Substituted piperidine compounds as renin inhibitors

Abstract

Compounds having formula I or II, pharmaceutical compositions containing the same, and their use as renin inhibitors.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 489,882, filed on 13 March 2023. [References]

[0002] All documents cited or referenced herein (including, but not limited to, all articles, patents, and published patent applications cited herein) ("Documents Cited herein"), and all documents cited or referenced in the Documents Cited herein, together with any manufacturer's instructions for use, descriptions, product specifications, and product manuals for any product mentioned herein or in any document incorporated herein by reference, are hereby incorporated herein by reference and may be adopted in practice of the Invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document were specifically and individually indicated to be incorporated by reference. Genbank sequences mentioned in this disclosure are incorporated by reference by the Genbank sequence as of the earliest effective filing date of this disclosure.

[0003] The citation or identification of any document in this application does not constitute an endorsement that such document is available as prior art of this disclosure.

[0004] This application relates to novel 3,5-substituted piperidine compounds and their derivatives having superior renin inhibitory activity compared to prior art molecules. The compounds and their derivatives disclosed herein are useful for treating diseases associated with renin activity, particularly those associated with excessive renin activity. [Background technology]

[0005] The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in regulating cardiovascular and renal physiology. The cascade of events in this system begins with the conversion of angiotensinogen to angiotensin I, and then to angiotensin II, which is catalyzed by angiotensin-converting enzyme (ACE) expressed on the surface of vascular endothelial cells, by plasma renin and circulating aspartate protease, which is synthesized in juxtaglomerular epithelioid cells and released in a controlled granular state (Castrop H et al., (2010) Physiol. Rev. 90(2):607-673). Angiotensin II can bind to angiotensin type I receptors, inducing sodium retention, vasoconstriction, and increased aldosterone secretion (Ames MK et al., (2019) J Vet Intern Med. 33(2):363-382). Aldosterone, a terminal hormone of the RAAS, is a key regulator of sodium, potassium, and fluid balance, while its release can induce sodium reabsorption by the renal tubules, followed by water reabsorption into the bloodstream, increasing the extracellular fluid volume in the body (Seelinger E. et al., (2005) Clin Exp Pharmacol Physiol. 32(5-6):394-399).

[0006] The renin-angiotensin-aldosterone system is normally stimulated in response to threats that impair blood pressure stability, and its chronic activation can lead to pathological remodeling and dysfunction in cardiovascular and renal tissues, resulting in cardiovascular disease, hypertension, diabetic nephropathy, heart failure, or other tissue / organ pathologies (Ames MK et al., (2019) supra).

[0007] RAAS suppression is a key strategy for mitigating these conditions. Inhibitors or components of RAAS include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and renin inhibitors. Among these, renin inhibitors, which block the first and rate-limiting steps of RAAS activation, have attracted considerable attention since the 1970s. However, it took researchers about 30 years to discover aliskiren, the first and only potent one with acceptable oral bioavailability, which was approved in 2007 for the clinical treatment of hypertension (Jensen C. et al., (2008) Nat Rev Drug Discov 7(5):399-410). Side effects observed in patients taking aliskiren include angioedema, hyperkalemia, diarrhea, headache, dizziness, and cough.

[0008] There is a need for more renin inhibitors that offer improved oral bioavailability, specificity, and efficacy with fewer side effects. [Overview of the project]

[0009] The inventors have invented a 3,5-substituted piperidine compound that has an excellent inhibitory effect on renin activity and is useful for the prevention or treatment of diseases associated with renin activity, such as excessive renin activity.

[0010] In one embodiment, the present application relates to compounds of formula I, or their respective geometric isomers, and pharmaceutically acceptable isotopic isomers, salts, prodrugs, and solvates. [ka] In the formula, R1 and R2 are independently a hydrogen atom, a deuterium atom, a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, or a C atom optionally substituted. 1~6 Alkyl alkyl groups, optionally substituted C 2~6 Alkenyl group, optionally substituted C 2~6 Alkynyl group, optionally substituted C 1~3An alkylthio group, optionally substituted C 1~3 An alkylsulfinyl group, optionally substituted C 1~3 An alkylsulfonyl group, optionally substituted C 1~6 An alkoxy group, optionally substituted C 1~6 AlkoxyC 1~6 An alkyl group, optionally substituted C 1~3 AlkylC 1~6 An alkoxy group, optionally substituted C 3~6 A cycloalkyl group, optionally substituted C 1~3 AlkylC 3~6 A cycloalkyl group, an optionally substituted amino group, optionally substituted C 1~3 An alkylamino group, an optionally substituted mercapto group, an optionally substituted aminocarbonyl group, an optionally substituted carbonyl group, optionally substituted C 1~6 An alkylcarbonyl group, or optionally substituted C 1~3 May be an alkoxycarbonyl group, n may be 0, 1, 2, or 3, X may be a methylene group, an oxygen atom, an amine group, a sulfinyl group, or a sulfonyl group, Ring A may be an optionally substituted 5- or 6-membered heterocycle containing one or more N, O, S, SO, and SO2, R3 is a hydrogen atom, a deuterium atom, a halogen atom, a hydroxyl group, a carboxyl group, optionally substituted C 1~6 An alkyl group, optionally substituted C 3~6 A cycloalkyl group, optionally substituted C 2~6 An alkenyl group, optionally substituted C 2~6 An alkynyl group, optionally substituted C 1~6 An alkoxy group, an optionally substituted amino group, an optionally substituted mercapto group, an optionally substituted aminocarbonyl group, optionally substituted C 1~6 An alkylcarbonyl group, optionally substituted C 1~6 AlkoxyC 1~6 An alkyl group, or optionally substituted C 1~3It may also be an alkoxycarbonyl group. R4 consists of a hydrogen atom, a halogen atom, a deuterium atom, a hydroxyl group, a cyano group, an optionally substituted amino group, and an optionally substituted C. 1~6 Alkyl group (e.g., hydroxyl C) 1~6 Alkyl alkyl groups, optionally substituted C 1~6 Haloalkyl groups, optionally substituted C 2~6 Alkenyl group, optionally substituted C 2~6 Alkynyl group, optionally substituted mercapto group, optionally substituted C 1~6 Alkyl sulfinyl group, optionally substituted C 1~6 Alkyl sulfonyl group, optionally substituted C 1~6 Alkoxy groups, optionally substituted C 1~6 Haloalkoxy group, optionally substituted C 3~6 Cycloalkyl groups, optionally substituted aminocarbonyl groups, optionally substituted C 1~6 Alkylcarbonyl group, optionally substituted C 1~6 Haloalkylcarbonyl group, optionally substituted C 1~3 Alkoxycarbonyl group, optionally substituted C 1~3 Haloalkoxycarbonyl group, optionally substituted C 1~6 Alkoxy C 1~6 Alkyl alkyl groups, optionally substituted C 1~6 Haloalkoxy C 1~6 Alkyl groups, 4-6 membered heterocyclic substituted formyl groups, where the 4-6 membered heterocyclic group may contain one or more N, O, S, SO, and SO2, and may be optionally substituted; optionally substituted 3-6 membered cyclic hydrocarbon groups; saturated or unsaturated optionally substituted 5 or 6 membered heterocyclic groups, where the heterocyclic group may contain one or more N, O, S, SO, and SO2, or may be optionally substituted amide groups. R5 is a hydrogen atom, deuterium atom, halogen atom, hydroxyl group, cyano group, mercapto group, or optionally substituted C 1~3 Alkyl sulfinyl group, optionally substituted C 1~3Alkyl sulfonyl group, optionally substituted C 1~3 Haloalkylsulfonyl group, optionally substituted amino group, optionally substituted C 1~6 Alkyl alkyl groups, optionally substituted C 1~6 Haloalkyl groups, optionally substituted C 2~6 Alkenyl group, optionally substituted C 2~6 Alkynyl group, optionally substituted C 1~6 Alkoxy groups, optionally substituted C 1~6 Haloalkoxy group, optionally substituted C 3~6 Cycloalkyl groups, optionally substituted C 3~6 Halocycloalkyl groups, optionally substituted C 1~3 Alkylthio group, optionally substituted C 1~3 Alkyl sulfinyl group, optionally substituted C 1~3 Haloalkylsulfinyl group, optionally substituted C 3~4 Cycloalkyl groups, optionally substituted aminocarbonyl groups, optionally substituted C 1~6 Alkylcarbonyl group, optionally substituted C 1~6 Alkoxy C 1~6 Alkyl alkyl groups, optionally substituted C 1~6 Haloalkoxy C 1~6 Alkyl alkyl groups, optionally substituted C 1~3 Alkoxycarbonyl group, or optionally substituted C 1~3 A haloalkoxycarbonyl group may also be used.

[0011] R1 and R2 may be attached to the same carbon atom or to different carbon atoms.

[0012] If X is a methylene group, it may be substituted with R1 and / or R2.

[0013] R1 and R2 are independently a halogen atom, a hydroxyl group, and C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, hydroxyl C 1~6 Alkyl alkyl group, C 1~6an alkoxy group, C 1~6 a haloalkoxy group, C 1~3 alkoxy C 1~3 an alkyl group, C 1~3 haloalkoxy C 1~3 an alkyl group, C 1~6 an alkylcarbonyl group, C 1~6 a haloalkylcarbonyl group, C 1~6 an alkylamino group, and C 1~6 It may have one or more substituents selected from the group consisting of a haloalkylamino group.

[0014] R3 is a halogen atom, a hydroxyl group, C 1~6 an alkyl group, C 1~6 a haloalkyl group, hydroxyl C 1~6 an alkyl group, C 1~6 an alkylcarbonyl group, C 1~6 a haloalkylcarbonyl group, C 1~3 alkoxy C 1~3 an alkyl group, C 1~3 haloalkoxy C 1~3 an alkyl group, C 1~6 an alkylamino group, and C 1~6 It may have one or more substituents selected from the group consisting of a haloalkylamino group.

[0015] Ring A is partially unsaturated or unsaturated and may be an optionally substituted 5- or 6-membered heterocycle containing one or more, for example, one or two, of N, O, S, SO, and SO2. In certain embodiments, ring A is partially unsaturated or unsaturated and may be an optionally substituted 6-membered heterocycle containing one, two, or three atoms selected from, for example, N, O, and S. In certain embodiments, ring A is partially unsaturated or unsaturated and may be an optionally substituted 6-membered heterocycle containing one, two, or three N atoms, for example. In certain embodiments, ring A may be an optionally substituted pyridine, an optionally substituted pyridazine, an optionally substituted pyrimidine, or an optionally substituted pyrazine. In certain embodiments, ring A may be an optionally substituted pyran, an optionally substituted thiopyran, an optionally substituted oxazine, an optionally substituted thiazine, an optionally substituted dioxine, an optionally substituted dithiin, or an optionally substituted triazine.

[0016] Ring A is a deuterium atom, a halogen atom, a cyano group, a hydroxyl group, C 1~6 alkyl group, C 1~6 haloalkyl group, C 2~6 alkenyl group, C 2~6 haloalkenyl group, C 2~6 alkynyl group, C 2~6 haloalkynyl group, C 3~6 cycloalkyl group, C 1~6 alkylsulfinyl group, C 1~6 haloalkylsulfinyl group, C 1~6 alkylsulfonyl group, C 1~6 haloalkylsulfonyl group, C 1~6 alkoxy group, C 1~6 haloalkoxy group, amino group, C 1~6 alkylcarbonyl group, C 1~6 haloalkylcarbonyl group, C 1~3 alkoxycarbonyl group, C 1~3 haloalkoxycarbonyl group, C 1~6 alkoxyC1~6 Alkyl alkyl group, C 1~6 Haloalkoxy C 1~6 It may have one or more substituents, for example, one or two, selected from the group consisting of alkyl groups or optionally substituted 5 or 6-membered heterocycles containing one or more N, O, S, SO, and SO2, where each substituent is a halogen atom, a hydroxyl group, C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cycloalkyl groups, hydroxyl C 1~6 Alkyl alkyl group, C 1~6 Alkylcarbonyl group, C 1~6 Haloalkylcarbonyl group, C 1~3 Alkoxy C 1~3 Alkyl alkyl group, C 1~3 Haloalkoxy C 1~3 Alkyl alkyl group, C 1~6 Alkylamino group, and C 1~6 The ring A may further contain one or more substituents selected from the group consisting of haloalkylamino groups, for example, one or two substituents. In certain embodiments, ring A may have C as a substituent. 1~6 It may have an alkyl group, which may be unsubstituted, a halogen atom, or C 1~3 Alkyl alkyl groups, and C 1~3 It may be substituted with one or more selected from the group consisting of haloalkyl groups. In certain embodiments, ring A is substituted with C 3~6 It may have a cycloalkyl group, which may be unsubstituted, a halogen atom, or C 1~3 Alkyl alkyl groups, and C 1~3 It may be substituted with one or more selected from the group consisting of haloalkyl groups. In certain embodiments, ring A may have an amino group as a substituent, which may be unsubstituted, C 1~3 Alkyl and C 1~3 It may be substituted with one or more selected from the group consisting of haloalkyl groups.

[0017] In a particular embodiment, ring A is as follows: [ka] It may be any one of the following: In the formula, R1', R2', and R3' are independently a hydrogen atom, a deuterium atom, a halogen atom, a cyano group, a hydroxyl group, or optionally substituted C 1~6 Alkyl alkyl groups, optionally substituted C 1~6 Haloalkyl groups, optionally substituted C 2~6 Alkenyl group, optionally substituted C 2~6 Haloalkenyl group, optionally substituted C 2~6 Alkynyl group, optionally substituted C 2~6 Haloalkynyl group, optionally substituted C 3~6 Cycloalkyl groups, optionally substituted C 1~6 Alkyl sulfinyl group, optionally substituted C 1~6 Haloalkylsulfinyl group, optionally substituted C 1~6 Alkyl sulfonyl group, optionally substituted C 1~6 Haloalkylsulfonyl group, optionally substituted C 1~6 Alkoxy groups, optionally substituted C 1~6 Haloalkoxy group, optionally substituted amino group, optionally substituted C 1~6 Alkylcarbonyl group, optionally substituted C 1~6 Haloalkylcarbonyl group, optionally substituted C 1~3 Alkoxycarbonyl group, optionally substituted C 1~3 Haloalkoxycarbonyl group, optionally substituted C 1~6 Alkoxy C 1~6 Alkyl alkyl groups, optionally substituted C 1~6 Haloalkoxy C 1~6 The alkyl group may be an optionally substituted 5 or 6-membered heteroring containing one or more N, O, S, SO, and SO2.

[0018] R1', R2', and R3' are independently a halogen atom, a hydroxyl group, and C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cycloalkyl groups, hydroxyl C1~6 Alkyl alkyl group, C 1~6 Alkylcarbonyl group, C 1~6 Haloalkylcarbonyl group, C 1~3 Alkoxy C 1~3 Alkyl alkyl group, C 1~3 Haloalkoxy C 1~3 Alkyl alkyl group, C 1~6 Alkylamino group, and C 1~6 It may have one or more substituents selected from the group consisting of haloalkylamino groups. In certain embodiments, R1', R2', and R3' are independently C 1~6 It may also be an alkyl group, which may be unsubstituted, a halogen atom, or C 1~3 Alkyl alkyl groups, and C 1~3 They may be substituted with one or more selected from the group consisting of haloalkyl groups. In certain embodiments, R1', R2', and R3' are independently C 3~6 It may also be a cycloalkyl group, which may be unsubstituted, or contain a halogen atom, C 1~3 Alkyl alkyl groups, and C 1~3 They may be substituted with one or more selected from the group consisting of haloalkyl groups. In certain embodiments, R1', R2', and R3' may independently be amino groups, which may be unsubstituted, halogen atoms, C 1~3 Alkyl alkyl groups, and C 1~3 It may be substituted with one or more selected from the group consisting of haloalkyl groups.

[0019] R4 is deuterium, halogen atom, hydroxyl group, cyano group, amino group, halo-substituted amino group, C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cycloalkyl groups, C 3~6 Halocycloalkyl group, C 1~3 Alkyl C 3~6 Cycloalkyl groups, C 1~3 Haloalkyl C 3~6 Cycloalkyl groups, hydroxyl C 1~6 Alkyl alkyl, hydroxyl C 3~6 Cycloalkyl groups, C 1~6Alkylcarbonyl group, C 1~6 Alkoxy group, C 1~6 Haloalkoxy group, C 1~6 Haloalkylcarbonyl group, C 3~6 Halocycloalkylcarbonyl group, C 1~3 Alkoxy C 1~3 Alkyl alkyl group, C 1~6 Alkylamino group, C 1~6 Haloalkylamino group, C 1~3 Haloalkoxy C 1~3 It may have substituents selected from the group consisting of three or six-membered heterocycles containing alkyl groups and one or more selected from the group consisting of N, O, S, SO, and SO2.

[0020] R5 may be attached to any carbon atom in the piperidine ring.

[0021] R5 consists of a deuterium atom, a halogen atom, a hydroxyl group, an amino group, and C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, hydroxyl C 1~6 Alkyl alkyl group, C 1~6 Alkylcarbonyl group, C 1~6 Haloalkylcarbonyl group, C 1~3 Alkoxy C 1~6 Alkyl alkyl group, C 1~3 Haloalkoxy C 1~6 Alkyl alkyl group, C 1~6 Alkylamino group, and C 1~6 It may have one or more substituents selected from the group consisting of haloalkylamino groups.

[0022] In certain embodiments, X may be a methylene group, an oxygen atom, or an amine group. If X is a methylene group, it may be unsubstituted or substituted with R1 and / or R2.

[0023] In certain embodiments, n may be 0 or 1.

[0024] In certain embodiments, R1 and R2 are independently a hydrogen atom, a halogen atom, a hydroxyl group, and C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group, amino group, aminocarbonyl group, C 1~6 Alkylcarbonyl group, C 1~6 Haloalkylcarbonyl group, C 1~6 Alkoxy C 1~6 Alkyl alkyl group, C 1~6 Haloalkoxy C 1~6 Alkyl alkyl group, C 1~3 Alkoxycarbonyl group, or C 1~3 It may also be a halolcoxycarbonyl group. In certain embodiments, these groups are, respectively, a halogen atom, a hydroxyl group, and C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, hydroxyl C 1~6 Alkyl alkyl group, C 1~6 Alkylcarbonyl group, C 1~6 Haloalkylcarbonyl group, C 1~3 Alkoxy C 1~3 Alkyl alkyl group, C 1~3 Haloalkoxy C 1~3 Alkyl alkyl group, C 1~6 Alkylamino group, and C 1~6 The material may contain one or more substituents, for example, one or two, selected from the group consisting of haloalkylamino groups. In certain embodiments, R1 and R2 are independently a hydrogen atom, a halogen atom, a hydroxyl group, and C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cycloalkyl groups (even if unsubstituted, contain halogen atoms, C) 1~3 Alkyl alkyl groups, and C 1~3 (may be substituted with one or more selected from the group consisting of haloalkyl groups), C 1~6 alkoxy groups (even if unsubstituted, they contain halogen atoms, C 1~3 Alkyl alkyl groups, and C 1~3(which may be substituted with one or more selected from the group consisting of haloalkyl groups), amino group (which may be unsubstituted, halogen atom, C) 1~3 Alkyl alkyl groups, and C 1~3 (which may be substituted with one or more selected from the group consisting of haloalkyl groups), aminocarbonyl group (which may be unsubstituted with a halogen atom, C 1~3 Alkyl alkyl groups, and C 1~3 (may be substituted with one or more selected from the group consisting of haloalkyl groups), C 1~6 Alkylcarbonyl group, C 1~6 Haloalkylcarbonyl group, C 1~6 Alkoxy C 1~6 Alkyl alkyl group, C 1~6 Haloalkoxy C 1~6 Alkyl alkyl group, C 1~3 Alkoxycarbonyl group, or C 1~3 It may also be a halolcoxycarbonyl group.

[0025] In certain embodiments, R1', R2', and R3' are independently a hydrogen atom, a halogen group, a hydroxyl group, and C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group, C 1~6 Haloalkoxy group, amino group, C 1~6 Alkylcarbonyl group, C 1~6 Haloalkylcarbonyl group, C 1~3 Alkoxycarbonyl group, C 1~3 Haloalkoxycarbonyl group, C 1~6 Alkoxy C 1~6 Alkyl alkyl group, C 1~6 Haloalkoxy C 1~6 The alkyl group may be a 5 or 6-membered heterocycle containing one or more N, O, S, SO, and SO2. In certain embodiments, these groups may be a halogen atom, a hydroxyl group, or C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, hydroxyl C 1~6 Alkyl alkyl group, C 1~6 Alkylcarbonyl group, C1~6 Haloalkylcarbonyl group, C 1~3 Alkoxy C 1~3 Alkyl alkyl group, C 1~3 Haloalkoxy C 1~3 Alkyl alkyl group, C 1~6 Alkylamino group, and C 1~6 The material may contain one or more substituents, for example, one or two, selected from the group consisting of haloalkylamino groups. In certain embodiments, R1', R2', and R3' are independently a hydrogen atom, a halogen group, a hydroxyl group, and C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cycloalkyl groups (even if unsubstituted, contain halogen atoms, C) 1~3 Alkyl alkyl groups, and C 1~3 (may be substituted with one or more selected from the group consisting of haloalkyl groups), C 1~6 Alkoxy group, C 1~6 Haloalkoxy group, amino group (this can be unsubstituted, even if it contains a halogen atom, C) 1~3 Alkyl alkyl groups, and C 1~3 (may be substituted with one or more selected from the group consisting of haloalkyl groups), C 1~6 Alkylcarbonyl group, C 1~6 Haloalkylcarbonyl group, C 1~3 Alkoxycarbonyl group, C 1~3 Haloalkoxycarbonyl group, C 1~6 Alkoxy C 1~6 Alkyl alkyl group, C 1~6 Haloalkoxy C 1~6 The alkyl group may be a 5- or 6-membered heterocycle containing one or more N, O, S, SO, and SO2.

[0026] In certain embodiments, R3 is a hydrogen atom, a deuterium atom, a halogen atom, C 1~6 Alkyl alkyl group, C 3~6 Cycloalkyl groups, C 1~6 Alkoxy group, amino group, aminocarbonyl group, C 1~6 Alkylcarbonyl group, C 1~6 Alkoxy C 1~6 Alkyl alkyl group, or C1~3 They may be alkoxycarbonyl groups. In certain embodiments, these groups may be a halogen atom, a hydroxyl group, or C, respectively. 1~6 Alkyl alkyl, hydroxyl C 1~6 Alkyl alkyl group, C 1~6 Alkylcarbonyl group, C 1~3 Alkoxy C 1~3 Alkyl alkyl groups, and C 1~6 It may contain one or more substituents, for example, one or two, selected from the group consisting of alkylamino groups. In certain embodiments, R3 is a hydrogen atom, a deuterium atom, a halogen atom, C 1~6 Alkyl compounds (which, even if unsubstituted, contain halogen atoms, C) 1~3 Alkyl alkyl groups, and C 1~3 (may be substituted with one or more selected from the group consisting of haloalkyl groups), C 3~6 Cycloalkyl groups (even if unsubstituted, contain halogen atoms, C) 1~3 Alkyl alkyl groups, and C 1~3 (may be substituted with one or more selected from the group consisting of haloalkyl groups), C 1~6 alkoxy groups (even if unsubstituted, they contain halogen atoms, C 1~3 Alkyl alkyl groups, and C 1~3 (which may be substituted with one or more selected from the group consisting of haloalkyl groups), amino group (which may be unsubstituted, halogen atom, C) 1~3 Alkyl alkyl groups, and C 1~3 (May be substituted with one or more selected from the group consisting of haloalkyl groups), aminocarbonyl group, C 1~6 Alkylcarbonyl group, C 1~6 Alkoxy C 1~6 Alkyl alkyl group, or C 1~3 It may also be an alkoxycarbonyl group.

