Source: https://patents.justia.com/patent/10421763
Timestamp: 2020-04-07 04:58:54
Document Index: 660675664

Matched Legal Cases: ['Application No. 61', 'art.\n1', '§ 371', '§ 371', '§ 371', '§ 371', '§ 371', '§ 371']

US Patent for Compositions of protein receptor tyrosine kinase inhibitors Patent (Patent # 10,421,763 issued September 24, 2019) - Justia Patents Search
Justia Patents Tricyclo Ring System Having The Seven-membered Hetero Ring As One Of The CyclosUS Patent for Compositions of protein receptor tyrosine kinase inhibitors Patent (Patent # 10,421,763)
Aug 14, 2017 - Purdue Pharma L.P.
This Application is a Continuation Application of U.S. patent application Ser. No. 13/133,565, which is a National Stage Application of International Application No. PCT/US2009/067197, filed on Dec. 8, 2009, which claims the benefit of priority to U.S. Provisional Patent Application No. 61/120,827, filed on Dec. 8, 2008, the entire contents of each of which are herein incorporated by reference in their entirety for all purposes.
Related U.S. patent application Ser. No. 14/256,094, filed on Apr. 18, 2014, which issued as U.S. Pat. No. 8,809,530, on Aug. 19, 2014, is a Divisional Application of U.S. patent application Ser. No. 13/133,565.
There are several examples of either ant-TrkA antibodies or anti-NGF antibodies known in the art. For example, PCT Publication Nos. WO 2006/131952, WO 2005/061540 and EP 1181318 disclose use of anti-TrkA antibodies as effective analgesics in in-vivo animal models of inflammatory and neuropathic pain. PCT Application Nos. WO 01/78698, WO 2004/058184 and WO 2005/019266 disclose the use of an NGF antagonist for preventing or treating pain. PCT Application WO 2004/096122 describes a method for the treatment or the prevention of pain with co-administration of an anti-NGF antibody and an opioid analgesic. PCT Application WO 2006/137106 discloses a method for the treatment or the prevention of pain with co-administration of an anti-TrkA antibody and an opioid analgesic. In addition, profound or significantly attenuated reduction of bone pain caused by prostate cancer metastasis has been achieved by utilization of an anti-NGF antibody (Sevik, M A, et al, Pain 115:128-141 (2005)).
The therapeutic implications of an effective Trk inhibitor may well go beyond pain therapy. The subversion of this receptor and its signaling pathway in certain malignancies has also been documented. The tyrosine kinase activity of Trk is believed to promote the unregulated activation of cell proliferation machinery. It is believed that inhibitors of TrkA, TrkB, or TrkC kinases, individually or in combination, have utility against some of the most common cancers such as brain, melanoma, multiple myeloma, squamous cell, bladder, gastric, pancreatic, breast, head, neck, esophageal, prostate, colorectal, lung, renal, ovarian, gynecological, thyroid cancer, and certain type of hematological malignancies. Lestaurtinib (CEP-701, Cephalon), an indolocarbazole inhibitor of several tyrosine kinases, including Flt-3 and TrkA, and CEP-751, a pan Trk inhibitor have been entered Phase II clinical trails for the treatment of acute myelogenous leukaemia (AML), pancreatic cancer and multiple myeloma (MM) and/or prostate cancer.
In one aspect, the present invention provides compounds having structural Formula (I):
A is C, N, O, S, NR1, C═CR1 (E and Z isomers), C═NR1 (E and Z isomers), C(R1R2), CR1═CR2—CR1′R2′ (E and Z isomers), or CR1═CR2—NR1′ (E and Z isomers);
when n is 2 or 3, any of two adjacent A, together with other atoms, form one or two rings where each of the rings is optionally substituted;
R1, R2, R3, R4, R5, R6, and R7 are independently hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, —CONR8R9, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl;
In another aspect, the present invention provides pharmaceutical compositions comprising one or more compounds as described above or a salt, solvate, or physiologically functional derivative thereof, and a pharmaceutically acceptable vehicle.
In still another aspect, the present invention provides methods for selectively inhibiting or antagonizing NGF receptor TrkA for treatment and/or prevention of pain, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, or a disease, disorder or injury relating to dysmyelination or demyelination, with therapeutic effective amount of the compound as described above, or a salt, solvate, or physiologically functional derivative thereof.
The present invention relates to novel synthetic small molecules that act as inhibitors and/or antagonists of the members of Trk family protein kinases, in particularly the NGF receptor, TrkA.
The term “a compound of the present invention”, “the compound of the present invention”, “compounds of the present invention”, or “the present compounds” refers to one or more compounds encompassed by the structural formulae and/or any subgeneric formulae disclosed herein and includes any specific compounds within these generic formula whose structure is disclosed herein. Compounds of the invention may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), the racemic mixtures, enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. The compounds of the invention may also exist in several tautomeric forms. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. Compounds also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 17O, 18O, etc. Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, the salt, hydrated, solvated, and N-oxide forms are within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline forms or an amorphous form. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
The term “physiologically functional derivative(s)” used herein refers to any physiologically tolerated derivative of a compound of the present invention, for example, an ester or prodrug, which, upon administration to a mammal, e.g., a human, are transformed directly or indirectly to a compound of formula (Ia), (Ic), (Ii), (II), or an active metabolite thereof. Physiologically functional derivatives include prodrugs of the compounds of the present invention. Examples of prodrug are described in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not.
“Alkyl” by itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. The term “alkyl” is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” are used. In some embodiments, an alkyl group comprises from 1 to 20 carbon atoms (C1-C20 alkyl). In other embodiments, an alkyl group comprises from 1 to 10 carbon atoms (C1-C10 alkyl). In still other embodiments, an alkyl group comprises from 1 to 6 carbon atoms (C1-C6 alkyl). Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.
“Arylalkyl,” by itself or as part of another substituent, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl group as, as defined herein. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl and/or arylalkynyl is used. In some embodiments, an arylalkyl group is (C6-C30) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C10) alkyl and the aryl moiety is (C6-C20) aryl. In other embodiments, an arylalkyl group is (C6-C20) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C8) alkyl and the aryl moiety is (C6-C12) aryl. In still other embodiments, an arylalkyl group is (C6-C15) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C8) alkyl and the aryl moiety is (C6-C10) aryl.
“Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkanyl, Heteroalkyldiyl and Heteroalkyleno” by themselves or as part of another substituent, refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyl and alkyleno groups, respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic groups. Typical heteroatomic groups which can be included in these groups include, but are not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR203R204—, ═N—N═, —N═N—, —N═N—NR205R206, —PR207—, —P(O)2—, —POR208—, —O—P(O)2—, —SO—, —SO2—, —SnR209R210, BR211R212, BOR213OR214 and the like, where R203, R204, R205, R206, R207, R208, R209, R210, R211, R212, R213 and R214 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.
“Heteroaryl,” by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring systems, as defined herein. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, furopyridine, and the like. In some embodiments, the heteroaryl group comprises from 5 to 20 ring atoms (5-20 membered heteroaryl). In other embodiments, the heteroaryl group comprises from 5 to 10 ring atoms (5-10 membered heteroaryl). Exemplary heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole and pyrazine.
“Heteroaryloxycarbonyl,” by itself or as part of another substituent, refers to a radical of the formula —C(O)—O—R201, where R201 is heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.
“Modulating” refers to adjusting, varying, or changing. As used herein, modulation of calcium ion channel includes antagonizing, agonizing, or partially antagonizing. That is, the compounds of the present invention may act as antagonists, agonists, or partial antagonists of the calcium ion channel activity.
“Parent Aromatic Ring System” refers to an unsaturated cyclic or polycyclic ring system having a conjugated it electron system. Specifically included within the definition of “parent aromatic ring system” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.
“Solvate” means a compound formed by solvation (the combination of solvent molecules with molecules or ions of the solute, i.e., a compound of the present invention), or an aggregate that consists of a solute ion or molecule (the compound of the present invention) with one or more solvent molecules.
“Substituted,” when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent(s). Substituent groups useful for substituting saturated carbon atoms in the specified group or radical include, but are not limited to —Ra, halo, —O−, ═O, —ORb, —SRb, —S−, ═S, —NRcRc, ═NRb, ═N—ORb, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)2Rb, —S(O)2NRb, —S(O)2O—, —S(O)2ORb, —OS(O)2Rb, —OS(O)2O—, —OS(O)2ORb, —P(O)(O−)2, —P(O)(ORb)(O−), —P(O)(ORb)(ORb), —C(O)Rb, —C(S)Rb, —C(NRb)Rb, —C(O)O−, —C(O)ORb, —C(S)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —OC(S)Rb, —OC(O)O−, —OC(O)ORb, —OC(S)ORb, —NRbC(O)Rb, —NRbC(S)Rb, —NRbC(O)O−, —NRbC(O)ORb, —NRbC(S)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rb and —NRbC(NRb)NRcRc, where Ra is selected from the group consisting of alkyl, substituted alkyl, arylalkyl, alkyldiyl, substituted alkyldiyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroalkyldiyl, substituted heteroalkyldiyl, heteroaryl, substituted heteroaryl, heteroarylalkyl substituted heteroarylalkyl; each Rb is independently hydrogen or Ra; and each Rc is independently Rb or alternatively, the two Rcs are taken together with the nitrogen atom to which they are bonded form a cycloheteroalkyl ring which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S. As specific examples, —NRcRc is meant to include —NH2, —NH-alkyl, N-pyrrolidinyl and N-morpholinyl.
Similarly, substituent groups useful for substituting unsaturated carbon atoms in the specified group or radical include, but are not limited to, —Ra, halo, —O−, —ORb, —SRb, —S−, —NRcRc, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —N3, —S(O)2Rb, —S(O)2O—, —S(O)2ORb, —OS(O)2Rb, —OS(O)2O—, —OS(O)2ORb, —P(O)(O−)2, —P(O)(ORb)(O−), —P(O)(ORb)(ORb), —C(O)Rb, —C(S)Rb, —C(NRb)Rb, —C(O)O−, —C(O)ORb, —C(S)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —OC(S)Rb, —OC(O)O−, —OC(O)ORb, —OC(S)ORb, —NRbC(O)Rb, —NRbC(S)Rb, —NRbC(O)O−, —NRbC(O)ORb, —NRbC(S)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rb and —NRbC(NRb)NRcRc, where Ra, Rb and Re are as previously defined.
Substituent groups useful for substituting nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include, but are not limited to, —Ra, —O−, —ORb, —SRb, —S−, —NRcRc, trihalomethyl, —CF3, —CN, —NO, —NO2, —S(O)2Rb, —S(O)2O—, —S(O)2ORb, —OS(O)2Rb, —OS(O)2O—, —OS(O)2ORb, —P(O)(O−)2, —P(O)(ORb)(O−), —P(O)(ORb)(ORb), —C(O)Rb, —C(S)Rb, —C(NRb)Rb, —C(O)ORb, —C(S)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —OC(S)Rb, —OC(O)ORb, —OC(S)ORb, —NRbC(O)Rb, —NRbC(S)Rb, —NRbC(O)ORb, —NRbC(S)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rb and —NRbC(NRb)NRcRc, where Ra, Rb and Re are as previously defined.
The term “reducing pain,” as used herein, refers to decreasing the level of pain a subject perceives relative to the level of pain the subject would have perceived were it not for the intervention. Where the subject is a person, the level of pain the person perceives can be assessed by asking him or her to describe the pain or compare it to other painful experiences. Alternatively, pain levels can be determined by measuring the subject's physical responses to the pain, such as the release of stress-related factors or the activity of pain-transducing nerves in the peripheral nervous system or the CNS. One can also determine pain levels by measuring the amount of a well-characterized analgesic required for a person to report that no pain is present or for a subject to stop exhibiting symptoms of pain. A reduction in pain can also be measured as an increase in the threshold at which a subject experiences a given stimulus as painful. In certain embodiments, a reduction in pain is achieved by decreasing “hyperalgesia,” the heightened sensitivity to a noxious stimulus, and such inhibition can occur without impairing “nociception,” the subject's normal sensitivity to a “noxious” stimulus.
“Inflammatory pain” refers to pain arising from inflammation. Inflammatory pain often manifests as increased sensitivity to mechanical stimuli (mechanical hyperalgesia or tenderness). For examples, inflammatory pain is due to a condition selected from the group consisting of: burn, sunburn, arthritis, colitis, carditis, dermatitis, myositis, neuritis, mucositis, urethritis, cystitis, gastritis, pneumonitis, and collagen vascular disease.
