Hydroquinazoline derivatives for the treatment of a disease or disorder

Abstract

The disclosure relates to a compound of Formula (I): (I) or a compound of Formula (II):, (II) or a pharmaceutically acceptable salt thereof wherein Ring A, Ra to Rc, R1 to R6, n1, R10 to R60, and n2 are as described herein, as well as compositions and methods of using such compounds.

Description

[0001] Docket No.: PAT059787-PCT-SEC01

[0002] HYDROQUINAZOLINE DERIVATIVES FOR THE TREATMENT OF A DISEASE OR DISORDER

[0003] RELATED APPLICATIONS

[0004]

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 688,555, filed August 29, 2024, and U.S. Provisional Application No. 63 / 688,559, filed August 29, 2024, 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 et al., 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] In a first aspect, the disclosure relates to a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0010] R1is H or (Ci-6)alkyl; each instance of R2is independently halogen, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; Docket No.: PAT059787-PCT-SEC01 each instance of R3is independently halogen, -CN, -C(=O)N(R3A)2, -C(=O)OR3B, -N(R3A)2, -N(R3A)C(=O)R3C, -N(R3A)C(=O)OR3B, -OC(=O)R3C, -OH, -OR3D, or (Ci.6)alkyl optionally substituted with halogen, -CN, or -OH; C3-6 cycloalkyl; optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, 0, and S; wherein the 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances of (Ci-6)alkyl, halogen, oxo, -CN, -OH, -0(Ci-6)alkyl, -NH2, or -C(=O)N(R3a)2(Ci-6)alkyl, or C3-6 cycloalkyl; each instance of R3ais independently H or (Ci-6)alkyl; each instance of R3Aand R3Bis independently H or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; each instance of R3Cis independently H, (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; C3-6 cycloalkyl; or 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; optionally wherein R3Aand R3Cor R3Aand R3Bare taken together with the intervening atoms to form an optionally substituted 5-6-membered heterocyclic ring or optionally substituted 5-6-membered heteroaryl ring; wherein the 5-6-membered heterocyclic ring or 5-6-membered heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, - OH, -C02H, -NH2, or (Ci-C6)alkyl; each instance of R3Dis independently (Ci-6)alkyl optionally substituted with halogen, -CN, or - OH; each of R41, R42, and R43is independently hydrogen or (Ci-6)alkyl; nl is 0, 1, 2, 3, 4, or 5; n is 1, 2, or 3; zl is 0, 1, 2, 3, 4, or 5; z2 is 0, 1, 2, 3, 4, or 5; each of Ra, Rb, and Rcis independently H or (Ci-C6)alkyl; and Docket No.: PAT059787-PCT-SEC01 each of R5and R6is independently -(Ci-6)alkyl.

[0011]

[0005] In another aspect, the disclosure relates to a compound of Formula (II): or a pharmaceutically acceptable salt thereof wherein:

[0012] R10is H or (Ci.6)alkyl;

[0013] R20is H, halogen, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl;

[0014] R30is halogen, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; each instance of R40is independently halogen, -CN, -OR40a, -C(=O)OR40b, -N(R40a)C(=O)R40c, - N(R40a)2, -C(=O)N(R40a)2, -C(=O)N(R40a)SO2(R40c), 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; (Ci-C6)alkyl optionally substituted with halogen, -CN, -OH, -C(=O)OR40b, - N(R40a)2, C3-6 cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, - NH2, or (Ci-Ce)alkyl; each instance of R40ais independently H or (Ci^)alkyl; each instance of R40bis independently H, (C3-C6)cycloalkyl, (Ci-6)alkyl optionally substituted with halogen, -CN, -OH, -NH2, 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -(Ci- Ce)alkoxy, -CO2H, -NH2, or (Ci-Ce)alkyl; each instance of R40cis independently H, (Ci-6)alkyl, (C3-C6)cycloalkyl, 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; each of Ra, Rb, Rc, R50, and R60is independently H or (Ci-Ce)alkyl; and n2 is 0, 1, 2, 3, 4, 5, or 6. Docket No.: PAT059787-PCT-SEC01

[0015]

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

[0016]

[0007] In another aspect, the present disclosure relates to a combination comprising a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof and one or more pharmaceutical agents.

[0008] In another aspect, the present disclosure relates to a method for treating a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or disorder is a cardiovascular disease or disorder. In some embodiments, the cardiovascular disease or disorder is selected from hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, cardiac dysrhythmia, atrial fibrillation (AF), new onset of atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, and myocardial infarction (MI). In some embodiments, the disease or disorder is disorder is a disorder or disease associated with natriuretic peptide receptor activity

[0017]

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

[0018]

[0010] In another aspect, the present disclosure relates to a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder.

[0019] [OH] In yet another aspect, the present disclosure relates to a compound of Formula (I) or (II) for use in the manufacture of a medicament for treating a disease or disorder.

[0020]

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

[0021]

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

[0022] DETAILED DESCRIPTION

[0023]

[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.

[0024]

[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 Docket No.: PAT059787-PCT-SEC01 testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

[0025] Compounds

[0026]

[0016] In one aspect, the disclosure therefore provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0027] R1is H or (Ci-ejalkyl; each instance of R2is independently halogen, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; each instance of R3is independently halogen, -CN, -C(=O)N(R3A)2, -C(=O)OR3B,

[0028] -N(R3A)2, -N(R3A)C(=O)R3C, -N(R3A)C(=O)OR3B, -OC(=O)R3C, -OH, -OR3D, or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; C3-6 cycloalkyl; optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, 0, and S; wherein the 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances of (Ci-ejalkyl, halogen, oxo, -CN, -OH, -0(Ci-6)alkyl, -NH2, or -C(=O)N(R3a)2(Ci-6)alkyl, or C3-6 cycloalkyl; each instance of R3ais independently H or (Ci-ejalkyl; Docket No.: PAT059787-PCT-SEC01 each instance of R3Aand R3Bis independently H or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; each instance of R3Cis independently H, (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; C3-6 cycloalkyl; or 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; optionally wherein R3Aand R3Cor R3Aand R3Bare taken together with the intervening atoms to form an optionally substituted 5-6-membered heterocyclic ring or optionally substituted 5-6-membered heteroaryl ring; wherein the 5-6-membered heterocyclic ring or 5-6-membered heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, - OH, -C02H, -NH2, or (Ci-C6)alkyl; each instance of R3Dis independently (Ci-6)alkyl optionally substituted with halogen, -CN, or - each of R41, R42, and R43is independently hydrogen or (Ci-6)alkyl; nl is 0, 1, 2, 3, 4, or 5; n is 1, 2, or 3; zl is 0, 1, 2, 3, 4, or 5; z2 is 0, 1, 2, 3, 4, or 5; each of Ra, Rb, and Rcis independently H or (Ci-Ce)alkyl; and each of R5and R6is independently -(Ci-6)alkyl.

[0029]

[0017] Unless specified otherwise, the term “compounds of the present disclosure” or “compound of the present disclosure” refers to compounds of Formula (I) or (II) 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.

[0030]

[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.

[0031]

[0019] In some embodiments, R1is H or (Ci-6)alkyl (e.g., Me, Et, Pr, Bu). In some embodiments, R1is H. In some embodiments, R1is straight-chain (Ci-6)alkyl or branched (Ci-6)alkyl. In some embodiments, R1is straight-chain (Ci-6)alkyl. In some embodiments, R1is straight-chain (Ci-6)alkyl Docket No.: PAT059787-PCT-SEC01

[0032] (e.g., -Me or -CH3, Et or -CH2CH3, nPr, nBu). In some embodiments, R1is straight-chain (Ci-6)alkyl, for example, straight-chain (Ci-3)alkyl (e.g., -Me or -CH3, Et or -CH2CH3, nPr). In some embodiments, R1is -CH3. In some embodiments, R1is -CH2CH3.

[0033]

[0020] There are nl instances of substituent R2attached to the phenyl ring in Formula (I). In some embodiments, nl is 0. In some embodiments, nl is 1. In some embodiments, nl is 2. In some embodiments, nl is 3. In some embodiments, nl is 4. In some embodiments, nl is 5. In some embodiments, nl is an integer from 0-3 (e.g., integer from 0-2, integer from 0-1). In some embodiments, R1is H and nl is 0.

[0034]

[0021] There are zl instances of substituent R3attached to the nitrogen-containing heterocyclyl group 0 of Ring / in Formula (I). In some embodiments, zl is 0. In some embodiments, zl is 1. In some embodiments, zl is 2. In some embodiments, zl is 3. In some embodiments, zl is 4. In some embodiments, zl is 5. In some embodiments, zl is an integer from 0-5 (e.g., integer from 0-3, 0-2, integer from 0-1).

[0035]

[0022] In some embodiments, at least one instance of R2is halogen, -CN, -OH, -CO2H, -NH2, or (Ci- Ce)alkyl. In some embodiments, at least one instance of R2is halogen (e.g., -Cl, -F, -Br, -I). In some embodiments, at least one instance of R2is -CN. In some embodiments, at least one instance of R2is - OH. In some embodiments, at least one instance of R2is -CO2H. In some embodiments, at least one instance of R2is -NH2. In some embodiments, at least one instance of R2is (Ci-C6)alkyl. Docket No.: PAT059787-PCT-SEC01 optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, 0, and S; wherein the optionally substituted 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances of (Ci-6)alkyl, halogen, oxo, -CN, -OH, (Ci-6)alkyl, or C3-6 cycloalkyl; z2 is 0, 1, 2, or 3; each instance of R3Aand R3Bis independently H or optionally substituted (Ci-6)alkyl; optionally wherein R3Aand R3Cor R3Aand R3Bare taken together with the intervening atoms to form an optionally substituted 5-6-membered heterocyclic or optionally substituted 5-6-membered heteroaryl ring; each instance of R3Cis independently H, optionally substituted (Ci-6)alkyl; R3Dis (Ci- e)alkyl optionally substituted with halogen, -CN, or -OH. Docket No.: PAT059787-PCT-SEC01

[0036]

[0024] In some embodiments, Ring ; wherein n is 1, 2, or 3, and zl is 1, 2, or

[0037] 3. In some embodiments, Ring ; wherein n is 1 or 2, and zl is 1, 2, or 3. In some embodiments, Ring ( NA— ; wherein n is 1 and zl is 1. In some embodiments,

[0038] Ring . In some embodiments, Ring , wherein at least one instance of R3is optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, 0, and S; wherein the 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances (e.g., 0, 1, 2, 3, 4, or 5 instances) of (Ci- e)alkyl, halogen, oxo, -CN, -OH, -O(Ci-6)alkyl, -NH2, or -C(=O)N(R3a)2(Ci-6)alkyl, or C3-6 cycloalkyl, and each instance of R3ais independently H or (Ci-6)alkyl. In some embodiments, Ring is , wherein at least one instance of R3is furan, thiophene, pyrrole, pyrrolidine, imidazoline, pyrazoline, isoxazole, isothiazole, imidazole, pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole, or tetrahydropyranopyrazole, morpholine, piperidine, piperazine, or pyrimidine, each of which is optionally substituted with z2 instances (e.g., 0, 1, 2, 3, 4, or 5 instances) of (Ci-6)alkyl, halogen, oxo, -CN, -OH, -O(Ci-6)alkyl, -NHz, or -C(=O)N(R3a)2(Ci-6)alkyl, or C3-6 cycloalkyl. In some embodiments, Ring wherein n is 1 and zl is 2. In some embodiments, Ring . In some embodiments, Docket No.: PAT059787-PCT-SEC01 ; wherein n is 1 and zl is 3. In some embodiments, Ring ; w eren n s , an z s or e.g., . n some em o mens, Ring , In some embodiments, Ring

[0039] (V)

[0040] ; wherein n is 2, and zl is 2. In some embodiments, Ring ' is ; w eren n is 2, and zl is 1. In some embodiments, Ring some embodiments, Ring In some embodiments, Ring

[0041] In some embodiments, Ring ; wherein n is 3, and zl is 1. In some embodiments, Ring Docket No.: PAT059787-PCT-SEC01

[0042]

[0026] In some embodiments, at least one instance of R3is halogen (e.g., -Cl, -F, -Br, -I), -CN, -

[0043] C(=O)N(R3A)2, -C(=O)OR3B, -N(R3A)C(=O)R3C, -N(R3A)C(=O)OR3B, -OC(=O)R3C, -OH, -OR3D, -

[0044] N(R3A)2, or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; C3-6 cycloalkyl; optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, 0, and S; wherein the 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances of (Ci^)alkyl, halogen, oxo, -CN, -OH, -0(Ci-6)alkyl, -NH2, or -C(=O)N(R3a)2(Ci. e)alkyl, or C3-6 cycloalkyl; each instance of R3ais independently H or (Ci-6)alkyl. In some embodiments, at least one instance of R3is halogen (e.g., -Cl, -F, -Br, -I), -CN, -C(=O)N(R3A)2, -C(=0)0R3B, - N(R3A)C(=O)R3C, -N(R3A)C(=O)OR3B, -0C(=0)R3C, -OH, -0R3D, or (Ci.6)alkyl optionally substituted with halogen, -CN, or -OH; C3-6 cycloalkyl; optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, 0, and S; wherein the 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances of (Ci- e)alkyl, halogen, oxo, -CN, -OH, -O(Ci^)alkyl, -NH2, or -C(=O)N(R3a)2(Ci-6)alkyl, or C3-6 cycloalkyl; each instance of R3ais independently H or (Ci-6)alkyl. In some embodiments, at least one instance of R3is halogen (e.g., -Cl, -F, -Br, -I). In some embodiments, at least one instance of R3is -CN. In some embodiments, at least one instance of R3is: -N(R3A)2, -C(=O)N(R3A)2, -N(R3A)C(=O)R3C, - N(R3A)C(=O)OR3B, or -OC(=O)R3C; and each instance of R3Ais independently H or (Ci-Ce)alkyl; and each of R3Band R3Cis (Ci-C6)alkyl. In some embodiments, at least one instance of R3is -C(=O)N(R3A)2, wherein at least one instance of R3Ais H or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH. In some embodiments, at least one instance of R3is -C(=O)N(R3A)2(e.g., -C(=0)NMe2, -C(=0)NH2, - Docket No.: PAT059787-PCT-SEC01

[0045] C(=O)NHMe)). In some embodiments, at least one instance of R3is: -NMe2, -C(=0)NMe2, - N(Me)C(=O)Me, -N(Me)C(=O)OMe, or -OC(=O)Me. In some embodiments, at least one instance of R3is -C(=0)NMe2. In some embodiments, at least one instance of R3is -N(R3A)2 (e.g., -NH2, -NMe2). In some embodiments, at least one instance of R3is -C(=O)OR3B, wherein R3Bis H or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH. In some embodiments, at least one instance of R3is - N(R3A)2, wherein at least one instance of R3Ais H or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH. In some embodiments, at least one instance of R3is -NMe2, -NHMe, or -NH2. In some embodiments, at least one instance of R3is -N(R3A)C(=O)R3C, wherein each instance of R3Aand R3Bis independently H or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; optionally wherein R3Aand R3Care taken together with the intervening atoms to form an optionally substituted 5-6-membered heterocyclic ring or optionally substituted 5-6-membered heteroaryl ring; wherein the 5-6-membered heterocyclic ring or 5-6-membered heteroaryl ring is optionally substituted with one or more (e.g., z3, such as an integer selected from 0-4 (e.g., 0, 1, 2) substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl (e.g., substituted with oxo). In some embodiments, at least one instance of R3is -N(R3A)C(=O)R3C, wherein each instance of R3Aand R3Bis independently H or (Ci- e)alkyl; optionally wherein R3Aand R3Care taken together with the intervening atoms to form an optionally substituted 5-6-membered heterocyclic ring; wherein the 5-6-membered heterocyclic ring is optionally substituted with one or more (e.g., z3, such as an integer selected from 0-4 (e.g., 0, 1, 2) substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, -NH2, or (Ci-C6)alkyl. In some embodiments, at least one instance of R3is In some embodiments, at least one instance of R3is -N(R3A)C(=O)R3C, wherein each instance of R3Aand R3Bis independently H or (Ci- e)alkyl optionally substituted with halogen, -CN, or -OH. In some embodiments, at least one instance of R3is -N(R3A)C(=O)R3C, and R3Ais H or (Ci-Ce)alkyl; and R3Cis (Ci-C6)alkyl. In some embodiments, at least one instance of R3is -N(Me)C(=O)Me, -NHC(=O)Me, or -N(Me)C(=O)Et (e.g., -N(Me)C(=O)Me). In some embodiments, z3 is an integer selected from 0-5, e.g., 0, 1, 2, 3, 4, or 5 (e.g., 0, 1, 2, 3). In some embodiments, z3 is 0. In some embodiments, z3 is 1. In some embodiments, at least one instance of R3is -N(R3A)C(=O)OR3B, wherein each instance of R3Aand R3Bis independently H or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; or optionally wherein R3Aand R3Bare taken together with the intervening atoms to form an optionally substituted 5-6-membered heterocyclic ring or optionally substituted 5-6-membered heteroaryl ring; wherein the 5-6-membered heterocyclic ring or 5-6- membered heteroaryl ring is optionally substituted with one or more (e.g., z3, such as an integer selected from 0-4 (e.g., 0, 1, 2) substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, -NH2, Docket No.: PAT059787-PCT-SEC01 or (Ci-C6)alkyl. In some embodiments, at least one instance of R3is -N(R3A)C(=O)OR3B, wherein each instance of R3Aand R3Bis independently H or (Ci-6)alkyl optionally substituted with halogen, -CN, or - OH. In some embodiments, at least one instance of R3is -N(Me)C(=O)OMe, -NHC(=O)OMe, - N(Me)C(=O)OEt (e.g., -N(Me)C(=O)OMe). In some embodiments, z3 is an integer selected from 0-5, e.g., 0, 1, 2, 3, 4, or 5 (e.g., 0, 1, 2, 3). In some embodiments, z3 is 0. In some embodiments, z3 is 1. In some embodiments, at least one instance of R3is -N(R3A)C(=O)OR3B, wherein each instance of R3Aand R3Bis independently H or (Ci-6)alkyl; or optionally wherein R3Aand R3Bare taken together with the intervening atoms to form an optionally substituted 5-6-membered heterocyclic ring; wherein the 5-6- membered heterocyclic ring is optionally substituted with one or more (e.g., z3, such as an integer selected from 0-4 (e.g., 0, 1, 2) substituents independently selected from halogen, oxo, -CN, -OH, - CO2H, -NH2, or (Ci-C6)alkyl. In some embodiments, at least one instance of R3is . In some

[0046] O embodiments, at least one instance of R3is . In some embodiments, at least one instance of In some embodiments, at least one instance of R3is some embodiments, at least one instance of R3is

[0047]

[0027] In some embodiments, at least one instance of R3is -OC(=O)R3C, wherein each instance of R3Cis independently H, (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; C3-6 cycloalkyl; or 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, or 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, at least one instance of R is -OC(=O)R , wherein each instance of R is independently H, (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH (e.g., R3is -OC(=O)Me).

[0048]

[0028] In some embodiments, at least one instance of R3is -OH, -OR3D, or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH. In some embodiments, at least one instance of R3is -OH. In some embodiments, at least one instance of R3is -OR3D; and R3Dis (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH (e.g., (Ci-3)alkyl optionally substituted with halogen). In some embodiments, at least one instance of R3is -O(Ci-3)alkyl optionally substituted with halogen (e.g., -Cl, -F, -Br, -I), such as -OCH2CF3. In some embodiments, at least one instance of R3is -OCH2CF3. In some embodiments, at least one instance of R3is (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH. In some Docket No.: PAT059787-PCT-SEC01 embodiments, at least one instance of R3is -CH3. In some embodiments, at least one instance of R3is - CH2CH3.

[0049]

[0029] In some embodiments, at least one instance of R3is C3-6 cycloalkyl; optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, 0, and S; wherein the 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances of (Ci-6)alkyl, halogen, oxo, -CN, -OH, -0(Ci-6)alkyl, -NH2, or -C(=O)N(R3a)2(Ci-6)alkyl, or C3-6 cycloalkyl. In some embodiments, at least one instance of R3is optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, 0, and S; wherein the 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances (e.g., 0, 1, 2, 3, 4, or 5 instances) of (Ci-6)alkyl, halogen, oxo, -CN, -OH, -0(Ci-6)alkyl, -NH2, or -C(=O)N(R3a)2(Ci-6)alkyl, or C3-6 cycloalkyl, and each instance of R3ais independently H or (Ci- 6)alkyl. In some embodiments, at least one instance of R3is H or (Ci-6)alkyl (e.g., Me, Et, Pr, Bu). In some embodiments, at least one instance of R3is furan, thiophene, pyrrole, pyrrolidine, imidazoline, pyrazoline, isoxazole, isothiazole, imidazole, pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole, or tetrahydropyranopyrazole, morpholine, piperidine, piperazine, or pyrimidine, each of which is optionally substituted with z2 instances (e.g., 0, 1, 2, 3, 4, or 5 instances) of (Ci-6)alkyl, halogen, oxo, -CN, -OH, -O(Ci^)alkyl, -NH2, or -C(=O)N(R3a)2(Ci-6)alkyl, or C3-6 cycloalkyl. In some embodiments, at least one instance of R3is monocyclic or bicyclic 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S. In some embodiments, at least one instance of R3is a bicyclic 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, comprising a 5-6 membered heteroaryl ring fused to a5-6 membered heterocyclyl ring. In some embodiments, at least one instance of R3is 5-9 membered heterocyclyl (e.g., monocyclic 5-9 membered heterocyclyl) comprising 1 to 3 heteroatoms selected from N, 0, and S, such as pyrrolidine). In some embodiments, at least one instance of R3is 5-9 membered heterocyclyl (e.g., bicyclic 5-9 membered heterocyclyl) comprising 1 to 3 heteroatoms selected from N, 0, and S, such as tetrahydropyranopyrazole some embodiments, at least one instance of R3is pyrrolidine. In some embodiments, at least one instance of R3is furan, imidazole, pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole, or tetrahydropyranopyrazole; wherein R3is optionally substituted with 1, 2, or 3 instances of (Ci-6)alkyl, halogen, oxo, -CN, -OH, -0(Ci-6)alkyl, -NH2, or - C(=O)N(R3a)2(Ci-6)alkyl, or C3-6 cycloalkyl. In some embodiments, at least one instance of R3is Docket No.: PAT059787-PCT-SEC01 substituted with 1, 2, or 3 instances of (Ci-6)alkyl (e.g., Me, Et, nPr, iPr), halogen (e.g., -Cl, -F, -Br, -I), oxo, -CN, -OH, -O(Ci.6)alkyl, -NH2, or -C(=O)N(R3a)2(Ci.6)alkyl (e.g., -C(=O)NMe2, -C(=O)NHMe), or C3-6 cycloalkyl (e.g., cyclopropyl). In some embodiments, R3is optionally substituted with z2 instances (e.g., 0, 1, 2, 3, 4, or 5 instances) of a substituent described herein. In some embodiments, R3is substituted with at least one (Ci-6)alkyl (e.g., Me, Et, nPr, iPr). In some embodiments, R3is substituted with at least one halogen (e.g., -Cl, -F, -Br, -I). In some embodiments, R3is optionally substituted with oxo (=0), -CN, -OH, -O(Ci-6)alkyl (e.g., -OMe), -NH2, or -C(=O)N(R3a)2(Ci-6)alkyl (e.g., -C(=0)NMe2,

[0050] -C(=O)NHMe), or C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).

[0051]

[0030] ; R3is furan, imidazole, pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole, or tetrahydropyranopyrazole; and R3is optionally substituted with 1 or 2 instances of (Ci-6)alkyl, halogen, (Ci-6)alkyl, oxo, C3-6 cycloalkyl, -OH, -C(=O)NMe2, -C(=O)NHMe, or

[0052] C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, at least one instance of R3is:

[0053] Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 hydrogen, halogen (e.g., -F, -Cl, or -Br), (Ci^)alkoxyl, (Ci-6)alkyl, or (Ci-C2)alkyl(C3-C6)cycloalkyl. In some embodiments, wherein each of R41, R42, and R43is independently hydrogen, Docket No.: PAT059787-PCT-SEC01 halogen (e.g., -F, -Cl, or -Br), (Ci-6)alkoxyl, (Ci-6)alkyl, or (Ci-C2)alkyl(C3-C6)cycloalkyl. In some embodiments, wherein each of R41, R42, and R43is independently hydrogen or (Ci- e)alkyl (e.g., (Ci-3)alkyl). In some embodiments, R41is H. In some embodiments, R41is (Ci-6)alkyl (e.g., (Ci-3)alkyl). In some embodiments, R42is H. In some embodiments, R42is (Ci-6)alkyl (e.g., (Ci-3)alkyl). In some embodiments, R43is H. In some embodiments, R43is (Ci-6)alkyl (e.g., (Ci-3)alkyl, such as Me, Et, nPr, iPr, nBu, t-Bu). In some embodiments, R43is (Ci-6)alkyl (e.g., (Ci-3)alkyl, such as Me, iPr). In some embodiments, R41and R42are each H, and R43is (Ci-6)alkyl (e.g., (Ci-3)alkyl, such as Me, Et, nPr, iPr, nBu, t-Bu). In some embodiments,

[0054]

[0032] In some embodiments, R41and R43are each H, and R42is (Ci-6)alkyl (e.g., (Ci-3)alkyl, such as

[0055] Me, iPr). In some embodiments, some embodiments,

[0056] In some embodiments, some embodiments, R42and R43are each H, and R41is (Ci-

[0057] N~NH e)alkyl (e.g., (Ci-3)alkyl, such as Me, Et, nPr, iPr, nBu, t-Bu). In some embodiments, R4is

[0058]

[0033] In some embodiments, each of Ra, Rb, and Rcis independently H or (Ci-Ce)alkyl (e.g., Me, Et, Pr). In some embodiments, each of Ra, Rb, and Rcis H. In some embodiments, each of Ra, Rb, and Rcis (Ci-C6)alkyl (e.g., (Ci-C^alkyl, for example, Me, Et, Pr).

