WO2013142396A1 - N3-substituted iminopyrimidinones as renin inhibitors, compositions, and their use - Google Patents

Abstract

In its many embodiments, the present invention provides provides certain N3-substituted iminopyrimidinones of Formula (I): and tautomers and stereoisomers thereof, and pharmaceutically acceptable salts of said compounds, said tautomeros and said stereoisomers, wherein each of the variables shown in the formula are as defined herein. The novel compounds of the invention are useful as renin inhibitors and/or for the treatment and prevention of various pathologies related thereto, including cardiovascular events, hypertension, and renal insufficiency. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, are also disclosed.

Description

TITLE OF THE INVENTION

N3 -SUBSTITUTED INOPYR IDINONES AS RENIN INHIBITORS, COMPOSITIONS, AND THEIR USE JOINT RESEARCH AGREEMENT

The claimed invention was made as a result of activities undertaken within the scope of a joint research agreement between Merck, Sharp & Dohme, Corp. (formerly Schering Corporation) and Albany Molecular, Inc. The agreement was executed on August 21, 2007. FIELD OF THE INVENTION

This invention relates to novel renin inhibitors of the general Formula (I). The invention also relates to processes for the preparation of such compounds, pharmaceutical compositions comprising one or more compounds of Formula (I), and to their use as renin inhibitors and in indications in which renin inhibition may be desirable, including but not limited to cardiovascular events, hypertension, and renal insufficiency.

BACKGROUND OF THE INVENTION

Aspartic proteases, including renin, ieta-secretase (BACE), Candida albican secreted aspartyl proteases, HIV protease, HTLV protease, and plasmepsins I and Π, are implicated in a number of disease states. In hypertension, elevated levels of angiotensin I, the product of renin-catalyzed cleavage of angiotensinogen, are present. Elevated levels of beta- amyloid, the product of BACE activity on amyloid precursor protein, are widely believed to be responsible for the amyloid plaques present in the brains of Alzheimer's disease patients.

Secreted aspartyl proteases play a role in the virulence of the pathogen Candida albicans. The viruses HIV and HTLV depend on their respective aspartic proteases for viral maturation.

Plasmodium falciparum uses plasmepsins I and Π to degrade hemoglobin.

In the renin-angiotensin system (RAS), biologically active peptide angiotensin II (Ang Π) is generated by a two-step mechanism. The highly specific renin enzyme cleaves angiotensinogen to angiotensin I (Ang I), which is then further processed to Ang II by the less specific angiotensin-converting enzyme (ACE). Ang II is known to act on four receptor subtypes, AT_1-4. ATi seems to transmit most of the known functions of Ang II, i.e.,

vasoconstriction, increased cardiac contractility, renal tubular sodium reabsorption, vascular and cardiac hypertrophy, etc. (see, e.g., Levy, B.I., Circulation, 2004, 109, 8). AT_2-4 are less well- characterized; AT₂ may antagonize the effects of ATi (see, e.g., Porrello, E.R., et al, Frontiers in Bioscience, 2009, 14, 958).

Modulation of the RAS thus represents a major target for the treatment of cardiovascular diseases. ACE inhibitors and angiotensin receptor blockers (ARBs) have been used to treat hypertension. In addition, ACE inhibitors are in clinical use for renal protection (Kshirsagar, K.V., et al, Americal Journal of Kidney Diseases, 2000, 35, 695), the prevention of congestive heart failure (Konstam M.A., et al, Circulation, 1992, 6, 431) and the treatment of myocardial infarction (Pfeffer, M.A., et al N. Engl Med, 1992, 327, 669).

Renin inhibitors present an attractive therapeutic approach due to the specificity of renin (Kleinert H.D., Cardiovasc. Drugs, 1995, 9, 645; Mclnnes, G.T., J. Human

Hypertension, 2007, 21, 766). Angiotensinogen is the only substrate known for renin. By contrast, ACE cleaves bradykinin in addition to Ang I, and Ang I can also be cleaved by chymase, a serine protease (Husain, A., J. Hypertens., 1993, 11, 1555). In some patients administration of ACE inhibitors leads to bradykinin accumulation, causing cough and potentially life-threatening angioneurotic edema (Israili, Z.H., et al, Annals of Internal Medicine, 1992, 117, 234). Importantly, because chymase is not inhibited by ACE inhibitors, the formation of Ang Π can still occur in patients treated with ACE inhibitors. As renin inhibitors would be expected to demonstrate a different pharmaceutical profile than ACE inhibitors and ARBs with regard to efficacy in blocking the RAS, they may represent an alternative to some of the more harmful aspects of these agents.

Renin inhibitors are known in the art. Among the early renin inhibitors discovered include peptidomimetics. Peptidomimetic renin inhibitors have seen limited clinical experience due to their peptidomimetic character, which imparts insufficient oral activity at a high cost of goods. Azizi M., et al, J. Hypertens., 1994, 12, 419; Neutel J. M., et al, Am. Heart, 1991, 122, 1094. Certain non-peptide renin inhibitors are described which exhibit good in vivo activity. (Oefner C, et al, Chem Biol, 1999, 6, 127; WO 97/09311; Maerki H.P., et al., 11 Farmaco, 2001, 56, 21). Renin inhibitors are disclosed or mentioned in the following patent and literature references:

WO2009056617, Herold, Peter, et al , Speedel Experimenta AG, Switz., PCT Int.

Appl. A2 20090507. Bezencon, Olivier, et al, Actelion Pharmaceuticals Ltd., Allschwil, Switz. Journal of Medicinal Chemistry ACS ASAP. Publisher: American Chemical Society, CODEN: JMCMAR ISSN: 0022-2623. AN 2009:427599 CAPLUS. Messerli, Franz H., Journal of the American College of Cardiology (2009), 53(6), 468-470. AN 2009:157358 CAPLUS. WO2009005002, Nakahira, Hiroyuki, et al, (Dainippon Sumitomo Pharma Co., Ltd., Japan). PCT Int. Appl. (2009). WO 2009001915 Al, Kuroita, Takanobu, et al, (Takeda Pharmaceutical Company Limited, Japan). PCT Int. Appl. (2008). US2008-146073 20080625, Yokokawa, Fumiaki, et al, U.S. Pat. Appl. Publ. (2008). WO2008153135 Al, Nakahira, Hiroyuki, et al, (Dainippon Sumitomo Pharma Co., Ltd., Japan). PCT Int. Appl. (2008).

WO2008153182 Al, Akatsuka, Hidenori, et al, (Mitsubishi Tanabe Pharma Corporation, Japan; Shanghai Pharmaceutical (Group) Co., Ltd.). PCT Int. Appl. (2008). WO2008141462 Al, Wu, Tom Yao-Hsiang, et al, (Merck Frosst Canada Ltd., Can.), PCT Int. Appl. (2008). WO2008139941 Al, Kuroita, Takanobu, et al, (Takeda Pharmaceutical Company Limited, Japan). PCT Int. Appl. (2008). WO2008136457 Al, Nakahira, Hiroyuki, et al, (Dainippon Sumitomo Pharma Co., Ltd., Japan). PCT Int. Appl. (2008). WO2008128832 Al, Almirante, Nicoletta, et al, (Nicox S. A., Fr.). PCT Int. Appl. (2008). WO2008121506 A2, Gwaltney, Stephen L., et al, (Takeda Pharmaceutical Company Limited, Japan). PCT Int. Appl. (2008). WO2008119772 Al, Kvarnstroem, Ingemar, et al, (Medivir AB, Swed.), PCT Int. Appl. (2008). 20080328. Priority: EP 2007-105324 20070330; EP 2007-105325 20070330. CAN 149:425652 AN 2008:1210636 CAPLUS. WO2008113835 Al, Herold, Peter, et al, PCT Int. Appl. (2008). WO2008107365 Al, Belda, Oscar, et al, (Medivir AB, Swed.), PCT Int. Appl. (2008).

WO2008093737 Al, Nakahira, Hiroyuki, et al, (Dainippon Sumitomo Pharma Co., Ltd., Japan). PCT Int. Appl. (2008). WO2008089005 A2, Kwok, Lily, et al, (Takeda Pharmaceutical Company Limited, Japan). PCT Int. Appl. (2008). WO2008077917 Al, Herold, Peter, et al, (Speedel Experimenta AG, Switz.). PCT Int. Appl. (2008). WO2008058387 Al, Dube, Daniel, et al, (Merck Frosst Canada Ltd., Can.). PCT Int. Appl. (2008). WO2008040764 Al, Herold, Peter, et al, (Speedel Experimenta AG, Switz.), PCT Int. Appl. (2008). WO2008019735 Al, Funke-Kaiser, Heiko, et al (Charite - Universitaetsmedizin Berlin, Germany), PCT Int. Appl. (2008). WO2006129237 A2, Bezencon, Olivier, et al, (Actelion Pharmaceuticals Ltd, Switz.; Chen, Austin, Chih-Yu). PCT Int. Appl. (2006). WO2007148774 Al, Miyazaki, Shojiro, et al, (Daiichi Sankyo Company, Limited, Japan). PCT Int. Appl. (2007). WO2007148775 Al , Miyazaki, Shojiro, et al, (Daiichi Sankyo Company, Limited, Japan), PCT Int. Appl. (2007). WO2007144769 A2 , Bocskei, Jozsef Zsolt, et al, (Sanofi-Aventis, Fr.), PCT Int. Appl. (2007). WO2007144129 A2, Maibaum, Juergen Klaus, et al, (Novartis A.-G., Switz.; Novartis Pharma G.m.b.H.), PCT Int. Appl. (2007). WO2007144128 Al, Maibaum, Juergen Klaus, et al, (Novartis A.-G., Switz.; Novartis Pharma G.m.b.H.), PCT Int. Appl. (2007). WO2007123718 Al, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA). PCT Int. Appl. (2007).

WO2007120523 A2, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA). PCT Int. Appl. (2007). WO2007117961 A2, Jones, Benjamin, et al, (Takeda Pharmaceutical Company

Limited, Japan). PCT Int. Appl. (2007). WO2007102127 A2, Bezencon, Olivier, et al, (Actelion Pharmaceuticals Ltd, Switz.). PCT Int. Appl. (2007). WO2007099509 A2, Bezencon, Olivier, et al, (Actelion Pharmaceuticals Ltd, Switz.), PCT Int. Appl. (2007). WO2007094513 A2, Kuroita, Takanobu, et al, (Takeda Pharmaceutical Company Limited, Japan), PCT Int. Appl. (2007). WO2007077005 Al, Ehara, Takeru, et al, (Novartis AG, Switz.; Novartis Pharma GmbH). PCT Int. Appl. (2007). WO2007039183 Al, Mickel, Stuart John, et al, (Novartis AG, Switz.; Novartis Pharma GmbH), PCT Int. Appl. (2007). WO2007031558 Al, Herold, Peter, et al, (Speedel Experimenta A.-G., Switz.). PCT Int. Appl. (2007). WO2007009250 Al, Bayly, Christopher I., et al, (Merck Frosst Canada Ltd., Can.). PCT Int. Appl. (2007). WO2007006534 A2, Breitenstein, Werner, et al, (Novartis A.-G., Switz.; Novartis Pharma G.m.b.H.). PCT Int. Appl. (2007). WO2008156832 A2, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA). PCT Int. Appl. (2008). WO2008156828 A2, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA). PCT Int. Appl. (2008). WO2008156817 A2, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA), PCT Int. Appl. (2008). WO2008156816 A2, Baldwin, John J., (Vitae Pharmaceuticals, Inc., USA), PCT Int. Appl. (2008). WO2008156831 A2, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA; SmithKline Beecham Corporation).

WO2008124575 , Baldwin, John J., et al, (Smithkline Beecham Corporation, USA; Vitae Pharmaceuticals, Inc.)., PCT Int. Appl. (2008). WO2008124582 Al, Baldwin, John J., et al, (Smithkline Beecham Corporation, USA; Vitae Pharmaceuticals, Inc.). PCT Int. Appl. (2008). WO2008124577 Al, Baldwin, John J., et al, (Smithkline Beecham Corporation, USA; Vitae Pharmaceuticals, Inc.). PCT Int. Appl. (2008). WO2008036247 Al, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA). PCT Int. Appl. (2008). WO2008036216 Al, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA), PCT Int. Appl. (2008). WO2007117482, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA; Smithkline Beecham Corporation). PCT Int. Appl. (2007). WO2007117559 A2, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA). PCT Int. Appl. (2007). WO2007117560 A2, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA). PCT Int. Appl. (2007). WO2007117557 A2, Baldwin, John J., et al, (Vitae Pharamceuticals, Inc., USA). PCT Int. Appl. (2007). WO2007070201 Al, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA), PCT Int. Appl. (2007). WO2006042150 Al, Baldwin, John J., et al, (Vitae Pharmaceuticals, Inc., USA), PCT Int. Appl. (2006).

WO2005058311 (Zhu, et al.), WO 2006065277, and WO2008103351, disclose certain substituted imino heterocyclic compounds, including certain substituted iminohydantoins and substituted iminopyrmidinones, as inhibitors of aspartyl protease. Additional disclosures of mono- and multicyclic iminoheterocyclic compounds are known in the art, including:

WO2006138266, WO2006138265, WO2006138195, WO2006138264, WO2009131975, WO2006138217, WO2007050721, WO2007053506, WO2007146225, WO2008073370, WO2008073365, WO2009131974, WO2011044187, WO2011044181, WO2011044185, and WO2011044184. Such compounds are not disclosed as being selective inhibitors of renin, however. There remains a need in the art for novel compounds that exhibit good potency and selectivity for renin over other aspartyl proteases. The present invention, surprisingly and advantageously, meets this and other needs.

