SUBSTITUTED PIPERIDINE COMPOUNDS AS RENIN INHIBITORS

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

INCORPORATION BY REFERENCE

All documents cited or referenced herein (including without limitation all literature documents, patents, published patent applications cited herein) (“herein cited documents”), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. Any Genbank sequences mentioned in this disclosure are incorporated by reference with the Genbank sequence to be that of the earliest effective filing date of this disclosure.

FIELD OF THE INVENTION

This application relates to novel 3, 5-substituted piperidine compounds and their derivatives, which have superior renin inhibitory activity over prior art molecules. The compounds, and their derivatives of the disclosure are useful for the treatment of diseases associated with renin activity, particularly diseases associated with excessive renin activity.

BACKGROUND OF THE INVENTION

The renin-angiotensin-aldosterone system (RAAS) plays a critical role in the regulation of cardiovascular and renal physiology. A cascade of events of this system begins with conversion of angiotensinogen to angiotensin I by plasma renin, a circulating aspartic protease synthesized in juxtaglomerular epithelioid cells and released in granules in a controlled manner, then to angiotensin II catalyzed by the angiotensin-converting enzyme (ACE) expressed on the surface of vascular endothelial cells (Castrop H et al., (2010)Physiol. Rev.90(2): 607-673). Angiotensin II may bind the angiotensin type-1 receptor to induce increased sodium retention, vasoconstriction, and aldosterone secretion (Ames M K et al., (2019)J Vet Intern Med.33(2): 363-382). While aldosterone, the terminal hormone of the RAAS, is the key regulator of sodium, potassium and body fluid balance, its release may trigger sodium reabsorption by renal tubules, followed by water reabsorption into the blood and extracellular fluid volume increase in the body (Seelinger E. et al., (2005)Clin Exp Pharmacol Physiol.32 (5-6): 394-399).

The renin-angiotensin-aldosterone system is stimulated under normal conditions in response to threats that compromise blood pressure stability, and its chronic activation may cause pathologic remodeling and dysfunction in cardiovascular and renal tissues, leading to cardiovascular disease, hypertension, diabetic kidney disease, heart failure, or other tissue/organ pathological conditions (Ames M K et al., (2019) supra).

RAAS suppression is a key strategy to relieve these conditions. Inhibitors to RRAS or its components include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and renin inhibitors. Among them, the renin inhibitors that block the first and rate-limiting step of RAAS activation attracted much attention since 1970s. However, it took the scientists about three decades to find the first and only potent one with acceptable oral bioavailability, aliskiren, which is approved in 2007 for clinical treatment of hypertension (Jensen C. et al., (2008)Nat Rev Drug Discov7(5): 399-410). Angioedema, high blood potassium level, diarrhea, headache, dizziness and cough were observed as adverse effects in patients taking aliskiren.

More renin inhibitors having improved oral bioavailability, specificity, and efficacy with less severe side effects are needed.

SUMMARY OF THE INVENTION

The present inventors have invented 3, 5-substituted piperidine compounds that have superior inhibitory effects on renin activity and are useful for prophylaxis or treatment of diseases associated with renin activity, e.g., excessive renin activity.

In one aspect, the present application relates to compounds of Formula I, or their respective geometric isomers, and pharmaecutically acceptable isotopic isomers, salts, prodrugs and solvates thereof,

wherein R1and R2may be independently a hydrogen atom, a deuterium atom, a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an optionally substituted C1-6alkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-3alkylthio group, an optionally substituted C1-3alkylsulfinyl group, an optionally substituted C1-3alkylsulfonyl group, an optionally substituted C1-6alkoxy group, an optionally substituted C1-6alkoxyC1-6alkyl group, an optionally substituted C1-3alkyl C1-6alkoxy group, an optionally substituted C3-6cycloalkyl group, an optionally substituted C1-3alkyl C3-6cycloalkyl group, an optionally substituted amino group, an optionally substituted C1-3alkyl amino group, an optionally substituted mercapto group, an optionally substituted aminocarbonyl group, an optionally substituted carbonyl group, an optionally substituted C1-6alkyl carbonyl group, or an optionally substituted C1-3alkoxycarbonyl 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 that contains one or more N, O, S, SO and SO2,
R3may be a hydrogen atom, a deuterium atom, a halogen atom, a hydroxyl group, a carboxyl group, an optionally substituted C1-6alkyl group, an optionally substituted C3-6cycloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-6alkoxy group, an optionally substituted amino group, an optionally substituted mercapto group, an optionally substituted aminocarbonyl group, an optionally substituted C1-6alkylcarbonyl group, an optionally substituted C1-6alkoxyC1-6alkyl group, or an optionally substituted C1-3alkoxycarbonyl group,
R4may be a hydrogen atom, a halogen atom, a deuterium atom, a hydroxyl group, a cyano group, an optionally substituted amino group, an optionally substituted C1-6alkyl group (e.g., a hydroxyl C1-6alkyl group), an optionally substituted C1-6haloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted mercapto group, an optionally substituted C1-6alkylsulfinyl group, an optionally substituted C1-6alkylsulfonyl group, an optionally substituted C1-6alkoxy group, an optionally substituted C1-6haloalkoxy group, an optionally substituted C3-6cycloalkyl group, an optionally substituted aminocarbonyl group, an optionally substituted C1-6alkylcarbonyl group, an optionally substituted C1-6haloalkylcarbonyl group, an optionally substituted C1-3alkoxycarbonyl group, an optionally substituted C1-3haloalkoxycarbonyl group, an optionally substituted C1-6alkoxyC1-6alkyl group, an optionally substituted C1-6haloalkoxyC1-6alkyl group, a 4- to 6-membered heterocycle substituted formyl group wherein the 4 to 6-membered heterocycle may contain one or more N, O, S, SO, and SO2and may be optionally substituted, an optionally substituted 3 to 6-membered cyclic hydrocarbon group, an optionally substituted 5- or 6-membered heterocycle, saturated or unsaturated, wherein the heterocycle may contain one or more N, O, S, SO, and SO2, or an optionally substituted amide group, and
R5may be a hydrogen atom, a deuterium atom, a halogen atom, a hydroxyl group, a cyano group, a mercapto group, an optionally substituted C1-3alkylsulfinyl group, an optionally substituted C1-3alkylsulfonyl group, an optionally substituted C1-3haloalkylsulfonyl group, an optionally substituted amino group, an optionally substituted C1-6alkyl group, an optionally substituted C1-6haloalkyl group, an optionally substituted C2-6alkenyl group, an optionally substituted C2-6alkynyl group, an optionally substituted C1-6alkoxy group, an optionally substituted C1-6haloalkoxy group, an optionally substituted C3-6cycloalkyl group, an optionally substituted C3-6halocycloalkyl group, an optionally substituted C1-3alkylthio group, an optionally substituted C1-3alkylsulfinyl group, an optionally substituted C1-3haloalkylsulfinyl group, an optionally substituted C3-4cycloalkyl group, an optionally substituted aminocarbonyl group, an optionally substituted C1-6alkylcarbonyl group, an optionally substituted C1-6alkoxyC1-6alkyl group, an optionally substituted C1-6haloalkoxyC1-6alkyl group, an optionally substituted C1-3alkoxycarbonyl group, or an optionally substituted C1-3haloalkoxycarbonyl group.