“Neuropathic pain” refers to pain arising from conditions or events that result in nerve damage. “Neuropathy” refers to a disease process resulting in damage to nerves. “Causalgia” denotes a state of chronic pain following nerve injury. “Allodynia” refers to a condition in which a person experiences pain in response to a normally nonpainful stimulus, such as a gentle touch. For examples, neuropathic pain is due to a condition selected from the group consisting of: causalgia, diabetes, collagen vascular disease, trigeminal neuralgia, spinal cord injury, brain stem injury, thalamic pain syndrome, complex regional pain syndrome type I/reflex sympathetic dystrophy, Fabry's syndrome, small fiber neuropathy, cancer, cancer chemotherapy, chronic alcoholism, stroke, abscess, demyelinating disease, viral infection, anti-viral therapy, AIDS, and AIDS therapy. Neuropathic pain is due to an agent selected from the group consisting of: trauma, surgery, amputation, toxin, and chemotherapy.
The phrase “a drug-related effect” refers to an in vivo effect that occurs in response to a drug. Exemplary effects include stimulant, sedative, hypnotic, and ataxic effects.
A “sedative effect” refers to a decrease in activity and/or excitement in a subject. A “hypnotic effect” includes an increase in drowsiness and/or a facilitation of the onset and/or maintenance of sleep.
An “ataxic effect” refers to a decrease in motor coordination.
“Substance abuse” includes a maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period: (1) recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home (e.g., repeated absences or poor work performance related to substance use; substance-related absences, suspensions, or expulsions from school; neglect of children or household); (2) recurrent substance use in situations in which it is physically hazardous (e.g., driving an automobile or operating a machine when impaired by substance use); (3) recurrent substance-related legal problems (e.g., arrests for substance-related disorderly conduct); and (4) continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g., arguments with spouse about consequences of intoxication, physical fights). (See American Psychiatric Association, Diagnostic Criteria for DSM-IV, Washington D.C., APA, 1994.)
A “drug of abuse” includes any substance, the excessive consumption or administration of which can result in a diagnosis of substance dependence or abuse as defined herein or as defined by the current DSM Criteria promulgated by the American Psychiatric Association or equivalent criteria. Drugs of abuse include, without limitation, an opioid, a psychostimulant, a cannabinoid, an empathogen, a dissociative drug, and ethanol. Thus, for example, heroin, cocaine, methamphetamines, cannabis, 3-4 methylenedioxy-methamphetamine (MDMA), barbiturates, phencyclidine (PCP), ketamine, and ethanol are all drugs of abuse, as defined herein.
A “neuroleptic” refers to a class of tranquilizing drugs, used to treat psychotic conditions, that modulate neurotransmitter activity in the central nervous system and can act by modulating acetylcholine, dopamine, norepinephrine, serotonin, or γ-aminobutyric acid (GABA) transmission.
A “benzodiazepine” is referred to a agent selected from the group consisting of: alprazolam, chlordiazepoxide, chlordiazepoxide hydrochloride, chlormezanone, clobazam, clonazepam, clorazepate dipotassium, diazepam, droperidol, estazolam, fentanyl citrate, flurazepam hydrochloride, halazepam, lorazepam, midazolam hydrochloride, oxazepam, prazepam, quazepam, temazepam, and triazolam.
A “barbiturate” referred to a agent selected from the group consisting of: amobarbital, amobarbital sodium, aprobarbital, butabarbital sodium, hexobarbital sodium, mephobarbital, metharbital, methohexital sodium, pentobarbital, pentobarbital sodium, phenobarbital, phenobarbital sodium, secobarbital, secobarbital sodium, talbutal, thiamylal sodium, and thiopental sodium.
The term “cancer” refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, for example, leukemia, lymphoma, blastoma, carcinoma and sarcoma. More particular examples of such cancers include chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL), squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal 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, which can, of course, 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 used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a compound” includes a combination of two or more compounds or molecules, and the like.
In one aspect, the present invention provides a compound having a structural formula (I):
A is C, N, O, S, NR1, C═CR1 (E and Z isomers), C═NR1 (E and Z isomers), C(R1R2),
CR1═CR2—CR1R2′ (E and Z isomers), or CR1═CR2—NR1′ (E and Z isomers);
when n is 2 or 3, any of two adjacent A, together with other atoms, form one or two rings
where each of the rings is optionally substituted;
R1, R2, R3, R4, R5, R6, and R7 are each independently hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, —CONR8R9, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl;
In one embodiment of formula (I), wherein m=0, n=1, and A=A1-X1.
A1-X1 is NR1, C═CR1 (E and Z isomers), C═NR1 (E and Z isomers), or C(R1R2).
(101) (103) (105) (107)
Compounds listed in Table 1.1 may also be represented by their chemical names as follows:
101 7-benzyl-8-oxo-N-[3-(pyrrolidin-1-yl)propyl]bicyclo[4.2.0]octa- 1,3,5-triene-3-carboxamide 103 (7E)-7-benzylidene-8-oxo-N-[3-(pyrrolidin-l- yl)propyl]bicyclo[4.2.0]octa-1,3,5-triene-3-carboxamide 105 7-benzyl-8-oxo-N-[3-(pyrrolidin-1-yl)propyl]-7- azabicyclo[4.2.0]octa-1,3,5-triene-3-carboxamide 107 (8Z)-8-benzylidene-7-oxo-N-[3-(pyrrolidin-l-yl)propyl]-2- azabicyclo[4.2.0]octa-1,3,5-triene-4-carboxamide
In one embodiment of formula (I), wherein m=1, n=1, and A=A2-X2.
A2-X2 is NR1, C═CR1 (E and Z isomers), C═NR1 (E and Z isomers), or C(R1R2).
In one embodiment of formula (III), the compound having a structure selected from the group consisting of:
(109) (111) (113) (115) (117)
109 4-{[1-(2-fluorobenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]methyl}- N-[3-(pyrrolidin-1-yl)propyl]benzamide 111 4-{(E)-[5-(2-fluorobenzyl)-6-oxo-5,6-dihydro-7H-pyrrolo[3,2- d]pyrimidin-7-ylidene]methyl}-N-[3-(pyrrolidin-l- yl)propyl]benzamide 113 4-{(Z)-[1-(2-fluorobenzyl)-2-oxo-1,2-dihydro-3H-indol-3- ylidene]methyl}-N-[3-(pyrrolidin-1-yl)propyl]benzamide 115 4-{[(3E)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydro-3H-indol-3- ylidene]amino}-N-[3-(pyrrolidin-1-yl)propyl]benzamide 117 4-{[(3Z)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydro-3H-indol-3- ylidene]amino}-N-[3-(pyrrolidin-1-yl)propyl]benzamide
In one embodiment of formula (I), wherein m=1, n=2, A=Z1 and A is represent by A4-A4′.
In one embodiment of formula (I), the compound having a structural formula (IV):
A4 and A4′ are independently selected from NR1, C═CR1 (E and Z isomers), C═NR1 (E and Z isomers), or C(R1R2); or alternatively, A4 and A4′, together with other atoms, form a ring which is optionally substituted; and the link between A4 and A4′ can be either single or double bond. The ring formed by A4 and A4′ with other atoms may be four-, five-, six-, seven-, or eight-membered carbocyclic or heterocyclic ring.
In one embodiment of formula (IV), wherein A4′ is C═X4 and the link between A4 and A4′ is a single bond.
In one embodiment of formula (IV), the compound having a structural formula (IVd):
or salt, solvate, or physiologically functional derivative thereof,
A4 and X4 are independently CR11R12 or NR11;
C═X4 can be either E and Z isomers;
(203) (205) (207) (209) (211) (213) (215) (217) (219) (221) (223) (225) (227) (229) (231) (233) (235) (237) (239) (241) (243) (245) (247) (249) (251) (253) (255) (257) (259) (261) (263) (265) (267) (269) (271) (273) (275) (277) (279) (281) (283) (285) (287) (291) (293) (295) (297) (299) (301) (303) (305) (307) (309) (311) (313) (315) (317) (319) (321) (323) (421) (423) (425) (427) (429) (431) (433) (435) (437) (439) (441) (443) (445) (447) (449) (451) (453) (455) (457) (459) (461) (463) (465) (467) (469) (471) (473) (475) (477) (479) (481) (483) (485) (487) (489)
203 (2Z)-2-benzylidene-N-[3-(4-benzylpiperidin-1-yl)propyl]-4-(4-fluorobenzyl)-3-oxo-3,4-dihydro- 2H-1,4-benzothiazine-6-carboxamide 205 N-[3-(4-benzylpiperidin-1-yl)propyl]-2-[(2E)-2-(3-bromo-4-methoxybenzylidene)-3-oxo-2,3- dihydro-4H-1,4-benzothiazin-4-yl]acetamide 207 4-{(E)-[4-(3-chlorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylidene]methyl}-N-[2- (dibutylamino)ethyl]benzamide 209 N-[3-(4-benzylpiperidin-l-yl)propyl]-2-[(2Z)-2-(3-chlorobenzylidene)-3-oxo-2,3-dihydro-4H-1,4- benzothiazin-4-yl]acetamide 211 (2Z)-2-benzylidene-N-{3-[cyclohexyl(methyl)amino]propyl}-4-(4-fluorobenzyl)-3-oxo-3,4- dihydro-2H-1,4-benzothiazine-6-carboxamide 213 (2Z)-2-benzylidene-N-[3-(4-benzylpiperidin-l-yl)propyl]-4-(3-methylbenzyl)-3-oxo-3,4-dihydro- 2H-1,4-benzothiazine-6-carboxamide 215 (2Z)-2-benzylidene-N-{3-[cyclohexyl(methyl)amino]propyl}-4-(3-methylbenzyl)-3-oxo-3,4- dihydro-2H-1,4-benzothiazine-6-carboxamide 217 N-[3-(4-benzylpiperidin-l-yl)propyl]-2-[(2E)-2-(3-bromobenzylidene)-3-oxo-2,3-dihydro-4H-1,4- benzothiazin-4-yl]acetamide 219 (2Z)-N-[2-(azepan-l-yl)ethyl]-2-benzylidene-4-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-1,4- benzothiazine-6-carboxamide 221 N-[2-(4-benzylpiperidin-1-yl)ethyl]-4-{(E)-[4-(2,5-dimethylbenzyl)-3-oxo-3,4-dihydro-2H-1,4- benzothiazin-2-ylidene]methyl}benzamide 223 (2Z)-2-benzylidene-N-[3-(2-ethylpiperidin-1-yl)propyl]-4-(4-fluorobenzyl)-3-oxo-3,4-dihydro-2H- 1,4-benzothiazine-6-carboxamide 225 4-{(E)-[4-(3-chlorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylidene]methyl)-N-{3- [cyclohexyl(methyl)amino]propyl}benzamide 227 (2Z)-N-[3-(azepan-1-yl)propyl]-2-benzylideiie-4-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-1,4- benzothiazine-6-carboxamide 229 (2Z)-2-benzylidene-4-(4-fluorobenzyl)-N-[3-(3-methylpiperidin-l-yl)propyl]-3-oxo-3,4-dihydro- 2H-1,4-benzothiazine-6-carboxamide 231 N-[2-(azepan-1-yl)ethyl]-4-{(E)-[4-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2- ylidene]methyl}benzamide 233 N-{3-[cyclohexyl(methyl)amino]propyl}-4-{(E)-[4-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-1,4- benzothiazin-2-ylidene]methyl}benzamide 235 N-[2-(azepan-1-yl)ethyl]-4-{(E)-[4-(3-chlorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2- ylidene]methyl}benzamide 237 (2Z)-N-{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}-2-[2-(4-methoxyphenyl)-2-oxoethylidene]-3- oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide 239 2-[(2Z)-2-(3-chlorobenzylidene)-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-N-{3-[4-(4- methoxyphenyl)piperazin-1-yl]propyl}acetamide 241 (2Z)-2-benzylidene-N-{3-[4-(2,5-dimethylphenyl)piperazin-1-yl]propyl}-4-(3-methylbenzyl)-3- oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxamide 243 4-{(E)-[4-(3-chlorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylidene]methyl}-N-[(1- ethylpyrrolidin-2-yl)methyl]benzamide 245 N-{3-[cyclohexyl(methyl)amino]propyl}-4-{(E)-[4-(2-methylbenzyl)-3-oxo-3,4-dihydro-2H-1,4- benzothiazin-2-ylidene]methyl}benzamide 247 (2Z)-2-benzylidene-N-[3-(3,5-dimethylpiperidin-l-yl)propyl]-4-(3-methylbenzyl)-3-oxo-3,4- dihydro-2H-1,4-benzothiazine-6-carboxamide 249 (2Z)-2-benzylidene-N-[3-(3,5-dimethylpiperidin-l-yl)propyl]-4-(4-fluorobenzyl)-3-oxo-3,4- dihydro-2H-1,4-benzothiazine-6-carboxamide 251 N-{3-[benzyl(methyl)amino]propyl}-4-{(E)-[4-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-1,4- benzothiazin-2-ylidene]methyl}benzamide 253 N-[2-(azepan-1-yl)ethyl]-2-[(2E)-2-(3-chlorobenzylidene)-3-oxo-2,3-dihydro-4H-1,4- benzothiazin-4-yl]acetamide 255 2-[(2E)-2-(3-bromo-4-methoxybenzylidene)-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-N-{3- [4-(2-fluorophenyl)piperazin-1-yl]propyl}acetamide 257 N-{3-[benzyl(methyl)amino]propyl}-2-[(2Z)-2-(3-chlorobenzylidene)-3-oxo-2,3-dihydro-4H-1,4- benzothiazin-4-yl]acetamide 259 2-[(2Z)-2-(3-chlorobenzylidene)-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-N-{3-[4-(2- fluorophenyl)piperazin-1-yl]propyl}acetamide 261 N-{2-[butan-2-yl(cyclohexyl)amino]ethyl}-4-{(E)-[4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-1,4- benzothiazin-2-ylidene]methyl)benzamide 263 N-{2-[cyclohexyl(methyl)amino]ethyl}-4-{(E)-[4-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-1,4- benzoxazin-2-ylidene]methyl)benzamide 265 2-[(2E)-2-(3-bromobenzylidene)-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-7V-[3-(3,5- dimethylpiperidin-1-yl)propyl}acetamide 267 N-{3-[benzyl(butyl)amino]propyl{-4-{(E)-[4-(3-chlorobenzyl)-3-oxo-3,4-dihydro-2H-1,4- benzothiazin-2-ylidene]methyl}benzamide 269 N-[2-(azepan-1-yl)ethyl]-2-[(2E)-2-(3-bromo-4-methoxybenzylidene)-3-oxo-2,3-dihydro-4H-1,4- benzothiazin-4-yl]acetamide 271 2-[(2Z)-2-(3-chlorobenzylidene)-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-N-{3-[4-(4- fluorophenyl)piperazin-1-yl]propyl}acetamide 273 2-[(2E)-2-(3-bromobenzylidene)-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-N-[3-(2- ethylpiperidin-1-yl)propyl]acetamide 275 N-{3-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]propyl}-4-{(E)-[4-(2-fluorobenzyl)-3-oxo-3,4- dihydro-2H-1,4-benzothiazin-2-ylidene]methyl}benzamide 277 N-[2-(dipropylamino)ethyl]-4-{(E)-[4-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin- 2-ylidene]methyl}benzamide 279 (2Z)-N-[2-(azepan-l-yl)ethyl]-2-benzylidene-4-(4-fluorobenzyl)-3-oxo-3,4-dihydro-2H-1,4- benzothiazine-6-carboxamide 281 4-{(E)-[4-(3-chlorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylidenee]methyl}-N-{3-[4- (2-fluorophenyl)piperazin-1-yl]propyl}benzamide 283 2-[(2Z)-2-(3-chlorobenzylidene)-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-N-{3-[4-(3- chlorophenyl)piperazin-1-yl]propyl}acetamide 285 2-[(2E)-2-(3-chlorobenzylidene)-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-N-[3-(2- ethylpiperidin-1-yl)propyl]acetamide 287 N-{3-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]propyl}-4-{(E)-[4-(3-methylbenzyl)-3-oxo-3,4- dihydro-2H-1,4-benzoxazin-2-ylidene]methyl}benzamide 291 (2Z)-2-benzylidene-N-[3-(3,4-dihydroisoquinolin-2(1H)-yl)propyl]-4-(3-methylbenzyl)-3-oxo-3,4- dihydro-2H-1,4-benzothiazine-6-carboxamide 293 2-[(2Z)-2-(3-bromo-4-methoxybenzylidene)-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-N-{3- [4-(4-fluorophenyl)piperazin-1-yl]propyl}acetamide 295 4-{(E)-[4-(3-chlorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylidene]methyl}-N-[2- (pyrrolidin-1-yl)ethyl]benzamide 297 2-[(2E)-2-(3-bromobenzylidene)-3-oxo-2,3-dihydro-4H1,4-benzothiazin-4-yl]-N-{2-[methyl(2- phenylethyl)amino]ethyl}acetamide 299 4-{(E)-[4-(3-chlorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-ylidene]methyl}-N-[3-(3- methylpiperidin-1-yl)propyl]benzamide 301 (2Z)-2-benzylidene-N-{3-[4-(4-methoxyphenyl)piperazin-1-yl]propyl)-4-(3-methylbenzyl)-3-oxo- 3,4-dihydro-2H-1,4-benzothiazine-6-carboxamide 303 (2Z)-N-[3-(azepan-l-yl)propyl]-2-benzylidene-4-(4-fluorobenzyl)-3-oxo-3,4-dihydro-2H-1,4- benzothiazine-6-carboxamide 305 N-{3-[4-(2-fluorophenyl)piperazin-1-yl]propyl}-4-{(E)-[4-(3-methylbenzyl)-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-ylidene]methyl}benzamide 307 N-{3-[4-(2-fluorophenyl)piperazin-1-yl]propyl)-4-{(E)-[4-(2-methylbenzyl)-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-ylidene]methyl}benzamide 309 N-{3-[4-(4-methoxyphenyl)piperazin-1-yl]propyl}-4-{(E)-[4-(4-methylbenzyl)-3-oxo-3,4-dihydro- 2H-1,4-benzothiazin-2-ylidene]methyl}benzamide 311 2-[(2E)-2-(3-chlorobenzylidene)-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-N-[3-(3- methylpiperidin-1-yl)propyl]acetamide 313 (2E)-2-(4-ethoxy-3-methoxybenzylidene)-N-{3-[4-(2-fluorophenyl)piperazin-l-yl]propyl)-4- methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxamide 315 2-[(2E)-2-(2-chlorobenzylidene)-3-oxo-2,3-dihydro-4h-1,4-benzothiazin-4-yl]-N-}3-[4-(4- fluorophenyl)piperazin-1-yl]propyl}acetamide 317 (2Z)-N-{3-[4-(2-fluorophenyl)piperazin-1-yl]propyl}-4-methyl-2-(3-methylbenzylidene)-3-oxo- 3,4-dihydro-2H-1,4-benzothiazine-6-carboxamide 319 2-[(2E)-2-(3-chlorobenzylidene)-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl]-N-[3-(3,5- dimethylpiperidin-1-yl)propyl]acetamide 321 (2E)-N-{3-[4-(2-fluorophenyl)piperazin-1-yl]propyl}-2-(2-methoxybenzylidene)-4-methyl-3-oxo- 3,4-dihydro-2H-1,4-benzothiazine-6-carboxamide 323 (2Z)-N-{3-[4-(4-fluorophenyl)piperazin-1-yl]propyl}-4-methyl-2-(2-methylbenzylidene)-3-oxo- 3,4-dihydro-2H-1,4-benzothiazine-6-carboxamide 421 4-{(Z)-[4-(4-chlorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylidene]methyl}-N- methylbenzamide 423 4-{(Z)-[4-(4-chlorobenzyl)-3-thioxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-2-ylidene]methyl}- N-methylbenzamide 425 N-methyl-4-[(Z)-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylidene)methyl]benzamide 427 N-methyl-4-[(1Z)-1-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylidene)-2- phenylethyl]benzamide 429 N-methyl-4-[(1Z)-1-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylidene)-3- phenylpropyl]benzamide 431 N-methyl-4-[(1Z)-1-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2(1H)-ylidene)-3- phenylpropyl]benzamide 433 N-methyl-4-[(1Z)-1-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2(1H)-ylidene)-2- phenylethyl]benzamide 435 4-{(Z)-[4-(cyclohexylmethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylidene]methyl}-N-[2-(2- methylpiperidin-1-yl)ethyl]benzamide 437 4-{(Z)-[4-(cyclohexylmethyl)-3-oxo-3,4-dihydropyrido[3,4-b]pyrazin-2(1H)-ylidene]methyl}-N- [2-(2-methylpiperidin-1-yl)ethyl]benzamide 439 4-{(Z)-[1-(cyclohexylmethyl)-2-thioxo-1,2-dihydro-3H-pyrido[2,3-b][1,4]oxazin-3- ylidene]methyl}-N-[2-(2-methylpiperidin-1-yl)ethyl]benzamide 441 4-{[(2Z)-1-benzyl-2-ethylidene-3-oxo-1,2,3,4-tetrahydroquinolin-4-yl]methyl}-N-[2-(piperidin-1- yl)ethyl]benzamide 443 4-{[(2Z)-1-benzyl-2-ethylidene-3-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl]methyl}-N-[2- (piperidin-1-yl)ethyl]benzamide 445 4-{[(3E)-4-benzyl-3-ethylidene-2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl]methyl}-N-[2- (piperidin-1-yl)ethyl]benzamide 447 4-{[(3E)-4-benzyl-3-ethylidene-2-thioxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl]methyl}-N-[2- (piperidin-1-yl)ethyl]benzamide 449 4-{[(3Z)-4-(cyclohexylmethyl)-3-ethylidene-2-oxo-3,4-dihydroquinolin-1(2H-yl]methyl)-N-[2- (piperidin-1-yl)ethyl]benzamide 451 (2Z)-2-benzylidene-3-oxo-N-[3-(2-propylpiperidin-1-yl)propyl]-3,4-dihydro-2H-1,4- benzothiazine-6-carboxamide 453 4-benzyl-N-[3-(2-ethylpiperidin-l-yl)propyl]-2-imino-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6- carboxamide 455 4-benzyl-N-[3-(2-ethylpiperidin-1-yl)propyl]-2-imino-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6- carboxamide 457 (2Z)-2-benzylidene-N-[3-(2-ethylpiperidin-1-yl)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6- carboxamide 459 (3Z)-3-benzylidene-N-[3-(2-ethylpiperidin-1-yl)propyl]-2-oxo-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazine-7-carboxamide 461 (3Z)-3-benzylidene-N-[3-(2-ethylpiperidin-1-yl)propyl]-2-oxo-2,3-dihydro-1H-pyrido[3,4- b][1,4]oxazine-7-carboxamide 463 (3Z)-3-benzylidene-N-[3-(2-ethylpiperidin-1-yl)propyl]-2-oxo-2,3-dihydro-1H-pyrido[3,4- b][1,4]thiazine-7-carboxamide 465 (2Z)-4-benzyl-2-ethylidene-N-[3-(2-ethylpiperidin-1-yl)propyl]-3-oxo-3,4-dihydro-2h-1,4- benzothiazine-6-carboxamide 467 (3Z)-1-benzyl-3-ethylidene-N-[3-(2-ethylpiperidin-1-yl)propyl]-2-oxo-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazine-7-carboxamide 469 (3Z)-1-(cyclohexylmethyl)-3-ethylidene-N-[3-(2-ethylpiperidin-1-yl)propyl]-2-oxo-2,3-dihydro- 1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide 471 (3Z)-1-(cyclohexylmethyl)-3-ethylidene-N-[3-(piperidin-1-yl)propyl]-2-thioxo-2,3-dihydro-1H- pyrido[2,3-6][1,4]oxazine-7-carboxamide 473 (2Z)-4-(cyclohexylmethyl)-2-ethylidene-3-imino-N-[3-(piperidin-1-yl)propyl]-3,4-dihydro-2H-1,4- benzothiazine-6-carboxamide 475 (2Z)-4-benzyl-2-ethylidene-3-imino-N-[3-(piperidin-1-yl)propyl]-3,4-dihydro-2H-1,4- benzothiazine-6-carboxamide 477 (3Z)-3-ethylidene-4-(4-fluorobenzyl)-2-oxo-N-[3-(piperidin-1-yl)propyl]-3,4-dihydro-2H-1,4- benzothiazine-7-carboxamide 479 (3Z)-3-ethylidene-4-(4-fluorobenzyl)-N-[3-(piperidin-l-yl)propyl]-2-thioxo-3,4-dihydro-2H-1,4- benzoxazine-7-carboxamide 481 4-{[4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]methyl}-N-[3-(pyrrolidin-1- yl)prpoyl]benzamide 483 4-{(Z)-[4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylidene]methyl}-N- methylbenzamide 485 4-{(E)-[4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylidene]methyl}-N- methylbenzamide 487 4-{[(2Z)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylidene]amino}-N- methylbenzamide 489 4-{[(2E)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-ylidene]amino}-N- methylbenzamide
In one embodiment of formula (IV), wherein the link of A4-A4′ is a double bond and A4′ is CR41.
