NZ786241A - 6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carboxamides as apj agonists - Google Patents
6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carboxamides as apj agonistsInfo
- Publication number
- NZ786241A NZ786241A NZ786241A NZ78624117A NZ786241A NZ 786241 A NZ786241 A NZ 786241A NZ 786241 A NZ786241 A NZ 786241A NZ 78624117 A NZ78624117 A NZ 78624117A NZ 786241 A NZ786241 A NZ 786241A
- Authority
- NZ
- New Zealand
- Prior art keywords
- substituted
- independently selected
- occurrence
- alkyl
- hydroxy
- Prior art date
Links
- 239000000556 agonist Substances 0.000 title abstract description 12
- RVVVQQNYGKCVMV-UHFFFAOYSA-N 4-hydroxy-6-oxo-1h-pyrimidine-5-carboxamide Chemical class NC(=O)C1=C(O)N=CNC1=O RVVVQQNYGKCVMV-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 171
- 239000000203 mixture Substances 0.000 claims abstract description 39
- -1 -O(CH2)1- 3OCH3 Chemical group 0.000 claims description 400
- 229910052801 chlorine Inorganic materials 0.000 claims description 130
- 229910052731 fluorine Inorganic materials 0.000 claims description 130
- 125000000217 alkyl group Chemical group 0.000 claims description 105
- 125000000623 heterocyclic group Chemical group 0.000 claims description 95
- 229910052794 bromium Inorganic materials 0.000 claims description 72
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 72
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 66
- 150000003839 salts Chemical class 0.000 claims description 66
- 238000000034 method Methods 0.000 claims description 57
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims description 53
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 52
- 229910052757 nitrogen Inorganic materials 0.000 claims description 50
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 40
- 229910052702 rhenium Inorganic materials 0.000 claims description 40
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 39
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 37
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 36
- 206010019280 Heart failures Diseases 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 33
- 229910052760 oxygen Inorganic materials 0.000 claims description 32
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 26
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- 125000003342 alkenyl group Chemical group 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 20
- 235000019256 formaldehyde Nutrition 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 125000004429 atom Chemical group 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 229910052701 rubidium Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 11
- 125000004122 cyclic group Chemical group 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims description 10
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 238000002560 therapeutic procedure Methods 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 208000029078 coronary artery disease Diseases 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 6
- 230000002107 myocardial effect Effects 0.000 claims description 6
- 125000003003 spiro group Chemical group 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
- 101100439663 Arabidopsis thaliana CHR7 gene Proteins 0.000 claims description 3
- 206010061216 Infarction Diseases 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 230000007574 infarction Effects 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 3
- 238000007634 remodeling Methods 0.000 claims description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
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- 239000003814 drug Substances 0.000 abstract description 34
- 238000005160 1H NMR spectroscopy Methods 0.000 description 573
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 263
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 234
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 234
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- 239000012071 phase Substances 0.000 description 231
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- 125000004356 hydroxy functional group Chemical group O* 0.000 description 205
- 239000000543 intermediate Substances 0.000 description 203
- 230000014759 maintenance of location Effects 0.000 description 202
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 144
- QGKGASXQTBQINX-UHFFFAOYSA-N 3,4-dihydro-1h-pyrimidin-2-one Chemical compound O=C1NCC=CN1 QGKGASXQTBQINX-UHFFFAOYSA-N 0.000 description 97
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 92
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- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-UHFFFAOYSA-N 0.000 description 80
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 79
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 45
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- 108010052412 Apelin Proteins 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- 125000001207 fluorophenyl group Chemical group 0.000 description 37
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- 101000793362 Homo sapiens Apelin receptor Proteins 0.000 description 36
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- BWVPHIKGXQBZPV-QKFDDRBGSA-N apelin Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N1[C@H](C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCSC)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(O)=O)CCC1 BWVPHIKGXQBZPV-QKFDDRBGSA-N 0.000 description 34
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- VDQQJMHXZCMNMU-UHFFFAOYSA-N 1-phenylpyrrolidine Chemical compound C1CCCN1C1=CC=CC=C1 VDQQJMHXZCMNMU-UHFFFAOYSA-N 0.000 description 33
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Abstract
The present invention provides compounds of Formula (I) wherein all variables are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are APJ agonists which may be used as medicaments.
Description
-HYDROXYOXO-1,4-DIHYDROPYRIMIDINECARBOXAMIDES AS APJ AGONISTS CROSS-REFERENCE TO D APPLICATIONS This application is a divisional of New d patent application 747568, which is the national phase entry of PCT international application (published as Provisional Application Serial No. ,780, filed March 24, 2016, each of which are incorporated herein in their entirety.
FIELD OF THE INVENTION The present invention provides novel 1,4-dihydropyrimidinecarboxamides, and their analogues thereof, which are APJ agonists, compositions containing them, and methods of using them, for example, for the ent or prophylaxis of heart failure, atherosclerosis, ischemic heart disease and related conditions.
OUND OF THE INVENTION Heart failure (HF) and related complications constitute major health burden in developed countries with an estimated prevalence of 5,700,000 in the United States alone (Roger, V.L. et al., Circulation, 125(1):e2-e220 (2012)). Despite considerable es in recent two decades, the prognosis remains very poor, with survival rates of only ~50% within s of diagnosis (Roger, V.L. et al., JAMA, 292(3):344-350 (2004)). In addition to poor survival, the impaired quality of life and recurrent hospitalizations constitute clear unmet medical need for development of novel treatment options.
HF is a al syndrome characterized by the inability of the heart to r sufficient supply of blood and oxygen to meet the lic demands of organs in the body. Main symptoms associated with HF include shortness of breath due to pulmonary edema, fatigue, reduced tolerance to exercise and lower extremity edemas. The etiology of HF is highly complex with multiple associated risk factors and potential causes.
Among the leading causes of HF are coronary artery disease and cardiac ischemia, acute myocardial infarction, intrinsic cardiomyopathies and chronic uncontrolled hypertension. HF can develop either acutely (functional impairment post myocardial [Link] http://www.ncbi.nlm.nih.gov/pubmed/15364861 [Link] http://www.ncbi.nlm.nih.gov/pubmed/15621035 [Link] http://www.ncbi.nlm.nih.gov/pubmed/12798955 infarction) or as a c condition, characterized by long-term maladaptive cardiac tissue remodeling, hypertrophy and cardiac dysfunction (for example due to uncontrolled long-term hypertension). According to the diagnostic criteria and type of ventricular dysfunction, HF is classified to two major groups, HF with ed ejection fraction" (HFrEF) or HF with "preserved ejection fraction" ). Both types are associated with r signs and symptoms, but differ in the type of ventricular functional impairment (Borlaug, B.A. et al., Eur. Heart J., 32(6):670-679 (2011)).
APJ receptor (APLNR) and its endogenous peptidic ligand apelin have been implicated as important modulators of cardiovascular on and candidates for therapeutic intervention in HF (for review see Japp, A.G. et al., m. Pharmacol., 75(10):1882-1892 (2008)).
Accumulated evidence from preclinical disease models and human heart failure patients have implicated apelin and APJ agonism as beneficial in the setting of HF. Mice lacking Apelin or APJ gene have impaired myocyte contractility (Charo, D.N. et al., Am.
J. Physiol. Heart Circ. Physiol., 297(5):H1904-H1913 (2009)). Apelin knockout (KO) mice develop progressive cardiac dysfunction with aging and are more susceptible to HF in the model of trans-aortic constriction (TAC) (Kuba, K. et al., Circ. Res., 101(4):e32 -42 (2007) ). The functional impairment in chronic HF is a result of prolonged demand on the heart and is associated with maladaptive cardiac remodeling, manifested by the cardiac hypertrophy, increased inflammation and interstitial fibrosis which eventually lead to se in cardiac mance.
Acute administration of apelin increases cardiac output in rodents under normal ions and also in models of heart failure (Berry, M.F., Circulation , 110(11 Suppl. 87-II193 (2004)). Increased c output is a result of direct augmentation of cardiac contractility and reduced peripheral vascular resistance in the arterial and venous beds (Ashley, E.A., Cardiovasc. Res., 65(1):73-82 (2005) ). Reduction in the vascular resistance leads to lower pre-load and after-load on the heart and thus lesser work load (Cheng, X. et al., Eur. J. Pharmacol., 470(3):171 -175 ( 2003)). Similar to rodent studies, acute infusion of apelin to healthy human subjects and patients with heart failure produces similar hemodynamic responses with increased c output and increased vasodilatory response in eral and coronary es (Japp, A.G. et al., Circulation, 121(16):1818-1827 (2010)).
[Link] http://www.ncbi.nlm.nih.gov/pubmed/11384769 [Link] http://www.ncbi.nlm.nih.gov/pubmed/21358420 [Link] /www.ncbi.nlm.nih.gov/pubmed/?term=Scimia+and+apelin [Link] http://www.ncbi.nlm.nih.gov/pubmed/22082814 [Link] http://www.ncbi.nlm.nih.gov/pubmed/?term=Sarzani+and+apelin The mechanisms underlying inotropic action of apelin are not well understood, but appear to be distinct from ally used β1-adrenergic agonists (dobutamine) due to lack of increase in heart rate. The vasodilatory action of apelin is ily mediated via endothelial nitric oxide synthase pathways (Tatemoto, K., Regul. Pept. , 99(2-3):87-92 (2001)). Apelin is induced under hypoxic ions, promotes enesis and has been shown to limit the t size in ischemia-reperfusion models in, J.C., Basic Res.
Cardiol., 102(6):518-528 (2007)).
In on to aforementioned studies evaluating acute administration of apelin, several studies have clearly demonstrated beneficial effects of prolonged administration of apelin in a number of chronic rodent models of HF, including the angiotensin II model, TAC model and rat Dahl ensitive model (Siddiquee, K. et al., J. Hypertens., 29(4):724-731 (2011); Scimia, M.C. et al., Nature , 488(7411):394-398 (2012); Koguchi, W. et al., Circ. J., 76(1):137-144 (2012)). In these studies, prolonged apelin infusion reduced cardiac rophy and cardiac fibrosis, and was associated with improvement in cardiac performance.
Genetic evidence is also emerging that rphisms in the APJ gene are associated with slower progression of HF (Sarzani, R. et al., J. Card. Fail., 13(7):521-529 (2007)). Importantly, while expression of APJ and apelin can be reduced or vary considerably with HF progression, the cardiovascular hemodynamic s of apelin are sustained in patients with developed HF and receiving standard of care therapy (Japp, A.G. et al., Circulation, 121(16):1818-1827 (2010)).
In summary, there is a significant amount of evidence to indicate that APJ receptor agonism plays a cardioprotective role in HF and would be of potential benefit to HF patients. Apelin's very short half life in circulation limits its therapeutic utility, and consequently, there is a need for APJ receptor agonists with improved pharmacokinetic and signaling profile while maintaining or enhancing the beneficial effects of endogenous APJ agonist apelin.
SUMMARY OF THE INVENTION The present invention provides hydropyrimidinecarboxamides, and their analogues thereof, which are useful as APJ agonists, including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof.
The present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, ceutically acceptable salts, or solvates thereof.
The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, ceutically acceptable salts, or solvates The compounds of the invention may be used in the ent and/or prophylaxis of multiple diseases or disorders associated with APJ, such as heart failure, coronary artery disease, cardiomyopathy, diabetes and related conditions including but not limited to acute coronary syndrome, myocardial ischemia, hypertension, pulmonary hypertension, coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injury, angina, renal disease, metabolic syndrome and insulin resistance.
The compounds of the invention may be used in therapy.
The compounds of the invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of multiple diseases or disorders ated with APJ.
The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other s).
Other es and advantages of the invention will be apparent from the ing detailed description and claims.
DETAILED PTION OF THE INVENTION I. COMPOUNDS OF THE INVENTION In a first aspect, the t disclosure provides, inter alia, a compound of Formula (I): or a stereoisomer, an enantiomer, a diastereoisomer, a er, a pharmaceutically acceptable salt, a prodrug, or a solvate thereof, wherein: alk is C1-6 alkylene substituted with 0-5 Re; ring B is independently selected from C3-6 cycloalkyl, C3-6 lkenyl, aryl, bicyclic carbocyclyl, and 6-membered heteroaryl; R1, at each occurrence, is independently selected from H, n, NO2, -(CH2)nORb, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, nCN, - (CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, -(CH2)nNRaC(=O)NRaRa, - (CH2)nNRaC(=O)ORb, -(CH2)nOC(=O)NRaRa, -(CH2)nC(=O)ORb, - (CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, -(CH2)nNRaS(O)pRc, C1-4 alkyl substituted with 0-3 Re, -(CH2)n-C3-6 carbocyclyl substituted with 0-3 Re, and - (CH2)n-heterocyclyl substituted with 0-3 Re; R2 is independently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl substituted with 0-3 Re, aryl substituted with 0-3 Re, heteroaryl substituted with 0- 3 Re, and C3-6 cycloalkyl substituted with 0-3 Re; provided when R2 is C1-5 alkyl, the carbon atoms and the groups attached thereto except the carbon atom attached to the dine ring may be replaced by O, N, and S; R3 is independently selected from H and C1-5 alkyl: R4 is ndently selected from -(CR7R7)n-R6, -(CR7R7)nOR6, 7)nS(O)pR6, - (CR7R7)nC(=O)R6, -(CR7R7)nNRaR6, -(CR7R7)nC(=O)NRaR6, - (CR7R7)nNRaC(=O)R6, -(CR7R7)nS(O)pNRaR6, and -(CR7R7)nNRaS(O)pR6; alternatively, R3 and R4 together with the nitrogen atom to which they are both attached form a heterocyclic ring or a spiro heterocyclic ring comprising carbon atoms and additional 1 to 4 heteroatoms selected from NR5a, O, and S and substituted with 0- R5; R5, at each occurrence, is independently at each occurrence, selected from OH, halogen, - (CR7R7)n-R6, -OR6, -S(O)pR6, -C(=O)R6, -NRaR6, -C(=O)NRaR6, -NRaC(=O)R6, - NRaC(=O)OR6, -OC(=O)NRaR6, -C(=O)OR6, -S(O)pNRaR6, -NRaS(O)pNRaR6, and -NRaS(O)pR6; R5a, at each occurrence, is independently selected from -C(=O)OR6, C(=O)NRaR6, - (CR7R7)n-R6, -C(=O)-R6, and -S(O)pR6; R6, at each occurrence, is independently selected from -(CR7R7)n-C3-10 carbocyclyl and - )n-heteroaryl, each tuted with 0-3 R8; R7, at each occurrence, is ndently selected from H, C1-4 alkyl, and -C3-12 carbocyclyl substituted with 0-3 Re; R8, at each ence, is independently selected from H, halogen, -(CH2)nORb, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -(CH2)nCN, - (CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, -(CH2)nNRaC(=O)NRaRa, - (CH2)nNRaC(=O)ORb, -(CH2)nOC(=O)NRaRa, -(CH2)nC(=O)ORb, - (CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, -(CH2)nNRaS(O)pRc, C1-5 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re, and - (CH2)n-heterocyclyl tuted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl tuted with 0-5 Re, C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl tuted with 0-5 Re, - (CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and n-heterocyclyl substituted with 0-5 Re; Rc, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, C3- 6carbocyclyl, and heterocyclyl; Re, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2)nORf, S(O)pRf, C(=O)NRfRf, NRfC(=O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and -(CH2)nNRfRf; Rf, at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl, and phenyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with kyl; n, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and p, at each occurrence, is independently selected from zero, 1, and 2.
In a second aspect, the present disclosure provides a compound of Formula (I), or a isomer, an enantiomer, a diastereoisomer, a tautomer, a ceutically acceptable salt, a prodrug, or a solvate thereof, within the scope of the first aspect, wherein: R1, at each occurrence, is independently selected from H, F, Cl, Br, NO2, -(CH2)nORb, - (CH2)nC(=O)Rb, -(CH2)nNRaRa, -(CH2)nCN, -(CH2)nC(=O)NRaRa, - (CH2)nNRaC(=O)Rb, C1-4 alkyl tuted with 0-3 Re and C3-6 cycloalkyl substituted with 0-3 Re; R2 is independently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl, aryl substituted with 0-3 Re, heteroaryl substituted with 0-3 Re, C3-6 cycloalkyl, – -4OC1-5alkyl, 1-4NHC1-5alkyl, and –(CH2)1-3OC3-6cycloalkyl; R3 and R4 together with the nitrogen atom to which they are both attached form a heterocyclic ring or a spiro heterocyclic ring selected from , , , , , , , , , , , , , and ; R5, at each occurrence, is independently selected from OH, -(CH2)n-R6, -(CR7R7)n-R6, OR6, -S(O)pR6, -C(=O)R6, -NRaR6, -C(=O)NRaR6, -NRaC(=O)R6, - NRaC(=O)OR6, -OC(=O)NRaR6, -C(=O)OR6, -S(O)pNRaR6, -NRaS(O)pNRaR6, and -NRaS(O)pR6; R5a, at each occurrence, is independently selected from OR6, C(=O)NRaR6, - (CR7R7)n-R6, -R6, and R6; R6, at each occurrence, is ndently selected from -(CR7R7)n-aryl, -(CR7R7)n-C3-6 lkyl, and -(CR7R7)n-heteroaryl, each substituted with 0-3 R8; R7, at each ence, is independently selected from H, C1-4 alkyl, and (CH2)n-C3-12 carbocyclyl substituted with 0-3 Re; R8, at each occurrence, is independently selected from H, F, Cl, Br, -ORb, - (CH2)nC(=O)Rb, nC(=O)ORb, -(CH2)nNRaRa, CN, -(CH2)nC(=O)NRaRa, - NHC(=O)ORb, C1-4 alkyl tuted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently ed from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - (CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, - (CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H, -(CH2)nORf, f, C(=O)NRfRf, NRfC(=O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and -(CH2)nNRfRf; Rf, at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl nally substituted with halogen and OH), C3-6 cycloalkyl, and phenyl; n, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and p, at each occurrence, is independently selected from zero, 1, and 2.
In a third aspect, the present disclosure provides a compound of Formula (II): or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, or a solvate thereof, within the scope of the first or second aspect, wherein: ring B is independently selected from , , , , , and ; R1, at each ence, is independently selected from H, F, Cl, OH, CN, OC1-4 alkyl, and C3-6 cycloalkyl; R2 is ndently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl, aryl tuted with 0-3 Re, heteroaryl substituted with 0-3 Re, C3-6 cycloalkyl, – -4OC1-5alkyl, and –(CH2)1-3OC3-6cycloalkyl; R3 and R4 together with the nitrogen atom to which they are both attached form a heterocyclic ring selected from , , , , , , ; R5, at each occurrence, is independently selected from OH, -(CH2)n-R6, -(CR7R7)n-R6, - OR6, -S(O)pR6, -C(=O)R6, -NRaR6, -C(=O)NRaR6, -NRaC(=O)R6, - NRaC(=O)OR6, -OC(=O)NRaR6, -C(=O)OR6, -S(O)pNRaR6, -NRaS(O)pNRaR6, and -NRaS(O)pR6; R5a, at each ence, is independently selected from -C(=O)OR6, C(=O)NRaR6, - (CR7R7)n-R6, -C(=O)-R6, and R6; R6, at each occurrence, is independently selected from -(CR7R7)n-aryl, -(CR7R7)n-C3-6 cycloalkyl, and -(CR7R7)n-heteroaryl, each tuted with 0-3 R8; R7, at each occurrence, is ndently selected from H, C1-4 alkyl, and (CH2)n-C3-12 carbocyclyl tuted with 0-3 Re; R8, at each occurrence, is independently selected from H, F, Cl, Br, -ORb, - (CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa, CN, -(CH2)nC(=O)NRaRa, C1- e, (CH e, 4 alkyl substituted with 0-3 R 2)n-C3-6 carbocyclyl substituted with 0-3 R and -(CH2)n-heterocyclyl substituted with 0-3 Re; Ra, at each ence, is ndently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - (CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is independently ed from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; n, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
In a fourth aspect, the present disclosure es a compound of Formula (II), or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, or a e thereof, within the scope of any of the first, second and third aspects, wherein: R1, at each occurrence, is independently selected from H, F, Cl, OH, and OC1-4 alkyl; R2 is independently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl, phenyl substituted with 0-3 Re, 6-membered heteroaryl substituted with 0-3 Re, C3-6 cycloalkyl; and CH2O(CH2)1-3CH3; R3 and R4 together with the nitrogen atom to which they are both attached form a cyclic ring selected from , , and ; R5 is independently at each occurrence, selected from OH, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; R8, at each occurrence, is independently selected from H, F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl tuted with 0-3 Re, and - (CH2)n-heterocyclyl substituted with 0-3 Re; R8a, at each occurrence, is independently selected from H, CH3, aryl substituted with 0-3 Re, and cyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; and n, at each occurrence, is independently selected from zero, 1, 2, and 3.
In a fifth aspect, the present sure provides a compound of Formula (III): (III) or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, or a solvate f, within the scope of the first or second aspect, wherein: ring B is independently selected from , , , , , and R1, at each occurrence, is independently selected from H, F, Cl, OH, and OC1-4 alkyl; R2 is independently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl, phenyl substituted with 0-1 Re, 6-membered heteroaryl substituted with 0-1 Re, and C3-6 cycloalkyl; and H2)1-3CH3; R5 is independently at each occurrence, selected from OH, , , , , , , , , , , , , , , , , , , , , and R8, at each occurrence, is independently selected from H, F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3, -C(=O)NH2, -(CH2)n-aryl substituted with 0-3 Re, n-C3-6 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 R8a, at each occurrence, is independently selected from H, CH3, aryl substituted with 0-3 Re, and heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, n-C4-6 cyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; n, at each occurrence, is independently ed from zero, 1, 2, and 3.
In a sixth aspect, the present disclosure provides a compound of Formula (III), or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, or a solvate thereof, within the scope of any of the first, second and third aspects, wherein: R1, at each occurrence, is independently selected from F, Cl, OH, -OCH3, and -OCD3; R2 is independently selected from C1-5 alkyl tuted with 0-3 Re; C2-5 alkenyl, phenyl substituted with 0-3 Re, 6-membered heteroaryl substituted with 0-3 Re, and C3-6 cycloalkyl; and CH2O(CH2)1-3CH3; R3 and R4 together with the nitrogen atom to which they are both attached form ; R5, at each occurrence, is ndently at each occurrence, selected from OH, F, and Cl; R5a is independently at each occurrence, selected from , , , , , , , , , , , , , , , and ; R8, at each occurrence, is independently selected from H, F, Cl, Br, -OCH3, -O(CH2)1- 3OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re; R8a, at each occurrence, is ndently selected from H, CH3, aryl substituted with 0-3 Re, and heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl tuted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - -C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is ndently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; n, at each occurrence, is independently selected from zero, 1, 2, and 3.
In a seventh aspect, the present disclosures provides a compound of Formula (I), or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically acceptable salt, a g, or a solvate thereof, within the scope of any of the first, second and third aspects, wherein: R1, at each ence, is independently ed from -CH2OH, -OCH3, -OCF3, -OCD3 - OCH2Ph, -C(=O)NRaRa, -NRaRa, CH3, CH2CH3, CH(CH3)2, and cyclopropyl; R2 is independently selected from C1-4 alkyl substituted with 0-3 Re; C2-4 l, phenyl substituted with 0-3 Re, 6-membered heteroaryl substituted with 0-3 Re, C3-6 cycloalkyl, and CH2O(CH2)1-3CH3; R3 is independently selected from H and C1-4 alkyl: R4 is independently ed from -(CHR7)1R6, -(CH2)1-3OR6, -(CH2)1-3NHR6, and - (CH2)0-3NHC(=O)R6; R6, at each occurrence, is independently selected from -(CR7R7)n-aryl, -(CR7R7)n-C3-6 cycloalkyl, and -(CR7R7)n-heteroaryl, each substituted with 0-3 R8; R7, at each occurrence, is independently selected from H, C1-4 alkyl, and aryl; R8, at each occurrence, is independently selected from H, F, Cl, -ORb, , C1-4 alkyl substituted with 0-3 Re, phenyl substituted with 0-3 Re, and heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-phenyl substituted with 0-5 Re, and -(CH2)n-heteroaryl substituted with 0-5 Re; Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is independently selected from C1-6 alkyl nally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 lkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; and n is independently selected from zero, 1, 2, 3, and 4.
In an eighth aspect, the present disclosure provides a nd, or a stereoisomer, an enantiomer, a reoisomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, or a solvate thereof, within the scope of the first, second, and third aspects, wherein: R1, at each occurrence, is independently selected from , -OCH3, -OCF3,OCH2Ph, -C(=O)NRaRa, -NRaRa, CH3, CH2CH3, CH(CH3)2, and cyclopropyl; R2 is independently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl, phenyl substituted with 0-3 Re, 6-membered aryl substituted with 0-3 Re, C3-6 cycloalkyl and CH2O(CH2)1-3CH3; R3 and R4 are ndently selected from C1-5 alkyl substituted with 0-3 R6; -(CH2)n-C3-6 carbocyclyl substituted with 0-3 R6, and -(CH2)n-heterocyclyl tuted with 0-3 R6, at each occurrence, is independently selected from H, halogen, -(CH2)nORb, - (CH2)nNRaRa, -(CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, - (CH2)nNRaC(=O)ORb, -(CH2)nOC(=O)NRaRa, -(CH2)nC(=O)ORb, - (CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, C1-5 alkyl substituted with 0-3 Re, phenyl substituted with 0-3 Re, and heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-phenyl substituted with 0-5 Re, and -(CH2)n-heteroaryl substituted with 0-5 Re; Rb, at each occurrence, is independently selected from H, C1-6 alkyl tuted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and n-heterocyclyl tuted with 0-5 Re; Re, at each occurrence, is independently selected from C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, =O, CO2H; n, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
In a ninth aspect, the present disclosure provides a compound selected from the exemplified examples or stereoisomers, enantiomers, diastereoisomers, ers, pharmaceutically acceptable salts, prodrugs, or solvates thereof.
In r , the present disclosure provides a compound selected from any subset list of nds within the scope of the eighth aspect.
In another aspect, the present disclosure provides nds of Formula (I), or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein: alk is C1-6 ne substituted with 0-5 Re; ring B is independently selected from C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl, bicyclic carbocyclyl, and 6-membered heteroaryl; R1, at each occurrence, is independently selected from H, halogen, NO2, -(CH2)nORb, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -(CH2)nCN, - (CH2)nC(=O)NRaRa, nNRaC(=O)Rb, -(CH2)nNRaC(=O)NRaRa, - (CH2)nNRaC(=O)ORb, -(CH2)nOC(=O)NRaRa, -(CH2)nC(=O)ORb, - (CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, -(CH2)nNRaS(O)pRc, C1-4 alkyl substituted with 0-3 Re, -(CH2)n-C3-6 carbocyclyl substituted with 0-3 Re, and - -heterocyclyl substituted with 0-3 Re; R2 is independently selected from C1-10 alkyl substituted with 0-3 Re; C2-5 alkenyl substituted with 0-3 Re, aryl substituted with 0-3 Re, heteroaryl substituted with 0- 3 Re, and C3-6 cycloalkyl substituted with 0-3 Re; provided when R2 is C1-10 alkyl, the carbon atoms and the groups attached thereto except the carbon atom attached to the pyrimidine ring may be replaced by O, N, and S; R3 is independently selected from H and C1-5 alkyl: R4 is independently selected from -(CR7R7)n-R6, -(CR7R7)nOR6, -(CR7R7)nS(O)pR6, - (CR7R7)nC(=O)R6, -(CR7R7)nNRaR6, -(CR7R7)nNRaC(=O)R6, - (CR7R7)nS(O)pNRaR6, and -(CR7R7)nNRaS(O)pR6; atively, R3 and R4 together with the nitrogen atom to which they are both attached form a heterocyclic ring or a spiro cyclic ring comprising carbon atoms and additional 1 to 4 heteroatoms ed from NR5a, O, and S and substituted with 0- 5 R5; R5, at each occurrence, is independently selected from OH, halogen, -(CR7R7)n-R6, -OR6, -S(O)pR6, -C(=O)R6, -NRaR6, -C(=O)NRaR6, -NRaC(=O)R6, -NRaC(=O)OR6, - NRaR6, -C(=O)OR6, NRaR6, -NRaS(O)pNRaR6, and -NRaS(O)pR6; R5a, at each occurrence is independently selected from -C(=O)OR6, C(=O)NRaR6, - (CR7R7)n-R6, -C(=O)-R6, and -S(O)pR6; R6, at each occurrence, is independently selected from 7)n-C3-10 carbocyclyl and - (CR7R7)n-heteroaryl, each substituted with 0-3 R8; R7, at each occurrence, is independently selected from H, C1-4 alkyl, and (CH2)n-C3-12 carbocyclyl substituted with 0-3 Re; R8, at each occurrence, is independently selected from H, halogen, -(CH2)nORb, =O, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, -(CH2)nNRaRa, -(CH2)nCN, - (CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, -(CH2)nNRaC(=O)NRaRa, - (CH2)nNRaC(=O)ORb, -(CH2)nOC(=O)NRaRa, -(CH2)nC(=O)ORb, - (CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, -(CH2)nNRaS(O)pRc, C1-5 alkyl tuted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re, and - (CH2)n-heterocyclyl substituted with 0-3 Re; Ra, at each ence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - (CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - (CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Rc, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, C3- 6carbocyclyl, and heterocyclyl; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 l, -(CH2)n-C3-6 cycloalkyl, - (CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)nORf, S(O)pRf, C(=O)NRfRf, NRfC(=O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and -(CH2)nNRfRf; Rf, at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl, and phenyl, or Rf and Rf together with the nitrogen atom to which they are both ed form a cyclic ring optionally substituted with C1-4alkyl; n, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and p, at each occurrence, is independently selected from zero, 1, and 2.
In r aspect, the present sure provides compounds of Formula (I), or isomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein: R1, at each occurrence, is independently selected from H, F, Cl, Br, NO2, -(CH2)nORb, - (CH2)nC(=O)Rb, -(CH2)nNRaRa, nCN, -(CH2)nC(=O)NRaRa, - NRaC(=O)Rb, C1-4 alkyl tuted with 0-3 Re and C3-6 cycloalkyl substituted with 0-3 Re; R2 is independently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl, aryl substituted with 0-3 Re, heteroaryl tuted with 0-3 Re, C3-6 cycloalkyl, – (CH2)1-4OC1-5alkyl, –(CH2)1-4NHC1-5alkyl, and –(CH2)1-3OC3-6cycloalkyl; R3 and R4 together with the nitrogen atom to which they are both ed form a heterocyclic ring or a spiro heterocyclic ring selected from , , , , , , , , , , , , , and ; R5, at each occurrence, is independently selected from OH, -(CH2)n-R6, -(CR7R7)n-R6, OR6, -S(O)pR6, -C(=O)R6, -NRaR6, -C(=O)NRaR6, -NRaC(=O)R6, - NRaC(=O)OR6, -OC(=O)NRaR6, -C(=O)OR6, -S(O)pNRaR6, -NRaS(O)pNRaR6, and -NRaS(O)pR6; R5a, at each occurrence, is independently selected from -C(=O)OR6, C(=O)NRaR6, - (CR7R7)n-R6, -C(=O)-R6, and -S(O)pR6; R6, at each occurrence, is independently selected from -(CR7R7)n-aryl, -(CR7R7)n-C3-6 cycloalkyl, and 7)n-heteroaryl, each substituted with 0-3 R8; R7, at each occurrence, is independently selected from H, C1-4 alkyl, and (CH2)n-C3-12 yclyl substituted with 0-3 Re; R8, at each ence, is independently selected from H, F, Cl, Br, -ORb, - (CH2)nC(=O)Rb, nC(=O)ORb, -(CH2)nNRaRa, CN, nC(=O)NRaRa, - NHC(=O)ORb, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the en atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; Rb, at each occurrence, is ndently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - (CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, n-C3-6 cycloalkyl, - (CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)nORf, S(O)pRf, RfRf, NRfC(=O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(=O)ORf, OC(=O)NRfRf and -(CH2)nNRfRf; Rf, at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl, and phenyl; n, at each ence, is independently ed from zero, 1, 2, 3, and 4; and p, at each occurrence, is independently ed from zero, 1, and 2.
In another aspect, the present disclosure provides compounds of Formula (II), or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates f, wherein: ring B is independently selected from , , , , , and ; R1, at each occurrence, is independently selected from H, F, Cl, OH, CN, C1-4 alkyl, OC1-4 alkyl, and C3-6 cycloalkyl; R2 is independently selected from C1-5 alkyl tuted with 0-3 Re; C2-5 alkenyl, aryl substituted with 0-3 Re, heteroaryl substituted with 0-3 Re, C3-6 cycloalkyl, – (CH2)1-4OC1-5alkyl, and –(CH2)1-3OC3-6cycloalkyl; R3 and R4 together with the nitrogen atom to which they are both attached form a heterocyclic ring selected from , , , , , , ; R5, at each occurrence, is independently selected from OH, -(CH2)n-R6, -(CR7R7)n-R6, - OR6, -S(O)pR6, -C(=O)R6, -NRaR6, -C(=O)NRaR6, -NRaC(=O)R6, - NRaC(=O)OR6, -OC(=O)NRaR6, -C(=O)OR6, -S(O)pNRaR6, -NRaS(O)pNRaR6, and -NRaS(O)pR6; R5a, at each occurrence, is independently ed from -C(=O)OR6, C(=O)NRaR6, - (CR7R7)n-R6, -C(=O)-R6, and R6; R6, at each ence, is independently selected from -(CR7R7)n-aryl, -(CR7R7)n-C3-6 cycloalkyl, and -(CR7R7)n-heteroaryl, each substituted with 0-3 R8; R7, at each occurrence, is independently selected from H, C1-4 alkyl, and (CH2)n-C3-12 carbocyclyl substituted with 0-3 Re; R8, at each occurrence, is independently ed from H, F, Cl, Br, -ORb, - C(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa, CN, -(CH2)nC(=O)NRaRa, C1- e, (CH e, 4 alkyl substituted with 0-3 R 2)n-C3-6 carbocyclyl substituted with 0-3 R and -(CH2)n-heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - (CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl nally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, and - OC1-4alkyl; and n, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the present disclosure provides compounds of a (II), or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates f, wherein: R1, at each occurrence, is independently selected from H, F, Cl, OH, CN, C1-4 alkyl, and OC1-4 alkyl; R2 is independently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl, phenyl substituted with 0-3 Re, 5- to 6-membered heteroaryl substituted with 0-3 Re, C3-6 cycloalkyl, and CH2O(CH2)1-3CH3; R3 and R4 together with the nitrogen atom to which they are both attached form a cyclic ring selected from , , and ; R5 is independently at each occurrence, selected from OH, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; R8, at each occurrence, is independently selected from H, F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and - (CH2)n-heterocyclyl substituted with 0-3 Re; R8a, at each occurrence, is independently selected from H, CH3, aryl substituted with 0-3 Re, and heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is independently ed from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, and - OC1-4alkyl; and n, at each occurrence, is independently selected from zero, 1, 2, and 3.
In r aspect, the present disclosure provides compounds of Formula (III), or stereoisomers, enantiomers, diastereoisomers, ers, pharmaceutically acceptable salts, prodrugs, or es thereof, wherein: ring B is independently selected from , , , , , and R1, at each occurrence, is independently selected from H, F, Cl, OH, CN, C1-4 alkyl, and OC1-4 alkyl; R2 is independently selected from C1-5 alkyl tuted with 0-3 Re; C2-5 alkenyl, phenyl substituted with 0-3 Re, 5- to 6-membered heteroaryl substituted with 0-3 Re, C3-6 cycloalkyl, and CH2O(CH2)1-3CH3; R5 is independently at each occurrence, selected from OH, , , , , , , , , , , , , , , , , , , , , and R8, at each occurrence, is independently selected from H, F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3, -C(=O)NH2, -(CH2)n-aryl substituted with 0-3 Re, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 R8a, at each ence, is independently ed from H, CH3, aryl substituted with 0-3 Re, and heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is ndently ed from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, and - (CH2)nOC1-4alkyl; and n, at each occurrence, is independently selected from zero, 1, 2, and 3.
In another , the present disclosure provides compounds of Formula (II), or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically able salts, prodrugs, or solvates thereof, wherein: R1, at each occurrence, is independently selected from F, Cl, OH, CH2CH3, -OCH3, and OCD3; R2 is independently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl, phenyl substituted with 0-3 Re, 5- to 6-membered heteroaryl substituted with 0-3 Re, C3-6 cycloalkyl, and CH2O(CH2)1-3CH3; R3 and R4 together with the nitrogen atom to which they are both attached form R5, at each occurrence, is independently selected from OH, F, and Cl; R5a, at each ence, is independently selected from , , , , , , , , , , , , , , , , and ; R8, at each occurrence, is independently selected from H, F, Cl, Br, -OCH3, -O(CH2)1- 3OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl tuted with 0-3 Re; R8a, at each occurrence, is independently selected from H, CH3, aryl substituted with 0-3 Re, and heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl tuted with 0-5 Re; Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - (CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 lkyl, -(CH2)n-C4-6 heterocyclyl, n-aryl, and -(CH2)n-heteroaryl; and n, at each ence, is independently selected from zero, 1, 2, and 3.
In another , the present disclosure provides compounds of Formula (I), or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein: R1, at each occurrence, is independently selected from -CH2OH, -OCH3, -OCH3, -OCF3, OCH2Ph, -C(=O)NRaRa, -NRaRa, CH3, , CH(CH3)2, and ropyl; R2 is ndently selected from C1-4 alkyl substituted with 0-3 Re; C2-4 alkenyl, phenyl substituted with 0-3 Re, 5- to 6-membered heteroaryl substituted with 0-3 Re, C3-6 cycloalkyl, and CH2O(CH2)1-3CH3; R3 is independently selected from H and C1-4 alkyl: R4 is independently selected from -(CHR7)1R6, -(CH2)1-3OR6, -(CH2)1-3NHR6, and - (CH2)0-3NHC(=O)R6; R6, at each occurrence, is independently selected from 7)n-aryl, -(CR7R7)n-C3-6 cycloalkyl, and -(CR7R7)n-heteroaryl, each substituted with 0-3 R8; R7, at each occurrence, is independently selected from H, C1-4 alkyl, and aryl; R8, at each occurrence, is independently selected from H, F, Cl, -ORb, -NRaRa, C1-4 alkyl substituted with 0-3 Re, phenyl substituted with 0-3 Re, and heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently ed from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-phenyl substituted with 0-5 Re, and -(CH2)n-heteroaryl substituted with 0-5 Re; Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl; and n is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the present sure provides compounds of Formula (IV): or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically able salts, prodrugs, or solvates thereof, wherein: R1, at each occurrence, is independently selected from F, Cl, OH, C1-2 alkyl, and OC1-2 alkyl; R2 is independently selected from -CH2CH2CH2CH3, -CH2CH2CH(CH3)2, CH2CH2CH2CF3, yclopropyl, -CH2CH2-cyclopropyl, cyclobutyl, cyclopentyl, CH2O(CH2)1-3CH3, CH2OCH(CH3)2, phenyl substituted with 0-2 Re, and 5- to 6-membered heteroaryl substituted with 0-2 Re; R5, at each occurrence, is ndently selected from , , , and R8, at each occurrence, is independently selected from F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3, -C(=O)NH2, -(CH2)n-aryl substituted with 0-3 Re, -(CH2)n-C3-6 cycloalkyl tuted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; and n is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the present disclosure provides compounds of Formula (IV), or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates f, wherein: R1 is both CH2CH3 or both OCH3; R2 is independently selected from , , , , and R5 is independently at each occurrence, selected from and R8, at each occurrence, is independently selected from F, Cl, Br, -OCH3, -OCF3, CN, CH3, and CF3; and Re, at each ence, is independently selected from F, Cl, Br, C1-3 alkyl, and ropyl.
In another aspect, the present disclosure provides compounds of Formula (V): or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates f, wherein: ring B is independently selected from , , , and ; R1, at each occurrence, is independently ed from H, F, Cl, OH, CN, and OC1-4 alkyl; R2 is independently selected from -CH2CH2CH2CH3, -CH2CH2CH(CH3)2, CH2CH2CH2CF3, -CH2-cyclopropyl, -CH2CH2-cyclopropyl, cyclobutyl, cyclopentyl, CH2O(CH2)1-3CH3, and (CH3)2, phenyl substituted with 0-2 Re, and 5- to 6-membered heteroaryl tuted with 0-2 Re; R5, at each occurrence, is independently selected from , , , and R8, at each occurrence, is independently selected from F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3, -C(=O)NH2, -(CH2)n-aryl substituted with 0-3 Re, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, n-C4-6 heterocyclyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; Re’ is independently selected from C1-2 alkyl, -CH2OC1-2 alkyl, and ropyl; and n is independently selected from zero, 1, 2, 3, and 4.
In another , the present disclosure provides compounds of Formula (VI): or stereoisomers, omers, reoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein: R1, at each occurrence, is independently ed from H, F, Cl, OH, CN, and OC1-4 alkyl; R2 is independently selected from -CH2CH2CH2CH3, -CH2CH2CH(CH3)2, CH2CH2CH2CF3, -CH2-cyclopropyl, -CH2CH2-cyclopropyl, cyclobutyl, cyclopentyl, CH2O(CH2)1-3CH3, and CH2OCH(CH3)2, , , , , and ; R5, at each occurrence, is independently selected from , , , and R8, at each occurrence, is independently selected from F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3, -C(=O)NH2, -(CH2)n-aryl substituted with 0-3 Re, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; Re’ is independently selected from C1-2 alkyl, -CH2OC1-2 alkyl, and ropyl; and n is ndently selected from zero, 1, 2, 3, and 4.
In another aspect, the present disclosure provides compounds of Formula (VII): (VII) or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates f, wherein: R1, at each occurrence, is independently selected from F, Cl, OH, C1-2 alkyl, and OC1-2 alkyl; R2 is ndently selected from 2CH2CH3, -CH2CH2CH(CH3)2, CH2CH2CH2CF3, -CH2-cyclopropyl, -CH2CH2-cyclopropyl, cyclobutyl, cyclopentyl, CH2O(CH2)1-3CH3, CH2OCH(CH3)2, phenyl substituted with 0-2 Re, and 5- to ered heteroaryl substituted with 0-2 Re; R3 and R4 together with the nitrogen atom to which they are both attached form a heterocyclic ring selected from and ; R5 is independently at each occurrence, selected from , , , and R5a is ; R8, at each occurrence, is independently selected from F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3, -C(=O)NH2, -(CH2)n-aryl tuted with 0-3 Re, -(CH2)n-C3-6 lkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; and n is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the present disclosure provides compounds of Formula (VIII): (VIII) or stereoisomers, enantiomers, diastereoisomers, tautomers, ceutically acceptable salts, prodrugs, or solvates thereof, wherein: R1 is both C1-2 alkyl or both -OC1-2 alkyl; R2 is independently selected from -CH2CH2CH2CH3, -CH2CH2CH(CH3)2, CH2CH2CH2CF3, -CH2-cyclopropyl, -CH2CH2-cyclopropyl, cyclobutyl, cyclopentyl, CH2O(CH2)1-3CH3, (CH3)2, phenyl substituted with 0-2 Re, and 5- to ered heteroaryl substituted with 0-2 Re; R5, at each occurrence, is independently selected from , , , and R8, at each occurrence, is independently selected from F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3, -C(=O)NH2, -(CH2)n-aryl substituted with 0-3 Re, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; and n is independently selected from zero, 1, 2, 3, and 4.
In another aspect, the present disclosure provides compounds of Formula (IX): or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates thereof, n: ring B is ; R1 is independently selected from H, F, Cl, OH, C1-3 alkyl, and OC1-3 alkyl; R1a is independently ed from F and Cl; R2 is independently selected from -CH2CH2CH2CH3, -CH2CH2CH(CH3)2, CH2CH2CH2CF3, yclopropyl, -CH2CH2-cyclopropyl, cyclobutyl, cyclopentyl, CH2O(CH2)1-3CH3, and CH2OCH(CH3)2, , , , , and ; R3 and R4 together with the en atom to which they are both attached form R5, at each occurrence, is independently selected from , , , and R8, at each occurrence, is independently selected from F, Cl, Br, -OCH3, -OCF3, CN, CH3, and CF3; and Re, at each occurrence, is independently selected from F, Cl, Br, and C1-3 alkyl.
In another embodiment of Formula (IX), ring B is , R1 is independently selected from H, F, Cl, OH, C1-3 alkyl, and OC1-3 alkyl, and other variables are as defined in Formula (IX).
In another embodiment of Formula (IX), ring B is , R1 is independently selected from H, F, Cl, OH, C1-3 alkyl, and OC1-3 alkyl, and other variables are as defined in a (IX).
In r embodiment of a (IX), ring B is , R1 is both CH2CH3 or both OCH3, R3 and R4 together with the nitrogen atom to which they are both attached form , and other variables are as defined in Formula (IX).
In another embodiment of Formula (IX), ring B is , R1 is both CH2CH3 or both OCH3, R3 and R4 together with the nitrogen atom to which they are both attached form , R5a is , and other variables are as defined in Formula (IX).
In another aspect, the present disclosure provides compounds of a (X): or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates thereof, n: ring B is independently selected from , , and ; R1, at each occurrence, is independently ed from H, F, Cl, OH, CN, and OC1-4 alkyl; R2 is independently selected from -CH2CH2CH2CH3, -CH2CH2CH(CH3)2, CH2CH2CH2CF3, -CH2-cyclopropyl, -CH2CH2-cyclopropyl, cyclobutyl, entyl, CH2O(CH2)1-3CH3, and CH2OCH(CH3)2, , , , and ; R3 and R4 together with the nitrogen atom to which they are both attached form R5, at each occurrence, is independently selected from , , , and R8, at each occurrence, is independently selected from F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3, -C(=O)NH2, -(CH2)n-aryl substituted with 0-3 Re, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl tuted with 0-3 Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; Re’ is independently selected from C1-2 alkyl, -CH2OC1-2 alkyl, and cyclopropyl; and n is ndently selected from zero, 1, 2, 3, and 4.
In another embodiment of Formula (X), ring B is , R1 is independently selected from H, F, Cl, and CN, R3 and R4 together with the nitrogen atom to which they are both attached form , and other variables are as defined in Formula (X).
In r embodiment of Formula (X), ring B is , R1 is independently ed from H, F, Cl, and CN, R3 and R4 together with the en atom to which they are both attached form ; R5a is , and other variables are as defined in Formula (X).