SUMMARY OF THE INVENTION

The present invention provides certain N3 -substituted iminopyrimidinone compounds, which are collectively or individually referred to herein as "compound(s) of the invention", as described in Formula (I) below and elsewhere herein. The present invention further provides compositions, including pharmaceutical compositions, comprising one or more compounds of the invention (e.g., one compound of the invention), or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of said compound(s) and/or said tautomer(s), optionally together with one or more additional therapeutic agents, optionally in an acceptable (e.g., pharmaceutically acceptable) carrier or diluent.

Moreover, the present invention further provides processes for the preparation of the compounds of the invention, as well as pharmaceutical compositions comprising one or more of said compounds in the free form or in pharmaceutically acceptable salt form, together with one or more customary pharmaceutical excipient(s). Combinations of the compounds of the invention together with one or more additional pharmaceutically active agents are also provided.

The present invention further provides methods for the inhibition of renin activity and of treatment, prevention, ameliroation and/or delaying onset of diseases or disorders in which the inhibition of renin has or may have a therapeutic effect. Such conditions include

hypertension, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, postinfarction cardiomyopathy, nephropathy, vasculopathy, neuropathy, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperadosteronism, anxiety states. In hypertension, elevated levels of antiogensin I, the product of renin catalyzed cleavage of angiotensinogen, are present. Thus, the compounds of the invention are contemplated for use in the treatment of hypertension, heart failure, including acute and chronic congestive heart failure; left ventricular dysfunction; cardiac hypertrophy; cardiac fibrosis; cardiomyopathy (e.g., diabetic cardiac myopathy and post-infarction cardiac myopathy); supraventricular and ventricular arrhythmias; atrial fibrillation; atrial flutter; detrimental vascular remodeling; myocardial infarction and its sequelae; atherosclerosis; angina (stable or unstable); renal failure conditions, including but not limited to diabetic nephropathy; glomerulonephritis; renal fibrosis;

scleroderma; glomerular sclerosis; microvascular complications, including diabetic retinopathy; renal vascular hypertension; vasculopathy; neuropathy; complications resulting from diabetes, including nephropathy, vasculopathy, retinopathy and neuropathy, diseases of the coronary vessels, proteinuria, albumenuria, post-surgical hypertension, metabolic syndrome, obesity, restenosis following angioplasty, eye diseases and associated abnormalities including raised intra-ocular pressure, glaucoma, retinopathy, abnormal vascular growth and remodeling, angiogenesis-related disorders, including neovascular age related macular degeneration;

hyperaldosteronism, anxiety states, and cognitive disoders. (Fischer N.D., et al, Expert Opin. Investig. Drugs., 2001, 10, 417-26.)

The present invention also provides methods of inhibiting renin activity, wherein said method comprises administering a compound of the invention in an amount sufficient to provide an effective amount for renin inhibition in an organism. These and other embodiments of the invention, which are described in detail below or will become readily apparent to those of ordinary skill in the art, are included within the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In each of the various embodiments of the compounds of the invention described herein, each variable (including those in each of Formula (I) and the various embodiments thereof) it shall be understood that each variable is to be selected independently of the others unless otherwise indicated.

Each of the various embodiments of the compounds of the invention described herein, including those in each of Formula (I) and the various embodiments thereof, and in each of the compounds of the examples, are intended to encompass all forms of the compounds such as, for example, any solvates, hydrates, stereoisomers, and tautomers of said compounds and of any pharmaceutically acceptable salts thereof, unless otherwise stated or shown.

In one embodiment, the compounds of the invention have the general structure shown in Formula (I):

(I)

or a tautomer thereof having the structural Formula (Γ):

(Γ)

or a pharmaceutically acceptable salt, solvate, ester, prodrug, or stereoisomer of said compound or said tautomer, wherein :

n and m are each an integer independently selected from 0 to 2;

W is selected from the group consisting of-C(O)- and -S(0)₂-; ring A is selected from the group consisting of phenyl, heteroaryl, and heterocycloalkyl;

-Li- is a divalent moiety selected from the group consisting of

-C(0)-N(RL1)-CH(RL2)-,

wherein

R^L1 and R^L3 (when present) are each independently selected from the group conisisting of H and methyl;

R^L2 is selected from the group consisting of H, -(Ci-C₆)alkyl, -(C Ce^eteroalkyl, and , -(C C₃)alkyl-N(R^L4)C(0)R^L5;

R^M is selected from the group consisting of H and -(Ci-C₃)alkyl;

R^L5 is selected from the group consisting of H, -(Ci-C₃)alkyl, -0(C₁-C₃)alkyl, and

-OH;

each R¹ (when present) is independently selected from the group consisting of halo, -CN, -(d-C₆)alkyl, -(C_rC₆)alkoxy, -(C_!-C₆)haloalkyl, -NHS(0)₂alkyl, and

-N((C]-C₆)alkyl)S(0)₂alkyl;

each R² (when present) is independently selected from the group consisting of halo, -CN, -(Ci-C₆)alkyl, -(Ci-C₆)haloalkyl, -NHS(0)₂alkyl, and -N((CrC₆)alkyl)S(0)₂alkyl;

R³ and R⁴ are each independently selected from the group consisting of H, F and alkyl, wherein said alkyl of R³ is unsubstituted or substituted with from 1-2 groups independently selected from the group consisting of halo, hydroxyl and alkoxy;

R⁵ is selected from the group consisting of H, -(Cj-C₆)alkyl, -(CrC₆)haloalkyl, and phenyl;

R⁶ is selected from the group consisting of H, -(Q-C^alkyl, cyclopropyl, cyclobutyl, and cyclopentyl, wherein each of said alkyl and said cyclopropyl, cyclobutyl, and cyclopentyl of R⁶ is unsubstituted or substituted with from 1-2 groups independently selected from the group consisting of halo, hydroxyl, and alkoxy; and

R⁷ is selected from the group consisting of H, -(C)-C₆)alkyl, and cyclopropyl, wherein each of said alkyl and said cyclopropyl of R⁷ is unsubstituted or substituted with from 1- 2 groups independently selected from the group consisting of halo, hydroxyl, and alkoxy.

In one embodiment, in each of Formulas (I) and (Γ):

each R¹ (when present) is independently selected from the group consisting of halo, -CN, -(CrC₆)alkyl, -(C_rC₆)alkoxy, -(CrC^haloalkyl, -NHS(0)₂alkyl, and

-N((C₁-C₆)alkyl)S(0)₂alkyl; and each R² (when present) is independently selected from the group consisting of halo, -CN, -(Ci-Ce)alkyl, -(CrC₆)haloalkyl; and the remaining variables are as defined in Formula (I) above.

In one embodiment, in each of Formulas (I) and (Γ), W is -C(O)-.

In one embodiment, in each of Formulas (I) and (Γ), W is -S(0)₂-.

In one embodiment, in each of Formulas (I) and (Γ), R³ is H and R⁴ is H.

In one embodiment, in each of Formulas (I) and (Γ), R⁶ and R⁷ are each independently selected from the group consisting of methyl, ethyl, propyl, /-propyl, rc-propyl, cyclopropyl, -butyl, w-butyl, and /-butyl.

In one embodiment, in each of Formulas (I) and (Γ), R⁶ is selected from the group consisting of methyl, ethyl, propyl, /-propyl, «-propyl, rc-butyl, /-butyl, /-butyl, cyclopropyl, and cyclobutyl; and R⁷ is selected from the group consisting of methyl and ethyl.

In one embodiment, in each of Formulas (I) and (Γ), R³ is H, R⁴ is selected from the group consisting of H and methyl, R⁶ is selected from the group consisting of methyl, ethyl, /- propyl, ^-propyl, cyclopropyl, /-butyl, H-butyl, /-butyl, and R⁷ is selected from the group consisting of methyl and ethyl.

In one embodiment, in each of Formulas (I) and (Γ), R⁵ is selected from the group consisting of H, methyl, and phenyl.

In one embodiment, in each of Formulas (I) and (Γ), R⁵ is selected from the group consisting of H and methyl.

In one embodiment, in each of Formulas (I) and (Γ), R⁵ is selected from the group consisting of phenyl.

In one embodiment, in each of Formulas (I) and (Γ), -Li- is

-C(0)-N(CH₃)-CH(R^L2)-, and R^L2 is selected from the group consisting of H, -(Ci-C₆)alkyl, -(Q- C₆)ether, and-(C₁-C₃)alkyl-N(R^L4)C(0)R^L5, wherein R^M is selected from the group consisting of H and -(Ci-C3)alkyl, and R^L5 is selected from the group consisting of H, -(Ci-C3)alkyl, -0(Ci- C₃)alkyl, and -OH.

hi one embodiment, in each of Formulas (I) and (Γ), -L_\- is -C(0)-NH-CH(R^L2)-, and R^L2 is selected from the group consisting of H, -(Ci-C6)alkyl, and -(CrC₆)ether.

Non-limiting examples of R^L2 include H, methyl, ethyl, propyl, /-propyl, ^-propyl, cyclopropyl, /-butyl, ra-butyl, /-butyl, -CH₂(CH₂)_p-0-(CH₂)_q(CH₃), wherein each of p and q are, independently, 0, 1, and 2.

-Li- is a divalent moiety selected from the group consisting of

-C(0)-N(RL1)-CH(RL2)-,

wherein

R^L1 and R^L3 (when present) are each independently selected from the group conisisting of H and methyl;

R^L2 is selected from the group consisting of H, -(C₁-C₆)alk;yl, -( -Ce^eteroalkyl,

R^M is selected from the group consisting of H and -(Ci-C₃)alkyl;

R^L5 is selected from the group consisting of H, -(Ci-C₃)alkyl, -0(C₁-C₃)alkyl, and

-OH;

In one embodiment, in each of Formulas (I) and (Γ), ring A is phenyl.

In one embodiment, in each of Formulas (I) and (Γ), ring A is heteroaryl. Non- limiting examples of ring A as heteroaryl include: thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, purazolyl, furazanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiadiazolyl, (e.g., 1,2,4-thiadiazolyl), pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridone, pyrazinyl, pyridone, pyrazinyl, pyridazinyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.

In one embodiment, in each of Formulas (I) and (Γ), ring A is heterocycloalkyl. Non-limiting examples of ring A as heterocycloalkyl include: piperidyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, and oxides thereof.

In one embodiment, in each of Formulas (I) and (Γ), ring A is selected from the group consisting of phenyl, thienyl, thiazolyl, isoxazylyl, pyridyl, pyrimidinyl, and pyrrolidinyl.

In one embodiment, in each of Formulas (I) and (Γ), -Li- is

-C(0)-N(R^L1)-CH(R^L2)-, and the moiety

is selected from the group consisting of

and each of n, m, R¹ and R² is as defined in Formula (I).

In one embodiment, in each of Formulas (I) and (Γ) I., -Lr - is a divalent moiety selected from the group consisting of

wherein R is selected from the group conisisting of H and methyl.

In one embodiment, in each of Formulas (I) and (Γ), -L_\- is a divalent moiety selected from the group consisting of

wherein R is selected from the group conisisting of H and methyl, and the moiety,

is selected from the group consisting of

wherein each of ring A, R¹, R², m, and n are as defined in Formulas (I) or (Γ) above.

In another version of the embodiment immediately above, ring A is phenyl and R¹, R², m, and n are as defined in Formulas (I) or (Γ) above.

In another version of the embodiment immediately above, ring A is heteroaryl, wherein said heteroaryl is selected from the group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, purazolyl, fiirazanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridone, pyrazinyl, pyridone, pyrazinyl, pyridazinyl, and triazinyl, and oxides thereof and R¹, R², m, and n are as defined in Formulas (I) or (Γ) above.

In another version of the embodiment immediately above, ring A is heterocycloalkyl, wherein said heterocycloalkyl is selected from the group consisting of piperidyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4- dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, and oxides thereof and R¹, R², m, and n are as defined in Formulas (I) or (Γ) above. In another version of the embodiment immediately above, ring A is selected from the group consisting of phenyl, thienyl, thiazolyl, isoxazylyl, pyridyl, pyrimidinyl, and pyrrolidinyl and R¹, R², m, and n are as defined in Formulas (I) or (Γ) above.

In another of each of the embodiments above in which R¹ is present, R¹ is selected from the group consisting of F, CI, CN, methyl, CF₃, -NHS(0)₂CH₃, and -N(CH₃)S(0)₂CH₃.

In another of each of the embodiments above in which R² is present, R² is selected from the group consisting of F, CI, CN, methyl, and CF_3.

Specific non-limiting examples of compounds of the invention are shown in the tables of examples below. While only one tautomeric form of each compound is shown in the tables, it shall be understood that all tautomeric forms of the compounds are contemplated as being within the scope of the non-limiting examples.

In another embodiment, 1 to 3 carbon atoms of the compounds of the invention may be replaced with 1 to 3 silicon atoms so long as all valency requirements are satisfied. In another embodiment, there is provided a composition comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent.

Definitions

The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names and chemical structures may be used interchangeably to describe that same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence the definition of "alkyl" applies to "alkyl" as well as the "alkyl" protion of "hydroxyalkyl", "haloalkyl", arylalkyl-, alkylaryl-, "alkoxy" etc.

It shall be understood that, in the various embodiments of the invention described herein, any variable not explicitly defined in the context of the embodiment is as defined in Formula (I).

In the various embodiments described herein, each variable is selected independently of the others unless otherwise indicated.

"Patient" includes both human and non-human animals. Non-human animals include those research animals and companion animals such as mice, rats, primates, monkeys, chimpanzees, great apes, canine (e.g., dogs), and feline (e.g., house cats).

