# Patent

## Title
Imidazopyridine compounds

## Abstract

An excellent drug for treating or preventing cardiovascular diseases, based on cGMP production enhancing action due to soluble guanylate cyclase activating action, is provided. It was found that imidazopyridine compounds having a carbamoyl group at the 3-position and a substituent bonded at the 8-position via an oxygen atom in an imidazo[1,2-a]pyridine skeleton exhibits a cGMP production enhancing action by a potent soluble guanylate cyclase activating action, and is useful as a drug for treating or preventing various soluble guanylate cyclase-related cardiovascular diseases, thereby completing the present invention.

## Background
TECHNICAL FIELD
The present invention relates to imidazopyridine compounds useful as active ingredients of pharmaceutical compositions, for example, pharmaceutical compositions for treating or preventing various cardiovascular diseases, which have soluble guanylate cyclase (sGC) activation based on improvement of cGMP signals.
BACKGROUND ART
cGMP (cyclic guanosine monophosphate) is an important intracellular messenger and is involved in the regulation of various physiological phenomena such as relaxation and proliferation of smooth muscle cells, aggregation and adhesion of platelets, and signaling of nerve cells, through the control of a cGMP-dependent protein kinase, a phosphodiesterase, and ion channels. The cGMP is catalytically produced from guanosine triphosphate (GTP) by a guanylate cyclase in the response to various extracellular and intracellular stimulation. There have been reported two groups of guanylate cyclases to date, that is, particulate guanylate cyclases stimulated by peptidic messengers (for example, atrial natriuretic peptides, brain natriuretic peptides, and the like) and soluble guanylate cyclase stimulated by nitric oxide (NO).
The sGC is one of the most important target molecules of NO that is a messenger which plays a very important role in maintaining homeostasis of the body, and forms an NO/sGC/cGMP pathway. It has been reported that this enzyme is constituted with two subunits, each of the heterodimer contains one heme, and the heme plays a central role in an activation mechanism. It is believed that when NO binds to the iron in the heme, the enzyme is changed to an active conformation. Therefore, there is no stimulation by NO with enzyme preparations containing no heme. Although carbon monoxide (CO) may also bind to the iron in the heme, but the stimulation by CO is significantly lower than that by NO.
The sGC is constituted with α and β subunits. Analysis of cGC from tissue-specific distributions and in different growth steps demonstrated multiple isotypes with different subunit compositions. The distribution of the respective subunits have been studied with mammals including a human, and it has been widely recognized that al and β1 subunits are expressed in many tissues and the α1β1 forms have a pattern of a heterodimer that works functionally. α2 subunits have been also recognized, which exist fewer organs as compared to the α1, and it has been reported that the α2 subunits are expressed more frequently than α1 in the brain, the lung, the colon, the heart, the spleen, the uterus, and the placenta. Subunits called α3 and β3 were isolated from the human brain, but are homologous to α1 and β1. In addition, according to recent studies, α2i subunits which contain an insert in the catalytic domain have identified. All of the subunits exhibit high homology in catalytic domain regions.
Under pathophysiological conditions, it has been reported that there is inhibition of the production of or promotion of the degradation of sGC activating factors such as NO for the reasons of increased generation of free radicals, and the like. With a decrease in the sGC activating factors, NO/sGC/cGMP signals are attenuated, which results in, for example, increased blood pressure, platelet activation, or increased cell proliferation and cell adhesion. As a result, a variety of cardiovascular diseases, specifically, hypertension (including pulmonary hypertension), atherosclerosis, peripheral arterial diseases, lumbar spinal canal stenosis, intermittent claudication, critical limb ischemia, stable or unstable angina pectoris, heart failure, thrombosis, stroke, and sexual dysfunction occur. Therefore, a new drug having a mechanism of selectively activating sGC is believed to have the potential of normalizing cGMP production, and thus or prevent such diseases can be treated or prevented.
As the sGC activator, there have been known, for example, “heme-dependent stimulants” which activate sGC depending on heme groups, such as NO donors as described later and the like, and “heme-independent activators” which are independent on the heme groups (Non-Patent Document 2).
For the activation of sGC, a group of compounds called NO donors such as organic nitrates have been widely used so far. These compounds are heme-dependent stimulants which activate sGC by being metabolized in vivo to produce NO, which then binds to a central iron atom of a heme. However, the NO donors have critical disadvantages such as expression of a resistance, a decrease in the effects and the like is expressed in addition to side-effects, and therefore, there is a demand for a novel sGC activator that does not have these disadvantages.
For example, compounds of the following formulae (a) to (c) have been reported as compounds having sGC activating action (Patent Document 1).




(Compounds of the formula (a) are pyrazolo[3,4]fused bicyclic compounds, and compounds of formulae (b) and (c) are imidazo[1,5]fused bicyclic compounds. Further, Q means substituted heterocycle in any one of the formulae (a) to (c). For details, refer to the document.)
In this document, there is no disclosure or suggestion of compounds having an imidazo[1,2-a]pyridine skeleton.
In addition, pyrazole derivatives or pyrazolo[3,4-b]pyridine derivatives are disclosed as the sGC activating compounds in International Publications WO 2000/06569, WO 2000/21954, WO 2001/83490, WO 2003/004503, WO 2003/095451, WO 2003/086407, WO 2003/097063, WO 2007/124854, WO 2007/128454, WO 2008/031513, WO 2008/061657, WO 2010/078900, and WO 2010/079120. However, in any of these documents, there is no disclosure or suggestion of compounds having an imidazo[1,2-a]pyridine skeleton.
Furthermore, compounds of the following formula (d) have been reported as sGC activators (Patent Document 2).




(wherein Z is O, S, or N(R7), R7 is H or alkyl, and R6 is aryl, arylalkenyl, heterocycle, -(alkenyl)-(heterocycle), or heterocycloalkyl).
However, this document does not disclose or suggest compounds having an imidazo[1,2-a]pyridine skeleton.
As other sGC activators, 1H-pyrazole-5-carboxylic acid derivatives (Patent Document 3), biaryl derivatives (Patent Document 4), and benzylindazole derivatives (Non-Patent Document 1) have been reported.
Furthermore, compounds having an imidazopyridine skeleton, for example, compounds of the following formula (e) useful for the treatment of gastrointestinal ulcer as an H+/K+-ATPase enzyme inhibitors have been reported (Non-Patent Document 3).




(wherein R means substituted alkoxy group, R′ means H or phenethyl, R2 means H or lower alkyl, and R3 means substituted alkyl or the like. For details, refer to the document).
This document does not disclose or suggest sGC activators, and compound of formula (I) of the present invention as described later has a different structure from that of the compound of the formula (e) in that the compound of formula (I) has an aminocarbonyl group at the 3-position.
Moreover, compounds of the formula (f) useful for the treatment of allergy, inflammation, pain, or the like as bradykinin antagonists have been reported (Patent Document 5).




(wherein R1 to R3 each mean hydrogen, lower alkyl, or the like, R4 means an aryl group which may have a suitable substituent, or the like, Q means O, NH, or the like, X1 means N or C—R5, Y1 and Y2 each mean a single bond or a lower alkylene group, and Ring A means 6-membered nitrogen-containing heterocycle. For details, refer to the document).
This document does not disclose or suggest sGC activators, and the compound of formula (I) of the present invention as described later has a different structure from that of the compound of formula (f) in that the compound of formula (I) has an aminocarbonyl group at the 3-position.
Furthermore, compounds of formula (g) with H+/K+-ATPase enzyme inhibitory activities and useful for the inhibition of gastric acid secretion have been reported (Patent Document 6).




(wherein R1 is CH3 or CH2OH, R2 and R3 are each lower alkyl, R4 is H or halogen, R5 is H, halogen, or lower alkyl, and X is NH or O. For details, refer to the document).
This document does not disclose or suggest sGC activators, and the compound of formula (I) of the present invention as described later have different structure from that of the compound of formula (g) in that the compound of formula (I) has an aminocarbonyl group at the 3-position.
Moreover, compounds of formula (h) have been reported as cardiac ion channel modulators and as antiarrhythmic agents (Patent Document 7).




(wherein R2, R15, R16, and R18 are each Br, Cl, F, carboxy, H, —OH, hydroxymethyl, or the like, and R1 is H, C1-6 alkyl, aryl, benzyl, or the like. For details, refer to the document).
This document does not disclose or suggest sGC activators, and the compound of formula (I) of the present invention as described later have different structure from that of the compound of formula (h) in that the compound of formula (I) has an aminocarbonyl group at the 3-position.
In addition, compound of formula (i) useful as a drug for treating bacterial infection, particularly tuberculosis, have been reported (Patent Document 8).




(wherein X, Y, and Z are each CH or the like, n is 0 or the like, m is 1 or the like, R1 is —C(O)N(R4)2 or the like, R2 is C1-10 alkyl or the like, R3 is —OR6 or the like, and R6 is C1-10 alkyl optionally substituted, or the like. For details, refer to the document).
This document specifically discloses a compound, in which X, Y, and Z are each CH, n is 0, R1 is —C(O)N(R4)2, R2 is C1-10 alkyl, m is 1, R3 is —OR6, and R6 is H, methyl, or difluoromethyl. However, this document does not disclose or suggest sGC activators, and the compound of formula (I) of the present invention as described later has a different structure from that of the compounds disclosed in this document in that the substituent A1 is lower alkyl.
RELATED ART
Patent Document


    [Patent Document 1] Pamphlet of International Publication WO 2008/031513
    [Patent Document 2] Pamphlet of International Publication WO 2003/076408
    [Patent Document 3] Pamphlet of International Publication WO 2000/027394
    [Patent Document 4] Pamphlet of International Publication WO 2001/032604
    [Patent Document 5] JP-A-H7-242666
    [Patent Document 6] Pamphlet of International Publication WO 1998/37080
    [Patent Document 7] Pamphlet of International Publication WO 2001/096335
    [Patent Document 8] Pamphlet of International Publication WO 2011/113606
    [Non-Patent Document 1] Blood (1994), Vol. 84, p. 4226
    [Non-Patent Document 2] Journal of Cardiovascular Pharmacology (2010), Vol. 56, p. 229
    [Non-Patent Document 3] Journal of Medicinal Chemistry (1985), Vol. 28, p. 876


DISCLOSURE OF INVENTION
Technical Problem
Problems to Be Solved by the Invention
Imidazopyridine compounds, useful as active ingredients of pharmaceutical compositions, for example, pharmaceutical compositions for treating or preventing various cardiovascular diseases, which have soluble guanylate cyclase (sGC) activities based on improvement of cGMP signals, are provided.
Means for Solving the Problems
The present inventors have made extensive studies on compounds having sGC activation, and as a result, they have found that compounds of formula (I) which are imidazo[1,2-a]pyridine compounds having a carbamoyl group at the 3-position and a substituent bonded at the 8-position via an oxygen atom, and a salt thereof have sGC activation, and are useful as active ingredients of pharmaceutical compositions for treating or preventing various sGC-related cardiovascular diseases, in particular, peripheral arterial diseases, intermittent claudication, critical limb ischemia, and hypertension (including pulmonary hypertension), thereby completing the present invention.
That is, the present invention relates to a compound of formula (I) or a salt thereof, and pharmaceutical compositions comprising the compound of formula (I) or a salt thereof and a pharmaceutically acceptable excipient.




[the symbols in the formula have the following meanings:
A1: R0, —R00-(aryl), halogeno-lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl,
R0: the same as or different from each other, and each representing lower alkyl,
R00: the same as or different from each other, and each representing lower alkylene,
R1: H, R0, halogen, —CN, —CO2H, —CO2R0, or —R00—OH,
R2: H, R0, C3-6 cycloalkyl, or halogeno-lower alkyl,
R3: H, R0, —R00—CO2H, or —R00—CO2R0,
R4: —Y-A2 or A3, or R3 and R4, together with N atom to which they are both bonded, may form a nitrogen-containing saturated heterocycle optionally substituted with at least one group selected from the group consisting of —OH, —R00—OH, —CO2H, —CO2R0, and phenyl,
Y: C1-10 alkylene optionally substituted with at least one group selected from Group G2, C2-10 alkenylene optionally substituted with at least one group selected from Group G2, or —SO2-(lower alkylene optionally substituted with at least one group selected from Group G2)-,
Group G2: —CO2H, —CO2R0, —OH, —OR0, —O—CO—R0, —OSi(R0)3, —NH2, —NHR0, —N(R0)2, —NH—CO—R0, —SR0, —CO—NH—SO2—R0, optionally substituted aryl, and optionally substituted heteroaryl,
A2: H, —OH, —O-(aryl), —CO—R0, —CO—R00—OH, —CO2—R00-(aryl), —CO—NH2, —CO—NHR0, —CO—N(R0)2, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl,
A3: H, cycloalkyl optionally substituted with at least one group selected from Group G1, heterocycloalkyl optionally substituted with at least one group selected from Group G1, aryl optionally substituted with at least one group selected from Group G1, or heteroaryl optionally substituted with at least one group selected from Group G1,
Group G1: R0, halogen-lower alkyl, —R00—OH, halogen, oxo, —NO2, —OH, —OR0, —O—R00—N(R0)2, —NH2, —CO—R0, —CO—R00—OH, —CO2H, —CO2R0, —CO—NH2, —CO—NHR0, —CO—N(R0)2, —CO2—R00-(phenyl), —SO2—R0, —SO2—NH2, —SO2—NHR0, —SO2—N(R0)2, —SO2—R00—CO2H, —SO2—R00—CO2R0, —SO2-(phenyl), —SO2—R00-(phenyl), —R00—CO2H, —R00—CO2R0, —R00—CO—NH2, —R00—CO—NHR0, —R00—CO—N(R0)2, —R00—NH2, —R00—NHR0, —R00-—N(R0)2, —R00-(phenyl), —R00-(phenylene)-R0, —R00-(cycloalkyl), —R00-(heterocycloalkyl), —R00-(monocyclic nitrogen-containing heteroaryl), cycloalkyl, phenyl, -(phenylene)-R0, -(phenylene)-CO2H, -(phenylene)-CO2R0, -(pyridinediyl)-CO2H, -(pyridinediyl)-CO2R0, -(piperidinediyl)-R0, -(phenylene)-R00—CO2H, —R00-(phenylene)-CO2H, —R00-(phenylene)-CO2R0, monocyclic nitrogen-containing heteroaryl, and heterocycloalkyl, and
R5: the same as or different from each other, and each representing H or R0,
provided that the compound of the formula (I) is neither 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxamide nor 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl](piperazin-1-yl)methanone)].
Furthermore, unless specifically described otherwise, when symbols in one formula in the present specification are also used in other formulae, same symbols denote same meanings.
Moreover, the present invention relates to pharmaceutical compositions for treating sGC-related cardiovascular diseases, which include compound of formula (I) or a salt thereof. Further, said pharmaceutical compositions include agents for treating sGC-related cardiovascular diseases, which includes compounds of the formula (I) or a salt thereof.
The present invention further relates to use of compound of formula (I) or a salt thereof for preparation of pharmaceutical compositions for treating or preventing sGC-related cardiovascular diseases, use of compound of formula (I) or a salt thereof for treating or preventing sGC-related cardiovascular diseases, compound of the formula (I) or a salt thereof for treating or preventing sGC-related cardiovascular diseases, and methods for treating or preventing sGC-related cardiovascular diseases, comprising administering to a subject an effective amount of compound of formula (I) or a salt thereof. In this regard, the “subjects” refer to humans or other animals in need of the prevention or treatment, and in a certain embodiment, humans in need of the prevention or treatment.
Effects of the Invention
Compound of formula (I) has an sGC activation and can be used as active ingredients of pharmaceutical compositions for treating or preventing sGC-related cardiovascular diseases, for example, hypertension, atherosclerosis, lumbar spinal canal stenosis, peripheral arterial diseases, intermittent claudication, critical limb ischemia, stable or unstable angina pectoris, heart failure, thrombosis, stroke, sexual dysfunction, pulmonary hypertension, or the like.


EMBODIMENTS FOR CARRYING OUT THE INVENTION
Hereinbelow, the present invention will be described in detail.
In the present specification, the “cardiovascular disease” refers to a disease based on the abnormal symptoms of circulatory organs such as heart, blood vessels, and the like. Among these, the “sGC-related cardiovascular disease” is known to be involved in an NO/sGC/cGMP system, and is a cardiovascular disease that can be treated or prevented by sGC activation. Examples thereof include hypertension (including pulmonary hypertension), atherosclerosis, lumbar spinal canal stenosis, peripheral arterial disease, intermittent claudication, critical limb ischemia, stable or unstable angina pectoris, heart failure, thrombosis, stroke, sexual dysfunction, and the like. In another embodiment, the “sGC-related cardiovascular disease” is intermittent claudication and critical limb ischemia caused by peripheral arterial diseases. In another embodiment, it is intermittent claudication caused by peripheral arterial diseases, and in another embodiment, critical limb ischemia caused by peripheral arterial diseases.
Here, examples of the peripheral arterial diseases include occlusive thrombotic vasculitis, peripheral arterial occlusive disease, Raynaud's disease, and Raynaud's syndrome.
The “peripheral arterial disease” is a disorder in which stenosis and occlusions caused by atherosclerosis, thrombosis and other impairments produce deficient blood flow, especially in the lower limbs. The symptoms are cold leg or feet, intermittent claudication, lower limb pain and critical limb ischemia (lower limb ulcers and necrosis). Diagnosis and treatment guidelines for peripheral arterial disease can be found in the following reference.

    Eur. J. Vasc. Endovasc. Surg, 2007, 33(1), S1


“Intermittent claudication” means in one embodiment, intermittent claudication caused by peripheral arterial diseases, and in another embodiment intermittent claudication caused by peripheral arterial occlusive disease.
“Critical limb ischemia” means in one embodiment, critical limb ischemia caused by peripheral arterial diseases, and in another embodiment critical limb ischemia caused by peripheral arterial occlusive disease.
Further, the “sGC-related cardiovascular disease” means in one embodiment, hypertension or pulmonary hypertension.
The “hypertension” means, in a one embodiment, essential hypertension, abnormal circadian blood pressure variability, renal parenchymal hypertension, renovascular hypertension, primary aldosteronism, Cushing's syndrome, hibernoma, or hypertension associated with endocrine diseases. The “pulmonary hypertension” is, in a certain embodiment, pulmonary arterial pulmonary hypertension, pulmonary hypertension associated with heart diseases, pulmonary hypertension associated with lung diseases such as chronic obstructive pulmonary diseases or interstitial lung diseases, or pulmonary hypertension associated with chronic thrombotic or obstructive diseases.
The “lower alkyl” is a monovalent group formed by the removal of any one hydrogen atom from a linear or branched saturated hydrocarbon having 1 to 6 carbon atoms (hereinafter simply referred to as C1-6), and it is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or the like, in another embodiment, C1-4 alkyl, and in a still another embodiment, methyl, ethyl, n-propyl, or isopropyl.
The “C1-10 alkylene” is a divalent group formed by the removal of any two hydrogen atoms from a linear or branched saturated hydrocarbon having 1 to 10 carbon atoms, and it is, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene, or the like, in another embodiment, methylene or ethylene, and in still another embodiment, methylene.
The “lower alkylene” means “C1-6 alkylene” among the “C1-10 alkylene” above, and it is, in a certain embodiment, methylene, ethylene, trimethylene, or the like, and in another embodiment, methylene or ethylene.
The “C2-10 alkenylene” is a divalent group formed by the removal of any two hydrogen atoms from a linear or branched hydrocarbon having a double bond and 2 to 10 carbon atoms. It is, in a certain embodiment, ethylidene, propenylene, or butenylene, in another embodiment, ethylidene, and in still another embodiment, trans-1,2-ethylidene.
The “cycloalkyl” is a C3-10 saturated hydrocarbon ring group, which may have a bridge, may be combined with another cycloalkyl to form a spiro ring, may partly have unsaturated bond and may be fused with a ring selected from a benzene ring, a furan ring, a thiophene ring, and a pyrrole ring. Examples of the “cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, indanyl, tetrahydronaphthyl, indanyl, indenyl, cyclohexenyl, spiro[3.5]nonyl, dihydrocyclopentathienyl, dihydrocyclopentafuranyl, dihydrocyclopentapyrrolyl, or the like. In a certain embodiment, “cycloalkyl” is a monocyclic C3-8 cycloalkyl, in another embodiment, cyclohexyl, and in still another embodiment, indanyl. Here, when fused with a pyrrole ring, the cycloalkyl is fused to a carbon-carbon bond of the pyrrole ring.
The “halogen” is F, Cl, Br, or I, and in a certain embodiment, F or Cl.
The “halogeno-lower alkyl” is C1-6 alkyl substituted with one or more halogen atoms, in a certain embodiment, C1-6 alkyl substituted with 1 to 5 halogen atoms, and in another embodiment, difluoromethyl or trifluoromethyl.
The “aryl” is a C6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, in a certain embodiment, phenyl or naphthyl, and in another embodiment, phenyl.
The “heteroaryl” means a 5- to 14-membered, monocyclic to tricyclic aromatic heterocyclic group containing 1 to 6 hetero atoms selected from N, O, and S as a ring-constituting atom. The “heteroaryl” is, in a certain embodiment, monocyclic heteroaryl, for example, pyridyl, pyrimidinyl, triazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, or the like, in another embodiment, bicyclic heteroaryl, for example, indolyl, quinolyl, quinoxalinyl, or the like, and in still another embodiment, pyridyl, thienyl, or indolyl.
The “nitrogen-containing saturated heterocycle” is a 5- to 8-membered saturated heterocycle that contains one nitrogen atom as a ring-constituting atom and may further contain one or two hetero atoms selected from N, O, and S, and it may be fused with a benzene ring. Examples of the nitrogen-containing saturated heterocyclic group include azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, azepanyl, diazepanyl, azocanyl, morpholinyl, thiomorpholinyl, tetrahydropyridinyl, and groups formed by fusion of any one of these ring groups with a benzene ring. The nitrogen-containing saturated heterocyclic group is, in another embodiment, pyrrolidinyl, piperidyl, piperazinyl, or indolin-1-yl, and in still another embodiment, pyrrolidinyl or indolin-1-yl.
The “monocyclic nitrogen-containing heteroaryl” means a monocycle containing a nitrogen atom as a ring-constituting atom among the “heteroaryl” above, and it is, in a certain embodiment, pyridyl, pyrimidinyl, thiazolyl, pyrazolyl, or oxadiazolyl, and in another embodiment, pyridyl.
The “heterocycloalkyl” is a 3- to 14-membered, saturated or partially unsaturated heterocyclic group that contains 1 to 6 hetero atoms selected from N, O, and S as a ring-constituting atom, and it may be bridged or fused. The “heterocycloalkyl” is, in a certain embodiment, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolyl, piperazinyl, morpholinyl, thiomorpholyl, oxazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, indolinyl, dihydrobenzofuranyl, or quinuclidinyl, and in another embodiment, pyrrolidinyl, piperidyl, or indolinyl.
The expression “optionally substituted” means non-substitution or substitution with 1 to 5 substituents. It is, in a certain embodiment, non-substitution or substitution with 1, 2, or 3 substituents, in another embodiment, non-substitution or substitution with 1 or 2 substituents, in still another embodiment, non-substitution or substitution with one substituent, in a further still another embodiment, substitution with two substituents, in a further still another embodiment, substitution with one substituent, and in a further still another embodiment, non-substitution. If it has a plurality of substituents, the substituents may be the same as or different from each other.
Examples of substituents of the “optionally substituted cycloalkyl”, “optionally substituted heterocycloalkyl”, “optionally substituted aryl”, or “optionally substituted heteroaryl” in A1 include, in a certain embodiment, a group selected from the group consisting of halogen, —CN, lower alkyl, and halogeno-lower alkyl. A1 is, in a certain embodiment, cycloalkyl, heterocycloalkyl optionally substituted with one or more F atoms, aryl optionally substituted with one or more F atoms, or heteroaryl optionally substituted with one or more F atoms. Further, A1 is, in another embodiment, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
Examples of the substituents of the “optionally substituted cycloalkyl”, “optionally substituted heterocycloalkyl”, “optionally substituted aryl”, and “optionally substituted heteroaryl” in A2 include in a certain embodiment, a group selected from the group consisting of —OH, oxo, —OR0, —O—R00—CO2R0, —O—R00—CO2H, CO2H, —CO—R0, —NH2, —NHR0, —N(R0)2, —NH—R00—OH, —CO2H, —CO2R0, —SO2—R0, —R00—CO2H, CO2H, —R00—CO2R0, halogen, phenyl, morpholyl, (piperidyl optionally substituted with carboxy or alkoxycarbonyl), R0, and halogeno-lower alkyl. A substituent is in another embodiment, R0, halogen, or —CO2H, and in still another embodiment, —CO2H.
A substituted examples of the substituent of the “optionally substituted aryl” and “optionally substituted heteroaryl” in Group G2 is, in a certain embodiment, a group selected from the group consisting of R0, —OH, halogen, oxo, —CO2H, and —OR0. The substituent is, in another embodiment, methyl, F, Cl, or methoxy.
Group G2 is, in one embodiment, unsubstituted aryl and unsubstituted heteroaryl.
Certain embodiments of the present invention are shown below.
(1) The compound of formula (I) or a salt thereof, wherein A1 is cycloalkyl, or phenyl optionally substituted with one or more halogen atoms; in another embodiment, the compound of formula (I) or a salt thereof, wherein A1 is cyclohexyl, or phenyl optionally substituted with one or more F atoms; in still another embodiment, the compound of the formula (I) or a salt thereof, wherein A1 is cyclohexyl; in further still another embodiment, the compound of the formula (I) or a salt thereof, wherein A1 is phenyl optionally substituted with one or more F atoms; and in further still another embodiment, the compound of the formula (I) or a salt thereof, wherein A1 is cyclohexyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, or 2,3,6-trifluorophenyl.
(2) The compound of formula (I) or a salt thereof, wherein R1 is H.
(3) The compound of formula (I) or a salt thereof, wherein R2 is methyl.
(4) The compound of formula (I) or a salt thereof, wherein R3 is H.
(5) The compound of formula (I) or a salt thereof, wherein R4 is —Y-A2; and in another embodiment, the compound of formula (I) or a salt thereof, wherein R4 is A3.
(5-1) The compound of formula (I) or a salt thereof, wherein R4 is —Y-A2, and A2 is H, —OH, or —CONH2, or phenyl, pyridyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazolyl, isoxazolyl, isoxadiazolyl, tetrazolyl, quinoxalinyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, tetrahydropyranyl, tetrahydrothiopyranyl, quinuclidyl, or monocyclic C3-8 cycloalkyl, each of which is optionally substituted with at least one group selected from the group consisting of —OH, oxo, —OR0, —O—R00—CO2R0, —O—R00—CO2H, —CO—R0, —NH2, —NHR0, —N(R0)2, —NH—R00—OH, —CO2H, —CO2R0, —SO2—R0, —R00—CO2H, —R00—CO2R0, halogen, phenyl, morpholyl, (piperidyl optionally substituted with carboxy or alkoxycarbonyl), R0, and halogeno-lower alkyl; in another embodiment, the compound of formula (I) or a salt thereof, wherein R4 is —Y-A2, and A2 is H, pyridyl, or phenyl optionally substituted with at least one group selected from the group consisting of R0, halogen, and —CO2H; and in still another embodiment, the compound of formula (I) or a salt thereof, wherein R4 is —Y-A2, and A2 is H, pyridyl, or phenyl optionally substituted with —CO2H.
(5-2) The compound of formula (I) or a salt thereof, wherein R4 is —Y-A2, and Y is C1-10 alkylene optionally substituted with at least one group selected from Group G2, C2-10 alkenylene optionally substituted with at least one group selected from Group G2, or —SO2— (lower alkylene optionally substituted with at least one group selected from Group G2)-; in another embodiment, the compound of formula (I) or a salt thereof, wherein R4 is —Y-A2, and Y is C1-10 alkylene optionally substituted with at least one group selected from Group G2 or C2-10 alkenylene optionally substituted with at least one group selected from Group G2; in still another embodiment, the compound of formula (I) or a salt thereof, wherein R4 is —Y-A2, and Y is C1-6 alkylene optionally substituted with at least one group selected from Group G2. Here, Group G2 is, in a certain embodiment, phenyl, pyridyl, thienyl, cyclopentyl, cyclohexyl, —CO2H, —CO2R0, —OH, and —OR0, each of which is optionally substituted with at least one group selected from the group consisting of halogen, —OR0, and R0; in another embodiment, pyridyl, phenyl, and cyclohexyl; in still another embodiment, —CO2H, —CO2R0, —OH, and —OR0; and in a further still another embodiment, —CO2H, —CO2R0, and —OH.
(5-3) The compound of formula (I) or a salt thereof, wherein R4 is A3, and A3 is cycloalkyl or heterocycloalkyl; in another embodiment, the compound of formula (I) or a salt thereof, wherein R4 is A3 and A3 is heterocycloalkyl; in still another embodiment, the compound of formula (I) or a salt thereof, wherein R4 is A3 and A3 is cycloalkyl; in a further still another embodiment, the compound of formula (I) or a salt thereof, wherein R4 is A3, and A3 is pyrrolidyl optionally substituted with at least one group selected from Group G1, piperidyl optionally substituted with at least one group selected from Group G1, or piperazyl optionally substituted with at least one group selected from Group G1; in a further still another embodiment, the compound of formula (I) or a salt thereof, wherein R4 is A3, and A3 is monocyclic C3-8 cycloalkyl optionally substituted with at least one group selected from Group G1, or indanyl optionally substituted with at least one group selected from Group G1; in a further still another embodiment, the compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is piperidyl optionally substituted with at least one group selected from Group G1, or pyrrolidyl optionally substituted with at least one group selected from Group G1; and in a further still another embodiment, the compound of formula (I) or a salt thereof, wherein R4 is A3, and A3 is indanyl optionally substituted with at least one group selected from Group G1. Here, the compound of formula (I) or a salt thereof, wherein Group G1 includes, in a certain embodiment, R0, —R00—OH, halogen, oxo, —OH, —OR0, —CO—R0, —CO—R00—OH, —CO2H, —CO2R0, —CO—NH2, —CO2—R00-(phenyl), —SO2—R0, —SO2—NH2,
—SO2—NHR0, —SO2—R00—CO2H, —SO2—R00—CO2R0, —SO2-(phenyl), —R00—CO2H, —R00—CO2R0, —R00-(phenyl), cycloalkyl, phenyl, -(phenylene)-CO2R0, -(piperidinediyl)-R0, —R00-(phenylene)-CO2H, and —R00-(phenylene)-CO2R0; Group G1 is, in another embodiment, halogen, —OH, —CO2H, —CO2R0, —CO2—R00-(phenyl), —SO2—R00—CO2R0, —R00—CO2H, —R00—CO2R0, and phenyl; in still another embodiment, R0; in a further still another embodiment, halogen, R0, —CO2H, and —OH; in a further still another embodiment, halogen, R0, —CO2H, and —OH; and in a further still another embodiment, —OH, phenyl, and —SO2—NH2.
(5-4) The compound of formula (I) or a salt thereof, which is selected from a compound group including the following (5-5) and (5-6).
(5-5) The compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is heterocycloalkyl, and Group G1 is R0, —R00—OH, halogen, oxo, —OH, —OR0, —CO—R0, —CO—R00—OH, —CO2H, —CO2R0, —CO—NH2, —CO2—R00-(phenyl), —SO2—R0, —SO2—NH2, —SO2—NHR0, —SO2—R00—CO2H, —SO2—R00—CO2R0, —SO2-(phenyl), —R00—CO2H, —R00—CO2R0, —R00-(phenyl), cycloalkyl, phenyl, -(phenylene)-CO2R0, -(piperidinediyl)-R0, —R00-(phenylene)-CO2H, and —R00-(phenylene)-CO2R0.
(5-6) The compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is cycloalkyl, and Group G1 is R0, halogen, —OH, —CO2H, —CO2R0, —CO2—R00-(phenyl), —SO2—R00—CO2R0, —R00—CO2H, —R00—CO2R0, and phenyl.
(5-7) The compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is cycloalkyl, and Group G1 is halogen and R0.
(5-8) The compound of formula (I) or a salt thereof, wherein R4 is —Y-A2, Y is C1-10 alkylene, C2-10 alkenylene, or —SO2—R00—, Group G2 is —CO2H, —CO2R0, —OH, and —OR0, and A2 is H, —OH or —CONH2, or phenyl, pyridyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazolyl, isoxazolyl, isoxadiazolyl, tetrazolyl, quinoxazolyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, tetrahydropyranyl, tetrahydrothiopyranyl, quinuclidyl, or monocyclic C3-8 cycloalkyl, each of which is optionally substituted with at least one group selected from the group consisting of —OH, oxo, —OR0, —O—R00—CO2R0, —O—R00—CO2H, —CO—R0, —NH2, —CO2H, —CO2R0, —SO2—R0, R00—CO2H, halogen, phenyl, morpholyl, 4-carboxypiperidyl, 4-alkoxycarbonylpiperidyl, 3-alkoxycarbonylpiperidyl, 3-carboxypiperidyl, R0, and halogeno-lower alkyl.
(5-9) The compound of formula (I) or a salt thereof, which is selected from the group consisting of the following (5-10), (5-11), and (5-13).
(5-10) The compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is pyrrolidyl optionally substituted with at least one group selected from Group G1, piperidyl optionally substituted with at least one group selected from Group G1, or piperazyl optionally substituted with at least one group selected from Group G1, and Group G1 is R0.
(5-11) The compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is monocyclic C3-8 cycloalkyl optionally substituted with at least one group selected from Group G1, or indanyl optionally substituted with at least one group selected from Group G1, and Group G1 is halogen, —CO2H, and —OH.
(5-12-1) The compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is monocyclic C3-8 cycloalkyl or indanyl, each optionally substituted with at least one group selected from Group G1, and Group G1 is —CO2H, —OH, halogen, and R0.
(5-12-2) The compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is indanyl optionally substituted with at least one group selected from Group G1, and Group G1 is halogen, —CO2H, —CO2R0, —R00—OH, and —OH.
(5-12-3) The compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is tetrahydronaphthyl optionally substituted with at least one group selected from Group G1, and Group G1 is —CO2H and —CO2R0.
(5-12-4) The compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is dihydrobenzofuranyl optionally substituted with at least one group selected from Group G1, and Group G1 is —CO2H and —CO2R0.
(5-13) The compound of formula (I) or a salt thereof, wherein R4 is Y is C1-10 alkylene optionally substituted with at least one group selected from Group G2, or C2-10 alkenylene optionally substituted with at least one group selected from Group G2, Group G2 is —CO2H, —CO2R0, and —OH, and A2 is H, or phenyl optionally substituted with at least one group selected from the group consisting of R0, halogen, and —CO2H.
(5-14) The compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is a group represented by the following formula (A) or (B):