In another aspect, the present ion provides a compound selected from 2-Butyl(3-(5-chloropyridinyl)pyrrolidinecarbonyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (1), (R)Butyl(2,6-dicyclopropylphenyl)hydroxy(3-phenylpyrrolidine carbonyl)pyrimidin-4(1H)-one (2), 1-(2,6-Dimethoxyphenyl)(ethoxymethyl)hydroxy(3-(pyridin yl)pyrrolidinecarbonyl)pyrimidin-4(1H)-one (3), (S)(2-Cyclopropylethyl)(2,6-dimethoxyphenyl)hydroxy(3- phenylpyrrolidinecarbonyl)pyrimidin-4(1H)-one (4), (R)(2,6-Bis(methoxy-d3)phenyl)butylhydroxy(3-phenylpyrrolidine carbonyl)pyrimidin-4(1H)-one (5), 2-Butylhydroxy((S)phenylpropyl)((R)phenylpyrrolidine carbonyl)pyrimidin-4(3H)-one (6), 1-(2,6-dimethoxyphenyl)hydroxy(3-(2-methoxyphenyl)pyrrolidine carbonyl)(5-methylpyridinyl)pyrimidin-4(1H)-one (7), (R)(butenyl)hydroxy(2-methoxymethylphenyl)(3- phenylpyrrolidinecarbonyl)pyrimidin-4(3H)-one, diastereomer 1 and diastereomer (8), 1-(2,6-dimethoxyphenyl)hydroxy(isopropoxymethyl)(3-(p- tolyl)azetidinecarbonyl)pyrimidin-4(1H)-one (9), 2-(cyclopropoxymethyl)(2,6-dimethoxyphenyl)(3-(2- fluorophenyl)pyrrolidinecarbonyl)hydroxypyrimidin-4(1H)-one (10), (R)(cyclopropoxymethyl)(2,6-dimethoxyphenyl)hydroxy(3- phenylpyrrolidinecarbonyl)pyrimidin-4(3H)-one (11), (R)(2,6-dimethoxyphenyl)hydroxy(isopropoxymethyl)(3- phenylpyrrolidinecarbonyl)pyrimidin-4(1H)-one (12), 2-(cyclopropoxymethyl)(2,6-dimethoxyphenyl)(3-(2- fluorophenyl)pyrrolidinecarbonyl)hydroxypyrimidin-4(1H)-one (13), (R)(2,6-dimethoxyphenyl)hydroxyisopentyl(3-phenylpyrrolidine carbonyl)pyrimidin-4(1H)-one (14), 2-(cyclopropoxymethyl)(2,6-dimethoxyphenyl)(3-(3- phenyl)pyrrolidinecarbonyl)hydroxypyrimidin-4(1H)-one (15), (S)(butenyl)(2,6-dimethoxyphenyl)hydroxy(3- phenylpyrrolidinecarbonyl)pyrimidin-4(3H)-one (16), (R)(2,6-diethylphenyl)hydroxy(isopropoxymethyl)(3- pyrrolidinecarbonyl)pyrimidin-4(3H)-one (17), 1-(2,6-diethylphenyl)hydroxy(isopropoxymethyl)(3-(pyridin rolidinecarbonyl)pyrimidin-4(1H)-one (18), 2-(cyclopropoxymethyl)(2,6-dimethoxyphenyl)hydroxy(3-(otolyl )pyrrolidinecarbonyl)pyrimidin-4(1H)-one (19), (R)(cyclobutoxymethyl)(2,6-dimethoxyphenyl)hydroxy(3- phenylpyrrolidinecarbonyl)pyrimidin-4(3H)-one (20), -(3-(4-chlorophenyl)pyrrolidinecarbonyl)(cyclopropoxymethyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (21), -(3-(2-chlorophenyl)pyrrolidinecarbonyl)(cyclopropoxymethyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (22), (R)(2,6-dimethoxyphenyl)(ethoxymethyl)hydroxy(3- phenylpyrrolidinecarbonyl)pyrimidin-4(1H)-one (23), (S)(2,6-dimethoxyphenyl)hydroxyisopentyl(3-phenylpyrrolidine carbonyl)pyrimidin-4(1H)-one (24), 1-(2,6-diethylphenyl)(3-(2-fluorophenyl)pyrrolidinecarbonyl)hydroxy (isopropoxymethyl)pyrimidin-4(1H)-one (25), -(3-(3-chlorophenyl)pyrrolidinecarbonyl)(2,6-dimethoxyphenyl) (ethoxymethyl)hydroxypyrimidin-4(1H)-one (26), (R)(butenyl)(2,6-dimethoxyphenyl)hydroxy(3- phenylpyrrolidinecarbonyl)pyrimidin-4(3H)-one (27), -(3-(3-chlorophenyl)pyrrolidinecarbonyl)(cyclopropylmethyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (28), (S)(2,6-dimethoxyphenyl)(ethoxymethyl)hydroxy(3- phenylpyrrolidinecarbonyl)pyrimidin-4(1H)-one (29), (R)cyclopentyl(2,6-dimethoxyphenyl)hydroxy(3-phenylpyrrolidine carbonyl)pyrimidin-4(3H)-one (30), (S)(cyclopropylmethyl)(2,6-dimethoxyphenyl)hydroxy(3- phenylpyrrolidinecarbonyl)pyrimidin-4(3H)-one (31), (R)(cyclopropylmethyl)(2,6-dimethoxyphenyl)hydroxy(3- pyrrolidinecarbonyl)pyrimidin-4(3H)-one (32), (S)(2,6-dimethoxyphenyl)hydroxy(3-phenylpyrrolidinecarbonyl) (4,4,4-trifluorobutyl)pyrimidin-4(1H)-one (33), (S)cyclopentyl(2,6-dimethoxyphenyl)hydroxy(3-phenylpyrrolidine carbonyl)pyrimidin-4(3H)-one (34), (R)(butenyl)hydroxy(2-methoxymethylphenyl)(3- phenylpyrrolidinecarbonyl)pyrimidin-4(3H)-one (35), (S)(2,6-dimethoxyphenyl)hydroxy(3-phenylpyrrolidinecarbonyl) (4,4,4-trifluorobutyl)pyrimidin-4(1H)-one (36), (R)(2,6-dimethoxyphenyl)hydroxy(3-phenylpyrrolidinecarbonyl) -trifluorobutyl)pyrimidin-4(1H)-one (40), 2-butyl(3-(5-chloropyridinyl)pyrrolidinecarbonyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (41), 2-[(tert-butoxy)methyl][3-(2-chlorophenyl)pyrrolidinecarbonyl](2,6- dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (42), 2-butyl[3-(2-chlorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) y-1,4-dihydropyrimidinone (43), 2-[(tert-butoxy)methyl](2,6-dimethoxyphenyl)[3-(4- fluorophenyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (44), 2-butyl[3-(4-chlorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy-1,4-dihydropyrimidinone (45), 2-butyl[3-(4-chlorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy-1,4-dihydropyrimidinone (46), 2-butyl(2,6-dimethoxyphenyl)hydroxy[3-(pyridinyl)pyrrolidine carbonyl]-1,4-dihydropyrimidinone (47), l(2,6-dimethoxyphenyl)hydroxy[3-(pyridinyl)pyrrolidine carbonyl]-1,4-dihydropyrimidinone (48), 1-(2,6-dimethoxyphenyl)(ethoxymethyl)[3-(2-fluorophenyl)pyrrolidine carbonyl]hydroxy-1,4-dihydropyrimidinone (49), 2-[(tert-butoxy)methyl](2,6-dimethoxyphenyl)[3-(2- fluorophenyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (50), 2-[(tert-butoxy)methyl](2,6-dimethoxyphenyl)hydroxy[(3R) pyrrolidinecarbonyl]-1,4-dihydropyrimidinone (51), 2-butyl(2,6-dimethoxyphenyl)[3-(2-fluorophenyl)pyrrolidinecarbonyl] hydroxy-1,4-dihydropyrimidinone (52), 2-butyl(2,6-dimethoxyphenyl)[3-(2-fluorophenyl)pyrrolidinecarbonyl] hydroxy-1,4-dihydropyrimidinone (53), 1-(2,6-dimethoxyphenyl)(ethoxymethyl)hydroxy[3-(pyridin yl)pyrrolidinecarbonyl]-1,4-dihydropyrimidinone (54), 1-(2,6-dimethoxyphenyl)(ethoxymethyl)hydroxy[3-(pyridin yl)pyrrolidinecarbonyl]-1,4-dihydropyrimidinone (55), 2-butyl(2,6-dimethoxyphenyl)(5-fluoro-2,3-dihydro-1H-isoindole carbonyl)hydroxy-1,4-dihydropyrimidinone (56), 1-(2,6-dimethoxyphenyl)(ethoxymethyl)[3-(4-fluorophenyl)pyrrolidine carbonyl]hydroxy-1,4-dihydropyrimidinone (57), benzyl N-[(3S)[2-butyl(2,6-dimethoxyphenyl)hydroxyoxo-1,4- dihydropyrimidinecarbonyl]pyrrolidinyl]carbamate (58), 5-[(3R)(benzyloxy)pyrrolidinecarbonyl]butyl(2,6-dimethoxyphenyl)- 6-hydroxy-1,4-dihydropyrimidinone (59), 2-butyl(2,6-dimethoxyphenyl)hydroxy{1H,2H,3H-pyrrolo[3,4- dinecarbonyl}-1,4-dihydropyrimidinone (60), 2-butyl(2,6-dimethoxyphenyl)hydroxy{5H,6H,7H-pyrrolo[3,4- b]pyridinecarbonyl}-1,4-dihydropyrimidinone (61), benzyl N-[(3R)[2-butyl(2,6-dimethoxyphenyl)hydroxyoxo-1,4- dihydropyrimidinecarbonyl]pyrrolidinyl]carbamate (62), -[(3S)(benzyloxy)pyrrolidinecarbonyl]butyl(2,6-dimethoxyphenyl)- 6-hydroxy-1,4-dihydropyrimidinone (63), 2-butyl(2,6-dimethoxyphenyl)hydroxy[(3S)[(pyridin yl)methoxy]pyrrolidinecarbonyl]-1,4-dihydropyrimidinone (64), utyl(2,6-dimethoxyphenyl)hydroxyoxo-1,4-dihydropyrimidine carbonyl]-2,3-dihydro-1H-isoindolecarbonitrile (65), 2-butyl(2,3-dihydro-1H-isoindolecarbonyl)(2,6-dimethoxyphenyl) y-1,4-dihydropyrimidinone (66), 2-butyl(2,6-dimethoxyphenyl){3-[(4-fluorophenyl)methyl]pyrrolidine carbonyl}hydroxy-1,4-dihydropyrimidinone (67), 2-butyl(2,6-dimethoxyphenyl)hydroxy[3-(pyridinyl)pyrrolidine carbonyl]-1,4-dihydropyrimidinone (68), 2-butyl(2,6-dimethoxyphenyl){4-[(3-fluorophenyl)methyl]piperazine carbonyl}hydroxy-1,4-dihydropyrimidinone (69), 2-butyl(2,6-dimethoxyphenyl)hydroxy[3-(pyridinyl)pyrrolidine carbonyl]-1,4-dihydropyrimidinone (70), 2-butyl(2,6-dimethoxyphenyl)hydroxy[4-(pyridinyl)piperidine carbonyl]-1,4-dihydropyrimidinone (71), 2-butyl(2,6-dimethoxyphenyl)hydroxy(4-phenylpiperidinecarbonyl)- 1,4-dihydropyrimidinone (72), -(3-benzylpyrrolidinecarbonyl)butyl(2,6-dimethoxyphenyl)hydroxy- 1,4-dihydropyrimidinone (73), 2-butyl(2,6-dimethoxyphenyl)[4-(4-fluorophenyl)piperidinecarbonyl] hydroxy-1,4-dihydropyrimidinone (74), 2-butyl(2,6-dimethoxyphenyl)hydroxy[3-(pyridinyl)pyrrolidine carbonyl]-1,4-dihydropyrimidinone (75), l(2,6-dimethoxyphenyl)hydroxy[3-(pyridinyl)pyrrolidine carbonyl]-1,4-dihydropyrimidinone (76), 2-butyl(2,6-dimethoxyphenyl)[3-(4-fluorophenyl)pyrrolidinecarbonyl] hydroxy-1,4-dihydropyrimidinone (77), 2-butyl(2,6-dimethoxyphenyl)[3-(3-fluorophenyl)pyrrolidinecarbonyl] hydroxy-1,4-dihydropyrimidinone (78), 2-butyl(2,6-dimethoxyphenyl)[3-(4-fluorophenyl)pyrrolidinecarbonyl] hydroxy-1,4-dihydropyrimidinone (79), 2-butyl(2,6-dimethoxyphenyl)[3-(3-fluorophenyl)pyrrolidinecarbonyl] y-1,4-dihydropyrimidinone (80), 1-(2,6-dimethoxyphenyl)(ethoxymethyl)[3-(4-fluorophenyl)pyrrolidine carbonyl]hydroxy-1,4-dihydropyrimidinone (81), 1-(2,6-dimethoxyphenyl)(ethoxymethyl)hydroxy[3-(pyridin yl)pyrrolidinecarbonyl]-1,4-dihydropyrimidinone (82), 1-(2,6-dimethoxyphenyl)(ethoxymethyl)[3-(3-fluorophenyl)pyrrolidine carbonyl]hydroxy-1,4-dihydropyrimidinone (83), 1-(2,6-dimethoxyphenyl)(ethoxymethyl)[3-(3-fluorophenyl)pyrrolidine carbonyl]hydroxy-1,4-dihydropyrimidinone (84), 1-(2,6-dimethoxyphenyl)(ethoxymethyl)hydroxy[3-(pyridin yl)pyrrolidinecarbonyl]-1,4-dihydropyrimidinone (85), 2-butyl(2,6-diethylphenyl)hydroxy[(3S)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (86), 2-butyl(2,6-dimethoxyphenyl)[3-(4-fluorophenyl)pyrrolidinecarbonyl] hydroxy-3,4-dihydropyrimidinone (87), 2-butyl[3-(3-chlorophenyl)azetidinecarbonyl](2,6-dimethoxyphenyl) hydroxy-3,4-dihydropyrimidinone (88), 2-butyl(2,6-diethylphenyl)[3-(4-fluorophenyl)pyrrolidinecarbonyl] y-3,4-dihydropyrimidinone (89), 2-butyl(2,6-diethylphenyl)hydroxy[(3R)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (90), 2-butyl(2,6-dimethoxyphenyl)hydroxy[(3S)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (91), -[3-(2-chlorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy[(propanyloxy)methyl]-1,4-dihydropyrimidinone (92), -dimethoxyphenyl)[3-(2-fluorophenyl)pyrrolidinecarbonyl] hydroxy[(propanyloxy)methyl]-1,4-dihydropyrimidinone (93), 1-(2,6-dimethoxyphenyl)[3-(4-fluorophenyl)pyrrolidinecarbonyl] hydroxy[(propanyloxy)methyl]-1,4-dihydropyrimidinone (94), 1-(2,6-dimethoxyphenyl)[3-(3-fluorophenyl)pyrrolidinecarbonyl] hydroxy[(propanyloxy)methyl]-1,4-dihydropyrimidinone (95), 2-(2-cyclopropylethyl)(2,6-dimethoxyphenyl)hydroxy[(3R) phenylpyrrolidinecarbonyl]-1,4-dihydropyrimidinone (96), 1-(2,6-dimethoxyphenyl)[3-(3-fluorophenyl)pyrrolidinecarbonyl] hydroxy[(propanyloxy)methyl]-1,4-dihydropyrimidinone (97), 1-(2,6-dimethoxyphenyl)hydroxy[3-(2-methylphenyl)pyrrolidine carbonyl][(propanyloxy)methyl]-1,4-dihydropyrimidinone (98), -dimethoxyphenyl)hydroxy[(propanyloxy)methyl]{3-[2- (trifluoromethyl)phenyl]pyrrolidinecarbonyl}-1,4-dihydropyrimidinone (99), lopropoxymethyl)(2,6-dimethoxyphenyl)[3-(4- fluorophenyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (100), 1-(2,6-dimethoxyphenyl)hydroxy[(propanyloxy)methyl]{3-[2- (trifluoromethyl)phenyl]pyrrolidinecarbonyl}-1,4-dihydropyrimidinone (1010 1-(2,6-dimethoxyphenyl)[3-(4-fluorophenyl)pyrrolidinecarbonyl] hydroxy[(propanyloxy)methyl]-1,4-dihydropyrimidinone (102), 2-(cyclopropoxymethyl)(2,6-dimethoxyphenyl)[3-(4- phenyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (103), 1-[2,6-bis(²H₃)methoxyphenyl]butylhydroxy[(3S)phenylpyrrolidine carbonyl]-1,4-dihydropyrimidinone (104), 1-(2,6-dimethoxyphenyl)hydroxy[3-(2-methylphenyl)pyrrolidine carbonyl][(propanyloxy)methyl]-1,4-dihydropyrimidinone (105), 1-[2,6-bis(²H₃)methoxyphenyl](ethoxymethyl)hydroxy[(3R) phenylpyrrolidinecarbonyl]-1,4-dihydropyrimidinone (106), 4-{1-[1-(2,6-dimethoxyphenyl)hydroxyoxo[(propanyloxy)methyl]- 1,4-dihydropyrimidinecarbonyl]pyrrolidinyl}benzonitrile (107), 4-{1-[1-(2,6-dimethoxyphenyl)hydroxyoxo[(propanyloxy)methyl]- 1,4-dihydropyrimidinecarbonyl]pyrrolidinyl}benzonitrile (108), 1-[2,6-bis(²H₃)methoxyphenyl](ethoxymethyl)hydroxy[(3S) phenylpyrrolidinecarbonyl]-1,4-dihydropyrimidinone (109), 1-(2,6-dimethoxyphenyl)hydroxy(3-phenylazetidinecarbonyl) [(propanyloxy)methyl]-1,4-dihydropyrimidinone (110), 1-(2,6-dimethoxyphenyl)hydroxy[3-(4-methylphenyl)azetidinecarbonyl]- 2-[(propanyloxy)methyl]-1,4-dihydropyrimidinone (111), 2-butyl(4,6-dimethoxypyrimidinyl)hydroxy[(3S)phenylpyrrolidine- onyl]-3,4-dihydropyrimidinone (112), 2-butyl(4,6-dimethoxypyrimidinyl)hydroxy[(3R)phenylpyrrolidine- 1-carbonyl]-3,4-dihydropyrimidinone (113), 2-butyl[3-(2-fluorophenyl)pyrrolidinecarbonyl]hydroxy[(1S) phenylpropyl]-3,4-dihydropyrimidinone (114), 2-butyl[3-(3-fluorophenyl)pyrrolidinecarbonyl]hydroxy[(1S) phenylpropyl]-3,4-dihydropyrimidinone (115), 2-butylhydroxy[(1R)methoxyphenylethyl][(3R) phenylpyrrolidinecarbonyl]-3,4-dihydropyrimidinone (116), 2-butylhydroxy[(1R)phenylethyl][(3R)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (117), 2-butyl[3-(2-fluorophenyl)pyrrolidinecarbonyl]hydroxy[(1S) phenylpropyl]-3,4-dihydropyrimidinone (118), l[3-(3-fluorophenyl)pyrrolidinecarbonyl]hydroxy[(1S) phenylpropyl]-3,4-dihydropyrimidinone (119), 2-butylhydroxy[(1S)(3-methoxyphenyl)ethyl][(3S) phenylpyrrolidinecarbonyl]-3,4-dihydropyrimidinone (120), 2-butylhydroxy[(1S)phenylpropyl][(3S)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (121), 2-butylhydroxy[(1R)(2-methoxyphenyl)ethyl][(3R) phenylpyrrolidinecarbonyl]-3,4-dihydropyrimidinone (122), 2-butylhydroxy(1-phenylethyl)[(3R)phenylpyrrolidinecarbonyl]- 3,4-dihydropyrimidinone (123), 2-butylhydroxy[(1R)phenylpropyl][(3R)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (124), 2-butylhydroxy[(1S)phenylethyl][(3S)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (125), 2-butyl[(1S)cyclopropylethyl]hydroxy[(3R)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (126), 2-butylhydroxy[(1R)methoxyphenylethyl][(3S) phenylpyrrolidinecarbonyl]-3,4-dihydropyrimidinone (127), 2-butylhydroxy[(1R)phenylpropyl][(3S)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (128), 2-butylhydroxy(2-methylphenylpropyl)[(3S)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (129), 2-butylhydroxy(2-methylphenylpropyl)[(3R)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (130), l[(1S)cyclopropylethyl]hydroxy[(3S)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (131), 2-butylhydroxy[(1R)phenylethyl][(3S)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (132), 2-butyl[1-(2-chlorophenyl)ethyl]hydroxy[(3S)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (133), 2-butyl[1-(2-chlorophenyl)ethyl]hydroxy[(3R)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (134), 2-butylhydroxy[(1R)(2-methoxyphenyl)ethyl][(3S) phenylpyrrolidinecarbonyl]-3,4-dihydropyrimidinone (135), 2-butylhydroxy(1-phenylethyl)[(3S)phenylpyrrolidinecarbonyl]- 3,4-dihydropyrimidinone (136), 2-butylhydroxy[(1S)phenylbutyl][(3R)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (137), ){2-butylhydroxyoxo[(3R)phenylpyrrolidinecarbonyl]- 1,6-dihydropyrimidinyl}ethyl]benzonitrile (138), 2-butylhydroxy[(1S)(3-methoxyphenyl)ethyl][(3R) phenylpyrrolidinecarbonyl]-3,4-dihydropyrimidinone (139), 2-butylhydroxy[(3R)phenylpyrrolidinecarbonyl][1-(pyridin yl]-3,4-dihydropyrimidinone (140), 2-butylhydroxy[(1S)phenylethyl][(3R)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (141), 2-butyl[(1R)cyclopropylethyl]hydroxy[(3R)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (142), 2-butyl[(1S)(4-fluorophenyl)ethyl]hydroxy[(3S)phenylpyrrolidine- 1-carbonyl]-3,4-dihydropyrimidinone (143), 2-butylhydroxy[(3S)phenylpyrrolidinecarbonyl][(1S)-1,2,3,4- tetrahydronaphthalenyl]-3,4-dihydropyrimidinone (144), 2-butyl[(1R)-2,3-dihydro-1H-indenyl]hydroxy[(3R) phenylpyrrolidinecarbonyl]-3,4-dihydropyrimidinone (145), 2-butylhydroxy[(3S)phenylpyrrolidinecarbonyl][1-(pyridin yl)ethyl]-3,4-dihydropyrimidinone (146), 2-butylhydroxy[(3R)phenylpyrrolidinecarbonyl][(1S)-1,2,3,4- tetrahydronaphthalenyl]-3,4-dihydropyrimidinone (147), 2-butylhydroxy[(3R)phenylpyrrolidinecarbonyl][1-(pyridin yl)ethyl]-3,4-dihydropyrimidinone (148), 3-[(1S){2-butylhydroxyoxo[(3S)phenylpyrrolidinecarbonyl]-1,6- dihydropyrimidinyl}ethyl]benzonitrile (149), 2-butylhydroxy[(3R)phenylpyrrolidinecarbonyl](propanyl)-3,4- dihydropyrimidinone (150), lhydroxy[(1S)(2-methoxyphenyl)ethyl][(3S) phenylpyrrolidinecarbonyl]-3,4-dihydropyrimidinone (151), 2-butylhydroxy[(1S)methoxyphenylethyl][(3R) phenylpyrrolidinecarbonyl]-3,4-dihydropyrimidinone (152), 2-butylhydroxy[(1S)phenylbutyl][(3S)phenylpyrrolidine carbonyl]-3,4-dihydropyrimidinone (153), 2-butylhydroxy[(1S)methoxyphenylethyl][(3S) phenylpyrrolidinecarbonyl]-3,4-dihydropyrimidinone (154), 2-butyl[(1R)cyclopropylethyl]hydroxy[(3S)phenylpyrrolidine yl]-3,4-dihydropyrimidinone (155), 2-butylhydroxy[(1S)(2-methoxyphenyl)ethyl][(3R) phenylpyrrolidinecarbonyl]-3,4-dihydropyrimidinone (156), 2-butyl[(1S)(4-fluorophenyl)ethyl]hydroxy[(3R)phenylpyrrolidine- 1-carbonyl]-3,4-dihydropyrimidinone (157), l[(1R)-2,3-dihydro-1H-indenyl]hydroxy[(3S) phenylpyrrolidinecarbonyl]-3,4-dihydropyrimidinone (158), 2-butylhydroxy[(3S)phenylpyrrolidinecarbonyl](propanyl)-3,4- dihydropyrimidinone (159), 1-(2,6-dimethoxyphenyl)hydroxy[3-(2-methoxyphenyl)pyrrolidine carbonyl][(propanyloxy)methyl]-1,4-dihydropyrimidinone (160), 1-(2,6-dimethoxyphenyl)hydroxy[3-(2-methoxyphenyl)pyrrolidine carbonyl][(propanyloxy)methyl]-1,4-dihydropyrimidinone (161), -[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy[(propanyloxy)methyl]-1,4-dihydropyrimidinone (162), -[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy[(propanyloxy)methyl]-1,4-dihydropyrimidinone (163), -[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy[(propanyloxy)methyl]-1,4-dihydropyrimidinone (164), 2-{1-[1-(2,6-dimethoxyphenyl)hydroxyoxo[(propanyloxy)methyl]- 1,4-dihydropyrimidinecarbonyl]pyrrolidinyl}benzonitrile (165), 5-[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy[(propanyloxy)methyl]-1,4-dihydropyrimidinone (166), 1-(2,6-dimethoxyphenyl)hydroxyoxo[(propanyloxy)methyl]- 1,4-dihydropyrimidinecarbonyl]pyrrolidinyl}benzonitrile (167), 2-(2-cyclopropylethyl)[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl] (2,6-dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (168), 2-(2-cyclopropylethyl)[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl] (2,6-dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (169), -[3-(5-chloropyridinyl)pyrrolidinecarbonyl](2-cyclopropylethyl)(2,6- dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (170), 5-[3-(5-chloropyridinyl)pyrrolidinecarbonyl](2-cyclopropylethyl)(2,6- oxyphenyl)hydroxy-1,4-dihydropyrimidinone (171), -[3-(5-chloropyridinyl)-2,5-dihydro-1H-pyrrolecarbonyl](2- cyclopropylethyl)(2,6-dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (172), 2-(2-cyclopropylethyl){4-[(2,3-difluorophenyl)methyl]piperazinecarbonyl}- 1-(2,6-dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (173), -[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl](2,6- diethylphenyl)hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (174), 2-(2-cyclopropylethyl)(2,6-dimethoxyphenyl)[3-(5-fluoropyridin yl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (175), -[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl](2- cyclopropylethyl)(2,6-dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (176), 2-(2-cyclopropylethyl)(2,6-dimethoxyphenyl)[3-(5-fluoropyridin yl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (177), 2-(2-cyclopropylethyl)(2,6-dimethoxyphenyl)[3-(3-fluoropyridin yl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (178), 2-(2-cyclopropylethyl)(2,6-dimethoxyphenyl)[3-(3-fluoropyridin yl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (179), 5-[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl](2- ropylethyl)(2,6-dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (180), 1-[(1S)(3,5-difluorophenyl)propyl](1-ethyl-1H-pyrazolyl)[3-(3- fluoropyridinyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (181), 1-[(1S)(3,5-difluorophenyl)propyl][3-(3,5-difluoropyridinyl)pyrrolidine- 1-carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (182), -[3-(5-chloropyridinyl)pyrrolidinecarbonyl][(1S)(3,5- difluorophenyl)propyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidin- 4-one (183), )(3,5-difluorophenyl)propyl][3-(3,5-difluoropyridinyl)pyrrolidine- 1-carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (184), 1-[(1S)(3,5-difluorophenyl)propyl][3-(5-fluoropyridinyl)pyrrolidine carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (185), 1-[(1S)(3,5-difluorophenyl)propyl](1-ethyl-1H-pyrazolyl)[3-(3- fluoropyridinyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (186), -[3-(5-chloropyridinyl)pyrrolidinecarbonyl][(1S)(3,5- difluorophenyl)propyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidin- 4-one (187), 1-[(1S)(3,5-difluorophenyl)propyl][3-(3,5-difluoropyridinyl)pyrrolidine- 1-carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (188), 1-[(1S)(3,5-difluorophenyl)propyl][3-(3-fluoropyridinyl)pyrrolidine carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (189), -[3-(5-chloropyridinyl)pyrrolidinecarbonyl][(1S)(3,5- difluorophenyl)propyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidin- 4-one (190), 1-[(1S)(3,5-difluorophenyl)propyl][3-(5-fluoropyridinyl)pyrrolidine carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (191), 1-[(1S)(3,5-difluorophenyl)propyl][3-(3,5-difluoropyridinyl)pyrrolidine- 1-carbonyl](1-ethyl-1H-pyrazolyl)hydroxy-1,4-dihydropyrimidinone (192), )(3,5-difluorophenyl)propyl][3-(2-fluorophenyl)pyrrolidine carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (193), 1-[(1S)(3,5-difluorophenyl)propyl][3-(4-fluorophenyl)pyrrolidine carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (194), 1-[(1S)(3,5-difluorophenyl)propyl]hydroxy[3-(2- methoxyphenyl)pyrrolidinecarbonyl](1-methyl-1H-pyrazolyl)-1,4- dihydropyrimidinone (195), 1-[(1S)(3,5-difluorophenyl)propyl][3-(2-fluorophenyl)pyrrolidine carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (196), 1-[(1S)(3,5-difluorophenyl)propyl][3-(4-fluorophenyl)pyrrolidine carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (197), 1-[(1S)(3,5-difluorophenyl)propyl]hydroxy[3-(2- methoxyphenyl)pyrrolidinecarbonyl](1-methyl-1H-pyrazolyl)-1,4- opyrimidinone (198), )(3,5-difluorophenyl)propyl][3-(5-fluoropyridinyl)pyrrolidine carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (199), 1-[(1S)(3,5-difluorophenyl)propyl][3-(4-fluoropyridinyl)pyrrolidine carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (200), 1-[(1S)(3,5-difluorophenyl)propyl][3-(3-fluoropyridinyl)pyrrolidine yl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (201), 1-[(1S)(3,5-difluorophenyl)propyl](1-ethyl-1H-pyrazolyl)[3-(4- fluoropyridinyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (202), 1-[(1S)(3,5-difluorophenyl)propyl][3-(4-fluoropyridinyl)pyrrolidine carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (203), 1-[(1S)(3,5-difluorophenyl)propyl][3-(3-fluoropyridinyl)pyrrolidine yl]hydroxy(4-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (204), 1-((S)(3,5-difluorophenyl)propyl)(3-(4-fluoropyridinyl)pyrrolidine carbonyl)hydroxy(4-methylthiazolyl)pyrimidin-4(1H)-one (205), 1-[(1S)(3,5-difluorophenyl)propyl][3-(5-fluoropyridinyl)pyrrolidine carbonyl]hydroxy(4-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (206), 1-[(1S)(3,5-difluorophenyl)propyl]hydroxy[3-(2- methoxyphenyl)pyrrolidinecarbonyl](4-methyl-1,3-thiazolyl)-1,4- dihydropyrimidinone (207), 1-[(1S)(3,5-difluorophenyl)propyl][3-(2-fluorophenyl)pyrrolidine carbonyl]hydroxy(4-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (208), -[3-(5-chloropyridinyl)pyrrolidinecarbonyl][(1S)(3,5- difluorophenyl)propyl]hydroxy(4-methyl-1,3-thiazolyl)-1,4-dihydropyrimidin one (209), 1-[(1S)(3,5-difluorophenyl)propyl][3-(3,5-difluoropyridinyl)pyrrolidine- 1-carbonyl]hydroxy(4-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (210), 1-[(1S)(3,5-difluorophenyl)propyl][3-(4-fluorophenyl)pyrrolidine carbonyl]hydroxy(4-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (211), 1-[(1S)(3,5-difluorophenyl)propyl](1-ethyl-1H-pyrazolyl)[3-(3- fluoropyridinyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (212), -[3-(5-chloropyridinyl)pyrrolidinecarbonyl][(1S)(3,5- difluorophenyl)propyl](1-ethyl-1H-pyrazolyl)hydroxy-1,4-dihydropyrimidin one (213), 5-[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl][(1S)(3,5- difluorophenyl)propyl](1-ethyl-1H-pyrazolyl)hydroxy-1,4-dihydropyrimidin one (214), 1-[(1S)(3,5-difluorophenyl)propyl][3-(3,5-difluoropyridinyl)pyrrolidine- 1-carbonyl](1-ethyl-1H-pyrazolyl)hydroxy-1,4-dihydropyrimidinone (215), 1-[(1S)(3,5-difluorophenyl)propyl](1-ethyl-1H-pyrazolyl)[3-(5- fluoropyridinyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (216), 1-[(1S)(3,5-difluorophenyl)propyl][3-(3,5-difluoropyridinyl)pyrrolidine- 1-carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (217), -[3-(5-chloropyridinyl)pyrrolidinecarbonyl][(1S)(3,5- difluorophenyl)propyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidin- 4-one (218), 1-[(1S)(3,5-difluorophenyl)propyl][3-(3-fluoropyridinyl)pyrrolidine carbonyl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (219), 1-[(1S)(3,5-difluorophenyl)propyl][3-(5-fluoropyridinyl)pyrrolidine yl]hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (220), 1-(2,6-diethylphenyl)hydroxy[(propanyloxy)methyl][3-(pyridin yl)pyrrolidinecarbonyl]-1,4-dihydropyrimidinone (221), -[4-(6-chloropyridinyl)piperidinecarbonyl](2,6-diethylphenyl) hydroxy[(propanyloxy)methyl]-3,4-dihydropyrimidinone (222), -[3-(4-chlorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl)(4- phenyl)hydroxy-1,4-dihydropyrimidinone (223), -dimethoxyphenyl)(4-fluorophenyl)hydroxy[3-(pyridin yl)pyrrolidinecarbonyl]-1,4-dihydropyrimidinone (224), 1-(2,6-dimethoxyphenyl)(4-fluorophenyl)[3-(2-fluorophenyl)pyrrolidine carbonyl]hydroxy-1,4-dihydropyrimidinone (225), 2-(cyclopropylmethyl)(2,6-dimethoxyphenyl)[3-(2- fluorophenyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (226), -[4-(6-chloropyridinyl)piperidinecarbonyl](cyclopropylmethyl)(2,6- dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (227), -[3-(4-chlorophenyl)pyrrolidinecarbonyl](cyclopropylmethyl)(2,6- dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (228), 5-[3-(2-chlorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl)(4- fluorophenyl)hydroxy-1,4-dihydropyrimidinone (229), 2-(cyclopropylmethyl)(2,6-dimethoxyphenyl)hydroxy[3-(pyridin yl)pyrrolidinecarbonyl]-1,4-dihydropyrimidinone (230), 1-(2,6-dimethoxyphenyl)[(4-fluorophenyl)methyl][3-(2- fluorophenyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (231), 1-(2,6-dimethoxyphenyl)[3-(4-fluorophenyl)pyrrolidinecarbonyl] hydroxy(5-methylpyridinyl)-1,4-dihydropyrimidinone (232), 1-(2,6-dimethoxyphenyl)[3-(2-fluorophenyl)pyrrolidinecarbonyl] hydroxy(5-methylpyridinyl)-1,4-dihydropyrimidinone (233), 1-(2,6-dimethoxyphenyl)hydroxy[3-(2-methoxyphenyl)pyrrolidine carbonyl](5-methylpyridinyl)-1,4-dihydropyrimidinone (234), -[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl)- 6-hydroxy(6-methylpyridinyl)-1,4-dihydropyrimidinone (235), -dimethoxyphenyl)[3-(2-fluorophenyl)pyrrolidinecarbonyl] hydroxy(6-methylpyridinyl)-1,4-dihydropyrimidinone (236), 2-{1-[2-(3-chlorophenyl)(2,6-dimethoxyphenyl)hydroxyoxo-1,4- dihydropyrimidinecarbonyl]pyrrolidinyl}benzonitrile (237), 2-(3-chlorophenyl)[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl](2,6- oxyphenyl)hydroxy-1,4-dihydropyrimidinone (238), 1-(2,6-dimethoxyphenyl)[3-(2-fluorophenyl)pyrrolidinecarbonyl] hydroxy(4-methylpyridinyl)-1,4-dihydropyrimidinone (239), 1-(2,6-dimethoxyphenyl)hydroxy(4-methylpyridinyl)oxo-1,4- dihydropyrimidinecarbonyl]pyrrolidinyl}benzonitrile (240), -[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(3-methylphenyl)-1,4-dihydropyrimidinone (241), 2-{1-[1-(2,6-dimethoxyphenyl)hydroxy(3-methylphenyl)oxo-1,4- dihydropyrimidinecarbonyl]pyrrolidinyl}benzonitrile (242 ), 2-{1-[2-(5-chloropyridinyl)(2,6-dimethoxyphenyl)hydroxyoxo-1,4- dihydropyrimidinecarbonyl]pyrrolidinyl}benzonitrile (243), -[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl)- 6-hydroxy(3-methylphenyl)-1,4-dihydropyrimidinone (244), 1-(2,6-dimethoxyphenyl)[3-(3-fluoropyridinyl)pyrrolidinecarbonyl] hydroxy(3-methoxyphenyl)-1,4-dihydropyrimidinone (245), 3,5-difluoropyridinyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl)- 6-hydroxy(3-methoxyphenyl)-1,4-dihydropyrimidinone (246), 2-(5-chloropyridinyl)[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6- dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (247), 5-[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (248), -[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (249), -[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (25 ), -[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) y(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (251), -[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(6-methylpyridinyl)-1,4-dihydropyrimidinone (252), 5-[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(6-methylpyridinyl)-1,4-dihydropyrimidinone (253), -[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(2-methylpyridinyl)-1,4-dihydropyrimidinone (254), 1-(2,6-dimethoxyphenyl)(4-fluoromethylphenyl)[3-(3-fluoropyridin yl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (255), -[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl)- 2-(4-fluoromethylphenyl)hydroxy-1,4-dihydropyrimidinone (256), -[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(2-methylpyridinyl)-1,4-dihydropyrimidinone (257), 1-(2,6-diethylphenyl)[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl] hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (258), -chlorofluoropyridinyl)pyrrolidinecarbonyl](2,6- dimethoxyphenyl)hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (259), 2-(5-chloropyridinyl)[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6- dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (260), -[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl](2,6- dimethoxyphenyl)hydroxy(3-methoxyphenyl)-1,4-dihydropyrimidinone (261), -[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(4-methylpyridinyl)-1,4-dihydropyrimidinone (262), 5-chlorofluoropyridinyl)pyrrolidinecarbonyl](2,6- dimethoxyphenyl)hydroxy(3-methylphenyl)-1,4-dihydropyrimidinone (263), -[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl](3-chlorophenyl) (2,6-dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (264), -chlorofluoropyridinyl)pyrrolidinecarbonyl](2,6- dimethoxyphenyl)(4-fluorophenyl)hydroxy-1,4-dihydropyrimidinone (265), -[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(2-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (266), 1-(2,6-diethylphenyl)[3-(2,6-difluorophenyl)pyrrolidinecarbonyl] hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (267), 1-(2,6-diethylphenyl)[3-(2-fluorophenyl)pyrrolidinecarbonyl]hydroxy (1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (268), -[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl)(1- ethyl-1H-pyrazolyl)hydroxy-1,4-dihydropyrimidinone (269), -[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) y(2-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (270), -[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(4-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (271), 1-(2,6-diethylphenyl)[3-(4-fluorophenyl)pyrrolidinecarbonyl]hydroxy (1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (272), 5-[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(4-methoxypyridinyl)-1,4-dihydropyrimidinone (273), -[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(5-methylpyridinyl)-1,4-dihydropyrimidinone (274), 1-(2,6-diethylphenyl)[3-(3-fluoropyridinyl)pyrrolidinecarbonyl] hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (275), -[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl)(1- ethyl-1H-pyrazolyl)hydroxy-1,4-dihydropyrimidinone (276), -[4-(2,3-difluorophenoxy)piperidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(2-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (277), -[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(4-methoxypyridinyl)-1,4-dihydropyrimidinone (278), 2-(6-chloropyridinyl)[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6- dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (279), 2-(5-chloropyridinyl)[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6- dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (280), 2-(6-chloropyridinyl)[3-(2,6-difluorophenyl)pyrrolidinecarbonyl](2,6- dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (281), -[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6-dimethoxyphenyl) hydroxy(5-methylpyridinyl)-1,4-dihydropyrimidinone (282), 1-(2,6-diethylphenyl)hydroxy(1-methyl-1H-pyrazolyl)[(3R) phenylpyrrolidinecarbonyl]-1,4-dihydropyrimidinone (283), 1-(2,6-dimethoxyphenyl)(1-ethyl-1H-pyrazolyl)hydroxy[(3R) phenylpyrrolidinecarbonyl]-1,4-dihydropyrimidinone (284), 1-(2,6-diethylphenyl)hydroxy(1-methyl-1H-pyrazolyl)[(3S) phenylpyrrolidinecarbonyl]-1,4-dihydropyrimidinone (285), 1-(2,6-dimethoxyphenyl)(1-ethyl-1H-pyrazolyl)hydroxy[(3S) phenylpyrrolidinecarbonyl]-1,4-dihydropyrimidinone (286), hloropyridinyl)[3-(2,4-difluorophenyl)pyrrolidinecarbonyl](2,6- dimethoxyphenyl)hydroxy-1,4-dihydropyrimidinone (287), 2-(1-ethyl-1H-pyrazolyl)hydroxy[(3S)phenylpyrrolidinecarbonyl]- 1-[3-(propanyl)phenyl]-1,4-dihydropyrimidinone (288), 1-(2,6-diethylphenyl)hydroxy[(3S)phenylpyrrolidinecarbonyl][1- nyl)-1H-pyrazolyl]-1,4-dihydropyrimidinone (289), -[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl](2,6- lphenyl)hydroxy[1-(propanyl)-1H-pyrazolyl]-1,4-dihydropyrimidin one (290), 2-(1-ethyl-1H-pyrazolyl)hydroxy[(3R)phenylpyrrolidinecarbonyl]- 1-[3-(propanyl)phenyl]-1,4-dihydropyrimidinone (291), 1-(2,6-diethylphenyl)[3-(3-fluoropyridinyl)pyrrolidinecarbonyl] hydroxy[1-(propanyl)-1H-pyrazolyl]-1,4-dihydropyrimidinone (292), -[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl](1-ethyl-1H-pyrazol yl)hydroxy[3-(propanyl)phenyl]-1,4-dihydropyrimidinone (293), 2-(1-ethyl-1H-pyrazolyl)[3-(2-fluorophenyl)pyrrolidinecarbonyl] hydroxy[3-(propanyl)phenyl]-1,4-dihydropyrimidinone (294), 1-(2,6-diethylphenyl)[3-(2-fluorophenyl)pyrrolidinecarbonyl]hydroxy opanyl)-1H-pyrazolyl]-1,4-dihydropyrimidinone (295), -[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl](2,6- diethylphenyl)hydroxy(2-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (296), 1-(2,6-diethylphenyl)[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl] hydroxy[2-(propanyl)-1,3-thiazolyl]-1,4-dihydropyrimidinone (297), 1-(2,6-diethylphenyl)[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl] y(2-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (298), 1-(2,6-diethylphenyl)hydroxy[(3S)phenylpyrrolidinecarbonyl][2- (propanyl)-1,3-thiazolyl]-1,4-dihydropyrimidinone (299), 1-(2,6-diethylphenyl)[3-(5-fluoropyridinyl)pyrrolidinecarbonyl] hydroxy[2-(propanyl)-1,3-thiazolyl]-1,4-dihydropyrimidinone (300), 1-(2,6-diethylphenyl)hydroxy(2-methyl-1,3-thiazolyl)[(3R) phenylpyrrolidinecarbonyl]-1,4-dihydropyrimidinone (301), 1-(2,6-diethylphenyl)[3-(3-fluoropyridinyl)pyrrolidinecarbonyl] hydroxy(2-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (302), 1-(2,6-diethylphenyl)hydroxy(2-methyl-1,3-thiazolyl)[(3S) phenylpyrrolidinecarbonyl]-1,4-dihydropyrimidinone (303), -[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl](2,6- diethylphenyl)hydroxy(1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (304), 1-(2,6-diethylphenyl)[3-(2-fluorophenyl)pyrrolidinecarbonyl]hydroxy (1-methyl-1H-pyrazolyl)-1,4-dihydropyrimidinone (305), -[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl](2,6- diethylphenyl)hydroxy(4-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (306), -diethylphenyl)[3-(3-fluoropyridinyl)pyrrolidinecarbonyl] hydroxy(4-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (307), 1-(2,6-diethylphenyl)(1-ethyl-1H-pyrazolyl)[3-(3-fluoropyridin rolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (308), 1-(2,6-diethylphenyl)[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl](1- ethyl-1H-pyrazolyl)hydroxy-1,4-dihydropyrimidinone (309), 1-(2,6-diethylphenyl)(1-ethyl-1H-pyrazolyl)[3-(2- fluorophenyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (310), -[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl](2,6- diethylphenyl)(1-ethyl-1H-pyrazolyl)hydroxy-1,4-dihydropyrimidinone (311), -[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl](2,6- diethylphenyl)hydroxy(4-methyl-1,3-thiazolyl)-1,4-dihydropyrimidinone (312), -[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl](2,6- diethylphenyl)(1-ethyl-1H-pyrazolyl)hydroxy-1,4-dihydropyrimidinone (313), 2-(4-fluoromethylphenyl)hydroxy[(1S)phenylpropyl][(3R) phenylpyrrolidinecarbonyl]-1,4-dihydropyrimidinone (314), -diethylphenyl)[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl](1- ethyl-1H-pyrazolyl)hydroxy-1,4-dihydropyrimidinone (315), 2-(1-cyclopropyl-1H-pyrazolyl)(2,6-diethylphenyl)hydroxy[(3S) phenylpyrrolidinecarbonyl]-1,4-dihydropyrimidinone (316), 1-(2,6-diethylphenyl)hydroxy[1-(2-methylpropyl)-1H-pyrazolyl][(3S)- 3-phenylpyrrolidinecarbonyl]-1,4-dihydropyrimidinone (317), 1-(2,6-diethylphenyl)[3-(5-fluoropyridinyl)pyrrolidinecarbonyl] hydroxy[1-(2-methylpropyl)-1H-pyrazolyl]-1,4-dihydropyrimidinone (318), 2-(1-cyclopropyl-1H-pyrazolyl)(2,6-diethylphenyl)[3-(3-fluoropyridin yl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (319), 1-(2,6-diethylphenyl)[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl] hydroxy[1-(2-methylpropyl)-1H-pyrazolyl]-1,4-dihydropyrimidinone (320), -[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl]hydroxy(4-methyl- 1,3-thiazolyl)[(1S)phenylpropyl]-1,4-dihydropyrimidinone (321), -[3-(5-fluoropyridinyl)pyrrolidinecarbonyl]hydroxy(4-methyl-1,3- thiazolyl)[(1S)phenylpropyl]-1,4-dihydropyrimidinone (322), 5-[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl]hydroxy(4- methyl-1,3-thiazolyl)[(1S)phenylpropyl]-1,4-dihydropyrimidinone (323), -[3-(2-fluorophenyl)pyrrolidinecarbonyl]hydroxy(4-methyl-1,3-thiazol- 2-yl)[(1S)phenylpropyl]-1,4-dihydropyrimidinone (324), 2-(1-cyclopropyl-1H-pyrazolyl)(2,6-diethylphenyl)[3-(3,5- difluoropyridinyl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (325), -[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl][(1S)(3,5- difluorophenyl)methylpropyl](1-ethyl-1H-pyrazolyl)hydroxy-1,4- dihydropyrimidinone (326), 1-[(1S)(3,5-difluorophenyl)methylpropyl][3-(3,5-difluoropyridin yl)pyrrolidinecarbonyl](1-ethyl-1H-pyrazolyl)hydroxy-1,4-dihydropyrimidin- 4-one (327), 2-(1-cyclopropyl-1H-pyrazolyl)(2,6-diethylphenyl)[3-(5-fluoropyridin yl)pyrrolidinecarbonyl]hydroxy-1,4-dihydropyrimidinone (328), 6-hydroxy[(1R)methoxyphenylethyl][(3R)phenylpyrrolidine carbonyl]propyl-3,4-dihydropyrimidinone (329), oxy[(1R)methoxyphenylethyl][(3S)phenylpyrrolidine carbonyl]propyl-3,4-dihydropyrimidinone (330), 3-[(1S){2-butylhydroxyoxo[(3R)phenylpyrrolidinecarbonyl]- 1,6-dihydropyrimidinyl}propyl]benzonitrile (331), 3-[(1S){2-butyl[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl] hydroxyoxo-1,6-dihydropyrimidinyl}propyl]benzonitrile (332), 3-[(1S){2-butyl[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl] hydroxyoxo-1,6-dihydropyrimidinyl}propyl]benzonitrile (333), ){4-hydroxyoxo[(3R)phenylpyrrolidinecarbonyl][(propan- 2-yloxy)methyl]-1,6-dihydropyrimidinyl}propyl]benzonitrile (334), 3-[(1S){2-butyl[3-(5-fluoropyridinyl)pyrrolidinecarbonyl]hydroxy- 1,6-dihydropyrimidinyl}propyl]benzonitrile (335), 3-[(1S){2-butyl[3-(5-fluoropyridinyl)pyrrolidinecarbonyl]hydroxy- 6-oxo-1,6-dihydropyrimidinyl}propyl]benzonitrile (336 ), 3-[(S)-{2-butyl[3-(5-chloropyridinyl)pyrrolidinecarbonyl]hydroxy oxo-1,6-dihydropyrimidinyl}(cyclopropyl)methyl]benzonitrile (337), 3-[(S)-{2-butyl[3-(5-chloropyridinyl)pyrrolidinecarbonyl]hydroxy oxo-1,6-dihydropyrimidinyl}(cyclopropyl)methyl]benzonitrile (338), 3-[(1S){2-butyl[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl] hydroxyoxo-1,6-dihydropyrimidinyl}propyl]benzonitrile (339), 2-butyl[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl]hydroxy[(1S)- 1-(3-methoxyphenyl)propyl]-3,4-dihydropyrimidinone (340), 2-butyl[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl][(1S) (3,5-difluorophenyl)propyl]hydroxy-3,4-dihydropyrimidinone (341), 2-butyl[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl][(1S) (3,5-difluorophenyl)propyl]hydroxy-3,4-dihydropyrimidinone (342), 2-butyl[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl]hydroxy[(1S)- 1-phenylpropyl]-3,4-dihydropyrimidinone (343), 2-butyl[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl]hydroxy [(1S)phenylpropyl]-3,4-dihydropyrimidinone (344), l[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl]hydroxy[(1S)- 1-phenylpropyl]-3,4-dihydropyrimidinone (345), 2-butyl[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl]hydroxy [(1S)phenylpropyl]-3,4-dihydropyrimidinone (346), 2-butyl[(1S)(3,5-difluorophenyl)propyl][3-(3,5-difluoropyridin yl)pyrrolidinecarbonyl]hydroxy-3,4-dihydropyrimidinone (347), 2-butyl[(1S)(3,5-difluorophenyl)propyl][3-(3,5-difluoropyridin rolidinecarbonyl]hydroxy-3,4-dihydropyrimidinone (348), 2-butyl[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl]hydroxy [(1R)methoxyphenylethyl]-3,4-dihydropyrimidinone (349), 2-butyl[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl]hydroxy [(1R)methoxyphenylethyl]-3,4-dihydropyrimidinone (350), 3-[(S)-{2-butyl[3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl]hydroxy- 6-oxo-1,6-dihydropyrimidinyl}(cyclopropyl)methyl]benzonitrile (351), 2-butyl[3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl]hydroxy [(1R)methoxyphenylethyl]-3,4-dihydropyrimidinone (352), 5‐[3‐(2,6‐difluorophenyl)pyrrolidine‐1‐carbonyl]‐1‐(2,6‐dimethoxyphenyl)-2‐ (ethoxymethyl)‐6‐hydroxy‐1,4‐dihydropyrimidin-4‐one (353), ‐[3‐(2,6‐difluorophenyl)pyrrolidine‐1‐carbonyl]‐1‐(2,6‐dimethoxyphenyl)‐2‐ (ethoxymethyl)‐6‐hydroxy‐1,4‐dihydropyrimidin‐4‐one (354), 2-butyl(4-(2,3-dichlorobenzyl)piperazinecarbonyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one0.011 (355), 2-butyl(3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (356), 2-butyl(3-(5-chlorofluoropyridinyl)pyrrolidinecarbonyl)(2,6- oxyphenyl)hydroxypyrimidin-4(1H)-one (357), 2-butyl(3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (358), 2-butyl(3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (359), -(3-(2,4-difluorophenyl)pyrrolidinecarbonyl)(2,6-dimethoxyphenyl) (ethoxymethyl)hydroxypyrimidin-4(1H)-one (360), -(3-(2,4-difluorophenyl)pyrrolidinecarbonyl)(2,6-dimethoxyphenyl) ymethyl)hydroxypyrimidin-4(1H)-one (361), 2-(1-(1-(2,6-dimethoxyphenyl)(ethoxymethyl)hydroxyoxo-1,4- dihydropyrimidinecarbonyl)pyrrolidinyl)benzonitrile (362), 2-(1-(1-(2,6-dimethoxyphenyl)(ethoxymethyl)hydroxyoxo-1,4- dihydropyrimidinecarbonyl)pyrrolidinyl)benzonitrile (363), 2-(1-(2-butyl(2,6-dimethoxyphenyl)hydroxyoxo-1,4-dihydropyrimidine- -carbonyl)pyrrolidinyl)benzonitrile (364), 2-butyl(2,6-dimethoxyphenyl)hydroxyoxo-1,4-dihydropyrimidine- 5-carbonyl)pyrrolidinyl)benzonitrile (365), 2-butyl(2,6-dimethoxyphenyl)(3-(3-fluoropyridinyl)pyrrolidine carbonyl)hydroxypyrimidin-4(1H)-one (366), 2-butyl(2,6-dimethoxyphenyl)(3-(3-fluoropyridinyl)pyrrolidine carbonyl)hydroxypyrimidin-4(1H)-one (367), 2-(1-(2-(tert-butoxymethyl)(2,6-dimethoxyphenyl)hydroxyoxo-1,4- dihydropyrimidinecarbonyl)pyrrolidinyl)benzonitrile (368), 2-(1-(2-(tert-butoxymethyl)(2,6-dimethoxyphenyl)hydroxyoxo-1,4- dihydropyrimidinecarbonyl)pyrrolidinyl)benzonitrile (369), 2-butyl(2,6-dimethoxyphenyl)(3-(5-fluoropyridinyl)pyrrolidine carbonyl)hydroxypyrimidin-4(1H)-one (370), 2-butyl(2,6-dimethoxyphenyl)(3-(5-fluoropyridinyl)pyrrolidine yl)hydroxypyrimidin-4(1H)-one (371), -(3-(3,5-difluoropyridinyl)pyrrolidinecarbonyl)(2,6-dimethoxyphenyl)- 2-(ethoxymethyl)hydroxypyrimidin-4(1H)-one (372), 2-butyl(4-(4-chlorophenoxy)piperidinecarbonyl)(2,6-dimethoxyphenyl)- 6-hydroxypyrimidin-4(1H)-one (373), 1-(2,6-dimethoxyphenyl)(ethoxymethyl)(4-(4-fluorobenzyl)piperidine carbonyl)hydroxypyrimidin-4(1H)-one (374), 4-chlorobenzyl)piperidinecarbonyl)(2,6-dimethoxyphenyl) (ethoxymethyl)hydroxypyrimidin-4(1H)-one (375), (S)(3-(benzyloxy)pyrrolidinecarbonyl)(2,6-dimethoxyphenyl) (ethoxymethyl)hydroxypyrimidin-4(1H)-one (376), -(4-(4-chlorophenoxy)piperidinecarbonyl)(2,6-dimethoxyphenyl) (ethoxymethyl)hydroxypyrimidin-4(1H)-one (377), -(4-(2-chlorofluorophenoxy)piperidinecarbonyl)(2,6-dimethoxyphenyl)- 2-(ethoxymethyl)hydroxypyrimidin-4(1H)-one (378), 1-(2,6-dimethoxyphenyl)(ethoxymethyl)(4-(2-fluorophenyl)piperidine carbonyl)hydroxypyrimidin-4(1H)-one (379), 2-butyl(2,6-dimethoxyphenyl)hydroxy(4-(4- (trifluoromethyl)benzyl)piperidinecarbonyl)pyrimidin-4(1H)-one (380), 2-butyl(4-(4-(tert-butyl)phenoxy)piperidinecarbonyl)(2,6- oxyphenyl)hydroxypyrimidin-4(1H)-one (381), 2-butyl(4-(2-chlorophenoxy)piperidinecarbonyl)(2,6-dimethoxyphenyl)- 6-hydroxypyrimidin-4(1H)-one (382), l(4-(2-chlorofluorophenoxy)piperidinecarbonyl)(2,6- oxyphenyl)hydroxypyrimidin-4(1H)-one (383), 2-butyl(4-(2-chlorofluorophenoxy)piperidinecarbonyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (384), 2-butyl(4-(2-chlorofluorophenoxy)piperidinecarbonyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (385), 2-butyl(4-(2-chloro-3,5-difluorophenoxy)piperidinecarbonyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (386), 2-butyl(4-(2,3-difluorophenoxy)piperidinecarbonyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (387), 2-butyl(4-(2,3-difluorobenzyl)piperazinecarbonyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one (388).
The invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also asses all combinations of alternative aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention.
Furthermore, any elements (including individual variable definitions) of an embodiment are meant to be combined with any and all other elements from any of the ments to describe additional embodiments. The present invention also provides a pharmaceutical composition comprising a compound of formula I, or an enantiomer, diastereomer, or a pharmaceutically-acceptable salt, and a pharmaceutically able carrier therefore.
In another embodiment, the compounds of the present invention have EC50 values 10 µM, using the APJ hcAMP assay disclosed herein, preferably, EC50 values 5 µM, more preferably, EC50 values 1 µM, even more preferably, EC50 values 0.5 µM, even more preferably, EC50 values 0.1 µM, even more preferably, EC50 values 0.01 µM.
In another aspect, the t invention provides compounds selected from any subset list of compounds ified in the present application.
In another aspect, the present invention provides nds selected from the subset in which the APJ hcAMP EC50 potency range is A.
In another aspect, the present invention provides compounds selected from the subset in which the APJ hcAMP EC50 potency range is B.
In another aspect, the present invention provides compounds selected from the subset in which the APJ hcAMP EC50 y range is C.
II. OTHER EMBODIMENTS OF THE INVENTION In r embodiment, the present invention provides a composition sing at least one of the compounds of the present invention or a isomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present ion or a isomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
In r embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a ceutically acceptable salt, or a solvate thereof.
In another embodiment, the present invention provides a process for making a compound of the present invention or a stereoisomer, a tautomer, a ceutically acceptable salt, or a solvate thereof.
In another embodiment, the present invention provides an intermediate for making a compound of the t invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
The present invention provides a pharmaceutical composition further sing additional therapeutic agent(s). In a preferred embodiment, the present invention provides pharmaceutical composition, wherein the additional therapeutic agent is, for example, angiotensin converting enzyme (ACE) inhibitor, nergic receptor blocker, angiotensin II receptor blocker, diuretic, aldosterone antagonist and lis compound.
In another embodiment, the present ion provides a method for the treatment and/or prophylaxis of multiple diseases or ers associated with APJ or apelin activity, comprising administering to a t in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present ion, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of eutic agent.
Examples of diseases or disorders associated with the activity of the APJ and apelin that can be prevented, modulated, or treated according to the present invention include, but are not limited to heart failure such as acute decompensated heart failure (ADHF), atrial fibrillation, coronary artery disease, peripheral vascular disease, atherosclerosis, diabetes, metabolic syndrome, hypertension, pulmonary hypertension, cerebrovascular disorders and the sequelae thereof, vascular disorders, angina, ia, stroke, myocardial infarction, acute coronary syndrome, reperfusion injury, angioplastic restenosis, vascular complications of es and obesity.
In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of heart e, coronary artery disease, peripheral vascular disease, atherosclerosis, es, metabolic syndrome, hypertension, pulmonary hypertension, atrial fibrillation, angina, ischemia, stroke, myocardial tion, acute coronary syndrome, reperfusion injury, angioplastic restenosis, vascular complications of diabetes, y, comprising stering to a patient in need of such treatment and/or prophylaxis a eutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the t invention and/or at least one other type of therapeutic agent.
In another embodiment, the present invention provides a method for the ent and/or prophylaxis of heart failure such as ADHF, comprising administering to a patient in need of such treatment and/or laxis a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in ation with another compound of the present invention and/or at least one other type of therapeutic agent.
In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of diabetes and obesity, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, ally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.
In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of hypertension, comprising administering to a patient in need of such treatment and/or prophylaxis a eutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.
In another embodiment, the present invention provides a method for the ent and/or prophylaxis of pulmonary hypertension, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in ation with another compound of the present invention and/or at least one other type of therapeutic agent.
In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of acute coronary syndrome and c ischemia, sing administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.
In another embodiment, the present ion provides a compound of the present invention for use in therapy.
In r embodiment, the present invention es a compound of the present invention for use in therapy for the treatment and/or prophylaxis of multiple diseases or disorders associated with APJ and apelin.
In another ment, the present invention also provides the use of a nd of the present invention for the manufacture of a medicament for the treatment and/or prophylaxis of multiple diseases or ers associated with APJ and apelin.
In another embodiment, the present invention provides a method for the treatment and/or prophylaxis of multiple es or disorders associated with APJ and apelin, comprising administering to a patient in need thereof a eutically effective amount of a first and second therapeutic agent, wherein the first therapeutic agent is a compound of the t ion. Preferably, the second therapeutic agent, for example selected inotropic agent such as β-adrenergic agonist (for example dobutamine).
In another embodiment, the present invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.
In another embodiment, the present invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, te or tial use in the treatment and/or prophylaxis of multiple diseases or disorders associated with APJ and apelin.
Where desired, the compound of the present ion may be used in combination with one or more other types of vascular agents and/or one or more other types of eutic agents which may be administered orally in the same dosage form, in a separate oral dosage form or by injection. The other type of cardiovascular agents that may be optionally employed in ation with the APJ agonist of the present invention may be one, two, three or more cardiovascular agents stered orally in the same dosage form, in a separate oral dosage form, or by injection to produce an additional pharmacological benefit.
The compounds of the present invention may be ed in combination with additional therapeutic agent(s) selected from one or more, preferably one to three, of the following therapeutic agents: anti-hypertensive agents, ACE inhibitors, mineralocorticoid receptor nists, angiotensin receptor blockers, calcium channel blockers, β- adrenergic or blockers, diuretics, vasorelaxation agents such as nitrates, antiatherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-thrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic , calcium channel blockers, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, ancreatic agents, lipid lowering agents, anorectic agents, memory enhancing , anti-dementia agents, cognition promoting agents, appetite suppressants, agents for treating heart failure, agents for treating peripheral arterial disease, agents for ng ant tumors, and antiinflammatory agents.
In another embodiment, additional therapeutic agent(s) used in combined pharmaceutical compositions or combined methods or combined uses, are selected from one or more, preferably one to three, of the following eutic agents in treating heart failure: ACE inhibitors, β-blockers, diuretics, mineralocorticoid receptor antagonists, renin inhibitors, calcium channel blockers, angiotensin II receptor nists, nitrates, digitalis compounds, inotropic agents.
The present ion may be embodied in other ic forms without parting from the spirit or essential attributes f. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also understood that each individual element of the ments is its own ndent embodiment.
Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
III. CHEMISTRY Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and tes thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring s, and the like can also be present in the compounds, and all such stable isomers are contemplated in the t invention.
Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or c forms. Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All ses used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are ed, they may be separated by tional methods, for example, by chromatography or onal crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be ted into another form. A free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers. Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which en atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.
As used herein, the term "alkyl" or "alkylene" is intended to e both branched and straight-chain saturated aliphatic hydrocarbon groups having the ied number of carbon atoms. For examples, "C1 to C12 alkyl" or "C1-12 alkyl" (or alkylene), is intended to e C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12 alkyl groups; "C4 to C18 alkyl" or "C4-18 alkyl" (or alkylene), is ed to include C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, and C18 alkyl groups. Additionally, for example, "C1 to C6 alkyl" or "C1-6 alkyl" denotes alkyl having 1 to 6 carbon atoms. Alkyl group can be unsubstituted or tuted with at least one hydrogen being replaced by r chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "C0 alkyl" or "C0 alkylene" is used, it is intended to denote a direct bond.
"Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, ably one to two, carbon-carbon double bonds that may occur in any stable point along the chain. For example, "C2 to C6 alkenyl" or "C2-6 alkenyl" (or lene), is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, enyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methylpropenyl, and 4-methylpentenyl.
"Alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either straight or ed configuration having one or more, preferably one to three, carbon-carbon triple bonds that may occur in any stable point along the chain. For example, "C2 to C6 alkynyl" or "C2-6 alkynyl" (or alkynylene), is intended to include C2, C3, C4, C5, and C6 l groups; such as l, propynyl, butynyl, pentynyl, and hexynyl.
When the term "hydrocarbon chain" is used, it is intended to e "alkyl", "alkenyl" and "alkynyl", unless otherwise specified.
The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. For e, "C1 to C6 " or "C1-6 alkoxy" (or alkyloxy), is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Example alkoxy groups include, but are not d to, methoxy, , propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as d above with the indicated number of carbon atoms attached through a sulphur bridge; for example methyl-S- and ethyl-S-.
"Halo" or "halogen" es fluoro, chloro, bromo, and iodo. "Haloalkyl" is intended to e both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogens.
Examples of haloalkyl include, but are not d to, fluoromethyl, difluoromethyl, oromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and hloropropyl. Examples of haloalkyl also include "fluoroalkyl" that is intended to include both branched and straight-chain saturated aliphatic arbon groups having the specified number of carbon atoms, tuted with 1 or more ne atoms.
"Haloalkoxy" or "haloalkyloxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, "C1-6 haloalkoxy", is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl-S-, and pentafluoroethyl-S-.
The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. For example, "C3 to C6 cycloalkyl" or "C3-6 cycloalkyl" is intended to include C3, C4, C5, and C6 cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, ropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". The term "cycloalkenyl" refers to cyclized alkenyl groups. C4-6 cycloalkenyl is intended to include C4, C5, and C6 cycloalkenyl groups. Example cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
As used herein, "carbocycle", "carbocyclyl", or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or bered bicyclic or lic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, entenyl, cyclohexyl, eptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, ]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, tyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of ycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, indanyl, and tetrahydronaphthyl. When the term "carbocycle" is used, it is intended to include "aryl." A bridged ring occurs when one or more, preferably one to three, carbon atoms link two non-adjacent carbon atoms.
Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
As used herein, the term "bicyclic carbocycle" or "bicyclic carbocyclic group" is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated, partially rated, or unsaturated. The ic carbocyclic group may be attached to its t group at any carbon atom which results in a stable ure. The bicyclic carbocyclic group described herein may be tuted on any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.
"Aryl" groups refer to monocyclic or bicyclic aromatic hydrocarbons, including, for e, phenyl, and naphthyl. Aryl es are well known and described, for example, in Lewis, R.J., ed., Hawley's Condensed Chemical Dictionary, 15th Edition, John Wiley & Sons, Inc., New York (2007). "C6-10 aryl" refers to phenyl and naphthyl.
The term "benzyl", as used herein, refers to a methyl group on which one of the en atoms is replaced by a phenyl group.
As used herein, the term "heterocycle", "heterocyclyl", or "heterocyclic group" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or ic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently ed from the group consisting of N, O and S; and including any polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p, n p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. When the term "heterocycle" is used, it is intended to include heteroaryl.
Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, othiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, nyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, l, furazanyl, imidazolidinyl, imidazolinyl, olyl, 1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, olinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, linyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, oxadiazolyl, 1,2,4-oxadiazolyl, oxadiazolyl, 1,3,4-oxadiazolyl, idinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, dinyl, donyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, olidonyl, 2H-pyrrolyl, yl, quinazolinyl, quinolinyl, 4H-quinolizinyl, alinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, ydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, lyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
Examples of 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, zolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, lyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, hiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.
Examples of 5- to 6-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, l, tetrazolyl, isoxazolyl, morpholinyl, yl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and lyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclic group" is ed to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently ed from the group consisting of N, O and S. Of the two fused rings, one ring is a - or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second ring. The second ring is a 5- or 6-membered monocyclic ring which is ted, partially unsaturated, or unsaturated, and comprises a 5-membered heterocycle, a 6-membered heterocycle or a carbocycle (provided the first ring is not benzo when the second ring is a carbocycle).
The bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The bicyclic cyclic group described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle s 1, then these heteroatoms are not nt to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of a ic heterocyclic group are, but not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, azolyl, benzimidazolyl, 4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, ,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.
As used herein, the term "aromatic heterocyclic group" or "heteroaryl" is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as , oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, olyl, indazolyl, thiadiazolyl, isothiazolyl, l, carbazolyl, benzimidazolyl, indolinyl, ioxolanyl, and benzodioxane. Heteroaryl groups are tuted or unsubstituted.
The nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if d). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p, wherein p is 0, 1 or 2).
Examples of 5- to 6-membered heteroaryls include, but are not limited to, nyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl.
Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more, preferably one to three, atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two en atoms, and a -nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the .
The term "counter ion" is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate or a positively charged species such as sodium (Na+), potassium (K+), ammonium (RnNHm+ where n=0-4 and m=0-4) and the like.
When a dotted ring is used within a ring structure, this indicates that the ring ure may be saturated, partially saturated or unsaturated.
As used herein, the term "amine protecting group" means any group known in the art of c synthesis for the protection of amine groups which is stable to an ester reducing agent, a tituted hydrazine, R4-M and R7-M, a nucleophile, a hydrazine reducing agent, an activator, a strong base, a hindered amine base and a cyclizing agent.
Such amine protecting groups fitting these criteria include those listed in Wuts, P.G.M. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and enesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic ate types such as tertbutyloxycarbonyl (Boc), carbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilane such as trimethylsilane; (7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such as triphenylmethyl, methyl, and benzyl; and tuted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilane types such as trimethylsilane.
As referred to , the term "substituted" means that at least one en atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound. Ring double bonds, as used , are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).
In cases wherein there are nitrogen atoms (e.g., amines) on nds of the present invention, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N→O) derivative.
When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for e, if a group is shown to be substituted with 0-3 R, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound l judgment, suitable for use in contact with the s of human beings and animals without excessive toxicity, tion, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, aceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent nd is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The ceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent nd formed, for example, from non-toxic inorganic or organic acids. For example, such conventional xic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and ; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, ic, citric, ascorbic, pamoic, , hydroxymaleic, phenylacetic, glutamic, c, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, esulfonic, ethane disulfonic, oxalic, and isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical s. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an c solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, l, panol, or itrile are preferred. Lists of suitable salts are found in Allen, Jr., L.V., ed., Remington: The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press, London, UK (2012), the disclosure of which is hereby incorporated by reference.
In addition, compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press (1985); b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs", Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and Development, pp. 113- 191, Harwood Academic Publishers (1991); c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992); d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and f) , J., ed., Prodrugs and Targeted Delivery (Methods and Principles in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011).
Compounds containing a carboxy group can form physiologically hydrolyzable esters that serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes.
Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. es of physiologically hydrolyzable esters of compounds of a I include C1-6alkyl, C1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1-6 alkanoyloxy-C1-6alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C1-6alkoxycarbonyloxy-C1-6alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, oxymethyl, phenylglycyloxymethyl, (5-methyloxo-1,3-dioxolenyl)-methyl), and other well-known physiologically hydrolyzable esters used, for example, in the llin and cephalosporin arts. Such esters may be prepared by conventional ques known in the art.
Preparation of prodrugs is well known in the art and described in, for example, King, F.D., ed., Medicinal Chemistry: Principles and Practice, The Royal y of Chemistry, Cambridge, UK (2nd n, reproduced (2006)); Testa, B. et al., Hydrolysis in Drug and g lism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, 3rd Edition, Academic Press, San Diego, CA (2008).
The present invention is ed to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, es of hydrogen include deuterium and m. Deuterium has one proton and one neutron in its nucleus and that has twice the mass of ordinary hydrogen. Deuterium can be represented by symbols such as "2H" or "D". The term "deuterated" herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen ), which is attached to carbon(s), with a deuterium atom. Isotopes of carbon include 13C and 14C.
Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise ed. Such compounds have a variety of potential uses, e.g., as standards and reagents in determining the ability of a potential pharmaceutical compound to bind to target proteins or receptors, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro.
The term "solvate" means a physical association of a compound of this invention with one or more t molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered ement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. "Solvate" asses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are lly known in the art.
Abbreviations as used herein, are defined as follows: "1 x" for once, "2 x" for twice, "3 x" for thrice, "ºC" for degrees Celsius, "eq" for lent or equivalents, "g" for gram or grams, "mg" for milligram or rams, "L" for liter or liters, "mL" for milliliter or iters, "μL" for microliter or microliters, "N" for normal, "M" for molar, "mmol" for millimole or millimoles, "min" for minute or min, "h" for hour or h, "rt" for room temperature, "RT" for retention time, "atm" for atmosphere, "psi" for pounds per square inch, "conc." for concentrate, "aq" for "aqueous", "sat" or "sat'd " for saturated, "MW" for molecular weight, "mp" for melting point, "MS" or "Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" for liquid tography mass spectrometry, "HPLC" for high re liquid chromatography, "RP HPLC" for reverse phase HPLC, "TLC" or "tlc" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear Overhauser effect spectroscopy, "1H" for proton, "δ" for delta, "s" for t, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, and "α", "β", "R", "S", "E", "Z" and "ee" are stereochemical designations ar to one d in the art.
AcOH or HOAc acetic acid ACN acetonitrile Alk Alkyl AlMe3 Trimethylaluminum BBr3 boron tribromide Bn benzyl Boc tert-butyloxycarbonyl BOP reagent benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate Bu butyl i-Bu yl t-Bu utyl t-BuOH tert-butanol Cbz carbobenzyloxy CDCl3 deutero-chloroform CD3OD deutero-methanol CH2Cl2 dichloromethane CH3CN acetonitrile CHCl3 chloroform DCM dichloromethane DIEA, DIPEA or diisopropylethylamine Hunig's base DMF dimethyl ide DMSO dimethyl sulfoxide Et ethyl Et3N or TEA triethylamine Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol HCl hydrochloric acid HPLC high-performance liquid chromatography K2CO3 potassium carbonate K2HPO4 potassium hydrogenphosphate LCMS liquid chromatography mass spectrometry LiHMDS lithium bis(trimethylsilyl)amide LG leaving group Me methyl MeOH methanol MgSO4 ium e MsOH or MSA methylsulfonic acid NaCl sodium chloride Na2CO3 sodium carbonate NaHCO3 sodium onate NaOH sodium hydroxide Na2SO4 sodium sulfate NH3 ammonia NH4Cl ammonium chloride NH4OAc ammonium acetate Pd(OAc)2 palladium(II) acetate Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) PG protecting group Ph phenyl Pr propyl i-Pr isopropyl i-PrOH or IPA isopropanol Rt retention time SiO2 silica oxide SFC supercritical fluid chromatography TEA triethylamine TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride THF tetrahydrofuran TiCl4 titanium tetrachloride T3P 1-propanephosphonic acid cyclic anhydride The compounds of the present invention can be synthesized using the s described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations n as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are med in a solvent or solvent e appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be tent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. Also, in the ption of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the ment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily ized by one skilled in the art. Restrictions to the tuents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
SYNTHESIS The compounds of Formula (I) may be prepared by the exemplary processes described in the following schemes and working es, as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working examples.
Protection and tection in the processes below may be d out by procedures generally known in the art (see, for example, Wuts, P.G.M. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007)). General methods of organic synthesis and functional group transformations are found in: Trost, B.M. et al., eds., Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, on Press, New York, NY ; Smith, M.B. et al., March's Advanced Organic try: Reactions, Mechanisms, and Structure. 6th Edition, Wiley & Sons, New York, NY (2007); Katritzky, A.R. et al, eds., Comprehensive Organic Functional Groups Transformations II, 2nd Edition, er Science Inc., own, NY (2004); Larock, R.C., Comprehensive Organic ormations, VCH Publishers, Inc., New York, NY (1999), and references therein.
As a person of ordinary skill in the art would be able to understand that a pyridone in a molecule may tautomerize to its keto and enol forms as shown in the following equation, wherein R1, R2, R3, and R4 are as defined above, this disclosure is intended to cover all possible tautomers even when a structure depicts only one of them.
Description of Analytical LCMS methods: Method A: Column: Waters y UPLC BEH C18, 2.1 x 50 mm, 1.7 m particles; Mobile Phase A: 5:95 ACN:water with 10 mM NH4OAc; Mobile Phase B: 95:5 ter with 10 mM NH4OAc; Temperature: 50 C; Gradient: 0-100% B over 3 minutes, then a 0.75 minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
Method B: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 m particles; Mobile Phase A: 5:95 ACN:water with 0.1% TFA; Mobile Phase B: 95:5 ACN:water with 0.1% TFA; ature: 50 C; Gradient: 0-100% B over 3 minutes, then a 0.75 minute hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.
Method C: Column: ENEX® Luna 3 μm C18 (2.0 x 30 mm); Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with 0.1% TFA; Gradient: 0-100% B over 2 minutes, then a 1 minute hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm.
Method D: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 m particles; Mobile Phase A: water with 0.1% TFA; Mobile Phase B: ACN with 0.1% TFA; Gradient: 2-98% B over 1 minute, then a 0.5 minute hold at 98% B; Flow: 0.8 mL/min; Detection: UV at 220 nm.
Generic Schemes [Link] http://www.ncbi.nlm.nih.gov/pubmed/20605969 Scheme 1 Step 1 bes the preparation of compounds of Formula G1c from a compound of Formula G1a, by acylating with a nitriles of Formula G1b in the presence of a Lewis acid (like AlMe3 or TMSOTF). Preferred solvents are aprotic ts (such as toluene and the like).
Step 2 bes the ation of pyrimidine compounds of Formula G1d from compounds of formula G1c by sation with triethyl methanetricarboxylate with or without base. Preferred solvents are aprotic solvents (like toluene and xylenes). Preferred bases are tertiary amines (such as TEA, DIEA and the like) and alkaline metal alkoxides (such as sodium ethoxide and the like). The condensation may also be accomplished with TMSCl in preferred solvents such as 1,2-dichloroethane.
Step 3 describes the preparation of compounds of Formula (I) by conversion of the ester of compounds of Formula G1d to an amide ). The sion of nds of Formula G1d to compounds of Formula (I) can be accomplished from the amine (NR3R4) in the presence of a Lewis acid (for example, AlMe3 or Zr(OtBu)4 ) with or without the addition of a coupling agent (for example, HOAt) in solvents such as toluene.