"Pharmaceutical composition" (or "pharmaceutically acceptable composition") means a composition suitable for administration to a patient. Such compositions may contain the neat compound (or compounds) of the invention or mixtures thereof, or salts, solvates, prodrugs, isomers, or tautomers thereof, or they may contain one or more pharmaceutically acceptable carriers or diluents. The term "pharmaceutical composition" is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.

"Halogen" and "halo" mean fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.

"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being as described herein or independently selected from the group consisting of halo, alkyl, haloalkyl, spirocycloalkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)₂, -0-C(0)-alkyl, -0-C(0)-aryl, -O- C(0)-cycloalkyl, carboxy and -C(0)0-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

"Haloalkyl" means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.

"Heteroalkyl" means an alkyl moiety as defined above, having one or more carbon atoms, for example one, two or three carbon atoms, replaced with one or more heteroatoms, which may be the same or different, where the point of attachment to the remainder of the molecule is through a carbon atom of the heteroalkyl radical. Suitable such heteroatoms include O, S, S(O), S(0)₂, and -NH-, -N(alkyl)-. Non-limiting examples include ethers, thioethers, amines, and the like.

"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non- limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2- enyl, n-pentenyl, octenyl and decenyl.

"Alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene. More generally, the suffix "ene" on alkyl, aryl, hetercycloalkyl, etc. indicates a divalent moiety, e.g., -CH₂CH₂- is ethylene, and is para-phenylene.

"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.

"Alkenylene" means a difunctional group obtained by removal of a hydrogen atom from an alkenyl group that is defined above. Non-limiting examples of alkenylene include -CH=CH-, -C(CH₃)=CH-, and -CH=CHCH₂-.

"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Monocyclic aryl" means phenyl.

"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more substituents, which may be the same or different, as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl (which alternatively may be referred to as thiophenyl), pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,

phthalazinyl, oxindolyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The term "monocyclic heteroaryl" refers to monocyclic versions of heteroaryl as described above and includes 4- to 7-membered monocyclic heteroaryl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, O, and S, and oxides thereof. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heteroaryl moities include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, pyridoneyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl), imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.

"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein. Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like. Further non-limiting examples of c cloalkyl include the following:

"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contain at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more

substituents, which may be the same or different, as described herein. The term "monocyclic cycloalkenyl" refers to monocyclic versions of cycloalkenyl groups described herein and includes non-aromatic 3- to 7-membered monocyclic cycloalkyl groups which contains one or more carbon-carbon double bonds. Non-limiting examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohetpenyl, cyclohepta-l,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.

"Heterocycloalkyl" (or "heterocyclyl") means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the

heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term "oxide," when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S,S-dioxide. "Heterocyclyl" also includes rings wherein =0 replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Such =0 groups may be referred to herein as "oxo." An example of such a moiety is pyrrolidinone (or

pyrrolidone): As used herein, the term "monocyclic heterocycloalkyl" refers monocyclic versions of the heterocycloalkyl moities decribed herein and include a 4- to 7- membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, S- oxide, S(O), and S(0)₂. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof. Non-limiting

examples of lower alkyl-substituted oxetanyl include the moiety:

.

"Heterocycloalkenyl" (or "heterocyclenyl") means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2- dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6- tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl,

dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H- pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" also includes rings wherein =0 replaces two

used herein, the term "monocyclic heterocycloalkenyl" refers to monocyclic versions of the heterocycloalkenyl moities described herein and include 4- to 7-membered monocyclic heterocycloalkenyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(0)₂. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocyloalkenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H- pyranyl, dihydrofuranyl, fluorodihydrofuranyl, dihydrothiophenyl, and dihydrothiopyranyl, and oxides thereof. It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent O or S, as well as there are no N

or S groups on carbon adjacent to another heteroatom.

, there is no -OH attached directly to carbons marked 2 and 5.

"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy and «-butoxy. The bond to the parent moiety is through the ether oxygen.

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

When a variable appears more than once in a group, e.g., R⁸ in -N(R⁶)₂, or a variable appears more than once in a structure presented herein, the variables can be the same or different.

The solid line , as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)-stereochemistry. For example:

The wavy line ' vw _{; as usec}} herein shown crossing a line representing a chemical bond, indicates a point of attachment to the rest of the compound. Lines drawn into the

ring systems, such as, for example n cates t at the indicated line (bond) may be attached to any of the substitutable ring atoms.

"Oxo" is defined as a oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, or other ring described herein,

In this specification, where there are multiple oxygen and/or sulfur atoms in a ring system, there cannot be any adjacent oxygen and/or sulfur present in said ring system.

As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:

In another embodiment, the compounds of the invention, and/or compositions comprising them, are present in isolated and/or purified form. The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be suitable for in vivo or medicinal use and/or characterizable by standard analytical techniques described herein or well known to the skilled artisan.

It shall be understood that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

Another embodiment provides prodrugs and/or solvates of the compounds of the invention. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and

Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

For example, if a compound of the invention or a pharmaceutically acceptable salt thereof, contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Cj- C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-

(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C₂-C3)alkyl (such as β- dimethylaminoethyl), carbamoyl-(Ci-C₂)alkyl, N,N-di (Ci-C₂)alkylcarbamoyl-(Cl-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C₂-C3)alkyl, and the like.

Similarly, if a compound of the invention contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C₁-C6)alkanoyloxymethyl, l-((C₁-C6)alkanoyloxy)ethyl, 1-methyl- l-((C₁-C6)alkanoyloxy)ethyl, (Ci-C6)alkoxycarbonyloxymethyl, N-(Ci-

C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl, a-amino(C]-C4)alkanyl, arylacyl and a-aminoacyl, or α-aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH)₂, -P(0)(0(Ci-C6)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.

If a compound of the invention incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Ci-Cio)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural a- aminoacyl, -C(OH)C(0)OY' wherein Y¹ is H, (C C₆)alkyl or benzyl, -C(OY²)Y³ wherein Y² is (Q-C4) alkyl and Y³ is (Ci-C₆)alkyl, carboxy (Ci-Ce)alkyl, amino(C₁-C4)aIkyl or mono-N- or di- N,N-(Ci-C₆)alkylaminoalkyl, -C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵ is mono-N- or di-N,N- (Ci-C6)alkylamino morpholino, piperidin-l-yl or pyrrolidin-l-yl, and the like.

One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including 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. "Solvate" encompasses both solution-phase and isolatable solvates. Non- limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H₂0.

One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example M. Caira et al, J.

Pharmaceutical Sci., 1993, 3, 601-611, describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.

Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above- noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.

Another embodiment provides pharmaceutically acceptable salts of the compounds of the invention. Thus, reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.

Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen- containing groups may be quarteraized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Another embodiment provides pharmaceutically acceptable esters of the compounds of the invention. Such esters include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, Ci^alkyl, or C_1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C_1-2o alcohol or reactive derivative thereof, or by a 2,3 -di (C_6-24)acyl glycerol.

As mentioned herein, another embodiment provides tautomers of the compounds of the invention, and salts, solvates, esters and prodrugs of said tautomers. It shall be understood that all tautomeric forms of such compounds are within the scope of the compounds of the invention. For example, all keto-enol and imine-enamine forms of the compounds, when present, are included in the invention. The compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.

Another embodiment provides for diastereomeric mixtures and individual enantiomers of the compounds of the invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure

enantiomers. Also, some of the compounds of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the compounds of the invention (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated as embodiments within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.).

Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

Another embodiment provides isotopically-labelled compounds of the invention. Such compounds are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ^,4C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ^3SS, ¹⁸F, and ³⁶C1, respectively.

Certain isotopically-labelled compounds of the invention (e.g., those labeled with ³H and ¹ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon- 14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

In the compounds of the invention, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium and deuterium (²H). The presence of deuterium in the compounds of the invention is indicated by "D". Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically- enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically-enriched reagents and/or intermediates.

Polymorphic forms of the compounds of the invention, and of the salts, solvates, esters and prodrugs of the compounds of the invention, are intended to be included in the present invention.

Another embodiment provides suitable dosages and dosage forms of the compounds of the invention. Suitable doses for administering compounds of the invention to patients may readily be determined by those skilled in the art, e.g., by an attending physician, pharmacist, or other skilled worker, and may vary according to patient health, age, weight, frequency of administration, use with other active ingredients, and/or indication for which the compounds are administered. Doses may range from about 0.001 to 500 mg/kg of body weight/day of the compound of the invention. In one embodiment, the dosage is from about 0.01 to about 25 mg/kg of body weight/day of a compound of the invention, or a pharmaceutically acceptable salt or solvate of said compound. In another embodiment, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application. In another embodiment, a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.

As discussed above, the amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.

When used in combination with one or more additional therapeutic agents ("combination therapy"), the compounds of this invention may be administered together or sequentially. When administered sequentially, compounds of the invention may be administered before or after the one or more additional therapeutic agents, as determined by those skilled in the art or patient preference.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.

Accordingly, another embodiment provides combinations comprising an amount of at least one compound of the invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional agents described above.

The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. Certain assays are exemplified elsewhere in this document.

Another embodiment provides for pharmaceutically acceptable compositions comprising a compound of the invention, either as the neat chemical or optionally further comprising additional ingredients. Such compositions are contemplated for preparation and use alone or in combination therapy. For preparing pharmaceutical compositions from the compounds of the invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington 's Pharmaceutical Sciences, 18 Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.

Non-limiting examples of additional active agents useful in combination therapies for the treatment of hypertension and hypertension-related disorders (US Patent No. 5,821,232; US Patent No. 6,716,875, US Patent No. 5,663,188, Fossa, A.A., et al, Synergistic effect on reduction in blood pressure with coadministration of a renin inhibitor or an angiotensin- converting enzyme inhibitor with an angiotensin II receptor antagonist, Drug Development Research, 1994, 53(4), 422-8)), include the following. Selection of such additional active ingredients will be according to the diseases or disorders present for which treatment is desired, as determined by the attending physician or other health care provider.

AlphaAAooksrs, >eta-blockers, calcium channel blockers, diuretics, natriuretics, saluretics, centrally acting antihypertensive, angiontensin convertingn enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin-recetor blockers (ARBs), aldosterone synthease inhibitors, aldosterone-receptor antagonists, and endothelin receptor antagonists.

Non-limiting examples of ρ/ζα-blockers include doxazosin, prazosin, tamsulosin, and terazosin.

Non-limiting examples of >eta-blockers include atenolol, bisoprol, metoprolol, acetutolol, esmolol, celiprolol, taliprolol, acebutolol, oxprenolol, pindolol, propanolol, bupranolol, penbutolol, mepindolol, carteolol, nadolol, carvedilol, and their pharmaceutically acceptable salts.

Non-limiting examples of calcium channel blockers include dihydropyridines (DHPs) and non-DHPs. Exemplary DHPs include amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, niludipine, nimodiphine, nisoldipine, nitrendipine, and nivaldipine, and their pharmaceutically acceptable salts.

Non-limiting examples of diuretics include thiazide derivatives, e.g., amiloride, chlorothiazide, hydrochlorothiazide, methylchlorothiazide, and chlorothalidon.

Non-limiting examples of ACE inhibitors include alacepril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spirapril, temocapril, trandolapril, and zofenopril. Preferred ACE inhibitors include benazepril, enalpril, lisinopril, and ramipril.

Non-limiting examples of dual ACE/NEP inhibitors include omapatrilat, fasidotril, and fasidotrilat.

Non-limiting examples of ARBs include candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan. Non-limiting examples of aldosterone synthease inhibitors include anastrozole, fadrozole, and exemestane.

Non-limiting examples of aldosterone receptor antagonists are spironolactone and eplerenone.

Non-limiting examples of and endothelin receptor antagonists include bosentan, enrasentan, atrasentan, darusentan, sitaxentan, and tezosentan and their pharmaceutically acceptable salts.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

Another embodiment provides for compositions comprising a compound of the invention formulated for transdermal delivery. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Another embodiment provides for compositions comprising a compound of the invention formulated for subcutaneous delivery. Another embodiment provides for compositions suitable for oral delivery. In some embodiments, it may be advantageous for the pharmaceutical preparation comprising one or more compounds of the invention be prepared in a unit dosage form. In such forms, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. Each of the foregoing alternatives, together with their corresponding methods of use, is considered as included in the various embodiments of the invention.

In another embodiment, the invention provides a method of inhibiting renin in a patient in need thereof comprising administering at least one compound of the invention, or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer, in a therapeutically effective amount to inhibit renin in said patient. In another embodiment, the invention provides a method of treating, preventing, and/or delaying the onset of one or more diseases or disorders for which the inhibition of renin is therapeutic. Non-limiting examples of such disease or disorders include: hypertension, heart failure, including acute and chronic congestive heart failure; left ventricular dysfunction; cardiac hypertrophy; cardiac fibrosis; cardiomyopathy (e.g., diabetic cardiac myopathy and post-infarction cardiac myopathy); supraventricular and ventricular arrhythmias; atrial fibrillation; atrial flutter; detrimental vascular remodeling; myocardial infarction and its sequelae; atherosclerosis; angina (stable or unstable); renal failure conditions, including but not limited to diabetic nephropathy; glomerulonephritis; renal fibrosis; scleroderma; glomerular sclerosis; microvascular complications, including diabetic retinopathy; renal vascular hypertension; vasculopathy; neuropathy; complications resulting from diabetes, including nephropathy, vasculopathy, retinopathy and neuropathy, diseases of the coronary vessels, proteinuria, albumenuria, post-surgical hypertension, metabolic syndrome, obesity, restenosis following angioplasty, eye diseases and associated abnormalities including raised intra-ocular pressure, glaucoma, retinopathy, abnormal vascular growth and remodeling, angiogenesis-related disorders, including neovascular age related macular degeneration; hyperaldosteronism, anxiety states, and cognitive disoders. (Fischer N.D., etal, Expert Opin, Investig. Drugs., 2001, 10, 417 '-26.)

