Hydroquinazoline derivatives and treatment of a disease or disorder using the same

Abstract

The disclosure relates to a compound having the structure of Formula (I): (I) or a pharmaceutically acceptable salt thereof wherein R1 to R10 are as described herein. Also provided herein are compositions and methods of using such compounds.

Description

[0001] Docket No.: PAT059786-WO-PCT

[0002] HYDROQUINAZOLINE DERIVATIVES AND TREATMENT OF A DISEASE OR DISORDER USING THE SAME

[0003] RELATED APPLICATIONS

[0004]

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 688,551, filed August 29, 2024, and U.S. Provisional Application No. 63 / 848,761, filed July 22, 2025, the entire contents of each of which are hereby incorporated by reference in their entireties.

[0005] BACKGROUND

[0006]

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

[0007]

[0003] It has been shown that an increase in ANP via infusions may be beneficial for patients with chronic heart failure with reduced ejection fraction (outbound pumping of blood by heart) (Yoshimura etal., 2001, Can J Physiol Pharmacol 79(8):730-735). However, there is a need for oral agents that are able to supplement or replace existing therapies.

[0008] SUMMARY

[0009]

[0004] Provided herein, inter alia, are compounds of substituted hydroquinazoline derivatives compounds and pharmaceutical compositions thereof. The compounds as used herein may function as activators of NPR1, e.g., for treating or preventing a disease or condition related to NPR1.

[0010]

[0005] In an aspect, the disclosure relates to a compound having the structure of Formula (I): Docket No.: PAT059786-WO-PCT or a pharmaceutically acceptable salt thereof, wherein: 5 to 6 membered heteroaryl optionally substituted with one or more (Ci-Ce)alkyl;

[0011] R2is (Ci-Ci2)alkyl, (C3-Ce)cycloalkyl, phenyl, or 5 to 6 membered heteroaryl, wherein each of the (Ci-Ci2)alkyl, the (C3-Ce)cycloalkyl, the phenyl, or the 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OR2A, -L2-OR2A, and (Ci-Ce)alkyl;

[0012] R3is -NRnR12;

[0013] R4is a 5- or 6-membered heteroaryl which is each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OR4A, -L4- OR4A, -C(O)NR4BR4C, -NR4BC(O)R4D, -NR4BC(O)OR4A, -C(O)OR4A, -L4- C(O)OR4A, (Ci-Ce)alkyl, (C3-C6)cycloalkyl-(Ci-C6)alkyl, and (Ci-C6)alkyl(C3- Cejcycloalkyl;

[0014] R7is a (C3-Cs) cycloalkyl which is optionally substituted with one or more substituents independently selected from halogen, (Ci-Ce)alkyl, -OR7A, -L7-OR7A, - C(O)NR7BR7C, -NR7BC(O)R7D, -NR7BC(O)OR7A, -C(O)OR7A, -C(O)NHSO2CH3, and -L7-C(O)OR7A; each R5, R8, R9, and R10is independently hydrogen, or (Ci-Ce)alkyl; each R6is hydrogen, (C3-Ce)cycloalkyl, or (Ci-Ce)alkyl;

[0015] R11and R12together with the nitrogen attached thereto are joined to form a 3- to 10- membered heterocyclyl, wherein the 3- to 10-membered heterocyclyl optionally comprises one or two heteroatoms selected from N, O, and S, and optionally is substituted with one or more selected from halogen, oxo, -CN, -OR3A, -L3-OR3A, - Docket No.: PAT059786-WO-PCT

[0016] C(O)NR3BR3C, -NR3BC(O)R3D, -NR3BC(O)OR3A, -C(O)OR3A, -L3-C(O)OR3A, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, and a 5 to 6-membered heterocyclyl which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -CO2H, oxo, and (Ci-Ce)alkyl; each L1, L2, L3, L4and L7is (Ci-Ce)alkylene; each R1A, R1D, R2A, R2D, R3A, R3D, R4A, R4D, R7A, and R7Dis independently hydrogen, (Ci-Ce)alkyl, or (Ci-Ce)haloalkyl; and each R1Band R1Cis independently hydrogen, optionally substituted (C3-Ce)cycloalkyl or optionally substituted (Ci-Ce)alkyl, wherein when substituted, the (C3- Cejcycloalkyl and (C3-Ce)cycloalkyl is substituted with one or more substituents independently selected from aryl (e.g., phenyl) ; or R1Band R1Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; each R2B, R2C, R3B, R3C, R4B, R4C, R7B, and R7Cis independently hydrogen, or (Ci- Cejalkyl; or R1Band R1Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; R2Band R2Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; R3Band R3Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; R4Band R4Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; or R7Band R7Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl.

[0017]

[0006] In an aspect, the present disclosure relates to a pharmaceutical composition including a compound of Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0018]

[0007] In an 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.

[0008] In an aspect, the present disclosure relates to a method for treating a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or disorder is a cardiovascular disease or disorder. In some embodiments, the Docket No.: PAT059786-WO-PCT cardiovascular disease or disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, cardiac dysrhythmia, atrial fibrillation (AF), new onset of atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, and myocardial infarction (MI). In some embodiments, the disease or disorder is disorder is a disorder or disease associated with natriuretic peptide receptor activity

[0019]

[0009] In an aspect, the present disclosure relates to a compound of Formula I or a pharmaceutically acceptable salt thereof for use as a medicament.

[0020]

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

[0021]

[0012] In an aspect, the present disclosure relates to use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the treatment of a disease or disorder.

[0022]

[0013] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.

[0023] DETAILED DESCRIPTION

[0024]

[0014] In certain aspects, the disclosure provides substituted hydroquinazoline derivatives compounds, and pharmaceutical compositions thereof. In particular, such substituted compounds are useful as activators of NPR1 and thus can be used to treat or prevent a disease or condition.

[0015] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by Docket No.: PAT059786-WO-PCT one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

[0025] Compounds

[0026]

[0016] In one aspect, the disclosure therefore provides a compound having the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: 5 to 6 membered heteroaryl optionally substituted with one or more (Ci-Ce)alkyl;

[0027] R2is (Ci-Ci2)alkyl, (C3-Ce)cycloalkyl, phenyl, or 5 to 6 membered heteroaryl, wherein each of the (Ci-Ci2)alkyl, the (C3-Ce)cycloalkyl, the phenyl, or the 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OR2A, -L2-OR2A, and (Ci-Ce)alkyl;

[0028] R3is -NRnR12;

[0029] R4is a 5- or 6-membered heteroaryl which is each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OR4A, -L4- OR4A, -C(O)NR4BR4C, -NR4BC(O)R4D, -NR4BC(O)OR4A, -C(O)OR4A, -L4- C(O)OR4A, (Ci-Ce)alkyl, (C3-C6)cycloalkyl-(Ci-C6)alkyl, and (Ci-C6)alkyl(C3- Ce)cycloalkyl;

[0030] R7is a (C3-Cs) cycloalkyl which is optionally substituted with one or more substituents independently selected from halogen, (Ci-Ce)alkyl, -OR7A, -L7-OR7A, - C(O)NR7BR7C, -NR7BC(O)R7D, -NR7BC(O)OR7A, -C(O)OR7A, -C(O)NHSO2CH3, and -L7-C(O)OR7A; Docket No.: PAT059786-WO-PCT each R5, R8, R9, and R10is independently hydrogen, or (Ci-Ce)alkyl; each R6is hydrogen, (C3-Ce)cycloalkyl, or (Ci-Ce)alkyl;

[0031] R11and R12together with the nitrogen attached thereto are joined to form a 3- to 10- membered heterocyclyl, wherein the 3- to 10-membered heterocyclyl optionally comprises one or two heteroatoms selected from N, O, and S, and optionally is substituted with one or more substituents independently selected from halogen, oxo, -CN, -0R3A, -L3-OR3A, -C(O)NR3BR3C, -NR3BC(O)R3D, -NR3BC(O)OR3A, - C(0)0R3A, -L3-C(O)OR3A, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, and a 5 to 6- membered heterocyclyl which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -CO2H, oxo, and (Ci-C6)alkyl; each L1, L2, L3, L4and L7is (Ci-Ce)alkylene; each R1A, R1D, R2A, R2D, R3A, R3D, R4A, R4D, R7A, and R7Dis independently hydrogen,, (Ci-Ce)alkyl, or (Ci-Ce)haloalkyl; each R1Band R1Cis independently hydrogen, optionally substituted (C3-Ce)cycloalkyl or optionally substituted (Ci-Ce)alkyl, wherein when substituted, the (C3- Cejcycloalkyl and (Ci-Ce)cycloalkyl is substituted with one or more substituents independently selected from aryl (e.g., phenyl) ; or R1Band R1Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; and each R2B, R2C, R3B, R3C, R4B, R4C, R7B, and R7Cis independently hydrogen, or (Ci- Cejalkyl; or R1Band R1Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; R2Band R2Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; R3Band R3Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; R4Band R4Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; or R7Band R7Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl. Docket No.: PAT059786-WO-PCT

[0032]

[0017] Unless specified otherwise, the term “compounds of the present disclosure” or “compound of the present disclosure” refers to compounds of Formula (I) thereof, subordinate formulae thereof, and exemplified compounds and salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), as well as inherently formed moieties.

[0033]

[0018] Various embodiments of the disclosure are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features of other embodiments to provide further embodiments.

[0034]

[0019] In some embodiments, the compound has the structure of Formula (F): or a pharmaceutically acceptable described herein.

[0035]

[0020] In some embodiments, the compound has the structure of Formula (I”): or a pharmaceutically acceptable salt thereof. R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10are as described herein.

[0036]

[0021] In a certain aspect, NR1BC(O)OR1A, -C(O)OR or 5 to 6 membered heteroaryl optionally substituted with -CbF. In some embodiments, L1is (Ci-C2)alkylene. In some embodiments, each R1AandR1Dis independently hydrogen, (Ci- Docket No.: PAT059786-WO-PCT

[0037] C4)alkyl or (C1-C4) haloalkyl. In some embodiments, each R1AandR1Dis independently hydrogen, -CH3, -CH2CH3, -CF3, -CHF2, or CH2F.

[0038]

[0022] In some embodiments, each R1Band R1Cis independently hydrogen, -CH3, embodiments, each R1Band R1Cis independently hydrogen or -CH3. In some embodiments, R1Band R1Ctogether with the atoms attached thereto are joined to form a 4 to 5 membered heterocyclyl.

[0039]

[0023] In some embodiments, R1is -CN.

[0040]

[0024] In some embodiments, R1is -OR1Aand R1Ais hydrogen or (Ci-C4)alkyl. In some embodiments, R1Ais hydrogen, -CH3, or -CH2CH3. In some embodiments, R1is -OH, -OCH3, or -OCH2CH3. In some embodiments, R1is -OH. In some embodiments, R1is -OCH3. In some embodiments, R1is -OCH2CH3.

[0041]

[0025] In some embodiments, R1is -i -OR1^ L1is (Ci-C2)alkylene, and R1Ais hydrogen or (Ci- C4)alkyl. In some embodiments, L1is -CH2-. In some embodiments, L1is -CH2CH2-. In some embodiments, R1Ais hydrogen, -CH3, or -CH2CH3. In some embodiments, R1is -CH2OCH3, - CH2OCH2CH3, -CH2OCH2F, -CH2OCHF2, or -CH2OCF3. In some embodiments, R1is - CH2OCH3. In some embodiments, R1is -CH2OCH2CH3. In some embodiments, R1is -

[0042] CH2OCHF2.

[0043]

[0026] In some embodiments, R1is -C(O)OR1Aand R1Ais hydrogen, (Ci-C4)alkyl, or (C3-

[0044] Cejcycloalkyl. In some embodiments, R1is -C(O)OR1Aand R1Ais hydrogen or (Ci-C4)alkyl. In v some embodiments, R1Ais hydrogen, -CH3, -CH2CH3, or . In some embodiments, R1Ais hydrogen, -CH3, or -CH2CH3. In some embodiments, R1is -C(O)OH. In some embodiments, R1is -C(O)OCH3. Docket No.: PAT059786-WO-PCT

[0045]

[0027] In some embodiments, R1is -L1-C(O)OR1A, L1is (Ci-C2)alkylene, and R1Ais hydrogen or (Ci-C4)alkyl. In some embodiments, L1is -CH2-. In some embodiments, L1is -CH2CH2-. In some embodiments, R1Ais hydrogen, -CH3, or -CH2CH3. In some embodiments, R1is - CH2C(O)OCH3or -CH2C(O)OCH2CH3.

[0046]

[0028] In some embodiments, R1is -C(O)NR1BRlcand each R1Band R1Cis independently hydrogen or (Ci-C4)alkyl. In some embodiments, each R1Band R1Cis independently hydrogen or -CH3. In some embodiments, R1Bis hydrogen. In some embodiments, R1Bis -CH3. In some embodiments, R1Bis hydrogen. In some embodiments, R1Cis -CH3. In some embodiments, R1is -C(O)NH2, -C(O)NHCH3or -C(O)N(CH3)2. In some embodiments, R1is -C(O)N(CH3)2.

[0047]

[0029] In some embodiments, R1is -C(O)NR1BRlcand R1Band R1Ctogether with the atoms attached thereto are joined to form a 4 to 5 membered heterocyclyl. In some embodiments, R1Band R1Ctogether with the atoms attached thereto are joined to form In some embodiments, R1Band R1Ctogether with the atoms attached thereto are joined to form some embodiments,

[0048]

[0030] In some embodiments, R1is -NR1BC(O)R1Dor -NR1BC(O)OR1Aand each R1Band R1Dis independently hydrogen or (Ci-C4)alkyl. In some embodiments, R1Bis hydrogen or -CH3. In some embodiments, R1Dis hydrogen or -CH3. In some embodiments, R1is -NH(CO)H, - NH(CO)CH3, -NHC(O)OH, -NCH3(CO)OH, or -NH(CO)OCH3.

[0049]

[0031] In some embodiments, R1is -C(O)N=S(O)R1AR1Dand each R1Aand R1Dis independently hydrogen or (Ci-C4)alkyl. In some embodiments, R1Ais hydrogen or -CH3. In some embodiments, R1Dis hydrogen or -CH3. In some embodiments, R1is -C(O)N=S(O)HCH3, - C(O)N=S(O)H2, or -C(O)N=S(O)(CH3)2. In some embodiments, R1is -C(O)N=S(O)(CH3)2.

[0032] In some embodiments, R1is -NR1BS(O)2R1Dand each R1Dand R1Bis independently hydrogen or (Ci-C4)alkyl. In some embodiments, R1Dis hydrogen or -CH3. In some Docket No.: PAT059786-WO-PCT embodiments, R1Bis hydrogen or -CH3. In some embodiments, R1is -NHS(O)2CH3 or - NCH3S(O)2CH3. In some embodiments, R1is -NHS(O)2CH3.

[0050]

[0033] In some embodiments, R1is -S(O)2R1Dand R1Dis hydrogen or (Ci-C4)alkyl. In some embodiments, R1Dis hydrogen or -CH3. In some embodiments, R1is -S(O)2H or -S(O)2CH3. In some embodiments, R1is -S(O)2CH3.

[0051]

[0034] In some embodiments, R1is or 5 to 6 membered heteroaryl optionally substituted with - Docket No.: PAT059786-WO-PCT

[0052]

[0036] In a certain aspect, R2is (C4-Cs)alkyl, (C5-Ce)cycloalkyl, phenyl, or 5 to 6 membered heteroaryl (e.g., pyridyl). Each of the (C4-Cs)alkyl, the (C5-Ce)cycloalkyl, the phenyl, or the 5 to 6 membered heteroaryl (e.g., pyridyl) is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from halogen, -CN, -OR2A, -L2-OR2A, and (Ci-Ce)alkyl, and L2is (Ci-C2)alkylene, and R2Ais hydrogen or (Ci-C4)alkyl. In some embodiments, R2is (C4- Cs)alkyl, (C5-Ce)cycloalkyl, phenyl, or pyridyl. In some embodiments, R2is (C4-Cs)alkyl, (C5- Ce)cycloalkyl, phenyl, or pyridyl substituted with one or more substituents (e.g., 1, 2, or 3) selected from -CN, -OR2A, -CH2-OR2A, and (Ci-C4)alkyl and R2Ais hydrogen or -CH3.

[0053]

[0037] In some embodiments, R2is a (C4-Cs)alkyl. In some embodiments, R2is a linear or branched (C4-Cs)alkyl. In some embodiments, R2is a linear or branched (C4-Ce)alkyl. In some embodiments, R2is a linear or branched (C6-Cs)alkyl. In some embodiments, R2is a linear (C4- Cs)alkyl. In some embodiments, R2is a butyl. In some embodiments, R2is a pentyl. In some embodiments, R2is a hexyl. In some embodiments, R2is a heptyl. In some embodiments, R2is an octanyl.

[0054]

[0038] In some embodiments, R2is a (Cs-Ce) cycloalkyl. In some embodiments, R2is a cyclopentyl. In some embodiments, R2is a cyclohexyl. In some embodiments, R2is a cyclopentyl substituted with one or more substituents (e.g., 1, 2, or 3) selected from halogen (e.g., -F, -Cl, or -Br), -CN, -OCH3, or CH3. In some embodiments, R2is a cyclohexyl substituted with one or more substituents (e.g., 1, 2, or 3) selected from halogen (e.g., -F, -Cl, or -Br), -CN, - OCH3, or CH3

[0055]

[0039] In some embodiments, R2is a phenyl. In some embodiments, R2is a phenyl substituted with one or more substituents (e.g., 1, 2, or 3) selected from halogen (e.g., -F, -Cl, or -Br), -CN, - OH, -OCH3, -CH2-OCH3, and (Ci-C2)alkyl. In some embodiments, R2is a phenyl substituted with one or more substituents (e.g., 1, 2, or 3) selected from halogen (e.g., -F, -Cl, or -Br), -CN, - OCH3, or CH3. In some embodiments, R2is a phenyl substituted with -F. In some embodiments, R2is a phenyl substituted with -CN. In some embodiments, R2is a phenyl substituted with - OR2Aand R2Ais hydrogen or (Ci-C4)alkyl. In some embodiments, R2is a phenyl substituted with -OR2Aand R2Ais hydrogen or -CH3. In some embodiments, R2is a phenyl substituted with

[0056] -OCH3. In some embodiments, some embodiments, Docket No.: PAT059786-WO-PCT

[0057]

[0040] In some embodiments, R2is a 5 membered heteroaryl optionally substituted with one or more substituents (e.g., 1, 2, or 3) selected from halogen (e.g., -F, -Cl, or -Br), -CN, -OH, or - OCH3, -CH2-OCH3, and (Ci-C2)alkyl. In some embodiments, R2is a 6 membered heteroaryl substituted with one or more substituents (e.g., 1, 2, or 3) selected from halogen (e.g., -F, -Cl, or -Br), -CN, -OH, or -OCH3, -CH2-OCH3, and (Ci-C2)alkyl. In some embodiments, R2is a pyridyl. In some embodiments, R2is a pyridyl substituted with one or more substituents (e.g., 1, 2, or 3) selected from halogen (e.g., -F, -Cl, or -Br), -CN, -OCH3, or CH3. In some embodiments,

[0058]

[0041] In a certain aspect, n is an integer of 1 to 4, and z3 is an integer of 0 to 3. Each R30is independently halogen, -OR3A, -NR3BC(O)R3D, (Ci-C4)alkyl, (Ci- C4)haloalkyl, or 5 to 6-membered heterocyclyl which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents from halogen, oxo, -CH3, and -OCH3. In some embodiments, two of R30are joined to form a 5 to 6 membered heterocyclyl optionally including one or two heteroatoms selected from N, O, and S.

[0059]

[0042] In some embodiments, each R3AandR3Dis independently hydrogen, (Ci-C4)alkyl, or (Ci- C4)haloalkyl. In some embodiments, each R3AandR3Dis independently hydrogen, -CH3, - CH2CH3, -CF3, -CHF2, or CH2F. In some embodiments, each R3Bis independently hydrogen or - CH3. Docket No.: PAT059786-WO-PCT

[0060]

[0043] In some embodiments, each R30is independently halogen, -OR3A, -NR3BC(O)R3D, (Ci- C4)alkyl, (Ci-C4)haloalkyl, or 5 to 6-membered heterocyclyl which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents from halogen, oxo, -CH3, and -OCH3. In some embodiments, each R3AandR3Dis independently hydrogen, (Ci-C4)alkyl, or (Ci-C4)haloalkyl. In some embodiments, each R3AandR3Dis independently hydrogen, -CH3, -CH2CH3, -CF3, - CHF2, or CH2F. In some embodiments, each R3Bis independently hydrogen or -CH3.

[0061]

[0044] In some embodiments, at least one of R30is halogen. In some embodiments, at least one of R30is -F. In some embodiments, at least one of R30is -Cl. In some embodiments, at least one of R30is -Br. In some embodiments, at least one of R30is -I.

[0062]

[0045] In some embodiments, at least one of R30is -OR3Aand R3Ais hydrogen. In some embodiments, at least one of R30is -OR3Aand or (Ci-C4)alkyl. In some embodiments, R3Ais - CH3, or -CH2CH3. In some embodiments, R30is -OH. In some embodiments, R30is -OCH3. In some embodiments, R30is -OCH2CH3.

[0063]

[0046] In some embodiments, at least one of R30is -OR3Aand R3Ais or (C1-C4) haloalkyl. In some embodiments, R3Ais -CH2F, -CHF2, or -CF3. In some embodiments, at least one of R30is - OCH2F. In some embodiments, at least one of R30is -OCHF2. In some embodiments, at least one of R30is -OCF3.

[0064]

[0047] In some embodiments, at least one of R30is -NR3BC(O)R3Dand each R3Band R3Dis independently hydrogen or (Ci-C4)alkyl. In some embodiments, R3Bis hydrogen or -CH3. In some embodiments, R3Dis hydrogen or -CH3. In some embodiments, at least one of R30is - NH(CO)H, -NH(CO)CH3, -NCH3(CO)H, or-NCH3(CO)CH3. In some embodiments, at least one of R30is -NH(CO)H. In some embodiments, at least one of R30is -NH(CO)CH3. In some embodiments, at least one of R30is -NCH3(CO)CH3.

[0065]

[0048] In some embodiments, R30is -C(O)OR3Aand R3Ais hydrogen or (Ci-C4)alkyl. In some embodiments, R3Ais hydrogen, -CH3, or -CH2CH3. In some embodiments, R30is -C(O)OH. In some embodiments, R30is -C(O)OCH3.

[0066]

[0049] In some embodiments, at least one of R30is (Ci-C4)alkyl. In some embodiments, at least one of R30is -CH3. In some embodiments, at least one of R30is -CH2CH3.

[0067]

[0050] In some embodiments, at least one of R30is (Ci-C4)haloalkyl. In some embodiments, at least one of R30is -CH2F, -CHF2, or -CF3. In some embodiments, at least one of R30is -CH2F. Docket No.: PAT059786-WO-PCT

[0068] In some embodiments, at least one of R30is -CHF2. In some embodiments, at least one of R30is

[0069] -CF3.

[0070]

[0051] In some embodiments, at least one of R30is a 5 to 6-membered heterocyclyl which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents from halogen, oxo, -CH3, and -OCH3. In some embodiments, at least one of R30is a 5 to 6-membered heterocyclyl which is substituted with one or more substituents (e.g., 1, 2, or 3) selected from halogen, oxo, -CH3,

[0071] 1, or 2. In some embodiments, R3is In some embodiments, Docket No.: PAT059786-WO-PCT

[0072]

[0054] In some embodiments, n is 2. In some embodiments, R3is

[0073] 1 , or 2. In some embodiments, R3is In some embodiments, R3is some embodiments, R3is In some embodiments, embodiments, R3is wherein each R30Aand R30Bis independently as described in R30above. In some embodiments, wherein each R30Aand R30Bis independently as described in R30above.

[0074]

[0055] In some embodiments, n is 3. In some embodiments, o

[0075] 1 , or 2. In some embodiments, R is N In some embodiments,

[0076] In some embodiments, R3is In some embodiments, R3is Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT

[0077]

[0064] In some embodiments, two of R30are joined to form a 5 to 6 membered heterocyclyl including one or two heteroatoms selected from N, S, and O. In some embodiments, two of R30are joined to form a 5 to 6 membered heterocyclyl containing nitrogen. In some embodiments, z3 is 3 and two of R30are joined to form a 5 to 6 membered heterocyclyl including one or two heteroatoms selected from N and O. In some embodiments, z3 is 3 and two of R30are joined to form a 5 to 6 membered heterocyclyl containing nitrogen. In some embodiments, z3 is 3, two of R30are joined to form a 5 to 6 membered heterocyclyl containing nitrogen, and the other R30is - OH, or -OCH3. Docket No.: PAT059786-WO-PCT

[0078]

[0067] In a certain aspect, R4is a 5- or 6-membered heteroaryl which is each optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from halogen, - C(O)OR4A, -L4-C(O)OR4A, (Ci-C2)alkyl, or (Ci-C2)alkyl(C3-C6)cycloalkyl. Each R4Ais independently hydrogen or (Ci-C4)alkyl; and L4is (C1-C2 alkylene). In some embodiments, R4is a 5- or 6-membered heteroaryl including 1 to 2 heteroatoms selected from N, O and S. ntly hydrogen, halogen, -C(O)OR4A, -L4-C(O)OR4A, (Ci-C2)alkyl, (C3-Ce)cycloalkyl-(Ci-C2)alkyl, or (Ci-C6)alkyl(C3-Ce)cycloalkyl; each R4Ais independently hydrogen or C1-C4 alkyl; and L4is Ci-

[0079] C2 alkylene.

[0080]

[0069] In some embodiments, each R41, R42, and R4is independently hydrogen, halogen, -C(O)OR4A, -L4-C(O)OR4A, (Ci-C4)alkyl, (Ci-C4)haloalkyl, or (C3- Docket No.: PAT059786-WO-PCT

[0081] C6)cycloalkyl-(Ci-C2)alkyl. In some embodiments, each R41, R42, and R4is independently hydrogen, halogen, -C(O)OR4A, -L4-C(O)OR4A, (Ci-C4)alkyl, or (C3- C6)cycloalkyl-(Ci-C2)alkyl. In some embodiments, each R4Ais independently hydrogen or Ci- C4 alkyl. In some embodiments, L4is -CH2-. In some embodiments, R4Ais hydrogen or -CH3. In some embodiments, each R41, R42, and R43is independently hydrogen, halogen (e.g., -F, -Cl, or -Br), -OCH3, -OH, -CH2-C(O)OH, -CH3, -CH2-CH3, or (C3-C5)cycloalkyl(Ci-C2)alkyl, or (Ci-C2)alkyl(C3 C5)cycloalkyl. In some embodiments, R41is hydrogen or -CH3. In some embodiments, R42is hydrogen, -CH3, -CH2-CH3, -CH2C(0)0H, . In some embodiments, R42is hydrogen, -CH3, -CH2-CH3, -CH2C(0)0H, or In some embodiments, R43is hydrogen, halogen, some embodiments, R43is hydrogen, halogen, or -OCH3. In some embodiments, R41is hydrogen, R42is hydrogen, -CH3, - hydrogen, -F, or -OCH3.

[0082] Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT

[0083]

[0072] In some embodiments, each of R41, R42, and R43is independently for each occurrence hydrogen, halogen, -C(O)OR4A, -L4-C(O)OR4A, (Ci-C4)alkyl, (C3- Ce)cycloalkyl(Ci-C2)alkyl, or (Ci-C2)alkyl(C3-C6)cycloalkyl. In some embodiments, each R4Ais independently hydrogen or C1-C4 alkyl. In some embodiments, L4is -CH2-. In some embodiments, R4Ais independently hydrogen or -CH3. In some embodiments, each R41, R42, and R43is independently hydrogen, or (Ci-C4)alkyl. In some embodiments, R41is hydrogen or -CH3. In some embodiments, R42is hydrogen or -CH3. In some embodiments, R43is hydrogen or -CH3. In some embodiments, R41and R42are hydrogen and R43is -CH3.

[0084]

[0073] In some embodiments,

[0085]

[0074] In some embodiments, each R41and R43is independently hydrogen, halogen, -C(O)OR4A, -L4-C(O)OR4A, (Ci-C4)alkyl, or (Ci-C2)alkyl(C3-C6)cycloalkyl. In some embodiments, each R4Ais independently hydrogen or C1-C4 alkyl. In some embodiments, L4is -CH2-. In some embodiments, R4Ais hydrogen or -CH3. In some embodiments, each R41and R43is independently hydrogen, or (Ci-C4)alkyl. In some embodiments, R41is hydrogen or -CH3. In some embodiments, R43is hydrogen or -CH3. In some embodiments, R41and R42are -CH3.

[0086]

[0075] In some embodiments,

[0087]

[0076] In some embodiments, each R41, R42, and R43is independently hydrogen, halogen, -C(O)OR4A, -L4-C(O)OR4A, (Ci-C4)alkyl, or (Ci-C2)alkyl(C3-C6)cycloalkyl. Docket No.: PAT059786-WO-PCT

[0088] In some embodiments, each R4Ais independently hydrogen or C1-C4 alkyl. In some embodiments, L4is -CH2-. In some embodiments, R4Ais independently hydrogen or -CH3. In some embodiments, each R41, R42, and R43is independently hydrogen, or (Ci-C4)alkyl. In some embodiments, R41is hydrogen or -CH3. In some embodiments, R42is hydrogen or -CH3. In some embodiments, R43is hydrogen or -CH3. In some embodiments, R41and R42are hydrogen and R43is -CH3. , each R41, R42, R43, and R44is independently hydrogen, halogen, -C(O)OR4A, -L4-C(O)OR4A, (Ci-C4)alkyl, or (Ci-C2)alkyl(C3- C6)cycloalkyl. In some embodiments, each R4Ais independently hydrogen or C1-C4 alkyl. In some embodiments, L4is -CH2-. In some embodiments, R4Ais independently hydrogen or -CH3. In some embodiments, each R41, R42, R43, and R44is independently hydrogen, or (Ci-C4)alkyl. In some embodiments, R41is hydrogen or -CH3. In some embodiments, R42is hydrogen or -CH3. In some embodiments, R43is hydrogen or -CH3. In some embodiments, R44is hydrogen or -CH3. In some embodiments, R41, R42, R43, and R44are hydrogen.

[0089]

[0079] In some embodiments, R4is

[0090]

[0080] In some embodiments, R4is Docket No.: PAT059786-WO-PCT

[0091] In some embodiments, R4is aryl. In some embodiments, R4is optionally substituted phenyl. In some embodiments,

[0092]

[0081]

[0093]

[0082] In a certain aspect, R5is hydrogen or (Ci-C4)alkyl. In some embodiments, R5is hydrogen. In some embodiments, R5is (Ci-C4)alkyl. In some embodiments, R5is -CH3. In some embodiments, R5is -CH2CH3.

[0094]

[0083] In a certain aspect, R6is hydrogen, (C3-Ce)alkyl, or (Ci-C4)alkyl. In a certain aspect, R6is hydrogen or (Ci-C4)alkyl. In some embodiments, R6is hydrogen. In some embodiments, R6is (Ci-C4)alkyl. In some embodiments, R6is -CH3. In some embodiments, R6is -CH2CH3. In some embodiments,

[0095]

[0084] In a certain aspect, R7is selected from (Cs-Cs) cycloalkyl optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from halogen (e.g., -F, -Cl, or -Br), - OR7A, -L7-OR7A, -C(O)NR7BR7C, -NR7BC(O)R7D, -NR7BC(O)OR7A, -C(O)OR7A, or -L7- C(O)OR7A. In some embodiments, each R7AandR7Dis independently hydrogen, or (Ci-C4)alkyl. In some embodiments, R7Band R7Cis independently hydrogen or -(Ci-C4)alkyl. In some embodiments, R7Band R7Care joined to form a 4 to 5 membered heterocyclyl. In some embodiments, L7is C1-C2 alkylene.