[0059]

[0034] In some embodiments, each of R5and R6is independently -(Ci-6)alkyl (e.g., Me, Et, Pr, Bu). In some embodiments, R5is Me. In some embodiments, R5is Et (-CH2CH3). In some embodiments, R5is Pr (e.g., nPr, iPr). In some embodiments, R6is Me. In some embodiments, R6is Et (-CH2CH3). In some Docket No.: PAT059787-PCT-SEC01 embodiments, R6is Pr (e.g., nPr, iPr). In some embodiments, R5and R6are each -CH3. In some embodiments, R5is -CH3 and R6is -CH2CH3. In some embodiments, R5is -CH2CH3 and R6is -CH3. , , , , p y ed

[0060] 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, 0, and S (e.g., furan, imidazole, pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole, or tetrahydropyranopyrazole); wherein the optionally substituted 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances of halogen, oxo, -CN, -OH, (Ci. e)alkyl (e.g., Me, Et, Pr), or C3-6 cycloalkyl; z2 is 0, 1, 2, or 3; each instance of R3Aand R3Bis independently H or optionally substituted (Ci-6)alkyl; R3Cis (Ci-6)alkyl (e.g., Me, Et, Pr); R3Dis (Ci- e)alkyl optionally substituted with halogen, are each H; and R42is (Ci-6)alkyl; each of Ra, Rb, and Rcis H; R5is -CH2CH3; and R6is -CH3. In some Docket No.: PAT059787-PCT-SEC01 optionally substituted with z2 instances (e.g., 0, 1, 2, or 3 instances) of halogen, oxo, -CN, -OH, (Ci- e)alkyl (e.g., Me, Et, Pr), or C3-6 cycloalkyl.

[0061]

[0036] In some embodiments, the compound is of Formula (I-A) or (I-B): or a pharmaceutically acceptable salt thereof.

[0062]

[0037] In some embodiments, the compound is of Formula (I-A): or a pharmaceutically acceptable salt thereof.

[0063]

[0038] In some embodiments, the compound is of Formula (I-B): or a pharmaceutically acceptable salt thereof.

[0064]

[0039] In some embodiments, the compound is of Formula (I-A) or (I-B): Docket No.: PAT059787-PCT-SEC01 or a pharmaceutically acceptable salt thereof, wherein:

[0065] R1is H or (Ci-6)alkyl; each instance of R2is independently halogen, -CN, -OH, -CO2H, -NH2, or (Ci-C6)alkyl;

[0066] Ring each instance of R3is independently halogen, -CN, -C(=O)N(R3A)2, -N(R3A)2, -C(=O)OR3B, - N(R3A)C(=O)R3C, -N(R3A)C(=O)OR3B, -OC(=O)R3C, -OH, -OR3D, or (Ci.6)alkyl optionally substituted with halogen, -CN, or -OH; C3-6 cycloalkyl; optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, 0, and S; wherein the 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances of (Ci- e)alkyl, halogen, oxo, -CN, -OH, -0(Ci-6)alkyl, -NH2, or -C(=O)N(R3a)2(Ci-6)alkyl, or C3-6 cycloalkyl; each instance of R3ais independently H or (Ci-6)alkyl; each instance of R3Aand R3Bis independently H or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; each instance of R3Cis independently H, (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; C3-6 cycloalkyl; or 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; optionally wherein R3Aand R3Cor R3Aand R3Bare taken together with the intervening atoms to form an optionally substituted 5-6-membered heterocyclic ring or optionally substituted 5-6-membered heteroaryl ring; wherein the 5-6-membered heterocyclic ring or 5-6-membered heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, - OH, -C02H, -NH2, or (Ci-C6)alkyl; each instance of R3Dis independently (Ci-6)alkyl optionally substituted with halogen, -CN, or - OH; Docket No.: PAT059787-PCT-SEC01 each of R41, R42, and R43is independently hydrogen or (Ci-6)alkyl; nl is 0, 1, 2, 3, 4, or 5; n is 1, 2, or 3; zl is 0, 1, 2, 3, 4, or 5; z2 is 0, 1, 2, 3, 4, or 5; each of Ra, Rb, and Rcis independently H or (Ci-Ce)alkyl; and each of R5and R6is independently -(Ci-6)alkyl.

[0067]

[0040] In some embodiments, the compound is of Formula (I-A) or (I-B): or a pharmaceutically acceptable salt thereof, wherein: each instance of R3is independently (Ci-6)alkyl, -C(=O)N(R3A)2, -N(R3A)C(=O)R3C, -

[0068] O O

[0069] N(R3A)C(=O)OR3B, -OC(=O)R3C, -OR3D, , or optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;

[0070] R41and R43are each H; and R42is (Ci-6)alkyl; each of Ra, Rb, and Rcis H;

[0071] R5and R6are independently (Ci-6)alkyl. Docket No.: PAT059787-PCT-SEC01

[0072]

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

[0073] Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01

[0074] Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01

[0075]

[0042] In another aspect, the disclosure therefore provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof wherein:

[0076] R10is H or (Ci.6)alkyl;

[0077] R20is H, halogen, -CN, -OH, -CO2H, -NH2, or (Ci-C6)alkyl;

[0078] R30is halogen, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; each instance of R40is independently halogen, -CN, -OR40a, -C(=O)OR40b, -N(R40a)C(=O)R40c, - N(R40a)2, -C(=O)N(R40a)2, -C(=O)N(R40a)SO2(R40c), 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; (Ci-Ce)alkyl optionally substituted with halogen, -CN, -OH, -C(=O)OR40b, - N(R40a)2, C3-6 cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -C02H, - NH2, or (Ci-C6)alkyl; each instance of R40ais independently H or (Ci-6)alkyl; each instance of R40bis independently H, (C3-C6)cycloalkyl, (Ci-6)alkyl optionally substituted with halogen, -CN, -OH, -NH2, 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, Docket No.: PAT059787-PCT-SEC01 and S; wherein the 5- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -(Ci- Ce)alkoxy, -CO2H, -NH2, or (Ci-C6)alkyl; each instance of R40cis independently H, (Ci-6)alkyl, (C3-C6)cycloalkyl, 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; each of Ra, Rb, Rc, R50, and R60is independently H or (Ci-Ce)alkyl; and n2 is 0, 1, 2, 3, 4, 5, or 6.

[0079]

[0043] In some embodiments, R10is H, halogen, -CN, -OH, -CO2H, -NH2, or (Ci-C6)alkyl. In some embodiments, R10is H or (Ci-6)alkyl (e.g., Me, Et, Pr, Bu). In some embodiments, R10is H. In some embodiments, R10is straight-chain (Ci-6)alkyl or branched (Ci-6)alkyl. In some embodiments, R10is straight-chain (Ci-6)alkyl (e.g., -Me or -CH3, Et or -CH2CH3, nPr, nBu). In some embodiments, R10is straight-chain (Ci-6)alkyl, for example, straight-chain (Ci-3)alkyl (e.g., -Me or -CH3, Et or -CH2CH3, nPr).

[0080]

[0044] In some embodiments, at least one instance of R20is halogen, -CN, -OH, -CO2H, -NH2, or (Ci- C6)alkyl. In some embodiments, at least one instance of R20is halogen (e.g., -Cl, -F, -Br, -I). In some embodiments, at least one instance of R20is -Cl, -F, -Br, -I. In some embodiments, at least one instance of R20is -Cl. In some embodiments, at least one instance of R20is -F. In some embodiments, at least one instance of R20is -Br. In some embodiments, at least one instance of R20is -I. In some embodiments, at least one instance of R20is -CN. In some embodiments, at least one instance of R20is - OH. In some embodiments, at least one instance of R20is -CO2H. In some embodiments, at least one instance of R20is -NH2. In some embodiments, at least one instance of R20is (Ci-C6)alkyl.

[0081]

[0045] In some embodiments, at least one instance of R30is halogen (e.g., -Cl, -F, -Br, -I), -CN, - C(=O)N(R30A)2, -C(=O)OR30B, -OH, -OR30D, -N(R3°A)2, or (Ci.6)alkyl optionally substituted with halogen, -CN, or -OH; each instance of R30Aand R30Bis independently H or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; each instance of R30Dis independently (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH. In some embodiments, at least one instance of R30is halogen (e.g., -Cl, -F, -Br, -I), -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl (e.g., Me, Et, Pr, Bu). In some embodiments, at least one instance of R30is halogen (e.g., -Cl, -F, -Br, -I). In some embodiments, at least one instance of R30is -Cl. In some embodiments, at least one instance of R30is -F. In some embodiments, at least one instance of R30is -Br. In some embodiments, at least one instance of R30is -I. In some embodiments, at least one instance of R30is -C(=O)N(R30A)2 (e.g., -C(=0)NMe2, -C(=O)NH2, - C(=0)NHMe)). In some embodiments, at least one instance of R30is -C(=0)NMe2. In some embodiments, at least one instance of R30is -C(=O)OR30B, wherein R30Bis H or (Ci-6)alkyl optionally Docket No.: PAT059787-PCT-SEC01 substituted with halogen, -CN, or -OH. In some embodiments, at least one instance of R30is -N(R30A)2, wherein at least one instance of R30Ais H or (Ci-6)alkyl optionally substituted with halogen, -CN, or - OH. In some embodiments, at least one instance of R30is -NMe?, -NHMe, or -NH2. In some embodiments, at least one instance of R30is -OR30D; and R30Dis (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH (e.g., (Ci-3)alkyl optionally substituted with halogen). In some embodiments, at least one instance of R30is -O(Ci-3)alkyl optionally substituted with halogen (e.g., -Cl, -F, -Br, -I), such as -OCH2CF3. In some embodiments, at least one instance of R30is (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH. In some embodiments, at least one instance of R30is (Ci-6)alkyl. In some embodiments, at least one instance of R30is straight-chain (Ci-6)alkyl (e.g., -Me or -CH3, Et or -CH2CH3, nPr, nBu). In some embodiments, at least one instance of R30is straight-chain (Ci-6)alkyl, for example, straight-chain (Ci-4)alkyl or straight-chain (Ci-3)alkyl (e.g., -Me or -CH3, Et or -CH2CH3, nPr). In some embodiments, at least one instance of R30is is straight-chain (Ci-4)alkyl or straight-chain (Ci-3)alkyl. In some embodiments, at least one instance of R30is -CH3. In some embodiments, at least one instance of R30is -CH2CH3. In some embodiments, at least one instance of R30is -CH2CH2CH3. In some embodiments, at least one instance of R30is -CH2CH2CH2CH3.

[0046] In some embodiments, in the moiety in Formula (II), there are n2 instances of substituent R40attached to the cyclohexyl group. In some embodiments, n2 is an integer between 0-6 (z.e., n2 is 0, 1, 2, 3, 4, 5, or 6, for example, 0, 1, 2, or 3). In some embodiments, n2 is 1, 2, or 4. In some embodiments, n2 is 1, 2, or 3. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 4.

[0082]

[0047] In some embodiments, the moiety is: Docket No.: PAT059787-PCT-SEC01 , ,

[0083]

[0048] In some embodiments, at least one instance of R40is halogen, -CN, -OR40a, -C(=O)OR40b, - N(R40a)C(=O)R40c, -N(R40a)2, -C(=O)N(R40a)2, -C(=O)N(R40a)SO2(R40c), 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; (Ci-Ce)alkyl optionally substituted with halogen, -CN, -OH, -C(=O)OR40b, -N(R40a)2, C3-6 cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, - Docket No.: PAT059787-PCT-SEC01

[0084] CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; each instance of R40ais independently H or (Ci-6)alkyl; each instance of R40bis independently H, (C3-C6)cycloalkyl, (Ci-6)alkyl optionally substituted with halogen, - CN, -OH, -NH2, 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -(Ci-C6)alkoxy, -CO2H, - NH2, or (Ci-Ce)alkyl; each instance of R40cis independently H, (Ci-6)alkyl, (C3-C6)cycloalkyl, 5- to 6- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S. In some embodiments, at least one instance of R40is halogen (e.g., -Cl, -F, -Br, -I). In some embodiments, at least one instance of R40is - CN. In some embodiments, at least one instance of R40is -OR40a, wherein R40ais H or (Ci^)alkyl.

[0049] In some embodiments, at least one instance of R40is -C(=O)OR40b, and R40bis H, (C3- C6)cycloalkyl, (Ci-6)alkyl optionally substituted with halogen, -CN, -OH, -NH2, 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -(Ci-C6)alkoxy, -CO2H, -NH2, or (Ci-C6)alkyl. In some embodiments, at least one instance of R40is -C(=O)OR40b, wherein R40bis H, unsubstituted (Ci- Ce)alkyl or (Ci-C6)alkyl substituted with 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S; and wherein the 5- to 6-membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, -NH2, or (Ci- Ce)alkyl. In some embodiments, at least one instance of R40is -C(=O)OR40b(e.g., -C(=0)0H, - C(=0)0Me, -C(=O)OEt). In some embodiments, at least one instance of R40is -C(=O)OR40b, wherein R40bis (Ci-Ce)alkyl (e.g., (Ci-3)alkyl) substituted with 5- to 6-membered monocyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S; and wherein the 5- to 6-membered monocyclic heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl (e.g., Me, Et, Pr). In some embodiments, at least one instance of R40is -C(=O)OR40b, wherein R40bis (Ci-Ce)alkyl (e.g., (Ci-3)alkyl) substituted with 5- to 6- membered monocyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S; and wherein the 5- to 6-membered monocyclic heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl (e.g., Me, Et, Pr), for example, wherein the 5- to 6-membered monocyclic heterocyclyl is tetrahydro furan, dioxole, dihydropyrrole, pyrrolidine, imdazoline, dihydropyrazole, tetrahydropyran, dioxane, morpholine, piperidine, or piperazine. In some embodiments, at least one instance of R40is -C(=O)OR40b Docket No.: PAT059787-PCT-SEC01 some embodiments, at least one instance of R40is -

[0085] N(R40a)C(=O)R40c, wherein R40ais H or (Ci.6)alkyl; R40cis independently H, (Ci-6)alkyl, (C3- C6)cycloalkyl, 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S. In some embodiments, at least one instance of R40is -N(R40a)C(=O)R40c(e.g., -NHC(=0)Me, -NMeC(=0)Me)). In some embodiments, at least one instance of R40is -N(R40a)2, wherein R40ais H or (Ci-6)alkyl. In some embodiments, at least one instance of R40is -N(R40a)2 (e.g., -NH2, -NMez). In some embodiments, at least one instance of R40is -C(=O)N(R40a)2, wherein R40ais H or (Ci-6)alkyl. In some embodiments, at least one instance of R40is -C(=O)N(R40a)2 (e.g., -C(=0)NH2, -C(=0)NMe2). In some embodiments, at least one instance of R40is -C(=O)N(R40a)SO2(R40c), R40ais H or (Ci.6)alkyl, R40cis H, (Ci.6)alkyl, or (C3- C6)cycloalkyl. In some embodiments, at least one instance of R40is -C(=O)N(R40a)SO2(R40c); and each of R40aand R40cis independently H or (Ci-6)alkyl (e.g., straight-chain (Ci-6)alkyl, for example, straightchain (Ci-4)alkyl). In some embodiments, at least one instance of R40is -C(=O)N(R40a)SO2(R40c) (e.g., ,?). In some embodiments, at least one instance of R40is 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6- membered heterocyclyl and 5- or 6-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, -NH2, or (Ci-C6)alkyl. In some embodiments, at least one instance of R40is: 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -CO2H, -NH2, or (Ci-C6)alkyl. In some embodiments, at least one instance of R40is 5- or 6-membered heteroaryl (e.g., 5- or 6-membered monocyclic heteroaryl) comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -CO2H, -NH2, or (Ci-C6)alkyl. In some embodiments, at least one instance of R40is: furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, pyrimidinyl, or isoxazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -CO2H, -NH2, or (Ci-C6)alkyl. In some embodiments, at least one instance of R40is: 5 -membered heteroaryl (e.g., furyl, thienyl, pyrrolyl, Docket No.: PAT059787-PCT-SEC01 pyridyl, pyrazolyl, isoxazolyl) comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -CO2H, -NH2, or (Ci-C6)alkyl. In some embodiments, at least one instance of R40is: furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, or isoxazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -CO2H, -NH2, or (Ci- x V A

[0086] 40 N~,„x ~OH

[0087] Ce)alkyl. In some embodiments, at least one instance of R is: O . In some embodiments,

[0088]

[0050] In some embodiments, at least one instance of R40is: (Ci-Ce)alkyl optionally substituted with halogen, -CN, -OH, -C(=O)OR40b, -N(R40a)2, C3-6 cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein each instance of R40ais independently H or (Ci- e)alkyl; each instance of R40bis independently H, (C3-C6)cycloalkyl, (Ci-6)alkyl optionally substituted with halogen, -CN, -OH, -NH2, 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -(Ci- Ce)alkoxy, -CO2H, -NH2, or (Ci-C6)alkyl. In some embodiments, at least one instance of R40is (Ci- Ce)alkyl (e.g., straight-chain (Ci-C6)alkyl). In some embodiments, at least one instance of R40is straight-chain (Ci-C6)alkyl. In some embodiments, R40is straight-chain (Ci-6)alkyl (e.g., -Me or -CH3, Et or -CH2CH3, nPr, nBu). In some embodiments, R40is straight-chain (Ci-6)alkyl, for example, straightchain (Ci-3)alkyl (e.g., -Me or -CH3, Et or -CH2CH3, nPr). In some embodiments, at least one instance of R40is: (Ci-Ce)alkyl optionally substituted with -N(R40a)2 (e.g., -NH2, -NHMe, -NMe2). In some embodiments, at least one instance of R40is: (Ci-C4)alkyl optionally substituted with -N(R40a)2 (e.g., - Docket No.: PAT059787-PCT-SEC01

[0089] NHz, -NHMe, -NMez). In some embodiments, at least one instance of R40is: (Ci-C3)alkyl optionally substituted with -N(R40a)z (e.g., -NHz, -NHMe, -NMez). In some embodiments, at least one instance of R40is: -(CHz)i-3N(R40a)z, and each instance of R40ais independently H or (Ci-6)alkyl. In some embodiments, at least one instance of R40is: -(CHz)i-3NMez (e.g., -(CHz)NMez, -(CHz)zNMez, - (CHz)3NMez). In some embodiments, at least one instance of R40is: (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH. In some embodiments, at least one instance of R40is: -(CHz)i-3N(R40a)z; - C(=O)OR40b, or -C(=O)N(R40a)SOz(R40c); each instance of R40ais independently H or (Ci-6)alkyl; R40bis H; 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S; 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; or (Ci-6)alkyl optionally substituted with halogen, -CN, -OH, (C3-C6)cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -COzH, -NHz, or (Ci-Ce)alkyl; and R40cis H, (Ci-6)alkyl, or (C3- C6)cycloalkyl. In some embodiments, at least one instance of R40is: -(CHz)i-3NMez; -C(=O)OR40b; or - C(=O)N(R40a)SOz(R40c); wherein R40bis H, unsubstituted (Ci-Ce)alkyl or (Ci-Ce)alkyl substituted with 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -COzH, -NHz, or (Ci-Ce)alkyl; and each of R40aand R40cis independently H or (Ci-6)alkyl. In some embodiments, at least one instance of R40is: -(CHz)zNMez, -C(=0)0H, Docket No.: PAT059787-PCT-SEC01 heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, - CN, -OH, -CO2H, -NH2, or (Ci-C6)alkyl; each instance of R40ais independently H or (Ci-6)alkyl; R40bis H, unsubstituted (Ci-Ce)alkyl or (Ci-Ce)alkyl substituted with 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, -

[0090]

[0052] In some embodiments, each of Ra, Rb, and Rcis independently H or (Ci-Ce)alkyl (e.g., Me, Et, Pr). In some embodiments, each of Ra, Rb, and Rcis H. In some embodiments, each of Ra, Rb, and Rcis (Ci-Ce)alkyl (e.g., (Ci-C4)alkyl, for example, Me, Et, Pr).

[0091]

[0053] In some embodiments, R50is H or (Ci-Ce)alkyl (e.g., Me, Et, Pr). In some embodiments, R50is H. In some embodiments, R50is (Ci-Ce)alkyl (e.g., Me, Et, Pr). In some embodiments, R50is straightchain (Ci-Ce)alkyl (e.g., Me, Et, Pr). In some embodiments, R50is -CH3. In some embodiments, R50is - CH2CH3. In some embodiments, R60is H or (Ci-Ce)alkyl (e.g., Me, Et, Pr).

[0092]

[0054] In some embodiments, R60is H. In some embodiments, R60is (Ci-Ce)alkyl (e.g., Me, Et, Pr). In some embodiments, R60is straight-chain (Ci-Ce)alkyl (e.g., Me, Et, Pr). In some embodiments, R60is - CH3. In some embodiments, R60is -CH2CH3. Docket No.: PAT059787-PCT-SEC01

[0093]

[0055] In some embodiments, R50is (Ci-Ce)alkyl (e.g., -CH3, -CH2CH3, -CH2CH2CH3) and R60is H. In some embodiments, R50is -CH2CH3 and R60is H. In some embodiments, R50is (Ci-Ce)alkyl (e.g., -CH3, -CH2CH3, -CH2CH2CH3) and R60is (Ci-C6)alkyl (e.g., -CH3, -CH2CH3, -CH2CH2CH3). In some embodiments, R50is -CH2CH3 and R60is -CH3.

[0094]

[0056] In some embodiments, R10is H; R20is H or halogen (e.g., -Cl, -F, -Br, -I); R30is (Ci-Ce)alkyl (e.g., Me, Et, Pr); n2 is 1, 2, or 3; at least one instance of R40is (Ci-Ce)alkyl, -(CH2)i<sN(R40a)2; - C(=O)OR40b, or -C(=O)N(R40a)SO2(R40c); or 5- or 6-membered heteroaryl (e.g., 5-membered heteroaryl (such as, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, isoxazolyl)) comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; each instance of R40ais independently H or (Ci-6)alkyl (e.g., Me, Et, Pr); R40bis H; 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S; 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; or (Ci-6)alkyl optionally substituted with halogen, -CN, -OH, (C3-C6)cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, - CN, -OH, -CO2H, -NH2, or (Ci-C6)alkyl; and R40cis H, (Ci-6)alkyl, or (C3-Cs)cycloalkyl; each of Ra, Rb, and Rcis H; R50is H or (Ci-C6)alkyl (e.g., -CH2CH3); and R60is H or (Ci-C6)alkyl (e.g., -CH3).

[0095]

[0057] In some embodiments, the compound is of Formula (II-A) or (II-B): or a pharmaceutically acceptable salt thereof.

[0096]

[0058] In some embodiments, the compound is of Formula (I-A): Docket No.: PAT059787-PCT-SEC01

[0097]

[0059] In some embodiments, the compound is of Formula (I-B): pharmaceutically acceptable salt thereof.

[0098]

[0060] In some embodiments, the compound is of Formula (II-A) or (II-B): or a pharmaceutically acceptable salt thereof, wherein:

[0099] R10is H or (Ci.6)alkyl;

[0100] R20is H, halogen, -CN, -OH, -CO2H, -NH2, or (Ci-C6)alkyl;

[0101] R30is halogen, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; each instance of R40is independently halogen, -CN, -OR40a, -C(=O)OR40b, -N(R40a)C(=O)R40c, - N(R40a)2, -C(=O)N(R40a)2, -C(=O)N(R40a)SO2(R40c), 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; (Ci-Ce)alkyl optionally substituted with halogen, -CN, -OH, -C(=O)OR40b, - N(R40a)2, C3-6 cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from Docket No.: PAT059787-PCT-SEC01

[0102] N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, - NH2, or (Ci-C6)alkyl; each instance of R40ais independently H or (Ci-6)alkyl; each instance of R40bis independently H, (C3-C6)cycloalkyl, (Ci-6)alkyl optionally substituted with halogen, -CN, -OH, -NH2, 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -(Ci- Ce)alkoxy, -CO2H, -NH2, or (Ci-C6)alkyl; each instance of R40cis independently H, (Ci-6)alkyl, (C3-C6)cycloalkyl, 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; each of Ra, Rb, Rc, R50, and R60is independently H or (Ci-Ce)alkyl; and n2 is 0, 1, 2, 3, 4, 5, or 6.

[0103]

[0061] In some embodiments, the compound is of Formula (I-A) or (I-B): or a pharmaceutically acceptable salt thereof, wherein:

[0104] R10is H;

[0105] R20is H or halogen;

[0106] R30is (Ci-C6)alkyl; n2 is 1, 2, or 3; at least one instance of R40is (Ci-C6)alkyl, -(CH2)i-3N(R40a)2; -C(=O)OR40b, or - C(=O)N(R40a)SO2(R40c); or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; Docket No.: PAT059787-PCT-SEC01 each instance of R40ais independently H or (Ci-6)alkyl;

[0107] R40bis H; 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S; 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, 0, and S; or (Ci-6)alkyl optionally substituted with halogen, -CN, -OH, (C3-C6)cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, 0, and S; wherein the 5- to 6-membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, - NH2, or (Ci-Ce)alkyl; and

[0108] R40Cis H, (Ci-6)alkyl, or (C3-C6)cycloalkyl; each of Ra, Rb, and Rcis H;

[0109] R50is H or -CH2CH3; and

[0110] R60is H or -CH3.

