Hydroquinazoline derivatives for the treatment of a disease or disorder

Abstract

The disclosure relates to a compound of Formula (I): (I) or a pharmaceutically acceptable salt thereof wherein Ra to Rd, and R2 to R5, are as described herein, as well as compositions and methods of using such compounds.

Description

[0001] Docket No.: PAT059789-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 / 688,564, filed August 29, 2024, the entire contents of which are hereby incorporated by reference in their entirety.

[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 selected from H and (Ci-Ce)alkyl;

[0011] R2is phenyl optionally substituted with 1 or 2 substituents selected from halo; Docket No.: PAT059789-PCT-SEC01

[0012] R3is H or (Ci-Ce)alkyl;

[0013] R4is a 5-membered heteroaryl comprising 2 heteroatoms selected from N, 0, and S, substituted with one or two substituents independently selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, and a 3- to 10-membered heterocycle optionally comprising 1 or 2 heteroatoms selected from N, 0, and S, wherein the (Ci-Ce)alkyl and (Ci-Ce)alkoxy is optionally substituted with with one or O more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from -CO2H and ;

[0014] R5is NR8R9;

[0015] R8and R9together with the N to which they are bound combine to form a 3 - to 10-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, 0, and S, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl; and

[0016] Ra, Rb, Rc, RdRf, and R8are each, independently H or (Ci-C6)alkyl.

[0017]

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

[0018]

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

[0019]

[0007] 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 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

[0020]

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

[0021]

[0009] In another aspect, the present disclosure relates to a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder. Docket No.: PAT059789-PCT-SEC01

[0022]

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

[0023] [OH] In still another aspect, the present disclosure relates to use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the treatment of a disease or disorder.

[0024]

[0012] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.

[0025] DETAILED DESCRIPTION

[0026]

[0013] 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.

[0027]

[0014] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by 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.

[0028] Compounds

[0029]

[0015] In one aspect, the disclosure therefore provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof wherein:

[0030] R1is selected from H and (Ci-Ce)alkyl;

[0031] R2is phenyl optionally substituted with 1 or 2 substituents selected from halo;

[0032] R3is H or (Ci-Ce)alkyl; Docket No.: PAT059789-PCT-SEC01

[0033] R4is a 5-membered heteroaryl comprising 2 heteroatoms selected from N, 0, and S, substituted with one or two substituents independently selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, and a 3- to 10-membered heterocycle optionally comprising 1 or 2 heteroatoms selected from N, 0, and S, wherein the (Ci-Ce)alkyl and (Ci-Ce)alkoxy is optionally substituted with with one or O more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from -CO2H and ;

[0034] R5is NR8R9;

[0035] R8and R9together with the N to which they are bound combine to form a 3 - to 10-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, 0, and S, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl; and

[0036] Ra, Rb, Rc, RdRf, and R8are each, independently H or (Ci-C6)alkyl.

[0037]

[0016] Unless specified otherwise, the term “compounds of the present disclosure” or “compound of the present disclosure” refers to compounds of Formula (I) 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.

[0038]

[0017] 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.

[0039]

[0018] In some embodiments, R1is selected from H, -CH3 and -CH2CH3. In some embodiments, R1is - CH2CH3.

[0040]

[0019] In some embodiments, R2is phenyl optionally substituted with fluoro. In some embodiments, R2is selected from

[0041]

[0020] In some embodiments, R3is selected from H and -CH3. In some embodiments, R3is H.

[0042]

[0021] In some embodiments, R4is pyrazolyl, substituted with one or two substituents independently selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy wherin the (Ci-Ce)alkyl and (Ci-Ce)alkoxy is optionally substituted with with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected

[0043] O from -CO2H and . In some embodiments, R4is pyrazolyl, substituted with one or two Docket No.: PAT059789-PCT-SEC01 substituents independently selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy wherein the (Ci- Ce)alkyl and (Ci-Ce)alkoxy is optionally substituted with with one substituent independently selected . In some embodiments, R4is selected from

[0044]

[0022] In some embodiments, R8and R9together with the N to which they are bound combine to form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, (Ci-Ce)alkyl, and (Ci- C6)haloalkyl. In some embodiments, R8and R9together with the N to which they are bound combine to form a 6- to 8-membered heterocycle, wherein the 6- to 8-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, (Ci-C6)alkyl, and (Ci-C6)haloalkyl. In some embodiments, R8and R9together with the N to which they are bound combine to form a 6- to 8-membered heterocycle, wherein the 6- to 8-membered heterocycle is substituted with one substituent independently selected from -CH3 and -CH2F.

[0045]

[0023] In some embodiments, R5is selected from

[0046]

[0024] In some embodiments, Ra, Rb, Rc, Rd, Rf, and R8are each, independently H or -CH3. In some embodiments, Rais H. In some embodiments, Rband Rcare each H. In some embodiments, Rdis -CH3. In some embodiments, R8is -CH3or -CH2CH3. In some embodiments, R8is -CH2CH3.

[0047]

[0025] In certain embodiments, the compound is a compound or a pharmaceutically acceptable salt thereof selected from: Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01

[0048] Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01

[0049]

[0026] 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 Docket No.: PAT059789-PCT-SEC01 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.

[0050]

[0027] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

[0051]

[0028] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0052]

[0029] 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.

[0053]

[0030] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0031] 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.

[0054]

[0032] 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.

[0055]

[0033] 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.

[0056]

[0034] 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. Docket No.: PAT059789-PCT-SEC01

[0057]

[0035] Further, incorporation of certain isotopes, particularly deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index or tolerability. It is understood that deuterium in this context is regarded as a substituent of a compound of the present disclosure. The concentration of deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this disclosure is denoted as being deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term “isotopic enrichment factor” can be applied to any isotope in the same manner as described for deuterium.

[0058]

[0036] 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,36C1,1231,1241,125I 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.

[0059]

[0037] 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 ( / )-. (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 Docket No.: PAT059789-PCT-SEC01

[0060] (S')- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.

[0061]

[0038] 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.

[0062]

[0039] 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.

[0063]

[0040] Any resulting racemates of compounds of the present disclosure or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present disclosure into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O.O'- -toluo l 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.

[0064] Pharmaceutical Compositions

[0065]

[0041] 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.

[0066]

[0042] 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 sodiumglucose co-transporter 2 inhibitor (SGLT2i), or combinations thereof.

[0067]

[0043] 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 Docket No.: PAT059789-PCT-SEC01 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.

[0068]

[0044] 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.

[0069]

[0045] 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.

[0070]

[0046] 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.

[0071]

[0047] 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.

[0072]

[0048] 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.

[0073]

[0049] 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 Docket No.: PAT059789-PCT-SEC01 species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated.

[0074] Methods of Use

[0075]

[0050] In yet another aspect, the present disclosure is directed to a method of treating or preventing a disease or disorder comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0076]

[0051] 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the disease or disorder is a cardiovascular disease or disorder.

[0077]

[0052] 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.

[0078]

[0053] 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). Docket No.: PAT059789-PCT-SEC01

[0079]

[0054] In some embodiments, the disease or disorder is a disorder or disease associated with natriuretic peptide receptor activity.

[0080]

[0055] 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.

[0081]

[0056] In another aspect, the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for use as a medicament.

[0082]

[0057] Another aspect of the present disclosure relates to a compound of Formula (I), 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).

[0083]

[0058] In another aspect, the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein in the treatment of a disease or disorder disclosed herein.

[0084]

[0059] 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.

[0085] Combination Therapy

[0086]

[0060] 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.

[0087]

[0061] 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 Docket No.: PAT059789-PCT-SEC01 the present disclosure and the other pharmaceutically active agent (s) in separate form, e.g. in the form of a kit.

[0088]

[0062] In another aspect, the disclosure includes a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in a combination therapy.

[0089]

[0063] Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I), 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.

[0090]

[0064] 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.

[0091]

[0065] 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, Docket No.: PAT059789-PCT-SEC01 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 lev albuterol), theophylline or ipratropium), or combinations thereof (e.g., a combination of fluticasone and salmeterol, a combination of budesonide and formoterol, or a combination of formoterol and mometasone). In some embodiments, a compound or a pharmaceutically acceptable salt thereof described herein can be combined with one or more of a beta-adrenoceptor antagonist (e.g., timolol, levobunolol, metipranolol, carteolol, or betaxolol), a carbonic anhydrase inhibitor (e.g., acetazolamide, dorzolamide, brinzolamide, or methazolamide), an alpha 2-adrenoceptor agonist (e.g., brimonidine or apraclonidine), a parasympathomimetic (e.g., cholinomimetics like pilocarpine), a prostaglandin analog (e.g., latanoprost, latanoprostene bunod, travoprost, bimatoprost, or tafluprost), a rho kinase inhibitor (e.g., netarsudil or ripasudil), or combinations thereof (e.g., a combination of rho kinase inhibitor and latanoprost).

[0092]

[0066] ‘ ‘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.

[0093] Method of Synthesizing the Compounds

[0094]

[0067] 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.

[0095]

[0068] The compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in Docket No.: PAT059789-PCT-SEC01 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).

[0096]

[0069] Those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0097]

[0070] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.

[0098] Definitions

[0099]

[0071] 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.

[0100]

[0072] 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.

[0101]

[0073] 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.

[0102] [074 An “alkyi” 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 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, Docket No.: PAT059789-PCT-SEC01 hexyl, pentyl and octyl. A Cs-Cs straight chained or branched alkyl group is also referred to as a ‘lower alkyl” group.

[0103]

[0075] The term “aryl”, as used herein, include single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0104]

[0076] 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.

[0105]

[0077] 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

[0106]

[0078] 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 Docket No.: PAT059789-PCT-SEC01 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.

[0107]

[0079] The term “cycloalkyl-alkyl”, as used herein, refers to an alkyl group substituted with a cycloalkyl group.

[0108]

[0080] The term “alkyl-cycloalkyl”, as used herein, refers to an cycloalkyl group substituted with an alkyl group.

[0109]

[0081] The terms “halo” and “halogen”, as used herein, means halogen and includes chloro, fluoro, bromo, and iodo.

[0110]

[0082] “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.

[0111]

[0083] "Haloalkoxy", as used herein, refers to an -O-haloalkyl group.

[0112]

[0084] The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyridyl N-oxide, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4- c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][l,6]naphthyridinyl, thieno[2,3- b]pyrazinyl, quinazolinyl, tetrazo lo[l, 5 -a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[l,2-a]pyrimidinyl, tetrahydropyrrolo[l,2-a]pyrimidinyl, 3,4-dihydro-2H-lA2-pyrrolo[2,l- b]pyrimidine, dibenzo [b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H- pyrido[3,4-b][l,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5- Docket No.: PAT059789-PCT-SEC01 naphthyridinyl, furo[3,2-b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo[l,2,3]triazolyl, imidazo[l,2- a]pyrimidinyl, [ 1 ,2,4]triazolo [4,3 -b]pyridazinyl, benzo [c] [ 1 ,2,5 ]thiadiazolyl, benzo [c] [ 1 ,2,5 ]oxadiazole, 1 ,3 -dihydro-2H-benzo [d]imidazol-2-one, 3 ,4-dihydro-2H-pyrazolo [ 1 ,5 -b] [ 1 ,2]oxazinyl, 4,5 ,6,7- tetrahydropyrazolo[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, 2,3- dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.

[0113]

[0085] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0114]

[0086] 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, dihydropyridinde, tetrahydropyridine, morpholine, lactones, lactams, azaadamantane and the like. Heterocyclyl groups can also be substituted by oxo groups. For example, “heterocyclyl” encompasses both pyrrolidine and pyrrolidinone.

[0115]

[0087] 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— ).

[0116]

[0088] The term “optionally substituted” means that a given chemical moiety (e.g., an alky 1 group) can (but is not required to) be bonded to other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen, wherein the substituents are as defined herein. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0117]

[0089] 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 Docket No.: PAT059789-PCT-SEC01 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.

[0090] The term “unsubstituted” means that the specified group bears no substituents.

[0118]

[0091] 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.

[0119]

[0092] The terms “pharmaceutically effective amount” or “therapeutically effective amount” or “effective amount” means an amount of a compound according to the disclosure which, when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue, system, or patient that is sought by a researcher or clinician. The amount of a compound according to the disclosure which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the disclosure, and the age, body weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.

[0120]

[0093] 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.

[0094] ‘ ‘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.

[0121]

[0095] 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).

[0122]

[0096] 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.

[0123]

[0097] 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 Docket No.: PAT059789-PCT-SEC01 physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.

[0124]

[0098] 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.

[0125]

[0099] “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.

[0126]

[0100] ‘ ‘Disorder” means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0127]

[0101] ‘ ‘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.

[0128]

[0102] “Compounds of the present disclosure”, “Compounds of Formula (I)”, “compounds of the disclosure”, and equivalent expressions (unless specifically identified otherwise) refer to compounds of Formula (I) as herein described including the salts particularly the pharmaceutically acceptable salts thereof, where the context so permits thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labelled compounds (including deuterium (“D”) substitutions).

[0129]

[0103] 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.

[0130] Examples

[0131]

[0104] 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.

[0132]

[0105] 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 Docket No.: PAT059789-PCT-SEC01 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.

[0133]

[0106] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker Avance spectrometer or Varian Oxford 400 MHz spectrometer unless otherwise noted. NMR spectra are given in ppm (8) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (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.

[0134]

[0107] 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.

[0135]

[0108] 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.

[0136]

[0109] Example 1 - Intermediate 1: 2.4-dichloro-6-phenyl-5.6.7.8-tetrahvdroquinazoline

[0137] Docket No.: PAT059789-PCT-SEC01

[0138]

[0110] 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 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).

[0139]

[0111] 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 °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). 'H 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).

[0140]

[0112] 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 Docket No.: PAT059789-PCT-SEC01 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 Na^SCh 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).

[0141]

[0113] 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- 5,6,7,8-tetrahydroquinazoline. Absolute stereochemistry was determined by small molecule X-ray crystallography.

[0142]

[0114] Example 2 - Intermediate 3: 2.4-dichloro-6-(3-fluorophenyl)-6-methyl-5.6,7,8- tetrahydroquinazoline

[0143] Docket No.: PAT059789-PCT-SEC01

[0144]

[0115] Step 1: To a solution of l-(3-fluorophenyl)ethan-l-one (100 g, 723.91 mmol) in THF (1 L) was added t-BuOK (130 g, 1160 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 1 h. Then a solution of (methoxymethyl)triphenylphosphonium chloride (372 g, 1090 mmol) in THF (1 L) was added dropwise at 0 °C. The reaction was allowed to warm to 20 °C and stirred for 16 h. TLC (Petroleum ether / Ethyl acetate = 10 / 1) showed starting material was consumed and one major new spot was formed. The reaction mixture was poured into petroleum ether (2 L) and then filtered. The filter was filtered through silica pad and concentrated under vacuum to afford desired product (E)-l-fluoro-3-(l- methoxyprop-l-en-2-yl)benzene (100 g, 602 mmol, 83.26% yield) as yellow oil which was used to next step directly.