[0096]

[0085] In some embodiments, integer of 0 to 3; and each R70is independently halogen (e.g., -F, -Cl, or -Br), -OR7A, -L7-OR7A, -C(O)NR7BR7C, - NR7BC(O)R7D, -NR7BC(O)OR7A, -C(O)OR7A, or -L7-C(O)OR7A. In some embodiments, each R7AandR7Dis independently hydrogen, or (Ci-C4)alkyl, and each R7Band R7Cis independently hydrogen or -(Ci-C4)alkyl. In some embodiments, each R7AandR7Dis independently hydrogen, or (Ci-C4)alkyl, and R7Band R7Care joined to form a 4 to 5 membered heterocyclyl. In some embodiments, L7is C1-C2 alkylene. Docket No.: PAT059786-WO-PCT

[0097]

[0086] In some embodiments, integer of 0 to 3; and each R70is independently halogen (e.g., -F, -Cl, or -Br), -OR7A, -L7-OR7A, -C(O)NR7BR7C, - NR7BC(O)R7D, -NR7BC(O)OR7A, -C(O)OR7A, or -L7-C(O)OR7AIn some embodiments, each R7AandR7Dis independently hydrogen, or (Ci-C4)alkyl, and each R7Band R7Cis independently hydrogen or -(Ci-C4)alkyl. In some embodiments, each R7AandR7Dis independently hydrogen, or (Ci-C4)alkyl, and R7Band R7Care joined to form a 4 to 5 membered heterocyclyl. In some embodiments, L7is C1-C2 alkylene.

[0098]

[0087] In some embodiments, R7is •z7 js aninteger of 0 to 3 ; and each R70is independently halogen (e.g., -F, -Cl, or -Br), -OR7A, -L7-OR7A, -C(O)NR7BR7C, -NR7BC(O)R7D, - NR7BC(O)OR7A, -C(O)OR7A, or -L7-C(O)OR7A. In some embodiments, each R7AandR7Dis independently hydrogen, or (Ci-C4)alkyl, and each R7Band R7Cis independently hydrogen or - (Ci-C4)alkyl. In some embodiments, each R7AandR7Dis independently hydrogen, or (Ci- C4)alkyl, and R7Band R7Care joined to form a 4 to 5 membered heterocyclyl. In some embodiments, each L7is independently C1-C2 alkylene.

[0099]

[0088] In some embodiments each R70is independently -L7-OR7A, -C(O)OR7A, -L7-C(O)OR7A, or -C(O)NR7BR7C. In some embodiments, R7Ais hydrogen or -CH3. In some embodiments, L7is -CH2-. In embodiments, each R7Band R7Cis independently hydrogen or -CH3. In some embodiments, R7Band R7Care joined to form a 4 to 5 membered heterocyclyl. In some embodiments, each R70is independently -CH2OCH3, -C(O)OH, -C(O)OCH3, -CH2-C(O)OH, -

[0100] CH2C(O)OCH3, -C(O)N(CH3)2, or O . In some embodiments, each R70is independently

[0101]

[0089] In some embodiments, z7 is 0, 1, or 2. In some embodiments, z7 is 0. In some embodiments, z7 is 1. In some embodiments, z7 is 2. Docket No.: PAT059786-WO-PCT

[0102]

[0090] In some embodiments, R7is and R70is independently -C(O)OH, - Docket No.: PAT059786-WO-PCT

[0103]

[0093] In some embodiments,

[0104]

[0094] In some embodiments, R7is selected from Docket No.: PAT059786-WO-PCT

[0105]

[0096] In a certain aspect, R8is hydrogen or (Ci-C4)alkyl. In some embodiments, R8is hydrogen. In some embodiments, R8is (Ci-C4)alkyl. In some embodiments, R8is -CH3. In some embodiments, R8is -CH2CH3.

[0106]

[0097] In a certain aspect, R9is hydrogen or (Ci-C4)alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is (Ci-C4)alkyl. In some embodiments, R9is -CH3. In some embodiments, R9is -CH2CH3.

[0107]

[0098] In a certain aspect, R10is hydrogen or (Ci-C4)alkyl. In some embodiments, R10is hydrogen. In some embodiments, R10is (Ci-C4)alkyl. In some embodiments, R10is -CH3. In some embodiments, R10is -CH2CH3. In some embodiments, R8, R9and R10are hydrogen.

[0108]

[0099] In a certain aspect, R2is a phenyl optionally substituted with one or more substituents independently selected from halogen, -CN, and -OR2A, and R2Ais (Ci-C4)alkyl; and R3is . R30, n and z3 are as described above.

[0109]

[0100] In a certain aspect, the compound has the structure of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: z2 is an integer of 0 to 2; each R20is halogen, -CN, and -OR2A; and Docket No.: PAT059786-WO-PCT

[0110] R2AIS (Ci-C4)alkyl.

[0111] R1, R4, R5, R6, R7, R8, R9, R10, R30, n, z2, and z3 are as described above.

[0112]

[0101] In some embodiments, are as described above.

[0113]

[0102] In some embodiments, the compound has the structure of Formula (II- A): or a pharmaceutically acceptable salt thereof, wherein: each R41, R42, and R43are independently hydrogen, halogen, -C(O)OR4A, -L4-C(O)OR4A, (Ci-Ce)alkyl, or (Ci-C6)alkyl(C3-Ce)cycloalkyl;

[0114] R4Ais hydrogen or C1-C4 alkyl; and

[0115] L4is C1-C2 alkylene.

[0116] R1, R5, R6, R7, R8, R9, R10, R20, R30, n, z2, and z3 are as described above.

[0117]

[0103] In some embodiments, above.

[0118]

[0104] In some embodiments, the compound has the structure of Formula (III-A-1): Docket No.: PAT059786-WO-PCT or a pharmaceutically acceptable salt thereof, wherein: each R70is independently -L7-OR7A, -C(O)OR7A, -L7-C(O)OR7A, or -C(O)NR7BR7C; z7 is an integer of 0 to 2; each R7AandR7Dis independently hydrogen, or -CH3, each R7Band R7Cis independently hydrogen or -CH3, or R7Band R7Care joined to form a 4 to 5 membered heterocyclyl, and each L7is independently C1-C2 alkylene.

[0119] R1, R5, R6, R7, R8, R9, R10, R20, R30, R41, R42, R43, z2, and z3 are as described above.

[0120]

[0105] In some embodiments, z7 is 0, 1 , or 2. In some embodiments, each R70is independently -

[0121]

[0106] In some embodiments, the compound has the structure of Formula (IV-A-1):

[0122] Docket No.: PAT059786-WO-PCT or a pharmaceutically acceptable salt thereof.

[0123] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, R70, z2, and z3 are as described above.

[0124]

[0107] In some embodiments, the compound has the structure of Formula (V-A-l): or a pharmaceutically acceptable salt thereof.

[0125] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, z2, and z3 are as described above.

[0126]

[0108] In some embodiments, two of R30together with the atoms attached thereto are joined to form a 5 to 6 membered heterocyclyl. In some embodiments, z3 is 3 and two of R30together with the atoms attached thereto are joined to form a 5 to 6 membered heterocyclyl optionally comprising one or two heteroatoms selected from N, O, and S. In some embodiments, two of n zN^

[0127] R30together with the atoms attached thereto are joined to form a N- . In some Docket No.: PAT059786-WO-PCT embodiments, two of R30together with the atoms attached thereto are joined to form a

[0128]

[0109] In some embodiments, the compound the structure of Formula (IV-A-la): or a pharmaceutically acceptable salt thereof.

[0129] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, R70, z2, and z3 are as described above.

[0130] [HO] In some embodiments, the compound has the structure of Formula (V-A-la):

[0131] Docket No.: PAT059786-WO-PCT -la) or a pharmaceutically acceptable salt thereof.

[0132] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, z2, and z3 are as described above.

[0133]

[0111] In some embodiments, the compound the structure of Formula (IV-A-lb): or a pharmaceutically acceptable salt thereof.

[0134] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, R70, z2, and z3 are as described above.

[0135]

[0112] In some embodiments, the compound the structure of Formula (V-A-lb): Docket No.: PAT059786-WO-PCT or a pharmaceutically acceptable salt thereof.

[0136] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, R70, z2, and z3 are as described above.

[0137]

[0113] In some embodiments, described above.

[0138]

[0114] In some embodiments, the compound the structure of Formula (III-A-2): or a pharmaceutically acceptable salt thereof.

[0139] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, R70, z2, z3, and z7 are as described above.

[0140]

[0115] In some embodiments, the compound has the structure of Formula (IV-A-2): Docket No.: PAT059786-WO-PCT or a pharmaceutically acceptable salt thereof.

[0141] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, R70, z2, and z3 are as described above.

[0142]

[0116] In some embodiments, the compound has the structure of Formula (V-A-2): or a pharmaceutically acceptable salt thereof.

[0143] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, z2, and z3 are as described above.

[0144]

[0117] In some embodiments, n is 3 and R7is . z7 and R70is as described above.

[0145]

[0118] In some embodiments, the compound has the structure of Formula (III-A-3): Docket No.: PAT059786-WO-PCT or a pharmaceutically acceptable salt thereof.

[0146] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, R70, z2, z3, and z7 are as described above.

[0147]

[0119] In some embodiments, the compound has the structure of Formula (IV-A-3): or a pharmaceutically acceptable salt thereof.

[0148] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, R70, z2, and z3 are as described above.

[0149]

[0120] In some embodiments, the compound has the structure of Formula (IV-A-3):

[0150] Docket No.: PAT059786-WO-PCT or a pharmaceutically acceptable salt thereof.

[0151] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, R70, z2, and z3 are as described above.

[0152]

[0121] In certain embodiments, n is 2 and R7is . z7 and R70is as described above. In some embodiments, some embodiments, R70is -C(O)OH.

[0153]

[0122] In some embodiments, the compound has the structure of Formula (V-A-4):

[0154] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, R70, z2, and z3 are as described above. Docket No.: PAT059786-WO-PCT

[0155]

[0123] In certain embodiments, n is 2 and R7is . z7 and R70is as described z

[0156] A — 7 izv above. In some embodiments, R7is R'°. In some embodiments, R70is -C(O)OH.

[0157]

[0124] In some embodiments, the compound has the structure of Formula (V-A-5):

[0158] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, z2, and z3 are as described above.

[0159]

[0125] In a certain aspect, each R41, R42, and R43are as described above.

[0160]

[0126] In some embodiments, the compound has the structure of Formula (II-B): or a pharmaceutically acceptable salt thereof.

[0161] R1, R5, R6, R7, R8, R9, R10, R20, R30, R41, R42, R43, n, z2, and z3 are as described above. Docket No.: PAT059786-WO-PCT

[0162]

[0127] In some embodiments, each R41, R42, and R43is independently hydrogen or -CH3. In some embodiments, R3is R30and z3 are as described above. In some embodiments, z3 is 0, 1 , or 2. In embodiments, R7is

[0163]

[0128] In some embodiments, the compound has the structure of Formula (V-B-l): or a pharmaceutical z2, and z3 are as described above.

[0164]

[0129] In some embodiments, the compound has the structure of Formula (V-B-l a):

[0165] Docket No.: PAT059786-WO-PCT -la), or a pharmaceutically acceptable salt thereof. R1, R5, R6, R7, R8, R9, R10, R20, R30, R41, R42, R43,and z2 are as described above.

[0166]

[0130] In a certain aspect, each R41and R43are as described above.

[0167]

[0131] In some embodiments, the compound has the structure of Formula (II-C): or a pharmaceutically acceptable salt thereof.

[0168] R1, R5, R6, R7, R8, R9, R10, R20, R30, R41, R43, n, z2, and z3 are as described above. Docket No.: PAT059786-WO-PCT

[0169]

[0132] In some embodiments, each R41and R43is independently hydrogen or -CH3. In some embodiments,

[0170] . In some embodiments, z3 is 0, 1 , or 2. In embodiments, R7is

[0171]

[0133] In some embodiments, the compound has the structure of Formula (V-C-l): or a pharmaceutical and z3 are as described above.

[0172]

[0134] In some embodiments, the compound has the structure of Formula (V-C-l a): Docket No.: PAT059786-WO-PCT or a pharmaceutica are as described above.

[0173]

[0135] In some embodiments, the compound has the structure of Formula (V-C-lb): -lb), or a pharmaceutically acceptable salt thereof. R1, R5, R6, R8, R9, R10, R20, R30, R41, R43, and z2 are as described above.

[0174]

[0136] In a certain aspect, each R41, R42, and R43are as described above.

[0175]

[0137] In some embodiments, the compound has the structure of Formula (II-D): Docket No.: PAT059786-WO-PCT or a pharmaceutically acceptable salt thereof. R1, R5, R6, R7, R8, R9, R10, R20, R30, R41, R42, R43, n, z2, and z3 are as described above.

[0176]

[0138] In some embodiments, each R41, R42, and R43is independently hydrogen or -CH3. In some embodiments, R3is embodiments, z3 is 0, 1, or 2. In embodiments,

[0177]

[0139] In some embodiments, the compound has the structure of Formula (V-D-l):

[0178] Docket No.: PAT059786-WO-PCT or a pharmaceutical and z2 are as described above.

[0179]

[0140] In some embodiments, the compound has the structure of Formula (V-D-la): or a pharmaceutically acceptable salt thereof.

[0180] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, n, and z2 are as described above.

[0181] R42

[0182] R42. _,R41

[0183] R44y

[0184]

[0141] In a certain aspect, R4is and each R41, R42, R43, and R44are as described above.

[0185]

[0142] In some embodiments, the compound has the structure of Formula (II-E): Docket No.: PAT059786-WO-PCT or a pharmaceutically R44, n, z2, and z3 are as described above.

[0186]

[0143] In some embodiments, each R41, R42, R43and R44is independently hydrogen or -CH3. In some embodiments, R3is embodiments, z3 is 0, 1, or 2. In embodiments,

[0187]

[0144] In some embodiments, the compound has the structure of Formula (V-E-l):

[0188] Docket No.: PAT059786-WO-PCT or a pharmaceutically z2, and z3 are as described above.

[0189]

[0145] In some embodiments in Formula (II -B), (II-C), (II-D), (II-E) or subordinates thereof, z3 is 0, 1 or 2, and each R30is independently -F, -CH3, or -OCH3. In some embodiments, R7is

[0190]

[0146] In a certain aspect, R2is a pyridyl optionally substituted with one or more substituents independently selected from halogen, -CN, and -OR2A, and R2Ais (Ci-C4)alkyl. In some embodiments, are as described above. In some embodiments, n is 2. In some embodiments, z3 is 0, 1 , or 2.

[0191]

[0147] In some embodiments, the compound has the structure of Formula (VI): Docket No.: PAT059786-WO-PCT or a pharmaceutically acceptable salt thereof.

[0192] R1, R4, R5, R6, R7, R8, R9, R10, R20, R30, n, z2, and z3 are as described above.

[0193]

[0148] In a certain aspect, R2is a Cs-Ce cycloalkyl optionally substituted with one or more substituents independently selected from halogen, -CN, and -OR2A, and R2Ais (Ci-C4)alkyl. In some embodiments, are as described above.

[0194]

[0149] In some embodiments, the compound has the structure of Formula (VII): or a pharmaceutically acceptable salt thereof.

[0195] R1, R4, R5, R6, R7, R8, R9, R10, R20, R30, n, z2, and z3 are as described above.

[0196]

[0150] In some embodiments, the compound has the structure of Formula (VIII): Docket No.: PAT059786-WO-PCT or a pharmaceutically acceptable salt thereof.

[0197] R1, R4, R5, R6, R7, R8, R9, R10, R20, R30, n, z2, and z3 are as described above.

[0198]

[0151] In some embodiments, in Formulae (V) to (VIII) or subordinates thereof, R4is each R41, R42, and R43is independently hydrogen or -CH3.

[0199]

[0153] In some embodiments, the compound has the structure of Formula (VI-1). or a pharmaceutically acceptable salt thereof.

[0200] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, R70, z2, and z3 are as described above.

[0201]

[0154] In some embodiments, the compound has the structure of Formula (VII-1). Docket No.: PAT059786-WO-PCT or a pharmaceutically acceptable salt thereof.

[0202] R1, R5, R6, R8, R9, R10, R20, R30, R41, R42, R43, R70, z2, and z3 are as described above.

[0203]

[0155] In some embodiments, the compound has the structure of Formula (VIII- 1): or a pharmaceutically acceptable salt thereof.

[0204] R1, R4, R5, R6, R7, R8, R9, R10, R20, R30, R70, n, z2, and z3 are as described above.

[0205]

[0156] In some embodiments, in Formula (VI) to (VIII) and subordinate thereof, z2 is 0, 1, or 2. In some embodiments, z3 is 0, 1 , or 2. In some embodiments, z2 is 0 and z3 is 1 . In some embodiments, R41and R43are hydrogen, and R42is -CH3. In some embodiments, each R30is independently -F, -CH3, or -OCH3. Docket No.: PAT059786-WO-PCT

[0206]

[0157] In some embodiments, R2is a Ci-Ce alkyl; each R41, R42, and R43is independently hydrogen or -CH3. In some embodiments, R1is -OH or -OCH3.

[0207]

[0158] In some embodiments, in Formula (I) and any subordinates thereof, R5is -CH3

[0208]

[0159] In some embodiments, in Formula (I) and any subordinates thereof, R6is -CH2CH3.

[0209]

[0160] In some embodiments, in Formula (I) and any subordinates thereof,

[0210]

[0161] In some embodiments, in Formula (I) and any subordinates thereof, R8, R9and R10are hydrogen.

[0211]

[0162] In a certain aspect, provided herein is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0212] Table 1 Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT

[0213] Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT

[0214] Docket No.: PAT059786-WO-PCT

[0215] Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT

[0216] Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT

[0217] Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT

[0218]

[0163] As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the present disclosure. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this disclosure and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. When both a basic group and an acid group are present in the same molecule, the compounds of the present disclosure may also form internal salts, e.g., zwitterionic molecules. Docket No.: PAT059786-WO-PCT

[0219]

[0164] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

[0220]

[0165] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0221]

[0166] 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.

[0222]

[0167] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0223]

[0168] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

[0224]

[0169] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0225]

[0170] In another aspect, the present disclosure provides compounds of the present disclosure in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, poly galacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form.

[0226]

[0171] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures Docket No.: PAT059786-WO-PCT depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into compounds of the disclosure include, for example, isotopes of hydrogen.

[0227]

[0172] Further, incorporation of certain isotopes, particularly deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index or tolerability. It is understood that deuterium in this context is regarded as a substituent of a compound of the present disclosure. The concentration of deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this disclosure is denoted as being deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term “isotopic enrichment factor” can be applied to any isotope in the same manner as described for deuterium.

[0228]

[0173] Other examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as3H,nC,13C,14C,15N,18F31P,32P,35S,36C1,123I,124I,125I respectively. Accordingly it should be understood that the disclosure includes compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as3H and14C, or those into which non-radioactive isotopes, such as2H and13C are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of the present disclosure can generally be prepared by conventional techniques Docket No.: PAT059786-WO-PCT known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

[0229]

[0174] Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present disclosure can be present in racemic or enantiomerically enriched, for example the ( / ?)-, (5)- 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 (5)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (£)- form.

[0230]

[0175] Accordingly, as used herein a compound of the present disclosure can be in the form of one of the possible stereoisomers, retainers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

[0231]

[0176] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0232]

[0177] Any resulting racemates of compounds of the present disclosure or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present disclosure into their optical antipodes, e.g, by fractional crystallization of a salt formed with an optically active acid, e.g, tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-(9,(9'- / ?-toluoyl tartaric acid, mandelic acid, malic acid or camphor- 10-sulfonic acid. Racemic compounds of the present disclosure or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0233] Pharmaceutical Compositions

[0234]

[0178] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, Docket No.: PAT059786-WO-PCT 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.

[0235]

[0179] In some embodiments, a pharmaceutical composition further comprises at least one additional pharmaceutically active agent. In some embodiments, the additional pharmaceutically active agent is selected from an ACE (angiotensin-converting-enzyme) inhibitor, an angiotensin receptor blocker (ARB), a neprilysin inhibitor, a beta blocker, a diuretic, a calcium channel blocker, a cardiac glycoside, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), or combinations thereof.

[0236]

[0180] The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration (e.g. by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also pertain to inhalation or intranasal application. The pharmaceutical compositions of the present disclosure can be made up in a solid form (including, without limitation, capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including, without limitation, solutions, suspensions or emulsions). Tablets may be either film coated or enteric coated according to methods known in the art. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.

[0237]

[0181] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds. Docket No.: PAT059786-WO-PCT

[0238]

[0182] The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

[0239]

[0183] Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

[0240]

[0184] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about

[0241] 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

[0242]

[0185] The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0243]

[0186] The pharmaceutical composition or combination of the present disclosure may, for example, be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50- 70 kg. In one embodiment, the compositions are in the form of a tablet that can be scored. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated.

[0244] Methods of Use

[0245]

[0187] In yet another aspect, the present disclosure is directed to a method of treating or preventing a disease or disorder comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a subordinate thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of Formula (I) or a subordinate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0246]

[0188] In another aspect, the present disclosure relates to a method for treating a disease or disorder comprising administering to a patient in need thereof an effective amount of a Docket No.: PAT059786-WO-PCT compound of Formula (I) or a subordinate thereof, 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.

[0247]

[0189] In certain embodiments, the cardiovascular disease or disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, cardiac dysrhythmia, atrial fibrillation (AF), new onset of atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, and myocardial infarction (MI). In some embodiments, the heart failure is selected from a heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute decompensated heart failure. In some embodiments, the hypertrophic cardiomyopathy is ventricular hypertrophy. In some embodiments, the hypertension is selected from resistant hypertension, hypertensive heart disease, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, resistant hypertension, and pulmonary arterial hypertension. In some embodiments, the hypertension is selected from resistant hypertension and hypertensive heart disease.

[0248]

[0190] In some embodiments, the disease or disorder is preeclampsia, asthma, glaucoma, a kidney disorder, and / or cytokine release syndrome in a subject in need of such treatment. In some embodiments, the kidney disorder is selected from: diabetic renal insufficiency, nondiabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute renal injury, contrast induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, renal vascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis, and polycystic kidney disease (PKD).

[0249]

[0191] In some embodiments, the disease or disorder is a disorder or disease associated with natriuretic peptide receptor activity.

[0250]

[0192] In another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described Docket No.: PAT059786-WO-PCT herein for the manufacture of a medicament for use to treat a disease or disorder disclosed herein.

[0251]

[0193] In another aspect, the present disclosure relates to a compound of Formula (I) or a subordinate thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for use as a medicament.

[0252]

[0194] Another aspect of the present disclosure relates to a compound of Formula (I) or a subordinate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for use in the in the treatment of a disease or disorder disclosed herein. In some embodiments, the disease or disorder is a cardiovascular disease or disorder (e.g., a cardiovascular disease or disorder as disclosed herein).

[0253]

[0195] In another aspect, the present disclosure relates to the use of a compound of Formula (I) or a subordinate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein in the treatment of a disease or disorder disclosed herein.

[0254]

[0196] The disclosed compounds of the disclosure can be administered in effective amounts to treat or prevent a disorder and / or prevent the development thereof in subjects.

[0255] Combination Therapy

[0256]

[0197] The compounds of the disclosure can be administered in therapeutically effective amounts in a combinational therapy with one or more pharmaceutically active agents (pharmaceutical combinations) or modalities, e.g., non-drug therapies. The compounds of the present disclosure may be administered either simultaneously with, or before or after, one or more other pharmaceutically active agent. The compound of the present disclosure may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents. A pharmaceutically active agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the present disclosure.

[0257]

[0198] In one embodiment, the disclosure provides a product comprising a compound of the present disclosure and at least one other pharmaceutically active agent as a combined preparation for simultaneous, separate or sequential use as disclosed herein. Products provided as a combined preparation include a composition comprising the compound of the present disclosure and the other pharmaceutically active agent(s) together in the same pharmaceutical composition Docket No.: PAT059786-WO-PCT as described herein, or the compound of the present disclosure and the other pharmaceutically active agent (s) in separate form, e.g. in the form of a kit.

[0258]

[0199] In another aspect, the disclosure includes a compound of Formula (I) or a subordinate thereof, or a pharmaceutically acceptable salt thereof, for use in a combination therapy.

[0259]

[0200] Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I) or a subordinate thereof, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more pharmaceutically active agent. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0260]

[0201] Combination therapy includes the administration of the subject compounds in further combination with other biologically active ingredients. For instance, the compounds of the application can be used in combination with other pharmaceutically active agents, preferably compounds that are able to enhance the effect of the compounds of the application. The compounds of the application can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy or treatment modality. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.

[0261]

[0202] Exemplary additional pharmaceutically active agents that may be used in combination with the compounds of the disclosure, include, but are not limited to an ACE (angiotensin- converting-enzyme) inhibitor, an angiotensin receptor blocker (ARB), a neprilysin inhibitor, a beta blocker, a diuretic, a calcium channel blocker, a cardiac glycoside, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), or combinations thereof. As a non-limiting set of examples, a compound or a pharmaceutically acceptable salt thereof described herein may be combined with an additional pharmaceutically active agent selected from enalapril, benazepril, captopril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, valsartan, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, sacubitril, bisoprolol, carvedilol, propanolol, metoprolol, metoprolol tartrate, metoprolol succinate, thiazide diuretics, loop diuretics, potassium-sparing diuretics, amlodipine, clevidipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, a digitalis glycoside, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and combinations thereof. Exemplary diuretics and digitalis glycosides include, but are not limited to, chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, bumetanide, ethacrynic acid, furosemide, Docket No.: PAT059786-WO-PCT torsemide, amiloride, eplerenone, spironolactonem, triamterene, digoxin, and combinations thereof. In some embodiments, a compound or a pharmaceutically acceptable salt thereof described herein may be combined with an angiotensin receptor-neprilysin inhibitor (ARNi) such as a combination of sacubitril and valsartan (e.g., Entresto®). In some embodiments, a compound or a pharmaceutically acceptable salt thereof described herein can be combined with one or more of a corticosteroid (e.g., an inhaled corticosteroid such as fluticasone, budesonide, mometasone, beclomethasone, ciclesonide, or fluticasone furoate; or an oral or intravenous corticosteroid such as prednisone or methylprednisolone), a leukotriene modifier (e.g., montelukast, zafirlukast, or zileuton), a bronchodilator (e.g., a long-acting beta agonist (e.g., salmeterol or formoterol), a short-acting beta agonist (e.g., albuterol or levalbuterol), theophylline or ipratropium), or combinations thereof (e.g., a combination of fluticasone and salmeterol, a combination of budesonide and formoterol, or a combination of formoterol and mometasone). In some embodiments, a compound or a pharmaceutically acceptable salt thereof described herein can be combined with one or more of a beta-adrenoceptor antagonist (e.g., timolol, levobunolol, metipranolol, carteolol, or betaxolol), a carbonic anhydrase inhibitor (e.g., acetazolamide, dorzolamide, brinzolamide, or methazolamide), an alpha 2-adrenoceptor agonist (e.g., brimonidine or apraclonidine), a parasympathomimetic (e.g., cholinomimetics like pilocarpine), a prostaglandin analog (e.g., latanoprost, latanoprostene bunod, travoprost, bimatoprost, or tafluprost), a rho kinase inhibitor (e.g., netarsudil or ripasudil), or combinations thereof (e.g., a combination of rho kinase inhibitor and latanoprost).

[0262]

[0203] ‘ ‘Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time and in any order, or in alternation and in any order, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be Docket No.: PAT059786-WO-PCT administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical.

[0263] Method of Synthesizing the Compounds

[0264]

[0204] The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

[0265]

[0205] The compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of Formula (I).

[0266]

[0206] Those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- Interscience, 1994).

[0267]

[0207] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0268] Definitions

[0269]

[0208] Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. For purposes of Docket No.: PAT059786-WO-PCT interpreting this specification, the following definitions will apply unless specified otherwise and whenever appropriate, terms used in the singular will also include the plural and vice versa.

[0270]

[0209] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “the pharmaceutical formulation” includes reference to one or more pharmaceutical formulations; and so forth.

[0271]

[0210] 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.

[0272]

[0211] An “alkyl” group or “alkane” is a straight chained or branched noil-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A Ci- straight chained or branched alkyl group is also referred to as a “lower alkyl” group.

[0273]

[0212] The term “aryl”, as used herein, include single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6- membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0274]

[0213] The term “Cx-Cy” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx-Cyalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight- chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms “C2-Cyalkenyl” and “C2-Cyalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible Docket No.: PAT059786-WO-PCT substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0275]

[0214] The terms “carbocycle”, and “carbocyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond. “Carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic

[0276]

[0215] A “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated. “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.

[0277]

[0216] The term “cycloalkyl-alkyl”, as used herein, refers to an alkyl group substituted with a cycloalkyl group.

[0278]

[0217] The term “alkyl-cycloalkyl”, as used herein, refers to a cycloalkyl group substituted with an alkyl group.

[0279]

[0218] The terms “halo” and “halogen”, as used herein, means halogen (e.g., a fluorine, chlorine, bromine, or iodine atom) and its radical, e.g., chloro (-C1), fluoro (-F), bromo (-Br), and iodo (-1). Docket No.: PAT059786-WO-PCT

[0280]

[0219] The term “haloalkyl”, as used herein, refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. “Fluoroalkyl”, as used herein, refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) fluoro groups.

[0281]

[0220] The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyridyl N-oxide, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3- c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo [3 ,4-c] pyridinyl, thieno [3 ,2-c] pyridinyl, thieno [2,3 -c] pyridinyl, thieno [2,3 -b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][l,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[l,2-a]pyrimidinyl, tetrahydropyrrolo[l,2-a]pyrimidinyl, 3,4-dihydro-2H-l A2-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, lH-pyrido[3,4- b][l,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5- naphthyridinyl, furo[3,2-b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo[l,2,3]triazolyl, imidazo[l,2-a]pyrimidinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][l,2,5]thiadiazolyl, benzo [c] [ 1 ,2, 5] oxadiazole, 1 , 3 -dihy dro-2H-benzo[d] imidazol-2-one, 3 ,4-dihy dro-2H- pyrazolo [ 1, 5 -b][ 1,2] oxazinyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridinyl, thiazolo[5,4 Docket No.: PAT059786-WO-PCT d]thiazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3, 4-dihydro-lH-isoquinolinyl, 2,3- dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.

[0282]

[0221] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0283]

[0222] The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. The polycyclic ring systems may be fused or bridged. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, azaadamantane and the like. Heterocyclyl groups can also be substituted by oxo groups. For example, “heterocyclyl” encompasses both pyrrolidine and pyrrolidinone.

[0284]

[0223] As used herein, the term “oxo” refers to a carbonyl group. When an oxo substituent occurs on an otherwise saturated group, such as with an oxo-substituted cycloalkyl group (e.g., 3-oxo-cyclobutyl), the substituted group is still intended to be a saturated group. When a group is referred to as being substituted by an “oxo” group, this can mean that a carbonyl moiety (i.e., — C(=O) — ) replaces a methylene unit (i.e., — CH2 — ).

[0285]

[0224] The term “optionally substituted” means that a given chemical moiety (e.g., an alky 1 group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen, wherein the substituents are as defined herein. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below. Docket No.: PAT059786-WO-PCT

[0286]

[0225] The term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0287]

[0226] The term “unsubstituted” means that the specified group bears no substituents.

[0288]

[0227] A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or nonhuman primate, such as a monkey, chimpanzee, baboon or, rhesus. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0289]

[0228] The terms “pharmaceutically effective amount” or “therapeutically effective amount” or “effective amount” means an amount of a compound according to the disclosure which, when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue, system, or patient that is sought by a researcher or clinician. The amount of a compound according to the disclosure which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the disclosure, and the age, body weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.

[0290]

[0229] As used herein, the term “pharmaceutical composition” refers to a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0291]

[0230] ‘ ‘Carrier” encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject. Docket No.: PAT059786-WO-PCT

[0292]

[0231] A subject is “in need of’ a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment (preferably, a human).

[0293]

[0232] As used herein, the term “inhibit”, “inhibition”, or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0294]

[0233] As used herein, the term “treat”, “treating", or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.

[0295]

[0234] As used herein, the term “prevent”, “preventing", or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0296]

[0235] “Pharmaceutically acceptable” means that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0297]

[0236] ‘ ‘Disorder” means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0298]

[0237] ‘ ‘Administer”, “administering”, or “administration” means to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body.

[0299]

[0238] “Compounds of the present disclosure”, “Compounds of Formula (I)”, “compounds of the disclosure”, and equivalent expressions (unless specifically identified otherwise) refer to compounds of Formula (I) as herein described including the salts particularly the pharmaceutically acceptable salts thereof, where the context so permits thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), retainers, tautomers, and isotopically labelled compounds (including deuterium (“D”) substitutions).

