PROCESS FOR THE PREPARATION OF A SUBSTITUTED IMIDAZOQUINOLINE
20220144822 · 2022-05-12
Inventors
Cpc classification
C07D215/46
CHEMISTRY; METALLURGY
Y02P20/55
GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
Y02A50/30
GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
International classification
Abstract
The present invention relates to a process for synthesizing N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide, an imidazoquinoline derivative useful as toll-like receptor agonist, in particular as an agonist of TLR7, which promotes induction of certain cytokines. Furthermore, the present invention also provides intermediates useful in the synthesis of N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide.
Claims
1. A process for synthesizing a compound having the formula (I): ##STR00013## or a solvate or salt thereof, the process comprising the following steps: a) providing a compound of formula (3): ##STR00014## or a solvate or salt thereof, wherein each of R.sup.1 and R.sup.2 is independently selected from the group consisting of —H and an amino protecting group, and at least one of R.sup.1 and R.sup.2 is an amino protecting group; b) reacting the compound of formula (3) or a solvate or salt thereof with one or more reagents to remove the amino protecting group(s) at position R.sup.1 and R.sup.2 to give a compound of formula (4): ##STR00015## or a solvate or salt thereof; c) reacting the compound of formula (4) or a solvate or salt thereof with one or more reagents for introducing (i) a tetrahydropyranyl group and (ii) an acetyl group to give a compound of formula (5): ##STR00016## or a s solvate or salt thereof; and d) subjecting the compound of formula (5) or a solvate or salt thereof to an oxidative amination reaction to give the compound of formula (I) or a solvate or salt thereof.
2. The process of claim 1, further comprising the step of (i) precipitating the compound of formula (4) or a solvate or salt thereof before step c); (ii) precipitating the compound of formula (5) or a solvate or salt thereof before step d); and/or (iii) precipitating the compound of formula (I) or a solvate or salt thereof after step d).
3. The process of claim 1 or 2, wherein each of R.sup.1 and R.sup.2 is independently selected from the group consisting of —H, tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxy carbonyl (Fmoc), benzyloxycarbonyl (Cbz), tosylate (Ts), benzyl (Bn), allyloxycarbonyl (Alloc), trityl (Trt), dimethoxytrityl (DMT), and monomethoxytrityl (MMT).
4. The process of any one of claims 1 to 3, wherein step a) comprises reacting a compound of formula (1): ##STR00017## or a solvate or salt thereof with HOOC(CH.sub.2).sub.2OCH.sub.3 (formula (2)) or a derivative thereof to give a compound of formula (3) or a solvate or salt thereof.
5. The process of claim 4, wherein the derivative of formula (2) is selected from the group consisting of carboxylic acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates.
6. The process of claim 4 or 5, wherein the derivative of formula (2) is an orthoester, preferably an orthoester having the formula (R.sup.10O).sub.3C(CH.sub.2).sub.2OCH.sub.3, wherein each R.sup.10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.
7. The process of any one of claims 4 to 6, wherein the reaction of the compound of formula (1) with the compound of formula (2) is performed (i) in a solvent, such as an aromatic solvent; (ii) in the presence of an acid; (iii) at a suitable temperature, such as between 0° C. and 120° C., e.g., at the reflux temperature of the solvent, if present; and/or (iv) for a sufficient amount of time, such as 30 min to 10 h.
8. The process of any one of claims 1 to 7, wherein step b) is performed (i) in a solvent, such as an aromatic solvent, e.g., the solvent used in step a); (ii) at a suitable temperature, such as between 0° C. and 40° C.; and/or (iii) for a sufficient amount of time, such as 30 min to 5 h.
9. The process of any one of claims 1 to 8, wherein each of R.sup.1 and R.sup.2 is independently selected from the group consisting of —H and tert-butyloxycarbonyl (Boc) and the one or more reagents to remove the amino protecting group(s) in step b) are selected from the group consisting of trifluoroacetic acid (TFA), HCl, CH.sub.3SO.sub.3H, and (H.sub.3C).sub.3SiCl (TMSCl).
10. The process of claim 9, wherein after the reaction of the compound of formula (3) or a solvate or salt thereof with one or more reagents to remove the amino protecting group(s), step b) further comprises adding a base.
11. The process of any one of claims 1 to 10, wherein the one or more reagents for introducing a tetrahydropyranyl group in step c) are tetrahydropyranone and a reducing agent, such as tetrahydropyranone and a borohydride.
12. The process of any one of claims 1 to 11, wherein in step c) the reaction of the compound of formula (4) or a solvate or salt thereof with one or more reagents for introducing a tetrahydropyranyl group is performed (i) in a solvent, such as a halogenated organic solvent; (ii) in the presence of an acid; (iii) at a suitable temperature, such as between −20° C. and 40° C.; and/or (iv) for a sufficient amount of time, such as 5 h to 24 h.
13. The process of any one of claims 1 to 12, wherein the one or more reagents for introducing an acetyl group in step c) are selected from acetic anhydride and acetic halides.
14. The process of any one of claims 1 to 13, wherein in step c) the reaction of the compound of formula (4) or a solvate or salt thereof with one or more reagents for introducing an acetyl group is performed (i) in a solvent, such as a halogenated organic solvent; (ii) at a suitable temperature, such as between 0° C. and 50° C.; and/or (iii) for a sufficient amount of time, such as 6 h to 48 h.
15. The process of any one of claims 1 to 14, wherein step d) comprises reacting the compound of formula (5) or a solvate or salt thereof with first (i) an oxidation agent, and then with (ii) an acylating agent and an aminating agent.
16. The process of claim 15, wherein the oxidation agent is selected from oxidation agents capable of forming N-oxides, such as 3-chloroperoxybenzoic acid, and the oxidation reaction is preferably performed (i) in a solvent, such as a halogenated organic solvent; (ii) at a suitable temperature, such as between −10° C. and 40° C.; and/or (iii) for a sufficient amount of time, such as 30 min to 12 h.
17. The process of claim 15 or 16, wherein the acylating agent is selected from the group consisting of alkysulfonyl halides and arylsulfonyl halides, such as methanesulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonyl chloride, and the reaction with the acylating agent is preferably performed (i) in a solvent, such as a halogenated organic solvent; (ii) at a suitable temperature, such as between −10° C. and 40° C.; and/or (iii) for a sufficient amount of time, such as 30 min to 12 h.
18. The process of any one of claims 15 to 17, wherein the aminating agent s selected from the group consisting of ammonia and its salts, such as aqueous NH.sub.3, ammonium hydroxide, ammonium carbonate, ammonium bicarbonate, or ammonium phosphate, and the reaction with the aminating agent is preferably performed (i) in a solvent, such as a halogenated organic solvent; (ii) at a suitable temperature, such as between −10° C. and 40° C.; and/or (iii) for a sufficient amount of time, such as 30 min to 12 h.
19. The process of any one of claims 1 to 18, wherein after step d) the process further comprises crystallizing the compound of formula (I) or a solvate or salt thereof, preferably from an alcoholic solvent.
20. The process of any one of claims 1 to 19, wherein one or more of steps a) to d) are performed in a chromatography-free manner.
21. A compound selected from the group consisting of: ##STR00018## and a solvate or salt thereof.
22. Use of a compound of claim 21 for synthesizing a compound of formula (I).
Description
BRIEF DESCRIPTION OF THE FIGURES
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DETAILED DESCRIPTION OF THE INVENTION
[0047] Although the present invention is further described in more detail below, it is to be understood that this invention is not limited to the particular methodologies, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
[0048] In the following, the elements of the present invention will be described in more detail. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and/or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise. For example, if in a preferred embodiment of the process of the present invention a solvent exchange is performed after step d) and in another preferred embodiment of the process of the present invention a crystallization step is performed after step d), then in a further preferred embodiment of the process of the present invention, a solvent exchange is performed after step d) and a crystallization step is performed after step d).
[0049] Preferably, the terms used herein are defined as described in “A multilingual glossary of biotechnological terms: (IUPAC Recommendations)”, H. G. W. Leuenberger, B. Nagel, and H. Kölbl, Eds., Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).
[0050] The practice of the present invention will employ, unless otherwise indicated, conventional chemistry methods which are explained in the literature in the field (cf., e.g., Organikum, Deutscher Verlag der Wissenschaften, Berlin 1990; Streitwieser/Heathcook, “Organische Chemie”, VCH, 1990; Beyer/Walter, “Lehrbuch der Organischen Chemie”, S. Hirzel Verlag Stuttgart, 1988; Carey/Sundberg, “Organische Chemie”, VCH, 1995; March, “Advanced Organic Chemistry”, John Wiley & Sons, 1985; Römpp Chemie Lexikon, Falbe/Regitz (Hrsg.), Georg Thieme Verlag Stuttgart, New York, 1989).
