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HK1025328A - Heteroaryl-hexanoic acid amide derivatives, their preparation and their use as selective inhibitors of mip-1-alpha binding to its ccr 1 receptor - Google Patents

Heteroaryl-hexanoic acid amide derivatives, their preparation and their use as selective inhibitors of mip-1-alpha binding to its ccr 1 receptor Download PDF

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Publication number
HK1025328A
HK1025328A HK00104627.3A HK00104627A HK1025328A HK 1025328 A HK1025328 A HK 1025328A HK 00104627 A HK00104627 A HK 00104627A HK 1025328 A HK1025328 A HK 1025328A
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Hong Kong
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alkyl
hydroxy
carboxylic acid
benzyl
amide
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HK00104627.3A
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Chinese (zh)
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M‧F‧布朗
J‧C‧卡斯
C‧S‧伯斯
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辉瑞大药厂
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Heteroaryl-hexanoic acid amide derivatives, their preparation and their use as selective inhibitors of MIP-1 alpha binding to its CCR1 receptor
Background
The present invention relates to novel hexanoic acid derivatives, methods of use thereof, and pharmaceutical compositions containing these compounds.
The compounds of the present invention are selective strong inhibitors of MIP-1 alpha binding to its CCR1 receptor on inflammatory or immunoregulatory cells, preferably leukocytes and lymphocytes. The CCR1 receptor is sometimes also referred to as CC-CKR1A receptor. These compounds may also inhibit MIP-1 α (and the chemotaxis of THP-1 cells and human leukocytes induced by the associated chemokines that exhibit interaction with CCR1 (e.g., RANTES and MCP-3)) and are useful in the treatment or prevention of autoimmune diseases (e.g., rheumatoid arthritis, type I diabetes (newly occurring), inflammatory bowel disease, ocular neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis and vasculitis), acute and chronic inflammation (e.g., osteoarthritis, adult respiratory distress syndrome, infant respiratory distress syndrome, ischemia reperfusion injury and glomerulonephritis), allergic diseases (e.g., asthma and atopic dermatitis), infections with inflammation (e.g., viral infections (including influenza and hepatitis) and Guillian-Barre syndrome), graft tissue rejection (chronic and acute), Organ rejection (chronic and acute), atherosclerosis, restenosis, HIV infection (using common receptors), and granulomatous diseases (including sarcoidosis, leprosy, and tuberculosis).
MIP-1 α and RANTES are soluble chemotactic peptides (chemokines) produced by inflammatory cells, particularly CD8+ lymphocytes, polymorphonuclear leukocytes (PMN) and macrophages, journal of biochemistry (J.biol.chem.), 270(30) 29671-. These chemokines act by inducing migration and activation of major inflammatory and immunoregulatory cells. Elevated chemokine concentrations have been found in the synovial fluid of rheumatoid arthritis patients, chronic and rejection tissue transplant patients, and nasal secretions of allergic rhinitis patients exposed to allergens (Teran et al, J.Immunol., 1806-1812(1996), Kuna et al, allergy clinical immunology (J.Allergy Clin.Immunol.) (1994)). Antibodies or gene disruption that interfere with chemokine/receptor interactions by neutralizing MIP1 α provide direct evidence for the role of MIP-1 α and RANTES in disease by limiting monocyte and lymphocyte recruitment (Smith et al, journal of immunology 153, 4704(1994) and Cook et al, Science (Science), 2691583 (1995)). All of these data indicate that CCR1 antagonists are effective in treating a variety of immune-related diseases. The compounds described herein are very selective inhibitors of CCR 1. No other small molecule antagonists of MIP-1 α/RANTES that interact with CCR1 have been found.
U.S. patent 4,923,864 (issued on 8/5 1990) discloses certain heterocyclic caproamide compounds useful in the treatment of hypertension.
PCT publication No. WO 89/01488 (published 2/23 1989) discloses renin inhibitory peptides having non-peptide bonds.
PCT publication No. WO93/025057 (published 1993 at 2/4) discloses dipeptide analogs for use in inhibiting retroviral proteases.
PCT publication No. WO93/17003 (published 1993 on 9/2) discloses other dipeptide analogs for use in inhibiting retroviral proteases.
PCT publication No. WO92/17490 (published 1993 at 10/15) discloses peptides containing at least one O-phosphate mono-or diester. The compound has retrovirus inhibitory activity.
European patent publication No. 708,085 (published 24/4/1996) discloses antiviral ethers of aspartic protease inhibitors.
Summary of The Invention
The present invention relates to compounds of the formula:
wherein R is1Is (C) optionally substituted by one or more substituents, preferably 1 to 3 substituents2-C9) Heteroaryl, said substituents being independently from each other selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
R2is phenyl- (CH)2)m-, naphthyl- (CH)2)m-、(C3-C10) Cycloalkyl- (CH)2)m-、(C1-C6) Alkyl or (C)2-C9) Heteroaryl- (CH)2)m-, where m is an integer of 0 to 4, wherein the phenyl- (CH)2)m-, naphthyl- (CH)2)m-、(C3-C10) Cycloalkyl- (CH)2)m-or (C)2-C9) Heteroaryl- (CH)2)mPhenyl, naphthyl, (C) in the radical3-C10) Cycloalkyl or (C)2-C9) The heteroaryl moiety may be optionally substituted with one or more substituents (preferably 1-3 substituents) independently selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, phenoxy, benzyloxy, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
R3is hydrogen, (C)1-C10) Alkyl, (C)3-C10) Cycloalkyl- (CH)2)n-、(C2-C9) Heterocycloalkyl- (CH)2)n-、(C2-C9) Heteroaryl- (CH)2)n-or aryl- (CH)2)n-; wherein n is an integer from 0 to 6;
wherein said R3Is (C)1-C10) Alkyl groups may be optionally substituted with one or more substituents (preferably 1-3 substituents) independently selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl radical、[(C1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group; wherein said (C)1-C10) Any carbon-carbon single bond of the alkyl group may optionally be replaced by a carbon-carbon double bond;
wherein said R3Is (C)3-C10) Cycloalkyl- (CH)2)nOf the radical (C)3-C10) The cycloalkyl moiety may be optionally substituted with 1 to 3 substituents independently selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, quilt(C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
wherein said R3Is (C)2-C9) Heterocycloalkyl- (CH)2)nOf the radical (C)2-C9) The heterocycloalkyl moiety may also contain 1 to 3 substituents independently of one another selected from nitrogen, sulfur, oxygen, > S (═ O), > SO2Or > NR6Wherein said (C)2-C9) Heterocycloalkyl- (CH)2)nOf the radical (C)2-C9) The heterocycloalkyl moiety may be optionally substituted on any ring carbon atom capable of otherwise forming a bond (preferably 1 to 3 substituents per ring), said substituents being independently selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
wherein said R3Is (C)2-C9) Heteroaryl- (CH)2)nOf the radical (C)2-C9) The heteroaryl moiety may also contain 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen, wherein (C) is2-C9) Heteroaryl- (CH)2)nOf the radical (C)2-C9) The heteroaryl moiety may be optionally substituted (preferably 1-3 substituents per ring) at any ring carbon atom capable of otherwise forming a bondThe radicals are independently of one another selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
wherein said R3Aryl group of (CH)2)n-the aryl part of the group is optionally substituted phenyl or naphthyl, wherein said phenyl and naphthyl may be optionally substituted with 1-3 substituents independently from each other selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
or, R3Together with the carbon to which they are attached form a 5-7 membered carbocyclic ring, wherein any carbon atom on the 5-membered carbocyclic ring may be optionally substituted with substituents independently selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group; wherein one of the carbon-carbon bonds of the 5-7 membered carbocyclic ring may optionally be fused with an optionally substituted benzene ring, wherein the substituents may be independently selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
R4is hydrogen, (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C ═ O) -, (C)3-C10) Cycloalkyl- (CH)2)p-、(C2-C9) Heterocycloalkyl- (CH)2)p-、(C2-C9) Heteroaryl- (CH)2)p-, phenyl- (CH)2)p-or naphthyl- (CH)2)p-, where p is an integer from 0 to 4; wherein said (C)2-C9) Heterocycloalkyl- (CH)2)p-、(C2-C9) Heteroaryl- (CH)2)p-, phenyl- (CH)2)p-or naphthyl- (CH)2)pOf (A), (B), (C) and (C)2-C9) Heterocycloalkyl group, (C)2-C9) Heteroaryl, phenyl and naphthyl groups may be optionally substituted on any ring atom capable of otherwise forming a bond with substituents (preferably 0-2 substituents per ring) independently selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkyl, hydroxy-(C1-C6) Alkyl, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
or R4And R5Together with the nitrogen atom to which they are attached form (C)2-C9) Heterocycloalkyl group of which said (C)2-C9) Any ring atom of the heterocycloalkyl group may be optionally substituted (preferably with 0 to 2 substituents) with a substituent selected from the group consisting of: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, (C) optionally substituted by one or more fluorine atoms, preferably 1 to 3 fluorine atoms1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
R5is hydrogen, (C)1-C6) Alkyl or amino;
R6is hydrogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy- (CH)2)g-、(C1-C6) Alkoxy (C ═ O) - (CH)2)g-、(C1-C6) Alkyl- (SO)2)-(CH2)g-、(C6-C10) Aryloxy radical- (CH)2)g-、(C6-C10) Aryloxy (C ═ O) - (CH)2)g-or (C)6-C10) Aryl- (SO)2)-(CH2)g-, wherein g is an integer of 0 to 4;
provided that when R is4Or R5One is hydrogen and R is4Or R5Is (C)1-C6) An alkyl group; r2Is (C)3-C10) Cycloalkyl or isopropyl and R3Is (C)3-C5) Alkyl, phenyl, methylvinyl, dimethylvinyl, halovinyl, hydroxy (C)1-C3) Alkyl or amino (C)1-C4) When alkyl is present, then R1Is not indol-5-yl, 6-azaindol-2-yl, 2, 3-dichloro-pyrrol-5-yl, 4-hydroxyquinolin-3-yl, 2-hydroxyquinoxalin-3-yl, 6-azaindolin-3-yl or optionally substituted indol-2 or 3-yl.
The invention also relates to pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids used to prepare the pharmaceutically acceptable acid addition salts of the above-described basic compounds of the present invention are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate) ].
The invention also relates to base addition salts of the compounds of formula I. Chemical bases which can be used for the preparation of pharmaceutically acceptable base addition salts of the compounds of formula I which are acidic are those which form non-toxic base salts with the compounds. Such non-toxic base salts include, but are not limited to, salts derived from pharmaceutically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium salts or water-soluble amine addition salts such as N-methylglucamine (meglumine), as well as other base salts of lower alkanol ammonium salts and pharmaceutically acceptable organic amines.
The compounds of the invention may contain olefinic double bonds. When such a linkage is present, the compounds of the present invention may exist in cis and trans configurations and mixtures thereof.
Unless otherwise stated, the alkyl and alkenyl groups mentioned herein and the alkyl portion of other groups mentioned herein (e.g. alkoxy) may be straight or branched chain and may also be cyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or straight or branched chain containing cyclic moieties. Branched groups such as 2-methylbutyl, 2-methylpentyl are defined as having the smallest number of carbons furthest from the point of attachment. Halogen includes fluorine, chlorine, bromine and iodine unless otherwise specified.
As used herein (C)3-C10) Cycloalkyl means cycloalkyl containing from 0 to 2 unsaturations, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1, 3-cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo [3.2.1]Octane, norbornyl, and the like.
As used herein (C)2-C9) Heterocycloalkyl is pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxy, benzopyranyl, isoxazolidinyl, 1, 3-oxazolidin-3-yl, isothiazolidinyl, 1, 3-thiazolidin-3-yl, 1.2-pyrazolidin-2-yl, 1, 3-pyrazolidin-1-yl, piperidyl, thiomorpholinyl, 1, 2-tetrahydrothiazin-2-yl, 1, 3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1, 2-tetrahydrodiazin-2-yl, 1, 3-tetrahydrodiazin-1-yl, tetrahydroazepine, piperazinyl, chromanyl and the like. As can be appreciated by those of ordinary skill in the art, the (C)2-C9) The heterocycloalkyl ring being through carbon or sp3The hybridized nitrogen heteroatom is linked.
As used herein (C)2-C9) Heteroaryl refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1, 3, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 3, 5-thiadiazolyl, thiazolyl, triazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1, 3, 5-oxadiazolyl, 1, 2, 4-oxadiazo,1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1, 2, 4-triazinyl, 1, 2, 3-triazinyl, 1, 3, 5-triazinyl, pyrrolo [3, 4-b ] yl]Pyridyl, cinnolinyl, pteridinyl, purinyl, 6, 7-dihydro-5H- [1]4-azoindenyl, benzo [ b ]]Thienyl, 5, 6, 7, 8-tetrahydroquinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thioindenyl, isothioindenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolinyl, diazanaphthyl, quinoxalinyl, quinazolinyl, benzoxazinyl, and the like. As can be appreciated by those of ordinary skill in the art, the (C)2-C9) The heterocycloalkyl ring being through a carbon atom or sp3The hybridized nitrogen heteroatom is linked.
Aryl as used herein refers to phenyl or naphthyl.
The compounds of the present invention include all conformational isomers (e.g., cis-trans isomers) and all optical isomers (e.g., enantiomers and diastereomers) of the compounds of formula I, as well as racemic, diastereomeric and other mixtures of such isomers.
Preferred compounds of formula I include compounds having the stereochemistry shown below.
Preferred compounds of formula I include those wherein R1Is optionally substituted pyrazolo [3, 4-b]Pyridyl, cinnolinyl, pyridyl, 6, 7-dihydro-5H- [1]4-azoindenyl, benzothiazolyl, indolyl, pyrazinyl, benzimidazolyl, benzofuranyl, benzo [ b]Thienyl, naphthyl, quinoxalinyl, isoquinolinyl, 5, 6, 7, 8-tetrahydroquinolin-3-yl or quinolinyl compounds, more preferably pyrazolo [3, 4-b ]]Pyridin-5-yl, cinnolin-4-yl, pyridin-2-yl, 6, 7-dihydro-5H- [1]4-indolizin-3-yl, benzothiazol-2-yl, indol-2-yl, pyrazin-2-yl, benzimidazol-2-yl, benzofuran-2-yl, benzo [ b ]]Thien-2-yl, naphthalene-2-yl, quinoxalines-2-yl, quinoxalin-6-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, 5, 6, 7, 8-tetrahydroquinolin-3-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl, with quinoxalin-6-yl, quinolin-2-yl, quinolin-3-yl, quinoxalin-2-yl, quinolin-4-yl or quinolin-6-yl being preferred.
Other preferred compounds of formula I include those wherein R2Is an optionally substituted phenyl, benzyl, naphthyl, cyclohexyl, thienyl, thiazolyl, pyridyl, oxazolyl, furyl or thienyl group, wherein the substituents are independently from each other selected from the group consisting of hydrogen, halogen, (C)1-C6) Alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, -C (═ O) -OH, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C ═ O) -, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2-N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, phenoxy and benzyloxy.
Other preferred compounds of formula I include those wherein R3Is optionally substituted (C)1-C10) Alkyl radicalBenzyl, pyranyl or (C)3-C10) Cycloalkyl- (CH)2)nThe compound of (A) wherein (C)1-C10) Any carbon-carbon single bond in the alkyl group may optionally be replaced by a carbon-carbon double bond; more preferred is optionally substituted n-butyl, tert-butyl, 2-methylpropyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-methyl-pentyl, allyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, cyclohexylmethyl or cycloheptyl, more preferred is one wherein the substituents are fluoro, (C)1-C6) Alkyl or hydroxy.
Examples of particularly preferred compounds of the formula I are the following:
7, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
8-fluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-7-fluoro-1 (S) - (3-fluoro-benzyl) -2(S) hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (2-fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4- (2, 6-dimethyl-tetrahydro-pyran-4-yl) -2(S) -hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -carbamoyl-pentyl) ] -amide;
quinoxaline-2-carboxylic acid [1(S) -cyclohexylmethyl-2 (S) -hydroxy-7-methyl-4 (R) -carbamoyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-4-methylcyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) - (4, -4-difluoro-1-hydroxy-cyclohexyl) -2(S) - (hydroxy-4-hydroxycarbamoyl-butyl) ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4 (S) - (4, -4-difluoro-cyclohexyl) -2(S) -hydroxy-butyl ] -amide;
quinoxaline-3-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -amide;
quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S) -hydroxy-7-methyl-1 (S) -thiophen-2-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-7-chloro-2 (S) -hydroxy-oct-6-enyl) ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenylpentyl) ] -amide;
n- (1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -5, 6-dichloro-nicotinamide;
quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S) -hydroxy-7-methyl-1 (S) -thiazol-4-ylmethyl-octyl) -amide;
benzothiazole-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) ] -amide; and
benzofuran-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) ] -amide.
