HK1232885A - Compositions of protein receptor tyrosine kinase inhibitors - Google Patents

Description

Tyrosine kinase protein receptor antagonists

The patent application is a divisional application of an invention patent application with the international application number of PCT/US2009/067197, the international application date of 2009, 12, month and 8, the application number of 200980150091.4 entering the Chinese national stage and the invention name of "tyrosine kinase protein receptor antagonist".

Cross reference to related applications

This application claims priority to U.S. patent provisional application No. 8, 12/2008 (61/120827) entitled "tyrosine kinase protein receptor antagonists". This document is incorporated by reference herein in its entirety as part of the present invention.

Technical Field

The present invention relates to the synthesis of substituted heterocyclic compounds and pharmaceutical compositions containing these compounds having the following functions: a receptor family of tyrosine kinases, tropomyosin-related kinases (trks), particularly the Nerve Growth Factor (NGF) -TrkA receptor, are capable of inhibiting or antagonizing. The invention also relates to the use of these compounds for the treatment and/or prophylaxis of the following conditions: pain, cancer, vascular restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder or injury associated with dysmyelination or demyelinating disease, or a disease or disorder associated with abnormal activity of the nerve growth factor TrkA.

Background

The receptor protein family of tyrosine kinases (Trk) has three family members: TrkA, TrkB and TrkC. They have high affinity binding to neurotrophic factor ligands and mediate the transduction of signals caused thereby. The prototypical members of these ligands are Nerve Growth Factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3-5(NT 3-5). In addition, a co-receptor lacking enzymatic activity, p75, has been identified to bind all neurotrophic factors (NTs) with low affinity and to modulate neurotrophic factor signaling. The key role of Trks and their ligands in the growth of the central and peripheral nervous system has been determined by mouse gene disruption studies. It is particularly important to note that the interaction of TrkA-NGF has been shown to be a prerequisite for the involvement of certain peripheral neurons in the regulation of pain signals. It was shown that an increase in TrkA expression is also closely associated with an increase in pain levels in pancreatic cancer (Zhu et al, J. Clin Oncology, 17:2419-2428 (1999)). Increased expression of nerve growth factor and TrkA has also been found in human osteoarthritic chondrocytes (Yanunong et al, J rheuma 41:1413-1418 (2002)).

TrkA (tropomyosin-receptor kinase a) is a cell surface receptor kinase. It contains an extracellular, a transmembrane, and a cytoplasmic kinase domain. Binding of a neurotrophic factor causes receptor oligomerization, phosphorylation at tyrosine residues in the kinase domain, and activation of intercellular signaling pathways, including: cascade of Ras protein-mitogen-activated protein kinase (Ras/MAPK), activation of phosphoinositide 3-kinase/protein kinase B (PI3K-Akt) signaling pathway, and IP 3-dependent Ca²⁺Is released. The activity of tyrosine kinases is an absolute requirement for signal transduction through such receptors. Receptors for nerve growth factor have also been found in a variety of cells outside the nervous system. TrkA is found, for example, in human monocytes, T-and B-lymphocytes, and mast cells.

There are several examples of anti-TrkA antibodies or anti-NGF antibodies known in the art. For example, PCT publication Nos. WO2006/131952, WO2005/061540, and EP 1181318 disclose: an anti-TrkA antibody is used as an effective analgesic in animal models of inflammation and neuropathic pain. PCT application Nos. WO01/78698, WO2004/058184 and WO2005/019266 disclose that an antagonist of NGF may prevent or treat pain. PCT application WO2004/096122 describes a method of treating or preventing pain using co-administration of an anti-NGF antibody and an opioid analgesic. PCT application WO2006/137106 discloses a method of treating or preventing pain using co-administration of an anti-TrkA antibody and an opioid analgesic. Furthermore, the use of anti-NGF antibodies can significantly reduce bone pain (Severk, horse, et al, J. pain 115:128-141 (2005)).

However, there are only a few known TrkA inhibitors other than antibodies, and very few (if any) inhibitors show high selectivity for TrkA kinase (including staurosporine-like TrkA inhibitors, CEP-751 and CEP-701). In this area of expertise, few synthetic organic molecules or compounds are available as direct TrkA or NGF inhibitors or antagonists, particularly in the treatment or prevention of pain. Although the complex crystal structure of NGF and TrkA receptors has been established (Nature J401: 184-188(1996) and 254:411(1991)), it is difficult to identify small organic compounds that are effective and specifically selective for anti-TrkA or anti-NGF.

The clinical use of a potent Trk inhibitor is likely to be more than pain management. The destructive nature of this receptor and its signaling pathway in certain malignancies is documented. Activation of Trk tyrosine kinase is thought to promote unrestricted activation of cell proliferation functions. It is believed that inhibitors of TrkA, TrkB, or TrkC kinases, alone or in combination, have been implicated in some of the most common cancers, such as brain cancer, melanoma, multiple myeloma, squamous cell carcinoma, bladder cancer, gastric cancer, pancreatic cancer, breast cancer, head cancer, neck cancer, esophageal cancer, prostate cancer, colorectal cancer, lung cancer, renal cancer, ovarian cancer, gynecological cancer, thyroid cancer, and some hematological tumors. Lestaurtinib (CEP-701, Cephalon corporation) is an indolocarbazole inhibitor of several tyrosine kinases, including the receptors Flt-3 and TrkA. Both CEP-701 and a pan-Trk inhibitor CEP-751 have entered phase II clinical trials for acute myeloid leukemia therapy (AML), pancreatic cancer and Multiple Myeloma (MM) and/or prostate cancer.

Of particular note are reports showing that the following events are associated with aberrant expression of nerve growth factor and TrkA receptor kinases: progression of human prostate and pancreatic ductal adenocarcinoma and activation of Trks chromosomal rearrangements in Acute Myeloid Leukemia (AML), thyroid and breast cancer; and receptor point mutations are predicted to be constitutively activated in colon tumors. In addition to these activation mechanisms, Trk receptors and ligands have been reported in the literature to be elevated in a variety of tumors, including multiple myeloma, melanoma, neuroblastoma, pancreatic cancer, and ovarian cancer. Neurotrophic factors and their corresponding Trk receptor subtypes have been shown to exert pleiotropic responses in malignant tumor cells, including enhancing tumor invasion and chemotaxis, activating apoptosis, stimulating clonal growth, and altering cell morphology. These effects are observed in all of the following cancers: prostate cancer, breast cancer, thyroid cancer, colon cancer, malignant melanoma, lung cancer, glioblastoma, pancreatic carcinoids and a variety of pediatric and neuroectodermal-derived tumors, including blastoma, neuroblastoma and medulloblastoma. Neurotrophic factors and their receptor subtypes have been implicated in the above cancers by autocrine or paracrine mechanisms involving the cells and surrounding parenchymal and interstitial tissues. Overall, the oncogenic properties of trks in many types of tumors make modulation of Trk receptor signaling a potentially attractive intervention point in different tumor therapies.

Since the therapeutic promise is associated with the inhibition of TrkA and the relative lack of potent and selective inhibitors, there is a great need in the market to find potent and specific subtype selective inhibitors of TrkA. In particular orally active small synthetic molecules which are likely to treat or prevent diseases or disorders associated with the activity of TrkA.

Summary of The Invention

The invention relates to the use of a series of small synthetic molecules as NGF receptor TrkA inhibitors and/or antagonists. Can be used as a medicament for treating and/or preventing a disease associated with the inhibition of TrkA, including pain, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, or a disease, disorder or injury associated with dysmyelination or demyelination.

In one aspect, the present invention provides a compound having the structural formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof:

wherein n is 1,2, or 3; m is 0,1, or 2;

a is C, N, O, S, NR¹,C＝CR¹(E and Z isomers), C ═ NR¹(E and Z isomers), C (R)¹R²),CR¹＝CR²-CR¹’R²' (E and Z isomers), or CR¹＝CR²-NR¹' (E and Z isomers);

b is C, N, O, S, NR³Or C (R)³R⁴)；

J, K, L, and M are each independently N or CR⁵；

Y is O, S, NR⁶Or C (R)⁶R⁷)；

R¹,R²,R¹’,R²’,R³,R⁴,R⁵,R⁶And R⁷Each independently is hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, -CONR⁸R⁹Alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl;

R⁸and R⁹Each independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl; or when R is⁸And R⁹When neither is hydrogen, R⁸And R⁹Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heteroalkyl or substituted heteroalkyl ring.

In another aspect, the invention includes a pharmaceutical composition that provides one or more of the compounds described above, or a salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable carrier.

In another aspect, the invention provides a method of selectively inhibiting or antagonizing the nerve growth factor receptor TrkA. The use of a therapeutically effective amount of such a compound, or a salt, solvate, or physiologically functional derivative thereof, for the treatment and/or prophylaxis of pain, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, or a disease, disorder or injury associated with dysmyelination or demyelination.

In another aspect, the invention provides a method of treating and/or preventing pain, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, or a disease, disorder or injury associated with dysmyelination or demyelination. Use of (a) a therapeutically effective dose of a compound as described above, or a salt, solvate, or physiologically functional derivative thereof, and (b) an opioid analgesic or an analgesic having at least one mechanism different from that of the TrkA antagonist.

Detailed Description

The invention relates to a novel synthesized small molecule which is used as Trk protein kinase family inhibitor and/or antagonist, in particular to nerve growth factor receptor TrkA.

Definition of terms

Unless otherwise indicated, the terms used in the claims and specification are defined as follows.

Term "One compound of the present invention”，“This compound of the invention”，“Compounds of the invention'or'Shown compounds"refers to compounds having one or more structures encompassed within the presently disclosed structural formula and/or any sub-structural formula derived therefrom, as well as including those specifically disclosed individually. The compounds of the invention may contain one or more chiral centers and/or double bonds, and stereoisomers thereof, such as double bond isomers (i.e., geometric isomers), racemic mixtures, enantiomers or diastereomers. Thus, the chemical structures described herein encompass all possible enantiomers and stereoisomers of the compounds of the invention, including pure forms of the stereoisomers (e.g., geometrically pure, optically pure or diastereomerically pure) as well as stereoisomeric mixtures of enantiomers. The compounds of the invention may also have several tautomeric forms. Thus, the chemical structures of the present invention encompass all possible tautomeric forms. Compounds also include isotopically labeled compounds. Wherein one or more atoms have a mass that is different from the conventional atomic mass found in nature. Examples of isotopes that may be incorporated into a compound include, but are not limited to:²H,³H,¹³C,¹⁴C,¹⁵N,¹⁷O,¹⁸o, and the like. The compounds may exist in unsolvated and solvated forms including hydrates and N-oxides. In general, the salt, hydrate, solvate and N-oxide forms of the compounds are included within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms of the compounds are equivalent for the contemplated uses. And are therefore included within the scope of the present invention.

The term used herein "Physiologically functional derivatives"refers to any physiologically tolerable derivative of a compound of the present invention. For example, an ester or prodrug, when administered to a mammal (e.g., a human), is converted, directly or indirectly, to a compound of structural formulae (I) to (VI) or an active metabolite thereof. Physiologically functional derivatives include prodrugs of the compounds of the invention. Examples of prodrugs are described in detail in the reference "Ooka et al, chemical bulletin 1994, 42, 57-61". Such prodrugs can be metabolized in vivo to the compounds of the invention. These prodrugs may or may not be active themselves.

“Alkyl radical"used herein alone or as part of a substituent group refers to a straight, branched or singly bonded cyclic radical containing 0 or 1 to more saturated or unsaturated bonds in the middle. These are fromThe free radical can be obtained by removing one hydrogen atom from a carbon atom in the following group: a single bond alkyl, alkenyl or alkynyl. Representative alkyl groups include, but are not limited to, methyl; ethyl groups such as ethyl, vinyl, and ethynyl; propyl groups such as propan-1-yl, propan-2-yl, cyclopropane-1-yl, 1-propen-2-yl, 2-propen-1-yl (allyl), 1-cyclopropene-1-yl, 1-cyclopropene-2-yl, 2-cyclopropene-1-yl, 1-propyn-1-yl, 2-propyn-1-yl, and the like; butyl, for example butan-1-yl, butan-2-yl, 2-methylpropan-1-yl, 2-methylpropan-2-yl, cyclobutane-1-yl, 1-buten-2-yl, 2-methyl-1-propen-1-yl, 2-buten-2-yl, 1, 3-dibuten-1-yl, 1, 3-dibuten-2-yl, 1-cyclobuten-1-yl, 1-cyclobuten-3-yl, 1, 3-cyclobutadien-1-yl, 1-butyn-1-yl, 1-butyn-3-yl, 3-butyn-1-yl, etc.); and other similar carbon chains.

As used herein, the term "alkyl" refers specifically to a group of any degree of saturation. For example, a carbon chain containing only single bonds, a group containing 1 or more carbon-carbon double bonds, a group containing 1 or more carbon-carbon triple bonds, and a group containing 1 or more carbon-carbon single bonds, double bonds, and triple bonds in combination. When the specific saturation is determined, the term: singly-bound alkyl, alkenyl, and alkynyl groups. In some embodiments, the alkyl chain length is from 1 to 20 carbon atoms (C)₁-C₂₀Alkyl groups). In other embodiments, the alkyl chain length is from 1 to 10 carbon atoms (C)₁-C₁₀Alkyl groups). In still other embodiments, the alkyl chain length is from 1 to 6 carbon atoms (C)₁-C₆Alkyl groups).

“Singly-bound alkyl", as a single term or as part of a substituent group, refers to a saturated branched, straight chain, or cyclic alkyl radical. These radicals can be obtained by removing a hydrogen atom from a carbon atom in an alkane radical. Specific examples are, but not limited to, methyl; ethyl (alkyl) group; a propyl (alkyl) group such as a 1-propyl group, a 2-propyl (isopropyl) group, a 1-cyclopropyl group, etc.; butanyl, e.g. 1-butyl, 2-butyl (sec-butyl), 2-methyl-1-propyl (iso-butyl)Butyl), 2-methyl-2-propyl (tert-butyl), 1-cyclobutyl, and the like; and other similar single-bond long alkyl chains.

“Alkenyl radical", as a single term or part of a substituent group, refers to an unsaturated, branched, straight chain or cyclic alkyl radical containing at least one carbon-carbon double bond. These radicals can be obtained by removing a hydrogen atom from a carbon atom in the olefin group. The double bonds of these groups may be in either the cis or trans conformation. Specific examples include, but are not limited to, vinyl; propenyl, such as 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl (allyl), 1-cyclopropene-1-yl, 2-cyclopropene-1-yl, and the like; butenyl, e.g., 1-buten-1-yl, 1-buten-2-yl, 2-methyl-1-propen-1-yl, 2-buten-2-yl, 1, 3-dibuten-1-yl, 1, 3-butadien-2-yl, 1-cyclobuten-1-yl, 1-cyclobuten-3-yl, 1, 3-cyclobutadien-1-yl, etc.), and other like long unsaturated alkyl chains.

“Alkynyl radical", as a separate term or part of a substituent, refers to an unsaturated, branched, straight chain or single bonded cyclic alkyl radical containing at least one carbon-carbon triple bond. These radicals can be obtained by removing a hydrogen atom from a carbon atom in an alkyne group. Specific examples, but not limited to, ethynyl; propynyl groups such as 1-propyn-1-yl group, 2-propyn-1-yl group and the like; butynyl groups such as 1-butyn-1-yl, 1-butyn-3-yl, 3-butyn-1-yl and the like; and other similar unsaturated long alkyl chains.