[0051] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated member, integer or step or group of members, integers or steps but not the exclusion of any other member, integer or step or group of members, integers or steps. The term “consisting essentially of” means excluding other members, integers or steps of any essential significance. The term “comprising” encompasses the term “consisting essentially of” which, in turn, encompasses the term “consisting of”. Thus, at each occurrence in the present application, the term “comprising” may be replaced with the term “consisting essentially of” or “consisting of”. Likewise, at each occurrence in the present application, the term “consisting essentially of” may be replaced with the term “consisting of”.
[0052] The terms “a”, “an” and “the” and similar references used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g., “such as”), provided herein is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0053] Where used herein, “and/or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “X and/or Y” is to be taken as specific disclosure of each of (i) X, (ii) Y, and (iii) X and Y, just as if each is set out individually herein.
[0054] In the context of the present invention, the terms “about” and “approximately” are used interchangeably and denote an interval of accuracy that the person of ordinary skill will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value by ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, and for example ±0.01%. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect.
[0055] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[0056] The use of any and all examples, or exemplary language (e.g., “such as”), provided herein is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0057] The term “alkyl” refers to a monoradical of a saturated straight or branched hydrocarbon. Preferably, the alkyl group comprises from 1 to 12 (such as 1 to 10) carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, iso-propyl (also called 2-propyl or 1-methylethyl), butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2-dimethyl-propyl, iso-amyl, n-hexyl, iso-hexyl, sec-hexyl, n-heptyl, iso-heptyl, n-octyl, 2-ethyl-hexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, and the like. A “substituted alkyl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1.sup.st level substituent, a 2.sup.nd level substituent, or a 3.sup.rd level substituent as specified herein, such as halogen, —OH, —NH.sub.2, —NHCH.sub.3, —N(CH.sub.3).sub.2, —CN, —OCH.sub.3, —OCF.sub.3, or optionally substituted aryl. Examples of a substituted alkyl include trifluoromethyl, 2-hydroxyethyl, 2-aminoethyl, 2-(dimethylamino)ethyl, arylalkyl (also called “aralkyl”, e.g., benzyl), or heteroarylalkyl (also called “heteroaralkyl”).
[0058] The term “alkenyl” refers to a monoradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Generally, the maximal number of carbon-carbon double bonds in the alkenyl group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkenyl group by 2 and, if the number of carbon atoms in the alkenyl group is uneven, rounding the result of the division down to the next integer. For example, for an alkenyl group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenyl group has 1 to 6 (such as 1 to 4), i.e., 1, 2, 3, 4, 5, or 6, carbon-carbon double bonds. Preferably, the alkenyl group comprises from 2 to 12 (such as 2 to 10) carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkenyl group comprises from 2 to 12 (e.g., 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5) carbon-carbon double bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds, such as 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon double bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bond(s) may be in cis (Z) or trans (E) configuration. Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl (i.e., allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl, and the like. If an alkenyl group is attached to a nitrogen atom, the double bond cannot be alpha to the nitrogen atom. A “substituted alkenyl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkenyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkenyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1.sup.st level substituent, a 2.sup.nd level substituent, or a 3.sup.rd level substituent as specified herein, such as halogen or optionally substituted aryl. An example of a substituted alkenyl is styryl (i.e., 2-phenylvinyl).
[0059] The term “alkynyl” refers to a monoradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Generally, the maximal number of carbon-carbon triple bonds in the alkynyl group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkynyl group by 2 and, if the number of carbon atoms in the alkynyl group is uneven, rounding the result of the division down to the next integer. For example, for an alkynyl group having 9 carbon atoms, the maximum number of carbon-carbon triple bonds is 4. Preferably, the alkynyl group has 1 to 6 (such as 1 to 4), i.e., 1, 2, 3, 4, 5, or 6, more preferably 1 or 2 carbon-carbon triple bonds. Preferably, the alkynyl group comprises from 2 to 12 (such as 2 to 10) carbon atoms (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, more preferably 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkynyl group comprises from 2 to 12 (such as 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (such as 1, 2, 3, 4, or 5 (preferably 1, 2, or 3)) carbon-carbon triple bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 (preferably 1 or 2) carbon-carbon triple bonds, such as 2 to 6 carbon atoms and 1, 2 or 3 carbon-carbon triple bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Exemplary alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 3-nonynyl, 4-nonynyl, 5-nonynyl, 6-nonynyl, 7-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 3-decynyl, 4-decynyl, 5-decynyl, 6-decynyl, 7-decynyl, 8-decynyl, 9-decynyl, and the like. If an alkynyl group is attached to a nitrogen atom, the triple bond cannot be alpha to the nitrogen atom. A “substituted alkynyl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkynyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkynyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1.sup.st level substituent, a 2.sup.nd level substituent, or a 3.sup.rd level substituent as specified herein, such as halogen or optionally substituted aryl.
[0060] The term “aryl” or “aromatic ring” refers to a monoradical of an aromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 14 (e.g., 5, 6, 7, 8, 9, or 10, such as 5, 6, or 10) carbon atoms which can be arranged in one ring (e.g., phenyl) or two or more condensed rings (e.g., naphthyl). Exemplary aryl groups include cyclopropenylium, cyclopentadienyl, phenyl, indenyl, naphthyl, azulenyl, fluorenyl, anthryl, and phenanthryl. Preferably, “aryl” refers to a monocyclic ring containing 6 carbon atoms or an aromatic bicyclic ring system containing 10 carbon atoms. Preferred examples are phenyl and naphthyl. Aryl does not encompass fullerenes. A “substituted aryl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an aryl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the aryl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1.sup.st level substituent, a 2.sup.nd level substituent, or a 3.sup.rd level substituent as specified herein, such as halogen, —OH, —NH.sub.2, —NHCH.sub.3, —N(CH.sub.3).sub.2, —CN, —OCH.sub.3, —OCF.sub.3, nitro, alkyl (e.g., C.sub.1-6 alkyl), alkenyl (e.g., C.sub.2-6 alkenyl), and alkynyl (e.g., C.sub.2-6 alkynyl). Examples of a substituted aryl include biphenyl, 2-fluorophenyl, 2-chloro-6-methylphenyl, anilinyl, 3-nitrophenyl, 4-hydroxyphenyl, methoxyphenyl (i.e., 2-, 3-, or 4-methoxyphenyl), and 4-ethoxyphenyl.
[0061] The term “heteroaryl” or “heteroaromatic ring” means an aryl group as defined above in which one or more carbon atoms in the aryl group are replaced by heteroatoms (such as O, S, or N). Preferably, heteroaryl refers to a five or six-membered aromatic monocyclic ring, wherein 1, 2, or 3 carbon atoms are replaced by the same or different heteroatoms of O, N, or S. Alternatively, it means an aromatic bicyclic or tricyclic ring system wherein 1, 2, 3, 4, or 5 carbon atoms are replaced with the same or different heteroatoms of O, N, or S. Preferably, in each ring of the heteroaryl group the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. For example, 3- to 14-membered heteroaryl encompasses monocyclic heteroaryl (e.g., 5- or 6-membered), bicyclic heteroaryl (e.g., 9- or 10-membered), and tricyclic heteroaryl (e.g., 13- or 14-membered). Exemplary heteroaryl groups include furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl (also called pyridinyl), pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, benzodiazinyl, quinoxalinyl, quinazolinyl, benzotriazinyl, pyridazinyl, phenoxazinyl, thiazolopyridinyl, pyrrolotriazolyl, phenothiazinyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, pyrrolizinyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, naphthyridinyl, cinnolinyl, pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolooxazolyl, and pyrrolopyrrolyl. Exemplary 5- or 6-membered heteroaryl groups include furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, and pyridazinyl. A “substituted heteroaryl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a heteroaryl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the heteroaryl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1.sup.st level substituent, a 2.sup.nd level substituent, or a 3.sup.rd level substituent as specified herein, such as halogen, —OH, —NH.sub.2, —NHCH.sub.3, —N(CH.sub.3).sub.2, —CN, —OCH.sub.3, —OCF.sub.3, alkyl (e.g., C.sub.1-6 alkyl), alkenyl (e.g., C.sub.2-6 alkenyl), and alkynyl (e.g., C.sub.2-6 alkynyl). Examples of a substituted heteroaryl include 2,4-dimethylpyridin-3-yl, 2-methyl-4-bromopyridin-3-yl, 3-methyl-2-pyridin-2-yl, 3-chloro-5-methylpyridin-4-yl, 4-chloro-2-methylpyridin-3-yl, 3,5-dimethylpyridin-4-yl, 2-methylpyridin-3-yl, 2-chloro-4-methyl-thien-3-yl, 1,3,5-trimethylpyrazol-4-yl, 3,5-dimethyl-1,2-dioxazol-4-yl, 1,2,4-trimethylpyrrol-3-yl, 3-phenylpyrrolyl, 2,3′-bifuryl, 4-methylpyridyl, 2-, or 3-ethylindolyl.