[0145]

[0116] Step 2: To a solution of (E)-l-fluoro-3-(l -methoxyprop- l-en-2-yl)benzene (150 g, 902.57 mmol) in THF (1.5 L) was added a solution of HBr (663 g, 2170.71 mmol, in AcOH) in H2O (300 mL) drop wise at 0 °C. The reaction was allowed to warm to 40 °C after the addition was completed and stirred for 3 h. TLC (Petroleum ether / Ethyl acetate = 10 / 1, Rf = 0.3) showed starting material was consumed and new spot was formed. The reaction mixture was separated and the water phase was extracted by EtOAc (100 Docket No.: PAT059789-PCT-SEC01 mL x 2). The combined organic layer was washed with brine, dried over anhydrous NazSCU, filtered and concentrated under vacuum to give 2-(3-fluorophenyl)propanal (150 g, crude) which was used to next step directly.

[0146]

[0117] Step 3: To a solution of 2-(3-fluorophenyl)propanal (140 g, crude) in toluene (1200 mL) was added but-3-en-2-one (96 g, 1380.25 mmol) and pTsOH HzO (35 g, 184.01 mmol) at 25 °C. The mixture was stirred at 80 °C for 16 h. TLC (Petroleum ether / Ethyl acetate = 10 / 1) showed starting material was consumed completely and major spot was formed. The reaction mixture was concentrated to remove toluene. The residue was purified by silica gel column chromatography (SiOz (1000 g, 1000 mesh), from Petroleum ether to Petroleum ether / Ethyl acetate = 2 / 1) and then the desired fraction was concentrated to afford 3'-fluoro-l-methyl-2,3-dihydro-[l,T-biphenyl]-4(lH)-one (120 g, 579.61 mmol, 98.65% purity, 48.09% yield over two step). LCMS: m / z = 1^2 [M+H]+, RT = 0.883 min;1H NMR (400 MHz, DMSO- d6) 8 = 7.41 (dt, J= 6.7, 8.0 Hz, 1H), 7.28 - 7.20 (m, 2H), 7.15 - 7.07 (m, 2H), 6.03 (d, J= 10.1 Hz,lH), 2.43 - 2.33 (m, 1H), 2.29 - 2.19 (m, 1H), 2.16 - 2.08 (m, 2H), 1.53 - 1.49 (m, 3H).

[0147]

[0118] Step 4: To a solution of 3'-fluoro-l-methyl-2,3-dihydro-[l,T-biphenyl]-4(lH)-one (60 g, 293.76 mmol) in MeOH (600 mL) was added Pd / C (62 g, 58.75mmol, 10% on carbon). The mixture was purge and degassed by Hz three times. The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered to remove Pd / C and the filterate was concentrated under vacuum. The residue was purified by silica gel column chromatography (From PE to PE / EA = 2 / 1) and concentrated to afford 4-(3- fluorophenyl)-4-methylcyclohexan-l-one (37.5 g, 62% yield, 88% purity). LCMS: RT = 0.909 min, m / z = 207.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) 8 7.45 - 7.37 (m, 1H), 7.36 - 7.29 (m, 2H), 7.09 - 7.01 (m, 1H), 2.40 - 2.29 (m, 4H), 2.19 -2.11 (m, 2H), 1.98 - 1.89 (m, 2H), 1.30 (s, 3H).

[0148]

[0119] Step 5: To a solution of 4-(3-fluorophenyl)-4-methylcyclohexan-l-one (100 g, 848.46 mmol) and NaH (8.14 g, 87.27 mmol, 60%) in THF (200 mL) was added a solution of diethylcarbonate (35 g, 169.69 mmol) in THF (100 mL) drop wise at 80 °C under Nz atmosphere. The mixture was stirred at 80 °C for 3 h. The reaction mixture was poured into HC1 (200 mL, IN) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (30 mL x 3), dried over anhydrous NazSCf. filtered and concentrated under vacuum to afford desired product ethyl 5-(3-fluorophenyl)-5-methyl-2- oxocyclohexane-1 -carboxylate (30 g, 56% yield, 88.11% purity) as yellow oil. LCMS: RT = 1.063 min, m / z = 279.2 [M+H]+; *H NMR (400 MHz, DMSO-d6) 8 ppm 7.32 - 7.41 (m, 1 H), 7.11 - 7.20 (m, 2 H), 7.02 (td, J= 8.28, 2.26 Hz, 1 H), 4.23 (q, J= 7.03 Hz, 2 H), 2.69 (br d, J= 15.94 Hz, 1 H), 2.47 - 2.56 (m, 1 H), 2.20 - 2.36 (m, 2 H), 2.03 - 2.16 (m, 1 H), 1.84 - 1.98 (m, 1 H); 1.73 - 1.84 (m, 1 H), 1.12 - 1.31 (m, 6 H).

[0149]

[0120] Step 6: To a solution of 5 -(3 -fluorophenyl)-5-methyl-2-oxocyclohexane-l -carboxylate (30 g, 107.79 mmol) in EtOH (300 mL) was added urea (13 g, 215.58 mmol) and NaOMe (12 g, 215.58 mmol). Docket No.: PAT059789-PCT-SEC01

[0150] The mixture was stirred at 80 °C for 16 h and the mixture was filtered to give 6-(3-fluorophenyl)-6- methyl-5,6,7,8-tetrahydroquinazoline-2,4(lH,3H)-dione (35 g crude) as yellow solid which was used to next step directly. LCMS: RT = 0.806 min, m / z = 275.2 [M+H]+.

[0151]

[0121] Step 7: To a solution of 6-(3-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinazoline-2,4(lH,3H)- dione (30 g, 109.49 mmol) and TEA (2.2 g, 16.41 mmol, 2.2 mL) in dioxane (200 mL) was added POCE (84 g, 546.87 mmol. 50.8 mL) drop wise at 0 °C. The mixture was warmed to 125 °C and stirred for 3 h and the reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography (Column: 300 g Si O2- PE and EA condition) and the product fractions were concentrated under vacuum to give 2,4-dichloro-6-(3-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinazoline (27 g, 80.7% yield) as yellow oil. LCMS: RT=1.028 min, m / z = 311.2 [M+H]+.

[0152]

[0122] Step 8: Racemate 2,4-dichloro-6-(3-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinazoline (64 g, 205.78 mmol) was separated by SFC (Column: DAICEL CHIRALPAK AY-H(250mm* 30mm, lOum), Condition: O.P / oNEE’HzO EtOH, Begin B%: 20% to End B%: 20%). The solution was concentrated under vacuum to yield:

[0153]

[0123] (R)-2,4-dichloro-6-(3-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinazoline (14.6 g, 45.65 mmol, 22.20% yield, 94.7% purity). LCMS: RT = 1.034 min, m / z = 312.2 [M+H]+, SFC: RT = 0.905 min; ’H NMR (400 MHz, DMSO-d6) 8 = 7.41 - 7.30 (m, 1H), 7.20 (br d, J= 11.4 Hz, 1H), 7.13 (br d, J = 7.8 Hz, 1H), 7.09 - 6.98(m, 1H), 3.21 (br d, J= 17.5 Hz, 1H), 3.00 - 2.78 (m, 2H), 2.59-2.52 (m, 1H), 2.40 - 2.16 (m, 1H), 2.11 - 1.89 (m, 1H), 1.34 (s, 3H)

[0154]

[0124] (S)-2,4-dichloro-6-(3-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinazoline (11.2 g, 36.01 mmol, 17.50% yield, 99.3% purity). LCMS: RT = 1.034 min, m / z = 312.2 [M+H]+, SFC: RT = 0.905 min; ’H NMR (400 MHz, DMSO-d6) 8 = 7.35 (dt, J= 6.6, 8.0 Hz, 1H), 7.20 (td, J= 2.2, 11.4 Hz, 1H), 7.13 (dd, J = 0.9, 8.0 Hz, 1H), 7.08 - 7.00 (m, 1H), 3.21 (d, J= 17.7 Hz, 1H), 3.05 - 2.81(m, 2H), 2.58 - 2.53 (m, 1H), 2.37 - 2.19 (m, 1H), 2.OO (ddd, J= 6.1, 8.2, 13.9 Hz, 1H), 1.36 -1.27 (m, 3H).

[0155]

[0125] Example 3 - Preparation of Intermediate 4: 2.4-dichloro-6-(3-fluorophenyl)-5.6,7,8- tetrahydroquinazoline

[0156] Docket No.: PAT059789-PCT-SEC01

[0157] Peak 1 Peak 2 lot. 4A int. 4B

[0158]

[0126] 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^ppfJCh’CLLCh (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 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 Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 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. LCMS: MS (ESI) m / z = 235.2 [M+H]+;1H 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). Docket No.: PAT059789-PCT-SEC01

[0159]

[0127] 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 Nz atmosphere. The suspension was degassed and purged with Hz 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]+, ^ NMR: 5 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).

[0160]

[0128] 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. NaHCOz 500 mL and brine 500 mL, dried over anhydrous NazSOr, 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) 5 7.38 - 7.30 (m, 1H), 7.17 - 7.10 (m, 2H), 7.06 - 6.98 (m, 1H), 3.15 - 3.04 (m, 1H), 2.63 - 2.52 (m, 2H), 2.31 - 2.21 (m, 2H), 2.12 - 2.02 (m, 2H), 1.96 - 1.80 (m, 2H).

[0161]

[0129] 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 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 (1 L) and extracted with EtOAc (1 L X 2). The combined organic layer was washed with sat. NaHCOz solution (800 mL) and brine (600 mL), dried over anhydrous NazSCU and concentrated under reduced pressure. The residue was purified by column chromatography (SiOz, 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) 5 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 Docket No.: PAT059789-PCT-SEC01

[0162] (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).

[0163]

[0130] 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).

[0164]

[0131] 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 Na?SO4, 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).

[0165]

[0132] 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% NHs^HzO MeOH]; B%: 30% - 30%, 2.8 min; 1100 min) to give:

[0166] (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) 8 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. Docket No.: PAT059789-PCT-SEC01

[0167] (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) 8 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.

[0168]

[0133] Example 4 - Preparation of Intermediate 6: methyl (lR.4r)-4-((R)-l-aminopropyl)cvclohexane- 1 -carboxylate

[0169] Step 3 Step 4

[0170] I nt. 6

[0171]

[0134] Step 1: To a solution of 3 -(methoxycarbonyl)bicyclo [1.1.1 ]pentane-l -carboxylic acid (253.0 g, 1.5 mol, 1.0 eq) in anhydrous THF (2500.0 mL) and was added dropwise boranemethyl sulfide complex (2232.0 mL, 2.0 mol / L, 4.5 mol, 3.0 eq) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. The reaction was monitored by GC. The reaction mixture was quenched with MeOH (750.0 mL) until no bubbles were generated at 25 °C. The mixture was concentrated under reduced pressure at 45 °C. The residue was dissolved in MTBE (5060.0 mL, 20 V), washed with saturated NaCl aqueous (759.0 mL x 2), and dried over anhydrous Na^SOr. filter and concentrated under reduced pressure to afford methyl 3- (hydroxymethyl)bicyclo[l.l.l]pentane-l -carboxylate (255.0 g, GC purity: 98.8%, crude yield: 100%) as a light-yellow solid. ‘H NMR (300 MHz, CDCL) 8 3.75 (s, 2H), 3.67 (s, 3H), 1.96 (dd, J= 9.2, 5.7 Hz, 6H).

[0172]

[0135] Step 2: To a solution of methyl 3 -(hydroxymethyl)bicyclo[l.l.l]pentane-l -carboxylate (255.0 g crude, 1.5 mol, 1.0 eq) in dry DCM (2500.0 mL) was added NaHCCL (250.0 g, 3.0 mol, 2 eq) and DMP Docket No.: PAT059789-PCT-SEC01

[0173] (753.3 g, 1.8 mol, 1.2 eq) at 0 °C, and the mixture was warmed to 25 °C and stirred for 2 h. The reaction was monitored by GC. The reaction mixture was filtered through a pad of celite, and the filter cake was washed with DCM (1000.0 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was diluted with EtOAc (5100.0 mL), and washed with saturated sodium thiosulfate aqueous (500.0 mL x 2) and saturated NaHCCL aqueous (500.0 mL), dried over anhydrous NazSCU, filtered and concentrated. The residue was purified by column with heptane / EA = 10 / 1 to afford methyl 3- formylbicyclo[l.l.l]pentane-l -carboxylate (187.0 g, purity: 83.4%, crude yield: 70.2%) as a white solid. ’H NMR (300 MHz, CDCL) 8 9.60 (s, 1H), 3.71 (s, 3H), 2.32 (s, 6H).

[0174]

[0136] Step 3: To a mixture of methyl 3 -formylbicyclo [l.l.l]pentane-l -carboxylate (180.0 g, 1.3 mol, 1.0 eq) in DCM (1800.0 mL, 10 V) was added (R)-(+)-2-Methyl-2-propanesulfmamide (156.8 g, 1.3 mol, 1.0 eq) at 25 °C, and the mixture was stirred for 72 h. The reaction was monitored by GC. The reaction mixture was diluted with HzO (900.0 mL), and separated. The aqueous phase was extracted with DCM (2700.0 mL, 15 V), and the combined organic phases were washed with saturated NaCl aqueous (500.0 mL), dried over anhydrous NazSCL. filtered and concentrated under reduced pressure. The mixture was purified by column with heptane / EA = 5 / 1 to afford methyl (R,E)-3-(((tert- butylsulfinyl)imino)methyl)bicyclo[l.l.l]pentane-l -carboxylate (210.0 g, purity: 59.2%, containing 40.8% of (R)-2-methylpropane-2-sulfinamide (crude yield of 63.0%) as an off-white solid which was used to the next step directly without further purification. ’H NMR (300 MHz, CDCL) 8 7.97 (s, 1H), 3.68 (s, 3H), 2.28 (s, 6H), 1.16 (s, 9H).