R6 is H, halogen, or lower alkyl, R7 is —CO2H, —CO2R0, —CN, —NO2, —SO3H, or —SO3R0, X is NH, NR0, O, S, or —HC═CH—, and n is 1 or 2.
(5-14-1) The compound or a salt thereof according to (5-14), wherein R4 is A3 and A3 is a group represented by the formula (A).
(5-14-2) The compound or a salt thereof according to (5-14), wherein R4 is A3 and A3 is a group represented by the formula (B).
(5-14-3) The compound or a salt thereof according to (5-14), wherein R4 is A3, A3 is a group represented by the formula (A) or the formula (B), and X is —HC═CH—.
(5-14-4) The compound or a salt thereof according to (5-14), wherein R4 is A3, A3 is a group represented by the formula (A), and X is S.
(5-14-5) The compound or a salt thereof according to (5-14), wherein R4 is A3, A3 is a group represented by the formula (B), and X is S.
(5-14-6) The compound or a salt thereof according to (5-14), wherein R4 is A3, A3 is a group represented by the formula (A) or the formula (B), X is —HC═CH—, and n is 1.
(5-14-7) The compound or a salt thereof according to (5-14), wherein R4 is A3, A3 is a group represented by the formula (A) or the formula (B), X is —HC═CH—, and n is 2.
(5-14-8) The compound or a salt thereof according to (5-14), wherein R4 is A3, A3 is a group represented by the formula (A) or the formula (B), X is —HC═CH—, and R6 is H, F, or methyl, in another embodiment, R6 is F or methyl, in still another embodiment, R6 is H, in still another embodiment, R6 is F, and in a further still another embodiment, R6 is methyl.
(5-14-9) The compound or a salt thereof according to (5-14), wherein R4 is A3, A3 is a group represented by the formula (A) or the formula (B), X is —HC═CH—, and R7 is —CO2H or —CO2R0, in still another embodiment, R7 is —CO2H, and in a further still another embodiment, R7 is —CO2R0.
(5-14-10) The compound or a salt thereof according to (5-14), wherein X is S or —HC═CH—.
(5-15) The compound of formula (I) or a salt thereof, wherein R4 is —Y-A2, —Y-A2 is a group represented by the following formula (C) or (D):




R8 is H or lower alkyl, and Ring Z is unsubstituted pyridyl.
(5-16) The compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is 1,3-dioxane optionally substituted with at least one group selected from Group G1, and Group G1 is phenyl optionally substituted with R0, R0, and pyridyl.
(5-17) The compound of formula (I) or a salt thereof, wherein R4 is —Y-A2, —Y-A2 is a group represented by the following formula (E):




and R9 is phenyl or lower alkyl.
(5-18) The compound of formula (I) or a salt thereof, wherein R4 is A3, A3 is a group represented by the following formula (F):




R10 is H or —OH, and R11 is H or —OH.
(5-19) The compound of formula (I) or a salt thereof, wherein R4 is —Y-A2, —Y-A2 is a group represented by the following formula (G):




and R12 is lower alkyl, cycloalkyl, or phenyl.
(6) The compound of the formula (I) or a salt thereof, wherein R5 is each H; and in another embodiment, the compound of the formula (I) or a salt thereof, wherein any one of R5's is H and another one is R0.
(7) The compound or a salt thereof, including the combinations of two or more of the groups as described in (1) to (4), (5) to (5-5), (5-9) to (5-12), (5-13), and (6).
(7-1) The compound or a salt thereof, including the combinations of two or more of the groups as described in (1) to (4), (5-6), (5-7), (5-12-1), (5-14), and (5-14-1) to (5-14-9).
(7-2) The compound or a salt thereof, including the combinations of two or more of the groups as described in (1) to (4), (5-12-2) to (5-12-4), (5-15-1), and (5-16) to (5-18).
Examples of the compound that is a combination of two or more of the groups as described in (1) to (6) include the following compounds or salts thereof.
(8) The compound of the formula (I) or a salt thereof, wherein R3 is H and R5 is each H.
(9) The compound or a salt thereof according to (8), wherein R2 is methyl and R1 is H.
(10) The compound or a salt thereof according to (9), wherein A1 is cyclohexyl or phenyl optionally substituted with one or more F atoms.
(11a) The compound or a salt thereof, which is selected from the compound group consisting of the following (11-1), (11-2), and (11-3).
(11-1) The compound or a salt thereof according to (10), wherein R4 is A3, A3 is pyrrolidyl optionally substituted with at least one group selected from Group G1 or piperidyl optionally substituted with at least one group selected from Group G1, and Group G1 is R0.
(11-2) The compound or a salt thereof according to (10), wherein R4 is A3, A3 is indanyl optionally substituted with at least one group selected from Group G1, and Group G1 is halogen, —CO2H, and —OH.
(11-3) The compound or a salt thereof according to (10), wherein R4 is —Y-A2, Y is C1-10 alkylene optionally substituted with at least one group selected from Group G2, Group G2 is —CO2H and —OH, and A2 is H, or phenyl optionally substituted with —CO2H.
(11b) The compound or a salt thereof, which is selected from the compound group consisting of (11-1), and the following (11-4) and (11-5).
(11-4) The compound or a salt thereof according to (10), wherein R4 is A3, A3 is indanyl optionally substituted with at least one group selected from Group G1, and Group G1 is halogen, R0, —CO2H, and —OH.
(11-5) The compound or a salt thereof according to (10), wherein R4 is —Y-A2, Y is C1-10 alkylene optionally substituted with at least one group selected from Group G2, Group G2 is —CO2H and —OH, and A2 is H, or phenyl optionally substituted with at least one group selected from the group consisting of R0, halogen, and —CO2H.
(11-6) The compound or a salt thereof according to (10), wherein R4 is —Y-A2, —Y-A2 is a group represented by the formula (C), and R8a is H.
(11-7) The compound or a salt thereof according to (10), wherein R4 is A3, A3 is cyclopentyl or piperidyl each of which is optionally substituted with at least one group selected from Group G1, and Group G1 is —OH, phenyl, and —SO2—NH2.
(11-8) The compound or a salt thereof according to (10), wherein R4 is A3, A3 is indanyl optionally substituted with at least one group selected from Group G1, and Group G1 is —CO2H and —OH.
(11-9) The compound of formula (I) or a salt thereof, wherein A1 is cyclohexyl, or phenyl optionally substituted with one or more F atom, R1 is H, R2 is R0, R3 is H, R5 is H, R4 is —Y-A2 or A3, Y is C1-10 alkylene optionally substituted with at least one group selected from Group G2, Group G2 is —CO2H and —OH, A2 is H, cycloalkyl, pyridyl, or phenyl optionally substituted with a group selected from lower alkyl and —CO2H, A3 is cycloalkyl selected from the group consisting of cyclopentyl, indanyl, dihydrocyclopentathienyl, dihydrocyclopentafuranyl, and dihydrocyclopentapyrrolyl, the above cycloalkyl is optionally substituted with at least one group selected from Group G1, or piperidyl or pyrrolidyl each optionally substituted with at least one group selected from Group G1, and Group G1 is R0, halogen, —CO2H, —OH, —CO2R0, —CN, —NO2, phenyl, —SO2—NH2, —SO3H, and —SO3R0.
(12) The compound of formula (I) or a salt thereof, wherein A1 is cycloalkyl optionally substituted or aryl optionally substituted, R1 is H, R0, halogen, —CN, —CO2H, —CO2R0, or —R00—OH, R2 is H, R0, or halogeno-lower alkyl, R3 is H, R0, —R00—CO2H, or —R00—CO2R0, R4 is A3, A3 is a group represented by the formula (A) or (B), R6 is H, halogen, or lower alkyl, R7 is —CO2H, —CO2R0, —CN, —NO2, —SO3H, or —SO3R0, X is NH, NR0, O, S, or —HC═CH—, and n is 1 or 2.
(12-1) The compound or a salt thereof as described in (11-9), wherein A1 is cyclohexyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, or 2,3,6-trifluorophenyl, R4 is a group represented by any one of the following formulae (A), (B), (C), (D), (E), (F), or (G):




wherein R6 is H, halogen, or R0, R7 is —CO2H, —CO2R0, —CN, —NO2, —SO3H, or —SO3R0, X is NH, NR0, O, S, or —HC═CH—, n is 1 or 2, R8 is H or lower alkyl, Z is pyridyl, R9 is phenyl or lower alkyl, R10 is H or —OH, R11 is H or —OH, and R12 is lower alkyl, cycloalkyl, or phenyl.
(12-2) The compound of formula (I) or a salt thereof, wherein A1 is cyclohexyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, or 2,3,6-trifluorophenyl, R1 is H, R2 is R0, R3 is H, R4 is —Y-A2, Y is C1-10 alkylene optionally substituted with at least one group selected from Group G2, Group G2 is —CO2H and —OH, and A2 is H, or phenyl optionally substituted with —CO2H.
(12-2-1) The compound or a salt thereof as described in (12-1), wherein R2 is methyl and R4 is a group represented by the formula (C) or (D).
(12-2-2) The compound or a salt thereof as described in (12-1), wherein R2 is methyl and R4 is a group represented by the formula (E).
(12-3) The compound of formula (I) or a salt thereof, wherein A1 is cyclohexyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, or 2,3,6-trifluorophenyl, R1 is H, R2 is R0, R3 is H, R4 is A3, A3 is indanyl optionally substituted with at least one group selected from Group G1, and Group G1 is halogen, —CO2H, and —OH.
(12-4) The compound of formula (I) or a salt thereof, wherein A1 is cyclohexyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, or 2,3,6-trifluorophenyl, R1 is H, R2 is R0, R3 is H, R4 is A3, A3 is cyclopentyl or piperidyl, and Group G1 is —OH, phenyl, and —SO2—NH2.
(12-5) The compound of formula (I) or a salt thereof, wherein A1 is cyclohexyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, or 2,3,6-trifluorophenyl, R1 is H, R2 is R0, R3 is H, R4 is A3, R5 is H, A3 is indanyl optionally substituted with at least one group selected from Group G1, and Group G1 is —CO2H and —OH.
(13) The compound or a salt thereof as described in (12-1), wherein A1 is 2,6-difluorophenyl, R2 is methyl, R4 is A3, A3 is a group represented by the formula (A) or the formula (B), X is —HC═CH—, n is 1, R5 is each H, R6 is F or methyl, and R7 is —CO2H.
(14) The compound or a salt thereof as described in (13), wherein R6 is F.
(15) The compound or a salt thereof as described in (13), wherein R6 is methyl.
(16) The compound or a salt thereof as described in (12), wherein A1 is cycloalkyl, R1 is H, R2 is methyl, R3 is H, X is —HC═CH—, n is 1, R5 is each H, R6 is F or methyl, and R7 is —CO2H.
(17) The compound or a salt thereof as described in (16), wherein R6 is F.
(17-1) The compound or a salt thereof as described in (12-1), wherein A1 is cyclohexyl or 2,6-difluorophenyl, R2 is methyl, R4 is A3, A3 is a group represented by the formula (A) or the formula (B), X is —HC═CH—, n is 1, R5 is each H, R6 is H, and R7 is —CO2H.
(18) The compound or a salt thereof as described in (16), wherein R6 is methyl.
(19) The compound of formula (I) or a salt thereof, wherein A1 is 2,3,6-trifluorophenyl, R1 is H, R2 is methyl, R3 is H, R4 is A3, A3 is a group represented by the formula (A) or the formula (B), X is —HC═CH—, n is 1, R5 is each H, R6 is H, and R7 is —CO2H.
(20) The compound of formula (I) or a salt thereof, wherein A1 is cycloalkyl, R1 is H, R2 is methyl, R3 is H, R4 is A3, A3 is a group represented by the formula (A) or the formula (B), X is —HC═CH—, n is 1, R5 is each H, R6 is H, and R7 is —CO2H.
(21) The compound of formula (I) or a salt thereof, wherein A1 is 2,6-difluorophenyl, R1 is H, R2 is methyl, R3 is H, R4 is A3, A3 is a group represented by the formula (A) or the formula (B), X is —HC═CH—, n is 1, R5 is each H, R6 is H, and R7 is —CO2H.
(22) The compound or a salt thereof as described in (12-1), wherein R2 is methyl and R4 is a group represented by the formula (F).
(23) The compound of or a salt thereof as described in (12-1), wherein R2 is methyl and R4 is a group represented by the formula (G).
Examples of the specific compounds included in the present invention are the following compounds.
Compounds or salts thereof selected from the group consisting of:

    (3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-3-phenylpropanoic acid,
    (1S,2R)-1-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]indane-2-carboxylic acid,
    (1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)indane-2-carboxylic acid,
    (1R,2S)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)indane-2-carboxylic acid,
    8-[(2,6-difluorobenzyl)oxy]-N-(1,3-dihydroxy-2-phenylpropan-2-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
    (1S,2R)-1-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-7-fluoroindane-2-carboxylic acid,
    (1S,2R)-1-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-4-methylindane-2-carboxylic acid,
    (1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-fluoroindane-2-carboxylic acid,
    (1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-7-fluoroindane-2-carboxylic acid,
    (1R,2S)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-7-fluoroindane-2-carboxylic acid,
    (1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-4-methylindane-2-carboxylic acid,
    (1S,2R)-1-[({2-methyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridin-3-yl}carbonyl)amino]indane-2-carboxylic acid,
    8-[(2,6-difluorobenzyl)oxy]-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
    8-[(2,6-difluorobenzyl)oxy-N-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
    8-[(2,3-difluorobenzyl)oxy]-N-(1,3-dihydroxy-2-phenylpropan-2-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
    8-[(2,6-difluorobenzyl)oxy]-N-[1,3-dihydroxy-2-(pyridin-2-yl)propan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
    8-(cyclohexylmethoxy)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
    8-[(2,6-difluorobenzyl)oxy]-N-[(2R)-1-hydroxypropan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
    8-[(2,6-difluorobenzyl)oxy]-N-[(2R)-1-hydroxy-3-methylbutan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, and
    N-(1,3-dihydroxy-2-phenylpropan-2-yl)-8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.


Furthermore, the following compounds are examples of specific compounds included in the present invention.
Compounds or salts thereof selected from the group consisting of:

    8-[(2,6-difluorobenzyl)oxy]-N-[(1R,2S,3S)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
    8-[(2,3-difluorobenzyl)oxy]-N-[(1R,2S,3S)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, and
    N-[(1R,2S,3S)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]-8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.


Still further, the following compounds are examples of specific compounds included in the present invention.
Compounds or salts thereof selected from the group consisting of:

    8-[(2,6-difluorobenzyl)oxy]-N-[(1R,2S,3R)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
    8-[(2,3-difluorobenzyl)oxy]-N-[(1R,2S,3R)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, and
    N-[(1R,2S,3R)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]-8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.


Still further, the following compounds are examples of specific compounds included in the present invention.
Compounds or pharmaceutically acceptable salts thereof selected from the group consisting of:

    8-[(2,6-difluorobenzyl)oxy]-N-[(1r,3R,4S)-3,4-dihydroxy-1-phenylcyclopentyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide and
    8-[(2,6-difluorobenzyl)oxy]-N-[(1s,3R,4S)-3,4-dihydroxy-1-phenylcyclopentyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.


Still further, the following compounds are examples of specific compounds included in the present invention.
Compounds or salts thereof selected from the group consisting of:

    8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-1-methylpiperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide,
    (3R)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-methylhexanoic acid,
    8-(cyclohexylmethoxy)-N-(1,3-dihydroxypropan-2-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
    8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-1-methylpyrrolidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide,
    3-[(1S)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid,
    8-[(2,6-difluorobenzyl)oxy]-N-(1-hydroxy-2-methylpropan-2-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
    8-[(2,6-difluorobenzyl)oxy]-N-[(1R,2S)-2,3-dihydroxy-1-phenylpropyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
    (3R)-4-cyclobutyl-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)butanoic acid,
    8-[(2,6-difluorobenzyl)oxy]-2-methyl-N-[(3S)-1-sulfamoylpiperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide, and
    8-[(2,6-difluorobenzyl)oxy]-2-methyl-N-[(3S)-piperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide.


The compound of formula (I) may exist in the form of tautomers or geometrical isomers depending on the kind of substituents. In the present specification, the compound of formula (I) shall be described in only one isomer form, yet the present invention includes any other isomers, in their isolated form, or as mixtures thereof.
In addition, the compound of formula (I) may have asymmetric carbon atoms or axial asymmetries in some cases, and therefore, optical isomers may exist based thereon. The present invention includes both isolated forms of optical isomers of the compound of formula (I) or any mixture thereof.
Moreover, the present invention also includes a pharmaceutically acceptable prodrugs of the compound of formula (I). Pharmaceutically acceptable prodrugs are compounds having groups that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like through solvolysis or under physiological conditions. Examples of the group forming the prodrug include the groups described in Prog. Med., 5, 2157-2161 (1985) and “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), Vol. 7, Drug Design, 163-198.
Furthermore, salts of the compound of formula (I) are pharmaceutically acceptable salts of the compound of formula (I) and may form an acid addition salt or a salt with a base depending on the kind of substituents. Specific examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditolyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like or organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like, salts with various amino acids or amino acid derivatives such as acetylleucine and the like, ammonium salts, etc.
In addition, the present invention also includes various hydrates or solvates, and polymorphic crystalline substances of the compound of formula (I) or d a salt thereof. In addition, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
(Preparation Methods)
The compound of formula (I) and salts thereof can be prepared using the characteristics based on the basic structure or the type of substituents thereof and by applying various known synthesis methods. During the preparation, replacing the relevant functional group with a suitable protective group (a group that can be easily converted into the relevant functional group) at the stage from starting material to an intermediate may be effective depending on the type of the functional group in the production technology in some cases. The protective group for such a functional group may include, for example, the protective groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)”, P. G. M. Wuts and T. W. Greene, and one of these may be selected and used as necessary depending on the reaction conditions. In this kind of method, a desired compound can be obtained by introducing the protective group, by carrying out the reaction and by eliminating the protective group as necessary.
In addition, prodrugs of the compound of formula (I) can be prepared by introducing a specific group or by carrying out the reaction using the obtained compound of formula (I) at the stage from a starting material to an intermediate, just as in the case of the above-mentioned protective group. The reaction can be carried out using methods known to a person skilled in the art, such as ordinary esterification, amidation, dehydration, and the like.
Hereinbelow, representative preparation methods for the compound of formula (I) will be described. Each production process may also be carried out with reference to the References appended in the present description. Further, the preparation methods of the present invention are not limited to the examples as shown below.
(General Production Processes)
(Production Process 1)




The compound of formula (I) can be prepared by reacting compound (II) with compound (III).
In this production process, compound (II) and compound (III) are used in equivalent amounts, or either thereof in an excess amount, and their mixture is stirred in a range of from cooling to heating, preferably at a temperature from −20° C. to 60° C., usually for about 0.1 hours to 5 days, in a solvent which is inert to the reaction, in the presence of a condensing agent. The solvent hereinused is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane, and the like, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetonitrile, or water, and any mixture thereof. Examples of condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), dicyclohexylcarbodiimide (DCC), 1,1′-carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), and phosphorous oxychloride. In some cases, it may be preferable for the reaction to use an additive (for example, 1-hydroxybenzotriazole (HOBt)). It is in some cases advantageous for smooth progress of the reaction to carry out the reaction in the presence of organic bases such as triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), and the like, or inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, and the like.
Furthermore, it is also possible to use a method in which compound (II) is converted to a reactive derivative and afterward reacted with compound (III). Examples of reactive derivatives of compound (II) include acid halides that can be obtained by the reaction with a halogenating agent such as phosphorus oxychloride, thionyl chloride, and the like, mixed acid anhydrides obtained by the reaction with isobutyl chloroformate or the like, active esters obtained by condensation with 1-hydroxybenzotriazole or the like, etc. The reaction of these reactive derivatives with compound (III) can be carried out in a range of from cooling to heating, and preferably from −20° C. to 60° C., in a solvent which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, and the like. For this reaction, for example, the following references may be referred to.

    “Organic Functional Group Preparations”, S. R. Sandler and W. Karo, 2nd edition, Vol. 1, Academic Press Inc., 1991
    The Chemical Society of Japan, “Courses in Experimental Chemistry (5th edition)” Vol. 16 (2005) (Maruzen)


In addition, further compounds of formula (I) can also be prepared from the compound of formula (I) prepared by this Production Process (for details, Examples as described later may be referred to).
(Production Process 2)




(wherein L represents a leaving group, for example, halogen).
Furthermore, the compound of formula (I) can be prepared by reacting compound (IV) with compound (Va) or compound (Vb).
Examples of the preparation method using compound (Va) include methods in which known diazocarboxylic esters or diazocarboxylic amides are used in combination with phosphines, (tributylphosphoraniliden)acetonitrile (Tsunoda reagent), or the like. These are the so-called Mitsunobu reaction, or any modified method thereof. These reactions are known to the skilled in the art.
In this reaction, compound (IV) and compound (Va) are used in equivalent amounts, or in an excess amount for either thereof, and their mixture is stirred in a range of from cooling to heating under refluxing, preferably at a temperature from 0° C. to 150° C., usually for about 0.1 hours to 5 days, in a solvent which is inert to the reaction. The solvent as used herein is not particularly limited, but examples thereof include, aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMSO, ethyl acetate, acetonitrile, and a mixture thereof.
For this reaction, for example, the following references may be referred to.

    Mitsunobu, O.; Synthesis (1981), 1
    Tsunoda, T. et al., Tetrahedron Letters (1995) 36, 2529, ibid, (1996) 37, 2463


On the other hand, when compound (Vb) is used, compound (IV) and compound (Vb) are used in equivalent amounts, or in an excess amount for either thereof, and their mixture is stirred in a range of from cooling to heating and refluxing, preferably at a temperature from 0° C. to 80° C., usually for about 0.1 hours to 5 days, in a solvent which is inert to the reaction, in the presence of a base. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, and any mixture thereof. Examples of bases include organic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, and the like, and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydride, potassium tert-butoxide, and the like. It may be advantageous in some cases to carry out the reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride, and the like.
For this reaction, for example, the following references may be referred to.

    “Organic Functional Group Preparations”, S. R. Sandler and W. Karo, 2nd edition, Vol. 1, Academic Press Inc., 1991
    The Chemical Society of Japan, “Courses in Experimental Chemistry (5th edition)” Vol. 14 (2005) (Maruzen)


(Starting Material Synthesis)




(wherein R is lower alkyl or the like, for example, methyl or ethyl).
The starting material compound (II) can be prepared by hydrolyzing compound (VIII) which is prepared by reacting compound (VI) with compound (VII).
The reaction for preparing the compound (VIII) can be carried out with the same reaction solvent and temperature as in Production Process 1 (for details, Examples as described later may be referred to).




(wherein P is a protective group, for example, benzyl).
The starting material compound (IV) can be prepared by reacting compound (IX) and compound (III) to prepare compound (X), which is thus subjected to deprotection. The reaction of compound (IX) with compound (III) can be carried out in the same way as in Production Process 1. Further, the deprotection can be carried out by known methods or those obvious to the skilled in the art.
The compounds of formula (I) can be isolated and purified as free compounds, salts, hydrates, solvates, or polymorphic crystalline substances thereof. Salts of the compound of formula (I) can be prepared by conventional salt forming reactions.
Isolation and purification are carried out by employing ordinary chemical operations such as extraction, fractional crystallization, fractional chromatography, and the like.
Various isomers can be prepared by selecting appropriate starting compounds or by separation using the difference in physicochemical properties between the isomers. For example, optical isomers can be obtained by means of a general optical resolution method for racemic products (for example, fractional crystallization for inducing diastereomer salts with optically active bases or acids, chromatography using a chiral column or the like, and others), and further, the isomers can also be prepared from an appropriate optically active starting compound.
TEST EXAMPLES
Pharmacological activities of the compound of formula (I) were confirmed in the following tests.
Test Example 1
Measurement of sGC Activation (Enzyme)
The activity of sGC was evaluated by measuring the amount of a cyclic guanosine monophosphate (cGMP) which is produced by human purified sGC.
A test compound was dissolved in DMSO and diluted 20-fold with ultrapure water. 2 μL of the diluted test compound solution (maximum concentration 100 μM), 2 μL of a substrate solution [0.5 μM TEBA, 0.03 μM dithiothreitol, 0.01 μM GTP, 0.04 μM MgCl2, and 0.03 μM sodium nitroprusside (SNP)], and 6 μL of a human enzyme suspension were added to 384-well plates (manufactured by Greiner Bio-One), and incubated at room temperature for one hour. The quantitative determination of cGMP is using HTRF which based on the competition between sample cGMP and fluorescent dye labeled cGMP for binding to a cGMP-specific antibody.
The test results of some Example compounds that are the compounds of the formula (I) of the present invention are shown below. The sGC activation of the test compound was calculated by taking the activation when the compound was not added as 100%. As compared with the activation when the compound was not added, it was recognized that a compound having a sGC activation of more than 300% has sGC activation. In addition, in Tables, Ex represents Example number in which the test compound is described and the sGC activation [%] represents sGC activation (%).
Furthermore, the EC50 [μM] value was calculated as another parameter for expressing sGC activation. This parameter indicates the concentration of the evaluated compound giving 50% of a maximum activation, which is calculated based on the maximum activation that compound of Example 102 is added, which is taken as 100%. In this connection, when a known sGC activator, YC-1 (Lificiguat, [5-(1-benzyl-1H-indazol-3-yl)-2-furyl]methanol), was evaluated according to the above Test Example 1, its maximum activation was 52% of the maximum activation for compound of Example 102. Further, “−” means no evaluation.











