Hydroquinazoline Derivatives for the Treatment of Diseases or Disorders - Patent application

Abstract

The present disclosure provides a compound of formula (I): [Formula 1] TIFF2026508349000156.tif35170 (In the formula, A, R a ~R d and R 4 ~R 7 are as described herein) or a pharmaceutically acceptable salt thereof, as well as compositions and methods of using such compounds.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 487,756, filed March 1, 2023, and U.S. Provisional Patent Application No. 63 / 550,180, filed February 6, 2024, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Heart failure is a major public health problem affecting over 20 million patients worldwide and is associated with high morbidity. Natriuretic peptide receptor 1 (NPR1, also known as NPRA) is a receptor guanylate cyclase that is activated by atrial natriuretic peptide (ANP), resulting in a decrease in blood pressure and blood volume. ANP binding induces receptor dimerization and twisting, which activates the guanylate cyclase domain and converts GTP to cGMP. ANP is removed by NPR3, a natriuretic peptide receptor lacking the guanylate cyclase domain, and degraded by neutral endopeptidase (NEP).

[0003] It has been shown that increasing ANP by infusion can be beneficial for patients with chronic heart failure who have a reduced ejection fraction (the outward pumping of blood by the heart) (Yoshimura et al., 2001, Can J Physiol Pharmacol 79(8):730-735). However, there is a need for oral agents that can supplement or replace existing treatments. Summary of the Invention

[0004] In a first aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, A is NR 1 or CR 2R 3 and R 1 and R 2 are each independently H, (C3-C6)cycloalkyl or (C6-C 10 ) aryl, (C6-C 10 ) aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C1-C6) alkyl, and (C3-C6) cycloalkyl; R 3 is H or (C1-C6) alkyl, R 4 (C6~C 10 ) aryl or 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, (C6-C 10 ) aryl or 5- or 6-membered heteroaryl are each optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, oxo, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl, (C-C)cycloalkyl-(C-C)alkyl, and (C-C)alkyl(C-C)cycloalkyl; R 5 is NR 8 R 9 and R 6 is selected from H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl-(C1-C6)alkyl; R 7 is (C3-C6)cycloalkyl or (C6-C 10 )aryl, (C3-C6)cycloalkyl and (C6-C 10 ) each aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, and —HOC—(C1-C6)alkyl; R 8 and R9 are each independently H, (C1-C6) alkyl, or a 3- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S; or R 8 and R 9 together with the N to which they are attached form a 3- to 10-membered heterocycle optionally containing 1 or 2 additional heteroatoms selected from N, O, and S, which 3- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl-(C-C)alkyl, (C-C)cycloalkyl, (C-C)alkyl-O—(C-C)alkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, and a 3- to 7-membered heterocycle containing 1 to 2 heteroatoms selected from N, O, and S; and R a , R b , R c and R d are each independently H or (C1-C6) alkyl. or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

[0011] In yet another aspect, the present disclosure relates to the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or disorder.

[0012] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0013] In certain aspects, the present disclosure provides substituted hydroquinazoline derivative compounds and pharmaceutical compositions thereof. In particular, such substituted compounds are useful as activators of NPR1 and therefore can be used to treat or prevent diseases or conditions.

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

[0015] compound Thus, in one aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, A is NR 1 or CR 2 R 3 and R 1 and R 2 are each independently H, (C3-C6)cycloalkyl or (C6-C 10 ) aryl, (C6-C 10 ) aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C1-C6) alkyl, and (C3-C6) cycloalkyl; R 3 is H or (C1-C6) alkyl, R 4 (C6~C 10 ) aryl or 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, (C6-C 10) aryl or 5- or 6-membered heteroaryl are each optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, oxo, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl, (C-C)cycloalkyl-(C-C)alkyl, and (C-C)alkyl(C-C)cycloalkyl; R 5 is NR 8 R 9 and R 6 is selected from H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl-(C1-C6)alkyl; R 7 is (C3-C6)cycloalkyl or (C6-C 10 )aryl, (C3-C6)cycloalkyl and (C6-C 10 ) each aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, and —HOC—(C1-C6)alkyl; R 8 and R 9 are each independently H, (C1-C6) alkyl, or a 3- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S; or R 8 and R 9together with the N to which they are attached form a 3- to 10-membered heterocycle optionally containing 1 or 2 additional heteroatoms selected from N, O, and S, which 3- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl-(C-C)alkyl, (C-C)cycloalkyl, (C-C)alkyl-O—(C-C)alkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, and a 3- to 7-membered heterocycle containing 1 to 2 heteroatoms selected from N, O, and S; and R a , R b , R c and R d are each independently H or (C1-C6) alkyl. or a pharmaceutically acceptable salt thereof.

[0016] Unless otherwise specified, the term "compounds of the present disclosure" refers to compounds of formula (I) of the present disclosure, and exemplified compounds, and salts thereof, and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitutions) and inherently formed moieties.

[0017] Various embodiments of the present disclosure are described herein, and it will be recognized that certain features specified in each embodiment may be combined with other certain features of other embodiments to provide further embodiments.

[0018] In some embodiments, A is NR 1 and R 1 is (C3-C6)cycloalkyl or (C6-C 10 ) aryl, (C6-C 10) aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C1-C6) alkyl, and (C3-C6) cycloalkyl. In some embodiments, A is NR 1 and R 1 is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C1-C6)alkyl, and (C3-C6)cycloalkyl (C6-C 10 In some embodiments, A is NR 1 and R 1 is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo and —CN (C6-C 10 In some embodiments, A is NR 1 and R 1 is phenyl optionally substituted with 1 or 2 substituents independently selected from halo and -CN. In some embodiments, A is NR 1 and R 1 is phenyl optionally substituted with one substituent independently selected from halo and -CN. In some embodiments, A is NR 1 and R 1 is phenyl optionally substituted with one substituent independently selected from fluoro and —CN.

[0019] In some embodiments, A is NR 1 and R 1 teeth, [ka] In some embodiments, A is selected from NR 1 and R 1 teeth, [ka] Selected from

[0020] In some embodiments, A is CR 2 R 3 and R 2 is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C1-C6)alkyl, and (C3-C6)cycloalkyl (C6-C 10 In some embodiments, A is CR 2 R 3 and R 2 is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo (C6-C 10 In some embodiments, A is CR 2 R 3 and R 2 is phenyl optionally substituted with 1 or 2 substituents independently selected from halo. In some embodiments, A is CR 2 R 3 and R 2 is phenyl optionally substituted with one substituent independently selected from halo. In some embodiments, A is CR 2 R 3 and R 2 is phenyl optionally substituted with one substituent independently selected from fluoro.

[0021] In some embodiments, A is CR 2 R 3 and R 2 teeth, [ka] is selected from.

[0022] In some embodiments, A is CR 2 R3 and R 3 is selected from H and —CH 3 .

[0023] In some embodiments, R 4 (C6~C 10 ) aryl or 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, (C6-C 10 )aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, -CN, -OH, -COH, and (C1-C6)alkyl, and a 5- or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, -CN, -OH, -COH, oxo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, and (C1-C6)alkyl(C3-C6)cycloalkyl. In certain embodiments, R 4 (C6~C 10 ) aryl or 5- or 6-membered heteroaryl containing 1 to 2 heteroatoms selected from N and S, (C6-C 10 )aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo and (C1-C6)alkyl, and a 5- or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from oxo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl-(C1-C6)alkyl.

[0024] In some embodiments, R 4is a 5- or 6-membered heteroaryl containing 1-2 heteroatoms selected from N and S, which is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from oxo, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl, and (C-C)cycloalkyl-(C-C)alkyl. In some embodiments, R 4 is a 5-membered heteroaryl containing 1-2 heteroatoms selected from N and S, which is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from oxo, (C-C)alkyl, (C-C)fluoroalkyl, (C-C)cycloalkyl, and (C-C)cycloalkyl-(C-C)alkyl. In some embodiments, R 4 is a 5-membered heteroaryl containing 1 to 2 heteroatoms selected from N and S, which is optionally substituted with 1 or 2 substituents independently selected from (C-C) alkyl, (C-C) fluoroalkyl, (C-C) cycloalkyl, and (C-C) cycloalkyl-(C-C) alkyl. In some embodiments, R 4 is a 5-membered heteroaryl containing two heteroatoms selected from N and S, which is optionally substituted with one or two substituents independently selected from (C-C) alkyl, (C-C) fluoroalkyl, (C-C) cycloalkyl, and (C-C) cycloalkyl-(C-C) alkyl.

[0025] In certain embodiments, R 4 is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, oxo, and (C1-C6) alkyl (C6-C 10 ) aryl. In certain embodiments, R 4 is phenyl optionally substituted with one or two substituents independently selected from halo, oxo, and (C1-C6) alkyl. In some embodiments, R 4is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo (C6-C 10 ) aryl.

[0026] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] is selected from.

[0027] In some embodiments, R 5 is NR 8 R 9 and R 8 and R 9 together with the N to which they are attached form a 3- to 10-membered heterocycle optionally containing 1 or 2 additional heteroatoms selected from N, O, and S, which 3- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl-(C-C)alkyl, (C-C)cycloalkyl, (C-C)alkyl-O—(C-C)alkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, and a 3- to 7-membered heterocycle containing 1 to 2 heteroatoms selected from N, O, and S.

[0028] In some embodiments, R 5 is NR 8 R9 and R 8 and R 9 together with the N to which they are attached form a 3-10 membered heterocycle optionally containing 1-2 additional O heteroatoms, which 3-10 membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl-(C-C)alkyl, (C-C)cycloalkyl, (C-C)alkyl-O—(C-C)alkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, and a 3-7 membered heterocycle containing 1-2 heteroatoms selected from N, O, and S.

[0029] In some embodiments, R 5 is NR 8 R 9 and R 8 and R 9 together with the N to which they are attached form a 3-10 membered heterocycle optionally containing 1-2 additional O heteroatoms, which 3-10 membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —OH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-O—(C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, and a 3-7 membered heterocycle containing a heteroatom selected from N, O, and S.

[0030] In some embodiments, R 5 is NR 8 R 9 and R 8 and R 9together with the N to which they are attached form a 5-10 membered heterocycle optionally containing 1-2 additional O heteroatoms, which 5-10 membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —OH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-O—(C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, and a 3-7 membered heterocycle containing a heteroatom selected from N and O. In some embodiments, the 5- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from fluoro, —OH, (C1-C6)alkyl, (C1-C6)fluoroalkyl, CHO—(C1-C6)alkyl, (C1-C6)hydroxyalkyl, and a 5-membered heterocycle containing a heteroatom selected from O. In some embodiments, the 5- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from fluoro, —OH, —CH, —CHF, —CFH, —CHCH, —CHOH, —OCH, and CHOCH. In some embodiments, the 5- to 10-membered heterocycle is optionally substituted with one or two substituents independently selected from fluoro, -OH, -CH, -CHF, -CFH, -CHCH, -CHOH, -OCH, and CHOCH. In some embodiments, the 5- to 10-membered heterocycle is optionally substituted with one substituent independently selected from (C-C)cycloalkyl and a 5-membered heterocycle containing a heteroatom selected from N and O.

[0031] In some embodiments, R 5 teeth, [ka] In certain embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] is selected from.

[0032] In some embodiments, R 5 is NR 8 R 9 and R 8 is selected from H and (C1-C6) alkyl. In some embodiments, R 5 is NR 8 R 9 and R 9 is selected from H(C1-C6) alkyl and 3-6 membered heterocycles containing O heteroatoms.

[0033] In some embodiments, R 6 is selected from (C1-C4) alkyl, (C3-C5) cycloalkyl, and (C3-C5) cycloalkyl-(C1-C4) alkyl. 6 are -CH3, -CH2CH3, [ka] is selected from.

[0034] In some embodiments, R 7 is (C3-C6)cycloalkyl or (C6-C 10 )aryl, (C3-C6)cycloalkyl and (C6-C 10 ) aryl are each optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —COH, and —CHCOH. In some embodiments, R 7 is (C5-C6)cycloalkyl or (C6-C 10 )aryl, (C-C)cycloalkyl and (C-C 10) aryl are each optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —COH, and —CHCOH. In some embodiments, R 7 is (C5-C6)cycloalkyl or (C6-C 10 )aryl, (C-C)cycloalkyl and (C-C 10 ) Aryl is each optionally substituted with one or two substituents independently selected from fluoro, —CO2H, and —CH2CO2H.

[0035] In certain embodiments, R 7 teeth, [ka] is selected from.

[0036] In some embodiments, R a , R b , R c and R d are each independently H or CH. In some embodiments, R a , R b , R c and R d are each H. In some embodiments, R a , R b and R c are each H. In some embodiments, R a is H. In some embodiments, R b and R c are each H. In some embodiments, R a , R b , R c and R d are each —CH3. In some preferred embodiments, R d is -CH3.

[0037] In some embodiments, the present disclosure provides a compound of formula (I): [ka] (In the formula, A is CR 2 R 3 and R 2 (C6~C 10 ) aryl, (C6-C 10 ) aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C1-C6) alkyl, and (C3-C6) cycloalkyl; R 3 is H or (C1-C6) alkyl, R 4 is a 5- or 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, wherein the 5- or 6-membered heteroaryl is each optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, oxo, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl, (C-C)cycloalkyl-(C-C)alkyl, and (C-C)alkyl(C-C)cycloalkyl; R 5 is NR 8 R 9 and R 6 is selected from H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl-(C1-C6)alkyl; R 7 is (C3-C6)cycloalkyl or (C6-C 10 )aryl, (C3-C6)cycloalkyl and (C6-C 10 ) each aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, and —HOC—(C1-C6)alkyl; R 8 and R 9are each independently H, (C1-C6) alkyl, or a 3- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S; or R 8 and R 9 together with the N to which they are attached form a 3- to 10-membered heterocycle optionally containing 1 or 2 additional heteroatoms selected from N, O, and S, which 3- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl-(C-C)alkyl, (C-C)cycloalkyl, (C-C)alkyl-O—(C-C)alkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, and a 3- to 7-membered heterocycle containing 1 to 2 heteroatoms selected from N, O, and S; and R a , R b , R c and R d are each independently H or (C1-C6) alkyl. or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the present disclosure provides a compound of formula (I): [ka] (In the formula, A is CR 2 R 3 and R 2 is phenyl, wherein the phenyl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C1-C6)alkyl, and (C3-C6)cycloalkyl; R 3 is H or (C1-C6) alkyl, R 4is (C6-C10)aryl or a 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, and (C6-C 10 ) aryl or 5- or 6-membered heteroaryl are each optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, oxo, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl, (C-C)cycloalkyl-(C-C)alkyl, and (C-C)alkyl(C-C)cycloalkyl; R 5 is NR 8 R 9 and R 6 is selected from H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl-(C1-C6)alkyl; R 7 is (C3-C6)cycloalkyl or (C6-C 10 )aryl, (C3-C6)cycloalkyl and (C6-C 10 ) each aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, and —HOC—(C1-C6)alkyl; R 8 and R 9 are each independently H, (C1-C6) alkyl, or a 3- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S; or R 8 and R 9together with the N to which they are attached form a 3- to 10-membered heterocycle optionally containing 1 or 2 additional heteroatoms selected from N, O, and S, which 3- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl-(C-C)alkyl, (C-C)cycloalkyl, (C-C)alkyl-O—(C-C)alkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, and a 3- to 7-membered heterocycle containing 1 to 2 heteroatoms selected from N, O, and S; and R a , R b , R c and R d are each independently H or (C1-C6) alkyl. or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the present disclosure provides a compound of formula (I): [ka] (In the formula, A is CR 2 R 3 and R 2 is phenyl, wherein the phenyl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C1-C6)alkyl, and (C3-C6)cycloalkyl; R 3 is H or (C1-C6) alkyl, R 4 is (C6-C10)aryl or a 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, and (C6-C 10) aryl or 5- or 6-membered heteroaryl are each optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, oxo, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl, (C-C)cycloalkyl-(C-C)alkyl, and (C-C)alkyl(C-C)cycloalkyl; R 5 is NR 8 R 9 and R 6 is selected from H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl-(C1-C6)alkyl; R 7 is (C3-C6)cycloalkyl or (C6-C 10 )aryl, (C3-C6)cycloalkyl and (C6-C 10 ) each aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, and —HOC—(C1-C6)alkyl; R 8 and R 9 are each independently H, (C1-C6) alkyl, or a 3- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S; or R 8 and R 9together with the N to which they are attached form a 3- to 10-membered heterocycle optionally containing 1 or 2 additional heteroatoms selected from N, O, and S, which 3- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl-(C-C)alkyl, (C-C)cycloalkyl, (C-C)alkyl-O—(C-C)alkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, and a 3- to 7-membered heterocycle containing 1 to 2 heteroatoms selected from N, O, and S; and R a , R b , R c and R d are each independently H or (C1-C6) alkyl. or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the present disclosure provides a compound of formula (I): [ka] (In the formula, A is NR 1 and R 1 (C6~C 10 ) aryl, (C6-C 10 ) aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C1-C6) alkyl, and (C3-C6) cycloalkyl; R 3 is H or (C1-C6) alkyl, R 4 (C6~C 10 ) aryl or 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, (C6-C 10) aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, and (C1-C6)alkyl; and 5- or 6-membered heteroaryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, oxo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, and (C1-C6)alkyl(C3-C6)cycloalkyl; R 5 is NR 8 R 9 and R 6 is selected from H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl-(C1-C6)alkyl; R 7 is (C3-C6)cycloalkyl or (C6-C 10 )aryl, (C3-C6)cycloalkyl and (C6-C 10 ) each aryl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —COH, and —HOC—(C1-C6)alkyl; R 8 and R 9 together with the N to which they are attached form a 3- to 10-membered heterocycle optionally containing 1 or 2 additional heteroatoms selected from N, O, and S, which 3- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, —CN, —OH, —COH, (C-C)alkyl, (C-C)haloalkyl, (C-C)cycloalkyl-(C-C)alkyl, (C-C)cycloalkyl, (C-C)alkyl-O—(C-C)alkyl, (C-C)hydroxyalkyl, (C-C)alkoxy, and a 3- to 7-membered heterocycle containing 1 to 2 heteroatoms selected from N, O, and S; and Ra , R b , R c and R d are each independently H or (C1-C6) alkyl. or a pharmaceutically acceptable salt thereof.

[0041] In certain embodiments, the compound is a compound selected from the following, or a pharmaceutically acceptable salt thereof:

[0042] [Table 1]

[0043] [Table 2]

[0044] [Table 3]

[0045] [Table 4]

[0046] [Table 5]

[0047] [Table 6]

[0048] [Table 7]

[0049] [Table 8]

[0050] Table 9

[0051] Table 10

[0052] Table 11

[0053] Table 12

[0054] Table 13

[0055] Table 14

[0056] Table 15

[0057] Table 16

[0058] Table 17

[0059] Table 18

[0060] Table 19

[0061] Table 20

[0062] Table 21

[0063] Table 22

[0064] Table 23

[0065] Table 24

[0066] Table 25

[0067] Table 26

[0068] Table 27

[0069] Table 28

[0070] Table 29

[0071] Table 30

[0072] Table 31

[0073] Table 32

[0074] Table 33

[0075] Table 34

[0076] Table 35

[0077] Table 36

[0078] Table 37

[0079] As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of a compound of the present disclosure. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compound of the present disclosure and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure can form acid salts and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. When both basic and acidic groups are present in the same molecule, the compounds of the present disclosure can also form internal salts, such as zwitterionic molecules.

[0080] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0081] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0082] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0083] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0084] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In particular embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly preferred salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0085] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0086] In another aspect, the present disclosure provides an agonist or antagonist of the present invention, comprising an agonist or antagonistic acid salt selected from the group consisting of acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutanate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl phosphate, lauric acid salt ... In some embodiments, the compounds of the present disclosure may be in the form of a methylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate salt.

[0087] Any formula provided herein is intended to represent the unlabeled form of compound as well as the isotopically labeled form.Isotopically labeled compound has the structure represented by the formula provided herein, except that one or more atoms are replaced with atoms having selected atomic mass or mass number.The isotope that can be incorporated into the compound of the present disclosure includes, for example, hydrogen isotopes.

[0088] Additionally, certain isotopes, especially deuterium (i.e. 2Incorporation of hydrogen atoms (H or D) may result in certain therapeutic advantages resulting, for example, from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, or improved therapeutic index or tolerability. It is understood that deuterium in this context is considered a substituent of the compounds of the present disclosure. The concentration of deuterium can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor," as used herein, means the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent of a compound of the present disclosure is designated as deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It is understood that the term "isotopic enrichment factor" can apply to any isotope in the same manner as described for deuterium.