IV. BIOLOGY APJ receptor was discovered in 1993 as an orphan G protein-coupled receptor (GPCR) and was subsequently found to recognize apelin peptide as its endogenous ligand. It belongs to class A of GPCRs and has a classical 7-transmembrane domain structure, ting greatest sequence homology to angiotensin AT1 receptor (for review see Pitkin, S.L. et al., Pharmacol. Rev., 62(3):331-342 (2010)). APJ is sed in wide variety of peripheral tissues and the CNS, and has relatively high expression in placenta, myocardium, vascular endothelial cells, smooth muscle cells as well as cardiac es (Kleinz, J.M. et al., Pharmacol. Ther., 107(2):198-211(2005)). Apelin peptide was originally identified in bovine stomach extract and remains to date the only known [Link] http://www.ncbi.nlm.nih.gov/pubmed/20605969 endogenous ligand and agonist of APJ receptor (Tatemoto, K. et al., Biochem. Biophys.
Res. Commun., 255:471-476 (1998)). Tissue expression of apelin gene mirrors closely the APJ expression pattern and has been postulated to act in an autocrine or paracrine manner, often exemplified by reference to "apelin-APJ system". Apelin gene encodes 77 amino acid precursor peptide that is cleaved to form mature secreted peptide undergoing further proteolytic ge forming shorter C-terminal fragments. Apelin-36, -17 and -13 represent the major active forms with the pyroglutamated form of apelin-13 being the most stable and the most abundant form present in the cardiac tissue re, J.J. et al., Hypertension, 54(3):598-604 (2009)). Apelin has very short half life in ation, estimated to be less than 5 minutes (Japp, A.G. et al., Circulation, 121(16):1818-1827 (2010)).
Activation of APJ or is known to inhibit forskolin-stimulated cyclic AMP (cAMP) levels in sis toxin-sensitive manner, indicating coupling to the Gi ns.
The binding affinity of apelin and the EC50 values in the cAMP assay are reported to be in the sub-nanomolar range (for review see Pitkin, S.L. et al., Pharmacol. Rev., 331-342(2010)). In addition to cAMP inhibition, APJ receptor activation also leads to β-arrestin recruitment, receptor internalization and activation of ellular -regulated kinases (ERKs) (for review see Kleinz, J.M. et al., Pharmacol. Ther.,107(2):198-211 ). Which of these signaling mechanisms contribute to modulation of downstream physiological effects of apelin is not clear at present. APJ receptor has been shown to interact with the AT1 receptor. While apelin does not bind AT1 and angiotensin II does not bind APJ, it has been postulated that certain physiological actions of apelin are mediated, at least in part, via functional antagonism of the ensin II and AT1 receptor pathway (Chun, A.J. et al., J. Clin. Invest., 118(10):3343-3354 (2008)).
It is also desirable and preferable to find compounds with advantageous and ed characteristics compared with known HF treatment agents, in one or more of the following categories that are given as examples, and are not intended to be limiting: (a) pharmacokinetic properties, including oral bioavailability, half life, and nce; (b) pharmaceutical ties; (c) dosage requirements; (d) factors that decrease blood drug concentration peak-to-trough characteristics; (e) factors that increase the concentration of active drug at the receptor; (f) factors that decrease the liability for clinical drug-drug interactions; (g) factors that decrease the potential for adverse side-effects, including selectivity versus other biological targets; and (h) improved therapeutic index.
As used , the term "patient" encompasses all ian s.
As used herein, the term "subject" refers to any human or man organism that could potentially benefit from treatment with an APJ agonist. Exemplary ts include human beings of any age with risk factors for development of heart failure and the sequelae thereof, angina, ischemia, cardiac ischemia, myocardial tion, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia, stroke, as well as atherosclerosis, ry artery e, acute coronary syndrome, and/or dyslipidemias.
As used herein, "treating" or "treatment" cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting the disease-state, i.e., arresting it development; and/or (b) relieving the disease-state, i.e., causing regression of the disease state.
As used herein, "prophylaxis" or "prevention" cover the preventive treatment of a subclinical disease-state in a mammal, particularly in a human, aimed at reducing the probability of the occurrence of a clinical disease-state. Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. "Prophylaxis" therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in a subject that has not yet presented with a clinical e state, whereas secondary tion is defined as ting a second occurrence of the same or r clinical disease state.
As used herein, "risk reduction" covers therapies that lower the incidence of development of a clinical disease state. As such, primary and secondary prevention therapies are examples of risk reduction.
"Therapeutically effective amount" is intended to include an amount of a nd of the present invention that is effective when administered alone or in combination to modulate APJ and/or to prevent or treat the disorders listed herein. When d to a ation, the term refers to combined amounts of the active ingredients that result in the preventive or therapeutic effect, whether administered in combination, serially, or simultaneously.
A. ASSAY METHODS Intracellular cAMP Accumulation Assay HEK293 cells stably expressing human APJ receptor were used to assess the ty of compounds. Cultured cells were detached and resuspended in the cAMP Homogeneous Time-Resolved Fluorescence (HTRF) assay buffer (Cisbio cat; #62AM4PEJ). The assay was performed in 384-well assay plates (Perkin-Elmer; cat 89) according to assay ol provided by the manufacturer. Serial ons of a compound together with assay buffer containing 0.2nM IBMX and 2 μM forskolin were added to each well containing 5,000 cells and incubated for 30 minutes at room temperature. Subsequently, cAMP D2 reagent was added in the lysis buffer followed by the EuK antibody (Cisbio; cat #62AM4PEJ) and ted for 60 min. The fluorescence emission ratio was measured using fluorometer. The intracellular cAMP trations (compound-stimulated inhibition of forskolin-mediated cAMP production) were ated by extrapolation from a standard curve using known cAMP concentrations.
The EC50 values were obtained by fitting the data to a sigmoidal concentration-response curve with variable slope. The maximal able inhibition of forskolin-induced cAMP levels (Ymax) for each compound was sed as relative percentage of inhibition attained using pyroglutamated apelin-13 ((Pyr1)apelin-13) peptide, which was set to 100%.
The examples disclosed below were tested in the APJ in vitro assays described above and were found having human APJ cyclic AMP (hcAMP) activity. The EC50 value of each compound is presented at the end of the example description.
The compounds of the present invention possess activity as ts of APJ receptor, and, therefore, may be used in the treatment of diseases associated with APJ activity. Accordingly, the compounds of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to, treating, preventing, or slowing the ssion of heart failure, coronary artery disease, peripheral vascular disease, atherosclerosis, diabetes, metabolic syndrome and the sequelae of thereof, hypertension, pulmonary hypertension, cerebrovascular disorders, atrial lation, angina, ischemia, stroke, myocardial infarction, acute coronary syndrome, reperfusion , angioplastic osis, vascular complications of diabetes and y.
The biological activity of the exemplified compounds of this invention determined by the assay described above is shown at the end of each example. The APJ cAMP EC50 potency ranges are as follows: A = 0.01 - 10 nM; B = 10.01 - 100 nM; C = 100.01 - 300 V. PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND COMBINATIONS The compounds of this invention can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, res, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; gually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or on techniques (e.g., as e injectable aqueous or ueous solutions or suspensions); y, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The term "pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating , disintegrating agents, wetting agents, emulsifying agents, suspending agents, ning agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. ceutically acceptable carriers are formulated according to a number of factors well within the w of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being ated; the subject to which the agent-containing ition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted.
Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of ent ingredients and additives in addition to the active agent, such additional ients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable rs, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, Jr., L.V. et al., Remington: The Science and Practice of Pharmacy (2 s), 22nd Edition, Pharmaceutical Press (2012), The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent ent; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated s, will range between about 0.001 to about 5000 mg per day, preferably n about 0.01 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a nt rate infusion. Compounds of this ion may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively ed to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 ram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition.
A typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. l n capsule.
A l injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of logical saline, to produce an injectable preparation.
The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of the present invention, alone or in combination with a pharmaceutical carrier. Optionally, compounds of the t invention can be used alone, in combination with other compounds of the ion, or in combination with one or more other therapeutic agent(s), e.g., agents used in treatment of heart failure or other pharmaceutically active material.
The nds of the present invention may be employed in combination with other APJ agonists or one or more other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: agents for treating heart e, antihypertensive , anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic , anti-hyperglycemic agents, anti-hyperinsulinemic agents, hrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering , anorectic agents, memory enhancing agents, anti-dementia agents, cognition promoting agents, appetite suppressants, and agents for treating peripheral arterial disease.
The compounds of the present invention may be employed in ation with additional therapeutic agent(s) selected from one or more, preferably one to three, of the following therapeutic agents in ng heart e and coronary artery disease: ACE inhibitors, β-blockers, diuretics, mineralocorticoid receptor antagonists, renin inhibitors, m channel blockers, ensin II receptor antagonists, nitrates, digitalis compounds, inotropic agents and β-receptor agonists, anti-hyperlipidemic , plasma HDL-raising agents, anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors (such as HMG CoA reductase inhibitors), LXR agonist, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (such as anion exchange , or quaternary amines (e.g., cholestyramine or colestipol), low density lipoprotein or inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B6, vitamin B12, anti-oxidant vitamins, anti-diabetes , platelet ation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives.
The compounds of the invention may be used in combination with one or more, preferably one to three, of the following anti-diabetic agents depending on the desired target therapy. Studies indicate that diabetes and hyperlipidemia modulation can be r ed by the addition of a second agent to the therapeutic regimen. Examples of anti-diabetic agents include, but are not limited to, ylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, ide, gliclazide, glynase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone), and related insulin sensitizers, such as selective and non-selective tors of PPARα, PPARβ and PPAR; dehydroepiandrosterone (also referred to as DHEA or its ated sulphate ester, DHEA-SO4); anti-glucocorticoids; TNFα inhibitors; dipeptidyl peptidase IV (DPP4) inhibitor (such as sitagliptin, saxagliptin),GLP-1 agonists or analogs (such as exenatide), α-glucosidase inhibitors (such as se, miglitol, and voglibose), pramlintide (a synthetic analog of the human hormone amylin), other insulin secretagogues (such as repaglinide, gliquidone, and nateglinide), n, as well as the therapeutic agents discussed above for treating heart failure and atherosclerosis.
The compounds of the invention may be used in combination with one or more, preferably one to three, of the following anti-obesity agents selected from phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentiramine, β3-adrenergic receptor agonist agents; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptins. Other agents used in treating obesity or obesity-related ers include neuropeptide Y, enterostatin, ytokinin, bombesin, amylin, histamine H3 receptors, dopamine D2 receptor modulators, melanocyte stimulating hormone, corticotrophin releasing factor, galanin and gamma amino butyric acid (GABA).
The above other therapeutic agents, when employed in combination with the compounds of the present invention may be used, for example, in those amounts indicated in the Physicians' Desk Reference, as in the patents set out above, or as otherwise determined by one of ry skill in the art.
Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ients. For this , when the compound of the present invention and a second therapeutic agent are ed in a single dosage unit they are ated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated.
By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the ed active ingredients but also to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is ed in the intestines. One of the active ingredients may also be coated with a material that s a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a r such as a low viscosity grade of hydroxypropyl cellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an onal barrier to interaction with the other component.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in te forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.
The compounds of the present invention can be administered alone or in combination with one or more additional eutic agents. By "administered in combination" or "combination therapy" it is meant that the compound of the present ion and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination, each component may be administered at the same time or sequentially in any order at different points in time.
Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the APJ receptor and apelin activity. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving APJ and apelin or anti-heart e activity. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown ty. This would ensure the experimenter that the assay was being performed properly and e a basis for comparison, especially if the test compound was a derivative of the nce compound. When developing new assays or protocols, compounds according to the present invention could be used to test their iveness.
The nds of the present invention may also be used in diagnostic assays ing APJ and apelin.
The present invention also encompasses an article of cture. As used , article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present invention, comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises a first therapeutic agent, sing a compound of the t ion or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the ent and/or prophylaxis of multiple diseases or disorders associated with APJ and apelin (as defined previously). In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent for the treatment and/or prophylaxis of multiple diseases or disorders associated with APJ and apelin. The article of manufacture can further comprise: (d) a second container, wherein ents (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries.
The first container is a acle used to hold a pharmaceutical composition.
This container can be for manufacturing, storing, shipping, and/or individual/bulk selling.
First container is intended to cover a , jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other ner used to manufacture, hold, store, or distribute a ceutical product.
The second container is one used to hold the first container and, optionally, the e insert. Examples of the second ner include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically ed to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container t being physically attached.
The package insert is a label, tag, marker, etc. that recites information ng to the pharmaceutical ition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration). Preferably, the e insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a ble material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.
VI. EXAMPLES The following Examples are offered as illustrative, as a partial scope and particular embodiments of the invention and are not meant to be limiting of the scope of the invention. Abbreviations and chemical s have their usual and customary meanings unless otherwise indicated. Unless otherwise indicated, the compounds described herein have been prepared, isolated and characterized using the schemes and other methods disclosed herein or may be prepared using the same.
Example 1 2-Butyl(3-(5-chloropyridinyl)pyrrolidinecarbonyl)(2,6-dimethoxyphenyl) hydroxypyrimidin-4(1H)-one Compound 1a. Ethyl 2-(2,6-dimethoxyphenyl)acetate To a solution of pentanenitrile (310 mg, 3.7 mmol) and 2-methoxy methylaniline (518 mg, 3.40 mmol) in toluene (13 mL) at RT was added a solution of trimethylaluminum in toluene (1.7 mL, 3.4 mmol) at 0 °C. The reaction mixture was heated at 110 °C for 1 h. The cooled reaction e was quenched with saturated on of Rochelle's salt (5 mL) and stirred at RT for 30 min. The reaction mixture was extracted with EtOAc (3x20 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated under d pressure. The residue was purified by silica gel chromatography g with 20-100% EtOAc/hexanes with 0.5% Et3N to give Compound 1a (450 mg, 56%) as a brown oil. LCMS (Method D) retention time = 0.65 min, m/z = 237.1 (M+H). 1H NMR (500MHz, chloroform-d) 6.88 (t, J=8.4 Hz, 1H), 6.51 (d, J=8.3 Hz, 2H), 4.68 - 3.89 (m, 2H), 3.71 (s, 6H), 2.33 (br. s., 2H), 1.84 - 1.52 (m, 2H), 1.49 - 1.24 (m, 2H), 0.89 (br. s., 3H).
Compound 1b. Ethyl 2-butyl(2, 6-dimethoxyphenyl)hydroxyoxo-1,4- opyrimidinecarboxylate A mixture of 1a (500 mg, 2.1 mmol) and triethyl methanetricarboxylate (590 mg, 2.5 mmol) in toluene (12 mL) was heated at 140 °C for 1 h in a microwave reactor. The on mixture was concentrated under d pressure and the residue was purified by silica gel chromatography eluting with 0-100% EtOAc/DCM to give Compound 1b (170 mg, 22%) as a brown solid. LCMS (Method D) retention time = 0.87 min, m/z = 377.3 (M+H). 1H NMR (400MHz, chloroform-d) 7.39 (t, J=8.5 Hz, 1H), 6.65 (d, J=8.6 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.78 (s, 6H), 2.49 - 2.18 (m, 2H), 1.70 - 1.53 (m, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.29 - 1.12 (m, 2H), 0.79 (t, J=7.3 Hz, 3H).
Compound 1c. 5-Chloro(pyrrolidinyl)pyridine Compound 1d. tert-Butyl 3-(5-chloropyridinyl)-2,5-dihydro-1H-pyrrolecarboxylate A mixture of utyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2,5- dihydro-1H-pyrrolecarboxylate (commercially available, 106 mg, 0.360 mmol), 2- bromochloropyridine (76 mg, 0.40 mmol), cesium carbonate (350 mg, 1.10 mmol) and PdCl2(dppf)-CH2Cl2 (18 mg, 0.022 mmol) in e (2.4 mL) and water (0.5 mL) was degassed and heated at 90°C for 14 h. The e was diluted with EtOAc, washed with brine, dried over sodium sulfate, ed and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-100% EtOAc/hexane to give 1d (50 mg, 0.18 mmol, 50 % yield) as a yellow solid. 1H NMR z, chloroform-d) 8.62 - 8.41 (m, 1H), 7.82 - 7.57 (m, 1H), 7.40 - 7.16 (m, 1H), 6.60 - 6.32 (m, 1H), 4.60 - 4.49 (m, 2H), 4.41 - 4.27 (m, 2H), 1.52 - 1.45 (m, 9H). nds 1e and 1f. tert-Butyl 3-(5-chloropyridinyl)pyrrolidinecarboxylate A mixture of 1d (530 mg, 1.90 mmol) and 5% Rh/C (390 mg, 0.190 mmol) in EtOH (8 mL) was stirred under hydrogen atmosphere (balloon) for 4 h. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified using silica gel chromatography eluting with 0-100% EtOAc/hexane, followed by chiral SFC preparative HPLC (column: Chiralpak IC, 30 x 250 mm, 5 micron; mobile phase: 10 % IPA/0.1%DEA/90% CO2; flow condition: 85 mL/min, 150 bar, 40 ºC; wavelength: 220 nm) to give nd 1e (designated as Isomer 1, 110 mg, 21% yield). Peak 1 retention time = 11.87 and Compound 1f (designated as Isomer 2, 118 mg, 22% yield). Peak 2 retention time = 13.24 (Chiralpak IC, 4.6 x 250 mm, 5 micron; mobile phase: 10% 1%DEA/90% CO2; flow condition: 2.0 mL/min, 150 bar, 40 ºC; wavelength: 220 nm. LCMS (Method B) Rt = 0.96 min, m/z = 283.2 (M+H). 1H NMR (400MHz, chloroform-d) 8.52 (d, J=2.2 Hz, 1H), 7.64 - 7.56 (m, 1H), 7.14 (d, J=8.4 Hz, 1H), 3.97 - 3.29 (m, 5H), 2.34 - 2.05 (m, 2H), 1.50 - 1.44 (m, 9H).
Compound 1c. tert-Butyl 3-(5-chloropyridinyl)-2,5-dihydro-1H-pyrrolecarboxylate (HCl salt) Compound 1e (110 mg, 0.38 mmol) and 4N HCl/dioxane (1.0 mL, 4.0 mmol) was stirred at rt for 5 h. The mixture was diluted with diethyl ether, and the solid was collected by filtration to give Compound 1c (89 mg, 0.35 mmol, 91 % yield) as a white solid. LCMS (Method B) Rt = 0.47 min, m/z = 183.1 (M+H). 1H NMR (500MHz, DMSO-d6) 7.79 (d, J=2.5 Hz, 1H), 7.24 - 6.97 (m, 1H), 6.83 - 6.56 (m, 1H), 3.01 (s, 1H), 2.83 (s, 2H), 2.77 - 2.67 (m, 1H), 2.54 (br. s., 2H), 1.85 - 1.57 (m, 1H), 1.53 - 1.14 (m, 1H).
Example 1. 2-Butyl(3-(5-chloropyridinyl)pyrrolidinecarbonyl)(2,6- dimethoxyphenyl)hydroxypyrimidin-4(1H)-one A mixture of nd 1b (15 mg, 0.040 mmol), Compound 1c (10 mg, 0.040 mmol) and DIEA (0.021 mL, 0.12 mmol) were dissolved in EtOH (0.5 mL) was heated at 160 °C for 1.5 h. Example 1 was isolated by prep HPLC (5.3 mg, 10 µmol, 26 % yield). 1H NMR (500MHz, DMSO-d 6) d 8.55 (br. s., 1H), 7.92 - 7.77 (m, 1H), 7.52 - 7.27 (m, 2H), 6.83 (br. s., 2H), 3.99 - 3.45 (m, 5H), 2.51 (br. s., 6H), 2.22 (br. s., 4H), 1.42 (br. s., 2H), 1.22 - 1.10 (m, 2H), 0.70 (d, J=6.3 Hz, 3H). LCMS retention time = 0.78 min, (M+H)+ = 513.3. (BEH C18, 1.5x50 mm, flow rate 2 mL/min, 1 min gradient with 2-98% ACN/water/ 0.2% TFA). Human APJ cAMP EC50 potency range A.
Example 2 (R)Butyl(2,6-dicyclopropylphenyl)hydroxy(3-phenylpyrrolidine carbonyl)pyrimidin-4(1H)-one Example 2a. 2,6-Dicyclopropylaniline A e of 2,6-dibromoaniline (0.50 g, 2.0 mmol), cyclopropylboronic acid (0.70 g, 8.0 mmol), ium phosphate (1.7 g, 8.0 mmol) and tricyclohexylphosphine (0.11 g, 0.40 mmol) in toluene (5 mL) and water (2 ml) was degassed with nitrogen then palladium acetate (0.12 g, 0.52 mmol) was added. The mixture was heated at 100 °C for 14 h. The reaction mixture was d to cool and ethyl acetate was added and the resulting mixture was washed with water, brine, dried over sodium sulfate and trated under reduced pressure. The residue was purified on silica gel chromatography eluting with 0-50% EtOAc/hexane to give Compound 2a (240 mg, 68%) as a yellow oil. LCMS (Method D) retention time = 0.80 min, m/z = 174.2 (M+H). 1H NMR (400MHz, DMSO-d6) 6.84 (d, J=7.7 Hz, 2H), 6.71 - 6.62 (m, 1H), 1.82 (tt, J=8.3, .4 Hz, 2H), 0.99 - 0.91 (m, 4H), 0.64 - 0.53 (m, 4H).
Example 2. (R)Butyl(2,6-dicyclopropylphenyl)hydroxy(3-phenylpyrrolidine- 1-carbonyl)pyrimidin-4(1H)-one Example 2 was prepared from Compound 2a following a r procedure as described for nd 1 (39% yield) as a clear oil. LCMS (Method A) retention time = 1.05 min, m/z = 498.2 (M+H). 1H NMR (400MHz, chloroform-d) d 7.37 - 7.11 (m, 6H), 6.80 (d, J=7.3 Hz, 2H), 3.95 - 3.22 (m, 4H), 2.39 - 2.24 (m, 3H), 2.08 - 1.92 (m, 1H), 1.72 (br. s., 3H), 1.43 (br. s., 2H), 1.31 - 1.17 (m, 3H), 0.91 - 0.57 (m, 11H). Human APJ cAMP Potency range A.
Example 3 1-(2,6-Dimethoxyphenyl)(ethoxymethyl)hydroxy(3-(pyridinyl)pyrrolidine carbonyl)pyrimidin-4(1H)-one Compound 3a. 2-Ethoxyacetamide To a stirred solution of 2-ethoxyacetic acid (1.5 g, 14 mmol) in DCM (20 mL) at 0 °C was added oxalyl chloride (8.65 mL, 17.3 mmol), followed by DMF (2 drops).
Cooling was removed and the reaction e was stirred at RT for 3h. The reaction mixture was concentrated under d pressure and dissolved in DCM (20 mL). a (20.6 mL, 144 mmol) (7 M in MeOH) was added carefully and the reaction mixture stirred for 16h. The reaction mixture was concentrated under reduced pressure, dissolved in DCM, filtered and washed with DCM. The filtrate was concentrated under reduced pressure to give Compound 3a (1.0 g, 67%) as a white solid. 1H NMR (500MHz, CDCl3) 6.51 (br s, 1H), 5.46 (br s, 1H), 3.94 (s, 2H), 3.59 (q, J = 6.8 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H).
Compound 3b. 2-Ethoxyacetonitrile To a stirred solution of Compound 3a (1.0 g, 9.7 mmol) in THF (10 mL) at 0 °C was added pyridine (1.57 mL, 19.4 mmol) followed by TFAA (6.85 mL, 48.5 mmol). The reaction e was stirred at RT for 1h. Aqueous NaHCO3 solution was added carefully to the reaction mixture until pH = 8 was attained. The reaction mixture was extracted with CH2Cl2 (2X). The combined organic layers were washed with 1N HCl, dried over MgSO4, filtered and concentrated in vacuo to give nd 3b (0.80 g, 97%) as a yellow . 1H NMR (500MHz, CDCl 3) 4.24 (s, 2H), 3.66 (q, J = 6.9 Hz, 2H), 1.27 (t, J = 6.9 Hz, 3H).
Compound 3c. N-(2,6-Dimethoxyphenyl)ethoxyacetimidamide Trimethylaluminum (2 M in toluene, 4.70 ml, 9.40 mmol) was added dropwise to a solution of 2,6-dimethoxyaniline (1.2 g, 7.8 mmol) and nd 3b (0.80 g, 9.4 mmol) in toluene (10 ml) while g in an ice bath. After addition was complete, the reaction mixture was heated to 110 °C and was stirred at this temperature for 14h. The reaction mixture was allowed to cool and was partitioned between a saturated solution of le's salt and EtOAc. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was added to a silica gel (120 g) column and was eluted with 0-20% of 20% MeOH/DCM in 0.5% TEA/DCM to give Compound 3c (1.1 g, 57%) as a brown liquid. MS m/z = 239.0 (M+H). 1H NMR (500MHz, CDCl3) 7.01(t, J = 8.3 Hz, 1H), 6.62 (d, J = 7.7 Hz, 2H), 5.32 (s, 2H), 4.88 (br s, 2H), 4.31 (s, 2H), 3.82 (s, 6H), 3.62-3.73 (m, 2H), 1.19-1.33 (m, 3H).
Example 3. e 3 was prepared from Compound 3c following a similar procedure as described for example 1 (1.2 mg, 1%) as a colorless film. LCMS (Method A) retention time = 1.15 min, m/z = 505.9 (M+H). 1H NMR (500MHz, DMSO-d 6) 7.87 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.42 (t, J = 7.0 Hz, 1H), 6.81 (d, J = 8.5 Hz, 2H), 4.80 (s, 2H), 3.95 (s, 2H), 3.76 (s, 6H), 3.33 (q, J = 6.7 Hz, 2H), 1.01 (t, J = 6.7 Hz, 3H). Human APJ cAMP Potency range A.
(S)(2-Cyclopropylethyl)(2,6-dimethoxyphenyl)hydroxy(3-phenylpyrrolidine- 1-carbonyl)pyrimidin-4(1H)-one Compound 4a. 2-Cyclopropylethyl 4-methylbenzenesulfonate To 2-cyclopropylethanol at 0 ºC (0.98 g, 11 mmol) and pyridine (2.4 mL, 30 mmol) in DCM (15 mL) was added 4-methylbenzenesulfonyl de (22 g, 11 mmol). The cold bath was d and the mixture allowed to warm to room temperature for 14 h. The reaction mixture was diluted with water and Et2O and the phases were separated. The organic phase was washed sequentially with water, 10% aqueous HCl and brine, dried (MgSO4) filtered and concentrated under reduced pressure to give Compound 4a (2.0 g, 74%) as a clear colorless oil. Compound 4a was used in the next step without further purification. MS m/z = 241.4 (M+H). 1H NMR (400MHz, chloroform-d) 7.77 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 4.06 (t, J=6.7 Hz, 2H), 2.42 (s, 3H), 1.56 - 1.45 (m, 2H), 0.70 - 0.57 (m, 1H), 0.44 - 0.32 (m, 2H), 0.04 - -0.10 (m, 2H).
Compound 4b. 3-Cyclopropylpropanenitrile To a solution of Compound 4a (1.0 g, 4.2 mmol) in DMF (5 mL) was added NaCN (0.60 g, 13 mmol) and TBAI (0.06 g, 0.2 mmol) and the reaction mixture was stirred at 90ºC for 14h. The on mixture was allowed to cool to room temperature, diluted with Et2O and brine and the phases were separated. The organic phase was washed with 10% s LiCl, dried over MgSO4, filtered and concentrated under reduced pressure to give Compound 4b (0.39 g, 99%) as a clear colorless oil, which was used in the next step without further purification. 1H NMR (chloroform-d) 2.27 (t, J=7.2 Hz, 2H), 1.34-1.46 (m, 2H), 0.62-0.74 (m, 1H), 0.34-0.45 (m, 2H), -0.05-0.04 (m, 2H).
Compound 4c. opropyl-N-(2,6-dimethoxyphenyl)propanimidamide To a mixture of Compound 4b (0.37 g, 3.9 mmol) and 2,6-dimethoxyaniline (0.5 g, 3 mmol) in toluene (5 mL), at 0ºC, was added a 2M solution of trimethylaluminum in hexane (2 ml, 4 mmol) dropwise. The on mixture was allowed to warm to room temperature and heated at 110ºC overnight. The reaction mixture was d to cool to RT and quenched with saturated s Rochelle’s salt and EtOAc. The phases were ted, the aqueous phase was extracted with EtOAc. The organic phases were combined and washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 30% .5% TEA in DCM to give Compound 4c (0.35 g, 44 % yield) as an orange oil. MS m/z = 249.4 (M+H). 1H NMR (methanol-d 4) 7.01 (t, J=8.3 Hz, 1H), 6.64 (d, J=8.3 Hz, 2H), 2.29-2.48 (m, 2H), 1.50-1.67 (m, 2H), 0.78-0.93 (m, 1H), 0.44 (s, 2H), 0.02-0.16 (m, 2H).
Example 4.
Example 4 was prepared from Compound 4c following a similar procedure as described for example 1 (15 mg, 59%) as a colorless film. LCMS (Method A) retention time = 1.42 min, m/z = 490.3 (M+H). 1H NMR (500 MHz, DMSO-d 6) d 7.22-7.29 (m, 1H), 7.06-7.21 (m, 4H), 6.70-6.83 (m, 2H), 3.18-3.88 (m, 14H), 2.27-2.36 (m, 3H), 2.12- 2.23 (m, 1H), 1.83-1.99 (m, 1H), 0.85 (dd, J=5.85, 15.44 Hz, 6H). Human APJ cAMP Potency range A.
Example 5 (R)(2,6-Bis(methoxy-d3)phenyl)butylhydroxy(3-phenylpyrrolidine carbonyl)pyrimidin-4(1H)-one Compound 5a. 1,3-Di[2H3]methoxynitrobenzene To a solution of 2-nitrobenzene-1,3-diol (1.75, 11.0 mmol) in acetone (175 mL) was added methyl-d3 iodide (4.9 g, 34 mmol) and K2CO3 (3.1 g, 23 mmol). The reaction e was stirred at 65 ºC for 14h. After cooling to RT, the mixture was concentrated under reduced re. The residue was diluted with water and extracted with EtOAc (3x). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 80% EtOAc/hexanes to give Compound 5a (1.4 g, 66%) as a light yellow foam. MS m/z = 190.4 (M+H). 1H NMR (chloroform-d) 7.25 (t, J=8.5 Hz, 1H), 6.55 (d, J=8.4 Hz, 2H).
Compound 5b. 2,6-Di[2H3]methoxyaniline To a solution of Compound 5a (1.4 g, 7.5 mmol) in a mixture of AcOH (40 mL), EtOH (40 mL) and H2O (20 mL) was added iron (2.5 g, 45 mmol) portionwise and the reaction mixture was stirred at 90 ºC for 14 h. The reaction e was allowed to cool to RT, poured onto ice, basified carefully with the on of solid Na2CO3 and extracted with EtOAc (3X). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give Compound 5b (1.2 g, 97%) as a dark solid. Compound 5a was used without further purification. MS m/z = 160.4 (M+H).
Compound 5c. N-(2,6-Di[2H3]methoxyphenyl)pentanimidamide To a mixture of Compound 4b (1.2 g, 7.2 mmol) and pentanenitrile (0.72 g, 8.6 mmol) in toluene (11 mL) at 0 ºC was added 2M trimethylaluminum in hexane (4.3 mL, 8.6 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and was heated at 100 °C for 14 h. The reaction mixture was allowed to cool to RT and quenched with ted aqueous Rochelle’s salt and EtOAc. The phases were separated and the aqueous phase was ted with EtOAc. The organic phases were ed and washed with brine, dried ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 30% MeOH/0.5% TEA in DCM to give Compound 5c (1.1 g, 64%) as an orange oil. MS m/z = 243.4 (M+H). 1H NMR (methanol-d 4) 7.01 (t, J=8.3 Hz, 1H), 6.64 (d, J=8.4 Hz, 2H), 2.22- 2.34 (m, 2H), 1.60-1.72 (m, 2H), 1.40-1.53 (m, 2H), 0.96 (t, J=6.7 Hz, 3H).
Compound 5d. Ethyl 2-butyl(2,6-di[2H3]methoxyphenyl)hydroxyoxo-1,4- dihydropyrimidinecarboxylate A on of Compound 5c (0.35 g, 1.4 mmol) and yl methanetricarboxylate (0.50 g, 2.2 mmol) in toluene (10 ml) was heated at 155ºC in a microwave reactor for 15 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel tography eluting with 0 to 100% EtOAc/hexanes to give Compound 5d (0.18 g, 33%) as a pale yellow solid. MS m/z = 383.4 (M+H). 1H NMR nol-d4) 7.88 (t, J=8.5 Hz, 1H), 7.22 (d, J=8.3 Hz, 2H), 4.73 (q, J=7.1 Hz, 2H), 2.75 (t, J=7.7 Hz, 2H), 1.88-1.97 (m, 2H), 1.72 (t, J=7.2 Hz, 3H), 1.56-1.65 (m, 2H), 1.16 (t, J=7.4 Hz, 3H) Example 5. (R)(2,6-Bis(methoxy-d3)phenyl)butylhydroxy(3- phenylpyrrolidinecarbonyl)pyrimidin-4(1H)-one Compound 5 was ed by the general procedures described in Example 1 (21 mg, 83% ). LCMS (Method A) Rt = 1.44 min, m/z = 484.0 (M+H). 1H NMR (500 MHz, DMSO-d6) d 7.22-7.29 (m, 1H), .21 (m, 4H), 6.70-6.83 (m, 2H), 3.18-3.88 (m, 14H), 2.27-2.36 (m, 3H), 2.12-2.23 (m, 1H), 1.83-1.99 (m, 1H), 0.85 (dd, J=5.85, 15.44 Hz, 6H) Human APJ cAMP Potency range A.
Example 6. 2-butylhydroxy((S)phenylpropyl)((R)phenylpyrrolidine carbonyl)pyrimidin-4(3H)-one Compound 6a. Ethyl pentanimidate hydrochloride Pentanenitrile (9 mL, 90 mmol) in EtOH (59.9 mL, 1030 mmol) was cooled to 0oC by ice bath. AcCl (48.64 mL, 685.0 mmol) was added dropwise over 3 hours. After complete addition, the reaction mixture was stirred at room temperature for 14h. The resulting solution was concentrated under reduced pressure and the e washed with Et2O (2 x) to remove residual HCl. The solid was suspended in 200 ml of Et2O and stored at 4°C for 14h. Compound 6a (14 g, 85 mmol, 99 % yield) was ed by tion as a white solid. 1H NMR (400MHz, CHLOROFORM-d) 4.64 (d, J=6.6 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 1.87 - 1.64 (m, 2H), 1.49 (t, J=6.2 Hz, 3H), 1.45 - 1.38 (m, 2H), 0.95 (t, J=7.3 Hz, 3H).
Compound 6b. (S)-N-(1-phenylpropyl)pentanimidamide To a solution of Compound 6a (1.35 g, 8.15 mmol) in Ethanol (15 mL) was added (S) phenylpropanamine (0.918 g, 6.79 mmol) at 0oC. The reaction mixture was stirred from 0oC to room temperature for 14h, followed by on of a in MeOH (14.55 mL, 102.0 mmol) and was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residual was dissolved in MeOH and purified by prep HPLC.
The fractions containing Compound 6b were collected and concentrated under reduced pressure. The e was dissolved in DCM and washed with 1N NaOH. The combined organic layer was washed with brine and concentrated to Compound 6b (710mg, 3.25 mmol, 47.9 % yield) as colorless oil. MS m/z = 219 [M+H]+. 1H NMR (400MHz, CHLOROFORM-d) 7.29 - 7.05 (m, 5H), 4.41 (br. s., 1H), 2.23 - 2.05 (m, 2H), 1.91 - 1.62 (m, 2H), 1.55 - 1.38 (m, 2H), 1.27 (sxt, J=7.4 Hz, 2H), 0.83 (td, J=7.4, 2.0 Hz, 6H).
Compound 6c. (S)-ethyl 2-butylhydroxyoxo(1-phenylpropyl)-1,6- dihydropyrimidinecarboxylate A mixture of Compound 6b (710 mg, 3.25 mmol), triethyl methanetricarboxylate (1.241 mL, 5.85 mmol) and Toluene (15 mL) was heated at 160oC for 1 hour in ave reactor. The mixture was cooled to room ature and loaded onto a 40 g ISCO column eluted with 0-70% EtOAc/DCM for 30min. The desired fraction was collected and concentrated to give Compound 6c (580 mg, 1.27 mmol, 39.0 % yield). MS m/z = 359.3 [M+H]+. 1H NMR (400MHz, METHANOL-d 4 at 333K) 7.43 - 7.35 (m, 2H), 7.33 - 7.26 (m, 3H), 6.26 (br. s., 1H), 4.43 - 4.30 (m, 2H), 2.75 - 2.51 (m, 3H), 2.47 - 2.24 (m, 1H), 1.67 - 1.51 (m, 1H), 1.40 - 1.28 (m, 4H), 1.26 - 1.13 (m, 2H), 1.04 (t, J=7.4 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H). 13C NMR (101MHz, METHANOL-d 4 at 333K) 171.0, 169.5, 162.5, 140.7, 130.1, 128.7, 127.7, 93.0, 62.9, 60.3, 36.1, 30.4, 30.3, 25.7, 23.3, 14.6, 13.9, 11.5.
Compound 6. 2-Butylhydroxy((S)phenylpropyl)((R)phenylpyrrolidine carbonyl)pyrimidin-4(3H)-one To a solution of nd 6c (50 mg, 0.139 mmol) and (R)phenylpyrrolidine, HCl (33.3 mg, 0.181 mmol) in l (1 mL) was added DIEA (0.073 mL, 0.418 mmol). The e was stirred in microwave reactor at 160oC for 1 hour. The crude sample was diluted with MeOH and purified with prep HPLC (4 injections) : Phenomenex AXIA Luna 75 x 30mm 5u: A: 10% ACN - 90% H2O -10mM TFA B: 90% ACN - 10% H2O - 10mM TFA wavelength 254 nm; flow rate 40 mL/min; gradient time 10 min; 0 to 100% B. Compound 6 (31 mg, 0.067 mmol, 48.4 % yield) was obtained. LCMS (Method A) Rt = 1.75 min, MS m/z = 460.1 [M+H]+. 1H NMR (400MHz, CHLOROFORM-d at 333K) 7.40 - 7.08 (m, 10H), 6.11 (br. s., 1H), 3.88 - 3.09 (m, 5H), 2.81 - 2.22 (m, 5H), 2.00 (quin, J=10.1 Hz, 1H), 1.69 (br. s., 1H), 1.58 - 1.38 (m, 1H), 1.27 (d, J=6.4 Hz, 2H), 1.04 (t, J=7.4 Hz, 3H), 0.84 (t, J=6.7 Hz, 3H).
Example 7 1-(2,6-dimethoxyphenyl)hydroxy(3-(2-methoxyphenyl)pyrrolidinecarbonyl) (5-methylpyridinyl)pyrimidin-4(1H)-one Compound 7a. N-(2,6-dimethoxyphenyl)methylnicotinimidamide To a solution of methoxyaniline (0.51 g, 3.3 mmol) and 5-methylnicotinonitrile (0.39 g, 3.3 mmol) in toluene (10 ml) at 0 °C was added dropwise TMS-OTf (1.2 ml, 6.5 mmol). The resulting mixture was stirred at 0 °C for 10 min and heated to 110 oC for 2 days. The reaction mixture was cooled to 0 °C, quenched with 1N HCl (10 mL) solution and diluted with EtOAc. The organic layer was washed with 1N HCl solution and dried over sodium sulfate, decanted and concentrated to give a brown oil. The residue was added to a silica gel (40 g) column and was eluted with 0-100% 1% Et3N/EtOAc in DCM. Collected fractions to give Compound 7a (0.65 g, 73 % yield) as an off white solid.
MS m/z = 272.2 (M+H). 1H NMR (500MHz, CHLOROFORM-d) 8.90 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 7.07 (t, J = 8.3 Hz, 1H), 6.68 (d, J = 8.3 Hz, 2H), 4.76 (br s, 2H), 3.84 (s, 6H), 2.43 (s, 3H).
Compound 7b. ethyl 1-(2,6-dimethoxyphenyl)hydroxy(5-methylpyridinyl) oxo-1,4-dihydropyrimidinecarboxylate To a mixture of nd 7a (75 mg, 0.28 mmol) and triethyl methanetricarboxylate (96 mg, 0.42 mmol) in Et3N (1.5 mL, 11 mmol) was added TMSCl (0.53 mL, 4.2 mmol) at 0 °C. The mixture was d for 10 min and heated to 110 oC for 20 hrs. The reaction mixture was concentrated in vacuo and d with EtOAc. The organic layer was washed with 0.1M HCl. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was added to a silica gel (12 g) column and was eluted with 0-100% EtOAc in hexanes, then 0-100% 1% TEA/EtOAc in DCM. Collected fractions to give Compound 7b (100 mg, 88 % yield) as a yellow solid. MS m/z = 412.2 (M+H). 1H NMR (500MHz, CHLOROFORM-d) 8.37 (s, 1H), 8.34 (s, 1H), 7.57 (s, 1H), 7.24 (t, J = 8.5 Hz, 1H), 6.47 (d, J = 8.5 Hz, 2H), 4.76 (br s, 2H), 3.84 (s, 6H), 2.43 (s, 3H).
Example 7. -dimethoxyphenyl)hydroxy(3-(2-methoxyphenyl)pyrrolidine carbonyl)(5-methylpyridinyl)pyrimidin-4(1H)-one To a stirred e of Compound 7b (12 mg, 0.029 mmol) and Compound 7c, isomer 1 (6.7 mg, 0.038 mmol) in toluene (1 ml) was added trimethylaluminum (0.029 ml, 0.058 mmol) dropwise. The reaction mixture was heated at 110 °C for 3 hrs. The reaction mixture was concentrated in vacuo and diluted with EtOAc/THF. The organic layer was washed with sat NH4Cl. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The e was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM um acetate; Gradient: 5-45% B over 19 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions ning the desired product were combined and dried via centrifugal evaporation to give Example 7 (3.7 mg, 24%). LCMS (Method A) Rt = 1.37 min, m/z = 543.1 (M+H). 1H NMR (500 MHz, DMSO-d6) 8.27-8.29 (m, 1H), 8.13-8.16 (m, 1H), 7.41-7.43 (m, 1H), 7.28 (t, J = 7.2 Hz, 1H), 7.19-7.26 (m, 2H), 6.96-7.01 (m, 1H), 6.89-6.92 (m, 1H), 6.53-6.61 (m, 2H), 3.76-3.85 (m, 6H), 3.65-3.70 (m, 3H), 3.37-3.63 (m, 5H), 2.17 (s, 3H), 2.11-2.15 (m, 1H), .02 (m, 1H). Human APJ cAMP Potency range A.
Example 8 (R)(butenyl)hydroxy(2-methoxymethylphenyl)(3-phenylpyrrolidine- 1-carbonyl)pyrimidin-4(3H)-one, diastereomer 1 and diastereomer 2 nd 8a. N-(2-methoxymethylphenyl)pentenimidamide trimethylaluminum (6.6 ml, 13 mmol) was added dropwise to a solution of oxymethylaniline (1.5 g, 11 mmol) and pentenenitrile (1.1 g, 13 mmol) in Toluene (10 ml) while cooling in an ice bath. After addition was complete, the reaction mixture was heated to 110 °C for 16 hrs. The reaction mixture was allowed to cool to RT and partitioned between saturated on of Rochelle's salt and EtOAc. The organic phase was dried, filtered and concentrated. The e was added to a silica gel (120 g) column and was eluted with 0- % 0.5% Et3N/DCM in 20% MeOH/DCM. Collected fractions to give Compound 8a (2.4 g, 100 % yield) as an off white solid. MS m/z = 219.1 (M+H). 1H NMR (500MHz, CHLOROFORM-d) 6.93 (t, J = 7.7 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), .06 (m, 1H), 5.16 (d, J = 17.1 Hz, 1H), 5.07 (d, J = 9.9 Hz, 1H), 4.27 (br s, 2H), 3.79 (s, 3H), 2.53-2.59 (m, 2H), 2.45-2.53 (m, 2H), 2.14 (s, 3H).
Compound 8b. ethyl 2-(butenyl)hydroxy(2-methoxymethylphenyl)oxo- 1,4-dihydropyrimidinecarboxylate A mixture of Compound 8a (15 mg, 0.069 mmol), acetic acid (7.9 µl, 0.14 mmol) and triethyl methanetricarboxylate (32 mg, 0.14 mmol) in toluene (1ml) was was heated at 140 °C for 105 min in a microwave reactor. The reaction mixture was concentrated in vacuo. The residue was added to a silica gel (12 g) column and was eluted with 20-100% EtOAc in hexanes. Collected fractions to give Compound 8b (24 mg, 100 % yield) as a clear liquid. MS m/z = 359.1 (M+H). 1H NMR (500MHz, FORM-d) 7.33 (t, J = 8.3 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.67-5.75 (m, 1H), 4.93- 4.98 (m, 2H), 4.42 (q, J = 7.2 Hz, 2H), 3.77 (s, 3H), .48 (m, 4H), 2.09 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H).
Example 8 and Example 8" were prepared from compound 8b following a similar procedure as described for compound 1. The e was purified via preparative LC/MS with the ing conditions: Column: XBridge C18, 19 x 200 mm, 5-μm les; Mobile Phase A: 5:95 acetonitrile: water with 10-M ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-M ammonium acetate; Gradient: 15-55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. The first eluting fraction was collect and the stereochemistry was assigned as Example 8 (11 mg, 33%). LCMS (Method A) Rt = 1.36 min, m/z = 460.4 (M+H). 1H NMR (500 MHz, DMSO-d6) 7.21- 7.41 (m, 6H), 6.95-7.08 (m, 2H), 5.67-5.76 (m, 1H), 4.87-4.98 (m, 2H), 3.64-3.81 (m, 5H), 3.27-3.47 (3H), 2.18-2.34 (m, 5H), 1.90-2.06 (m, 4H). Human APJ cAMP y range A.
The second eluting fraction was collect and the stereochemistry was ed as Example 8" (3.4 mg, 11%). LCMS (Method A) Rt = 1.37 min, m/z = 460.4 (M+H). 1H NMR (500 MHz, DMSO-d6) 7.20-7.41 (m, 6H), 6.95-7.07 (m, 2H), 5.65-5.77 (m, 1H), .97 (m, 2H), 3.63-3.79 (m, 5H), 3.28-3.52 (3H), 2.19-2.34 (m, 5H), 1.89-2.06 (m, 4H).
Human APJ cAMP Potency range A.
Example 9. 1-(2,6-dimethoxyphenyl)hydroxy(isopropoxymethyl)(3-(ptolyl )azetidinecarbonyl)pyrimidin-4(1H)-one.
Compound 9a. tert-butyl 3-iodoazetidinecarboxylate To a solution of tert-butyl 3-hydroxyazetidinecarboxylate (400 mg, 2.31 mmol) in toluene (23 ml), imidizole (472 mg, 6.93 mmol), triphenylphosphine (1.21 g, 4.62 mmol) and iodine (879 mg, 3,46 mmol) were added sively and the reaction mixture was heated at 110 °C for 4 h. The cooled reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with Et2O (2 X). The Et2O layers were ed and the composite was treated with iodine until a persistent brown color occurred and the mixture was stirred at RT overnight. The Et2O on was treated with saturated aqueous Na2S2O3 until colorless, the phases were split and the organic phase was dried over over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 20% EtOAc in hexane to give Compound 9a (594 mg, 91 % yield) as a clear colorless oil. MS m/z = 284.0, (M+H) 1H NMR (CHLOROFORM-d) : 4.57 (t, J=8.4 Hz, 2H), 4.36-4.44 (m, 1H), 4.18-4.26 (m, 2H), 1.37 (s, 9H).
Compound 9b. tert-butyl olyl)azetidinecarboxylate To a 0oC solution of compound a (100 mg, 0.35 mmol), (1R, 2R)-N1, N1, N2, N2- tetramethylcyclohexane-1, 2, diamine (3.61 mg, 0.0210 mmol) and 0.05M cobalt(II) chloride in THF (0.35 ml, 0.018 mmol) was added 0.5M p-tolylmagnesium e (0.848 ml, 0.424 mmol) dropwise. The reaction e was allowed to cool to RT and was stirred for 14 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with Et2O (2 X). The Et2O layers were combined and the composite was dried over over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 20% EtOAc in hexane to give Compound 9b (72 mg, 82 % yield) as a clear colorless oil. MS m/z = 249.2 (M+H), 1H NMR (CHLOROFORM-d) : 7.01-7.22 (m, 4H), 4.16-4.32 (m, 2H), 3.81-3.95 (m, 2H), 3.54-3.71 (m, 1H), 2.25 (s, 3H), 1.38 (s, 9H).