Other examples of compounds of formula I are as follows:
quinoxaline-2-carboxylic acid (4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-1-thiazol-4-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid (7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-thiazol-4-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-2-hydroxy-4- (1-hydroxy-4-methylcyclohexyl) -1-thiazol-4-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -1-thiazol-4-ylmethyl-butyl) -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-1-thiazol-4-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [4- (4, -4-difluoro-cyclohexyl) -2-hydroxy-4-hydroxycarbamoyl-1-thiazol-4-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-1- (3, 5-difluoro-benzyl) -7-fluoro-2-hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1- (3, 5-difluoro-benzyl) -7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-1- (3, 5-difluoro-benzyl) -2-hydroxy-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1- (3, 5-difluoro-benzyl-2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-1- (3, 5-difluoro-benzyl) -4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid [1- (3, 5-difluoro-benzyl) -4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-4-hydroxycarbamoyl-butyl ] -amide;
quinoxaline-2-carboxylic acid (4-carbamoyl-2-hydroxy-7-methyl-1-pyridin-2-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid (7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-pyridin-2-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-4- (2, 6-dimethyl-tetrahydro-pyran-4-yl) -2-hydroxy-1-pyridin-2-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -1-pyridin-2-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid (4-carbamoyl-4-cyclohexyl-2-hydroxy-1-pyridin-2-ylmethyl-butyl) -amide;
quinoxaline-2-carboxylic acid [4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-4-hydroxycarbamoyl-1-pyridin-2-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid (4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-1-pyridin-3-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid (2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-pyridin-3-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-2-hydroxy-4- (1-hydroxy-4-methyl-cyclohexyl) -1-pyridin-3-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [4- (2, 6-dimethyl-tetrahydro-pyran-4-yl) -2-hydroxy-4-hydroxycarbamoyl-1-pyridin-3-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-1-pyridin-3-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid (4-cyclohexyl-2-hydroxy-4-hydroxycarbamoyl-1-pyridin-3-ylmethyl-butyl) -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-7-fluoro-1- (4-fluoro-benzyl) -2-hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [ 7-fluoro-1- (4-fluoro-benzyl) -2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl-amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-1- (4-fluoro-benzyl) -2-hydroxy-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1- (4-fluoro-benzyl) -2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-4- (4, 4-difluoro-cyclohexyl) -1- (4-fluoro-benzyl) -2-hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid [4- (4, 4-difluoro-cyclohexyl) -1- (4-fluoro-benzyl) -2-hydroxy-4-hydroxycarbamoyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-1- (3-fluoro-benzyl) -2-hydroxy-4- (1-hydroxy-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [ 7-fluoro-1- (3-fluoro-benzyl) -2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-4- (2, 6-dimethyl-tetrahydro-pyran-4-yl) -1- (3-fluoro-benzyl) -2-hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid [1- (3-fluoro-benzyl) -2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-4- (4, 4-difluoro-cyclohexyl) -1- (3-fluoro-benzyl) -2-hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-cyclohexyl-1- (3-fluoro-benzyl) -2-hydroxy-4-hydroxycarbamoyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-1- (2-fluoro-benzyl) -2-hydroxy-4- (1-hydroxy-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [ 7-fluoro-1- (2-fluoro-benzyl) -2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-4- (2, 6-dimethyl-tetrahydropyran-4-yl) -1- (2-fluoro-benzyl) -2-hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid [1- (2-fluoro-benzyl) -2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-4- (4, 4-difluoro-cyclohexyl) -1- (2-fluoro-benzyl) -2-hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-cyclohexyl-1- (2-fluoro-benzyl) -2-hydroxy-4-hydroxycarbamoyl-butyl ] -amide;
quinoxaline-2-carboxylic acid (4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-1-thiophen-2-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid (7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-thiophen-2-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-2-hydroxy-4- (1-hydroxy-4-methyl-cyclohexyl) -1-thiophen-2-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -1-thiophen-2-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-1-thiophen-2-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-4-hydroxycarbamoyl-1-thiophen-2-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-2-hydroxy-7-methyl-1- (3-trifluoromethyl-benzyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [ 7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1- (3-trifluoromethyl-benzyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-carbamoyl-4- (4-hydroxy-2, 6-dimethyl-tetrahydro-pyran-4-yl) -1- (3-trifluoromethyl-benzyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -1- (3-trifluoromethyl-benzyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid { 4-carbamoyl-4-cyclohexyl) -2-hydroxy-1- (3-trifluoromethyl-benzyl) -butyl } -amide;
quinoxaline-2-carboxylic acid { 4-hydroxycarbamoyl-4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-1- (3-trifluoromethyl-benzyl) -butyl } -amide;
quinoxaline-2-carboxylic acid [ 7-fluoro-2-hydroxy-4-carbamoyl-7-methyl-1- (3-trifluoromethoxy-benzyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-hydroxycarbamoyl-2-hydroxy-7-methyl-1- (3-trifluoromethoxy-benzyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-carbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -1- (3-trifluoromethoxy-benzyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-hydroxycarbamoyl-4- (4-hydroxy-2, 6-dimethyl-tetrahydropyran-4-yl) -1- (3-trifluoromethoxy-benzyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid { 4-carbamoyl-4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-1- (3-trifluoromethoxy-benzyl) -butyl } -amide;
quinoxaline-2-carboxylic acid { 4-hydroxycarbamoyl-4-cyclohexyl) -2-hydroxy-1- (3-trifluoromethoxy-benzyl) -butyl } -amide;
quinoxaline-2-carboxylic acid [ 7-fluoro-2-hydroxy-4-carbamoyl-7-methyl-1- (4-trifluoromethoxy-benzyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [ 7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1- (4-trifluoromethoxy-benzyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-carbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -1- (4-trifluoromethoxy-benzyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -1- (4-trifluoromethoxy-benzyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid { 4-carbamoyl-4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-1- (4-trifluoromethoxy-benzyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid { 4-hydroxycarbamoyl-4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-1- (4-trifluoromethoxy-benzyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-2-hydroxy-7-methyl-1- (2-trifluoromethyl-benzyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [ 7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1- (2-trifluoromethoxy-benzyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-carbamoyl-4- (4-hydroxy-2, 6-dimethyl-tetrahydropyran-4-yl) -1- (2-trifluoromethoxy-benzyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -1- (2-trifluoromethoxy-benzyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid { 4-carbamoyl-4-cyclohexyl) -2-hydroxy-1- (2-trifluoromethoxy-benzyl) -butyl } -amide;
quinoxaline-2-carboxylic acid { 4-hydroxycarbamoyl-4- {4, 4-difluoro-cyclohexyl) -2-hydroxy-1- (2-trifluoromethoxy-benzyl) -butyl } -amide;
quinoxaline-2-carboxylic acid [ 7-fluoro-2-hydroxy-4-carbamoyl-7-methyl-1- [3- (1-hydroxy-1-methyl-ethyl) -benzyl ] -octyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-hydroxycarbamoyl-2-hydroxy-7-methyl-1- [3- (1-hydroxy-1-methyl-ethyl) -benzyl ] -octyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-carbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -1- [3- (1-hydroxy-1-methyl-ethyl) -benzyl ] -butyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-hydroxycarbamoyl-4- (4-hydroxy-2, 6-dimethyl-tetrahydropyran-4-yl) -1-3- (1-hydroxy-1-methyl-ethyl) -benzyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid { 4-carbamoyl-4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-1- [3- (1-hydroxy-1-methyl-ethyl) -benzyl ] -butyl ] -amide;
quinoxaline-2-carboxylic acid { -4-hydroxycarbamoyl-4- (cyclohexyl) -2-hydroxy-1- [3- (1-hydroxy-1-methyl-ethyl) -benzyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 7-fluoro-2-hydroxy-4-carbamoyl-7-methyl-1-thiophen-3-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-1-thiophen-3-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-carbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -1-thiophen-3-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -1-thiophen-3-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-carbamoyl-4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-1-thiophen-3-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [ 4-hydroxycarbamoyl-4- (4, 4-difluoro-cyclohexyl) -2-hydroxy-1-thiophen-3-ylmethyl-butyl ] -amide;
[1, 8] naphthyridine-3-carboxylic acid (1-benzyl-4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-octyl) -amide;
[1, 8] naphthyridine-3-carboxylic acid (1-benzyl-7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl) -amide;
[1, 8] naphthyridine-3-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
[1, 8] naphthyridine-3-carboxylic acid [ 1-benzyl-2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
[1, 5] naphthyridine-3-carboxylic acid (1-benzyl-4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-octyl) -amide;
[1, 5] naphthyridine-3-carboxylic acid (1-benzyl-7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl) -amide;
[1, 5] naphthyridine-3-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
[1, 5] naphthyridine-3-carboxylic acid [ 1-benzyl-2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
[1, 8] naphthyridine-2-carboxylic acid (1-benzyl-4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-octyl) -amide;
[1, 8] naphthyridine-2-carboxylic acid (1-benzyl-7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl) -amide;
[1, 8] naphthyridine-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
[1, 8] naphthyridine-2-carboxylic acid [ 1-benzyl-2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
[1, 6] naphthyridine-2-carboxylic acid (1-benzyl-4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-octyl) -amide;
[1, 6] naphthyridine-2-carboxylic acid (1-benzyl-7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl) -amide;
[1, 6] naphthyridine-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
[1, 6] naphthyridine-2-carboxylic acid [ 1-benzyl-2-hydroxy-4-hydroxycarbamoyl-4- (1-hydroxy-4-methylcyclohexyl) -butyl ] -amide;
quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoxaline-2-carboxylic acid (6-chloro-1 (S) -cyclohexylmethyl-2 (S) -hydroxy-4 (S) -methylcarbamoyl-hept-6-enyl) -amide;
quinoline-3-carboxylic acid (2(S) -hydroxy-1 (S) -isobutyl-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -sec-butyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoxaline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-hept-6-enyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-hept-6-enyl) -amide;
n-1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -5-phenyl-nicotinamide;
quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -cyclohexylmethyl-4 (R) -dimethylcarbamoyl-2 (S) -4-hydroxy-6-methyl-hept-6-enyl) amide;
quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
isoquinoline-4 (R) -carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoline-3-carboxylic acid (4(R) -carbamoyl-1 (S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-heptyl) -amide;
quinoline-3-carboxylic acid (5-cyclohexyl-1 (S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (S) -methylcarbamoyl-heptyl) -amide;
quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-5-phenyl-pentyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-5-phenyl-pentyl) -amide;
quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -butylcarbamoyl-2 (S) -hydroxy-6-methyl-heptyl) -amide;
quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -cyclobutylcarbamoyl-2 (S) -hydroxy-6-methyl-heptyl-amide;
quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -benzylcarbamoyl-2 (S) -hydroxy-6-methyl-heptyl) -amide;
quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -cyclopropylcarbamoyl-2 (S) -hydroxy-6-methyl-heptyl) -amide;
quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (S) -methylcarbamoyl-heptyl) -amide;
quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -ethylcarbamoyl-2 (S) -hydroxy-6-methyl-heptyl) -amide;
quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -propylcarbamoyl-heptyl) -amide;
quinoline-3-carboxylic acid [ 1-benzyl-2 (S) -hydroxy-4 (R) - (2(S) -hydroxy-ethylcarbamoyl) -6-methyl-heptyl ] -amide;
cinnoline-4 (R) -carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
isoquinoline-4 (R) -carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
n-1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -5-bromo-nicotinamide;
quinoline-3-carboxylic acid 1(R) -cyclohexylmethyl-2 (R) -hydroxy-6-methyl-4 (S) -methylcarbamoyl-heptyl) -amide;
quinoxaline-2-carboxylic acid [1- (4-benzyloxy-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl ] -amide;
quinoline-3-carboxylic acid [1- (4-benzyloxy-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl ] -amide;
isoquinoline-1-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoline-4 (R) -carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoline-6-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoline-3-carboxylic acid [2(S) -hydroxy-1- (4-hydroxy-benzyl) -6-methyl-4 (R) methylcarbamoyl-heptyl ] -amide;
quinoline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
naphthalene-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoline-3-carboxylic acid 1(S) -benzyl-5-cyclohex-1-enyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
quinoline-3-carboxylic acid [ 1-benzyl-2 (S) -hydroxy-6-methyl-4 (R) - (3-methyl-butylcarbamoyl) -heptyl ] -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (S) -methylcarbamoyl-heptyl) -amide;
4- {3(S) -hydroxy-7-methyl-5 (R) -methylcarbamoyl-2 (S) - [ (quinoline-3-carbonyl) -amino ] -octyl } -phenyl trifluoromethanesulfonate;
4- {3(S) -hydroxy-7-methyl-5 (R) -methylcarbamoyl-2 (S) - [ (quinoxaline-2-carbonyl) -amino ] -octyl } -phenyl trifluoromethanesulfonate;
quinoline-3-carboxylic acid 1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
isoquinoline-3-carboxylic acid 1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
n-1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -5-bromo-nicotinamide;
quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -prop-2-ynylcarbamoyl-heptyl) -amide;
quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -hydroxycarbamoyl-6-methyl-heptyl) -amide;
quinoline-3-carboxylic acid 2(S) -hydroxy-1 (S) - (4-methoxy-benzyl) -6-methyl-4 (R) -methylcarbamoyl-heptyl ] -amide;
isoquinoline-3-carboxylic acid (5-cyclohexyl-1 (S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
5-bromo-N- (5-cyclohexyl-1 (S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -nicotinamide;
quinoxaline-2-carboxylic acid [2(S) -hydroxy-1 (S) - (4-methoxy-benzyl) -6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
isoquinoline-4 (R) -carboxylic acid (5-cyclohexyl-1 (S) cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
quinoline-2-carboxylic acid 1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
isoquinoline-4 (R) -carboxylic acid 1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
quinoxaline-2-carboxylic acid [2(S) -hydroxy-1 (S) - (4-hydroxy-benzyl) -6-methyl-4 (R) -methylcarbamoyl-heptyl ] -amide;
quinoxaline-2-carboxylic acid (5-cyclohexyl-1 (S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
quinoline-3-carboxylic acid [1(S) - (4-chloro-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) - (4-chloro-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl ] -amide;
quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
quinoline-3-carboxylic acid [1(S) - (4-chloro-benzyl) -5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
quinoxaline-2-carboxylic acid [1(S) - (4-chloro-benzyl) -5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl ] -amide;
quinoline-2-carboxylic acid [1(S) - (4-chloro-benzyl) -5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl ] -amide;
benzofuran-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
n-1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -5, 6-dichloro-nicotinamide;
quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
n-1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -5-bromo-nicotinamide;
5, 6, 7, 8-tetrahydro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
quinoline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
isoquinoline-4 (R) -carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
quinoxaline-2-carboxylic acid [1- (3, 4-dichloro-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
benzo [ b ] thiophene-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
2-methyl-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
6, 7-dimethoxy-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
6, 7-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
1H-benzimidazole-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
5-methyl-pyrazine-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoline-3-carboxylic acid [1(S) - (4-fluoro-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) - (4-fluoro-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl ] -amide;
5-chloro-1H-indole-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide;
2-methoxy-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
5, 6-dichloro-1H-benzimidazole-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
benzothiazole-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
7, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
6, 7, 8-trifluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
5, 8-dimethyl-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -butylcarbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoline-3-carboxylic acid [1(S) - (3, 4-dichloro-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl ] -amide;
5, 6, 7, 8-tetrahydroquinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
quinoline-3-carboxylic acid 1(S) -benzyl-5-cyclopentyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-5-cyclopentyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
n-1(S) -benzyl-5-cyclopentyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -5-bromo-nicotinamide;
5, 6, 7, 8-tetrahydro-quinoline-3-carboxylic acid 1(S) -benzyl-5-cyclopentyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-5-cyclopentyl-2 (S) -hydroxy-pentyl) -amide;
6, 7-dihydro-5H- [1] 4-indolizine-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
quinoxaline-2-carboxylic acid [1(S) - (4, 4-difluoro-cyclohexylmethyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) - (4, 4-difluoro-cyclohexylmethyl) -2(S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl ] -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -ethylcarbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -propylcarbamoyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -cyclopropylcarbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -cyclobutylcarbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid [1(S) - (4-difluoromethoxy-benzyl) -2(S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl ] -amide;
4- {3(S) -hydroxy-7-methyl-5 (R) -methylcarbamoyl-2 (S) - [ (quinoxaline-2-carbonyl) amino ] -octyl } -benzoic acid methyl ester;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-butyl) -amide;
6, 7, 8-trifluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
6, 7, 8-trifluoro-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide;
6, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
6, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -butylcarbamoyl-5-cyclopentyl-2 (S) -hydroxy-pentyl) -amide;
6-methyl-pyridine-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-8-methyl-4 (R) methylcarbamoyl-nonyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-8-methyl-nonyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -biphenyl-4 (R) -ylmethyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-oct-6-enyl) -amide;
quinoxaline-2-carboxylic acid (2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-1 (S) -naphthalen-2-ylmethyl-heptyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7, 7-dimethyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7, 7-dimethyl-4 (R) -methylcarbamoyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenyl-pentyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -biphenyl-4 (R) -ylmethyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-5- (4, 4-difluoro-cyclohexyl) -2(S) -hydroxy-4 (R) -methylcarbamoyl-pentyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-5- (4, 4-difluoro-cyclohexyl) -2(S) -hydroxy-pentyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) - (3-fluoro-benzyl) -2(S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (3(S) -fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-oct-6-enyl) -amide;
6, 7, 8-trifluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-nonyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methylnonyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-nonyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -dimethylcarbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide;
7, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-5-phenyl-pentyl) -amide;
7, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) methylcarbamoyl-octyl) -amide;
8-fluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-non-6-enyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-non-6-enyl) amide;
7, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide;
8-fluoro-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide;
4(S) -hydroxy-2 (R) - (3-methyl-butyl) -6-phenyl-5 (S) - (quinoxaline-2 (R) -carbonyl) -amino ] -hexanoic acid;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-nonyl) -amide;
2- {2(S) -hydroxy-4-phenyl-3 (S) - [ (quinoxaline-2-carbonyl) -amino ] -butyl } -N1, N4-dimethyl-succinamide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4-ethylcarbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -butylcarbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid [ 7-fluoro-1 (S) - (4-fluoro-benzyl) -2(S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (3, 4-dichloro-benzyl) -7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
7, 8-difluoro-quinoline-3-carboxylic acid [4(R) -carbamoyl-1 (S) - (3, 4-dichloro-benzyl) -7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S) -hydroxy-7-methyl-1 (S) -4-phenethyl-octyl) -amide;
7, 8-difluoro-quinoline-3-carboxylic acid [4(R) -carbamoyl-7-fluoro-1 (S) - (4-fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-7-fluoro-1 (S) - (4-fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid {1(S) - [4(R) - (3-methyl-butyl) -5-oxo-tetrahydrofuran-2-yl ] -2(S) -phenyl-ethyl } -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (4-methyl-piperazine-1-carbonyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5- (tetrahydropyran-4 (R) -yl) -pentyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (piperidine-1-carbonyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (morpholine-4 (R) -carbonyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (3-morpholin-4-yl-propionyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-3- (2-carbamoyl-indan-2-yl) -2(S) -hydroxypropyl ] -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-7-phenyl-hept-6-enyl) -amide;
quinoline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7 methyl-octyl) -amide;