[0300]

[0239] In a specific embodiment, the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range. Docket No.: PAT059786-WO-PCT

[0301] EXAMPLES

[0302]

[0240] The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims.

[0303]

[0241] Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.

[0304]

[0242] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker Avance spectrometer or Varian Oxford 400 MHz spectrometer unless otherwise noted. NMR spectra are given in ppm (8) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (82.50), methanol (8 3.31), chloroform (8 7.26) or other solvent as indicated in NMR spectral data. A small amount of dry sample (2-5 mg) is dissolved in an appropriate deuterated solvent (1 mL). Mass spectra (ESP MS) were collected using a Waters System (Acquity UPLC and a Micromass ZQ mass spectrometer) or Agilent-1260 Infinity (6120 Quadrupole); all masses reported are the m / z of the protonated parent ions unless recorded otherwise. The chemical names were generated using ChemBioDraw Ultra vl4 from CambridgeSoft.

[0305]

[0243] Temperatures are given in degrees Celsius. As used herein, unless specified otherwise, the term "room temperature" or "ambient temperature" means a temperature of from 15 degrees centigrade to 30 degrees centigrade, such as of from 20 degrees centigrade to 30 degrees centigrade, such as of from 20 degrees centigrade to 25 degrees centigrade. If not mentioned Docket No.: PAT059786-WO-PCT otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

[0306]

[0244] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present disclosure are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art.

[0307] Example 1 - Preparation of Intermediate 2,4-dichloro-6-methoxy-6-phenyl-5.6,7,8- tetrahydroquinazoline

[0308]

[0245] Step 1: To a solution of l,4-dioxaspiro[4.5]decan-8-one (935.0 g, 5.99 mol, 1 eq) in THF (7.7 L, 8.2 V) at 0 °C under N2 was added dropwise a solution of phenylmagnesium chloride (4.5 L, 8.98 mol, 2.000 molar, 1.5 Eq). The reaction mixture was stirred at the same temperature Docket No.: PAT059786-WO-PCT for 1 hours. HPLC showed the reaction was completed. Saturated NH4CI (aq) (10.3 L) was added and extracted with ethyl acetate (10.3 L x 2) and the combined organic phases were washed with brine (10.3 L). The organic phases were collected, dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by silica gel column eluting with (0-20 % EA in PE) to give 8-phenyl-l,4-dioxaspiro[4.5]decan-8-ol (702.8 g, 99.4% purity, 97.4% assay, 48.8% yield) as a white solid. 'H NMR (400 MHz, CDC13) 8 7.45 - 7.34 (m, 2H), 7.25 - 7.18 (m, 2H), 7.16 - 7.08 (m, 1H), 3.92 - 3.81 (m, 4H), 2.02 (dtd, J= 26.2, 13.4, 3.9 Hz, 4H), 1.74 - 1.63 (m, 2H), 1.61 - 1.45 (m, 3H).

[0309]

[0246] Step 2: To a solution of 8-phenyl-l,4-dioxaspiro[4.5]decan-8-ol (679 g, 2.90 mol, 1 eq) in THF (6.2 L) was added slowly sodium hydride (173.9 g, 60% Wt, 4.36 mol, 1.5 eq) at 0 °C. The reaction mixture was stirred at 0 °C for Ih and then added iodomethane (1234.0 g, 8.69 mol, 3 eq). The reaction mixture was allowed to warm to rt and stirred at rt for overnight. HPLC showed the reaction was completed. The reaction was quenched by ice water (6.2 L) and extracted by ethyl acetate (6.2 L x2) , the combined organic phases were washed with brine (6.2 L). The organic phases were collected, dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by silica pad eluted by PE / EA = 10 / 1 to give 8- methoxy-8-phenyl-l,4-dioxaspiro[4.5]decane (709.0 g, 99.2% purity, 93.4% assay, 94.7% yield) as white solid. 'H NMR (400 MHz, CDC13) 8 7.25 (dd, J= 8.2, 1.0 Hz, 2H), 7.17 (dd, J = 10.3, 4.8 Hz, 2H), 7.08 (ddd, J= 7.2, 4.3, 1.1 Hz, IH), 3.91 - 3.63 (m, 4H), 2.83 (s, 3H), 2.02 - 1.71 (m, 6H), 1.62 - 1.37 (m, 2H).

[0310]

[0247] Step 3: To a solution of 8-methoxy-8-phenyl-l,4-dioxaspiro[4.5]decane (700 g, 2.82 mol, 1 eq) in THF (3.5 L, 5 V) was added 3N HC1(2.8 L, 4 V). The reaction mixture was stirred at rt for 4h. Ethyl acetate(3.5 L) was added and the separated aqueous layer was extracted with ethyl acetate (3.5 L). The combined organic layers were washed with H2O (7 L) and saturated sodium bicarbonate solution (7 L x 1), brine (3.5L x 1), dried over Na2SO4 and concentrated under vacuum. The crude was rection again and repeat treatment operation once to give 4-methoxy-4- phenylcyclohexan-l-one (551.3 g, 98.3% purity, 89.0% assay, 85.2% yield) as white solid. 'H NMR (300 MHz, CDC13) 8 7.33 - 7.04 (m, 5H), 2.90 (s, 3H), 2.70 - 2.51 (m, 2H), 2.32 - 2.08 (m, 4H), 2.04 - 1.86 (m, 2H).

[0311]

[0248] Step 4: To a solution of 4-methoxy-4-phenylcyclohexan-l-one (450 g, 2.20 mol, 1 eq) in toluene (3.2 L) was added diethyl carbonate (1301.2 g, 11.01 mol, 5 eq) and then added Docket No.: PAT059786-WO-PCT slowly t-BuOK (543.8 g, 4.85 mol, 2.2 eq) at 25 °C, the reaction mixture was warmed to 90 oC for Ih. HPLC showed the reaction was completed. Then the mixture was cooled to 20 oC. The reaction mixture was pour into 13% citric acid aqueous solution (8.76 Kg, 5.51 mol, 2.5eq) and IP AC (2.25L, 5 V), the separated aqueous layer was extracted with IP AC (1.8 L x 2), the combined organic phases were washed with 5% brine (2.7 L x 2), dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by silica gel column eluting with (0-1 % EA in PE) to give ethyl 5-methoxy-2-oxo-5-phenylcyclohexane-l -carboxylate (296.6 g, 66.4% purity, 81.4% assay and 228.9g, 84.2% purity, 98.3% assay, total yield 76.5% yield) as a green solid. IH NMR (400 MHz, CDC13) 8 12.30 (s, IH), 7.45 - 7.27 (m, 5H), 4.22 (q, J= 7.1 Hz, 2H), 3.02 (s, 3H), 2.71 (d, J= 16.5 Hz, IH), 2.63 - 2.44 (m, 2H), 2.33 - 2.05 (m, 3H), 1.29 (t, J= 7.1 Hz, 3H).

[0312]

[0249] Step 5: To a solution of ethyl 5-methoxy-2-oxo-5-phenylcyclohexane-l -carboxylate (232.0 g, 81.4% assay, 683.4 mmol, 1.0 eq) and urea (100.9 g, 1.68 mol, 2.46 eq) in ethanol (4.7 L) at room temperature, sodium methoxide (302.4 g, 30% in methanol, 1.68 mol, 2.46 eq) was added. The resulting reaction mixture was stirred at 80 °C for 16 h. HPLC showed the reaction was completed. The reaction mixture was cooled to room temperature and evaporated to dryness. The solid was added to H2O (1.4 L, 6 V) and 36% hydrochloric acid solution (212.6 g, 2.5 eq) stirred for 4h, the precipitated solid was filtered, washed with water (500 mL, 2V) and dried. The crude product was triturated with PE (1.5 L), filtered, washed with PE (150 mL) and dried to afford 6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diol (118.9 g, 97.7% purity, 96.9% assay, 61.9% yield) as grey white solid. 'H NMR (400 MHz, DMSO) 8 10.96 (s, IH), 10.73 (s, IH), 7.46 - 7.34 (m, 4H), 7.34 - 7.26 (m, IH), 2.86 (s, 3H), 2.62 (d, J= 16.7 Hz, IH), 2.49 - 2.38 (m, 2H), 2.28 - 2.15 (m, 2H), 2.07 (dt, J= 15.0, 6.4 Hz, IH).

[0313]

[0250] Step 6: To a mixture of 6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diol (60.0 g, 96.9% assay, 213.5 mmol, 1.0 eq) in toluene (600 mL, 10 V) and POCI3 (67.6 g, 0.44 mol, 2.06 eq) was added N, N-Diisopropylethylamine (57.0 g, 0.44 mol, 2.06 eq). After addition, the resulting mixture was heated to 80 °C and stirred for 16 h. The reaction was monitored by HPLC. The reaction mixture was cooled down to 60 °C and concentrated under vacuum, the residual solvents were removed by azeotropy with dichloromethane (244 ml, 4V). The residue was dissolved in dichloromethane (720 ml, 12V) then pour into ice water slowly (1.2 L, 20V) at 0 °C . The aqueous phase was extracted with di chloromethane (360 ml, 6 V) again , the organic Docket No.: PAT059786-WO-PCT phases were washed with H2O (360 ml x 1), dried over anhydrous Na2SO4 and the filtrate was concentrated to get crude residue, which was purified by silica gel column with PE / EA = 20 / 1 to afford desired product .Then the solid was triturated with PE (1.5L) for 2h, filtered, washed with PE (150mL) and dried to afford 2,4-dichloro-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazoline (43.4 g, 96.6% purity, 99.3% assay, 65.3% yield) as a white solid.

[0314]

[0251] Step 7: Racemic 2,4-dichloro-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazoline (30.0 g) was separated by chiral SFC(Instrument: Thar350 preparative SFC, Column: ChiralPak IG, 300x50mm I. D. ,10pm, Mobile phase: A for CO2 and B for Ethanol, Gradient: B 25%, Flow rate: 200 mL / min, Back pressure: 100 bar, Column temperature: 38°C , Wavelength: 240nm, Cycle time: -5.70 min, Sample preparation: Compound was dissolved in -350 ml ethanol / DCM (1 / 1), Injection: 4 ml per injection.) to give (S)-2,4-dichloro-6-methoxy-6-phenyl-5,6,7,8- tetrahydroquinazoline (11.1 g, 99.9% purity, 99.9% chiral purity), and (R)-2,4-dichloro-6- methoxy-6-phenyl-5,6,7,8-tetrahydroquinazoline (11.5 g, 99.9% purity, 98.4% chiral purity). 'H NMR (300 MHz, CDC13) 8 7.48 - 7.29 (m, 5H), 3.29 - 3.04 (m, 2H), 3.04 - 2.83 (m, 5H), 2.52 (ddt, J= 13.9, 5.8, 2.8 Hz, 1H), 2.28 (ddd, J= 14.0, 11.5, 6.0 Hz, 1H).

[0315] Example 2 - Preparation of Intermediate methyl 2,4-dichloro-6-phenyl-5.6,7,8- tetrahvdroquinazoline-6-carboxylate

[0316]

[0252] Step 1: To a solution of methyl 2-phenylacetate (520.0 g, 3.46 mol, 1.0 eq) and methyl acrylate (655.8 g, 7.62 mol, 2.2 eq) in THF (7.8 L, 15 V) was added a solution of KOBu (466.2 g, 4.16 mol, 1.2 eq) in THF (4.16 L) dropwise at 20-25 °C under N2, and the mixture was stirred at 25 °C for 1 h. HPLC showed the reaction was completed. The mixture was poured into 1 N HC1 aqueous (4.16 L, 4.16 mol, 1.2 eq) and stirred for 0.5 h at 25 °C. The mixture was extracted Docket No.: PAT059786-WO-PCT with EA (5.2 L x 3, 10 V x 3), and the combined organic layers were washed with brine (2.6 L x 2, 5 V x 2), dried over Na2SO4, filtered and concentrated to give crude dimethyl 4-oxo-l- phenylcy cl ohexane- 1,3 -di carboxylate (1.04 kg, 85.9% purity) as a yellow oil.JH NMR (300 MHz, DMSO-t / e) 8 11.98 (s, 1H), 7.51 - 7.14 (m, 5H), 3.83 - 3.71 (m, 3H), 3.61 - 3.53 (m, 3H), 2.97 (d, J= 15.9 Hz, 1H), 2.63 (d, J= 15.9 Hz, 1H), 2.41 - 2.27 (m, 2H), 2.17 (ddd, J= 19.0, 15.0, 8.9 Hz, 2H).

[0317]

[0253] Step 2: To a solution of dimethyl 4-oxo-l -phenylcyclohexane- 1,3 -di carboxy late (1.04 kg, 3.58 mol, 1.0 eq) in MeOH (18.7 L, 18 V) was added urea (430.3 g, 7.16 mol, 2.0 eq) and 25wt% NaOMe-MeOH solution (1.55 kg, 7.16 mol, 2.0 eq) at 25 °C under N2, and the reaction mixture was warmed to 65-70 °C and stirred for 16 h. The mixture was cooled to 10-20 °C, and 4N HC1 aqueous was added dropwise to adjust pH to 7-8. The mixture was stirred at 10-20 °C for 1 h and filtered. The filter cake was washed with Me0H:H20 (1 : 1 , 2.08 L) and dried to give methyl 2,4- dihydroxy-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxylate (368.0 g, 35.4% yield overall 2 steps) as a white solid.

[0318]

[0254] Step 3: To a solution of methyl 2,4-dihydroxy-6-phenyl-5,6,7,8-tetrahydroquinazoline-6- carboxylate (400.0 g, 1.33 mol, 1.0 eq) in toluene (3.2 L, 8 V) was added POCh (1.43 kg, 9.32 mol, 7.0 eq) and DIEA (172.1 g, 1.33 mol, 1.0 eq) at 20-25 °C under N2, and the mixture was warmed to 85 °C and stirred for 18 h. LCMS showed the reaction was completed. The reaction mixture was cooled to 60 °C and concentrated. PhMe (800.0 mL x 3, 2 V x 3) was added for solvent replacement to remove most of POCh (3 times), and then DCM (4.0 L, 10 V) was added into the residue. The mixture was added into H2O (4.0 L, 10 V) at 20±5 °C and stirred for 1 h. 4N NaOH aqueous was added dropwise to adjust pH to 6-7, and the mixture was stirred for 0.5 h and separated. The aqueous layer was extracted with DCM (2.0 L x 2, 5 V x 2), and the combined organic layers were washed with brine (1.6 L x 2, 4 V x 2), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column eluting with EA to give methyl 2,4- dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxylate (170.0 g, 97.6% purity, 37.9% yield) as a white solid. 'H NMR (300 MHz, CDCh) 8 7.47 - 7.27 (m, 5H), 3.68 (d, J = 12.5 Hz, 3H), 3.55 (d, J= 17.8 Hz, 1H), 3.11 (d, J= 17.6 Hz, 1H), 2.96 - 2.80 (m, 2H), 2.73 - 2.56 (m, 1H), 2.53 - 2.32 (m, 1H). LCMS (ESI): [M+H]+337.0, 339.0.

[0319]

[0255] Step 4: Racemic 2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxylate (170 g) was separated by chiral SFC (Instrument: Thar350 preparative SFC, Column: ChiralCel OX, Docket No.: PAT059786-WO-PCT

[0320] 300x50mm I.D., 10pm, Mobile phase: A for CO2 and B for Ethanol, Gradient: B 30%, Flow rate: 200 mL / min, Back pressure: 100 bar, Column temperature: 38 °C, Wavelength: 254nm, Cycle time: ~2min, Sample preparation: Compound was dissolved in -800 ml ethanol / DCM (1 / 1), Injection: 2 ml per injection) to afford methyl (S)-2,4-dichloro-6-phenyl-5, 6,7,8- tetrahydroquinazoline-6-carboxylate (55.0 g, 97.8% purity, 98.8% chiral purity, 32.4% yield) and methyl (R)-2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxylate (53.0 g, 99.6% purity, 99.3% chiral purity, 31.2% yield).

[0321] Example 3 - Preparation of Intermediate 2,4-dichloro-6-phenyl-5,6, 7,8-tetrahvdroquinazoline-6- carbonitrile

[0322]

[0256] Step 1 : Under N2, to a solution of 2-phenylacetonitrile (480.0 g, 4.10 mol, 1.0 eq) and methyl acrylate (706.0 g, 8.20 mol, 2.0 eq) in THF(7.2 L, 15 V) was added t-BuOK (552.0 g, 4.92 mol, 1.2 eq) in portions at 20 °C. The reaction mixture was stirred at 20 °C for 1 h. HPLC showed the reaction was completed. The reaction mixture was acidified with aqueous 3 N HC1 aq. (1.4 L) to adjust pH = 6-7. To the resulting mixture was added MTBE (7.2 L, 15 V) and H2O (5 L, 10.4 V), and then stirred for 15 min. After phase separation, the organic layer was washed with brine (5 L, 10.4 V), dried over Na2SO4 and concentrated under vacuum to give the crude product, which was purified by silica gel column eluting with PE / EA = 10 / 1-2 / 1 to give methyl 5-cyano-2-oxo-5-phenylcyclohexane-l -carboxylate (908.0 g, 97.7% purity, 86.1% yield) as a yellow solid. 'H NMR (400 MHz, CDCh) 8 12.25 (s, 1H), 7.50 (d, J= 7.4 Hz, 2H), 7.39 (dt, J = 25.8, 7.2 Hz, 3H), 3.78 (s, 3H), 3.01 (d, J= 16.2 Hz, 1H), 2.90 - 2.77 (m, 1H), 2.68 (d, J= 16.2 Hz, 1H), 2.50 (ddd, J= 18.8, 5.2, 2.7 Hz, 1H), 2.25 (qdd, J= 16.9, 8.8, 4.7 Hz, 2H). Docket No.: PAT059786-WO-PCT

[0323]

[0257] Step 2: To a solution of methyl 5-cyano-2-oxo-5-phenylcyclohexane-l-carboxylate (1650.6 g, 6.42 mol, 1.0 eq) and urea (770.6 g, 12.83 mol, 2.0 eq) in ethanol (16.5 L, 10 V) was added 30% MeONa in MeOH (2310.4 g, 12.83 mol, 2.0 eq). The reaction mixture was heated to 80 °C and stirred for 16 h. HPLC showed the reaction was completed. The reaction mixture was cooled to room temperature and concentrated under vacuum to dryness. The residual was dissolved in H2O (17 L, 10 V), and then 2 N HC1 aq. (13.6 L) was added dropwise. The resulting suspension was stirred for 3 h at 20-25 °C. After filtration, the collected solid was washed with H2O (3.2 L, 2 V). The filter cake was triturated with MTBE (17 L, 10 V) at 20-25 °C for 16 h, filtered, washed with MTBE (1.7 L, 1 V) and dried under vacuum to afford 2,4-dihydroxy-6- phenyl-5,6,7,8-tetrahydroquinazoline-6-carbonitrile (500.0 g, 97.9% purity, 29.1% yield) as white solid.XH NMR (400 MHz, DMSO) 8 11.03 (d, J= 84.7 Hz, 2H), 7.56 (d, J= 7.5 Hz, 2H),

[0324] 7.47 (t, J= 7.6 Hz, 2H), 7.39 (t, J= 7.2 Hz, 1H), 2.92 (d, J= 16.5 Hz, 1H), 2.73 - 2.52 (m, 3H), 2.32 (dd, J= 8.9, 4.9 Hz, 2H).

[0325]

[0258] Step 3: Under N2, 2,4-dihydroxy-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carbonitrile (500.0 g, 1.87 mol, 1.0 eq) was added to POCI3 (5.0 L, 10 V). The resulting mixture was heated to 100 °C and stirred for 16 h. HPLC showed the reaction was completed. The reaction mixture was cooled to 60 °C and concentrated under vacuum. The residual POCI3 was removed by azeotropy with toluene (1.4 L x 3). The residue was dissolved in toluene (4 L), and then poured into ice water (7 L) slowly at 20 °C. The aqueous phase was extracted with dichloromethane (750 ml), the combined organic phases were washed with 5% brine (3 L x 3). The organic layer was dried over Na2SO4 and concentrated in Vacuo to give 2,4-dichloro-6-phenyl-5,6,7,8- tetrahydroquinazoline-6-carbonitrile (301.5 g, 98.3% purity, 53.0% yield) as a white solid. 'H NMR (400 MHz, CDCI3) 8 7.59 - 7.38 (m, 5H), 3.55 - 3.33 (m, 2H), 3.21 - 3.08 (m, 2H), 2.56 -

[0326] 2.47 (m, 1H), 2.39 (ddd, J= 13.7, 11.5, 5.5 Hz, 1H).

[0327]

[0259] Step 4: 2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carbonitrile (300.0 g) was separated by chiral SFC (Instrument: Thar 350 preparative SFC; Column: ChiralPak AD, 300x50mm I. D. ,10pm; Mobile phase: A for CO2 and B for Ethanol; Gradient: B 55%; Flow rate: 200 mL / min; Back pressure: 100 bar; Column temperature: 38°C; Wavelength: 280nm; Cycle time: ~6min; Sample preparation: Compound was dissolved in -990 ml Ethanol / DCM; Injection: 18 ml per injection) to give (S)-2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline-6- Docket No.: PAT059786-WO-PCT carbonitrile (104.6 g, 99.4% purity, >99.0% ee), and (R)-2,4-dichloro-6-phenyl-5, 6,7,8- tetrahydroquinazoline-6-carbonitrile (104.4 g, 99.0% purity, >99.0% ee).

[0328] Example 4 - Preparation of Intermediate (S)-2.4-dichloro-6-((difluoromethoxy)methyl)-6- phenyl-5.6.7.8-tetrahvdroquinazoline

[0329]

[0260] Step 1: To a solution of methyl (S)-2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline- 6-carboxylate (314.0 mg, 1 Eq, 931.2 pmol) in THF (4.000 mL) was added DIBAL-H (529.7 mg, 3.725 mL, 1.000 molar, 4 Eq, 3.725 mmol) at 0 °C. Then the mixture was stirred at rt for 4 hr. LCMS showed desired mass was detected. The reaction mixture was quenched by aq. seignette salt (1.7 mL) under N2, then the solid was filtered. The filtrate was dissolved with H2O (17 ml) and extracted with DCM, the combined organic layers was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the crude product. The crude was purified by silica gel flash chromatography (0 - 100% ethyl acetate / heptane) to afford (S)-(2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazolin-6-yl)methanol (244 mg, 85%). LCMS Method 1 (Acidic): Rt = 0.98 mm, MS (ESI+) m / z 309.1 (M+H)+.

[0330]

[0261] Step 2: In a plastic via, (S)-(2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazolin-6- yl)methanol (205.0 mg, 1 Eq, 663.0 pmol) and potassium hydrogen fluoride (207.1 mg, 4 Eq, 2.652 mmol) was dissolved in DCM (0.600 mL) / H2O (600 pL), followed by adding TMSCF2Br (269.3 mg, 206.2 pL, 2 Eq, 1.326 mmol), the reaction was stirred at rt overnight. LC / MS showed 62% conversion, To the reaction mixture was added another one eq. TMSCF2Br and 2 eq. potassium hydrogen fluoride. The reaction was stirred at rt for another 3 hr. LC / MS showed completed conversion. The reaction was diluted with H2O, extracted with DCM 3 times. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (0 - 50% ethyl acetate / heptane) to afford (S)-2,4-dichloro-6-((difhioromethoxy)methyl)-6-phenyl-5,6,7,8-tetrahydroquinazoline (207 mg, 87%). LCMS Method 2 (Basic): Rt = 1.20 mm, MS (ESI+) m / z 357.0 (M-H)'. Docket No.: PAT059786-WO-PCT

[0331] Example 5 - Preparation of Intermediate methyl (R)-3-(l-(methylamino) propyllbicvclol 1.1.1 Ipentane- 1 -carboxylate

[0332]

[0262] Step 1: To a solution of 3-(methoxycarbonyl)bicyclo[l.l.l]pentane-l -carboxylic acid (253.0 g, 1.5 mol, 1.0 eq) in anhydrous THF (2500.0 mL) and was added dropwise boranemethyl sulfide complex (2232.0 mL, 2.0 mol / L, 4.5 mol, 3.0 eq) 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 generated 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 NaCl aqueous (759.0 mL x 2), and dried over anhydrous Na2SO4, filter and concentrated under reduced pressure to afford methyl 3-(hydroxymethyl)bicyclo[l.l.l]pentane-l- carboxylate (255.0 g, GC purity: 98.8%, crude yield: 100%) as a light-yellow solid.1H NMR (300 MHz, CDCh) 8 3.75 (s, 2H), 3.67 (s, 3H), 1.96 (dd, J= 9.2, 5.7 Hz, 6H).

[0333]

[0263] Step 2: To a solution of methyl 3-(hydroxymethyl)bicyclo[l.l.l]pentane-l -carboxylate (255.0 g crude, 1.5 mol, 1.0 eq) in dry DCM (2500.0 mL) was added NaHCCh (250.0 g, 3.0 mol, Docket No.: PAT059786-WO-PCT

[0334] 2 eq) and DMP (753.3 g, 1.8 mol, 1.2 eq) at 0 °C, and 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 pad of celite, and the filter cake was washed with DCM (1000.0 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was diluted with EtOAc (5100.0 mL), and washed with saturated sodium thiosulfate aqueous (500.0 mL x 2) and saturated NaHCCh aqueous (500.0 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column with heptane / EA = 10 / 1 to afford methyl 3 -formylbicyclo[l.l. l]pentane-l -carboxylate (187.0 g, purity: 83.4%, crude yield: 70.2%) as a white solid.JH NMR (300 MHz, CDCh) 8 9.60 (s, 1H), 3.71 (s, 3H), 2.32 (s, 6H).

[0335]

[0264] Step 3: To a mixture of methyl 3-formylbicyclo[l.l.l]pentane-l-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 H2O (900.0 mL), and separated. The aqueous phase was extracted with DCM (2700.0 mL, 15 V), and the combined organic phases were washed with saturated NaCl aqueous (500.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The mixture was purified by column with heptane / EA = 5 / 1 to afford methyl (R,E)-3-(((tert-butylsulfinyl)imino)methyl)bicyclo[l.l.l]pentane-l-carboxylate (210.0 g, purity: 59.2%, containing 40.8% of (R)-2-methylpropane-2-sulfinamide (crude yield of 63.0%) as an off- white solid which was used to the next step directly without further purification. 'H NMR (300 MHz, CDCh) 8 7.97 (s, 1H), 3.68 (s, 3H), 2.28 (s, 6H), 1.16 (s, 9H).

[0336]

[0265] Step 4: To a solution of methyl (R,E)-3-(((tert- butylsulfinyl)imino)methyl)bicyclo[l.l.l]pentane-l -carboxylate (200.0 g, 0.77 mol, 1.0 eq) in dry THE (1600.0 mL) was added dropwise ethyl magnesium bromide (777.0 mL, 1.5 mol, 2mol / L, 2.0 eq) at -78 °C, and the mixture was stirred for 2 h. The reaction was monitored by HPLC. The reaction mixture was quenched with saturated NH4Q aqueous (1200.0 mL) at -78 °C. The reaction mixture was warmed up to 25 °C. The mixture was extracted with EtOAc (3000.0 mL x 2), and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column with heptane / EA = 3 / 1 to crude product as a yellow oil. The crude product was purified by preparatory-HPLC to afford 27.0 g of methyl (S)-3-(l-((tert-butylsulfinyl)amino)-113-propyl)bicyclo[l.l.l]pentane-l- carboxylate with 93.9% purity and 81.0 g of methyl (R)-3-(l-((tert-butylsulfinyl)amino)-113- Docket No.: PAT059786-WO-PCT propyl)bicyclo[l.l.l]pentane-l -carboxylate with 97.2% purity.JH NMR (300 MHz, CDCh) 8 3.65 (d, J= 8.7 Hz, 3H), 3.11 (td, J= 8.3, 4.5 Hz, 1H), 2.87 (d, J= 7.7 Hz, 1H), 1.99 (qd, J = 9.6, 1.8 Hz, 6H), 1.55 (ddd, J= 14.1, 7.4, 4.5 Hz, 1H), 1.41 - 1.25 (m, 1H), 1.25 - 1.11 (m, 9H), 0.93 (t, J = 7.4 Hz, 3H).

[0337]

[0266] Step 5: To a solution of methyl (R)-3-(l-((tert-butylsulfinyl)amino)-113- propyl)bicyclo[l.l.l]pentane-l -carboxylate (63.0 g, 0.21 mol, 1.0 eq) in dry THF (0.7 L) was added LiHMDS (2 M, 210.0 mL, 0.42 mol, 2.0 eq) at 0 °C under N2, and the reaction mixture was stirred for 0.5 h at 0 °C. Then Mel (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 x 3), and the combined organic phases were washed with saturated NaCl aqueous (500.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford methyl (R)-3-(l-((tert-butylsulfinyl)(methyl)amino)-113- propyl)bicyclo[l. l.l]pentane-l-carboxylate (55.0 g, purity: 82.1%, crude yield: 83.2%). 'H NMR (300 MHz, CDCh) 8 3.66 (s, 3H), 3.11 (dd, J= 8.7, 6.6 Hz, 1H), 2.49 (s, 3H), 2.13 (dd, J = 9.5, 1.8 Hz, 3H), 2.00 (dd, J= 9.5, 1.8 Hz, 3H), 1.62 - 1.46 (m, 2H), 1.23 (dd, J= 9.0, 5.2 Hz, 2H), 1.23 - 1.11 (m, 9H), 0.98 (t, J = 7.4 Hz, 3H).

[0338]

[0267] Step 6: Methyl (R)-3-(l-((tert-butylsulfinyl)(methyl)amino)-113- propyl)bicyclo[l.l.l]pentane-l -carboxylate (55.0 g, 182.5 mmol, 1.0 eq) was added into 4M HC1 in 1, 4-di oxane (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 swapped with MTBE (110.0 mL x 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 afford methyl (R)-3-(l-(methylamino)propyl)bicyclo[l.l.l]pentane-

[0339] 1 -carboxylate hydrochloride (25.5 g, yield: 59.8%) as a white solid. 'H NMR (300 MHz, MeOD) 8 3.70 (s, 2H), 3.20 - 3.07 (m, 1H), 2.73 (s, 3H), 2.19 (dd, J= 4.4, 1.3 Hz, 6H), 1.75 (t, J = 7.6 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H).

[0340] Example 6 - Preparation of Intermediate methyl (!R,4r)-4-((R)-l- (methylami no (propyl level ohexane- 1 -carboxylate hydrochloride Docket No.: PAT059786-WO-PCT

[0341]

[0268] Step 1: To a solution (lr,4r)-4-(methoxycarbonyl)cyclohexane-l -carboxylic acid (140 g, 751 mmol, 1 eq) in CH2CI2 (700 mL) was added DMF (549 mg, 7.52 mmol, 578 uL, 0.01 eq) under an atmosphere of nitrogen. The reaction was cooled to 0 °C and then (COC1)2 (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)Ch (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 ZnEt2 (1 M, 902 mL, 1.2 eq) was added slowly at 0 °C. After addition, the mixture stirred at 25 °C for 10 h. TLC (Petroleum ether / Ethyl acetate = 5 / 1, Rf / reactant = 0.20, Rf / new spot = 0.55) showed that the material was consumed and desired new spot was formed. The reaction mixture was quenched by addition ice sat. NH4Q (1000 mL) and extracted with CH2CI2 (600 mL x 3), the combined organic layers were washed with brine (1000 mL), dried over, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 4 / 1 to 1 / 4) to get a product methyl (lr,4r)-4-propionylcyclohexane-l -carboxylate (170 g, 514 mmol, 68.4% yield, 60.0% purity) was obtained as a light yellow oil. NMR (400 MHz, CDCh) 83.60 (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, Docket No.: PAT059786-WO-PCT

[0342] 3H), 1.68 - 1.61 (m, 1H), 1.45 - 1.35 (m, 1H), 1.33 (br d, J = 10.4 Hz, 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).

