g, 34.35 mL, 68.70 mmol). The resulting reaction mixture was stirred at 25 °C for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was quenched with saturated solution of ammonium chloride (30 mL), extracted with ethyl acetate (3 X 40 mL). Collected organic layers, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude residue compound as a dark brown solid (12 g). The crude was purified by flash column chromatography on silica where the product was eluted with 20 to 30% ethyl acetate in w-heptane to give IM72-1 (8.20 g, 84 % yield) as a yellow oily compound. *H NMR (DMSO-<fc) 89.94 (s, 1H), 8.10 (dd, J= 2.4, 4.4 Hz, 1H), 7.34-7.29 (m, 1H), 7.21-7.17 (m, 1H), 4.78 (t, J= 6.0 Hz, 1H), 3.28 (s, 6H), 2.76 (d, J= 5.6 Hz, 2H).

[0562]

[0333] Step 2: 5-chloro-8-fluoroquinolin-2(lH)-one (IM72-2)

[0563]

[0334] To a stirring solution of IM72-1 (8.20 g, 31.34 mmol) in DCM (200 mL) at 0 °C was added H2SO4 (46.10 g, 25.05 mL, 470.0 mmol) slowly. After stirring for 10 min, the reaction mixture was allowed to stir at 25 °C for 12 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice. The resulting white solid was isolated by filtration, washed twice with toluene (2 X 100 mL) and dried under reduced pressure to afford IM72-2 (6.00 g, 96 %yield) as apale-yellow solid. MS (m / z) [M+H]+= 198.1, Rt = 1.17 min. [Method-L7], 'HNMR (DMSO-O 8 12.00 (bs, 1H), 8.07 (dd, J= 1.2, 8.4 Hz, 1H), 7.48-7.43 (m, 1H), 7.32-7.29 (m, 1H), 6.71 (d, J= 10.0 Hz, 1H).

[0564]

[0335] Step 3: 2,5-dichloro-8-fluoroquinoline. (IM72-3)

[0565]

[0336] To the compound IM72-2 (6.00 g, 30.37 mmol) at 0 °C, POC13(32.90 g, 20.00 mL, 214.6 mmol) was added slowly. After stirring for 10 min, the reaction mixture was heated to 100 °C and stirred for 2 h. Progress of the reaction was monitored by TLC and LCMS. Upon completion, the mixture was quenched using the reverse quenching method — by slowly adding it to chilled saturated sodium bicarbonate solution (400 mL) — and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over sodium sulphate, filtered, and concentrated to afford crude 2,5-dichloro-8-fluoroquinoline IM72-3 (6.20 g, 90 % yield) as a brown solid. MS (m / z) [M+H]+= 216.0. Rt = 1.16 min. [Method-L7], ’H NMR (DMSO-t / e) 88.63 (dd, J= 1.2, 7.2 Hz, 1H), 7.87-7.84 (m, 2H), 7.76-7.71 (m, 1H).

[0566]

[0337] Step 4'. 5-chloro-8-fluoroquinolin-2-amine (Intermediate 72)

[0567]

[0338] To a mixture of IM72-3 (6.20 g, 28.70 mmol) in acetamide (16.95 g, 287.0 mmol) was added K2CO3 (19.83 g, 143.5 mmol). The reaction mixture was allowed to stir at 200 °C for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was cooled down to room temperature, diluted with cold water (50 mL) and extracted with ethyl acetate (3 X 100 mL). Combined organic layers, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude. The crude was purified by flash column chromatography on silica gel (eluted with 20 to 30% ethyl acetate in w-heptane) to give 5-chloro-8-fluoroquinolin-2-amine (6.20 g, Purity: 45%) as a beige solid crude. The crude was once again re-purified by flash column chromatography on silica gel (eluted with 20 to 30% ethyl acetate in w-heptane) to give 5-chloro-8-fluoroquinolin-2-amine (5.50 g, Purity: 71%) as a beige solid. The purified 5-chloro-8-fluoroquinolin-2-amine (5.50 g, Purity: 71%) was diluted in ethyl acetate (30 mL), acidified using 6M HC1 to pH-2 and extracted with ethyl acetate (2 X 30 mL) to remove impurity. The aqueous layer was basified using saturated lithium hydroxide solution to pH-11, resulting in precipitation of the product. The precipitate was filtered and dried to afford Intermediate 72 (910.0 mg, 15.82 % yield) as a beige solid. MS (m / z) [M+H]+= 197.0. Rt = 5.68 min. [Method-L7], *H NMR (DMSO-6) 88.12 (dd, J= 1.6Hz, 9.2Hz, 1H), 7.34 - 7.29 (m, 1H), 7.23 - 7.20 (m, 1H), 6.99 - 6.93 (m, 3H).

[0568]

[0339] Example 24 - Synthesis of N-(4-fluoro-1H-benzo[d]imidazol-2-yl)-1,9-dioxaspiro[5.5]undecane- 4-carboxamide (Compound 1)

[0569]

[0570] Step. To IB (3.40 mg, 22.5 pmol) at room temperature was added a solution of 1A (3.00 mg, 15.0 pmol) and N-methylimidazole (4.31 mg, 52.4 pmol) in MeCN (120 pL), followed by a solution of chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (8.41 mg, 30.0 pmol) in MeCN (30 pL). The resulting mixture was stirred at room temperature overnight. After this time, solvent was removed under reduced pressure in a genevac. The crude product was dissolved in 7:2:1 acetonitrile:water:dimethyl sulfoxide, passed through a 20 pm fritted filter, and injected onto prep HPLC. Purified by MicroCycle Prep HPLC Method 1 and immediately quantitated by CAD-equipped LCMS (MicroCycle LCMS Method 1). Solvent was removed under a Porvair Sciences Ultravap Mistral evaporator, then the purified solid was immediately reconstituted in DMSO to afford N-(4-fluoro-lH-benzo[d]imidazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide (1) as a solution in

[0571] DMSO. MicroCycle LCMS Method 1, Rt= 1.00 min., MS m / z [M+l]+= 334.3. MicroCycle LCMS Method 2, Rt = 0.94 min., MS m / z [M+l]+= 334.5. 1H NMR (400 MHz, DMSO) 8 12.32 (d, J = 2.2 Hz, 1H), 11.71 (s, 1H), 7.30 (dd, J = 8.0, 1.0 Hz, 1H), 7.04 (td, J = 8.0, 4.9 Hz, 1H), 6.91 (ddd, J = 11.1, 8.1, 1.0 Hz, 1H), 3.74 (ddd, J = 11.9, 5.1, 1.7 Hz, 1H), 3.70 - 3.47 (m, 6H), 2.99 - 2.91 (m, 1H), 2.03 - 1.93 (m, 1H), 1.88 (ddd, J = 13.0, 3.8, 1.7 Hz, 1H), 1.78 - 1.70 (m, 1H), 1.59 (dddt, J = 34.3, 18.5, 10.1, 4.7 Hz, 3H), 1.48 - 1.42 (m, 1H).

[0572]

[0340] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0573] Table 15

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0341] Example 25: Synthesis of N-(4.6-difluorobenzo[d1thiazol-2-yl)-6-oxo-l-pentylpiperidine-3-carboxamide (Compound 9)

[0580]

[0581] Step 1: To a solution of 2B (3.21 mg, 15.0 pmol) in DMA (75 pL) at room temperature was added a solution of 2A (2.00 mg, 10.7 pmol) in MeCN (107 pL), a solution of chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (6.03 mg, 21.5 pmol) in MeCN (31 pL), andN-methylimidazole (3.09 mg, 37.6 pmol). The resulting mixture was stirred at room temperature overnight. After this time, solvent was removed under reduced pressure in a genevac. The crude product was dissolved in 7:2:1 acetonitrile:water:dimethyl sulfoxide, passed through a 20 pm fritted filter, and injected onto prep HPLC. Purified by MicroCycle Prep HPLC Method 1 and immediately quantitated by CAD-equipped LCMS (MicroCycle LCMS Method 1). Solvent was removed under a Porvair Sciences Ultravap Mistral evaporator, then the purified solid was immediately reconstituted in DMSO to afford N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-pentylpiperidine-3-carboxamide (9) as a solution in DMSO. MicroCycle LCMS Method 1: Rt = 1.53 min.; MS m / z [M+H]+= 382.0. MicroCycle LCMS Method 2: Rt = 1.49 min.; MS m / z [M+H]+= 382.1. 1H NMR (400 MHz, DMSO) 8 12.82 (s, 1H), 7.82 (ddd, J = 8.3, 2.4, 1.0 Hz, 1H), 7.39 (ddd, J = 10.8, 9.6, 2.4 Hz, 1H), 3.58 - 3.43 (m, 2H), 3.28 - 3.18 (m, 1H), 3.14 - 3.02 (m, 1H), 2.34 - 2.24 (m, 2H), 2.07 (dd, J = 11.3, 6.7 Hz, 1H), 1.98 - 1.88 (m, 1H), 1.47 (p, J = 7.4 Hz, 2H), 1.36 - 1.14 (m, 5H), 0.85 (t, J = 7.1 Hz, 3H).

[0582]

[0342] MicroCycle HPLC / LCMS Methods:

[0343] MicroCycle Prep HPLC Method 1:

[0583]

[0344] Instrument: Waters AutoPurification HPLC with Waters 2767 sample manager; Column: Waters X-bridge BEH C-18 stationary phase, 10mm ID x 150mm length, 5 um pore size; Injection volume: 300 pL; UV: Waters 2998 photodiode array detector; MS: Waters QDa mass spectrometer; Flow rate: 10 mL / min. Acidic gradient: Formic acid, 7.5% in water, pumped at 0.3mL / min for a final concentration of 0.2% formic acid.

[0584] Gradient details:

[0585]

[0586]

[0345] MicroCycle Prep HPLC Method 2:

[0587]

[0346] Instrument: Waters AutoPurification HPLC with Waters 2767 sample manager; Column: Waters X-bridge BEH C-18 stationary phase, 10mm ID x 150mm length, 5 pm pore size; Injection volume: 300 pL; UV: Waters 2998 photodiode array detector; MS: Waters QDa mass spectrometer; Flow rate: 10 mL / min. Basic gradient: Ammonium acetate, 375 mM in water, pumped at 0.3 mL / min for a final concentration of 11 mM ammonium acetate.

[0588] Gradient details:

[0589]

[0590]

[0347] MicroCycle LCMS Method 1 (Product Analysis - Acidic):

[0348] Instrument: Waters Acquity Classic; Column: Waters Acquity UPLC BEH Cl 8 column, 2.1x50mm, 1.7 pm pore size; 3 min run time, 98% Solvent A from 0 to 0.1 min, 98 → 2% solvent A from 0.1 to 2.10 min, 2% solvent A from 2.1 to 2.6 min, 2 → 98% solvent A from 2.6 to 2.7 min, 98% solvent A from 2.7 to 3 min. Solvents: Solvent A = 0.1% formic acid in water (v / v), solvent B = 0.1% formic acid in acetonitrile (v / v). Injection volume 1 pL; Acquity UPLC Photodiode Array Detector 200-400, Waters SQ Detector 2 mass spectrometer (mass detection 150-1500 amu), Thermo Corona Veo RS Charged Aerosol Detector; column at 50 °C, flow rate 1.0 mL / min.

[0591]

[0349] MicroCycle LCMS Method 2 (Product Analysis - Acidic):

[0592]

[0350] Instrument: Waters Acquity Classic; Column: Waters Acquity UPLC BEH Cl 8 column, 2.1x50mm, 1.7 pm pore size; 3 min run time, 98% Solvent A from 0 to 0.1 min, 98 → 2% solvent A from 0.1 to 2.10 min, 2% solvent A from 2.1 to 2.6 min, 2 → 98% solvent A from 2.6 to 2.7 min, 98% solvent A from 2.7 to 3 min. Solvents: Solvent A = 0.1% formic acid in water (v / v), solvent B = 0.1% formic acid in acetonitrile (v / v). Injection volume 1 pL; Acquity UPLC Photodiode Array Detector 200-400, Waters SQ Detector 2 mass spectrometer (mass detection 150-1500 amu), Thermo Corona Veo RS Charged Aerosol Detector; column at 55 °C, flow rate 1.0 mL / min.

[0593]

[0351] Example 26: Synthesis of (S)-N-(4.6-difluorobenzo[d]thiazol-2-yl)-1.9-dioxaspiro[5.5]undecane- 4-carboxamide (Compound 10)

[0594]

[0595]

[0352] Step 1. Racemic IB (13.20 g, 1 Eq, 65.92 mmol) was purified by chiral SFC, which gave two enantiomeric isomers. Peak 1 (Rt = 2.52 min.) is the undesired R isomer. Peak 2 (Rt =3.82 min.) is the desired S isomer 3B (3.950 g, 18 mmol, 27 % yield, 98.6% e.e.). ‘H NMR (400 MHz, DMSO) 8 12.23 (s, 1H), 3.71 - 3.41 (m, 6H), 2.63 (tt, J = 12.3, 3.8 Hz, 1H), 2.00 (dq, J = 14.1, 2.7 Hz, 1H), 1.78 (ddd, J = 13.2, 3.9, 1.7 Hz, 1H), 1.71 (ddq, J = 13.1, 4.2, 2.2 Hz, 1H), 1.57 (ddd, J = 13.5, 10.4, 4.8 Hz, 1H), 1.51 -1.36 (m, 3H), 1.29 (t, J = 12.9 Hz, 1H).

[0596]

[0353] Chiral SFC conditions: Column Chiralpak IG 30x250mm 5um - (CPC072); Flow rate 150g per minute; Cosolventl5% MeOH in CO2; Detection 211nm; BPR Set Point 125bar; Injection size 99.0mg (33.0mg / mL in MeOH); System CA SFC150MGM.

[0597]

[0354] Step 2. To a solution of 3B (3.626 g, 19.48 mmol) in DMF (40.000 mL) was added 2A (3.900 g, 19.48 mmol), EDC (5.601 g, 29.22 mmol), and HOBt (4.474 g, 29.22 mmol) at room temperature. The resulting mixture was stirred for 4 days. LCMS showed 82% conversion to the desired product (Rt = 0.81min.). The crude was then diluted with 200mL of EtOAc. The organic solution was washed with water (3x), brine, dried over sodium sulfate, concentrated, and purified with ISCO (330g silica gel column, 0-100% EtOAc in heptane, product came out ~54% EtOAc as the second peak), affording 10 (3.100 g, 8.32 mmol, 42.7 %, 98.9% Purity) as white powder after under high vacuum overnight. LCMS method (basic, monitoring): Rt = 0.81 min., MS m / z [M+H]+= 369.2, ’H NMR (400 MHz, CD2C12) 8 9.64 (s, 1H), 7.41 (dd, J = 7.6, 3.5 Hz, 1H), 7.17 - 6.46 (m, 1H), 3.92 - 3.82 (m, 1H), 3.82 - 3.72 (m, 1H), 3.69 - 3.50 (m, 4H), 2.85 (tt, J = 12.5, 4.1 Hz, 1H), 2.11 - 1.97 (m, 1H), 1.86 (tdd, J = 12.9, 4.8, 2.3 Hz, 3H), 1.77 - 1.62 (m, 2H), 1.59 - 1.40 (m, 2H).

[0598]

[0355] LCMS Method conditions: The retention times in minutes (Rt) were obtained on a Waters AcQuity UPLC with a Waters Qda mass spectrometer using an AcQuity UPLC BEH C18 1.7pm 2.1x30mm column at an oven temperature of 50 °C. A gradient of water (5 mM ammonium hydroxide) / acetonitrile (5 mM ammonium hydroxide) 98 / 2 to 2 / 98 was applied over 1.5 min., then held for 0.3 min. (1 mL / min.). Electrospray mass spectra (+) and (-) with UV detection 210-400 nm (Waters AcQuity UPLC PDA).

[0599]

[0356] Example 27: Synthesis of A-(4.6-difluorobcnzo|d|thiazol-2-yl)tctrahvdro-2 / / -pyran-4-carboxamide (Compound 11).

[0600] 125 TFFH

[0601]

[0602]

[0357] Step 1. To the solution of 2A (50.0 mg, 268.81 pmol) in DMF (1 ml) was added 4B (46.7 mg, 295.73 pmol, 1.1 equiv.) and DIPEA (52.1 mg, 0.4 mmol, 1.5 equiv.). Then TFFH (88.7 mg, 0.034 mmol, 1.25 equiv.) was added. The resulting mixture was stirred at room temperature overnight. The reaction completion was determined by LCMS analysis. The reaction mixture was purified by preparative HPLC (0-1.3-5.3 min H₂O / ACN / 0.1%NH₄HCO₃, flow: 30 ml / min (loading pump 4 ml / min ACN) target mass 298 column: XBridge BEH C18 5um 130A) to afford 11 (42.0 mg, 140.79 pmol, 52.4% yield). LCMS: m / z [M+H]+= 327.2 Rt = 1.409 min. 1H NMR (600 MHz, DMSO-d6) 8 12.63 (s, 1H), 7.77 (dd, J = 2.45, 8.27 Hz, 1H), 7.37 - 7.31 (m, 1H), 3.66 (dd, J = 4.83, 11.82 Hz, 1H), 3.56 (td, J = 2.47, 12.23 Hz, 1H), 2.95 (tt, J = 3.78, 12.50 Hz, 1H), 1.73 (dd, J = 4.58, 13.59 Hz, 1H), 1.69 (d, J = 12.21 Hz, 1H), 1.54 (qd, J = 5.03, 12.52 Hz, 1H), 1.41 (t, J = 12.70 Hz, 1H), 1.17 (s, 3H), 1.14 (s, 3H).

[0603]

[0358] Analytical Methods Details:

[0604] Unless stated, all materials were purchased from commercial sources and used without any further treatment.

[0605]

[0359] NMR

[0606] Instrument specifications:

[0607] Agilent ProPulse 600

[0608] Bruker AVANCE DRX 500

[0609] Varian UNITYplus 400

[0610] Raw NMR data (FID) to be provided on request.

[0611]

[0360] LCMS Specifications and Method Details:

[0612] SUPOR 30 - Acidic Ol

[0613] Application: initial purity check for all compounds with m / z up to 600

[0614] Column: Agilent Poroshell 120 SB-C184.6x30mm 2.7 pm

[0615] Column Temperature: 60°C

[0616] Mobile phase: A - water (0.1% formic acid), B - acetonitrile (0.1% formic acid)

[0617] Flow rate: 3 ml / min

[0618] Gradient: 0.01 min - 1% B, 1.5 min - 100% B, 1.73 min - 100% B

[0619] MS Ionization mode: Electrospray ionization (ESI)

[0620] MS Scan range: 83 - 600 m / z

[0621] UV detection: 215 nm, 254nm, 280 nm

[0622]

[0361] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0623] Table 16

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0362] Example 28: Synthesis of / V-(4.6-difluoro-lZ7-benzo[6nimidazol-2-yl)tetrahvdro-2Z7-pyran-4- carboxamide (Compound 21)

[0630]

[0631] 3A 5B 21

[0632]

[0363] Step 1. To a mixture of 3A (0.25 g, 1 eq, 1.478 mmol) and 5B (0.192 g, 1 eq, 1.478 mmol) in DMF (5.00 mL) were added DIPEA (0.772 mL, 3 eq, 4.434 mmol) and HATU (0.84 g, 1.5 Eq, 2.217 mmol). The reaction mixture was heated to 100 °C for 16 h. The reaction was monitored using TLC and LCMS. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2x25 mL). The combined organic layers were washed with water (20 mL), dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude material. The crude material was purified by reverse phase HPLC (Acetonitrile / 5mM ammonium bicarbonate in water) to afford 21 as a white solid (0.188 g, 45.2%). Rt = 5.845 min., LCMS m / z [M + H]+= 282.1.1H NMR (400 MHz, DMSO-d6): S 12.43 (s, 1H), 11.7 (s, 1H), 7.10 (dd, J = 2, 8.4 Hz, 1H), 6.91- 6.97 (m, 1H), 3.89-3.92 (m, 2H), 3.32-3.38 (m, 2H), 2.71-2.79 (m, 1H), 1.63-1.78 (m, 4H).

[0633]

[0364] Prep HPLC conditions:

[0634] Analytical conditions: Mobile phase (A ): 5mM Ammonium bicarbonate in water

[0635] Mobile phase (B): Acetonitrile

[0636] Gradient (T / %B):0 / l 0,8 / 90, 12 / 98, 13 / 10, 15 / 10

[0637] Flow rate: LO mL / min

[0638] Column Details: Column Name: X-Bridge C18

[0639] Column Dimension: 100 mm x 4.6 mm x 3.5 pm

[0640] Column No: 2020-008

[0641]

[0365] Analytical LCMS method conditions:

[0642] Mobile Phase (A): 0.1% Formic Acid in water

[0643] Mobile Phase (B): ACN

[0644] Gradient (T / %B): 0 / / 10, 3.8 / 10, 5 / 50, 8 / 70, 12 / 10, 15 / 10

[0645] Flow rate: 0.3 ml / min; Column Name: BEH Cl 8

[0646] Column Dimension: 100 mm X 2.1 mm X 1.7 pm

[0647]

[0366] Example 29: Synthsis of N-(4.6-difluoro-lH-benzo[d1imidazol-2-yl)-l,9-dioxaspiro[5.51undecane-4-carboxamide (Compound 22)

[0648]

[0649] Step 1: N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide (Compound 22).

[0650] To a stirred solution of 3A (150 mg, 0.8 mmol) in DMF (2 mL) at 0 °C were added IB (213.09 mg, 1.06 mmol), EDC. HCI (229.2 mg, 1.2 mmol), HOBt (162 mg, 1.2 mmol), and DIPEA (0.4 mL). The reaction was stirred at 50 °C for 16 h. LCMS indicated that desired product was formed. Reaction mixture was concentrated under reduced pressure. Residue was diluted with water (3 mL) and extracted with EtOAc (5 mL x2). Organic fraction was dried over Na^SO-i. filtered and concentrated under reduced pressure to furnish its crude form. Crude product was purified by combi flash chromatography (eluted on 30% EtOAc - Heptane) to obtain desired product in 90% purity, which was further purified using Prep HPLC to afford 22 (58 mg, 20% yield) as off-white solid. Rt = 6.011 min., LCMS m / z [M+H]+= 352.1. ’H-NMR (400 MHz, DMSO- 6): 8 12.41 (s, 1 H), 11.73 (s, 1 H), 7.11 (dd, JI = 8.8 Hz, J2=2.0 Hz, 1 H), 6.97 - 6.91 (m, 1 H), 3.74 - 3.71 (m, 1 H), 3.66 - 3.49 (m, 5 H), 2.97 - 2.91 (m, 1 H), 1.98 - 1.85 (m, 2 H), 1.73 - 1.49 (m, 4 H), 1.45 - 1.36 (m, 2 H).

[0651]

[0367] Prep HPLC conditions:

[0652] Mobile phase A: 5mM Ammonium bicarbonate in Water

[0653] Mobile phase B: Acetonitrile

[0654] Gradient: 0 / 30; 2 / 30; 15 / 70, 18 / 90, 18.2 / 99, 20 / 99; 20.2 / 30; 23 / 30

[0655] Flow: 18.0mL / min

[0656] Column Name: Sunfire Cl 8

[0657] Column Dimension: 250 mm x 19 mm X 5u

[0658]

[0368] Analytical LCMS method conditions:

[0659] Mobile Phase (A): 0.1% Formic Acid in water

[0660] Mobile Phase (B): ACN

[0661] Gradient (T / %B): 0 / / 10, 3.8 / 10, 5 / 50, 8 / 70, 12 / 10, 15 / 10 Flow rate: 0.3 ml / min;

[0662] Column Name: BEH Cl 8

[0663] Column Dimension: 100 mm X 2.1 mm X 1.7 pm

[0664]

[0369] Example 30: Synthesis of N-(4.6-difluorobenzo[d]thiazol-2-yl)-l-(2-methoxyethyl)-6-oxopiperidine-3 -carboxamide (Compound 23),

[0665]

[0666]

[0370] Step 7: A mixture of 6C (1 g, 1 Eq, 6 mmol), 2-methoxyethan-l -amine (1 g, 3 Eq, 0.02 mol) in methanol (10 mL) was stirred at 70 °C for 16 h. LCMS indicated formation of desired product. Reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted on 50% EtOAc - heptane) to afford 6D (1.000 g, 4.6 mmol, 70 %, 97% purity) as colourless liquid. LCMS m / z [M+H]+= 212.1.

[0667]

[0371] Step 2: A stirred solution of 6D (1.000 g, 1 Eq, 4.734 mmol) in methanol (10.00 mL) was purged with nitrogen for 5 minutes. Palladium on carbon (604.6 mg, 1.2 Eq, 5.681 mmol) was added, and reaction was allowed to stir at room temperature for 16 h under hydrogen atmosphere with 80 psi pressure. LCMS indicated that desired product was formed. The reaction mixture was filtered through a bed of celite and washed with methanol. Filtrate was concentrated in vacuo to give crude 6E (0.900 g, 4.1 mmol, 87 %, 99% Purity) as a colourless oil. LCMS m / z [M+H]+= 216.0.

[0668]

[0372] Step 3: To a stirred solution of 6E (0.95 g, 1 Eq, 4.4 mmol) in methanol: THF:water (8.000 mL) (2:3:3) was added LiOH (320 mg, 3 eq., 13 mmol) and reaction was stirred at RT for 3 h. LCMS indicated that desired product was formed. Reaction mixture was concentrated under reduced pressure. The residue was diluted with FLO (2 mL) and acidified with IM HC1 (5 mL), the compound was extracted with ethyl acetate (2 X 25 mL). The combined organic extract was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude 6B (0.7 g, 80% yield). LCMS m / z [M+H]+= 202.2.