R1and R2may attach to the same carbon atom or different carbon atoms.

When X is a methylene group, it may be substituted by R1and/or R2,

R1and R2may independently have one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a hydroxyl C1-6alkyl group, a C1-6alkoxy group, a C1-6haloalkoxy group, a C1-3alkoxyC1-3alkyl group, a C1-3haloalkoxyC1-3alkyl group, a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-6alkyl amino group, and a C1-6haloalkyl amino group.

R3may have one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a hydroxyl C1-6alkyl group, a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-3alkoxyC1-3alkyl group, a C1-3haloalkoxyC1-3alkyl group, a C1-6alkyl amino group, and a C1-6haloalkyl amino group.

Ring A may be an optionally substituted 5- or 6-membered heterocycle, partially unsaturated or unsaturated, containing one or more, e.g., one or two, N, O, S, SO and SO2. In certain embodiments, ring A may be an optionally substituted 6-membered heterocycle, partially unsaturated or unsaturated, containing one or more, e.g., one, two or three atoms selected from N, O and S. In certain embodiments, ring A may be an optionally substituted 6-membered heterocycle, partially unsaturated or unsaturated, containing one or more, e.g., one, two or three N atoms. 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 dioxin, an optionally substituted dithiin, or an optionally substituted triazine.

Ring A may have one or more, e.g., one or two, substituents selected from the group consisting of a deuterium atom, a halogen atom, a cyano group, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a C2-6alkenyl group, a C2-6haloalkenyl group, a C2-6alkynyl group, a C2-6haloalkynyl group, a C3-6cycloalkyl group, a C1-6alkylsulfinyl group, a C1-6haloalkylsulfinyl group, a C1-6alkylsulfonyl group, a C1-6haloalkylsulfonyl group, a C1-6alkoxy group, a C1-6haloalkoxy group, an amino group, a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-3alkoxycarbonyl group, a C1-3haloalkoxycarbonyl group, a C1-6alkoxyC1-6alkyl group, a C1-6haloalkoxyC1-6alkyl group, or an optionally substituted 5 or 6-membered heterocycle containing one or more N, O, S, SO, and SO2, wherein the substituents may be each further contain one or more, e.g., one or two, substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a C3-6cycloalkyl group, a hydroxyl C1-6alkyl group, a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-3alkoxyC1-3alkyl group, a C1-3haloalkoxyC1-3alkyl group, a C1-6alkyl amino group and a C1-6haloalkyl amino group. In certain embodiments, Ring A may have a C1-6alkyl group, as the substituent, which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group. In certain embodiments, Ring A may have a C3-6cycloalkyl group, as the substituent, which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group. In certain embodiments, Ring A may have an amino group, as the substituent, which may be unsubstituted or substituted with one or more selected from the group consisting of a C1-3alkyl group and a C1-3haloalkyl group.

In certain embodiments, ring A may be any one of following:

R1′, R2′, and R3′ may independently have one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a C3-6cycloalkyl group, a hydroxyl C1-6alkyl group, a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-3alkoxyC1-3alkyl group, a C1-3haloalkoxyC1-3alkyl group, a C1-6alkyl amino group and a C1-6haloalkyl amino group. In certain embodiments, R1′, R2′, and R3′ may be independently a C1-6alkyl group which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group. In certain embodiments, R1′, R2′, and R3′ may be independently a C3-6cycloalkyl group which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group. In certain embodiments, R1′, R2′, and R3′ may be independently an amino group which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group.

R4may have one or more substituents selected from the group consisting of a deuterium, a halogen atom, a hydroxyl group, a cyano group, an amino group, a halo-substituted amino group, a C1-6alkyl group, a C1-6haloalkyl group, a C3-6cycloalkyl group, a C3-6halocycloalkyl group, a C1-3alkyl C3-6cycloalkyl group, a C1-3haloalkyl C3-6cycloalkyl group, a hydroxyl C1-6alkyl group, a hydroxyl C3-6cycloalkyl group, a C1-6alkylcarbonyl group, a C1-6alkoxy group, a C1-6haloalkoxy group, a C1-6haloalkylcarbonyl group, a C3-6halocycloalkylcarbonyl group, a C1-3alkoxyC1-3alkyl group, a C1-6alkyl amino group, a C1-6haloalkyl amino group, a C1-3haloalkoxyC1-3alkyl group, and a 3- or 6-membered heterocycle which contains one or more selected from the group consisting of N, O, S, SO and SO2.

R5may attach to any carbon atom in the piperidine ring.

R5may have one or more substituents selected from the group consisting of a deuterium atom, a halogen atom, a hydroxyl group, an amino group, a C1-6alkyl group, a C1-6haloalkyl group, a hydroxyl C1-6alkyl group, a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-3alkoxyC1-6alkyl group, a C1-3haloalkoxyC1-6alkyl group, a C1-6alkyl amino group, and a C1-6haloalkyl amino group.

In certain embodiments, X may be a methylene group, an oxygen atom, or an amine group. When X is a methylene group, it may be unsubstituted or substituted by R1and/or R2.

In certain embodiments, n may be 0 or 1.

In certain embodiments, R1and R2may be independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a C3-6cycloalkyl group, a C1-6alkoxy group, an amino group, an aminocarbonyl group, a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-6alkoxyC1-6alkyl group, a C1-6haloalkoxyC1-6alkyl group, a C1-3alkoxycarbonyl group or a C1-3halolkoxycarbonyl group. In certain embodiments, these groups may each contain one or more, e.g., one or two, substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a hydroxyl C1-6alkyl group, a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-3alkoxyC1-3alkyl group, a C1-3haloalkoxyC1-3alkyl group, a C1-6alkylamino group and a C1-6haloalkylamino group. In certain embodiments, R1and R2may be independently a hydrogen atom, a halogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a C3-6cycloalkyl group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), a C1-6alkoxy group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), an amino group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), an aminocarbonyl group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-6alkoxyC1-6alkyl group, a C1-6haloalkoxyC1-6alkyl group, a C1-3alkoxycarbonyl group or a C1-3halolkoxycarbonyl group.