[0062] The term “cycloalkyl” or “cycloaliphatic” represents cyclic non-aromatic versions of “alkyl” and “alkenyl” with preferably 3 to 14 carbon atoms, such as 3 to 12 or 3 to 10 carbon atoms, i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 3 to 7 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclononyl, cyclononenyl, cyclodecyl, cyclodecenyl, and adamantyl. The term “cycloalkyl” is also meant to include bicyclic and tricyclic versions thereof. If bicyclic rings are formed it is preferred that the respective rings are connected to each other at two adjacent carbon atoms, however, alternatively the two rings are connected via the same carbon atom, i.e., they form a spiro ring system or they form “bridged” ring systems. Preferred examples of cycloalkyl include C.sub.3-8-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, and bicyclo[4.2.0]octyl. Cycloalkyl does not encompass fullerenes. A “substituted cycloalkyl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a cycloalkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the cycloalkyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1.sup.st level substituent, a 2.sup.nd level substituent, or a 3.sup.rd level substituent as specified herein, such as halogen, —OH, —NH.sub.2, —NHCH.sub.3, —N(CH.sub.3).sub.2, —CN, —OCH.sub.3, —OCF.sub.3, ═O, ═S, ═NH, alkyl (e.g., C.sub.1-6 alkyl), alkenyl (e.g., C.sub.2-6 alkenyl), and alkynyl (e.g., C.sub.2-6 alkynyl). Examples of a substituted cycloalkyl include oxocyclohexyl, oxocyclopentyl, fluorocyclohexyl, and oxocyclohexenyl.
[0063] The term “heterocyclyl” or “heterocyclic ring” means a cycloalkyl group as defined above in which from 1, 2, 3, or 4 ring carbon atoms in the cycloalkyl group are replaced by heteroatoms (such as those selected from the group consisting of O, S, S(O), S(O).sub.2, N, B, Si, and P, preferably selected from the group consisting of O, S, S(O).sub.2, and N, more preferably selected from the group consisting of O, S, and N). If a ring of the heterocyclyl group only contains one type of heteroatom, the maximum number of said heteroatom in the ring of said heterocyclyl group may be as follows: 2 O atoms (preferably 1 O atom); 2 S atoms (preferably 1 S atom); 4 N atoms (such as 1, 2, or 3 N atoms); 2 B atoms (preferably 1 B atom); 1 Si atom; and/or 1 P atom. If a ring of the heterocyclyl group contains two or more types of heteroatoms, the maximum number of said heteroatoms in the ring of said heterocyclyl group may be as follows: 1 O atom; 1 S atom; 2 N atoms (preferably 1 N atom); 1 B atom; 1 Si atom; and/or 1 P atom, wherein the maximum total number of heteroatoms in the ring of said heterocyclyl group is 4 and the maximum total number of each heteroatom in the ring of said heterocyclyl group is as follows: 1 O atom; 1 S atom; 1 or 2 N atoms; 1 B atom (preferably 0 B atom); 1 Si atom (preferably 0 Si atom); and/or 1 P atom (preferably 0 P atom). In one embodiment, the heteroatoms of the heterocyclyl group are selected from the group consisting of O, S, and N. In this embodiment, preferably, in each ring of the heterocyclyl group the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. For example, 3- to 14-membered heterocyclyl encompasses monocyclic heterocyclyl (e.g., 3-, 4-, 5-, 6-, or 7-membered, preferably 4- to 7-membered), bicyclic heterocyclyl (e.g., 8-, 9-, or 10-membered), and tricyclic heterocyclyl (e.g., 12-, 13-, or 14-membered). If a heterocyclyl group comprises two or more rings, these rings either are fused (such as in quinolinyl or purinyl), are a spiro moiety, are a bridged structure, are linked via a double bond, or are a combination thereof. In other words, an unsubstituted heterocyclyl group does not encompass two heterocyclyl groups linked via a single bond. The term “heterocyclyl” is also meant to encompass partially or completely hydrogenated forms (such as dihydro, tetrahydro, hexahydro, octahydro, decahydro, dodecahydro, etc., or perhydro forms) of the above-mentioned heteroaryl groups. Exemplary heterocyclyl groups include azetidinyl, morpholino, isochromanyl, chromanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, triazininanyl; dihydro forms of pyrrolyl, imidazolyl, and pyrazolyl; di- and tetrahydro forms of furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, thiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, and triazinyl; di-, tetra- and hexahydro forms of pyrimidinyl, pyridazinyl, pyrrolothiazolyl, and pyrrolizinyl. A “substituted heterocyclyl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the heterocyclyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1.sup.st level substituent, a 2.sup.nd level substituent, or a 3.sup.rd level substituent as specified herein, such as halogen, —OH, —NH.sub.2, —NHCH.sub.3, —N(CH.sub.3).sub.2, —CN, —OCH.sub.3, —OCF.sub.3, ═O, ═S, ═NH, alkyl (e.g., C.sub.1-6 alkyl), alkenyl (e.g., C.sub.2-6 alkenyl), and alkynyl (e.g., C.sub.2-6 alkynyl).
[0064] The expression “partially hydrogenated form” of an unsaturated compound or group as used herein means that part of the unsaturation has been removed by formally adding hydrogen to the initially unsaturated compound or group without removing all unsaturated moieties. The phrase “completely hydrogenated form” of an unsaturated compound or group is used herein interchangeably with the term “perhydro” and means that all unsaturation has been removed by formally adding hydrogen to the initially unsaturated compound or group. For example, partially hydrogenated forms of a 5-membered heteroaryl group (containing 2 double bonds in the ring, such as furan) include dihydro forms of said 5-membered heteroaryl group (such as 2,3-dihydrofuran or 2,5-dihydrofuran), whereas the tetrahydro form of said 5-membered heteroaryl group (e.g., tetrahydrofuran, i.e., THF) is a completely hydrogenated (or perhydro) form of said 5-membered heteroaryl group. Likewise, for a 6-membered heteroaryl group having 3 double bonds in the ring (such as pyridyl), partially hydrogenated forms include di- and tetrahydro forms (such as di- and tetrahydropyridyl), whereas the hexahydro form (such as piperidinyl in case of the heteroaryl pyridyl) is the completely hydrogenated (or perhydro) derivative of said 6-membered heteroaryl group. Consequently, a hexahydro form of an aryl or heteroaryl can only be considered a partially hydrogenated form according to the present invention if the aryl or heteroaryl contains at least 4 unsaturated moieties consisting of double and triple bonds between ring atoms.
[0065] The term “aromatic” as used in the context of hydrocarbons means that the whole molecule has to be aromatic. For example, if a monocyclic aryl is hydrogenated (either partially or completely) the resulting hydrogenated cyclic structure is classified as cycloalkyl for the purposes of the present invention. Likewise, if a bi- or polycyclic aryl (such as naphthyl) is hydrogenated the resulting hydrogenated bi- or polycyclic structure (such as 1,2-dihydronaphthyl) is classified as cycloalkyl for the purposes of the present invention (even if one ring, such as in 1,2-dihydronaphthyl, is still aromatic). A similar distinction is made within the present application between heteroaryl and heterocyclyl. For example, indolinyl, i.e., a dihydro variant of indolyl, is classified as heterocyclyl for the purposes of the present invention, since only one ring of the bicyclic structure is aromatic and one of the ring atoms is a heteroatom.
[0066] The term “polycyclic” as used herein means that the structure has two or more (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10), preferably, 2, 3, 4, or 5, more preferably, 2, 3, or 4, rings. Therefore, according to the invention, the term “polycyclic” does not encompass monocyclic structures, wherein the structures only contain one ring. Examples of polycyclic groups are fused structures (such as naphthyl or anthryl), spiro compounds, rings that are linked via single or double bonds (such as biphenyl), and bridged structures (such as bornyl). Exemplary polycyclic structures are those aryl, heteroaryl, cycloalkyl, and heterocyclyl groups specified above which have at least two rings.
[0067] The term “halogen” or “halo” means fluoro, chloro, bromo, or iodo.
[0068] The term “azido” means —N.sub.3.
[0069] The term “N-oxide” means an amine oxide or amine-N-oxide which is a chemical compound containing the functional group (R.sup.n).sub.3N.sup.+—O.sup.− or (R.sup.n).sub.3N.sup.+—OH, i.e., an N—O coordinate covalent bond, wherein R.sup.n is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more (such as 1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R.sup.20, the R.sup.20 preferably being a 1.sup.st level substituent, a 2.sup.nd level substituent, or a 3.sup.rd level substituent as specified herein.