[0089] Other examples of isotopes that may be incorporated into compounds of the present disclosure include: 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 and isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. Thus, the present disclosure provides, for example, 3 H and 14 Radioactive isotopes such as C or 2 H and 13It should be understood that compounds incorporating one or more of any of the above isotopes are included, including those in which a non-radioactive isotope such as C is present. Such isotopically labeled compounds may be useful in metabolic studies, including drug or substrate tissue distribution assays. 14 C), reaction kinetic studies (e.g., 2 H or 3 H), positron emission tomography (PET) or single photon emission computed tomography (SPECT), or in detection or imaging techniques, or in radiotherapy of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations, substituting the appropriate isotopically labeled reagent for the previously used unlabeled reagent.

[0090] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present disclosure can be present in racemic or enantiomerically enriched, such as the (R), (S), or (R,S) configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) or (S) configuration. Substituents of atoms having unsaturated double bonds can exist in cis-(Z) or trans-(E) form, where possible.

[0091] Thus, as used herein, a compound of the present disclosure may be in the form of one of its possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as a substantially pure geometric (cis or trans) stereoisomer, diastereomer, optical isomer (enantiomer), racemate, or mixtures thereof.

[0092] Any resulting mixture of stereoisomers can be separated on the basis of the physical chemical differences of the components into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0093] Any resulting racemic forms of the compounds or intermediates of the present disclosure can be separated into their optical antipodes by known methods, such as, for example, separation of their diastereomeric salts obtained with optically active acids or bases and liberation of the optically active acidic or basic compounds. Thus, compounds of the present disclosure can be resolved into their optical antipodes using a basic moiety, for example, by fractional crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic compounds or racemic intermediates of the present disclosure can also be separated by chiral chromatography, such as, for example, high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0094] Pharmaceutical Composition In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein.

[0095] In some embodiments, the pharmaceutical composition further comprises at least one additional pharmaceutically active agent, hi some embodiments, the additional pharmaceutically active agent is selected from an ACE (angiotensin-converting enzyme) inhibitor, an angiotensin receptor blocker (ARB), a neprilysin inhibitor, a beta-blocker, a diuretic, a calcium channel blocker, a cardiac glycoside, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), or a combination thereof.

[0096] Pharmaceutical compositions may be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also involve inhalation or intranasal application. Pharmaceutical compositions of the present disclosure may be configured in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets may be either film-coated or enteric-coated according to methods known in the art. Typically, pharmaceutical compositions are tablets or gelatin capsules containing the active ingredient in combination with one or more of the following: a) diluents such as, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants such as, for example, silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; Tablets also include: c) binders, such as, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, if desired; d) disintegrating agents, such as, for example, starch, agar, alginic acid or its sodium salt or effervescent mixtures, and e) Absorbents, colorants, flavors and sweeteners.

[0097] Liquids, particularly injectable compositions, can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed compounds are dissolved in or mixed with a pharmaceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins, such as albumin, chylomicron particles, or serum proteins, can be used to solubilize the disclosed compounds.

[0098] The disclosed compounds may also be formulated as suppositories which may be prepared from fatty emulsions or suspensions, using polyalkylene glycols, such as propylene glycol, as the carrier.

[0099] Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolving in liquid prior to injection.

[0100] The compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compounds by weight or volume.

[0101] Dosage regimens using the disclosed compounds are selected depending on a variety of factors, including the type, species, age, weight, sex, and condition of the patient, the severity of the condition being treated, the route of administration, the patient's renal or hepatic function, and the particular disclosed compound being used. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, combat, or arrest the progress of the condition.

[0102] The pharmaceutical compositions or combinations of the present disclosure may be, for example, in a unit dosage of about 1 to 1000 mg of active ingredient for a subject weighing about 50 to 70 kg. In one embodiment, the composition is in the form of a tablet that can be divided. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof will depend on the subject's species, weight, age, and individual condition, disorder, or disease being treated, and its severity.

[0103] How to use In yet another aspect, the present disclosure relates to a method of treating or preventing a disease or disorder, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0104] In another aspect, the present disclosure relates to a method of treating a disease or disorder, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the disease or disorder is a cardiovascular disease or disorder.

[0105] In certain embodiments, the cardiovascular disease or disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina pectoris, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, cardiac arrhythmias, atrial fibrillation (AF), new-onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, and myocardial infarction (MI). In some embodiments, the heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute decompensated heart failure. In some embodiments, the hypertrophic cardiomyopathy is ventricular hypertrophy. In some embodiments, the hypertension is selected from resistant hypertension, hypertensive heart disease, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, resistant hypertension, and pulmonary arterial hypertension. In some embodiments, the hypertension is selected from resistant hypertension and hypertensive heart disease.

[0106] In some embodiments, the disease or disorder is preeclampsia, asthma, glaucoma, renal damage and / or cytokine release syndrome in a subject in need of such treatment. In some embodiments, the renal damage is selected from diabetic renal failure, non-diabetic renal failure, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast-induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary renal disease, renovascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD).

[0107] In some embodiments, the disease or disorder is a disorder or condition associated with natriuretic peptide receptor activity.

[0108] Another aspect of the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as described herein, for the manufacture of a medicament for the treatment of a disease or disorder disclosed herein.

[0109] In another aspect, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use as a medicament.

[0110] Another aspect of the present disclosure relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein, for use in treating a disease or disorder disclosed herein. In some embodiments, the disease or disorder is a cardiovascular disease or disorder (e.g., a cardiovascular disease or disorder disclosed herein).

[0111] In another aspect, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the treatment of a disease or disorder disclosed herein.

[0112] The disclosed compounds of the present disclosure can be administered in an amount effective to treat or prevent, and / or prevent the onset of, a disorder in a subject.

[0113] Combination therapy The compounds of the present disclosure can be administered in therapeutically effective amounts in combination therapy with one or more pharmaceutically active agents (pharmaceutical combinations) or therapies, such as non-drug therapies. The compounds of the present disclosure can be administered simultaneously with, before, or after one or more other pharmaceutically active agents. The compounds of the present disclosure can be administered separately, by the same or different administration route, or together with other agents in the same pharmaceutical composition. The pharmaceutically active agent can be, for example, a chemical compound, a peptide, an antibody, an antibody fragment, or a nucleic acid, which is therapeutically active or enhances therapeutic activity when administered to a patient in combination with a compound of the present disclosure.

[0114] In one embodiment, the present disclosure provides a product comprising a compound of the present disclosure and at least one other pharmaceutically active agent as a combined preparation for simultaneous, separate, or sequential use as disclosed herein. Products provided as combined preparations include compositions comprising a compound of the present disclosure and the other pharmaceutically active agent together in the same pharmaceutical composition as described herein, or compositions comprising a compound of the present disclosure and the other pharmaceutically active agent in separate forms, for example, in the form of a kit.

[0115] In another aspect, the disclosure includes a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination therapy.

[0116] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more pharmaceutically active agents. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant.

[0117] Combination therapy includes the administration of the present compound in further combination with other biologically active ingredients. For example, the compounds of the present application can be used in combination with other pharmaceutically active agents, preferably compounds that can enhance the effects of the compounds of the present application. The compounds of the present application can be administered simultaneously (as a single formulation or separate formulations) or sequentially with other drug therapies or treatments. Generally, combination therapy contemplates the administration of two or more drugs during a single treatment cycle or course of treatment.

[0118] Exemplary additional pharmaceutically active agents that may be used in combination with the compounds of the present disclosure include, but are not limited to, ACE (angiotensin-converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), neprilysin inhibitors, beta-blockers, diuretics, calcium channel blockers, cardiac glycosides, sodium-glucose cotransporter 2 inhibitors (SGLT2i), or combinations thereof. As a non-limiting set of examples, the compounds described herein or pharmaceutically acceptable salts thereof include enalapril, benazepril, fosinopril, captopril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, valsartan, azilsartan, candesartan, eprosartan, irbesartan, losartan, telmisartan, sacubitril, bisoprolol, carvedilol, propanolol, thiazolinone ... The diuretics and digitalis glycosides may be combined with an additional pharmaceutically active agent selected from benzodiazepine, metoprolol, metoprolol tartrate, metoprolol succinate, thiazide diuretics, loop diuretics, amlodipine, clevidipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, digitalis glycosides, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and combinations thereof. Exemplary diuretics and digitalis glycosides include, but are not limited to, chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, eplerenone, spironolactonem, triamterene, digoxin, and combinations thereof. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof may be combined with an angiotensin receptor-neprilysin inhibitor (ARNi), such as a combination of sacubitril and valsartan (e.g., Entresto®).In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, may be combined with one or more of a corticosteroid (e.g., an inhaled corticosteroid such as fluticasone, budesonide, mometasone, beclomethasone, ciclesonide, or fluticasone furoate, or an oral or intravenous corticosteroid such as prednisone or methylprednisolone), a leukotriene modifier (e.g., montelukast, zafirlukast, or zileuton), a bronchodilator (e.g., a long-acting beta-agonist (e.g., salmeterol or formoterol), a short-acting beta-agonist (e.g., albuterol or levalbuterol), theophylline, or ipratropium), or a combination thereof (e.g., a combination of fluticasone and salmeterol, a combination of budesonide and formoterol, or a combination of formoterol and mometasone). In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof may be combined with one or more of a beta-adrenergic receptor antagonist (e.g., timolol, levobunolol, metipranolol, carteolol, or betaxolol), a carbonic anhydrase inhibitor (e.g., acetazolamide, dorzolamide, brinzolamide, or methazolamide), an alpha2-adrenergic receptor agonist (e.g., brimonidine or apraclonidine), a parasympathomimetic (e.g., a cholinomimetic such as pilocarpine), a prostaglandin analog (e.g., latanoprost, latanoprost bunod, travoprost, bimatoprost, or tafluprost), a rho-kinase inhibitor (e.g., netarsudil or ripasudil), or a combination thereof (e.g., a combination of a rho-kinase inhibitor and latanoprost).

[0119] "Combination therapy" is intended to encompass sequential administration of these therapeutic agents, with each therapeutic agent being administered at different times and in any order, or alternating and in any order, and with at least two of these therapeutic agents being administered substantially simultaneously. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single capsule containing a fixed ratio of each therapeutic agent, or a single capsule multiple times for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same or different routes. For example, a first therapeutic agent of a selected combination can be administered by intravenous injection, while other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection. The order in which the therapeutic agents are administered is not strictly important.

[0120] Compound synthesis method The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are illustrated in the schemes shown below.

[0121] Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, as illustrated in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are used as needed in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage in the compound synthesis, using methods readily apparent to those skilled in the art. The selected processes and reaction conditions and the order of their execution shall be consistent with the preparation of compounds of formula (I).

[0122] Those skilled in the art will recognize whether a stereocenter exists in compounds of formula (I). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis), including not only the racemate but also the individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0123] The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic and / or enzymatic processes.

[0124] General Reaction Scheme 1 [ka] In the formula, A, R a ~R d and R 4 ~R 7 is defined herein for formula (I).

[0125] A general scheme for preparing compounds of formula (I) is described in General Reaction Scheme I. Ia: CO cross-coupling step, e.g., DIPEA, MeCN, 80°C, 40 hours; Ib: CN cross-coupling step, e.g., DIPEA, MeCN, 100°C, 72 hours; Ic: CN cross-coupling step, followed by hydrolysis, e.g., DIPEA, i-PrOH, 110°C, 48 hours, purification, followed by treatment with 4N aqueous NaOH in THF / MeOH. Step Ia: Compounds of formula INT-(II) can be prepared by reacting compounds of formula INT-(I) with 2,3,5,6-tetrafluorophenol and a base such as DIPEA in a suitable solvent such as MeCN at 80°C for 40 hours, followed by flash column chromatography. Compounds of formula INT-(I) can be prepared by any suitable known method, including, for example, the methods shown for preparing intermediates 1-5 in Examples 1-5 below. Step Ib: Compounds of formula INT-(II) can be prepared by reacting compounds of formula INT-(II) and INT-(VI) with a base such as DIPEA in a suitable solvent such as MeCN at 100°C for 72 hours (see, for example, Intermediates 6-8 in the exemplary preparation), followed by flash column chromatography. Step Ic: Compounds of formula (I) can be prepared by the following sequence: compounds of formula INT-(III) and INT-(VII) with a base such as DIPEA in a suitable solvent such as i-PrOH at 110°C for 40 hours (see, for example, Intermediate 9 in the exemplary preparation), followed by flash column chromatography or used as a crude material after concentration. The material is then treated with a base such as NaOH in THF / MeOH / water, followed by reverse-phase purification to give compounds of formula (I).

[0126] General Reaction Scheme II [ka] In the formula, A, R a ~R d and R 4 ~R 7is defined herein for formula (I).

[0127] A general scheme for preparing compounds of formula (I) is described in General Reaction Scheme II. II.a: CN cross-coupling step, e.g., DIPEA, MeCN, 70°C, 3 hours; II.b: CN cross-coupling step, followed by hydrolysis, e.g., DIPEA, MeCN, 160°C, 48 hours in a microwave reactor, purification, and then treatment with 4N aqueous NaOH in THF / MeOH. Step II.a: Compounds of formula INT-(V) can be prepared by reacting compounds of formula INT-(I) with compounds of formula INT-(VII) and a base such as DIPEA in a suitable solvent such as MeCN at 70°C for 3 hours (see, e.g., Intermediate 9 in the exemplary preparation), followed by flash column chromatography. Compounds of formula INT-(I) can be prepared by any suitable known method, including, for example, the methods shown for preparing Intermediates 1-5 in Examples 1-5 below. Step II.b: Compounds of formula (I) can be prepared by the following sequence: Compounds of formula INT-(V) and INT-(VI) are reacted with a base such as DIPEA in a suitable solvent such as i-PrOH at a temperature of 160° C. for 480 hours (see, for example, intermediates 6-8 in the exemplary preparation), followed by flash column chromatography or used as crude material after concentration. The material is then treated with a base such as NaOH in THF / MeOH / water, followed by reverse phase purification to give compounds of formula (I).

[0128] definition Terms not specifically defined herein should be given the meaning that could be given them by one of ordinary skill in the art in light of the present disclosure and the context. For purposes of interpreting this specification, the following definitions shall apply unless otherwise noted and whenever appropriate, and terms used in the singular shall include the plural and vice versa.

[0129] It must be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "pharmaceutical formulation" includes reference to one or more pharmaceutical formulations, etc.

[0130] The term "alkoxy," as used herein, refers to an alkyl group, preferably a lower alkyl group having an oxygen attached thereto, e.g., -O(alkyl). Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, and the like. Representative substituted alkoxy groups include, but are not limited to, -OCF3, and the like.

[0131] An "alkyl" group or "alkane" is a completely saturated, straight-chain or branched-chain non-aromatic hydrocarbon. Typically, a straight-chain or branched-chain alkyl group has 1 to about 20 carbon atoms, preferably 1 to about 10, unless otherwise defined. Examples of straight-chain and branched-chain alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight-chain or branched-chain alkyl groups are also referred to as "lower alkyl" groups.

[0132] The term "aryl," as used herein, includes monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is 5- to 7-membered, more preferably 6-membered. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is aromatic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0133] "C x ~C y The term "C" when used with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups containing x to y carbons in the chain. For example, "C x ~C y The term "alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups containing x to y carbons in the chain. C0 alkyl indicates a hydrogen when the group is in a terminal position and a bond when it is internal. "C2 to C y Alkenyl" and "C2-C y The term "alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively.

[0134] As used herein, the terms "carbocycle" and "carbocyclic" refer to saturated or unsaturated rings in which each atom of the ring is carbon. The term carbocycle includes both aromatic and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings in which all carbon atoms are saturated and cycloalkene rings that contain at least one double bond. "Carbocycle" includes 5- to 7-membered monocyclic and 8- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, or three or more atoms are shared between two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, such as phenyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocyclic when valences allow.

[0135] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings.

[0136] The term "cycloalkyl-alkyl," as used herein, refers to an alkyl group substituted with a cycloalkyl group.

[0137] The term "alkyl-cycloalkyl," as used herein, refers to a cycloalkyl group substituted with an alkyl group.

[0138] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo and iodo.

[0139] "Haloalkyl," as used herein, refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like. "Fluoroalkyl," as used herein, refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) fluoro groups.

[0140] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic ring structures, preferably 5- to 7-membered rings, more preferably 5- or 6-membered rings, which ring structures include at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyridyl N-oxide, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2 -b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzo[1,2-a]pyridinyl, Zothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1, 6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1Δ2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[l,5-a] Pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4 d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.

[0141] The term "heteroatom," as used herein, means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0142] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, whose ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl," "heterocycle," and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is heterocyclic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Polycyclic ring systems may be fused or bridged. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, azaadamantane, and the like. Heterocyclyl groups may also be substituted with an oxo group. For example, "heterocyclyl" includes both pyrrolidine and pyrrolidinone.

[0143] As used herein, the term "oxo" refers to a carbonyl group. When an oxo substituent is present on an otherwise saturated group, such as in the case of an oxo-substituted cycloalkyl group (e.g., 3-oxo-cyclobutyl), the substituted group is still intended to be saturated. When a group is referred to as being substituted with an "oxo" group, this can mean that a carbonyl moiety (i.e., -C(=O)-) replaces a methylene unit (i.e., -CH2-).

[0144] The term "optionally substituted" means that a given chemical moiety (e.g., an alkyl group) can be (but need not be) attached to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents other than hydrogen, where the substituents are as defined herein. As used herein, "optionally substituted" can also refer to substituted or unsubstituted, the meanings of which are described below.

[0145] The term "substituted" means that the specified group or moiety bears one or more suitable substituents, and the substituents may be linked to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl is linked to one atom of the aryl by a bond or by being fused to the aryl and sharing two or more common atoms.

[0146] The term "unsubstituted" means that the specified group bears no substituents.

[0147] A "patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0148] The terms "pharmaceutically effective amount" or "therapeutically effective amount" or "effective amount" refer to an amount of a compound according to the present disclosure that, when administered to a patient in need thereof, is sufficient to treat a disease state, condition, or disorder for which the compound has utility. Such an amount will be sufficient to elicit the biological or medical response of a tissue, system, or patient that is desired by a researcher or clinician. The amount of a compound according to the present disclosure that constitutes a therapeutically effective amount will vary depending on factors such as the compound and its biological activity, the composition used for administration, the time of administration of the compound, the route of administration, the rate of excretion, the duration of treatment, the type and severity of the disease state or disorder being treated, drugs used in combination or concomitantly with the compound of the present disclosure, and the patient's age, weight, general health, sex, and dietary habits. Such a therapeutically effective amount can be routinely determined by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.

[0149] As used herein, the term "pharmaceutical composition" refers to a compound of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0150] "Carrier" encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body to another organ or part of the body of a subject.

[0151] A subject (preferably a human) is "in need of" such treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0152] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0153] As used herein, the terms "treat," "treatment," or "treating" any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of its clinical symptoms), or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible by the patient.

[0154] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder or delaying the onset or progression of the disease or disorder.

[0155] "Pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal being treated therewith.

[0156] "Disorder" means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0157] "Administer," "administering," or "administration" means either administering a disclosed compound, or a pharmaceutically acceptable salt or composition of a disclosed compound, directly to a subject, or administering a prodrug derivative or analog of the compound, or a pharmaceutically acceptable salt or composition of the compound, to a subject, which is capable of forming an equivalent amount of the active compound in the subject's body.

[0158] "Compounds of the disclosure," "compounds of Formula (I)," "compounds of the disclosure," and equivalent expressions (unless expressly stated otherwise) refer to compounds of Formula I described herein, where the context so permits, including salts thereof, particularly pharmaceutically acceptable salts thereof, as well as stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium ("D") substitution).

[0159] In certain embodiments, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range. [Example]

[0160] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of the disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate particular embodiments, and no limitation on the scope of the disclosure is intended thereby. It should further be understood that various other embodiments, modifications, and equivalents thereof that may themselves suggest themselves to those skilled in the art can be used without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0161] The compounds of the present disclosure can be prepared by methods known in the art of organic synthesis. It is understood that in all of the methods, protecting groups for sensitive or reactive groups can be used as needed in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Buts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art.