R41 is hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, —C(O)NR42R43, —NR42R43, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl, or substituted heteroalkyl;
R42 and R43 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl, or substituted heteroalkyl, or alternatively, R42 and R43, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl ring.
In one embodiment of formula (IVa), the compound having a structure selected from the group consisting of:
(491) (493) (495)
Compounds listed in Table 1.4 may also be represented by their chemical names as follows:
491 N-[3-(azepan-1-yl)propyl]-2-benzyl-4-(4-fluorobenzyl)-3-oxo- 3,4-dihydropyrido[2,3-b]pyrazine-6-carboxamide 493 N-[3-(azepan-1-yl)propyl]-7-benzyl-5-(4-fluorobenzyl)-6-oxo- 5,6-dihydroquinoline-3-carboxamide 495 6-benzyl-8-(4-fluorobenzyl)-7-oxo-N-[3-(pyrrolidin-1-yl)propyl]- 7,8-dihydropyrido[2,3-b]pyrazine-2-carboxamide
In one embodiment of formula (IV), wherein A4 and A4′ along with other atoms form a 5, 6, or 7-member ring system.
R ring is an aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl or substituted heteroaryl ring. The R ring may be a four-, five-six-, or seven-membered carbocyclic or heterocyclic ring.
In one embodiment of formula (IVb), wherein R ring is a 5-member ring system.
In one embodiment of formula (IVb), the compound having a structural formula (IVb.0):
A4-Q1, Q1-Q2, Q2-X3, A4′-X3, A4-A4′ are independently single or double bond;
Q1, Q2, and X3 are independently S, O, N, N(R15), C(R15), C(R15R16);
A4 and A4′ are independently N, C, or CR17;
In one embodiment of formula (IVb.0), the compound having a structure selected from the group consisting of:
(497) (499) (501) (503)
Compounds listed in Table 1.5 may also be represented by their chemical names as follows:
497 N-{3-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]propyl}-4- oxo-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-7- carboxamide 499 5-benzyl-N-{3-[4-(5-chloro-2-methylphenyl)piperazin-1- yl]propyl}-4-oxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2- a]quinoxaline-7-carboxamide 501 5-benzyl-4-oxo-N-[3-(4-phenylpiperazin-1-yl)propyl]-4,5- dihydrofuro[3,2-c]quinoline-7-carboxamide 503 5-(2-fluorobenzyl)-N-[3-(4-phenylpiperazin-1-yl)propyl]-4-thioxo- 3,3a,4,5-tetrahydroimidazo[1,5-a]quinoxaline-7-carboxamide
In one embodiment of formula (IVb.0), wherein A4-Q1 and Q2-X3 are double bond, and Q1-Q2, A4′-X3, and A4-A4′ are single bond.
In one embodiment of formula (IVb.0), the compound having a structural formula (IVb.1):
A4 is C;
A4′ is N or CR18;
(505) (507) (509) (511)
Compounds listed in Table 1.6 may also be represented by their chemical names as follows:
505 N-{3-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]propyl}-4-oxo- 4,5-dihydro-3aH-cyclopenta[a]naphthalene-7-carboxamide 507 5-(2-fluorobenzyl)-2-methyl-N-[3-(4-phenylpiperazin-1-yl)propyl]- 4-thioxo-4,5-dihydro-3aH-cyclopenta[c]quinoline-7-carboxamide 509 6-benzyl-5-oxo-N-[3-(4-phenylpiperazin-1-yl)propyl]-5,6- dihydropyrrolo[1,2-c]quinazoline-8-carboxamide 511 5-benzyl-N-{3-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]propyl}- 4-oxo-4,5-dihydro-3aH-pyrrolo[3,2-c]quinoline-7-carboxamide
A4-U1, U1—U2, U2—U3, U3—X3, A4′-X3, A4-A4′ are independently single or double bond; U1, U2, U3, and X3 are independently S, O, N, N(R20), C(R20), C(R20OR21);
A4 and A4′ are independently N, C, or CR22
(515) (517) (519) (521)
515 N-{3-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]propyl}-9-oxo- 4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide 517 5-benzyl-N-{3-[4-(5-chloro-2-methylphenyl)piperazin-1- yl]propyl}-6-oxo-6,6a,7,8,9,10-hexahydro-5H- pyrido[1,2-a]quinoxaline-3-carboxamide 519 5-benzyl-6-oxo-N-[3-(4-phenylpiperazin-1-yl)propyl]- 5,6,7,8,9,10-hexahydrophenanthridine-3-carboxamide 521 5-(2-fluorobenzyl)-N-[3-(4-phenylpiperazin-1-yl)propyl]- 6-thioxo-6,8-dihydro-5H-pyrido[1,2-a]quinoxaline- 3-carboxamide
In one embodiment of formula (IVb.2), wherein U1, U2, U3, X3, A4′, and A4 form a 6-membered cycloheteo ring.
In one embodiment of formula (IVb.2), wherein A4 is N, and B is NR5.
(201) (289) (551) (553) (555) (557)
201 N-{3-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]propyl}-6-oxo- 6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline- 3-carboxamide 289 N-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-6-oxo- 6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline- 3-carboxamide 551 N-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-6-oxo- 6,8,9,10-tetrahydro-5H-pyrido[1,2-a]quinoxaline- 3-carboxamide 553 N-(3-{4-[5-chloro-2-(trifluoromethyl)phenyl]piperazin-1-yl} propyl)-5-methyl-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a] quinoxaline-3-carboxamide 555 N-({2-[4-(3-chlorophenyl)piperazin-1-yl]cyclopropyl}methyl)-6- oxo-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline- 3-carboxamide 557 N-{3-[4-(1,3-benzodioxol-5-yl)piperazin-1-yl]propyl}-6-oxo- 6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline- 3-carboxamide
In one embodiment of formula (IVb.2), wherein U1, U2, U3, X3, A4′, and A4 form an benzene ring.
In one embodiment of formula (IVb.2), the compound having a structural formula (IVb.22):
(525) (527) (529) (531) (535) (537)
525 N-{3-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]propyl}-9- oxo-9,10-dihydrophenanthrene-2-carboxamide 527 5-(2-fluorobenzyl)-N-[3-(4-phenylpiperazin-1-yl)propyl]-6- thioxo-5,6-dihydrophenanthridine-3-carboxamide 529 6-benzyl-5-oxo-N-[3-(4-phenylpiperazin-1-yl)propyl]-5,6- dihydrobenzo[c][2,6]naphthyridine-8-carboxamide 531 5-benzyl-N-{3-[4-(5-chloro-2-methylphenyl)piperazin-1- yl]propyl}-6-oxo-5,6-dihydrophenanthridine-3-carboxamide 535 N-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-6-oxo-5,6- dihydrophenanthridine-3-carboxamide 537 N-[3-(morpholin-4-yl)propyl]-6-oxo-5,6- dihydrophenanthridine-3-carboxamide
In one embodiment of formula (I), wherein m=1; n=3; A is “Z3, A4-X4, and A5-X5”; B is Z4.
In one embodiment of formula (I), the compound having a structural of formula (V):
A4-X4, A5-X5 are independently NR1, C═CR1 (E and Z isomers), C═NR1, C═(O) or C(R1R2);
(801) (803) (805) (807) (809)
801 4-{(Z)-[5-(2-fluorobenzyl)-4-oxo-4,5-dihydro-1,5- benzothiazepin-2(3H)-ylidene]methyl}-N-[3- (pyrrolidin-1-yl)propyl]benzamide 803 4-{(E)-[5-(2-fluorobenzyl)-4-oxo-4,5-dihydro-1,5- benzothiazepin-2(3H)-ylidene]methyl}-N-[3- (pyrrolidin-1-yl)propyl]benzamide 805 4-{[(2Z)-5-(2-fluorobenzyl)-4-oxo-4,5- dihydro-1,5- benzothiazepin-2(3H)-ylidene]amino}-N-[3- (pyrrolidin-1-yl)propyl]benzamide 807 4-{[(2E)-5-(2-fluorobenzyl)-4-oxo-4,5-dihydro-1,5- benzothiazepin-2(3H)-ylidene]amino}-N-[3- (pyrrolidin-1-yl)propyl]benzamide 809 4-{2-[5-(2-fluorobenzyl)-4-oxo-2,3,4,5-tetrahydro- 1,5-benzothiazepin-3yl]ethyl}-N-[3- (pyrrolidin-1-yl)propyl]benzamide
In one embodiment of formula (V), wherein Z3-A4 is double bond, A4-X4 is CR1, A5-X5 is C(R1R2), NR1, C═CR1 (E and Z isomers), or C═NR1 (E and Z isomers).
(811) (813) (815) (817)
Compounds listed in Table 2.1 may also be represented by their chemical names as follows:
811 2-benzyl-5-(4-fluorobenzyl)-3-methyl-4-oxo-N- [3-(pyrrolidin-1-yl)propyl]-4,5-dihydro-3H-1- benzazepine-7-carboxamide 813 (7E)-N-[3-(azepan-1-yl)propyl]-7-benzylidene-5- (4-fluorobenzyl)-6-oxo-6,7-dihydro-5H- pyrido[3,2-b]azepine-3-carboxamide 815 2-benzyl-5-(4-fluorobenzyl)-4-oxo-N-[3- (pyrrolidin-1-yl)propyl]-4,5-dihydro-1,5- benzothiazepine-7-carboxamide 817 N-[3-(azepan-1-yl)propyl]-3-benzyl-1-(4- fluorobenzyl)-5-methyl-2-oxo-2,5-dihydro-1H- pyrido[2,3-b][1,4]diazepine-8-carboxamide
Z3-Q3, Q3-Q4, Q4-X4, A4-X4, Z3-A4 are independently single or double bond;
Q3, Q4, and X4 are independently S, O, N, N(R16), C(R16), C(R16R17);
Z3 and A4 are independently N, C, or CR18;
(1101) (1103) (1105) (1107)
1101 (7aS,10aS)-N-[2-(4-benzylpiperidin-1-yl)ethyl]- 5-(2-chloro-5-fluorobenzyl)-6-oxo- 5,6,7,7a,8,9,10,10a-octahydrobenzo[b] cyclopenta[d]azepine-3-carboxamide 1103 (11bR)-7-benzyl-N-[2-(4-benzylpiperidin-1- yl)ethyl]-6-oxo-2,3,5,6,7,11b-hexahydro-1H- pyrrolo[1,2-d][1,4]benzodiazepine-9-carboxamide 1105 (3aS)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-6-(3- fluorobenzyl)-5-oxo-3a,4,5,6-tetrahydro-3H- thieno[3,4-d][1]benzazepine-8-carboxamide 1107 (7aR)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-5-methyl- 6-oxo-6,7,7a,8,9,10-hexahydro-5H- pyrrolo[1,2-a][1,5]benzodiazepine-3-carboxamide
In one embodiment of formula (Vc), the compound having the structural formula (Vc. 1):
X4, Q3 and Q4 are independently N or CR16
In one embodiment of formula (Vc. 1), the compound having a structure selected from the group consisting of:
(1121) (1123) (1125) (1127)
Compounds listed in Table 2.3 may also be represented by their chemical names as follows:
1121 6-(2-chloro-5-fluorobenzyl)-5-oxo-N-[2-(4- phenylpiperazin-1-yl)ethyl]-5,6-dihydro-4H- thieno[2,3-d][1]benzazepine-8-carboxamide 1123 N-[2-(4-benzylpiperidin-1-yl)ethyl]-6-(3- fluorobenzyl)-5-oxo-3,4,5,6-tetrahydro[1,2,3] triazolo[4,5-d][1]benzazepine-8-carboxamide 1125 6-(2-chlorobenzyl)-N-{2-[4-(cyclopenta-1,3- dien-1-yl)piperazin-1-yl]ethyl}-5-oxo-5,6- dihydro-4H-[1,3]oxazolo[5,4-d][1]benzazepine- 8-carboxamide 1127 N-[2-(4-cyclohexylpiperazin-1-yl)ethyl]-5- methyl-6-oxo-5,6,7,8-tetrahydrobenzo[b] cyclopenta[d]azepine-3-carboxamide
In one embodiment of formula (V), wherein R3 forms a 6-member ring system with A4-X4.