[0669]

[0373] Step 4. To amixture of 2A (300.0 mg, 1 Eq, 1.611 mmol) and 6B (391.0 mg, 1.2 Eq, 1.934 mmol) in DCM (3.0 mL) at 0 °C was added propylphosphonic anhydride (1.025 g, 948.6 qL, 2 Eq, 3.223 mmol) and DIPEA (624.8 mg, 842 qL, 3 Eq, 4.834 mmol). The reaction was stirred at ambient temperature for 16 h. Progress of the reaction was monitored by TLC. The reaction mixture was quenched with cold water (2 mL), and the compound was extracted with ethyl acetate (2 X 5 mL). The combined organic extract was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude. Crude product was purified by flash column chromatography on silica gel (eluted with 5% MeOH-DCM) to obtain desired product with 93% purity, which was further purified by prep HPLC to afford 23 (0.1 g, 16% yield) as white solid. Rt = 6.119 min., LCMS m / z M+H)+= 370.1, *H NMR (400 MHz, DMSO): 8 =12.82 (s, 1 H), 7.81 (dd, JI = 8.4 Hz, J2 = 1.6 Hz, 1 H), 7.40 - 7.35 (td, JI = 11.2 Hz, J2 = 2.4 Hz, 1 H), 3.61 - 3.37 (m, 6 H), 3.23 (s, 3 H), 3.09 - 3.02 (m, 1 H), 2.36 - 2.23 (m, 2 H), 2.10 - 2.04 (m, 1 H), 1.98 -1.88 (m, 1 H).

[0670]

[0374] Prep HPLC conditions:

[0671] Mobile phase (A): 0.1% Formic acid in water

[0672] Mobile phase (B):

[0673] ACN; Gradient (A: B): 0 / 20; 2 / 20;20 / 85’;21 / 20;

[0674] Flow rate: 18.0 mL / min

[0675] Column Name: Sunfire Cl 8;

[0676] Column Dimension: 250 mm x 20 mm x 5 pm;

[0677] Column No: 2024-08

[0678]

[0375] Analytical LCMS method conditions:

[0679] Mobile Phase (A): 0.1% Formic Acid in water

[0680] Mobile Phase (B): ACN

[0681] Gradient (T / %B): 0 / / 10, 3.8 / 10, 5 / 50, 8 / 70, 12 / 10, 15 / 10

[0682] Flow rate: 0.3 ml / min;

[0683] Column Name: BEH Cl 8

[0684] Column Dimension: 100 mm X 2.1 mm X 1.7 qm

[0685]

[0376] Example 31: -Synthesis of / V-(4.6-difluorobenzo[ |thiazol-2-yl)-6-oxo-l-(tetrahydro-2Z7-pyran-4-yl)piperidine-3 -carboxamide (Compound 24),

[0686]

[0687]

[0377] Step 1: The stirred solution of 6C (1.0 g, 1 eq, 6.488 mmol) and tctrahydro-2 / / -pyran-4-aminc (1.969 g, 3 eq, 19.47 mmol) in methanol (10.0 mL) was refluxed for 12 h. The reaction was monitored by TLC and LCMS. After completion of starting material, the reaction mass was cooled to room temperature. Reaction mixture was concentrated to get crude compound. The crude was purified by column chromatography using combi-flash product eluted at 30% ethyl acetate in heptane to afford 7D (0.850 g, 47 %, 85% purity) as a pale-yellow gummy. LCMS m / z [M+H]+= 238.2.

[0688]

[0378] Step 2: To a mixture of 7D (0.870 g, 1 eq, 3.67 mmol) in methanol (20.00 mL) was added Pd / C (780 mg, 50% Wt,). The reaction mixture applied H2(60 psi) for 16 h. The reaction monitored by LCMS and TLC. After, the reaction mixture was filtered through celite bed and washed with methanol (100 mL). The filtrate was concentrated and then purified by Combiflash column chromatography. The compound eluted at 5% methanol in DCM to afford 7E (0.700 g, 78 %, 98% Purity) as a pale yellow gummy compound. LCMS m / z [M+H]+= 242.1.

[0689]

[0379] Step 3: To a stirred solution of 7E (700.0 mg, 1 eq, 2.901 mmol) in THF (3 mL), water (3 mL) and methanol (1.5 mL) was added lithium hydroxide hydrate (365.2 mg, 3 eq, 8.703 mmol). Reaction was stirred at room temperature for 3h. Reaction mixture was concentrated, then acidified with IN HC1 (5 mL) and extracted with 10% MeOH in DCM (5 X 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford 7B (600.0 mg, 55 %, 60% purity) as a pale-yellow gum. LCMS m / z [M+H]+= 228.2.

[0690]

[0380] Step 4: To a stirred solution of 7B (0.400 g, 1 eq, 1.76 mmol) and 2A (328 mg, 1 eq, 1.76 mmol) in DCM (0.500 mL) was added / V-ethyl- / V-isopropylpropan-2-amine (227 mg, 307 pL. 1 eq, 1.76 mmol) and propylphosphonic anhydride (560 mg, 518 pL, 1 eq, 1.76 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with NaHCCf solution (10 mL) and extracted with DCM (10 mL, twice). The combined organic layers was dried over Na2SO4, filtered and the solvent was removed under reduced pressure to afford crude product. The crude material was purified by prep HPLC to afford 24 (65 mg, 9.2 %) as an off-white solid. Rt = 6.093 min. LCMS m / z [M+H]+= 396.2, 'H-NMR (DMSO-D6, 400MHz):

[0691] 8 12.78 (s, 1H), 7.80 (d, J= 8 Hz, 1H), 7.38 (t, J= 10.8 Hz, 1H), 4.51 (t, J= 12 Hz, 1H), 3.91 - 3.87 (m, 2H), 3.56 - 3.52 (m, 1H), 3.39 - 3.31 (m, 3H), 3.03 - 3.01 (m, 1H), 2.38 - 2.28 (m, 2H), 2.07 - 1.89 (m, 2H), 1.81 - 1.66 (m, 2H), 1.42 (br, 2H).

[0692]

[0381] Prep HPLC Condition:

[0693] Mobile phase (A): 0.1% Formic acid in water

[0694] Mobile phase (B) Acetonitrile

[0695] Gradient (T / %): 0 / 10 10 / 90 12 / 98 12.1 / 10 15 / 10

[0696] Flow rate: l. O mL / min

[0697] Column Name: Sunfire Cl 8

[0698]

[0382] Analytical LCMS method conditions:

[0699] Mobile Phase (A): 0.1% Formic Acid in water

[0700] Mobile Phase (B): ACN

[0701] Gradient (T / %B): 0 / / 10, 3.8 / 10, 5 / 50, 8 / 70, 12 / 10, 15 / 10

[0702] Flow rate: 0.3 ml / min;

[0703] Column Name: BEH Cl 8

[0704] Column Dimension: 100 mm X 2.1 mm X 1.7 pm

[0705]

[0383] Example 32: Synthesis of N-(4.6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-phenylpiperidine-3-carboxamide (Compound 25),

[0706]

[0707]

[0384] Step 1: To a solution of 8B (150 mg, 1.07 mmol) in DCM (6 mL) was added Ghosez reagent (285.94 mg, 2.14 mmol) and stirred for 30 min. A solution of 2A in THF (0.2 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 16 h. LCMS indicated that desired product was formed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ice cold water (2 mL) and extracted with DCM (2 X 5 mL). Organic extract was dried over Na^SO-i. filtered and then concentrated under reduced pressure to furnish its crude form. Crude product was purified by combi flash chromatography (eluted on 20% EtOAc - heptane) to obtain desired product with 90% purity, which was further purified by prep HPLC to afford 25 (136 mg, 33% yield) as white solid. Rt = 6.550 min., MS m / z [M+H]+= 388.1. ’H-NMR (400 MHz, DMSO-t / 6): 8 12.84 (s, 1 H), 7.81 (dd, JI = 8.4 Hz, J2 = 1.6 Hz, 1 H), 7.40 - 7.38 (m, 3 H), 7.32 - 7.30 (m, 2 H), 7.25 (m, 1 H), 3.91 - 3.88 (m, 2 H), 3.35 - 3.28 (m, 1 H), 2.51 - 2.48 (m, 2 H), 2.21 - 2.18 (m, 2 H).

[0708]

[0385] Prep HPLC Condition:

[0709] Mobile phase A: 5 mM Ammonium bicarbonate in Water

[0710] Mobile phase B: Acetonitrile

[0711] Gradient: 0 / 30; 2 / 30; 15 / 70, 18 / 90,18.2 / 99, 20 / 99; 20.2 / 30; 23 / 30,

[0712] Flow:18.0mL / min

[0713] Column Name: Sunfire Cl 8; Column

[0714] Dimension: 250 mm x 19 mm X 5u

[0715]

[0386] Analytical Conditions:

[0716] Mobile Phase (A): 0.1% Formic Acid in water

[0717] Mobile Phase (B): ACN

[0718] Gradient (T / %B): 0 / / 10, 3.8 / 10, 5 / 50, 8 / 70, 12 / 10, 15 / 10

[0719] Flow rate: 0.3 ml / min;

[0720] Column Name: BEH Cl 8

[0721] Column Dimension: 100 mm X 2.1 mm X 1.7 pm

[0722]

[0387] Example 33: Synthesis of N-(4.6-difluorobenzo[d1thiazol-2-yl)-l-isopropyl-6-oxopiperidine-3-carboxamide (Compound 26),

[0723]

[0724]

[0388] Step 1: To a stirred solution of 2A (250 mg, 1.34 mmol) in DCM (3 mL) at 0°C were added 9B (298 mg, 1.6 mmol), T3P (0.58 mL, 2.01 mmol), and DIPEA (0.68 mL). Reaction was stirred at RT for 16 h. LCMS indicated that desired product was formed. Reaction mixture was diluted with ice cold water (5 mL) and extracted with DCM (2 x 5 mL). Organic extract was dried over Na^ Th. filtered and concentrated under reduced pressure to furnish its crude form. Crude product was purified by combi flash chromatography (eluted on 70% EtOAc in heptane) to afford 26 (89.5 mg, 19% yield) as an off-white solid. Rt = 9.309 min., MS m / z [M+H]+= 352.1, ’H-NMR (400 MHz, DMSO- 6): 8 12.82 (s, 1 H), 7.81 (dd, JI = 8.0 Hz; J2 = 1.6 Hz, 1 H), 7.40 - 7.35 (m, 1 H), 4.74 - 4.64 (m, 1 H), 3.50 (dd, JI = 12.4 Hz; J2 = 4.8 Hz, 1 H), 3.34 - 3.29 (m, 1 H), 3.04 - 2.97 (m, 1 H), 2.38 - 2.23 (m, 2 H), 2.06 - 1.88 (m, 2 H), 2.11(t, J= 7.2 Hz, 6 H).

[0725]

[0389] Analytical Conditions:

[0726] Mobile Phase (A): 0.1% Ammonia in water

[0727] Mobile Phase (B): ACN

[0728] Gradient (T / %B): 0 / 2,4.0 / 2,6.0 / 2,8 / 50,12 / 80,13 / 2,15 / 2

[0729] Flow rate: 0.8 ml / min

[0730] Column Name: X-Bridge C18

[0731] Column Dimension: 100 mm X 4.6 mm X 3.5 pm

[0732] Column No: 2023-240

[0733] Sample in DMSO; Blank RT in PDA:7.8 to 8.5, 10.2 to 12.0

[0734]

[0390] Example 34: Synthesis of tert-butyl (lR.2R,5S)-2-(3-((4.6-difluorobenzo[d1thiazol-2-vDcarbamovDpiperidine-l-carbonvD-3-azabicvclo[3. L01hexane-3-carboxylate (Compound 29),

[0735]

[0736]

[0737]

[0391] To a vial charged with 4,6-difluorobenzo[d]thiazol-2-amine [CAS 119256-40-5] (500.0 mg, 1 Eq, 2.686 mmol) and l-(tert-butoxycarbonyl)piperidine-3 -carboxylic acid [CAS 84358-12-3] (677.3 mg, 1.1 Eq, 2.954 mmol), a 13.43 mL solution of HATU (1.123 g, 1.1 Eq, 2.954 mmol) in DMF was added, followed by N-methylmorpholine (814.9 mg, 886 pL, 3 Eq, 8.057 mmol). The reaction vial was shaken overnight at room temperature. The reaction was diluted with 50 mL ethyl acetate and 30 mL water. The organic layer was separated, concentrated down overnight under reduced pressure, and carried to the next step without further purification. The crude mixture was dissolved in 10 mL of a 10% TFA in DCM solution. The reaction vial was shaken at room temperature for an hour, concentrated under reduced pressure, and carried to the next step without further purification.

[0738]

[0739]

[0392] To a reaction vial containing (1R,2R, 5 S)-3-(tert-butoxycarbonyl)-3 -azabicyclo [3.1.0]hexane-2-carboxylic acid (10B) (9.08 mg, 40.00 pmol), a solution of N-(4,6-difluorobenzo[d]thiazol-2-yl)piperidine-3 -carboxamide (4A) (15.25 mg, 78% Wt, 40.00 pmol) in 200 uL of DMF, followed by a solution of HATU (16.73 mg, 44.00 pmol) in 200 uL of DMF, and N-methylmorpholine (13.2 pL, 120.0 pmol) were added. The reaction vials were shaken overnight at room temperature. A workup was performed using 3 mL of ethyl acetate and 2 mL of water. The organic layer was separated and concentrated under reduced pressure, diluted in DMSO, and purified by prep-HPLC eluting with acetonitrile in water (5-95%) containing 0.1% formic acid modifier to afford 27 (2.4 mg, 4.7 pmol). LCMS m / z [M+H]+= 507.3. ’H NMR (400 MHz, MeOD) 87.51 (ddt, J= 7.9, 3.6, 2.0 Hz, 1H), 7.07 (dddt, J = 10.7, 9.5, 2.5, 1.3 Hz, 1H), 4.79 - 4.66 (m, 1H), 4.65 - 4.41 (m, 1H), 4.28 (td, J= 34.6, 13.0 Hz, 1H), 4.07 (d, J= 14.7 Hz, 1H), 3.62 (ddt, J= 10.1, 6.1, 3.6 Hz, 1H), 3.57 - 3.46 (m, 1H), 3.25 - 2.95 (m, 1H), 2.95 - 2.61 (m, 1H), 2.25 - 2.08 (m, 1H), 2.05 - 1.76 (m, 2H), 1.74 - 1.48 (m, 3H), 1.47 - 1.39 (m, 7H), 1.37 (d, J = 3.3 Hz, 2H), 0.84 (dt, J= 9.2, 5.1 Hz, 1H), 0.33 (dt, J= 12.8, 4.5 Hz, 1H).

[0740]

[0393] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0741] Table 17

[0742]

[0743]

[0744]

[0394] LC / MS method description:

[0745] Conditions: 2-98% B

[0746] Flow Rate: 1 mL / min

[0747] Temperature: 40 °C

[0748] Column: Waters BEH C18 2.1x50 mm 1.7 μm

[0749] Gradient - Solvent A: Water with 0.1% Formic Acid

[0750] Solvent B: Acetonitrile with 0.1% Formic Acid

[0751]

[0395] Example 35: Synthesis of N-(4.6-difluoro-lH-benzo[d1imidazol-2-yl)-6-oxo-l-phenylpiperidine- 3-carboxamide (Compound 32)

[0752]

[0753]

[0396] To a stirred solution of 4,6-difluoro-lH-benzo[d]imidazol-2-amine (3A) (350 mg, 1 Eq, 2.1 mmol) and 6-oxo-l-phenylpiperidine-3-carboxylic acid (8B) (544 mg, 1.2 Eq, 2.48 mmol) in DMF (20 mL) was added with l-(3-Dimethylaminopropyl)-3-ethylcarbodiimideHydrochloride (EDC.HCl) (595 mg, 1.5 Eq, 3.1 mmol), 1-Hydroxy-1H-benzotriazole (363 mg, 370 μL, 1.3 Eq, 2.69 mmol) and Diisopropylethylamine (802 mg, 1.07 mL, 3 Eq, 6.2 mmol). The reaction was allowed to stir for at room temperature 3 hours. Progress of the reaction monitored by TLC and LCMS. LCMS indicated that desired product was formed. Reaction mixture is diluted with ice cold water (40 mL) and washed with ethyl acetate twice (2 x 40 mL). Combined organic layers are dried over sodium sulfate and concentrated using reduced vacuum to afford brown solid, the crude product is further purified using combiflash column (0 - 10 % MeOH in DCM, eluting at 6 % MeOH in DCM), to afford N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-phenylpiperidine-3-carboxamide (8C) (520 mg, 1.4 mmol, 67.8% Yield) brown solid. 8C was further separated using chiral prep HPLC. Peak 2 at 3.243min as collected and concentrated as brown solid (32) (135.5mg, 361.2 pmol, 17.5% yield). MS m / z [M+H]+= 371.201H-NMR (400 MHz, DMSO-6): 8 12.46 (s, 1H), 11.90 (s, 1H), 7.37 - 7.41 (m, 2H), 7.30 (d, J = 7.6 Hz, 2H), 7.25 (t, J = 7.2Hz, 1H), 7.10 - 7.12 (m, 1H), 6.92 - 6.98 (m, 1H), 3.87 (d, J = 6.4 Hz, 2H), 3.19 - 3.26 (m, 1H), 2.49 - 2.50 (m, 2H), 2.11 - 2.24 (m, 2H)

[0754]

[0397] Example 36: Synthesis of N-(4.6-difluoro-lH-benzo[d]imidazol-2-yl)-l-isopropyl-6-oxopiperidine-3 -carboxamide (Compound 33)

[0755]

[0756]

[0398] To a mixture of 4,6-difluoro-lH-benzo[d]imidazol-2-amine (3A) (400 mg, 1 Eq, 2.36 mmol) and l-isopropyl-6-oxopiperidine-3 -carboxylic acid (9B) (525 mg, 1.2 Eq, 2.8 mmol)

[0757] in DMF (3 mL) at 0 °C was added 1-Hydroxy-1H-benzotriazole (HOBt) (639 mg, 650 μL, 2 Eq, 4.73 mmol), l-(3-Dimethylaminopropyl)-3-ethylcarbodiimideHydrochloride (EDCI) (906 mg, 2 Eq, 4.73 mmol), and DIPEA (917 mg, 1.2 mL, 3 Eq, 7.1 mmol). The reaction was stirred at 50 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. LCMS indicated that desired product was formed. Reaction mixture was quenched with cold water (2 mL), and extracted with DCM (2 X 5 mL). Combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude. The crude was purified by prep HPLC by using below mentioned prep conditions, collected fractions were concentrated to afford N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-l-isopropyl-6-oxopiperidine-3 -carboxamide (33) (40 mg, 5% yield) as white solid. MS m / z [M+H]+= 337.1 'H NMR (400 MHz, DMSO): 8 -12.41 (s, 1 H). 11.91 (s, 1 H), 7.12 (dd. JI - 8.4 Hz. J2 - 1.6 Hz, 1 H). 6.98 - 6.93 (m, 1 H), 4.73 - 4.64 (m, 1 H), 3.61 - 3.29 (m, 2 H),2.98 - 2.96 (m, 1 H), 2.38 - 2.22 (m, 2 H), 2.02 -1.89 (, 2 H), 1.06 - 1.03 (m„ 6 H).

[0758]

[0399] Prep HPLC conditions:- Mobile phase (A):0.1% Formic acid in water

[0759] Mobile phase (B ): Acetonitrile

[0760] Gradient(T / %):0 / 20; 2 / 20; 20 / 70; 21 / 99

[0761] Flow rate: 18 mL / min

[0762] Column Details:

[0763] Column Name: Sunfire Cl 8

[0764] Column Dimension: 250 mm x 19 mm x 5 pm

[0765] Column No: 2024-08

[0766] [4091 Example 37: Synthesis of Step-4: N-(4.6-difluoro-lH-benzold]imidazol-2-yl)-6-oxo-l-(pentan-3-yl)piperidine-3 -carboxamide (Compound 34):

[0767]

[0768]

[0401] Step-1: A solution of methyl 2-oxo-2H-pyran-5-carboxylate (6C) (1 g, 6.49 mmol), pentan-3-amine (11D) (1.7 g, 2.3 mL, 19.5 mmol) in Methanol (10 mL) was heated to 70°C for 16 h. The progress of the reaction was monitored by TLC (7:3 Ethyl acetate: Hexane, SM material was completed) and LC-MS. After the completion of the reaction, reaction mixture was quenched with ice-cold water (100 mL). Aqueous layer was extracted with ethyl acetate (2 X 100 mL) and combine organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The crude was purified by MPLC (using gradient elution of 0-70% of ethyl acetate in heptane) to afford title compound (700 mg, 3.135 mmol, 48.3 %) as dark yellow liquid. [M+H]+m / z = 224.2

[0402] Step-2: To a stirred solution methyl 6-oxo-1-(pentan-3-yl)-1,6-dihydropyridine-3-carboxylate (11E) (0.7 g, 3.14 mmol) in Methanol (5 mL), Pd / C (334 mg, 3.14 mmol) was added at room temperature. Resultant mixture was kept under Hydrogen atmosphere at 50-PSI pressure and heated to 80 °C in Parr Shaker for 16 h. Progress of the reaction was monitored by TLC (1:9 Methanol: DCM, SM material was completed) and LC-MS. After the completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite bed. Celite bed was further washed with MeOH and combine filtrate was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude was taken for next step (350 mg) without further purification. [M+H]+m / z = 228.0

[0769]

[0403] Step-3: To a stirred solution methyl 6-oxo-1-(pentan-3-yl)piperidine-3-carboxylate (11F) (350 mg, 1.54 mmol) in THF (2 mL), Water (2 mL) and Methanol (2 mL), LiOH (40 mg, 1.5 mmol) was added at 0 °C. Reaction mixture was allowed to warm upto room temperature and stirred for additional 2 h. Progress of the reaction was monitored by TLC (1:9 Methanol: DCM, SM material was completed) and LC-MS. After the completion of the reaction, the reaction mixture was neutralized with 2M HC1 solution until pH 7 (on pH paper). Resultant aqueous layer was extracted with 10% MeOH in DCM (2 X 50 mL). Combine organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude. Crude was taken for next step without further purification (11B) (150 mg). [M+H]+ m / z = 214.1

[0770]

[0404] Step-4: To a stirred solution of 4,6-difluoro-1H-benzo[d]imidazol-2-amine (3A) (150 mg, 886.9 pmol), 6-oxo- 1 -(pentan -3 -yl)piperidine-3 -carboxylic acid (227 mg, 1.064 mmol) in DMF (1 mL), 1-Hydroxy-lH-benzotriazole (179 mg, 1.33 mmol) and l-(3-Dimethylaminopropyl)-3-ethylcarbodiimideHydrochloride (EDCI) (306 mg, 1.6 mmol) were added. Resultant mixture was heated at 100 °C and stirred for 12 h. Progress of the reaction was monitored by LCMS and TLC (1:9 Methanol: DCM, SM material was completed). After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with ice-cold water (100 mL). Aqueous layer was extracted with ethyl acetate (2 X 100 mL) and combine organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Crude was further purified using MPLC (using gradient elution of 0-100% of ethyl acetate in heptane) to afford 70 mg of title compound with 85% purity. The compound was further purified by preparative-HPLC using below mentioned condition to afford title compound (34) (4 mg, 27.1 pmol, 1.2 %, 99.4% Purity) as an off-white solid. [M+H]+m / z = 365.11H NMR (400 MHz, DMSO-d6): 6 12.361 (s, 2H), 7.12 (d, J= 7.6 Hz, 1H), 6.97-6.92 (t, J =10.4 Hz 1H), 4.35-4.31 (m, 1H), 3.22-3.170 (m, 2H), 2.99 (s, 1H), 2.44-2.36 (m, 1H), 2.33-2.08 (m, 1H), 2.07-1.96 (m, 2H), 1.57-1.38 (m, 4H), 0.85-0.73 (m, 6H).

[0771]

[0405] Preparative HPLC Method:

[0772] Column Name: X-Bridge C18 Mobile phase (A): 0.1% Ammonia in Water

[0773] Mobile phase (B): Acetonitrile

[0774] Gradient: 0 / 20,5 / 90,7 / 98,8 / 98,8.5 / 20,10 / 20

[0775] Flow rate: 1.0 mL / min

[0776] Retention time: 4.32, 85 %

[0777] After purification, fraction were collected and lyophilized.

[0778]

[0406] Example 38: Synthesis of N-(4.7-difluorobenzo[d1thiazol-2-yl)-l,9-dioxaspiro[5.51undecane-4-carboxamide (Compound 35)

[0779]

[0780]

[0407] To a mixture of 4,7-difluorobenzo[d]thiazol-2-amine (5A) (61.9 mg, 1 Eq, 333 μmol) and 1,9-dioxaspiro[5.5]undecane-4-carboxylic acid (1B) (80 mg, 1.2 Eq, 399 μmol) in pyridine (5.0 mL) was added POCl3 (51.0 mg, 0.031 mL, 1 Eq, 333 μmol). The reaction was stirred at 25 °C for 3 hours.