[0027] In certain embodiments, R4 is a hydrogen atom, a deuterium atom, a halogen atom, a hydroxyl group, an amino group, or optionally substituted C 1~6 Alkyl alkyl groups, optionally substituted C 3~6 Cycloalkyl groups, optionally substituted C 1~6Alkoxy groups, optionally substituted aminocarbonyl groups, optionally substituted C 1~6 Alkylcarbonyl group, optionally substituted C 1~3 Alkoxycarbonyl group, optionally substituted C 1~6 Alkoxy C 1~6 Alkyl groups, optionally substituted 3- to 6-membered cyclic hydrocarbon groups, saturated or partially unsaturated 5- or 6-membered heterocycles, where the heterocycle may contain one or more, for example, 1, 2, or 3, N, O, S, SO, and SO2, and for example, optionally substituted C 1~6 Alkyl alkyl groups, optionally substituted C 3~6 A cycloalkyl group, an optionally substituted 3- to 6-membered cyclic hydrocarbon group, an optionally substituted 3 or 6-membered heterocycle containing one or more N, O, S, SO, and SO2, or a 4- to 6-membered heterocycle-substituted formyl group, where the heterocycle may contain one or more, for example, one or two, N, O, S, SO, and SO2 atoms, for example, a halogen atom, an optionally substituted C 1~6 Alkylcarbonyl group, optionally substituted C 1~6 They may be optionally substituted with alkyl groups. In certain embodiments, these groups may be a halogen atom, a hydroxyl group, or C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cycloalkyl groups, C 3~6 Halocycloalkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkoxy group, hydroxyl C 1~6 Alkyl alkyl, hydroxyl C 3~6 Cycloalkyl groups, C 1~6 Alkylcarbonyl group, C 1~6 Haloalkylcarbonyl group, C 3~6 Halocycloalkylcarbonyl group, C 1~3 Alkoxy C 1~3 Alkyl alkyl group, C 1~6 Alkylamino group, C 1~6 Haloalkylamino group, and C 1~3 Haloalkoxy C 1~3It may contain one or more substituents selected from the group consisting of alkyl groups, for example, one or two substituents. In certain embodiments, R4 is unsubstituted or a halogen atom, C 1~3 Alkyl alkyl groups, and C 1~3 A 3- to 6-membered cyclic hydrocarbon group substituted with one or more elements selected from the group consisting of haloalkyl groups; containing one or more elements selected from the group consisting of N, O, S, SO, and SO2, and being unsubstituted, or containing a halogen atom, a hydroxyl group, C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cycloalkyl groups, C 3~6 Halocycloalkyl groups, hydroxyl C 1~6 Alkyl alkyl, hydroxyl C 3~6 Cycloalkyl groups, C 1~6 Alkylcarbonyl group, C 3~6 Halocycloalkylcarbonyl group, C 1~6 Haloalkyl group, C 3~6 Halocycloalkyl group, C 1~6 Haloalkylcarbonyl group, C 3~6 Halocycloalkylcarbonyl group, C 1~3 Alkoxy C 1~3 Alkyl alkyl group, C 1~6 It contains one or more selected from the group consisting of alkylamino groups, N, O, S, SO, and SO2, and is unsubstituted, or contains a halogen atom, C 1~3 Alkyl alkyl groups, and C 1~3 A 3- or 6-membered heterocycle substituted with a haloalkyl group, and an unsubstituted or halogen atom, C 1~3 Alkyl alkyl groups, and C 1~3 A 5 or 6-membered unsaturated heterocycle substituted with one or more 3- to 6-membered cyclic hydrocarbon groups selected from the group consisting of haloalkyl groups; a 4- to 6-membered heterocycle substituted formyl group, where the heterocycle contains one or more selected from the group consisting of N, O, S, SO, and SO2, and is unsubstituted or a halogen atom, a hydroxyl group, C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cycloalkyl groups, C 3~6Halocycloalkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkoxy group, hydroxyl C 1~6 Alkyl alkyl, hydroxyl C 3~6 Cycloalkyl groups, C 1~6 Alkylcarbonyl group, C 3~6 Halocycloalkylcarbonyl group, C 1~6 Haloalkyl group, C 3~6 Halocycloalkyl group, C 1~6 Haloalkylcarbonyl group, C 3~6 Halocycloalkylcarbonyl group, C 1~3 Alkoxy C 1~3 Alkyl alkyl groups, and C 1~6 Substituted by one or more groups selected from the group consisting of alkylamino groups; or hydroxyl C 1~6 Alkyl alkyl groups are also acceptable.

[0028] In certain embodiments, R5 is a hydrogen atom, a halogen atom, a hydroxyl group, C 1~6 Alkoxy group, C 1~6 Haloalkoxy group, amino group, C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cycloalkyl groups, C 1~3 Alkyl sulfinyl group, C 1~3 Haloalkylsulfinyl group, C 1~3 Alkyl sulfonyl group, C 1~3 Haloalkylsulfonyl group, aminocarbonyl group, C 1~6 Alkylcarbonyl group, C 1~6 Alkoxy C 1~6 Alkyl alkyl group, C 1~6 Haloalkoxy C 1~6 Alkyl alkyl group, C 1~3 Alkoxycarbonyl group, or C 1~3 They may be haloalkoxycarbonyl groups. In certain embodiments, these groups may be a halogen atom, a hydroxyl group, or C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, hydroxyl C 1~6 Alkyl alkyl group, C 1~6 Alkylcarbonyl group, C1~6 Haloalkylcarbonyl group, C 1~3 Alkoxy C 1~6 Alkyl alkyl group, C 1~3 Haloalkoxy C 1~6 It may contain one or more substituents, for example, one or two, selected from the group consisting of alkyl groups and amino groups. In certain embodiments, R5 is a hydrogen atom, a halogen atom, a hydroxyl group, C 1~6 Alkoxy group, C 1~6 Haloalkoxy group, amino group (this can be unsubstituted, even if it contains a halogen atom, C) 1~3 Alkyl alkyl groups, and C 1~3 (may be substituted with one or more selected from the group consisting of haloalkyl groups), C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cycloalkyl groups (even if unsubstituted, contain halogen atoms, C) 1~3 Alkyl alkyl groups, and C 1~3 (may be substituted with one or more selected from the group consisting of haloalkyl groups), C 1~3 Alkyl sulfinyl group, C 1~3 Haloalkylsulfinyl group, C 1~3 Alkyl sulfonyl group, C 1~3 Haloalkylsulfonyl group, aminocarbonyl group (this may be unsubstituted, even if it contains a halogen atom, C) 1~3 Alkyl alkyl groups, and C 1~3 (may be substituted with one or more selected from the group consisting of haloalkyl groups), C 1~6 Alkylcarbonyl group, C 1~6 Alkoxy C 1~6 Alkyl alkyl group, C 1~6 Haloalkoxy C 1~6 Alkyl alkyl group, C 1~3 Alkoxycarbonyl group, or C 1~3 A haloalkoxycarbonyl group may also be used.

[0029] In another embodiment, the present application relates to compounds of formula II, or their respective geometric isomers, and pharmaceutically acceptable isotopic isomers, salts, prodrugs, and solvates. [ka] In the formula, R1, R2, R3, R5, X, n, ring A, R1', R2', and R3' are defined as above, if they exist. In the formula, R6 and R7 are independently a hydrogen atom, a deuterium atom, a halogen atom, a cyano group, a hydroxyl group, or a C atom optionally substituted. 1~3 Alkyl alkyl groups, optionally substituted C 3~6 Cycloalkyl groups, or optionally substituted C 1~3 It may also be an alkoxy group.

[0030] R6 and R7 independently consist of one or more, for example, one or two, halogen atoms, hydroxyl groups, and C 1~3 Alkyl alkyl group, C 1~3 Haloalkyl group, hydroxyl C 1~3 Alkyl alkyl group, C 1~3 Alkoxy group, C 1~3 It may have substituents selected from the group consisting of haloalkoxy groups and amino groups.

[0031] In certain embodiments, R6 and R7 are independently a hydrogen atom, a deuterium atom, a halogen atom, a cyano group, a hydroxyl group, and C 1~3 Alkyl alkyl group, C 1~3 Haloalkyl group, C 3~6 Cycloalkyl groups, C 3~6 Halocycloalkyl group, C 1~3 Alkoxy group, or C 1~3 A haloalkoxy group is also acceptable.

[0032] R6 and R7 may be attached to the same atom in the ring.

[0033] In certain embodiments, the compounds of the present disclosure are (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3-fluoroazetidine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3,3-difluoropyrrolidine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(4,4-difluoropiperidine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(4-trifluoromethoxypiperidine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3R)-methylmorpholine-N-carbonyl]-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(2,2-dimethylmorpholine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{2-tert-butyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclobutylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3,3-difluorocyclobutyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3S)-ethylmorpholine-N-carbonyl]-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,2,4-oxadiazole-3-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3-methyl-1,2,4-oxadiazole-5-yl)-piperidine, (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-(oxetane-3-ylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-[3-(3-trans-methoxy)cyclobutyl]aminopyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}amino-(5R)-[(3S)-3-methylmorpholine-4-carbonyl]-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[5-(oxetan-3-yl)-1,3,4-oxadiazole-2-yl]-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-hydroxymethyl-piperidine, (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-piperidine, (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(3-methyl-1,2,4-oxadiazole-5-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,2,4-oxadiazole-3-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(1,2,4-oxadiazole-3-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-[5-trifluoromethyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine, and (3S)-{N-(2-methylpropyl),N-{2-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine You may choose from the group consisting of the following:

[0034] In a particular embodiment, the compound is (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine (compound 21).

[0035] Further disclosures include methods for preparing the compounds of this disclosure, intermediate compounds, their respective geometric isomers, pharmaceutically acceptable isotopic isomers, salts, prodrugs, and solvates, as well as pharmaceutical compositions comprising an effective amount of the compounds of this disclosure, each having a pharmaceutically acceptable carrier, their respective geometric isomers, pharmaceutically acceptable isotopic isomers, salts, prodrugs, and solvates.

[0036] In a third aspect, the present application provides methods for using the compounds of the present disclosure, their respective geometric isomers, pharmaceutically acceptable isotopic isomers, salts, prodrugs, and solvates, as selective renin inhibitors and for the treatment of diseases associated with renin / RAAS activity, such as hypertension, cardiovascular disease, diabetic nephropathy, and heart failure. Renin activity or RAAS activity can be inhibited using the pharmaceutical compositions of the present disclosure. The pharmaceutical compositions of the present disclosure may be used in the preparation of agents for the treatment of diseases associated with renin activity.

[0037] This application provides a method for inhibiting renin activity in a subject requiring such inhibition, the method comprising the step of administering the pharmaceutical composition of this disclosure to the subject. The subject may be a human being. The subject may be suffering from a disease caused by abnormal renin activity, such as hypertension, cardiovascular disease, diabetic nephropathy, and heart failure. In certain embodiments, the subject may be suffering from hypertension and related complications.

[0038] This application provides a method for inhibiting RAAS activity in a subject requiring such inhibition, the method comprising the step of administering the pharmaceutical composition of this disclosure to the subject. The subject may be a human. The subject may have a disease caused by abnormal RAAS activity, such as hypertension, cardiovascular disease, diabetic nephropathy, and heart failure. In certain embodiments, the subject may have hypertension and related complications.

[0039] The present application provides a method for treating or alleviating a disease associated with renin / RAAS activity, for example, abnormal renin / RAAS activity, in a subject requiring such treatment, the method comprising the step of administering the pharmaceutical composition of the present disclosure to the subject. The subject may be a human. The disease may be hypertension, cardiovascular disease, diabetic nephropathy, or heart failure. In a particular embodiment, the disease is hypertension.

[0040] Other features and advantages of this disclosure are evident from the following detailed description and examples, but these should not be construed as limitations. All references, GenBank entries, patents, and patent application publications cited throughout this application are expressly incorporated herein by reference.

[0041] Therefore, it is the purpose of this disclosure not to include any previously known products, processes for producing products, or methods for using products, to the extent that the applicant hereby discloses a waiver of all previously known products, processes, or methods, for which the applicant reserves rights. It should be further noted that this disclosure is not intended to include, within the scope of this disclosure, any products, processes for producing products, or methods for using products that do not conform to the specification requirements and implementability requirements of the USPTO (United States Patent Act §112, first paragraph) or EPO (EPC Section 83), for which the applicant reserves rights and hereby discloses a waiver of all previously described products, processes for producing products, or methods for using products. Compliance with EPC Section 53(c) and EPC Rules 28(b) and (c) may be advantageous in implementing this disclosure. All rights to expressly waive any embodiments that are subject to the applicant's licensed patents in the lineage of this application, or other lineages, or in prior applications of third parties are expressly reserved. Nothing in this specification shall be construed as a promise.

[0042] In this disclosure, specifically in the claims and / or paragraphs, terms such as “comprises,” “comprised,” “comprising,” and similar terms may have meanings attributable to them under U.S. patent law, for example, they may mean “includes,” “included,” “including,” and similar terms, and terms such as “consisting essentially of” and “consists essentially of” may have meanings attributable to them under U.S. patent law, for example, they may enable elements that are not expressly described but exclude elements found in the prior art or that affect the fundamental or novel features of this disclosure. [Modes for carrying out the invention]

[0043] This application provides novel 3,5-substituted piperidine compounds and their derivatives that selectively and effectively inhibit renin activity. These compounds and their derivatives may be used to inhibit RAAS activity and treat or alleviate diseases associated with abnormal renin / RAAS activity, including but not limited to hypertension, cardiovascular disease, diabetic nephropathy, and heart failure.

[0044] In the first embodiment, the compound of the present disclosure is a compound of formula I or formula II illustrated below: [ka] , [ka] It has a structure, In the formula, R1, R2, X, n, ring A, R3, R4, R5, R6, R7, R1', R2', and R3' are defined above, if they exist.

[0045] Exemplary compounds of formula I or formula II are listed in Table 1 below. Table 1. Exemplary Compounds of the Present Disclosure [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0046] The various terms used throughout this specification and the claims, unless otherwise limited in specific examples, individually or as part of a larger group, have the following meanings:

[0047] The term "optionally substituted" means that the group may be unsubstituted or substituted with one or more types of substituents.

[0048] The term "deuterium," also known as heavy hydrogen, refers to an isotope of hydrogen whose nucleus contains one proton and one neutron. Deuterium is abundant in the ocean.

[0049] The term "halogen" or "halo" encompasses six elements of Group 17 of the periodic table, including fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and tennessine (Ts). Preferred halogens in this application are fluorine (F), chlorine (Cl), bromine (Br), and iodine (I), in particular fluorine (F), chlorine (Cl), and bromine (Br).

[0050] "Carboxyl" refers to a functional group (-COOH) that contains or consists of a carbonyl group (C=O) and has a hydroxyl group (OH) attached to the same atom.

[0051] As used herein, the term "cyano" refers to a functional group (-C≡N) containing a carbon atom triple-bonded to a nitrogen atom.

[0052] The term "alkyl" includes straight-chain or branched radicals having from 1 to about 20 carbon atoms, or preferably from 1 to about 12 carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having from 1 to about 10 carbon atoms. Most preferred are lower alkyl radicals having from 1 to about 8, such as from 1 to about 6, or from 1 to about 3 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, and the like.

[0053] The term "alkenyl" includes straight-chain or branched radicals having from 2 to about 20 carbon atoms, or preferably from 2 to about 12 carbon atoms, and having at least one carbon-carbon double bond. More preferred alkenyl radicals are "lower alkenyl" radicals having from 2 to about 10 carbon atoms, and more preferably from about 2 to about 8, such as from 2 to about 6, from 2 to 5, or from 2 to 4 carbon atoms. Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl" include radicals having the "cis" and "trans" orientations, or alternatively, the "E" and "Z" orientations.

[0054] The term "alkylthio" includes radicals containing a straight-chain or branched alkyl of from 1 to about 10 carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are lower alkylthio radicals having an alkyl radical of from 1 to about 8, such as from 1 to 6, or from 1 to 3 carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio, and hexylthio.

[0055] The term "alkynyl" encompasses straight-chain or branched radicals having at least one carbon-carbon triple bond and containing from 2 to about 20 carbon atoms, or preferably from 2 to about 12 carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having from 2 to about 10 carbon atoms, and more preferably from about 2 to about 8, for example, 2 to about 6, 2 to 5, 2 to 4 carbon atoms. Examples of alkynyl radicals include propargyl, 1-propynyl, 2-propynyl, 1-butyne, 2-butynyl, and 1-pentynyl.

[0056] The term "amide" refers to the -C(=O)N= radical.

[0057] The term "sulfinyl" refers to the -S(=O)- radical, while the term "alkylsulfinyl" encompasses radicals containing a straight-chain or branched alkyl radical of 1 to about 10 carbon atoms attached to the divalent -S(=O)- radical. More preferred alkylsulfinyl radicals are lower alkylsulfinyl radicals having an alkyl radical of 1 to about 8, for example, 1 to 6, 1 to 3 carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl, and hexylsulfinyl.

[0058] The term "sulfonyl" means the divalent radical -SO2- whether used alone or linked to other terms such as alkylsulfonyl, while the term "alkylsulfonyl" encompasses an alkyl radical attached to the sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having 1 to about 6, for example, 1 to 3 carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl, and propylsulfonyl. The "alkylsulfonyl" radical may be further substituted with one or more halo atoms such as fluoro, chloro, or bromo to give a haloalkylsulfonyl radical.

[0059] The term "alkoxy" encompasses linear or branched oxy-containing radicals, each having an alkyl moiety of 1 to about 20 carbon atoms, or preferably 1 to about 12 carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having 1 to about 10 carbon atoms, more preferably 1 to about 8, for example, 1 to 6, 1, or 3 carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, and tert-butoxy.

[0060] The term "cycloalkyl" refers to a cyclic saturated or unsaturated monovalent hydrocarbon radical having 3 to 12 carbon atoms. This term encompasses saturated carbocyclic radicals having 3 to about 12 carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having 3 to about 8, for example, 3 to 6, or 3 to 4 carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0061] The term "hydroxylcycloalkyl" encompasses cycloalkyl radicals as defined above, each substituted with one or more hydroxyl groups, and hydroxyl C 3~6 Cycloalkyl and hydroxyl C 3~4 Examples include cycloalkyl compounds.

[0062] The term "mercapto" refers to a functional group (-SH) that contains a sulfur atom bonded to a hydrogen atom.

[0063] The term "carbonyl," whether used alone or in conjunction with other terms such as "alkylcarbonyl," refers to a chemical organic functional group consisting of a carbon atom double-bonded to an oxygen atom, i.e., -(C=O)-. The term "alkylcarbonyl" includes radicals having an alkyl radical attached to a carbon atom in a carbonyl radical, as defined above. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, and hexylcarbonyl. The term "aminocarbonyl" encompasses radicals having an amino group attached to a carbon atom in a carbonyl radical. The term "alkoxycarbonyl" refers to radicals containing an alkoxy radical attached to a carbon atom in a carbonyl radical, as defined above. Examples of such "alkoxycarbonyl" radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and hexyloxycarbonyl.

[0064] The terms "heterocyclic" or "heterocyclyl" encompass saturated, partially unsaturated, and unsaturated heteroatom-containing ring-shaped radicals, the heteroatoms of which may be selected from nitrogen, sulfur, and oxygen. Examples of saturated heterocyclyl radicals include saturated 3-6 membered heteromonocyclic groups containing 1-4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl); saturated 3-6 membered heteromonocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms (e.g., morpholinyl); and saturated 3-6 membered heteromonocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran, and dihydrothiazole. Examples of unsaturated heterocyclic radicals include pyridine and diazines (including pyridazine, pyrimidine, and pyrazine). Partially unsaturated or unsaturated six-membered heterocyclic radicals also include pyran, thiopyran, oxazine, thiazine, dioxin, dithiine, and triazine. Heterocyclyl radicals may also contain pentavalent nitrogen, such as in tetrazolium and pyridinium radicals. The term “heterocyclic” also encompasses radicals in which heterocyclyl radicals are fused with aryl or cycloalkyl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and similar compounds.

[0065] The term "cyclic hydrocarbon group" refers to a saturated, partially unsaturated, or unsaturated carbon chain in a cyclic structure.

[0066] The term "formyl" refers to a functional group that contains or consists of a carbonyl group bonded to a hydrogen atom.

[0067] The term "hydroxylalkyl" encompasses alkyl radicals as defined above, each substituted with one or more, for example, one or two hydroxyl radicals.

[0068] The term "alkylamino" encompasses amino radicals, each substituted with one or two alkyl groups as defined above. Preferred alkylamino radicals have alkyl radicals having about 1 to about 20 carbon atoms, or preferably 1 to about 12, 1 to 6, or 1 to 3 carbon atoms. Examples of such radicals may be monosubstituted N-alkylaminos or disubstituted N,N-alkylaminos, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, or similar.

[0069] The terms “haloalkyl,” “halocycloalkyl,” “haloalkoxy,” “halosubstituted amino,” “haloalkylcarbonyl,” and “halocycloalkylcarbonyl,” and similar terms, respectively, encompass alkyl, cycloalkyl, alkoxy, amino, alkylcarbonyl, cycloalkylcarbonyl, and other radicals as defined above, each substituted with one or more halogens, for example, 1, 2, 3, or 4, as defined above.

[0070] The term "alkoxyalkyl" encompasses alkyl radicals as defined above, having one or more alkoxy radicals as defined above, which are attached to an alkyl radical, i.e., to form monoalkoxyalkyl and dialoxyalkyl radicals.

[0071] The terms "pyran" or "oxine" refer to a six-membered heterocyclic non-aromatic ring consisting of five carbon atoms and one oxygen atom, having two double bonds, and include 2H-pyran and 4H-pyran.

[0072] The term "thiopyran" refers to a heterocyclic compound containing five carbon atoms and one sulfur atom, having two double bonds, and includes 2H-thiopyran and 4H-thiopyran.

[0073] The term "oxazine" encompasses a heterocyclic radical containing one oxygen and one nitrogen atom in a six-membered ring with two double bonds, including 1,2-oxazine, 1,3-oxazine, and 1,4-oxazine.

[0074] The term "thiazine" encompasses a radical containing a ring of four carbons, one nitrogen, and one sulfur atom, including 1,2-thiazine, 1,3-thiazine, and 1,4-thiazine.

[0075] The term "dithiin" encompasses a radical containing two sulfur and four carbon atoms with two double bonds, including 1,2-dithiin and 1,4-dithiin.

[0076] The term "triazine" encompasses a radical having a six-membered benzene-like ring each having three carbon and three nitrogen atoms, including 1,2,3-triazine, 1,2,4-triazine, and 1,3,5-triazine.

[0077] The term "aryl", alone or in combination, generally means a carbocyclic aromatic system containing one or more rings, and such rings may be attached together in a pendant fashion or fused. The term "aryl" encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane, and biphenyl.

[0078] The term "substituted" refers to a given structure that is substituted for a deuterium atom, halogen atom, cyano group, mercapto group, hydroxyl group, carboxyl group, alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, amino group, alkylthio group, hydroxylalkyl group, alkoxyalkyl group, alkylcarbonyl group, aminocarbonyl group, alkylamino group, cycloalkyl group, alkylsulfinyl group, alkylsulfonyl group, amino group, alkylcarbonyl group, alkoxycarbonyl group, heterocyclyl group, hydroxylcycloalkyl group, haloalkyl group, halocycloalkyl group, haloalkylcarbonyl group, halocycloalkyl This refers to the replacement of one or more hydrogen radicals with radicals of certain substituents, including but not limited to, carbonyl groups, alkylthioalkyl groups, alkylsulfonylalkyl groups, aminocarbonylcycloalkyl groups, aminocarbonyl heterocyclyl groups, alkylaminocarbonyl groups, trifluoromethyl groups, alkylaminoalkyl groups, aminoalkylamino groups, carboxyalkyl groups, alkoxycarbonylalkyl groups, aminocarbonylalkyl groups, carboxylic acids, sulfonic acids, sulfonyls, phosphonic acids, pyridines, pyridazines, pyrimidines, pyrazines, pyrans, thiopyrans, oxazines, thiazines, dioxins, dithiines, and triazines. It is understood that substituents may be further substituted.

[0079] The chemical substructures defined and referenced throughout may be monovalent (e.g., alkyl, aryl, etc.) or polyvalent substructures under appropriate structural circumstances that are obvious to those skilled in the art. For example, an "alkyl" substructure may be considered to belong to a monovalent radical (e.g., CH3-CH2-), or in other examples, a divalent linkage substructure may be "alkyl," in which case those skilled in the art will understand that alkyl is a divalent radical (e.g., -CH2-CH2-) and is equivalent to the term "alkylene." Similarly, where a divalent substructure is required and explicitly stated as "alkoxy," "alkylamino," "aryloxy," "alkylthio," "aryl," "heteroaryl," "alkyl," "alkenyl," "alkynyl," or "cycloalkyl," those skilled in the art will understand that the terms "alkoxy," "alkylamino," "aryloxy," "alkylthio," "aryl," "heteroaryl," "alkyl," "alkenyl," "alkynyl," or "cycloalkyl" refer to the corresponding divalent substructure.

[0080] The term "compound" is defined herein to include pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereoisomers, racemates, and the like of compounds having the formulas described herein.

[0081] The term “treatment” refers to any process, action, application, therapy, or similar, wherein mammals, including humans, are the subject of medical assistance aimed at directly or indirectly improving the health status of the mammal.

[0082] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that, within the bounds of lawful and medical judgment, is suitable for use in contact with human and lower animal tissues without unwarranted toxicity, inflammation, allergic response, and similar effects, and that is commensurate with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge, et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Salts can be prepared by reacting a free basic functional group with a suitable organic or inorganic acid, either in situ or separately, during the final isolation and purification of the compounds of this disclosure. Examples of pharmaceutically acceptable non-toxic acid addition salts include, but are not limited to, salts of amino groups formed by inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or by organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, lactobionic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfons, benzoates, bisulfates, borates, butyrates, camphorates, camphor sulfons, citrates, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptons, glycerophosphates, glucons, hemisulfons, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfons, and lactobionates. This includes, but is not limited to, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, valersates, and similar substances.Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and similar compounds. Furthermore, pharmaceutically acceptable salts, where appropriate, include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylic acids, sulfuric acid, phosphoric acid, nitric acid, alkyls having one to six carbon atoms, sulfonic acids, and aryl sulfonates.

[0083] The term "geometric isomer" encompasses chemical species that contain the same type and proportion of atoms and bonds, but have different spatial arrangements of atoms.

[0084] The term "isotopomer" also refers to isomers that have the same number of isotopes of each element, but with the isotopic atoms located in different positions.

[0085] As used herein, the term “pharmaceutically acceptable prodrug” refers to a prodrug of a compound of the Disclosure that is suitable for use in contact with human and lower animal tissues without excessive toxicity, inflammation, allergic response, and the like, within the bounds of lawful and medical judgment, is commensurate with a reasonable benefit / risk ratio, and is effective for its intended use, as well as, where possible, a zwitterionic form of the compound of the Disclosure. As used herein, “prodrug” means a compound that can be converted in vivo to a compound of the Disclosure by metabolic means (e.g., by hydrolysis). Various forms of prodrugs are described in, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed.) "Design and Application of Prodrugs, Textbook of Drug Design and Development", Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8: 1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77: 285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrugs" This is known in the field, as discussed in "Metabolism: Chemistry, Biochemistry and Enzymology," John Wiley and Sons, Ltd. (2002).