[0162] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either a Bruker Avance spectrometer or a Varian Oxford 400 MHz spectrometer unless otherwise noted. NMR spectra are given in ppm (δ), and coupling constants, J, are reported in hertz. Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26), or other solvents, as indicated in the NMR spectral data. A small amount of dried sample (2–5 mg) was dissolved in an appropriate deuterated solvent (1 mL). Mass spectra (ESI-MS) were collected using a Waters System (Acquity UPLC and Micromass ZQ mass spectrometer) or an Agilent-1260 Infinity (6120 Quadrupole); all masses reported are the m / z of the protonated parent ion unless otherwise noted. Chemical names were generated using CambridgeSoft's ChemBioDraw Ultra v14.

[0163] Temperatures are given in °C. As used herein, unless otherwise specified, the term "room temperature" or "ambient temperature" means a temperature between 15°C and 30°C, e.g., 20°C and 30°C, e.g., 20°C and 25°C. Unless otherwise specified, all evaporations are carried out under reduced pressure, typically about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical methods, e.g., microanalysis, and spectroscopic characteristics, e.g., MS, IR, NMR, etc. Abbreviations used are those commonly used in the art.

[0164] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present disclosure are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art.

[0165] Example 1 - Intermediate 1: 2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline [ka] Step 1: To a stirred solution of diethyl carbonate (2110.0 mL, 17.0 mol, 5.0 eq) in tetrahydrofuran (2.4 L) was added NaH (165 g, 4.1 mol, 1.2 eq, 60% dispersion in mineral oil) in small portions at room temperature. The resulting mixture was heated to 80° C., and then a solution of 4-phenylcyclohexanone (600.0 g, 3.4 mol) in tetrahydrofuran (2.4 L) was added dropwise over 1 h. The reaction mixture was then stirred at 80° C. for 1 h, quenched with saturated aqueous NH4Cl (1.2 L) at 0° C., and then extracted with EtOAc (3×5.0 L). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated to give a crude residue, which was purified on a silica gel column with heptane / EtOAc=100 / 1 to give the target compound ethyl 2-oxo-5-phenylcyclocarboxylic acid-1-carboxylate (771.8 g, purity: 64.5%, crude yield: 86.4%) as a colorless liquid. 1H NMR(400MHz,DMSO)δ 7.42-7.05(m,5H),4.19-4.10(m,2H),2.84-2.66(m,1H),2.52-2.43(m,2H),2.41-2. 27(m,1H),2.17(ddd,J=33.6,21.5,2.3Hz,2H),1.93-1.75(m,2H),1.26-1.12(m,3H).

[0166] Step 2: To a solution of ethyl 2-oxo-5-phenylcyclocarboxylic acid-1-carboxylate (700.0 g, 2.8 mol, 1.0 eq) and urea (341 g, 5.7 mol, 2.0 eq) in ethanol (12.5 L) was added sodium methoxide (1570.0 mL, 20% in methanol, 5.7 mol, 2.0 eq) at room temperature. The resulting reaction mixture was stirred at 80 °C for 16 hours. The reaction was monitored by HPLC. The reaction mixture was cooled to room temperature. The precipitated solid was filtered, washed with methyl tetrabutyl ether (1 L × 3), and dried to give 6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione as an off-white solid (510 g, purity: 98.6%, yield: 74%). 1 H NMR(400MHz,DMSO)δ 7.47-7.01(m,5H),5.43(s,1H),2.81-2.64(m,1H),2.57(d,J=4.6Hz,1H),2.43-2.22(m, 2H),2.11(dd,J=15.5,10.6Hz,1H),1.88(d,J=10.3Hz,1H),1.77(dt,J=11.7,6.2Hz,1H).

[0167] Step 3: To a mixture of 6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (500.0 g, 2.1 mol, 1.0 eq) in POCl3 (2.0 L, 4.0 V) was added N,N-diisopropylethylamine (266 g, 2.1 mol, 1.0 eq) dropwise over 30 minutes at room temperature under a nitrogen atmosphere. After the addition, the resulting mixture was heated to 120 °C and stirred for 16 hours. The reaction was monitored by HPLC. The reaction mixture was cooled to 25 °C in air and diluted with dichloromethane (2.0 L). The diluted suspension was concentrated in vacuo to remove most of the POCl3. The residue was dissolved in dichloromethane (6.0 L), and the remaining POCl3 was quenched by the addition of ice water (10.0 L) at 0 °C. The aqueous phase was extracted again with dichloromethane (3.0 L), dried over anhydrous Na2SO4, and the filtrate was concentrated to give a crude residue, which was purified on a silica gel column with heptane / EtOAc = 20 / 1 wp to give the desired product 2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline (266.0 g, purity: 99.2%, yield: 46%) as a yellow solid. LCMS: m / z = 257.00 [M+H] + ; 1 H NMR(400MHz,DMSO)δ 7.46-7.02(m,5H),3.17-2.88(m,4H),2.75(dd,J=16.9,11.0Hz,1H),2.14-1.90(m,2H).

[0168] Step 4: Racemic 2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline (266.0 g) was purified by chiral SFC (Chiralcel OJ-H, flow rate: 4 ml / min, cosolvent: 40%, cosolvent: methanol, injection volume: 2 μl, outlet pressure: 100 bar, T temperature: 35 °C) to give 105.0 g, 99.7% ee of (R)-2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline and 105.0 g, 98.6% ee of 2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline. The absolute stereochemistry was determined by small molecule X-ray crystallography.

[0169] Example 2 - Intermediate 2: 2,4-Dichloro-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline [ka] Step 1: To a solution of 2-phenylpropanal (430 g, 3.20 mol, 430 mL, 1 eq) in toluene (1.50 L) was added PPAS·HO (121 g, 640 mmol, 0.2 eq) and but-3-en-2-one (336 g, 4.81 mol, 400 mL, 1.5 eq) at 25 °C. The mixture was stirred at 80 °C for 16 h. TLC (petroleum ether / ethyl acetate = 10 / 1, Rf / reactants = 0.45, Rf / product = 0.45) showed the disappearance of the starting material and the formation of a new spot. The reaction mixture (860 g total) was combined, cooled to room temperature, and slowly added to water (5.00 L). The mixture was extracted with EtOAc (5.00 L). The organic layer was washed with saturated K2CO3 solution (3.00 L), brine (3.00 L), dried over Na2SO4, filtered, and concentrated. The product was used directly in the next step. 1-Methyl-2,3-dihydro-[1,1'-biphenyl]-4(1H)-one (1.20 kg, crude product) was obtained as a yellow oil.

[0170] Step 2: To a solution of 1-methyl-2,3-dihydro-[1,1'-biphenyl]-4(1H)-one (200 g, 1.07 mol, 1 eq, crude product) in EtOAc (1.00 L) was added Pd / C (20.0 g, 107 mmol, 10% purity, 0.1 eq) under a N atmosphere. The mixture was degassed and purged with H (50 Psi) for 3 min. The mixture was stirred at 40 °C for 12 h. TLC (petroleum ether / ethyl acetate = 10 / 1, Rf / reactant = 0.45, Rf / product = 0.65) showed the disappearance of the starting material and the formation of a new spot. The reaction mixture was filtered, and the cake was washed with EtOAc (600 mL × 3). The filtrate was concentrated. The product was purified by silica gel column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1). 4-Methyl-4-phenylcyclohexan-1-one (438 g, 2.33 mol, 54.1% yield) was obtained as a yellow oil. 1 H NMR(400MHz CDCl3)δ 7.50-7.45(m,2H),7.44-7.37(m,2H),7.30-7.24(m,1H),2.59-2.47(m,2H),2.44-2.28(m,4H),2.03-1.91(m,2H),1.35(s,3H).

[0171] Step 3: To a solution of 4-methyl-4-phenylcyclohexan-1-one (608 g, 5.15 mol, 624 mL, 5 eq) in THF (1.16 L) was slowly added NaH (49.4 g, 1.24 mol, 60% purity, 1.2 eq) at 20 °C. A solution of diethyl carbonate (194 g, 1.03 mol, 1 eq) in THF (388 mL) was added dropwise over 0.5 h at 80 °C. The mixture was stirred at 80 °C for 1 h. TLC (petroleum ether / ethyl acetate = 10 / 1, Rf / reactant = 0.40, Rf / product = 0.55) showed the disappearance of the starting material and the formation of a new spot. The reaction mixture was quenched with saturated NH4Cl (2 L) and extracted with EtOAc (400 mL). The organic layer was separated, washed with brine (700 mL × 2), dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel column chromatography (SiO2, petroleum ether). Ethyl 5-methyl-2-oxo-5-phenylcyclocarboxylic acid-1-carboxylate (325 g, 1.25 mol, 60.5% yield) was obtained as a yellow oil. 1 H NMR,(400MHz CDCl3)δ 7.32-7.22(m,4H),7.19-7.10(m,1H),4.22(q,J=7.2Hz,2H),4.07(q,J=7.2Hz,1H),2.82-2.70(m,1H),2.29(br d,J=16.4Hz,1H),2.25-2.17(m,1H),2.06-2.00(m,2H),1.82-1.73(m,1H),1.33-1.23(m,6H).

[0172] Step 4: To a mixture of ethyl 5-methyl-2-oxo-5-phenylcyclocarboxylic acid-1-carboxylate (295 g, 1.13 mol, 1 eq) in EtOH (2.95 L) was slowly added urea (136 g, 2.27 mol, 121 mL, 2 eq) and NaOMe (122 g, 2.27 mol, 2 eq). The mixture was stirred at 80 °C for 12 h. HPLC showed that approximately 7.2% of the starting material remained, and approximately 77.5% of the desired peak was detected at 220 nm. The reaction mixture was concentrated to remove most of the ethanol, and the product was triturated with MTBE (1.50 L) at 20 °C for 0.5 h. 6-Methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (210 g, crude product) was obtained as a white solid and used directly in the next step.

[0173] Step 5: To a mixture of 6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (200 g, 780 mmol, 1 eq) in dioxane (2.00 L) was added EtN (236 g, 2.34 mol, 325 mL, 3 eq), followed by the dropwise addition of POCl (1.20 kg, 7.80 mol, 725 mL, 10 eq) over 0.5 h at 0-5 °C. The mixture was stirred at 125 °C for 5 h. LCMS showed the reaction had disappeared and a new peak with the desired mass had formed. The reaction mixture was concentrated under reduced pressure and diluted with CHCl (3.00 L). The mixture was added to saturated NaHCO solution (5.00 L) and stirred at 20-40 °C for 0.5 h. The mixture was filtered through celite. The organic layer was separated, washed with brine (1.00 L), dried over Na2SO4, filtered, and concentrated. The product was purified by silica gel column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1). 2,4-Dichloro-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline (65.0 g, 220 mmol, 28.3% yield, 99.6% purity) was obtained as a yellow solid. LCMS: RT = 0.862 min, MS (ESI) m / z = 292.9 [M+H] + ; 1H NMR(400MHz CDCl3)δ 7.35-7.20(m,5H),3.38-3.34(m,1H),2.93-2.86(m,1H),2.87-2.80(m,1H),2 .60(dd,J=2.8,5.2Hz,1H),2.34-2.31(m,1H),2.01-1.97(m,1H),1.43(s,3H).

[0174] Step 6: Chiral separation of 2,4-dichloro-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline (65.0 g, 221 mmol, 1 eq) was carried out by SFC (column: DAICEL CHIRALPAK AY (250 mm × 50 mm, 10 μm); mobile phase: [0.1% NH₃·HO EtOH]; B%: 15% to 15%, 2.2; 2105 min). The product was concentrated. (R)-2,4-dichloro-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline (27.0 g) eluted as peak 1, and ((S)-2,4-dichloro-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline (24.0 g) eluted as peak 2, yielding a yellow oil.

[0175] Example 3 - Intermediate 3: 2,4-dichloro-6-(3-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinazoline [ka] Step 1: To a solution of 1-(3-fluorophenyl)ethan-1-one (100 g, 723.91 mmol) in THF (1 L) was added t-BuOK (130 g, 1160 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 1 h. Then, a solution of (methoxymethyl)triphenylphosphonium chloride (372 g, 1090 mmol) in THF (1 L) was added at 0° C. The reaction was warmed to 20° C. and stirred for 16 h. TLC (petroleum ether / ethyl acetate = 10 / 1) showed that the starting material was consumed and one major new spot was formed. The reaction mixture was poured into petroleum ether (2 L) and then filtered. The mixture was filtered through a pad of silica and concentrated under vacuum to give the desired product (£)-1-fluoro-3-(1-methoxyprop-1-en-2-yl)benzene (100 g, 602 mmol, 83.26% yield) as a yellow oil, which was used directly in the next step.

[0176] Step 2: To a solution of (E)-1-fluoro-3-(1-methoxyprop-1-en-2-yl)benzene (150 g, 902.57 mmol) in THF (1.5 L) was added a solution of HBr (663 g, 2170.71 mmol, in AcOH) in HO (300 mL) dropwise at 0 °C. After the addition was complete, the reaction was warmed to 40 °C and stirred for 3 h. TLC (petroleum ether / ethyl acetate = 10 / 1, Rf = 0.3) showed that the starting material was consumed and a new spot had formed. The reaction mixture was separated, and the aqueous phase was extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine and dried over anhydrous NaSO. Filtration and concentration under vacuum gave 2-(3-fluorophenyl)propanal (150 g, crude product), which was used directly in the next step.

[0177] Step 3: To a solution of 2-(3-fluorophenyl)propanal (140 g, crude product) in toluene (1200 mL) was added but-3-en-2-one (96 g, 1380.25 mmol) and pTsOH·HO (35 g, 184.01 mmol) at 25 °C. The mixture was stirred at 80 °C for 16 h. TLC (petroleum ether / ethyl acetate = 10 / 1) showed that the starting material was consumed and a major spot was formed. The reaction mixture was concentrated to remove toluene. The residue was purified by silica gel column chromatography (SiO2 (1000 g, 1000 mesh), petroleum ether to petroleum ether / ethyl acetate = 2 / 1), and then the desired fractions were concentrated to give 3'-fluoro-1-methyl-2,3-dihydro-[1,1'-biphenyl]-4(1H)-one (120 g, 579.61 mmol, 98.65% purity, 48.09% yield for two steps). LCMS: m / z = 205.2 [M+H] + ,RT=0.883min; 1 H NMR(400MHz,DMSO-d6)δ=7.41(dt,J=6.7,8.0Hz,1H),7.28-7.20(m,2H),7.15-7.07(m,2H),6.0 3(d,J=10.1Hz,1H),2.43-2.33(m,1H),2.29-2.19(m,1H),2.16-2.08(m,2H),1.53-1.49(m,3H).

[0178] Step 4: To a solution of 3'-fluoro-1-methyl-2,3-dihydro-[1,1'-biphenyl]-4(1H)-one (60 g, 293.76 mmol) in MeOH (600 mL) was added Pd / C (62 g, 58.75 mmol, 10% on carbon). The mixture was purged with H2 three times and degassed. The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered to remove Pd / C, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE to PE / EA = 2 / 1) and concentrated to give 4-(3-fluorophenyl)-4-methylcyclohexan-1-one (37.5 g, 62% yield, 88% purity). LCMS: RT = 0.909 min, m / z = 207.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 7.45-7.37(m,1H),7.36-7.29(m,2H),7.09-7.01(m,1H),2.40-2.29(m,4H),2.19-2.11(m,2H),1.98-1.89(m,2H),1.30(s,3H).

[0179] Step 5: To a solution of 4-(3-fluorophenyl)-4-methylcyclohexan-1-one (100 g, 848.46 mmol) and NaH (8.14 g, 87.27 mmol, 60%) in THF (200 mL) was added a solution of diethyl carbonate (35 g, 169.69 mmol) in THF (100 mL) dropwise at 80 °C under a N atmosphere. The mixture was stirred at 80 °C for 3 h. The reaction mixture was poured into HCl (200 mL, 1 N) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the desired product, ethyl 5-(3-fluorophenyl)-5-methyl-2-oxocyclohexane-1-carboxylate (30 g, 56% yield, 88.11% purity), as a yellow oil. LCMS: RT = 1.063 min, m / z = 279.2 [M+H]. + ; 1 H NMR(400MHz,DMSO-d6)δ ppm 7.32-7.41(m,1H),7.11-7.20(m,2H),7.02(td,J=8.28,2.26Hz,1H),4.23(q,J=7.03Hz,2H),2.69(br d,J=15.94Hz,1H),2.47-2.56(m,1H),2.20-2.36(m,2H),2.03-2.16(m,1H),1.84-1.98(m,1H);1.73-1.84(m,1H),1.12-1.31(m,6H).

[0180] Step 6: To a solution of 5-(3-fluorophenyl)-5-methyl-2-oxocyclohexane-1-carboxylate (30 g, 107.79 mmol) in EtOH (300 mL) was added urea (13 g, 215.58 mmol) and NaOMe (12 g, 215.58 mmol). The mixture was stirred at 80 °C for 16 h, and the mixture was filtered to give 6-(3-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (35 g crude) as a yellow solid, which was used directly in the next step. LCMS: RT = 0.806 min, m / z = 275.2 [M+H] + .

[0181] Step 7: To a solution of 6-(3-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (30 g, 109.49 mmol) and TEA (2.2 g, 16.41 mmol, 2.2 mL) in dioxane (200 mL) was added POCl (84 g, 546.87 mmol, 50.8 mL) dropwise at 0 °C. The mixture was warmed to 125 °C and stirred for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (column: 300 g SiO, PE and EA conditions), and the product fractions were concentrated in vacuo to give 2,4-dichloro-6-(3-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinazoline (27 g, 80.7% yield) as a yellow oil. LCMS: RT=1.028 min, m / z=311.2[M+H] + .

[0182] Step 8: Racemic 2,4-dichloro-6-(3-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinazoline (64 g, 205.78 mmol) was separated by SFC (column: DAICEL CHIRALPAK AY-H (250 mm × 30 mm, 10 μm), conditions: 0.1% NH₃·HO in EtOH, starting B%: 20% to ending B%: 20%). The solution was concentrated in vacuo to give the following: (R)-2,4-Dichloro-6-(3-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinazoline (14.6 g, 45.65 mmol, 22.20% yield, 94.7% purity). LCMS: RT = 1.034 min, m / z = 312.2 [M+H] + ,SFC:RT=0.905min; 1 H NMR(400MHz,DMSO-d6)δ=7.41-7.30(m,1H),7.20(br d,J=11.4Hz,1H),7.13(br d,J=7.8Hz,1H),7.09-6.98(m,1H),3.21(br d,J=17.5Hz,1H),3.00-2.78(m,2H),2.59-2.52(m,1H),2.40-2.16(m,1H),2.11-1.89(m,1H),1.34(s,3H) (S)-2,4-Dichloro-6-(3-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinazoline (11.2 g, 36.01 mmol, 17.50% yield, 99.3% purity). LCMS: RT=1.034 min, m / z=312.2 [M+H] + ,SFC:RT=0.905min; 1 H NMR(400MHz,DMSO-d6)δ=7.35(dt,J=6.6,8.0Hz,1H),7.20(td,J=2.2,11.4Hz,1H),7.13(dd,J=0.9,8.0Hz,1H),7.08-7.00(m,1H),3. 21(d,J=17.7Hz,1H),3.05-2.81(m,2H),2.58-2.53(m,1H),2.37-2.19(m,1H),2.00(ddd,J=6.1,8.2,13.9Hz,1H),1.36-1.27(m,3H).

[0183] Example 4 - Preparation of Intermediate 4: 2,4-dichloro-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline [ka] Step 1: A stirred suspension of 1-fluoro-3-iodobenzene (140 g, 630 mmol, 74.0 mL, 1.00 eq), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (149 g, 561 mmol, 0.89 eq), and CsCO (308 g, 945 mmol, 1.50 eq) in dioxane (1200 mL) / HO (300 mL) (8 / 2) was degassed with argon for 15 min. Pd(dppf)Cl·CHCl (29.8 g, 36.5 mmol, 0.058 eq) was then added and degassed again for 5 min. The reaction mixture was then heated to 70 °C for 16 h. TLC (petroleum ether / ethyl acetate = 10 / 1, reactant Rf = 0.50, new spot Rf = 0.34) showed complete consumption of the starting material and the detection of a new spot. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was diluted with HO (1.5 L) and extracted with EtOAc (1.5 L × 2). The combined organic layers were washed with brine (2 L × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (137 g, 584 mmol, 92.7% yield) as a brown oil. LCMS: MS (ESI) m / z = 235.2 [M+H] + ; 1 H NMR:(400MHz,DMSO-d6)δ 7.52-7.45(m,1H),7.40-7.31(m,2H),7.23-7.15(m,1H),6.26-6.21(m,1H),4.06-4.0 2(m,4H),2.76-2.55(m,3H),1.97-1.89(m,2H),1.33-1.27(m,1H),1.23-1.19(m,1H).