[0070] The term “optionally substituted” indicates that one or more (such as 1 to the maximum number of hydrogen atoms bound to a group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atom(s) may be replaced with a group (i.e., a 1.sup.st level substituent) different from hydrogen such as alkyl (preferably, C.sub.1-6 alkyl), alkenyl (preferably, C.sub.2-6 alkenyl), alkynyl (preferably, C.sub.2-6 alkynyl), aryl (preferably, 6- to 14-membered aryl), heteroaryl (preferably, 3- to 14-membered heteroaryl), cycloalkyl (preferably, 3- to 14-membered cycloalkyl), heterocyclyl (preferably, 3- to 14-membered heterocyclyl), halogen, —CN, azido, —NO.sub.2, —OR.sup.71, —N(R.sup.72)(R.sup.73), —S(O).sub.0-2R.sup.71, —S(O).sub.1-2OR.sup.71, —OS(O).sub.1-2R.sup.71, —OS(O).sub.1-2OR.sup.71, —S(O).sub.1-2N(R.sup.72)(R.sup.73), —OS(O).sub.1-2N(R.sup.72)(R.sup.73), —N(R.sup.71)S(O).sub.1-2R.sup.71, —NR.sup.71S(O).sub.1-2OR.sup.71, —NR.sup.71S(O).sub.1-2N(R.sup.72)(R.sup.73), —OP(O)(OR.sup.71).sub.2, —C(═X.sup.1)R.sup.71, —C(═X.sup.1)X.sup.1R.sup.71, —X.sup.1C(═X.sup.1)R.sup.71, and —X.sup.1C(═X.sup.1)X.sup.1R.sup.71, and/or any two 1.sup.st level substituents which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group may join together to form ═X.sup.1, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups of the 1.sup.st level substituent may themselves be substituted by one or more (e.g., one, two or three) substituents (i.e., a 2.sup.nd level substituent) selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, 6- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, —CF.sub.3, —CN, azido, —NO.sub.2, —OR.sup.81, —N(R.sup.82)(R.sup.83), —S(O).sub.0-2R.sup.81, —S(O).sub.1-2OR.sup.81, —OS(O).sub.1-2R.sup.81, —OS(O).sub.1-2OR.sup.81, —S(O).sub.1-2N(R.sup.82)(R.sup.83), —OS(O).sub.1-2N(R.sup.82)(R.sup.83), —N(R.sup.81)S(O).sub.1-2R.sup.81, —NR.sup.81S(O).sub.1-2OR.sup.81, —NR.sup.8'S(O).sub.1-2N(R.sup.82)(R.sup.83), —OP(O)(OR.sup.81).sub.2, —C(═X.sup.2)R.sup.81, —C(═X.sup.2)X.sup.2R.sup.81, —X.sup.2C(═X.sup.2)R.sup.81, and —X.sup.2C(═X.sup.2)X.sup.2R.sup.81, and/or any two 2.sup.nd level substituents which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group being a 1.sup.st level substituent may join together to form ═X.sup.2, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, 6- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl groups of the 2.sup.nd level substituent is optionally substituted with one or more (e.g., one, two or three) substituents (i.e., a 3.sup.rd level substituent) independently selected from the group consisting of C.sub.1-3 alkyl, halogen, —CF.sub.3, —CN, azido, —NO.sub.2, —OH, —O(C.sub.1-3 alkyl), —OCF.sub.3, —S(C.sub.1-3 alkyl), —NH.sub.2, —NH(C.sub.1-3 alkyl), —N(C.sub.1-3 alkyl).sub.2, —NHS(O).sub.2(C.sub.1-3 alkyl), —S(O).sub.2NH.sub.2-z(C.sub.1-3 alkyl).sub.z, —C(═O)OH, —C(═O)O(C.sub.1-3 alkyl), —C(═O)NH.sub.2-z(C.sub.1-3 alkyl), —NHC(═O)(C.sub.1-3 alkyl), —NHC(═NH)NH.sub.z-2 (C.sub.1-3 alkyl), and —N(C.sub.1-3 alkyl)C(═NH)NH.sub.2-z(C.sub.1-3 alkyl).sub.z, wherein each z is independently 0, 1, or 2 and each C.sub.1-3 alkyl is independently methyl, ethyl, propyl or isopropyl, and/or any two 3.sup.rd level substituents which are bound to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclyl group being a 2.sup.nd level substituent may join together to form ═O, ═S, ═NH, or ═N(C.sub.1-3 alkyl);
[0071] wherein
[0072] each of R.sup.71, R.sup.72, and R.sup.73 is independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein each of the C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups is optionally substituted with one, two or three substituents independently selected from the group consisting of C.sub.1-3 alkyl, halogen, —CF.sub.3, —CN, azido, —NO.sub.2, —OH, —O(C.sub.1-3 alkyl), —OCF.sub.3, ═O, —S(C.sub.1-3 alkyl), —NH.sub.2, —NH(C.sub.1-3 alkyl), —N(C.sub.1-3 alkyl).sub.2, —NHS(O).sub.2(C.sub.1-3 alkyl), —S(O).sub.2NH.sub.2-z(C.sub.1-3 alkyl).sub.z, —C(═O)(C.sub.1-3 alkyl), —C(═O)OH, —C(═O)O(C.sub.1-3 alkyl), —C(═O)NH.sub.2-z(C.sub.1-3 alkyl), —NHC(═O)(C.sub.1-3 alkyl), —NHC(═NH)NH.sub.z-2(C.sub.1-3 alkyl), and —N(C.sub.1-3 alkyl)C(═NH)NH.sub.2-z(C.sub.1-3 alkyl), wherein each z is independently 0, 1, or 2 and each C.sub.1-3 alkyl is independently methyl, ethyl, propyl or isopropyl;
[0073] each of R.sup.81, R.sup.82, and R.sup.83 is independently selected from the group consisting of H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl, wherein each of the C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl groups is optionally substituted with one, two or three substituents independently selected from the group consisting of C.sub.1-3 alkyl, halogen, —CF.sub.3, —CN, azido, —NO.sub.2, —OH, —O(C.sub.1-3 alkyl), —OCF.sub.3, ═O, —S(C.sub.1-3 alkyl), —NH.sub.2, —NH(C.sub.1-3 alkyl), —N(C.sub.1-3 alky).sub.2, —NHS(O).sub.2(C.sub.1-3 alkyl), —S(O).sub.2NH.sub.2-z(C.sub.1-3 alkyl).sub.z, —C(═O)(C.sub.1-3 alkyl), —C(═O)OH, —C(═O)O(C.sub.1-3 alkyl), —C(═O)NH.sub.2-z(C.sub.1-3 alkyl).sub.z, —NHC(═O)(C.sub.1-3 alkyl), —NHC(═NH)NH.sub.z-2(C.sub.1-3 alkyl), and —N(C.sub.1-3 alkyl)C(═NH)NH.sub.2-z(C.sub.1-3 alkyl).sub.z, wherein each z is independently 0, 1, or 2 and each C.sub.1-3 alkyl is independently methyl, ethyl, propyl or isopropyl; and
[0074] each of X.sup.1 and X.sup.2 is independently selected from O, S, and N(R.sup.84), wherein R.sup.84 is H or C.sub.1-3 alkyl.