[0086] As used herein, the term “subject” refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. The subject also refers to, for example, dogs, cats, horses, cattle, pigs, guinea pigs, fish, birds, and the like.

[0087] The compounds of this disclosure may be modified by adding appropriate functionalities to enhance their selective biological properties. Such modifications are known in the art and may include increasing biopenetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increasing oral availability, increasing solubility to enable administration by injection, altering metabolism, and altering excretion rates.

[0088] The synthesized compounds can be separated from the reaction mixture and further purified by methods such as column chromatography, high-pressure liquid chromatography, or recrystallization. As can be recognized by those skilled in the art, further methods for synthesizing the compounds of the formulas herein will be obvious to those skilled in the art. Additionally, the various synthesis steps may be carried out in an alternating order or sequence to give the desired compounds. The synthetic chemical transformations and protecting group methodologies (protection and deprotection) useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW. Greene and PGMWuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[0089] The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereoisomers, and other stereoisomeric forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry, or as (D)- or (L)- with respect to amino acids. This disclosure is intended to include all such possible isomers, and their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above or by splitting racemic mixtures. Splitting can be performed in the presence of a splitting agent by chromatography, by repeated crystallization, or by any combination of these techniques known to those skilled in the art. Further details relating to splitting can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Where a compound described herein contains an olefinic double bond, other unsaturated or other geometrically asymmetrical center, unless otherwise specified, the compound is intended to include both E and Z geometric isomers and / or cis and trans isomers. Similarly, all tautomeric forms are also intended to be included. Any carbon-carbon double bond configuration appearing herein is selected for convenience only, and no particular configuration is intended to be specified unless the text so states; therefore, a carbon-carbon double bond or carbon-heteroatom double bond arbitrarily described herein as trans may be cis, trans, or a mixture of the two in any proportion.

[0090] The compounds disclosed herein exhibit inhibitory effects on human renin activity, and IC 50 This refers to values ​​less than 250.0 nM, less than 200.0 nM, less than 150.0 nM, less than 100.0 nM, less than 50.0 nM, less than 30.0 nM, less than 20.0 nM, less than 10.0 nM, less than 5.0 nM, or even less than 2.0 nM.

[0091] The pharmaceutical compositions of this disclosure comprise a therapeutically effective amount of the compound of this disclosure, formulated together with one or more pharmaceutically acceptable carriers or excipients.

[0092] As used herein, the term “pharmaceutically acceptable carrier or excipient” means any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid. Some examples of materials that can act as pharmaceutically acceptable carriers are sugars such as lactose, glucose, and sucrose; cyclodextrins such as alpha-(α), beta-(β), and gamma-(γ) cyclodextrins; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil Oils such as oat oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; water free of pyrogens; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solution; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate. Depending on the discretion of the formulation, colorants, release agents, coating agents, sweeteners, flavoring agents, preservatives, and antioxidants may also be present in the composition.

[0093] The pharmaceutical compositions of this disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, or via an implantable reservoir, preferably by oral or injectable administration. The pharmaceutical compositions of this disclosure may contain any conventional non-toxic, pharmaceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation may be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the formulated compound or its delivery form. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-sacral, intrasternal, intrathecal, intrafocal, and intracranial injection or infusion techniques.

[0094] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0095] Injectable preparations, such as injectable aqueous or oily sterile suspensions, may be formulated using suitable dispersing or wetting agents and suspending agents according to the known art. Injectable sterile preparations may also be injectable sterile solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be employed include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixative oils are conventionally employed as solvents or suspension media. For this purpose, any low-irritation fixative oil, including synthetic mono or diglycerides, may be employed. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations. Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterile agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other injectable sterile media before use.

[0096] In many cases, it is desirable to slow the absorption of a drug from subcutaneous or intramuscular injection in order to prolong the drug's effect. This may be achieved by using a liquid suspension of crystalline or amorphous material having poor water solubility. In this case, the rate of drug absorption may depend on the rate of dissolution, and therefore on the crystal size and morphology. Alternatively, delayed absorption of parenterally administered drug forms is achieved by dissolving or suspending the drug in an oil vehicle. Injectable depot formulations are prepared by forming a microencapsulation matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the properties of the specific polymer employed, the rate of drug release can be controlled. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Depot injectable formulations are also prepared by capturing the drug in liposomes or microemulsions that are compatible with body tissues.

[0097] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffering agent.

[0098] Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol and the like.

[0099] Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and outer shells, such as enteric coatings and other coatings, which are well known in the pharmaceutical technology. They may optionally contain opacifying agents, and may be composed in such a way that they release only the active ingredient, or optionally in a delayed form, preferably in a specific part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0100] The “therapeutic effective dose” of the compounds disclosed herein means the amount of the compound that gives a therapeutic effect, for example, a reduction in abnormal renin / RAAS activity in the treated subject with a reasonable benefit / risk ratio applicable to any medical procedure. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an expression of or sensation of an effect). The effective dose of the compounds described above may range from about 0.1 mg / kg to about 500 mg / kg. The effective dose will also vary depending on the route of administration and the possibility of concomitant use with other agents. However, it will be understood that the total daily dose of the compounds and compositions disclosed herein will be determined by the attending physician within the bounds of lawful and medical judgment. The level of a specific therapeutically effective dose for any particular patient will depend on a variety of factors, including the disorder being treated and its severity; the activity of the specific compound being employed; the specific composition being employed; the patient's age, weight, overall health, sex, and diet; the timing, route of administration, and excretion rate of the specific compound being employed; the duration of treatment; drugs used in combination with or concurrently with the specific compound being employed; and similar factors well known in the medical technology field.

[0101] The total daily dose of any of the compounds of this disclosure administered to humans or other animals, either as a single dose or in divided doses, may range in quantity from, for example, 0.01 to 50 mg / kg body weight, or more generally from 0.1 to 25 mg / kg body weight.

[0102] Lower or higher doses than those listed above may be required. Specific doses and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, weight, overall health, sex, diet, administration time, excretion rate, drug combinations, severity and course of the disease, condition, or symptom, the patient's predisposition to the disease, condition, or symptom, and the judgment of the treating physician.

[0103] In response to the improvement of the patient's condition, maintenance doses of the compounds, compositions, or combinations of the disclosed herein may be administered as needed. Subsequently, when symptoms have been alleviated to a desired level, the dose and / or frequency of administration may be reduced, depending on the symptoms, to a level that maintains the improved condition. However, the patient may require long-term, intermittent treatment in response to any recurrence of disease symptoms.

[0104] Compounds of formula I, or pharmaceutically acceptable salts thereof, may be prepared by any process known to be applicable to the preparation of chemically related compounds, including a preferred process for producing certain intermediates. The required starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in the attached non-limiting examples. Alternatively, the required starting materials may be obtained by procedures similar to those illustrated, which are within the ordinary art of chemists.

[0105] This disclosure further provides methods for the prevention or treatment of diseases or conditions related to abnormal renin activity or RAAS activity. In one embodiment, this disclosure further provides the use of the pharmaceutical composition of this disclosure in the manufacture of agents for stopping or reducing diseases related to abnormal renin / RAAS activity. The disease may be hypertension, cardiovascular disease, diabetic nephropathy, or heart failure. In a particular embodiment, the disease is hypertension. In one embodiment, this disclosure relates to a method for treating hypertension in a subject in need thereof, comprising the step of administering a therapeutically effective amount of the compound of this disclosure to the subject. In one embodiment, this disclosure relates to a method for inhibiting renin or RAAS activity in a subject in need thereof, comprising the step of administering the pharmaceutical composition of this disclosure to the subject.

[0106] Formulating oral compositions in unit dose forms is particularly advantageous for ease of administration and dose uniformity. As used herein, unit dose forms refer to physically distinct units suitable as unit doses for the subject being treated; each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect in conjunction with the necessary pharmaceutical carrier. The specifications for unit dose forms in this disclosure are determined and directly depend on the specific characteristics of the active compound, the particular therapeutic effect to be achieved, and the inherent constraints in the art for formulating such an active compound to treat an individual.

[0107] The pharmaceutical composition may be contained in a container, pack, or dispenser along with instructions for administration.

[0108] The preparation of pharmaceutical compositions containing active ingredients is well understood in the art and involves processes such as mixing, granulation, or tablet formation. In many cases, the active therapeutic ingredient is mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. For oral administration, the activator is mixed with additives conventional for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by conventional methods into forms suitable for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic, or oily solutions, and the like, as detailed above.

[0109] The amount of compound administered to a patient is less than the amount that causes toxicity in the patient. In certain embodiments, the amount of compound administered to a patient is less than the amount at which the concentration of the compound in the patient's plasma equals or exceeds the toxic level of the compound. In implementing this disclosure, the optimal amount of compound to be administered to a patient will depend on the specific compound used and the type of cancer being treated. [Examples]

[0110] The compounds described herein will be better understood in connection with the following representative synthetic schemes illustrating how the compounds of this disclosure may be prepared, which are for illustrative purposes only and do not limit the scope of this disclosure. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including, but not limited to, those relating to the chemical structures, substituents, derivatives, formulations, and / or methods of this disclosure, may be made without departing from the spirit of this disclosure and the scope of the appended claims. Example 1. Synthesis of the intermediate Synthesis of intermediate compound A [ka] Step A: Synthesis of dimethylpiperidine-3,5-dicarboxylate (Compound 1) [ka]

[0111] A solution of 3,5-dimethylpyridine-3,5-dicarboxylate (34.1 g, 174.716 mmol, 1.0 eq) and PtO2 (0.79 g, 3.494 mmol, 0.02 eq) in AcOH was stirred at room temperature under a hydrogen atmosphere for 24 hours. The resulting mixture was filtered; the filter cake was washed with AcOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. Compound 1 (35.1 g, unrefined) was obtained as a yellow oil. LCMS(ESI)[M+H] + :202. Step B: Synthesis of 1-tert-butoxylcarbonyldimethylpiperidine-3,5-dicarboxylate (Compound 2) [ka]

[0112] A solution of compound 1 (31 g, 154.059 mmol, 1.0 eq), Et3N (77.95 g, 770.295 mmol, 5.0 eq), and Boc2O (50.43 g, 231.089 mmol, 1.5 eq) in DCM was stirred at room temperature for 15 hours. The residue was purified by silica gel column chromatography and eluted with PE / EA (2:1) to obtain compound 2 (32 g, 69%) as a yellow oil. LCMS(ESI)[M+H] + :302. Step C: Synthesis of 1-tert-butoxycarbonylpiperidine-3,5-dicarboxylic acid (Compound 3) [ka]

[0113] A solution of compound 2 (31 g, 102.874 mmol, 1.0 eq) and potassium carbonate (42.96 g, 308.622 mmol, 3.0 eq) in MeOH and H2O was stirred at 70°C for 15 hours. The mixture was acidified to pH 3 with HCl (aqueous solution). The resulting mixture was extracted with HCl (3 × 200 mL). The mixed organic layers were dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded compound 3 (25 g, 89%) as a white solid. LCMS(ESI)[M+H] + :274. Step D: Synthesis of 7-tert-butoxylcarbonyl-2,4-dioxo-3-oxa-7-azabicyclo[3.3.1]nonane (compound 4) [ka]

[0114] A solution of compound 3 (25 g, 91.480 mmol, 1.0 eq) in acetic anhydride (300 mL, 2938.612 mmol, 32.1 eq) was stirred at 140°C for 15 hours. The resulting mixture was concentrated under vacuum. This yielded compound 4 (21.4 g, unpurified) as an off-white solid. LC-MS(ESI)[M+H] + :256. Step E: Synthesis of 1-(tert-butoxycarbonyl)-(5R)-(methoxycarbonyl)piperidine-(3S)-carboxylic acid (compound 5) [ka]

[0115] To a solution of compound 4 (10 g, 39.174 mmol) and (DHQD)2AQN (3.34 g, 3.917 mmol) in a mixture of THF (250 mL) and Et2O (700 mL), MeOH (16 mL, 395.18 mmol) in Et2O (50 mL) at -78 °C was added dropwise. The reaction mixture was stirred at -78 °C for 10 hours and then warmed to room temperature. The reaction mixture was acidified with 1N HCl (pH=3) and then extracted with SiO (100 × 3 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the monoester. The unpurified monoester was dissolved in EtOH (60 mL) at 80 °C. (R)-1-phenylethylamine (4.6 mL, 37.988 mmol) at 80 °C was added to the mixture and then stirred overnight at room temperature. The resulting crystals were filtered off and washed with acetonitrile to obtain the monoester. The intermediate salt in CH2Cl2 was then acidified by adding 1N HCl (pH=3~4). The resulting mixture was extracted with CH2Cl2 (100 × 3 mL), and the resulting organic extract was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0%~50% gradient over 20 minutes, UV 254 nm. This yielded compound 5 (2.2 g, 19.55%) as an off-white solid. LCMS(ESI)[M+H] + :288. Step F: Synthesis of methyl 1-tert-butoxylcarbonyl-(3S)-[(benzyloxy)carbonyl]amino-piperidine-(5R)-carboxylate (compound 6) [ka]

[0116] A solution of compound 5 (300 mg, 1.044 mmol, 1.0 eq), diphenyl phosphoryl azide (324.7 mg, 1.180 mmol, 1.1 eq), and triethylamine (169.1 mg, 1.670 mmol, 1.6 eq) in toluene was stirred at room temperature under a nitrogen atmosphere for 3 hours. Benzyl alcohol (225.8 mg, 2.088 mmol, 2.0 eq) was added to the above mixture. The resulting mixture was stirred at 100°C for an additional 4 hours. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. This yielded compound 6 (280 mg, 68.33%) as a yellow oil. LCMS(ESI)[M+H] + :393. Step G: Synthesis of methyl 1-tert-butoxylcarbonyl(3S)-amino-piperidine-(5R)-carboxylate (compound 7) [ka]

[0117] A solution of compound 6 (1 g, 2.548 mmol, 1 eq) and Pd / C (0.1 g, 0.255 mmol, 0.1 eq) (20 mL) in methanol was stirred at room temperature under a hydrogen atmosphere for 1 hour. The precipitated solid was collected by filtration and washed with MeOH (3 × 3 mL). The resulting mixture was concentrated under vacuum. This yielded compound 7 (600 mg, 91.16%) as a yellow solid. LCMS(ESI)[M+H] + :259. Step H: Synthesis of methyl 1-tert-butoxylcarbonyl-(3S)-(2-methylpropyl)aminopiperidine(5R)-carboxylate (compound A) [ka]

[0118] A solution of compound 7 (215 mg, 0.751 mmol, 1.0 eq), isobutyraldehyde (64.9 mg, 0.901 mmol, 1.2 eq), and sodium triacetoxyborate (477.4 mg, 2.253 mmol, 3.0 eq) in MeOH was stirred at room temperature for 15 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. This yielded compound A (170 mg, 72.00%) as a yellow oil. LCMS(ESI)[M+H] + :315. Synthesis of intermediate compound B [ka] Step A: Synthesis of methyl 5-cyclopropyl-3-fluoropyridine-2-carboxylate (Compound 8) [ka]

[0119] A solution of 1,4-dioxane and methyl 5-bromo-3-fluoropyridine-2-carboxylate (3.3 g, 14.101 mmol, 1.0 eq), cyclopropyltrifluoro-lambda-4-borane potassium (6.26 g, 42.303 mmol, 3.0 eq), Pd(dppf)Cl2 (1.25 g, 1.410 mmol, 0.1 eq), and K2CO3 (5.85 g, 42.303 mmol, 3 eq) in H2O was stirred at 85°C for 2 hours under a nitrogen atmosphere. The resulting mixture was extracted with RINKAN (3 × 100 mL). The mixed organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Compound 8 (1.2 g, 43.60%) was obtained as an off-white solid. LCMS(ESI)[M+H] + :196. Step B: Synthesis of methyl 5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]aminopyridine-2-carboxylate (compound 9) [ka]

[0120] A solution of compound 8 (300 mg, 1.537 mmol, 1.0 eq), (1r,3r)-3-methoxycyclobutan-1-amine (155.5 mg, 1.537 mmol, 1.0 eq), and DIEA (595.9 mg, 4.611 mmol, 3.0 eq) in NMP was stirred at 140°C for 2 hours under a nitrogen atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water; 0% to 50% gradient over 20 minutes; UV 254 nm. This yielded compound 9 (196 mg, 46.15%) as a yellow solid. LCMS(ESI)[M+H] + :277. Step C: Synthesis of 5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]aminopyridine 2-carboxylic acid (compound B) [ka]

[0121] A solution of compound 9 (196 mg, 0.709 mmol, 1.0 eq) and lithium hydroxide monohydrate (148.8 mg, 3.545 mmol, 5.0 eq) in THF and H2O was stirred at room temperature for 2 hours. The mixture was acidified to pH 5 using AcOH. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. This yielded compound B (170 mg, 91.37%) as a yellow solid. LCMS(ESI)[M+H] + :263. Example 2. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3-fluoroazetidine-N-carbonyl)-piperidine (also known as Compound 10, 5-cyclopropyl-N-[5-(3-fluoroazetidine-1-carbonyl)piperidine-3-yl]-N-(2-methylpropyl)-3-{[(1r,3r)-3-methoxycyclobutyl]amino}pyridine-2-carboxamide) [ka] Synthesis of methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylate [ka]

[0122] Solutions of compound A (220 mg, 0.700 mmol, 1.0 eq), compound B (183.5 mg, 0.700 mmol, 1.0 eq), N,N-diisopropylethylamine (271.3 mg, 2.100 mmol, 3.0 eq), and HATU (319.3 mg, 0.840 mmol, 1.2 eq) in DMF were stirred at room temperature for 2 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. This yielded methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate (230 mg, 58.83%) as a yellow oil. LCMS(ESI)[M+H] + :559. Synthesis of 1-tert-butoxylcarbonyl(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylic acid (compound C) [ka]

[0123] A solution of methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate (578 mg, 1.035 mmol, 1.0 eq) and lithium hydroxide monohydrate (217.1 mg, 5.175 mmol, 5.0 eq) in THF / H2O was stirred overnight at room temperature. The mixture was acidified to pH 5 using AcOH. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. Compound C (480 mg, 85.18%) was obtained as a yellow solid. LCMS(ESI)[M+H] + :545. Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3-fluoroazetidinyl-N-carbonyl)-piperidine [ka]

[0124] A solution of compound C (100 mg, 0.184 mmol, 1.0 eq), 3-fluoroazetidine (15.2 mg, 0.202 mmol, 1.1 eq), N,N-diisopropylethylamine (71.2 mg, 0.552 mmol, 3.0 eq), and HATU (53.1 mg, 0.221 mmol, 1.2 eq) in DMF was stirred at room temperature for 2 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3-fluoroazetidinyl-N-carbonyl)-piperidine (95 mg, 85.99%) as a yellow oil. LCMS(ESI)[M+H] + :602 Synthesis of compound 10 [ka]

[0125] A solution of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3-fluoroazetidinyl-N-carbonyl)-piperidine (100 mg, 0.166 mmol, 1.0 equiv) in DCM and TFA was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 9 with saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. Compound 10 (18.4 mg, 18.40%) was obtained as a white solid. LCMS(ESI)[M+H] + :502.30. 1H NMR(400MHz,DMSO-d6)δ7.63(d,J=19.6Hz,1H),6.46(d,J=7.8Hz,1H),5.74-5.23(m,2H),4.62-3.58(m,7H),3.20- 3.24(m,2H),3.14(s,3H),3.01-2.64(m,2H),2.42-1.46(m,11H),0.94(m,6H),0.76(d,J=5.5Hz,2H),0.60(s,2H). Example 3. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3,3-difluoropyrrolidine-N-carbonyl)-piperidine (also known as Compound 11, 5-cyclopropyl-N-[5-(3,3-difluoropyrrolidine-1-carbonyl)piperidine-3-yl]-N-(2-methylpropyl)-3-{[(1r,3r)-3-methoxycyclobutyl]amino}pyridine-2-carboxamide) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3,3-difluoropyrrolidine-N-carbonyl)-piperidine [ka]

[0126] A solution of compound C (100 mg, 0.184 mmol, 1.0 eq), 3,3-difluoropyrrolidine (23.6 mg, 0.221 mmol, 1.2 eq), N,N-diisopropylethylamine (71.2 mg, 0.552 mmol, 3.0 eq), and HATU (83.8 mg, 0.221 mmol, 1.2 eq) in DMF was stirred at room temperature for 2 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3,3-difluoropyrrolidine-N-carbonyl)-piperidine (98 mg, 84.22%) as a yellow oil. LCMS(ESI)[M+H] + :634. Synthesis of compound 11 [ka]

[0127] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3,3-difluoropyrrolidine-N-carbonyl)-piperidine (96 mg, 0.151 mmol, 1.0 eq) in DCM / TFA was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 9 with saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. Compound 11 (50 mg, 61.85%) was obtained as a white solid. LCMS(ESI)[M+H] + :534.30. 1H NMR(400MHz,DMSO-d6)δ7.63(d,J=12.7Hz,1H),6.58-6.37(m,1H),5.69-5.46(m,1H),4. 17-3.79(m,4H),3.66(d,J=13.2Hz,2H),3.53-3.42(m,1H),3.29-3.18(m,2H),3.14(s,3 H),3.03-2.67(m,3H),2.56(d,J=17.4Hz,2H),2.40-2.21(m,5H),2.03(s,3H),1.94-1.8 4(m,2H),1.82-1.49(m,1H),1.07-0.84(m,6H),0.75(d,J=5.4Hz,2H),0.65-0.50(m,2H). Example 4. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(4,4-difluoropiperidine-N-carbonyl)-piperidine (also known as Compound 12, 5-cyclopropyl-N-[5-(4,4-difluoropiperidine-1-carbonyl)piperidine-3-yl]-N-(2-methylpropyl)-3-{[(1r,3r)-3-methoxycyclobutyl]amino}pyridine-2-carboxamide) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(4,4-difluoropiperidine-N-carbonyl)-piperidine [ka]

[0128] Solutions of compound C (100 mg, 0.184 mmol, 1.0 eq), 4,4-difluoropiperidine (26.7 mg, 0.221 mmol, 1.2 eq), N,N-diisopropylethylamine (71.2 mg, 0.552 mmol, 3.0 eq), and HATU (53.1 mg, 0.221 mmol, 1.2 eq) in DMF were stirred at room temperature for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(4,4-difluoropiperidine-N-carbonyl)-piperidine (96 mg, 80.72%) as a yellow oil. LCMS(ESI)[M+H] + :648. Synthesis of compound 12 [ka]

[0129] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(4,4-difluoropiperidine-N-carbonyl)-piperidine (98 mg, 0.151 mmol, 1.0 eq) in DCM / TFA was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 9 with saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. Compound 12 (50 mg, 60.35%) was obtained as a white solid. LCMS(ESI)[M+H] + :548.35. 1H NMR(400MHz,DMSO-d6)δ7.63(d,J=13.3Hz,1H),6.46(d,J=8.7Hz,1H),5.55(m,1H),3.94(m,3H),3.77-3.46(m,5H),3.23(m,2H), 3.14(s,3H),3.01-2.53(m,4H),2.29(m,4H),2.16-1.69(m,10H),1.05-0.85(m,6H),0.76(d,J=5.7Hz,2H),0.61(d,J=6.4Hz,2H). Example 5. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(4-trifluoromethoxypiperidine-N-carbonyl)-piperidine (also known as Compound 13, 5-cyclopropyl-N-(2-methylpropyl)-3-{[(1r,3r)-3-methoxycyclobutyl]amino}-N-{5-[4-(trifluoromethoxy)piperidine-1-carbonyl]piperidine-3-yl}pyridine-2-carboxamide) [ka] Synthesis of N-tert-butoxycarbonyl 4-(trifluoromethoxy)piperidine [ka]

[0130] A solution of N-tert-butoxycarbonyl 4-hydroxypiperidine (2 g, 9.937 mmol, 1 eq), oxo(trifluoromethanesulfonyl) silver (10.21 g, 39.748 mmol, 4 eq), potassium fluoride (2.31 g, 39.748 mmol, 4 eq), 2-fluoropyridine (2.89 g, 29.811 mmol, 3 eq), trifluoromethyltrimethylsilane (4.24 g, 29.811 mmol, 3 eq), and selectfluor (15.84 g, 44.716 mmol, 4.5 eq) in toluene was stirred at room temperature under a nitrogen atmosphere for 15 hours. The resulting mixture was extracted with toluene (3 × 50 mL). The mixed organic layer was dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl ether (4:1) to obtain N-tert-butoxycarbonyl 4-(trifluoromethoxy)piperidine (1.6 g, 59.80%) as a yellow oil. LCMS(ESI)[M+H] + :270. 1 H NMR(300MHz,CDCl3)δ4.43(m,1H),3.71(m,2H),3.29(m,2H),1.91(m,2H),1.75(m,2H),1.48(s,9H). 19 F NMR(282MHz,CDCl3)δ-57.94(s,3F). Synthesis of 4-(trifluoromethoxy)piperidine [ka]