[0111]

[0062] In certain embodiments, the compound is a compound, or a pharmaceutically acceptable salt thereof selected from: Docket No.: PAT059787-PCT-SEC01

[0112] Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01

[0113]

[0063]

[0114]

[0064] 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.

[0115]

[0065] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

[0116]

[0066] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0117]

[0067] 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.

[0118]

[0068] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Docket No.: PAT059787-PCT-SEC01

[0119]

[0069] 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.

[0120]

[0070] 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.

[0121]

[0071] In another aspect, the present disclosure provides compounds of the present disclosure in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form.

[0122]

[0072] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into compounds of the disclosure include, for example, isotopes of hydrogen.

[0123]

[0073] 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 Docket No.: PAT059787-PCT-SEC01 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.

[0124]

[0074] 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,1241,125I respectively. Accordingly it should be understood that the disclosure includes compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as3H and14C, or those into which non-radio active isotopes, such as2H and13C are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically- labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

[0125]

[0075] 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 (7?)-. (S)- or (7 / ..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 (7?)- or (S)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.

[0126]

[0076] Accordingly, as used herein a compound of the present disclosure can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

[0127]

[0077] 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.

[0128]

[0078] 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 Docket No.: PAT059787-PCT-SEC01 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-QO'-p-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.

[0129] Pharmaceutical Compositions

[0130]

[0079] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein.

[0131]

[0080] 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.

[0132]

[0081] 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. Docket No.: PAT059787-PCT-SEC01

[0133]

[0082] 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.

[0134]

[0083] 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.

[0084] 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.

[0135]

[0085] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

[0136]

[0086] 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.

[0137]

[0087] 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.

[0138] Methods of Use

[0139]

[0088] 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 (II), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Docket No.: PAT059787-PCT-SEC01

[0140]

[0089] In another aspect, the present disclosure relates to a method for treating a disease or disorder comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the disease or disorder is a cardiovascular disease or disorder.

[0141]

[0090] 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.

[0142]

[0091] In some embodiments, the disease or disorder is preeclampsia, asthma, glaucoma, a kidney disorder, and / or cytokine release syndrome in a subject in need of such treatment. In some embodiments, the kidney disorder is selected from: diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute renal injury, contrast induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, renal vascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis, and polycystic kidney disease (PKD).

[0143]

[0092] In some embodiments, the disease or disorder is a disorder or disease associated with natriuretic peptide receptor activity.

[0144]

[0093] In another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for the manufacture of a medicament for use to treat a disease or disorder disclosed herein.

[0145]

[0094] In another aspect, the present disclosure relates to a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for use as a medicament. Docket No.: PAT059787-PCT-SEC01

[0146]

[0095] Another aspect of the present disclosure relates to a compound of Formula (I) or (II), 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).

[0147]

[0096] In another aspect, the present disclosure relates to the use of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein in the treatment of a disease or disorder disclosed herein.

[0148]

[0097] 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.

[0149] Combination Therapy

[0150]

[0098] 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.

[0151]

[0099] In one embodiment, the disclosure provides a product comprising a compound of the present disclosure and at least one other pharmaceutically active agent as a combined preparation for simultaneous, separate or sequential use as disclosed herein. Products provided as a combined preparation include a composition comprising the compound of the present disclosure and the other pharmaceutically active agent(s) together in the same pharmaceutical composition as described herein, or the compound of the present disclosure and the other pharmaceutically active agent (s) in separate form, e.g. in the form of a kit.

[0152]

[0100] In another aspect, the disclosure includes a compound of Formula (I) or (II)or a pharmaceutically acceptable salt thereof, for use in a combination therapy.

[0153]

[0101] Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I) or (II), 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. Docket No.: PAT059787-PCT-SEC01

[0154]

[0102] 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.

[0155]

[0103] Exemplary additional pharmaceutically active agents that may be used in combination with the compounds of the disclosure, include, but are not limited to an ACE (angiotensin-converting-enzyme) inhibitor, an angiotensin receptor blocker (ARB), a neprilysin inhibitor, a beta blocker, a diuretic, a calcium channel blocker, a cardiac glycoside, a sodium-glucose co -transporter 2 inhibitor (SGLT2i), or combinations thereof. As a non-limiting set of examples, a compound or a pharmaceutically acceptable salt thereof described herein may be combined with an additional pharmaceutically active agent selected from enalapril, benazepril, captopril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, valsartan, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, sacubitril, bisoprolol, carvedilol, propanolol, metoprolol, metoprolol tartrate, metoprolol succinate, thiazide diuretics, loop diuretics, potassium-sparing diuretics, amlodipine, clevidipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, a digitalis glycoside, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and combinations thereof. Exemplary diuretics and digitalis glycosides include, but are not limited to, chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, eplerenone, spironolactonem, triamterene, digoxin, and combinations thereof. In some embodiments, a compound or a pharmaceutically acceptable salt thereof described herein may be combined with an angiotensin receptor-neprilysin inhibitor (ARNi) such as a combination of sacubitril and valsartan (e.g., Entresto®). In some embodiments, a compound or a pharmaceutically acceptable salt thereof described herein can be combined with one or more of a corticosteroid (e.g., an inhaled corticosteroid such as fluticasone, budesonide, mometasone, beclomethasone, ciclesonide, or fluticasone furoate; or an oral or intravenous corticosteroid such as prednisone or methylprednisolone), a leukotriene modifier (e.g., montelukast, zafirlukast, or zileuton), a bronchodilator (e.g., a long-acting beta agonist (e.g., salmeterol or formoterol), a short-acting beta agonist (e.g., albuterol or 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 Docket No.: PAT059787-PCT-SEC01 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).

[0156]

[0104] ‘ ‘Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time and in any order, or in alternation and in any order, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical.

[0157] Method of Synthesizing the Compounds

[0158]

[0105] 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.

[0159]

[0106] The compounds of Formula (I) or (II) 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) or (II).

[0160]

[0107] Those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I) or (II). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the Docket No.: PAT059787-PCT-SEC01 synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0161]

[0108] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0162] Definitions

[0163]

[0109] Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. For purposes of interpreting this specification, the following definitions will apply unless specified otherwise and whenever appropriate, terms used in the singular will also include the plural and vice versa.

[0164] [HO] 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.

[0165] [Hl] 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.

[0166]

[0112] An “’alkyl” group or “alkane’’ is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from I 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 Cr-C& straight chained or branched alkyl group is also referred to as a “lower alkyl” group.

[0167]

[0113] 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, cyclo alkynyls, aryls, heteroaryls, and / or heterocyclyls. Docket No.: PAT059787-PCT-SEC01

[0168] Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0169]

[0114] 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 substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0170]

[0115] 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

[0171]

[0116] 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.

[0172]

[0117] The term “cycloalkyl-alkyl”, as used herein, refers to an alkyl group substituted with a cyclo alkyl group.

[0173]

[0118] The term “alkyl-cycloalkyl”, as used herein, refers to an cycloalkyl group substituted with an alkyl group. Docket No.: PAT059787-PCT-SEC01

[0174]

[0119] The terms “halo” and “halogen”, as used herein, means halogen and includes chloro, fluoro, bromo, and iodo.

[0175]

[0120] “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.

[0176]

[0121] 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 hetero aromatic, 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, dihydrob enzothi azine, 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, tetrahydropyrrole [ 1 ,2-a]pyrimidinyl, 3 ,4-dihydro-2H- 1 A2-pyrrolo [2, 1 -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][l,2,5]oxadiazole,

[0177] 1.3 -dihydro-2H-benzo [d]imidazol-2-one, 3 ,4-dihydro-2H-pyrazolo [ 1 ,5 -b] [ 1 ,2]oxazinyl, 4,5 ,6,7- tetrahydropyrazolo[l,5-a]pyridinyl, thiazolo[5,4 d]thiazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3, 4-dihydro-lH-isoquinolinyl,

[0178] 2.3 -dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl. Docket No.: PAT059787-PCT-SEC01

[0179]

[0122] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0180]

[0123] 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.

[0181]

[0124] 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 — ).

[0182]

[0125] 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).

[0183] 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.

[0184]

[0126] 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.

[0185]

[0127] The term “unsubstituted” means that the specified group bears no substituents.

[0186]

[0128] 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.

[0187]

[0129] The terms “pharmaceutically effective amount” or “therapeutically effective amount” or “effective amount” means an amount of a compound according to the disclosure which, when Docket No.: PAT059787-PCT-SEC01 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.

[0188]

[0130] 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.

[0189]

[0131] ‘ ‘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.

[0190]

[0132] 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).

[0191]

[0133] 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.

[0192]

[0134] 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.

[0193]

[0135] 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.

[0194]

[0136] “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. Docket No.: PAT059787-PCT-SEC01

[0195]

[0137] ‘ ‘Disorder” means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0196]

[0138] ‘ ‘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.

[0197]

[0139] “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) or (ii)as herein described including the salts particularly the pharmaceutically acceptable salts thereof, where the context so permits thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labelled compounds (including deuterium (“D”) substitutions).

[0198]

[0140] 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.

[0199] Examples

[0200]

[0141] 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.

[0201]

[0142] 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.

[0202]

[0143] 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 Docket No.: PAT059787-PCT-SEC01 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 (8 2.50), 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 (ESI-MS) were collected using a Waters System (Acquity UPLC and a Micromass ZQ mass spectrometer) or Agilent- 1260 Infinity (6120 Quadrupole); all masses reported are the m / z of the protonated parent ions unless recorded otherwise. The chemical names were generated using ChemBioDraw Ultra vl4 from CambridgeSoft.

[0203]

[0144] Temperatures are given in degrees Celsius. As used herein, unless specified otherwise, the term "room temperature" or "ambient temperature" means a temperature of from 15 degrees centigrade to 30 degrees centigrade, such as of from 20 degrees centigrade to 30 degrees centigrade, such as of from 20 degrees centigrade to 25 degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g.. MS, IR, NMR. Abbreviations used are those conventional in the art.

[0204]

[0145] 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.

[0205]

[0146] Example 1 - Intermediate 1: 2,4-dichloro-6-Dhenyl-5,6,7,8-tetrahvdroquinazoline .

[0206]

[0147] Step 1: To a stirred solution of diethyl carbonate (2110.0 mL, 17.0 mol, 5.0 eq) in tetrahydrofuran (2.4 L) at room temperature, NaH (165 g, 4.1 mol, 1.2 eq, 60% dispersion in mineral oil) was added portions wise. The resulting mixture was heated to 80 °C and then the solution of 4- phenylcyclohexanone (600.0 g, 3.4 mol) in tetrahydrofuran (2.4 L) was added dropwise over 1 h. The Docket No.: PAT059787-PCT-SEC01 reaction mixture was then stirred at 80 °C for 1 h and quenched with saturated aqueous NH4CI (1.2 L) solution at 0 °C and then extracted with EtOAc (3 x 5.0 L). The combined organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated to get crude residue, which was purified by silica gel column with Heptane / EtOAc = 100 / 1 to afford desired compound ethyl 2-oxo-5- phenylcyclohexane-1 -carboxylate (771.8 g, purity: 64.5%, 86.4% crude yield) as colorless liquid.JH NMR (400 MHz, DMSO) 8 7.42 - 7.05 (m, 5H), 4.19 - 4.10 (m, 2H), 2.84 - 2.66 (m, 1H), 2.52 - 2.43 (m, 2H), 2.41 - 2.27 (m, 1H), 2.17 (ddd, J= 33.6, 21.5, 2.3 Hz, 2H), 1.93 - 1.75 (m, 2H), 1.26 - 1.12 (m, 3H).

[0207]

[0148] Step 2: To a solution of ethyl 2-oxo-5 -phenylcyclohexane- 1 -carboxylate (700.0 g, 2.8 mol, 1.0 eq) and urea (341 g, 5.7 mol, 2.0 eq) in ethanol (12.5 L) at room temperature, sodium methoxide (1570.0 mL, 20% in methanol, 5.7 mol, 2.0 eq) was added. The resulting reaction mixture was stirred at 80

[0208] °C for 16 h. The reaction was monitored by HPLC. The reaction mixture was cooled to room temperature. The precipitated solid was filtered, washed with methyl tertbutylether (1 L x 3) and dried to get 6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4(lH,3H)-dione as an off -white solid (510 g, purity: 98.6%, 74% yield).1H NMR (400 MHz, DMSO) 8 7.47 - 7.01 (m, 5H), 5.43 (s, 1H), 2.81 - 2.64 (m, 1H), 2.57 (d, J = 4.6 Hz, 1H), 2.43 - 2.22 (m, 2H), 2.11 (dd, J= 15.5, 10.6 Hz, 1H), 1.88 (d, J= 10.3 Hz, 1H), 1.77 (dt, J = 11.7, 6.2 Hz, 1H).

[0209]

[0149] Step 3: To a mixture of 6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4(lH,3H)-dione (500.0 g, 2.1 mol, 1.0 eq) in POCI3 (2.0 L, 4.0 V) was added N, N-Diisopropylethylamine (266 g, 2.1 mol, 1.0 eq) dropwise over 30 min at room temperature under nitrogen atmosphere. After addition, the resulting mixture was heated to 120 °C and stirred for 16 h. The reaction was monitored by HPLC. The reaction mixture was cooled down to 25 °C in the air and diluted with dichloromethane (2.0 L). The diluted suspension was concentrated under vacuum to remove the most POCI3. The residue was dissolved in dichloromethane (6.0 L) and then residual POCI3 was quenched by adding ice water (10.0 L) at 0 °C . The aqueous phase was extracted with dichloromethane (3.0 L) again, dried over anhydrous NazSOi and the filtrate was concentrated to get crude residue, which was purified by silica gel column with Heptane / EtOAc = 20 / 1 to afford desired product 2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline (266.0 g, purity: 99.2%, 46% yield) as a yellow solid. LCMS: m / z = 257.00 [M+H]+;1H NMR (400 MHz, DMSO) 8 7.46 - 7.02 (m, 5H), 3.17 - 2.88 (m, 4H), 2.75 (dd, J= 16.9, 11.0 Hz, 1H), 2.14 -1.90 (m, 2H).

[0210]

[0150] Step 4: Racemic 2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline (266.0 g) was purified by chiral SFC (Chiralcel OJ-H, Flowrate: 4 ml / min, Co-Solvent: 40%, Co-Solvent: Methanol, Injected Volume: 2 pl, Outlet Pressure: 100 bar, Temperature: 35 °C) to afford 105.0 g, 99.7% ee of (R)-2,4- dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline and 105.0 g, 98.6% ee of (S)-2,4-dichloro-6-phenyl- Docket No.: PAT059787-PCT-SEC01

[0211] 5,6,7,8-tetrahydroquinazoline. Absolute stereochemistry was determined by small molecule X-ray crystallography.

[0212]

[0151] Example 2 - Intermediate 2: 2,4-dichloro-6-methyl-6-Dhenyl-5,6,7,8-tetrahvdroquinazoline

[0213]

[0152] Step 1: To a solution of 2-phenylpropanal (430 g, 3.20 mol, 430 mL, 1 eq) in toluene (1.50 L) was added PPAS’EEO (121 g, 640 mmol, 0.2 eq) and but-3-en-2-one (336 g, 4.81 mol, 400 mL, 1.5 eq) at 25 °C. The mixture was stirred at 80 °C for 16 h. TLC (Petroleum ether / Ethyl acetate = 10 / 1, Rf / reactant = 0.45, Rf / product = 0.45) indicated that starting material was disappeared and the new spots were formed. The reaction mixture (totally 860 g) was combined and cooled to room temperature and added into water (5.00 L) slowly. The mixture was extracted with EtOAc (5.00 L). The organic layer was washed with sat. K2CO3 solution (3.00 L), brine (3.00 L), dried over NazSO^ filtered and concentrated. The product was used to next step directly. l-methyl-2,3-dihydro-[l,T-biphenyl]-4(lH)- one (1.20 kg, crude) was obtained as yellow oil.

[0214]

[0153] Step 2: To a solution of l-methyl-2,3-dihydro-[l,l'-biphenyl]-4(lH)-one (200 g, 1.07 mol, 1 eq, crude) in EtOAc (1.00 L) was added Pd / C (20.0 g, 107 mmol, 10% purity, 0.1 eq) under N2 atmosphere. The mixture was degassed and purged with H2(50 Psi) for 3 times. The mixture was stirred at 40 °C for 12 h. TLC (Petroleum ether / Ethyl acetate = 10 / 1, Rf / reactant = 0.45, Rf / product = 0.65) indicated that starting materail was disappeared and the new spots were formed. The reaction mixture was filtered and the cake was washed with EtOAc (600 mL x 3). The filtrate was concentrated. The product was purified Docket No.: PAT059787-PCT-SEC01 by silica gel column chromatography (SiCL, Petroleum ether / Ethyl acetate = 10 / 1). 4-methyl-4- phenylcyclohexan-l-one (438 g, 2.33 mol, 54.1% yield) was obtained as a yellow oil.1H NMR (400 MHz CDC13) 8 7.50 - 7.45 (m, 2H), 7.44 - 7.37 (m, 2H), 7.30 - 7.24 (m, 1H), 2.59 - 2.47 (m, 2H), 2.44 - 2.28 (m, 4H), 2.03 - 1.91 (m, 2H), 1.35 (s, 3H).

[0215]

[0154] Step 3: To a solution of 4-methyl-4-phenylcyclohexan-l-one (608 g, 5.15 mol, 624 mL, 5 eq) in THF (1.16 L) was added NaH (49.4 g, 1.24 mol, 60% purity, 1.2 eq) at 20 °C slowly. A solution of diethylcarbonate (194 g, 1.03 mol, 1 eq) in THF (388 mL) was added drop wise at 80 °C, over 0.5 h. The mixture was stirred at 80 °C for 1 h. TLC (Petroleum ether / Ethyl acetate = 10 / 1, Rf / reactant = 0.40, Rf / product = 0.55) indicated that starting material was disappeared and the new spot was formed. The reaction mixture was quenched with sat. NH4CI (2 L) and extracted with EtOAc (400 mL). The organic layer was separated, washed with brine (700 mL x 2), dried over NazSCL. filtered and concentrated. The product was purified by silica gel column chromatography (SiCL, Petroleum ether). Ethyl 5-methyl-2- oxo-5-phenylcyclohexane-l-carboxylate (325 g, 1.25 mol, 60.5% yield) was obtained as yellow oil. ’ H NMR, (400 MHz CDCI3) 8 7.32 - 7.22 (m, 4H), 7.19 - 7.10 (m, 1H), 4.22 (q, J= 7.2 Hz, 2H), 4.07 (q, J = 7.2 Hz, 1H), 2.82 - 2.70 (m, 1H), 2.29 (br d, J= 16.4 Hz, 1H), 2.25 - 2.17 (m, 1H), 2.06 - 2.00 (m, 2H), 1.82 - 1.73 (m, 1H), 1.33 - 1.23 (m, 6H).

[0216]

[0155] Step 4: To a mixture of ethyl 5-methyl-2-oxo-5-phenylcyclohexane-l-carboxylate (295 g, 1.13 mol, 1 eq) in EtOH (2.95 L) was added urea (136 g, 2.27 mol, 121 mL, 2 eq) and NaOMe (122 g, 2.27 mol, 2 eq) slowly. The mixture was stirred at 80 °C for 12 h. HPLC indicated that the ~7.2% of the starting material was remained and ~77.5% of the desired peak was detected on 220 nm. The reaction mixture was concentrated to remove most of the ethanol. The product was triturated with MTBE (1.50 L) at 20 °C for 0.5 h. 6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4(lH,3H)-dione (210 g, crude) was obtained as white solid and used to next step directly.

[0217]

[0156] Step 5: To a mixture of 6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4(lH,3H)-dione (200 g, 780 mmol, 1 eq) in dioxane (2.00 L) was added EtsN (236 g, 2.34 mol, 325 mL, 3 eq) and followed by POCL (1.20 kg, 7.80 mol, 725 mL, 10 eq) dropwise at 0-5 °C over 0.5 h. The mixture was stirred at 125 °C for 5 h. LCMS indicated that the reactant was disappeared and the new peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure and diluted with CH2Q2 (3.00 L). The mixture was added into sat. NaHCCL solution (5.00 L) and stirred at 20 - 40 °C for 0.5 h. The mixture was filtered with celite. The organic layer was separated, washed with brine (1.00 L), dried over NazSOr, filtered and concentrated. The product was purified by silica gel column chromatography (SiOz, Petroleum ether / Ethyl acetate = 10 / 1 to 5 / 1). 2,4-dichloro-6-methyl-6-phenyl- 5,6,7,8-tetrahydroquinazoline (65.0 g, 220 mmol, 28.3% yield, 99.6% purity) was obtained as yellow solid. LCMS: RT = 0.862 min, MS (ESI) m / z = 292.9 [M+H]+; ’H NMR (400 MHz CDCI3) 8 7.35 - Docket No.: PAT059787-PCT-SEC01

[0218] 7.20 (m, 5H), 3.38 - 3.34 (m, 1H), 2.93 - 2.86 (m, 1H), 2.87 - 2.80 (m, 1H), 2.60 (dd, J= 2.8, 5.2 Hz,

[0219] 1H), 2.34 - 2.31 (m, 1H), 2.01 - 1.97 (m, 1H), 1.43 (s, 3H).

[0220]

[0157] Step 6: Chiral separation of 2,4-dichloro-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline (65.0 g, 221 mmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK AY (250 mm x 50 mm, 10 pm); mobile phase: [0.1% NH3«H2O EtOH]; B%: 15% - 15%, 2.2; 2105 min). The product was concentrated. (R)-2,4-dichloro-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline (27.0 g) eluted as Peak

[0221] 1 and (S)-2,4-dichloro-6-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline (24.0 g) eluted as Peak 2 and obtained as yellow oil.

[0222]

[0158] Example 3 - Preparation of Intermediate 4: 2,4-dichloro-6-(3-fluorophenyl)-5,6,7,8- tetrahydroquinazoline

[0223]

[0159] Step 1: The stirred suspension of l-fluoro-3 -iodobenzene (140 g, 630 mmol, 74.0 mL, 1.00 eq), 4,4,5,5-tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (149 g, 561 mmol, 0.89 eq) and CS2CO3 (308 g, 945 mmol, 1.50 eq) in dioxane (1200 mL) / H2O (300 mL) (8 / 2) was degassed with argon for 15 min. Then Pd(dppf)C12,CH2C12 (29.8 g, 36.5 mmol, 0.058 eq) was added and again degassed for 5 min. Then the reaction mixture was heated to 70 °C for 16 h. TLC (Petroleum Docket No.: PAT059787-PCT-SEC01 ether / Ethyl acetate = 10 / 1, reactant Rf = 0.50, new spot Rf = 0.34) showed starting material was consumed completely and a new spot was detected. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was diluted with H2O (1.5 L) and extracted with EtOAc (1.5 L x 2). The combined organic layers were washed with brine (2 L x 2), dried over Na^SOr. filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate =1 / 0 to 5 / 1) to give 8-(3-fluorophenyl)-l,4- dioxaspiro[4.5]dec-7-ene (137 g, 584 mmol, 92.7% yield) as brown oil. [M+H]+; ’H NMR: (400 MHz, DMSO-d6) 8 7.52 - 7.45 (m, 1H), 7.40 - 7.31 (m, 2H), 7.23 - 7.15 (m, 1H), 6.26 - 6.21 (m, 1H), 4.06 - 4.02 (m, 4H), 2.76 - 2.55 (m, 3H), 1.97 - 1.89 (m, 2H), 1.33 - 1.27 (m, 1H), 1.23 - 1.19 (m, 1H).

[0224]

[0160] Step 2: To a solution of 8-(3-fluorophenyl)-l,4-dioxaspiro[4.5]dec-7-ene (80.0 g, 341 mmol, 1.00 eq) in EtOH (880 mL) was added Pd / C (8.00 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 psi) at 20 °C for 12 h. TLC (Petroleum ether / Ethyl acetate = 10 / 1, reactant Rf = 0.35, new spot Rf = 0.42) showed that starting material was consumed and a new spot was detected. The reaction mixture was filtered through celite pad and washed with excess of EtOH (1 L) and EtOAc (1 L), the filtrate was concentrated to get desired compound. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 5 / 1) to give 8-(3-fluorophenyl)-l,4-dioxaspiro[4.5]decane (74.4 g, 314 mmol, 92.2% yield) as colorless oil. LCMS: MS (ESI) m / z = 237.1 [M+H]+, 'H NMR: 8 7.36 - 7.27 (m, 1H), 7.11 - 6.92 (m, 3H), 3.92 - 3.85 (m, 4H), 2.68 - 2.57 (m, 1H), 1.82 - 1.70 (m, 4H), 1.69 (s, 4H).

[0225]

[0161] Step 3: To a solution of 8-(3-fluorophenyl)-l,4-dioxaspiro[4.5]decane (74.4 g, 314 mmol, 1.00 eq) in dioxane (620 mL) / H20 (310 mL) (2 / 1) was added HC1 (12 M, 309 mL, 11.7 eq). The mixture was stirred at 20 °C for 3 h. LCMS show that starting material was consumed and desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was extracted with EtOAc (500 mL x 2) and the combined organic layers were washed with sat. NaHCOs 500 mL and brine 500 mL, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product 4-(3-fluorophenyl)cyclohexan-l-one (64.5 g, crude) was used into the next step without further purification as colorless oil. LCMS: product RT = 0.836 min, MS (ESI) m / z = 193.2 [M+H]+; ’H NMR: (400 MHz, DMSO-d6) 8 7.38 - 7.30 (m, 1H), 7.17

[0226] - 7.10 (m, 2H), 7.06 - 6.98 (m, 1H), 3.15 - 3.04 (m, 1H), 2.63 - 2.52 (m, 2H), 2.31 - 2.21 (m, 2H), 2.12 - 2.02 (m, 2H), 1.96 - 1.80 (m, 2H).