[0184] Step 2: To a solution of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (80.0 g, 341 mmol, 1.00 eq) in EtOH (880 mL) was added Pd / C (8.00 g, 10% purity) under a N atmosphere. The suspension was degassed three times with H, and the purged mixture was stirred under H (15 psi) at 20 °C for 12 h. TLC (petroleum ether / ethyl acetate = 10 / 1, reactant Rf = 0.35, new spot Rf = 0.42) indicated that the starting material had been consumed and a new spot had been detected. The reaction mixture was filtered through a celite pad, washed with excess EtOH (1 L) and EtOAc (1 L), and the filtrate was concentrated to give the desired compound. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate=5 / 1) to give 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]decane (74.4 g, 314 mmol, 92.2% yield) as a colorless oil. LCMS: MS(ESI) m / z=237.1 [M+H] + , 1 H NMR:δ 7.36-7.27(m,1H),7.11-6.92(m,3H),3.92-3.85(m,4H),2.68-2.57(m,1H),1.82-1.70(m,4H),1.69(s,4H).

[0185] Step 3: To a solution of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]decane (74.4 g, 314 mmol, 1.00 eq) in dioxane (620 mL) / HO (310 mL) (2 / 1) was added HCl (12 M, 309 mL, 11.7 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was consumed and the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was extracted with EtOAc (500 mL × 2), and the combined organic layers were washed with 500 mL of saturated NaHCO and 500 mL of brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the residue. The crude product, 4-(3-fluorophenyl)cyclohexan-1-one (64.5 g, crude) was used in the next step as a colorless oil without further purification. LCMS: Product RT=0.836 min, MS(ESI) m / z=193.2[M+H] + ; 1 H NMR:(400MHz,DMSO-d6)δ 7.38-7.30(m,1H),7.17-7.10(m,2H),7.06-6.98(m,1H),3.15-3.04(m,1H), 2.63-2.52(m,2H),2.31-2.21(m,2H),2.12-2.02(m,2H),1.96-1.80(m,2H).

[0186] Step 4: To a stirred solution of diethyl carbonate (245 g, 2.08 mol, 251 mL, 5.00 eq) in THF (400 mL) was added NaH (19.9 g, 498 mmol, 60.0% purity, 1.20 eq) in portions at 25 °C. The resulting mixture was heated to 80 °C, and then a solution of 4-(3-fluorophenyl)cyclohexan-1-one (79.9 g, 415 mmol, 1.00 eq) in THF (400 mL) was added over approximately 20 min. The reaction mixture was then stirred at 80 °C for 30 min. LCMS showed that the starting material was consumed and the desired compound was detected. The reaction mixture was quenched with saturated NH Cl solution (1 L) and extracted with EtOAc (1 L × 2). The combined organic layers were washed with saturated NaHCO (800 mL) and brine (600 mL), dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1, target spot Rf = 0.33) to give ethyl 5-(3-fluorophenyl)-2-oxocyclohexane-1-carboxylate (65.3 g, 247 mmol, 59.4% yield) as a pale yellow oil. LCMS product RT = 1.005 min, MS (ESI) m / z = 265.2 [M+H]. + ; 1 H NMR:(400MHz,DMSO-d6)δ 7.40-7.29(m,1H),7.19-7.09(m,2H),7.08-6.97(m,1H),4.21(br s,3H),2.88-2.69(m,1H),2.49-2.41(m,1H),2.35-2.04(m,2H),2.01- 1.92(m,1H),1.90-1.80(m,1H),1.77-1.41(m,1H),1.22-1.17(m,3H).

[0187] Step 5: To a stirred solution of ethyl 5-(3-fluorophenyl)-2-oxocyclohexane-1-carboxylate (75.0 g, 283 mmol, 1.00 eq) in EtOH (1680 mL) was added urea (34.0 g, 567 mmol, 30.4 mL, 2.00 eq), followed by NaOMe (30.6 g, 567 mmol, 2.00 eq), and the reaction mixture was heated to 80 °C for 16 h. LCMS indicated that the starting material had been consumed and the desired compound was detected. The reaction mixture was filtered, and the solid was washed with MBTE (900 mL) and water (500 mL) and concentrated under reduced pressure to give a residue. The crude product, 6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (48.5 g, crude), was used in the next step without further purification as a white solid. LCMS: Product RT=0.777 min, MS(ESI) m / z=261.0[M+H] + ; 1 H NMR:(400MHz,DMSO-d6)δ 7.39-7.28(m,1H),7.15-7.06(m,2H),7.04-6.96(m,1H),2.84-2.70(m,1H),2.60-2.52(m,1H), 2.44-2.37(m,1H),2.34-2.25(m,1H),2.18-2.05(m,1H),1.94-1.84(m,1H),1.82-1.71(m,1H).

[0188] Step 6: To a stirred suspension of 6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (44.0 g, 169 mmol, 1.00 eq) in dioxane (1760 mL) was added TEA (5.65 g, 55.7 mmol, 7.77 mL, 0.33 eq) followed by POCl (259 g, 1.69 mol, 157 mL, 10.0 eq) (dropwise) at 0 °C, and the reaction mixture was heated to 130 °C for 3 h. LCMS showed that the starting material was consumed and the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was slowly diluted with HO (300 mL), adjusted to pH 7 with saturated NaHCO (700 mL), then extracted with EtOAc (1 L × 3), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (3 x 20 mL) at 25°C for 2 h to give 2,4-dichloro-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (24.5 g, 82.4 mmol, 48.7% yield) as a yellow solid. LCMS: Product RT = 1.020 min, MS (ESI) m / z = 296.7 [M+H] + ; 1 H NMR: (400 MHz, chloroform-d) δ 7.38-7.30 (m, 1H), 7.09-7.03 (m, 1H), 7.01-6.93 (m, 2H), 3.22-2.96 (m, 4H), 2.79-2.67 (m, 1H), 2.30-2.19 (m, 1H), 2.08-1.92 (m, 1H).

[0189] Step 7: Racemic 2,4-dichloro-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline was purified by SFC (Column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); Mobile phase: [0.1% NH H O MeOH]; B%: 30%–30%, 2.8 min; 1100 min) to give: (R)-2,4-Dichloro-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (10.6 g, ee>99%): LCMS: Product RT=1.047 min, MS(ESI) m / z=297.2 [M+H] + ;1 H NMR: (400 MHz, chloroform-d) δ 7.37-7.30 (m, 1H), 7.08-7.03 (m, 1H), 7.03-6.93 (m, 2H), 5.32-5.30 (m, 1H), 3.20-2.98 (m, 4H), 2.80-2.69 (m, 1H), 2.29-2.20 (m, 1H), 2.06-1.94 (m, 1H) as a yellow solid. (S)-2,4-Dichloro-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (12.0 g, ee>99%): LCMS: RT=1.005 min, MS(ESI) m / z=296.7 [M+H] + ; 1 H NMR: (400 MHz, chloroform-d) δ 7.39-7.31 (m, 1H), 7.08-7.03 (m, 1H), 7.03-6.94 (m, 2H), 3.20-2.97 (m, 4H), 2.79-2.69 (m, 1H), 2.29-2.20 (m, 1H), 2.07-1.94 (m, 1H) as a yellow solid.

[0190] Example 5 - Preparation of Intermediate 5: (R)-2,4-dichloro-6-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline [ka] Step 1: 4,5,5-Tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (10 g, 37.6 mmol), 1-bromo-4-fluorobenzene (7.89 g, 45.1 mmol), Na2CO3 (15.93 g, 150 mmol) were mixed in 1,4-dioxane (150 mL) and water (37.5 mL). The mixture was degassed with nitrogen for 5 minutes. PdCl2(dppf)·CHCl2 adduct (1.534 g, 1.879 mmol) was added, and the reaction was heated at 90 °C overnight. LCMS indicated the reaction was complete. The crude product was cooled to room temperature, diluted with EtOAc, and filtered through celite (the celite was flushed with EtOAc). The filtrate was concentrated and purified on 2 x 120 g silica columns with 0-20% EtOAc / heptane to give 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (7.33 g, 31.3 mmol, 83% yield) as a white solid. LCMS (basic): RT = 1.03 min; MS m / z = 387.2 [M+H] + .

[0191] Step 2: A solution of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (3.67 g, 15.67 mmol) in EtOH (50 mL) was evacuated and backfilled with nitrogen three times. Pd-C (aqueous) 50% (1.667 g, 1.567 mmol) was added. A hydrogen balloon at 1 atmosphere pressure was attached via an adapter. The reaction flask was evacuated and backfilled with hydrogen three times. The reaction was stirred under hydrogen at room temperature for 1 hour. LCMS showed the reaction was complete. The flask was evacuated to remove hydrogen, filtered through celite (flushed with DCM), and concentrated to give 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decane (3.3 g, 13.97 mmol, 89% yield) as a white solid. This material was used directly in the next step. LCMS (basic): Rt = 1.08 min; MS not observed. TLC: Rf = 0.6, 1:1 EtOAc / heptane.

[0192] Step 3: To a solution of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decane (4.63 g, 19.59 mmol) in DCM (15 mL) was added TFA (30.2 mL, 392 mmol). The resulting mixture was stirred at room temperature for 2 days. LCMS indicated the reaction was incomplete. Additional TFA (12 mL) was added. The reaction was continued for another day. The mixture was concentrated, diluted with EtOAc, and washed with saturated NaHCO3, water, and brine. It was then dried over Na2SO4 and concentrated on a rotary evaporator. The residue was purified by chromatography (120 g silica gel column, 0-50% EtOAc / heptane; the product was eluted at approximately 30% EtOAc / heptane) to give 4-(4-fluorophenyl)cyclohexan-1-one (3.1 g, 16.13 mmol, 82% yield) as a colorless oil. LCMS (basic): Rt=0.93 min; MS m / z=192.5[M+H]+.

[0193] Step 4: To a stirred solution of diethyl carbonate (19.60 mL, 162 mmol) in anhydrous THF (20 mL) was added NaH (0.776 g, 19.41 mmol) in mineral oil. A solution of 4-(4-fluorophenyl)cyclohexan-1-one (3.11 g, 16.18 mmol) in anhydrous THF (10 mL) was added. The reaction was stirred at room temperature for 30 minutes, then heated to 75 °C and stirred under nitrogen for 1.5 hours. TLC showed no starting material remaining, instead a major new spot. LCMS showed a major new peak and almost no starting material remaining. The reaction was cooled to 0 °C, quenched with 30 mL of saturated NH4Cl, and extracted with 150 mL of EtOAc. The organic layer was washed with brine and dried over sodium sulfate. This was then concentrated on a rotary evaporator and purified by ISCO (120 g silica gel column, 0-20% EtOAc / heptane) to give ethyl 5-(4-fluorophenyl)-2-oxocyclohexane-1-carboxylate (2.5 g, 9.46 mmol, 58.5% yield). LCMS (basic): Rt = 1.28 min, MS m / z = 265.2 [M+H]. +TLC: Rf=0.80, 1:1 EtOAc / heptane. The product contained minor impurities. It was used "as is" in the next step.

[0194] Step 5: To a solution of ethyl 5-(4-fluorophenyl)-2-oxocyclohexane-1-carboxylate (4.25 g, 16.08 mmol) in MeOH (40 mL) was added urea (1.931 g, 32.2 mmol) and NaOMe (1.737 g, 32.2 mmol). The mixture was heated to 75° C. under nitrogen for 20 h. LCMS showed the reaction was complete (LCMS: RT=0.74 min MS m / z=261.1 [M+H]). + ). A white precipitate was observed. The reaction was cooled to room temperature, and the precipitate was filtered, washed with Et2O, and dried to give the desired product, 6-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (2.5 g, 59.4% yield). LCMS (basic): RT = 0.74 min, MS m / z = 261.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 7.36-7.21(m,2H),7.11(t,J=8.8Hz,2H),2.75(dtd,J=14.3,7.7,3.5Hz,1H),2.55(dd,J=15.8,5.0Hz, 1H),2.45-2.21(m,2H),2.09(dd,J=16.0,10.9Hz,1H),1.95-1.82(m,1H),1.73(td,J=11.9,5.4Hz,1H).

[0195] Step 6: To a stirred suspension of 6-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (2.5 g, 9.61 mmol) and TEA (3.21 mL, 23.05 mmol) in 1,4-dioxane (10 mL) was added POCl (8.95 mL, 96 mmol) dropwise over 10 minutes at 0 °C. The resulting reaction mixture was stirred at 125 °C for 23 hours (a dark precipitate was observed). LCMS indicated the reaction was complete. The crude product was concentrated under reduced pressure to remove 1,4-dioxane and excess POCl. The resulting residue was poured into ice water and stirred for approximately 30 minutes. The mixture was extracted with EtOAc and DCM. The separated organic layer was washed with half-saturated NaHCO3, brine, concentrated, and purified by ISCO (120 g silica gel column, 0-50% EtOAc / heptane) to give the racemic product (1.51 g, 4.83 mmol, 50.3% yield) as a beige solid. This material was separated by chiral SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3·HO MeOH]; B%: 30%-30%, 2.8 min; 1100 min) to give the enantiomeric product (R)-2,4-dichloro-6-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (peak 1, 630 mg, 42% yield). LCMS (basic): RT = 1.20 min, MS = 299.3 [M+H]. + ; 1 H NMR(400MHz, methylene chloride-d2)δ 7.37-7.23(m,2H),7.17-7.05(m,2H),3.23-2.97(m,4H),2.82-2.68(m,1H),2.23(ddq,J=13.7,5.8,2.9Hz,1H),2.11-1.91(m,1H).

[0196] Example 6 - Preparation of Intermediate 6: (R)-3-(1-(methylamino)propyl)bicyclo[1.1.1]pentane-1-carboxylate hydrochloride [ka] Step 1: To a solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (253.0 g, 1.5 mol, 1.0 eq) in anhydrous THF (2500.0 mL) was added borane methyl sulfide complex (2232.0 mL, 2.0 mol / L, 4.5 mol, 3.0 eq) dropwise at 0° C., and the reaction mixture was stirred at 0° C. for 2 h. The reaction was monitored by GC. The reaction mixture was quenched with MeOH (750.0 mL) until no bubbles were produced at 25° C. The mixture was concentrated under reduced pressure at 45° C. The residue was dissolved in MTBE (5060.0 mL, 20 V), washed with saturated aqueous NaCl (759.0 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (255.0 g, GC purity: 98.8%, crude yield: 100%) as a pale yellow solid. 1 H NMR(300MHz, CDCl3)δ 3.75(s,2H),3.67(s,3H),1.96(dd,J=9.2,5.7Hz,6H).

[0197] Step 2: To a solution of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (crude product 255.0 g, 1.5 mol, 1.0 eq) in dry DCM (2500 mL) was added NaHCO (250.0 g, 3.0 mol, 2 eq) and DMP (753.3 g, 1.8 mol, 1.2 eq) at 0 °C. The mixture was warmed to 25 °C and stirred for 2 h. The reaction was monitored by GC. The reaction mixture was filtered through a celite pad, and the filter cake was washed with DCM (1000 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was diluted with EtOAc (5100 mL), washed with saturated aqueous sodium thiosulfate solution (500 mL × 2) and saturated aqueous NaHCO (500 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on a column with heptane / EA=10 / 1 to give methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (187.0 g, purity: 83.4%, crude yield: 70.2%) as a white solid. 1H NMR(300MHz,CDCl3)δ 9.60(s,1H),3.71(s,3H),2.32(s,6H).

[0198] Step 3: To a mixture of methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (180.0 g, 1.3 mol, 1.0 eq) in DCM (1800.0 mL, 10 V) was added (R)-(+)-2-methyl-2-propanesulfinamide (156.8 g, 1.3 mol, 1.0 eq) at 25 °C, and the mixture was stirred for 72 h. The reaction was monitored by GC. The reaction mixture was diluted with HO (900.0 mL) and separated. The aqueous layer was extracted with DCM (2700.0 mL, 15 V), and the combined organic layers were washed with saturated aqueous NaCl (500.0 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography with heptane / EA=5 / 1 to give methyl (R,E)-3-(((tert-butylsulfinyl)imino)methyl)bicyclo[1.1.1]pentane-1-carboxylate (210.0 g, purity: 59.2%, containing 40.8% (R)-2-methylpropane-2-sulfinamide (crude yield: 63.0%) as an off-white solid, which was used directly in the next step without further purification. 1 H NMR(300MHz,CDCl3)δ 7.97(s,1H),3.68(s,3H),2.28(s,6H),1.16(s,9H).

[0199] Step 4: To a solution of (R,E)-methyl 3-(((tert-butylsulfinyl)imino)methyl)bicyclo[1.1.1]pentane-1-carboxylate (200.0 g, 0.77 mol, 1.0 eq) in dry THF (1600.0 mL) was added ethylmagnesium bromide (777.0 mL, 1.5 mol, 2 mol / L, 2.0 eq) dropwise at −78° C., and the mixture was stirred for 2 h. The reaction was monitored by HPLC. The reaction mixture was quenched with saturated aqueous NH4Cl (1200.0 mL) at −78° C. The reaction mixture was warmed to 25° C. The mixture was extracted with EtOAc (3000.0 mL × 2), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with heptane / EA = 3 / 1 to give a crude product as a yellow oil. The crude product was purified by preparative HPLC to give 27.0 g of methyl (S)-3-(1-((tert-butylsulfinyl)amino)-113-propyl)bicyclo[1.1.1]pentane-1-carboxylate (purity 93.9%) and 81.0 g of methyl (R)-3-(1-((tert-butylsulfinyl)amino)-113-propyl)bicyclo[1.1.1]pentane-1-carboxylate (purity 97.2%). 1 H NMR(300MHz,CDCl3)δ 3.65(d,J=8.7Hz,3H),3.11(td,J=8.3,4.5Hz,1H),2.87(d,J=7.7Hz,1H),1.99(qd,J=9.6,1.8Hz,6 H),1.55(ddd,J=14.1,7.4,4.5Hz,1H),1.41-1.25(m,1H),1.25-1.11(m,9H),0.93(t,J=7.4Hz,3H).

[0200] Step 5: To a solution of (R)-methyl 3-(1-((tert-butylsulfinyl)amino)-113-propyl)bicyclo[1.1.1]pentane-1-carboxylate (63.0 g, 0.21 mol, 1.0 eq) in dry THF (0.7 L) under N was added LiHMDS (2 M, 210.0 mL, 0.42 mol, 2.0 eq) at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h. Then, MeI (59.6 g, 0.42 mol, 2.0 eq) was added dropwise at 0 °C, and the mixture was warmed to 25 °C and stirred for 2 h. The reaction was monitored by HPLC. The reaction mixture was quenched with ice water (1200.0 mL). The mixture was extracted with EtOAc (1000.0 mL × 3), and the combined organic layers were washed with saturated aqueous NaCl (500.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (R)-methyl 3-(1-((tert-butylsulfinyl)(methyl)amino)-113-propyl)bicyclo[1.1.1]pentane-1-carboxylate (55.0 g, purity: 82.1%, crude yield: 83.2%). 1 H NMR(300MHz,CDCl3)δ 3.66(s,3H),3.11(dd,J=8.7,6.6Hz,1H),2.49(s,3H),2.13(dd,J=9.5,1.8Hz,3H),2.00(dd,J=9.5, 1.8Hz,3H),1.62-1.46(m,2H),1.23(dd,J=9.0,5.2Hz,2H),1.23-1.11(m,9H),0.98(t,J=7.4Hz,3H).