In certain embodiments, R1′, R2′, and R3′ may independently be a hydrogen atom, a halogen group, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a C3-6cycloalkyl group, a C1-6alkoxy group, a C1-6haloalkoxy group, an amino group, a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-3alkoxycarbonyl group, a C1-3haloalkoxycarbonyl group, a C1-6alkoxyC1-6alkyl group, a C1-6haloalkoxyC1-6alkyl group, or a 5- or 6-membered heterocycle containing one or more N, O, S, SO, and SO2. In certain embodiments, these groups may each contain one or more, e.g., one or two, substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a hydroxyl C1-6alkyl group, a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-3alkoxyC1-3alkyl group, a C1-3haloalkoxyC1-3alkyl group, a C1-6alkyl amino group, and a C1-6haloalkyl amino group. In certain embodiments, R1′, R2′, and R3′ may independently be a hydrogen atom, a halogen group, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a C3-6cycloalkyl group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), a C1-6alkoxy group, a C1-6haloalkoxy group, an amino group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-3alkoxycarbonyl group, a C1-3haloalkoxycarbonyl group, a C1-6alkoxyC1-6alkyl group, a C1-6haloalkoxyC1-6alkyl group, or a 5- or 6-membered heterocycle containing one or more N, O, S, SO, and SO2.

In certain embodiments, R3may be a hydrogen atom, a deuterium atom, a halogen atom, a C1-6alkyl group, a C3-6cycloalkyl group, a C1-6alkoxy group, an amino group, an aminocarbonyl group, a C1-6alkylcarbonyl group, a C1-6alkoxyC1-6alkyl group, or a C1-3alkoxycarbonyl group. In certain embodiments, these groups may each contain one or more, e.g., one or two, substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6alkyl group, a hydroxyl C1-6alkyl group, a C1-6alkylcarbonyl group, a C1-3alkoxyC1-3alkyl group, and a C1-6alkyl amino group. In certain embodiments, R3may be a hydrogen atom, a deuterium atom, a halogen atom, a C1-6alkyl group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), a C3-6cycloalkyl group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), a C1-6alkoxy group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), an amino group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), an aminocarbonyl group, a C1-6alkylcarbonyl group, a C1-6alkoxyC1-6alkyl group, or a C1-3alkoxycarbonyl group.

In certain embodiments, R4may be a hydrogen atom, a deuterium atom, a halogen atom, a hydroxyl group, an amino group, an optionally substituted C1-6alkyl group, an optionally substituted C3-6cycloalkyl group, an optionally substituted C1-6alkoxy group, an optionally substituted aminocarbonyl group, an optionally substituted C1-6alkylcarbonyl group, an optionally substituted C1-3alkoxycarbonyl group, an optionally substituted C1-6alkoxyC1-6alkyl group, an optionally substituted 3- to 6-membered cyclic hydrocarbon group, a 5- or 6-membered saturated or partially unsaturated heterocycle wherein the heterocycle may contain one or more, e.g., one, two or three, N, O, S, SO and SO2and optionally substituted by e.g., an optionally substituted C1-6alkyl group, an optionally substituted C3-6cycloalkyl group, an optionally substituted 3 to 6-membered cyclic hydrocarbon group, an optionally substituted 3- or 6-membered heterocycle which contains one or more N, O, S, SO and SO2, or a 4- to 6-membered heterocycle substituted formyl group wherein the heterocycle may contain one or more, e.g., one or two, N, O, S, SO, and SO2and optionally substituted by e.g., a halogen atom, an optionally substituted C1-6alkylcarbonyl group, an optionally substituted C1-6alkyl group.

In certain embodiments, these groups may each contain one or more, e.g., one or two, substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a C3-6cycloalkyl group, a C3-6halocycloalkyl group, a C1-6alkoxy group, a C1-6haloalkoxy group, a hydroxyl C1-6alkyl group, a hydroxyl C3-6cycloalkyl group, a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C3-6halocycloalkylcarbonyl group, a C1-3alkoxyC1-3alkyl group, a C1-6alkyl amino group, a C1-6haloalkyl amino group, and a C1-3haloalkoxyC1-3alkyl group. In certain embodiment, R4may be a 3 to 6-membered cyclic hydrocarbon group which is unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group; a 5- or 6-membered unsaturated heterocycle which contains one or more selected from the group consisting of N, O, S, SO and SO2and is unsubstituted or substituted by one or more selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a C3-6cycloalkyl group, a C3-6halocycloalkyl group, a hydroxyl C1-6alkyl group, a hydroxyl C3-6cycloalkyl group, a C1-6alkylcarbonyl group, a C3-6halocycloalkylcarbonyl group, a C1-6haloalkyl group, a C3-6halocycloalkyl group, a C1-6haloalkylcarbonyl group, a C3-6halocycloalkylcarbonyl group, a C1-3alkoxyC1-3alkyl group, a C1-6alkyl amino group, a 3- or 6-membered heterocycle which contains one or more selected from the group consisting of N, O, S, SO and SO2and is unsubstituted or substituted by a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group, and a 3 to 6-membered cyclic hydrocarbon group which is unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group; a 4- to 6-membered heterocycle substituted formyl group wherein the heterocycle contains one or more selected from the group consisting of N, O, S, SO, and SO2and is unsubstituted or substituted by one or more selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a C3-6cycloalkyl group, a C3-6halocycloalkyl group, a C1-6alkoxy group, a C1-6haloalkoxy group, a hydroxyl C1-6alkyl group, a hydroxyl C3-6cycloalkyl group, a C1-6alkylcarbonyl group, a C3-6halocycloalkylcarbonyl group, a C1-6haloalkyl group, a C3-6halocycloalkyl group, a C1-6haloalkylcarbonyl group, a C3-6halocycloalkylcarbonyl group, a C1-3alkoxyC1-3alkyl group, and a C1-6alkyl amino group; or a hydroxyl C1-6alkyl group.

In certain embodiments, R5may be a hydrogen atom, a halogen atom, a hydroxyl group, a C1-6alkoxy group, a C1-6haloalkoxy group, an amino group, a C1-6alkyl group, a C1-6haloalkyl group, a C3-6cycloalkyl group, a C1-3alkylsulfinyl group, a C1-3haloalkylsulfinyl group, a C1-3alkylsulfonyl group, a C1-3haloalkylsulfonyl group, an aminocarbonyl group, a C1-6alkylcarbonyl group, a C1-6alkoxyC1-6alkyl group, a C1-6haloalkoxyC1-6alkyl group, a C1-3alkoxycarbonyl group, or a C1-3haloalkoxycarbonyl group. In certain embodiments, these groups may each contain one or more, e.g., one or two, substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-6alkyl group, a C1-6haloalkyl group, a hydroxyl C1-6alkyl group, a C1-6alkylcarbonyl group, a C1-6haloalkylcarbonyl group, a C1-3alkoxyC1-6alkyl group, a C1-3haloalkoxyC1-6alkyl group, and an amino group. In certain embodiments, R5may be a hydrogen atom, a halogen atom, a hydroxyl group, a C1-6alkoxy group, a C1-6haloalkoxy group, an amino group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), a C1-6alkyl group, a C1-6haloalkyl group, a C3-6cycloalkyl group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), a C1-3alkylsulfinyl group, a C1-3haloalkylsulfinyl group, a C1-3alkylsulfonyl group, a C1-3haloalkylsulfonyl group, an aminocarbonyl group (which may be unsubstituted or substituted with one or more selected from the group consisting of a halogen atom, a C1-3alkyl group and a C1-3haloalkyl group), a C1-6alkylcarbonyl group, a C1-6alkoxyC1-6alkyl group, a C1-6haloalkoxyC1-6alkyl group, a C1-3alkoxycarbonyl group, or a C1-3haloalkoxycarbonyl group.