PREPARATIVE EXAMPLES

In general, the compounds in the invention may be produced by a variety of processes know to those skilled in the art and by know processes analogous thereto. The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art. The practitioner is not limited to these methods.

One skilled in the art will recognize that one route will be optimized depending on the choice of appendage substituents. Additionally, one skilled in the art will recognize that in some cases the order of steps has to be controlled to avoid functional group incompatibility.

The prepared compounds may be analyzed for their composition and purity as well as characterized by standard analytical techniques such as, for example, elemental analysis, NMR, mass spectroscopy and IR spectra.

One skilled in the art will recognize that reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective equivalents. Hence, when a specific solvent or reagent is mentioned, it is meant to be an illustrative example of the conditions desirable for that particular reaction scheme and in the preparations and examples described below.

Where NMR data are presented, 1H spectra were obtained on either a Varian VXR-200 (200 MHz, ¾, Varian Gemini-300 (300 MHz), Varian Mercury VX-400 (400MHz), or Bruker-Biospin AV-500 (500MHz), and are reported as ppm with number of protons and multiplicities indicated parenthetically. Where LC/Mass Spec (LCMS) data are presented, analyses was performed using an Applied Biosystems API- 100 mass spectrometer and CI 8 column, 10-95% CH3CN-H₂O (with 0.05% TFA) gradient. The observed parent ion is given as determined using electrospray ionization.

The invention disclosed herein is exemplified by the following illustrative processes which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art. Ammonia: NH₃

[1,1 '-Bis(diphenylphosphino)ferrocene]- Example: Ex.

dichloropalladium(II): PdCl₂dppf Grams: g

Borane dimethylsulfide complex: BH₃"Me₂S or Hexanes: hex

BH₃ DMS 40 High performance liquid chromatography:

1 -(3 -Dimethylaminopropyl)-3 - HPLC

ethylcarbodiimide hydrochloride: EDCI Hours: hrs or h

1,2-dichloroethane: DCE 1 -Hydroxy-7-azabenzotriazole: HO At 3-Chloroperoxybenzoic acid: mCPBA or 1-Hydroxybenzotriazole: HOBt or HOBT

MCPBA 45 Hydrogen: H₂

Atmosphere: atm Hydrogen chloride: HC1

Benzoyl isothiocyanate: BzNCS Isopropyl magnesium chloride: iPrMgCl n-Butyllithium: nBuLi or n-BuLi Iodomethane: Mel

Carbon dioxide: C0₂ Lithium aluminum hydride: LAH

Carbon tetrachloride: CC1₄ 50 Lithium borohydride: LiBH₄

Carboxybenzyl: CBz Lithium chloride: LiCl

Chlorotitanium triisopropoxide: ClTi( OPr)₃ Liquid chromatography mass Spectrometry:

Copper cyanide: CuCN LCMS

l,4-Diazabicyclo[2.2.2]octane: DABCO Lithium diisopropylamide: LDA

Diisopropyl azodicarboxylate: DIAD 55 Mass-to-charge ratio: m/z

Dichloromethane: DCM Methanesulfonyl chloride: MeS0₂Cl

Diisopropylethylamine: DIPEA Methanol: MeOH

4-(Dimethylamino)pyridine: DMAP Methyl magnesium bromide: MeMgBr Dimethylformamide: DMF Methyl magnesium chloride: MeMgCl

Dimethylsulfide: Me₂S 60 Microliters: μΐ or

Dimethylsulfoxide: DMSO Milligrams: mg

Ether or diethyl ether: Et₂0 Milliliters: mL

Ethyl: Et Millimoles: mmol

Ethyl acetate: EtOAc Minutes: min

Ethyl alcohol: EtOH 65 Normal: N Ν-ί-Butoxycarbonylamide: BocNH₂ Tetrahydrofuran: THF

Nuclear magnetic resonance spectroscopy: (R)-Tetrahydro-l-methyl-3,3-diphenyl-lH,3H- NMR 20 pyrrolo[l,2-c][l ,

Palladium(II) acetate: Pd(OAc)₂ 3,2]oxazaborole: (R)-(+)-2-methyl-CBS Palladium(II) hydroxide: Pd(OH)₂ oxazaborolidine

Potassium trimethylsilanolate: KOTMS Thiophosgene: CSC1₂

Retention time: TR Titanium(IV) isopropoxide: Ti(OEt)₄

Room temperature (ambient, ~25°C): rt or RT 25 Tributylphosphine: Bu₃P

Ruthenium(III) trichloride: RuCl₃ Triphenylphosphine: Ph₃P

Sodium bicarbonate: NaHC0₃ Triethylamine: Et₃N

Sodium borohydride: NaBH Trifluoroacetic acid: TFA

Sodium hydride: NaH Trifluoroacetic acid anhydride: TFAA

Sodium methoxide: NaOMe or MeONa 30 Trimethylaluminum: AlMe₃ or Me₃Al Sodium periodate: NaI0₄ Titanium(IV) isopropoxide: Ti(/OPr)

Sodium sulfate: Na₂S0₄ Tosyl: tos

tert-Butoxycarbonyl: t-Boc or Boc Watt: W

tert-Butoxycarbonyl anhydride Boc₂0

Method A:

Method A is a general alternate method for compounds of formula (I) that relies on the formation of intermediate A8. In this method, a ketone represented by structure Al is condensed with a sulfoxamine such as A2 to provide an imine A3. This imine A3 is subsequently reacted with an appropriate ester A4 under basic conditions to give intermediate A5 according to the procedures of Ellman et al. Deprotection under acidic conditions to give amino ester A6 and coupling with a protected isothiocyanate (shown here for example using 2,4 dimethoxybenzyl isothiocyanate 1-3) affords an iminopyrimidinone A7. Removal of the protecting group under hydrogenolysis conditions gives intermediate A8. Condensation of A8 with alcohols such as A9 provides compounds of type A10 which can be further reacted under acidic conditions to provide the compound of formula (I).

Method A'

A modification of this route provided a convergent synthesis as shown here:

(I) Compounds A-6 are condensed with the Boc-protected thioureas 1-4 using a reagent such as a carbodiimide to provide the compounds A- 10 which are elaborated into compounds of formula I as in method A.

A representative example that was prepared according to Method A' is illustrated below:

Intermediates A6 and 1-4 are reacted with a coupling reagent such as EDCI with triethylamine in DMF to give the ester 9. This is converted to the acid using potassium trimethylsilanolate to give 10 which is condensed with (S)-methylbenzyl amine using a carbodiimide peptide coupling reagent such as EDCI with HOBT in DMF. The amide 11 is then treated with HC1 in dioxane to provide example 1-1.

Method B:

Method B is a general alternate method for compounds of formula (I) that relies on using compounds such as B9 ( in place of A9) wherein the ring A contains a functional group (such as CI, Br, I, C0₂Me, furan or CN) to provide compounds BIO. The functional group ("FG") is then converted into the -Li-phenyl-(R²)_m substitutent and then subsequently deprotected to provide compounds of formula I.

Synthesis Of Intermediate 1-3:

Intermediate 1-2, Step 1

To a solution of 2,4-dimethoxybenzylamine 1-1 (6.6 mL, 43.5 mmol) in DCM (85 mL) was added saturated aqueous sodium bicarbonate solution (85 mL) and the mixture was stirred vigorously at RT for 15 min. Stirring was stopped then thiophosgene (6.6 mL, 87 mmol) was added via syringe to the bottom layer. The mixture was stirred at RT for 90 min then the aqueous layer was separated and the organic layer was washed with brine, dried over Na₂S0₄ and concentrated in vacuo twice from DCM to give 9.1 g (100%) of 1-2 as yellow oil.

Intermediate 1-3, Step 2

To a suspension of 60% sodium hydride in hexanes (3.4 g, 85 mmol) in anhydrous THF (100 mL) at 0 °C was added tert-butylcarbamate (7.4 g, 63 mmol) and the mixture was stirred for 15 min. A solution of Intermediate 1-2 from Step 1 (9.1 g, 43.5 mmol) in anhydrous THF (50 mL) was then added over 15 min and the reaction was allowed to warm up to RT and stirred overnight. The final mixture was quenched with water and 10% aqueous phosphoric acid until neutral pH, extracted with EtOAc, dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 80:20) to afford 10.61 g (75%) of 1-3 as a light yellow solid.

Synthesis Of Intermediate 1-4:

BocHN

To an ice cold solution of N,N-bisboc-thiourea (335.8 g) in THF (4.5 L) was added NaH (35 g) in a 12 L 3-neck RBF. After 1 hr at this temperature TFAA was added over 30 min, keeping the temperature close to 3°C. After stirring for an additional 1 hr a THF solution the amine 1-5 ( 133.7 g) in THF (0.3 L) was added over 30 min, keeping the temp at 3°C. After stirring for 90 minutes the reaction mixture was poured into 18 L cold water. 2 L brine was added to this solution and the resulting solution was extracted with 8L EtOAc and, subsequently, 4L EtOAc. The combined organic layer was dried over MgS0₄, filtered, and concentrated to dryness. The residue was further azeotroped with hexane 4L, and solidified upon cooling. The solid was filtered, and washed with cold pentane. The solid residue was triturated with 40/60 isopropanol:pentane, chilled and filtered. The solid was further washed with 40/60

isopropanol:pentane (cold) 3 x 200 ml, filtered and dried under vacuum to give the desired product as a white solid, 230 g, 92% yield.

EXAMPLE 1

Example 1, Step 1

To a solution of (R)-(+)-2-methyl-2-propanesulfinamide 1-2 (35.8 g, 295 mmol) in anhydrous THF (100 mL) was added 3-methyl-2-butanone 1-1 (21.2 g, 246 mmol) followed by titanium(IV) ethoxide (102 mL, 492 mmol) and the reaction was stirred at 75°C overnight. The final mixture was cooled to 0°C, diluted with DCM (150 mL), stirred 15 min, then ice-cold saturated aqueous sodium bicarbonate solution (32 mL) was added slowly. The slurry was stirred 20 min then filtered and concentrated in vacuo to afford 48.6 g (100%) of intermediate 1- 3 as yellow oil. Example 1, Step 2

To a solution of diisopropylamine (114 mL, 808 mmol) in anhydrous THF (350 mL) at -10°C was added 2.5N n-butyllithium in hexanes (323 mL, 808 mmol). The reaction was stirred 30 min at -10°C then cooled to -78°C and methylacetate (53 mL, 673 mmol) was added followed 1 h later by chlorotitanium triisopropoxide (225 mL, 942 mmol). After 40 minutes, a solution of intermediate 1-3 from Step 1 (51 g, 269 mmol) in anhydrous THF (50 mL) was then added dropwise and the mixture was stirred 5 h at -78°C followed by quenching with ice-cold half-saturated aqueous ammonium chloride solution (400 mL). The slurry was diluted with EtOAc then filtered, rinsing with EtOAc and water. The organic layer was washed with brine, dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 75:25) to afford 36.0 g (51%) of intermediate 1-4 as yellow oil. Example 1, Step 3

To a solution of intermediate 1-4 from Step 2 (47.2 g, 179 mmol) in MeOH (400 mL) at 0°C was added 4N HC1 in 1,4-dioxane (269 mL, 1075 mmol) over 30 min. The reaction was then stirred 90 min at RT followed by azeotropic concentration with toluene to provide 35.0 g (100%) of intermediate 1-5 as solid.

Example 1, Step 4

A solution of intermediate 1-5 from Step 3 (35.0, 179 mmol) in anhydrous DMF (350 mL) was treated with diisopropylethylamine (103 mL, 590 mmol) for 30 min then EDCI (39.4 g, 206 mmol) was added followed by intermediate 1-3 (64.2 g, 196 mmol). The reaction was heated at 65°C overnight then cooled, diluted with EtOAc and washed with brine. The organic layer was dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes/A 100:0 to 70:30 where A = DCM:EtOAc 3:2) to afford 47.8 g (64%) of intermediate 1-6 as off-white solid. Example 1, Step 5

A solution of intermediate 1-6 from Step 4 (47.8 g, 114 mmol) and 20% palladium hydroxide (17.4 g) in MeOH (3 L) was hydrogenated at 1 atm overnight then filtered over Celite, concentrated in vacuo and triturated with hexanes to provide intermediate 1-7 as first crop. The filtrate was concentrated in vacuo and purified by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 70:30) to give a second crop of intermediate 1-7 for a total of 28.4 g (93%) as off-white solid. Example 1, Step 6

A solution of intermediate 1-7 from Step 5 (550 mg, 1.70 mmol), methyl 3- (hydroxymethyl)benzoate 1-8 (568 mg, 3.42 mmol) and tributylphosphine (1.53 mL, 6.15 mmol) in anhydrous THF (5.0 mL) at 0°C was treated with diisopropyl azadicarboxylate (1.04 mL, 5.29 mmol) and the reaction was allowed to warm up to RT and stirred overnight. The mixture was concentrated in vacuo and the residue was purified by chromatography over silica gel (eluting with A/EtOAc 80:20 to 30:70 where A=hexanes/toluene 1:1) to afford 0.36 g (51%) of intermediate 1-9.

Example 1, Step 7

To a solution of intermediate 1-9 from Step 6 (400 mg, 0.958 mmol) in anhydrous THF (25 mL) was added potassium trimethylsilanolate (191 mg, 1.34 mmol). The mixture was stirred at RT for 2.5 h then concentrated in vacuo. The residue was taken up in EtOAc and extracted with diluted aqueous NaOH solution. The aqueous layer was neutralized to pH~4 with IN aqueous HC1 solution, extracted with EtOAc, dried over Na₂S0₄ and concentrated in vacuo to produce 231 mg (60%) of intermediate 1-10.