TABLE 1







Ex
sGC activation [%]
EC50 [μM]




















Ex 12
—
3.0



Ex 102
—
2.8



Ex 104
>1000
—



Ex 110
>1000
—



Ex 119
—
2.9



Ex 126
—
11



Ex 179
—
2.7



Ex 205
>1000
—



Ex 244
>1000
—



Ex 226
>1000
6.7



Ex 247
—
2.4



Ex 251
>1000
6.1



Ex 259
>1000
—



Ex 321
>1000
4.5



Ex 323
—
13



Ex 341
 980
6.9



Ex 424
>1000
2.4



Ex 430
—
2.6



Ex 434
—
7.3



Ex 436
>1000
—



Ex 633
 830
—



Ex 693
>1000
17



Ex 695
>1000
—



Ex 698
>1000
19



Ex 699
>1000
15



Ex 702
>1000
6.2



Ex 704
>1000
11



Ex 705
—
11



Ex 706
>1000
4.7



Ex 759
—
2.2



Ex 760
—
5.9



Ex 766
—
17



Ex 767
—
3.0



Ex 772
—
5.4



Ex 776
—
15



Ex 778
—
6.3



Ex 797
—
8.9



Ex 798
—
8.6



Ex 822
—
5.6



Ex 828
—
7.6



Ex 829
—
2.7



Ex 834
—
4.1










Test Example 2
Blood Flow Increasing In Vivo
The hind limb blood flow in rats anesthetized with pentobarbital was measured by the following test method.
Wistar male rats were used. An administration liquid was prepared by adding N,N-dimethyl formamide, Polyethylene Glycol 400, TWEEN 80, a 0.5% methyl cellulose aqueous solution, a 0.5 M aqueous sodium bicarbonate solution, and 0.1 M hydrochloric acid to the test compound and dissolving the test compound in an appropriate manner depending on the compound. Thus prepared administration liquid was orally administered, and 2 hours later, the hind limb blood flow was measured using a laser blood flow imaging device (PIM II Integral) under anesthesia with intraperitoneal administration of 60 mg/kg of pentobarbital.
The compounds of Examples 244, 259, and 341 of the present invention each exhibited a blood flow increasing effect at a dose of 30 mg/kg. Further, the compounds of Examples 12, 102, 119, 179, 247, 251, 321, 424, 430, 693, 698, 699, 702, 704, 706, 759, 760, 767, and 834 each exhibited a blood flow increasing effect at a dose of 10 mg/kg.
Test Example 3
Measurement of Antihypertensive Effect In Vivo
Wistar male rats were used. Three days prior to administration of a drug, a cannula (PE-50, Becton, Dickinson and Company, Japan) filled with heparin physiological saline (200 U/mL, Ajinomoto Pharmaceuticals Co., Ltd.) was inserted and placed in the common carotid artery under anesthesia with intraperitoneal administration of 60 mg/kg of pentobarbital. The other end of the cannula was exposed to the back neck through the subcutaneous. After the recovery period, the placed cannula was connected to a pressure transducer (Life Kit DTS DX-100, Nihon Kohden Corporation) to record the blood pressure waveform through a Polygraph (AP-641G, Nihon Kohden Co., Ltd.) and PowerLab (ML870 PowerLab8/30 (AD Instruments Japan)). The heart rate was calculated using a heart rate measuring unit (AT-601G, Nihon Kohden Co., Ltd.). After stabilization of the blood pressure, the drug was orally administered to measure the blood pressure and the heart rates. The test compounds were administered by appropriately adding N,N-dimethylformamide, Polyethylene Glycol 400, TWEEN 80, a 0.5% aqueous methylcellulose solution, and a 0.5 M aqueous sodium bicarbonate solution, and 0.1 M hydrochloric acid therein according to the compounds and dissolving it.
The results from the measurement according to Test Example 3 are shown below according to the following criteria with a maximum value of the mean blood pressure reduction. A: <20 mmHg, B: 20 to 40 mmHg, and C: >40 mmHg