In another aspect, the present application relates to compounds of Formula II, or their respective geometric isomers, and pharmaceutically acceptable isotopic isomers, salts, prodrugs and solvates thereof,

R6and R7may independently have one or more, e.g., one or two, substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C1-3alkyl group, a C1-3haloalkyl group, a hydroxyl C1-3alkyl group, a C1-3alkoxy group, a C1-3haloalkoxy group, and an amino group.

In certain embodiments, R6and R7may be independently a hydrogen atom, a deuterium atom, a halogen atom, a cyano group, a hydroxyl group, a C1-3alkyl group, a C1-3haloalkyl group, a C3-6cycloalkyl group, a C3-6halocycloalkyl group, a C1-3alkoxy group, or a C1-3haloalkoxy group.

R6and R7may attach to the same atom in the ring.

In certain embodiments, the compound is (3S)—[N-(2-methylpropyl), N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-(5R)-[(3S)-methylmorpholine-N-carbonyl]-piperidine (Compound 21).

Also disclosed are the methods for preparing the compounds, the intermediate compounds, their respective geometric isomers, pharmaceutically acceptable isotopic isomers, salts, prodrugs and solvates thereof, of the disclosure, as well as pharmaceutical compositions comprising an effective amount of the compounds, their respective geometric isomers, pharmaceutically acceptable isotopic isomers, salts, prodrugs and solvates thereof, of the disclosure with a pharmaceutically acceptable carrier.

In a third aspect, the present application provides a method of using the compounds, their respective geometric isomers, pharmaceutically acceptable isotopic isomers, salts, prodrugs and solvates thereof, of the disclosure, as selective renin inhibitors, and for treatment of diseases associated with renin/RAAS activity such as hypertension, cardiovascular disease, diabetic kidney disease, and heart failure. The pharmaceutical composition of the disclosure may be used to inhibit renin activity, or the RAAS activity. The pharmaceutical composition of the disclosure may be used in preparation of a medicament for treating diseases associated with renin activity.

The present application provides a method for inhibiting renin activity in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of the disclosure. The subject may be human. The subject may suffer from a disease caused by abnormal renin activity, such as hypertension, cardiovascular disease, diabetic kidney disease, and heart failure. In certain embodiments, the subject may suffer from hypertension and related complications.

The present application provides a method for inhibiting RAAS activity in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of the disclosure. The subject may be human. The subject may suffer from a disease caused by abnormal RAAS activity, such as hypertension, cardiovascular disease, diabetic kidney disease, and heart failure. In certain embodiments, the subject may suffer from hypertension and related complications.

The present application provides a method for treating or alleviating a disease associated with renin/RAAS activity, e.g., abnormal renin/RAAS activity, in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of the disclosure. The subject may be human. The disease may be hypertension, cardiovascular disease, diabetic kidney disease, or heart failure. In certain embodiments, the disease is hypertension.

Other features and advantages of the instant disclosure will be apparent from the following detailed description and examples, which should not be construed as limiting. The contents of all references, Genbank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.

Accordingly, it is an object of the disclosure not to encompass within the disclosure any previously known product, process of making the product, or method of using the product such that Applicants reserve the right and hereby disclose a disclaimer of any previously known product, process, or method. It is further noted that the disclosure does not intend to encompass within the scope of the disclosure any product, process, or making of the product or method of using the product, which does not meet the written description and enablement requirements of the USPTO (35 U.S.C. § 112, first paragraph) or the EPO (Article 83 of the EPC), such that Applicants reserve the right and hereby disclose a disclaimer of any previously described product, process of making the product, or method of using the product. It may be advantageous in the practice of the disclosure to be in compliance with Art. 53(c) EPC and Rule 28(b) and (c) EPC. All rights to explicitly disclaim any embodiments that are the subject of any granted patent(s) of applicant in the lineage of this application or in any other lineage or in any prior filed application of any third party is explicitly reserved. Nothing herein is to be construed as a promise.

DETAILED DESCRIPTION OF THE INVENTION

The present application provides novel 3, 5-substituted piperidine compounds and their derivatives which selectively and effectively inhibit renin activity. The compounds and their derivatives may be used to inhibit RAAS activity and treat or alleviate disease associated with abnormal renin/RAAS activity, including, but not limited to, hypertension, cardiovascular disease, diabetic kidney disease, and heart failure.

In a first embodiment, the compound of the disclosure has a structure of formula I or formula II illustrated below:

The exemplary compounds of formula I or formula II are set forth in Table 1 below.

TABLE 1Exemplary compounds of the disclosureCompound10111213141516171819202122232425262728293031323334353637383940414243444546

Various terms used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group, have the following meanings.

The term “optionally substituted” means a group may be unsubstituted or substituted by one or more substituents.

The term “deuterium”, also called heavy hydrogen, refers to an isotope of hydrogen, the nucleus of which contains one proton and one neutron. Deuterium is abundant in oceans.

The term “halogen” or “halo” embraces six elements in Group 17 of the periodic table, including fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At) and tennessine (Ts).

Preferred halogens in the present application are fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), especially fluorine (F), chlorine (Cl), and bromine (Br).

The “carboxyl” refers to a functional group (—COOH) containing or consisting of a carbonyl group (C═O) with a hydroxyl group (O—H) attached to the same atom.

The term “cyano” herein refers to a functional group (—C—N) containing a carbon atom with a triple bond to a nitrogen atom.

The term “alkyl” embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about eight, e.g., one to about six, one 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.

The term “alkenyl” embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are “lower alkenyl” radicals having two to about ten carbon atoms and more preferably about two to about eight, e.g., two to about six, two to five, two to four, carbon atoms. Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms “alkenyl”, and “lower alkenyl”, embrace radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.

The term “alkylthio” embraces radicals containing a linear or branched alkyl of one to about ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are lower alkylthio radicals having alkyl radicals of one to about eight, e.g., one to six, one to three, carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.

The term “alkynyl” embraces linear or branched radicals having at least one carbon-carbon triple bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are “lower alkynyl” radicals having two to about ten carbon atoms and more preferably about two to about eight, e.g., two to about six, two to five, two to four, carbon atoms. Examples of alkynyl radicals include propargyl, 1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl.

The term “amide” refers to the —C(═O)N=radical.

The term “sulfinyl” refers to the —S(═O)— radical, while the term “alkylsulfinyl” embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms, attached to a divalent —S(═O)— radical. More preferred alkylsulfinyl radicals are lower alkylsulfinyl radicals having alkyl radicals of one to about eight, e.g., one to six, one to three, carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsufinyl, ethylsufinyl, butylsufinyl and hexylsulfinyl.

The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, denotes the divalent radicals —SO2—, while the term “alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are “lower alkylsulfonyl” radicals having one to about six, e.g., one to three, carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The “alkylsulfonyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals.