[0075] Typical 1.sup.st level substituents are preferably selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, 6- to 14-membered (such as 6- to 10-membered) aryl, 3- to 14-membered (such as 5- or 6-membered) heteroaryl, 3- to 14-membered (such as 3- to 7-membered) cycloalkyl, 3- to 14-membered (such as 3- to 7-membered) heterocyclyl, halogen, —CN, azido, —NO.sub.2, —OR.sup.71, —N(R.sup.72)(R.sup.73), —S(O).sub.0-2R.sup.71, —S(O).sub.1-2OR.sup.71, —OS(O).sub.1-2R.sup.71, —OS(O).sub.1-2OR.sup.71, —S(O).sub.1-2N(R.sup.72)(R.sup.73), —OS(O).sub.1-2N(R.sup.72)(R.sup.73), —N(R.sup.71)S(O).sub.1-2R.sup.71, —NR.sup.71S(O).sub.1-2OR.sup.71, —C(═X.sup.1)R.sup.71, —C(═X.sup.1)X.sup.1R.sup.71, —X.sup.1C(═X.sup.1)R.sup.71, and —X.sup.1C(═X.sup.1)X.sup.1R.sup.71, such as C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered (such as 5- or 6-membered) heterocyclyl, halogen, —CF.sub.3, —CN, azido, —NO.sub.2, —OH, —O(C.sub.1-3 alkyl), —S(C.sub.1-3 alkyl), —NH.sub.2, —NH(C.sub.1-3 alkyl), —N(C.sub.1-3 alkyl).sub.2, —NHS(O).sub.2(C.sub.1-3 alkyl), —S(O).sub.2NH.sub.2-z(C.sub.1-3 alkyl), —C(═O)OH, —C(═O)O(C.sub.1-3 alkyl), —C(═O)NH.sub.2-z(C.sub.1-3 alkyl), —NHC(═O)(C.sub.1-3 alkyl), —NHC(═NH)NH.sub.z-2(C.sub.1-3 alkyl).sub.z, and —N(C.sub.1-3 alkyl)C(═NH)NH.sub.2-z(C.sub.1-3 alkyl), wherein each z is independently 0, 1, or 2 and each C.sub.1-3 alkyl is independently methyl, ethyl, propyl or isopropyl; wherein X.sup.1 is independently selected from O, S, NH and N(CH.sub.3); and each of R.sup.71, R.sup.72, and R.sup.73 is as defined above or, preferably, is independently selected from the group consisting of H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, 5- or 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 5- or 6-membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one, two or three substituents independently selected from the group consisting of C.sub.1-3 alkyl, halogen, —CF.sub.3, —CN, azido, —NO.sub.2, —OH, —O(C.sub.1-3 alkyl), —S(C.sub.1-3 alkyl), —NH.sub.2, —NH(C.sub.1-3 alkyl), —N(C.sub.1-3 alkyl).sub.2, —NHS(O).sub.2(C.sub.1-3 alkyl), —S(O).sub.2NH.sub.2-z(C.sub.1-3 alkyl).sub.z, —C(═O)OH, —C(═O)O(C.sub.1-3 alkyl), —C(═O)NH.sub.2-z(C.sub.1-3 alkyl).sub.z, —NHC(═O)(C.sub.1-3 alkyl), —NHC(═NH)NH.sub.z-2(C.sub.1-3 alkyl), and —N(C.sub.1-3 alkyl)C(═NH)NH.sub.2-z(C.sub.1-3 alkyl).sub.z, wherein each z is independently 0, 1, or 2 and each C.sub.1-3 alkyl is independently methyl, ethyl, propyl or isopropyl. Particular examples of 1.sup.st level substituents are independently selected from the group consisting of C.sub.1-3 alkyl, phenyl, imidazolyl, thiazolyl, cyclopentyl, cyclohexyl, dihydrothiazolyl, thiazolidinyl, halogen, —CF.sub.3, —CN, —OH, —O(C.sub.1-3 alkyl), —S(C.sub.1-3 alkyl), —NH.sub.2, —NH(C.sub.1-3 alkyl), —N(C.sub.1-3 alkyl).sub.2, —NHS(O).sub.2(C.sub.1-3 alkyl), —C(═O)OH, —C(═O)O(C.sub.1-3 alkyl), —C(═O)NH.sub.2-z(C.sub.1-3 alkyl), —NHC(═O)(C.sub.1-3 alkyl), —NHC(═NH)NH.sub.z-2(C.sub.1-3 alkyl), and —N(C.sub.1-3 alkyl)C(═NH)NH.sub.2-z(C.sub.1-3 alkyl).sub.z, wherein each z is independently 0, 1, or 2 and each C.sub.1-3 alkyl is independently methyl, ethyl, propyl or isopropyl. Particularly preferred 1.sup.st level substituents are independently selected from the group consisting of C.sub.1-3 alkyl, phenyl, thiazolidinyl, halogen (such as F, Cl, or Br), —NH.sub.2, —NHS(O).sub.2(C.sub.1-3 alkyl), —NHC(═O)(C.sub.1-3 alkyl), and —NHC(═NH)NH.sub.z-2(C.sub.1-3 alkyl).sub.z, wherein z is 0, 1, or 2 and each C.sub.1-3 alkyl is independently methyl, ethyl, propyl or isopropyl.
[0076] Typical 2.sup.nd level substituents are preferably selected from the group consisting of C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, 6- or 10-membered aryl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, 5- or 6-membered heterocyclyl, halogen, ═O, ═S, —CF.sub.3, —CN, azido, —NO.sub.2, —OH, —O(C.sub.1-3 alkyl), —S(C.sub.1-3 alkyl), —NH.sub.2, —NH(C.sub.1-3 alkyl), —N(C.sub.1-3 alkyl).sub.2, —NHS(O).sub.2(C.sub.1-3 alkyl), —S(O).sub.2NH.sub.2-z(C.sub.1-3 alkyl).sub.z, —C(═O)OH, —C(═O)O(C.sub.1-3 alkyl), —C(═O)NH.sub.2-z(C.sub.1-3 alkyl), —NHC(═O)(C.sub.1-3 alkyl), —NHC(═NH)NH.sub.z-2(C.sub.1-3 alkyl), and —N(C.sub.1-3 alkyl)C(═NH)NH.sub.2-z(C.sub.1-3 alkyl), wherein each z is independently 0, 1, or 2 and each C.sub.1-3 alkyl is independently methyl, ethyl, propyl or isopropyl. Particular examples of 2.sup.nd level substituents are independently selected from the group consisting of C.sub.1-3 alkyl, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, 5- or 6-membered heterocyclyl, halogen, ═O, ═S, —CF.sub.3, —CN, —OH, —O(C.sub.1-3 alkyl), —S(C.sub.1-3 alkyl), —NH.sub.2, —NH(C.sub.1-3 alkyl), —N(C.sub.1-3 alkyl).sub.2, —NHS(O).sub.2(C.sub.1-3 alkyl), —C(═O)OH, —C(═O)O(C.sub.1-3 alkyl), —C(═O)NH.sub.2-z(C.sub.1-3 alkyl), —NHC(═O)(C.sub.1-3 alkyl), —NHC(═NH)NH.sub.z-2(C.sub.1-3 alkyl).sub.z, and —N(C.sub.1-3 alkyl)C(═NH)NH.sub.2-z(C.sub.1-3 alkyl), wherein each z is independently 0, 1, or 2 and each C.sub.1-3 alkyl is independently methyl, ethyl, propyl or isopropyl. Particularly preferred 2.sup.nd level substituents are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, phenyl, ═O, and ═S.
[0077] Typical 3.sup.rd level substituents are preferably selected from the group consisting of C.sub.1-3 alkyl, phenyl, halogen, —CF.sub.3, —OH, —OCH.sub.3, —SCH.sub.3, —NH.sub.2-z(CH.sub.3).sub.z, —C(═O)OH, and —C(═O)OCH.sub.3, wherein z is 0, 1, or 2 and C.sub.1-3 alkyl is methyl, ethyl, propyl or isopropyl. Particularly preferred 3.sup.rd level substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, halogen (such as F, Cl, or Br), and —CF.sub.3, such as halogen (e.g., F, Cl, or Br), and —CF.sub.3.
[0078] The term “optional” or “optionally” as used herein means that the subsequently described event, circumstance or condition may or may not occur, and that the description includes instances where said event, circumstance, or condition occurs and instances in which it does not occur.
[0079] “Isomers” are compounds having the same molecular formula but differ in structure (“structural isomers”) or in the geometrical (spatial) positioning of the functional groups and/or atoms (“stereoisomers”). “Enantiomers” are a pair of stereoisomers which are non-superimposable mirror-images of each other. A “racemic mixture” or “racemate” contains a pair of enantiomers in equal amounts and is denoted by the prefix (±). “Diastereomers” are stereoisomers which are non-superimposable and which are not mirror-images of each other. “Tautomers” are structural isomers of the same chemical substance that spontaneously and reversibly interconvert into each other, even when pure, due to the migration of individual atoms or groups of atoms; i.e., the tautomers are in a dynamic chemical equilibrium with each other. Examples of tautomers are the isomers of the keto-enol-tautomerism. “Conformers” are stereoisomers that can be interconverted just by rotations about formally single bonds, and include—in particular—those leading to different 3-dimensional forms of (hetero)cyclic rings, such as chair, half-chair, boat, and twist-boat forms of cyclohexane.
[0080] “Polymorphism” as referred to herein means that a solid material (such as a compound) is able to exist in more than one form or crystalline structure, i.e., “polymorphic modifications” or “polymorphic forms”. The terms “polymorphic modifications”, “polymorphic forms”, and “polymorphs” are used interchangeable in the present invention. According to the present invention, these “polymorphic modifications” include crystalline forms, amorphous forms, solvates, and hydrates Mainly, the reason for the existence of different polymorphic forms lies in the use of different conditions during the crystallization process, such as the following: [0081] solvent effects (the packing of crystal may be different in polar and nonpolar solvents); [0082] certain impurities inhibiting growth pattern and favor the growth of a metastable polymorphs; [0083] the level of supersaturation from which material is crystallized (in which generally the higher the concentration above the solubility, the more likelihood of metastable formation); [0084] temperature at which crystallization is carried out; [0085] geometry of covalent bonds (differences leading to conformational polymorphism); [0086] change in stirring conditions.