[0781] LCMS indicated that desired product was formed. The reaction was quenched by adding ice-cold water (15 mL) and extracted with ethyl acetate (3 X 20 mL). Combined organic extract was dried over sodium sulfate and concentrated under reduced pressure to furnish crude product. The crude product was purified on an ISCO (heptane / EtOAc = 70:30 to 60:40; 40 g SiO2) to obtain N-(4,7-difluorobenzo[d]thiazol-2-yl)-1,9-dioxaspiro[5.5]undecane-4-carboxamide (35) (89.5 mg, 242 μmol, 72.7 %, 99.7% Purity) as a white powder. (M+H)+m / z: = 369.1. 'H-NMR (400 MHz, DMSO-d6): 6 12.92 (s, 1H), 7.34 (dd, J = 4.00, 9.80 Hz, 1H), 7.22 (dd, J = 3.20, 8.80 Hz, 1H), 3.75-3.71 (m, 1H), 3.67-3.50 (m, 5H), 3.00 (t, J = 3.60 Hz, 1H), 1.94 (q, J = 13.20 Hz, 2H), 1.76 (d, J = 12.00 Hz, 1H), 1.64-1.53 (m, 3H), 1.41 (q, J = 12.80 Hz, 2H)

[0782]

[0408] Example 39: Synthesis of N-(4.6-difluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide (Compound 36)

[0783]

[0784]

[0409] To a stirred solution of 6-oxo-1-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxylic acid (7B) (200 mg, 0.88 mmol) and 4,6-difluoro-1H-benzo[d]imidazol-2-amine (3A) (149 mg, 0.88 mmol) in DMF (10 mL) was added Triethylamine (0.37 mL, 2.64 mmol), 1-Hydroxy-1H-benzotriazole (178 mg, 1.32 mmol) and l-(3-Dimethylaminopropyl)-3-ethylcarbodiimideHydrochloride (EDCI) (304 mg, 1.58 mmol). Reaction mixture was heated to 100 °C and stirred for 16 hours. LCMS indicated formation of desired product. Reaction mixture was diluted with ethyl acetate (10 mL), washed with water (20 mL), and brine solution (20 mL). Organic layer was separated, dried over anhydrous sodium sulphate, filtered and evaporated under reduce pressure to obtain crude. Crude was further purified by flash column chromatography on silica gel using 0%-100% ethyl acetate in n-heptane as eluent. The fractions were collected and concentrated under reduce pressure to obtain 200 mg of the racemic compound in 60% purity. The racemic compound obtained was further purified by preparative HPLC condition using below condition:

[0785]

[0410] Column: X-bridge C18 column (250 mm x 19 mm x 5 pm)

[0786] Mobile phase (A): 0.1% Ammonia in Water

[0787] Mobile phase (B): ACN

[0788] Gradient condition (A: B): 0 / 20; 02 / 20; 17 / 50;; 17.1 / 98 19 / 98

[0789] Flow rate: 18.0 mL / min.

[0790]

[0411] Pure fractions were collected and lyophilized to obtain 50 mg of racemic compound (racemic).

[0791]

[0412] The racemic compound was further purified using chiral preparative HPLC technique using condition described later. Peak-2 was collected with 30 mg, with achiral purity 77.4%.

[0792]

[0413] Column: CHIRALPAK IG (250 mm x 21 mm x 5 pm)

[0793] Mobile phase (A): n-Hexane

[0794] Mobile phase (B): IPA with 0.1% DEA

[0795] Isocratic (A: B): 50:50

[0796] Flow rate: 18.0 mL / min.

[0797]

[0414] Peak-2 was again purified achirally by following preparative HPLC condition

[0798]

[0415] Column: X-bridge Cl 8 (250 mm x 19 mm x 5 pm)

[0799] Mobile phase (A): 0.1%Formic acid in water

[0800] Mobile phase (B): CAN

[0801] Gradient condition (A: B): 0 / 30; 02 / 30; 16 / 70 16.1 / 98 18 / 98

[0802] Flow rate: 18.0 mL / min.

[0803]

[0416] Pure fractions were collected and lyophilized to obtain Peak-2 (36) (7 mg, 2% yield) as white solids. [M+H]+m / z = 379.3.1H NMR (400 MHz, DMSO-d6): 8 12.42 (s, 1H), 11.84 (s, 1H), 7.11 (dd, JI = 4.0 Hz, J2= 8.0 Hz, 1H), 6.98-6.93 (m, 1H), 4.55-4.49 (m, 1H), 3.93-3.86 (m, 2H), 3.53-3.49 (m, 1H), 3.39-3.34 (m, 3H), 3.00-2.98 (m, 1H), 2.36-2.30 (m, 2H), 2.01-1.96 (m, 2H), 1.78-1.70 (m, 2H), 1.46-1.40 (m, 2H).

[0804]

[0417] Example 40: Synthesis of N-(4-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide (Compound 37, Compound 37a, Compound 37b, Compound 37c, Compound 37d.

[0805]

[0806]

[0418] Step 7: 7V-(4-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide (3)(compound 37)

[0807]

[0419] To a stirred solution of Intermediate 11 (2.0 g, 1 Eq, 10.78 mmol) in DMF (20.0 mL) at room temperature was added Intermediate 15 (2.41 g, 1.2 Eq, 12.93 mmol) and allowed to stir for 5 min. To this reaction mixture 1 -(3 -Dim ethylaminopropyl)-3 -ethylcarbodiimide Hydrochloride (EDC.HCl) (3.1 g, 1.5 Eq, 16.16 mmol), 1 -Hydroxybenzotriazole - hydrate (2.15 g, 1.3 Eq, 14.01 mmol) and DIPEA (4.18 g, 5.63 mL, 3 Eq, 32.33 mmol) were added and allowed to stir for 16 h at 100 °C. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction. The reaction mixture was diluted with ice-cold water (200 mL) and extracted with ethyl acetate (2 X 200 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure using rotavapor to get (2.68 g of crude). The crude was purified by combiflash flash using eluent: 0 - 20% MeOH / DCM = 05:95 to 10:90; a 40 g NCC column via 100-200 mesh silica to obtain 7V-(4-chloro-6-fluoro-lH- benzo[d]imidazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide 37 (1.35 g mixture of 4 isomers). The diastereomeric mixture 37 was subjected to chiral HPLC separation using Method-Cl 1. Four peaks separated were collected, organic solvent was distilled under vacuum and lyophilized separately using ACN and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, respectively:

[0808]

[0420] Analytical characterization of compound 37a (Peak 1):

[0809]

[0421] (231.0 mg, 6.05% yield, 99.95% Purity) as an off-white. Solid. MS (m / z) [M+H]+= 354.2, Rt = 6.46 min., [Method-L28],1HNMR (400 MHz, DMSO-6) 8 12.43 (s, 1H), 11.90 (s, 1H), 7.21 (dd, J= 2.4 Hz, 8.8 Hz, 1H), 7.14 (dd, J= 2.4 Hz, 10.4 Hz, 1H), 3.85 - 3.75 (m, 3H), 3.61 - 3.46 (m, 3H), 2.87 -2.81 (m, 1H), 2.17 - 2.11 (m, 1H), 1.88 - 1.81 (m, 2H), 1.75 - 1.72 (m, 1H), 1.67 - 1.57 (m, 2H). [a]D25-27.0 (c = 0.03333 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0810]

[0422] Analytical characterization of compound 37b (Peak 2)

[0811]

[0423] (221.0 mg, 5.79% yield, 99.95% Purity, 98.11% chiral purity) as an off-white solid. MS (m / z) [M+H]+= 354.2, Rt = 6.468 min. [Method- L28],1HNMR (400 MHz, DMSO-6) 8 12.43 (s, 1H), 11.90 (s, 1H), 7.21 (dd, J= 2.4 Hz, 8.8 Hz, 1H), 7.14 (dd, J= 2.4 Hz, 10.4 Hz, 1H), 3.85 - 3.75 (m, 3H), 3.61 - 3.46 (m, 3H), 2.87 - 2.81 (m, 1H), 2.17 - 2.11 (m, 1H), 1.88 - 1.81 (m, 2H), 1.75 - 1.72 (m, 1H), 1.67 - 1.57 (m, 2H). [α]D25+33.0 (c = 0.03333 g / 100mL, methanol). Absolute stereochemistry unknown.

[0812]

[0424] Analytical characterization of compound 37c (Peak 3)

[0813] (221.0 mg, 3.17% yield, 99.96% Purity, 98.03 % chiral purity) as an off-white solid. MS (m / z) [M+H]+= 354.2, Rt = 6.49 min., Purity 99.96 % [Method- L28], ’H NMR (400 MHz, DMSO-O 8 12.43 (s, 1H), II.88 (s, 1H), 7.23 - 7.20 (m,lH), 7.14 (dd, J= 2.4 Hz, 10 Hz, 1H), 3.94 - 3.91 (m, 1H), 3.82 - 3.71 (m, 3H), 3.46 - 3.59 (m, 2H), 2.65 - 2.71 (m, 1H), 1.59-1.93 (m, 6H). [a]D25-9.0 (c = 0.03333 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0814]

[0425] Analytical characterization of compound 37d (Peak 4)

[0815]

[0426] (147.0 mg, 3.85% yield, 99.88% Purity, 98.38% chiral purity) as an off-white solid. MS (m / z) [M+H]+= 354.2, Rt = 6.500 min., Purity 99.88% [Method- L28], ’H NMR (400 MHz, DMSO-O 8 12.43 (s, 1H), 11.88 (s, 1H), 7.23 - 7.20 (m, 1H), 7.14 (dd, Jl= 2.4 Hz, 10.4 Hz, 1H), 3.94 - 3.91 (m, 1H), 3.82 -3.71 (m, 3H), 3.59 - 3.50 (m, 2H), 2.71 - 2.61 (m, 1H), 1.93-1.65 (m, 6H). [a]D25+21.003 (c = 0.03333 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0816]

[0427] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates. Table 18

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0428] Example 41: Synthesis of N-(7-chlorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide (Compound 45, Compound 45a, Compound 45b, Compound 45c, Compound 45d.

[0829]

[0830]

[0429] Step 7: A-(7-chlorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide (Compound 45)

[0831]

[0430] To a stirred solution of 7-chlorobenzo[d]thiazol-2-amine (1.0 g, 5.41 mmol), Intermediate 15 (1.11 g, 5.95 mmol) in DMF (10.0 m ) were added DIPEA (2.8 mL, 16.25 mmol), HBTU (3.08 g, 1.5 Eq, 8.12 mmol) at 25 °C and stirred at 100 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 X 75 mL). The combined organic layers were washed with ice-cold water (2 X 20 mL) and brine (20 mL). The organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure using rotavpour to get the crude mixture (2.5 g). The crude mixture was purified by combiflash purifier using 80 g NCC column via 100-200 mesh silica gel and the desired product was eluted between 70% to 75% ethyl acetate in hexane. The pure fraction was concentrated under reduced pressure using rotavapor to get the product 45 (1.8 g, contains fluorine impurity generated from HBTU reagent). Then the product was dissolved in ethyl acetate (150 mL) and washed with water (10 x 20 mL) to remove this fluorine impurity. The ethyl acetate layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to get the 45 N-(7-chlorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide (1.5 g, diastereomeric mixture). The diastereomeric racemic 45 was subjected to chiral HPLC separation using Method-C15. Four peaks separated were collected, organic solvent was distilled under vacuum and lyophilized separately using ACN and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, respectively:

[0832]

[0431] Analytical characterization of Compound 45a (Peak-1)

[0432] 0.260 g 13.59% yield, 99.85% purity, 99.94 % ee) as an off-white solid. MS (m / z) [M+H]+= 353.0; Rt = 6.689 min. [Method-L29],1H NMR(400 MHz, DMSO-6) 8 12.62 (s, 1H), 7.71 (d, J= 7.6 Hz, 1H), 7.47 (t, J= 8 Hz, 1H), 7.40 (d, J= 7.20 Hz, 1H), 3.85-3.74 (m, 3H), 3.61-3.31 (m, 3H), 2.95-2.89 (m, 1H), 2.19-2.12 (m, 1H), 1.90-1.75 (m, 3H), 1.67-1.56 (m, 2H). [a]D25-48.606 (c = 0.03333 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0833]

[0433] Analytical characterization of Compound 45b (Peak-2)

[0834]

[0434] 0.235 mg 12.28% yield, 99.93% purity, 99.88 % ee) as an off-white solid. MS (m / z) [M+H]+= 353.1, Rt = 6.67 min. [Method-L29],1HNMR(400 MHz, DMSO-d6) δ 12.62 (s, 1H), 7.72 (d, J= 4.4 Hz, 1H), 7.47 (t, J= 8 Hz, 1H), 7.40 (d, J= 7.60 Hz, 1H), 3.85-3.77 (m, 3H), 3.61-3.46 (m, 3H), 2.96-2.90 (m, 1H), 2.18-2.12 (m, 1H), 1.86-1.75 (m, 3H), 1.67-1.58 (m, 2H). [a]D25+103.81 (c = 0.03333 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0835]

[0435] Analytical characterization of Compound 45c (Peak-3)

[0836]

[0436] 0.150 g, 7.83% yield, 99.87% purity, 99.66 % ee) as an off-white solid. MS (m / z) [M+H]+= 353.1, Rt= 6.758 min. [Method-L29],1HNMR(400 MHz, DMSO-d6) δ 12.60 (s, 1H), 7.71 (d, J= 7.6 Hz, 1H), 7.47 (t, J= 8 Hz, 1H), 7.40 (d, J= 7.20 Hz, 1H), 3.94-3.92 (m, 1H), 3.82-3.71 (m, 3H), 3.59-3.48 (m, 2H), 2.79-2.72 (m, 1H), 1.95-1.59 (m, 6H). [a]D25+99.613 (c = 0.03333 g / lOOmL, methanol).

[0837] Absolute stereochemistry unknown.

[0838]

[0437] Analytical characterization of Compound 45d (Peak-4)

[0839]

[0438] 0.060 g, 3.13% yield, 99% purity, 99.22 % ee) as an off-white solid. MS (m / z) [+H]+= 353.0, Rt = 9.204 min. [Method-L8],1HNMR(400 MHz, DMSO-d6) δ 12.60 (s, 1H), 7.72 (d, J= 7.6Hz, 1H), 7.40-7.49 (m, 2H), 3.92-3.94 (d, J= 9.6Hz, 1H), 3.71-3.81 (m, 3H), 3.48-3.60 (m, 2H), 2.74-2.80 (m, 1H), 1.65-1.95 (m, 6H). [α]D25-45.00 (c = 0.03333 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0840]

[0439] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0841] Table 19

[0842]

[0843]

[0844]

[0440] Example 42: Synthesis of A-(4-chloro-6-fluorobenzo[d1thiazol-2-yl)-2,6-dioxaspiro[4.51decane-9-carboxamide (Compound 46, Compound 46a. Compound 46b. Compound 46c, Compound 46d.

[0845]

[0846] (Peak-3) {Peak-4)

[0847]

[0441] Step-01: A-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide 3 (Compound 46)

[0848]

[0442] To a stirred solution of Intermediate 1 (1.0 g, 1 Eq, 4.93 mmol), Intermediate 15 (1.01 g, 1.1 Eq, 5.42 mmol) in pyridine (15.00 mL) was added POCI3 (0.91 g, 545.7 pL, 1.2 Eq, 5.92 mmol) at 0 °C. The reaction mixture was stirred for Ih at 0 °C. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution (100 mL) extracted with ethyl acetate (2 X 75 mL) and washed with brine solution (50 mL). The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to get crude residue (2.1 g). The crude residue was purified by combiflash column chromatography using 40 g NCC column via 100-200 mesh silica and eluents: heptane / EtOAc = 70:30 to 65:35 and to afford diastereomeric mixture of 46, A-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide (1.5 g diastereomeric mixture).

[0849]

[0443] The diastereomeric mixture 46 were further separated by Chiral HPLC using Method-C49, which separated only two fractions. These two fractions were concentrated and further subjected to chiral HPLC separation using Method-C49 to get four peaks. Four peaks separated were collected, organic solvent was distilled under vacuum and lyophilized separately using ACN and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, respectively:

[0850]

[0444] Analytical characterization of Compound 46a (Peak-1)

[0851]

[0445] 90.00 mg, 4.89 % yield, 99.50% purity, 99.93 % ee. MS (m / z) [M+H]+= 371.0, Rt = 6.570 min.

[0852] [Method-L29]1HNMR(400 MHz, DMSO-d6) δ 12.80 (s, 1H), 7.93 (dd, J= 2.4 Hz, 8.4 Hz 1H), 7.53 (dd, J = 2.4 Hz, 8.8 Hz 1H), 3.75-3.80 (m, 3H), 3.47-3.61 (m, 3H), 2.88-2.95 (m, IH), 2.11-2.18 (m, IH), 1.83-1.90 (m, 2H), 1.74-1.77 (m, 1H), 1.57-1.68 (m, 2H). [a]D25+81.00 (c = 0.03333 g / lOOmL, methanol) Absolute stereochemistry unknown.

[0853]

[0446] Analytical characterization of Compound 46b (Peak-2)

[0854]

[0447] 75.00 mg, 4.09% yield. MS (m / z) [M+H]+= 370.9, Rt= 6.585 min. [Method-L29], ‘H NMR(400 MHz, DMSO-O 8 12.80 (s, 1H), 7.93 (dd, J = 2.4 Hz, 8.4 Hz 1H), 7.55 (dd, J = 2.4 Hz, 9.2 Hz 1H), 3.74-3.85 (m, 3H), 3.46-3.60 (m, 3H), 2.88-2.94 (m, 1H), 2.11-2.17 (m, 1H), 1.82-1.89 (m, 2H), 1.73-1.76 (m, 1H), 1.56-1.66 (m, 2H). [a]D25-69.002 (c = 0.03333 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0855]

[0448] Analytical characterization of Compound 46c (Peak-3)

[0856]

[0449] 130.0 mg, 7.07% yield. MS (m / z) [M+H]+= 371.1, Rt = 6.695 min. [Method-L17]. ‘H NMR(400 MHz, DMSO-d6): δ 12.79 (s, 1H), 7.93 (dd, J = 2.4 Hz, 8.4 Hz 1H), 7.56 (dd, J = 2.8 Hz, 9.2 Hz 1H), 3.92 (d, J = 9.6 Hz, 1H), 3.71-3.82 (m, 3H), 3.58-3.60 (d, J = 9.6 Hz, 1H), 3.47-3.53 (m, 1H), 2.72-2.78 (m, 1H), 1.61-1.92 (m, 6H). [α]D25+28.20 (c = 0.03333 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0857]

[0450] Analytical characterization of Compound 46d (Peak-4)

[0858]

[0451] 95.00 mg, 5.18 % yield. MS (m / z) [M+H]+= 370.9, Rt = 6.695 min. [Method-L17], ‘H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 7.93 (dd, J= 2.0 Hz, 8.4 Hz 1H), 7.56 (dd, J= 1.6 Hz, 8.8 Hz 1H), 3.92 (d, J= 9.6 Hz, 1H), 3.71-3.81 (m, 3H), 3.58 (d, J= 9.6 Hz, 1H), 3.47-3.53 (m, 1H), 2.71-2.77 (m, 1H), 1.58-1.95 (m, 6H). [α]D25-18.00 (c = 0.03333 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0859]

[0452] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0860] Table 20

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0453] Example 43: Synthesis of N-(7-chloro-4-methylbenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide (Compound 62)

[0895]

[0896]

[0454] Step 1: N-(7-chloro-4-methylbenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide, Compound 62

[0897]

[0455] To a stirred solution of 7-chloro-4-methylbenzo[d]thiazol-2-amine (533.5 mg, 1 Eq, 2.68 mmol), Intermediate 15 (500.0 mg, 1 Eq, 2.68 mmol) in DCM (10.00 mL) at 25 °C were added triethylamine (271.7 mg, 374 pL. 1 Eq, 2.68 mmol) and propylphosphonic anhydride (854.4 mg, 790.3 pL, 50% Wt, 1 Eq, 2.68 mmol). The reaction mixture was allowed to stir at 25 °C for 40 h. Reaction was monitored by TLC & LCMS. The reaction mixture was evaporated under reduced pressure using rotavapor and the residue diluted with water (20 mL) and extracted with 10%MeOH in DCM (3 X 30mL). Combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure using rotavour to yield crude. The residue was purified by combi flash column chromatography on silica gel (eluent: heptane / EtOAc = 60:40 to 50:50; a 40 g NCC using a 25 g solid cartridge). The crude diastereomeric compound 62 (300 mg) was further purified by prep-HPLC using Method-H7.

[0898]

[0456] Fractions were collected, organic solvent was distilled under vacuum and lyophilized separately using ACN and water to yield 61, Diastereomeric mixture) (143.0 mg, 387.8 pmol, 14.44 %, 99.48% Purity) as a white solid. MS (m / z) [M + H]+= 367.1, Rt = 7.060 and 7.117 min. (Two peaks with same mass) [Method-L28]. ’H NMR(400 MHz, DMSO-6) 8 12.68 (s, 1H), 7.29 (s, 2H), 3.83-3.71 (m, 3H), 3.60-3.46 (m, 3H), 2.95-2.67 (m, 1H), 2.54 (s, 3H), 1.88-1.63 (m, 6H).

[0899]

[0457] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0900]

[0458] Table 21:

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0459] Example 44: Synthesis of N-(4-chlorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide (Compound 63, Compound 63a. Compound 63b. Compound 63c, Compound 63d).

[0913]

[0914] Peak-3 Peak-4

[0915]

[0460] Step 1: N-(4-chlorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide (Compound 63)

[0916]

[0461] To a stirred solution of Intermediate 15 (500.0 mg, 1 Eq, 2.68 mmol) and 4-chlorobenzo[d]thiazol-2-amine (594.1 mg, 1.2 Eq, 3.22 mmol) in DMF (5.00 mL) were added TFFH (709.23 mg, 1 Eq, 2.68 mmol) and DIPEA (347.05 mg, 468 μL. 1 Eq, 2.68 mmol) and stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction. The reaction mixture diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to get crude (0.8 g). The crude was Purified by combiflash purifier (70% EA: Heptane and a 40 g NCC using a 25 g solid cartridge) to get as diastereomeric mixture 63 (600 mg) as an off white solid. The diastereomeric compound 63 was subjected to chiral HPLC separation using Method-C49. Four peaks separated were collected, organic solvent was distilled under vacuum and lyophilized separately using ACN and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, respectively:

[0917]

[0462] Analytical characterization of Compound 63a (Peak-1)

[0918]

[0463] 50.00 mg, 5.27 % yield, 99.79% Purity. MS (m / z) [M+H]+= 353.0, Rt = 8.90 min. [Method-L10], ‘HNMR (400 MHz, DMSO d&) 8 12.79 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.53 (d, J= 7.6 Hz, 1H), 7.30 (t, J= 7.8 Hz, 1H), 3.85-3.78 (m, 3H), 3.57 (t, J= 9.6 Hz, 1H), 3.47 (d, J = 9.4 Hz, 1H), 2.94-2.89 (m, 1H), 2.16-2.12 (m, 1H), 1.88-1.83 (m, 2H), 1.76 (d, J = 12.5 Hz, 1H), 1.63 (t, J = 12.3 Hz, 2H). [a]D25+24.00 (c = 0.08333 g / 100mL, methanol). Absolute stereochemistry unknown.

[0919]

[0464] Analytical characterization of Compound 63b (Peak-2)

[0920]

[0465] 61.00 mg, 6.41 yield %, 99.62% Purity. MS (m / z) [M+H]+= 353.0, Rt = 9.00 min. Method-L10. ‘HNMR (400 MHz, DMSO d&) 8 12.78 (s, 1H), 7.96 (d, J =5.2 Hz, 1H), 7.53 (d, J = 8 Hz, 1H), 7.30 (t, J = 7.60 Hz, 1H), 3.92 (d, J =9.2 Hz, 1H), 3.80 (dd, J = 3.20, 12.00 Hz, 1H), 3.73 (t, J = 6.00 Hz, 2H), 3.60 (d, J = 9.69 Hz, 1H), 3.50 (dt, J= 2.40, 16.53 Hz, 1H), 2.78-2.72 (m, 1H), 1.96-1.82 (m, 3H), 1.77-1.62 (m, 3H). [α]D25+8.57.00 (c = 0.0466 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0921]

[0466] Analytical characterization of Compound 63c (Peak-3)

[0922]

[0467] 85.00 mg, 8.83 % yield, 98.51% Purity. MS (m / z) [M+H]+= 353.1, Rt= 6.56 min. Method-L17. ‘HNMR (400 MHz, DMSO d6. 8 12.78 (s, 1H), 7.97 (dd, J= 1.20, 8.00 Hz, 1H), 7.53 (dd, J= 1.20, 7.80 Hz, 1H), 7.30 (t, J= 7.60 Hz, 1H), 3.93 (d, J = 9.60 Hz, 1H), 3.82-3.78 (m, 1H), 3.73 (q, J = 5.60 Hz, 2H), 3.60 (d, J = 9.60 Hz, 1H), 3.51 (dt, J = 2.80, 16.93 Hz, 1H), 2.78-2.72 (m, 1H), 1.93-1.83 (m, 3H), 1.78-1.65 (m, 3H). [α]D25-11.45 (c = 0.0366 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0923]

[0468] Analytical characterization of Compound 63d -(Peak-4)

[0924]

[0469] 73.00 mg, 7.67 % yield, 99.62% Purity. LCMS (m / z): [M+H]+= 353.2, Rt= 6.55 min. Methodic. ‘H NMR (400 MHz, DMSO d&) 8 12.78 (s, 1H), 7.97 (dd, J= 0.80, 8.00 Hz, 1H), 7.53 (dd, J= 0.80, 7.80 Hz, 1H), 7.30 (t, J= 7.60 Hz, 1H), 3.85-3.74 (m, 3H), 3.60-3.46 (m, 3H), 2.94-2.88 (m, 1H), 2.17-2.11 (m, 1H), 1.89-1.82 (m, 2H), 1.77-1.73 (m, 1H), 1.67-1.59 (m, 2H). [a]D25-24.551 (c = 0.0366 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0925]

[0470] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0926]

[0471] Table 22:

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0472] Example 45: Synthesis of A-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahvdro-2H-pyran-4-yl)piperidine-3 -carboxamide. Compound 64

[0951]

[0952]

[0473] Step 1: (S)-N-(4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)-1,9-dioxaspiro[5.5]undecane-4-carboxamide 6B

[0953]

[0474] To a solution of A (1.0g, 1 Eq., 2.32 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.18 g, 2 Eq, 4.65 mmol) in 1,4-Dioxane (20.00 mL) was added Potassium acetate (457.2 mg, 2 Eq, 4.66 mmol) and purged with nitrogen gas for 10 minutes followed by the addition of [1,1'-[Bis(diphenylphosphino)ferrocene]dichloropalladium(II)Complex]. DCM (190.2 mg, 0.1 Eq., 232.9 µmol) and stirred at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (2 X 50 mL). Combined organic layer was washed with brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to obtain 6B (1.5 g, 91% yield, 67% Purity) crude as pale-yellow solid. The crude compound 6B was taken in next step without further purification. MS (m / z) [M+H]+= 477.1, Rt = 1.86 min, purity 67 % Method-L6.