The term “alkoxy” embraces linear or branched oxy-containing radicals each having alkyl portions of one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having one to about ten carbon atoms and more preferably having one to about eight, e.g., one to six, one or three, carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.

The term “cycloalkyl” refers to cyclic saturated or unsaturated monovalent hydrocarbon radical of three to twelve carbon atoms. The term embraces saturated carbocyclic radicals having three to about twelve carbon atoms. The term “cycloalkyl” embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to about eight, e.g., three to six, three to four, carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “hydroxyl cycloalkyl” embraces cycloalkyl radicals, as defined above, each substituted with one or more hydroxyl groups, such as hydroxyl C3-6cycloalkyl, and hydroxyl C3-4cycloalkyl.

The term “mercapto” refers to a functional group (—SH) containing a sulfur atom bonded to a hydrogen atom.

The term “carbonyl”, whether used alone or with other terms such as “alkylcarbonyl”, denotes a chemically organic functional group composed of a carbon atom double-bonded to an oxygen atom, i.e., —(C═O)—. The term “alkylcarbonyl” includes radicals having an alkyl radical, as defined above, attached to the carbon atom in a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl and hexylcarbonyl. The term “aminocarbonyl” embraces radicals having an amino group, attached to the carbon atom in the carbonyl radical. The term “alkoxycarbonyl” means a radical containing an alkoxy radical, as defined above, attached to the carbon atom in a carbonyl radical. Examples of such “alkoxycarbonyl” radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.

The term “heterocycle” or “heterocyclyl” embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocycle radicals include pyridine, and diazine (including pyridazine, pyrimidine, and pyrazine). The partial unsaturated or unsaturated 6-membered heterocycle radicals also include pyran, thiopyran, oxazine, thiazine, dioxin, dithiin, and triazine. Heterocyclyl radicals may include a pentavalent nitrogen, such as in tetrazolium and pyridinium radicals. The term “heterocycle” also embraces radicals where heterocyclyl radicals are fused with aryl or cycloalkyl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.

The term “cyclic hydrocarbon group” refers to a saturated, partially unsaturated, or unsaturated carbon chain in a ring structure.

The term “formyl” refers to a functional group containing or consisting of a carbonyl group bonded to a hydrogen atom.

The term “hydroxyl alkyl” embraces alkyl radicals, as defined above, each substituted with one or more, e.g., one or two, hydroxyl radicals.

The term “alkyl amino” embraces amino radicals each substituted with one or two alkyl groups as defined above. Preferred alkylamino radicals have alkyl radicals having about one to about twenty carbon atoms or, preferably, one to about twelve, one to six, or one to three, carbon atoms. Examples of such radicals may be monosubstituted N-alkylamino or disubstituted N,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.

The term “alkoxyalkyl” embraces alkyl radicals, as defined above, having one or more alkoxy radicals, as defined above, attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.

The term “pyran” or “oxine” is a six-membered heterocyclic, non-aromatic ring, consisting of five carbon atoms and one oxygen atom with two double bonds, including 2H-pyran, and 4H-pyran.

The term “thiopyran” is a heterocyclic compound containing five carbon atoms and one sulfur atom with two double bonds, including 2H-thiopyran and 4H-thiopyran.

The term “oxazine” embraces heterocyclic radicals containing one oxygen and one nitrogen atom in a doubly unsaturated six-membered ring, including 1,2-oxazine, 1,3-oxazine, and 1,4-oxazine.

The term “thiazine” embraces radicals containing a ring of four carbon, one nitrogen and one sulfur atom, including 1,2-thiazine, 1,3-thiazine and 1,4-thiazine.

The term “dithiin” embraces radicals containing two sulfur and four carbon atoms, with two double bonds, including 1,2-dithiin and 1,4-dithiin.

The term “triazine” embraces radicals each with a six-membered benzene-like ring having three carbon and three nitrogen atoms, including 1,2,3-trizine, 1,2,4-triazine, and 1,3,5-triazine.

The term “aryl”, alone or in combination, generally means a carbocyclic aromatic system containing one, or more rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.

The term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to, a deuterium atom, a halogen atom, a cyano group, a mercapto group, a hydroxyl group, a carboxyl group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an cycloalkyl group, an amino group, an alkylthio group, a hydroxyl alkyl group, an alkoxy alkyl group, an alkylcarbonyl group, an aminocarbonyl group, an alkyl amino group, a cycloalkyl group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, an alkylcarbonyl group, an alkoxycarbonyl group, a heterocyclyl group, a hydroxyl cycloalkyl group, a haloalkyl group, a halocycloalkyl group, a haloalkylcarbonyl group, a halocycloalkylcarbonyl group, an alkylthioalkyl group, an alkylsulfonylalkyl group, an aminocarbonylcycloalkyl, an aminocarbonylheterocyclyl, an alkylaminocarbonyl, trifluoromethyl, an alkylaminoalkyl group, an aminoalkylamino group, an carboxyalkyl group, an alkoxycarbonylalkyl group, an aminocarbonylalkyl group, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, pyridine, pyridazine, pyrimidine, pyrazine, pyran, thiopyran, oxazine, thiazine, dioxin, dithiin, and triazine. It is understood that the substituent may be further substituted.

Chemical moieties are defined and referred to throughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.) or multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, an “alkyl” moiety can be referred to a monovalent radical (e.g. CH3—CH2—), or in other instances, a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., —CH2—CH2—), which is equivalent to the term “alkylene”. Similarly, in circumstances in which divalent moieties are required and are stated as being “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 moiety.

The term “compound” is defined herein to include pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereoisomers, racemates and the like of the compounds having a formula as set forth herein.

The term “treatment” refers to any process, action, application, therapy, or the like, wherein a mammal, including a human being, is subject to medical aid with the object of improving the mammal's condition, directly or indirectly.

The term “geometric isomer” embraces chemical species which contain the same type and quantity of atoms and bonds but have different spatial arrangements of the atoms.

The term “isotopic isomer”, also referred to as “isotopomer”, embraces isomers with isotopic atoms, having the same number of each isotope of each element but differing in their positions.

The term “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present disclosure. “Prodrug”, as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of the disclosure. Various forms of prodrugs are known in the art, for example, as discussed in 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 Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

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

The compounds of this disclosure may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. 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.

The compounds of the disclosure show inhibitory effects on human renin activity, with IC50less 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.

The pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of a compound of the present disclosure formulated together with one or more pharmaceutically acceptable carriers or excipients.

By a “therapeutically effective amount” of a compound of the disclosure is meant an amount of the compound which confers a therapeutic effect, e.g., reduction of abnormal renin/RAAS activity, on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). An effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.

The total daily dose of the compounds of this disclosure administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.

A compound of the formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds, including suitable processes for making certain intermediates. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of a chemist.