[0087] Polymorphic forms may have different chemical, physical, and/or pharmacological properties, including but not limited to, melting point, X-ray crystal and diffraction pattern, chemical reactivity, solubility, dissolution rate, vapor pressure, density, hygroscopicity, flowability, stability, compactability, and bioavailability. Polymorphic forms may spontaneously convert from a metastable form (unstable form) to the stable form at a particular temperature. According to Ostwald's rule, in general it is not the most stable but the least stable polymorph that crystallizes first. Thus, quality, efficacy, safety, processability and/or manufacture of a chemical compound, such as a compound of the present invention, can be affected by polymorphism. Often, the most stable polymorph of a compound (such as a compound of the present invention) is chosen due to the minimal potential for conversion to another polymorph. However, a polymorphic form which is not the most stable polymorphic form may be chosen due to reasons other than stability, e.g. solubility, dissolution rate, and/or bioavailability.
[0088] The term “crystalline form” of a material as used herein means that the smallest components (i.e., atoms, molecule or ions) of said material form crystal structures. A “crystal structure” as referred to herein means a unique three-dimensional arrangement of atoms or molecules in a crystalline liquid or solid and is characterized by a pattern, a set of atoms arranged in a particular manner, and a lattice exhibiting long-range order and symmetry. A lattice is an array of points repeating periodically in three dimensions and patterns are located upon the points of a lattice. The subunit of the lattice is the unit cell. The lattice parameters are the lengths of the edges of a unit cell and the angles between them. The symmetry properties of the crystal are embodied in its space group. In order to describe a crystal structure the following parameters are required: chemical formula, lattice parameters, space group, the coordinates of the atoms and occupation number of the point positions.
[0089] The term “amorphous form” of a material as used herein means that the smallest components (i.e., atoms, molecule or ions) of said material are not arranged in a lattice but are arranged randomly. Thus, unlike crystals in which a short-range order (constant distances to the next neighbor atoms) and a long-range order (periodical repetition of a basic lattice) exist, only a short-range order exists in an amorphous form.
[0090] The term “solvate” as used herein refers to an addition complex of a dissolved material in a solvent (such as an organic solvent (e.g., an aliphatic alcohol (such as methanol, ethanol, n-propanol, isopropanol), acetone, acetonitrile, ether, and the like), water or a mixture of two or more of these liquids), wherein the addition complex exists in the form of a crystal or mixed crystal. The amount of solvent contained in the addition complex may be stoichiometric or non-stoichiometric. A “hydrate” is a solvate wherein the solvent is water.
[0091] In isotopically labeled compounds one or more atoms are replaced by a corresponding atom having the same number of protons but differing in the number of neutrons. For example, a hydrogen atom may be replaced by a deuterium atom. Exemplary isotopes which can be used in the compounds of the present invention include deuterium, .sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18F, .sup.32P, .sup.32S, .sup.35S, .sup.36Cl, and .sup.125I.
[0092] The compounds which are used and/or synthesized in the process of the invention and which contain a basic functionality may form salts, in particular pharmaceutically acceptable salts, with a variety of inorganic or organic acids. The compounds which are used and/or synthesized in the process of the invention and which contain an acidic functionality may form salts, in particular pharmaceutically acceptable salts, with a variety of inorganic or organic bases. Exemplary inorganic and organic acids/bases as well as exemplary acid/base addition salts of these compounds are given below. The compounds which are used and/or synthesized in the process of the invention and which contain both basic and acidic functionalities may be converted into either base or acid addition salt. The neutral forms of the compounds which are used and/or synthesized in the process of the invention may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The salts are preferably pharmaceutically acceptable salts.
[0093] The term “pharmaceutically acceptable” refers to the non-toxicity of a material which does not interact with the (e.g., therapeutic) action of the active component of a pharmaceutical composition.
[0094] “Pharmaceutically acceptable salts” comprise, for example, acid addition salts which may, for example, be formed by mixing a solution of compounds with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, for example, Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci., 66, pp. 1-19 (1977)).
[0095] The expression “reflux temperature” as used herein in conjunction with a reaction mixture refers to the boiling point of the liquid contained in the reaction mixture which has the lowest boiling point of all liquids contained in the reaction mixture.
[0096] Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
[0097] In a preferred embodiment, the product obtained by the process of the invention (in particular the compound of formula (I)) is substantially free of contaminants.
[0098] The term “substantially free of contaminants” as used herein in conjunction with product obtained by the process of the invention means that the amount of contaminants in the product obtained by the process of the invention is at most 5% by weight (preferably at most 4% by weight, at most 3% by weight, at most 2% by weight, at most 1% by weight, at most 0.5% by weight, at most 0.1% by weight, at most 0.05% by weight, at most 0.01% by weight, at most 0.005% by weight, at most 0.001% by weight), based on the total weight of said product.
[0099] The term “chromatography-free manner” as used herein in the context of the synthesis of a compound of interest (such as a compound of formula (I) or a solvate or salt thereof or an intermediate of any one of formulas (3), (4), and (5)) means that in at least one of the steps of said synthesis (preferably in all steps of said synthesis) the separation of the compound of interest from other compounds (such as contaminants) is achieved by means other than chromatography, preferably by means of precipitating the compound of interest, optionally washing the precipitated compound of interest with a suitable solvent (in particular, a solvent in which the compound of interest is poorly soluble), and optionally drying the precipitated compound of interest. However, the term “chromatography-free manner” as used herein in the context of the synthesis of a compound of interest does not mean that the analysis of a sample obtained during the synthesis is performed using chromatography (i.e., a process for synthesizing a compound of interest which is performed in a chromatography-free manner merely excludes preparative steps using chromatography, but does not exclude analytical steps using chromatography).
[0100] The term “equivalent” as used herein means the amount of a compound containing 1 mole of hydrogen (i.e., 1.008 g of hydrogen) or 1 mole of a different element (e.g., 12.011 g for carbon or 15.999 g for oxygen). For example, a solution of NaOH having a concentration of 40 g/l is equivalent to (i) a solution of KOH having a concentration of 56.5 g/l, (ii) a solution of HCl having a concentration of 36.5 g; or (iv) a solution of H.sub.2SO.sub.4 having a concentration of 49 g/l. Furthermore, in the context of, for example, a condensation reaction of a first compound with a second compound, wherein the first and second compounds react in a molar ratio of 1:1, the term “1 equivalent” means that x moles (e.g., x=2) of the first compound and x moles of the second compound are used, i.e., the molar amount of the first compound is the same as the molar amount of the second compound.
[0101] The terms “poorly soluble” compound and “insoluble” compound are used herein interchangeably in the context with a solvent and mean that under standard conditions less than 0.5 parts by weight of the compound (preferably, less than 0.4 parts by weight, such as less than 0.3 parts by weight, less than 0.2 parts by weight, less than 0.1 parts by weight, less than 0.09 parts by weight, less than 0.08 parts by weight, less than 0.07 parts by weight, less than 0.06 parts by weight, less than 0.05 parts by weight, less than 0.04 parts by weight, less than 0.03 parts by weight, less than 0.02 parts by weight, less than 0.01 parts by weight, less than 0.009 parts by weight, less than 0.005 parts by weight, or less than 0.004 parts by weight) dissolve in 100 parts by weight of the solvent.
[0102] The term “standard conditions” as used herein refers to a temperature of 25° C. and an absolute pressure of 101.325 kPa.
[0103] In a first aspect, the present invention is directed to a process for synthesizing N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide, i.e. a compound of formula (I), a solvate or salt thereof. Within the context of the present invention, novel intermediates are generated as part of the novel synthesis process. Together, the present invention provides an improved, efficient process for the synthesis of N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide, a solvate or salt thereof.
[0104] More specifically, the present invention relates to a process for synthesizing N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide, a solvate or salt thereof, the process comprising the following steps:
[0105] a) providing a compound of formula (3):
##STR00006##
[0106] or a solvate or salt thereof, wherein each of R.sup.1 and R.sup.2 is independently selected from the group consisting of —H and an amino protecting group, and at least one of R.sup.1 and R.sup.2 is an amino protecting group;
[0107] b) reacting the compound of formula (3) or a solvate or salt thereof with one or more reagents to remove the amino protecting group(s) at position R.sup.1 and R.sup.2 to give a compound of formula (4):
##STR00007##
[0108] or a solvate or salt thereof;
[0109] c) reacting the compound of formula (4) or a solvate or salt thereof with one or more reagents for introducing (i) a tetrahydropyranyl group and (ii) an acetyl group to give a compound of formula (5):
##STR00008##
[0110] or a s solvate or salt thereof; and
[0111] d) subjecting the compound of formula (5) or a solvate or salt thereof to an oxidative amination reaction to give the compound of formula (I) or a solvate or salt thereof.