[0227]

[0162] Step 4: To a stirred solution of diethyl carbonate (245 g, 2.08 mol, 251 mL, 5.00 eq) in THF (400 mL) at 25 °C, NaH (19.9 g, 498 mmol, 60.0% purity, 1.20 eq) was added portionwise. The resulting mixture was heated to 80 °C and then a solution of 4-(3-fluorophenyl)cyclohexan-l-one (79.9 g, 415 Docket No.: PAT059787-PCT-SEC01 mmol, 1.00 eq) in THF (400 mL) was added dropwise over ~ 20 min. The reaction mixture was then stirred at 80 °C for 30 min. LCMS showed the starting material was consumed and desired compound was detected. The reaction mixture was quenched with sat. NH4CI solution (I L) and extracted with EtOAc (1 L X 2). The combined organic layer was washed with sat. NaHCCL solution (800 mL) and brine (600 mL), dried over anhydrous Na^STh and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 10 / 1, desired spot Rf = 0.33) to give ethyl 5 -(3 -fluorophenyl)-2-oxocyclohexane-l -carboxylate (65.3 g, 247 mmol, 59.4% yield) as light yellow oil. LCMS product RT = 1.005 min, MS (ESI) m / z = 265.2 [M+H]+; ’H NMR: (400 MHz, DMSO-d6) 8 7.40 - 7.29 (m, 1H), 7.19 - 7.09 (m, 2H), 7.08 - 6.97 (m, 1H), 4.21 (br s, 3H), 2.88 - 2.69 (m, 1H), 2.49 - 2.41 (m, 1H), 2.35 - 2.04 (m, 2H), 2.01 - 1.92 (m, 1H), 1.90 - 1.80 (m, 1H), 1.77 - 1.41 (m, 1H), 1.22 - 1.17 (m, 3H).

[0228]

[0163] Step 5: To a stirred solution of ethyl 5-(3-fluorophenyl)-2-oxocyclohexane-l-carboxylate (75.0 g, 283 mmol, 1.00 eq) in EtOH (1680 mL) was added urea (34.0 g, 567 mmol, 30.4 mL, 2.00 eq) and followed by NaOMe (30.6 g, 567 mmol, 2.00 eq) and the reaction mixture was heated to 80 °C for 16 h. LCMS showed the starting material was consumed and desired compound was detected. The reaction mixture was filtered, the solid was washed with MBTE (900 mL) and water (500 mL), and concentrated under reduced pressure to give a residue. The crude product 6-(3-fluorophenyl)-5, 6,7,8- tetrahydroquinazoline-2,4(lH,3H)-dione (48.5 g, crude) was used into the next step without further purification as a white solid. LCMS: product RT = 0.777 min, MS (ESI) m / z = 261.0 [M+H]+; 1H NMR: (400 MHz, DMSO-d6) 8 7.39 - 7.28 (m, 1H), 7.15 - 7.06 (m, 2H), 7.04 - 6.96 (m, 1H), 2.84 - 2.70 (m, 1H), 2.60 - 2.52 (m, 1H), 2.44 - 2.37 (m, 1H), 2.34 - 2.25 (m, 1H), 2.18 - 2.05 (m, 1H), 1.94 - 1.84 (m, 1H), 1.82 - 1.71 (m, 1H).

[0229]

[0164] Step 6: To a stirred suspension of 6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2,4(lH,3H)- dione (44.0 g, 169 mmol, 1.00 eq) in dioxane (1760 mL) were added TEA (5.65 g, 55.7 mmol, 7.77 mL, 0.33 eq) and followed by POCL (259 g, 1.69 mol, 157 mL, 10.0 eq) (dropwise) at 0 °C and the reaction mixture was heated to 130 °C for 3 h. LCMS showed the starting material was consumed and desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was slowly diluted with H2O (300 mL) and was adjusted to pH 7 with sat. NaHCCL (700 mL), then extracted with EtOAc (1 L x 3), dried over anhydrous NazSO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (20 mL 3 times) at 25 °C for 2 h to give 2,4-dichloro-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (24.5 g, 82.4 mmol, 48.7% yield) as a yellow solid. LCMS: product RT = 1.020 min, MS (ESI) m / z = 296.7 [M+H]+; ’H NMR: (400 MHz, CHLOROFORM-d) 8 7.38 - 7.30 (m, 1H), 7.09 - 7.03 (m, 1H), 7.01 - 6.93 (m, 2H), 3.22 - 2.96 (m, 4H), 2.79 - 2.67 (m, 1H), 2.30 - 2.19 (m, 1H), 2.08 - 1.92 (m, 1H). Docket No.: PAT059787-PCT-SEC01

[0230]

[0165] Step 7: Racemic 2,4-dichloro-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline was purified by SFC (column: DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 um); mobile phase: [0.1% NEfi^HzO MeOH]; B%: 30% - 30%, 2.8 min; 1100 min) to give:

[0231] (R)-2,4-dichloro-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (10.6 g, >99% ee): LCMS: product RT = 1.047 min, MS (ESI) m / z = 297.2 [M+H]+; ’ H NMR: (400 MHz, CHLOROFORM-d) 5 7.37 - 7.30 (m, 1H), 7.08 - 7.03 (m, 1H), 7.03 - 6.93 (m, 2H), 5.32 - 5.30 (m, 1H), 3.20 - 2.98 (m, 4H), 2.80 - 2.69 (m, 1H), 2.29 - 2.20 (m, 1H), 2.06 - 1.94 (m, 1H) as a yellow solid.

[0232] (S)-2,4-dichloro-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (12.0 g, >99% ee): LCMS: RT = 1.005 min, MS (ESI) m / z = 296.7 [M+H]+; ’H NMR: (400 MHz, CHLOROFORM-d) 5 7.39 - 7.31 (m, 1H), 7.08 - 7.03 (m, 1H), 7.03 - 6.94 (m, 2H), 3.20 - 2.97 (m, 4H), 2.79 - 2.69 (m, 1H), 2.29 - 2.20 (m, 1H), 2.07 - 1.94 (m, 1H) as a yellow solid.

[0233]

[0166] Example 4 - Preparation of Intermediate 3A and 3B: methyl (lR,4r)-4-((R)-l-

[0234] (methylamino)propyDcvclohexane-l-carboxylate hydrochloride

[0235]

[0167] Step 1: To a solution (lr,4r)-4-(methoxycarbonyl)cyclohexane-l-carboxylic acid (140 g, 751 mmol, 1 eq) in CH2Q2 (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)C12 (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 Docket No.: PAT059787-PCT-SEC01 was quenched by addition ice sat. NH4CI (1000 mL) and extracted with CH2Q2 (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 (SiCL, 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.JH NMR (400 MHz, CDCh) 8 3.60 (s, 3H), 2.44 - 2.36 (m, 1H), 2.30 - 2.14 (m, 2H), 2.04 - 1.93 (m, 4H), 1.92 - 1.84 (m, 1H), 1.82 -1.69 (m, 3H), 1.68 - 1.61 (m, 1H), 1.45 - 1.35 (m, 1H), 1.33 (br d, J= 10.4 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).

[0236]

[0168] 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 cl8 250 mm * 100 mm * 10 um; mobile phase: [water (lOmM NH4HCO3) - ACN], B%: 45.0% - 65.0%, 20 minutes) to give desired product ethyl (lR,4r)-4-((E)-l-(((R)-tert- butylsulfinyl)imino)propyl)cyclohexane-l -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, CDCL) 8 4.08 (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).

[0237]

[0169] 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 NaBH4 (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 NH4CI (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 Cl 8 (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-butylsulfmyl)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]+; Docket No.: PAT059787-PCT-SEC01

[0238] ’H NMR ( 400 MHz, CDC13) 5 4.03 (q, J= 7.2 Hz, 2H), 3.02 (d, J= 7.6 Hz, 1H), 2.95 - 2.86 (m, 1H), 2.22 - 2.09 (m, 1H), 2.02 - 1.90(m, 2H), 1.84 - 1.74 (m, 1H), 1.70 (br d, J= 12.8 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).

[0239]

[0170] Step 4: To a solution of ethyl (lR,4r)-4-((R)-l-(((R)-tert- butylsulfmyl)amino)propyl)cyclohexane-l -carboxylate (55.0 g, 173 mmol, 1 eq) in THF (1100 mL) 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 NazSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOz, 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 min, m / z = 332.3 [M+H]+;1H NMR (400 MHz, CDCI3) 5 4.12 - 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).

[0240]

[0171] Step 5: To a solution of ethyl (lR,4r)-4-((R)-l-(((R)-tert- butylsulfmyl)(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, CDCI3) 5 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).

[0241]

[0172] Example 5 - Preparation of Intermediate Docket No.: PAT059787-PCT-SEC01

[0242] Step 1 : To a solution of (R)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diol (10.00 g, 1 Eq, 35.82 mmol) in THF (20.00 mL) was added NaOH (2.866 g, 2 Eq, 71.64 mmol) in Water (72.00 mL). Then the reaction mixture was stirred at 75 °C for 16 hour. LCMS showed 74.36% of desired mass was detected. The reaction mixture was acidified by citric acid to pH=3-4 then added EA (200 mL). The white precipitate formed and filtered. The filtrate was extracted with EtOAc (50 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford the residue. The residue was triturated with EtOAc (20 mL). The resulting solid was collected by filtration, washed with PE, and dried under reduced pressure to afford compound 9 (5.000 g, 15.28 mmol, 42.65 %, 79.66% Purity) as a yellow solid. LCMS: Rt = 0.492 min, [M+H]+= 260.9, ’H NMR (400 MHz, DMSO-d6) 8 =13.46 - 12.40 (m, 1H), 7.37 - 7.26 (m, 4H), 7.24 - 7.18 (m, 1H), 2.93 - 2.83 (m, 1H), 2.81 - 2.59 (m, 3H), 2.44 - 2.32 (m, 1H), 2.02 - 1.82 (m, 2H).

[0243] Step 2: To a solution of (R)-2-chloro-6-phenyl-5,6,7,8-tetrahydroquinazolin-4-ol (6.000 g, 1 Eq, 23.01 mmol) and compound tert-butyl (lR,4r)-4-((R)-l-(methylamino)propyl)cyclohexane-l -carboxylate (7.053 g, 1.2 Eq, 27.62 mmol) in NMP(18 mL) was added DIEA (14.87 g, 20.0 mL, 5 Eq, 115.1 mmol) . After addition, the reaction mixture was stirred at 110 °C for 16 hour. LCMS showed 33.8% of desired MW. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (50 mL*3). The combined organic phase was washed with sat.NaCl (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the residue. The residue was triturated with PE:EA(5: 1, 50 mL) and filtered to give tert-butyl (lR,4r)-4-((R)-l-(((R)-4-hydroxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (4.000 g, 5.792 mmol, 25.17 %, 69.45% Purity) as a gray solid. LCMS: Rt = 0.553 min, [M+H]+= 480.4.

[0244]

[0173] Step 3: To a solution of tert-butyl (lR,4r)-4-((R)-l-(((R)-4-hydroxy-6-phenyl-5, 6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l-carboxylate (3.600 g, 1 Eq, 7.505 mmol) in DCM (36.000 mL) was DIEA (1.455 g, 1.96 mL, 1.5 Eq, 11.26 mmol) and Tf2O (3.176 g, 1.902 mL, 1.5 Eq, 11.26 mmol) at 0 °C. After addition, the reaction mixture was stirred at 0 °C for 2 hour LCMS showed a major peak of desired MW. The reaction mixture was diluted with water (10 mL), extracted with DCM (10 mL*3) and washed with brine (10 mL). The organic layer was dried with anhydrous Na S2O4 , filtered and concentrated under vacuum to get the residue. The residue was purified by flash on silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~80% Ethyl acetate / Petroleum ethergradient @ 80 mL / min) and concentrated under vacuum to afford tert-butyl (lR,4r)-4-((R)-l-(methyl((R)-6-phenyl-4-(((trifluoromethyl)sulfonyl)oxy)-5, 6,7,8 - tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l-carboxylate (3.800 g, 5.540 mmol, 73.81 %, 89.18% Purity) as a green oil. LCMS: Rt = 0.923 min, [M+H] =612.1, 'H NMR (400 MHz, DMSO-d6) 8 = 7.39 - 7.28 (m, 4H), 7.27 - 7.21 (m, 1H), 2.82 (s, 2H), 2.86 (s, 2H), 2.79 - 2.71 (m, 2H), 2.00 (br d, J = Docket No.: PAT059787-PCT-SEC01

[0245] 7.8 Hz, 3H), 1.89 (br d, J= 12.5 Hz, 3H), 1.54 - 1.42 (m, 4H), 1.38 (d, J= 3.4 Hz, 10H), 1.33 - 1.15 (m, 4H), 1.10 - 0.89 (m, 3H), 0.88 - 0.81 (m, 3H).

[0246]

[0174] Example 6 - Preparation of Intermediate 8: methyl (lR,4r)-4-((R)-l- aminopropyDcvclohexane-l-carboxylate lot. 8

[0247]

[0175] 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 min, m / z = 200.2 [M+H]+; *H NMR (400MHz, DMSO-d6) 8 8.18 - 7.83 (m, 3H), 3.59 (s, 3H), 2.91 - 2.76 (m, 1H), 2.30 - 2.17 (m, 1H), 1.93 (br s, 2H), 1.72 (br s, 2H), 1.65 - 1.44 (m, 3H), 1.29 (br s, 2H), 1.11 (s, 2H), 0.91 (t, J= 7.4 Hz, 3H).

[0248]

[0176] Example 7 - Preparation of Intermediate 5: (lR)-l-(4-(methoxycarbonyl)-4- methvkvclohexyl)-N-methylpropan-l-aminium Docket No.: PAT059787-PCT-SEC01

[0249]

[0177] 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 NazSCL 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 using 10% ethyl acetate in ether. The pure fractions were collected and concentrated under reduced pressure to get methyl (lR,4r)-4-((R)-l-((tert-butoxycarbonyl)amino)propyl)cyclohexane- 1-carboxylate (3.600 g, 11 mmol, 62 %, 95% Purity) as a white solid. LCMS: m / z = 200.2 [M-100+H]+.

[0250]

[0178] 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 NH4C1 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 Na^SCL 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]+.

[0251]

[0179] 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 -78 ° C 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 NH4CI solution (20 mL). The product was extracted with ethyl acetate (3 x 100 mL). The organic layer was separated and dried over anhydrous NazSC 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 Docket No.: PAT059787-PCT-SEC01 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)-l-((tert- butoxycarbonyl)(methyl)amino)propyl)-l -methylcyclohexane- 1 -carboxylate as a Pale yellow liquid (0.9 g). LCMS: m / z +228.2 (M-100+H)+.

[0252]

[0180] Step 4: To a stirred mixture of methyl 4-((R)-l-((tert-butoxycarbonyl)(methyl)amino)propyl)-l- m ethylcyclohexane- 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)+.

[0253]

[0181] Example 8 - General method for amine intermediates synthesis - Preparation of Intermediate 9 : (R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethan-l-amine dihydrochloride

[0254]

[0182] 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 MgSOr. The solid was filtered off and concentrated under reduced pressure. The crude Docket No.: PAT059787-PCT-SEC01 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-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)-2-oxoethyl)carbamate as a white solid (6.16 g, 93%). MS m / z = 337.1 [M+H]+.

[0255]

[0183] Step 2: To a solution of tert-butyl ((R)-l-(l -methyl- lH-pyrazol-4-y l)-2-((S)-3 -methylpiperidin-

[0256] 1-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 30 min then concentrated. The residue was diluted with MeOH (10 mL) then pyridine (5.91 ml, 73.1 mmol) was added to the soluiton. 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)-

[0257] 2-((S)-3-methylpiperidin-l-yl)ethyl)carbamate as a colorless oil (1.83 g, 78% yield). MS m / z = 323.3 [M+H]+.

[0258]

[0184] Step 3: To a solution of tert-butyl ((R)-l-(l -methyl- lH-pyrazol-4-y l)-2-((S)-3 -methylpiperidin- l-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)- 1-(1 -methyl- 1H- 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]+.

[0259] Example 9 - Synthesis of (lR,4r)-4-( -l-(methyl((6RS)-4-((2-(3-(l-methyl-lH-pyrazol-3- yl)piperidin-l-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahvdroquinazolin-2-yl)amino)DroDyl)cvclohexane-l-carboxylic acid (Compound 13)

[0260] Docket No.: PAT059787-PCT-SEC01

[0261]

[0185] Step 1: To a solution of (R)-2-((tert-butoxycarbonyl)amino)-2-(l-methyl-lH-pyrazol-4-yl)acetic acid (28 g, 109.8 mmol) and N,O-dimethylhydroxylamine hydrochloride (16 g, 164.7 mmol) in DCM (600 mL) was added DIPEA (114 mL, 658.8 mmol) and T4P (98 mL, 164.7mmol, 50% in EA) at 0°C, after addition, the mixture was stirred at 20°C for 15 hrs. The reaction mixture was poured into Sat.NaHCOs (1000 mL) and then extracted with DCM (1000 mL*3), the combined organic phase was washed with citric acid solution (1000 mL), Sat.NaHCCL (1000 mL), then dried by NazSCU, filtered and concentrated to give tert-butyl (R)-(2-(methoxy(methyl)amino)-l-(l-methyl-lH-pyrazol-4-yl)-2- oxoethyl)carbamate (30 g, lOOmmol, 91.9% yield) as a white solid. The crude product was used in the next step directly without purification.XH NMR (400 MHz, DMSO-d6) 8 = 7.62 (s, 1H), 7.36 (s, 1H), Docket No.: PAT059787-PCT-SEC01

[0262] 7.27 (br d, J= 8.4 Hz, 1H), 5.50 (br d, J= 8.0 Hz, 1H), 3.77 (s,3H), 3.65 (s, 3H), 3.08 (s, 3H), 1.37 (s, 9H).

[0263]

[0186] Step 2: To a solution of tert-butyl (R)-(2-(methoxy(methyl)amino)-l-(l-methyl-lH-pyrazol-4- yl)-2-oxoethyl)carbamate (30 g, 7 mmol) in DCM (200 mL) was added HCl / Dioxane (200 mL, 2M) at 0°C, after addition, the mixture was stirred at 20°C for 15 hrs. LCMS showed starting material was consumed and desired molecular weight was detected. The reaction mixture was concentrated to give compound (R)-2-amino-N-methoxy-N-methyl-2-(l-methyl-lH-pyrazol-4-yl)acetamide (24 g crude, HC1 salt, quant.) as a white solid. The crude product was used in the next step directly without purification. LCMS m / z: =199.2 (M+H)+

[0264]

[0187] Step 3: To a solution of tert-butyl (lR,4r)-4-((R)-l-(methyl((R)-6-phenyl-4- (((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l- carboxylate (22 g, 35.9 mmol) and (R)-2-amino-N-methoxy-N-methyl-2-(l-methyl-lH-pyrazol-4- yl)acetamide (11.4 g, 57.5 mmol, which was basified by -OH ion exchange resin from 14 g of HC1 salt) in DMA (220 mL) was added Et3N (10 mL, 71.9 mmol) at 20°C, after addition, the mixture was stirred at 80°C for 15 hrs. LCMS showed desired molecular weight was detected. The reaction mixture was poured into H2O (500 mL) and then extracted with EA (500 mL*3), the combined organic phase was washed with brine (1 L), dried by Na2SO4, filtered and concentrated to get the crude product. The crude product was purified by column chromatography on silica gel (eluted with 0-60 % EA in PE) to give tert-butyl (lR,4r)-4-((R)-l-(((R)-4-(((R)-2-(m ethoxy(methyl)amino)-l-(l -methyl- lH-pyrazol-4-yl)-2- oxoethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l- carboxylate (18.2 g, 27.5 mmol, 76%yield, 99% purity) as ayellow solid and a less pure batch (3.5 g, 5.3mmol, 14.6% yield, 95% purity) as a white solid^H NMR (400 MHz, CHLOROFORM-d) 8 = 7.51 (s, 1H), 7.40 - 7.22 (m, 6H), 6.20 (br s, 1H), 5.15 (br d, J= 6.8 Hz, 1H), 4.60(br s, 1H), 3.86 (s, 3H), 3.66 (s, 3H), 3.23 (s, 3H), 3.02 - 2.92 (m, 1H), 2.87 (s, 3H), 2.81 - 2.61 (m, 3H), 2.35 (m, 1H), 2.16 -2.04 (m, 2H), 2.00 - 1.82 (m, 5H), 1.79 - 1.61 (m, 2H), 1.52 - 1.21 (m, 13H), 1.11 - 0.95 (m, 1H), 0.83 - 0.72 (m, 3H).

[0265]

[0188] Step 4: A tert-butyl (lR,4r)-4-((R)-l-(((R)-4-(((R)-2-(methoxy(methyl)amino)-l-(l-methyl-177- pyrazol-4-yl)-2-oxoethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (500.0 mg, 757.74 pmol) was dissolved in THF (10.3 ml). The reaction mixture was cooled to -78 °C. Then solution of LiAlH4 (86 mg, 2.27 mmol) in THF (2.5 ml) was added dropwise over 1 min at -78 °C. Then the reaction mixture was stirred at -65...- 60 °C for 2 hours. After that period the reaction mass was carefully quenched with 12.2 ml 10 % aq. sol. of Rochelle salt at -60 °C. The reaction mixture was allowed to reach room temperature. Then EtOAc (25 ml) was added, and the mixture was stirred at room temperature for 30 min. Then it was poured into Docket No.: PAT059787-PCT-SEC01 water (25 ml). Aqueous layer was separated and then additionally extracted with EtOAc (2 x 25 ml). Combined organic layer was dried over Na2SO4, filtered and evaporated to give tert-butyl ( l / ?.4r)-4- ((R)-l -(methyl((R)-4-(((R)-l-(l -methyl- 177-pyrazol-4-yl)-2-oxoethyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l-carboxylate (471 mg, 86% purity, 0.674 mmol, 89% yield). It was used in the next step without further purification. LCMS m / z = 601.2 (M+H)+.

[0266]

[0189] Step 5: A tert-butyl (lR,4r)-4-((R)-l-(methyl((R)-4-(((R)-l-(l-methyl-177-pyrazol-4-yl)-2- oxoethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l-carboxylate (78.0 mg, 129.83 pmol) and 3 -(1 -methyl- lH-pyrazol-3-yl)piperidine (21.42 mg, 129.83 pmol) were dissolved in DCM (420 mkl). Then acetic acid (8.57 mg, 142.81 pmol) was added. Then sodium bis(acetyloxy)boranuidyl acetate (41.3 mg, 194.75 pmol) was added portionwise into the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After that period, it was analyzed by LCMS that showed full conversion: 58% of target product and side products. The solvent was removed in vacuo. The residue was diluted with 10% aq. sol. of Na2CO3 (5 ml). Then it was extracted with EtOAc (3 x 10 ml). Combined organic layer was dried over Na2SO4, filtered and evaporated to give tert-butyl (lR,4r)-4-((lR)-l-(methyl((6RS)-4-((2-(3-(l-methyl-lH- pyrazol-3 -yl)piperidin- 1 -yl)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)ethyl)amino)-6-phenyl-5 ,6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l-carboxylate (120 mg, 60% purity, 0.066 mmol, 50% yield). It was used in the next step without further purification. LCMS m / z = 750.4 (M+H)+.

[0267]

[0190] Step 6: A give tert-butyl (lR,4r)-4-((lR)-l-(methyl((6RS)-4-((2-(3-(l-methyl-lH-pyrazol-3- yl)piperidin-l-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane-l -carboxylate (120.0 mg, 109.65 pmol) was dissolved in DCM (590 mkl). Then 4M HCl*dioxane (590 mkl, 2.36 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After that period the reaction mass was analyzed with LCMS that showed full conversion. The solvent was removed in vacuo and the crude residue (86 mg) was analyzed by LCMS that showed 60% of target product. The crude residue was purified by pHPLC (H2O / MeCN+NH3) to give (lR,4r)-4-((lR)-l-(methyl((6RS)-4-((2-(3-(l-methyl-lH-pyrazol-3-yl)piperidin-l-yl)-l-(l -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l- carboxylic acid (24 mg, 0.035 mmol, 32% yield). LCMS m / z [M+H]+ = 695.4,XH NMR (600 MHz, DMSO-d6) 8 12.18 - 11.86 (m, 1H), 11.27 - 10.99 (m, 1H), 7.69 - 7.51 (m, 2H), 7.40 (s, 1H), 7.38 - 7.29 (m, 6H), 7.25 (s, 1H), 6.10 - 6.08 (m, 1H), 3.79 - 3.74 (m, 5H), 3.74 - 3.69 (m, 4H), 3.25 - 2.94 (m, 3H), 2.93 - 2.84 (m, 5H), 2.83 - 2.60 (m, 4H), 2.36 - 2.07 (m, 3H), 2.06 - 1.87 (m, 2H), 1.86 - 1.35 (m, 3H), 1.34 - 1.20 (m, 2H), 1.19 - 0.46 (m, 3H). Docket No.: PAT059787-PCT-SEC01

[0268]

[0191] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates. Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01

[0269]

[0192] Example 10 - Preparation of Intermediate Docket No.: PAT059787-PCT-SEC01

[0270]

[0193] Step 1: To a solution of tert-butyl (S)-piperidin-3-ylcarbamate (2.000 g, 1 Eq, 9.986 mmol) in THF (20.00 m ) was LAH (1.518 g, 16.00 m , 2.500 molar, 4.006 Eq, 40.00 mmol) under N2 at 20°C. The mixture was stirred at 80°C for 3 h. TLC(DCM:MeOH=10: l) showed reactantl (Rf=0.5) consumed and a new spot (Rf=0.1) formed. The reaction mixture was quenched by Na2SO4« 10H2O(l .5 g), stirred for 0.5h, then filtered and concentrated under reduced pressure to give the crude product (S)-N- methylpiperidin-3 -amine (1.600 g, 14.01 mmol, 140.3 %) as yellow oil which was used for next step directly.