“Dialkyl radical", as a single term or as part of a substituent group, refers to a saturated or unsaturated, branched, straight chain or monocyclic divalent hydrocarbon group. This group may be formed by the following group without one hydrogen atom on each of the two atoms: alkane, alkene or alkyne; or by removing two hydrogen atoms from the same atom of the aforementioned carbon chain. Each valence of the two monovalent or divalent radicals may form a bond with the same or different atoms. Exemplary bisalkyl groups include, but are not limited to, methane bisA group; ethane-diyl such as ethane-1, 1-diyl, ethane-1, 2-diyl, ethylene-1, 1-diyl, ethylene-1, 2-diyl; propane diyl groups such as propane-1, 1-diyl group, propane-1, 2-diyl group, propane-2, 2-diyl group, propane-1, 3-diyl group, cyclopropane-1, 1-diyl group, cyclopropane-1, 2-diyl group, 1-propene-1, 1-diyl group, 1-propene-1, 2-diyl group, 2-propene-1, 2-diyl group, 1-propene-1, 3-diyl group, 1-cyclopropene-1, 2-diyl group, 2-cyclopropene-1, 1-diyl group, 1-propyne-1, 3-diyl group and the like; butane-diyl group such as butane-1, 1-diyl group, butane-1, 2-diyl group, butane-1, 3-diyl group, butane-1, 4-diyl group, butane-2, 2-diyl group, 2-methylpropane-1, 1-diyl group, 2-methylpropane-1, 2-diyl group, cyclobutane-1, 1-diyl group, cyclobutane-1, 2-diyl group, cyclobutane-1, 3-diyl group, 1-butene-1, 1-diyl group, 1-butene-1, 2-diyl group, 1-butene-1, 3-diyl group, 1-butene-1, 4-diyl group, 2-methyl-1-propene-1, 1-diyl group, 2-methylene-propane-1, 1-diyl, 1, 3-butadiene-1, 2-diyl, 1, 3-butadiene-1, 3-diyl, 1, 3-butadiene-1, 4-diyl, 1-cyclobutene-1, 2-diyl, 1-cyclobutene-1, 3-diyl, 2-cyclobutene-1, 2-diyl, 1, 3-cyclobutadiene-1, 3-diyl, 1-butyne-1, 4-diyl, 1, 3-butyne-1, 4-diyl, and the like; and so on. When saturation is clear, the following names are used: single-bonded alkyl diradicals, alkenyl diradicals and/or alkynyl diradicals. In some embodiments, the single-bonded alkyl diradical is of chain length C1-C20, more preferably of chain length C1-C10, and most preferably of chain length C1-C6.

“Alkylene radical", as a single term or part of a substituent, means that there are two terminal monovalent radicals on a linear alkyl diradical. It can be obtained by removing one hydrogen atom from each of the two terminal atoms in the following groups: straight-chain alkanes, alkenes, or alkynes. Typical alkylene groups include, but are not limited to: a methylene group; ethylene groups such as ethylene group, vinylene group, and ethynylene group; propylene groups such as propylene group, [1 ]]Propylene group, [1,2 ]]Propylenediyl, [1 ]]Propynyl and the like; such as butylene, [1 ]]Butylene alkyl group, [2 ]]Butylene alkyl group, [1,3 ]]Butanediyl group, [1 ]]Butynylene, [2 ]]Butynylene, [1,3 ]]Butynediyl, and the like. When the degree of saturation is determined,the terms single-bonded alkylene, alkenylene and/or alkynylene will be used.

“Acyl radical", as a separate term or part of a substituent, refers to a radical-C (O) R²⁰⁰Wherein R is²⁰⁰Represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an aralkyl group, a substituted aralkyl group, a heteroalkanyl group, a substituted heteroalkanyl group, a heteroaralkyl group, or a substituted heteroaralkyl group (see further definitions herein). Representative examples are, but not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

“Amino group", as a separate term or part of a substituent, refers to a radical-NR^aR^bAt R^aAnd R^bIndependently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkyl (as otherwise defined herein), or R^aAnd R^bTogether with the other atoms to which they are attached, form a heteroalkyl ring. Representative examples include, but are not limited to, amino, -NHCH₃，-N(CH₃)₂，-NH-phenyl，-NH-CH₂Phenyl, pyrrole, etc.

“Aryl radicals", as a single term or part of a substituent group, refers to a monovalent aromatic hydrocarbon group. Aryl groups can be obtained by removing one hydrogen from the corresponding aromatic ring. Representative substituents may be derived by removing one hydrogen from the following aromatic groups, but are not limited to aceanthrene, acenaphthene (naftalene), acephenanthrene, anthracene, azulene, benzene, chrysidine, coronene, fluoranthene, fluorene, hexacene, hexaphene, asymmetric indacene, symindacene, indane, indene, naphthalene, octaphene, ovalene, 2, 4-pentadiene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, heptapleizene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.In some embodiments, the aryl chain length is from 6 to 20 carbon atoms. In other embodiments, the aryl chain length is from 6 to 15 carbon atoms. In still other embodiments, the aryl chain length is from 6 to 10 carbon atoms.

“Aralkyl radical", as a single term or part of a substituent, refers to an alkyl group having an aromatic substituent. Representative substituents are, but are not limited to, benzyl, 2-benzene-1-ethyl, 2-benzene-1-ethylene, naphthylmethyl, 2-naphthalene-1-ethyl, 2-naphthalene-1-ethylene, naphthobenzyl, 2-naphtho-1-phenylethyl, and the like. When specific alkyl groups are identified, the following terminology: aryloxyalkyl, aralkenyl and aralkynyl are used. In some embodiments, the aralkyl chain length is from 6 to 30 carbon atoms. For example, an aralkyl group can have an alkyl moiety (single-bond alkyl, alkenyl, or alkynyl) of 1 to 10 carbon atoms and an aryl group of 6 to 20 carbon atoms. In other embodiments, the aryl chain length is from 6 to 20 carbon atoms. For example, an aralkyl group has an alkyl moiety (a single-bond alkyl, alkenyl, or alkynyl group) of 1 to 8 carbon atoms and an aryl group of 6 to 20 carbon atoms. In still other embodiments, the aryl chain length is from 6 to 12 carbon atoms. For example, an aralkyl group has an alkyl moiety (a single-bond alkyl, alkenyl, or alkynyl group) of 1 to 5 carbon atoms and an aryl group of 6 to 10 carbon atoms.

“Aryloxy radical", used as a single term or part of a substituent group, all mean that the formula-O-R²⁰¹Free radical of (A), R²⁰¹Is in the form of an aryl, substituted aryl, aralkyl, or substituted aralkyl group.

“Aryloxy carbonyl group", as a separate term or part of a substituent, refers to a radical-C (O) -O-R²⁰³Wherein R is²⁰³Represents aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, or substituted heteroaralkyl.

“Cycloalkyl radicals'or'Carbocyclic group"used as a separate term or part of a substituent group" means a saturated groupAnd or unsaturated cyclic alkyl group. When saturation is determined, the following terms are used: a single bonded cycloalkyl, cycloalkenyl, or cycloalkynyl group. Specific examples are, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and like substituents. In some embodiments, the cycloalkyl chain length is from 3 to 10 carbon atoms. In other embodiments, the cycloalkyl chain length is from 3 to 7 carbon atoms.

“Heterocycloalkyl radicals'or'Heterocyclic radical"used as a separate term or part of a substituent group" refers to a saturated or unsaturated cyclic alkyl group. Heteroatoms often used are, but not limited to: nitrogen, phosphorus, oxygen, sulfur, silicon, and the like. When saturation is determined, the following terms are used: single bond heterocycloalkyl, heterocycloalkenyl. Specific examples are, but not limited to, epoxides, cyclic nitrides, cyclic sulfides, imidazoles, morpholines, piperazines, piperidines, pyrazolidines, pyrrolines, quinuclidines, and similar substituents. In some embodiments, the heterocyclyl chain length has from 3 to 10 carbon atoms. In other embodiments, the heterocyclyl chain length has from 5 to 7 carbon atoms.

The heterocyclic group may be attached to a heteroatom, for example an alkyl group of chain length 1 to 6 carbons attached to the nitrogen. Specific examples include: azomethionyl, azomethylmorpholinyl, azomethinyl.

“Heteroalkyl radicals"," single-bond heteroalkyl, "heteroalkenyl," and "heteroalkynyl," used alone or as part of a substituent, all refer to an alkyl chain, single-bond alkyl chain, alkenyl chain, alkynyl chain that contains a heteroatom or heteroatom group. Representative substituents are, but not limited to, O, S, N, Si, -NH-, -S (O) -, -S (O)₂-,-S(O)NH-,-S(O)₂NH-and the like or combinations. The heteroatom or heteroatom group may be an alkyl, alkenyl, or alkynyl group attached in the chain. Heteroatom groups frequently present are, but are not limited to, -O-, -S-, -O-, -S-, -O-S-, -NR-³⁵R³⁶-,＝N-N＝,-N＝N-,-N＝N-NR³⁷R³⁸,-PR³⁹-,-P(O)₂-,-POR⁴⁰-,-O-P(O)₂-,-SO-,-SO₂-,-SnR⁴¹R⁴²-and analogous groups thereof, wherein R³⁵,R³⁶,R³⁷,R³⁸,R³⁹,R⁴⁰,R⁴¹And R⁴²Each optionally one of: a hydrogen atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an aralkyl group, a substituted aralkyl group, a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, a substituted heterocycloalkyl group, a heteroalkyl group, a substituted heteroalkyl group, a heteroaryl group, a substituted heteroaryl group, a heteroaralkyl group, or a substituted heteroaralkyl group.

“Heteroaryl radical"used alone as a term or part of a substituent group" refers to a substituent group in which a hydrogen atom in an aromatic group containing a heteroatom or heteroatom group is removed. Heteroaryl groups that are often found are, but are not limited to, acridine, carboline, chroman, benzopyran, cinnoline, furan, imidazole, indazole, indole, dihydrocarbazole, indolizine, isobenzofuran, isobenzopyran, isoindole, isoindoline, isovaniline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrane, quinazoline, quinoline, quinolizidine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene and similar compounds. In some embodiments, the heteroaryl group has 5 to 20 ring-forming atoms. In other embodiments, the heteroaryl group has 5 to 10 ring-forming atoms. Examples include substituents derived from furan, thiophene, pyrrole, thiophene, furan, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole and pyrazine.

“Heteroaralkyl radicals"used alone as a term or part of a substituent group" means that one hydrogen atom of an acyclic alkyl group, usually attached to the end of the chain or sp3 carbon atom, is replaced by a heteroaryl group. When the alkyl moiety is defined, the following terms will be used: heteroaralkyl, heteroaralkenyl, orAnd heteroarylalkynyl groups. In some embodiments, the entire chain has 6 to 21 heavy atoms. For example, a monoalkyi, alkenyl or alkynyl moiety has a chain length of 1 to 6 carbons and a heteroaryl moiety has 5 to 15 atoms. In other embodiments, heteroaralkyl contains 6 to 13 atoms. For example, a monoalkyi, alkenyl or alkynyl moiety has a chain length of 1 to 3 carbons and a heteroaryl moiety has 5 to 10 atoms.

“Heteroaryloxy radicals"used alone or as part of a substituent group, all mean according to the formula-O-R²⁰¹Wherein R is²⁰¹Is heteroaryl, substituted heteroaralkyl, or substituted heteroaralkyl.

“Heteroaryloxycarbonyl radicals", whether used by itself as a term or part of a substituent, means according to the formula-C (O) -O-R²⁰¹Wherein R is²⁰¹Is heteroaryl, substituted heteroaralkyl, or substituted heteroaralkyl.

“Regulating"or" modulation "means to adjust, change, diversify. As used herein, modulation of calcium ion channels includes antagonism, stimulation, or local antagonism. That is, the compounds in this patent may be useful as antagonists, stimulators or local antagonists of calcium ion channels.

“Total aromatic ring system"means an unsaturated (poly) ring system containing conjugated pi electrons. It is specifically contemplated that the aromatic parent ring system comprises a fused ring system. Fused ring systems refer to one or more aromatic rings or one or more saturated or unsaturated rings. For example, fluorene, indane, indene, perylene, and the like. Representative total aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthene (perylene), acephenanthrylene, anthracene, azulene, benzene, chrysidine, coronene, fluoranthene, fluorene, hexacene, hexaphene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, octaphene, ovalene, 2, 4-pentadiene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.

“Total heteroaromatic ring system"refers to the replacement of one or more carbons (and their hydrogens) of a general aromatic ring system with the same or different heteroatoms. Heteroatoms which are frequently present are, but are not limited to, N, P, O, S, Si, and the like. It is specifically noted that the total heteroaromatic ring system includes fused ring systems. Fused ring systems refer to one or more aromatic rings or one or more saturated or unsaturated rings. For example, benzodioxan, benzofuran, chroman, benzopyran, indole, dihydrocarbazole, xanthene, and the like. Representative total heteroaromatic ring systems are, but not limited to, arsenoindole, carbazole, -carboline, chroman, benzopyran, cinnoline, furan, imidazole, indazole, indole, dihydrocarbazole, indolizine, isobenzofuran, isobenzopyran, isoindole, isovaniline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyridine, quinazoline, quinoline, quinolizidine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene and similar compounds.

“Patient's health'OR (treatment)'Target"includes, but is not limited to, animals, such as mammals, and more preferably humans.

“Prevention of"in verbs and nouns both refer to a reduced risk of acquiring a disease or disorder (i.e., at least causing one of the clinical symptoms of such a disease to not continue to worsen, even though the patient may have been exposed to or predisposed to the disease, but has not experienced or exhibited symptoms of the disease).

“Protecting group"means that an inert molecular group is attached to a reactive functional group to reduce or prevent further reaction of the reactive functional group. Examples of protecting groups can be found in the following documents: green et al, "protecting groups in organic chemistry" (Willi, second edition 1991) and Harrison et al. "organic Synthesis method compilation", first volume 1-8 (John. Willi father and son publishing)1971 to 1996). Representative amino protecting groups include, but are not limited to, acyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), Trimethylsilyl (TMS), 2-triethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl, allyloxycarbonyl, 9-Fluorenylmethoxycarbonyl (FMOC), nitro 3, 4-dimethoxybenzyloxycarbonyl (NVOC), and the like. Representative hydroxy protecting groups include, but are not limited to, groups that acylate or alkylate a hydroxy group. For example anisole and trityl ethers, as well as alkyl ethers, tetrahydropyran ethers, trialkylsilyl ethers and allyl ethers.

“Salt (salt)"refers to a salt of a compound and has the same desired pharmacological activity as the compound itself. Such salts are: (1) adding acid salt, which is formed by adding inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with the addition of an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-isethionic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, dinaphthalenesulfonic acid, 4-p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2 ] sulfonic acid]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, hexadiene diacid, and the like; or (2) salts of compounds in which the acidic proton is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or salts formed by the action of organic bases, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like.

“Solvates"refers to a solvated compound (solvent molecule or composition of solute molecules or ions, where solute molecules refer to compounds of the invention) or a combination comprising one solute ion or molecule (compound of the invention) and more than one solvent molecule.

“Is pharmaceutically acceptableBy "is meant suitable for direct application to human and animal tissues without undue toxicity, irritation, allergic response, and the like. Or, in the case of complete medical judgment within the intended range of application, is effective and has a reasonable long-term efficacy/risk ratio.

“Prodrug'or'Soft medicine"refers to a precursor of a pharmacologically active compound. The precursor itself may or may not have pharmacological activity. However, under active supervision, the precursor may be metabolically or otherwise converted into a pharmacologically active compound, composition or drug. For example, a prodrug or soft drug is an ester or ether of a drug. Many prodrugs have been discovered and synthesized by various pharmaceutical companies. For example, H. Bindgao and J. Moss, J.Med. 78:122-126 (1989). Thus, one of ordinary skill in the art would know how to prepare such precursors, prodrugs or soft drugs using conventional organic synthesis techniques.

“Substitution", when used to modify a specified group or radical, means that one or more of the specified groups or radicals are independently substituted with the same or different substituents. Substituents which can replace a saturated carbon atom in a given group or radical are, but not limited to, -R^aHalogen, -O^-,＝O,-OR^b,-SR^b,-S^-,＝S,-NR^cR^c,＝NR^b,＝N-OR^bTrihalomethyl, -CF₃,-CN,-OCN,-SCN,-NO,-NO₂,＝N₂,-N₃,-S(O)₂R^b,-S(O)₂NR^b,-S(O)₂O^-,-S(O)₂OR^b,-OS(O)₂R^b,-OS(O)₂O^-,-OS(O)₂OR^b,-P(O)(O^-)₂,-P(O)(OR^b)(O^-),-P(O)(OR^b)(OR^b),-C(O)R^b,-C(S)R^b,-C(NR^b)R^b,-C(O)O^-,-C(O)OR^b,-C(S)OR^b,-C(O)NR^cR^c,-C(NR^b)NR^cR^c,-OC(O)R^b,-OC(S)R^b,-OC(O)O^-,-OC(O)OR^b,-OC(S)OR^b,-NR^bC(O)R^b,-NR^bC(S)R^b,-NR^bC(O)O^-,-NR^bC(O)OR^b,-NR^bC(S)OR^b,-NR^bC(O)NR^cR^c,-NR^bC(NR^b)R^band-NR^bC(NR^b)NR^cR^cWherein R is^aIs selected from the following groups: alkyl, cycloalkyl, heteroalkyl, heteroalkanyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; each R^bIndependently selected from hydrogen atom or R^a(ii) a Each R^cIndependently selected from R^bOr alternatively, two R^cTogether with the nitrogen atom, form a 4,5, 6 or 7 membered heterocycloalkyl group. Heterocycloalkyl groups may include 1 to 4 heteroatoms, which may be the same or different: oxygen, nitrogen and sulfur. To give an example, -NR^cR^cThe method comprises the following steps: amino, aminoalkyl, N-pyrrolidinyl and N-morpholinyl.