[0201] Step 6: (R)-methyl 3-(1-((tert-butylsulfinyl)(methyl)amino)-113-propyl)bicyclo[1.1.1]pentane-1-carboxylate (55.0 g, 182.5 mmol, 1.0 eq) was added to 4 M HCl in 1,4-dioxane (467.0 mL, 1.8 mol, 10.0 eq) at 0° C., and the mixture was warmed to 25° C. and stirred for 2 h. The reaction was monitored by HPLC. The reaction mixture was concentrated under reduced pressure and exchanged with MTBE (110.0 mL × 2). The residue was triturated with MTBE / EtOAc (50 / 1, 165.0 mL) at 25° C. for 2 h. The mixture was filtered, and the filter cake was triturated with MTBE (275.0 mL, 5 V) at 25° C. for 2 h. The mixture was filtered and the filter cake was dried to give (R)-methyl 3-(1-(methylamino)propyl)bicyclo[1.1.1]pentane-1-carboxylate hydrochloride (25.5 g, yield: 59.8%) as a white solid. 1 H NMR(300MHz,MeOD)δ 3.70(s,2H),3.20-3.07(m,1H),2.73(s,3H),2.19(dd,J=4.4,1.3Hz,6H),1.75(t,J=7.6Hz,2H),1.07(t,J=7.5Hz,3H).

[0202] Example 7 - Preparation of Intermediate 7: Methyl (1R,4r)-4-((R)-1-(methylamino)propyl)cyclohexane-1-carboxylate hydrochloride [ka] Step 1: To a solution of (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (140 g, 751 mmol, 1 eq) in CHCl (700 mL) under a nitrogen atmosphere was added DMF (549 mg, 7.52 mmol, 578 μL, 0.01 eq). The reaction was cooled to 0 °C, and then (COCl) (101 g, 796 mmol, 69.7 mL, 1.06 eq) was added dropwise. The reaction was stirred at 25 °C for 10 h. Pd(dppf)Cl (16.5 g, 22.5 mmol, 0.03 eq) was added to the reaction, followed by THF (700 mL). The mixture was then cooled to 0 °C, and a solution of ZnEt (1 M, 902 mL, 1.2 eq) was added slowly at 0 °C. After the addition, the mixture was stirred at 25 °C for 10 h. TLC (petroleum ether / ethyl acetate = 5 / 1, Rf / reactant = 0.20, Rf / new spot = 0.55) indicated the material had been consumed and a new spot of interest had formed. The reaction mixture was quenched by the addition of ice-saturated NH4Cl (1000 mL) and extracted with C2Cl2 (600 mL × 3). The combined organic layers were washed with brine (1000 mL), dried, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1 to 1 / 4) to give the product, methyl (1r,4r)-4-propionylcyclohexane-1-carboxylate (170 g, 514 mmol, 68.4% yield, 60.0% purity), as a pale yellow oil. 1 H NMR(400MHz,CDCl3)δ 3.60(s,3H),2.44-2.36(m,1H),2.30-2.14(m,2H),2.04-1.93(m,4H),1.92-1 .84(m,1H),1.82-1.69(m,3H),1.68-1.61(m,1H),1.45-1.35(m,1H),1.33(br d,J=10.4Hz,1H),1.45-1.30(m,1H),1.33-1.24(m,1H),1.23-1.15(m,1H),1.00-0.92(m,1H).

[0203] Step 2: To a solution of methyl (1R,4r)-4-propionylcyclohexane-1-carboxylate (340 g, 1.71 mol, 1 eq) was added Ti(OEt) (782 g, 3.43 mol, 711 mL, 2 eq) and (R)-2-methylpropane-2-sulfinamide (228 g, 1.89 mol, 1.1 eq). The mixture was stirred at 75 °C for 5 h. TLC (petroleum ether / ethyl acetate = 5 / 1, Rf / reactant = 0.45, Rf / new spot = 0.20) indicated the material had been consumed and the desired spot had formed. The reaction was cooled to 25 °C, diluted with 800 mL of EtOAc, and quenched with HO (229 g). The resulting suspension was stirred vigorously and filtered through a short plug of celite. The cake solid was washed with EtOAc (1500 mL × 2), and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the product (230 g crude). The product was then purified by preparative HPLC (Phenomenex Luna C18 250 mm × 100 mm × 10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 45.0% to 65.0%, 20 min) to give the desired product (1R,4R)-4-((E)-1-(((R)-tert-butylsulfinyl)imino)propyl)cyclohexane-1-carboxylate (98.0 g, 304 mmol, 17.7% yield, 98.0% purity) as a pale yellow oil. LCMS: RT = 0.938 min, m / z = 316.3 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ 4.08(q,J=7.2Hz,2H),2.78-2.57(m,1H),2.32-2.14(m,2H),2.08-1.97(m,2H) ,1.95-1.78(m,2H),1.85-1.77(m,1H),1.53-1.28(m,4H),1.24-1.11(m,13H).

[0204] Step 3: To a solution of ethyl (1R,4r)-4-((E)-1-(((R)-tert-butylsulfinyl)imino)propyl)cyclohexane-1-carboxylate (96.0 g, 304 mmol, 1 eq) and Ti(OEt) (208 g, 912 mmol, 189 mL, 3 eq) in THF (960 mL) and EtOAc (240 mL) was added NaBH (34.5 g, 912 mmol, 3 eq) at −78 °C. The resulting mixture was continuously stirred at −78 to 0 °C for 2 h (the −78 °C bath was removed and placed in an ice bath). The mixture was then stirred at 0 °C for 2 h. The reaction was cooled again to −78 °C and quenched with NH Cl (137 mL). The mixture was warmed to 25 °C, filtered, and the cake was washed with EtOAc (1000 mL × 2). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (Phenomenex luna C18 (250 × 70 mm, 10 μm), mobile phase: [water (10 mM NH4HCO3)-ACN], B%: 45% to 70%, 20 min) to give the desired product (1R,4r)-4-((R)-1-(((R)-tert-butylsulfinyl)amino)propyl) ethyl cyclohexane-1-carboxylate (58.0 g, 178 mmol, 58.7% yield, 97.8% purity) as a pale yellow oil. LCMS: RT = 0.886 min, m / z = 318.2 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ 4.03(q,J=7.2Hz,2H),3.02(d,J=7.6Hz,1H),2.95-2.86(m,1H),2.22-2.09(m,1H),2.02-1.90(m,2H),1.84-1.74(m,1H),1.70(br d,J=12.8Hz,1H),1.56-1.43(m,2H),1.43-1.28(m,3H),1.22-1.10(m,12H),1.06-0.93(m,1H),0.85(t,J=7.2Hz,3H).

[0205] Step 4: To a solution of ethyl (1R,4r)-4-((R)-1-(((R)-tert-butylsulfinyl)amino)propyl)cyclohexane-1-carboxylate (55.0 g, 173 mmol, 1 eq) in THF (1100 mL) at −70° C. was added LiHMDS (1 M, 207 mL, 1.2 eq). The mixture was then stirred at 0° C. for 30 min. CHI (122 g, 866 mmol, 53.9 mL, 5 eq) was added at 0° C., and the reaction mixture was slowly warmed to 25° C. for 2 h. LCMS showed that the material had been consumed and the desired spot had formed. The reaction mixture was quenched by the addition of ice-saturated NH4Cl (300 mL) and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the product (1R,4r)-4-((R)-1-(((R)-tert-butylsulfinyl)(methyl)amino)propyl)ethyl cyclohexane-1-carboxylate (32.0 g, 90.7 mmol, 52.3% yield, 94.0% purity) as a yellow oil. LCMS: RT = 0.978 min, m / z = 332.3 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ 4.12-4.00(m,2H),2.74(td,J=8.8,4.0Hz,1H),2.48-2.40(m,3H),2.23-2.08(m,1H),2.06-1.92(m,3H),1.80(br d,J=12.8Hz,1H),1.72-1.62(m,1H),1.58-1.46(m,1H),1.44-1.27(m,3H),1.24-1.10(m,11H),1.07-0.88(m,5H).

[0206] Step 5: To a solution of ethyl (1R,4r)-4-((R)-1-(((R)-tert-butylsulfinyl)(methyl)amino)propyl)cyclohexane-1-carboxylate (64.0 g, 193 mmol, 1 eq) in MeOH (448 mL) was added HCl / MeOH (4 M, 448 mL, 9.28 eq) at 0° C., and the resulting mixture was continued to stir at 25° C. for 5 h. LCMS showed that the material was consumed and the desired spot was formed. The reaction mixture was concentrated to give the product as a yellow oil. The product was then dissolved in EtOAc / MTBE (1 / 10, 220 mL) to give the product as a white solid. The product was triturated with MTBE (100 mL) at 25° C. for 10 min to give methyl (1R,4r)-4-((R)-1-(methylamino)propyl)cyclohexane-1-carboxylate hydrochloride (36.2 g, 144 mmol, 75.0% yield). LCMS: RT=0.341 min, m / z=213.9 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ 9.49-8.92(m,2H),3.63(s,3H),2.68(t,J=5.2Hz,4H),2.38-2.21(m,1H),2.13-2.02(m,2H),1 .97-1.84(m,2H),1.83-1.72(m,3H),1.53-1.38(m,3H),1.37-1.24(m,1H),1.12-1.04(m,3H).

[0207] Example 8 - Preparation of Intermediate 8: Methyl (1R,4r)-4-((R)-1-aminopropyl)cyclohexane-1-carboxylate [ka] Ethyl (1R,4r)-4-((R)-1-(((R)-tert-butylsulfinyl)amino)propyl)cyclohexane-1-carboxylate (75 g, 236 mmol) was dissolved in MeOH (400 mL). HCl in MeOH (295 mL, 4 mol / L in MeOH) was added at 0° C. The resulting mixture was continuously stirred at 0° C. for 2 hours. The reaction was concentrated under reduced pressure. The residue was triturated with MTBE (800 mL) to give methyl (1R,4r)-4-((R)-1-aminopropyl)cyclohexane-1-carboxylate (40.6 g, 203 mmol, yield: 93.7%) as a white solid. LCMS: RT=0.215 min, m / z=200.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.18-7.83(m,3H),3.59(s,3H),2.91-2.76(m,1H),2.30-2.17(m,1H),1.93(br s,2H),1.72(br s,2H),1.65-1.44(m,3H),1.29(br s,2H),1.11(s,2H),0.91(t,J=7.4Hz,3H).

[0208] Example 9 - General Method for the Synthesis of Amine Intermediates - Preparation of Intermediate 9 [ka] Step 1: (S)-3-Methylpiperazine hydrochloride (3.19 g, 23.50 mmol), (R)-2-((tert-butoxycarbonyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)acetic acid (5 g, 19.59 mmol), and EtN (10.92 mL, 78 mmol) were dissolved in DCM (75 mL). The solution was cooled to 0 °C, and T3P (50% in EtOAc) (23.56 mL, 39.2 mmol) was slowly added. Once the solution became cloudy, the mixture was stirred at room temperature for 2 h. LC-MS indicated the reaction was complete. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with water, saturated NaHCO3 solution, brine, and dried over MgSO4. The solid was filtered off and concentrated under reduced pressure. The crude material was purified by ISCO combi-flash chromatography (ELSD detection) using a 120 g silica column packed with DCM and eluted with a gradient of 20-100% EtOAc in heptane. The product-containing fractions were combined, concentrated under reduced pressure, and dried overnight under vacuum to give tert-butyl ((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)-2-oxoethyl)carbamate as a white solid (6.16 g, 93%). MS m / z=337.1 [M+H] + .

[0209] Step 2: To a solution of tert-butyl ((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)-2-oxoethyl)carbamate (2.46 g, 7.31 mmol) in THF (18.28 ml) was added BH3·DMS (2 M in THF) (18.28 ml, 36.6 mmol, 5.0 equiv) at 0 °C. The mixture was then warmed to 25 °C and stirred overnight. LC-MS showed that all starting material was consumed. The reaction mixture was quenched with MeOH until no more bubbles were observed. The mixture was stirred for 30 minutes and then concentrated. The residue was diluted with MeOH (10 mL), and then pyridine (5.91 ml, 73.1 mmol) was added to the solution. The resulting solution was stirred at room temperature for 2 days. The reaction mixture was concentrated, diluted with MeOH, and purified by reverse-phase column chromatography (20-80% MeCN / water (with 0.1% NH4OH modifier), 150 g ISCO gold C18 column), followed by lyophilization to give tert-butyl ((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)carbamate as a colorless oil (1.83 g, 78% yield). MS m / z = 323.3 [M+H] + .

[0210] Step 3: To a solution of tert-butyl ((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)carbamate (1.64 g, 5.09 mmol) in MeOH (10 ml) was added HCl (6.36 ml, 25.4 mmol, 4N in dioxane). The reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and dried overnight under vacuum to give (R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethan-1-amine hydrochloride as a pale solid in quantitative yield. MS m / z=223.3 [M+H] + .

[0211] Example 10 - Preparation of Intermediate 10: (3R,5R)-3-Methoxy-5-methylpiperazine [ka] Step 1: To a solution of tert-butyl (3R,5R)-3-hydroxy-5-methylpiperazine-1-carboxylate (4500.0 mg, 1 Eq, 20.902 mmol) in THF (104 mL) was added NaH (2.090 g, 60 wt%, 2.5 Eq, 52 mmol) at 0 °C. The reaction mixture was then stirred at 0 °C for 0.5 h, and MeI (7.42 g, 3.27 mL, 2.5 Eq, 52 mmol) was added dropwise. The mixture was stirred at 25 °C for an additional 1.5 h. LCMS showed that one major peak with the desired mass was detected. The mixture was quenched with NH Cl (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic phase was dried over anhydrous Na SO , filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent 0-100% EtOAc / heptane) and the eluent was concentrated to give the desired product as a colorless oil. LCMS m / z [M-55] + =174.2.

[0212] Step 2: To a solution of tert-butyl (3R,5R)-3-methoxy-5-methylpiperazine-1-carboxylate (4.4 g, 1 Eq, 19 mmol) in MeOH (50 mL) was added HCl (4N in dioxane) (3.5 g, 24 mL, 4.000 mol, 5 Eq, 96 mmol) at 0° C. The reaction mixture was then stirred at room temperature for 2 hours. LC-MS showed that all starting material had been consumed. The mixture was concentrated under reduced pressure to give a colorless oil. The crude product was used in the next step without further purification. LCMS m / z [M+H] + =130.1.

[0213] Example 11 - Preparation of Intermediate 11: 2-((tert-butoxycarbonyl)amino)-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)acetic acid [ka] Step 1: To a solution of ethyl 2-((diphenylmethylene)amino)acetate (1.25 g, 4.68 mmol), 4-bromo-3-fluoro-1-methyl-1H-pyrazole (0.92 g, 5.14 mmol) in toluene (30 mL) was added KPO (2.98 g, 14.03 mmol) and Pd(t-BuP) (0.24 g, 0.468 mmol) under N at 25 °C. The mixture was then stirred at 100 °C for 16 h. LCMS showed that the desired mass was detected. The reaction mixture was poured into HO (50 mL), and the aqueous layer was extracted with EA (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient @100 mL / min) and then concentrated to give ethyl 2-((diphenylmethylene)amino)-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)acetate (250 mg, 60% purity) as a yellow oil. LCMS m / z [M+H] + =366.0.

[0214] Step 2: To a solution of ethyl 2-((diphenylmethylene)amino)-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)acetate (250 mg, 0.41 mmol, 60% purity) in dioxane (2 mL) was added 4 M HCl / dioxane (2 mL). The mixture was stirred at 25° C. for 4 h. LCMS showed that the desired mass was detected. The mixture was added to HO (4 mL) and then extracted with PE (4 mL×3). The aqueous phase (0.41 mmol in HO (4 mL)) was carried on to the next step without further purification. The combined organic layers were discarded. LCMS m / z [M+H] + =202.1.

[0215] Step 3: To a mixture of ethyl 2-amino-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)acetate (0.41 mmol, in 4 mL of HO) in THF (4 mL) was added NaHCO (345 mg, 4.10 mmol) and BocO (179 mg, 0.82 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h. LCMS showed that the desired mass was detected. The mixture was extracted with EA (15 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give ethyl 2-((tert-butoxycarbonyl)amino)-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)acetate (200 mg, crude) as a yellow oil. LCMS m / z [M-55] + =246.2.

[0216] Step 4: A solution of 2-((tert-butoxycarbonyl)amino)-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)ethyl acetate (200 mg, crude) in THF / MeOH / 4M NaOH = 2:1:1 (4 mL) was stirred at 40 °C for 1 h. LCMS showed that the desired mass was detected. The reaction mixture was concentrated to give a residue. The residue was added to HO (4 mL) and extracted with PE (4 mL × 3). The aqueous phase was adjusted to pH ∼5 with 1 N HCl and extracted with EA (5 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give 2-((tert-butoxycarbonyl)amino)-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)acetic acid (110 mg, crude) as a yellow gum.

[0217] Example 12 Synthesis of (1R,4r)-4-((R)-1-(((R)-6-(2-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid (Compound 48) and (1R,4r)-4-((R)-1-(((S)-6-(2-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid (Compound 141) [ka] Step 1: To a flask containing 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (5 g, 18.79 mmol), 1-fluoro-2-iodobenzene (5 g, 22.54 mmol), and sodium carbonate (7.96 g, 75 mmol) was added dioxane (75 mL) and water (18.75 mL). The reaction mixture was degassed with nitrogen for 5 minutes, then PdCl(dppf)·CHCl adduct (0.767 g, 0.939 mmol) was added and heated at 90 °C overnight. The reaction was monitored by LCMS and cooled to room temperature. The reaction was diluted with EtOAc, filtered through celite, and washed with EtOAc. The filtrate was concentrated and purified by chromatography (40 g, silica gel, 0-20% EtOAc / heptane) to give 8-(2-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (4.26 g, 18.18 mmol, 97% yield). LCMS: m / z = 235.2 [M+H] + ; 1H NMR(400MHz,chloroform-d)δ 7.26-7.17(m,1H),7.11(ddd,J=7.3,5.1,2.0Hz,1H),7.05-6.88(m,2H),5.83-5.67(m,1H), 3.96(s,4H),2.57(ddt,J=6.3,3.9,1.9Hz,2H),2.40(q,J=2.6Hz,2H),1.84(t,J=6.5Hz,2H).

[0218] Step 2: To a solution of 8-(2-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (4.26 g, 18.18 mmol) in MeOH (100 mL) was added Pd / C (10%, 1.355 g) and flushed with hydrogen three times. The resulting solution was stirred under a hydrogen balloon for 16 hours. The mixture was flushed with nitrogen and filtered through celite. The filtrate was concentrated to give the desired product, 8-(2-fluorophenyl)-1,4-dioxaspiro[4.5]decane, which was carried on directly to the next step. LCMS: m / z=237 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ 7.37-7.24 (m, 1H), 7.18 (tdd, J = 7.4, 5.1, 1.8 Hz, 1H), 7.10 (td, J = 7.6, 1.4 Hz, 1H), 7.06-6.95 (m, 1H), 4.01 (s, 4H), 3.03-2.86 (m, 1H), 1.96-1.65 (m, 9H).

[0219] Step 3: The crude 8-(2-fluorophenyl)-1,4-dioxaspiro[4.5]decane residue was dissolved in DCM (15 mL) and added to TFA (28.0 mL, 364 mmol) at room temperature. The mixture was stirred at room temperature for 2 days. LCMS showed one single peak of the desired product. The mixture was concentrated, diluted with EtOAc, washed with saturated aqueous sodium bicarbonate, water, brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography (silica gel 120 g, 0-50% EtOAc / heptane) to give 4-(2-fluorophenyl)cyclohexan-1-one (3.6 g, 98% yield). 1H NMR (400 MHz, chloroform-d) δ 7.61-7.22 (m, 2H), 7.10 (dt, J = 26.2, 8.5 Hz, 2H), 3.61-3.28 (m, 1H), 2.82-2.44 (m, 4H), 2.44-2.17 (m, 2H), 2.17-1.87 (m, 2H).

[0220] Step 4: NaH (1.032 g, 25.8 mmol) was added portionwise to diethyl carbonate (23.45 mL, 194 mmol) at room temperature. 4-(2-fluorophenyl)cyclohexan-1-one (3.1 g, 16.13 mmol) was then added portionwise to the reaction mixture. The reaction was heated to 60 °C, resulting in the formation of bubbles and rising. The reaction was cooled and rinsed with THF (20 mL). This mixture was heated to 75 °C for 2 h. The reaction was cooled to room temperature and then neutralized with 2 M aqueous HCl. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (80 g, silica gel EtOAc / heptane 0–30%) to give ethyl 5-(2-fluorophenyl)-2-oxocyclohexane-1-carboxylate (2.6 g, 54.9% yield). LCMS: m / z=263[M−H] + .