[0271]

[0194] Step 2: To a solution of (R)-2-((tert-butoxycarbonyl)amino)-2-(l-methyl-lH-pyrazol-4-yl)acetic acid (1.500 g, 1 Eq, 5.876 mmol) and (S)-N-methylpiperidin-3-amine (1.342 g, 2 Eq, 11.75 mmol) in DCM (15.00 mb) was added TEA (1.784 g, 2.46 mb, 3 Eq, 17.63 mmol) and T3P (8.468 g, 50% Wt, 2 Eq, 11.75 mmol)at 0 °C. After addition, the reaction mixture was stirred at 25 °C for 0.5 hour. LCMS showed 62.4% of desired MW. The reaction mixture was diluted with water (10 mL), extracted with DCM (10 mL*3) and washed with brine (10 mL). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuum to get the residue. The crude product was purified by reversed phase column chromatography (80 g of SepaFlash® Spherical C18, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% FA / 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), concentrated under vacuum to remove MeCN and then added sat.NaHCO3 to adjust PH=8, extracted with EtOAc (20 mL*3) and washed with brine (8 mL). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford tert-butyl ((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 -(methylamino)piperidin- 1 -y l)-2 - oxoethyljcarbamate (600.0 mg, 1.654 mmol, 28.14 %, 96.87% Purity) as yellow solid. LCMS: Rt =0.474 min, [M+H] = 352.2. Docket No.: PAT059787-PCT-SEC01

[0272]

[0195] Step 3: To a solution of tert-butyl ((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- (methylamino)piperidin-l-yl)-2-oxoethyl)carbamate (600.0 mg, 1 Eq, 1.707 mmol) in THF (1.000 mL) was added LAH (162.0 mg, 1.707 mL, 2.500 molar, 2.5 Eq, 4.268 mmol)) at 0°C under N2 for 5min. The mixture was stirred 25°C for 4 h. LCMS showed a major peak of desired MW. The reaction was quenched with Na2SO4«10H2O(lg) filtered and concentrated under reduced pressure to give a residue. The obtained product tert-butyl ((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-(methylamino)piperidin-l- yl)ethyl)carbamate (400.0 mg, 903.5 p mol, 52.93 %, 76.23% Purity) as a yellow oil was taken to the next step without further purification. LCMS: Rt = 0.348 min, [M+H] =338.4.

[0273]

[0196] Step 4: To a solution of tert-butyl ((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- (methylamino)piperidin-l-yl)ethyl)carbamate (400.0 mg, 1 Eq, 1.185 mmol) in THF (1.000 mL) was added TEA (239.9 mg, 330 pL, 2 Eq, 2.371 mmol) and methyl carbonochloridate (168.0 mg, 1.5 Eq, 1.778 mmoljat 0 °C. After addition, the reaction mixture was stirred at 0 °C for 1 hour. LCMS showed a major peak of desired MW. The reaction mixture was quenched with sat.Na2CO3(10 mL) and diluted with water (5 mL), extracted with EA (10 mL*3) and washed with brine (10 mL). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuum to get the residue. The crude product was purified by reversed phase column chromatography (80 g of SepaFlash® Spherical C18, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% FA / 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), concentrated under vacuum to remove MeCN and then added sat.NaHCO3 to adjust PH=8, extracted with EtOAc (10 mL*3) and washed with brine (8 mL). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford methyl ((S)-l-((R)-2-((tert-butoxycarbonyl)amino)-2-(l-methyl- lH-pyrazol-4-yl)ethyl)piperidin-3-yl)(methyl)carbamate (240.0 mg, 607 pmol, 51.2 %, 100% Purity) as a yellow oil. LCMS: Rt =0.391 min, [M+H] =396.1.

[0274]

[0197] Step 5: To a solution of methyl ((S)-l-((R)-2-((tert-butoxycarbonyl)amino)-2-(l -methyl- 1H- pyrazol-4-yl)ethyl)piperidin-3-yl)(methyl)carbamate (240.0 mg, 1 Eq, 606.8 pmol) in DCM (1.000 mL) was added HCl / dioxane (145.8 mg, 2.000 mL, 2.000 molar, 6.592 Eq, 4.000 mmol). After addition, the reaction mixture was stirred at 25 °C for 1 hour. LCMS showed a major peak of desired MW. The reaction mixture concentrated to get the residue. The residue was dissolved in MeOH (10 mL) was added Ion exchange resin (CAS :9017-79-2, [Ambersep 900(OH)]). After the pH=9-10, the mixture was stirred 25°C for 0.5 h, filtered and concentrated to afford methyl ((S)-l-((R)-2-amino-2-(l-methyl-lH-pyrazol- 4-yl)ethyl)piperidin-3-yl)(methyl)carbamate (180.0 mg, 512.6 pmol, 84.47 %, 84.12% Purity) as a yellow oil. LCMS: Rt =0.632 min, [M+H] =296.3.

[0275]

[0198] Example 11 - Preparation of Intermediate 6 Docket No.: PAT059787-PCT-SEC01

[0276]

[0199] Step 1: To a mixture of (R)-2-((tert-butoxycarbonyl)amino)-2-(l-methyl-lH-pyrazol-4-yl)acetic acid (2.600 g, 1 Eq, 10.19 mmol) and benzyl (S)-piperidin-3-ylcarbamate (2.864 g, 1.2 Eq, 12.22 mmol) in DCM (25.00 mL) was added Et3N (3.092 g, 4.26 m , 3 Eq, 30.56 mmol) and then T3P (14.68 g, 50% Wt, 2 Eq, 20.37 mmol) was added to the mixture at 0°C. The mixture was stirred at 0°C for 1 h. LCMS showed a major peak of desired mass was detected. The mixture was adjusted to pH~10 with sat. NaHCO3 solution (50 mL) and diluted with TEO (10 mL), then extracted with DCM (50 mL*3). The organic phase was washed with brine (50 mL). Then the organic phase was dried over anhydrous Na^SO-i. filtered and concentrated to give the residue. The crude residue was purified by reversed phase (120 g of SepaFlash® Spherical C18, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% FA and B for acetonitrile; gradient: B 5 - 95% in 25 min, flow rate: 80 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) after purification, the aqueous phase was basified by saturated NaHCO3 solution to pH=8-9 and extracted with EA (200 mL*3). The combined organic phase was dried over anhydrous Na^SO-i. filtered and concentrated to afford tert-butyl ((R)-2-((S)-3- (((benzyloxy)carbonyl)amino)piperidin-l-yl)-l-(l-methyl-lH-pyrazol-4-yl)-2-oxoethyl)carbamate (4.500 g, 9.2 mmol, 90 %, 96% Purity) as colorless oil. LCMS: Rt =0.501 min, [M+H]+=472.2. Docket No.: PAT059787-PCT-SEC01

[0277]

[0200] Step 2: To a solution of tert-butyl ((R)-2-((S)-3-(((benzyloxy)carbonyl)amino)piperidin-l-yl)-l- (l-methyl-lH-pyrazol-4-yl)-2-oxoethyl)carbamate (4.500 g, 1 Eq, 9.543 mmol) in THF (45.00 mL) was added BH3.DMS (7.61 g, 9.500 mL, 10.00 molar, 9.955 Eq, 95.00 mmol) slowly at 0°C under N2. The mixture was stirred 20°C for 14 h. LCMS showed a major peak desired mass was detected. The reaction mixture was slowly quenched with MeOH (200 mL) until no bubbles released. The mixture was stirred for 2h at 60°C and then concentrated to give tert-butyl ((R)-2-((S)-3- (((benzyloxy)carbonyl)amino)piperidin-l-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)carbamate (4.300 g, 9.397 mmol, 98.48 %) as yellow oil which was used for next step directly. The obtained product was taken to the next step without further purification. LCMS: Rt =0.437 min, [M+H]+ = 458.2.

[0278]

[0201] Step 3: To a solution of tert-butyl ((R)-2-((S)-3-(((benzyloxy)carbonyl)amino)piperidin-l-yl)-l- (l-methyl-lH-pyrazol-4-yl)ethyl)carbamate (4.300 g, 1 Eq, 9.397 mmol) in MeOH (60.00 mL) was added PdOH2 (4.000 g, 50% Wt, 1.516 Eq, 14.24 mmol) at Ar2. Then the mixture was stirred at 25°C for 12h under H2 (15 psi). LCMS showed 79% of desired mass. The reaction mixture was filtered through a pad of Celite and the filtered was washed with MeOH (500 mL) then the filtrate was concentrated to give a residue. The residue was purified by reversed phase column chromatography (220 g of SepaFlash® Spherical C18, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% NH3«H2O and B for acetonitrile; gradient: B 5 - 95% in 20 min, flow rate: 80 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) and lyophilization to give tert-butyl ((R)-2-((S)-3-aminopiperidin-l-yl)-l- (l-methyl-lH-pyrazol-4-yl)ethyl)carbamate (3.000 g, 7.8 mmol, 83 %, 84% Purity) as yellow oil. LCMS: Rt = 0.301 min, [M+H] =324.2.

[0279]

[0202] Step 4: To a solution of tert-butyl ((R)-2-((S)-3-aminopiperidin-l-yl)-l-(l -methyl- lH-pyrazol-4- yl)ethyl)carbamate (950.00 mg, 1 Eq, 2.9372 mmol) and TEA (445.82 mg, 614 pL, 1.5 Eq, 4.4058 mmol) in THF (9.000 mL) was added 4 -chlorobutanoyl chloride (496.93 mg, 1.2 Eq, 3.5246 mmol) in THF (1.000 mL) at 0°C. The mixture was stirred at 0°Cfor 2h. LCMS showed desired mass was detected. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (30 mL*2). The combined organic was dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The crude product was purified by reversed phase column chromatography (80 g of SepaFlash® Spherical C18, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% FA and B for acetonitrile; gradient: B 5 - 95% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm), after purification, then concentrated to remove organic solvents. The aqueous phase was basified by sat. NaHCO3 solution to pH=8-9. Then the mixture was extracted with EA (50 mL*2). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford tert-butyl ((R)-2- ((S)-3-(4-chlorobutanamido)piperidin-l-yl)-l-(l -methyl- lH-pyrazol-4-yl)ethyl)carbamate (300.0 mg, 0.68 mmol, 24 %, 97% Purity) as yellow oil. LCMS: Rt =0.416 min, [M+H]+ =428.3, ’H NMR (400 Docket No.: PAT059787-PCT-SEC01

[0280] MHz, CHLOROFORM-d) 5 = 7.41 (s, 1H), 7.37 (s, 1H), 5.54 - 5.37 (m, 1H), 4.99 - 4.89 (m, 1H), 4.31 - 4.25 (m, 1H), 3.87 (s, 4H), 3.66 - 3.56 (m, 2H), 3.18 - 2.94 (m, 3H), 2.84 - 2.74 (m, 1H), 2.71 - 2.62 (m, 1H), 2.61 - 2.52 (m, 1H), 2.47 - 2.44 (m, 1H), 2.15 - 2.10 (m, 1H), 2.08 - 2.00 (m, 1H), 1.88 - 1.78 (m, 1H), 1.70 - 1.61 (m, 1H), 1.59 - 1.52 (m, 1H), 1.46 (s, 9H).

[0281]

[0203] Step 5: To a solution of tert-butyl ((R)-2-((S)-3-(4-chlorobutanamido)piperidin-l-yl)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)carbamate (280.00 mg, 1 Eq, 654.25 pmol) in THF (14.00 mL) was added t-BuOK (220.24 mg, 226 pL, 3 Eq, 1.9628 mmol). After addition, the reaction mixture was stirred at 25 °C for 1 hour. LCMS showed starting material was consumed completely and major peak with desired mass was detected. The reaction mixture was diluted with water (15 mL), then concentrated under vacuum to remove MeCN, extracted with EtOAc (20 mL*2). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuum to get the crude product. The crude product 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% 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), concentrated under vacuum to remove MeCN and then lyophilized to afford tert-butyl ((R)-l-(l-methyl-lH-pyrazol-4-yl)-2- ((S)-3-(2-oxopyrrolidin-l-yl)piperidin-l-yl)ethyl)carbamate (250.0 mg, 0.58 mmol, 89 %, 91% Purity) as yellow oil used for next step directly. LCMS: Rt = 0.392 min, [M+H]+ = 392.3.

[0282]

[0204] Step 6: To a solution of tert-butyl ((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-(2-oxopyrrolidin- l-yl)piperidin-l-yl)ethyl)carbamate (250.0 mg, 1 Eq, 638.5 pmol) in DCM (0.500 mL) was added HC1 (364.6 mg, 5.000 mL, 2.000 molar, 15.66 Eq, 10.00 mmol). After addition, the reaction mixture was stirred at 25 °C for 1 hour. LCMS showed major peak with desired mass was detected. The reaction mixture was concentrated to get the crude product. The residue was dissolved by MeOH (5 mL) and adjusted pH= 8 by ion exchange resin (Ambersep@900 (OH), 9017-92-2), filtered and concentrated to get the residue. The residue was dissolved by DCM (10 mL), dried by anhydrous Na2SO4, filtered and concentrated to afford l-((S)-l-((R)-2-amino-2-(l -methyl- 1 H-pyrazol-4-yl)ethyl)p iperidin-3- yl)pyrrolidin-2-one (170.0 mg, 0.48 mmol, 76 %, 83% Purity) as yellow oil which was used for next step directly. LCMS: Rt = 0.408 min, [M-NH2]+ = 275.3.

[0283]

[0205] Example 12 - Preparation of Intermediate 7 Docket No.: PAT059787-PCT-SEC01

[0284]

[0206] Step 1: To a solution of tert-butyl ((R)-2-((S)-3-aminopiperidin-l-yl)-l-(l -methyl- lH-pyrazol-4- yl)ethyl)carbamate (400.0 mg, 1 Eq, 1.237 mmol) in THF (6.000 mL) was added K2CO3 (427.3 mg, 2.5 Eq, 3.092 mmol) and 2-bromoethan-l-ol (1.545 g, 10 Eq, 12.37 mmol). Then the mixture was stirred at 60°C for 2 h. LCMS showed a major peak of desired mass. The reaction mixture was diluted with H2O (10 mL) and extracted with EA (10 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford: tert-butyl ((R)-2-((S)-3-((2-hydroxyethyl)amino)piperidin- l-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)carbamate (450.0 mg, 1.1 mmol, 89 %, 90% Purity) as yellow oil. It was used for next step directly without further purification. LCMS: Rf =0.332 min, m / z=368.3 [M+H],

[0285]

[0207] Step 2: To a solution of tert-butyl ((R)-2-((S)-3-((2-hydroxyethyl)amino)piperidin-l-yl)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)carbamate (0.450 g, 1 Eq, 1.22 mmol) in THF (20.000 mL) was added CDI (596 mg, 3 Eq, 3.67 mmol), then the mixture was stirred at 80°C for 3h. LCMS showed 57% of desired mass was detected. The reaction mixture was diluted with H2O (10 mL) and EA (5 mL), the aqueous layer was extracted 3 times with EA (5 mL), and the combined organic extracts were washed with sat.NaCl solution (5 mL), dried over NaSO4, filtered and concentrated to give a residue. The residue 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% NH3«H2O and B for acetonitrile; gradient: B 0 - 80% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength:220 nm / 254 nm) and concentrated to remove MeCN. The residue was adjusted to PH=8 with aq. NaHCO3 solution and extracted with EA (20 mL*3). The combined organic was dried over anhydrous Na2SO4, filtered and concentrated to afford: tert-butyl ((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-(2-oxooxazolidin-3-yl)piperidin-l- yl)ethyl)carbamate (200.0 mg, 0.47 mmol, 39 %, 93% Purity) as white oil. LCMS: Rt =0.472 min, [M+H] = 394.2.

[0286]

[0208] Step 3: A solution of tert-butyl ((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-(2-oxooxazolidin-3- yl)piperidin-l-yl)ethyl)carbamate (200.0 mg, 1 Eq, 508.3 pmol) in DCM (0.500 mL) was added HC1, Docket No.: PAT059787-PCT-SEC01

[0287] 1,4-dioxane (747.4 pg, 3.000 mL, 2.000 mmolar, 0.01180 Eq, 6.000 pmol). The resulting mixture was stirred at 25°C for 1 h. LCMS showed 75% of desired MW was detected. The reaction was concentrated to afford 3-((S)-l-((R)-2-amino-2-(l-methyl-lH-pyrazol-4-yl)ethyl)piperidin-3-yl)oxazolidin-2-one hydrochloride (160.0 mg, 0.36 mmol, 72 %, 75% Purity) as white solid. LCMS: Rt =0.122 min, [M+H] = 294.1.

[0288]

[0209] Example 13 - Preparation of Intermediate

[0289]

[0210] Step 1: EtsN (773 mg, 1.06 mL, 3 Eq, 7.64 mmol), 3-(furan-2-yl)pyrrolidine (349 mg, 1 Eq, 2.55 mmol)and (R)-2-((tert-butoxycarbonyl)amino)-2-(l -methyl- lH-pyrazol-4-yl)acetic acid (0.650 g, 1 Eq, 2.55 mmol) were dissolved in Dichloromethane (8.000 mL). The solution was cooled down to 0 °C and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (1.62 g, 2 Eq, 5.09 mmol) (50% in EtOAc) was added slowly. The solution became unclear and mixture was stirred at room temperature for 8 h. The reaction mixture was partitioned between DCM and water, the organic phase was washed with water, saturated NaHCCL solution, brine and dried over NazSCL. The product was concentrated under reduced pressure to give tert-butyl (( lR)-2-(3 -(furan-2-yl)pyrro lidin- l-yl)-l-(l -methyl- lH-pyrazol-4-yl)- 2-oxoethyl)carbamate (0.978 g, 2.5 mmol, 97 %, 95% Purity). LCMS: RT=1.208 min, MS: 375 [M+H]+.

[0290]

[0211] Step 2: To a solution of tert-butyl ((lR)-2-(3-(furan-2-yl)pyrrolidin-l-yl)-l-(l-methyl-lH- pyrazol-4-yl)-2-oxoethyl)carbamate (0.950 g, 1 Eq, 2.54 mmol) in Tetrahydro furan (15.00 mL) was added BEp.DMS (964 mg, 1.20 mL, 5 Eq, 12.7 mmol) at 0 °C. Then the mixture was warmed to 25 °C and stirred overnight. The RXN mixture was quenched with MeOH until no more bubbling observed. The mixture was stirred for 30 min then concentrated. The residue was diluted with MeOH (10 mL) and heated to 60 °C . The resulting solution was stirred overnight. The mixture was concentrated under reduced pressure and purified via FC(ISCO® Interchim; 40g SiO2, MTBE / Methanol with Methanol from 0~100%(l-20CV), flow rate = 40mL / min, Rf = 5, 5-7, 4CV) to give 0.33 g of racemic product. LCMS: RT=0.996 min, MS: 361 [M+H]+.

[0291]

[0212] Then it was separated by chiral chromatography(Chiralpak IC (250x4.6 mm, 5 mkm)— IC00CE- BN039— 10 Mobile Phase: Hexane:IPA:MeOH, 70:15:15 Flow Rate: 0.6 ml / min) to give Peak 1, tertbutyl ((R)-2-((R)-3-(furan-2-yl)pyrrolidin-l-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)carbamate (0.138 g, Docket No.: PAT059787-PCT-SEC01

[0292] 383 pmol, 15.1 %) LCMS: RT=1.213 min , MS: 361 [M+H]+and Peak 2, tert-butyl ((R)-2-((S)-3-(furan-

[0293] 2-yl)pyrrolidin-l-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)carbamate (0.128 g, 355 pmol, 14.0 %), LCMS: RT=1.237 min, MS: 361 [M+H]+.

[0294]

[0213] Step 3: A solution of tert-butyl ((R)-2-((R)-3-(furan-2-yl)pyrrolidin-l-yl)-l-(l-methyl-lH- pyrazol-4-yl)ethyl)carbamate (0.138 g, 1 Eq, 383 pmol) in Dichloromethane (4.000 mL) / TFA (218 mg, 147 pL, 5 Eq, 1.91 mmol) was stirred overnight at r.t. The mixture was evaporated to obtain (R)-2-((R)-

[0295] 3-(furan-2-yl)pyrrolidin-l-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-amine trifluoroacetate (0.139 g, 371 pmol, 97.0 %), LCMS: RT=0.554 min, MS: 261 [M+H]+

[0296]

[0214] Example 14 - Preparation of Intermediate

[0297]

[0215] Step 1: Cesium (I) carbonate (3.63 g, 11.15 mmol) was added to a solution of ethyl 2-[(tert- butoxy)carbonyl]amino-2-(lH-pyrazol-4-yl)acetate (1.5 g, 5.57 mmol) in MeCN (20 mL), and treated with iodomethane-d3 (807.9 mg, 5.57 mmol) . Then the reaction mass was stirred overnight at r.t., diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, dried over Na^SO-i. and concentrated under reduced pressure to obtain ethyl 2-((tert-butoxycarbonyl)amino)-2-(l- (methyl-d3)-lH-pyrazol-4-yl)acetate (1.53 g, 82.0% purity, 4.38 mmol, 78.6% yield), that was used in the next step without further purification. LCMS: RT=1. 175 min, MS: 287[M+H]+.XH NMR (500 MHz,DMSO) 8 7.66 (s, 1H), 7.38 (s, 1H), 5.05 (s, 1H), 4.15 - 3.93 (m, 2H), 1.39 - 1.34 (m, 13H), 1.17 - 1.11 (m, 3H). Docket No.: PAT059787-PCT-SEC01

[0298]

[0216] Step 2: To a solution of ethyl 2-((tert-butoxycarbonyl)amino)-2-(l-(methyl-d3)-lH-pyrazol-4- yl)acetate (5.710 g, 78% Wt, 1 Eq, 15.55 mmol) in MeOH (30 ml) was added KOH (960.0 mg, 1.10 Eq, 17. 11 mmol). After 8 hours reaction mixture was reduced under vacuo to give potassium 2-((tert- butoxycarbonyl)amino)-2-(l-(methyl-d3)-lH-pyrazol-4-yl)acetate (5.510 g, 15 mmol, 99 %, 83% Purity). LCMS: RT=0.925 min, MS: 259 [M+H]+.

[0299]

[0217] Step 3: (S)-3 -methylpiperidine hydrochloride (474 mg, 1.15 Eq, 3.49 mmol), potassium 2-((tert- butoxycarbonyl)amino)-2-(l-(methyl-d3)-lH-pyrazol-4-yl)acetate (0.900 g, 1 Eq, 3.04 mmol) and TEA (1.23 g, 1.69 mL, 4 Eq, 12.1 mmol) were dissolved in Dichloromethane (12.00 mL). The solution was cooled down to 0 °C and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (2.13 g, 2.2 Eq, 6.68 mmol) (50% in EtOAc) was added slowly. The solution became unclear and mixture was stirred at room temperature for 8 h. The reaction mixture was partitioned between DCM and water, the organic phase was washed with water, saturated NaHCCh solution, brine and dried over NazSOv The solid was filtered off and concentrated under reduced pressure. The product was concentrated under reduced pressure to give tert-butyl (l-(l-(methyl-d3)-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)-2- oxoethyl)carbamate (0.960 g, 2.6 mmol, 86 %, 92% Purity). RT=1.243 min, MS: 340 [M+H]+.

[0300]

[0218] Step 4: To a solution of tert-butyl (l-(l-(methyl-d3)-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin- l-yl)-2-oxoethyl)carbamate (0.950 g, 92% Wt, 1 Eq, 2.57 mmol) in Tetrahydrofuran (10.00 mL) BH3.DMS (978 mg, 1.22 mL, 5 Eq, 12.9 mmol) was added at 0 °C. Then the mixture was warmed to 25 °C and stirred overnight. The RXN mixture was quenched with MeOH until no more bubbling observed. The mixture was stirred for 30 min then concentrated. The residue was diluted with MeOH (10 mL) and heated to 60 °C . The resulting solution was stirred overnight. The mixture was concentrated under reduced pressure and purified via FC (Companion. 40g SiO2, Hex / thf from 0~100% (run length = 26 c.v.), flow rate=40 mL / min, Rv = 12-17CV, 60 / 40 - 50 / 50 eluents ratio) to give 0.56 g of diastereomers mixture. LCMS: RT=0.940 min, MS: 326 [M+H]+.Then it was separated by chiral chromatography(Chiralpak IG (250x4.6 mm, 5 mkm)— IG00CE-AX023— SFC-1 Mobile Phase: COz:MeOH, 80:20) to give Peak 1 tert-butyl ((S)-l-(l-(methyl-d3)-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)carbamate (0.230 g, 707 pmol, 27.4 %, 100% Purity) LCMS: RT=1.083 min, MS: 326 [M+H]+and Peak 2 tert-butyl ((R)-l-(l-(methyl-d3)-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)carbamate (0.220 g, 676 pmol, 26.3 %, 100% Purity). LCMS: RT=1.111 min, MS: 326 [M+H]+.