6, 7-dihydro-5H- [1] 4-indolizine-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-4-carbamoyl-4 (S) -cyclohexyl-2 (S) -hydroxy-butyl) -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-4-carbamoyl-4 (S) -cyclohexyl-2 (S) -hydroxy-butyl) -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-4-carbamoyl-4 (S) -cyclohexyl-2 (S) -hydroxy-butyl) -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-4-carbamoyl-4 (S) -cyclopentyl-2 (S) hydroxy-butyl) -amide;
quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
n-1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -5-bromo-nicotinamide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1- (2(S) -fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (2(S) -fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-4 (S) - (4-isopropyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S) -hydroxy-7-methyl-1 (S) -thiophen-2-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S) -hydroxy-7-methyl-1 (S) -thiazol-4 (R) -ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4 (S) - (3, 3,5, 5-tetramethyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy- (S) -indan-2-yl-butyl) -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-4 (S) -cycloheptyl-2 (S) -hydroxy-butyl) -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-propyl-octyl) -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-propyl-oct-5-enyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2, 7-dihydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-7-chloro-2 (S) -hydroxy-4 (R) -methylcarbamoyl-hept-6-enyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-7-chloro-2 (S) -hydroxy-4 (R) -methylcarbamoyl-hept-6-enyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-6-chloro-2 (S) -hydroxy-4 (S) -methylcarbamoyl-hept-6-enyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-6-chloro-2 (S) -hydroxy-hept-6-enyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-6-cyclopropyl-2 (S) -hydroxy-hexyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-6-cyclopropyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-hexyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-4 (S) - (4-methyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-4 (S) -indan-2-yl-butyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5- (4-trifluoromethoxy-phenyl) -pentyl ] -amide;
quinoxaline-2-carboxylic acid [ 1-benzyl-4 (R) -carbamoyl-5- (4-fluoro-phenyl) -2(S) -hydroxy-pentyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-chloro-2 (S) -hydroxy-hept-6-enyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-chloro-2 (S) -hydroxy-hept-6-enyl) -amide;
3-hydroxy-quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -benzylcarbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [ (pyridin-3-ylmethyl) -carbamoyl ] -octyl } -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-8, 8-trifluoro-2 (S) -hydroxy-4 (R) -methylcarbamoyl-7-trifluoromethyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-8, 8-trifluoro-2 (S) -hydroxy-7-trifluoromethyl-octyl) -amide;
quinoxaline-2-carboxylic acid [2(S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-1 (S) - (4-methylcarbamoyl-benzyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-5-ethyl-2 (S) -hydroxyheptyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4 (S) - (tetrahydro-pyran-4-yl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (2(R) -pyridin-2-yl-ethylcarbamoyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) - (3, 4-dimethoxy-benzylcarbamoyl) -7-fluoro-2 (S) -hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-6-methoxy-hexyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-chloro-2 (S) -hydroxy-oct-6-enyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-7-chloro-2 (S) -hydroxy-4 (R) -methylcarbamoyl-oct-6-enyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-4 (S) - (3, 5-dimethyl-cyclohexyl) -2(S) -hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [ (pyridin-2-ylmethyl) -carbamoyl ] -octyl } -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - [2- (4-hydroxy-phenyl) -ethylcarbamoyl ] -7-methyl-octyl } -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [ (thiophen-2-ylmethyl) -carbamoyl ] -octyl } -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-6-phenoxy-hexyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-6-isopropoxy-hexyl) -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [2- (4-sulfamoyl-phenyl) -ethylcarbamoyl ] -octyl } -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [ (pyridin-4-ylmethyl) -carbamoyl ] -octyl } -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4- (2-ethylsulfanyl-ethylcarbamoyl) -7-fluoro-2 (S) -hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - (2-methoxy-ethylcarbamoyl) -7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (2-pyridin-3-yl-ethylcarbamoyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (2-pyridin-4 (R) -yl-ethylcarbamoyl) -octyl ] -amide;
quinoxaline-6-carboxylic acid 1(S) -benzyl-4 (R) carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-6-tert-butoxy-4 (R) -carbamoyl-2 (S) -hydroxy-hexyl) -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [2-1(S) -methyl-1H-pyrrol-2-yl) -ethylcarbamoyl ] -octyl } -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4- (1, 1-dioxo-hexahydro-thiopyran-4-yl) -2(S) -hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - [2- (6-methoxy-1H-indol-3-yl) -ethylcarbamoyl ] -7-methyl-octyl } -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - (2-methoxy-benzylcarbamoyl) -7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - (3-methoxy-benzylcarbamoyl) -7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (2-thiophen-2-yl-ethylcarbamoyl) -octyl ] -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - [2- (1H-indol-3-yl) -ethylcarbamoyl ] -7-methyl-octyl } -amide;
quinoxaline-2-carboxylic acid {4(R) - [2- (4-amino-phenyl) -ethylcarbamoyl ] -1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl } -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-4 (R) - [2- (3, 5-dimethoxy-phenyl) -ethylcarbamoyl ] -7-fluoro-2 (S) -hydroxy-7-methyl-octyl } -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-4 (R) - [2- (3, 4-dimethoxy-phenyl) -ethylcarbamoyl ] -7-fluoro-2 (S) -hydroxy-7-methyl-octyl } -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-4 (R) - [ (furan-2-ylmethyl) -carbamoyl ] -2(S) -hydroxy-7-methyl-octyl } -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-4 (R) - [2- (2, 5-dimethoxy-phenyl) -ethylcarbamoyl ] -7-fluoro-2 (S) -hydroxy-7-methyl-octyl } -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - (4-methoxy-benzylcarbamoyl) -7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-6-cyclohexyloxy-2 (S) -hydroxy-hexyl) -amide;
quinoxaline-2-carboxylic acid {4(R) - [ (1H-benzoimidazol-2-ylmethyl) -carbamoyl ] -1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl } -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - (2(S) -hydroxymethyl-pyrrolidine-1-carbonyl) -7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [ (tetrahydrofuran-2-ylmethyl) -carbamoyl ] -octyl } -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4-carbamoyl-4 (S) - (4, 4-difluoro-cyclohexyl) -2(S) -hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) - (2, 3-dimethoxy-benzylcarbamoyl) -7-fluoro-2 (S) -hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4- (2, 6-dimethyl-tetrahydro-pyran-4-yl) -2(S) -hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-7-fluoro-1 (S) - (3-fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl ] -amide;
7, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
n-1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -5, 6-dichloro-nicotinamide;
benzofuran-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
cinnoline-4 (R) -carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-7-fluoro-2 (S) -hydroxy-1- (4-iodo-benzyl) -7-methyl-octyl ] -amide;
pyrazine-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
6, 7, 8-trifluoro-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoline-6-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
isoquinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
2-methoxy-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
1H-benzimidazole-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
benzothiazole-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
5-methyl-pyrazine-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) carbamoyl-2 (S) -hydroxy-5-pyridin-3-yl-pentyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-cyclohexyl) -butyl ] -amide;
quinoline-3-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -amide;
quinoline-2-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -amide;
fluoro-quinoline-3-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -amide;
n- (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -5, 6-dichloro-nicotinamide;
n- (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -5-bromo-nicotinamide;
quinoxaline-2-carboxylic acid (4(R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-1-phenyl-octyl) -amide;
quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-pyridin-2-yl-pentyl) -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-cyclohexyl) -1(S) -thiophen-2-ylmethyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (4-hydroxy-tetrahydro-thiopyran-4-yl) -butyl ] -amide;
1, 3-dimethyl-1H-pyrazolo [3, 4-b ] pyridine-5-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) -methoxycarbamoyl-7-methyl-octyl) -amide;
7, 8-difluoro-quinoline-3-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenyl-pentyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-5- (2-chloro-phenyl) -2(S) -hydroxy-pentyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-o-tolyl-pentyl ] -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-2 (S) -hydroxy-4 (R) -hydroxycarbamoyl-5-phenyl-pentyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-cyclopentyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-5- (3, 4-dichlorophenyl) -2(S) -hydroxy-pentyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-5- (2-fluoro-phenyl) -2(S) -hydroxy-pentyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-cyclopentyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-3-methylcyclopentyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-4-methylcyclohexyl) -butyl ] -amide;
n- (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenyl-pentyl) -5-bromo-nicotinamide;
8-fluoro-quinoxaline-3-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenyl-pentyl) -amide;
6, 7-dihydro-5H- [1] 4-indolizine-3-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenyl-pentyl) -amide;
quinoline-3-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenyl-pentyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl 4(S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-3, 5-dimethylcyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-3, 5-dimethyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-cycloheptyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-cycloheptyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-5- (3-fluoro-phenyl) -2(S) -hydroxy-pentyl ] -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-m-tolyl-pentyl) -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-2 (S) -hydroxy-4-isobutylcarbamoyl-butyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (2-hydroxy-adamantan-2-yl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (9-hydroxy-bicyclo [3.3.1] non-9-yl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) - (2-hydroxy-adamantan-2-yl) -4-hydroxycarbamoyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) - (9-hydroxy-bicyclo [3.3.1] non-9-yl) -4-hydroxycarbamoyl-butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5- (3-methoxy-phenyl) -pentyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-4-propyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-4-propyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5- (4-methoxy-phenyl) -pentyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4 (S) - (4-ethyl-1-hydroxycyclohexyl) -2-hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-4, 4-dimethyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-4, 4-dimethyl-cyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4- (4, 4-difluoro-1-hydroxy-cyclohexyl) -2-hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (3-fluoro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (3, 5-difluoro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (3-chloro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) - (3-chloro-benzyl) -2(S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl ] -amide;
7, 8-difluoro-quinoline-3-carboxylic acid (1S) -benzyl-4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-octyl) -amide;
6, 7, 8-trifluoro-quinoline-3-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid [1(S) - (3, 5-difluoro-benzyl) -2(S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid (1(S) -benzyl-2 (S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl) -amide;
7, 8-difluoro-quinoline-3-carboxylic acid (1(S) -benzyl-4 (R) -ethylcarbamoyl-2 (S), 7-dihydroxy-7-methyl-octyl) -amide;
n- (1(S) -benzyl-4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-octyl) -4-trifluoromethyl-nicotinamide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (2-chloro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl ] -amide;
7, 8-difluoro-quinoline-3-carboxylic acid [ (4R) -carbamoyl-1 (S) - (3-fluoro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) - (2-fluoro-benzyl) -2(S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-1 (S) thiophen-2-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (2-fluoro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) - (3, 4-difluoro-benzyl) -2(S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (3, 4-difluoro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-1 (S) -naphthalen-1-ylmethyl-octyl) -amide;
6, 7, 8-trifluoro-quinoline-3-carboxylic acid [4(R) -carbamoyl-1 (S) - (3-fluoro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-1 (S) -naphthalen-2-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid (2(S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-1 (S) -naphthalen-2-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid (1(S) -benzo [ b ] thiophen-3-ylmethyl-4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-octyl) -amide;
quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (4-hydroxy-phenyl) -pentyl ] -amide;
quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (3-hydroxy-phenyl) -pentyl I-amide;
quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (2-hydroxy-phenyl) -pentyl) -amide;
quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (2-hydroxy-5-methyl-phenyl) -pentyl ] -amide;
quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (2-hydroxy-3-methyl-phenyl) -pentyl ] -amide;
quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-5- (3-ethoxy-2-hydroxy-phenyl) -2-hydroxy-pentyl ] -amide;
quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (4-hydroxy-3, 5-dimethyl-phenyl) -pentyl) -amide;
quinoxaline-2-carboxylic acid (1-benzyl-4-carbamoyl-2, 6-dihydroxy-6-methyl-heptyl) -amide;
quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (1-hydroxy-cyclohexyl) -pentyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) - (4, 4-difluoro-1-hydroxy-cyclohexyl) -2(S) -hydroxy-4-hydroxycarbamoyl-butyl) -amide; and
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-4-trifluoromethyl-cyclohexyl-butyl ] -amide.
The invention also relates to a pharmaceutical composition for the treatment or prevention of the following diseases in mammals, preferably humans: autoimmune diseases (e.g., rheumatoid arthritis, type I diabetes (newly-occurring), inflammatory bowel disease, ocular neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis and vasculitis), acute and chronic inflammation (e.g., osteoarthritis, adult respiratory distress syndrome, infant respiratory distress syndrome, ischemia reperfusion injury and glomerulonephritis), allergic diseases (e.g., asthma and atopic dermatitis), infections with inflammation (e.g., viral infections (including influenza and hepatitis) and Guillian-Barre syndrome), graft tissue rejection, atherosclerosis, restenosis, HIV infection (using common receptors), and granulomatosis (including sarcoidosis, leprosy and tuberculosis), the compositions comprise a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent the disorder and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for the treatment or prevention of a disease which can be treated or prevented by inhibiting MIP-1 α binding to the receptor CCR1 in a mammal, preferably a human, comprising a disease treating or preventing effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Examples of such diseases are those listed in the preceding paragraph.
The invention also relates to a method for the treatment or prevention of the following diseases in mammals, preferably humans: autoimmune diseases (e.g., rheumatoid arthritis, type I diabetes (newly-occurring), inflammatory bowel disease, ocular neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis and vasculitis), acute and chronic inflammation (e.g., osteoarthritis, adult respiratory distress syndrome, infant respiratory distress syndrome, ischemia reperfusion injury and glomerulonephritis), allergic diseases (e.g., asthma and atopic dermatitis), infections with inflammation (e.g., viral infections (including influenza and hepatitis) and Guillian-Barre syndrome), graft tissue rejection, atherosclerosis, restenosis, HIV infection (using common receptors), and granulomatosis (including sarcoidosis, leprosy and tuberculosis), the method comprises administering to a mammal in need of such treatment or prevention an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to treat or prevent the disease.
The present invention also relates to a method of treating or preventing a disease which can be treated or prevented by antagonizing the CCR1 receptor in a mammal, preferably a human, which comprises administering to a mammal in need of such treatment or prevention an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to treat or prevent the disease.
The invention also relates to a pharmaceutical composition for the treatment or prevention of the following diseases in mammals, preferably humans: autoimmune diseases (e.g., rheumatoid arthritis, type I diabetes (newly-occurring), inflammatory bowel disease, ocular neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis and vasculitis), acute and chronic inflammation (e.g., osteoarthritis, adult respiratory distress syndrome, infant respiratory distress syndrome, ischemia reperfusion injury and glomerulonephritis), allergic diseases (e.g., asthma and atopic dermatitis), infections with inflammation (e.g., viral infections (including influenza and hepatitis) and Guillian-Barre syndrome), graft tissue rejection, atherosclerosis, restenosis, HIV infection (using common receptors), and granulomatosis (including sarcoidosis, leprosy and tuberculosis), the compositions comprise a compound of formula I or a pharmaceutically acceptable salt thereof in an amount effective to antagonize CCR1 receptor and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for the treatment or prophylaxis of a disease which is treatable or preventable by antagonism of CCR1 in a mammal, preferably a human, which composition comprises an effective CCR1 receptor antagonising amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The invention also relates to a method for the treatment or prevention of the following diseases in mammals, preferably humans: autoimmune diseases (e.g., rheumatoid arthritis, type I diabetes (newly-occurring), inflammatory bowel disease, ocular neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis and vasculitis), acute and chronic inflammation (e.g., osteoarthritis, adult respiratory distress syndrome, infant respiratory distress syndrome, ischemia reperfusion injury and glomerulonephritis), allergic diseases (e.g., asthma and atopic dermatitis), infections with inflammation (e.g., viral infections (including influenza and hepatitis) and Guillian-Barre syndrome), graft tissue rejection, atherosclerosis, restenosis, HIV infection (using common receptors), and granulomatosis (including sarcoidosis, leprosy and tuberculosis), the method comprises administering to a mammal in need of such treatment or prevention a compound of formula I or a pharmaceutically acceptable salt thereof, in an amount effective for antagonism of the CCR1 receptor.
The invention also includes pharmaceutical compositions comprising prodrugs of compounds of formula I and methods of treatment or prevention using prodrugs of compounds of formula I. Compounds of formula I containing a free amino, amido, hydroxy or carboxy group may be converted into prodrugs. Such prodrugs include compounds wherein an amino acid residue or a polypeptide chain consisting of two or more (e.g., 2,3 or 4) amino acid residues is covalently bonded via a peptide bond to an amino, hydroxyl or carboxyl group of a compound of formula I. Amino acid residues include the 20 natural amino acids, generally indicated by 3 letters, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include those described above wherein carbonates, carbamates, amides and alkyl esters are pendant from the formula I compound through the carbonyl carbon prodrugA compound to which substituents are covalently bound. Prodrugs also include compounds of formula I wherein the secondary amide and its beta-hydroxy group are taken together to form a group of the formulaWherein R is1、R2、R3、R4And R5As defined in formula I, U and V are independently of one another carbonyl, methylene, SO2Or SO3And b is an integer of 0 to 3, wherein each methylene group may be optionally substituted with a hydroxyl group. Detailed Description
The compounds of formula I can be prepared according to the following reaction schemes and discussions. G, n, m, p, R in the schemes and discussions, unless otherwise stated1-R6 and structural formula I are as previously defined. Reaction scheme 1Scheme 1 describes the preparation of compounds of formula I having the exact stereochemistryOrThe compounds of formulae Ia and Ib, or various intermediates thereof, may be isolated by column chromatography according to methods well known to those skilled in the art to give pure compounds of formulae Ia and Ib.
According to scheme 1, wherein R4And R5Compounds of formula I in which one or both are not hydrogen are prepared from compounds of formula II (i.e., IIa and IIb) by reaction with a compound of formula R4R5The compound of NH is obtained by reaction in a polar solvent at a temperature of about 0 ℃ to about 100 ℃, preferably the boiling point of the solvent used (i.e. 65 ℃ when methanol is used as solvent). Suitable solvents include alcohols such as methanol, ethanol or butanol; ethers, such as glyme or dioxane, preferably the acid catalyst is used with the ether solvent. The preferred solvent is dioxane.
Or, wherein R4And R5Compounds of formula I in which one or both are hydrogen can be prepared from compounds of formula II (i.e., IIa and IIb) by reaction with ammonia or other volatile aminesIn a polar solvent at a temperature of from about-10 ℃ to about 35 ℃, preferably about 30 ℃. Suitable solvents include alcohols such as methanol, ethanol or butanol; ethers, such as glyme or dioxane, preferably the acid catalyst is used with the ether solvent. The preferred solvent is methanol.
A compound of formula II is prepared by reacting a compound of formula III (i.e., IIIa and IIIb) with a compound of formula R1CO2Acid coupling of H. The coupling reaction is generally carried out at a temperature of from about-30 to about 80 deg.C, preferably from about 0 deg.C to about 25 deg.C. Examples of suitable coupling agents which can activate carboxylic acid functional groups are dicyclohexylcarbodiimide/hydroxybenzotriazole (DCC/HBT), N-3-dimethylaminopropyl-N' -Ethylcarbodiimide (EDC)/HBT, 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), Carbonyldiimidazole (CDI)/Dimethylaminopyridine (DMAP) and diethylphosphoryl cyanide. This coupling is carried out in an inert solvent, preferably an aprotic solvent, such as acetonitrile, dichloromethane, chloroform and dimethylformamide. The preferred solvent is dichloromethane.
A discussion of other conditions used for amide coupling is found in Houben-Weyl, volume XV, part II, eds. Wunsch, George Theime Veriag, 1974, Stuttgart and M.Bodanszky, Principles of peptide Synthesis (Principles of peptide Synthesis), Springer-Verlag, Berlin (1984) and Peptides, assays, syntheses and Biology (Peptides, Analysis, Synthesis and Biology) (E.Gross and J.Meienhofer eds.), Vois 1-5(Academic Press, New York) 1979-1983.