[0175]

[0137] Step 4: To a solution of methyl (R,E)-3-(((tert-butylsulfinyl)imino)methyl)bicyclo[l.l.l]pentane- 1-carboxylate (200.0 g, 0.77 mol, 1.0 eq) in dry THF (1600.0 mL) was added dropwise ethyl magnesium bromide (777.0 mL, 1.5 mol, 2mol / L, 2.0 eq) at -78 °C, and the mixture was stirred for 2 h. The reaction was monitored by HPLC. The reaction mixture was quenched with saturated NH4CI aqueous (1200.0 mL) at -78 °C. The reaction mixture was warmed up to 25 °C. The mixture was extracted with EtOAc (3000.0 mL x 2), and the combined organic layers were dried over anhydrous NazSO4, filtered and concentrated under reduced pressure. The residue was purified by column with heptane / EA = 3 / 1 to crude product as a yellow oil. The crude product was purified by preparatory-HPLC to afford 27.0 g of methyl (S)-3-(l- ((tert-butylsulfinyl)amino)-l 13 -propyl)bicyclo[l. l.l]pentane-l -carboxylate with 93.9% purity and 81.0 g of methyl (R)-3-(l-((tert-butylsulfinyl)amino)-l 13 -propyl)bicyclo[l.l. l]pentane-l -carboxylate with 97.2% purity. *H NMR (300 MHz, CDCL) 8 3.65 (d, J= 8.7 Hz, 3H), 3.11 (td, J= 8.3, 4.5 Hz, 1H), 2.87 (d, J= 7.7 Hz, 1H), 1.99 (qd, J= 9.6, 1.8 Hz, 6H), 1.55 (ddd, J= 14.1, 7.4, 4.5 Hz, 1H), 1.41 - 1.25 (m, 1H), 1.25 - 1.11 (m, 9H), 0.93 (t, J = 7.4 Hz, 3H).

[0176]

[0138] Step 5: To a solution of methyl (R)-3-(l-((tert-butylsulfinyl)amino)-113- propyl)bicyclo[l.l.l]pentane-l -carboxylate (63.0 g, 0.21 mol, 1.0 eq) in dry THF (0.7 L) was added Docket No.: PAT059789-PCT-SEC01

[0177] LiHMDS (2 M, 210.0 mL, 0.42 mol, 2.0 eq) at 0 °C under N2, and the reaction mixture was stirred for 0.5 h at 0 °C. Then Mel (59.6 g, 0.42 mol, 2.0 eq) was added dropwise at 0 °C, and the mixture was warmed to 25 °C and stirred for 2 h. The reaction was monitored by HPLC. The reaction mixture was quenched with ice-water (1200.0 mL). The mixture was extracted with EtOAc (1000.0 mL 3), and the combined organic phases were washed with saturated NaCl aqueous (500.0 mL), dried over anhydrous NazSCL, filtered and concentrated under reduced pressure to afford methyl (R)-3-(l-((tert- butylsulfinyl)(methyl)amino)-l 13 -propyl)bicyclo[l.l.l]pentane-l -carboxylate (55.0 g, purity: 82.1%, crude yield: 83.2%). ’H NMR (300 MHz, CDCI3) 8 3.66 (s, 3H), 3.11 (dd, J= 8.7, 6.6 Hz, 1H), 2.49 (s, 3H), 2.13 (dd, J= 9.5, 1.8 Hz, 3H), 2.00 (dd, J= 9.5, 1.8 Hz, 3H), 1.62 - 1.46 (m, 2H), 1.23 (dd, J= 9.0, 5.2 Hz, 2H), 1.23 - 1.11 (m, 9H), 0.98 (t, J= 7.4 Hz, 3H).

[0178]

[0139] Step 6: Methyl (R)-3 -(l-((tert-butylsulfinyl)(methyl)amino)- 113 -propyl)bicyclo[ 1.1.1 ]pentane-l- carboxylate (55.0 g, 182.5 mmol, 1.0 eq) was added into 4M HC1 in 1, 4-dioxane (467.0 mL, 1.8 mol, 10.0 eq) at 0 °C, and the mixture was warmed to 25 °C and stirred for 2 h. The reaction was monitored by HPLC. The reaction mixture was concentrated under reduced pressure, and swapped with MTBE (110.0 mL x 2). The residue was triturated with MTBE / EtOAc (50 / 1, 165.0 mL) at 25 °C for 2 h. The mixture was filtered, and the filter cake was triturated with MTBE (275.0 mL, 5 V) at 25 °C for 2 h. The mixture was filtered, and the filter cake was dried to afford methyl (R)-3-(l- (methylamino)propyl)bicyclo[l.l. l]pentane-l -carboxylate hydrochloride (25.5 g, yield: 59.8%) as a white solid. *H NMR (300 MHz, MeOD) 8 3.70 (s, 2H), 3.20 - 3.07 (m, 1H), 2.73 (s, 3H), 2.19 (dd, J = 4.4, 1.3 Hz, 6H), 1.75 (t, J= 7.6 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H).

[0179]

[0140] Example 5 - Preparation of Intermediate 7: methyl (!R,4r)-4-((R)-l-

[0180] (methylamino)propyl)cvclohexane-l -carboxylate hydrochloride Docket No.: PAT059789-PCT-SEC01

[0181]

[0141] 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 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, CDCL) 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).

[0182]

[0142] 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 (SiOz, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to get a product (230 g crude). The product was then purified by Prep-HPLC (Phenomenex luna cl 8 250 mm * 100 mm * 10 um; mobile phase: [water (lOmM NH4HCO3) - ACN], B%: 45.0% - 65.0%, 20 minutes) to give desired product ethyl (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).

[0183]

[0143] Step 3: To a solution of ethyl (lR,4r)-4-((E)-l-(((R)-tert-butylsulfinyl)imino)propyl)cyclohexane- 1-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 Docket No.: PAT059789-PCT-SEC01 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 C18 (250 * 70 mm, 10 um), mobile phase: [water (lOmM NH4HCO3)- ACN], B%: 45% - 70%, 20 minutes) to give desired product ethyl (lR,4r)-4-((R)-l-(((R)-tert- butylsulfinyl)amino)propyl)cyclohexane-l -carboxylate (58.0 g, 178 mmol, 58.7% yield, 97.8% purity) as a light yellow oil. LCMS: RT = 0.886 min, m / z = 318.2 [M+H]+; ’H NMR ( 400 MHz, CDCh) 8 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).

[0184]

[0144] Step 4: To a solution of ethyl (lR,4r)-4-((R)-l-(((R)-tert- butylsulfinyl)amino)propyl)cyclohexane-l -carboxylate (55.0 g, 173 mmol, 1 eq) in THF (1100 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 (Si O2- 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, CDCL) 8 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).

[0185]

[0145] Step 5: To a solution of ethyl (lR,4r)-4-((R)-l-(((R)-tert- butylsulfinyl)(methyl)amino)propyl)cyclohexane-l -carboxylate (64.0 g, 193 mmol, 1 eq) in MeOH (448 mL) were added HCl / MeOH (4 M, 448 mL, 9.28 eq) at 0 °C, the resulting mixture was continued and stirred at 25 °C for 5 h. LCMS showed that the material was consumed and desired product was formed. The reaction mixture was concentrated to get a product as a yellow oil. Then the product was dissolved into EtOAc / MTBE (1 / 10, 220 mL) and concentrated to get a product as a white solid. The product was triturated with MTBE (100 mL) at 25 °C for 10 minutes to get methyl (lR,4r)-4-((R)-l- (methylamino)propyl)cyclohexane-l -carboxylate hydrochloride (36.2 g, 144 mmol, 75.0% yield).

[0186] LCMS: RT = 0.341 min, m / z = 213.9 [M+H]+;1H NMR (400 MHz, CDCh) 8 9.49 - 8.92 (m, 2H), 3.63 Docket No.: PAT059789-PCT-SEC01

[0187] (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).

[0188]

[0146] Example 6 - Preparation of Intermediate 8: methyl (lR.4r)-4-((R)-l-aminopropyl)cvclohexane-

[0189] 1 -carboxylate

[0190]

[0147] 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).

[0191]

[0148] Example 7 - Preparation of Intermediate 9: 2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)-l-(l- methyl- 1 H-pyrazol-4-yl)ethan- 1 -amine

[0192] Docket No.: PAT059789-PCT-SEC01

[0193] Int. 9

[0194]

[0149] Step 1 : To a solution of tert-butyl (3R,5R)-3-hydroxy-5-methylpiperidine-l-carboxylate (4500.0 mg, 1 Eq, 20.902 mmol) in THF (104 m ) was added NaH (2.090 g, 60% Wt, 2.5 Eq, 52 mmol) at 0°C. Then the reaction mixture was stirred at 0°C for 0.5 h and Mel (7.42 g, 3.27 mL, 2.5 Eq, 52 mmol) was added dropwise. The mixture was stirred at 25°C for another 1.5 h. LCMS showed one major peak with desired mass was detected. The mixture was quenched with saturated NH4CI (100 mL) and extracted with EtOAc (100 mL*2). The combined organic phase was dried over anhydrous NazSCU, filtered and concentrated to afford the residue. The residue was purified by flash silica gel chromatography(ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-100% EtOAc / Heptane) and the eluent was concentrated to give desired product as a colorless oil. LCMS m / z [M-55]+= 174.2.

[0195]

[0150] Step 2: To a solution of tert-butyl (3R,5R)-3-methoxy-5-methylpiperidine-l-carboxylate (4.4 g, 1 Eq, 19 mmol) in MeOH (50 mL) was added HC1 (4N in dioxane) (1.5 g, 24 mL, 4.000 molar, 5 Eq, 96 mmol) at 0°C. Then the reaction mixture was stirred at rt for 2 h and LC-MS indicated all SM was consumed. The mixture was concentrated under reduced pressure to give a colorless oil. The crude product was used next step without further purification. LCMS m / z [M+H]+= 130.1.

[0196]

[0151] Step 3: (3R,5R)-3-m ethoxy-5 -methylpiperidine hydrochloride (1.60 g, 1.2 Eq, 9.64 mmol), (R)-2- ((tert-butoxycarbonyl)amino)-2-(l-methyl-lH-pyrazol-4-yl)acetic acid (2.05 g, 8 mmol) and Et,N (4.48 ml, 32 mmol) were dissolved in DCM (40 ml). The solution was cooled down to 0 °C and T3P (50% in EtOAc) (9.55 ml, 16 mmol) was added slowly. The solution became unclear and mixture was stirred at room temperature for 2 h. LC-MS indicated complete reaction. The reaction mixture was partitioned between EtOAc and water, the organic phase was washed with water, saturated NaHCOs solution, brine and dried over MgSO4. The solid was filtered off and concentrated under reduced pressure. The crude Docket No.: PAT059789-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)-2-((3 R,5R)-3 -m ethoxy-5 -methylpiperidin- 1 -yl)- 1 -(1 -methyl- 1 H-pyrazol-4-yl)-2- oxoethyl)carbamate as a white solid (1.94 g, 66%). MS m / z = 367.2 [M+H]+.

[0197]

[0152] Step 4: To a solution of tert-butyl ((R)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)-l-(l- methyl-lH-pyrazol-4-yl)-2-oxoethyl)carbamate (4.64 g, 12.66 mmol) in THF (32 ml) was added BH3.DMS (2M in THF) (31.65 ml, 63.3 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 (20 mL) then heated at 50 °C for 16 hr. 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)-2-((3R,5R)-3 -m ethoxy-5 -methylpiperidin- 1 -yl)- 1 -( 1 -methyl- 1 H-pyrazol-4- yl)ethyl)carbamate as a colorless oil (3.18 g, 71% yield). MS m / z = 353.3 [M+H]+.

[0198]

[0153] Step 5: To a solution of tert-butyl ((R)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)carbamate (3.18 g, 9.02 mmol) in MeOH (20 ml) was added HC1 (11..28 ml, 45.1 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)-2-((3R,5R)-3 -methoxy-5 -methylpiperidin- 1 -yl)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)ethan- 1 -amine dihydrochloride as a light pale solid in quantitative yield. MS m / z = 253.3 [M+H]+.

[0199]

[0154] Example 8 - Preparation of Intermediate 10:

[0200]

[0155] Step 1: To a solution of 2-methyl-lH-imidazole (5.0 g, 60.90 mmol) in THF (50 mL) were added NaH (3.65 g, 91.35 mmol, 60%) at 0°C. The reaction mixture was stirred at 0°C for 0.5 h under N2. Then Docket No.: PAT059789-PCT-SEC01

[0201] SEMC1 (12.18 g, 73.08 mmol) was added to the above mixture at 0°C. The reaction mixture was stirred for another 15.5 h at 25°C under N2. LCMS showed major peak with desired mass was detected. The reaction mixture was quenched with saturated NH4C1 (100 mL) and extracted with EA (50 mL*3). The combined organic phase was dried by anhydrous Na2SO4, filtered and concentrated to afford the residue. The residue was purified by combi-flash on silica gel column chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ethergradient @ 100 mL / min) and then concentrated to afford 2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole (8.5 g, 39.62 mmol, 65% yield, 99% purity) as yellow. ‘H NMR (400 MHz, DMSO-d6) 8 = 7.14 (d, J = 1.3 Hz, 1H), 6.72 (d, J= 1.3 Hz, 1H), 5.24 (s, 2H), 3.49 - 3.41 (m, 2H), 2.30 (s, 3H), 0.87 - 0.79 (m, 2H), -0.05 (s, 9H).

[0202]

[0156] Step 2: To a solution of 1 -methyl- lH-pyrazole-4-carbaldehyde (2 g, 18.16 mmol) and 2- methylpropane-2-sulfinamide (3.30 g, 27.24 mmol) in DCM (40 mL) was added CuSO4 (5.8 g, 36.33 mmol). The mixture was stirred at 30°C for 16h. The reaction mixture was filtered off and the filtrate was concentrated to get the residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-100% EA / PE) and the eluent was concentrated to give (Z)-2-methyl-N-((l-methyl-lH-pyrazol-4-yl)methylene)propane-2-sulfmamide (3.3 g, 15.47 mmol, 90% purity, 85% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) 8 = 8.93 (s, 1H), 8.86 (s, 1H), 8.47 (s, 1H), 4.44 - 4.38 (m, 4H), 1.64 (s, 9H), 1.59 (s, 7H).