Also, substituents that can replace an unsaturated carbon atom in a given group or radical are, but not limited to: -R^aHalogen, -O^-,-OR^b,-SR^b,-S^-,-NR^cR^cTrihalomethyl, -CF₃,-CN,-OCN,-SCN,-NO,-NO₂,-N₃,-S(O)₂R^b,-S(O)₂O^-,-S(O)₂OR^b,-OS(O)₂R^b,-OS(O)₂O^-,-OS(O)₂OR^b,-P(O)(O^-)₂,-P(O)(OR^b)(O^-),-P(O)(OR^b)(OR^b),-C(O)R^b,-C(S)R^b,-C(NR^b)R^b,-C(O)O^-,-C(O)OR^b,-C(S)OR^b,-C(O)NR^cR^c,-C(NR^b)NR^cR^c,-OC(O)R^b,-OC(S)R^b,-OC(O)O^-,-OC(O)OR^b,-OC(S)OR^b,-NR^bC(O)R^b,-NR^bC(S)R^b,-NR^bC(O)O^-,-NR^bC(O)OR^b,-NR^bC(S)OR^b,-NR^bC(O)NR^cR^c,-NR^bC(NR^b)R^band-NR^bC(NR^b)NR^cR^cWherein R is^a,R^bAnd R^cAs previously defined.

Substituents that may be substituted for the nitrogen atom in the heteroalkyl and heteroalkanyl groups are, but not limited to: -R^a,-O^-,-OR^b,-SR^b,-S^-,-NR^cR^cTrihalomethyl, -CF₃,-CN,-NO,-NO₂,-S(O)₂R^b,-S(O)₂O^-,-S(O)₂OR^b,-OS(O)₂R^b,-OS(O)₂O^-,-OS(O)₂OR^b,-P(O)(O^-)₂,-P(O)(OR^b)(O^-),-P(O)(OR^b)(OR^b),-C(O)R^b,-C(S)R^b,-C(NR^b)R^b,-C(O)OR^b,-C(S)OR^b,-C(O)NR^cR^c,-C(NR^b)NR^cR^c,-OC(O)R^b,-OC(S)R^b,-OC(O)OR^b,-OC(S)OR^b,-NR^bC(O)R^b,-NR^bC(S)R^b,-NR^bC(O)OR^b,-NR^bC(S)OR^b,-NR^bC(O)NR^cR^c,-NR^bC(NR^b)R^band-NR^bC(NR^b)NR^cR^cWherein R is^a,R^bAnd R^cAs previously defined.

Substituents which may be substituted for other atoms are common knowledge in the art and are not specifically described.

The substituent may contain a substituent.

Of diseases or disorders "Treatment of'or'Treatment of", in some embodiments, refers to the reduction or prevention of a disease or disorder (i.e., the inhibition or reduction of the development of a disease or at least one of its clinical symptoms). In other embodiments, the treatment or therapyMeans that the improvement in at least one physical indicator may not be apparent in the patient. In still other embodiments, treatment or therapy refers to the inhibition of a disease or disorder, either physically (e.g., stabilization of an apparent symptom) or physiologically (e.g., stabilization of a physical parameter), or both. Also in some embodiments, treating or treating refers to delaying the onset of a disease or disorder.

“Therapeutically effective doseBy "is meant that the amount of drug administered is sufficient to effect treatment of such diseases in a regulatory treatment. The therapeutically effective dose is determined by the following factors: drugs, diseases, severity of drugs and age, weight, etc. of the patient.

“Carrier"refers to a diluent, excipient, or vehicle for administration.

Some reference examples and documents are selectively shown and pointed out in detail in the present invention in some embodiments. While the invention will be described with respect to certain specific examples and embodiments in a selective manner, it will be understood that the selective manner is not intended to limit the invention to these embodiments. On the contrary, the invention is intended to cover alternatives, modifications and equivalents, which may be included within the spirit and scope of the invention as defined and claimed.

Term "ReceptorsBy "is meant that a molecule or complex of molecules (typically, but not necessarily, a protein) can bind to a particular ligand or ligands. The receptor can be said to be a receptor for such a ligand. In many cases, binding of the ligand receptor induces one or more biological responses. A "modulator" of a polypeptide is either an inhibitor or an enhancer of the function or action of the polypeptide. Similarly, a "modulator" of a signaling pathway is an inhibitor or enhancer of at least one function of a signaling pathway. Aspects of the polypeptide modulator are defined below; these definitions also apply to the regulator of the signal path, as is well within the skill of the art.

A "Non-selectionSexual ofA "polypeptide modulator" is a modulator. At one concentration, the modulator modulates a particular polypeptide as well as other family polypeptide members.

At one concentration,'Selectivity is"the polypeptide modulator modulates a particular polypeptide significantly without significant modulation by other polypeptide members of the same family.

When the modulator interacts directly with the polypeptide to effect modulation, the modulator is said to be "Acting directly on"polypeptide".

When the modulator acts to modulate a polypeptide as a result of direct interaction with other molecules, the modulator is said to act "indirectly on" the polypeptide.

Of a polypeptide "Inhibitors'or'Antagonists"is an agent that reduces the activity or function of a polypeptide by any mechanism (relative to a lesser amount of agent not observed or present). One polypeptide inhibitor may affect: (1) expression of a polypeptide, stability of an mRNA, protein trafficking, modification (e.g., phosphorylation), or degradation of a polypeptide, or (2) one or more normal operations or functions of a polypeptide. An inhibitor of a polypeptide may be non-selective or selective. The first inhibitors (antagonists) are generally small molecules that selectively act directly on the target polypeptide.

“ReversibleAn "inhibitor is one whose effect is reversible (i.e., does not irreversibly inactivate a target polypeptide).

“Competitiveness of"a polypeptide inhibitor competes with a component required for the function of another polypeptide when bound to the polypeptide. For example, TrkA function requires ATP and substrate binding. Accordingly, a competitive inhibitor of TrkA may, for example, bind TrkA at the ATP or substrate binding site. This is usually a reversible inhibition, which can be modulated by increasing the concentration of ATP or substrate in the reaction mixture. Such inhibitors are said to compete with ATP or substrates, respectively, to inhibit TrkA.

A "Non-competitive"typically binds at a different binding site than is required for the function of the polypeptide. This inhibition cannot be reversed by increasing the concentration of the components required for polypeptide function.

Polypeptides as referred to herein "Allosteric modulators", typically an enzyme or a receptor, is a modulator. This modulator binds at an inactive site of the polypeptide to induce shape allosteric changes in the polypeptide of interest.

The terms mentioned herein "Polypeptides"and"Protein"is a polymer of amino acids, unless otherwise limited, and includes atypical amino acids that function in a similar manner to natural amino acids.

Term of what is called "Specific binding"refers to preferential binding between binding partners at a particular site (e.g., between two polypeptides, a polypeptide and a nucleic acid molecule, or between two nucleic acid molecules). The term "specifically binds" means that the binding (e.g., affinity) to a preferred target molecule/sequence is at least 2-fold, preferably at least 5-fold more, and most preferably at least 10-20-fold more for non-specific target molecules (e.g., a randomly generated molecule without characteristic sites).

Phrase "An effective amount"and"In a sufficient amount"refers to an amount of a biologically active agent that produces a desired biological activity.

The term "co-administration" or "co-administration" when used in reference to the administration of a Trk (i.e., TrkA) antagonist and an additional agent means that the antagonist and the additional agent are administered such that they are at least partially physiologically active for an overlapping period of time. Thus, the TrkA antagonist may be administered simultaneously and/or sequentially with another agent. In sequential administration, some substantial delay (e.g., minutes or even hours or days) may occur even before the second dose is administered. The first dose will still be physiologically active as long as the second dose is administered or is active in the patient.

The term "as used herein"Reducing painBy "is meant reducing the patientThe perceived level of pain (relative to the non-intervention case). If the patient is a person, the level of pain perceived can be assessed by asking him or her to describe the pain or to compare with other pain experiences. In addition, the degree of pain can be obtained by measuring the physical response of the subject to pain, such as stress release-related factors or the activity of pain-transducing nerves in the peripheral or central nervous system. The degree of pain can also be measured by the dosage of the analgesic. The dosage of the analgesic is determined by the patient feeding back that the pain has disappeared or that the symptoms of the pain have disappeared. Another measure to reduce pain is an increase in the threshold for an observed subject experiencing a painful stimulus. In some embodiments, this can be achieved by reducing "Allergy (S)", a high alertness to a noxious stimulus to reduce pain. The inhibiting effect can be achieved without detriment "Injury due to wound Feeling of harm", pair"Is harmful to"normal sensitivity to stimuli, is achieved.

In the reference to reduce pain "Object of need"refers to an animal or human, preferably a human, who is expected to experience pain in the near future. Such animals or humans may have a persistent condition causing current pain and may continue to cause pain. Alternatively, the animal or human has, is experiencing, or is about to experience, a process or event that is usually painful. Chronic pain such as diabetic nervousness and collagen vascular disease belong to the first group of examples; dental work, especially accompanied by inflammation or nerve damage, and toxin exposure (including exposure to chemotherapeutic drugs) belong to the latter category.

“Inflammatory pain"refers to pain caused by inflammation. Inflammatory pain often manifests itself as an increasing sensitivity to mechanical stimuli (mechanical pain or tenderness). For example, inflammatory pain is caused by the following conditions: burns, sunburn, arthritis, colitis, myocarditis, dermatitis, myositis, neuritis, mucositis, urethritis, cystitis, gastritis, pneumonia, and collagen vascular disease.

“Neuropathic pain"refers to pain caused by a condition or event that results in nerve damage. "neurological (neurologic) disease" refers to a diseaseNerve damage is caused in the course of disease. "causalgia" represents a chronic pain state after nerve injury. "allodynia" refers to a condition where an individual feels pain to a normal painless stimulus, such as a gentle touch. For example, neuropathic pain is caused by the following conditions: causalgia, diabetes mellitus, collagen vascular disease, trigeminal neuralgia, spinal cord injury, brainstem injury, thalamic pain syndrome, complex regional pain syndrome type I/reflex sympathetic dystrophy selected condition, fabry's syndrome, small fibroid disease, cancer chemotherapy, chronic alcoholism, stroke, abscess, demyelinating disease, viral infection, antiviral therapy, aids, and aids therapy. Neuropathic pain can also come from: trauma, surgery, amputation, toxins, and chemotherapy.

The term "as used herein"Generalized pain disorder"is an idiopathic pain syndrome group (e.g., fibromyalgia, irritable bowel syndrome, and temporomandibular joint disorder). To this end, presently unknown, discrete or generalized pain in the pathogenesis, and the diagnosis of one of the pairs that characterize inflammation or lesions as a direct cause of pain, are excluded.

A "Analgesic agent"refers to a molecule or combination of molecules that reduces pain.

“Acute disease"and"Chronic disease"the difference between the pains is the time difference: acute pain is felt soon after the event that causes the pain (e.g., inflammation or nerve injury) occurs (e.g., usually within about 48 hours, more typically within 24 hours, most typically within 12 hours). In contrast, chronic pain is not felt until a considerable time has elapsed after the event that caused the pain. This delay in time is at least about 48 hours, more typically at least about 96 hours later, and most typically at least about one week later.

Phrase "Drug related Effect"means to address the in vivo effects after administration. Typical effects include the effects of stimulants, sedation, hypnosis and ataxia. "Sedative Effect"refers to the target subject activity andand/or reduced excitation. "hypnotic effects" include increased drowsiness and/or convenient onset and/or maintenance of sleep. "Ataxia effect"refers to a decrease in motor coordination.

Term "Use of undesirable substancesBy "is meant that the use of any substance adversely affects the user beyond any benefit that may be generated by that substance. Substances used in an undesirable manner are generally administered to the body by any route of administration (usually self-administration) or are consumed to produce a pleasant human effect on the user. The substance may be a single substance (e.g., cocaine) or a substance (e.g., a common food). Adverse consequences may include, for example, adverse effects on health, ability to care for oneself, making and maintaining person-to-person relationships, and/or work ability. The adverse effect of the drug is obvious to the control of the general users, and the drug is reduced or ended; alternatively, the user's family members and/or friends may wish to see user control, reduce or end use. Adverse substance use may include uncontrolled cravings for medications; drug dependence, including psychological and/or physical dependence; and adverse drug use; as well as any symptoms and/or abuse of the substance dependence and individual described below.

“Substance abuse"including the inappropriate use of a substance results in clinically significant damage or distress. As shown in one (or more) of the following, over a 12 month period: periodic substance use thus fails to fulfill major obligations in work, school or home (e.g., constant absenteeism or poor performance in connection with medication use; medication-related absence, downtime, or removal by school; neglect for children or home); (ii) periodic use of substances that are harmful to the body (e.g., driving a car or operating machinery in the presence of a substance damage); (iii) periodic use of contraband (e.g., apprehended due to undetected act on medication); and (iv) continuing to use the substance (e.g., as a result of quarreling to a spouse, or even fighting) regardless of persistent or recurrent social or human relationship problems caused or exacerbated by the substance. (see American psychiatric Association, DSM-IV diagnostic standards, Washington D.C., 1994.)

“Drug abuse"includes excessive consumption or administration of any substance. Substance dependence or abuse may be diagnosed according to the above definitions or the standards promulgated by the american psychiatric association or equivalents. Drugs of abuse include, but are not limited to: opiates, psychostimulants, marijuana, neuroleptic, a free drug, and alcohol. Thus, for example, heroin, cocaine, methamphetamine, cannabis, 3-4 methylenedioxymethamphetamine (ecstasy), barbital, phencyclidine (PCP), ketamine, and ethanol are all drugs of abuse.

“Tranquilizer"refers to a class of sedative drugs. It is capable of modulating the demand for neurotransmitter activity in the central nervous system and may also treat mental states by modulating acetylcholine, dopamine, norepinephrine, serotonin, or gamma aminobutyric acid (GABA) transport.

Term "NeurosteroidsExamples of neurosteroids include 3 α,5 α -tetrahydroprogesterone, 3 α,5 β -tetrahydroprogesterone and 3 α,5 α -tetrahydrodeoxycorticosterone.

A "Benzodiazepines"is selected from: alprazolam, chlordiazepoxide, clomeprobamate, clonazepam, dipotassium chlordiazepoxide, diazepam, fluoropiperidine, sulazepam, fentanyl citrate, flurazepam hydrochloride, halazepam, lorazepam, midazolam hydrochloride, a group of agents, noroxazepam, pramipepam, quazepam, temazepam and triazolam were selected.

“Barbital"is selected from: amobarbital, sodium amobarbital, alprenbital, sodium butabarbital, sodium cyclohexarbital, mefenobarbital, methabarbital, sodium methohexital, pentobarbital, sodium pentobarbital, phenobarbital, sodium phenobarbital, tolperistat, secobarbital, sodium talbarbital,sodium thiopentobarbital, and thiopental sodium.

The term "as used herein"Combination of"is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which directly or indirectly combines the specified ingredients in the specified amounts. Pharmaceutical combinations are a set of products covered by the following: active and inert ingredients (carriers in combination), as well as any product which results, directly or indirectly, from combination, complexation or polymerization of any two or more of the ingredients, or decomposition of one or more of the ingredients, or reaction or interaction of one or more of the ingredients. Thus, the pharmaceutical combinations of the present invention include any mixture comprising one of the compounds of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient must be compatible with the other ingredients and not deleterious to the recipient thereof.