[0954]

[0475] Step 2: (S)-A-(7-cyclopropyl-4-fluorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide, Compound 64

[0955]

[0476] To a solution of 6B (300.0 mg, 67% Wt, 1 Eq., 421.9 µmol) and 6C (85.05 mg, 1.2 Eq., 506.3 µmol) in 1,4-Dioxane: water (5:1 mL) was added Cesium carbonate (275.0 mg, 67.52 µL, 2 Eq., 843.9 µmol). The mixture was purged with nitrogen gas for 10 minutes followed by the addition of [1,1 [Bis(diphenylphosphino)ferrocene. DCM (34.46 mg, 0.1 Eq., 42.19 µmol) and stirred at 100 °C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After 3 h, reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (2 X lOmL). Combined organic layer was washed with brine solution (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to obtain crude. The obtained crude compound was dissolved in THF (10 ml) and added Quadrasil AP (100 mg), the resulted mixture was stirred at room temperature for 1 h. Then the mixture was filtered through celite bed and the filtrate was concentrated to get the crude compound. Crude was purified using flash chromatographic technique using silica gel (60-120) and 0%-100% ethyl acetate in n-heptane as eluent (desired compound eluted at 45% ethyl acetate in n-heptane). Pure fractions were collected and concentrated under vacuum to obtain Compound 64 with crude material 70 mg with 69 % purity. The compound 64 was subjected to prep HPLC purification Method-H8. Pure fractions from prep-HPLC were collected, organic solvent was distilled under vacuum and lyophilized separately using ACN and water to yield Compound 64 (25.00 mg, 15.16 % yield, 99.88% Purity) as white solid. LCMS (ES) m / z [M+H]+= 391.3, Rt = 6.91, purity 98.88%. [Method-L6], ‘HNMR (400 MHz, DMSO-O 8 12.64 (s, 1H), 7.17 (dd, J= 8.4 Hz, 10.4 Hz, 1H), 6.97-6.93 (m, 1H), 3.75-3.71 (m, 1H), 3.66-3.50 (m, 5H), 3.01-2.95 (m, 1H), 2.07-1.88 (m, 3H), 1.75-1.72 (m, 1H), 1.67-1.36 (m, 5H), 1.02-0.98 (m, 2H), 0.77-0.74 (m, 2H). [α]D25+24.00 (c = 0.0333 g / 100mL, methanol). Absolute stereochemistry known.

[0956]

[0477] Example 46: Synthesis of: N-(4-chloro-6-fluorobenzo[d1thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide Compound 65, Compound 65a, Compound 65b

[0957]

[0958]

[0478] To a stirred solution of Intermediate 1 (500.0 mg, 1 Eq, 2.468 mmol) and Intermediate 17 (616.9 mg, 1.1 Eq, 2.714 mmol) in Pyridine (5.000 mL) was added POCl₃ (1.135 g, 690.0 µL, 3 Eq, 7.403 mmol) drop wise at 0 °C and the reaction mixture was stirred at 0 °C for 30 min. The progress of reaction was monitored by TLC and LCMS. After 30 min, the reaction mixture was quenched with ice and excess of pyridine was distilled under pressure, crude obtained was basified using saturated solution of NaHCO3 (20 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic extract was given brine wash, dried over sodium sulfate and distilled under reduced pressure to afford the crude solid. The crude was purified by Combiflash column chromatography using 0-100 % ethyl acetate in n-heptane as eluent followed by 0-20 % Methanol in DCM. Pure fractions were collected and distilled under reduced pressure to afford compound 65 (290 mg with 96.8% purity). The racemic compound (65) was subjected to chiral separation using Method-C41. Each of the two peaks was separated, organic solvent was distilled under reduced pressure and lyophilized using CH3CN and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, as an off-white solid respectively:

[0959]

[0479] Analytical characterisation of compound 65a (Peak-1)

[0960] 80.00 mg, 7.760 % yield, 98.58% Purity. MS (m / z) [M+H]+= 412.2, Rt = 6.43 min. [Method-L17],1HNMR (400 MHz, DMSO-d₆) δ 12.92 (bs, 1H), 7.93 (dd, J= 8.4, 2.4 Hz, 1H), 7.55 (dd, J= 9.2, 2.4 Hz, 1H), 4.55-4.49 (m, 1H), 3.92-3.86 (m, 2H), 3.56-3.52 (m, 1H), 3.38-3.33 (m, 3H), 3.04-3.00 (m, 1H), 2.42 - 2.27 (m, 2H), 2.05 - 1.99 (m, 2H), 1.96-1.65 (m, 2H), 1.44-1.39 (m, 2H). [α]D25+ 7.80 (c = 0.03333 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0961]

[0480] Analytical characterisation of compound 65b (Peak -2):

[0962] 75.00 mg, 7.340 % yield, 99.46% Purity. MS (m / z) [M+H]+= 412.2, Rt = 6.44 min. [Method-L17],1HNMR (400 MHz, DMSO-d₆) δ 12.92 (bs, 1H), 7.93 (dd, J = 8, 1.6 Hz, 1H), 7.55 (dd, J = 9.2, 2 Hz, 1H), 4.54-4.48 (m, 1H), 3.91-3.87 (m, 2H), 3.56 - 3.52 (m, 1H), 3.38 - 3.33 (m, 3H), 3.03-3.01 (m, 1H), 2.38 - 2.25 (m, 2H), 2.02-1.91 (m, 2H), 1.78 - 1.66 (m, 2H), 1.44 - 1.42 (m, 2H). [α]D25-3.000 (c = 0.03333 g / lOOmL, methanol). Absolute stereochemistry unknown.

[0963]

[0481] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0964] Table 23:

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0482] Example 47: N-(4,6-difluoro-1H-benzo[d]imidazol-2-yl)-1-isopropyl-6-oxopiperidine-3-carboxamide Compound 87, Compound 87a, Compound 87b

[0981]

[0982]

[0483] Step 7: N-(4,6-difluoro-1H-benzo[d]imidazol-2-yl)-1-isopropyl-6-oxopiperidine-3-carboxamide compound 87

[0983]

[0484] To a stirred mixture of Intermediate 21 (1.50 g, 1 Eq., 8.098 mmol), HOBt (1.86 g, 1.5 Eq., 12.15 mmol) and EDC.HCl (2.32 g, 1.5 Eq, 12.15 mmol), triethylamine (2.458 g, 3.39 mL, 3 Eq., 24.30 mmol) in DMF (15 mL), 4,6-difluoro-lH-benzo[d]imidazol-2-amine (1.37 g, 1 Eq., 8.09 mmol) was added. The reaction mixture was stirred at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting materials, the reaction mixture was allowed to cool down to rt. Then, the ice-cold water (30 mL) was added to reaction mixture and extracted with ethyl acetate (40 mL X 3 times). The combined extract was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The obtained crude was purified by prep-HPLC using Method-H37 to obtain pure racemic compound 87 as a pale brown solid (610 mg). The pure racemic compound was subjected to chiral separation using Method-C52. Two peaks separated by chiral prep-HPLC were collected, organic solvent was distilled under reduced pressure and lyophilized using ACN and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, as an off-white solid respectively:

[0984]

[0485] Analytical characterisation of compound 87a (Peak-1)

[0985]

[0486] 204.00 mg, 7.5 % yield, 99.69% Purity. MS (m / z) [M+H]+= 337.1, Rt = 7.036 min.. [Method-L15], 'HNMR (400 MHz, DMSO-6) 8 11.97 (bs, 2H), 7.11 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 6.98 - 6.92 (dt, J= 10.8, 2.00 Hz, 2H), 4.73 - 4.64 (m, 1H), 3.48-3.44 (m, 1 H), 3.34-3.29 (m, 1H), 2.36-2.22 (m, 2H), 2.02-1.89 (m, 2H), 1.08-1.00 (m, 6H). Absolute stereochemistry unknown.

[0986]

[0487] Analytical characterisation of compound 87b - (Peak-2)

[0987]

[0488] 201.00 mg, 7.37 % yield, 99.69% Purity. MS (m / z) [M+H]+= 337.1, Rt = 7.305 min. [Method-L15], 'HNMR (400 MHz, DMSO-6) 8 11.90 (bs, 2H), 7.11 (dd, J= 8.4 Hz, 2.0 Hz, 1H), 6.96 (dt, J = 10.8, 2.40 Hz, 2H), 4.73-4.66 (m, 1H), 3.48-3.44 (m, 1 H), 3.01-2.94 (m, 1H), 2.38-2.22 (m, 2H), 2.04-1.89 (m, 2H), 1.11-1.03 (m, 6H). Absolute stereochemistry unknown.

[0988]

[0489] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0989] Table 24:

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0490] Example 48:: N-(4,6-difluoro-1H-benzo[d]imidazol-2-yl)-1-isopropyl-6-oxo-5-phenylpiperidine-3-carboxamide Compound 95, Compound 95a, Compound 95b, Compound 95a-1, Compound 95a-2, Compound 95b-1, Compound 95b-2

[0998]

[0999]

[0491] Step 1: N-(4,6-difluoro-1H-benzo[d]imidazol-2-yl)-1-isopropyl-6-oxo-5-phenylpiperidine-3-carboxamide (95)

[1000]

[0492] To a stirred mixture of Intermediate 29 (0.600 g, 1 Eq., 2.30 mmol) and 4,6-difluoro-lH-benzo[d]imidazol-2-amine (0.466 g, 1.2 Eq., 2.76 mmol) in DMF (2.000 mL) was added Fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH) (0.606 g, 1 Eq., 2.30 mmol) followed by DIPEA (0.890 g, 1.2 mL, 3 Eq., 6.89 mmol). The reaction mixture was stirred to 100°C for 16 h; progress of the reaction was monitored by TLC & LCMS. After complete consumption of starting materials, reaction mixture was quenched with ice-cold water and stirred the mixture for 15 min. The obtained precipitate was filtered, washed with distilled water and dried under vacuum. Then the residue was triturated with diethyl ether and dried under vacuum. The crude was further purified by flash column chromatography on silica gel using 0 - 5% methanol in DCM as eluent (desired compound eluted at 1-2 % methanol in DCM). Two sets of the fractions were collected separately. The first set of fractions was concentrated under reduced pressure to obtain diastereomeric pair-1, compound 95a (200 mg) and the second set of fractions to obtain diastereomeric pair-2, compound 95b (200 mg) of the desired compound. The pure diastereomeric pair-1 and diastereomeric pair-2 were subjected to Chiral prep HPLC using Method-C37. From chiral prep HPLC of diastereomer pair-1 and pair-2, the pure fractions belonging to each of the two peaks were collected separately, concentrated under reduced pressure and lyophilized using acetonitrile and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, as an off-white solid respectively:

[1001]

[0493] Analytical characterisation of compound 95a-l - (Peak-1):

[1002]

[0494] 41.00 mg, 99.41 pmol, 4.33% yield, 99.22 % purity. MS (m / z) [M+H]+= 413.2, Rt = 6.61 min.

[1003] [Method-L14], ‘HNMR (400 MHz, DMSO-O 8 12.42 (bs, 1H), 11.97 (bs, 1H), 7.32-7.28 (m, 2H), 7.23-7.20 (m, 3H), 7.11 (dd, J= 12.0, 4.0 Hz, 1H), 6.96 (td, J= 12.0, 4.0 Hz, 1H), 4.71-4.64 (m, 1H), 3.66 -3.61 (m, 2H), 3.50 - 3.43 (m, 1H), 3.18 - 3.12 (m, 1H), 2.33 - 2.26 (m, 1H), 2.15 - 2.06 (m, 1H), 1.11-1.06 (m, 6H). [OI]D25+ 7.20 (c = 0.033 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1004]

[0495] Analytical characterisation of compound 95b-l (Peak-2):

[1005]

[0496] 21.00 mg, 48.20 pmol, 2.1% yield, 99.90 % purity. MS (m / z) [M+H]+= 413.2 [M+H]+. Rt = 6.73 min [Method-L14], ‘HNMR (400 MHz, DMSO-6) 8 12.41 (bs, 1H), 11.91 (bs, 1H), 7.34-7.30 (m, 2H), 7.25-7.18 (m, 3H), 7.10 (dd, J= 8.60, 2.00 Hz, 1H), 6.95 (td, J= 10.4, 2.00 Hz, 1H), 4.78-4.72 (m, 1H), 3.74 (t, J= 6.8 Hz, 1H), 3.6 (dd, J= 12.4, 5.2 Hz, 1H), 3.51-3.42 (m, 1H), 3.12 (bs, 1H), 2.42-2.32 (m, 1H), 2.14-2.08 (m, 1H), 1.26-1.08 (m, 6H). [a]D25- 63.06 (c = 0.066 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1006]

[0497] Analytical characterisation of compound 95a-2 (Peak-3):

[1007]

[0498] 18.00 mg, 41.10 pmol, 1.8% yield, 99.31% purity. MS (m / z) [M+H]+= 413.20. Rt = 6.60 min.

[1008] [Method-L14], ‘HNMR (400 MHz, DMSO-O 8 12.40 (bs, 1H), 11.95 (bs, 1H), 7.32-7.28 (m, 2H), 7.22-7.20 (m, 3H), 7.11 (dd, J= 8.8, 2.0 Hz, 1H), 6.95 (td, 10.8, 2.0 Hz, 1H), 4.71-4.64 (m, 1H), 3.65-3.60 (m, 2H), 3.47 (t, J= 10 Hz, 1H), 3.15-3.11 (m, 1H), 2.31-2.27 (m, 1H), 2.11-2.05 (m, 1H), 1.10-1.08 (m, 6H). [OI]D25-6.00 (c=0.033 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1009]

[0499] Analytical characterisation of compound 95b-2 - (Peak-4):

[1010]

[0500] 27.00 mg, 47.56 pmol, 2.1 % yield, 98.35 % purity. MS (m / z) [M+H]+= 413.2 [Method-L14], ‘H NMR (400 MHz, DMSO-d6) δ 12.43 (bs, 1H), 11.92 (bs, 1H), 7.34-7.30 (m, 2H), 7.25-7.18 (m, 3H), 7.11 (dd, J = 8.8, 2.0 Hz, 1H), 6.94 (td, J= 10.8, 2.0 Hz, 1H), 4.78-4.72 (m, 1H), 3.74 (t, 6.8 Hz, 1H), 3.62-3.57 (m, 1H), 3.51-3.48 (m, 1H), 3.17-3.12 (m, 1H), 2.42-2.35 (m, 1H), 2.14-2.08 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H), 1.09 (d, J= 6.8 Hz, 3H). [α]D25+ 63.002 (c = 0.033 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1011]

[0501] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[1012]

[0502] Table 25:

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[0503] Example 49: Synthesis of N-(4,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-oxo-1-((R)-tetrahydro-

[1027]

[1028] 2H-pyran-3-yl)piperidine-3 -carboxamide Compound 101, Compound 101a. Compound 101b

[1029]

[1030]

[0504] Step 1: N-(4,6-difluoro-1H-benzo[d]imidazol-2-yl)-6-oxo-1-((R)-tetrahydro-2H-pyran-3-yl)piperidine-3-carboxamide, Compound 101

[1031]

[0505] To a mixture of Intermediate 19 (2.000 g, 1 Eq., 8.800 mmol), CAS # 1388063-46-4 (1.637 g, 1.1 Eq., 9.681 mmol) and DIPEA (3.412 g, 4.60 mL, 3 Eq., 26.40 mmol) in DMF (20.000 mL), O-(Benzotriazol-l-yl)-A, A, A’, A’-tetramethyluroniumTetrafluoroborate (TBTU) (4.239 g, 1.5 Eq., 13.20 mmol) was added at 25 °C. The reaction mixture was stirred at 110 °C for 16 h; progress of the reaction was monitored by LCMS. After completion of starting material, reaction was diluted with cold water (30 ml) and extracted with ethyl acetate (50 ml X 2). The combined organic layers were washed with NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified through silica gel flash column chromatography 10% MeOH in DCM to afford compound 101 (Racemate) (440 mg, 95% purity) as a pale brown solid. The racemate was subjected to chiral separation using below Method-C12. The pure fractions belonging to each peak were separately collected, distilled under reduced pressure to get the solid and finally lyophilized to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, as an off-white solid respectively:

[1032]

[0506] Analytical characterization of compound 101a -(Peak-1):

[1033]

[0507] 100 mg, 263.7 pmol, 2.99 % yield, 99.79 % Purity. MS (m / z) [M+H]+= 379.3, Rt = 6.03 min. [Method-L12], *H NMR (400 MHz, DMSO-t / e) 8 12.26 -12.08 (m, 2H), 7.1 l(d, J =7.6 Hz, 1H), 6.95 (d, J =10.6 Hz, 1H), 4.34-4.29 (m, 1H), 3.75-3.67 (m, 1H), 3.60-3.57 (m, 1H), 3.53-3.50 (m, 1H), 3.48-3.40 (m, 2H), 3.25-3.19 (m, 1H), 3.03-2.95 (m, 1H), 2.40-2.33 (m, 2H), 2.07-1.87 (m, 2H), 1.79-1.52 (m, 4H).

[1034] [α]D25- 3.000 (c = 0.033g / 100mL, methanol). Absolute stereochemistry unknown

[1035]

[0508] Analytical characterization compound 101b - (Peak-2):

[1036] 60 mg, 157.9 pmol, 1.79 % yield, 99.69 % Purity. MS (m / z) [M+H]+= 379.3, Rt = min. [Method-L12], ’H NMR (400 MHz, DMSO-6) δ 12.34-11.92 (m, 2H), 7.11 (dd, J= 8.8, 2.0 Hz, 1H), 6.96 (t, J =10.8 Hz, 1H), 4.34-4.28 (m, 1H), 3.75-3.72 (m, 1H), 3.65-3.55 (m, 2H), 3.37-3.35 (m, 2H), 3.21(t, J =11 Hz, 1H), 2.99 (bs, 1H), 2.38-2.24 (m, 2H), 2.03-1.90 (m, 2H), 1.84-1.76 (m, 1H), 1.69-1.54 (m, 3H). [a]D25+ 15.002 (c = 0.033g / 100mL, methanol). Absolute stereochemistry unknown

[1037]

[0509] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[1038] Table 26:

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[0510] Example 50: Synthesis of 1-(3-oxabicyclo[3.1.0]hexan-6-yl)-N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-6-oxopiperidine-3-carboxamide Compound 109, Compound IM-44, Compound 109a, Compound 109b

[1047]

[1048]

[0511] Step 7: l-(3-oxabicyclo[3.1.0]hexan-6-yl)-N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-6-oxopiperidine-3 -carboxamide Compound 109

[1049]

[0512] To a stirred solution of CAS # 693248-55-4 (31.46 mg, 2 Eq., 2.3339 mmol) in IPA (4.000 mL) was added TEA (590.43 mg, 813 pL. 5 Eq., 5.8348 mmol) and stirred for 10 mins. Intermediate 8 (400.00 mg, 1 Eq., 1.1670 mmol) was then added and the resulting reaction mixture was stirred for 48 h at 70 °C. Progress of reaction was monitored by TLC and LCMS (Note: 10 % of IM-44 was observed in crude LCMS). The reaction mixture was concentrated under reduced pressure, the obtained crude solid was diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The combined organic extract was washed with brine, dried over Na2SO4and distilled under reduced pressure. The crude obtained was purified by Combiflash column chromatography using 0-100 % Ethyl acetate in heptane, followed by 0-20% MeOH / DCM to afford compound 109 (racemic) (300 mg with 74 % purity) as an off-white solid. The compound was further subjected to prep-HPLC using Method-H15. The fractions containing pure compound were concentrated under reduced pressure to get the compound followed by lyophilization using acetonitrile and water to obtain pure racemic compound 109 (100 mg, 97.11 % LCMS purity). The racemic compound 109 was subjected to chiral HPLC by using Method-C28. The pure fractions corresponding to each peak were collected separately, organic solvent was distilled under reduced pressure and lyophilized using ACN and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, as an off-white solid respectively:

[1050]

[0513] Analytical characterization compound 109a of (Peak-1)

[1051]

[0514] 40.00 mg, 97.27 pmol, 8.336 % yield, 99.67% Purity. MS (m / z) [M+H]+= 410.2, Rt = 6.40 min.

[1052] [Method-29], ’H NMR (400 MHz, DMSO-t / e) 8 12.99 (s, 1H), 7.44-7.35 (m, 2H), 3.82 (d, J= 8.4 Hz, 2H), 3.63-3.61 (m, 2H), 3.53-3.44 (m, 1H), 3.43-3.41 (m, 1H), 3.09-3.02 (m, 1H), 2.34 (s, 1H), 2.30-2.22 (m, 2H), 2.05-2.03 (m, 1H), 1.98-1.86 (m, 3H). [a]D25+ 7.801 (c = 0.066 g / 100 mL, methanol). Absolute stereochemistry unknown

[1053]

[0515] Analytical characterization of compound 109b (Peak-2):

[1054]

[0516] 30.00 mg, 72.78 pmol, 6.237 % yield, 99.43% Purity. MS (m / z) [M+H]+= 410.1, Rt = 5.41 [Method-14].1H NMR (400 MHz, DMSO-6) δ 13.00 (s, 1H), 7.42-7.37 (m, 2H), 3.82 (d, J= 8.4 Hz, 2H), 3.62 (dd, J= 8.4, 2.4 Hz, 2H), 3.53-3.41 (m, 2H), 3.08-3.03 (m, 1H), 2.34-2.26 (m, 3H), 2.07-2.03 (m, 1H), 1.98-1.88 (m, 3H). [α]D25- 6.375 (c = 0.05333 g / 100 mL, methanol). Absolute stereochemistry unknown

[1055]

[0517] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[1056] Table 27:

[1057]

[1058]

[1059]

[1060]

[1061]

[0518] Example 51: Synthesis of (ls.3s)-3-(5-((7-chloro-4-fluorobenzo[d1thiazol-2-yl)carbamoyl)-2-oxopiperidin-l-yl)cyclobutane-l -carboxylic acid Compound IM-45, Compound 113, Compound 113 a, Compound 113b

[1062]

[1063]

[0519] Step 7: Zc / 7-butyl (ls,3s)-3-(5-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)-2-oxopiperidin- 1 -yl)cyclobutane- 1 -carboxylate (IM-45)

[1064]

[0520] Compound 6A was synthesized by following the procedure described using Intermediate 8 (1.000 g, 1 Eq., 2.917 mmol) and CAS # 957793-95-2 (999.2 mg, 2 Eq., 5.835 mmol) Yield: 44.80%. MS (m / z) [M+H]+= 482.1, Rt = 1.84 min.

[1065]

[0521] Step 2: (ls,3s)-3-(5-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)-2-oxopiperidin-l-yl)cyclobutane-l -carboxylic acid Compound 113

[1066]

[0522] To a stirred solution of IM-45 (0.630 g, 1 Eq., 1.31 mmol) in 1,4-dioxane (10.00 mL) was added 4 M HC1 in 1,4-dioxane (3.27 mL, 10 Eq., 13.1 mmol) and the reaction mixture was stirred at rt for 16 h. After complete consumption of starting material, the reaction mixture was concentrated under reduced pressure and the material obtained was triturated with w-pentane to obtain 113 as a brown gummy material. The crude 113 was further purified by Prep-HPLC using Method-H23. The fractions containing pure compound were collected and concentrated under reduced pressure to obtain the racemic pure compound 113 (70 mg, 99% purity). The racemic compound was subjected to chiral separation using Method-C5. The pure fractions corresponding to each peak were collected separately; then concentrated under reduced pressure to obtain the solid and lyophilized using acetonitrile and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, as an off-white solid respectively:

[1067]

[0523] Analytical characterization of compound 113a (Peak-1):

[1068]

[0524] 8.00 mg, 18.48 pmol, 1.41 %, 98.35% Purity. MS (m / z) [M+H]+= 426.2, Rt = 6.27 min.

[1069] [Method-L17]. ¹H NMR (400 MHz, DMSO-d₆) 8 12.80 (bs, 1H), 7.41-7.32 (m, 2H), 4.90 - 4.81 (m, 1H), 3.66-3.62 (m, 1H), 3.45-3.39 (m, 1H), 3.04-3.01 (m, 1H), 2.77- 2.68 (m, 1H), 2.39-2.20 (m, 6H), 2.07- 2.01 (m, 1H), 1.97-1.92 (m, 1H). [a]D25- 29.40 (c = 0.03333 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1070]

[0525] Analytical characterization of compound 113b (Peak-2):

[1071]

[0526] 13.00 mg, 30.03 pmol, 2.30 %, 98.36% Purity. MS (m / z) [M+H]+= 426.2, Rt = 6.27 min.

[1072] [Method-L17], ‘HNMR (400 MHz, DMSO-O 8 13.02 (bs, 1H), 12.27 (bs, 1H), 7.44-7.35 (m, 2H), 4.90-4.81 (m, 1H), 3.65 (dd, J= 12.0, 4.4 Hz, 1H), 3.45-3.39 (m, 1H), 3.09-3.02 (m, 1H), 2.75 (t, J= 8.6 Hz, 1H), 2.39-2.18 (m, 6H), 2.08-1.98 (m, 1H), 1.95-1.91 (m, 1H). [a]D25+ 15.001 (c = 0.033 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1073]

[0527] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[1074] Table 28:

[1075]

[1076]

[1077]

[1078]

[0528] Example 52: Synthesis ofA-(4,6-difluorobenzo[d1thiazol-2-yl)-l-(3-methoxybicyclo[l.l.l]pentan-l-yl)-6-oxopiperidine-3-carboxamide Compound 116

[1079]

[1080] Step 1

[1081]

[0529] Step-1'. A-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(3-methoxybicyclo[l.l.l]pentan-l-yl)-6-oxopiperidine-3 -carboxamide

[0530] To a stirred solution of CAS # 119256-40-5 (93.37 mg, 1.2 Eq, 501.5 pmol) and Intermediate 36 (100.0 mg, 1 Eq, 417.9 pmol) in DCM (2.000 mL), T3P (265.9 mg, 0.2460 m, 2.000 Eq, 835.8 pmol) and TEA (127 mg, 0.175 mL, 3.00 Eq, 1.26 mmol) were added at rt. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. Reaction mixture was diluted with DCM (30 mL), washed with water (20 mL x 2), brine (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the crude material. The crude material was purified by Combiflash column chromatography using 50-70% ethyl acetate in n-hexane. The crude was further purified by Prep-HPLC using Method-Hl 1 to afford compound 116 (Racemate) (4.4 mg, 10.70 pmol, 2.56 % yield, 99.1%) as a white solid. MS (m / z) [M+H]+= 408.2, Rt = 5.844 min.