[0203]

[0157] Step 3: To a solution of 2-m ethyl- l-((2-(trimethylsilyl)ethoxy)m ethyl)- IH-imidazole (1 g, 4.71 mmol) in THF (20 mL) was added t-BuLi (4.35 mL, 5.65 mmol) at -60°C under N2. Then the mixture was stirred at -60°C for 0.5h under N2. Then the mixture was added to (Z)-2-methyl-N-((l-methyl-lH- pyrazol-4-yl)methylene)propane-2-sulfinamide (1.21 g, 5.65 mmol) in THF (10 mL) at -60° C under N2. The reaction mixture was stirred for another 2.5h under N2. LCMS showed desired mass was detected. The reaction mixture was quenched with saturated NH4C1 solution (100 mL) and extracted with EA (50 mL*2). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford the residue. The crude residue was purified by reversed phase (105 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 30 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) to afford 2-methyl-N-(l-(l -methyl- lH-pyrazol-4-yl)-2-(l-((2-(trimethylsilyl)ethoxy)m ethyl)- lH-imidazol-2- yl)ethyl)propane-2-sulfinamide (800 mg, 77% purity) as yellow oil. Then the product was purified by reversed phase column chromatography (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: 85 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) and then concentrated under vacuum to remove MeCN. The aqueous phase was adjusted to pH=8-9 by sat. NaHCO3 solution, extracted with EA (30 Docket No.: PAT059789-PCT-SEC01 mL*3), then combined organic phase was dried by anhydrous Na2SO4, filtered and concentrated to afford 2-methyl-N-(l-(l-m ethyl- lH-pyrazol-4-yl)-2-(l-((2-(trimethylsilyl)ethoxy)m ethyl)- lH-imidazol-2- yl)ethyl)propane-2-sulfinamide (350 mg, 0.732 mmol, 15% yield, 89% purity) as yellow oil, LCMS: Rt= 0.539 min, [M+H]+= 426.2.

[0204]

[0158] Step 4: To a solution of 2-methyl-N-(l-(l-methyl-lH-pyrazol-4-yl)-2-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)ethyl)propane-2-sulfinamide (300 mg, 0.705 mmol) in DCM (3 mL) was added HCl / dioxane (10 mL, 4M) and TFA (5 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 4 h. LCMS showed major peak with desired mass was detected. The residue was concentrated to get the crude product. The crude product was dissolved by MeOH (3 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 Intermdiate 10 (140 mg, 89% yield, crude) as yellow oil which was used for next step directly. LCMS: Rt= 0.109min, [M+H]+= 192.2.

[0205]

[0159] Example 9 - Preparation of Intermediate 11 : ethyl 2-(4-(l-amino-2-((S)-3-methylpiperidin-l- vDethyl)- 1 H-pyrazoL 1 -yljacetate

[0206]

[0160] Step 1: To a mixture of 2-((tert-butoxycarbonyl)amino)-2-(lH-pyrazol-4-yl)acetic acid (2.700 g, 1 Eq, 11.19 mmol) and (S)-3 -methylpiperidine hydrochloride (1.822 g, 1.2 Eq, 13.43 mmol) in DCM (90.00 mL) was added Et3N (3.397 g, 4.68 mL, 3 Eq, 33.58 mmol) and then T3P (16.13 g, 50% Wt, 2 Eq, 22.38 mmol, 163755-62-2) was added slowly to the mixture at 0°C. The mixture was stirred at 0°C for 0.5 h. LCMS showed 69% of desired mass was detected. The mixture was diluted with H O (100 mL), then extracted with DCM (100 mL*3). The organic phase was washed with saturated NaHCO3 aqueous Docket No.: PAT059789-PCT-SEC01 solution (100 mL*3) and Sat.NaCl (100 mL), The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give the residue. The residue was combined with pilot batch to purify. The combined residue was purified by reversed phase column chromatography (220 g of SepaFlash® Spherical C18, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% FA and B for acetonitrile; gradient: B 5 - 80% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) after purification, the aqueous phase was basified by saturated NaHCO3 solution (100 mL) to pH=8-9 and extracted with DCM (100 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford: tert-butyl (2-((S)-3-methylpiperidin-l-yl)-2-oxo-l-(lH-pyrazol-4- yl)ethyl)carbamate (3.400 g, 10 mmol, 92 %, 98% Purity) as yellow soild. LCMS: Rt =0.465 min, [M+H] =323.2,1H NMR (400 MHz, CHLOROFORM-d) 8 = 9.36 - 8.50 (m, 1H), 7.59 (br d, J= 8.5 Hz, 2H), 6.07 (br d, J= 4.9 Hz, 1H), 5.72 - 5.58 (m, 1H), 4.62 - 4.32 (m, 1H), 3.76 - 3.54 (m, 1H), 3.00 - 2.50 (m, 1H), 2.44 - 2.25 (m, 1H), 1.85 - 1.57 (m, 2H), 1.42 (br d, J= 4.3 Hz, 9H), 1.39 - 1.21 (m, 1H), 1.14 - 1.00 (m, 1H), 1.00 - 0.79 (m, 3H), 0.73 (br d, J= 6.1 Hz, 1H).

[0207]

[0161] Step 2: To a mixture of tert-butyl (2-((S)-3-methylpiperidin-l-yl)-2-oxo-l-(lH-pyrazol-4- yl)ethyl)carbamate (2.600 g, 1 Eq, 8.064 mmol) and K2CO3 (2.229 g, 2 Eq, 16.13 mmol) in MeCN (40.00 mL) was added ethyl 2-chloroacetate (1.186 g, 1.2 Eq, 9.677 mmol). The mixture was stirred at 60°C for 48h. LCMS showed 94% of desired mass was detected. The mixture was diluted with H2O (100 mL), then extracted with EA (100 mL*3). The organic phase was washed with Sat.NaCl (50 mL), Then the organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give the residue. The residue was purified by reversed phase column chromatography (220 g of SepaFlash® Spherical Cl 8, 20 - 45 pm, 100 A; mobile phase: A for H2O + 0.1% FA and B for acetonitrile; gradient: B 5 - 100% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) after purification, the aqueous phase was basified by saturated NaHCO3 solution (100 mL) to pH=8-9 and extracted with EA (150 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford: ethyl 2-(4-(l-((tert-butoxycarbonyl)amino)-2-((S)-3-methylpiperidin-l-yl)-2-oxoethyl)-lH- pyrazol-l-yl)acetate (3.200 g, 7.1 mmol, 87 %, 90% Purity) as yellow oil. LCMS: Rt =0.509 min, [M+H]+ =409.2.

[0208]

[0162] Step 3: To a solution of ethyl 2-(4-(l-((tert-butoxycarbonyl)amino)-2-((S)-3-methylpiperidin-l- yl)-2-oxoethyl)-lH-pyrazol-l-yl)acetate (3.200 g, 1 Eq, 7.834 mmol) in THF (120.00 mL) was added BH3.DMS (1.785 g, 2.350 mL, 10.00 molar, 3 Eq, 23.50 mmol) slowly at 0°C under N2. The mixture was stirred 25°C for 12 h. LCMS showed desired mass was detected. The reaction mixture was slowly quenched with EtOH (150 mL) until no bubbles released. The mixture was stirred for 2h at 60°C and then concentrated to give a residue. LCMS showed 79% of desired mass and 11% of reaction 1 remained. The residue was purified by reversed phase column chromatography (80 g of SepaFlash® Spherical C18, 20 - Docket No.: PAT059789-PCT-SEC01

[0209] 45 gm, 100 A; mobile phase: A for H2O + 0.1% FA and B for acetonitrile; gradient: B 5 - 50% in 15 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) after purification, the aqueous phase was basified by saturated NaHCO3 solution (50 mL) to pH=8-9 and extracted with EA (100 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford: ethyl 2-(4-( 1 -((tert-butoxycarbonyl)amino)-2-((S)-3 -methylpiperidin- 1 -yl)ethyl)- 1 H-pyrazol- 1 - yl)acetate (2.200 g, 5.0 mmol, 64 %, 90% Purity) as yellow oil. LCMS: Rt =0.453 min, [M+H] = 395.4, 'H NMR (400 MHz, CHLOROFORM-d) 8 = 7.50 (s, 1H), 7.45 (s, 1H), 5.31 (s, 1H), 4.86 (s, 2H), 4.78 (br s, 1H), 4.26 - 4.20 (m, 2H), 2.96 - 2.49 (m, 4H), 1.84 - 1.53 (m, 6H), 1.44 (s, 9H), 1.32 - 1.25 (m, 3H), 0.96 - 0.82 (m, 4H).

[0210]

[0163] Step 4: To a solution of ethyl 2-(4-(l-((tert-butoxycarbonyl)amino)-2-((S)-3-methylpiperidin-l- yl)ethyl)-l H-pyrazol- l-yl)acetate (2.200 g, 1 Eq, 5.576 mmol) in DCM (5.000 mL) was added 2M HCl / dioxane, 1,4-dioxane (4.9828 g, 20.000 mL, 2.000 molar, 7.173 Eq, 40.000 mmol). The resulting mixture was stirred at 20°C for 2 h. LCMS showed a major peak of desired mass was detected. The reaction was concentrated to remove the solvent to afford: ethyl 2-(4-(l-amino-2-((S)-3-methylpiperidin- 1 -yljethyl)- 1 H-pyrazol- l-yl)acetate hydrochloride (2.800 g, 7.623 mmol, 136.7 %) as white solid. The obtained product was taken to the next step without further purification. LCMS: Rt =0.375 min, [M-NH2] = 295.1,

[0211]

[0164] Example 10 - Preparation of Intermediate 12: (R)-3-m ethoxy-3 -methylpiperidine

[0212] Step 1 Step 2 Step 3 !nt. 12

[0213] Step 1: To a solution of (R)-3-methylpiperidin-3-ol, AA - Hydrochloride (6.500 g, 1 Eq, 42.86 mmol), TEA (17.35 g, 23.9 mL, 4 Eq, 171.5 mmol) in DCM (100.00 mL) was added boc2o (23.39 g, 24.6 mL, 2.5 Eq, 107.2 mmol) portion-wise and then stirred at room temperature for 16h. Mixture was concentrated and the residue was partitioned between EtOAc and water. The organic phase was separated and the aqueous phase further extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated. Crude residue was purified by silica gel column with 0-10% DCM / MeOH over 20 column volumes using 214 nm detection to afford desired compound tert-butyl (R)- 3 -hydroxy-3 -methylpiperidine- 1 -carboxylate (6.000 g, 75% purity, 50% yield) as a clear oil.1H NMR (400 MHz, DMSO) 8 4.41 (s, 1H), 3.12 (d, J= 36.1 Hz, 4H), 1.69 - 1.55 (m, 1H), 1.46 (dd, J= 7.4, 4.6 Hz, 2H), 1.38 (s, 10H), 1.05 (s, 3H). Docket No.: PAT059789-PCT-SEC01

[0214] Step 2: To a 0°C stirred solution of tert-butyl (R)-3 -hydroxy-3 -m ethylpiperidine- 1 -carboxylate (6.000 g, 1 Eq, 27.87 mmol) in tetrahydrofuran (100.000 mL) was added sodium hydride (3.344 g, 60% Wt, 3 Eq, 83.61 mmol) portion-wise. Mixture was stirred for 15 min at 0°C, followed by dropwise addition of iodomethane (11.87 g, 5.228 mL, 3 Eq, 83.61 mmol). The mixture was warmed to room temperature and stirred for 16h. Reaction was monitored using TLC (10% MeOH / DCM, KMnO4 stain). Mixture was quenched with sat NH4C1 (aq) and then extracted with DCM (3x). The combined organic extracts were dried over sodium sulfate and concentrated. Crude residue was purified by silica gel column with 0.1- 30% EtOAc / Hep for 20 column volumes using 214 nm detection to afford desired compound tert-butyl (R)-3-m ethoxy-3 -methylpiperidine- 1 -carboxylate (4.000g, 91% purity, 57% yield) as a clear oil.JH NMR (400 MHz, DMSO) 8 3.64 (dt, J= 13.6, 1.6 Hz, 2H), 3.09 (s, 3H), 2.82 (d, J= 13.0 Hz, 2H), 1.71 - 1.50 (m, 2H), 1.39 (s, 11H), 1.03 (s, 3H).

[0215] Step 3: To tert-butyl (R)-3-methoxy-3 -methylpiperidine- 1 -carboxylate (4.000 g, 1 Eq, 17.44 mmol) was added HC1 in dioxane (3.646 g, 25.000 mL, 4.000 molar, 5.733 Eq, 100.00 mmol). Mixture was stirred at room temperature for Ih and then concentrated to afford desired compound (R)-3-m ethoxy-3 - methylpiperidine, AA - Hydrochloride (Int 1, 2.860g, 95% purity, 94% yield) as a white solid.1H NMR (400 MHz, MeOD) 5 3.24 (s, 4H), 3.23 - 3.16 (m, IH), 2.97 - 2.83 (m, 2H), 2.07 (ddtd, J= 14.4, 4.2, 2.8, 1.5 Hz, IH), 1.90 (dtdd, J= 14.4, 13.3, 4.5, 3.8 Hz, IH), 1.77 - 1.67 (m, IH), 1.49 (ddd, J= 14.5, 13.3, 4.3 Hz, IH), 1.21 (s, 3H).

[0216]

[0165] Example 11 - Preparation of Intermediate 13: 2-((tert-butoxycarbonyl)amino)-2-(3-fluoro-l- methyl- 1 H-pyrazol-4-yl)acetic acid

[0217] Step 3 step 4

[0218]

[0166] int. 13 Docket No.: PAT059789-PCT-SEC01

[0219]

[0167] Step 1 : To a solution of ethyl 2-((diphenylmethylene)amino)acetate (1.25 g, 4.68 mmol) 4- bromo-3-fluoro-l-methyl-lH-pyrazole (0.92 g, 5.14 mmol) in Toluene (30 mL) was added K3PO4 (2.98 g, 14.03 mmol) and Pd(t-BusP)2 (0.24 g, 0.468 mmol) at 25°C under N2. Then the mixture was stirred at 100°C for 16 h. LCMS showed desired mass was detected. The reaction mixture was poured into H2O (50 mL) and the aqueous layer was extracted with EA (50mL*3). The combined organic phase was dried over Na2SC>4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) then concentrated to afford ethyl 2-((diphenylmethylene)amino)-2-(3-fluoro-l-methyl-lH- pyrazol-4-yl)acetate (250 mg, 60% purity) as a yellow oil. LCMS m z [M+H]+= 366.0.