TABLE 1-1







Administration dose
Blood pressure



(mg/kg po)
reduction




















Ex 180
30
B



Ex 422
30
C



Ex 431
10
B



Ex 434
30
C



Ex 827
10
B










In Test Examples 1 and 2 above, it was confirmed in several Example compounds of the present invention that they have sGC activation and blood flow improving action. Accordingly, the compound of formula (I) can be used for treating sGC-related cardiovascular diseases, in particular, peripheral arterial diseases, as well as intermittent claudication and critical limb ischemia caused by the aforesaid peripheral arterial diseases or the like.
In addition, in Test Example 3 above, it was confirmed that in several Example compounds of the present invention that they have antihypertensive effect. Accordingly, the compound of formula (I) can be used for treating hypertension, or the like.
Pharmaceutical compositions containing one or more kinds of compound of formula (I) or a salt thereof as an active ingredient can be prepared using excipients that are usually used in the art, that is, excipients for pharmaceutical preparation, carriers for pharmaceutical preparation, and the like according to the methods usually used.
Administration can be accomplished either by oral administration via tablets, pills, capsules, granules, powders, solutions, and the like, or parenteral administration, such as injections such as intraarticular, intravenous, and intramuscular injections, suppositories, ophthalmic solutions, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalers, and the like.
Solid compositions for oral administration are used in the form of tablets, powders, granules, or the like. In such solid compositions, one or more active ingredient(s) are mixed with at least one inactive excipient. In a conventional method, the composition may contain inactive additives, such as lubricants, disintegrating agents, stabilizers, or solubilization assisting agents. If necessary, tablets or pills may be coated with sugar or s gastric- or enteric-soluble substances films.
Liquid compositions for oral administration comprises pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and also comprises generally used inert diluents, for example, purified water or ethanol (EtOH). In addition to the inert diluent, liquid compositions may also contain auxiliary agents, such as solubilization assisting agents, moistening agents, and suspending agents, sweeteners, flavors, aromatics, or antiseptics.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Examples of non-aqueous solvents include alcohols such as ethanol. Such compositions may further contain tonicity agents, antiseptics, moistening agents, emulsifying agents, dispersing agents, stabilizers, or solubilization assisting agents. These are sterilized, for example, by filtration through bacteria retaining filter, blendings of bactericide, or irradiation. In addition, these can also be used by preparing sterile solid compositions, and dissolving or suspending in sterile water or sterile solvents for injection prior to its use.
Agents for external use includes ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments, and the like. The agents contain generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
As transmucosal agents such as inhalers, transnasal agents, and the like, those in the form of a solid, liquid, or semi-solid state are used, and can be prepared in accordance with conventionally known methods. For example, known excipients, and furthermore pH adjusting agents, antiseptics, surfactants, lubricants, stabilizers, thickening agents, or the like may be appropriately added thereto. For their administration, appropriate devices for inhalation or blowing can be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with pharmaceutically acceptable carriers, using a known device or sprayer, such as a measured administration inhalation device, and the like. Dry powder inhalers or the like may be for single or multiple administration use, and dry powder or powder-containing capsules may be used. Alternatively, these may be pressurized aerosol spray which uses appropriate ejection agents, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, carbon dioxide, and the like.
For oral administration, daily dose is generally from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and more preferably from 0.1 to 10 mg/kg, per body weight, administered in one portion or in 2 to 4 separate portions. In the case of intravenous administration, daily dose is suitably administered from about 0.0001 to 10 mg/kg per body weight, once a day or two or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or two or more times a day. Doses are appropriately determined according to the individual according to the symptoms, age, gender, and the like.
Although varying depending on administration routes, dosage forms, administration sites, or the types of excipients and additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in a certain embodiment, 0.01 to 50% by weight of one or more kinds of the compound of formula (I) or a salt thereof, as the active ingredient.
The compound of formula (I) can be used in combination with various therapeutic or prophylactic agents for the diseases for which the compound of formula (I) is considered to be effective, as described above. The combined preparation may be administered simultaneously, or separately and continuously, or at a desired time interval. The preparations to be administered simultaneously may be a mixture, or may be prepared individually.
EXAMPLES
Hereinbelow, the preparation methods for the compound of formula (I) will be described in more detail with reference to Examples. The present invention is not limited to the compounds described in Examples as described below. Further, the production processes for the starting compounds will be described in Preparation Examples. The compound of formula (I) is prepared by using a combination of the preparation methods or a method apparent to a person skilled in the art, in addition to Production Processes described in Examples.
Moreover, the following abbreviations may be used in some cases in Examples, Preparation Examples, and Tables as described later.
PEx: Preparation Example number, Ex: Example number, Str: Structural formula, Dat: Physicochemical data (ESI+: ESI−MS [M+H]+ or ESI−MS [M]+; ESI−: ESI−MS [M−H]−; FAB+: FAB−MS [M+H]+ or FAB−MS [M]+; EI+: EI [M]+; APCI/ESI+: APCI/ESI−MS [M+H]+ or APCI/ESI−MS [M]+ (APCI/ESI means simultaneous measurement of APCI and ESI); A/E−:APCI/ESI−MS [M−H]− (APCI/ESI means simultaneous measurement of APCI and ESI); NMR: δ (ppm) of a peak in 1HNMR, and unless otherwise described, 400 MHz), Me: methyl, Et: ethyl, nPr: n-propyl, iPr: isopropyl, nBu: n-butyl, iBu: isobutyl, tBu: tert-butyl, cBu: cyclobutyl, cPr: cyclopropyl, neoPen: neopentyl, cPen: cyclopentyl, nHex: n-hexyl, cHex: cyclohexyl, cHep: cycloheptyl, cOct: cyclooctyl, Ph: phenyl, Bn: benzyl, Ac: acetyl, Boc: tert-butoxycarbonyl, Z: benzyloxycarbonyl, TBS: tert-butyldimethylsilyl, Syn: Preparation method (in which the number in the section of Syn indicates that the compound is prepared by the same method as the compound having the Preparation Example compound number or Example compound number. For example, for example, the compound of Ex2 in the section of Syn is prepared by the same method as the compound of Example 2; the compound of PEx2 in the section of Syn is prepared by the same method as the compound of Preparation Example 2; the compound of PEx1, 16 in the section of Syn is prepared by the same method as the compound of Preparation Example 1 followed by the same method as the Preparation Example 16), (cis) denotes that the relative configuration of the compound is a cis isomer, (trans) denotes that the relative configuration of the compound is a trans isomer, and (rac) denotes that the compound is a racemate, and the racemate is a mixture of an optically active body and its enantiomer (mirror image isomer) at a rate of 1:1, and means an optically inactive compound.
Furthermore, in the present specification, regarding to compounds with asymmetric carbons, when a substituent bonded to a chiral center has no notation regarding to its configuration, then it means that the configuration of the substituent has not been determined.
Furthermore, in the structural formulae in Tables as described later, when any substituent bonded to chiral centers is illustrated with a planar structure, and when there is no notation regarding the configuration of the substituent, then it means that the configuration of the substituent has not been determined.
Furthermore, for convenience, concentration mol/l is expressed as M. For example, a 1 M aqueous sodium hydroxide solution means a 1 mol/l aqueous sodium hydroxide solution.
Furthermore, the compounds of Preparation Example 29 to 100, 103, 108, 118 to 128, 132 to 134, 138, 141 to 164, 177, 202 to 238, and 241 to 277 and 202 to 279 were prepared in the same manner as the methods of Preparation Examples 1 to 28, 101 to 102, 104 to 107, 109 to 117, 129 to 131, 135 to 137, 139 to 140, and 165 to 201 as described later, and thus, they are described only in Tables as described later. For each Preparation Example Compounds, their chemical structures are shown in Tables 2 to 20 as described later and physicochemical data and preparation methods are shown in Tables 21 to 31 as described later.
Preparation Example 1
A suspension of 1 g of 5-methyl-2-nitropyridin-3-ol, 1.35 ml of (bromomethyl)cyclohexane, and 1.79 g of potassium carbonate in 10 ml of DMF was stirred at 78° C. for 12 hours. After leaving to be cooled at room temperature, to the reaction mixture were added water and hexane/ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.8 g of 3-(cyclohexylmethoxy)-5-methyl-2-nitropyridine.
Preparation Example 2
To a solution of 1.8 g of 3-(cyclohexylmethoxy)-5-methyl-2-nitropyridine in 16 ml of THF was added 325 mg of 10% palladium-carbon (wet), followed by stirring for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure to obtain 1.38 g of 3-(cyclohexylmethoxy)-5-methylpyridin-2-amine.
Preparation Example 3
To a solution of 2 g of 3-(cyclohexylmethoxy)pyridin-2-amine in 10 ml of acetic acid was added 1.90 g of N-bromosuccinimide over 30 minutes under ice-cooling, followed by stirring for 30 minutes under ice-cooling. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.25 g of 5-bromo-3-(cyclohexylmethoxy)pyridin-2-amine.
Preparation Example 4
To a solution of 1.38 g of 3-(cyclohexylmethoxy)-5-methylpyridin-2-amine in 24 ml of toluene were added 1.21 ml of ethyl 2-chloro-3-oxobutanoate and 1.23 ml of triethylamine, followed by stirring at 110° C. for 3 days. After leaving to be cooled at room temperature, water and diisopropyl ether were added thereto to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.52 g of ethyl 8-(cyclohexylmethoxy)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate.
Preparation Example 5
To 2.16 g of ethyl 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate were added 20 ml of THF, 40 ml of ethanol, and 20 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring for 4 days. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added thereto. The insoluble material was collected by filtration and dried to obtain 1.99 g of 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid.
Preparation Example 6
To a solution of 5.2 g of 8-(benzyloxy)-N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 70 ml of ethanol was added 1.0 g of 10% palladium-carbon (wet), followed by stirring for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered over Celite, the solvent was then evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To the obtained purified product were added hexane and diisopropyl ether, followed by stirring, and the resulting solid was collected by filtration and dried to obtain 3.5 g of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethyl]-8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Preparation Example 7
To a solution of 2 g of methyl 3-cyclopropyl-3-oxopropanoate in 20 ml of dichloromethane was added dropwise 1.24 ml of sulfuryl chloride under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction mixture was added water under ice-cooling, and chloroform was further added thereto to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.48 g of methyl 2-chloro-3-cyclopropyl-3-oxopropanoate.
Preparation Example 8
To a suspension of 300 mg of {4-amino-1-[(benzyloxy)carbonyl]piperidin-4-yl}acetic acid in 6 ml of methanol was added 150 μl of thionyl chloride, followed by stirring for 2 days. The reaction mixture was concentrated under reduced pressure, ether was added thereto, and the resulting solid was collected by filtration and dried to obtain 350 mg of benzyl 4-amino-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate hydrochloride.
Preparation Example 9
To a solution of 1.07 g of tert-butyl(diethoxyphosphoryl)acetate in 50 ml of THF was added 3.8 ml of a 1.12 M methylmagnesium bromide/THF solution, followed by stirring for 30 minutes. To the obtained reaction mixture was added a solution of 500 of n-pentanal in 5 ml of THF, followed by heating to reflux for 3 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ether to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 726 mg of tert-butyl (2E)-hepta-2-noate.
Preparation Example 10
To a solution of 1.3 ml of (1R)—N-benzyl-1-phenylethanamine in 15 ml of THF was added 3.7 ml of a 1.65 M n-butyllithium/hexane solution at −78° C., followed by stirring at the same temperature for 1 hour. Then, a solution of 710 mg of tert-butyl (2E)-hepta-2-noate in 5 ml of THF was slowly added dropwise at the same temperature, followed by stirring at the same temperature for 3 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by warming to room temperature, and ethyl acetate was added thereto to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.27 g of tert-butyl (3R)-3-{benzyl[(1R)-1-phenylethyl]amino}heptanoate. Further, the structure of the product was determined in accordance to a reference (Tetrahedron Asymmetry, 17 (2006) 1793-1811, and the like) by S. G. Davis, et al.
Preparation Example 11
To a solution of 1.15 g of tert-butyl (3R)-3-{benzyl[(1R)-1-phenylethyl]amino}heptanoate in 30 ml of methanol was added 450 mg of 10% palladium-carbon, followed by stirring overnight under a hydrogen atmosphere at 4 atm. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 460 mg of tert-butyl (3R)-3-aminoheptanoate.
Preparation Example 12
To a suspension of 510 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid in dichloromethane were added 0.30 ml of oxalyl dichloride and one drop of DMF under ice-cooling, followed by stirring at room temperature for 30 minutes, and the solvent was evaporated under reduced pressure to obtain 603 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid chloride hydrochloride.
Preparation Example 13
To a solution of 2 g of methyl 5-hydroxy-6-nitronicotinate, 1.62 ml of (2-fluorophenyl)methanol, and 3.99 ml of tributylphosphine in 40 ml of THF was added 2.54 ml of diethyl azodicarboxylate under ice-cooling, followed by stirring for 1 hour under ice-cooling and at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.58 g of methyl 5-[(2-fluorobenzyl)oxy]-6-nitronicotinate.
Preparation Example 14
To a solution of 2.5 g of methyl 5-[(2-fluorobenzyl)oxy]-6-nitronicotinate in 25 ml of THF were added 50 ml of ethanol, 25 ml of water, 218 mg of ammonium chloride, and 1.37 g of iron, followed by heating to reflux for 2 hours. After leaving to be cooled at room temperature, the reaction mixture was filtered over Celite, and to the filtrate were added a saturated aqueous sodium hydrogen carbonate solution and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain 2.25 g of methyl 6-amino-5-[(2-fluorobenzyl)oxy]nicotinate.
Preparation Example 15
To a suspension of 2.15 g of methyl 6-amino-5-[(2-fluorobenzyl)oxy]nicotinate in 43 ml of ethanol was added 1.09 ml of bromoacetone, followed by stirring at 80° C. for 4 hours. To the reaction mixture was added 1.09 ml of bromoacetone, followed by stirring at 80° C. for 4 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure, followed by extracting with ethyl acetate and washing with saturated brine. After drying over anhydrous magnesium sulfate and then filtering, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.39 g of methyl 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylate.
Preparation Example 16
To 350 mg of 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid were added 18 ml of ethanol and 200 μl of sulfuric acid, followed by heating to reflux overnight. Under reduced pressure, the solvent was removed by filtration to around one third of the amount thereof, and a saturated aqueous sodium hydrogen carbonate solution and chloroform were then added thereto to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 330 mg of ethyl 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylate.
Preparation Example 17
A mixture of 1 g of N-methyl-2-nitrobenzenesulfonamide, 2.3 g of tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate, 2.5 g of triphenylphosphine, 4.2 ml of diethyl azodicarboxylate, and 40 ml of toluene was stirred at 80° C. for 2 hours, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in chloroform was added silica gel, followed by filtration, and the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in 3 ml of dichloromethane was added 3 ml of trifluoroacetic acid, followed by stirring for 1 hour. The solvent was evaporated under reduced pressure, and an aqueous sodium carbonate solution and chloroform were then added thereto to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 890 mg of N-[(2R)-2-amino-2-phenylethyl]-N-methyl-2-nitrobenzenesulfonamide.
Preparation Example 18
To a solution of 200 mg of 8-(cyclohexylmethoxy)-N-(2,2-dimethoxyethyl)-2-methylimidazolo[1,2-a]pyridine-3-carboxamide in 2 mL of dioxane was added 6 M hydrochloric acid, followed by stirring for 7 hours. To the reaction mixture were added saturated brine and ethyl acetate to carry out a layer separation operation. To the obtained aqueous layer was added a 1 M aqueous sodium hydroxide solution, and the resulting solid was collected by filtration and dried to obtain 165 mg of 8-(cyclohexylmethoxy)-2-methyl-N-(2-oxoethyl)imidazolo[1,2-a]pyridine-3-carboxamide.
Preparation Example 19
To a solution of 160 mg of ethyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}piperidine-4-carboxylate in 1.5 mL of dichloromethane was added 0.7 mL of trifluoroacetic acid, followed by stirring for 1 hour. The solvent was evaporated under reduced pressure, and a saturated aqueous sodium carbonate solution and a chloroform-methanol mixed solution were added thereto in this order to carry out a layer separation operation. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 120 mg of ethyl 1-[(2R)-2-amino-2-phenylethyl]piperidine-4-carboxylate.
Preparation Example 20
To a solution of 1 g of (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl methanesulfonate in 5 mL of THF were added 0.4 mL of ethyl piperidine-4-carboxylate and 1 mL of diisopropylethylamine, followed by stirring at 70° C. for 14 hours, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 160 mg of ethyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}piperidine-4-carboxylate.
Preparation Example 21
To 223 mg of tert-butyl (2E)-3-(4-cyanophenyl)acrylate were added 12 mL of methanol, 5 ml of THF, 1 ml of an acetic acid solution, and 90 mg of 10% palladium-carbon in this order, followed by stirring for 3 hours under hydrogen at 3 atm. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to obtain 177 mg of tert-butyl 3-[4-(aminomethyl)phenyl]propanoate.
Preparation Example 22
To a solution of 280 mg of ethyl 2-(4-cyanophenyl)-2-methylpropanoate in 10 ml of ethanol were added 2 mL of 1 M hydrochloric acid and 120 mg of 10% palladium-carbon in this order, followed by stirring for 3 hours under a hydrogen atmosphere at 3 atm. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure and dried to obtain 345 mg of, ethyl 2-[4-(aminomethyl)phenyl]-2-methylpropanoate hydrochloride.
Preparation Example 23
A mixture of 1 g of tert-butyl (2-bromobenzyl)carbamate, 1.12 g of ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate, 16 mg of palladium acetate, 72 mg of dicyclohexyl(2′,6′-dimethoxybiophenyl-2-yl)phosphine, 1.5 g of potassium phosphate, and 20 mL of toluene was stirred at 100° C. for 5 days. To the reaction mixture was added ether, followed by filtration through silica gel. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 412 mg of ethyl (2E)-3-(2-{[(tert-butoxycarbonyl)amino]methyl}phenyl)acrylate.
Preparation Example 24
To a suspension of 320 mg of 60% sodium hydride in 4 mL of DMF were added 500 mg of ethyl(4-cyanophenyl)acetate and a solution of 0.41 mL of methyl iodide in 2 mL of DMF under ice-cooling, followed by stirring at room temperature for 1 day. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 280 mg of ethyl 2-(4-cyanophenyl)-2-methylpropanoate.
Preparation Example 25
To a solution of 1 g of (3S)-3-amino-2-hydroxyhexanoic acid hydrochloride in 10 mL of methanol was added 10 mL of a 4 M hydrogen chloride/dioxane solution, followed by stirring overnight, and the solvent was evaporated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added thereto to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 425 mg of methyl (2R,3S)-3-amino-2-hydroxyhexanoate and 130 mg of methyl (2S,3S)-3-amino-2-hydroxyhexanoate.
Preparation Example 26
To a solution of 500 mg of tert-butyl (3S)-piperidin-3-yl carbamate and 900 mg of [3-(methoxycarbonyl)phenyl]boric acid in 10 mL of dichloromethane were added Molecular Sieves 4A, 460 mg of copper (II) acetate, and 0.70 mL of triethylamine in this order, followed by stirring overnight. The reaction mixture was filtered over Celite, and then to the filtrate were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 380 mg of methyl 3-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}benzoate.
Preparation Example 27
To a solution of 300 mg of tert-butyl (3S)-piperidin-3-yl carbamate and 6 mL of N-methyl-2-pyrrolidone were added 310 mg of methyl 6-chloropyridine-2-carboxylate and 0.55 mL of diisopropylethylamine, followed by stirring at 130° C. overnight. After leaving to be cooled, to the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 215 mg of methyl 6-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridine-2-carboxylate.
Preparation Example 28
To 2.02 g of tert-butyl (3S)-piperidin-3-yl carbamate were added 4.86 g of sulfamide and 30 mL of dioxane, followed by stirring at 95° C. overnight. After leaving to be cooled, the solvent was evaporated under reduced pressure, and water and chloroform were added thereto to carry out a layer separation operation. The organic layer was washed with an aqueous citric acid solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue was added 30 mL of a 4 M hydrogen chloride-ethyl acetate solution, followed by stirring for 40 minutes. The resulting solid was collected by filtration and dried to obtain 1.51 g of (3S)-3-aminopiperidine-1-sulfonamide hydrochloride.
Preparation Example 101
To 2.36 g of 2a,3,4,8b-tetrahydronaphtho[1,2-b]azet-2(1H)-one was added 50 ml of a 10% hydrogen chloride/methanol solution, followed by stirring at 90° C. for 6 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure. To the obtained residue were added methanol and diethyl ether, and the insoluble material was collected by filtration and dried to obtain 3.08 g of methyl rac-(1S,2S)-1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylate hydrochloride.
Preparation Example 102
To a suspension of 750 mg of rac-(1R,2R)-1-[(tert-butoxycarbonyl)amino]indane-2-carboxylic acid in 15 ml of methanol was added 0.40 ml of thionyl chloride, followed by stirring overnight. The solvent was evaporated to about a half amount thereof under reduced pressure, to the obtained residue was added diethyl ether, and the insoluble material was collected by filtration and dried to obtain 512 mg of methyl rac-(1R,2R)-1-aminoindane-2-carboxylate hydrochloride.
Preparation Example 104
A mixture of 2.64 g of (2-bromo-5-methylphenyl)methanol, 246 mg of bis(dibenzylideneacetone)palladium, 2.95 ml of tert-butylacrylate, 442 mg of tris(2-methylphenyl)phosphine, 2.5 ml of triethylamine, and 24 ml of DMF was stirred at 100° C. for 24 hours. After leaving to be cooled at room temperature, water and ethyl acetate were added thereto to carry out a layer separation operation. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.32 g of tert-butyl (2E)-3-[2-(hydroxymethyl)-4-methylphenyl]acrylate.
Preparation Example 105
To a solution of 2.32 g of tert-butyl (2E)-3-[2-(hydroxymethyl)-4-methylphenyl]acrylate in 46 ml of THF were added 4.64 g of carbon tetrabromide and 3.67 g of triphenylphosphine under ice-cooling, followed by stirring at the same temperature for 2.5 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.73 g of tert-butyl (2E)-3-[2-(bromomethyl)-4-methylphenyl]acrylate.
Preparation Example 106
To a solution of 1.5 ml of (1R)—N-benzyl-1-phenylethanamine in 40 ml of THF was added 4.35 ml of n-butyllithium (1.62 M hexane solution) at −78° C., followed by stirring for 30 minutes. At the same temperature, a solution of 1.00 g of tert-butyl (2E)-3-[2-(bromomethyl)-4-methylphenyl]acrylate in 5 ml of THF was added thereto, followed by stirring for 1.5 hours. To the reaction mixture was added water, followed by warming to room temperature. The solvent was evaporated under reduced pressure and ethyl acetate was then added thereto to carry out a layer separation operation. The organic layer was washed with a 1 M aqueous citric acid solution, water, and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.17 g of tert-butyl (1S,2R)-1-{benzyl[(1R)-1-phenylethyl]amino}-5-methylindane-2-carboxylate. Further, the present Preparation Example is in accordance with the method described in a reference (Synlett, 1999, No. 12, 1919-1920 by D. A. Price).
Preparation Example 107
To 1.10 g of tert-butyl (1S,2R)-1-{benzyl[(1R)-1-phenylethyl]amino}-5-methylindane-2-carboxylate was added 30 ml of a 10% hydrogen chloride/methanol solution, followed by stirring at 60° C. for 5 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added thereto to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 828 mg of methyl S,2R)-1-{benzyl[(1R)-1-phenylethyl]amino}-5-methylindane-2-carboxylate.
Preparation Example 109
To a solution of 1.67 g of methyl (1S,2R)-1-{benzyl[(1R)-1-phenylethyl]amino}-6-methylindane-2-carboxylate in 27 ml of acetic acid was added 500 mg of 10% palladium-carbon (wet), followed by stirring for 18 hours under a hydrogen atmosphere at 4 atm. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. To the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution, chloroform, and methanol to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To a solution of the obtained purified product in methanol was added 3 ml of a 10% hydrogen chloride/methanol solution. The solvent was evaporated under reduced pressure to obtain 803 mg of methyl (1S,2R)-1-amino-6-methylindane-2-carboxylate hydrochloride.
Preparation Example 110
To a solution of 789 mg of tert-butyl (2E)-3-[2-(hydroxymethyl)-3-methylphenyl]acrylate in 16 ml of methanol was added 82 mg of nickel chloride (II). Then, 240 mg of sodium borohydride was added thereto under ice-cooling, followed by stirring for 4 hours under ice-cooling. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 790 mg of tert-butyl 3-[2-(hydroxymethyl)-3-methylphenyl]propanoate.
Preparation Example 111
To a solution of 770 mg of tert-butyl 3-[2-(hydroxymethyl)-3-methylphenyl]propanoate in 16 ml of dimethylsulfoxide were added 4 ml of triethylamine and 1.22 g of a sulfur trioxide pyridine complex, followed by stirring at room temperature for 5 hours. To the reaction mixture were added diluted hydrochloric acid and ethyl acetate to carry out a layer separation operation. The organic layer was sequentially washed with water, saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 707 mg of tert-butyl 3-(2-formyl-3-methylphenyl)propanoate.
Preparation Example 112
To a solution of 305 mg of tert-butyl 3-(2-formyl-3-methylphenyl)propanoate in 3 ml of THF 3 ml were added 298 mg of (S)-2-methyl-2-propanesulfinamide and 0.62 ml of tetraethyl orthotitanate, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into ice water and the insoluble material was filtered through Celite. To the filtrate was added chloroform to carry out a layer separation operation. The organic layer was washed with water and subsequentially with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 336 mg of tert-butyl 3-{2-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]-3-methylphenyl}propanoate.
Preparation Example 113
To a solution of 1.122 g of tert-butyl 3-{2-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]-3-fluorophenyl}propanoate (compound of Preparation Example 129) in 26.7 ml of THF was added 9.5 ml of lithium bis(trimethylsilyl)amide (1 M THF solution) at −78° C., followed by stirring at the same temperature for 8.5 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 390 mg of tert-butyl (1S,2R)-1-{[(S)-tert-butylsulfinyl]amino}-7-fluoroindane-2-carboxylate (Preparation Example 113a), and 130 mg of each of tert-butyl (1R,2R)-1-{[(S)-tert-butylsulfinyl]amino}-7-fluoroindane-2-carboxylate and tert-butyl (1S,2S)-1-{[(S)-tert-butylsulfinyl]amino}-7-fluoroindane-2-carboxylate (Preparation Example 113b and Preparation Example 113c).
Preparation Example 114
To a solution of 140 mg of tert-butyl (1S,2R)-1-{[(S)-tert-butylsulfinyl]amino}-7-methylindane-2-carboxylate in 9.1 ml of ethyl acetate was added 0.88 ml of a 4 M hydrogen chloride/ethyl acetate solution, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and to the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 88 mg of tert-butyl (1S,2R)-1-amino-7-methylindane-2-carboxylate.
Preparation Example 115
To 12 mg of tert-butyl (1S,2R)-1-{[(S)-tert-butylsulfinyl]amino}-7-fluoroindane-2-carboxylate (compound of Preparation Example 113a) was added 0.4 ml of a 10% hydrogen chloride/methanol solution, followed by stirring for 1 hour under ice-cooling. To the reaction mixture was added 1 ml of a 10% hydrogen chloride/methanol solution, followed by stirring at 50° C. for 6 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure, and then to the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 6 mg of methyl (1S,2R)-1-amino-7-fluoroindane-2-carboxylate.
Preparation Example 116
A suspension of 1 g of 2-bromothiophene-3-carbaldehyde, 3.8 ml of tert-butyl acrylate, 120 mg of palladium acetate, 420 mg of tetra-n-butylammonium bromide, and 610 mg of potassium carbonate in 10 ml of DMF was stirred at 100° C. overnight. After leaving to be cooled, the insoluble material was filtered through Celite, and to the filtrate were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 660 mg of tert-butyl (2E)-3-(3-formyl-2-thienyl)acrylate.
Preparation Example 117
To a solution of 650 mg of tert-butyl (2E)-3-(3-formyl-2-thienyl)acrylate in 15 ml of methanol was added 150 mg of 10% palladium-carbon, followed by stirring for 5 hours under a hydrogen atmosphere. After filtration through Celite, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 530 mg of tert-butyl 3-(3-formyl-2-thienyl)propanoate.
Preparation Example 129
tert-Butyl 3-{2-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]-3-fluorophenyl}propanoate was prepared using (S)-2-methyl-2-propanesulfinamide by the same method as in Preparation Example 112 as described above.
Preparation Example 130
tert-Butyl 3-(2-{(E)-[(tert-butylsulfinyl)imino]methyl}-3-fluorophenyl)propanoate as a racemate was prepared using 2-methyl-2-propanesulfinamide as a racemate by the same method as in Preparation Example 112 as described above.
Preparation Example 131
tert-Butyl 3-{2-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]-3-fluorophenyl}propanoate was prepared using (R)-2-methyl-2-propanesulfinamide by the same method as in Preparation Example 112 as described above.
Preparation Example 135
tert-Butyl rac-(1R,2R)-1-[(tert-butylsulfinyl)amino]-7-fluoroindane-2-carboxylate was prepared using tert-butyl 3-(2-{(E)-[(tert-butylsulfinyl)imino]methyl}-3-fluorophenyl)propanoate (compound of Preparation Example 130) as a racemate by the same method as in Preparation Example 113 as described above.
Preparation Example 136
tert-Butyl (1R,2S)-1-[(R)-tert-butylsulfinyl]amino-7-fluoroindane-2-carboxylate was prepared using tert-butyl 3-{2-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]-3-fluorophenyl}propanoate (compound of Preparation Example 131) by the same method as in Preparation Example 113 as described above. Further, the compound of Preparation Example 136 and the compound of Preparation Example 113a are enantiomers (mirror image isomers) with respect to each other.
Preparation Example 137
To a solution of 120 mg of tert-butyl (5R,6S)-4-{[(S)-tert-butylsulfinyl]amino}-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate (compound of Preparation Example 143) in 7 ml of ethyl acetate was added 0.7 ml of a 4 M hydrogen chloride/ethyl acetate solution, followed by stirring for 2 hours. The solvent was evaporated under reduced pressure, and then to the obtained residue was added diisopropyl ether. The insoluble material was collected by filtration and dried to obtain 80 mg of tert-butyl (5R,6S)-6-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate hydrochloride.
Preparation Example 139
Preparation was carried out using the compound of Preparation Example 135 by the same method as in Preparation Example 115 as described above.
Preparation Example 140
Preparation was carried out using the compound of Preparation Example 136 by the same method as in Preparation Example 115 as described above. Further, the compound of Preparation Example 140 and the compound of Preparation Example 115 are enantiomers (mirror image isomers) with respect to each other.
Preparation Example 165
To 820 mg of tert-butyl[(1S)-1-(3-bromophenyl)ethyl]carbamate were added 113 mg of 1,3-bis(diphenylphosphino)propane, 62 mg of palladium acetate, 0.84 ml of triethylamine, 8 ml of DMF, and 12 ml of methanol, followed by stirring at room temperature for 1 hour. While stirring at room temperature, carbon monooxide was intaken for 10 minutes, followed by stirring at 80° C. overnight under a carbon monooxide atmosphere. 113 mg of 1,3-bis(diphenylphosphino)propane and 62 mg of palladium acetate were added thereto, followed by stirring at 80° C. overnight. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 577 mg of methyl 3-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}benzoate.
Preparation Example 166
To a solution of 1 g of tert-butyl[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate in 10 ml of THF was added 16.9 ml of a 0.5 M potassium hexamethyldisilazane/toluene solution at −78° C., followed by stirring for 30 minutes. 0.92 ml of chlorodimethyl ether was added thereto at −78° C., followed by warming to room temperature for 3 hours. 4 ml of a 0.5 M potassium hexamethyldisilazane/toluene solution and 0.31 ml of chlorodimethyl ether were added thereto at −78° C., followed by stirring at room temperature for 2 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 311 mg of tert-butyl [(1R,2R)-2-(methoxymethoxy)-2,3-dihydro-1H-inden-1-yl](methoxymethyl)carbamate.
Preparation Example 167
A solution of 2.75 g of tert-butyl[(1R,2R)-2-(methoxymethoxy)-2,3-dihydro-1H-inden-1-yl](methoxymethyl)carbamate in 55 ml of carbon tetrachloride was heated at an outer temperature of 100° C., and a mixture of 1.53 g of N-bromosuccinimide and 95 mg of 2,2′-azodiisobutyronitrile was added portionwise thereto over 30 minutes at an interval of 5 minutes, followed by stirring at an outer temperature of 100° C. for 1 hour. The insoluble material was filtered, and an aqueous sodium thiosulfate solution and chloroform were added thereto to carry out a layer separation operation. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 984 mg of tert-butyl[(1R,2S)-3-bromo-2-(methoxymethoxy)-2,3-dihydro-1H-inden-1-yl](methoxymethyl)carbamate.
Preparation Example 168
To 983 mg of tert-butyl[(1R,2S)-3-bromo-2-(methoxymethoxy)-2,3-dihydro-1H-inden-1-yl](methoxymethyl)carbamate were added 1.39 g of potassium acetate and 15 ml of N-methyl-2-pyrrolidone, followed by stirring at 70° C. for 15 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 436 mg (Preparation Example 168a) and 106 mg (Preparation Example 168b), respectively, of (2S,3R)-3-[(tert-butoxycarbonyl)(methoxymethyl)amino]-2-(methoxymethoxy)-2,3-dihydro-1H-inden-1-yl acetate, as two kinds of single isomers, each having an undetermined configuration at the 1-position of an indane ring.
Preparation Example 169
To 235 mg of tert-butyl (3aR,8aR)-8-acetoxy-2-oxo-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazole-3(3aH)-carboxylate were added 2.4 ml of THF, 0.24 ml of water, and 229 mg of sodium hydroxide, followed by stirring for 4 hours. To the reaction mixture were added water and chloroform to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 66 mg (Preparation Example 169a) and 28 mg (Preparation Example 169b), respectively, of tert-butyl[(1R,2R)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]carbamate, as two kinds of single isomers, each having an undetermined configuration at the 3-position of an indane ring.
Preparation Example 170
To a solution of 700 mg of tert-butyl[(1R,2R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-1-phenylpropyl]carbamate in 35 ml of THF was added 1.2 g of triphenylphosphine, 766 mg of 4-nitrobenzoic acid, and 2.4 ml of a 1.9 M diisopropyl azodicarboxylate/toluene solution under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 638 mg of (6S,7R)-2,2,3,3,11,11-hexamethyl-9-oxo-7-phenyl-4,10-dioxa-8-aza-3-siladodecan-6-yl 4-nitrobenzoate.
Preparation Example 171
To a solution of 106 mg of the compound of Preparation Example 168b in 6 ml of methanol was added 117 mg of potassium carbonate, followed by stirring for 2 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 82 mg of tert-butyl[(1R,2S)-3-hydroxy-1-(methoxymethoxy)-2,3-dihydro-1H-inden-1-yl](methoxymethyl)carbamate as a single isomer having an undetermined configuration at the 3-position of an indane ring.
Preparation Example 172
To a solution of 190 mg of the compound of Preparation Example 171 in 3 ml of methanol was added 3 ml of 4 M hydrogen chloride/dioxane solution, followed by stirring for 20 hours. The solvent was evaporated under reduced pressure to obtain 110 mg of (2S,3R)-3-aminoindane-1,2-diol hydrochloride as a compound having an undetermined configuration at the 1-position of an indane ring. This was used for the next step without purification.
Preparation Example 173
To a solution of 1 g of methyl 3-oxoindane-1-carboxylate in 10 ml of toluene were added 0.78 ml of (1S)-1-(4-methoxyphenyl)ethanamine and 100 mg of p-toluenesulfonic acid monohydrate, followed by heating to reflux for 5 hours using a Dean-Stark type reflux device. Then, 634 mg of magnesium sulfate was added thereto, followed by heating to reflux for 5 hours using a Dean-Stark type reflux device. Further, 634 mg of magnesium sulfate was added thereto, followed by heating to reflux for 5 hours using a Dean-Stark type reflux device. The insoluble material was removed by filtration and the solvent was then evaporated under reduced pressure to obtain an intermediate product. To a solution of the obtained intermediate product in 17 ml of ethanol was added 209 mg of sodium borohydride under ice-cooling, followed by stirring for 1 hour under ice-cooling. The solvent was evaporated under reduced pressure, and to the obtained residue were added water, a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.195 g of methyl (3S)-3-{[(1S)-1-(4-methoxyphenyl)ethyl]amino}indane-1-carboxylate.
Preparation Example 174
To 713 mg of methyl 1-oxoindane-5-carboxylate were added 612 mg of (1S)-1-(4-methoxyphenyl)ethanamine, 0.23 ml of acetic acid, 600 mg of Molecular Sieves 4A, and 12 ml of toluene, followed by heating to reflux using a Dean-Stark type reflux device for 4 hours under reduced pressure (213 mbar). Then, 0.23 ml of acetic acid and 300 mg of Molecular Sieves 4A were added thereto, followed by heating to reflux using a Dean-Stark type reflux device for 4 hours under reduced pressure (213 mbar). The insoluble material was removed by filtration and the solvent was then evaporated under reduced pressure to obtain an intermediate product. To a solution of the obtained intermediate product in 13 ml of ethanol was added 161 mg of sodium borohydride under ice-cooling, followed by stirring for 1 hour under ice-cooling. The solvent was evaporated under reduced pressure, and to the obtained residue were added water, a saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 452 mg of methyl (1S)-1-{[(1S)-1-(4-methoxyphenyl)ethyl]amino}indane-5-carboxylate.
Preparation Example 175
To a solution of 850 mg of tert-butyl[2-(3-bromophenyl)propan-2-yl]carbamate in 8.5 ml of THF was added 4.1 ml of a 1.65 M n-butyllithium/hexane solution at −78° C., followed by stirring at the same temperature for 30 minutes. Then, 0.85 ml of methyl chloroformate was added dropwise thereto at −78° C., followed by stirring at the same temperature for 1 hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 199 mg of methyl 3-{2-[(tert-butoxycarbonyl)amino]propan-2-yl}benzoate.
Preparation Example 176
To 452 mg of methyl (1S)-1-{[(1S)-1-(4-methoxyphenyl)ethyl]amino}indane-5-carboxylate were added 34 ml of trifluoroacetic acid and 1.03 g of pentamethylbenzene, followed by stirring at 70° C. for 4 days, and the solvent was evaporated under reduced pressure. To the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution and chloroform to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 165 mg of methyl (1S)-1-aminoindane-5-carboxylate.
Preparation Example 178
To a mixed solution of 1.55 g of 1-methyl-3-(nitromethyl)benzene in 15 ml of ethanol and 6 ml of dioxane were added 0.05 ml of a 1 M aqueous sodium hydroxide solution and 1.89 ml of a 37% aqueous formalin solution, followed by stirring for 15 hours. 0.05 ml of a 1 M aqueous sodium hydroxide solution and 0.83 ml of a 37% aqueous formalin solution were added thereto, followed by stirring at 50° C. for 2 hours, and the solvent was evaporated under reduced pressure. To the obtained residue was added ethyl acetate, followed by washing with saturated brine and drying over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.91 g of 2-(3-methylphenyl)-2-nitropropane-1,3-diol.
Preparation Example 179
To a solution of 2 g of ethylpyridin-3-yl acetate in 40 ml of DMF were added 1.09 g of paraformaldehyde and 165 mg of sodium ethoxide, followed by stirring for 19 hours. Acetic acid was added thereto under ice-cooling and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.29 g of ethyl 3-hydroxy-2-(hydroxymethyl)-2-(pyridin-3-yl)propanoate.
Preparation Example 180
To a mixture of 1.25 g of ethyl 3-hydroxy-2-(hydroxymethyl)-2-(pyridin-3-yl)propanoate in 13 ml of acetone were added 0.75 ml of 2,2-dimethoxypropane and 105 mg of p-toluenesulfonic acid monohydrate, followed by stirring for 12 hours. Then, 1.06 g of p-toluenesulfonic acid monohydrate was added thereto, followed by stirring for 6 hours. Further, 0.75 ml of 2,2-dimethoxypropane was added thereto, followed by stirring at 50° C. for 30 minutes, and the solvent was evaporated under reduced pressure. To the obtained residue were added 13 ml of acetone and 0.78 ml of 2-methoxy-1-propene at room temperature, followed by stirring for 30 minutes. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.16 g of ethyl 2,2-dimethyl-5-(pyridin-3-yl)-1,3-dioxane-5-carboxylate.
Preparation Example 181
To a mixed solution of 0.86 g of tert-butyl (1-phenylcyclopenta-3-en-1-yl)carbamate and 0.47 g of 4-methylmorpholine N-oxide in 22 ml of THF and 8.7 ml of water was added 0.42 ml of a 2.5% osmium tetraoxide/tert-butanol solution, followed by stirring for 2 hours and leaving to stand for 4 days. To the reaction mixture were added an aqueous sodium thiosulfate solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 512 mg (Preparation Example 181a) and 126 mg (Preparation Example 181b), respectively, of tert-butyl [(3R,4S)-3,4-dihydroxy-1-phenylcyclopentyl]carbamate, as two kinds of single isomers, each having an undetermined configuration at the 1-position.
Preparation Example 182
A mixture of 620 mg of tert-butyl[(1R,2R)-2,3-dihydroxy-1-phenylpropyl]carbamate, 0.37 g of tert-butyldimethylchlorosilane, 0.19 g of imidazole, and 9.3 ml of dichloromethane was stirred for 2 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 705 mg of tert-butyl[(1R,2R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-1-phenylpropyl]carbamate.
Preparation Example 183
To 500 mg of methyl 6,6a-dihydro-1aH-indeno[1,2-b]oxirene-1a-carboxylate were added 860 mg of sodium azide, 309 mg of ammonium chloride, 4 ml of methanol, and 0.5 ml of water, followed by stirring at 80° C. for 2 hours. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution, water, and ethyl acetate to carry out a layer separation operation, and the organic layer was dried over anhydrous magnesium sulfate. To a solution of the obtained intermediate product in ethyl acetate-methanol was added 61 mg of 10% palladium-carbon (wet), followed by stirring for 6 hours under a hydrogen atmosphere. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure to obtain 0.51 g of methyl rac-(1R,2R)-1-amino-2-hydroxyindane-1-carboxylate.
Preparation Example 184
To 1.09 g of 2,2-dimethyl-5-(pyridin-3-yl)-1,3-dioxane-5-carboxylic acid were added 20 ml of toluene, 0.9 ml of triethylamine, 2.4 ml of benzyl alcohol, and 1.3 ml of diphenylphosphoryl azide, followed by stirring at 100° C. for 17 hours. After leaving to be cooled, to the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.01 g of benzyl[2,2-dimethyl-5-(pyridin-3-yl)-1,3-dioxan-5-yl]carbamate.
Preparation Example 185
To a solution of 340 mg of sodium 2,2-dimethyl-5-(pyridin-2-yl)-1,3-dioxane-5-carboxylate in 5 ml of dioxane and 1 ml of water was added 0.21 ml of isobutyl chloroformate under ice-cooling, followed by stirring for 1 hour. A solution of 850 mg of sodium azide in 3 ml of water was added thereto, followed by stirring for 10 minutes under ice-cooling. To the reaction mixture were added water and diethyl ether to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue was added 5 ml of toluene, followed by stirring at 100° C. for 5 minutes. After leaving to be cooled, 0.7 ml of benzyl alcohol was added thereto at room temperature, followed by stirring at 100° C. for 19 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 223 mg of benzyl[2,2-dimethyl-5-(pyridin-2-yl)-1,3-dioxan-5-yl]carbamate.
Preparation Example 186
To a mixture of 1.6 g of 2,2-dimethyl-5-(3-methylphenyl)-5-nitro-1,3-dioxane in 24 ml of ethanol was added a suspension of a Raney nickel (manufactured by Aldrich, product obtained by washing 1 ml of an aqueous suspension with water and ethanol) in 9 ml of ethanol, followed by stirring for 22 hours under a hydrogen atmosphere at 4 atm. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.55 g of 2,2-dimethyl-5-(3-methylphenyl)-1,3-dioxan-5-amine.
Preparation Example 187
A suspension of 3.0 g of methyl 3-formylbenzoate, 2.25 g of (R)-2-methyl-2-propanesulfinamide, and 6.0 g of copper (II) sulfate in 50 ml of dichloromethane was stirred overnight. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 700 mg of methyl 3-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate.
Preparation Example 188
A suspension of 3.0 g of methyl 3-formylbenzoate, 2.5 g of (S)-2-methyl-2-propanesulfinamide, 250 mg of pyridinium paratoluene sulfonate, and 11 g of magnesium sulfate in 50 ml of dichloromethane was stirred overnight. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 3.0 g of methyl 3-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]benzoate.
Preparation Example 189
To a solution of 500 mg of methyl 3-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]benzoate in 12 ml of THF was added 0.50 ml of a 1 M diethylzinc/hexane solution at −78° C., followed by stirring at the same temperature for 5 minutes. 0.80 ml of a 3 M ethylmagnesium bromide/diethyl ether solution was added thereto at −78° C., followed by stirring at the same temperature for 2 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 447 mg of methyl 3-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}propyl]benzoate.
Preparation Example 190
To a solution of 1 ml of diisopropylamine in 5 ml of THF was added 4.4 ml of a 1.6 M n-butyllithium/hexane solution under ice-cooling, followed by stirring at the same temperature for 15 minutes. 0.6 ml of methyl acetate was added thereto at −78° C., followed by stirring at the same temperature for 20 minutes. A solution of 3.6 g of chlorotitanium (IV) triisopropoxide in 7 ml of THF was added thereto, followed by stirring at the same temperature for 20 minutes. A solution of 500 mg of N-[(E)-(2,3-dimethylphenyl)methylene]-2-methylpropane-2-(R)-sulfinamide in 5 ml of THF was added thereto at −78° C., followed by stirring at the same temperature for 4 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 592 mg of methyl (3S)-3-{[(R)-tert-butylsulfinyl]amino}-3-(2,3-dimethylphenyl)propanoate.
Preparation Example 191
A suspension of 1 g of 2,2-dimethylspiro[1,3-dioxane-5,2′-inden]-1′(3′H)-one, 329 mg of hydroxylamine hydrochloride, and 388 mg of sodium acetate in 5 ml of ethanol was stirred for 12 hours. Then, 1.2 ml of triethylamine was added thereto, followed by stirring at room temperature for 3 days and further stirring at 50° C. for 1 hour. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.0 g of N-hydroxy-2,2-dimethylspiro[1,3-dioxane-5,2′-inden]-1′(3′H)-imine.
Preparation Example 192
To a suspension of 384 mg of lithium aluminum hydride in 22 ml of diethyl ether were added 0.5 g of N-hydroxy-2,2-dimethylspiro[1,3-dioxane-5,2′-inden]-1′(3′H)-imine and 5 ml of THF under ice-cooling, followed by stirring at 40° C. for 8 hours. 0.55 ml of water, 0.55 ml of a 15% aqueous sodium hydroxide solution, and 1.65 ml of water were added thereto under ice-cooling. After filtration through Celite, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 146 mg of 2,2-dimethyl-1′,3′-dihydrospiro[1,3-dioxane-5,2′-inden]-1′-amine.
Preparation Example 193
A mixture of 1 g of tert-butyl[(1S)-1-(3-bromophenyl)ethyl]carbamate, 18 mg of bis(tri-tert-butylphosphine)palladium (0), 180 mg of zinc fluoride, 1 ml of [(1-methoxy-2-methylpropa-1-en-1-yl)oxy](trimethyl)silane, and 10 ml of DMF was stirred at 80° C. overnight and at 100° C. for 5 hours. 25 mg of bis(tri-tert-butylphosphine)palladium (0) and 0.34 ml of [(1-methoxy-2-methylpropa-1-en-1-yl)oxy](trimethyl)silane were added thereto, followed by stirring at 80° C. for 3 days. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 281 mg of methyl 2-(3-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)-2-methylpropanoate.
Preparation Example 194
To a solution of 130 mg of 2-(trimethylsilyl)ethyl rac-[(2R,3S)-2,3-dihydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl]carbamate in 4 ml of THF was added 70 mg of 55% sodium hydride under ice-cooling, followed by stirring at the same temperature for 1 hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation, followed by drying over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 70 mg of 2-(trimethylsilyl)ethyl rac-[(1R,2S,3R)-2,3-dihydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl]carbamate and 45 mg of rac-(3aR,8S,8aR)-8-hydroxy-3a-methyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazol-2-one.
Preparation Example 195
To a solution of 3.4 g of 1-methyl-1H-indene in 136 ml of ether was added 16.2 ml of a 1.62 M n-butyllithium/hexane solution at −78° C., followed by stirring at room temperature for 30 minutes. To the reaction mixture were added 15.5 ml of tetra-iso-propyl titanate and 2.41 ml of methyl chloroformate at −78° C., followed by stirring at −78° C. for 2 hours. To the reaction mixture were added 1 M hydrochloric acid and ethyl acetate to carry out a layer separation operation, followed by drying over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.57 g of methyl 1-methyl-1H-indene-1-carboxylate.
Preparation Example 196
To a solution of 1.0 g of tert-butyl (3S)-piperidin-3-yl carbamate in 20 ml of DMF were added 0.77 ml of methyl 2-fluorobenzoate and 1.4 g of potassium carbonate, followed by stirring at 130° C. overnight. After leaving to be cooled, to the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 590 mg of methyl 2-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}benzoate.
Preparation Example 197
To a solution of 280 mg of methyl 3-[(2S)-2-{[(1S)-1-phenylethyl]amino}propyl]benzoate in 6.8 ml of ethanol were added 30 mg of 20% palladium-carbon hydroxide (wet) and 320 mg of ammonium formate, followed by stirring at 80° C. for 4 hours. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. To the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution and chloroform to carry out a layer separation operation, followed by drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 180 mg of methyl 3-[(2S)-2-aminopropyl]benzoate.
Preparation Example 198
To a solution of 300 mg of tert-butyl[(1R,2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-1-phenylpropyl]carbamate and 5 ml of methanol was added 5 ml of a 4 M hydrogen chloride/dioxane solution, followed by stirring for 2 hours. The solvent was evaporated under reduced pressure to obtain 171 mg of (2S,3R)-3-amino-3-phenylpropane-1,2-diol hydrochloride.
Preparation Example 199
To 448 mg of (2R,3R)-3-amino-3-phenylpropane-1,2-diol hydrochloride were added 18 ml of dichloromethane, 0.77 ml of triethylamine, and 0.53 g of di-tert-butyl dicarbonate, followed by stirring for 3 hours, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 620 mg of tert-butyl[(1R,2R)-2,3-dihydroxy-1-phenylpropyl]carbamate.
Preparation Example 200
To a solution of 300 mg of N-[(2E)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ylidene]-2-methylpropane-2-(S)-sulfinamide in 2 ml of toluene was added 0.62 ml of a 2.0 M trimethylaluminum/toluene solution at −78° C., followed by stirring for 30 minutes. Further, 3.2 ml of a 0.5 Methyllithium/benzene-cyclohexane solution was added thereto at −78° C., followed by stirring for 1 hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 160 mg of N-[(2R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylbutan-2-yl]-2-methylpropane-2-(S)-sulfinamide.
Preparation Example 201
To a solution of 97 mg of N-[(2R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylbutan-2-yl]-2-methylpropane-2-(S)-sulfinamide in 1 ml of methanol was added 1.3 ml of a 4 M hydrogen chloride/dioxane solution, followed by stirring for 2 hours. The solvent was evaporated under reduced pressure to obtain 63 mg of (2R)-2-amino-2-methylbutan-1-ol hydrochloride.
Preparation Example 239
Preparation was carried out using the compound of Preparation Example 168a by the same method as in Preparation Example 171 as described above.
Preparation Example 240
Preparation was carried out using the compound of Preparation Example 239 by the same method as in Preparation Example 172 as described above.
Preparation Example 278
Preparation was carried out using the compound of Preparation Example 181a by the same method as in Example 5 as described below.
Preparation Example 279
Preparation was carried out using the compound of Preparation Example 181b by the same method as in Example 5 as described below.
Hereinafter, Preparation Examples for the compounds of the formula (I) of the present invention are shown as Examples. Further, for the respective Example Compounds, the structures are shown in Tables 32 to 99, and the physicochemical data and preparation methods are shown in Tables 100 to 131. Since the compounds of Examples 36 to 660, 662, 664 to 668, 670 to 672, 675 to 682, 686 to 692, 694, 696 to 697, 700 to 701, 706 to 708, and 715 to 757, 760 to 765, 768 to 796 and 799 to 885 were prepared in the same manner as the methods of Examples 1 to 35, 661, 663 and 709 to 714, they are described only in Tables as described later.
Example 1
To a solution of 600 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid in 10 ml of DMF were added 500 mg of tert-butyl (3S)-3-aminopiperidine-1-carboxylate, 518 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, and 366 mg of 1-hydroxybenzotriazole, followed by stirring overnight. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 808 mg of tert-butyl (3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)piperidine-1-carboxylate.
Example 2
A mixture of 120 mg of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethyl]-8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxamide, 60 μl of cyclopentylmethanol, 156 μl of (tributylphosphoranylidene)acetonitrile, and 2.4 ml of toluene was stirred at 110° C. for 16 hours, followed by purification using silica gel chromatography, to obtain 100 mg of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethyl]-8-(cyclopentylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Example 3
To a solution of 370 mg of ethyl 3-{[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethyl]carbamoyl}-8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylate in 12 ml of THF was added 1.22 ml of a 1 M tetrabutylammonium fluoride/THF solution, followed by stirring for 30 minutes. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 220 mg of ethyl 8-[(2-fluorobenzyl)oxy]-3-{[(1R)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylimidazo[1,2-a]pyridine-6-carboxylate.
Example 4
To a solution of 90 mg of 6-bromo-8-(cyclohexylmethoxy)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 1.8 ml of N-methyl-2-pyrrolidone were added 54 mg of zinc cyanide and 27 mg of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II), followed by stirring at 180° C. for 30 minutes under a condition for microwave irradiation. To the reaction mixture was added 46 mg of zinc cyanide, followed by further stirring at 180° C. for 30 minutes under a condition for microwave irradiation. To the reaction mixture were added ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, followed by filtration through Celite. A layer separation operation of the obtained filtrate was carried out, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 7 mg of 6-cyano-8-(cyclohexylmethoxy)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Example 5
To a solution of 1.44 g of tert-butyl 4-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)piperidine-1-carboxylate in 15 ml of ethyl acetate was added 3.8 ml of a 4 M hydrogen chloride/ethyl acetate solution, followed by stirring for 1 day. The reaction mixture was concentrated under reduced pressure, and to the obtained residue were added ethyl acetate and ethanol. The resulting solid was collected by filtration and dried to obtain 1.29 g of 8-(cyclohexylmethoxy)-2-methyl-N-(piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride.
Example 6
To a suspension of 400 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-pyrrolidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride, 0.26 ml of triethylamine, and 0.23 ml of a 37% aqueous formaldehyde solution in 11 ml of dichloroethane was added 592 mg of sodium triacetoxyborohydride under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 249 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-1-methylpyrrolidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide.
Example 7
To a suspension of 307 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-piperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride, 335 mg of potassium carbonate, 5 ml of acetonitrile, and 5 ml of DMF was added 92 μl of bromoethyl acetate under ice-cooling, followed by stirring for 3 hours under ice-cooling. To the reaction mixture were added water and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 299 mg of ethyl[(3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)piperidin-1-yl]acetate.
Example 8
To a mixture of 150 mg of methyl 4-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]piperidine-4-carboxylate dihydrochloride, 150 μl of triethylamine, and 5 ml of dichloromethane was added 25 μl of acetyl chloride under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 135 mg of methyl 1-acetyl-4-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]piperidine-4-carboxylate.
Example 9
To a mixture of 150 mg of methyl 4-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]piperidine-4-carboxylate dihydrochloride, 150 μl of triethylamine, and 5 ml of dichloromethane was added 35 μl of methanesulfonyl chloride under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 85 mg of methyl 4-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]-1-(methylsulfonyl)piperidine-4-carboxylate.
Example 10
To a solution of 200 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-piperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride in 5 ml of isopropylalcohol were added 220 μl of triethylamine and 72 μl of (trimethylsilyl)isocyanate, followed by stirring for 6 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order, and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained solid was suspended in ethyl acetate, and 120 μl of 4 M hydrogen chloride/ethyl acetate solution was added thereto, followed by stirring. The resulting solid was collected by filtration and dried to obtain 170 mg of N-[(3S)-1-carbamoylpiperidin-3-yl]-8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxamide hydrochloride.
Example 11
To 200 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-piperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride were added 5 ml of pyridine and 217 mg of sulfamide, followed by heating to reflux for 4 hours. After leaving to be cooled at room temperature, to the reaction mixture were added water and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained solid was suspended in ethyl acetate, and 120 μl of a 4 M hydrogen chloride/ethyl acetate solution was added thereto. The resulting solid was collected by filtration and dried to obtain 151 mg of N-[(3S)-1-(aminosulfonyl)piperidin-3-yl]-8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxamide hydrochloride.
Example 12
To a solution of 216 mg of tert-butyl (3R)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-methylhexanoate in 2 ml of dichloromethane was added 2 ml of trifluoroacetic acid, followed by stirring overnight. The solvent was evaporated under reduced pressure, and water, a saturated aqueous sodium hydrogen carbonate solution, 1 M hydrochloric acid, and chloroform were added thereto to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To the obtained purified product were added ethyl acetate and diisopropyl ether, and the resulting solid was collected by filtration and dried to obtain 147 mg of (3R)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-methylhexanoic acid.
Example 13
To a solution of 290 mg of 8-(cyclohexylmethoxy)-N-[(1S)-1-(2-fluorophenyl)-3-hydroxypropyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in dichloromethane was added 300 mg of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, followed by stirring overnight. To the reaction mixture were added saturated aqueous sodium bicarbonate, an aqueous sodium thiosulfate solution, and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue and 230 μl of 2-methyl-2-butene in 6.5 ml of dioxane was added 1.7 ml of an aqueous solution of 93 mg of sodium chlorite and 315 mg of sodium dihydrogen phosphate in a water bath, followed by stirring for 30 minutes in a water bath. To the reaction mixture were added water, 1 M hydrochloric acid, and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To the obtained purified product was added diisopropyl ether, and the resulting solid was filtered and dried to obtain 80 mg of (3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-3-(2-fluorophenyl)propanoic acid.
Example 14
To a suspension of 20 mg of lithium aluminum hydride in 5 ml of THF was added a solution of 220 mg of methyl (2R)-2-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-3-(2-methylphenyl)propanoate in 2 ml of THF under ice-cooling, followed by stirring for 7 hours under ice-cooling. To the reaction mixture was added 180 mg of sodium sulfate decahydrate, followed by stirring for a while. The reaction mixture was filtered over Celite, the solvent was then evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained purified product was dissolved in ethyl acetate and a 4 M hydrogen chloride/ethyl acetate solution was added thereto. The solvent was evaporated under reduced pressure, and then diisopropyl ether was added thereto, followed by stirring. The resulting solid was collected by filtration and dried to obtain 72 mg of 8-(cyclohexylmethoxy)-N-[(1R)-2-hydroxy-1-(2-methylbenzyl)ethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide hydrochloride.
Example 15
To a solution of 185 mg of methyl (2E,4S)-4-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-4-phenylbuta-2-enoate in 3.7 ml of ethyl acetate was added 20 mg of 10% palladium-carbon, followed by stirring for 8 hours under a hydrogen atmosphere. The reaction mixture was filtered over Celite and the solvent was evaporated under reduced pressure to obtain 165 mg of methyl (4S)-4-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-4-phenylbutanoate.
Example 16
To 245 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-1-methylpyrrolidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide were added 12 ml of ethyl acetate and 364 μl of a 4 M hydrogen chloride/ethyl acetate solution, followed by stirring. The resulting solid was collected by filtration and dried to obtain 258 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-1-methylpyrrolidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide hydrochloride.
Example 17
To a solution of 280 mg of ethyl 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylate, 208 mg of 4-(dimethylamino)pyridine, and 5 ml of chloroform was added 191 μl of trichloroacetyl chloride under ice-cooling, followed by stirring at room temperature for 1 hour and at 65° C. overnight. After leaving to be cooled at room temperature, the solvent was evaporated under reduced pressure, and to the obtained residue were added acetonitrile and 429 mg of (1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethanamine, followed by stirring overnight. To the reaction mixture were added water and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 370 mg of ethyl 3-{[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl ethyl]carbamoyl}-8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylate.
Example 18
To a mixture of 100 mg of 8-[(2-fluorobenzyl)oxy]-3-{[(1R)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid, 28 μl of 4-methylmorpholine, and 0.7 ml of dimethoxyethane was added 34 μl of isobutyl chloroformate under ice-cooling, followed by stirring at room temperature overnight. The insoluble material was removed by filtration, and then to the filtrate were added 16 mg of sodium borohydride and 210 μl of methanol under ice-cooling, followed by stirring for 30 minutes under ice-cooling. To the reaction mixture were added a saturated aqueous ammonium chloride solution and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 21 mg of 8-[(2-fluorobenzyl)oxy]-6-(hydroxymethyl)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Example 19
To a suspension of 300 mg of 8-(cyclohexylmethoxy)-N-[(1R)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 6 ml of ethanol was added 0.13 ml of hydrazine monohydrate, followed by stirring at 85° C. for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 200 mg of N-[(1R)-2-amino-1-phenylethyl]-8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Example 20
To a solution of 1.2 g of benzyl 4-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate in 30 ml of methanol was added 300 mg of 10% palladium-carbon, followed by stirring overnight under a hydrogen atmosphere. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure to obtain 900 mg of methyl[4-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)piperidin-4-yl]acetate.
Example 21
To a suspension of 300 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid in 5 ml of THF was added 253 mg of 1,1′-carbonyldiimidazole, followed by stirring at 60° C. for 1 hour. Subsequently, 283 mg of 3-(aminosulfonyl)propyl acetate and 389 μl of 1,8-diazabicyclo[5.4.0]-7-undecene were added thereto under ice-cooling, followed by stirring at room temperature overnight. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. Since the reaction was not completed, to the obtained purified product were added again 57 mg of 3-(aminosulfonyl)propyl acetate, 60 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, 38 mg of 4-(dimethylamino)pyridine, and 2 ml of DMF, followed by stirring at room temperature overnight. To the reaction mixture were added a saturated aqueous ammonium chloride solution and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To the obtained product were added ethyl acetate and ethanol, followed by stirring. The resulting solid was collected by filtration and dried to obtain 149 mg of 3-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)sulfonyl]propyl acetate.
Example 22
To 130 mg of 3-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)sulfonyl]propyl acetate were added 2 ml of methanol, 2 ml of THF, and 1 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring for 8.5 hours. The solvent was evaporated under reduced pressure and to the obtained residue were added water and 1 M hydrochloric acid. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography. To the obtained purified product were added ethyl acetate and hexane, followed by stirring. The resulting solid was collected by filtration and dried to obtain 41 mg of 8-(cyclohexylmethoxy)-N-[(3-hydroxypropyl)sulfonyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Example 23
To a mixture of 8.7 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 5.1 mg of cyclopropylamine, 4.1 mg of 1-hydroxybenzotriazole, 1 ml of DMF, and 28 μl of diisopropylethylamine was added 50 mg of polystyrene N-cyclohexylcarbodiimide-N′-propyloxymethyl (PS-Carbodiimide manufactured by Biotage), followed by stirring at room temperature for 16 hours. Subsequently, 1 ml of DMF, 50 mg of macroporious triethylammonium methylpolystyrene carbonate (MP-Carbonate manufactured by Biotage) and 50 mg of polystyrene methyl isocyanate (PS-Isocyanate manufactured by Biotage), followed by stirring at room temperature for 3 hours. The resin of the reaction mixture was removed by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (high performance liquid chromatography) to obtain 8.7 mg of 8-(cyclohexylmethoxy)-N-cyclopropyl-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Example 24
To a mixture of 5.8 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 6.1 mg of (S)-(+)-2-phenylglycine methyl ester hydrochloride, 2.7 mg of 1-hydroxybenzotriazole, 700 μl of DMF, and 19 μl of diisopropylethylamine was added 50 mg of polystyrene N-cyclohexylcarbodiimide-N′-propyloxymethyl (PS-Carbodiimide manufactured by Biotage), followed by stirring at room temperature for 20 hours. Subsequently, 50 mg of macroporous triethylammonium methylpolystyrene carbonate (MP-Carbonate manufactured by Biotage) and 50 mg of polystyrene methyl isocyanate (PS-Isocyanate manufactured by Biotage) were added thereto, followed by stirring at room temperature for 2 hours. The resin was removed by filtration, the filtrate was concentrated under reduced pressure, and to the obtained residue were added 100 μl of THF, 200 μl of methanol, and 50 μl of a 1 M aqueous sodium hydroxide solution, followed by stirring at 50° C. for 20 hours. To the reaction mixture that had been left to be cooled to room temperature were added 0.5 ml of water and 50 μl of 1 M hydrochloric acid, followed by concentration under reduced pressure. The obtained residue was purified by preparative HPLC to obtain 6.7 mg of (2S)-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)(phenyl)acetic acid.
Example 25
To a mixture of 5.8 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 7.1 mg of tert-butyl (3R)-3-amino-4-phenylbutanoate, 2.7 mg of 1-hydroxybenzotriazole, 700 μl of DMF, and 19 μl of diisopropylethylamine was added 50 mg of polystyrene N-cyclohexylcarbodiimide-N′-propyloxymethyl (PS-Carbodiimide manufactured by Biotage), followed by stirring at room temperature for 20 hours. To the reaction mixture were added 50 mg of macroporous triethylammonium methylpolystyrene carbonate (MP-Carbonate manufactured by Biotage) and 50 mg of polystyrene methyl isocyanate (PS-Isocyanate manufactured by Biotage), followed by stirring at room temperature for 2 hours. The resin was removed by filtration, the filtrate was concentrated under reduced pressure, and to the obtained residue were added 100 μl of 1,4-dioxane and 200 μl of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by preparative HPLC to obtain 5.6 mg of (3R)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-4-phenylbutanoic acid.
Example 26
A mixture of 8.5 mg of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethyl]-8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxamide, 5.6 mg of α-bromo-2,5-difluorotoluene, 5.0 mg of potassium carbonate, and 700 μl of DMF was stirred at 30° C. for 28 hours. To the reaction mixture were added 1 ml of water, 0.5 ml of saturated brine, and 4 ml of chloroform to carry out a layer separation operation. The organic layer was concentrated under reduced pressure, and to the residue were added 300 μl of THF and 300 μl of 1 M hydrochloric acid, followed by stirring at room temperature for 6 hours. To the reaction mixture were added 300 μl of a 1 M aqueous sodium hydroxide solution and 100 of saturated aqueous sodium bicarbonate, followed by extraction with 3 ml of chloroform. The solvent was evaporated under reduced pressure and the obtained residue was purified by preparative HPLC to obtain 6.3 mg of 8-[(2,5-difluorobenzyl)oxy]-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Example 27
To a solution of 250 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-piperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride in 10 ml of methanol were added 157 μl of triethylamine, 300 mg of Molecular Sieves 3A, 323 μl of acetic acid, 1.53 ml of [(1-ethoxy cyclopropyl)oxy](trimethyl)silane, and 146 mg of sodium cyanoborohydride under ice-cooling, followed by stirring for 6 hours under heating to reflux. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. To the obtained residue were added saturated aqueous sodium bicarbonate and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To a mixture of the obtained purified product, ethyl acetate, and methanol was added a 4 M hydrogen chloride/ethyl acetate solution under ice-cooling, and the solvent was evaporated under reduced pressure. To the obtained residue was added ethyl acetate and hexane, followed by stirring. The resulting solid was collected by filtration and dried to obtain 136 mg of 8-(cyclohexylmethoxy)-N-[(3S)-1-cyclopropylpiperidin-3-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide dihydrochloride.
Example 28
To a solution of 200 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(1R)-2-{methyl[(2-nitrophenyl)sulfonyl]amino}-1-phenylethyl]imidazo[1,2-a]pyridine-3-carboxamide in 3 ml of DMF were added 140 mg of potassium carbonate and 50 mg of 4-methylbenzenethiol, followed by stirring for 3 hours. To the reaction mixture were added water and chloroform/methanol (9/1) to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 80 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(1R)-2-(methylamino)-1-phenylethyl]imidazo[1,2-a]pyridine-3-carboxamide.
Example 29
To a solution of 150 mg of methyl (2S,4S)-4-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-1-methylpyrrolidine-2-carboxylate and 4 ml of dichloromethane was added dropwise 1.5 ml of a 1 M diisobutylaluminum hydride/toluene solution under ice-cooling, followed by stirring for 2 hours under ice-cooling. Subsequently, 1 M hydrochloric acid was added thereto, the reaction mixture was filtered over Celite, and to the filtrate were added ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography. To a solution of the obtained purified product in ethyl acetate was added a hydrogen chloride/ethyl acetate solution, and the resulting solid was collected by filtration and dried to obtain 25 mg of 8-(cyclohexylmethoxy)-N-[(3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide dihydrochloride.
Example 30
To a solution of 32 mg of N-[(6-chloropyridin-3-yl)methyl]-8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 0.6 ml of N-methyl-2-pyrrolidone was added 0.05 ml of ethyl piperidine-4-carboxylate to carry out a reaction at 150° C. for 30 minutes and further at 200° C. for 30 minutes under microwave irradiation. 24 mg of potassium carbonate was added thereto to carry out a reaction at 240° C. for 2 hours under microwave irradiation. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography. To the obtained purified product were added hexane and isopropyl ether, and the resulting solid was collected by filtration and dried to obtain 14 mg of 1-{4-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]pyridin-2-yl}piperidine-4-carboxylic acid.
Example 31
To a solution of 70 mg of N-[(6-chloropyridin-3-yl)methyl]-8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridine-3-carboxamide in 1 mL of N-methyl-2-pyrrolidone was added 0.12 mL of ethyl piperidine-3-carboxylate to carry out a reaction at 240° C. for 50 minutes under microwave irradiation. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 43 mg of ethyl 1-{5-[({[8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]pyridin-2-yl}piperidine-3-carboxylate.
Example 32
To a solution of 270 mg of methyl N-{[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}serinate in 7 mL of methanol were added 210 mg of bisguanidine and 115 mg of sodium methoxide, followed by stirring at 65° C. for 8 hours. After leaving to be cooled, the insoluble material was collected by filtration, and washed with methanol, water, and hexane in this order to obtain 75 mg of 8-(cyclohexylmethoxy)-N-[1-(4,6-diamino-1,3,5-triazin-2-yl)-2-hydroxyethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Example 33
A mixture of 860 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 992 mg of 1-benzyl-4-methylpiperidine-4-amine dihydrochloride, 170 mg of O-(7-azabenzotriazole-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate, 3 mL of diisopropylethylamine, and 10 mL of DMF was stirred for 1 day. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1.25 g of N-(1-benzyl-4-methylpiperidin-4-yl)-8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridine-3-carboxamide.
Example 34
A mixture of 1.15 g of N-(1-benzyl-4-methylpiperidin-4-yl)-8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridine-3-carboxamide, 0.4 mL of 1-chloroethyl chloroformate, and 15 mL of dichloroethane was heated to reflux overnight. After leaving to be cooled at room temperature, the solvent was evaporated under reduced pressure, and to the residue was added 15 mL of methanol, followed by heating to reflux for 6 hours. After leaving to be cooled at room temperature, the solvent was evaporated under reduced pressure, and to the residue were added a saturated aqueous sodium hydrogen carbonate solution and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 426 mg of 8-(cyclohexylmethoxy)-2-methyl-N-(4-methylpiperidin-4-yl)imidazolo[1,2-a]pyridine-3-carboxamide.
Example 35
To a solution of 100 mg of (3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridin-3-yl]carbonyl}amino)-3-phenylpropanoic acid in 1 mL of DMF was added 43 mg of 1,1′-carbonyldiimidazole, followed by stirring for 30 minutes. To the reaction solution were added 24 mg of methanesulfonamide and 0.039 mL of 1,8-diazabicyclo[5.4.0]-7-undecene, followed by stirring for 5 hours. To the reaction mixture were added 1 M hydrochloric acid and ethyl acetate to carry out a layer separation operation. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. To the purified product were added ethyl acetate and hexane, and the resulting solid was collected by filtration and dried to obtain 41 mg of 8-(cyclohexylmethoxy)-2-methyl-N-{(1S)-3-[(methylsulfonyl)amino]-3-oxo-1-phenylpropyl}imidazolo[1,2-a]pyridine-3-carboxamide.
Example 661
To a suspension of 149 mg of methyl (1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-methylindane-2-carboxylate in 6 ml of dioxane was added 6 ml of 3 M hydrochloric acid, followed by stirring at 80° C. for 4 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure, and then to the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution, an aqueous citric acid solution, and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and the insoluble material was collected by filtration and dried to obtain 126 mg of (1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-methylindane-2-carboxylic acid.
Example 663
4.5 mg of sodium was added to and dissolved in 6 ml of methanol. To the reaction mixture was added 300 mg of methyl rac-(1R,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-1,2,3,4-tetrahydronaphthalene-2-carboxylate, followed by stirring at 90° C. for 5 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure, and then to the obtained residue were added a 10% aqueous citric acid solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and washed with ethyl acetate-hexane to obtain 139 mg of methyl rac-(1R,2S)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-1,2,3,4-tetrahydronaphthalene-2-carboxylate.
Example 669
Methyl (1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-4-methylindane-2-carboxylate was prepared using the compound of Preparation Example 123 by the same method as in Example 1 as described above.
Example 673
Methyl (1S,2R)-1-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-4-methylindane-2-carboxylate was prepared using the compound of Preparation Example 123 by the same method as in Example 1 as described above.
Example 674
Methyl (1S,2R)-1-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-7-fluoroindane-2-carboxylate was prepared using the compound of Preparation Example 115 by the same method as in Example 1 as described above.
Example 683
Methyl rac-(1R,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-7-fluoroindane-2-carboxylate as a racemate of cis isomers was prepared using the compound of Preparation Example 139 by the same method as in Example 1 as described above.
Example 684
Methyl (1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-7-fluoroindane-2-carboxylate was prepared using the compound of Preparation Example 115 by the same method as in Example 1 as described above.
Example 685
Methyl (1R,2S)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-7-fluoroindane-2-carboxylate was prepared using the compound of Preparation Example 140 by the same method as in Example 1 as described above. Further, the compound of Example 684 and the present compound of Example 685 are enantiomers (mirror image isomers) with respect to each other.
Example 693
Preparation was carried out by the same method as in Example 661 as described above using the compound of Example 669.
Example 695
Preparation was carried out by the same method as in Example 661 as described above using the compound of Example 663.
Example 698
Preparation was carried out by the same method as in Example 661 as described above using the compound of Example 673.
Example 699
Preparation was carried out by the same method as in Example 661 as described above using the compound of Example 674.
Example 702
Preparation was carried out by the same method as in Example 661 as described above using the compound of Example 678.
Example 703
Preparation was carried out by the same method as in Example 661 as described above using the compound of Example 683.
Example 704
Preparation was carried out by the same method as in Example 661 as described above using the compound of Example 684.
Example 705
Preparation was carried out by the same method as in Example 661 as described above using the compound of Example 685.
Example 709
To 301 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[2,2-dimethyl-5-(3-methylphenyl)-1,3-dioxan-5-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide were added 3 ml of dioxane, 3 ml of methanol, and 6 ml of 1 M hydrochloric acid, followed by stirring for 14 hours. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution, water, and ethyl acetate under ice-cooling to carry out a layer separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography. To the obtained purified product were added hexane and ethyl acetate, and the insoluble material was collected by filtration and dried to obtain 172 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[1,3-dihydroxy-2-(3-methylphenyl)propan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Example 710
To 252 mg of diethyl[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]malonate were added 4 ml of ethanol, 0.23 ml of a 20% sodium ethoxide/ethanol solution, and 0.31 ml of 1-iodobutane, followed by stirring at 70° C. for 3 hours. Subsequently, 11 mg of sodium ethoxide was added thereto, followed by stirring at 70° C. for 1 hour. To the reaction mixture were added an aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 69 mg of diethyl butyl[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]malonate.
Example 711
To a mixture of 68 mg of diethyl butyl[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]malonate in 1.4 ml of ethanol was added a solution of 35 mg of calcium chloride in 0.34 ml of water. Subsequently, 24 mg of sodium borohydride was added thereto under ice-cooling, followed by stirring for 1 hour under ice-cooling and at room temperature for 4 hours. Further, 2 ml of ethanol, a solution of 35 mg of calcium chloride in 0.34 ml of water, and 24 mg of sodium borohydride were added thereto followed by stirring at room temperature for 15 hours. Further, a solution of 35 mg of calcium chloride in 0.34 ml of water and 24 mg of sodium borohydride were added thereto, followed by stirring at room temperature for 15 hours. To the reaction mixture were added 1 M hydrochloric acid and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 32 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[1-hydroxy-2-(hydroxymethyl)hexan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Example 712
To a solution of 229 mg of methyl rac-(1R,2R)-1-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-2-hydroxyindane-1-carboxylate in 3.4 ml of ethanol and 0.68 ml of THF was added 68 mg of sodium borohydride under ice-cooling, followed by stirring at room temperature for 4 hours. To the reaction mixture were added 1 M hydrochloric acid and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. To the obtained purified product was added diisopropyl ether, and the resulting solid was collected by filtration and dried to obtain 74 mg of rac-8-[(2,6-difluorobenzyl)oxy]-N-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)-2,3-dihydro-1H-indan-1-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Example 713
To 100 mg of 1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}oxy)-1H-benzotriazole were 1.7 ml of dichloromethane, 0.065 ml of (S)-(−)-1-phenylethylamine, and 0.07 ml of triethylamine, followed by stirring overnight. To the reaction mixture were added water and chloroform to carry out a layer separation operation, followed by drying over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. To the obtained purified product was added diisopropyl ether, and the resulting solid was collected by filtration and dried to obtain 80 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(1S)-1-phenylethyl]imidazo[1,2-a]pyridine-3-carboxamide.
Example 714
To a mixture of 100 mg of the compound of Example 766 in 3.3 ml of THF and 1.7 ml of water was added 65 mg of sodium periodate under ice-cooling, followed by stirring at room temperature for 2 hours and at 50° C. for 3 hours. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the obtained residue in 2 ml of THF and 2 ml of methanol was added 39 mg of sodium borohydride under ice-cooling, followed by stirring for 1 hour under ice-cooling and at room temperature for 1 hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution, ethyl acetate, and water to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained purified product was washed with ethyl acetate and hexane to obtain 33 mg of 8-[(2,6-difluorobenzyl)oxy]-N-(1,5-dihydroxy-3-phenylpentan-3-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Example 758
Preparation was carried out using the compound of Preparation Example 240 by the same method as in Example 1 as described above.
Example 759
Preparation was carried out using the compound of Preparation Example 172 by the same method as in Example 1 as described above.
Example 766
Preparation was carried out using the compound of Preparation Example 278 by the same method as in Example 1 as described above.
Example 767
Preparation was carried out using the compound of Preparation Example 279 by the same method as in Example 1 as described above.
Example 797
Preparation was carried out using the compound of Preparation Example 172 by the same method as in Example 1 as described above.
Example 798
Preparation was carried out using the compound of Preparation Example 172 by the same method as in Example 1 as described above.