Example 1, Step 8

A solution of intermediate 1-10 from Step 7 (116 mg, 0.29 mmol), (R)-alpha- methylbenzylamine (55.6 L, 0.43 mmol), 1-hydroxybenzotriazole (58.3 mg, 0.43 mmol) and EDCI (165 mg, 0.86 mmol) in anhydrous tetrahydrofuran (5 mL) was stirred at RT for 16 h. The reaction was concentrated in vacuo and purified by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 50:50) to afford 0.12 g (82%) of intermediate 1-11.

Example 1, Step 9

Intermediate 1-11 from Step 8 (0.12 g, 0.24 mmol) was treated with a 20% TFA solution in DCM (2 mL) for 2 h at RT. The mixture was concentrated in vacuo and purified by C18 reverse phase HPLC chromatography [eluting with CH₃CN/H₂0 (0.1% TFA) 10:90 to 100:0]. The compound was then converted to the corresponding hydrochloride salt and lyophilized to provide 93.0 mg (96%) of Example 1 as a white solid. ^!H NMR (CD₃OD) 57.80 (d, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.48 (q,lH), 7.47 (s, 1H), 7.38 (d,2H), 7.32 (t, 2H), 7.23 (t, 2H), 5.22 (q, 1H), 5.13 (s, 2H), 2.94 (q, 2H), 1.86 (m, 1H), 1.56 (d, 3H), 1.29 (s, 3H), 0.94 (d, 3H), 0.92 (d, 3H). Mass Spec (ESI) mlz: 407.2 [M+H]⁺. The compounds in Table 1 were prepared following procedures similar to those of Example 1 including removing the Boc-protecting group with HCl in 1,4-dioxane as described in Step 4 or Example 3.

-42-

EXAMPLE 2

2-7 Example 2

Example 2, Step 1

To a solution of ethyl-3-fluoro-5-iodobenzoate 2-1 (2.0 g, 6.8 mmol) in anhydrous THF (10 mL) at -78°C was added 2N isopropyl magnesium chloride in THF (4.76 mL, 9.52 mmol) dropwise and the resulting solution was further stirred at -78°C for 30 min. After this time, dry CuCN (731 mg, 8.16 mmol) and LiCl (692 mg, 16.3 mmol) were added all at once to the reaction mixture. The reaction was warmed up to -50°C in 30 min and acetyl chloride 2-2 (1.6 mL, 22.5 mmol) was added to the reaction dropwise for 5 min at this temperature. The reaction mixture was allowed to warm up to RT in 60 min, then diluted with EtOAc and quenched with saturated aqueous ammonium chloride solution. The organic layer was separated; the aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes/EtOAc 99.5:0.5 to 70:30) to afford 1.1 g (77%) of intermediate 2-3 as a colorless white powder.

Example 2, Step 2

A solution of 2N borane dimethylsulfide complex in anhydrous THF (2.5 mL, 5.0 mmol) and IN (R)-(+)-2 -methyl-CBS oxazaborolidine in toluene (5.0 mL, 5.0 mmol) in anhydrous THF (8 mL) was cooled to -70°C and stirred for 10 min. Intermediate 2-3 from Step 1 (1.0 g, 4.76 mmol) in anhydrous THF (3 mL) was added dropwise over 10 min and the reaction mixture was further stirred at -70°C for 1.5 h and then gradually warmed up to -40°C over 60 min. The reaction mixture was quenched with saturated aqueous ammonium chloride, allowed to warm up to 0°C, diluted with EtOAc and allowed to stir for 5 min more. The final mixture was washed with water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes/EtOAc 99.5:0.5 to 60:40) to give 860 mg (86%, ee = 95% by Chiralpak AD) of intermediate 2-4. Example 2, Step 3

Intermediate 2-4 from Step 2 (825 mg, 3.89 mmol) was reacted with intermediate 1-7 from Step 5 of Example 1 and using conditions similar to the ones described in Step 6 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes/EtOAc 99.5:0.5 to 65:35), 886 mg (59%, ee = 95% by Chiralpak AD) of intermediate 2- 5 as a white solid.

Example 2, Step 4

Intermediate 2-5 from Step 3 (878 mg, 1.89 mmol) was subjected to conditions similar to the ones described in Step 7 of Example 1 to provide 825 mg (100%) of intermediate 2-6 as a white solid.

Example 2, Step 5 Intermediate 2-6 from Step 4 (400 mg, 0.918 mmol) was reacted with (S)-alpha- methylbenzylamine using conditions similar to the ones described in Step 8 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes EtOAc 100:0 to 65:35), 372 mg (75%) of intermediate 2-7. (R)-l-phenylethanamine could be used, as an altermative to (S)-alpha-methylbenzylamine, as in Table 1, example 1-H.

Example 2, Step 6

Intermediate 2-7 from Step 5 (370 mg, 0.66 mmol) was subjected to Boc-removal conditions similar to the ones described in Step 9 of Example 1 to provide, after purification by chromatography over silica gel (eluting with DCM/MeOH 100:0 to 90: 10), conversion to the HCl salt and lyophilization, 70 mg (26%) of Example 2 as a white solid. DMSO-d₆) δ 9.74 (s, 1H), 8.91 (d, 1H), 7.67 (d, 1H), 7.63 (s, 1H), 7.30-7.45 (m, 3H), 7.20-7.30 (m, 2H), 5.54 (br s, 1H), 5.17 (m, 1H), 2.89 (d, 1H), 2.73 (d, 1H), 2.30 (s, 3H), 1.79 (d, 3H), 1.49 (d, 3H), 1.17 (s, 3H), 0.91 (d, 3H), 0.87 (d, 3H). Mass Spec (ESI) mlz: 439.7 [M+H]⁺.

The compounds in Table 2 were prepared following procedures similar to those of

Example 2 including using procedures similar to those of Examples 1 and 3.

EXAMPLE 3

Example 3, Step 1

Methyl 3-acetylbenzoate was subjected to asymmetric reduction conditions similar to the ones described in Step 2 of Example 2 to provide intermediate 3-2 as a white solid.

Example 3, Step 2

Intermediate 3-2 from Step 1 (825 mg, 3.89 mmol) was reacted with intermediate

1-7 from Step 5 of Example 1 and using conditions similar to the ones described in Step 6 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes/EtOAc 99.5:0.5 to 65:35), 886 mg (59%, ee = 95% by Chiralpak AD) of intermediate 3- 3 as a white solid.

Example 3, Step 3

DABCO-Me3Al Complex 3-4 was prepared according to a modification of Angew. Chem. Int. Ed. 2005, 44, 2232 -2234: 2N AlMe₃ in toluene (0.90 mL, 18 mmol) was added to a solution of freshly sublimed DABCO (1.12 g,10.0 mmol) in toluene (5 mL) at 0°C very slowly. The reaction was stirred for 1 h at 0°C, the resulting white precipitate was allowed to settle, and the supernatant toluene was removed by cannula. Dry Et₂0 (20 mL) was added, swirled with the solid, the solid was allowed to settle and the supernatant liquid removed by cannula. The process was repeated 4 times and the residual slurry was evaporated to dryness to yield 1.40 g (55%) of intermediate 3-4 as a white solid.

To a stirred solution of intermediate 3-4 (51.2 mg, 0.20 mmol) in anhydrous THF (1 mL) was added benzylamine 3-5 (31.1 mg, 0.20 mmol). The solution was heated at 40°C for 1 h. Intermediate 3-3 from Step 2 (60.4 mg, 0.14 mmol) was then added and the solution was heated at 55°C for 16 h. The reaction mixture was cooled to RT and quenched with 2N aqueous HC1 (3 mL) dropwise, followed by extraction with Et₂0. The organic phase was separated and filtered through a small plug of silica. Removal of the solvent in vacuo gave 76.1 mg (98%) of intermediate 3-6.

Example 3, Step 4

A solution of intermediate 3-6 from Step 3 (195 mg, 0.35 mmol) in DCM (4 mL) was treated with 4N HC1 in 1,4-dioxane (8 mL) and heated at 45°C for 2 h. The mixture was concentrated in vacuo and purified by C 18 reverse phase HPLC chromatography [eluting with CH₃CN (0.1% TFA)/H₂0 (0.1% TFA) 10:90 to 100:0] to give 118 mg (94%) of Example 3 as a white solid. 1H NMR (CD₃OD) 5D 10.95 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.44 (m, 1H), 7.20- 7.44 (m, 7H), 6.53 (m, 1H), 6.25 (m, 1H), 5.17 (m, 1H), 2.92 (d, J = 16.4 Hz, 1H), 2.68 (d, J = 16.4 Hz, lH), 1.83 (m, 1H), 1.80 (d, J = 6.8 Hz, 3H), 1.51 (d, J = 6.8 Hz, 3H), 1.30 (s, 3H), 0.94 (dd, J = 6.8 Hz, 3H), 0.90 (dd, J = 6.8, 3H). Mass Spec (ESI) mlz: 456.2 [M+H]⁺.

The compounds in Table 3 were prepared following procedures similar to those of Example 3 including using procedures similar to those of Examples 1 and 2.

EXAMPLE 4

Example 4, Step 1

The starting carboxylic acid 4-1 was prepared as described in Eur. J. Org Chem,

2002, 2508. A solution of this acid 4-1 ( 232 mg, 1.05 mmol), (S)-alpha-methylbenzylamine (0.20 mL, 1.58 mmol), 1-hydroxybenzotriazole (214 mg, 1.58 mmol) and EDCI (606 mg, 3.16 mmol) in anhydrous DCM (10 mL) was stirred at RT for 48 h. The reaction was concentrated in vacuo and purified by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 90:10) to afford 255 mg (75%) of intermediate 4-2.

Example 4, Step 2

Intermediate 4-2 from Step 1 (255 mg, 0.79 mmol) was reacted with intermediate 1-7 from Step 5 of Example 1 and using conditions similar to the ones described in Step 6 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes/EtOAc 80:20 to 50:50), 144.0 mg (32%) of intermediate 4-3.

Example 4, Step 3

Intermediate 4-3 from Step 2 (40.0 mg, 0.014 mmol) was subjected to Boc- removal conditions similar to the ones described in Step 9 or Example 1 to provide, after purification by CI 8 reverse phase HPLC chromatography [eluting with CH₃CN/H₂0 (0.1% TFA) 10:90 to 100:0] and conversion to the hydrochloride salt, 23.6 mg (71%) of Example 4 as a white solid. Ή NMR (CD₃OD) 5 D7.65 (d, 1H), 7.44 (d,lH), 7.21-7.31 (m, 5H), 7.15 (t,lH), 5.07 (m, 3H), 3.23 (s, 1H), 2.83 (dd, 2H), 1.78 (m, 1H), 1.40 (d, 3H), 1.16 (s, 3H), 0.86 (d, 3H), 0.84 (d, 3H). Mass spec (ESI) m/z: 475.3 [M+H]⁺.

The compound in Table 4 was prepared from 3-benzoylbenzoic acid following procedures similar to those of Example 4 and including an extra step of reduction of the product of Step 1 with sodium borohydride.

EXAMPLE 5

Example 5, Step 1

To a solution of starting aldehyde 5-1 (3.98 g, 19.6 mmol) in MeOH (20 mL) at 0°C was added sodium borohydride (1.48 g, 39.2 mmol). The reaction was stirred at 0°C for 5 min then warmed up to RT and allowed to stir for an additional 30 min. The final mixture was diluted with EtOAc and brine, and the organic layer was dried over Na₂S0₄ and concentrated in vacuo to provide 3.92 g (98%) of intermediate 5-2.

Example 5, Step 2

A mixture of intermediate 5-2 product of Step 1 (1.00 g, 4.88 mmol), potassium furan-2-yl-trifluoroborate (1.48 g, 8.54 mmol), and Pd(dppf)Cl₂ CH₂C1₂ (0.398 g, 0.488 mmol) in a 9: 1 tert-butanol/ 2M aqueous potassium carbonate solution (5 mL) was heated at 80°C for 4 h. After cooling to RT, the mixture was diluted with water, extracted with DCM, dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes/EtOAc 85:15 to 20:80) to afford 0.68 g (72%) of intermediate 5-3.

Example 5, Step 3

Intermediate 5-3 from Step 2 (0.87 g, 3.24 mmol) was reacted with intermediate 1-7 from Step 5 of Example 1 and using conditions similar to the ones described in Step 6 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes/EtOAc 80:20 to 50:50), 0.68 g (47%) of intermediate 5-4.

Example 5, Step 4

A solution of the intermediate 5-4 from Step 3 (0.68 g, 1.50 mmol), sodium periodate (2.51 g, 11.7 mmol), and ruthenium trichloride hydrate in a 5:5:7 CH₃CN/CC1₄/H₂0 solution (17 mL) was stirred vigorously at RT for 10 min then acidified to pH 4 with IN HC1 aqueous solution and filtered over Celite. The solution was extracted with EtOAc and IN HC1 aqueous solution. The organic layer was then extracted with diluted sodium hydroxide solution. The aqueous layer was neutralized with IN HC1 aqueous solution then extracted with EtOAc, dried over Na₂S0₄ and concentrated in vacuo to yield 498 mg (77%) of intermediate 5-5. Example 5, Step 5

Intermediate 5-5 from Step 4 (498 mg, 1.18 mmol) was reacted with (S)-alpha- methylbenzylamine usingconditions similar to the ones described in Step 8 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 40:60), 336 mg (51%) of intermediate 5-6. (R)-alpha-methylbenzylamine could be used as an alternative to (S)-alpha-methylbenzylamine as in Table 1, example 1-H.