[0220]

[0168] Step 2: To a solution of ethyl 2-((diphenylmethylene)amino)-2-(3-fluoro-l-methyl-lH- pyrazol-4-yl)acetate (250 mg, 0.41 mmol, 60% purity) in dioxane (2 mL) was added 4M HCl / dioxane (2 mL). The resulting mixture was stirred at 25°C for 4 h. LCMS showed desired mass was detected. The mixture was added H2O (4 mL) and then extracted with PE (4 mL*3), The aqueous phase (0.41 mmol, in H2O (4 mL)) was taken to the next step without further purification. The combined organic phase was discarded. LCMS m / z [M+H]+= 202.1.

[0221]

[0169] Step 3: To a mixture of ethyl 2-amino-2-(3-fluoro-l-methyl-lH-pyrazol-4-yl)acetate (0.41 mmol, in H2O (4 mL)) in THF (4 mL) was added NaHCCL (345 mg, 4.10 mmol) and BOC2O (179 mg, 0.82 mmol). The resulting mixture was stirred at 25°C for 16 h. LCMS showed desired mass was detected. The mixture was extracted with EA (15 mL*3). The combined organic was dried over anhydrous Na2SO4, filtered, and concentrated to give ethyl 2-((tert-butoxycarbonyl)amino)-2-(3- fluoro-l-methyl-lH-pyrazol-4-yl)acetate (200 mg, crude) as yellow oil. LCMS m / z [M-55]+= 246.2.

[0222]

[0170] Step 4: A solution of ethyl 2-((tert-butoxycarbonyl)amino)-2-(3-fluoro-l-methyl-lH-pyrazol- 4-yl)acetate (200 mg, Crude) in THF / MeOH / 4M NaOH=2: 1 : 1 (4 mL) was stirred at 40°C for 1 h. LCMS showed desired mass was detected. The reaction mixture was concentrated to give the residue. The residue was added H2O (4 mL) and extracted with PE (4 mL*3), The aqueous phase was adjusted PH~5 with IN HC1 and extracted with EA (5 mL*3). The combined organic was dried over anhydrous Na2SO4, filtered, and concentrated to give 2-((tert-butoxycarbonyl)amino)-2-(3-fluoro-l-methyl-lH-pyrazol- 4-yl)acetic acid (110 mg, crude) as yellow gum.

[0223]

[0171] Example 12 - Preparation of Intermediate #: potassium 2-((tert-butoxycarbonyl)amino)-2-(2.4- dimethylthiazol-5 -vDacetate Docket No.: PAT059789-PCT-SEC01

[0224] BQC2O, TEA, MeOH KOH, MeOH

[0225] 0.. rt, 10h rt, 8 h

[0226] Step 3

[0227]

[0172] Step 1: A solution of ammonium chloride (2.841 g, 1.5 Eq, 53.12 mmol) in Water (10.00 mL) was added to a solution of potassium cyanide (3.229 g, 1.4 Eq, 49.58 mmol) in ammonia hydroxide (3.616 g, 4.60 mL, 3 Eq, 106.2 mmol). To this mixture, a solution of 2,4-dimethylthiazole-5-carbaldehyde (5.000 g, 1 Eq, 35.41 mmol) in Methanol (10.00 mL) was added and left overnight. Then Methanol (10.00 mL) was evaporated under reduced pressure, and then the mixture was extracted with CH2Q2 (5x 30 ml). The combined organic layers were dried over Na2SC>4 and concentrated in vacuo to give crude 2- amino-2-(2,4-dimethylthiazol-5-yl)acetonitrile (6.810 g, 13 mmol, 38 %, 33% Purity), that was used in the next step without further purification. LCMS m / z 168 [M+H]+.

[0228]

[0173] Step 2: Crude compound 2-amino-2-(2,4-dimethylthiazol-5-yl)acetonitrile (6.410 g, 39% Wt, 1 Eq, 14.95 mmol) was dissolved in Methanol (60.00 mL), thionyl chloride (8.892 g, 5.455 mL, 5 Eq, 74.74 mmol) was added dropwise and then heated to 60 °C for 12 hours. Then the reaction mixture was cooled down and concentrated to obtain crude methyl 2-amino-2-(2,4-dimethylthiazol-5-yl)acetate hydrochloride (8.080 g, 13 mmol, 89 %, 39% Purity), which was used in next step without further purification. LCMS m / z = 658 [M-H]-. ‘H NMR (400 MHz, DMSO) 8 9.2 (s, 3H), 7.6 - 7.16 (m, 7H), 5.7 - 5.48 (m, 1H), 3.74 (s, 3H), 2.63 (s, 3H), 2.37 (s, 3H), 2.3 (d, J= 3.9 Hz, 1H).

[0229]

[0174] Step 3: BOC2O (3.039 g, 3.20 mL, 1.2 Eq, 13.93 mmol)was added portion wise at 0 °C to a mixture of methyl 2-amino-2-(2,4-dimethylthiazol-5-yl)acetate hydrochloride (8.080 g, 34% Wt, 1 Eq, 11.61 mmol) and TEA (2.936 g, 4.04 mL, 2.5 Eq, 29.01 mmol) in Methanol (25.00 mL), and the reaction mass was left to stir overnight at r.t. After 1 hr, the mixture was washed with water, dried over Na2SC>4, and concentrated in vacuo to give 8.1 g of crude product. After FC (Companion. 330g SiO2, Hex / thf from 0—100% (run length = 16 c.v.), flow rate=100 mL / min, Rv = 7,5-14CV, 70 / 20 eluents ratio), methyl 2- Docket No.: PAT059789-PCT-SEC01

[0230] ((tert-butoxycarbonyl)amino)-2-(2,4-dimethylthiazol-5-yl)acetate (1.850 g, 6.159 mmol, 53.07 %) was obtained.

[0231]

[0175] 'H NMR (500 MHZ,CDC13) 8 5.49 (d, J= 28.5 Hz, 2H), 3.74 (s, 3H), 2.61 (s, 3H), 2.42 (s, 3H), 1.42 (s, 9H).

[0232]

[0176] Step 4: To a solution of methyl 2-((tert-butoxycarbonyl)amino)-2-(2,4-dimethylthiazol-5- yl)acetate (1.850 g, 1 Eq, 6.159 mmol) in MeOH (30 ml), KOH (380.1 mg, 1.1 Eq, 6.775 mmol) was added. After 8 hours reaction mixture was reduced under vacuo to give potassium 2-((tert- butoxycarbonyl)amino)-2-(2,4-dimethylthiazol-5-yl)acetate (2.050 g, 5.6 mmol, 91 %, 89% Purity). LCMS: RT=0.967, m / z = 278[M+H]+.

[0233]

[0177] Example 13 - Preparation of Compound # 7: 3-((R)-l-(((R)-4-(((R)-2-((3R,5R)-3-methoxy-5- methylpiperidin- 1 -yl)- 1 -(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5.6, 7.8-tetrahydroquinazolin- 2-yl)(methyl)amino)propyl)bicvclo [1.1.1 Ipentane- 1 -carboxylic acid

[0234]

[0178] Step 1: To a solution of (R)-2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline (200.0 mg, 1

[0235] Eq, 716.4 pmol) and (R)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)-l-(l-methyl-lH-pyrazol-4- yl)ethan-l -amine (217.0 mg, 1.2 Eq, 859.7 pmol) in MeCN (2.000 mL) was added DIEA (277.8 mg, 374 pL, 3 Eq, 2.149 mmol). The mixture was stirred at 60°C for 16h. 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 give a residue. The crude residue was purified by reversed phase (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 25 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) after purification, the aqueous phase was basified by saturated NaHCO3 solution (20 mL) to pH=8-9 and extracted with EA (30 mL*3). The combined organic phase was dried over anhydrous Docket No.: PAT059789-PCT-SEC01

[0236] Na2SO4, filtered and concentrated to afford (R)-2-chloro-N-((R)-2-((3R,5R)-3-methoxy-5- methylpiperidin- 1 -yl)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)ethyl)-6-phenyl-5 ,6,7,8-tetrahydroquinazolin-4-amine (300.0 mg, 0.59 mmol, 82 %, 97% Purity) as yellow solid. LCMS: Rt = 0.465 min, [M+H]+ = 495.2, ‘H NMR (400 MHz, CHLOROFORM-d) 8 = 7.41 (d, J= 1.4 Hz, 2H), 7.35 - 7.30 (m, 2H), 7.26 - 7.21 (m, 2H), 6.01 (br d, J= 4.3 Hz, 1H), 5.21 - 5.11 (m, 1H), 3.84 (s, 3H), 3.30 (br d, J= 3.4 Hz, 1H), 3.OO (s, 4H), 2.87 - 2.80 (m, 2H), 2.79 - 2.60 (m, 5H), 2.43 - 2.28 (m, 2H), 2.18 - 2.11 (m, 1H), 2.00 - 1.90 (m, 1H), 1.90 - 1.74 (m, 3H), 1.11 - 1.02 (m, 1H), 0.93 - 0.76 (m, 4H).

[0237]

[0179] Step 2: To a solution of (R)-2-chloro-N-((R)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l-yl)-l- (l-methyl-lH-pyrazol-4-yl)ethyl)-6-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine (290.00 mg, 1 Eq, 585.78 pmol) in DCM (0.500 mL) was added methyl (R)-3-(l- (methylamino)propyl)bicyclo[l.l.l]pentane-l -carboxylate (410.76 mg, 3 Eq, 1.7573 mmol), the mixture was stirred at 130°C for 24h in a sealed tube. TLC (EA) showed a new spot (R=0.2) formed. LCMS showed desired mass was detected. The mixture was diluted with MeOH (1 mL). The mixture 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 - 50% in 15 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) after purification, the aqueous phase was basified by saturated NaHCO3 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 give a residue. Then the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of EA: PE=0~100%) and concentrated to afford: methyl 3-((R)-l-(((R)-4-(((R)-2- ((3R,5R)-3 -m ethoxy-5 -methylpiperidin- 1 -yl)- 1 -(1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl- 5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)bicyclo[l.l.l]pentane-l-carboxylate (80.00 mg, 122 pmol, 20.8 %, 100% Purity) as yellow solid. LCMS: Rt = 0.910 min, [M+H]+ =656.5.

[0238]

[0180] Step 3: To a solution of methyl 3-((R)-l-(((R)-4-(((R)-2-((3R,5R)-3-methoxy-5-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)bicyclo[l. l.l]pentane-l -carboxylate (80.00 mg, 1 Eq, 122.0 pmol) in THF (1.000 mL) and MeOH (0.500 mL) was added NaOH (48.79 mg, 304.9 pL, 4.000 molar, 10 Eq, 1.220 mmol). Then the reaction mixture was stirred at 40°C for 0.5 h. LCMS showed a major peak of desired mass. The mixture was adjusted to pH=8 by IM citric acid and then concentrated under vacuum to remove MeOH / THF. The residue was dissolved with EtOH (0.5 mL) to get a mixture. The mixture was purified by reversed phase column chromatography (80 g of SepaFlash® Spherical 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: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) then lyophilized to afford 3 -((R)- 1 -(((R)-4-(((R)-2-((3R,5R)-3 -m ethoxy-5 -methylpiperidin- 1 -yl)- 1 -( 1 -methyl- 1 H-pyrazol-4- Docket No.: PAT059789-PCT-SEC01 yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)bicyclo[l.l.l]pentane- 1-carboxylic acid (47.27 mg, 73.65 pmol, 60.38 %, 100.00% Purity) as white solid LCMS m / z [M+H]+= 642.5,1H NMR (400 MHz, DMSO-d6 ) 8 = 7.49 (s, 1H), 7.36 - 7.29 (m, 5H), 7.24 - 7.19 (m, 1H), 6.25 - 6.16 (m, 1H), 5.48 - 5.18 (m, 1H), 4.90 - 4.73 (m, 1H), 3.74 (s, 3H), 3.09 (s, 3H), 2.92 - 2.83 (m, 1H), 2.79 (s, 4H), 2.65 - 2.53 (m, 6H), 2.32 - 2.16 (m, 2H), 1.98 - 1.55 (m, 12H), 1.53 - 1.42 (m, 2H), 1.19 - 1.09 (m, 1H), 0.83 - 0.77 (m, 3H), 0.76 - 0.69 (m, 3H).

[0239]

[0181] 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.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01

[0240] Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01

[0241] Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01

[0242]

[0182] Example 14 - Preparation of intermediate 14: tert-butyl (lR,4r)-4-((R)-l-(methyl((R)-6-phenyl-4-

[0243] (((trifluoromcthyl )sulfonyl )o xy )-5.6.7.8-tctrahvdroquinazolin-2-yl )amino)propyl )cvclohcxanc- 1 - carboxylate Docket No.: PAT059789-PCT-SEC01

[0244]

[0183] 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]+= 260.9,1H 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).

[0245]

[0184] 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.

[0246]

[0185] 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-tetrahydroquin azolin -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= 7.8 Hz, 3H), 1.89 (br d, Docket No.: PAT059789-PCT-SEC01

[0247] 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),

[0248] 0.88 - 0.81 (m, 3H).

[0249]

[0186] Example 15 - Preparation of Compound #31: (!R,4r)-4-((lR)-l-(((6R)-4-((2-((S)-3- cvanopiperidin- 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

[0250]

[0187] 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, Docket No.: PAT059789-PCT-SEC01 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.NaHCOs (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.JH NMR (400 MHz, DMSO-d6) 8 = 7.62 (s, 1H), 7.36 (s, 1H), 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).

[0251]

[0188] 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)+

[0252]

[0189] 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

[0253] ( 1 R,4r)-4-((R)- 1 -(((R)-4-(((R)-2-(methoxy(methyl)amino)- 1 -( 1 -methyl- 1 H-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 a yellow 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).

[0254]

[0190] 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 Docket No.: PAT059789-PCT-SEC01

[0255] (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 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 (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 (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)+.

[0256]

[0191] 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 (180.0 mg, 299.6 pmol) and (S)-piperidine-3 -carbonitrile hydrochloride (82.27 mg, 449.4 pmol), were dissolved in DCM (420 mkl). Then acetic acid (18 mg, 299.6 pmol) was added. Then sodium bis (acetyloxy )boranuidyl acetate (94.8 mg, 449.4 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-(((6R)-4-((2-((S)-3-cyanopiperidin-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 (170 mg, 244.6 umol, 81% yield). It was used in the next step without further purification. LCMS m / z = 695.6 (M+H)+.