[1082] [Method-L29], ‘HNMR (400 MHz, DMSO-6) 8 12.81 (s, 1H), 7.80 (d, J= 8 Hz, 1H), 7.37 (t, J= 10.4 Hz, 1H), 3.56 - 3.52 (m, 1H), 3.40 (t, J = 9.6 Hz, 1H), 3.19 (s, 3H), 3.06-3.04 (m, 1H), 2.23-2.26 (m, 2H), 2.16 (s, 6H), 2.07 - 1.86 (m, 2H) (two protons are merged in the DMSO moisture peak).

[1083]

[0531] Example 53: Synthesis of (> M-N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l- (cvclobutanecarbonvDpiperidine-3-carboxamide Compound 117

[1084]

[1085] Intermediate 33 Step 1

[1086]

[0532] Step 7: (S)-N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l -(cyclobutanecarbonyl)piperidine-3-carboxamide

[1087]

[0533] To a mixture of Intermediate 39 (200.0 mg, 1 Eq., 571.05 pmol), TEA (173.35 mg, 239 pL, 3 Eq., 1.71 mmol) in DCM (5.0 mL) at 0 °C were added cyclobutanecarbonyl chloride (CAS # 5006-22-4) (74.474 mg, 1.1 Eq., 628.16 pmol) and stirred at 25 °C for 1 h. Progress of the reaction was monitored by TLC and LCMS. LCMS shown product formation. Reaction mass was diluted with water and extracted with DCM (20 mL x 2). Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. Then the crude was purified by flash column chromatography on silica gel where the product was eluted with 30 to 40% ethyl acetate in heptane to give off-white solid (100 mg). Further, the crude solid was purified by prep-HPLC using the Method-H43. The pure fractions containing the compound were distilled under reduced pressure and the final compound was lyophilized (using acetonitrile and water) to afford compound 117 (26.00 mg, 11.48 % yield, 571.05 pmol, 99.85% Purity) as a white solid. MS (m / z) [M+H]+= 396.2. Rt = 7.18 min. [Method-L29], ’H NMR (400 MHz, DMSO- d₆) δ 12.94 (s, 1H), 7.44-7.35 (m, 2H), 4.39-4.17 (m, 1H), 3.85-3.58 (m,1H), 3.48-3.46 (m, 1H), 3.37 -3.32 (m, 1H), 3.20-3.13 (m, 1H), 3.03-2.95 (m, 1H), 2.72-2.62 (m, 1H), 2.20-2.00 (m, 4H), 1.90-1.84 (m, 1H), 1.72-1.69 (m, 3H), 1.34-1.29 (m, 1H) [a]D25+88.51 (c = 0.0666 g / lOOmL, methanol). Absolute stereochemistry known.

[1088]

[0534] Example 54: Synthesis of (. S')-4-(3-((7-chloro-4-fluorobcnzo|dlthiazol-2-yl)carbamoyl)pipcridin-l-yl)-4 -oxobutanoic acid compound 118

[1089]

[1090] intermediate 33 Step 1

[1091]

[0535] To a mixture of Intermediate 39 (400.0 mg, 1 Eq., 1.142 mmol), TEA (346.7 mg, 478 pL, 3 Eq., 3.426 mmol) in DCM (10.00 mL) at 0 °C were added dihydrofuran-2,5-dione (CAS # 108-30-5) (91.43 mg, 0.8 Eq., 913.7 pmol) and stirred at 25 °C for 1 h. Progress of the reaction was monitored by TLC and LCMS. LCMS shown product formation. Reaction mass was concentrated completely under reduced pressure and the obtained solid was triturated with diethyl ether to afford the crude. The crude was further purified by prep-HPLC using Method-H44. The fractions containing the desired compound were collected, distilled under reduced pressure and then lyophilized to afford compound 118 (100.0 mg, 214.4 pmol, 18.77 % yield, 98.59 % Purity) as a white solid. MS (m / z) [M+H]+= 414.2, Rt = 5.30 min.

[1092] [Method-L30]. ¹HNMR (400 MHz, DMSO-d₆) 8 12.47 (bs, 1H), 7.44-7.35 (m, 2H), 4.46-4.18 (m, 1H), 4.06-3.81(m, 1H), 3.32-3.19 (m, 1H), 3.06 -3.03 (m, 1H), 2.88-2.82 (m, 2H), 2.73-2.70 (m, 2H), 2.44-2.41 (m, 2H), 2.07-2.02 (m, 1H), 1.74-1.68 (m, 2H), 1.46-1.29 (m, 1H). [a]D25+ 86.71 (c = 0.0333 g / 100 mL, methanol).

[1093]

[0536] Example 55: Synthesis of (> M-N-(4.6-difluorobenzo[d]thiazol-2-yl)-l-(pyridazine-4-carbonyl)piperidine-3-carboxamide compound 119

[1094]

[1095]

[0537] Step 7: (S)-N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(pyridazine-4-carbonyl)piperidine-3-carboxamide

[1096]

[0538] To a mixture of Intermediate 41 (300.0 mg, 1 Eq., 810.3 pmol), pyridazine-4-carboxylic acid CAS # 50681-25-9 (120.7 mg, 1.2 Eq., 972.3 pmol) and 1 -Hydroxy- IH-benzotriazole (164.2 mg, 167 pL, 1.5 Eq., 1.215 mmol) in DMF (5.000 mL) were added l-(3-Dimethylaminopropyl)-3-ethylcarbodiimideHydrochloride (EDC.HCl) (279.6 mg, 1.8 Eq., 1.459 mmol), TEA (246.0 mg, 339 pL, 3 Eq, 2.431 mmol) at 25 °C. The reaction mixture was heated to 100 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. LCMS shown product formation. The reaction mixture was diluted with water and extracted with ethyl acetate (25mL x2). Combined organic layers were dried over Na₂SO₄, filtered and solvent was concentrated under reduced pressure. The crude was further purified by prep-HPLC using Method-47. The fractions containing the desired product were distilled under reduced pressure and then lyophilized to afford compound 119 (170.0 mg, 51.77 % yield, 419.5 pmol, 99.54 %) as a white solid. MS (m / z) [M+H]+= 404.3, Rt = 6.21 min. [Method-L14], ’H NMR (400 MHz, DMSO-de) 8 12.66 (bs, 1H), 9.37-9.27 (m, 2H), 7.81-7.71 (m, 2H), 7.40-7.33 (m, 1H), 4.49-4.09 (m, 1H), 3.65 (d,.7=10.4 Hz, 1H), 3.44-3.38 (m, 1H), 3.21-3.15 (m, 1H), 2.83-2.76 (m, 1H), 2.07 (s, 1H), 1.80-1.78 (m, 2H), 1.53-1.52 (m, 1H). [< X]D25+84.0 (c = 0.0333 g / 100 mL, methanol). Absolute stereochemistry known.

[1097]

[0539] Example 56: Synthesis of N-(4.6-difluorobenzo[d1thiazol-2-yl)-l-(pyridazine-4-carbonyl)piperidine-3 -carboxamide Compound 120

[1098]

[1099] Intermediate 40

[1100] Step “I

[1101]

[0540] Step 1: 7V-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(pyridazine-4-carbonyl)piperidine-3-carboxamide

[0541] To a solution of pyridazine-4-carboxylic acid (CAS # 50681-25-9) (100 mg, 0.80 mmol) in THF (5 mL) was added DIPEA (0.702 mL, 4.0 mmol), Propylphosphonic anhydride (T3P) (0.284 mL, 0.967 mmol) and Intermediate 40 (296 mg, 0.886 mmol) sequentially at 0°C and stirred for 10 min. Reaction mixture was warm to room temperature and stirred for 16 hours. LCMS indicated product formation. Reaction mixture was diluted with water (5 mL) and aqueous layer was extracted with EtOAc (10 mL x2). Combine organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column using 30 - 40 % of EtOAc. The obtained crude was further purified by Prep-HPLC using Method-H61. The fractions containing the desired compound were distilled under reduced pressure and then lyophilized to afford compound 120 (Racemate) (17 mg, 5.2 % yield, 41.96 pmol, 99.58% Purity) as a white solid. MS (m / z) [M+H]+= 404.2, Rt = 6.21 min. [Method-L14], ¹H NMR (400 MHz, DMSO-d₆) 8 12.74 (s, 1H), 9.37-9.31 (m, 1H), 9.27 (s, 1H), 7.81-7.71 (m, 2H), 7.39- 7.32 (m, 1H), 4.49 - 4.09 (m, 1H), 3.66-3.41 (m, 1H), 3.25-3.12 (m, 2H), 2.81-2.67 (m,1H), 2.07-2.0 (m, 1H), 1.84-1.71 (m, 2H), 1.56-1.50 (m, 1H). Racemic mixture.

[1102]

[0542] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[1103] Table 29:

[1104]

[1105]

[1106]

[0543] Example 57: Synthesis of N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-1-(3-cyano-3- methylbutanoyl)piperidine-3 -carboxamide Compound 123

[1107]

[1108] Step 1

[1109]

[0544] Step 7: A-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-(3-cyano-3-methylbutanoyl)piperidine-3- carboxamide

[1110]

[0545] In a 100 mL sealed tube, to a mixture of Intermediate 37 (2000.00 mg, 1 Eq, 6.3739 mmol) in DMF (15.00 mL) at room temperature were added DIPEA (2.4715 g, 3.33 mL, 3 Eq, 19.122 mmol), HATU (3.1507 g, 1.3 Eq, 8.2861 mmol) and 3 -cyano-3 -methylbutanoic acid (CAS # 99839-17-5) (810.38 mg, 1 Eq, 6.3739 mmol). After stirring for 10 min, the reaction mixture was heated to 110 °C for 3 h. Progress of the reaction was monitored by TLC and LCMS. After 3 h, the reaction mixture was concentrated. The reaction mixture was diluted with NaHCO3 (5 mL) and then extracted with EtOAc (2 x 3 mL). The separated organic layer was concentrated and the obtained residue was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 50:50 to 40:60) to give desired product (1.6 g, yield 61%, purity 76%) as a brown solid. 100 mg of this crude compound was further purified by prep-HPLC using Method-H48. The fractions containing the concentrated and lyophilized to afford compound 123 as a white solid. MS (m / z) [M+H]+=423.0, Rt = 6.86 min. [Method-L17], ¹H NMR (400 MHz, DMSO-d₆) 8 12.96 (s, 1H), 7.38-7.33 (m, 2H), 4.47-4.21 (m, 1H), 4.00-3.75 (m, 1H), 3.23-3.04 (m, 1H), 2.93-2.64 (m, 4H), 2.08-2.03 (m, 1H), 1.79-1.70 (m, 2H), 1.38 (s, 7H). Racemic mixture

[0546] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[1111] Table 30:

[1112]

[1113]

[1114]

[0547] Example 58: Synthesis of (lS,3r)-3-((S)-3-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)cvclobutane-l -carboxylic acid IM-46, Compound 126

[1115]

[1116]

[0548] Step 7: methyl (lS,3r)-3-((S)-3-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)cyclobutane-l -carboxylate, IM-46 ()

[1117]

[0549] To a mixture of trans-3-(methoxycarbonyl)cyclobutane-l -carboxylic acid (CAS # 1401103-71-6) (126.44 mg, 1.4 Eq., 799.47 pmol) in DMF (3.000 mL) DIPEA (221.43 mg, 298 pL, 3 Eq, 1.7132 mmol), HOBt (131.18 mg, 1.5 Eq, 856.58 pmol), l-(3-Dimethylaminopropyl)-3-ethylcarbodiimideHydrochloride (EDC.HCl) (164.21 mg, 1.5 Eq, 856.58 pmol) were added at at 25 °C. At the same temperature, Intermediate 38 (200.00 mg, 1 Eq, 571.05 pmol) was added and reaction mixture was allowed to stir for 4 h. Progress of reaction was monitored by TLC & LCMS. After complete consumption of starting material, reaction was diluted with water (15 ml) and extracted with EtOAc (3x15 mL). The combined organic extracts were washed with brine solution (10 ml), dried over Na₂SO₄, filtered and distilled under reduced pressure to get IM-46 (250.0 mg, 472 pmol, 82.7 % yield, 85.7% Purity) as a white solid. The compound was used in the next reaction without further purification. MS (m / z) [M+H]+= 454.1, Rt = 1.80 min.

[1118]

[0550] Step 2: (lS,3r)-3-((S)-3-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)cyclobutane-l -carboxylic acid Compound 126

[1119]

[0551] To a solution of IM-46 (250.0 mg, 85.7% Wt, 1 Eq, 472.0 pmol) in MeOH (2.000 mL), THF (2.000 mL) and Water (1.000 mL), LiOH (56.52 mg, 5 Eq, 2.360 mmol) was added. The reaction mixture was allowed to stir at room temperature for 3 h. Progress of reaction monitored by TLC & LCMS. The reaction solvent was concentrated; the reaction mixture was diluted with water (20 ml) and washed with ethyl acetate (20 mlx3). Then for aqueous layer was acidify using 2N HC1 and extracted twice using DCM to get Compound 126 (70 mg, 95.86%). The crude product was purified by prep-HPLC using Method-H50. The fractions containing the desired product were concentrated and lyophilized to yield 126 (40.00 mg, 90.5 pmol, 19.2 %, 99.5% Purity) as an off-white solid. MS (m / z) [M+H]+= 440.2, Rt = 5.88 min. [Method-L29], ¹H NMR (400 MHz, DMSO-d₆) δ 12.89 (bs, 1H), 12.21 (bs, 1H), 7.43-7.34 (m, 2H), 4.40-4.19 (m, 1H), 3.79-3.45 (m, 2H), 3.16 (t, J= 12 Hz, 1H), 3.04-2.89 (m, 2H), 2.73-2.60 (m, 1H), 2.46-2.33 (m, 4H), 2.01-1.98 (m, 1H), 1.78-1.69 (m, 2H), 1.42-1.29 (m, 1H). [a]D25+ 36.601 (cone. 0.0333 g / 100 mL, methanol). Absolute stereochemistry known.

[1120]

[0552] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[1121] Table 31:

[1122]

[1123]

[1124]

[1125]

[0553] Example 59: Synthesis of (S')-N-(4.6-difluorobenzo[d1thiazol-2-yl)-l-((R)-pyrrolidine-3-carbonyl)piperidine-3-carboxamide. Compound 134

[1126]

[1127]

[0554] Step 1: tert-butyl (R)-3-((S)-3-((4,6-difluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)pyrrolidine-l -carboxylate Compound IM-47 ()

[1128]

[0555] To a stirred solution of Intermediate 41 (500 mg, 1 Eq., 1.682 mmol) and (R)-l-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (CAS # 72925-16-7) (362 mg, 1 Eq, 1.682 mmol) in DMF (5.0 m ), and HATU (959.3 mg, 1.5 Eq, 2.523 mmol) was added DIPEA (0.732 mL, 2.5 Eq, 4.204 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 16 h and the reaction progress was monitored by LCMS and TLC analysis. LCMS indicated formation of desired product. After complete consumption of starting material, the reaction mixture was quenched with ice cold water and solid was precipitated. The obtained precipitated was filtered, washed with ice water and dried under reduced pressure. The crude solid was triturated with n-pentane to afford desired compound IM-47 as an off-white solid (830 mg, 13.678 mmol, 99.8%). The compound was used in the next step without further purification. MS (m / z) [M+H]+= 495.0, Rt = 1.79 min.

[1129]

[0556] Step 2: (S)-N-(4,6-difluorobenzo[d]thiazol-2-yl)-l -((R)-pyrrolidine-3-carbonyl)piperidine-3-carboxamide Compound 134

[1130]

[0557] To a stirred mixture of IM-47 (830.0 mg, 1 Eq, 1.678 mmol) in 1,4-Dioxane (2.000 mL) at 0 °C, was added 4 M HC1 in 1,4-Dioxane (2.098 L, 4.000 mmolar, 5 Eq, 8.391 mmol) and stirred at rt for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction solvent was concentrated (720 mg, yield; 99.5%). 300 mg of crude was purified by prep-HPLC using Method-H69. The fractions containing the desired product were lyophilized to yield compound 134 as a colourless solid (90 mg, 32% yield, 98.99 % purity). MS (m / z) [M+H]+= 396.3, Rt = 5.97 min. [Method-L29],1H NMR (400 MHz, DMSO-d₆): δ 8.36 (s, 1H), 7.77 (d, J= 8.1 Hz, 1H), 7.35 (dd, J - 2.40, 9.60 Hz, 1 H ), 4.41-4.10 (m, 2H), 3.87-3.39 (m, 2H), 3.34-3.00 (m, 3H), 2.96 (t, 11.2 Hz, 1H), 2.71 (t, 11.2 Hz, 1H), 2.40-2.45 (m, 1H), 2.10-2.02 (m, 2H), 1.92-1.71 (m, 3H), 1.44-1.31 (m, 1 H). [a]D25+ 99.01 (c = 0.0333 g / 100 mL, methanol). Absolute stereochemistry known.

[0558] Example 60: Synthesis of l-methoxy-2-methylpropan-2-yl (R)-3-((S)-3-((4,6-difluorobenzo [d]thiazol-2-yl)carbamoyl)piperidine- 1 -carbonyl)pyrrolidine- 1 -carboxylate. Compound 135

[1131]

[1132]

[0559] Step 7: 1 -methoxy -2 -methylpropan-2-yl (perfluorophenyl) carbonate (IM-48)

[1133]

[0560] To a solution of l-methoxy-2-methylpropan-2-ol (CAS # 3587-64-2) (1.000 g, 1 Eq, 9.602 mmol) in ACN (20.000 mL), triethylamine (2.915 g, 4.01 mL, 3 Eq, 28.80 mmol) at 0 °C followed by bis(perfluorophenyl) carbonate (4.541 g, 1.2 Eq, 11.52 mmol) were added. The reaction mixture was stirred at 25 °C for 12 h. Progress of the reaction was monitored by TLC. TLC shown new spot formation. Reaction mixture was diluted with water and extracted with ethyl acetate (10 mL x 2).

[1134] Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to get IM-48 (2.000 g, 6.365 mmol, 66.29 %) as an orange liquid. The compound was taken to next step without further purification. The compound IM-48 was not ionized in LCMS and 1H-NMR also inconclusive.

[1135]

[0561] Step 2: 1 -methoxy -2 -methylpropan-2-yl (7?)-3-((S)-3-((4,6-difluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine- 1 -carbonyl)pyrrolidine- 1 -carboxylate, Compound 135

[1136]

[0562] To a mixture of 134 (1.000 g, 1 Eq, 2.321 mmol), TEA (704.5 mg, 970 pL. 3 Eq, 6.962 mmol) in DCM (20.000 mL) was added IM-48 (802.1 mg, 1.1 Eq, 2.553 mmol). The reaction mixture was stirred at 25 °C for 12 h. Progress of the reaction was monitored by LCMS. LCMS shown product formation. Reaction mass was diluted with water and extracted with DCM (20 mL x 2) and the combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel eluted with 5 to 10% methanol in DCM. Further, the crude was subjected to prep-HPLC using Method-H46. The fractions containing the desired product were lyophilized to yield compound 135 (96.00 mg, 182.7 pmol, 7.874 % yield, 99.85% purity) as a white solid. MS (m / z) [M+H]+= 525.4, Rt = 6.84 min. [Method-L14],1HNMR (400 MHz, DMSO-d₆) δ 12.76 (s, 1H), 7.82-7.78 (m, 1H), 7.40-7.35 (t, J= 12.0 Hz 1H), 4.41-4.24 (m, 1H), 4.16-3.87 (m,lH), 3.57-3.43 (m, 4H), 3.33-3.22 (m, 5H), 3.18-3.11 (m, 2H), 2.95-2.59 (s, 2H), 2.90-1.95 (s, 2H), 1.88-1.69 (m, 3H), 1.43-1.36 (m, 7H). [α]D25+61.5 (c = 0.033 g / 100 mL, methanol). Absolute stereochemistry known.

[1137]

[0563] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[1138] Table 32:

[1139]

[1140]

[0564] Example 61: Synthesis of Isopropyl (lR.2S,5S)-2-((S)-3-((7-chloro-4-fluoro-lH- benzo[d]imidazol-2-yl)carbamoyl)piperidine-l-carbonyl)-3-azabicvclo[3. L0]hexane-3-carboxylate. Compound 137

[1141]

[1142]

[0565] Step 1: (lR,2S,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid IM-49

[1143]

[0566] To a mixture of Intermediate (3.000 g, 1 Eq, 9.452 mmol) in Ethanol (35.000 mL), was added 10 % Palladium carbon (3.018 g, 3 Eq, 28.36 mmol) at room temperature. The reaction was allowed to stir at 25 °C for 3 h under H₂ atmosphere (H₂ Bladder). The reaction was monitored using TLC.

[1144]

[0567] The reaction mixture was filtered through celite, washed with MeOH (150 mL), filtrate was concentrated in vacuum to afford IM-49 (2.100 g, 97 % yield, 99% Purity) as white solid which was used in the next reaction without further purification. MS (m / z) [M-H]+= 226.1, Rt = 5.44 min.

[1145]

[0568] Step 2 tert-butyl (lR,2S,5S)-2-((S)-3-((7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)carbamoyl)piperidine- 1 -carbonyl)-3 -azabicyclo [3.1.0]hexane-3 -carboxylate, IM-50

[1146]

[0569] To a solution of Intermediate 42 (1600.00 mg, 1 Eq., 4.8021 mmol) in DMF (8.0 mL) at room temperature, IM-49 (1.0913 g, 1 Eq, 4.8021 mmol), DIPEA (1.8620 g, 2.51 mL, 3 Eq., 14.406 mmol) and 1 -Hydroxy- IH-benzo triazole (973.35 mg, 990 pL, 1.5 Eq., 7.2031 mmol) and l-(3-Dimethylaminopropyl)-3-ethylcarbodiimideHydrochloride (EDC.HCl) (1.3808 g, 1.5 Eq., 7.2031 mmol) were added. After stirring for 10 min at rt, the reaction mixture was heated to 100 °C for 12 h. After 12 h, the reaction mixture was concentrated; diluted with NaHCCE (10 mL) and then extracted with EtOAc (10 mLx2). The separated organic layer was concentrated and the residue was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 70:30 to 60:40; a 24 g Redisep Silver column via liquid injection) to give IM-50 (1.300 g, 50 %, 93% Purity) as a brown oil. MS (m / z) [M+H]+= 506.2, Rt = 1.44 min.

[1147]

[0570] Step 3: Synthesis of (S)-l-((lR,2S,5S)-3-azabicyclo[3.1.0]hexane-2-carbonyl)-N-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)piperidine-3-carboxamide IM-51 ()

[1148]

[0571] To a solution of IM-50 (1.600 g, 1 Eq., 3.162 mmol) in 1,4-Dioxane (5.000 mL) at 25 °C were added 4M HC1 solution in 1,4-dioxane (461.2 mg, 3.162 mL, 4.0 molar, 4 Eq, 12.65 mmol). After stirring for 10 min, the reaction mixture was allowed to stir at rt 12 h. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was concentrated; the residue was washed with w-pentane (60 mL), ether (50 mL) and dried under vacuum to give IM-51 (1.300 g, 71 % yield, 70% Purity) as a brown oil. The compound was used in the next reaction without further purification. MS (m / z) [M+H]+= 406.20

[1149]

[0572] Step 4: isopropyl (lR,2S,5S)-2-((S)-3-((7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)carbamoyl)piperidine- l-carbonyl)-3 -azabicyclo [3.1.0]hexane-3 -carboxylate, compound 137

[1150]

[0573] To the mixture IM-51 (1100.0 mg, 1 Eq., 2.4869 mmol) in DMF (6.000 mL) and TEA (503.30 mg, 693 pL, 2 Eq, 4.9738 mmol), isopropyl carbonochloridate (CAS # 108-23-6) (304.77 mg, 2.4869 mL, 1.000 molar, 1 Eq, 2.4869 mmol) was added dropwise at 0 °C. The resulting reaction mixture was allowed to stir for another 1 h. Progress of the reaction was monitored by TLC and LCMS. After 1 h, the mixture was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL x2). The separated organic layer was dried with Na2SO4and concentrated on vacuum. The residue was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 85:15 to 70:30; a 12 g Redisep Silver column via liquid injection). The product was further purified by prep HPLC using Method-H49 The fractions containing pure compounds were concentrated to afford compound 137 (160.0 mg, 13.06 % yield, 99.89% Purity) as white solid. MS (m / z) [M+H]+= 492.30, Rt = 7.15 min. [Method-L29], *HNMR (400 MHz, DMSO-6) δ 12.60 (s, 1H), 11.97 (m, 1H), 7.19-7.17 (dd, J= 8.2, 3.2 Hz, 1H), 6.99-6.95 (m, 1H), 4.72-4.39 (m, 3H), 4.19-3.98 (m, 1H), 3.51-3.39 (m, 2H), 3.22-3.12 (m, 1H), 2.90-2.76 (m, 1H), 2.60-2.56 (m, 1H), 2.12-2.07 (m, 1H), 1.18-1.72 (m, 2H), 1.59-1.37 (m, 3H), 1.23-1.11 (m, 5H), 1.02-0.97 (m, 1H), 0.75-0.70 (m, 1H), 0.29-0.24 (m, 1H). [a]D25+153.020 (c = 0.0333 g / 100 ml, Methanol).