[0221] Step 5: To a flask containing ethyl 5-(2-fluorophenyl)-2-oxocyclohexane-1-carboxylate (2.3 g, 8.70 mmol) and urea (1.045 g, 17.40 mmol) was added NaOMe (0.940 g, 17.40 mmol) and MeOH (volume: 20 mL). The mixture was heated at 70 °C for 16 h. The reaction was cooled to room temperature, and the precipitate was filtered, washed with EtO, and dried to give 6-(2-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2,4-diol (2.1 g, 93% yield). LCMS: m / z = 261.1 [M+H] + ; 1H NMR(400MHz, methanol-d4)δ 8.57(s,1H),7.34(td,J=7.6,1.9Hz,1H),7.24(tdd,J=7.3,5.2,1.8Hz,1H),7.18-7.11(m,1H),7.11-6.96(m,1H),3.19( tq,J=9.0,4.6Hz,1H),2.75(dd,J=16.2,5.3Hz,1H),2.69-2.49(m,2H),2.45-2.30(m,1H),2.00(dq,J=10.9,5.4Hz,2H).

[0222] Step 6: To a solution of 6-(2-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2,4-diol (2.1 g, 8.07 mmol) and EtN (2.68 mL, 19.36 mmol) in dioxane (8 mL) was added POCl (7.52 mL, 81 mmol) slowly at 0 °C. The mixture was heated at 97 °C for 40 h. The reaction mixture was concentrated, poured into ice-cold water, and stirred for 30 min. The mixture was extracted with EtOAc (4 × 100 mL) until the aqueous layer was free of product. The organic layers were combined and concentrated. The residue was purified by chromatography (silica gel 120 g, 0-30% EtOAc / heptane) to give 2,4-dichloro-6-(2-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (0.4 g, 17% yield). LCMS: m / z = 297 [M+H] + ; 1 H NMR (400 MHz, methanol-d₄) δ 7.46-7.25 (m, 2H), 7.25-7.04 (m, 2H), 3.85-3.68 (m, 1H), 3.47-3.36 (m, 1H), 3.20-2.94 (m, 2H), 2.83 (ddd, J = 17.7, 11.3, 1.5 Hz, 1H), 2.25-2.05 (m, 2H).

[0223] Step 7: A solution of 2,4-dichloro-6-(2-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (0.4 g, 1.346 mmol), 2,3,5,6-tetrafluorophenol (0.268 g, 1.615 mmol), and DIPEA (0.306 mL, 1.750 mmol) in CHCN (2 mL) was stirred at 80 °C for 40 h. The residue was purified by chromatography (120 g, silica gel, 0-7%, then isocratic 7% EtOAc / heptane) to give 2-chloro-6-(2-fluorophenyl)-4-(2,3,5,6-tetrafluorophenoxy)-5,6,7,8-tetrahydroquinazoline (560 mg, 97% yield). LCMS: m / z = 427.1 [M+H] + ; 1 H NMR(400MHz, methanol-d4)δ 7.58-7.46(m,1H),7.46-7.38(m,1H),7.31(tdd,J=7.0,5.1,1.6Hz,1H),7.20(t,J=7.3Hz,1H),7.13(dd,J=10.8,8.2Hz,1H),3.46(ddd ,J=11.4,6.1,2.5Hz,1H),3.22(dd,J=17.3,4.9Hz,1H),3.13-2.99(m,2H),2.90(dd,J=17.3,11.2Hz,1H),2.22(tt,J=8.9,4.0Hz,2H).

[0224] Step 8: To 2-chloro-6-(2-fluorophenyl)-4-(2,3,5,6-tetrafluorophenoxy)-5,6,7,8-tetrahydroquinazoline (280 mg, 0.656 mmol), (1R,4r)-4-((R)-1-(methylamino)propyl)cyclohexane-1-carboxylate (263 mg, 0.919 mmol) in anhydrous acetonitrile (volume: 0.4 mL) in a 5 mL microwave vial was added DIPEA (0.458 mL, 2.62 mmol). The resulting mixture was heated to 100° C. for 72 hours. The reaction mixture was purified by chromatography (40 g, silica gel 0-10% EtOAc / heptane) to give methyl (1R,4r)-4-((1R)-1-((6-(2-fluorophenyl)-4-(2,3,5,6-tetrafluorophenoxy)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylate (176 mg, 44% yield). LCMS: m / z=604.3 [M+H] + ; 1 H NMR (400 MHz, methanol-d4) δ 7.36(s,1H),7.30(td,J=7.6,1.8Hz,1H),7.16(tdd,J=7.3,5.1,1.8Hz,1H), 7.07(td,J=7.6,1.4Hz,1H),7.03-6.93(m,1H),3.74(s,1H),3.54(s,3H),2. 95(dd,J=16.2,5.2Hz,1H),2.76(d,J=17.6Hz,4H),2.62(dd,J=16.2,11.3Hz ,1H),2.06(s,5H),1.90-1.67(m,3H),1.55-1.12(m,6H),0.45-0.68(m,5H).

[0225] Step 9: A solution of (R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethan-1-amine (103 mg, 0.350 mmol), (1R,4r)-4-((1R)-1-((6-(2-fluorophenyl)-4-(2,3,5,6-tetrafluorophenoxy)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)methyl cyclohexane-1-carboxylate (176 mg, 0.292 mmol) and DIPEA (0.204 mL, 1.166 mmol) in isopropanol (0.25 mL) in a chem-glass pressure vessel (20 ml) was stirred at 110° C. for 2 days. 100 mg of (R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethan-1-amine (100 mg, 0.34 mmol) and DIPEA (0.2 ml, 1.16 mmol) were added and heated at 105° C. for 2 days. The mixture was concentrated in vacuo and the residue was purified by chromatography (40 g, silica gel 0-85% EtOAc / DCM) to give methyl (1R,4r)-4-((1R)-1-((6-(2-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylate (0.1 g, 52% yield). LCMS: m / z=660.4 [M+H] + .

[0226] Step 10: To a solution of methyl (1R,4r)-4-((1R)-1-((6-(2-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylate (100 mg, 0.152 mmol) in MeOH (2 mL) and water (0.5 mL) was added NaOH (4 M aqueous solution, 0.379 mL, 1.515 mmol) and stirred at 50° C. for 30 min. The reaction mixture was subjected to SFC chiral separation (column 2.0 × 25.0 cm ChromegaChiral CC4(ES)). Industries), methanol / acetonitrile (1:3) (containing 30 mM ammonium acetate), 65% co-solvent, 70 g / min, 100 bar, 25°C), to give (1R,4r)-4-((R)-1-(((R)-6-(2-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl (1R,4r)-4-((R)-1-(((S)-6-(2-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid (21 mg, yield 20%) and (1R,4r)-4-((R)-1-(((S)-6-(2-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid (19 mg, yield 18%) were obtained.

[0227] (1R,4r)-4-((R)-1-(((R)-6-(2-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid: LCMS m / z=646.5 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 7.53-7.37(m,2H),7.37-7.25(m,2H),7.19(q,J=10.1,8.6Hz,2H),6.13(d,J=7.5Hz,1H),5.31(s,1H),4.49(s,1H),3.75(s,3H),3.18 (s,2H),2.89-2.58(m,7H),2.29(dd,J=23.7,10.7Hz,2H),2.09(s,3H),2.03-1.46(m,12H),1.25(t,J=41.8Hz,6H),1.02-0.46(m,7H).

[0228] (1R,4r)-4-((R)-1-(((S)-6-(2-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid: LCMS m / z=646.5 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 7.54-7.40(m,2H),7.40-7.23(m,2H),7.19(q,J=8.6,7.7Hz,2H),6.14(s,1H),5.31(s,1H),4.50(s,1H),3.75(s,3H),3.18(s,2H),2.71 (q,J=24.6,23.9Hz,7H),2.31(d,J=15.6Hz,2H),2.09(s,3H),1.91(s,6H),1.79-1.44(m,6H),1.25(t,J=40.5Hz,6H),0.98-0.63(m,7H).

[0229] Example 13 Synthesis of (1R,4r)-4-((R)-1-(methyl((R)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-1-carboxylic acid (Compound 40) [ka] Step 1: A solution of (R)-2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline (1265 mg, 4.53 mmol), (R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethan-1-amine dihydrochloride (1338 mg, 4.53 mmol) and DIPEA (2769 μL, 15.86 mmol) in MeCN (volume: 22 mL) was stirred at 70° C. for 3 h. MeCN was removed under reduced pressure, and the residue was then extracted with EtOAc / water. The combined organic layers were washed with brine, dried over NaSO and concentrated. The residue was purified by flash column chromatography (0-20% MeOH (0.1N NH3) / DCM) to give (R)-2-chloro-N-((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)-6-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine as a pale solid (949 mg, 45%). MS: m / z = 465.1 [M+H] + .

[0230] Step 2: A solution of (R)-2-chloro-N-((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)-6-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine (920 mg, 1.98 mmol), (1R,4r)-methyl 4-((R)-1-(methylamino)propyl)cyclohexane-1-carboxylate (844 mg, 3.96 mmol) and DIPEA (1.727 mL, 9.89 mmol) in MeCN (4 mL) was heated in a microwave reactor at 160° C. for 2 days. The reaction mixture was diluted with EtOAc, washed with brine, dried over NaSO and concentrated. The residue was purified by flash column chromatography (0-20% MeOH (0.1N NH3) / DCM) to give methyl (1R,4r)-4-((R)-1-(methyl(R)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-1-carboxylate as a pale solid (832 mg, 65%). MS: m / z = 642.4 [M+H]. + .

[0231] Step 3: To a solution of (1R,4r)-4-((R)-1-(methyl((R)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)methyl cyclohexane-1-carboxylate (832 mg, 1.296 mmol) in THF (6 mL) and MeOH (3 mL) was added NaOH (4 N aqueous solution) (1.620 mL, 6.48 mmol). The resulting suspension was stirred at 50° C. for 30 min, then the solvent was removed under reduced pressure and then diluted with DMSO. The suspension was purified by reverse-phase column (150 g ISCO gold C-18 column, 20-70% MeCN / water, containing 0.1% NH4OH as a modifier). Pure fractions were combined and lyophilized to give (1R,4r)-4-((R)-1-(methyl((R)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-1-carboxylic acid sodium salt as a white solid (445 mg, 43%). MS: m / z = 628.5 [M+H] + ; 1 H NMR (400 MHz, methanol-d4) δ 7.49(s,1H),7.40(s,1H),7.38-7.30(m,4H),7.25-7.19(m,1H),5.49(s,1H) ,4.54(s,1H),3.86(s,3H),3.05-2.94(m,2H),2.93-2.82(m,5H),2.78-2.71( m,3H),2.64(dd,J=12.8,5.3Hz,1H),2.47-2.36(m,1H),2.16-1.95(m,5H),1. 94-1.62(m,7H),1.58-1.25(m,6H),1.06-0.84(m,5H),0.79(t,J=7.2Hz,4H).

[0232] The following compounds were prepared by the above procedure or by modifying the above procedure using the corresponding intermediates.

[0233] Table 38

[0234] Table 39

[0235] Table 40

[0236] Table 41

[0237] Table 42

[0238] Table 43

[0239] Table 44

[0240] Table 45

[0241] Table 46

[0242] Table 47

[0243] Table 48

[0244] Table 49

[0245] Table 50

[0246] Table 51

[0247] Table 52

[0248] Table 53

[0249] Table 54

[0250] Table 55

[0251] Table 56

[0252] Table 57

[0253] Table 58

[0254] Table 59

[0255] Table 60

[0256] Table 61

[0257] Table 62

[0258] Table 63

[0259] Table 64

[0260] Table 65

[0261] Table 66

[0262] Table 67

[0263] Table 68

[0264] Table 69

[0265] [Table 70]

[0266] [Table 71]

[0267] [Table 72]

[0268] Example 14: Synthesis of (1R,4r)-4-((R)-1-((6-phenyl-4-(((R)-1-phenyl-2-(pyrrolidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)propyl)cyclohexane-1-carboxylic acid (Compound 131) [ka] Step 1: (R)-1-Phenyl-2-(pyrrolidin-1-yl)ethan-1-amine (230 mg, 0.874 mmol) and DIPEA (0.763 mL, 4.37 mmol) were combined with MeCN (3 mL), followed by the addition of 2,4-dichloro-6-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (245 mg, 0.874 mmol) in one portion. The reaction was stirred at 70° C. overnight, at which point LCMS confirmed the formation of the desired product. It was then concentrated under reduced pressure. The crude material was directly purified by ISCO combiflash chromatography (24 grams, 0-20% (0.1% ammonia in MeOH / DCM) to give the desired product (R)-2-chloro-6-phenyl-N-(1-phenyl-2-(pyrrolidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (163 mg, 0.376 mmol, 43% yield). MS: m / z = 434.1 [M+H] + .

[0269] Step 2: To a microwave vial containing ethyl (1R,4r)-4-((R)-1-aminopropyl)cyclohexane-1-carboxylate (159 mg, 0.636 mmol) and ethyl (1R,4r)-4-((R)-1-aminopropyl)cyclohexane-1-carboxylate (138 mg, 0.318 mmol) was added MeCN (0.7 ml, ratio: 1.000) and 2,2,2-trifluoroethanol (0.700 ml, ratio: 1.000). The reaction was heated in a microwave reactor at 175 °C for 2 hours, at which time LCMS confirmed the formation of the desired product. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO, brine, dried over MgSO, and concentrated under reduced pressure to give the crude product. This was purified by ISCO combiflash chromatography (12 grams, 0-10% (0.1% ammonia in MeOH) / DCM) to give the desired product (1R,4r)-4-((R)-1-((6-phenyl-4-(((R)-1-phenyl-2-(pyrrolidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)propyl)ethyl cyclohexane-1-carboxylate (20 mg, 0.033 mmol, 10.3% yield). MS: m / z = 611.3 [M+H] + .

[0270] Step 3: To a vial containing ethyl (1R,4r)-4-((R)-1-((6-phenyl-4-(((R)-1-phenyl-2-(pyrrolidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)propyl)cyclohexane-1-carboxylate (20 mg, 0.033 mmol) was added THF (1 mL, ratio: 2), MeOH (0.500 mL, ratio: 1.000), followed by 3.75 N NaOH (0.087 mL, 0.327 mmol). The mixture was stirred at 60° C. for 1 hour, at which time LCMS confirmed the formation of the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with ACN, water, and MeOH and purified by preparative HPLC (25-50% acetonitrile / water, 5 mM NH4OH, wavelength 393, low threshold). The desired fractions were combined and lyophilized to give the desired product (1R,4r)-4-((R)-1-((6-phenyl-4-(((R)-1-phenyl-2-(pyrrolidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)propyl)cyclohexane-1-carboxylic acid (9.3 mg, 0.014 mmol, 44.1% yield). MS: m / z = 583.2 [M+H] + ; 1 H NMR(400MHz, methanol-d4)δ 7.31-7.00(m,10H),6.76(tt,J=7.2,1.0Hz,1H),5.33(dd,J=10.7,3.9Hz,1H),4 .13-3.88(m,2H),3.66-3.52(m,1H),3.50-3.33(m,2H),3.10(dd,J=12.7,10.8H z,1H),2.63-2.51(m,6H),1.89-1.80(m,1H),1.77-1.67(m,6H),1.56-1.47(m,2 H),1.39-1.32(m,1H),1.27-1.10(m,4H),0.84-0.72(m,4H),0.65-0.49(m,1H).

[0271] Example 15 Synthesis of (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(4-fluoropiperidin-1-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-1-carboxylic acid (Compound 142) [ka] Step 1: (R)-2,4-Dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline (740 mg, 2.65 mmol), 2-(4-fluoropiperidin-1-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-amine bishydrochloride (720 mg, 3.18 mmol, prepared according to Intermediate 8), and DIPEA (1.389 ml, 7.95 mmol) in MeCN (10 ml) were heated at 80° C. overnight, at which point LCMS confirmed the formation of the desired product. The reaction mixture was concentrated under reduced pressure and partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO solution, washed with brine, and dried over MgSO. The solid was filtered off, and the resulting solution was concentrated under reduced pressure. This was purified by ISCO combiflash chromatography (40 grams, 0-100% (10% MeOH in DCM / DCM)) to give the desired product (6R)-2-chloro-N-(2-(4-fluoropiperidin-1-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethyl)-6-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine (480 mg, 1.023 mmol, 38.6% yield). MS: m / z = 469.2 [M+H] + .

[0272] Step 2: To a microwave vial containing ethyl (1R,4r)-4-((R)-1-aminopropyl)cyclohexane-1-carboxylate (213 mg, 0.853 mmol) and (6R)-2-chloro-N-(2-(4-fluoropiperidin-1-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethyl)-6-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine (200 mg, 0.426 mmol) was added MeCN (1 ml, ratio: 1.000) and 2,2,2-trifluoroethanol (1 ml, ratio: 1.000). The reaction was heated in a microwave reactor at 165 °C for 1.5 hours, at which time LCMS confirmed the formation of the desired product. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO, brine, dried over MgSO, and concentrated under reduced pressure. This was purified by ISCO combiflash chromatography (24 grams, 0-20% (0.1% ammonia in MeOH / DCM) to give the desired product (1R,4r)-4-((1R)-1-(((6R)-4-((2-(4-fluoropiperidin-1-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)ethyl cyclohexane-1-carboxylate (109 mg, 0.169 mmol, 39.6% yield). MS: m / z = 646.4 [M+H] + .

[0273] Step 3: To a vial containing ethyl (1R,4r)-4-((1R)-1-(((6R)-4-((2-(4-fluoropiperidin-1-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-1-carboxylate (109 mg, 0.169 mmol) was added THF (1 mL, ratio: 2), MeOH (0.500 mL, ratio: 1.000), followed by 3.75 N NaOH (0.450 mL, 1.688 mmol). The mixture was stirred at 60° C. for 1 hour, at which time LCMS confirmed the formation of the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with ACN, water, and MeOH and purified by basic preparative HPLC (15-40% acetonitrile / water, 5 mM NH4OH, wavelength 396, mass detector). The desired fractions were combined and lyophilized to give the desired product (31 mg, 0.046 mmol, 27.2% yield). MS: m / z = 618.3 [M+H] + ; 1 H NMR(400MHz, methanol-d4)δ 7.42(s,1H),7.30(d,J=0.8Hz,1H),7.27-7.20(m,4H),7.17-7.09(m,1H),5.49(dd,J=9.7,5.0Hz,1H),4.63-4.44(m,1H),3.74(s,3H),2 .97-2.78(m,2H),2.70-2.42(m,7H),2.38-2.27(m,2H),2.08-1.52(m,13H),1.45-1.22(m,4H),1.02-0.86(m,2H),0.83(t,J=7.3Hz,3H).

[0274] The following compounds were prepared by the above procedure or by modifying the above procedure using the corresponding intermediates.

[0275] [Table 73]

[0276] [Table 74]

[0277] Table 75

[0278] Table 76

[0279] Table 77

[0280] Table 78

[0281] Table 79

[0282] Table 80

[0283] Table 81

[0284] Table 82

[0285] Table 83

[0286] Table 84

[0287] Table 85

[0288] Table 86

[0289] Table 87

[0290] Table 88

[0291] Table 89

[0292] Table 90

[0293] Table 91

[0294] Table 92

[0295] Table 93

[0296] Table 94

[0297] [Table 95]

[0298] [Table 96]

[0299] [Table 97]

[0300] [Table 98]

[0301] Example 16 Synthesis of (1R,4r)-4-((R)-1-((6-cyclohexyl-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid (Compound 152) [ka] Step 1: A solution of tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (3 g, 9.86 mmol), LiOH (0.828 g, 19.73 mmol) in THF (24 mL, ratio: 2) and water (12 mL, ratio: 1.000) was stirred at 65 °C for 4.5 hours, at which time LCMS confirmed the formation of the desired product. HCl (2N) solution was added to neutralize the reaction. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. This was purified by ISCO combiflash chromatography (80 grams, 0-100% EtOAc / DCM) to give the desired product, tert-butyl 2-chloro-4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (1.15 g, 4.02 mmol, 40.8% yield). MS: m / z = 286.0 [M+H] + .

[0302] Step 2: A microwave vial containing tert-butyl 2-chloro-4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (600 mg, 2.100 mmol), methyl (1R,4r)-4-((R)-1-(methylamino)propyl)cyclohexane-1-carboxylate hydrochloride (661 mg, 2.310 mmol) in anhydrous CHCN (3.5 mL) and DIPEA (1.467 mL, 8.40 mmol) was irradiated at 150 °C for 3.5 h, at which time LCMS confirmed the formation of the desired product. The crude product was filtered to remove precipitate and concentrated. This was purified by ISCO combiflash chromatography (40 grams 0-10% MeOH / DCM) to give the product tert-butyl 4-hydroxy-2-(((R)-1-((1r,4R)-4-(methoxycarbonyl)cyclohexyl)propyl)(methyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (405 mg, 0.876 mmol, 41.7% yield). MS: m / z = 463.3 [M+H] + .