Term "Cancer treatment"refers to or describes a physiological condition in a mammal that does not govern cell growth. Examples of cancer include, for example, leukemia, lymphoma, blastoma, carcinoma, and sarcoma. More specific examples of such cancers include: chronic myelogenous leukemia, acute lymphocytic leukemia, philadelphia chromosome positive acute lymphocytic leukemia (ph + ALL), squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, kidney cancer, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, cervical cancer, gastric cancer, bladder cancer, liver cancer, breast cancer, colon cancer, head and neck cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinus natural killer, multiple myeloma, Acute Myelogenous Leukemia (AML) and chronic lymphocytic leukemia (CML).

It is to be understood that this invention is not limited to particular methods, reagents, compounds, compositions, or biological systems. They may all vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. As an additional requirement of using this specification, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes two or more compounds or molecules, and the like.

The invention relates to compounds and uses thereof

In one aspect, the present invention provides a compound having the structural formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof:

wherein n is equal to 1,2, or 3; m is equal to 0,1, or 2;

a is C, N, O, S, NR¹,C＝CR¹(E and Z isomers), C ═ NR¹(E and Z isomers), C (R)¹R²),CR¹＝CR²-CR¹’R²' (E and Z isomers), or CR¹＝CR²-NR¹' (E and Z isomers);

b is C, N, O, S, NR³Or C (R)³R⁴)；

J, K, L, and M are each independently N or CR⁵；

Y is O,S,NR⁶Or C (R)⁶R⁷)；

R¹,R²,R¹’,R²’,R³,R⁴,R⁵,R⁶And R⁷Each independently is a hydrogen atom, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, -CONR⁸R⁹Alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl;

R⁸and R⁹Each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl; or when R is⁸And R⁹Are not both hydrogen, R⁸And R⁹Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.

In one embodiment of formula (I), wherein m is 0, n is 1, and a is a₁-X₁。

In one embodiment of structural formula (I), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (II):

wherein A is₁-X₁Is NR¹,C＝CR¹(E and Z isomers), C ═ NR¹(E and Z isomers), or C (R)¹R²)。

In one embodiment, examples of compounds according to formula (II) are:

TABLE 1.1

The names of the compounds in table 1.1 are as follows:

in one embodiment of formula (I), wherein m ═ 1, n ═ 1, and a ═ a₂-X₂。

In one embodiment of structural formula (I), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (III):

wherein A is₂-X₂Is NR¹,C＝CR¹(E and Z isomers), C ═ NR¹(E and Z isomers), or C (R)¹R²)。

In one embodiment, examples of compounds according to structural formula (III) are:

TABLE 12

The names of the compounds in table 1.2 are as follows:

in one embodiment of formula (I), wherein m ═ 1, n ═ 2, and a ═ a₄-A₄’。

In one embodiment of structural formula (I), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (IV):

wherein A is₄And A₄' independently of one another are NR¹,C＝CR¹(E and Z isomers), C ═ NR¹(E and Z isomers)) Or C (R)¹R²) (ii) a And A₄And A₄The bond between' may be a single bond or a double bond.

In one embodiment of structural formula (IV), wherein A₄' is C ═ CX₄And A₄And A₄' between them is a single bond.

In one embodiment of structural formula (IV), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (IVd):

wherein A is₄And X₄Each independently is NR¹¹Or C (R)¹¹R¹²)；

C＝X₄May be an E or Z isomer; and

R¹¹and R¹²Each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, and substituted heteroalkyl.

In one embodiment, examples of compounds according to structural formula (IVd) are:

TABLE 1.3

The chemical names of the compounds in table 1.3 are as follows:

in one embodiment of structural formula (IV), A₄-A₄` Intermedially is a double bond and A₄Is' is CR⁴¹。

In one embodiment of structural formula (IV), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (IVa):

wherein R is⁴¹Is a hydrogen atom, a halogen, an acyl group, a substituted acyl group, an alkoxycarbonyl group, a substituted alkoxycarbonyl group, an aryloxycarbonyl group, a substituted aryloxycarbonyl group, a-C (O) NR⁴²R⁴³，-NR⁴²R⁴³Alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl.

R⁴²And R⁴³Each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl; or R⁴²And R⁴³Together with the nitrogen atom to which they are attached, form a 4,5, 6, or 7 membered heteroalkyl ring.

In one embodiment, examples of compounds according to structural formula (IVa) are:

TABLE 1.4

The chemical names of the compounds listed in table 1.4 are as follows:

in a particular embodiment of formula (IV), A₄And A₄Together with the other atoms, form a 5, 6 or 7 membered ring.

In one embodiment of structural formula (IV), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (IVb):

wherein the R ring is an aromatic ring, a substituted aromatic ring, a single-bond carbocyclic ring, a substituted carbocyclic ring, a heteroalkyl ring, a substituted heteroalkyl ring, a heteroaromatic ring, or a substituted heteroaromatic ring.

In one embodiment of formula (IVb), the R ring is a 5-membered ring.

In one embodiment of structural formula (IVb), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (ivb.0):

wherein A is₄-Q₁,Q₁-Q₂,Q₂-X₃,A₄’-X₃,A₄-A₄' each option is a single or double bond;

Q₁,Q₂and X₃Are each selected from S, O, N, N (R)¹⁵),C(R¹⁵) Or C (R)¹⁵R¹⁶)；

A₄And A₄' selected from N, C, or CR¹⁷(ii) a And

R¹⁵，R¹⁶and R¹⁷Each independently selected from the group consisting of hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl.

In one embodiment, examples of compounds according to structural formula (ivb.0) are:

watch 15

The chemical names of the compounds listed in table 1.5 are as follows:

in a particular embodiment of formula (IVb.0), A₄-Q₁And Q₂-X₃Are both double bonds, and Q₁-Q₂,A₄’-X₃And A and₄-A₄' are all single bonds.

In one embodiment of structural formula (ivb.0), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (ivb.1):

wherein A is₄Is C; a. the₄Is N or CR¹⁸；

Q₁,Q₂And X₃Each being selected from N or CR¹⁹；

R¹⁸And R¹⁹Each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, and substituted heteroalkyl.

In one embodiment, examples of compounds according to structural formula (IVb.1) are:

TABLE 1.6

The chemical names of the compounds listed in table 1.6 are as follows:

in one embodiment of formula (IVb), the R ring is a 6-membered ring.

In one embodiment of structural formula (IVb), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (ivb.2):

wherein A is₄-U₁,U₁-U₂,U₂-U₃,U₃-X₃,A₄’-X₃And A and₄-A₄' each option is a single or double bond;

U₁,U₂,U₃and X₃Are each selected from S, O, N, N (R)²⁰),C(R²⁰) Or C (R)²⁰R²¹)；

A₄And A₄' selected from N, C, or CR²²(ii) a And

R²⁰，R²¹and R²²Each independently selected from the group consisting of hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroAralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl.

In one embodiment, examples of compounds according to structural formula (IVb.2) are:

TABLE 1.7

The chemical names of the compounds listed in table 1.7 are as follows:

in a particular embodiment of formula (IVb.2), U₁,U₂,U₃,X₃,A₄', and A₄Forming a 6-membered heteroalkyl ring.

In a particular embodiment of formula (IVb.2), A₄Is N and B is NR⁵。

In one embodiment of structural formula (ivb.2), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (ivb.21):

in one embodiment, examples of compounds according to structural formula (ivb.21) are:

watch 18

The chemical names of the compounds listed in table 1.8 are as follows:

in a particular embodiment of formula (IVb.2), U₁，U₂，U₃，X₃，A₄' and A₄Forming an aromatic ring.

In one embodiment of structural formula (ivb.2), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (ivb.22):

in one embodiment, examples of compounds according to structural formula (IVb.22) are:

TABLE 1.9

The chemical names of the compounds listed in table 1.9 are as follows:

in one embodiment of formula (I), m is 1, n is 3, and a is "Z₃,A₄-X₄,A₅-X₅", B is Z₄。

In one embodiment of structural formula (I), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (V):

wherein A is₄-X₄,A₅-X₅Each is selected from NR¹，C＝CR¹(E and Z isomers), C ═ NR¹C ═ O or C (R)¹R²)；

Z₃And Z₄Are each selected from O, S, NR³Or C (R)³R⁴)。

In one embodiment, examples of compounds according to structural formula (V) are:

TABLE 2.0

The chemical names of the compounds listed in table 2.0 are as follows:

in one embodiment of formula (V), Z₃-A₄Is a double bond, A₄-X₄Is CR¹，A₅-X₅Is C (R)¹R²),NR¹,C＝CR¹(E and Z isomers), or C ═ NR¹(E and Z isomers).

In one embodiment of structural formula (V), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (Va):

wherein Z₃And Z₄Are each selected from O, S, NR³Or C (R)³R⁴)。

In one embodiment of formula (V), A₄-A₅Is a double bond, A₄(X₄) Is CR¹，A₅(X₅) Is CR²。

In one embodiment of structural formula (V), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (Vb):

in one embodiment, examples of compounds according to structural formulae (Va) and (Vb) are:

TABLE 2.1

The chemical names of the compounds listed in table 2.1 are as follows:

in one embodiment of formula (V), Z₃Is NR³Or C (R)³R⁴)。

In one embodiment of formula (V), R³Is a with A₄-X₄Together form a 5-membered ring.

In one embodiment of structural formula (V), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (Vc):

wherein Z₃-Q₃,Q₃-Q₄,Q₄-X₄,A₄-X₄And Z is₃-A₄Each independently is a double or single bond;

Q₃,Q₄and X₄Each being S, O, N, N (R)¹⁶),C(R¹⁶),C(R¹⁶R¹⁷)；

Z₃And A₄Each being selected from N, C or CR¹⁸；

R¹⁶，R¹⁷And R¹⁸Each independently selected from the group consisting of hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl.

In one embodiment, examples of compounds according to structural formula (Vc) are:

TABLE 2.2

The chemical names of the compounds listed in table 2.2 are as follows:

in one embodiment of formula (Vc), Z₃-Q₃And Q₄-X₄Are both double bonds.

In one embodiment of formula (Vc), Z₃-A₄,Q₃-Q₄And A and₄-X₄are all single bonds.

In one embodiment of structural formula (Vc), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has a structural formula (vc.1):

wherein Z₃Is C;

A₄is N or CR¹⁸(ii) a And

X₄,Q₃and Q₄Each being selected from N or CR¹⁶。

In one embodiment, examples of compounds according to formula (vc.1) are:

TABLE 2.3

The chemical names of the compounds listed in table 2.3 are as follows:

at the knotIn one embodiment of formula (V), R³And A₄-X₄Together forming a six-membered ring.

In one embodiment of structural formula (V), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (Vd):

wherein Z₃-U₄U₄-U₅,U₅-U₆,U₆-X₄,A₄-X₄And Z is₃-A₄Each is selected to be a double bond or a single bond;

U₄,U₅,U₆and X₄Is S, O, N, N (R)¹⁹),C(R¹⁹),C(R¹⁹R²⁰)；

Z₃And A₄Each being selected from N, C or CR²¹；

R¹⁹，R²⁰And R²¹Each independently selected from the group consisting of hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl.

In one embodiment, examples of compounds corresponding to structural formula (Vd) are:

TABLE 2.4

The chemical names of the compounds listed in table 2.4 are as follows:

in one embodiment of formula (Vd), Z₃-U₄U₄-U₅,U₅-U₆,U₆-X₄,A₄-X₄And Z is₃-A₄Together forming an aromatic ring.

In one embodiment of structural formula (Vd), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has a structural formula (vd.1):

wherein Z₃And A₄Is C; u shape₄,U₅,U₆And X₄Each being selected from N or CR¹⁹。

In one embodiment, examples of compounds according to structural formula (vd.1) are:

TABLE 2.5

The chemical names of the compounds listed in table 2.5 are as follows:

in one embodiment of formula (V), A₅-X₅And A₄-X₄Together forming a six-membered ring.

In one embodiment of structural formula (V), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (Ve):

wherein A is₄-X₄,X₄-Q₆,Q₆-X₅,A₅-X₅,A₄-A₅Each independently is a double or single bond;

X₄,X₅and Q₆Each independently being S, O, N, N (R)²²),C(R²²) Or C (R)²²R²³)；

A₄And A₅Each independently is N, C or CR²⁴；

R²²，R²³And R²⁴Each independently selected from the group consisting of hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl.

In one embodiment, examples of compounds according to structural formula (Ve) are:

TABLE 2.6

The chemical names of the compounds listed in table 2.6 are as follows:

in one embodiment of formula (Ve), Q₆-X₅And A₄-X₄Are both double bonds.

In one embodiment of formula (Ve), A₄-A₅，X₄-Q₆And A₅-X₅Are all single bonds.

In one embodiment of structural formula (Ve), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has a structure of structural formula (ve.1):

wherein A is₄And A₅Are all C;

X₅is S, O, N, NR²⁴Or CR²⁴(ii) a And

X₄and Q₆Each being selected from N or CR²⁰。

In one embodiment, examples of compounds according to structural formula (ve.1) are:

TABLE 2.7

The chemical names of the compounds listed in table 2.7 are as follows:

in one embodiment of formula (V), A₄-X₄And A₅-X₅Together forming a six-membered ring.

In one embodiment of structural formula (V), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (Vf):

wherein A is₄-X₄,X₄-Q₆,Q₆-X₅,A₅-X₅,A₄-A₅Each independently is a double or single bond;

X₄,X₅,U₇and U is₈Each independently being S, O, N, N (R)²⁵),C(R²⁵) Or C (R)²⁵R²⁶)；

A₄And A₅Each being selected from N, C or CR²⁷；

R²⁵，R²⁶And R²⁷Each independently selected from the group consisting of hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl.

In one embodiment, examples of compounds corresponding to structural formula (Vf) are:

TABLE 2.8

The chemical names of the compounds listed in table 2.8 are as follows:

in one embodiment of structural formula (Vf), A₅-X₅And A₄-X₄Together forming an aromatic ring.

In one embodiment of structural formula (Vf), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has a structure of structural formula (vf.1):

wherein A is₄And A₅Are all C; and X₄,X₅,U₇And U is₈Each independently is N or CR²⁵。

In one embodiment, examples of compounds according to structural formula (vf.1) are:

TABLE 2.9

The chemical names of the compounds listed in table 2.9 are as follows:

in one embodiment of formula (I), n ═ 3, m ═ 0, and a are“A₆₁-A₆₂-A₆₃”。

In one embodiment of structural formula (I), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (VI):

wherein A is₆₁,A₆₂And A₆₃Each independently is C, N, O, S, NR¹,C＝CR¹(E and Z isomers), C ═ NR¹(E and Z isomers), or C (R)¹R²)；

A₆₁-A₆₂And A₆₂-A₆₃Each independently is a single or double bond.

In one embodiment of formula (VI), A₆₁And A₆₂Are all C and form a five-membered ring with the other three atoms.

In one embodiment of structural formula (VI), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has structural formula (VIa):

wherein A is₆₄Is O or S; a. the₆₅Is N or CR²⁵；

R⁶⁶Is hydrogen, alkyl, or substituted alkyl.

In a particular embodiment of formula (VIa), A₆₃Is C, A₆₃And R⁶⁶Together with the other four atoms to form a substituted six-membered aromatic ring.

In one embodiment of structural formula (VIa), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has the structural formula (via.1):

wherein R is⁶⁷，R⁶⁸And R⁶⁹Each independently selected from hydrogen atom, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, -CONR⁷⁰R⁷¹，-NR⁷⁰R⁷¹Alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl;

R⁷⁰and R⁷¹Each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl; or alternatively, R⁷⁰And R⁷¹Together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heteroalkyl ring.

In one embodiment of formula (VIa.1), J, K, L and M are all CR⁵，R⁶⁸Is H, R⁶⁷Is a substituted six-membered heteroalkyl ring, and R⁶⁹is-NHR⁷⁰。

In one embodiment of structural formula (via.1), the compound, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, has a structural formula (via.11):

wherein nn is an integer from 0 to 4; a. the₆₆Is NR⁷³Or CR⁷³R⁷⁴；

R⁷²，R⁷³And R⁷⁴Each independently selected from hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, -CONR⁷⁵R⁷⁶，S(O)₂NR⁷⁵R⁷⁶Alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl;

R⁷⁵and R⁷⁶Each independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl; or alternatively, R⁷⁵And R⁷⁶Together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heteroalkyl ring.