[1151]

[0574] Example 62: Synthesis of Isopropyl (R)-3-((S)-3-((7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)carbamoyl)piperidine-l-carbonyl)pyrrolidine-l -carboxylate, Compound 138

[1152]

[1153]

[0575] Step 7: 1-isopropyl 3-methyl (R)-pyrrolidine- 1,3 -dicarboxylate IM-52:

[1154]

[0576] To a Stirred a mixture of (R)-methyl pyrrolidine-3 -carboxylate hydrochloride (CAS # 874964-22-4) (2.0 g, 1 Eq., 12.08 mmol) in DCM (20.0 mL) was added TEA (4.21 mL, 2.5 Eq, 30.19 mmol) at 0 °C and stirred for 5 mins. Then, Isopropyl chloroformate (CAS # 108-23-6) (1.63 g, 13.28 mL, 1.000 molar, 1.1 Eq., 13.28 mmol) was added and stirred for 4 hours at rt. Progress of the reaction monitored by TLC & LCMS. After completion of the reaction, water was added and extracted with EtOAc (50 mL x2); organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated. The crude was purified by column chromatography column using combi flash. The compound eluted at 20% EtOAc in Heptane; pure fractions were concentrated to afford IM-52 (1.1 g, Yield: 40.7 %, 96.1% Purity) as pale-yellow liquid. MS (m / z) [M+H]+= 216.10, Rt = 1.68 min.

[1155]

[0577] Step 2: ( / ?)- 1 -(isopropoxycarbonyl) pyrrolidine-3 -carboxylic acid IM-53 (): To a solution of IM-52 (1.600 g, 1 Eq, 7.433 mmol) in MeOH (7.0 mL), LiOH (0.53 g, 3 Eq, 22.30 mmol, dissolved in 7.0 mL of water) was added. Then the reaction mixture stirred at rt for 2 hours. The progress of the reaction was monitored by TLC & LCMS. After completion of the reaction, the solvent was concentrated under reduced pressure and residue was diluted with water (25 mL). The compound was acidified with 1 N HC1 and then the compound was extracted with Ethyl acetate (3 x 50 mL), combined organic layer were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford IM-53 (1.1 g, Yield: 62.7 %, 85.3% Purity) as pale-yellow Liquid. MS (m / z) [M+H]+= 202.1, Rt = 1.32 min.

[1156]

[0578] Step 3: isopropyl (R)-3-((S)-3-((7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)carbamoyl)piperidine- 1 -carbonyl)pyrrolidine- 1 -carboxylate, Compound 138

[1157]

[0579] To a mixture of compound Intermediate 42 (1.500 g, 1 Eq, 4.502 mmol) and IM-53 (0.99 g, 1.1 Eq, 4.952 mmol) in DMF (1.000 mL), DIPEA (2.35 mL, 3 Eq, 13.51 mmol) followed by O-(Benzotriazol-l-yl)-N, N, N’, N’-tetramethyluroniumTetrafluoroborate(TBTU) (2.168 g, 1.5 Eq, 6.753 mmol) were added. Then the reaction mixture stirred at 110 °C for 4 hours, progress of the reaction was monitored by TLC & LCMS. After completion of the reaction, water was added to the reaction mixture and the compound extracted with ethyl acetate (50mL x3). The combined organic layers were dried over anhydrous sodium sulphate, concentrated. The residue was purified by column chromatography column using combi flash (The compound was eluted at 100% EtOAc in Heptane). The fractions containing compound were concentrated. The crude was further purified by prep-HPLC purification using Method-L29. The fractions containing pure compound were collected, concentrated and lyophilized using acetonitrile: water under vaccume to afford compound 138 (0.085 g, Yield: 3.907 %, 99.32% Purity) as an off-white solid. MS (m / z) [M+H]+= 480.3, Rt = 7.00 min. [Method-H67]. ’H NMR (400 MHz, DMSO-6) δ 12.53 (bs, 1H) 11.93 (bs, 1H), 7.17 (dd, 4.0, 8.4 Hz, 1H), 6.99 (t, J= 9.6Hz, 1H), 4.76 - 4.74 (m, 1H), 4.46 - 4.21 (m, 1H), 4.13 - 3.89 (m, 1H), 3.56 - 3.08 (m, 6H), 2.90 - 2.67 (m, 2H), 2.07 - 1.90 (m, 2H), 1.82 - 1.70 (m, 3H), 1.43 - 1.31 (m, 1H), 1.18 - 1.17 (m, 6H). [a]D25+63.00 (c = 0.033g / 100mL, methanol). Absolute stereochemistry known

[1158]

[0580] Example 63: Synthesis of (Y)-N-(7-chloro-4-fluoro-lH-benzo[d1imidazol-2-yl)-l-((R)-l-isobutyrylpyrrolidine-3-carbonyl)piperidine-3 -carboxamide Compound 139

[1159]

[1160] Step 3

[1161]

[0581] Step 7: methyl (R)- l-isobutyrylpyrrolidine-3 -carboxylate, IM-54

[1162]

[0582] To a stirred solution of methyl (7?)-pyrrolidine-3 -carboxylate hydrochloride (CAS # 874964-22-4) (1.000 g, 1 Eq., 4.949 mmol) in DCM (10.00 mL), TEA (2.07 mL, 3 Eq., 14.85 mmol) followed by isobutyryl chloride (CAS # 79-30-1) (0.632 g, 0.622 mL, 1.2 Eq., 5.938 mmol) were added at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting materials, water (30 ml) was added and compound was extracted with 5% MeOH in DCM (30 ml x 2). The combined organic layer was dried over Na2SO4and concentrated. The crude was purified by combi-flash using 60% EtoAc in Hexane to get methyl IM-54 (0.950 g, 4.7 mmol, 95 % yield, 99 % purity) as colourless liquid. MS (m / z) [M+H]+= 200.10. Rt = 1.29 min.

[1163]

[0583] Step 2 ( / ?)- l-isobutyrylpyrrolidine-3 -carboxylic acid, IM-55 ()

[1164]

[0584] IM-55 was synthesized by adopting the procedure described using IM-54 (0.950 g, 1 Eq, 4.768 mmol) and LiOH (0.571 g, 0.352 mL, 5 Eq, 23.84 mmol, dissolved in 5.0 mL of water). IM-55 obtained 0.700 g Yield, 3.481 mmol, 73.00 % yield, 92.10 % purity) as colourless liquid. MS (m / z) [M+H]+= 186.2

[1165]

[0585] Step 3: (Y)-N-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-l-((7?)-l-isobutyrylpyrrolidine-3-carbonyl)piperidine-3-carboxamide Compound 139

[1166]

[0586] Compound 139 was synthesized by adopting the procedure described using IM-55 (0.275 g, 1.1 Eq., 1.488 mmol), Intermediate 42 (0.500 g, 1 Eq., 1.353 mmol) in DMF at 110 °C for over the period of 16 h. The crude was purified by using Method-H56 to yield compound 139 (0.03 g, 0.062 mmol, 4.590 % yield, 96.01% purity) as an off-white solid. MS (m / z) [M+H]+= 464.3, Rt = 6.67 min. [Method-L29], 'HNMR (400 MHz, DMSO-6) δ 12.04 (bs, 2H), 7.16-6.98 (m, 2H), 4.43-3.92 (m, 2H), 3.65-3.48 (m, 3H), 3.16-3.14 (m, 1H) 2.92-2.90 (m, 1H), 2.67-2.50 (m, 3H), 2.02-1.90 (m, 3H), 1.81-1.71 (m, 3H), 1.45-1.33 (m, 1H), 0.99-0.87 (m, 6H). [a]D25+ 6.00 (c = 0.033g / 100mL, methanol). Absolute stereochemistry known.

[1167]

[0587] Example 64: Synthesis of (S)-N-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-l-((R)-l- (isopropylsulfonyl)pyrrolidine-3-carbonyl)piperidine-3-carboxamide. Compound 140

[1168]

[1169]

[0588] Step 7: methyl (R)-l-(isopropylsulfonyl)pyrrolidine-3 -carboxylate (IM-56):

[1170]

[0589] IM-56 was prepared by adopting the procedure described using (7?)-pyrrolidine-3 -carboxylate hydrochloride (CAS # 874964-22-4) (2.0 g, 1 Eq., 12.08 mmol, TEA (4.2 mL, 2.5 Eq, 30.19 mmol) and propane-2-sulfonyl chloride (CAS # 10147-37-2) (1.89 g, 1.1 Eq., 13.28 mmol). (12A: 2.0 g, Yield: 67.4 %, 95.8% Purity) as pale-yellow liquid. MS (m / z) [M+H]+= 236.1, Rt = 1.54 min.

[1171]

[0590] Step 2: (R)- 1 -(isopropylsulfonyl) pyrrolidine-3 -carboxylic acid (IM-57):

[1172]

[0591] IM-57 was prepared by adopting the procedure described using IM-56 (10 (2.5 g, 1 Eq., 10.62 mmol) in MeOH (10.0 mL), LiOH (0.763 g, 3 Eq, 31.87 mmol, dissolved in 10 mL of Water). (12B: 2.0 g, Yield: 84.0 %, 99% Purity) as pale-yellow Liquid. MS (m / z) [M+H]+= 222.1, Rt = 0.8 min.

[1173]

[0592] Step 3: (S)-N-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-l-((R)-l-(isopropylsulfonyl)pyrrolidine-3-carbonyl)piperidine-3-carboxamide, Compound 140

[1174]

[0593] Compound 140 was prepared by adopting the procedure described using compound Intermediate 42 (1.5 g, 1 Eq., 4.502 mmol), IM-57 (1.096 g, 1.1 Eq, 4.952 mmol), DIPEA (2.35 mL, 3 Eq., 13.51 mmol) and O-(Benzotriazol-l-yl)-N, N, N’, N’-tetramethyluroniumTetrafluoroborate (TBTU) (2.168 g, 1.5 Eq, 6.753 mmol). The crude was purified by reverse phase column using flash column chromatography to yield compound 140 (0.180 g, Yield: 7.946 %, 99.36% Purity) as an off white solid. MS (m / z) [M+H]+= 499.3, Rt = 7.11 min. [Method-L8], ’H NMR (400 MHz, DMSO-tk) 8 12.11 (bs, 2H), 7.19 - 7.16 (dd, J = 8.6, 3.6 Hz, IH), 6.99 (t, J= 9.2 Hz, IH), 4.43 - 4.23 (m, IH), 4.12 - 3.86 (m, IH), 3.67 - 3.23 (m, 6H), 3.13 (t, J= 11.6 Hz, IH), 2.96 -2.68 (m, 2H), 2.16 - 1.71 (m, 5H), 1.47 - 1.41 (m, IH), 1.31 - 1.19 (m, 6H). [a]p25+54.00 (c = 0.033g / 100mL, methanol). Absolute stereochemistry known.

[1175]

[0594] Example 65: Synthesis of Isopropyl (R)-3-((S)-3-((4.6-difluorobenzo[d]thiazol-2-vDcarbamovDpiperidine-l-carbonyl)pyrrolidine-l -carboxylate, Compound 141

[1176]

[1177]

[0595] Step 7: isopropyl (R)-3-((S)-3-((4,6-difluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)pyrrolidine- 1 -carboxylate

[1178]

[0596] To a stirred mixture of compound 134 (350.0 mg, 1 Eq., 812.3 pmol) and TEA (164.4 mg, 226 pL, 2 Eq., 1.625 mmol) in DMF (3.500 mL), isopropyl carbonochloridate (CAS # 108-23-6) (398.2 mg, 446 pL, 30% Wt, 1.2 Eq., 974.7 pmol) was added at 0 °C. The mixture was then allowed to stirred at rt for 1 h; progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was added with ice-water (10 mL) and compound was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated to get the crude (350 mg). The residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate in heptane using 60-65%; a 24g Redisep Silver column using a 5 g solid cartridge). The compound obtained was further triturated with diethyl ether (5 mL) to get compound 141 (83 mg, 21% yield). MS (m / z) [M+H]+= 481.0 [M+H]+Rt = 8.36 min. [Method-L8],!H NMR (400 MHz, DMSO-6) δ 12.75 (s, 1H), 7.81-7.78 (m, IH), 7.50-7.35 (m, IH), 4.78-4.72 (m, 1H), 4.38-4.15 (m, IH), 4.13-3.52 (m, 4H), 3.50-3.26 (m, 4H), 3.24-2.98 (m, 2H), 2.96-2.90 (m, 1H), 2.04-2.01 (m, 2H), 1.98-1.68 (m, 3H), 1.46-1.28 (m, IH), 1.18-1.15 (m, 6H). Absolute stereochemistry known

[0597] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[1179] Table 33:

[1180]

[1181]

[1182]

[0598] Example 66: Synthesis of tert-butyl (S)-3-((S)-3-((4.6-difluorobenzold1thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)pyrrolidine-l -carboxylate, Compound 145

[1183]

[1184]

[0599] Step 1: tert-butyl (S)-3-((S)-3-((4,6-difluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)pyrrolidine- 1 -carboxylate

[1185]

[0600] To a stirred pre-cooled solution of Intermediate 41 (200.00 mg, 1 Eq., 599.20 pmol) in DCM (5.0 mL), TEA (181.90 mg, 251 pL, 3 Eq., 1.7976 mmol), (S)-l-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (CAS # 140148-70-5) (193.47 mg, 1.5 Eq., 898.80 pmol) and Propylphosphonic anhydride (571.96 mg, 529.1 pL, 50% Wt, 1.5 Eq, 898.80 pmol) were added at 0 °C. The resulting solution was then allowed to stirred at 25 °C for 5 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction was quenched with water (10 mL) and compound was extracted using DCM (2 x 10 mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 230-400 mesh silica gel. The desired product was eluted between 45% to 50% ethyl acetate in hexane. The crude compound was further purified by prep-HPLC using Method-H70 to get compound 145 (180.0 mg, 363 pmol, 60.6 %, 99.7% Purity) as an off-white solid. MS (m / z) [M+H]+= 495.0, Rt = 8.62 min. [Method-L8], *HNMR (400 MHz, DMSO-6) δ 12.75 (s, 1H), 7.80-7.79 (m, 1H), 7.37 (t, J= 10.00 Hz, 1H), 4.35-3.84 (m, 2H), 3.47-3.36 (m, 3H), 3.29-3.25 (m, 2H), 3.15-2.94 (m, 1H), 2.94-2.63 (m, 2H), 2.04-2.01 (m, 2H), 1.89-1.73 (m, 3H), 1.40 (s, 10H). [a]D25+87.00 (c = 0.029 g / 100 mL, Methanol). Absolute stereochemistry known.

[1186]

[0601] Example 67: Synthesis of tert-butyl (S)-2-((S)-3-((4.6-difluorobenzo[d1thiazol-2-yDcarbamoyDpiperidine-l-carbonyl)pyrrolidine-l -carboxylate, Compound 146

[1187]

[1188] To a stirred mixture of Intermediate 41 (500.00 mg, 1 Eq., 1.6817 mmol), l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (EDC.HCl) (967.14 mg, 3 Eq., 5.0451 mmol) and (tert-butoxycarbonyl)- L-proline (CAS # 140148-70-5) (361.98 mg, 1 Eq., 1.6817 mmol) in DMF (10.00 mL), HOBt (772.60 mg, 3 Eq, 5.0451 mmol) and DIPEA (1.0868 g, 1.46 mL, 5 Eq, 8.4084 mmol) were added at 25°C in a 10-20 mL microwave vial. The reaction was irradiated in a microwave apparatus (Biotage Initiator) at 110 °C for 1 hour and then vial was allowed to cooled to rt in the microwave cavity. Reaction was monitored by TLC & LCMS. Reaction mixture was concentrated under reduced pressure, quenched with ice cold water (20 mL) and the compound was extracted with ethyl acetate (3 x 80 mL). Combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was then purified by prep-HPLC using Method-H71. The fractions containing pure compound were concentrated under reduced pressure to furnish compound 146 (76.00 mg, 152.9 pmol, 9.094 %, 99.519% Purity) as off-white powder. MS (m / z) [M+H]+= 495.10, Rt = 9.69 min. [Method-L8], ‘H NMR (400 MHz, DMSO-6) δ 12.92-12.75 (m, 1H), 7.95-7.75 (m, 1H), 7.40-7.34 (t, J = 10.8 Hz, 1H), 4.65-4.59 (m, 1H), 4.36-3.76 (m, 2H), 3.23-3.20 (m, 1H), 3.13-2.92 (m, 1H), 2.67-2.61 (m, 2H), 2.25-2.19 (m, 1H), 2.11-2.04 (m, 1H), 1.81-1.726 (m, 5H), 1.52 (s, 1H), 1.38-1.27 (m, 10H). Chiral HPLC RT: 4.70 min., Purity: 99.74%. [a]D25+ 68.079, (c = 0.06667 g / 100 ml, Methanol). Absolute stereochemistry known.

[1189]

[0602] Example 68: Synthesis of N-(4.6-difluorobenzo[d1thiazol-2-yl)-l-(tetrahvdro-2H-pyran-4-carbonyl)piperidine-3-carboxamide. Compound 147, Compound 147a. Compound 147b

[1190]

[1191] (Peak-1) (Peak-2)

[1192]

[0603] Step 7: methyl l-(tetrahydro-2H-pyran-4-carbonyl)piperidine-3 -carboxylate (IM-58)

[0604] To a stirred solution of methyl piperidine-3 -carboxylate (CAS # 50585-89-2) (1.927 g, 1 Eq., 13.46 mmol) in Ethyl acetate (20.00 mL) was added TEA (4.086 g, 5.63 mL, 3 Eq., 40.38 mmol) at 0 °C and stirred for 15 min. Then, tetrahydro-2H-pyran-4-carbonyl chloride (CAS # 40191-32-0) (2.000 g, 1 Eq., 13.46 mmol) was added. The resulting reaction mixture was stirred at 55 °C for 2 h; progress of reaction was monitored by TLC and LCMS. After completion of the reaction, mixture was diluted water (20 mL) and compound was extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The obtained crude was purified by combi flash chromatography by silica gel using 2-3% Methanol in DCM to get IM-58 (1.800 g, 6.47 mmol, 48.0 % yield, 91.7% Purity) as yellow colour liquid. MS (m / z) [M+H]+= 256.10, Rt = 1.19 min.

[1193]

[0605] Step 2: l-(tetrahydro-2H-pyran-4-carbonyl)piperidine-3 -carboxylic acid (IM-59)

[1194] To a stirred solution of IM-58 (1.800 g, 1 Eq, 7.050 mmol) in THF:water (8:2 mL), Lithium Hydroxide (844.3 mg, 5 Eq., 35.25 mmol) was added and the reaction mixture was stirred at 25 °C for 16 h. The progress of reaction mixture was monitored by TLC & LCMS. After completion the reaction, the mixture was concentrated under reduced pressure and acidify with 2M HC1 solution. Compound was extracted using 20% MeOH / DCM (150mL x 2); combined organic layer were washed with brine solution (100 mL) and then dried over Na2SO4and concentrated under reduced pressure to get IM-59 (1.500 g, 6.217 mmol, 88.18 %) as a white solid. 15B was was used in next step without further purification. MS (m / z) [M+H]+= 242.1, Rt = 0.33 min.

[1195]

[0606] Step 3: N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(tetrahydro-2H-pyran-4-carbonyl)piperidine-3-carboxamide, Compound 147

[1196]

[0607] To a stirred solution of IM-59 (1.400 g, 1 Eq., 5.802 mmol) in DCM (20.00 mL), DIPEA (3.750 g, 5.05 mL, 5 Eq., 29.01 mmol) followed by propylphosphonic anhydride (2.769 g, 2.562 mL, 1.5 Eq., 8.703 mmol) were added at 0 °C. After stirred at rt for 15 minutes, 4,6-difluorobenzo[d]thiazol-2-amine (CAS #119256-40-5) (1.080 g, 1 Eq., 5.802 mmol) was added and stirred at rt for 16 h. Progress of this reaction was monitored by TLC & LCMS. After completion of reaction, mixture was diluted with water (10 mL) and extracted using DCM (3 x 200mL). The combined organic layer was washed with brine solution (50mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude. The crude was purified by combi flash chromatography by silica gel using 2-3% Methanol in DCM to get compound 147 (Racemate). The racemic mixture was submitted for chiral prep-HPLC using Method-C54 The two fractions were collected separately, concentrated under reduced pressure to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, as an off-white solid respectively:

[1197]

[0608] Analytical Characterization of compound 147a - (Peak-1):

[0609] 195.0 mg, 474.8 pmol, 8.183 %, 99.69% Purity. MS (m / z) [M+H]+= 410.3, Rt = 6.60 min. [Method-L29], *H NMR (400 MHz, DMSO-O 8 12.74 (s, 1H), 7.85-7.80 (m, 1H), 7.40-7.37 (t, J=10 Hz, 1H), 4.41-4.11 (m, 2H), 3.91-3.85 (m, 2H), 3.42-3.36 (m, 2H), 3.15-2.88 (m, 2H), 2.70-2.60 (m, 2H).

[1198] 2.04-2.0 (m, 1H), 1.84-1.04 (m, 7H). [a]D25+ 129.91, (c = 0.06667 g / 100 ml, Methanol). Absolute stereochemistry unknown.

[1199]

[0610] Analytical Characterization of compound 147b - (Peak-2):

[1200]

[0611] 200.0 mg, 486.6 pmol, 8.387 %, 99.62% Purity. MS (m / z) [M+H]+= 410.3, Rt = 6.59 min. [Method-L29], ’H NMR (400 MHz, DMSO-O 8 12.74 (s, 1H), 7.81-7.80 (m, 1H), 7.40-7.37 (t, J=10 Hz 1H), 4.41-4.11 (m, 2H), 3.91-3.78 (m, 2H), 3.42-3.36 (m, 2H), 3.14-2.88 (m, 2H), 2.70-2.60 (m, 2H). 2.04-2.0 (m, 1H), 1.84-1.04 (m, 7H). [a]D25-68.70, (c = 0.06667 g / 100 ml, Methanol). Absolute stereochemistry unknown.

[1201]

[0612] Example 69: Synthesis of (S)-N-(4.6-difluorobenzo[d]thiazol-2-yl)-l-(pyrrolidine-l-carbonyl)piperidine-3 -carboxamide, Compound 149

[1202]

[1203]

[0613] Step 7: (S)-N-(4,6-difluorobenzo[d]thiazol-2-yl)-l -(pyrrolidine- l-carbonyl)piperidine-3-carboxamide

[1204]

[0614] To a solution of Intermediate 41 (0.300 g, 1 Eq., 899 pmol) in DCM (5 mL), pyrrolidine (76.7 mg, 1.2 Eq, 1.08 mmol) was added and stirred the reaction mixture for 10 min at rt. Then, TEA (728 mg, 1.00 mL, 8 Eq., 7.19 mmol) followed by triphosgene (400 mg, 1.5 Eq., 1.35 mmol) was added. The reaction stirred at 0 °C for 3 h; progress of the reaction monitored by TLC and LCMS The reaction solvent was concentrated; water (10 mL) was added to residue and compound was extracted using ethyl acetate (3 x 20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. The crude which was purified using flash chromatography (30% ethyl acetate / hexane) and further purified by prep-HPLC using Method-H64 to yield compound 149 (0.050 g, 0.11 mmol, 13 % yield, 99.56% Purity). MS (m / z) [M+H]+= 395.30, Rt = 7.07 min. [Method-L29], ‘H NMR (400 MHz, DMSO-6) δ 12.69 (s, 1H), 7.79 (dd, J= 1.6, 8.4, Hz, 1H), 7.36 (dd, J = 8.2, 1.6 Hz, 1H), 3.78-3.75 (m, 1H), 3.59-3.56 (m, 1H), 3.27-3.24 (m, 4H), 2.93-2.88 (m, 1H), 2.76-2.70 (m, 2H), 2.02-1.99 (m, 1H), 1.73-1.58 (m, 6H), 1.48-1.42 (m, 1H). Absolute stereochemistry known.

[0615] Example 70: Synthesis of (S)-N-(4-fluoro-7-isopropoxybenzo[d]thiazol-2-yl)-1.9- dioxaspiro[5.5]undecane-4-carboxamide Compound 160

[1205]

[1206]

[0616] Step 7: (S)-A-(4-fluoro-7-hydroxybenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4- carboxamide

[1207]

[0617] To a solution of 6B (900.0 mg, 1 Eq, 1.889 mmol) in MeOH (1.00 mL) and water (0.20 mL) was added 30% hydrogen peroxide (1.928 g, 1.8 mL, 30 Eq, 56.68 mmol) at 0 °C and resulting mixture was stirred at 25 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic layer was washed with brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude. The obtained crude was purified by flash chromatography (using silica gel (60-120), 0%-100% ethyl acetate and n-heptane as eluent) to get the crude product (250.0 mg, 36.69 % yield, 85% purity). 100 mg of the crude compound was further purified by prep HPLC purification (using Method-H83). Pure fractions were collected, concentrated under reduced pressure followed by lyophilization afforded (0.015 g, 2.0% yield, 98.31% purity) as a white solid.

[1208]

[0618] Analytical characterization of Compound 6C

[1209]

[0619] MS (m / z) [M+H]+= 367.2, Rt = 4.45 min, [Method-L],1H NMR (400 MHz, DMSO-6) 8 12.59 (s, 1H), 10.25 (s, 1H), 7.06 (td, J= 10.4, 8.8 Hz, 1H), 6.63 (dd, J= 8.4, 3.2 Hz, 1H), 3.72 (dd, J= 11.6, 4.0 Hz, 1H), 3.63-3.52 (m, 5H), 2.99-2.93 (m, 1H), 1.97-1.87 (m, 2H), 1.75-1.72 (m, 1H), 1.60-1.55 (m, 3H), 1.49-1.39 (m, 2H). [«]D25+15.00 (C = 0.0333 g / 100 mL, methanol). Absolute stereochemistry known.