Example S, Step 6

Intermediate 5-6 from Step 5 was subjected to Boc-removal conditions similar to the ones described in Step 9 of Example 1 to provide, after purification over CI 8 reverse phase HPLC chromatography [eluting with CH₃CN/H₂0 (0.1% TFA) 10:90 to 100:0], conversion to the hydrochloride salt and lyophilization, 243 mg (89%) of Example 5 as a white solid. Ή NMR (CD₃OD) 8D 7.89 (m,lH), 7.75 (dd, 1H), 7.38 (d, 2H), 7.31 (t, 2H), 7.24 (m 2H), 5.20 (q, 1H), 5.15 (q, 2H), 3.34 (s, 2H), 2.92 (dd, 2H), 1.90 (m, 1H), 1.55 (d, 3H), 1.29 (s, 3H), 0.97 (d, 3H), 0.95 (d, 3H). Mass Spec (ESI) m/z: 425.2 [M+H]⁺.

The compounds in Table 5 were prepared following procedures similar to those of

Example 5 including using procedures similar to those of Examples 1, 2 and 3.

TABLE 5

EXAMPLE 6

Example 6, Step 1

To a solution of 3-bromo-4-benzoic acid 6-1 (4.0 g, 17.0 mmol) in anhydrous

THF (18 mL) was slowly added BH₃.DMS (1.6 g, 20.4 mmol) at 0°C then the reaction was refluxed at 80°C for 90 min. The mixture was cooled and concentrated in vacuo, diluted with water and extracted with DCM. The organic layer was washed with saturated aqueous sodium bicarbonate solution then brine, dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes EtOAc 100:0 to 0: 100) to afford 3.4 g (90%) of intermediate 6-2.

Example 6, Step 2

Intermediate 6-2 from Step 1 (3.0 g, 13.4 mmol) was reacted with intermediate 1- 7 from Step 5 of Example 1 using conditions similar to the ones described in Step 6 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 0:100), 4.50 g (85%) intermediate 6-3.

Example 6, Step 3

To a solution of intermediate 6-3 from Step 2 (3.0 g, 6.35 mmol) in anhydrous

THF (25 mL) at 0°C was slowly added 3N methylmagnesium chloride in THF (2.65 mL, 7.93 mmol). The reaction was stirred 10 min at 0°C then cooled to -78°C and treated with 2.5N n- BuLi in hexanes (5.7 mL, 14.29 mmol). After stirring 45 min at this temperature, C0₂ gas was bubbled into the reaction via cannula and more anhydrous THF (20 mL) was added to the mixture. The reaction was allowed to warm up to RT while continuing to bubble C0₂ and stirred for 10 min then before adding ice-cold IN aqueous HC1 (150 mL). The final mixture was extracted with EtOAc, dried over Na₂S04 and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 0:100) to afford 2.24 g (80%) of intermediate 6-4.

Example 6, Step 4

Intermediate 6-3 from Step 3 (120 mg, 0.27 mmol) was reacted with (S)-l-(3- chlorophenyl)ethanamine using conditions similar to the ones described in Step 8 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 50:50), 120 mg (75%) of intermediate 6-5.

Example 6, Step 5

Intermediate 6-5 from Step 4 (120 mg, 0.21 mmol) was subjected to Boc-removal conditions similar to the ones described in Step 4 of Example 3 to provide 100 mg of Example 6 as a white solid. 1H NMR (CD₃OD) δ 7.48 (d, 1H), 7.44 (m, 1H), 7.37 (dd, 1H), 7.32-7.35 (m, 2H), 7.31 (d, 1H), 7.27 (m, 1H), 5.19 (m, 1H), 3.74 (m, 1H), 3.55 (m, 1H), 3.01 (d, 1H), 2.82 (d, 1H), 1.87 (m, 1H), 1.51 (d, 3H), 1.29 (s, 3H), 0.97 (d, 3H), 0.95 (d, 3H). Mass Spec (ESI) m/z: 475.0 [M+H]⁺.

The compounds in Table 6 were prepared following procedures similar to those of Example 6 including using procedures similar to those of Examples 1, 2 and 3.

TABLE 6

EXAMPLE 7

Example 7, Step 1

A solution of (2-chloropyridin-4-yl)methanol 7-1 (220.0 mg, 1.39 mmol), benzeneacetamide 7-2 (207.1 mg, 1.53 mmol), potassium carbonate (404.3 mg, 2.92 mmol), palladium acetate (12.5 mg, 0.056 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (64.5 mg, 0.11 mmol) in anhydrous 1,4-dioxane (6.0 mL) under nitrogen was microwaved on variable power (400 W max) for a total of 1.5 h. After cooling to RT, the mixture was diluted with EtOAc, filtered over Celite and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes/EtOAc 80:20 to 10:90) to afford 75.3 mg (22%) of intermediate 7-3.

Example 7, Step 2

Intermediate 7-3 from Step 1 (3.0 g, 13.4 mmol) was reacted with intermediate 1- 7 from Step 5 of Example 1 and using conditions similar to the ones described in Step 6 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes/Et₂0 90:10 to 0:100 then with DCM/2N NH₃ in MeOH 100:0 to 90:10), 31.7 mg (21%) of intermediate 7-4.

Example 7, Step 3

A solution of intermediate 7-4 from Step 2 (31.7 mg, 0.0642 mmol) in DCM (1.5 mL) and 4N HC1 in 1,4-dioxane (3.0 mL) was heated at 45°C for 2 h then cooled and diluted with additional DCM (2 mL). The resultant solution was poured into hexanes (300 mL), stirred for 10 min then filtered through a Buchner funnel, washing with hexanes. The oil that remained was dissolved in a mixture of DCM and MeOH and then filtered through the same Buchner funnel, washing with DCM and MeOH. The mixture was concentrated in vacuo and the product triturated with DCM and hexanes to provide 28.2 mg (94%) of Example 7 as a solid. 1H NMR (CD₃OD) δ D8.32 (br s, 1H), 7.60 (br s,lH), 7.46 (br s, 1H), 7.26-7.39 (m, 5H), 5.33 (q, 2H), 3.90 (s, 2H), 3.04 (dd, 2H), 1.99 (m, 1H), 1.38 (s, 3H), 1.02 (d, 6H). Mass Spec (ESI) mlz: 394.2 [M+H]⁺.

EXAMPLE 8

Example 8, Step 1

The starting carboxylic acid 8-1 was prepared as described in Organometallics, 2008, 27, 1850. To a solution of this acid 8-1 (0.39 g, 2.0 mmol), EDCI (0.77 g, 4.0 mmol), HOAt (0.41 g, 3.0 mmol) and DMAP (0.25 g, 2.0 mmol) in anhydrous DCM (10 mL) was added 3-chlorobenzylamine (0.37 mL, 3.0 mmol), then DIPEA (1.05 mL, 6.03 mmol) and the reaction was stirred 16 h. The reaction mixture was washed with 10% aqueous citric acid and extracted twice with DCM. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by

chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 80:20) to produce 0.46 g (73%) of intermediate 8-2.

Example 8, Step 2

To an ice-cold solution of 2N LAH in THF (0.5 mL, 1.0 mmol) in anhydrous THF

(5 mL) was added intermediate 8-2 from Step 1 (0.45 g, 1.4 mmol) dropwise. The reaction was allowed to warm to RT then quenched with saturated aqueous sodium sulfate solution, extracted with Et₂0, dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 0:100) to give 0.16 g (40%) of intermediate 8-3.

Example 8, Step 3

Intermediate 8-3 from Step 2 (0.21 g, 0.67 mmol) was reacted with intermediate 1-7 from Step 5 of Example 1 using conditions similar to the ones described in Step 6 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes/Et₂0 100:0 to 50:50), 0.21 g (70%) of intermediate 8-4. Example 8, Step 4

Intermediate 8-4 from Step 3 (0.20 g, 0.37 mmol) was subjected to Boc-removal conditions similar to the ones described in Step 4 of Example 3 to provide, after purification by chromatography over silica gel (eluting with DCM/MeOH 100:0 to 95:5), 46 mg of Example 8 as a solid. Ή NMR (DMSO-d₆) δ 8.9 (d, IH), 7.30-7.45 (m, 4H), 7.20-7.30 (m, 3H), 5.08 (AB system, 2H), 2.87 (d, IH), 2.82 (d, IH), 2.30 (s, 3H), 1.80 (m, IH), 1.14 (s, 3H), 0.89 (d, 3H), 0.87 (d, 3H). Mass Spec (ESI) mlz: 441.4 [M+H]⁺.

The compounds in Table 8 were prepared following procedures similar to those of Example 8 including using procedures similar to those of Examples 1, 2 and 3.

EXAMPLE 9

Example 9

Example 9, Step 1

To a solution of starting aniline 9-1 (10.0 g, 47.8 mmol) in anhydrous acetonitrile

(100 mL) at RT was added dimethylsulfide (6.5 ml, 71.7 mmol) followed by slow addition of isoamyl nitrite (3.2 ml, 24 mmol). The reaction was stirred and heated to reflux for 4 hours then cooled to 60°C and stirred overnight. The reaction was concentrated in vacuo and purified by chromatography over silica gel (eluting with hexanes/EtOAc 95:5 to 20:80) to afford 3.28 g (29%) of intermediate 9-2.

Example 9, Step 2

To a solution of intermediate 9-2 from Step 1 (3.0 g, 12.5 mmol) in DCM (100 mL) was added 70% mCPBA (4.3 g, 25 mmol) and the reaction was stirred at RT for 2 h. The final mixture was diluted with saturated aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes EtOAc 85:15 to 20:80) to afford 3.1 g (92%) of intermediate 9-3. Example 9, Step 3

To a solution of intermediate 9-3 from Step 2 (1.0 g, 3.7 mmol) in anhydrous THF (10 mL) at 0°C was added lithium borohydride (56 mg, 2.6 mmol) in one portion. The reaction was stirred 15 min at 0°C, 30 min at RT then 1 h at 60°C. The reaction mixture was quenched with IN aqueous HCl, extracted with DCM, dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes/EtOAc 80:20 to 10:90) to produce 0.68 g (75%) of intermediate 9-4.

Example 9, Step 4

Intermediate 9-4 from Step 3 (0.15 g, 0.56 mmol) was reacted with intermediate 1-7 from Step 5 of Example 1 and using conditions similar to the ones described in Step 6 of Example 1 to provide, after purification over silica gel (eluting with hexanes EtOAc 80:20 to 50:50), 0.16 g (58%) of intermediate 9-5.

Example 9, Step 5

Intermediate 9-5 from Step 4 (100 mg, 0.20 mmol) was reacted with (S)-l- phenylethanamine using conditions similar to the ones described in Step 3 of Example 3 to provide, after purification by chromatography over silica gel (eluting with hexanes EtOAc 100:0 to 40:60), 62 mg (53%) of intermediate 9-6.

Example 9, Step 6

Intermediate 9-6 from Step 5 (62 mg, 0.11 mmol) was subjected to Boc-removal conditions similar to the ones described in Step 4 of Example 3 to provide 50.3 mg (91%) of Example 9 as a solid. 1H NMR (CD₃OD) δ 9.15 (d, IH), 8.23 (s, IH), 8.05 (dd, 2H), 7.42 (m, 2H), 7.35 (m 2H), 7.25 (m, 2H), 5.35 (d, 2H), 5.25 (t, 2H), 5.15 (d, 2H), 3.87 (m, IH), 3.72 (m, 1 H), 3.65 (m, IH), 3.02 (s, 3H), 1.65 (d, 3H), 1.15 (m, 2H), 0.53 (m, 2H), 0.32 (m, IH), 0.16 (m, 1 H) Mass Spec (ESI) mlr. 483.2 [M+H]⁺.

EXAMPLE 10

Example 10

Example 10, Step 1

To a solution of starting aniline 10-1 (10.0 g, 47.8 mmol) in DCE (100 mL) at RT was added methanesulfonyl chloride (7.5 ml, 95.6 mmol) followed by Hunig's base (N,N- diisopropylethylamine) (20 ml, 119.5 mmol) and catalytic amount of DMAP. The reaction was stirred at RT for 48 hours. The final mixture was diluted with DCM and IN aqueous HCl then extracted with DCM. The combined organic layers were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes/EtOAc 95:5 to 20:80) to afford 3.40 g (25%) of intermediate 10-2.

Example 10, Step 2

To a solution of intermediate 10-2 from Step 1 (3.0 g, 10.5 mmol) and άι-tert- butyldicarbonate (3.4 g, 15.75 mmol) in DCE (100 mL) was added triethylamine (2.9 ml, 21 mmol) and a catalytic amount of DMAP. The reaction was stirred at RT overnight then concentrated in vacuo and purified by chromatography over silica gel (eluting with

hexanes/EtOAc 85:15 to 20:80) to afford 2.8 g (70%) of intermediate 10-3. Example 10, Step 3

To a solution of intermediate 10-3 from Step 2 (1.0 g, 2.6 mmol) in anhydrous THF (10 mL) at 0 C was added lithium borohydride (40 mg, 1.8 mmol) in one portion. The reaction was stirred 15 min at 0°C, 30 min at RT then 1 h at 60°C. The reaction mixture was quenched with IN aqueous HC1 until pH~4, extracted with DCM, dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes/EtOAc 80:20 to 10:90) to produce 0.63 g (68%) of intermediate 10-4.

Example 10, Step 4

Intermediate 10-4 from Step 3 (0.15 g, 0.56 mmol) was reacted with intermediate 1-7 from Step 5 of Example 1 and using conditions similar to the ones described in Step 6 of Example 1 to provide, after purification over silica gel (eluting with hexanes/EtOAc 80:20 to 50:50), 0.22 g (65%) of intermediate 10-5.