In one embodiment, examples of compounds according to structural formula (via.11) are:

TABLE 3.0

The chemical names of the compounds listed in table 3.0 are as follows:

description of the Synthesis

Several synthetic methods for the compounds of the present invention are illustrated in the following schemes and examples. Starting materials are known to organic chemists or as specified. Abbreviations used herein are as follows: me: a methyl group; et: an ethyl group; t-Bu: a tertiary butyl group; ar: aromatic hydrocarbon; ph: benzene; bn: benzyl, BuLi, butyl lithium; piv is pive; ac is acetyl; THF, tetrahydrofuran; DMSO is dimethyl sulfoxide; CCl₄Carbon tetrachloride; EDC N- (3-dimethylaminopropyl) N' -ethylcarbodiimide; boc is tert-butyloxycarbonyl; et (Et)₃N is triethylamine; DCM is dichloromethane; DCE is dichloroethane; DME (dimethoxyethane); DBA is diethylamine; DAST, diethylaminosulfur trifluoride; EtMgBr is ethyl manganese bromide; BSA is bovine serum albumin; TFA is trifluoroacetic acid; DMF is N, N-dimethylformamide; SOCl₂Thionyl chloride; CDI carbonyl diimidazole; rt is room temperature; HPLC, high performance liquid chromatography; TLC, thin layer chromatography. The compounds of the present invention can be prepared by a variety of methods.

The synthetic steps described below for the compounds of the invention may include one or more protection and deprotection steps (e.g., formation and elimination of acetal groups). In addition, the synthetic procedures described below include various purifications such as column chromatography, flash chromatography, thin layer chromatography, recrystallization, distillation, high performance liquid chromatography, etc.; also included are various known methods for identifying and quantifying the products of chemical reactions, such as proton and carbon-13 NMR: (¹H and¹³c NMR), infrared and ultraviolet spectra (IR and UV), X-ray crystallography, Elemental Analysis (EA) high performance liquid chromatography and Mass Spectrometry (MS). Methods of protection and deprotection, purification and identification, and quantification are well known in the art of chemical synthesis.

Scheme 1. example of synthesis of compound according to structural formula IVd (compound 481):

4- (2-fluorobenzyl) -2H-benzo [ b ] [1,4] thiazin-3 (4H) -one (2):

a mixture of 0.75g of t-BuOK to 1.0 g (6.1 mmol) of 4- (2-fluorobenzyl) -2H-benzo [ b ] [1,4] thiazin-3 (4H) -one and 0.76 ml (1.05 eq) of 1- (bromomethyl) -2-fluorobenzene in DMF (10 ml) was added at 0 ℃. The reaction mixture was warmed to room temperature and stirred overnight. Water was added and the desired solid filtered and rinsed with clear water. Drying in vacuo afforded 4- (2-fluorobenzyl) -2H-benzo [ b ] [1,4] thiazin-3 (4H) -one (1.51 g, 91%).

4- { (Z) - [4- (2-fluorobenzyl) -3, 4-dihydro-3-carbonylbenzo [ b ] [1,4] thiazin-2-ylidene ] methyl } benzoic acid (3):

4- (2-Fluorobenzyl) -2H-benzo [ b ] [1,4] thiazin-3- (4H) -one (1 g, 3.66 mmol) and methyl 4-formylbenzoate (1.2 g) were dissolved in tetrahydrofuran (20 mL), followed by addition of NaOEt (1 g). The reaction solution was maintained at 70 ℃ overnight, and then quenched by addition of hydrochloric acid solution (5%, 10 ml). The resulting mixture was extracted twice with ethyl acetate (50 ml). The remaining organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under vacuum to give 4- ((Z) - (4- (2-fluorobenzyl) -3, 4-dihydro-3-carbonylbenzo [ b ] [1,4] thiazin-2-ylidene) methyl) benzoic acid (1.13 g, 71%).

4- { (Z) - [4- (2-fluorobenzyl) -3, 4-dihydro-3-carbonylbenzo [ b ] [1,4] thiazin-2-ylidene ] methyl } -N- [3- (pyrrolidin-1-yl) propyl ] benzamide (compound 481):

0.23 ml of (COCl)₂To 4- { (Z) - [4- (2-fluorobenzyl) -3, 4-dihydro-3-carbonylbenzo [ b ]][1,4]Thiazin-2-subunit]Methyl } benzoic acid (704 mg, 1.74 mmol) and dimethylformamide (2 drops) in dichloromethane (10 ml). Inverse directionThe reaction solution was stirred at room temperature for 1 hour and then the solvent was evaporated to give an acid chloride. This acid chloride was dissolved in dichloromethane (10 ml) and then added to a solution of 3- (pyrrolidin-1-yl) propan-1-amine (267 mg) and DIPEA (0.3 ml) in dichloromethane (10 ml). The mixture was stirred at room temperature for 6 hours. The solution was washed with saturated sodium bicarbonate (50 ml) and water (50 ml), and dried over anhydrous magnesium sulfate. The residue after filtration was purified by chromatography (5:1 dichloromethane: methanol) to give 4- { (Z) - [4- (2-fluorobenzyl) -3, 4-dihydro-3-carbonylbenzo [ b ]][1,4]Thiazin-2-subunit]Methyl } -N- [3- (pyrrolidin-1-yl) propyl]Benzamide (797 mg, 89%). Nuclear magnetic resonance (300 megahertz, CD)₃OD) data: 7.94(d,2H),7.89(s,1H),7.77(d,2H),7.36-7.25(m 2H),7.16(m,2H),7.12-7.02(m,4H),5.44(s,2H),3.52(t,2H),3.30(m,4H),3.14(t,2H),2.15-1.98(m, 6H). LCMS (ESI +) m/z: 516(M + H)

Scheme 2. example of synthesis of compound according to structural formula IVb (compound 201):

methyl 1- [4- (methoxycarbonyl) -2-nitrophenyl ] piperidine-2-carboxylate (4):

cesium carbonate (12.7 g) was added to a solution of methyl 4-fluoro-3-nitrobenzoate (6.46 g, 32.5 mmol) and methylpiperidine-2-carboxylate (5.57 g, 1.2 eq) in DMF (80 ml). The reaction mixture was stirred at 55 ℃ overnight. Filtering and evaporating the filtrate to obtain solid. Recrystallization from ethyl acetate/n-hexane gave methyl 1- [4- (methoxycarbonyl) -2-nitrophenyl ] piperidine-2-carboxylate (9.4 g, 90%).

Methyl 6,6a,7,8,9, 10-hexahydro-6-oxo-5H-pyrido [1,2-a ] quinoxaline-3-carboxylate (5):

methyl 1- [4- (methoxycarbonyl) -2-nitrophenyl ] piperidine-2-carboxylate (1.3 g, 4.0 mmol) was dissolved in ethyl acetate (20 ml) and 1N hydrochloric acid (20 ml) and zinc (0.80 g). The reaction mixture was refluxed overnight and then cooled to room temperature. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed to give methyl 6,6a,7,8,9, 10-hexahydro-6-oxo-5H-pyrido [1,2-a ] quinoxaline-3-carboxylate (0.92 g, 88%).

6,6a,7,8,9, 10-hexahydro-6-oxo-5H-pyrido [1,2-a ] quinoxaline-3-carboxylic acid (6):

methyl 6,6a,7,8,9, 10-hexahydro-6-oxo-5H-pyrido [1,2-a ] quinoxaline-3-carboxylate (0.762 g, 0.29 mmol) and LiOH (0.25 g) were mixed with methanol (5 ml), tetrahydrofuran (5 ml) and water (2 ml). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated to near dryness. The pH was adjusted to about 2 by the addition of 2N hydrochloric acid. Filtration and drying gave 6,6a,7,8,9, 10-hexahydro-6-oxo-5H-pyrido [1,2-a ] quinoxaline-3-carboxylic acid as a white solid (0.72 g, 100%).

2- {3- [4- (5-chloro-2-methylphenyl) piperazin-1-yl ] propyl } isoindoline-1, 3-dione (9):

a solution of 2- (3-bromopropyl) isoindoline-1, 3-dione (2.68 g, 10 mmol) and sodium iodide (20 mmol) in acetone was refluxed for 5 hours, and 1- (5-chloro-2-methylphenyl) piperazine (2.11 g, 10.0 mmol) was added. Reflux continued for an additional 12 hours and then cooled to room temperature. Filtration through celite, concentration and recrystallization of the crude product gave a white solid (title compound 9, 3.21 g, 81%).

3- [4- (5-chloro-2-methylphenyl) piperazin-1-yl ] propan-1-amine (10):

a solution of 2- (3- (4- (5-chloro-2-methylphenyl) piperazin-1-yl) propyl) isoindoline-1, 3-dione (397 mg, 1.0 mmol) and hydrazine monohydrate (52 mg, 1.04 mmol) in ethanol (5 ml) was heated to 70 ℃. After 12 hours cooling to room temperature, the solid was filtered and the filtrate evaporated to give the title compound. No purification is required.

(6aS/R) N- {3- [4- (5-chloro-2-methylphenyl) piperazin-1-yl ] propyl } -6-carbonyl-6, 6a,7,8,9, 10-hexahydro-5H-pyrido [1,2-a ] quinoxaline-3-carboxamide (Compound 201):

EDC (0.377 g, 2.0 mmol) was added to a solution of 6,6a,7,8,9, 10-hexahydro-6-oxo-5H-pyrido [1,2-a ] quinoxaline-3-carboxylic acid (200 mg, 0.80 mmol), 3- (4- (5-chloro-2-methylphenyl) piperazin-1-yl) propan-1-amine (1.0 mmol), DMAP (10 mg) and DIPEA (0.30 ml) in DMF (5 ml). The reaction was stirred at room temperature overnight. After removal of the solvent, ethyl acetate (60 ml) was added. The organic layer was washed with saturated sodium bicarbonate (10 ml) and water (10 ml), and then dried over anhydrous magnesium sulfate. After filtration and concentration, purification with a 0-10% methanol in dichloromethane and a chromatography column gave N- {3- [4- (5-chloro-2-methylphenyl) piperazin-1-yl ] propyl } -6-carbonyl-6, 6a,7,8,9, 10-hexahydro-5H-pyrido [1,2-a ] quinoxaline-3-carboxamide as a white solid (6.28 g, 78%). Nuclear magnetic resonance (300 mhz, dmso-D6), ppm: 10.48(s,1H),8.27(t,1H),7.41(dd,1H),7.29(d,1H),7.15(d,1H),6.97(d,1H),6.96(s,1H),6.83(d,1H),3.83(d,1H),3.57(dd,1H),3.26(q,2H),2.84(M,4H),2.73(dt,1H),2.40(t,2H),2.20(s,3H),2.00(M,1H),1.83(M,1H),1.69(M,3H),1.52-1.33(M,3H). Mass Spectrum (ESI +) M/z 496,498(M + H).

Scheme 3 Synthesis example of a Compound corresponding to Structure VI (Compound 703):

synthesis of compound 703: sodium nitrite (0.57 g, 8.3 mmol) was slowly added (over 20 minutes) to 5.2 ml of concentrated sulfuric acid (30-40 ℃). The mixture was stirred for 30 minutes. Then 2.9 g of compound 1 are added. After stirring for a further 4 hours (50-55 ℃ C.), the reaction mixture was poured onto ice (50 g). The yellow precipitate was filtered and washed with 50 ml of ice water and 150 ml of 1:1 ethanol/ether. The wet cake was added to 100 ml of an aqueous solution of sodium azide (0.78 g, 12 mmol) and stirred for 30 minutes. The product was filtered and washed with 100 ml of clean water and 50 ml of 9:1 acetone/water. The product mixture was heated to 70 ℃ in 30 ml of toluene for 8 hours. The suspension was then filtered, washed with 50 ml of methanol and dried to give a yellow solid. Nuclear magnetic resonance (400 megahertz, carbon tetrachloride and DMSO-d6), ppm: 10.31(br t,1H),8.45(d,1H),8.06(d,1H),7.63(m,1H),7.54(m,1H),7.46(s,1H),6.41(d,1H),6.36(d,1H),6.08(s,1H),4.75(d,2H),3.94(m,4H),2.59(m,4H),2.38(m,2H),1.60(m,2H),0.89(t, 3H).

Other compounds of the invention can be synthesized as well according to the above scheme. The spectral data for some of the synthesized compounds are listed as examples below:

compound 205:¹HNMR(400MHz,CCl₄and DMSO-d6),ppm:7.87(d,1H),7.69(s,1H),7.66(dd,1H),7.28(d,1H),7.20(m,3H),7.13-6.96(m,7H),4.50(s,2H)3.94(s,3H),3.18(q,2H),2.83(m,2H),2.49(t,2H),2.26(m,2H),1.80-1.11(m,9H).

compound 207:¹HNMR(400MHz,CCl₄and DMSO-d6),ppm:8.00(br s,1H),7.91(d,2H),7.89(s,1H),7.32-6.94(m,8H),5.32(s,2H),3.33(q,2H),2.55(t,2H),2.43(m,4H),1.45-1.25(m,8H),0.82(t,6H).

compound 209:¹HNMR(400MHz,CCl₄and DMSO-d6),ppm:77.95(br s,1H),7.73(s,1H),7.62(s,1H),7.55(d,1H)7.43(t,1H),7.33(d,1H),7.26(d,1H),7.22-7.14(m,3H),7.10-6.95(m,5H),4.52(s,2H),3.14(q,2H),2.80(m,2H),2.47(m,2H),2.45(m,2H),1.77(m,2H),1.55(m,4H),1.43(m,1H),1.18(m,2H).

compound 211:¹HNMR(400MHz,DMSO-d6),ppm:8.23(t,1H),7.84(s,1H),7.62(m,3H),7.42(m,3H),7.34(m,3H),7.26(d,1H),7.01(t,2H),5.40(s,2H),3.23(q,2H),2.40(m,2H),2.28(m,1H),2.15(s,3H),1.75-1.50(m,7H),1.20-1.00(m,5H).

compound 213:¹HNMR(400MHz,CCl₄and DMSO-d6),ppm:8.31(br s,1H),7.85(s,1H),7.62(m,2H),7.55(s,1H),7.50-7.25(m,5H),7.21-6.95(m,9H),5.37(s,2H),3.10(m,2H),2.79(m,2H),2.48(m,2H),2.30(s,3H),2.25(m,2H),1.78(m,2H),1.70-1.35(m,5H),1.19(m,2H).

compound 215:¹HNMR(400MHz,DMSO-d6),ppm:8.29(br s,1H),7.87(s,1H),7.62(m,2H),7.52(s,1H),7.42(m,3H),7.30(m,7.33(m,1H),7.26(m,1H),7.13(m,1H),7.10-6.93(m,3H),5.33(s,2H),3.18(m,2H),2.40(m,2H),2.26(s,3H),2.22(m,1H),2.10(s,3H),1.69(m,4H),1.57(m,3H),1.20-1.00(m,5H).

compound 217:¹HNMR(400MHz,CCl₄and DMSO-d6),ppm:7.95(t,1H),7.78(s,1H),7.74(s,1H),7.61(d,1H),7.49(d,1H),7.37(t,1H),7.27(d,1H),7.24-7.14(m,3H),7.12-6.98(m,5H),4.54(s,2H),3.17(q,2H),2.81(m,2H),2.47(m,2H),2.26(m,2H),1.77(m,2H),1.55(m,4H),1.45(m,1H),1.20(m,2H).

compound 219:¹HNMR(400MHz,DMSO-d6),ppm:8.06(br s,1H),7.58(s,1H),7.63(d,2H),7.58(s,1H),7.44(m,3H),7.35(m,1H),7.27(d,1H),7.17(t,1H),7.11(s,1H),7.08(d,1H),7.00(d,1H),5.38(s,2H),3.32(m,2H),2.65(m,6H),2.31(s,3H),1.55(m,8H).

compound 701:¹HNMR(400MHz,DMSO-d6),ppm:10.16(br s,1H),8.42(d,1H),8.06(d,1H),7.63(m,1H),7.52(m,1H),5.96(s,1H),3.79(m,4H),3.54(m,6H),2.69(m,4H),2.31(m,1H),1.95(m,2H),1.61(m,4H),1.62(m,1H),1.20(m,8H).

compound 705:¹HNMR(400MHz,CCl₄and DMSO-d6),ppm:10.31(br t,1H),8.45(d,1H),8.06(d,1H),7.63(m,1H),7.54(m,1H),7.46(s,1H),6.41(d,1H),6.36(d,1H),6.06(s,1H),4.78(d,2H),3.94(m,4H),3.84(M,1H),3.57(m,2H),2.67(m,4H),2.52(m,2H).