[0257]

[0192] Step 6: A tert-butyl (lR,4r)-4-((lR)-l-(((6R)-4-((2-((S)-3-cyanopiperidin-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 (170.0 mg, 244.6 pmol) was dissolved in DCM (2 ml). Then 4M HCl*dioxane (1.22 ml, 4.88 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 was purified by pHPLC (EEO / MeCN+NEE) to give ( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-((S)-3 -cyanop iperidin- 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 (19 mg, 0.029 mmol, 12% yield) as white solid. LCMS m / z [M+H]+ = 639.6, 1H NMR (400 MHz, MeOD) 8 7.58 (s, 1H), 7.43 (s, 1H), 7.39 - 7.29 (m, 4H), 7.27 - 7.18 (m, 1H), 5.51 (s, 1H), 4.48 (s, 1H), 3.84 (s, 3H), 3.09 - 2.63 (m, 12H), 2.60 (d, J = 12.6 Docket No.: PAT059789-PCT-SEC01

[0258] Hz, 2H), 2.31 (s, 1H), 2.18 - 1.89 (m, 6H), 1.82 (s, 2H), 1.74 - 1.22 (m, 8H), 1.16 - 0.78 (m, 3H), 0.65 (s, 2H).

[0259]

[0193] The following compounds were made using the above procedure or modifications to the above procedure using the corresponding intermediates. Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01

[0260]

[0194] Example 16 - Preparation of Compound 20 : (lR,4r)-4-((R)-l-(((R)-4-(((R)-l-(l-(2-ethoxy-2- oxoethyl)-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5.6.7.8- tetrahvdroquinazolin-2-yl)(methyl)amino)propyl)cvclohexane- 1 -carboxylic acid

[0261]

[0195] Step 1: 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 (400.00 mg, 1 Eq, 653.89 pmol)in ACN (2.000 mL) was added ethyl 2-(4-(l-amino-2-((S)-3- methylpiperidin-l-yl)ethyl)-lH-pyrazol-l-yl)acetate (360.95 mg, 80% Wt, 1.5 Eq, 980.84 pmol)and DIEA (253.55 mg, 342 pL, 3 Eq, 1.9617 mmol). Then the mixture was stirred at 60 °C for 50 hour. LCMS showed desired mass was detected. The reaction mixture was combined with another batch to work-up. The combined organic phase was 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 25 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 NaHCO3 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,4r)-4-((lR)-l-(((6R)-4-((l-(l-(2-ethoxy-2-oxoethyl)-lH-pyrazol-4- yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (210.0 mg, 0.27 mmol, 42 %, 99% Purity) as yellow oil. LCMS: Rt =0.486min, [M+H] =756.5. The mixture was purified Chiral-HPLC Separation (Instrument: CASWH-PREP-HPLC-J; DAICEL CHIRALPAK IC (250mm*30mm, lOum), Condition: Hexane-EtOH(0.1%NH3H2O), Begin B: 5, End B: 5; Gradient Time(min): 4.2; FlowRate(ml / min): 120) and then concentrated to get the crude of Pl and P2. The crudes were 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 - 80% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm), after purification, then concentrated to remove organic Docket No.: PAT059789-PCT-SEC01 solvents and lyophilized to give the desired peak 2 isomer tert-butyl (lR,4r)-4-((R)-l-(((R)-4-(((R)-l-(l- (2-ethoxy-2-oxoethyl)-lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l-carboxylate (80.00 mg, 105.2 n mol, 37.88 %, 99.43% Purity) as yellow gum. LCMS: Rt =1.169min, [M+H] =756.5.

[0262]

[0196] Step 2: A solution of tert-butyl (lR,4r)-4-((R)-l-(((R)-4-(((R)-l-(l-(2-ethoxy-2-oxoethyl)-lH- pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (80.000 mg, 1 Eq, 105.81 pmol) in 2M HCl / dioxane (1.000 mL) was stirred at 25 °C for 30 min. LCMS showed desired mass was detected. The reaction mixture was dried by N2 flow, added H2O (20 mL) to give the mixture. The mixture was lyophilized to give (lR,4r)-4-((R)-l-(((R)-4-(((R)-l-(l-(2-ethoxy-2-oxoethyl)-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylic acid (69.29 mg, 93.31 pmol, 88.18 %, 94.257% Purity) as white solid. LCMS m / z [M+H]+= 700.6, ’H NMR (400 MHz, DMSO-d6 ) 8 = 7.85 - 7.71 (m, 1H), 7.58 - 7.51 (m, 1H), 7.42 - 7.32 (m, 4H), 7.30 - 7.21 (m, 1H), 6.01 - 5.93 (m, 1H), 4.98 (s, 2H), 4.20 - 4.09 (m, 2H), 3.86 - 3.73 (m, 1H), 3.48 - 3.24 (m, 3H), 3.03 - 2.92 (m, 6H), 2.90 - 2.77 (m, 2H), 2.64 - 2.55 (m, 1H), 2.49 - 2.45 (m, 1H), 2.41 - 2.30 (m, 1H), 2.25 - 2.05 (m, 3H), 1.99 - 1.71 (m, 8H), 1.59 - 1.38 (m, 3H), 1.35 - 1.18 (m, 5H), 1.15 - 1.02 (m, 2H), 0.97 - 0.84 (m, 3H), 0.81 - 0.58 (m, 4H)

[0263]

[0197] Example 17 - Preparation of Compound 19: (lR,4r)-4-((R)-l-(((R)-4-(((R)-l-(3-(2-ethoxy-2- oxoethoxy)-! -methyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5.6,7,8- tetrahvdroquinazolin-2-yl)(methyl)amino)propyl)cvclohexane- 1 -carboxylic acid

[0264] Docket No.: PAT059789-PCT-SEC01

[0265]

[0198] Step 1: To a solution of 4-bromo-l -methyl- lH-pyrazol-3-ol 1 (5.0 g, 1 Eq, 28 mmol) and K2CO3 (5.9 g, 1.5 Eq, 42 mmol) in DMF (50.000 mL) was addedBenzyl bromide (5.8 g, 4.0 mL, 1.2 Eq, 34 mmol). The reaction mixture was stirred at 25°C for 10 min. The reaction mixture was stirred at 50°C for 12 h. TLC (PE: EA=5: 1) showed a new spot (Rf =0.6) formed. LCMS showed 67% of desired mass. The reaction mixture was diluted with water (150 mL) and extracted with EA (100 mL*3). And the combined organic extracts were washed with sat.NaCl solution (10 mL*3), dried over NaSO4, filtered and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel Docket No.: PAT059789-PCT-SEC01

[0266] (eluent: PE to EA =100:0 to 60:40; a 120 g Redisep Silver column via liquid injection) to give 3- (benzyloxy)-4-bromo-l -methyl- IH-pyrazole (7.000 g, 26.20 mmol, 93 %, 100.00% Purity) as a white oil. LCMS: Rt= 0.547 min, [M+H] = 269.0.

[0267]

[0199] Step 2: To a solution of 3-(benzyloxy)-4-bromo-l-methyl-lH-pyrazole (6.000 g, 1 Eq, 22.46 mmol) and ethyl 2-((diphenylmethylene)amino)acetate (7.205 g, 1.2 Eq, 26.95 mmol) in Toluene (90.00 mL) was added Potassium phosphate, tribasic (14.30 g, 5.578 mL, 3 Eq, 67.38 mmol) and Bis[tris(tert- butyl)phosphine]palladium, 20.9% Pd (1.148 g, 0.1 Eq, 2.246 mmol) at 25°C under N2 for 5min. Then the mixture was stirred at 100°C for 12h. LCMS showed 28% of desired mass. TLC (PE: EA=5:1) showed a new spot (Rf=0.2) formed. The reaction mixture was combined with pilot batch to workup. The mixture was poured into H2O (200 mL) and extracted with EA (200mL*3). The combined organic phase was dried over Na2SO4, filtered and concentrated to afford the residue. The residue was purified by flash silica gel

[0268]

[0200] Chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0-50% EA / PE) and the eluent was concentrated to give: ethyl 2-(3-(benzyloxy)-l-methyl-lH-pyrazol-4-yl)-2- ((diphenylmethylene)amino)acetate (4.000 g, 8.574 mmol, 38.17 %, 97.219% Purity) as ayellow oil. LCMS: Rt = 0.753 min, [M+H] = 454.2, ‘H NMR (400 MHz, DMSO-d6) 8 = 7.60 (s, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.36 (m, 6H), 7.35 - 7.26 (m, 5H), 7.11 - 7.06 (m, 2H), 5.08 (s, 2H), 4.95 (s, 1H), 4.05 - 4.00 (m, 2H), 3.68 (s, 3H), 1.14 - 1.08 (m, 3H).

[0269] Step 3: To a solution of ethyl 2-(3-(benzyloxy)-l-methyl-lH-pyrazol-4-yl)-2- ((diphenylmethylene)amino)acetate (4.000 g, 1 Eq, 8.820 mmol) in 1,4-Dioxane (10.00 mL) and Water (10.00 mL) was added HC1, 1,4-dioxane (9.966 g, 40.00 mL, 2.000 molar, 9.071 Eq, 80.00 mmol). The resulting mixture was stirred at 25°C for 3 h. LCMS showed desired mass was detected. The mixture was added H2O (30 mL) and then extracted with PE (30 mL*3), aqueous phase ethyl 2-amino-2-(3-(benzyloxy)- 1 -methyl- lH-pyrazol-4-yl)acetate Hydrochloride, water as a 8.820 mmol in water (10 mL) was used to next step directly. The combined organic phase was discarded. LCMS: Rt =0.387 min, [M-NH2] = 273.1.

[0270]

[0201] Step 4: To a solution of ethyl 2-amino-2-(3 -(benzyloxy)- 1 -methyl- lH-pyrazol-4-yl)acetate Hydrochloride, water (2.500 g, 824.4 mL, 8.820 mmolar, 1 Eq, 7.271 mmol) in THF (30.00 mL) was added Sodium bicarbonate (12.22 g, 5.66 mL, 20 Eq, 145.4 mmol)and boc2o (3.174 g, 3.34 mL, 2 Eq, 14.54 mmol). The resulting mixture was stirred at 25°C for 12 h. LCMS showed a major peak of desired mass. The mixture was extracted with EA (100 mL*3). The combined organic phase was separated then dried over anhydrous Na2SO4, filtered and concentrated to give ethyl 2-(3-(benzyloxy)-l-methyl-lH- pyrazol-4-yl)-2-((tert-butoxycarbonyl)amino)acetate (3.000 g, 7.2 mmol, 99 %, 93% Purity) crude product as yellow oil. The crude product was used for next step directly without further purification. LCMS: Rt =0.570 min, [M+H] =390.2. Docket No.: PAT059789-PCT-SEC01

[0271]

[0202] Step 5: To a solution ethyl 2-(3-(benzyloxy)-l-methyl-lH-pyrazol-4-yl)-2-((tert- butoxycarbonyl)amino)acetate (3.000 g, 85% Wt, 1 Eq, 6.548 mmol) in THF (10.00 mL) and MeOH (5.000 mL) was added NaOH, water (2.321 g, 10.00 mL, 4.000 molar, 6.109 Eq, 40.00 mmol). The mixture was stirred at 40°C for 2h. LCMS showed a major peak of desired mass was detected. The reaction mixture was concentrated to give the residue, the residue was extracted with EA (50 mL*2). The organic phase was discarded and the aqueous phase was adjusted PH~5 with 2N HC1 (10 mL) and concentrated to give the mixture. The mixture was extracted with EA (30 mL*3). The combined organic phase was dried by anhydrous Na2SO4, filtered and concentrated to afford: 2-(3 -(benzyloxy)- 1-methyl- lH-pyrazol-4-yl)-2-((tert-butoxycarbonyl)amino)acetic acid (2.000 g, 5.5 mmol, 84 %, 99% Purity) as yellow oil. LCMS: Rt =0.497 min, [M+H] =362.1.

[0272]

[0203] Step 6: To a mixture of 2-(3-(benzyloxy)-l-methyl-lH-pyrazol-4-yl)-2-((tert- butoxycarbonyl)amino)acetic acid (1.500 g, 1 Eq, 4.151 mmol) and (S)-3 -methylpiperidine hydrochloride (494.0 mg, 1.2 Eq, 4.981 mmol) in DCM (15.000 mL) was added Et3N (1.260 g, 1.74 mL, 3 Eq, 12.45 mmol) and then T3P (5.981 g, 50% Wt, 2 Eq, 8.301 mmol, 163755-62-2) was added to the mixture at 0°C. The mixture was stirred at 0°C for 1 h. LCMS showed 70% of desired mass was detected. The mixture was adjusted to pH~10 with sat. NaHCO3 (30 mL) solution and diluted with H O (10 mL), then extracted with DCM (50 mL*3). The organic phase was washed with Sat.NaCl (30 mL), the organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give the residue. The residue was combined with pilot batch to purify, the mixture was purified by reversed phase column chromatography (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 20 min, flow rate: 80 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) and then adjust to pH~8 with sat. NaHCO3 solution (30 mL), extracted with EA (40 mL*3), washed with sat. NaCl (30 mL), Then the organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give tert-butyl (l-(3-(benzyloxy)-l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)-2-oxoethyl)carbamate (2.200 g, 4.962 mmol, 119.6 %, 99.823% Purity) as yellow oil. LCMS: Rt =0.600 min, [M+H] = 443.2.

[0273]

[0204] Step 7: To a solution of tert-butyl (1 -(3 -(benzyloxy)- 1 -methyl- lH-pyrazol-4-y l)-2-((S)-3- methylpiperidin-l-yl)-2-oxoethyl)carbamate (2.400 g, 1 Eq, 5.423 mmol) in THF (50.00 mL) was added BH3.DMS (4.119 g, 5.423 mL, 10.00 molar, 10 Eq, 54.23 mmol) at 0°C under N2 for lOmin. Then the mixture was stirred 20°C for 16 h. LCMS showed 63% of desired mass. The reaction mixture was slowly quenched with MeOH (100 mL) until no bubbles released. The mixture was stirred for 2h at 60°C and then concentrated to afford tert-butyl (l-(3-(benzyloxy)-l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)carbamate (2.000 g, 2.9 mmol, 54 %, 63% Purity) as a white oil which was used for next step without further purification. LCMS: Rt =0.487 min, [M+H] = 429.4. Docket No.: PAT059789-PCT-SEC01

[0274]

[0205] Step 8: To a solution of tert-butyl (1 -(3 -(benzyloxy)- 1 -methyl- lH-pyrazol-4-y l)-2-((S)-3- methylpiperidin-l-yl)ethyl)carbamate (1.000 g, 63% Wt, 1 Eq, 1.470 mmol) in MeOH (20.00 mL) was added Pd-C (1.000 g, 10% Wt, 0.6392 Eq, 939.7 pmol) at 25°C under H2 (15 Psi). Then the reaction mixture was stirred at 25°C for 12h. LCMS (WXW-YWANG1-100- EXP069-P1A) showed SM was consumed and a major peak of desired mass. The reaction mixture was filtered through a pad of Celite and washed with MeOH (100 mL*2), the filter was concentrated under vacuum to get tert-butyl (l-(3- hydroxy-l-m ethyl- lH-pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)carbamate (550.0 mg, 1.4 mmol, 95 %, 86% Purity) as white oil. LCMS: Rt =0.391 min, [M+Na]+ = 339.4.