[0131] A solution of N-tert-butoxycarbonyl 4-(trifluoromethoxy)piperidine (100 mg, 0.371 mmol, 1 eq) in HCl in 1,4-dioxane was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. This yielded 4-(trifluoromethoxy)piperidine (70 mg, unpurified) as a yellow solid. LC-MS(ESI)[M+H] + :170. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(4-trifluoromethoxypiperidine-N-carbonyl)-piperidine [ka]

[0132] A solution of compound C (100 mg, 0.184 mmol, 1 eq), 4-(trifluoromethoxy)piperidine (70 mg, unpurified), N,N-diisopropylethylamine (118.6 mg, 0.920 mmol, 5 eq), and HATU (83.8 mg, 0.221 mmol, 1.2 eq) in DMF was stirred at room temperature for 2 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(4-trifluoromethoxypiperidine-N-carbonyl)-piperidine (110 mg, 86.11%) as a yellow oil. LCMS(ESI)[M+H] + :696. Synthesis of compound 13 [ka]

[0133] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(4-trifluoromethoxypiperidine-N-carbonyl)-piperidine (100 mg, 0.144 mmol, 1 eq) and HCl in 1,4-dioxane (4 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 9 with saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. Compound 13 (30 mg, 35.04%) was obtained as a white solid. LCMS(ESI)[M+H] + :596.3. 1 H NMR(300MHz,DMSO-d6)δ7.63(s,1H),6.48(s,1H),5.55(d,J=34.8Hz,1H),4.67(s,1H),4.18-3.58(m,5H),3.14(m,7H),2.99-2. 68(m,3H),2.57(m,1H),2.31(m,4H),2.15-1.85(m,8H),1.56(m,2H),0.95(m,6H),0.76(d,J=4.9Hz,2H),0.61(d,J=6.4Hz,2H). Example 6. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3R)-methylmorpholine-N-carbonyl]-piperidine (also known as Compound 14, 5-cyclopropyl-N-{5-[(3R)-3-methylmorpholine-4-carbonyl]piperidine-3-yl}-N-(2-methylpropyl)-3-{[(1r,3r)-3-methoxycyclobutyl]amino}pyridine-2-carboxamide) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3R)-methylmorpholine-N-carbonyl]-piperidine [ka]

[0134] HATU (100.5 mg, 0.264 mmol, 1.2 eq) was added to a stirred mixture of compound C (120 mg, 0.220 mmol, 1.0 eq), (3R)-3-methylmorpholine (26.7 mg, 0.264 mmol, 1.2 eq), and DIEA (85.4 mg, 0.660 mmol, 3.0 eq) in DMF (2 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for an additional 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3R)-methylmorpholine-N-carbonyl]-piperidine (110 mg, 79.53%) as a yellow oil. LCMS(ESI)[M+H] + :629. Synthesis of compound 14 [ka]

[0135] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3R)-methylmorpholine-N-carbonyl]-piperidine (100 mg, 0.159 mmol, 1 eq) in dioxane (1 mL), HCl-dioxane (1 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 8 with saturated Na2CO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 70% gradient over 20 minutes; detector, UV 254 nm. Compound 14 (26.0 mg, 30.93%) was obtained as a white solid. LCMS(ESI)[M+H] + :528.40. 1 H NMR(300MHz,DMSO-d6)δ7.62(s,1H),6.49(s,1H),5.54(d,J=34.1Hz,1H),4.33(s,1H),4.17-3.90(m,3H),3.90-3.75(m,1H),3.76-3. 55(m,2H),3.53-3.37(m,3H),3.15(s,3H),3.02-2.64(m,4H),2.56(s,1H),2.38-2.20(m,3H),2.17-1.65(m,6H),1.36-0.49(m,14H). Example 7. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine (also known as Compound 15, 5-cyclopropyl-N-{5-[(3S)-3-methylmorpholine-4-carbonyl]piperidine-3-yl}-N-(2-methylpropyl)-3-{[(1r,3r)-3-methoxycyclobutyl]amino}pyridine-2-carboxamide) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine [ka]

[0136] HATU (100.5 mg, 0.264 mmol, 1.2 eq) was added to a stirred mixture of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[(1R,3R)-3-methoxycyclobutyl]aminopyridine-2-carbonyl}}aminopiperidine-(5R)-carboxylic acid (120 mg, 0.220 mmol, 1 eq), (3S)-3-methylmorpholine (26.7 mg, 0.264 mmol, 1.2 eq), and DIEA (85.4 mg, 0.660 mmol, 3.0 eq) in DMF (2 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred for an additional 1 hour at room temperature. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine (100 mg, 72.30%) as a yellow oil. LCMS(ESI)[M+H] + :629. Synthesis of compound 15 [ka]

[0137] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine (100 mg, 0.159 mmol, 1.0 eq) in dioxane (1 mL), HCl-dioxane (1 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 8 with saturated Na2CO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. Compound 15 (48.5 mg, 57.70%) was obtained as a white solid. LCMS(ESI)[M+H] + :528.40. 1 H NMR(300MHz,DMSO-d6)δ7.62(s,1H),6.48(s,1H),5.55(d,J=32.6Hz,1H),4.15-3.88(m,3H),3.82(d,J=8.7Hz,1H),3.61(d,J=12.0 Hz,2H),3.15(s,6H),3.03-2.63(m,3H),2.61-2.54(m,2H),2.40-2.16(m,4H),2.03(s,3H),1.96-1.73(m,3H),1.35-0.51(m,14H). Example 8. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(2,2-dimethylmorpholine-N-carbonyl)-piperidine (also known as Compound 16, 5-cyclopropyl-N-[5-(2,2-dimethylmorpholine-4-carbonyl)piperidine-3-yl]-N-(2-methylpropyl)-3-{[(1r,3r)-3-methoxycyclobutyl]amino}pyridine-2-carboxamide) [ka] Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(2,2-dimethylmorpholine-N-carbonyl)-piperidine [ka]

[0138] HATU (100.5 mg, 0.264 mmol, 1.2 eq) was added to a stirred mixture of compound C (120 mg, 0.220 mmol, 1.0 eq), (3R)-3-methylmorpholine (26.7 mg, 0.264 mmol, 1.2 eq), and DIEA (85.4 mg, 0.660 mmol, 3.0 eq) in DMF (2 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for an additional 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(2,2-dimethylmorpholine-N-carbonyl)-piperidine (110 mg, 79.53%) as a yellow oil. LCMS(ESI)[M+H] + :643. Synthesis of (3S,5R)-3-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-5-(2,2-dimethylmorpholine-N-carbonyl)-piperidine (compound 16) [ka]

[0139] To a stirred mixture of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(2,2-dimethylmorpholine-N-carbonyl)-piperidine (100 mg, 0.156 mmol, 1.0 eq) in dioxane (1 mL), a solution of HCl in dioxane (1 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 8 with saturated Na2CO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes, UV 254 nm. This yielded compound 16 (54.8 mg, 64.93%) as a white solid. LC-MS(ESI)[M+H] + :542.4. 1 H NMR(300MHz,DMSO-d6)δ7.62(s,1H),6.48(s,1H),5.55(d,J=39.0Hz,1H),4.04-3.85(m,2H),3.73-3.37(m,4H),3.04-2.55(s,3H),3.04-2 .55(m,4H),2.38-2.19(m,4H),2.17-1.68(m,7H),1.21-1.04(m,6H),1.00(d,J=7.9Hz,2H),0.90(d,J=6.6Hz,4H)0.75(s,2H),0.61(d,2H). Example 9. (3S)-{N-(2-methylpropyl),N-{2-tert-butyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (also known as Compound 17, 2-tert-butyl-N-(2-methylpropyl)-N-[5-(morpholine-4-carbonyl)pyrimidine-3-yl]-4-{[(1r,3r)-3-methoxycyclobutyl]amino}pyrimidine-5-carboxamide) [ka] Synthesis of ethyl 2-tert-butyl-4-oxo-5H-pyrimidine-5-carboxylate [ka]

[0140] A solution of 2,2-dimethylpropanimidoamide (200 mg, 1.997 mmol, 1.0 eq), 1,3-diethyl 2-(ethoxymethylidene)propanediote (518.1 mg, 2.396 mmol, 1.2 eq), and EtONa (135.8 mg, 1.997 mmol, 1.0 eq) in EtOH (3 mL) was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was acidified to pH 6 with concentrated HCl. The residue was washed with ethyl acetate (3 × 10 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with petroleum ether / SiO2 (1:1) to obtain ethyl 2-tert-butyl-4-oxo-5H-pyrimidine-5-carboxylate (185 mg, 41.31%) as a yellow solid. LCMS(ESI)[M+H] + :225. Synthesis of ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate [ka]

[0141] A mixture of ethyl 2-tert-butyl-4-oxo-5H-pyrimidine-5-carboxylate (100 mg, 0.446 mmol, 1.0 eq) and phosphorus oxychloride (341.8 mg, 2.230 mmol, 5.0 eq) in triethylamine (2 mL) was stirred at 100°C for 30 minutes under a nitrogen atmosphere. The residue was washed with water (3 × 3 mL). The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate (70 mg, 64.68%) as a colorless oil. LCMS(ESI)[M+H] + :244. Synthesis of ethyl 2-tert-butyl-4-[3-(trans-methoxy)cyclobutyl]aminopyrimidine-5-carboxylate [ka]

[0142] DIEA (639.1 mg, 4.944 mmol, 3.0 eq) was added to a stirred mixture of ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate (400 mg, 1.648 mmol, 1.0 eq) and 3-trans-methoxycyclobutan-1-amine (183.4 mg, 1.813 mmol, 1.1 eq) in NMP (4 mL). The mixture was stirred at 140 °C for 2 hours under a nitrogen atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded ethyl 2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]aminopyrimidine-5-carboxylate (280 mg, 55.27%) as a red oil. LCMS(ESI)[M+H] + :308. Synthesis of 2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]aminopyrimidine-5-carboxylic acid [ka]

[0143] To a stirred mixture of ethyl 2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]aminopyrimidine-5-carboxylate (270 mg, 0.878 mmol, 1.0 eq) and LiOH (184.3 mg, 4.390 mmol, 5.0 eq) in THF (2 mL), H2O (2.0 mL) was added at 25°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes, UV 254 nm. This yielded 2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]aminopyrimidine-5-carboxylic acid (220 mg, 89.66%) as a yellow solid. LCMS(ESI)[M+H] + :280 Synthesis of methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-piperidine-(5R)-carboxylate [ka]

[0144] HATU (290.2 mg, 0.763 mmol, 1.2 eq) was added to a stirred solution of compound A (200 mg, 0.636 mmol, 1.0 eq), 2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]aminopyrimidine-5-carboxylic acid (213.2 mg, 0.763 mmol, 1.2 eq), and DIEA (246.6 mg, 1.908 mmol, 3.0 eq) in DMF (3 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}aminopiperidine-(5R)-carboxylate (240 mg, 65.53%) as a yellow oil. LCMS(ESI)[M+H] + :577. Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-piperidine-(5R)-carboxylic acid [ka]

[0145] To a stirred solution of methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}aminopiperidine-(5R)-carboxylate (160 mg, 0.278 mmol, 1.0 eq) and lithium hydrate (58.3 mg, 1.390 mmol, 5.0 eq) in THF (2 mL), H2O (2 mL) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 1 hour. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}aminopiperidine-(5R)-carboxylic acid (150 mg, 96.09%) as a yellow oil. LCMS(ESI)[M+H] + :563. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine [ka]

[0146] HATU (105.6 mg, 0.277 mmol, 1.2 eq) was added to a stirred mixture of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}aminopiperidine-(5R)-carboxylic acid (130 mg, 0.231 mmol, 1.0 eq), morpholine (24.2 mg, 0.277 mmol, 1.2 eq), and DIEA (89.7 mg, 0.693 mmol, 3.0 eq) in DMF (3 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at room temperature for an additional 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (140 mg, 95.89%) as a yellow oil. LCMS(ESI)[M+H] + :632. Synthesis of Compound 17 [ka]

[0147] To a stirred mixture of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (80 mg, 0.127 mmol, 1.0 eq) in DCM (1 mL), TFA (1 mL) was added at 25°C. The resulting mixture was stirred for an additional 1 hour at 25°C. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 8 with saturated Na2CO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. Compound 17 (36.3 mg, 53.93%) was obtained as a white solid. LCMS(ESI)[M+H] + :531.70. 1 H NMR(300MHz,DMSO-d6)δ8.02(s,1H),6.95(s,1H),4.65-4.43(m,1H),3.93(d,J=5.3,4.8Hz,1H),3.70(s,1H),3.48(d,J=29.8Hz,8H ),3.15(s,5H),2.93(d,J=7.5Hz,1H),2.84-2.55(m,3H),2.39-2.15(m,6H),2.03-1.75(m,3H),1.29(s,9H),0.82(d,J=6.5Hz,6H). Example 10. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (also known as Compound 18, 5-cyclopropyl-N-(2-methylpropyl)-N-[5-(morpholine-4-carbonyl)piperidine-3-yl]-3-{[(1r,3r)-3-methoxycyclobutyl]amino}pyridine-2-carboxamide) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine [ka]

[0148] A solution of compound C (100 mg, 0.184 mmol, 1.0 eq), morpholine (19.2 mg, 0.221 mmol, 1.2 eq), N,N-diisopropylethylamine (71.2 mg, 0.552 mmol, 3.0 eq), and HATU (83.8 mg, 0.221 mmol, 1.2 eq) in DMF was stirred at room temperature for 2 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (98 mg, 86.97%) as a yellow oil. LCMS(ESI)[M+H]+:614. Synthesis of compound 18 [ka]

[0149] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (100 mg, 0.163 mmol, 1.0 eq) in DCM and TFA was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 9 with saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. Compound 18 (37.2 mg, 44.45%) was obtained as a white solid. LCMS(ESI)[M+H] + :514.3. 1 H NMR(400MHz,DMSO-d6)δ7.62(d,J=6.1Hz,1H),6.46(d,J=7.4Hz,1H),5.60(d,J=5.9Hz,1H),3.95(m,2H),3.53(m,6H),3.32(s,3H) ),3.21(m,2H),3.14(s,3H),3.02-2.66(m,4H),2.54(m,1H),2.41-1.68(m,9H),0.94(m,6H),0.75(m,2H),0.60(d,J=6.4Hz,2H). Example 11. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (also known as Compound 19, 5-cyclopropyl-N-(2-methylpropyl)-N-[5-(morpholine-4-carbonyl)piperidine-3-yl]-3-{[(1s,3s)-3-methoxycyclobutyl]amino}pyridine-2-carboxamide) [ka] Synthesis of methyl 5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]aminopyridine-2-carboxylate [ka]

[0150] DIEA (198.6 mg, 1.536 mmol, 3 eq) was added at room temperature to a stirred solution of methyl 5-cyclopropyl-3-fluoropyridine-2-carboxylate (100 mg, 0.512 mmol, 1 eq) and 3-cis-methoxycyclobutan-1-amine (62.1 mg, 0.614 mmol, 1.2 eq) in NMP. The resulting mixture was stirred at 140°C for 1 hour under a nitrogen atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded methyl 5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]aminopyridine-2-carboxylate (110 mg, 77.70%) as a yellow oil. LCMS(ESI)[M+H] + :277. Synthesis of 5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]aminopyridine-2-carboxylic acid [ka]

[0151] To a stirred solution of methyl 5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]aminopyridine-2-carboxylate (100 mg, 0.362 mmol, 1 eq) in THF / H2O, LiOH (43.3 mg, 1.810 mmol, 5 eq) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The residue was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded 5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]aminopyridine-2-carboxylic acid (89 mg, 93.76%) as a yellow oil. LCMS(ESI)[M+H] + :263. Synthesis of methyl 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylate [ka]

[0152] HATU (173.9 mg, 0.457 mmol, 1.2 eq) was added at room temperature to a stirred solution of 5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carboxylic acid (100 mg, 0.381 mmol, 1 eq), compound A (143.8 mg, 0.457 mmol, 1.2 eq), and DIEA (147.8 mg, 1.143 mmol, 3 eq) in DMF. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded methyl 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate (110 mg, 51.64%) as a yellow oil. LCMS(ESI)[M+H] + :559. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylic acid [ka]

[0153] To a stirred solution of methyl 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate (100 mg, 0.179 mmol, 1 eq) in THF / H2O, LiOH (21.4 mg, 0.895 mmol, 5 eq) was added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The residue was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid (89 mg, 91.29%) as a yellow oil. LCMS(ESI)[M+H] + :545. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine [ka]

[0154] HATU (209.42 mg, 0.552 mmol, 3 eq) was added at room temperature to a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid (100 mg, 0.184 mmol, 1 eq), morpholine (19.1 mg, 0.221 mmol, 1.2 eq), and DIEA (28.4 mg, 0.221 mmol, 1.2 eq) in DMF. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (102 mg, 90.52%) as a yellow oil. LCMS(ESI)[M+H] + :614. Synthesis of compound 19 [ka]

[0155] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (60 mg, 0.098 mmol, 1 eq) in dioxane (1 mL) was stirred, and then a solution of HCl in dioxane (1 mL) was added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The residue was neutralized to pH 8 with saturated Na2CO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. Compound 19 (39.0 mg, 77.67%) was obtained as a white solid. LCMS(ESI)[M+H] + :514. 1 H NMR(300MHz,DMSO-d6)δ7.63(s,1H),6.57(s,1H),5.46(d,J=24.3,7.0Hz,1H),3.60 (m,12H),3.21(m,2H),3.13(s,3H),3.00-2.80(m,2H),2.73(d,J=6.7,3.2Hz,3H),2 .60-2.53(m,1H),2.45-2.21(m,1H),2.07(m,1H),1.87(m,3H),1.59(m,2H),1.00(d ,J=6.4,4.1Hz,2H),0.89(d,J=6.7Hz,4H),0.81-0.71(m,2H),0.61(d,J=6.4Hz,2H). Example 12. (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclobutylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine (also known as Compound 19, 3-(cyclobutylamino)-5-cyclopropyl-N-(2-methylpropyl)-N-[5-(morpholine-4-carbonyl)piperidine-3-yl]pyridine-2-carboxamide) [ka] Synthesis of methyl 3-(cyclobutylamino)-5-cyclopropylpyridine-2-carboxylate [ka]

[0156] DIEA (595.9 mg, 4.6 mmol, 3 eq) was added at room temperature to a stirred mixture of methyl 5-cyclopropyl-3-fluoropyridine-2-carboxylate (300 mg, 1.5 mmol, 1 eq) and cyclobutylamine (327.9 mg, 4.6 mmol, 3 eq) in NMP (5 mL). The mixture was stirred at 140 °C for 2 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient over 20 minutes; detector, UV 254 nm. This yielded methyl 3-(cyclobutylamino)-5-cyclopropylpyridine-2-carboxylate (110 mg, 29.06%) as a yellow oil. LCMS(ESI)[M+H] + :247. Synthesis of 3-(cyclobutylamino)-5-cyclopropylpyridine-2-carboxylic acid [ka]

[0157] To a stirred mixture of methyl 3-(cyclobutylamino)-5-cyclopropylpyridine-2-carboxylate (110 mg, 0.44 mmol, 1 eq) and LiOH (53.4 mg, 2.235 mmol, 5 eq) in THF (1 mL), H2O (1 mL) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient over 20 minutes; detector, UV 254 nm. This yielded 3-(cyclobutylamino)-5-cyclopropylpyridine-2-carboxylic acid (100 mg, 96.40%) as a yellow oil. LCMS(ESI)[M+H] + :233. Synthesis of methyl 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclobutylamino)-pyridine-2-carbonyl]amino-piperidine-(5R)-carboxylate [ka]

[0158] DIEA (183.6 mg, 1.42 mmol, 3 eq) was added at room temperature to a stirred solution of 3-(cyclobutylamino)-5-cyclopropylpyridine-2-carboxylic acid (110 mg, 0.47 mmol, 1 eq), compound A (178.68 mg, 0.569 mmol, 1.2 eq), and HATU (216.1 mg, 0.57 mmol, 1.2 eq) in DMF (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient over 20 minutes; detector, UV 254 nm. This yielded methyl 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclobutylamino)-pyridine-2-carbonyl]amino-piperidine-(5R)-carboxylate (120 mg, 47.93%) as a yellow oil. LCMS(ESI)[M+H] + :529. Synthesis of 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-[(5-cyclopropyl-3-cyclobutylamino)-pyridine-2-carbonyl]amino-piperidine-(5R)-carboxylic acid [ka]

[0159] H2O (1 mL) was added at room temperature to a stirred mixture of methyl 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclobutylamino)-pyridine-2-carbonyl]aminopiperidine-(5R)-carboxylate (110 mg, 0.21 mmol, 1 eq) and LiOH (24.9 mg, 1.04 mmol, 5 eq) in THF (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient over 20 minutes; detector, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-[(5-cyclopropyl-3-cyclobutylamino)-pyridine-2-carbonyl]amino-piperidine-(5R)-carboxylic acid (98 mg, 91.52%) as a yellow oil. LCMS(ESI)[M+H] + :515. Synthesis of 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclobutylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine [ka]

[0160] DIEA (71.5 mg, 0.55 mmol, 3 eq) was added at room temperature to a stirred solution of 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-[(5-cyclopropyl-3-cyclobutylamino)-pyridine-2-carbonyl]aminopiperidine-(5R)-carboxylic acid (95 mg, 0.18 mmol, 1 eq), morpholine (19.3 mg, 0.22 mmol, 1.2 eq), and HATU (84.2 mg, 0.222 mmol, 1.2 eq) in DMF (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient over 20 minutes; detector, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclobutylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine (100 mg, 92.80%) as a yellow oil. LCMS(ESI)[M+H] + :584. Synthesis of compound 20 [ka]

[0161] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclobutylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine (100 mg, 0.17 mmol, 1 eq) in dioxane (1 mL), a solution of HCl in 1,4-dioxane (1 mL, 32.91 mmol, 192.13 eq) was added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 8 with saturated Na2CO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient over 20 minutes; detector, UV 254 nm. This yielded compound 20 (63.7 mg, 76.89%) as a white solid. LC-MS(ESI)[M+H] + :484.40. 1 H NMR(300MHz,DMSO-d6)δ7.61(s,1H),6.55(s,1H),5.65-5.39(m,1H),4.16 -3.63(m,2H),3.54(s,8H),3.20(d,J=8.0Hz,2H),2.77(d,J=46.4Hz,3H),2 .54(s,1H),2.33(d,J=6.1Hz,3H),2.08(s,2H),1.96-1.47(m,7H),0.99(d, J=8.1Hz,2H),0.89(d,J=6.7Hz,4H),0.81-0.70(m,2H),0.69-0.51(m,2H). Example 13: (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine (also known as Compound 21, 5-cyclopropyl-3-(cyclopropylamino)-N-[(5R)-5-[(3S)-3-methylmorpholine-4-carbonyl]piperidine-3-yl]-N-(2-methylpropyl)pyridine-2-carboxamide) [ka] Synthesis of methyl 5-cyclopropyl-3-(cyclopropylamino)pyridine-2-carboxylate [ka]

[0162] DIEA (595.9 mg, 4.61 mmol, 3 equiv) was added at room temperature to a stirred mixture of methyl 5-cyclopropyl-3-fluoropyridine-2-carboxylate (300 mg, 1.54 mmol, 1 equiv) and aminocyclopropane (263.2 mg, 4.61 mmol, 3 equiv) in NMP (5 mL). The mixture was stirred at 140 °C for 2 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient over 20 minutes; detector, UV 254 nm. This yielded methyl 5-cyclopropyl-3-(cyclopropylamino)pyridine-2-carboxylate (120 mg, 33.61%) as a yellow oil. LCMS(ESI)[M+H] + :233. Synthesis of 5-cyclopropyl-3-(cyclopropylamino)pyridine-2-carboxylic acid [ka]

[0163] A mixture of methyl 5-cyclopropyl-3-(cyclopropylamino)pyridine-2-carboxylate (120 mg, 0.52 mmol, 1 eq) and LiOH (61.8 mg, 2.58 mmol, 5 eq) in THF (1 mL) was stirred, and H2O (1 mL) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient over 20 minutes; detector, UV 254 nm. This yielded 5-cyclopropyl-3-(cyclopropylamino)pyridine-2-carboxylic acid (102 mg, 90.46%) as a yellow oil. LCMS(ESI)[M+H] + :219. Synthesis of methyl 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-piperidine-(5R)-carboxylate [ka]

[0164] DIEA (186.5 mg, 1.44 mmol, 3 eq) was added at room temperature to a stirred solution of 5-cyclopropyl-3-(cyclopropylamino)pyridine-2-carboxylic acid (105 mg, 0.48 mmol, 1 eq), compound A (181.5 mg, 0.57 mmol, 1.2 eq), and HATU (219.5 mg, 0.57 mmol, 1.2 eq) in DMF (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 70% gradient over 20 minutes; detector, UV 254 nm. This yielded methyl 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-piperidine-(5R)-carboxylate (120 mg, 48.47%) as a yellow oil. LCMS(ESI)[M+H] + :515. Synthesis of 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-piperidine-(5R)-carboxylic acid [ka]

[0165] H2O (1 mL) was added at room temperature to a stirred mixture of methyl 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]aminopiperidine-(5R)-carboxylate (110 mg, 0.21 mmol, 1 eq) and LiOH (25.5 mg, 1.07 mmol, 5 eq) in THF (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient over 20 minutes; detector, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-piperidine-(5R)-carboxylic acid (90 mg, 84.11%) as a yellow oil. LCMS(ESI)[M+H] + :501. Synthesis of 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine [ka]