The present disclosure further provides methods for the prevention or treatment of diseases or conditions involving abnormal renin activity or RAAS activity. In one embodiment, the disclosure further provides for the use of the pharmaceutical composition of the disclosure in the manufacture of a medicament for halting or decreasing diseases involving abnormal renin/RAAS activity. The disease may be hypertension, cardiovascular disease, diabetic kidney disease, or heart failure. In certain embodiments, the disease is hypertension. In one embodiment, the disclosure relates to a method of treating hypertension in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of the disclosure. In one embodiment, the disclosure relates to a method of inhibiting renin or RAAS activity in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of the disclosure.

The preparation of pharmaceutical compositions that contain an active component is well understood in the art, for example, by mixing, granulating, or tablet-forming processes. The active therapeutic ingredient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. For oral administration, the active agents are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions and the like as detailed above.

The amount of the compound administered to the patient is less than an amount that would cause toxicity in the patient. In certain embodiments, the amount of the compound that is administered to the patient is less than the amount that causes a concentration of the compound in the patient's plasma to equal or exceed the toxic level of the compound. The optimal amount of the compound that should be administered to the patient in the practice of the present disclosure will depend on the particular compound used and the type of cancer being treated.

EXAMPLES

The compounds described herein will be better understood in connection with the following representative synthetic schemes that illustrate the methods by which the compounds of the disclosure may be prepared, which are intended as an illustration only and not limiting of the scope of the disclosure. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the disclosure may be made without departing from the spirit of the disclosure and the scope of the appended claims.

Example 1. Synthesis of intermediates

Synthesis of intermediate compound A

A solution of 3,5-dimethyl pyridine-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 for 24 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered; the filter cake was washed with AcOH (3×10 mL). The filtrate was concentrated under reduced pressure. This resulted in Compound 1 (35.1 g, crude) as a yellow oil. LCMS (ESI) [M+H]+: 202.

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 for 15 h at 70° C. The mixture was acidified to pH 3 with HCl (aq.). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 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-azabicycle[3.3]nonane Compound 4)

Step E Synthesis of 1-(tert-butoxycarbonyl)-(5R)-(methoxycarbonyl)piperidine-(3S)-carboxylic acid (Compound 5)

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) was added dropwise MeOH (16 mL, 395.18 mmol) in Et2O (50 mL) at −78° C. The reaction mixture was stirred at −78° C. for 10 h and then warmed up to room temperature. The reaction mixture was acidified by 1N HCl (pH=3) and then extracted with EtOAc (100×3 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the mono-ester. The crude mono-ester was dissolved in EtOH (60 mL) at 80° C. To the mixture was added (R)-1-phenylethylamine (4.6 mL, 37.988 mmol) at 80° C., followed by stirring at room temperature overnight. The resulting crystals were filtered off and washed with acetonitrile to give the mono-ester. The intermediate salt in CH2Cl2was then acidified by addition of 1N HCl (pH=3-4). The resulting mixture was extracted with CH2Cl2(100×3 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 20 min, UV 254 nm. This resulted in Compound 5 (2.2 g, 19.55%) as off-white solid. LCMS (ESI) [M+H]+: 288.

A solution of Compound 5 (300 mg, 1.044 mmol, 1.0 eq), diphenylphosphoryl azide (324.7 mg, 1.180 mmol, 1.1 equiv) and triethylamine (169.1 mg, 1.670 mmol, 1.6 eq) in toluene was stirred for 3 h at room temperature under nitrogen atmosphere. To the above mixture was added benzyl alcohol (225.8 mg, 2.088 mmol, 2.0 eq). The resulting mixture was stirred for additional 4 h at 100° C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 20 min; UV 254 nm. This resulted in Compound 6 (280 mg, 68.33%) as a yellow oil. LCMS (ESI) [M+H]+: 393.

A solution of Compound 6 (1 g, 2.548 mmol, 1 eq) and Pd/C (0.1 g, 0.255 mmol, 0.1 eq) in methanol (20 mL) was stirred for 1 h at room temperature under hydrogen atmosphere. The precipitated solids were collected by filtration and washed with MeOH (3×3 mL). The resulting mixture was concentrated under vacuum. This resulted in Compound 7 (600 mg, 91.16%) as a yellow solid. LCMS (ESI) [M+H]+: 259.

Synthesis of intermediate compound B

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 for 2 h at room temperature. The mixture was acidified to pH 5 with AcOH. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 20 min, UV 254 nm. This resulted in Compound B (170 mg, 91.37%) as a yellow solid. LCMS (ESI) [M+H]+: 263.

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

A solution 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 (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 with AcOH. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 20 min; UV 254 nm. This resulted in Compound C (480 mg, 85.18%) as a yellow solid. LCMS (ESI) [M+H]+: 545.

Synthesis of Compound 10

Synthesis of Compound 11

Synthesis of Compound 12

Synthesis of 4-(trifluoromethoxy)piperidine

A solution of N-tert-butoxycarbonyl 4-(trifluoromethoxy) piperidine (100 mg, 0.371 mmol, 1 eq) in a solution of HCl in 1,4-dioxane was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 4-(trifluoromethoxy)piperidine (70 mg, crude) as a yellow solid. LCMS (ESI) [M+H]+: 170.

Synthesis of Compound 13

Synthesis of Compound 14

Synthesis of Compound 15

Synthesis of ethyl 2-tert-butyl-4-oxo-5H-pyrimidine-5-carboxylate

Synthesis of ethyl 2-tert-butyl-4-chloropyridimine-5-carboxylate

Synthesis of ethyl 2-tert-butyl-4-[3-(trans-methoxy)cyclobutyl]amino-pyrimidine-5-carboxylate

Synthesis of ethyl 2-tert-butyl-4-[3-(trans-methoxy)cyclobutyl]amino-pyrimidine-5-carboxylate acid

To a stirred mixture of ethyl 2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]amino-pyrimidine-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) were added H2O (2.0 mL) at 25° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient in 20 min, UV 254 nm. This resulted in 2-tert-butyl-4-[(3-trans-methoxy)cyclobutyl]amino-pyrimidine-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

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

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}amino-piperidine-(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) was added H2O (2 mL) at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 20 min, UV 254 nm. This resulted in 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 (150 mg, 96.09%) as a yellow oil. LCMS (ESI) [M+H]+: 563.

Synthesis of Compound 17

Synthesis of Compound 18

Synthesis of methyl 5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino-pyridine-2-carboxylate

Synthesis of methyl 5-cyclopropyl-3-[3-(cis-methoxy)cyclobutyl]amino-pyridine-2-carboxylic acid

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

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

Synthesis of Compound 19

Synthesis of methyl-3-(cyclobutylamino)-5-cyclopropylpyridine-2-carboxylate

Synthesis of methyl-3-(cyclobutylamino)-5-cyclopropylpyridine-2-carboxylic acid

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) were added H2O (1 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 3-(cyclobutylamino)-5-cyclopropylpyridine-2-carboxylic acid (100 mg, 96.40%) as a yellow oil. LCMS (ESI) [M+H]+: 233.