[0303] Step 3: To a solution of tert-butyl 4-hydroxy-2-(((R)-1-((1r,4R)-4-(methoxycarbonyl)cyclohexyl)propyl)(methyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (400 mg, 0.865 mmol) in MeOH (1.667 ml) was added 4N HCl in dioxane (2.162 ml, 8.65 mmol) and stirred at room temperature for 1.5 hours, at which time LCMS confirmed the formation of the desired product. The reaction mixture was concentrated under reduced pressure and azeotroped twice with DCM. The resulting residue was dried under vacuum for several hours to give the desired product (1R,4r)-4-((R)-1-((4-hydroxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylate (351 mg, 0.880 mmol, 100% yield). MS: m / z = 363.2 [M+H] + .

[0304] Step 4: To a vial was added cyclohexanone (0.016 μl, 0.153 mmol) and (1R,4r)-4-((R)-1-((4-hydroxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylate (60.9 mg, 0.168 mmol), followed by DCE (1.5 mL) under N. This was stirred for 15 minutes, then sodium triacetoxyborohydride (64.8 mg, 0.306 mmol) was added and stirring continued overnight, at which point LCMS showed the reaction was incomplete. An additional 2 eq of cyclohexanone was added and stirred for 15 minutes. Then 2 eq of sodium triacetoxyborohydride was added and stirred for an additional 1 hour, at which point LCMS confirmed the formation of the desired product. This was directly purified by ISCO combiflash chromatography (24 g 0-30% MeOH / DCM) to give the desired product (1R,4r)-4-((R)-1-((6-cyclohexyl-4-hydroxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)(methyl)amino)propyl)methyl cyclohexane-1-carboxylate (57.5 mg, 0.129 mmol, 85% yield). MS: m / z = 445.3 [M+H] + .

[0305] Step 5: To a solution of methyl (1R,4r)-4-((R)-1-((6-cyclohexyl-4-hydroxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylate (57.5 mg, 0.129 mmol) in anhydrous ACN (0.3 mL) in a microwave vial was added POCl (0.036 mL, 0.388 mmol) dropwise at room temperature. The reaction mixture was heated at 80 °C for 60 min, at which time LCMS confirmed the formation of the desired product. It was diluted with EtOAc and quenched by careful addition of saturated aqueous NaHCO solution. The two phases were separated, and the aqueous phase was extracted twice with EtOAc, dried over NaSO, and concentrated. This was further dried under high vacuum to give the desired product, methyl (1R,4r)-4-((R)-1-((4-chloro-6-cyclohexyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylate (60 mg, 0.130 mmol, 100% yield). MS: m / z = 463.2 [M+H] + .

[0306] Step 6: To a microwave vial containing (1R,4r)-4-((R)-1-((4-chloro-6-cyclohexyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)(methyl)amino)propyl)methyl cyclohexane-1-carboxylate (60 mg, 0.130 mmol), (R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethan-1-amine (38.3 mg, 0.130 mmol) in CHCN (0.5 mL) was added HCl in dioxane (0.032 mL, 0.130 mmol) and heated under microwave irradiation at 120° C. for 7 hours, followed by an additional heating at 130° C. for 1 hour, at which time LCMS showed approximately 35% formation of the desired product. The reaction mixture was concentrated in vacuo. This was further dried under high vacuum to give the desired crude product (1R,4r)-4-((R)-1-((6-cyclohexyl-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)(methyl)amino)propyl)methyl cyclohexane-1-carboxylate (84 mg, 0.052 mmol, 40% yield). MS: m / z = 649.4 [M+H] + .

[0307] Step 7: To a vial containing methyl (1R,4r)-4-((R)-1-((6-cyclohexyl-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylate (84 mg, 0.052 mmol) was added THF (0.4 ml, ratio: 2) and MeOH (0.200 ml, ratio: 1.000), followed by 4 M NaOH (0.065 ml, 0.259 mmol). The mixture was stirred at 50° C. for 1.5 hours, at which time LCMS confirmed the formation of the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with MeOH and purified by basic preparative HPLC (25-50% acetonitrile / water, 5 mM NH4OH, wavelength 396, mass detector). The desired fractions were combined and lyophilized to give the desired product (1R,4r)-4-((R)-1-((6-cyclohexyl-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid (10 mg, 0.014 mmol, 27.9% yield). LCMS: m / z = 635.5 [M+H] + ; 1 H NMR(400MHz, methanol-d4)δ 7.45(s,1H),7.36(s,1H),5.46(s,1H),4.47(s,1H),3.82(s,3H),3.54-3.37(m,2H),2.92-2.74(m,8H),2.68- 2.62(m,2H),2.53-2.45(m,1H),2.04-1.91(m,5H),1.88-1.59(m,11H),1.51-1.20(m,11H),0.92-0.67(m,9H).

[0308] Example 17: Synthesis of (1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid (Compound 23) [ka] Step 1: A solution of (R)-2,4-dichloro-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (10 g, 33.7 mmol), 2,3,5,6-tetrafluorophenol (6.71 g, 40.4 mmol), and DIPEA (7.64 mL, 43.7 mmol) in CHCN (volume: 50 mL) was stirred at 80 °C for 40 h. The mixture was concentrated, EtOAc (200 mL) was added, and the mixture was washed with saturated aqueous NaHCO, water, and brine, dried over NaSO, and concentrated. LCMS showed the presence of product in the aqueous layer, so it was neutralized to pH = 4 using 6 N aqueous HCl and extracted with EtOAc (200 mL). The organic layer was dried over NaSO and concentrated. The residue was purified by chromatography (2 × 330 g, 0-5% silica gel and isocratic 5% EtOAc / heptane) to give the desired product. 1 H NMR(400MHz,DMSO-d6)δ 8.01(tt,J=10.9,7.3Hz,1H),7.40(td,J=8.0,6.0Hz,1H),7.33-7.18(m,2H),7.08(td,J=9.1,8. 7,2.6Hz,1H),3.24-2.91(m,4H),2.85(dd,J=16.6,11.1Hz,1H),2.10(td,J=8.0,7.3,3.4Hz,2H).

[0309] Step 2: (R)-2-chloro-6-(3-fluorophenyl)-4-(2,3,5,6-tetrafluorophenoxy)-5,6,7,8-tetrahydroquinazoline (8.6 g, 20.15 mmol), (1R,4r)-4-((R)-1-(methylamino)propyl)cyclohexane-1-carboxylate (8.08 g, 28.2 mmol) in anhydrous acetonitrile (volume: 12 mL) were added to DIPEA (14.08 mL, 81 mmol) in a 100 mL pressure vessel. The resulting mixture was heated to 100 °C for 72 h. The reaction mixture was diluted with EtOAc (250 mL), washed with saturated aqueous NaHCO, water, and brine, then dried over NaSO, and concentrated. The residue was purified by flash chromatography (330 g, silica gel, 0-10% EtOAc / heptane; product eluted with approximately 9% EtOAc / heptane). 1 H NMR(400MHz,DMSO-d6)δ 8.06-7.91(m,1H),7.38(td,J=7.8,6.0Hz,1H),7.23(dd,J=10.1,2.8Hz,2H),7.06(td,J= 8.8,2.2Hz,1H),3.69(s,1H),3.58(s,3H),3.08(dt,J=10.7,6.0Hz,1H),2.95(dd,J=16.1, 5.0Hz,1H),2.89-2.71(m,4H),2.65(dd,J=15.8,11.5Hz,1H),2.04(tt,J=10.8,5.2Hz,2H ),1.80(dd,J=34.3,12.7Hz,2H),1.55-1.10(m,5H),0.92-0.77(m,2H),0.59-0.43(m,3H).

[0310] Step 3: A solution of (R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethan-1-amine bishydrochloride (1.174 g, 3.98 mmol), (1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(2,3,5,6-tetrafluorophenoxy)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)methyl cyclohexane-1-carboxylate (2 g, 3.31 mmol) in iPrOH (volume: 3 mL) and DIPEA (2.315 mL, 13.25 mmol) was stirred at 110° C. for 3 days. The mixture was added to EtOAc (100 ml), washed with saturated NaHCO solution and brine, dried over NaSO, and concentrated. The residue was purified by flash column chromatography (0-25% EtOAc / heptane to elute starting material, 40-85% EtOAc / DCM to elute product, 120 silica column, single injection) to give the desired product (1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)methyl cyclohexane-1-carboxylate as a pale solid (1.25 g). LCMS: m / z=660.4 [M+H] + .

[0311] Step 4: To a solution of methyl (1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylate (1.05 g, 1.591 mmol) in MeOH (volume: 12 mL, ratio: 2.000) and water (volume: 6 mL, ratio: 1.000) was added NaOH (4 M, 3.98 mL, 15.91 mmol) and stirred at 50 °C for 30 min. The mixture was concentrated by half and purified by reverse phase column (120 g ISCO gold Direct loading onto a C-18 column (10-60% MeCN / water, containing 0.1% NH4OH as a modifier) ​​gave 0.77 g of (1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid. LCMS: m / z = 646.7 [M+H] + ; 1 H NMR(400MHz, methanol-d4)δ 7.39(s,1H),7.35-7.17(m,2H),7.12-6.96(m,2H),6.84(td,J=8.6,2.7Hz,1H), 5.41(d,J=9.5Hz,1H),4.39(s,1H),3.73(s,3H),3.01-2.82(m,3H),2.77(s,4H) ,2.66(dq,J=15.9,10.7,8.1Hz,4H),2.42-2.19(m,1H),2.10-1.50(m,12H),1.5 0-1.05(m,6H),0.94-0.73(m,5H),0.67(t,J=7.2Hz,3H),0.50(d,J=12.7Hz,1H).

[0312] The following compounds were prepared by the above procedure or by modifying the above procedure using the corresponding intermediates.

[0313] [Table 99]

[0314] Example 18 Synthesis of (1R,4r)-4-((R)-1-((6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid (Compound 55) [ka] Step 1: To a solution of 1-bromo-3-fluorobenzene (30 g, 209.52 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (73.33 g, 419.04 mmol) in toluene (500 mL) was added t-BuONa (40.27 g, 139.68 mmol), esphos (8.60 g, 20.95 mmol), and Pd(dba) (9.59 g, 10.48 mmol) at 25 °C under N. The mixture was then stirred at 110 °C for 16 h and then degassed with N three times. LCMS showed that the desired mass was detected. The reaction mixture was poured into HO (1000 mL), acidified with 3 N HCl to pH = 1, and then extracted with EtOAc (800 mL × 2). The aqueous phase was adjusted to pH 7-8 by the addition of NaHCO. Extraction with EtOAc (800 mL x 3) was carried out, and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give 8-(3-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (42 g, 91.28% purity) as a yellow oil. LCMS: RT = 0.651 min, m / z = 238.1 [M+H] + .

[0315] Step 2: To a solution of 8-(3-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (42 g, 177.01 mmol) in dioxane / HO (450 mL, V / V = 2 / 1) was added concentrated HCl (150 mL) at 25 °C. The mixture was then stirred at 60 °C for 24 h. TLC (petroleum ether / ethyl acetate = 5 / 1) showed that most of the starting material (Rf = 0.5) was consumed, and one major spot (Rf = 0.4) was detected. The reaction mixture was poured into HO (1000 mL) and basified with 6 N NaOH solution to adjust the pH to 7-8. The mixture was extracted with EtOAc (1000 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by combiflash silica gel column chromatography (PE to 50% EA) and concentrated to give 1-(3-fluorophenyl)piperidin-4-one (20 g, 95% purity) as a colorless oil. LCMS: RT=0.723 min, m / z=194.0 [M+H] + .

[0316] Step 3: To a solution of diethyl carbonate (36.68 g, 310.53 mmol) in THF (60 mL) was added NaH (2.98 g, 60%, 74.53 mmol) in small portions. The mixture was then heated to 80 °C, and a solution of 1-(3-fluorophenyl)piperidin-4-one (12 g, 62.11 mmol) in THF (60 mL) was added dropwise. The reaction mixture was stirred at 80 °C for 2 hours. TLC (petroleum ether / ethyl acetate = 5 / 1) showed that the starting material (Rf = 0.4) was completely consumed, and one major spot (Rf = 0.8) was detected. The reaction mixture was quenched with saturated NH4Cl solution (300 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by combiflash silica gel column chromatography (PE to 50% EA) and concentrated to give ethyl 1-(3-fluorophenyl)-4-oxopiperidine-3-carboxylate (8.0 g, 80% purity) as a colorless oil. LCMS: RT=0.927 min, m / z=266.0 [M+H]+ .

[0317] Step 4: To a solution of ethyl 1-(3-fluorophenyl)-4-oxopiperidine-3-carboxylate (4 g, 15.08 mmol) in EtOH (100 mL) was added urea (1.81 g, 30.16 mmol) and NaOMe (1.63 g, 30.16 mmol) at 25 °C. The mixture was then stirred at 80 °C for 16 h. LCMS showed that one major peak with the desired mass was detected. The precipitate was filtered and dried under reduced pressure to give 6-(3-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (1.2 g, 87% purity) as a yellow solid. LCMS: RT = 0.683 min, m / z = 262.0 [M+H] + .

[0318] Step 5: To a solution of 6-(3-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (1.2 g, 4.59 mmol) in dioxane (10 mL) was added POCl (7 mL) at 25 °C. The reaction mixture was then heated to 125 °C and stirred for 16 h. LCMS showed that one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove POCl. The residue was then diluted with EA (50 mL) and washed with saturated NaHCO solution (50 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to petroleum ether / ethyl acetate = 2 / 1) and concentrated to give 2,4-dichloro-6-(3-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (400 mg, purity 87%) as a yellow solid. LCMS: RT = 0.910 min, m / z = 297.9 [M+H] + .

[0319] Step 6: To a solution of 2,4-dichloro-6-(3-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (150 mg, 0.503 mmol) and 1-(1-methyl-1H-pyrazol-4-yl)-2-(piperidin-1-yl)ethan-1-amine bishydrochloride (212 mg, 0.603 mmol) in MeCN (2 mL) was added DPIEA (325 mg, 2.52 mmol). The mixture was then stirred at 80 °C for 4 hours. LCMS showed that one major peak with the desired mass was detected. The reaction mixture was diluted with HO (5 mL) and extracted with ethyl acetate (3 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to ethyl acetate) and concentrated to give 2-chloro-6-(3-fluorophenyl)-N-(1-(1-methyl-1H-pyrazol-4-yl)-2-(piperidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (100 mg, 96% purity) as a yellow solid. LCMS: RT=0.731 min, m / z=470.1 [M+H] + .

[0320] Step 7: To a solution of 2-chloro-6-(3-fluorophenyl)-N-(1-(1-methyl-1H-pyrazol-4-yl)-2-(piperidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (100 mg, 0.425 mmol) in ACN (0.5 mL) was added DPIEA (82 mg, 0.638 mmol) and methyl (1R,4r)-4-((R)-1-aminopropyl)cyclohexane-1-carboxylate hydrochloride (100 mg, 0.212 mmol) at 25 °C. The mixture was then stirred at 160 °C under microwave irradiation for 10 h. LCMS showed complete consumption of the starting material and one major peak with the desired mass. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by preparative TLC (EA) to give methyl (1R,4r)-4-((1R)-1-((6-(3-fluorophenyl)-4-((1-(1-methyl-1H-pyrazol-4-yl)-2-(piperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)propyl)cyclohexane-1-carboxylate (120 mg, 82% purity) as a yellow oil. LCMS: RT=0.724 min, m / z=633.3 [M+H] + .

[0321] Step 8: To a solution of methyl (1R,4r)-4-((1R)-1-((6-(3-fluorophenyl)-4-((1-(1-methyl-1H-pyrazol-4-yl)-2-(piperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)propyl)cyclohexane-1-carboxylate (100 mg, 0.158 mmol) in THF / HO (1 mL, V / V=1 / 1) was added LiOH·HO (33 mg, 0.790 mmol) at 25° C. The mixture was then stirred at 25° C. for 4 hours. LCMS showed that the starting material was completely consumed and the desired mass was detected. Saturated citric acid solution was added to the reaction mixture to adjust the pH to 7. The mixture was concentrated to remove THF. The aqueous phase was purified by preparative HPLC (Column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm, Conditions: water (10 mM NH4HCO3) to ACN, Start B: 24, End B: 44, Gradient Time (min): 8, Retention Time at 100% B (min): 2, Flow Rate (mL / min): 30) to give 19.8 mg of (1R,4r)-4-((R)-1-((6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazol-4-yl)-2-((S)-3-methylpiperidin-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid as a yellow solid. LCMS: RT=0.820 min, m / z=619.7[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 7.50(s,1H),7.36(s,1H),7.26-7.17(m,1H),6.88-6.78(m,2H),6.49(dt,J=2.1,8.3Hz,1H),6.12(br d,J=7.8Hz,1H),5.51-5.38(m,2H),3.97(s,1H),3.78(s,2H),3.74-3.65 (m,1H),3.56-3.46(m,2H),2.78-2.62(m,4H),2.62-2.56(m,2H),2.47(br d,J=5.6Hz,4H),2.09-1.96(m,2H),1.88(br d,J=11.3Hz,2H),1.79-1.66(m,2H),1.59-1.15(m,12H),1.04-0.91(m,2H),0.85(br t,J=7.3Hz,3H).

[0322] The following compounds were prepared by the above procedure or by modifying the above procedure using the corresponding intermediates.

[0323] [Table 100]

[0324] [Table 101]

[0325] [Table 102]

[0326] [Table 103]

[0327] Example 19 -Biological Assay - Cellular cGMP Production The functional activity of the 174 compounds described was tested in an intracellular cGMP production assay using CHO-K1 cells expressing human NPR1 (DiscoverX (catalog no. 93-0804C2)) and CHO-K1 cells expressing monkey NPR1 (generated in-house using pcDNA3.1(-)Neo-CynoNPR1). To examine the functional properties of the compounds, we monitored the production of cyclic guanosine 3',5'-cyclic monophosphate (cGMP) upon stimulation by binding to NPR1 expressed on the cell surface of CHO-K1 cells. Cellular cGMP is a major second messenger mediating cellular activity and is synthesized by activated NPR1 triggered by binding of its natural ligand, ANP. Therefore, we used a commercially available assay kit (CisBio HTRF Assay Kit (catalog no. 62GM2PEB)). The assay was performed according to the manufacturer's instructions with minor modifications. Briefly, 2 × 10 human NPR1 cells were cultured in 100 mL of PBS. 4 2.5 x 10 monkey NPR1 cells were added to a culture medium containing 2.5 x 10 cells / mL. 4 The cells were adjusted to 1 mL / mL and 20 μL / well was seeded into a 384-well microtiter plate and incubated overnight. All compound stocks were diluted to 2x the final assay concentration in PBS + 0.1% BSA. After adding 10 μL / well of assay buffer (PBS + 0.1% BSA + 1 mM IBMX) and 10 μL / well of various concentrations of compound (12-point dose-response assays with 3-fold dilutions from a maximum concentration of 30 μM), the plate was incubated at 37°C for 30 minutes to allow for cGMP generation. In parallel, a standard curve was generated using calibrators (included in the kit). Cells were lysed, and a mixture of cGMP-d2 and anti-cGMP-cryptate was added and incubated for 1 hour at room temperature. Readings were taken using an Envision plate reader (PerkinElmer) with an excitation wavelength of 317 nm and an emission wavelength of 665 nm. cGMP concentration (Delta F [%]) was calculated using the following formula: ratio=[(A 665nm / B 620nm ) x 10 4]Average Ratio = (Σ Ratio / 2) CV = [(Standard Deviation / Average Ratio) × 100] Delta F = [((Calibrator or Sample Ratio - Ratio neg ) / ratio neg )×100] ratio neg : Negative control

[0328] An ANP (Phoenix Pharmaceuticals, catalog number 005-06) dose-response curve was used as a control for each assay run, and the Amax (maximum cGMP production achieved) for each compound was expressed as a percentage of the maximum cGMP produced with ANP.

[0329] [Table 104]

[0330] [Table 105]

[0331] [Table 106]

[0332] [Table 107]

[0333] [Table 108]

[0334] [Table 109]

[0335] [Table 110]

[0336] equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed by the following claims.