[0343]

[0269] Step 2: To a solution of methyl (lR,4r)-4-propionylcyclohexane-l-carboxylate (340 g, 1.71 mol, 1 eq) was added Ti(OEt)4 (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) showed that the material was consumed and desired spot was formed. The reaction was cooled to 25 °C and diluted with 800 mL of EtOAc and quenched with H2O (229 g), the resulting suspension was stirred intensely and filtered through a short plug of celite, the cake solid was washed with EtOAc (1500 mL x 2), the filtrate was concentrated in vacuum to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to get a product (230 g crude). The product was then purified by Prep-HPLC (Phenomenex luna cl 8 250 mm * 100 mm * 10 um; mobile phase: [water (lOmM NH4HCO3) - ACN], B%: 45.0% - 65.0%, 20 minutes) to give desired product ethyl (1 R,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 light yellow oil. LCMS: RT = 0.938 min, m / z = 316.3 [M+H]+; 'H NMR (400 MHz, CDCh) 84.08 (q, J= 7.2 Hz, 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).

[0344]

[0270] Step 3: To a solution of ethyl (lR,4r)-4-((E)-l-(((R)-tert- butylsulfinyl)imino)propyl)cyclohexane-l -carboxylate ( 96.0 g, 304 mmol, 1 eq) and Ti(OEt)4 (208 g, 912 mmol, 189 mL, 3 eq) in THF (960 mL) and EtOAc (240 mL) was added NaBHi (34.5 g, 912 mmol, 3 eq) at -78 °C, The resulting mixture was continued and stirred at -78 - 0 °C for 2 h (removed -78 °C bath and put into ice bath). Then the mixture was stirred at 0 °C for 2 h. The reaction was re-cooled to -78 °C and quenched with NH4Q (137 mL). The mixture was allowed to warm to 25 °C and filtrated, the cake was washed with EtOAc (1000 mL x 2). The combined organic layers were concentrated in vacuum to get a residue. The residue was purified by Prep-HPLC (Phenomenex luna C18 (250 * 70 mm, 10 um), mobile phase: [water (lOmM NH4HCO3)-ACN], B%: 45% - 70%, 20 minutes) to give desired product ethyl (lR,4r)-4-((R)-l- (((R)-tert-butylsulfinyl)amino)propyl)cyclohexane-l-carboxylate (58.0 g, 178 mmol, 58.7% yield, 97.8% purity) as a light yellow oil. LCMS: RT = 0.886 min, m / z = 318.2 [M+H]+; 'H NMR ( 400 MHz, CDCh) 84.03 (q, J= 7.2 Hz, 2H), 3.02 (d, J= 7.6 Hz, 1H), 2.95 - 2.86 (m, Docket No.: PAT059786-WO-PCT

[0345] 1H), 2.22 - 2.09 (m, 1H), 2.02 - 1.90(m, 2H), 1.84 - 1.74 (m, 1H), 1.70 (br d, J= 12.8 Hz, 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 = 7.2 Hz, 3H).

[0346]

[0271] Step 4: To a solution of ethyl (lR,4r)-4-((R)-l-(((R)-tert- butylsulfinyl)amino)propyl)cyclohexane-l -carboxylate (55.0 g, 173 mmol, 1 eq) in THF (1100 mb) at -70 °C was added LiHMDS (IM, 207 mL, 1.2 eq) and then the mixture was stirred at 0 °C for 30 min, at 0 °C, CH3I (122 g, 866 mmol, 53.9 mL, 5 eq) was added and the reaction mixture was slowly warm to 25 °C for 2 h. LCMS showed that the material was consumed and desired spot was formed. The reaction mixture was quenched by addition ice sat. NH4CI (300 mL), extracted with EtOAc (300 mL x 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 (SiCh, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to give desired product ethyl (lR,4r)-4-((R)-l-(((R)-tert- butylsulfinyl)(methyl)amino)propyl)cyclohexane-l -carboxylate (32.0 g, 90.7 mmol, 52.3% yield, 94.0% purity) as a yellow oil. LCMS: RT = 0.978 mm, m / z = 332.3 [M+H]+; 'H NMR (400 MHz, CDCh) 84.12 - 4.00 (m, 2H), 2.74 (td, J= 8.8, 4.0 Hz, 1H), 2.48 - 2.40 (m, 3H), 2.23 - 2.08 (m, 1H), 2.06 - 1.92 (m, 3H), 1.80 (br d, J= 12.8 Hz, 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).

[0347]

[0272] Step 5: To a solution of ethyl (lR,4r)-4-((R)-l-(((R)-tert- butylsulfinyl)(methyl)amino)propyl)cyclohexane-l -carboxylate (64.0 g, 193 mmol, 1 eq) in MeOH (448 mL) were added HCl / MeOH (4 M, 448 mL, 9.28 eq) at 0 °C, the resulting mixture was continued and stirred at 25 °C for 5 h. LCMS showed that the material was consumed and desired product was formed. The reaction mixture was concentrated to get a product as a yellow oil. Then the product was dissolved into EtOAc / MTBE (1 / 10, 220 mL) and concentrated to get a product as a white solid. The product was triturated with MTBE (100 mL) at 25 °C for 10 minutes to get methyl (lR,4r)-4-((R)-l-(methylamino)propyl)cyclohexane-l-carboxylate hydrochloride (36.2 g, 144 mmol, 75.0% yield). LCMS: RT = 0.341 min, m / z = 213.9 [M+H]+; 'H NMR (400 MHz, CDCh) 8 9.49 - 8.92 (m, 2H), 3.63 (s, 3H), 2.68 (t, J= 5.2 Hz, 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). Docket No.: PAT059786-WO-PCT

[0348] Example 7 - Preparation of Intermediate methyl (lR,4r)-4-((R)-l-aminopropyl)cvclohexane-l- carboxylate (hydrogen chloride salt)

[0349]

[0273] Ethyl (lR,4r)-4-((R)-l-(((R)-tert-butylsulfinyl)amino)propyl)cyclohexane-l -carboxylate (75 g, 236 mmol) was dissolved in MeOH (400 mL). HC1 in MeOH (295 mL, 4 mol / L in MeOH) was added at 0 °C. The resulting mixture was continued and stirred at 0 °C for 2 h. The reaction was concentrated in vacuum. The residue was triturated with MTBE (800 mL) to give methyl (lR,4r)-4-((R)-l-aminopropyl)cyclohexane-l-carboxylate (40.6 g, 203 mmol, yield: 93.7 %) as white solid. LCMS: RT = 0.215 mm, m / z = 200.2 [M+H]+;1H NMR (400MHz, DMSO-d6) 88.18 - 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 = 7.4 Hz, 3H).

[0350] Example 8 - Preparation of Intermediate (R)-l-((lr,4R)-4-(methoxymethyl)cvclohexyl)-N- methylpropan- 1 -amine Docket No.: PAT059786-WO-PCT mL, 1.3 Eq, 6.523 mmol) was added at 5-10 C. The reaction mixture was stirred for 5 hours at room temperature. The reaction mixture was concentrated and dried under high vacuum to afford (lR,4r)-4-((R)-l-((tert-butoxycarbonyl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid. The obtained product was taken to the next step without further purification. Rt 0.60 mins (ELSD); MS (ESI") m / z 298.2 (M-H)'.

[0351]

[0275] Step 2: To a solution of (lR,4r)-4-((R)-l-((tert- butoxycarbonyl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid (200.0 mg, 1 Eq, 668.0 pmol) in THF (3.000 mL) was added BH3.DMS (152.2 mg, 178 pL, 3 Eq, 2.004 mmol) at 0 °C under N2. The mixture was stirred at room temperature (22 °C) for 16 h. After that time, LCMS monitoring showed desired mass was detected. The reaction mixture was slowly quenched with MeOH until no bubbles released. The mixture was stirred at 60°C for 2h. The reaction mixture was concentrated. The residue was purified by flash column chromatography on silica gel (eluent: heptane / [EtOAc / EtOH (3: 1)] = 100:0 to 0: 100 (ELSD to monitor); a 12 g Redisep Silver column using a 5 g solid cartridge (DCM to dissolve)) to give tert-butyl ((R)-l- ((lr,4R)-4-(hydroxymethyl)cyclohexyl)propyl)(methyl)carbamate (175.0 mg, 613.1 pmol, 91.79 %) as a colorless oil. Rt 1.08 mins (ELSD); MS (ESI+) m / z 186.3 (M-Boc).

[0352]

[0276] Step 3: A solution of tert-butyl ((R)-l-((lr,4R)-4- (hydroxymethyl)cyclohexyl)propyl)(methyl)carbamate (175.0 mg, 1 Eq, 613.1 pmol) in THF (3.000 mL) was added to a stirred ice-cooled suspension of sodium hydride (73.57 mg, 60% Wt, 3 Eq, 1.839 mmol) in THF (5.000 mL). The mixture was stirred for 10 min and after that time methyl iodide (261.1 mg, 115.0 pL, 3 Eq, 1.839 mmol) was added. The reaction was removed from the ice-bath and was stirred at room temperature for 5 hours. The reaction mixture was put in an ice-bath and slowly diluted with water and then diluted with DCM. The layers were separated. The aqueous layer was extracted twice with DCM, and the combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 100:0 to 0: 100 (ELSD); a 12 g Redisep Silver column using a 5 g solid cartridge (DCM to dissolve)) to give tert- butyl ((R)-l- ((lr,4R)-4-(methoxymethyl)cyclohexyl)propyl)(methyl)carbamate (109.0 mg, 364.0 pmol, 59.37 %) as a colorless oil. Rt 1.35 mins; MS (ESI+) m / z 200.3 (M-Boc)+.

[0353]

[0277] Step 4: In a 40 mL vial, a solution of tert-butyl ((R)-l-((lr,4R)-4- (methoxymethyl)cyclohexyl)propyl)(methyl)carbamate (110.0 mg, 1 Eq, 367.3 pmol) in DCM Docket No.: PAT059786-WO-PCT

[0354] (1.000 mL) was prepared. The vial was set up in a water-ice bath. Once the vial was cool, HC1 in dioxane (66.96 mg, 459.2 pL, 4.000 molar, 5 Eq, 1.837 mmol) was added. After 10 min, the vial was taken out of the water-ice bath and the reaction was allowed to reach room temperature. After 1 hour, the reaction was monitored with LCMS and complete conversion was observed. The reaction mixture was concentrated and dried under high vacuum to afford (R)-l- ((lr,4R)-4-(methoxymethyl)cyclohexyl)-N-methylpropan-l -amine hydrochloride. The obtained product was taken to the next step without further purification. Rt 0.15 mins (ELSD); MS (ESI") m / z 198.2 (M-H)-.

[0355] Example 9 - Preparation of Intermediate (lR)-l-(4-(methoxycarbonyl)-4-methylcvclohexyl)-N- methylpropan- 1 -aminium

[0356]

[0278] Step 1 : To a stirred mixture of methyl (lR,4r)-4-((R)-l -aminopropyl)cyclohexane-l- carboxylate hydrochloride, (5.000 g, 1 Eq, 18.37 mmol) and triethylamine (9.293 g, 12.8 mL, 5 Eq, 91.84 mmol) in THF (50.00 mL) and water (5.556 mL), 4-dimethylaminopyridine (224.4 mg, 0.1 Eq, 1.837 mmol) and di-tert-butyl dicarbonate (6.013 g, 6.15 mL, 1.5 Eq, 27.55 mmol) were added at 0 °C and resulting reaction mixture was stirred at room temperature for 16 h. The completion of the reaction was monitored by TLC and LCMS. Then reaction mixture was concentrated under reduced pressure and diluted with water (50 mL) and extracted using ethyl acetate (3 x 120 mL). The organic layer was washed with water (2 x 100 mL) and dried over anhydrous Na2SO4 and concentrated under reduced pressure to get a brown semi-solid (6 g). The crude was purified by flash column chromatography on silica gel. The desired product was eluted usingl0% ethyl acetate in ether. The pure fractions were collected and concentrated under reduced pressure to Docket No.: PAT059786-WO-PCT get methyl (lR,4r)-4-((R)-l-((tert-butoxycarbonyl)amino)propyl)cyclohexane-l -carboxylate (3.600 g, 11 mmol, 62 %, 95% Purity) as a white solid. LCMS: m / z = 200.2 [M-100+H]+.

[0357]

[0279] Step 2: To a stirred mixture of methyl (ls,4s)-4-(l-((tert- butoxycarbonyl)amino)propyl)cyclohexane-l -carboxylate (3.500 g, 1 Eq, 11.69 mmol) in DMF (30.00 mL), sodium hydride (1.169 g, 0.97 mL, 60% wt, 2.5 Eq, 29.22 mmol) was added at 0 °C and stirred for 1 h. Afterwards, methyl iodide (4.978 g, 2.269 mL, 3 Eq, 35.07 mmol) in 5 mL THF was added to the reaction mixture. The resulting reaction mixture was stirred at room temperature for 32 h. TLC and LCMS was used to monitor the progress of the reaction. The reaction mixture was quenched with saturated NH4CI solution (50 mL) at 0 °C and extracted with ethyl acetate (3 xlOO mL). The organic layers were combined and washed with ice-cold water (2 x 70 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get gummy semi-solid (4 g).The crude was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 90:10 to 80:20) to give methyl (ls,4s)-4-(l-((tert-butoxycarbonyl)(methyl)amino) propyl)cyclohexane-l -carboxylate (1.100 g, 3.367 mmol, 28.80 %, 95.93% Purity) as a white solid. LCMS: m / z=214.2 [M- 100+H]+.

[0358]

[0280] Step 3: To a mixture of methyl (lR,4r)-4-((R)-l-((tert- butoxycarbonyl)(methyl)amino)propyl)cyclohexane-l -carboxylate (1.100 g, 1 Eq, 3.509 mmol)in THF (15.000 mL), lithium diisopropylamide solution (1.504 g, 7.019 mL, 2.000 molar, 4 Eq, 14.04 mmol) was added at -780C and the reaction mixture was stirred for 1 h at 0 °C. After 1 h, the mixture of methyl iodide (996.3 mg, 0.4541 mL, 2.000 Eq, 7.019 mmol) in 1 mL THF was added to the reaction mixture at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. TLC and LCMS monitored the progress of the reaction. The reaction mixture was quenched with saturated NH4Q solution (20 mL). The product was extracted with ethyl acetate (3 x 100 mL). The organic layer was separated and dried over anhydrous Na2SO4. The obtained organic layer was concentrated under reduced pressure to get a pale yellow semi-solid (1 g). The crude was purified by flash column chromatography on gel. The desired product was eluted in 30% ethyl acetate in hexane. The pure fractions were collected and concentrated under reduced pressure to get methyl 4-((R)- 1 -((tert-butoxycarbonyl)(methyl)amino)propyl)- 1 -methylcyclohexane- 1 - carboxylate as a Pale yellow liquid (0.9 g). LCMS: m / z +228.2 (M-100+H)+. Docket No.: PAT059786-WO-PCT

[0359]

[0281] Step 4: To a stirred mixture of methyl 4-((R)-l-((tert-butoxycarbonyl)(methyl)amino)propyl) methylcyclohexane- 1 -carboxylate (0.400 g, 1 Eq, 1.22 mmol) in DCM (10.00 mL), hydrogen chloride (4 M in 1,4-dioxane, 556 mg, 0.606 mL, 12.5 Eq, 15.3 mmol) was added at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h. TLC and LCMS monitored the progress of the reaction. The reaction mixture was concentrated under reduced pressure to get a white solid. The residue was triturated with diethyl ether and pentane and dried under reduced pressure to get a white solid (0.320 g). LCMS: m / z +228.2 (M+H)+.

[0360] Example 10- Preparation of Intermediate methyl (R)-2-(3-(l- (methylamino)propyl)bicvclo[ 1.1.1 Ipentan- 1 -yl)acetate

[0361]

[0282] Step 1: To methyl (R)-3-(l-(methylamino)propyl)bicyclo[l.l.l]pentane-l-carboxylate hydrochloride (2.500 g, 1 Eq, 10.70 mmol) in THF (35.65 mL) at room temperature was added K2CO3 (4.434 g, 3 Eq, 32.09 mmol) and Cbz-Cl (2.189 g, 1.832 mL, 1.2 Eq, 12.83 mmol). The mixture was stirred at room temperature for 16h. The mixture was quenched with water, and then extracted twice with ethyl acetate, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane). LCMS consistent with the desired product (3.71 g, 100% yield): LCMS rt 1.16 min, MS m / z 332.4 [M+H]+.

[0362]

[0283] Step 2: To a solution of methyl (R)-3-(l- (((benzyloxy)carbonyl)(methyl)amino)propyl)bicyclo[l.l. l]pentane-l -carboxy late (3.710 g, 1 Eq, 11.19 mmol) in THF (24.88 mL) and MeOH (12.44 mL) at 0 C was added NaOH (1.791 g, 8.956 mL, 5.000 molar, 4 Eq, 44.78 mmol). The solution was stirred at room temperature for 16 h. LC-MS indicated all SM was converted to desired product. The mixture was concentrated in vacuo, and then acidified to pH~3 and extracted twice with ethyl acetate, dried over magnesium Docket No.: PAT059786-WO-PCT sulfate, filtered and concentrated in vacuo. The crude product was used as is for next step(quant. Yield). LCMS consistent with the desired product: rt 0.57 min, MS m / z 318.2 [M+H]+.

[0363]

[0284] Step 3: To a vial containing (R)-3-(l- (((benzyloxy)carbonyl)(methyl)amino)propyl)bicyclo[l.l. l]pentane-l -carboxy lie acid (4.000 g, 1 Eq, 12.60 mmol) in DCM (50.41 mL) was cooled under an ice bath, oxalyl chloride (2.239 g, 1.544 mL, 1.400 Eq, 17.64 mmol) was added, followed by DMF (92.13 mg, 97.6 pL, 0.100 Eq, 1.260 mmol). After addition, the mixture warm to RT and stirred for 4h. The mixture was concentrated, toluene was added, and the mixture concentrated again, this was repeated one more time to afford a crude product after high vac. drying. The material will be used in the next step as is.

[0364]

[0285] Step 4: To benzyl (R)-(l-(3-(chlorocarbonyl)bicyclo[l.l.l]pentan-l- yl)propyl)(methyl)carbamate (4.231 g, 1 Eq, 12.60 mmol) in CH3CN (25.20 mL) at 0C was added dropwise (Trimethylsilyl)diazomethane solution (2.878 g, 12.60 mL, 2.000 molar, 2 Eq, 25.20 mmol). The mixture was then stirred at room temperature for Ih. The mixture was then concentrated in vacuo and used as is for next step.

[0365]

[0286] Step 5: To benzyl (R)-(l-(3-(2-diazoacetyl)bicyclo[l.l.l]pentan-l- yl)propyl)(methyl)carbamate (4.302 g, 1 Eq, 12.60 mmol) in MeOH (25.00 mL) at 0C was added dropwise silverbenzoate (2.885 g, 1 Eq, 12.60 mmol). The mixture was then stirred at room temperature for Ih. The mixture was then filtered and concentrated in vacuo. The residue was then purified by silica gel chromatography (0-100% EtOAc / heptane) and the desired fractions were concentrated. MS m / z 346.1 [M+H]+.

[0366]

[0287] Step 6: To methyl (R)-2-(3-(l- (((benzyloxy)carbonyl)(methyl)amino)propyl)bicyclo[l.l.l]pentan-l-yl)acetate (2.466 g, 1 Eq, 7.139 mmol) in MeOH (23.80 mL) at room temperature was added Pd / C 10% Degusssa type (379.9 mg, 10% Wt, 0.05 Eq, 356.9 pmol). The reaction was then put under latm of hydrogen (balloon) and stirred at room temperature for 16 h. concentrated to give a pale liquid in quant yield (1.6 g). MS m / z 212.4 [M+H]+. Docket No.: PAT059786-WO-PCT

[0367] Example 11 - General method for amine intermediates synthesis: preparation of Intermediate (R)-l-( 1 -methyl- lH-vyrazol-4-yl)-2-( S)-3-methylviveridin-l-yl)ethan-l -amine e , ays

[0368] Step 2 Step 3

[0369]

[0288] Step 1 : (S)-3-methylpiperidine hydrochloride (3.19 g, 23.50 mmol), (R)-2-((tert- butoxycarbonyl)amino)-2-(l -methyl- lH-pyrazol-4-yl)acetic acid (5 g, 19.59 mmol) and EbN (10.92 ml, 78 mmol) were dissolved in DCM (75 ml). The solution was cooled down to 0 °C and T3P (50% in EtOAc) (23.56 ml, 39.2 mmol) was added slowly. The solution became unclear and mixture was stirred at room temperature for 2 h. LC-MS indicated complete reaction. The reaction mixture was partitioned between EtOAc and water, the organic phase was washed with water, saturated NaHCOs 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), eluting with a gradient of 20-100% EtOAc in heptane, using a 120 g silica column, loading with DCM. The product containing fractions were combined, concentrated under reduced pressure and dried under vacuum overnight to give tert- butyl ((R)-l- (1 -methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperi din- 1 -yl)-2-oxoethyl)carbamate as a white solid (6.16 g, 93%). MS m / z = 337.1 [M+H]+.

[0370]

[0289] Step 2: To a solution of tert-butyl ((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)-2-oxoethyl)carbamate (2.46 g, 7.31 mmol) in THF (18.28 ml) was added BH3.DMS (2M in THF) (18.28 ml, 36.6 mmol, 5.0 equiv.) at 0 °C. Then the mixture was warmed to 25 °C and stirred overnight. LC-MS indicated all starting material was consumed. The RXN mixture was quenched with MeOH until no more bubbling observed. The mixture was stirred for Docket No.: PAT059786-WO-PCT

[0371] 30 min then concentrated. The residue was diluted with MeOH (10 mL) then pyridine (5.91 ml, 73.1 mmol) was added to the solution. The resulting solution was stirred at rt for 2 days. RXN mixture was concentrated and diluted with MeOH for reverse phase column chromatography purification (20-80% MeCN / Water with 0.1% NH4OH modifier, 150 g ISCO gold C18 column) and lyophilization drying to give tert-butyl ((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)carbamate as a colorless oil (1.83 g, 78% yield). MS m / z = 323.3 [M+H]+.

[0372]

[0290] Step 3: To a solution of tert-butyl ((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-1 -yl)ethyl)carbamate (1.64 g, 5.09 mmol) in MeOH (10 ml) was added HC1 (6.36 ml, 25.4 mmol, 4 N in Dioxane) solution. The reaction was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and dried under vacuum for overnight to give (R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethan-l-amine dihydrochloride as a light pale solid in quantitative yield. MS m / z = 223.3 [M+H]+.

[0373] Example 12 - Preparation of Intermediate N-((3S)-l-(2-amino-2-(l-(cvclopropylmethyl)-lH- pyrazol-4-yl)ethyl)piperidin-3-yl)-N-methylacetamide

[0374] Step 3 Step 4

[0375]

[0291] Step 1: 2-((tert-butoxycarbonyl)amino)-2-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)acetic acid (400.0 mg, 1.354 mmol) and diisopropylethylamine (699 pL, 4.063 mmol) were dissolved in DCM (5.000 mL) and the mixture was cooled to 0 °C. Then N,O-dimethylhydroxylamine Docket No.: PAT059786-WO-PCT hydrochloride (158.5 mg, 1.625 mmol) and propylphosphonic anhydride (T3P, 50% in EtOAc) (1.595 mL, 2.709 mmol) were added to the reaction mixture, and the reaction was allowed to reach room temperature and stirred for 16 h. The reaction mixture was concentrated. The mixture was diluted with saturated NaHCCh solution and then diluted with DCM. The layers were separated. The aqueous layer was extracted twice with DCM, and the combined organic extracts were dried over MgSO4, filtered and concentrated to obtain tert-butyl (l-(l-(cyclopropylmethyl)- lH-pyrazol-4-yl)-2-(methoxy(methyl)amino)-2-oxoethyl)carbamate with quantitative yield. The obtained product was taken to the next step without further purification. MS m / z = 339.3 [M+H]+, 'H NMR (400 MHz, DMSO) 8 7.71 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.52 (d, J= 8.4 Hz, 1H), 3.90 (d, J= 7.1 Hz, 2H), 3.65 (s, 3H), 3.09 (s, 3H), 1.49 - 1.46 (m, 1H), 1.38 (s, 9H), 0.56 - 0.46 (m, 2H), 0.37 - 0.30 (m, 2H).

[0376]

[0292] Step 2: tert-butyl (l-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)-2- (methoxy(methyl)amino)-2-oxoethyl)carbamate (200.0 mg, 591.0 pmol) was dissolved in THF (5.000 mL) in a round bottomed flask. The flask was sealed with a septum and the mixture was purged with nitrogen and cooled to -78 °C in a dry ice-acetone bath. Diisobutylaluminum hydride in toluene (827.4 pL, 1.000 molar, 827.4 pmol) was added dropwise and the reaction mixture was stirred for 1 h. After that time, more diisobutylaluminum hydride in toluene (827.4 pL, 1.000 molar, 827.4 pmol) was added dropwise and the reaction mixture was stirred at -78 °C for another 1 h. The reaction was quenched with 1 mL of MeOH and 3 mL of Rochelle's salt. The reaction was warmed to room temperature and allowed to stir for 1 h. The mixture was diluted with EtOAc. The layers were separated. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to obtain tert-butyl (1-(1 -(cyclopropylmethyl)- 1H- pyrazol-4-yl)-2-oxoethyl)carbamate (120.0 mg, 50% Wt from NMR, 214.8 pmol, 22% yield). The obtained product was taken to the next step without further purification. MS m / z = 298.3 [M+H]+; 'H NMR (400 MHz, CDC13) 8 9.58 (s, 1H), 7.63 - 7.48 (m, 2H), 5.48 - 5.25 (m, 2H), 3.98 (d, J= 7.1 Hz, 2H), 1.59 - 1.38 (m, 10H), 0.66 (d, J = 7.6 Hz, 2H), 0.38 (d, J= 5.5 Hz, 2H).

[0377]

[0293] Step 3: A mixture of (S)-N-methyl-N-(piperidin-3-yl)acetamide (50.34 mg, 322.2 pmol) , tert-butyl (l-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)-2-oxoethyl)carbamate (120.0 mg, 50% Wt, 214.8 pmol) and acetic acid (61.48 pL, 1.074 mmol) in MeOH (7.000 mL) was stirred at 0 °C for 0.5 h. Then, at the same temperature, sodium triacetoxyborohydride (227.6 mg, 1.074 Docket No.: PAT059786-WO-PCT mmol) was added in portions and the reaction mixture was stirred at 22 °C for 3 hour. The reaction mixture was concentrated. The mixture was diluted with saturated NaHCCh solution and then diluted with DCM. The layers were separated. The aqueous layer was extracted three times with DCM, and the combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (Redisep Rf Reversed- phase C18 Gold column, water / CH3CN (using 0.1% formic acid) = 95:5 to 0: 100) to give tertbutyl (l-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)-2-((S)-3-(N-methylacetamido)piperidin-l- yl)ethyl)carbamate (22.00 mg, 52.43 pmol, 24.41% yield) as a brown solid. MS m / z = 420.5 [M+H]+.

[0378]

[0294] Step 4: To a solution of tert-butyl (l-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)-2-((S)-3- (N-methylacetamido)piperidin-l-yl)ethyl)carbamate (22.00 mg, 52.43 pmol) in DCM (3.000 mb) at 0 °C was added HC1 in dioxane (65.54 pL, 4 molar, 262.2 pmol). After 10 min, the vial was taken out of the water-ice bath and the reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated. The obtained product was dried under high vacuum overnight. N-((3S)-l-(2-amino-2-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)ethyl)piperidin-3-yl)-N- methylacetamide hydrochloride (18.7 mg, 52.4 pmol) was obtained as a brown gum with quantitative yield. The obtained product was taken to the next step without further purification. MS m / z = 320.4 [M+2H]+.

[0379] Example 13- Preparation of Intermediate ethyl 2-(4-(l-amino-2-((S)-3-methylpiperidin-l- vDethyl)- 1 H-pyrazol- 1 -vDacetate Docket No.: PAT059786-WO-PCT

[0380]

[0295] Step 1: To a mixture of 2-((tert-butoxycarbonyl)amino)-2-(lH-pyrazol-4-yl)acetic acid (2.700 g, 1 Eq, 11.19 mmol) and (S)-3 -methylpiperidine hydrochloride (1.822 g, 1.2 Eq, 13.43 mmol) in DCM (90.00 mL) was added Et3N (3.397 g, 4.68 mL, 3 Eq, 33.58 mmol) and then T3P (16.13 g, 50% Wt, 2 Eq, 22.38 mmol, 163755-62-2) was added slowly to the mixture at 0°C. The mixture was stirred at 0°C for 0.5 h. LCMS showed 69% of desired mass was detected. The mixture was diluted with H O (100 mL), then extracted with DCM (100 mL*3). The organic phase was washed with saturated NaHCCh aqueous solution (100 mL*3) and Sat.NaCl (100 mL), The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give the residue. The residue was combined with pilot batch to purify. The combined residue was purified by reversed phase column chromatography (220 g of SepaFlash® Spherical Cl 8, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% FA and B for acetonitrile; gradient: B 5 - 80% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) after purification, the aqueous phase was basified by saturated NaHCCh solution (100 mL) to pH=8-9 and extracted with DCM (100 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford: tert-butyl (2-((S)-3-methylpiperidin-l-yl)-2-oxo-l-(lH-pyrazol-4-yl)ethyl)carbamate (3.400 g, 10 mmol, 92 %, 98% Purity) as yellow solid. LCMS: Rt =0.465 mm, [M+H] =323.2, 'H NMR (400 MHz, CHLOROFORM-d) 8 = 9.36 - 8.50 (m, 1H), 7.59 (br d, J = 8.5 Hz, 2H), 6.07 (br d, J= 4.9 Hz, 1H), 5.72 - 5.58 (m, 1H), 4.62 - 4.32 (m, 1H), 3.76 - 3.54 (m, 1H), 3.00 - 2.50 (m, 1H), 2.44 - 2.25 (m, 1H), 1.85 - 1.57 (m, 2H), 1.42 (br d, J= 4.3 Hz, 9H), 1.39 - 1.21 (m, 1H), 1.14 - 1.00 (m, 1H), 1.00 - 0.79 (m, 3H), 0.73 (br d, J= 6.1 Hz, 1H).

[0381]

[0296] Step 2: To a mixture of tert-butyl (2-((S)-3-methylpiperidin-l-yl)-2-oxo-l-(lH-pyrazol-4- yl)ethyl)carbamate (2.600 g, 1 Eq, 8.064 mmol) andK2CO3 (2.229 g, 2 Eq, 16.13 mmol) inMeCN (40.00 mL) was added ethyl 2-chloroacetate (1.186 g, 1.2 Eq, 9.677 mmol). The mixture was stirred at 60°C for 48h. LCMS showed 94% of desired mass was detected. The mixture was diluted with H2O (100 mL), then extracted with EA (100 mL*3). The organic phase was washed with Sat.NaCl (50 mL), Then the organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give the residue. The residue was purified by reversed phase column chromatography (220 g of SepaFlash® Spherical Cl 8, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% FA and B for acetonitrile; gradient: B 5 — 100% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) after purification, the aqueous phase was basified by saturated NaHCCh solution (100 mL) to pH=8-9 and extracted with EA (150 mL*3). Docket No.: PAT059786-WO-PCT

[0382] The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford: ethyl 2-(4-( 1 -((tert-butoxycarbony l)amino)-2-((S)-3 -methy Ipiperidin- 1 -yl)-2-oxoethyl)- lH-pyrazol-l-yl)acetate (3.200 g, 7.1 mmol, 87 %, 90% Purity) as yellow oil. LCMS: Rt =0.509 mm, [M+H]+=409.2.

[0383]

[0297] Step 3: To a solution of ethyl 2-(4-(l-((tert-butoxycarbonyl)amino)-2-((S)-3- methylpiperidin-l-yl)-2-oxoethyl)-lH-pyrazol-l-yl)acetate (3.200 g, 1 Eq, 7.834 mmol) in THF (120.00 mL) was added BH3.DMS (1.785 g, 2.350 mL, 10.00 molar, 3 Eq, 23.50 mmol) slowly at 0°C under N2. The mixture was stirred 25°C for 12 h. LCMS showed desired mass was detected. The reaction mixture was slowly quenched with EtOH (150 mL) until no bubbles released. The mixture was stirred for 2h at 60 °C and then concentrated to give a residue. LCMS showed 79% of desired mass and 11% of reaction 1 remained. The residue was purified by reversed phase column chromatography (80 g of SepaFlash® Spherical Cl 8, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% FA and B for acetonitrile; gradient: B 5 - 50% in 15 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) after purification, the aqueous phase was basified by saturated NaHCCh solution (50 mL) to pH=8-9 and extracted with EA (100 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford: ethyl 2-(4-(l -((tert-butoxycarbonyl)amino)-2-((S)-3-methylpiperidin- 1 -yl)ethyl)- 1H- pyrazol- 1 -yl)acetate (2.200 g, 5.0 mmol, 64 %, 90% Purity) as yellow oil. LCMS: Rt =0.453 min, [M+H] = 395.4, 'H NMR (400 MHz, CHLOROFORM-d) 8 = 7.50 (s, 1H), 7.45 (s, 1H), 5.31 (s, 1H), 4.86 (s, 2H), 4.78 (br s, 1H), 4.26 - 4.20 (m, 2H), 2.96 - 2.49 (m, 4H), 1.84 - 1.53 (m, 6H), 1.44 (s, 9H), 1.32 - 1.25 (m, 3H), 0.96 - 0.82 (m, 4H).