TABLE 2





PEx
Str
















1






 


2






 


3






 


4






 


5






 


6






 


7






 


8






 


9






 


10






 


11






 


12






 


13






 


14






 


15






 


16





















TABLE 3





PEx
Str







17






 


18






 


19






 


20






 


21






 


22






 


23






 


24






 


25






 


26






 


27






 


28






 


29






 


30






 


31






 


32






 


33






 


34






 


35






 


36





















TABLE 4





PEx
Str







37






 


38






 


39






 


40






 


41






 


42






 


43






 


44






 


45






 


46






 


47






 


48






 


49






 


50






 


51






 


52






 


53






 


54





















TABLE 5





PEx
Str







55






 


56






 


57






 


58






 


59






 


60






 


61






 


62






 


63






 


64






 


65






 


66






 


67






 


68






 


69






 


70





















TABLE 6





PEx
Str







71






 


72






 


73






 


74






 


75






 


76






 


77






 


78






 


79






 


80






 


81






 


82






 


83






 


84





















TABLE 7





PEx
Str







85






 


86






 


87






 


88






 


89






 


90






 


91






 


92






 


93






 


94






 


95






 


96






 


97






 


98






 


99





















TABLE 8





PEx
Str







100






 


101






 


102






 


104






 


105






 


106






 


107






 


108






 


109






 


110






 


111






 


112






 


  113a





















TABLE 9





PEx
Str







 113b






 


  113c






 


114






 


115






 


116






 


117






 


118






 


119






 


120






 


121






 


122






 


123






 


124






 


125





















TABLE 10





PEx
Str







127






 


128






 


129






 


130






 


131






 


132






 


133






 


134






 


135






 


136






 


137






 


138






 


139






 


140





















TABLE 11





PEx
Str







141






 


142






 


143






 


144






 


145






 


146






 


147






 


148






 


149






 


150






 


151






 


152






 


153






 


154






 


155






 


156





















TABLE 12





PEx
Str







157






 


158






 


159






 


160






 


161






 


162






 


163






 


164





















TABLE 13





PEx
Str







165






 


166






 


167






 


  168a






 


 168b






 


  169a






 


 169b






 


170






 


171






 


172






 


173






 


174






 


175























TABLE 14







PEx 
Str









176 







 



177 







 



178 







 



179 







 



180 







 



181a 







 



181b 







 



182 







 



183 







 



184 







 



185 







 



186 







 



187 







 



188 
























TABLE 15







PEx 
Str









189 







 



190 







 



191 







 



192 







 



193 







 



194a 







 



194b 







 



195 







 



196 







 



197 







 



198 







 



199 







 



200 







 



201 







 



202 







 



203 







 



204 
























TABLE 16







PEx 
Str









205 







 



206 







 



207 







 



208 







 



209 







 



210 







 



211 







 



212 







 



213 







 



214 







 



215 







 



216 







 



217 







 



218 







 



219 







 



230 






















TABLE 17





PEx 
Str







221 






 


222 






 


223 






 


224a 






 


224b 






 


225a 






 


225b 






 


226 






 


227 






 


228 






 


229 






 


230 






 


231 






 


232 























TABLE 18







PEx 
Str









233 







 



234 







 



235 







 



236 







 



237a 







 



237b 







 



238 







 



239 







 



240 







 



241 







 



242 







 



243 







 



244 







 



245 
























TABLE 19







PEx 
Str









246 







 



247 







 



248 







 



249 







 



250 







 



251 







 



252 







 



253 







 



254 







 



255 







 



256 







 



257 







 



258 







 



259 







 



260 







 



261 
























TABLE 20







PEx 
Str









262 







 



263 







 



264 







 



265 







 



266 







 



267 







 



268 







 



269 







 



270 







 



271 







 



272 







 



273 







 



274 







 



275 







 



276 







 



277 







 



278 







 



279 























TABLE 21





PEx
Syn
Dat

















1
PEx1
ESI+: 251


2
PEx2
ESI+: 221


3
PEx3
ESI+: 285


4
PEx4
ESI+: 331


5
PEx5
ESI+: 301


6
PEx6
ESI+: 426


7
PEx7
CI+: 177, 179


8
PEx8
ESI+: 307


9
PEx9
ESI+: 185


10
PEx10
ESI+: 396


11
PEx11
ESI+: 202


12
PEx12
NMR(DMSO-d6): 1.07-1.36 (5H, m), 1.63-1.80 (2H,




m), 1.82-1.96 (2H, m), 2.76 (3H, s), 4.13 (2H, d,




J = 6 Hz), 7.52-7.47 (1H, m), 7.58 (1H, d, J = 8 Hz),




9.08 (1H, d, J = 6 Hz)


13
PEx13
FAB+: 307


14
PEx14
EI: 276


15
PEx15
EI: 314


16
PEx16
ESI+: 329


17
PEx17
ESI+: 336


18
PEx18
ESI+: 330


19
PEx19
ESI+: 277


20
PEx20
ESI+: 377


21
PEx21
NMR(CDCl3): 1.42 (9H, s), 2.52 (2H, t, J = 8 Hz),




2.89 (2H, t, J = 8 Hz), 3.84 (2H, s), 7.17 (2H, d,




J = 8 Hz), 7.23 (2H, d, J = 8 Hz)