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, A is NR １ or CR ２ R ３ And, R １ and R ２ are each independently H, (C ３ ~C ６ ) cycloalkyl or (C ６ ~C １０ ) aryl, and the (C ６ ~C １０ ) aryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halo, -CN, -OH, -CO ２ H, (C １ ~C ６ ) alkyl and (C ３ ~C ６ ) cycloalkyl, R ３ is H or (C １ ~C ６ ) is alkyl, R ４ is, (C ６ ~C １０ ) A five-membered or six-membered heteroaryl containing aryl or one, two, three or four heteroatoms selected from N, O and S, and the (C ６ ~C １０ ) Aryl or the aforementioned 5-membered or 6-membered heteroaryl is a halo, -CN, -OH, -CO ２ H, oxo, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Haloalkyl, (C ３ ~C ６ ) Cycloalkyl, (C ３ ~C ６ ) Cycloalkyl-(C １ ~C ６ ) alkyl and (C １ ~C ６ ) Alkyl (C ３ ~C ６ ) Each substituent is optionally substituted with one, two, three, four, or five substituents independently selected from the cycloalkyl group. R ５ NR ８ R ９ And, R ６ H, (C １ ~C ６ ) alkyl, (C ３ ~C ６ ) Cycloalkyl and (C ３ ~C ６ ) Cycloalkyl-(C １ ~C ６ ) Selected from alkyl groups, R ７ is, (C ３ ~C ６ ) Cycloalkyl or (C ６ ~C １０ ) is aryl, and the (C ３ ~C ６ ) Cycloalkyl and (C ６ ~C １０ ) Aryls are halo, -CN, -OH, -CO ２ H and HO ２ C - (C １ ~C ６ ) Each substituent is optionally substituted with one, two, three, four, or five substituents independently selected from the alkyl group. R ８ and R ９ These are H and (C) respectively, independently. １ ~C ６ ) A 3- to 6-membered heterocycle containing alkyl or 1 to 3 heteroatoms selected from N, O and S, or R ８ and R ９ Together with the N to which they are bonded, they form a 3- to 10-membered heterocycle that optionally contains one or two additional heteroatoms selected from N, O, and S, wherein the 3- to 10-membered heterocycle is composed of halo, -CN, -OH, and -CO ２ H, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Haloalkyl, (C ３ ~C ６ ) Cycloalkyl-(C １ ~C ６ ) alkyl, (C ３ ~C ６ ) Cycloalkyl, (C １ ~C ６ ) Alkyl-O-(C １ ~C ６ ) alkyl, (C １ ~C ６ ) Hydroxyalkyl, (C １ ~C ６ ) optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from an alkoxy and a 3-7 membered heterocycle containing 1-2 heteroatoms selected from N, O, and S, and R ａ 、R ｂ 、R ｃ and R ｄ are each independently H or (C １ ~C ６ ) alkyl) A compound of or a pharmaceutically acceptable salt thereof.

2. A is NR １ and R １ is phenyl optionally substituted with one or two substituents independently selected from halo and -CN, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. A is NR １ And R １ teeth, 【Chemistry 2】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

4. A is CR ２ R ３ And R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a phenyl optionally substituted with one or two substituents independently selected from the halo.

5. A is CR ２ R ３ And R ２ teeth, 【Transformation 3】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

6. R ４ is, halo, oxo, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Haloalkyl, (C ３ ~C ６ ) Cycloalkyl and (C ３ ~C ６ ) Cycloalkyl-(C １ ~C ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, comprising a five-membered or six-membered heteroaryl compound containing one or two heteroatoms selected from N and S, which are optionally substituted with one, two, or three substituents independently selected from alkyl.

7. R ４ is, halo, oxo, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Fluoroalkyl, (C ３ ~C ６ ) Cycloalkyl and (C ３ ~C ６ ) Cycloalkyl-(C １ ~C ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a five-membered heteroaryl compound comprising one or two heteroatoms selected from N and S, optionally substituted with one, two, or three substituents independently selected from alkyl.

8. R ４ Hello, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Fluoroalkyl, (C ３ ~C ６ ) Cycloalkyl and (C ３ ~C ６ ) Cycloalkyl-(C １ ~C ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a five-membered heteroaryl compound comprising one or two heteroatoms selected from N, optionally substituted with one, two, or three substituents independently selected from alkyl.

9. R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a phenyl optionally substituted with one, two, or three substituents independently selected from the halo.

10. R ４ teeth, 【Chemistry 4】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

11. R ５ NR ８ R ９ And R ８ and R ９ These, together with the N to which they are bonded, form a 5- to 10-membered heterocycle that optionally contains one or two additional O heteroatoms, and the 5- to 10-membered heterocycle is a halo, -OH, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Haloalkyl, (C ３ ~C ６ ) Cycloalkyl, (C １ ~C ６ ) Alkyl-O-(C １ ~C ６ ) alkyl, (C １ ~C ６ ) Hydroxyalkyl, (C １ ~C ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is optionally substituted with one, two, or three substituents independently selected from a 3- to 7-membered heterocycle containing an alkoxy and a heteroatom selected from N and O.

12. The aforementioned 5- to 10-membered heterocycles are fluoro, -OH, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Fluoroalkyl, CH ３ O-(C) １ ~C ６ ) alkyl, (C １ ~C ６ The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the compound is optionally substituted with one, two, or three substituents independently selected from a five-membered heterocycle containing a heteroatom selected from hydroxyalkyl and O.

13. The aforementioned 5- to 10-membered heterocycles are fluoro, -OH, -CH ３ ien-CH ２ F, -CF 2 H, -CH ２ CH ３ ien-CH ２ OH, -OCH ３ and -CH ２ OCH ３ The compound according to claim 11 or a pharmaceutically acceptable salt thereof, optionally substituted with one, two, or three substituents independently selected from the above.

14. R ５ NR ８ R ９ And R ８ and R ９ These, together with the N to which they are bonded, form a 5- to 10-membered heterocycle, and the 5- to 10-membered heterocycle is composed of halo, -OH, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Haloalkyl, (C ３ ~C ６ ) Cycloalkyl, (C １ ~C ６ ) Alkyl-O-(C １ ~C ６ ) alkyl, (C １ ~C ６ ) Hydroxyalkyl, and (C １ ~C ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one, two, or three substituents independently selected from the alkoxy.

15. R ５ teeth, 【Transformation 5】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

16. R ６ is, (C １ ~C ４ ) alkyl, (C ３ ~C ５ ) Cycloalkyl and (C ３ ~C ５ ) Cycloalkyl-(C １ ~C ４ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from alkyl groups.

17. R ６ is, -CH ３ , and -CH ２ CH ３ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

18. R ７ is, (C ５ ~C ６ ) Cycloalkyl or (C ６ ~C １０ ) Selected from the aryl group, and the (C ５ ~C ６ ) Cycloalkyl and (C ６ ~C １０ ) Aryl is fluoro, -CO ２ H and -CH ２ CO ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each substituent is optionally substituted with one or two substituents independently selected from H.

19. R ７ teeth, 【Transformation 7】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

20. R ａ , R ｂ , R ｃ and R ｄ These are, independently, H or -CH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

21. A is CR2R3, R2 is a phenyl molecule that is optionally substituted with one or two substituents independently selected from the halo. R3 is H, R4 is a five-membered heteroaryl containing one or two heteroatoms selected from N and S, which is optionally substituted with one, two, or three substituents independently selected from halo, oxo, (C1-C6) alkyl, (C1-C6) fluoroalkyl, (C3-C6) cycloalkyl and (C3-C6) cycloalkyl-(C1-C6) alkyl. R5 is NR8 R9, and R8 and R9, together with the N to which they are bonded, form a 5-10 membered heterocycle optionally containing 1-2 additional O heteroatoms, and the 5-10 membered heterocycle is optionally substituted with 1, 2, or 3 substituents independently selected from halo, -OH, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-O-(C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy, and a 3-7 membered heterocycle containing heteroatoms selected from N and O. R6 is selected from (C1-C4) alkyl groups. R7 is selected from (C5-C6) cycloalkyl or (C6-C10) aryl, and the (C5-C6) cycloalkyl and (C6-C10) aryl are each optionally substituted with one or two substituents independently selected from fluoro, -CO₂H, and -CH₂CO₂H. Ra, Rb, Rc, and Rd are each independently H or -CH3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

22. A is CR2R3, R2 is a phenyl molecule that is optionally substituted with one or two substituents independently selected from the halo. R3 is H, R4 is a five-membered heteroaryl containing one or two heteroatoms selected from N, which is optionally substituted with one, two, or three substituents independently selected from halo, (C1-C6) alkyl, (C1-C6) fluoroalkyl, (C3-C6) cycloalkyl, and (C3-C6) cycloalkyl-(C1-C6) alkyl. R5 is NR8 R9, and R8 and R9, together with the N to which they are bonded, form a 5- to 10-membered heterocycle, and the 5- to 10-membered heterocycle is optionally substituted with 1, 2, or 3 substituents independently selected from a 5-membered heterocycle containing a heteroatom selected from fluoro, -OH, (C1-C6)alkyl, (C1-C6)fluoroalkyl, CH3O-(C1-C6)alkyl, (C1-C6)hydroxyalkyl, and O. R6 is selected from (C1-C4) alkyl groups. R7 is selected from (C5-C6) cycloalkyl or (C6-C10) aryl, and the (C5-C6) cycloalkyl and (C6-C10) aryl are each optionally substituted with one or two substituents independently selected from fluoro, -CO₂H, and -CH₂CO₂H. Ra, Rb, Rc, and Rd are each independently H or -CH3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

23. 3-((R)-1-(((R)-4-(((R)-2-(azepan-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-6-methyl-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(azepan-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((R)-1-(((R)-4-(((S)-2-(azepan-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-6-(4-fluorophenyl)-6-methyl-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(methyl((R)-6-methyl-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((R)-1-(methyl((R)-6-methyl-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 3-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((S)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-ethyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 3-((R)-1-(((R)-4-(((R)-2-((S)-3-(fluoromethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 3-((R)-1-(((R)-4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-6-(4-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1,5-dimethyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-ethyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-ethyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((S)-3-(fluoromethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-6-(2-fluorophenyl)-6-methyl-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1S,4r)-1-fluoro-4-((S)-1-(methyl((S)-4-(((S)-1-(1-methyl-1H-pyrazole-4-yl)-2-((R)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-isopropyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1S)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(2,4-dimethylthiazole-5-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((1R)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1S)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(4-methylthiazole-5-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 3-((1R)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-2-((S)-3-(methoxymethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((S)-1-(((S)-4-(((R)-2-((R)-3-(fluoromethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((S)-6-(3-fluorophenyl)-4-(((R)-1-phenyl-2-(piperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1R,3R,5R,7R)-2-azaadamantan-2-yl)-1-(1-ethyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 2-((1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexyl)acetic acid, (1R,4r)-4-((R)-1-(methyl((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((R)-1-(((R)-4-(((R)-2-(9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(2-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 3-((1R)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-ethyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 3-((S)-1-(((R)-4-(((R)-2-((S)-3-(fluoromethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, 3-((R)-1-(methyl((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((R)-1-(((R)-4-(((R)-1-(1,5-dimethyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-cyclopropyl(((R)-6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)methyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-6-(2-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-phenylethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((S)-4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(azepan-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((S)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-ethyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((S)-3-(difluoromethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-((6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(2-azabicyclo[2.2.1]heptan-2-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((3S,5R)-3,5-dimethylpiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(2-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-((R)-2-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-ethyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(methyl((R)-6-methyl-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 2-((1R,4r)-4-((R)-1-(methyl((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexyl)acetic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(2-azabicyclo[2.2.1]heptan-2-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((1S)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((5R,7R)-2-azaadamantan-2-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-2-((S)-3-(hydroxymethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((S)-2-((S)-3-methylpiperidine-1-yl)-1-(4-methylthiazole-5-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 3-(1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)-1l3-propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((S)-6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-((4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((1R)-1-(((6R)-4-(((1S)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(2-methylthiazole-5-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(3-azabicyclo[4.1.0]heptan-3-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-((1R,5S)-3-hydroxy-9-azabicyclo[3.3.1]nonane-9-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-((4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1S)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(2-methylthiazole-5-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1S,4s)-1-fluoro-4-((R)-1-(methyl((R)-4-(((S)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((S)-3-(methoxymethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((R)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-6-phenyl-4-(((R)-1-phenyl-2-(pyrrolidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(2-azabicyclo[2.2.1]heptan-2-yl)-1-(4-fluorophenyl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((S)-3-(fluoromethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1S)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1,5-dimethyl-1H-pyrazole-3-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1,5-dimethyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((R)-2-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-ethyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((S)-3-(hydroxymethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(azepan-1-yl)-1-(1-ethyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(3,3-dimethylpiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((R)-2-ethylpiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-cyclopropyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1R,3R,5R,7R)-2-azaadamantan-2-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-((6-(3-fluorophenyl)-4-(((R)-1-phenyl-2-(pyrrolidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-isopropyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(methyl((S)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1,3-dimethyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-((R)-2-(hydroxymethyl)piperidine-1-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1S)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazole-3-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-((6-(2-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-((1-(1-(fluoromethyl)-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(((1S,5S)-9-azabicyclo[3.3.1]nonane-9-yl)-1-phenylethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-(2-oxa-7-azaspiro[4.5]decane-7-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-((6-(4-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((1R)-1-(((6R)-4-(((1S)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(2,4-dimethylthiazole-5-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-((1R,5S)-3-hydroxy-9-azabicyclo[3.3.1]nonan-9-yl)-1-phenylethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((1R)-1-(((6R)-4-(((1S)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(4-methylthiazole-5-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((S)-1-(4-methylthiazole-5-yl)-2-(piperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((S)-6-phenyl-4-(((R)-1-phenyl-2-(pyrrolidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)aminopropyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((S)-4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-((1R,5S)-3-hydroxy-9-azabicyclo[3.3.1]nonane-9-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(methyl((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((S)-1-(2-methylthiazole-5-yl)-2-(piperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-cyclopropyl(methyl((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)methyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-(4-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-1-(1-ethyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-2-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-((6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(methyl((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((R)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-(6-azaspiro[3.5]nonane-6-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1S)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(2-methylthiazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(2-azabicyclo[2.2.1]heptan-2-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((S)-3-hydroxypiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1S,4r)-4-((S)-1-(((S)-6-(3-fluorophenyl)-6-methyl-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((R)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-((6-phenyl-4-(((R)-1-phenyl-2-(pyrroridine-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-isopropyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)(cyclopropyl)methyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((S)-3-methoxypiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-((S)-2-(hydroxymethyl)piperidine-1-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(2-azabicyclo[2.2.1]heptan-2-yl)-1-phenylethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(4,4-difluoroazepan-1-yl)-1-(1-ethyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-((1R,5S)-6-hydroxy-3-azabicyclo[3.1.1]heptan-3-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-2-cyclopropyl-1-((6-phenyl-4-(((R)-1-phenyl-2-(pyrroridine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)ethyl)cyclohexane-1-carboxylic acid, 3-(1-(((R)-4-(((S)-1-(1,3-dimethyl-1H-pyrazole-5-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)-1l3-propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((S)-6-(2-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(4-fluoropiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(3-fluoro-3-methylpiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(methyl((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-(4-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(methyl((R)-6-phenyl-4-(((R)-1-phenyl-2-(pyrrolidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-(cyclopropylmethyl)-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-ethyl-6-oxo-1,6-dihydropyridine-3-yl)-2-(piperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((R)-2-(hydroxymethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(4,4-difluoroazepan-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(4-methoxypiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-((6-cyclohexyl-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, 4-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-ethyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)ethyl)benzoic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-(4-hydroxypiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, 3-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((S)-1-(1-methyl-1H-pyrazole-5-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(3-fluoropiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-((6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1S,4r)-4-((1S)-1-((6-phenyl-4-(((R)-1-phenyl-2-(pyrrolidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)ethyl)cyclohexane-1-carboxylic acid, 4-((R)-1-(((R)-6-phenyl-4-(((R)-1-phenyl-2-(pyrrolidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)ethyl)benzoic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(2-azabicyclo[2.2.1]heptan-2-yl)-1-phenylethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((S)-1-(1-methyl-1H-pyrazole-5-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-(2-oxa-7-azaspiro[4.5]decane-7-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-ethyl-1H-pyrazole-4-yl)-2-((S)-3-hydroxypiperidine-1-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1S)-2-(8-azabicyclo[3.2.1]octan-8-yl)-1-(1-methyl-1H-pyrazole-5-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(dimethylamino)-1-phenylethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)aminopropyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-6-phenyl-4-(((R)-1-phenyl-2-((tetrahydro-2H-pyran-4-yl)amino)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(methyl((R)-6-phenyl-4-(((R)-2-(piperidine-1-yl)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, 4-((R)-1-(((R)-4-(((R)-2-((1S,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)ethyl)-2-fluorobenzoic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1R,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-((6-(3-chlorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, 4-((R)-1-(((R)-4-(((R)-1-(1-isopropyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)ethyl)benzoic acid, 3-((R)-1-(((R)-4-(((S)-2-((1R,5R)-9-azabicyclo[3.3.1]nonan-9-yl)-1-(1-methyl-1H-pyrazole-5-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid, (1R,4r)-4-((R)-1-(methyl((R)-4-(((R)-2-methyl-1-(1-methyl-1H-pyrazole-4-yl)-2-(piperidine-1-yl)propyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-((6-(3-cyanophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((1R)-1-(((6R)-4-(((1R)-2-(3-(fluoromethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((1R,6S)-2-azabicyclo[4.1.0]heptan-2-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(((1S,6R)-2-azabicyclo[4.1.0]heptan-2-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((R)-3-ethyl-3-hydroxypiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((3R,4R)-4-hydroxy-3-methylpiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(methyl((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-(5-azaspiro[2.5]octan-5-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((R)-3-methoxypyrrolidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((R)-3-hydroxy-3-methylpiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((3R,5R)-3-methoxy-5-methylpiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((3S,5S)-3-methoxy-5-methylpiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, (1R,4r)-4-((R)-1-(((R)-4-(((S)-1-(3-fluoro-1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid, and (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((S)-3-hydroxy-3-methylpiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid A compound selected from or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the following: 【Transformation 8】 3-((R)-1-(((R)-4-(((R)-2-(azepan-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid; 【Chemistry 9】 (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-(azepan-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid; 【Chemistry 10】 3-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)bicyclo[1.1.1]pentane-1-carboxylic acid; 【Chemistry 11】 (1R,4r)-4-((R)-1-(((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid; 【Chemistry 12】 (1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-2-((S)-3-(methoxymethyl)piperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid; 【Chemistry 13】 (1R,4r)-4-((R)-1-(((S)-6-(3-fluorophenyl)-4-(((R)-1-phenyl-2-(piperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)aminopropyl)cyclohexane-1-carboxylic acid; 【Chemistry 14】 2-((1R,4r)-4-((R)-1-(((R)-6-(3-fluorophenyl)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexyl)acetic acid; 【Chemistry 15】 (1R,4r)-4-((R)-1-(methyl((R)-4-(((R)-1-(1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)amino)propyl)cyclohexane-1-carboxylic acid; 【Chemistry 16】 (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((3R,4R)-4-hydroxy-3-methylpiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid; 【Chemistry 17】 (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((3R,5R)-3-methoxy-5-methylpiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid; [Chemistry 18] (1R,4r)-4-((R)-1-(((R)-4-(((S)-1-(3-fluoro-1-methyl-1H-pyrazole-4-yl)-2-((S)-3-methylpiperidine-1-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid; or 【Chemistry 19】 (1R,4r)-4-((R)-1-(((R)-4-(((R)-2-((S)-3-hydroxy-3-methylpiperidine-1-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2-yl)(methyl)amino)propyl)cyclohexane-1-carboxylic acid.

25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a sodium salt.

26. A pharmaceutical composition comprising the compound described in Claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

27. The pharmaceutical composition according to claim 26, further comprising at least one additional pharmaceutically active agent.

28. A method for treating or preventing a cardiovascular disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of the compound described in Claim 1 or a pharmaceutically acceptable salt thereof.

29. The method according to claim 28, wherein the cardiovascular disease or disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina pectoris, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, cardiac arrhythmias, atrial fibrillation (AF), new onset of atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, adverse vascular remodeling, plaque stabilization, and myocardial infarction (MI).

30. The method according to claim 29, wherein the heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with maintained ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute decompensated heart failure.

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