[1210]

[0620] Step 2: (S)-N-(4-fluoro-7-isopropoxybenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4- carboxamide 160

[1211]

[0621] To a solution of 6C (0.300 g, 1 Eq, 819 pmol) and 2-bromopropane (201 mg, 2 Eq, 1.64 mmol) in DMF (5.000 mL) were added potassium carbonate (226 mg, 95.9 qL, 2 Eq, 1.64 mmol) and potassium iodide (27.2 mg, 12.8 qL, 0.2 Eq, 164 qmol) at 0 °C and resulting mixture was stirred at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). Combined organic layer was washed with brine solution (20 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude mixture. The crude was purified using flash chromatographic technique using silica gel (60-120) and 0%-100% ethyl acetate in w-heptane as eluent where the desired peak eluted at 65% ethyl acetate in w-heptane. Pure fractions were collected and concentrated under reduced pressure to obtain 80 mg of desired compound with 97.5% purity as an off white solid. The compound was further purified by chiral prep-HPLC using Method-C74. After purification, pure fractions were collected, solvent was concentrated under reduced pressure and lyophilized using ACN and water to obtain the title compound (0.055 g 16.2% yield, 98.76% purity, >99% ee) as a white solid.

[1212]

[0622] Analytical characterization of Compound 160

[1213]

[0623] MS (m / z) [M+H]+= 409.3, Rt = 5.71 min. [Method-L32], *H NMR (400 MHz, DMSO-6) 8 12.65 (s, 1H), 7.22-7.17 (m, 1H), 6.89 (dd, J= 8.8, 3.2 Hz, 1H), 4.75-4.69 (m, 1H), 3.74-3.70 (m, 1H), 3.66-3.49 (m, 5H), 3.01-2.95 (m, 1H), 2.08-1.72 (m, 2H), 1.66-1.60 (m, 1H), 1.59-1.50 (m, 3H), 1.49-1.42 (m, 2H), 1.38-1.31 (m, 6H). [a]o25+18.00 (c = 0.066 g / 100 mL, methanol). Absolute stereochemistry known.

[1214]

[0624] Example 71: Synthesis of A-(7-chloro-4-fluoro-lZ7-benzo[<7|imidazol-2-yl)-2,5-dioxaspiro[3.51nonane-8-carboxamide Compounds 161a and 161b

[1215]

[1216] ,.

[1217] Step 1

[1218] intermediate 61

[1219]

[1220]

[1221] (Peak-1) (Peak-2)

[1222]

[0625] Step 7: 7V-(7-chloro-4-fluoro-177-benzo[<7|imidazol-2-yl)-2,5-dioxaspiro[3.5]nonane-8-carboxamide (8A)

[1223]

[0626] To a stirred solution of Intermediate 9 (200.0 mg, 1.078 mmol) and Intermediate 61 (278.3 mg, 1.616 mmol) in DMF (5.00 mL) were added TBTU (519.0 mg, 1.616 mmol) and DIPEA (418 mg, 0.563 mL, 3.23 mmol) at 25 °C and stirred at 100 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layers were washed with ice-cold water (2 X 20 mL) and brine (20 mL). The organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude mixture (250 mg). The crude was purified by flash column chromatography silica gel using 0-60 % EtOAc in w-pentane, to afford 8A (200 mg, 78% purity, racemic mixture) as an off white solid. The crude was subjected to prep-HPLC purification using Method-H87. The fractions containing the desired product were concentrated under reduced pressure to afford 8A (95 mg, 99.88% purity, racemic mixture) as an off white solid. The racemic mixture 8A was subjected to chiral HPLC using Method-C49. The two fractions were concentrated lyophilized separately using ACN and water to afford the title compounds.

[1224]

[0627] Analytical characterization of compound 161a Peak-1

[1225]

[0628] 0.028 g, 7.637 % yield, 99.86% purity, 99.65 % ee as an off-white solid. MS (m / z) [M + H]+= 340.2, Rt = 4.865 min. [Method-L32],1HNMR(400 MHz, DMSO-6) 8 12.60 (s, 1H), 11.93 (s, 1H), 7.19-7.16 (m, 1H), 6.99 (t, J= 9.2 Hz, 1H), 4.55-4.51 (m, 2H), 4.40-4.33 (m, 2H), 3.87-3.84 (m, 1H), 3.44-3.41 (m, 1H), 2.74 (m, 1H), 2.36 (d, J= 11.6 Hz, 1H), 1.72-1.58 (m, 3H). [OC]D25+23.183 (c = 0.0733g / 100 mL, ACN). Absolute stereochemistry unknown.

[1226]

[0629] Analytical characterization of compound 161b Peak-2

[1227]

[0630] 0.027 g, 7.357 % yield, 99.77% purity, 99.34 % ee as an off-white solid. MS (m / z) [M + H]+= 340.2, Rt = 4.864 min, [Method-L32],1HNMR(400 MHz, DMSO-6) δ 12.60 (s, 1H), 11.93 (s, 1H), 7.19-7.16 (m, 1H), 6.99 (t, J= 9.2 Hz, 1H), 4.55-4.51 (m, 2H), 4.40-4.33 (m, 2H), 3.87-3.84 (m, 1H), 3.44-3.41 (m, lH), 2.74 (m, 1H), 2.36 (d, J= 11.6 Hz, 1H), 1.72-1.58 (m, 3H). [OC]D25- 42.001 (c =0.050 g / 100 mL, ACN). Absolute stereochemistry unknown.

[1228]

[0631] Example 72: Synthesis of N-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-l-((3R,4S)-3-hvdroxytetrahvdro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide Compounds 197a and 197b

[1229]

[1230] (Peak-2)

[1231]

[0632] Step 1: N-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-l-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3 -carboxamide (8 A)

[1232]

[0633] A solution of Intermediate 1 (1.0 g, 1 Eq, 4.9 mmol) and Intermediate 59 (1.3 g, 1 Eq, 4.9 mmol) in pyridine (10.000 mL) was cooled to 0 °C, then added POCl₃ (2.3 g, 13 Eq, 15 mmol) and the reaction mixture was stirred at 0°C for 30 min. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-cold water and added saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate (100 mL), washed with water (100 mL) and brine (10 mL). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude. The crude mixture was purified by combi flash purifier on silica gel using 5% MeOH in DCM as eluent. The pure fraction was concentrated under reduced pressure to get the product 8A (600 mg). MS (m / z) [M+H]+= 442.1, Rt = 1.338 min.

[0634] Step 2 A-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-l-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3 -carboxamide (8B)

[1233]

[0635] To a stirred solution of 8 A (0.500 g, 1.13 mmol) in DCM (5.000 mL) at 0 °C was added BBr₃ (1.42 g, 5 Eq, 5.66 mmol) dropwise and the resulting mixture was stirred at 0 °C for 2 h. The progress of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was diluted with DCM (15 mL) and quenched with saturated solution of NaHCO3 (pH: 8-9) at 0 °C. Organic layer was separated, washed with brine, dried over Na₂SO₄. filtered and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by combiflash purifier using silica gel and the desired product eluted at 5% MeOH in DCM. The pure fraction was concentrated under reduced pressure to get the product 8B (450 mg, 18% yield, diastereomeric mixture). The diastereomeric 8B was subjected to chiral HPLC separation using method-C89. Two peaks separated were collected, organic solvent was distilled under vacuum and lyophilized separately using ACN and water to afford the title compounds in an enantiomeric excess of 99.12 % ee and 97.54 % ee respectively:

[1234]

[0636] Analytical characterization of compound 197a (Peak-1)

[1235]

[0637] 88.0 mg, 17.26% yield, 98.40% purity, 99.12 % ee as an off-white solid. MS (m / z) [M+H]+= 428.3, Rt = 4.33 min. [Method-L31], ‘HNMR (400 MHz, DMSO-O 8 12.91 (s, 1H), 7.94 (dd, J= 8.4, 2.0 Hz, 1H), 7.56 (dd, J = 9.2, 2.0 Hz, 1H), 4.9O (d, J= 4.0 Hz, 1H), 4.22 (td, J= 4.4Hz, 11.6 Hz, 1H), 3.86-3.80 (m, 2H), 3.64-3.63(m, 1H), 3.56-3.42 (m, 2H), 3.14 (s, 1H), 3.32 (s, 1H), 2.99 (t, J= 10.4 Hz, 1H), 2.33 (t, J= 10.4 Hz, 2H), 2.08-1.96 (m, 2H), 1.73-1.64 (m, 1H), 1.47 (d, J= 10.0 Hz, 1H). [a]D25+30.604 (c = 0.03333 g / 100 mL, ACN). Absolute stereochemistry unknown.

[1236]

[0638] Analytical characterization of compound 197b (Peak-2)

[1237]

[0639] 75.0 mg, 15.12% yield, 97.63% purity, 97.54 % ee as an off-white solid. MS (m / z) [M+H]+= 428.3, Rt = 4.28 min. [Method-L31],1HNMR (400 MHz, DMSO-O 8 12.94 (s, 1H), 7.95 (dd, J = 8.4, 2.4 Hz, 1H), 7.56 (dd, J = 9.2, 2.4 Hz, 1H), 4.98 (d, J= 4.0 Hz, 1H), 4.28 (td, J= 4.4Hz, 11.6 Hz, 1H), 3.84-3.81 (m, 2H), 3.63-3.59 (m, 2H), 3.43 (t, J= 11.2 Hz, 1H), 3.22 (s, 1H), 2.97 (t, J= 10.4 Hz, 2H), 2.44-2.22 (m, 2H), 2.03 (bs, 1H), 1.95-1.84 (m, 1H), 1.84-1.71 (m, 1H), 1.46 (d, J= 9.2Hz, 1H). [a]D25-22.0 (c = 0.03333 g / 100 mL, ACN). Absolute stereochemistry unknown.

[1238]

[0640] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[1239]

[0641] Table 34:

[1240]

[1241]

[1242]

[1243]

[0642] Example 73: Synthesis of A-(7-chloro-4-fluoro-lH-benzo[dlimidazol-2-yl)-l-((3S.4R)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide Compounds 200a and 200b

[1244]

[1245] intermediate 9 p

[1246]

[1247]

[0643] Step 7: A-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-l-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3 -carboxamide (9A)

[1248]

[0644] To a stirred solution of Intermediate 9 (400.0 mg, 2.155 mmol) in DMF (10.000 mL), Intermediate 58 (554.5 mg, 2.155 mmol), HBTU (1.226 g, 1.5 Eq, 3.233 mmol) and DIPEA (835.7 mg, 1.13 mL, 3 Eq, 6.466 mmol) were added at rt. The reaction mixture was stirred at same temperature for 16 h and progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude mixture was purified by combi flash purifier using 0-100 % ethyl acetate in n-heptane as eluent followed by 0-15% MeOH in DCM. The pure fraction was concentrated under reduced pressure to get the product 9A (580 mg, 63% yield diastereomeric mixture) as an off-white solid. Compound (9A) was subjected to chiral HPLC separation using Method-C81. Two peaks separated were collected, organic solvent was distilled under vacuum and lyophilized separately using ACN and water to afford (Peak-1) and (Peak-2).

[1249]

[0645] Analytical characterization compound 200a of (Peak-1)

[1250]

[0646] 155.0 mg, 17.55% yield, 99.94% purity, >99.0% ee as an off-white solid. MS (m / z) [M+H]+= 425.3, Rt = 4.54 min. [Method-L31],1HNMR (400 MHz, DMSO-O d 12.68-12.01 (m, 2H), 7.19-7.16 (m, 1H), 7.01 - 6.99 (m, 1H), 4.38 - 4.34 (m, 1H), 4.14-4.10 (m, 1H), 3.82-3.78 (m, 1H), 3.50-3.42 (m, 4H), 3.32-3.30 (m, 3H), 3.1-3.05 (m, 1H), 2.99-2.94 (m, 1H), 2.38-2.28 (m, 2H) 2.03-2.00 (m, 2H), 1.80- 1.70 (m, 1H), 1.53-1.51 (m, 1H). [a]D25-30.004 (c = 0.03333 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1251]

[0647] Analytical Characterisation compound 202b of (Peak -2)

[1252]

[0648] 140.0 mg, 15.85% yield, 99.18% Purity, 99.86% ee as an off-white solid. MS (m / z) [M+H]+= 425.3, Rt = 4.584 min [Method-L31],1HNMR (400 MHz, DMSO-O d 12.05 (m, 2H), 7.20-7.17 (m, 1H), 7.02-6.97 (m, 1H), 4.38-4.31 (m, 1H), 4.16-4.08 (m, 1H), 3.85-3.81 (m, 1H), 3.68-3.64 (m, 1H), 3.42-3.35 (m, 2H), 3.32-3.26 (m, 4H), 3.05-2.90 (m, 2H), 2.50-2.40 (m, 1H), 2.40-2.35 (m, 1H), 2.07-1.91 (m, 1H), 1.89-1.77 (m, 2H) 1.51-1.49 (m, 1H). [a]D25-9.001 (c = 0.03333 g / lOOmL, methanol) Absolute stereochemistry unknown.

[1253]

[0649] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[1254]

[0650] Table 35

[1255]

[1256]

[1257]

[0651] Example 74: Synthesis ofA''-(4-chloro-l H-bcnzo|d|imidazol-2-yl)-l-((3S.4R.)-3-methoxytetrahvdro-2H-pyran-4-yl)-6-oxopiperidine-3 -carboxamide 202a and 202b

[1258]

[1259] intermediate 71

[1260] Step 1 10A

[1261]

[1262] (Peak-1) (Peak-2)

[1263]

[0652] Step 1: A-(4-chloro-l H-benzo[d]imidazol-2-yl)-l -((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3 -carboxamide (Compound 10A)

[1264]

[0653] To a stirred solution of Intermediate 71 (0.900 g, 5.37 mmol) and Intermediate 58 (1.11 g, 4.30 mmol) in DMF (20.00 mL), DIPEA (2.08 g, 2.81 mL, 3 Eq., 16.1 mmol), and PyBOP (6.99 g, 2.5 Eq, 13.4 mmol) were added at 0 °C. The reaction mixture was stirred at 100°C for 16 h. Progress of the reaction was monitored by TLC & LCMS. After completion of the reaction, the reaction mixture was diluted with ice-cold water (25 mL) and extracted with EtOAc (25 mL X 2). The combined organic layer was washed with brine (25 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude mixture was purified by combi flash purifier using silica gel column and the desired product eluted between 1.8 to 2% MeOH in DCM to afford compound 10A. The compound 10A was further purified by reveres phase flash column chromatography using 0.1% Formic acid in ACN to afford product 10A (0.600 g, 27.4% yield, diastereomer) as a white solid. Compound 10A was subjected to chiral HPLC separation using Method-C85. Two peaks separated were collected, organic solvent was distilled under reduced pressure and lyophilized separately using ACN and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, respectively:

[1265]

[0654] Analytical characterization of compound 202a (Peak-1)

[1266] 0.18 g, 8.25 % yield, 99.57 % purity, 99.74 % ee as a white solid. MS (m / z) [M+H]+= 407.1, Rt = 5.412 min. [Method-L31] 'H NMR (400 MHz, DMSO-t / e) d 12.35 (s, 1H), 12.02 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.17 (d, J= 7.2 Hz, 1H), 7.06 (t, J= 7.6 Hz, 1H), 4.33-4.40 (m, 1H), 4.14-4.10 (m, 1H), 3.75 (dd, J= 4.4, 11.2 Hz, 1H), 3.54-3.41 (m, 3H), 3.32-3.24 (m, 4H), 3.06 (t, J= 6.4 Hz, 1H), 3.01-2.94 (m, 1H), 2.39-2.26 (m, 2H), 2.02-1.99 (m, 2H), 1.81-1.73 (m, 1H), 1.53-1.49 (m, 1H). [a]D25-22.50 (c = 0.066 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1267]

[0655] Analytical characterization of compound 202b (Peak-2)

[1268]

[0656] 0.145 g, 6.90 % yield, 99.21% purity, 99.74 % ee as a white solid. MS (m / z) [M+H]+= 407.3, Rt = 4.509 min. [Method-L31], *HNMR (400 MHz, DMSO-<fc) d 12.4 (s, 1H), 12.02 (s, 1H), 7.43 (d, 7=7.6 Hz, 1H), 7.17 (d, 7=7.2 Hz, 1H), 7.07 (t, J = 8 Hz, 1H), 4.37-4.16 (m, 1H), 4.15-4.12 (m, 1H), 3.83 (dd, 7=4.4, 11.2 Hz, 1H), 3.66-3.65 (m, 1H), 3.39-3.29 (m, 3H), 3.24 (s, 3H), 2.93 (t, 7=10.8 Hz, 2H), 2.46-2.40 (m, 1H), 2.07-2.05 (m, 1H), 1.94 -1.82 (m, 1H), 1.79-1.52 (m, 2H), 1.23-1.17 (m, 1H). [a]D25-18.00 (c = 0.066 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1269]

[0657] Example 75: Synthesis of A''-(4.6-difluorobcnzo|dlthiazol-2-yl)-l-(2-mcthoxycthyl)-6-oxopiperidine-3 -carboxamide 203a and 203b

[1270]

[1271] (Peak-1) (Peak-2)

[1272]

[0658] Step 1: Synthesis of 2V-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(l-methyl-lH-pyrazol-4-yl)-6-oxopiperidine-3 -carboxamide (11 A)

[1273]

[0659] To a stirred solution of Intermediate 62 (575.5 mg, 2.57 mmol) in DCM (5.00 mL) was added 1-Chloro-N,N,2-Trimethylpropenylamine (862 mg, 0.853 mL, 6.45 mmol) at 0 °C and stirred at rt for 1.5 h. Then solution of CAS no. 119256-40-5 (400.0 mg, 2.148 mmol) in Pyridine (ImL) / THF (3mL) was added by at 0 °C and stirred at rt for 16 h. The progress of the reaction was monitored by TLC and LCMS. After 16 h, the reaction mixture was diluted with ice-cold water (15 mL) and extracted with DCM (40 mL). The organic layer was washed with brine (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to get the crude (0.6 g). The crude mixture was purified by combi flash purifier using 70% ethyl acetate in heptane as eluent. The pure fraction was concentrated under reduced pressure to get the product 11A (300 mg, 35% yield, racemic mixture). The enantiomeric mixture 11A was subjected to chiral SFC separation using Method-C67. Separated two peaks were collected, organic solvent was distilled under reduced pressure and lyophilized separately using ACN and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, respectively:

[1274]

[0660] Analytical characterization of compound 203a (Peak-2)

[1275]

[0661] 65.00 mg, 7.73 % yield, 99.70% purity, 99.98% ee, as a white solid. MS m / z [M+H]+= 392.2, Rt = 4.183 min. [Method-L31], ‘HNMR (400 MHz, DMSO-6) 8 12.86 (s, 1H), 8.01 (s, 1H), 7.79-7.82 (m, 1H), 7.61 (s, 1H), 7.37 (td, J = 11.2,9.2 Hz, 1H), 3.80-3.91 (m, 5H), 3.21-3.31 (m, 1H), 2.45-2.50 (m, 2H), 2.00-2.17 (m, 2H). [a]o25+15.00 (c = 0.0666 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1276]

[0662] Analytical characterization of compound 203b (Peak-2)

[1277]

[0663] 105.0 mg, 11.50 yield%, 99.54% purity, 99.96% ee, as a white solid. MS m / z [M+H]+= 392.2, Rt = 4.22 min [Method-L32], *H NMR (400 MHz, DMSO-O 8 12.86 (s, 1H), 8.01 (s, 1H), 7.80-7.82 (m, 1H), 7.62 (s, 1H), 7.38 (td, J = 11.6,2.0 Hz, 1H), 3.87-3.92 (m 1H), 3.80-3.84 (m, 4H), 3.21-3.32 (m, 1H), 2.45-2.50 (m, 2H), 2.02-2.17 (m, 2H). [OC]D25-15.00 (c = 0.0666 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1278]

[0664] Example 76: Synthesis of A-(4.6-difluorobenzo[d]thiazol-2-yl)-5-(tetrahvdro-2H-pyran-4-yl)-2-oxa-5-azaspiro[3.5]nonane-7-carboxamide 205a and 205b

[1279]

[1280] (Peak-1) (Peak-2)

[1281]

[0665] Step 1: 2V-(4,6-difluorobenzo[d]thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-2-oxa-5-azaspiro[3.5]nonane-7-carboxamide (Compound 12A)

[0666] To a stirred solution of 4,6-difluorobenzo[d]thiazol-2-amine (CAS # 119256-40-5) (125.00 mg, 0.671 mmol) in DMF (5.0 mL) were added Intermediate 60 (198.92 mg, 0.738 mmol) and LiOH (16.08 mg, 0.671 mmol) and the reaction mixture was stirred at 80 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted using water (50 mL) and extracted with ethyl acetate (2 xlOO mL). The combined organic extracts were washed with water (40 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain the crude material. The crude mixture was purified by combi flash purifier and the desired product eluted between 45% to 55% ethyl acetate in heptane. The pure fractions were combined and concentrated under reduced pressure to get the product 12A (60 mg, 30% yield, racemic mixture) as enantiomeric mixture. The enantiomeric mixture 12A was subjected to chiral SFC separation using Method-C89. Separated two peaks were collected, organic solvent was distilled under reduced pressure and lyophilized separately using ACN and water to afford the title compounds. To further enhance the purity, each of the isomer was purified through reverse phase column chromatography on Cl 8 column using combi flash purifier (eluent: 0.1 % formic acid in water / ACN). Pure fraction containing product was concentrated under reduced pressure and lyophilized separately using ACN and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >98% ee, respectively.’

[1282]

[0667] Analytical characterization of compound 205a Peak-1

[1283]

[0668] 3.8 mg 1.33% yield, 97.77% purity, 99.68 % ee as an off-white solid. MS (m / z) [M+H]+= 424.3; Rt = 5.003 min. [Method-L31],1HNMR(400 MHz, DMSO-6) 8 12.71 (bs, 1H), 8.30 (s, 1H), 7.78 (d, J = 8 Hz, 1H), 7.35 (t, J= 10.8 Hz, 1H), 4.68 (d, J= 6.4 Hz, 1H), 4.47 (d, J= 5.6 Hz, 1H), 4.37 (d, J= 5.6 Hz, 1H), 4.14 (d, J= 6 Hz, 1H), 3.86 (t, J= 11.2 Hz, 2H), 3.16-3.07 (m, 2H), 2.82-2.76 (m, 1H), 2.50- 2.42 (m, 3H), 2.05 (d, J= 12 Hz, 1H), 1.90-1.70 (m, 4H), 1.58-1.49 (m, 3H). [a]D25+51.607 (c = 0.03333 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1284]

[0669] Analytical characterization of compound 205b Peak-2

[1285] 7.9 mg. 2.78% yield, 99.77% purity, 98.12 % ee as an off-white solid. MS (m / z) [M+H]+= 424.3; Rt = 5.005 min. [Method-L31],1HNMR(400 MHz, DMSO-6) 8 12.71 (bs, 1H), 8.24 (s, 1H), 7.78 (d, J= 6.8 Hz, 1H), 7.36 (td, J = 2.4, 10.8 Hz, 1H), 4.68 (d, J= 6 Hz, 1H), 4.47 (d, J= 5.6 Hz, 1H), 4.37 (d, J = 5.6 Hz, 1H), 4.14 (d, J= 6.4 Hz, 1H), 3.86 (t, J= 11.2 Hz, 2H), 3.39-3.07 (m, 3H), 2.79-2.77 (m, 1H), 2.50- 2.43 (m, 2H), 2.05 (d, J= 12 Hz, 1H), 1.90-1.70 (m, 4H), 1.58-1.49 (m, 3H). [a]D25-24.003 (C=0.0333 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1286]

[0670] Example 77: of N-(7-chloro-4-fluorobenzo[dlthiazol-2-yl)-l-(3-cvano-3-methylbutanoyl)piperidine-3-carboxamide 206a and 206b

[1287]

[1288]

[0671] Step 7: 7V-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-(3-cyano-3-methylbutanoyl)piperidine-3-carboxamide

[1289]

[0672] To a solution of Intermediate 37 (2.0 g, 6.3739 mmol) and DMF (15.00 mL) in a seal tube were added DIPEA (2.4715 g, 3.33 mL, 3 Eq, 19.122 mmol), HATU (3.1507 g, 1.3 Eq, 8.2861 mmol) and 3-cyano-3 -methylbutanoic acid (CAS # 99839-17-5) (810.38 mg, 1 Eq, 6.3739 mmol), and the tube was closed. After stirring for 10 min at room temperature the reaction mixture was heated to 110 °C. Progress of the reaction was monitored by TLC and LCMS. After 3 h, the reaction mixture was concentrated under reduced pressure at rotavapor. The reaction mixture was diluted with NaHCO3 (5 mL) and then extracted with EtOAc (2 x 3 mL). The organic layer was concentrated under reduced pressure to get the crude material. The crude material was purified by combi flash purifier on silica gel and the desired product eluted between 50% to 60% ethyl acetate in heptane. The pure fraction was concentrated under reduced pressure to get the product (1.6 g, 59% yield, racemic mixture). The racemic compound was subjected to chiral HPLC separation using Method-C68. Separated two peaks were collected, organic solvent was distilled under reduced pressure and lyophilized separately using ACN and water to afford the title compounds as separate enantiomers in an enantiomeric excess of >99% ee, respectively.

[1290]

[0673] Analytical characterization of compound 206a Peak-1

[1291]

[0674] 35 mg, 1.35 % yield, 99.82% purity, > 99 % ee as a white solid. MS (m / z) [M+H]+= 423.3, Rt =5.66 min., [Method-L17], ’H NMR (400 MHz, DMSO-6) 8 12.96 (s, 1H), 7.45-7.35 (m, 2H), 4.47-4.25 (m, 1H), 4.02-3.76 (m, 1H), 3.25-3.05 (m, 2H), 2.94-2.62 (m, 4H), 2.07-2.04 (m, 1H), 1.80-1.67 (m, 2H), 1.38 (s, 6H). [«]D25+16.400 (c = 0.1000 g / 100 mL, methanol). Absolute stereochemistry unknown.