To a stirred mixture of methyl 1-tert-butoxycarbonyl-(3S)—[N-(2-methylpropyl), N-(5-cyclopropyl-3-cyclobutylamino)-pyridine-2-carbonyl]amino-piperidine-(5R)-carboxylate (110 mg, 0.21 mmol, 1 eq) and LiOH (24.9 mg, 1.04 mmol, 5 eq) in THF (1 mL) were added H2O (1 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 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 Compound 20

Synthesis of methyl-5-cyclopropyl-3-(cyclopropylamino)pyridine-2-carboxylate

Synthesis of methyl-5-cyclopropyl-3-(cyclopropylamino)pyridine-2-carboxylic acid

To a stirred 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) were added H2O (1 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 5-cyclopropyl-3-(cyclopropylamino)pyridine-2-carboxylic acid (102 mg, 90.46%) as a yellow oil. LCMS (ESI) [M+H]+: 219.

To a stirred mixture of methyl 1-tert-butoxycarbonyl-(3S)—[N-(2-methylpropyl), N-(5-cyclopropyl-3-cyclopropylamino)pyridine-2-carbonyl]amino-piperidine-(5R)-carboxylate (110 mg, 0.21 mmol, 1 eq) and LiOH (25.5 mg, 1.07 mmol, 5 eq) in THF (1 mL) were added H2O (1 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 60% gradient in 20 min; detector, UV 254 nm. This resulted in 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 Compound 21

Synthesis of Compound 22

Synthesis of Compound 23

Synthesis of 3,3-difluorocyclobutane-1-carbohydrazide

To a stirred solution of methyl 3,3-difluorocyclobutane-1-carboxylate (500 mg, 3.331 mmol, 1 eq) in MeOH were added N2H4·H2O (1667.2 mg, 33.310 mmol, 10 e) at room temperature. The resulting mixture was stirred for 15 h at 80° C. The resulting mixture was concentrated under reduced pressure. This resulted in 3,3-difluorocyclobutane-1-carbohydrazide (450 mg, 90.0%) as a white solid. LCMS (ESI) [M+H]+: 151.

Synthesis of Compound 24

Synthesis of Compound 25

Synthesis of 1-tert-butoxycarbonyl-(3S)-(2-methylpropylamino)piperidine

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 were added diacetyl peroxide and sodiumboranyl acetate (317 mg, 1.5 mmol, 3 eq) at room temperature. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient in 20 min; UV 254 nm. This resulted in 1-tert-butoxycarbonyl-(3S)-(2-methylpropylamino)piperidine (120 mg, 94%) as a white solid. LCMS (ESI) [M+H]+: 257.

Synthesis of Compound 26

Synthesis of Compound 27

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 was added DIEA (98 mg, 0.76 mmol, 2 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient in 20 min; UV 254 nm. This resulted in 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 Compound 28

A solution of 1-tert-butoxycarbonyl-(3S)—{N-(2-methylpropyl), N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-piperidine-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 for 10 h at room temperature. To the above mixture was added acetamide oxime (31 mg, 0.41 mmol, 1.5 eq) at room temperature. The resulting mixture was stirred for additional 15 h at room temperature and then at 100° C. for 1 h. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 70% gradient in 20 min, UV 254 nm. This resulted in 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-oxadiazol-5-yl)-piperidine (80 mg, 50%) as a yellow oil. LCMS (ESI) [M+H]+: 583.

Synthesis of Compound 29

Synthesis of methyl-5-cyclopropyl-3-(oxetan-3-ylamino)pyrimidine-2-carboxylate

Synthesis of methyl-5-cyclopropyl-3-(oxetan-3-ylamino)pyrimidine-2-carboxylic acid

To a stirred solution of methyl 5-cyclopropyl-3-(oxetan-3-ylamino)pyridine-2-carboxylate (85 mg, 0.34 mmol, 1 eq) and LiOH (41 mg, 1.7 mmol, 5 eq) in THE were added H2O (0.5 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The residue was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient in 20 min; UV 254 nm. This resulted in 5-cyclopropyl-3-(oxetan-3-ylamino)pyridine-2-carboxylic acid (65 mg, 81%) as yellow oil. LCMS (ESI) [M+H]+: 235.

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

Synthesis of Compound 30

Synthesis of methyl 3-(3-trans-methoxy)cyclobutyl-amino-pyridine-2-carboxylate

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 was added Pd2dba3(127 mg, 0.14 mmol, 0.1 eq) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The precipitated solids were 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 with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 10 min; UV 254 nm. This resulted in methyl 3-(3-(trans-methoxy)cyclobutyl-amino-pyridine-2-carboxylate (115 mg, 35%) as a yellow oil. LCMS (ESI) [M+H]+: 237.

Synthesis of methyl 3-[(3-trans-methoxy)cyclobutyl]-amino-pyridine-2-carboxylic acid

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 were added H2O (1 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The mixture was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 40% gradient in 20 min; UV 254 nm. This resulted in 3-[(3-trans-methoxy)cyclobutyl]amino-pyridine-2-carboxylic acid (98 mg, 95%) as a yellow oil. LCMS (ESI) [M+H]+: 223.

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

Synthesis of Compound 31

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 was added Burgess reagent (239 mg, 1.0 mmol, 4 eq) at room temperature. The resulting mixture was stirred for 20 min at 120° C. under nitrogen atmosphere. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient in 10 min; UV 254 nm. This resulted in 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-oxadiazol-2-yl)-piperidine (98 mg, 67%) as a yellow oil. LCMS (ESI) [M+H]+: 581.

Synthesis of Compound 32

Synthesis of methyl 4-chloro-6-cyclopropylpyridazine-3-carboxylate

Synthesis of methyl 6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino-pyridazine-3-carboxylate

Synthesis of 6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino-pyridazine-3-carboxylic acid

To a stirred solution of methyl (3S)—{N-(2-methylpropyl), N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}amino-piperidine-(5R)-carboxylate (110 mg, 0.19 mmol, 1.0 eq) and H2O (1 mL) in THF (2 mL) was added lithium hydroxide (23.3 mg, 0.98 mmol, 5.0 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. After completion of reaction, the mixture was acidified to pH 6 with citric acid. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 60% gradient in 20 min; UV 254 nm to afford (3S)—{N-(2-methylpropyl), N-{6-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino}pyridazine-3-carbonyl}amino-piperidine-(5R)-carboxylic acid (95 mg, 89%) as a yellow oil. LCMS (ESI) [M+H]+: 546.

Synthesis of Compound 33

Synthesis of oxetane-3-carbohydrazide

A solution of methyl oxetane-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 for 48 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with EtOAc (10 mL). This resulted in oxetane-3-carbohydrazide (800 mg, crude) as a yellow solid. LCMS (ESI) [M+H]+: 117.