In one embodiment of formula (V), the compound having the structural formula (Vd):
Z3—U4 U4—U5, U5—U6, U6—X4, A4-X4, Z3-A4 are independently single or double bond; U4, U5, U6, and X4 are independently S, O, N, N(R19), C(R19), C(R19R20);
Z3 and A4 are independently N, C, or CR21
(1131) (1133) (1135) (1137)
1131 (7aS,11aS)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-5- (2-chloro-5-fluorobenzyl)-6-oxo- 6,7,7a,8,9,10,11,11a-octahydro-5H- dibenzo[b,d]azepine-3-carboxamide 1133 (12aR)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-5- (3-fluorobenzyl)-6-oxo-5,6,7,9,10,11,12,12a- octahydropyrido[1,2-d][1,4]benzodiazepine- 3-carboxamide 1135 (4aR)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-7- (2-chlorobenzyl)-6-oxo-3,4,4a,5,6,7- hexahydrothiopyrano[4,3-d][1]benzazepine- 9-carboxamide 1137 (7aR)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-5- methyl-6-oxo-5,6,7,7a,8,9,10,11- octahydropyrido[1,2-a][1,5]benzodiazepine- 3-carboxamide
In one embodiment of formula (Vd), wherein Z3—U4 U4—U5, U5—U6, U6—X4, A4-X4, Z3-A4 together form an aromatic system.
Z3 and A4 are C;
U4, U5, U6, and X4 are independently N or CR19
In one embodiment of formula (Vd.1), the compound having a structure selected from the group consisting of:
(1141) (1143) (1145) (1147)
1141 5-(2-chloro-5-fluorobenzyl)-6-oxo-N-[2-(4- phenylpiperazin-1-yl)ethyl]-6,7-dihydro-5H- dibenzo[b,d]azepine-3-carboxamide 1143 N-[2-(4-benzylpiperidin-1-yl)ethyl]-7-(3- fluorobenzyl)-6-oxo-6,7-dihydro-5H-pyrido [3,2-d][1]benzazepine-9-carboxamide 1145 5-(2-chlorobenzyl)-N-{2-[4-(cyclopenta-1,3-dien- 1-yl)piperazin-1-yl]ethyl}-6-oxo-6,7-dihydro- 5H-pyrido[2,3-a][3]benzazepine-3-carboxamide 1147 N-[2-(4-cyclohexylpiperazin-1-yl)ethyl]-7-methyl- 6-oxo-6,7-dihydro-5H-pyrido[4,3-d][1] benzazepine-9-carboxamide
In one embodiment of formula (V), wherein A4-X4 and A5-X5 form a 5-member ring system.
In one embodiment of formula (V), the compound having the structural formula (Ve):
A4-X4, X4-Q6, Q6-X5, A5-X5, A4-A5 are independently single or double bond;
X4, X5, and Q6 are independently S, O, N, N(R22), C(R22), or C(R22R23);
(1201) (1203) (1205) (1207)
Compounds listed in Table 2.6 may also be represented by their chemical names as follows:
1201 (3aS,10aS)-N-[2-(4-benzylpiperidin-1-yl)ethyl]- 9-(2-chloro-5-fluorobenzyl)-10-oxo-2,3,3a,9,10,10a- hexahydro-1H-benzo[b]cyclopenta[f][1,4]thiazepine- 7-carboxamide 1203 (11aS)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-6-(2-chloro- 5-fluorobenzyl)-5-oxo-1,2,3,5,6,11a-hexahydropyrrolo [2,1-b][1,3,5]benzothiadiazepine-8-carboxamide 1205 (10aR)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-9- (2-chloro-5-fluorobenzyl)-10-oxo-4,9,10,10a- tetrahydro-1H-thieno[3,4-b][1,5]benzodiazepine- 7-carboxamide 1207 (11aR)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-10-methyl- 5,11-dioxo-2,3,5,10,11,11a-hexahydro-1H- pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxamide
In one embodiment of formula (Ve), wherein A4-X4 and Q6-X5 are double bond.
In one embodiment of formula (Ve), the compound wherein A4-A5, X4-Q6, and A5-X5 are single bond.
X5 is S, O, N, NR24, or CR24
X4, and Q6 are independently N or CR20.
In one embodiment of formula (Ve. 1), the compound having a structure selected from the group consisting of:
(1215) (1217) (1219) (1211)
Compounds listed in Table 2.7 may also be represented by their chemical names as follows:
1215 9-(2-chloro-5-fluorobenzyl)-10-oxo-N-[2-(4-phenylpiperazin- 1-yl)ethyl]-9,10-dihydrothieno[3,2-b][1,5] benzothiazepine-7-carboxamide 1217 N-[2-(4-benzylpiperidin-1-yl)ethyl]-9-(2-chloro- 5-fluorobenzyl)-10-oxo-9,10-dihydro-1H- [1,2,3]triazolo[4,5-b][1,5]benzoxazepine-7-carboxamide 1219 9-(2-chloro-5-fluorobenzyl)-N-{2-[4-(cyclopenta-1,3- dien-1-yl)piperazin-1-yl]ethyl}-10-oxo-9,10- dihydro-4H-furo[3,2-b][1,5]benzodiazepine-7-carboxamide 1221 N-[2-(4-cyclohexylpiperazin-1-yl)ethyl]-5-methyl-4,10- dioxo-3,4,5,10-tetrahydrobenzo[b]cyclopenta[e]azepine- 7-carboxamide
In one embodiment of formula (V), wherein A4-X4 and A5-X5 form a 6-member ring system.
In one embodiment of formula (V), the compound having the structural formula (Vf):
A4-X4, X4-U7, U7-U8, U8-X5, A5-X5, and A4-A5 are independently single or double bond;
X4, U7, U8, and X5 are independently S, O, N, N(R25), C(R25), or C(R25R26);
A4 and A5 are independently N, C, or CR27
(1225) (1227) (1229) (1231)
1225 (4aS,11aS)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-10-(2-chloro- 5-fluorobenzyl)-11-oxo-1,2,3,4,4a,10,11,11a- octahydrodibenzo[b,f][1,4]thiazepine-8-carboxamide 1227 (11aS)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-5-(2-chloro- 5-fluorobenzyl)-6-oxo-5,6,9,10,11,11a-hexahydro-8H- pyrido[2,1-b][1,3,5]benzothiadiazepine-3-carboxamide 1229 (4aR)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-6-(2-chloro-5- fluorobenzyl)-5-oxo-3,4,4a,5,6,11-hexahydrothiopyrano [3,4-b][1,5]benzodiazepine-8-carboxamide 1231 (6aR)-N-[2-(4-benzylpiperidin-1-yl)ethyl]-5-methyl-6,12- dioxo-5,6,6a,7,8,9,10,12-octahydropyrido [2,1-c][1,4]benzodiazepine-3-carboxamide
In one embodiment of formula (Vf), the compound having the structural formula (Vf. 1):
X4, U7, U8, and X5 are independently N or CR25
In one embodiment of formula (Vf. 1), the compound having a structure selected from the group consisting of:
(1235) (1237) (1239) (1241) (1243) (1245)
1235 10-(2-chloro-5-fluorobenzyl)-11-oxo-N-[2-(4-phenylpiperazin-1- yl)ethyl]-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide 1237 N-[2-(4-benzylpiperidin-1-yl)ethyl]-6-(3-fluorobenzyl)-5-oxo- 5,6-dihydropyrido[2,3-b][1,5]benzoxazepine- 8-carboxamide 1239 N-{2-[4-(cyclopenta-1,3-dien-1-yl)piperazin-1-yl]ethyl}-5- (5-fluoro-2-methylbenzyl)-6-oxo-6,11-dihydro-5H- dipyrido[3,2-b:2′,3′-e][1,4]diazepine-3-carboxamide 1241 N-[2-(4-cyclohexylpiperazin-1-yl)ethyl]-6-methyl-5,11-dioxo- 6,11-dihydro-5H-pyrido[4,3-c][1]benzazepine-8-carboxamide 1243 N-[2-(4-benzylpiperidin-1-yl)ethyl]-10-(2-chloro- 5-fluorobenzyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4] thiazepine-8-carboxamide 1245 10-(3-chlorobenzyl)-11-oxo-N-[3-(4-phenylpiperazin-1-yl) propyl]-10,11-dihydrodibenzo [b,f][1,4]thiazepine-8-carboxamide
In one embodiment of formula (I), wherein n=3, m=0, and A is “A61-A62-A63”.
A61, A62 and A63 are independently C, N, O, S, NR1, C═CR1 (E and Z isomers), C═NR1 (E and Z isomers), or C(R1R2);
In one embodiment of formula (VI), wherein A61 and A62 are C, and they along with three other atoms form a 5-member ring.
A64 is O or S;
A65 is N or CR1;
In one embodiment of formula (VIa), the compound having a structural formula (VIa.1):
R67, R68 and R69 are independently hydrogen, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, —CONR70R71, —NR70R71, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl, or substituted heteroalkyl;
R70 and R71 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl or alternatively, R70 and R71, taken together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl ring;
In one embodiment of formula (VIa.1), wherein J, K, L and M are CR5, R68 is H, R67 is a substituted 6-member cycloheteroalkyl ring, and R69 is —NHR70.