[0675] Analytical characterization of compound 206b Peak-2

[1292]

[0676] 35 mg, 1.35 % yield, 99.88% purity, 99.24 % ee as a white solid. MS (m / z) [M+H]+= 423.3, Rt = 5.69 min. [Method-L17], ‘H NMR (400 MHz, DMSO-d₆) δ 12.96 (s, 1H), 7.44-7.35 (m, 2H), 4.46-4.24 (m, 1H), 4.01-3.75 (m, 1H), 3.25-3.05 (m, 2H), 2.94-2.65 (m, 4H), 2.08-2.04 (m, 1H), 1.80-1.68 (m, 2H), 1.38 (s, 6H). [«]D25-83.002 (c = 0.1000 g / 100 mL, methanol). Absolute stereochemistry unknown.

[1293]

[0677] Example 78 - Biological assay - Cellular cGMP Production

[1294]

[0678] The 36 compounds described were tested for their functional activity in a cellular cGMP production assay using human NPR1 expressing CHO-K1 cells (DiscoverX (Cat. #93-0804C2) For the functional characterization of the compounds, the production of cyclic guanosine 3',5'-cyclic monophosphate (cGMP) upon binding to and stimulation of NPR1 expressed on the cell surface of CHO-K1 cells treated with the EC20 of human ANP (Phoenix Pharmaceuticals (Cat. #005-06)) was monitored. Cellular cGMP is a major second messenger that mediates cell activities and is synthesized by activated NPR1 triggered by binding of the natural ligand ANP. Therefore, a commercial assay kit was used (CisBio HTRF Assay Kit (Cat. # 62GM2PEB)). The assay was performed according to manufacturer’s instructions with minor deviations. In brief, human NPR1 cells were adjusted to 2 xlO4cells / mL and 20 pL / well were seeded in 384-well microtiter plates and incubated overnight. All compound stocks were diluted in PBS + 0.1 % BSA at 2-fold the final assay concentration. After addition of 10 pL / well of assay buffer (PBS + 0.1% BSA +1 mM IBMX) and 10 pL / well of the compounds in different concentrations (12-point dose-response with 3-fold dilutions from a top concentration of 30 pM), the plate was incubated for 30 min at 37°C to allow for cGMP production. In parallel, a standard curve using a calibrator (contained in the kit) was generated. The cells were lysed and a mix of cGMP-d2 and anti-cGMP-cryptate was added and incubated for Ih at room temperature. The readout was performed using an Envision plate reader (PerkinElmer) with an excitation wavelength of 317 nm and an emission wavelength of 665 nm. cGMP concentration (Delta F [%]) was calculated according to the following formulae::

[1295] Ratio = [(A665nm / B620nm)* 104]

[1296] Mean Ratio = (Σratios / 2)

[1297] CV = [(Std deviation / Mean ratio)* 100]

[1298] Delta F = [((Calibrator or sample Ratio - Rationeg) / Rationeg)*100]

[1299] Rationeg: negative control

[1300]

[0679] An ANP (Phoenix Pharmaceuticals (Cat. #005-06)) dose-response curve was used as a control for each assay run. Table 36: In vitro functional data

[1301]

[1302]

[1303]

[1304]

[1305]

[1306]

[1307]

[1308] Equivalents

[1309]

[0680] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I)or a pharmaceutically acceptable salt thereof wherein:R2and R3are each independently selected from H, (C1-C6)alkyl, and (Ci-Ce)alkoxy; orR2and R3together with the carbon to which they are bound combine to form a (C3-C6)cycloalkyl or a 3- to 10-membered heterocycle containing 0;Rais independently for each occurrence selected from halo, (C1-C6)alkyl, (Ci-C6)haloalkyl, (C3- C6)cycloalkyl, (Ci-Ce)alkoxy, or (Ci-C6)haloalkoxy;Rbis H or (C1-C6)alkyl;Rd1is H, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, 6 membered heterocycle containing N, 0, or S, or heteroaryl, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (Ci-C6)alkyl, the (Ci-C6)alkyl, the (C3- C6)cycloalkyl, and the 6 membered heterocycle are optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from halo, -OH, -COOH, (C1-C6)haloalkoxy, (C1-C6)alkoxy, and a 5 or 6 membered heterocycle containing O;Rd2is H, aryl or heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (C1-C6)alkyl;Rd3is H or (C1-C6)alkyl;Rd4is H, (C1-C6)alkyl, C3-C6)cycloalkyl, or aryl, wherein the aryl is optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from halo and (C1-C6)alkyl;Reis (C1-C6)alkyl, (C3-C6)cycloalkyl, 5 or 6 membered heterocycle containing N, 0, or S, and heteroaryl, wherein the (C1-C6)alkyl, (C3-C6)cycloalkyl, 5 or 6 membered heterocycleand heteroaryl are each independently substituted with (Ci-C6)alkyl, -CN, -W is N or S; andp is an integer selected from 1, 2, 3, and 4.

2. The compound of claim 1, wherein W is S.

3. The compound of claim 1, wherein W is N.

4. The compound of any one of claims 1-3, wherein the compound is of formula5. The compound of any one of claims 1-3, wherein the compound is of formula6. The compound of any one of claims 1-3, wherein the compound is of formula7. The compound of any one of claims 1-3, wherein the compound is of formula8. The compound of any one of claims 1-7, wherein Rais independently for each occurrence selected from halo, (Ci-C3)alkyl and (Ci-C3)alkoxy, and (Ci-C3)haloalkoxy.

9. The compound of any one of claims 1-7, wherein Rais independently for each occurrence selected from fluoro, chloro, bromo, -OCH3, -OCF3,and cyclopropyl.

10. The compound of any one of claims 1-7, wherein Rais independently for each occurrence selected from fluoro.

12. The compound of any one of claims 1-11, wherein R1isandR2and R3are each independently selected from H, (Ci-C6)alkyl, and (Ci-C6)alkoxy; orR2and R3together with the carbon to which they are bound combine to form a (C3-C6)cycloalkyl or a 6-membered heterocycle containing 0.

13. The compound of any one of claims 1-12, whereinR2and R3together with the carbon to which they are bound combine to form a (C4-C6)cycloalkyl.

14. The compound of any one of claims 1-13, wherein R1is selected from15. The compound of any one of claims 1-10, wherein16. The compound of any one of claims 1-10 and 15, wherein Rxis; and Rdlis (Ci- Ce)alkyl, (C3-C6)cycloalkyl, Ce aryl, 6 membered heterocycle containing 0, or heteroaryl, wherein the C6 aryl and heteroaryl are each optionally substituted with one or two substituents selected from (Ci-C2)alkyl, the (C1-C6)alkyl is optionally substituted with one or more substituents (e.g., 1, 2, 3, or 4) selected from (Ci-C2)alkoxy.

17. The compound of any one of claims 1-10, 15 and 16, wherein R.1is; and Rdlis (Ci- Ce)alkyl, (C3-C6)cycloalkyl, Ce aryl, 6 membered heterocycle containing 0, or a 5 membered heteroaryl containing N, wherein the C6 aryl is optionally substituted with one or two substituents selected from (Ci-C2)alkyl, the 5 membered heteroaryl containing N is optionally substituted with one or two substituents (e.g., 1, 2, 3, or 4) selected from (Ci-C2)alkyl, and the (C1-C6)alkyl is optionally substituted with one or two substituents selected from (Ci-C2)alkoxy.

18. The compound of any one of claims 1-10 and 15-17, wherein R.1isand Rd2is H, C6 aryl or 5 or 6 membered heteroaryl containing N or S, wherein the heteroaryl is optionally substituted with one or two substituents selected from (Ci-C6)alkyl.

19. The compound of any one of claims 1-10 and 15-18, wherein R1is selected from20. The compound of any one of claims 1-10 and 15, wherein(C3-C6)cycloalkyl, 5 or 6 membered heterocycle containing N, or heteroaryl, wherein the (C3-C6)cycloalkyl, 5 or 6 membered heterocycle containing N, and heteroaryl are each independentlysubstituted with (C1-C6)alkyl,21. The compound of any one of claims 1-10, 15 and 20, wherein R1is selected from22. The compound of any one of claims 1-21, wherein Rbis H or -CH3.

23. The compound of any one of claims 1-22, wherein Rbis H.

24. The compound of any one of claims 1-23, wherein p is an integer selected from 1 and 2.

25. The compound of any one of claims 1-24, wherein p is an integer selected from 1.

26. The compound of claim 1, wherein the compound is selected fromN-(4-fluoro-lH-benzo[d]imidazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(7-chlorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(6-fluorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(6-chlorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(6-methoxybenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;(S)-N-(4,6-difluorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-carboxamide;N-(7-chloro-4-methoxybenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4 -carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-5-oxaspiro[3.5]nonane-8-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-oxaspiro[5.5]undecane-4-carboxamide;N-(5,7-difluoro-lH-benzo[d]imidazol-2-yl)tetrahydro-2H-pyran-4-carboxamide;N-(5,7-difluoro-lH-benzo[d]imidazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(4,7-difluorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-methyl-6-oxopiperidine-3 -carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-2-(thiophen-2-yl)-l-(p-tolyl)piperidine-3-carboxamide; N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide; rac-(2R,3R)-l-cyclopropyl-N-(4,6-difluorobenzo[d]thiazol-2-yl)-2-(l-m ethyl- lH-imidazol-2-yl)-6-oxopiperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(3,4-dimethylphenyl)-6-oxopiperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-(o-tolyl)piperidine-3-carboxamide;rac-(2R,3R)-N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-methyl-6-oxo-2-phenylpiperidine-3-carboxamide; N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-methyl-2-(l-methyl-lH-pyrazol-4-yl)-6-oxopiperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-isopropyl-6-oxopiperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-phenylpiperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(2-methoxyethyl)-6-oxopiperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-pentylpiperidine-3-carboxamide;tert-butyl (lR,2R,5S)-2-(3-((4,6-difluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)-3-azabicyclo [3.1.0]hexane-3 -carboxylate(lR,2R)-2-(3-((4,6-difluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)cyclobutane-l-carboxylic acid;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(2,5-dimethyloxazole-4-carbonyl)piperidine-3-carboxamide; N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(imidazo[l,2-a]pyridine-7-carbonyl)piperidine-3-carboxamide; tert-butyl (lR,2S,5S)-2-(3-((4,6-difluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)-3-azabicyclo [3.1.0]hexane-3 -carboxylate;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-phenylpiperidine-3-carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-l-isopropyl-6-oxopiperidine-3-carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-(pentan-3-yl)piperidine-3-carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide N-(4-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;(S)-N-(4-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;(S)-N-(5-chloro-7-fluoro-lH-benzo[d]imidazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;(S)-N-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(4-chloro-7-fluoro-lH-benzo[d]imidazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;(R)-N-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide; N-(4-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4 -carboxamide;(S)-N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(7-chlorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;N-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;N-(4-chloro-7-fluorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l,8-dioxaspiro[4.5]decane-3-carboxamide;(R)-N-(4-chlorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;(S)-N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;(S)-N-(7-chlorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-5-oxaspiro[3.5]nonane-8-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxaspiro[4.5]decane-9-carboxamide;(S)-N-(4,7-difluorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;N-(7-chloro-6-fluorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;N-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-l,8-dioxaspiro[4.5]decane-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-2,5-dioxaspiro[3.5]nonane-8-carboxamide;N-(4,7-difluorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;(S)-N-(7-bromo-4-fluorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(7-chloro-4-methylbenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;N-(4-chlorobenzo[d]thiazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;N-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide; N-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide; N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4- yl)piperidine-3-carboxamide; N-(4-chloro-7-fluorobenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide; N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-(pentan-3-yl)piperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-((S)-tetrahydro-2H-pyran-3-yl)piperidine-3- carboxamide; N-(6-chloro-4-methylbenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-(pyridin-3-yl)piperidine-3-carboxamide;N-(7-chloro-4-methylbenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-((R)-tetrahydro-2H-pyran-3-yl)piperidine-3-carboxamide; N-(7-chloro-6-fluorobenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(4-chloro-7-methylbenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(7-chlorobenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(4-chlorobenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide; N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(2-methoxyethyl)-6-oxopiperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-6-oxo-l-((S)-tetrahydrofuran-3-yl)piperidine-3-carboxamide; N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-(pyridin-2-yl)piperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-(pyridin-4-yl)piperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-((R)-l-methoxypropan-2-yl)-6-oxopiperidine-3-carboxamide; N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(l,3-dimethoxypropan-2-yl)-6-oxopiperidine-3-carboxamide; N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-isopropyl-6-oxopiperidine-3-carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-l-isopropyl-6-oxopiperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(2-methoxyethyl)-5-oxopyrrolidine-3 -carboxamide;N-(4-chloro-7-fluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-((S)-tetrahydrofuran-3-yl)piperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-(2-hydroxy-2-methylpropyl)-6-oxopiperidine-3-carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-((S)-tetrahydrofuran-3-yl)piperidine-3-carboxamide; l-(bicyclo[l.l.l]pentan-l-yl)-N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxopiperidine-3-carboxamide; N-(5-chloro-7-fluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-l-isopropyl-6-oxo-5-phenylpiperidine-3-carboxamide;5-cyclohexyl-N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-l-isopropyl-6-oxopiperidine-3-carboxamide; N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-5-(4-fluorophenyl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3 -carboxamide;N-(5,7-difluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-((S)-tetrahydro-2H-pyran-3-yl)piperidine-3-carboxamide;N-(4-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(4-chloro-7-fluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-((S)-tetrahydro-2H-pyran-3-yl)piperidine-3-carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-((R)-tetrahydro-2H-pyran-3-yl)piperidine-3-carboxamide;N-(4,6-difluoro- 1 H-benzo [d]imidazol-2-yl)- 1 -(1,3 -dimethoxypropan-2-yl)-6-oxopiperidine-3 -carboxamide;N-(4-chloro-7-fluoro-lH-benzo[d]imidazol-2-yl)-l-((R)-l-hydroxypropan-2-yl)-6-oxopiperidine-3-carboxamide;N-(6-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-l-(2-hydroxyethyl)-6-oxopiperidine-3-carboxamide; N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-phenylpiperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-(2-hydroxyethyl)-6-oxopiperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-3-carboxamide;N-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-l-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-3-carboxamide;1 -(3 -oxabicyclo [3.1.0]hexan-6-yl)-N-(7 -chloro -4 -fluorobenzo [d]thiazol-2-yl)-6-oxopiperidine-3 -carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-(l,3-dimethoxypropan-2-yl)-6-oxopiperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;(ls,3s)-3-(5-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)-2-oxopiperidin-l-yl)cyclobutane-l-carboxylic acid;(lr,3r)-3-(5-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)-2-oxopiperidin-l-yl)cyclobutane-l-carboxylic acid;3-((5-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)-2-oxopiperidin-l-yl)methyl)cyclobutane-l-carboxylic acid;N-(4,6-difluorobenzo [d]thiazol-2-yl)- 1 -(3 -methoxybicyclo [1.1.1 ]pentan- 1 -yl)-6-oxopiperidine-3 -carboxamide;(S)-N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-(cyclobutanecarbonyl)piperidine-3-carboxamide;(S)-4-(3-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)piperidin-l-yl)-4-oxobutanoic acid;(S)-N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(pyridazine-4-carbonyl)piperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(pyridazine-4-carbonyl)piperidine-3-carboxamide;(S)-N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-(oxetane-3-carbonyl)piperidine-3-carboxamide;(R)-N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-(oxetane-3-carbonyl)piperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(2,5-dimethyloxazole-4-carbonyl)piperidine-3-carboxamide; N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-(3-cyano-3-methylbutanoyl)piperidine-3-carboxamide; N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-(tetrahydro-2H-pyran-4-carbonyl)piperidine-3-carboxamide; (S)-N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(oxetane-3-carbonyl)piperidine-3-carboxamide;(1S,3r)-3-((S)-3-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-1-carbonyl)cyclobutane-1-carboxylic acid;(lR,2R)-2-((S)-3-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)cyclobutane-1 -carboxylic acid;(lS,2S)-2-((S)-3-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)cyclobutane-1 -carboxylic acid;(lR,3s)-3-((S)-3-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)cyclobutane-1 -carboxylic acid;(S)- 1 -(2-(3 -((7-chloro-4-fluorobenzo [d]thiazol-2-yl)carbamoyl)piperidin- 1 -yl)-2-oxoethyl)cyclobutane- 1 -carboxylic acid;(S)-4-(3-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)piperidin-l-yl)-3,3-dimethyl-4-oxobutanoic acid;(S)-4-(3-((7-chloro-4-fluorobenzo[d]thiazol-2-yl)carbamoyl)piperidin-l-yl)-2,2-dimethyl-4-oxobutanoic acid;(lR,2R)-2-((S)-3-((4,6-difluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)cyclobutane-l-carboxylic acid;(S)-N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-((R)-pyrrolidine-3-carbonyl)piperidine-3-carboxamide;1 -methoxy-2-methylpropan-2-yl (R)-3 -((S)-3 -((4,6-difluorobenzo [d]thiazol-2-yl)carbamoyl)piperidine- 1 -carbonyl)pyrrolidine- 1 -carboxylate;l-methoxy-2-methylpropan-2-yl (R)-3-((S)-3-((7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)carbamoyl)piperidine- 1 -carbonyl)pyrrolidine- 1 -carboxylate;Isopropyl (lR,2S,5S)-2-((S)-3-((7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)carbamoyl)piperidine-l-carbonyl)-3 -azabicyclo [3.1,0]hexane-3-carboxylate;Isopropyl (R)-3-((S)-3-((7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)carbamoyl)piperidine-l-carbonyl)pyrrolidine- 1 -carboxylate;(S)-N-(7-chloro-4-fluoro- 1 H-benzo [d]imidazol-2-yl)- 1 -((R)- 1 -isobutyrylpyrrolidine-3 -carbonyl)piperidine-3-carboxamide;(S)-N-(7-chloro-4-fluoro-1H-benzo[d]imidazol-2-yl)-1-((R)-1-(isopropylsulfonyl)pyrrolidine-3-carbonyl)piperidine-3-carboxamide;Isopropyl (R)-3-((S)-3-((4,6-difluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)pyrrolidine-l-carboxylate;(S)-N-(4,6-difluorobenzo[d]thiazol-2-yl)- 1 -((R)- 1 -(3-methylbutanoyl)pyrrolidine-3 -carbonyl)piperidine-3-carboxamide;(S)-N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-((R)-l-(isopropylsulfonyl)pyrrolidine-3-carbonyl)piperidine- 3-carboxamide;(S)-N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-((R)-l-isobutyrylpyrrolidine-3-carbonyl)piperidine-3-carboxamide;tert-butyl (S)-3-((S)-3-((4,6-difluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)pyrrolidine-l-carboxylate;tert-butyl (S)-2-((S)-3-((4,6-difluorobenzo[d]thiazol-2-yl)carbamoyl)piperidine-l-carbonyl)pyrrolidine-l-carboxylate;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(tetrahydro-2H-pyran-4-carbonyl)piperidine-3-carboxamide; (S)-N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(pyrrolidine-l-carbonyl)piperidine-3-carboxamide;N-(6-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-l,8-dioxaspiro[4.5]decane-3-carboxamide;N-(7-chlorobenzo[d]thiazol-2-yl)-2,5-dioxaspiro[3.5]nonane-8-carboxamide;N-(7-chloro-6-fluorobenzo[d]thiazol-2-yl)-l,8-dioxaspiro[4.5]decane-3-carboxamide;(S)-N-(4-bromo-7-fluorobenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(4-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-l,8-dioxaspiro[4.5]decane-3-carboxamide;N-(4-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-2,5-dioxaspiro[3.5]nonane-8-carboxamide;N-(4-chloro-lH-benzo[d]imidazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;(2r,4s)-N-(4-chloro-7-fluoro-lH-benzo[d]imidazol-2-yl)-6-oxaspiro[3.5]nonane-2-carboxamide;(2s,4r)-N-(4-chloro-7-fluoro-lH-benzo[d]imidazol-2-yl)-6-oxaspiro[3.5]nonane-2-carboxamide;N-(6-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;N-(4,7-difluoro-lH-benzo[d]imidazol-2-yl)-2,6-dioxaspiro[4.5]decane-9-carboxamide;(S)-N-(4-fluoro-7-isopropoxybenzo[d]thiazol-2-yl)-l,9-dioxaspiro[5.5]undecane-4-carboxamide;N-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-2,5-dioxaspiro[3.5]nonane-8-carboxamide;N-(4,7-difluorobenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide; N-(4,7-difluorobenzo[d]thiazol-2-yl)-l-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-5-methyl-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(7-cyclopropyl-4-fluorobenzo[d]thiazol-2-yl)-6-oxo-l-((S)-tetrahydro-2H-pyran-3-yl)piperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-methyl-2-(l-methyl-lH-pyrazol-4-yl)-6-oxopiperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(5-chloro-7-fluoro-lH-benzo[d]imidazol-2-yl)-l-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(4-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-l,4-dimethyl-6-oxopiperidine-3 -carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-l-isopropyl-4-methyl-6-oxopiperidine-3-carboxamide;N-(4-chloro-7-fluoro-lH-benzo[d]imidazol-2-yl)-5-(4-fluorophenyl)-l-isopropyl-6-oxopiperidine-3-carboxamide;N-(4-chloro-7-fluoro-lH-benzo[d]imidazol-2-yl)-l,4-dimethyl-6-oxopiperidine-3 -carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-5-methyl-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l,4-dimethyl-6-oxopiperidine-3 -carboxamide;N-(7-cyclopropyl-4-fluorobenzo[d]thiazol-2-yl)-6-oxo-l-((S)-tetrahydrofuran-3-yl)piperidine-3-carboxamide;N-(4-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-l-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(4-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-l-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(5,7-difluoro-lH-benzo[d]imidazol-2-yl)-l-(2-hydroxy-2-methylpropyl)-4-methyl-6-oxopiperidine-3-carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-4-ethyl-l-methyl-6-oxopiperidine-3-carboxamide;N-(5,7-difluoro-lH-benzo[d]imidazol-2-yl)-l -((3 R,4S)-3 -methoxytetr ahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-6-oxo-5-phenyl-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(4,6-difluoro-lH-benzo[d]imidazol-2-yl)-5-(4-fluorophenyl)-l-isopropyl-6-oxopiperidine-3-carboxamide;N-(5-chloro-8-fluoroquinolin-2-yl)-5-methyl-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;6-oxo-l-(tetrahydro-2H-pyran-4-yl)-N-(7-(trifluoromethyl)benzo[d]thiazol-2-yl)piperidine-3-carboxamide;N-(5,7-difluoro-lH-benzo[d]imidazol-2-yl)-4-methyl-6-oxo-l-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-3-carboxamide;N-(7-methylbenzo[d]thiazol-2-yl)-6-oxo-l-(tetrahydro-2H-pyran-4-yl)piperidine-3-carboxamide;N-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-6-oxo-l-((S)-tetrahydro-2H-pyran-3-yl)piperidine-3-carboxamide;l-(3-oxabicyclo[3.1.0]hexan-6-yl)-N-(4,7-difluorobenzo[d]thiazol-2-yl)-6-oxopiperidine-3-carboxamide; N-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-6-oxo-l-((R)-tetrahydro-2H-pyran-3-yl)piperidine-3-carboxamide;N-(7-chlorobenzo[d]thiazol-2-yl)-l-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l -((3 R,4R)-3-m ethoxytetr ahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(6-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(4-chlorobenzo[d]thiazol-2-yl)-l-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-l-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-isopropyl-6-oxo-2-(pyridin-3-yl)piperidine-3-carboxamide; N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-6-oxo- 1-((R)- 1,1,1 -trifluoroprop an -2 -yl)piperidine-3-carboxamide;N-(4-chloro-6-fluorobenzo[d]thiazol-2-yl)-l-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(7-chloro-4-fluoro-lH-benzo[d]imidazol-2-yl)-l-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(7-chloro-5-fluoro-lH-benzo[d]imidazol-2-yl)-l -((3 S,4R)-3-m ethoxytetr ahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(4-chloro-l H-benzo[d]imidazol-2-yl)-l -((3 S,4R)-3-m ethoxytetr ahydro-2H-pyran-4-yl)-6-oxopiperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-l-(2-methoxyethyl)-6-oxopiperidine-3-carboxamide;N-(4,6-difluorobenzo[d]thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-2-oxa-5-azaspiro[3.5]nonane-7-carboxamide;N-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-((lR,2R)-2-cyanocyclobutane-l-carbonyl)piperidine-3-carboxamide; andN-(7-chloro-4-fluorobenzo[d]thiazol-2-yl)-l-(3-cyano-3-methylbutanoyl)piperidine-3-carboxamide.

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof and one or more (e.g., 1, 2, 3, 4, or 5) pharmaceutically acceptable carriers.

28. The pharmaceutical composition of claim 27, further comprising at least one additional pharmaceutically active agent.

29. The pharmaceutical composition of claim 28, wherein the additional pharmaceutically active agent is selected from an ACE (angiotensin-converting-enzyme) inhibitor, an angiotensin receptor blocker (ARB), a neprilysin inhibitor, a beta blocker, a diuretic, a calcium channel blocker, a cardiac glycoside, a sodium -glucose co-transporter 2 inhibitor (SGLT2i), an angiotensin receptor-neprilysin inhibitor (ARNi), a corticosteroid, a leukotriene modifier, a bronchodilator, a beta-adrenoceptor antagonist, a carbonic anhydrase inhibitor, an alpha 2-adrenoceptor agonist, a parasympathomimetic, a prostaglandin analog, a rho kinase inhibitor, and combinations thereof.

30. A method for treating or preventing a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of the claims 1 to 26 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of claims 27 to 29.

31. The method of claim 30, wherein the disease or disorder is a cardiovascular disease or disorder.

32. The method of claim 31, wherein the cardiovascular disease or disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, cardiac dysrhythmia, atrial fibrillation(AF), new onset of atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, and myocardial infarction (MI).

33. The method of claim 32, wherein the heart failure is selected from a heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute decompensated heart failure.

34. The method of claim 31, wherein the disease or disorder is preeclampsia, asthma, glaucoma, a kidney disorder, and / or cytokine release syndrome in a subject in need of such treatment.

35. The method of claim 31, wherein the disease or disorder is a disorder or disease associated with natriuretic peptide receptor activity.

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