compound 707:¹HNMR(400MHz,CDCl₃),ppm:11.92(s,1H),8.58(d,1H),8.14(m,3H),7.76(t,1H),7.66(t,1H),7.47(d,2H),6.40(s,1H),3.94(m,7H),2.78(m,4H),2.32(m,1H),1.90(m,4H),1.69(m,1H),1.23(m,5H).

compound 709:¹HNMR(400MHz,CCl₄and DMSO-d6),ppm:10.31(br t,1H),8.45(d,1H),8.06(d,1H),7.63(m,1H),7.54(m,1H),7.46(s,1H),6.41(d,1H),6.36(d,1H),6.08(s,1H),4.74(d,2H),3.94(m,4H),2.73(m,4H),2.31(m,1H),1.81(m,4H),1.62(m,1H),1.15(m,5H).

compound 711:¹HNMR(400MHz,DMSO-d6),ppm:10.14(t,1H),8.42(d,1H),8.07(d,1H),7.89(t,1H),7.83(t,1H),6.09(s,1H),3.95(m,4H),3.56(m,2H),2.70(m,4H),2.31(m,1H),2.85-2.40(m,9H),1.24(m,4H),1.10(m,1H),0.97(t,3H).

compound 1021:¹HNMR(400MHz,CCl₄and DMSO-d6),ppm:11.70(br s,1H),10.38(d,1H),9.98(s,1H),8.64(m,1H),8.32(d,1H),8.27(d,1H),7.95(m,2H),7.85(d,1H),7.51(t,1H),7.38(t,1H),6.97(m,1H),6.82(s,1H),6.75(d,1H),3.71(m,2H),3.49(m,2H),3.38(m,2H),3.11(m,6H),2.28(s,3H),2.20(s,3H),2.14(m,2H).

compound 1033:¹HNMR(400MHz,DMSO-d6),ppm:11.85(s,1H),8.42(d,1H),8.10(d,1H),8.02(d,2H),7.79(t,1H),7.64(t,1H),7.50(d,2H),7.31(s,1H)7.17(d,1H),6.91(d,1H),6.42(s,1H),3.92(m,4H),3.79(s,3H),3.52(s,2H),2.62(m,4H).

compound 1035:¹HNMR(400MHz,DMSO-d6),ppm:10.16(s,1H),8.42(m,1H),8.06(m,1H),7.63(m,1H),7.52(m,1H),6.10(s,1H),4.01(m,4H),3.58(m,2H),2.79(m,5H),2.37(m,2H),2.00-1.80(m,6H),1.63(m,1H)1.28(m,4H),1.10(m,1H).

compound 1039:¹HNMR(300MHz,DMSO-d6),ppm:11.8(s,1H),8.50(m,1H),8.28(m,1H),8.15(m,2H),8.0(m,1H),7.95(m,1H),7.86(m,2H),6.50(m,1H),4.2(m,1H),3.5(m,9H),2.05(m,2H),1.80(m,2H),1.6(m,1H),1.3(m,5H).

compound 1041:¹HNMR(300MHz,DMSO-d6),ppm:11.82(s,1H),8.50(m,1H),8.20(m,1H),8.0(m,2H),7.92(m,1H),7.7(m,2H),7.0(m,2H),6.60(s,1H),4.86(m,1H),3.75(m,9H),2.15(m,2H),2.0(s,3H),1.86(m,2H),1.6(m,1H),1.36(m,5H).

compound 1043:¹HNMR(300MHz,DMSO-d6),ppm:12.28(s,1H),8.70(s,1H),8.26(m,2H),7.88(m,2H),7.70(m,2H),7.52(m,2H),7.18(s,1H),3.75(m,9H),2.16(m,2H),1.86(m,2H),1.6(m,1H),1.40(m,5H).

compound 1045:¹HNMR(300MHz,DMSO-d6),ppm:11.8(s,1H),8.52(m,1H),8.20(m,1H),7.98(m,2H),7.8(m,1H),7.70(m,1H),7.36(m,2H),6.38(m,1H),3.98(m,1H),3.5(m,8H),2.85(s,3H),2.1(s,3H),1.76(m,2H),1.4(m,2H).

compound 1047:¹HNMR(300MHz,DMSO-d6),ppm:11.8(s,1H),8.50(m,1H),8.20(m,1H),7.90(m,2H),7.70(m,2H),7.42(m,2H),6.50(m,1H),4.82(m,1H),3.75(m,9H),2.15(m,2H),1.86(m,2H),1.6(m,1H),1.36(m,5H).

compound 1049:¹HNMR(300MHz,DMSO-d6),ppm:11.8(s,1H),8.52(m,1H),8.20(m,1H),7.98(m,2H),7.8(m,1H),7.78(m,1H),7.4(m,2H),6.4(m,1H),4.60(m,1H),2.5(m,5H),1.9(m,4H),1.4(m,10H).

compound 1243:¹HNMR(400MHz,CCl₄and DMSO-d6),ppm:8.11(br s,1H),8.01(s,1H),7.64(m,2H),7.57(m,2H),7.41(m,1H),7.32(m,2H),7.17(m,2H),7.10-7.02(m,4H),6.94(dt,1H),5.72(d,1H),5.00(d,1H),3.31(q,2H),2.82(m,2H),2.45(m,2H),2.35(t,2H),1.90(m,2H),1.51(m,2H),1.47(m,1H),1.20(m,2H).

description of the biological Activity

Micelle assay method for measuring compound inhibition activity radioactively: the final reaction volume was 25. mu.l of TrkA (h) (3 nmol) and kinase reaction buffer (20 mM heparin sodium (pH 7.5), 10 mM magnesium chloride, 1 mM EGTA, 0.02% Bridgman-35, 0.02 mg/ml bovine serum albumin, 0.1 mM sodium orthovanadate, 2 mM dithiothreitol, 1% dimethyl sulfoxide), 0.2 mg/ml zymolyte PolyEY (4:1) and 2 mM manganese chloride, and [ 33P-ATP-](specific activity about 500cpm/pmol, meet desired concentration) were incubated together. The addition of MgATP in combination elicits a reaction. After at least 40 minutes of incubation at room temperature, the reaction was stopped by adding 5. mu.l of 3% phosphoric acid solution. Then, 10. mu.l of the reaction solution was filtered using a P30 continuous filter. Washed 3 times with 75 mmol of phosphoric acid for 5 minutes and once with methanol, then dried and counted by scintillation. TrkA: the recombinant human intracellular cytoplasmic segment (amino acids 441-. By in vitro activation of autophosphorylation. Molecular weight 42.8 kDa. Zymolyte of kinase: poly (EY) of TrK; poly (EY) (4:1) with 2 millimoles of manganese chloride, with an average molecular weight of 16kDa (standard conditions, unless otherwise specified): 30 nmol of TrKA, 0.2 mg/ml of poly (EY) +2 mmolManganese chloride, and 10 micromoles of (. gamma. -³³P]) ATP. Other similar assay conditions using cytoplasmic and recombinant human protein kinase domains can also be used to measure the activity of other kinases.

The antagonistic activity of TrkA kinase of the compounds useful in the present invention can be determined using the above assay. In particular, exemplary compounds of the invention, including tables 1.1 through 3.0, have demonstrated TrkA kinase antagonism (general IC) in the above experiments₅₀Less than 25 micromoles). Preferred compounds of the invention exhibit IC against TrkA kinase activity in the above experiments₅₀Is less than 2.5 micromolar. Further preferred compounds of the invention exhibit IC against TrkA kinase activity in the above experiments₅₀Is less than 0.25 micromolar. The more preferred compounds of the invention exhibit IC against TrkA kinase activity in the above experiments₅₀Is less than 0.1 micromolar. For example, IC of Compound A in the present invention₅₀Is 0.085 micromolar; IC of Compound B in the present invention₅₀IC of 0.007 micromolar but antagonizing a protein kinase of similar structure₅₀More than 10 micromoles: TrkB, TrkC, ABL1, AKT1, ALK5/TGFB-R1, ARAF, AXL, BMX, BTK, CDK1/cyclinB, CDK 1/cyclinA, CDK 1/cyclinE, c-methionine, c-Src, EPHA1, FES/FPS, FGFR1, FGR, FLT1, FLT1 (CD), FMS, FYN, IGF-1R, IR, ITK, JAK 1, JNK 1, LCK, LYN, MEK1, MEK1, MLK1/MAP3K 1, MUSK, P38 1/MAPK 1, P38 1/MAPK 1, PDGFRA, PDGFRb, PKA, PKCalpha, PKCALAPI, CdbetaI, CdbetaII, PKxelta, PKCmekTakta, PKCmekB, PKCzocta, PKCmax 1, PKCtCtCG 1, PKCtCtCtCG 1, PKCtCtCtCtCtCtCT, VEGFR 1, PKCtCtCtCtCtCtC 1, PKCtCtCtC 1, PKCtCtCtCtCtCtCtCtC 1, PKCtCtCtCtCtCtCtCtCtCtCtCtC 1, PKCtCtC. These results demonstrate the intrinsic activity of the compounds and may be used as selective antagonists of TrkA kinase activity subtype.

Determination of the inhibitory Effect of Compounds based on the function of Whole Living cells: there are several ways to measure the activity of TrkA throughout its length. The activity can be naturally compoundedIn this cell-based assay, in the context of U2OS cells, a small peptide epitope (peak) is a (human full-length protein) that expresses C-TrkA to the cell, this is expressed along with larger sequences, called the enzyme receptor (EA), which is linked to a cytoplasmic protein SHC1 that interacts intracellularly with TrkA. nerve growth factor receptor-induced activation of TrkA leads to homogeneous or heterogeneous TrkA dimers in cross-phosphorylation. the binding of the SHC1-EA fusion to the phosphorylated TrkA receptor forces PK and the fragment of TrkA to phosphorylate, this interaction produces a complementary β -chemiluminescence enzyme, which is detected using a chemoluminescent substrate.

In this cell-based functional assay, compound C of the invention inhibits NGF-induced TrkA activity at low nanomolar (cellular IC)₅₀0.047 micromoles, average of three measurements). While having virtually no effect on the process of stimulation of TrkB by BDNF or TrkC by NT3 (in both cases, IC₅₀All greater than 10 micromolar, three replicates of the test, pan-kinase inhibitor, staurosporine or internal agonist K-252a as positive control and one negative control compound). Another example is the EC of Compound E in the present invention₅₀＝0.22μM。

Effect of inhibitory patterns on ATP. The detection of TrkA kinase was performed at room temperature. Four concentrations of compound (0, 0.037, 0.11 and 0.33 micromolar) were added to the enzyme/substrate mix using acoustic techniques and incubated for 40 minutes to ensure that all compounds reached equilibrium and bound to the enzyme. Then, different concentrations of ATP (10, 100, 200, 350 and 500 micromoles of adenosine triphosphate and 0.2 mg/ml of poly (EY)) were added to the above mixture to start the reaction. Activity was monitored every 5-15 minutes. Such kinetic analysis indicates, for example, that compound D inhibits ATP-noncompetitive TrkA: laienweiThe difference in Vmax is shown in the fra-birk double reciprocal plot, but km is absent under 4 conditions.

Suppression of mode effects on substrates. The manner of kinase detection is similar to that of ATP studies. Different concentrations of compounds (0, 0.037, 0.11 and 0.33 micromolar) were added to the enzyme/substrate mix using acoustic techniques and incubated for 40 minutes to ensure that all compounds reached equilibrium and bound to the enzyme. Then, 10 micromoles of ATP and various concentrations of substrate (0.02, 0.05, 0.1, 0.2 and 0.5 mg/ml poly (EY)) were added to initiate the reaction. Activity was monitored every 5-15 minutes. Such kinetic analysis indicates, for example, that compound D inhibits TrkA: the difference in Vmax is shown in the lenweifer-birk double reciprocal plots under 4 conditions, but km is absent.

Neuropathic pain model of Chronic Crush Injury (CCI) in rats. The CCI model is one of the most commonly used models of mononeuropathic pain. It is described in detail first by Bennett and Xie (Bennett GJ, Xie YK, J.painful, 1988; 33(1): 87-107). It mimics important clinical chronic pain symptoms like mechanical hyperalgesia and thermal hyperalgesia. According to the Bennett and Xie method, chronic sciatic nerve crush injury is caused by loosely tying four ligatures to the left sciatic nerve. This process results in tactile allodynia in the left hind limb. Calibrated von frey filaments were used to determine the lowest mechanical (tactile) threshold that evokes a reflex withdrawal of an active paw in the rat hindpaw. Rats were allowed to acclimatize in a mesh cage for 15-20 minutes prior to von frey testing. Paw Withdrawal Thresholds (PWTs) using von frey filaments were evaluated before CCI surgery (pre-operative day 0 baseline). Before dosing on day 14, the baseline before dosing was recorded for each mouse. Only rats that did not exhibit motor dysfunction (e.g., paw dragging or dropping) and PWTs below 4 grams were included in the study. CCI-rats (4-6 per group) were used alone without drug. The oral vehicle was 0.5% sodium carboxymethylcellulose/0.1% tween 80 in distilled water. The positive control gabapentin is dissolved in the vehicle; the oral dosage is 100 mg/kg (oral gavage). Suspending the test compound in a carrier; it is administered orally in a dose of 50 mgKg and 100 mg/kg. Each CCI mouse was given a single oral dose 2 hours prior to PWT assessment: test compound, gabapentin or vehicle control.

The results show, for example, that oral administration of Compound D of the present invention can significantly reduce mechanorethically induced pain in a CCI rat neuropathic pain model, and is dose-dependent. In addition, compound D is more effective than gabapentin (the current gold standard drug for neuropathic pain treatment) in inhibiting mechanical pain of neuropathic pain in cervicitis by more than about 98% at the same oral dose of 100 mg/kg. Even 50 mg/kg of compound D is more than about 28% effective than 100 mg/kg gabapentin administered orally. Notably, CCI rats fed gabapentin showed lethargy or uncoordinated movement. This is consistent with the known side effects of gabapentin. However, CCI rats fed compound D had no such or other abnormal effects.

In addition, CCI mice orally fed Compound D at a single dose of 100 mg/kg also showed no statistically significant difference in the anti-nociceptive effects between day 14 and day 20 in the same group of rats. This indicates that compound D has no tolerance problems.

Single neuropathological pain rat model for Spinal Nerve Ligation (SNL). The procedure is as described in gold and Bell (gold SH, Bell JM, J. ache, 1992, 50(3): 355-63). This process will lead to tactile allodynia in the left hind limb (rat). Only rats that did not exhibit motor dysfunction (e.g., paw dragging or dropping) and had PWT values below 4.0 grams were included in the study. Dose response of the test compounds in the anti-hyperalgesia test: at 14 days post-surgery, rats will be gavage with one of four doses of test compound, vehicle or positive control. PWT was determined by calibrating von frey filaments at time point 0 (pre-dose baseline, immediately before dosing), 0.5, 1,2, 4 and 6 hours. Influence of endurance: after 6 days of testing on day 14, i.e. day 20 after surgery, the same procedure and the same (effective) dose on day 14 were repeated for the same group of mice. Comparing the anti-hyperalgesia effect results of day 14 and day 20 of the test compoundTo see if any animal had tolerated the effect of the test compound. Inverse hyperalgesia effects of repeated dosing of test compounds: administration of the test compound will begin on day 7 post-surgery, once daily for 7 days. PWT will be determined by calibrating von frey filaments once a day, 2 hours after dosing. After 7 days of dosing, the measurement will continue for 7 days, with measurements every other day (no further dosing). PWT will depend on the specific point in time mentioned above. The effects of thermal hyperalgesia. Thermal hyperalgesia can be assessed by subjecting SNL rats (test compound, one dose) to a plantar test at the time points described above with a single dose of the test compound at the time points described above.