In one embodiment of formula (VIa.1), the compound having a structure formula (VIa.11):
nn is an integer from 0 to 4;
A66 is NR73, or CR73R74;
R72, R73, and R74 are independently hydrogen, halogen, cyano, nitro, amino, substituted amino, sulfonyl, substituted sulfonyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, —CONR75R76, S(O)2NR75R76, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl or substituted heteroalkyl;
In one embodiment of formula (VIa.11), the compounds having the following structures:
(11) (13) (15) (17) (41) (43) (1001) (1003) (1005) (1007) (1009) (1011) (1013) (1015) (1017) (1019) (701) (703) (705) (707) (709) (711) (713) (715) (717) (1035) (1037) (1021) (1023) (1025) (1027) (1029) (1031) (1033) (1039) (1041) (1043) (1045)
Compounds listed in Table 3.0 may also be represented by their chemical names as follows:
11 5-[(furan-2-ylmethyl)amino]-3-(4-propylpiperazin-1-yl)-6H- furo[4′,3′,2′:5,10]anthra[2,3-d][1,3]dioxol-6-one 13 2-[(4-cyclohexylpiperazin-1-yl)methyl]-5-[(furan-2-ylmethyl) amino]-6H-anthra[9,1-bc]furan-6-one 15 4-{[3-(4-cyclohexylpiperazin-1-yl)-2-methyl-6-oxo-6H-furo [4′,3′,2′:5,10]anthra[2,3-d][1,3amino}benzoic acid 17 5-[(3-ethoxypropyl)amino]-2-{[4-(furan-2-ylcarbonyl)piperazin- 1-yl]methyl}-6H-anthra[9,1-bc]furan-6-one 41 5-[(furan-2-ylmethyl)amino]-3-(4-propylpiperazin-1-yl)-6H- [1,3]dioxolo[6,7]anthra[1,9-cd]isoxazol-6-one 43 4-{[3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-[1,3]dioxolo [6,7]anthra[1,9-cd]isoxazol-5-yl]amino}benzoic acid 1001 5-[(1,4-dioxan-2-ylmethyl)amino]-3-(4-methylpiperazin-1-yl)- 6H-anthra]1,9-cd]isoxazol-6-one 1003 5-(benzylamino)-3-(4-methylpiperazin-1-yl)-6H-anthra [1,9-cd]isoxazol-6-one 1005 5-[(cyclopenta-1,3-dien-1-ylmethyl)amino]-3-(4-methylpiperazin- 1-yl)-6H-anthra[1,9-cd]isoxazol-6-one 1007 3-(4-methylpiperazin-1-yl)-5-[(1H-pyrrol-2-ylmethyl)amino]- 6H-anthra[1,9-cd]isoxazol-6-one 1009 3-(4-methylpiperazin-1-yl)-5-[(pyrazin-2-ylmethyl)amino]- 6H-anthra[1,9-cd]isoxazol-6-one 1011 5-[(hydroxymethyl)amino]-3-(4-methylpiperazin-1-yl)- 6H-anthra[1,9-cd]isoxazol-6-one 1013 N-[3-(4-methylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd] isoxazol-5-yl]glycine 1015 5-[2-(furan-2-yl)ethyl]-3-(4-methylpiperazin-1-yl)- 6H-anthra[1,9-cd]isoxazol-6-one 1017 5-[2-(1,4-dioxan-2-yl)ethyl]-3-(4-methylpiperazin-1-yl)- 6H-anthra[1,9-cd]isoxazol-6-one 1019 5-[2-(1,4-dioxin-2-yl)ethyl]-3-(4-methylpiperazin-1-yl)- 6H-anthra[1,9-cd]isoxazol-6-one 701 4-{[3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra [1,9-cd]isoxazol-5-yl]amino}benzoic acid 703 3-(4-cyclohexylpiperazin-1-yl)-5-[(furan-2-ylmethyl)amino]- 6H-anthra[1,9-cd]isoxazol-6-one 705 5-[(furan-2-ylmethyl)amino]-3-(4-propylpiperazin-1-yl)- 6H-anthra[1,9-cd]isoxazol-6-one 707 5-[(furan-2-ylmethyl)amino]-3-[4-(2-hydroxyethyl)piperazin-1-yl]- 6H-anthra[1,9-cd]isoxazol-6-one 709 3-(4-cyclohexylpiperazin-1-yl)-5-[(3-ethoxypropyl)amino]- 6H-anthra[1,9-cd]isoxazol-6-one 711 5-(butylamino)-3-(4-cyclohexylpiperazin-1-yl)- 6H-anthra[1,9-cd]isoxazol-6-one 713 5-[(furan-2-ylmethyl)amino]-3-(4-methylpiperazin-1-yl)- 6H-anthra[1,9-cd]isoxazol-6-one 715 5-(cyclohexylamino)-3-(4-cyclohexylpiperazin-1-yl)- 6H-anthra[1,9-cd]isoxazol-6-one 717 3-[4-(1,3-benzodioxo1-5-ylmethyl)piperazin-1-yl]-5-[4- (furan-2-ylcarbonyl)piperazin-1-yl]-6H-anthra [1,9-cd]isoxazol-6-one 1021 methyl 4-{[3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra [1,9-cd]isoxazol-5-yl]amino}benzoate 1023 methyl 4-{[3-(morpholin-4-yl)-6-oxo-6H-anthra[1,9-cd] isoxazol-5-yl]amino}benzoate 1025 methyl 4-{[6-oxo-3-(4-propylpiperazin-1-yl)-6H-anthra [1,9-cd]isoxazol-5-yl]amino}benzoate 1027 ethyl 4-{[3-(4-methylpiperazin-1-yl)-6-oxo-6H-anthra [1,9-cd]isoxazol-5-yl]amino}benzoate 1029 5-[(4-ethoxyphenyl)amino]-3-(4-propylpiperazin-1-yl)- 6H-anthra[1,9-cd]isoxazol-6-one 1031 5-(2,3-dihydro-1,4-benzodioxin-6-ylamino)-3-(4- propylpiperazin-1-yl)-6H-anthra[1,9-cd]isoxazol-6-one 1033 4-({3-[4-(5-chloro-2-methoxybenzyl)piperazin-1-yl]-6-oxo- 6H-anthra[1,9-cd]isoxazol-5-yl}amino)benzoic acid 1035 4-{[3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra [1,9-cd]isoxazol-5-yl]amino}butanoic acid 1037 N-(3-{4-[3-(4-chlorophenyl)propyl]piperazin-1-yl}- 6-oxo-6H-anthra[1,9-cd]isoxazol-5-y)glycine 1039 3-(4-cyclohexylpiperazin-1-yl)-5-{[4-(1H-tetrazol-5-yl) phenyl]amino}-6H-anthra[1,9-cd]isoxazol-6-one 1041 N-[(4-{[3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra [1,9-cd]isoxazol-5-yl]amino}phenyl)sulfonyl]acetamide 1043 3-(4-cyclohexylpiperazin-1-yl)-5-{[4-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)phenyl]amino}- 6H-anthra[1,9-cd]isoxazol-6-one 1045 4-({3-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-6-oxo-6H- anthra[1,9-cd]isoxazol-5-yl}amino)benzoic acid
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein. The following abbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; BuLi: butyllithium; Piv: pivaloyl; Ac: acetyl; THF: tetrahydrofuran; DMSO: dimethylsulfoxide; EDC: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; Boc: tert-butyloxy carbonyl; Et3N: triethylamine; DCM: dichloromethane; DCE: dichloroethane; DME: dimethoxyethane; DBA: diethylamine; DAST: diethylaminosulfur trifluoride; EtMgBr: ethylamgnesium bromide; BSA: bovine serum albumin; TFA: trifluoracetic acid; DMF: N,N-dimethylformamide; SOCl2: thionyl chloride; CDI: carbonyl diirnidazole; rt: room temperature; HPLC: high performance liquid chromatography; TLC: thin-layer chromatography. The compounds described herein may be prepared in a variety of ways known to one skilled in the art.
The procedures described herein for synthesizing compounds the present invention may include one or more steps of protection and deprotection (e.g., the formation and removal of acetal groups). In addition, the synthetic procedures disclosed below can include various purifications, such as column chromatography, flash chromatography, thin-layer chromatography (TLC), recrystallization, distillation, high-pressure liquid chromatography (HPLC) and the like. Also, various techniques well known in the chemical arts for the identification and quantification of chemical reaction products, such as proton and carbon-13 nuclear magnetic resonance (1H and 13C NMR), infrared and ultraviolet spectroscopy (IR and UV), X-ray crystallography, elemental analysis (EA), HPLC and mass spectroscopy (MS) can be used as well. Methods of protection and deprotection, purification and identification and quantification are well known in the chemical arts.
4-(2-fluorobenzyl)-2H-benzo[b][1,4]thiazin-3 (4H)-one (2)
To a mixture of 2H-benzo[b][1,4]thiazin-3(4H)-one (1.0 g, 6.1 mmole) and 1-(bromomethyl)-2-fluorobenzene (0.76 mL, 1.05 equiv) in DMF (10 mL) was added t-BuOK (0.75 g) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. Water was added and the resulted solid was filtrated, rinsed with water, and dried under vacuum to provide 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-oxobenzo[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 mmole) and methyl 4-formylbenzoate (1.2 g) were dissolved in THF (20 mL) and to the solution was added NaOEt (1 g). The reaction solution was heated at 70° C. overnight and aqueous HCl (5%, 10 mL) was added to quench the reaction. The mixture was extracted with EtOAc (50 mL) twice and combined organic layers were dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under vacuum to give 4-((Z)-(4-(2-fluorobenzyl)-3,4-dihydro-3-oxobenzo[b][1,4]thiazin-2-ylidene)methyl)benzoic acid (1.13 g, 71%).
4-((Z)-(4-(2-fluorobenzyl)-3,4-dihydro-3-oxobenzo[b][1,4]thiazin-2-ylidene)methyl)-N-(3-(pyrrolidin-1-yl)propyl)benzamide (cpd 481)
To a solution of 4-((Z)-(4-(2-fluorobenzyl)-3,4-dihydro-3-oxobenzo[b][1,4]thiazin-2-ylidene)methyl)benzoic acid (704 mg, 1.74 mmole) and DMF (2 drops) in Methylene chloride (10 mL) was added (COCl)2 (0.23 mL) dropwise. The reaction solution was stirred at room temperature for 1 h and the solvent was evaporated to give the acid chloride. To another solution of 3-(pyrrolidin-1-yl)propan-1-amine (267 mg) and DIPEA (0.3 mL) in Methylene chloride (10 mL) was added the above acid chloride in Methylene chloride (10 mL). The mixture was stirred at room temperature for 6 h. The solution was washed with saturated sodium bicarbonate (50 mL), water (50 mL) and dried over anhydrous magnesium sulfate. After filtration, the residue was purified through chromatography (CH2Cl2:MeOH 5:1) to give 4-((Z)-(4-(2-fluorobenzyl)-3,4-dihydro-3-oxobenzo[b][1,4]thiazin-2-ylidene)methyl)-N-(3-(pyrrolidin-1-yl)propyl)benzamide (797 mg, 89%). HNMR (300 MHz, CD3OD), ppm: 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)
Methyl 1-(4-(methoxycarbonyl)-2-nitrophenyl)piperidine-2-carboxylate (4)
To a mixture of methyl 4-fluoro-3-nitrobenzoate (6.46 g, 32.5 mmole) and methyl piperidine-2-carboxylate (5.57 g, 1.2 equiv) in DMF (80 mL) was added Cs2CO3 (12.7 g). The reaction mixture was stirred at 55° C. overnight. The solid was filtered and the filtrate was evaporated. The residue was recrystallized with EtOAc/Hexane to give 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 mmole) was dissolved in EtOAc (20 mL) and 1N HCl (20 mL) and to the solution was added Zinc (0.80 g). The reaction mixture was reflux overnight 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 mmole) and LiOH (0.25 g) were suspended in MeOH (5 mL), THF (5 ml) and Water (2 mL). The mixture was stirred at room temperature overnight. The reaction was evaporated to near dryness, and 2N HCl was added to adjust the PH about 2. The solid was filtered and dried to provide 6,6a,7,8,9,10-hexahydro-6-oxo-5H-pyrido[1,2-a]quinoxaline-3-carboxylic acid as white solid (0.72 g, 100%). 2-(3-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)propyl)isoindoline-1,3-dione (9) A mixture of 2-(3-bromopropyl)isoindoline-1,3-dione (2.68 g, 10 mmol) and NaI (20 mmol) in acetone was refluxed for 5 h, then to it was added 1-(5-chloro-2-methylphenyl)piperazine (2.11 g, 10.0 mmol). The reflux was continued for 12 h. Reaction was then cooled to room temperature, filtered through celite and concentrated. The crude product was recrystalized from acetone to give the title compound as a white solid (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 at 70° C. for 12 h. After the reaction cooled to room temperature, the solid was filtered off, and filtrate was evaporated to give the title compound, used without further purification.
(6aS/R)—N-{3-[4-(5-chloro-2-methylphenyl)piperazin-1-yl]propyl}-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-3-carboxamide (cpd 201)
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 mmole), 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) was added EDC (0.377 g, 2.0 mmole). The reaction solution was stirred at room temperature overnight. The solvent removed and EtOAc (60 mL) was added. The organic layer was washed with saturated sodium bicarbonate (10 mL), water (10 mL) and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by column chromatography with 0-10% methanol in dichloromethane to provide the N-(3-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)propyl)-6,6a,7,8,9,10-hexahydro-6-oxo-5H-pyrido[1,2-a]quinoxaline-3-carboxamide as white solid (6.28 g, 78%). 1HNMR (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). MS (ESI+) M/z: 496, 498 (M+H).
The synthesis of compound 703 was carried out as: NaNO2 (0.57 g, 8.3 mmol) was added to 5.2 mL concentrated H2SO4 at 30-40° C. over 20 minutes. The mixture was stirred for 30 minutes. Then 2.9 g compound 1 was added to the solution and the solution was stirred for 4 hours at 50-55° C. The resulting solution was poured into ice (50 g) and the yellow precipitate was filtered, washed with 50 mL ice-water, followed by 150 mL 1:1 mixture of ethanol-ether. The wet filter cake was added to a solution of NaN3 (0.78 g, 12 mmol) in 100 mL of water and stirred for 30 minutes. The product was filtered, washed with 100 mL water, followed by 50 mL of a mixture (9:1) of acetone and water. The product was suspended in 30 mL toluene and heated to 70° C. for 8 hours. Then the suspension was filtered, washed with 50 mL of methanol and dried to give yellow solid.
1HNMR (400 MHz, CCl4 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).
Examples for Spectral Information for Other Compounds
Compound 205: 1HNMR (400 MHz, CCl4 and 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 (400 MHz, CCl4 and 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 (400 MHz, CCl4 and 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 (400 MHz, 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 (400 MHz, CCl4 and 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 (400 MHz, 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 (400 MHz, CCl4 and 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 (400 MHz, 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 of the disclosure: 1HNMR (400 MHz, 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 of the disclosure: 1HNMR (400 MHz, CCl4 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), 4.74 (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 of the disclosure: 1HNMR (400 MHz, CCl4 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), 6.06 (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 of the disclosure: 1HNMR (400 MHz, 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 711: 1HNMR (400 MHz, 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 1033: 1HNMR (400 MHz, 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 (400 MHz, 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 1243: 1HNMR (400 MHz, CCl4 and 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).