22
PEx22
NMR(DMSO-d6): 1.12 (3H, t, J = 8 Hz), 1.49 (6H,




s), 3.98 (2H, s), 4.06 (2H, q, J = 7 Hz), 7.34 (2H,




d, J = 8 Hz), 7.46 (2H, d, J = 8 Hz), 8.44 (3H, br s)


23
PEx23
NMR(CDCl3): 1.34 (3H, t, J = 7 Hz), 1.46 (9H, s),




4.27 (2H, q, J = 7 Hz), 4.46 (2H, d, J = 5 Hz),




4.73 (1H, brs), 6.37 (1H, d, J = 16 Hz), 7.28-7.36




(3H, m), 7.57 (1H, d, J = 8 Hz), 7.95 (1H, d, J =




16 Hz)


24
PEx24
NMR(CDCl3): 1.18 (3H, t, J = 7 Hz), 1.58 (6H, s),




4.13 (2H, q, J = 7 Hz), 7.45 (2H, dt, J = 9, 2 Hz),




7.62 (2H, dt, J = 9, 2 Hz)


















TABLE 22





PEx
Syn
Dat







25
PEx25
ESI+: 162


26
PEx 26
ESI+: 335


27
PEx 27
ESI+: 336


28
PEx28
ESI+: 180


29
PEx11
CI+: 228


30
PEx11
ESI+: 214


31
PEx15
ESI+: 303


32
PEx3
ESI+: 241


33
PEx4
ESI+: 317


34
PEx4
ESI+: 329


35
PEx4
ESI+: 311


36
PEx4
ESI+: 317


37
PEx4
ESI+: 371


38
PEx4
ESI+: 329


39
PEx4
ESI+: 347


40
PEx4
ESI+: 351


41
PEx5
ESI+: 301


42
PEx5
ESI+: 289


43
PEx5
ESI+: 343


44
PEx5
ESI+: 283


45
PEx5
ESI+: 319


46
PEx5
ESI+: 275


47
PEx5
ESI+: 303


48
PEx5
ESI+: 367


49
PEx5
ESI+: 323, 325


50
PEx5
ESI+: 303


51
PEx5
ESI+: 315


52
PEx9
ESI+: 197


53
PEx9
CI+: 199


54
PEx9
CI+: 225


55
PEx9
EI: 210


56
PEx9
ESI+: 197


57
Ex2
ESI+: 518


58
PEx10
ESI+: 410


















TABLE 23





PEx
Syn
Dat







59
Ex2
ESI+: 535


60
PEx20
ESI+: 377


61
Ex2
ESI+ 518


62
PEx10
ESI+: 408


63
Ex2
ESI+: 518


64
Ex1
ESI+: 376


65
PEx10
ESI+: 408


66
PEx19
ESI+: 277


67
PEx11
ESI+: 202


68
PEx10
ESI+: 408


69
PEx10
ESI+: 410


70
PEx12
NMR(DMSO-d6): 1.07-1.36 (5H, m), 1.63-1.80




(2H, m), 1.82-1.96 (2H, m), 2.49-2.53 (2H, m), 2.76




(3H, s), 4.13 (2H, d, J = 6 Hz), 7.52-7.47 (1H, m),




7.58 (1H, d, J = 8 Hz), 9.08 (1H, d, J = 6 Hz)


71
PEx9, 10
ESI+: 394


72
PEx9, 10
ESI+: 443


73
PEx 11
ESI+: 200


74
PEx9, 10
ESI+: 394


75
PEx11
ESI+: 250


76
PEx11
ESI+: 200


77
PEx10
ESI+: 416


78
PEx10
ESI+: 444


79
PEx10
ESI+: 370


80
PEx14
EI: 276


81
PEx15
EI: 314


82
PEx10
ESI+: 444


83
PEx11
ESI+: 250


84
PEx10
ESI+: 432


85
PEx11
ESI+: 238


86
PEx10
ESI+: 396


87
PEx10
ESI+: 422


88
Ex5
ESI+: 206


89
PEx11
ESI+: 214


90
PEx10
ESI+: 408


















TABLE 24





PEx
Syn
Dat







91
PEx10
ESI+: 436


92
PEx5
ESI+: 289


93
PEx11
ESI+: 234


94
PEx11
ESI+: 214


95
Ex5
ESI+: 235


96
PEx11
ESI+: 216


97
Ex5
ESI+: 236


98
PEx4
ESI+: 395


99
PEx11
ESI+: 242


















TABLE 25





PEx
Syn
Dat







100
PEx1
ESI+: 365


101
PEx101
APCI/ESI+: 206


102
PEx 102
ESI+: 192


104
PEx104
ESI+: 249


105
PEx105
ESI+: 311, 313


106
PEx106
ESI+: 442


107
PEx107
ESI+: 400


108
PEx11
ESI+: 206


109
PEx109
ESI+: 206


110
PEx110
ESI+: 273 [M + Na]+


111
PEx111
ESI+: 249


112
PEx112
ESI+: 352


 113a
PEx113
ESI+: 356




NMR(CDCl3): 1.21 (9H, s), 1.48 (9H, s), 3.15 (1




H, dd, J = 6.6, 16.4 Hz), 3.40 (1H, dd, J = 9.0,




16.4 Hz), 3.50 (1H, ddd, J = 5.4, 6.6, 9.0 Hz),




3.98 (1H, d, J = 3.4 Hz), 5.38 (1H, dd, J = 3.4,




5.0 Hz), 6.89 (1H, dt, Jd = 0.5 Hz, Jt = 9.0 Hz),




7.02 (1H, d, J = 7.5 Hz), 7.23-7.28 (1H, m)


 113b
PEx113
ESI+: 356




NMR(CDCl3): 1.15 (9H, s), 1.52 (9H, s), 3.08 (1




H, dd, J = 8.2, 16.1 Hz), 3.33 (1H, ddd, J = 6.8,




8.2, 10.2 Hz), 3.59 (1H, dd, J = 10.2, 16.1 Hz),




4.38 (1H, d, J = 3.9 Hz), 5.18 (1H, dd, J = 3.9,




6.8 Hz), 6.90 (1H, t, J = 8.6 Hz), 7.05 (1H, d,




J = 7.6 Hz), 7.25-7.30 (1H, m)


 113c
PEx113
ESI+: 356




NMR(CDCl3): 1.14 (9H, s), 1.51 (9H, s), 3.10 (1




H, dd, J = 8.1, 16.1 Hz), 3.27 (1H, dd, J = 8.0,




16.0 Hz), 3,42 (1H, dt, Jd = 6,3 Hz, Jt = 8.1 Hz),




4.50 (1H, d, J = 6.0 Hz), 5.22 (1H, t, J = 6.2




Hz), 6.91 (1H, t, J = 8.7 Hz), 7.02 (1H, d, J =




7.4 Hz), 7.22-7.27 (1H, m)


114
PEx114
ESI+: 248


115
PEx115
ESI+: 210


116
PEx116
ESI+: 239


117
PEx117
ESI+: 241


118
Ex15
NMR(CDCl3): 1.41 (9H, s), 2.60 (2H, t, J = 7




Hz), 3.26 (2H, t, J = 7 Hz), 7.04 (1H, dd, J = 1,




5 Hz), 7.65 (1H, d, J = 5 Hz), 10.07 (1H, d, J =




1 Hz)


119
PEx1
ESI+: 347


120
PEx11
ESI+: 234


121
PEx11
ESI+: 210


122
PEx5
ESI+: 337


123
PEx109
ESI+: 206


124
PEx109
ESI+: 210


125
PEx110
ESI+: 277 [M + Na]+


















TABLE 26





PEx
Syn
Dat







127
PEx112
ESI+: 344


128
PEx112
ESI+: 344


129
PEx112
APCI/ESI+: 356


130
PEx112
ESI+: 356


131
PEx112
ESI+: 356


132
PEx113
ESI+: 352


133
PEx113
ESI+: 344


134
PEx111
ESI+: 275 [M + Na]+


135
PEx113
ESI+: 356


136
PEx113
ESI+: 356


137
PEx137
ESI+: 240


138
PEx137
ESI+: 240


139
PEx115
ESI+: 210


140
PEx115
ESI+: 210


141
PEx116
NMR(CDCl3): 1.55 (9H, s), 6.39 (1H, d, J = 16




Hz), 7.37 (1H, d, J = 5 Hz), 7.68 (1H, d, J = 5 Hz),




8.07 (1H, d, J = 16 Hz), 10.22 (1H, d, J = 1 Hz)


142
PEx5
ESI+: 319


143
PEx113
ESI+: 344


144
PEx104
ESI+: 253


145
PEx104
ESI+: 249


146
PEx104
ESI+: 253


147
PEx104
EI: 248


148
PEx104
EI: 252


149
PEx105
EI: 314


150
PEx105
EI: 310, 312


151
PEx105
ESI+: 315, 317


152
PEx105
EI: 310, 312


153
PEx105
ESI+: 337, 339 [M + Na]+


154
PEx106
ESI+: 446


155
PEx106
ESI+: 442


















TABLE 27





PEx
Syn
Dat







156
PEx106
ESI+: 442


157
PEx106
ESI+: 446


158
PEx106
ESI+: 446


159
PEx106
ESI+: 428


160
PEx107
ESI+: 404


161
PEx107
ESI+: 404


162
PEx107
ESI+: 400


163
PEx107
ESI+: 400


164
PEx107
APCI/ESI+: 404


















TABLE 28





PEx
Syn
Dat







165
PEx165
ESI−: 324[M + HCOO]−


166
PEx166
ESI+: 360 [M + Na]+


167
PEx167
ESI+: 438, 440 [M + Na]+


 168a
PEx168
ESI+: 418 [M + Na]+


 168b
PEx168
ESI+: 418 [M + Na]+


 169a
PEx169
ESI+: 266


 169b
PEx169
ESI+: 266


170
PEx170
ESI+: 531


171
PEx171
ESI+: 376 [M + Na]+


172
PEx172
ESI+: 166


173
PEx173
APCI/ESI+: 326


174
PEx174
ESI+: 326


175
PEx175
ESI+: 294


176
PEx176
ESI+: 192


177
Ex5
ESI+: 180


178
PEx178
APCI/ESI+: 212


179
PEx179
APCI/ESI+: 226


180
PEx180
APCI/ESI+: 266


 181a
PEx 181
ESI+: 294




NMR(CDCl3): 1.43 (9H, brs), 2.50-2.59 (4H, m),




4.02 (4H, brs), 5.12 (1H, brs), 7.27-7.30 (1H, m),




7.35-7.43 (4H, m)


 181b
PEx 181
ESI+: 294




NMR(CDCl3): 1.39 (9H, brs), 2.24-2.32 (4H, m),




2.64 (2H, brs), 4.37-4.43 (2H, m), 4.80 (1H,




brs), 7.19-7.23 (1H, m), 7.32 (2H, t, J = 7.4 Hz),




7.41-7.43 (2H, m)


182
PEx182
ESI+: 382


183
PEx183
ESI+: 208


184
PEx184
APCI/ESI+: 343


185
PEx185
APCI/ESI+: 343


186
PEx186
APCI/ESI+: 222


187
PEx187
ESI+: 268


188
PEx188
ESI+: 268


189
PEx189
ESI+: 298


190
PEx190
ESI+: 312


191
PEx191
ESI+: 248


192
PEx192
ESI+: 234


193
PEx193
ESI+: 322


 194a
PEx194
ESI+: 324


 194b
PEx194
EI: 205


195
PEx195
EI: 188


















TABLE 29





PEx
Syn
Dat







196
PEx196
ESI+: 335


197
PEx197
ESI+: 194


198
PEx198
ESI+: 168


199
PEx199
ESI+: 268


200
PEx200
ESI+: 322


201
PEx201
ESI+: 104


202
Ex1
ESI+: 406


203
Ex19
ESI+: 196


204
Ex20
APCI/ESI+: 209


205
Ex20
APCI/ESI+: 209


206
Ex5
ESI+: 235


207
Ex5
ESI+: 235


208
Ex5
ESI+: 236


209
Ex5
ESI+: 236


210
Ex5
ESI+: 222


211
Ex5
ESI+: 166


212
Ex5
ESI+: 166


213
Ex5
ESI+: 194


214
Ex5
ESI+: 180


215
Ex5
ESI+: 180


216
Ex6
ESI+: 298


217
Ex9
CI+: 290


218
PEx1
ESI+: 363


219
PEx1
ESI+: 365


220
PEx10
ESI+: 436


221
PEx11
NMR(CDCl3): 1.22-1.74 (22H, m), 2.16 (1H, dd, J =




9.8 Hz, 15.4 Hz), 2.35 (1H, dd, J = 3.5 Hz, 15.4 Hz),




3.03-3.13 (1H, m)


222
PEx188
ESI+: 298


223
PEx112
ESI+: 292


 224a
PEx113
ESI+: 298




NMR(CDCl3): 1.24 (9H, s), 3.65 (1H, d, J = 7.0 Hz),




3.82 (3H, s), 5.03 (1H, d, J = 4.7 Hz), 5.30 (1H, dd,




J = 4.9, 7.0 Hz), 6.96 (1H, d, J = 8.1 Hz), 7.01 (1H,




t, J = 7.5 Hz), 7.25-7.31 (1H, m), 7.48 (1H, d, J =




7.5 Hz)


 224b
PEx113
ESI+: 298




NMR(CDCl3): 1.18 (9H, s), 3.50 (1H, d, J = 9.1 Hz),




3.82 (3H, s), 5.21 (1H, d, J = 8.4 Hz), 5.31 (1H, t,




J = 8.7 Hz), 6.93 (1H, d, J = 8.2 Hz), 7.01 (1H,




t, J = 7.5 Hz), 7.24-7.30 (1H, m), 7.57 (1H, d, J =




7.3 Hz)


 225a
PEx113
ESI+: 298




NMR(CDCl3): 1.24 (9H, s), 3.68 (1H, d, J = 7.1 Hz),




3.82 (3H, s), 5.03 (1H, d, J = 4.8 Hz), 5.30 (1H, dd,




J = 4.8, 7.0 Hz), 6.95 (1H, d, J = 8.1 Hz), 7.00 (1H,




dt, J = 0.8, 7.5 Hz), 7.26-7.31 (1H, m), 7.48 (1H, d,




J = 7.5 Hz)


 225b
PEx113
ESI+: 298




NMR(CDCl3): 1.18 (9H, s), 3.51 (1H, d, J = 9.1 Hz),




3.82 (3H, s), 5.21 (1H, d, J = 8.3 Hz), 5.31 (1H, t, J =




8.7 Hz), 6.93 (1H, d, J = 8.1 Hz), 7.01 (1H, dt, J =




0.9, 7.5 Hz), 7.27 (1H, dt, J = 1.3, 7.8 Hz), 7.57 (1H,




d, J = 7.5 Hz)


















TABLE 30





PEx
Syn
Dat







226
PEx114
ESI+: 208


227
PEx12
ESI+: 337, 339


228
PEx137
ESI+: 208


229
PEx137
ESI+: 194


230
PEx137
ESI+: 206


231
PEx137
ESI+: 194


232
PEx137
ESI+: 194


233
PEx137
ESI+: 194


234
PEx137
ESI+: 194


235
PEx168
ESI+: 356[M + Na]+


236
PEx169
ESI+: 180


 237a
PEx170, 171
ESI+: 324


 237b
PEx170, 171
ESI+: 324


238
PEx171
ESI+: 382


239
PEx171
ESI+: 376[M + Na]+


240
PEx172
ESI+: 166


241
PEx174
ESI+: 326


242
PEx174
ESI+: 326


243
PEx176, Ex16
ESI+: 192


244
PEx176, Ex16
ESI+: 192


245
PEx176, Ex16
ESI+: 192


246
PEx178
ESI+: 234 (M + Na)+


247
PEx179
APCI/ESI+: 226


248
PEx179
ESI+: 326


249
PEx180
APCI/ESI+: 274 [M + Na]+


250
PEx180
APCI/ESI+: 274 [M + Na]+


251
PEx178
ESI+: 193


252
PEx180
CI+: 233


253
PEx180
APCI/ESI+: 266


254
PEx181
ESI+: 324


255
PEx184
ESI+: 290


256
PEx186
APCI/ESI+: 222


257
PEx186
ESI+: 208


258
PEx186
APCI/ESI+: 222


















TABLE 31





PEx
Syn
Dat







259
PEx187
ESI+: 238


260
PEx188
ESI+: 298


261
PEx189
ESI+: 312


262
PEx189
ESI+: 310


263
PEx199
ESI+: 260


264
PEx200
ESI+: 350


265
PEx200
ESI+: 336


266
PEx201
ESI+: 132


267
PEx201
ESI+: 118


268
PEx22
NMR(DMSO-d6): 1.52 (6H, s), 3.60 (3H, s), 4.03




(2H, s), 7.28-7.42 (3H, m), 7.45 (1H, s), 8.10-8.35




(3H, br)


269
PEx26
ESI+: 335


270
PEx27
ESI+: 336


271
PEx27
ESI+: 336


272
PEx5
ESI+: 335


273
PEx5
ESI+: 337


274
PEx5
APCI/ESI+: 238


275
PEx5
APCI/ESI+: 238


276
PEx5
ESI+: 175


277
PEx9
NMR(CDCl3): 1.29-1.82 (21H, m), 2.24-2.36 (1H,




m), 5.67 (1H, dd, J = 1.2 Hz, 15.7 Hz), 6.85 (1H, dd,




J = 7.6 Hz, 15.7 Hz)


278
Ex5
ESI+: 194




NMR(DMSO-d6): 2.22 (2H, dd, J = 4.2, 14.8 Hz),




2.38 (2H, dd, J = 6.5, 14.8 Hz), 4.09-4.14 (2H, m),




4.80-5.60 (2H, br), 7.33-7.38 (1H, m), 7.43 (2H, t,




J = 7.2 Hz), 7.47-7.51 (2H, m), 8.34 (3H, brs)


279
Ex5
ESI+: 194




NMR(DMSO-d6): 2.21 (2H, dd, J = 5.7, 14.6 Hz),




2.31 (2H, dd, J = 6.1, 14.6 Hz), 4.23 (2H, t, J = 4.4




Hz), 4.81 (2H, brs), 7.32-7.36 (1H, m), 7.43 (2H, t,




J = 7.4 Hz), 7.53-7.57 (2H, m), 8.46 (3H, brs)



















TABLE 32







Ex 
Str



















1 







 



2 







 



3 







 



4 







 



5 







 



6 







 



7 







 



8 







 



9 







 



10 







 



11 







 



12 







 



13 







 



14 
























TABLE 33







Ex 
Str









15 







 



16 







 



17 







 



18 







 



19 







 



20 







 



21 







 



22 







 



23 







 



24 







 



25 







 



26 







 



27 







 



28 
























TABLE 34







Ex 
Str









29 







 



30 







 



31 







 



32 







 



33 







 



34 







 



35 







 



36 







 



37 







 



38 







 



39 







 



40 
























TABLE 35







Ex 
Str









41 







 



42 







 



43 







 



44 







 



45 







 



46 







 



47 







 



48 







 



49 







 



50 







 



51 







 



52 







 



53 







 



54 







 



55 







 



56 
























TABLE 36







Ex 
Str









57 







 



58 







 



59 







 



60 







 



61 







 



62 







 



63 







 



64 







 



65 







 



66 







 



67 







 



68 







 



69 







 



70 






















TABLE 37





Ex 
Str







71 






 


72 






 


73 






 


74 






 


75 






 


76 






 


77 






 


78 






 


79 






 


80 






 


81 






 


82 






 


83 






 


84 






 


85 






 


86 























TABLE 38







Ex 
Str



















87 







 



88 







 



89 







 



90 







 



91 







 



92 







 



93 







 



94 







 



95 







 



96 







 



97 







 



98 







 



99 







 



100 
























TABLE 39







Ex 
Str









101 







 



102 







 



103 







 



104 







 



105 







 



106 







 



107 







 



108 







 



109 







 



110 







 



111 







 



112 







 



113 







 



114 
























TABLE 40







Ex
Str









115







 



116







 



117







 



118







 



119







 



120







 



121







 



122







 



123







 



124







 



125







 



126






















TABLE 41





Ex
Str







127






 


128






 


129






 


130






 


131






 


132






 


133






 


134






 


135






 


136






 


137






 


138






 


139






 


140





















TABLE 42





Ex
Str







141






 


142






 


143






 


144






 


145






 


146






 


147






 


148






 


149






 


150






 


151






 


152























TABLE 43







Ex
Str









153







 



154







 



155







 



156







 



157







 



158







 



159







 



160







 



161







 



162







 



163







 



164







 



165







 



166
























TABLE 44







Ex
Str









167







 



168







 



169







 



170







 



171







 



172







 



173







 



174







 



175







 



176







 



177







 



178







 



179







 



180







 



181







 



182
























TABLE 45







Ex
Str









183







 



184







 



185







 



186







 



187







 



188







 



189







 



190







 



191







 



192







 



193







 



194
























TABLE 46







Ex
Str









195







 



196







 



197







 



198







 



199







 



200







 



201







 



202







 



203







 



204







 



205







 



206







 



207







 



208
























TABLE 47







Ex
Str









209







 



210







 



211







 



212







 



213







 



214







 



215







 



216







 



217







 



218







 



219







 



220







 



221







 



222







 



223







 



224






















TABLE 48





Ex
Str







225






 


226






 


227






 


228






 


229






 


230






 


231






 


232






 


233






 


234






 


235






 


236






 


237






 


238





















TABLE 49





Ex
Str







239






 


240






 


241






 


242






 


243






 


244






 


245






 


246






 


247






 


248






 


249






 


250






 


251






 


252






 


253






 


254





















TABLE 50





Ex
Str







255






 


256






 


257






 


258






 


259






 


260






 


261






 


262






 


263






 


264






 


265






 


266






 


267






 


268























TABLE 51







Ex
Str



















269







 



270







 



271







 



272







 



273







 



274







 



275







 



276







 



277







 



278







 



279







 



280
























TABLE 52







Ex
Str









281







 



282







 



283







 



284







 



285







 



286







 



287







 



288







 



289







 



290







 



291







 



292







 



293







 



294
























TABLE 53







Ex
Str









295







 



296







 



297







 



298







 



299







 



300







 



301







 



302







 



303







 



304







 



305







 



306






















TABLE 54





Ex
Str







307






 


308






 


309






 


310






 


311






 


312






 


313






 


314






 


315






 


316





















TABLE 55





Ex 
Str







317 






 


318 






 


319 






 


320 






 


321 






 


322 






 


323 






 


324 






 


325 






 


326 






 


327 






 


328 





















TABLE 56





Ex 
Str







329 






 


330 






 


331 






 


332 






 


333 






 


334 






 


335 






 


336 






 


337 






 


338 






 


339 






 


340 























TABLE 57







Ex 
Str









341 







 



342 







 



343 







 



344 







 



345 







 



346 







 



347 







 



348 







 



349 







 



350 







 



351 







 



352 







 



353 







 



354 






















TABLE 58





Ex 
Str







355 






 


356 






 


357 






 


358 






 


359 






 


360 






 


361 






 


362 






 


363 






 


364 






 


365 






 


366 























TABLE 59







Ex 
Str









367 







 



368 







 



369 







 



370 







 



371 







 



372 







 



373 







 



374 







 



375 







 



376 







 



377 







 



378 






















TABLE 60





Ex 
Str







379 






 


380 






 


381 






 


382 






 


383 






 


384 






 


385 






 


386 






 


387 






 


388 






 


389 






 


390 






 


391 






 


392 























TABLE 61







Ex 
Str









393 







 



394 







 



395 







 



396 







 



397 







 



398 







 



399 







 



400 







 



401 







 



402 







 



403 







 



404 






















TABLE 62





Ex 
Str







405 






 


406 






 


407 






 


408 






 


409 






 


410 






 


411 






 


412 






 


413 






 


414 






 


415 






 


416 






 


417 






 


418 





















TABLE 63





Ex 
Str







419 






 


420 






 


421 






 


422 






 


423 






 


424 






 


425 






 


426 






 


427 






 


428 






 


429 






 


430 





















TABLE 64





Ex 
Str







431 






 


432 






 


433 






 


434 






 


435 






 


436 






 


437 






 


438 






 


439 






 


440 






 


441 






 


442 





















TABLE 65





Ex 
Str







443 






 


444 






 


445 






 


446 






 


447 






 


448 






 


449 






 


450 






 


451 






 


452 





















TABLE 66





Ex 
Str







453 






 


454 






 


455 






 


456 






 


457 






 


458 






 


459 






 


460 






 


461 






 


462 





















TABLE 67





Ex 
Str







463 






 


464 






 


465 






 


466 






 


467 






 


468 






 


469 






 


470 






 


471 






 


472 





















TABLE 68





Ex 
Str







473 






 


474 






 


475 






 


476 






 


477 






 


478 






 


479 






 


480 






 


481 






 


482 






 


483 






 


484 






 


485 






 


486 






 


487 






 


488 





















TABLE 69





Ex 
Str







489 






 


490 






 


491 






 


492 






 


493 






 


494 






 


495 






 


496 






 


497 






 


498 






 


499 






 


500 






 


501 






 


502 






 


503 






 


504 





















TABLE 70





Ex
Str







505






 


506






 


507






 


508






 


509






 


510






 


511






 


512






 


513






 


514






 


515






 


516






 


517






 


518





















TABLE 71





Ex
Str







519






 


520






 


521






 


522






 


523






 


524






 


525






 


526






 


527






 


528






 


529






 


530






 


531






 


532






 


533






 


534





















TABLE 72





Ex
Str







535






 


536






 


537






 


538






 


539






 


540






 


541






 


542






 


543






 


544






 


545






 


546






 


547






 


548






 


549






 


550





















TABLE 73





Ex
Str







551






 


552






 


553






 


554






 


555






 


556






 


557






 


558






 


559






 


560






 


561






 


562






 


563






 


564






 


565






 


566





















TABLE 74





Ex
Str







567






 


568






 


569






 


570






 


571






 


572






 


573






 


574






 


575






 


576






 


577






 


578






 


579






 


580






 


581






 


582





















TABLE 75





Ex
Str







583






 


584






 


585






 


586






 


587






 


588






 


589






 


590






 


591






 


592






 


593






 


594






 


595






 


596





















TABLE 76





Ex
Str







597






 


598






 


599






 


600






 


601






 


602






 


603






 


604






 


605






 


606






 


607






 


608






 


609






 


610























TABLE 77







Ex
Str









611







 



612







 



613







 



614







 



615







 



616







 



617







 



618







 



619







 



620







 



621







 



622







 



623







 



624






















TABLE 78





Ex
Str







625






 


626






 


627






 


628






 


629






 


630






 


631






 


632






 


633






 


634






 


635






 


636





















TABLE 79





Ex
Str







637






 


638






 


639






 


640






 


641






 


642






 


643






 


644






 


645






 


646






 


647






 


648






 


649






 


650























TABLE 80







Ex
Str









651







 



652







 



653







 



654







 



655







 



656







 



657







 



658






















TABLE 81





Ex
Str







659






 


660






 


661






 


662






 


663






 


664






 


665






 


666






 


667






 


668






 


669






 


670






 


671






 


672





















TABLE 82





Ex
Str







673






 


674






 


675






 


676






 


677






 


678






 


679






 


680






 


681






 


682






 


683






 


684






 


685






 


686





















TABLE 83





Ex
Str







687






 


688






 


689






 


690






 


691






 


692






 


693






 


694






 


695






 


696






 


697






 


698





















TABLE 84





Ex
Str







699






 


700






 


701






 


702






 


703






 


704






 


705






 


706






 


707






 


708






 


709






 


710





















TABLE 85





Ex
Str







711






 


712






 


713






 


714






 


715






 


716






 


717






 


718






 


719






 


720






 


721






 


722





















TABLE 86





Ex
Str







723






 


724






 


725






 


726






 


727






 


728






 


729






 


730





















TABLE 87





Ex
Str







731






 


732






 


733






 


734






 


735






 


736






 


737






 


738






 


739






 


740





















TABLE 88





Ex
Str







741






 


742






 


743  744






 









 


745






 


746






 


747






 


748






 


749






 


750






 


751






 


752























TABLE 89







Ex
Str









753







 



754







 



755 756







 











 



757







 



758 759







 











 



760







 



761







 



762






















TABLE 90





Ex
Str







763






 


764






 


765






 


766 767






 









 


768






 


769 770






 









 


771






 


772






 


773






 


774





















TABLE 91





Ex
Str







775






 


776






 


777






 


778






 


779






 


780






 


781






 


782






 


783






 


784






 


785






 


788






 


786






 
























TABLE 92





Ex
Str







787






 









 


789






 


790






 


791






 


792






 


793






 


794






 


795






 


796






 


797






 









 


798






 
























TABLE 93





Ex
Str







799






 


800






 


801






 


802






 


803






 


804






 


805






 


806






 


807






 


808






 


809






 


810





















TABLE 94





Ex
Str







811






 


812






 


813






 


814






 


815






 


816






 


817






 


818






 


819






 


820






 


821






 


822






 


823






 


824





















TABLE 95





Ex
Str







825






 


826






 


827






 


828






 


829






 


830






 


831






 


832






 


833






 


834






 


835






 


836





















TABLE 96





Ex
Str







837






 


838






 


839






 


840






 


841






 


842






 


843






 


844






 


845






 


846






 


847






 


848





















TABLE 97





Ex
Str







 


849






 


850






 


851






 


852






 


853






 


854






 


855






 


856






 


857






 


858






 


859






 


860





















TABLE 98





Ex
Str







861






 


862






 


863






 


864






 


865






 


866






 


867






 


868






 


869






 


870 871






 









 


872





















TABLE 99





Ex
Str







873






 


874






 


875






 


876






 


877






 


878






 


879






 


880






 


881






 


882






 


883






 


884






 


885






 


886






 


887






 


888






 


889






 


890






 


891






 