[0275]

[0206] Step 9: To a solution of tert-butyl (l-(3-hydroxy-l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)carbamate (500.0 mg, 80% Wt, 1 Eq, 1.182 mmol) in DCM (2.000 mL) was added HC1, 1,4-dioxane (1.246 g, 5.000 mL, 2.000 molar, 8.461 Eq, 10.00 mmol) at 25°C under N2. The mixture was stirred 25°C for 1 h. LCMS (WXW-YWANG1-100-EXP098-P1A) showed 70% of desired mass was detected. The reaction mixture was concentrated to afford: 4-(l-amino-2-((S)-3- methylpiperidin-l-yl)ethyl)-l -methyl- lH-pyrazol-3-ol (450.0 mg, 1.1 mmol, 97 %, 70% Purity) as yellow oil and it was used for next step directly. LCMS: Rt =0.166 min, [M+H] = 239.1.

[0276]

[0207] Step 10: To a solution of (R)-2,4-dichloro-6-phenyl-5,6,7,8-tetrahydroquinazoline (260.000 mg, 1 Eq, 931.37 pmol) in MeCN (5.000 mL) was added DIEA (601.89 mg, 811 pL, 5 Eq, 4.6568 mmol) and 4- (l-amino-2-((S)-3-methylpiperidin-l-yl)ethyl)-l-m ethyl- lH-pyrazol-3-ol (438.74 mg, 70% Wt, 1.2 Eq, 1.1176 mmol). The mixture was stirred at 60°C for 12h. LCMS showed 38% of desired mass was detected and 19% of SM remained. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (15 mL*3). And the combined organic extracts were washed with saturated NaCl. aq (15 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The crude 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 aqueous phase was basified by saturated NaHCO3 solution (30 mL) to pH=8-9 and extracted with EA (30 mL*3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford 4-(l-(((R)-2-chloro-6- phenyl-5,6,7,8-tetrahydroquinazolin-4-yl)amino)-2-((S)-3 -methylpiperidin- 1 -yljethyl)- 1 -methyl- 1H- pyrazol-3-ol (400.0 mg, 831.5 pmol, 89.28 %, 100.00% Purity) as yellow oil. LCMS: Rt = 0.448 min, [M+H] = 481.2,1H NMR (400 MHz, DMSO-d6) 8 = 11.95 (br s, 1H), 7.38 - 7.32 (m, 4H), 7.27 - 7.17 (m, 2H), 7.17 - 7.08 (m, 1H), 5.45 - 5.31 (m, 1H), 3.51 (d, J= 0.6 Hz, 3H), 3.10 - 2.90 (m, 2H), 2.85 - 2.62 (m, 5H), 2.44 - 2.30 (m, 1H), 2.12 - 2.01 (m, 1H), 1.90 (br s, 2H), 1.81 - 1.37 (m, 6H), 0.94 - 0.79 (m, 4H). Docket No.: PAT059789-PCT-SEC01

[0277]

[0208] Step 11: To a solution of 4-(l-(((R)-2-chloro-6-phenyl-5,6,7,8-tetrahydroquinazolin-4-yl)amino)- 2-((S)-3-methylpiperidin-l-yl)ethyl)-l-m ethyl- lH-pyrazol-3-ol (400.0 mg, 1 Eq, 831.5 pmol) and Cs2CO3 (812.8 mg, 3 Eq, 2.495 mmol) in DMF (4.000 mL) was added ethyl 2-bromoacetate (166.6 mg, 1.2 Eq, 997.8 pmol). The mixture was stirred 100°C for 0.5h. LCMS showed a major peak of desired mass was detected. The reaction mixture was quenched by H2O (10 mL) and extracted with EA (10 mL*3) and the combined organic extracts were washed with sat.NaCl solution (10 mL*3), dried over NaSO4, filtered and concentrated to give a 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 - 100% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm) after purification, the aqueous phase was basified by saturated NaHCO3 solution (15 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: ethyl 2-((4-(l-(((R)-2-chloro-6-phenyl-5,6,7,8- tetrahydroquinazolin-4-yl)amino)-2-((S)-3-methylpiperidin-l-yl)ethyl)-l-methyl-lH-pyrazol-3- yl)oxy)acetate (350.0 mg, 0.57 mmol, 68 %, 92% Purity) as yellow solid. LCMS: Rt = 0.498 min, [M+H] = 567.2, ’H NMR (400 MHz, DMSO-d6) 8 = 7.40 (d, J= 15.5 Hz, 1H), 7.37 - 7.30 (m, 4H), 7.27 - 7.20 (m, 1H), 6.91 - 6.84 (m, 1H), 5.43 - 5.24 (m, 1H), 4.80 - 4.62 (m, 2H), 4.12 - 4.02 (m, 2H), 3.58 (s, 3H), 2.98 - 2.83 (m, 2H), 2.78 - 2.59 (m, 5H), 2.40 - 2.29 (m, 1H), 1.99 - 1.80 (m, 3H), 1.61 - 1.44 (m, 3H), 1.40 - 1.18 (m, 3H), 1.18 - 1.13 (m, 3H), 0.86 - 0.74 (m, 4H).

[0278]

[0209] Step 12: To a solution of ethyl 2-((4-(l-(((R)-2-chloro-6-phenyl-5,6,7,8-tetrahydroquinazolin-4- yl)amino)-2-((S)-3-methylpiperidin-l-yl)ethyl)-l-methyl-lH-pyrazol-3-yl)oxy)acetate (350.00 mg, 1 Eq, 617.14 pmol) in DCM (2.000 mL) was added tert-butyl (lR,4r)-4-((R)-l- (methylamino)propyl)cyclohexane-l -carboxylate (472.85 mg, 3 Eq, 1.8514 mmol) in a 5 mL microwave tube equipped with a stir-bar. Then the mixture was concentrated under vacuum to remove DCM and the tube was filled with nitrogen before it was capped. The residue was heated to 120°C (oil bath) and stirred for 18h under N2. LCMS showed 45% of desired mass was detected. The reaction mixture was dissolved in EtOH (3 mL) to give a mixture. The mixture 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 - 80% in 20 min, flow rate: 60 mL / min; column temperature: RT, wavelength: 220 nm / 254 nm), after purification, then concentrated to remove MeCN and lyophilized to give tert-butyl (lR,4r)-4-((lR)-l-(((6R)-4-((l-(3-(2-ethoxy-2-oxoethoxy)-l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (150.0 mg, 190.8 pmol, 30.92 %) as crude product as a yellow solid. LCMS: Rt =0.516 min, [M+H] =786.5. Docket No.: PAT059789-PCT-SEC01

[0279]

[0210] Step 13: A solution of tert-butyl (lR,4r)-4-((lR)-l-(((6R)-4-((l-(3-(2-ethoxy-2-oxoethoxy)-l- methyl- 1 H-pyrazol-4-yl)-2-((S)-3 -methylpiperidin- 1 -yl)ethyl)amino)-6-phenyl-5 ,6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l-carboxylate (125.0 mg, 1 Eq, 159.0 pmol) (crude) in DCM (1.500 mL) was added TFA (0.300 mL). The mixture was stirred 25°C for 0.5 h. LCMS showed two peaks of desired mass was detected. The reaction mixture was concentrated to remove the DCM and adjust pH~8 by saturated NaHCO3 aqueous solution (2 mL) to get a mixture. The mixture was purified by reversed phase column chromatography (Instrument: CASWH-GX-AR, Method: Column Waters Xbridge 150*25mm* 5um, Condition: water (NH4HCO3)-MeCN, Begin B: 40, End B: 70, Gradient Time (min): 9, 100%B Hold Time (min): 2, FlowRate (ml / min): 25.), after Prep-HPLC purification, and then concentrated to remove MeCN and lyophilized to give peak 2 isomer (lR,4r)-4- ((R)- 1 -(((R)-4-(((R)- 1 -(3 -(2-ethoxy-2-oxoethoxy)- 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 -methylpiperidin- 1 - yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l- carboxylic acid (10.26 mg, 14.06 pmol, 8.839 %, 100.00% Purity) as a white solid. LCMS m / z [M+H]+= 730.6,1H NMR (400 MHz, DMSO-d6 ) 8 = 12.28 - 11.58 (m, 1H), 7.40 - 7.27 (m, 5H), 7.26 - 7.18 (m, 1H), 6.24 - 5.83 (m, 1H), 5.42 - 5.21 (m, 1H), 4.80 - 4.63 (m, 2H), 4.59 - 4.47 (m, 1H), 4.13 - 3.99 (m, 2H), 3.57 (s, 3H), 2.94 - 2.85 (m, 2H), 2.83 - 2.70 (m, 4H), 2.68 - 2.54 (m, 4H), 2.34 - 2.24 (m, 1H), 2.05

[0280] - 1.97 (m, 1H), 1.95 - 1.77 (m, 5H), 1.76 - 1.48 (m, 6H), 1.45 - 1.21 (m, 6H), 1.18 - 1.07 (m, 4H), 1.01 - 0.89 (m, 1H), 0.86 - 0.76 (m, 4H), 0.74 - 0.54 (m, 4H)

[0281]

[0211] Example 18 - Preparation of Compound 18 (lR,4r)-4-((lR)-l-((6-cvclohexyl-4-(((R)-l-(l- methyl- 1 H-pyrazol-4-yl)-2-(( S)-3 -methylpiperidin- 1 -yl)ethyl)amino)-5 ,6,7,8 -tetrahydroquinazolin-2-

[0282] Docket No.: PAT059789-PCT-SEC01 yl)(methyl)amino)propyl)cvclohexane-l -carboxylic acid

[0283]

[0212] Step 1: To a stirred suspension of NaH (887.5 mg, 60% Wt, 1.6 Eq, 22.186 mmol) in acetonitrile (20.000 mL), dimethyl carbonate (6.245 g, 5.84 mL, 5 Eq, 69.333 mmol) was added drop wise. The resulting mixture was heated to 80 °C and then [l,T-bi(cyclohexan)]-4-one (2500.00 mg, 1 Eq, 13.867 mmol) was added dropwise. The mixture was stirred at this temperature for 3 hr. The reaction mixture was cooled to room temp, and quenched with saturated aqueous NH4C1 solution at 0 °C and then extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated to get crude product, which was purified with flash column chromatography on silica gel. The desired product was eluted using 0-20% ethyl acetate in heptane. The pure fractions were collected and concentrated under reduced pressure to get methyl 3-oxo-[l,l'-bi(cyclohexane)]-4- carboxylate (2.900 g, 12.17 mmol, 87.75 %) as a white solid. LCMS: m / z = 239.4 [M+H]+.

[0284]

[0213] Step 2: To a solution of methyl 3-oxo-[l,l'-bi(cyclohexane)]-4-carboxylate (280.00 mg, 1 Eq, 939.87 pmol) in acetonitrile (10.00 mL) was added methyl (lR,4r)-4-((R)-l-(l- methylguanidino)propyl)cyclohexane-l -carboxylate hydrochloride salt (0.190 molar in acetonitrile, 301.70 mg, 5.4414 mL, 1.1 Eq, 1.0339 mmol) and then DBU (572.35 mg, 566.7 pL, 4 Eq, 3.7595 mmol)) at 20°C. After addition, the mixture was stirred at 80°C for 2 h. LC-MS showed the most of start Docket No.: PAT059789-PCT-SEC01 materials was converted into the desired product. After concentrated to dryness, the residue was purified with flash column chromatography on silica gel. The desired product was eluted using 0-100% ethyl acetate / heptane. The pure fractions were collected and concentrated under reduced pressure to get product methyl (1 R,4r)-4-((l R)- 1 -((6-cyclohexyl-4-hydroxy-5 ,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (260.0 mg, 586.1 pmol, 62.36 %). LCMS: m / z = 444.2 [M+H]+.

[0285]

[0214] Step 3: Racemic methyl (lR,4r)-4-((lR)-l-((6-cyclohexyl-4-hydroxy-5, 6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l-carboxylate (260.0 mg, 586.1 pmol) was resolved by chiral SFC (ColumnTek EnantioCel® C4-5, 250 (L) x 4.6 (ID) mm, Flowrate: 2 ml / min, CoSolvent: 40% EtOH with 0.1% diethylamine, Outlet Pressure: 100 bar) to afford 120.0 mg, 99.7% ee of peakl and 132 mg, 97.5% ee of 132 mg of peak 2. Absolute stereochemistry was not determined.

[0286]

[0215] Step 4: To a solution of above methyl (lR,4r)-4-((lR)-l-((6-cyclohexyl-4-hydroxy-5, 6,7,8- tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l-carboxylate, peak 2 (130 mg, 293 umol) in DCM (10.000 mL) was added DIPEA (113.63 mg, 153 pL, 3 Eq, 879.11 pmol) and Tf2O (99.209 mg, 351.64 pL, 1.000 molar in DCM, 351.64 pmol) at 0°C, after addition, the mixture was stirred at 20°C for 1 hr. LCMS showed starting material was consumed and desired molecular weight was detected. The reaction mixture was added FEO and then extracted with DCM, the combined organic phase was washed with brine, dried by NazSCU, filtered and concentrated to get the crude product. The crude product was purified by column chromatography on silica gel (eluted with 0-10 % EtOAc in Heptane) to give methyl (lR,4r)-4-((lR)-l-((6-cyclohexyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (150 mg, 89%) as a white solid. LCMS m / z [M+H]+ = 576.5.