Compound 9c. 3-(p-tolyl)azetidine To a solution of compound b (71.5 mg, 0.289 mmol) in DCM (2 ml) was added TFA (165 mg, 1.45 mmol) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was trated under reduced pressure to give compound 9c that was used without r purification (76 mg, 100 % yield) as a yellow oil. MS m/z = 148.1 (M+H), (M+H) 1H NMR (CHLOROFORM-d) : 7.06-7.22 (m, 4H), 4.23-4.33 (m, 2H), 4.07- 4.22 (m, 3H), 2.21-2.33 (s, 3H) Ex Structure Name Chiral amine ediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 2-(cyclopropoxymethyl) 1H NMR z, DMSO- 1.17 A (2,6-dimethoxyphenyl)(3- d6) .30 (m, 2H), 7.14 A (2-fluorophenyl)pyrrolidine- (m, 1H), 6.99-7.05 (m, 2H), 510.3 1-carbonyl) 10.65, 99.5% 6.59-6.64 (m, 2H), 3.52-3.76 hydroxypyrimidin-4(1H)- Chiralpak IF, 4.6 x 250 (m, 11H), 3.47 (s, 2H), 3.11 one mm, 5 micron; (br s, 1H), 2.08 (br s, 1H), mobile phase: 15% 1.80-1.87 (m, 1H), 0.12-0.15 IPA/90% CO2; (m, 2H), 0.02 (d, J = 14.1 Hz, Flow Conditions: 2.0 2H) mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 1) 11 (R) 1H NMR (500MHz, DMSO- 1.23 A (cyclopropoxymethyl) d6) 7.21-7.26 (m, 1H), 6.98- A (2,6-dimethoxyphenyl) 7.13 (m, 5H), 6.57-6.62 (m, 492.1 hydroxy(3- 2H), 3.73-3.80 (m, 2H), 3.50- phenylpyrrolidine 3.54 (m, 6H), 3.41 (s, 2H), carbonyl)pyrimidin-4(3H)- 3.05-3.30 (m, 4H), 2.06 (br s, one 1H), 1.69-1.72 (m, 1H), 0.11 (br s, 2H), 0.01 (d, J = 11.3 Hz, 2H) Ex ure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 12 (R)(2,6- 1H NMR (500MHz, DMSO- 1.29 A dimethoxyphenyl) d6) 7.36-7.42 (m, 1H), 7.28- A hydroxy 7.32 (m, 4H), 7.20-7.25 (m, 494.2 (isopropoxymethyl)(3- 1H), 6.74-6.80 (m, 2H), 3.80- phenylpyrrolidine 3.89 (m, 2H), 3.68-3.75 (m, carbonyl)pyrimidin-4(1H)- 6H), 3.62 (s, 2H), 3.23-3.51 one (m, 4H), 2.24 (br s, 1H), 1.89- 1.95 (m, 1H), 0.86-0.90 (m, 13 lopropoxymethyl) 1H NMR (500MHz, DMSO- 1.14 A (2,6-dimethoxyphenyl)(3- d6) 7.21-7.30 (m, 2H), 7.13 A (2-fluorophenyl)pyrrolidine- (m, 1H), 6.99-7.03 (m, 2H), 509.9 1-carbonyl) 10.65, 99.5% 6.60-6.65 (m, 2H), 3.73-3.77 hydroxypyrimidin-4(1H)- Chiralpak IF, 4.6 x 250 (m, 2H), 3.07-3.58 (m, 12H), one mm, 5 micron; 2.09 (br s, 1H), 1.81-1.89 (m, mobile phase: 15% 1H), 0.13-0.16 (m, 2H), 0.02 IPA/90% CO2; (d, J = 13.0 Hz, 2H) Flow Conditions: 2.0 , 150 bar, 40°C, wavelength: 220 nm (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 14 (R)(2,6- 1H NMR (500MHz, DMSO- 1.52 A dimethoxyphenyl) d6) 7.44-7.49 (m, 1H), 7.27- A hydroxyisopentyl(3- 7.36 (m, 4H), .26 (m, 492.2 phenylpyrrolidine 1H), 6.79-6.86 (m, 2H), 3.71- carbonyl)pyrimidin-4(1H)- 3.81 (m, 6H), 3.64 (br s, 2H), one 3.26-3.51 (m, 3H), 2.23 (br s, 3H), .98 (m, 1H), 1.34 (br s, 3H), 0.66 (br s, 6H) 2-(cyclopropoxymethyl) 1H NMR (500MHz, DMSO- 1.27 A (2,6-dimethoxyphenyl)(3- d6) 7.15-7.27 (m, 2H), 6.94- A (3-fluorophenyl)pyrrolidine- 7.00 (m, 2H), 6.87 (t, J = 7.9 510.2 1-carbonyl) Hz, 1H), .64 (m, 2H), hydroxypyrimidin-4(1H)- 3.73-3.75 (m, 2H), 3.53-3.57 one (m, 6H), 3.45 (s, 2H), 3.07- 3.33 (m, 4H), 2.08 (br s, 1H), 1.72-1.80 (m, 1H), 0.12 (br s, 2H), 0.02 (d, J = 12.5 Hz, 2H) 16 (S)(butenyl)(2,6- 1H NMR (500MHz, DMSO- 1.35 A dimethoxyphenyl) d6) 7.44-7.49 (m, 1H), 7.27- A hydroxy(3- 7.35 (m, 4H), 7.21-7.26 (m, 476.1 phenylpyrrolidine 1H), 6.81-6.88 (m, 2H), 5.71 carbonyl)pyrimidin-4(3H)- (br s, 1H), 4.88-4.96 (m, 2H), one 3.73-3.77 (m, 6H), 3.64 (br s, 2H), 3.36-3.48 (m, 2H), 3.30 (t, J = 10.7 Hz, 1H), .36 (m, 3H), 1.90-1.97 (m, 1H) Ex ure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 17 (R)(2,6-diethylphenyl) 1H NMR (500MHz, DMSO- 1.65 A hydroxy d6) 7.20-7.41 (m, 8H), 3.86- A (isopropoxymethyl)(3- 3.91 (m, 1H), 3.72-3.75 (m, 490.2 phenylpyrrolidine 2H), 3.51-3.62 (m, 2H), 3.33- carbonyl)pyrimidin-4(3H)- 3.40 (m, 1H), 3.14-3.23 (m, one 2H), 2.32-2.44 (m, 2H), 2.17- 2.29 (m, 3H), 1.93 (br s, 1H), 0.98-1.14 (m, 6H), 0.81-0.85 (m, 6H) 18 1-(2,6-diethylphenyl) 1H NMR (500MHz, DMSO- 1.35 A hydroxy d6) 8.46-8.50 (m, 1H), 7.69- A (isopropoxymethyl)(3- 7.74 (m, 1H), 7.18-7.42 (m, 491.1 (pyridinyl)pyrrolidine 7.62, 93.4% 5H), 3.67-3.72 (m, 3H), 3.38- carbonyl)pyrimidin-4(1H)- Chiralpak AD-3, 4.6 x 150 3.55 (m, 3H), 3.12-3.21 (m, one mm, 3 ; 2H), 2.27-2.41 (m, 3H), 2.11- mobile phase: 25% 2.27 (m, 3H), 2.02-2.08 (m, MeOH:DEA /75% CO2; 1H), 0.92-1.16 (m, 6H), 0.80- Flow Conditions: 1.0 0.83 (m, 6H) mL/min, 150 bar, 45°C, wavelength: 220 nm (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 19 2-(cyclopropoxymethyl) 1H NMR (500MHz, DMSO- 1.19 A (2,6-dimethoxyphenyl) d6) .28 (m, 1H), 7.13 A hydroxy(3-(o- (br s, 1H), 6.94-7.05 (m, 3H), 506.1 pyrrolidine 12.72, >99% 6.60-6.65 (m, 2H), 3.47-3.77 carbonyl)pyrimidin-4(1H)- Lux Cellulose-4 21 x 250 (m, 13H), 3.08-3.20 (m, 1H), one mm, 5 micron; mobile 2.13-2.19 (m, 3H), 2.03 (br s, phase: 15% IPA:heptane 1H), 1.77 (br s, 1H), 0.12-0.16 (1:1)/85% CO2; flow (m, 2H), 0.02 (d, J = 16.3 Hz, condition: 2.0 mL/min, 150 2H) bar, 40°C, wavelength: 220 nm (Isomer 1) (R)(cyclobutoxymethyl)- 1H NMR (500MHz, DMSO- 1.36 A 3-(2,6-dimethoxyphenyl) d6) 7.27-7.38 (m, 5H), 7.20- A hydroxy(3- 7.25 (m, 1H), 6.71-6.77 (m, 506.0 pyrrolidine 2H), 3.69-3.73 (m, 6H), 3.62- carbonyl)pyrimidin-4(3H)- 3.67 (m, 2H), 3.22-3.58 (m, one 6H), 2.24 (br s, 1H), 1.92 (br s, 1H), 1.46-1.56 (m, 4H), 1.30-1.37 (m, 2H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 21 5-(3-(4- 1H NMR (500MHz, DMSO- 1.38 A chlorophenyl)pyrrolidine d6) 7.15-7.28 (m, 6H), 6.60- A carbonyl) 6.65 (m, 2H), 3.70-3.75 (m, 526.2 (cyclopropoxymethyl) 6.69, 99.8% 2H), 3.55-3.59 (m, 6H), 3.06- (2,6-dimethoxyphenyl) Chiralcel OJ-H 4.6 x 250 3.41 (m, 6H), 2.11 (br s, 1H), hydroxypyrimidin-4(1H)- mm; mobile phase: 15% 1.73-1.80 (m, 1H), 0.13-0.16 one IPA/85% CO2; Flow (m, 2H), 0.02 (d, J = 14.7 Hz, Conditions: 3.0 mL/min, 2H) 140 bar, 40°C, wavelength: 220 nm 22 5-(3-(2- 1.23 A chlorophenyl)pyrrolidine A carbonyl) 526.1 (cyclopropoxymethyl) 8.29, 98.2% (2,6-dimethoxyphenyl) pak ID, 4.6 x 250 hydroxypyrimidin-4(1H)- mm, 5 micron; mobile phase: 10% MeOH/90% CO2; Flow Conditions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 23 (R)(2,6- 1H NMR (500MHz, DMSO- 1.20 A oxyphenyl) d6) 7.29-7.35 (m, 4H), 7.23- A (ethoxymethyl)hydroxy- 7.25 (m, 2H), 6.80-6.86 (m, 480.1 -(3-phenylpyrrolidine 2H), 3.94-4.00 (m, 2H), 3.68- carbonyl)pyrimidin-4(1H)- 3.78 (m, 7H), 3.65 (s, 2H), one 3.44-3.49 (m, 1H), 3.25-3.32 (m, 1H), 3.17 (t, J = 9.2 Hz, 2H), 2.21 (br s, 1H), 1.90-2.00 (m, 1H), 0.97-1.03 (m, 3H) 24 (S)(2,6- 1H NMR (500MHz, DMSO- 1.52 A dimethoxyphenyl) d6) 7.42-7.48 (m, 1H), 7.27- A hydroxyisopentyl(3- 7.35 (m, 4H), 7.21-7.26 (m, 492.2 phenylpyrrolidine 1H), .88 (m, 2H), 3.73- carbonyl)pyrimidin-4(1H)- 3.77 (m, 6H), 3.64 (br s, 2H), one 3.26-3.49 (m, 3H), 2.22 (br s, 3H), 1.90-1.99 (m, 1H), 1.35 (br s, 3H), 0.66 (br s, 6H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with ion time S Rt cAMP (min) EC50 Metho y d range 1-(2,6-diethylphenyl)(3- 1.51 A (2-fluorophenyl)pyrrolidine- A 1-carbonyl)hydroxy 508.4 (isopropoxymethyl)pyrimidi 10.65, 99.5% n-4(1H)-one Chiralpak IF, 4.6 x 250 mm, 5 micron; mobile phase: 15% IPA/90% CO2; Flow Conditions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 2) 26 5-(3-(3- Racemic pyrolidine 1H NMR (500MHz, DMSO- 1.39 A chlorophenyl)pyrrolidine amine d6) 7.24-7.45 (m, 5H), 6.78- A carbonyl)(2,6- 6.83 (m, 2H), 3.88-3.96 (m, 513.9 dimethoxyphenyl) 2H), .77 (m, 6H), 3.65 (ethoxymethyl) (s, 2H), 3.37-3.54 (m, 3H), hydroxypyrimidin-4(1H)- 3.25-3.31 (m, 1H), 2.27 (br s, one 1H), 1.93-1.99 (m, 1H), 0.96- 1.01 (m, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 27 (R)(butenyl)(2,6- 1H NMR (500MHz, DMSO- 1.35 A dimethoxyphenyl) d6) 7.43-7.49 (m, 1H), 7.27- A hydroxy(3- 7.35 (m, 4H), 7.20-7.26 (m, 476.1 phenylpyrrolidine 1H), 6.82-6.89 (m, 2H), 5.71 carbonyl)pyrimidin-4(3H)- (br s, 1H), 4.88-4.97 (m, 2H), one 3.70-3.79 (m, 6H), 3.64 (br s, 2H), .47 (m, 2H), 3.30 (t, J = 9.8 Hz, 1H), 2.21-2.35 (m, 3H), 1.91-1.98 (m, 1H) 28 5-(3-(3- Racemic dine 1H NMR (500MHz, DMSO- 1.53 A chlorophenyl)pyrrolidine amine d6) 7.41-7.47 (m, 1H), 7.25- A carbonyl) 7.39 (m, 4H), 6.78-6.84 (m, 509.9 (cyclopropylmethyl)(2,6- 2H), 3.73-3.76 (m, 6H), 3.58- dimethoxyphenyl) 3.69 (m, 4H), 3.39-3.49 (m, hydroxypyrimidin-4(1H)- 1H), 2.26 (br s, 1H), 2.16 (br one s, 2H), 1.89-1.99 (m, 1H), 0.80 (br s, 1H), 0.40 (br s, 2H), 0.00 (br s, 2H) 29 (S)(2,6- 1H NMR (500MHz, DMSO- 1.19 A dimethoxyphenyl) d6) .46 (m, 1H), 7.20- A (ethoxymethyl)hydroxy- 7.37 (m, 5H), 6.77-6.86 (m, 480.0 -(3-phenylpyrrolidine 2H), .97 (m, 2H), 3.67- carbonyl)pyrimidin-4(1H)- 3.79 (m, 6H), 3.35-3.66 (m, one 5H), 3.24-3.34 (m, 2H), 2.27 (br s, 1H), 1.90-2.00 (m, 1H), 0.96-1.01 (m, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with ion time S Rt cAMP (min) EC50 Metho Potency d range cyclopentyl(2,6- 1H NMR (500MHz, DMSO- 1.52 A dimethoxyphenyl) d6) 7.38-7.47 (m, 1H), 7.27- A hydroxy(3- 7.36 (m, 4H), 7.21-7.27 (m, 490.1 phenylpyrrolidine 1H), 6.77-6.86 (m, 2H), 3.70- carbonyl)pyrimidin-4(3H)- 3.79 (m, 6H), 3.59-3.67 (m, one 4H), .53 (m, 2H), 2.26 (br s, 1H), 1.90-1.99 (m, 1H), 1.73-1.84 (m, 2H), 1.52-1.69 (m, 4H), 1.41 (br s, 2H) 31 (S)(cyclopropylmethyl)- 1H NMR (500MHz, DMSO- 1.34 A 3-(2,6-dimethoxyphenyl) d6) 7.42-7.50 (m, 1H), 7.26- A hydroxy(3- 7.36 (m, 4H), 7.21-7.26 (m, 476.1 phenylpyrrolidine 1H), 6.79-6.89 (m, 2H), 3.72- carbonyl)pyrimidin-4(3H)- 3.77 (m, 6H), 3.64 (br s, 2H), one 3.36-3.46 (m, 2H), 3.27-3.35 (m, 1H), 2.28 (br s, 1H), 2.17 (br s, 2H), 1.91-2.00 (m, 1H), 0.82 (br s, 1H), 0.41 (br s, 2H), 0.01 (br s, 2H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 32 (R)(cyclopropylmethyl)- 1H NMR (500MHz, DMSO- 1.33 A 3-(2,6-dimethoxyphenyl) d6) 7.42-7.49 (m, 1H), 7.26- A hydroxy(3- 7.35 (m, 4H), 7.20-7.26 (m, 476.4 phenylpyrrolidine 1H), 6.80-6.87 (m, 2H), 3.72- carbonyl)pyrimidin-4(3H)- 3.76 (m, 6H), 3.64 (br s, 2H), one 3.35-3.53 (m, 2H), 3.28-3.34 (m, 1H), 2.26 (br s, 1H), 2.17 (br s, 2H), 1.91-1.98 (m, 1H), 0.82 (br s, 1H), 0.40 (br s, 2H), 0.01 (br s, 2H) 33 (S)(2,6- 1H NMR (500MHz, DMSO- 1.53 A dimethoxyphenyl) d6) 7.40-7.49 (m, 1H), 7.20- A hydroxy(3- 7.36 (m, 5H), 6.78-6.87 (m, 532.1 phenylpyrrolidine 2H), 3.69-3.80 (m, 6H), 3.63 carbonyl)(4,4,4- (br s, 4H), 3.35-3.54 (m, 1H), trifluorobutyl)pyrimidin- 2.16-2.34 (m, 5H), .98 4(1H)-one (m, 1H), 1.75 (br s, 2H) 34 (S)cyclopentyl(2,6- 1H NMR z, DMSO- 1.52 A dimethoxyphenyl) d6) .48 (m, 1H), 7.27- A hydroxy(3- 7.36 (m, 4H), .27 (m, 490.0 phenylpyrrolidine 1H), 6.77-6.85 (m, 2H), 3.69- carbonyl)pyrimidin-4(3H)- 3.79 (m, 6H), 3.60-3.69 (m, one 4H), 3.27-3.52 (m, 2H), 2.26 (br s, 1H), 1.90-1.98 (m, 1H), 1.72-1.84 (m, 2H), 1.51-1.70 (m, 4H), 1.40 (br s, 2H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range (R)(butenyl) 1H NMR z, DMSO- 1.37 A hydroxy(2-methoxy d6) .41 (m, 6H), 6.97- A methylphenyl)(3- 7.09 (m, 2H), 5.72 (br s, 1H), 460.4 phenylpyrrolidine 4.90-4.96 (m, 2H), 3.75-3.77 carbonyl)pyrimidin-4(3H)- (m, 3H), 3.73 (br s, 2H), 3.65- one 3.69 (m, 2H), .37 (m, 1H), 2.22-2.33 (m, 5H), 2.00- 2.03 (m, 2H), 1.90-1.98 (m, 36 (2,6- 1H NMR (500MHz, DMSO- 2.00 B dimethoxyphenyl) d6) 7.54 (t, J = 8.24 Hz, 1H), A hydroxy(3- 6.91 (d, J = 8.54 Hz, 2H), 3.81 443.0 phenylpyrrolidine (s, 6H), 2.32-2.36 (m, 2H), carbonyl)(4,4,4- 2.31 (s, 3H), 2.13 (s, 3H), trifluorobutyl)pyrimidin- 1.48-1.57 (m, 2H), 1.16-1.25 4(1H)-one (m, 2H), 0.76 (t, J = 7.02 Hz, 40 (R)(2,6- 1H NMR (500MHz, DMSO- 1.48 A dimethoxyphenyl) d6) 7.42-7.50 (m, 1H), 7.20- A hydroxy(3- 7.37 (m, 5H), 6.79-6.89 (m, 531.9 phenylpyrrolidine 2H), 3.69-3.80 (m, 6H), 3.64 carbonyl)(4,4,4- (br s, 4H), 3.27-3.50 (m, 1H), trifluorobutyl)pyrimidin- 2.17-2.36 (m, 5H), 1.89-1.99 4(1H)-one (m, 1H), 1.77 (br s, 2H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 41 l(3-(5- 1H NMR (500MHz, DMSO- 0.78 A chloropyridin d6) d 8.55 (br. s., 1H), 7.92 - A yl)pyrrolidinecarbonyl)- 7.77 (m, 1H), 7.52 - 7.27 (m, 513.3 1-(2,6-dimethoxyphenyl) 2H), 6.83 (br. s., 2H), 3.99 - hydroxypyrimidin-4(1H)- 13.24, 91% 3.45 (m, 5H), 2.51 (br. s., 6H), one Chiralpak IC, 4.6 x 250 2.22 (br. s., 4H), 1.42 (br. s., mm, 5 micron; mobile 2H), 1.22 - 1.10 (m, 2H), 0.70 phase: 10% (d, J=6.3 Hz, 3H) IPA/0.1%DEA/90% CO2; flow condition: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm 42 2-[(tert-butoxy)methyl] 1H NMR (500MHz, DMSO- 0.88 A [3-(2- d6) d 7.55 - 7.37 (m, 3H), 7.28 A chlorophenyl)pyrrolidine (dd, J=14.7, 6.5 Hz, 2H), 6.84 542.3 carbonyl](2,6- 8.29, 98.2% - 6.73 (m, 2H), 3.87 (br. s., dimethoxyphenyl) 2H), 3.73 (br. s., 2H), 3.62 - Chiralpak ID, 4.6 x 250 hydroxy-1,4- 3.23 (m, 2H), 2.51 (br. s., 7H), mm, 5 micron; dihydropyrimidinone 2.34 - 1.84 (m, 2H), 0.83 (d, mobile phase: 10% J=11.3 Hz, 9H) MeOH/90% CO2; Flow Conditions: 2.0 , 150 bar, 40°C, wavelength: 220 nm (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 43 2-butyl[3-(2- 1H NMR (500MHz, DMSO- 0.87 A chlorophenyl)pyrrolidine d6) d 7.43 (br. s., 3H), 7.30 A carbonyl](2,6- (br. s., 2H), 6.83 (br. s., 2H), 512.2 dimethoxyphenyl) 8.29, 98.2% 3.71 (d, J=15.6 Hz, 3H), 3.41 hydroxy-1,4- (br. s., 2H), 2.51 (br. s., 6H), Chiralpak ID, 4.6 x 250 opyrimidinone 2.22 (d, J=6.0 Hz, 3H), 2.03 mm, 5 micron; (br. s., 1H), 1.39 (br. s., 2H), mobile phase: 10% 1.19 - 1.03 (m, 2H), 0.78 - MeOH/90% CO2; 0.56 (m, 3H) Flow ions: 2.0 mL/min, 150 bar, 40°C, Wavelength (Isomer 2) 44 2-[(tert-butoxy)methyl] 1H NMR (500MHz, DMSO- 0.85 A imethoxyphenyl)[3- d6) d 7.33 (d, J=16.2 Hz, 3H), A (4-fluorophenyl)pyrrolidine- 7.24 - 7.08 (m, 3H), 6.84 - 526.4 1-carbonyl]hydroxy-1,4- 9.93, 99% 6.69 (m, 2H), 3.95 - 3.19 (m, dihydropyrimidinone Whelk-O 1 (R,R), 4.6 x 9H), 2.55 (s, 3H), 2.29 - 2.18 250 mm, 5 micron; (m, 1H), 1.99 - 1.84 (m, 1H), mobile phase: 15% 0.82 (d, J=13.0 Hz, 9H) IPA/85%CO2; Flow Conditions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 45 l[3-(4- 1H NMR (500MHz, DMSO- 0.90 A chlorophenyl)pyrrolidine d6) d 7.49 - 7.28 (m, 5H), 6.87 A carbonyl](2,6- - 6.76 (m, 2H), 3.81 - 3.16 (m, 512.2 dimethoxyphenyl) 6.69, 99.8% 6H), 2.52 (br. s., 6H), 2.18 (br. y-1,4- Chiralcel OJ-H 4.6 x 250 s., 3H), 1.42 (d, J=6.4 Hz, dihydropyrimidinone mm; mobile phase: 15% 2H), 1.13 (d, J=7.0 Hz, 2H), IPA/85% CO2; Flow 0.79 - 0.63 (m, 3H) Conditions: 3.0 mL/min, 140 bar, 40°C, wavelength: 220 nm (Isomer 1) 46 2-butyl[3-(4- 1H NMR (500MHz, DMSO- 0.90 A chlorophenyl)pyrrolidine d6) d 7.36 (br. s., 4H), 6.89 - A carbonyl](2,6- 6.71 (m, 2H), 3.75 (br. s., 2H), 512.3 dimethoxyphenyl) 7.71, 99.8% 3.59 - 3.58 (m, 1H), 3.58 - hydroxy-1,4- Chiralcel OJ-H 4.6 x 250 3.19 (m, 4H), 2.52 (br. s., 6H), opyrimidinone mm; mobile phase: 15% 2.32 - 2.21 (m, 1H), 2.15 (d, IPA/85% CO2; Flow J=6.1 Hz, 2H), 1.41 (d, J=6.4 Conditions: 3.0 mL/min, Hz, 2H), 1.12 (d, J=7.3 Hz, 140 bar, 40°C, 2H), 0.76 - 0.61 (m, 3H) wavelength: 220 nm (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 47 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.57 A dimethoxyphenyl) d6) d 8.74 (d, J=8.5 Hz, 2H), A hydroxy[3-(pyridin 7.88 - 7.73 (m, 2H), 7.47 (d, 479.3 yl)pyrrolidinecarbonyl]- 6.86, 99% J=8.2 Hz, 1H), 6.91 - 6.76 (m, 1,4-dihydropyrimidinone Chiralpak AS-H, 4.6 x 250 2H), 3.81 - 3.41 (m, 3H), 2.52 mm, 5 micron; (br. s., 6H), 2.46 - 2.46 (m, mobile phase: 10% 1H), 2.39 - 2.39 (m, 1H), 2.46 MeOH/0.1%DEA/90% - 2.33 (m, 1H), 2.25 (d, J=7.3 CO2; Flow Conditions: 2.0 Hz, 2H), 2.10 - 1.92 (m, 1H), , 150 bar, 40°C, 1.50 - 1.31 (m, 2H), 1.15 (br. wavelength: 220 nm s., 2H), 0.71 (q, J=7.7 Hz, 3H) 48 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.57 A dimethoxyphenyl) d6) d 8.74 (d, J=8.5 Hz, 2H), A y[3-(pyridin 7.88 - 7.73 (m, 2H), 7.47 (d, 479.1 yl)pyrrolidinecarbonyl]- 8.10, 98.6% J=8.2 Hz, 1H), 6.91 - 6.76 (m, 1,4-dihydropyrimidinone Chiralpak AS-H, 4.6 x 250 2H), 3.81 - 3.41 (m, 3H), 2.52 mm, 5 micron; (br. s., 6H), 2.46 - 2.46 (m, mobile phase: 10% 1H), 2.39 - 2.39 (m, 1H), 2.46 MeOH/0.1%DEA/90% - 2.33 (m, 1H), 2.25 (d, J=7.3 CO2; Flow Conditions: 2.0 Hz, 2H), 2.10 - 1.92 (m, 1H), mL/min, 150 bar, 40°C, 1.50 - 1.31 (m, 2H), 1.15 (br. wavelength: 220 nm s., 2H), 0.71 (q, J=7.7 Hz, 3H) (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 49 1-(2,6-dimethoxyphenyl) 1H NMR z, DMSO- 0.79 A (ethoxymethyl)[3-(2- d6) d 7.51 - 7.27 (m, 3H), 7.22 A fluorophenyl)pyrrolidine - 7.16 (m, 2H), 6.83 (d, J=7.9 498.3 carbonyl]hydroxy-1,4- 10.65, 99.5% Hz, 2H), 3.97 (d, J=6.7 Hz, dihydropyrimidinone Chiralpak IF, 4.6 x 250 2H), 3.77 (br. s., 3H), 3.63 - mm, 5 micron; 3.55 (m, 1H), 3.70 - 3.54 (m, mobile phase: 15% 2H), 3.45 - 3.11 (m, 2H), 2.52 IPA/90% CO2; (br. s., 6H), 2.31 - 2.22 (m, Flow ions: 2.0 1H), 2.11 - 1.95 (m, 1H), 1.06 mL/min, 150 bar, 40°C, - 0.87 (m, 3H) wavelength: 220 nm (Isomer 2) 50 2-[(tert-butoxy)methyl] 1H NMR (500MHz, DMSO- 0.85 A (2,6-dimethoxyphenyl)[3- d6) d 7.39 (s, 3H), 7.16 (d, A (2-fluorophenyl)pyrrolidine- J=14.0 Hz, 2H), 6.88 - 6.65 526.3 1-carbonyl]hydroxy-1,4- 10.65, 99.5% (m, 2H), 3.99 - 3.21 (m, 11H), dihydropyrimidinone Chiralpak IF, 4.6 x 250 2.56 (s, 2H), 2.27 (br. s., 1H), mm, 5 ; 2.08 - 1.94 (m, 1H), 0.85 (d, mobile phase: 15% J=10.7 Hz, 9H) IPA/90% CO2; Flow Conditions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 1) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 51 2-[(tert-butoxy)methyl] 1H NMR (500MHz, DMSO- 0.84 A (2,6-dimethoxyphenyl) d6) d 7.51 - 7.19 (m, 6H), 6.80 A hydroxy[(3R) (d, J=8.9 Hz, 2H), 4.05 - 3.14 508.4 phenylpyrrolidine (m, 11H), 2.56 (s, 2H), 2.33 - yl]-1,4- 2.22 (m, 1H), 2.01 - 1.86 (m, dihydropyrimidinone 1H), 0.83 (s, 9H) 52 l(2,6- 1H NMR (500MHz, DMSO- 0.83 A dimethoxyphenyl)[3-(2- d6) d 7.48 - 7.36 (m, 2H), 7.30 A fluorophenyl)pyrrolidine (d, J=6.1 Hz, 1H), 7.23 - 7.09 496.2 carbonyl]hydroxy-1,4- 12.48, 99.5% (m, 2H), 6.90 - 6.72 (m, 2H), dihydropyrimidinone Chiralpak IF, 4.6 x 250 3.87 - 3.29 (m, 5H), 2.52 (br. s., 6H), 2.29 - 2.11 (m, 3H), mm, 5 micron; mobile phase: 15% 2.05 - 1.94 (m, 1H), 1.50 - IPA/85%CO2; 1.35 (m, 2H), 1.20 - 1.07 (m, Flow Conditions: 2.0 2H), 0.71 (d, J=7.6 Hz, 3H) mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 53 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.83 A oxyphenyl)[3-(2- d6) d 7.48 - 7.36 (m, 2H), 7.30 A fluorophenyl)pyrrolidine (d, J=6.1 Hz, 1H), 7.23 - 7.09 496.3 yl]hydroxy-1,4- 10.65, 99.5% (m, 2H), 6.90 - 6.72 (m, 2H), dihydropyrimidinone Chiralpak IF, 4.6 x 250 3.87 - 3.29 (m, 5H), 2.52 (br. mm, 5 micron; s., 6H), 2.29 - 2.11 (m, 3H), mobile phase: 15% 2.05 - 1.94 (m, 1H), 1.50 - IPA/90% CO2; 1.35 (m, 2H), 1.20 - 1.07 (m, Flow Conditions: 2.0 2H), 0.71 (d, J=7.6 Hz, 3H) , 150 bar, 40°C, wavelength: 220 nm (Isomer 1) 54 1-(2,6-dimethoxyphenyl) 1H NMR (400MHz, 0.53 A (ethoxymethyl)hydroxy- chloroform-d) d 8.53 (d, A -[3-(pyridin J=4.2 Hz, 1H), 7.64 - 7.56 (m, 481.3 yl)pyrrolidinecarbonyl]- 7.62, 93.4% 1H), 7.38 (t, J=8.5 Hz, 1H), 1,4-dihydropyrimidinone Chiralpak AD-3, 4.6 x 150 7.20 - 7.09 (m, 2H), 6.65 (d, J=8.4 Hz, 2H), 4.07 (s, 2H), mm, 3 micron; mobile phase: 25% 3.76 (s, 9H), 3.46 (d, J=7.0 MeOH:DEA /75% CO2; Hz, 4H), 2.34 - 2.14 (m, 2H), Flow Conditions: 1.0 1.11 (t, J=6.9 Hz, 3H) mL/min, 150 bar, 45°C, wavelength: 220 nm (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho y d range 55 1-(2,6-dimethoxyphenyl) 1H NMR (400MHz, 0.52 A (ethoxymethyl)hydroxy- chloroform-d) d 8.53 (d, A -[3-(pyridin J=4.2 Hz, 1H), 7.64 - 7.56 (m, 481.2 yl)pyrrolidinecarbonyl]- 6.77, 99% 1H), 7.38 (t, J=8.5 Hz, 1H), hydropyrimidinone Chiralpak AD-3, 4.6 x 150 7.20 - 7.09 (m, 2H), 6.65 (d, mm, 3 micron; J=8.4 Hz, 2H), 4.07 (s, 2H), mobile phase: 25% 3.76 (s, 9H), 3.46 (d, J=7.0 MeOH:DEA /75% CO2; Hz, 4H), 2.34 - 2.14 (m, 2H), Flow Conditions: 1.0 1.11 (t, J=6.9 Hz, 3H) mL/min, 150 bar, 45°C, wavelength: 220 nm Isomer 56 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.80 A dimethoxyphenyl)(5- d6) d 7.47 - 7.32 (m, 2H), 7.26 A fluoro-2,3-dihydro-1H- - 7.07 (m, 2H), 6.83 (d, J=8.5 468.3 isoindolecarbonyl) Hz, 2H), 4.73 (s, 4H), 2.56 (s, hydroxy-1,4- 6H), 2.28 - 2.13 (m, 2H), 1.49 dihydropyrimidinone - 1.36 (m, 2H), 1.21 - 1.12 (m, 2H), 0.73 (t, J=7.3 Hz, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 57 1-(2,6-dimethoxyphenyl) 1H NMR (500MHz, DMSO- 0.79 A (ethoxymethyl)[3-(4- d6) d 7.35 (d, J=19.5 Hz, 3H), A fluorophenyl)pyrrolidine 7.19 - 7.08 (m, 2H), 6.85 - 498.3 carbonyl]hydroxy-1,4- 10.7, 90% 6.72 (m, 2H), 3.97 - 3.51 (m, dihydropyrimidinone Whelk-O 1 (R,R), 4.6 x 7H), 3.31 - 3.22 (m, 2H), 2.56 250 mm, 5 micron; (s, 6H), 2.31 - 2.15 (m, 1H), mobile phase: 15% 1.99 - 1.85 (m, 1H), 0.97 (d, IPA/85%CO2; J=6.4 Hz, 3H) Flow Conditions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm 58 benzyl N-[(3S)[2-butyl 1H NMR z, DMSO- 0.80 B (2,6-dimethoxyphenyl) d6) d 7.67 - 7.28 (m, 7H), 6.83 A hydroxyoxo-1,4- (d, J=8.2 Hz, 2H), 5.02 (d, 551.3 dihydropyrimidine J=11.6 Hz, 2H), 4.10 - 3.92 carbonyl]pyrrolidin (m, 1H), 3.75 (br. s., 3H), 3.18 yl]carbamate (s, 1H), 2.56 (s, 6H), 2.20 (t, J=7.5 Hz, 2H), 2.10 - 1.96 (m, 1H), 1.85 - 1.70 (m, 1H), 1.49 - 1.36 (m, 2H), 1.25 - 1.09 (m, 2H), 0.72 (t, J=7.3 Hz, 3H) Ex Structure Name Chiral amine ediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 59 5-[(3R) 1H NMR (500MHz, DMSO- 0.83 A (benzyloxy)pyrrolidine d6) d 7.46 (s, 1H), 7.37 - 7.23 A carbonyl]butyl(2,6- (m, 5H), 6.84 (d, J=8.2 Hz, 508.3 dimethoxyphenyl) 2H), 4.56 - 4.41 (m, 2H), 4.25 hydroxy-1,4- - 4.11 (m, 1H), 3.77 (br. s., dihydropyrimidinone 3H), 3.18 (s, 1H), 2.52 (br. s., 6H), 2.22 (t, J=7.5 Hz, 2H), 2.05 - 1.90 (m, 2H), 1.45 (br. s., 2H), 1.16 (d, J=7.3 Hz, 2H), 0.72 (t, J=7.3 Hz, 3H) 60 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.57 B dimethoxyphenyl) d6) d 8.77 - 8.67 (m, 1H), 8.65 A hydroxy{1H,2H,3H- - 8.57 (m, 1H), 7.75 - 7.62 (m, 451.3 pyrrolo[3,4-c]pyridine 1H), 7.48 (t, J=8.4 Hz, 1H), carbonyl}-1,4- 6.87 (d, J=8.5 Hz, 2H), 4.88 - dihydropyrimidinone 4.72 (m, 4H), 2.56 (s, 6H), 2.30 (br. s., 2H), 1.47 (br. s., 2H), 1.18 (d, J=7.3 Hz, 2H), 0.73 (t, J=7.3 Hz, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 61 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.61 B dimethoxyphenyl) d6) d 8.55 - 8.34 (m, 1H), 7.79 A hydroxy{5H,6H,7H- (dd, J=18.8, 7.5 Hz, 1H), 7.53 451.2 o[3,4-b]pyridine - 7.39 (m, 1H), 7.31 (d, J=3.7 carbonyl}-1,4- Hz, 1H), 6.83 (d, J=8.5 Hz, dihydropyrimidinone 2H), 4.77 - 4.51 (m, 4H), 2.56 (s, 6H), 2.24 - 2.13 (m, 2H), 1.52 - 1.38 (m, 2H), 1.25 - 1.09 (m, 2H), 0.73 (t, J=7.3 Hz, 3H) 62 benzyl N-[(3R)[2-butyl- 1H NMR (500MHz, DMSO- 0.80 B 1-(2,6-dimethoxyphenyl) d6) d 7.67 - 7.28 (m, 7H), 6.83 A hydroxyoxo-1,4- (d, J=8.2 Hz, 2H), 5.02 (d, 551.3 dihydropyrimidine J=11.6 Hz, 2H), 4.10 - 3.92 carbonyl]pyrrolidin (m, 1H), 3.75 (br. s., 3H), 3.18 yl]carbamate (s, 1H), 2.56 (s, 6H), 2.20 (t, J=7.5 Hz, 2H), 2.10 - 1.96 (m, 1H), 1.85 - 1.70 (m, 1H), 1.49 - 1.36 (m, 2H), 1.25 - 1.09 (m, 2H), 0.72 (t, J=7.3 Hz, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with ion time S Rt cAMP (min) EC50 Metho Potency d range 63 5-[(3S) 1H NMR (500MHz, DMSO- 0.83 A (benzyloxy)pyrrolidine d6) d 7.46 (s, 1H), 7.37 - 7.23 A carbonyl]butyl(2,6- (m, 5H), 6.84 (d, J=8.2 Hz, 508.3 dimethoxyphenyl) 2H), 4.56 - 4.41 (m, 2H), 4.25 hydroxy-1,4- - 4.11 (m, 1H), 3.77 (br. s., dihydropyrimidinone 3H), 3.18 (s, 1H), 2.52 (br. s., 6H), 2.22 (t, J=7.5 Hz, 2H), 2.05 - 1.90 (m, 2H), 1.45 (br. s., 2H), 1.16 (d, J=7.3 Hz, 2H), 0.72 (t, J=7.3 Hz, 3H) 64 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.59 A dimethoxyphenyl) d6) d 8.65 - 8.47 (m, 1H), 7.98 A hydroxy[(3S)[(pyridin- - 7.86 (m, 1H), 7.63 - 7.36 (m, 509.3 2-yl)methoxy]pyrrolidine 4H), 6.85 (d, J=8.2 Hz, 2H), carbonyl]-1,4- 4.65 (br. s., 2H), 4.27 (br. s., dihydropyrimidinone 1H), 3.57 - 3.30 (m, 1H), 2.56 (s, 6H), 2.25 (t, J=7.5 Hz, 2H), 2.11 - 1.91 (m, 4H), 1.45 (br. s., 2H), 1.22 - 1.11 (m, 2H), 0.72 (t, J=7.3 Hz, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 65 2-[2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.75 A dimethoxyphenyl) d6) d 7.93 - 7.83 (m, 1H), 7.77 A hydroxyoxo-1,4- (br. s., 1H), 7.64 - 7.54 (m, 475.3 opyrimidine 1H), 7.52 - 7.40 (m, 1H), 6.86 carbonyl]-2,3-dihydro-1H- (d, J=8.5 Hz, 2H), 4.83 - 4.65 isoindolecarbonitrile (m, 4H), 2.56 (s, 6H), 2.34 - 2.23 (m, 2H), 1.54 - 1.38 (m, 2H), 1.24 - 1.10 (m, 2H), 0.73 (t, J=7.2 Hz, 3H) 66 2-butyl(2,3-dihydro-1H- 1H NMR (500MHz, DMSO- 0.78 A isoindolecarbonyl) d6) d 7.45 (s, 1H), 7.40 - 7.23 A (2,6-dimethoxyphenyl) (m, 4H), 6.84 (d, J=8.5 Hz, 450.3 hydroxy-1,4- 2H), 4.68 (d, J=10.4 Hz, 4H), dihydropyrimidinone 2.56 (s, 6H), 2.27 - 2.18 (m, 2H), 1.55 - 1.41 (m, 2H), 1.24 - 1.11 (m, 2H), 0.73 (t, J=7.2 Hz, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 67 2-butyl(2,6- Racemic pyrolidine amine 1H NMR (500MHz, DMSO- 0.87 A dimethoxyphenyl){3-[(4- d6) d 7.45 (t, J=8.2 Hz, 1H), A fluorophenyl)methyl]pyrroli 7.32 (br. s., 1H), 7.07 (br. s., 510.3 dinecarbonyl} 3H), 6.83 (d, J=8.2 Hz, 2H), hydroxy-1,4- 3.79 - 3.74 (m, 2H), 3.01 (s, dihydropyrimidinone 2H), 2.69 (br. s., 2H), 2.52 (br. s., 6H), 2.47 - 2.36 (m, 1H), 2.19 (br. s., 2H), 1.96 - 1.81 (m, 1H), 1.60 - 1.52 (m, 1H), 1.43 (br. s., 2H), 1.15 (d, J=6.7 Hz, 2H), 0.72 (t, J=7.3 Hz, 68 2-butyl(2,6- 1H NMR (400MHz, 0.58 A oxyphenyl) chloroform-d) d 8.84 (d, A hydroxy[3-(pyridin J=4.4 Hz, 1H), 8.39 - 8.04 (m, 479.2 yl)pyrrolidinecarbonyl]- 7.62, 93.4% 1H), 7.79 - 7.61 (m, 2H), 7.42 1,4-dihydropyrimidinone pak AD-3, 4.6 x 150 (t, J=8.5 Hz, 1H), 6.68 (d, mm, 3 micron; J=8.4 Hz, 2H), 4.12 - 3.61 (m, mobile phase: 25% 11H), 2.58 - 2.48 (m, 1H), MeOH:DEA /75% CO2; 2.37 (br. s., 2H), 2.23 - 2.08 Flow Conditions: 1.0 (m, 1H), 1.57 (quin, J=7.6 Hz, mL/min, 150 bar, 45°C, 2H), 1.30 - 1.13 (m, 2H), 0.76 wavelength: 220 nm (t, J=7.4 Hz, 3H) (Isomer 2) Ex ure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 69 2-butyl(2,6- 1H NMR z, 0.65 A dimethoxyphenyl){4-[(3- chloroform-d) d 7.53 - 7.33 A fluorophenyl)methyl]piperaz (m, 2H), 7.22 - 7.07 (m, 3H), 525.3 inecarbonyl}hydroxy- 6.70 (d, J=8.6 Hz, 2H), 4.15 1,4-dihydropyrimidinone (br. s., 2H), 3.93 - 3.02 (m, 14H), 2.40 (br. s., 2H), 1.61 - 1.41 (m, 2H), 1.30 - 1.12 (m, 2H), 0.75 (t, J=7.2 Hz, 3H) 70 2-butyl(2,6- 1H NMR (400MHz, 0.58 A dimethoxyphenyl) chloroform-d) d 8.84 (d, A hydroxy[3-(pyridin J=4.4 Hz, 1H), 8.39 - 8.04 (m, 479.3 yl)pyrrolidinecarbonyl]- 6.77, 99% 1H), 7.79 - 7.61 (m, 2H), 7.42 1,4-dihydropyrimidinone Chiralpak AD-3, 4.6 x 150 (t, J=8.5 Hz, 1H), 6.68 (d, mm, 3 micron; J=8.4 Hz, 2H), 4.12 - 3.61 (m, mobile phase: 25% 11H), 2.58 - 2.48 (m, 1H), MeOH:DEA /75% CO2; 2.37 (br. s., 2H), 2.23 - 2.08 Flow Conditions: 1.0 (m, 1H), 1.57 (quin, J=7.6 Hz, mL/min, 150 bar, 45°C, 2H), 1.30 - 1.13 (m, 2H), 0.76 wavelength: 220 nm (t, J=7.4 Hz, 3H) (Isomer 1) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 71 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.59 A dimethoxyphenyl) d6) d 8.77 - 8.67 (m, 2H), 7.73 A hydroxy[4-(pyridin (d, J=5.8 Hz, 2H), 7.47 (s, 479.3 yl)piperidinecarbonyl]- 1H), 6.85 (d, J=8.5 Hz, 2H), 1,4-dihydropyrimidinone 3.76 (br. s., 4H), 3.07 (t, J=12.1 Hz, 1H), 2.52 (br. s., 6H), 2.25 (t, J=7.5 Hz, 2H), 1.88 (br. s., 2H), 1.68 - 1.38 (m, 4H), 1.22 - 1.05 (m, 2H), 0.72 (t, J=7.3 Hz, 3H) 72 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.86 B oxyphenyl) d6) d 7.42 (t, J=8.4 Hz, 1H), A hydroxy(4- 7.33 - 7.26 (m, 2H), 7.23 - 492.3 phenylpiperidine 7.16 (m, 3H), 6.82 (d, J=8.5 carbonyl)-1,4- Hz, 2H), 3.74 (br. s., 5H), 2.52 dihydropyrimidinone (br. s., 6H), 2.15 (t, J=7.5 Hz, 2H), 1.92 (s, 2H), 1.77 (br. s., 2H), 1.48 - 1.38 (m, 2H), 1.20 - 1.08 (m, 2H), 0.72 (t, J=7.3 Hz, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 73 5-(3-benzylpyrrolidine Racemic pyrolidine 1H NMR (500MHz, DMSO- 0.87 A carbonyl)butyl(2,6- amine d6) d 7.42 (t, J=8.4 Hz, 1H), A dimethoxyphenyl) 7.34 - 7.13 (m, 5H), 6.81 (d, 492.3 hydroxy-1,4- J=8.5 Hz, 2H), 3.74 (br. s., dihydropyrimidinone 2H), 3.00 (d, J=8.9 Hz, 1H), 2.66 (br. s., 1H), 2.52 (br. s., 6H), 2.38 (br. s., 1H), 2.13 (br. s., 2H), 1.92 (s, 3H), 1.59 - 1.50 (m, 1H), 1.42 (br. s., 2H), 1.18 - 1.08 (m, 2H), 0.71 (t, J=7.3 Hz, 3H) 74 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.87 B dimethoxyphenyl)[4-(4- d6) d 7.48 - 7.37 (m, 1H), 7.29 A phenyl)piperidine - 7.17 (m, 2H), 7.10 (t, J=8.9 510.3 carbonyl]hydroxy-1,4- Hz, 2H), 6.82 (d, J=8.5 Hz, dihydropyrimidinone 2H), 3.74 (br. s., 5H), 2.52 (br. s., 6H), 2.18 (t, J=7.6 Hz, 2H), 1.82 - 1.65 (m, 2H), 1.43 (dt, J=15.0, 7.6 Hz, 4H), 1.18 - 1.10 (m, 2H), 0.71 (t, J=7.3 Hz, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho y d range 75 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.58 A dimethoxyphenyl) d6) d 8.75 - 8.55 (m, 2H), 8.22 A hydroxy[3-(pyridin - 8.08 (m, 1H), 7.75 - 7.63 (m, 479.2 yl)pyrrolidinecarbonyl]- 12.0, 87.4% 1H), 7.47 (q, J=8.9 Hz, 1H), 1,4-dihydropyrimidinone Chiralpak AD-3, 4.6 x 150 6.91 - 6.76 (m, 2H), 3.82 - mm, 3 micron; 3.35 (m, 6H), 2.52 (br. s., 6H), mobile phase: 20% 2.42 - 2.30 (m, 1H), 2.25 (d, .1%DEA / 80% J=7.3 Hz, 2H), 1.44 (d, J=6.4 CO2; Hz, 2H), 1.15 (br. s., 2H), 0.77 Flow ions: 1.0 - 0.65 (m, 3H) mL/min, 150 bar, 45°C, wavelength: 260 nm (Isomer 2) 76 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.58 A dimethoxyphenyl) d6) d 8.75 - 8.55 (m, 2H), 8.22 A hydroxy[3-(pyridin - 8.08 (m, 1H), 7.75 - 7.63 (m, 479.2 yl)pyrrolidinecarbonyl]- 10.3, 92% 1H), 7.47 (q, J=8.9 Hz, 1H), 1,4-dihydropyrimidinone Chiralpak AD-3, 4.6 x 150 6.91 - 6.76 (m, 2H), 3.82 - mm, 3 micron; 3.35 (m, 6H), 2.52 (br. s., 6H), mobile phase: 20% 2.42 - 2.30 (m, 1H), 2.25 (d, MeOH:0.1%DEA / 80% J=7.3 Hz, 2H), 1.44 (d, J=6.4 CO2; Hz, 2H), 1.15 (br. s., 2H), 0.77 Flow Conditions: 1.0 - 0.65 (m, 3H). mL/min, 150 bar, 45°C, wavelength: 260 nm (Isomer 1) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 77 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.87 A dimethoxyphenyl)[3-(4- d6) d 7.91 (s, 1H), 7.43 - 7.23 A fluorophenyl)pyrrolidine (m, 3H), 7.08 (t, J=8.1 Hz, 496.1 carbonyl]hydroxy-1,4- 9.93, 99% 2H), 6.82 - 6.69 (m, 2H), 3.66 dihydropyrimidinone Whelk-O 1 (R,R), 4.6 x (s, 2H), 3.58 (br. s., 2H), 2.46 250 mm, 5 micron; (br. s., 6H), 2.22 - 2.06 (m, mobile phase: 15% 3H), 1.87 (s, 2H), 1.36 (d, IPA/85%CO2; J=6.7 Hz, 2H), 1.08 (br. s., Flow Conditions: 2.0 2H), 0.70 - 0.59 (m, 3H). mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 1) 78 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.84 A dimethoxyphenyl)[3-(3- d6) d 7.97 (s, 1H), 7.49 - 7.32 A fluorophenyl)pyrrolidine (m, 2H), 7.15 (dd, , 8.7 496.1 carbonyl]hydroxy-1,4- 9.81, 99.5% Hz, 2H), 7.06 (t, J=8.1 Hz, opyrimidinone Whelk-O 1 (R,R), 4.6 x 1H), 6.87 - 6.74 (m, 2H), 3.74 250 mm, 5 micron; - 3.19 (m, 6H), 2.52 (br. s., mobile phase: 15% 6H), 2.34 - 2.22 (m, 1H), 2.16 IPA/85%CO2; (d, J=6.7 Hz, 2H), 1.42 (d, Flow Conditions: 2.0 J=5.8 Hz, 2H), 1.20 - 1.10 (m, mL/min, 150 bar, 40°C, 2H), 0.77 - 0.65 (m, 3H) ngth: 220 nm (Isomer 1) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 79 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.83 A dimethoxyphenyl)[3-(4- d6) d 7.50 - 7.30 (m, 3H), 7.14 A fluorophenyl)pyrrolidine (t, J=7.9 Hz, 2H), 6.88 - 6.75 496.1 carbonyl]hydroxy-1,4- 9.93, 99% (m, 2H), 3.79 - 3.61 (m, 6H), dihydropyrimidinone Whelk-O 1 (R,R), 4.6 x 2.52 (br. s., 6H), 2.30 - 2.09 250 mm, 5 micron; (m, 3H), 1.48 - 1.37 (m, 2H), mobile phase: 15% 1.22 - 1.10 (m, 2H), 0.81 - IPA/85%CO2; 0.65 (m, 3H) Flow Conditions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 1) 80 2-butyl(2,6- 1H NMR (500MHz, DMSO- 0.87 A oxyphenyl)[3-(3- d6) d 7.97 (s, 1H), 7.53 - 7.31 A fluorophenyl)pyrrolidine (m, 2H), 7.23 - 7.11 (m, 2H), 496.2 carbonyl]hydroxy-1,4- 10.72, 92% 7.09 - 7.02 (m, 1H), 6.89 - dihydropyrimidinone O 1 (R,R), 4.6 x 6.76 (m, 2H), 3.74 - 3.24 (m, 250 mm, 5 micron; 6H), 2.52 (br. s., 6H), 2.32 - mobile phase: 15% 2.22 (m, 1H), 2.16 (d, J=6.4 IPA/85%CO2; Hz, 2H), 1.43 (br. s., 2H), 1.15 Flow ions: 2.0 (br. s., 2H), 0.78 - 0.65 (m, mL/min, 150 bar, 40°C, 3H) wavelength: 220 nm (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 81 1-(2,6-dimethoxyphenyl) 1H NMR (500MHz, DMSO- 0.81 A (ethoxymethyl)[3-(4- d6) d 7.41 - 7.29 (m, 3H), 7.13 A fluorophenyl)pyrrolidine (d, J=4.6 Hz, 2H), 6.81 - 6.70 498.2 carbonyl]hydroxy-1,4- 9.93, 99% (m, 2H), 3.88 - 3.81 (m, 2H), dihydropyrimidinone Whelk-O 1 (R,R), 4.6 x 3.74 (br. s., 4H), 3.65 - 3.59 250 mm, 5 micron; (m, 1H), 3.29 - 3.19 (m, 2H), mobile phase: 15% 2.52 (br. s., 6H), 1.92 (s, 3H), IPA/85%CO2; 0.96 (dt, J=13.4, 6.9 Hz, 3H) Flow Conditions: 2.0 , 150 bar, 40°C, wavelength: 220 nm (Isomer 1) 82 1-(2,6-dimethoxyphenyl) 1H NMR (500MHz, DMSO- 0.52 A (ethoxymethyl)hydroxy- d6) d 8.72 - 8.46 (m, 2H), 7.58 A -[3-(pyridin - 7.37 (m, 2H), 6.90 - 6.76 (m, 481.2 yl)pyrrolidinecarbonyl]- 12.0, 87.4% 2H), 3.97 (d, J=8.9 Hz, 2H), 1,4-dihydropyrimidinone Chiralpak AD-3, 4.6 x 150 3.80 - 3.62 (m, 5H), 3.31 (dd, mm, 3 micron; J=12.7, 6.6 Hz, 2H), 2.52 (br. mobile phase: 20% s., 6H), 2.40 - 2.29 (m, 1H), MeOH:0.1%DEA / 80% 2.07 - 1.95 (m, 1H), 1.05 - CO2; 0.94 (m, 3H) Flow ions: 1.0 mL/min, 150 bar, 45°C, wavelength: 260 nm (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 83 1-(2,6-dimethoxyphenyl) 1H NMR (500MHz, DMSO- 0.79 A ymethyl)[3-(3- d6) d 7.45 (br. s., 1H), 7.39 - A fluorophenyl)pyrrolidine 7.33 (m, 1H), 7.20 - 7.02 (m, 498.2 carbonyl]hydroxy-1,4- 10.72, 92% 4H), 6.87 - 6.77 (m, 2H), 3.97 dihydropyrimidinone Whelk-O 1 (R,R), 4.6 x (d, J=6.1 Hz, 2H), 3.80 - 3.63 250 mm, 5 micron; (m, 5H), 3.31 (br. s., 2H), 2.52 mobile phase: 15% (br. s., 6H), 2.29 (br. s., 1H), IPA/85%CO2; 1.97 (br. s., 1H), 1.04 - 0.88 Flow Conditions: 2.0 (m, 3H) mL/min, 150 bar, 40°C, ngth: 220 nm (Isomer 2) 84 1-(2,6-dimethoxyphenyl) 1H NMR (500MHz, DMSO- 0.79 A (ethoxymethyl)[3-(3- d6) d 7.53 - 7.41 (m, 1H), 7.40 A fluorophenyl)pyrrolidine - 7.32 (m, 1H), 7.15 (br. s., 498.3 carbonyl]hydroxy-1,4- 9.81, 99.5% 4H), 6.90 - 6.68 (m, 2H), 3.97 dihydropyrimidinone Whelk-O 1 (R,R), 4.6 x (d, J=5.8 Hz, 2H), 3.85 - 3.60 250 mm, 5 ; (m, 4H), 3.34 - 3.25 (m, 2H), mobile phase: 15% 3.21 - 3.17 (m, 1H), 2.52 (br.
IPA/85%CO2; s., 6H), 2.28 (br. s., 1H), 2.04 - Flow Conditions: 2.0 1.90 (m, 1H), 0.99 (d, J=6.4 mL/min, 150 bar, 40°C, Hz, 3H) wavelength: 220 nm (Isomer 1) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 85 1-(2,6-dimethoxyphenyl) 1H NMR (500MHz, DMSO- 0.52 A ymethyl)hydroxy- d6) d 8.72 - 8.46 (m, 2H), 7.58 A -[3-(pyridin - 7.37 (m, 2H), 6.90 - 6.76 (m, 481.2 yl)pyrrolidinecarbonyl]- 10.3, 92% 2H), 3.97 (d, J=8.9 Hz, 2H), 1,4-dihydropyrimidinone Chiralpak AD-3, 4.6 x 150 3.80 - 3.62 (m, 5H), 3.31 (dd, mm, 3 micron; J=12.7, 6.6 Hz, 2H), 2.52 (br. mobile phase: 20% s., 6H), 2.40 - 2.29 (m, 1H), MeOH:0.1%DEA / 80% 2.07 - 1.95 (m, 1H), 1.05 - CO2; 0.94 (m, 3H) Flow Conditions: 1.0 mL/min, 150 bar, 45°C, wavelength: 260 nm (Isomer 1) 86 l(2,6- 1H NMR (500MHz, DMSO- 1.05 A diethylphenyl)hydroxy d6) d 7.48 - 7.40 (m, 1H), 7.37 A [(3S)phenylpyrrolidine - 6.98 (m, 7H), 2.56 (s, 6H), 474.2 carbonyl]-3,4- 2.39 - 2.09 (m, 6H), 2.02 - dihydropyrimidinone 1.85 (m, 1H), 1.58 - 1.43 (m, 2H), 1.21 - 1.04 (m, 6H), 0.99 (br. s., 2H), 0.78 - 0.59 (m, Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho y d range 87 2-butyl(2,6- Racemic pyrolidine 1H NMR (500MHz, DMSO- 0.91 A dimethoxyphenyl)[3-(4- amine d6) d 7.50 - 7.42 (m, 1H), 7.40 A fluorophenyl)pyrrolidine - 7.30 (m, 2H), 7.14 (br. s., 496.0 carbonyl]hydroxy-3,4- 2H), 6.84 (d, J=7.9 Hz, 2H), dihydropyrimidinone 4.00 - 3.50 (m, 2H), 3.46 - 3.35 (m, 1H), 2.59 - 2.54 (m, 6H), 2.24 (d, J=6.7 Hz, 3H), 1.99 - 1.82 (m, 1H), 1.52 - 1.39 (m, 2H), 1.22 - 1.09 (m, 2H), 0.71 (d, J=7.6 Hz, 3H) 88 2-butyl[3-(3- 1H NMR (500MHz, DMSO- 0.87 A chlorophenyl)azetidine d6) d 7.48 - 7.35 (m, 3H), 7.34 A carbonyl](2,6- - 7.27 (m, 2H), 6.83 (d, J=8.5 498.0 dimethoxyphenyl) Hz, 2H), 4.39 (t, J=9.3 Hz, hydroxy-3,4- 2H), 3.85 (d, J=6.4 Hz, 1H), dihydropyrimidinone 3.74 (s, 6H), 2.54 (s, 2H), 2.22 (t, J=7.6 Hz, 2H), 1.43 (t, J=7.5 Hz, 2H), 1.19 - 1.09 (m, 2H), 0.70 (t, J=7.3 Hz, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 89 2-butyl(2,6- Racemic pyrolidine 1H NMR (500MHz, DMSO- 1.06 A diethylphenyl)[3-(4- amine d6) d 7.48 - 7.26 (m, 5H), 7.18 A fluorophenyl)pyrrolidine - 7.07 (m, 2H), 3.61 - 3.23 (m, 492.1 carbonyl]hydroxy-3,4- 8H), 2.37 - 2.17 (m, 2H), 2.17 dihydropyrimidinone - 2.09 (m, 2H), 2.01 - 1.83 (m, 1H), 1.56 - 1.45 (m, 2H), 1.22 - 1.04 (m, 6H), 1.01 - 0.93 (m, 2H), 0.73 (d, J=7.9 Hz, 3H) 90 2-butyl(2,6- 1H NMR (400MHz, 1.05 A diethylphenyl)hydroxy chloroform-d) d 7.31 (br. s., A [(3R)phenylpyrrolidine- 8H), 2.45 - 1.99 (m, 13H), 474.3 onyl]-3,4- 1.72 - 1.58 (m, 2H), 1.16 (br. dihydropyrimidinone s., 8H), 0.80 (t, J=7.3 Hz, 3H) 91 2-butyl(2,6- 1H NMR (400MHz, DMSO- 0.88 A dimethoxyphenyl) d6) d 7.32 (br. s., 6H), 6.92 - A hydroxy[(3S) 6.77 (m, 2H), 5.77 (s, 1H), 478.1 pyrrolidine 3.96 - 3.21 (m, 10H), 2.31 - carbonyl]-3,4- 2.16 (m, 3H), 2.01 - 1.86 (m, dihydropyrimidinone 1H), 1.53 - 1.37 (m, 2H), 1.21 - 1.11 (m, 2H), 0.71 (d, J=8.1 Hz, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with ion time S Rt cAMP (min) EC50 Metho Potency d range 92 5-[3-(2- 1H NMR (500 MHz, DMSO- 1.26 A chlorophenyl)pyrrolidine d6) d 7.35-7.52 (m, 3H), 7.22- A carbonyl](2,6- 7.35 (m, 2H), 6.72-6.84 (m, 528.0 dimethoxyphenyl) 12.48, 99.5% 2H), 3.86-3.93 (m, 2H), 3.19- hydroxy[(propan Chiralpak IF, 4.6 x 250 3.86 (m, 12H), 2.17-2.32 (m, yloxy)methyl]-1,4- mm, 5 micron; 1H), 1.93-2.08 (m, 1H), 0.80- dihydropyrimidinone mobile phase: 15% 0.93 (m, 6H) IPA/85%CO2; Flow Conditions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 2) 93 -dimethoxyphenyl) 1H NMR (500 MHz, DMSO- 1.18 A [3-(2- d6) d 7.33-7.46 (m, 2H), 7.23- A fluorophenyl)pyrrolidine 7.33 (m, 1H), 7.10-7.22 (m, 512.1 carbonyl]hydroxy 10.65, 99.5% 2H), 6.71-6.85 (m, 2H), 3.89 [(propanyloxy)methyl]- Chiralpak IF, 4.6 x 250 (d, J=10.01 Hz, 2H), 3.19-3.77 1,4-dihydropyrimidinone (m, 12H), 2.18-2.29 (m, 1H), mm, 5 micron; mobile phase: 15% 1.93-2.05 (m, 1H), 0.87 (dd, % CO2; J=5.72, 10.60 Hz, 6H) Flow Conditions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 1) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 94 1-(2,6-dimethoxyphenyl) 1H NMR (500 MHz, DMSO- 1.21 A [3-(4- d6) d 7.33 (d, J=6.31 Hz, 3H), A fluorophenyl)pyrrolidine 7.04-7.18 (m, 3H), .77 512.3 carbonyl]hydroxy 9.93, 99% (m, 1H), 3.72 (d, J=8.58 Hz, [(propanyloxy)methyl]- O 1 (R,R), 4.6 x 2H), 2.91-3.64 (m, 12H), 2.14- 1,4-dihydropyrimidinone 250 mm, 5 micron; 2.33 (m, 1H), 1.77-1.91 (m, mobile phase: 15% 1H), 0.82 (dd, J=5.60, 13.59 IPA/85%CO2; Hz, 6H) Flow Conditions: 2.0 , 150 bar, 40°C, wavelength: 220 nm (Isomer 1) 95 1-(2,6-dimethoxyphenyl) 1H NMR (500 MHz, 1.34 A [3-(3- methanol-d4) d 7.42-7.54 (m, A fluorophenyl)pyrrolidine 1H), 7.28-7.36 (m, 1H), 7.10- 512.3 carbonyl]hydroxy 10.72, 92% 7.17 (m, 1H), .10 (m, [(propanyloxy)methyl]- Whelk-O 1 (R,R), 4.6 x 1H), 6.91-6.98 (m, 1H), 6.73- 1,4-dihydropyrimidinone 250 mm, 5 micron; 6.85 (m, 2H), 4.08 (br. s., 2H), mobile phase: 15% 3.76-3.85 (m, 6H), 3.65-3.72 IPA/85%CO2; (m, 2H), 3.54-3.63 (m, 1H), Flow Conditions: 2.0 3.42-3.53 (m, 3H), 2.26-2.40 mL/min, 150 bar, 40°C, (m, 1H), 2.01-2.14 (m, 1H), wavelength: 220 nm 1.01 (br. s., 6H) (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho y d range 96 2-(2-cyclopropylethyl) 1H NMR (400 MHz, 1.46 A (2,6-dimethoxyphenyl) methanol-d4) d .53 (m, A hydroxy[(3R) 1H), 7.27-7.33 (m, 4H), 7.16- 490.1 phenylpyrrolidine 7.26 (m, 1H), 6.76-6.89 (m, carbonyl]-1,4- 2H), 3.74-3.85 (m, 6H), 3.66 dihydropyrimidinone (br. s., 2H), 3.54-3.63 (m, 1H), .51 (m, 2H), 2.40-2.54 (m, 2H), 2.25-2.39 (m, 1H), 2.01-2.15 (m, 1H), 1.33-1.50 (m, 2H), 0.53-0.68 (m, 1H), 0.25-0.42 (m, 2H), -0.22--0.09 (m, 2H) 97 1-(2,6-dimethoxyphenyl) 1H NMR (500 MHz, DMSO- 1.23 A [3-(3- d6) Shift 7.39-7.48 (m, 1H), A fluorophenyl)pyrrolidine 9.81, 99.5% 7.31-7.38 (m, 1H), 7.09-7.20 512.3 carbonyl]hydroxy Whelk-O 1 (R,R), 4.6 x (m, 2H), 7.05 (t, J=8.29 Hz, [(propanyloxy)methyl]- 250 mm, 5 micron; 1H), 6.73-6.85 (m, 2H), 2.83- 1,4-dihydropyrimidinone mobile phase: 15% 3.98 (m, 12H), 2.27 (br. s., IPA/85%CO2; 1H), 1.86-2.02 (m, 1H), 0.76- Flow Conditions: 2.0 0.93 (m, 6H) mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 1) Ex ure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 98 1-(2,6-dimethoxyphenyl) 1H NMR (500 MHz, DMSO- 1.22 A hydroxy[3-(2- d6) d 7.22-7.29 (m, 1H), 7.06- A methylphenyl)pyrrolidine 7.21 (m, 4H), 6.70-6.83 (m, 508.1 carbonyl][(propan 14.99, >99% 2H), 3.18-3.88 (m, 14H), 2.27- yloxy)methyl]-1,4- Lux Cellulose-4 21 x 250 2.36 (m, 3H), 2.12-2.23 (m, dihydropyrimidinone 1H), 1.83-1.99 (m, 1H), 0.85 mm, 5 micron; mobile phase: 15% IPA:heptane (dd, , 15.44 Hz, 6H) (1:1)/85% CO2; flow condition: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm r 2) 99 1-(2,6-dimethoxyphenyl) 1H NMR (500 MHz, DMSO- 1.41 A hydroxy[(propan d6) d 7.22-7.29 (m, 1H), 7.06- A yloxy)methyl]{3-[2- 7.21 (m, 4H), 6.70-6.83 (m, 562.4 (trifluoromethyl)phenyl]pyrr 5.27, >99% 2H), 3.18-3.88 (m, 14H), 2.27- olidinecarbonyl}-1,4- Chiralpak IF, 4.6 x 250 2.36 (m, 3H), 2.12-2.23 (m, dihydropyrimidinone mm, 5 micron; 1H), 1.83-1.99 (m, 1H), 0.85 mobile phase: 10% (dd, J=5.85, 15.44 Hz, 6H) MeOH/90% CO2; Flow ions: 2.0 mL/min, 150 bar, 40°C, Wavelength: 220 nm (Isomer 1) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 100 2-(cyclopropoxymethyl) 1H NMR (500 MHz, DMSO- 1.26 A (2,6-dimethoxyphenyl)[3- d6) d 7.22-7.27 (m, 1H), 7.12- A (4-fluorophenyl)pyrrolidine- 7.22 (m, 4H), 6.89-7.03 (m, 510.2 1-carbonyl]hydroxy-1,4- 9.93, 99% 1H), 6.53-6.67 (m, 1H), 3.74 dihydropyrimidinone