Streptozotocin induced diabetic polyneuropathic pain model ^a . Diabetic peripheral neuropathy is due to long-term complications of diabetes. The rats were injected with streptozotocin (streptozotocin, 50 mg/kg, dissolved in citric acid buffer at pH 4.5 before injection) in the abdominal cavity to induce insulin-dependent diabetes mellitus and to produce tactile allodynia. After one week, blood samples were drawn from the tail vein and blood glucose levels were monitored using standard test strips and color. Blood glucose level only>An animal of 350 mg/dl would be considered diabetic and included in the test. Approximately 2 to 3 weeks after STZ injection, neuropathic pain (tactile allodynia) will begin in the hindpaw. After 4 weeks, a steady level of allodynia is usually achieved. At this point, mice below 4.5 grams PWT will participate in the test compound. The allodynic state will remain unchanged until 8 weeks after STZ injection. All animals will be observed and weighed regularly daily during the study period. This neuropathic pain model mimics the symptoms of neuropathy in diabetic patients (Linqi JJ, san Shi, et al, Eur. J. Pharmacol. 1999; 364(2-3): 141-6; Kalcatt NA, J. neurology & science & technology 2004; 220(1-2): 137-9). Dose response of test compounds against hyperalgesia: at 28 days post STZ injection, mice will be orally gavaged with one of four doses of test compound, or control (vehicle and anode controls), and PWT will be determined using calibrated von frey filaments at time point 0 (immediately prior to dosing, pre-dose baseline), 0.5, 1,2, 4 and 6 hours.Influence of endurance: after 6 days of testing on day 28, i.e. after 34 days of STZ injection, the same procedure and same (effective) dose on day 28 was repeated for the same group of rats. The anti-nociceptive effect of the test compounds was compared to the results on day 28 and day 34 to see if any of the compounds had an effect on tolerance in the animals. The effect of repeated administration of the compounds on paradoxical pain was tested: administration of test compound (i.p.) was started on day 21 after STZ injection, once daily for 7 consecutive days. PWT was determined by calibrating von frey filaments once a day, 1 hour after dosing. After 7 days of dosing, the measurement will continue every other day for 7 consecutive days (no further dosing). PWT is determined at the above time point. Thermal hyperalgesia can be assessed by conducting a sole test of the test compound at the time points described above (test compound, one dose) on STZ mice in a single dose of the sole test at the time points described above. PWL will be determined at the time points given above.

Therapeutic uses

According to the present invention, a compound of the present invention, or a salt, solvate, ester and/or prodrug thereof, or a pharmaceutical composition containing the compound, or a salt, solvate, ester and/or prodrug thereof, can be administered to a patient, preferably a human, suffering from a variety of diseases. These include cancer, anxiety, generalized pain states, acute pain, chronic pain, inflammatory pain, and neuropathic pain.

While the invention has been described and illustrated in certain preferred embodiments, those skilled in the art will recognize that: various changes, modifications and substitutions may be made to the compounds within the spirit and scope of the invention.

Therapeutic/prophylactic administration

The compounds shown, or salts, solvates, esters, and/or prodrugs thereof, or pharmaceutical compositions containing the present compounds or salts, solvates, esters, and/or prodrugs thereof, may be conveniently used in human medicine. As in the preceding paragraph "Therapeutic uses") the above-mentioned (a) is,the compounds presented are useful for the treatment or prevention of various diseases.

When used to treat or prevent the above-mentioned diseases or disorders, the compounds presented may be administered alone or in combination with other active agents (e.g., other analgesics).

The present invention provides therapeutic and prophylactic methods of using one or more compounds of the present invention, or salts, solvates, esters, and/or prodrugs thereof, to administer to a patient in need thereof, as well as such therapeutically effective dosages. The patient may be an animal, more preferably a mammal, most preferably a human.

The compounds shown, or salts, solvates, esters, and/or prodrugs thereof, can be administered orally. The compounds shown, or salts, solvates, esters, and/or prodrugs thereof, may also be administered by any other convenient route, for example: by injection or intravenous injection, or by absorption through the mucosal epithelium lining of the skin (e.g., oral mucosa, rectal and intestinal mucosa, etc.). Administration may be systemic or local. Various delivery systems (e.g., in liposome capsules, microparticles, microcapsules, capsules, etc.) are known for the delivery of compounds and/or pharmaceutical compositions. Methods of administration include, but are not limited to, subcutaneous, intramuscular, intraperitoneal, intravenous, subcutaneous, nasal, epidural, oral, sublingual, nasal, intracerebral, intravaginal, transdermal, rectal, pulmonary, or topical, particularly to the ear, nose, eye, or skin. The preferred mode of administration is left to the discretion of the physician and will depend in part on the medical conditions at the time. In most cases, administration will result in the release of the present compounds, or salts, solvates, esters and/or prodrugs thereof, into the blood of the patient.

In particular embodiments, it may be desirable to administer one or more compounds, or salts, solvates, esters and/or prodrugs thereof, to a localized area in need of treatment. This can be achieved without limitation, for example, by local infusion during surgery, by local application such as with post-operative wound dressings, by injection through catheters, by suppositories, or by implantation of porous, non-porous, or gelatinous materials, including silicone rubber or fibrous membranes. In some embodiments, the drug may be injected directly into the disease site (or primary site) of cancer or arthritis.

In certain embodiments, it may be desirable to introduce one or more of the compounds displayed, or salts, solvates, esters and/or prodrugs thereof, into the central nervous system of a patient by any suitable route, including intraventricular, intrathecal and epidural injection. The ventricular injection may be via a ventricular catheter, for example, attached to a ventricular reservoir.

The compounds presented, or salts, solvates, esters, and/or prodrugs thereof, can also be administered directly to the lungs by inhalation. For administration by inhalation, the compounds shown, or salts, solvates, esters, and/or prodrugs thereof, may be conveniently delivered to the lungs via various arrangements. For example, metered dose inhalers ("MDIs") which employ a canister containing a suitable low boiling point propellant, (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluorohexane, carbon dioxide or any other suitable gas) to carry the compound directly to the lungs.

Alternatively, the present compounds, (or salts, solvates, esters, and/or prodrugs thereof) may be administered to the lungs using a dry powder inhaler ("DPI") device. Dry powder inhaler devices typically use a mechanism such as gas bursting to create a cloud-like dry powder within a container that can then be inhaled into the lungs by a patient. Dry powder inhaler devices are also well known in the art. One popular improvement is the use of multi-dose dry powder inhaler devices ("MDDPIs") to administer more than one therapeutic dose. For example, capsules and gelatin cartridges for inhalation or pneumoperitoneum may be formulated to contain a dry powder mixture of the compound of the invention and a suitable powder base, such as lactose or starch.

Another type of device that may be used to deliver the compounds displayed, or salts, solvates, esters, and/or prodrugs thereof, to the lungs is a liquid spray device, available from suppliers such as aladem corporation, haworth, california. Liquid spray systems use very small nozzle holes to aerosolize the liquid medicament, which can then be inhaled directly into the lungs.

In some embodiments, nebulizers are used to deliver the present compounds, or salts, solvates, esters, and/or prodrugs thereof, to the lungs. Nebulizers utilize, for example, ultrasonic energy to form readily inhalable fine particles to nebulize liquid pharmaceutical formulations (e.g., forskoel et al, uk journal of cancer, 1999, 80, supple, 2, 96). Nebulizers are commercially available from commercial suppliers such as Sheffield/systemic pulmonary delivery company and Andont and Bartley lung treatment companies.

In other embodiments, an electrohydrodynamic ("ballistic") aerosolization device is used to deliver the present compounds, or salts, solvates, esters, and/or prodrugs thereof, to the lungs. A jet spray device uses electrical energy to atomize a liquid drug or suspension (see, e.g., nokes et al, U.S. patent No. 4765539). The electrochemical performance of such formulations is an important parameter that can be optimized in delivering the compounds displayed, or salts, solvates, esters, and/or prodrugs thereof, to the lungs. Such optimization can be performed by one skilled in the art. A plume spray device may be more effective for pulmonary delivery than other similar devices.

In other embodiments, the compounds shown, or salts, solvates, esters, and/or prodrugs thereof, may be delivered using vesicles, particularly liposomes (see Lange, 1990, J.Sci., 249: 1527-1533; Trait et al, "liposomes in infectious diseases and cancers", Lopetz-Bairestan and Fiderler (eds.), List, New York, p. 353-365 (1989)).

In other embodiments, the compounds shown, or salts, solvates, esters, and/or prodrugs thereof, may be delivered via a sustained release system. In other embodiments, the sustained release system is an oral sustained release system. In yet other embodiments, a pump may be used in a sustained release system (see, Lange, supra; Sefton, 1987, a critical review of biomedical engineering, 14: 201; Sharek et al, 1989, New England journal of medicine 321: 574).

In other embodiments, the polymeric material may be used in pharmaceutical compositions containing the present compounds, or salts, solvates, esters, and/or prodrug components thereof. (examples of polymeric materials, see "controlled release medical applications", Lange & Weiss (eds.), CRC Press, bocardon, Florida (1974); "controlled drug bioavailability", drug product design and Performance, Shimoron and Bobo (eds.), Weili, New York (1984); Raney and Pipas, 1983, journal of macromolecular science-polymer chemistry and physical review, 23: 61; see also Levy et al, 1985, journal of science, 228: 190; Diu Run et al, 1989, Neugen, 25: 351; Hover et al, 1989, J Neugu et al, 71: 105). In other specific descriptions, the high molecular material can be used as a component of an oral drug sustained-release preparation. Sample polymers include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxyethylcellulose (most preferably, hydroxypropylmethylcellulose). Other cellulose ethers have been described (Aldman, J. International pharmaceuticals, 1984,5(3) 1-9). Factors that influence drug release are well known in the art (bangba et al, journal of international agents, 1979,2, 307).

In other embodiments, the enteric formulation may be used for oral sustained release administration. Coating materials include, but are not limited to, polymers whose solubility varies with pH (i.e., pH-dependent controlled release), polymers that swell slowly or pH-dependent, disintegrate or erode (i.e., time-controlled release), polymers that are degradable by enzymes (i.e., enzyme controlled release), and polymers that form a hard layer and are destroyed by an increase in pressure (i.e., pressure controlled release).

In still other embodiments, the osmotic delivery system is used for oral sustained release administration (Vilman et al, drug discovery and Industrial, 2000,26: 695-. In still other embodiments, OROS^TMOsmotic devices are used in oral sustained release devices (seivers et al, U.S. patent No. 3845770; seivers et al, U.S. patent No. 3,916,899).

In still other embodiments, a controlled release system can be placed in the vicinity of the target site of the present compounds, or salts, solvates, esters and/or prodrugs thereof, so that only a small fraction of the systemic dose is required (see, e.g., Goodeson, "controlled release medical applications", Vol. 2, 115-138 (1984)). Other delivery systems discussed in Lange (1990, science 249: 1527-.

Pharmaceutical compositions of the invention

In one aspect, the invention provides pharmaceutical combinations comprising one or more of the compounds of the invention, including compounds according to formulae (I) to (VI) and subgeneric groups thereof, and "The invention relates to compounds and uses thereofAny of the embodiments described in the section.

Pharmaceutical compositions are shown comprising a therapeutically effective amount of one or more compounds of the invention, or salts, solvates, esters, and/or prodrugs thereof, (preferably in pure form); together with an amount of a pharmaceutically acceptable carrier; and a dosage form suitable for administration to a patient. When used in a patient, the compounds presented and pharmaceutically acceptable carriers are preferably sterile. Water is the preferred vehicle for intravenous administration. Physiological saline, dextrose solution and glycerol can be used as liquid carriers, particularly for injectable solutions. Suitable carriers for pharmaceutical agents also include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The pharmaceutical compositions shown may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. In addition, auxiliaries, stabilizers, thickeners, lubricants and colorants may also be used.

The pharmaceutical composition can be manufactured by the conventional method: mixing, dissolving, granulating, making into ball sugar, polishing, emulsifying, encapsulating, embedding or lyophilizing. The pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients and auxiliaries to better formulate the compounds of the invention into useful medicaments. The correct dosage form depends on the choice of route of administration.

Current pharmaceutical compositions may be in the form of: solutions, suspensions, emulsions, tablets, pills, granules, capsules containing liquids, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other suitable form. In some embodiments, the pharmaceutically acceptable carrier is a capsule (see, e.g., grignard wald et al, U.S. patent No. 5698155). Examples of other suitable pharmaceutical carriers have been described (see leimington, science and practice of pharmacy, philadelphia pharmacy and science institute, 20 th edition, 2000).

For topical administration, the compound formulations may be solutions, gels, creams, suspensions, and the like, as are well known in the art.

Systemic administration forms include injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as transdermal, transmucosal, buccal or pulmonary administration. The systemically administered dosage form may also be used in combination with another active agent, such as another anti-cancer agent.

In some embodiments, the compounds, or salts, solvates, esters, and/or prodrugs thereof, are routinely formulated for human intravenous administration. Typically, the compound is dissolved with an intravenous compound in sterile isotonic aqueous buffer. The compounds displayed, or salts, solvates, esters, and/or prodrugs thereof, may be prepared for injection in aqueous solution, preferably in a buffer such as hanks 'solution, ringer's solution, or physiological saline. Excipients such as suspension stabilizing and/or dispersing agents may be included in the solution. If necessary, the pharmaceutical composition may further include a dissolution agent. The pharmaceutical composition for intravenous injection may optionally include a local anesthetic such as lidocaine to reduce pain at the injection site. In general, the pharmaceutical ingredients may be presented as a unit, either alone or in admixture, for example, as a lyophilized powder or water-free concentrate in a sealed container, such as an ampoule or vial, indicating the amount of active agent. When the compounds, or salts, solvates, esters, and/or prodrugs thereof, are administered by infusion, the vials may be filled with sterile infusion pharmaceutical grade water or saline. When the compounds shown, or salts, solvates, esters, and/or prodrugs thereof, are administered by injection, an ampule of sterile water for injection or saline may be used to mix the drugs.

For transmucosal administration, the formulation may be formulated with a suitable barrier penetrant. Such penetrants are common in the art.

Pharmaceutical compositions for oral administration may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or tinctures. Oral pharmaceutical compositions may contain one or more of the options, for example, a sweetening agent, such as fructose, aspartame or saccharin, a flavoring agent, such as peppermint, oil of wintergreen, or cherry coloring and a protective agent to provide a pharmaceutically palatable preparation. In addition, the tablets or pills may be coated to delay disintegration and absorption of the pharmaceutical ingredients in the gastrointestinal tract, thereby providing a long-lasting medicinal effect. Osmotic pressure push drug release mechanisms on permselective membranes are also suitable for oral administration of the compounds of the invention. At these latter platforms, the liquid in the environment surrounding the capsule is absorbed by the propellant and expands, thereby releasing the pharmaceutical composition from the small opening. These delivery platforms may provide a substantially zero order release rather than the peak characteristics of an immediate release formulation. Time delay materials such as glyceryl monostearate or glyceryl stearate may also be used. Oral dosage forms may include standard carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. These carriers are preferably pharmaceutical grade standards.

For oral liquid preparations such as suspensions, tinctures and solutions, suitable carriers, excipients or diluents include water, saline, alkyl glycols (e.g., propylene glycol), polyethylene glycol (e.g., polyethylene glycol) oils, alcohols, microacid buffers at pH4-6 (e.g., acetic acid, citric acid, ascorbic acid, about 5.0 to 50.0 millimoles), and the like. In addition, flavoring agent, antiseptic, coloring agent, bile salt, acyl carnitine, etc. can also be added.

For oral mucosal administration, the pharmaceutical composition can be made into conventional dosage forms such as tablet, lozenge, etc.

Liquid pharmaceutical formulations suitable for use in nebulizers and liquid spray settings and jet spray devices generally comprise a compound of the invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is a liquid, such as alcohol, water, polyethylene glycol, or a perfluorocarbon. Alternatively, another material may be added to alter the solution or suspension aerosol characteristics of the compound. Such materials are preferably liquids, such as alcohols, glycols, polyglycols or fatty acids. Other suitable aerosol devices are well known in the art for preparing liquid drug solutions or suspensions (see, e.g., pizza early, U.S. Pat. No. 5112598; pizza early, U.S. Pat. No. 5556611).

The compounds shown, or salts, solvates, esters, and/or prodrugs thereof, may also be formulated in rectal or vaginal pharmaceutical compositions. For example, suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the dosage forms described above, the compounds shown, or salts, solvates, esters, and/or prodrugs thereof, may also be used as implants. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds shown, or salts, solvates, esters, and/or prodrugs thereof, may be formulated as implants from suitable polymeric or hydrophobic materials (e.g., as an acceptable oil emulsion) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

Therapeutic dosage

The dose of the compound, or salt, solvate, ester, and/or prodrug thereof, shown will generally be an effective amount of the compound to achieve the intended purpose. In treating or preventing diseases or disorders characterized by reduced apoptosis, a therapeutically effective dose of the compound and/or pharmaceutical composition is used.