Example 10, Step 5

Intermediate 10-5 from Step 4 (100 mg, 0.20 mmol) was reacted with (S)-l- phenylethanamine using conditions similar to the ones described in Step 3 of Example 3 to provide, after purification by chromatography over silica gel (eluting with hexanes/EtOAc 100:0 to 40:60), 62 mg (54%) of intermediate 10-6.

Example 10, Step 6

Intermediate 9-6 from Step 5 (62 mg, 0.10 mmol) was subjected to Boc-removal conditions similar to the ones described in Step 4 of Example 3 to provide 43.3 mg (92%) of Example 10 as a white solid. 1H NMR (CD₃OD) δ D7.35 (d, 2H), 7.23 (m, 2H), 7.12 (m, 2H), 7.05 (m, 2H), 5.02 (m 3H), 4.85 (d, 2H), 3.52 (m, IH), 3.84 (m, IH), 3.43 (m, IH), 2.82 (s, 3H), 2.72 (s, 3H), 1.35 (d, 2H), 1.05 (m, 2H), 0.93 (m, 2H), 0.77 (m, IH), 0.53 (m, 2H), 0.32 (m, IH), 0.16 (m, 1 H) Mass Spec (ESI) m/z 498.2 [M+H]⁺.

The compound in Table 10 was prepared following procedures similar to those of

Example 10 including using procedures similar to those of Examples 1, 2 and 3.

TABLE 10

EXAMPLE 11

Example 11, Step 1

To a solution of p-methoxybenzylamine 11-1 (19.6 mL, 150 mmol) and pyridine (19.4 mL, 240 mmol) in anhydrous DCE at 0°C was slowly added methanesulfonyl chloride (11.6 mL, 150 mmo ) then the reaction was stirred at RT for 24h. The final mixture was diluted with DCM then washed with aqueous IN HC1, brine, dried over Na₂S0₄ and concentrated in vacuo. The residue was taken up in ~20 mL ice-cooled EtOH, stirred 30 min then filtered, rinsing with EtOH then pentane to give 17.1 g (53%) of intermediate 11-2.

Example 11, Step 2

To a solution of intermediate 11-1 from Step 1 (3.23 g, 15.0 mmol), alcohol 11-3 (3.22 g, 15.7 mmol) and triphenylphosphine (4.20 g, 16.0 mmol) in anhydrous THF (40 mL) was added diisopropylazadicarboxylate (3.15 mL, 16.0 mmol) slowly at 0°C then the reaction was stirred at RT overnight. The crude was diluted with half-brine, extracted with EtOAc, dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluting with hexanes EtOAc 99:1 to 0:100) to afford 4.46 g of crude intermediate 11-4. Example 11, Step 3

To a solution of intermediate 1-3 from Example 1, Step 2 (1.32 g, 7.00 mmol) in anhydrous THF (25 mL) at -78°C was slowly added 2.5N n-butyllithium in hexanes (3.65 mL, 9.07 mmol) over 5 min then the reaction was stirred 30 min at -78°C followed by the addition of intermediate 11-4 from Step 2 (3.65 g, 9.07 mmol) in anhydrous THF (10 mL). The reaction was stirred 45 min at -78°C then allowed to warm to and stirred 10 min. The final mixture was diluted with water and brine, extracted with EtOAc then purified by chromatography over silica gel (eluting with hexanes/EtOAc 99:1 to 0:100) to give 3.20 g of crude intermediate as a mixture of debrominated (ll-5b) and brominated (ll-5a) material.

Example 11, Step 4

To a solution of intermediates ll-5a and ll-5b from Step 3 (3.38 g) in DCM (21 mL) and MeOH (7 mL) was added 4N HC1 in 1,4-dioxane (8.6 mL, 34.3 mmol) and the reaction was stirred 90 min at RT. The solution was concentrated in vacuo and co-evaporated three times with toluene. The residue was taken up in DCM (25 mL) and TFA (6.60 mL, 85.6 mmol) was added followed by 1,3-dimethoxybenzene (4 mL). The reaction was stirred at 40°C over 3 days. The final mixture was concentrated, diluted with water and Et₂0 and washed with water. The Et₂0 layer was then extracted with IN aqueous HC1 then the pooled aqueous layers were slowly neutralized with solid sodium carbonate until pH~10, extracted with DCM, dried over Na₂S0₄ and concentrated in vacuo to give 1.44 g of crude intermediate as a mixture of debrominated (11- 6b) and brominated (ll-6a) material.

Example 11, Step 5

To a solution of intermediates ll-6a and ll-6b from Step 4 (1.44 g) in DCM (20 mL) was added benzoyl isothiocyanate (775 uL, 5.75 mmol). The reaction was stirred at RT overnight then concentrated to provide 2.25 g of crude. This crude was taken up in MeOH (25 mL) and treated with 25% MeONa in MeOH (2.75 mL). The reaction was stirred 1 h at RT then concentrated, diluted with water and DCM, then treated with saturated aqueous sodium bicarbonate (20 mL). The mixture was then acidified with IN HC1 until pH~6, extracted with DCM, dried over Na₂S0₄ and concentrated in vacuo to give 2.50 g of crude intermediate as a mixture of debrominated (ll-7b) and brominated (ll-7a) material.

Example 11, Step 6

To a solution of intermediates ll-7a and ll-7b from Step 5 (2.50 g) in EtOH (55 mL) was added iodomethane (0.35 mL, 5.50 mmol) and the reaction was stirred at RT overnight. The reaction was concentrated then diluted with half-saturated aqueous sodium bicarbonate, extracted with EtOAc, dried over Na₂S0₄ and concentrated in vacuo. The residue was diluted with propanenitrile and heated at 85°C for 2h. The mixture was concentrated then worked up with DCM and half-saturated aqueous sodium bicarbonate, extracting well with DCM then concentrated in vacuo and purified by chromatography over silica gel (eluting with

hexanes/EtOAc 99: 1 to 0: 100) to provide 235 mg of brominated intermediate ll-8a and 796 mg of debrominated intermediate ll-8b.

Example 11, Step 7

A solution of intermediate ll-8a from Step 6 (235 mg, 0.60 mmol), di-tert- butyldicarbonate (218 mg, 1.00 mmol) and triethylamine (0.14 mL, 1.00 mmol) in anhydrous DCM (5 mL) was stirred at RT over approximately 60 hours then concentrated in vacuo and purified by chromatography over silica gel (eluting with hexanes/EtOAc 99:1 to 70:30) to afford 305 mg (100%) of intermediate 11-9. Example 11, Step 8

To a solution of intermediate 11-9 from Step 7 (178 mg, 0.36 mmol) in anhydrous THF (1.5 mL) at 0°C was slowly added 3N methylmagnesium chloride in THF (0.15 mL, 0.45 mmol) and the reaction was stirred 15 min at this temperature. The mixture was then cooled to - 78°C then treated with 2.5N n-butyllithium in hexanes (0.32 mL, 0.81 mmol), stirred 45 min at - 78°C then C0₂ was bubbled into the solution. The reaction was then allowed to warm to RT, stirred 15 min then treated with ice-cold 0.2N aqueous HC1, extracted with EtOAc, dried over Na₂S0₄ and concentrated. The residue was purified over silica gel (eluting with hexanes EtOAc 99:1 to 0:100) to afford 84.1 mg of intermediate 11-10 as well as 77 mg of crude starting material.

Example 11, Step 9

Intermediate 11-10 from Step 8 (42 mg, 0.092 mmol) was reacted with (S)-3- methoxy-l-phenylpropan-1 -amine hydrochloride using conditions similar to the ones described in Step 8 of Example 1 to provide, after purification by chromatography over silica gel (eluting with hexanes/EtOAc 99:1 to 40:60), 40.7 mg (73%) of intermediate 11-11.

Example 11, Step 10

Intermediate 11-1 from Step 9 (40.7 mg, 0.067 mmol) was subjected to Boc- removal conditions similar to the ones described in Step 4 of Example 3 to provide 33.2 mg (98%) of Example 11 as a white solid. Ή NMR (CD₃OD) δ 8.92 (d, 1H), 7.73 (s, 1H), 7.61 (d, 1H), 7.35 (m, 5H), 7.25 (m 1H), 5.25 (m, 2H), 5.08 (d, 1H), 4.11 (d, 1H), 3.83 (d, 1H), 3.79 (m, IH), 3.59 (s, 3H), 3.50 (m, IH), 3.42 (m, 2H), 3.35 (s, 3H), 2.15 (m, 2H), 2.02 (m, IH), 0.95 (d, 3 H), 0.87 (d, 3H). Mass Spec (ESI) mlz: 505.0 [M+H]⁺.

Additional non-limiting examples of compounds of the invention, each of which was made by the method indicated, are shown in the table below. While only one tautomeric form of each compound is shown in the tables, it shall be understood that all tautomeric forms of the compounds are contemplated as being within the scope of the non-limiting examples.

Biological Assays Materials

The Europium/QSY-7-labeled BACEl FRET peptide substrate (QSY7- EISEVNLDAEFC-Eu-amide) was custom synthesized by PerkinElmer (Turku, Finland). This peptide is derived from the amyloid precursor protein sequence and contains the familial AD Swedish mutation at the BACE cleavage site (ΚΜ^→ΝΙ,^8ννβ, underlined above), which significantly enhances BACEl -mediated proteolysis. This peptide also contains the

QSY7:Europium dononacceptor pair for use in time-resolved FRET assays. Recombinant soluble human BACEl, comprised of amino acids 1-454, was expressed and purified from E. coli. The N-terminal pro-domain was autocatalytically cleaved to yield soluble mature BACEl (autoBACEl) comprised of amino acids 41-454 (Lot# 55290-lOOC)⁶. AutoBACEl was used in all in vitro BACEl enzymatic assays. Purified soluble mature mouse BACEl enzyme was purchased from R&D Systems. Purified human liver cathepsin D (Athens Research), recombinant human cathepsin E (R&D Systems), recombinant human renin (Proteos), and purified human gastric pepsin (Sigma-Aldrich) were used for in vitro counterscreen assays. Proteolytic activity of cathepin D, cathepsin E and pepsin was measured using the FRET peptide substrate Mca-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(Dnp)-D-Arg-NH2 (Bachem), while proteolytic activity of renin was measured using the FRET peptie substrate Arg-Glu(EDAN^~ S)-Ile- His-Pro-Phe-His-Leu- Val-Ile-His-Thr-Lys(dabcyl)-Arg (Molecular Probes/Invitrogen).

FRET PROTEASE ASSAYS BACE1

Inhibitor IC_50s at purified human autoBACEl determined in a time-resolved endpoint proteolysis assay that measures hydrolysis of the QSY7-EISEVNLDAEFC-Eu-amide FRET peptide substrate (BACE-HTRF assay). BACE-mediated hydrolysis of this peptide results in an increase in relative fluorescence (RFU) at 620 nm after excitation with 320 nm light.

Inhibitor compounds, prepared at 3x the desired final concentration in lx BACE assay buffer (20 mM sodium acetate pH 5.0, 10% glycerol, 0.1% Brij-35) supplemented with 7.5% DMSO were pre-incubated with an equal volume of autoBACEl enzyme diluted in lx BACE assay buffer (final enzyme concentration 1 nM) in black 384- well NUNC plates for 30 minutes at 30°C. The assay was initiated by addition of an equal volume of the QSY7-EISEVNLDAEFC-Eu-amide substrate (200 nM final concentration, K_m=8 μΜ for autoBACEl) prepared in lx BACE assay buffer supplemented with 7.5% DMSO and incubated for 90 minutes at 30°C. DMSO was present at 5% final concentration in the assay. Following laser excitation of sample wells at 320 nm, the fluorescence signal at 620 nm was collected for 400 ms following a 50 μβ delay on a RUBYstar HTRF plate reader (BMG Labtechnologies). Raw RFU data was normalized to maximum (1.0 nM BACE/DMSO) and minimum (no enzyme/DMSO) RFU values. IC_50s were determined by nonlinear regression analysis (sigmoidal dose response, variable slope) of percent inhibition data with minimum and maximum values set to 0 and 100 percent respectively.

Similar IC₅o_s were obtained when using raw RFU data. The Ki values were calculated from the IC50 using the Cheng-Prusoff equation.

Cathepsin D

Human cathepsin D (CatD, 0.156 nM) was pre-incubated with compounds diluted in lx CatD assay buffer (100 mM sodium acetate pH 5.0, 0.02% Brij-35, 1.0% DMSO) for 30 minutes at 37°C in 384 well plates followed by addition of the Mca-Gly-Lys-Pro-Ile-Leu-Phe- Phe-Arg-Leu-Lys(Dnp)-D-Arg-NH2 substrate (2.5 μΜ final concentration assay buffer, K_m=4.3 μΜ). DMSO was present at 1% final concentration in the assay. Following a 45 minute incubation at 37°C, plates were read on a Molecular Devices Flex Station set at 328 nm excitation and 393 nm emission. IC50 and K; values were determined as for BACE assays.

Renin

Human renin (2.5 nM) was pre-incubated with compounds diluted in lx renin assay buffer (50 mM Tris HC1 pH 8.0, 100 mM NaCl, 0.1% Brij-35 with 15% DMSO) for 30 minutes at 37°C in 384 well plates followed by addition of the Arg-Glu(EDANS)-Ile-His-Pro- Phe-His-Leu-Val-Ile-His-Thr-Lys(dabcyl)-Arg substrate (5 μΜ final concentration, K_m=5.4 μΜ). DMSO was present at 5% final concentration in the assay. Following a two hour incubation at 37°C, plates were read on a Molecular Devices Flex Station set at 340 nm excitation and 490 nm emission. IC50 and Kj values were determined as for BACE assays.