892






















TABLE 100





Ex
Syn
Dat

















1
Ex1
ESI+: 471


2
Ex2
ESI+: 508


3
Ex3
ESI+: 492


4
Ex4
ESI+: 433


5
Ex5
ESI+: 371


6
Ex6
ESI+: 371


7
Ex7
ESI+: 457


8
Ex8
ESI+: 485


9
Ex9
ESI+: 521


10
Ex10
ESI+: 414


11
Ex11
ESI+: 450


12
Ex12
NMR(DMSO-d6): 0.91 (3H, d, J = 6.6 Hz), 0.93 (3H,




d, J = 6.5 Hz), 1.01-1.36 (6H, m), 1.53-1.90 (8H, m),




2.43-2.56 (2H, m), 2.51 (3H, s), 3.95 (2H, d, J = 6.1




Hz), 4.37-4.48 (1H, m), 6.77 (1H, d, J = 7.0 Hz), 6.85




(1H, t, J = 7.2 Hz), 7.71 (1H, d, J = 9.0 Hz), 8.46 (1H,




d, J = 6.1 Hz), 12.22 (1H, s); ESI+: 416


13
Ex13
ESI+: 454


14
Ex14
ESI+: 436


15
Ex15
ESI+: 464


16
Ex16
ESI+: 371


17
Ex17
ESI+: 606


18
Ex18
ESI+: 450


19
Ex19
ESI+: 407


20
Ex20
ESI+: 443


21
Ex21
ESI+: 452


22
Ex22
ESI+: 410


23
Ex23
ESI+: 328


24
Ex24
ESI+: 422


25
Ex25
ESI+: 450


26
Ex26
ESI+: 438


27
Ex27
ESI+: 411


28
Ex28
ESI+: 421


29
Ex29
ESI+: 401


30
Ex30
ESI+: 506


















TABLE 101





Ex
Syn
Dat







31
Ex31
ESI+: 534


32
Ex32
ESI+: 441


33
Ex33
ESI+: 475


34
Ex34
ESI+: 385


35
Ex35
ESI+: 513


36
Ex1
ESI+: 462


37
Ex1
ESI+: 504


38
Ex1
ESI+: 402


39
Ex1
ESI+: 416


40
Ex1
ESI+: 374


41
Ex1
ESI+: 388


42
Ex1
ESI+: 402


43
Ex1
ESI+: 402


44
Ex1
ESI+: 456


45
Ex1
ESI+: 516


46
Ex1
ESI+: 480


47
Ex1
ESI+: 472


48
Ex1
ESI+: 437


49
Ex1
ESI+: 451


50
Ex1
ESI+: 457


51
Ex1
ESI+: 471


52
Ex1
ESI+: 450


53
Ex1
ESI+: 374


54
Ex1
ESI+: 486


55
Ex1
ESI+: 442


56
Ex1
ESI+: 430


57
Ex1
ESI+: 456, 458


58
Ex1
ESI+: 431


59
Ex1
ESI+: 464


60
Ex1
ESI+: 456, 458


















TABLE 102





Ex
Syn
Dat







61
Ex1
ESI+: 577


62
Ex1
ESI+: 518


63
Ex1
ESI+: 456, 458


64
Ex1
ESI+: 458


65
Ex1
ESI+: 472


66
Ex1
ESI+: 457


67
Ex1
ESI+: 440


68
Ex1
ESI+: 440


69
Ex1
ESI+: 440


70
Ex1
ESI+: 498


71
Ex1
ESI+: 415


72
Ex1
ESI+: 484


73
Ex1
ESI+: 537


74
Ex1
ESI+: 458


75
Ex1
ESI+: 428


76
Ex1
ESI+: 543


77
Ex1
ESI+: 484


78
Ex1
ESI+: 414


79
Ex1
ESI+: 499


80
Ex1
ESI+: 464


81
Ex1
ESI+: 456


82
Ex1
ESI+: 456


83
Ex1
ESI+: 486


84
Ex1
ESI+: 456


85
PEx11, Ex1
ESI+: 472


86
Ex1
ESI+: 471


87
Ex1
ESI+: 498


88
Ex1
ESI+: 515


89
Ex1
ESI+: 487


90
Ex1
ESI+: 357


















TABLE 103





Ex
Syn
Dat

















91
Ex1
ESI+: 512


92
Ex1
ESI+: 498


93
Ex1
ESI+: 484


94
Ex1
ESI+: 606


95
Ex1
ESI+: 473


96
Ex1, 16
ESI+: 360


97
Ex1, 16
ESI+: 374


98
Ex1, 16
ESI+: 409


99
Ex1, 16
ESI+: 409


100
Ex1, 16
ESI+: 409


101
Ex1, 16
ESI+: 435


102
Ex1, 16
ESI+: 408


103
Ex1, 16
ESI+: 360


104
Ex1, 16
ESI+: 342


105
Ex1, 16
ESI+: 401


106
Ex1, 16
ESI+: 386


107
Ex1, 16
ESI+: 422


108
Ex1, 16
ESI+: 462


109
Ex1, 16
ESI+: 374


110
Ex1, 16
ESI+: 388


111
Ex1, 16
ESI+: 422


112
Ex1, 16
ESI+: 360


113
Ex1, 16
ESI+: 346


114
Ex1, 16
ESI+: 388


115
Ex1, 16
ESI+: 420


116
Ex1, 16
ESI+: 332


117
Ex1, 16
ESI+: 346


118
Ex1, 16
ESI+: 388


119
Ex1, 16
ESI+: 438


120
Ex1, 16
ESI+: 461


















TABLE 104





Ex
Syn
Dat







121
Ex1, 16
ESI+: 374


122
Ex1, 16
ESI+: 394


123
Ex1, 16
ESI+: 440


124
Ex1, 16
ESI+: 440


125
Ex1, 16
ESI+: 440


126
Ex1, 16
NMR(DMSO-d6): 1.05-1.36 (5H, m), 1.63-1.79 (3H,




m), 1.82-1.95 (3H, m), 2.66 (3H, s), 3.53-3.63 (4H, m),




3.97-4.07 (1H, m), 4.11 (2H, d, J = 6.1 Hz), 7.37 (1H,




t, J = 7.3 Hz), 7.44 (1H, d, J = 7.9 Hz), 8.29 (1H, d,




J = 6.7 Hz), 8.63 (1H, d, J = 6.5 Hz); ESI+: 362


127
Ex1, 16
ESI+: 406


128
Ex1, 16
ESI+: 406


129
Ex1, 16
ESI+: 436


130
Ex1, 16
ESI+: 394


131
Ex1, 16
ESI+: 395


132
Ex1, 16
ESI+: 422


133
Ex1, 16
ESI+: 456, 458


134
Ex1, 16
ESI+: 452


135
Ex1, 16
ESI+: 318


136
Ex1, 16
ESI+: 450


137
Ex1, 16
ESI+: 420


138
Ex1, 16
ESI+: 420


139
Ex1, 16
ESI+: 420


140
Ex1, 16
ESI+: 420


141
Ex1, 16
ESI+: 359


142
Ex1, 16
ESI+: 376


143
Ex1, 16
ESI+: 376


144
Ex1, 16
ESI+: 442, 444


145
Ex1, 16
ESI+: 440


146
Ex1, 16
ESI+: 440


147
Ex1, 16
ESI+: 441


148
Ex1, 16
ESI+: 362


149
Ex1, 16
ESI+: 362


150
Ex1, 16
ESI+: 442, 444


















TABLE 105





Ex
Syn
Dat







151
Ex1, 16
ESI+: 414


152
Ex1, 16
ESI+: 429


153
Ex1, 16
ESI+: 376


154
Ex1, 16
ESI+: 426


155
Ex1, 16
ESI+: 426


156
Ex1, 16
ESI+: 438


157
Ex1, 16
ESI+: 438


158
Ex1, 16
ESI+: 438


159
Ex1, 16
ESI+: 390


160
Ex1, 16
ESI+: 394


161
Ex1, 16
ESI+: 392


162
Ex1, 16
ESI+: 414


163
Ex1, 16
ESI+: 398


164
Ex1, 16
ESI+ 398


165
Ex1, 16
ESI+: 399


166
Ex1, 16
ESI+: 372


167
Ex1, 16
ESI+: 386


168
Ex1, 16
ESI+: 422


169
Ex1, 16
ESI+: 434


170
Ex1, 16
ESI+: 415


171
Ex12
ESI+: 442


172
Ex12
ESI+: 402


173
Ex12
ESI+: 416


174
Ex12
ESI+: 428


175
Ex12
ESI+: 428


176
Ex12
ESI+: 416


177
Ex12
ESI+: 430


178
Ex12
ESI+: 442


179
Ex12
ESI+: 428


180
Ex12
ESI+: 442


















TABLE 106





Ex
Syn
Dat







181
Ex12, 16
ESI+: 374


182
Ex13
ESI+: 470, 472


183
Ex13
ESI+: 470, 472


184
Ex13
ESI+: 470, 472


185
Ex13
ESI+: 454


186
Ex13
ESI+: 454


187
Ex16
ESI+: 464


188
Ex16
ESI+: 402


189
Ex16
ESI+: 462


190
Ex2
ESI+: 558


191
Ex2
ESI+: 522


192
Ex2
ESI+: 510


193
Ex2
ESI+: 562


194
Ex2
ESI+: 536


195
Ex2
ESI+: 550


196
Ex2
ESI+: 540


197
Ex2
ESI+: 540


198
Ex2
ESI+: 556, 558


199
Ex2
ESI+: 572


200
Ex3
ESI+: 426


201
Ex3, 16
ESI+: 458


202
Ex3, 16
ESI+: 444


203
Ex3, 16
ESI+: 408


204
Ex3, 16
ESI+: 394


205
Ex3, 16
ESI+: 396


206
Ex3, 16
ESI+: 448


207
Ex3, 16
ESI+: 422


208
Ex3, 16
ESI+: 436


209
Ex3, 16
ESI+: 426


210
Ex3, 16
ESI+: 442, 444


















TABLE 107





Ex
Syn
Dat







211
Ex5
ESI+: 371


212
Ex5
ESI+: 357


213
Ex5
ESI+: 331


214
Ex5
ESI+: 357


215
Ex5
ESI+: 443


216
Ex5
ESI+: 399


217
Ex5
ESI+: 371


218
Ex5
ESI+: 415


219
Ex5
ESI+: 387


220
Ex5
ESI+: 373


221
Ex6
ESI+: 457


222
Ex6
ESI+: 457


223
Ex6
ESI+: 429


224
Ex6
ESI+: 387


225
Ex6, 16
ESI+: 401


226
Ex6, 16
ESI+: 385


227
Ex6, 16
ESI+: 385


228
Ex6, 16
ESI+: 371


229
Ex6, 16
ESI+: 415


230
Ex6, 16
ESI+: 413


231
Ex7, 16
ESI+: 399


232
Ex8
ESI+: 462


233
Ex8
ESI+: 485


234
Ex8, 16
ESI+: 413


235
Ex8, 16
ESI+: 399


236
Ex8, 16
ESI+: 413


237
Ex9
ESI+: 521


238
Ex9, 16
ESI+: 449


239
PEx1, Ex3, 16
ESI+: 382


240
PEx1, Ex3, 16
ESI+: 396


















TABLE 108





Ex
Syn
Dat







241
PEx1, Ex3, 16
ESI+: 396


242
PEx1, Ex3, 16
ESI+: 394


243
PEx1, Ex3, 16
ESI+: 396


244
PEx1, Ex3, 16
ESI+: 456


245
PEx1, Ex3, 16
ESI+: 456


246
PEx12, Ex8
ESI+: 450


247
Ex1
ESI+: 480


248
PEx5
ESI+: 422


249
PEx5
ESI+: 436


250
PEx5
ESI+: 422


251
PEx5
NMR(DMSO-d6): 1.01-1.34 (5H, m), 1.63-1.77




(3H, m), 1.77-1.90 (3H, m), 2.55 (3H, s), 2.82




(1H, dd, J = 5.9, 15.7 Hz), 2.91 (1H, dd, J = 8.7,




15.7 Hz), 3.95 (2H, d, J = 6.2 Hz), 5.41-5.49




(1H, m), 6.77 (1H, dd, J = 0.9, 7.8 Hz), 6.84 (1H,




dd, J = 6.9, 7.6 Hz), 7.25 (1H, t, J = 7.3 Hz),




7.35 (2H, t, J = 7.6 Hz), 7.45 (2H, d, J = 7.3




Hz), 8.38 (1H, d, J = 8.4 Hz), 8.43 (1H, dd,




J = 0.9, 6.8 Hz), 12.39 (1H, s); ESI+: 436


252
PEx5
ESI+: 448


253
PEx5
ESI+: 450


254
PEx5
ESI+: 490


255
PEx5
ESI+: 388


256
PEx5
ESI+: 346


257
PEx5
ESI+: 360


258
PEx5
ESI+: 374


259
PEx5
ESI+: 388


260
PEx5
ESI+: 442


261
PEx5
ESI+: 466


262
PEx5
ESI+: 429


263
PEx5
ESI+: 360


264
PEx5
ESI+: 428


265
PEx5
ESI+: 464


266
PEx5
ESI+: 504


267
PEx5
ESI+: 563


268
PEx5
ESI+: 429


269
PEx5
ESI+: 507


270
PEx5
ESI+: 471


















TABLE 109





Ex
Syn
Dat







271
PEx5
ESI+: 443


272
PEx5
ESI+: 430


273
PEx5
ESI+: 414


274
PEx5
ESI+: 400


275
PEx5
ESI+: 450


276
PEx5
ESI+: 429


277
PEx5
ESI+: 442


278
PEx5
ESI+: 442


279
PEx5
ESI+: 507


280
PEx5
ESI+: 471


281
PEx5
ESI+: 443


282
PEx5
ESI+: 442


283
PEx5
ESI+: 401


284
PEx5
ESI+: 415


285
PEx5, Ex16
ESI+: 423


286
PEx5, Ex16
ESI+: 423


287
PEx5, Ex16
ESI+: 436


288
PEx5, Ex16
ESI+: 450


289
PEx5, Ex16
ESI+: 434


290
Ex 6
ESI+: 519


291
PEx5
ESI+: 505


292
Ex1, 16
ESI+: 477


293
Ex1
ESI+: 440


294
PEx5
ESI+: 412


295
Ex1
ESI+: 413, 415


296
Ex1
ESI+: 288


297
Ex1
ESI+: 413


298
Ex31, 16
ESI+: 534.5


299
Ex3, 16
ESI+: 404


300
Ex1
ESI+: 547


301
Ex1
ESI+: 464


302
PEx5
ESI+: 450


303
Ex3, 16
ESI+: 404


304
Ex3, 16
ESI+: 421


















TABLE 110





Ex
Syn
Dat







305
PEx1
ESI+: 508


306
PEx5
ESI+: 480


307
Ex3, 16
ESI+: 404


308
PEx5
ESI+: 519


309
PEx5
ESI+: 506


310
Ex 1
ESI+: 547


311
PEx5
ESI+: 519


312
Ex1
ESI+: 471


313
PEx 5
ESI+: 443


314
Ex1
ESI+: 408


315
PEx5
ESI+: 506


316
PEx12, Ex8
ESI+: 318


317
PEx12, Ex8
ESI+: 332


318
Ex6
ESI+: 471


319
PEx5
ESI+: 443


320
Ex1
ESI+: 504


321
Ex12
NMR(DMSO-d6): 1.01-1.36 (5H, m), 1.62-1.77




(3H, m), 1.78-1.91 (3H, m), 2.55 (3H, s), 3.10 (1H,




dd, J = 9.0, 15.3 Hz), 3.22-3.37 (2H, m), 3.96 (2H,




d, J = 6.2 Hz), 5.79 (1H, t, J = 8.5 Hz), 6.80 (1H,




d, J = 7.1 Hz), 6.90 (1H, t, J = 7.3 Hz), 7.21-7.32




(4H, m), 8.43 (1H, d, J = 8.7 Hz), 8.55 (1H, d, J =




6.1 Hz), 12.00-12.80 (1H, br); ESI+: 448


322
Ex1
ESI+: 450


323
PEx5
NMR(DMSO-d6): 1.01-1.34 (5H, m), 1.53 (3H,




d, J = 7.0 Hz), 1.63-1.77 (3H, m), 1.78-1.90




(3H, m), 2.58 (3H, s), 3.95 (2H, d, J = 6.1 Hz),




5.18-5.27 (1H, m), 6.77 (1H, d, J = 7.2 Hz), 6.83




(1H, t, J = 7.2 Hz), 7.48 (1H, t, J = 7.7 Hz), 7.69




(1H, d, J = 7.8 Hz), 7.83 (1H, d, J = 7.7 Hz),




8.05 (1H, s), 8.41 (2H, d, J = 6.7 Hz), 12.93 (1H,




s); ESI+: 436


324
PEx5
ESI+: 422


325
Ex1
ESI+: 502


326
Ex1
ESI+: 484


327
Ex9
ESI+: 521


328
Ex1
ESI+: 470


329
Ex1
ESI+: 520


330
Ex1
ESI+: 470


















TABLE 111





Ex
Syn
Dat







331
Ex1
ESI+: 520


332
Ex1
ESI+: 508


333
Ex1
ESI+: 450


334
Ex1
ESI+: 506


335
Ex1
ESI+: 466


336
Ex1
ESI+: 528


337
Ex1
ESI+: 478


338
Ex1
ESI+: 432


339
Ex1
ESI+: 432


340
Ex1
ESI+: 390


341
Ex6, 16
ESI+: 371


342
Ex1, 16
ESI+: 362


343
Ex1, 16
ESI+: 441


344
Ex19
ESI+: 407


345
Ex1
ESI+: 472


346
Ex1
ESI+: 456


347
PEx15
ESI+: 303


348
Ex12
ESI+: 456


349
Ex6
ESI+: 385


350
Ex1
ESI+: 376


351
Ex1
ESI+: 438


352
Ex1
ESI+: 442


353
PEx5
ESI+: 428


354
Ex1, 16
ESI+: 411


355
Ex11
ESI+: 450


356
Ex11
ESI+: 436


357
Ex1
ESI+: 473


358
Ex5
ESI+: 373


359
Ex6, 16
ESI+: 387


360
Ex1
ESI+: 406


















TABLE 112





Ex
Syn
Dat







361
Ex1
ESI+: 515


362
Ex5
ESI+: 415


363
PEx5
ESI+: 401


364
Ex6
ESI+: 429


365
Ex1, 16
ESI+: 413


366
Ex6, 16
ESI+: 413


367
Ex9, 16
ESI+: 475


368
PEx5
ESI+: 415


369
Ex1
ESI+: 436


370
Ex13
ESI+: 450


371
Ex11
ESI+: 436


372
Ex1, 16
ESI+: 415


373
Ex1, 16
ESI+: 397


374
Ex27, 16
ESI+: 397


375
PEx5
ESI+: 493


376
Ex9, 16
ESI+: 449


377
Ex1
ESI+: 473


378
Ex5
ESI+: 373


379
Ex6
ESI+: 387


380
Ex1
ESI+: 473


381
Ex5
ESI+: 373


382
Ex6
ESI+: 387


383
Ex1, 16
ESI+: 430


384
Ex1, 16
ESI+: 413


385
Ex12
ESI+: 446


386
Ex12
ESI+: 428


387
Ex1
ESI+: 471


388
Ex5
ESI+: 371


389
Ex12
ESI+: 414


390
Ex27, 16
ESI+: 397


















TABLE 113





Ex
Syn
Dat







391
Ex9, 16
ESI+: 435


392
Ex12
ESI+: 464


393
Ex9, 16
ESI+: 449


394
Ex8, 16
ESI+: 413


395
Ex6
ESI+: 385


396
Ex1
ESI+: 529


397
Ex5
ESI+: 429


398
PEx5
ESI+: 401


399
Ex9, 16
ESI+: 435


400
Ex12
ESI+: 414


401
Ex6
ESI+: 443


402
PEx5
ESI+: 415


403
Ex1
ESI+: 436


404
Ex6, 16
ESI+: 425


405
Ex6, 16
ESI+: 468


406
Ex9, 16
ESI+: 511


407
Ex1, 16
ESI+: 415


408
Ex1, 16
ESI+: 397


409
PEx11, Ex1
ESI+: 446


410
PEx5
ESI−: 418


411
Ex1
ESI+: 506


412
Ex12
ESI+: 464


413
Ex12
ESI+: 450


414
Ex1
ESI+: 436


415
Ex1
ESI+: 436


416
Ex1
ESI+: 436


417
Ex1
ESI+: 450


418
Ex12
ESI+: 452


419
PEx5
ESI+: 436


420
Ex1, 16
ESI+: 438


















TABLE 114





Ex
Syn
Dat







421
Ex12
ESI+: 450


422
Ex1, 16
ESI+: 426


423
Ex1, 16
ESI+: 456


424
Ex1, 16
ESI+: 468




NMR(DMSO-d6): 2.70 (3H, s), 3.99 (4H, s), 5.45 (2H,




s), 7.19-7.37 (6H, m), 7.39-7.43 (2H, m), 7.45-7.66




(2H, m), 7.85-8.10 (1H, m), 8.65 (1H, d, J = 6.9 Hz)


425
PEx5
ESI+: 418


426
PEx5
ESI+: 418


427
Ex12
ESI+: 472


428
PEx5
ESI+: 452


429
PEx5
ESI+: 450


430
Ex1, 16
ESI+: 450




NMR(DMSO-d6): 2.63 (3H, s), 2.79 (1H, dd, J = 7.9,




15.5 Hz), 3.19 (1H, dd, J = 7.3, 15.5 Hz), 4.40-4.50




(1H, m), 5.33 (1H, t, J = 7.8 Hz), 5.47 (2H, s), 7.18-




7.30 (6H, m), 7.37-7.50 (1H, m), 7.55-7.70 (2H, m),




8.79 (1H, d, J = 6.7 Hz), 8.84-8.96 (1H, m)


431
Ex1, 16
ESI+: 450


432
Ex1, 16
ESI+: 450


433
Ex1
ESI+: 534


434
Ex12
ESI+: 478


435
Ex1, 16
ESI+: 444


436
Ex1, 16
ESI+: 456


437
Ex6, 16
ESI+: 399


438
Ex9, 16
ESI+: 478


439
Ex1, 16
ESI+: 346


440
Ex1
ESI+: 478


441
Ex1
ESI+: 476


442
Ex1
ESI+: 302


443
PEx5
ESI+: 450


444
PEx5
ESI+: 448


445
Ex9, 16
ESI+: 464


446
Ex6
ESI+: 519


447
PEx5
ESI+: 464


448
Ex1
ESI+: 478


449
Ex1
ESI+: 492


450
Ex1
ESI+: 484


















TABLE 115





Ex
Syn
Dat







451
PEx5
ESI+: 505


452
PEx5
ESI+: 470


453
PEx5
ESI+: 464


454
Ex1
ESI+: 442


455
PEx5
ESI+: 428


456
Ex1
ESI+: 506


457
Ex12
ESI+: 450


458
Ex1
ESI+: 408


459
Ex6
ESI+: 519


460
PEx1, Ex3, 16
ESI+: 444


461
PEx5
ESI+: 505


462
Ex1
ESI+: 480


463
Ex1
ESI+: 394


464
Ex1
ESI+: 427


465
Ex1
ESI+: 441


466
PEx5
ESI+: 413


467
PEx5
ESI+: 466


468
PEx5
ESI+: 413


469
PEx1
ESI+: 480


470
PEx5
ESI+: 452


471
PEx1
ESI+: 494


472
PEx5
ESI+: 466


473
Ex23
ESI+: 330


474
Ex23
ESI+: 344


475
Ex23
ESI+: 330


476
Ex23
ESI+: 344


477
Ex1
ESI+: 505


478
Ex23
ESI+: 342


479
Ex23
ESI+: 356


480
Ex23
ESI+: 370


















TABLE 116





Ex
Syn
Dat







481
Ex23
ESI+: 384


482
Ex23
ESI+: 358


483
Ex23
ESI+: 408


484
Ex23
ESI+: 360


485
Ex23
ESI+: 438


486
Ex23
ESI+: 376


487
Ex23
ESI+: 374


488
Ex23
ESI+: 412


489
Ex23
ESI+: 412


490
Ex23
ESI+: 386


491
Ex23
ESI+: 346


492
Ex23
ESI+: 360


493
Ex23
ESI+: 360


494
Ex23
ESI+: 372


495
Ex23
ESI+: 400


496
Ex23
ESI+: 420


497
Ex23
ESI+: 359


498
Ex23
ESI+: 387


499
Ex23
ESI+: 373


500
Ex23
ESI+: 401


501
Ex23
ESI+: 399


502
Ex23
ESI+: 399


503
Ex23
ESI+: 385


504
Ex23
ESI+: 399


505
Ex23
ESI+: 399


506
Ex23
ESI+: 415


507
Ex23
ESI+: 413


508
Ex23
ESI+: 399


509
Ex23
ESI+: 397


510
Ex23
ESI+: 397


















TABLE 117





Ex
Syn
Dat







511
Ex23
ESI+: 428


512
Ex23
ESI+: 414


513
Ex23
ESI+: 413


514
Ex23
ESI+: 399


515
Ex23
ESI+: 413


516
Ex23
ESI+: 399


517
Ex23
ESI+: 399


518
Ex23
ESI+: 449


519
Ex23
ESI+: 463


520
Ex23
ESI+: 379


521
Ex23
ESI+: 379


522
Ex23
ESI+: 379


523
Ex23
ESI+: 393


524
Ex23
ESI+: 393


525
Ex23
ESI+: 393


526
Ex23
ESI+: 407


527
Ex23
ESI+: 407


528
Ex23
ESI+: 378


529
Ex23
ESI+: 392


530
Ex23
ESI+: 392


531
Ex23
ESI+: 392


532
Ex23
ESI+: 396


533
Ex23
ESI+: 396


534
Ex23
ESI+: 392


535
Ex23
ESI+: 406


536
Ex23
ESI+: 406


537
Ex23
ESI+: 410


538
Ex23
ESI+: 454


539
Ex23
ESI+: 406


540
Ex23
ESI+: 408


















TABLE 118





Ex
Syn
Dat







541
Ex23
ESI+: 408


542
Ex23
ESI+: 422


543
Ex23
ESI+: 422


544
Ex23
ESI+: 463


545
Ex23
ESI+: 408


546
Ex23
ESI+: 447


547
Ex23
ESI+: 447


548
Ex23
ESI+: 461


549
Ex23
ESI+: 465


550
Ex23
ESI+: 372


551
Ex23
ESI+: 386


552
Ex23
ESI+: 386


553
Ex23
ESI+: 386


554
Ex23
ESI+: 400


555
Ex23
ESI+: 433


556
Ex23
ESI+: 408


557
Ex23
ESI+: 413


558
Ex23
ESI+: 375


559
Ex26
ESI+: 422


560
Ex26
ESI+: 380


561
Ex26
ESI+: 382


562
Ex26
ESI+: 368


563
Ex26
ESI+: 410


564
Ex26
ESI+: 480, 482


565
Ex26
ESI+: 416


566
Ex26
ESI+: 436, 438


567
Ex26
ESI+: 427


568
PEx5
ESI+: 491


569
Ex26
ESI+: 438


570
Ex26
ESI+: 454, 456


















TABLE 119





Ex
Syn
Dat







571
Ex26
ESI+: 434


572
Ex26
ESI+: 438


573
Ex26
ESI+: 454, 456


574
Ex26
ESI+: 456


575
Ex26
ESI+: 488


576
Ex26
ESI+: 456


577
Ex26
ESI+: 420


578
Ex26
ESI+: 438


579
Ex26
ESI+: 438


580
Ex26
ESI+: 420


581
Ex26
ESI+: 416


582
Ex26
ESI+: 403


583
Ex26
ESI+: 442, 444


584
Ex26
ESI+: 444, 446


585
Ex26
ESI+: 407


586
Ex26
ESI+: 443, 445


587
Ex26
ESI+: 423


588
Ex24
ESI+: 436


589
Ex24
ESI+: 376


590
Ex1
ESI+: 506


591
Ex24
ESI+: 438


592
Ex24
ESI+: 386


593
Ex24
ESI+: 402


594
Ex24
ESI+: 420


595
Ex24
ESI+: 402


596
Ex24
ESI+: 430


597
Ex24
ESI+: 500, 502


598
Ex24
ESI+: 428


599
Ex24
ESI+: 428


600
Ex24
ESI+: 400


















TABLE 120





Ex
Syn
Dat







601
Ex24
ESI+: 386


602
Ex24
ESI+: 400


603
Ex24
ESI+: 402


604
Ex24
ESI+: 450


605
Ex24
ESI+: 514, 516


606
Ex24
ESI+: 480


607
Ex24
ESI+: 478


608
Ex24
ESI+: 464


609
Ex24
ESI+: 504


610
Ex24
ESI+: 481


611
Ex24
ESI+: 452


612
Ex24
ESI+: 504


613
Ex24
ESI+: 480


614
Ex24
ESI+: 514, 516


615
Ex24
ESI+: 450


616
Ex24
ESI+: 450


617
Ex24
ESI+: 464


618
Ex24
ESI+: 514, 516


619
Ex24
ESI+: 478


620
Ex24
ESI+: 496


621
Ex24
ESI+: 494


622
Ex24
ESI+: 464


623
Ex24
ESI+: 472


624
Ex24
ESI+: 464


625
Ex24
ESI+: 430


626
Ex24
ESI+: 414


627
Ex24
ESI+: 400


628
Ex24
ESI+: 436


629
Ex24
ESI+: 374


630
Ex24
ESI+: 428


















TABLE 121





Ex
Syn
Dat







631
Ex24
ESI+: 414


632
Ex24
ESI+: 414


633
Ex24
ESI+: 422


634
Ex24
ESI+: 422


635
Ex24
ESI+: 436


636
Ex24
ESI+: 428


637
Ex24
ESI+: 436


638
Ex24
ESI+: 436


639
Ex24
ESI+: 505


640
Ex23
ESI+: 370


641
PEx5
ESI+: 492


642
Ex25
ESI+: 414


643
Ex23
ESI+: 368


644
Ex23
ESI+: 368


645
Ex23
ESI+: 412


646
Ex23
ESI+: 369


647
Ex23
ESI+: 382


648
Ex23
ESI+: 381


649
Ex23
ESI+: 399


650
Ex23
ESI+: 447


651
Ex23
ESI+: 413, 415


652
Ex23
ESI+: 410


653
Ex23
ESI+: 422


654
Ex23
ESI+: 404


655
Ex23
ESI+: 418


656
Ex1
ESI+: 450


657
Ex1,16
ESI+: 456


658
Ex1,16
ESI+: 406


















TABLE 122





Ex
Syn
Dat







659
Ex1
ESI+: 476


660
Ex12
ESI+: 454


661
Ex661
ESI+: 462


662
PEx5
ESI+: 448


663
Ex663
APCI/ESI+: 476


664
PEx11,
ESI+: 480



Ex1


665
Ex1
ESI+: 462


666
Ex1
ESI+: 504


667
Ex1
ESI+: 480


668
Ex1
ESI+: 476


669
Ex1
ESI+: 476


670
Ex1
APCI/ESI+: 476


671
Ex1
ESI+: 510


672
Ex1
ESI+: 480


673
Ex1
ESI+: 506


674
Ex1
ESI+: 510


675
Ex1
ESI+: 518


676
Ex1
ESI+: 474


677
Ex1
ESI+: 492


678
Ex1
ESI+: 510


679
Ex1
ESI+: 510


680
Ex1
ESI+: 540


681
Ex1
ESI+: 510


682
Ex1
ESI+: 540


683
Ex1
ESI+: 480


684
Ex1
ESI+: 480


685
Ex1
ESI+: 480


686
Ex12
ESI+: 448


687
Ex12
ESI+: 462


688
Ex12
ESI+: 484


689
Ex12
ESI+: 454


690
Ex12
ESI+: 484


















TABLE 123





Ex
Syn
Dat







691
Ex661
ESI+: 466


692
Ex661
ESI+: 462


693
Ex661
ESI+: 462




NMR (DMSO-d6): 1.01-1.36 (5H, m), 1.62-1.77 (3H,




m), 1.77-1.90 (3H, m), 2.24 (3H, s), 2.54 (3H, s),




2.99 (1H, dd, J = 8.7, 15.6 Hz), 3.19-3.36 (2H, m),




3.96 (2H, d, J = 6.2 Hz), 5.79 (1H, t, J =




8.5 Hz), 6.80 (1H, dd, J = 0.8, 7.8 Hz), 6.89




(1H, t, J = 7.3 Hz), 7.06-7.18 (3H, m), 8.41




(1H, d, J = 8.7 Hz), 8.55 (1H, dd, J = 0.8,




6.8 Hz), 12.48 (1H, s)


694
Ex661
APCI/ESI+: 462


695
Ex661
APCI/ESI+: 462


696
Ex661
ESI+: 496


697
Ex661
EI: 466


698
Ex661
ESI+: 492




NMR (DMSO-d6): 2.24 (3H, s), 2.51 (3H, s), 2.99 (1H,




dd, J = 8.7, 15.6 Hz), 3.19-3.36 (2H, m), 5.32 (2H, s),




5.79 (1H, t, J = 8.5 Hz), 6.96 (1H, t, J = 7.2 Hz),




7.03 (1H, dd, J = 0.9, 7.8 Hz), 7.06-7.18 (3H, m),




7.19-7.27 (2H, m), 7.54-7.63 (1H, m), 8.43 (1H, d, J =




8.7 Hz), 8.61 (1H, dd, J = 0.9, 6.8 Hz), 12.48




(1H, s)