Wherein R is3Is (C)1-C10) Alkyl, (C)3-C10) Cycloalkyl- (CH)2)n-、(C2-C9) Heterocycloalkyl- (CH)2)n-、(C2-C9) Heteroaryl- (CH)2)n-or aryl- (CH)2)nThe compounds of formula III of (I) can be prepared by deprotecting the compounds of formula IV (i.e. IVa and IVb). Suitable protecting groups of formula P include benzyloxycarbonyl, tert-butoxycarbonyl or 9-fluorenyl-methyleneoxycarbonyl.
For example:
(a) if the protecting group P of the compound of formula IV is a benzyloxycarbonyl group, this protecting group can be removed by hydrogenation with a noble metal catalyst such as palladium or palladium hydroxide adsorbed on carbon in the presence of hydrogen. The hydrogenation is generally carried out at a temperature of from about 0 ℃ to about 100 ℃, preferably from about 20 ℃ to 50 ℃.
(b) If the protecting group P is t-butyloxycarbonyl, this protecting group can be removed by acidolysis. The acid hydrolysis may be carried out with hydrogen chloride in dioxane or with trifluoroacetic acid in dichloromethane at a temperature of from about-30 ℃ to about-70 ℃, preferably from about-5 ℃ to about 35 ℃.
(c) If the protecting group P is 9-fluorenylmethylenoxycarbonyl, this group can be removed by treatment with a base of the amine type, preferably piperidine. The reaction may be carried out at about 10 ℃ to about 100 ℃, preferably 25 ℃, with piperidine as a solvent.
Wherein R is3Is substituted (C)1-C10) Alkyl, (C)3-C10) Cycloalkyl- (CH)2)n-or (C)2-C9) Heterocycloalkyl- (CH)2)nThe compound of formula III (III) can be prepared from the compound of formula IV, wherein R is as defined in formula IV, by methods well known to those of ordinary skill in the art3Is (C)1-C10) Alkyl, (C)3-C10) Cycloalkyl- (CH)2)n-or (C)2-C9) Heterocycloalkyl- (CH)2)nOne of the carbon-carbon single bonds may be replaced by a carbon-carbon double bond. Specifically, as in R3An example of introducing a substituent into the group, wherein R3Is substituted by 1-3 fluorine (C)1-C10) Alkyl compounds of formula III may be prepared from those in which R is3Is (C)1-C10) Alkyl and said (C)1-C10) Compounds of formula IV in which one of the carbon-carbon single bonds of the alkyl group has been replaced by a carbon-carbon double bond are prepared by reaction with a solution of hydrogen fluoride in pyridine, i.e. pyridinium poly (hydrogen fluoride), in a reaction-inert solvent. Suitable solvents includeCyclohexane, toluene or benzene, preferably benzene. The reaction is carried out at a temperature of from about-78 ℃ to about 35 ℃. Preferably, the reaction is carried out in benzene at about 25 ℃.
Wherein R is3Is (C)1-C10) Alkyl, (C)3-C10) Cycloalkyl- (CH)2)n-、(C2-C9) Heterocycloalkyl- (CH)2)n-、(C2-C9) Heteroaryl- (CH)2)n-or aryl- (CH)2)nAnd wherein n is other than zero, can be prepared by reacting a compound of formula V with a compound of formula R3The compound of-L (wherein L is a leaving group) is prepared by reacting in an aprotic polar solvent in the presence of a strong base. Suitable leaving groups include chloro, fluoro, bromo, iodo, mesylate, triflate or tosylate. Preferably the leaving group is triflate, iodine or bromine. Triflates can be conveniently prepared according to the method of Beard et al (J. org. chem., 38, 3673 (1973)). Suitable bases include lithium dialkylamides, such as lithium N-isopropyl-N-cyclohexylamide or potassium hydride. Suitable solvents include ethers (such as THF, glyme or dioxane), benzene or toluene, preferably THF. The above reaction is carried out at a temperature of about-78 ℃ to about 0 ℃, preferably-78 ℃.
Or, wherein R3Is (C)1-C10) Alkyl, (C)3-C10) Cycloalkyl- (CH)2)n-or (C)2-C9) Heterocycloalkyl- (CH)2)nThe compound of formula IV can be prepared by reacting a compound of formula V with R3The aldehyde or ketone precursor is subjected to aldol condensation to obtain the product. For example, a compound of formula V may be reacted with a compound of formula R3Reaction of an (═ O) compound in the presence of a base to form an aldol intermediate of the formulaThe aldol can be isolated and converted into the final product or directly into the compound of formula IV in the same reaction step by loss of water. The extent of the reaction of the compound of formula II to the aldol product of formula I can be determined by one or more analytical methods such as Thin Layer Chromatography (TLC) or mass spectrometryAnd (4) evaluating. In some cases, it may be possible or desirable to isolate the intermediate of formula VI. In this case, the conversion of the compound of formula VI to the compound of formula IV can be carried out by eliminating water by methods well known to those skilled in the art, for example by heating the compound of formula VI to reflux in a solvent such as benzene, toluene or xylene in the presence of a catalytic amount of phosphorus pentoxide, benzenesulfonic acid or p-toluenesulfonic acid and removing the water formed, preferably (methoxycarbonylsulfamoyl) -triethylammonium hydroxide (Burgess reagent). The water removal technique involves the use of molecular sieves or the separation of water in the form of an azeotrope with the solvent using a Dean-Stark trap.
The aldol condensation reaction is typically carried out in a polar solvent such as DMSO, DMF, Tetrahydrofuran (THF), methanol, or ethanol at a temperature of about-78 ℃ to about 80 ℃. Preferably, the reaction is carried out in THF at about-78 deg.C. Suitable bases for the aldol forming step include potassium carbonate (K)2CO3) Sodium carbonate (Na)2CO3) Sodium hydride (NaH), sodium methoxide, potassium tert-butoxide, lithium diisopropylamide, pyrrolidine and piperidine. Lithium diisopropylamide is preferred. For a description of aldol condensation see "Modern Synthetic Reactions" Herbet O.House, 2 nd edition, W.A. Benjamin, Menlo Park, California, 629-682(1972), J.Organic chemistry, 49, 2455(1984) and tetrahedra (Tetrahedron), 38(20), 3059 (1983).
Wherein R is3Unsaturated compounds of formula IV can be converted to saturated analogs by hydrogenating compounds containing a carbon-carbon double bond using conventional techniques well known to those skilled in the art. For example, the reduction of the double bond may be carried out with hydrogen (H)2) With catalysts such as palladium on carbon (Pd/C), palladium-barium sulfate (Pd/BaSO)4) Platinum/carbon (Pt/C) or tris (triphenylphosphine) rhodium chloride (Wilkinson's catalyst) in a suitable solvent such as methanol, ethanol, THF, dioxane or ethyl acetate, at pressures of from about 1 to about 5 atmospheres and temperatures of from about 10 ℃ to about 60 ℃, see Catalytic Hydrogenation in organic synthesis (Catalytic Hydrogenation in organic Synthesis), Paul Rylander, Academic Press Inc., San Diego, 31-63 (1979). The following conditions are preferred: palladium on charcoal, methanol, 25 c and a hydrogen pressure of 50 psig. In the above method1H2By using2H2Or3H2Instead, hydrogen isotopes (i.e., deuterium and tritium) can also be introduced using this method.
Alternative methods using reagents such as ammonium formate and palladium on carbon in methanol at reflux temperature and under an inert gas atmosphere (e.g., nitrogen or argon) can also be effective in reducing the carbon-carbon double bond of the compound of formula I. Another approach involves the selective reduction of carbon-carbon double bonds. This can be achieved by using samarium and iodine or samarium iodide (Smi)2) This is done in methanol or ethanol at about room temperature, see R.Yanada et al, synthetic letters (Synlett.), 443-4 (1995).
The compounds of formula V may be prepared by methods well known to those skilled in the art or may be purchased commercially. In particular, the compounds of the formulae Va and Vb (see below) can be prepared by the method of Fray et al (J. org. chem., 51, 4828-4833(1986)) using (S) -aldehydes of the formulaThe compounds of formula VII may be prepared by reduction of an amino acid or amino ester to an alcohol (Stanfield et al, J. org. chem. Soc. Jpn., 57, 2327(1984)), and oxidation of the alcohol to an aldehyde of formula VII (Luly et al, J. org. chem. Soc. Jpn., 57, 2327(1984)), and then oxidation of the alcohol to the aldehyde of formula VII (Luly et al, J. org. chem., 53(26), 6109-6122(1988) and Denis et al, J. org. chem., 56(24), 6939-6942 (1991)). Unnatural amino acids can be prepared according to methods of Myers et al, tetrahedron letters (Tet. Lett.)36, (1995) and Myers et al, J.Am.chem.Soc., 117, 8488-8489 (1995).
Alternatively, the compounds of formula V may be prepared by the method of DeCamp et al (tetrahedron letters, 32, 1867 (1991)).
Compounds of formula I having the exact stereochemistryCan be prepared according to scheme 1 using the secondary lactone diastereomer of the formulaThe compounds can be prepared from (S) -aldehydes by the method of Fray (supra), or by using diastereomer pairs of the formulaThis compound can be prepared from the corresponding (R) -aldehyde according to the method of Fray (supra).
Radical R3The aldehyde or ketone precursors of (a) are either commercially available (e.g., cyclohexanone) or can be prepared by methods well known to those of ordinary skill in the art, see journal of the American chemical society, 90, 7001(1968) and journal of organic chemistry, 40, 574 (1975).
The pressure of each reaction is not critical unless otherwise specified. Generally, the reaction is carried out at a pressure of about 1 to 3 atmospheres, preferably at atmospheric pressure (about 1 atmosphere).
The compounds of formula I which are basic can form various salts with various inorganic and organic acids. Although for animal administration the salts must be pharmaceutically acceptable, in practice it is generally necessary to isolate the compound of formula I from the reaction mixture first in the form of a pharmaceutically unacceptable salt, then convert it to the free base compound by treatment with a basic agent and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the present invention are readily prepared by treating the basic compound with substantially equivalent amounts of the selected inorganic or organic acid in an aqueous or suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt was obtained.
The acids used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of the present invention are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, and pamoate [ i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate) ].
The compounds of formula I, which are also acidic, may form base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly sodium and potassium salts. These salts are prepared by conventional methods. Chemical bases useful in preparing the pharmaceutically acceptable base salts of the present invention are those that form non-toxic base salts with the acidic compounds of formula I described herein. Such non-toxic base salts include those derived from pharmaceutically acceptable cations such as sodium, potassium, calcium, magnesium, and the like. These salts are readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, it can be prepared by mixing an acidic compound and a lower alkanol solution of the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same manner as described above. In each case, it is preferred to employ stoichiometric amounts of the reagents to ensure complete and maximum product yield of the reaction.
The compounds of formula I and their pharmaceutically acceptable salts (hereinafter collectively referred to as "active compounds") are potent antagonists of the CCR1 receptor. The active compounds are useful in the treatment or prevention of autoimmune diseases (e.g., rheumatoid arthritis, type I diabetes (newly occurring), inflammatory bowel disease, ocular neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis and vasculitis), acute and chronic inflammation (e.g., osteoarthritis, adult respiratory distress syndrome, infant respiratory distress syndrome, ischemia reperfusion injury and glomerulonephritis), allergic diseases (e.g., asthma and atopic dermatitis), infections with inflammation (e.g., viral infections (including influenza and hepatitis) and Guillian-Barre syndrome), transplant tissue rejection, atherosclerosis, restenosis, HIV infections (using common receptors), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis).
The activity of the compounds of the invention can be assessed according to methods known to those of ordinary skill in the art. Examples of methods for determining migration induced by CCR1 can be found in Coligan, j.e., kruisbeam, a.m., Margulies, d.h., Shevach, e.m., Strober, w. eds: modern methods of immunology (Current Protocols immunology), 6.12.1-6.12.3(John Wiley and Sons, NY, 1991). Specific examples of measuring the migration inhibitory activity of the compound will be described in detail below. Chemotaxis assay
Standard 48 or 96 well Boyden chambers with 5 micron polycarbonate filters can be used to evaluate compounds for inhibition of chemotaxis for various chemokines. All reagents and cells were prepared in standard RPMI (Biowhitikker Inc.) tissue culture supplemented with 1mg/ml bovine serum albumin. In summary, MIP-1 α (Peprotech.Inc., P.O.Box 275, Roeky Hill NJ) or other experimental agonist was placed in the lower chamber of the Boyden chamber. The polycarbonate filter was then covered and the upper chamber was fastened. The amount of agonist selected is that amount measured to produce the greatest amount of chemotaxis in the system (e.g., for MIP-1 α, a suitable amount is 1 nM).
Then, THP-1 cells (ATCC TIB-202), primary human monocytes or primary lymphocytes isolated by conventional techniques were added to the upper chamber in triplicate with various concentrations of test compound. Compound dilutions can be prepared using conventional serological techniques and mixed with the cells prior to addition to the chamber.
After incubation at 37 ℃ for a suitable time (e.g., 3.5 hours for THP-1 and 90 minutes for primary monocytes), the chamber was removed, the cells in the upper chamber were aspirated, the upper portion of the filter paper was wiped and the amount of migration of the cells was measured as follows.
For THP-1 cells, the chamber (96-well chamber produced by Neuroprobe) can be centrifuged to remove the cells from the lower chamber and the number of cells quantified using a standard curve by changing the color of the dye fluorescein diacetate.
For primary human monocytes or lymphocytes, filter paper can be used with Dif QuickDyes (American Scientific Products) were stained and the amount of cell migration was determined by microscopy.
The number of cell migrations in the presence of compound was divided by the number of cell migrations in the control wells (without compound). The quotient was determined as the percent inhibition of the compound, which was plotted against the concentration of the compound used using conventional plotting techniques. A linear fit analysis was then performed on all tested concentrations to determine the 50% inhibition point. The linear fit to all data points must have a correlation coefficient (R-squared) of > 90% to ensure an efficient analysis.
IC of all tested compounds of the invention in chemotaxis assay50Are all less than 25. mu.M.
The compositions of the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the present invention may be formulated for oral, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation. The compounds of the invention may also be formulated for sustained release administration.
Compositions for oral administration may be in the form of, for example, tablets or capsules which may be prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silicon dioxide); disintegrants (e.g. potato starch or sodium starch glycolate) or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be in the form of, for example, solutions, syrups or suspensions, or in the form of a dry product for constitution with water or other suitable vehicle before use. The liquid preparation may be prepared by a conventional method using a pharmaceutically acceptable additive such as a suspending agent (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fat); emulsifying agents (e.g., lecithin or acacia); a non-aqueous carrier (e.g., almond oil, oily esters, or ethyl alcohol) and a preservative (e.g., methyl or propyl parabens or sorbic acid).
Compositions for buccal administration may be in the form of tablets or lozenges formulated in conventional manner.
The active compounds of the present invention may also be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain adjuvants such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution in a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
The active ingredients of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are generally delivered in the form of a solution or suspension by squeezing the patient from a pump spray container, or in the form of an aerosol spray from a pressurized container or nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve arrangement to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
For the average adult patient, the recommended oral, parenteral or buccal administration of the active compounds according to the invention for the treatment of the above-mentioned diseases, such as rheumatoid arthritis, is 0.1 to 1000mg/kg of active ingredient per unit dose, which may be administered 1 to 4 times per day.
For an average adult patient, an aerosol formulation for the treatment of the above-mentioned conditions (e.g., rheumatoid arthritis) is preferably provided containing from 20 μ g to 1000 μ g of a compound of the present invention per metered dose or "puff" of aerosol. The total daily dose of the aerosol is 0.1mg-1000 mg. Administration may be effected several times per day, for example 2,3, 4 or 8 times, with 1, 2 or 3 doses each.
The active ingredients may also be formulated into sustained release formulations according to methods well known to those of ordinary skill in the art. Examples of such formulations are found in us patents 3,538,214, 4,060,598, 4,173,626, 3,119,742 and 3,492,397.
The compounds of the invention may also be used in combination therapy with other therapeutic agents, for example, immunosuppressants such as cyclosporin A and FK-506, Cellcept , rapamycin, leuflonamide or with conventional anti-inflammatory agents (e.g., cyclooxygenase/lipoxygenase inhibitors) such as tenidap, aspirin, acetaminophen, naproxen and piroxicam, steroids including prednisone, azathioprine and biologicals such as OKT-3, anti-IL-2 monoclonal antibodies (e.g., TAC).
The following examples illustrate the preparation of the compounds of the present invention. The melting point is uncorrected. NMR data are reported in ppm (δ) and referenced to the deuterium peak lock signal from the sample solvent (deuterated chloroform, if not otherwise specified). Commercial reagents were used without purification. THF means tetrahydrofuran. DMF refers to N, N-dimethylformamide. Chromatography refers to column chromatography, carried out with 32-63mm silica gel under nitrogen pressure (flash chromatography). Low Resolution Mass Spectrometry (LRMS) in Hewlett Packard5989Measured by the Chemical Ionization (ammonium) method, or on a Fisons (or Micro Mass) Atmospheric Pressure Chemical Ionization (APCI) platform using 50/50 acetonitrile/water mixture containing 0.1% formic acid as the ionizing agent. The room temperature is 20-25 ℃. All anhydrous reactions were carried out under nitrogen atmosphere for ease of handling and maximum yield. Concentrating under reduced pressureMeaning that a rotary evaporator is used. The name of the compound of the present invention is given by Autonom 2.0 PC version of Beilstein information system GmbH (IBSN 3-89536-976-4). EXAMPLE 1 quinoline-3-carboxylic acid (1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-hept-6-enyl) -amide method A quinoline-3-carboxylic acid {1- [4- (2-methylpropen-2-yl) -5-oxo-tetrahydro-furan-2-yl ] -A]-2-cyclohexyl-ethyl } -amide
To a solution of 1- {4- (2-methylpropen-2-yl) - [ 5-oxo-tetrahydrofuran-2-yl ] -2-cyclohexyl-ethyl } -carbamic acid tert-butyl ester (302mg, 0.83mmol) (prepared according to the method of Fray (supra) but using (S) -2- (tert-butoxycarbonylamino) -3-cyclohexyl-1-propanal as the starting aldehyde) in 15ml dichloromethane was added 1.5ml trifluoroacetic acid. The mixture was stirred at room temperature under nitrogen for 2 hours, then the solvent was removed by azeotropic distillation under reduced pressure, using toluene as co-solvent during the distillation. The resulting crude oil was dissolved in dichloromethane (5ml) and quinoline-3-carboxylic acid (210mg, 1.26mmol), Hydroxybenzotriazole (HOBT) (188mg, 1.39mmol), triethylamine (0.25ml, 1.80mmol) and N-3-dimethylaminopropyl-N' -Ethylcarbodiimide (EDC) (248mg, 1.29mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The solution was transferred to a separatory funnel with 15ml of dichloromethane, then washed with 10% citric acid, saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The crude oil remaining was purified by silica gel chromatography eluting with 3: 1 hexane: ethyl acetate to give quinoline-3-carboxylic acid {1(S) - [4(R) - (2-methylpropen-2 (S) -yl) -5-oxo-tetrahydro-furan-2 (S) -yl ] -2-cyclohexyl-ethyl } -amide (236mg, 67%) as a white foam.