As stated above, the novel compounds of the invention exhibit good potency for renin, and, surprisingly and advantageously, good selectivity for renin over other aspartyl proteases such as BACE and cathepsin D. Supporting biological data for these properties of the compounds of the invention are recited in the table below.

Renin Ki BACE1 Ki Cathepsin D

Example

nM μΜ Ki nM

1-AK 16.0 >10.0 440

1-AL 8.3 >10.0 92

1-AL 8.3 >10.0 92

1-AM 4.7 >10.0 120

1-AN 1.3 >10.0 100

1-AO 5.7 >10.0 240

1-AP 4.6 >10.0 390

1-AQ 3.8 >10.0 140

1-AR 5.3 >10.0 320

1-AS 1.8 28% @ 10 μΜ 380

1-AT 0.7 >10.0 140

1-AU 1.2 >10.0 210

1-AV 0.9 39% @ 10 μΜ

1-AW 110.0 14% @ 10 μΜ 540

1-AX 16.0 >10.0 220

1-AY 8.8 >10.0 200

1-B 24.0 >10.0 420

1-C 11.0 >10.0 76

1-D 28.0 >10.0 210

1-E 45.0 >10.0 360

1-F 220.0 >10.0

1-G 5.2 >10.0 400 Renin Ki BACE1 Ki Cathepsin D

Example

nM μΜ Ki nM

1-H 11.0 >10.0 360

1-1 1.0 >10.0 183

1-K 0.5 >10.0 220

1-L 14.0 20% @ 10 μΜ 210

1-M 0.8 >10.0 400

1-N 1.0 >10.0 140 l-O 1.1 >10.0 130

1-P 0.7 >10.0 70

1-T 0.7 22% @ 10 μΜ 76

1-U 1.0 0.44

1-V 7.6 >10.0 540

1-W 0.9 >10.0 280

1-X 60.0 >10.0 38

1-Y 0.6 >10.0 420

1-Z 0.5 >10.0 260

1- 86.0 11% @ 10 μΜ 2800

2-A 1.5 >10.0 110

2-B 1.0 >10.0 44

2-C 0.6 >10.0 50

2-D 1.2 >10.0 85

2- 1.2 >10.0 82

3-A 2.4 >10.0 2400 Renin Ki BACE1 Ki Cathepsin D

Example

nM μΜ Ki nM

3-B 2.4 >10.0 3400

3-C 1.0 14% @ 10 μΜ 700

3-D 0.4 22% @ 10 μΜ

3-E 0.4 10% @ 10 μΜ

3-F 17.0 8% @ 10 μΜ

3-G 1.8 >10.0 223

3-G 1.8 >10.0 223

3-H 0.9 >10.0 40

3- 1.8 >10.0 223

4-A 5.2 >10.0 20

4 27.0 >10.0 2200 ^'

5 1.6 0.64 950

5-A 40.0 0.22 1200

5-B 11.0 >10.0 2000

5-C 0.8 >10.0 160

5-D 230.0 >10.0 2300

5-E 140.0 16% @ 10 μΜ

6-A 3.3 >10.0 2120

6-B 4.8 21% @ 10 μΜ

6-C 0.9 12% @ 10 μΜ 1500

6-D 0.4 0.43

6 4.2 >10.0 520 Renin Ki BACE1 Ki Cathepsin D

Example

nM μΜ Ki nM

7 310.0 >10.0 3700

8-A 40.0 5% @10 μΜ 2000

8-B 68.0 >10.0 1500

8-C 200.0 >10.0 1100

8-D 280.0 >10.0 1900

8-E 4.2 4% @ 10 μΜ 2600

8 78.0 >10.0 440

9 380.0 >10.0 2600

10-A 140.0 16% @ 10 μΜ

10-A 140.0 16% @ 10 μΜ

10 33.0 >10.0 4400

11 7.8 24% @ 10 μΜ 630

MA-2 9.9

MA-3 1.2

MA-4 1.2

MA-5 2.3

MA-6 3.2

MA-7 96.0

MA-8 27.0

MA-9 13.0 9% @ 10 μΜ 5300

MB-47 72.0

MB-1 0.5 0.65 2000 Renin Ki BACH Ki Cathepsin D

Example

nM μΜ Ki nM

MB-2 0.7 0.67 660

MB-3 1.1 >10.0 190

MB-4 1.0 0.92 220

MB-5 3.6 >10.0 2800

MB-7 13.0 >10.0 1405

MB-8 91.0 4% @ 10 μΜ 540

MB-9 6.2 8% @ 10 μΜ 1000

MB-10 31.5 17% @ 10 μΜ 800

MB-11 0.6 13% @ 10 μΜ 1325

MB-12 3.8 >10.0 360

MB-13 39.0 0.49 380

MB-14 2.2 0.27 390

MB-15 13.0 >10.0 1000

MB-16 50.0 >10.0 760

MB-17 35.0 >10.0 1400

MB-18 17.0 >10.0 1200

MB-19 44.5 9% @ 10 μΜ 1350

MB-20 62.0 4% @ 10 μΜ 1100

MB-22 66.3 >10.0 2800

MB-23 2.7 18% @ 10 μΜ 1200

MB-25 45.0 7% @ 10 μΜ 1900

MB-26 0.9 >10.0 290 Renin Ki BACE1 Ki Cathepsin D

Example

nM μΜ KinM

MB-28 88.0 >10.0 4800

MB-29 6.0 >10.0 800

MB-30 13.5 >10.0 1200

MB-33 0.9 20%@10μΜ 994

MB-34 14.0 16%@10μΜ 2800

MB-37 46.0 >10.0 1600

MB-38 27.0 0.77 830

MB-39 19.5 >10.0 213

MB-40 14.0 >10.0 1400

MB-42 14.0

MB-43 3.0

MB-44 3.4

MB-45 3.1

MB-46 1.1

MB-85 18.0

MB-86 5.6

MB-87 6.8

MB-88 24.0

MB-89 0.8 26%@10μΜ

MB-90 0.5 35% @ 10 μΜ

MB-91 0.7 21% @ 10 μΜ

MB-50 6.0 11% @ 10 μΜ Renin Ki BACE1 Ki Cathepsin D

Example

iiM μΜ KinM

MB-51 2.0 16% @ 10 μΜ

MB-52 1.3 26% @ 10 μΜ

MB-53 1.4 13% @ 10 μΜ 624

MB-54 0.9 17%@10μΜ

MB-55 0.8 >10.0 700

MB-56 3.8 35% @ 10 μΜ 560

MB-57 65.0 33%@10μΜ

MB-58 24.0 41%@10μΜ

MB-59 7.8 20% @ 10 μΜ

MB-60 26.0 29%@10μΜ

MB-61 36.0 15%@10μΜ

MB-62 7.8 >10.0 1600

MB-63 10.0 10% @ 10 μΜ 220

MB-64 22.0 >10.0 180

MB-66 0.7 >10.0 31

MB-67 12.0 16% @ 10 μΜ 340

MB-68 24.0 >10.0 2300

MB-69 32.0 3%@ 10 μΜ 310

MB-70 28.0 >10.0 130

MB-71 39.0 >10.0 390

MB-72 11.0 >10.0 580

0.3% @ 10

MB-73 36.0 390 μΜ Renin Ki BACE1 Ki Cathepsin D

Example

nM μΜ Ki nM

MB-74 60.0 >10.0 9500

MB-75 0.4 11% @ 10 μΜ 143

MB-76 0.4 7% @ 10 μΜ 91

MB-77 0.5 8% @ 10 μΜ 128

MB-78 3.6 20% @ 10 μΜ 257

MB-79 78.0 7% @ ΙΟ μΜ 2536

MB-80 57.0 7% @ 10 μΜ

MB-81 15.0 -7% @ 10 μΜ 6700

MB-82 52.0 6% @ 10 μΜ 1800

MB-83 29.0 27% @ 10 μΜ 420

MB-84 44.0 >10.0 540

Antihypertensive Effects

The antihypertensive effect of the compound from example 1 -I at 10 mpk PO was determined using the DTG rat model described by R.St-Jacgues, R, et al., "Characterization of a stable, hypertensive rat model suitable for the consecutive evaluation of human renin inhibitors," Journal of the Renin-Angiotensin-Aldosterone System, September 2011, 12(3):133-45. The time course for the decrease in blood pressure in mm Hg is shown in the table below.

Claims

WHAT IS CLAIMED:

1. A compound, or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said compound or said stereoisomer, said compound having the structural Formula (I):

(I)

or a tautomer thereof having the structural Formula (Γ):

(Γ)

or a pharmaceutically acceptable salt, solvate, ester, prodrug, or stereoisomer of said compound or said tautomer, wherein :

n and m are each an integer independently selected from 0 to 2;

W is selected from the group consisting of -C(O)- and -S(0)₂-;

ring A is selected from the group consisting of phenyl, heteroaryl, and heterocycloalkyl;

-L is a divalent moiety selected from the group consisting of

-C(0)-N(RL1)-CH(RL2)-,

wherein

R^L1 and R^L3 (when present) are each independently selected from the group conisisting of H and methyl; R^L2 is selected from the group consisting of H, -(Ci-C₆)alkyl, -(Ci-C₆)heteroalkyl, and , -(C₁-C₃)alkyl-N(R^L4)C(0)R^L5;

R^u is selected from the group consisting of H and -(Ci-C₃)alkyl;

R^L5 is selected from the group consisting of H, -(C!-C3)alkyl, -0(Ci-C₃)alkyl, and -OH;

each R¹ (when present) is independently selected from the group consisting of halo, -CN, -(C₁-C₆)alkyl, -(C₁-C₆)alkoxy, -(C C₆)haloalkyl, -NHS(0)₂alkyl, and

■N((Ci-C₆)alkyl)S(0)₂alkyl;

each R² (when present) is independently selected from the group consisting of halo, -CN, -(C_rC₆)alkyl, -(Ci-C₆)haloalkyl, -NHS(0)₂alkyl, and -N((Ci-C₆)alkyl)S(0)₂alkyl;

R³ and R⁴ are each independently selected from the group consisting of H, F and alkyl, wherein said alkyl of R³ is unsubstituted or substituted with from 1-2 groups independently selected from the group consisting of halo, hydroxyl and alkoxy;

R⁵ is selected from the group consisting of H, -(Ci-C6)alkyl, -(Ci-C₆)haloalkyl, and phenyl;

R⁶ is selected from the group consisting of H, -(Ci-C6)alkyl, cyclopropyl, cyclobutyl, and cyclopentyl, wherein each of said alkyl and said cyclopropyl, cyclobutyl, and cyclopentyl of R⁶ is unsubstituted or substituted with from 1-2 groups independently selected from the group consisting of halo, hydroxyl, and alkoxy; and

R⁷ is selected from the group consisting of H, -(C₁-C₆)alkyl, and cyclopropyl, wherein each of said alkyl and said cyclopropyl of R⁷ is unsubstituted or substituted with from 1- 2 groups independently selected from the group consisting of halo, hydroxyl, and alkoxy.

2. A compound of claim 1 , or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein:

R³ is H and R⁴ is H.

3. A compound of claim 2, or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein:

R⁶ and R⁷ are each independently selected from the group consisting of methyl, ethyl, propyl, z^'-propyl, «-propyl, cyclopropyl, /-butyl, H-butyl, and t-butyl.

4. A compound of claim 3, or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein: R⁵ is selected from the group consisting of H, methyl, and phenyl.

5. A compound of claim 4, or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein:

-Lr is -C(0)-N(CH₃)-CH(R^L2)-, wherein

R^L2 is selected from the group consisting of H, -(C₁-C₆)alkyl, -(Ci-C6)heteroalkyl, and , -(Ci-C₃)alkyl-N(R^M)C(0)R^L5;

R is selected from the group consisting of H and -(Ci-C₃)alkyl; and

R^L5 is selected from the group consisting of H, -(CrC₃)alkyl, -0(C₁-C₃)alkyl, and

-OH.

6. A compound according to claim 4, or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein: - is -C(0)-N(R )-CH(R^L L^Z2)x-, and the moiety

is selected from the group consisting of

7. A compound of claim 4, or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein:

-Li- is a divalent moiety selected from the group consisting of

wherein R is selected from the group conisisting of H and methyl, and the moiety,

is selected from the group consisting of

8. A compound according to any one of claims 1-5, or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein:

- Ill -

9. A pharmaceutical composition comprising at least one compound of claim 1, or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a

pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

10. A pharmaceutical composition of claim 9, wherein said at least one additional therapeutic agent is at least one agent selected from:

/i/pAa-blockers, £eto-blockers, calcium channel blockers, diuretics, natriuretics, saluretics, centrally acting antihypertensive, angiontensin convertingn enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin-recetor blockers (ARBs), aldosterone synthease inhibitors, aldosterone-receptor antagonists, and endothelin receptor antagonists.

11. A method of treating, preventing, and/or delaying the onset of a disease or disorder selected from hypertension, congestive heart failure; left ventricular dysfunction; cardiac hypertrophy; cardiac fibrosis; cardiomyopathy, ventricular arrhythmia; atrial fibrillation; atrial flutter; detrimental vascular remodeling; myocardial infarction and its sequelae; atherosclerosis; angina; renal failure, diabetic nephropathy, glomerulonephritis; renal fibrosis; scleroderma; glomerular sclerosis; microvascular complications, renal vascular hypertension; vasculopathy; neuropathy; diseases of the coronary vessels, proteinuria, albumenuria, post-surgical hypertension, metabolic syndrome, obesity, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, retinopathy, abnormal vascular growth and remodeling, neovascular age related macular degeneration; hyperaldosteronism, anxiety states, and cognitive disoder, wherein said method comprises administering a compound according to claim 1.

12. A method of claim 11, wherein said disease or disorder is hypertension.