Compound inhibition in a radiometric based mixed micelle assay: In a final reaction volume of 25 μL, TrkA (h) (3 nM) is incubated with the kinase reaction buffer (20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij 35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO), 0.2 mg/ml substrate PolyEY(4:1) and 2 nM MnCl2, and [33P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for at least 40 minutes at room temperature, the reaction is stopped by the addition of L of a 3% phosphoric acid solution. 10 μL of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. TrkA: Recombinant Human Cytoplasmic Domain (amino acids 441-796), Histidine-tagged, expressed in insect cells. Activated in vitro via auto-phosphorylation. Mw=42.8 kDa. Substrates for kinases: poly(EY) for TRKA; poly(EY)(4:1) with 2 mM MnCl2, average Mw=16 kDa Standard conditions (unless otherwise specified): 30 nM TRKA, 0.2 mg/ml poly(EY)+2 mM MnCl2, and 10 μM ([γ-33P]) ATP. Using the similar assay condition with other kinases of recombinant human cytoplasmic domain, the activities of other kinases could be also measured.
The TrkA kinase antagonist activity of a compound which may be used in the present invention may be determined by these assays. In particular, the compounds of the present invention aforementioned examples, including tables 1.1 to 3.0 had activity in antagonizing the TrkA kinase activity in the aforementioned assays, generally with an IC50 of less than about 25 μM. Preferred compounds within the present invention had activity in antagonizing the TrkA kinase activity in the aforementioned assays with an IC50 of less than about 2.5 μM. Further preferred compounds within the present invention had activity in antagonizing the TrkA kinase activity in the aforementioned assays with an IC50 of less than about 0.25 μM. The much further preferred compounds within the present invention had activity in antagonizing the TrkA kinase activity in the aforementioned assays with an IC50 of less than about 0.1 μM. For examples, Compound A of the present invention (i.e., Compound 201) has an IC50 of 0.085 μM; Compound B of the present invention has an IC50 of 0.007 μM and has more than about 10 μM of the IC50 values antagonizing, for instances, the following structurally related protein kinases, TrkB, TrkC, ABL1, AKT1, ALK5/TGFB-R1, ARAF, AXL, BMX, BTK, CDK1/cyclinB, CDK2/cyclinA, CDK2/cyclinE, c-MET, c-Src, EPHA1, FES/FPS, FGFR1, FGR, FLT1, FLT3 (CD), FMS, FYN, IGF-1R, IR, ITK, JAK3, JNK3, LCK, LYN, MEK1, MEK2, MLK1/MAP3K9, MUSK, P38a/MAPK14, P38b/MAPK11, PDGFRa, PDGFRb, PKA, PKCalpha, PKCbetaI, PKCbetaII, PKCdelta, PKCepsilon, PKCeta, PKCgamma, PKCiota, PKCmu/PKD1, PKCtheta, PKCzeta, PKD2/PRKD2, PKGla, PKGlb, RAF1, RET, TEC, TGFbR2, TIE2/TEK, VEGFR2/KDR, VEGFR3/FLT4 (duplicate, with a positive control compound of a pan-kinase inhibitor, staurosporine or K-252a). Such a result is indicative of the intrinsic activity of the compounds in use as isoform-selective antagonists of TrkA kinase activity.
Compound Inhibition in a Live, Whole Cell Based Functional Assay:
There are several methods to measure whole length TrkA activation stimulated by its natural ligand or angonist NGF in live cells. For example, the PathHunter Profiling services offered by DiscoveRx (Fremont, Calif.). The PathHunter technology is an adaptation of enzyme fragment complementation that provides a novel, generic functional cell-based assay format for detecting protein-protein interactions. In this cell-based assay approach, with U2OS cell background, a small peptide epitope (PK) is expressed recombinantly on the intracellular C-terminus of TrkA (human full length). This is co-expressed with a larger sequence, termed enzyme acceptor (EA) that is attached to a cytoplasmic protein SHC1 which will interact with TrkA intracellularly. NGF induced activation of TrkA receptor causes either homo- or hetero-dimerization of TrkA resulting in cross-phosphorylation. The SHC1-EA fusion protein then binds the phosphorylated TrkA receptor forcing complementation of the PK and EA fragment. This interaction generates an active beta-galactosidase enzyme, which is detected using a chemiluminescent substrate.
In such cell-based functional assays, Compound C of the present invention inhibits NGF stimulated TrkA activation at low nanomolar concentration (cellular IC50=0.047 μM, mean of triplicate), while virtually has no effect on either BDNF stimulated TrkB, or NT3 stimulated TrkC activation (IC50>10 μM in both cases, triplicate, with a postive control compound of pan-kinase inhibitor, staurosporine or K-252a, an internal agonist control and a negative control compound).
Mode of Inhibition with Respect to ATP.
The TrkA kinase assays were performed at room temperature. Four concentrations of compounds (0, 0.037, 0.11, and 0.33 μM) were added into Enzyme/substrate mixture using acoustic technology, and incubated for 40 min to ensure all compounds were equilibrated and bound to the enzyme. Then various concentrations of ATP (10, 100, 200, 350, and 500 μM ATP with 0.2 mg/ml poly(EY)) were added to initiate the reaction. The activity was monitored every 5-15 min for time course. Such kinetic analysis shows that Compound D, for example, inhibits TrkA non-competitively with respect to ATP: Lineweaver-Burk double-reciprocal plots showing differences in Vmax but not in km for the 4 conditions.
Mode of Inhibition with Respect to Substrate.
The kinase assays were performed similar manner to ATP study. Various concentrations of compounds (0, 0.037, 0.11, and 0.33 μM) were added into Enzyme/substrate mixture using acoustic technology, and incubated for 40 min to ensure all compounds were equilibrated and bound to the enzyme. Then 10 μM 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. The activity was monitored every 5-15 min for time course. Such kinetic analysis shows that Compound D, for example, inhibits TrkA non-competitively with respect to substrate: Lineweaver-Burk double-reciprocal plots showing differences in Vmax but not in km for the 4 conditions.
Chronic Constriction Injury (CCI) Model of Neuropathic Pain in Rats.
The CCI model is one of the most commonly used mono-neuropathic pain model firstly described in details by Bennett and Xie (Bennett G J, Xie Y K. Pain. 1988; 33(1):87-107). It mimics important clinical chronic pain symptoms such as mechanical allodynia and thermal hyperalgesia. Chronic constriction injury of the sciatic nerve was produced by tying four loose ligatures around the left sciatic nerve according to the method of Bennett and Xie. This procedure resulted in tactile allodynia in the left hindpaw. Calibrated von Frey filaments were used to determine the lowest mechanical (tactile) threshold required to evoke a brisk paw withdrawal reflex in the rat hindpaws. Rats were allowed to acclimatize in wire mesh cages for 15-20 min prior to von Frey testing. Assessment of paw withdrawal thresholds (PWTs) using von Frey filaments was undertaken prior to CCI-surgery (pre-surgery baseline on day 0). Before the drug dosing on day 14, the pre-dose baseline was recorded for each rat. Rats were included in the study only if they did not exhibit motor dysfunction (e.g., paw dragging or dropping) and their PWT was below to 4 g. Drug-naïve CCI-rats (n=4-6 per group) were used. The oral vehicle was 0.5% CMC-Na/0.1% Tween 80 in distilled water. The positive control gabapentin was dissolved in the vehicle and orally given at 100 mg/kg (by oral gavage). Test compound was suspended in the vehicle and orally given at 50 mg/kg and 100 mg/kg. Each CCI-rat was administered a single oral dose of test compound, gabapentin or vehicle control, 2 hours before assessment of PWT.
The results have demonstrated that oral administration of, for example, Compound D of present invention significantly reduced mechanical allodynia in CCI rats of neuropathic pain model in a dose-dependent manner. In addition, at the same oral dose of 100 mg/kg, Compound D is about 98% more effective in suppressing mechanical allodynia in CCI neuropathic pain compared to gabapentin, the current gold standard medication for neuropathic pain, while even 50 mg/kg oral Compound D is about 28% more effective than 100 mg/kg oral gabapentin. Of note, CCI-rats dosed with gabapentin have shown drowsiness or motor incoordination, which is consistent with known side effect of gabapentin. However, no such effect or other abnormality was observed in CCI-rats dosed with Compound D.
Spinal Nerve Ligation (SNL) Mono-Neuropathic Pain Model in Rats.
The surgical procedure will be performed according to the method firstly described by Kim and Chung (Kim S H, Chung J M. Pain. 1992; 50(3):355-63.). This procedure will result in tactile allodynia in the left hindpaw. Rats will be included in the study only if they do not exhibit motor dysfunction (e.g., paw dragging or dropping) and their PWT is below to 4.0 g. The dose-response anti-allodynia effects of test compound: on day 14 after surgery, rats will be treated with test compound at one of four doses, vehicle or positive control by oral gavage, and PWT is determined by calibrated von Frey filaments at time points of 0 (right before the drug dosing, Pre-Dose Baseline), 0.5, 1, 2, 4 and 6 hr. Tolerance effects: 6 days following the day 14 test, i.e. on day 20 after surgery, the same procedure on day 14 will be repeated on day 20 with the same group of CCI-rats treated with the same (effective) dose as on day 14. The results of anti-allodynia effects of test compound as tested on day 14 and on day 20 will be compared to see if there is any tolerance effect of test compound in animals. The anti-allodynia effects of repeated administration of test compound: Administration of test compound will start on day 7 after surgery, once a day for 7 days. PWT will be determined by calibrated von Frey filaments once a day, 2 hour after compound dosing. After 7 days dosing, the measurement will be continued, every other day without compound dosing for another 7 days. PWT will be determined at the time points as given above. Thermal hyperalgesia effects. Thermal hyperalgesia may be assessed in the SNL rats by plantar test with a single dose of TEST COMPOUND at the time points given above.
D2.2.3. Streptozotocin-Induced Diabetic Poly-Neuropathic Pain Model(a).
Diabetic peripheral neuropathy is a long-term complication of diabetes mellitus. Rats will receive i.p. injections of streptozotocin (STZ, 50 mg/kg dissolved in citrate buffer at pH 4.5 immediately before the injection) to induce insulin-dependent diabetes mellitus and produce tactile allodynia. One week later, blood glucose level will be assayed, from samples taken from the tail vein, using standard test strips and colorimeter. Only animals with a blood glucose level >350 mg/dL will be considered diabetic and included for the testing. Typical features of neuropathic pain (tactile allodynia) will be developed in hindpaws beginning around 2 to 3 weeks after STZ injection. After 4 weeks, a stable level of allodynia will be usually reached. At this point, the rats with PWT below 4.5 g will be enrolled for compound testing. The allodynic state will remain intact until the 8th week after STZ injection. All animals will be observed daily and weighed regularly during the study period. This model of neuropathic pain mimics the symptoms of neuropathy in diabetic patients (Lynch J J, 3rd, et al Eur J Pharmacol. 1999; 364(2-3):141-6; Calcutt N A, J Neurol Sci. 2004; 220(1-2):137-9). The dose-response anti-allodynia effects of test compound: On day 28 after STZ injection, rats will be treated with test compound at one of four doses, or controls (vehicle and positive) by oral gavage, and PWT will be determined by calibrated von Frey filaments at time points of 0 (right before the drug dosing, Pre-Dose Baseline), 0.5, 1, 2, 4 and 6 hr. Tolerance effects: 6 days following the day 28 test, i.e. on day 34 after STZ injection, the same procedure on day 28 will be repeated on day 34 with the same group of STZ-rats treated with the same (effective) dose as on day 28. The two results of anti-allodynia effects of test compound as measured on day 28 and on day 34 will be compared to see if there is any tolerance effect of test compound in animals. The anti-allodynia effects of repeated administration of test compound: Administration (p.o.) of test compound will start on day 21 after STZ injection, once a day for 7 days. PWT will be determined by calibrated von Frey filaments once a day, 1 hour after compound dosing. After 7 days dosing, the measurement will be continued, every other day without compound dosing for another 7 days. PWT is determined at the time points as given above. The thermal hyperalgesia assessment by plantar test may be performed in STZ models with a single dose and PWL will be determined, at time points as given above.
The present compounds, or salts, solvates, esters, and/or prodrugs thereof, may also be administered directly to the lung by inhalation. For administration by inhalation, the present compounds, or salts, solvates, esters, and/or prodrugs thereof, may be conveniently delivered to the lung by a number of different devices. For example, a Metered Dose Inhaler (“MDI”), which utilizes canisters that contain a suitable low boiling propellant, (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or any other suitable gas), may be used to deliver compounds of the invention directly to the lung.
Alternatively, a Dry Powder Inhaler (“DPI”) device may be used to administer the present compounds, or salts, solvates, esters, and/or prodrugs thereof, to the lung. DPI devices typically use a mechanism such as a burst of gas to create a cloud of dry powder inside a container, which may then be inhaled by the patient. DPI devices are also well known in the art. A popular variation is the multiple dose DPI (“MDDPI”) system, which allows for the delivery of more than one therapeutic dose. For example, capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch for these systems.