[0287]

[0216] Step 5: To a solution of methyl (lR,4r)-4-((lR)-l-((6-cyclohexyl-4- (((trifluoromethyl)sulfonyl)oxy)-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l- carboxylate (100.000 mg, 1 Eq, 173.70 pmol) and (R)-l-(l-methyl-lH-pyrazol-4-yl)-2-((S)-3- methylpiperidin-l-yl)ethan-l -amine (57.932 mg, 1.5 Eq, 260.56 pmol) in Acetonitrile (2.000 mL) was added DIPEA (179.61 mg, 242 pL, 8 Eq, 1.3896 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 HzO (10 mL) and then extracted with EA (10 mL*3), the combined organic phase was washed with brine (10 mL), dried by NazSCL. filtered and concentrated to get the crude product methyl (lR,4r)-4-

[0288] ((1 R)- 1 -((6-cyclohexyl-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)cyclohexane-l-carboxylate. The crude product was used to next step without further purification. LCMS m / z [M+H]+ = 648.5. Docket No.: PAT059789-PCT-SEC01

[0289]

[0217] Step 6: To a solution of crude methyl (lR,4r)-4-((lR)-l-((6-cyclohexyl-4-(((R)-l-(l-methyl-lH- pyrazol-4-yl)-2-((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane-l -carboxylate (112 mg, 173 umol) in THF (1 mL) and MeOH (0.5) was added NaOH (4N aq solution) (0.13 mL, 0.52 mmol). The resulting suspension was stirred 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-((lR)-l-((6-cyclohexyl-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 (31 mg, 27%) as a white solid. LCMS m / z [M+H]+ = 634.5, ‘ H NMR (400 MHz, MeOD) 8 7.43 (s, 1H), 7.31 (s, 1H), 5.30-5.25 (m, 1H) 4.38-4.33 (m, 1H), 3.76 (s, 3H), 2.95 - 2.69 (m, 6H), 2.67 - 2.27 (m, 4H), 2.08 - 1.52 (m, 17H), 1.50 - 0.93 (m, 14H), 0.91 - 0.53 (m, 9H).

[0290]

[0218] The following compound was made using the above procedure using the above methyl (lR,4r)-4- ((lR)-l-((6-cyclohexyl-4-hydroxy-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylate, peak 1

[0291]

[0219] Example 19 - Biological assay - Cellular cGMP Production

[0292]

[0220] 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 Docket No.: PAT059789-PCT-SEC01 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:

[0293] Ratio = [(A665imi / B620imi)* 104]

[0294] Mean Ratio = (Sratios / 2) CV = [(Std deviation / Mean ratio)* 100] Delta F = [((Calibrator or sample Ratio - Rationeg) / Rationeg)*100] Rationeg: negative control

[0295]

[0221] 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.

[0296] Table 1 : In vitro functional data Docket No.: PAT059789-PCT-SEC01 Docket No.: PAT059789-PCT-SEC01

[0297] *ND = not determined

[0298] Equivalents

[0299]

[0222] 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.: PAT059789-PCT-SEC01CLAIMSWhat is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof wherein:R1is selected from H and (Ci-Ce)alkyl;R2is phenyl optionally substituted with 1 or 2 substituents selected from halo;R3is H or (Ci-Ce)alkyl;R4is a 5-membered heteroaryl comprising 2 heteroatoms selected from N, 0, and S, substituted with one or two substituents independently selected from (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (Ci-C6)haloalkoxy, and a 3- to 10-membered heterocycle optionally comprising 1 or 2 heteroatoms selected from N, 0, and S, wherein the (Ci-Ce)alkyl and (Ci-Ce)alkoxy is optionally substituted with with one orO more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from -CO2H and;R5is NR8R9;R8and R9together with the N to which they are bound combine to form a 3 - to 10-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, 0, and S, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl; andRa, Rb, Rc, RdRf, and R8are each, independently H or (Ci-C6)alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1is selected from H, -CH3 and -CH2CH3.

3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1is - CH2CH3.

4. The compound of any one of claims 1 to 3, wherein R2is phenyl optionally substituted with fluoro.Docket No.: PAT059789-PCT-SEC015. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, whereinR2is selected from6. The compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R3is selected from H and -CH3.

7. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R3is H.

8. The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R4is pyrazolyl, substituted with one or two substituents independently selected from (Ci-Ce)alkyl, (Ci- Ce)alkoxy, (Ci-C6)haloalkoxy wherin the (Ci-Ce)alkyl and (Ci-Ce)alkoxy is optionally substituted withO with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from -CO2H and9. The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R4is pyrazolyl, substituted with one or two substituents independently selected from (Ci-Ce)alkyl, (Ci- Ce)alkoxy, (Ci-C6)haloalkoxy wherein the (Ci-Ce)alkyl and (Ci-Ce)alkoxy is optionally substituted withO with one substituent independently selected from -CO2H and10. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, whereinDocket No.: PAT059789-PCT-SEC0111. The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R8and R9together with the N to which they are bound combine to form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more (e.g.,1, 2, 3, 4, or 5) substituents independently selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl.

12. The compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R8and R9together with the N to which they are bound combine to form a 6- to 8-membered heterocycle, wherein the 6- to 8-membered heterocycle is optionally substituted with one or more (e.g., 1,2, 3, 4, or 5) substituents independently selected from halo, (Ci-Ce)alkyl, and (Ci-C6)haloalkyl.

13. The compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R8and R9together with the N to which they are bound combine to form a 6- to 8-membered heterocycle, wherein the 6- to 8-membered heterocycle is substituted with one substituent independently selected from -CH3 and -CH2F.

14. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R5is selected from15. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein Ra, Rb, Rc, Rd, Rf, and R8are each, independently H or -CH3.

16. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein Rais H.

17. The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein Rband Rcare each H.

18. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein Rdis -CH3.

19. A compound or a pharmaceutically acceptable salt thereof selected from(1 R,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-4-(((R)-l -(3-methoxy- 1 -methyl- lH-pyrazol-4-yl)-2- ((S)-3-methylpiperidin-l-yl)ethyl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l- carboxylic acid;Docket No.: PAT059789-PCT-SEC01(1 R,4r)-4-((R)- 1 -(((R)-4-(((R)-2-((S)-3 -(fluoromethyl)piperidin- 1 -yl)- 1 -(3 -methoxy- 1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid;(lR,4r)-4-((R)-l-(((R)-4-(((R)-2-((S)-3-(fluoromethyl)piperidin-l-yl)-l-(l-methyl-lH-pyrazol-4- yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l- carboxylic acid;(lRS,4SR)-4-((RS)-l-(((RS)-4-(((RS)-2-((lS,5S)-9-azabicyclo[3.3.1]nonan-9-yl)-l-(3-methoxy- 1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5, 6,7, 8-tetr ahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid;(1 R,4r)-4-((R)- 1 -(((R)-4-(((R)-2-((S)-3 -(fluoromethyl)piperidin- 1 -yl)- 1 -(3 -methoxy- 1 -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l- carboxylic acid; rac-(lR,4r)-4-((lR)-l-(((6R)-4-(((lR)-2-(8-azabicyclo[3.2.1]octan-8-yl)-l-(3-methoxy-l -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid;3 -((R)- 1 -(((R)-4-(((R)-2-((3R,5R)-3 -methoxy-5 -methyip iperidin- 1 -yl)- 1 -( 1 -methyl- 1 H-pyrazol-4- yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)bicyclo[l.l.l]pentane- 1 -carboxylic acid;(1 R,4r)-4-((R)- 1 -(((R)-4-(((R)-2-((3R,5R)-3 -ethoxy-5 -methyip iperidin- 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;(1 R,4r)-4-((R)- 1 -(((R)-4-(((S)- 1 -(3 -(difluoromethoxy)- 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 - methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid;(1 R,4r)-4-((R)-l-(((R)-4-(((R)-2-((3R,5R)-3-hydroxy-5-methylpiperidin-l-yl)-l-(l -methyl- 1H- 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-((6-cyclohexyl-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- 1 -carboxylic acid;(lR,4r)-4-((lR)-l-(methyl((6R)-4-(((lR)-l-(l -methyl- lH-pyrazol-4-yl)-2-(2-methyl-7- azabicyclo[2.2.1]heptan-7-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid;Docket No.: PAT059789-PCT-SEC01(lR,4r)-4-((R)-l-(methyl((R)-4-(((R)-2-((S)-3-methylpiperidin-l-yl)-l-(l-(oxetan-3-yl)-lH- pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l- carboxylic acid; rac-(lR,4r)-4-((lR)-l-(((6R)-4-(((lR)-2-(8-azabicyclo[3.2.1]octan-8-yl)-l-(3-methoxy-l -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid;(1 RS, 4 SR)-4-(( 1 RS)- 1 -(methyl((6RS)-4-((2-(methyl(( 1 S,4S)-quinuclidin-3 -yl)amino)- 1 -( 1 - methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid;(1 R,4r)-4-((R)- 1 -(((R)-4-(((R)- 1 -(3 -(difluoromethoxy)- 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 - methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid;4-((l R)-l-(methyl((6R)-4-((l-(l-m ethyl- lH-pyrazol-4-yl)-2-(5-methyl-3,6-dihydropyridin- l(2H)-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l- carboxylic acid;(lR,4r)-4-((lR)-l-((6-cyclohexyl-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- 1 -carboxylic acid;(1 R,4r)-4-((R)- 1 -(((R)-4-(((R)- 1 -(3 -(2-ethoxy-2-oxoethoxy)- 1 -methyl- 1 H-pyrazol-4-yl)-2-((S)-3 - methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid;(1 R,4r)-4-((R)- 1 -(((R)-4-(((R)- 1 -( 1 -(2-ethoxy-2-oxoethyl)- 1 H-pyrazol-4-yl)-2-((S)-3 - methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid;(lR,4r)-4-((lR)-l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(l-oxa-6-azaspiro[3.4]octan- 6-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l -carboxylic acid;(1 R,4r)-4-((R)- 1 -(((R)-4-(((R)- 1 -( 1 -(2,2-difluoroethyl)- 1 H-pyrazol-4-yl)-2-((3R,5 R)-3 -methoxy- 5-methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid; rac-(lR,4r)-4-((lR)-l-(methyl((6R)-4-((2-(methyl((l-methylazetidin-3-yl)methyl)amino)-l-(l- methyl-lH-pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid;Docket No.: PAT059789-PCT-SEC01(lR,4r)-4-((lR)-l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(l-oxa-6- azaspiro[3.5]nonan-6-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid;(1 R,4r)-4-((R)- 1 -(((R)-4-(((R)-2-((R)-3 -methoxypiperidin- 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;(lR,4r)-4-((lR)-l-(((6R)-4-(((lR)-2-(3-fluoro-8-azabicyclo[3.2.1]octan-8-yl)-l-(l-methyl-lH- pyrazol-4-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid; rac-(lR,4r)-4-((lR)-l-(((6R)-4-((2-(ethyl(l-methylpyrrolidin-3-yl)amino)-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-((R)- 1 -(((R)-4-(((R)- 1 -( 1 -(carboxymethyl)- 1 H-pyrazol-4-yl)-2-((S)-3 -methylpiperidin- l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l- carboxylic acid; rac-(lR,4r)"4-((lR)-l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-((4aS,7aS)-l- methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid; rac-( 1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-((cyclopropylmethyl)(oxetan-3 -yl)amino)- 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;(1 R,4r)-4-(( 1 R)- 1 -(((6R)-4-((2-((S)-3 -cyanopiperidin- 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;(lR,4r)-4-((R)-l-(((R)-4-(((S)-2-((S)-3-(fluoromethyl)piperidin-l-yl)-l-(3-methoxy-l -methyl- lH-pyrazol-4-yl)ethyl)amino)-6-(3-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid;(1 R,4r)-4-((R)- 1 -(((R)-4-(((R)- 1 -(3 -fluoro- 1 -methyl- 1 H-pyrazol-4-yl)-2-((R)-3 -methoxy-3 - methylpiperidin-l-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid;(lR,4r)-4-((lR)-l-(((6R)-4-((2-(4,6-dim ethyl- l,4-diazepan-l-yl)-l-(l-methyl-lH-pyrazol-4- yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l- carboxylic acid;Docket No.: PAT059789-PCT-SEC01 rac-(lR,4r)-4-((lR)-l-(((6R)-4-((2-(3-oxa-7-azabicyclo[3.3.1]nonan-7-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-(5-methyl-2,5- diazabicyclo[4.1.0]heptan-2-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid; rac-(lR,4r)-4-((lR)-l-(methyl((6R)-4-((l-(l-methyl-lH-pyrazol-4-yl)-2-(7-methyl-2,7- diazaspiro[4.4]nonan-2-yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2- yl)amino)propyl)cyclohexane- 1 -carboxylic acid; rac-(lR,4r)-4-((R)-l-(((R)-4-(((R)-2-(lH-imidazol-2-yl)-l-(l-methyl-lH-pyrazol-4- yl)ethyl)amino)-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)(methyl)amino)propyl)cyclohexane-l- carboxylic acid;(lR,4r)-4-((lR)-l-(((6S)-4-((2-(8-azabicyclo[3.2.1]octan-8-yl)-l-(2,4-dimethylthiazol-5- yl)ethyl)amino)-6-methoxy-6-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l- carboxylic acid;(lR,4r)-4-((R)-l-(((R)-6-(3-fluorophenyl)-4-(((R)-2-((3R,5R)-3-methoxy-5-methylpiperidin-l- yl)-l-(l-methyl-lH-pyrazol-4-yl)ethyl)amino)-6-methyl-5,6,7,8-tetrahydroquinazolin-2- yl)(methyl)amino)propyl)cyclohexane- 1 -carboxylic acid; rac-( 1 R,4r)-4-((R)- 1 -(((R)-4-(((S)-2-(azepan- 1 -yl)- 1 -(2,4-dimethylthiazol-5 -yl)ethyl)amino)-6- phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l-carboxylic acid; and(lR,4r)-4-((R)-l-(((R)-4-(((R)-2-(azepan-l-yl)-l-(2,4-dimethylthiazol-5-yl)ethyl)amino)-6- phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)amino)propyl)cyclohexane-l-carboxylic acid.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof and one or more (e.g., 1, 2, 3, 4, or 5) pharmaceutically acceptable carriers.

21. The pharmaceutical composition of claim 20, further comprising at least one additional pharmaceutically active agent.

22. The pharmaceutical composition of claim 21, 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 carbonicDocket No.: PAT059789-PCT-SEC01 anhydrase inhibitor, an alpha 2-adrenoceptor agonist, a parasympathomimetic, a prostaglandin analog, a rho kinase inhibitor, and combinations thereof.

23. A method for treating or preventing a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of the claims 1 to 19 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of claims 20 to 22.

24. The method of claim 23, wherein the disease or disorder is a cardiovascular disease or disorder.

25. The method of claim 24, 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).

26. The method of claim 25, 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.

27. The method of claim 23, 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.

28. The method of claim 23, wherein the disease or disorder is a disorder or disease associated with natriuretic peptide receptor activity.

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