[0384]

[0298] Step 4: To a solution of ethyl 2-(4-(l-((tert-butoxycarbonyl)amino)-2-((S)-3- methylpiperidin-l-yl)ethyl)-lH-pyrazol-l-yl)acetate (2.200 g, 1 Eq, 5.576 mmol) in DCM (5.000 mL) was added 2M HCl / dioxane, 1,4-dioxane (4.9828 g, 20.000 mL, 2.000 molar, 7.173 Eq, 40.000 mmol). The resulting mixture was stirred at 20°C for 2 h. LCMS showed a major peak of desired mass was detected. The reaction was concentrated to remove the solvent to afford: ethyl 2-(4-(l-amino-2-((S)-3-methylpiperidin-l-yl)ethyl)-lH-pyrazol-l-yl)acetate hydrochloride (2.800 g, 7.623 mmol, 136.7 %) as white solid. The obtained product was taken to the next step without further purification. LCMS: Rt =0.375 min, [M-NH2] = 295.1 Docket No.: PAT059786-WO-PCT

[0385] Example 14 - Preparation of Intermediate (R)-l-((S)-2-amino-2-(3-fluoro-l-methyl-lH-pyrazol-

[0386] 4-yl)ethyl)-3-ethylpiperidin-3-ol

[0387]

[0299] Step 1: The mixture of 3-ethylpiperidin-3-ol (5.482 g, 1 Eq, 42.43 mmol), sodium bicarbonate (3.565 g, 1 Eq, 42.43 mmol) in THF (64.00 mL) / H20 (64.00 mL) was stirred for 10 min, then benzyl carbonochloridate (7.462 g, 6.244 mL, 97% Wt, 1 Eq, 42.43 mmol) was added at rt, the resulting mixture was stirred at rt overnight. After the reaction was completed, the organic phase was separated, to the organic phase was added EtOAc , and the resulting organic mixture was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude was purified by silica gel flash chromatography (0 - 60% ethyl acetate / heptane) to afford the racemic product (11.17 g, 100%).

[0388]

[0300] The racemic mixture was separated by chiral separation (SFC with column, AD 3 pm 3x100mm column) to obtain peak 1, benzyl fS')-3-ethyl-3-hydroxypiperidine- l -carboxylate (4.57g, 41%), and benzyl (R)-3-ethyl-3-hydroxypiperidine-l-carboxylate (4.1 g, 37%).

[0389]

[0301] Chiral separation -peak- 1 (benzyl (5)-3-ethyl-3-hydroxypiperidine-l -carboxylate) :JH NMR (400 MHz, CDCh) 8 7.36 (d, J= 4.4 Hz, 4H), 7.33 - 7.27 (m, 1H), 5.14 (s, 2H), 3.89 (d, J = 13.1 Hz, 1H), 3.14 - 2.84 (m, 2H), 1.87 - 1.63 (m, 2H), 1.50 (q, J= 7.8 Hz, 6H), 0.94 (t, J = 7.5 Hz, 3H).

[0390]

[0302] Chiral separation -peak-2 (benzyl ( / )-3-ethyl-3-hydroxypiperidine- l -carboxylate): 'H NMR (400 MHz, CDCh) 8 7.36 (d, J= 4.4 Hz, 4H), 7.33 - 7.27 (m, 1H), 5.14 (s, 2H), 3.89 (d, J = 12.8 Hz, 1H), 3.19 - 2.82 (m, 2H), 1.89 - 1.61 (m, 2H), 1.61 - 1.36 (m, 6H), 0.94 (t, J= 7.5 Hz, 3H). Docket No.: PAT059786-WO-PCT

[0391]

[0303] Step 2: The mixture of benzyl ( / )-3-ethyl-3-hydroxypiperidine- l -carboxylate (4030 mg, 1 Eq, 15.30 mmol), Pd / C (325.7 mg, 50% Wt, 0.1 Eq, 1.530 mmol) in MeOH (150 mL) was stirred at rt under H2 ballon for 4 hr. After the reaction was completed, the reaction solution was filtered through Celite. and filate was concentrated under reduced pressure to give desired product, (R)-3-ethylpiperidin-3-ol (1.97 g 100%).

[0392]

[0304] 'H NMR (400 MHz, CDCI3) 5 3.73 (d, J = 53.0 Hz, 2H), 3.08 (ddd, J = 12.3, 4.5, 2.5 Hz, 1H), 2.87 (dt, J= 12.2, 1.9 Hz, 1H), 2.61 - 2.50 (m, 2H), 1.87 (qt, J= 12.8, 4.4 Hz, 1H), 1.78 - 1.64 (m, 1H), 1.56 (ddq, J= 13.6, 5.4, 2.9 Hz, 1H), 1.48 (q, J= 7.7 Hz, 2H), 1.33 (td, J = 13.2, 4.7 Hz, 1H), 0.93 (t, J= 7.6 Hz, 3H).

[0393]

[0305] Step 3: To a mixture of 2-((tert-butoxycarbonyl)amino)-2-(3-fluoro-l-methyl-lH- pyrazol-4-yl)acetic acid (1.897 g, 1 Eq, 6.943 mmol)and (R)-3-ethylpiperidin-3-ol (897.0 mg, 1 Eq, 6.943 mmol) in DCM (20.00 mL) was added TEA (3.513 g, 4.84 mL, 5 Eq, 34.71 mmol) and T3P (8.836 g, 8.266 mL, 50% Wt, 2 Eq, 13.89 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed the desired product mass. The mixture was diluted with H2O and extracted with DCM (x3). The combined organic phase was washed with aq. NaHCCh solution (30 mL), brine (30 mL), the organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified using Cl 8 column with basic condition to give tert-butyl (2-((R)-3 -ethy 1-3 -hydroxypiperi din- l-yl)-l -(3 -fluoro- 1 -methyl- lH-pyrazol-4- yl)-2-oxoethyl)carbamate (1.617 g, 61%).

[0394]

[0306] Step 4: To a solution of tert-butyl (2-((R)-3-ethyl-3-hydroxypiperidin-l-yl)-l-(3-fluoro-l- methyl-lH-pyrazol-4-yl)-2-oxoethyl)carbamate (1.671 g, 1 Eq, 4.347 mmol) in THF (24.00 mL) was added BH3.DMS (3.302 g, 4.12 mL, 10 Eq, 43.470 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 5 mins, then warmed to rt and stirred at rt for 3hr. The reaction mixture was cooled to 0 °C and slowly quenched with MeOH until no bubbles were released. The mixture was stirred for Ih at 60°C, then was concentrated to afford the crude product. The crude was purified by silica gel flash chromatography (0 - 100% ethyl acetate / heptane) to afford 836 mg racemic mixture (52%). LCMS Method 2 (Basic): Rt = 1.00 min, MS (ESI+) m / z 371.2 (M+H)".

[0395]

[0307] The racemic mixture was separated by chiral separation (SFC with column, IC 2 pm 3x100mm column) to obtain peak 1, tert-butyl ((S)-2-((R)-3-ethyl-3-hydroxypiperidin-l-yl)-l- Docket No.: PAT059786-WO-PCT

[0396] (3 -fluoro- 1 -methyl- lH-pyrazol-4-yl)ethyl)carbamate (321 mg, 20%), and peak 2, tert-butyl ((R)- 2-((R)-3-ethyl-3-hydroxypiperidin-l-yl)-l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)ethyl)carbamate (487 mg, 30%). The absolute structures were confirmed by VCD (Electronic / Vibrational Circular Dichroism).

[0397]

[0308] Step 5: To the solution of tert-butyl ((S)-2-((R)-3-ethyl-3-hydroxypiperidin-l-yl)-l-(3- fluoro-1 -methyl- lH-pyrazol-4-yl)ethyl)carbamate (311.0 mg, 1 Eq, 839.5 pmol) in MeOH (5.500 mL) was added HC1 in dioxane, 4M (153.0 mg, 1.049 mL, 4.000 molar, 5 Eq, 4.197 mmol) at 0 °C, after stirred at 0 °C for 10 min, the mixture was warmed up to rt, and stirred at rt for 2 hr. TLC showed 45% product formation, added another HC1 in dioxane, 4M (153.0 mg, 1.049 mL, 4.000 molar, 5 Eq, 4.197 mmol), at 0 °C for 5 min, then rt overnight. LC / MS showed starting material disappeared, the reaction solution was concentrated. The residue was dissolved in MeOH, added Ion exchange resin (CAS: 9017-79-2, [Ambersep 900(OH)) stirred at rt, until pH reached to 9-10, filtered out resin, washed with MeOH, concentrated the filtrate, obtained 206 mg desired product (91%). LCMS Method 2 (Basic): Rt = 0.73 min, MS (ESI+) m / z 271.0 ion of Intermediate (3R,5R)-3-methoxy-5-methylpiperidine

[0398]

[0309] Step 1 : To a solution of tert-butyl (3R,5R)-3-hydroxy-5-methylpiperidine-l-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. Then the reaction mixture was stirred at 0°C for 0.5 h and Mel (7.42 g, 3.27 mL, 2.5 Eq, 52 mmol) was added dropwise. The mixture was stirred at 25°C for another 1.5 h. LCMS showed one major peak with desired mass was detected. The mixture was quenched with saturated NH4Q (100 mL) and extracted with EtOAc (100 mL*2). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford the residue. The residue was purified by flash silica gel chromatography(ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0- Docket No.: PAT059786-WO-PCT

[0399] 100% EtOAc / Heptane) and the eluent was concentrated to give desired product as a colorless oil. LCMS m / z [M-55]+= 174.2.

[0400]

[0310] Step 2: To a solution of tert-butyl (3R,5R)-3-methoxy-5-methylpiperidine-l- carboxylate (4.4 g, 1 Eq, 19 mmol) in MeOH (50 mL) was added HC1 (4N in dioxane) (3.5 g, 24 mL, 4.000 molar, 5 Eq, 96 mmol) at 0°C. Then the reaction mixture was stirred at rt for 2 h and LC-MS indicated all SM was consumed. The mixture was concentrated under reduced pressure to give a colorless oil. The crude product was used next step without further purification. LCMS m / z [M+H]+= 130.1.

[0401] Example 16 - Preparation of Intermediate (R)-3-methoxy-3-methylpiperidine

[0402] Step 3

[0403]

[0311] Step 1: To a solution of (R)-3-methylpiperi din-3 -ol, AA - Hydrochloride (6.500 g, 1 Eq, 42.86 mmol), TEA (17.35 g, 23.9 mL, 4 Eq, 171.5 mmol) in DCM (100.00 mL) was added boc2o (23.39 g, 24.6 mL, 2.5 Eq, 107.2 mmol) portion- wise and then stirred at room temperature for 16h. Mixture was concentrated and the residue was partitioned between EtOAc and water. The organic phase was separated and the aqueous phase further extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated. Crude residue was purified by silica gel column with 0-10% DCM / MeOH over 20 column volumes using 214 nm detection to afford desired compound tert-butyl (R)-3 -hydroxy-3 - methylpiperidine-1 -carboxylate (6.000 g, 75% purity, 50% yield) as a clear oil. 'H NMR (400 MHz, DMSO) 84.41 (s, 1H), 3.12 (d, J= 36.1 Hz, 4H), 1.69 - 1.55 (m, 1H), 1.46 (dd, J= 7.4, 4.6 Hz, 2H), 1.38 (s, 10H), 1.05 (s, 3H). Docket No.: PAT059786-WO-PCT

[0404]

[0312] Step 2: To a 0 °C stirred solution of tert-butyl (R)-3 -hydroxy-3 -methylpiperidine- 1- carboxylate (6.000 g, 1 Eq, 27.87 mmol) in tetrahydrofuran (100.000 mL) was added sodium hydride (3.344 g, 60% Wt, 3 Eq, 83.61 mmol) portion-wise. Mixture was stirred for 15 min at 0°C, followed by dropwise addition of iodomethane (11.87 g, 5.228 mL, 3 Eq, 83.61 mmol). The mixture was warmed to room temperature and stirred for 16h. Reaction was monitored using TLC (10% MeOH / DCM, KMnO4 stain). Mixture was quenched with sat NH4Q (aq) and then extracted with DCM (3x). The combined organic extracts were dried over sodium sulfate and concentrated. Crude residue was purified by silica gel column with 0.1-30% EtOAc / Hep for 20 column volumes using 214 nm detection to afford desired compound tert-butyl (R)-3-methoxy-3- methylpiperidine-1 -carboxylate (4.000g, 91% purity, 57% yield) as a clear oil.JH NMR (400 MHz, DMSO) 8 3.64 (dt, J = 13.6, 1.6 Hz, 2H), 3.09 (s, 3H), 2.82 (d, J= 13.0 Hz, 2H), 1.71 - 1.50 (m, 2H), 1.39 (s, 11H), 1.03 (s, 3H).

[0405]

[0313] Step 3: To tert-butyl (R)-3-methoxy-3-methylpiperidine-l-carboxylate (4.000 g, 1 Eq, 17.44 mmol) was added HC1 in dioxane (3.646 g, 25.000 mL, 4.000 molar, 5.733 Eq, 100.00 mmol). Mixture was stirred at room temperature for Ih and then concentrated to afford desired compound (R)-3-methoxy-3 -methylpiperidine, AA - Hydrochloride (2.860g, 95% purity, 94% yield) as a white solid. 'H NMR (400 MHz, MeOD) 8 3.24 (s, 4H), 3.23 - 3.16 (m, IH), 2.97 - 2.83 (m, 2H), 2.07 (ddtd, J= 14.4, 4.2, 2.8, 1.5 Hz, IH), 1.90 (dtdd, J= 14.4, 13.3, 4.5, 3.8 Hz, IH), 1.77 - 1.67 (m, IH), 1.49 (ddd, J= 14.5, 13.3, 4.3 Hz, IH), 1.21 (s, 3H).

[0406] Docket No.: PAT059786-WO-PCT

[0407] Example 17 - Preparation of Intermediate 2-((tert-butoxycarbonyl)amino)-2-(3-fluoro- l -methyl- lH-pyrazol-4-yl)acetic acid

[0408]

[0314] Step 1 : To a solution of ethyl 2-((diphenylmethylene)amino)acetate (1.25 g, 4.68 mmol) 4-bromo-3-fluoro-l-methyl-lH-pyrazole (0.92 g, 5.14 mmol) in Toluene (30 mL) was added K3PO4 (2.98 g, 14.03 mmol) and Pd(t-BusP)2 (0.24 g, 0.468 mmol) at 25°C under N2. Then the mixture was stirred at 100°C for 16 h. LCMS showed desired mass was detected. The reaction mixture was poured into H2O (50 mL) and the aqueous layer was extracted with EA (50mL*3). The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) then concentrated to afford ethyl 2-((diphenylmethylene)amino)-2-(3-fluoro-l-methyl-lH-pyrazol-4-yl)acetate (250 mg, 60% purity) as a yellow oil. LCMS m / z [M+H]+= 366.0.

[0409]

[0315] Step 2: To a solution of ethyl 2-((diphenylmethylene)amino)-2-(3-fluoro-l-methyl-lH- pyrazol-4-yl)acetate (250 mg, 0.41 mmol, 60% purity) in dioxane (2 mL) was added 4M HCl / dioxane (2 mL). The resulting mixture was stirred at 25°C for 4 h. LCMS showed desired mass was detected. The mixture was added H2O (4 mL) and then extracted with PE (4 mL*3), The aqueous phase (0.41 mmol, in H2O (4 mL)) was taken to the next step without further purification. The combined organic phase was discarded. LCMS m / z [M+H]+= 202.1.

[0410]

[0316] Step 3: To a mixture of ethyl 2-amino-2-(3-fluoro-l-methyl-lH-pyrazol-4-yl)acetate (0.41 mmol, in H2O (4 mL)) in THF (4 mL) was added NaHCCh (345 mg, 4.10 mmol) and BOC2O Docket No.: PAT059786-WO-PCT

[0411] (179 mg, 0.82 mmol). The resulting mixture was stirred at 25°C for 16 h. LCMS showed desired mass was detected. The mixture was extracted with EA (15 mL*3). The combined organic was dried over anhydrous Na2SO4, filtered, and concentrated to give ethyl 2-((tert- butoxycarbonyl)amino)-2-(3-fluoro-l-methyl-lH-pyrazol-4-yl)acetate (200 mg, crude) as yellow oil. LCMS m / z [M-55]+= 246.2.

[0412]

[0317] Step 4: A solution of ethyl 2-((tert-butoxycarbonyl)amino)-2-(3-fluoro-l-methyl-lH- pyrazol-4-yl)acetate (200 mg, Crude) in THF / MeOH / 4M NaOH=2: 1 : 1 (4 m ) was stirred at 40°C for 1 h. LCMS showed desired mass was detected. The reaction mixture was concentrated to give the residue. The residue was added H2O (4 mL) and extracted with PE (4 mL*3), The aqueous phase was adjusted PH~5 with IN HC1 and extracted with EA (5 mL*3). The combined organic was dried over anhydrous Na2SO4, filtered, and concentrated to give 2-((tert- butoxycarbonyl)amino)-2-(3-fluoro-l-methyl-lH-pyrazol-4-yl)acetic acid (110 mg, crude) as yellow gum.

[0413] Example 18 - Preparation of Compound 6

[0414]

[0318] Step 1: A solution of (S)-2,4-dichloro-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazoline (100 mg, 0.32 mmol), (7?)-l-(l-methyl-lH-pyrazol-4-yl)-2-((5)-3-methylpiperidin-l-yl)ethan-l- amine dihydrochloride (105 mg, 0.35 mmol) and DIPEA (225 pl, 15.86 mmol) in MeCN (Volume: 1.6 mL) was stirred at 70 °C for 3 h. MeCN was removed under reduced pressure then the residue was extracted with EtOAc / water. The combined organic layer was washed with Docket No.: PAT059786-WO-PCT brine, dried over Na2SO4 and concentrated. The residue was purified through flash column chromatography (0-20% MeOH (0.1 N NH3) / DCM) to (S)-2-chloro-6-methoxy-N-((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l -yl)ethyl)-6-phenyl-5, 6,7,8- tetrahydroquinazolin-4-amine as a light pale solid (70 mg, 43%). MS: m / z = 495.4 [M+H]+.

[0415]

[0319] Step 2: A solution of (S)-2-chloro-6-methoxy-N-((R)-l-(l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)-6-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine (70 mg, 0.14 mmol), methyl (lR,4r)-4-((R)-l-(methylamino)propyl)cyclohexane-l-carboxylate hydrochloride (141 mg, 0.56 mmol) in MeCN (0.15 mL) and 2,2,2-Trifluoroethanol (0.15 mb) was heated at 140 °C in a micro wave reactor for 6 days. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated. The residue was purified through flash column chromatography (0-20% MeOH(0.1 N NH3) / DCM) to give of methyl (lR,4r)-4-((R)-l-(((S)-6- methoxy-4-(((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 -methylpiperidin- 1 -yl)ethyl)amino)-6- phenyl-5, 6, 7, 8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylate as a light pale solid (20 mg, 21%). MS: m / z = 672.5 [M+H]+.

[0416]

[0320] Step 3: To a solution of methyl (lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (20 mg, 0.03 mmol) in THF (0.2 mL) and MeOH (0.1 mL) was added NaOH (4N aq solution) (37 uL, 0.15 mmol). The resulting sulotion was stirred at 50 °C for 30 min then solvent was removed under reduced pressure then diluted with DMSO. The suspension was purified by Prep HPLC. (15-50% MeCN / water, with 10 mM NH4OH as modifier). The pure fractions was combined and lyophilization drying gave (lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4- yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid sodium salt as a white solid (6 mg, 29%). MS: m / z = 658.5 [M+H]+;1HNMR (400 MHz CD3OD) 8 7.48 - 7.37 (m, 3H), 7.35 - 7.26 (m, 3H), 7.22-7.19 (m, 1H), 5.43 (s, 1H), 4.40 (s, 1H), 3.77 (s, 3H), 2.96 (s, 3H), 2.94 - 2.82 (m, 2H), 2.78 (s, 4H), 2.74 - 2.58 (m, 4H), 2.56-2.42 (m, 1H), 2.41-2.30 (m, 1H), 2.26-2.13 (m, 1H), 2.06-1.65 (m, 7H), 1.63-1.49 (m, 3H), 1.47-1.06 (m, 6H), 0.92-0.77 (m, 2H), 0.76 (d, J= 12.7, Hz, 3H), 0.69 (t, J= 7.2 Hz, 3H), 0.60-0.38(m, 1H).

[0417]

[0321] The following compounds , including the title compound, were made using the above procedure or modifications to the above procedure using the corresponding intermediates. Docket No.: PAT059786-WO-PCT

[0418] Table 2 Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT

[0419] Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT

[0420] Example 19- Preparation of Intermediate methyl (lR,4r)-4-((R)-l-(l- methyl yuanidinojpropyl (cyclohexane- 1 -carboxylate

[0421]

[0322] Step 1: To a solution of methyl (lR,4r)-4-((R)-l-(methylamino)propyl)cyclohexane-l- carboxylate (10.00 g, 1 Eq, 46.88 mmol) and l,3-Bis(tert-butoxycarbonyl)-2-methylisothiourea (17.02 g, 1.25 Eq, 58.60 mmol) in MeCN (100.0 mL) was added Et3N (15.65 g, 21.6 mL, 3.3 Eq, 154.7 mmol) and Silver carbonate (12.93 g, 2.13 mL, 1 Eq, 46.88 mmol). Then the reaction mixture was stirred at 30°C for 12h. LCMS showed a major peak of desired mass and TLC (PE:EA=5:1) showed a new spot (Rf=0.6) formed. The reaction mixture was filtered off and the filtered was washed with EA (300 mL) and DCM (100 mL) then the filtrate was concentrated to give a residue.

[0422]

[0323] The residue was purified by flash silica gel chromatography (ISCO®; 300 g SepaFlash® Silica Flash Column, Eluent of EA:PE=0%~20%) and concentrated to afford: methyl (lR,4r)-4- ((R)- 1 -((E)-2, 3 -bis(tert-butoxy carbonyl)- 1 -methylguanidino)propyl)cyclohexane- 1 -carboxylate (17.00 g, 34 mmol, 73 %, 92% Purity) as white oil which was determined by HNMR and LCMS.

[0423]

[0324] LCMS: Rt =0.502 mm, [M+H]+ = 456.3, H NMR (400 MHz, CHLOROFORM-d) 8 = 10.17 (br s, 1H), 4.51 (br s, 1H), 3.65 (s, 3H), 2.81 (s, 3H), 2.28 - 2.17 (m, 1H), 2.04 - 1.95 (m, 2H), 1.89 - 1.67 (m, 3H), 1.51 - 1.45 (m, 18H), 1.45 - 1.28 (m, 4H), 1.18 - 1.04 (m, 2H), 0.96 - 0.83 (m, 3H)

[0424]

[0325] Step 2: A solution of methyl (lR,4r)-4-((R)-l-((E)-2,3-bis(tert-butoxycarbonyl)-l- methylguanidino)propyl)cyclohexane-l -carboxylate (17.00 g, 1 Eq, 37.31 mmol) in DCM (10.00 mL) was added 2M HCl / diocane (10.9 g, 150 mL, 2.000 molar, 8.04 Eq, 300 mmol) was stirred at 15 °C for 12 h. LCMS showed a major peak of desired mass. The reaction mixture was concentrated under vacuum to remove the solvent to give the product methyl (lR,4r)-4-((R)-l- (l-methylguanidino)propyl)cyclohexane-l -carboxylate, dihydrochloride (16.00 g, 30 mmol, 80 Docket No.: PAT059786-WO-PCT

[0425] %, 61% Purity) as white solid which was used for next step directly. LCMS: Rt=0.445 min, [M+H]+= 256.2,

[0426] Example 20 - Preparation of Compound 50

[0427]

[0326] Step 1: Methyl 8-oxo-l,4-dioxaspiro[4.5]decane-7-carboxylate (4250 mg, 1 Eq, 19.84 mmol) then DBU (4.531 g, 4.486 mL, 1.5 Eq, 29.76 mmol) were added to acetonitrile stock solution containing methyl (lR,4r)-4-((R)-l-(l-methylguanidino)propyl)cyclohexane-l- carboxylate, dihydrochloride (6.947 g, 1.2 Eq, 23.81 mmol). The resulting solution was heated Docket No.: PAT059786-WO-PCT

[0428] 80 °C for 2.5 hr. The reaction mixture was diluted with H2O (100 mL) and extracted with EA (30 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Heptane @ 80 mL / min) to afford methyl (lR,4r)-4-((R)-l-((4-hydroxy-7,8-dihydro-5H-spiro[quinazoline-6,2'-

[0429] [1.3]dioxolan]-2-yl)(methyl)amino)propyl)cyclohexane-l-carboxylate (4.74 g, 10.00 mmol, 51 %, 90% Purity) as a yellow solid. LCMS m / z [M+H]+ = 420.5.

[0430]

[0327] Step 2: added at moderate dropwise rate over 5min to 0 °C To a solution of methyl (lR,4r)-4-((R)-l-((4-hydroxy-7,8-dihydro-5H-spiro[quinazoline-6,2'-[l,3]dioxolan]-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (4.650 g, 1 Eq, 11.08 mmol) and DIPEA (3.725 g, 5.02 mL, 2.6 Eq, 28.82 mmol) in DCM (55.42 mL). was added IM triflicanhydride in DCM (7.818 g, 27.71 mL, 1.000 molar, 2.5 Eq, 27.71 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 hr. The solution was concentrated and the residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Heptane @ 80 mL / min) to afford methyl (lR,4r)-4-((R)-l-(methyl(4- (((trifhioromethyl)sulfonyl)oxy)-7,8-dihydro-5H-spiro[quinazoline-6,2'-[l,3]dioxolan]-2- yl)amino)propyl)cyclohexane-l -carboxylate (4.50 g, 7.3 mmol, 66 %, 90% Purity) as a white solid. LCMS m / z [M+H]+= 552.4.

[0431]

[0328] Step 3: DMAP (174.4 mg, 0.15 Eq, 1.428 mmol) then DIPEA (4.921 g, 6.63 mL, 4.0 Eq, 38.07 mmol) added to RB flask charged with methyl (lR,4r)-4-((R)-l-(methyl(4- (((trifluoromethyl)sulfonyl)oxy)-7,8-dihydro-5H-spiro[quinazohne-6,2'-[l,3]dioxolan]-2- yl)amino)propyl)cyclohexane-l -carboxylate (5.250 g, 1 Eq, 9.518 mmol) and (R)-l-(l-methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethan-l -amine (2.328 g, 1.1 Eq, 10.47 mmol) in Acetonitrile (47.59 mL). Reaction mixture was stirred at 70 °C o / n.

[0432]

[0329] The reaction mixture was cooled to rt and purified by reverse-phase flash column chromatography to yield methyl (lR,4r)-4-((R)-l-(methyl(4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)- 2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-7,8-dihydro-5H-spiro[quinazoline-6,2'-

[0433] [1.3]dioxolan]-2-yl)amino)propyl)cyclohexane-l-carboxylate (2.670 g, 4.280 mmol, 44.97 %). LCMS m / z [M+H]+= 624.6.

[0434]

[0330] Step 4: Formic Acid (38.471 mL) added to RB flask, methyl (lR,4r)-4-((R)-l-(methyl(4- (((R)-l -(1 -methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-7,8-dihydro-5H- Docket No.: PAT059786-WO-PCT spiro[quinazoline-6,2'-[l,3]dioxolan]-2-yl)amino)propyl)cyclohexane-l -carboxylate (2400.00 mg, 1 Eq, 3.8471 mmol). Reaction mixture was heated at 45 °C for 16h. Reaction mixture was concentrated in vacuo to ca. 10ml. The liquor was then slowly added to a stirred solution of aqueous sodium bicarbonate and extracted into DCM x3. The combined organic layers were dried over magnesium sulfate, filter and concentrated to give methyl (lR,4r)-4-((R)-l-(methyl(4- (((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-oxo-5,6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l -carboxylate formate salt as a brown oil in quant. Yield. LCMS m / z [M+H]+= 580.5.

[0435]

[0331] Step 5: Under nitrogen, methyl (lR,4r)-4-((R)-l-(methyl(4-(((R)-l-(l-methyl-lH- pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-oxo-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane-l -carboxylate formate (50.00 mg, 1.000 Eq, 79.90 pmol) was dissolved in THF (1.000 mL), followed by lanthanum(III) dilithium chloride 0.6M in THF (31.64 mg, 159.8 pL, 0.600 molar, 1.200 Eq, 95.87 pmol). Reaction was stirred for 1 hour at 23 °C. Then cooled to 0 °C and slowly added cyclohexylmagnesium chloride (34.25 mg, 239.7 pL, 1.000 molar, 3.000 Eq, 239.7 pmol). The reaction mixture was kept stirring at 0 °C for 20 hour while warming up to 23 °C. At 0 °C added more cyclohexylmagnesium chloride (34.25 mg, 239.7 pL, 1.000 molar, 3.000 Eq, 239.7 pmol) and stirred for another 20 hour at 23 °C. The reaction mixture was quenched with saturated NH4Q (5 mL) and extracted with EA (5 mL*3). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to afford 277 mg crude methyl (lR,4r)-4-((lR)-l-((6-cyclohexyl-6-hydroxy-4- (((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylate as a dark brown solid. MS m / z (M+H)+664.6. Material was used as crude in the next step without further purification.