Whelk-O 1 (R,R), 4.6 x (d, J=13.43 Hz, 2H), 3.58 (br. 250 mm, 5 micron; s., 3H), 3.53 (s, 3H), 3.46 (br. mobile phase: 15% s., 1H), .39 (m, 2H), IPA/85%CO2; 3.18-3.25 (m, 1H), 3.03-3.15 Flow Conditions: 2.0 (m, 2H), 2.00-2.12 (m, 1H), mL/min, 150 bar, 40°C, 1.71-1.80 (m, 1H), .21 wavelength: 220 nm (m, 2H), -0.07-0.06 (m, 2H) (Isomer 1) 101 1-(2,6-dimethoxyphenyl) 1H NMR (500 MHz, DMSO- 1.46 A hydroxy[(propan d6) d 7.59-7.77 (m, 3H), 7.32- A yloxy)methyl]{3-[2- 7.52 (m, 2H), 6.69-6.88 (m, 562.0 (trifluoromethyl)phenyl]pyrr 6.02, 98.8% 2H), 3.18-3.95 (m, 14H), 2.17- olidinecarbonyl}-1,4- Chiralpak IF, 4.6 x 250 2.30 (m, 1H), .13 (m, dihydropyrimidinone mm, 5 micron; 1H), .91 (m, 6H) mobile phase: 10% MeOH/90% CO2; Flow Conditions: 2.0 mL/min, 150 bar, 40°C, Wavelength: 220 nm (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 102 1-(2,6-dimethoxyphenyl) 1H NMR (500 MHz, DMSO- 1.34 A [3-(4- d6) d .38 (m, 2H), 7.08- A fluorophenyl)pyrrolidine 7.25 (m, 3H), 6.75-6.87 (m, 512.3 carbonyl]hydroxy 10.7, 90% 2H), 3.21-4.00 (m, 14H), 2.19- [(propanyloxy)methyl]- Whelk-O 1 (R,R), 4.6 x 2.34 (m, 1H), 1.88-2.01 (m, 1,4-dihydropyrimidinone 250 mm, 5 micron; 1H), 0.84-0.97 (m, 6H) mobile phase: 15% IPA/85%CO2; Flow ions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 2) 103 2-(cyclopropoxymethyl) 1H NMR (500 MHz, DMSO- 1.26 A (2,6-dimethoxyphenyl)[3- d6) d .38 (m, 2H), 7.08- A (4-fluorophenyl)pyrrolidine- 7.25 (m, 3H), 6.75-6.87 (m, 510.2 1-carbonyl]hydroxy-1,4- 10.7, 90% 2H), 3.21-4.00 (m, 14H), 2.19- dihydropyrimidinone Whelk-O 1 (R,R), 4.6 x 2.34 (m, 1H), 1.88-2.01 (m, 250 mm, 5 micron; 1H), 0.84-0.97 (m, 6H) mobile phase: 15% IPA/85%CO2; Flow Conditions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho y d range 104 1-[2,6- 1H NMR (500 MHz, DMSO- 1.68 A bis(²H₃)methoxyphenyl] d6) d 7.39-7.53 (m, 1H), 7.19- B butylhydroxy[(3S) 7.35 (m, 5H), .88 (m, 484.1 phenylpyrrolidine 2H), 3.80-3.94 (m, 1H), 3.56- carbonyl]-1,4- 3.70 (m, 2H), 3.23-3.51 (m, dihydropyrimidinone 2H), 2.14-2.34 (m, 3H), 1.86- 2.03 (m, 1H), 1.36-1.54 (m, 2H), 1.08-1.23 (m, 2H), 0.62- 0.80 (m, 3H) 105 1-(2,6-dimethoxyphenyl) 1H NMR (500 MHz, DMSO- 1.23 A hydroxy[3-(2- d6) d 7.35-7.45 (m, 1H), 7.26 A methylphenyl)pyrrolidine (d, J=6.48 Hz, 1H), 7.06-7.20 507.9 carbonyl][(propan 12.72, >99% (m, 3H), 6.71-6.84 (m, 2H), yloxy)methyl]-1,4- Lux Cellulose-4 21 x 250 3.88 (d, J=14.73 Hz, 2H), dihydropyrimidinone mm, 5 micron; mobile .83 (m, 12H), 2.27-2.36 phase: 15% IPA:heptane (m, 3H), 2.13-2.25 (m, 1H), (1:1)/85% CO2; flow 1.84-1.99 (m, 1H), 0.87 (dd, condition: 2.0 mL/min, 150 J=5.85, 14.60 Hz, 6H) bar, 40°C, ngth: 220 nm (Isomer 1) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 106 1-[2,6- 1H NMR (500 MHz, DMSO- 1.37 A bis(²H₃)methoxyphenyl] d6) d 7.37-7.45 (m, 1H), 7.21- A (ethoxymethyl)hydroxy- 7.36 (m, 5H), 6.70-6.85 (m, 486.0 -[(3R) 2H), 3.82-3.95 (m, 2H), 3.14- pyrrolidine 3.75 (m, 7H), 2.17-2.37 (m, carbonyl]-1,4- 1H), 1.86-2.01 (m, 1H), 0.89- dihydropyrimidinone 1.06 (m, 3H) 107 4-{1-[1-(2,6- 1H NMR (500 MHz, DMSO- 1.23 A dimethoxyphenyl) d6) d 7.37-7.45 (m, 1H), 7.21- A hydroxyoxo[(propan- 7.36 (m, 5H), 6.70-6.85 (m, 519.2 2-yloxy)methyl]-1,4- 5.72, 97.2% 2H), 3.82-3.95 (m, 2H), 3.14- dihydropyrimidine Chiralpak AS-H 4.6 x 250 3.75 (m, 7H), 2.17-2.37 (m, carbonyl]pyrrolidin mm; mobile phase: 20% 1H), 1.86-2.01 (m, 1H), 0.89- yl}benzonitrile MeOH/80% CO2; Flow 1.06 (m, 3H) Conditions: 2.0 , 150 bar, 40°C, wavelength: 220 nm (Isomer 2) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 108 4-{1-[1-(2,6- 1H NMR (500 MHz, DMSO- 1.22 A dimethoxyphenyl) d6) Shift 7.72-7.84 (m, 2H), A yoxo[(propan- 4.55, >99.0% 7.48-7.60 (m, 2H), 7.30-7.44 519.2 2-yloxy)methyl]-1,4- Chiralpak AS-H 4.6 x 250 (m, 1H), 6.68-6.81 (m, 2H), dihydropyrimidine 3.84 (d, J=14.95 Hz, 2H), mm; mobile phase: 20% carbonyl]pyrrolidin MeOH/80% CO2; Flow 3.19-3.77 (m, 12H), .32 yl}benzonitrile ions: 2.0 mL/min, (m, 1H), 1.88-1.99 (m, 1H), 150 bar, 40°C, 0.86 (dd, J=5.30, 13.90 Hz, wavelength: 220 nm 6H) (Isomer 1) 109 1-[2,6- 1H NMR (500 MHz, DMSO- 1.35 A bis(²H₃)methoxyphenyl] d6) d 7.35-7.44 (m, 1H), 7.20- A (ethoxymethyl)hydroxy- 7.34 (m, 5H), 6.70-6.83 (m, 486.1 -[(3S)phenylpyrrolidine- 2H), 3.87 (d, J=14.34 Hz, 2H), 1-carbonyl]-1,4- 3.33-3.75 (m, 5H), 3.17-3.33 dihydropyrimidinone (m, 2H), .32 (m, 1H), 1.87-1.98 (m, 1H), 0.89-1.04 (m, 3H) 110 1-(2,6-dimethoxyphenyl) 1H NMR (500 MHz, DMSO- 1.15 B hydroxy(3- d6) d 7.31-7.39 (m, 5H), 7.21- A phenylazetidine 7.27 (m, 1H), 6.75 (d, J=8.41 480.1 carbonyl)[(propan Hz, 2H), 3.72-4.38 (m, 7H), yloxy)methyl]-1,4- 3.71 (br. s., 6H), 3.19-3.29 (m, dihydropyrimidinone 1H), 0.85 (d, J=6.06 Hz, 6H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 111 1-(2,6-dimethoxyphenyl) 1H NMR (500 MHz, DMSO- 1.30 B hydroxy[3-(4- d6) d 7.35 (t, J=8.20 Hz, 1H), A methylphenyl)azetidine 7.20-7.27 (m, 2H), .17 494.4 carbonyl][(propan (m, 2H), 6.74 (d, J=8.16 Hz, yloxy)methyl]-1,4- 1H), 4.28 (br. s., 2H), 3.19- dihydropyrimidinone 4.04 (m, 13H), 2.26 (br. s., 3H), 1.91 (s, 2H), 0.84 (d, J=5.81 Hz, 6H) 112 2-butyl(4,6- 1H NMR (400MHz, methanol- 1.95 A dimethoxypyrimidinyl)- d4) d 8.56 (s, 1H), 7.32 (m, C 6-hydroxy[(3S) 5H), 4.01 (s, 6H), 3.89 (m, 480.1 phenylpyrrolidine 2H), 3.49 (m, 3H), 2.42 (m, carbonyl]-3,4- 3H), 2.18 - 2.04 (m, 1H), 1.70 dihydropyrimidinone - 1.53 (m, 2H), 1.36 - 1.20 (m, 2H), 0.84 (m, 3H) 113 2-butyl(4,6- 1H NMR (400MHz, methanol- 1.95 A dimethoxypyrimidinyl)- d4) d 8.56 (s., 1H), 7.30 (m, C 6-hydroxy[(3R) 5H), 4.00 (s, 6H), 3.88 (m, 480.1 pyrrolidine 2H), 3.48 (m, 3H), 2.41 (m, carbonyl]-3,4- 3H), 2.17 - 1.98 (m, 1H), 1.69 dihydropyrimidinone - 1.49 (m, 2H), 1.28 (m, 2H), 0.83 (m, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 114 2-butyl[3-(2- 1H NMR (500MHz, DMSO- 1.67 A fluorophenyl)pyrrolidine d6) 7.42 - 7.02 (m, 9H), 3.74 A carbonyl]hydroxy - 2.88 (m, 5H), 2.37 (d, J=9.2 478.0 1-phenylpropyl]-3,4- 10.65, 99.5% Hz, 2H), 2.18 (br. s., 2H), 1.92 dihydropyrimidinone Chiralpak IF, 4.6 x 250 (br. s., 2H), 1.76 - 1.09 (m, mm, 5 micron; 4H), 0.97 - 0.48 (m, 6H) mobile phase: 15% IPA/90% CO2; Flow Conditions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 1) 115 2-butyl[3-(3- 1H NMR (500MHz, DMSO- 1.79 A fluorophenyl)pyrrolidine d6) 7.44 - 6.89 (m, 9H), 3.97 A carbonyl]hydroxy - 3.09 (m, 5H), 2.42 (br. s., 478.0 1-phenylpropyl]-3,4- 2H), 2.24 (br. s., 2H), 1.90 (s, dihydropyrimidinone 12.48, 99.5% 2H), 1.73 - 1.09 (m, 4H), 1.00 Chiralpak IF, 4.6 x 250 - 0.68 (m, 6H). mm, 5 micron; mobile phase: 15% IPA/85%CO2; Flow ions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 2) Ex Structure Name Chiral amine ediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 116 2-butylhydroxy[(1R)- 1H NMR (500MHz, DMSO- 1.65 A 2-methoxyphenylethyl]- d6) 7.46 - 6.85 (m, 10H), A -[(3R) 5.47 (br. s., 1H), 4.34 - 3.41 475.9 phenylpyrrolidine (m, 7H), 3.26 (s, 3H), 2.93 - carbonyl]-3,4- 2.59 (m, 2H), 2.28 - 1.78 (m, dihydropyrimidinone 2H), 1.54 (br. s., 2H), 1.40 - 1.12 (m, 2H), 0.97 - 0.51 (m, 117 lhydroxy[(1R)- 1H NMR (500MHz, DMSO- 1.63 A 1-phenylethyl][(3R) d6) 7.41 - 6.99 (m, 10H), A phenylpyrrolidine 3.94 - 3.30 (m, 5H), 2.17 (br. 446.0 carbonyl]-3,4- s., 1H), 1.87 (s, 1H), 1.74 (br. dihydropyrimidinone s., 3H), 1.44 (br. s., 1H), 1.21 - 0.92 (m, 3H), 0.67 (br. s., 3H). 118 2-butyl[3-(2- 1H NMR (500MHz, DMSO- 1.66 A fluorophenyl)pyrrolidine d6) 7.53 - 7.05 (m, 9H), 4.10 A carbonyl]hydroxy - 3.23 (m, 5H), 2.46 - 2.32 (m, 478.1 [(1S)phenylpropyl]-3,4- 9.81, 99.5% 1H), 2.24 (br. s., 2H), 2.03 - dihydropyrimidinone Whelk-O 1 (R,R), 4.6 x 1.90 (m, 1H), 1.73 - 1.11 250 mm, 5 micron; (m,4H), 0.96 - 0.70 (m, 6H) mobile phase: 15% IPA/85%CO2; Flow Conditions: 2.0 , 150 bar, 40°C, wavelength: 220 nm (Isomer 1) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with ion time S Rt cAMP (min) EC50 Metho Potency d range 119 2-butyl[3-(3- 1H NMR (500MHz, DMSO- 1.71 A fluorophenyl)pyrrolidine d6) 7.06 (d, J=9.0 Hz, 9H), A yl]hydroxy 10.72, 92% 4.00 - 3.08 (m, 5H), 2.24 (br. 478.4 [(1S)phenylpropyl]-3,4- Whelk-O 1 (R,R), 4.6 x s., 2H), 1.90 (br. s, 2H), 1.69 - dihydropyrimidinone 250 mm, 5 micron; 1.14 (m, 4H), 1.07 - 0.55 (m, mobile phase: 15% 6H) IPA/85%CO2; Flow Conditions: 2.0 mL/min, 150 bar, 40°C, wavelength: 220 nm (Isomer 2) 120 2-butylhydroxy[(1S)- 1H NMR (500MHz, DMSO- 1.56 A 1-(3-methoxyphenyl)ethyl]- d6) 7.36 - 7.13 (m, 5H), 6.92 A -[(3S)phenylpyrrolidine- - 6.78 (m, 1H), 6.76 - 6.67 (m, 476.4 1-carbonyl]-3,4- 2H), 6.65 - 6.53 (m, 1H), 4.15 dihydropyrimidinone - 3.75 (m, 1H), 3.65 (br. s., 3H), 3.46 - 3.07 (m, 4H), 2.29 - 2.16 (m, 1H), 1.99 - 1.86 (m, 1H), 1.77 (br. s., 3H), 1.57 - 0.93 (m, 4H), 0.81 - 0.45 (m, Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 121 2-butylhydroxy[(1S)- 1H NMR (500MHz, DMSO- 1.82 A 1-phenylpropyl][(3S) d6) 7.42 - 7.09 (m, 10H), A phenylpyrrolidine 4.23 - 3.17 (m, 5H), 2.41 (br. 460.0 carbonyl]-3,4- s., 1H), 2.23 (br. s., 1H), 1.90 opyrimidinone (s, 2H), 1.66 - 1.00 (m, 4H), 0.94 - 0.51 (m, 6H) 122 2-butylhydroxy[(1R)- 1H NMR (500MHz, DMSO- 1.83 A 1-(2-methoxyphenyl)ethyl]- d6) 7.54 - 7.45 (m, 1H), 7.37 A -[(3R) - 7.15 (m, 6H), 7.05 - 6.73 (m, 476.1 phenylpyrrolidine 2H), 4.03 - 3.13 (m, 5H), 2.93 carbonyl]-3,4- - 2.57 (m, 2H), 2.20 (br. s., dihydropyrimidinone 1H), 2.03 - 1.68 (m, 4H), 1.62 - 1.01 (m, 4H), 0.78 (br. s., 123 2-butylhydroxy(1- 1H NMR (500MHz, DMSO- 1.71 A phenylethyl)[(3R) d6) 7.42 - 7.07 (m, 10H), A pyrrolidine 4.02 - 3.05 (m, 5H), 2.22 (br. 446.0 carbonyl]-3,4- s., 1H), 1.91 (s, 1H), 1.86 - dihydropyrimidinone 1.72 (m, 3H), 1.52 (br. s., 1H), 1.40 - 0.95 (m, 3H), 0.89 - 0.59 (m, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 124 2-butylhydroxy[(1R)- 1H NMR (500MHz, DMSO- 1.73 A 1-phenylpropyl][(3R) d6) 7.51 - 6.99 (m, 10 H), A phenylpyrrolidine 4.01 - 3.13 (m, 5H), 2.43 (br. 460.2 carbonyl]-3,4- s., 1H), 2.30 - 2.06 (m, 2H), dihydropyrimidinone 1.90 (s, 1H), 1.71 - 0.97 (m, 4H), 0.94 - 0.47 (m, 6H) 125 lhydroxy[(1S)- 1H NMR (500MHz, DMSO- 1.68 A 1-phenylethyl][(3S) d6) 7.38 - 7.19 (m, 10H), A phenylpyrrolidine 4.03 - 3.13 (m, 5H), 2.64 (br. 446.1 carbonyl]-3,4- s., 2H), 2.23 (br. s., 1H), 2.03 - dihydropyrimidinone 1.89 (m, 1H), 1.83 (br. s., 3H), 1.61 - 1.08 (m, 4H), 0.75 (br. s., 3H) 126 2-butyl[(1S) 1H NMR (500MHz, DMSO- 1.74 A cyclopropylethyl] d6) 7.47 - 6.83 (m, 5H), 4.05 A y[(3R) - 3.44 (m, 5H), 2.58 (br. s., 410.1 phenylpyrrolidine 1H), 2.20 (br. s., 1H), 1.99 - carbonyl]-3,4- 1.81 (m, 2H), 1.63 - 1.24 (m, dihydropyrimidinone 6H), 0.86 (d, J=7.6 Hz, 3H), 0.64 - -0.26 (m, 4H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 127 2-butylhydroxy[(1R)- 1H NMR z, DMSO- 1.64 B 2-methoxyphenylethyl]- d6) 7.52 - 6.91 (m, 10H), A )phenylpyrrolidine- 4.55 - 3.76 (m, 4H), 3.61 - 476.2 1-carbonyl]-3,4- 3.07 (m, 6H), 2.94 - 2.57 (m, dihydropyrimidinone 2H), 2.21 (br. s., 1H), 1.90 (s, 1H), 1.69 - 1.12 (m, 4H), 0.96 - 0.61 (m, 3H). 128 2-butylhydroxy[(1R)- 1H NMR (500MHz, DMSO- 1.74 B 1-phenylpropyl][(3S) d6) 7.45 - 7.10 (m, 10H), A phenylpyrrolidine 3.89 (s, 5H), 2.43 (br. s., 1H), 459.9 carbonyl]-3,4- 2.24 (br. s., 2H), 1.90 (s, 1H), dihydropyrimidinone 1.74 - 0.97 (m, 4H), 0.93 - 0.52 (m, 6H). 129 2-butylhydroxy(2- 1H NMR (500MHz, DMSO- 1.73 B methylphenylpropyl) d6) 7.58 (br. s., 1H), 7.43 - A [(3S)phenylpyrrolidine 7.17 (m, 9H), 6.39 and 4.79 474.0 carbonyl]-3,4- (br. s., 1H), 3.95 - 3.12 (m, dihydropyrimidinone 5H), 2.90 (br. s., 2H), 2.42 - 2.32 (m, 1H), 2.24 (br. s., 1H), 1.90 (s, 1H), 1.78 - 1.62 (m, 1H), 1.41 (br. s., 1H), 1.26 - 1.06 (m, 2H), 0.99 - 0.38 (m, Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 130 2-butylhydroxy(2- 1H NMR (500MHz, DMSO- 1.72 B methylphenylpropyl) d6) 7.54 (br. s., 1H), 7.38 - A [(3R)phenylpyrrolidine- 7.04 (m, 9H), 6.35 and 4.78 474.0 1-carbonyl]-3,4- (br. s., 1H), 3.67 - 3.05 (m, dihydropyrimidinone 5H), 3.01 - 2.79 (m, 2H), 2.36 (br. s., 1H), 2.21 (br. s., 1H), 1.86 (br. s., 1H), 1.68 (br. s., 1H), 1.38 (br. s., 1H), 1.25 - 0.98 (m, 2H), 0.97 - 0.26 (m, 131 2-butyl[(1S) 1H NMR (500MHz, DMSO- 1.62 B cyclopropylethyl] d6) 7.61 - 6.79 (m, 5H), 3.94 A hydroxy[(3S) - 3.27 (m, 5H), 2.59 (br. s., 410.1 pyrrolidine 2H), 2.21 (br. s., 21H), 2.00 - carbonyl]-3,4- 1.83 (m, 2H), 1.62 - 1.19 (m, dihydropyrimidinone 7H), 0.86 (d, J=7.6 Hz, 3H), 0.61 - -0.01 (m, 4H) 132 2-butylhydroxy[(1R)- 1H NMR (500MHz, DMSO- 1.74 B 1-phenylethyl][(3S) d6) 7.43 - 6.94 (m, 10H), A phenylpyrrolidine 4.11 - 3.04 (m, 5H), 2.22 (br. 446.1 yl]-3,4- s., 1H), 1.90 (s, 1H), 1.85 - dihydropyrimidinone 1.70 (m, 3H), 1.67 - 0.97 (m, 4H), 0.73 (br. s., 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 133 2-butyl[1-(2- 1H NMR (500MHz, DMSO- 1.80 B chlorophenyl)ethyl] d6) 7.80 - 7.60 (m, 1H), 7.49 A hydroxy[(3S) - 7.08 (m, 9H), 3.93 - 2.94 (m, 480.3 phenylpyrrolidine 5H), 2.21 (br. s., 1H), 1.97 - carbonyl]-3,4- 1.87 (m, 1H), 1.80 (br. s., 3H), opyrimidinone 1.58 - 1.05 (m, 4H), 0.89 - 0.61 (m, 3H) 134 l[1-(2- 1H NMR (500MHz, DMSO- 1.85 B chlorophenyl)ethyl] d6) 7.68 (br. s., 1H), 7.45 - A hydroxy[(3R) 6.96 (m, 9H), 4.23 - 3.09 (m, 480.1 phenylpyrrolidine 5H), 2.76 - 2.53 (m, 2H), 2.17 carbonyl]-3,4- (br. s., 1H), 1.95 - 1.64 (m, dihydropyrimidinone 4H), 1.54 - 1.04 (m, 4H), 0.81 - 0.57 (m, 3H) 135 2-butylhydroxy[(1R)- 1H NMR (500MHz, DMSO- 1.83 B 1-(2-methoxyphenyl)ethyl]- d6) 7.49 (dd, J=18.0, 7.9 Hz, A -[(3S)phenylpyrrolidine- 1H), 7.40 - 7.07 (m, 6H), 7.01 476.1 1-carbonyl]-3,4- - 6.59 (m, 2H), 3.99 - 2.96 (m, dihydropyrimidinone 8H), 2.90 - 2.59 (m, 2H), 2.26 - 2.09 (m, 1H), 1.90 (br. s., 1H), 1.79 (br. s., 3H), 1.51 (br. s., 1H), 1.36 - 0.97 (m, 3H), 0.80 (br. s., 3H) Ex Structure Name Chiral amine ediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 136 2-butylhydroxy(1- 1H NMR (500MHz, DMSO- 1.71 B phenylethyl)[(3S) d6) 7.44 - 7.06 (m, 10H), A phenylpyrrolidine 3.97 - 3.04 (m, 5H), 2.22 (br. 446.3 carbonyl]-3,4- s., 1H), 1.91 (s, 1H), 1.84 - dihydropyrimidinone 1.73 (m, 3H), 1.63 - 1.02 (m, 4H), 0.96 - 0.51 (m, 3H) 137 2-butylhydroxy[(1S)- 1H NMR (500MHz, DMSO- 1.78 B 1-phenylbutyl][(3R) d6) 7.43 - 7.21 (m, 10H), A phenylpyrrolidine 3.68 - 2.85 (m, 5H), 2.42 - 474.4 carbonyl]-3,4- 2.17 (m, 3H), 1.90 (br. s., 1H), dihydropyrimidinone 1.46 - 1.05 (m, 4H), 1.02 - 0.47 (m, 8H) 138 3-[(1S){2-butyl 1H NMR z, DMSO- 1.43 B hydroxyoxo[(3R) d6) 7.63 (br. s., 2H), 7.50 (d, A phenylpyrrolidine J=14.0 Hz, 2H), 7.36 - 7.17 471.1 carbonyl]-1,6- (m, 4H), 7.10 (br. s., 1H), 3.98 dihydropyrimidin - 3.27 (m, 5H), 2.95 - 2.69 (m, yl}ethyl]benzonitrile 2H), 2.18 (br. s., 2H), 1.82 (br. s., 3H), 1.66 - 1.23 (m, 4H), 0.83 (br. s., 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 139 2-butylhydroxy[(1S)- (NMR peaks are too week to 1.56 B ethoxyphenyl)ethyl]- summarize) A -[(3R) 476.3 phenylpyrrolidine carbonyl]-3,4- dihydropyrimidinone 140 2-butylhydroxy[(3R)- 1H NMR (500MHz, DMSO- 1.17 B 3-phenylpyrrolidine d6) 8.39 (d, J=11.6 Hz, 2H), A carbonyl][1-(pyridin 7.55 (br. s., 1H), 7.42 - 6.93 447.2 yl)ethyl]-3,4- (m, 6H), 3.96 - 2.95 (m, 5H), dihydropyrimidinone 2.26 - 2.00 (m, 2H), 1.80 (br. s., 3H), 1.60 - 1.09 (m, 4H), 0.78 (br. s., 3H) 141 2-butylhydroxy[(1S)- 1H NMR (500MHz, DMSO- 169 B 1-phenylethyl][(3R) d6) 7.43 - 7.11 (m, 10H), A pyrrolidine 4.00 - 2.98 (m, 5H), 2.63 (br. 446.1 carbonyl]-3,4- s., 2H), 2.23 (br. s., 1H), 2.01 - dihydropyrimidinone 1.77 (m, 4H), 1.61 - 1.11 (m, 4H), 0.76 (br. s., 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 142 2-butyl[(1R) 1H NMR (500MHz, DMSO- 1.60 B cyclopropylethyl] d6) 7.54 - 7.02 (m, 5H), 4.00 A y[(3R) - 3.12 (m, 5H), 2.91 - 2.57 (m, 410.1 phenylpyrrolidine 2H), 2.24 (br. s., 1H), 2.03 - carbonyl]-3,4- 1.87 (m, 2H), 1.66 - 1.30 (m, dihydropyrimidinone 7H), 0.89 (d, J=9.2 Hz, 3H), 0.61 - -0.02 (m, 4H) 143 2-butyl[(1S)(4- 1H NMR (500MHz, DMSO- 1.54 B fluorophenyl)ethyl] d6) 7.36 - 7.07 (m, 9H), 3.68 A hydroxy[(3S) (d, J=9.7 Hz, 2H), 3.46 - 3.10 464.2 phenylpyrrolidine (m, 3H), 2.95 - 2.59 (m, 2H), carbonyl]-3,4- 2.20 (br. s., 1H), 1.97 - 1.65 dihydropyrimidinone (m, 4H), 1.64 - 0.97 (m, 4H), 0.76 (br. s., 3H) 144 2-butylhydroxy[(3S)- 1H NMR z, DMSO- 1.66 B 3-phenylpyrrolidine d6) 7.34 - 6.81 (m, 8H), 6.74 A carbonyl][(1S)-1,2,3,4- - 6.48 (m, 1H), 5.26 (br. s., 472.2 tetrahydronaphthalenyl]- 1H), 3.87 - 2.86 (m, 5H), 2.86 3,4-dihydropyrimidinone - 2.58 (m, 4H), 2.40 - 2.08 (m, 2H), 2.08 - 1.82 (m, 4H), 1.74 (br. s., 1H), 1.58 (d, J=6.5 Hz, 1H), 1.33 (d, J=6.6 Hz, 2H), 1.03 - 0.42 (m, 3H).
Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 145 2-butyl[(1R)-2,3-dihydro- 1H NMR (500MHz, DMSO- 1.60 B 1H-indenyl]hydroxy- d6) 7.44 - 7.01 (m, 8H), 6.97 A -[(3R) - 6.67 (m, 1H), 5.77 (d, J=8.3 458.2 phenylpyrrolidine Hz, 1H), 3.94 - 3.03 (m, 5H), carbonyl]-3,4- 3.00 - 2.69 (m, 4H), 2.43 (br. dihydropyrimidinone s., 1H), 2.29 - 1.99 (m, 2H), 1.96 - 1.55 (m, 3H), 1.52 - 1.03 (m, 2H), 1.00 - 0.40 (m, 146 2-butylhydroxy[(3S)- 1H NMR (500MHz, DMSO- 1.18 B 3-phenylpyrrolidine d6) 8.37 (d, J=12.6 Hz, 2H), A carbonyl][1-(pyridin 7.53 (d, J=17.6 Hz, 1H), 7.39 - 447.4 yl)ethyl]-3,4- 7.06 (m, 6H), 4.08 - 3.01 (m, dihydropyrimidinone 5H), 2.18 (br. s., 1H), 1.93 - 1.65 (m, 4H), 1.58 - 1.03 (m, 4H), 0.76 (br. s., 3H) 147 lhydroxy[(3R)- 1H NMR (500MHz, DMSO- 1.69 B ylpyrrolidine d6) 7.36 - 6.99 (m, 7H), 6.98 A carbonyl][(1S)-1,2,3,4- - 6.55 (m, 2H), 5.34 (d, J=9.4 472.3 tetrahydronaphthalenyl]- Hz, 1H), 4.20 - 3.02 (m, 5 H), 3,4-dihydropyrimidinone 3.00 - 2.62 (m, 4H), 2.40 - 1.84 (m, 6H), 1.81 - 1.56 (m, 2H), 1.52 - 1.06 (m, 2H), 0.96 - 0.45 (m, 3H) Ex Structure Name Chiral amine ediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho y d range 148 2-butylhydroxy[(3R)- 1H NMR (500MHz, DMSO- 1.15 B 3-phenylpyrrolidine d6) 8.52 - 8.24 (m, 2H), 7.30 A carbonyl][1-(pyridin - 7.06 (m, 7H), 5.80 - 5.36 (m, 447.0 yl)ethyl]-3,4- 1H), 3.72 - 2.96 (m, 5H), 2.92 dihydropyrimidinone - 2.55 (m, 2H), 2.16 (br. s., 1H), 1.85 (s, 1H), 1.76 (br. s., 3H), 1.63 - 1.00 (m, 4H), 0.78 (br. s., 3H) 149 3-[(1S){2-butyl 1H NMR (500MHz, DMSO- 1.42 B hydroxyoxo[(3S) d6) 7.70 (br. s., 2H), 7.53 A phenylpyrrolidine (br. s., 2H), 7.39 - 7.07 (m, 471.3 carbonyl]-1,6- 5H), 5.52 (br. s., 1H), 4.03 - dihydropyrimidin 3.08 (m, 5H), 2.97 - 2.62 (m, yl}ethyl]benzonitrile 2H), 2.29 - 1.95 (m, 2H), 1.83 (br. s., 3H), 1.70 - 1.19 (m, 4H), 0.84 (br. s., 3H) 150 2-butylhydroxy[(3R)- 1H NMR (500MHz, DMSO- 1.44 B 3-phenylpyrrolidine d6) 7.36 - 7.19 (m, 5H), 4.47 A carbonyl](propanyl)- (br. s., 1H), 4.06 - 3.01 (m, 384.2 3,4-dihydropyrimidinone 5H), 2.88 - 2.65 (m, 2H), 2.24 (br. s., 1H), 1.98 - 1.87 (m, 1H), 1.61 (br. s., 2H), 1.50 (d, J=9.5 Hz, 6H), 1.38 (br. s., 2H), 0.91 (d, J=8.2 Hz, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho y d range 151 2-butylhydroxy[(1S)- 1H NMR (500MHz, DMSO- 1.73 B 1-(2-methoxyphenyl)ethyl]- d6) 7.49 (d, J=8.5 Hz, 1H), A -[(3S)phenylpyrrolidine- 7.39 - 7.12 (m, 6H), 7.02 - 476.3 1-carbonyl]-3,4- 6.83 (m, 2H), 5.31 - 5.02 (m, dihydropyrimidinone 1H), 3.79 (s, 3H), 3.71 - 2.98 (m, 5H), 2.81 - 2.56 (m, 2H), 2.26 - 2.06 (m, 2H), 1.96 - 1.68 (m, 3H), 1.61 - 1.01 (m, 4H), 0.90 - 0.64 (m, 3H) 152 2-butylhydroxy[(1S)- 1H NMR (500MHz, DMSO- 1.64 B 2-methoxyphenylethyl]- d6) 7.42 - 7.15 (m, 10H), A -[(3R) 5.43 (br. s., 1H), 4.38 - 3.10 476.2 phenylpyrrolidine (m, 10H), 2.94 - 2.58 (m, 2H), yl]-3,4- 2.21 (br. s., 1H), 1.90 (s, 1H), dihydropyrimidinone 1.70 - 1.08 (m, 4H), 0.99 - 0.61 (m, 3H) 153 2-butylhydroxy[(1S)- 1H NMR (500MHz, DMSO- 1.82 B 1-phenylbutyl][(3S) d6) 7.40 - 7.20 (m, 10H), A phenylpyrrolidine 4.07 - 3.08 (m, 5H), 3.00 - 474.2 carbonyl]-3,4- 2.57 (m, 2H), 2.44 - 2.17 (m, dihydropyrimidinone 3H), 1.90 (br. s., 1H), 1.65 - 1.10 (m, 4H), 0.98 - 0.43 (m, Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 154 2-butylhydroxy[(1S)- 1H NMR (500MHz, DMSO- 1.65 B 2-methoxyphenylethyl]- d6) 7.42 - 7.10 (m, 10H), A -[(3S)phenylpyrrolidine- 5.46 (br. s., 1H), 4.42 - 3.08 476.2 1-carbonyl]-3,4- (m, 10 H), 2.98 - 2.58 (m, 2H), dihydropyrimidinone 2.25 - 2.09 (m, 1H), 1.90 (s, 1H), 1.71 - 0.99 (m, 4H), 0.93 - 0.59 (m, 3H). 155 2-butyl[(1R) 1H NMR (500MHz, DMSO- 1.60 C cyclopropylethyl] d6) 7.37 - 7.13 (m, 5H), 3.94 A hydroxy[(3S) - 3.06 (m, 5H), 2.56 (br. s., 410.1 phenylpyrrolidine 2H), 2.20 (br. s., 1H), 1.90 (d, carbonyl]-3,4- J=9.8 Hz, 1H), 1.64 - 1.21 (m, dihydropyrimidinone 7H), 0.85 (d, J=9.5 Hz, 3H), 0.59 - -0.03 (m, 4H) 156 2-butylhydroxy[(1S)- 1H NMR (500MHz, DMSO- 1.74 C ethoxyphenyl)ethyl]- d6) 7.44 (dd, J=17.5, 7.8 Hz, A -[(3R) 1H), 7.32 - 7.05 (m, 6H), 6.99 476.3 phenylpyrrolidine - 6.65 (m, 2H), 5.14 (t, J=7.3 carbonyl]-3,4- Hz, 1H), 3.90 - 2.94 (m, 8H), dihydropyrimidinone 2.88 - 2.55 (m, 2H), 2.25 - 1.97 (m, 1H), 1.86 (s, 1H), 1.75 (br. s., 3H), 1.53 - 1.07 (m, 4H), 0.86 - 0.60 (m, 3H) Ex Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ # with retention time S Rt cAMP (min) EC50 Metho Potency d range 157 2-butyl[(1S)(4- 1H NMR (500MHz, DMSO- 1.62 C fluorophenyl)ethyl] d6) 7.37 - 6.95 (m, 9H), 3.88 A hydroxy[(3R) - 2.94 (m, 5H), 2.66 (d, J=18.2 464.3 phenylpyrrolidine Hz, 2H), 2.21 (br. s., 1H), 1.95 carbonyl]-3,4- - 1.62 (m, 4H), 1.63 - 0.95 (m, dihydropyrimidinone 4H), 0.75 (br. s., 3H). 158 2-butyl[(1R)-2,3-dihydro- 1H NMR (500MHz, DMSO- 1.60 C 1H-indenyl]hydroxy- d6) 7.50 - 6.71 (m, 9H), 5.78 A -[(3S)phenylpyrrolidine- and 5.23 (d, J=7.9 Hz, 1H), 458.1 1-carbonyl]-3,4- 4.08 (q, J=7.1 Hz, 1H), 3.90 - dihydropyrimidinone 2.98 (m, 4H), 2.95 - 2.74 (m, 4H), 2.30 - 2.04 (m, 1H), 1.97 - 1.62 (m, 3H), 1.59 - 0.99 (m, 4H), 0.97 - 0.22 (m, 3H) 159 2-butylhydroxy[(3S)- 1H NMR z, DMSO- 1.61 C 3-phenylpyrrolidine d6) 7.32 (br. s., 5H), 4.48 A yl](propanyl)- (br. s., 1H), 3.85 (d, J=7.6 Hz, 406.3 3,4-dihydropyrimidinone 1H), 3.72 - 3.53 (m, 2H), 3.44 (M+N (d, J=15.9 Hz, 2H), 2.84 - 2.58 a) (m, 2H), 2.24 (br. s., 1H), 2.01 - 1.84 (m, 1H), 1.61 (br. s., 2H), 1.54 - 1.43 (m, 6H), 1.43 - 1.23 (m, 2H), 1.00 - 0.75 (m, Ex# Structure Name Chiral amine ediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 160 1-(2,6- 1H NMR (500 MHz, DMSO- 1.28 A dimethoxyphen d6) δ 7.46 - 7.35 (m, 1H), 7.28 A yl)hydroxy- - 7.17 (m, 2H), 7.03 - 6.95 524.3 -[3-(2- 10.40, 96.9% (m, 1H), 6.94 - 6.86 (m, 1H), methoxyphenyl Chiralpak IC, 4.6 x 250 mm, 6.83 - 6.72 (m, 2H), 3.93 - )pyrrolidine 5 micron; 3.84 (m, J=13.0 Hz, 3H), 3.83 carbonyl] mobile phase: 15% - 3.76 (m, J=14.1 Hz, 4H), [(propan IPA:Heptane (1:1) /85% 3.76 - 3.68 (m, J=18.8 Hz, yloxy)methyl]- CO2; 6H), 3.66 - 3.58 (m, 4H), 2.21 1,4- Flow ions: 2 mL/min, - 2.08 (m, 1H), 2.03 - 1.93 dihydropyrimid 150 bar, 40°C, (m, 1H), 0.87 (br dd, J=12.3, inone wavelength: 220 nm (isomer 6.1 Hz, 6H) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 161 1-(2,6- 1H NMR (500 MHz, DMSO- 1.28 A dimethoxyphen d6) δ 7.41 (q, J=8.8 Hz, 1H), A yl)hydroxy- 7.22 (br d, J=7.4 Hz, 2H), 524.4 -[3-(2- 11.13, 97.1% 7.05 - 6.94 (m, 1H), 6.94 - methoxyphenyl Chiralpak IC, 4.6 x 250 mm, 6.85 (m, 1H), 6.84 - 6.72 (m, )pyrrolidine 5 ; 2H), 3.93 - 3.84 (m, J=12.1 yl] mobile phase: 15% Hz, 4H), 3.83 - 3.67 (m, 9H), [(propan IPA:Heptane (1:1) /85% 3.62 (br s, 2H), 3.34 - 3.12 yloxy)methyl]- CO2; (m, 2H), 2.23 - 2.09 (m, 1H), 1,4- Flow Conditions: 2 mL/min, 1.98 (br d, J=9.5 Hz, 1H), dihydropyrimid 150 bar, 40°C, 0.87 (br dd, J=11.9, 6.0 Hz, inone wavelength: 220 nm (isomer 6H) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 162 5-[3-(2,4- 1H NMR (500 MHz, DMSO- 1.35 A difluorophenyl) d6) δ 7.51 - 7.35 (m, 2H), 7.26 A pyrrolidine - 7.15 (m, 1H), 7.09 - 6.97 530.3 carbonyl] (m, 1H), 6.86 - 6.71 (m, 2H), (2,6- 3.88 (br d, J=11.3 Hz, 3H), dimethoxyphen 2.53, 92.7% 3.79 - 3.68 (m, 6H), 3.64 (s, yl)hydroxy- Chiralpak IC, 4.6 x 250 mm, 4H), 3.51 - 3.19 (m, 1H), 2.31 2-[(propan 5 micron; - 2.16 (m, 1H), 2.05 - 1.93 yloxy)methyl]- mobile phase: 10% IPA/90% (m, 1H), 0.88 (br dd, J=11.0, 1,4- CO2; 6.1 Hz, 6H) dihydropyrimid Flow Conditions: 3 , ne 140 bar, 45°C, wavelength: 200-400 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 163 5-[3-(2,4- 1H NMR (500 MHz, DMSO- 1.34 A difluorophenyl) d6) δ 7.42 (br d, J=7.9 Hz, A pyrrolidine 2H), 7.19 (br s, 1H), 7.03 (br 530.2 carbonyl] s, 1H), 6.88 - 6.72 (m, 2H), (2,6- 3.90 (br d, J=9.2 Hz, 3H), oxyphen 2.78, 95.7% 3.72 (br d, J=17.1 Hz, 6H), yl)hydroxy- Chiralpak IC, 4.6 x 250 mm, 3.63 (s, 4H), 3.36 - 3.21 (m, 2-[(propan 5 micron; 1H), 2.23 (br d, J=5.2 Hz, yloxy)methyl]- mobile phase: 10% IPA/90% 1H), 2.05 - 1.93 (m, 1H), 0.87 1,4- CO2; (br dd, J=10.1, 6.1 Hz, 6H) opyrimid Flow Conditions: 3 mL/min, inone 140 bar, 45°C, wavelength: 200-400 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 164 5-[3-(2,6- 1H NMR (500 MHz, DMSO- 1.15 A rophenyl) d6) δ 7.50 - 7.40 (m, 1H), 7.39 A pyrrolidine - 7.29 (m, 1H), 7.13 - 7.02 530.4 carbonyl] (m, 2H), 6.81 (br t, J=9.9 Hz, (2,6- 5.4, >99.7% 2H), 4.01 - 3.85 (m, 4H), 3.65 dimethoxyphen Whelko, 5 x 50 cm, 10 - 3.50 (m, 9H), 3.46 - 3.22 yl)hydroxy- micron; (m, 1H), 2.20 (br d, J=10.1 2-[(propan mobile phase: 20% IPA/80% Hz, 2H), 0.88 (br dd, J=17.2, yloxy)methyl]- CO2; 5.6 Hz, 6H) 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 165 2-{1-[1-(2,6- 1H NMR (500 MHz, DMSO- 1.08 A dimethoxyphen d6) δ 7.81 (br d, J=6.4 Hz, A yl)hydroxy- 1H), 7.68 (br s, 1H), 7.58 (br 518.9 4-oxo 5.68, >99% s, 1H), 7.45 (br t, J=7.5 Hz, [(propan Chiralpak IC, 4.6 x 250 mm, 2H), 6.80 (br s, 2H), 3.90 (br yloxy)methyl]- 5 micron; s, 4H), 3.72 (br d, J=16.8 Hz, 1,4- mobile phase: 15% 9H), 3.54 - 3.19 (m, 1H), 2.32 dihydropyrimid IPA/0.1% DEA /85% CO2; (br s, 1H), 2.06 (br d, J=8.9 ine Flow Conditions: 2 , Hz, 1H), 0.88 (br d, J=8.5 Hz, carbonyl]pyrrol 150 bar, 45°C, 6H) idin ngth: 220 nm (isomer yl}benzonitrile 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 166 5-[3-(2,6- 1H NMR (500 MHz, DMSO- 1.14 A rophenyl) d6) δ 7.48 - 7.30 (m, 2H), 7.17 A pyrrolidine - 7.03 (m, 2H), 6.79 (br dd, 529.9 carbonyl] J=13.6, 8.1 Hz, 2H), 3.98 - (2,6- 5.9, >99.7% 3.82 (m, 4H), 3.80 - 3.58 (m, dimethoxyphen Whelko, 5 x 50 cm, 10 9H), 3.41 (br s, 1H), 2.31 - yl)hydroxy- micron; 2.10 (m, 2H), 0.87 (br dd, 2-[(propan mobile phase: 20% % J=18.4, 5.8 Hz, 6H) yloxy)methyl]- CO2; 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 167 2-{1-[1-(2,6- 1H NMR (500 MHz, DMSO- 1.07 A dimethoxyphen d6) δ 7.86 - 7.76 (m, 1H), 7.67 A yl)hydroxy- (br s, 1H), 7.57 (br d, J=7.3 518.9 4-oxo 4.87, >99% Hz, 1H), 7.50 - 7.30 (m, 2H), [(propan Chiralpak IC, 4.6 x 250 mm, 6.79 (br s, 2H), 3.90 (br d, yloxy)methyl]- 5 micron; J=11.3 Hz, 4H), 3.76 - 3.39 1,4- mobile phase: 15% (m, 9H), 3.33 - 3.20 (m, 1H), dihydropyrimid 1% DEA /85% CO2; 2.32 (br s, 1H), 2.06 (br d, ine Flow Conditions: 2 mL/min, J=5.2 Hz, 1H), 0.87 (br dd, carbonyl]pyrrol 150 bar, 45°C, , 5.3 Hz, 6H) idin wavelength: 220 nm (isomer yl}benzonitrile 1) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 168 2-(2- 1H NMR (500 MHz, DMSO- 1.36 A cyclopropylethy d6) δ 8.67 (br s, 1H), 8.14 - A l)[3-(3,5- 8.01 (m, 1H), 7.67 (br d, 526.9 difluoropyridin- J=6.5 Hz, 1H), 7.05 (br t, 2- J=8.5 Hz, 2H), 4.09 - 3.76 yl)pyrrolidine- 5.6, >99.7% (m, 10H), 3.71 - 3.56 (m, 1-carbonyl] Whelko, 5 x 50 cm, 10 1H), 2.51 (br d, J=6.7 Hz, (2,6- micron; 3H), 2.38 - 2.23 (m, 1H), 1.53 dimethoxyphen mobile phase: 20% % (br s, 2H), 0.79 (br s, 1H), yl)hydroxy- CO2; 0.49 (br s, 2H), 0.00 (br s, 1,4- Flow Conditions: 350 2H) dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 169 2-(2- 1H NMR (500 MHz, DMSO- 1.24 A cyclopropylethy d6) δ 8.66 (br s, 1H), 8.10 (br A l)[3-(3,5- t, J=8.7 Hz, 1H), 7.65 (br s, 527.4 difluoropyridin- 1H), 7.13 - 6.95 (m, 2H), 4.16 2- - 3.82 (m, 10H), 3.80 - 3.65 yl)pyrrolidine- 6.3, >99.7% (m, 1H), 2.59 - 2.38 (m, 3H), 1-carbonyl] Whelko, 5 x 50 cm, 10 2.37 - 2.24 (m, 1H), 1.53 (br (2,6- ; s, 2H), 0.78 (br s, 1H), 0.48 dimethoxyphen mobile phase: 20% IPA/80% (br s, 2H), 0.00 (br s, 2H) yl)hydroxy- CO2; 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 170 5-[3-(5- 1H NMR (500 MHz, DMSO- 1.41 A chloropyridin- d6) δ 8.75 (br s, 1H), 8.06 (dd, A 2- J=8.1, 2.0 Hz, 1H), 7.78 - 525.0 rolidine- 7.52 (m, 2H), 7.04 (br s, 2H), 1-carbonyl] 7.9, >99.7% 3.94 (br d, J=17.1 Hz, 10H), (2- Whelko, 5 x 50 cm, 10 3.65 (br s, 1H), 2.61 - 2.38 cyclopropylethy ; (m, 3H), 2.34 - 2.17 (m, 1H), l)(2,6- mobile phase: 20% IPA/80% 1.54 (br s, 2H), 0.79 (br s, dimethoxyphen CO2; 1H), 0.48 (br s, 2H), 0.00 (br yl)hydroxy- Flow Conditions: 350 s, 2H) 1,4- mL/min, 30°C, wavelength: dihydropyrimid 220 nm (isomer 2) inone Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 171 5-[3-(5- 1H NMR (500 MHz, DMSO- 1.42 A chloropyridin- d6) δ 8.76 (br s, 1H), 8.08 (br A 2- d, J=7.9 Hz, 1H), 7.64 (dt, 525.2 yl)pyrrolidine- J=16.0, 8.1 Hz, 2H), 7.19 - 1-carbonyl] 6.8, >99.7% 6.95 (m, 2H), 4.13 - 3.74 (m, (2- Whelko, 5 x 50 cm, 10 10H), 3.71 - 3.55 (m, 1H), cyclopropylethy micron; 2.51 (br d, J=6.2 Hz, 3H), l)(2,6- mobile phase: 20% IPA/80% 2.34 - 2.19 (m, 1H), 1.53 (br dimethoxyphen CO2; d, J=6.6 Hz, 2H), 0.79 (br d, yl)hydroxy- Flow Conditions: 350 J=3.5 Hz, 1H), 0.49 (br s, 1,4- mL/min, 30°C, wavelength: 2H), 0.00 (br s, 2H) dihydropyrimid 220 nm (isomer 1) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 172 5-[3-(5- achiral 1H NMR (500 MHz, DMSO- 1.42 A chloropyridin- d6) δ 8.85 - 8.69 (m, 1H), 8.12 A 2-yl)-2,5- (br d, J=8.3 Hz, 1H), 8.03 - 523.4 dihydro-1H- 7.86 (m, 1H), 7.64 (br t, J=7.8 pyrrole Hz, 1H), 7.02 (br d, J=8.4 Hz, yl](2- 2H), 6.99 - 6.85 (m, 1H), 4.80 cyclopropylethy - 4.43 (m, 4H), 3.95 (br d, l)(2,6- J=5.7 Hz, 6H), 2.52 (br d, dimethoxyphen J=6.8 Hz, 2H), 1.55 (br d, yl)hydroxy- J=7.2 Hz, 2H), 0.79 (br s, 1,4- 1H), 0.48 (br s, 2H), 0.00 (br dihydropyrimid s, 2H) inone Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 173 2-(2- achiral 1H NMR (500 MHz, DMSO- 1.43 A cyclopropylethy d6) δ 7.64 (br t, J=8.3 Hz, A l){4-[(2,3- 1H), 7.55 (br d, J=9.4 Hz, 555.2 difluorophenyl) 1H), 7.49 - 7.35 (m, 2H), 7.03 methyl]piperazi (br d, J=8.3 Hz, 2H), 3.94 (br necarbonyl}- s, 6H), 3.85 - 3.74 (m, 2H), 1-(2,6- 2.58 (br s, 8H), 2.44 (br s, dimethoxyphen 2H), 1.53 (br d, J=6.9 Hz, yl)hydroxy- 2H), 0.79 (br s, 1H), 0.49 (br 1,4- d, J=6.4 Hz, 2H), 0.00 (br s, dihydropyrimid 2H) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 174 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.29 A 3-fluoropyridin- d6) δ 8.47 (br d, J=18.3 Hz, A 2- 1H), 8.06 (br t, J=10.3 Hz, 551.3 yl)pyrrolidine- 1H), 7.55 (br d, J=5.8 Hz, 1-carbonyl] 1H), 7.45 - 7.32 (m, 1H), 7.27 (2,6- 6.8, >99.7% - 7.15 (m, 2H), 5.56 (br d, lphenyl)- Whelko, 5 x 50 cm, 10 J=5.8 Hz, 1H), 4.12 - 3.73 6-hydroxy(1- micron; (m, 4H), 3.70 (br d, J=6.3 Hz, methyl-1H- mobile phase: 20% IPA/80% 3H), 3.60 (br t, J=9.6 Hz, pyrazolyl)- CO2; 1H), 2.37 - 2.06 (m, 6H), 1.11 1,4- Flow Conditions: 350 - 0.89 (m, 6H) dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 175 2-(2- 1H NMR (500 MHz, DMSO- 1.24 A cyclopropylethy d6) Shift 8.71 (br s, 1H), 8.00 A l)(2,6- - 7.81 (m, 1H), 7.66 (br s, 508.9 dimethoxyphen 2H), 7.14 - 6.93 (m, 2H), 4.16 yl)[3-(5- 8.4, >99.7% - 3.71 (m, 11H), 2.61 - 2.37 fluoropyridin Whelko, 5 x 50 cm, 10 (m, 3H), 2.35 - 2.15 (m, 1H), yl)pyrrolidine- micron; 1.54 (br s, 2H), 0.79 (br s, 1-carbonyl] mobile phase: 10% IPA/90% 1H), 0.49 (br s, 2H), 0.00 (br y-1,4- CO2; s, 2H) dihydropyrimid Flow ions: 340 inone mL/min, 45°C, wavelength: 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 176 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.50 A 3-fluoropyridin- d6) δ 8.67 (br s, 1H), 8.25 (br A 2- d, J=9.8 Hz, 1H), 7.64 (br s, 543.0 yl)pyrrolidine- 1H), 7.03 (br s, 2H), 4.12 - 1-carbonyl] 3.80 (m, 10H), 3.79 - 3.56 (m, (2- 6.8, >99.7% 1H), 2.59 - 2.38 (m, 3H), 2.37 ropylethy Whelko, 5 x 50 cm, 10 - 2.23 (m, 1H), 1.53 (br s, l)(2,6- micron; 2H), 0.78 (br s, 1H), 0.48 (br dimethoxyphen mobile phase: 20% % s, 2H), 0.00 (br s, 2H) yl)hydroxy- CO2; 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 177 2-(2- 1H NMR (500 MHz, DMSO- 1.26 A cyclopropylethy d6) δ 8.70 (br s, 1H), 8.00 - A l)(2,6- 7.80 (m, 1H), 7.65 (br d, 509.0 dimethoxyphen J=7.3 Hz, 2H), 7.04 (br s, yl)[3-(5- 7.7, >95.5% 2H), 4.07 - 3.74 (m, 10H), fluoropyridin Whelko, 5 x 50 cm, 10 3.67 (br d, J=6.4 Hz, 1H), yl)pyrrolidine- micron; 2.60 - 2.37 (m, 3H), 2.33 - 1-carbonyl] mobile phase: 10% % 2.17 (m, 1H), 1.54 (br s, 2H), hydroxy-1,4- CO2; 0.79 (br s, 1H), 0.49 (br s, dihydropyrimid Flow Conditions: 340 2H), 0.00 (br s, 2H) inone mL/min, 45°C, wavelength: 220 nm (isomer 1) 178 2-(2- 1H NMR (500 MHz, DMSO- 1.12 A cyclopropylethy d6) δ 8.59 (br s, 1H), 7.89 (br A 2,6- t, J=9.2 Hz, 1H), 7.66 (br s, 509.3 dimethoxyphen 1H), 7.61 - 7.52 (m, 1H), 7.04 yl)[3-(3- 8.5, >99.8% (br s, 2H), 4.13 - 3.58 (m, fluoropyridin Whelko, 5 x 50 cm, 10 11H), 2.53 (br d, J=7.1 Hz, rolidine- micron; 3H), 2.34 (br s, 1H), 1.53 (br 1-carbonyl] mobile phase: 10% IPA/90% s, 2H), 0.78 (br s, 1H), 0.48 hydroxy-1,4- CO2; (br s, 2H), 0.00 (br s, 2H) dihydropyrimid Flow Conditions: 340 inone mL/min, 45°C, wavelength: 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 179 2-(2- 1H NMR (500 MHz, DMSO- 1.13 A cyclopropylethy d6) δ 8.58 (br s, 1H), 7.88 (br A l)(2,6- t, J=8.7 Hz, 1H), 7.66 (br s, 509.2 dimethoxyphen 1H), 7.61 - 7.51 (m, 1H), 7.04 yl)[3-(3- 9.5, >99.8% (br s, 2H), 4.13 - 3.82 (m, fluoropyridin Whelko, 5 x 50 cm, 10 10H), 3.77 (br d, J=8.9 Hz, yl)pyrrolidine- micron; 1H), 2.61 - 2.40 (m, 3H), 2.34 1-carbonyl] mobile phase: 10% IPA/90% (br s, 1H), 1.54 (br s, 2H), y-1,4- CO2; 0.79 (br s, 1H), 0.48 (br s, dihydropyrimid Flow Conditions: 340 2H), 0.00 (br s, 2H) inone mL/min, 45°C, wavelength: 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 180 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.31 A 3-fluoropyridin- d6) Shift 8.70 (br d, J=7.1 Hz, A 2- 1H), 8.27 (br d, J=8.2 Hz, 543.3 rolidine- 1H), 7.78 - 7.50 (m, 1H), 7.03 1-carbonyl] (br t, J=9.1 Hz, 2H), 4.20 - (2- 7.6, >99.7% 3.65 (m, 11H), 2.44 (br s, cyclopropylethy Whelko, 5 x 50 cm, 10 3H), 2.38 - 2.22 (m, 1H), 1.52 l)(2,6- micron; (br d, J=7.1 Hz, 2H), 0.79 (br dimethoxyphen mobile phase: 20% IPA/80% s, 1H), 0.48 (br d, J=7.4 Hz, yl)hydroxy- CO2; 2H), 0.00 (br s, 2H) 1,4- Flow ions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 2) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 181 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.28 A difluorophenyl) d6) δ 8.37 (br s, 1H), 8.05 - A propyl](1- 7.82 (m, 1H), 7.76 - 7.58 (m, 553.4 ethyl-1H- 1H), 7.37 (br s, 1H), 7.19 - pyrazolyl) 9.5, >99.8% 6.88 (m, 2H), 6.71 (br s, 1H), [3-(3- Whelko, 5 x 50 cm, 10 6.19 - 5.86 (m, 1H), 4.17 (br fluoropyridin micron; d, J=7.0 Hz, 4H), 3.93 - 3.60 yl)pyrrolidine- mobile phase: 10% IPA/90% (m, 1H), 3.59 - 3.25 (m, 3H), 1-carbonyl] CO2; 2.35 - 2.01 (m, 4H), 1.35 (br hydroxy-1,4- Flow Conditions: 340 d, J=6.7 Hz, 3H), 0.94 - 0.64 dihydropyrimid mL/min, 45°C, wavelength: (m, 3H) ne 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 182 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.17 A difluorophenyl) d6) Shift 8.44 (br s, 1H), 8.06 A propyl][3- - 7.92 (m, 1H), 7.87 (br t, 557.0 (3,5- J=8.7 Hz, 1H), 7.53 (br s, difluoropyridin- 1H), 7.03 (br s, 1H), 6.90 (br 2- 6.3, >99.7% d, J=17.7 Hz, 2H), 3.85 (br s, rolidine- Whelko, 5 x 50 cm, 10 4H), 3.68 - 3.53 (m, 1H), 3.46 1-carbonyl] ; (br s, 3H), 3.32 - 3.13 (m, hydroxy(1- mobile phase: 20% IPA/80% 1H), 2.36 - 1.99 (m, 4H), 0.87 methyl-1H- CO2; - 0.64 (m, 3H) pyrazolyl)- Flow Conditions: 350 1,4- mL/min, 30°C, wavelength: dihydropyrimid 220 nm (isomer 2) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 183 5-[3-(5- 1H NMR (500 MHz, DMSO- 1.22 A chloropyridin- d6) Shift 8.70 - 8.44 (m, 1H), A 2- 7.99 (br s, 1H), 7.91 - 7.76 555.5 yl)pyrrolidine- (m, 1H), 7.57 (br s, 1H), 7.48 1-carbonyl] 7.9, >99.7% - 7.28 (m, 1H), 7.05 - 6.83 [(1S)(3,5- Whelko, 5 x 50 cm, 10 (m, 3H), 3.86 (br s, 4H), 3.71 difluorophenyl) micron; - 3.23 (m, 5H), 2.39 - 2.13 propyl] mobile phase: 20% IPA/80% (m, 3H), 2.10 - 1.96 (m, 1H), hydroxy(1- CO2; 0.75 (br s, 3H) -1H- Flow Conditions: 350 pyrazolyl)- mL/min, 30°C, wavelength: 1,4- 220 nm (isomer 2) dihydropyrimid inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 184 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.54 A difluorophenyl) d6) Shift 8.40 (br s, 1H), 7.79 A ][3- (br d, J=7.7 Hz, 2H), 7.16 - 557.2 (3,5- 6.79 (m, 2H), 6.66 (br s, 1H), difluoropyridin- 6.25 - 5.81 (m, 1H), 3.86 (br 2- 6.3, >99.7% s, 4H), 3.71 - 3.29 (m, 5H), yl)pyrrolidine- Whelko, 5 x 50 cm, 10 2.31 - 1.96 (m, 4H), 0.90 - 1-carbonyl] micron; 0.60 (m, 3H) hydroxy(1- mobile phase: 20% IPA/80% methyl-1H- CO2; pyrazolyl)- Flow Conditions: 350 1,4- , 30°C, wavelength: dihydropyrimid 220 nm (isomer 2) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 185 )(3,5- 1H NMR (500 MHz, DMSO- 1.22 A difluorophenyl) d6) Shift 8.59 - 8.35 (m, 1H), A propyl][3-(5- 7.81 (br s, 1H), 7.71 - 7.52 539.0 fluoropyridin (m, 1H), 7.47 - 7.28 (m, 1H), yl)pyrrolidine- 8.4, >99.7% 7.11 - 6.84 (m, 2H), 6.72 (br onyl] Whelko, 5 x 50 cm, 10 s, 1H), 6.07 (br d, J=6.1 Hz, hydroxy(1- micron; 1H), 3.86 (br d, J=3.0 Hz, methyl-1H- mobile phase: 10% IPA/90% 4H), 3.69 - 3.13 (m, 5H), 2.47 pyrazolyl)- CO2; - 2.36 (m, 1H), 2.25 (br d, 1,4- Flow Conditions: 340 J=6.8 Hz, 2H), 2.02 (br d, dihydropyrimid mL/min, 45°C, wavelength: J=11.4 Hz, 1H), 0.76 (br s, inone 220 nm (isomer 2) 3H) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 186 )(3,5- 1H NMR (500 MHz, DMSO- 1.44 A difluorophenyl) d6) Shift 8.38 (br d, J=6.7 Hz, A propyl](1- 1H), 7.89 (br s, 1H), 7.67 (br 553.0 ethyl-1H- d, J=8.1 Hz, 1H), 7.37 (br s, pyrazolyl) 8.5, >99.8% 1H), 7.16 - 6.86 (m, 2H), 6.70 [3-(3- Whelko, 5 x 50 cm, 10 (br s, 1H), 6.20 - 5.92 (m, fluoropyridin micron; 1H), 4.17 (br s, 4H), 3.91 - yl)pyrrolidine- mobile phase: 10% IPA/90% 3.43 (m, 4H), 2.34 - 2.02 (m, onyl] CO2; 4H), 1.34 (br d, J=6.6 Hz, hydroxy-1,4- Flow Conditions: 340 3H), 0.90 - 0.67 (m, 3H) dihydropyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 187 5-[3-(5- 1H NMR (500 MHz, DMSO- 1.36 A chloropyridin- d6) Shift 8.53 (br d, J=9.3 Hz, A 2- 1H), 8.06 (br s, 1H), 7.85 (br 554.9 yl)pyrrolidine- d, J=8.1 Hz, 1H), 7.65 (br s, 1-carbonyl] 1H), 7.49 - 7.31 (m, 1H), 7.07 6.8, >99.7% [(1S)(3,5- Whelko, 5 x 50 cm, 10 (br s, 1H), 6.95 (br s, 2H), difluorophenyl) micron; 3.86 (br s, 4H), 3.77 - 3.62 propyl] mobile phase: 20% IPA/80% (m, 3H), 3.60 - 3.31 (m, 2H), hydroxy(1- CO2; 2.46 - 2.16 (m, 3H), 2.12 - -1H- Flow Conditions: 350 1.96 (m, 1H), 0.84 - 0.63 (m, pyrazolyl)- mL/min, 30°C, ngth: 3H) 1,4- 220 nm (isomer 1) dihydropyrimid inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 188 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.69 A difluorophenyl) d6) δ 8.58 - 8.32 (m, 1H), 8.09 A propyl][3- - 7.95 (m, 1H), 7.87 (br s, 557.3 (3,5- 1H), 7.57 (br s, 1H), 7.20 - difluoropyridin- 6.77 (m, 3H), 4.00 - 3.80 (m, 2- 5.6, >99.7% 4H), 3.50 (br s, 5H), 2.45 - yl)pyrrolidine- Whelko, 5 x 50 cm, 10 2.26 (m, 2H), 2.24 - 2.01 (m, 1-carbonyl] micron; 2H), 0.75 (br d, J=7.6 Hz, hydroxy(1- mobile phase: 20% IPA/80% 3H) methyl-1H- CO2; pyrazolyl)- Flow ions: 350 1,4- mL/min, 30°C, wavelength: opyrimid 220 nm (isomer 1) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 189 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.37 A rophenyl) d6) δ 8.37 (br s, 1H), 7.83 (br A propyl][3-(3- s, 1H), 7.73 - 7.59 (m, 1H), 539.0 fluoropyridin 7.37 (br d, J=4.0 Hz, 1H), yl)pyrrolidine- 9.5, >99.8% 7.15 - 6.87 (m, 2H), 6.70 (br 1-carbonyl] Whelko, 5 x 50 cm, 10 s, 1H), 6.23 - 5.95 (m, 1H), hydroxy(1- micron; 3.88 (br d, J=7.7 Hz, 4H), methyl-1H- mobile phase: 10% IPA/90% 3.66 (br s, 5H), 2.33 - 2.01 pyrazolyl)- CO2; (m, 4H), 0.88 - 0.69 (m, 3H) 1,4- Flow Conditions: 340 dihydropyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 2) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 190 5-[3-(5- 1H NMR (500 MHz, DMSO- 1.45 A chloropyridin- d6) Shift 8.66 - 8.44 (m, 1H), A 2- 7.98 - 7.74 (m, 2H), 7.56 - 554.9 yl)pyrrolidine- 7.25 (m, 1H), 7.16 - 6.85 (m, 1-carbonyl] 7.9, >99.7% 2H), 6.69 (br s, 1H), 6.04 (br [(1S)(3,5- Whelko, 5 x 50 cm, 10 d, J=6.1 Hz, 1H), 3.88 (br s, difluorophenyl) micron; 4H), 3.63 (br s, 5H), 2.34 - propyl] mobile phase: 20% % 2.12 (m, 3H), 2.10 - 1.95 (m, hydroxy(1- CO2; 1H), 0.78 (br d, J=6.1 Hz, 3H) methyl-1H- Flow Conditions: 350 pyrazolyl)- mL/min, 30°C, wavelength: 1,4- 220 nm (isomer 2) dihydropyrimid inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 191 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.13 A difluorophenyl) d6) δ 8.59 - 8.40 (m, 1H), 8.08 A ][3-(5- - 7.83 (m, 1H), 7.65 (br t, 539.4 fluoropyridin J=7.7 Hz, 1H), 7.57 - 7.30 yl)pyrrolidine- 7.7, >95.5% (m, 2H), 7.21 - 7.00 (m, 1H), 1-carbonyl] Whelko, 5 x 50 cm, 10 6.98 - 6.79 (m, 2H), 3.84 (br hydroxy(1- micron; d, J=6.1 Hz, 4H), 3.56 (br d, methyl-1H- mobile phase: 10% IPA/90% J=1.2 Hz, 5H), 2.35 - 2.13 pyrazolyl)- CO2; (m, 3H), 2.12 - 1.93 (m, 1H), 1,4- Flow Conditions: 340 0.83 - 0.60 (m, 3H) dihydropyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 192 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.51 A difluorophenyl) d6) δ 8.55 - 8.34 (m, 1H), 8.01 A propyl][3- - 7.74 (m, 2H), 7.17 - 6.83 571.0 (3,5- (m, 2H), 6.69 (br s, 1H), 6.23 difluoropyridin- - 5.83 (m, 1H), 4.16 (br s, 2- 5.6, >99.7% 4H), 3.59 (br s, 3H), 3.47 - yl)pyrrolidine- Whelko, 5 x 50 cm, 10 3.20 (m, 1H), 2.33 - 2.01 (m, 1-carbonyl] micron; 4H), 1.33 (br s, 3H), 0.90 - (1-ethyl-1H- mobile phase: 20% IPA/80% 0.65 (m, 3H) pyrazolyl) CO2; hydroxy-1,4- Flow Conditions: 350 