LRMS：421(MH+)；1H NMR(300MHz，CDCl3): δ 0.90-1.89(m, 13H), 1.63(S, 3H), 2.03-2.14(m, 2H), 2.38(m, 2H), 2.48(d, 1H, J ═ 14.6Hz), 2.73(m, 1H), 4.63(m, 2H), 4.69(S, 1H), 4.79(S, 1H), 6.9(brs, 1H), 7.59(t, 1H, J ═ 7.8Hz), 7.77(t, 1H, J ═ 8.4Hz), 7.88(d, 1HJ ═ 8.3Hz), 8.08(d, 1H, J ═ 8.4Hz), 8.67(S, 1H), 9.37(d, 1H, J ═ 2.1Hz), method B quinoline-3-carboxylic acid (1(S) -cyclohexyl) -1(S) -2.14 (S, 1H), method BMethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-hept-6-enyl) -amide
Methylamine was passed into a solution of product of method A (55mg, 0.129mmol) in methanol (2.5 ml). The solution was stirred at room temperature for 2 hours, then the solvent was evaporated under reduced pressure to give the title compound as a pure white solid.
LRMS：453(MH+)，421，283，173.1H NMR(300MHz，CDCl3): δ 0.82-1.87(m, 13H), 1.65(S, 3H), 2.13(dd, 1H, J ═ 14.1, 8.7Hz), 2.38(d, 1H, J ═ 14.2Hz), 2.71(d, 3H, J ═ 4.7Hz)2.74(m, 1H), 3.77(d, 1H, J ═ 8.7), 4.23(br, 1H), 4.69(S, 1H) 472 (S, 1H), 5.03(br, 1H), 6.60(q, 1H, J ═ 4.7Hz), 7.24(d, 1H, J ═ 9.3), 7.54(t, 1H, J ═ 7.1), 7.73(t, 1H, J ═ 7.1H, 7.81(d, 1H, J ═ 9.3), 7.54(t, 1H, J ═ 7.1H), 7.73(t, 7.81, 7.7H, 7.81, J ═ 9.7.2H), 7(t, 7.7.7, 7.8H, 7.7, 7H, 7.7H, 7H, 7.7 (t, 8H) -7H, 7.7.7.7.7.7H), 7.7.8 (H) -2 (t, 7H) -2.7H) -2 (t, 8H) -2 Allylic alkylation of amines C {1(S) - [4(R) - (3-methyl-but-2-enyl) -5-oxo-tetrahydrofuran-2 (S) -yl]-2-phenyl-ethyl } -carbamic acid tert-butyl ester
Tetrahydrofuran (40ml) and 1, 1, 1, 3, 3, 3-hexamethyldisilazane (8ml, 37.8mmol) were added sequentially to a flame dried round bottom flask under nitrogen. The mixture was cooled to 0 ℃ and n-butyllithium (14.5ml of a 2.5M solution in hexane, 36.0mmol) was added. The mixture was stirred for 15 minutes and then cooled to-78 ℃ in a dry ice/acetone bath. Dropping {1(S) - [ 5-oxo-tetrahydrofuran-2 (S) -yl via syringe]-2-phenyl-ethyl } -carbamic acid tert-butyl ester (5g, 16.4mmol) (prepared according to the method of Fray (J. org. chem., 51, 4828, 1986)) in tetrahydrofuran (50ml) and stirring was continued for 30 min. A solution of 4-bromo-2-methyl-2-butene (2.07ml, 18.0mmol) in THF (40ml) was added dropwise via syringe. Stirring was continued for 3 hours during which time the temperature rose to-60 ℃. The reaction was quenched by slowly adding saturated aqueous ammonium chloride (25 ml). After warming to room temperature, the solution was diluted with ether (300ml) and transferred to a separatory funnel. The organic phase was washed with saturated aqueous citric acid (2X 10)0ml), saturated aqueous sodium bicarbonate (2X 100ml) and 100ml brine. The organic phase is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. Thin layer chromatography with 1: 2 hexane/ether showed the product RfIs 0.8. The resulting crude oil was chromatographed on silica gel (225g) eluting with 2: 1 hexane/diethyl ether to give 4.73g (77%) of the title compound. TLC: 1: 2 Hexane/Ether Rf：0.8。
1H NMR(400MHz，CDCl3): δ 7.27ppm (5H, m), 5.02(1H, b), 4.52(1H, D, J ═ 9.3Hz), 4.42(1H, t, J ═ 7.1Hz), 3.98(1H, dt, J ═ 8.5, 7.8Hz), 2.93(2H, m), 2.88(1H, b), 2.68(1H, m), 2.41(1H, m), 2.24(1H, m), 1.92(1H, m), 1.65(3H, S), 1.58(3H, S).1.37(9H, S). method D5(S) - (1(S) -oxy-2-phenyl-ethyl) -3(R) - (3-fluoro-3-methyl-butyl) -dihydro-furan-2-one
To a solution of the product of Process C (9.81g, 26.3mmol) in dry benzene (300ml) was added HF-pyridine (88 ml). The resulting solution was stirred at room temperature for 4 hours and then transferred to a 4L beaker. Ice was added to it, followed by 2M aqueous sodium hydroxide to slowly adjust the pH to 8-9. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, then filtered and concentrated. Silica gel chromatography gave the title compound (5.68g, 74%). Process E quinoxaline-2-carboxylic acid {1(S) - "(4 (R) - (3-fluoro-3-methyl-butyl) -5-oxo-tetrahydrofuran-2 (S) -yl ] -2-phenyl-ethyl } -amide
To a solution of quinoxalinecarboxylic acid (5.05g, 29.0mmol) in dichloromethane (100ml) was added Dimethylaminopyridine (DMAP) (3.55g, 29.0mmol) and EDCI (5.55g, 29.0 mmol). The solution was stirred for 10 minutes, then the product of method D above (5.68g, 19.4mmol) was added in one portion. The solution was stirred for 12 hours, then diluted with ether and washed with saturated brine. The organic phase was dried over magnesium sulfate, then filtered and concentrated. The crude product was purified by silica gel chromatography to give the title compound (5.62g, 64%). Method F quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (R) -benzylcarbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide
To a solution of the product of method E (0.10g, 0.22mmol) in dioxane (2ml) was added glacial acetic acid (0.038ml, 0.66mmol) and benzylamine (ca. 1ml, excess). The resulting solution was heated to reflux for 1 hour, cooled to room temperature and diluted with water. The solution was diluted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel followed by recrystallization from dichloromethane/hexane afforded the title compound (0.068, 56%). m.p.183-184 ℃. EXAMPLE 3 method F' quinoxaline-2-carboxylic acid (1-benzyl-7-fluoro-2-hydroxy-4-hydroxycarbamoyl-7-methyl-octyl) -amide
Hydroxylamine hydrochloride (1.55g, 22.4mmol) and KOH (1.51, 26.7mmol) were mixed in dry methanol (20ml) and stirred under a dry nitrogen atmosphere for 30 minutes, then filtered. To the resulting filtrate was added the product of method E (500mg, 1.17mmol), and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (50ml) and then transferred to a separatory funnel. The organic layer was washed with water and brine, and then dried over magnesium sulfate. After filtration and evaporation of the solvent in vacuo, the remaining residue was recrystallized (dichloromethane/hexane) to yield a pale yellow solid (330mg, 58%), m.p.165-166 ℃. EXAMPLE 4 quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide method G hydrogenation of olefins {1(S) - [4(R) - (3-methyl-butyl) -5-oxo-tetrahydrofuran-2 (S) -yl ] -2-phenyl-ethyl } -carbamic acid tert-butyl ester
The product of example 2, method C above (3.0g, 8.04mmol) was placed in a 250ml Parr shaker bottle and dissolved with ethanol (50 ml). To the solution was added palladium on carbon (0.30g, 10% palladium content) under nitrogen. The mixture was placed in a Parr shaker hydrogenator and hydrogenated at 50psi at room temperature for 5 hours. The hydrogenation mixture was diluted with ethyl acetate and poured onto a pad of celite and washed with copious amounts of ethyl acetate. The solvent was evaporated in vacuo from the filtrate to give the title compound, 2.63g (88%).
1H NMR(400MHz，CDCl3)：δ7.27(5H，m)，4.54(1H，d，J＝9.8Hz)，4.46(1H，t，J＝6.9)，4.0(1H，dt)，2.89(2H，d，J＝8.1)，2.57(1H，m)，2.32(1H，b)，1.89(1H，m)，1.79(1H，m)，1.52(2H，m)，1.37(9H，s)，1.23(2H，m)，0.86(6H，d，J＝6.6Hz).
The product of method G was converted to the title compound in analogy to methods A and B, except that quinoline-3-carboxylic acid was replaced by quinoxaline-2-carboxylic acid and methylamine was replaced by ammonia to yield 0.095G (72%) of the title compound.
1H NMR(400MHz，CDCl3)δ9.61(1H，s)，8.32(1H，d，J＝8.9Hz)，8.16(2H，m)，7.86(2H，m)，7.28(10H，m)，7.19(1H，m)，5.70(1H，b)，5.29(1H，b)，4.27(1H，m)，8.21(1H，d，J＝4.4Hz)，3.91(1H，m)，3.11(2H，m)，2.46(1H，m)，1.74(1H，t，J＝6.4Hz)，1.61(1H，m)，1.42(2H，m)，1.17(1H，m)，1.09(1H，m)，0.81(3H，d，J＝7.1Hz)，0.79(3H，d，J＝7.1Hz).13CNMR(100MHz，CDCl3): d179.11, 163.73, 143.90, 143.76, 143.15, 140.28, 137.96, 131.68, 130.84, 129.84, 129.44, 129.25, 128.58, 126.60, 68.55, 55.90, 43.44, 38.39, 36.90, 36.70, 29.77, 28.03, 22.42 example 5 quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7, 7-dimethyl-octyl) -amide process H triflate alkylation {1- [4- (3, 3-dimethyl-butyl) -5-oxo-tetrahydrofuran-2-yl]-2-phenyl-ethyl } -carbamic acid tert-butyl ester
Tetrahydrofuran (2ml) and 1, 1, 1, 3, 3, 3-hexamethyldisilazane (0.82ml, 3.88mmol) were added to a flame dried round bottom flask under nitrogen. The mixture was cooled to 0 ℃ and n-butyllithium (1.48ml of a 2.5M solution in hexane, 3.72mmol) was added dropwise via syringe. The mixture was stirred for 15 minutes and then cooled to-78 ℃. A solution of {1(S) - [ 5-oxo-tetrahydrofuran-2 (S) -yl ] -2-phenyl-ethyl } -carbamic acid tert-butyl ester (O.52g, 1.69mmol) (prepared according to the method of Fray (supra)) in tetrahydrofuran (2ml) was added slowly via syringe and the solution was stirred for 1 h. A solution of the desired triflate, namely 3, 3-dimethylbutyl trifluoromethanesulfonate (0.92g, 3.37mmol) (prepared according to the method of Beard et al, J. org. chem., 38, 3673, 1973) in tetrahydrofuran (2ml) was added dropwise via syringe and the mixture was stirred at-78 ℃ for 2 hours. The reaction was terminated by adding saturated aqueous ammonium chloride (25 ml). After warming to room temperature, the mixture was diluted with ethyl acetate (40ml), transferred to a separatory funnel and washed with a saturated aqueous ammonium chloride solution (2X 40ml), a saturated aqueous sodium bicarbonate solution (2X 40ml) and 40ml brine. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting crude oil was chromatographed on silica gel (25g) eluting with 100ml of 5: 1 hexane/ethyl acetate and 400ml of 4: 1 hexane/ethyl acetate in that order. 0.36g (50%) of the title compound are obtained.
TLC: (4: 1 Hexane/Ethyl acetate) Rf：0.3。1H NMR(400MHz，CDCl3)：δ7.25(m，7H)，6.92(t，1H，J＝7.5Hz)，6.85(d，2H，J＝8.1Hz)，4.67(d，2H，J＝6.0Hz)，4.49(t，1H，J＝9.6Hz)，4.06(m，3H)，2.89(m，3H)，2.43(m，1H)，2.26(m，1H)2.05(m，1H)，1.95(m，1H)1.37(s，9H).
The product of Process H was converted to the title compound in analogy to the processes A and B of example 1, except that quinoxaline-2-carboxylic acid was used instead of quinoline-3-carboxylic acid and ammonia was used instead of methylamine. EXAMPLE 6 quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-cyclohexyl) -butyl ] -amide quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-cyclohexyl) -butyl ] -amide procedure I {1(S) - [4(S) - (1-hydroxy-cyclohexyl) -5-oxo-tetrahydrofuran-2 (S) -yl ] -2-phenyl-ethyl } -carbamic acid tert-butyl ester
To a solution of diisopropylamine (0.90ml, 6.88mmol) in THF (10ml) at 0 deg.C was added a solution of n-butyllithium (2.7ml of a 2.5M solution in hexane, 6.71 mmol). The solution was stirred for 15 minutes and then cooled to-78 ℃. A solution of {1(S) - [ 5-oxo-tetrahydrofuran-2 (S) -yl ] -2-phenyl-ethyl } -carbamic acid tert-butyl ester (1.0g, 3.27mmol, prepared according to example 2, method C) in tetrahydrofuran (10ml) was added dropwise thereto and the reaction was stirred for a further 30 minutes. To this was added the appropriate ketone (e.g. cyclohexanone) (0.37ml, 3.60mmol) and the solution was warmed to room temperature. The reaction was terminated by adding saturated aqueous sodium bicarbonate solution and the mixture was extracted with diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography gave a mixture of the separable diastereomers {1(S) - [4(S) - (1-hydroxy-cyclohexyl) -5-oxo-tetrahydrofuran-2 (S) -yl ] -2-phenyl-ethyl } -carbamic acid tert-butyl ester (0.687g) and {1(S) - [4(R) - (1-hydroxy-cyclohexyl) -5-oxo-tetrahydrofuran-2 (S) -yl ] -2-phenyl-ethyl } -carbamic acid tert-butyl ester (0.269g) in 67% overall yield.
The product of Process I was converted to the title compound in analogy to the processes A and B of example 1, except that quinoxaline-2-carboxylic acid was used instead of quinoline-3-carboxylic acid and ammonia was used instead of methylamine. Example 7 fluoro-quinoline-3-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -amide fluoro-quinoline-3-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -amide method J {1(S) - [4(S) - (1-hydroxy-cyclohexyl) -5-oxo-tetrahydro-furan-2 (S) -yl ] -2-phenyl-ethyl } -carbamic acid tert-butyl ester
To a solution of the title compound of example 5, method I (1.38g, 3.42mmol) in benzene (40ml) was added (methoxycarbonylsulfamoyl) -triethylammonium hydroxide inner salt (Burgess reagent) (1.30g, 5.47mmol) and the solution was heated at reflux for 2 h. The reaction solution was diluted with ether and washed with saturated brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give the crude elimination product. This was dissolved directly in 5: 1 tetrahydrofuran/methanol (30ml) and transferred to a Parr flask containing 10% palladium on charcoal (1 g). The mixture was hydrogenated at 35psi for 1.5 hours, then filtered through a pad of celite and the filtrate was concentrated. Silica gel chromatography gave a mixture of the separable diastereomers {1(S) - [4(S) - (1-hydroxy-cyclohexyl) -5-oxo-tetrahydrofuran-2 (S) -yl ] -2-phenyl-ethyl } -carbamic acid tert-butyl ester (0.53g) and {1(S) - [4(R) - (1-hydroxy-cyclohexyl) -5-oxo-tetrahydrofuran-2 (S) -yl ] -2-phenyl-ethyl } -carbamic acid tert-butyl ester (0.29g) in 62% overall yield.
The product of method J was converted to the title compound in analogy to methods A and B of example 1, except that quinoxaline-2-carboxylic acid was used instead of quinoline-3-carboxylic acid and ammonia was used instead of methylamine. Examples 8 to 312
The compounds in Table 1 were prepared as described above, if desired with the appropriate R2Aldehyde, R3Radicals (e.g. allyl halides, alkyl triflates, ketones, etc.), R1Carboxylic acid or R4And R5Amine substitution.