[0436]

[0332] Step 6: LiOH (69.94 mg, 2.9204 mL, 1.000 molar, 7.000 Eq, 2.9204 mmol) was added to a solution of crude methyl (lR,4r)-4-((lR)-l-((6-cyclohexyl-6-hydroxy-4-(((R)-l-(l-methyl-lH- pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (277.00 mg, 1.000 Eq, 417.20 pmol) in MeOH (500.0 pL) / THF (500.0 pL) / Water (500.0 pL). Reaction stirred at 23 °C for 2 hour. The reaction mixture was concentrated under reduced pressure. The dark red, milky emulsion was diluted with some MeOH before loading onto a Celite containing cartridge and then purified by Docket No.: PAT059786-WO-PCT

[0437] Cl 8 RP ISCO. Purified by reverse-phase chromatography (50 g C-18 column, 25-60 % acetonitrile / H2O + 0.1 % ammonium hydroxide). Combined product-containing fractions and lyophilized. Desired isomer (lR,4r)-4-((lR)-l-((6-cyclohexyl-6-hydroxy-4-(((R)-l-(l-methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid was isolated as first peak and dried under lyophilization to afford a white solid. LC / MS Product Analysis-Basic: Rt = 1.83 min., LCMS m / z [M+H]+= 650.6, 'H NMR (400 MHz, MeOD) 8 8.45 (s, 1H), 7.33 (d, J= 35.3 Hz, 2H), 3.75 (s, 3H), 2.90 - 2.70 (m, 4H), 2.68 (s, 3H), 2.57 (dd, J= 12.7, 5.7 Hz, 1H), 2.41 (d, J = 18.0 Hz, 1H), 2.36 - 2.14 (m, 2H), 1.95 - 1.80 (m, 6H), 1.78 - 1.66 (m, 7H), 1.66 - 1.55 (m, 6H), 1.53 - 1.39 (m, 3H), 1.36 - 1.26 (m, 4H), 1.23 - 1.14 (m, 4H), 1.14 - 1.02 (m, 3H), 0.78 (d, J= 6.2 Hz, 3H), 0.61 (t, J= 7.2 Hz, 3H)

[0438]

[0333] The following compounds , including the title compound, were made using the above procedure or modifications to the above procedure using the corresponding intermediates. Table 3 Docket No.: PAT059786-WO-PCT

[0439] Example 21 - Preparation of intermediate methyl (lR,4r)-4-((lR)-l-((4-hydroxy-6-

[0440] (methylsulfonyl)-6-phenyl-5.6.7.8-tetrahydroquinazolin-2- yl ((methyl (amino (propyl (cyclohexane- 1 -carboxylate Docket No.: PAT059786-WO-PCT

[0441]

[0334] Step 1: ((methylsulfonyl)methyl)benzene (250.0 mg, 1 Eq, 1.469 mmol) in dry THF (15.00 mL) was treated with methyl acrylate (379.3 mg, 399 pL, 3 Eq, 4.406 mmol) and then dropwise with potassium tert-butoxide in THF (181.3 mg, 1.615 mL, 1.000 molar, 1.1 Eq, 1.615 mmol)and was stirred at r.t following by tlc / lcms. added ethyl acetate (x2) and water, then acidified to pH =5, the organics were washed with brine and combined, dried (MgSO4). the crude oil. The residue was chromatographed on the ISCO (12g silica) eluting 0-100% ethyl acetate in heptane, methyl 4-hydroxy-l-(methylsulfonyl)-l,2,5,6-tetrahydro-[l,l'-biphenyl]-3- carboxylate (186.0 mg, 599.3 pmol, 40.81 %) obtained as a colorless oily solid. LCMS m / z [M+H]+= 311.1,

[0442]

[0335] Step 2: methyl 4-hydroxy-l-(methylsulfonyl)-l,2,5,6-tetrahydro-[l,l'-biphenyl]-3- carboxylate (186.0 mg, 1 Eq, 599.3 pmol) and methyl (lR,4r)-4-((R)-l-(l- methylguanidino)propyl)cyclohexane-l -carboxylate hydrochloride (209.9 mg, 1.2 Eq, 719.2 pmol) were combined in Acetonitrile (1.000 mL) and treated with DBU (365.0 mg, 361.3 pL, 4 Eq, 2.397 mmol) then warmed to 80 °C for 3 hour before cooling to rt, and evaporating to dryness, The residue was chromatographed on the ISCO (12g silica) eluting 50-100% ethyl acetate in heptane, to give as a pale oil methyl (lR,4r)-4-((lR)-l-((4-hydroxy-6- (methylsulfonyl)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (130.0 mg, 252.1 pmol, 42.07 %). LCMS m / z [M+H]+= 516.4.

[0443] Docket No.: PAT059786-WO-PCT

[0444] Example 22 - Prepartion of Intermediate methyl (lR,4r)-4-((lR)-l-((4-hydroxy-5a-phenyl- 5a.6.6a.7-tetrahvdro-5H-cvclopropa[g1quinazolin-2-yl)(methyl)amino)propyl)cvclohexane-l- carboxylate

[0445]

[0336] Stepl: To a solution of l,4-dioxaspiro[4.5]decan-8-one (15.00 g, 1 Eq, 96.04 mmol) in THF (300.00 mL) at 0 °C under N2 was added dropwise a solution of phenyl magnesium chloride (19.72 g, 144.1 mL, 1.000 molar, 1.5 Eq, 144.1 mmol). The reaction mixture was stirred at the same temperature for 1 hour before allowed to warm to rt. The mixture was stirred at rt for overnight. Saturated NH4C1 (aq) (40 ml) was added and extracted with ethyl acetate (40 ml x 2). The organic phases were collected, dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by ISCO eluted by 0-100% ethyl acetate in heptane to give 8-phenyl-l,4-dioxaspiro[4.5]decan-8-ol (16.00 g, 68.29 mmol, 71.10 %). (400 MHz, CDCh) 8 7.55 (d, J= 7.8 Hz, 2H), 7.37 (t, J= 7.6 Hz, 2H), 7.29 (t, J= 3.7 Hz, 1H), 4.10 - 3.88 (m, 4H), 2.33 - 1.91 (m, 4H), 1.91 - 1.43 (m, 4H).

[0446]

[0337] Step 2: 8-phenyl-l,4-dioxaspiro[4.5]decan-8-ol (16.00 g, 68.29 mmol, mixed with Ethyleneglycol (826.5 mg, 742.6 pL, 1 Eq, 13.32 mmol) and p-Toluene sulfonic acid monohydrate (126.6 mg, 102 pL, 0.05 Eq, 665.8 pmol) in Toluene (50.00 mL) was heated under reflux while azeotropically removing water with a Dean-Stark apparatus. After refluxing overnight, the Docket No.: PAT059786-WO-PCT mixture was cooled to room temperature and evaporated to dryness. The crude product was purified by ISCO eluted by 0-100% ethyl acetate in heptane to give 8-phenyl-l,4- dioxaspiro[4.5]dec-7-ene (1.800 g, 8.323 mmol, 62.50 %) as colorless oil.

[0447] 'H NMR (400 MHz, CDC13) 87.32 (dd, J = 7.8, 1.9 Hz, 2H), 7.23 (dd, J = 8.4, 6.6 Hz, 2H), 7.18 - 7.11 (m, 1H), 5.91 (td, J = 4.0, 2.0 Hz, 1H), 3.96 (s, 4H), 2.60 (tt, J = 6.5, 2.1 Hz, 2H), 2.41 (dd, J = 4.0, 2.3 Hz, 2H), 1.86 (t, J = 6.6 Hz, 2H).

[0448]

[0338] Step 3: To a solution 8-phenyl-l,4-dioxaspiro[4.5]dec-7-ene (1.410 g, 1 Eq, 6.519 mmol) and methylene iodide (5.238 g, 1.576 mL, 3 Eq, 19.56 mmol) in DCM (10.000 mL) was added diethylzinc (1.610 g, 13.04 mL, 1.000 molar, 2 Eq, 13.04 mmol) at 0 °C. The reaction mixture was allowed to warm to rt and stir for 16 h. Saturated (aq) sodium bicarbonate (10 ml) was added. The mixture was extracted with ethyl acetate (10 ml x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated dryness. The residue was purified by ISCO eluted by 0-60% ethyl acetate in heptane to give 6-phenylspiro [bicyclo [4.1.0]heptane-3,2'- [l,3]dioxolane] (1.270 g, 5.514 mmol, 84.58 %). MS m / z = 231.4 [M+H]+.

[0449]

[0339] Step 4: To a solution of 6-phenylspiro[bicyclo[4.1.0]heptane-3,2'-[l,3]dioxolane] (1.270 g, 1 Eq, 5.514 mmol) in THF (2.000 mL) was added HC1 (aq) 37% (875.0 mg, 2.000 mL, 12.000 molar, 4.352 Eq, 24.00 mmol). Then the reaction mixture was stirred at rt for 4 h. The reaction mixture was treated with ethyl acetate (30mL) / water (20 ml). The organic phase was collected, dried over anhydrous MgSO4 and evaporated to dryness. The crude product was purified by ISCO eluted by 0-100% ethyl acetate in heptane to give 6-phenylbicyclo[4.1.0]heptan-3-one (900.00 mg, 4.8322 mmol, 87.63 %). 'H NMR (400 MHz, CDCh) 8 7.40 - 7.31 (m, 4H), 7.24 (tt, J= 5.9, 2.8 Hz, 1H), 2.89 (dd, J= 18.5, 5.1 Hz, 1H), 2.71 (dd, J= 18.6, 2.5 Hz, 1H), 2.56 - 2.40 (m, 2H), 2.35 - 2.19 (m, 2H), 1.63 - 1.48 (m, 2H), 1.18 - 0.98 (m, 2H).

[0450]

[0340] Step 5: To a stirred solution of 6-phenylbicyclo [4.1.0]heptan-3-one (744.0 mg, 1 Eq, 3.995 mmol) in THF (3.995 mL) at rt, sodium hydride (263.6 mg, 60% Wt, 1.65 Eq, 6.591 mmol) was added portions dropwise. The resulting mixture was warmed to 80 °C and then the solution of diethyl carbonate (2.359 g, 5 Eq, 19.97 mmol) in THF (998.7 pL) was added dropwise. The reaction mixture was then stirred at 80 °C for 3 hours. Light brown solution became darker throughout reaction time. The reaction mixture was cooled to rt, then quenched with saturated NH4Q (20 mL) at rt and extracted with EA (20 mLx2). The combined organic phase was washed with brine (50 mL), Docket No.: PAT059786-WO-PCT dried under MgS04, filtered, and concentrated in vacuo to give crude as an oil. The residue was purified by ISCO eluted by 0-100% ethyl acetate in heptane to give ethyl 3-oxo-6- phenylbicyclo[4.1.0]heptane-2-carboxylate (822.0 mg, 3.182 mmol, 79.66 %).MS m / z 259. (M+l).

[0451]

[0341] Step 6: To ethyl 3-oxo-6-phenylbicyclo[4.1.0]heptane-2-carboxylate (822.0 mg, 1 Eq, 3.182 mmol) was added a solution of methyl (lR,4r)-4-((R)-l-(l-methylguanidino)propyl)cyclohexane-l- carboxylate hydrochloride in acetonitrile (10.000 mL), then l,8-Diazabicyclo[5.4.0]undec-7-ene (1.453 g, 1.428 mL, 3 Eq, 9.546 mmol) at 20° C. After addition, the mixture warmed to 80 °C and stirred at 80 °C for overnight. The reaction mixture evaporated to dryness to give brown oil. Crude was purified by ISCO eluted by 0-100% ethyl acetate in heptane to give methyl (lR,4r)-4-((lR)-l-((4- hydroxy-5a-phenyl-5a, 6,6a, 7-tetrahydro-5H-cyclopropa[g]quin azo lin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (520.0 mg, 1.157 mmol, 36.35 %). MS m / z: 451.1(M+1).

[0452] Example 23 - Preparation of Intermediate methyl (lK4r)-4-((lR)-l-((4-hydroxy-6-methoxy-6- phenyl-6.6a.7.7a-tetrahvdro-5H-cvclopropa[h]quinazolin-2- yl)(methyl)amino)propyl)cvclohexane- 1 -carboxylate

[0453]

[0342] Stepl : A solution of Trimethylsilyl triflate (8.704 g, 7.229 mL, 4 Eq, 39.16 mmol) in DCM (30.00 mL) was added over a 10 min period to a stirred solution of 4-methoxy-4- phenylcyclohexan- 1 -one (2.000 g, 1 Eq, 9.791 mmol) and triethylamine (1.486 g, 2.05 mL, 1.5 Eq, 14.69 mmol) at 0 0C. The mixture was stirred for Ih before the reaction was quenched by the addition of saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, dried, and evaporated under reduced pressure to leave a crude residue. The residue was purified by ISCO eluted by 0-100% ethyl acetate in heptane to give (1-methoxy-l, 2,3,6- tetrahydro-[l,l'-biphenyl]-4-yl)oxy)trimethylsilane (2.200 g, 7.958 mmol, 81.28 %) as a Docket No.: PAT059786-WO-PCT colorless oil. 1H NMR (400 MHz, CDC13) 8 7.27 (dd, J = 7.5, 1.8 Hz, 2H), 7.23 - 7.15 (m, 2H), 7.12 (d, J = 1.5 Hz, OH), 7.10 (s, OH), 7.08 (s, OH), 4.80 - 4.67 (m, 1H), 2.84 (s, 3H), 2.53 - 1.77 (m, 6H), 1.71 - 1.46 (m, 1H), 1.10 (s, 1H), 0.99 (d, J = 11.3 Hz, 1H), 0.87 - 0.62 (m, 1H), -0.00 (s, 10H).

[0454]

[0343] Step 2: Palladium diacetate (2.680 g, 1.5 Eq, 11.94 mmol) was added to ((1-methoxy- l,2,3,6-tetrahydro-[l,l'-biphenyl]-4-yl)oxy)trimethylsilane (2.200 g, 1 Eq, 7.958 mmol) in acetonitrile (30.00 mL) and the mixture was stirred for overnight at room temperature. The solvent was then evaporated under reduced pressure and the black residue was filtered through a pad of silica using EtOAc as the eluent. The filtration was evaporated to dynes. The residue was purified by ISCO eluted by 0-100% in heptane to give l-methoxy-2,3-dihydro-[l,l'-biphenyl]- 4(lH)-one (1.100 g, 5.439 mmol, 68.34 %) a pale-yellow oil. MS m / z = 203.2 [M+H]+.

[0455]

[0344] 1H NMR (400 MHz, CDC13) 87.34 - 7.14 (m, 5H), 6.99 (dd, J = 10.4, 1.0 Hz, 1H), 6.12 (d, J = 10.4 Hz, 1H), 3.06 (s, 3H), 2.58 - 2.41 (m, 1H), 2.40 - 2.19 (m, 1H), 2.19 - 2.01 (m, 2H).

[0456]

[0345] Step 3: To suspension of sodium hydride (239.3 mg, 60% Wt, 1.1 Eq, 5.983 mmol) in DMSO (10.00 mL) was added trimethylsulfoxonium iodide (1.343 g, 98% Wt, 1.1 Eq, 5.983 mmol). After 20 min, a solution of l-methoxy-2,3-dihydro-[l,l'-biphenyl]-4(lH)-one (1.100 g, 1 Eq, 5.439 mmol) in DMSO (4.0 mL) was added dropwise and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with ice water and extracted with EtOAc. The organic phases were combined, dried over Na2SO4 and concentrated under vacuum. The crude mixture was purified by ISCO eluted by 0-100% ethyl acetate in heptane followed by Cl 8 ISCO eluted by 15% -100% MeCN in water modified by 0.1% NH4OH to give 5-methoxy-5-phenylbicyclo[4.1.0]heptan-2-one (590.0 mg, 2.728 mmol, 50.16 %). MS m / z = 217.1 [M+H]+.

[0457]

[0346] Step 4: To a stirred solution of 5-methoxy-5-phenylbicyclo[4.1.0]heptan-2-one (373.70 mg, 1 Eq, 1.7279 mmol) in THF (5.000 mL) at rt, sodium hydride (49.76 mg, 1.2 Eq, 2.0734 mmol) was added portions dropwise. The resulting mixture was cooled ed to 0 °C and then diethyl carbonate (1.0206 g, 5 Eq, 8.6393 mmol) was added dropwise. The reaction mixture was then stirred at 80 °C for 3 hours. Light brown solution became darker throughout reaction time. The reaction mixture was cooled to rt, then quenched with saturated NH4C1 (20 mL) at rt and extracted with EA (20 mLx2). The combined organic phase was washed with brine (50 mL), Docket No.: PAT059786-WO-PCT dried under MgS04, filtered, and concentrated in vacuo to give crude as an oil. The crude residue was purified by ISCO eluted by 0-100% ethyl acetate in heptane to give ethyl 5- methoxy-2-oxo-5-phenylbicyclo[4.1.0]heptane-3-carboxylate (402.0 mg, 1.394 mmol, 80.69 %). MS m / z = 259.1 [M+H]+.

[0458]

[0347] Step 5: To ethyl 5-methoxy-2-oxo-5-phenylbicyclo[4.1.0]heptane-3-carboxylate was added a solution of methyl (lR,4r)-4-((R)-l-(l-methylguanidino)propyl)cyclohexane-l- carboxylate hydrochloride (466.8 mg, 1.02 Eq, 1.422 mmol) in acetonitrile (1.000 mL), then 1,8- diazabicyclo[5.4.0]undec-7-ene (636.8 mg, 625.5 pL, 3 Eq, 4.183 mmol) at 20°C. After addition, the mixture warmed to 80 °C and stirred at 80 °C for overnight. The reaction mixture evaporated to dryness to give brown oil. Crude was purified by ISCO eluted by 0-100% ethyl acetate in heptane to give methyl (lR,4r)-4-((lR)-l-((4-hydroxy-6-methoxy-6-phenyl-6,6a,7,7a-tetrahydro- 5H-cyclopropa[h]quinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (200.0 mg, 417.0 pmol, 29.91 %). MS m / z: 560.3 (M+l)+.

[0459] Docket No.: PAT059786-WO-PCT

[0460] Example 24 - Preparation of Compound 16

[0461]

[0348] Step 1 : To a solution of l,4-dioxaspiro[4.5]decan-8-one (10.00 g, 1 Eq, 64.03 mmol) in THF (100.0 mL) was added (3-fluorophenyl)magnesium bromide (19.14 g, 96.04 mL, 1.000 molar, 1.5 Eq, 96.04 mmol) under N2 at 0 °C. The mixture was stirred atO °C~ 20 °C for 3 Docket No.: PAT059786-WO-PCT hour. TLC (PE:EA=3:1) showed two new spots(Rf=0.4 & 0.1) was formed. The reaction mixture was quenched with saturated NH4Q (200 mL) and extracted with EA (80 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford the residue. The residue was purified by purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ethergradient @ 100 mL / min) and the eluent was concentrated to afford 8-(3-fluorophenyl)-l,4-dioxaspiro[4.5]decan- 8-0I (4.500 g, 14 mmol, 22 %, 80% Purity) as yellow oil.

[0462] 'H NMR (400 MHz, CHLOROFORM-d) 8 = 7.33 - 7.23 (m, 3H), 6.97 - 6.89 (m, 1H), 4.02 - 3.94 (m, 4H), 2.21 - 2.07 (m, 4H), 1.83 - 1.76 (m, 2H), 1.73 - 1.66 (m, 2H).

[0463]

[0349] Step 2: To a solution of 8-(3-fhrorophenyl)-l,4-dioxaspiro[4.5]decan-8-ol (4.000 g, 1 Eq, 15.85 mmol) in DMF (40.000 mL) was added NaH (1.268 g, 60% Wt, 2 Eq, 31.71 mmol) at 0 °C and stirred for 0.5 hour. Mel (6.751 g, 2.974 mL, 3 Eq, 47.56 mmol) was added to the above mixture atO °C. The reaction mixture was stirred at 20 °C for 16 hour. TLC (PE:EA=5:1) showed 1 (Rf=0.2) was consumed and a new spot (Rf=0.4) was formed. The reaction mixture was quenched with saturated NH4CI (150 mL) and extracted with EA (50 mL*3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ethergradient @ 80 mL / min) and the eluent was concentrated to afford 8-(3- fluorophenyl)-8-methoxy-l,4-dioxaspiro[4.5] decane (3.000 g, 11.27 mmol, 71.05 %) as yellow oil. 'H NMR (400 MHz, CHLOROFORM-d) 8 = 7.34 - 7.27 (m, 1H), 7.21 - 7.17 (m, 1H), 7.16 - 7.10 (m, 1H), 7.00 - 6.91 (m, 1H), 4.03 - 3.93 (m, 4H), 3.01 (s, 3H), 2.06 - 1.96 (m, 6H), 1.71 - 1.62 (m, 2H).

[0464]

[0350] Step 3: To a solution of 8-(3-fluorophenyl)-8-methoxy-l,4-dioxaspiro[4.5]decane (3.000 g, 1 Eq, 11.27 mmol)in 1,4-Dioxane (22.00 mL) and Water (11.00 mL) was added dropwise HC1 (4.813 g, 11.00 mL, 12.00 molar, 11.72 Eq, 132.0 mmol). The mixture was stirred at 25 °C for 16 hour. TLC (PE:EA=3: 1) showed 2 (Rf=0.5)was consumed and a new spot (Rf=0.45) was formed. The reaction mixture was combined with previous batch (250 mg scale), then diluted with water (60 mL) and extracted with EtOAc (30 mL*3). The combined organic layer was washed with Sat. NaHCCh solution (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 and concentrated to give crude product 4-(3 -fluor ophenyl)-4-methoxycyclohexan-l -one (2.800 g, 12.60 mmol, 111.8 Docket No.: PAT059786-WO-PCT

[0465] %) as a yellow solid. 'H NMR (400 MHz, CHLOROFORM-d) 8 = 7.40 - 7.32 (m, 1H), 7.22 - 7.17 (m, 1H), 7.17 - 7.12 (m, 1H), 7.04 - 6.97 (m, 1H), 3.11 (s, 3H), 2.84 - 2.71 (m, 2H), 2.45 - 2.29 (m, 4H), 2.17 - 2.05 (m, 2H).

[0466]

[0351] Step 4: To a solution of 4-(3-fluorophenyl)-4-methoxycyclohexan-l-one (crude) (2.400 g, 1 Eq, 10.80 mmol) in THF (24.000 mL) was added LiHMDS (2.168 g, 12.96 mL, 1.000 molar, 1.2 Eq, 12.96 mmol) at -70 °C under N2. After stirring the reaction for i hour at -70 °C, methyl carbonocyanidate (1.010 g, 1.1 Eq, 11.88 mmol) was added to the above mixture. The resulting reaction mixture was stirred at -70 °C for 1 hour. TLC (PE:EA=5:1) showed 3 (Rf=0.3) was consumed and a new spot (Rf=0.5) was formed. The mixture was poured into aq. NH4CI solution (100 mL) and combined with previous batch (100 mg scale), then extracted with EA (30 mL*3). The combined organic was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ethergradient @ 60 mL / min) and the eluent was concentrated to afford methyl 3'-fluoro-4- hydroxy-l-methoxy-l,2,5,6-tetrahydro-[l,l'-biphenyl]-3-carboxylate (1.800 g, 6.422 mmol, 59.47 %) as yellow solid. 'H NMR (400 MHz, CHLOROFORM-d) 8 =12.20 (s, 1H), 7.40 - 7.29 (m, 1H), 7.22 - 7.10 (m, 2H), 7.05 - 6.96 (m, 1H), 3.77 (s, 3H), 3.13 - 3.00 (m, 3H), 2.76 - 2.65 (m, 1H), 2.61 - 2.41 (m, 2H), 2.29 - 2.15 (m, 2H), 2.12 - 2.02 (m, 1H).

[0467]

[0352] Step 5: To a solution of methyl 3'-fluoro-4-hydroxy-l-methoxy-l,2,5,6-tetrahydro-[l,l'- biphenyl] -3 -carboxylate (1.800 g, 1 Eq, 6.422 mmol) and methyl (lR,4r)-4-((R)-l-(l- methylguanidino)propyl)cyclohexane-l -carboxylate, dihydrochloride (2.249 g, 1.2 Eq, 7.706 mmol)in MeCN (18.00 mL) was added DBU (3.911 g, 3.872 mL, 4 Eq, 25.69 mmol). The reaction mixture was stirred at 80 °C for 2 hours. LCMS showed 68% of desired mass was detected. The reaction mixture was combined with previous batch (110 mg scale), then diluted with H2O (100 mL) and extracted with EA (30 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ethergradient @ 80 mL / min) and the eluent was concentrated to afford methyl (lR,4r)-4-((R)-l-(((S)-6-(3-fluorophenyl)-4-hydroxy-6-methoxy-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (2.000 g, 4.080 mmol, 63.54 %, 99.066% Purity) as a yellow. LCMS: Rt = 0.504 mm, [M+H]+= 486.3, 'H NMR (400 MHz, DMSO-d6) 8 Docket No.: PAT059786-WO-PCT

[0468] = 10.78 (s, 1H), 7.50 - 7.37 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.20 - 7.09 (m, 2H), 3.57 (s, 3H), 2.90 (s, 3H), 2.75 (s, 3H), 2.71 - 2.62 (m, 1H), 2.59 - 2.51 (m, 2H), 2.31 - 2.05 (m, 4H), 1.97 - 1.76 (m, 3H), 1.74 - 1.61 (m, 1H), 1.60 - 1.12 (m, 6H), 1.12 - 0.98 (m, 1H), 0.97 - 0.83 (m, 1H), 0.75 - 0.64 (m, 3H).

[0469]

[0353] Step 6: To a solution of methyl (lR,4r)-4-((R)-l-(((S)-6-(3-fluorophenyl)-4-hydroxy-6- methoxy-5, 6, 7, 8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (1.800 g, 1 Eq, 3.707 mmol) in DCM (18.000 mL) was added DIEA (718.6 mg, 969 pL, 1.5 Eq, 5.560 mmol) and Tf20 (1.569 g, 939.3 pL, 1.5 Eq, 5.560 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 3 hours. LCMS showed 96% of desired mass was detected. TLC (PE:EA=5: 1) showed one new spot (Rf=0.5) was formed. The mixture was combined with the 0.2 g batch, then diluted with H2O (100 mL) and extracted with DCM (30 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give a residue.

[0470]

[0354] The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ethergradient @ 80 mL / min) and the eluent was concentrated to give methyl (lR,4r)-4-((lR)-l-((6-(3-fluorophenyl)-6-methoxy-4- (((trifhioromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (2.400 g, 3.886 mmol, 104.8 %) as yellow solid. LCMS: Rt=0.741 mm, [M+H]+= 618.3.

[0471]

[0355] 1HNMR(400 MHz, CHLOROFORM-d) 8 = 7.43 - 7.33 (m, 1H), 7.24 - 7.13 (m, 2H), 7.08 - 6.99 (m, 1H), 3.73 - 3.61 (m, 3H), 3.05 (s, 3H), 3.03 - 2.65 (m, 7H), 2.48 - 2.36 (m, 1H), 2.30 - 2.15 (m, 2H), 2.05 - 2.00 (m, 1H), 1.99 - 1.87 (m, 2H), 1.84 - 1.72 (m, 1H), 1.64 - 1.55 (m, 2H), 1.52 - 1.30 (m, 4H), 1.16 - 1.02 (m, 1H), 1.01 - 0.89 (m, 1H), 0.82 - 0.69 (m, 3H).

[0472]

[0356] Step 7: To a solution of methyl (lR,4r)-4-((lR)-l-((6-(3-fluorophenyl)-6-methoxy-4- (((trifhioromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (200.00 mg, 1 Eq, 323.80 pmol) and (R)-2- ((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)-l-(l -methyl- lH-pyrazol-4-yl)ethan-l -amine (122.57 mg, 1.5 Eq, 485.70 pmol) in MeCN (2.000 mL) was added DIEA (125.55 mg, 169 pL, 3 Eq, 971.41 pmol). The reaction mixture was stirred at 60°C for 16 h. LCMS showed 76% of desired mass was detected. The mixture was diluted with H2O (10 mL), extracted with EA (10 mL*3), washed with brine (10 mL), Then the organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give the residue. The residue was purified by reversed phase column Docket No.: PAT059786-WO-PCT chromatography (80 g of SepaFlash® Spherical Cl 8, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% FA and B for acetonitrile; gradient: B 5 - 90% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) after purification, the aqueous phase was basified by saturated NaHCCh solution (20 mL) to pH=8-9 and extracted with EA (20 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford methyl (lR,4r)-4-((lR)-l-((6-(3-fluorophenyl)-6-methoxy-4-(((R)-2-((3R,5R)-3-methoxy-5- methylpiperidin- 1 -yl)-l -(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-5, 6,7, 8-tetrahydroquinazolin- 2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (170.0 mg, 0.23 mmol, 71 %, 98% Purity) as yellow solid. LCMS: Rt = 0.443 mm, [M+H]+=720.5.

[0473]

[0357] Step 8: 200 mg of methyl (lR,4r)-4-((lR)-l-((6-(3-fluorophenyl)-6-methoxy-4-(((R)-2-

[0474] ((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-5,6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (200.0 mg, 1 Eq, 277.8 pmol) was purified by SFC Separation (Instrument: ACSWH-PREP-SFC-I, Method:, Column: DAICEL CHIRALPAK IG(250mm*50mm,10um), Condition: CO2-

[0475] EtOH(0.1%NH3H2O), Begin B: 35, End B: 35, Gradient Time(min): 10.5, FlowRate(ml / min): 150) and the eluent was concentrated to give peaks of methyl (lR,4r)-4-((R)-l-(((R)-6-(3- fhiorophenyl)-6-methoxy-4-(((R)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)-l-(l -methyl- lH-pyrazol-4-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (90.00 mg, 125 pmol, 45.0 %, 100% Purity) as yellow oil (LCMS: Rt = 0.437 min, [M+H]+= 720.5 and SFC: Rt= 1.978 min, de value: >99%, IG-3-EtOH (DEA)-5-40-3ML-35T.lcm), and methyl (lR,4r)-4-((R)-l-(((S)-6-(3-fluorophenyl)-6- methoxy-4-(((R)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)-l-(l-methyl-lH-pyrazol-4- yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l- carboxylate (80.00 mg, 0.11 mmol, 39 %, 98% Purity) as yellow oil (LCMS: Rt = 0.430 min, [M+H]+= 720.5, 5-95AB_lmin_220&254.1cm, SFC: Rt= 2.099 mm, de value: >98%, IG-3-EtOH (DEA)-5-40-3ML-35T.lcm).

[0476]

[0358] Step 9: To a solution of methyl (lR,4r)-4-((R)-l-(((S)-6-(3-fluorophenyl)-6-methoxy-4- (((R)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)-l-(l-methyl-lH-pyrazol-4- yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l- carboxylate (80.00 mg, 1 Eq, 111.1 pmol) in THF (1.000 mL) and MeOH (0.500 mL) was added NaOH (44.45 mg, 277.8 pL, 4.000 molar, 10 Eq, 1.111 mmol). Then the reaction mixture was Docket No.: PAT059786-WO-PCT stirred at 40°C for 0.5 h. LCMS showed a major peak of desired mass. The mixture was adjust to pH=8 by IM citric acid and then concentrated under vacuum to remove MeOH / THF. The residue was dissolved with EtOH (0.5 mL) to get a mixture. The mixture was purified by reversed phase column chromatography (80 g of SepaFlash® Spherical Cl 8, 20 - 45 pm, 100 A; mobile phase: A for FEO + 0.1% NH3 H2O and B for acetonitrile; gradient: B 5 - 95% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) then lyophilized to afford (lR,4r)-4-((R)-l-(((S)-6-(3-fluorophenyl)-6-methoxy-4-(((R)-2-((3R,5R)-3-methoxy-5- methylpiperidin- 1 -yl)-l -(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-5, 6,7, 8-tetrahydroquinazolin- 2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid (51.84 mg, 73.4 pmol, 66.1 %, 100% Purity) as white solid. LCMS: Rt=0.421 mm, [M+H]+= 706.4, 'H NMR (400 MHz, DMSO-d6) 8 = 7.56 - 7.41 (m, 2H), 7.38 - 7.27 (m, 2H), 7.27 - 7.21 (m, 1H), 7.18 - 7.11 (m, 1H), 6.29 - 6.17 (m, 1H), 5.51 - 5.14 (m, 1H), 4.58 - 4.34 (m, 1H), 3.74 (s, 3H), 3.14 (s, 3H), 2.93 (s, 3H), 2.84 - 2.77 (m, 1H), 2.77 - 2.67 (m, 3H), 2.66 - 2.52 (m, 6H), 2.40 - 2.31 (m, 1H), 2.28 - 2.15 (m, 3H), 1.94 - 1.81 (m, 4H), 1.81 - 1.74 (m, 1H), 1.72 - 1.56 (m, 3H), 1.37 - 1.04 (m, 6H), 0.87 - 0.77 (m, 4H), 0.73 - 0.60 (m, 3H), 0.54 - 0.40 (m, 1H).

[0477]

[0359] The following compounds , including the title compound, were made using the above procedure or modifications to the above procedure using the corresponding intermediates. Table 4 Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT

[0478] Docket No.: PAT059786-WO-PCT

[0479] Example 25 - Preparation of Compound 74

[0480]

[0360] Step 1 : 2-phenylacetic acid (6.126 g, 1 Eq, 44.99 mmol) was suspended in tert Butyl acetate (40.000 mL). The reaction mixture was cooled to 0-5°C using an ice bath. Perchloric acid 70% (12.91 g, 8.974 mL, 70% Wt, 2 Eq, 89.99 mmol) was added dropwise within 14 min keeping the temperature below 8°C. The reaction mixture stirred at 0-5°C for 1 h and then allowed to warm to rt and was continued at rt for 3 h. The reaction mixture was carefully poured into ice cold sat. aq NaHCCh solution. The pH was adjusted to 11 using NaOH (6M). The solution was transferred into a separation funnel and was extracted twice with ethyl acetate and twice with DCM. The combined organics were washed with NaOH (2M), dried over Na2SO4, filtered, evaporated off and dried to give tert-butyl 2-phenylacetate (3.500 g, 18.20 mmol, 41%). Docket No.: PAT059786-WO-PCT

[0481] 1H NMR (400 MHz, CDC13) 8 7.40 - 7.29 (m, 3H), 7.29 - 7.17 (m, 2H), 3.55 (s, 2H), 1.46 (s, 9H).