[0301]

[0219] Step 5: A solution of tert-butyl ((R)-l-(l-(methyl-d3)-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)carbamate (0.220 g, 1 Eq, 676 pmol) in MeOH (3ml) / HC1 (98.6 mg, 4 Eq, 2.70 mmol) was stirred overnight at r.t. The mixture was evaporated to obtain (R)-l-(l-(methyl-d3)-lH- Docket No.: PAT059787-PCT-SEC01 pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethan-l-amine di-hydrochloride (0.198 g, 664 pmol, 98.2 %, 100% Purity) LCMS: RT=0.228 min, MS: 226 [M+H]+.

[0302]

[0220] Example 15 - Synthesis of (!R,4r)-4-((R)-l-(((R)-4-(((R)-2-((S)-3-acetoxy-3- methylpiperidin-l-yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahvdroauinazolin-2-yl)(methyl)amino)DroDyl)cvclohexane-l-carboxylic acid (Compound 7)

[0303]

[0221] Step 1: To a solution of (R)-2-((tert-butoxycarbonyl)amino)-2-(l-methyl-lH-pyrazol-4-yl)acetic acid (450.0 mg, 1 Eq, 1.763mmol) and (S)-3-methylpiperidin-3-ol (320.8 mg, 1.2 Eq, 2.115 mmol) in DCM (5.000 mL) and DMF (0.500 mL)was added DIEA (227.8 mg, 307 pL, 1 Eq, 1.763 mmol) and T3P (635.1 mg, 1 Eq, 1.763 mmol). After addition, the reaction mixture was stirred at 25 °C for 1 hour. LCMS showed a major peak of desired MW. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (20 mL*3) and washed with brine (10mL*3). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuum to get theresidue. The crude product 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 / H2O and B for acetonitrile; gradient: B 5 - 95% in 20 min, flowrate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm), concentrated under Docket No.: PAT059787-PCT-SEC01 vacuum to removeMeCN and then added sat.NaHCO3 to adjust PH=8, extracted with EtOAc (20 mL*3) and washed with brine (8 mL). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford tert-butyl ((R)-2-((S)-3-hydroxy-3-methylpiperidin-l-yl)-l-(l- methyl-lH-pyrazol-4-yl)-2-oxoethyl)carbamate (400.0 mg, 1.135 mmol, 64.38 %) as ayellow oil, LCMS: Rt = 0.423 min, [M+H] =353.2.

[0304]

[0222] Step 2: To a solution of tert-butyl ((R)-2-((S)-3 -hydroxy-3 -methylpiperidin- l-yl)-l-(l-m ethyl - lH-pyrazol-4-yl)-2-oxoethyl)carbamate (400.0 mg, 1 Eq, 1.135 mmol) in THF (4.000 mL) was added BH3.DMS (862.1 mg, 1.135 mL, 10.00 molar, 10 Eq, 11.35 mmol) at 0°C under N2 for 5min. The mixture was stirred 25°C for 12 h. The reaction mixture was slowly quenched with MeOH (10 mL) until no bubbles released. The mixture was stirred for Ih at 60°C. LCMS showed 41.5% of desired MW. The reaction mixture was concentrated to get the crude product and 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 / H2O and B for acetonitrile; gradient: B 5 - 95% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220nm / 254 nm), concentrated under vacuum to remove MeCN and then lyophilized to afford tert-butyl ((R)-2-((S)-3-hydroxy-3-methylpiperidin-l-yl)-l-(l-methyl-lH-pyrazol- 4-yl)-2-oxoethyl)carbamate (290.0 mg, 851 pmol, 75.0 %, 99.3%Purity) as yellow oil. LCMS: Rt = 0.361 min, [M+H] =339.2,

[0305]

[0223] Step 3: To a solution of tert-butyl ((R)-2-((S)-3 -hydroxy-3 -methylpiperidin- l-yl)-l-(l-m ethyl - lH-pyrazol-4-yl)-2-oxoethyl)carbamate (290.00 mg, 1 Eq, 856.85 pmol) in Pyridine (2.000 mL) was added Ac2O (2.164 g, 2.000 mL, 24.74 Eq, 21.20 mmol). The mixture was stirred at 60 °C for 12 hour.showed desired MW. The reaction was concentrated to get the residue. The crude product 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 / 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), concentrated under vacuum to remove MeCN and then added sat.NaHCO3 to adjust PH=8, extracted with EtOAc (20 mL*3) and washed with brine (8 mL). The organic layer was dried with anhydrous Na2SO4 , filtered and concentrated under vacuum to afford (S)-l-((R)-2-((tert-butoxycarbonyl)amino)-2-(l -methyl- 1H- pyrazol-4-yl)ethyl)-3-methylpiperidin-3-yl acetate (210.0 mg, 550 pmol, 64.2 %, 99.6% Purity) as a yellow oil. LCMS: Rt = 0.398 min, [M+H] =381.2,

[0306]

[0224] Step 4: To a solution of (S)-l-((R)-2-((tert-butoxycarbonyl)amino)-2-(l-methyl-lH-pyrazol-4- yl)ethyl)-3-methylpiperidin-3-yl acetate (210.0 mg, 1 Eq, 551.9 pmol) in DCM (0.500 mL) was added HCl / dioxane (291.7 mg, 2.000 mL, 4.000 molar, 14.49 Eq, 8.000 mmol). After addition, the reaction mixture was stirred at 25 °C for 2 hour. LCMS showed a major peak of desired MW. The reaction mixture concentrated to get the residue. The residue was dissolved in MeOH (10 mL) was added Ion Docket No.: PAT059787-PCT-SEC01 exchange resin (CAS :9017-79-2, [Ambersep 900(OH)]). After the pH=9-10, the mixture was stirred 25°C for 0.5 h, filtered and concentrated to afford: (S)-l-((R)-2-amino-2-(l-methyl-lH-pyrazol-4- yl)ethyl)-3 -methyip iperidin-3-yl acetate (145.0 mg, 488 pmol, 88.4 %, 94.3% Purity) as ayellow oil. LCMS: Rt = 0.493min, [M-NH2] =264.2.

[0307]

[0225] Step 5: To a solution of (S)-l-((R)-2-amino-2-(l-methyl-lH-pyrazol-4-yl)ethyl)-3- methylpiperidin-3-yl acetate (200.00 mg, 1 Eq, 326.95 pmol) and tert-butyl (lR,4r)-4-((R)-l- (methyl((R)-6-phenyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane-l -carboxylate (110.00 mg, 1.2 Eq, 392.34 pmol) in ACN (2.000 mL)was added DIEA (211.29 mg, 285 pL, 5 Eq, 1.6347 mmol). After addition, the reaction mixture was stirred at 80 °C for 48 hour. LCMS showed 63% of desired MW. The reaction mixture was concentrated under vacuum to get the residue. The crude product was purified by reversed phase column chromatography (80 g of SepaFlash® Spherical C18, 20 -45 pm, 100 A; mobile phase: A for H2O + 0.1% FA / 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), concentrated under vacuum to remove MeCN and then lyophilization to afford tert-butyl (lR,4r)-4-((R)-l-(((R)-4-(((R)-2-((S)-3-acetoxy-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 -carboxylate (60.00 mg, 80.9 pmol, 24.7 %, 100% Purity) and purified by SFC seperation (Instrument: ACSWH-PREP-SFC-K; Column: DAICEL CHIRALPAK IG (250mm*30mm,10um); Condition: CO2-ACN / i-PrOH(0.1% NH3H2O); Begin B: 22; End B: 22;

[0308] Gradient Time(min) 5.5; FlowRate(ml / min): 150)as a yellow oil. LCMS: Rt = 0.475min, [M+H] =742.4.

[0309]

[0226] Step 6: To a solution of tert-butyl (lR,4r)-4-((R)-l-(((R)-4-(((R)-2-((S)-3-acetoxy-3- methylpiperidin- 1 -yl)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)ethyl)amino)-6-phenyl-5 ,6,7,8 -tetrahydroquinazolin- 2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (50.00 mg, 1 Eq, 67.38 pmol)in dioxane (0.200 mL) was added 4M HCl / dioxane (1.000 mL). Then the mixture was stirred at 25 °C for 1 hour. LCMS showed desired mass. The reaction mixture was dried by N2 flow, added H2O (20 mL) to give the solution. The mixture was lyophilized to give (lR,4r)-4-((R)-l-(((R)-4-(((R)-2-((S)-3-acetoxy-3- methylpiperidin- 1 -yl)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)ethyl)amino)-6-phenyl-5 ,6,7,8 -tetrahydroquinazolin- 2-yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid (43.91 mg, 60.8 pmol, 90.2 %, 100% Purity) as white solid. LCMS: Rt =0.443min, [M+H] =686.5, ’H NMR (400 MHz, DMSO-d6) 8 = 7.68 - 7.58 (m, 1H), 7.41 (s, 1H), 7.38 - 7.31 (m, 4H), 7.28 - 7.21 (m, 1H), 5.99 - 5.74 (m, 1H), 4.61 - 4.28 (m, 1H), 3.95 - 3.60 (m, 5H), 3.51 - 3.32 (m, 2H), 3.05 - 2.74 (m, 8H), 2.46 - 2.36 (m, 1H), 2.16 - 1.81 (m, 11H), 1.80 - 1.66 (m, 3H), 1.62 - 1.46 (m, 3H), 1.43 - 1.34 (m, 4H), 1.34 - 1.15 (m, 3H), 1.09 - 0.93 (m, 1H), 0.81 - 0.75 (m, 3H), 0.66 - 0.39 (m, 1H). Docket No.: PAT059787-PCT-SEC01

[0310]

[0227] 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.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01

[0311]

[0228] Example 16 - Synthesis of (lR,4r)-4-((((R)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5.6.7.8-tetrahvdroguinazolin-2- yllaminolmethvDcvclohexane-l-carboxylic acid (Compound 55) Docket No.: PAT059787-PCT-SEC01

[0312]

[0229] Step 1: A solution of (R)-2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline (1265 mg, 4.53 mmol), (R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 -methylpiperidin- 1 -yl)ethan- 1 -amine dihydrochloride (1338 mg, 4.53 mmol) and DIPEA (2769 pl, 15.86 mmol) in MeCN (Volume: 22 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 brine, dried over Na^SCh and concentrated. The residue was purified through flash column chromatography (0-20% MeOH (0.1 N NEy / DCM) to give (R)-2-chloro-N-((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 -methylpiperidin- 1 -yl)ethyl)-6-phenyl- 5,6,7,8-tetrahydroquinazolin-4-amine as a light pale solid (949 mg, 45%). MS: m / z = 465.1 [M+H]+.

[0313]

[0230] Step 2: A solution of (R)-2-chloro-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 (100.00 mg, 172.08 pmol)) and methyl (lr,4r)-4-(aminomethyl)cyclohexane-l-carboxylate hydrochloride (178.71 mg, 860.42 pmol)) in MeCN (172.08 pL) and 2,2,2-Trifluoroethanol (172.08 pL) was heated at 130 °C in a microwave reactor for 18 hr. The reaction mixture was diluted with EtOAc, washed with brine, dried over NazSC and concentrated. The residue was purified through flash column chromatography (0-20% MeOH(0.1 N NEy / DCM) to give methyl (lR,4r)-4-((((R)-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)methyl)cyclohexane-l -carboxylate as a light pale solid (80 mg, 62%). MS: m / z = 600.4 [M+H]+.

[0314]

[0231] Step 3: To a solution methyl (lR,4r)-4-((((R)-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)methyl)cyclohexane-l -carboxylate (80 mg, 1.296 mmol) in THF (1 mL) and MeOH (0.5 mL) was added NaOH (4N aq solution) (133 uL mL, 533 pmol). The resulting suspension was stirred Docket No.: PAT059787-PCT-SEC01 at 50 °C for 30 min then solvent was removed under reduced pressure then diluted with DMSO. The suspension was purified by reverse phase column. (50 g ISCO gold C-18 column, 20-70% MeCN / water, with 0.1% NH4OH as modifier). The pure fractions was combined and lyophilization drying gave (lR,4r)-4-((((R)-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)methyl)cyclohexane-l -carboxylic acid as a white solid (46 mg, 70%). LCMS m / z [M+H]+ = 586.4,

[0315]

[0232] The following compounds , including the title compound, were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0316]

[0233] Example 17 - Synthesis of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl (lR,4r)-4-((R)-l-(((R)-6- (3-fluorophenyl)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)- 5,6,7,8-tetrahvdroquinazolin-2-yl)amino)DroDyl)cvclohexane-l-carboxylate (Compound 49) Docket No.: PAT059787-PCT-SEC01

[0317]

[0234] To a 5 mL vial containing methyl (lR,4r)-4-((RS)-l-(((R)-6-(3-fluorophenyl)-4-(((RS)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane-l -carboxylate (710.0 mg, 1 Eq, 1.099 mmol) dissolved in a mixture of THF (5.000 mL) and MeOH (2.500 mL) was added 4M NaOH (439.7 mg, 10.99 mL, 1.000 molar, 10 Eq, 10.99 mmol). After the reaction mixture was heated to 50 oC for Ih, the reaction mixture was evaporated to dryness. The residue was redissolved in 2 ml of DMF and then 4-(chloromethyl)-5- methyl-l,3-dioxol-2-one (163.3 mg, 1 Eq, 1.099 mmol). The reaction mixture was heated at 70 oC for overnight. The final product was purified by reverse ISCO basic method to give (5-methyl-2-oxo-l,3- dioxol-4-yl)m ethyl ( 1 RS,4SR)-4-((RS)- 1 -(((R)-6-(3 -fluorophenyl)-4-(((RS)- 1 -( 1 -methyl- 1 H-pyrazol-4- yl)-2-((SR)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane-l -carboxylate (25.00 mg, 33.61 pmol, 3.057 %). LCMS m / z [M+H]+ = 744.5, 'H NMR (400 MHz, CDC13) 8 7.32 - 7.20 (m, 2H), 7.14 (s, IH), 6.96 (d, J= 7.8 Hz, IH), 6.89 (t, J= 8.4 Hz, 2H), 4.72 (s, 2H), 3.77 (s, 3H), 3.67 - 3.47 (m, IH), 3.05 - 2.35 (m, 8H), 2.35 - 2.00 (m, 7H), 2.00 - 1.08 (m, 18H), 0.97 - 0.77 (m, 5H), 0.75 (d, J= 6.5 Hz, 3H).

[0318]

[0235] Example 18 - Synthesis of rac-3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-4-(((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahvdroguinazolin- 2-yl)(methyl)amino)propyl)cvdohexyl)isoxazol-5-ol (Compound 51)

[0319]

[0236] Step 1: To a stirred solution of rac-(lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-4-(((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- Docket No.: PAT059787-PCT-SEC01 yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid (80.00 mg, 1 Eq, 123.9 pmol) in THF (1.000 mL) was added CDI (30.13 mg, 19.24 pL, 1.5 Eq, 185.8 pmol) in one portion. The reaction mixture was heated at reflux for 3h. A suspension of Ethyl potassium Malonate (84.33 mg, 0.19 mL, 4 Eq, 495.5 pmol) and Magnesium chloride (47.17 mg, 28.40 pL, 4 Eq, 495.5 pmol) in THF (1 mL) was added and the resulting reaction mixture was heated at reflux overnight. LC-MS Indicates reaction is completed. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated. To the crude was added DCM and submitted to ISCO (12g) with 60% EtOAc in Heptane to afford desired compound rac-ethyl 3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)-3-oxopropanoate (31 mg white solid, 32% yield). LCMS: m / z = 717.1 [M+H]+;

[0320]

[0237] Step 2: To a stirred solution of rac-ethyl 3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)-3-oxopropanoate (30.00 mg, 85% Wt, 1 Eq, 35.62 pmol) in EtOH (1.000 mL) was added hydroxylamine (7.058 mg, 50% Wt, 3 Eq, 106.8 pmol) and hydroxylamine (7.058 mg, 50% Wt, 3 Eq, 106.8 pmol). The reaction mixture was stirred at room temperature for 16h. LCMS indicates reaction is completed. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4 and concentrated. The crude material was purified via Prep HPLC (Basic_35- 60%-Acetonitrile; Column: Waters XBridge C18 OBD 30 x 50 mm) to give rac-3-((lR,4r)-4-((R)-l- (((R)-6-(3-fluorophenyl)-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)cyclohexyl)isoxazol-5-ol (13.5 mg, 53% yield). LCMS m / z = 685.6 [M+H]+; ’H NMR (400 MHz, MeOD) 8 7.42 (s, 1H), 7.32 - 7.20 (m, 2H), 7.11 - 6.98 (m, 2H), 6.91 - 6.82 (m, 1H), 5.42 (s, 1H), 4.47 (s, 1H), 4.40 (s, 1H), 3.76 (s, 3H), 3.0 (m, 3H), 2.91 (s, 3H), 2.80 (m, 3H), 2.77 (m, 3H), 2.45 (m, 1H), 2.23 (t, J= 13.7 Hz, 1H), 2.13 (m, 1H), 2.07 - 1.77 (m, 7H), 1.75- 1.60 (m, 3H), 1.58 - 1.22 (m, 8H), 1.08-0.89 (d, J= 11.9 Hz, 2H), 0.85 (d, J= 6.4 Hz, 3H), 0.78 (t, J= 7.2 Hz, 3H).

[0321]

[0238] Example 19 - Synthesis of rac-(lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-4-(((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5.6.7.8-tetrahvdroquinazolin- 2-yl)(methyl)amino)propyl)-N-(methylsulfonyl)cvclohexane-l-carboxamide (Compound 50) Docket No.: PAT059787-PCT-SEC01

[0322]

[0239] A stirred solution of rac-(lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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 (25.00 mg, 1 Eq, 38.71 pmol), Methylsulfonamide (7.364 mg, 5.992 pL, 2 Eq, 77.41 pmol), 4-Dimethylaminopyridine (DMAP) (7.093 mg, 1.5 Eq, 58.06 pmol) and l-(3-Dimethylaminopropyl)-3-ethylcarbodiimideHydrochloride (EDCI) (11.13 mg, 1.5 Eq, 58.06 pmol)in DCM (1.000 mL) was stirred at rt overnight. 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 rac-(lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)- 4-(((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 -methylpiperidin- 1 -yl)ethyl)amino)-5 ,6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)-N-(methylsulfonyl)cyclohexane-l -carboxamide (16.5 mg, 56% yield). LCMS m / z = 723.5 [M+H]+; ’H NMR (400 MHz, MeOD) 8 7.42 (s, 1H), 7.32 - 7.20 (m, 2H), 7.11 - 6.98 (m, 2H), 6.91 - 6.82 (m, 1H), 5.42 (s, 1H), 4.47 (s, 1H), 4.40 (s, 1H), 3.76 (s, 3H), 2.91 (m, 6H), 2.80 (s, 3H), 2.71 (s, 3H), 2.75 - 2.54 (m, 2H), 2.34 (t, J= 13.7 Hz, 1H), 2.07 - 1.66 (m, 9H), 1.60 (t, J= 15.1 Hz, 4H), 1.47 - 1.10 (m, 7H), 0.86 (d, J= 11.9 Hz, 2H), 0.77 (d, J= 6.4 Hz, 3H), 0.69 (t, J = 7.2 Hz, 3H).

[0323]

[0240] Example 20 - Synthesis of (R)-N2-((R)-l-((lr,4R)-4- ((dimethylamino)methyl)cvclohexyl)propyl)-N4-((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethvD-6-phenyl-5,6,7,8-tetrahvdroquinazoline-2,4-diamine (Compound 48)

[0324] Docket No.: PAT059787-PCT-SEC01

[0325]

[0241] Step 1: To a mixture of (lR,4r)-4-((R)-l-(((R)-l-phenylethyl)amino)propyl)cyclohexane-l- carboxylic acid (500.00 mg, 1 Eq, 1.7276 mmol) and dimethylamine, AA - Hydrochloride (211.3 mg, 1.5 Eq, 2.5914 mmol) in DCM (5.000 mL) was added Et3N (874.08 mg, 1.20 mL, 5 Eq, 8.6380 mmol) and T3P (2.4895 g, 50% Wt, 2 Eq, 3.4552 mmol, CAS: 163755-62-2). The mixture was stirred at 25 °C for 1 hour. LCMS showed 92% of desired mass was detected. The mixture was diluted with H2O (30 mL) and extracted with DCM (10 mL*3). The combined organic phase was washed with aq. NaHCO3 solution (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. 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 0 - 95% in 30 min, flow rate: 80 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) and concentrated to remove MeCN. The residue was adjust to PH=8 with aq. NaHCO3 solution and extracted with DCM (30 mL*3). The combined organic was dried over anhydrous Na2SO4, filtered and concentrated to afford (1 R,4r)-N,N-dimethyl-4-((R)- 1 -(((R)- 1 -phenylethyl)amino)propyl)cyclohexane-l - carboxamide (400.0 mg, 1.26 mmol, 73.2 %, 100% Purity) as a white gum. LCMS: Rt = 0.428 min, [M+H]+ = 317.1. (400 MHz, CHLOROFORM-d) 8 = 7.38 - 7.28 (m, 4H), 7.26 - 7.19 (m, 1H), 3.90 - 3.78 (m, 1H), 3.05 (s, 3H), 2.94 (s, 3H), 2.53 - 2.39 (m, 1H), 2.21 - 2.10 (m, 1H), 1.88 - 1.73 (m, 3H), 1.68 - 1.61 (m, 1H), 1.60 - 1.48 (m, 3H), 1.41 - 1.35 (m, 1H), 1.31 (d, J = 6.4 Hz, 3H), 1.29 - 1.03 (m, 4H), 0.87 - 0.74 (m, 3H),

[0326]

[0242] Step 2: To a solution of (lR,4r)-N,N-dimethyl-4-((R)-l-(((R)-l- phenylethyl)amino)propyl)cyclohexane-l -carboxamide (400.0 mg, 1 Eq, 1.264 mmol) in MeOH (4.000 mL) was added PdOH2 (88.74 mg, 0.5 Eq, 631.9 pmol) under N2. The mixture was stirred at 25 °C for 3 hour under a balloon of H2 (15 psi). The reaction mixture was filtered and washed with MeOH (5 mL*3). The filter was concentrated to afford (lR,4r)-4-((R)-l-aminopropyl)-N,N-dimethylcyclohexane- Docket No.: PAT059787-PCT-SEC01

[0327] 1-carboxamide (250.0 mg, 1.2 mmol, 91 %, 98% Purity) as a white gum. LCMS: Rt = 0.326 min, [M- NH2]+ = 196.1, 'H NMR (400 MHz, METHAN0L-d4) 8 = 3.10 (s, 3H), 2.92 (s, 3H), 2.67 - 2.56 (m, 1H), 2.47 - 2.40 (m, 1H), 1.87 - 1.72 (m, 4H), 1.58 - 1.42 (m, 3H), 1.39 - 1.29 (m, 2H), 1.27 - 1.09 (m, 2H), 1.00 - 0.88 (m, 3H).

[0328]

[0243] Step 3: A mixture of (R)-2-chloro-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 (50.000 mg, 1 Eq, 107.52 pmol) and (lR,4r)-4-((R)-l-aminopropyl)-N,N-dimethylcyclohexane-l-carboxamide (57.076 mg, 2.5 Eq, 268.79 pmol) in a tube was stirred at 120 °C for 24 hour. LCMS showed 70% of desired mass was detected. The mixture was diluted with MeCN (0.5 mL) and combined with pilot batch to give a solution. The solution 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 0 - 95% in 30 min, flow rate: 80 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) and concentrated to remove MeCN. The residue was adjust to PH=8 with aq. NaHCO3 solution and extracted with EA (20 mL*3). The combined organic was dried over anhydrous Na2SO4, filtered and concentrated to afford ( 1 R,4r)-N,N-dimethyl-4-((R)- 1 -(((R)-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)amino)propyl)cyclohexane- 1-carboxamide (45.00 mg, 68.90 pmol, 64.08 %, 98.135% Purity) as a yellow solid. LCMS: Rt = 0.934 min, [M+H]+ = 641.5.

[0329]

[0244] Step 4: To a solution of (lR,4r)-N,N-dimethyl-4-((R)-l-(((R)-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-carboxamide (40.00 mg, 1 Eq, 62.41 pmol) in THF (0.400 mL) was added HA1H4 (7.105 mg, 74.89 pL, 2.500 molar, 3 Eq, 187.2 pmol) at 0°C. Then the mixture was stirred at 0 °C for 1 hour. LCMS showed 82% of desired mass was detected. The reaction was quenched with Na2SO4«10 H2O (65 mg) and combined with pilot batch, then filtered and washed with THF(10 mL *3), the combined phase was concentrated to give the residue. The solution was purified by reversed phase column chromatography (80 g of SepaFlash® Spherical C18, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% FA and B for acetonitrile; gradient: B 0 - 95% in 30 min, flow rate: 80 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) and then lyophilized to afford (R)-N2-((R)-l-((lr,4R)-4- ((dimethylamino)methyl)cyclohexyl)propyl)-N4-((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine formate salt (30.44 mg, 45.2 pmol, 72.5 %, 100% Purity) as white solid. LCMS m / z [M+H]+= 627.5, ’H NMR (400 MHz, DMSO-d6 ) 8 = 8.31 (s, 1H), 7.49 (s, 1H), 7.37 - 7.30 (m, 4H), 7.29 (s, 1H), 7.25 - 7.18 (m, 1H), 6.80 - 6.54 (m, 1H), 6.54 - 6.36 (m, 1H), 5.50 - 5.36 (m, 1H), 3.74 (s, 3H), 2.92 - 2.70 (m, 4H), 2.68 - 2.54 (m, Docket No.: PAT059787-PCT-SEC01

[0330] 4H), 2.26 - 2.18 (m, 1H), 2.09 (s, 6H), 1.98 (d, J= 6.8 Hz, 2H), 1.94 - 1.83 (m, 3H), 1.75 - 1.58 (m, 6H), 1.56 - 1.45 (m, 3H), 1.40 - 1.23 (m, 4H), 1.05 - 0.59 (m, 12H)

[0331]

[0245] The following compounds, including the title compound, were made using the above procedure or modifications to the above procedure using the corresponding intermediates.