TABLE 1
Examples Name (R) M.P.(℃) LRMS
8. Quinoxaline-2-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl amide 455
9. Quinoxaline-2-carboxylic acid (6-chloro-1-cyclohexylmethyl-2 (S) -hydroxy-4 (S) -methylcarbamoyl-hept-6-enyl) -amide
10. Quinoxaline-3-carboxylic acid (2(S) -hydroxy-1 (S) -isobutyl-6-methyl-4 (R) -methylcarbamoyl-4-heptyl) -amide 155-157 414
11. Quinoxaline-2-carboxylic acid 1(S) -sec-butyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl-amide 69-71 415
12 Quinoxaline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-hept-6-enyl) -amide 452
13. Quinoxaline-2-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -4-methylcarbamoyl-hept-6-enyl) amide 453
14. N-1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -5-phenyl-nicotinamide 115-119
15. Quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 162-163
16 Quinoxaline-2-carboxylic acid 1(S) -cyclohexylmethyl-4 (R) -dimethylcarbamoyl-2 (S) -hydroxy-6-methyl-hept-6-enyl) -amide 467
17 Quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (S) -methylcarbamoyl-heptyl) -amide 171-175 453，436
18 Quinoxaline-2-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (S) -methylcarbamoyl-heptyl-amide 455，437
19 Isoquinoline-4-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (S) -methylcarbamoyl-heptyl) -amide 180-182 454
20 Quinoline-3-carboxylic acid (4(R) -carbamoyl-1 (S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-heptyl) -amide 186-188 440，478，423
21 Quinoline-3-carboxylic acid (5-cyclohexyl-1 (S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide 170.5-172.5 494
22 Quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methyl-carbamoyl-heptyl) -amide 454
23 Quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (S) -methylcarbamoyl-heptyl) -amide 200-201.5 454
24 Quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methyl-carbamoyl-5-phenyl-pentyl) -amide 199-200.5 488
25 Quinoxaline-2-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-5-phenyl-pentyl) -amide 109-110.5 489
26 Quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -butylcarbamoyl-2 (S) -hydroxy6-methyl-4-heptyl) -amide 142-144 490，417
27 Quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -cyclobutylcarbamoyl-2 (S) -hydroxy-6-methyl-heptyl) -amide 148-150 488，417
28 Quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -benzylcarbamoyl-2 (S) -hydroxy-6-methyl-heptyl) -amide 158-162 524，417
29 Quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -cyclopropylcarbamoyl-2 (S) -hydroxy-6-methyl-heptyl) -amide 174-179 474
30 Quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (S) -methylcarbamoyl-heptyl) -amide 190-192.5 448
31 Quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -ethylcarbamoyl-2 (S) -hydroxy-6-methyl-heptyl) -amide 175-176 462
32 Quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -propylcarbamoyl-heptyl-amide 476
33 Quinoline-3-carboxylic acid [ 1-benzyl-2 (S) -hydroxy-4 (R) - (2-hydroxy-ethylcarbamoyl) -6-methyl-heptyl]-amides of 158-162 478
34 Cinnoline-4 (R) -carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 185-186.5 449
35 Isoquinoline-4-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 200-201 448
36 Quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl-amide 166-167 449
37 N-1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -5-bromo-nicotinamide 184.5-185.5 478
38 Quinoline-3-carboxylic acid 1(R) -cyclohexylmethyl-2 (R) -hydroxy-6-methyl-4 (S) -methylcarbamoyl-heptyl) -amide 454
39 Quinoxaline-2-carboxylic acid [1(S) - (4-benzyloxy-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl]-amides of 196-197 554
40 Quinoline-3-carboxylic acid [1(S) - (4-benzyloxy-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl]-amides of 178-179 555
41 Isoquinoline-1-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 178-179 448
42 Quinoline-4-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methyl-carbamoyl-heptyl) -amide 189-192 448
43 Quinoline-6-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 165-167 448
44 Quinoline-3-carboxylic acid [2(S) -hydroxy-1 (S) - (4-hydroxy-benzyl) -6-methyl-4 (R) -methylcarbamoyl-heptyl]-amides of 220.5-222.5 464
45 Quinoline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 160-161.5 449
46 Naphthalene-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 218-220 447
47 Quinoline-3-carboxylic acid 1(S) -benzyl-5-cyclohex-1-enyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide 172-174 486
48 Quinoline-3-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) - (3-methyl-butylcarbamoyl) -heptyl]-amides of 153-154 504
49 Quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (S) -methylcarbamoyl-heptyl-amide 157-163 449
50 Trifluoromethanesulfonic acid 4- {3(S) -hydroxy-7-methyl-5 (R) -methylcarbamoyl-2 (S) - [ (quinoline-3-carbonyl) -amino [ ] -methyl]-octyl } -phenyl ester 168-170 596
51 Trifluoromethanesulfonic acid 4- {3(S) -hydroxy-7-methyl-5 (R) -methylcarbamoyl-2 (S) - [ (quinoxaline-2-carbonyl) -amino [ ] -methyl]-octyl } -phenyl ester 597
52 Quinoline-3-carboxylic acid 1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide 185-187 488
53 Quinoxaline-2-carboxylic acid 1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide 132-134 489，471
54 Isoquinoline-3-carboxylic acid 1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide 150.5-151.5 488
55 N-1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -5-bromo-nicotinamide 199-200.5 518
56 Quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -prop-2-ynylcarbamoyl-heptyl) -amide 472
57 Quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -hydroxycarbamoyl-6-methyl-heptyl-amide 456，438，423
58 Quinoline-3-carboxylic acid 2(S) -hydroxy-1 (S) - (4-methoxy-benzyl) -6-methyl-4 (R) -methylcarbamoyl-heptyl]-amides of 176-177 478
59 Isoquinoline-3-carboxylic acid (5-cyclohexyl-1 (S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide 205-207 494
60 5-bromo-N- (5-cyclohexyl-1 (S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -nicotinamide 173.5-175 444
61 Quinoxaline-2-carboxylic acid [2(S) -hydroxy-1 (S) - (4-methoxy-benzyl) -6-methyl-4 (R) -methylcarbamoyl-heptyl]-amides of 479
62 Isoquinoline-4-carboxylic acid (5-cyclohexyl-1 (S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide 220.5-224 494
63 Quinoline-2-carboxylic acid 1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide 120-122 488
64 Isoquinoline-4-carboxylic acid 1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide 177-180 488
65 Quinoxaline-2-carboxylic acid [2(S) -hydroxy-1 (S) - (4-hydroxy-benzyl) -6-methyl-4 (R) -methylcarbamoyl-heptyl]-amides of 170-172 465
66 Quinoxaline-2-carboxylic acid (5-cyclohexyl-1 (S) -cyclohexylmethyl-2 (S) -hydroxy-4 (R) -methylcarbamoylpentyl) -amide 496
67 Quinoline-3-carboxylic acid [1(S) - (4-chloro-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -Methylcarbamoyl-heptyl radical]-amides of 212.5-213.5 482
68 Quinoxaline-2-carboxylic acid [1(S) - (4-chloro-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl]-amides of 483
69 Quinoline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 173.5-175 468，450
70 Quinoxaline-2-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) amide 78-80 470
71 Quinoline-3-carboxylic acid [1(S) - (4-chloro-benzyl) -5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl]-amides of 198-201 522
72 Quinoxaline-2-carboxylic acid [1(S) - (4-chloro-benzyl) -5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl]-amides of 523
73 Quinoline-2-carboxylic acid [1(S) - (4-chloro-benzyl) -5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl]-amides of 522
74 Benzofuran-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 181-183 437
75 N-1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -5, 6-dichloro-nicotinamide 195-196 466，432
76 Quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 188-190 462
77 N-1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -5-bromo-nicotinamide 188-189 490
78 5, 6, 7, 8-tetrahydroquinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 142.5-144.5 452
79 Quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 147-149 463
80 Quinoline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 156-158 462
81 Isoquinoline-4-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 199-202 462
82 Quinoxaline-2-carboxylic acid [1(S) - (3, 4-dichloro-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl]-amides of 517，483
83 Benzo [ b ]]Thiophene-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 179-181 453
84 2-methyl-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 225-226.5 462
85 6, 7-dimethoxy-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 211-214 508
86 6, 7-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 187-189 484，466
87 1H-benzimidazole-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 136-140 437
88 5-methyl-pyrazine-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 171.5-172.5 413
89 Quinoline-3-carboxylic acid [1(S) - (4-fluoro-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl]-amides of 184-186 466
90 Quinoxaline-2-carboxylic acid [1(S) - (4-fluoro-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl]-amides of 153-156 467
91 5-chloro-1H-indole-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 245-247 470
92 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide 194-194.5 449，432
93 2-methoxy-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 175-181 478
94 5, 6-dichloro-1H-benzimidazole-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 114-117 505
95 Benzothiazole-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 86-89 454
96 7, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 179-182 484
97 6, 7, 8-trifluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 156-161 502，484
98 5, 8-dimethyl-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl) -amide 197-199 476
99 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -butylcarbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide 103-106 505
100 Quinoline-3-carboxylic acid [1(S) - (3, 4-dichloro-benzyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl]-amides of 516
101 5, 6, 7, 8-tetrahydro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 169.5-172.5 466
102 Quinoline-3-carboxylic acid 1(S) -benzyl-5-cyclopentyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide 176-178 474
103 Quinoxaline-2-carboxylic acid 1(S) -benzyl-5-cyclopentyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide 120-122 475
104 N-1(S) -benzyl-5-cyclopentyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -5-bromo-nicotinamide 194-198 504
105 5, 6, 7, 8-tetrahydro-quinoline-3-carboxylic acid 1(S) -benzyl-5-cyclopentyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) -amide 143-146 478
106 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-5-cyclopentyl-2 (S) -hydroxy-pentyl) -amide 217-219 461，444
107 6, 7-dihydro-5H- [1]4-Azindene-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 154.-156 452，349
108 Quinoxaline-2-carboxylic acid [1(S) - (4, 4-difluorocyclohexylmethyl) -2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl]-amides of 95-98 491，473
109 Quinoxaline-2-carboxylic acid [1(S) - (4, 4-difluorocyclohexylmethyl) -2(S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl]-amides of 95-98 506，488
110 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -ethylcarbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide 129-133 478
111 Quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -propylcarbamoyl-octyl) -amide 125-130 492
112 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -cyclopropylaminomethylAcyl-2 (S) -hydroxy-7-methyl-octyl) -amides 168-169 490，472
113 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -cyclobutylcarbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide 148-150 504，486
114 Quinoxaline-2-carboxylic acid [1(S) - (4-difluoromethoxy-benzyl) -2(S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl]-amides of 151-154 530
115 4{3(S) -hydroxy-7-methyl-5 (R) -methylcarbamoyl-2 (S) - [ (quinoxaline-2-carbonyl) -amino]-octyl } -benzoic acid methyl ester 87-95 508
116 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4-carbamoyl-2 (S) -hydroxy-butyl) -amide 379
117 6, 7, 8-Trifluoroquinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 206-207 516，498
118 6, 7, 8-Trifluoroquinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide 205-206 502，485
119 6, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 198-200 498
120 6, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide 188-190 484，467
121 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -butylcarbamoyl-5-cyclopentyl-2 (S) -hydroxy-pentyl) -amide 102-104 517，499
122 6-methyl-pyridine-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-6-methyl-4 (R) -methylCarbamoyl-heptyl) -amides 74-76
123 Quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-8-methyl-4 (R) -methylcarbamoyl-nonyl) -amide 145.5-146.5 477
124 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-8-methyl-nonyl-amides 163-165 463
125 Quinoxaline-2-carboxylic acid 1(S) -biphenyl-4-ylmethyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 123-125 539，521，508
126 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-oct-6-enyl) -amide 168-170 447，430
127 Quinoxaline-2-carboxylic acid (2(S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-1 (S) -naphthalen-2-ylmethyl-heptyl) -amide 121-123
128 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7, 7-dimethyl-octyl) -amide 77-79 463，446
129 Quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7, 7-dimethyl-4 (R) -methylcarbamoyl-octyl) -amide 195-199 477，459
130 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) hydroxy-5-phenyl-pentyl) -amide 168-172 469，452
131 Quinoxaline-2-carboxylic acid 1(S) -biphenyl-4-ylmethyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide 205-206 508
132 Quinoxaline-2-carboxylic acid [1(S) -benzyl-5- (4, 4-difluoro-cyclohexyl) -2(S) -hydroxy-4 (R) -methylcarbamoyl-pentyl]-amides of 170-172 525，507
133 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-5- (4, 4-difluoro-cyclohexyl) -2(S) -hydroxy-pentyl]-amides of 174-176 511，493
134 Quinoxaline-2-carboxylic acid [1(S) - (3-fluoro-benzyl) -2(S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl]-amides of 158.5-159.5 481，463
135 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (3-fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl]-amides of 191-191.5 467，449
136 Quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-oct-6-enyl) -amide 65-68 461，443
137 6, 7, 8-trifluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7 (S) -methyl-4 (R) -methylcarbamoyl-nonyl) -amide 158-161 541，523
138 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7 (S) -methyl-nonyl) -amide 185-187 446
139 Quinoxaline-2-carboxylic acid 1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 148-150 482，463
140 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 184-186 467，449
141 Quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -ethylcarbamoyl-nonyl-amide 137-139.5 478
142 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -dimethylcarbamoyl-2 (S) -Hydroxy-7-methyl-octyl) -amide 68-70
143 7, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-5-phenyl-pentyl) -amide 175 (decomposition) 518，500
144 7, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 198-201 498，480
145 8-fluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide 179-183 480，462
146 Quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-non-6-enyl) -amide 130-132 462，448
147 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-non-6-enyl) -amides 154-155 448，430
148 7, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide 188-190 485，467
149 8-fluoro-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-7-methyl-octyl) -amide 192-196 466，449
150 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-nonyl) -amides 188.5-189.5 450
151 2(S) - {2(S) -hydroxy-4-phenyl-3 (S) - [ (quinoxaline-2-carbonyl) -amino]-butyl } -N1, N4-dimethyl-succinamide 178-180
152 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -ethylcarbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) amide 105-108 496
153 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -butylcarbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 110-112 523，505
154 Quinoxaline-2-carboxylic acid [ 7-fluoro-1 (S) - (4-fluoro-benzyl) -2(S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl]-amides of 145-147 499
155 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (3, 4-dichloro-benzyl) -7-fluoro-2 (S) -hydroxy-7-methyl-octyl]-amides of 206-207 536，518
156 7, 8-difluoro-quinoline-3-carboxylic acid [4(R) -carbamoyl-1 (S) - (3, 4-dichloro-benzyl) -7-fluoro-2 (S) -hydroxy-7-methyl-octyl]-amides of 187-189 571
157 Quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S) -hydroxy-7-methyl-1 (S) -phenethyl-octyl) -amide 223-225 478
158 7, 8-difluoro-quinoline-3-carboxylic acid [4(R) -carbamoyl-7-fluoro-1 (S) - (4-fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl]-amides of 208-210 463，445
159 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-7-fluoro-1 (S) - (4-fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl]-amides of 520
160 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (4-methyl-piperazine-1-carbonyl) octyl]-amides of 551
161 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5- (tetrahydropyran-4 (R) -yl) -pentyl]-amides of 212-214 477，459
162 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (piperidine-1-carbonyl) -octyl]-amides of 536
163 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (morpholine-4-carbonyl) -octyl]-amides of 537
164 Quinoxaline-2-carboxylic acid [1(S) -benzyl-3- (2-carbamoyl-indan-2-yl) -2(S) -hydroxy-propyl]-amides of 90-100 481，464
165 Quinoxaline-2-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-7-phenyl-hept-6-enyl) -amide 212-216 (decomposition)
166 Quinoline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 163.5-165 466，449
167 6, 7-dihydro-5H- [1]4-Azindene-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 175-178 456
168 Quinoxaline-2-carboxylic acid (1(S) -benzyl-4-carbamoyl-4 (S) -cyclohexyl-2(S) -hydroxy-butyl) -amide 222-223 461，444
169 Quinoxaline-2-carboxylic acid (1(S) -benzyl-4-carbamoyl-4 (S) -cyclohexyl-2 (S) -hydroxy-butyl) -amide 178-180 461，444
170 Quinoxaline-2-carboxylic acid (1(S) -benzyl-4-carbamoyl-4 (S) -cyclohexyl-2 (S) -hydroxy-butyl) -amide 229-232 447
171 Quinoxaline-2-carboxylic acid (1(S) -benzyl-4-carbamoyl-4 (S) -cyclopentyl-2 (S) -hydroxy-butyl) -amide 126-128 447
172 Quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 200-202 466，449
173 N-1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -5-bromo-nicotinamide 181-183 476
174 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1- (2(S) -fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl]-amides of 184-187 466，448
175 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (2-fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl]-amides of 213-215 466
176 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (4-isopropyl-cyclohexyl) -butyl]-amides of 502
177 Quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S) -hydroxy-7-methyl-1 (S) -thiophen-2-ylmethyl-octyl) -amide 454，436
178 Quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S) -hydroxy-7-methyl-1 (S) -thiazol-4-ylmethyl-octyl) amide 195-196 456
179 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (3, 3,5, 5-tetramethyl-cyclohexyl) -butyl]-amides of 188-190 516
180 Quinoxaline-2-carboxylic acid (1(S) -benzyl 4(S) -carbamoyl-2 (S) -hydroxy-4-indan-2-yl-butyl) -amide 495
181 Quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-4-cycloheptyl-2 (S) -hydroxy-butyl) -amide 216-217 474，457
182 Quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-5-propyl-octyl) -amide 477
183 Quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-5-propyl-oct-5-enyl) -amide
184 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-octyl) -amide
185 Quinoxaline-2-carboxylic acid 1(S) -benzyl-7-chloro-2 (S) -hydroxy-4 (R) -methylcarbamoyl-hept-6-enyl) -amide 467，449
186 Quinoxaline-2-carboxylic acid 1(S) -benzyl-7-chloro-2 (S) -hydroxy-4 (R) -methylcarbamoyl-hept-6-enyl) -amide 467，449.
187 Quinoxaline-2-carboxylic acid 1(S) -benzyl-6-chloro-2 (S) -hydroxy-4 (S) -methylcarbamoyl-hept-6-enyl) -amide 160-162 467，449.