[0166] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]aminopiperidine-(5R)-carboxylic acid (385 mg, 0.77 mmol, 1 eq) and HATU (350.8 mg, 0.924 mmol, 1.2 eq) in DMF (7 mL), (3S)-3-methylmorpholine (93.3 mg, 0.924 mmol, 1.2 eq) was added and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was complete, the resulting mixture was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine (433 mg, 96.48%) as a white solid. LCMS(ESI)[M+H] + :584. Synthesis of Compound 21 [ka]

[0167] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine (430 mg, 0.737 mmol, 1 eq) in DCM (5 mL), TFA (1 mL) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was basicized to pH 8 using saturated NaHCO3 (aqueous solution). The aqueous layer was extracted with CH2Cl2 (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (375 mg) was purified by prep-HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH--HPLC; flow rate: 25 mL / min; gradient: 45%B~67%B, 67%B, 7 mins; wavelength: 220 nm; RT1 (min): 6.06; runs: 0) to obtain compound 21 (308.1 mg, 86.48%) as a white solid. LCMS(ESI)[M+H] + :484.2. 1 H NMR(400MHz,DMSO-d6)δ7.64(s,1H),7.02-6.92(m,1H),5.73(d,J=55.2Hz,1H),4.17(d,J=127.1Hz,2H),3.82(d,J=8.8Hz,1H),3.7 5-3.56(m,2H),3.54-3.37(m,2H),3.27-3.09(m,3H),2.99-2.65(m,3H),2.46-1.98(m,4H),1.98-1.72(m,3H),1.33-0.28(m,17H). Example 14. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine (also known as Compound 22, 5-cyclopropyl-N-[(5R)-5-(5-methyl-1,3,4-oxadiazole-2-yl)piperidine-3-yl]-N-(2-methylpropyl)-3-{[(1r,3r)-3-methoxycyclobutyl]amino}pyridine-2-carboxamide) [ka] Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N'-acetylhydrazinecarbonyl)-piperidine [ka]

[0168] A solution of compound C (100 mg, 0.184 mmol, 1.0 eq), uranioborane (70.2 mg, 0.276 mmol, 1.5 eq), and N,N-diisopropylethylamine (118.6 mg, 0.920 mmol, 5.0 eq) in DMF was stirred at room temperature for 10 minutes. Acetohydrazide (27.2 mg, 0.368 mmol, 2.0 eq) was added to the above mixture. The resulting mixture was stirred at room temperature for an additional 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N'-acetylhydrazinecarbonyl)-piperidine (107 mg, 97.01%) as a yellow oil. LCMS(ESI)[M+H]+ :601. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine [ka]

[0169] A solution of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N'-acetylhydrazinecarbonyl)-piperidine (100 mg, 0.166 mmol, 1.0 eq) and Burgess reagent (158.7 mg, 0.664 mmol, 4.0 eq) in DCE was stirred at 120°C for 30 minutes under a nitrogen atmosphere. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (10:1) to obtain 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine (44 mg, 45.36%) as a yellow oil. LCMS(ESI)[M+H] + :583. Synthesis of compound 22 [ka]

[0170] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine (40 mg, 0.069 mmol, 1.0 eq) in HCl in 1,4-dioxane was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 9 with saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. Compound 22 (20 mg, 60.37%) was obtained as a white solid. LCMS(ESI)[M+H] + :483.25. 1 H NMR(400MHz,DMSO-d6)δ7.64(d,J=18.8Hz,1H),6.47(d,J=10.9Hz,1H),5.68(d,J=5. 8Hz,1H),4.19-3.88(m,2H),3.77(s,1H),3.28-3.19(m,3H),3.14(s,3H),3.04-2.75 (m,4H),2.71-2.59(m,2H),2.45(d,J=5.3Hz,3H),2.37-2.18(m,4H),2.03(d,J=8.4H z,3H),1.91(m,1H),1.03-0.85(m,6H),0.76(d,J=5.9Hz,2H),0.62(d,J=6.5Hz,2H). Example 15. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine (also known as Compound 23, 5-cyclopropyl-N-[(5R)-5-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)piperidine-3-yl]-N-(2-methylpropyl)-3-{[(1r,3r)-3-methoxycyclobutyl]amino}pyridine-2-carboxamide) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N'-cyclopropanecarbonylhydrazinecarbonyl)-piperidine [ka]

[0171] A solution of compound C (150 mg, 0.275 mmol, 1 eq), TBTU (132.6 mg, 0.413 mmol, 1.5 eq), N,N-diisopropylethylamine (71.2 mg, 0.550 mmol, 2 eq), and cyclopropanecarborazide (55.1 mg, 0.550 mmol, 2 eq) in DMF was stirred at room temperature for 2 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N'-cyclopropanecarbonylhydrazinecarbonyl)-piperidine (160 mg, 92.69%) as a yellow oil. LCMS(ESI)[M+H] + :627. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine [ka]

[0172] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N'-cyclopropanecarbonylhydrazinecarbonyl)-piperidine (160 mg, 0.255 mmol, 1 eq) and Burgess reagent (243.3 mg, 1.020 mmol, 4 eq) in DCE was stirred at 120°C for 20 minutes. The residue was purified by prep-TLC(CH2Cl2 / MeOH 20:1) to obtain 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine (56 mg, 36.04%) as a yellow oil. LCMS(ESI)[M+H] + :609. Synthesis of compound 23 [ka]

[0173] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine (50 mg, 0.082 mmol, 1 eq) and HCl (gas) in 1,4-dioxane (2 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 9 with saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes, UV 254 nm. Compound 23 (25 mg, 59.84%) was obtained as a white solid. LCMS(ESI)[M+H] + :509.3. 1H NMR(300MHz,DMSO-d6)δ7.64(d,J=12.2Hz,1H),6.48(s,1H),5.79-5.35(m,1H),4.20-3.66(m,3H),3.23(m,2H),3.14( m,4H),3.06-2.71(m,3H),2.62(m,1H),2.42(m,1H),2.36-1.50(m,9H),1.16-0.81(m,10H),0.76(m,2H),0.62(m,2H). Example 16. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3,3-difluorocyclobutyl-1,3,4-oxadiazole-2-yl)-piperidine (also known as Compound 24, 5-cyclopropyl-N-[(5R)-5-[5-(3,3-difluorocyclobutyl)-1,3,4-oxadiazole-2-yl]piperidine-3-yl]-N-(2-methylpropyl)-3-{[(1r,3r)-3-methoxycyclobutyl]amino}pyridine-2-carboxamide) [ka] Synthesis of 3,3-difluorocyclobutane-1-carbohydrazide [ka]

[0174] To a stirred solution of methyl 3,3-difluorocyclobutane-1-carboxylate (500 mg, 3.331 mmol, 1 eq) in MeOH, N2H4.H2O (1667.2 mg, 33.310 mmol, 10 eq) was added at room temperature. The resulting mixture was stirred at 80°C for 15 hours. The resulting mixture was concentrated under reduced pressure. This yielded 3,3-difluorocyclobutane-1-carbohydrazide (450 mg, 90.0%) as a white solid. LCMS(ESI)[M+H] + :151. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[N'-(3,3-difluorocyclobutyl)carbonylhydrazinecarbonyl]-piperidine [ka]

[0175] A solution of compound C (150 mg, 0.275 mmol, 1 eq), 3,3-difluorocyclobutane-1-carbohydrazide (82.6 mg, 0.550 mmol, 2 eqs), and DIEA (177.9 mg, 1.375 mmol, 5 eqs) in DMF was stirred for 10 minutes, and TBTU (132.6 mg, 0.413 mmol, 1.5 eq) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[N'-(3,3-difluorocyclobutyl)carbonylhydrazinecarbonyl]-piperidine (170 mg, 91.21%) as a yellow oil. LCMS(ESI)[M+H] + :677. 1 H NMR(300MHz,DMSO-d6)δ10.01(s,2H),7.63(s,1H),6.50(s,1H),5.74(d,J=96.0Hz,1H),3.89(m,6H),3.16(m,5H),2.92(m, 1H),2.84-2.59(m,5H),2.30(m,3H),2.13-1.77(m,6H),1.34(d,J=53.2Hz,9H),1.06-0.82(m,6H),0.69(d,J=31.5Hz,4H). 19F NMR(282MHz,DMSO-d6)δ-80.56(d,J=189.7Hz,1F), -95.02(d,J=189.4Hz,1F). Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3,3-difluorocyclobutyl-1,3,4-oxadiazole-2-yl)-piperidine [ka]

[0176] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[N'-(3,3-difluorocyclobutyl)carbonylhydrazinecarbonyl]-piperidine (150 mg, 0.222 mmol, 1 eq) in DCE (2 mL), Burgess's reagent (211.2 mg, 0.888 mmol, 4 eq) was added at room temperature. The resulting mixture was stirred at 120 °C for 20 minutes. The residue was purified by prep-TLC (CH2Cl2 / MeOH 20:1) to obtain 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3,3-difluorocyclobutyl-1,3,4-oxadiazole-2-yl)-piperidine (crude product) as a yellow oil. LCMS(ESI)[M+H]+:659. Synthesis of Compound 24 [ka]

[0177] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3,3-difluorocyclobutyl-1,3,4-oxadiazole-2-yl)-piperidine (45 mg, 0.068 mmol, 1 equiv) in DCM (1 mL) was added to TFA (0.2 mL) and stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 9 with saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 00% to 60% gradient over 20 minutes, UV 254 nm. Compound 24 (16.7 mg, 43.76%) was obtained as a white solid. LCMS(ESI)[M+H] + :559.3. 1 H NMR(300MHz,DMSO-d6)δ7.65(d,J=12.7Hz,1H),6.49(s,1H),5.84-5.39(m,1H),4.16-3.59(m,4H),2.84-3.24(m ,12H),2.63(m,1H),2.39-2.18(m,4H),2.15-1.80(m,5H),1.07-0.85(m,6H),0.76(s,2H),0.63(d,J=6.2Hz,2H). Example 17. (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine (compound 25) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine [ka]

[0178] DIEA (76 mg, 0.6 mmol, 3 eq) was added at room temperature to a stirred solution of 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]aminopiperidine-(5R)-carboxylic acid (98 mg, 0.2 mmol, 1 eq), morpholine (20 mg, 0.23 mmol, 1.2 eq), and HATU (89 mg, 0.23 mmol, 1.2 eq) in DMF (2 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 70% gradient over 20 minutes; detector, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine (105 mg, 94%) as a yellow oil. LCMS(ESI)[M+H] + :570. Synthesis of Compound 25 [ka]

[0179] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine (100 mg, 0.2 mmol, 1 eq) in dioxane (1 mL), a solution of HCl in 1,4-dioxane (1 mL, 32 mmol) was added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The mixture was basicized to pH 8 using saturated Na2CO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient over 20 minutes; detector, UV 254 nm. Compound 25 (77.5 mg, 94%) was obtained as a white solid. LCMS(ESI)[M+H] + :470.35. 1 H NMR(300MHz,DMSO-d6)δ7.65(s,1H),6.97(s,1H),5.73(d,J=41.0Hz,1H),3.54(s,5H),3.41(s,3H),3.17(d,J=7.2Hz,2H),3.03-2.63(m,3H),2.39 (s,2H),2.33-2.19(m,1H),2.15-1.67(m,4H),1.02(d,J=8.0Hz,2H),0.8 7(d,J=6.7Hz,4H),0.80-0.68(m,4H),0.57(s,2H),0.34(d,J=8.5Hz,2H). Example 18. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine (Compound 26) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-(2-methylpropylamino)piperidine [ka]

[0180] Diacetyl peroxide and sodium boranyl acetate (317 mg, 1.5 mmol, 3 eq) were added at room temperature to a stirred solution of 1-tert-butoxycarbonyl-(3S)-aminopiperidine (100 mg, 0.5 mmol, 1 eq) and isobutyraldehyde (43 mg, 0.6 mmol, 1.2 eq) in MeOH. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-(2-methylpropylamino)piperidine (120 mg, 94%) as a white solid. LCMS(ESI)[M+H] + :257. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine [ka]

[0181] HATU (142 mg, 0.4 mmol, 1.2 eq) was added at room temperature to a stirred solution of 1-tert-butoxycarbonyl-(3S)-(2-methylpropylamino)piperidine (80 mg, 0.31 mmol, 1 eq), compound B (98 mg, 0.4 mmol, 1.2 eq), and DIEA (121 mg, 0.9 mmol, 3 eq) in DMF. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine (110 mg, 70%) as a yellow oil. LCMS(ESI)[M+H] + :501. Synthesis of Compound 26 [ka]

[0182] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine (100 mg, 0.2 mmol, 1 eq) in dioxane (1 mL) was stirred, and a solution of HCl in dioxane was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was basicized to pH 8 using saturated Na2CO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 10 minutes; UV 254 nm. This yielded compound 26 (44 mg, 55%) as an off-white oil. LCMS(ESI)[M+H] + :401.25. 1H NMR(400MHz,DMSO-d6)δ7.62(d,J=13.8Hz,1H),6.46(s,1H),5.52(s,1H),4.11-3.85(m,2H),3.58(s,1H),3.25-3.07(m,6H),3.04-2.61(m,3H), 2.40-2.15(m,3H),2.12-1.76(m,5H),1.71-1.46(m,2H),1.24-1.08(m, 1H),1.03-0.95(m,2H),0.89(d,J=6.7Hz,4H),0.75(s,2H),0.60(s,2H). Example 19. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3S)-ethylmorpholine-N-carbonyl]-piperidine (Compound 27) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3S)-ethylmorpholine-N-carbonyl]-piperidine [ka]

[0183] (3S)-ethylmorpholine (23 mg, 0.2 mmol, 1.2 eq) was added to a stirred solution of compounds C (90 mg, 0.2 mmol, 1.0 eq), HATU (75.3 mg, 0.19 mmol, 1.2 eq), and DIEA (64.0 mg, 0.49 mmol, 3.0 eq) in DMF. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was complete, the residue was purified by reverse-phase flash chromatography using UV254nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes to obtain 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3S)-ethylmorpholine-N-carbonyl]-piperidine (95 mg, 90%) as a yellow solid. LCMS(ESI)[M+H] + :642. 1 H NMR(400MHz,chloroform-d)δ7.62(s,1H),6.63-6.35(m,1H),5.95(d,J=178.4Hz,1H),4.51-4.12(m,3H),4.09-3.78(m,5H),3.78-3.31(m,5H),3.27( s,3H),3.17-2.55(m,4H),2.46-2.33(m,3H),2.28-2.09(m,4H),1.94-1. 68(m,4H),1.41(d,J=41.9Hz,9H),1.17-0.83(m,8H),0.82-0.61(m,4H). Synthesis of Compound 27 [ka]

[0184] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3S)-ethylmorpholine-N-carbonyl]-piperidine (95 mg, 0.15 mmol, 1.0 eq) in DCM (2 mL), TFA (0.5 mL) was added under a nitrogen atmosphere at room temperature for 20 minutes and the mixture was stirred. After the reaction was complete, the mixture was basicized to pH 9 with saturated Na2CO3 (aqueous solution). The aqueous layer was extracted with ELISA (3 × 10 mL). The mixed organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC under the following conditions to obtain compound 27 (37 mg, 46%) as a white solid. LCMS(ESI)[M+H] + :542.35. 1 H NMR(400MHz,DMSO-d6)δ7.61(d,J=10.0Hz,1H),6.47(s,1H),5.63-5.44(m,1H),4.30-4.01(m, 1H),4.00-3.89(m,2H),3.86-3.50(m,4H),3.48-3.35(m,1H),3.30-3.18(m,3H),3.16(s,3H),3 .00-2.65(m,3H),2.63-2.53(m,1H),2.42-2.16(m,4H),2.13-1.95(m,3H),1.96-1.69(m,3H), 1.68-1.47(m,2H),1.07-0.95(m,2H),0.94-0.83(m,4H),0.83-0.68(m,5H),0.67-0.52(m,2H). Example 20. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,2,4-oxadiazole-3-yl)-piperidine (Compound 28) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine-(5R)-carboxamide [ka]

[0185] HATU (167 mg, 0.44 mmol, 1.2 eq) was added at room temperature to a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-5-carboxylic acid (200 mg, 0.37 mmol, 1 eq), NH4Cl (98 mg, 1.8 mmol, 5 eq), and DIEA (142 mg, 1.1 mmol, 3 eq) in DMF. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxamide (196 mg, 98%) as a yellow oil. LCMS(ESI)[M+H] + :544. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-cyanopiperidine [ka]

[0186] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxamide (280 mg, 0.5 mmol, 1 eq) in pyridine (3 mL), phosphorus oxychloride (79 mg, 0.5 mmol, 1 eq) was added at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 10 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-cyano-piperidine (208 mg, 76.83%) as a yellow oil. LCMS(ESI)[M+H] + :526. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N-hydroxycarbamimidoyl)-piperidine [ka]

[0187] DIEA (98 mg, 0.76 mmol, 2 eq) was added to a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-cyano-piperidine (200 mg, 0.38 mmol, 1 eq) and hydroxylamine hydrochloride (12 mg, 0.76 mmol, 2 eq) in EtOH under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N-hydroxycarbamimidoyl)-piperidine (110 mg, 52%) as a yellow solid. LCMS(ESI)[M+H] + :559. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,2,4-oxadiazole-3-yl)-piperidine [ka]

[0188] Et3N (95 mg, 0.94 mmol, 5 eq) was added at room temperature to a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N-hydroxycarbamimidoyl)-piperidine (105 mg, 0.19 mmol, 1 eq) and acetic anhydride (58 mg, 0.56 mmol, 3 eq) in ACN. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,2,4-oxadiazole-3-yl)-piperidine (61 mg, 56%) as a yellow solid. LCMS(ESI)[M+H] + :583. Synthesis of compound 28 [ka]

[0189] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,2,4-oxadiazole-3-yl)-piperidine (55 mg, 0.09 mmol, 1 eq) in 1,4-dioxane was stirred, and a solution of HCl in dioxane was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was basicized to pH 8 using saturated Na2CO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes; UV 254 nm. Compound 28 (26.5 mg, 58%) was obtained as a white oil. LCMS(ESI)[M+H] + :483.30. 1 H NMR(300MHz,DMSO-d6)δ7.64(d,J=13.2Hz,1H),6.47(s,1H),5.57(d,J=35.6Hz,1H),4.19-3.68(m,3H),3.29-3.18(m,2H),3.14(s,3H),3.06-2. 81(m,2H),2.78-2.53(m,5H),2.48-1.78(m,9H),1.74-1.11(m,1H),1.0 9-0.95(m,2H),0.95-0.83(m,4H),0.81-0.71(m,2H),0.70-0.56(m,2H). Example 21. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3-methyl-1,2,4-oxadiazole-5-yl)-piperidine (Compound 29) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3-methyl-1,2,4-oxadiazole-5-yl)piperidine [ka]

[0190] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-5-carboxylic acid (150 mg, 0.28 mmol, 1.0 eq) and carbonyldiimidazole (67 mg, 0.4 mmol, 1.5 eq) in DMF was stirred at room temperature for 10 hours. To the above mixture, acetamidooxime (31 mg, 0.41 mmol, 1.5 eq) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 15 hours, then at 100°C for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3-methyl-1,2,4-oxadiazole-5-yl)-piperidine (80 mg, 50%) as a yellow oil. LCMS(ESI)[M+H] + :583. Synthesis of compound 29 [ka]

[0191] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3-methyl-1,2,4-oxadiazole-5-yl)-piperidine (80 mg, 0.14 mmol, 1.0 eq) in 1,4-dioxane was stirred, and then a solution of HCl in 1,4-dioxane (2 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The mixture was acidified to pH 9 using saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. Compound 29 (15.5 mg, 23%) was obtained as a white solid. LCMS(ESI)[M+H] + :483.30. 1 H NMR(300MHz,DMSO-d6)δ7.64(d,J=13.1Hz,1H),6.48(s,1H),5.68(m,1H),4.14-3.67(m,3H),3.23(m,3H),3.14(s,3H),2.97(m,3 H),2.65(m,1H),2.28(m,7H),2.16-1.95(m,3H),1.91-1.82(m,2H),0.99(m,2H),0.89(d,J=6.6Hz,4H),0.76(s,2H),0.62(s,2H). Example 22. (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-(oxetane-3-ylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine (compound 30) [ka] Synthesis of methyl 5-cyclopropyl-3-(oxetane-3-ylamino)pyridine-2-carboxylate [ka]

[0192] To a stirred solution of methyl 5-cyclopropyl-3-fluoropyridine-2-carboxylate (300 mg, 1.5 mmol, 1 eq) and oxetane-3-amine (135 mg, 1.8 mmol, 1.2 eq) in NMP, DIEA (238 mg, 1.8 mmol, 1.2 eq) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120°C for 1 hour under a nitrogen atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded methyl 5-cyclopropyl-3-(oxetane-3-ylamino)pyridine-2-carboxylate (90 mg, 24%) as a yellow oil. LCMS(ESI)[M+H] + :249. Synthesis of 5-cyclopropyl-3-(oxetane-3-ylamino)pyridine-2-carboxylic acid [ka]

[0193] To a stirred solution of methyl 5-cyclopropyl-3-(oxetane-3-ylamino)pyridine-2-carboxylate (85 mg, 0.34 mmol, 1 eq) and LiOH (41 mg, 1.7 mmol, 5 eq) in THF, H2O (0.5 mL) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded 5-cyclopropyl-3-(oxetane-3-ylamino)pyridine-2-carboxylic acid (65 mg, 81%) as a yellow oil. LCMS(ESI)[M+H] + :235. Synthesis of methyl 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate [ka]

[0194] HATU (117 mg, 0.3 mmol, 1.2 eq) was added at room temperature to a stirred solution of 5-cyclopropyl-3-(oxetane-3-ylamino)pyridine-2-carboxylic acid (60 mg, 0.25 mmol, 1 eq), compound A (97 mg, 0.3 mmol, 1.2 eq), and DIEA (99 mg, 0.76 mmol, 3 eq) in DMF. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes; UV 254 nm. This yielded methyl 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate (103 mg, 76%) as a yellow oil. LCMS(ESI)[M+H] + :531. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid (compound D) [ka]

[0195] To a stirred solution of methyl 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate (98 mg, 0.2 mmol, 1 eq) and LiOH (22 mg, 0.9 mmol, 5 eq) in THF, H2O (1 mL) was added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The residue was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes; UV 254 nm. Compound D (80 mg, 84%) was obtained as a yellow oil. LCMS(ESI)[M+H] + :517. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine [ka]

[0196] HATU (66 mg, 0.17 mmol, 1.2 eq) was added at room temperature to a stirred solution of compound D (75 mg, 0.15 mmol, 1 eq), morpholine (15 mg, 0.2 mmol, 1.2 eq), and DIEA (56 mg, 0.44 mmol, 3 eq) in DMF. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (70 mg, 82%) as a yellow oil. LCMS(ESI)[M+H]+ :586. Synthesis of compound 30 [ka]

[0197] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (60 mg, 0.10 mmol, 1 eq) in DCM, TFA (0.3 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under vacuum and basicized to pH 8 using saturated Na2CO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes; UV 254 nm. Compound 30 (26 mg, 53%) was obtained as a white solid. LCMS(ESI)[M+H] + :486.3. 1 H NMR(300MHz,DMSO-d6)δ7.66(s,1H),6.42(s,1H),6.09-5.82(m,1H),4.90-4.75(m,2H),4.71-4.54(m,1H),4.44-4.30(m,2H),3.71-3.38( m,8H),3.28-3.16(m,2H),3.05-2.52(m,4H),2.42-2.20(m,2H),2.18-1.49(m,5H),1.06-0.82(m,6H),0.76(d,2H),0.61(d,J=6.4Hz,2H). Example 23. (3S)-{N-(2-methylpropyl),N-[3-(3-trans-methoxy)cyclobutyl]aminopyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine (compound 31) [ka] Synthesis of methyl 3-(3-(trans-methoxy)cyclobutyl-aminopyridine-2-carboxylate) [ka]

[0198] Pd2dba3 (127 mg, 0.14 mmol, 0.1 eq) was added at room temperature to a stirred solution of methyl 3-bromopyridine-2-carboxylate (300 mg, 1.4 mmol, 1 eq), 3-trans-methoxycyclobutan-1-amine (154.5 mg, 1.53 mmol, 1.1 eq), XantPhos (161 mg, 0.28 mmol, 0.2 eq), and Cs2CO3 (1357 mg, 4.17 mmol, 3 eq) in dioxane. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The precipitated solid was collected by filtration and washed with CH2Cl2 (3 × 10 mL). The resulting mixture was concentrated under reduced pressure and dissolved in DMSO. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 10 minutes; UV 254 nm. This yielded methyl 3-(3-(trans-methoxy)cyclobutyl-aminopyridine-2-carboxylate (115 mg, 35%) as a yellow oil. LCMS(ESI)[M+H]+:237. Synthesis of 3-[(3-trans-methoxy)cyclobutyl]aminopyridine-2-carboxylic acid [ka]

[0199] To a stirred solution of methyl 3-(3-(trans-methoxy)cyclobutyl-amino-pyridine-2-carboxylate (110 mg, 0.47 mmol, 1 eq) and LiOH (556 mg, 2.3 mmol, 5 eq) in THF, H2O (1 mL) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 40% gradient over 20 minutes; UV 254 nm. This yielded 3-[(3-trans-methoxy)cyclobutyl]amino-pyridine-2-carboxylic acid (98 mg, 95%) as a yellow oil. LCMS(ESI)[M+H]+:223. Synthesis of methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylate [ka]