Another type of device that may be used to deliver the present compounds, or salts, solvates, esters, and/or prodrugs thereof, to the lung is a liquid spray device supplied, for example, by Aradigm Corporation, Hayward, Calif. Liquid spray systems use extremely small nozzle holes to aerosolize liquid drug formulations that may then be directly inhaled into the lung. In some embodiments, a nebulizer is used to deliver the present compounds, or salts, solvates, esters, and/or prodrugs thereof, to the lung. Nebulizers create aerosols from liquid drug formulations by using, for example, ultrasonic energy to form fine particles that may be readily inhaled (see e.g., Verschoyle et al., British J. Cancer, 1999, 80, Suppl. 2, 96. Nebulizers are available from a number of commericial sources such as Sheffield/Systemic Pulmonary Delivery Ltd. Aventis and Batelle Pulmonary Therapeutics.
In other embodimenst, an electrohydrodynamic (“EHD”) aerosol device is used to deliver the present compounds, or salts, solvates, esters, and/or prodrugs thereof, to the lung. EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions (see e.g., Noakes et al., U.S. Pat. No. 4,765,539). The electrochemical properties of the formulation may be important parameters to optimize when delivering the present compounds, or salts, solvates, esters, and/or prodrugs thereof, to the lung with an EHD aerosol device and such optimization is routinely performed by one of skill in the art. EHD aerosol devices may more efficiently deliver drugs to the lung than existing pulmonary delivery technologies.
In other embodiments, the present compounds, or salts, solvates, esters, and/or prodrugs thereof, can be delivered via sustained release systems. In still other embodiments, the sustained release system is an oral sustained release systems. In still other embodiments, a pump may be used (See, Langer, supra; Sefton, 1987, CRC Crit RefBiomed Eng. 14:201; Saudek et al., 1989, N. Engl. J Med. 321:574).
In still other embodiments, polymeric materials can be used in the pharmaceutical compositions containing the present compounds, or salts, solvates, esters, and/or prodrugs thereof. (for exemplary polymeric materials, see “Medical Applications of Controlled Release,” Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,” Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61; see also Levy et al., 1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105). In still other embodiments, polymeric materials are used for sustained release delivery of oral pharmaceutical compositions. Exemplary polymers include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred, hydroxypropyl methylcellulose). Other cellulose ethers have been described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3) 1-9). Factors affecting drug release are well known to the skilled artisan and have been described in the art (Bamba et al., Int. J. Pharm., 1979, 2, 307).
Liquid drug formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices will typically include a compound of the invention with a pharmaceutically acceptable vehicle. In some embodiments, the pharmaceutically acceptable vehicle is a liquid such as alcohol, water, polyethylene glycol or a perfluorocarbon. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of compounds disclosed herein. Preferably, this material is liquid such as an alcohol, glycol, polyglycol or a fatty acid. Other methods of formulating liquid drug solutions or suspension suitable for use in aerosol devices are known to those of skill in the art (see, e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611).
The present compounds, or salts, solvates, esters, and/or prodrugs thereof, are preferably assayed in vitro and in vivo, for the desired therapeutic or prophylactic activity, prior to use in humans. For example, in vitro assays can be used to determine whether administration of a specific compound of the invention or a combination of compounds is preferred for inducing apoptosis in cells which over-express bcl-2 proteins. The present compounds, or salts, solvates, esters, and/or prodrugs thereof, may also be demonstrated to be effective and safe using animal model systems.
In certain embodiments of the present invention, the present compounds, or salts, solvates, esters, and/or prodrugs thereof, can be used in combination therapy with at least one additional active or therapeutic agent. The present compounds, or salts, solvates, esters, and/or prodrugs thereof, and the at least one additional active or therapeutic agent can act additively or, more preferably, synergistically. In some embodiments, the present compounds, or salts, solvates, esters, and/or prodrugs thereof are administered concurrently, sequentially, or separately with the administration of another therapeutic agent. Exemplary active or chemotherapeutic agents include, but are not limited to, aceglatone, aclarubicin, altretamine, aminoglutethimide; 5-aminogleavulinic acid, amsacrine, anastrozole, ancitabine hydrochloride, 17-la antibody, antilymphocyte immunoglobulins, antineoplaston a10, asparaginase, pegaspargase, azacitidine, azathioprine, batimastat, benzoporphyrin derivative, bicalutamide, bisantrene hydrochloride, bleomycin sulphate, brequinar sodium, broxuridine, busulphan, campath-ih, caracemide, carbetimer, carboplatin, carboquone, carmofur, carmustine, chlorambucil, chlorozotocin, chromomycin, cisplatin, cladribine, corynebacterium parvum, cyclophosphamide, cyclosporin, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, diaziquone, dichlorodiethylsulphide, didemnin b., docetaxel, doxifluridine, doxorubicin hychloride, droloxifene, echinomycin, edatrexate, elliptinium, elmustine, enloplatin, enocitabine, epirubicin hydrochloride, estramustine sodium phosphate, etanidazole, ethoglucid, etoposide, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flutamide, formestane, fotemustine, gallium nitrate, gencitabine, gusperimus, homoharringtonine, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosine, improsulfan tosylate, inolimomab, interleukin-2; irinotecan, jm-216, letrozole, lithium gamolenate, lobaplatin, lomustine, lonidamine, mafosfamide, meiphalan, menogaril, mercaptopurine, methotrexate, methotrexate sodium, miboplatin, miltefosine, misonidazole, mitobronitol, mitoguazone dihydrochioride, mitolactol, mitomycin, mitotane, mitozanetrone hydrochloride, mizoribine, mopidamol, muitlaichilpeptide, muromonab-cd3, mustine hydrochloride, mycophenolic acid, mycophenolate mofetil, nedaplatin, nilutamide, nimustine hydrochloride, oxaliplatin, paclitaxel, pcnu, penostatin, peplomycin sulphate, pipobroman, pirarubicin, piritrexim isethionate, piroxantrone hydrochloride, plicamycin, porfimer sodium, prednimustine, procarbazine hydrochloride, raltitrexed, ranimustine, razoxane, rogletimide, roquinimex, sebriplatin, semustine, sirolimus, sizofiran, sobuzoxane, sodium bromebrate, sparfosic acid, sparfosate sodium, sreptozocin, sulofenur, tacrolimus, tamoxifen, tegafur, teloxantrone hydrochloride, temozolomide, teniposide, testolactone, tetrasodium mesotetraphenylporphine-sulphonate, thioguanine, thioinosine, thiotepa, topotecan, toremifene, treosulfan, trimetrexate, trofosfamide, tumor necrosis factor, ubenimex, uramustine, vinblastine sulphate, vincristine sulphate, vindesine sulphate, vinorelbine tartrate, vorozole, zinostatin, zolimomab aritox, and zorubicin hydrochloride, and the like, either individually or in any combination, an inhibitor of protein kinase A (PKA), an inhibitor of cAMP signaling, a nonsteroidal anti-inflammatory drug, a prostaglandin synthesis inhibitor, a local anesthetic, an anticonvulsant, an antidepressant, an opioid receptor agonist, and a neuroleptic, a benzodiazepine, a barbiturate, a neurosteroid and a inhalation anesthetic, a anesthetic and another pain killer.
All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The foregoing detailed description has been given for clearness of understanding only and no unnecessary limitations should be understood therefrom as modifications will be obvious to those skilled in the art. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art.
1. A compound having a structural formula (IVb.21): or a salt, ester, or prodrug thereof, wherein
J, K, and M are CH, and L is C—CONR8R9;
U1, U2, and X3 are independently C(R20) or C(R20R21);
U3 is C(R20R21);
A4′ is C or CR22;
N—U1, U2—U3, and U3—X3 are a single bond;
A4′-X3 and U1—U2 are independently single or double bond;
R5 is hydrogen, alkyl, arylalkyl, or substituted arylalkyl;
R8 is hydrogen and R9 is C1-6 alkyl substituted with an N-piperazinyl ring which is substituted at the nitrogen atom by phenyl, substituted phenyl, or 5-10 membered heteroaryl; and
R20, R21, and R22 are hydrogen.
4. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of claim 1, or a salt, ester, or prodrug thereof, and at least one pharmaceutically acceptable vehicle.
5. The pharmaceutical composition of claim 4, wherein the composition is formulated as: an oral unit dosage form, an intravenous unit dosage form, an intranasal unit dosage form, a suppository unit dosage form, an intradermal unit dosage form, an intramuscular unit dosage form, an intraperitoneal unit dosage form, a subcutaneous unit dosage form, an epidural unit dosage form, a sublingual unit dosage form, or an intracerebral unit dosage form.
6. The pharmaceutical composition of claim 4, wherein the composition is formulated as: an oral unit dosage form, which is suitable for administration of about 0.001 mg to about 200 mg of the compound per kilogram body weight to a patient in need thereof.
7. The pharmaceutical composition of claim 4, wherein the composition is formulated as: an intravenous unit dosage form, which is suitable for administration of about 0.01 mg to about 100 mg of the compound per kilogram of body weight to a patient in need thereof.
8. The pharmaceutical composition of claim 4, wherein the composition is formulated as:
(a) an intranasal unit dosage form, which is suitable for administration of about 0.01 mg to about 1 mg of the compound per kilogram of body weight to a patient in need thereof;
(b) a suppository unit dosage form, which is suitable for administration of about 0.01 mg to about 50 mg of the compound per kilogram of body weight to a patient in need thereof and comprises active ingredient in the range of about 0.5% to about 10% by weight; or
(c) an intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, or intracerebral unit dosage form, which is suitable for administration of about 0.001 mg to about 200 mg of the compound per kilogram of body weight to a patient in need thereof.
9. The pharmaceutical composition of claim 4, which is in a form selected from: tablets, pills, pellets, capsules, powders, lozenges, granules, solutions, suspensions, emulsions, syrups, elixirs, sustained-release formulations, aerosols, and sprays.
10. The pharmaceutical composition of claim 4, which is in the form of a tablet, a capsule, or an oral liquid preparation.
11. The pharmaceutical composition of claim 5, wherein the composition is formulated as an oral unit dosage form and further comprises one or more optional agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, preserving agents, time delay or delay disintegration materials, standard oral vehicles, suitable carriers, excipients, and diluents.
12. The pharmaceutical composition of claim 4, further comprising: at least one additional active agent selected from the group consisting of: an inhibitor of protein kinase A (PKA), an inhibitor of cAMP signaling, a nonsteroidal anti-inflammatory drug, a prostaglandin synthesis inhibitor, a local anesthetic, an anticonvulsant, an antidepressant, an opioid receptor agonist, a neuroleptic, an agonist of GABAA receptor, an analgesic or anti-cancer agent that acts by a mechanism different from a TrkA antagonist, a benzodiazepine, a barbiturate, a neurosteroid, an inhalation anesthetic, an anesthetic, an anticancer drug, a modulator of mGluR5 receptor, and a combination thereof.
13. The pharmaceutical composition of claim 4, wherein the compound is selected from the group consisting of:
14. A method of treating pain in a patient suffering therefrom, comprising: administering to the patient a compound of claim 1, or a salt, ester, or prodrug thereof.
wherein said pain is selected from the group consisting of: acute pain, chronic pain, inflammatory pain, neuropathic pain, tonic pain, persistent pain, postoperative pain, chemical-induced pain, chemotherapy-induced pain, cancer-pain, drug-induced pain, bone pain, arthritis pain, osteoarthritis pain, fibromyalgia, diabetic neuropathic pain, a generalized pain disorder, pain associated with alcohol-induced hyperalgesia, and a combination thereof.
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Patent Publication Number: 20180086777
Inventors: Jay Jie-Qiang Wu (Fremont, CA), Ling Wang (Fremont, CA)
Application Number: 15/676,039
International Classification: A61K 31/496 (20060101); A61K 31/497 (20060101); A61K 45/06 (20060101); C07D 403/14 (20060101); C07D 407/12 (20060101); C07D 413/10 (20060101); C07D 413/12 (20060101); C07D 417/12 (20060101); C07D 471/04 (20060101); C07D 487/04 (20060101); C07D 491/04 (20060101); C07D 215/20 (20060101); C07D 221/06 (20060101); C07D 223/32 (20060101); C07D 241/44 (20060101); C07D 261/20 (20060101); C07D 265/36 (20060101); C07D 279/16 (20060101); C07D 295/13 (20060101); C07D 307/77 (20060101); C07D 498/06 (20060101); C07D 493/06 (20060101); C07D 495/04 (20060101); C07D 498/04 (20060101); C07D 513/04 (20060101);