188 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-6-chloro-2 (S) -hydroxy-hept-6-enyl) -amides 203-204.5
189 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (S) -carbamoyl-6-cyclopropyl-2 (S) -hydroxy-hexyl-amide 171-174 447，429
190 Quinoxaline-2-carboxylic acid 1(S) -benzyl-6-cyclopropyl-2 (S) -hydroxy-4 (R) -carbamoyl-hexyl-amides 146-148 461，443
191 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-4 (S) - (4-methyl-cyclohexyl) -butyl]-an amide; 218-220 475，457
192 quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4-indan-2-yl-butyl) -amide 190-191 495，477
193 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5- (4-trifluoromethoxy-phenyl) -pentyl]-amides of 184-187 553，536
194 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-5- (4-fluoro-phenyl)) -2(S) -hydroxy-pentyl]-amides of 164-166 487，470
195 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-chloro-2 (S) -hydroxy-hept-6-enyl) -amides 165-166 436
196 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-chloro-2 (S) -hydroxy-hept-6-enyl) -amides 158-160 436
197 3-hydroxy-quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 185-189 483，465
198 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -benzylcarbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 183-184
199 Quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [ (pyridin-3-ylmethyl) -carbamoyl]-octyl } -amide 188-191
200 Quinoxaline-2-carboxylic acid 1(S) -benzyl-8, 8-trifluoro-2 (S) -hydroxy-4 (R) -methylcarbamoyl-7-trifluoromethyl-octyl) -amide 571，553
201 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-8, 8-trifluoro-2 (S) -hydroxy-7-trifluoromethyl-octyl) -amide 187-193 553
202 Quinoxaline-2-carboxylic acid [2(S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-1 (S) - (4-methylcarbamoyl-benzyl) -octyl]-amides of 170-173 502
203 Quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-5-ethyl-2 (S) -hydroxy-heptyl) -amide 215-218 448，431
204 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (tetrahydropyran-4-yl) -butyl) -amide 151-154
205 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (2-pyridin-2-yl-ethylcarbamoyl) -octyl]-amides of 155-156 572
206 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) - (3, 4-dimethoxy-benzylcarbamoyl) -7-fluoro-2 (S) -hydroxy-7-methyl-octyl]-amides of 162-164 617
207 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-6-methoxy-hexyl-amide 420
208 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-chloro-2 (S) -hydroxy-oct-6-enyl) -amide 172-175 450
209 Quinoxaline-2-carboxylic acid 1(S) -benzyl-7-chloro-2 (S) -hydroxy-4 (R) -methylcarbamoyl-oct-6-enyl) -amide 108-111 463
210 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-4- (3, 5-dimethylcyclohexyl) -2(S) -hydroxy-butyl]-amides of 221-222 489，471
211 Quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [ (pyridin-2-ylmethyl) -carbamoyl]-octyl } -amide 138-140 557，540
212 Quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - [2- (4-hydroxy-phenyl) -ethylcarbamoyl]-7-methyl-octyl } -amide 138-140 587，569
213 Quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) -4- [ (thiophen-2-ylmethyl) -carbamoyl]-octyl } -amide 174-175 563，545
214 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-6-phenoxy-hexyl-amides 194.5-196.5 482
215 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-6-isopropoxy-hexyl-amides 113-118(Mix) 448
216 Quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [2- (4-aminosulfonyl-phenyl) -ethylcarbamoyl]-octyl } -amide 207-210 650
217 Quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [ (pyridin-4-ylmethyl) -carbamoyl]-octyl } -amide 100-104 558
218 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) - (2-ethylsulfanyl-ethylcarbamoyl) -7-fluoro-2 (S) -hydroxy-7-methyl-octyl]-amides of 78-79 555，537
219 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - (2-methoxy-ethylcarbamoyl) -7-methyl-octyl]-amides of 48-50 507
220 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (2-pyridin-3-yl-ethylcarbamoyl) -octyl]-amides of 154-155 572
221 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (2-pyridin-4-yl-ethylcarbamoyl) -octyl]-amides of 78-80 572
222 Quinoxaline-6-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 190-192 467
223 Quinoxaline-2-carboxylic acid 1(S) -benzyl-6-tert-butoxy-4 (R) -carbamoyl-2 (S) -hydroxy-hexyl) -amide 184-189 479，461
224 Quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [ 2-1-methyl-1H-pyrrol-2-yl) -ethylcarbamoyl]-octyl } -amide 100-105 574
225 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4- (1, 1-dioxo-thiopyran-4-yl) -2(S) -hydroxy-butyl]-amides of 140-150 511，494
226 Quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - [2- (6-methoxy-1H-indol-3-yl) -ethylcarbamoyl]-7-methyl-octyl } -amide 640，622
227 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - (2-methoxy-benzylcarbamoyl) -7-methyl-octyl]-amides of 135 587，569
228 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - (3-methoxy-benzylcarbamoyl) -7-methyl-octyl]-amides of 587，569
229 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (2-thiophen-2-yl-ethylcarbamoyl) -octyl]-amides of 152-154 577
230 Quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - [2- (1H-indol-3-yl) -ethylcarbamoyl]-7-methyl-octyl } -amide 107-108 610
231 Quinoxaline-2-carboxylic acid {4(R) - [2- (4-amino-phenyl) -ethylcarbamoyl]-1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl } -amide 586
232 Quinoxaline-2-carboxylic acid {1(S) -benzyl-4 (R) - [2- (3, 5-dimethoxy-phenyl) -ethylcarbamoyl]-7-fluoro-2 (S) -hydroxy-7-methyl-octyl } -amide 109-112 631，613
233 Quinoxaline-2-carboxylic acid {1(S) -benzyl-4 (R) - [2- (3, 4-dimethoxy-phenyl) -ethylcarbamoyl]-7-fluoro-2 (S) -hydroxy-7-methyl-octyl } -amide 631，613
234 Quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-4 (R) - [ (furan-2-ylmethyl) -carbamoyl]-2(S) -hydroxy-7-methyl-octyl } -amide 155.5-156.5 547
235 Quinoxaline-2-carboxylic acid {1(S) -benzyl-4 (R) - [2- (2, 5-dimethoxy-phenyl) -ethylcarbamoyl]-7-fluoro-2 (S) -hydroxy-7-methyl-octyl } -amide 631，613
236 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - (4-methoxy-benzylcarbamoyl) -7-methyl-octyl]-amides of 114-115 587，569
237 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-6-cyclohexyloxy-2 (S) -hydroxy-hexyl) -amides 150-152 505，487
238 Quinoxaline-2-carboxylic acid {4(R) - [ (1H-benzimidazol-2-ylmethyl) -carbamoyl]-1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl } -amide 596
239 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) - (2(S) -hydroxymethyl-pyrrolidine-1-carbonyl) -7-methyl-octyl]-amides of 217-219 551，533
240 Quinoxaline-2-carboxylic acid {1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - [ (tetrahydrofuran-2-ylmethyl) carbamoyl]-octyl } -amide 111-115 551，533
241 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4- (4, 4-difluoro-cyclohexyl) -2(S) -hydroxy-butyl } -amide 176-179 497，478
242 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) - (2, 3-dimethoxy-benzylcarbamoyl) -7-fluoro-2 (S) -hydroxy-7-methyl-octyl]-amides of 99-101
243 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-cyclohexyl) -butyl]-an amide; 187-189 477，379
244 quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4- (2, 6-dimethyl-tetrahydropyran-4-yl) -2(S) -hydroxy-butyl]-amides of 195-198 491
245 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-7-fluoro-1 (S) - (3-fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl]-amides of 225-227 485，467
246 7, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide ＞220 502，485
247 N-1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -5, 6-dichloro-nicotinamide ＞220 484，466
248 Benzofuran-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octanAcyl) -amides 190-192 455，438
249 Cinnoline-4-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 198-199.5 469，451
250 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-7-fluoro-2 (S) -hydroxy-1 (S) - (4-iodobenzyl) -7-methyl-octyl]Amides of carboxylic acids 185.5-187.5 593，576
251 Pyrazine-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 211-212 417，319
252 6, 7, 8-trifluoro-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 19-197 520，503
253 Quinoline-6-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide, 170-173 466，449
254 isoquinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 194-197 466，448
255 2-methoxy-quinoline-3-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 213-216 496，479
256 1H-benzimidazole-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 168-169 456，438
257 Benzothiazole-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 152.5-155 472，455
258 5-methyl-pyrazine-2-carboxylic acid 1(S) -benzyl-4(R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 194-197 431
259 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-pyridin-3-yl-pentyl) -amide 470，453
260 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-cyclohexyl) -butyl]-amides of 210-211 477，459
261 Quinoline-3-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -amide 231 460，443
262 Quinoline-2-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -amide 208-210 460，443
263 Fluoro-quinoline-3-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -amide 238-240 478，461
264 N- (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -5, 6-dichloro-nicotinamide 174-177 461
265 N- (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -5-bromo-nicotinamide 255-256 475，458
266 Quinoxaline-2-carboxylic acid (4(R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-1 (S) -phenyl-octyl) -amide 159-160.5 453
267 Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-pyridin-2-yl-pentyl) -amide 470，453
268 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-cyclohexyl) -1(S) -thiophen-2-ylmethyl-butyl]-amides of 206-207 482
269 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy- (4-hydroxy-tetrahydro-thiopyran-4-yl) -butyl]-amides of 123-125 495，379
270 1, 3-dimethyl-1H-pyrazolo [3, 4-b]Pyridine-5-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -amide 189.5-191 484，467
271 Quinoxaline-2-carboxylic acid (1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl) -amide 165-166
272 Quinoxaline-2-carboxylic acid (1(S) -benzyl-7-fluoro-2 (S) -hydroxy-4 (R) -methoxycarbamoyl-7-methyl-octyl) -amide
273 7, 8-difluoro-quinoline-3-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenyl-pentyl) -amide 233-235
274 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-5- (2-chloro-phenyl) -2(S) -hydroxy-pentyl]-amides of 182-185
275 Quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-o-tolyl-pentyl) -amide 168-171
276 Quinoxaline-2-carboxylic acid (1(S) -benzyl-2 (S) -hydroxy-4 (R) -hydroxycarbamoyl-5-phenyl-pentyl) -amide 190-192
277 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-cyclopentyl) -butyl]-amides of 192-195 463，446
278 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl]-amides of 230-233 490
279 Quinoxaline-2-carboxylic acid [1 (C)S) -benzyl-4 (S) -carbamoyl-5- (3, 4-dichloro-phenyl) -2(S) -hydroxy-pentyl]-amides of 199-201
280 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-5- (2-fluoro-phenyl) -2(S) -hydroxy-pentyl]-amides of 171-173
281 Quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-cyclopentyl) -butyl]-amides of 110-112 477
282 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-3-methyl-cyclopentyl) -butyl]-amides of 187-188 476
283 Quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-4-methyl-cyclohexyl) -butyl]-amides of 114-116 506
284 N- (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenyl-pentyl) -5-bromo-nicotinamide 494，496
285 8-fluoro-quinoline-3-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenyl-pentyl) -amide 206-209
286 6, 7-dihydro-5H- [1]4-Azindene-3-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenyl-pentyl) -amide 182-186
287 Quinoline-3-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenyl-pentyl) -amide 203-206
288 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-3, 5-dimethyl-cyclohexyl) -butyl]-amides of 234-236 504
289 Quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-3, 5-dimethyl-cyclohexyl) -butyl]-amides of 520
290 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-cycloheptyl) -butyl]-amides of 189-191 491
291 Quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-cycloheptyl) -butyl]-amides of 118-119 506
292 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-5- (3-fluoro-phenyl) -2(S) -hydroxy-pentyl]-amides of 176-179
293 Quinoxaline-2-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-m-tolyl-pentyl) -amide 178-179
294 Quinoxaline-2-carboxylic acid (1(S) -benzyl-2 (S) -hydroxy-4-isobutylcarbamoyl-butyl) -amide 146-148
295 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (2-hydroxy-adamantan-2-yl) -butyl]-amides of 206-207 528
296 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (9-hydroxy-bicyclo [ 3.3.1)]-non-9-yl) -butyl]-amides of 268-269 516
297 Quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) - (2-hydroxy-adamantan-2-yl) -4-hydroxycarbamoyl-butyl]-amides of 133-134 544
298 Quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) - (9-hydroxy-bicyclo [ 3.3.1)]-nonan-9-yl) -4-hydroxycarbamoyl-butyl]-amides of 130-132 532
299 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5- (3-methoxy-phenyl) -pentyl]-amides of 147-148
300 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -aminoFormyl-2 (S) -hydroxy-4- (1-hydroxy-4-propyl-cyclohexyl) -butyl]-amides of 227-228 519
301 Quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-4-propyl-cyclohexyl) -butyl]-amides of 115-117 533
302 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5- (4-methoxy-phenyl) -pentyl]-amides of 500，483
303 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4 (S) - (4-ethyl-1-hydroxy-cyclohexyl) -2-hydroxy-butyl]Amides of carboxylic acids 246-248 504
304 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-4, 4-dimethyl-cyclohexyl) -butyl]-amides of 210-211 505
305 Quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-4, 4-dimethyl-cyclohexyl) -butyl]-amides of 118-123 520
306 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4- (4, 4-difluoro-1-hydroxy-cyclohexyl) -2(S) -hydroxy-butyl]-amides of 207.5-208.5
307 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) - (4, 4-difluoro-1-hydroxy-cyclohexyl) -2(S) -hydroxy-4-hydroxycarbamoyl-butyl]-amides of 130-131 572
308 Quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-2 (S) -hydroxy-4- (1-hydroxy-4-trifluoromethyl-cyclohexyl) -butyl]-amides of 250-252 545
309 Quinoxaline-3-carboxylic acid 1(S) -cyclohexylmethyl-2 (S) -hydroxy-6-methyl-4 (R) -methylcarbamoyl-heptyl-amide 94-98 454
310 Quinoxaline-2-carboxylic acid [1(S) -benzyl-7-fluoro-2 (S) -hydroxy-7-methyl-4 (R) - (pyrrolidine-1-carbonyl) -octyl]-amides of 174-175.5 522
311 N- (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -5-bromo-nicotinamide 218-220 470
312 Quinoxaline-2-carboxylic acid (1(S) -benzyl-7-fluoro-4 (R) -hydrazinocarbonyl-2 (S) -hydroxy-7-methyl-octyl) -amide 147-149 482，467
Example 313
Quinoxaline-2-carboxylic acid 1(S) -benzyl-4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyloctyl) -amide
To the lactone of example 2, method C (100mg, 0.27mmol) was added neat trifluoroacetic acid (1 mL). The resulting solution was stirred for 1 hour, and then trifluoroacetic acid was distilled off in vacuo. The remaining residue was dissolved in dichloromethane (10mL) and triethylamine (0.15mL, 1.07 mmol). Quinoxalinyl chloride solid (58mg, 0.3mmol) was added and the mixture was stirred for 18 hours. The mixture was transferred to a separatory funnel and washed with citric acid (2X 10mL), NaHCO3(10mL) and brine (10 mL). The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was taken up on silicaChromatography on gel (10g) eluting with 2: 1 hexane: ethyl acetate afforded 99mg of quinoxaline amide. The material was dissolved in methanol and ammonia gas was bubbled for 5 minutes. The resulting solution was stirred for 16 hours and then the solvent was distilled off in vacuo. The remaining residue was recrystallized (dichloromethane/methanol/hexane) to give the title compound (90mg, 72%).1H NMR(400MHz，CD3OD): d 9.38(1H, s), 8.21(1H, dd, J ═ 4.4, 2.5Hz), 8.14(1H, dd, J ═ 4.4, 2.5Hz), 7.93(2H, m), 7.26(2H, d, J ═ 6.9Hz), 7.17(2H, t, J ═ 7.1Hz), 7.09(1H, t, J ═ 7.3Hz), 4.30(1H, m), 3.75(1H, m), 3.03-2.98(2H, m), 2.47(1H, m), 1.77(1H, m), 1.56(2H, m), 1.4(2H, m), 1.07(6H, s). Example 314-
The compounds in Table 2 were prepared as described above, using the appropriate R if necessary2Aldehyde, R3Radical, R1Carboxylic acid or R4And R5Amine substitution. TABLE 2
Examples Name (R) M.P.(℃) LRMS
314 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (3-fluoro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl]-amides of 153-155 483.，465.，448
315 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (3, 5-difluoro-benzyl) -2(S),7-dihydroxy-7-methyl-octyl]-amides of 162-163 500，483，466
316 Quinoxaline-2-carboxylic acid 4(R) -carbamoyl-1 (S) - (3-chloro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl]Amides of carboxylic acids 161-163 499，481，464
317 Quinoxaline-2-carboxylic acid [1(S) - (3-chloro-benzyl) -2(S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl]-amides of 108-111 497，464
318 7, 8-difluoro-quinoline-3-carboxylic acid (1S) -benzyl-4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-octyl) -amide 171-173 501，484
319 6, 7, 8-trifluoro-quinoline-3-carboxylic acid (1(S) -benzyl-4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-octyl) -amide 185-188 519，502
320 Quinoxaline-2-carboxylic acid [1(S) - (3, 5-difluoro-benzyl) -2(S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl]-amides of 98-100 517
321 Quinoxaline-2-carboxylic acid (1(S) -benzyl-2 (S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl) -amide 108-110 482，464，447
322 7, 8-difluoro-quinoline-3-carboxylic acid (1(S) -benzyl 4(R) -ethylcarbamoyl-2 (S), 7-dihydroxy-7-methyl-octyl) -amide 507，484，447
323 N- (1(S) -benzyl-4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-octyl) -4-trifluoromethyl-nicotinamide 131-135 482，464，447
324 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (2-chloro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl]Amides of carboxylic acids
325 7, 8-difluoro-quinoline-3-carboxylic acid [ (4R) -carbamoyl-1 (S) - (3-fluoro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl]-amides of 174-177 518
326 Quinoxaline-2-carboxylic acid [1(S) - (2-fluoro-benzyl) -2(S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl]-amides of 130-131 499
327 Quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-1 (S) -thiophen-2-ylmethyl-octyl) -amide 158-159 471，453，436
328 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (2-fluoro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl]-amides of 147-148 483
329 Quinoxaline-2-carboxylic acid [1(S) - (3, 4-difluoro-benzyl) -2(S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-octyl]-amides of 150-153 517，499，466
330 Quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1 (S) - (3, 4-difluoro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl]-amides of 110-120 501，483，466
331 Quinoxaline-2-carboxylic acid (4 (R-carbamoyl-2 (S), 7-dihydroxy-7-methyl-1 (S) -naphthalen-1-ylmethyl-octyl) -acyl 155-158 515，497，480
332 6, 7, 8-trifluoro-quinoline-3-carboxylic acid [4(R) -carbamoyl-1 (S) - (3-fluoro-benzyl) -2(S), 7-dihydroxy-7-methyl-octyl]Amides of carboxylic acids 183-185 536，518