The effective amount of the compounds, or salts, solvates, esters and/or prodrugs thereof, which can treat a particular disease or condition disclosed herein will depend upon the nature of the disease or condition as determined by standard clinical techniques well known in the art. In addition, in vitro or in vivo experiments can be used to help determine the optimal dosage range. The dosage of the present compounds or salts, solvates, esters and/or prodrugs thereof, administered will of course depend, among other factors, on the patient to be treated: the weight of the patient, the severity of the condition, the mode of administration and the judgment of the prescribing physician.

For example, dosing of the pharmaceutical composition may be administered in one, multiple or controlled release delivery. In some embodiments, the compounds displayed, or salts, solvates, esters, and/or prodrugs thereof, are delivered by oral sustained release. Administration may be repeated intermittently, either alone or in combination with other drugs, and may be continuous, as long as effective treatment is desired.

Suitable oral dosage ranges depend on the potency of the compounds, but are generally in the range of about 0.001 mg to 200 mg of the compounds of the invention per kg of body weight. Dosage ranges can be readily determined by ordinary skill in the art.

Suitable intravenous doses range from about 0.01 mg to 100 mg per kg of body weight. Suitable dosages for nasal administration will generally range from about 0.01 mg to about 1 mg per kg of body weight. Suppositories will generally contain from about 0.01 mg to about 50 mg of the compound of the invention per kg of body weight, including from about 0.5% to 10% by weight of the active ingredient. The recommended intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual or intracerebral dosage ranges are from about 0.001 to about 200 milligrams per kilogram of body weight. Effective doses can be extrapolated from dose-response curves in vitro and in animal model experiments. Such animal models and systems are well known in the art.

Preferably, a therapeutically effective dose of the present compounds or salts, solvates, esters, and/or prodrugs thereof will be therapeutically effective without causing substantial toxicity. Toxicity of the compounds shown, or salts, solvates, esters, and/or prodrugs thereof, can be determined by one skilled in the art following standard pharmaceutical procedures. The dose ratio between toxic and therapeutic effects is the therapeutic index. The compounds or salts, solvates, esters, and/or prodrugs thereof are shown to generally exhibit a relatively high therapeutic index in the treatment of apoptotic diseases. The dosage of the present compounds or salts, solvates, esters, and/or prodrugs thereof is preferably such that the circulating concentration range includes effective but little or no toxicity.

Combination therapy

In certain embodiments of the invention, the compounds shown, or salts, solvates, esters, and/or prodrugs thereof, may be used in combination therapy with at least one other active or therapeutic agent. The compounds, or salts, solvates, esters, and/or prodrugs thereof, shown may be additive or more preferably synergistic with at least one other active or therapeutic agent. In some embodiments, the compounds shown, or salts, solvates, esters, and/or prodrugs thereof, may be administered simultaneously, sequentially, or separately with another therapeutic agent. Active or chemotherapeutic agents include, but are not limited to, the following examples: acetoglucuronolactone, aclarubicin, altretamine, aminoglutethimide, 5-aminolevulinic acid, amsacrine, anastrozole, amcitabine hydrochloride, type 17-1A antibody, antilymphocyte immunoglobulin, a10 anticancer agent, asparaginase, pemetrexed, azacitidine, azathioprine, palmasine, benzoporphyrin derivative, bicalutamide, bisantrene hydrochloride, bleomycin sulfate, brequinar sodium, bromouridine, malilan, kaposi, transus, cametamine, carbendazim, carboplatin, carmofur, carmustine, chlorambucil, streptozocin chloride, chromomycin, cisplatin, cladribine, corynebacterium parvum, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, diaquone, dichlorodiethylsulfide, tunicamycin bay, docetaxel, doxifluridine, doxorubicin hydrochloride, droloxifene, echinomycin, edatrexate, eletriuminium, emestin, enloplatin, enocitabine, epirubicin hydrochloride, estramustine sodium phosphate, etanidazole, etoglut, etoposide, fadrozole, fazarabine hydrochloride, fenvqamine, fluorouracil, fludarabine phosphate, fluorouracil, flutamide, formestane, formestine, gallium nitrate, gemcitabine, guanipimox, piceatin, hydroxyurea, idarubicin hydrochloride, ifosfamide, imofofenacin, improvatelevox, imomab, interleukin-2, irinotecan, jm-216, letrozole, lithium galarmortex, lobaplatin, lomustine, lonidamine, macsfamide, melphalan, melnoluril, mercaptopurine, methotrexate sodium, prapterin, tebuformone, neonidazole, dibromomannitol, mitoguazone dihydrochloride, dibromodulcitol, mitomycin, mitotane, mizoribine hydrochloride, mopidamol, mottlet polypeptide (muitaichilpeptide), Moluotuzide-CD 3, mechlorethamine hydrochloride, mycophenolic acid, mycophenolate mofetil, nevada, nilutamide, nimustine hydrochloride, oxaliplatin, paclitaxel, PCNU (1- (2-chloroethyl) -3- (2, 6-dicarbonyl-3-piperidinyl) -1-nitrosourea-N- (2-chloroethyl) -N' - (2, 6-dicarbonyl-3-piperidinyl) -N-nitrosourea), pinostitadine (penostatin), pelubicin sulfate, pipobroman, pirarubicin, piroctone, piroxantrone hydrochloride, plicamycin, porfimer sodium, poiyinimustine, carbahydrazine hydrochloride trametexil, ramustine, propyleneimine, luogurimine, roquetiazole, speplatin, sirolimus, siropyran, sobuzole, tryptophane, foscarnet, sodium acetoacetaspartate, streptozotocin, sulfochlorpheniramine, tacrolimus, tamoxifen, tegafur, tiloxanide, temozolomide hydrochloride, teniposide, testolactone, sodium phosphate porphyrin sulfonate, guanine, thioinosine, thiotepa, promeotide, toremifene, troosufan, trimetrexed, trofosfamide, tumor necrosis factor, ubenimex, uramustine, vinblastine sulfate, vincristine sulfate, vindesine sulfate, vinorelbine tartrate, vorozole, neat butamine, azomomab, and zorubicin hydrochloride, alone or in any combination. Protein kinase a (pka) inhibitors, cAMP signaling pathway inhibitors, nonsteroidal anti-inflammatory drugs, prostaglandin synthesis inhibitors, local anesthetics, anticonvulsants, antidepressants, opioid receptor agonists, antipsychotics, benzodiazepines, barbiturates, neurosteroids and inhalation anesthetics, and other analgesics.

All publications and patent applications are herein incorporated by reference to the same extent as if each individual patent application was specifically and individually indicated to be incorporated by reference. The foregoing detailed description is illustrative rather than limiting in nature. Corresponding modifications will be apparent in the art. This is not an admission: any information provided herein is prior art or relevant to the presently claimed invention, or a specific or implicit reference to any publication is prior art.

The invention described herein embodies the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate for the reading. The inventors have for their invention intended to be carried out without specific reference thereto. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination which comprises all the possible variations of the elements described above is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims (29)

1. A polycyclic compound having the structural formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof:

wherein n is 1,2, or 3;

m is 0 or 1;

a is C, N, O, S, NR¹,C＝CR¹(E and Z isomers), C ═ NR¹(E and Z isomerismBody), C (R)¹R²),CR¹＝CR²-CR¹’R²' (E and Z isomers), or CR¹＝CR²-NR¹' (E and Z isomers);

b is C, N, O, S, NR³Or C (R)³R⁴)；

J, K, L, and M are each independently N or CR⁵；

Y is O,S,NR⁶,or C(R⁶R⁷)；

R¹,R²,R¹’,R²’,R³,R⁴,R⁵,R⁶And R⁷Each independently is a hydrogen atom, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, -CONR⁸R⁹Alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl; and

R⁸and R⁹Each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl; or when R is⁸And R⁹Are not both hydrogen, R⁸And R⁹Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heteroalkyl ring.

2. The compound of claim 1, wherein m-1, n-2, and a-a₄-A₄', or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, according to structural formula (IV):

wherein A is₄And A₄' independently of one another are NR¹,C＝CR¹(E and Z isomers), C ═ NR¹(E and Z are different from each otherStructural body), or C (R)¹R²) (ii) a And A₄And A₄The bond between' may be a single bond or a double bond.

3. The compound of claim 2, wherein a₄' is C ═ CX₄And A₄And A₄' between which is a single bond, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, according to structural formula (IVd):

wherein A is₄And X₄Each independently is C (R)¹¹R¹²) Or NR¹¹；

C＝X₄May be an E or Z isomer; and

R¹¹and R¹²Each independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl.

4. The compound of claim 3 comprising:

or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.

5. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, according to structural formula (IVb):

wherein the R ring is an aromatic ring, a substituted aromatic ring, a single-bond carbocyclic ring, a substituted carbocyclic ring, a heteroalkyl ring, a substituted heteroalkyl ring, a heteroaromatic ring, or a substituted heteroaromatic ring.

6. The compound of claim 5, wherein the R ring is a 6-membered ring, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, according to structural formula (IVb.2):

wherein A is₄-U₁,U₁-U₂,U₂-U₃,U₃-X₃,A₄’-X₃And A and₄-A₄' each option is a single or double bond;

U₁,U₂,U₃and X₃Are each selected from S, O, N, N (R)²⁰),C(R²⁰) Or C (R)²⁰R²¹)；

A₄And A₄' selected from N, C, or CR²²；

R²⁰，R²¹And R²²Each independently selected from the group consisting of a hydrogen atom, a halogen, an acyl group, a substituted acyl group, an alkoxycarbonyl group, a substituted alkoxycarbonyl group, an aryloxycarbonyl group, a substituted aryloxycarbonyl group, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an aralkyl group, a heteroaryl group, a substituted aralkyl group, a heteroaralkyl group, a substituted heteroaralkyl group, or a heteroalkyl group.

7. The compound of claim 6 comprising:

8. the compound of claim 6, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, according to structural formula (ivb.21):

9. the compound of claim 8 comprising:

10. the compound of claim 6, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, according to structural formula (ivb.22):

11. the compound of claim 10 comprising:

12. the compound of claim 1, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, according to structural formula (V):

wherein A is₄-X₄,A₅-X₅Each is selected from NR¹,C＝CR¹(E and Z isomers), C ═ NR¹C ═ O or C (R)¹R²)；

Z₃And Z₄Are each selected from O, S, NR³Or C (R)³R⁴) (ii) a Or also, Z₃-A₄-X₄Or X₄-A₄-A₅-X₅Together with the other atoms, form a 6 or 7 membered or substituted ring.

13. The compound of claim 12 comprising:

14. the compound of claim 12, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, according to structural formula (Vd):

wherein Z₃-U₄U₄-U₅,U₅-U₆,U₆-X₄,A₄-X₄And Z is₃-A₄Each is selected to be a double bond or a single bond;

U₄,U₅,U₆and X₄Is S, O, N, N (R)¹⁹),C(R¹⁹) Or C (R)¹⁹R²⁰)；

Z₃And A₄Each being selected from N, C or CR²¹；

R¹⁹，R²⁰And R²¹Each independently selected from hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, or heteroalkyl.

15. The compound of claim 14 comprising:

16. the compound of claim 12, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, having the structural formula (vf.1):

wherein X₄,X₅,U₇And U is₈Each independently is N or CR²⁵。

17. The compound of claim 16 comprising:

18. the compound of claim 1, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, having the structural formula (VI):

wherein A is₆₁,A₆₂And A₆₃Each independently selected from C, N, O, S, NR¹,C＝CR¹(E and Z isomers), C ═ NR¹(E and Z isomers), or C (R)¹R²)；

A₆₁-A₆₂And A₆₂-A₆₃Each independently selected is a single or double bond.

19. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, having the structural formula (VIa):

wherein A is₆₄Is O or S;

A₆₅is N or CR²⁵；

R⁶⁶Is hydrogen, alkyl, or substituted alkyl.

20. The compound of claim 19, or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, having the structural formula (via.11):

wherein nn is an integer from 0 to 4;

A₆₆is NR⁷³Or CR⁷³R⁷⁴；

R⁷²，R⁷³And R⁷⁴Each independently selected from hydrogen atom, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, -CONR⁷⁵R⁷⁶，S(O)₂NR⁷⁵R⁷⁶Alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl;

R⁷⁵and R⁷⁶Each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, heteroaryl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, heteroalkyl, or substituted heteroalkyl; or alternatively, R⁷⁵And R⁷⁶Together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heteroalkyl ring.

21. The compound of claim 20 comprising:

22. a pharmaceutical combination comprising a therapeutically effective amount thereof, or a salt, solvate, or physiologically functional derivative thereof; and at least one pharmaceutically acceptable carrier; wherein the compound is according to any one of claims 1 to 21.

23. A method of treating a disease, disorder, symptom or condition associated with irregular TrkA activity in a patient comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 22, or a salt, solvate, or physiologically functional derivative thereof.

24. A pharmaceutical combination comprising a compound according to claims 1 to 22, which can be administered orally, by injection, or in a depot patch/implant.

25. A pharmaceutical combination comprising: (a) a compound according to any one of claims 1 to 22, or a salt, solvate, or physiologically functional derivative thereof, and (b) at least one of the following active agents: protein Kinase A (PKA) inhibitors, cAMP signal inhibitors, non-steroidal anti-inflammatory drugs, prostaglandin synthesis inhibitors, local anesthetics, anticonvulsants, antidepressants, opioid receptor agonists, antipsychotics, GABA antagonists_AReceptor agonists, analgesic or anticancer agents with a different mechanism from TrkA antagonists, benzodiazepines, barbiturates, neurosteroids and an inhalation anesthetic, anticancer drug, mGluR5 receptor modulator, and combinations thereof.

26. A method of treating a disease, disorder, symptom or condition associated with irregular TrkA activity in a patient comprising administering a therapeutically effective amount of:

(a) a compound of any one of claims 1 to 22, or a salt, solvate, or physiologically functional derivative thereof,

and (b) inhibitors of Protein Kinase A (PKA), inhibitors of cAMP signaling, nonsteroidal anti-inflammatory drugs, inhibitors of prostaglandin synthesis, local anesthetics, anticonvulsants, antidepressants, opioid receptor agonists, antipsychotics, GABA antagonists_AReceptor agonists, analgesic or anticancer agents with a different mechanism from TrkA antagonists, benzodiazepines, barbiturates, neurosteroids and an inhalation anesthetic, anticancer drug, mGluR5 receptor modulator, and combinations thereof.

27. The method of claims 23 and 26, wherein the disease, disorder, symptom or condition is selected from the group consisting of: acute pain, chronic pain, inflammatory pain, neuropathic pain, ankylosing pain, persistent pain, post-operative pain, chemo-induced pain, chemotherapy-induced pain, cancer pain, drug-induced pain, skeletal pain, hyperalgesia with alcohol, generalized pain disorder, anxiety, skeletal muscle spasm, seizure, epilepsy, restenosis, atherosclerosis, psoriasis, pain caused by thrombosis, burns, post-traumatic stress disorder, cardiac disease, smoking, inflammation and immune-mediated diseases (including microbial infections and organ transplants), cancer (including breast cancer, head and neck cancer, prostate cancer and lung cancer), diseases, disorders or injuries associated with dysmyelination or demyelination, and combinations thereof.

28. The method of claim 27, wherein the disease, disorder, symptom or condition is due to or associated with: causalgia, diabetes mellitus, collagen vascular disease, trigeminal neuralgia, spinal cord injury, brainstem injury, thalamic pain syndrome, complex regional pain syndrome type I/reflex sympathetic dystrophy, fabry syndrome, small fiber neuropathy, cancer chemotherapy, chronic alcoholism, stroke, abscess, demyelinating diseases, viral infection, antiviral therapy, aids therapy, burn, sunburn, arthritis, colitis, myocarditis, dermatitis, myositis, neuritis, mucositis, urethritis, cystitis, gastritis, pneumonia, collagen vascular disease, trauma, surgery, amputation, toxins, inappropriate use of drugs, drug dependence, use or abuse of alcohol, use or abuse of undesirable substances, use or abuse of drugs, drug-related effects, (cancer cell) metastasis, fibromyalgia, irritable bowel syndrome, temporomandibular joint disorders, inflammation, immunological disorders, or combinations thereof.

29. A kit comprising a compound according to any one of claims 1 to 21 or a pharmaceutical combination according to claim 22, 24 or 25.