[0200] To a solution of 3-[(3-trans-methoxy)cyclobutyl]aminopyridine-2-carboxylic acid (130 mg, 0.59 mmol, 1 eq), compound A (184 mg, 0.59 mmol, 1 eq), and DIEA (227 mg, 1.76 mmol, 3 eq) in DMF (2 mL), HATU (267 mg, 0.7 mmol, 1.2 eq) was added. The mixture was stirred at room temperature for 1 hour. The mixture was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 40% to 80% gradient over 20 minutes; UV 254 nm. This yielded methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylate (150 mg, 50%) as a yellow oil. LCMS(ESI)[M+H] + :519. Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylic acid [ka]

[0201] To a stirred solution of methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate (120 mg, 0.23 mmol, 1 eq) and LiOH (28 mg, 1.2 mmol, 5 eq) in THF, H2O (1 mL) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 40% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid (105 mg, 90%) as a yellow oil. LCMS(ESI)[M+H]+:505. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N'-cyclopropanecarbonylhydrazinecarbonyl)-piperidine [ka]

[0202] To a stirred solution of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid (115 mg, 0.23 mmol, 1 eq), DIEA (88.3 mg, 0.68 mmol, 3 eq), and TBTU (88 mg, 0.27 mmol, 1.2 eq) in DMF, cyclopropanecarbohydrazide (27.3 mg, 0.27 mmol, 1.2 eq) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N'-cyclopropanecarbonylhydrazinecarbonyl)-piperidine (121 mg, 90%) as a yellow oil. LCMS(ESI)[M+H]+:587. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine [ka]

[0203] To a stirred solution of I2 (104 mg, 0.41 mmol, 2 eq) and PPh3 (107 mg, 0.41 mmol, 2 eq) in DCE, TEA (83 mg, 0.82 mmol, 4 eq) and 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N'-cyclopropanecarbonylhydrazinecarbonyl)-piperidine (120 mg, 0.21 mmol, 1 eq) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine (100 mg, 86%) as a yellow oil. LCMS(ESI)[M+H]+:569. Synthesis of compound 31 [ka]

[0204] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine (100 mg, 0.18 mmol, 1 eq) in DCM (0.5 mL), TFA (0.5 mL) was added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The mixture was basicized to pH 8 using saturated Na2CO3 (aqueous solution). The resulting mixture was concentrated under vacuum. The precipitated solid was collected by filtration and washed with DMSO (2 × 2 mL). The crude product (100 mg) was purified by prep-HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 17%B~47%B, 47%B, 7 mins; wavelength: 220 nm; RT1 (min): 6.07; runs: 0) to obtain compound 31 (43 mg, 52%) as a white solid. LCMS(ESI)[M+H]+:469.30.1NMR(300MHz,DMSO-d6)δ7.95-7.73(m,1H),7.33-7 .13(m,1H),7.00-6.82(m,1H),5.68-5.37(m,1H),4.28-3.61(m,3H),3.29-3.09 (m,7H),3.09-2.87(m,2H),2.85-2.57(m,1H),2.46(s,1H),2.38-1.99(m,7H), 1.99-1.47(m,1H),1.21-1.04(m,2H),1.04-0.77(m,6H),0.62(d,J=6.6Hz,2H). Example 24. (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine (compound 32) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(N'-cyclopropanecarbonylhydrazinecarbonyl)-piperidine [ka]

[0205] TBTU (119 mg, 0.37 mmol, 1.2 eq) was added at room temperature to a stirred solution of compound D (160 mg, 0.31 mmol, 1 eq), cyclopropanecarborazide (62 mg, 0.62 mmol, 2 eq), and DIEA (120 mg, 0.93 mmol, 3 eq) in DMF. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 10 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(N'-cyclopropanecarbonylhydrazinecarbonyl)-piperidine (150 mg, 80%) as a yellow oil. LCMS(ESI)[M+H] + :599. Synthesis of 1-tert-butoxycarbonyl(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine [ka]

[0206] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(N'-cyclopropanecarbonylhydrazinecarbonyl)-piperidine (150 mg, 0.25 mmol, 1 eq) in DCE, Burgess reagent (239 mg, 1.0 mmol, 4 eq) was added at room temperature. The resulting mixture was stirred at 120°C for 20 minutes under a nitrogen atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 10 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine (98 mg, 67%) as a yellow oil. LCMS(ESI)[M+H] + :581. Synthesis of compound 32 [ka]

[0207] To a stirred solution of 1-tert-butoxycarbonyl(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine (75 mg, 0.13 mmol, 1 eq) in DCM (0.5 mL), TFA (0.5 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under vacuum and basicized to pH 8 using saturated Na2CO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes; UV 254 nm. Compound 32 (35 mg, 57%) was obtained as a white solid. LCMS(ESI)[M+H]+:481.25.1H NMR(300MHz,DMSO-d6)δ7.67(d,J=13.0Hz,1H),6.44(d,J=7.8Hz,1H),6.20-5 .87(m,1H),4.95-4.73(m,2H),4.73-4.54(m,1H),4.46-4.32(m,2H),4.27-3.7 0(m,1H),3.24(d,3H),3.12-2.59(m,4H),2.38-2.02(m,3H),2.00-1.76(m,2H ),1.17-1.06(m,2H),1.04-0.84(m,8H),0.82-0.71(m,2H),0.70-0.57(m,2H). Example 25. (3S)-{N-(2-methylpropyl),N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}amino-(5R)-[(3S)-3-methylmorpholine-4-carbonyl]-piperidine (compound 33) [ka] Synthesis of methyl 4-chloro-6-cyclopropylpyridazine-3-carboxylate [ka]

[0208] To a stirred solution of methyl 4,6-dichloropyridazine-3-carboxylate (3 g, 14.5 mmol, 1.0 eq), Pd(PPh3)4 (0.79 g, 0.68 mmol, 0.1 eq), cyclopropyltrifluoro-lambda-4-borane potassium (2.14 g, 14.49 mmol, 1.0 eq), and H2O (10 mL) in dioxane (30 mL), K2CO3 (6.01 g, 43.47 mmol, 3.0 eq) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 85°C for 2 hours under a nitrogen atmosphere. The resulting mixture was extracted with SiO2 (100 mL). The mixed organic layer was washed with water (3 × 100 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography. Elution with PE / EA (1:1) yielded methyl 4-chloro-6-cyclopropylpyridazine-3-carboxylate (310 mg, 10%) as a yellow oil. LCMS(ESI)[M+H] + :212. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.01 (s, 1H), 4.06 (s, 3H), 2.61-2.45 (m, 1H), 1.41-1.20 (m, 2H), 0.98-0.81 (m, 2H). Synthesis of methyl 6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]aminopyridazine-3-carboxylate [ka]

[0209] To a stirred solution of methyl 4-chloro-6-cyclopropylpyridazine-3-carboxylate (300 mg, 1.4 mmol, 1.0 eq) in anhydrous NMP (5 mL), DIEA (547 mg, 4.2 mmol, 3.0 eq) and (1R,3R)-3-methoxycyclobutane-1-amine hydrochloride (233 mg, 1.7 mmol, 1.2 eq) were added under a nitrogen atmosphere at room temperature. The reaction mixture was stirred at 140 °C for 2 hours. After the reaction was complete, the residue was purified by reverse-phase flash chromatography using UV 254 nm under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 0% to 50% gradient over 20 minutes to obtain methyl 6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]aminopyridazine-3-carboxylate (140 mg, 36%) as a yellow oil. LCMS(ESI)[M+H] + :278. Synthesis of 6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]aminopyridazine-3-carboxylic acid [ka]

[0210] To a stirred solution of methyl 6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]aminopyridazine-3-carboxylate (120 mg, 0.43 mmol, 1.0 eq) and H2O (1 mL) in THF (2 mL), lithium hydroxide (52 mg, 2.2 mmol, 5.0 eq) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was acidified to pH 6 with citric acid. The residue was purified by reverse-phase flash chromatography using UV 254 nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 60% gradient over 20 minutes to obtain 6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]aminopyridazine-3-carboxylic acid (100 mg, 88%) as a yellow oil. LCMS(ESI)[M+H] + :264. 1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),6.59(s,1H),4.23-4.10(m,1H),4.08-3.9 6(m,1H),3.17(s,3H),2.48-2.38(m,2H),2.24-2.09(m,3H),1.16-1.07(m,4H). Synthesis of methyl(3S)-{N-(2-methylpropyl),N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}aminopiperidine-(5R)-carboxylate [ka]

[0211] Compound A (119 mg, 0.38 mmol, 1.0 eq) was added to a stirred solution of 6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]aminopyridazine-3-carboxylic acid (100 mg, 0.38 mmol, 1.0 eq), DIEA (147.2 mg, 1.14 mmol, 3.0 eq), and HATU (173.3 mg, 0.45 mmol, 1.2 eq) in DMF (2 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. After the reaction was complete, the residue was purified by reverse-phase flash chromatography using UV254nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 60% gradient over 10 minutes to obtain methyl(3S)-{N-(2-methylpropyl),N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}aminopiperidine-(5R)-carboxylate (110 mg, 52%) as a yellow oil. LCMS(ESI)[M+H] + :560. Synthesis of (3S)-{N-(2-methylpropyl),N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}amino-piperidine-(5R)-carboxylic acid [ka]

[0212] Lithium hydroxide (23.3 mg, 0.98 mmol, 5.0 eq) was added to a stirred solution of methyl(3S)-{N-(2-methylpropyl),N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}aminopiperidine-(5R)-carboxylate (110 mg, 0.19 mmol, 1.0 eq) and H2O (1 mL) in THF (2 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. After the reaction was complete, the mixture was acidified to pH 6 with citric acid. The residue was purified by reverse-phase flash chromatography using UV254nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes to obtain (3S)-{N-(2-methylpropyl),N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}aminopiperidine-(5R)-carboxylic acid (95 mg, 89%) as a yellow oil. LCMS(ESI)[M+H] + :546. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}amino-(5R)-[(3S)-methylmorpholine-4-carbonyl]-piperidine [ka]

[0213] (3S)-3-methylmorpholine (21 mg, 0.2 mmol, 1.2 eq) was added to a stirred solution of (3S)-{N-(2-methylpropyl),N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}aminopiperidine-(5R)-carboxylic acid (95 mg, 0.17 mmol, 1.0 eq), DIEA (68 mg, 0.5 mmol, 3.0 eq), and HATU (79 mg, 0.21 mmol, 1.2 eq) in DMF (2 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. After the reaction was complete, the residue was purified by reverse-phase flash chromatography using UV254nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes to obtain 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}amino-(5R)-[(3S)-methylmorpholine-4-carbonyl]-piperidine (90 mg, 82%) as a yellow oil. LCMS(ESI)[M+H] + :629. Synthesis of compound 33 [ka]

[0214] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}amino-(5R)-[(3S)-methylmorpholine-4-carbonyl]-piperidine (90 mg, 0.14 mmol, 1.0 eq) in DCM (2 mL), TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 20 minutes. The mixture was basicized to pH 9 using saturated Na2CO3 (aqueous solution). The aqueous layer was extracted with ELISA (3 × 10 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC under the following conditions to obtain compound 33 (33.3 mg, 44%) as a white solid. LCMS(ESI)[M+H] + :529.30. 1 H NMR(400MHz,DMSO-d6)δ6.47-6.41(m,1H),6.39-6.10(m,1H),4.42-4.13(m,1H),4.08-3.9 9(m,1H),3.98-3.90(m,1H),3.89-3.72(m,1H),3.66-3.38(m,3H),3.29-3.17(m,3H),3.14( s,3H),3.04-2.78(m,2H),2.77-2.65(m,1H),2.63-2.54(m,1H),2.48-2.41(m,1H),2.40-2. 28(m,3H),2.27-2.02(m,5H),1.99-1.52(m,2H),1.33-0.87(m,12H),0.62(d,J=6.5Hz,2H). Example 26. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[5-(oxetan-3-yl)-1,3,4-oxadiazole-2-yl]-piperidine (compound 34) [ka] Synthesis of oxetane-3-carbohydrazide [ka]

[0215] A solution of methyloxetane-3-carboxylate (1 g, 8.6 mmol, 1.0 eq) and diimine hydrate hydrogen (3.4 g, 69 mmol, 8.0 eq) in MeOH was stirred at room temperature for 48 hours. The resulting mixture was concentrated under vacuum. The residue was purified by grinding with SiO2 (10 mL). This yielded oxetane-3-carbohydrazide (800 mg, unpurified) as a yellow solid. LCMS(ESI)[M+H] + :117. Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(2-(oxetane-3-carbonyl)hydrazine-1-carbonyl)-piperidine [ka]

[0216] A solution of compound C (530 mg, 0.97 mmol, 1.0 eq), DIEA (377 mg, 2.92 mmol, 3.0 eq), and TBTU (468 mg, 1.46 mmol, 1.5 eq) in DMF was stirred at room temperature for 10 minutes. Oxetane-3-carbohydrazide (452 ​​mg, 3.9 mmol, 4.0 eq) was added to the above mixture at room temperature. The resulting mixture was stirred at room temperature for an additional 4 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(2-(oxetane-3-carbonyl)hydrazine-1-carbonyl)-piperidine (310 mg, 50%) as an off-white solid. LCMS(ESI)[M+H] + :643.1 H NMR(300MHz,DMSO-d6)δ10.01(s,1H),9.87(s,1H),7.64(s,1H),6.50(s,1H),5.76(m,1H),4.75-4.48(m,3H),4.10-3.66(m,7H),3.15(s,3 H),2.82(m,3H),2.31(m,4H),2.16-1.84(m,6H),1.55-1.13(m,9H),1.00(d,J=8.2Hz,2H),0.90(d,J=6.4Hz,4H),0.75(s,2H),0.64(s,2H). Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[5-(oxetan-3-yl)-1,3,4-oxadiazole-2-yl)-piperidine [ka]

[0217] A solution of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(2-(oxetane-3-carbonyl)hydrazine-1-carbonyl)-piperidine (160 mg, 0.25 mmol, 1.0 eq) and Burgess reagent (237 mg, 1.0 mmol, 4.0 eq) in DCE was stirred at 120°C for 20 minutes under a nitrogen atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[5-(oxetan-3-yl)-1,3,4-oxadiazole-2-yl)-piperidine (45 mg, 29%) as an off-white solid. LCMS(ESI)[M+H] + :625. Synthesis of compound 34 [ka]

[0218] A solution of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[5-(oxetan-3-yl)-1,3,4-oxadiazole-2-yl)-piperidine (130 mg, 0.21 mmol, 1.0 eq) in DCM / TFA was stirred at room temperature for 30 minutes. The mixture was acidified to pH 9 using saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. Compound 34 (49 mg, 45%) was obtained as a white solid. LCMS(ESI)[M+H]+ :525.30. 1 H NMR(300MHz,DMSO-d6)δ7.65(d,J=13.7Hz,1H),6.49(s,1H),5.82-5.45(m,1H) ,4.90(m,2H),4.75(m,2H),4.54(d,J=8.2Hz,1H),4.18-3.66(m,3H),3.24(m,3 H),3.14(s,3H),3.10-2.79(m,3H),2.72-2.57(m,1H),2.29(m,4H),1.98(m,5H) ),1.06-0.97(m,2H),0.90(d,J=6.6Hz,4H),0.76(s,2H),0.63(d,J=6.4Hz,2H). Example 27. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-hydroxymethyl-piperidine (Compound 35) [ka] [ka]

[0219] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-hydroxymethylpiperidine (70 mg, 0.13 mmol, 1.0 eq) in DCM / TFA was stirred at room temperature for 30 minutes. The mixture was acidified to pH 9 using saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. Compound 34 (32.3 mg, 57%) was obtained as a white solid. LCMS(ESI)[M+H] + :431.25. 1H NMR(300MHz,DMSO-d6)δ7.63(d,J=9.1Hz,1H),6.48(s,1H),5.52(d,J=5.9Hz ,1H),4.41(s,1H),3.79(d,J=97.8Hz,3H),3.15(m,7H),3.03-2.64(m,3H),2 .43(m,1H),2.30(m,2H),2.15-1.74(m,6H),1.53(m,1H),1.42-1.16(m,1H), 1.05-0.95(m,2H),0.89(d,J=6.6Hz,4H),0.76(s,2H),0.60(d,J=6.3Hz,2H). Example 28. (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-piperidine (compound 36) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}aminopiperidine [ka]

[0220] HATU (142 mg, 0.37 mmol, 1.2 eq) was added at room temperature to a stirred solution of 1-tert-butoxycarbonyl-(3S)-(2-methylpropylamino)piperidine (80 mg, 0.31 mmol, 1 eq), 5-cyclopropyl-3-(oxetane-3-ylamino)pyridine-2-carboxylic acid (88 mg, 0.37 mmol, 1.2 eq), and DIEA (121 mg, 0.94 mmol, 3 eq) in DMF (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}aminopiperidine (100 mg, 68%) as a yellow solid. LCMS(ESI)[M+H] + :473. Synthesis of Compound 36 [ka]

[0221] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}aminopiperidine (100 mg, 0.212 mmol, 1 eq) in DCM (0.5 mL), TFA (0.5 mL) was added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The mixture was basicized to pH 8 using saturated NaHCO3 (aqueous solution). The crude product (100 mg) was purified by prep-HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 19%B~45%B, 45%B, 7 mins; wavelength: 220 nm; RT1 (min): 5.57; runs: 0) to obtain compound 36 (33 mg, 41%) as an off-white oil. LCMS(ESI)[M+H] + :373.20. 1 H NMR(300MHz,DMSO-d6)δ7.66(d,J=9.8Hz,1H),6.43(d,J=7.2Hz,1H),5.94(d ,J=6.2Hz,1H),4.91-4.77(m,2H),4.72-4.57(m,1H),4.42-4.30(m,2H),3.61 -3.47(m,1H),3.21(d,J=7.5Hz,3H),3.04-2.54(m,3H),2.44-1.95(m,2H),1 .94-1.36(m,5H),1.03-0.85(m,6H),0.81-0.72(m,2H),0.61(d,J=6.5Hz,2H) Example 29. (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]-pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine (compound 37) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(N'-acetylhydrazinecarbonyl)-piperidine [ka]

[0222] To a stirred solution of compound D (210 mg, 0.41 mmol, 1 eq), TBTU (157 mg, 0.5 mmol, 1.2 eq), and DIEA (158 mg, 1.2 mmol, 3 eq) in DMF, acetohydrazide (36 mg, 0.5 mmol, 1.2 eq) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 70% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(N'-acetylhydrazinecarbonyl)-piperidine (200 mg, 86%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ9.98-9.70(m,2H),7.66(s,1H),6.46(d,J=21.2Hz,1H ),6.11(d,J=95.6Hz,1H),4.88-4.75(m,2H),4.70-4.56(m,1H),4.47-4.32(m, 2H),4.20-3.56(m,4H),3.25-3.08(m,1H),3.06-2.58(m,2H),2.41-2.04(m,2 H),2.03-1.78(m,6H),1.49-1.20(m,9H),1.04-0.57(m,10H).LCMS(ESI)[M+H] + :573. Synthesis of 1-tert-butoxycarbonyl(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine [ka]

[0223] A solution of PPh3 (164.8 mg, 0.628 mmol, 2 eq) in DCM was treated with I2 (159.5 mg, 0.63 mmol, 2 eq) under a nitrogen atmosphere at room temperature for 10 minutes, followed by the addition of TEA (127 mg, 1.3 mmol, 4 eq) and 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(N'-acetylhydrazinecarbonyl)-piperidine (180 mg, 0.31 mmol, 1 eq). The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was quenched with NaSO3 at room temperature. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes; using UV 254 nm. This yielded 1-tert-butoxycarbonyl(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine (80 mg, 46%) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δ7.72-7.60(m,1H),6.46(d,J=17.1Hz,1H),6.12(d,J=111.4H z,1H),4.89-4.78(m,2H),4.70-4.57(m,1H),4.46-4.33(m,2H),4.31-3.47(m,4H),3 .26-3.12(m,2H),3.11-2.75(m,2H),2.49-2.41(m,3H),2.36-2.21(m,1H),2.19-2.0 2(m,1H),1.95-1.62(m,2H),1.51-1.21(m,9H),1.03-0.60(m,10H).LCMS(ESI)[M+H] + :555. Synthesis of Compound 37 [ka]

[0224] To a stirred solution of 1-tert-butoxycarbonyl(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine (65 mg, 0.12 mmol, 1 eq) in CH2Cl2, TFA (0.3 mL) was added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes. The mixture was basicized to pH 8 using saturated NaHCO3 (aqueous solution). The crude product (65 mg) was purified by prep-HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 21%B~45%B, 45%B, 7 mins; wavelength: 220 nm; RT1 (min): 5.65; runs: 0) to obtain compound 37 (24.3 mg, 46%) as a white solid. LC-MS(ESI)[M+H] + :455.25. 1H NMR(300MHz,DMSO-d6)δ7.67(d,J=13.8Hz,1H),6.44(d,J=8.3Hz,1H),6.16-5.88 (m,1H),4.92-4.76(m,2H),4.72-4.54(m,1H),4.46-4.32(m,2H),3.92(d,J=104. 8Hz,1H),3.28-3.20(m,2H),3.19-3.08(m,1H),3.07-2.73(m,3H),2.71-2.53(m, 1H),2.48-2.36(m,4H),2.33-2.17(m,2H),1.99-1.50(m,2H),1.04-0.55(m,10H). Example 30. (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]-pyridine-2-carbonyl}amino-(5R)-(3-methyl-1,2,4-oxadiazole-5-yl)-piperidine (compound 38) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]-pyridine-2-carbonyl}amino-(5R)-(3-methyl-1,2,4-oxadiazole-5-yl)-piperidine [ka]

[0225] A solution of compound D (150.0 mg, 0.29 mmol, 1.0 eq) and carbonyldiimidazole (141 mg, 0.87 mmol, 3.0 eq) in DMF was stirred at room temperature under a nitrogen atmosphere for 5 hours. Acetamido oxime (64.5 mg, 0.87 mmol, 3.0 eq) was added to the above mixture at room temperature. The resulting mixture was stirred at room temperature for an additional 15 hours, and then at 100°C for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]-pyridine-2-carbonyl}amino-(5R)-(3-methyl-1,2,4-oxadiazole-5-yl)-piperidine (80.0 mg, 50%) as a yellow oil. LCMS(ESI)[M+H] + :555. Synthesis of compound 38 [ka]

[0226] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]-pyridine-2-carbonyl}amino-(5R)-(3-methyl-1,2,4-oxadiazole-5-yl)-piperidine (60.0 mg, 0.11 mmol, 1.0 eq) in DCM / TFA (1.5:0.5 mL) was stirred at room temperature for 0.5 hours. The mixture was acidified to pH 9 using saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. Compound 38 (21.6 mg, 43.93%) was obtained as a white solid. LCMS(ESI)[M+H] + :455.30. 1H NMR(400MHz,DMSO-d6)δ7.67(d,J=19.5Hz,1H),6.44(d,J=13.0Hz,1H),6.01(m,1H),4.83(m,2H),4.63(m,1H),4.37(m,2H),3.76(d,J=11.6Hz) ,1H),3.75-3.71(m,1H),3.23(m,3H),3.07-2.88(m,3H),2.73-2.57(m ,1H),2.46(m,1H),2.31(d,4H),2.18-1.85(m,2H),1.14-0.50(m,10H). Example 31. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,2,4-oxadiazole-3-yl)-piperidine (Compound 39) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,2,4-oxadiazole-3-yl)-piperidine [ka]

[0227] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[(1R,3R)-3-methoxycyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N-hydroxycarbamimidoyl)-piperidine (110 mg, 0.2 mmol, 1 eq) in triethyl orthoformate (1 mL), BF3.Et2O (2.7 mg, 0.02 mmol, 0.1 eq) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for 1 hour under a nitrogen atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,2,4-oxadiazole-3-yl)-piperidine (95 mg, 85%) as a yellow oil. LCMS(ESI)[M+H] + :569. Synthesis of compound 39 [ka]

[0228] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,2,4-oxadiazole-3-yl)-piperidine (80 mg, 0.14 mmol, 1 eq) in DCM (0.4 mL), TFA (0.4 mL) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was basicized to pH 8 using saturated NaHCO3 (aqueous solution). The crude product (80 mg) was purified by prep-HPLC using the following conditions (column: XBridge Prep C18 OBD column, 30*50 mm, 5 μm 13 nm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22%B~45%B, 45%B, 8 mins; wavelength: 220 nm; RT1 (min): 8.4; runs: 0) to obtain compound 39 (32.6 mg, 49%) as a white solid. LC-MS (ESI) [M+H] + :469.20. 1 H NMR(400MHz,DMSO-d6)δ9.51(d,J=5.3Hz,1H),7.64(d,J=19.8Hz,1H),6.47(d,J=8.8Hz,1H),5.73-5.4 6(m,1H),4.20-3.71(m,3H),3.31-3.19(m,2H),3.19-3.05(m,4H),3.04-2.93(m,1H),2.91-2.83(m,1H) ),2.78(s,1H),2.70-2.54(m,1H),2.47-2.36(m,1H),2.36-2.25(m,2H),2.25-2.16(m,1H),2.13-1.96 (m,3H),1.96-1.79(m,2H),1.05-0.95(m,2H),0.95-0.81(m,4H),0.81-0.70(m,2H),0.70-0.56(m,2H). Example 32. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine (compound 40) [ka] Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(hydrazinecarbonyl)-piperidine [ka]