[0332]

[0246] Example 21- Synthesis of (R)-N2-(((lr,4R)-4-((dimethylamino)methyl)cvclohexyl)methyl)-

[0333] N4-((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)-6-phenyl-5,6,7,8- tetrahvdroquinazoline-2,4-diamine (Compound 54)

[0334]

[0247] Step 1: To a solution of (R)-2-chloro-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 (100 mg, 0.215 mmol) in DCM (1 mL) was added tert-butyl (((lr,4r)-4-(aminomethyl)cyclohexyl)methyl)carbamate (156 mg, 0.645 mmol), the mixture was stirred at 90°C for 12h in a sealed tube. LCMS showed a major peak of desired mass was detected. The reaction mixture was diluted with H2O (5 mL) and extracted with EA (5 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford the residue. The residue was purified by reversed phase (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 - 95% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) after purification, the Docket No.: PAT059787-PCT-SEC01 aqueous phase was basified by saturated NaHC03 solution (10 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 tert-butyl (((lR,4r)-4-((((R)-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)methyl)cyclohexyl)methyl)carbamate (60 mg, 0.089 mmol, 41% yield, 98%purity) as yellow oil. LCMS: Rt =0.461 min, [M+H]+ =671.5.

[0335]

[0248] Step 2: A solution of tert-butyl (((lR,4r)-4-((((R)-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)methyl)cyclohexyl)methyl)carbamate (60 mg, 0.089 mmol) in 2M HCl / dioxane (1 mL). The resulting mixture was stirred at 25°C for 1 h. LCMS(C-11129-111-P1A1) showed a major peak desired MW was detected. The reaction was concentrated to afford (R)-N2-(((lr,4R)-4- (aminomethyl)cyclohexyl)methyl)-N4-((R)-l -(1 -methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l- yl)ethyl)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine (60 mg, HC1 salt) as white solid. LCMS: Rt =0.468 min, [M+H]+ = 571.5.

[0336]

[0249] Step 3: To a mixture of (R)-N2-(((lr,4R)-4-(aminomethyl)cyclohexyl)methyl)-N4-((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)-6-phenyl-5,6,7,8-tetrahydroquinazoline- 2,4-diamine (50 mg, 0.082 mmol) in DCM (0.5 mL) was added Et3N (25 mg, 0.247 mmol) and HCHO (20 mg, 0.247 mmol, 37% in H2O) in DCM (0.5 mL) then NaBH3CN (16 mg, 0.247 mmol) was added at 0°C. Then the mixture was stirred for 3 h at 25 °C. LCMS showed 69% of desired mass was detected. The mixture was diluted with H2O (5 mL) and extracted with DCM (5 mL*2). The organic phase was combined and dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was combined with C-l 1129-113 to purify, the residue was purified by reversed phase (40 g of SepaFlash® Spherical C18, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% FA and B for acetonitrile; gradient: B 5 - 40% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm), then concentrated to remove MeCN and lyophilized to give (R)-N2-(((lr,4R)-4- ((dimethylamino)methyl)cyclohexyl)methyl)-N4-((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 - methylpiperidin-l-yl)ethyl)-6-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine (8.91 mg, 0.014 mmol, 18% yield, 99.59%purity) as white solid. LCMS m / z [M+H]+= 599.5,1H NMR (400 MHz, DMSO-d6 ) 8 = 8.27 (s, 2H), 7.49 (s, 1H), 7.36 - 7.28 (m, 5H), 7.25 - 7.19 (m, 1H), 6.71 - 6.42 (m, 1H), 5.52 - 5.39 (m, 1H), 3.74 (s, 3H), 3.14 - 2.98 (m, 3H), 2.92 - 2.84 (m, 1H), 2.81 - 2.73 (m, 2H), 2.71 - 2.65 (m, 1H), 2.64 - 2.57 (m, 1H), 2.57 - 2.52 (m, 2H), 2.29 - 2.20 (m, 1H), 2.15 (s, 6H), 2.10 - 2.05 (m, 2H), 1.96 - 1.84 (m, 3H), 1.78 - 1.65 (m, 5H), 1.65 - 1.58 (m, 1H), 1.57 - 1.49 (m, 2H), 1.46 - 1.22 (m, 4H), 0.92 - 0.71 (m, 8H). Docket No.: PAT059787-PCT-SEC01

[0337]

[0250] Example 22 - Synthesis of (R)-6-(3-fluorophenyl)-N2-methyl-N2-((R)-l-((lr,4R)-4-(5- methyl-1.3.4-oxadiazol-2-yl)cvdohexyl)propyl)-N4-((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)-5,6,7,8-tetrahvdroguinazoline-2,4-diamine (Compound 56)

[0338]

[0251] To a mixture of of rac-(lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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 (40.00 mg, 1 Eq, 61.93 pmol) and acetohydrazide (6.882 mg, 1.5 Eq, 92.90 pmol) in Ethyl acetate (2.000 mL) was added TEA (18.80 mg, 25.9 pL, 3 Eq, 185.8 pmol) followed by Propylphosphonic anhydride (98.53 mg, 91.14 pL, 50% Wt, 2.5 Eq, 154.8 pmol) in drops. The reaction mixture was heated at 80°C under N2 atmosphere overnight. LCMS indicates reaction is completed. The reaction mixture was cooled to RT and poured into water. The product was extracted with EtOAc (15 mL X2). The organic phase was dried over MgSO4. Cone, and the crude product was purified by Prep HPLC (Basic_65-95%-Acetonitrile_5.1min, Column: Waters XBridge C18 OBD 30 x 50 mm) to give (R)-6-(3-fluorophenyl)-N2-methyl-N2-((R)-l-((lr,4R)-4-(5- methyl-l,3,4-oxadiazol-2-yl)cyclohexyl)propyl)-N4-((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)-5,6,7,8-tetrahydroquinazoline-2,4-diamine (10.50 mg, 24 % yield). LCMS m / z = 684.4 [M+H]+; ’H NMR (400 MHz, MeOD) 8 7.36 (s, 1H), 7.30 (s, 1H), 7.23 (td, J= 7.9, 6.0 Hz, 1H), 7.07 (d, J= 7.8 Hz, 1H), 7.00 (dt, J= 10.4, 2.2 Hz, 1H), 6.84 (td, J = 8.5, 2.6 Hz, 1H), 5.31 (s, 1H), 4.46 (s, 1H), 3.73 (s, 3H), 2.91 (s, 1H), 2.83 (s, 1H), 2.73 (d, .7= 22.1 Hz, 1H), 2.72 (s, 3H), 2.70 - 2.62 (m, 2H), 2.63 (s, 3H), 2.51 (dd, J= 12.8, 5.0 Hz, 1H), 2.39 (s, 3H), 2.32 (dd, J= 15.4, 11.0 Hz, 1H), 2.03 (t, J= 15.1 Hz, 2H), 1.89 (dd, J= 14.6, 8.6 Hz, 4H), 1.72 - 1.50 (m, 5H), 1.48-1.25 (m, 8H), 0.94 (s, 1H), 0.75 (d, J= 6.4 Hz, 3H), 0.68 (t, J= 7.2 Hz, 3H), 0.54 (s, 1H).

[0339]

[0252] Example 23 - Synthesis of 3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-4-(((R)-l-(l-methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahvdroguinazolin-2- yl)(methyl)amino)propyl)cvclohexyl)-l,2,4-oxadiazol-5(4H)-one (Compound 57) Docket No.: PAT059787-PCT-SEC01

[0340]

[0253] Step 1: To a stirred solution of rac-(lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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 (100.00 mg, 1 Eq, 154.83 pmol) in DMF (2.500 mL) were added ammonium chloride (16.56 mg, 11.28 pL, 2 Eq, 309.66 pmol), HATU (88.309 mg, 1.5 Eq, 232.24 pmol) and Diisopropylethylamine (60.035 mg, 79.9 pL, 3 Eq, 464.49 pmol). The reaction mixture was stirred at rt overnight. LCMS indicates reaction is completed. 10 mL water was added, and extracted twice with 10 mL EtOAc, dried over magnesium sulfate, filtered and concentrated in vacuo. To the crude was added DCM and submitted to ISCO (4g) with 0% Methanol with Ammonium in DCM to 20% Methanol with Ammonium in DCM. To give (lRS,4r)-4-((RS)-l-(((RS)-6-(3-fluorophenyl)-4- (((RS)-l-(l-methyl-lH-pyrazol-4-yl)-2-((SR)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l-carboxamide (100.0 mg, 90% yield ). LCMS m / z = 645.6 [M+H]+.

[0341]

[0254] Step 2: To a stirred solution of (lRS,4r)-4-((RS)-l-(((RS)-6-(3-fluorophenyl)-4-(((RS)-l-(l- methyl-lH-pyrazol-4-yl)-2-((SR)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxamide (100.0 mg, 1 Eq, 155.1 pmol) in DCM (2.000 mL) was added Burgess Reagent (73.91 mg, 2 Eq, 310.1 pmol). Then the reaction mixture was stirred at room temperature for 3 hours. LCMS indicates reaction is completed. The mixture was concentrated by vacuum, then DCM was added (~20 mL). The mixture was then washed with ~15 mL sodium bicarbonate. The organic phase was dried over magnesium sulfate and concentrated in vacuo. To the crude was added DCM and submitted to ISCO (4g) with 0% Methanol with Ammonium in DCM to 20% Methanol with Ammonium in DCM. To give (lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-4-(((R)-l-(l- m ethyl- lH-pyrazol-4-yl)-2-((S)-3 -methylpiperidin- 1 -yl)ethyl)amino)-5 ,6,7,8-tetrahydroquinazolin-2- Docket No.: PAT059787-PCT-SEC01 yl)(methyl)amino)propyl)cyclohexane-l -carbonitrile (60.60 mg, 62.3 % yield). LCMS m / z = 627.6 [M+H]+.

[0342]

[0255] Step 3: To (lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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 -carbonitrile (30.00 mg, 1 Eq, 33.50 pmol) in EtOH (1.500 mL) at room temperature was added hydroxylamine hydrochloride (5.820 mg, 2.5 Eq, 83.75 pmol) and triethylamine (33.90 mg, 46.7 pL, 10 Eq, 335.0 pmol). The mixture was stirred at 80 °C for 16 hours. Ethyl acetate was added (~5 mL), and then washed with ~2 mL of water, and then ~2 mL of brine. The organic phase was dried over magnesium sulfate, concentrated in vacuo and left on high vacuum pump for 16 h to give (lR,4r,E)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)-N'- hydroxycyclohexane- 1-carboximidamide as crude product. The crude material was used directly for the next step without further purification. LCMS m / z = 660.6 [M+H]+.

[0343]

[0256] Step 4: The above crude material was diluted in DMF (1.500 mL), and CDI (11.95 mg, 2.2 Eq, 73.70 pmol) and DBU (15.30 mg, 15.03 pL, 3 Eq, 100.5 pmol) were added. The mixture was stirred at room temperature for 3 hours. LCMS indicates reaction was completed. 10 mL water was added, and extracted twice with EtOAc, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via Prep reverse HPLC. (Basic_ 35-60% Acetonitrile_5.1min, Column: Waters XBridge Cl 8 OBD 30 x 50 mm) to give 3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)-l,2,4-oxadiazol-5(4H)-one (3.4 mg, 14 % yield ). LCMS m / z = 686.6 [M+H]+; *H NMR (400 MHz, MeOD) 8 7.41 (s, 1H), 7.32 (s, 1H), 7.20 (s, 1H), 7.08 (d, J= 7.7 Hz, 1H), 7.05 - 6.98 (m, 1H), 6.87 (td, J= 8.3, 2.3 Hz, 1H), 5.40 (s, 1H), 4.45 (d, J= 17.0 Hz, 1H), 3.74 (s, 3H), 2.89 (dd, J= 23.3, 12.2 Hz, 2H), 2.81 (s, 3H), 2.72 (s, 2H), 2.67 (d, J= 5.0 Hz, 1H), 2.36 (t, J = 13.7 Hz, 1H), 2.21 (s, 2H), 2.05 (d, J= 12.6 Hz, 1H), 1.91 (d, J= 12.2 Hz, 4H), 1.73 (s, 3H), 1.58 (d, J = 16.2 Hz, 3H), 1.39 (s, 9H), 0.87 (dd, J= 34.3, 12.3 Hz, 1H), 0.79 - 0.66 (m, 8H), 0.54 (s, 1H).

[0344]

[0257] Example 24 - Synthesis of (3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-4-(((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahvdroquinazolin- 2-yl)(methyl)amino)propyl)cvclohexyl)-l,2,4-oxadiazole-5(4H)-thione (Compound 58) Docket No.: PAT059787-PCT-SEC01

[0345]

[0258] To ( 1 R,4r,E)-4-((R)- 1 -(((R)-6-(3 -fluorophenyl)-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)-N'- hydroxycyclohexane-l-carboximidamide (32.00 mg, 1 Eq, 48.49 pmol) in CH3CN (1.000 mL) at room temperature was added Di-lH-imidazol-l-ylmethanethione (19.01 mg, 15 pL, 2.2 Eq, 106.7 pmol) and DBU (29.53 mg, 29.01 pL, 4 Eq, 194.0 pmol). The mixture was stirred at 23 °C for 16 hours. LCMS indicates reaction is completed. Mixture was washed with ~10 mL water and ~5 mL brine. Extracted twice with ~10 mL EtOAc and concentrated in vacuo. The residue was purified via Prep reverse HPLC (Basic_ 35-60% Acetonitrile_5.1min, Column: Waters XBridge C18 OBD 30 x 50 mm) to give 3- (( 1 R,4r)-4-((R)- 1 -(((R)-6-(3 -fluorophenyl)-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)cyclohexyl)- l,2,4-oxadiazole-5(4H)-thione (13 mg, 36 % yield). LCMS m / z = 702.5 [M+H]+;1H NMR (400 MHz, MeOD) 8 7.36 (s, 1H), 7.28 (s, 1H), 7.23 (td, J= 8.0, 6.1 Hz, 1H), 7.07 (dt, J= 7.8, 1.2 Hz, 1H), 7.00 (dt, J= 10.5, 2.1 Hz, 1H), 6.87 - 6.79 (m, 1H), 5.33 (s, 1H), 4.44 (s, 1H), 3.73 (s, 3H), 2.95 - 2.81 (m, 2H), 2.78 - 2.69 (m, 5H), 2.65 (dd, J= 15.6, 5.7 Hz, 3H), 2.51 (dd, J= 12.8, 5.1 Hz, 1H), 2.30 (s, 2H), 2.00 (d, J= 12.4 Hz, 1H), 1.92 - 1.79 (m, 4H), 1.76 - 1.60 (m, 5H), 1.60 - 1.49 (m, 4H), 1.48 - 1.17 (m, 7H), 0.75 (d, J= 6.3 Hz, 4H), 0.67 (t, J= 7.3 Hz, 3H).

[0346]

[0259] Example 25 - Synthesis of 5-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-4-(((R)-l-(l-methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5.6.7.8-tetrahvdroguinazolin-2- yl)(methyl)amino)propyl)cvdohexyl)-l,2-dihvdro-3H-pyrazol-3-one (Compound 59) Docket No.: PAT059787-PCT-SEC01

[0347]

[0260] Step 1: To a stirred solution of rac-(lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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 (80.00 mg, 1 Eq, 123.9 pmol) in THF (1.000 mL) was added CDI (30.13 mg, 19.24 pL, 1.5 Eq, 185.8 pmol) in one portion. The reaction mixture was heated at reflux for 3h. A suspension of Ethyl potassiumMalonate (84.33 mg, 0.19 mL, 4 Eq, 495.5 pmol) and Magnesium chloride (47.17 mg, 28.40 pL, 4 Eq, 495.5 pmol) in THF (1 mL) was added and the resulting reaction mixture was heated at reflux overnight. LC-MS indicates reaction is completed. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated. To the crude was added DCM and submitted to ISCO (12g) with 60% EtOAc in Heptane to afford desired compound rac-ethyl 3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)-3-oxopropanoate (31 mg white solid, 32% yield). LCMS m / z = 717.1 [M+H]+.

[0348]

[0261] Step 2: To a stirred solution of rac-ethyl 3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)-3-oxopropanoate (30.00 mg, 1 Eq, 41.90 pmol) in EtOH (1.000 mL) and THF (0.500 mL) was added hydrazine hydrate (2.098 mg, 2.038 pL, 1 Eq, 41.90 pmol). The reaction mixture was microwaved at 80 °C for 60 min. LCMS indicates reaction is completed. The reaction mixture was diluted with EtOAc, washed with H20 and brine. Extracted with EtOAc and dried over MgSO4 and concentrated. The crude material was purified via Prep HPLC (Basic_ 45-70%- Acetonitrile; Column: Waters XBridge C18 OBD 30 x 50 mm) to give 5-((lR,4r)-4-((R)-l-(((R)-6-(3- fluorophenyl)-4-(((R)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 -methylpiperidin- 1 -yl)ethyl)amino)-5 ,6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexyl)-l,2-dihydro-3H-pyrazol-3-one (12.8 mg, 42% yield). LCMS m / z = 684.6 [M+H]+;1H NMR (400 MHz, MeOD) 8 7.35 (s, 1H), 7.31 (s, 1H), 7.23 (td, J= 7.9, 6.0 Hz, 1H), 7.07 (d, J= 7.7 Hz, 1H), 7.00 (dt, J= 10.3, 2.2 Hz, 1H), 6.84 (td, J= 8.5, 2.6 Hz, 1H), 5.32 (s, 1H), 4.44 (s, 1H), 3.71 (s, 3H), 2.98 - 2.79 (m, 2H), 2.78 - 2.56 (m, 10 H), 2.51 (dd, J = 12.9, 5.0 Hz, 1H), 2.30 (dd, J= 30.2, 15.8 Hz, 2H), 2.00 (d, J= 12.7 Hz, 1H), 1.93 - 1.76 (m, 4H), 1.67 (t, J= 10.7 Hz, 3H), 1.60 - 1.49 (m, 3H), 1.49 - 1.23 (m, 6H), 1.21 - 1.06 (m, 1H), 0.96 - 0.79 (m, 2H), 0.75 (d, J= 6.4 Hz, 4H), 0.67 (t, J= 7.1 Hz, 3H), 0.51 (s, 1H).

[0349]

[0262] Example 26 - Synthesis of 5-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-4-(((R)-l-(l-methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahvdroquinazolin-2- yl)(methyl)amino)DroDyl)cvclohexyl)isoxazol-3-ol (Compound 60) Docket No.: PAT059787-PCT-SEC01

[0350]

[0263] Step 1: To a stirred solution of rac-ethyl 3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)-3-oxopropanoate (60.00 mg, 1 Eq, 83.80 pmol) in NMP (2.000 mL) was added N,N-dimethylpyridin-4-amine (30.71 mg, 3 Eq, 251.4 pmol) and O-(tetrahydro-2H- pyran-2-yl)hydroxylamine (29.45 mg, 3 Eq, 251.4 pmol). The reaction mixture was microwaved at 120 OC for 2h. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over Mg2SO4 and concentrated to give crude product 3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)-3 -oxo-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide. The crude was used for the next step reaction.

[0351]

[0264] Step 2: To a stirred solution of 3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-4-(((R)-l-(l- m ethyl- lH-pyrazol-4-yl)-2-((S)-3 -methylpiperidin- 1 -yl)ethyl)amino)-5 ,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexyl)-3-oxo-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide (27.00 mg, 1 Eq, 34.31 pmol) in MeOH (1.600 mL) was added concentrated Hydrogen chloride (367 mg, 0.400 mL, 294 Eq, 10.1 mmol). The reaction mixture was stirred at rt for 45 mins. LCMS Indicates reaction is completed. The reaction mixture was diluted with EtOAc and washed with ~5 mL water and ~2 mL saturated NaHCOs. Extracted twice with ~10 mL EtOAc. Dried over MgSO4 and concentrated. The crude material was purified via Prep HPLC (Basic_ 35-60 %- Acetonitrile; Column: Waters XBridge C18 OBD 30 x 50 mm) to give 5-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)isoxazol-3-ol (2 mg, 8.1% yield). LCMS m / z = 685.3 [M+H]+; ’H NMR (400 MHz, MeOD) 8 7.35 (s, 1H), 7.30 - 7.20 (m, 2H), 7.07 (d, J= 7.7 Hz, 1H), 7.01 (d, J= 10.4 Hz, 1H), 6.87 - 6.81 (m, 1H), 5.26 (s, 1H), 3.73 (s, 3H), 3.39 - 3.37 (m, 1H), 3.04 (d, J= 1.6 Hz, 1H), 2.90 (d, J = 9.7 Hz, 2H), 2.73 (d, J = 11.0 Hz, 5H), 2.65 (t, J = 7.8 Hz, 3H), 2.52 (dd, J= 12.8, 4.8 Hz, 1H), 2.31 (dd, J= 29.9, 15.4 Hz, 2H), 1.99 (t, J= 13.8 Hz, 2H), 1.88 (dd, J= 24.2, 13.3 Hz, 4H), 1.72 - 1.50 (m, 6H), 1.28 (d, J= 39.9 Hz, 6H), 1.19 (s, 1H), 1.12 (d, J= 13.6 Hz, 1H), 0.81 (s, 1H), 0.75 (d, J = 6.3 Hz, 4H), 0.67 (t, J= 7.2 Hz, 3H). Docket No.: PAT059787-PCT-SEC01

[0352]

[0265] Example 27 - Synthesis of (R)-N2-((R)-l-((lr,4R)-4-(l,3,4-oxadiazol-2- yl)cvclohexyl)propyl)-6-(3-fluorophenyl)-N2-methyl-N4-((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)- 3-methylDiDeridin-l-yl)ethyl)-5,6,7,8-tetrahvdroquinazoline-2,4-diamine (Compound 61)

[0353]

[0266] To a mixture of rac-(lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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 (30.00 mg, 1 Eq, 46.45 pmol) and formic acidhydrazide (4.185 mg, 1.5 Eq, 69.67 pmol) in Ethyl acetate (2.000 mL) was added TEA (14.10 mg, 19.4 pL, 3 Eq, 139.3 pmol) followed by Propylphosphonic anhydride (73.90 mg, 68.36 pL, 50% Wt, 2.5 Eq, 116.1 pmol)in drops. The reaction mixture was heated at 80°C under N2 atmosphere overnight. The completion of reaction was confirmed by LC-MS. The reaction mixture was cooled to RT and poured to water. The product was extracted with EtOAc (15 mL X2). The organic phase was dried over MgSO4. Cone, and the crude product was purified by by Prep HPLC (Basic_ 55-80% Acetonitrile_5.1min, Column: Waters XBridge C18 OBD 30 x 50 mm) to give (R)-N2-((R)-l-((lr,4R)-4-(l,3,4-oxadiazol-2- yl)cyclohexyl)propyl)-6-(3-fluorophenyl)-N2-methyl-N4-((R)- 1-(1 -methyl- lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)-5,6,7,8-tetrahydroquinazoline-2,4-diamine (11.50 mg, 35 % yield). LCMS m / z = 670.5 [M+H]+; *H NMR (400 MHz, MeOD) 8 8.73 (s, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 7.23 (td, J = 8.0, 6.0 Hz, 1H), 7.11 - 6.96 (m, 2H), 6.89 - 6.79 (m, 1H), 5.31 (s, 1H), 4.47 (s, 2H), 3.73 (s, 3H), 2.92 (dd, J= 7.5, 5.1 Hz, 1H), 2.83 (d, J= 10.3 Hz, 1H), 2.72 (s, 4H), 2.78 - 2.60 (m, 4H), 2.64 (s, 2H), 2.51 (dd, J= 12.9, 5.0 Hz, 1H), 2.38 - 2.27 (m, 1H), 2.12 - 1.97 (m, 2H), 1.96 - 1.83 (m, 5H), 1.72 - 1.28 (m, 7H), 0.96 (s, 1H), 0.87 - 0.72 (m, 5H), 0.68 (t, J= 7.2 Hz, 4H), 0.55 (s, 1H).