[0482]

[0361] Step 2: tert-butyl 2-phenylacetate (3.500 g, 1 Eq, 18.20 mmol) and methyl acrylate (3.448 g, 3.6 mL, 2.2 Eq, 40.05 mmol) were dissolved in THF (20.00 mL) of THF (0.33M) in a round bottom. The potassium 2-methylpropan-2-olate (2.451 g, 1.2 Eq, 21.85 mmol) in THF was added with stirring) and the reaction mixture is allowed to stir for 1 h at room temperature. The reaction mixture was treated with water (50 ml) and extracted with ethyl acetate (40 mlx3). The organic layers were combined, dried with Na2SO4 and concentrated in Vacuo to give 1 -(tert- butyl) 3-methyl 4-oxo-l-phenylcyclohexane-l,3-dicarboxylate (3.400 g, 10.23 mmol, 56%). MS m / z = 331.4 [M-H]-.

[0483]

[0362] Step 3: To a solution ofl -(tert-butyl) 3-methyl 4-oxo-l-phenylcyclohexane-l,3- dicarboxylate (2.300 g, 1 Eq, 6.919 mmol) in acetonitrile (10.00 mL) methyl (lR,4r)-4-((R)-l-(l- methylguanidino)propyl)cyclohexane-l -carboxy late hydrochloride (2.423 g, 16.12 mL, 1.2 Eq, 8.303 mmol) and then DBU (4.214 g, 4.139 mL, 4 Eq, 27.68 mmol)at 20°C. After addition, the mixture was stirred at 80°C for 16 h. LC-MS showed the most of start materials was converted into the desired product. The reaction mixture was evaporated to dryness. The crude product was purified by ISCO eluted by 0-100% ethyl acetate in heptane to give tert-butyl 4-hydroxy-2-(((R)- l-((lr,4R)-4-(methoxycarbonyl)cyclohexyl)propyl)(methyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazoline-6-carboxylate (1.83 g, 52%). MS m / z = 538.4 [M+H]+.

[0484]

[0363] Step 4: To a solution of tert-butyl 4-hydroxy-2-(((R)-l-((lr,4R)-4- (methoxycarbonyl)cyclohexyl)propyl)(methyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-6- carboxylate (967.0 mg, 1 Eq, 1.798 mmol) and triethylamine (727.9 mg, 1.00 mL, 4 Eq, 7.194 mmol) in DCM (2.000 mL)) was drop wise added trifluoromethanesulfonic anhydride (2.030 g, 7.194 mL, 1.000 molar, 4 Eq, 7.194 mmol)at 0 oC (ice bath) . The reaction mixture was stirred at 0 oC for Ih. The reaction mixture was evaporated to dryness and the crude product was purified by ISCO eluted by 0-100% ethyl acetate in heptane to give tert-butyl 2-(((R)-l-((lr,4R)-4- (methoxycarbonyl)cyclohexyl)propyl)(methyl)amino)-6-phenyl-4- (((trifhioromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydroquinazoline-6-carboxylate (0.67 g, 1.0 mmol, 56%) as oil. MS m / z = 670.4 [M+H]+.

[0485]

[0364] Step 5 : (R)- 1 -( 1 -methyl- 1 H-pyrazol-4-y l)-N2,N2-dipropylethane- 1 ,2-diamine (381.9 mg, 1.5 Eq, 1.718 mmol tert-butyl 2-(((R)-l-((lr,4R)-4- Docket No.: PAT059786-WO-PCT

[0486] (methoxy carbonyl)cyclohexyl)propyl)(methyl)amino)-6-phenyl-4- (((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydroquinazoline-6-carboxylate (767.0 mg, 1 Eq, 1.145 mmol), DMAP (27.98 mg, 0.2 Eq, 229.0 pmol) and DIPEA (592.1 mg, 798 pL, 4.0 Eq, 4.581 mmol) were dissolved in MeCN (4.000 mL) in a 20.0 mL vial equipped with a stir-bar. The reaction was heated to 80 oC overnight. LCMS showed the desired product as major peak. The reaction mixture was evaporated to dryness, re-dissolved in 5 ml of DCM and loaded into 24 g ISCO eluted by 0-100% ethyl acetate / ethanol (3:l / v:v) in heptane to give tert-butyl (S)-2-(((R)- l-((lr,4R)-4-(methoxycarbonyl)cyclohexyl)propyl)(methyl)amino)-4-(((R)-l-(l -methyl- 1H- pyrazol-4-yl)-2-((RS)-3-methylpiperidin-l -yl)ethyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazoline-6-carboxylate (0.57 g, 0.77 mmol, 67%). MS m / z = 742.4 [M+H]+.

[0487]

[0365] Step 6: tert-butyl (S)-2-(((R)-l-((lr,4R)-4- (methoxycarbonyl)cyclohexyl)propyl)(methyl)amino)-4-(((R)-l-(l -methyl- lH-pyrazol-4-yl)-2- ((RS)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-6- carboxylate (100.0 mg, 1 Eq, 134.8 pmol), and 2,2,2-trifluoroacetic acid (15.37 mg, 1.000 mL, 1 Eq, 134.8 pmol) were mixed in DCM (2.000 mL). The mixture was stirred at rt for 3h. The mixture was evaporated and the residue was purified through reverse phase flash column chromatography (Prep HPLC Column: Long Column Switching Dimensions: 30 mm x 100 mm 5 pm, Flow Rate: 75.0 ml / min, 15-40% Solvent: A2 Water+lOmM NH4OH, Solvent: B2 ACN+lOmM NH4OH Wavelength 1 : 214nm and 254 nm) to afford two isomers. Desired fraction was dried with lyophilization to afford 2-(((R)-l-((lr,4R)-4- (methoxycarbonyl)cyclohexyl)propyl)(methyl)amino)-4-(((R)-l-(l -methyl- lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxylic acid as a white solid. LCMS m / z [M+H]+= 686.6, 1H NMR (400 MHz, MeOD) 8 7.56 (s, 1H), 7.54 - 7.37 (m, 3H), 7.31 (t, J = 7.6 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 5.52 (s, 1H), 4.54 (d, J = 50.3 Hz, 1H), 3.87 (s, 3H), 3.66 (s, 3H), 2.87 (s, 8H), 2.75 - 2.46 (m, 3H), 2.46 - 2.10 (m, 3H), 2.10 - 1.64 (m, 9H), 1.64 - 1.17 (m, 5H), 0.92 (d, J = 6.4 Hz, 6H), 0.79 (t, J = 7.3 Hz, 3H), 0.55 (d, J = 13.7 Hz, 1H). Docket No.: PAT059786-WO-PCT

[0488] Example 26 - Preparation of Compound 56

[0489]

[0366] Step 1: To a solution of 2-(((R)-l-((lr,4R)-4- (methoxycarbonyl)cyclohexyl)propyl)(methyl)amino)-4-(((R)-l-(l -methyl- lH-pyrazol-4-yl)-2- ((RS)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxylic acid (150.0 mg, 1 Eq, 218.7 pmol) in DCM (2.000 mL) were added slowly oxalyl dichloride (277.6 mg, 188 pL, 10 Eq, 2.187 mmol), followed by a catalytic amount of DMF (1 drop) at rt. After stirring for 1 h, the reaction mixture was evaporated to dryness. The residue was redissolved in 2 ml of DCM and acetyl hydrazine (32.40 mg, 2 Eq, 437.4 pmol) and triethylamine (44.26 mg, 60 pL, 2 Eq, 437.4 pmol) were added. After the resultant reaction mixture was stirred at rt for 1 h. LC-MS showed the starting material was converted into the desired product. The reaction mixture was evaporated to dryness and purified by ISCO eluted by 0-100% ethyl acetate / ethanol (3:l / v:v) in heptane to give diastereomer mixture of methyl (lR,4r)-4-((lR)-l-((6-(2- acetylhydrazine- 1 -carbonyl)-4-(((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2-((RS)-3 -methylpiperidin- 1 - yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylate (70.00 mg, 94.34 pmol, 43%). MS m / z = 742.6 [M+H]+.

[0490]

[0367] Step 2: To a stirring solution of methyl (lR,4r)-4-((lR)-l-((6-(2-acetylhydrazine-l- carbonyl)-4-(((R)-l -(1 -methyl- lH-pyrazol-4-yl)-2-((RS)-3-methylpiperidin- 1 -yl)ethyl)amino)-6- Docket No.: PAT059786-WO-PCT phenyl-5, 6, 7, 8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (70.00 mg, 1 Eq, 94.34 pmol) in DCM (5 mL) was added TsCl (71.94 mg, 4 Eq, 377.4 pmol), followed by triethylamine (38.19 mg, 53 pL, 4 Eq, 377.4 pmol). The mixture was stirred at 30 °C for 30 min. The reaction mixture was evaporated to dryness and the crude product was purified by ISCO eluted by 0-100% ethyl acetate / ethanol (v:v / 3: 1) in heptane to give methyl (lR,4r)-4- ((lR)-l-(methyl(6-(5-methyl-l,3,4-oxadiazol-2-yl)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2- ((RS)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylate (38.00 mg, 52.49 pmol, 56%). MS m / z = 724.5 [M+H]+.

[0491]

[0368] Step 3: To a 5 mL vial containing rac-methyl (lR,4r)-4-((lR)-l-(methyl(6-(5-methyl- l,3,4-oxadiazol-2-yl)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l- yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l- carboxylate (25.000 mg, 1 Eq, 34.532 pmol) dissolved in a mixture of THF (1000.0 pL) and MeOH (500.00 pL) was added 4M NaOH (13.81 mg, 345.32 pL, 1.000 molar, 10 Eq, 345.32 pmol). The reaction mixture was heated to 50 oC for Ih. LCMS showed that reaction was complete and mixture combined with previous batch. The reaction mixture was cooled to room temp and concentrated to remove THF. The remaining solution was diluted with water and ACN and purified via reverse phase flash column chromatography (Prep HPLC Column: Long Column Switching Dimensions: 30 mm x 100 mm 5 pm, Flow Rate: 75.0 ml / min, 15-40% Solvent: A2 Water+10mM NH4OH, Solvent: B2 ACN+10mM NH4OH Wavelength 1 : 214nm and 254 nm) to afford two isomers. Desired peak fraction was collected, frozen, and lyophilized to yield rac-(lR,4r)-4-((lR)-l-(methyl(6-(5-methyl-l, 3, 4-oxadiazol-2-yl)-4-(((R)-l-(l -methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l -carboxylic acid (2.000 mg, 2.8 pmol, 8%, 99% Purity). LCMS m / z [M+H]+= 710.1, 'H NMR (400 MHz, MeOD) 8 7.47 (s, IH), 7.35 (s, IH), 7.26 (d, J= 4.3 Hz, 4H), 7.23 - 7.12 (m, IH), 5.46 (dd, J= 10.3, 4.5 Hz, IH), 3.77 (s, 3H), 3.10 - 2.78 (m, 5H), 2.78 - 2.40 (m, 8H), 2.38 (s, 3H), 2.16 - 1.00 (m, 17H), 1.00 - 0.72 (m, 5H), 0.65 (q, J = 6.1 Hz, 3H), 0.45 (d, J= 13.2 Hz, IH).

[0492]

[0369] The following compounds , including the title compound, were made using the above procedure or modifications to the above procedure using the corresponding intermediates. Docket No.: PAT059786-WO-PCT

[0493] Table 5 Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT

[0494] Example 27- Preparation of Compound 81

[0495]

[0370] Step 1: A solution of 2-(((lR)-l-(4-

[0496] (methoxycarbonyl)cyclohexyl)propyl)(methyl)amino)-4-(((R)-l-(l -methyl- lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxylic acid, Al - Trifluoroacetate (300.00 mg, 1 Eq, 375.03 pmol), Diphenylphosphoryl azide (619.25 mg, 485.3 pL, 6 Eq, 2.2502 mmol), TEA (379.50 mg, 523 pL, 10 Eq, 3.7503 mmol) in toluene (1.000 mL) was refluxed for 2h for reaction completion. Then mixture was cooled to room Docket No.: PAT059786-WO-PCT temperature and water (0.5 g, 0.500 mL, 7e+l Eq, 0.03 mol) was added. Reaction was refluxed for 16h. Mixture was cooled to room temperature and then diluted with EtOAc. The organic phase was separated and the aqueous phase further extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated. Crude was purified by C18 column with 25-80% ACN / Water+ 0.01% NH-iOH for 20 column volumes to afford desired compound methyl (lR,4r)-4-((lR)-l-((6-amino-4-(((R)-l-(l-methyl-lH-pyrazol- 4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (50 mg, 90% purity, 18% yield) as a clear yellow oil. LCMS m / z [M+H]+= 657.6

[0497]

[0371] Step 2: A mixture of triethylamine (38.51 mg, 53.0 pL, 5 Eq, 380.6 pmol), acetic acid (5.485 mg, 5.22 pL, 1.2 Eq, 91.34 pmol), 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3- tetramethylisouronium hexafluorophosphate(V) (34.73 mg, 1.2 Eq, 91.34 pmol), in Acetonitrile (0.500 mL) was stirred for 10 minutes, methyl (lR,4r)-4-((lR)-l-((6-amino-4-(((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (Int 1, 50.00 mg, 1 Eq, 76.11 pmol) was then added and stirred at room temperature for 16h. Mixture was concentrated and crude residue was carried forward into next step. LCMS m / z [M+H]+= 699.6

[0498]

[0372] Step 3: To a solution of methyl (lR,4r)-4-((lR)-l-((6-acetamido-4-(((R)-l-(l-methyl-lH- pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin- 2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (55.00 mg, 1 Eq, 78.69 pmol) in Tetrahydrofuran (1.000 mL) and Methanol (500.0 pL) was added aq. KOH (44.15 mg, 157.4 pL, 5.000 molar, 10 Eq, 786.9 pmol) and stirred at 50°C for 0.5h. Mixture was cooled to room temperature and concentrated. Crude residue was purified by reverse phase flash column chromatography (Prep HPLC Column: Long Column Switching Dimensions: 30 mm x 100 mm

[0499] 5 pm, Flow Rate: 75.0 ml / min, 10-30% Solvent: A2 Water+lOmM NH4OH, Solvent: B2 ACN+lOmM NH4OH Wavelength 1 : 214nm and 254 nm) to afford desired (lR,4r)-4-((R)-l- (((S)-6-acetamido-4-(((R)- 1 -(1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 -methy Ipiperidin- 1 - yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid (5 mg, 20% yield) as a white solid. LCMS m / z [M+H]+= 685.7, 'H NMR (400 MHz, Methanol-d4) 87.54 - 7.29 (m, 6H), 7.24 (t, J= 7.3 Hz, 1H), 5.52 (s, 1H), 4.52 (s, 1H), Docket No.: PAT059786-WO-PCT

[0500] 3.86 (s, 3H), 3.11 - 2.76 (m, 8H), 2.64 (d, J= 31.6 Hz, 1H), 2.31 (s, 1H), 2.14 - 1.17 (m, 21H), 0.92 (t, J= 11.3 Hz, 6H), 0.77 (t, J= 7.2 Hz, 3H), 0.64 (s, 1H).

[0501] Example 28- Preparation of Compound 82

[0502]

[0373] Step 1: A mixture of methyl (lR,4r)-4-((lR)-l-((6-amino-4-(((R)-l-(l-methyl-lH- pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin- 2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (Int 1, 50.000 mg, 1 Eq, 76.113 pmol), methanesulfonyl chloride (13.077 mg, 8.84 pL, 1.5 Eq, 114.17 pmol), DIPEA (19.675 mg, 26.5 pL, 2 Eq, 152.23 pmol), and DMAP (1.8597 mg, 0.2 Eq, 15.223 pmol) in tetrahydrofuran (1.000 mL) was stirred at room temperature for 16h. The mixture was then partitioned between EtOAc and water. The organic phase was separated, and the aqueous phase was further extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated. Crude residue was carried forward into next step.

[0503]

[0374] Step 2: To a solution of methyl (lR,4r)-4-((lR)-l-(methyl(4-(((R)-l-(l-methyl-lH- pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-(methylsulfonamido)-6-phenyl- 5, 6, 7, 8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l -carboxylate (120.0 mg, 1 Eq, 163.3 pmol) in tetrahydrofuran (1.000 mL) and MeOH (500.0 pL) was added aq KOH (91.61 mg, 326.5 pL, 5.000 molar, 10 Eq, 1.633 mmol) and stirred at 50°C for 0.5h. Mixture was cooled to room temperature and concentrated. Crude residue purified by by reverse phase flash column Docket No.: PAT059786-WO-PCT chromatography (Prep HPLC Column: Long Column Switching Dimensions: 30 mm x 100 mm 5 pm, Flow Rate: 75.0 ml / min, 10-30% Solvent: A2 Water+lOmM NH4OH, Solvent: B2 ACN+lOmM NH4OH Wavelength 1 : 214 nm and 254 nm) yield to afford desired peak compound (lR,4r)-4-((R)-l-(methyl((S)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-(methylsulfonamido)-6-phenyl-5, 6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l -carboxylic acid (0.5 mg, 2% yield) as a white solid. 'H NMR (400 MHz, MeOD) 8 7.66 - 7.49 (m, 3H), 7.48 - 7.38 (m, 3H), 7.35 (t, J = 7.3 Hz, 1H), 5.52 (s, 1H), 4.53 (d, J= 35.2 Hz, 1H), 3.86 (s, 3H), 3.21 (d, J= 16.3 Hz, 1H), 3.11 - 2.75 (m, 9H), 2.67 (s, 1H), 2.53 (d, J= 18.5 Hz, 1H), 2.30 (s, 4H), 2.13 (s, 1H), 1.99 (d, J = 13.5 Hz, 2H), 1.94 - 1.85 (m, 2H), 1.85 - 1.54 (m, 6H), 1.54 - 1.18 (m, 5H), 0.90 (d, J= 6.3 Hz, 5H), 0.75 (d, J= 7.1 Hz, 3H), 0.60 (d, J= 13.1 Hz, 1H).

[0504] Docket No.: PAT059786-WO-PCT

[0505] Example 29- Preparation of Compound 70

[0506]

[0375] Stepl: A solution of methyl (S)-2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline-6- carboxylate (1.660 g, 1 Eq, 4.923 mmol), (R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethan-l -amine hydrochloride (1.401 g, 1.1 Eq, 5.415 mmol) and DIPEA (1.909 g, 2.6 mL, 3 Eq, 14.77 mmol)) in EtOH (30.00 mL) was heated at 70°C for 16h. The reaction mixture was evaporated to dryness and purified by ISCO eluted by 0-100% ethyl acetate / ethanol(3: l / v:v) in heptane to give methyl (S)-2-chloro-4-(((R)-l-(l-methyl-lH-pyrazol- 4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-6- carboxylate (2.546 g, 4.867 mmol, 98.87 %). MS m / z = 523.4 [M+H]+

[0507]

[0376] Step 2: methyl (S)-2-chloro-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin- 1 -yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxylate and Docket No.: PAT059786-WO-PCT tert-butyl (lR,4r)-4-((R)-l-(methylamino)propyl)cyclohexane-l -carboxylate (2.519 g, 2 Eq, 9.865 mmol) were dissolved in DCM (10.00 mL). The mixture was concentrated to dryness by evaporation. The mixture was capped and heated at 130 °C for 16 h. The reaction mixture was dissolved in 5 ml of DCM and purified by ISCO eluted by 0-100% ethyl acetate / EtOH (V:V / 3: 1) to give methyl (S)-2-(((R)-l-((lr,4R)-4-(tert-butoxycarbonyl)cyclohexyl)propyl)(methyl)amino)- 4-(((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 -methy Ipiperidin- 1 -y l)ethyl)amino)-6-pheny 1- 5,6,7,8-tetrahydroquinazoline-6-carboxylate (830.0 mg, 1.119 mmol, 22.68 %). MS m / z = 742.7 [M+H]+.

[0508]

[0377] Step 3: To a solution of methyl (S)-2-(((R)-l-((lr,4R)-4-(tert- butoxycarbony l)cyclohexyl)propyl)(methyl)amino)-4-(((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxylate (830. O mg, 1 Eq, 1.119 mmol) in DCM (8.000 mL) was added 2,2, 2-trifluoroacetic acid (127.5 mg, 4.000 mL, 1 Eq, 1.119 mmol). The resultant mixture at rt was stirred for overnight and then evaporated to dryness to give (lR,4r)-4-((R)-l-(((S)-6-(methoxycarbonyl)-4-(((R)-l-(l-methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid (0.68 g, 0.98 mmol, 88 %) as yellow solid, which was directly used in next step without further purification. MS m / z = 686.2 [M+H]+.

[0509]

[0378] Step 4: (lR,4r)-4-((R)-l-(((S)-6-(methoxycarbonyl)-4-(((R)-l-(l-methyl-lH-pyrazol-4- yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid (104.0 mg, 1 Eq, 151.6 pmol), dimethylamine hydrochloride (18.55 mg, 1.5 Eq, 227.4 pmol), HATU (86.48 mg, 1.5 Eq, 227.4 pmol) and DIPEA (196.0 mg, 264 pL, 10 Eq, 1.516 mmol) were combined in MeCN (2.000 mL). The mixture was stirred at room temperature for overnight. The reaction mixture was evaporated to dryness and purified by ISCO eluted by 0-30% methanol in DCM to give methyl (S)-2-(((R)-l-((lr,4R)-4-(dimethylcarbamoyl)cyclohexyl)propyl)(methyl)amino)-4-(((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l -yl)ethyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazoline-6-carboxylate (90 mg, 0.13 mmol, 83 %). MS m / z = 713.6 [M+H]+.

[0510]

[0379] Step 5: To a 5 mL vial containing methyl (S)-2-(((R)-l-((lr,4R)-4- (dimethylcarbamoyl)cyclohexyl)propyl)(methyl)amino)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxylate Docket No.: PAT059786-WO-PCT dissolved in a mixture of THF (1.400 mb) and MeOH (700.0 pL) was added lithium hydroxide (33.59 mg, 701.3 pL, 2.000 molar, 10 Eq, 1.403 mmol). The reaction mixture was heated to 80 oC for 16h. The reaction mixture was cooled to room temp and concentrated to remove THF. The remaining solution was diluted with water and MeCN and purified via reverse phase HPLC. Product peak was collected, frozen, and lyophilized to yield (S)-2-(((R)-l-((lr,4R)-4- (dimethylcarbamoyl)cyclohexyl)propyl)(methyl)amino)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxylic acid (24.10 mg, 34.48 pmol, 24.58%). LCMS m / z [M+H]+= 699.5, 'H NMR (400 MHz, MeOD) 8 7.41 (s, 1H), 7.37 - 7.21 (m, 5H), 7.17 (t, J= 7.1 Hz, 1H), 5.37 (s, 1H), 4.43 (d, J = 45.4 Hz, 1H), 3.76 (s, 3H), 3.14 (s, 1H), 3.02 - 2.80 (m, 3H), 2.98 (s, 6H), 2.69 (d, J= 22.2 Hz, 5H), 2.51 (d, J= 12.8 Hz, 3H), 2.36 - 2.17 (m, 1H), 2.17 - 1.44 (m, 11H), 1.42 - 1.03 (m, 5H), 1.03 - 0.73 (m, 5H), 0.67 (d, J= 7.4 Hz, 3H), 0.47 (d, J= 13.3 Hz, 1H).

[0511]

[0380] The following compounds, including the title compound, were made using the above procedure or modifications to the above procedure using the corresponding intermediates. Table 6 _ Docket No.: PAT059786-WO-PCT

[0512] Example 30- Preparation of Compound 201

[0513]

[0381] A stirred solution of (lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol- 4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid (35.00 mg, 1 Eq, 53.20 pmol), Methylsulfonamide (10.12 mg, 8.235 pL, 2 Eq, 106.4 pmol), 4-Dimethylaminopyridine (9.749 mg, 1.5 Eq, 79.80 pmol) and l-(3-Dimethylaminopropyl)-3- ethylcarbodiimideHydrochloride(EDCI) (15.30 mg, 1.5 Eq, 79.80 pmol)in DCM (1.000 mL) was stirred at rt overnight. LCMS indicates reaction is completed. The reaction was quenched with H2O, extracted with DCM (5 mL x2). washed with H2O and brine, dried over Na2SO4 and concentrated. The crude was purified through Prep HPLC (Basic_25-50%- Acetonitrile.5.1min, Column: Waters XBridge C18 OBD 30 x 50 mm) to give (lR,4r)-4-((R)-l- (((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l- yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)-N- (methylsulfonyl)cyclohexane-l -carboxamide (30 mg, 73% yield). LCMS m / z = 735.6 [M+H]+; 'H NMR (400 MHz, MeOD) 8 7.43 - 7.36 (m, 3H), 7.35 - 7.27 (m, 3H), 7.27 - 7.18 (m, 1H), 5.39 (s, 1H), 4.39 (s, 1H), 3.75 (s, 3H), 2.93 (d, J = 17.0 Hz, 6H), 2.89 (s, 1H), 2.76 (d, J = 17.6 Hz, 6H), 2.65 - 2.49 (m, 5H), 2.35 (d, J = 13.3 Hz, 1H), 2.18 (s, 1H), 2.01 - 1.90 (m, 2H), 1.88 - 1.76 (m, 4H), 1.66 (d, J = 3.8 Hz, 2H), 1.62 (s, 2H), 1.58- 1.20 (m, 7H), 0.88 - 0.76 (m, 5H), 0.69 (t, J = 7.2 Hz, 3H), 0.52 (d, J = 12.8 Hz, 1H). Docket No.: PAT059786-WO-PCT

[0514] Example 31 - Biological assay of cellular cGMP production

[0515]

[0382] The compounds described were tested for their functional activity in a cellular cGMP production assay using human NPR1 expressing CH0-K1 cells (DiscoverX (Cat. #93-0804C2). For the functional characterization of the compounds, the production of cyclic guanosine 3', 5'- cyclic monophosphate (cGMP) upon binding to and stimulation of NPR1 expressed on the cell surface of CH0-K1 cells was monitored. Cellular cGMP is a major second messenger that mediates cell activities and is synthesized by activated NPR1 triggered by binding of the natural ligand ANP. Therefore, a commercial assay kit was used (CisBio HTRF Assay Kit (Cat. # 62GM2PEB)). The assay was performed according to manufacturer’s instructions with minor deviations. In brief, human NPR1 cells were adjusted to 2 xlO4cells / mL and 20 pL / well were seeded in 384- well microtiter plates and incubated overnight. All compound stocks were diluted in PBS + 0.1 % BSA at 2-fold the final assay concentration. After addition of 10 pL / well of assay buffer (PBS + 0.1% BSA +1 mM IBMX) and 10 pL / well of the compounds in different concentrations (12-point dose- response with 3 -fold dilutions from a top concentration of 30 pM), the plate was incubated for 30 min at 37°C to allow for cGMP production. In parallel, a standard curve using a calibrator (contained in the kit) was generated. The cells were lysed and a mix of cGMP-d2 and anti-cGMP-cryptate was added and incubated for Ih at room temperature. The readout was performed using an Envision plate reader (PerkinElmer) with an excitation wavelength of 317 nm and an emission wavelength of 665 nm. cGMP concentration (Delta F [%]) was calculated according to the following formulae:

[0516] RatlO=[(A665nm / B620nm)* 104] Mean Ratio = (Sratios / 2) CV = [(Std deviation / Mean ratio)* 100] Delta F = [((Calibrator or sample Ratio - Rationeg) / Rationeg)* 100] Rationeg: negative control

[0517]

[0383] An ANP (Phoenix Pharmaceuticals (Cat. #005-06)) dose-response curve was used as a control for each assay run, and Amax (the maximum cGMP production achieved) for each compound was expressed as a percentage of the maximum cGMP produced with ANP. Docket No.: PAT059786-WO-PCT

[0518] Table 7: In vitro functional data Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT Docket No.: PAT059786-WO-PCT

[0519] Equivalents

[0520]

[0384] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

Docket No.: PAT059786-WO-PCTCLAIMSWHAT IS CLAIMED IS:

1. A compound having a structure of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:5 to 6 membered heteroaryl optionally substituted with one or more (Ci-Ce)alkyl;R2is (Ci-Ci2) alkyl, (C3-Ce)cycloalkyl, phenyl, or 5 to 6 membered heteroaryl, wherein each of the (Ci-Ci2) alkyl, the (C3-Ce)cycloalkyl, the phenyl, or the 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OR2A, -L2-OR2A, and (Ci-Ce)alkyl;R3is -NRnR12;R4is a 5- or 6-membered heteroaryl which is each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OR4A, -L4- OR4A, -C(O)NR4BR4C, -NR4BC(O)R4D, -NR4BC(O)OR4A, -C(O)OR4A, -L4- C(O)OR4A, (Ci-Ce)alkyl, (C3-C6)cycloalkyl-(Ci-C6)alkyl, and (Ci-C6)alkyl(C3- Ce)cycloalkyl;R7is a (C3-Cs) cycloalkyl which is optionally substituted with one or more substituents independently selected from halogen, , (Ci-Ce)alkyl, -OR7A, -L7-OR7A, - C(O)NR7BR7C, -NR7BC(O)R7D, -NR7BC(O)OR7A, -C(O)OR7A, -C(O)NHSO2CH3, and -L7-C(O)OR7A; each R5, R8, R9, and R10is independently hydrogen, or (Ci-Ce)alkyl; each R6is hydrogen, (C3-Ce)cycloalkyl, or (Ci-Ce)alkyl;Docket No.: PAT059786-WO-PCTR11and R12together with the nitrogen attached thereto are joined to form a 3- to 10- membered heterocyclyl, wherein the 3- to 10-membered heterocyclyl optionally comprises one or two heteroatoms selected from N, O, and S, and optionally is substituted with one or more selected from halogen, oxo, -CN, -OR3A, -L3-OR3A, - C(O)NR3BR3C, -NR3BC(O)R3D, -NR3BC(O)OR3A, -C(O)OR3A, -L3-C(O)OR3A, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, and a 5 to 6-membered heterocyclyl which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -CO2H, oxo, and (Ci-Ce)alkyl; each L1, L2, L3, L4and L7is (Ci-Ce) alkylene; each R1A, R1D, R2A, R2D, R3A, R3D, R4A, R4D, R7A, and R7Dis independently hydrogen, (Ci-Ce)alkyl, or (Ci-Ce)haloalkyl; each R1Band R1Cis independently hydrogen, optionally substituted (C3-Ce)cycloalkyl or optionally substituted (Ci-Ce)alkyl, wherein when substituted, the (C3- Cejcycloalkyl and (Ci-Ce)cycloalkyl is substituted with one or more substituents independently selected from aryl (e.g., phenyl) ; or R1Band R1Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; and each R2B, R2C, R3B, R3C, R4B, R4C, R7B, and R7Cis independently hydrogen, or (Ci- Cejalkyl; or R1Band R1Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; R2Band R2Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; R3Band R3Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; R4Band R4Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl; or R7Band R7Ctogether with the atoms attached thereto are optionally joined to form a 3 to 6 membered heterocyclyl.

2. The compound of claim 1, wherein:Docket No.: PAT059786-WO-PCT5 to 6 membered heteroaryl optionally substituted with -CH3;L1is (Ci-C2) alkylene; each R1AandR1Dis independently hydrogen, -CH3, -CH2CH3, -CF3, -CHF2, or CH2F; and each R1Band R1Cis independently hydrogen or -CH3, or R1Band R1Ctogether with the atoms attached thereto are joined to form a 4 to 5 membered heterocyclyl.

3. The compound of claim 1 or 2, wherein R1is -CN, -OH, -OCH3, -OCH2CH3, -CH2OCH3, -CH2OCH2CH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -C(O)OH, -C(O)OCH3, -C(O)NH2, - C(0)NHCH3, -C(O)N(CH3)2, -NH(C0)CH3, -NCH3(CO)CH3, -C(O)N=S(O)(CH3)2, -5. The compound of any one of claims 1 to 4, wherein:n is an integer of 1 to 4; z3 is an integer of 0 to 3;Docket No.: PAT059786-WO-PCT each R30is independently halogen, -OR3A, -NR3BC(O)R3D, -C(O)OR3A, (Ci-C4)alkyl, (Ci- C4)haloalkyl, or 5 to 6-membered heterocyclyl which is optionally substituted with one or more substituents from halogen, oxo, -CH3, and -OCH3; each R3AandR3Dis independently hydrogen, -CH3, -CH2CH3, -CF3, -CHF2, or CH2F; and each R3Bis independently hydrogen or -CH3; and optionally two of R30are joined to form a 5 to 6 membered heterocyclyl optionally comprising one or two heteroatoms selected from N, O, and S.