[0229] To a stirred solution of compound C (200 mg, 0.37 mmol, 1 eq), HATU (168 mg, 0.44 mmol, 1.2 eq), and DIEA (142 mg, 1.1 mmol, 3 eq) in DMF (3 mL), diimine hydrate hydrogen (90.0 mg, 1.8 mmol, 5 eq) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(hydrazinecarbonyl)-piperidine (175 mg, 85%) as a yellow oil. LCMS(ESI)[M+H]+:559. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine [ka]

[0230] To a stirred solution of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(hydrazinecarbonyl)-piperidine (150 mg, 0.27 mmol, 1 eq) in triethyl orthoformate (2 mL), boron trifluoride etherate (0.4 mg, 0.003 mmol, 0.01 eq) was added at room temperature. The resulting mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine (80 mg, 52%) as a yellow oil. LCMS(ESI)[M+H]+:569. Synthesis of compound 40 [ka]

[0231] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine (60 mg, 0.11 mmol, 1 eq) in DCM (0.5 mL), TFA (0.5 mL) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was basicized to pH 8 using saturated NaHCO3 (aqueous solution). The resulting mixture was concentrated under reduced pressure. The crude product (60 mg) was purified by prep-HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 26%B~47%B, 47%B, 7 mins; wavelength: 220 nm; RT1 (min): 6.11; runs: 0) to obtain compound 40 (25.3 mg, 51%) as a white solid. LCMS(ESI)[M+H]+: 469.35. 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.64(d,J=18.3Hz,1H),6.48(s,1H),5 .59(d,J=64.8Hz,1H),4.17-3.87(m,3H),3.86-3.71(m,1H),3.27-3.17(m, 3H),3.14(s,3H),3.11-2.84(m,3H),2.67-2.59(m,1H),2.36-2.18(m,4H), 2.12-1.86(m,4H),1.03-0.81(m,6H),0.79-0.70(m,2H),0.67-0.57(m,2H). Example 33. (3S)-{N-(2-cyclopropylmethyl,N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine (compound 41) [ka] Synthesis of methyl 1-tert-butoxylcarbonyl-(3S)-(2-cyclopropylmethyl)aminopiperidine(5R)-carboxylate [ka]

[0232] A solution of methyl 1-tert-butoxylcarbonyl(3S)-amino-piperidine-(5R)-carboxylate (600.0 mg, 2.3 mmol, 1.0 eq), cyclopropanecarbaldehyde (195 mg, 2.8 mmol, 1.2 eq), and sodium triacetoxyborate (1477 mg, 7 mmol, 3.0 eq) in MeOH was stirred at room temperature for 2 hours. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient over 20 minutes, UV 254 nm. This yielded methyl 1-tert-butoxylcarbonyl-(3S)-(2-cyclopropylmethyl)amino-piperidine(5R)-carboxylate (560 mg, 77%) as a yellow oil. LCMS(ESI)[M+H] + :313. Synthesis of methyl 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate [ka]

[0233] A solution of methyl 1-tert-butoxylcarbonyl-(3S)-(2-cyclopropylmethyl)aminopiperidine(5R)-carboxylate (180 mg, 0.57 mmol), compound B (150 mg, 0.57 mmol, 1.0 eq), N,N-diisopropylethylamine (222 mg, 1.7 mmol, 3.0 eq), and HATU (261 mg, 0.7 mmol, 1.2 eq) in DMF was stirred at room temperature for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded methyl 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate (260 mg, 82%) as a yellow oil. LCMS(ESI)[M+H] + :557. 1 H NMR (400MHz, chloroform-d) δ7.65(d,J=1.8Hz,1H),6.42(s,1H),5.90(d,J=81.7Hz,1H),4.28(s,2H),4.02(m,3H),3.70(s,3H),3.27( s,3H),2.66(m,3H),2.40(m,4H),2.15(m,2H),1.83(m,2H),1.73(s,1H),1.44(s,9H),1.14-0.93(m,3H),0.72(m,2H),0.49(m,4H). Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid [ka]

[0234] A solution of methyl 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate (260.0 mg, 0.47 mmol, 1.0 eq) and lithium hydrate (98 mg, 2.34 mmol, 5.0 eq) in THF / H2O (8:4 mL) was stirred at room temperature for 2 hours. The mixture was acidified to pH 4 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid (240 mg, 95%) as a yellow solid. LCMS(ESI)[M+H] + :543. 1 H NMR(400MHz,DMSO-d6)δ12.56(s,1H),7.62(s,1H),6.49(s,1H),5.67(d,J=54.9Hz,1H),4.37-3.63(m,5H),3.31(s,3H),3.14(s,3H),3 .03-2.58(m,2H),2.31(m,2H),2.06(m,4H),1.89(m,2H),1.33(d,J=71.6Hz,9H),0.98(m,2H),0.74(d,J=5.8Hz,2H),0.56-0.17(m,4H). Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N'-acetylhydrazinecarbonyl)-piperidine [ka]

[0235] A solution of 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid (150 mg, 0.28 mmol, 1.0 eq), N,N-diisopropylethylamine (178.6 mg, 1.38 mmol, 5.0 eq), and TBTU (133.1 mg, 0.41 mmol, 1.5 eq) in DMF was stirred at room temperature for 10 minutes. To the above mixture, acetohydrazide (30.7 mg, 0.41 mmol, 1.5 eq) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N'-acetylhydrazinecarbonyl)-piperidine (130.0 mg, 79%) as a yellow oil. LCMS(ESI)[M+H] + :599. 1 H NMR(300MHz,DMSO-d6)δ9.89(d,J=13.0Hz,2H),9.78(s,1H),7.63(s,1H),6. 50(s,1H),5.71(d,J=50.5Hz,1H),4.15-3.65(m,5H),3.34(s,2H),3.15(s,3 H),3.08-2.59(m,2H),2.30(d,J=6.0Hz,3H),2.03-1.89(m,3H),1.84(s,3H) ,1.35(d,J=50.8Hz,9H),1.15-0.93(m,3H),0.75(m,3H),0.59-0.21(m,4H). Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine [ka]

[0236] A solution of iodine (110.2 mg, 0.43 mmol, 2.0 eq) and triphenylphosphine (113.9 mg, 0.43 mmol, 2.0 eq) in DCM was stirred at room temperature for 10 minutes under a nitrogen atmosphere. Triethylamine (87.9 mg, 0.87 mmol, 4.0 eq) and 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(N'-acetylhydrazinecarbonyl)-piperidine (130 mg, 0.22 mmol, 1.0 eq) were added to the above mixture at room temperature. The resulting mixture was stirred for an additional 2 hours at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient over 20 minutes, UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine (70 mg, 56%) as a yellow oil. LCMS(ESI)[M+H] + :581. Synthesis of compound 41 [ka]

[0237] A solution of 1-tert-butoxycarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine (70.0 mg, 0.12 mmol, 1.0 eq) in DCM / TFA (1.5:0.5 mL) was stirred at room temperature for 30 minutes. The mixture was acidified to pH 9 using saturated NaHCO3 (aqueous solution). The residue was purified by reverse flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient over 20 minutes, UV 254 nm. Compound 41 (42 mg, 73%) was obtained as a white solid. LCMS(ESI)[M+H] + :481.30. 1 H NMR(400MHz,DMSO-d6)δ7.73(d,J=22.4Hz,1H),6.57(s,1H),5.85-5.53(m,1H ),4.37-3.78(m,3H),3.43-3.29(m,2H),3.23(s,3H),3.16-2.87(m,3H),2.80 -2.63(m,1H),2.60(m,4H),2.46-2.28(m,4H),2.21-2.09(m,2H),2.00(m,2H) ,1.26-0.77(m,5H),0.56(d,J=8.1Hz,1H),0.41(d,J=8.6Hz,2H),0.00(s,1H). Example 34. (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(1,2,4-oxadiazole-3-yl)-piperidine (compound 42) [ka] Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-piperidine-(5R)-carboxamide [ka]

[0238] To a stirred solution of compound D (870 mg, 1.7 mmol, 1 eq) and DIEA (652.9 mg, 5.052 mmol, 3 eq) in DMF (10 mL), NH4Cl (180.1 mg, 3.368 mmol, 2 eq) and HATU (960 mg, 2.526 mmol, 1.5 eq) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-piperidine-(5R)-carboxamide (850 mg, 98%) as a yellow solid. LCMS(ESI)[M+H]+:516. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-cyanopiperidine [ka]

[0239] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}aminopiperidine-(5R)-carboxamide (850 mg, 1.648 mmol, 1 eq) and phosphorus oxychloride (252.7 mg, 1.648 mmol, 1 eq) in pyridine (8 mL) was stirred at room temperature under a nitrogen atmosphere for 45 minutes. The reaction was quenched with water at room temperature. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 60% gradient over 20 minutes; using UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-cyano-piperidine (405 mg, 49%) as a yellow solid. LCMS(ESI)[M+H]+:498. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(N-hydroxycarbamimidoyl)-piperidine [ka]

[0240] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-cyano-piperidine (405 mg, 0.814 mmol, 1 eq), hydroxylamine hydrochloride (113.1 mg, 1.628 mmol, 2 eq), and DIEA (210.3 mg, 1.628 mmol, 2 eq) in EtOH (5 mL) was stirred at 70°C for 30 minutes under a nitrogen atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(N-hydroxycarbamimidoyl)piperidine (220 mg, 51%) as a yellow solid. LCMS(ESI)[M+H]+:531. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]-pyridine-2-carbonyl}amino-(5R)-(1,2,4-oxadiazole-3-yl)-piperidine [ka]

[0241] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(N-hydroxycarbamimidoyl)piperidine (220 mg, 0.42 mmol, 1 eq) and 4-methylbenzene-1-sulfonic acid (7.1 mg, 0.04 mmol, 0.1 eq) in triethyl orthoformate (2.5 mL) was stirred at 125°C for 30 minutes under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]-pyridine-2-carbonyl}amino-(5R)-(1,2,4-oxadiazole-3-yl)-piperidine (132 mg, 59%) as a yellow oil. LCMS(ESI)[M+H]+:541. Synthesis of compound 42 [ka]

[0242] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]-pyridine-2-carbonyl}amino-(5R)-(1,2,4-oxadiazole-3-yl)-piperidine (125 mg, 0.231 mmol, 1 eq) in DCM (1 mL), TFA (1 mL) was added and the mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes. The mixture was basicized to pH 8 using saturated Na2CO3 (aqueous solution). The crude product (125 mg) was purified by prep-HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18%B~50%B, 50%B, 7.5 mins; wavelength: 220 nm; RT1 (min): 6.23; runs: 0) to obtain compound 42 (63 mg, 62%) as a white solid. LC-MS (ESI) [M+H] + :441.20. 1 H NMR(300MHz,DMSO-d6)δ9.51(d,J=5.2Hz,1H),7.68(d,J=14.7Hz,1H),6.44(d,J=10.6Hz,1H),6.16-5.83 (m,1H),4.90-4.78(m,2H),4.74-4.56(m,1H),4.45-4.33(m,2H),4.24-3.67(m,1H),3.29-3.18(m,2H),3. 15(d,J=13.7Hz,1H),3.06-2.85(m,2H),2.84-2.71(m,1H),2.70-2.54(m,1H),2.49-2.32(m,1H),2.30-2. 00(m,2H),1.97-1.50(m,2H),1.03-0.95(m,2H),0.95-0.83(m,4H),0.82-0.71(m,2H),0.69-0.58(m,2H). Example 35. (3S)-{N-(2-methylpropyl),N-[5-trifluoromethyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (compound 43) [ka] Synthesis of methyl 3-(oxetane-3-ylamino)-5-(trifluoromethyl)pyridine-2-carboxylate [ka]

[0243] A solution of methyl 3-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (950 mg, 3.35 mmol, 1 eq), oxetane-3-amine (293 mg, 4.0 mmol, 1.2 eq), Pd2(dba)3 (306 mg, 0.34 mmol, 0.1 eq), and Xantphos (387 mg, 0.67 mmol, 0.2 eq) in 1,4-dioxane was treated with Cs2CO3 (3269 mg, 10 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 85°C for 2 hours under a nitrogen atmosphere. The resulting mixture was extracted with CH2Cl2 (3 × 20 mL). The mixed organic layers were washed with CH2Cl2 (3 × 300 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain methyl 3-(oxetane-3-ylamino)-5-(trifluoromethyl)pyridine-2-carboxylate (330 mg, 36%) as a yellow solid. LCMS(ESI)[M+H] + :277. Synthesis of 3-(oxetane-3-ylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid [ka]

[0244] To a stirred solution of methyl 3-(oxetane-3-ylamino)-5-(trifluoromethyl)pyridine-2-carboxylate (330 mg, 1.195 mmol, 1 eq) and H2O (3 mL) in THF (3 mL), LiOH (143.0 mg, 5.975 mmol, 5 eq) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 40% gradient over 20 minutes; UV 254 nm. This yielded 3-(oxetane-3-ylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (305 mg, 97.37%) as a yellow solid. LCMS(ESI)[M+H] + :263. Synthesis of methyl 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-trifluoromethyl-3-(oxetane-3-ylamino]pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylate [ka]

[0245] Compound A (144 mg, 0.46 mmol, 1.2 eq) and HATU (217 mg, 0.57 mmol, 1.5 eq) were added to a stirred solution of 3-(oxetane-3-ylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (100 mg, 0.38 mmol, 1 eq) and DIEA (147.8 mg, 1.143 mmol, 3 eq) in DMF (1.5 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded methyl 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-frifluoromethyl-3-(oxetane-3-ylamino]pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylate (130 mg, 61%) as a yellow oil. LCMS(ESI)[M+H] + :559. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-trifluoromethyl-3-(oxetane-3-ylamino]pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylic acid [ka]

[0246] A stirred solution of methyl 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-frifluoromethyl-3-(oxetane-3-ylamino]pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate (120 mg, 0.22 mmol, 1 eq) and H2O (1 mL) in THF (1 mL) was mixed with LiOH (26 mg, 1.1 mmol, 5 eq) and stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was acidified to pH 6 with citric acid. The following conditions were observed: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 40% gradient over 20 minutes; purification was performed by reverse flash chromatography using UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-trifluoromethyl-3-(oxetane-3-ylamino]pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid (105 mg, 90%) as a yellow oil. LCMS(ESI)[M+H] + :545. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-trifluoromethyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine [ka]

[0247] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-trifluoromethyl-3-(oxetane-3-ylamino]pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid (120 mg, 0.22 mmol, 1 eq) and DIEA (85.4 mg, 0.660 mmol, 3 eq) in DMF (1.5 mL), morpholine (23.0 mg, 0.264 mmol, 1.2 eq) and HATU (100.4 mg, 0.264 mmol, 1.2 eq) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 10 minutes; using UV 254 nm. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-trifluoromethyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (110 mg, 81.34%) as a yellow oil. LCMS(ESI)[M+H] + :614. Synthesis of compound 43 [ka]

[0248] A solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-[5-trifluoromethyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine (120 mg, 0.20 mmol, 1 eq) and TFA (1 mL) in DCM (1 mL) was stirred at room temperature under a nitrogen atmosphere for 15 minutes. The mixture was basicized to pH 8 using saturated Na2CO3 (aqueous solution). The crude product (120 mg) was purified by prep-HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18%B~50%B, 50%B, 7.5 mins; wavelength: 220 nm; RT1 (min): 6.23; runs: 0) to obtain compound 43 (63 mg, 63%) as a white solid. LC-MS (ESI) [M+H] + :514.25. 1 H NMR(300MHz,DMSO-d6)δ8.25-8.11(m,1H),7.12(d,J=1.8Hz,1H),6.52-6.25(m,1H),4.88-4.80(m,2H),4.80-4.66(m,1H),4.52-4.42(m,2H) ,3.66-3.36(m,9H),3.30-2.65(m,5H),2.63-2.54(m,1H),2.47-1.99( m,3H),1.97-1.55(m,2H),0.93(d,J=6.6Hz,4H),0.65(d,J=6.5Hz,2H). Example 36. (3S)-{N-cyclopropylmethyl,N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine (compound 44) [ka] Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(hydrazinecarbonyl)-piperidine [ka]

[0249] Diimine hydrate hydrogen (66.8 mg, 1.364 mmol, 2 eq) was added to a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid (370 mg, 0.68 mmol, 1 eq), DIEA (264 mg, 2.0 mmol, 3.00 eq), and HATU (311 mg, 0.82 mmol, 1.2 eq) in DMF (4 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The residue was purified by reverse flash chromatography using UV 254 nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(hydrazinecarbonyl)-piperidine (140 mg, 37%) as a white solid. LCMS(ESI)[M+H] + :557. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine [ka]

[0250] 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(hydrazinecarbonyl)-piperidine (130 mg, 0.23 mmol, 1 eq) and triethyl orthoformate (1.5 mL) were stirred together, and 4-methylbenzene-1-sulfonic acid (4.0 mg, 0.02 mmol, 0.1 eq) was added. The resulting mixture was stirred under a nitrogen atmosphere at 125°C for 15 minutes. The residue was purified by reverse flash chromatography using UV 254 nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes. This yielded 1-tert-butoxycarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine (60 mg, 45%) as a white solid. LCMS(ESI)[M+H] + :567. Synthesis of compound 44 [ka]

[0251] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine (50 mg, 0.09 mmol, 1 eq) in DCM (0.5 mL), TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes. The mixture was basicized to pH 8 using saturated NaHCO3 (aqueous solution). The crude product (50 mg) was purified by prep-HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH--HPLC; flow rate: 25 mL / min; gradient: 43%B~66%B, 66%B, 7 mins; wavelength: 220 nm; RT1 (min): 5.78; runs: 0) to obtain compound 44 (19 mg, 45%) as a white solid. LC-MS(ESI)[M+H] + :467.15. 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.63(d,J=20.7Hz,1H),6.48(s,1H),5.57(d,J= 20.9Hz,1H),4.31-3.69(m,3H),3.26-3.18(m,2H),3.17-3.10(m,3H),3.00(d,J=54.2 Hz,3H),2.75-2.53(m,2H),2.35-2.20(m,4H),2.05(s,3H),1.95-1.86(m,1H),1.18-0 .92(m,3H),0.80(d,J=40.0Hz,3H),0.47(d,J=7.7Hz,1H),0.33(s,2H),-0.09(s,1H). Example 37. (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine (compound 45) [ka] Synthesis of tert-butyl N-[3-trans-(methoxy-d3)cyclobutyl]carbamate [ka]

[0252] To a stirred solution of tert-butyl N-(3-trans-hydroxycyclobutyl) carbamate (1 g, 5.34 mmol, 1 eq) and iodine (methane-d3) (2323 mg, 16 mmol, 3 eq) in THF, NaH (385 mg, 16 mmol, 3 eq) was added under a nitrogen atmosphere at 0°C. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (5 mL). The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded tert-butyl N-[3-trans-(methoxy-d3)cyclobutyl] carbamate (520 mg, 48%) as a white solid. LCMS(ESI)[M+H] + :205. 1 H NMR(400MHz,DMSO-d6)δ7.15(d,1H),4.02-3.91(m,1H),3.91-3.83(m,1H),2.17-2.00(m,4H),1.37(s,9H). Synthesis of 3-trans-(methoxy-d3)cyclobutan-1-amine [ka]

[0253] To a stirred solution of tert-butyl N-[3-trans-(methoxy-d3)cyclobutyl]carbamate (510 mg, 2.5 mmol, 1 eq) in dioxane (5 mL), a solution of HCl in 1,4-dioxane (5 mL) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered, and the filter cake was washed with diethyl ether (3 × 30 mL). The filtrate was concentrated under reduced pressure. This yielded 3-trans-(methoxy-d3)cyclobutan-1-amine (270 mg, unpurified) as a white solid. LCMS(ESI)[M+H] + :105. Synthesis of methyl 5-cyclopropyl-3-[3-trans-(methoxy-d3)cyclobutyl]aminopyridine-2-carboxylate [ka]

[0254] Methyl 5-cyclopropyl-3-fluoropyridine-2-carboxylate (585 mg, 3.0 mmol, 1.2 eq) was added to a stirred solution of 3-trans-(methoxy-d3)cyclobutan-1-amine (260 mg, 2.5 mmol, 1 eq) and DIEA (968 mg, 7.5 mmol, 3 eq) in NMP. The resulting mixture was stirred at 140°C for 4 hours under a nitrogen atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded methyl 5-cyclopropyl-3-[3-trans-(methoxy-d3)cyclobutyl]aminopyridine-2-carboxylate (150 mg, 22%) as a yellow oil. LCMS(ESI)[M+H] + :280. Synthesis of 5-Cyclopropyl-3-[3-(Trans-methoxy-d3)cyclobutyl]aminopyridine 2-carboxylic acid [ka]

[0255] To a stirred solution of methyl 5-cyclopropyl-3-[3-trans-(methoxy-d3)cyclobutyl]aminopyridine-2-carboxylate (140 mg, 0.50 mmol, 1 eq) and H2O (0.5 mL) in THF (0.5 mL), LiOH (60 mg, 2.5 mmol, 5 eq) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 40% gradient over 10 minutes; UV 254 nm. This yielded 5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]aminopyridine-2-carboxylic acid (110 mg, 83%) as a yellow solid. LCMS(ESI)[M+H] + :266. Synthesis of methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylate [ka]

[0256] Compound A (156 mg, 0.5 mmol, 1.2 eq) was added at room temperature to a stirred solution of 5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]aminopyridine-2-carboxylic acid (110 mg, 0.42 mmol, 1 eq), HATU (189.1 mg, 0.498 mmol, 1.2 eq), and DIEA (160.7 mg, 1.245 mmol, 3 eq) in DMF (1.5 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes; UV 254 nm. This yielded methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylate (180 mg, 77%) as a yellow oil. LCMS(ESI)[M+H] + :562. Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylic acid [ka]

[0257] LiOH (36 mg, 1.5 mmol, 5 eq) was added at room temperature to a stirred solution of methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylate (170 mg, 0.3 mmol, 1 eq) and H2O (1 mL) in THF (1 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 40% gradient over 200 mins; UV 254 nm. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid (150 mg, 90%) as a white solid. LCMS(ESI)[M+H] + :548. Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(hydrazinecarbonyl)-piperidine [ka]

[0258] To a stirred solution of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine-(5R)-carboxylic acid (140 mg, 0.26 mmol, 1 eq), DIEA (40 mg, 0.31 mmol, 1.2 eq), and HATU (116.6 mg, 0.31 mmol, 1.2 eq) in DMF (1.5 mL), diimine hydrate hydrogen (25.08 mg, 0.512 mmol, 2 eq) was added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes; using UV 254 nm. This yielded 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(hydrazinecarbonyl)-piperidine (115 mg, 80%) as a yellow oil. LCMS(ESI)[M+H] + :562. Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine [ka]

[0259] To a stirred solution of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(hydrazinecarbonyl)-piperidine (150 mg, 0.27 mmol, 1 eq) in triethyl orthoformate (1.5 mL), p-toluenesulfonic acid (4.6 mg, 0.027 mmol, 0.1 eq) was added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 125 °C for 20 minutes. The residue was purified by reverse flash chromatography using UV 254 nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 50% gradient over 20 minutes. This yielded 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine (70 mg, 45%) as a white solid. LCMS(ESI)[M+H] + :572. Synthesis of compound 45 [ka]

[0260] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine (65 mg, 0.11 mmol, 1 eq) in DCM (0.5 mL), TFA (0.5 mL) was added at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 30 minutes. The mixture was basicized to pH 8 using saturated Na2CO3 (aqueous solution). The crude product (65 mg) was purified by prep-HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH--HPLC; flow rate: 25 mL / min; gradient: 45%B~67%B, 67%B, 7 mins; wavelength: 220 nm; RT1 (min): 6.06; runs: 0) to obtain compound 45 (29 mg, 54%) as a white solid. LC-MS(ESI)[M+H] + :472.20. 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.65(d,J=16.3Hz,1H),6.49(s,1H),5. 60(d,J=64.0Hz,1H),4.16-3.73(m,3H),3.28-3.15(m,3H),3.10-2.80(m,3H ),2.71-2.55(m,1H),2.36-2.19(m,4H),2.17-1.97(m,3H),1.97-1.53(m,2H ),1.07-0.95(m,2H),0.90(d,J=6.6Hz,4H),0.76(s,2H),0.69-0.56(m,2H). Example 38. (3S)-{N-(2-methylpropyl),N-{2-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine (Compound 46) [ka] Synthesis of ethyl 2-cyclopropyl-4-oxo-5H-pyrimidine-5-carboxylate [ka]

[0261] To a stirred solution of cyclopropanecarboximamide (1 g, 12 mmol, 1.0 eq) in ethanol (20 mL), 1,3-diethyl 2-(ethoxymethylidene)propanediote (3.1 g, 14.3 mmol, 1.2 eq) was added at room temperature under a nitrogen atmosphere. The resulting mixture was then stirred overnight at room temperature under a nitrogen atmosphere. The mixture was acidified to pH 6 with HCl (2 M). The aqueous layer was extracted with toluene (3 × 30 mL). The mixed organic layers were dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to obtain ethyl 2-cyclopropyl-4-oxo-5H-pyrimidine-5-carboxylate (750 mg, 30%) as a white solid. LCMS(ESI)[M+H] + :209. Synthesis of ethyl 4-chloro-2-cyclopropylpyrimidine-5-carboxylate [ka]