[0354]

[0267] Example 28 - Synthesis of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((lR,4S)-4-((R)-l- (methyl((R)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6- phenyl-5,6,7,8-tetrahvdroquinazolin-2-yl)amino)propyl)cvclohexane-l-carbonyl)oxy)tetrahvdro- 2H-pyran-2-carboxylic acid (Compound 62) Docket No.: PAT059787-PCT-SEC01

[0355]

[0268] In a plastic baker 100 mL 0.2 M UDPGA(uridine 5 '-diphosphoglucuronic acid) aq. solution, 100 mL 0.1 M MgC12 aq. solution, 100 mL 1.0 M HEPES(4-(2-Hydroxyethyl)piperazine-l -ethanesulfonic acid) buffer aq. pH 7.0 were mixed first with 100 mL of sheep liver S9 fraction and then 250 mg (lR,4r)- 4-((R)- 1 -(methyl((R)-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)amino)propyl)cyclohexane-l-carboxylic acid in 20 mL DMSO solution were added. Incubation of the reaction overnight at 37°C and 120 rpm. The reaction was acidified to pH 5 with acetic acid then quenched with 400 mL of MeOH / ACN mixture v / v=l / l, shaken for 10 min then centrifuged for 15 minutes. The supernatant was filtered and the filtrate was pumped with 10Vol.-%, rest 90% = formic acid aq. 0.05% on an 5*20 cm self-packed steel RP18 column. Subsequent chromatography with UV detection and: phase A = formic acid 0.05 % aq., phase B = ACN, gradient from 10-75 % B in 30 min, flow of 120mL / min. The fractions containing the product were combined and evaporated to half of their original volume to reduce the ACN concentration then the residual solution was acidified with 0.1 mL TFA and directly pumped on a 2.4*25 cm NUCLEODUR 100-5 Cl 8 ec column. Subsequent chromatography with UV detection and: phase A = TFA 0.05 % aq., phase B = ACN, gradient from 10-60 % B in 30 min, flow of 35 mL / min. One pure fraction with product was obtained, directly frozen in dry ice and lyophilized over 3 days to give desired product (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((lR,4S)-4-((R)-l-(methyl((R)-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-carbonyl)oxy)tetrahydro-2H-pyran-2-carboxylic acid (65 mg, 20 % yield). LCMS m / z [M+H]+= 804.8,1H NMR (400 MHz, DMSO-d6) 8 = 13.09 - 12.66 (m, 1H), 11.40 - 11.13 (m, 1H), 10.00 - 9.75 (m, 1H), 8.33 - 8.17 (m, 1H), 7.61 (s, 1H), 7.42 (s, 1H), 7.38 - 7.34 (m, 5H), 7.30 - 7.22 (m, 1H), 5.80 - 5.68 (m,lH), 5.41 - 5.25 (m,4H), 4.45 - 4.35 (m, 1H), 3.79 (s, 4H), 3.77- 3.61 (m, 3H), 3.54- 3.37 (m, 3H), 3.35- 3.25 (m, 3H), 3.22- 3.09 (m, 3H), 2.91 (s, 5H), 2.87 (br s, 1H), 2.83 - 2.77 (m, 1H), 2.77 - 2.67 (m, 2H), 2.65 - 2.56 (m, 1H) 2.41 - 2.35 (m, 1H), 2.23 - 2.11 (m, 1H), 2.O1 (br Docket No.: PAT059787-PCT-SEC01 s, 2H), 1.98 - 1.89 (m, 2H), 1.88 - 1.83 (m, 2H), 1.82 - 1.76 (m, 1H), 1.76 - 1.64 (m, 5H), 1.50 - 1.41 (m, 3H), 1.37 - 1.19 (m, 4H),1.10 - 0.94 (m, 3H), 0.87 (br d, J= 6.16 Hz, 4H), 0.75 - 0.72 (m, 1H), 0.70 (br s, 2H), 0.54 - 0.41 (m, 1H).

[0356]

[0269] Example 29 - Biological assay - Cellular cGMP Production

[0357]

[0270] The 174 compounds described were tested for their functional activity in a cellular cGMP production assay using human NPR1 expressing CHO-K1 cells (DiscoverX (Cat. #93-0804C2). For the functional characterization of the compounds, the production of cyclic guanosine 3',5'-cyclic monophosphate (cGMP) upon binding to and stimulation of NPR1 expressed on the cell surface of CHO-K1 cells 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:

[0358] Ratio = [(A665imi / B620imi)* 104] Mean Ratio = (Sratios / 2) CV = [(Std deviation / Mean ratio)* 100]

[0359] Delta F = [((Calibrator or sample Ratio - Rationeg) / Rationeg)*100] Rationeg: negative control

[0360]

[0271] 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.

[0361] Table 1 : In vitro functional data Docket No.: PAT059787-PCT-SEC01 Docket No.: PAT059787-PCT-SEC01

[0362] *ND = not determined

[0363] Equivalents

[0364]

[0272] 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.: PAT059787-PCT-SEC01CLAIMSWhat is claimed is:A compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof, wherein:R1is H or (Ci-e)alkyl; each instance of R2is independently halogen, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl;each instance of R3is independently halogen, -CN, -C(=O)N(R3A)2, -C(=O)OR3B, -N(R3A)2, -N(R3A)C(=O)R3C, -N(R3A)C(=O)OR3B, -OC(=O)R3C, -OH, -OR3D, or (Ci-6)alkyl optionally substituted with halogen, -CN, or -OH; C3-6 cycloalkyl; optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; wherein the 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances of (Ci-e)alkyl, halogen, oxo, -CN, -OH, -O(Ci-e)alkyl, -NH2, or - C(=O)N(R3a)2(Ci-6)alkyl, or C3-6 cycloalkyl; each instance of R3ais independently H or (Ci-e)alkyl; each instance of R3Aand R3Bis independently H or (Ci-e)alkyl optionally substituted with halogen, -CN, or -OH; each instance of R3Cis independently H, (Ci-e)alkyl optionally substituted with halogen, -CN, or -OH; C3-6 cycloalkyl; or 5-9 membered heterocyclyl comprising 1 to 3 heteroatomsDocket No.: PAT059787-PCT-SEC01 selected from N, O, and S, or 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; optionally wherein R3Aand R3Cor R3Aand R3Bare taken together with the intervening atoms to form an optionally substituted 5-6-membered heterocyclic ring or optionally substituted 5-6-membered heteroaryl ring; wherein the 5-6-membered heterocyclic ring or 5-6- membered heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; each instance of R3Dis independently (Ci-e)alkyl optionally substituted with halogen, - CN, or -OH;each of R41, R42, and R43is independently hydrogen or (Ci-e)alkyl; nl is 0, 1, 2, 3, 4, or 5; n is 1, 2, or 3; zl is 0, 1, 2, 3, 4, or 5; z2 is 0, 1, 2, 3, 4, or 5; each of Ra, Rb, and Rcis independently H or (Ci-Ce)alkyl; and each of R5and R6is independently -(Ci-6)alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is H and nl is 0.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, whereinRi •ng 0zi-s:Docket No.: PAT059787-PCT-SEC01each instance of R3is independently (Ci-e)alkyl, -N(R3A)2, -C(=O)N(R3A)2, - N(R3A)C(=O)R3C, -N(R3A)C(=O)OR3B, -OC(=O)R3C, -OR3D, optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; wherein the optionally substituted 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances of halogen, oxo, -CN, -OH, (Ci- e)alkyl, or C3-6 cycloalkyl; z2 is 0, 1, 2, or 3; each instance of R3Aand R3Bis independently H or (Ci-e)alkyl optionally substituted with halogen, -CN, or -OH; optionally wherein R3Aand R3Cor R3Aand R3Bare taken together with the intervening atoms to form an optionally substituted 5-6-membered heterocyclic or optionally substituted 5- 6-membered heteroaryl ring; wherein the 5-6-membered heterocyclic ring or 5-6-membered heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, oxo, - CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; each instance of R3Cis independently H, optionally substituted (Ci-e)alkyl;R3Dis (Ci-e)alkyl optionally substituted with halogen, -CN, or -OH.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, . . . wherein Ringv-- / is:Docket No.: PAT059787-PCT-SEC015. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof,6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein Ring7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R3is: -N(R3A)2, -C(=O)N(R3A)2, -N(R3A)C(=O)R3C, - N(R3A)C(=O)OR3B, or -OC(=O)R3C; and each instance of R3Ais independently H or (Ci-Ce)alkyl; each of R3Band R3Cis (Ci-Ce)alkyl.Docket No.: PAT059787-PCT-SEC018. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R3is:

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R3is optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; wherein the 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances of (Ci-e)alkyl, halogen, oxo, -CN, -OH, -O(Ci-e)alkyl, -NH2, or -C(=O)N(R3a)2(Ci- e)alkyl, or C3-6 cycloalkyl.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R3is furan, imidazole, pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole, or tetrahydropyranopyrazole; wherein R3is optionally substituted with 1, 2, or 3 instances of (Ci-e)alkyl, halogen, oxo, -CN, -OH, -O(Ci-e)alkyl, -NH2, or - C(=O)N(R3a)2(Ci-6)alkyl, or C3-6 cycloalkyl.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein RingR3is furan, imidazole, pyrazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole, or tetrahydropyranopyrazole; andR3is optionally substituted with 1 or 2 instances of (Ci-e)alkyl, halogen, (Ci-e)alkyl, oxo, C3-6 cycloalkyl, -OH, -C(=O)NMe2, -C(=O)NHMe,Docket No.: PAT059787-PCT-SEC0112. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R3is:

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof,Docket No.: PAT059787-PCT-SEC0114. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R4is:Docket No.: PAT059787-PCT-SEC0115. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each of Ra, Rb, and Rcis H.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R5is -CH2CH3.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R6is -CH3.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein:R1is H; nl is 0;each instance of R3is independently (Ci-e)alkyl, -N(R3A)2, -C(=O)N(R3A)2, - MM o N(R3A)C(=O)R3C, -N(R3A)C(=O)OR3B, -OC(=O)R3C, -OR3D, M11— / , , or optionally substituted 5-9 membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, or optionally substituted 5-6 membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;Docket No.: PAT059787-PCT-SEC01 wherein the optionally substituted 5-9 membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with z2 instances of halogen, oxo, -CN, -OH, (Ci- e)alkyl, or C3-6 cycloalkyl; z2 is 0, 1, 2, or 3; each instance of R3Aand R3Bis independently H or optionally substituted (Ci-e)alkyl;R3Cis (Ci-e)alkyl;R3Dis (Ci-e)alkyl optionally substituted with halogen, -CN, or -OH;R41and R43are each H; and R42is (Ci-e)alkyl; each of Ra, Rb, and Rcis H;R5is -CH2CH3; andR6is -CH3.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:4-((lR)-l-(methyl((6R)-6-methyl-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-(N- methylacetamido)piperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(methyl((R)-4-(((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-(2- oxopyrrolidin-l-yl)piperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(((6R)-4-(((lR)-l-(l-isopropyl-lH-pyrazol-4-yl)-2-(3-(N- methylacetamido)piperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,( 1 R,4r)-4-((R)- 1 -(((R)-4-(((R)- 1 -( 1 -isopropyl- 1 H-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- 1 -carboxylic acid,Docket No.: PAT059787-PCT-SEC01 rac-( 1 R,4r)-4-((R)- 1 -(methyl((R)-4-(((R)- 1 -(1 -methyl- 1 H-pyrazol-4-y l)-2-((S)-3 -(2- oxooxazolidin-3-yl)piperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((R)-4-(((R)-2-((S)-3-((methoxycarbonyl)(methyl)amino)piperidin-l- yl)-l -(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6, 7, 8-tetrahy droquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((R)-l-(((R)-4-(((R)-2-((S)-3-acetoxy-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- 1 -carboxylic acid, rac-(lR,4r)-4-((R)-l-(((R)-4-(((R)-2-((S)-3-(dimethylcarbamoyl)piperidin-l-yl)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(3-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)pyrrolidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahydroquinazolin-2-yl)amino)propy l)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(((6R)-4-((2-(3-(5-cyclopropyl-lH-l,2,4-triazol-3-yl)piperidin-l-yl)- 1-(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6, 7, 8-tetrahy droquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(3 -(furan-2-yl)pyrrolidin- 1 -yl)- 1 -( 1 -methyl- 1 H-pyrazol- 4-yl)ethyl)amino)-6-phenyl-5, 6, 7, 8-tetrahy droquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(3 -( 1 H-imidazol-2-y l)piperidin- 1 -y 1)- 1 -( 1 -methyl- 1 H- pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6, 7, 8-tetrahy droquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(methyl((6RS)-4-((2-(3 -( 1 -methyl- 1 H-pyrazol-3 -yl)piperidin- 1 -yl)- 1 - (l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)- l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(3-(l -methyl- 1H- pyrazol-4-yl)piperidin-l -yl)ethyl)amino)-6-phenyl-5, 6, 7, 8-tetrahy droquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,Docket No.: PAT059787-PCT-SEC01( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(3 -hydroxy-3 -(1 -isopropyl- 1 H- 1 ,2,3-triazol-4- yl)piperidin-l -yl)-l-(l -methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(3 -hydroxy-3 -( 1 H- 1 ,2, 3 -triazol-4-yl)piperidin- 1 -yl)- 1 -( 1 - methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(((6R)-4-((2-(3-(l-ethyl-l,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3- yl)piperidin-l -yl)-l-(l -methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(3-(5-oxo-2,5- dihydro-lH-l,2,4-triazol-3-yl)piperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahydroquinazolin-2-yl)amino)propy l)cyclohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(methy l((6R)-4-((2-(3 -(4-methyl- 1 H-pyrazol- 1 -yl)piperidin- 1 -yl)- 1 - (l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(3 -(2-hydroxy- 1 H-imidazol- 1 -yl)piperidin- l-yl)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(3-(l-methyl-lH- pyrazol-5-yl)piperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(3-(thiazol-2- yl)piperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(methyl((6R)-4-((2-(3-(l-methyl-lH-imidazol-5-yl)piperidin-l-yl)-l- (l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(3 -hydroxy-3 -(1 -isopropyl- 1 H- 1 ,2,3 -triazol-4- yl)pyrrolidin- 1 -yl)- 1 -(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,Docket No.: PAT059787-PCT-SEC01(lR,4r)-4-((lR)-l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(3-(4-methyl-5- (methylcarbamoyl)oxazol-2-yl)piperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahydroquinazolin-2-yl)amino)propy l)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(3-(2,2,2- trifluoroethoxy)piperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(methy l((6R)-4-((2-(3 -(1 -methyl- 1 H- 1 ,2,4-triazol-3 -yl)piperidin- 1 - yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(3-(2-methyl-2H- tetrazol-5-yl)piperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(3 -( 1 ,3 ,4-thiadiazol-2-yl)piperidin- 1 -yl)- 1 -( 1 -methyl- 1 H- pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)- l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(3-(l -methyl- 1H- pyrazol-4-yl)pyrrolidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(methyl((6R)-4-((2-(3-(l-methyl-lH-pyrazol-3-yl)pyrrolidin-l-yl)-l- (l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(3-(5-oxo-4,5- dihydro-l,3,4-oxadiazol-2-yl)piperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahydroquinazolin-2-yl)amino)propy l)cyclohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(((6R)-4-((2-(3,3-dimethyl-4-(3-methyl-lH-pyrazol-5-yl)pyrrolidin-l- yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(3 -(4-fluoro- 1 -methyl- 1 H-pyrazol-3 -yl)pyrrolidin- 1 -y 1)- l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,Docket No.: PAT059787-PCT-SEC01( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(3 -(4-(dimethylcarbamoyl)- 1 H-pyrazol-3 -yl)piperidin- 1 - yl)-l -(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6,7, 8-tetrahy droquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(methy l((6R)-4-((2-(3 -(2-methyl- 1 H-imidazol- 1 -yl)piperidin- 1 -yl)- 1 - (l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid,(lR,4r)-4-((lR)-l-(((6R)-4-((2-(3-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-3- hydroxypyrrolidin-l-yl)-l-(l -methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cy clohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(3 -( 1 ,2,4-oxadiazol-3 -yl)piperidin- 1 -yl)- 1 -( 1 -methyl- 1 H- pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6, 7, 8-tetrahy droquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid,( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(3 -( 1 H- 1 ,2,3 -triazol- 1 -yl)piperidin- 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,( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(4-(dimethylamino)azepan- 1 -yl)- 1 -( 1 -methyl- 1 H- pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6, 7, 8-tetrahy droquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid, rac-( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-(4-(dimethylamino)piperidin- 1 -yl)- 1 -( 1 -methyl- 1 H- pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6, 7, 8-tetrahy droquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid, rac-( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-([ 1 ,3 '-bipyrrolidin] - l'-yl)- 1 -( 1 -methyl- 1 H-pyrazol-4- yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid rac-( 1 R,4r)-4-((R)- 1 -(((R)-4-(((R)-2-((S)-3 -(furan-2-y l)pyrrolidin- 1 -yl)- 1 -( 1 -methyl- 1 H- pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6, 7, 8-tetrahy droquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid, rac-( lR,4r)-4-((R)- 1 -(((R)-4-(((R)-2-((R)-3-(furan-2-yl)pyrrolidin- 1 -yl)- 1 -(1-methyl-lH- pyrazol-4-yl)ethyl)amino)-6-phenyl-5, 6, 7, 8-tetrahy droquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid,Docket No.: PAT059787-PCT-SEC01 rac-(lR,4r)-4-((R)-l-(methyl((R)-4-(((R)-l-(l-(methyl-d3)-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cy clohexane- 1 -carboxylic acid, rac-(lR,4r)-4-((R)-l-(((R)-4-(((S)-2-(azepan-l-yl)-l-(l,5-dimethyl-lH-pyrazol-4- yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid, and rac-( 1 R,4r)-4-((R)- 1 -(((R)-4-(((R)-2-(azepan- 1 -yl)- 1 -( 1 , 5 -dimethyl- 1 H-pyrazol-4- yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid.

20. A compound of Formula (II):or a pharmaceutically acceptable salt thereof wherein:R10is H or (Ci-e)alkyl;R20is H, halogen, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl;R30is halogen, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; each instance of R40is independently halogen, -CN, -OR40a, -C(=O)OR40b, - N(R40a)C(=O)R40c, -N(R40a)2, -C(=O)N(R40a)2, -C(=O)N(R40a)SO2(R40c), 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; (Ci-Ce)alkyl optionally substituted with halogen, -CN, -OH, -C(=O)OR40b, -N(R40a)2, C3-6 cycloalkyl, or 5- to 6- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, or 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; wherein the 5- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl are each optionally substitutedDocket No.: PAT059787-PCT-SEC01 with one or more substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, - NH2, or (Ci-Ce)alkyl; each instance of R40ais independently H or (Ci-e)alkyl; each instance of R40bis independently H, (C3-Ce)cycloalkyl, (Ci-e)alkyl optionally substituted with halogen, -CN, -OH, -NH2, 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; wherein the 5- to 6-membered heterocyclyl and 5- or 6- membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -(Ci-Ce)alkoxy, -CO2H, -NH2, or (Ci- Ce)alkyl; each instance of R40cis independently H, (Ci-e)alkyl, (C3-Ce)cycloalkyl, 5- to 6- membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, or 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; each of Ra, Rb, Rc, R50, and R60is independently H or (Ci-Ce)alkyl; and n2 is 0, 1, 2, 3, 4, 5, or 6.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R10is H.

22. The compound of claim 20 or 21, or a pharmaceutically acceptable salt thereof, wherein R20is H or halogen.

23. The compound of any one of claims 20-22, or a pharmaceutically acceptable salt thereof, wherein R20is -F.

24. The compound of any one of claims 20-23, or a pharmaceutically acceptable salt thereof, wherein R30is (Ci-Ce)alkyl.

25. The compound of any one of claims 20-24, or a pharmaceutically acceptable salt thereof, wherein R30is -CH3.Docket No.: PAT059787-PCT-SEC0126. The compound of any one of claims 20-25, or a pharmaceutically acceptable salt thereof, wherein n2 is 1, 2, or 3.

27. The compound of any one of claims 20-26, or a pharmaceutically acceptable salt thereof, wherein the moietyis:

28. The compound of any one of claims 20-27, or a pharmaceutically acceptable salt29. The compound of any one of claims 20-28, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R40is: -(CH2)i-3N(R40a)2; -C(=O)OR40b, or - C(=O)N(R40a)SO2(R40c); each instance of R40ais independently H or (Ci-e)alkyl;R40bis H; 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; or (Ci-e)alkyl optionally substituted with halogen, -CN, -OH, (C3-Ce)cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; wherein the 5- to 6-membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, - CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; andR40Cis H, (Ci-e)alkyl, or (C3-Ce)cycloalkyl.Docket No.: PAT059787-PCT-SEC0130. The compound of any one of claims 20-29, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R40is: -C(=O)OR40b;R40bis H, unsubstituted (Ci-Ce)alkyl or (Ci-Ce)alkyl substituted with 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; wherein the 5- to 6-membered heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, -OH, -CO2H, -NH2, or (Ci- Ce)alkyl.

31. The compound of any one of claims 20-29, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R40is:

32. The compound of any one of claims 20-29, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R40is: 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, - CO2H, -NH2, or (Ci-Ce)alkyl.

33. The compound of any one of claims 20-29, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R40is: furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, or isoxazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl.

34. The compound of any one of claims 20-29, or a pharmaceutically acceptable saltN / "-OH thereof, wherein at least one instance of R is: ODocket No.: PAT059787-PCT-SEC0135. The compound of any one of claims 20-34, or a pharmaceutically acceptable salt thereof, wherein each of Ra, Rb, and Rcis H.

36. The compound of any one of claims 20-35, or a pharmaceutically acceptable salt thereof, wherein R50is H.

37. The compound of any one of claims 20-35, or a pharmaceutically acceptable salt thereof, wherein R50is -CH2CH3.

38. The compound of any one of claims 20-37, or a pharmaceutically acceptable salt thereof, wherein R60is H.

39. The compound of any one of claims 20-38, or a pharmaceutically acceptable salt thereof, wherein:R10is H;R20is H or halogen;R30is (Ci-C6)alkyl; n2 is 1, 2, or 3; at least one instance of R40is (Ci-Ce)alkyl, -(CH2)i-3N(R40a)2; -C(=O)OR40b, or - C(=O)N(R40a)SO2(R40c); or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; wherein the 5- or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -CO2H, -NH2, or (Ci- Ce)alkyl; each instance of R40ais independently H or (Ci-e)alkyl;R40bis H; 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S; or (Ci-e)alkyl optionally substituted with halogen, -CN, -OH, (C3-Ce)cycloalkyl, or 5- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S; wherein the 5- to 6-membered heterocyclyl and 5-6 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, oxo, - CN, -OH, -CO2H, -NH2, or (Ci-Ce)alkyl; andDocket No.: PAT059787-PCT-SEC01R40Cis H, (Ci-e)alkyl, or (C3-Ce)cycloalkyl; each of Ra, Rb, and Rcis H;R50is H or -CH2CH3; andR60is H or -CH3.

40. The compound of any one of claims claims 20-39, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:(R)-N2-((R)- 1 -((lr,4R)-4-((dimethylamino)methyl)cyclohexyl)propyl)-N4-((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l -yl)ethyl)-6-phenyl-5, 6,7,8- tetrahydroquinazoline-2,4-diamine,(5-methyl-2-oxo-l,3-dioxol-4-yl)methyl (lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-4- (((R)-l -(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5, 6,7,8- tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l -carboxylate, rac-( 1 R,4r)-4-((R)- 1 -(((R)-6-(3 -fluor ophenyl)-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)-N-(methylsulfonyl)cyclohexane-l -carboxamide, rac-3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)isoxazol-5-ol,(R)-N2-((S)-l-((lr,4S)-4-((dimethylamino)methyl)cyclohexyl)propyl)-N4-((R)-l-(l- methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l -yl)ethyl)-6-phenyl-5, 6,7,8- tetrahydroquinazoline-2,4-diamine,1 -methy l-4-((R)- 1 -(methyl((R)-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)amino)propyl)cy clohexane- 1 -carboxylic acid,(R)-N2-(((lr,4R)-4-((dimethylamino)methyl)cyclohexyl)methyl)-N4-((R)-l-(l -methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)-6-phenyl-5,6,7,8-tetrahydroquinazoline- 2,4-diamine,(lR,4r)-4-((((R)-4-(((R)-l -(1 -methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l- yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)methyl)cyclohexane-l- carboxylic acidDocket No.: PAT059787-PCT-SEC01(R)-6-(3-fluorophenyl)-N2-methyl-N2-((R)-l-((lr,4R)-4-(5-methyl-l,3,4-oxadiazol-2- yl)cyclohexyl)propyl)-N4-((R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l- yl)ethyl)-5,6,7,8-tetrahydroquinazoline-2,4-diamine, 3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)-l,2,4-oxadiazol-5(4H)-one, 3-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)-l,2,4-oxadiazole-5(4H)-thione, 5-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)-l,2-dihydro-3H-pyrazol-3-one, 5-((lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-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)cyclohexyl)isoxazol-3-ol,(R)-N2-((R)-l-((lr,4R)-4-(l,3,4-oxadiazol-2-yl)cyclohexyl)propyl)-6-(3-fluorophenyl)- N2-methyl-N4-((R)-l -(l-methyl-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)-5, 6,7,8- tetrahydroquinazoline-2,4-diamine, and(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((lR,4S)-4-((R)-l-(methyl((R)-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-carbonyl)oxy)tetrahydro-2H-pyran-2- carboxylic acid.

41. A pharmaceutical composition comprising a compound according to any one of claims 1-40, or a pharmaceutically acceptable salt thereof, and one or more (e.g., 1, 2, 3, 4, or 5) pharmaceutically acceptable carriers.

42. The pharmaceutical composition of claim 41, further comprising at least one additional pharmaceutically active agent.Docket No.: PAT059787-PCT-SEC0143. The pharmaceutical composition of claim 42, wherein the additional pharmaceutically active agent is selected from an ACE (angiotensin-converting-enzyme) inhibitor, an angiotensin receptor blocker (ARB), a neprilysin inhibitor, a beta blocker, a diuretic, a calcium channel blocker, a cardiac glycoside, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), an angiotensin receptor-neprilysin inhibitor (ARNi), a corticosteroid, a leukotriene modifier, a bronchodilator, a beta-adrenoceptor antagonist, a carbonic anhydrase inhibitor, an alpha 2- adrenoceptor agonist, a parasympathomimetic, a prostaglandin analog, a rho kinase inhibitor, and combinations thereof.

44. 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 claims 1-40, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 41-43.

45. The method of claim 44, wherein the disease or disorder is a cardiovascular disease or disorder.

46. The method of claim 45, 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).

47. The method of claim 46, 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.Docket No.: PAT059787-PCT-SEC0148. The method of claim 44, 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.

49. The method of claim 44, wherein the disease or disorder is a disorder or disease associated with natriuretic peptide receptor activity.

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