6. The compound of claim 5, wherein each R30is independently halogen, -OH, -CH3, - CH2F, -CHF2, -CF3, -0CH3, -OCH2F, -OCHF2, -OCF3, -OCH2CH3, -NHC(0)CH3, -7. The compound of any one of claims 1 to 6, wherein R2is a phenyl optionally substituted with one or more substituents independently selected from halogen, -CN, and -OR2A, and R2Ais (C1-C4) alkyl.

8. The compound of any one of claims 1 to 7, wherein the compound the structure of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: z2 is an integer of 0 to 2; each R20is halogen, -CN, and -OR2A; andDocket No.: PAT059786-WO-PCTR2AIS (C1-C4) alkyl.

9. The compound of any one of claims 1 to 8, wherein:each R41, R42, R43, and R44is independently hydrogen, halogen, -C(O)OR4A, -L4-C(O)OR4A, (Ci-Ce)alkyl, (C3-C6)cycloalkyl-(Ci-C2)alkyl, or (Ci-C2)alkyl-(C3- Ce)cycloalkyl; each R4Ais independently hydrogen or C1-C4 alkyl; andL4is Ci-C2alkylene.

10. The compound of any one of claims 1 to 9, wherein the compound the structure ofFormula (III- A):or a pharmaceutically acceptable salt thereof, wherein:Docket No.: PAT059786-WO-PCT each R41, R42, and R43is independently hydrogen, halogen, -C(O)OR4A, -L4-C(O)OR4A, (Ci-C4)alkyl, or (C3-Ce)cycloalkyl-(Ci-C2)alkyl;R4Ais hydrogen or (C1-C4) alkyl; andL4is (C1-C2) alkylene.

11. The compound of any one of claim 1 to 10, wherein:z7 is an integer of 0 to 3; and each R70is independently halogen, -OR7A, -L7-OR7A, -C(O)NR7BR7C, -NR7BC(O)R7D, - NR7BC(O)OR7A, -C(O)OR7A, or -L7-C(O)OR7A; each R7AandR7Dis independently hydrogen, or (C1-C4) alkyl, each R7Band R7Cis independently hydrogen or -(C1-C4) alkyl, or R7Band R7Care joined to form a 4 to 5 membered heterocyclyl, andL7is C1-C2 alkylene.

12. The compound of any one of claims 1 to 11, wherein the compound the structure ofFormula (III-A-1):or a pharmaceutically acceptable salt thereof,Docket No.: PAT059786-WO-PCT wherein: each R70is independently -L7-OR7A, -C(O)OR7A, -L7-C(O)OR7A, or -C(O)NR7BR7C; z7 is an integer of 0 to 2; each R7AandR7Dis independently hydrogen, or -CH3, each R7Band R7Cis independently hydrogen or -CH3, or R7Band R7Care joined to form a 4 to 5 membered heterocyclyl, and each L7is independently C1-C2 alkylene.

13. The compound of any one of claims 1 to 12, wherein z7 is 0, 1, or 2; and each R70is independently14. The compound of any one of claims 1 to 13, wherein the compound the structure ofFormula (IV-A-1):or a pharmaceutically acceptable salt thereof.Docket No.: PAT059786-WO-PCT15. The compound of any one of claims 1 to 14, wherein z3 is 3 and two of R30together with the atoms attached thereto are joined to form a 5 to 6 membered heterocyclyl optionally comprising one or two heteroatoms selected from N, O, and S.The compound of claim 15, whereinThe compound of any one of claims 1 to 11 , wherein18. The compound of any one of claims 1 to 11 , wherein1, or 2.

19. The compounds of any one of claims 10 to 18, wherein:R41is hydrogen;R42is hydrogen,R43is hydrogen, halogen, or -OCH3.

20. The compound of any one of claims 1 to 9, wherein:Docket No.: PAT059786-WO-PCT each R41, R42, and R43is independently hydrogen or -CH3;z3 is 0, 1, or 2.

21. The compound of any one of claims 1 to 9, whereineach R41and R43is independently hydrogen or -CH3;z3 is 0, 1, or 2.

22. The compound of any one of claims 1 to 9, whereineach R41, R42, and R43is independently hydrogen or -CH3;Docket No.: PAT059786-WO-PCT23. The compound of any one of claims 1 to 9, whereinz3 is 0, 1, or 2.

24. The compound of any one of claims 1 to 6, wherein:R2is a pyridyl optionally substituted with one or more substituents independently selected from halogen, -CN, and -OR2A, and R2Ais (C1-C4) alkyl;each R41, R42, and R43is independently hydrogen or -CH3.

25. The compound of any one of claims 1 to 6, wherein:R2is a C5-C6 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, -CN, and -OR2A, and R2Ais (C1-C4) alkyl;Docket No.: PAT059786-WO-PCTeach R41, R42, and R43is independently hydrogen or -CH3.

26. The compound of any one of claims 1 to 6, wherein:R1is -OH;R2is a Ci-Ce alkyl;each R41, R42, and R43is independently hydrogen or -CH3.

27. The compound of any one of claims 20 to 26, wherein z3 is 0, 1 or 2, each R30is independently -F, -CH3, or -OCH3.

28. The compound of any one of claims 20 to 27, wherein:Docket No.: PAT059786-WO-PCTR70is independently -29. The compound of any one of claims 1 to 28, wherein:

30. The compound of any one of claims 1 to 29, wherein R5is -CH3.

31. The compound of any one of claims 1 to 30, wherein R6is -CH2CH3.

32. The compound of any one of claims 1 to 31 wherein R8, R9and R10are hydrogen.

33. A compound or a pharmaceutically acceptable salt thereof selected from(lR,4r)-4-((lR)-l-(((6S)-4-(((lR)-2-(8-azabicyclo[3.2.1]octan-8-yl)-l-(l-methyl-lH- pyrazol-4-yl)ethyl)amino)-6-(3-fluorophenyl)-6-methoxy-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid,( 1 R,4r)-4-((R)- 1 -(((S)-6-ethoxy-4-(((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2-(piperidin- 1 - yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l -(((S)-6-(3-fluorophenyl)-6-methoxy-4-(((R)-l -(1 -methyl- IH-pyrazol- 4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-((l-(3-methoxy-l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059786-WO-PCT(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,6-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)spiro[3.3]heptane-2-carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-ethoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-(((lR)-2-(3-(fluoromethyl)piperidin-l-yl)-l-(l-methyl-lH- pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-ethoxy-4-(((R)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)- l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,( 1 R,4r)-4-((R)- 1 -(((S)-6-methoxy-4-(((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2-(piperidin- 1 - yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l -(((S)-6-(2-fluorophenyl)-6-methoxy-4-(((R)-l-(l -methyl- IH-pyrazol- 4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,3 -((R)- 1 -(((S)-4-(((R)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3-methylpiperidin- l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,(lR,4r)-4-((R)- 1 -(((S)-4-(((R)- 1 -(3 -fluoro- 1 -methyl- lH-pyrazol-4-yl)-2-(piperidin- 1 - yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059786-WO-PCT(lR,4r)-4-((R)-l-(((S)-6-(3-fluorophenyl)-6-methoxy-4-(((R)-2-((3R,5R)-3-methoxy-5- methylpiperidin- 1 -yl)-l -(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-5, 6,7, 8-tetrahydroquinazolin- 2-yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,( 1 R,4r)-4-((R)- 1 -(((S)-4-(((R)-2-((R)-3 -hydroxy-3 -methylpiperi din- 1 -yl)- 1 -( 1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,3-((R)-l-(((S)-6-methoxy-4-(((R)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-(3-methoxy-8- azabicyclo[3.

2. l]octan-8-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-(((lR)-2-(3-methoxy-8-azabicyclo[3.

2. l]octan-8- yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l- yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-(((lR)-2-(3-fluoro-8-azabicyclo[3.2.1]octan-8-yl)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-(2-fluorophenyl)-6-methoxy-4-(((R)-2-((3R,5R)-3-methoxy-5- methylpiperidin- 1 -yl)-l -(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-5, 6,7, 8-tetrahydroquinazolin- 2-yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-((R)-3-(fluoromethyl)pyrrolidin-l-yl)-l-(l-methyl-lH- pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-2-((R)-3-methoxy-3-methylpiperidin-l-yl)-l- (l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059786-WO-PCT(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-((S)-3-(fluoromethyl)pyrrolidin-l-yl)-l-(l -methyl- 1H- pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((l-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)-2-((3R,5R)-3- methoxy-5-methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-((3R,5R)-3- methoxy-5-methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-((3R,5R)-3- methoxy-5-methylpiperidin-l -yl)ethyl)amino)-6-methoxy-6-phenyl-5, 6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-(((lR)-2-(3-methoxy-8-azabicyclo[3.

2. l]octan-8- yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-(3-methoxy-8- azabicyclo[3.

2. l]octan-8-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-2-((S)-3-methoxypiperidin-l-yl)-l-(l -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-2-((S)-3-methoxy-3-methylpiperidin-l-yl)-l- (l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,( 1 R,4r)-4-((R)- 1 -(((S)-6-methoxy-4-(((R)-2-((R)-3 -methoxypiperidin- 1 -yl)- 1 -( 1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-((lR,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059786-WO-PCT(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-2-((S)-3-methoxyazepan-l-yl)-l-(l-methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-l-(l-(carboxymethyl)-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-((lR,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-l-(3- fluoro-l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-((S)-2-(fluoromethyl)piperidin-l-yl)-l-(l -methyl- 1H- pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,( 1 R,4r)-4-((R)- 1 -(((S)-4-(((R)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol-4-yl)-2-((R)-3 - methoxy-3-methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-((l-(3-methoxy-l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-2-((R)-3-methoxyazepan-l-yl)-l-(l -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-((6-(2-fluorophenyl)-6-methoxy-4-(((R)-2-((R)-3-methoxy-3- methylpiperidin- 1 -yl)-l -(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-5, 6,7, 8-tetrahydroquinazolin- 2-yl)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,( 1 R,4r)-4-((R)- 1 -(((S)-4-(((R)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol-4-yl)-2-((R)-3 - methoxypiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-l-(l-(carboxymethyl)-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-(3-fluorophenyl)-6-methoxy-5,6,7,8-tetrahydroquinazolin- 2-yl)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,Docket No.: PAT059786-WO-PCT(lR,4r)-4-((lR)-l-((6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-((3R,5R)-3-(difluoromethoxy)-5-methylpiperidin-l-yl)- l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-((6-(3-fluorophenyl)-6-hydroxy-4-(((R)-l-(l-methyl-lH-pyrazol-4- yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-hydroxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-((6-cyclohexyl-6-hydroxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-((6-cyclopentyl-6-hydroxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-((6-(3-cyanophenyl)-6-hydroxy-4-(((R)-l-(l-methyl-lH-pyrazol-4- yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-((6-butyl-6-hydroxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(methyl((S)-6-(3-methyl-l, 2, 4-oxadiazol-5-yl)-4-(((R)-l-(l -methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane- 1 -carboxylic acid, rac-(lR,4r)-4-((R)-l-(((S)-6-(dimethylcarbamoyl)-4-(((R)-l-(l-methyl-lH-pyrazol-4- yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059786-WO-PCT rac-(lR,4r)-4-((lR)-l-(methyl(6-(5-methyl-l,3,4-oxadiazol-2-yl)-4-(((R)-l-(l-methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l -(((S)-6-(methoxycarbonyl)-4-(((R)-l-(l -methyl- lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,( 1 R,4r)-4-((R)- 1 -(((S)-6-(azetidine- 1 -carbonyl)-4-(((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid, rac-(lR,4r)-4-((lR)-l-((6-(methoxycarbonyl)-6-(2-methoxyphenyl)-4-(((R)-l-(l -methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid, rac-(lR,4r)-4-((R)-l-(((S)-6-cyano-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l -(((S)-6-cyano-4-(((R)-l-(l -methyl- lH-pyrazol-4-yl)-2-((S)-3-(2- oxooxazolidin-3-yl)piperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-cyano-4-(((R)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)- l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(S)-2-(((R)-l-((lr,4R)-4-(methoxymethyl)cyclohexyl)propyl)(methyl)amino)-4-(((R)-l- (1 -methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazoline-6-carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-cyano-4-(((R)-2-((R)-3-methoxypiperidin-l-yl)-l-(l -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,( 1 R,4r)-4-((R)- 1 -(((S)-6-cyano-4-(((R)-2-((R)-3 -methoxy-3 -methylpiperidin- 1 -yl)- 1-(1- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059786-WO-PCT(lR,4r)-4-((R)-l-(((S)-6-(methoxymethyl)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)- 3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid, rac-(lR,4r)-4-((lR)-l-((6-(methoxycarbonyl)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid, rac-2-(((R)-l-((lr,4R)-4-carboxycyclohexyl)propyl)(methyl)amino)-4-(((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-(pyridin-2-yl)-5,6,7,8- tetrahydroquinazoline-6-carboxylic acid,(lR,4r)-4-((R)-l-(methyl((S)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-6-(pyrrolidine-l-carbonyl)-5, 6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(S)-2-(((R)- 1 -((lr,4R)-4-(dimethylcarbamoyl)cyclohexyl)propyl)(methyl)amino)-4- (((R)-l-(l -methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl- 5,6,7,8-tetrahydroquinazoline-6-carboxylic acid,(S)-2-(((R)- 1 -cy clohexylpropyl)(methyl)amino)-4-(((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-y 1)- 2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxylic acid,(lR,4r)-4-((R)-l -(((S)-6-((difluoromethoxy)methyl)-4-(((R)-l-(l -methyl- lH-pyrazol-4- yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(S)-2-(methyl((R)-l-((lr,4R)-4-(pyrrolidine-l-carbonyl)cyclohexyl)propyl)amino)-4- (((R)-l-(l -methyl- lH-pyrazol-4-yl)-2-((S)-3 -methylpiperidin- l-yl)ethyl)amino)-6-phenyl- 5,6,7,8-tetrahydroquinazoline-6-carboxylic acid,2-(((R)- 1 -(( 1 r,4R)-4-(methoxycarbony l)cyclohexyl)propyl)(methyl)amino)-4-(((R)- 1 -( 1 - methyl- lH-pyrazol-4-yl)-2-((S)-3 -methylpiperidin- 1 -yl)ethyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazoline-6-carboxylic acid,( 1 R,4r)-4-((R)- 1 -(((S)-6-cyano-4-(((R)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol-4-y l)-2-((R)-3 - methoxy-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059786-WO-PCT rac-(lR,4r)-4-((lR)-l-((6-cyano-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(S)-2-(((R)-l-((lr,4R)-4-carboxycyclohexyl)propyl)(methyl)amino)-4-(((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahydroquinazoline-6-carboxylic acid, rac-(lR,4r)-4-((lR)-l-((6-cyano-6-(2-methoxyphenyl)-4-(((R)-l-(l-methyl-lH-pyrazol- 4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-((dimethyl(oxo)-X6-sulfaneylidene)carbamoyl)-4-(((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid, rac-(lR,4r)-4-((lR)-l-((6-(methoxycarbonyl)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-acetamido-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(methyl((S)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-(methylsulfonamido)-6-phenyl-5, 6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(methyl(4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-(methylsulfonyl)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((S)-l-(l-methyl-lH-pyrazol-3-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((2-((lR,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-l-(2,4- dimethylthiazol-5-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid,Docket No.: PAT059786-WO-PCT(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((S)-l-(l-methyl-lH-pyrazol-5-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-((2-(3-methoxy-8-azabicyclo[3.2.1]octan-8-yl)-l- (l-methyl-lH-pyrazol-3-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-((6-methoxy-4-((2-(3-methoxy-8-azabicyclo[3.2.1]octan-8-yl)-l-(l- methyl-lH-pyrazol-3-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-((2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)-1-(l-methyl-lH-pyrazol-5-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((2-(3-fluoro-8-azabicyclo[3.2.1]octan-8-yl)-l-(l-methyl-lH- pyrazol-5-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-((2-((R)-3-methoxy-3-methylpiperidin-l-yl)-l- (l-methyl-lH-pyrazol-5-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-2-((R)-3-methoxy-3-methylpiperidin-l-yl)-l- (pyridin-2-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((l-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)-2-((S)-3-(N- methylacetamido)piperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((2-(8-azabicyclo[3.2.1]octan-8-yl)-l-(2,4-dimethylthiazol-5- yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-(dimethylcarbamoyl)-4-(((R)-l-(3-fluoro-l-methyl-lH-pyrazol- 4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059786-WO-PCT( 1 R,4r)-4-((R)- 1 -(((S)-6-(dimethylcarbamoyl)-4-(((S)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol- 4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,( 1 R,4r)-4-((R)- 1 -(((S)-6-(dimethylcarbamoyl)-4-(((S)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol- 4-yl)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(methyl((S)-6-(methyl((lr,3S)-3-phenylcyclobutyl)carbamoyl)-4-(((R)- 1-(1 -methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l -yl)ethyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(methyl((S)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-1 -yl)ethyl)amino)-6-phenyl-6-((3-phenylcyclobutyl)carbamoyl)-5, 6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-((2,3-dihydro-lH-inden-2-yl)carbamoyl)-4-(((R)-l-(l -methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(methyl((6S)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-1 -yl)ethyl)amino)-6-phenyl-6-((3-phenylcyclopentyl)carbamoyl)-5, 6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l -(((S)-6-(benzylcarbamoyl)-4-(((R)-l-(l -methyl- lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-((2,3-dihydro-lH-inden-2-yl)carbamoyl)-4-(((R)-2-((R)-3- methoxy-3-methylpiperidin-l-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((R)-4-(((R)-2-(azepan-l-yl)-l-(l-methyl-lH-pyrazol-4- yl)ethyl)amino)-6-(N-methylcyclobutanecarboxamido)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-(azepan-l-yl)-l-(l -methyl- lH-pyrazol-4- yl)ethyl)amino)-6-(N-methylcyclobutanecarboxamido)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059786-WO-PCT l-ethyl-4-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,3 -((R)- 1 -(((S)-4-(((S)-2-(azepan- 1 -yl)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol-4- yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((l-(3-(benzyloxy)-l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,3-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclobutane-l -carboxylic acid,( 1 R,4r)-4-((R)- 1 -(((S)-4-(((S)-2-((R)-3 -ethyl-3 -hydroxypiperidin- 1 -y 1)- 1 -(3 -fluoro- 1 - methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-((R)-3-ethyl-3-hydroxypiperidin-l-yl)-l-(3-fluoro-l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lRS,4SR)-4-((RS)-l-(((SR)-4-(((SR)-2-((lR,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)- l-(2,4-dimethylthiazol-5-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid, rac-(lR,4r)-4-((R)-l-(((S)-4-(((S)-l-(2,4-dimethylthiazol-5-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid, rac-( 1 R,4r)-4-((R)- 1 -(((S)-4-(((R)- 1 -(2,4-dimethylthiazol- 5-yl)-2-((S)-3 - methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid, rac-(lR,4r)-4-((R)-l-(((S)-4-(((S)-l-(2,4-dimethylthiazol-5-yl)-2-(piperidin-l- yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid,Docket No.: PAT059786-WO-PCT(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-((lR,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-l-(2,4- dimethylthiazol-5-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((S)-2-((S)-3-ethyl-3-hydroxypiperidin-l-yl)-l-(3-fluoro-l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-((S)-3-ethyl-3-hydroxypiperidin-l-yl)-l-(3-fluoro-l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid, rac-(lR,4r)-4-((R)-l-(((S)-4-(((R)-l-(2,4-dimethylthiazol-5-yl)-2-(piperidin-l- yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid, rac-3-((R)-(((S)-4-(((R)-2-(azepan-l -yl)-l-(l -methyl- lH-pyrazol-4-yl)ethyl)amino)-6- methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)(cyclopropyl)methyl)bicyclo [1.1.1 ]pentane- 1 -carboxylic acid, rac-3 -((R)- 1 -(((S)-4-(((R)-2-(azepan- 1 -yl)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol-4- yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid, rac-3-((R)-cyclopropyl(((R)-6-methoxy-4-(((S)-l-(l-methyl-lH-pyrazol-4-yl)-2-((R)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)methyl)bicyclo[l .1.1 ]pentane-l -carboxylic acid, rac-( 1 R,4r)-4-(( 1 R)- 1 -(((6S)-4-((( 1 R)-2-(3 -azabicyclo [4.1.0]heptan-3 -yl)- 1 -( 1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-((l-(5-methoxy-l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid, rac-6-((R)-l-(((S)-4-(((R)-2-(azepan-l-yl)-l-(l -methyl- lH-pyrazol-4-yl)ethyl)amino)-6- methoxy-6-phenyl-5,6,7,8-tetrahydroquinazohn-2-yl)(methyl)amino)propyl)spiro[3.3]heptane-2- carboxylic acid,Docket No.: PAT059786-WO-PCT2-(3 -((R)- 1 -(((S)-4-(((R)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)acetic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-((l-(5-methoxy-l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-((S)-3-fluoro-3-methylpiperidin-l-yl)-l-(l-methyl-lH- pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-((R)-3-fluoro-3-methylpiperidin-l-yl)-l-(l-methyl-lH- pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid, rac-(lR,4r)-4-((R)-cyclopropyl(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)methyl)cyclohexane-l -carboxylic acid,3-(( 1R)- 1 -(((6S)-4-((2-(3 -azabicyclo[3.3.1 ]nonan-3-yl)- 1 -(3 -fluoro- 1 -methyl- 1 H- pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,3-(( 1R)- 1 -(((6S)-4-((2-(3 -azabicyclo[3.3.1 ]nonan-3-yl)- 1 -(3 -fluoro- 1 -methyl- 1 H- pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,3-((lR)-l-(((6S)-4-((l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-((S)-3- (fluoromethyl)piperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,3-((lR)-l-(((6S)-4-((l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-((S)-3- (fluoromethyl)piperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,3 -(( 1 R)- 1 -(((6S)-6-methoxy-4-(( 1 -(2-methylpyridin-3 -yl)-2-(piperidin- 1 - yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,Docket No.: PAT059786-WO-PCT3 -(( 1 R)- 1 -(((6S)-6-methoxy-4-(( 1 -(2-methylpyridin-3 -yl)-2-(piperidin- 1 - yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid, rac-(lR,4r)-4-((R)-cyclopropyl(((R)-6-methoxy-4-(((S)-l-(l-methyl-lH-pyrazol-4-yl)-2- ((R)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)methyl)cyclohexane-l -carboxylic acid, rac-(lR,4r)-4-((lR)-l-(((6S)-4-(((lR)-2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid, rac-(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-2-((R)-3-methoxypyrrolidin-l-yl)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid, rac-(lR,4r)-4-((lR)-l-(((6S)-4-(((lR)-2-(l-fhioro-5-azaspiro[2.4]heptan-5-yl)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,4-((R)- 1 -(((S)-4-(((R)-2-(azepan- 1 -yl)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)ethyl)amino)-6- methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[2.2.1]heptane-l -carboxylic acid,3-((lR)-l-(((6S)-4-((2-(7-azabicyclo[2.2.1]heptan-7-yl)-l-(2,5-dimethylthiophen-3- yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,3-(( 1R)- 1 -(((6S)-4-((2-(3 -azabicyclo[3.3.1 ]nonan-3-yl)- 1 -(3 -fluoro- 1 -methyl- 1 H- pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,3-((lR)-l-(((6S)-4-((l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-((S)-3- (fluoromethyl)piperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6S)-4-((( 1 R)-2-(4-fluoroazepan- 1 -yl)- 1 -( 1 -methyl- 1 H-pyrazol-4- yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059786-WO-PCT3-((R)- 1 -(((S)-4-(((R)-2-(azepan- 1 -yl)- 1 -(1 -(2,2-difluoroethyl)- lH-pyrazol-4- yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,2-(3 -((R)- 1 -(((S)-4-(((R)-2-(azepan- 1 -yl)- 1 -(1 -methyl- 1 H-pyrazol-4-yl)ethyl)amino)-6- methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetic acid, rac-3-((R)-l-(((S)-4-(((R)-2-(azepan-l-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6- methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 Jpentane- 1 -carboxylic acid, (lR,4r)-4-((R)-l-(((S)-4-(((R)-2-(azepan-l-yl)-l-(l -methyl- lH-pyrazol-4- yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-(((lR)-2-(l,l-difluoro-5-azaspiro[2.4]heptan-5-yl)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,4-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[2.2.1]heptane-l -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6S)-4-(( 1 -(2-fluorophenyl)-2-((S)-3 -methylpiperidin- 1 - yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6S)-4-(( 1 -(2-fluorophenyl)-2-((S)-3 -methylpiperidin- 1 - yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((l-(2-fluorophenyl)-2-((3R,5R)-3-methoxy-5- methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((l-(3-fluoropyridin-2-yl)-2-((S)-3-methylpiperidin-l- yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059786-WO-PCT(lR,4r)-4-((lR)-l-(((6S)-4-((l-(3-fluoropyridin-2-yl)-2-((S)-3-methylpiperidin-l- yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,4-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)- 1 -methylcyclohexane- 1 -carboxylic acid,4-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)- 1 -methylcyclohexane- 1 -carboxylic acid, rac-3-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6S)-4-((( 1 S)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol-4-yl)-2-(3 -methoxy- 8-azabicyclo[3.2.1]octan-8-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6S)-4-((( 1 R)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol-4-yl)-2-(3 -methoxy- 8-azabicyclo[3.2.1]octan-8-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,2-(3-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)acetic acid,( 1 R,4r)-4-(( 1 R)- 1 -((6-cyclopropoxy-4-(((R)- 1 -(1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 - methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-2-((lR,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-l-(3- methoxy-l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((S)-2-((lR,5S)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-l-(3- methoxy-l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,Docket No.: PAT059786-WO-PCT rac-( lR,4r)-4-((R)- 1 -(((S)-6-(methoxy-d3)-4-(((R)- 1 -(l-methyl-lH-pyrazol-4-yl)-2-((S)- 3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-2-((lR,3R,5S)-3-methoxy-8- azabicyclo[3.

2. l]octan-8-yl)-l-(l-methyl-lH-pyrazol-5-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((S)-2-((lR,3S,5S)-3-methoxy-8- azabicyclo[3.

2. l]octan-8-yl)-l-(l-methyl-lH-pyrazol-5-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-l-(l-(2,2-difluoroethyl)-lH-pyrazol-4-yl)-2-((R)-3- methoxypiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-(((lS)-l-(3-methoxy-l-methyl-lH-pyrazol-4-yl)- 2-(3-methoxy-8-azabicyclo[3.

2. l]octan-8-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-(((lR)-l-(3-methoxy-l-methyl-lH-pyrazol-4-yl)- 2-(3-methoxy-8-azabicyclo[3.2.1]octan-8-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((2-(7-azabicyclo[2.2.1]heptan-7-yl)-l-(3-methoxy-l-methyl- lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((2-(7-azabicyclo[2.2.1]heptan-7-yl)-l-(3-methoxy-l-methyl- lH-pyrazol-4-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-((l-(3-methoxy-l-methyl-lH-pyrazol-4-yl)-2- ((R)-3-methoxy-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((S)-l-(l-methyl-lH-pyrazol-3-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid,Docket No.: PAT059786-WO-PCT(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-3-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((S)-l-(l-methyl-lH-pyrazol-5-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-5-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-l-(l-(2,2-difluoroethyl)-lH-pyrazol-4-yl)-2-((R)-3- methoxy-3-methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-((l-(3-methoxy-l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-6-methoxy-4-((l-(3-methoxy-l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((S)-l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-4-(((R)-l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,6-((S)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)spiro[3.3]heptane-2-carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-((l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-(3-methoxy-8- azabicyclo[3.

2. l]octan-8-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059786-WO-PCT(lR,4r)-4-((lR)-l-(((6S)-4-((l-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-(3-methoxy-8- azabicyclo[3.

2. l]octan-8-yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol- 4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,2-(3 -((R)- 1 -(((S)-4-(((R)-2-(azepan- 1 -y 1)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol-4- yl)ethyl)amino)-6-(3-fluorophenyl)-6-methoxy-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)acetic acid,2-(3 -((R)- 1 -(((S)-4-(((S)-2-(azepan- 1 -yl)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol-4- yl)ethyl)amino)-6-(3-fluorophenyl)-6-methoxy-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)acetic acid, rac-( 1 R,4r)-4-((R)- 1 -(((S)-4-(((R)-2-(azepan- 1 -yl)- 1 -(1 -methyl- 1 H-pyrazol-4- yl)ethyl)amino)-6-(2-fluorophenyl)-6-methoxy-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,2-(3 -((R)- 1 -(((S)-6-(3 -fluorophenyl)-6-methoxy-4-(((R)- 1 -(1 -methyl- 1 H-pyrazol-4-yl)- 2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)acetic acid,(lR,4r)-4-((lR)-l-((6-(2-fluorophenyl)-6-methoxy-4-(((R)-2-((R)-3-methoxypiperidin- l-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-((6-(3-fluorophenyl)-6-methoxy-4-(((R)-2-((R)-3-methoxypiperidin-1-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-((4-(((R)-l-(l-(2,2-difluoroethyl)-lH-pyrazol-4-yl)-2-((R)-3- methoxypiperidin-l-yl)ethyl)amino)-6-(3-fluorophenyl)-6-methoxy-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((S)-6-(3-fluorophenyl)-6-methoxy-4-(((R)-2-((R)-3-methoxy-3- methylpiperidin- 1 -yl)-l -(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-5, 6,7, 8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,Docket No.: PAT059786-WO-PCT(lR,4r)-4-((lR)-l-((4-(((R)-l-(l-(2,2-difluoroethyl)-lH-pyrazol-4-yl)-2-((R)-3- methoxy-3-methylpiperidin-l-yl)ethyl)amino)-6-(2-fluorophenyl)-6-methoxy-5,6,7,8- tetrahy droquinazolin-2-y l)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-((6-(2-fluorophenyl)-6-methoxy-4-(((R)-2-((R)-3-methoxy-3- methylpiperidin- 1 -yl)-l -(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-5, 6,7, 8-tetrahydroquinazolin- 2-yl)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-((6-cyclohexyl-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(((6S)-4-(((R)-2-(azepan-l-yl)-l-(l-methyl-lH-pyrazol-4- yl)ethyl)amino)-6-methoxy-6-phenyl-6,6a,7,7a-tetrahydro-5H-cyclopropa[h]quinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,(lR,4r)-4-((lR)-l-(methyl(4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-5a-phenyl-5a,6,6a,7-tetrahydro-5H-cyclopropa[g]quinazolin- 2-yl)amino)propyl)cyclohexane-l -carboxylic acid, and(lR,4r)-4-((R)-l-(((S)-6-methoxy-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)-N-(methylsulfonyl)cyclohexane-l -carboxamide.

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

35. The pharmaceutical composition of claim 34, further comprising at least one additional pharmaceutically active agent.

36. The pharmaceutical composition of claim 35, wherein the additional pharmaceutically active agent is selected from an ACE (angiotensin-converting-enzyme) inhibitor, an angiotensin receptor blocker (ARB), a neprilysin inhibitor, a beta blocker, a diuretic, a calcium channel blocker, a cardiac glycoside, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), an angiotensin receptor-neprilysin inhibitor (ARNi), a corticosteroid, a leukotriene modifier, a bronchodilator, a beta-adrenoceptor antagonist, a carbonic anhydrase inhibitor, an alpha 2-Docket No.: PAT059786-WO-PCT adrenoceptor agonist, a parasympathomimetic, a prostaglandin analog, a rho kinase inhibitor, and combinations thereof.

37. A method for treating or preventing a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of the claims 1 to 33 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of claims 34 to 36.

38. The method of claim 37, wherein the disease or disorder is a cardiovascular disease or disorder.

39. The method of claim 38, wherein the cardiovascular disease or disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, cardiac dysrhythmia, atrial fibrillation (AF), new onset of atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, and myocardial infarction (MI).

40. The method of claim 39, wherein the heart failure is selected from a heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute decompensated heart failure.

41. The method of claim 37, wherein the disease or disorder is preeclampsia, asthma, glaucoma, a kidney disorder, and / or cytokine release syndrome in a subject in need of such treatment.

42. The method of claim 37, wherein the disease or disorder is a disorder or disease associated with natriuretic peptide receptor activity.

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