[0262] To a stirred solution of ethyl 2-cyclopropyl-4-oxo-5H-pyrimidine-5-carboxylate (750 mg, 3.6 mmol, 1.0 eq) in triethylamine (10 mL), phosphorus oxychloride (2761 mg, 18 mmol, 5.0 eq) was added at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was extracted with Â10 mL (30 mL). The mixed organic layers were washed with water (3 × 30 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure and purified by reverse-phase flash chromatography using UV 254 nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes. This yielded ethyl 4-chloro-2-cyclopropylpyrimidine-5-carboxylate (300 mg, 37%) as a yellow oil. LCMS(ESI)[M+H] + :227. Synthesis of ethyl 2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]aminopyrimidine-5-carboxylate [ka]

[0263] To a stirred solution of ethyl 4-chloro-2-cyclopropylpyrimidine-5-carboxylate (300 mg, 1.32 mmol, 1.0 eq) and DIEA (513.2 mg, 3.97 mmol, 3.0 eq) in NMP (5 mL), (1R,3R)-3-methoxycyclobutane-1-amine hydrochloride (218.5 mg, 1.59 mmol, 1.2 eq) was added. The resulting mixture was stirred at 140 °C under a nitrogen atmosphere for 4 hours. After the reaction was complete, the residue was purified by reverse-phase flash chromatography using UV 254 nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes, to obtain ethyl 2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]aminopyrimidine-5-carboxylate (150 mg, 39%) as a yellow oil. LCMS(ESI)[M+H] +:292. Synthesis of 2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]aminopyrimidine-5-carboxylic acid [ka]

[0264] To a stirred solution of ethyl 2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]aminopyrimidine-5-carboxylate (150 mg, 0.51 mmol, 1.0 eq) and H2O (1 mL) in THF (2 mL), lithium hydrate (108 mg, 2.57 mmol, 5.0 eq) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was acidified to pH 6 with citric acid and purified by reverse-phase flash chromatography using UV 254 nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 60% gradient over 20 minutes to obtain 2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]aminopyrimidine-5-carboxylic acid (120 mg, 89%) as a yellow oil. LCMS(ESI)[M+H] + :264. 1 H NMR(300MHz,DMSO-d6)δ13.24(s,1H),8.56(s,1H),8.44(s,1H),4.66-4.47(m,1H),4.06-3.9 2(m,1H),3.16(s,3H),2.41-2.27(m,2H),2.28-2.11(m,2H),2.00(m,1H),1.08-0.93(m,4H). Synthesis of methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-piperidine-(5R)-carboxylate [ka]

[0265] Compound A (143.3 mg, 0.45 mmol, 1.0 eq) was added to a stirred solution of 2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]aminopyrimidine-5-carboxylic acid (120 mg, 0.45 mmol, 1.0 eq), DIEA (17.6 mg, 0.14 mmol, 3.0 eq), and HATU (207.9 mg, 0.55 mmol, 1.2 eq) in DMF (4 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. After the reaction was complete, the residue was purified by reverse-phase flash chromatography using UV254nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 10 minutes to obtain methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}aminopiperidine-(5R)-carboxylate (130 mg, 51%) as a yellow solid. LCMS(ESI)[M+H] + :560. Synthesis of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-piperidine-(5R)-carboxylic acid [ka]

[0266] Lithium hydrate (48.7 mg, 1.16 mmol, 5.0 eq) was added to a stirred solution of methyl 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}aminopiperidine-(5R)-carboxylate (130 mg, 0.23 mmol, 1.0 eq) and H2O (1 mL) in THF (2 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. After the reaction was complete, the mixture was acidified to pH 6 with citric acid and purified by reverse-phase flash chromatography using UV254nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 20 minutes; to obtain 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}aminopiperidine-(5R)-carboxylic acid (100 mg, 79%) as a yellow oil. LCMS(ESI)[M+H] + :545. 1 H NMR(400MHz,DMSO-d6)δ12.56(s,1H),7.92(s,1H),6.98(s,1H),4.59-4.45(m,1H),4.13-3.89(m,3H),3.87-3.46(m,2 H),3.23-3.09(m,5H),2.80-2.57(m,1H),2.39-2.12(m,6H),2.01-1.88(m,3H),1.45-1.21(m,9H),1.00-0.73(m,10H). Synthesis of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{2-tert-butyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine [ka]

[0267] (3S)-3-methylmorpholine (22.2 mg, 0.22 mmol, 1.2 eq) was added to a stirred solution of 1-tert-butoxylcarbonyl-(3S)-{N-(2-methylpropyl),N-{2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}aminopiperidine-(5R)-carboxylic acid (100 mg, 0.18 mmol, 1.0 eq), DIEA (71 mg, 0.55 mmol, 3.0 eq), and HATU (84 mg, 0.22 mmol, 1.2 eq) in DMF at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After the reaction was complete, the residue was purified by reverse-phase flash chromatography using UV254nm under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 0% to 60% gradient over 10 minutes, to obtain 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{2-tert-butyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine (95 mg, 82%) as a yellow solid. LCMS(ESI)[M+H] + :629. 1 ¹H NMR (400MHz, chloroform-d) δ 8.00 (s, 1H), 6.81 (d, J=37.0Hz, 1H), 4.66-4.50 (m, 1H), 4.07-3.98 (m, 2H), 3.98-3.84 (m, 2H), 3.80-3.68 (m, 1H), 3.68-3.46 (m, 3H), 3.2 6(s,3H),3.21-2.89(m,3H),2.85-2.52(m,3H),2.51-2.25(m,6H),2.24-2.12(m, 2H),2.02-1.84(m,2H),1.51-1.34(m,9H),1.30-1.21(m,3H)1.18-0.83(m,10H). Synthesis of compound 46 [ka]

[0268] To a stirred solution of 1-tert-butoxycarbonyl-(3S)-{N-(2-methylpropyl),N-{2-tert-butyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine (95 mg, 0.11 mmol, 1.0 eq) in DCM (2 mL), TFA (0.5 mL) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 20 minutes. The mixture was basicized to pH 9 using saturated Na2CO3 (aqueous solution). The aqueous layer was extracted with ELISA (3 × 10 mL). The mixed organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC under the following conditions to obtain compound 46 (37 mg, 46%) as a white solid. LCMS(ESI)[M+H] + :529.30. 1 H NMR(400MHz,DMSO-d6)δ7.89(s,1H),6.91(s,1H),4.58-4.43(m,1H),4.41-4.28(m,1 H),4.05-3.87(m,2H),3.85-3.74(m,1H),3.61(d,J=11.5Hz,2H),3.48-3.37(m,1H),3 .28-3.18(m,1H),3.17-3.05(m,5H),2.92-2.53(m,5H),2.39-2.13(m,6H),2.07-1.8 6(m,3H),1.87-1.72(m,1H),1.24-1.03(m,3H),0.98-0.89(m,4H),0.88-0.70(m,6H). Example 39. Exemplary inhibitory effects of compounds of the present disclosure.

[0269] Exemplary compounds of this disclosure were tested for their inhibitory effects on human renin activity using a commercially available renin assay kit (SensoLyte® 520 Renin Assay Kit Fluorimetric) in accordance with the product's instructions for use.

[0270] In short, recombinant human renin (from the kit) was incubated with the compound or buffer of this disclosure at 37°C for 30 minutes before substrate addition. After incubation at 37°C for 15 minutes, fluorescence intensity was measured at 530 nm. The data was analyzed by Prism, and IC50 was obtained. 50 An S-shaped curve was used for the calculation.

[0271] The results are summarized in Table 2. Table 2. Exemplary inhibitory effects of compounds in this disclosure on human renin activity. [Table 2]

[0272] The present invention has been illustrated by the above description and examples. The examples are not intended to be limiting in any way. As used throughout, ranges are used as a simplified notation to describe each individual value within a range. Any value within a range can be selected as the end of the range.

Claims

1. Equation I 【Chemistry 1】 Compounds or geometric isomers thereof, pharmaceutically acceptable isotopic isomers, salts, prodrugs, or solvates thereof R １ and R ２ are each independently a hydrogen atom, a deuterium atom, a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an optionally substituted C １～６ alkyl group, an optionally substituted C ２～６ alkenyl group, an optionally substituted C ２～６ alkynyl group, an optionally substituted C １～３ alkylthio group, an optionally substituted C １～３ alkylsulfinyl group, an optionally substituted C １～３ alkylsulfonyl group, an optionally substituted C １～６ alkoxy group, an optionally substituted C １～６ alkoxy C １～６ alkyl group, an optionally substituted C １～３ alkyl C １～６ alkoxy group, an optionally substituted C ３～６ cycloalkyl group, an optionally substituted C １～３ alkyl C ３～６ cycloalkyl group, an optionally substituted amino group, an optionally substituted C １～３ alkylamino group, an optionally substituted mercapto group, an optionally substituted aminocarbonyl group, an optionally substituted carbonyl group, an optionally substituted C １～６ alkylcarbonyl group, or an optionally substituted C １～３ alkoxycarbonyl group, n is 0, 1, 2, or 3. X is a methylene group, an oxygen atom, an amine group, a sulfinyl group, or a sulfonyl group. Ring A consists of one or more N, O, S, SO, and SO ２ A optionally substituted 5 or 6-membered heteroring containing, R ３ C is a hydrogen atom, deuterium atom, halogen atom, hydroxyl group, carboxyl group, or optionally substituted C １～６ Alkyl alkyl groups, optionally substituted C ３～６ Cycloalkyl groups, optionally substituted C ２～６ Alkenyl group, optionally substituted C ２～６ Alkynyl group, optionally substituted C １～６ Alkoxy groups, optionally substituted amino groups, optionally substituted mercapto groups, optionally substituted aminocarbonyl groups, optionally substituted C １～６ Alkylcarbonyl group, optionally substituted C １～６ Alkoxy C １～６ Alkyl alkyl groups, or optionally substituted C １～３ It is an alkoxycarbonyl group, R ４ This includes hydrogen atoms, halogen atoms, deuterium atoms, hydroxyl groups, cyano groups, optionally substituted amino groups, and optionally substituted C １～６ Alkyl alkyl groups, optionally substituted C １～６ Haloalkyl groups, optionally substituted C ２～６ Alkenyl group, optionally substituted C ２～６ Alkynyl group, optionally substituted mercapto group, optionally substituted C １～６ Alkyl sulfinyl group, optionally substituted C １～３ Alkylsulfonyl group, optionally substituted C １～６ Alkoxy groups, optionally substituted C １～６ Haloalkoxy group, optionally substituted C ３～６ Cycloalkyl groups, optionally substituted aminocarbonyl groups, optionally substituted C １～６ Alkylcarbonyl group, optionally substituted C １～６ Haloalkylcarbonyl group, optionally substituted C １～３ Alkoxycarbonyl group, optionally substituted C １～３ Haloalkoxycarbonyl group, optionally substituted C １～６ Alkoxy C １～６ Alkyl alkyl groups, optionally substituted C １～６ Haloalkoxy C １～６ Alkyl group, 4-6 member heterocyclic substituted formyl group, where the 4-6 member heterocyclic group is one or more N, O, S, SO, and SO ２ Optionally substituted 3- to 6-membered cyclic hydrocarbon groups, optionally substituted 5 or 6-membered heterorings, where the heteroring is one or more N, O, S, SO, and SO ２ It may contain, or is an optionally substituted amide group, R ５ C is a hydrogen atom, deuterium atom, halogen atom, hydroxyl group, cyano group, mercapto group, or optionally substituted C １～３ Alkyl sulfinyl group, optionally substituted C １～３ Alkylsulfonyl group, optionally substituted C １～３ Haloalkylsulfonyl group, optionally substituted amino group, optionally substituted C １～６ Alkyl alkyl groups, optionally substituted C １～６ Haloalkyl groups, optionally substituted C ２～６ Alkenyl group, optionally substituted C ２～６ Alkynyl group, optionally substituted C １～６ Alkoxy groups, optionally substituted C １～６ Haloalkoxy group, optionally substituted C ３～６ Cycloalkyl groups, optionally substituted C ３～６ Halocycloalkyl groups, optionally substituted C １～３ Alkylthio group, optionally substituted C １～３ Alkyl sulfinyl group, optionally substituted C １～３ Haloalkylsulfinyl group, optionally substituted C ３～４ Cycloalkyl groups, optionally substituted aminocarbonyl groups, optionally substituted C １～６ Alkylcarbonyl group, optionally substituted C １～６ Alkoxy C １～６ Alkyl alkyl groups, optionally substituted C １～６ Haloalkoxy C １～６ Alkyl alkyl groups, optionally substituted C １～３ Alkoxycarbonyl group, or optionally substituted C １～３ It is a haloalkoxycarbonyl group. Compounds or their geometric isomers, pharmaceutically acceptable isotopic isomers, salts, prodrugs, or solvates.

2. The compound according to claim 1, or a geometric isomer, pharmaceutically acceptable isotopic isomer, salt, prodrug, or solvate thereof, wherein ring A is an optionally substituted five or six-membered unsaturated heteroring containing one or two atoms selected from N, O, and S.

3. Ring A is as follows: 【Chemistry 2】 It is one of them, R １ ', R ２ ', and R ３ ' are independently a hydrogen atom, a deuterium atom, a halogen atom, a cyano group, a hydroxyl group, an optionally substituted C １～６ alkyl group, an optionally substituted C １～６ haloalkyl group, an optionally substituted C ２～６ alkenyl group, an optionally substituted C ２～６ haloalkenyl group, an optionally substituted C ２～６ alkynyl group, an optionally substituted C ２～６ haloalkynyl group, an optionally substituted C ３～６ cycloalkyl group, an optionally substituted C １～６ alkylsulfinyl group, an optionally substituted C １～６ haloalkylsulfinyl group, an optionally substituted C １～６ alkylsulfonyl group, an optionally substituted C １～６ haloalkylsulfonyl group, an optionally substituted C １～６ alkoxy group, an optionally substituted C １～６ haloalkoxy group, an optionally substituted amino group, an optionally substituted C １～６ alkylcarbonyl group, an optionally substituted C １～６ haloalkylcarbonyl group, an optionally substituted C １～３ alkoxycarbonyl group, an optionally substituted C １～３ haloalkoxycarbonyl group, an optionally substituted C １～６ alkoxyC １～６ alkyl group, an optionally substituted C １～６ haloalkoxyC １～６ alkyl group, or an optionally substituted 5- or 6-membered heterocycle containing one or more N, O, S, SO, and SO ２ and is optionally substituted The compound described in claim 2, or its geometric isomers, pharmaceutically acceptable isotopic isomers, salts, prodrugs, or solvates.

4. R １ and R ２ These are independently a hydrogen atom, a halogen atom, a hydroxyl group, and C １～６ alkyl group, C １～６ Haloalkyl group, unsubstituted or halogen atom, C １～３ Alkyl groups, and C １～３ C substituted with one or more C selected from the group consisting of haloalkyl groups ３～６ Cycloalkyl groups, unsubstituted or halogen atoms, C １～３ Alkyl groups, and C １～３ C substituted with one or more C selected from the group consisting of haloalkyl groups １～６ alkoxy group, unsubstituted or halogen atom, C １～３ Alkyl groups, and C １～３ One or more substituted amino groups selected from the group consisting of haloalkyl groups, unsubstituted or halogen atoms, C １～３ Alkyl groups, and C １～３ One or more substituted aminocarbonyl groups selected from the group consisting of haloalkyl groups, C １～６ Alkylcarbonyl group, C １～６ Haloalkylcarbonyl group, C １～６ Alkoxy C １～６ alkyl group, C １～６ Haloalkoxy C １～６ alkyl group, C １～３ Alkoxycarbonyl group, or C １～３ The compound according to claim 1, or a geometric isomer thereof, a pharmaceutically acceptable isotopic isomer, a salt, a prodrug, or a solvate thereof, which is a haloalkoxycarbonyl group.

5. R １ ', R ２ ', and R ３ ' is independently a hydrogen atom, a halogen group, a hydroxyl group, and C １～６ alkyl group, C １～６ Haloalkyl group, unsubstituted or halogen atom, C １～３ Alkyl groups, and C １～３ C substituted with one or more C selected from the group consisting of haloalkyl groups ３～６ Cycloalkyl groups, unsubstituted or halogen atoms, C １～３ Alkyl groups, and C １～３ C substituted with one or more C selected from the group consisting of haloalkyl groups １～６ Alkoxy group, C １～６ Haloalkoxy group, amino group, C １～６ Alkylcarbonyl group, C １～６ Haloalkylcarbonyl group, C １～３ Alkoxycarbonyl group, C １～３ Haloalkoxycarbonyl group, C １～６ Alkoxy C １～６ Alkyl alkyl group, or C １～６ Haloalkoxy C １～６ The compound according to claim 3, or a geometric isomer thereof, a pharmaceutically acceptable isotopic isomer, a salt, a prodrug, or a solvate, which is an alkyl group.

6. R ３ is a hydrogen atom, deuterium atom, halogen atom, unsubstituted, or halogen atom, C １～３ Alkyl groups, and C １～３ C substituted with one or more C selected from the group consisting of haloalkyl groups １～６ Alkyl alkyl group, unsubstituted or halogen atom, C １～３ Alkyl groups, and C １～３ C substituted with one or more C selected from the group consisting of haloalkyl groups ３～６ Cycloalkyl groups, unsubstituted or halogen atoms, C １～３ Alkyl groups, and C １～３ C substituted with one or more C selected from the group consisting of haloalkyl groups １～６ alkoxy group, unsubstituted or halogen atom, C １～３ Alkyl groups, and C １～３ One or more substituted amino groups, aminocarbonyl groups, C selected from the group consisting of haloalkyl groups. １～６ Alkylcarbonyl group, C １～６ Alkoxy C １～６ Alkyl alkyl group, or C １～３ The compound according to claim 1, or a geometric isomer thereof, a pharmaceutically acceptable isotopic isomer, a salt, a prodrug, or a solvate thereof, which is an alkoxycarbonyl group.

7. R ４ is either unsubstituted or a halogen atom, C １～３ Alkyl groups, and C １～３ One or more substituted 3- to 6-membered cyclic hydrocarbon groups selected from the group consisting of haloalkyl groups; N, O, S, SO, and SO ２ It contains one or more selected from the group consisting of, and is unsubstituted, or a halogen atom, a hydroxyl group, C １～６ alkyl group, C １～６ Haloalkyl group, C ３～６ Cycloalkyl groups, C ３～６ Halocycloalkyl groups, hydroxyl C １～６ Alkyl alkyl, hydroxyl C ３～６ Cycloalkyl groups, C １～６ Alkylcarbonyl group, C ３～６ Halocycloalkylcarbonyl group, C １～６ Haloalkyl group, C ３～６ Halocycloalkyl group, C １～６ Haloalkylcarbonyl group, C ３～６ Halocycloalkylcarbonyl group, C １～３ Alkoxy C １～３ alkyl group, C １～６ Alkylamino group, N, O, S, SO, and SO ２ It contains one or more selected from the group consisting of, and is unsubstituted or a halogen atom, C １～３ Alkyl groups, and C １～３ A 3- or 6-membered heterocycle substituted with a haloalkyl group, and an unsubstituted or halogen atom, C １～３ Alkyl groups, and C １～３ A 5 or 6-membered unsaturated heterocycle substituted by one or more 3- to 6-membered cyclic hydrocarbon groups selected from the group consisting of haloalkyl groups; a 4- to 6-membered heterocycle-substituted formyl group, where the heterocycle is N, O, S, SO, and SO ２ It contains one or more selected from the group consisting of, and is unsubstituted, or a halogen atom, a hydroxyl group, C １～６ alkyl group, C １～６ Haloalkyl group, C ３～６ Cycloalkyl groups, C ３～６ Halocycloalkyl group, C １～６ Alkoxy group, C １～６ Haloalkoxy group, hydroxyl C １～６ Alkyl alkyl, hydroxyl C ３～６ Cycloalkyl groups, C １～６ Alkylcarbonyl group, C ３～６ Halocycloalkylcarbonyl group, C １～６ Haloalkyl group, C ３～６ Halocycloalkyl group, C １～６ Haloalkylcarbonyl group, C ３～６ Halocycloalkylcarbonyl group, C １～３ Alkoxy C １～３ Alkyl groups, and C １～６ Substituted by one or more selected from the group consisting of alkylamino groups; or hydroxyl C １～６ The compound according to claim 1, or its geometric isomers, pharmaceutically acceptable isotopic isomers, salts, prodrugs, or solvates, which are alkyl groups.

8. R ５ is a hydrogen atom, a halogen atom, a hydroxyl group, C １～６ Alkoxy group, C １～６ Haloalkoxy group, unsubstituted or halogen atom, C １～３ Alkyl groups, and C １～３ One or more substituted amino groups selected from the group consisting of haloalkyl groups, C １～６ alkyl group, C １～６ Haloalkyl group, unsubstituted or halogen atom, C １～３ Alkyl groups, and C １～３ C substituted with one or more C selected from the group consisting of haloalkyl groups ３～６ Cycloalkyl groups, C １～３ Alkyl sulfinyl group, C １～３ Haloalkylsulfinyl group, C １～３ Alkyl sulfonyl group, C １～３ Haloalkylsulfonyl group, unsubstituted or halogen atom, C １～３ Alkyl groups, and C １～３ One or more substituted aminocarbonyl groups selected from the group consisting of haloalkyl groups, C １～６ Alkylcarbonyl group, C １～６ Alkoxy C １～６ alkyl group, C １～６ Haloalkoxy C １～６ alkyl group, C １～３ Alkoxycarbonyl group, or C １～３ The compound according to claim 1, or a geometric isomer thereof, a pharmaceutically acceptable isotopic isomer, a salt, a prodrug, or a solvate thereof, which is a haloalkoxycarbonyl group.

9. Formula II 【Transformation 3】 Compounds or geometric isomers thereof, pharmaceutically acceptable isotopic isomers, salts, prodrugs, or solvates thereof R １ , R ２ , R ３ , R ５ X, n, and ring A are defined as in claim 1, R ６ and R ７ These are independently hydrogen atoms, deuterium atoms, halogen atoms, cyano groups, hydroxyl groups, and optionally substituted C １～３ Alkyl alkyl groups, optionally substituted C ３～６ Cycloalkyl groups, or optionally substituted C １～３ It is an alkoxy group. Compounds or their geometric isomers, pharmaceutically acceptable isotopic isomers, salts, prodrugs, or solvates.

10. R ６ and R ７ These are independently a hydrogen atom, a deuterium atom, a halogen atom, a cyano group, a hydroxyl group, and C １～３ alkyl group, C １～３ Haloalkyl group, C ３～６ Cycloalkyl groups, C ３～６ Halocycloalkyl group, C １～３ Alkoxy group, or C １～３ A compound according to claim 9, or a geometric isomer thereof, a pharmaceutically acceptable isotopic isomer, a salt, a prodrug, or a solvate thereof, which is a haloalkoxy group.

11. (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3-fluoroazetidine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3,3-difluoropyrrolidine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(4,4-difluoropiperidine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(4-trifluoromethoxypiperidine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3R)-methylmorpholine-N-carbonyl]-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(2,2-dimethylmorpholine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{2-tert-butyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclobutylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3,3-difluorocyclobutyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}aminopiperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[(3S)-ethylmorpholine-N-carbonyl]-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,2,4-oxadiazole-3-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(3-methyl-1,2,4-oxadiazole-5-yl)-piperidine, (3S)-[N-(2-methylpropyl),N-(5-cyclopropyl-3-(oxetane-3-ylamino)pyridine-2-carbonyl)]amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-{N-(2-methylpropyl),N-[3-(3-trans-methoxy)cyclobutyl]aminopyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}amino-(5R)-[(3S)-3-methylmorpholine-4-carbonyl]-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-[5-(oxetan-3-yl)-1,3,4-oxadiazole-2-yl]-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-hydroxymethyl-piperidine, (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}aminopiperidine, (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(3-methyl-1,2,4-oxadiazole-5-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,2,4-oxadiazole-3-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-cyclopropylmethyl,N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(5-methyl-1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(1,2,4-oxadiazole-3-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-[5-trifluoromethyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-(5R)-(morpholine-N-carbonyl)-piperidine, (3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine, (3S)-{N-(2-methylpropyl),N-{5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazole-2-yl)-piperidine, and (3S)-{N-(2-methylpropyl),N-{2-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyrimidine-5-carbonyl}amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine A compound according to claim 1 or a geometric isomer thereof, a pharmaceutically acceptable isotopic isomer, a salt, a prodrug, or a solvate, selected from the group consisting of the above.

12. A pharmaceutical composition comprising an effective amount of the compound described in claim 1, or a geometric isomer, pharmaceutically acceptable isotopic isomer, salt, prodrug, or solvate thereof, and a pharmaceutically acceptable carrier.

13. A method for inhibiting renin activity in a subject requiring such inhibition, comprising the step of administering the pharmaceutical composition according to claim 12 to the subject.

14. A method for treating a disease associated with renin activity in a subject requiring such treatment, comprising the step of administering the pharmaceutical composition according to claim 12 to the subject.

15. The method according to claim 14, wherein the disease is hypertension, cardiovascular disease, diabetic nephropathy, or heart failure.

16. The method according to claim 15, wherein the disease is hypertension.

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