333 Quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-1 (S) -naphthalen-2-ylmethyl-octyl) -amide 104-106 515，497
334 Quinoxaline-2-carboxylic acid (2(S), 7-dihydroxy-4 (R) -hydroxycarbamoyl-7-methyl-1 (S) -naphthalen-2-ylmethyl-octyl) -amide 98-100 498，480
335 Quinoxaline-2-carboxylic acid (1(S) -benzo [ b ]]Thien-3-ylmethyl-4 (R) -carbamoyl-2 (S), 7-dihydroxy-7-methyl-octyl) -amide 163-164 521，503，486
336 Quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (4-hydroxy-phenyl) -pentyl]-amides of 190.5-191.5
337 Quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (3-hydroxy-phenyl) -pentyl]-amides of
338 Quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (2-hydroxy-phenyl) -pentyl]-amides of
339 Quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (2-hydroxy-5-methyl-phenyl) -pentyl]-amides of
340 Quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (2-hydroxy-3-methyl-phenyl) -pentyl]-amides of
341 Quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-5- (3-ethoxy-2-hydroxy-phenyl) -2-hydroxy-pentyl]-amides of
342 Quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (4-hydroxy-3, 5-dimethyl-phenyl) -pentyl]-amides of
343 Quinoxaline-2-carboxylic acid (1-benzyl-4-carbamoyl-2, 6-dihydroxy-methyl-heptyl) -amide
344 Quinoxaline-2-carboxylic acid [ 1-benzyl-4-carbamoyl-2-hydroxy-5- (1-hydroxy-cyclohexyl) -pentyl]-amides of

Claims (46)

1. A compound of the formula:
wherein R is1Is optionally substituted by one or more substituents (C)2-C9) Heteroaryl, said substituents being independently from each other selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, optionally substituted by one or more fluorine atoms (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
R2is phenyl- (CH)2)m-, naphthyl- (CH)2)m-、(C3-C10) Cycloalkyl- (CH)2)m-、(C1-C6) Alkyl or (C)2-C9) Heteroaryl- (CH)2)m-, where m is an integer of 0 to 4, wherein the phenyl- (CH)2)m-, naphthyl- (CH)2)m-、(C3-C10) Cycloalkyl- (CH)2)m-or (C)2-C9) Heteroaryl- (CH)2)mPhenyl, naphthyl, (C) in the radical3-C10) Cycloalkyl or (C)2-C9) The heteroaryl moiety may be optionally substituted with one or more substituents independently selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, optionally substituted by one or more fluorine atoms (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, phenoxy, benzyloxy, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
R3is hydrogen, (C)1-C10) Alkyl, (C)3-C10) Cycloalkyl- (CH)2)n-、(C2-C9) Heterocycloalkyl- (CH)2)n-、(C2-C9) Heteroaryl- (CH)2)n-or aryl- (CH)2)n-; wherein n is an integer from 0 to 6;
wherein said R3Is (C)1-C10) The alkyl group may optionally be substituted by one orA plurality of substituents, independently of each other, selected from the group consisting of: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, optionally substituted by one or more fluorine atoms (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2 amino, amino (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) Alkane (I) and its preparation methodradical-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group; wherein said (C)1-C10) Any carbon-carbon single bond of the alkyl group may optionally be replaced by a carbon-carbon double bond;
wherein said R3Is (C)3-C10) Cycloalkyl- (CH)2)nOf the radical (C)3-C10) The cycloalkyl moiety may be optionally substituted with 1 to 3 substituents independently selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, optionally substituted by one or more fluorine atoms (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
wherein said R3Is (C)2-C9) Heterocycloalkyl- (CH)2)nOf the radical (C)2-C9) The heterocycloalkyl moiety may also contain 1 to 3 substituents independently of one another selected from nitrogen, sulfur, oxygen, > S (═ O), > SO2Or > NR6Wherein said (C)2-C9) Heterocycloalkyl- (CH)2)nOf the radical (C)2-C9) The heterocycloalkyl moiety may be optionally substituted on any ring carbon atom capable of otherwise forming a bond, said substituents being independently selected from: hydrogen, halogen, CN, optionally substituted by one or more fluorine atomsIs (C)1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, optionally substituted by one or more fluorine atoms (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
wherein said R3Is (C)2-C9) Heteroaryl- (CH)2)nOf the radical (C)2-C9) The heteroaryl moiety may also contain 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen, wherein (C) is2-C9) Heteroaryl- (CH)2)nOf the radical (C)2-C9) The heteroaryl moiety may be optionally substituted on any ring carbon atom capable of otherwise forming a bond, said substituents being independently selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, optionally substituted by one or more fluorine atoms (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
wherein said R3Aryl group of (CH)2)n-the aryl part of the group is optionally substituted phenyl or naphthyl, wherein said phenyl and naphthyl may be optionally substituted with 1-3 substituents independently from each other selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, optionally substituted by one or more fluorine atoms (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
or, R3Together with the carbon to which they are attached form a 5-7 membered carbocyclic ring, wherein any carbon atom on the 5-membered carbocyclic ring may be optionally substituted with substituents independently selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, optionally substituted by one or more fluorine atoms (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group; wherein one of the carbon-carbon bonds of the 5-7 membered carbocyclic ring may optionally be fused with an optionally substituted benzene ring, wherein the substituents may be independently selected from: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, optionally substituted by one or more fluorine atoms (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
R4is hydrogen, (C)1-C6) Alkyl, hydroxy, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C ═ O) -, (C)3-C10) Cycloalkyl- (CH)2)p-、(C2-C9) Heterocycloalkyl- (CH)2)p-、(C2-C9) Heteroaryl- (CH)2)p-, phenyl- (CH)2)p-or naphthyl- (CH)2)p-, where p isAn integer of 0 to 4; wherein said (C)2-C9) Heterocycloalkyl- (CH)2)p-、(C2-C9) Heteroaryl- (CH)2)p-, phenyl- (CH)2)p-or naphthyl- (CH)2)pOf (A), (B), (C) and (C)2-C9) Heterocycloalkyl group, (C)2-C9) Heteroaryl, phenyl and naphthyl may be optionally substituted on any ring atom capable of otherwise forming a bond with a substituent selected from the group consisting of: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, optionally substituted by one or more fluorine atoms (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
or R4And R5Together with the nitrogen atom to which they are attached form (C)2-C9) Heterocycloalkyl group of which said (C)2-C9) Any ring atom of the heterocycloalkyl group may be optionally substituted with a substituent selected from the group consisting of: hydrogen, halogen, CN, (C) optionally substituted by one or more fluorine atoms1-C6) Alkyl, hydroxy- (C)1-C6) Alkyl, optionally substituted by one or more fluorine atoms (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, HO- (C ═ O) -, (C)1-C6) alkyl-O- (C ═ O) -, HO- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) alkyl-O- (C ═ O) - (C)1-C6) Alkyl, (C)1-C6) Alkyl- (C ═ O) -O-, (C)1-C6) Alkyl- (C ═ O) -O- (C)1-C6) Alkyl, H (O ═ C) -, H (O ═ C) (C)1-C6) Alkyl, (C)1-C6) Alkyl (O ═ C) -, (C)1-C6) Alkyl (O ═ C) (C)1-C6) Alkyl radical, NO2Amino group, (C)1-C6) Alkylamino [ (C)1-C6) Alkyl radical]2Amino group, amino group (C)1-C6) Alkyl, (C)1-C6) Alkylamino radical (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2Amino (C)1-C6) Alkyl, H2N-(C＝O)-、(C1-C6) alkyl-NH- (C ═ O) -, [ (C)1-C6) Alkyl radical]2N-(C＝O)-、H2N(C＝O)-(C1-C6) Alkyl, (C)1-C6) alkyl-HN (C ═ O) - (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-(C＝O)-(C1-C6) Alkyl, H (O ═ C) -NH-, (C)1-C6) Alkyl (C ═ O) -NH, (C)1-C6) Alkyl (C ═ O) - [ NH ═ O) - [](C1-C6) Alkyl, (C)1-C6) Alkyl (C ═ O) - [ N (C) — (C)1-C6) Alkyl radical](C1-C6) Alkyl, (C)1-C6) alkyl-S-, (C)1-C6) Alkyl- (S ═ O) -, (C)1-C6) alkyl-SO2-、(C1-C6) alkyl-SO2-NH-、H2N-SO2-、H2N-SO2-(C1-C6) Alkyl, (C)1-C6) alkyl-HN-SO2-(C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-SO2-(C1-C6) Alkyl, CF3SO3-、(C1-C6) alkyl-SO3-, phenyl, (C)3-C10) Cycloalkyl group, (C)2-C9) Heterocycloalkyl and (C)2-C9) A heteroaryl group;
R5is hydrogen, (C)1-C6) Alkyl or amino;
R6is hydrogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy- (CH)2)g-、(C1-C6) Alkoxy (C ═ O) - (CH)2)g-、(C1-C6) Alkyl- (SO)2)-(CH2)g-、(C6-C10) Aryloxy radical- (CH)2)g-、(C6-C10) Aryloxy (C ═ O) - (CH)2)g-or (C)6-C10) Aryl- (SO)2)-(CH2)g-, wherein g is an integer of 0 to 4;
provided that when R is4Or R5One is hydrogen and R is4Or R5Is (C)1-C6) An alkyl group; r2Is (C)3-C10) Cycloalkyl or isopropyl and R3Is (C)3-C5) Alkyl, phenyl, methylvinyl, dimethylvinyl, halovinyl, hydroxy (C)1-C3) Alkyl or amino (C)1-C4) When alkyl is present, then R1Is not indol-5-yl, 6-azaindol-2-yl, 2, 3-dichloro-pyrrol-5-yl, 4-hydroxyquinolin-3-yl, 2-hydroxyquinoxalin-3-yl, 6-azaindolin-3-yl or optionally substituted indol-2 or 3-yl.
2. The compound of claim 1, wherein the compound of formula I has an exact stereochemistry as shown in the following formula
Wherein R is1、R2、R3、R4And R5As defined in claim 1.
3. The compound of claim 1, wherein R1Is optionally substituted pyrazolo [3, 4-b]Pyridyl, cinnolinyl, pyridyl, 6, 7-dihydro-5H- [1]4-azoindenyl, benzothiazolyl, indolyl, pyrazinyl, benzimidazolyl, benzofuranyl, benzo [ b]Thienyl, naphthyl, quinoxalinyl, isoquinolinyl, 5, 6, 7, 8-tetrahydroquinolin-3-yl or quinolinyl.
4. The compound of claim 2, wherein R1Is optionalSubstituted pyrazolo [3, 4-b]Pyridyl, cinnolinyl, pyridyl, 6, 7-dihydro-5H- [1]4-azoindenyl, benzothiazolyl, indolyl, pyrazinyl, benzimidazolyl, benzofuranyl, benzo [ b]Thienyl, naphthyl, quinoxalinyl, isoquinolinyl, 5, 6, 7, 8-tetrahydroquinolin-3-yl or quinolinyl.
5. The compound of claim 1, wherein R1Is optionally substituted pyrazolo [3, 4-b]Pyridin-5-yl, cinnolin-4-yl, pyridin-2-yl, 6, 7-dihydro-5H- [1]4-indolizin-3-yl, benzothiazol-2-yl, indol-2-yl, pyrazin-2-yl, benzimidazol-2-yl, benzofuran-2-yl, benzo [ b ]]Thien-2-yl, naphthalene-2-yl, quinoxalin-6-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, 5, 6, 7, 8-tetrahydroquinolin-3-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl.
6. The compound of claim 2, wherein R1Is optionally substituted pyrazolo [3, 4-b]Pyridin-5-yl, cinnolin-4-yl, pyridin-2-yl, 6, 7-dihydro-5H- [1]4-indolizin-3-yl, benzothiazol-2-yl, indol-2-yl, pyrazin-2-yl, benzimidazol-2-yl, benzofuran-2-yl, benzo [ b ]]Thien-2-yl, naphthalene-2-yl, quinoxalin-6-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, 5, 6, 7, 8-tetrahydroquinolin-3-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl.
7. The compound of claim 1, wherein R1Is optionally substituted quinoxalin-2-yl, quinoxalin-6-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl.
8. The compound of claim 2, wherein R1Is optionally substituted quinoxalin-2-yl, quinoxalin-6-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl.
9. The compound of claim 1, wherein R2Is an optionally substituted benzyl group.
10. The compound of claim 2, wherein R2Is an optionally substituted benzyl group.
11. The compound of claim 3, wherein R2Is an optionally substituted benzyl group.
12. The compound of claim 4, wherein R2Is an optionally substituted benzyl group.
13. The compound of claim 5, wherein R2Is an optionally substituted benzyl group.
14. The compound of claim 6, wherein R2Is an optionally substituted benzyl group.
15. The compound of claim 7, wherein R2Is an optionally substituted benzyl group.
16. The compound of claim 8, wherein R2Is an optionally substituted benzyl group.
17. The compound of claim 1, wherein R3Is optionally substituted (C)1-C10) Alkyl or (C)3-C10) Cycloalkyl- (CH)2)n-。
18. The compound of claim 2, wherein R3Is optionally substituted (C)1-C10) Alkyl or (C)3-C10) Cycloalkyl- (CH)2)n-。
19. The compound of claim 6, wherein R3Is optionally takenGeneration (C)1-C10) Alkyl or (C)3-C10) Cycloalkyl- (CH)2)n-。
20. The compound of claim 8, wherein R3Is optionally substituted (C)1-C10) Alkyl or (C)3-C10) Cycloalkyl- (CH)2)n-。
21. The compound of claim 1, wherein R3Is optionally substituted n-butyl, tert-butyl, 2-methylpropyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl or cyclohexylmethyl.
22. The compound of claim 2, wherein R3Is optionally substituted n-butyl, tert-butyl, 2-methylpropyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl or cyclohexylmethyl.
23. The compound of claim 6, wherein R3Is optionally substituted n-butyl, tert-butyl, 2-methylpropyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl or cyclohexylmethyl.
24. The compound of claim 8, wherein R3Is optionally substituted n-butyl, tert-butyl, 2-methylpropyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, 2-methyl-pentyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl or cyclohexylmethyl.
25. The compound of claim 1, wherein R3Substituted by fluorine or hydroxy.
26. The compound of claim 2, wherein R3Substituted by fluorine or hydroxy.
27. The compound of claim 21, wherein R3Substituted by fluorine or hydroxy.
28. The compound of claim 22, wherein R3Substituted by fluorine or hydroxy.
29. The compound of claim 23, wherein R3Substituted by fluorine or hydroxy.
30. The compound of claim 24, wherein R3Substituted by fluorine or hydroxy.
31. The compound of claim 1, wherein R3Is 4, 4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, isobutyl or 1-hydroxy-cyclohexyl.
32. The compound of claim 2, wherein R3Is 4, 4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, 2-methylpropyl, 2-hydroxy-2-methyl-butyl, 2-hydroxy-2-methyl-propyl or 1-hydroxy-cyclohexyl.
33. The compound of claim 6, wherein R3Is 4, 4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, 2-methylpropyl, 2-hydroxy-2-methyl-butyl, 2-hydroxy-2-methyl-propyl or 1-hydroxy-cyclohexyl.
34. The compound of claim 8, wherein R3Is 4, 4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, 2-methylpropyl, 2-hydroxy-2-methyl-butyl, 2-hydroxy-2-methyl-propyl or 1-hydroxy-cyclohexyl.
35. The compound of claim 16, wherein R3Is 4, 4-difluoro-cyclohexylmethyl, 2-fluoro-2-methyl-butyl, 2-methylpropyl, 2-hydroxy-2-methyl-butyl, 2-hydroxy-2-methyl-propyl or 1-hydroxy-cyclohexyl.
36. The compound of claim 1, wherein R4And R5Independently of one another, from hydrogen, hydroxyl, amino, methyl or ethyl.
37. The compound of claim 6, wherein R4And R5Independently of one another, from hydrogen, hydroxyl, amino, methyl or ethyl.
38. The compound of claim 8, wherein R4And R5Independently of one another, from hydrogen, hydroxyl, amino, methyl or ethyl.
39. The compound of claim 21, wherein R4And R5Independently of one another, from hydrogen, hydroxyl, amino, methyl or ethyl.
40. The compound of claim 1, wherein the compound is:
7, 8-difluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
8-fluoro-quinoline-3-carboxylic acid 1(S) -benzyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl) -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-7-fluoro-1- (3(S) -fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [4(R) -carbamoyl-1- (2(S) -fluoro-benzyl) -2(S) -hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4 (S) - (2, 6-dimethyl-tetrahydropyran-4-yl) -2(S) -hydroxy-butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-5-cyclohexyl-2 (S) -hydroxy-4 (R) -methylcarbamoyl-pentyl) ] -amide;
quinoxaline-2-carboxylic acid [1(S) -cyclohexylmethyl-2 (S) -hydroxy-7-methyl-4 (R) -methylcarbamoyl-octyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-2 (S) -hydroxy-4 (S) -hydroxycarbamoyl-4- (1-hydroxy-4-methylcyclohexyl) -butyl ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) - (4, 4-difluoro-1-hydroxy-cyclohexyl) -2(S) - (hydroxy-4-hydroxycarbamoyl-butyl) ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (S) -carbamoyl-4 (S) - (4, 4-difluoro-cyclohexyl) -2(S) -hydroxy-butyl ] -amide;
quinoline-3-carboxylic acid (1(S) -benzyl-4 (S) -carbamoyl-4-cyclohexyl-2 (S) -hydroxy-butyl) -amide;
quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S) -hydroxy-7-methyl-1 (S) -thiophen-2-ylmethyl-octyl) -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-7-chloro-2 (S) -hydroxy-oct-6-enyl) ] -amide;
quinoxaline-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-2 (S) -hydroxy-5-phenylpentyl) ] -amide;
n- (1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) -5, 6-dichloro-nicotinamide;
quinoxaline-2-carboxylic acid (4(R) -carbamoyl-2 (S) -hydroxy-7-methyl-1 (S) -thiazol-4 (R) -ylmethyl-octyl) -amide;
benzothiazole-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) ] -amide; or
Benzofuran-2-carboxylic acid [1(S) -benzyl-4 (R) -carbamoyl-7-fluoro-2 (S) -hydroxy-7-methyl-octyl) ] -amide.
41. A pharmaceutical composition for treating or preventing autoimmune diseases, acute and chronic inflammation, allergic diseases, infections accompanied by inflammation, viral infections, graft tissue rejection, atherosclerosis, restenosis, HIV infection, and granulomatous diseases in a mammal, said composition comprising a compound of claim 1 in an amount effective to treat or prevent said diseases and a pharmaceutically acceptable carrier.
42. A pharmaceutical composition for the treatment or prevention of a disease in a mammal which is treatable or preventable by inhibiting MIP-1 α binding to the receptor CCR1, said composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof in an amount effective for the treatment or prevention of said disease and a pharmaceutically acceptable carrier.
43. A method for the treatment or prophylaxis of autoimmune diseases, acute and chronic inflammation, allergic diseases, infections accompanied by inflammation, viral infections, graft tissue rejection, atherosclerosis, restenosis, HIV infection and granulomatous diseases in a mammal, which comprises administering to a mammal in need of such treatment or prophylaxis an amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, effective to treat or prevent said disease.
44. A method for the treatment or prevention of a disease which is treatable or preventable by antagonism of the CCR1 receptor in a mammal, which method comprises administering to a mammal in need of such treatment or prevention a disease treating or preventing effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
45. A pharmaceutical composition for the treatment or prophylaxis of autoimmune diseases, acute and chronic inflammation, allergic diseases, infections accompanied by inflammation, viral infections, graft tissue rejection, atherosclerosis, restenosis, HIV infection and granulomatous diseases in a mammal, said composition comprising a CCR1 receptor antagonizing effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
46. A pharmaceutical composition for the treatment or prevention of a disease in a mammal which is treatable or preventable by antagonism of the CCR1 receptor, said composition comprising a CCR1 receptor antagonistically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
HK00104627.3A 1997-02-26 1998-02-05 Heteroaryl-hexanoic acid amide derivatives, their preparation and their use as selective inhibitors of mip-1-alpha binding to its ccr 1 receptor HK1025328A (en)

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