dihydropyrimid , 30°C, wavelength: inone 220 nm (isomer 1) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 193 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.37 A difluorophenyl) d6) Shift 7.95 - 7.76 (m, 1H), A propyl][3-(2- 7.52 - 7.35 (m, 1H), 7.34 - 537.9 fluorophenyl)py 10.65, 99.5% 7.24 (m, 1H), 7.22 - 7.11 (m, ine Chiralpak IF, 4.6 x 250 mm, 2H), 7.10 - 6.81 (m, 2H), 6.77 carbonyl] 5 micron; - 6.57 (m, 1H), 6.23 - 5.85 hydroxy(1- mobile phase: 15% IPA/90% (m, 1H), 3.88 (br d, J=9.7 Hz, methyl-1H- CO2; 4H), 3.53 (br s, 5H), 2.37 - pyrazolyl)- Flow Conditions: 2.0 2.12 (m, 3H), 2.04 - 1.84 (m, 1,4- mL/min, 150 bar, 40°C, 1H), 0.91 - 0.60 (m, 3H) dihydropyrimid wavelength: 220 nm (Isomer inone 2) 194 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.38 A rophenyl) d6) Shift 7.85 (br s, 1H), 7.33 A propyl][3-(4- (br s, 1H), 7.19 (br s, 1H), 537.8 fluorophenyl)py 10.7, 90% 7.14 - 7.04 (m, 2H), 7.02 - rrolidine Whelk-O 1 (R,R), 4.6 x 250 6.88 (m, 2H), 6.74 (br s, 1H), carbonyl] mm, 5 micron; 6.13 (br s, 1H), 3.88 (br s, hydroxy(1- mobile phase: 15% 4H), 3.68 (br s, 5H), 2.27 (br methyl-1H- IPA/85%CO2; dd, J=12.7, 6.6 Hz, 3H), 1.99 pyrazolyl)- Flow Conditions: 2.0 - 1.72 (m, 1H), 0.78 (br s, 3H) 1,4- mL/min, 150 bar, 40°C, dihydropyrimid ngth: 220 nm (Isomer inone 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 195 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.39 A difluorophenyl) d6) δ 7.82 (br d, J=10.5 Hz, A propyl] 1H), 7.21 (br t, J=6.9 Hz, 550.1 hydroxy[3- 11.13, 97.1% 2H), 7.08 - 6.82 (m, 4H), 6.66 (2- Chiralpak IC, 4.6 x 250 mm, (br s, 1H), 6.18 - 5.94 (m, yphenyl 5 micron; 1H), 3.86 (br d, J=10.1 Hz, )pyrrolidine mobile phase: 15% 4H), 3.82 - 3.71 (m, 3H), 3.67 carbonyl](1- IPA:Heptane (1:1) /85% (br d, J=9.0 Hz, 4H), 3.46 - methyl-1H- CO2; 3.26 (m, 1H), 2.32 - 2.03 (m, pyrazolyl)- Flow ions: 2 mL/min, 3H), 2.00 - 1.88 (m, 1H), 0.86 1,4- 150 bar, 40°C, - 0.59 (m, 3H) dihydropyrimid wavelength: 220 nm (isomer inone 2) Ex# Structure Name Chiral amine ediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 196 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.27 A rophenyl) d6) δ 8.05 (br s, 1H), 7.63 (br A propyl][3-(2- s, 1H), 7.44 - 7.25 (m, 2H), 538.0 fluorophenyl)py 10.65, 99.5% 7.24 - 7.07 (m, 3H), 6.96 (br rrolidine Chiralpak IF, 4.6 x 250 mm, s, 2H), 3.87 (br d, J=6.2 Hz, carbonyl] 5 micron; 4H), 3.53 (br s, 5H), 2.44 - hydroxy(1- mobile phase: 15% IPA/90% 2.14 (m, 3H), 2.06 - 1.89 (m, methyl-1H- CO2; 1H), 0.86 - 0.62 (m, 3H) pyrazolyl)- Flow Conditions: 2.0 1,4- mL/min, 150 bar, 40°C, dihydropyrimid wavelength: 220 nm (Isomer inone 2) 197 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.34 A difluorophenyl) d6) δ 8.07 (br s, 1H), 7.66 (br A ][3-(4- s, 1H), 7.39 - 7.26 (m, 1H), 538.4 fluorophenyl)py 10.7, 90% 7.24 - 7.17 (m, 1H), 7.10 (dt, rrolidine O 1 (R,R), 4.6 x 250 J=16.7, 8.4 Hz, 3H), 7.00 - carbonyl] mm, 5 micron; 6.87 (m, 2H), 4.06 - 3.71 (m, hydroxy(1- mobile phase: 15% 4H), 3.66 - 3.24 (m, 5H), 2.48 methyl-1H- IPA/85%CO2; - 2.13 (m, 3H), 1.98 - 1.71 pyrazolyl)- Flow Conditions: 2.0 (m, 1H), 0.75 (br d, J=6.9 Hz, 1,4- mL/min, 150 bar, 40°C, 3H) dihydropyrimid wavelength: 220 nm (Isomer inone 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 198 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.42 A rophenyl) d6) δ 8.18 - 7.99 (m, 1H), 7.65 A propyl] (br s, 1H), 7.34 - 7.19 (m, 550.2 hydroxy[3- 11.13, 97.1% 2H), 7.17 - 7.03 (m, 1H), 7.02 (2- Chiralpak IC, 4.6 x 250 mm, - 6.93 (m, 3H), 6.92 - 6.82 methoxyphenyl 5 micron; (m, 1H), 3.88 (br d, J=8.5 Hz, )pyrrolidine mobile phase: 15% 4H), 3.82 - 3.72 (m, 3H), 3.59 carbonyl](1- IPA:Heptane (1:1) /85% (br s, 4H), 3.45 - 3.19 (m, methyl-1H- CO2; 1H), 2.46 - 2.24 (m, 2H), 2.20 pyrazolyl)- Flow ions: 2 mL/min, - 2.07 (m, 1H), 1.97 (br s, 1,4- 150 bar, 40°C, 1H), 0.82 - 0.62 (m, 3H) dihydropyrimid wavelength: 220 nm (isomer inone 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 199 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.19 A difluorophenyl) d6) δ 8.48 (br d, J=7.0 Hz, A propyl][3-(5- 1H), 7.81 (br d, J=8.2 Hz, 539.4 fluoropyridin 1H), 7.65 (td, J=8.7, 2.7 Hz, rolidine- 7.7, >95.5% 1H), 7.50 - 7.32 (m, 1H), 7.17 1-carbonyl] Whelko, 5 x 50 cm, 10 - 6.84 (m, 2H), 6.62 (br s, hydroxy(1- micron; 1H), 6.12 - 5.82 (m, 1H), 3.87 methyl-1H- mobile phase: 10% IPA/90% (br d, J=7.3 Hz, 4H), 3.67 - pyrazolyl)- CO2; 3.22 (m, 5H), 2.36 - 2.13 (m, 1,4- Flow Conditions: 340 3H), 2.09 - 1.94 (m, 1H), 0.88 dihydropyrimid mL/min, 45°C, wavelength: - 0.58 (m, 3H) inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 200 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.19 A difluorophenyl) d6) δ 8.66 - 8.46 (m, 1H), 7.89 A propyl][3-(4- (br s, 1H), 7.18 (br s, 1H), 539.4 fluoropyridin 10.34, 97.5% 7.05 - 6.85 (m, 3H), 6.78 (br yl)pyrrolidine- Chiralpak IC, 4.6 x 250 mm, s, 1H), 6.34 - 6.08 (m, 1H), 1-carbonyl] 5 micron; 3.90 (br s, 4H), 3.77 - 3.23 hydroxy(1- mobile phase: 10% IPA: (m, 5H), 2.47 - 2.18 (m, 3H), methyl-1H- DEA /90% CO2; 2.17 - 1.98 (m, 1H), 0.89 - pyrazolyl)- Flow Conditions: 2 mL/min, 0.72 (m, 3H) 1,4- 150 bar, 40°C, dihydropyrimid wavelength: 254 nm (isomer inone 2) 201 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.19 A rophenyl) d6) δ 8.48 - 8.29 (m, 1H), 7.81 A propyl][3-(3- (br s, 1H), 7.73 - 7.57 (m, 539.4 fluoropyridin 1H), 7.46 - 7.29 (m, 1H), 7.10 yl)pyrrolidine- 8.5, >99.8% - 6.82 (m, 2H), 6.64 (br s, 1-carbonyl] Whelko, 5 x 50 cm, 10 1H), 6.12 - 5.87 (m, 1H), 3.87 hydroxy(1- micron; (br d, J=5.0 Hz, 4H), 3.80 - methyl-1H- mobile phase: 10% IPA/90% 3.50 (m, 4H), 3.47 - 3.22 (m, pyrazolyl)- CO2; 1H), 2.34 - 2.03 (m, 4H), 0.88 1,4- Flow Conditions: 340 - 0.66 (m, 3H) opyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 202 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.40 A difluorophenyl) d6) δ 8.68 - 8.42 (m, 1H), 7.94 A ](1- (br s, 1H), 7.45 - 7.15 (m, 553.2 ethyl-1H- 10.34, 97.5% 2H), 7.13 - 6.84 (m, 2H), 6.77 pyrazolyl) Chiralpak IC, 4.6 x 250 mm, (br s, 1H), 6.28 - 6.06 (m, [3-(4- 5 micron; 1H), 4.19 (br d, J=6.2 Hz, pyridin mobile phase: 10% IPA: 4H), 3.64 (br s, 3H), 3.45 - yl)pyrrolidine- DEA /90% CO2; 3.18 (m, 1H), 2.40 - 2.16 (m, 1-carbonyl] Flow Conditions: 2 mL/min, 3H), 2.15 - 1.97 (m, 1H), 1.55 hydroxy-1,4- 150 bar, 40°C, - 1.24 (m, 3H), 0.79 (br t, dihydropyrimid wavelength: 254 nm (isomer J=7.3 Hz, 3H) inone 2) 203 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.24 A difluorophenyl) d6) Shift 8.65 - 8.43 (m, 1H), A propyl][3-(4- 8.06 - 7.86 (m, 1H), 7.47 (br 539.2 fluoropyridin 10.34, 97.5% s, 1H), 7.31 (br dd, J=19.9, yl)pyrrolidine- Chiralpak IC, 4.6 x 250 mm, 10.6 Hz, 1H), 7.24 - 7.12 (m, 1-carbonyl] 5 micron; 1H), 6.98 - 6.77 (m, 2H), 6.55 hydroxy(1- mobile phase: 10% IPA: - 6.34 (m, 1H), 3.80 (br s, methyl-1H- DEA /90% CO2; 4H), 3.63 - 3.21 (m, 5H), 2.23 lyl)- Flow Conditions: 2 mL/min, (br d, J=7.1 Hz, 3H), 2.11 - 1,4- 150 bar, 40°C, 1.97 (m, 1H), 0.75 (br s, 3H) dihydropyrimid wavelength: 254 nm (isomer inone 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 204 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.44 A difluorophenyl) d6) δ 8.36 (br s, 1H), 7.67 (br A propyl][3-(3- s, 2H), 7.37 (br s, 1H), 7.19 - 556.4 fluoropyridin 6.83 (m, 3H), 4.05 - 3.55 (m, yl)pyrrolidine- 9.5, >99.8% 4H), 3.51 - 3.13 (m, 2H), 2.45 1-carbonyl] Whelko, 5 x 50 cm, 10 - 2.30 (m, 5H), 2.27 - 2.02 hydroxy(4- micron; (m, 2H), 0.80 (br d, J=6.7 Hz, methyl-1,3- mobile phase: 10% IPA/90% 3H) thiazolyl)- CO2; 1,4- Flow Conditions: 340 dihydropyrimid mL/min, 45°C, wavelength: ne 220 nm (isomer 2) 205 1-((S)(3,5- 1H NMR (500 MHz, DMSO- 1.44 A difluorophenyl) d6) δ 8.68 - 8.43 (m, 1H), 7.73 A )(3-(4- (br s, 1H), 7.23 - 7.13 (m, 556.4 fluoropyridin 10.34, 97.5% 2H), 7.12 - 6.97 (m, 3H), 3.99 Chiralpak IC, 4.6 x 250 mm, yl)pyrrolidine- - 3.43 (m, 5H), 3.17 (s, 1H), 1-carbonyl) 5 micron; 2.43 (br s, 5H), 2.32 - 2.17 hydroxy(4- mobile phase: 10% IPA: (m, 1H), 2.16 - 1.98 (m, 1H), thiazol- DEA /90% CO2; 0.83 (br t, J=7.2 Hz, 3H) 2-yl)pyrimidin- Flow Conditions: 2 mL/min, 4(1H)-one 150 bar, 40°C, wavelength: 254 nm (isomer Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 206 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.49 A rophenyl) d6) δ 8.60 - 8.38 (m, 1H), 7.83 A propyl][3-(5- - 7.57 (m, 2H), 7.51 - 7.27 555.8 fluoropyridin (m, 1H), 7.20 - 6.89 (m, 3H), yl)pyrrolidine- 8.4, >99.7% 3.61 (br s, 6H), 3.47 - 3.17 1-carbonyl] Whelko, 5 x 50 cm, 10 (m, 1H), 2.42 (br s, 5H), 2.31 y(4- micron; - 2.12 (m, 1H), 2.11 - 1.95 methyl-1,3- mobile phase: 10% IPA/90% (m, 1H), 0.81 (br t, J=7.2 Hz, thiazolyl)- CO2; 3H) 1,4- Flow Conditions: 340 dihydropyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 207 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.37 A difluorophenyl) d6) δ 7.55 (br d, J=11.6 Hz, A propyl] 1H), 7.30 - 7.17 (m, 2H), 7.08 567.2 y[3- 11.13, 97.1% - 6.93 (m, 3H), 6.92 - 6.85 (2- pak IC, 4.6 x 250 mm, (m, 1H), 6.78 (br s, 1H), 3.85 methoxyphenyl 5 micron; - 3.70 (m, 3H), 3.62 (br s, )pyrrolidine mobile phase: 15% 5H), 3.42 - 3.19 (m, 1H), 2.38 carbonyl](4- IPA:Heptane (1:1) /85% (br d, J=10.7 Hz, 5H), 2.26 methyl-1,3- CO2; (br dd, J=12.8, 7.0 Hz, 1H), thiazolyl)- Flow Conditions: 2 mL/min, 2.17 - 2.03 (m, 1H), 0.90 - 1,4- 150 bar, 40°C, 0.68 (m, 3H) dihydropyrimid wavelength: 220 nm (isomer inone 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 208 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.66 A difluorophenyl) d6) δ 7.69 (br d, J=8.9 Hz, A propyl][3-(2- 1H), 7.46 - 7.24 (m, 2H), 7.22 555.2 fluorophenyl)py 10.65, 99.5% - 7.12 (m, 2H), 7.11 - 6.85 rrolidine Chiralpak IF, 4.6 x 250 mm, (m, 3H), 3.65 (br d, J=10.0 carbonyl] 5 micron; Hz, 5H), 3.46 - 3.22 (m, 1H), hydroxy(4- mobile phase: 15% IPA/90% 2.46 - 2.31 (m, 5H), 2.22 (br methyl-1,3- CO2; s, 1H), 2.07 - 1.87 (m, 1H), thiazolyl)- Flow ions: 2.0 0.95 - 0.62 (m, 3H) 1,4- mL/min, 150 bar, 40°C, dihydropyrimid wavelength: 220 nm (Isomer inone 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 209 5- 1H NMR (500 MHz, DMSO- 1.60 A chloropyridin- d6) δ 8.65 - 8.42 (m, 1H), 7.84 A 2- (br s, 1H), 7.63 (br s, 1H), 572.0 yl)pyrrolidine- 7.49 - 7.15 (m, 1H), 7.13 - 1-carbonyl] 7.9, >99.7% 6.70 (m, 3H), 3.88 - 3.54 (m, [(1S)(3,5- Whelko, 5 x 50 cm, 10 5H), 3.37 - 3.12 (m, 1H), 2.39 difluorophenyl) micron; (br s, 5H), 2.27 - 2.11 (m, propyl] mobile phase: 20% IPA/80% 1H), 2.04 (br d, J=16.2 Hz, y(4- CO2; 1H), 0.80 (br d, J=5.8 Hz, methyl-1,3- Flow Conditions: 350 3H) thiazolyl)- mL/min, 30°C, wavelength: 1,4- 220 nm (isomer 2) dihydropyrimid inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 210 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.58 A rophenyl) d6) δ 8.54 - 8.34 (m, 1H), 7.91 A propyl][3- - 7.80 (m, 1H), 7.76 - 7.54 574.4 (3,5- (m, 1H), 7.21 - 6.76 (m, 3H), difluoropyridin- 3.96 - 3.57 (m, 5H), 3.52 - 2- 6.3, >99.7% 3.20 (m, 1H), 2.43 - 2.29 (m, yl)pyrrolidine- Whelko, 5 x 50 cm, 10 5H), 2.25 - 2.01 (m, 2H), 0.90 1-carbonyl] micron; - 0.64 (m, 3H) hydroxy(4- mobile phase: 20% IPA/80% methyl-1,3- CO2; thiazolyl)- Flow Conditions: 350 1,4- mL/min, 30°C, wavelength: dihydropyrimid 220 nm (isomer 2) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 211 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.65 A difluorophenyl) d6) δ 7.55 (br s, 1H), 7.34 (br A propyl][3-(4- d, J=5.8 Hz, 1H), 7.21 (br s, 555.4 phenyl)py 10.7, 90% 1H), 7.17 - 7.05 (m, 2H), 7.05 rrolidine Whelk-O 1 (R,R), 4.6 x 250 - 6.86 (m, 2H), 6.80 (br s, carbonyl] mm, 5 micron; 1H), 3.71 - 3.23 (m, 5H), 3.22 hydroxy(4- mobile phase: 15% - 3.04 (m, 1H), 2.38 (br s, methyl-1,3- IPA/85%CO2; 3H), 2.35 - 2.09 (m, 3H), 1.94 thiazolyl)- Flow Conditions: 2.0 - 1.76 (m, 1H), 0.92 - 0.72 1,4- mL/min, 150 bar, 40°C, (m, 3H) dihydropyrimid wavelength: 220 nm r inone 2) 212 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.28 A difluorophenyl) d6) δ 8.37 (br s, 1H), 8.09 - A propyl](1- 7.84 (m, 1H), 7.77 - 7.57 (m, 553.4 ethyl-1H- 1H), 7.37 (br s, 1H), 7.19 - pyrazolyl) 9.5, >99.8% 6.88 (m, 2H), 6.71 (br s, 1H), [3-(3- Whelko, 5 x 50 cm, 10 6.20 - 5.97 (m, 1H), 4.17 (br fluoropyridin micron; d, J=7.0 Hz, 4H), 3.94 - 3.61 yl)pyrrolidine- mobile phase: 10% % (m, 2H), 3.59 - 3.30 (m, 2H), 1-carbonyl] CO2; 2.36 - 2.00 (m, 4H), 1.35 (br hydroxy-1,4- Flow ions: 340 d, J=6.7 Hz, 3H), 0.92 - 0.66 dihydropyrimid mL/min, 45°C, wavelength: (m, 3H) inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 213 5-[3-(5- 1H NMR (500 MHz, DMSO- 1.47 A chloropyridin- d6) δ 8.64 - 8.44 (m, 1H), 7.98 A 2- - 7.69 (m, 2H), 7.52 - 7.23 569.0 yl)pyrrolidine- (m, 1H), 7.19 - 6.85 (m, 2H), 1-carbonyl] 7.9, >99.7% 6.75 (br s, 1H), 6.10 (br s, [(1S)(3,5- Whelko, 5 x 50 cm, 10 1H), 4.17 (br d, J=5.1 Hz, difluorophenyl) micron; 4H), 3.68 (br s, 3H), 3.47 - ](1- mobile phase: 20% IPA/80% 3.17 (m, 1H), 2.36 - 2.12 (m, 1H- CO2; 3H), 2.10 - 1.95 (m, 1H), 1.34 pyrazolyl) Flow Conditions: 350 (br s, 3H), 0.78 (br d, J=5.0 hydroxy-1,4- mL/min, 30°C, wavelength: Hz, 3H) dihydropyrimid 220 nm (isomer 2) inone Ex# Structure Name Chiral amine ediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 214 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.49 A 3-fluoropyridin- d6) δ 8.62 - 8.36 (m, 1H), 8.01 A 2- (br t, J=11.1 Hz, 1H), 7.83 (br 587.3 yl)pyrrolidine- s, 1H), 7.16 - 6.81 (m, 2H), 1-carbonyl] 6.75 - 6.47 (m, 1H), 6.16 - [(1S)(3,5- 7.6, >99.7% 5.67 (m, 1H), 4.14 (br s, 4H), rophenyl) Whelko, 5 x 50 cm, 10 3.94 - 3.54 (m, 2H), 3.53 - propyl](1- micron; 3.25 (m, 2H), 2.10 (s, 4H), ethyl-1H- mobile phase: 20% IPA/80% 1.33 (br d, J=5.5 Hz, 3H), pyrazolyl) CO2; 0.78 (br s, 3H) hydroxy-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 215 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.43 A difluorophenyl) d6) δ 8.46 (br s, 1H), 7.93 (br A propyl][3- d, J=19.8 Hz, 2H), 7.09 - 6.93 571.0 (3,5- (m, 2H), 6.76 (br s, 1H), 6.27 ropyridin- - 6.02 (m, 1H), 4.20 (br d, 2- 6.3, >99.7% J=6.7 Hz, 4H), 3.97 - 3.60 yl)pyrrolidine- Whelko, 5 x 50 cm, 10 (m, 2H), 3.59 - 3.22 (m, 2H), 1-carbonyl] micron; 2.40 - 2.02 (m, 4H), 1.37 (br (1-ethyl-1H- mobile phase: 20% IPA/80% d, J=5.5 Hz, 3H), 0.80 (br d, pyrazolyl) CO2; J=6.1 Hz, 3H) y-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 216 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.44 A difluorophenyl) d6) δ 8.48 (br s, 1H), 7.86 (br A propyl](1- s, 1H), 7.65 (br s, 1H), 7.50 - 552.9 ethyl-1H- 7.31 (m, 1H), 7.00 (br s, 2H), pyrazolyl) 7.7, >95.5% 6.63 (br s, 1H), 6.12 - 5.84 [3-(5- Whelko, 5 x 50 cm, 10 (m, 1H), 4.16 (br d, J=5.5 Hz, fluoropyridin ; 4H), 3.86 - 3.28 (m, 4H), 2.22 yl)pyrrolidine- mobile phase: 10% IPA/90% (br s, 3H), 2.11 - 1.94 (m, 1-carbonyl] CO2; 1H), 1.34 (br d, J=6.1 Hz, hydroxy-1,4- Flow Conditions: 340 3H), 1.01 - 0.69 (m, 3H) dihydropyrimid , 45°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine ediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 217 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.17 A difluorophenyl) d6) δ 8.44 (br s, 1H), 8.08 - A propyl][3- 7.82 (m, 2H), 7.53 (br s, 1H), 557.0 (3,5- 7.19 - 6.98 (m, 1H), 6.90 (br difluoropyridin- d, J=17.7 Hz, 2H), 3.85 (br s, 2- 6.3, >99.7% 4H), 3.46 (br s, 5H), 2.41 - yl)pyrrolidine- Whelko, 5 x 50 cm, 10 2.01 (m, 4H), 0.87 - 0.67 (m, 1-carbonyl] micron; 3H) hydroxy(1- mobile phase: 20% IPA/80% methyl-1H- CO2; pyrazolyl)- Flow ions: 350 1,4- mL/min, 30°C, wavelength: dihydropyrimid 220 nm (isomer 2) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 218 5- 1H NMR (500 MHz, DMSO- 1.22 A chloropyridin- d6) δ 8.71 - 8.41 (m, 1H), 7.99 A 2- (br s, 1H), 7.91 - 7.76 (m, 555.5 yl)pyrrolidine- 1H), 7.57 (br s, 1H), 7.47 - 1-carbonyl] 7.9, >99.7% 7.26 (m, 1H), 7.04 - 6.81 (m, [(1S)(3,5- Whelko, 5 x 50 cm, 10 3H), 3.86 (br s, 4H), 3.72 - difluorophenyl) micron; 3.25 (m, 5H), 2.40 - 2.14 (m, propyl] mobile phase: 20% IPA/80% 3H), 2.11 - 1.96 (m, 1H), 0.75 hydroxy(1- CO2; (br s, 3H) methyl-1H- Flow Conditions: 350 pyrazolyl)- mL/min, 30°C, wavelength: 1,4- 220 nm (isomer 2) opyrimid inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 219 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.09 A difluorophenyl) d6) δ 8.37 (br s, 1H), 7.98 (br A propyl][3-(3- s, 1H), 7.66 (br d, J=7.6 Hz, 539.0 fluoropyridin 1H), 7.56 (br s, 1H), 7.36 (br yl)pyrrolidine- 9.5, >99.8% s, 1H), 7.20 - 6.72 (m, 2H), 1-carbonyl] Whelko, 5 x 50 cm, 10 5.73 - 5.19 (m, 1H), 3.85 (br y(1- micron; s, 4H), 3.49 (br s, 5H), 2.36 - methyl-1H- mobile phase: 10% IPA/90% 2.00 (m, 4H), 0.89 - 0.65 (m, pyrazolyl)- CO2; 3H) 1,4- Flow Conditions: 340 dihydropyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 220 1-[(1S)(3,5- 1H NMR (500 MHz, DMSO- 1.10 A difluorophenyl) d6) δ 8.55 - 8.37 (m, 1H), 7.99 A propyl][3-(5- (br d, J=14.0 Hz, 1H), 7.76 - 539.1 fluoropyridin 7.49 (m, 2H), 7.50 - 7.27 (m, yl)pyrrolidine- 8.4, >99.7% 1H), 7.05 - 6.78 (m, 2H), 5.70 1-carbonyl] Whelko, 5 x 50 cm, 10 - 5.21 (m, 1H), 3.85 (br s, hydroxy(1- micron; 4H), 3.64 (br s, 4H), 3.46 - methyl-1H- mobile phase: 10% % 3.27 (m, 1H), 2.35 - 2.12 (m, pyrazolyl)- CO2; 3H), 2.09 - 1.96 (m, 1H), 0.82 1,4- Flow Conditions: 340 - 0.59 (m, 3H) dihydropyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 221 1-(2,6- 1H NMR (500 MHz, DMSO- 1.15 B diethylphenyl)- d6) δ 8.69 (br d, J=16.1 Hz, A 6-hydroxy 2H), 7.77 (br d, J=4.9 Hz, 491.0 [(propan 6.86, 99% 1H), 7.67 (br d, J=5.0 Hz, yloxy)methyl]- Chiralpak AS-H, 4.6 x 250 1H), 7.52 - 7.38 (m, 1H), 7.34 -[3-(pyridin mm, 5 micron; - 7.20 (m, 2H), 4.09 - 3.88 yl)pyrrolidine- mobile phase: 10% (m, 1H), 3.87 - 3.71 (m, 6H), 1-carbonyl]- MeOH/0.1%DEA/90% CO2; 3.66 - 3.35 (m, 1H), 3.33 - 1,4- Flow Conditions: 2.0 3.12 (m, 1H), 2.45 - 2.28 (m, opyrimid mL/min, 150 bar, 40°C, 4H), 2.25 - 2.10 (m, 1H), 2.09 inone wavelength: 220 nm (Isomer - 1.88 (m, 1H), 1.08 (br d, 1) J=7.3 Hz, 5H), 0.91 - 0.76 (m, 6H) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 222 5-[4-(6- achiral 1H NMR (500 MHz, DMSO- 1.49 C chloropyridin- d6) δ 8.42 - 8.19 (m, 1H), 7.87 A 3-yl)piperidine- - 7.58 (m, 1H), 7.53 - 7.36 539.2 1-carbonyl] (m, 1H), 7.29 (br s, 1H), 7.22 (2,6- - 7.01 (m, 2H), 4.70 - 4.44 diethylphenyl)- (m, 1H), 4.05 - 3.78 (m, 2H), 6-hydroxy 3.52 (br s, 4H), 2.42 - 2.14 an (m, 1H), 1.98 - 1.44 (m, 8H), yloxy)methyl]- 1.25 - 0.95 (m, 6H), 0.78 (br 3,4- s, 6H) dihydropyrimid 223 5-[3-(4- 1H NMR (500 MHz, DMSO- 1.44 B chlorophenyl)p d6) δ 7.35 (br s, 4H), 7.31 - A yrrolidine 7.15 (m, 3H), 7.03 (q, J=8.7 550.1 6.69, 99.8% carbonyl] Hz, 2H), 6.71 - 6.48 (m, 2H), (2,6- Chiralcel OJ-H 4.6 x 250 4.01 - 3.47 (m, 10H), 3.39 (br dimethoxyphen mm; mobile phase: 15% s, 1H), 2.39 - 2.13 (m, 2H) yl)(4- IPA/85% CO2; Flow fluorophenyl)- Conditions: 3.0 mL/min, 140 6-hydroxy-1,4- bar, 40°C, dihydropyrimid wavelength: 220 nm (Isomer inone 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 224 1-(2,6- 1H NMR (500 MHz, DMSO- 1.03 B dimethoxyphen d6) δ 8.48 (br s, 2H), 7.46 - A yl)(4- 7.31 (m, 2H), 7.24 (br dd, 517.3 fluorophenyl)- 6.86, 99% J=18.4, 8.6 Hz, 3H), 7.14 - 6-hydroxy[3- Chiralpak AS-H, 4.6 x 250 6.96 (m, 2H), 6.57 (br s, 2H), (pyridin mm, 5 micron; 3.98 - 3.49 (m, 10H), 3.43 (br rolidine- mobile phase: 10% s, 1H), 2.30 (br d, J=5.5 Hz, 1-carbonyl]- MeOH/0.1%DEA/90% CO2; 1H), 2.05 - 1.91 (m, 1H) 1,4- Flow Conditions: 2.0 dihydropyrimid , 150 bar, 40°C, inone wavelength: 220 nm r 225 1-(2,6- 1H NMR (500 MHz, DMSO- 1.25 A dimethoxyphen d6) δ 7.53 - 7.36 (m, 1H), 7.34 A yl)(4- - 7.12 (m, 6H), 7.11 - 6.93 534.2 fluorophenyl)- 10.65, 99.5% (m, 2H), 6.55 (br d, J=8.6 Hz, -[3-(2- Chiralpak IF, 4.6 x 250 mm, 2H), 4.02 - 3.45 (m, 10H), fluorophenyl)py 5 micron; 3.44 - 3.27 (m, 1H), 2.25 (br rrolidine mobile phase: 15% IPA/90% s, 1H), 2.08 - 1.94 (m, 1H) carbonyl] CO2; hydroxy-1,4- Flow ions: 2.0 dihydropyrimid mL/min, 150 bar, 40°C, inone wavelength: 220 nm (Isomer Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 226 2- 1H NMR (500 MHz, DMSO- 1.36 A (cyclopropylme d6) δ 7.41 (br s, 2H), 7.32 (br A thyl)(2,6- d, J=6.1 Hz, 1H), 7.26 - 7.11 494.3 dimethoxyphen 10.65, 99.5% (m, 2H), 6.92 - 6.73 (m, 2H), yl)[3-(2- Chiralpak IF, 4.6 x 250 mm, 3.75 (br d, J=18.8 Hz, 6H), fluorophenyl)py 5 micron; 3.62 (br d, J=7.0 Hz, 2H), rrolidine mobile phase: 15% IPA/90% 3.52 - 3.41 (m, 1H), 3.35 (br carbonyl] CO2; t, J=8.9 Hz, 2H), 2.27 (br s, hydroxy-1,4- Flow Conditions: 2.0 1H), 2.20 - 2.10 (m, 2H), 2.07 dihydropyrimid mL/min, 150 bar, 40°C, - 1.97 (m, 1H), 0.81 (br s, inone wavelength: 220 nm (Isomer 1H), 0.40 (br d, J=7.8 Hz, 1) 2H), 0.01 (br d, J=7.2 Hz, Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 227 5-[4-(6- achiral 1H NMR (500 MHz, DMSO- 1.28 B chloropyridin- d6) δ 8.27 (br s, 1H), 7.71 (br A 3-yl)piperidine- d, J=7.9 Hz, 1H), 7.55 - 7.38 525.3 1-carbonyl] (m, 2H), 6.83 (br d, J=8.5 Hz, (cyclopropylme 2H), 3.90 (br s, 6H), 3.73 (br 1-(2,6- s, 4H), 3.01 - 2.81 (m, 1H), dimethoxyphen 2.18 (br d, J=6.7 Hz, 2H), yl)hydroxy- 1.96 - 1.72 (m, 2H), 1.55 (br 1,4- s, 2H), 0.78 (br d, J=5.5 Hz, dihydropyrimid 1H), 0.40 (br d, J=7.3 Hz, inone 2H), 0.00 (br d, J=3.7 Hz, 228 5-[3-(4- 1H NMR (500 MHz, DMSO- 1.47 A chlorophenyl)p d6) δ 7.55 - 7.43 (m, 1H), 7.43 A yrrolidine - 7.31 (m, 4H), 6.96 - 6.78 510.2 carbonyl] 6.69, 99.8% (m, 2H), 3.86 - 3.63 (m, (cyclopropylme Chiralcel OJ-H 4.6 x 250 10H), 3.51 - 3.22 (m, 1H), thyl)(2,6- mm; mobile phase: 15% 2.28 (br s, 1H), 2.19 - 2.06 oxyphen IPA/85% CO2; Flow (m, 3H), 0.84 (br d, J=5.5 Hz, yl)hydroxy- Conditions: 3.0 mL/min, 140 1H), 0.51 - 0.33 (m, 2H), 0.01 1,4- bar, 40°C, (br d, J=9.4 Hz, 2H) dihydropyrimid wavelength: 220 nm (Isomer inone 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 229 5-[3-(2- 1H NMR (500 MHz, DMSO- 1.43 A chlorophenyl)p d6) δ 7.45 (br t, J=7.7 Hz, A yrrolidine 2H), 7.38 - 7.23 (m, 2H), 7.22 549.9 carbonyl] 8.29, 98.2% - 7.08 (m, 3H), 6.97 (q, J=9.1 (2,6- Chiralpak ID, 4.6 x 250 mm, Hz, 2H), 6.59 - 6.42 (m, 2H), dimethoxyphen 5 micron; 3.94 - 3.47 (m, 11H), 2.30 - yl)(4- mobile phase: 10% 2.14 (m, 1H), 2.04 - 1.92 (m, fluorophenyl)- MeOH/90% CO2; 1H) 6-hydroxy-1,4- Flow ions: 2.0 dihydropyrimid mL/min, 150 bar, 40°C, inone Wavelength (Isomer 2) 230 2- 1H NMR (500 MHz, DMSO- 1.02 B (cyclopropylme d6) δ 8.48 (br s, 2H), 7.55 - B thyl)(2,6- 7.40 (m, 1H), 7.33 (br d, 477.0 dimethoxyphen 6.86, 99% J=9.8 Hz, 2H), 6.91 - 6.74 yl)hydroxy- Chiralpak AS-H, 4.6 x 250 (m, 2H), 3.96 - 3.53 (m, 8H), -[3-(pyridin mm, 5 micron; 3.50 - 3.26 (m, 3H), 2.29 (br yl)pyrrolidine- mobile phase: 10% s, 1H), 2.15 (br t, J=7.3 Hz, onyl]- MeOH/0.1%DEA/90% CO2; 2H), 2.04 - 1.86 (m, 1H), 0.79 1,4- Flow Conditions: 2.0 (br s, 1H), 0.38 (br d, J=8.2 dihydropyrimid mL/min, 150 bar, 40°C, Hz, 2H), 0.00 (br s, 2H) inone ngth: 220 nm (Isomer Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 231 1-(2,6- 1H NMR (500 MHz, DMSO- 1.36 B dimethoxyphen d6) δ 7.47 - 7.34 (m, 2H), 7.28 A yl)[(4- (br d, J=5.7 Hz, 1H), 7.15 (br 548.4 fluorophenyl)m 10.65, 99.5% d, J=6.2 Hz, 2H), 7.07 - 6.91 ethyl][3-(2- Chiralpak IF, 4.6 x 250 mm, (m, 2H), 6.80 (br d, J=5.0 Hz, fluorophenyl)py 5 micron; 2H), 6.73 - 6.57 (m, 2H), 3.70 rrolidine mobile phase: 15% IPA/90% - 3.47 (m, 8H), 3.43 (br s, carbonyl] CO2; 4H), 3.36 - 3.26 (m, 1H), 2.22 hydroxy-1,4- Flow ions: 2.0 (br s, 1H), 2.05 - 1.92 (m, 1H) dihydropyrimid mL/min, 150 bar, 40°C, inone wavelength: 220 nm (Isomer 232 1-(2,6- 1H NMR (500 MHz, DMSO- 1.11 A dimethoxyphen d6) δ 8.28 (br d, J=9.2 Hz, A yl)[3-(4- 1H), 8.14 (br d, J=18.0 Hz, 531.1 fluorophenyl)py 9.93, 99% 1H), 7.53 - 7.30 (m, 3H), 7.28 rrolidine Whelk-O 1 (R,R), 4.6 x 250 - 7.04 (m, 3H), 6.73 - 6.49 carbonyl] mm, 5 micron; (m, 2H), 3.95 - 3.49 (m, hydroxy(5- mobile phase: 15% 10H), 3.47 - 3.22 (m, 1H), methylpyridin- IPA/85%CO2; 2.34 - 2.21 (m, 1H), 2.16 (br 3-yl)-1,4- Flow ions: 2.0 d, J=8.9 Hz, 4H) dihydropyrimid mL/min, 150 bar, 40°C, inone wavelength: 220 nm (isomer Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 233 1-(2,6- 1H NMR (500 MHz, DMSO- 1.05 A dimethoxyphen d6) δ 8.27 (br d, J=8.5 Hz, A yl)[3-(2- 1H), 8.13 (br d, J=15.6 Hz, 531.3 fluorophenyl)py 10.65, 99.5% 1H), 7.41 (br d, J=11.9 Hz, rrolidine Chiralpak IF, 4.6 x 250 mm, 2H), 7.34 - 7.25 (m, 1H), 7.24 yl] 5 micron; - 7.06 (m, 3H), 6.77 - 6.43 hydroxy(5- mobile phase: 15% % (m, 2H), 3.96 - 3.49 (m, methylpyridin- CO2; 10H), 3.47 - 3.24 (m, 1H), 3-yl)-1,4- Flow Conditions: 2.0 2.24 (br s, 1H), 2.20 - 2.10 dihydropyrimid mL/min, 150 bar, 40°C, (m, 3H), 2.08 - 1.95 (m, 1H) inone wavelength: 220 nm (Isomer Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 234 - 1H NMR (500 MHz, DMSO- 1.07 A dimethoxyphen d6) δ 8.28 (br d, J=8.5 Hz, A yl)hydroxy- 1H), 8.15 (br d, J=15.9 Hz, 543.4 -[3-(2- 10.40, 96.9% 1H), 7.42 (br d, J=11.3 Hz, methoxyphenyl Chiralpak IC, 4.6 x 250 mm, 1H), 7.34 - 7.11 (m, 3H), 7.08 )pyrrolidine 5 micron; - 6.95 (m, 1H), 6.95 - 6.82 carbonyl](5- mobile phase: 15% (m, 1H), 6.56 (br d, J=8.5 Hz, methylpyridin- IPA:Heptane (1:1) /85% 2H), 3.81 (br d, J=11.3 Hz, 3-yl)-1,4- CO2; 3H), 3.72 - 3.48 (m, 10H), dihydropyrimid Flow ions: 2 mL/min, 3.46 - 3.17 (m, 1H), 2.23 - inone 150 bar, 40°C, 2.07 (m, 4H), 1.99 (br d, wavelength: 220 nm (isomer J=9.2 Hz, 1H) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 235 5-[3-(3,5- 1H NMR (500 MHz, DMSO- 1.19 A difluoropyridin- d6) δ 8.49 (br d, J=6.2 Hz, A 2- 1H), 8.03 - 7.85 (m, 1H), 7.59 550.2 yl)pyrrolidine- (q, J=8.0 Hz, 1H), 7.31 - 7.19 onyl] (m, 1H), 7.19 - 6.96 (m, 2H), (2,6- 5.6, >99.7% 6.48 (br d, J=8.5 Hz, 2H), dimethoxyphen Whelko, 5 x 50 cm, 10 3.94 - 3.72 (m, 2H), 3.72 - yl)hydroxy- micron; 3.38 (m, 9H), 2.36 - 2.20 (m, 2-(6- mobile phase: 20% IPA/80% 1H), 2.17 (br d, J=9.7 Hz, methylpyridin- CO2; 4H) 2-yl)-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, ngth: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 236 1-(2,6- 1H NMR (500 MHz, DMSO- 1.26 A dimethoxyphen d6) δ 7.60 (q, J=8.2 Hz, 1H), A yl)[3-(2- 7.48 - 7.38 (m, 1H), 7.35 - 531.2 fluorophenyl)py 10.65, 99.5% 7.22 (m, 2H), 7.21 - 7.03 (m, rrolidine Chiralpak IF, 4.6 x 250 mm, 4H), 6.60 - 6.45 (m, 2H), 4.01 carbonyl] 5 micron; - 3.72 (m, 1H), 3.68 - 3.46 hydroxy(6- mobile phase: 15% % (m, 10H), 2.34 - 2.21 (m, methylpyridin- CO2; 1H), 2.21 - 2.15 (m, 3H), 2.09 2-yl)-1,4- Flow Conditions: 2.0 - 1.96 (m, 1H) dihydropyrimid , 150 bar, 40°C, inone wavelength: 220 nm (Isomer Ex# Structure Name Chiral amine ediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 237 2-{1-[2-(3- 1H NMR (500 MHz, DMSO- 1.35 A chlorophenyl)- d6) δ 7.82 (br d, J=6.7 Hz, A 1-(2,6- 1H), 7.73 - 7.56 (m, 2H), 7.45 557.2 dimethoxyphen 4.87, >99% (br s, 1H), 7.32 (br d, J=9.4 yl)hydroxy- Chiralpak IC, 4.6 x 250 mm, Hz, 1H), 7.27 - 7.06 (m, 4H), 4-oxo-1,4- 5 micron; 6.72 - 6.40 (m, 2H), 3.97 - dihydropyrimid mobile phase: 15% 3.60 (m, 10H), 3.57 (br s, ine 1% DEA /85% CO2; 1H), 2.42 - 2.25 (m, 1H), 2.13 carbonyl]pyrrol Flow Conditions: 2 mL/min, - 1.95 (m, 1H) idin 150 bar, 45°C, yl}benzonitrile wavelength: 220 nm (isomer Ex# Structure Name Chiral amine ediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 238 2-(3- 1H NMR (500 MHz, DMSO- 1.31 A chlorophenyl)- d6) δ 8.49 (br d, J=7.3 Hz, A -[3-(3,5- 1H), 7.92 (br s, 1H), 7.36 - 569.1 difluoropyridin- 6.97 (m, 5H), 6.64 - 6.41 (m, 2- 2H), 3.98 - 3.53 (m, 10H), yl)pyrrolidine- 5.6, >99.7% 3.51 - 3.12 (m, 1H), 2.30 - 1-carbonyl] Whelko, 5 x 50 cm, 10 2.06 (m, 1H), 1.90 (s, 1H) (2,6- micron; oxyphen mobile phase: 20% IPA/80% yl)hydroxy- CO2; 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 239 1-(2,6- 1H NMR (500 MHz, DMSO- 1.29 A dimethoxyphen d6) δ 8.07 (br dd, J=13.7, 4.3 A yl)[3-(2- Hz, 1H), 7.49 - 7.37 (m, 1H), 531.2 fluorophenyl)py 10.65, 99.5% 7.34 - 7.25 (m, 2H), 7.23 - rrolidine Chiralpak IF, 4.6 x 250 mm, 7.00 (m, 4H), 6.49 (br d, yl] 5 micron; J=8.6 Hz, 2H), 3.95 - 3.25 hydroxy(4- mobile phase: 15% IPA/90% (m, 11H), 2.32 - 2.17 (m, methylpyridin- CO2; 4H), 2.11 - 1.95 (m, 1H) 2-yl)-1,4- Flow Conditions: 2.0 dihydropyrimid mL/min, 150 bar, 40°C, inone wavelength: 220 nm (Isomer Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 240 2-{1-[1-(2,6- 1H NMR (500 MHz, DMSO- 1.31 A dimethoxyphen d6) δ 8.49 (br d, J=7.3 Hz, A yl)hydroxy- 1H), 7.92 (br s, 1H), 7.35 - 569.1 2-(4- 4.87, >99% 7.01 (m, 5H), 6.64 - 6.40 (m, methylpyridin- pak IC, 4.6 x 250 mm, 2H), 3.96 - 3.32 (m, 10H), 2-yl)oxo- 5 micron; 3.30 - 3.12 (m, 1H), 2.30 - 1,4- mobile phase: 15% 2.06 (m, 1H), 2.00 - 1.68 (m, dihydropyrimid IPA/0.1% DEA /85% CO2; 1H) ine Flow Conditions: 2 , carbonyl]pyrrol 150 bar, 45°C, idin wavelength: 220 nm (isomer yl}benzonitrile 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 241 5-[3-(2,6- 1H NMR (500 MHz, DMSO- 1.45 A difluorophenyl) d6) δ 7.45 - 7.33 (m, 1H), 7.22 A pyrrolidine (q, J=8.4 Hz, 1H), 7.15 - 6.94 548.2 carbonyl] (m, 6H), 6.69 - 6.49 (m, 2H), (2,6- 5.4, >99.7% 3.91 - 3.51 (m, 11H), 2.32 - dimethoxyphen , 5 x 50 cm, 10 2.08 (m, 5H) yl)hydroxy- micron; 2-(3- mobile phase: 20% IPA/80% methylphenyl)- CO2; 1,4- Flow Conditions: 350 dihydropyrimid , 30°C, wavelength: inone 220 nm (isomer 1) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 242 1-(2,6- 1H NMR (500 MHz, DMSO- 1.40 A dimethoxyphen d6) δ 7.83 (br d, J=7.3 Hz, A yl)hydroxy- 1H), 7.75 - 7.55 (m, 2H), 7.51 537.1 2-(3- 4.87, >99% - 7.40 (m, 1H), 7.20 (q, J=9.0 methylphenyl)- Hz, 1H), 7.16 - 6.93 (m, 4H), Chiralpak IC, 4.6 x 250 mm, 4-oxo-1,4- 5 micron; 6.56 (br d, J=4.9 Hz, 2H), dihydropyrimid mobile phase: 15% 3.95 - 3.43 (m, 10H), 3.42 - ine IPA/0.1% DEA /85% CO2; 3.12 (m, 1H), 2.35 (br d, carbonyl]pyrrol Flow Conditions: 2 mL/min, J=4.3 Hz, 1H), 2.24 - 2.11 idin 150 bar, 45°C, (m, 3H), 2.11 - 1.99 (m, 1H) yl}benzonitrile wavelength: 220 nm (isomer Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 243 2-{1-[2-(5- 1H NMR (500 MHz, DMSO- 1.21 A chloropyridin- d6) δ 8.52 (br d, J=14.6 Hz, A 3-yl)(2,6- 1H), 8.37 - 8.21 (m, 1H), 7.82 558.3 dimethoxyphen 4.87, >99% (br t, J=6.7 Hz, 1H), 7.74 - hydroxy- Chiralpak IC, 4.6 x 250 mm, 7.58 (m, 3H), 7.51 - 7.37 (m, 4-oxo-1,4- 5 micron; 1H), 7.33 - 7.10 (m, 1H), 6.75 dihydropyrimid mobile phase: 15% - 6.44 (m, 2H), 3.99 - 3.75 ine IPA/0.1% DEA /85% CO2; (m, 1H), 3.75 - 3.39 (m, carbonyl]pyrrol Flow Conditions: 2 mL/min, 10H), 2.43 - 2.21 (m, 1H), idin 150 bar, 45°C, 2.17 - 1.96 (m, 1H) yl}benzonitrile wavelength: 220 nm (isomer Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 244 3,5- 1H NMR (500 MHz, DMSO- 1.34 A difluoropyridin- d6) δ 8.48 (br s, 1H), 8.00 - A 2- 7.85 (m, 1H), 7.26 - 6.85 (m, 549.4 yl)pyrrolidine- 5H), 6.64 - 6.39 (m, 2H), 4.08 1-carbonyl] - 3.80 (m, 1H), 3.79 - 3.32 (2,6- 5.6, >99.7% (m, 10H), 2.29 - 2.06 (m, dimethoxyphen Whelko, 5 x 50 cm, 10 4H), 1.95 - 1.68 (m, 1H) hydroxy- micron; 2-(3- mobile phase: 20% IPA/80% methylphenyl)- CO2; 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 245 1-(2,6- 1H NMR (500 MHz, DMSO- 1.16 A dimethoxyphen d6) δ 8.41 (br s, 1H), 7.80 - A yl)[3-(3- 7.63 (m, 1H), 7.38 (br d, 547.3 fluoropyridin J=3.7 Hz, 1H), 7.20 - 6.98 yl)pyrrolidine- 8.5, >99.8% (m, 2H), 6.91 - 6.64 (m, 3H), 1-carbonyl] Whelko, 5 x 50 cm, 10 6.63 - 6.40 (m, 2H), 3.94 - hydroxy(3- micron; 3.39 (m, 14H), 2.50 - 2.31 (m, methoxyphenyl mobile phase: 10% % 1H), 2.29 - 2.06 (m, 1H) )-1,4- CO2; dihydropyrimid Flow Conditions: 340 inone , 45°C, wavelength: 220 nm (isomer 1) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 246 5-[3-(3,5- 1H NMR (500 MHz, DMSO- 1.29 A difluoropyridin- d6) δ 8.43 (br s, 1H), 7.82 (br A 2- t, J=9.0 Hz, 1H), 7.28 - 7.04 565.2 yl)pyrrolidine- (m, 2H), 6.83 (br s, 2H), 6.72 1-carbonyl] (br d, J=11.6 Hz, 1H), 6.56 (2,6- 5.6, >99.7% (br s, 2H), 4.09 - 3.38 (m, dimethoxyphen Whelko, 5 x 50 cm, 10 14H), 2.36 - 2.18 (m, 1H), yl)hydroxy- micron; 2.19 - 2.04 (m, 1H) 2-(3- mobile phase: 20% % methoxyphenyl CO2; )-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 247 2-(5- 1H NMR (500 MHz, DMSO- 1.29 A chloropyridin- d6) δ 8.52 (br d, J=14.0 Hz, A 3-yl)[3-(2,6- 1H), 8.39 - 8.21 (m, 1H), 7.79 569.3 difluorophenyl) - 7.60 (m, 1H), 7.35 (br d, pyrrolidine 5.4, >99.7% J=6.4 Hz, 1H), 7.25 (q, J=8.9 yl] Whelko, 5 x 50 cm, 10 Hz, 1H), 7.09 (br d, J=7.3 Hz, (2,6- micron; 2H), 6.77 - 6.51 (m, 2H), 3.98 dimethoxyphen mobile phase: 20% IPA/80% - 3.22 (m, 11H), 2.21 (br s, yl)hydroxy- CO2; 2H) 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 248 5-[3-(2,4- 1H NMR (500 MHz, DMSO- 1.11 A difluorophenyl) d6) δ 7.58 - 7.36 (m, 3H), 7.29 A pyrrolidine - 7.16 (m, 1H), 7.04 (br d, 538.2 carbonyl] J=6.0 Hz, 1H), 6.92 - 6.72 (2,6- (m, 3H), 3.95 - 3.78 (m, 1H), dimethoxyphen 2.53, 92.7% 3.76 - 3.48 (m, 13H), 2.24 (br yl)hydroxy- Chiralpak IC, 4.6 x 250 mm, s, 1H), 2.10 - 1.94 (m, 1H) 2-(1-methyl- 5 micron; 1H-pyrazol mobile phase: 10% IPA/90% yl)-1,4- CO2; dihydropyrimid Flow Conditions: 3 mL/min, inone 140 bar, 45°C, ngth: 200-400 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho y d range 249 5-[3-(2,6- 1H NMR (500 MHz, DMSO- 1.19 A difluorophenyl) d6) δ 7.60 - 7.42 (m, 2H), 7.36 A pyrrolidine (br d, J=5.0 Hz, 1H), 7.09 (br 538.2 carbonyl] d, J=9.9 Hz, 2H), 6.94 - 6.70 (2,6- 5.4, >99.7% (m, 3H), 3.94 - 3.39 (m, dimethoxyphen Whelko, 5 x 50 cm, 10 14H), 2.36 - 2.09 (m, 2H) yl)hydroxy- micron; 2-(1-methyl- mobile phase: 20% IPA/80% 1H-pyrazol CO2; yl)-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 250 5-[3-(2,4- 1H NMR (500 MHz, DMSO- 1.06 A rophenyl) d6) δ 7.56 (br s, 1H), 7.50 - A pyrrolidine 7.31 (m, 2H), 7.31 - 7.17 (m, 538.1 carbonyl] 1H), 7.04 (s, 1H), 6.80 - 6.64 (2,6- (m, 2H), 5.87 (br s, 1H), 3.80 dimethoxyphen 2.53, 92.7% - 3.51 (m, 13H), 3.49 - 3.22 yl)hydroxy- Chiralpak IC, 4.6 x 250 mm, (m, 1H), 2.33 - 2.21 (m, 1H), 2-(1-methyl- 5 micron; 2.10 - 1.94 (m, 1H) 1H-pyrazol mobile phase: 10% IPA/90% yl)-1,4- CO2; dihydropyrimid Flow Conditions: 3 mL/min, inone 140 bar, 45°C, wavelength: 200-400 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 251 5-[3-(2,6- 1H NMR (500 MHz, DMSO- 1.26 A difluorophenyl) d6) δ 7.56 - 7.21 (m, 3H), 7.19 A pyrrolidine - 6.95 (m, 2H), 6.77 - 6.48 537.9 carbonyl] (m, 2H), 5.82 (br s, 1H), 3.87 (2,6- 5.4, >99.7% - 3.25 (m, 14H), 2.29 - 2.05 dimethoxyphen Whelko, 5 x 50 cm, 10 (m, 2H) yl)hydroxy- micron; 2-(1-methyl- mobile phase: 20% % 1H-pyrazol CO2; yl)-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 252 5-[3-(2,6- 1H NMR (500 MHz, DMSO- 1.20 A difluorophenyl) d6) δ 8.33 - 8.12 (m, 1H), 7.59 A pyrrolidine - 7.30 (m, 2H), 7.22 (q, J=8.8 549.3 carbonyl] Hz, 1H), 7.16 - 6.98 (m, 3H), (2,6- 5.4, >99.7% 6.68 - 6.45 (m, 2H), 3.91 - oxyphen Whelko, 5 x 50 cm, 10 3.49 (m, 10H), 3.47 - 3.26 (m, yl)hydroxy- micron; 1H), 2.42 - 2.29 (m, 3H), 2.26 2-(6- mobile phase: 20% IPA/80% - 2.11 (m, 2H) methylpyridin- CO2; 3-yl)-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 253 5-[3-(2,4- 1H NMR (500 MHz, DMSO- 1.17 A difluorophenyl) d6) δ 8.24 (br d, J=13.7 Hz, A pyrrolidine 1H), 7.46 (br dd, , 7.4 548.9 carbonyl] Hz, 2H), 7.29 - 7.15 (m, 2H), (2,6- 7.14 - 6.93 (m, 2H), 6.72 - dimethoxyphen 2.53, 92.7% 6.49 (m, 2H), 3.94 - 3.49 (m, yl)hydroxy- Chiralpak IC, 4.6 x 250 mm, 10H), 3.46 - 3.26 (m, 1H), 2-(6- 5 micron; 2.41 - 2.32 (m, 3H), 2.23 (br methylpyridin- mobile phase: 10% % s, 1H), 2.06 - 1.92 (m, 1H) 3-yl)-1,4- CO2; dihydropyrimid Flow Conditions: 3 mL/min, inone 140 bar, 45°C, wavelength: 200-400 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 254 5-[3-(2,4- 1H NMR (500 MHz, DMSO- 1.08 A difluorophenyl) d6) δ 8.38 - 8.16 (m, 1H), 7.56 A pyrrolidine - 7.34 (m, 1H), 7.33 - 7.16 549.2 carbonyl] (m, 2H), 7.14 - 6.99 (m, 2H), (2,6- 6.93 (br d, J=10.4 Hz, 1H), dimethoxyphen 2.53, 92.7% 6.69 - 6.52 (m, 2H), 3.93 - yl)hydroxy- Chiralpak IC, 4.6 x 250 mm, 3.52 (m, 10H), 3.34 (br d, 2-(2- 5 ; J=5.9 Hz, 1H), 2.40 - 2.31 methylpyridin- mobile phase: 10% IPA/90% (m, 3H), 2.27 (br s, 1H), 2.08 4-yl)-1,4- CO2; - 1.94 (m, 1H) dihydropyrimid Flow ions: 3 mL/min, inone 140 bar, 45°C, wavelength: 200-400 nm (isomer 1) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 255 1-(2,6- 1H NMR (500 MHz, DMSO- 1.20 A dimethoxyphen d6) δ 8.40 (br s, 1H), 7.71 (br A yl)(4-fluoro- t, J=9.1 Hz, 1H), 7.49 - 7.35 549.2 3- (m, 1H), 7.32 - 7.15 (m, 2H), methylphenyl)- 8.5, >99.8% 7.13 - 6.92 (m, 2H), 6.61 (br -[3-(3- Whelko, 5 x 50 cm, 10 s, 2H), 3.96 - 3.40 (m, 11H), fluoropyridin ; 2.28 (br s, 1H), 2.21 - 2.04 yl)pyrrolidine- mobile phase: 10% IPA/90% (m, 4H) 1-carbonyl] CO2; hydroxy-1,4- Flow Conditions: 340 dihydropyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 256 3,5- 1H NMR (500 MHz, DMSO- 1.38 A difluoropyridin- d6) δ 8.47 (br s, 1H), 7.91 (br A 2- t, J=9.3 Hz, 1H), 7.37 - 7.16 567.3 yl)pyrrolidine- (m, 2H), 7.13 - 6.94 (m, 2H), 1-carbonyl] 6.61 (br d, J=4.8 Hz, 2H), (2,6- 5.6, >99.7% 4.04 - 3.55 (m, 10H), 3.55 - dimethoxyphen Whelko, 5 x 50 cm, 10 3.40 (m, 1H), 2.35 - 2.23 (m, yl)(4-fluoro- micron; 1H), 2.11 (br s, 4H) 3- mobile phase: 20% % methylphenyl)- CO2; 6-hydroxy-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 257 5-[3-(2,6- 1H NMR (500 MHz, DMSO- 1.05 A difluorophenyl) d6) δ 8.25 (br dd, , 4.2 A pyrrolidine Hz, 1H), 7.46 - 7.30 (m, 1H), 549.1 carbonyl] 7.26 - 7.16 (m, 1H), 7.14 - (2,6- 5.4, >99.7% 6.97 (m, 3H), 6.96 - 6.82 (m, dimethoxyphen Whelko, 5 x 50 cm, 10 1H), 6.64 - 6.42 (m, 2H), 4.15 yl)hydroxy- micron; - 3.47 (m, 10H), 3.46 - 3.25 2-(2- mobile phase: 20% % (m, 1H), 2.41 - 2.27 (m, 4H), methylpyridin- CO2; 2.26 - 2.13 (m, 1H) 4-yl)-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 258 1-(2,6- 1H NMR (500 MHz, DMSO- 1.19 A diethylphenyl)- d6) δ 8.45 (br d, J=18.3 Hz, A -[3-(3,5- 1H), 8.01 - 7.83 (m, 1H), 7.53 535.3 difluoropyridin- (br d, J=6.2 Hz, 1H), 7.38 (q, 2- J=7.9 Hz, 1H), 7.24 - 7.12 yl)pyrrolidine- 5.6, >99.7% (m, 2H), 5.56 (br d, J=4.5 Hz, 1-carbonyl] Whelko, 5 x 50 cm, 10 1H), 3.97 - 3.61 (m, 7H), 3.57 hydroxy(1- ; - 3.25 (m, 1H), 2.33 - 2.07 methyl-1H- mobile phase: 20% IPA/80% (m, 6H), 1.09 - 0.88 (m, 6H) pyrazolyl)- CO2; 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, ngth: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 259 5-chloro- 1H NMR (500 MHz, DMSO- 1.03 A 3-fluoropyridin- d6) δ 8.47 (br d, J=10.4 Hz, A 2- 1H), 8.17 - 7.93 (m, 1H), 7.63 555.1 rolidine- - 7.47 (m, 1H), 7.35 (br d, 1-carbonyl] J=6.9 Hz, 1H), 6.81 - 6.56 (2,6- 6.8, >99.7% (m, 2H), 6.03 - 5.76 (m, 1H), dimethoxyphen Whelko, 5 x 50 cm, 10 3.62 (d, J=5456.4 Hz, 13H), yl)hydroxy- micron; 3.39 - 3.14 (m, 1H), 2.27 (br 2-(1-methyl- mobile phase: 20% IPA/80% d, J=7.2 Hz, 1H), 2.11 (br d, 1H-pyrazol CO2; J=12.9 Hz, 1H) yl)-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine ediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 260 2-(5- 1H NMR (500 MHz, DMSO- 1.26 A chloropyridin- d6) δ 8.55 (br d, J=9.5 Hz, A 3-yl)[3-(2,4- 1H), 8.31 (br d, J=16.1 Hz, 569.4 difluorophenyl) 1H), 7.70 (br d, J=13.3 Hz, idine 1H), 7.54 - 7.39 (m, 1H), 7.33 carbonyl] 2.53, 92.7% - 7.15 (m, 2H), 7.09 - 6.97 (2,6- Chiralpak IC, 4.6 x 250 mm, (m, 1H), 6.74 - 6.54 (m, 2H), dimethoxyphen 5 micron; 4.06 - 3.44 (m, 10H), 3.43 - yl)hydroxy- mobile phase: 10% IPA/90% 3.23 (m, 1H), 2.37 - 2.15 (m, 1,4- CO2; 1H), 2.10 - 1.89 (m, 1H) dihydropyrimid Flow Conditions: 3 mL/min, inone 140 bar, 45°C, wavelength: 200-400 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 261 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.26 A 3-fluoropyridin- d6) δ 8.47 (br s, 1H), 8.02 (br A 2- d, J=9.8 Hz, 1H), 7.34 - 7.07 581.1 yl)pyrrolidine- (m, 2H), 6.84 (br s, 2H), 6.74 1-carbonyl] (br d, J=12.3 Hz, 1H), 6.58 (2,6- 6.8, >99.7% (br d, J=4.5 Hz, 2H), 4.03 - dimethoxyphen , 5 x 50 cm, 10 3.41 (m, 13H), 3.38 - 3.22 (m, yl)hydroxy- micron; 1H), 2.27 (br d, J=7.3 Hz, 2-(3- mobile phase: 20% IPA/80% 1H), 2.18 - 2.02 (m, 1H) methoxyphenyl CO2; )-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine ediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 262 5-[3-(2,4- 1H NMR (500 MHz, DMSO- 1.22 A difluorophenyl) d6) δ 8.09 (br dd, J=11.7, 4.2 A pyrrolidine Hz, 1H), 7.55 - 7.39 (m, 1H), 549.2 carbonyl] 7.30 (br d, J=5.2 Hz, 1H), (2,6- 7.26 - 7.09 (m, 3H), 7.04 (br dimethoxyphen 2.53, 92.7% t, J=8.3 Hz, 1H), 6.64 - 6.45 yl)hydroxy- Chiralpak IC, 4.6 x 250 mm, (m, 2H), 4.15 - 3.43 (m, 2-(4- 5 micron; 10H), 3.41 - 3.26 (m, 1H), methylpyridin- mobile phase: 10% IPA/90% 2.36 - 2.16 (m, 4H), 2.11 - 2-yl)-1,4- CO2; 1.94 (m, 1H) dihydropyrimid Flow Conditions: 3 mL/min, inone 140 bar, 45°C, wavelength: 200-400 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 263 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.68 A 3-fluoropyridin- d6) δ 8.49 (br s, 1H), 8.06 (br B 2- d, J=9.3 Hz, 1H), 7.32 - 7.14 565.2 yl)pyrrolidine- (m, 1H), 7.12 - 7.03 (m, 3H), onyl] 7.03 - 6.90 (m, 1H), 6.55 (br (2,6- 6.8, >99.7% d, J=4.4 Hz, 2H), 3.97 - 3.54 dimethoxyphen Whelko, 5 x 50 cm, 10 (m, 10H), 3.53 - 3.22 (m, yl)hydroxy- micron; 1H), 2.36 - 2.21 (m, 1H), 2.21 2-(3- mobile phase: 20% IPA/80% - 2.03 (m, 4H) methylphenyl)- CO2; 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 264 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.40 A 3-fluoropyridin- d6) δ 8.47 (br s, 1H), 8.03 (br A 2- d, J=9.5 Hz, 1H), 7.37 (br s, 585.1 yl)pyrrolidine- 1H), 7.31 - 7.11 (m, 4H), 6.60 1-carbonyl] (br d, J=4.2 Hz, 2H), 4.03 - (3- 6.8, >99.7% 3.35 (m, 11H), 2.27 (br s, chlorophenyl)- Whelko, 5 x 50 cm, 10 1H), 2.19 - 2.05 (m, 1H) 1-(2,6- micron; dimethoxyphen mobile phase: 20% IPA/80% yl)hydroxy- CO2; 1,4- Flow ions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine ediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 265 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.30 A ropyridin- d6) δ 8.48 (br s, 1H), 8.04 (br A 2- d, J=9.0 Hz, 1H), 7.37 - 7.15 568.9 yl)pyrrolidine- (m, 3H), 7.12 - 6.95 (m, 2H), 1-carbonyl] 6.68 - 6.47 (m, 2H), 4.01 - (2,6- 6.8, >99.7% 3.27 (m, 11H), 2.25 (br d, dimethoxyphen Whelko, 5 x 50 cm, 10 J=12.1 Hz, 1H), 2.18 - 2.01 yl)(4- micron; (m, 1H) fluorophenyl)- mobile phase: 20% IPA/80% 6-hydroxy-1,4- CO2; dihydropyrimid Flow Conditions: 350 inone mL/min, 27°C, wavelength: 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 266 5-[3-(2,4- 1H NMR (600 MHz, DMSO- 1.19 A difluorophenyl) d6) δ 7.59 - 7.38 (m, 2H), 7.33 A pyrrolidine - 7.16 (m, 2H), 7.11 - 6.99 555.2 carbonyl] (m, 1H), 6.72 - 6.55 (m, 2H), (2,6- 3.88 - 3.69 (m, 1H), 3.67 - dimethoxyphen 2.53, 92.7% 3.48 (m, 10H), 2.45 - 2.36 (m, yl)hydroxy- Chiralpak IC, 4.6 x 250 mm, 3H), 2.30 - 2.20 (m, 1H), 2.03 2-(2-methyl- 5 micron; - 1.94 (m, 1H) 1,3-thiazol mobile phase: 10% IPA/90% 4- CO2; dihydropyrimid Flow Conditions: 3 mL/min, ne 140 bar, 45°C, wavelength: 200-400 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 267 - 1H NMR (500 MHz, DMSO- 1.27 A diethylphenyl)- d6) δ 7.52 (br d, J=14.6 Hz, A 2,6- 1H), 7.35 (br dd, J=14.2, 7.3 534.0 difluorophenyl) Hz, 2H), 7.17 (br dd, J=18.5, pyrrolidine 5.4, >99.7% 7.6 Hz, 2H), 7.14 - 7.02 (m, carbonyl] Whelko, 5 x 50 cm, 10 2H), 5.58 (br d, J=11.6 Hz, hydroxy(1- micron; 1H), 3.93 - 3.63 (m, 7H), 3.62 methyl-1H- mobile phase: 20% IPA/80% - 3.31 (m, 1H), 2.35 - 2.13 pyrazolyl)- CO2; (m, 6H), 1.13 - 0.80 (m, 6H) 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 268 1-(2,6- 1H NMR (500 MHz, DMSO- 1.29 A diethylphenyl)- d6) δ 7.53 (br d, J=7.9 Hz, A -[3-(2- 1H), 7.43 - 7.25 (m, 2H), 7.23 516.0 fluorophenyl)py 10.65, 99.5% - 7.09 (m, 5H), 5.56 (br s, rrolidine Chiralpak IF, 4.6 x 250 mm, 1H), 3.95 - 3.55 (m, 7H), 3.52 carbonyl] 5 micron; - 3.30 (m, 1H), 2.33 - 2.14 hydroxy(1- mobile phase: 15% IPA/90% (m, 5H), 2.10 - 1.92 (m, 1H), methyl-1H- CO2; 1.11 - 0.77 (m, 6H) pyrazolyl)- Flow ions: 2.0 1,4- mL/min, 150 bar, 40°C, dihydropyrimid wavelength: 220 nm r inone 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 269 5-[3-(2,4- 1H NMR (500 MHz, DMSO- 1.21 A difluorophenyl) d6) δ 7.61 (br s, 1H), 7.49 - A pyrrolidine 7.39 (m, 1H), 7.39 - 7.30 (m, 552.2 yl] 1H), 7.27 - 7.15 (m, 1H), 7.04 (2,6- (br s, 1H), 6.82 - 6.59 (m, dimethoxyphen 2.53, 92.7% 2H), 6.07 (br s, 1H), 4.13 - yl)(1-ethyl- Chiralpak IC, 4.6 x 250 mm, 3.78 (m, 4H), 3.76 - 3.42 (m, 1H-pyrazol 5 micron; 8H), 3.40 - 3.25 (m, 1H), 2.32 yl)hydroxy- mobile phase: 10% IPA/90% - 2.18 (m, 1H), 2.09 - 1.93 1,4- CO2; (m, 1H), 1.14 (q, J=6.6 Hz, dihydropyrimid Flow Conditions: 3 mL/min, 3H) inone 140 bar, 45°C, ngth: 200-400 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 270 5-[3-(2,6- 1H NMR (500 MHz, DMSO- 1.09 A difluorophenyl) d6) δ 7.54 - 7.42 (m, 1H), 7.40 A pyrrolidine - 7.31 (m, 1H), 7.29 - 7.18 555.0 carbonyl] (m, 1H), 7.15 - 7.01 (m, 2H), (2,6- 5.4, >99.7% 6.68 - 6.53 (m, 2H), 4.08 - dimethoxyphen Whelko, 5 x 50 cm, 10 3.77 (m, 1H), 3.73 - 3.42 (m, hydroxy- micron; 10H), 2.45 - 2.35 (m, 3H), 2-(2-methyl- mobile phase: 20% IPA/80% 2.28 - 2.10 (m, 2H) 1,3-thiazol CO2; yl)-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: ne 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 271 5-[3-(2,6- 1H NMR (500 MHz, DMSO- 1.17 A difluorophenyl) d6) δ 7.46 (br d, J=8.9 Hz, A pyrrolidine 1H), 7.43 - 7.30 (m, 2H), 7.18 555.0 carbonyl] - 6.99 (m, 2H), 6.83 - 6.64 (2,6- 5.4, >99.7% (m, 2H), 4.09 - 3.85 (m, 1H), dimethoxyphen Whelko, 5 x 50 cm, 10 3.73 - 3.44 (m, 10H), 2.29 - yl)hydroxy- ; 2.17 (m, 2H), 2.14 - 2.06 (m, 2-(4-methyl- mobile phase: 20% IPA/80% 3H) 1,3-thiazol CO2; yl)-1,4- Flow Conditions: 350 dihydropyrimid , 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine ediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 272 1-(2,6- 1H NMR (500 MHz, DMSO- 1.36 A diethylphenyl)- d6) δ 7.75 - 7.65 (m, 1H), 7.53 A -[3-(4- - 7.44 (m, 2H), 7.40 - 7.25 516.3 fluorophenyl)py 9.93, 99% (m, 2H), 7.21 - 7.04 (m, 3H), rrolidine Whelk-O 1 (R,R), 4.6 x 250 5.75 - 5.55 (m, 1H), 4.02 - carbonyl] mm, 5 micron; 3.41 (m, 8H), 2.34 - 2.15 (m, hydroxy(1- mobile phase: 15% 6H), 1.09 - 0.86 (m, 6H) -1H- IPA/85%CO2; pyrazolyl)- Flow Conditions: 2.0 1,4- mL/min, 150 bar, 40°C, dihydropyrimid wavelength: 220 nm (isomer inone 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 273 2,6- 1H NMR (500 MHz, DMSO- 1.12 A difluorophenyl) d6) δ 8.04 (br d, J=16.0 Hz, A pyrrolidine 1H), 7.43 - 7.31 (m, 1H), 7.23 565.3 carbonyl] - 7.04 (m, 3H), 6.93 (br d, (2,6- 5.4, >99.7% J=19.6 Hz, 1H), 6.80 (br d, dimethoxyphen Whelko, 5 x 50 cm, 10 J=7.2 Hz, 1H), 6.49 (br d, yl)hydroxy- micron; J=7.1 Hz, 2H), 3.98 - 3.46 2-(4- mobile phase: 20% IPA/80% (m, 14H), 2.34 - 2.10 (m, 2H) methoxypyridin CO2; yl)-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: ne 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 274 5-[3-(2,6- 1H NMR (600 MHz, DMSO- 1.12 A difluorophenyl) d6) δ 8.23 - 8.03 (m, 1H), 7.65 A pyrrolidine - 7.50 (m, 1H), 7.46 - 7.31 548.9 carbonyl] (m, 2H), 7.27 - 7.15 (m, 1H), (2,6- 5.4, >99.7% 7.09 (q, J=8.1 Hz, 2H), 6.68 - dimethoxyphen , 5 x 50 cm, 10 6.47 (m, 2H), 3.82 - 3.51 (m, yl)hydroxy- micron; 10H), 3.34 (dq, J=14.8, 5.4 2-(5- mobile phase: 20% IPA/80% Hz, 1H), 2.33 - 2.14 (m, 5H) pyridin- CO2; 2-yl)-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 275 - 1H NMR (600 MHz, DMSO- 1.09 A diethylphenyl)- d6) δ 8.50 - 8.28 (m, 1H), 7.79 A -[3-(3- - 7.60 (m, 1H), 7.47 (br d, 517.0 fluoropyridin J=12.7 Hz, 1H), 7.41 - 7.25 yl)pyrrolidine- 8.5, >99.8% (m, 2H), 7.19 - 7.03 (m, 2H), 1-carbonyl] Whelko, 5 x 50 cm, 10 5.65 (br s, 1H), 4.10 - 3.57 hydroxy(1- micron; (m, 7H), 3.40 - 3.26 (m, 1H), methyl-1H- mobile phase: 10% IPA/90% 2.33 - 2.10 (m, 6H), 1.10 - pyrazolyl)- CO2; 0.89 (m, 6H) 1,4- Flow Conditions: 340 dihydropyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 276 5-[3-(2,6- 1H NMR (500 MHz, DMSO- 1.23 A rophenyl) d6) δ 7.57 (br d, J=10.6 Hz, A pyrrolidine 1H), 7.44 - 7.26 (m, 2H), 7.09 552.0 yl] (br d, J=10.2 Hz, 2H), 6.67 (2,6- 5.4, >99.7% (br d, J=8.7 Hz, 2H), 6.06 (br dimethoxyphen Whelko, 5 x 50 cm, 10 d, J=10.6 Hz, 1H), 3.94 (br s, yl)(1-ethyl- micron; 2H), 3.78 - 3.36 (m, 11H), 1H-pyrazol mobile phase: 20% IPA/80% 2.31 - 2.12 (m, 2H), 1.12 (br yl)hydroxy- CO2; d, J=3.8 Hz, 3H) 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 277 5-[4-(2,3- achiral 1H NMR (500 MHz, DMSO- 1.23 A difluorophenox d6) δ 7.57 (br s, 1H), 7.30 (br A y)piperidine d, J=16.7 Hz, 1H), 7.22 - 7.05 585.0 carbonyl] (m, 3H), 6.98 (br s, 1H), 6.66 (2,6- (br s, 1H), 3.98 - 3.22 (m, dimethoxyphen 11H), 2.46 - 2.36 (m, 3H), yl)hydroxy- 2.11 - 1.86 (m, 2H), 1.82 - 2-(2-methyl- 1.47 (m, 2H) 1,3-thiazol yl)-1,4- dihydropyrimid inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 278 5-[3-(2,4- 1H NMR (500 MHz, DMSO- 1.13 A difluorophenyl) d6) δ 8.06 (br d, J=7.2 Hz, A pyrrolidine 1H), 7.46 (br d, J=6.1 Hz, 565.0 yl] 1H), 7.30 - 7.11 (m, 2H), 7.09 (2,6- - 7.00 (m, 1H), 6.93 (br d, dimethoxyphen 2.53, 92.7% J=7.6 Hz, 1H), 6.82 (br s, yl)hydroxy- Chiralpak IC, 4.6 x 250 mm, 1H), 6.52 (br t, J=9.2 Hz, 2-(4- 5 micron; 2H), 3.79 - 3.70 (m, 3H), 3.67 methoxypyridin mobile phase: 10% IPA/90% - 3.44 (m, 10H), 3.43 - 3.24 yl)-1,4- CO2; (m, 1H), 2.24 (br s, 1H), 2.06 dihydropyrimid Flow Conditions: 3 mL/min, - 1.95 (m, 1H) inone 140 bar, 45°C, wavelength: 200-400 nm (isomer 1) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 279 2-(6- 1H NMR (500 MHz, DMSO- 1.27 A chloropyridin- d6) δ 8.17 (br d, J=14.0 Hz, A 3-yl)[3-(2,4- 1H), 7.70 - 7.56 (m, 1H), 7.47 569.2 difluorophenyl) (br d, J=9.2 Hz, 1H), 7.37 (br pyrrolidine t, J=9.2 Hz, 1H), 7.29 - 7.15 carbonyl] 2.53, 92.7% (m, 2H), 7.03 (br s, 1H), 6.73 (2,6- Chiralpak IC, 4.6 x 250 mm, - 6.46 (m, 2H), 3.95 - 3.46 dimethoxyphen 5 micron; (m, 11H), 2.22 (br s, 1H), yl)hydroxy- mobile phase: 10% IPA/90% 2.05 - 1.91 (m, 1H) 1,4- CO2; dihydropyrimid Flow Conditions: 3 mL/min, inone 140 bar, 45°C, wavelength: 0 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 280 2-(5- 1H NMR (600 MHz, DMSO- 1.29 A chloropyridin- d6) δ 8.42 - 8.23 (m, 1H), 7.98 A 2-yl)[3-(2,6- - 7.85 (m, 1H), 7.50 (br dd, 569.2 difluorophenyl) J=20.0, 8.1 Hz, 1H), 7.37 (br pyrrolidine 5.4, >99.7% s, 1H), 7.27 - 7.16 (m, 1H), carbonyl] Whelko, 5 x 50 cm, 10 7.10 (br d, J=8.5 Hz, 2H), (2,6- micron; 6.68 - 6.44 (m, 2H), 3.95 - dimethoxyphen mobile phase: 20% IPA/80% 3.50 (m, 10H), 3.40 - 3.27 (m, yl)hydroxy- CO2; 1H), 2.28 - 2.16 (m, 2H) 1,4- Flow Conditions: 350 opyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 281 2-(6- 1H NMR (500 MHz, DMSO- 1.18 A chloropyridin- d6) δ 8.22 - 8.10 (m, 1H), 7.69 A 3-yl)[3-(2,6- - 7.52 (m, 1H), 7.36 (br dd, 569.0 difluorophenyl) J=14.6, 7.9 Hz, 2H), 7.28 - idine 5.4, >99.7% 7.17 (m, 1H), 7.10 (q, J=8.1 carbonyl] , 5 x 50 cm, 10 Hz, 2H), 6.65 - 6.51 (m, 2H), (2,6- micron; 3.78 - 3.54 (m, 10H), 3.51 - dimethoxyphen mobile phase: 20% IPA/80% 3.31 (m, 1H), 2.32 - 2.10 (m, yl)hydroxy- CO2; 2H) 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 282 2,4- 1H NMR (500 MHz, DMSO- 1.16 A difluorophenyl) d6) δ 8.09 (br d, J=12.6 Hz, A pyrrolidine 1H), 7.63 - 7.41 (m, 2H), 7.34 549.1 carbonyl] (br d, J=7.9 Hz, 1H), 7.28 - (2,6- 7.11 (m, 2H), 7.05 (br s, 1H), dimethoxyphen 2.53, 92.7% 6.61 - 6.43 (m, 2H), 3.89 - yl)hydroxy- Chiralpak IC, 4.6 x 250 mm, 3.70 (m, 1H), 3.68 - 3.31 (m, 2-(5- 5 ; 10H), 2.33 - 2.15 (m, 4H), methylpyridin- mobile phase: 10% IPA/90% 2.00 (br d, J=4.6 Hz, 1H) 2-yl)-1,4- CO2; dihydropyrimid Flow Conditions: 3 mL/min, inone 140 bar, 45°C, wavelength: 200-400 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 283 1-(2,6- R-isomer 1H NMR (500 MHz, DMSO- 1.27 A diethylphenyl)- d6) δ 7.50 (br d, J=10.4 Hz, A 6-hydroxy(1- 1H), 7.40 - 7.19 (m, 6H), 7.19 498.0 -1H- - 7.07 (m, 2H), 5.62 (br s, pyrazolyl) 1H), 3.95 - 3.72 (m, 1H), 3.67 [(3R) (br d, J=10.9 Hz, 7H), 2.37 - phenylpyrrolidi 2.15 (m, 6H), 1.14 - 0.81 (m, necarbonyl]- 6H) dihydropyrimid inone 284 1-(2,6- R isomer 1H NMR (500 MHz, DMSO- 1.09 A dimethoxyphen d6) δ 7.56 (br d, J=9.3 Hz, A (1-ethyl- 1H), 7.40 - 7.14 (m, 6H), 6.74 516.0 1H-pyrazol - 6.59 (m, 2H), 6.06 (br d, yl)hydroxy- J=5.7 Hz, 1H), 4.06 - 3.82 -[(3R) (m, 2H), 3.78 - 3.45 (m, phenylpyrrolidi 10H), 3.44 - 3.21 (m, 1H), necarbonyl]- 2.25 (br s, 1H), 2.03 - 1.84 1,4- (m, 1H), 1.22 - 1.06 (m, 3H) dihydropyrimid inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 285 1-(2,6- S isomer 1H NMR (500 MHz, DMSO- 1.37 A diethylphenyl)- d6) δ 7.50 (br d, J=9.7 Hz, A 6-hydroxy(1- 1H), 7.41 - 7.20 (m, 6H), 7.19 498.2 methyl-1H- - 7.06 (m, 2H), 5.61 (br s, pyrazolyl) 1H), 3.96 - 3.45 (m, 7H), 3.43 3- - 3.22 (m, 1H), 2.35 - 2.14 phenylpyrrolidi (m, 6H), 1.11 - 0.82 (m, 6H) necarbonyl]- dihydropyrimid inone 286 1-(2,6- S isomer 1H NMR (500 MHz, DMSO- 1.10 A dimethoxyphen d6) δ 7.55 (br d, J=9.3 Hz, A yl)(1-ethyl- 1H), 7.36 - 7.17 (m, 6H), 6.73 516.2 1H-pyrazol - 6.57 (m, 2H), 6.06 (br d, yl)hydroxy- J=6.6 Hz, 1H), 4.01 - 3.81 -[(3S) (m, 2H), 3.77 - 3.42 (m, pyrrolidi 10H), 3.41 - 3.22 (m, 1H), necarbonyl]- 2.25 (br s, 1H), 1.91 (s, 1H), 1,4- 1.20 - 1.06 (m, 3H) dihydropyrimid inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 287 2-(5- 1H NMR (500 MHz, DMSO- 1.33 A chloropyridin- d6) δ 8.26 - 8.18 (m, 1H), 7.81 A 2-yl)[3-(2,4- (br d, J=5.8 Hz, 1H), 7.44 - 569.2 difluorophenyl) 7.32 (m, 1H), 7.29 - 7.16 (m, pyrrolidine 1H), 7.15 - 6.97 (m, 3H), 6.57 yl] 2.53, 92.7% - 6.37 (m, 2H), 3.92 - 3.70 (2,6- Chiralpak IC, 4.6 x 250 mm, (m, 1H), 3.67 - 3.29 (m, dimethoxyphen 5 micron; 10H), 2.21 (br d, J=3.5 Hz, yl)hydroxy- mobile phase: 10% IPA/90% 1H), 2.01 - 1.92 (m, 1H) 1,4- CO2; dihydropyrimid Flow Conditions: 3 mL/min, inone 140 bar, 45°C, wavelength: 200-400 nm (isomer 1) 288 2-(1-ethyl-1H- S isomer 1H NMR (500 MHz, DMSO- 1.40 A pyrazolyl) d6) δ 7.58 (br d, J=10.1 Hz, A hydroxy 1H), 7.42 - 7.15 (m, 7H), 7.10 498.2 [(3S) - 6.96 (m, 2H), 6.02 - 5.81 phenylpyrrolidi (m, 1H), 4.08 - 3.55 (m, 6H), necarbonyl]- 3.54 - 3.27 (m, 1H), 2.90 - propan 2.75 (m, 1H), 2.34 - 2.20 (m, nyl]-1,4- 1H), 2.05 - 1.86 (m, 1H), 1.19 dihydropyrimid - 1.03 (m, 9H) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 289 1-(2,6- S isomer 1H NMR (600 MHz, DMSO- 1.52 A diethylphenyl)- d6) δ 7.62 (br d, J=10.9 Hz, A 6-hydroxy 1H), 7.38 - 7.27 (m, 4H), 7.27 526.3 [(3S) - 7.20 (m, 2H), 7.19 - 7.09 phenylpyrrolidi (m, 2H), 6.28 (br d, J=15.5 necarbonyl]- Hz, 1H), 4.38 - 4.23 (m, 2H), 2-[1-(propan 3.98 - 3.50 (m, 3H), 3.47 - yl)-1H-pyrazol- 3.26 (m, 1H), 2.36 - 2.14 (m, 3-yl]-1,4- 5H), 2.01 - 1.87 (m, 1H), 1.13 dihydropyrimid - 1.04 (m, 6H), 1.01 - 0.85 ne (m, 6H) 290 5-[3-(5-chloro- 1H NMR (600 MHz, DMSO- 1.54 A 3-fluoropyridin- d6) δ 8.54 - 8.39 (m, 1H), 8.13 A 2- - 7.96 (m, 1H), 7.60 (br d, 579.1 yl)pyrrolidine- J=9.5 Hz, 1H), 7.36 - 7.23 1-carbonyl] (m, 1H), 7.13 (br dd, J=12.1, (2,6- 7.6, >99.7% 8.1 Hz, 2H), 6.26 (br d, diethylphenyl)- Whelko, 5 x 50 cm, 10 J=18.6 Hz, 1H), 4.27 (br d, oxy[1- micron; J=6.3 Hz, 2H), 3.96 - 3.43 (propanyl)- mobile phase: 20% IPA/80% (m, 4H), 2.34 - 2.06 (m, 6H), 1H-pyrazol CO2; 1.07 (br d, J=4.0 Hz, 6H), 4- Flow Conditions: 350 1.01 - 0.84 (m, 6H) dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 291 2-(1-ethyl-1H- R isomer 1H NMR (600 MHz, DMSO- 1.41 A pyrazolyl) d6) δ 7.58 (br d, J=11.9 Hz, A hydroxy 1H), 7.43 - 7.15 (m, 7H), 7.12 497.9 [(3R) - 6.96 (m, 2H), 6.00 - 5.79 phenylpyrrolidi (m, 1H), 4.09 - 3.77 (m, 2H), necarbonyl]- 3.69 - 3.25 (m, 5H), 2.97 - 1-[3-(propan 2.79 (m, 1H), 2.28 (br s, 1H), yl)phenyl]-1,4- 2.04 - 1.88 (m, 1H), 1.23 - dihydropyrimid 0.99 (m, 9H) inone 292 1-(2,6- 1H NMR (600 MHz, DMSO- 1.38 A diethylphenyl)- d6) δ 8.38 (br d, J=18.4 Hz, A 3- 1H), 7.85 - 7.55 (m, 2H), 7.46 545.0 pyridin - 7.01 (m, 4H), 6.62 - 6.43 yl)pyrrolidine- 9.5, >99.8% (m, 1H), 4.40 - 3.78 (m, 2H), 1-carbonyl] Whelko, 5 x 50 cm, 10 3.78 - 3.41 (m, 4H), 2.38 - hydroxy[1- micron; 2.02 (m, 6H), 1.16 (br t, J=7.3 (propanyl)- mobile phase: 10% IPA/90% Hz, 6H), 1.11 - 0.79 (m, 6H) 1H-pyrazol CO2; yl]-1,4- Flow ions: 340 dihydropyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 293 5-[3-(3,5- 1H NMR (600 MHz, DMSO- 1.30 A difluoropyridin- d6) δ 8.31 (br d, J=9.7 Hz, A 2- 1H), 7.73 (q, J=10.0 Hz, 1H), 535.2 yl)pyrrolidine- 7.39 (br d, J=9.7 Hz, 1H), 1-carbonyl] 7.17 - 7.00 (m, 2H), 6.90 - (1-ethyl-1H- 6.3, >99.7% 6.73 (m, 2H), 5.78 (br d, pyrazolyl) Whelko, 5 x 50 cm, 10 J=17.6 Hz, 1H), 3.93 - 3.57 hydroxy[3- micron; (m, 6H), 3.57 - 3.28 (m, 1H), (propan mobile phase: 20% IPA/80% 2.76 - 2.59 (m, 1H), 2.08 (br nyl]-1,4- CO2; d, J=15.5 Hz, 1H), 2.04 - 1.88 dihydropyrimid Flow Conditions: 350 (m, 1H), 1.02 - 0.89 (m, 9H) inone mL/min, 30°C, wavelength: 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 294 2-(1-ethyl-1H- 1H NMR (600 MHz, DMSO- 1.87 A lyl) d6) δ 9.16 - 8.93 (m, 3H), 8.75 A [3-(2- - 8.50 (m, 5H), 8.26 (br s, 1031.1 fluorophenyl)py 10.65, 99.5% 1H), 7.33 (br s, 1H), 4.05 - (2M+ rrolidine Chiralpak IF, 4.6 x 250 mm, 3.65 (m, 2H), 3.53 - 3.20 (m, H) carbonyl] 5 micron; 5H), 3.00 - 2.86 (m, 1H), 2.14 hydroxy[3- mobile phase: 15% IPA/90% - 2.00 (m, 1H), 1.94 - 1.77 (propan CO2; (m, 1H), 1.35 - 1.07 (m, 9H) yl)phenyl]-1,4- Flow Conditions: 2.0 dihydropyrimid , 150 bar, 40°C, inone wavelength: 220 nm (Isomer Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 295 1-(2,6- 1H NMR (600 MHz, DMSO- 1.56 A diethylphenyl)- d6) δ 7.62 (br d, J=10.5 Hz, A -[3-(2- 1H), 7.37 (dt, J=14.6, 7.4 Hz, 544.2 fluorophenyl)py 10.65, 99.5% 1H), 7.34 - 7.25 (m, 2H), 7.23 rrolidine Chiralpak IF, 4.6 x 250 mm, - 7.09 (m, 4H), 6.28 (br d, carbonyl] 5 micron; J=15.1 Hz, 1H), 4.37 - 4.20 hydroxy[1- mobile phase: 15% % (m, 1H), 3.97 - 3.31 (m, 5H), (propanyl)- CO2; 2.37 - 2.13 (m, 5H), 2.06 - 1H-pyrazol Flow ions: 2.0 1.96 (m, 1H), 1.10 - 1.05 (m, yl]-1,4- mL/min, 150 bar, 40°C, 6H), 1.02 - 0.83 (m, 6H) dihydropyrimid wavelength: 220 nm (Isomer inone 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho y d range 296 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.45 A 3-fluoropyridin- d6) δ 8.45 (br d, J=18.6 Hz, A 2- 1H), 8.01 (br t, J=9.8 Hz, 568.0 yl)pyrrolidine- 1H), 7.47 (br d, J=13.7 Hz, 1-carbonyl] 1H), 7.30 - 7.17 (m, 1H), 7.05 (2,6- 7.6, >99.7% (br dd, J=12.5, 7.6 Hz, 2H), diethylphenyl)- Whelko, 5 x 50 cm, 10 3.94 - 3.48 (m, 4H), 3.47 - 6-hydroxy(2- micron; 3.23 (m, 1H), 2.43 - 2.19 (m, methyl-1,3- mobile phase: 20% IPA/80% 8H), 2.19 - 2.06 (m, 1H), 1.14 thiazolyl)- CO2; - 0.85 (m, 6H) 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 297 1-(2,6- 1H NMR (500 MHz, DMSO- 1.58 A diethylphenyl)- d6) δ 8.52 - 8.40 (m, 1H), 7.95 A -[3-(3,5- - 7.82 (m, 1H), 7.72 (br d, 580.3 difluoropyridin- J=17.4 Hz, 1H), 7.24 - 7.09 2- (m, 1H), 6.99 (br dd, J=13.3, yl)pyrrolidine- 6.3, >99.7% 7.2 Hz, 2H), 3.99 - 3.38 (m, 1-carbonyl] Whelko, 5 x 50 cm, 10 5H), 3.02 - 2.88 (m, 1H), 2.33 hydroxy[2- ; (dt, J=14.8, 7.2 Hz, 4H), 2.24 (propanyl)- mobile phase: 20% IPA/80% - 2.13 (m, 2H), 1.11 - 0.87 1,3-thiazol CO2; (m, 12H) yl]-1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, ngth: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 298 1-(2,6- 1H NMR (500 MHz, DMSO- 1.37 A diethylphenyl)- d6) δ 8.45 (br d, J=18.0 Hz, A -[3-(3,5- 1H), 7.92 - 7.84 (m, 1H), 7.47 552.3 difluoropyridin- (br d, J=14.0 Hz, 1H), 7.29 - 2- 7.15 (m, 1H), 7.10 - 6.96 (m, yl)pyrrolidine- 6.3, >99.7% 2H), 3.97 - 3.38 (m, 5H), 2.44 onyl] Whelko, 5 x 50 cm, 10 - 2.08 (m, 9H), 1.15 - 0.89 hydroxy(2- micron; (m, 6H) methyl-1,3- mobile phase: 20% % thiazolyl)- CO2; 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm r 2) 299 1-(2,6- S isomer 1H NMR (500 MHz, DMSO- 1.73 A diethylphenyl)- d6) δ 7.66 (br d, J=13.7 Hz, A 6-hydroxy 1H), 7.39 - 7.18 (m, 5H), 7.17 543.3 [(3S) - 7.08 (m, 1H), 6.97 (br dd, phenylpyrrolidi J=11.0, 7.6 Hz, 2H), 3.96 - necarbonyl]- 3.72 (m, 1H), 3.68 - 3.23 (m, 2-[2-(propan 4H), 3.03 - 2.84 (m, 1H), 2.44 yl)-1,3-thiazol- - 2.13 (m, 6H), 1.11 - 0.87 4-yl]-1,4- (m, 12H) dihydropyrimid inone Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 300 1-(2,6- 1H NMR (500 MHz, DMSO- 1.51 A diethylphenyl)- d6) δ 8.56 - 8.41 (m, 1H), 7.73 A -[3-(5- (br d, J=15.6 Hz, 1H), 7.70 - 562.3 fluoropyridin 7.60 (m, 1H), 7.53 - 7.37 (m, yl)pyrrolidine- 7.7, >95.5% 1H), 7.23 - 7.09 (m, 1H), 6.99 1-carbonyl] Whelko, 5 x 50 cm, 10 (br dd, J=13.6, 7.2 Hz, 2H), hydroxy[2- ; 4.11 - 3.82 (m, 1H), 3.80 - (propanyl)- mobile phase: 10% IPA/90% 3.35 (m, 4H), 3.02 - 2.89 (m, 1,3-thiazol CO2; 1H), 2.42 - 2.16 (m, 5H), 2.12 yl]-1,4- Flow Conditions: 340 - 1.96 (m, 1H), 1.12 - 0.87 dihydropyrimid mL/min, 45°C, wavelength: (m, 12H) inone 220 nm (isomer 1) 301 1-(2,6- R isomer 1H NMR (500 MHz, DMSO- 1.44 A diethylphenyl)- d6) δ 7.57 (br d, J=8.9 Hz, A 6-hydroxy(2- 1H), 7.41 - 7.18 (m, 6H), 7.15 515.4 methyl-1,3- - 7.04 (m, 2H), 4.04 - 3.85 thiazolyl) (m, 1H), 3.82 - 3.30 (m, 4H), [(3R) 2.44 - 2.14 (m, 8H), 2.03 - phenylpyrrolidi 1.84 (m, 1H), 1.11 - 0.86 (m, arbonyl]- 6H) dihydropyrimid inone Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 302 1-(2,6- 1H NMR (500 MHz, DMSO- 1.24 A diethylphenyl)- d6) δ 8.35 (br d, J=3.7 Hz, A -[3-(3- 1H), 7.74 - 7.60 (m, 1H), 7.55 534.1 fluoropyridin - 7.30 (m, 2H), 7.27 - 7.13 yl)pyrrolidine- 9.5, >99.8% (m, 1H), 7.01 (br dd, J=17.5, 1-carbonyl] Whelko, 5 x 50 cm, 10 6.9 Hz, 2H), 3.95 - 3.42 (m, hydroxy(2- micron; 5H), 2.44 - 2.06 (m, 9H), 1.10 methyl-1,3- mobile phase: 10% IPA/90% - 0.85 (m, 6H) thiazolyl)- CO2; 1,4- Flow Conditions: 340 opyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 2) 303 - S isomer 1H NMR (500 MHz, DMSO- 1.40 A diethylphenyl)- d6) δ 8.61 - 8.42 (m, 1H), 8.07 A 6-hydroxy(2- - 7.91 (m, 2H), 7.69 - 7.45 515.2 methyl-1,3- (m, 1H), 7.39 - 7.16 (m, 4H), thiazolyl) 7.14 - 6.98 (m, 1H), 3.75 - [(3S) 3.22 (m, 5H), 2.40 - 2.13 (m, phenylpyrrolidi 8H), 1.94 (s, 1H), 1.11 - 0.85 necarbonyl]- (m, 6H) dihydropyrimid inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 304 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.33 A 3-fluoropyridin- d6) δ 8.47 (br d, J=18.3 Hz, A 2- 1H), 8.15 - 7.95 (m, 1H), 7.44 551.2 yl)pyrrolidine- (br d, J=10.4 Hz, 1H), 7.35 - 1-carbonyl] 7.19 (m, 1H), 7.09 (br dd, (2,6- 6.8, >99.7% J=14.6, 7.6 Hz, 2H), 5.65 (br diethylphenyl)- , 5 x 50 cm, 10 d, J=5.6 Hz, 1H), 3.97 - 3.70 6-hydroxy(1- micron; (m, 1H), 3.70 - 3.26 (m, 7H), -1H- mobile phase: 20% IPA/80% 2.37 - 2.02 (m, 6H), 1.12 - pyrazolyl)- CO2; 0.76 (m, 6H) 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 305 1-(2,6- 1H NMR (500 MHz, DMSO- 1.27 A diethylphenyl)- d6) δ 7.54 (br d, J=7.9 Hz, A -[3-(2- 1H), 7.38 (br d, J=7.0 Hz, 516.3 fluorophenyl)py 10.65, 99.5% 2H), 7.29 (br d, J=5.8 Hz, rrolidine Chiralpak IF, 4.6 x 250 mm, 1H), 7.24 - 7.04 (m, 4H), 5.59 carbonyl] 5 micron; (br s, 1H), 3.99 - 3.73 (m, hydroxy(1- mobile phase: 15% IPA/90% 1H), 3.73 - 3.32 (m, 7H), 2.35 -1H- CO2; - 2.14 (m, 5H), 2.09 - 1.96 lyl)- Flow Conditions: 2.0 (m, 1H), 1.11 - 0.83 (m, 6H) 1,4- mL/min, 150 bar, 40°C, dihydropyrimid wavelength: 220 nm (Isomer inone 2) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 306 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.46 A 3-fluoropyridin- d6) δ 8.47 (br d, J=19.9 Hz, A 2- 1H), 8.14 - 7.95 (m, 1H), 7.44 568.1 yl)pyrrolidine- - 7.18 (m, 2H), 7.16 - 7.00 1-carbonyl] (m, 2H), 3.99 - 3.39 (m, 5H), (2,6- 6.8, >99.7% 2.38 - 2.08 (m, 8H), 2.00 (br diethylphenyl)- Whelko, 5 x 50 cm, 10 d, J=6.6 Hz, 1H), 1.10 - 0.82 6-hydroxy(4- micron; (m, 6H) methyl-1,3- mobile phase: 20% IPA/80% thiazolyl)- CO2; 1,4- Flow Conditions: 350 dihydropyrimid , 27°C, wavelength: inone 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 307 1-(2,6- 1H NMR (500 MHz, DMSO- 1.33 A diethylphenyl)- d6) δ 8.38 (br d, J=18.1 Hz, A -[3-(3- 1H), 7.78 - 7.61 (m, 1H), 7.51 534.2 fluoropyridin - 7.22 (m, 3H), 7.20 - 7.02 yl)pyrrolidine- 9.5, >99.8% (m, 2H), 3.97 - 3.54 (m, 4H), 1-carbonyl] Whelko, 5 x 50 cm, 10 3.54 - 3.27 (m, 1H), 2.34 - hydroxy(4- micron; 2.09 (m, 5H), 2.08 - 1.91 (m, methyl-1,3- mobile phase: 10% IPA/90% 4H), 1.14 - 0.78 (m, 6H) thiazolyl)- CO2; 1,4- Flow Conditions: 340 opyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 2) 308 1-(2,6- 1H NMR (500 MHz, DMSO- 1.19 A diethylphenyl)- d6) δ 8.47 - 8.27 (m, 1H), 7.65 A 2-(1-ethyl-1H- (br d, J=8.9 Hz, 1H), 7.53 (br 531.3 pyrazolyl) s, 1H), 7.43 - 7.21 (m, 2H), 9.5, >99.8% [3-(3- 7.10 (br s, 2H), 5.97 (br s, fluoropyridin Whelko, 5 x 50 cm, 10 1H), 4.13 - 3.49 (m, 7H), 2.37 yl)pyrrolidine- micron; - 2.04 (m, 6H), 1.19 - 0.77 onyl] mobile phase: 10% % (m, 9H) hydroxy-1,4- CO2; dihydropyrimid Flow Conditions: 340 inone mL/min, 45°C, wavelength: 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 309 - 1H NMR (500 MHz, DMSO- 1.30 A lphenyl)- d6) δ 8.45 (br d, J=18.6 Hz, A -[3-(3,5- 1H), 7.88 (q, J=9.4 Hz, 1H), 549.1 difluoropyridin- 7.52 (br d, J=9.9 Hz, 1H), 2- 7.34 - 7.20 (m, 1H), 7.10 (br yl)pyrrolidine- 6.3, >99.7% dd, J=13.5, 7.6 Hz, 2H), 5.94 1-carbonyl] Whelko, 5 x 50 cm, 10 (br d, J=12.2 Hz, 1H), 4.04 - (1-ethyl-1H- micron; 3.67 (m, 6H), 3.55 (br d, pyrazolyl) mobile phase: 20% IPA/80% J=18.0 Hz, 1H), 2.33 - 2.03 hydroxy-1,4- CO2; (m, 6H), 1.07 (q, J=6.9 Hz, dihydropyrimid Flow Conditions: 350 3H), 1.02 - 0.85 (m, 6H) inone mL/min, 30°C, wavelength: 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 310 1-(2,6- 1H NMR (500 MHz, DMSO- 1.40 A diethylphenyl)- d6) δ 7.58 - 7.34 (m, 2H), 7.34 A 2-(1-ethyl-1H- - 7.23 (m, 3H), 7.22 - 7.05 530.1 pyrazolyl) 10.65, 99.5% (m, 3H), 6.46 (br d, J=14.0 [3-(2- Chiralpak IF, 4.6 x 250 mm, Hz, 1H), 4.07 - 3.70 (m, 6H), fluorophenyl)py 5 micron; 3.65 - 3.38 (m, 1H), 2.35 - rrolidine mobile phase: 15% IPA/90% 2.12 (m, 5H), 2.07 - 1.94 (m, carbonyl] CO2; 1H), 1.19 (q, J=6.6 Hz, 3H), hydroxy-1,4- Flow Conditions: 2.0 1.05 - 0.79 (m, 6H) dihydropyrimid , 150 bar, 40°C, inone wavelength: 220 nm (Isomer Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 311 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.40 A 3-fluoropyridin- d6) δ 8.45 (br d, J=18.6 Hz, A 2- 1H), 8.01 (br t, J=10.4 Hz, 565.1 yl)pyrrolidine- 1H), 7.62 - 7.44 (m, 1H), 7.36 1-carbonyl] - 7.20 (m, 1H), 7.17 - 7.01 (2,6- 7.6, >99.7% (m, 2H), 5.92 (br d, J=11.5 diethylphenyl)- Whelko, 5 x 50 cm, 10 Hz, 1H), 4.05 - 3.70 (m, 4H), 2-(1-ethyl-1H- micron; 3.65 - 3.35 (m, 3H), 2.35 - pyrazolyl) mobile phase: 20% IPA/80% 2.04 (m, 6H), 1.14 - 0.78 (m, hydroxy-1,4- CO2; 9H) opyrimid Flow Conditions: 350 inone mL/min, 27°C, wavelength: 220 nm (isomer 2) Ex# Structure Name Chiral amine ediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 312 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.46 A 3-fluoropyridin- d6) δ 8.47 (br d, J=19.2 Hz, A 2- 1H), 8.11 - 7.98 (m, 1H), 7.45 568.3 yl)pyrrolidine- (br d, J=8.2 Hz, 1H), 7.38 - 1-carbonyl] 7.29 (m, 1H), 7.15 (br s, 2H), (2,6- 7.6, >99.7% 3.97 - 3.52 (m, 4H), 3.49 - diethylphenyl)- Whelko, 5 x 50 cm, 10 3.30 (m, 1H), 2.33 - 2.08 (m, 6-hydroxy(4- micron; 5H), 2.08 - 1.98 (m, 4H), 1.09 methyl-1,3- mobile phase: 20% IPA/80% - 0.81 (m, 6H) thiazolyl)- CO2; 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 313 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.30 A 3-fluoropyridin- d6) δ 8.44 (br d, J=16.5 Hz, A 2- 1H), 8.00 (br s, 1H), 7.53 (br 565.1 yl)pyrrolidine- s, 1H), 7.35 (br s, 2H), 7.25 1-carbonyl] (br s, 1H), 6.56 (br s, 1H), (2,6- 7.6, >99.7% 3.99 (br d, J=6.1 Hz, 2H), diethylphenyl)- Whelko, 5 x 50 cm, 10 3.63 (br s, 4H), 3.49 (br d, 2-(1-ethyl-1H- micron; J=6.1 Hz, 1H), 2.37 - 2.00 pyrazolyl) mobile phase: 20% % (m, 6H), 1.20 (br s, 3H), 1.05 hydroxy-1,4- CO2; - 0.75 (m, 6H) dihydropyrimid Flow Conditions: 350 inone , 27°C, wavelength: 220 nm (isomer 2) 314 2-(4-fluoro R-isomer 1H NMR (500 MHz, DMSO- 1.70 A methylphenyl)- d6) δ 7.32 (br d, J=3.1 Hz, A 6-hydroxy 6H), 7.28 - 7.09 (m, 7H), 3.94 512.0 [(1S) - 3.80 (m, 1H), 3.73 - 3.24 phenylpropyl]- (m, 4H), 3.22 - 3.10 (m, 1H), -[(3R) 2.45 - 2.15 (m, 6H), 2.00 - pyrrolidi 1.84 (m, 1H), 0.88 - 0.71 (m, necarbonyl]- 3H) dihydropyrimid inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 315 1-(2,6- 1H NMR (500 MHz, DMSO- 1.27 A diethylphenyl)- d6) δ 8.56 - 8.41 (m, 1H), 7.93 A -[3-(3,5- (br d, J=7.3 Hz, 1H), 7.54 (br 548.9 difluoropyridin- s, 2H), 7.44 - 7.28 (m, 2H), 2- 6.71 - 6.50 (m, 1H), 4.01 (br yl)pyrrolidine- 6.3, >99.7% d, J=6.6 Hz, 2H), 3.92 - 3.26 1-carbonyl] Whelko, 5 x 50 cm, 10 (m, 5H), 2.35 - 1.97 (m, 6H), (1-ethyl-1H- micron; 1.21 (br s, 3H), 1.08 - 0.78 pyrazolyl) mobile phase: 20% IPA/80% (m, 6H) y-1,4- CO2; dihydropyrimid Flow Conditions: 350 inone , 30°C, wavelength: 220 nm (isomer 2) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 316 2-(1- S isomer 1H NMR (500 MHz, DMSO- 1.72 A cyclopropyl- d6) δ 7.71 (br d, J=10.1 Hz, A azol 1H), 7.37 - 7.27 (m, 4H), 7.27 524.0 yl)(2,6- - 7.18 (m, 2H), 7.18 - 7.04 diethylphenyl)- (m, 2H), 6.25 (br d, J=11.3 6-hydroxy Hz, 1H), 3.88 (br d, J=11.3 [(3S) Hz, 1H), 3.79 - 3.36 (m, 4H), phenylpyrrolidi 3.35 - 3.14 (m, 1H), 2.39 - necarbonyl]- 2.13 (m, 5H), 2.00 - 1.85 (m, 1,4- 1H), 1.07 - 0.83 (m, 6H), 0.74 dihydropyrimid (br s, 2H), 0.59 (br s, 2H) inone 317 1-(2,6- S isomer 1H NMR (500 MHz, DMSO- 1.72 B diethylphenyl)- d6) δ 7.57 (br d, J=10.3 Hz, A 6-hydroxy[1- 1H), 7.40 - 7.18 (m, 6H), 7.17 540.1 (2- - 7.03 (m, 2H), 6.04 (br d, methylpropyl)- J=7.9 Hz, 1H), 4.00 - 3.82 1H-pyrazol (m, 1H), 3.81 - 3.53 (m, 5H), yl][(3S) 3.52 - 3.25 (m, 1H), 2.36 - phenylpyrrolidi 2.15 (m, 5H), 2.02 - 1.87 (m, necarbonyl]- 1H), 1.85 - 1.69 (m, 1H), 1.09 1,4- - 0.85 (m, 6H), 0.68 - 0.52 dihydropyrimid (m, 6H) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 318 1-(2,6- 1H NMR (500 MHz, DMSO- 1.51 A diethylphenyl)- d6) δ 8.50 (br d, J=19.6 Hz, A -[3-(5- 1H), 7.80 - 7.58 (m, 2H), 7.53 559.4 fluoropyridin - 7.38 (m, 1H), 7.38 - 7.27 yl)pyrrolidine- 8.4, >99.7% (m, 1H), 7.24 - 7.04 (m, 2H), 1-carbonyl] Whelko, 5 x 50 cm, 10 6.04 (br d, J=9.3 Hz, 1H), y[1- micron; 4.03 - 3.43 (m, 6H), 3.33 (br (2- mobile phase: 10% IPA/90% s, 1H), 2.37 - 2.15 (m, 5H), methylpropyl)- CO2; 2.15 - 1.97 (m, 1H), 1.90 - 1H-pyrazol Flow Conditions: 340 1.60 (m, 1H), 1.10 - 0.82 (m, yl]-1,4- mL/min, 45°C, wavelength: 6H), 0.60 (br d, J=5.7 Hz, opyrimid 220 nm (isomer 2) 6H) inone Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 319 2-(1- 1H NMR (500 MHz, DMSO- 1.26 A cyclopropyl- d6) δ 8.55 - 8.27 (m, 1H), 7.86 A 1H-pyrazol - 7.58 (m, 2H), 7.53 - 7.24 543.3 yl)(2,6- (m, 2H), 7.19 - 6.90 (m, 2H), diethylphenyl)- 9.5, >99.8% 6.43 - 6.11 (m, 1H), 3.96 - -[3-(3- Whelko, 5 x 50 cm, 10 3.41 (m, 4H), 3.38 - 3.16 (m, fluoropyridin micron; 2H), 2.35 - 1.92 (m, 6H), 1.11 yl)pyrrolidine- mobile phase: 10% IPA/90% - 0.85 (m, 6H), 0.80 - 0.67 1-carbonyl] CO2; (m, 2H), 0.65 - 0.43 (m, 2H) y-1,4- Flow Conditions: 340 dihydropyrimid mL/min, 45°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 320 1-(2,6- 1H NMR (500 MHz, DMSO- 1.61 B diethylphenyl)- d6) δ 8.45 (br s, 1H), 8.03 - A -[3-(3,5- 7.85 (m, 1H), 7.50 (br s, 1H), 577.3 difluoropyridin- 7.30 - 7.13 (m, 1H), 7.09 - 2- 6.97 (m, 2H), 6.35 - 6.06 (m, yl)pyrrolidine- 6.3, >99.7% 1H), 3.90 - 3.43 (m, 6H), 3.40 1-carbonyl] Whelko, 5 x 50 cm, 10 - 3.22 (m, 1H), 2.39 - 1.98 hydroxy[1- micron; (m, 6H), 1.23 (br s, 1H), 1.14 (2- mobile phase: 20% % - 0.76 (m, 6H), 0.55 (br d, propyl)- CO2; J=5.8 Hz, 6H) 1H-pyrazol Flow Conditions: 350 yl]-1,4- mL/min, 30°C, wavelength: dihydropyrimid 220 nm (isomer 2) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 321 5-[3-(3,5- 1H NMR (500 MHz, DMSO- 1.43 A difluoropyridin- d6) δ 8.43 (br s, 1H), 7.92 - A 2- 7.78 (m, 1H), 7.53 (br s, 1H), 537.9 yl)pyrrolidine- 7.35 - 6.99 (m, 4H), 6.85 - 1-carbonyl] 6.65 (m, 1H), 3.84 - 3.40 (m, hydroxy(4- 6.3, >99.7% 5H), 3.39 - 3.21 (m, 1H), 2.44 -1,3- Whelko, 5 x 50 cm, 10 - 2.28 (m, 4H), 2.22 - 1.98 thiazolyl) micron; (m, 3H), 0.94 - 0.78 (m, 3H) [(1S) mobile phase: 20% IPA/80% phenylpropyl]- CO2; 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 322 5-[3-(5- 1H NMR (500 MHz, DMSO- 1.51 A fluoropyridin d6) Shift 8.56 - 8.40 (m, 1H), A yl)pyrrolidine- 7.64 (br d, J=8.5 Hz, 1H), 520.2 1-carbonyl] 7.56 (br s, 1H), 7.37 - 7.08 y(4- 8.4, >99.7% (m, 5H), 6.80 (br d, J=4.9 Hz, methyl-1,3- Whelko, 5 x 50 cm, 10 1H), 3.92 - 3.72 (m, 1H), 3.67 thiazolyl) micron; - 3.30 (m, 4H), 3.29 - 3.18 [(1S) mobile phase: 10% % (m, 1H), 2.40 (br s, 4H), 2.27 phenylpropyl]- CO2; - 2.11 (m, 1H), 2.08 - 1.93 1,4- Flow Conditions: 340 (m, 2H), 0.87 (br d, J=7.3 Hz, dihydropyrimid mL/min, 45°C, wavelength: 3H) inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 323 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.64 A 3-fluoropyridin- d6) δ 8.44 (br d, J=18.9 Hz, A 2- 1H), 8.00 (br d, J=10.1 Hz, 554.1 rolidine- 1H), 7.66 (br s, 1H), 7.36 - onyl] 7.10 (m, 4H), 7.06 - 6.89 (m, hydroxy(4- 7.6, >99.7% 1H), 3.62 (br s, 5H), 3.47 - methyl-1,3- Whelko, 5 x 50 cm, 10 3.31 (m, 1H), 2.42 (br s, 3H), thiazolyl) micron; 2.31 - 2.01 (m, 4H), 0.87 (br [(1S) mobile phase: 20% IPA/80% s, 3H) phenylpropyl]- CO2; 1,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 324 5-[3-(2- 1H NMR (500 MHz, DMSO- 1.58 A fluorophenyl)py d6) δ 7.60 - 7.46 (m, 1H), 7.42 A rrolidine - 7.00 (m, 8H), 6.86 - 6.65 519.1 carbonyl] 10.65, 99.5% (m, 1H), 3.79 - 3.52 (m, 4H), hydroxy(4- Chiralpak IF, 4.6 x 250 mm, 3.51 - 3.26 (m, 2H), 2.43 - methyl-1,3- 5 micron; 2.27 (m, 4H), 2.22 - 2.05 (m, thiazolyl) mobile phase: 15% IPA/90% 1H), 1.99 - 1.82 (m, 2H), 0.94 [(1S) CO2; - 0.73 (m, 3H) phenylpropyl]- Flow ions: 2.0 1,4- mL/min, 150 bar, 40°C, dihydropyrimid wavelength: 220 nm (Isomer inone 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 325 2-(1- 1H NMR (500 MHz, DMSO- 1.32 A cyclopropyl- d6) δ 8.57 - 8.36 (m, 1H), 7.95 A 1H-pyrazol - 7.80 (m, 1H), 7.62 (br d, 561.0 yl)(2,6- J=10.4 Hz, 1H), 7.33 - 7.16 diethylphenyl)- (m, 1H), 7.06 (br dd, J=14.0, -[3-(3,5- 6.3, >99.7% 7.3 Hz, 2H), 6.23 (br d, difluoropyridin- Whelko, 5 x 50 cm, 10 J=15.0 Hz, 1H), 3.99 - 3.53 2- micron; (m, 5H), 3.45 (br s, 1H), 2.36 yl)pyrrolidine- mobile phase: 20% IPA/80% - 2.05 (m, 6H), 1.09 - 0.84 onyl] CO2; (m, 6H), 0.70 (br d, J=4.3 Hz, y-1,4- Flow Conditions: 350 2H), 0.57 (br s, 2H) dihydropyrimid mL/min, 30°C, wavelength: inone 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with ion time S Rt cAMP (min) EC50 Metho Potency d range 326 5-[3-(5-chloro- 1H NMR (500 MHz, DMSO- 1.62 A 3-fluoropyridin- d6) δ 8.58 - 8.37 (m, 1H), 8.12 A 2- - 7.88 (m, 2H), 7.36 - 7.06 601.2 rolidine- (m, 2H), 7.03 - 6.72 (m, 1H), 1-carbonyl] 5.95 (br d, J=8.5 Hz, 1H), [(1S)(3,5- 7.6, >99.7% 4.27 (br d, J=6.4 Hz, 2H), difluorophenyl) Whelko, 5 x 50 cm, 10 3.83 - 3.34 (m, 5H), 3.25 (br micron; s, 1H), 2.36 - 1.89 (m, 3H), methylpropyl]- mobile phase: 20% IPA/80% 1.54 - 1.35 (m, 3H), 0.85 (br 2-(1-ethyl-1H- CO2; d, J=4.3 Hz, 6H) pyrazolyl) Flow Conditions: 350 hydroxy-1,4- mL/min, 27°C, wavelength: dihydropyrimid 220 nm (isomer 2) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 327 )(3,5- 1H NMR (500 MHz, DMSO- 1.63 A difluorophenyl) d6) δ 8.46 (br d, J=13.2 Hz, A 1H), 8.08 - 7.78 (m, 2H), 7.39 585.2 methylpropyl]- - 6.93 (m, 2H), 6.85 - 6.58 -[3-(3,5- (m, 1H), 5.90 - 5.57 (m, 1H), difluoropyridin- 6.3, >99.7% 4.40 - 4.14 (m, 2H), 4.11 - 2- Whelko, 5 x 50 cm, 10 3.53 (m, 5H), 3.48 - 3.28 (m, yl)pyrrolidine- micron; 1H), 2.40 - 1.97 (m, 3H), 1.43 1-carbonyl] mobile phase: 20% IPA/80% (q, J=7.4 Hz, 3H), 1.00 - 0.61 (1-ethyl-1H- CO2; (m, 6H) pyrazolyl) Flow Conditions: 350 hydroxy-1,4- mL/min, 30°C, wavelength: dihydropyrimid 220 nm (isomer 2) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 328 2-(1- 1H NMR (500 MHz, DMSO- 1.26 A cyclopropyl- d6) δ 8.49 (br d, J=18.8 Hz, A azol 1H), 7.88 - 7.59 (m, 2H), 7.56 543.1 yl)(2,6- - 7.37 (m, 1H), 7.34 - 7.18 diethylphenyl)- 8.4, >99.7% (m, 1H), 7.16 - 6.90 (m, 2H), -[3-(5- Whelko, 5 x 50 cm, 10 6.23 (br d, J=15.9 Hz, 1H), fluoropyridin micron; 4.25 - 3.48 (m, 6H), 2.32 - yl)pyrrolidine- mobile phase: 10% IPA/90% 2.14 (m, 5H), 2.11 - 1.98 (m, 1-carbonyl] CO2; 1H), 1.10 - 0.85 (m, 6H), 0.84 hydroxy-1,4- Flow Conditions: 340 - 0.66 (m, 2H), 0.64 - 0.43 dihydropyrimid mL/min, 45°C, wavelength: (m, 2H) inone 220 nm (isomer 2) 329 6-hydroxy 1H NMR (500 MHz, DMSO- 1.38 B [(1R) d6) δ 7.47 - 6.93 (m, 10H), A methoxy 5.71 - 5.09 (m, 1H), 4.39 - 462.2 phenylethyl] 3.72 (m, 2H), 3.44 - 2.63 (m, [(3R) 4H), 2.59 - 2.48 (m, 6H), 1.96 phenylpyrrolidi - 1.28 (m, 3H), 2.34 - 1.22 necarbonyl]- (m, 1H), 1.04 - 0.27 (m, 3H) 2-propyl-3,4- opyrimid inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 330 6-hydroxy 1H NMR (500 MHz, DMSO- 1.37 B [(1R) d6) δ 7.36 - 7.16 (m, 10H), A methoxy 5.76 - 5.35 (m, 1H), 4.40 - 462.0 phenylethyl] 3.48 (m, 2H), 3.44 - 2.63 (m, [(3S) 4H), 2.59 - 2.48 (m, 6H), 1.96 phenylpyrrolidi - 1.28 (m, 2H), 1.73 - 1.27 arbonyl]- (m, 2H), 1.04 - 0.59 (m, 3H) 2-propyl-3,4- opyrimid inone 331 3-[(1S){2- 1H NMR (500 MHz, DMSO- 1.53 A butyl d6) δ 7.75 (br s, 2H), 7.57 (br A hydroxyoxo- s, 2H), 7.31 (br s, 3H), 7.26 - 485.0 -[(3R) 7.05 (m, 2H), 5.50 - 5.31 (m, phenylpyrrolidi 1H), 3.91 (s, 5H), 2.88 (br d, necarbonyl]- J=9.5 Hz, 2H), 2.23 (br d, 1,6- J=5.8 Hz, 2H), 1.92 (s, 2H), dihydropyrimid 1.74 - 1.25 (m, 4H), 0.89 (br in d, J=6.1 Hz, 6H) yl}propyl]benz onitrile Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 332 3-[(1S){2- 1H NMR (METHANOL-d 4, 1.33 A butyl[3-(3,5- 500MHz, at 333K): = 8.29 A difluoropyridin- (s, 1H), 7.67 (s, 1H), 7.61 (d, 522.3 2- 5.6, >99.7% J=7.4 Hz, 2H), 7.52 (d, J=8.3 yl)pyrrolidine- , 5 x 50 cm, 10 Hz, 1H), 7.41-7.48 (m, 1H), 1-carbonyl] micron; 3.83 (d, J=7.2 Hz, 2H), 3.71 hydroxyoxo- mobile phase: 20% % (br. s., 2H), 3.56 (br. s., 1H), 1,6- CO2; 2.78 (br. s., 2H), 2.54-2.62 dihydropyrimid Flow Conditions: 350 (m, 1H), 2.47 (br. s., 1H), in mL/min, 30°C, wavelength: 2.20-2.34 (m, 2H), 1.68 (br. yl}propyl]benz 220 nm s., 1H), 1.32 (br. s., 2H), 1.02 onitrile (isomer-1) (t, J=7.4 Hz, 3H), 0.87 ppm (br. s., 3H) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 333 3-[(1S){2- 1H NMR (500 MHz, DMSO- 1.33 A butyl[3-(3,5- d6) δ 8.41 (br. s., 1H), 7.86 (d, A difluoropyridin- J=8.5 Hz, 1H), 7.33-7.77 (m, 522.1 2- 6.3, >99.7% 4H), 5.36 (br. s., 1H), 2.61- yl)pyrrolidine- Whelko, 5 x 50 cm, 10 3.79 (m, 5H), .25 (m, 1-carbonyl] micron; 4H), 1.48-1.72 (m, 2H), 1.11- hydroxyoxo- mobile phase: 20% IPA/80% 1.43 (m, 2H), 0.23-0.96 ppm 1,6- CO2; (m, 6H) opyrimid Flow Conditions: 350 in mL/min, 30°C, wavelength: yl}propyl]benz 220 nm onitrile (isomer-2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 334 3-[(1S){4- 1H NMR (500 MHz, DMSO- 1.41 A hydroxyoxo- d6) δ .93 (m, 9H), 5.27 A -[(3R) (br. s., 1H), 4.13-4.75 (m, 501.1 phenylpyrrolidi 2H), 3.09-3.38 (m, 2H), 2.32- necarbonyl]- 2.46 (m, 2H), 2.06-2.26 (m, 2-[(propan 1H), 1.68-1.94 (m, 2H), 0.97- yloxy)methyl]- 1.15 (m, 6H), 0.88 ppm (d, 1,6- J=7.1 Hz, 3H) dihydropyrimid in yl}propyl]benz onitrile Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 335 3-[(1S){2- 1H NMR (500 MHz, DMSO- 1.52 A butyl[3-(5- d6) δ 8.47 (br. s., 1H), 7.27- A fluoropyridin 7.7, >95.5% 7.92 (m, 6H), 6.63 and 5.28 504.3 rolidine- Whelko, 5 x 50 cm, 10 (br. s., 1H), 3.10-4.20 (m, onyl] micron; 3H), 2.61-2.92 (m, 2H), 2.40 hydroxyoxo- mobile phase: 10% IPA/90% (br. s., 1H), 1.96-2.25 (m, 1,6- CO2; 3H), 1.58 (d, J=7.4 Hz, 2H), dihydropyrimid Flow Conditions: 340 1.16-1.43 (m, 2H), 0.85 ppm in mL/min, 45°C, wavelength: (dd, J=12.5, 6.8 Hz, 6H) yl}propyl]benz 220 nm onitrile (isomer-1) 336 3-[(1S){2- 1H NMR (500 MHz, DMSO- 1.30 A butyl[3-(5- d6) δ .57 (m, 1H), 7.10- A fluoropyridin 8.4, >99.7% 7.85 (m, 6H), 6.59 and 5.27 504.4 yl)pyrrolidine- Whelko, 5 x 50 cm, 10 (br. s., 1H), 2.59-2.97 (m, 1-carbonyl] micron; 2H), 2.29-2.43 (m, 2H), 1.85- hydroxyoxo- mobile phase: 10% IPA/90% 2.24 (m, 3H), 1.55 (br. s., 1,6- CO2; 2H), 1.09-1.41 (m, 2H), 0.42- opyrimid Flow Conditions: 340 0.90 ppm (m, 6H) in mL/min, 45°C, wavelength: yl}propyl]benz 220 nm onitrile (isomer-2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 337 3-[(S)-{2-butyl- 1H NMR (500 MHz, DMSO- 1.41 A -[3-(5- d6) δ 8.52 (br. s., 1H), 7.05- A chloropyridin- 6.8, >99.7% 8.16 (m, 6H), 5.85 and 4.56 532.4 2- Whelko, 5 x 50 cm, 10 (br. s., 1H), 2.58-2.81 (m, yl)pyrrolidine- micron; 2H), 1.95-2.42 (m, 3H), 1.12- 1-carbonyl] mobile phase: 20% IPA/80% 1.77 (m, 3H), 0.66-1.12 (m, hydroxyoxo- CO2; 5H), 0.57 (br. s., 3H), 0.29 1,6- Flow Conditions: 350 ppm (br. s., 1H). dihydropyrimid , 30°C, wavelength: in 220 nm (isomer-1) yl}(cyclopropyl )methyl]benzon itrile Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 338 3-[(S)-{2-butyl- 1H NMR (500 MHz, DMSO- 1.41 A -[3-(5- d6) δ 8.53 (br. s., 1H), 6.82- A chloropyridin- 7.9, >99.7% 8.27 (m, 6H), 5.75 and 4.53 532.3 2- , 5 x 50 cm, 10 (br. s., 1H), 3.09-3.68 (m, yl)pyrrolidine- micron; 2H), 1.76-2.43 (m, 3H), 1.13- 1-carbonyl] mobile phase: 20% % 1.73 (m, 3H), 0.62-1.07 (m, hydroxyoxo- CO2; 5H), 0.54 (br. s., 3H), 0.30 1,6- Flow Conditions: 350 ppm (br. s., 1H) dihydropyrimid mL/min, 30°C, wavelength: in 220 nm (isomer-2) yl}(cyclopropyl )methyl]benzon itrile Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 339 ){2- 1H NMR (500 MHz, DMSO- 1.54 A -[3-(5- d6) δ 8.44 (br. s., 1H), 7.99 (d, A chloro J=9.2 Hz, 1H), 7.36-7.78 (m, 538.3 fluoropyridin 6.8, >99.7% 4H), 6.39-6.75 and 5.06-5.67 yl)pyrrolidine- Whelko, 5 x 50 cm, 10 (m, 1H), 3.48 (m., 4H), 2.60- 1-carbonyl] micron; 2.94 (m, 2H), 2.43 (br. s., hydroxyoxo- mobile phase: 20% IPA/80% 2H), 1.97-2.29 (m, 3H), 1.48- 1,6- CO2; 1.76 (m, 2H), 1.36 (br. s., dihydropyrimid Flow Conditions: 350 2H), 0.85 ppm (d, J=7.3 Hz, in mL/min, 27°C, wavelength: 6H) yl}propyl]benz 220 nm (isomer-1) onitrile Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 340 2-butyl[3- 1H NMR (500 MHz, DMSO- 1.62 A (3,5- d6) δ 8.43 (br. s., 1H), 7.85 A difluoropyridin- (br. s., 1H), 7.25 (br. s., 1H), 527.0 2- 5.6, >99.7% 6.43-6.98 (m, 3H), 3.64-3.05 yl)pyrrolidine- Whelko, 5 x 50 cm, 10 (m, 7H), .03 (m, 2H), 1-carbonyl] micron; 1.98-2.43 (m, 4H), 0.95-1.78 hydroxy mobile phase: 20% IPA/80% (m, 4H), 0.20-0.88 ppm (m, [(1S)(3- CO2; 6H) methoxyphenyl Flow Conditions: 350 )propyl]-3,4- mL/min, 30°C, wavelength: opyrimid 220 nm inone (isomer-1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 341 2-butyl[3-(5- 1H NMR (500 MHz, DMSO- 1.76 A chloro d6) δ 8.39 (br. s., 1H), 7.95 (d, A fluoropyridin J=8.5 Hz, 1H), 6.75-7.37 (m, 549.2 yl)pyrrolidine- 7.6, >99.7% 3H), 6.50 and 5.21 (br. s., onyl] Whelko, 5 x 50 cm, 10 1H), 3.87- 2.97 (m, 5H), 2.56- 1-(3,5- micron; 2.91 (m, 2H), 2.02-2.41 (m, difluorophenyl) mobile phase: 20% IPA/80% 4H), 1.15-1.62 (m, 4H), 0.50- propyl] CO2; 0.93 ppm (m, 6H) y-3,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: ne 220 nm (isomer-2) 342 2-butyl[3-(5- 1H NMR (500 MHz, DMSO- 1.69 A chloro d6) δ 8.43 (br. s., 1H), 7.99 (d, A fluoropyridin J=9.2 Hz, 1H), 6.79-7.38 (m, 549.3 yl)pyrrolidine- 6.8, >99.7% 3H), 6.62 and 5.28 (br. s., 1-carbonyl] Whelko, 5 x 50 cm, 10 1H), 3.05-4.12 (m, 7H), 2.59- [(1S)(3,5- micron; 2.96 (m, 2H), 1.94-2.45 (m, difluorophenyl) mobile phase: 20% IPA/80% 4H), 0.94-1.74 (m, 4H), 0.44- propyl] CO2; 0.90 ppm (m, 6H) hydroxy-3,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer-1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 343 2-butyl[3- 1H NMR (500 MHz, DMSO- 1.47 A (3,5- d6) δ 8.42 (br. s., 1H), 7.84 A difluoropyridin- (br. s., 1H), 7.05-7.50 (m, 497.5 2- 5.6, >99.7% 5H), 6.14-6.79 (m, 1H), 3.15 yl)pyrrolidine- Whelko, 5 x 50 cm, 10 (s, 5H), 2.40 (br. s., 2H), onyl] micron; 2.00-2.30 (m, 4H), 0.98 (d, hydroxy mobile phase: 20% IPA/80% J=6.2 Hz, 4H), 0.50-0.90 ppm 1- CO2; (m, 6H) phenylpropyl]- Flow Conditions: 350 3,4- mL/min, 30°C, wavelength: dihydropyrimid 220 nm inone (isomer-1) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho y d range 344 2-butyl[3-(5- 1H NMR (500 MHz, DMSO- 1.67 A chloro d6) δ 8.35-8.53 (m, 1H), 7.96 A fluoropyridin (br. s., 1H), 6.99-7.46 (m, 513.2 yl)pyrrolidine- 6.8, >99.7% 5H), 2.51-4.14 (m, 5H), 2.36 1-carbonyl] Whelko, 5 x 50 cm, 10 (br. s., 2H), 1.93-2.22 (m, hydroxy micron; 4H), 0.91-1.79 (m, 4H), 0.60- [(1S) mobile phase: 20% IPA/80% 0.86 ppm (m, 6H) phenylpropyl]- CO2; 3,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer-1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 345 2-butyl[3- 1H NMR (500 MHz, DMSO- 1.56 A (3,5- d6) δ 8.43 (d, J=15.7 Hz, 1H), A difluoropyridin- 7.85 (br. s., 1H), 7.15-7.41 497.0 2- 6.3, >99.7% (m, 5H), 2.61-3.55 (m, 5H), yl)pyrrolidine- Whelko, 5 x 50 cm, 10 2.42 (br. s., 2H), 1.94-2.27 1-carbonyl] micron; (m, 4H), 0.94-1.77 (m, 4H), y mobile phase: 20% IPA/80% 0.60-0.90 ppm (m, 6H) [(1S) CO2; propyl]- Flow Conditions: 350 3,4- mL/min, 30°C, wavelength: dihydropyrimid 220 nm inone (isomer-2) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 346 2-butyl[3-(5- 1H NMR (500 MHz, DMSO- 1.67 A chloro d6) δ 8.44 (d, J=17.7 Hz, 1H), A fluoropyridin 7.99 (d, J=8.5 Hz, 1H), 7.10- 512.9 yl)pyrrolidine- 7.6, >99.7% 7.47 (m, 5H), .87 (m, 1-carbonyl] Whelko, 5 x 50 cm, 10 5H), 2.40 (br. s., 2H), 1.91- hydroxy micron; 2.32 (m, 4H), 0.96-1.81 (m, [(1S) mobile phase: 20% IPA/80% 4H), 0.52-0.93 ppm (m, 6H) phenylpropyl]- CO2; 3,4- Flow Conditions: 350 dihydropyrimid mL/min, 27°C, wavelength: inone 220 nm (isomer-2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 347 2-butyl[(1S)- 1H NMR (500 MHz, DMSO- 1.50 A 1-(3,5- d6) δ 8.39 (br. s., 1H), 7.75- A difluorophenyl) 8.02 (m, 1H), 7.05 (br. s., 533.4 propyl][3- 5.6, >99.7% 1H), 6.82 (br. s., 2H), 6.55 (3,5- Whelko, 5 x 50 cm, 10 and 5.23 (s, 1H), 2.57-3.85 difluoropyridin- micron; (m, 5H), 1.91-2.38 (m, 5H), 2- mobile phase: 20% IPA/80% 0.91-1.69 (m, 5H), 0.43-0.88 yl)pyrrolidine- CO2; ppm (m, 6H) 1-carbonyl] Flow Conditions: 350 hydroxy-3,4- mL/min, 30°C, ngth: dihydropyrimid 220 nm inone (isomer-1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 348 2-butyl[(1S)- 1H NMR (500 MHz, DMSO- 1.50 A 1-(3,5- d6) δ 8.15-8.58 (m, 1H), 7.82 A difluorophenyl) (br. s., 1H), 6.99-7.27 (m, 533.4 propyl][3- 6.3, >99.7% 1H), 6.69-6.94 (m, 2H), 6.30- (3,5- , 5 x 50 cm, 10 6.62 and 4.97-5.36 (m, 1H), difluoropyridin- micron; 2.59-3.69 (m, 7H), 2.10 (br. 2- mobile phase: 20% IPA/80% s., 4H), 0.91-1.68 (m, 4H), rolidine- CO2; 0.48-0.86 ppm (m, 6H) 1-carbonyl] Flow Conditions: 350 hydroxy-3,4- mL/min, 30°C, wavelength: dihydropyrimid 220 nm inone (isomer-2) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 349 2-butyl[3- 1H NMR (500 MHz, DMSO- 1.44 A (3,5- d6) δ 8.38 (br. s., 1H), 7.84 A difluoropyridin- (br. s., 1H), 6.92-7.38 (m, 513.4 2- 6.3, >99.7% 5H), 5.17-5.70 (m, 1H), 4.21 yl)pyrrolidine- Whelko, 5 x 50 cm, 10 (d, J=7.1 Hz, 2H), 2.93-3.74 1-carbonyl] micron; (m, 8H), 2.68 (br. s., 2H), hydroxy mobile phase: 20% IPA/80% .30 (m, 2H), 0.93-1.68 [(1R) CO2; (m, 4H), 0.77 ppm (br. s., 3H) methoxy Flow Conditions: 350 phenylethyl]- mL/min, 30°C, wavelength: 3,4- 220 nm dihydropyrimid (isomer-2) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 350 l[3-(5- 1H NMR (500 MHz, DMSO- 1.48 A chloro d6) δ 8.45 (br. s., 1H), 8.01 A fluoropyridin (br. s., 1H), 6.95-7.62 (m, 529.4 yl)pyrrolidine- 6.8, >99.7% 5H), 4.99-5.87 (m, 1H), 3.92- 1-carbonyl] Whelko, 5 x 50 cm, 10 4.44 (m, 2H), 3.07-3.88 (m, hydroxy micron; 8H), 2.72 (br. s., 2H), 1.94- [(1R) mobile phase: 20% IPA/80% 2.32 (m, 2H), 1.03-1.79 (m, y CO2; 4H), 0.80 ppm (br. s., 3H) phenylethyl]- Flow Conditions: 350 3,4- mL/min, 27°C, wavelength: dihydropyrimid 220 nm (isomer-1) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 351 3-[(S)-{2-butyl- 1H NMR (500 MHz, DMSO- 1.49 A -[3-(3,5- d6) δ 8.33-8.48 (m, 1H), 7.15- A difluoropyridin- 7.98 (m, 5H), 5.83 and 4.57 534.1 2- 6.3, >99.7% (br. s., 1H), 2.58-4.01 (m, yl)pyrrolidine- Whelko, 5 x 50 cm, 10 5H), .30 (m, 3H), 1.16- 1-carbonyl] micron; 1.71 (m, 4H), 0.64-1.05 (m, hydroxyoxo- mobile phase: 20% % 5H), 0.17-0.61 ppm (m, 4H) 1,6- CO2; dihydropyrimid Flow Conditions: 350 in mL/min, 30°C, wavelength: yl}(cyclopropyl 220 nm )methyl]benzon (isomer-2) itrile Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 352 2-butyl[3-(5- 1H NMR (500 MHz, DMSO- 1.52 A d6) δ .55 (m, 1H), 7.96 A fluoropyridin (d, J=9.7 Hz, 1H), 6.82-7.67 528.9 yl)pyrrolidine- 7.6, >99.7% (m, 5H), 5.22-5.89 (m, 1H), 1-carbonyl] Whelko, 5 x 50 cm, 10 3.92-4.57 (m, 2H), 2.95-3.89 y micron; (m, 6H), 2.59-2.87 (m, 2H), [(1R) mobile phase: 20% IPA/80% 1.90-2.26 (m, 2H), 0.93-1.77 methoxy CO2; (m, 4H), 0.77 ppm (br. s., 3H) phenylethyl]- Flow Conditions: 350 3,4- mL/min, 27°C, wavelength: dihydropyrimid 220 nm (isomer-2) inone Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range difluorophenyl) 1H NMR (400MHz, pyrrolidine‐1‐ METHANOL-d4) 7.55 - carbonyl]‐1‐ 7.46 (m, 1H), 7.38 - 7.25 (m, (2,6‐ .9, >99.7% 1H), 6.98 (s, 2H), 6.88 - 6.72 0.78 dimethoxyphen Whelko, 5 x 50 cm, 10 (m, 2H), 4.13 (br. s., 2H), B A yl)‐2‐ micron; mobile phase: 20% 3.93 - 3.67 (m, 11H), 3.45 516.1 (ethoxymethyl)‐ IPA/80% CO2; Flow (br. s., 2H), 2.48 - 2.20 (m, 6‐hydroxy‐ ions: 350 mL/min, 2H), 1.12 (br. s., 3H) °C, wavelength: 220 nm dihydropyrimid (isomer 2) in‐4‐one Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 354 2,6‐ difluorophenyl) 1H NMR (400MHz, pyrrolidine‐1‐ METHANOL-d4) 7.55 - carbonyl]‐1‐ 7.46 (m, 1H), 7.38 - 7.25 (m, (2,6‐ 1H), 6.98 (s, 2H), 6.88 - 6.72 0.078 dimethoxyphen 5.4, ’ Whelko, 5 x 50 cm, 10 (m, 2H), 4.13 (br. s., 2H), B A yl)‐2‐ micron; mobile phase: 20% 3.93 - 3.67 (m, 11H), 3.45 516.1 (ethoxymethyl)‐ IPA/80% CO2; Flow (br. s., 2H), 2.48 - 2.20 (m, 6‐hydroxy‐ ions: 350 mL/min, 2H), 1.12 (br. s., 3H) °C, wavelength: 220 nm dihydropyrimid (isomer 1) in‐4‐one 355 2-butyl(4- (2,3- 1H NMR (500MHz, DMSO- dichlorobenzyl) d6) 7.76 (d, J=7.9 Hz, 1H), piperazine 7.65 (d, J=7.6 Hz, 1H), 7.52 - carbonyl) 7.43 (m, 2H), 6.85 (d, J=8.5 0.68 (2,6- Hz, 2H), 4.42 (br. s., 2H), B A dimethoxyphen 3.76 (s, 6H), 2.51 (br. s., 8H), 575.0 yl) 2.27 (t, J=7.3 Hz, 2H), 1.48 - hydroxypyrimid 1.38 (m, 2H), 1.21 - 1.08 (m, in-4(1H)- 2H), 0.70 (t, J=7.3 Hz, 3H) one0.011 Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range l(3-(5- 1H NMR (500MHz, DMSO- chloro d6) 8.46 (br. s., 1H), 8.03 fluoropyridin (d, J=9.0 Hz, 1H), 7.45 (br. s., yl)pyrrolidine- 1H), 6.83 (d, J=7.5 Hz, 2H), 1-carbonyl) 6.8, >99.7% 3.88 - 3.35 (m, 10H), 2.23 (d, B A (2,6- Whelko, 5 x 50 cm, 10 J=6.5 Hz, 3H), 2.10 (br. s., 531.0 oxyphen micron; 1H), 1.41 (br. s., 2H), 1.19 - yl) mobile phase: 20% IPA/80% 1.06 (m, 2H), 0.69 (d, J=6.5 hydroxypyrimid CO2; Flow Conditions: 350 Hz, 3H) in-4(1H)-one mL/min, 27°C, wavelength: 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 2-butyl(3-(5- 1H NMR (500MHz, DMSO- d6) 8.46 (br. s., 1H), 8.03 fluoropyridin (d, J=9.0 Hz, 1H), 7.45 (br. s., yl)pyrrolidine- 1H), 6.83 (d, J=7.5 Hz, 2H), 1-carbonyl) 7.6, >99.7% 3.88 - 3.35 (m, 10H), 2.23 (d, B A (2,6- Whelko, 5 x 50 cm, 10 J=6.5 Hz, 3H), 2.10 (br. s., 531.0 dimethoxyphen ; 1H), 1.41 (br. s., 2H), 1.19 - yl) mobile phase: 20% IPA/80% 1.06 (m, 2H), 0.69 (d, J=6.5 hydroxypyrimid CO2; Flow Conditions: 350 Hz, 3H) in-4(1H)-one mL/min, 27°C, wavelength: 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 2-butyl(3- (3,5- 1H NMR (500MHz, DMSO- difluoropyridind6 ) 8.45 (br. s., 1H), 7.87 (br. s., 1H), 7.43 (br. s., 1H), yl)pyrrolidine- 0.80 6.82 (br. s., 2H), 3.75 (br. s., 1-carbonyl) 6.3, >99.7% B A 8H), 3.57 - 3.33 (m, 3H), 2.29 (2,6- Whelko, 5 x 50 cm, 10 515.1 - 2.05 (m, 4H), 1.41 (br. s., dimethoxyphen micron; 2H), 1.13 (br. s., 2H), 0.69 yl) mobile phase: 20% IPA/80% (br. s., 3H) ypyrimid CO2; Flow Conditions: 350 in-4(1H)-one mL/min, 30°C, wavelength: 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 2-butyl(3- (3,5- 1H NMR (500MHz, DMSO- difluoropyridind6 ) 8.45 (br. s., 1H), 7.87 (br. s., 1H), 7.43 (br. s., 1H), yl)pyrrolidine- 0.80 6.82 (br. s., 2H), 3.75 (br. s., 1-carbonyl) 5.6, >99.7% B A 8H), 3.57 - 3.33 (m, 3H), 2.29 (2,6- Whelko, 5 x 50 cm, 10 515.1 - 2.05 (m, 4H), 1.41 (br. s., dimethoxyphen micron; 2H), 1.13 (br. s., 2H), 0.69 yl) mobile phase: 20% IPA/80% (br. s., 3H) hydroxypyrimid CO2; Flow Conditions: 350 in-4(1H)-one , 30°C, wavelength: 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range -(3-(2,4- difluorophenyl) pyrrolidine 1H NMR (500MHz, carbonyl) METHANOL-d4) 8.04 - (2,6- 7.32 (m, 2H), 7.14 - 6.68 (m, 0.82 dimethoxyphen 2.53, 92.7% 4H), 4.13 (br. s., 2H), 3.84 B A yl) Chiralpak IC, 4.6 x 250 mm, (br. s., 13H), 2.44 - 2.29 (m, 516.1 (ethoxymethyl)- 5 ; mobile phase: 1H), 2.20 - 2.09 (m, 1H), 1.13 6- 10% % CO2; Flow (br. s., 3H) hydroxypyrimid Conditions: 3 mL/min, 140 in-4(1H)-one bar, 45°C, wavelength: 200- 400 nm (isomer 1) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range -(3-(2,4- difluorophenyl) pyrrolidine 1H NMR (500MHz, carbonyl) METHANOL-d4) 8.04 - (2,6- 7.32 (m, 2H), 7.14 - 6.68 (m, 0.82 dimethoxyphen 2.78, 95.7% 4H), 4.13 (br. s., 2H), 3.84 B A yl) Chiralpak IC, 4.6 x 250 mm, (br. s., 13H), 2.44 - 2.29 (m, 516.1 (ethoxymethyl)- 5 micron; mobile phase: 1H), 2.20 - 2.09 (m, 1H), 1.13 6- 10% IPA/90% CO2; Flow (br. s., 3H) hydroxypyrimid Conditions: 3 mL/min, 140 in-4(1H)-one bar, 45°C, wavelength: 200- 400 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 362 1-(2,6- 1H NMR (500MHz, DMSO- dimethoxyphen d6) 7.86 - 7.78 (m, 1H), yl) 7.70 - 7.63 (m, 1H), 7.61 - (ethoxymethyl)- 5.68, >99% 7.53 (m, 1H), 7.50 - 7.38 (m, 6-hydroxy pak IC, 4.6 x 250 mm, 0.83 2H), 6.86 - 6.74 (m, 2H), 3.95 oxo-1,4- 5 micron; mobile phase: B A (d, J=9.5 Hz, 2H), 3.78 - 3.35 dihydropyrimid 15% IPA/0.1% DEA /85% 505.0 (m, 10H), 3.35 - 3.20 (m, ine CO2; Flow Conditions: 2 2H), 2.40 - 2.26 (m, 1H), 2.06 carbonyl)pyrrol mL/min, 150 bar, 45°C, (br. s., 1H), 1.02 - 0.90 (m, idin wavelength: 220 nm (isomer 3H) yl)benzonitrile 2) 363 2-(1-(1-(2,6- 1H NMR (500MHz, DMSO- dimethoxyphen d6) 7.86 - 7.78 (m, 1H), yl) 7.70 - 7.63 (m, 1H), 7.61 - (ethoxymethyl)- 4.87, >99% 7.53 (m, 1H), 7.50 - 7.38 (m, 6-hydroxy Chiralpak IC, 4.6 x 250 mm, 0.83 2H), 6.86 - 6.74 (m, 2H), 3.95 oxo-1,4- 5 micron; mobile phase: B A (d, J=9.5 Hz, 2H), 3.78 - 3.35 dihydropyrimid 15% IPA/0.1% DEA /85% 505.0 (m, 10H), 3.35 - 3.20 (m, ine CO2; Flow Conditions: 2 2H), 2.40 - 2.26 (m, 1H), 2.06 yl)pyrrol mL/min, 150 bar, 45°C, (br. s., 1H), 1.02 - 0.90 (m, idin wavelength: 220 nm 3H) yl)benzonitrile (isomer1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 2-(1-(2-butyl 1H NMR z, DMSO- (2,6- d6) 7.82 (t, J=6.1 Hz, 1H), dimethoxyphen 7.72 - 7.56 (m, 2H), 7.49 - yl)hydroxy- 5.68, >99% 7.38 (m, 2H), 6.88 - 6.76 (m, 4-oxo-1,4- pak IC, 4.6 x 250 mm, 2H), 4.05 - 3.36 (m, 11H), micron; mobile phase: B A dihydropyrimid 2.35 - 2.28 (m, 1H), 2.24 - % IPA/0.1% DEA /85% 503.0 ine 2.12 (m, 2H), 2.08 - 1.97 (m, carbonyl)pyrrol CO2; Flow Conditions: 2 1H), 1.50 - 1.32 (m, 2H), 1.20 idin mL/min, 150 bar, 45°C, - 1.03 (m, 2H), 0.78 - 0.60 yl)benzonitrile wavelength: 220 nm (isomer (m, 3H) 2-(1-(2-butyl 1H NMR (500MHz, DMSO- (2,6- d6) 7.82 (t, J=6.1 Hz, 1H), dimethoxyphen 7.72 - 7.56 (m, 2H), 7.49 - yl)hydroxy- 4.87, >99% 7.38 (m, 2H), 6.88 - 6.76 (m, 4-oxo-1,4- Chiralpak IC, 4.6 x 250 mm, 2H), 4.05 - 3.36 (m, 11H), micron; mobile phase: B A dihydropyrimid 2.35 - 2.28 (m, 1H), 2.24 - % IPA/0.1% DEA /85% 503.0 ine 2.12 (m, 2H), 2.08 - 1.97 (m, carbonyl)pyrrol CO2; Flow Conditions: 2 1H), 1.50 - 1.32 (m, 2H), 1.20 - mL/min, 150 bar, 45°C, - 1.03 (m, 2H), 0.78 - 0.60 yl)benzonitrile wavelength: 220 nm (m, 3H) (isomer1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 366 2-butyl(2,6- 1H NMR (400MHz, 0.77 A dimethoxyphen METHANOL-d4) 8.31 - B yl)(3-(3- 8.17 (m, 1H), 7.49 - 7.32 (m, 497.3 fluoropyridin 2H), 7.22 (dt, J=8.5, 4.2 Hz, yl)pyrrolidine- 1H), 6.73 (d, J=8.4 Hz, 2H), 1-carbonyl) 9.5, >99.8% 3.94 - 3.46 (m, 11H), 2.27 (d, hydroxypyrimid Whelko, 5 x 50 cm, 10 J=7.9 Hz, 4H), 1.44 (br. s., in-4(1H)-one micron; mobile phase: 10% 2H), 1.17 - 1.04 (m, 2H), 0.67 % CO2; Flow (t, J=7.4 Hz, 3H) Conditions: 340 mL/min, 45°C, wavelength: 220 nm (isomer 2) 367 2-butyl(2,6- 1H NMR (400MHz, 0.77 A dimethoxyphen METHANOL-d4) 8.31 - B yl)(3-(3- 8.17 (m, 1H), 7.49 - 7.32 (m, 497.3 fluoropyridin 2H), 7.22 (dt, J=8.5, 4.2 Hz, yl)pyrrolidine- 1H), 6.73 (d, J=8.4 Hz, 2H), 1-carbonyl) 8.5, >99.8% 3.94 - 3.46 (m, 11H), 2.27 (d, hydroxypyrimid Whelko, 5 x 50 cm, 10 J=7.9 Hz, 4H), 1.44 (br. s., in-4(1H)-one ; mobile phase: 10% 2H), 1.17 - 1.04 (m, 2H), 0.67 IPA/90% CO2; Flow (t, J=7.4 Hz, 3H) Conditions: 340 , 45°C, wavelength: 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 368 2-(1-(2-(tertbutoxymethyl )- 1H NMR (500MHz, DMSO- 1-(2,6- d6) 7.88 - 7.76 (m, 1H), dimethoxyphen 5.68, >99% 7.71 - 7.54 (m, 2H), 7.50 - hydroxy- Chiralpak IC, 4.6 x 250 mm, 7.35 (m, 2H), 6.86 - 6.70 (m, 0.83 1,4- 5 micron; mobile phase: 2H), 3.86 (br. s., 2H), 3.17 (s, B A dihydropyrimid 15% IPA/0.1% DEA /85% 11H), 2.37 - 2.26 (m, 1H), 533.1 ine CO2; Flow Conditions: 2 2.11 - 2.00 (m, 1H), 0.82 (d, carbonyl)pyrrol mL/min, 150 bar, 45°C, J=14.6 Hz, 9H) idin wavelength: 220 nm (isomer yl)benzonitrile 2) 369 2-(1-(2-(tertbutoxymethyl )- 1H NMR (500MHz, DMSO- 1-(2,6- d6) 7.88 - 7.76 (m, 1H), dimethoxyphen 4.87, >99% 7.71 - 7.54 (m, 2H), 7.50 - yl)hydroxy- pak IC, 4.6 x 250 mm, 7.35 (m, 2H), 6.86 - 6.70 (m, 0.83 4-oxo-1,4- 5 micron; mobile phase: 2H), 3.86 (br. s., 2H), 3.17 (s, B A dihydropyrimid 15% IPA/0.1% DEA /85% 11H), 2.37 - 2.26 (m, 1H), 533.1 ine CO2; Flow Conditions: 2 2.11 - 2.00 (m, 1H), 0.82 (d, carbonyl)pyrrol mL/min, 150 bar, 45°C, J=14.6 Hz, 9H) idin wavelength: 220 nm yl)benzonitrile (isomer1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range l(2,6- 1H NMR (400MHz, dimethoxyphen METHANOL-d4) 8.30 (br. yl)(3-(5- s., 1H), 7.33 (s, 3H), 6.80 - 0.75 fluoropyridin 6.67 (m, 2H), 3.81 - 3.44 (m, B A yl)pyrrolidine- 8.4, >99.7% 497.3 1-carbonyl) Whelko, 5 x 50 cm, 10 11H), 2.28 (t, J=7.6 Hz, 4H), 1.43 (br. s., 2H), 1.18 - 1.03 hydroxypyrimid micron; mobile phase: 10% IPA/90% CO2; Flow (m, 2H), 0.74 - 0.56 (m, 3H) in-4(1H)-one Conditions: 340 mL/min, 45°C, ngth: 220 nm (isomer 2) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 2-butyl(2,6- 1H NMR (400MHz, dimethoxyphen METHANOL-d4) 8.30 (br. yl)(3-(5- s., 1H), 7.33 (s, 3H), 6.80 - 0.75 fluoropyridin 6.67 (m, 2H), 3.81 - 3.44 (m, B A yl)pyrrolidine- 7.7, >95.5% 497.3 1-carbonyl) Whelko, 5 x 50 cm, 10 11H), 2.28 (t, J=7.6 Hz, 4H), 1.43 (br. s., 2H), 1.18 - 1.03 hydroxypyrimid ; mobile phase: 10% IPA/90% O2; Flow (m, 2H), 0.74 - 0.56 (m, 3H) in-4(1H)-one Conditions: 340 mL/min, 45°C, wavelength: 220 nm (isomer 1) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 372 5-(3-(3,5- difluoropyridin- 2- 1H NMR (500 MHz, DMSO- yl)pyrrolidine- d6) δ 8.46 (br d, J=4.6 Hz, onyl) 1H), 8.00 - 7.82 (m, 1H), 7.40 (2,6- 5.6, >99.7% (br d, J=6.1 Hz, 1H), 6.88 - dimethoxyphen Whelko, 5 x 50 cm, 10 6.73 (m, 2H), 4.07 - 3.44 (m, yl) micron; mobile phase: 20% 11H), 3.26 (br s, 2H), 2.55 (s, (ethoxymethyl)- IPA/80% CO2; Flow 2H), 2.30 - 2.04 (m, 2H), 1.05 6- Conditions: 350 mL/min, - 0.85 (m, 3H) hydroxypyrimid 30°C, ngth: 220 nm in-4(1H)-one (isomer 1) 373 1H NMR (500 MHz, DMSO- 2-butyl(4-(4- d6) δ 7.44 (t, J=8.5 Hz, 1H), chlorophenoxy) 7.30 (br d, J=8.8 Hz, 2H), piperidine 7.00 (br d, J=8.8 Hz, 2H), carbonyl) 0.97 6.82 (d, J=8.5 Hz, 2H), 3.73 (2,6- B A (s, 9H), 2.19 (br d, J=7.8 Hz, dimethoxyphen 542.0 2H), 1.91 (s, 4H), 1.64 - 1.46 yl) (m, 2H), 1.46 - 1.37 (m, 2H), hydroxypyrimid 1.20 - 1.06 (m, 2H), 0.69 (t, in-4(1H)-one J=7.3 Hz, 3H) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 374 1H NMR (500MHz, DMSO- 1-(2,6- d6) 7.43 (t, J=8.5 Hz, 1H), dimethoxyphen 7.22 - 7.15 (m, 2H), 7.11 - yl) 7.04 (m, 2H), 6.80 (d, J=8.5 (ethoxymethyl)- Hz, 2H), 3.92 (s, 2H), 3.72 (s, 0.86 -(4-(4- 6H), 3.30 - 3.22 (m, 2H), 2.55 B A fluorobenzyl)pi (s, 3H), 2.46 (d, J=6.9 Hz, 526.1 ne 2H), 1.76 - 1.65 (m, 1H), 1.61 carbonyl) - 1.44 (m, 2H), 1.18 - 0.99 hydroxypyrimid (m, 2H), 0.96 (t, J=6.9 Hz, in-4(1H)-one 375 5-(4-(4- 1H NMR (500 MHz, DMSO- benzyl)pi d6) δ 7.41 (br t, J=8.4 Hz, peridine 1H), 7.30 (br d, J=8.1 Hz, carbonyl) 2H), 7.18 (br d, J=8.1 Hz, (2,6- 2H), 6.79 (br d, J=8.5 Hz, 0.95 dimethoxyphen 2H), 3.97 - 3.51 (m, 8H), 3.24 B A yl) (br d, J=6.9 Hz, 2H), 2.55 (s, 542.0 (ethoxymethyl)- 4H), 2.48 - 2.43 (m, 2H), 1.90 6- (s, 2H), 1.74 - 1.62 (m, 1H), hydroxypyrimid 1.60 - 1.33 (m, 2H), 0.95 (s, in-4(1H)-one 3H) Ex# Structure Name Chiral amine ediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 376 (S)(3- (benzyloxy)pyrr 1H NMR (500MHz, DMSO- olidine d6) 7.43 (s, 1H), 7.37 - 7.25 carbonyl) (m, 5H), 6.81 (d, J=8.3 Hz, (2,6- 1.58 2H), 4.52 - 4.40 (m, 2H), 4.21 dimethoxyphen B A - 4.12 (m, 1H), 3.93 (s, 2H), yl) 509.2 3.74 (s, 6H), 3.57 - 3.21 (m, (ethoxymethyl)- 6H), 2.03 - 1.92 (m, 2H), 0.97 (t, J=6.9 Hz, 3H) hydroxypyrimid in-4(1H)-one 377 5-(4-(4- 1H NMR (500MHz, DMSO- chlorophenoxy) d6) 7.47 - 7.36 (m, 1H), dine 7.34 - 7.27 (m, 2H), 7.01 (d, carbonyl) J=8.7 Hz, 2H), 6.79 (d, J=8.4 (2,6- Hz, 2H), 4.60 (br. s., 1H), 0.90 dimethoxyphen 3.89 (s, 2H), 3.73 (br. s., 6H), B A yl) 3.36 - 3.16 (m, 2H), 2.55 (s, 544.0 (ethoxymethyl)- 3H), 1.91 (s, 3H), 1.67 - 1.47 6- (m, 2H), 0.97 (t, J=6.9 Hz, hydroxypyrimid 3H) in-4(1H)-one Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 378 5-(4-(2-chloro- fluorophenoxy) 1H NMR (500MHz, DMSO- dine d6) 7.50 - 7.36 (m, 1H), carbonyl) 7.23 (d, J=8.8 Hz, 1H), 6.87 - (2,6- 6.74 (m, 3H), 4.81 - 4.66 (m, B A dimethoxyphen 1H), 3.88 (br. s., 2H), 3.73 (s, 562.0 yl) 6H), 3.30 - 3.20 (m, 2H), 2.55 (ethoxymethyl)- (s, 3H), 1.91 (s, 4H), 1.73 - 6- 1.50 (m, 2H), 0.96 (br. s., 3H) hydroxypyrimid in-4(1H)-one 379 1-(2,6- dimethoxyphen 1H NMR (500MHz, DMSO- yl) d6) 7.42 (s, 1H), 7.28 - 7.20 (ethoxymethyl)- (m, 2H), 7.18 - 7.10 (m, 2H), -(4-(2- 6.80 (d, J=8.5 Hz, 2H), 3.91 B A fluorophenyl)pi (s, 2H), 3.73 (br. s., 6H), 3.51 511.2 peridine - 2.98 (m, 6H), 1.82 - 1.46 carbonyl) (m, 5H), 0.97 (t, J=6.9 Hz, hydroxypyrimid 3H) in-4(1H)-one Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 380 1H NMR (500MHz, DMSO- 2-butyl(2,6- d6) 7.63 (d, J=8.0 Hz, 2H), dimethoxyphen 7.51 - 7.31 (m, 3H), 6.84 (d, yl)hydroxy- J=8.5 Hz, 2H), 3.82 - 3.68 -(4-(4- 1.0 (m, 5H), 2.58 (d, J=6.9 Hz, uoromethyl B A 2H), 2.55 (s, 2H), 2.21 (t, )benzyl)piperidi 574.0 J=7.5 Hz, 2H), 1.84 - 1.71 ne (m, 1H), 1.62 - 1.36 (m, 4H), carbonyl)pyrimi 1.23 (s, 3H), 1.20 - 0.96 (m, din-4(1H)-one 4H), 0.70 (t, J=7.3 Hz, 3H) 381 2-butyl(4-(4- 1H NMR (500MHz, DMSO- (tertd6 ) 7.45 (s, 1H), 7.27 (d, butyl)phenoxy) J=8.6 Hz, 2H), 6.92 - 6.78 dine (m, 4H), 4.63 - 4.48 (m, 1H), 1.1 carbonyl) 3.75 (s, 6H), 2.52 - 2.48 (m, B B (2,6- 4H), 2.25 - 2.15 (m, 2H), 2.00 564.1 dimethoxyphen - 1.82 (m, 2H), 1.68 - 1.37 yl) (m, 4H), 1.24 (s, 9H), 1.19 - hydroxypyrimid 1.09 (m, 2H), 0.71 (s, 3H) in-4(1H)-one Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 382 1H NMR (500MHz, DMSO- 2-butyl(4-(2- d6) 7.52 - 7.36 (m, 2H), phenoxy) 7.33 - 7.16 (m, 2H), 6.96 (t, piperidine J=7.1 Hz, 1H), 6.87 - 6.76 carbonyl) 0.94 (m, 2H), 4.79 - 4.63 (m, 1H), (2,6- B A 3.75 (s, 6H), 2.21 (br. s., 2H), dimethoxyphen 542.0 1.91 (s, 3H), 1.72 - 1.55 (m, yl) 2H), 1.44 (br. s., 2H), 1.23 (s, hydroxypyrimid 3H), 1.15 (d, J=7.3 Hz, 2H), in-4(1H)-one 0.71 (t, J=7.3 Hz, 3H) 383 1H NMR (500 MHz, DMSO- 2-butyl(4-(2- d6) δ 7.45 (t, J=8.4 Hz, 1H), chloro 7.37 - 7.24 (m, 2H), 7.21 - fluorophenoxy) 7.08 (m, 1H), 6.83 (d, J=8.5 dine Hz, 2H), 4.38 (br s, 1H), 3.74 0.91 carbonyl) (s, 8H), 3.17 (s, 2H), 2.25 - B A (2,6- 2.17 (m, 2H), 1.96 - 1.85 (m, 560.0 dimethoxyphen 2H), 1.76 - 1.56 (m, 2H), 1.47 yl) - 1.37 (m, 2H), 1.18 - 1.09 hydroxypyrimid (m, 2H), 0.69 (t, J=7.3 Hz, in-4(1H)-one Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 384 2-butyl(4-(2- 1H NMR (500 MHz, DMSO- chloro d6) δ 7.46 (t, J=8.5 Hz, 1H), fluorophenoxy) 7.37 - 7.29 (m, 1H), 7.15 - piperidine 7.08 (m, 1H), 6.99 (t, J=8.6 yl) Hz, 1H), 4.79 (br s, 1H), 3.75 B A (2,6- (s, 6H), 3.64 - 3.25 (m, 4H), 560.0 dimethoxyphen 2.26 - 2.17 (m, 2H), 1.99 - yl) 1.84 (m, 2H), 1.74 - 1.54 (m, hydroxypyrimid 2H), 1.44 (br s, 2H), 1.23 (s, in-4(1H)-one 3H), 0.71 (t, J=7.3 Hz, 4H) 385 2-butyl(4-(2- 1H NMR (500MHz, DMSO- chloro d6) 7.55 - 7.35 (m, 2H), fluorophenoxy) 7.28 - 7.05 (m, 1H), 6.93 - piperidine 6.63 (m, 3H), 4.76 (br. s., carbonyl) 1H), 3.75 (s, 6H), 2.51 (br. s., B A (2,6- 4H), 2.26 - 2.14 (m, 2H), 1.99 560.0 dimethoxyphen - 1.85 (m, 2H), 1.73 - 1.53 yl) (m, 2H), 1.51 - 1.37 (m, 2H), ypyrimid 1.23 - 1.07 (m, 2H), 0.70 (t, in-4(1H)-one J=7.3 Hz, 3H) Ex# Structure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 386 1H NMR (600MHz, DMSO- 2-butyl(4-(2- d6) 7.45 (t, J=8.3 Hz, 1H), chloro-3,5- 7.17 (d, J=10.7 Hz, 1H), 7.05 difluorophenox (t, J=9.0 Hz, 1H), 6.84 (d, y)piperidine J=8.5 Hz, 2H), 4.87 - 4.73 carbonyl) (m, 1H), 3.75 (br. s., 6H), B A (2,6- 3.53 - 3.21 (m, 5H), 2.29 - 577.9 dimethoxyphen 2.12 (m, 2H), 1.98 - 1.84 (m, yl) 2H), 1.74 - 1.54 (m, 2H), 1.49 hydroxypyrimid - 1.33 (m, 2H), 1.15 (d, J=7.1 in-4(1H)-one Hz, 2H), 0.71 (t, J=7.2 Hz, 387 1H NMR (500MHz, DMSO- 2-butyl(4- d6) 7.46 (t, J=8.5 Hz, 1H), (2,3- 7.17 - 7.07 (m, 2H), 7.04 - rophenox 6.92 (m, 1H), 6.84 (d, J=8.5 y)piperidine Hz, 2H), 4.68 (br. s., 1H), carbonyl) 3.75 (s, 6H), 3.37 - 3.20 (m, A (2,6- 1H), 2.26 - 2.18 (m, 2H), 2.00 544.0 dimethoxyphen - 1.87 (m, 2H), 1.71 - 1.48 yl) (m, 2H), 1.48 - 1.37 (m, 2H), hydroxypyrimid 1.29 - 1.20 (m, 3H), 1.19 - in-4(1H)-one 1.09 (m, 2H), 0.70 (t, J=7.3 Hz, 3H) Ex# ure Name Chiral amine intermediate 1H NMR LC/M hAPJ with retention time S Rt cAMP (min) EC50 Metho Potency d range 388 2-butyl(4- 1H NMR (500MHz, DMSO- (2,3- d6) 7.55 - 7.42 (m, 2H), difluorobenzyl) 7.38 - 7.28 (m, 2H), 6.85 (d, piperazine J=8.5 Hz, 2H), 4.32 - 4.14 0.65 carbonyl) (m, 2H), 3.75 (s, 6H), 2.51 B A (2,6- (br. s., 8H), 2.26 (t, J=7.3 Hz, 543.1 dimethoxyphen 2H), 1.41 (d, J=7.2 Hz, 2H), yl) 1.14 (d, J=7.2 Hz, 2H), 0.69 hydroxypyrimid (t, J=7.3 Hz, 3H) in-4(1H)-one
Claims (17)
1. A compound of Formula (I): 5 (I) or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: alk is C1-6 alkylene substituted with 0-5 Re; ring B is independently selected from C3-6 cycloalkyl, C3-6 cycloalkenyl, aryl, bicyclic 10 carbocyclyl, and 6-membered heteroaryl; R1, at each occurrence, is independently selected from H, halogen, NO2, -(CH2)nORb, (CH2)nS(O)pRc, -(CH2)nC(=O)Rb, nNRaRa, -(CH2)nCN, - (CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, -(CH2)nNRaC(=O)NRaRa, - (CH2)nNRaC(=O)ORb, -(CH2)nOC(=O)NRaRa, nC(=O)ORb, - 15 (CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, -(CH2)nNRaS(O)pRc, C1-4 alkyl tuted with 0-3 Re, -(CH2)n-C3-6 carbocyclyl substituted with 0-3 Re, and - -heterocyclyl tuted with 0-3 Re; R2 is independently selected from C1-10 alkyl substituted with 0-3 Re; C2-5 alkenyl substituted with 0-3 Re, aryl substituted with 0-3 Re, heteroaryl substituted with 0- 20 3 Re, and C3-6 cycloalkyl substituted with 0-3 Re; provided when R2 is C1-5 alkyl, the carbon atoms and the groups attached thereto except the carbon atom attached to the pyrimidine ring may be ed by O, N, and S; R3 is independently selected from H and C1-5 alkyl: R4 is independently ed from -(CR7R7)n-R6, -(CR7R7)nOR6, -(CR7R7)nS(O)pR6, - 25 (CR7R7)nC(=O)R6, -(CR7R7)nNRaR6, -(CR7R7)nNRaC(=O)R6, - (CR7R7)nS(O)pNRaR6, and -(CR7R7)nNRaS(O)pR6; alternatively, R3 and R4 together with the nitrogen atom to which they are both attached form a heterocyclic ring or a spiro cyclic ring comprising carbon atoms and onal 1 to 4 atoms selected from NR5a, O, and S and substituted with 0- 5 R5; R5, at each occurrence, is independently selected from OH, halogen, -(CR7R7)n-R6, -OR6, -S(O)pR6, -C(=O)R6, -NRaR6, -C(=O)NRaR6, -NRaC(=O)R6, -NRaC(=O)OR6, - 5 OC(=O)NRaR6, -C(=O)OR6, -S(O)pNRaR6, -NRaS(O)pNRaR6, and -NRaS(O)pR6; R5a, at each occurrence, is independently ed from -C(=O)OR6, C(=O)NRaR6, - (CR7R7)n-R6, -C(=O)-R6, and -S(O)pR6; R6, at each occurrence, is ndently selected from -(CR7R7)n-C3-10 carbocyclyl and - (CR7R7)n-heteroaryl, each substituted with 0-3 R8; 10 R7, at each occurrence, is ndently selected from H, C1-4 alkyl, and n-C3-12 carbocyclyl substituted with 0-3 Re; R8, at each occurrence, is independently selected from H, halogen, -(CH2)nORb, =O, (CH2)nS(O)pRc, nC(=O)Rb, -(CH2)nNRaRa, -(CH2)nCN, - (CH2)nC(=O)NRaRa, -(CH2)nNRaC(=O)Rb, -(CH2)nNRaC(=O)NRaRa, - 15 (CH2)nNRaC(=O)ORb, -(CH2)nOC(=O)NRaRa, -(CH2)nC(=O)ORb, - (CH2)nS(O)pNRaRa, -(CH2)nNRaS(O)pNRaRa, -(CH2)nNRaS(O)pRc, C1-5 alkyl substituted with 0-3 Re, -(CH2)n-C3-6 carbocyclyl substituted with 0-3 Re, and - (CH2)n-heterocyclyl tuted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 20 Re, C2-6 alkenyl tuted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - (CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; Rb, at each occurrence, is independently ed from H, C1-6 alkyl substituted with 0-5 25 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - (CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Rc, at each occurrence, is independently selected from C1-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, C3- 30 6carbocyclyl, and heterocyclyl; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, n-aryl, -(CH2)n-heteroaryl, -(CH2)nORf, -S(O)pRf, -C(=O)NRfRf, -NRfC(=O)Rf, -S(O)pNRfRf, -NRfS(O)pRf, -NRfC(=O)ORf, - OC(=O)NRfRf and -(CH2)nNRfRf; Rf, at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl 5 (optionally substituted with halogen and OH), C3-6 cycloalkyl, and phenyl, or Rf and Rf together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C1-4alkyl; n, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and p, at each ence, is independently selected from zero, 1, and 2.
2. The compound according to claim 1, or a isomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1, at each occurrence, is independently selected from H, F, Cl, Br, NO2, -(CH2)nORb, - C(=O)Rb, -(CH2)nNRaRa, -(CH2)nCN, -(CH2)nC(=O)NRaRa, - 15 (CH2)nNRaC(=O)Rb, C1-4 alkyl substituted with 0-3 Re, and C3-6 cycloalkyl substituted with 0-3 Re; R2 is independently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl, aryl substituted with 0-3 Re, heteroaryl substituted with 0-3 Re, C3-6 cycloalkyl, – (CH2)1-4OC1-5alkyl, 1-4NHC1-5alkyl, and –(CH2)1-3OC3-6cycloalkyl; 20 R3 and R4 together with the nitrogen atom to which they are both attached form a heterocyclic ring or a spiro heterocyclic ring selected from , , , , , , , , , , , , , and ; R5, at each occurrence, is independently selected from OH, -(CR7R7)n-R6, -OR6, - S(O)pR6, -C(=O)R6, -NRaR6, -C(=O)NRaR6, -NRaC(=O)R6, -NRaC(=O)OR6, - 5 OC(=O)NRaR6, -C(=O)OR6, -S(O)pNRaR6, -NRaS(O)pNRaR6, and -NRaS(O)pR6; R5a, at each occurrence, is independently selected from -C(=O)OR6, -C(=O)NRaR6, - )n-R6, -C(=O)-R6, and R6; R6, at each occurrence, is independently selected from -(CR7R7)n-aryl, -(CR7R7)n-C3-6 cycloalkyl, and -(CR7R7)n-heteroaryl, each tuted with 0-3 R8; 10 R7, at each ence, is independently selected from H, C1-4 alkyl, and n-C3-12 carbocyclyl substituted with 0-3 Re; R8, at each ence, is independently selected from H, F, Cl, Br, -ORb, - (CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa, CN, -(CH2)nC(=O)NRaRa, - NHC(=O)ORb, C1-4 alkyl substituted with 0-3 Re, (CH2)n-C3-6 carbocyclyl 15 substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; 20 Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - (CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, -CO2H, 25 C1-6 alkyl substituted with 0-5 Rf, C2-6 alkenyl, C2-6 alkynyl, n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, - (CH2)nORf, -S(O)pRf, -C(=O)NRfRf, =O)Rf, -S(O)pNRfRf, -NRfS(O)pRf, - NRfC(=O)ORf, -OC(=O)NRfRf and -(CH2)nNRfRf; Rf, at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C1-5alkyl (optionally substituted with halogen and OH), C3-6 cycloalkyl, and ; 5 n, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and p, at each occurrence, is independently selected from zero, 1, and 2.
3. The compound according to claim 2 having Formula (II): 10 (II) or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: ring B is independently selected from , , , , , and 15 ; R1, at each occurrence, is independently ed from H, F, Cl, OH, CN, C1-4 alkyl, OC1- 4 alkyl, and C3-6 cycloalkyl; R2 is ndently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl, aryl substituted with 0-3 Re, heteroaryl substituted with 0-3 Re, C3-6 lkyl, – 20 (CH2)1-4OC1-5alkyl, and –(CH2)1-3OC3-6cycloalkyl; R3 and R4 together with the nitrogen atom to which they are both attached form a heterocyclic ring selected from , , , , , , ; R5, at each occurrence, is independently ed from OH, -(CR7R7)n-R6, -OR6, - S(O)pR6, -C(=O)R6, , NRaR6, -NRaC(=O)R6, -NRaC(=O)OR6, - 5 OC(=O)NRaR6, -C(=O)OR6, -S(O)pNRaR6, -NRaS(O)pNRaR6, and -NRaS(O)pR6; R5a is independently selected from OR6, -C(=O)NRaR6, -(CR7R7)n-R6, -C(=O)-R6, and -S(O)pR6; R6, at each occurrence, is independently selected from 7)n-aryl, -(CR7R7)n-C3-6 cycloalkyl, and -(CR7R7)n-heteroaryl, each substituted with 0-3 R8; 10 R7, at each occurrence, is independently selected from H, C1-4 alkyl, and (CH2)n-C3-12 carbocyclyl substituted with 0-3 Re; R8, at each occurrence, is independently selected from H, F, Cl, Br, -ORb, - (CH2)nC(=O)Rb, -(CH2)nC(=O)ORb, -(CH2)nNRaRa, CN, -(CH2)nC(=O)NRaRa, C1- e, -(CH e, 4 alkyl substituted with 0-3 R 2)n-C3-6 carbocyclyl substituted with 0-3 R 15 and -(CH2)n-heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl tuted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; 20 Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - (CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is ndently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 25 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, and - (CH2)nOC1-4 alkyl; and n, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.
4. A compound according to claim 3, or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1, at each occurrence, is independently ed from H, F, Cl, OH, CN, C1-4 alkyl, and OC1-4 alkyl; 5 R2 is independently selected from C1-5 alkyl tuted with 0-3 Re; C2-5 alkenyl, phenyl substituted with 0-3 Re, 5- to 6-membered aryl substituted with 0-3 Re, C3-6 cycloalkyl, and CH2O(CH2)1-3CH3; R3 and R4 together with the nitrogen atom to which they are both attached form a heterocyclic ring selected from 10 , , and ; R5 is independently at each occurrence, selected from OH, , , , , , , , , , , 15 , , , , , , , , , , , , , , , , , , , , and ; R8, at each occurrence, is independently selected from H, F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and - 5 (CH2)n-heterocyclyl substituted with 0-3 Re; R8a, at each occurrence, is ndently selected from H, CH3, aryl substituted with 0-3 Re, and heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl 10 substituted with 0-5 Re; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, and - (CH2)nOC1-4alkyl; and 15 n, at each occurrence, is independently selected from zero, 1, 2, and 3.
5. A compound according to claim 4, having Formula (III): (III) 20 or a isomer, an omer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt f, wherein: ring B is independently selected from , , , , , and R1, at each occurrence, is independently selected from H, F, Cl, OH, CN, C1-4 alkyl, and 5 OC1-4 alkyl; R2 is independently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 l, phenyl substituted with 0-3 Re, 5- to 6-membered heteroaryl substituted with 0-3 Re, C3- 6 cycloalkyl, and CH2O(CH2)1-3CH3; R5 is independently at each occurrence, selected from OH, 10 , , , , , , , , , , , , , , , , , , , , and R8, at each occurrence, is independently selected from H, F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3, NH2, -(CH2)n-aryl substituted with 0-3 Re, -(CH2)n-C3-6 5 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 R8a, at each occurrence, is independently selected from H, CH3, aryl substituted with 0-3 Re, and heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 10 Re, -(CH2)n-C3-10carbocyclyl tuted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), -OH, -OCH3, -OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, and - 15 (CH2)nOC1-4alkyl; and n, at each occurrence, is independently ed from zero, 1, 2, and 3.
6. A compound ing to claim 3, or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: 20 R1, at each occurrence, is independently selected from F, Cl, -OH, -CH2CH3, -OCH3, and -OCD3; R2 is independently selected from C1-5 alkyl substituted with 0-3 Re; C2-5 alkenyl, phenyl substituted with 0-3 Re, 5- to 6-membered heteroaryl tuted with 0-3 Re, C3-6 cycloalkyl, and -CH2O(CH2)1-3CH3; 25 R3 and R4 together with the nitrogen atom to which they are both attached form R5, at each occurrence, is independently at each occurrence, selected from -OH, F, and R5a, at each occurrence, is independently selected from 5 , , , , , , , , , , , , , , and ; 10 R8, at each occurrence, is independently selected from H, F, Cl, Br, -OCH3, -O(CH2)1- 3OCH3, -OCF3, =O, CN, CH3, CF3 -(CH2)n-aryl, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re; R8a, at each occurrence, is independently selected from H, CH3, aryl substituted with 0-3 Re, and heterocyclyl tuted with 0-3 Re; 15 Ra, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl tuted with 0-5 Re; Rb, at each occurrence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, - -C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl tuted with 0-5 Re; Re, at each ence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 5 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; and n, at each occurrence, is ndently selected from zero, 1, 2, and 3.
7. A compound according to claim 1, or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: 10 R1, at each occurrence, is independently selected from -CH2OH, -OCH3, -OCH3, -OCF3, OCH2Ph, -C(=O)NRaRa, -NRaRa, CH3, CH2CH3, CH(CH3)2, and cyclopropyl; R2 is independently selected from C1-4 alkyl tuted with 0-3 Re; C2-4 l, phenyl substituted with 0-3 Re, 5- to 6-membered heteroaryl substituted with 0-3 Re, C3-6 cycloalkyl, and CH2O(CH2)1-3CH3; 15 R3 is independently selected from H and C1-4 alkyl: R4 is independently selected from -(CHR7)1R6, -(CH2)1-3OR6, -(CH2)1-3NHR6, and - (CH2)0-3NHC(=O)R6; R6, at each occurrence, is independently selected from -(CR7R7)n-aryl, -(CR7R7)n-C3-6 cycloalkyl, and 7)n-heteroaryl, each substituted with 0-3 R8; 20 R7, at each ence, is independently selected from H, C1-4 alkyl, and aryl; R8, at each occurrence, is independently selected from H, F, Cl, -ORb, -NRaRa, C1-4 alkyl substituted with 0-3 Re, phenyl substituted with 0-3 Re, and heterocyclyl substituted with 0-3 Re; Ra, at each occurrence, is ndently selected from H, C1-6 alkyl substituted with 0-5 25 Re, -(CH2)n-phenyl substituted with 0-5 Re, and -(CH2)n-heteroaryl substituted with 0-5 Re; Rb, at each ence, is independently selected from H, C1-6 alkyl substituted with 0-5 Re, -(CH2)n-C3-10carbocyclyl substituted with 0-5 Re, and -(CH2)n-heterocyclyl substituted with 0-5 Re; 30 Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, -(CH2)n-heteroaryl; and n is independently selected from zero, 1, 2, 3, and 4.
8. A compound according to claim 5, having Formula (IV): 5 (IV) or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1, at each occurrence, is independently selected from F, Cl, OH, C1-4 alkyl, and OC1-4 alkyl; 10 R2 is independently selected from -CH2CH2CH2CH3, -CH2CH2CH(CH3)2, CH2CH2CH2CF3, -CH2-cyclopropyl, 2-cyclopropyl, cyclobutyl, entyl, CH2)1-3CH3, -CH2OCH(CH3)2, phenyl substituted with 0-2 Re, and 5- to 6-membered heteroaryl substituted with 0-2 Re; R5, at each occurrence, is independently selected from 15 , , , and R8, at each occurrence, is independently selected from F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3, -C(=O)NH2, -(CH2)n-aryl tuted with 0-3 Re, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 20 Re; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; and n is independently selected from zero, 1, 2, 3, and 4.
9. A compound according to claim 8, or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1 is both CH2CH3 or both OCH3; R2 is independently selected from 5 , , , , and R5 is independently at each occurrence, selected from and R8, at each ence, is independently ed from F, Cl, Br, -OCH3, -OCF3, CN, 10 CH3, and CF3; and Re, at each occurrence, is independently selected from F, Cl, Br, C1-3 alkyl, and cyclopropyl.
10. A compound according to claim 5, having Formula (V): or a isomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: ring B is independently selected from , , , and ; R1, at each occurrence, is independently selected from H, F, Cl, OH, CN, and OC1-4 alkyl; R2 is independently selected from 2CH2CH3, -CH2CH2CH(CH3)2, CH2CH2CH2CF3, -CH2-cyclopropyl, -CH2CH2-cyclopropyl, cyclobutyl, 5 cyclopentyl, CH2O(CH2)1-3CH3, and CH2OCH(CH3)2, phenyl substituted with 0-2 Re, and 5- to ered heteroaryl substituted with 0-2 Re; R5, at each occurrence, is independently selected from , , , and 10 R8, at each occurrence, is independently selected from F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3, -C(=O)NH2, -(CH2)n-aryl substituted with 0-3 Re, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 15 6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 cyclyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; Re’ is independently selected from C1-2 alkyl, -CH2OC1-2 alkyl, and cyclopropyl; and n is independently selected from zero, 1, 2, 3, and 4. 20
11. A compound according to claim 10, having Formula (VI): or a stereoisomer, an omer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1, at each occurrence, is independently selected from H, F, Cl, OH, CN, and OC1-4 alkyl; 5 R2 is independently selected from -CH2CH2CH2CH3, -CH2CH2CH(CH3)2, CH2CH2CH2CF3, -CH2-cyclopropyl, -CH2CH2-cyclopropyl, cyclobutyl, cyclopentyl, CH2O(CH2)1-3CH3, and CH2OCH(CH3)2, , , , , and ; R5, at each ence, is independently selected from 10 , , , and R8, at each occurrence, is independently selected from F, Cl, Br, -OCH3, -OCF3, =O, CN, CH3, CF3, -C(=O)NH2, -(CH2)n-aryl substituted with 0-3 Re, -(CH2)n-C3-6 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl tuted with 0-3 15 Re; Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, -CO2H, C1-6 alkyl (optionally substituted with F and Cl), -OH, -OCH3, -OCF3, n-C3- 6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; Re’ is ndently selected from C1-2 alkyl, -CH2OC1-2 alkyl, and cyclopropyl; and 20 n is independently selected from zero, 1, 2, 3, and 4.
12. A compound according to claim 3, having Formula (VII): (VII) or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: 5 R1, at each occurrence, is independently selected from F, Cl, -OH, C1-2 alkyl, and -OC1-2 alkyl; R2 is independently selected from -CH2CH2CH2CH3, 2CH(CH3)2, - CH2CH2CH2CF3, -CH2-cyclopropyl, -CH2CH2-cyclopropyl, cyclobutyl, cyclopentyl, -CH2O(CH2)1-3CH3, -CH2OCH(CH3)2, phenyl substituted with 0-2 10 Re, and 5- to 6-membered aryl substituted with 0-2 Re; R3 and R4 er with the nitrogen atom to which they are both ed form a heterocyclic ring selected from and ; R5 is independently at each occurrence, selected from 15 , , , and R5a is ; R8, at each occurrence, is independently selected from F, Cl, Br, -OCH3, -OCF3, CN, CH3, CF3, -C(=O)NH2, -(CH2)n-aryl substituted with 0-3 Re, -(CH2)n-C3-6 20 cycloalkyl substituted with 0-3 Re, and -(CH2)n-heterocyclyl substituted with 0-3 Re, at each occurrence, is independently selected from F, Cl, Br, CN, NO2, =O, CO2H, C1- 6 alkyl (optionally substituted with F and Cl), -OH, -OCH3, -OCF3, -(CH2)n-C3-6 cycloalkyl, -(CH2)n-C4-6 heterocyclyl, -(CH2)n-aryl, and -(CH2)n-heteroaryl; and n is ndently selected from zero, 1, 2, 3, and 4.
13. A compound according to any one of claims 1-12, wherein the compound is selected from the exemplified es or a stereoisomer, an enantiomer, a diastereoisomer, a er, or a pharmaceutically acceptable salt f. 10
14. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-12, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.
15. The compounds ing to anyone of claims 1-12 or composition according 15 to claim 13 for use in therapy.
16. A method of treating cardiovascular diseases, comprising administering to a patient in need there of a therapeutically effective amount of the pharmaceutical composition of claim 14.
17. The method of claim 16 wherein said cardiovascular diseases are coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart e, heart failure with preserved ejection fraction, myopathy, myocardial infarction, left ventricular dysfunction, left ventricular dysfunction after myocardial 25 infarction, cardiac hypertrophy, myocardial remodeling, myocardial remodeling after infarction or after cardiac surgery and ar heart diseases.
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