[0112] In one embodiment of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0113] In any of the above embodiments of the process of the first aspect, step a) may comprise reacting a compound of formula (1):
##STR00009##
[0114] or a solvate or salt thereof with HOOC(CH.sub.2).sub.2OCH.sub.3 (formula (2)) or a derivative thereof to give a compound of formula (3) or a solvate or salt thereof. In this embodiment (such as in the process as specified in any one of
[0115] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0116] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0117] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0118] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0119] In any of the above embodiments of the process of the first aspect, the reaction of the compound of formula (1) with the compound of formula (2) may be performed for a sufficient amount of time (in particular of the process of the invention as specified in any one of
[0120] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0121] In step b) of the process of the first aspect, the compound of formula (3) or a solvate or salt thereof is reacted with one or more reagents to remove the amino protecting group(s) at position R.sup.1 and R.sup.2 to give a compound of formula (4):
##STR00010##
[0122] or a solvate or salt thereof. Thus, in other words, in step b) the protected primary amino group of the compound of formula (3) is deprotected in order to give the compound of formula (4) having a free primary amino group.
[0123] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0124] (1) Boc: addition of a strong acid (e.g., selected from the group consisting of trifluoroacetic acid (TFA; e.g., 25-50% in DCM), HCl (e.g., 4-6 M in an organic solvent), CH.sub.3SO.sub.3H (e.g., 2 M in dioxane), and (H.sub.3C).sub.3SiCl (TMSCl; e.g., 1 M TMSCl-phenol in DCM));
[0125] (2) Trt: addition of a strong acid (e.g., TFA (e.g., 1% in DCM or 0.2%, 1% H.sub.2O in DCM), HOBt (e.g., 0.1 M in 2,2,2-trifluoroethanol), or trichloroacetic acid (TCA; e.g., 3% in DCM));
[0126] (3) Fmoc: addition of a base, in particular a secondary amine (e.g., NH.sub.3 (e.g., as liquid; about 10 h), morpholine or piperidine (within minutes), diethylamine (DEA; e.g., 10%), dimethylacetamide (DMA; e.g., 2 h), or polymeric (silica gel or polystyrene) secondary amines (i.e., piperazine or piperidine) in organic solvents;
[0127] (4) Cbz: catalytical hydrogenolysis or addition of a strong acid (e.g., HBr (e.g., in in acetic acid), TFA (e.g., at high temperature; TFA-thioanisole), HF (e.g., liquid), or BBr.sub.3);
[0128] (5) Alloc: Pd-catalyzed transfer of the allyl group to a nucleophile or scavenger (e.g., Pd(PPh).sub.3; scavengers: H.sub.3N.BH.sub.3, Me.sub.2NH.BH.sub.3 or PhSiH.sub.3 in organic solvents)
[0129] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0130] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0131] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0132] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0133] In any of the above embodiments of the process of the first aspect, in which in step b) an acid is added (in particular in the embodiments of the process of the invention as specified in any one of
[0134] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0135] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in
[0136] In step c) of the process of the first aspect, the compound of formula (4) or a solvate or salt thereof is reacted with one or more reagents for introducing (i) a tetrahydropyranyl group and (ii) an acetyl group to give a compound of formula (5):
##STR00011##
[0137] or a s solvate or salt thereof. Thus, in other words, in step c) the primary amino group is converted into a tertiary amino group bearing a tetrahydropyranyl group and an acetyl group.
[0138] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0139] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0140] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0141] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0142] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0143] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0144] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0145] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0146] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0147] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0148] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0149] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0150] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0151] It is to be understood that in any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0152] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0153] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in
[0154] In step d) of the process of the first aspect, the compound of formula (5) or a solvate or salt thereof is subjected to an oxidative amination reaction to give the compound of formula (I) or a solvate or salt thereof. In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0155] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0156] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0157] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0158] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0159] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0160] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0161] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0162] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0163] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0164] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0165] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0166] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in
[0167] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in
[0168] In one mode (in particular of the embodiments of the process of the invention as specified in any one of
[0169] In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
[0170] In particular, the present inventors found that it is possible to avoid chromatography in the preparative steps of the process of the first aspect and that by using alternative means, especially precipitating the compound of interest (i.e., a compound of formula (I) or a solvate or salt thereof or an intermediate of any one of formulas (3), (4), and (5)), the compound of formula (I) or a solvate or salt thereof can be obtained in a much larger scale, in higher yield and in a purity similar to that achieved by a comparative process for synthesizing N-(4-(4-amino-2-(2-methoxy ethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide which uses several chromatographic purification steps.
[0171] In a second aspect, the present invention provides a compound selected from the group consisting of:
##STR00012##
[0172] and a solvate or salt thereof. These compounds are intermediates useful in the process of the first aspect.
[0173] In a third aspect, the present invention provides a use of a compound of the second aspect for synthesizing a compound of formula (I). In this respect, it is noted that the embodiments specified above for the first aspect equally apply to the third aspect. Thus, for example, in one embodiment of the third aspect, a compound of formula (5) or a solvate or salt thereof is subjected to an oxidative amination reaction to give the compound of formula (I) or a solvate or salt thereof and, optionally, the compound of formula (I) or a solvate or salt is crystallized, preferably from an alcoholic solvent.
EXAMPLES
Abbreviations
[0174] The following abbreviations are used throughout description: SM: starting material for the respective synthetic step; IPC: In-Process Control; DCM: dichloromethane; TBME: tert-butyl methyl ether; MeOH: methanol; EtOH: ethanol; HCl: hydrochloric acid; NaOH: sodium hydroxide; Ac.sub.2O: acetic anhydride; HPLC: High Performance Liquid Chromatography; LOD: Loss On Drying; IPA: 2-propanol; pTSCl or TsCl: p-toluenesulfonyl chloride; PTSA: p-toluenesulfonic acid; STAB: sodium triacetoxyborohydride; eq.: equivalent(s); vol.: volume(s); NMR: Nuclear Magnetic Resonance; ppm: parts per million; THP: tetrahydropyranyl; Ac.sub.2O: acetic anhydride; mCPBA: 3-chloroperoxybenzoic acid.
Example 1—Synthesis of N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Using the Process of the Present Invention
[0175] Step a): Providing a Compound of Formula (3)
[0176] Compound 1 (1 eq.), p-toluenesulfonic acid monohydrate (0.05 eq.) and toluene (10 vol.) were charged to a reactor. After addition of 1,1,1,3-tetramethoxypropane (1.2 eq.) the contents of reactor were adjusted to reflux at approx. 95° C. and the content of compound 1 was monitored using HPLC.
[0177] Step b): Preparing a Compound of Formula (4)
[0178] When the content of compound 1 dropped to ≤1.0% area of the initial area (determined by HPLC), the contents of reactor were adjusted to 10 to 15° C., 6 N HCl (5 vol.) were added to reactor over approx. 1 h, whereby the temperature was maintained ≤25° C. The contents of the reactor were agitated at 20° C. to 25° C. for at least 2 hours and the reaction completion was monitored by HPLC. The lower aqueous layer containing the desired product was collected, the upper organic layer was discharged, the collected aqueous layer containing the desired product was transferred into the reactor, DCM (5 vol.) was added, the reaction mixture was agitated for 15 min and allowed to settle for 15 min. The lower organic layer was discharged, water (2 vol.) was added to reactor, and the contents of reactor were adjusted to 0° C. to 5° C. NaOH (11 eq.) was added to the reactor portion-wise while maintaining the temperature ≤30° C. After the pH of the reaction mixture was adjusted to ≥12, the temperature of the reaction mixture was increased to 20° C. to 25° C., DCM (5 vol.) was added, and the reaction mixture was agitated for 15 min and allowed to settle for 15 min. The lower organic layer containing the desired product was collected, DCM (5 vol.) was added, and the reaction mixture was agitated for 15 min and allowed to settle for 15 min. The lower organic layer containing the product was collected, the upper aqueous layer was discharged, and the 2 collected organic layers were combined in the reactor. A solvent exchange to ethanol was performed until the amount of DCM in the reaction mixture was ≤1%. The amount of compound 4 was determined, fumaric acid (1 eq. based on the determined amount of compound 4) was added, and the reaction mixture was agitated at 20° C. to 25° C. for at least 12 hours to precipitate the compound of formula (4) as fumaric acid addition salt. TBME (10 vol.) was added over at least 30 min and the reaction mixture was agitated at 20° C. to 25° C. for 1 to 2 hours. The precipitate was collected using filtration under nitrogen, the reactor was washed with TBME (2×3 vol.) and this washing solution was used to wash the precipitate under nitrogen. The collected precipitate was dried at 40° C. to 45° C. for at least 12 hours.