Synthesis of Compound 34

Synthesis of Compound 36

Synthesis of Compound 37

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 for 5 h at room temperature under nitrogen atmosphere. To the above mixture was added acetamide oxime (64.5 mg, 0.87 mmol, 3.0 eq) at room temperature. The resulting mixture was stirred for additional 15 h at room temperature and then 100° C. for 1 h. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient in 20 min, UV 254 nm. This resulted in 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-oxadiazol-5-yl)-piperidine (80.0 mg, 50%) as a yellow oil. LCMS (ESI) [M+H]+: 555.

Synthesis of Compound 38

Synthesis of Compound 39

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) was added Boron trifluoride etherate (0.4 mg, 0.003 mmol, 0.01 eq) at room temperature. The resulting mixture was stirred for 1 h at 90° C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 20 min; UV 254 nm. This resulted in 1-tert-butoxycarbonyl-(3S)—{N-(2-methylpropyl), N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}pyridine-2-carbonyl}amino-(5R)-(1,3,4-oxadiazol-2-yl)-piperidine (80 mg, 52%) as a yellow oil. LCMS (ESI) [M+H]+: 569.

Synthesis of Compound 40

Synthesis of methyl 1-tert-butoxylcarbonyl-(3S)-(2-cyclopropylmethyl)amino-piperidine (5R)-carboxylate

Synthesis of methyl 1-tert-butoxylcarbonyl-(3S)-{N-cyclopropylmethyl, N-{5-cyclopropyl-3-[3-(trans-methoxy)cyclobutyl]amino}-pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylate

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 for 10 min at room temperature under nitrogen atmosphere. To the above mixture was added 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) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 60% gradient in 20 min, UV 254 nm. This resulted in 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-oxadiazol-2-yl)-piperidine (70 mg, 56%) as a yellow oil. LCMS (ESI) [M+H]+: 581.

Synthesis of Compound 41

A solution of 1-tert-butoxycarbonyl-(3S)—{N-(2-methylpropyl), N-[5-cyclopropyl-3-(oxetan-3-yl)amino]pyridine-2-carbonyl}amino-piperidine-(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 for 45 min at room temperature under nitrogen atmosphere. The reaction was quenched with water at room temperature. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 60% gradient in 20 min; UV 254 nm. This resulted in 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 Compound 42

Synthesis of methyl 3-(oxetan-3-ylamino)-5-(trifluoromethyl)pyridine-2-carboxylate

Synthesis of 3-(oxetan-3-ylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid

To a stirred solution of methyl 3-(oxetan-3-ylamino)-5-(trifluoromethyl)pyridine-2-carboxylate (330 mg, 1.195 mmol, 1 eq) and H2O (3 mL) in THE (3 mL) was added LiOH (143.0 mg, 5.975 mmol, 5 eq) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The residue was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 40% gradient in 20 min; UV 254 nm. This resulted in 3-(oxetan-3-ylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (305 mg, 97.37%) as a yellow solid. LCMS (ESI) [M+H]+: 263.

To a stirred solution of methyl 1-tert-butoxycarbonyl-(3S)—{N-(2-methylpropyl), N-[5-trifluoromethyl-3-(oxetan-3-ylamino]pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylate (120 mg, 0.22 mmol, 1 eq) and H2O (1 mL) in THF (1 mL) was added LiOH (26 mg, 1.1 mmol, 5 eq) and stirred for 1 h at room temperature under nitrogen atmosphere. The residue was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 40% gradient in 20 min; UV 254 nm. This resulted in 1-tert-butoxycarbonyl-(3S)—{N-(2-methylpropyl), N-[5-trifluoromethyl-3-(oxetan-3-ylamino]pyridine-2-carbonyl}amino-piperidine-(5R)-carboxylic acid (105 mg, 90%) as a yellow oil. LCMS (ESI) [M+H]+: 545.

Synthesis of Compound 43

Synthesis of Compound 44

Synthesis of 3-trans-(methoxy-d3)cyclobutan-1-amine

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) was added a solution of HCl in 1,4-dioxane (5 mL). The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was filtered, the filter cake was washed with diethyl ether (3×30 mL). The filtrate was concentrated under reduced pressure. This resulted in 3-trans-(methoxy-d3)cyclobutan-1-amine (270 mg, crude) as a white solid. LCMS (ESI) [M+H]+: 105.

Synthesis of methyl 5-cyclopropyl-3-[3-trans-(methoxy-d3)cyclobutyl]amino-pyridine-2-carboxylate

Synthesis of 5-cyclopropyl-3-[3-(trans-methoxy-d3)cyclobutyl]amino-pyridine 2-carboxylic acid

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

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}amino-piperidine-(5R)-carboxylate (170 mg, 0.3 mmol, 1 eq) and H2O (1 mL) in THF (1 mL) was added LiOH (36 mg, 1.5 mmol, 5 eq) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The residue was acidified to pH 6 with citric acid. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 40% gradient in 200 min; UV 254 nm. This resulted in 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 (150 mg, 90%) as a white solid. LCMS (ESI) [M+H]+: 548.

Synthesis of Compound 45

Synthesis of ethyl 2-cyclopropyl-4-oxo-5H-pyrimidine-5-carboxylate

To a stirred solution of cyclopropanecarboximidamide (1 g, 12 mmol, 1.0 eq) in ethanol (20 mL) was added 1,3-diethyl 2-(ethoxymethylidene)propanedioate (3.1 g, 14.3 mmol, 1.2 eq) at room temperature under nitrogen atmosphere. Then the resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The mixture was acidified to pH 6 with HCl (2 M). The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 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

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) was added phosphorus oxychloride (2761 mg, 18 mmol, 5.0 eq) at room temperature. The resulting mixture was stirred overnight at 100° C. under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (30 mL). The combined organic layers were washed with water (3×30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 60% gradient in 20 min; UV 254 nm. This resulted in 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]amino-pyrimidine-5-carboxylate

Synthesis of 2-cyclopropyl-4-[3-(trans-methoxy)cyclobutyl]amino-pyrimidine-5-carboxylic acid

Synthesis of Compound 46

Example 39. Inhibitory Effects of Exemplary Compounds of the Disclosure

The exemplary compounds of the disclosure were tested for their inhibitory effects on human renin activity, using a commercially available renin assay kit (SensoLyte® 520 Renin Assay Kit Fluorimetric), following the manufacture's manual.

Briefly, human recombinant renin (from the kit) was incubated with the compound of the disclosure or buffer for 30 min at 37° C. before substrate addition. Fluorescence intensity was measured at 530 nm after an incubation of 15 min at 37° C. Data was analyzed by Prism and fitted into a sigmodal curve for IC50calculation.

The results were summarized in Table 2.

TABLE 2Inhibitory effect of compounds of thedisclosure on human renin activityCompound No.Example No.IC50(nM)1021.81131.21241.61353.81461.21571.01681.61791.518101.219111.520121.921131.422141.323151.224161.02517<102618<202719<2502820<102921<103022<103123<103224<103325<2503426<103527<203628<503729<203830<503931<104032<104133<104234<304335<104436<104537<104638<250

The invention has been illustrated by the above descriptions and examples. The examples are not intended to be limiting in any way. As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range.