699
Ex661
ESI+: 496




NMR (DMSO-d6): 2.47 (3H, s), 3.06-3.18 (1H, m),




3.33-3.43 (2H, m), 5.31 (2H, s), 5.97 (1H, t, J = 7.7 Hz),




6.95 (1H, t, J = 7.2 Hz), 6.99-7.06 (2H, m),




7.12 (1H, d, J = 7.5 Hz), 7.19-7.27 (2H, m), 7.32 (1H,




dt, Jd = 5.2, Jt = 7.7 Hz), 7.58 (1H, tt, J = 6.7,




8.5 Hz), 8.51-8.57 (2H, m), 12.56 (1H, s)


700
Ex661
ESI+: 460


701
Ex661
ESI+: 478


















TABLE 124





Ex
Syn
Dat







702
Ex661
ESI+: 496




NMR (DMSO-d6): 2.52 (3H, s), 3.10 (1H, dd, J = 8.9,




15.3 Hz), 3.22-3.38 (2H, m), 5.37 (2H, s),




5.79 (1H, t, J = 8.5 Hz), 6.97 (1H, t, J = 7.2 Hz),




7.03 (1H, dd, J = 0.9, 7.8 Hz), 7.22-7.33 (5H, m),




7.66 (1H, dq, Jd = 5.1, Jq = 9.6 Hz), 8.47




(1H, d, J = 8.8 Hz), 8.63 (1H, dd, J = 0.9,




6.8 Hz), 12.20-12.70 (1H, br)


703
Ex661
ESI+: 466


704
Ex661
NMR (DMSO-d6): 1.00-1.35 (5H, m), 1.62-1.77 (3H,




m), 1.77-1.90 (3H, m), 2.50 (3H, s), 3.05-3.18 (1H, m),




3.32-3.43 (2H, m), 3.96 (2H, d, J = 6.2 Hz), 5.96 (1H, t,




J = 7.6 Hz), 6.79 (1H, d, J = 7.6 Hz), 6.88




(1H, t, J = 7.3 Hz), 7.02 (1H, t, J = 9.0 Hz),




7.12 (1H, d, J = 7.5 Hz), 7.29-7.35 (1H, m),




8.46 (1H, d, J = 6.7 Hz), 8.52 (1H, d, J = 8.8 Hz),




12.55 (1H, s);




ESI+: 466


705
Ex661
ESI+: 466




NMR (DMSO-d6): 1.00-1.34 (5H, m), 1.62-1.77 (3H,




m), 1.77-1.90 (3H, m), 2.50 (3H, s), 3.05-3.18 (1H, m),




3.32-3.43 (2H, m), 3.96 (2H, d, J = 6.1 Hz), 5.97 (1H, t,




J = 7.7 Hz), 6.79 (1H, d, J = 7.0 Hz), 6.88




(1H, t, J = 7.3 Hz), 7.02 (1H, t, J = 9.0 Hz),




7.12 (1H, d, J = 7.5 Hz), 7.29-7.35 (1H, m),




8.46 (1H, dd, J = 0.9, 6.8 Hz), 8.52 (1H, d, J = 8.9 Hz),




12.57 (1H, s)


706
Ex661
ESI+: 466




NMR (DMSO-d6): 1.01-1.36 (5H, m), 1.62-1.78 (3H,




m), 1.78-1.91 (3H, m), 2.54 (3H, s), 3.10 (1H, dd, J =




9.1, 16.2 Hz), 3.23-3.42 (2H, m), 3.96 (2H, d, J =




6.1 Hz), 5.73 (1H, t, J = 8.4 Hz), 6.81 (1H,




d, J = 7.4 Hz), 6.90 (1H, t, J = 7.3 Hz), 7.06




(1H, dt, Jd = 2.3, Jt = 8.8 Hz), 7.12 (1H, dd,




J = 2.1, 9.1 Hz), 7.31 (1H, dd, J = 5.3, 8.1 Hz),




8.42 (1H, d, J = 8.6 Hz), 8.55 (1H, d, J = 6.8 Hz),




12.40-12.70 (1H, br)


707
Ex1
ESI+: 462


708
Ex1
ESI+: 492


709
Ex709
APCI/ESI+: 482


710
Ex710
ESI+: 532


711
Ex711
ESI+: 448


712
Ex712
ESI+: 480


713
Ex713
ESI+: 392


714
Ex714
ESI+: 496


715
Ex1
ESI+: 512


















TABLE 125





Ex
Syn
Dat







716
Ex1
NMR (CDCl3): 1.00-1.12 (2H, m), 1.15-1.38 (3H,




m), 1.66-1.81 (3H, m), 1.94-2.10 (3H, m), 2.85




(3H, s), 3.04 (2H, d, J = 5.0 Hz), 3.66 (3H, s),




3.95 (2H, d, J = 6.6 Hz), 5.68-5.74 (1H, m), 6.62




(1H, d, J = 7.7 Hz), 6.77 (1H, t, J = 7.1 Hz),




7.29 (1H, dd, J = 4.9 Hz, 8.0 Hz), 7.50 (1H, d,




J = 8.0 Hz), 7.71 (1H, d, J = 8.0 Hz),




8.54 (1H, d, J = 4.8 Hz), 8.67 (1H, s),




9.00 (1H, d, J = 6.8 Hz)


717
Ex1
ESI+: 478


718
Ex1
ESI+: 480


719
Ex1
ESI+: 454


720
Ex1
ESI+: 501


721
Ex1
ESI+: 409


722
Ex1
ESI+: 505


723
Ex1
ESI+: 498


724
Ex1
ESI+: 439


725
Ex1
ESI+: 450


726
Ex1
ESI+: 468


727
Ex1
ESI+: 505


728
Ex1
ESI+: 478


729
Ex1
ESI+: 508


730
Ex1
ESI+: 480


731
Ex1
ESI+: 506


732
Ex1
ESI+: 506


733
Ex1
ESI+: 508


734
Ex1
ESI+: 476


735
Ex1
ESI+: 466


736
Ex1
ESI+: 528


737
Ex1
ESI+: 478


738
Ex1
ESI+: 464


739
Ex1
ESI+: 472


740
PEx10, 11,
ESI+: 498



Ex1


741
Ex1
ESI+: 464


742
Ex1
ESI+: 464


















TABLE 126





Ex
Syn
Dat







743
Ex1
ESI+: 464


744
Ex1
ESI+: 464


745
Ex1
ESI+: 528


746
Ex1
ESI+: 414


747
Ex1
ESI+: 437


748
Ex1
ESI+: 476


749
Ex1
ESI+: 492


750
Ex1
ESI+: 522


751
Ex1
ESI+: 522


752
Ex1
ESI+: 464


753
Ex1
ESI+: 494


754
Ex1
ESI+: 462


755
Ex1
ESI+: 466


756
Ex1
ESI+: 466


757
Ex1
APCI/ESI+: 392


758
Ex1
ESI+: 466




NMR (DMSO-d6): 2.55 (3H, s), 4.11 (1H, q, J = 7.2 Hz),




4.74 (1H, t, J = 6.4 Hz), 5.20 (1H, t, J = 8.4 Hz),




5.32 (2H, s), 5.58 (1H, d, J = 6.3 Hz), 5.76 (1H, d, J =




5.9 Hz), 6.96 (1H, t, J = 7.2 Hz), 7.03 (1H, dd, J =




0.9, 7.7 Hz), 7.18-7.35 (6H, m), 7.59 (1H, tt, J = 6.7,




8.4 Hz), 8.33 (1H, d, J = 8.8 Hz), 8.64 (1H, dd, J =




0.8, 6.8 Hz)


759
Ex1
ESI+: 466




NMR (DMSO-d6): 2.53 (3H, s), 4.18 (1H, q, J = 6.4 Hz),




4.82 (1H, t, J = 5.1 Hz), 5.06 (1H, d, J = 5.1 Hz),




5.10 (1H, d, J = 6.9 Hz), 5.32 (2H, s), 5.45 (1H, t, J =




7.9 Hz), 6.96 (1H, t, J = 7.2 Hz), 7.02 (1H, dd,




J = 0.9, 7.8 Hz), 7.19-7.40 (6H, m), 7.59 (1H, tt,




J = 6.7, 8.5 Hz), 8.26 (1H, d, J = 8.8 Hz), 8.64




(1H, dd, J = 0.8, 6.7 Hz)


760
Ex1
ESI+: 468


761
Ex1
ESI+: 476


762
Ex1
ESI+: 496


763
Ex1
ESI+: 432


















TABLE 127





Ex
Syn
Dat







764
Ex1
ESI+: 482


765
Ex1
APCI/ESI+: 509


766
Ex1
ESI+: 494




NMR (DMSO-d6): 2.37 (4H, d, J = 5.3 Hz), 2.63 (3H,




s), 4.04-4.12 (2H, m), 4.69 (2H, d, J = 4.5 Hz),




5.31 (2H, s), 6.87 (1H, t, J = 7.3 Hz), 6.98 (1H, dd,




J = 0.7, 7.7 Hz), 7.17 (1H, t, J = 7.2 Hz), 7.23




(2H, t, J = 8.0 Hz), 7.30 (2H, t, J = 7.8 Hz),




7.37 (2H, dd, J = 1.2, 8.4 Hz), 7.58 (1H, tt, J =




6.7, 8.5 Hz), 8.21 (1H, s), 8.52 (1H, dd, J = 0.8,




6.9 Hz)


767
Ex1
ESI+: 494




NMR (DMSO-d6): 2.12 (2H, dd, J = 6.0, 14.2 Hz),




2.57 (3H, s), 2.64 (2H, dd, J = 6.2, 14.2 Hz), 4.10-4.18




(2H, m), 4.62 (2H, d, J = 4.3 Hz), 5.31 (2H, s), 6.89




(1H, t, J = 7.3 Hz), 6.98 (1H, d, J = 7.0 Hz), 7.17




(1H, t, J = 7.3 Hz), 7.23 (2H, t, J = 8.0 Hz), 7.30




(2H, t, J = 7.7 Hz), 7.46 (2H, dd, J = 1.1, 8.4 Hz),




7.59 (1H, tt, J = 6.7, 8.4 Hz), 8.19 (1H, s), 8.37 (1H, dd,




J = 0.8, 6.9 Hz)


768
Ex1
ESI+: 492


769
Ex1
ESI+: 462


770
Ex1
ESI+: 462


771
Ex1
ESI+: 432


772
Ex1
ESI+: 390




NMR (DMSO-d6): 1.35 (6H, s), 2.49 (3H, s), 3.52 (2H,




d, J = 5.7 Hz), 4.99 (1H, t, J = 5.7 Hz), 5.30 (2H, s),




6.91 (1H, t, J = 7.2 Hz), 6.99 (1H, dd, J = 0.9, 7.7 Hz),




7.14 (1H, s), 7.23 (2H, t, J = 8.0 Hz), 7.58 (1H, tt, J =




6.7, 8.5 Hz), 8.60 (1H, dd, J = 0.9, 6.9 Hz)


773
Ex1
ESI+: 404


774
Ex709
ESI+: 451


775
Ex1
ESI+: 418


776
Ex1
ESI+: 376


777
Ex1
ESI+: 390


778
Ex1
ESI+: 404


















TABLE 128





Ex
Syn
Dat







779
Ex1
ESI+: 402


780
Ex1
ESI+: 494


781
Ex1
APCI/ESI+: 478


782
Ex1
ESI+: 468


783
Ex1
ESI+: 468


784
Ex1
ESI+: 480


785
Ex1
ESI+: 480


786
Ex1
ESI+: 480


787
Ex1
ESI+: 480


788
Ex1
ESI+: 508


789
Ex1
ESI+: 452


790
Ex1
ESI+: 452


791
Ex1
ESI+: 480


792
Ex1
ESI+: 508


793
Ex1
ESI+: 424


794
Ex1
ESI+: 493


795
Ex1
ESI+: 493


796
Ex1
ESI+: 439


797
Ex1
ESI+: 466




NMR (DMSO-d6): 2.55 (3H, s), 4.15-4.22 (1H, m),




4.82 (1H, brs), 5.04-5.12 (2H, m), 5.41 (2H, s), 5.45




(1H, t, J = 7.9 Hz), 6.92-7.01 (2H, m), 7.25-7.40




(5H, m), 7.42-7.54 (2H, m), 8.27 (1H, d, J = 8.8




Hz), 8.63 (1H, dd, J = 1.0, 6.6 Hz)


798
Ex1
ESI+: 448




NMR (DMSO-d6): 2.54 (3H, s), 4.15-4.22 (1H, m),




4.82 (1H, d, J = 5.1 Hz), 5.03-5.13 (2H, m), 5.34




(2H, s), 5.45 (1H, t, J = 7.9 Hz), 6.92-7.00 (2H, m),




7.25-7.40 (6H, m), 7.44-7.51 (1H, m), 7.63 (1H, dt, Jd =




1.7 Hz, Jt = 7.6 Hz), 8.26 (1H, d, J = 8.8 Hz), 8.62




(1H, dd, J = 1.1, 6.6 Hz)


799
Ex1,16
ESI+: 383


800
Ex1,16
ESI+: 432


801
Ex1,16
ESI+: 450


802
Ex1,16
ESI+: 450


803
Ex1,16
ESI+: 468


804
Ex1,16
ESI+: 468


805
Ex1,16
ESI+: 438


806
Ex1,16
ESI+: 456


807
Ex1,16
ESI+: 474


808
Ex1,16
ESI+: 474


808
Ex1,16
ESI+: 474


809
Ex1,16
ESI+: 468


810
Ex1.16
ESI+: 464


811
Ex1
ESI+: 462


812
Ex12
ESI+: 456


















TABLE 129





Ex
Syn
Dat







813
Ex12
ESI+: 472


814
Ex12
ESI+: 442


815
Ex12
ESI+: 472


816
Ex12
ESI+: 452


817
Ex14
ESI+: 464


818
Ex16
ESI+: 466


819
Ex27,16
ESI+: 441


820
Ex31
ESI+: 438


821
Ex31,
ESI+: 506



PEx5,Ex16


822
Ex5
ESI+: 401


823
Ex6
ESI+: 549


824
Ex1, PEx5
ESI+: 448


825
Ex661
ESI+: 448


826
Ex661
ESI+: 448


827
Ex709
APCI/ESI+: 482


828
Ex709
ESI+: 450


829
Ex709
ESI+: 468




NMR (DMSO-d6): 2.67 (3H, s), 3.98 (4H, d,




J = 5.5 Hz), 5.05 (2H, t, J = 5.5 Hz), 5.41




(2H, s), 6.90 (1H, t, J = 7.3 Hz), 6.98 (1H, dd,




J = 0.8, 7.7 Hz), 7.21 (1H, tt, J = 1.2,




7.3 Hz), 7.26-7.33 (3H, m), 7.40-7.54 (5H, m),




8.62 (1H, dd, J = 0.9, 6.9 Hz)


830
Ex709
ESI+: 486


831
Ex709
APCI/ESI+: 482


832
Ex709
APCI/ESI+: 469


833
Ex709
ESI+: 494


834
Ex709
APCI/ESI+: 469




NMR (DMSO-d6): 2.70 (3H, s), 3.99 (2H, dd, J =




6.2, 10.9 Hz), 4.21 (2H, dd, J = 5.4, 10.9 Hz), 4.94




(2H, t, J = 5.8 Hz), 5.32 (2H, s), 6.94 (1H, t, J =




7.3 Hz), 7.03 (1H, dd, J = 0.8, 7.8 Hz), 7.19-7.31




(3H, m), 7.54-7.63 (2H, m), 7.79 (1H, dt, Jd =




1.8 Hz, Jt = 7.8 Hz), 8.01 (1H, s), 8.53 (1H, ddd,




J = 0.9, 1.8, 4.9 Hz), 8.76 (1H, dd, J = 0.9,




6.9 Hz)


















TABLE 130





Ex
Syn
Dat







835
Ex713
ESI+: 406


836
Ex8
APCI/ESI+: 522


837
Ex8
APCI/ESI+: 522


838
Ex8
APCI/ESI+: 522


839
Ex8
ESI+: 534


840
Ex8
APCI/ESI+: 509


841
Ex8
ESI+: 496


842
Ex8
ESI+: 484


843
PEx12, Ex8
ESI+: 490


844
PEx12, Ex8
ESI+: 508


845
PEx12, Ex8
ESI+: 526


846
PEx165
ESI+: 464


847
PEx5
ESI+: 437


848
PEx5
ESI+: 464


849
PEx5
ESI+: 466


850
PEx5
ESI+: 440


851
PEx5
ESI+: 484


852
PEx5
ESI+: 491


853
PEx5
ESI+: 436


854
PEx5
ESI+: 440


855
PEx5
ESI+: 464


856
PEx5
ESI+: 491


857
PEx5
ESI+: 494


858
PEx5
ESI+: 466


859
PEx5
ESI+: 492


860
PEx5
ESI+: 492


861
PEx5
ESI+: 480


862
Ex1, PEx5
ESI+: 448


863
PEx5
ESI+: 462


864
PEx5
ESI+: 452


865
PEx5
ESI+: 450


866
PEx5
ESI+: 458


867
PEx5
ESI+: 464


868
PEx5
ESI+: 450


















TABLE 131





Ex
Syn
Dat







869
PEx5
ESI+: 450


870
PEx5
ESI+: 450


871
PEx5
ESI+: 450


872
PEx5
ESI+: 400


873
PEx5
ESI+: 462


874
PEx5
ESI+: 423


875
PEx5
ESI+: 478


876
PEx5
ESI+: 494


877
PEx5
ESI+: 480


878
PEx5
ESI+: 450


879
PEx5
ESI+: 448


880
PEx5
ESI+: 448


881
PEx5
ESI+: 480


882
PEx5
ESI+: 466


883
PEx5
ESI+: 450




NMR (DMSO-d6): 1.00-1.33 (5H, m), 1.62-1.90




(6H, m), 1.72 (6H, s), 2.65 (3H, s), 3.95 (2H, d, J =




6.2 Hz), 6.76 (1H, dd, J = 0.9, 7.7 Hz), 6.81 (1H,




t, J = 7.1 Hz), 7.45 (1H, t, J = 7.8 Hz), 7.70




(1H, dq, Jd = 7.9 Hz, Jq = 1.0 Hz),




7.78 (1H, dt, Jd = 7.8 Hz, Jt = 1.2 Hz),




8.05 (1H, t, J = 1.7 Hz), 8.17 (1H, s), 8.32 (1H,




dd, J = 0.9, 6.7 Hz), 12.70-13.00 (1H, br)


884
PEx5
ESI+: 494


885
PEx5, Ex16
ESI+: 494


886
Ex709
ESI+: 469


887
Ex1
ESI+: 491


888
Ex1
ESI+: 509


889
Ex1
ESI+: 392


890
Ex1
ESI+: 392


891
Ex1
ESI+: 362


892
Ex709
ESI+: 451









INDUSTRIAL APPLICABILITY
The compound of formula (I) has an sGC activation and can be used as an active ingredient of a pharmaceutical composition for treating or preventing sGC-related cardiovascular diseases, for example, hypertension, atherosclerosis, lumbar spinal canal stenosis, peripheral arterial diseases, as well as intermittent claudication and critical limb ischemia caused by the aforesaid peripheral arterial diseases, stable or unstable angina pectoris, heart failure, thrombosis, stroke, sexual dysfunction, pulmonary hypertension, or the like.

## Claims

1. A compound of formula (I)




wherein:
A1 is cyclohexyl, or phenyl optionally substituted with one or more F atoms,
R1 is H,
R2 is R0,
R3 is H,
R5 is H,
R4 is -Y-A2 or A3,
Y is C1-10 alkylene optionally substituted with at least one group selected from Group G2,
Group G2 is —CO2H and —OH,
A2 is H, cycloalkyl, pyridyl, or phenyl optionally substituted with a group selected from the group consisting of lower alkyl and —CO2H,
A3 is cycloalkyl selected from the group consisting of cyclopentyl, indanyl, dihydrocyclopentathienyl, dihydrocyclopentafuranyl, and dihydrocyclopentapyrrolyl, the above cycloalkyl is optionally substituted with at least one group selected from Group G1, or piperidyl or pyrrolidyl each optionally substituted with at least one group selected from Group G1,
Group G1 is R0, halogen, —CO2H, —OH, —CO2R0, —CN, —NO2, phenyl, and —SO2—NH2, and
each R0 is independently lower alkyl,
or a salt thereof.

2. The compound according to claim 1, wherein A1 is cyclohexyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, or 2,3,6-trifluorophenyl, and R4 is a group represented by any one of the following formulae (A), (B), (C), (D), (E), (F), and (G):



wherein
R6 is H, halogen, or R0,
R7 is —CO2H, —CO2R0, or —NO2,
X is NH, NR0, O, S, or —HC═CH—,
n is 1,
R8 is H or lower alkyl,
Z is pyridyl,
R9 is phenyl or lower alkyl,
R10 is H or —OH,
R11 is H or —OH, and
R12 is lower alkyl, cycloalkyl, or phenyl,
or a salt thereof.

3. The compound according to claim 2, wherein
A1 is 2,6-difluorophenyl,
R2 is methyl,
R4 is a group represented by the formula (A) or the formula (B),
X is —HC═CH—,
R6 is F, and
R7 is —CO2H,
or a salt thereof.

4. The compound according to claim 2, wherein R2 is methyl and R4 is a group represented by the formula (C) or the formula (D), or a salt thereof.

5. The compound according to claim 2, wherein
A1 is cyclohexyl or 2,6-difluorophenyl,
R2 is methyl,
R4 is a group represented by the formula (A) or the formula (B),
X is —HC═CH—,
R6 is H, and
R7 is —CO2H,
or a salt thereof.

6. The compound according to claim 2, wherein R2 is methyl and R4 is a group represented by the formula (E), or a salt thereof.

7. The compound according to claim 2, wherein R2 is methyl and R4 is a group represented by the formula (F), or a salt thereof.

8. The compound according to claim 2, wherein R2 is methyl and R4 is a group represented by the formula (G), or a salt thereof.

9. The compound according to claim 2, which is selected from
the group consisting of:
(3 S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-3-phenylpropanoic acid,
(1S,2R)-1-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]indane-2-carboxylic acid,
(1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)indane-2-carboxylic acid,
(1R,2S)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)indane-2-carboxylic acid,
8-[((2,6-difluorobenzyl)oxy]-N-(1,3-dihydroxy-2-phenylpropan-2-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
(1S,2R)-1-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-7-fluoroindane-2-carboxylic acid,
(1S,2R)-1-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-4-methylindane-2-carboxylic acid,
(1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-fluomindane-2-carboxylic acid,
(1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-7-fluoroindane-2-carboxylic acid,
(1R,2S)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-7-fluoroindane-2-carboxylic acid,
(1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-4-methylindane-2-carboxylic acid,
(1S,2R)-1-[({2-methyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridin-3-yl}carbonyl)amino]indane-2-carboxylic acid,
8-[((2,6-difluorobenzyl)oxy]-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
8-[((2,6-difluorobenzyl)oxy-N-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
8-[((2,3-difluorobenzyl)oxy]-N-(1,3-dihydroxy-2-phenylpropan-2-yl)-2-methylimidazo
[1,2-a]pyridine-3-carboxamide,
8-[((2,6-difluorobenzyl)oxy]-N-[1,3-dihydroxy-2-(pyridin-2-yl)propan-2-yl]-2-methylimidazo[,2-a]pyridine-3-carboxamide,
8-((cyclohexylmethoxy)-N-[(1R)-2-hydroxy-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
8-[((2,6-difluorobenzyl)oxy]-N-[(2R)-1-hydroxypropan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
8-[((2,6-difluorobenzyl)oxy]-N-[(2R)-1-hydroxy-3-methylbutan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, and
N-(1,3-dihydroxy-2-phenylpropan-2-yl)-8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
or a salt thereof.

10. The compound according to claim 2, which is selected from
the group consisting of:
8-[((2,6-difluorobenzyl)oxy]-N-[(1R,2S,3 S)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
8-[((2,3-difluorobenzyl)oxy]-N-[(1R,2S,3 S)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, and
N-[(1R,2S,3 S)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]-8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
or a salt thereof.

11. The compound according to claim 2, which is selected from
the group consisting of:
8-[((2,6-difluorobenzyl)oxy]-N-[(1R,2S,3R)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
8-[((2,3-difluorobenzyl)oxy]-N-[(1R,2S,3R)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, and
N-[(1R,2S,3R)-2,3-dihydroxy-2,3-dihydro-1H-inden-1-yl]-8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
or a salt thereof.

12. The compound according to claim 1, which is selected from
the group consisting of:
8-[((2,6-difluorobenzyl)oxy]-N-[(1r,3R,4 S)-3,4-dihydroxy-1-phenylcyclopentyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, and
8-[((2,6-difluorobenzyl)oxy]-N-[(1s,3R,4S)-3,4-dihydroxy-1-phenylcyclopentyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
or a salt thereof.

13. The compound according to claim 1, which is selected from
the group consisting of:
8-((cyclohexylmethoxy)-2-methyl-N-[(3 S)-1-methylpiperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide,
(3R)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-methylhexanoic acid,
8-((cyclohexylmethoxy)-N-(1,3-dihydroxypropan-2-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
8-((cyclohexylmethoxy)-2-methyl-N-[(3 S)-1-methylpyrrolidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide,
3-[((1 S)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid,
8-[((2,6-difluorobenzyl)oxy]-N-(1-hydroxy-2-methylpropan-2-yl)-2-methylimidazo [1,2-a]pyridine-3-carboxamide,
8-[((2,6-difluorobenzyl)oxy]-N-[(1R,2S)-2,3-dihydroxy-1-phenylpropyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide,
(3R)-4-cyclobutyl-3-({[8-(cyclohexylmethoxy)-2-methylimidazo1,2-a]pyridin-3-yl]carbonyl}amino)butanoic acid,
8-[((2,6-difluorobenzyl)oxy]-2-methyl-N-[(3 S)-1-sulfamoylpiperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide, and
8-[((2,6-difluorobenzyl)oxy]-2-methyl-N-[(3 S)-piperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide,
or a salt thereof.

14. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1, and a pharmaceutically acceptable excipient.

15. A method for treating occlusive thrombotic vasculitis, peripheral arterial occlusive disease, intermittent claudication, critical limb ischemia, Raynaud's disease, Raynaud's syndrome, hypertension, or pulmonary hypertension, comprising administering to a subject an effective amount of the compound or a salt thereof according to claim 1.