TABLE-US-00001 TABLE 1 Input Output Yield Purity by HPLC 7.30 Kg 8.50 Kg 92% 95.428% area
[0179] Step c): Preparing a Compound of Formula (5)
[0180] Compound 4 as fumaric acid addition salt (1 eq.) obtained from step b), DCM (5 vol.), and 2 M NaOH (10 vol.) were added to a reactor, and the reaction mixture was agitated for 15 min and allowed to settle for 15 min. The lower organic layer containing compound 4 as free base was collected, the aqueous phase was extracted with DCM (5 vol.), and the lower organic layer was collected. After discharging the upper aqueous layer, the 2 organic layers were charged into the reactor, MgSO.sub.4 (0.2 wt.-%) were added to the reactor, the reaction mixture was agitated for 5 min and the contents of the reactor filtered to remove MgSO.sub.4. The filtrate was charged into a new clean reactor, tetrahydropyranone (1.1 eq.) and acetic acid (1 eq.) were added, and the temperature of the reaction mixture was adjusted to −10° C. to 0° C. STAB (1.8 eq.) was added portion-wise while maintaining the temperature ≤0° C. After completion of the addition, the temperature was increased to 20° C. to 25° C., the reaction mixture was agitated for at least 18 hours, and the reaction completion was monitored by HPLC. Once the content of compound 4 Target was ≤0.50% of the initial area, the reaction mixture was cooled to 10° C. to 15° C. and slowly quenched by the addition of 2 M NaOH (10 vol.) while maintaining the temperature ≤25° C. After completion of the NaOH addition, the reaction mixture was agitated for 15 min and allowed to settle for 15 min. The lower organic layer containing the desired product was collected, the upper aqueous layer was extracted with DCM (10 vol.), the lower organic layer containing the desired product was collected, and the upper aqueous layer was discharged. MgSO.sub.4 (0.2 wt.-%) was added to the reactor and the 2 organic layers were charged into the reactor and the reaction mixture was agitated for at least 15 min. MgSO.sub.4 was removed by filtration and the MgSO.sub.4 cake was washed with DCM (1 vol.). The filtrates were combined in a clean reactor and reduced to approx. 10 to 12 vol. under reduced pressure at 35° C. to 40° C. The temperature of the reaction mixture was adjusted to 20° C. to 25° C., acetic anhydride (1 eq.) was added slowly while maintaining the temperature between 20° C. and 30° C. After completion of the addition, the temperature of the reaction mixture was adjusted to 20° C. to 25° C., the reaction mixture was agitated for at least 24 hours, and the content of the tetrahydropyranyl adduct and STAB was monitored using HPLC. Once the content of each the tetrahydropyranyl adduct and STAB was ≤0.50% of the initial area, the reaction was slowly quenched by the addition of 5% NaHCO.sub.3 solution (10 vol.), and the reaction was agitated for 15 min and allowed to settle for 15 min. The lower organic layer containing the desired product was collected and charged into a clean reactor. MgSO.sub.4 (0.2 wt.-%) was added, the reaction mixture was agitated for at least 15 min and then filtered to remove MgSO.sub.4. The reactor was washed with DCM (1 vol.) and this washing solution was used to rinse the MgSO.sub.4 cake. The filtrates were recharged into a clean reactor and reduced to 6-7 vol. under reduced pressure at ≤30° C. A solvent exchange to TBME was performed until the content of DCM in the reaction mixture was ≤10%. Then, TBME (3 vol.) was added, the temperature of the reaction mixture was adjusted to 20° C. to 25° C. and the reaction mixture was agitated for at least 1 hour. The suspension was filtered under nitrogen and the reactor and filter cake were washed with TBME (2×2 vol.). The collected precipitate was dried at 35° C. to 40° C. for at least 12 hours.
TABLE-US-00002 TABLE 2 Input Output Yield Purity by HPLC 8.40 Kg 6.41 Kg 74% 94.88% area
[0181] Step d): Preparing a Compound of Formula (I)
[0182] Compound 5 (1 eq.) obtained from step c) was charged in a reactor, DCM (10 vol.) was added, and the temperature of the reaction mixture was adjusted to −10° C. to 0° C. 70% mCPBA (1.5 eq.) was added to the reactor portion-wise while maintaining the temperature ≤0° C. After completion of the addition the temperature of the reaction mixture was adjusted to 20° C. to 25° C., the reaction mixture was agitated for at least 2 hours, and the content of compound 5 in the reaction mixture was monitored using HPLC. Once the content of compound 5 in the reaction mixture was ≤4% of the initial amount, the temperature of the reaction mixture was adjusted to 0° C. to 5° C. and ammonium hydroxide (10 vol.) was added while maintaining the temperature ≤20° C. After completion of the addition, the temperature of the reaction mixture was adjusted to 0° C. to 5° C. pTsCl (1.5 eq.) dissolved in DCM (3 vol.) was slowly added to the reactor while maintaining the temperature ≤10° C. After completion of the addition, the temperature of the reaction mixture was adjusted to 20° C. to 25° C., the reaction mixture was agitated for at least 2 hours, and the content of the N-oxide intermediate in the reaction mixture was monitored using HPLC. Once the content of the N-oxide intermediate in the reaction mixture was ≤0.5% of the initial amount, the temperature of the reaction mixture was adjusted to 30° C. to 35° C. and the reaction mixture was agitated for at least 2 hours. The temperature of the reaction mixture was adjusted to 20° C. to 25° C., the lower organic layer containing the desired product was collected, charged into a clean reactor, MgSO.sub.4 (0.2 wt.-%) was added, and the reaction mixture was agitated for at least 15 min. The reaction mixture was filtered to remove MgSO.sub.4, the reactor was washed with DCM (1 vol.) and this washing solution was used to rinse the MgSO.sub.4 cake. The filtrates were combined in a clean reactor and reduced to approx. 10 vol. under reduced pressure at 35° C. to 40° C., and the content of the compound of formula (I) in the resulting solution was determined.
TABLE-US-00003 TABLE 3 Input Output Yield 6.35 Kg 7.7 Kg* 113%
[0183] Step e): Precipitating the Compound of Formula (I)
[0184] The crude solution of the compound of formula (I) (1 eq.) obtained from step d) was charged into a reactor. A solvent exchange to IPA was performed until the content of DCM in the reaction mixture was ≤1%. Then, the temperature of the reaction mixture was adjusted to 5° C. to 10° C. and the reaction mixture was agitated for at least 1 h. The suspension was filtered, the reactor was washed with IPA (2 vol.), the washing solution was cooled to 5° C. to 10° C. and then used to rinse the filter cake. The reactor was washed with TBME (2×5 vol.) and each washing solution was used to rinse the filter cake. The collected precipitate was dried at 35° C. to 40° C. for at least 12 hours
TABLE-US-00004 TABLE 4 Input Output Yield Purity by HPLC 3.00 Kg 1.62 Kg 54%* 96.18% area 3.00 Kg 1.70 Kg 57%* Not proceeded to step 4 *Yield typical. Expected yield = 45 to 60% theoretical as input is crude product.
[0185] Step f): Crystallization of the Compound of Formula (I)
[0186] 5% water in ethanol (10 vol.) was charged into a reactor and the compound of formula (I) (1 eq.) obtained from step e) was added. The temperature of the reaction mixture was adjusted to 65° C. to 70° C. and held for at 30 min to 1 hour. Once all of the compound of formula (I) was dissolved, the solution was filtered and the filtrate was charged into a clean reactor preheated to 65° C. to 70° C. The temperature of the solution was adjusted to 45° C. to 50° C. over 3 h±30 mins. A seed crystal of the compound of formula (I) was added, temperature of the reaction mixture was adjusted to 0° C. to 5° C. over at least 7 h, and the reaction mixture was agitated at 0° C. to 5° C. for at least 2 hours. The suspension was filtered, the reactor was washed with 5% water in ethanol (2 vol.), the temperature of the washing solution was adjusted to 0° C. to 5° C. and used to rinse the filter cake. The reactor was washed with TBME (2 vol.) and the washing solution was used to rinse the filter cake. Optionally, the crystallization step was repeated.
TABLE-US-00005 TABLE 5 Input Output Yield Purity by HPLC 1.60 Kg 1.19 Kg 71% 99.0% area
[0187] The overall yield of the process of the present invention, the amount of compound of formula (I) produced by said process, and the time required for the synthesis are given in Table 6, below.
Example 2—Comparative Synthesis of N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide Using Chromatographic Purification Steps (Comparative Process B)
[0188] N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide was prepared according to the process set forth in
TABLE-US-00006 TABLE 6 Process of the present Comparative invention process B Overall yield 31% 11% Chromatographic purifications 0 3 Amount produced 1.19 kg 10.42 g Purity 99.0% 99.5% Time 7.5 weeks 5 weeks
[0189] As can be seen from the results presented in Table 6, the process of the present invention provides much higher yields than the comparative process B and is capable of providing the compound of formula (I) in much higher amounts (about 1.2 kg vs. about 10 g, i.e., a factor of more than 10.sup.2) than the comparative process B and in a purity comparable to that achieved by using the comparative process B.